Preparation method of cephalotin acid

A technology of cephalothinic acid and thiopheneacetic acid, which is applied in the direction of organic chemistry, can solve the problems of strong irritating odor, unfriendly environment, instability, etc., and achieve the effects of being conducive to industrial production, simplifying process operation, and mild reaction conditions

Active Publication Date: 2015-05-13
浙江东邦药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above methods all use thiophene acetyl chloride as a raw material, because it has a strong pungent odor, is very unstable, and is easy to change color and degrade, so it has brought certain limitations to industrial production.
On the other hand, although thiopheneacetic acid is relatively stable in chemical properties relative to thiophene acetyl chloride, and has no strong pungent smell, it is more friendly to the environment; however, it is difficult to react with thiophene acetic acid and amino nucleus 7-ACA, and generally requires Dehydration is carried out under high temperature conditions, and the chlorinating agent phosphorus oxychloride is added to facilitate the reaction, however, β-lactam compounds are easy to degrade under high temperature conditions, and the chlorinating agent phosphorus oxychloride is also very unfriendly to the environment hazardous chemicals

Method used

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  • Preparation method of cephalotin acid
  • Preparation method of cephalotin acid
  • Preparation method of cephalotin acid

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Add 2-thiopheneacetic acid 71g (0.5mol) in the three-necked flask of 2000mL, organic solvent dichloromethane 600mL, then add 90mL triethylamine and trifluoroacetic acid succinimide ester 127g (0.6mol), then control the temperature at 15 Under the condition of ℃~20℃, keep stirring and react for 3 hours. After the reaction is completed, filter with suction to obtain the reaction solution containing active ester, and slowly add the reaction solution containing active ester dropwise to the pre-prepared 1000mL di In methyl chloride solvent, and control the temperature under the condition of 15 ℃ ~ 20 ℃ to carry out the condensation reaction for 1 hour, after the condensation reaction is completed, add 10wt% hydrochloric acid solution dropwise to the reaction solution to adjust the pH value to 1.5 ~ 2.0, then statically Place and separate layers, collect the organic phase, quickly add the collected organic phase to 1000mL sodium bicarbonate aqueous solution, and adjust the pH ...

Embodiment 2

[0023] Add 2-thiopheneacetic acid 71g (0.5mol) in the there-necked flask of 2000mL, organic solvent chloroform 500mL and DMF100mL, add 90mL triethylamine and trifluoroacetic acid succinimide ester 106g (0.5mol) again, then control temperature at 10 Under the condition of ℃~20℃, keep stirring and react for 4 hours. After the reaction is completed, filter with suction to obtain the reaction solution containing active ester. Slowly add the active ester solution dropwise to the pre-prepared 1000mL chloroform solvent containing 109g 7-ACA. And control the temperature under the condition of 35 ℃ to carry out the condensation reaction for 1 hour. After the condensation reaction is completed, add 10 wt% hydrochloric acid solution dropwise to the reaction solution to adjust the pH value to 1.5-2.0. Then, let stand, separate layers, and collect the organic phase , quickly add the collected organic phase to 1000mL of sodium bicarbonate aqueous solution, and adjust the pH value to 6.5-7.0,...

Embodiment 3

[0025] Add 71g (0.5mol) of 2-thiopheneacetic acid in a 2000mL three-necked flask, 600mL of organic solvent ethylene glycol dimethyl ether, then add 80mL of morpholine and 212g (1.0mol) of succinimide trifluoroacetate, and then control the temperature Insulated and stirred for 4.5 hours under the condition of 10°C to 15°C, after the reaction was completed, suction filtered to obtain a reaction solution containing active ester, which was slowly added dropwise to the pre-prepared solution containing 136g (0.5mol) 7-ACA in 1000mL of ethylene glycol dimethyl ether solvent, and control the temperature at 15°C to 25°C for condensation reaction for 1 hour. After the condensation reaction is over, add 10wt% hydrochloric acid solution dropwise to the reaction solution to adjust the pH value to 1.5-2.0, then, stand still, separate layers, collect the organic phase, quickly add the collected organic phase to 1000mL sodium bicarbonate aqueous solution, and adjust the pH value to 6.5-7.0, st...

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Abstract

The invention relates to a preparation method of cephalotin acid and belongs to the technical field of drug synthesis. In order to solve the existing problem that the environment is severely polluted and the reaction temperature is high, the invention provides the preparation method of cephalotin acid. The method comprises the following steps: on the premise of an organic alkali, carrying out reaction on 2-thiopheneacetic acid and trifluoroacetic succinimide at (-20-40 DEG C) to obtain a solution containing activated esters; and then carrying out condensation reaction on the solution containing activated esters and 7-ACA at 10-35 DEG C to obtain the cephalotin acid. The method provided by the invention has the effects that the reaction condition is mild, the beta-lactam compound is not degraded and the method is environment-friendly, and the process operation is simplified.

Description

technical field [0001] The invention relates to a preparation method of cephalothin acid, which belongs to the technical field of medicine synthesis. Background technique [0002] Cefalotin is an important intermediate raw material for the synthesis of cephalosporin antibiotics, especially an important intermediate for the synthesis of cefalotin sodium and cefoxitin sodium antibacterial drugs. And the synthetic method of cephalothin acid at home and abroad mainly adopts the following two methods to synthesize: one, by dissolving 7-ACA in the alkaline aqueous phase system, then at low temperature, dripping thiophene acetyl chloride reaction, crystallization, Obtain the product cephalothin acid; 2. Add 7-ACA to the organic solvent, add a silylating agent to protect and dissolve the 7-ACA in the organic solvent, then add thiophene acetyl chloride dropwise to react, and finally obtain the product cephalosporin by phase inversion crystallization Thiophenoic acid. For example, C...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/34C07D501/06
CPCC07D501/06C07D501/34
Inventor 黄伟平池正明何发明池瀛李日生卢俊虞正烨
Owner 浙江东邦药业有限公司
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