GATIFLOXACIN

BMS-206584, CG-5501, AM-1155, Zymar, Bonoq, Gatiflo, AM-1155

(±)-1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Gatifloxacin sold under the brand names Gatiflo, Tequin and Zymar, is an antibiotic of the fourth-generation fluoroquinolonefamily,^[1] that like other members of that family, inhibits the bacterial enzymes DNA gyrase and topoisomerase IV. Bristol-Myers Squibb introduced Gatifloxacin in 1999 under the proprietary name Tequin for the treatment of respiratory tract infections, having licensed the medication from Kyorin Pharmaceutical Company of Japan. Allergan produces it in eye-drop formulation under the names Zymar and Zymaxid. In many countries, gatifloxacin is also available as tablets and in various aqueous solutions forintravenous therapy.

Originally developed at Kyorin, gatifloxacin was first licensed to Gruenenthal in Europe, and that company still maintains rights to the oral and injectable formulations of the product. In October 1996, Kyorin licensed gatifloxacin to BMS, granting the company development and marketing rights in the U.S., Canada, Australia, Mexico, Brazil and certain other markets. In 2006, rights to the compound were returned by BMS. Subsequently, Senju and Kyorin signed a licensing agreement regarding the development of ethical eye drops containing the fluoroquinolone. In April 2000, Sumitomo Dainippon Pharma agreed to comarket the oral formulation in Japan. In August of that year, Allergan in-licensed gatifloxacin from Kyorin, gaining development and commercialization rights to the drug in all territories except Japan, Korea, China and Taiwan. The India-based Lupin Pharmaceuticals signed an agreement in June 2004 with Allergan to promote the ophthalmic solution of gatifloxacin in the pediatric specialty area in the U.S. PediaMed Pharmaceuticals also holds rights to the drug. In 2009, Kyorin licensed the drug candidate to Senju in China.

Gatifloxacin is the common name for (±)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (1), one of the most important broad-spectrum antibacterial agents and a member of the fourth-generation fluoroquinolone family.(1)Fluoroquinolones inhibit the enzyme DNA gyrase (topoisomerase II), which is responsible for the supercoiling of the DNA double helix, preventing the replication and repair of bacterial DNA and RNA.(2) Gatifloxacin (1) reached the market in 1999 under the brand name Tequin for the treatment of respiratory tract infections. The drug is available as tablets and aqueous solutions for intravenous therapy as well as eye drop formulation (Zymar).

To date, there are several processes described for the preparation of gatifloxacin, which can be grouped into two main categories: direct substitution of the 7-position fluorine atom of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (2) by 2-methylpiperazine (Scheme 1),(3-5) and through boron chelate-type intermediates to overcome the diminished reactivity induced by the 8-methoxy group, which uses as starting material the ethyl ester derivative 3 (Scheme 2).(6-9)

SCHEME1

1. 1.
   Mather, R.; Karenchak, L. M.; Romanowski, E. G.; Kowalski, R. P. Am. J. Ophthalmol.2002, 133 ( 4) 463
2. 2.
   Corey, E. J.; Czakó, B.; Kürti, L. Molecules and Medicine; Wiley: NJ, 2007; p 135.
3. 3.
   Masuzawa, K.; Suzue, S.; Hirai, K.; Ishizaki, T. 8-Alkoxyquinolonecarboxylic acid and salts thereof excellent in the selective toxicity and process of preparing the same EP 0 230 295 A3, 1987.
4. 4.
   Niddam-Hildesheim, V.; Dolitzky, B.-Z.; Pilarsky, G.; Steribaum, G. Synthesis of Gatifloxacin WO 2004/069825 A1, 2004.
5. 5.
   Ruzic, M; Relic, M; Tomsic, Z; Mirtek, M. Process for the preparation of Gatifloxacin and regeneration of degradation products WO 2006/004561 A1, 2006.
6. 6.
   Iwata, M.; Kimura, T.; Fujiwara, Y.; Katsube, T. Quinoline-3-carboxylic acid derivatives, their preparation and use EP 0 241 206 A2, 1987.
7. 7.
   Sanchez, J. P.; Gogliotti, R. D.; Domagala, J. M.; Garcheck, S. J.; Huband, M. D.; Sesnie,J. A.; Cohen, M. A.; Shapiro, M. A. J. Med. Chem. 1995, 38, 4478
8. 8.
   Satyanarayana, C.; Ramanjaneyulu, G. S.; Kumar, I. V. S. Novel crystalline forms of Gatifloxacin WO 2005/009970 A1 2005.
9. 9.
   Takagi, N.; Fubasami, H.; Matsukobo, H.; (6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-O3,O4)bis(acyloxy-O)borates and the salts thereof, and methods for their manufacture EP 0 464 823 A1, 1991.

………………………….

WO 2005009970

http://www.google.com/patents/WO2005009970A1?cl=en

preparation of Gatifloxacin hemihydrate from Ethyl-1- Cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-l, 4-dihydro-3-quinoline carboxylate through boron difluoride chelate. Ethyl-1-cyclopropyl- 6, 7-difluoro-8-methoxy-4-oxo-l, 4-dihydro-3-quinoline carboxylate is reacted with aqueous hydrofluoroboric acid followed by condensation with 2-methyl piperazine in polar organic solvent resulting in an intermediate l-Cyclopropyl-7- (3-methyl piperazin-1- yl). -6-fluoro-8-methoxy-4-oxo-l, 4-dihydro-3-quinoline carboxylic acid boron difluoride chelate. This intermediate may be further hydrolyzed to yield Gatifloxacin. Gatifloxacin so obtained may needs purification to yield high purity product. However to obtain directly high purity Gatifloxacin it is desirable to isolate the intermediate by cooling to low temperatures . Treating with an alcohol or mixture of alcohols purifies this intermediate. The purified condensed chelate in aqueous ethanol on hydrolysis with triethylamine followed by crystallization in ethanol gives Gatifloxacin hemihydrate with high purity.

STAGE – I:

 

Ethyl l-cyclopropyl-6,7-difluoro-8-met oxy l-Cycloproρyl-6, 7-difluoro-8-methoxy -4-oxo-l, -dihydro-3-quinoline -4-oxo-l, 4-dihydro-3-quinoline carboxylate carboxylic acid boron difluoride chelate

STAGE – II :

 

l-Cycloprop l-7- ( 3-methylpiperazin-l-yl.

6-fluoro~8-methoxy-4-oxo-l , 4-dihydro-3- carboxylicacid borondifluoride chelate quinoline carboxylicacid borondifluoride chelate

STAGE -III :

 

l-Cyclopropyl-7- (3- ethylpiperaz.in-l-yl . GATIFLOXACIN

-6-fluoro-8-methoxy-4-oxo-l , 4-dihydro-3- quinoline carboxylicacid borondifluoride chelate

Example-I: Preparation of Gatifloxacin • with isolation of intermediate (boron difluoride chelate derivative)

Stage-1: Preparation of l-cyclopropyl-6, 7-di luoro-8-methoxy-4-oxo- 1, 4-dihydro-3-quinoline carboxylic acid boron difluoride chelate. Ethyl-l-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-l, -dihydro-3- quinόline carboxylate (100g)is suspended in ,40%aq..hydrofluoroboric acid -(1000 ml). Temperature of • the reaction mass is raised and maintained at 95°C to 100°C for 5hrs followed by cooling to 30°C – 35°C. Water (400 ml) is added and maintained at 25°C – 30°C for 2hrs . Product is filtered, washed with water (500 ml) and dried at 40°C – 45°C to constant weight. Dry weight of the product: 101.6 g (Yield: 95.8 %)

Stage-2: Preparation of 1- Cyclopropyl-7- (3-methylpiperazin-l-yl) – 6-fluoro-8-methoxy-4-oxo-l, -dihydro-3-quinoline carboxylic acid boron difluoride chelate

100 g of Boron difluoride chelate derivative prepared as above in stage-1 is suspended in acetonitrile (800 ml) , to that 2-methyl piperazine (44.0 g, 1.5 mole equiv.) is added and mixed for 15 min to obtain a clear solution. The reaction mass is maintained at 30°C – 35°C for 12 hrs followed by cooling to -10°C to -5°C. The reaction mass is maintained at -10°C to -5°C for 1 hr. The product is filtered and dried at 45°C – 50°C to constant weight. Dry weight of the product: 116.0 g (Yield: 93.9 %) .

The condensed chelate (100 g) prepared as above is suspended in methanol (1500 ml), maintained at 40°C – 45°C for 30 min. The reaction mass is gradually cooled, maintained for 1 hr at -5°C to 0°C. The product is filtered, washed with methanol (50 ml) and dried at 45°C – 50°C to constant weight. Dry weight of the product: 80.0 g (Yield: 80.0 %)

Stage -3: Preparation of Gatifloxacin (Crude)

The pure condensed chelate (100.0 g) prepared as above in stage-2 is suspended in 20% aq. ethanol (1000 ml) , the temperature is raised and maintained at 75°C to 80°C for 2 hrs. The reaction mass is cooled, filtered to remove insolubles, distilled under vacuum to remove solvent. Fresh ethanol (200 ml) is added and solvent is removed under vacuum at temperature below 50°C. Ethanol (200 ml) is added to the residue and gradually cooled to -10°C to -5°C. The reaction mass is mixed at -10°C to -5°C for 1 hr and then filtered. The wet cake is washed with ethanol (25 ml) and dried at 45°C – 50°C to constant weight.

The dry weight of the Gatifloxacin is 83.3 g (Yield: 91.7 %)

Stage- 4: Purification of crude Gatifloxacin

Crude Gatifloxacin (100.0 g) prepared as above in stage-3 is suspended in methanol (4000 ml), the temperature is raised and maintained at 60°C to 65°C for 20 min. to get a clear solution. Activated carbon (5 g) is added, maintained for 30 min and the solution is filtered. The filtrate is concentrated to one third of its original volume under vacuum at temperature below 40°C. The reaction mass is gradually cooled and maintained at -10°C to -5°C for 2 hrs. The product is filtered, washed with methanol (50 ml) and dried at 45°C – 50°C to constant weight. The dry weight of the pure Gatifloxacin is 76.0 g (Yield: 76.0 %)

Example-II: Preparation of Gatifloxacin without isolation of intermediate (boron difluoride chelate derivative)

Stage-1: Preparation of l-cyclopropyl-6, 7-difluoro-8-methoxy-4- oxo-1, 4-dihydro-3-quinoline carboxylic acid boron difluoride chelate.

Ethyll-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-l, 4-dihydro-3- quinoline carboxylate (lOOg) is suspended in 40% aq. hydrofluoroboric acid (1000 ml) . Temperature of the reaction mass is raised and maintained at 95°C to 100°C for 5 hrs followed by cooling to 30°C – 35°C. 400 ml DM water is added, maintained at 25°C – 30°C for 2hrs . The product is filtered, washed with DM water (500 ml) and dried at 40°C – 45°C to constant weight. The dry wt is 102.5 g (Yield: 96.6 %)

Stage – 2: Preparation of Gatifloxacin (Crude)

The boron difluoride chelate derivative (100 g) prepared as above in stage-1 is suspended in acetonitrile (800 ml) , 2-methyl piperazine (44 g, 1.5 mole equiv.) is added and mixed for 15 min to obtain a clear solution. The reaction mass is maintained at 30°C – 35°C for 12 hrs. Removed the solvent by vacuum distillation. 20% Aq. ethanol (1000 ml) is added, raised the temperature and maintained at 75°C to 80°C for 2 hrs. The reaction mass is cooled, filtered to remove insolubles. The filtrate is distilled under vacuum to remove solvent completely. Fresh ethanol (250 ml) is added and distilled under vacuum at temperature below 50°C. Fresh Ethanol (250 ml) is added to the residue and gradually cooled to -10°C to -5°C. The reaction mass is maintained at -10°C to -5°C for 1 hr and filtered. The wet cake is washed with ethanol (30 ml) and dried at 45°C – 50°C to constant weight.

The dry weight of the Gatifloxacin is 73.5 g (Yield: 65.4 %)

Stage -3: Purification of crude Gatifloxacin

Crude Gatifloxacin (80.0 g) prepared as above in stage-2 is suspended in methanol (2000 ml) , the temperature is raised and maintained at 60°C to 65°C for 20 min. to get a clear solution. The reaction mixture is filtered. The filtrate is gradually cooled and maintained at -10°C to -5°C for 2 hrs. The product is filtered, washed with methanol (50 ml) and dried at 45°C – 50°C to constant weight.

The dry weight of the pure Gatifloxacin is 56.0 g (Yield: 70.0 %)

……………………….

WO 2005047260

http://www.google.co.in/patents/WO2005047260A1?cl=en

Gatifloxacin is the international common name of l-cyclopropyl-6-fluoro-l, 4-dihydro-8-methoxy- 1- (3-methyl-l-piperazinyl) -4-oxo-3-guinolin-carboxylic acid of formula (I) , with application in medicine and known for its antibiotic activity:

 

European patent application EP-A-230295 discloses a process for obtaining gatifloxacin that consists on the reaction of compound (II) with 2-

 

In this process the gatifloxacin is isolated in the form of a hemihydrate after a laborious process of column chromatography and recrystallisation in methanol, which contributes towards making the final yield lower than 20% by weight. Moreover, in said process an undesired by-product is formed, resulting from demethylation at position 8 of the ring. European patent application EP-A-241206 discloses a process for preparing gatifloxacin, whose final steps are as follows:

 

(III) H ft N Me H DMSO

Gatifloxacin (I)

(IV) This process uses the intermediate compound (III) , which has been prepared and isolated in a separate operation, while the intermediate compound (IV) is also isolated before proceeding to its conversion into gatifloxacin by treatment with ethanol in the presence of triethylamine. The overall yield from these three steps is lower than 40%. These disadvantages — a synthesis involving several steps, low yields, and the need to isolate the intermediate products — hinder the production of gatifloxacin on an industrial scale. There is therefore a need to provide a process for preparing gatifloxacin with a good chemical yield, without the need to isolate the intermediate compounds and that substantially avoids demethylation in position 8 of the ring. The processes termed in English “one pot” are characterised in that the synthesis is carried out in the same reaction vessel, without isolating the intermediate compounds, and by means of successive addition of the reacting compounds. The authors of the present invention have discovered a simplified process for preparing gatifloxacin which does not require isolation of the intermediate compounds .

 

Example 1: Preparing gatifloxacin from compound (II) 10 g (0.0339 moles, 1 equivalent) of compound

(II) is placed in a flask, 30 ml of acetonitryl (3 volumes) is added and this is heated to a temperature of 76-80° C.

Once reflux has been attained, and being the temperature maintained, 3.28 g (0.0203 moles, 0.6 equivalents) of hexamethyldisilazane (HMDS) is added with a compensated adding funnel. Once addition is completed, the reaction is maintained with stirring for 1 hour at a temperature of 76-80° C. Once this period has elapsed, the reaction mixture is cooled to a temperature ranging between 0 and 15° C, and 5.78 g (0.0407 moles, 1.2 equivalents) of boron trifluoride ethyletherate is added while keeping the temperature below 15° C. Once addition is completed, the temperature is allowed to rise to 15- 25° C and it is kept under these conditions for approximately 2 hours. The pH of the mixture is then adjusted to an approximate value of 9 with triethylamine (approximately 2 ml) . To the resulting suspension is added a solution of 10.19 g (0.1017 moles, 3 equivalents) of 2-methylpiperazine in 28 ml of acetonitryl, while maintaining the temperature between 15 and 25° C. The resulting amber solution is kept with stirring under these conditions for approximately 3 hours . Once the reaction has been completed, the solution is distilled at low pressure until a stirrable paste is obtained. At this point 50 ml of methanol is added, the resulting suspension is raised to a temperature of 63-67° C and is kept under these conditions for approximately 5 hours . Once the reaction has been completed, the mixture is cooled to a temperature of 25-35° C in a water bath, and then at a temperature of 0-5° C in a water/ice bath for a further 1 hour. The resulting precipitate is filtered, washed with cold methanol (2 x 10 ml) and dried at 40° C in a vacuum oven to constant weight. 10.70 g of crude gatifloxacin is obtained, having a water content of 2.95% by weight. The yield of the process is 81.8%.

The crude product is crystallised in methanol by dissolving 20 g of crude gatifloxacin in 1 1 of methanol (50 volumes) at a temperature of 63-67° C. Once all the product has been dissolved, the solution is left to cool to a temperature of 30-40° C, and then to a temperature of 0-5° C in a water/ice bath, maintaining it under these conditions for 1 hour. The resulting suspension is filtered and the solid retained is washed with 20 ml (1 volume) of cold methanol. The solid obtained is dried at 40° C in a vacuum oven to provide 18.65 g of gatifloxacin with a water content of 2.36% by weight.

The overall yield from the compound (II) is 77.7%, with a purity exceeding 99.8% as determined by HPLC chromatography. The content of by-product resulting from demethylation in position 8 of the ring is lower than 0.1% as determined by HPLC chromatography.

Systematic (IUPAC) name
1-cyclopropyl-6-fluoro- 8-methoxy-7-(3-methylpiperazin-1-yl)- 4-oxo-quinoline-3-carboxylic acid
Clinical data
Trade names	Zymar
AHFS/Drugs.com	monograph
MedlinePlus	a605012
Legal status	℞ (Prescription only)
Routes of administration	Oral (discontinued), Intravenous(discontinued) ophthalmic
Pharmacokinetic data
Protein binding	20%
Half-life	7 to 14 hours
Identifiers
CAS Registry Number	112811-59-3
ATC code	J01MA16 S01AE06
PubChem	CID: 5379
DrugBank	DB01044
ChemSpider	5186
UNII	81485Y3A9A
KEGG	D08011
ChEBI	CHEBI:5280
ChEMBL	CHEMBL31
NIAID ChemDB	044913
Chemical data
Formula	C19H22FN3O4
Molecular mass	375.394 g/mol

PAPER

An improved process to obtain gatifloxacin (1) through use of boron chelate intermediates has been developed. The methodology involves an initial activation step which accelerates the formation of the first chelate under low-temperature conditions and prevents demethylation of the starting material. To increase the overall yield and to avoid the isolation and manipulation of the resulting intermediates, the process has been designed to be carried out in one pot. As a result, we present here an easy, scaleable and substantially impurity-free process to obtain gatifloxacin (1) in high yield.

A High-Throughput Impurity-Free Process for Gatifloxacin

F. Javier Villasante *, Lourdes Gude , Sara P. Fernández , Olga Alonso , Elena García and Antonio Cosme

Department of Research & Development, Química Sintética S.A., c/ Dulcinea s/n, 28805 Alcalá de Henares, and Department of Organic Chemistry, University of Alcalá, 28871 Madrid, Alcalá de Henares, Spain

Org. Process Res. Dev., 2008, 12 (5), pp 900–903

DOI: 10.1021/op800042a

http://pubs.acs.org/doi/full/10.1021/op800042a

gatifloxacin (1) as white crystals. Yield 32.3 kg, (93%); purity by HPLC 99.87%; Assay by HPLC 100.8%; mp 167−168 °C(18) (Lit. (J. Med. Chem. 1995, 38, 4478)159−162 °C).

18

DSC analysis showed two endothermic peaks at 166.2 °C (T onset = 164.3 °C) and 190.0 °C (T onset = 188.2 °C) and an exothermic one at 168.1 °C. The shape of this DSC curve is characteristic of a monotropic transition between crystalline forms

Water content by Karl Fischer 3.0%(19) MS m/z 376 (M+ + H);

19

Although there are several hydrates described for gatifloxacin such as, among others, the hemimydrate, sesquihydrate, and pentahydrate(Raghavan, K. S.; Ranadive, S. A.;Gougoutas, J. Z.; Dimarco, J. D.; Parker, W. L.; Dovich, M.; Neuman, A.Gatifloxacin pentahydrate. WO 2002/22126 A1, 2002) , the Gatifloxacin obtained by the present procedure does not seem to form a stoichometric hydrate, but instead it retains moisture.

Thus, the product is usually obtained with a Karl-Fischer value below 1% after drying, but it can absorb moisture until a final content of about 3%. This water content can vary between 2.0% and 3.5%, depending on the relative humidity of the environment. DSC analysis revealed a broad endothermic signal with minimum at 76 °C, while TGA analysis showed that the product loses all the water below 80 °C.

No loss of weight is registered when the product melts, and the weight is constant until the decomposition of the material at about 200 °C. On the basis of these results, it can be said that the water content of the gatifloxacin obtained by the present process is retained moisture instead of water belonging to the lattice. The shape of the derivative of the weight curve at the beginning of the analysis shows that the sample has already lost part of the moisture when the register starts. This is probably due to the sample starting to lose weight when makes contact with the dry atmosphere of the TGA oven that could explain the different values obtained for water content of the analyzed sample by TGA (1.90%) and Karl-Fischer (2.64%) methods.

 1H NMR (DMSO-d6) δ 0.97 (d, J = 6.1 Hz, 3H), 1.04 (m, 2H), 1.15 (m, 2H), 2.75−2.94 (m, 4H) 3.14 (m, 1H), 3.30 (m, 2H), 3.74 (s, 3H), 4.15 (m, 1H), 7.70 (d, JH−F = 12.2 Hz, 1H), 8.67 (s, 1H). 

13C NMR (DMSO-d6) δ 8.40, 8.42, 18.66, 40.28, 45.46, 50.17, 50.29 (d, JC−F = 3.44 Hz), 57.36 (d, JC−F = 3.74 Hz), 62.15, 106.0 (d, JC−F = 22.7 Hz), 106.04, 120.05 (d, JC−F = 8.6 Hz), 133.6 (d, JC−F = 1.1 Hz), 138.9 (d, JC−F = 11.9 Hz), 145.2 (d, JC−F = 5.87 Hz), 149.88, 155.06 (d, JC−F = 249.2 Hz), 165.56, 175.56 (d, JC−F = 3.3 Hz).

 19F NMR (DMSO-d6) δ −120.4 (d, J = 12.2 Hz).

Anal. Calcd for C19H22N3O4F + 3.0% H2O; C, 58.95; H, 6.07; N, 10.85. Found: C, 58.90; H, 5.82; N, 10.90.

Boron content 170 ppm.(The respective boron contents found for batches 2 and 3 were 160 and 300 ppm)

Side-effects and removal from the market

A Canadian study published in the New England Journal of Medicine in March 2006 claims Tequin can have significant side effectsincluding dysglycemia.^[2] An editorial by Dr. Jerry Gurwitz in the same issue called for the Food and Drug Administration (FDA) to consider giving Tequin a black box warning.^[3] This editorial followed distribution of a letter dated February 15 by Bristol-Myers Squibb to health care providers indicating action taken with the FDA to strengthen warnings for the medication.^[4] Subsequently it was reported on May 1, 2006 that Bristol-Myers Squibb would stop manufacture of Tequin, end sales of the drug after existing stockpiles were exhausted, and return all rights to Kyorin.^[5]

Union Health and Family Welfare Ministry of India on 18 March 2011 banned the manufacture, sale and distribution of Gatifloxacin as it caused certain adverse side effects^[6]

Contraindications

Diabetes^[7]

Availability

Gatifloxacin is currently available only in the US and Canada as an ophthalmic solution.

In China it is sold in tablet as well as in eye drop formulations.

Ophthalmic anti-infectives are generally well tolerated. The concentration of the drug observed following oral administration of 400 mg gatifloxacin systemically is approximately 800 times higher than that of the 0.5% Gatifloxacin eye drop. Given as an eye drop, Gatifloxacin Ophthalmic Solution 0.3% & 0.5% cause very low systemic exposures. Therefore, the systemic exposures resulting from the gatifloxacin ophthalmic solution are not likely to pose any risk for systemic toxicities.

• The reaction of 1-bromo-2,4,5-trifluoro-3-methoxybenzene (I) with CuCN and N-methyl-2-pyrrolidone at 150 C gives 2,4,5-trifluoro-3-methoxybenzonitrile (II), which by treatment with concentrated H2SO4 yields the benzamide (III) The hydrolysis of (III) with H2SO4 -. water at 110 C affords 2,4,5-trifluoro-2-methoxybenzoic acid (IV), which by reaction with SOCl2 is converted into the acyl chloride (V). The condensation of (V) with diethyl malonate by means of magnesium ethoxide in toluene affords diethyl 2- (2,4,5-trifluoro-3-methoxybenzoyl) malonate (VI), which by treatment with p-toluenesulfonic acid in refluxing water gives ethyl 2- (2,4,5-trifluoro-3-methoxybenzoyl) acetate (VII). The condensation of (VII) with triethyl orthoformate in refluxing acetic anhydride yields 3-ethoxy -2- (2,4,5-trifluoro-3-methoxybenzoyl) acrylic acid ethyl ester (VIII), which is treated with cyclopropylamine (IX) to afford the corresponding cyclopropylamino derivative (X). The cyclization of (X) by means of NaF in refluxing DMF gives 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (XI), which is hydrolyzed with H2SO4 in acetic acid to yield the corresponding free acid (XII). Finally, this compound is condensed with 2-methylpiperazine (XIII) in hot DMSO.

 

Title: Gatifloxacin CAS Registry Number: 112811-59-3 CAS Name: 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid Trademarks: Tequin (BMS); Zymar (Allergan) Molecular Formula: C19H22FN3O4 Molecular Weight: 375.39 Percent Composition: C 60.79%, H 5.91%, F 5.06%, N 11.19%, O 17.05% Literature References: Fluorinated quinolone antibacterial. Prepn: K. Masuzawa et al., EP 230295; eidem, US 4980470 (1987, 1990 both to Kyorin); J. P. Sanchez et al., J. Med. Chem. 38, 4478 (1995); of the sesquihydrate: T. Matsumoto et al., US5880283 (1999 to Kyorin). In vitro antibacterial activity: A. Bauernfeind, J. Antimicrob. Chemother. 40, 639 (1997); H. Fukuda et al., Antimicrob. Agents Chemother. 42, 1917 (1998). Clinical pharmacokinetics: M. Nakashima et al., ibid. 39, 2635 (1995). Clinical study in urinary tract infection: H. Nito, 10th Mediterranean Congr. Chemother. 1996, 327; in respiratory tract infection: S. Sethi, Expert Opin. Pharmacother. 4, 1847 (2003). Properties: Pale yellow prisms from methanol as hemihydrate, mp 162°. Melting point: mp 162°   Derivative Type: Sesquihydrate CAS Registry Number: 180200-66-2 Manufacturers’ Codes: AM-1155 Molecular Formula: C19H22FN3O4.1½H2O Molecular Weight: 384.40 Percent Composition: C 59.37%, H 6.03%, F 4.94%, N 10.93%, O 18.73% Therap-Cat: Antibacterial. Keywords: Antibacterial (Synthetic); Quinolones and Analogs

References

1.  Burka JM, Bower KS, Vanroekel RC, Stutzman RD, Kuzmowych CP, Howard RS (July 2005). “The effect of fourth-generation fluoroquinolones gatifloxacin and moxifloxacin on epithelial healing following photorefractive keratectomy”. Am. J. Ophthalmol. 140 (1): 83–7. doi:10.1016/j.ajo.2005.02.037.PMID 15953577.
2.  Park-Wyllie, Laura Y.; David N. Juurlink; Alexander Kopp; Baiju R. Shah; Therese A. Stukel; Carmine Stumpo; Linda Dresser; Donald E. Low; Muhammad M. Mamdani (March 2006).“Outpatient Gatifloxacin Therapy and Dysglycemia in Older Adults”. The New England Journal of Medicine 354 (13): 1352–1361. doi:10.1056/NEJMoa055191. PMID 16510739. Retrieved 2006-05-01. Note: publication date 30 March; available on-line 1 March
3.  Gurwitz, Jerry H. (March 2006). “Serious Adverse Drug Effects — Seeing the Trees through the Forest”. The New England Journal of Medicine 354 (13): 1413–1415.doi:10.1056/NEJMe068051. PMID 16510740. Retrieved2006-05-01.
4.  Lewis-Hall, Freda (February 15, 2006). “Dear Healthcare Provider:” (PDF). Bristol-Myers Squibb. Retrieved May 1, 2006.
5.  Schmid, Randolph E. (May 1, 2006). “Drug Company Taking Tequin Off Market”. Associated Press. Archived from the original on November 25, 2007. Retrieved 2006-05-01.^{[dead link]}
6.  “Two drugs banned”. The Hindu (Chennai, India). 19 March 2011.
7.  Peggy Peck (2 May 2006). “Bristol-Myers Squibb Hangs No Sale Sign on Tequin”. Med Page Today. Retrieved 24 February2009.

 

EP0610958A2 *	20 Jul 1989	17 Aug 1994	Ube Industries, Ltd.	Intermediates in the preparation of 4-oxoquinoline-3-carboxylic acid derivatives
ES2077490A1 *				Title not available

Citing Patent	Filing date	Publication date	Applicant	Title
WO2008126384A1	31 Mar 2008	23 Oct 2008	Daiichi Sankyo Co Ltd	Method for producing quinolone carboxylic acid derivative
CN101659654B	28 Aug 2008	6 Nov 2013	四川科伦药物研究有限公司	2-Methylpiperazine fluoroquinolone compound and preparation method and application thereof
CN102351843A *	18 Aug 2011	15 Feb 2012	张家口市格瑞高新技术有限公司	Synthesis method of 2-methyl piperazine lomefloxacin
EP1832587A1 *	2 Mar 2007	12 Sep 2007	Quimica Sintetica, S.A.	Method for preparing moxifloxacin and moxifloxacin hydrochloride
US7365201	2 Mar 2006	29 Apr 2008	Apotex Pharmachem Inc.	Process for the preparation of the boron difluoride chelate of quinolone-3-carboxylic acid
US7875722	30 Sep 2009	25 Jan 2011	Daiichi Sankyo Company, Limited	Method for producing quinolone carboxylic acid derivative

EP0464823A1 *	Jul 4, 1991	Jan 8, 1992	Kyorin Pharmaceutical Co., Ltd.	(6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-O3,O4)bis(acyloxy-O)borates and the salts thereof, and methods for their manufacture
US4997943 *	Mar 31, 1987	Mar 5, 1991	Sankyo Company Limited	Quinoline-3-carboxylic acid derivatives

Citing Patent	Filing date	Publication date	Applicant	Title
CN101659654B	Aug 28, 2008	Nov 6, 2013	四川科伦药物研究有限公司	2-Methylpiperazine fluoroquinolone compound and preparation method and application thereof
CN102351843A *	Aug 18, 2011	Feb 15, 2012	张家口市格瑞高新技术有限公司	Synthesis method of 2-methyl piperazine lomefloxacin

* Cited by examiner

 

TAKE A TOUR

 

 

TAKE A TOUR

 

Amritsar, punjab, India

1. Amritsar – Wikipedia, the free encyclopedia

   https://en.wikipedia.org/?title=Amritsar

   Amritsar is one of the largest cities of the Punjab state in India. The city origin lies in the village of Tung, and was named after the lake founded by the fourth Sikh  …

   ‎Sri Guru Ram Dass Jee - ‎Amritsar district - ‎Amritsar Cantonment - ‎Category:Amritsar

   GOLDEN TEMPLE
   

   .

   Tandoori chicken at Surjit Food Plaza. amritsar

   Bullet marks on the walls of the park premises

   The Jallianwalla Bagh in 1919, months after the massacre

   Mealtime at the Golden Temple Amritsar

    

   Golden Temple – Harmandir Sahib: Free food for everyone

   Sri Guru Ram Dass Jee International Airport in Amritsar

   Amritsar – Wagah Border – Street food stall | Explore bernic… |

   Charles W. Bartlett, Amritsar (The Lake by the Golden Temple) 1920

   tandoori chicken

   Khalsa College

   • Golden Temple

   • Maharaja Ranjit Singh’s Ram Bagh Gardens

   • Golden Temple

   • Durgiana Temple

   • The holy water

   • Jallianwala Bagh

   • Jallianwala Bagh

   • The holy water

   • Golden Temple

   • Golden Temple

   • Sikh Gurdwara

   • The holy water

   Night view of the Harmandir Sahib

   ///////////

Dr. Sun K. Kim is a Quality-by-Design Evangelist, transforming how Product Development is executed in the Biologics, Pharmaceutical and Medical Devices industry. In addition, he teaches at Keio University and Stanford University. His current focus of research is Quality-by-Design, Agile Development of Drugs and Therapeutics.

He received his MS and PHD in Mechanical Engineering at Stanford University. Sun was recently a Professor at Keio University in Japan. Prior to Silicon Valley days, he served in the Korean Army and worked at BMW in Munich, Germany

• sun@qbdworks.com
• https://www.linkedin.com/in/kimsunkist
• http://www.leanqbd.com/
• http://qbdworks.com/
• http://www.slideshare.net/kimsunkist
• Twitter…….https://twitter.com/kimsunkist

Publications

A New Project-Based Curriculum of Design Thinking with Systems Engineering Techniques

International Journal of System of Systems Engineering

2013

Agile Project Management for Root Cause Analysis Projects

International Conference on Engineering Design

2013

A New Project-Based Curriculum of Design Thinking with Systems Engineering Techniques

Council of Engineering Systems Universities

2012

Evaluation of Design for Service Innovation Curriculum: Validation Framework and Preliminary Results

nternational Journal of Services Technology and Management

2011

A Validation Regarding Effectiveness of Scenario Graph

ASME International Design Engineering Technical Conferences

2011

Wants Chain Analysis: Human-centered Method for Analyzing and Designing Social Systems

International Conference on Engineering Design

2011

Scenario-based Amorphous Design (SAD) Framework for a Location-based Services Technology

Mobile Human Computer Interaction

2010

Transforming Seamless Positioning Technology into a Business using a Systems Design Approach—Scenario-based Amorphous Design

IEEE- International Systems Conference

2010

Design for Service Innovation: A Methodology for Designing Service as a Business for Manufacturing Companies

International Journal of Services Technology and Management

2010

Preliminary Validation of Scenario-based Design for Amorphous Systems

International Conference on Systems Engineering

2010

Tools for Project-based Active Learning of Amorphous Systems Design: Scenario Prototyping and Cross Team Peer Evaluation

ASME International Design Engineering Technical Conferences

2009

Active Learning Project Sequence: Capstone Experience for Multi-disciplinary System Design and Management Education

International Conference on Engineering Design

2009

Demystifying Ambiguity in The Design of Amorphous Systems

International Conference on Systems Engineering

2009

Scenario-based Design for Amorphous Systems

ASME International Mechanical Engineering Congress and Exposition

2008

Analysis and Design Methodology for Recognizing Opportunities and Difficulties for Product-based Services

Information Processing Society of Japan (IPSJ) Journal

2007

Scenario Graph: Discovering new business opportunities and Failure Modes,”

ASME International Design Engineering Technical Conferences

2007

Analysis and Design Methodology for Product-based Services

Annual Conference of the Japanese Society for Artificial Intelligence

2007

Analysis and Design Methodology for Recognizing Opportunities and Difficulties for Product-based Services

PICMET

2007

CUT PASTE FROM

KIM SUN SPEAKS

About QbDWorks…http://qbdworks.com/about/

Are you a Scientist in the Pharmaceutical, Biopharmaceutical or Medical Devices industries?

Then you are probably asking:

• Does Quality-by-Design actually work?
• Or is it just another program like Lean or Six Sigma?
• How do I implement QbD successfully?
• How do I persuade my management?
• What is the first step?

As a QbD practitioner, I had the same questions and am trying to answer them as I test different elements of QbD.

Through our members’ successes and failures in QbD, you can save time by not having to repeat them yourself. There are many lessons learned and knowledge that you can share with your QbD team.

Who are You?

My name is Sun Kim. I currently practice Quality-by-Design, transforming how Product Development is executed in Biopharmaceutical, Pharmaceutical, Biologics, and Medical Device industries.

In addition, I teach at Stanford University. My focus of research is Lean Quality by Design.

I received my MS and PHD in Mechanical Engineering at Stanford University and was recently an Asst.  Professor at Keio University in Japan. Prior to Silicon Valley days, I served in the Korean Army and worked at BMW AG in Munich, Germany, where my lifelong pursuit of “Product Development Methodology” began.

Why is an Engineer working in the Bio/pharmaceutical Industry?

Thanks for asking! When working at BMW, as a member of the elite “KREATIV” (Creative) team, my goal was to develop the best technologies and products for the automotive industry. However our approach was somewhat adhoc and heuristics-based. I knew there was a better way.

So I set my heart to learn how best products are developed across all industries. This led me to my PhD research at Stanford University.

Little did I know this would turn out to be more than just a graduate program. On top of the typical coursework, research and publishing, my schedule was packed with hands-on consulting/research projects with GE Healthcare, GE Aviations, Toyota, Nissan, Toshiba, Medtronic, Johnson & Johnson, Startup’s etc.

After contributing to the product development approaches for the Academia, Fortune 500 and Startup’s, I knew my heart was always with Health Care. So I returned to the benches and trenches.

For the last 10 years, I have been working in the Biopharmaceutical, Pharmaceutical and Medical Devices Industry, to make Quality by Design a reality.

So please join me in this Quality by Design journey.

Sign up to connect to the community and receive updates.

Together, we can change how drugs and therapies are developed for our patients and families.

Let’s Connect!

If you’d like to connect, please invite me:

www.linkedin.com/in/kimsunkist/

Previously I worked (full time or consulting) with:

The views expressed on this website are personal opinions and in no way reflect the position of any organization.

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Join me on Linkedin

Join me on Facebook FACEBOOK

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FREEMONT CALFORNIA

LAKE ELIZABETH

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Join me on Linkedin

Join me on Facebook FACEBOOK

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////

11-Chloro-1-undecene

SOCl2

+

+

Operating scheme

8 must-see places in Southeast Asia for great views: bucket list 2015

Southeast Asia is more than food and culture; here are 8 eye-candy places with magnificent views for a highly memorable trip!

 

Not just a melting pot of cultures, religions, history and food, Southeast Asia offers many picturesque spots that your eyes will thank you for. Whether it’s enjoying a sunset from a mountain top or just taking in the bucolic sights of Mother Nature’s hand-sculpted terrains, you’ll attest that these 8 suggestions offer some pretty unique charms that take your breath away.

 

1. Inle Lake, Myanmar

Myanmar has become a hotspot for the intrepid traveller and opens up plenty of opportunities to lap up many of its natural scenic wonders. If you’re heading there, a must-see place is Inle Lake renowned for its vast body of water where one can spot fishing communities and homes built on stilts.

Not only is the lake famous for its photogenic quality, you can hire guides to visit fish farms and shop at handicraft stores. Inle Lake’s picturesque charm comes from watching leg-rowing fisherman haul their catch during sunset. Find cheap flights to the capital Naypyidaw and best time to travel there is between November and February.

Read more: Top 10 things to do in Myanmar

Be mesmerised by the scenic Inle Lake in Myanmar

 

 

2. Tiger’s Nest Monastery, Bhutan

Perched some 3,000 metres above sea level and build in 1692, Bhutan’s Taktsang monastery, or more popularly known as Tiger’s Nest, is a must-see when you come to this nation steeped in Buddhist history. Getting there is not for the faint-hearted as one has to traipse through a hilly, rocky and undulating path to reach the peak.

Do hire guides to reach the apex successfully, and you’ll be rewarded by 360-views of sylvan mountain tops. Spring time from March to May is the best time to visit Bhutan and Drukair Royal Airlines of Bhutan flies theredirect.

Read more: 5 tips on tipping when travelling in Southeast Asia

Take in the lofty, airy views of Tiger’s Nest in Bhutan

 

 

3. Mount Kinabalu, Sabah, Malaysia

Recognised as one of the tallest peaks in Southeast Asia, Mount Kinabalu is a trekker’s dream come true. Getting to the summit takes about two days to accomplish. There is a 4-km climb to Laban Rata lodge where you can rest and replenish on sustenance. The next day is a 2-km climb to Low’s Peak.

The trek may be arduous but with lush rainforest terrain, there’s always something new at every corner to keep you distracted. About a kilometer away from the peak, the terrain changes to rock, stone and pebbles complemented by vegetation normally found in cooler climes. To catch the sunrise on the second day, it’s advisable to depart at 2am but remember to bring extra clothing as the mercury will drop to 2 degrees Celsius.

Read more: 5 fun extreme sports in Singapore for the adventure seekers

The scenic misty peaks of Mt. Kinabalu also offer spots for picturesque photos

 

 

4. Palawan Island, Luzon, Philippines

Recently coined by Huffington Post as “The Most Beautiful Island In the World” while Conde Nast Traveler’sReader Choice Awards named it “The Top Island in the World”, Palawan island is quite the magnificent sight. With its beautiful azure waters infused with emerald hues, it’s also hard to refute such claims.

Dotting the waters are jungled-filled islands, each with a distinctive hill rising above the ocean. Just by half-hour domestic flight from Manila airport, once you soar above Palawan’s oceanic landscape, you’ll feel like you’ve reached Shangri-la. Whether it’s island-hopping or sea kayaking, fun-filled times are never in short supply.

Read more: 12 best beaches in Asia Pacific

The beaches of Palawan have powdery white sand!

 

 

5. Penang National Park, Malaysia

Penang is truly a foodie paradise but many people are flocking there for other reasons, one being its attractive natural environment. Located just west of mainland Malaysia, a flight from Singapore is slightly over an hour.

With plenty of diverse lifestyle choices and entertainment options, Penang also has its idyllic charms. Aside from its UNESCO-designated George Town, the Penang National Park located on the North-Western side of the island rewards one with rich rainforests, a diverse ecosystem and some 1,381 hectares of wetlands to indulge trekking fanatics and eco-photographers.

Read more: Best cruises from Singapore

Unique flora and fauna found at Penang National Park makes for picture perfect memories too

 

 

6. Tanah Lot Temple, Bali, Indonesia

Bali is never in short supply of mysticism and wonder. A two-hour flight out of Singapore is all it takes to enjoy a short vacation. And of course, visiting its picturesque sea temple on the west coast of Bali, Tanah Lot, promises many Kodak moments. A simple traipse during low-tide rewards a sight to behold too – a Hindu shrine ensconced among lush trees perched on a rock is postcard-worthy from any angle. Framed by crashing waves, Tanah Lot Temple brims with a dab of fable and mysticism that makes it a must-see when visiting Bali!

Read more: Top 5 places to go diving in Southeast Asia

Tanah Lot in Bali offers scenic views of splendid structures amidst crashing waves

 

 

7. Angkor Wat, Siem Reap, Cambodia

Angkor Wat became even more famous, thanks to the Tomb Raider movie starring Angelina Jolie. Founded in the 12th Century, it is also the 7th Wonder of the World. This Khmer temple’s architecture will seize the gaze of any first-time visitor. At the centre of this city, within a moat, is a towering stupa that provides sylvan views of its 3.6km, vine-covered outer wall. Just 5.5km north of Siem Reap, the Angkor Archaeological Park is a must-see for travellers with a penchant for history and artefacts.

Read more: Top 10 most romantic places in Asia (part 2)

Angkor Wat’s lush views are both captivating and mysterious

 

 

8. Halong Bay, Hanoi, Vietnam

Halong Bay, which means “Bay of Descending Dragons”, is a unique karst topography carved out by Mother Nature. The UNESCO World Heritage site offers views of vertical formations which are rich in dense vegetation. A boat cruise meandering through any of the 1,969 islets is both tranquil and insightful. Avoid the monsoons from June to September and from January to March, but visit the high seasons to enjoy sunny skies that won’t put a damper on your exploration plans of the natural outlying islets. After a three-hour fight to Hanoi from Singapore, take a five-hour road trip via mini bus to the port; it costs around USD 6 (SGD 7.50) and can be arranged upon arrival.

Read more: Top 10 most romantic places in Asia (part 1)

Halong Bay in Vietnam promises oceanic vistas

 

 

All these places will astound you in a multi-sensory way. Whichever activity you decide to experience at these destinations, you’ll agree that many good memories await.

  DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

 amcrasto@gmail.com

///////////

trans-Cinnamamide/(2E)-3-Phenyl-2-propenamide

1H NMR

NH3

+

  DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

Denpasar, bali, indonesia

 amcrasto@gmail.com

/////////

A novel approach to access ortho iodinated phenols using cyclic hypervalent iodine reagents through palladium(II) catalyzed C–H activation has been developed through weak coordination. The reaction showed excellent regioselectivity, reactivity and good functional group tolerance. A unique mechanism was proposed.

Pd(II) catalyzed ortho C–H iodination of phenylcarbamates at room temperature using cyclic hypervalent iodine reagents

Xiuyun Sun,^a   Xia Yao,^a   Chao Zhang^a and   Yu Rao*^a

*Corresponding authors

^aMOE Key Laboratory of Protein Sciences, Department of Pharmacology and Pharmaceutical Sciences, School of Medicine and School of Life Sciences, Tsinghua University, Beijing 100084, China

E-mail: yrao@mail.tsinghua.edu.cn

Chem. Commun., 2015,51, 10014-10017

DOI: 10.1039/C5CC02533H

http://pubs.rsc.org/en/content/articlelanding/2015/cc/c5cc02533h#!divAbstract

yu rao

Zhang Chao

 Tsinghua University, Beijing

///

Nonanedioic acid Azelaic acid

KMnO4 / KOH

; Side reactions

1H NMR

Azelaic acid(123-99-9)¹³CNMR

IR

Operating scheme

	round bottom flask 250 mL			three-necked flask 1000 mL
	reflux condenser			internal thermometer
	addition funnel with pressure balance			heatable magnetic stirrer with magnetic stir bar
	KPG stirrer			beaker 400 mL
	beaker 250 mL			Erlenmeyer flask 250 mL
	separating funnel			rotary evaporator
	suction filter			suction flask
	exsiccator with drying agent			oil bath

PESHAWAR, PAKISTAN FOOD

Peshawar is one the oldest cities of South Asia. It is an entrance point of Pakistan from the Afghanistan. It was an important city of Subcontinent and a meeting and marketing place for the public of Middle East, India and central Asia. Afghan warriors used this way to enter into subcontinent.

.

NALLI GOSHT

Pakistani cooks prepare food for refugees in the Jalozai camp in Peshawar,

Food being prepared at Qissa Khuwani Bazaar in Peshawar on the eve of Eid Milad-

The Big Pot Tea Man of Peshawar

//////

  DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

 amcrasto@gmail.com

/////////

http://www.google.com/patents/WO2008022462A1?cl=en

1 H-NMR Spectrum of Compound 35…………3-[3-(benzoylamino)-4-hydroxylphenyl] propanoic acid

¹H-NMR (Acetone-D₆) δ: 2.60 (t, 2H, J = 7.4, H- 3), 2.84 (t, 2H, J = 7.9, H-2), 6.89 (d, IH, J = 8.2, H-8), 7.00 (dd, IH, J = 2.1 , 8.25, H- 9), 7.57 (m, 4H, H-5, H-4′, H-5′, H-6¹), 8.05 (d, 2H, J = 8.2, H-3′, H-7′), 9.07 (broad s, IH, NH), 9.54 (broad s, IH, OH), 10.58 (broad s, IH, CO₂H).

¹³C-NMR Spectrum of Compound 35

¹³C-NMR (Acetone- D₆) δ: 30.87 (C- 3), 36.21 (C- 2), 118.69 (C- 8), 123.31 (C-5), 123.41 (C- 6), 126.88 (C- 9), 127.37 (C- 4), 128.54 (C-4¹, C-6¹), 129.61 (C-3¹, C-7′), 132.99 (C-5¹), 134.99 (C-2¹), 148.03 (C-7), 167.34 (C-I¹), 173.94 (C-I ).

¹³C-NMR Spectrum of Compound 35

COSY-NMR Spectrum of Compound 35

COSY-NMR Spectrum of Compound 35

HETCOR-NMR Spectrum of Compound 35

3-[3-(benzoylamino)-4-hydroxylphenyl] propanoic acid 35:

To a solution of 32 (222 mg, 1.06 mmol, leq.) dissolved in THF (20 mL) was added the catalyst 10 % palladium-on-charcoal (15 % by mass, 33 mg). The resulting mixture was then placed on a hydrogenator, flushed (5 times) with hydrogen and left to agitate under pressure (36 psi.) overnight (12 hrs) while recharging hydrogen pressure twice (36 psi.) until hydrogen up-take by reaction mixture stopped (pressure did not decrease for 1-2 hrs.). The reaction mixture was vacuum filtered through Celite ‘ rinsing with THF. To the filtered solution containing 33 was directly added BzCl (154 mg, 1.1 mmol, 1 eq.) and left to stir at room temperature for 30 min. Then 10 % HCl (25 mL) was added and stirring continued an additional 5 min. followed by extraction with CIT₂Cl₂ (2 x 35 mL). The organic fractions were combined, dried (MgSO₄), and evaporated off solvent. The resulting mixture was re-crystallized with Hexane/ Acetone to afford an off white solid (250 mg) with an 83 % yield from compound 32. Molecular Formula – C₁₆Hi₅NO₄. Formula Weight – 285.295 g mole^“1.

FT-IR (KBR disk) cm^{” 1} : 3201 (NH, OH), 1692 (CO₂H), 1636 (NHAc).

¹H-NMR (Acetone-D₆) δ: 2.60 (t, 2H, J = 7.4, H- 3), 2.84 (t, 2H, J = 7.9, H-2), 6.89 (d, IH, J = 8.2, H-8), 7.00 (dd, IH, J = 2.1 , 8.25, H- 9), 7.57 (m, 4H, H-5, H-4′, H-5′, H-6¹), 8.05 (d, 2H, J = 8.2, H-3′, H-7′), 9.07 (broad s, IH, NH), 9.54 (broad s, IH, OH), 10.58 (broad s, IH, CO₂H).

¹³C-NMR (Acetone- D₆) δ: 30.87 (C- 3), 36.21 (C- 2), 118.69 (C- 8), 123.31 (C-5), 123.41 (C- 6), 126.88 (C- 9), 127.37 (C- 4), 128.54 (C-4¹, C-6¹), 129.61 (C-3¹, C-7′), 132.99 (C-5¹), 134.99 (C-2¹), 148.03 (C-7), 167.34 (C-I¹), 173.94 (C-I ).

/////////////////////////////////////////

¹H-NMR Spectrum of Compound (+/-V36

13 C-NMR Spectrum of Compound (+/-V36

N-(l-oxaspiro[4.5]deca-6,9-dien-2,8-dion-7-yl)acetamide (+/-)-36: To a solution of 34 (122 mg, .547 mmol, 1 eq.) dissolved in acetone (10 mL, 0 ⁰C) was added PIFA (306 mg, .71 1 mmol, 1.3 eq.) in one portion and stirred for 20-25 minutes (confirmed by tic: [1 : 1] EtOAc/Hexane). The reaction mixture was diluted with ethyl acetate (15 mL), washed with cold water (10 mL), dried organic fraction (MgSO₄) and evaporated off solvent to afford a Tan solid. The crude product was purified by re-dissolving with CHCI₃, filtering of the solution through Celite ^®, evaporating off the solvent and placing it under vacuum overnight to afford an off white solid (120 mg, 98 % yield). Molecular Formula – C_{1 1}Hi iNO₄. Formula Weight – 221.209 g mole^“1. FT-IR (KBR disk) cm^“1: 3333 (NH), 1777 (lactone), 1668 (amide), 1650 (ketone), 1620 (α, β-conjugation to ketone). ¹H-NMR (CDCl₃) δ: 2.17 (s, 3H, H-2′), 2.44 (m, 2H, H-4), 2.81 (m, 2H, H-3), 6.35 (d, IH, J = 10.0, H-9), 6.94 (dd, IH, J = 3.1, 10.0, H- 10), 7.75 (d, IFI, J = 3.1, H-6), 7.99 (broad s, IH, NH). ¹³C-NMR (CDCl₃) δ: 24.86 (C- 2′), 28.36 (C- 4), 32.91 (C- 3), 79.76 (C-5), 124.30 (C- 6), 127.12 (C- 9), 131.55 (C- 7), 148.37 (C-10), 169.51 (C-I’), 175.46 (C-2), 179.40 (C- 8).

////////////////////

¹H-NMR Spectrum of Compound 32

(2E)-3-(4-hydroxyl-3-nitrophenyl) acrylic acid 32: To a solution of 4- hydroxyl-3-nitrobenzaldehyde (1.073 g, 6.43 mmol, 1 eq.) dissolved in pyridine (25 mL) was added piperidine (25 drops) and the resulting mixture was stirred (4-5 min.). Malonic acid (1.671 g, 16.1 mmol, 2.5 eq.) was then added in one portion and the resulting mixture was warmed (60-63 ⁰C) and stirred overnight (12-14 hrs, confirmed by tic: EtOAc, mini work up, 10 % HCl and EtOAc). The reaction was cooled and acidified (50 % HCl) until yellow precipitate formed (pH~2). This yellow precipitate was extracted with ethyl acetate (2 x 150 niL). The organic fractions were combined and washed with brine (150 mL), dried (MgSO₄), and the solvent was evaporated to afford a yellow solid. Removed excess solvent by vacuum and used without further purification (1.250 g, 93 % yield). Molecular Formula – CgH₇NO₅. Formula Weight – 209.156 g mole^“1. FT-IR (KBR disk) cm^“1: 2942 (OH), 1684 (CO₂H), 1626 (C=C), 1533,1270 (NO₂). ¹FI-NMR (Acetone-D₆) δ: 2.87 (broad s, IH, OH), 6.58 (d, IH, J= 16.0, H-2), 7.27 (d, IH, J= 8.8, H-8), 7.70 (d, IH, J= 16.4, H-3), 8.08 (d, IH, J= 2.2, 8.5, H-9), 8.40 (d, IFI, J = 2.2, FI-5), 10.67 (broad s, I H, CO₂FI). The¹³C-NMR of this compound agrees with the previously published data.⁵²

Con Dao Island, Vietnam

Con Dao Island, Vietnam

Con Dao travel guide – Wikitravel

Axitinib (AG013736; trade name Inlyta) is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models^[2] and has shown partial responses in clinical trials with renal cell carcinoma (RCC)^[3] and several other tumour types.^[4] It was approved by the U.S. Food and Drug Administration after showing a modest increase in progression-free survival,^[5] though there have been reports of fatal adverse effects.^[6]

Axitinib, a small-molecule indazole derivative chemically known as (E)-N-methyl-2-(3-(2-(pyridin-2-yl)-vinyl)-1H-indazol-6-ylthio)benzamide developed by Pfizer, was approved in January 2012 by the U.S. FDA with the trade name Inlyta. It selectively inhibits vascular endothelial growth factor receptors for the treatment of renal cell carcinoma

On January 27, 2012, axitinib was approved with the trade name INLYTA for treatment of patients in the United States with advanced renal cell carcinoma after failure of one prior systemic therapy.

It has received FDA (27 January 2012), EMA (13 September 2012), MHRA (3 September 2012) and TGA (26 July 2012) approval for use as a treatment for renal cell carcinoma.^{[11][12][13][14]}

A study published in 2015^[15] showed that axitinib effectively inhibits a mutated gene (BCR-ABL1[T315I]) that is common in chronic myeloid leukemias and adult acute lymphoblastic leukemias which have become resistant to other tyrosine kinase inhibitors likeimatinib. This is one of the first examples of a new indication for an existing drug being discovered by screening known drugs using a patient’s own cells.

The discovery and development of an efficient synthesis route to axinitib is reported. The first-generation route researched by Pfizer implemented two Pd-catalyzed coupling reactions as key steps. In this work, the development of Heck-type and C–S coupling reactions catalyzed by CuI is briefly described, using an economial and practical protocol. Aspects of this route, such as selecting optimal ligands, solvent, and other conditions, are discussed in detail. The scale-up experiment was carried out to provide more than 300 g of active pharmaceutical ingredients of axitinib in Form XLI with 99.9% purity in 39% yield. In short, we provide a new choice of synthesis route to axitinib, through two copper-catalyzed coupling reactions with good yield.

(E)-N-Methyl-2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthiol)benzamide (Axitinib) Form XLI (326.4 g in 96% yield with purity 99.91%). Residual Cu content was determined to be 2.2 ppm by atomic absorption spectroscopy: mp 227.7 °C; 

1H NMR (300 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.29 (d, J = 5.4 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 16.4 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.63–7.44 (m, 3H), 7.29 (p, J = 7.4, 6.6 Hz, 3H), 7.19 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 2.78 (d, J = 4.6 Hz, 3H); 

13C NMR (75 MHz, DMSO-d6) δ 167.89, 154.86, 149.54, 142.01, 141.86, 136.92, 136.88, 135.67, 132.52, 130.32, 129.99, 129.25, 127.80, 126.15, 125.59, 123.66, 122.68, 122.50, 121.79, 120.29, 114.76, 26.13.

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Axitinib (Axitinib, AG-013736, CAS: 319460-85-0) is a Pfizer research and development by the United States of new, mainly targeting VEGFR kinase GABA, inhibiting angiogenesis anticancer small molecule drug, trade name Inlyta, for other systems therapy for advanced renal cell carcinoma (Renal Cell Carcinoma, RCC), 2008 has been approved in the domestic clinical, and Pfizer’s cancer drug Sutent another similar imatinib (Sunitinib) , Axitinib also potent and selective multi-targeted tyrosine kinase inhibitor, can inhibit the vascular endothelial growth factor receptor (Vascular EndothelialGrowth Factor Rec India tor, VEGFR), including VEGFl receptor, VECF2 receptors and VECF3 receptor, can inhibit platelet-derived growth factor receptor (Platelet-derived growth factor receptor, PDGFR) and c_KIT. Axitinib is called sunitinib second generation, better than sunitinib adverse reactions.

Axitinib (II) chemical name 6- [2_ (methylcarbamoyl) phenylsulfanyl] -3-E- [2_ (Batch-2-yl) ethenyl] indazole structural formula as follows:

Axitinib (II)

Assi synthesis method for Nepal mainly in the following three ways:

(I) Patent US20060094881 (Agouron Pharmaceuticals), EP2163544 (Pfizer) reported the first synthesis method Axitinib to 3,6-diiodo-indazole as a starting material, first-iodo-6-position is substituted mercapto group, protection of the NH group, then the Heck reaction occurs (pyridine-2-yl) vinyl 3-position, after deprotection Axitinib whole synthesis route is as follows:

Axitinib Scheme I

This method although the synthesis route is shorter, but the catalyst and reagents used relatively expensive and require purified through the column, the total yield is low, is not conducive to industrial production.

[0004] (2) The second method of synthesis Axitinib e.g. W00102369 (Agouron Pharmaceuticals), US6531491 (Agouron Pharmaceuticals) reported in 6-nitro-indazole as a starting material, the 3-position first iodo, followed by the protecting group NH, Suzuki coupling reaction with boronic acid to give 3- styryl styryl-position, a nitro group reduced to an amino group, an amino diazotization reaction was iodo, the 3-position of the styrene-based ozone of the obtained aldehyde, followed by Wittig reaction to give the 3-position (pyridin-2-yl) ethenyl, 6-position is substituted mercapto iodine, alkaline hydrolysis then amidated, and finally deprotection Axitinib, the entire reaction formula as follows:

Axitinib Scheme 2

The method of synthesis route is long, harsh reaction conditions, complex process, the total yield is low, does not apply to industrial production.

[0005] (3) The third method is W02006048745 (Pfizer) discloses to 6-nitro-indazole as a starting material, the 3-position iodo first, followed by the protecting group NH, 3- bits Heck coupling reaction, a nitro group reduced to an amino group, an amino diazotization reaction was iodo, iodo-6-position is substituted mercapto group, and finally deprotected to give Axitinib, the entire reaction is as follows:

This method has an advantage over the first two methods, it is possible to enlarge the production, but the reaction was not complete in the reaction step, will generate new impurities through the column needs to be purified.

SYNTHESIS

aReagents and conditions: (a) I2, K2CO3, DMF; (b) CH2Cl2, CH3SO3H, dihydrofuran; (c) compound B, i-Pr2EtN, Pd(OAc)2, (o-Tol)3P, DMF; (d) iron, EtOH, NH4Cl; (e) AcOH, NaNO2, CH2Cl2, I2/KI; (f) compound C, Pd(dppf)Cl2, Cs2CO3, DMF; (h) 1, p-TsOH, MeOH; 2, NaHCO3; (i) AcOH, MeOH, Pd removal, recrystallization.

 http://www.google.com/patents/WO2006048745A1?cl=en

Example 15: Final deprotectioπ step to produce 6-r2-(methylcarbamoyl)phenylsulfanyll-3-E-f2- (pyridine-2-yl)ethenyllindazole

N-1 THP 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole (355 g) was suspended in 2,485 ml_ of methanol, after which p-toluenesulfonic acid monohydrate (718 g) was added. The mixture was then heated to 65 ⁰C (hard reflux) for 4 hours under argon while the reaction was monitored by HPLC (gluco method). Heating continued until less than 1% of the N-1 THP protected starting material persisted. The heating was then removed and the reaction was cooled to room temperature. The solid was filtered and the wet cake was washed with methanol (2 volumes, 710 mL) then the solids were rinsed with ethyl acetate (2 volumes, 710 mL). The wet cake was transferred to a reactor containing sodium bicarbonate (126.84 g), deionized water (1800 mL), and ethyl acetate (975 mL), which was then stirred for 2 hours at 2O⁰C. The solids were filtered and washed with 5 volumes of deionized water (1800 mL), then with 2 volumes of ethyl acetate (760 mL), and then dried in a vacuum oven at 40⁰C for 16 hours. The isolated yield for the reaction was 92.5% (274 g). The isolated material was identified as crystalline Form III free base (0.5 ethyl acetate solvate). ¹H NMR, 300 MHz, (DMSO-D6), ppm; 13.35 (1 H, s), 8.60 (1 H, d, J=3.8 Hz), 8.39 (1 H, m), 8.23 (1 H, d, J=8.5 Hz), 7.95 (1 H, d, J=16.4 Hz), 7.82 (1 H, ddd, J=7.7, 7.6, 1.8 Hz), 7.67 (1 H, d, J=7.8 Hz), 7.60 (a H, s), 7.57 (1 H, d, J=16.4 Hz), 7.49 (1 H, dd, J=7.1 , 1.6 Hz), 7.35-7.26 (3 H, m), 7.19 (1 H, d, J=8.4 Hz), 7.04 (1 H, d, J=7.8 Hz), 2.77 (3 H, d, J=4.6 Hz). ¹³C NMR, 75 MHz, (DMSO-D6) ppm: 168.23, 155.18, 149.81 , 142.35, 142.22, 137.31 , 136.00, 132.89, 130.64, 130.36, 129.51 , 128.14, 126.50, 125.93, 124.08, 123.01 , 122.85, 122.12, 120.642, 115.08, 26.45.

Example 21 : Preparation of 6-F2-(methylcarbamovDphenylsulfanyll-3-Z-r2-(pyridine-2- vDethenyllindazole

To a 100 ml_ 3-neck flask containing a solution of 0.95 g of 6-[2- (methylcarbamoyl)phenylsulfanyl]-3-[2-(pyridine-2-yl)ethynyl]indazole was added 2.5 g of phenyliodide diacetate followed by 1.0 mL of H₂NNH₂ H₂O. After the bubbling had settled, more phenyliodide diacetate and H₂NNH₂ H₂O were added in small portions, until LC/MS indicated the disappearance of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-[2-(pyridine-2-yl)ethynyl]indazole and the formation of 6-[2-(methylcarbamoyl)phenylsuIfanyl]-3-Z-[2-(pyridine-2-yl)ethenyl]indazole. Example 22: Palladium removal and polymorph control of 6-[2-(methylcarbamoyl)phenylsulfanvn- 3-E-r2-(pyridine-2-vDethenyllindazole

4) MeOH, reflux

Polymorph Form IV

5) HOAc/Xylenes

To a 12 L 3-neck flask, equipped with a mechanical stirrer, was added 160.20 g of 6-[2- (methylc'arbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole and 1.6 L of DMA and 1.6 L of THF. After stirring for 20 minutes, the mixture became homogeneous. To the clear solution was added 800.99 g of 10% cysteine-silica and the resulting mixture was allowed to stir at room temperature overnight.

The mixture was filtered through a medium sintered glass fritted funnel, and the cake was washed with a solution of 500 mL of DMA and 500 mL of THF. The cake was further washed with 2.0 L of THF and the filtrate was collected into a separate flask. The volatile parts in the latter filtrate were removed in vacuo and the residue was combined with the main filtrate. The combined filtrate was recharged back into the 12 L flask, followed by 800 g of 10% cysteine-silica. The flask was equipped with a mechanical stirrer and stirred over the weekend at room temperature. The mixture was then filtered through a medium sintered glass fritted funnel and the silica was washed with a mixture of solvents of 500 ml. of DMA and 500 ml_ of THF, followed by 3.0 L of THF. The volatile parts in the filtrate were removed in vacuo and the remaining solution was transferred to a 22 L 3-neck flask and treated with 12 L of water (added over a 20 minute period of time), a thick precipitate formed at this stage. After stirring overnight, the mixture was filtered and the cake was washed with 2.0 L of water and sucked dry.

The cake was charged to a 5 L 3-neck flask, followed by 1.6 L of THF and 160 mL of DMF. The flask was equipped with a mechanical stirrer, a reflux condenser and the mixture was heated at reflux for 8 hours. After cooling overnight, the mixture was filtered through sharkskin filter paper and sucked dry. The cake was charged to a 5 L 3-neck flask and 1.6 L of MeOH was added. The flask was equipped with a mechanical stirrer, a water condenser and the contents were heated at reflux for 6 hours. After cooling overnight, the mixture was filtered through sharkskin filter paper and sucked dry.

The cake was dissolved into 1.6 L of HOAc with the assistance of gentle heating in the water bath of a rotary evaporator. The solution was filtered through #3 filter paper and the total volume of the filtrate was reduced to ~500 mL in volume on the rotary evaporator at 60 °C/60 mmHg. At this stage, the bulk of the mixture remained a yellow solution and a small amount of precipitate formed. To the flask was charged 500 mL of xylenes (precipitate formed) and the total volume was reduced to -500 mL in volume on the rotary evaporator at 60°C/60 mmHg. The process was repeated two more times. After cooling, the mixture was filtered, the cake was washed with 500 mL of xylenes and sucked dry. The cake was transferred to a glass dish and further dried at 80°C/27 inch vacuum overnight.

The cake was off-white in color and weighed 108.38g. X-ray powder diffraction analysis indicated that a crystalline form was present, which was characterized as Form IV by a powder X- ray diffraction pattern comprising peaks at the following approximate diffraction angles (20): 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.2, 20.5, 21.6, 23.2, 24.2, 24.8, 26.2, and 27.5.

While the invention has been illustrated by reference to specific and preferred embodiments, those skilled in the art will recognize that variations and modifications may be made through routine experimentation and practice of the invention. Thus, the invention is intended not to be limited by the foregoing description, but to be defined by the appended claims and their equivalents.

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Chekal, B. P.; Guinness, S. M.; Lillie, B. M.; McLaughlin, R. W.; Palmer, C. W.; Post, R. J.; Sieser, J. E.; Singer, R. A.; Sluggett, G. W.; Vaidyanathan, R.; Withbroe, G. Org. Process Res. Dev. 2014, 18, 266 http://pubs.acs.org/doi/abs/10.1021/op400088k

The manufacturing process of axitinib (1) involves two Pd-catalyzed coupling reactions, a Migita coupling and a Heck reaction. Optimization of both of these pivotal bond-formation steps is discussed as well as the approach to control impurities in axitinib. Essential to the control strategy was the optimization of the Heck reaction to minimize formation of impurities, in addition to the development of an efficient isolation of crude axitinib to purge impurities.

Babu, S.; Dagnino, R., Jr.; Ouellette, M. A.; Shi, B.; Tian, Q.; Zook, S. E. PCT Int. Appl. WO/2006/048745, 2006.

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 http://www.google.com/patents/CN103570696A?cl=en

formula:

A Axitinib intermediate (1) production method, based on 6-nitro-indazole as a starting material, in the first catalyst is reacted with 3,4-dihydro -2H- pyran, bits of NH the protecting group tetrahydro -2H- pyran-2-yl, then the three iodide, to give the key intermediate in high yield 3-iodo-6-nitro-1- (tetrahydro -2H- pyrazol pyran-2-yl) -1H- indazole (I), comprising the following synthetic steps:

(1) 6-nitro-indazole dissolved in an aprotic solvent, and 3,4-dihydro -2H- pyran catalyst, 6-nitro-indazole in the catalyst and the 3,4-dihydro -2H – pyran reaction, the protecting group NH-position, was prepared to give 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, the reaction equation is:

Wherein the 3,4-dihydro -2H- pyran an amount of 3 equivalents wide;

Aprotic solvent is acetonitrile, ethyl acetate, toluene or xylene;

The catalyst is 2,3-dichloro-5,6-dicyano-p-benzoquinone, p-toluenesulfonic acid or methanesulfonic acid;

The reaction temperature is 7 (T90 ° C, the reaction time is 1 to 4 hours;

(2) 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole dissolved in a polar aprotic solvent, iodine was added and the acid-binding agent, an inorganic base, to afford 3- iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I), the reaction equation is:

Wherein the polar aprotic solvent is N, N- dimethylformamide (DMF), N, N- dimethylacetamide, N, N- diethylformamide, N, N- diethyl-acetamide ;

Inorganic base acid binding agent is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, cesium carbonate, lithium hydroxide;

The reaction temperature is 2 (T40 ° C, the reaction time is 8 to 20 hours.

[0009] A Axitinib intermediate (1) in preparation for the Nepalese Asif application, based on intermediate (1) and 2-vinyl pyridine Heck coupling reaction, followed sequentially nitro reduction and the diazotization reaction of iodine, and finally with a 2-mercapto–N- methylbenzamide was prepared by deprotection docking axitinib, including the following synthetic steps:

(I) Intermediate (1) and be given 2_ vinylpyridine Jie Heck coupling reaction to give (E) _6_ nitro _3- [2_ (P than-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, the reaction equation is:

(2) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- nitro indazole group reduction reaction, to give (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, The reaction equation is:

(3) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole diazo of the iodide to give (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole The reaction equation is:

(4) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole with 2- mercapto-methylbenzamide reaction -N-, to give (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyrazol pyran-2-yl) -1H- indazol-6-yl] thio} benzamide, the reaction equation is:

(5) (E) -N- methyl-2- {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H- indazol-6-yl] thio} benzamide deprotected Axitinib (II), the reaction equation is:

Example 1

A Assi intermediates for preparing Nigeria, comprising the steps of:

Synthesis of (I) 6- nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

A 5L reaction flask was added acetonitrile (2L), followed by addition of 6-nitro-indazole (163.1g, 1.0mol), 3, 4- dihydro -2H- pyran (168.2g, 2.0mol), 2,3- dichloro-5,6-dicyano-p-benzoquinone (22.7g, 0.1mol), was heated to 820C under reflux for 2 hours to complete the reaction, cooled to room temperature, rotary evaporated to dryness, added water and dichloromethane 2L 2L, stirring I hour, delamination, the organic phase washed with brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness, and then dissolved in acetonitrile and 2L, stirring ice-salt bath chilled to _5 ° C for 2 hours, suction filtered, the filter cake washed with a small amount of cold acetonitrile, recrystallized from ethanol, 60 ° C and dried in vacuo 12 hours to give an off-white solid, 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 236.3 g, yield 95.6%, m.p. 110 ~ 120 ° C, 1Η NMR (CDCl3): δ 1.30-1.83 (m, 6Η, Η3, _Η5,), 3.82-3.93 (m, 2Η, Η6 ‘), 5.86 (m , 1Η, Η2 ‘), 8.10-8.12 (m, 2Η, Η3, Η5), 8.31 (m, 1Η; Η4), 8.55 (s, 1Η, Η7);

The reaction equation is as follows:

(2) 3-iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I),

5L reaction flask in DMF 700mL, followed by addition of 6-nitro-_1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole (225.0g, 0.91mol, l.0eq) and potassium carbonate ( 251.6g, 1.82mol, 2.0eq), ice-cooled (10 ° C or less), followed by stirring, iodine (415.8g, 1.64mol, 1.8eq) was dissolved in DMF 300mL, was added dropwise to the reaction system, addition time 2 hours , the reaction system was stirred at 25 ° C for 16 hours to complete the reaction, sodium thiosulfate was added (223.0g, 1.41mol, 1.55eq) and 1.50g of potassium carbonate aqueous solution (1.5L), while maintaining the internal temperature 30 ° C Hereinafter, stirred for 30 minutes at room temperature, water was added with stirring 2L, solid precipitated, stirred for 30 minutes at room temperature, suction filtered, the filter cake was washed with water, 60 ° C and dried in vacuo 12 hours to give a pale yellow solid (Ι), 326.5g, yield 96.2%, m.p. 135 ~ 137 ° C / H NMR (DMS0_d6): δ 1.60-1.61 (m, 2H, H4,, H5 ‘), 1.73-1.76 (m, 1H, H5′), 2.01-2.04 (m, 2H, H3 ‘, H4′), 2.35-2.38 (m, 1H, H3 ‘), 3.81-3.87 (m, 2H, H6′), 6.11-6.14 (dd, 1H, H2 ‘), 7.70-7.72 (d , 1H, H4),

8.05-8.07 (dd, 1H, H5), 8.79 (s, 1H, H7).

The reaction equation is as follows:

A Axitinib intermediate (1) in the preparation for the Nepalese Asif applications, including the following synthetic steps:

Synthesis of (I) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

A 5L reaction flask was added DMF (2L), followed by addition of the intermediate (1) (312.0g, 0.84mol), 2- vinylpyridine (127.5g, 1.21mol), N, N- diisopropylethylamine ( 205.3g, 1.59mol), tri-o-tolylphosphine (22.3g, 0.073mol) and palladium chloride (4.9g, 0.028mol), nitrogen, and heated to 100 ° C for 12 hours to complete the reaction, cooled to 45 ° C, isopropanol was added 1L, stirring at 45 ° C for 30 minutes, diluted with water and 5L, stirring at room temperature for I h, suction filtered, washed with water, isopropanol was added to the filter cake 1.2L, stirred at 55 ° C for 30 minutes, then stirred at room temperature for 30 minutes, suction filtered, the filter cake washed with cold isopropanol, 50 ° C and dried under vacuum for 12 hours to give (E) -6- nitro-3- [2- (pyridin-2 - yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 275.3g, 94.0% yield, m.p. 175 ~ 176 ^, ¾ NMR (DMSO-Cl6): δ 1.63-1.64 (m, 2H, H4 ‘, H5′), 1.79-1.81 (m, 1H, H5 ‘), 2.05-2.07 (m, 2H, H3′, H4 ‘), 2.44-2.50 (m, 1H , H3 ‘), 3.86-3.90 (m, 2H, H6′), 6.15-6.18 (dd, 1H, H2 ‘), 7.30-7.33 (dd, 1H, pyridine H5), 7.65-7.69 (d, 1H, J = 16Hz, vinyl H2), 7.72-7.74 (d, 1H, pyridine H4), 7.82-7.86 (m, 1H, pyridine H3), 7.96-8.00 (d, 1H, J = 16Hz, vinyl HI), 8.07 -8.10 (dd, 1H, H4), 8.44-8.46 (d, 1H, H5), 8.63-8.64 (d, 1H, pyridine H6), 8.77-8.78 (d, 1H, H7);

The reaction equation is as follows:

Synthesis of (2) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2Η-) -1H- indazole

5L reaction flask in ethanol HOOmLdjC 1000mL and ammonium chloride (300.0g, 5.61mol), was dissolved with stirring, followed by addition of (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (255.0g, 0.73mol), was added iron powder (162.6g, 2.91mol), heated to 50 ° C the reaction was stirred for 2 hours to completion of the reaction, was cooled to 22 ° C, tetrahydrofuran 2L, stirred for I hour at room temperature, filtered through Celite, the filter cake washed with tetrahydrofuran and the filtrate was rotary evaporated to dryness, cooled to room temperature, water was added 2L, stirred for I hour at room temperature, pumping filtered, the filter cake washed with petroleum ether, 50 ° C and dried under vacuum for 12 hours to give a pale yellow solid 206.5g, (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole, yield 88.6%, m.p. 162 ~ 164 ° C / H NMR (CDCl3): δ 1.63-1.77 (m, 2H, H4 ‘, H5 ‘), 2.02-2.06 (m, 1H, H5′), 2.17-2.18 (m, 1H, H4 ‘), 2.55-2.60 (m, 1H, H3′) 3.70-3.72 (m, 2H, H3 ‘, H6 ‘), 3.91 (s, 2H, NH2), 4.04-4.07 (m, 1H, H6′), 5.57-5.60 (dd, 1H, H2 ‘), 6.64-6.66 (dd, 1H, H5), 6.74-6.75 (d, 1H, H7), 7.13-7.16 (dd, 1H, pyridine H5), 7.48-7.50 (d, 1H, pyridine H4), 7.49-7.53 (d, 1H, J = 16Hz, vinyl H2), 7.64 -7.68 (m, 1H, pyridine H3), 7.78-7.82 (d, 1H, J = 16Hz, vinyl Hl), 7.82-7.83 (d, 1H, H4), 8.60-8.61 (d, 1H, pyridine H6) ;

The reaction equation is as follows:

Synthesis of (3) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole

A 5L reaction flask was added 600mL of water and sodium nitrite (70.2g, 1.02mol), stirred and dissolved, and cooled to (TC, (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl ] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (200.0g, 0.62mol) was dissolved in glacial acetic acid 1.3L, dropwise added to the system dropwise over I h, a solution process maintain an internal temperature of 0 ° C, the same temperature for I hour, dropping HCl solution (concentrated hydrochloric acid 112mL, water 200mL) at O ​​° C, the dropping time of 10 minutes, with the temperature for I h, TLC plate tracking point diazonium salt formation reaction (PE: EA = 1: 1). dropwise 800mL dichloromethane between 0 ° C, the dropping time of 5 minutes, potassium iodide (207.3g, l.25mol) and iodine (79.2g, 0.31mol) was dissolved water 600mL, in (TC dropwise added to the system at the same temperature for 2 hours to complete the reaction. The reaction mixture was poured into the system to 20% sodium thiosulfate solution (2L) and dichloromethane SOOmL and stirred, layered , the aqueous phase was extracted with dichloromethane frozen (2x800mL), dichloromethane phases were combined burning, 3M sodium hydroxide solution was added dropwise 3.5L, adjust the aqueous phase pH = 9 ~ 12, and water was added ammonia 200mL 400mL, stirred for 30 minutes , separated and the aqueous phase was extracted with dichloromethane (2×1.2L), the organic phases were combined, rotary evaporated to dryness, and purified through silica gel to give (E) -6- iodo-3- [2- (pyridin-2-yl ) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 176.0g, 65.4% yield, m.p. 142 ~ 143 ° C, 1H NMR (DMS0_d6): δ 1.58- 1.61 (m, 2H, H4 ‘, H5,) 1.72-1.78 (m, 1H, H5,), 1.97-2.04 (m, 2H, H3,, H4,), 2.38-2.44 (m, 1H, H3,) , 3.79-3.81 (m, 1H, H6,), 3.88-3.90 (m, 1H, H6,), 5.91-5.94 (dd, 1H, H2,), 7.29-7.31 (m, 1H, pyridine H5), 7.56 -7.60 (d, 1H ,, J = 16Hz, vinyl H2), 7.57-7.59 (m, 1H, pyridine H4), 7.69-7.71 (d, 1H, pyridine H3), 7.80-7.84 (m, 1H, H4 ), 7.89-7.93 (d, 1H, J = 16Hz, vinyl HI), 8.01-8.03 (d, 1H, H5), 8.25 (s, 1H, H7), 8.61-8.62 (d, 1H, pyridine H6) ;

The reaction equation is as follows:

(4) (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole 6-ylthio} benzamide]

A 5L reaction flask was added DMF (1750mL) and (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1H- indazole (175.0g, 0.41mol), nitrogen, was added [1, I, - bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (14.9g, 0.018mmol ), cesium carbonate (198.3g, 0.61mol) and dichloromethane 20mL, was added 2-mercapto -N- methylbenzamide (84.9g, 0.5Imol), heated to 80 ° C for 16 hours to complete the reaction, spin distilled was removed DMF, cooled to room temperature, ethyl acetate was added 3L, water 4L, stirred for 40 minutes, the organic phase was separated, washed with brine, layered, dried over sodium sulfate, filtered, and rotary evaporated to dryness, to give (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H- indazol-6-yl] thio } benzamide, 165.6g, a yield of 86.7%, the melting point of 142 ~ 143 ° C;

The reaction equation is as follows:

(5) Synthesis of axitinib

In a 2L reaction flask was added (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H - indazol-6-yl] thio} benzamide (150.0g, 0.32mol), p-toluenesulfonic acid monohydrate (303.2g, 1.59mol), methanol (800mL) and water (150mL), nitrogen, heated to 65 ° C for 4 hours, spin evaporated to dryness and ethanol (800mL), 65 ° C was stirred for I hour, the ethanol was removed by rotary evaporation, then repeated three times, TLC spot plate tracking reaction (petroleum ether: ethyl acetate = 1: 1). Completion of the reaction, cooled to room temperature, rotary evaporated to dryness, water was added 500mL, stirred for I h, filtered, and the filter cake was washed with methanol and ice, and then added to the reaction vessel, ethyl acetate was added 450mL, stirred at 65 ° C 30 minutes. cooled to room temperature, suction filtered, the filter cake washed with ethyl acetate and freeze paint, water paint, 50 ° C and dried under vacuum for 12 hours to give a white solid 117.5g, Axitinib (II), yield 95.4%, HPLC purity 98.8 % / H NMR (DMS0_d6): δ 2.78 (d, 3H, CH3), 7.05 (dd, 1H), 7.19 (dd, 1H), 7.36-7.23 (m, 3H), 7.50 (dd, 1H), 7.58 ( d, 1H), 7.61 (s, 1H), 7.66 (d, 1H), 7.85-7.76 (m, 1H), 7.96 (d, 1H, J = 16Hz), 8.21 (d, 1H), 8.39 (q, 1H), 8.61 (d, 1H), 13.35 (s, 1H).

The reaction equation is as follows:

Example 2

A Assi intermediates for preparing Nigeria, comprising the steps of:

Synthesis of (1) 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

A 5L reaction flask was added ethyl acetate (2L), followed by addition of 6-nitro-indazole (163.14g, 1.0mol), 3, 4- dihydro -2H- pyran (210.3g, 2.5mol), toluene acid (20.7g, 0.12mol), heated to 78 ° C under reflux for 3 hours to complete the reaction, cooled to room temperature, rotary evaporated to dryness, added water and dichloromethane 2L 2L, stirred for I hour, stratification, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness, and then dissolved in acetonitrile and 2L, stirring ice-salt bath chilled to _5 ° C for 2 hours, suction filtered, the filter cake washed with a small amount of cold acetonitrile, recrystallized from ethanol , 60 ° C and dried in vacuo 12 hours to give an off-white solid 223.3g, 6- nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, yield 90.3%, m.p. 110 ^ 11 TC;

The reaction equation is as follows:

(2) 3-iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I),

5L reaction flask in DMF 700mL, followed by addition of 6-nitro-_1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole (200.0g, 0.81mol, l.0eq) and sodium hydroxide (64.7g, 1.62mol, 2.0eq), ice-cooled (10 ° C or less), followed by stirring, iodine (369.6g, 1.46mol, 1.8eq) was dissolved in DMF 300mL, was added dropwise to the reaction system, addition time 2 hours, the reaction system was stirred at 25 ° C for 12 hours to complete the reaction, sodium thiosulfate was added (198.2g, 1.25mol, 1.55eq) and 1.50g of potassium carbonate aqueous solution (1.5L), while maintaining the temperature of 30 ° C or less, and stirred for 30 minutes at room temperature, water was added with stirring 2L, solid precipitated, stirred for 30 minutes at room temperature, suction filtered, the filter cake was washed with water, 60 ° C and dried in vacuo 12 hours to give a pale yellow solid

(1), 294.3g, 97.5% yield, m.p. 136 ~ 137. . .

[0014] The reaction equation is as follows:

A Axitinib intermediate (1) in the preparation for the Nepalese Asif applications, including the following synthetic steps:

Synthesis (1) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2Η-) -1H- indazole

A 5L reaction flask was added DMF (2L), followed by addition of the intermediate (1) (312.0g, 0.84mol), 2- vinylpyridine (127.5g, 1.21mol), N, N- diisopropylethylamine ( 205.3g, 1.59mol), tri-o-tolylphosphine (22.3g, 0.073mol) and palladium chloride (4.9g, 0.028mol), nitrogen, and heated to 100 ° C for 12 hours to complete the reaction, cooled to 45 ° C, isopropanol was added 1L, stirring at 45 ° C for 30 minutes, diluted with water and 5L, stirring at room temperature for I h, suction filtered, washed with water, isopropanol was added to the filter cake 1.2L, stirred at 55 ° C for 30 minutes, then stirred at room temperature for 30 minutes, suction filtered, the filter cake washed with cold isopropanol, 50 ° C and dried under vacuum for 12 hours to give (E) -6- nitro-3- [2- (pyridin _2 _-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 275.3g, 94.0% yield, m.p. 175 ~ 176 ^, ¾ NMR (DMSO-Cl6): δ 1.63-1.64 (m, 2H, H4 ‘, H5′), 1.79-1.81 (m, 1H, H5 ‘), 2.05-2.07 (m, 2H, H3′, H4 ‘), 2.44-2.50 (m, 1H , H3 ‘), 3.86-3.90 (m, 2H, H6′), 6.15-6.18 (dd, 1H, H2 ‘), 7.30-7.33 (dd, 1H, pyridine H5), 7.65-7.69 (d, 1H, J = 16Hz, vinyl H2), 7.72-7.74 (d, 1H, pyridine H4), 7.82-7.86 (m, 1H, pyridine H3), 7.96-8.00 (d, 1H, J = 16Hz, vinyl HI), 8.07 -8.10 (dd, 1H, H4), 8.44-8.46 (d, 1H, H5), 8.63-8.64 (d, 1H, pyridine H6), 8.77-8.78 (d, 1H, H7);

The reaction equation is as follows:

Synthesis of (2) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

5L reaction flask in ethanol HOOmLdjC 1000mL and ammonium chloride (300.0g, 5.61mol), was dissolved with stirring, followed by addition of (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (255.0g, 0.73mol), was added iron powder (162.6g, 2.91mol), heated to 50 ° C the reaction was stirred for 2 hours to completion of the reaction, was cooled to 22 ° C, tetrahydrofuran 2L, stirred for I hour at room temperature, filtered through Celite, the filter cake washed with tetrahydrofuran and the filtrate was rotary evaporated to dryness, cooled to room temperature, water was added 2L, stirred for I hour at room temperature, pumping filtered, the filter cake washed with petroleum ether, 50 ° C and dried under vacuum for 12 hours to give a pale yellow solid 206.5g, (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole, yield 88.6%, m.p. 162 ~ 164 ° C / H NMR (CDCl3): δ 1.63-1.77 (m, 2H, H4 ‘, H5 ‘), 2.02-2.06 (m, 1H, H5′), 2.17-2.18 (m, 1H, H4 ‘), 2.55-2.60 (m, 1H, H3′) 3.70-3.72 (m, 2H, H3 ‘, H6 ‘), 3.91 (s, 2H, NH2), 4.04-4.07 (m, 1H, H6′), 5.57-5.60 (dd, 1H, H2 ‘), 6.64-6.66 (dd, 1H, H5), 6.74-6.75 (d, 1H, H7), 7.13-7.16 (dd, 1H, pyridine H5), 7.48-7.50 (d, 1H, pyridine H4), 7.49-7.53 (d, 1H, J = 16Hz, vinyl H2), 7.64 -7.68 (m, 1H, pyridine H3), 7.78-7.82 (d, 1H, J = 16Hz, vinyl Hl), 7.82-7.83 (d, 1H, H4), 8.60-8.61 (d, 1H, pyridine H6) ;

The reaction equation is as follows:

Synthesis of (3) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole

A 5L reaction flask was added 600mL of water and sodium nitrite (70.2g, 1.02mol), stirred and dissolved, and cooled to (TC, (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl ] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (200.0g, 0.62mol) was dissolved in glacial acetic acid 1.3L, dropwise added to the system dropwise over I h, a solution process maintain an internal temperature of 0 ° C, the same temperature for I hour, dropping HCl solution (concentrated hydrochloric acid 112mL, water 200mL) at O ​​° C, the dropping time of 10 minutes, with the temperature for I h, TLC plate tracking point diazonium salt formation reaction (PE: EA = 1: 1). dropwise 800mL dichloromethane between 0 ° C, the dropping time of 5 minutes, potassium iodide (207.3g, l.25mol) and iodine (79.2g, 0.31mol) was dissolved water 600mL, in (TC dropwise added to the system at the same temperature for 2 hours to complete the reaction. The reaction mixture was poured into the system to 20% sodium thiosulfate solution (2L) and dichloromethane SOOmL and stirred, layered , the aqueous phase was extracted with dichloromethane frozen (2x800mL), dichloromethane phases were combined burning, 3M sodium hydroxide solution was added dropwise 3.5L, adjust the aqueous phase pH = 9 ~ 12, and water was added ammonia 200mL 400mL, stirred for 30 minutes , separated and the aqueous phase was extracted with dichloromethane (2×1.2L), the organic phases were combined, rotary evaporated to dryness, and purified through silica gel to give (E) -6- iodo-3- [2- (pyridin-2-yl ) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 176.0g, 65.4% yield, m.p. 142 ~ 143 ° C, 1H NMR (DMS0_d6): δ 1.58- 1.61 (m, 2H, H4 ‘, H5,) 1.72-1.78 (m, 1H, H5,), 1.97-2.04 (m, 2H, H3,, H4,), 2.38-2.44 (m, 1H, H3,) , 3.79-3.81 (m, 1H, H6,), 3.88-3.90 (m, 1H, H6,), 5.91-5.94 (dd, 1H, H2,), 7.29-7.31 (m, 1H, pyridine H5), 7.56 -7.60 (d, 1H ,, J = 16Hz, vinyl H2), 7.57-7.59 (m, 1H, pyridine H4), 7.69-7.71 (d, 1H, pyridine H3), 7.80-7.84 (m, 1H, H4 ), 7.89-7.93 (d, 1H, J = 16Hz, vinyl HI), 8.01-8.03 (d, 1H, H5), 8.25 (s, 1H, H7), 8.61-8.62 (d, 1H, pyridine H6) ;

The reaction equation is as follows:

(4) (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole 6-ylthio} benzamide]

A 5L reaction flask was added DMF (1750mL) and (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1H- indazole (175.0g, 0.41mol), nitrogen, was added [1, I, - bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (14.9g, 0.018mmol ), cesium carbonate (198.3g, 0.61mol) and dichloromethane 20mL, was added 2-mercapto -N- methylbenzamide (84.9g, 0.5Imol), heated to 80 ° C for 16 hours to complete the reaction, spin distilled was removed DMF, cooled to room temperature, ethyl acetate was added 3L, water 4L, stirred for 40 minutes, the organic phase was separated, washed with brine, layered, dried over sodium sulfate, filtered, and rotary evaporated to dryness, to give (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H- indazol-6-yl] thio } benzamide, 165.6g, a yield of 86.7%, the melting point of 142 ~ 143 ° C;

The reaction equation is as follows:

(5) Synthesis of axitinib

In a 2L reaction flask was added (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H - indazol-6-yl] thio} benzamide (150.0g, 0.32mol), p-toluenesulfonic acid monohydrate (303.2g, 1.59mol), methanol (800mL) and water (150mL), nitrogen, heated to 65 ° C for 4 hours, spin evaporated to dryness and ethanol (800mL), 65 ° C was stirred for I hour, the ethanol was removed by rotary evaporation, then repeated three times, TLC spot plate tracking reaction (petroleum ether: ethyl acetate = 1: 1). Completion of the reaction, cooled to room temperature, rotary evaporated to dryness, water was added 500mL, stirred for I h, filtered, and the filter cake was washed with methanol and ice, and then added to the reaction vessel, ethyl acetate was added 450mL, stirred at 65 ° C 30 minutes. cooled to room temperature, suction filtered, the filter cake washed with ethyl acetate and freeze paint, water paint, 50 ° C and dried under vacuum for 12 hours to give a white solid 117.5g, Axitinib (II), yield 95.4%, HPLC purity 98.8 % / H NMR (DMS0_d6): δ 2.78 (d, 3H, CH3), 7.05 (dd, 1H), 7.19 (dd, 1H), 7.36-7.23 (m, 3H), 7.50 (dd, 1H), 7.58 ( d, 1H), 7.61 (s, 1H), 7.66 (d, 1H), 7.85-7.76 (m, 1H), 7.96 (d, 1H, J = 16Hz), 8.21 (d, 1H), 8.39 (q, 1H), 8.61 (d, 1H), 13.35 (s, 1H).

The reaction equation is as follows:

Example 3

A Assi intermediates for preparing Nigeria, comprising the steps of:

Synthesis of (1) 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

5L reaction flask in toluene (2L), followed by addition of 6-nitro-indazole (163.lg, 1.0mol), 3,4- dihydro -2H- pyran (193.5g, 2.3mol), methanesulfonic acid (14.4g, 0.15mol), heated to 85 ° C under reflux for 3.5 hours, to complete the reaction, cooled to room temperature, rotary evaporated to dryness, added water and dichloromethane 2L 2L, stirred for I hour, stratification, the organic phase was washed with brine wash, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness, and then dissolved in acetonitrile and 2L, stirring ice-salt bath chilled to _5 ° C for 2 hours, suction filtered, the filter cake washed with a small amount of cold acetonitrile and paint, and recrystallized from ethanol , 60 ° C and dried in vacuo 12 hours to give an off-white solid, 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 234.4g, 94.8% yield, m.p. 111 ~ 112.. ;

The reaction equation is as follows:

(2) 3-iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I),

5L reaction flask in DMF 700mL, followed by addition of 6-nitro-_1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole (225.0g, 0.91mol, 1.0eq) and potassium hydroxide ( 102.lg, 1.82mol, 2.0eq), ice-cooled below 10 ° C, with stirring, iodine (415.8g, 1.64mol, 1.8eq) was dissolved in DMF 300mL, was added dropwise to the reaction system dropwise over 2 hours, The reaction system was stirred at 30 ° C for 10 hours to complete the reaction, sodium thiosulfate was added (223.0g, 1.41mol, 1.55eq) and 1.50g of potassium carbonate aqueous solution (1.5L), while maintaining the internal temperature below 30 ° C , stirred for 45 minutes at room temperature, water was added with stirring 2L, solid precipitated, stirred for 45 minutes at room temperature, suction filtered, the filter cake was washed with water, 60 ° C and dried in vacuo 12 hours to give a pale yellow solid

(1), 317.2g, 93.4% yield, m.p. 135 ~ 136 ° C.

The reaction equation is as follows:

A Axitinib intermediate (1) in the preparation for the Nepalese Asif applications, including the following synthetic steps:

Synthesis (1) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

A 5L reaction flask was added DMF (2L), followed by addition of the intermediate (1) (312.0g, 0.84mol), 2- vinylpyridine (127.5g, 1.21mol), N, N- diisopropylethylamine ( 205.3g, 1.59mol), tri-o-tolylphosphine (22.3g, 0.073mol) and palladium chloride (4.9g, 0.028mol), nitrogen, and heated to 100 ° C for 12 hours to complete the reaction, cooled to 45 ° C, isopropanol was added 1L, stirring at 45 ° C for 30 minutes, diluted with water and 5L, stirring at room temperature for I h, suction filtered, washed with water, isopropanol was added to the filter cake 1.2L, stirred at 55 ° C for 30 minutes, then stirred at room temperature for 30 minutes, suction filtered, the filter cake washed with cold isopropanol, 50 ° C and dried under vacuum for 12 hours to give (E) -6- nitro-3- [2- (pyridin _2 _-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 275.3g, 94.0% yield, m.p. 175 ~ 176 ^, ¾ NMR (DMSO-Cl6): δ 1.63-1.64 (m, 2H, H4 ‘, H5′), 1.79-1.81 (m, 1H, H5 ‘), 2.05-2.07 (m, 2H, H3′, H4 ‘), 2.44-2.50 (m, 1H , H3 ‘), 3.86-3.90 (m, 2H, H6′), 6.15-6.18 (dd, 1H, H2 ‘), 7.30-7.33 (dd, 1H, pyridine H5), 7.65-7.69 (d, 1H, J = 16Hz, vinyl H2), 7.72-7.74 (d, 1H, pyridine H4), 7.82-7.86 (m, 1H, pyridine H3), 7.96-8.00 (d, 1H, J = 16Hz, vinyl HI), 8.07 -8.10 (dd, 1H, H4), 8.44-8.46 (d, 1H, H5), 8.63-8.64 (d, 1H, pyridine H6), 8.77-8.78 (d, 1H, H7);

The reaction equation is as follows:

Synthesis of (2) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

5L reaction flask in ethanol HOOmLdjC 1000mL and ammonium chloride (300.0g, 5.61mol), was dissolved with stirring, followed by addition of (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (255.0g, 0.73mol), was added iron powder (162.6g, 2.91mol), heated to 50 ° C the reaction was stirred for 2 hours to completion of the reaction, was cooled to 22 ° C, tetrahydrofuran 2L, stirred for I hour at room temperature, filtered through Celite, the filter cake washed with tetrahydrofuran and the filtrate was rotary evaporated to dryness, cooled to room temperature, water was added 2L, stirred for I hour at room temperature, pumping filtered, the filter cake washed with petroleum ether, 50 ° C and dried under vacuum for 12 hours to give a pale yellow solid 206.5g, (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole, yield 88.6%, m.p. 162 ~ 164 ° C / H NMR (CDCl3): δ 1.63-1.77 (m, 2H, H4 ‘, H5 ‘), 2.02-2.06 (m, 1H, H5′), 2.17-2.18 (m, 1H, H4 ‘), 2.55-2.60 (m, 1H, H3′) 3.70-3.72 (m, 2H, H3 ‘, H6 ‘), 3.91 (s, 2H, NH2), 4.04-4.07 (m, 1H, H6′), 5.57-5.60 (dd, 1H, H2 ‘), 6.64-6.66 (dd, 1H, H5), 6.74-6.75 (d, 1H, H7), 7.13-7.16 (dd, 1H, pyridine H5), 7.48-7.50 (d, 1H, pyridine H4), 7.49-7.53 (d, 1H, J = 16Hz, vinyl H2), 7.64 -7.68 (m, 1H, pyridine H3), 7.78-7.82 (d, 1H, J = 16Hz, vinyl Hl), 7.82-7.83 (d, 1H, H4), 8.60-8.61 (d, 1H, pyridine H6) ;

The reaction equation is as follows:

Synthesis of (3) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole

A 5L reaction flask was added 600mL of water and sodium nitrite (70.2g, 1.02mol), stirred and dissolved, and cooled to (TC, (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl ] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (200.0g,

0.62mol) was dissolved in glacial acetic acid 1.3L, dropwise added to the system dropwise over I hour, added dropwise to maintain the internal temperature process 0 ° C, the same temperature for I h, HCl solution was added dropwise at O ​​° C (112mL of concentrated hydrochloric acid , water 200mL), was added dropwise for 10 minutes, with the temperature for I h, TLC plate tracking point diazonium salt formation reaction (PE: EA = 1: 1). Solution of methylene chloride at 0 ° C and 800mL, dropping time of 5 minutes, potassium iodide (207.3g, l.25mol) and iodine (79.2g, 0.31mol) dissolved in water 600mL, at (TC dropwise added to the system, same temperature for 2 hours to complete the reaction. The reaction system was poured into a mixture of 20% sodium thiosulfate solution (2L) and dichloromethane SOOmL and stirred, layers were separated, the aqueous phase was extracted with dichloromethane frozen (2x800mL ), methylene chloride phases were combined burning, 3M sodium hydroxide solution was added dropwise 3.5L, adjust the aqueous phase pH = 9 ~ 12, and water was added ammonia 200mL 400mL, stirred for 30 minutes, separated and the aqueous phase extracted with dichloromethane ( 2×1.2L), the organic phases were combined, rotary evaporated to dryness, and purified through silica gel to give (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H – pyran-2-yl) -1H- indazole, 176.0g, 65.4% yield, m.p. 142 ~ 143 ° C, 1H NMR (DMS0_d6): δ 1.58-1.61 (m, 2H, H4 ‘, H5,) 1.72-1.78 (m, 1H, H5,), 1.97-2.04 (m, 2H, H3,, H4,), 2.38-2.44 (m, 1H, H3,), 3.79-3.81 (m, 1H, H6,) , 3.88-3.90 (m, 1H, H6,), 5.91-5.94 (dd, 1H, H2,),

7.29-7.31 (m, 1H, pyridine H5), 7.56-7.60 (d, 1H ,, J = 16Hz, vinyl H2), 7.57-7.59 (m, 1H, pyridine H4), 7.69-7.71 (d, 1H, pyridine H3), 7.80-7.84 (m, 1H, H4), 7.89-7.93 (d, 1H, J = 16Hz, vinyl HI), 8.01-8.03 (d, 1H, H5), 8.25 (s, 1H, H7 ), 8.61-8.62 (d, 1H, pyridine H6); reaction equation is as follows:

(4) (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole 6-ylthio} benzamide]

A 5L reaction flask was added DMF (1750mL) and (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1H- indazole (175.0g, 0.41mol), nitrogen, was added [1, I, - bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (14.9g, 0.018mmol ), cesium carbonate (198.3g, 0.61mol) and dichloromethane 20mL, was added 2-mercapto -N- methylbenzamide (84.9g, 0.5Imol), heated to 80 ° C for 16 hours to complete the reaction, spin distilled was removed DMF, cooled to room temperature, ethyl acetate was added 3L, water 4L, stirred for 40 minutes, the organic phase was separated, washed with brine, layered, dried over sodium sulfate, filtered, and rotary evaporated to dryness, to give (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H- indazol-6-yl] thio } benzamide, 165.6g, a yield of 86.7%, the melting point of 142 ~ 143 ° C;

The reaction equation is as follows:

(5) Synthesis of axitinib

In a 2L reaction flask was added (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H - indazol-6-yl] thio} benzamide (150.0g, 0.32mol), p-toluenesulfonic acid monohydrate (303.2g, 1.59mol), methanol (800mL) and water (150mL), nitrogen, heated to 65 ° C for 4 hours, spin evaporated to dryness and ethanol (800mL), 65 ° C was stirred for I hour, the ethanol was removed by rotary evaporation, then repeated three times, TLC spot plate tracking reaction (petroleum ether: ethyl acetate = 1: 1). Completion of the reaction, cooled to room temperature, rotary evaporated to dryness, water was added 500mL, stirred for I h, filtered, and the filter cake was washed with methanol and ice, and then added to the reaction vessel, ethyl acetate was added 450mL, stirred at 65 ° C 30 minutes. cooled to room temperature, suction filtered, the filter cake washed with ethyl acetate and freeze paint, water paint, 50 ° C and dried under vacuum for 12 hours to give a white solid 117.5g, Axitinib (II),

yield 95.4%, HPLC purity 98.8 % / H NMR (DMS0_d6): δ 2.78 (d, 3H, CH3), 7.05 (dd, 1H), 7.19 (dd, 1H), 7.36-7.23 (m, 3H), 7.50 (dd, 1H), 7.58 ( d, 1H), 7.61 (s, 1H), 7.66 (d, 1H), 7.85-7.76 (m, 1H), 7.96 (d, 1H, J = 16Hz), 8.21 (d, 1H), 8.39 (q, 1H), 8.61 (d, 1H), 13.35 (s, 1H).

The reaction equation is as follows:

SEE NMR……….

http://orgspectroscopyint.blogspot.in/2015/07/axitinib.html

………..

http://dmd.aspetjournals.org/content/suppl/2014/03/07/dmd.113.056531.DC1/Supplemental__Data_Figures_56531.pdf

MASS

References

WO 2015097605

Mylan Laboratories Ltd.

Process for the preparation of sofosbuvir

02 July 2015

The present disclosure relates to processes for the preparation of sofosbuvir or of its pharmaceutically acceptable salts. The present disclosure also provides intermediates useful in the synthesis of sofosbuvir.

Kaushik, Vipin Kumar; Vakiti, Srinivas; Ravi, Vijaya Krishna; Tirumalaraju, Bhavanisankar

Nucleoside phosphoramidates are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

Sofosbuvir (PSI-7977) is a nucleotide analog inhibitor of HCV NS5B polymerase, which is developed by Pharmasset and used for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen.

SOVALDI® tablets contain sofosbuvir, which is chemically named as (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2yl)methoxy)-(phenoxy)phosphorylamino) propanoate and is represented by the following chemical structure:

Formula-1

Sofosbuvir and a process for the preparation are disclosed in U.S. Patent No. 7,964,580 B2 and PCT Publication No. WO 2008/121634 A2, which are hereby incorporated by reference.

The present disclosure provides a novel process for the preparation of sofosbuvir or its pharmaceutically acceptable salts that employs novel intermediates.

 
सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।

SUMMARY OF THE DISCLOSURE

A first aspect of the present disclosure is to provide a process for the preparation of sofosbuvir or its pharmaceutically acceptable salts.

In one embodiment, the present disclosure provides a process for the preparation of sofosbuvir or its pharmaceutically acceptable salts that includes the steps of:

a) reacting the compound of formula 4 with a compound of formula 5 to get a compound of formula 3;

4

b) hydrolyzing the compound of formula 3 to get a compound of formula 2; and

3 2

c) optionally deprotecting the compound of formula 2 to get sofosbuvir of formula 1 or its pharmaceutically acceptable salts.

1

2

wherein R is hydrogen or any hydroxy protecting group and X is a leaving group such as tosylate, camphorsulfonate, mesylate, trifluoroacetate, trifluorosulfonate, an aryloxide, heteroaryl oxide or an aryloxide or heteroaryl oxide substituted with at least one electron-withdrawing group.

In another embodiment, the present disclosure provides a novel intermediate of formula 3a.

In an additional embodiment, the present disclosure provides a crystalline compound of formula 3a, which is characterized by a powdered X-ray diffraction pattern as shown in Figure 1.

In September 2014, Gilead entered into non-exclusive licensing agreements with various generic companies (including Mylan) to manufacture and supply generic sofosbuvir. In April 2015, Mylan launched its generic version of the drug as MyHep, in India

scheme-II.

Sofosbuvir

Scheme-II

In another embodiment the present disclosure provides a process for the preparation of sofosbuvir as shown in below scheme-Ill.

Example 3: Preparation of sofosbuvir (formula 1).

N-Benzoyl Sofosbuvir (6 g) was added to 70% w/w aqueous acetic acid (90 mL) and the contents were stirred at 90-95 °C. After completion of the reaction, which was monitored by qualitative HPLC, the reaction mass was cooled to ambient temperature, diluted with water and filtered through a Hyflo filter. Thereafter, obtained filtrate was extracted with ethyl acetate which was further washed with ~4%w/w aqueous hydrochloric acid followed by ~9%w/w aqueous sodium carbonate solution. Finally, the ethyl acetate layer was washed with water and dried. The dried layer was concentrated under reduced pressure at 60-65 °C. Thereafter, the concentrated mass was dissolved in a mixture of 5% isopropanol in methylene dichloride and isopropyl ether was added to precipitate the product. After stirring at 0-5 °C for 2 hours, the product was filtered, washed with methylene dichloride/isopropyl ether mixture, which was recrystallized with methylene dichloride/isopropyl ether mixture to yield sofosbuvir as white crystals (3 g)……https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015097605&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Gregg Alton, Executive Vice-President, Corporate and Medical Affairs, Gilead Sciences said it makes an important milestone in the company’s ongoing effort to make its hepatitis-C medicines accessible to as many patients, in as many places, as quickly as possible.Sovaldi is sold by Mylan’s dedicated sales force as part of its Hepato Care segment.

,,,,,,,,,,

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LIONEL MY SON

GMP……API PILOT PLANT

PRESENTATION

Pilot plant and scale-up techniques are both integral and critical to drug discovery and development process for new medicinal products. A major decision focuses on that point where the idea or process is advanced from a research oriented program targeted towards commercialization.

The speed of drug discovery has been accelerating at an exponential rate. The past two decades particular have witnessed amazing inventions and innovations in pharmaceutical research, resulting in the ability to produce new drugs faster than even before.

The new drug applications (NDAs) and abbreviated new drug applications (ANDA) are all-time high. The preparation of several clinical batches in the pilot plant provides its personnel with the opportunity to perfect and validate the process. Also different types of laboratories have been motivated to adopt new processes and technologies in an effort to stay at the forefront scientific innovation.

 MY PRESENTATION

Pharmaceutical pilot plants that can quickly numerous short-run production lines of multiple batches are essential for ensuring success in the clinical testing and bougainvilleas study phases. Drug formulation research time targets are met by having a well-designed facility with the appropriate equipment mix, to quickly move from the laboratory to the pilot plant scale 1. In pilot plant, a formula is transformed into a viable, robust product by the development of a reliable and practical method of manufacture that effects the orderly transition from laboratory to routine processing in a full scale production facility where as the scale up involves the designing of prototype using the data obtained from the pilot plant model.

Pilot plant studies must includes a close examination of formula to determine its ability to withstand batch-scale and process modifications; it must includes a review of range of relevant processing equipment also availability of raw materials meeting the specification of product and during the scale up efforts in the pilot plant production and process control are evaluated, validated and finalized.

In addition, appropriate records and reports issued to support Good Manufacturing Practices and to provide historical development of the production formulation, process, equipment train, and specifications

A manufacturer’s decision to scale up / scale down a process is ultimately rooted in the economics of the production process, i.e., in the cost of material, personnel, and equipment associated with the process and its control.

 When developing technologies, there are a number of steps required between the initial concept and completion of the final production plant. These steps include the development of the commercial process, optimization of the process, scale-up from the bench to a pilot plant, and from the pilot plant to the full scale process. While the ultimate goal is to go directly from process optimization to full scale plant, the pilot plant is generally a necessary step.

Reasons for this critical step include: understanding the potential waste streams, examination of macro-processes, process interactions, process variations, process controls, development of standard operating procedures, etc. The information developed at the pilot plant scale allows for a better understanding of the overall process including side processes. Therefore, this step helps to build the information base so that the technology can be permitted and safely implemented.

Should be versatile pilot plant that is entirely GMP and facilitates the development of API’s in scalable, safe and environmentally friendly ways.

The combination of  facilities,  experience and flexibility enable  an integral Contract Manufacturing service ranging from laboratory to industrial scale; it should manufacture under regulation small amounts of high added value active substances or key intermediate products.

Product quality: Operations that depend on people for executing manual recipes are subject to human variability. How precisely are the operators following the recipe? Processes that are sensitive to variations in processing will result in quality variation. Full recipe automation that controls most of the critical processing operations provides very accurate, repeatable material processing. This leads to very highly consistent product quality.

 Improved production: Many biotech processes have extremely long cycle times (some up to 6 months), and are very sensitive to processing conditions. It is not uncommon for batches to be lost for unexplained reasons after completing a large portion of the batch cycle time. The longer the batch cycle time and the more sensitive production is to processing conditions, the more batch automation is justified. Imagine losing a batch of very valuable product because the recipe was not precisely followed!

 Process optimization: Increasing the product yield can be done by making small changes in processing conditions to improve the chemical conversions or biological growth conditions. Manual control offers a limited ability to finely implement small changes to processing conditions due to the inherent lack of precision in human control. Conversely, computers are very good at controlling conditions precisely. In addition, advanced control capabilities such as model predictive control can greatly improve process optimization. This results in higher product yield and lower production cost. This consideration is highly relevant to pilot plant facilities where part of the goal is to learn how to make the product.

 Recordkeeping: A multi-unit recipe control system is capable of collecting detailed records as to how a batch was made and relates all data to a single batch ID. Data of this nature can be very valuable for QA reporting, QA deviation investigations, and process analysis.

 Safety: Operators spend less time exposed to chemicals when the process is fully automated as compared to manual control. Less exposure to the process generally results in a safer process.

A good batch historian should be able to collect records for a production run to include the following information:  Product and recipe identification

 User defined report parameters

 Formulation data and relevant changes

 Procedural element state changes (Operations, unit procedures, procedures)

 Phase state changes

 Operator changes

 Operator prompts and responses

 Operator comments

 Equipment acquisitions and releases

 Equipment relationships

 Campaign creation data (recipe, formula values, equipment, etc.)

 Campaign modifications

 Campaign execution activity

 Controller I/O subsystem events from the Continuous Historian

 Process alarms

 Process events

 Device state changes.

Raw materials

Buildings and facilities. GMPs under the 21 Code of Federal Regulations (CFR) Part 211.42 state that buildings or areas used in the receiving, storage, and handling of raw materials should be of suitable size, construction and location to allow for the proper cleaning, maintenance, and operation (7). The common theme for this section of CFR Parts 210 and 211 is the prevention of errors and contamination. In principle, the requirements for buildings and facilities used in early phase manufacturing are not significantly different than those for later phases or even commercial production. However, there are some areas that are unique to early clinical trial manufacturing.

Control of materials. The CFR regulations under Part 211.80 provide good direction with respect to lot identification, inventory, receipt, storage, and destruction of materials (7). The clear intent is to ensure patient safety by establishing controls that prevent errors or cross-contamination and ensure traceability of components from receipt through clinical use. In general, the requirements for the control of materials are identical across all phases of development, so it is important to consider these requirements when designing a GMP facility within a laboratory setting.

For example, all materials must be assigned a unique lot number and have proper labeling. An inventory system must provide for tracking each lot of each component with a record for each use. Upon receipt, each lot should be visually examined for appropriate labeling and for evidence of tampering or contamination. Materials should be placed into quarantine or in the approved area or reject area with proper labeling to identify the material and prevent mix-ups with other materials in the storage area. Provision should be made for materials with special storage requirements (e.g., refrigeration, high security). The storage labeling should match the actual conditions that the material is being stored and should include expiry/retest dates for approved materials. Although such labeling is inconvenient for new materials where the expiration or retest date may change as more information is known, this enables personnel to be able to determine quickly whether a particular lot of a material is nearing or exceeding the expiration or retest date. General expiry/retest dates for common materials should be based on manufacturer’s recommendation or the literature.

Finally, there are clear regulatory and environmental requirements for the destruction of expired or rejected materials. It is important to observe regional and international requirements regarding the use of animal sourced materials (12). It is recommended to use materials that are not animal sourced and that there be available certification by the raw material manufacturers that they contain no animal sourced materials. If animal sourced raw materials must be used, then certifications by the raw material manufacturers that they either originate from certified and approved (by regulatory bodies) sources for use in human pharmaceuticals, or that the material has been tested to the level required for acceptance by regulatory agencies (following US, EU, or Japanese guidelines, as applicable) is required.

Direct advantages for customers 

• Shorter implementation time for product by determination of the product suitability as well as the necessary process cycle
• Optimized adjustment of the processing times in the production lines (trains) by relatively precise estimation of the drying times
• Definition of effective cleaning processes (CIP/WIP and SIP)
• Definition of the selection criteria based on the weighting of the customer, e.g.: drying time, quality (form of crystal, activity, etc.), cleanout, ability of CIP, price

An overview of further trials and test functions, that can be realized in the new pilot plant facility:

• Product tests for determination of suitability
• Scale-up tests as basis for the extrapolation on production batches regarding drying time, filling degree, crystalline transformation and grain spectrum
• Optimization of the process cycle
• Optimization of the machine
• Data acquisition and analysis

SEE THIS SECTION IN ACTION…………..KEEP WATCHING

Case study 1

Designed and equipped for the manufacturing of solid oral dosage form

http://www.idifarma.com/us/index.php?option=com_content&view=article&id=106

Designed and equipped for the manufacturing of solid oral dosage forms, specialized in high-activity substances (cytostatic, cytotoxic, hormonal, hormone inhibitors). It has ancillary areas for the proper management of materials intended for clinical trials of new drugs.

Equipment:

• • Oystar Hüttlin Pilotmix 75T single-pot high shear mixer.
• • Container mixer, 60 and 200 liters containers.
• • Fette 1200iC rotary tablet press, fully equipped for formulation development and manufacturing.
• • Oystar Manesty XL Lab 01 tablet coater, with interchangeable drums.
• • IMA Clinipack blister machine.
• • Quadro Comill sieve
• • Capsunorm 2000 manual capsul filler
• • Sepha press-out deblister
• • Fette Gratex deduster
• • Process control laboratory: Dr. Schleuniger tablet hardness tester, Erweka tablet disintegration tester, Erweka friability tester, Mettler Toledo moisture content determination equipment.

…………………………….

CASE STUDY 2

OPERATION OF PILOT PLANT FOR CLINICAL LOTS OF BIOPHARMACEUTICALS

http://www.peq.coppe.ufrj.br/biotec/presentations/Papamichael_RioDeJaneiro2009_secure.pdf

 

 

 

 

 

 CASE STUDY 3

Good Manufacturing Practices in Active Pharmaceutical Ingredients Development

 http://apic.cefic.org/pub/5gmpdev9911.pdf

Example below

3. Introduction Principles basic to the formulation of this guideline are: ·

Development should ensure that all products meet the requirements for quality and purity which they purport or are represented to possess and that the safety of any subject in clinical trials will be guaranteed. ·

During Development all information directly leading to statements on quality of critical intermediates and APIs must be retrievable and/or reconstructable. ·

The system for managing quality should encompass the organisational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity. All quality related activities should be defined and documented. Any GMP decision during Development must be based on the principles above.

During the development of an API the required level of GMP control increases. Using these guidelines, the appropriate standard may be implemented according to the intended use of the API. Firms should apply proper judgement, to discern which aspects need to be addressed during different development stages (non-clinical, clinical, scale-up from laboratory to pilot plant to manufacturing site).

Suppliers of APIs and/or critical intermediates to pharmaceutical firms should be notified on the intended use of the materials, in order to apply appropriate GMPs. The matrix (section 8) should be used in conjunction with text in section 7, as is only intended as an initial guide.  READ MORE AT….  http://apic.cefic.org/pub/5gmpdev9911.pdf

 

CASE STUDY 4

http://www.steroglass.it/doc_area_download/ita/process/20LT_PILOT_PLANT.pdf

 

 

CASE STUDY 5

 

Health Canada

http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/question/gmp-bpf-eng.php

The Good Manufacturing Practices questions and answers (GMP Q&A) presented below have been updated following the issuance of the “Good Manufacturing Practices Guidelines, 2009 Edition Version 2 (GUI-0001)“.

This Q&A list will be updated on a regular basis.

Premises – C.02.004

Equipment – C.02.005

Personnel – C.02.006

Sanitation – C.02.007 & C.02.008

Raw Material Testing – C.02.009 & C.02.010

Manufacturing Control – C.02.011 & C.02.012

Quality Control Department – C.02.013, C.02.014 & C.02.015

Packaging Material Testing – C.02.016 & C.02.017

Finished Product Testing – C.02.018 & C.02.019

Records – C.02.020, C.02.021, C.02.022, C.02.023 & C.02.024

Samples – C.02.025 & C.02.026

Stability – C.02.027 & C.02.028

Sterile Products – C.02.029

 

 

 

CASE STUDY 6

http://www.pharmtech.com/early-development-gmps-drug-product-manufacturing-small-molecules-industry-perspective-part-iii?rel=canonical

Also

• Part VII GMPs for Small Molecule Drugs in Early Development Workshop Summary
• Early Development GMPs for Small-Molecule Specifications: An Industry Perspective (Part V)
• Early Development GMPs for Stability (Part IV)
• GMPs for Method Validation in Early Development: An Industry Perspective (Part II)
• GMPs for Small-Molecule Drugs in Early Development (Part I)
• GMPs for Small-Molecule Drugs in Early Development: Workshop Summary-Part VI

CASE STUDY 7

 

 http://www.niper.gov.in/tdc_2013.pdf

 

 

 

CASE STUDY 8

Multi-kilo scale-up under GMP conditions

Examples of flow processes being used to produce exceptionally large amounts of material are becoming increasingly common as industrial researchers become more knowledgeable about the benefits of continuous reactions. The above examples from academic groups serve to illustrate that reactions optimized in small reactors processing tens to hundreds of mg hour⁻¹ of material can be scaled up to several grams per hour. Projects in process chemistry are often time-sensitive, however, and production of multiple kg of material may be needed in a short amount of time. An example of how the efficient scaling of a flow reaction can save time and reduce waste is provided by a group of researchers at Eli Lilly in their kg synthesis of a key drug intermediate under GMP conditions . In batch, ketoamide 13 was condensed with NH₄OAc and cyclized to form imidazole 14 at 100 °C in butanol on a 1 gram scale. However, side product formation became a significant problem on multiple runs at a 250 g scale. It was proposed that this was due to slow heat up times of the reactor with increasing scale, as lower temperatures seemed to favour increased degradation over productivecyclization. Upon switching to a 4.51 mL flow reactor, another optimization was carried out which identified methanol as a superior solvent that had been neglected in batch screening due to its low boiling point at atmospheric pressure. Scale-up to a 7.14 L reactor proceeded smoothly without the need for reoptimization, and running on this scale with a residence time of 90 minutes for a six-day continuous run provided 29.2 kg of product after recrystallization (approximately 207 g hour⁻¹). The adoption of a flow protocol by a group of industrial researchers in a scale-up with time constraints demonstrates both the effectiveness and maturity of flow chemistry. While the given reaction was used to produce kilograms of material for a deadline, continuous operation without further optimization could produce over 1 metric tonne of product per year in a reactor that fits into a GC oven.

	Scheme 20 Kilogram-scale synthesis of an imidazole API precursor.

 

 

 

…………………………….

Definitions

Plant:  A plant is a place where an industrial or manufacturing process takes place. It may also be expressed as a place where the 5 M’s that are; man, materials, money, method and materials are brought together for the manufacture of products.

Pilot Plant: A part of a manufacturing industry where a laboratory scale formula is transformed into a viable product by development of reliable practical procedures of manufacturing.

Scale-Up: This is the art of designing a prototype based on the information or data obtained from a pilot plant model.

cGMP: current Good Manufacturing Processes refer to an established system of ensuring that products are consistently produced and controlled according to quality standards. It is designed to minimize risk involved in any industrial design. GMP covers all aspects of production from the starting materials, premises and equipment to the training and personal hygiene of staff within industries. Detailed, written procedures are essential for each process that could affect the quality of the finished product. There must be a system to provide documented proof that correct procedures are consistently followed at each step in the manufacturing process every time a product is made.

SCALING UP FROM PILOT PLANTS

When scaling up, it is of utmost importance to consider all aspects of risk and futuristic expansion. The pilot plant is usually a costly apparatus and therefore the decision of building it is always a hard one. The function of a pilot plant is not just to prove that the laboratory experiments work, but;

1. To test technologies that are about to be implemented on industrial plants before establishment
2. To evaluate performance specifications before the actual installation of industrial plant.
3. Evaluation of reliability of mathematical models within real environment.
4. Economic considerations for production involving process optimization and automated control systems.

GMP GENERAL PRACTISES

Facilities and Equipment Systems

• Ø Cleaning and maintenance
• Ø Facility layout and air handling systems for prevention of cross-contamination (e.g. Penicillin, beta-lactams, steroids, hormones, cytotoxic, etc.)
• Ø Specifically designed areas for the manufacturing operations performed by the firm to prevent contamination or mix-ups.

Facilities

• Ø General air handling systems
• Ø Control system for implementing changes in the building
• Ø Lighting, potable water, washing and toilet facilities, sewage and refuse disposal
• Ø Sanitation of the building, use of rodenticides, fungicides, insecticides, cleaning and sanitizing agents. 

GMP FOR PLANT DESIGN

The application of GMP to plant design is primary to the establishment of such plants. Regulatory boards have precedence over these operations helping to establish a proper and functional system in plant design.

Design Review

l  Conceptual drawings;

From plant design drawings which are inspected and approved by cGMP regulatory bodies (such as Department of Petroleum Resources in Nigeria), approvals are issued depending on adherence to specifications such as muster points, proper spacing of fuel sources from combustion units and other more elaborate considerations.

l  Proposed plant layouts;

A choice of location for plant and layout play an important role on environmental impact. Hence, environmental impact assessment is a major part of GMP. Industries must be located at least 100M from closest residential quarter (depending of materials processed in plant).

l  Flow diagrams for facility

For optimization and efficiency purposes, flow diagrams for complete refinery process are important for review with intent to ensure they conform to GMP

l  Critical systems and areas

Some areas in a plant may require extra safety precautions in operations. The cGMP makes provision for such special considerations with the creation of customized set of operational guidelines that ensure safety and wellness of staff and environment alike.

cGMP EXAMPLE:  FOOD PROCESSING PLANT

Outlined below are the cGMP considerations in the establishment and handling of a food processing plant.

Safety of Water

1. Process water is safe, if private supply should be tested at least annually.

2. Backflow prevention by an air gap or back flow prevention device. Sinks that are used to prepare food must have an air-gap. 

Food Contact Surface

1. Designed, maintained, and installed so that it is easy to clean and to withstand the use, environment, and cleaning compounds.

2. If cleaning is necessary to protect against microorganisms, food-contact surfaces shall be cleaned in this sequence: wash with detergent, rinse with clear water, and then use an approved sanitizer. The sanitizer used shall be approved for use on food-contact surfaces. UA three-compartment ware washing sink or other equivalent methods shall be used for this purpose.

3. Gloves shall be clean/sanitary. Outer garments suitable.

Prevention of Cross-Contamination

1. Food handlers use good hygienic practices; hands shall be washed before starting work, after absence from work station, or when they become contamination (such as with eating or smoking).

2. Signs shall be posted in processing rooms and other appropriate areas directing employees that handle unprotected food, food-contact surfaces, food packaging materials to wash their hands prior to starting to work, after each absence from the work station, and whenever hands may become contaminated.

3. Plant design so that the potential for contamination of food, food-contact surfaces, or packaging materials is reduced to the extent possible.

4. Physical separation of raw and finished products. 

Hand Washing Sinks and Toilet Facilities

1. Hand washing sinks, properly equipped, shall be conveniently located to exposed food processing areas. Ware washing sinks shall not be used for this purpose.

2. Adequate supply of hot and cold water under pressure.

3. Toilet facilities; adequate and accessible, self-closing doors.

4. Sewage disposal system shall be installed and maintained according to State law.

Protection from Adulteration (Food, Food Contact Surfaces, and Packaging Materials)

1. Food processing equipment designed to preclude contamination with lubricants, fuel, metal fragments, contaminated water, or other sources of contamination.

2. Food processed so that production methods to not contaminate the product.

3. Raw materials, works-in-process, filling, assembly, packaging, and storage and transportation conducted so that food is not contaminated.

4. Protection from drip and condensate overhead.

5. Ventilation adequate and air not blown on food or food-contact surfaces.

6. Lights adequately shielded.

7. Compressed air or gas mechanically introduced adequately filtered. 

Scope of services

• Engineering support
• Representation of the construction owner (equipment, construction: supervision of general contractors, GMP concept draft)
• Basic and detailed design
• Support during the implementation phase
• Clean room planning (incl. lab areas)
• Construction management
• Qualification
• Validation support

Toxic Items: Labelling, Use, and Storage

1. Products used approved and used according to product’s label.

2. Sanitizer used on food-contact surfaces must be approved for that use.

3. Shall be securely stored, so unauthorized use is prevented.

Personnel Disease Control

1. Food handler, who has illness or open lesion, or other source of microbiological contamination that presents a reasonable possibility of contamination of food, food-contact surfaces, or packaging materials shall be excluded from such operations.

2. Adequate training in food protection, dangers of poor personal hygiene, and unsanitary practices shall be provided.

3. Management shall provide adequate supervision and competent training to ensure compliance with these provisions.

Pest Control

1. Management shall provide an adequate pest control program so that pests are excluded from the plant.

2. Program shall ensure that only approved pesticides are used and applied per the product’s label. 

Plant Construction and Design

1. Walls, floors, and ceilings constructed so that they can be adequately cleaned and kept in good repair.

2. Adequate lighting provided.

3. Adequate ventilation or controls to minimize odours and vapours.

4. Adequate screening or protection of outer openings.

5. Grounds maintained free of litre, weeds, and pooling water.

6. Roads, yards, and parking lots maintained so that food is not contaminated.

Equipment

1. Equipment, utensils, and seams on equipment – adequately cleanable, properly maintained, designed, and made of safe materials.

2. Refrigerators and freezers equipped with adequate thermometer.

3. Instruments and control devices – accurate and maintained.

4. Compressed air or gas designed/treated so that food is not contaminated.

Equipment. Most equipment used to manufacture early GMP drug product is be managed under a qualification, preventive maintenance, and calibration program for the GMP facility. However, in early development, there may occasionally be a need to use equipment that is not part of such a program. Rather than performing a comprehensive qualification for a piece of equipment not expected to be frequently used, an organization may choose to qualify it for a single step or campaign. Documentation from an installation qualification/operational qualification (IQ/OQ) and or performance verification at the proposed operating condition is sufficient. For example, if solution preparation needs a mixer with a rotation speed of 75 rpm, then documentation in the batch record using a calibrated tachometer to verify that the mixer was operating at 75 rpm will suffice.

The use of dedicated or disposable equipment or product contact parts may be preferable to following standard cleaning procedures to ensure equipment is clean and acceptable for use. However, not all equipment or equipment parts are disposable or may have a substantial cost that makes disposal prohibitive. In that case, the product contact parts could be dedicated to a specific drug substance for use in drug product manufacture. Dedicating product contact parts to a compound may be costly and may be avoided in some cases by carefully considering product changeover and effective cleaning methods when purchasing equipment.

Another item to consider with respect to equipment, is that the more complicated the equipment is to run or maintain, the less desirable it might be for early GMP batches. In most cases, simple equipment is adequate and will uses less material and consume less total time for preparation, operation, and cleaning activities.

Weights and Measures

1. Scales used to measure net weight of contents shall be designed so they can be calibrated.

2. Products in interstate commerce – net weights/measurements also in metric.

 

CONCLUSION

Plant establishment is an activity that has kept rising from the inception of the industrial revolution until date. Giving rise to increase in raw material demand, increased pollution levels, higher energy demand, and overall greater economic output. As history and record keeping has served for an even longer period, it becomes necessary for adaptation to be made to avoid incidents and accidents that have occurred previously and also those that can be anticipated without actual devastating effect.

The development of the GMP is as a result of observed challenges in industry and environment over years of industrialization. It becomes necessary to upset these poor trends that have developed as a result of industrialization by so doing increasing the pros and reducing the cons.

GMP protects consumer, produce, equipment, and conserves the processes as a whole, leading to a more efficient sustainable process defining a new standard for yields and profit and eliminating the tendency of compromise made by industrialists to increase overall profits at the risk of staff and environment.

 

Batch documentation and execution

Batch record documentation preparation. Manufacturing documentation is a basic requirement for all phases of clinical development. 21 CFR Parts 211.186 and 211.188 describe master production and batch production records, respectively (7). The stated purpose of the master production record is to “assure uniformity from batch to batch.” Although the record assurance is important for a commercial validated manufacturing process, it does not necessarily apply to clinical-development batches. Material properties, manufacturing scale, and quality target product profile frequently change from batch to batch. Therefore, batch production records are the appropriate documentation for clinical trial supplies. Batch production records for Phase 1 materials should minimally include:

• Name, strength, and description of the dosage form
• A complete list of active and inactive ingredients, including weight or measure per dosage unit and total weight or measure per unit
• Theoretical batch size (number of units)
• Manufacturing and control instructions.

These minimum requirements are consistent with the FDA Guidance for Industry: cGMP for Early Phase Investigational Drugs, which requires a record of manufacturing that details the materials, equipment, procedures used and any problems encountered during manufacturing (2). The records should allow for the replication of the process. On this basis, there is flexibility in the manner for which documentation of batch activities can occur, provided that the documentation allows for the post execution review by the quality unit and for the retention of these records.

 

Batch documentation approvals. Review and approval of executed batch records by the Quality unit is required per 21 CFR Part 211.192 (7). This review and approval is required for all stages of clinical manufacturing. Pre-approvals of batch records should be governed by internal procedures as there is no requirement in CFR 21 that the Quality unit pre-approves the batch record (though this is highly recommended in order to minimize the chance of errors). Indeed, Table I shows that pre-approval of batch records by the Quality Unit is practiced by all 10 companies that participated in the IQ Consortium’s drug-product manufacturing survey related to early development. Batch records must be retained for at least 1 year after the expiration of the batch according to CFR Part 211.180, but many companies keep their GMP records archived for longer terms.

Room clearance. 21 CFR Part 211.130 requires inspection of packaging and labeling facilities immediately before use to ensure that all drug products from previous operations have been removed. This inspection should be documented and can be performed by any qualified individual.

Although line clearance for bulk manufacture is not specifically mentioned in the CFR, it is expected that a room clearance be performed. At a minimum, this clearance should be performed prior to the initiation of a new batch (i.e., prior to batch materials entering a processing room).

Hold time. During the early stages of development, final dosage form release testing confirms product quality and support establishment of hold times later in the clinical development. There is no requirement to establish hold times for work in process in early development. Specific formulation and stability experience, which is usually limited at this stage of development, should be leveraged to assess any substantial variations from expected batch processing times. The data gathered from these batches and subsequent development can be used to help establish hold times for future batches. (Exceptions to this approach may include solution or suspension preparations used in solid dosage form manufacturing, where procedures typically govern allowable hold times to ensure the absence of microbial contamination in the final product.)

Change control. Changes to raw materials, processes, and products during early development are inevitable. It is not required that these changes be controlled by a central system but rather may be appropriately documented in technical reports and manufacturing batch records. Any changes in manufacturing process from a previous batch should be captured as part of the batch record documentation and communicated to affected areas. The rationale for these changes should also be documented as this serves as a source for development history reports and for updating regulatory filings. The authors recommend that those changes that could affect a regulatory filing be captured in a formal system.

Process changes. Process parameters should be recorded but do not need to be predetermined because processes may not be fixed or established in early development. Given the limited API availability in early development, a clinical batch is often the first time a product is manufactured at a particular scale or using a particular process train. Therefore, process changes should be expected. Process trains and operating parameters must be documented in the batch record but changes should not trigger an exception report or CAPA. Changes should be documented as an operational note or modification to the batch record in real time. Such changes driven by technical observations should not require prior approval by the Quality unit, but should have the appropriate scientific justification (via formulator/scientist) or the appropriate flexibility built into the batch record to allow for the changes. This documentation should be available for Quality review prior to product disposition.

Calculation of yield. Actual yields should be calculated for major processing steps to further process understanding and enable optimization of processes. Expected yield tolerances are not always applicable to early development manufacture. At this stage of early development, when formulation and process knowledge is extremely limited, there may be no technical basis for setting yield tolerances and, therefore, this yield may not be an indicator of the quality of the final product.

In-process controls and R&D sampling. In-process tests and controls should follow basic requirements of GMPS to document consistency of the batch. For capsule products, these requirements may include capsule weights and physical inspection. For tablet products, compression force or tablet hardness and weights should be monitored together with appearance. R&D sampling, defined as samples taken for purposes of furthering process understanding but not utilized for batch disposition decisions, is a normal part of all phases of clinical manufacturing. In early development manufacturing, a sampling plan is required for in-process control tests, but not for R&D samples. However, for the purpose of material accountability, R&D sampling should be documented as part of batch execution. For these samples, testing results may be managed separately, and are not required to be included in regulatory documentation.

Facilities and equipment

Regardless of the scale of manufacturing, the facility used for manufacturing clinical trial supplies must meet the basic GMP requirements as described in the regulations and guidance documents. Below are three scenarios for early development and the advantages of each as pertaining to early development. The first involves a pilot plant facility designed and equipped for routine GMP operations. The second scenario aims to establish a GMP area within a laboratory environment. The third example focuses on conducting GMP manufacturing or leveraging the practice of pharmacy in close proximity to the clinical site.

GMP facility for drug-product manufacture. The traditional approach in GMP drug-product manufacture is to use a dedicated facility (often called a pilot plant) for early phase clinical trials. Advantages of this approach include that the quality systems for the facility (i.e., maintenance, calibration, cleaning, change management, CAPA, and documentation) are well defined, and that training and other activities required for maintaining GMP compliance are centralized. Other drivers to use a pilot plant in early development may be the need for specialized equipment, or larger batch sizes in special situations.

GMP area within a laboratory setting. In some cases, it may be advantageous to establish a GMP area within a “laboratory setting” (i.e., a drug-development facility not dedicated to the production of clinical supplies) for the manufacture of drug product in early development. The rationale for this approach might be to avoid the significant investment in setting up a dedicated facility and to create simpler, more flexible systems that meet GMP requirements but are tailored for the specific activity envisioned. Examples where this approach might be considered include the need for special containment not available in the pilot-plant; the need to work with radioactive or hazardous materials, use of controlled substances and the production of “one-off manufactured” product used for proof of concept. The business rationale should be documented and approved by the manufacturing and Quality groups. As long as the appropriate GMP controls are maintained, especially as related to operator safety, cleaning, and prevention of cross-contamination, there is no compliance barrier to using “lab-type” facilities for the manufacturing of early phase clinical batches. Before GMP manufacturing is initiated, however, a risk assessment should be conducted and documented. Inclusion of representatives from Quality, analytical, clinical manufacturing, product development, and environmental health and safety would be prudent. When selecting/designing an early development clinical manufacturing facility, consideration should be made for the receipt, storage, dispensing, and movement of materials. The manufacturing processes in the nondedicated area must protect the product, patient, and the manufacturing operators.

Additionally, companies should consider what items are appropriate for the manufacture. For example, the use of a certified laminar flow hood may be a better choice for manufacturing than a fume hood, because the former is designed to prevent contamination of the product, protect the operator, and the laboratory environment. In addition, with the appropriate cleaning, a laminar flow hood can more easily be used for multiple products. Small scale/manual equipment or procedures may be the best approach because the space is likely to be limited. With a small batch size, the use of small scale or manual equipment/procedures will minimize yield loss. Additional measures to be assessed include appropriate gowning and operator personal protection devices, area and operator monitoring for potent or radiolabeled drug exposure, and so forth.

Documentation of the facility preparation, product manufacture, and the return of the facility to the previous state, if needed, is recommended. This documentation should describe the rationale for the manufacture in the nondedicated area, risk assessment, preparation of the area, cleaning procedures, and list of responsible persons. This documentation can reference existing procedures or standard operating procedures (SOPs) along with documents associated with the meetings and preparation for the manufacture of the batch. Batch records and cleaning records should be part of the documentation and should follow the company’s data-retention policy.

Receipt and approval

Specifications. It is a GMP requirement that all raw materials for the manufacture of drug product have appropriate specifications to ensure quality. The compendial requirements should be used for setting specifications provided the material is listed in at least one pharmaceutical compendium (e.g., US, European, and Japanese Pharmacopeias). It is important that the use of materials meeting the requirements of a single compendium is acceptable for use in early phase clinical studies conducted in the US, Europe, and Japan. For example, a material that meets USP criteria and is used in the manufacture of a drug product should be acceptable for use in early clinical studies in the European Union. In the absence of a pharmaceutical compendium monograph, the vendor specification and/or alternative compendial specifications such as USP’s Food Chemical Codex should guide specification setting. In any case, the sponsor is responsible for the establishment of appropriate specifications. Therefore, it is the authors’ position that good practice is to have at least a basic understanding of the manufacture, chemistry, and toxicology of the materials to guide appropriate specification setting.

Material testing and evaluation. The minimum testing required for incoming materials is visual inspection and identification. However, as mentioned above, the appropriate tests should be determined for the material based on the knowledge of the manufacture, chemistry, and toxicology. If the vendor is qualified, then the certificate of analysis may be acceptable in conjunction with the visual inspection and identification testing (see “Vendor Qualification” section below).

Approval for use. Ideally, manufacture of a bulk drug product should begin with approved material specifications and with materials that are fully tested and released. However, there are circumstances where it may not be feasible to start manufacture with approved specifications and fully tested and released materials, including API. Manufacturing prior to final release (sometimes called manufacturing “at risk”) may be acceptable, however, because the quality system ensures that all specifications are approved, test results are within specifications, and all relevant documents are in place before the product is released for administration to humans. The “risk” must lie fully with the manufacturer and not with the patient.

Vendor qualification. Vendors supplying excipients, raw materials, or API must be qualified by the sponsor. Appropriate qualification should depend on the stage of development and an internal risk assessment. For, example if a vendor has a history of supplying the pharmaceutical industry and the material is to be used in early development, a paper assessment (e.g., a questionnaire) should be sufficient. If a supplier does not have a history of supplying the pharmaceutical industry, a risk assessment should be performed and depending on the outcome a site audit may be required prior to accepting material for use.

Ideally, vendors should be qualified prior to using raw materials for manufacture. However, it is acceptable for qualification to proceed in parallel as long as documentation/risk assessments are available prior to product release and as in the previous section all risk lies with the manufacturer and not the patient.

 

A production mixing unit is usually not geometrically similar to the mixer used for process development. Such differences can make scale-up from the laboratory or pilot plant challenging. A solution to these problems is to systematically calculate and evaluate mixing characteristics for each geometry change.

Geometric similarity is often used in mixing scale-up because it greatly simplifies design calculations. Geometric similarity means that a single ratio between small scale and large scale applies to every length dimension (see figure). With geometric similarity, all of the length dimensions in the large-scale equipment are set by the corresponding dimensions in the small-scale equipment. The only remaining variable for scale-up to large-scale mixing is the rotational speed — one or more mixing characteristics, such as tip speed, can be duplicated by the appropriate selection of a large-scale mixer speed.

The two most popular and effective geometric scale-up methods are equal tip speed and equal power per volume. Equal tip speed results when the small-scale mixer speed is multiplied by the inverse geometric ratio of the impeller diameters to get the large-scale mixer speed:

N2 = N1(D1/D2)

Equal power per volume involves a similar calculation, except the geometry ratio is raised to the two-thirds power:

N2 = N1(D1/D2)(2/3)

This expression for power per volume only applies strictly for turbulent conditions, where the power number is constant, but is approximately correct for transition-flow mixing.

Avoid mix-ups
As we have seen, taking successive steps allows the development of alternative solutions to scale-up. Similar methods can be used to scale-down process problems for investigation in a pilot-plant or laboratory simulation. Here, too, non-geometric similarity often is a problem. Such scale-down calculations should help pinpoint appropriate operating speeds to test in the small-scale mixer.
In any scale-up or scale-down evaluation, some variables can be held constant while others must change. For example, even with geometric similarity, scale-up will result in less surface per volume because surface area increases as the length squared and volume increases as length cubed. Similarly, keeping blend time constant rarely is practical with any significant scale change. Larger tanks take longer to blend than smaller ones. Also, Reynolds number is expected to increase as size increases. In addition, standard operating speeds or available impeller sizes may necessitate a final adjustment to the scale-up calculations.

Rules for scale-up always have exceptions but understanding the effects of scale-up, especially non-geometric scale-up, can provide valuable guidance. Indeed, appreciation of the tradeoffs involved in non-geometric scale-up may be crucial for success with large-scale mixing processes.

 REFERENCES

1  https://docs.google.com/viewer?url=http%3A%2F%2Fwww.sunbio.com%2Fsub%2FSunbio%2520GMP%2520Capabilty.ppt

2 http://apic.cefic.org/pub/5gmpdev9911.pdf

3 http://www.pharmtech.com/early-development-gmps-drug-product-manufacturing-small-molecules-industry-perspective-part-iii?rel=canonical

“ICH Q7a. Good Manufacturing Practice for Active Pharmaceutical Ingredients” (Draft 6, October 19th, 1999, section 19).

“ICH Q6a. Specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances”.

“Good Manufacturing Practices for Active Pharmaceutical Ingredients” (EFPIA / CEFIC Guideline, August, 1996).

“Quality Management System for Active Pharmaceutical Ingredients Manufacturers” (APIC/CEFIC May 1998).

“Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients”, The International Pharmaceutical Excipients Council (October 1995).

“21 Code of Federal Regulations, parts 210 to 211″, U.S. Food & Drug Administration. “Guide to inspection of Bulk Pharmaceutical Chemicals”, U.S. Food & Drug Administration, (Revised Edition: May 1994).

“Guidance for Industry. ANDAs: Impurities in Drug Substances”, U.S. Food and Drug Administration, CDER (June 1998).

“Guideline on the Preparation of Investigational New Drug Products”, U.S. Food & Drug Administration, CDER (March 1991).

“EC Guides to GMP, Annex 13: Manufacture of Investigational Medicinal Products” (Revised Dec. 1996).

“GMP Compliance during Development”, David J. DeTora. Drug Information Journal, 33, 769-776, 1999.

FDA Guidance documents on internet address: http://www.fda.gov/cder/guidance /index.htm

EMEA Guidance documents on internet address: http://www.eudra.org.

………………..

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////////

CANAGLIFLOZIN

Canagliflozin
Canagliflozin is a highly potent and selective subtype 2 sodium-glucose transport protein (SGLT2) inhibitor to CHO- hSGLT2, CHO- rSGLT2 and CHO- mSGLT2 with IC50 of 4.4 nM, 3.7 nM and 2 nM, respectively.

M.F.C24H25FO5S

M.Wt: 444.52

CAS No: 842133-18-0

(1S)-1,5-Anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol

1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene

NMR…..http://file.selleckchem.com/downloads/nmr/S276003-Canagliflozin-HNMR-Selleck.pdf

Canagliflozin Hemihydrate (1S)-1,5-Anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hydrate (2:1)

928672-86-0

Canagliflozin (INN, trade name Invokana) is a drug of the gliflozin class, used for the treatment of type 2 diabetes.^[1][2] It was developed by Mitsubishi Tanabe Pharma and is marketed under license by Janssen, a division of Johnson & Johnson.^[3]

U.S. Patent No, 7,943,788 B2 (the ’788 patent) discloses canagliflozin or salts thereof and the process for its preparation.

U.S. Patent Nos. 7,943,582 B2 and 8,513,202 B2 discloses crystalline form of 1 -(P-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene hemihydrate and process for preparation thereof. The US ’582 B2 and US ’202 B2 further discloses that preparation of the crystalline form of hemi-hydrate canagliflozin typically involves dissolving in a good solvent (e.g. ketones or esters) crude or amorphous compound prepared in accordance with the procedures described in WO 2005/012326 pamphlet, and adding water and a poor solvent (e.g. alkanes or ethers) to the resulting solution, followed by filtration.

U.S. PG-Pub. No. 2013/0237487 Al (the US ’487 Al) discloses amorphous dapagliflozin and amorphous canagliflozin. The US ’487 Al also discloses 1:1 crystalline complex of canagliflozin with L-proline (Form CS1), ethanol solvate of a 1: 1 crystalline complex of canagliflozin with D-proline (Form CS2), 1 :1 crystalline complex of canagliflozin with L-phenylalanine (Form CS3), 1:1 crystalline complex of canagliflozin with D-proline (Form CS4).

The US ’487 Al discloses preparation of amorphous canagliflozin by adding its heated toluene solution into n-heptane. After drying in vacuo the product was obtained as a white solid of with melting point of 54.7°C to 72.0°C. However, upon repetition of the said experiment, the obtained amorphous canagliflozin was having higher amount of residual solvents. Therefore, the amorphous canagliflozin obtained by process as disclosed in US ’487 Al is not suitable for pharmaceutical preparations.

The US ’487 Al further discloses that amorphous canagliflozin obtained by the above process is hygroscopic in nature which was confirmed by Dynamic vapor sorption (DVS) analysis. Further, it was observed that the amorphous form underwent a physical change between the sorption/desorption cycle, making the sorption/desorption behavior different between the two cycles. The physical change that occurred was determined to be a conversion or partial conversion from the amorphous state to a crystalline state. This change was supported by a change in the overall appearance of the sample as the humidity increased from 70% to 90% RH.

The canagliflozin assessment report EMA/718531/2013 published by EMEA discloses that Canagliflozin hemihydrate is a white to off-white powder^ practically insoluble in water and freely soluble in ethanol and non-hygroscopic. Polymorphism has been observed for canagliflozin and the manufactured Form I is a hemihydrate, and an unstable amorphous Form II. Form I is consistently produced by the proposed commercial synthesis process. Therefore, it is evident from the prior art that the reported amorphous form of canagliflozin is unstable and hygroscopic as well as not suitable for pharmaceutical preparations due to higher amount of residual solvents above the ICH acceptable limits.

Medical use

13. Canagliflozin is an antidiabetic drug used to improve glycemic control in people with type 2 diabetes. In extensive clinical trials, canagliflozin produced a consistent dose-dependent reduction in HbA1c of 0.77% to 1.16% when administered as monotherapy, combination with metformin, combination with metformin & Sulfonyulrea, combination with metformin & pioglitazone and In combination with insulin from a baselines of 7.8% to 8.1%, in combination with metformin, or in combination with metformin and a sulfonylurea. When added to metformin Canagliflozin 100mg was shown to be non-inferior to both Sitagliptin 100mg and glimiperide in reductions on HbA1c at one year, whilst canagliflozin 300mg successfully demontrated statistical superiority over both Sitagliptin and glimiperide in HbA1c reductions. Secondary efficacy endpoint of superior body weight reduction and blood pressure reduction (versus Sitagliptin and glimiperide)) were observed as well. Canagliflozin produces beneficial effects on HDL cholesterol whilst increasing LDL cholesterol to produce no change in total cholesterol.^[4][5]
    

    Contraindications

    Canagliflozin has proven to be clinically effective in people with moderate renal failure and treatment can be continued in patients with renal impairment.

    Adverse effects

    Canagliflozin, as is common with all sglt2 inhibitors, increased (generally mild) urinary tract infections, genital fungal infections, thirst,^[6] LDL cholesterol, and was associated with increased urination and episodes of low blood pressure.

    There are concerns it may increase the risk of diabetic ketoacidosis.^[7]

    Cardiovascular problems have been discussed with this class of drugs.^{[citation needed]} The pre-specified endpoint for cardiovascular safety in the canagliflozin clinical development program was Major Cardiovascular Events Plus (MACE-Plus), defined as the occurrence of any of the following events: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or unstable angina leading to hospitalization. This endpoint occurred in more people in the placebo group (20.5%) than in the canagliflozin treated group (18.9%).

    Nonetheless, an FDA advisory committee expressed concern regarding the cardiovascular safety of canagliflozin. A greater number of cardiovascular events was observed during the first 30 days of treatment in canagliflozin treated people (0.45%) relative to placebo treated people (0.07%), suggesting an early period of enhanced cardiovascular risk. In addition, there was an increased risk of stroke in canagliflozin treated people. However none of these effects were seen as statistically significant. Additional cardiovascular safety data from the ongoing CANVAS trial is expected in 2015.^[8]

    Interactions

    The drug may increase the risk of dehydration in combination with diuretic drugs.

    Because it increases renal excretion of glucose, treatment with canagliflozin prevents renal reabsorption of 1,5-anhydroglucitol, leading to artifactual decreases in serum 1,5-anhydroglucitol; it can therefore interfere with the use of serum 1,5-anhydroglucitol (assay trade name, GlycoMark) as a measure of postprandial glucose excursions.^[9]

    Mechanism of action

    Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the renal glucose reabsorption (SGLT1 being responsible for the remaining 10%). Blocking this transporter causes up to 119 grams of blood glucose per day to be eliminated through the urine,^[10] corresponding to 476 kilocalories. Additional water is eliminated by osmotic diuresis, resulting in a lowering of blood pressure.

    This mechanism is associated with a low risk of hypoglycaemia (too low blood glucose) compared to other antidiabetic drugs such as sulfonylurea derivatives and insulin.^[11]

    History

    On July 4, 2011, the European Medicines Agency approved a paediatric investigation plan and granted both a deferral and a waiver for canagliflozin (EMEA-001030-PIP01-10) in accordance with EC Regulation No.1901/2006 of the European Parliament and of the Council.^[12]

    In March 2013, canagliflozin became the first SGLT2 inhibitor to be approved in the United States.^[13]

    SYNTHESIS

…………

Canagliflozin is an API that is an inhibitor of SGLT2 and is being developed for the treatment of type 2 diabetes mellitus.[0011] The IUPAC systematic name of canagliflozin is (25^,,3/?,4i?,55′,6 ?)-2-{3-[5-[4-fluoro- phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol, and is also known as (15)-l,5-anhydro-l-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4- methylphenyl]-D-glucitol and l-( -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2- thienylmethyl]benzene. Canagliflozin is a white to off-white powder with a molecular formula of C₂4H₂₅F0₅S and a molecular weight of 444.52. The structure of canagliflozin is shown as compound B.

Compound B – Canagliflozin

[0012] In US 2008/0146515 Al, a crystalline hemihydrate form of canagliflozin (shown as Compound C) is disclosed, having the powder X-ray diffraction (XRPD) pattern comprising the following 2Θ values measured using CuKa radiation: 4.36±0.2, 13.54±0.2, 16.00±0.2, 19.32±0.2, and 20.80±0.2. The XRPD pattern is shown in Figure 24. A process for the preparation of canagliflozin hemihydrate is also disclosed in US 2008/0146515 Al.

 

Compound C – hemihydrate form of canagliflozin

[0013] In US 2009/0233874 Al, a crystalline form of canagliflozin is disclosed.

WO 2005/012326 pamphlet discloses a class of compounds that are inhibitors of sodium-dependent glucose transporter (SGLT) and thus of therapeutic use for treatment of diabetes, obesity, diabetic complications, and the like. There is described in WO 2005/012326 pamphlet 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene of formula (I):

 

Example 1 Crystalline 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene was prepared in a similar manner as described in WO 2005/012326.

(1) To a solution of 5-bromo-1-[5-(4-fluorophenyl)-2-thienylmethyl]-2-methylbenzene (1, 28.9 g) in tetrahydrofuran (480 ml) and toluene (480 ml) was added n-butyllithium (1.6M hexane solution, 50.0 ml) dropwise at −67 to −70° C. under argon atmosphere, and the mixture was stirred for 20 minutes at the same temperature. Thereto was added a solution of 2 (34.0 g) in toluene (240 ml) dropwise at the same temperature, and the mixture was further stirred for 1 hour at the same temperature. Subsequently, thereto was added a solution of methanesulfonic acid (21.0 g) in methanol (480 ml) dropwise, and the resulting mixture was allowed to warm to room temperature and stirred for 17 hours. The mixture was cooled under ice—water cooling, and thereto was added a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the combined organic layer was washed with brine and dried over magnesium sulfate. The insoluble was filtered off and the solvent was evaporated under reduced pressure. The residue was triturated with toluene (100 ml)—hexane (400 ml) to give 1-(1-methoxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]-benzene (3) (31.6 g). APCI-Mass m/Z 492 (M+NH₄).

(2) A solution of 3 (63.1 g) and triethylsilane (46.4 g) in dichloromethane (660 ml) was cooled by dry ice-acetone bath under argon atmosphere, and thereto was added dropwise boron trifluoride•ethyl ether complex (50.0 ml), and the mixture was stirred at the same temperature. The mixture was allowed to warm to 0° C. and stirred for 2 hours. At the same temperature, a saturated aqueous sodium hydrogen carbonate solution (800 ml) was added, and the mixture was stirred for 30 minutes. The organic solvent was evaporated under reduced pressure, and the residue was poured into water and extracted with ethyl acetate twice. The organic layer was washed with water twice, dried over magnesium sulfate and treated with activated carbon. The insoluble was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 ml), and thereto were added diethyl ether (600 ml) and H₂O (6 ml). The mixture was stirred at room temperature overnight, and the precipitate was collected, washed with ethyl acetate-diethyl ether (1:4) and dried under reduced pressure at room temperature to give 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate (33.5 g) as colorless crystals.

mp 98-100° C. APCI-Mass m/Z 462 (M+NH₄). ¹H-NMR (DMSO-d₆) δ 2.26 (3H, s), 3.13-3.28 (4H, m), 3.44 (1H, m), 3.69 (1H, m), 3.96 (1H, d, J=9.3 Hz), 4.10, 4.15 (each 1H, d, J=16.0 Hz), 4.43 (1H, t, J=5.8 Hz), 4.72 (1H, d, J=5.6 Hz), 4.92 (2H, d, J=4.8 Hz), 6.80 (1H, d, J=3.5 Hz), 7.11-7.15 (2H, m), 7.18-7.25 (3H, m), 7.28 (1H, d, J=3.5 Hz), 7.59 (2H, dd, J=8.8, 5.4 Hz).

Anal. Calcd. for C₂₄H₂₅FO₅S.0.5H₂O: C, 63.56; H, 5.78; F, 4.19; S, 7.07. Found: C, 63.52; H, 5.72; F, 4.08; S, 7.00.

1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene

 

Example 2An amorphous powder of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene (1.62 g) was dissolved in acetone (15 ml), and thereto were added H₂O (30 ml) and a crystalline seed. The mixture was stirred at room temperature for 18 hours, and the precipitate was collected, washed with acetone—H₂O (1:4, 30 ml) and dried under reduced pressure at room temperature to give 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate (1.52 g) as colorless crystals. mp 97-100° C.

there are a significant number of other β-C-arylglucoside derived drug candidates, most of which differ only in the aglycone moiety (i.e., these compounds comprise a central 1-deoxy-glucose ring moiety that is arylated at CI). It is this fact that makes them attractive targets for a novel synthetic platform technology, since a single methodology should be able to furnish a plurality of products. Among β-C-arylglucosides that possess known SGLT2 inhibition also currently in clinical development are canagliflozin, empagliflozin, and ipragliflozin.

Dapagliflozin                             Canagliflozin

Ipragliflozin …………………Empagliflozin

[0007] A series of synthetic methods have been reported in the peer-reviewed and patent literature that can be used for the preparation of β-C-arylglucosides. These methods are described below and are referred herein as the gluconolactone method, the metalated glucal method, the glucal epoxide method and the glycosyl leaving group substitution method.

[0008] The gluconolactone method: In 1988 and 1989 a general method was reported to prepare C-arylglucosides from tetra-6>-benzyl protected gluconolactone, which is an oxidized derivative of glucose (see J. Org. Chem. 1988, 53, 752-753 and J. Org. Chem. 1989, 54, 610- 612). The method comprises: 1) addition of an aryllithium derivative to the hydroxy-protected gluconolactone to form a hemiketal (a.k.ci., a lactol), and 2) reduction of the resultant hemiketal with triethylsilane in the presence of boron trifluoride etherate. Disadvantages of this classical, but very commonly applied method for β-C-arylglucoside synthesis include:

1) poor “redox economy” (see J. Am. Chem. Soc. 2008, 130, 17938-17954 and Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN- 10: 0120594757); pg 38)— that is, the oxidation state of the carbon atom at CI, with respect to glucose, is oxidized in the gluconolactone and then following the arylation step is reduced to provide the requisite oxidation state of the final product. 2) due to a lack of stereospecificity, the desired β-C-arylglucoside is formed along with the undesired a-C-arylglucoside stereoisomer (this has been partially addressed by the use of hindered trialkylsilane reducing agents (see Tetrahedron: Asymmetry 2003, 14, 3243-3247) or by conversion of the hemiketal to a methyl ketal prior to reduction (see J. Org. Chem. 2007, 72, 9746-9749 and U.S. Patent 7,375,213)).

Oxidation Reduction

Glucose Gluconoloctone Hemiketal a-anomer β-anomer

R = protecting group

[0009] The metalated glucal method: U.S. Patent 7,847,074 discloses preparation of SGLT2 inhibitors that involves the coupling of a hydroxy-protected glucal that is metalated at CI with an aryl halide in the presence of a transition metal catalyst. Following the coupling step, the requisite formal addition of water to the C-arylglucal double bond to provide the desired C-aryl glucoside is effected using i) hydroboration and oxidation, or ii) epoxidation and reduction, or iii) dihydroxylation and reduction. In each case, the metalated glucal method represents poor redox economy because oxidation and reduction reactions must be conducted to establish the requisite oxidation states of the individual CI and C2 carbon atoms.

[0010] U.S. Pat. Appl. 2005/0233988 discloses the utilization of a Suzuki reaction between a CI -boronic acid or boronic ester substituted hydroxy-protected glucal and an aryl halide in the presence of a palladium catalyst. The resulting 1- C-arylglucal is then formally hydrated to provide the desired 1- C-aryl glucoside skeleton by use of a reduction step followed by an oxidation step. The synthesis of the boronic acid and its subsequent Suzuki reaction, reduction and oxidation, together, comprise a relatively long synthetic approach to C-arylglucosides and exhibits poor redox economy. Moreover, the coupling catalyst comprises palladium which is toxic and therefore should be controlled to very low levels in the drug substance.

R = protecting group; R’ = H or alkyl

[0011] The glucal epoxide method: U.S. Patent 7,847,074 discloses a method that utilizes an organometallic (derived from the requisite aglycone moiety) addition to an electrophilic epoxide located at C1-C2 of a hydroxy-protected glucose ring to furnish intermediates useful for SGLT2 inhibitor synthesis. The epoxide intermediate is prepared by the oxidation of a hydroxy- protected glucal and is not particularly stable. In Tetrahedron 2002, 58, 1997-2009 it was taught that organometallic additions to a tri-6>-benzyl protected glucal-derived epoxide can provide either the a-C-arylglucoside, mixtures of the a- and β-C-arylglucoside or the β-C-arylglucoside by selection of the appropriate counterion of the carbanionic aryl nucleophile (i.e., the

organometallic reagent). For example, carbanionic aryl groups countered with copper (i.e., cuprate reagents) or zinc (i.e., organozinc reagents) ions provide the β-C-arylglucoside, magnesium ions provide the a- and β-C-arylglucosides, and aluminum (i.e., organoaluminum reagents) ions provide the a-C-arylglucoside.

 

or Zn[0012] The glycosyl leaving group substitution method: U.S. Patent 7,847,074, also disclosed a method comprising the substitution of a leaving group located at CI of a hydroxy-protected glucosyl species, such as a glycosyl halide, with a metalated aryl compound to prepare SGLT2 inhibitors. U.S. Pat. Appl. 2011/0087017 disclosed a similar method to prepare the SGLT2 inhibitor canagliflozin and preferably diarylzinc complexes are used as nucleophiles along with tetra- >-pivaloyl protected glucosylbromide.

Glucose Glucosyl bromide β-anomer

[0013] Methodology for alkynylation of 1,6-anhydroglycosides reported in Helv. Chim. Acta. 1995, 78, 242-264 describes the preparation of l,4-dideoxy-l,4-diethynyl^-D-glucopyranoses (a. La., glucopyranosyl acetylenes), that are useful for preparing but-l,3-diyne-l,4-diyl linked polysaccharides, by the ethynylating opening (alkynylation) of partially protected 4-deoxy-4-C- ethynyl-l,6-anhydroglucopyranoses. The synthesis of β-C-arylglucosides, such as could be useful as precursors for SLGT2 inhibitors, was not disclosed. The ethynylation reaction was reported to proceed with retention of configuration at the anomeric center and was rationalized (see Helv. Chim. Acta 2002, 85, 2235-2257) by the C3-hydroxyl of the 1,6- anhydroglucopyranose being deprotonated to form a C3-0-aluminium species, that coordinated with the C6-oxygen allowing delivery of the ethyne group to the β-face of the an oxycarbenium cation derivative of the glucopyranose. Three molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6-anhydroglucopyranose. The

ethynylaluminium reagent was prepared by the reaction of equimolar (i.e., 1:1) amounts of aluminum chloride and an ethynyllithium reagent that itself was formed by the reaction of an acetylene compound with butyllithium. This retentive ethynylating opening method was also applied (see Helv. Chim. Acta. 1998, 81, 2157-2189) to 2,4-di-<9-triethylsilyl- 1,6- anhydroglucopyranose to provide l-deoxy-l-C-ethynyl- -D-glucopyranose. In this example, 4 molar equivalents of the ethynylaluminium reagent was used per 1 molar equivalent of the 1,6- anhydroglucopyranose. The ethynylaluminium regent was prepared by the reaction of equimolar (i.e., 1: 1) amounts of aluminum chloride and an ethynyl lithium reagent that itself was formed by reaction of an acetylene compound with butyllithium.

[0014] It can be seen from the peer-reviewed and patent literature that the conventional methods that can be used to provide C-arylglucosides possess several disadvantages. These include (1) a lack of stereoselectivity during formation of the desired anomer of the C- arylglucoside, (2) poor redox economy due to oxidation and reduction reaction steps being required to change the oxidation state of CI or of CI and C2 of the carbohydrate moiety, (3) some relatively long synthetic routes, (4) the use of toxic metals such as palladium, and/or (5) atom uneconomic protection of four free hydroxyl groups. With regard to the issue of redox economy, superfluous oxidation and reduction reactions that are inherently required to allow introduction of the aryl group into the carbohydrate moiety of the previously mention synthetic methods and the subsequent synthetic steps to establish the required oxidation state, besides adding synthetic steps to the process, are particular undesirable for manufacturing processes because reductants can be difficult and dangerous to operate on large scales due to their flammability or ability to produce flammable hydrogen gas during the reaction or during workup, and because oxidants are often corrosive and require specialized handling operations (see Anderson, N. G. Practical Process Research & Development, 1st Ed.; Academic Press, 2000 (ISBN-10: 0120594757); pg 38 for discussions on this issue).

[0015] In view of the above, there remains a need for a shorter, more efficient and

stereoselective, redox economic process for the preparation of β-C-arylglucosides. A new process should be applicable to the industrial manufacture of SGLT2 inhibitors and their prodrugs,

EXAMPLE 22 – Synthesis of 2,4-di-0-feri-butyldiphenylsUyl-l-C-(3-((5-(4- fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)- -D-glucopyranoside (2,4-di-6>-TBDPS- canagliflozin; (IVi”))

 

[0227] 2-(5-Bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (1.5 g, 4.15 mmol) and magnesium powder (0.33 g, 13.7 mmol) were placed in a suitable reactor, followed by THF (9 mL) and 1,2-dibromoethane (95 μί). The mixture was heated to reflux. After the reaction was initiated, a solution of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (2.5 g, 6.92 mmol) in THF (15mL) was added dropwise. The mixture was stirred for another 2 hours under reflux, and was then cooled to ambient temperature and titrated to determine the concentration. The thus prepared 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl magnesium bromide (0.29 M in THF, 17 mL, 5.0 mmol) and A1C1₃ (0.5 M in THF, 4.0 mL, 2.0 mmol) were mixed at ambient temperature to give a black solution, which was stirred at ambient temperature for 1 hour. To a solution of l ,6-anhydro-2,4-di-6>-ieri-butyldiphenylsilyl- -D-glucopyranose (0.64 g, 1.0 mmol) in PhOMe (3.0 mL) at ambient temperature was added rc-BuLi (0.4 mL, 1.0 mmol, 2.5 M solution in Bu₂0). After stirring for about 5 min the solution was then added into the above prepared aluminum mixture via syringe, followed by additional PhOMe (1.0 mL) to rinse the flask. The mixture was concentrated under reduced pressure (50 torr) at 60 °C (external bath temperature) to remove low-boiling point ethereal solvents, and PhOMe (6 mL) was then added. The remaining mixture was heated at 150 °C (external bath temperature) for 5 hours at which time HPLC assay analysis indicated a 68% yield of 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5- (4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)- -D-glucopyranoside. After cooling to ambient temperature, the reaction was treated with 10% aqueous NaOH (1 mL), THF (10 mL) and diatomaceous earth at ambient temperature, then the mixture was filtered and the filter cake was washed with THF. The combined filtrates were concentrated and the crude product was purified by silica gel column chromatography (eluting with 1 :20 MTBE/rc-heptane) to give the product 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4- methylphenyl)- -D-glucopyranoside (0.51 g, 56%) as a white powder.

1H NMR (400 MHz, CDC1₃) δ 7.65 (d, J= 7.2 Hz, 2H), 7.55 (d, J= 7.2 Hz, 2H), 7.48 (dd, J= 7.6, 5.6 Hz, 2H), 7.44-7.20 (m, 16H), 7.11-6.95 (m, 6H), 6.57 (d, J= 3.2 Hz, IH), 4.25 (d, J= 9.6 Hz, IH), 4.06 (s, 2H), 3.90-3.86 (m, IH), 3.81-3.76 (m, IH), 3.61-3.57 (m, IH), 3.54-3.49 (m, 2H), 3.40 (dd, J= 8.8, 8.8 Hz, IH), 2.31 (s, 3H), 1.81 (dd, J= 6.6, 6.6 Hz, IH, OH), 1.19 (d, J= 4.4 Hz, IH, OH), 1.00 (s, 9H), 0.64 (s, 9H); ¹³C NMR (100 MHz, CDC1₃) δ 162.1 (d, J= 246 Hz, C), 143.1 (C), 141.4 (C), 137.9 (C), 136.8 (C), 136.5 (C), 136.4 (CH x2), 136.1 (CH x2), 135.25 (C), 135.20 (CH x2), 135.0 (CH x2), 134.8 (C), 132.8 (C), 132.3 (C), 130.9 (d, J= 3.5 Hz, C), 130.5 (CH), 130.0 (CH), 129.7 (CH), 129.5 (CH), 129.4 (CH), 129.2 (CH), 127.6 (CH x4), 127.5 (CH x2), 127.2 (CH x2), 127.1 (d, J= 8.2 Hz, CH x2), 127.06 (CH), 126.0 (CH), 122.7 (CH), 115.7 (d, J= 21.8 Hz, CH x2), 82.7 (CH), 80.5 (CH), 79.4 (CH), 76.3 (CH), 72.9 (CH), 62.8 (CH₂), 34.1(CH₂), 27.2 (CH₃ x3), 26.7 (CH₃ x3), 19.6, (C), 19.3 (CH₃),19.2 (C); LCMS (ESI) m/z 938 (100, [M+NH₄]⁺), 943 (10, [M+Na]⁺).

EXAMPLE 23 – Synthesis of canagliflozin (l-C-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)- 4-methylphenyl)- -D-glucopyranoside; (Ii))

[0228] A mixture of the 2,4-di-6>-ieri-butyldiphenylsilyl-l-C-(3-((5-(4-fluorophenyl)thiophen- 2-yl)methyl)-4-methylphenyl)- -D-glucopyranoside (408 mg, 0.44 mmol) and TBAF (3.5 mL, 3.5 mmol, 1.0 M in THF) was stirred at ambient temperature for 4 hours. CaC0₃ (0.73 g), Dowex 50WX8-400 ion exchange resin (2.2 g) and MeOH (5mL) were added to the product mixture and the suspension was stirred at ambient temperature for 1 hour and then the mixture was filtered through a pad of diatomaceous earth. The filter cake was rinsed with MeOH and the combined filtrates was evaporated under vacuum and the resulting residue was purified by column chromatography (eluting with 1 :20 MeOH/DCM) affording canagliflozin (143 mg, 73%).

1H NMR (400 MHz, DMSO-J₆) δ 7.63-7.57 (m, 2H), 7.28 (d, J= 3.6 Hz, 1H), 7.23-7.18 (m, 3H), 7.17-7.12 (m, 2H), 6.80 (d, J= 3.6 Hz, 1H), 4.93 (br, 2H, OH), 4.73 (br, 1H, OH), 4.44 (br,IH, OH), 4.16 (d, J= 16 Hz, 1H), 4.10 (d, J= 16 Hz, 1H), 3.97 (d, J= 9.2 Hz, 1H), 3.71 (d, J=I I.6 Hz, 1H), 3.47-3.43 (m, 1H), 3.30-3.15 (m, 4H), 2.27 (s, 3H);

¹³C NMR (100 MHz, DMSO- d₆) δ 161.8 (d, J= 243 Hz, C), 144.1 (C), 140.7 (C), 138.7 (C), 137.8 (C), 135.4 (C), 131.0 (d, J= 3.1 Hz, C), 130.1 (CH), 129.5 (CH), 127.4 (d, J= 8.1 Hz, CH x2), 126.8 (CH), 126.7 (CH), 123.9 (CH), 116.4 (d, J= 21.6 Hz, CH x2), 81.8 (CH), 81.7 (CH), 79.0 (CH), 75.2 (CH), 70.9 (CH), 61.9 (CH₂), 33.9 (CH₂), 19.3 (CH₃);

LCMS (ESI) m/z 462 (100, [M+NH₄]⁺), 467 (3, [M+Na]⁺).

Example 1 – Synthesis of l,6-anhydro-2,4-di-6>-ieri-butyldiphenylsilyl- -D-glucopyranose (II”)

 

III II”

[0206] To a suspension solution of l,6-anhydro- -D-glucopyranose (1.83 g, 11.3 mmol) and imidazole (3.07 g, 45.2 mmol) in THF (10 mL) at 0 °C was added dropwise a solution of TBDPSC1 (11.6 mL, 45.2 mmol) in THF (10 mL). After the l,6-anhydro-P-D-gJucopyranose was consumed, water (10 mL) was added and the mixture was extracted twice with EtOAc (20 mL each), washed with brine (10 mL), dried (Na₂S0₄) and concentrated. Column

chromatography (eluting with 1 :20 EtOAc/rc-heptane) afforded 2,4-di-6>-ieri-butyldiphenylsilyl- l,6-anhydro- “D-glucopyranose (5.89 g, 81%).

1H NMR (400 MHz, CDC1₃) δ 7.82-7.70 (m, 8H), 7.49-7.36 (m, 12H), 5.17 (s, IH), 4.22 (d, J= 4.8 Hz, IH), 3.88-3.85 (m, IH), 3.583-3.579 (m, IH), 3.492-3.486 (m, IH), 3.47-3.45 (m, IH), 3.30 (dd, J= 7.4, 5.4 Hz, IH), 1.71 (d, J= 6.0 Hz, IH), 1.142 (s, 9H), 1.139 (s, 9H); ¹³C NMR (100 MHz, CDCI₃) δ 135.89 (CH x2), 135.87 (CH x2), 135.85 (CH x2), 135.83 (CH x2), 133.8 (C), 133.5 (C), 133.3 (C), 133.2 (C), 129.94 (CH), 129.92 (CH), 129.90 (CH), 129.88 (CH), 127.84 (CH₂ x2), 127.82 (CH₂ x2), 127.77 (CH₂ x4), 102.4 (CH), 76.9 (CH), 75.3 (CH), 73.9 (CH), 73.5 (CH), 65.4 (CH₂), 27.0 (CH₃ x6), 19.3 (C x2).

 

Canagliflozin

Systematic (IUPAC) name
(2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
Clinical data
Trade names	Invokana
AHFS/Drugs.com	entry
Pregnancy category	US: C (Risk not ruled out)
Legal status	US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	65%
Protein binding	99%
Metabolism	Hepatic glucuronidation
Biological half-life	11.8 (10–13) hours
Excretion	Fecal and 33% renal
Identifiers
CAS Registry Number	842133-18-0
ATC code	A10BX11
PubChem	CID: 24812758
IUPHAR/BPS	4582
DrugBank	DB08907
ChemSpider	26333259
UNII	6S49DGR869
ChEBI	CHEBI:73274
ChEMBL	CHEMBL2103841
Synonyms	JNJ-28431754; TA-7284; (1S)-1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol
Chemical data
Formula	C24H25FO5S
Molecular mass	444.52 g/mol

1H NMR PREDICT

  13C NMR PREDICT

  COSY PREDICT

References

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Trimyristin

Trimyristin is an ester with the chemical formula C₄₅H₈₆O₆. It is a saturated fat which is the triglyceride of myristic acid. Trimyristin is a white to yellowish-gray solid that is insoluble in water, but soluble in ethanol, benzene, chloroform, dichloromethane, and ether.

Occurrence

Trimyristin is found naturally in many vegetable fats and oils.

Isolation from nutmeg

The isolation of trimyristin from powdered nutmeg is a common introductory-level college organic chemistry experiment. It is an uncommonly simple natural product extraction because nutmeg oil generally consists of over eighty percent trimyristin. Trimyristin makes up between 20-25% of the overall mass of dried, ground nutmeg. Separation is generally carried out by steam distillation and purification uses extraction from ether followed by distillation or rotary evaporation to remove the volatile solvent. The extraction of trimyristin can also be done with diethyl ether at room temperature, due to its high solubility in the ether. The experiment is frequently included in curricula, both for its relative ease and to provide instruction in these techniques.

¹H-NMR

Operating scheme

Substances required

Educts		Amount	Risk	Safety
Nutmeg		25 g	R	S
Solvents		Amount	Risk	Safety
Ethanol	F	~ 150 mL	R 11	S 2-7-16
tert-Butyl methyl ether	F Xi	150 mL	R 11-38	S 2-9-16-24
Others		Amount	Risk	Safety
Iodine	Xn N	0.1 g	R 20/21-50	S 2-23.2-23.4-25-61
Solvents for analysis		Amount	Risk	Safety
Cyclohexane	F Xn N	?	R 11-38-50/53-65-67	S 2-9-16-33-60-61-62
Acetic acid ethyl ester	F Xi	?	R 11-36-66-67	S 2-16-26-33

Substances produced

Equipment

	round bottom flask 250 mL			Soxhlet extractor 100 mL
	glass wool			extraction cone
	heatable magnetic stirrer with magnetic stir bar			oil bath
	reflux condenser			rotary evaporator
	ice bath			exsiccator with drying agent
	suction filter			suction flask

Simple evaluation indices

Chromatogram

¹³C-NMR

IR

Trimyristin^[1]

Names
IUPAC name 1,3-Di(tetradecanoyloxy)propan-2-yl tetradecanoate
Other names Glyceryl trimyristate; Glycerol tritetradecanoate;[2] 1,2,3-Tritetradecanoylglycerol[3]
Identifiers
CAS Registry Number	555-45-3
ChemSpider	10675
EC number	209-099-7
InChI[show]
Jmol-3D images	Image
PubChem	11148
SMILES[show]
UNII	18L31PSR28
Properties
Chemical formula	C45H86O6
Molar mass	723.18 g·mol−1
Appearance	White-yellowish gray solid
Odor	Nutmeg-like
Density	0.862 g/cm3 (20 °C)[4] 0.8848 g/cm3 (60 °C)[2]
Melting point	56–57 °C (133–135 °F; 329–330 K)
Boiling point	311 °C (592 °F; 584 K)
Solubility	Slighty soluble in alcohol, ligroin Soluble in (C2H5)2O, acetone, C6H6,[2] CH2Cl2, CHCl3
Refractive index (nD)	1.4428 (60 °C)[2]
Structure
Crystal structure	Triclinic (β-form)[3]
Space group	P1 (β-form)[3]
Lattice constant	a = 12.0626 Å, b = 41.714 Å, c = 5.4588 Å (β-form)[3] α = 73.888°, β = 100.408°, γ = 118.274°
Thermochemistry
Specific heat capacity (C)	1013.6 J/mol·K (β-form, 261.9 K) 1555.2 J/mol·K (331.5 K)[5][6]
Std molar entropy (So298)	1246 J/mol·K (liquid)[6]
Std enthalpy of formation (ΔfHo298)	−2355 kJ/mol[6]
Std enthalpy of combustion (ΔcHo298)	27643.7 kJ/mol[6]
Hazards
NFPA 704	[7] 0 1 0
Flash point	> 110 °C (230 °F; 383 K)[7]
Autoignition temperature	421.1 °C (790.0 °F; 694.2 K)[7]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

7. References
8. Merck Index, 11th Edition, 9638.
10. Lide, David R., ed. (2009). CRC Handbook of Chemistry and Physics (90th ed.). Boca Raton, Florida: CRC Press. ISBN 978-1-4200-9084-0.
12. Van Langevelde, A.; Peschar, R.; Schenk, H. (2001). “Structure of β-trimyristin and β-tristearin from high-resolution X-ray powder diffraction data”. Acta Crystallographica Section B Structural Science 57 (3): 372. doi:10.1107/S0108768100019121. edit
14. Sharma, Someshower Dutt; Kitano, Hiroaki; Sagara, Kazunobu (2004). “Phase Change Materials for Low Temperature Solar Thermal Applications” (PDF). http://www.eng.mie-u.ac.jp. Mie University. Retrieved 2014-06-19.
16. Charbonnet, G. H.; Singleton, W. S. (1947). “Thermal properties of fats and oils”. Journal of the American Oil Chemists Society 24 (5): 140. doi:10.1007/BF02643296. edit
18. Trimyristin in Linstrom, P.J.; Mallard, W.G. (eds.) NIST Chemistry WebBook, NIST Standard Reference Database Number 69. National Institute of Standards and Technology, Gaithersburg MD. http://webbook.nist.gov (retrieved 2014-06-19)

“MSDS of Trimyristin”

.

http://www.fishersci.ca

. Fisher Scientific. Retrieved 2014-06-19.

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Processes for the preparation of lorcaserin

Zydus Cadila Healthcare Ltd

WO 2015102017, 09 July2015 

On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity such as high blood pressure or type 2 diabetes.

On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who “have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol

Useful for treating obesity.

The present invention relates to stable crystalline Form I of Iorcaserin hydrochloride of Formula (IA) and processes for its preparation. The invention also relates to processes for the preparation of lorcaserin and pharmaceutically acceptable salts, solvates and hydrates thereof.

Stable crystalline form I of lorcaserin hydrochloride and its process of preparation are claimed.  Represents the first patenting from Cadila on lorcaserin, which was developed and launched by Arena Pharma and Eisai.

In July 2015, Newport Premium™ reported that Cadila is potentially interested in lorcaserin.

Lorcaserin hydrochloride is an agonist of the 5-HT_2c receptor and shows effectiveness at reducing obesity in animal models and humans developed by Arena Pharmaceuticals. It is chemically represented as (R)-8-chloro-l -methyl -2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride having Formula (I) as depicted herein below.

(IA)

U.S. Patent No. 6,953,787 B2 discloses compound of Formula (I) and pharmaceutically acceptable salt, solvates or hydrates thereof and process for preparation thereof.

U.S. Patent No. 8,168,624 B2 discloses (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride hemihydrate and process for its preparation. The patent also discloses crystalline Form I, Form II and Form III of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride. The crystalline Form

I and Form II are reported as anhydrous, non-solvated crystal forms. The crystalline Form III displays a dehydration feature calculated as a 3.7% weight loss which is consistent with the theoretical weight loss of 3.7% for a hemihydrate.

The patent discloses that anhydrous Form I and Form II readily converts to a hemihydrate, upon exposure to moisture. The dynamic vapor sorption (DVS) data for each of the three crystal forms reveals the hygroscopic nature of both Forms I and II, which readily adsorb moisture at relative humidity (RH) greater than about 40-60%. In addition, both Forms I and II were calculated to adsorb about 3.8% moisture between about 40 and about 80% RH which is consistent with conversion to the hemihydrate (Form III). X-ray powder diffraction (XRPD) carried out on both Forms I and II after the DVS cycle confirmed this conversion. In contrast, the DVS data in connection with Form III shows that it is substantially non-hygroscopic, adsorbing less than 0.5% water at 90% RH and the XRPD pattern showed no change in crystalline form after the DVS cycle.

International (PCT) Publication Nos. WO 2003/086306 Al, WO 2005/019179 Al, WO 2006/069363 Al, WO 2007/120517 Al, WO 2008/07011 1 Al and WO 2009/1 1 1004 Al disclose various synthetic approaches for the preparation of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms and intermediates.

International (PCT) Publication No. WO 2006/071740 Al discloses combination of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents. International (PCT) Publication No. WO 2012/030938 Al discloses various salts of lorcaserin with optically active acids.

U.S. PG-Pub No. US 2014/0187538 Al discloses amorphous lorcaserin hydrochloride and amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers and processes for their preparation.

International (PCT) Publication No. WO 2014/135545 Al discloses solid dispersion comprising amorphous lorcaserin hydrochloride and one or more pharmaceutically acceptable water soluble polymers.

see…..https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015102017&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example-7: Preparation of crystalline Form I of lorcaserin hydrochloride. In a round bottom flask, 560g of methyl ethyl ketone and 40 ml water were taken and 100 g of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine was added and stirred for 10 minutes. The reaction mass heated to 55 to 60°C and 19.3 g of. L-(+)-tartaric acid was added slowly and stirred for one to two hours. The reaction mass was further stirred at 10-15°C for an hour and the product was filtered and washed with a mixture of methyl ethyl ketone and water. The wet cake and 150 ml methyl ethyl ketone were taken in another flask and heated to 75-80°C. 20-25 ml water was, added and stirred for an hour. Further, the reaction mass was stirred for an hour at 0-5°C. The product was filtered and washed with methyl ethyl ketone.

100 g tartrate salt of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine and 300 mL water were taken in another round bottom flask. 200 mL methylene dichloride was added and the reaction mass was cooled to 10-20°C. 17.2 g sodium hydroxide dissolved in 89 ml water was added into the reaction mass at 10-20°C. The reaction mass was stirred for an hour at 25-30°C and the layers were separated. The solvent was removed from the organic layer under vacuum and then 100 mL ethyl acetate was added into that and distilled out. Further, 100 mL ethyl acetate was added and stirred for 15 minutes. The reaction mass was filtered through a hyflow bed and the filtrate was treated with dry HC1 gas till a pH of 1.5 to 2.5 was obtained at 0-10°C and it was stirred for about 30 minutes to an hour. The product was then filtered and washed with ethyl acetate and then dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride. Yield: 87.5-98.6 %.

Example-8: Preparation of crystalline Form I of lorcaserin hydrochloride

In a round bottom flask, 2.20 g lorcaserin, 30 mL methylene chloride, 17.4 mL of 1M HCI in ether were added and the mixture was stirred for 5-15 minutes at room temperature. The solvent was removed under reduced pressure to give a white solid. This solid was again dissolved in 30 ml methylene chloride, 17.4 mL of 1M HCI solution and stirred for 5-15 minutes at room temperature. The solvent was removed under reduced pressure to give lorcaserin hydrochloride. The product was dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride.

Example-9: Preparation of crystalline Form I lorcaserin hydrochloride

50 g of lorcaserin hydrochloride hemihydrate and 50 g of hydroxypropylmethyl cellulose (HPMC) 3CPC were mixed in a blender at 25°C to 35°C. The mixture was mixed for 30 minutes and unloaded. The solid thus obtained was dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride.

Pankaj R. Patel (right), Chairman and Managing Director,

/////////

Fispemifene, HM 101

Fispemifene; UNII-3VZ2833V08;

cas 341524-89-8

2-[2-[4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenoxy]ethoxy]ethanol

Treatment of Hypogonadism

Androgen Decline in the Aging Male (Andropause) in phase 2

Fispemifene is the Z-isomer of the compound of formula (I)

WO 01/36360 describes a group of SERMs, which are tissue-specific estrogens and which can be used in women in the treatment of climacteric symptoms, osteoporosis, Alzheimer’s disease and/or cardiovascular diseases without the carcinogenic risk. Certain compounds can be given to men to protect them against osteoporosis, cardiovascular diseases and Alzheimer’s disease without estrogenic adverse events (gynecomastia, decreased libido etc.). Of the compounds described in said patent publication, the compound (Z)-2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol (also known under the generic name fispemifene) has shown a very interesting hormonal profile suggesting that it will be especially valuable for treating disorders in men. WO 2004/108645 and WO 2006/024689 suggest the use of fispemifene for treatment or prevention of age-related symptoms in men, such as lower urinary tract symptoms and diseases or disorders related to androgen deficiency in men.

Quatrx had been conducting phase II clinical development for the treatment of androgen decline in the aging male. Unlike testosterone replacement therapies that are typically topical or injection therapies, fispemifene is an oral treatment and is not a formulation of testosterone. Fispemifene utilizes the body’s normal feedback mechanism to increase testosterone levels. Originally developed at Hormos, QuatRx gained rights to the drug candidate following a merger of the companies pursuant to which Hormos became a wholly-owned subsidiary of QuatRx.

Known methods for the syntheses of compounds like ospemifene and fispemifene include rather many steps. WO 02/090305 describes a method for the preparation of fispemifene, where, in a first step, a triphenylbutane compound with a dihydroxysubstituted butane chain is obtained. This compound is in a second step converted to a triphenylbutene where the chain is 4-chlorosubstituted. Then the desired Z-isomer is crystallized. Finally, the protecting group is removed to release the ethanol-ethoxy chain of the molecule.

Fispemifene is a selective estrogen receptor modulator (SERM) studied in phase II clinical trials at Forendo Pharma for the treatment low testosterone in men. The compound is also in phase II clinical studies at Apricus for the treatment of men with secondary hypogonadism.

In 2013, Forendo Pharma acquired the drug from Hormos Medical for the treatment of male low testosterone.

In 2014, Apricus Biosciences acquired U.S. rights for development and commercialization

PATENT

https://www.google.com/patents/US7504530

EXAMPLE 2 2-{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxy}-ethanol (Compound I)

{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxy}-acetic acid ethyl ester was dissolved in tetrahydrofuran at room temperature under nitrogen atmosphere. Lithium aluminium hydride was added to the solution in small portions until the reduction reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride solution. The product was extracted into toluene, which was dried and evaporated in vacuo. The residue was purified with flash chromatography with toluene/triethyl amine (9.5:0.5) as eluent. Yield 68%.

¹H NMR (200 MHz, CDCl₃):

2.92 (t, 2H, ═CH ₂CH₂Cl),

3.42 (t, 2H, ═CH₂ CH₂ Cl),

3.59-3.64 (m, 2H, OCH₂CH₂O CH₂CH ₂OH),

3.69-3.80 (m, 4H, OCH₂ CH ₂OCH ₂ CH₂OH),

3.97-4.02 (m, 2H, OCH₂CH₂OCH₂CH₂OH),

6.57 (d, 2H, aromatic proton ortho to oxygen),

6.78 (d, 2H, aromatic proton meta to oxygen),

7.1-7.43 (m, 10H, aromatic protons).

………….

PATENT

WO 2001036360

https://www.google.com/patents/WO2001036360A1?cl=en

……………

PATENT

WO 2002090305

 http://www.google.co.in/patents/WO2002090305A1?cl=en

EXAMPLE

a) [2-(2-chloroethoxy)ethoxymethyl]benzene

is prepared from benzyl bromide and 2-(2-chloroethoxy)ethanol by the method described in literature (Bessodes, 1996).

b) {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl}phenylmethanone

The mixture of 4-hydroxybenzophenone (16.7 g, 84.7 mmol) and 48 % aqueous sodium hydroxide solution (170 ml) is heated to 80 °C. Tetrabutylammonium bromide (TBABr) (1.6 g, 5.1 mmol) is added and the mixture is heated to 90 °C. [2-(2-Chloroethoxy)ethoxymethyl]benzene (18. g, 84.7 mmol) is added to the mixture during 15 min and the stirring is continued for additional 3.5 h at 115-120 °C. Then the mixture is cooled to 70 °C and 170 ml of water and 170 ml of toluene are added to the reaction mixture and stirring is continued for 5 min. The layers are separated and the aqueous phase is extracted twice with 50 ml of toluene. The organic phases are combined and washed with water, dried with sodium sulphate and evaporated to dryness. Yield 31.2 g.

Another method to prepare {4-[2-(2-benzyloxyethoxy)ethoxy]phenyl}phenyl- methanone is the reaction of 2-(2-benzyloxyethoxy)ethyl mesylate with 4- hydroxybenzophenone in PTC-conditions.

Η NMR (CDCI3): 3.64-3.69 (m, 2H), 3.74-3.79 (m, 2H), 3.90 (dist.t, 2H), 4.22 (dist.t, 2H), 4.58 (s, 2H), 6.98 (d, 2H), 7.28-7.62 (m, 8H), 7.75 (td, 2H), 7.81 (d, 2H).

c) 1- {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl} – 1 ,2-diphenyl -butane- 1 ,4-diol

R = BENZYL

Lithium aluminum hydride (1.08 g, 28.6 mmol) is added into dry tetrahydrofuran (60 ml) under nitrogen atmosphere. Cinnamaldehyde (6.65 g, 50 mmol) in dry tetrahydrofuran (16 ml) is added at 24-28 °C. The reaction mixture is stirred at ambient temperature for 1 h. {4-[2-(2- Benzyloxyethoxy)ethoxy]phenyl}-phenyl-methanone (14.0 g, 37 mmol) in dry tetrahydrofuran (16 ml) is added at 50-55 °C. The reaction mixture is stirred at 60 °C for 3 h. Most of tetrahydrofuran is evaporated. Toluene (70 ml) and 2 M aqueous hydrogen chloride (50 ml) are added. The mixture is stirred for 5 min and the aqueous layer is separated and extracted with toluene (30 ml). The toluene layers are combined and washed with 2M HC1 and water, dried and evaporated. The product is crystallized from isopropanol as a mixture of stereoisomers (8.8 g, 50 %).

Η NMR (CDCI3 ): 1.75-2.10 (m, 2H), 3.20-4.16 (m, 1 OH), 4.52 and 4.55 (2s, together 2H), 6.61 and 6.88 (2d, together 2H), 6.95-7.39 (m, 15H), 7.49 and 7.57 (2d, together 2H).

d) Z- 1 – {4-[2-(2-Benzyloxyethoxy)ethoxy]phenyl} -4-chloro- 1 ,2-diphenyl-but- 1-ene

R = BENZYL

1 – {4- [2-(2-Benzyloxy-ethoxy)ethoxy]phenyl} – 1 ,2-diphenyl -butane- 1 ,4-diol (10.0 g, 19.5 mmol) is dissolved in toluene (50 ml). Triethylamine (2.17 g, 21.4 mmol) is added to the solution and the mixture is cooled to -10 °C. Thionyl chloride (6.9 g, 58.5 mmol) is added to the mixture at -10 – ±0 °C. The mixture is stirred for 1 hour at 0-5 °C, warmed up to 70 °C and stirred at this temperature for 4 hours. Solvent is evaporated, the residue is dissolved to toluene, washed three times with 1M HC1 solution and twice with water. The Z-isomer of the product is crystallized from isopropanol-ethyl acetate. Yield 3.0 g. The filtrate is purified by flash chromatography to give E-isomer.

Z-isomer: Η NMR (CDCI3): 2.91 (t, 2H), 3.41 (t, 2H), 3.55-3.85 (m, 6H), 3.99 (dist.t, 2H), 4.54 (s, 2H), 6.40 (s, 1H), 6.56 (d, 2H), 6.77 (d, 2H), 7.10- 7.50 (m, 15H)

E-isomer: 1H NMR (CDCI3): 2.97 (t, 2H), 3.43 (t, 2H), 3.65-3.82 (m, 4H), 3.88 (dist.t, 2H), 4.15 (dist.t, 2H), 4.58 (s, 2H), 6.86 -7.45 (m, 19H)

FINAL STEP

e) 2- {2-[4-(4-Chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethoxy } ethanol:

Z- 1 – {4-[2-(2-Benzyloxy-ethoxy)ethoxy]phenyl} -4-chloro- 1 ,2-diphenyl -but- 1-ene (3.8 g, 7.4 mmol) is dissolved in ethyl acetate under nitrogen atmosphere , Zn powder (0.12 g, 1.85 mmol) and acetyl chloride (1.27 g, 16.3 mmol) are added and the mixture is stirred at 50 °C for 3 h (Bhar, 1995). The reaction mixture is cooled to room temperature, water (10 ml) is added and stirring is continued for additional 10 min. The aqueous layer is separated and the organic phase is washed with 1 M aqueous hydrogen chloride solution and with water. Ethyl acetate is evaporated and the residue is dissolved in methanol (16 ml) and water (4 ml). The acetate ester of the product is hydrolysed by making the mixture alkaline with sodium hydroxide (1 g) and stirring the mixture at room temperature for 1 h. Methanol is evaporated, water is added and the residue is extracted in ethyl acetate and washed with 1 M hydrogen chloride solution and with water. Ethyl acetate is evaporated and the residue is dissolved in toluene (25 ml), silica gel (0.25 g) is added and mixture is stirred for 15 min. Toluene is filtered and evaporated to dryness. The residue is crystallised from heptane-ethyl acetate (2:1). The yield is 71 %.

Z-isomer: 1H NMR (CDCI3): 2.92 (t, 2H), 3.41 (t, 2H), 3.58-3.63 (m, 2H), 3.69-3.80 (m, 4H), 3.96-4.01 (m, 2H), 6.56 (d, 2H), 6.78 (d, 2H), 7.10-7.40 (m, 10H).

Z ISOMER IE FISPEMIFENE

E-2- {2- [4-(4-Chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethoxy} ethanol is prepared analogously starting from E-l-{4-[2-(2-benzyloxy- ethoxy)ethoxy]phenyl} -4-chloro- 1,2-diphenyl-but-l-ene. The product is purified by flash chromatography with toluene-methanol (10:0.5) as eluent.

E-isomer: 1H NMR (CDCI3): 2.97 (t, 2H), 3.43 (t, 2H), 3.65-3.79 (m, 4H), 3.85-3.90 (m, 2H), 4.13-4.17 (m, 2H), 6.85-7.25 (m, 2H).

Debenzylation of 1 – {4-[2-(2-benzyloxy-ethoxy)ethoxy]phenyl} -4-chloro- 1 ,2- diphenyl-but- 1-ene is also carried out by hydrogenation with Pd on carbon as a catalyst in ethyl acetate-ethanol solution at room temperature.

………….

PATENT

http://www.google.com/patents/US5491173