Title of Invention	A PROCESS FOR THE PREPARATION OF (Z)-(6R, 7R)-3-(ACETOXYMETHYL)-7-[2-2AMINO-1,3-THIAZOL-4-YL)-2-METHOXYIMINOACETAMIDO]-8-OXO-5-THIA-1-AZABICYCLO [4,2,0] OCT-2-EN-2-CARBOXYLIC ACID (CEFOTAXIME ACID)
Abstract	The present invention relates to an improved process for the preparation of (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetamido]-8-oxo-5-thia-l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid) is described, where S-(2-benzothiazolyl-2-(2-aminothiazol-4-yl)-2-methoxyimino thioacetate (MAEM) is condense with 7-amino-3-acetoxymethyl-3-cephem-4- carboxylic acid (7-ACA) in presence of suitable base and mixture of organic solvent and water to obtain require product with high yield.

Title of Invention

A PROCESS FOR THE PREPARATION OF (Z)-(6R, 7R)-3-(ACETOXYMETHYL)-7-[2-2AMINO-1,3-THIAZOL-4-YL)-2-METHOXYIMINOACETAMIDO]-8-OXO-5-THIA-1-AZABICYCLO [4,2,0] OCT-2-EN-2-CARBOXYLIC ACID (CEFOTAXIME ACID)

Abstract

The present invention relates to an improved process for the preparation of (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetamido]-8-oxo-5-thia-l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid) is described, where S-(2-benzothiazolyl-2-(2-aminothiazol-4-yl)-2-methoxyimino thioacetate (MAEM) is condense with 7-amino-3-acetoxymethyl-3-cephem-4- carboxylic acid (7-ACA) in presence of suitable base and mixture of organic solvent and water to obtain require product with high yield.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) and THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See section 10 and rule 13] 1. Title: A process for the preparation of (Z)-(6R, 7R)-3-(aeetoxymethyl)-7-[2-(2-amino-l,3-thiazol-4-yI)-2-methoxyiminoacetamido]-8-oxo-5-thia-l-azabicyclo [4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid). Applicant: Claris Lifesciences Limited, Claris Corporate Headquarters, Nr.Parimal Crossing, Ellisbridge, Ahmedabad - 380 006, Gujarat, India. The following specification particularly describes the invention and the manner in which it is to be performed. DESCRIPTION Field of Invention : The present invention relates to an improved process for the production of (Z)-(6R, 7R)-3-(acetoxmethyl)-7-[2-(2-amino-l,3-thiazol-4-yl)-2-rnethoxyiminoacetamido]-S-oxo-5-thia -l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid). The synthesis of Cefotaxime acid comprises the condensation of S-(2-benzothiazoyl)-2-(2-arnino-thaiazol-4-yl)-2-rnethoxyimino thioacetate with 7-amino-3-acetoxyrnethyl-3-cephem-4-carbcoxylic acid in presence of aqueous organic solvent and organic base. Cefotaxime acid is subsequently isolated by organic acid. BACKGROUND OF THE INVENTION Cephalosporin: Any of a group of broad-spectrum derived from species of fungi of the genus Cephalosporium and is related to the penicillins in both structure and mode of action but relatively penicillinase-resistant antibiotics. These antibiotics have low toxicity for the host, considering their broad antibacterial spectrum. They have the active nucleus of beta-lactam ring, which results in a variety of antibacterial and pharmacological characteristics when modified mainly by substitution at 3 and 7 positions. Their antibacterial activities result from the inhibition of mucopeptide synthesis in the cell wall. They are widely used to treat gonorrhea, meningitis, pneumococcal, staphylococcal and streptococcal infections. The cephalosporin class of antibiotics is usually divided into generations by their antimicrobial properties. Three generations of cephalosporins are recognised and the fourth has been grouped. Each newer generation of cephalosporins has broader range of activity against Gram-negative organisms but a narrower range of activity against Gram-positive organisms than the 2 preceding generation. The newer agents have much longer half-lives resulting in the decrease of dosing frequency. Accordingly, the third-generation cephalosporins can penetrate into tissues well and thus antibiotic levels are good in various body fluids. Cefotaxime is a third-generation cephalosporin antibiotics, it has broad-spectrum activity against both Gram-positive and Gram-negative organism. The bactericidal activity of Cefotaxime works by inhibiting bacterial cell wall biosynthesis. Cefotaxime shows high affinity for penicillin-binding proteins (PBP) in the cell wall including PBP lb and PBP III. A positive feature of Cefotaxime is that it displays a resistance to penicillinases and is useful to treat infections that are resistant to penicillin derivatives. Cefotaxime has in vitro activity against a wide range of Gram-positive and Gram-negative organisms. Cefotaxime should be administered by both Intravenous as well as Intramuscular route. DESCRIPTION OF THE PRIOR ART Cephalosporin antibiotics inhibit bacteria by interfering with the synthesis of essential structural components of the bacterial cell wall. They are considered as highly effective antibiotics with low toxicity and are used for treating a wide variety of bacterial infections. A number of cephalosporin derivatives have been discovered with increased potency and improved stability. Ochiai et al. (U.S. Patent No. USG409SSSS) described cephem compounds and processes for their preparation. Heyrnes et al. (U.S. Patent No.4,152,432) described 3- aeetoxymethyl-7-(iminoacetamido) cephalosporonic acid derivatives, in particular Cefotaxime, and process for preparing the derivatives. The "third-generation cephalosporins" generally consist of 3-methyl-3-cephem-4-carboxylic acid derivatives substituted in the 7p-position by an a- 3 (2-aminothia3zol-4-yl)-α-hyclroxyimirnoacetamido group, in which the hydroxy group is free or substituted with an alliyl group, optionally substituted by a carboxy group, and substituted on the methyl group in the 3-position with the residue of a nucleophilic compound. The above mentioned third-generation cephalosporins have been described for the first time in the published German application DE2556736 (corresponding to U.S. Pat. No. US055S3216) and, principally are compounds encompassed by the general formula A Formula A wherein R4 is the residue of a nucleophilic compound and R3 is a hydroxy group which may be protected, including their pharrnaceutically acceptable esters, the respective salts and the relative solvates. Among these third-generation cephalosporins, the 7(β.-[α-(2-aminothiazol-4-yl)-a-hydroxyimino]acetamido-3-methyl-3-cephem-4-carbo.xylic acid derivatives of formula A, in which Rs is methoxy and R4 is a 2-furoylthio group (Ceftiofur), an acetoxy group (Cefotaxime) or a l,2,5,6-tetrahydro-2-methyl-5,6-dio::o-l,2,4-triazin-3-ylthio group (Ceftriaxone) are particularly interesting compounds. The 7β-[a-(2-aminothiazol-4-yl)-α-hydroxyiminojacetamido-3-methyl-3-cephem-4-carboxylic acid derivatives in which the 3-rnethyl group is substituted with the residue of a nucleophilic compound are prepared 4 according to the general method, described in DE2556736 and U.S. Pat. No US05583216, which comprises introducing the α-(2-aminothiaizol-4-yl)-a-hydroxyiminoacetyl radical, wherein the hydroxy and amino groups are suitably protected, onto the amino group of a 7β -amino-3-methylcephem-4-carboxylic acid in which the methyl group is substituted with the residue of a nucleophilic compound. Finally, T. Aoki et al. (Tetrahedron 1983, 34/15, 2515-2556 in particular pages 2520-2525) disclose the synthesis of diphenylrnethyl 7β -(2-thienylaceta.rnino)-3-( 1 -methyl- lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate, which involves the preparation of diphenylrnethyl 7β -(2-thienylacetamino)-3-(l-methyl-lH-tetrazol-5-yl)-3-methylthiocephem- 4-carboxylate via the corresponding 3-methylthio-3-chloromethylcephern analog and the reaction of said diphenylrnethyl 7p-(2-thienylacetarnino)-3-(1 -methyl-1 H-tetrasol-5-yl)-3-rnethylthiocephem-4-carboxylate with m-chloroperbensoic acid in order to remove methylmercaptan and form a 3-(l-methyl-lH-tetrazol-5-yl)-3-cephem structure via the corresponding 1-oxide. However, the method described by Aoki et al. is not transposable to the preparation of third-generation cephalosporins because the reactants employed affect the amino group, which is present on the thiazole ring and is sensitive thereto. U.S. Pat. No. US04767S52 (1988) discloses a process for the preparation of known 2-oxyiminoacelamido-3-cephem-4-carboxylic acid derivatives, including Cefotaxime and Ceftriaxone, by acylating 7-amino-3-cephem-4-earboxylic acid derivatives already substituted at the 3- position with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothi:a2;ol-4-yl)-2-methoxyiminoacetate, the latter being often referred to as MAEM. As the first step in the process disclosed in that patent, 7-amino-cephalosporanic acid (7-ACA) already suitably substituted at the 3-position is acylated at the 7-position using MAEM as the acylating agent. Thus MAEM has become the standard 5 acylating agent for the preparation of cephalosporins having an oximino group and a 2-aminothiazolyl group in the 7-acylamiclo-side chain. US Patent No. US05317099 describes a process for the synthesis of p-lactam derivatives such as Cefotaxime and Ceftriaxone in which silylated 7-ACA is acylated with acyloxyphosphonium chloride derivative of 2-(2-aminothiazol-4-yl)-2-syn-methoxyimino acetic acid, which in turn is prepared from triphenylphosphine (TPP), hexachloroe thane or carbon tetrachloride and 2-(2-aminothiazol-4-yl)-2-syn-methoxyimino acetic acid. Since, TPP is used as reactant and hence the overall cost becomes high. US Patent No. US050379SS describes a process for the production of cephalosporins, in particular Cefotaxime and Ceftriaxone, in which an activated form of an organic acid, i.e., 2-(2-aminothiazol-4-yl)-2-oxyiminoacetyl sulfitedialkylfonniminium halide hyclrohalide is coupled with a 7-arniriocephalosporanic acid derivative. The compound of 2-(2-aminothiasol-4-yl)-2-oxyiminoacetyl sulfitedialkylfomimirnium halide hyclrohalide was prepared by reacting 2-(2-aminothiacol-4-yl)-2-oximino acetic acid with dimethylformiminium chloride chlorosulfite which in turn was prepared by reacting approximately equimolar quantities of thionyl chloride and dimethylformamicle at room temperature in specific solvents only like benzene or toluene and hence suffers from a limitation. Object of the present invention is to over come the above said problem and provide a simple, very mild reaction condition, shorter time, and cost-effective method for preparation of Cefotaxime acid in pure form. SUMMARY OF THE INVENTION The present invention relates to a simple, efficient and commercially feasible method for the production of a Cefotaxime acid. The process of the 6 invention involves commercially cheaper and readily available raw materials and shorter reaction time and easy isolation process to obtain Cefotaxime acid in pure form. The present invention relates to a method for manufacture of (2)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-l,3-thiazol-4-yl)-2-methoxyiminoacetamido]-8-oxo-5-thia-1 -acabicyclo[4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid). The embodiment provides the production of Cefotaxime acid. The process comprises the reaction of S- (2-benzothiazolyl-2-(2- aminothia3ol-4-yl)-2-methoxyimino thioacetate with 7-Amino-3-cephem-4-carboxylic acid in aqueous tetra hydro furan and organic base triethylamine. Isolation of (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetamido]-S-oxo-5-thia-l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid) with para-toluene sulphonic acid monohydrate. Filter the product with vacuum filtration. Wash the product with acetone. After washing collect the wet cake and dry at 45°C under vacuum. Finally, (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacei;amido]-S-oxo-5-l;hia-l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid) is obtained in pure form. DETAIL DESCRIPTION OF THE INVETNION The present invention relates to a method for manufacture of (Z)-(6R, 7R)-3-(aceto;vymethyl)-7-[2-(2-amino-l,3-thia3ol-4-yl)-2-metho.xyiminoacetamido]- 7 S-oxo-5-thia - l-azabicyelo[4,2,0]oct-2-en-2-carboxyIic acid (Cefotaxime acid).The process of present invention comprises following steps: 1. 7-ACA (7-Amino-3-acetoxymethyl-3-eephem-4-carbo,xylic acid) reacts with MAEM (S- (2-benzothiasolyl)-2-(2-amino-thiazol-4-yl)-2-methoxyimino thioacetate) in presences of aqueous organic solvent and organic base. a) 7-ACA (7-Amino-3-acetoxymethyl-3-cephern-4-carboxylic acid) suspended in a mixture of organic solvent and water, and than cooled the reaction mass between 5°C to 10°C. The organic solvent are ethyl acetate, ether, tetrahydrofuran, N, N-dimethyl foramide, acetone, dioxane, acetonitrile, carbon tetrachloride and mixture thereof. b) Add organic base drop wise with constant stirring within 10 min. to 20 rnin. and than stir the reaction mass for about 15 min. to 45 min. at same temperature. The organic base are trie thy lamine, 2,3-pieoline, 2,4 -picoline, 1,4-dimethyl piperazine, N-ethylpiperidine, N-methyl morpholine, tri methyl aniline, pyridine, dimethyl amino pyridine, N-methyl piperidine, N-rnethyl pyridine, N-ethyl dimethyl aniline, diethyl amine, N-ethyldimethyl amine, diisopropyl ethyl amine, N,N-dimethyl aniline and tributyl amine. c) Add MAEM (S- (2-benzothiazolyl)-2-(2-arnino-thiazol-4-yl)-2-methoxyimino thioacetate) portion wise with constant stirring within. Compound other than MAEM that can react with 7-ACA (7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid) to manufacture Cefotaxime acid are 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-aminothia3ol-4-yl)-2-metho.xyirnino acetate or 2-mercapto-5-phenyl-l/3,4-oxacliazolyl-(Z)-2-(2-aminothiazol-4-yl)-2imethoxyimino acetate can be used. 8 2. Monitor the reaction by high performance liquid chromatography (HPLC) till the unreacted 7-ACA less than 2 %. 3. After completion of reaction, isolate Cefotaxime acid with suitable organic acids. Add organic acid portion wise to the reaction mass at 5°C to 10°C temperature with constant stirring. Stir the reaction mass over night at ambient temperature and than cool it between 5°C and 10°C, stir for 3 hrs. to 5 hrs. at same temperature for complete isolation of product. a) Organic acids used for the isolation of Cefotaxime are para-toluene sulphonic acid monohydrate, methane sulfonic acid, benzene sulfonic acid and hydrochloric acid. 4. After complete isolation, filter the product by vacuum filtration. c Wash the cake with sufficient amount of acetone. After washing collect the wet cake and dry it at about 40°C to 50°C under vacuum up to moisture content less than equal to 2 %. Example: 1 10 gm 7-ACA suspended in a mixture of 45 ml tetrahydrofuran and 5 ml water, and than cooled the reaction mass between 5°C to 10°C. Add 6.40 ml triethylarnine drop wise with constant stirring within 20 min. and than stir the reaction mass for 30 min. to 60 min. at same temperature. Add 16.O8 gm MAEM portion wise with constant stirring within 10 min. Monitor the reaction by HPLC till the unreacted 7-ACA less than 2 %. After completion of reaction, add S.14 gm benzene sulphonic acid portion wise at above temperature with constant stirring. Stir the reaction mass for overnight at ambient temperature and than cool it between 5°C and 10°C, Stir for 3 hrs. 9 to 5 hrs. at same temperature for complete isolation of the product. After complete isolation, filter the product by vacuum filtration. Wash the cake with 50 ml acetone. After washing collect the wet cake and dry it at 45°C under vacuum up to moisture content less than equal to 2 %. Example: 2 25 gm 7-ACA suspended in a mixture of 112.5 ml tetrahydrofuran and 12.5 ml water, and than cooled the reaction mass between 5°C to 10°C. Add 16.0 ml trie thy lamine drop wise with constant stirring within 20 min. and than stir the reaction mass for 30 min. to 60 min. at same temperature. Add 40.21 gni MAEM portion wise with constant stirring. Monitor the reaction by HPLC till the unreacted 7-ACA less than 2 %. After completion of reaction, add 12.36 gm methane sulphonic acid portion wise at above said temperature with constant stirring. Stir the reaction mass for overnight at ambient temperature and than cool it between 5°C and 10°C, Stir for 3 hrs. to 5 hrs. at same temperature for complete isolation of the product. After complete isolation, filter the product by vacuum filtration. Wash the cake with 125 ml acetone. After washing collect the wet cake and dry it at 45°C under vacuum to get the titled product. Example: 3 10 gm 7-ACA are suspended in a mixture of 45 ml tetrahyclrofuran and 5 ml water, and than cooled the reaction mass between 5°C to 10°C. Add 6.40 ml triethylamine drop wise with constant stirring within 20 min. and than stir the reaction mass for 30 min. to 60 min. at same temperature. Add 16.08 gin MAEM portion wise with constant stirring. Monitor the reaction by HPLC till the unreactecl 7-ACA less than 2 %. After completion of reaction, adjust 3.5pH with concentrated hydrochloric acid at above said temperature with constant stirring. Stir the reaction mass for overnight at ambient 10 temperature and than cool it between 5°C and 10°C, Stir for 3 hrs. to 5 hrs. at same temperature for complete isolation of the product. After complete isolation, filter the product by vacuum filtration. Wash the cake with 50 ml acetone. After washing collect the wet cake and dry it at 45°C under vacuum to get the titled product. Example: 4 50 grn 7-ACA are suspended in a mixture of 225 ml tetrahydrofuran and 25 ml water, and than cooled the reaction mass between 5°C to 10°C. Add 25.37 ml N-methyl morpholine drop wise with constant stirring within 20 min, and than stir the reaction mass for 30 min. to 60 min. at same temperature. Add 80.42 gm MAEM portion wise with constant stirring. Monitor the reaction by HPLC till the unreacted 7-ACA less than 2%. After completion of reaction, add 4S.95 gm p-toluene sulphonic acid monohydrate portion wise at above said temperature with constant stirring. Stir the reaction mass for overnight at ambient temperature and than cool it between 5°C and 10°C, Stir for 3 hrs. to 5 hrs. at same temperature for complete isolation of the product. After complete isolation, filter the product by vacuum filtration. Wash the cake with 250 ml acetone. After washing collect the wet cake and dry it at 45°C under vacuum to get the titled product. Example: 5 25 grn 7-ACA and 40.21 gm MAEM are suspended in a mixture of 112.5 ml tetrahydrofuran and 12.5 ml water, and than cooled the reaction mass between 5°C to 10°C. Add 16.0 ml triethylamine drop wise with constant stirring within 20 min. Monitor the reaction by HPLC till the 7-ACA less than 2 % observed. After completion of reaction, add solution of 24.0 grn p-toluene sulphonic acid monohydrate in 30.0 ml acetone is added drop wise 11 at above said temperature with constant stirring. Stir the reaction mass for overnight at ambient temperature and than cool it between 5°C and 10°C, Stir for 3 hrs. to 5 hrs. at same temperature for complete isolation of the product. After complete isolation, filter the product by vacuum filtration. Wash the cake with 125 ml acetone. After washing collect the wet cake and dry it at 45°C under vacuum to get the titled product. Example: 6 100 gm 7-ACA are suspended in a mixture of 450 ml THF and 50ml water, and than cooled the reaction mass between 5°C to 10°C. Add 63.96 ml trie thy lamine drop wise with constant stirring within 20 min. and than stir the reaction mass for 30 min. to 60 min. at same temperature. Acid 160.84 gm MAEM portion wise with constant stirring. Monitor the reaction by HPLC till the 7-ACA less than 2 °o observed. After completion of reaction, add 97.90 gm para -toluene sulphonic acid monohydrate portion wise at above said temperature with constant stirring. Stir the reaction mass for overnight at ambient temperature and than cool it between 5°C and 10°C, Stir for 3 hrs. to 5 hrs. at same temperature for complete isolation of the product. After complete isolation, filter the product by vacuum filtration. Wash the cake with 500 ml acetone. After washing collect the wet cake and dry it at 45°C under vacuum to get the titled product. 12 We claim, 1. A process of manufacturing a compound of (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-l,3-thiazol-4-yl)-2-methoxyiminoacetamido]-S-oxo-5-thia -l-asabicyclo[4,2,0]oct-2-en-2-carboxylic acid the said method comprising: a) Contacting of a compound of the 7-Amino-3-cephern-4-carboxylic acid (7-ACA), suspended in a mixture of organic solvent and water in presence of organic base, with a compound of the S- (2-benzothiazolyl-2-(2- aminothiazol-4-yl)-2-methoxyimino thioacetatle (MAEM); b) Isolation of (Z)-(6R,7R)-3-Acetoxy-rnethyl)-7-(2-arninothiazole-4-yl)-2-methoxyimino)acetoamido)-S-oxo-5-thia-l-aza-bicyclo (4,2,0)oct-2-en-2-carboxylic acid in presence of suitable organic acids. 2. The process of claim 1 wherein step (a), the said ratio of organic solvent and water is about 3 to 5 : 0.3 to 0.5. 3. The process of claim 2, wherein the said organic solvent are ethyl acetate, ether, tetrahydrofuran, N,N-dimethyl foramide, acetone, dioxane, acetonitrile, carbon tetrachloride and mixture thereof. 4. The process of claim 3, wherein the said organic solvent is tetrahydrofuran. 5. The process of claim 1, wherein step (a), the said organic base are triethyl amine, 2,3-pieoline, 2,-1-picoline, 1,4-dimethyl piperazine, N-ethylpipericline, N-methyl morpholine, trimethyl aniline, pyridine, dimethyl amino pyridine, N-methyl piperidine, N-methyl pyridine, N-ethyl dimethyl aniline, diethyl amine, N-ethyldimethyl amine, diisopropyl ethyl amine, N,N-climethyl aniline and tributyl amine. 6. The process of claim 5, wherein the organic base is triethyl amine. 13 7. The process of claim 1, wherein the contact time for step (a), is about 15 mi.n to about 60 min., with stirring and maintaining temperature about -10°C to 30°C. 8. The process of claim 1, wherein step (a), compound other than MAEM are 2-mereapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-aminothiacol-4-yl)-2-methoxyimino acetate or 2-mercapto-5-phenyl-1,3,4-oxadiazolyl-(Z)-2-(2-aminothia3ol-4-yl)-2-methoxyimino acetate can be used. 9. The process of claim 1, wherein step (b), suitable organic acids are para-toluene sulphonic acid monohydrate, methane sulfonic acid, benzene sulfonic acid and hydrochloric acid. 10. The process of claim 1, wherein step (b), the reaction mixture is stirred for over night at ambient temperature and than cooled at about 10°C to about 20°C and stirred for about 1 to 5 hours to get wet cake. 11. The process of claim 10, wherein the slurry is filter, washed and dried. 12. The process of claim 11, wherein wash the wet cake with acetone. 13. The process of claim 11, wherein dry the wet cake at about 40°C to about 50°C. 14. The process of claim 13, wherein dry the wet cake till moisture content is less than 2%. 15. The process of claim 1, where in unreacted 7-Amino-3-cephem-4- carboxylic acid is not more than 2% by HPLC.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
and
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10 and rule 13]
1. Title: A process for the preparation of (Z)-(6R, 7R)-3-(aeetoxymethyl)-7-[2-(2-amino-l,3-thiazol-4-yI)-2-methoxyiminoacetamido]-8-oxo-5-thia-l-azabicyclo [4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid).
Applicant: Claris Lifesciences Limited,
Claris Corporate Headquarters, Nr.Parimal Crossing, Ellisbridge, Ahmedabad - 380 006, Gujarat, India.
The following specification particularly describes the invention and the manner in
which it is to be performed.

DESCRIPTION
Field of Invention :
The present invention relates to an improved process for the production of (Z)-(6R, 7R)-3-(acetoxmethyl)-7-[2-(2-amino-l,3-thiazol-4-yl)-2-rnethoxyiminoacetamido]-S-oxo-5-thia -l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid). The synthesis of Cefotaxime acid comprises the condensation of S-(2-benzothiazoyl)-2-(2-arnino-thaiazol-4-yl)-2-rnethoxyimino thioacetate with 7-amino-3-acetoxyrnethyl-3-cephem-4-carbcoxylic acid in presence of aqueous organic solvent and organic base. Cefotaxime acid is subsequently isolated by organic acid.
BACKGROUND OF THE INVENTION
Cephalosporin: Any of a group of broad-spectrum derived from species of fungi of the genus Cephalosporium and is related to the penicillins in both structure and mode of action but relatively penicillinase-resistant antibiotics. These antibiotics have low toxicity for the host, considering their broad antibacterial spectrum. They have the active nucleus of beta-lactam ring, which results in a variety of antibacterial and pharmacological characteristics when modified mainly by substitution at 3 and 7 positions. Their antibacterial activities result from the inhibition of mucopeptide synthesis in the cell wall. They are widely used to treat gonorrhea, meningitis, pneumococcal, staphylococcal and streptococcal infections. The cephalosporin class of antibiotics is usually divided into generations by their antimicrobial properties. Three generations of cephalosporins are recognised and the fourth has been grouped. Each newer generation of cephalosporins has broader range of activity against Gram-negative organisms but a narrower range of activity against Gram-positive organisms than the
2

preceding generation. The newer agents have much longer half-lives resulting in the decrease of dosing frequency. Accordingly, the third-generation cephalosporins can penetrate into tissues well and thus antibiotic levels are good in various body fluids.
Cefotaxime is a third-generation cephalosporin antibiotics, it has broad-spectrum activity against both Gram-positive and Gram-negative organism. The bactericidal activity of Cefotaxime works by inhibiting bacterial cell wall biosynthesis. Cefotaxime shows high affinity for penicillin-binding proteins (PBP) in the cell wall including PBP lb and PBP III. A positive feature of Cefotaxime is that it displays a resistance to penicillinases and is useful to treat infections that are resistant to penicillin derivatives. Cefotaxime has in vitro activity against a wide range of Gram-positive and Gram-negative organisms. Cefotaxime should be administered by both Intravenous as well as Intramuscular route.
DESCRIPTION OF THE PRIOR ART
Cephalosporin antibiotics inhibit bacteria by interfering with the synthesis of essential structural components of the bacterial cell wall. They are considered as highly effective antibiotics with low toxicity and are used for treating a wide variety of bacterial infections. A number of cephalosporin derivatives have been discovered with increased potency and improved stability. Ochiai et al. (U.S. Patent No. USG409SSSS) described cephem compounds and processes for their preparation. Heyrnes et al. (U.S. Patent No.4,152,432) described 3- aeetoxymethyl-7-(iminoacetamido) cephalosporonic acid derivatives, in particular Cefotaxime, and process for preparing the derivatives.
The "third-generation cephalosporins" generally consist of 3-methyl-3-cephem-4-carboxylic acid derivatives substituted in the 7p-position by an a-
3

(2-aminothia3zol-4-yl)-α-hyclroxyimirnoacetamido group, in which the hydroxy group is free or substituted with an alliyl group, optionally substituted by a carboxy group, and substituted on the methyl group in the 3-position with the residue of a nucleophilic compound.
The above mentioned third-generation cephalosporins have been described for the first time in the published German application DE2556736 (corresponding to U.S. Pat. No. US055S3216) and, principally are compounds encompassed by the general formula A
Formula A

wherein R4 is the residue of a nucleophilic compound and R3 is a hydroxy group which may be protected, including their pharrnaceutically acceptable esters, the respective salts and the relative solvates. Among these third-generation cephalosporins, the 7(β.-[α-(2-aminothiazol-4-yl)-a-hydroxyimino]acetamido-3-methyl-3-cephem-4-carbo.xylic acid derivatives of formula A, in which Rs is methoxy and R4 is a 2-furoylthio group (Ceftiofur), an acetoxy group (Cefotaxime) or a l,2,5,6-tetrahydro-2-methyl-5,6-dio::o-l,2,4-triazin-3-ylthio group (Ceftriaxone) are particularly interesting compounds.
The 7β-[a-(2-aminothiazol-4-yl)-α-hydroxyiminojacetamido-3-methyl-3-cephem-4-carboxylic acid derivatives in which the 3-rnethyl group is substituted with the residue of a nucleophilic compound are prepared
4

according to the general method, described in DE2556736 and U.S. Pat. No US05583216, which comprises introducing the α-(2-aminothiaizol-4-yl)-a-hydroxyiminoacetyl radical, wherein the hydroxy and amino groups are suitably protected, onto the amino group of a 7β -amino-3-methylcephem-4-carboxylic acid in which the methyl group is substituted with the residue of a nucleophilic compound.
Finally, T. Aoki et al. (Tetrahedron 1983, 34/15, 2515-2556 in particular pages 2520-2525) disclose the synthesis of diphenylrnethyl 7β -(2-thienylaceta.rnino)-3-( 1 -methyl- lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate, which involves the preparation of diphenylrnethyl 7β -(2-thienylacetamino)-3-(l-methyl-lH-tetrazol-5-yl)-3-methylthiocephem- 4-carboxylate via the corresponding 3-methylthio-3-chloromethylcephern analog and the reaction of said diphenylrnethyl 7p-(2-thienylacetarnino)-3-(1 -methyl-1 H-tetrasol-5-yl)-3-rnethylthiocephem-4-carboxylate with m-chloroperbensoic acid in order to remove methylmercaptan and form a 3-(l-methyl-lH-tetrazol-5-yl)-3-cephem structure via the corresponding 1-oxide. However, the method described by Aoki et al. is not transposable to the preparation of third-generation cephalosporins because the reactants employed affect the amino group, which is present on the thiazole ring and is sensitive thereto.
U.S. Pat. No. US04767S52 (1988) discloses a process for the preparation of known 2-oxyiminoacelamido-3-cephem-4-carboxylic acid derivatives, including Cefotaxime and Ceftriaxone, by acylating 7-amino-3-cephem-4-earboxylic acid derivatives already substituted at the 3- position with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothi:a2;ol-4-yl)-2-methoxyiminoacetate, the latter being often referred to as MAEM. As the first step in the process disclosed in that patent, 7-amino-cephalosporanic acid (7-ACA) already suitably substituted at the 3-position is acylated at the 7-position using MAEM as the acylating agent. Thus MAEM has become the standard
5

acylating agent for the preparation of cephalosporins having an oximino group and a 2-aminothiazolyl group in the 7-acylamiclo-side chain.
US Patent No. US05317099 describes a process for the synthesis of p-lactam derivatives such as Cefotaxime and Ceftriaxone in which silylated 7-ACA is acylated with acyloxyphosphonium chloride derivative of 2-(2-aminothiazol-4-yl)-2-syn-methoxyimino acetic acid, which in turn is prepared from triphenylphosphine (TPP), hexachloroe thane or carbon tetrachloride and 2-(2-aminothiazol-4-yl)-2-syn-methoxyimino acetic acid. Since, TPP is used as reactant and hence the overall cost becomes high.
US Patent No. US050379SS describes a process for the production of cephalosporins, in particular Cefotaxime and Ceftriaxone, in which an activated form of an organic acid, i.e., 2-(2-aminothiazol-4-yl)-2-oxyiminoacetyl sulfitedialkylfonniminium halide hyclrohalide is coupled with a 7-arniriocephalosporanic acid derivative. The compound of 2-(2-aminothiasol-4-yl)-2-oxyiminoacetyl sulfitedialkylfomimirnium halide hyclrohalide was prepared by reacting 2-(2-aminothiacol-4-yl)-2-oximino acetic acid with dimethylformiminium chloride chlorosulfite which in turn was prepared by reacting approximately equimolar quantities of thionyl chloride and dimethylformamicle at room temperature in specific solvents only like benzene or toluene and hence suffers from a limitation.
Object of the present invention is to over come the above said problem and provide a simple, very mild reaction condition, shorter time, and cost-effective method for preparation of Cefotaxime acid in pure form.
SUMMARY OF THE INVENTION
The present invention relates to a simple, efficient and commercially feasible method for the production of a Cefotaxime acid. The process of the
6

invention involves commercially cheaper and readily available raw materials and shorter reaction time and easy isolation process to obtain Cefotaxime acid in pure form.
The present invention relates to a method for manufacture of (2)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-l,3-thiazol-4-yl)-2-methoxyiminoacetamido]-8-oxo-5-thia-1 -acabicyclo[4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid).

The embodiment provides the production of Cefotaxime acid. The process comprises the reaction of S- (2-benzothiazolyl-2-(2- aminothia3ol-4-yl)-2-methoxyimino thioacetate with 7-Amino-3-cephem-4-carboxylic acid in aqueous tetra hydro furan and organic base triethylamine. Isolation of (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetamido]-S-oxo-5-thia-l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid) with para-toluene sulphonic acid monohydrate. Filter the product with vacuum filtration. Wash the product with acetone. After washing collect the wet cake and dry at 45°C under vacuum. Finally, (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacei;amido]-S-oxo-5-l;hia-l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid) is obtained in pure form.
DETAIL DESCRIPTION OF THE INVETNION
The present invention relates to a method for manufacture of (Z)-(6R, 7R)-3-(aceto;vymethyl)-7-[2-(2-amino-l,3-thia3ol-4-yl)-2-metho.xyiminoacetamido]-
7

S-oxo-5-thia - l-azabicyelo[4,2,0]oct-2-en-2-carboxyIic acid (Cefotaxime acid).The process of present invention comprises following steps:
1. 7-ACA (7-Amino-3-acetoxymethyl-3-eephem-4-carbo,xylic acid) reacts with MAEM (S- (2-benzothiasolyl)-2-(2-amino-thiazol-4-yl)-2-methoxyimino thioacetate) in presences of aqueous organic solvent and organic base.
a) 7-ACA (7-Amino-3-acetoxymethyl-3-cephern-4-carboxylic acid) suspended in a mixture of organic solvent and water, and than cooled the reaction mass between 5°C to 10°C. The organic solvent are ethyl acetate, ether, tetrahydrofuran, N, N-dimethyl foramide, acetone, dioxane, acetonitrile, carbon tetrachloride and mixture thereof.
b) Add organic base drop wise with constant stirring within 10 min. to 20 rnin. and than stir the reaction mass for about 15 min. to 45 min. at same temperature. The organic base are trie thy lamine, 2,3-pieoline, 2,4 -picoline, 1,4-dimethyl piperazine, N-ethylpiperidine, N-methyl morpholine, tri methyl aniline, pyridine, dimethyl amino pyridine, N-methyl piperidine, N-rnethyl pyridine, N-ethyl dimethyl aniline, diethyl amine, N-ethyldimethyl amine, diisopropyl ethyl amine, N,N-dimethyl aniline and tributyl amine.
c) Add MAEM (S- (2-benzothiazolyl)-2-(2-arnino-thiazol-4-yl)-2-methoxyimino thioacetate) portion wise with constant stirring within. Compound other than MAEM that can react with 7-ACA (7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid) to manufacture Cefotaxime acid are 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-aminothia3ol-4-yl)-2-metho.xyirnino acetate or 2-mercapto-5-phenyl-l/3,4-oxacliazolyl-(Z)-2-(2-aminothiazol-4-yl)-2imethoxyimino acetate can be used.
8

2. Monitor the reaction by high performance liquid chromatography (HPLC) till the unreacted 7-ACA less than 2 %.
3. After completion of reaction, isolate Cefotaxime acid with suitable organic acids.
Add organic acid portion wise to the reaction mass at 5°C to 10°C temperature with constant stirring. Stir the reaction mass over night at ambient temperature and than cool it between 5°C and 10°C, stir for 3 hrs. to 5 hrs. at same temperature for complete isolation of product.
a) Organic acids used for the isolation of Cefotaxime are para-toluene sulphonic acid monohydrate, methane sulfonic acid, benzene sulfonic acid and hydrochloric acid.
4. After complete isolation, filter the product by vacuum filtration.

c

Wash the cake with sufficient amount of acetone. After washing collect the wet cake and dry it at about 40°C to 50°C under vacuum up to moisture content less than equal to 2 %.

Example: 1
10 gm 7-ACA suspended in a mixture of 45 ml tetrahydrofuran and 5 ml water, and than cooled the reaction mass between 5°C to 10°C. Add 6.40 ml triethylarnine drop wise with constant stirring within 20 min. and than stir the reaction mass for 30 min. to 60 min. at same temperature. Add 16.O8 gm MAEM portion wise with constant stirring within 10 min. Monitor the reaction by HPLC till the unreacted 7-ACA less than 2 %. After completion of reaction, add S.14 gm benzene sulphonic acid portion wise at above temperature with constant stirring. Stir the reaction mass for overnight at ambient temperature and than cool it between 5°C and 10°C, Stir for 3 hrs.
9

to 5 hrs. at same temperature for complete isolation of the product. After complete isolation, filter the product by vacuum filtration. Wash the cake with 50 ml acetone. After washing collect the wet cake and dry it at 45°C under vacuum up to moisture content less than equal to 2 %.
Example: 2
25 gm 7-ACA suspended in a mixture of 112.5 ml tetrahydrofuran and 12.5 ml water, and than cooled the reaction mass between 5°C to 10°C. Add 16.0 ml trie thy lamine drop wise with constant stirring within 20 min. and than stir the reaction mass for 30 min. to 60 min. at same temperature. Add 40.21 gni MAEM portion wise with constant stirring. Monitor the reaction by HPLC till the unreacted 7-ACA less than 2 %. After completion of reaction, add 12.36 gm methane sulphonic acid portion wise at above said temperature with constant stirring. Stir the reaction mass for overnight at ambient temperature and than cool it between 5°C and 10°C, Stir for 3 hrs. to 5 hrs. at same temperature for complete isolation of the product. After complete isolation, filter the product by vacuum filtration. Wash the cake with 125 ml acetone. After washing collect the wet cake and dry it at 45°C under vacuum to get the titled product.
Example: 3
10 gm 7-ACA are suspended in a mixture of 45 ml tetrahyclrofuran and 5 ml water, and than cooled the reaction mass between 5°C to 10°C. Add 6.40 ml triethylamine drop wise with constant stirring within 20 min. and than stir the reaction mass for 30 min. to 60 min. at same temperature. Add 16.08 gin MAEM portion wise with constant stirring. Monitor the reaction by HPLC till the unreactecl 7-ACA less than 2 %. After completion of reaction, adjust 3.5pH with concentrated hydrochloric acid at above said temperature with constant stirring. Stir the reaction mass for overnight at ambient
10

temperature and than cool it between 5°C and 10°C, Stir for 3 hrs. to 5 hrs. at same temperature for complete isolation of the product. After complete isolation, filter the product by vacuum filtration. Wash the cake with 50 ml acetone. After washing collect the wet cake and dry it at 45°C under vacuum to get the titled product.
Example: 4
50 grn 7-ACA are suspended in a mixture of 225 ml tetrahydrofuran and 25 ml water, and than cooled the reaction mass between 5°C to 10°C. Add 25.37 ml N-methyl morpholine drop wise with constant stirring within 20 min, and than stir the reaction mass for 30 min. to 60 min. at same temperature. Add 80.42 gm MAEM portion wise with constant stirring. Monitor the reaction by HPLC till the unreacted 7-ACA less than 2%. After completion of reaction, add 4S.95 gm p-toluene sulphonic acid monohydrate portion wise at above said temperature with constant stirring. Stir the reaction mass for overnight at ambient temperature and than cool it between 5°C and 10°C, Stir for 3 hrs. to 5 hrs. at same temperature for complete isolation of the product. After complete isolation, filter the product by vacuum filtration. Wash the cake with 250 ml acetone. After washing collect the wet cake and dry it at 45°C under vacuum to get the titled product.
Example: 5
25 grn 7-ACA and 40.21 gm MAEM are suspended in a mixture of 112.5 ml tetrahydrofuran and 12.5 ml water, and than cooled the reaction mass between 5°C to 10°C. Add 16.0 ml triethylamine drop wise with constant stirring within 20 min. Monitor the reaction by HPLC till the 7-ACA less than 2 % observed. After completion of reaction, add solution of 24.0 grn p-toluene sulphonic acid monohydrate in 30.0 ml acetone is added drop wise
11

at above said temperature with constant stirring. Stir the reaction mass for overnight at ambient temperature and than cool it between 5°C and 10°C, Stir for 3 hrs. to 5 hrs. at same temperature for complete isolation of the product. After complete isolation, filter the product by vacuum filtration. Wash the cake with 125 ml acetone. After washing collect the wet cake and dry it at 45°C under vacuum to get the titled product.
Example: 6
100 gm 7-ACA are suspended in a mixture of 450 ml THF and 50ml water, and than cooled the reaction mass between 5°C to 10°C. Add 63.96 ml trie thy lamine drop wise with constant stirring within 20 min. and than stir the reaction mass for 30 min. to 60 min. at same temperature. Acid 160.84 gm MAEM portion wise with constant stirring. Monitor the reaction by HPLC till the 7-ACA less than 2 °o observed. After completion of reaction, add 97.90 gm para -toluene sulphonic acid monohydrate portion wise at above said temperature with constant stirring. Stir the reaction mass for overnight at ambient temperature and than cool it between 5°C and 10°C, Stir for 3 hrs. to 5 hrs. at same temperature for complete isolation of the product. After complete isolation, filter the product by vacuum filtration. Wash the cake with 500 ml acetone. After washing collect the wet cake and dry it at 45°C under vacuum to get the titled product.
12

We claim,
1. A process of manufacturing a compound of (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-l,3-thiazol-4-yl)-2-methoxyiminoacetamido]-S-oxo-5-thia -l-asabicyclo[4,2,0]oct-2-en-2-carboxylic acid the said method comprising:
a) Contacting of a compound of the 7-Amino-3-cephern-4-carboxylic acid (7-ACA), suspended in a mixture of organic solvent and water in presence of organic base, with a compound of the S- (2-benzothiazolyl-2-(2- aminothiazol-4-yl)-2-methoxyimino thioacetatle (MAEM);
b) Isolation of (Z)-(6R,7R)-3-Acetoxy-rnethyl)-7-(2-arninothiazole-4-yl)-2-methoxyimino)acetoamido)-S-oxo-5-thia-l-aza-bicyclo (4,2,0)oct-2-en-2-carboxylic acid in presence of suitable organic acids.

2. The process of claim 1 wherein step (a), the said ratio of organic solvent and water is about 3 to 5 : 0.3 to 0.5.
3. The process of claim 2, wherein the said organic solvent are ethyl acetate, ether, tetrahydrofuran, N,N-dimethyl foramide, acetone, dioxane, acetonitrile, carbon tetrachloride and mixture thereof.
4. The process of claim 3, wherein the said organic solvent is tetrahydrofuran.
5. The process of claim 1, wherein step (a), the said organic base are triethyl amine, 2,3-pieoline, 2,-1-picoline, 1,4-dimethyl piperazine, N-ethylpipericline, N-methyl morpholine, trimethyl aniline, pyridine, dimethyl amino pyridine, N-methyl piperidine, N-methyl pyridine, N-ethyl dimethyl aniline, diethyl amine, N-ethyldimethyl amine, diisopropyl ethyl amine, N,N-climethyl aniline and tributyl amine.
6. The process of claim 5, wherein the organic base is triethyl amine.
13

7. The process of claim 1, wherein the contact time for step (a), is about 15 mi.n to about 60 min., with stirring and maintaining temperature about -10°C to 30°C.
8. The process of claim 1, wherein step (a), compound other than MAEM are 2-mereapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-aminothiacol-4-yl)-2-methoxyimino acetate or 2-mercapto-5-phenyl-1,3,4-oxadiazolyl-(Z)-2-(2-aminothia3ol-4-yl)-2-methoxyimino acetate can be used.
9. The process of claim 1, wherein step (b), suitable organic acids are para-toluene sulphonic acid monohydrate, methane sulfonic acid, benzene sulfonic acid and hydrochloric acid.

10. The process of claim 1, wherein step (b), the reaction mixture is stirred for over night at ambient temperature and than cooled at about 10°C to about 20°C and stirred for about 1 to 5 hours to get wet cake.
11. The process of claim 10, wherein the slurry is filter, washed and dried.
12. The process of claim 11, wherein wash the wet cake with acetone.

13. The process of claim 11, wherein dry the wet cake at about 40°C to about 50°C.
14. The process of claim 13, wherein dry the wet cake till moisture content is less than 2%.
15. The process of claim 1, where in unreacted 7-Amino-3-cephem-4-
carboxylic acid is not more than 2% by HPLC.

Documents:

1136-MUM-2008-ABSTRACT(3-6-2011).pdf

1136-mum-2008-abstract.doc

1136-mum-2008-abstract.pdf

1136-mum-2008-assignment(28-5-2008).pdf

1136-MUM-2008-CLAIMS(AMENDED)-(3-6-2011).pdf

1136-MUM-2008-CLAIMS(AMENDED)-(30-7-2012).pdf

1136-mum-2008-claims.doc

1136-mum-2008-claims.pdf

1136-MUM-2008-CORRESPONDENCE 10-7-2008.pdf

1136-MUM-2008-CORRESPONDENCE(21-10-2011).pdf

1136-mum-2008-correspondence.pdf

1136-mum-2008-description(complete).doc

1136-mum-2008-description(complete).pdf

1136-mum-2008-form 1.pdf

1136-MUM-2008-FORM 18 4-8-2008.pdf

1136-MUM-2008-FORM 2(TITLE PAGE)-(3-6-2011).pdf

1136-mum-2008-form 2(title page).pdf

1136-mum-2008-form 2.doc

1136-mum-2008-form 2.pdf

1136-mum-2008-form 3.pdf

1136-mum-2008-form 5.pdf

1136-mum-2008-form 9 (4-8-2008).pdf

1136-mum-2008-power of attorney.pdf

1136-MUM-2008-REPLY TO EXAMINATION REPORT(3-6-2011).pdf

1136-MUM-2008-REPLY TO HEARING(30-7-2012).pdf

1136-MUM-2008-SPECIFICATION(AMENDED)-(3-6-2011).pdf

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Patent Number

254005

Indian Patent Application Number

1136/MUM/2008

PG Journal Number

37/2012

Publication Date

14-Sep-2012

Grant Date

12-Sep-2012

Date of Filing

28-May-2008

Name of Patentee

CLARIS LIFESCIENCES LIMITED

Applicant Address

CLARIS LIFESCIENCES LTD. CLARIS CORPORATE HEADQUARTERS, NR. PARIMAL CROSSING, ELLISBRIDGE, AHMEDABAD

Inventors:

#	Inventor's Name	Inventor's Address
1	MAJMUDAR CHETAN S.	CLARIS LIFESCIENCES LTD. CLARIS CORPORATE HEADQUARTERS, NR. PARIMAL CROSSING, ELLISBRIDGE, AHMEDABAD-380006.
2	CHAKRAVARTY PRADEEP	CLARIS LIFESCIENCES LTD. CLARIS CORPORATE HEADQUARTERS, NR. PARIMAL CROSSING, ELLISBRIDGE, AHMEDABAD-380006.
3	ASHARA MAUSAMI JAYESHKUMAR	CLARIS LIFESCIENCES LTD. CLARIS CORPORATE HEADQUARTERS, NR. PARIMAL CROSSING, ELLISBRIDGE, AHMEDABAD-380006.
4	PATEL KETANKUMAR ARVINDBHAI	CLARIS LIFESCIENCES LTD. CLARIS CORPORATE HEADQUARTERS, NR. PARIMAL CROSSING, ELLISBRIDGE, AHMEDABAD-380006.

PCT International Classification Number

C07D501/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA