An improved synthesis of ceftiofur intermediate

A technology for cephem and aminocephalosporanic acid, which is applied in the directions of organic active ingredients, medical preparations containing active ingredients, organic chemistry, etc., and can solve the problems of inability to obtain separation and poor stability.

Inactive Publication Date: 2005-07-13
ORCHID CHEM & PHARM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When this method was applied to the condensation of 7-ACA and furyl-2-carbonylthiol, the reaction mixture was associated with several impurities which could not be isolated even in the final purification steps
Later, after several experiments, we found that the stability of furyl-2-carbonylthiol in solid form is not good, because furyl-2-carbonylthiol belongs to heterocyclic thiocarbonic acid rather than heterocyclic thiols

Method used

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  • An improved synthesis of ceftiofur intermediate
  • An improved synthesis of ceftiofur intermediate
  • An improved synthesis of ceftiofur intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment -I

[0025] 7-Amino-3-(2-furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid

[0026] Sodium sulfide (54.6 g) was added to water (600 ml), and furyl-2-carbonyl chloride (50.0 g) was added at a temperature of 20° C. within 1.0 hour. Ethyl acetate was added thereto, and the pH of the material was adjusted to 1.0 with hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to afford furyl-2-carbonylthiol in ethyl acetate.

[0027] Ethyl acetate (350 ml) was added to another flask, and boron trifluoride gas (124.0 g) was bubbled thereinto. 7-Amino-cephalosporanic acid (91.0 g) was added to the boron trifluoride solution at 10.0°C, followed by a solution of furyl-2-carbonylthiol in ethyl acetate (prepared above). After stirring at 30-40°C for 4-5 hours, the reaction was complete. After the reaction was complete, the mixture was poured into ice-cold water. Aqueous ammonia was added to adjust the pH of the solution to 3.45-3.55. The prec...

Embodiment -II

[0029] 7-Amino-3-(2-furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid

[0030] Sodium sulfide (36.4 g) was added to water (400 ml), and furyl-2-carbonyl chloride (33.3.0 g) was added within 1.0 hour at a temperature of 20°C. Ethyl acetate was added thereto, and the pH of the material was adjusted to 1.0 with hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to afford furyl-2-carbonylthiol in ethyl acetate.

[0031] In another flask containing acetonitrile (350ml) was bubbled boron trifluoride gas (85.0g). 7-Amino-cephalosporanic acid (60.6 g) was added to the boron trifluoride solution at 10.0°C, followed by a solution of furyl-2-carbonylthiol in ethyl acetate (prepared above). After stirring at 30-40°C for 4-5 hours, the reaction was complete. After the reaction was complete, the material was poured into ice-cold water. Aqueous ammonia was added to adjust the pH of the solution to 3.45-3.55. The precipitated solid wa...

Embodiment -III

[0033] 7-Amino-3-(2-furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid

[0034] Sodium sulfide (54.6 g) was added to water (600 ml), and furyl-2-carbonyl chloride (50.0 g) was added at a temperature of 20° C. within 1.0 hour. Ethyl acetate was added thereto, and the pH of the material was adjusted to 1.0 with hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to afford furyl-2-carbonylthiol in ethyl acetate.

[0035] To another flask containing acetonitrile (350ml) was added 7-amino-cephalosporanic acid (91.0g) at room temperature, followed by 45-48% boron trifluoride etherate (275.5ml) at 10.0°C. To this was added a solution of furyl-2-carbonylthiol in ethyl acetate (prepared above). After stirring at 40-50°C for 4-5 hours, the reaction was complete. After the reaction was completed, the reaction mixture was poured into ice-cold water. Sodium carbonate solution was added to adjust the pH of the solution to 3.45-3.55. T...

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Abstract

The present invention relates to a process for preparation of 7-amino-3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid (I) by the condensation of 7-aminocephalosporanic acid (II) with furyl-2-carbonylthiol (III) in the presence of borontrifluoride or its complex, in an organic solvent or mixture of solvents at 0-50° C.

Description

technical field [0001] The present invention discloses the use of boron trifluoride or its complex as a condensing agent, through which 7-aminocephalosporanic acid (7-amino cephalosporanic acid, 7-ACA) represented by formula (II) and furyl group represented by formula (III) - An improved method for preparing 7-amino-3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid represented by formula (I) by condensation of 2-carbonylthiol. [0002] Background technique [0003] Ceftiofur is the generic name for compounds of formula (IV) [0004] [0005] Ceftiofur acid, its alkali metal, alkaline earth metal and ammonium salts are first reported in US Patent 4,464,367. Ceftiofur is the condensation product of 7-ACA with furyl-2-carbonylthiol and 2-(2-aminothiazol-4-yl)-2-methoxyimino)acetic acid at the 3-position and 7-position respectively. 7-amino-3-[2-(furylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid represented by formula (I) is a key intermediate, which determin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/00C07D501/04C07D501/14C07D501/36
CPCC07D501/00C07D501/18
Inventor 普拉穆德·纳拉扬·德什潘德包萨希卜·潘德哈里纳特·卡丹格里苏鲁利查米·森希尔·库马尔高塔姆·库马尔·达斯
Owner ORCHID CHEM & PHARM LTD
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