Title of Invention	CEFTIOFUR, ITS INTERMEDIATE AND A PROCESS FOR THE PREPARATION OF THE SAME
Abstract	A process for the preparation of certiofur of tge following formula where is H or Na, by cycileing intermediate of the following formula where X is Cl or Br with thiouren in the presence of seected solvents.

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This invention relates to ceftiofur, its intermediate and a process for the preparation of the same. This invention relates to a new method of preparation of syn 7-[2-(amino-l,3-thia7.ol-4-yI)-2-(methoxyimino)acctamido]-3-[2-furylcarb()nyllhi(>nielhyI|-3-cephcni-4-carboxylic acid, also t known as Ceftiofur (Formula I), a cephalosporin antibiotic useful for treating bovine respiratory disease. This invention further describes preparation of ceftiofur starting from 7-amino-3-(2-furylcarbonylthiomethyl)-3-ccphem-4-carboxylic acid (Formula II) (hereafter referred as FURACA) through Furaca (Formula II) in presence of tricthylaminc to yield trilylccftiofur which on treatment with aqueous formic acid yielded Ceftiofur (Formula I). US patent 5583216 by Takeda Chemical Industries Ltd., describes a process to prepare cephem compounds and claims acylation whereby (2-amino-4-thiazolyl)-2-methoxyimino acetyl group is introduced on 7-amino group of a cephem moiety. It is known in literature that thiazolc ring formation as a final step has been used for preparation of cephalosporin antibiotics but no report appeared so far for preparation of Ceftiofur by such methodology. The yields by this process are cither generally low or have not been reported (Ref. USP 4458072, USP 4482710). The present invention relates to a process for preparing ceftiofur (Formula I) in good yield starting from Furaca (Formula II), which comprises the following: (a) condensation of 4-bromo-2-mclhoxyimino-3-oxobutyryl chloride with silylnted Furaca. r (b) Isolation of resulting product, 7-|4-l3ronio-2-incthoxyimino-3-oxobulyramido|-3-[2- fury1carbonylthiomethyl]-3-cephem-4-carboxylic acid (herein referred as Bromo intermediate) (Formula IV) in pure form is prepared in high purity and good yield starting from /e/7-butyl acctoacetate (Ref. USP 5095149). / Acid chloride of Formula VI is reacted with a silylnted Furaca in a suitable solvent(s). Suitable solvents include Methylene chloride, N,N-Dimethylformamide, N,N-Dimetylacetamide, Acetonitrile, Toluene or mixtures thereof. Particularly preferred solvent is Methylene chloride. Silylation of Furaca is effected using silylating agents such as Hexarnethyl disilazane, Trimethylsilyl chloride, Bistrimelhylsilyl urea, N,0-Bistrimethylsilyl acctamide or monotrimelhylsilyl acctamide in presence of a catalyst such as acetamide and imidazole. Choice of silylation conditions and silyaling reagent is found to be critical for achieving desired purity during condensation with acid chloride (Formula VI). It is observed that monolrimethylsilyl acctamide in methylene chloride at 20-25°C1 silylatcs Furaca in l h. Longer periods during silylation leads to impurities which arc difficult to eliminate during workup and further contaminate the finished product. Imidazole has been found to be the catalyst of choice in silylation step. Condensation of compound of Formula VI with silylatcd furnace gives Bromo intermediate (Formula IV). Bromo intermediate of Formula IV is cyclizcd with thiourea in presence of sodium acetate; However Ceftiofur obtained is impure and further purifications are difficult, time consuming and do not result in product of good quality. It lias been surprisingly found that Bromo intermediate (Formula IV) has not been hitherto reported and as such constitute novelty of this invention. The present inventors have found that Bromo compound of Formula IV can be isolated in pure form and only such a pure material gives Ceftiofur of high purity after cyclisation with thiourea. Isolation of pure bromo intermediate forms part of the inventive step of the process. In a further aspect of the present invention 7-[4-Chloro-2-mcthoxyimino-3-oxobutyramido]-3-[2-furylcarbonylthiomethyl]-3-cephem-4-carboxylic acid (herein referred as Chloro intermediate) of Formula VII has been prepared starting from 4-chloro-2-methoxyimino-3-oxo-butyric acid and constitutes novelty of the invention. This is cyclized to yield Ceftiofur sodium. The following examples illustrate the invention. EXAMPLE 1 PREPARA TJON OF CEFTIOFUR SODIUM Preparation of Ceftiofur sodium involves the following stages. STAGE I Step A: Silylation of Furaca (Solution A) To a suspension of Furaca (3.4 g, 0.01 moles) in methylene chloride (35 ml) at room temperature, added monotrimethylsilyl acetamide solution (3.94 g, 0.03 moles), catalytic amount of imidazole and stirred for 1 h 15 min to get a clear solution. This solution is cooled to -20 to -24°C until use. Step B: Preparation of 4-bronw-2-methoxyimino-3-oxobntyryt chloride (Solution B) 4-Bromo-2-mcthoxyimino-3-oxobutyric acid (2.57 g) is added to methylene chloride (20 ml) and the solution is cooled to -2()"C. Phosphorous pentachloride (2.5 g) is added in small lots over a period of 5 min while maintaining temperature at -20°C to -15°C\ Thereafter, the temperature is slowly raised to -5°C and stirred reaction mass at -5°C to 0°C till starting material's absence is noted on TLC (takes -30 min). Aqueous workup was done to remove inorganic impurities and by products and organic layer was dried over anhydrous sodium sulfate. This solution is taken as such for next stage. Step C; Preparation of 7-[4-Bromo-2-methoxyimino-3-oxohutyramidoJ-3-l2-furylcarbonylthiomethyll-3-cephem-4-carhoxylic acid (BROMO INTERMEDIA TE) Solution B is added to solution A, maintaining temperature below -18°C in -5 min. Temperature of reaction mass is allowed to rise to -I()to-5°C and stirring continued till starting material, Furaca is less than 2% by HPLC. Chilled water (35 ml) is added and the reaction mass stirred at 3-5°C for 10 min and filtered suspension, if any. Organic layer is separated and stirred at 3-5°C whereupon product, Bromo intermediate precipitates out. The filtered solid is stirred for 1 h at 3-5°C, filtered, washed with methylene chloride and dried to yield 3.6 g of Bromo intermediate having purity of >93% by HPLC analysis (65.9% of theory). The structure is confirmed by spectroscopic data. 'H NMR (300 MHz) (DMSO-d6) 5: 3.57 (dd, 211, SCH2), 4.11 (dd, 211, CH2SCO), 4.04 (s, 3H, OCH3), 4.64 (s, 211, CH2-Br), 5.14 (dd, III, 6-H, J - 4.85 Hz), 5.78 (dd, 1H, 7-H, J - 4.78 Hz, 8.24 Hz), 6.77 (dd, 1H, Furyl-H), 7.44 (d, 111, Furyl-I I) 8.06 (d, 1H, Furyl-H) 9.46 d, 1H, CONH,J-8.38Hz) IR:(KBr)cm_l : 1780.6, 1722.8, 1659, 1631, 1595 Mass (Positive ion mode): 546, 548 (MM) 563, 565 (M i-Na) corresponding to 35CK 37CI isotopes) STAGE// Preparation of ceftiofur sodium A solution of Bromo intermediate (3 g; 5.49 m. moles) in tetrahydrofuran (7.5 ml) is added to a mixture of water (15 ml), tetrahydrofuran (7.5 ml). Thiourea (0.63 g; 8.29 m. moles) and Sodium acetate trihydrate (3 g; 22 m. moles) at 10°C in -15 min. pll drops slowly to 5.5-6.0. The reaction mass is stirred till IIPLC analysis showed disappearance of starting material (4-5 h). Sodium chloride is added and pH lowered to 3.0 by addition of cone, hydrochloric acid. Tetrahydrofuran layer is separated, treated with activated carbon and converted into Ceftiofur sodium by adding sodium 2-ethylhexanoate (5.5 g, 24.6% w/w solution in TIIF). Precipitation of Ceftiofur sodium is carried out by adding the solution to tetrahydrofuran (80 ml). The precipitated solid is filtered, washed with acetone (20 ml) and dried to get 2.7 g of Ceftiofur sodium (90% of theory). 'H NMR (300 MHz) (DMSO-d6) 5: 3.32 (dd, 211, SCH2), 3.83 (s, 311, OCH3), 4.1 (dd, 2H, CH2SCO), 4.98 (d, 1H, 6-H), 5.55 (dd, 111, 7-H), 6.73 (s, 1H, thiazolyl-H) 6.75 (dd, IIL Furyl-H) 7.23, (s, 211, NII2) 7.38 (d, 111, Furyl-I I), 8.03 (s, 111, Furyl-I I), 9.52 (d, 111, CONI1) Mass (Positive ion mode): 524(M+II); 546(M i-Na) EXAMPLE 2: PREPARA TION OF CEFTIOFUR SODIUM STAGE I Step A: Preparation of4-hromo-2-methoxyiinino-3-oxohtttyryl chloride 4-Bromo-2-methoxyimino-3-oxobutyric acid (14.8 g, 0.066 moles) is dissolved in methylene chloride (90 ml) at 0°C. This solution is cooled to -20° and added N,N-DirnethyIformamide (4.92 g). Oxalyl chloride (8.55 g, 0.067 moles ) is added slowly maintaining temperature at -20°C to -18°C. The reaction mixture is stirred for 45 min at -!5°C to -20°C to ensure completion of reaction. The resulting product 4-bromo-2-methoxyimino-3-oxobutyryl chloride is taken as such for condensation. Step B: Preparation of4-bromo-2-methoxyimino-3-oxobufyryl chloride Furaca (20.4 g; 0.06 moles) is suspended in methylene chloride (120 ml) at 25°C and added trimethylsilylacelamide solution in methylene chloride (90 ml containing 23.6 g of trimethylsilylacetamide; 0.18 moles). Stirring the reaction mass at 25°C for 75-90 min resulted in a clear solution containing silylated Furaca. The reaction mass is cooled to -20°C and added acetamidc (10.62 g). Step C: Preparation of7-[4-1iromo-2-methoxyiniino-3-oxobutyraniido]-3-I2-furytcarhonylthiomethylJ-3-cephem-4-carboxytic acid (BROMO INTERMEDIA TE) 4-Bromo-2-methoxyimino-3-oxobutyryl chloride, prepared as above in step A is added to silylated Furaca {Step 13) at -18 to -20°C in 10 min. The temperature of reaction mass is raised slowly to -5 to -10°C and stirred for 1 h at this temperature. Thereafter, cold water (180 ml, 5°C) is added to the reaction mass and stirred at 2-3"C for 5 min and clarified suspension, if any. Separated organic layer and extracted aqueous layer with methylene chloride (20 ml). Combined organic layer is washed with cold water (150 ml, 5°C) and organic layer stirred at 2-5°C. Bromo intermediate precipitates within 5 min. Continued stirring at 2-5°C for 30 min and filtered the solid. The product is washed successively with cold water (40 ml, 5°C) followed by methylene chloride (40 ml) and dried under reduced pressure to get 25 g of Bromo intermediate (75% of theory). STAGE II Preparation of Ceftiofur sodium Bromo intermediate as obtained in the previous example is converted into Ceftiofur sodium by following procedure given in Example I. EXAMPLE 3: PREPARA TION OF CEFTIOFUR SODIUM Preparation of 4-bronio-2-methoxyin?ino~3~oxobntyryf chloride We Claim: 1. A process for the preparation of ceftiofur of the following formula: where X is CI or Br, with thiourea in the presence of solvents selected from ethanol, tetrahydrofuran. water or a mixture of any of the foregoing, the intermediate (X=C1) being prepared by condensing furaca with 4-chloro-2-methoxvmiino-3-oxobutvric acid or its acid halide, the intermediate ( X=Br')being prepared by condensing furaca with 4-bromo-2-methoxyimino-3-oxobutyric acid or its acid halide. 2 A process as claimed in Claim 1 wherein the acid halide is acid chloride or acid bromide. 3, A process for the preparation of ceftiofur substantially as herein described and exemplified. 4. A process for the preparation of the said intermediate substantially as herein described and exemplified.

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