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Preparation method of tazobactam diphenyl methyl ester

A technology of Zobactam diphenylmethyl ester and Penicillium sulfoxide diphenylmethyl ester, applied in the field of medicine, can solve the problem of large by-products of isomers in azidation reaction, affecting product yield and quality, and increasing costs, etc. problems, to achieve the effect of reducing isomer by-products, low cost, and easy operation

Active Publication Date: 2021-01-05
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Among the above two synthetic routes, the isomer by-products of the azidation reaction in the route one is relatively large, which affects the product yield and quality, and the route two requires the use of an extremely excessive amount of 1H-1,2,3-triazole, and 1H The price of -1,2,3-triazole is high, so the cost of this route is greatly increased

Method used

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  • Preparation method of tazobactam diphenyl methyl ester
  • Preparation method of tazobactam diphenyl methyl ester
  • Preparation method of tazobactam diphenyl methyl ester

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Add 352g of compound III dichloromethane feed liquid (containing 0.10mol compound III) into a 500mL reaction flask, cool down to 0-10°C, add 36.24g m-chloroperoxybenzoic acid (0.21mol) dropwise, and control the temperature to 0 -10°C, heat preservation reaction for 2.5 hours; after the reaction is completed, add saturated aqueous sodium bicarbonate solution dropwise to pH=7-8, let stand for stratification, and wash the material twice with 100 g of dichloromethane to obtain the dichloromethane of compound IV. methane feed liquid;

[0029] Add the dichloromethane feed liquid of the above compound IV into a 500mL reaction flask, control the temperature at 20-30°C, and start to dropwise add 10.37g of azidotrimethylsilane (0.09mol) dichloromethane solution and saturated aqueous sodium bicarbonate solution at the same time , during the dropping process, adjust the dropping rate of the aqueous sodium bicarbonate solution to control the pH of the feed solution=3.0-5.0; after th...

Embodiment 2

[0032] Add 352g of compound III dichloromethane feed liquid (containing 0.10mol compound III) into a 500mL reaction flask, cool down to 0-10°C, add 35.38g m-chloroperoxybenzoic acid (0.205mol) dropwise, and control the temperature to 0 -10°C, heat preservation reaction for 3 hours; after the reaction is completed, add saturated aqueous sodium bicarbonate solution dropwise to pH=7-8, let stand for stratification, and wash the dichloromethane feed solution twice with 100g water respectively to obtain the dichloromethane of compound IV. methane feed liquid;

[0033] Add the dichloromethane feed solution of the above-mentioned compound IV into a 500mL reaction flask, control the temperature at 20-30°C, and start to dropwise add 10.60g of azidotrimethylsilane dichloromethane solution (0.092mol) and saturated aqueous sodium bicarbonate solution at the same time , during the dropping process, adjust the dropping speed of the aqueous sodium bicarbonate solution to control the pH of th...

Embodiment 3

[0036] Add 352g of compound III dichloromethane feed solution (containing 0.10mol compound III) into a 500mL reaction flask, cool down to 0-10°C, add 37.10g m-chloroperoxybenzoic acid (0.215mol) dropwise, and control the temperature to 0 -10°C, heat preservation reaction for 2 hours; after the reaction is completed, add saturated aqueous sodium bicarbonate solution dropwise to pH=7-8, let stand for stratification, and wash the dichloromethane feed solution twice with 100g water respectively to obtain the dichloromethane of compound IV. methane feed liquid;

[0037] Add the dichloromethane feed solution of the above compound IV into a 500mL reaction flask, control the temperature at 20-30°C, and start to dropwise add 10.14g of azidotrimethylsilane (0.088mol) in dichloromethane solution and saturated aqueous sodium bicarbonate solution at the same time , during the dropping process, adjust the dropping rate of the aqueous sodium bicarbonate solution to control the pH of the feed...

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Abstract

The invention discloses a preparation method of tazobactam diphenyl methyl ester. According to the route, penicillium sulfoxide acid diphenyl methyl ester debromide (compound I) is used as an initialraw material, and the tazobactam diphenyl methyl ester is obtained through the steps of thermal cracking ring opening, chloromethylation, oxidation, azidation and cyclization in sequence. According tothe method, a route of firstly oxidizing and then constructing a side chain is adopted, and sodium azide or 1H-1,2,3-triazole is replaced by azido trimethylsilane to construct the side chain, so thatthe generation of isomer byproducts is reduced, the purity and yield are relatively high, the cost is relatively low, the operation is simple and convenient, the post-treatment is simple, and the technical scheme facilitates industrial production.

Description

technical field [0001] The invention relates to a preparation method of tazobactam diphenylmethyl ester, which belongs to the technical field of medicine. Background technique [0002] Tazobactam, chemical name: 3-methyl-7-oxo-3-(1H-1,2,3-triazole-1-methylene)-4-thia-1-aza Bicyclo[3.2.0]heptane-2-carboxylic acid-4,4-dioxide, whose structural formula is shown below, is a new type of penicillane sulfone β-lactamase inhibitor developed by Dapeng Pharmaceutical Company of Japan. Its structure is to add a triazole ring on the basis of sulbactam to improve the effect of inhibiting enzymes. Tazobactam is the β-lactamase inhibitor with the best clinical effect at present, and has the characteristics of high stability, low activity, low toxicity and strong enzyme inhibitory activity. In 1992, the compound drug tazobactam sodium / piperacillin sodium (1:8) of tazobactam was first launched in France for the treatment of various bacterial infections. β-Azidomethylated penicillane sulfo...

Claims

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Application Information

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IPC IPC(8): C07D499/04C07D499/87
CPCC07D499/04C07D499/87
Inventor 吕德帅孟令华王欣翟长均李东建王仕川孙明尧
Owner 山东安信制药有限公司
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