FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
and
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10 and rule I31
1. Title: A process for the preparation of Cefotax|me acid.

2. Applicant:

Claris Lifesciences Limited,
Claris Corporate Headquarters,
Nr.Parimal Crossing,
Eilisbridge, Ahmedabad-380006, 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 process for the production of Cefotaxime acid by condensation of 7-amino-3-acetoxymethyl-3-cephem-4- carboxylic acid in dichloromethane and base with S-(2~be^_Zothiazoyl}-2-(2-aminothiazol-4-yl)-2-methoxyimino thioacetate. Cefotaxime acid is subsequently isolated by organic acid.
BACKGROUND OF THE INVENTION
The invention relates to a process for the production of Cefotaxime acid of fiyrcnuia-?

Formula-I Cefotaxime acid is "third-generation cephalosporins" consist of 3-methyl-3-cephem-4-carboxylic acid derivatives substituted in the 7p-position by an a-(2-aminothiazol-4-yl)-a-hydroxyiminoacetamido group, in which the hydroxy group is free or substituted with an alkyl group, optionally substituted by a carboxy group, and substituted on the methyl group in die 3-position with the residue of a nucleophilic compound.
According to processes known in the production of Cefotaxime acid in which amine group may be introduced of the side chain into 7-ACA of formula-II.
2


HOO
Formula-II The best known method for introduction of the side chain into 7-ACA is the reaction with a reactive thioester, i.e. S- (2-benzothiazoIyl-2-(2-aminothiazol-4-yl)-2-methoxyimino thioacetate (MAEM) of formula-Ill

US 4767852 discloses a process for the preparation of known 2-oxyiminoacetamido-3-cephem-4-carboxylic acid derivatives, including Cefotaxime and Ceftriaxone, by acylating 7-amino-3-cephem-4- carboxylic acid derivatives already substituted at the 3- position with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothia2ol-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 in dichloromethane. Thus, MAEM has become the standard acylating agent for the preparation of cephalosporins having an oximino group and a 2-aminothiazolyl group in the 7-acylamido-side chain.
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US 5317099 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), hexachloroethane 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 5037988 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 sulfitedialkylformiminium halide hydrohalide is coupled with a 7-aminocephalosporanic acid derivative. The compound of 2-(2-aminothiazol-4-yl)-2-oxyiminoacetyl sulfitedialkylformiminium halide hydrohalide was prepared by reacting 2~(2-aminothiazol-4-yl)-2-oximino acetic acid with dimethylformiminium chloride chlorosulfite which in turn was prepared by reacting approximately equimolar quantities of thionyl chloride and dimethylformamide 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 invention involves commercially cheaper and readily available raw materials and shorter reaction time and easy isolation process to obtain Cefotaxime acid in pure form.
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The present invention relates to a method for manufacture of (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-l,3-thiazol-4-yl)-2-methoxyiminoacetamido]-8-oxo-5-thia-l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid). The compound of formula 1 represent a known class of valuable cephalosporin antibiotic disclosed in numerous patents and publications.
0—ChL
N

Formula-I The embodiment provides the production of Cefotaxime acid. The process comprises the reaction of S- (2-benzothiazolyl-2-(2- aminothiazol-4-yl)-2-methoxyimino thioacetate with 7-Amino-3-cephem-4-carboxylic acid in dichloromethane and organic base triethylamine. Isolation of (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-l)3-thiazol~4-yl)-2-methoxyiminoacetamido]-8-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 water. After washing collect the wet cake and dry at 45°C under vacuum. Finally, (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-l,3-thiazol~4-yl)-2-methoxyiminoacetamido]-8-oxo-5-thia-l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid) is obtained in pure form.
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DETAIL DESCRIPTION OF THE INVETNION

The present invention provides a method for manufacture of (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-arnino-l,3-thiazol-4-yl)-2-methoxyiminoacetarnido]-8-oxo-5-thia -l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid (Cefotaxime acid) of formula-I
HoN
^
0—CH3
0
HO' Formula-I by reacting 7-ACA (7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid) of formula-II reacts with MAEM (S- (2-benzothiazolyl)-2-(2-amino-thiazol-4-yl)-2-methoxyimino thioacetate) of formula-Ill in dichloromethane. The process of the invention comprises:
1. 7-ACA (7-Ammo-3-acetoxymethyl-3-cephem-4-carboxylic acid) is acylated with MAEM (S- (2-benzothiazolyl)-2-(2-amino-thiazol-4-yl)-2-methoxyimino thioacetate) in presences of dichloromethane and organic base. 7-ACA (7-Amino-3-acetoxymethyl-3-cephern-4-carboxylic acid) suspended in dichloromethane, and than cooled the reaction mass between 5°C to 10°C. Add organic base drop wise with constant stirring within 10 min. to 20 min. and than stir the reaction mass for about 15 min. to 45 min. at same temperature. The organic base are triethylamine, 2,3-picoline, 2,4 -picoline, 1,4-dimethyl piperazine, N-ethylpiperidine, N-methyl morpholine, tri methyl aniline, pyridine, dimethyl amino pyridine, N-methyl piperidine, N-methyl
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pyridine, N-ethyl dimethyl aniline, diethyl amine, N-ethyldimethyl amine, diisopropyl ethyl amine, N,N-dimethyl aniline and tributyl amine. Add MAEM (S- (2-benzothiazolyl)-2-(2-ammo-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-l,3,4-thiadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate or 2-mercapto-5-phenyl-l)3,4-oxadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate can be used. Monitor the reaction by high performance liquid chromatography (HPLC) till the unreacted 7-ACA less than 2 %.
2. After completion of reaction, the mixture was extracted with water. The combined both extracted aqueous layer and back wash with dichloromethane. Separate the aqueous layer.
3. Collect aqueous layer and adjust temperature and than add sodium hydrosulphite, EDTA and charcoal into aqueous solution. Aqueous layer is subjected to filtration.
4. After filtration, isolate Cefotaxime acid with suitable organic acids. Add organic acid portion wise to the reaction mass at 5°C to 10DC 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. Organic acids used for the isolation of Cefotaxime are para-toluene sulphonic acid monohydrate, methane sulfonic acid, benzene sulfonic acid and hydrochloric acid. After complete isolation, filter the product by vacuum filtration. 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.
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Example: 1
A suspension of 100 gm 7-ACA in 1700 ml dichloromethane, was chilled to 0°C to 15°C and 63.96 ml of triethylamine were added with constant stirring, and than reaction mass stir for 30 min at same temperature. Add 160.84 gm MAEM was added portion wise with stirring. Monitor reaction by HPLC up to complete reaction. After completion of Reaction, the mixture was extracted with 900 ml of water. Collect aqueous layer and back wash with 700 ml dichloromethane. Separate the aqueous layer and than add Charcoal into aqueous solution. Maintain degassing under vacuum at same temperature. Filter, and cooled it up to between 15°C. Add 97.90 gm p-Toluene sulphonic acid monohydrate in to the reaction mass with control addition and stirring at same temperature. Stir for 2 hrs at same temperature. After maintaining the temperature stir the reaction mass at ambient temperature for overnight and than cool for completed isolation. Filter and wash the product with Water. After washing collect the wet cake and dry it.
Example: 2
A suspension of 10 gm 7-ACA in 170 ml dichloromethane, was chilled to 0°C to 15°C and 6.4 ml of triethylamine were added with constant stirring, and than reaction mass stir for 30 min at same temperature. Add 16.08 gm MAEM was added portion wise with stirring. Monitor reaction by HPLC up to complete reaction. After completion of Reaction, the mixture was extracted with 90 ml of water. Collect aqueous layer and back wash with 70 ml dichloromethane. Separate the aqueous layer and than add Charcoal into aqueous solution. Maintaindegassing under vacuum at same temperature. Filter and cooled it up to between 15°C. Add 8.14 gm Benzene sulphonic acid
8

in to the reaction mass with control addition and stirring at same temperature. Stir for 2 hrs at same temperature. After maintaining the temperature stir the reaction mass at ambient temperature for overnight and than cool for completed isolation. Filter and wash the product with Water. After washing collect the wet cake and dry it.
Example: 3
A suspension of 50 gm 7-ACA in 850 ml dichloromethane, was chilled to 0°C to 15°C and 25.37 ml of N-methyl morpholine were added with constant stirring, and than reaction mass stir for 30 min at same temperature. Add 80.42 gm MAEM was added portion wise with stirring. Monitor reaction by HPLC up to complete reaction. After completion of Reaction, the mixture was extracted with 450 ml of water. Collect aqueous layer and back wash with 350 ml dichloromethane. Separate the aqueous layer and than add Charcoal into aqueous solution. Maintain degassing under vacuum at same temperature. Filter and cooled it up to between 15°C. Add 48.95 gm p-Toluene sulphonic acid monohydrate in to the reaction mass with control addition and stirring at same temperature. Stir for 2 hrs at same temperature. After maintaining the temperature stir the reaction mass at ambient temperature for overnight and than cool for completed isolation. Filter and wash the product with Water. After washing collect the wet cake and dry it.
Example^ 4
A suspension of 25 gm 7-ACA in 425 ml dichloromethane, was chilled to 0°C to 15DC and 16 ml of triethylamine were added with constant stirring, and than reaction mass stir for 30 min at same temperature. Add 40.21 gm MAEM
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was added portion wise with stirring. Monitor reaction by HPLC up to complete reaction. After completion of Reaction, the mixture was extracted with 900 ml of water. Collect aqueous layer and back wash with 175 ml dichloromethane. Separate the aqueous layer and than add Charcoal into aqueous solution. Maintain degassing under vacuum at same temperature. Filter and cooled it up to between 15°C. Add 12.36 gm Methane sulphonic acid in to the reaction mass with control addition and stirring at same temperature. Stir for 2 hrs at same temperature. After maintaining the temperature stir the reaction mass at ambient temperature for overnight and than cool for completed isolation. Filter and wash the product with Water. After washing collect the wet cake and dry it.
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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]-8-oxo-5-thia -l-azabicyclo[4,2,0]oct-2-en-2 carboxylic acid formula I the said methocl comprising:

H5N
o—CH3

Formula I
a) Contacting of a compound of the 7-Amino-3-cephem-4-carboxylic acid (7-ACA) formula II, suspended in dichloromethane in presence of organic base, with a compound of the S- (2-benzothiazolyl-2-(2- aminothiazol-4-yl)-2-methoxyimino thioacetate (MAEM) formula III;


H,N
CH, + H2N
HO" ^O

Formula II

Formula III

b) Extraction of the aqueous layer;
c) Isolation of (Z)-(6R,7R)-3-Acetoxy-m.ethyl)-7-(2-aminothiazole-4-yl)-2-methoxyimino)acetoamido)-8-0xo-5-thia-l-aza-bicyclo (4,2,0)oct-2-en-2-carboxylic acid in presence of suitable acids.
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2. The process of claim 1, wherein step (a), the said organic base are triethy] amine, 2,3-picoline, 2,4-picoline, 1,4-dimethy] piperazine, N-ethylpiperidine, N-methyl morpholine, trimethyl aniline, pyridine, dimethyl amino pyridine, N-methyl piperidine, N-methyl pyridine, N-ethy] dimethyl aniline, diethyl amine, N-ethyldimethyl amine, diisopropyl ethyl amine, N,N-dimethyl aniline and tributyl amine.
3. The process of claim 1, wherein step (a), compound other than MAEM are 2-mercapto-5-methyl-l,3,4-thiadia2olyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate or 2-mercapto-5-phenyl-l,3,4-oxadiazolyl-(Z)-2-(2-aminot±riazol-4-yl)-2-methoxyimino acetate can be used.
4. The process of claim 1, wherein step (d), suitable acids are para-toluene sulphonic acid monohydrate, methane sulfonic acid, benzene sulfonic acid and hydrochloric acid.
5. The process of claim I, wherein step (dj, 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
t cake.
6. The process of claim 1, where in unreacted 7~Amino-3-cephem-4-
carboxylic acid is not more than 2% by HPLC.
DATE and SIGNATURE
Date : 8th November 2008
Signature : A A /\ \j
Name : ChetanjS. Majmudar
Designation: Director
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