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Preparation method of active diester of ethyl 2-2-acetate

A technology of ceftazidime side chain acid and ceftazidime, which is applied in the field of preparation of ceftazidime side chain acid active diester, can solve the problem of not finding ceftazidime side chain acid active diester and the like, and achieves the effects of improving purity and improving yield

Inactive Publication Date: 2018-11-20
SHANDONG JINCHENG PHARMACCUTICAL CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no report on the preparation of ceftazidime side chain acid active diester in patents or literature

Method used

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  • Preparation method of active diester of ethyl 2-2-acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] In the 250mL there-necked flask equipped with reflux condenser, thermometer and mechanical stirring, add 27.3g ceftazidime side-chain diacids, 73g dibenzothiazole disulfide, 100g methylene chloride, at room temperature, add 19.4g dodecylamine dropwise, After the dropwise addition, stir for 20min, continue to add 8.5g of 4-dimethylaminopyridine to the reaction solution, then lower the temperature to 20-30°C and start to add 40g of triethyl phosphite dropwise for 1.5h. After adding triethyl phosphite, continue to add dropwise a mixed solution of 13.3g N,N-xylaniline and 75mL acetonitrile at this temperature for 30 minutes. Recover 60g of methylene chloride under reduced pressure at 25-30°C for 60 minutes, and control the crystallization rate of the product by controlling the distillation rate of methylene chloride, so that the product crystallizes slowly at a uniform speed. , purity>99%, yield 87%.

Embodiment 2

[0025] In the 250mL there-necked flask equipped with reflux condenser, thermometer and mechanical stirring, add 27.3g ceftazidime side-chain diacids, 80g dibenzothiazole disulfide, 105g dichloromethane, at room temperature, drop tetradecylamine 22.4g, After the dropwise addition, stir for 20min, continue to add 7.3g of 4-dimethylaminopyridine to the reaction solution, then cool down to 20-30°C and start to dropwise add 36.5g of triethyl phosphite for reaction, the dropping time is 2h, dropwise After adding triethyl phosphite, continue to add dropwise a mixed solution of 13.1g N,N-xylaniline and 80mL acetonitrile at this temperature for 30 minutes, and keep the reaction for 2 hours after adding dropwise. After the reaction is completed, control the temperature at 25- 30°C, 60g of dichloromethane was recovered under reduced pressure for 50 minutes. By controlling the distillation rate of dichloromethane and the crystallization rate of the product, the product was crystallized slo...

Embodiment 3

[0027] In the 250mL there-necked flask equipped with reflux condenser, thermometer and mechanical stirring, add 27.3g ceftazidime side-chain diacids, 69g dibenzothiazole disulfide, 100g methylene chloride, at room temperature, add 18.5g dodecylamine dropwise, After the dropwise addition, stir for 20min, continue to add 6.5g of 4-dimethylaminopyridine to the reaction solution, then lower the temperature to 20-30°C and start to add 39g of triethyl phosphite dropwise for reaction, the dropwise addition time is 1h, dropwise After finishing triethyl phosphite, continue to add dropwise a mixed solution of 12.8g N,N-xylaniline and 75mL acetonitrile at this temperature for 30 minutes. ℃, 50g of dichloromethane was recovered under reduced pressure in 60 minutes, and by controlling the distillation rate of dichloromethane, the crystallization rate of the product was controlled to make the product crystallize slowly at a uniform speed. 99%, yield 84%.

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Abstract

The invention belongs to the technical field of synthesis of medical intermediates, and specifically relates to a preparation method of active diester of ethyl 2-2-acetate. The method comprises the following steps: adding dioic ethyl 2-2-acetate and dibenzothiazyl disulfide to dichloromethane; dropwise adding long-chain organic amine; then adding 4-dimethylaminopyridine to reacting liquid after dropwise adding; decreasing the temperature; dropwise adding triethyl phosphite to react; adding a mixing solution of N, N-xylidine and acetonitrile; recovering dichloromethane in a pressure reduction manner after reaction; and performing suction filtration to obtain the active diester of ethyl 2-2-acetate after recovering. According to the method, dioic ethyl 2-2-acetate and dibenzothiazyl disulfide are reacted to obtain the active diester of ethyl 2-2-acetate under the composite catalyzing of N, N-xylidine ternary organic base; the purity and the yield of the active diester are improved; the purity of the obtained product is more than 99%; and the yield is more than 83%.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, in particular to a preparation method of ceftazidime side chain acid active diester. Background technique [0002] Ceftazidime is an important third-generation semi-synthetic cephalosporin antibiotic, which has the characteristics of strong bactericidal activity, broad antibacterial spectrum, and strong enzyme resistance, so it is widely used in clinical practice. [0003] During the synthetic process of ceftazidime side chain acid active ester, because raw material ceftazime side chain acid contains unavoidable impurity ceftazime side chain diacid, therefore in the process of synthesizing ceftazime side chain acid active ester, ceftazime side chain acid active diester normal crystal package Miscellaneous in the product, seriously affects the quality of ceftazidime. The structure of the active diester of ceftazidime side chain acid is shown in the following form...

Claims

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Application Information

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IPC IPC(8): C07D277/74
CPCC07D277/74
Inventor 郑庚修付凯侯乐伟蔡会敏
Owner SHANDONG JINCHENG PHARMACCUTICAL CHEM CO LTD
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