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Synthesis method of cefbuperazone

A synthetic method, the technology of cefbuperazone, applied in the field of medicine, can solve the problems of increasing the difficulty of large-scale production, aggravating environmental hazards, and high requirements for preparation scale, and achieves easy operation and control, easy realization, and simple synthetic route design reasonable effect

Inactive Publication Date: 2013-10-16
HAINAN HERUI PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This product is a drug with a large dosage, which requires high preparation scale, and the method of column chromatography to refine the intermediate will inevitably increase the difficulty of large-scale production and greatly increase the production cost, and benzene is a kind of solvent , its extensive use will inevitably aggravate the harm to the environment

Method used

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  • Synthesis method of cefbuperazone
  • Synthesis method of cefbuperazone
  • Synthesis method of cefbuperazone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] (1) Preparation of 7-MAC silyl compound

[0050]

[0051] 7-MAC 7-MAC silyl compound

[0052] Add 1.05kg of 7-MAC, 6.4kg of dichloromethane and 0.22kg of trimethylchlorosilane into the reaction tank, control the temperature at 20-25°C and stir for 40min, then cool down to below -5°C for use.

[0053] (2) preparation of cefbuperazone side chain acid chloride

[0054]

[0055] Cefbuperazone Side Chain Cefbuperazone Side Chain Acid Chloride

[0056] Add 0.61kg of cefbuperazone side chain, 0.19kg of tetrahydrofuran and 5.3kg of dichloromethane into the reaction tank. After stirring and dissolving, cool down to -30~-25°C and slowly add 0.33kg of phosphorus oxychloride dropwise. During the process, the temperature was controlled not to exceed -20°C, and the dripping was completed within 30 minutes, and the reaction was stirred for another 30 minutes.

[0057] (3) preparation of cefbuperazone diphenylmethyl ester

[0058]

[0059] Cefbuperazone Side Chain Acid Chlor...

Embodiment 2

[0066] (1) Preparation of 7-MAC silyl compound

[0067]

[0068] 7-MAC 7-MAC silyl compound

[0069] Add 1.05kg of 7-MAC, 6.4kg of acetonitrile and 0.48kg of hexamethyldisilazane (HMDS) into the reaction tank, control the temperature at 15-20°C and stir for 45min, then cool down to below -5°C for use.

[0070] (2) preparation of cefbuperazone side chain acid chloride

[0071]

[0072] Cefbuperazone Side Chain Cefbuperazone Side Chain Acid Chloride

[0073] Add 0.57kg of cefbuperazone side chain, 0.19kg of tetrahydrofuran and 5.3kg of dichloromethane in the reaction tank, after stirring and dissolving, cool down to -30~-25°C, slowly add 0.466kg of phosphorus trichloride dropwise, drop During the addition process, the temperature was controlled not to exceed -20°C, and the dripping was completed within 30 minutes, and the reaction was stirred for another 30 minutes.

[0074] (3) preparation of cefbuperazone diphenylmethyl ester

[0075]

[0076] Cefbuperazone Side C...

Embodiment 3

[0083] (1) Preparation of 7-MAC silyl compound

[0084]

[0085] 7-MAC 7-MAC silyl compound

[0086] Add 1.05kg of 7-MAC, 6.4kg of N,N-dimethylformamide and 0.22kg of trimethylchlorosilane into the reaction tank, control the temperature at 25-30°C and stir for 35min, then cool down to below -5°C and wait use.

[0087] (2) preparation of cefbuperazone side chain acid chloride

[0088]

[0089] Cefbuperazone Side Chain Cefbuperazone Side Chain Acid Chloride

[0090] Add 0.61kg of cefbuperazone side chain, 0.19kg of tetrahydrofuran and 5.3kg of dichloromethane into the reaction tank. After stirring and dissolving, drop the temperature to -30~-25°C and slowly add 0.39kg of phosphorus oxychloride dropwise. During the process, the temperature was controlled not to exceed -20°C, and the dripping was completed within 30 minutes, and the reaction was stirred for another 30 minutes.

[0091] (3) preparation of cefbuperazone diphenylmethyl ester

[0092]

[0093] Cefbuperaz...

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Abstract

The invention relates to a synthesis method of cefbuperazone, and the synthesis method comprises the following steps: (1) protecting 7beta-amino-7alpha-methoxy-3-[(1-methyl-1H-tetrazol-5-yl)S-methyl]-3-cephalosporin-en-4-carboxylic acid diphenyl methyl ester (7-MAC) with an amino group protective agent to obtain 7-MAC silane; (2) reacting cefbuperazone lateral chain with a halide to obtain cefbuperazone lateral chain acyl halide; (3) reacting 7-MAC silane with cefbuperazone lateral chain acyl halide to obtain an intermediate product, namely cefbuperazone diphenyl methyl ester; and (4) removing the protective group from cefbuperazone diphenyl methyl ester to obtain cefbuperazone, wherein the amino group protective group is hexamethyl disilylamine, trimethyl chlorosilane, N,O-bis(trimethylsilyl) acetamide or N,N-bis(trimethylsilyl)-2,2,2-trifluoroacetamide. The synthesis method is easy for realization and has the advantages of simple and reasonable synthesis route design, mild reaction conditions, simple, safe and controllable reaction process and high yield of cefbuperazone, and the intermediate product is easy to separate and purify.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a synthetic method of cefbuperazone. Background technique [0002] Cefbuperazone (cefbuperazone), the chemical name is (6R, 7S)-7-[[(2R, 3S)-2-[(4-ethyl-2,3-dioxopiperazine-1-formyl) Amino]-3-hydroxybutyryl]amino]-7-methoxy-3-[(1-methyltetrazol-5-yl)thiomethyl]-8-oxo-5-thia-1- Azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, molecular formula: C 22 h 29 N 9 o 9 S 2 , molecular weight: 627.65, chemical structural formula: [0003] [0004] Cefbuperazone is a third-generation cephalosporin antibiotic developed by Japan Toyama Chemical Industry Pharmaceutical Co., Ltd. in the 1970s and listed in 1985. Cefbuperazone is a broad-spectrum antibacterial drug against G+, G- bacteria and anaerobic bacteria All have effects, and the effect on anaerobic bacteria is better than that of general third-generation cephalosporins. Cephbuperazone has increased enzyme resistance due to the i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/57C07D501/04
CPCY02P20/55
Inventor 朱正兵郭子维
Owner HAINAN HERUI PHARMA
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