NZ314377A - Preparation of cephalosporin antibiotics - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 314377 s New Zealand No. 314377 International No. PCT/ TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 01.05.1996;18.03.1996; Complete Specification Filed: 10.03.1997 Classification:^) C07D501/06 Publication date: 19 December 1997 Journal No.: 1423 NO DRAWINGS NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: Process for producing cephalosporin antibiotics Name, address and nationality of applicant(s) as in international application form: RANBAXY LABORATORIES LIMITED, an Indian company of 19, Nehru Place, New Delhi 110 019, India 31437/ PATENTS FORM NO. Fee No. 1 & 4: $340.00 PATENTS ACT 1953 COMPLETE SPECIFICATION % % PROCESS FOR PRODUCING CEPHALOSPORIN ANTIBIOTICS WE RANBAXY LABORATORIES LIMITED, an Indian company of 19, Nehru Place, New Delhi 110 019, INDIA hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed to be particularly described in and by the following statement: 1 (Followed by Page 1 A) 314377 3542-29.6 PROCESS FOR PRODUCING CEPHALOSPORIN ANTIBIOTICS ? Inventors: 1) Jag Mohan Khanna 2) Vijay Kumar Handa 3) Ramesh Dandala 4) Ram Chander Aryan BACKGROUND of the invention The present invention relates to a new process for the preparation of t antibiotic substances belonging to the cephalosporin class of compounds. More specifically, the present invention relates to a new process for the preparation of cefotaxime, cefetamet, and ceftriaxone sodium. The latter compounds belong to a known class of valuable cephalosporanic antibiotics disclosed, for example, in U.S. 4,098,888 (1978) as well as numerous other patents and other publications. ' This class of antibiotics is characterized by the presence of an oximino group and a 2-aminothiazolyl heterocyclic ring in the 7-acylamido side-chain attached to the cephalosporin nucleus. This class of compounds is also characterized by suitable substituents at the 3-position of the cephalosporin nucleus. It is known that the oximino group in the 7-acylamido side-chain may have the syn or anti configuration, but that the syn isomers have higher antibiotic activity. See, e.g., U.S. 4,152,432 (1979) and U.S. 4,224,371 (1980).

Conventionally, this class of compounds is prepared by first introducing the suitable substituent into the 3-position of the cephalosporin nucleus, and then attaching the suitable substituent to the nitrogen in the 7-position. Thus, U.S. 4,767,852 (1988) discloses a process 1A 314377 production of known 2-oximinoacetamido-3-cephem-4-carboxylic acid derivatives, including cefotaxime and ceftriaxone, by acyiating 7-amino-3-cephem-4-carboxylic acid derivatives already substituted at the 3-position 2* with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate, the latter often being referred to as MAEM. Similarly, U.S. 5,026,843 (1991) discloses a process for preparing ceftriaxone disodium salt hemiheptahydrate. As the first step in the process disclosed in that patent, 7-amino-cephalosporanic acid (7-AC A) already suitably substituted at the 3-position is acylated at the 7-position using MAEM as the acyiating agent. Thus, MAEM has become the standard acyiating agent for the preparation of cephalosporins having an oximino group and a 2-aminothioazolyl group in the 7-acylamido side-chain.

However, there are certain disadvantages to using MAEM as the acyiating agent. In particular, a by-product of this reaction is the toxic compound 2-mercaptobenzothiazole. See, e.g.. Chemical Abstracts 111. 19243p (1989). Therefore, there has been an ongoing search for new acyiating agents which are capable of introducing the 2-aminothiazolyi group as part of the 7-acylamido side-chain in good yield, but without producing this toxic by-product.

In Tetrahedron Letters 31. 6481 (1990), Walker, D.Q., reports the use of certain thioesters, including 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2)-tritylaminothiazol-4-yl)-2-methoxyiminoacetateand2-mercapto-5-methyl -1,3,4-thiadiazoly!-(Z)-2-(2-ami no thiazo l-4-y I) - 2-methoxyiminoacetate, as acyiating agents in the synthesis of cefe 2 314377 sulfate. Yields are reported to be in the range of 54-73% when using the latter thioester, which are far below the yields of 85-97% reported for the production of cefotaxime and ceftriaxone when using MAEM as the acyiating agent. See, e.g.. Examples 1 and 3 of U.S. 4,767,852 and the Example of U.S. 5,026,843.

SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a new process for producing cephalosporin antibiotics, specifically cefotaxime, cefetamet and ceftriaxone sodium of high purity and in good yield.

According to the present invention syn isomers of the formula I R, is hydrogen or a carboxy protecting group such as pivaloyloxymethyl, and 314377 R2 is acetoxymethyl, methyl, or (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thiomethyl, * *» or a pharmaceutically acceptable salt form thereof are prepared by reacting 2-mercapto-5-methyl-1,3,4~thiadiazolyl-{Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate of formula II with cephalosporins of formula III in which R, and R2 are as defined above. 3*4*77 Particularly preferred compounds produced by the inventive process are syn R2 is acetoxymethyl (cefotaxime), R2 is methyl (cefetamet), or , R2 is (2f5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thiomethyl (ceftriaxone).

The present invention provides a method by which the syn isomers of the previously mentioned cephalosporins may be obtained in high purity and in good yield without the necessity for protecting the amino group of the' acyiating 8gent. Additionally, yields are comparable to those obtained when using MAEM as the acyiating agent, but without the production of the toxic by-product 2-mercaptobenzothiazole.

The cephalosporins produced by the present process are of great therapeutical interest due to their effective antibacterial activity and are useful in the treatment of several infections.

The process is suitably carried out in an aqueous medium at a temperature of -5 to + 20°C in the presence of suitable organic solvents, such as, 314377 tetrahydrofuran, N,N-dimethylacetamide,N,N-dimethylformamide,dioxane, and suitable mixtures thereof, or in an inert organic solvent, such as, chlorinated hydrocarbons, ethyl acetate or ether. Preferably, the reaction is carried out in the presence of tetrahydrofuran and N,N-dimethylacetamide. Desirably, the reaction is also carried out in the presence of a tertiary amine such as triethylamine, N-methylpiperidine, pyridine, 1,8-diazabicycloundecene, N-methylmorpholine, 4-dimethylaminopyridine, or mixtures thereof.

The following examples illustrate the inventive process.

EXAMPLE 1 3-Acetoxymethyl-7-l(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylic acid (Cefotaxime).

A mixture of tetrahydrofuran (89 ml), water (89 ml) and N,N-dimethylacetamide (14 ml) was stirred under nitrogen atmosphere and at 0-5 °C, 7-aminocephalosporanic acid (8.16g) was added followed by 2-mercapto-5-methyl-1,3,4-thiadiozolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate (11.34g). Triethylamine was added to the stirred reaction mixture to maintain the pH between 7-8. The gradual disappearance of 7-aminocephalosporanic acid was monitored using HPLC.

After 3 hours of stirring, the reaction mixture was extracted with methylene chloride and the aqueous layer was treated with activated carbon. 6 v * * i, •' V s 314377 Isopropyl alcohol (75 ml) was then added to the filtrate and the contents were acidified at 0-5°C with 2N HCI to pH 2.8-3.0. The resulting precipitate was filtered and washed successively with water and isopropyl alcohol, and then dried under reduced pressure to obtain cefotaxime of high purity.

Yield: 13.3 gm (97.5% of theoretical yield) example? 3-Methyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylic acid (Cefetamet).

A mixture of tetrahydrofuran (238 ml), water (200 ml) and N,N~dimethylacetamide (30 ml) was cooled to 0 - 10°C under nitrogen atmosphere. 7-Amino-3-desacetoxycephalosporanic acid (21.7 g) was added followed by 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate (37.8 g). Triethylamine was added to maintain the pH between 6.8 - 8.5 and when the amount of 7-. amino-3-desacetoxycephalosporanic acid was less than 0.5%, water was added. The pH was adjusted to 6.0 - 6.4- by adding a few drops of acetic acid. Methylene chloride was then added. The aqueous layer was separated, acidified to pH 2.8 - 3.5 with 2N HCI (at 3-5°C), and the resulting precipitate was filtered. It was dried under reduced pressure at 40°C to obtain 35.7g of cefetamet of 99% purity.

Yield: 35.7g (88.5% of theoretical yield) 31437/ examptf 3 7-[[2-(2-Aminothiazol-4-yl)-2-syn-methoxytmino]acetamido]-3-[[2,5-dihydro- 6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thio]methyl]-3-cephem-4-carboxylic acid disodium salt hemiheptahydrate (Ceftriaxone sodium).

To a solution of tetrahydrofuran (56 ml), water (29.68 ml), and N,N-dimethylacetamide (11.87 ml) at 0 - 5°C, under nitrogen atmosphere, 7-amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thio]methyll-3-cephem-4-carboxylic acid (7.42g) was added followed by 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate (7.56 g). Triethylamine (4.04 g) was added and the mixture was stirred at 18-20°C while maintaining the pH between 7-8 for 3 to 4 hours. Methylene chloride was added and the aqueous layer was separated. Thereafter, a solution of sodium 2-ethylhexanoate (11.62 g) in acetone was added to the aqueous layer at 18-20°C and the reaction mixture was stirred for 1 hour to get crystals of ceftriaxone sodium. More acetone was & jded slowly to complete crystallization and the product was filtered and washed with acetone. The product thus obtained was dried under reduced pressure to give substantially pure ceftriaxone sodium. Yield: 12 g (90% of theoretical yield) example 4 3-Acetoxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino) acetamido]-3-cephem-4-carboxylic acid (Cefotaxime)2,2'-Dithio-b< 8 31437 7 methyl-1,3,4-thiadiazole (48.09g) and (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (23.38 g) were suspended in tetrahydrofuran (297 ml) and triphenylphosphine (48.09) was added at 20-25°C. This mixture was stirred for half an hour to generate 2-mercapto-5-methyl-1,3,4-thiadiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate in solution. Thereafter, the reaction mixture was cooled to 3-5 °C, diluted with N,N-dimethylacetamide (46.8 ml), water (297 ml) and 7-aminocephalosporanic acid (27.2 g) was added, followed by triethylamine addition in 20 mjn. The reaction was continued for 3-4 hours at 3-5 °C. Thereafter, acetic acid (18 g) and water (100 ml) were added and the aqueous layer was thoroughly extracted with methylene chloride to remove tetrahydrofuran and other byproducts. The aqueous phase containing triethylamine salt of cefotaxime acid was mixed with excess isopropyl alcohol (250 ml) and acidified to pH 2.80 at 0-5°C with hydrochloric acid to precipitate cefotaxime acid. The mixture was then filtered, the solids washed with water, isopropyl alcohol and dried to obtain cefotaxime acid.

Yield: 42 g (92% of theoretical yield) While the invention has been described by reference to specific examples, this was for purposes of illustration only. Numerous alternative embodiments will be apparent to those skilled in the art and were considered to be within the scope of the invention. 9

Claims (13)

WHAT WE CLAIM IS: 314377

1. A process for preparing a compound of formula I C—CO—NH— N. OCHj o I J R2 OOORJ wherein R, represents hydrogen or a carboxy protecting group, and R2 represents acetoxymethyl, methyl, or (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yi)thiomethyl, or a pharmaceutically acceptable salt form thereof, which comprises acyiating a compound of formula III m OOORi in which R, and R2 are as defined above, with a reactive derivative of formula II n 10 314377

2. The process of claim 1 wherein R2 is acetoxymethyl.

3. The process of claim 1 wherein R2 is methyl.

4. The process of claim 1 wherein R2 is (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-l,2,4-triaziii-3-yl)thiomethyl.

5. The process of claim 1 wherein Ri is hydrogen.

6. The process of claim 1 wherein Ri is an alkali metal salt.

7. The process of claim 1 wherein Ri is pivaloyloxymethyl.

8. The process of claim 1 wherein said compound of formula 1 is a syn isomer.

9. The process of any one of the preceding claims wherein said acylation is performed in the presence of an organic solvent and water.

10. The process of claim 10 wherein said organic solvent is selected from the group consisting of tetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide, dioxane, and 11

11. The process of any one of claims 1 through 8 wherein said acylation is performed in the presence of a tertiary amine.

12. The process of claim 11 wherein said organic base is selected from the group consisting of triethylamine, N-methylmorpholine, pyridine, 1,8-diazabicycloundecene, and 4-dimethylaminopyridine, and mixtures thereof.

13. The process of any one of the preceding claims wherein said acylation is carried out at a temperature in the range of -5 to +20°C. 14 The process for preparing a compound of formula I substantially as herein described and with reference to the accompanying examples. Ranbaxy Laboratories Limited By its Attorneys END OF CLAIMS