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Method for preparing oxygen cephalosporin compound

A compound and oxycephalosporin technology, applied in the field of drug synthesis, can solve the problems of high production equipment requirements, unfavorable industrialized production, unfriendly environment, etc., and achieve the effects of being beneficial to production operations, beneficial to industrialized production, and reducing production costs

Active Publication Date: 2015-03-11
浙江东邦药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] (1) The reaction steps are long, requiring four-step reactions, and there are many side reactions in the reaction process, which are difficult to control;
[0010] (2) Liquid chlorine needs to be used in the process of manufacturing, which is not friendly to the environment, and has high requirements for production equipment, which is not conducive to industrial production

Method used

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  • Method for preparing oxygen cephalosporin compound
  • Method for preparing oxygen cephalosporin compound
  • Method for preparing oxygen cephalosporin compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Formula I compound 7-(benzoyl)amino)-7-methoxy-(3-((1-methyl-1H-tetrazol-5-yl)thio)methyl)-8-oxo-5 -The preparation method of oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester:

[0041]

[0042]Add 500mL of dichloromethane into a 2000mL four-neck flask, then add 47g (0.1mol) of the compound of formula II, wherein R in the compound of formula II is hydrogen, stir until dissolved and clear, cool down to -45°C with liquid nitrogen, and then slowly add 15g (0.14mol) of tert-butyl hypochlorite, start dropwise adding methanol solution of lithium methoxide, of which 15g (0.4mol) of lithium methoxide and 150mL of methanol, control the temperature at -45°C during the dropwise addition, after the dropwise addition , continue to react under the condition of controlling the temperature at -45°C for 2.0 hours. After the reaction, use TLC to detect, the mobile phase is petroleum ether: ethyl acetate ratio of 2:1, the test result shows that the reaction is com...

Embodiment 2

[0045] Formula I compound 7-(benzoyl)amino)-7-methoxy-(3-((1-methyl-1H-tetrazol-5-yl)thio)methyl)-8-oxo-5 -The preparation method of oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester

[0046]

[0047] Add 550mL of chloroform into a 2000mL four-neck flask, then add 47g (0.1mol) of the compound of formula II, wherein R in the compound of formula II is hydrogen, stir until dissolved and clear, cool down to -50°C with liquid nitrogen, and then slowly add 10.8g (0.1mol) tert-butyl hypochlorite, start dropwise adding the methanol solution of lithium methoxide, wherein, the lithium methoxide in the methanol solution of lithium methoxide is 19g (0.5mol), the methanol is 200mL, and the temperature is controlled at -50 during the dropwise addition. ℃, after the dropwise addition is completed, continue to react under the condition of controlling the temperature at -50°C for 2.5 hours. Add 20mL of acetic acid, stir for 20 minutes, then add 500mL of sodium thiosul...

Embodiment 3

[0050] Formula I compound 7-(benzoyl)amino)-7-methoxy-(3-((1-methyl-1H-tetrazol-5-yl)thio)methyl)-8-oxo-5 -The preparation method of oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester

[0051]

[0052] Add 550mL of dichloromethane and 50ml of dioxane into a 2000mL four-neck flask, then add 47g (0.1mol) of the compound of formula II, wherein R in the compound of formula II is hydrogen, stir until dissolved and clear, and cool down to -60°C, then slowly add 21.7g (0.2mol) of tert-butyl hypochlorite, and start to add the methanol solution of lithium methoxide dropwise. Among them, the amount of lithium methoxide in the methanol solution of lithium methoxide is 13.3g (0.35mol), and the amount of methanol is 180mL , during the dropwise addition, the temperature was controlled at -60°C. After the dropwise addition, the reaction was continued at -60°C for 3.0 hours. After the reaction, TLC was used for detection, and the mobile phase was petroleum ether: ethyl...

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Abstract

The invention relates to a method for preparing an oxygen cephalosporin compound, and belongs to the technical field of medicine synthesis. In order to solve the technical problems that a synthetic route of a compound is too long and the problem caused by chlorine in the oxygen cephalosporin compound formula I, the aims of simplified process and environment friendliness are fulfilled. The method for preparing the oxygen cephalosporin compound comprises the following steps of: reacting a compound, lithium methoxide and hypochlorous acid tert-butyl ester in a formula II to acquire a compound in a formula III in an organic solvent; and performing condensation reaction on the compound in the formula III and a compound of 1-methyl-5-tetrazole-thione in a formula IV under the condition of existence of an apply acid agent and a condensating agent to acquire corresponding final products. With the adoption of the method, the oxygen cephem and 1-methyl-5-tetrazole-thione are used as initial raw materials, the product is synthetized by means of one-pot, so that the side reaction influence is avoided; the production process is simplified; the product yield is high; the molar yield can reach over 65 percent; and the purity can reach over 95 percent.

Description

technical field [0001] The invention relates to an antibiotic drug compound, in particular to a preparation method of an Oxycephalosporin compound, and belongs to the technical field of drug synthesis. Background technique [0002] Because of its special structure, Oxycephem antibiotics, such as Latamoxef, Fluoxefem, etc., have an α-methoxyl group at the 7th position of the mother nucleus. Due to the steric hindrance of the methoxyl group, it can prevent the interaction between enzyme molecules and antibiotics. The β-lactam ring is close, so that the β-lactam ring of the antibiotic will not be destroyed by the enzyme molecule before preventing the synthesis of the bacterial cell wall, which improves the stability of the drug against β-lactamase and improves the activity against anaerobic bacteria. Bacteria are very Less drug resistance, such as oxycephem antibiotics Latamoxef compound. [0003] [0004] In the preparation process of the existing oxycephem antibiotic comp...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D505/18C07D505/06
Inventor 黄伟平池正明卢峻李日生池瀛虞正烨
Owner 浙江东邦药业有限公司
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