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A technology of cefoperazone acid and synthesis method, which is applied in the field of medicine, can solve the problems of harsh reaction conditions, long reaction time, and high cost of raw materials, and achieve the effects of reducing side reactions and increasing reaction yield
Inactive Publication Date: 2012-07-04
YIYUAN XINQUAN CHEM
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For the reported synthetic methods, there are disadvantages of high raw material cost, low product yield, poor quality and harsh reaction conditions, long reaction time, which is not conducive to continuous and large-scale industrial production.
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Embodiment 1
[0025] 1. Preparation of 7-TMCA hydrochloride
[0026] Under nitrogen, dissolve 15.4g of 1-methyl-5-mercapto-1,2,3,4-tetrazolium into 157.0mL of boron trifluoride acetonitrile, keep the reaction for 1h, and add 36.0g of 7-ACA three times , stirred at 25-30°C for 2h, then added 80mL of concentrated hydrochloric acid dropwise within 0.5h, added 80mL of water, kept at 15°C, stirred for 2h, stirred at 5°C for 1h, suction filtered, and the filter cake was washed with acetonitrile-acetone (1:1 V / V) 40 mL was washed three times, and vacuum-dried at 48-50° C. to obtain 46.10 g of white crystals.
[0027] 25.0g of 7-TMCA hydrochloride and 80mL of N,N-dimethylacetamide were stirred and dissolved, and 6mL of trimethylchlorosilane was added dropwise under cooling in an ice bath, and stirred at 15-20°C for 1h to obtain a 7-TMCA solution , which is the solution ①.
[0034] In a 500mL round bottom flask, add 165mL boron trifluoride acetonitrile, 37g 7-ACA and 15.6g 1-methyl-5-mercapto-1,2,3,4-tetrazolium in sequence, stir rapidly, and the reaction temperature is 25 ~30°C, reaction time 2.5h, then add 85mL of concentrated hydrochloric acid dropwise within 0.5h, add 75mL of water, keep warm at 15°C, stir for 1.5h, filter with suction, wash the crystal with 40mL of acetonitrile-acetone (1:1 V / V) for 3 The second time, 45.8 g of white crystals were obtained by vacuum drying at 48-50°C.
[0035] 25.0g of 7-TMCA hydrochloride and 80mL of N,N-dimethylacetamide were stirred and dissolved, and 6mL of trimethylchlorosilane was added dropwise under cooling in an ice bath, and stirred at 15-20°C for 1h to obtain a 7-TMCA solution , which is the solution ①.
[0036] 2. Preparation of HO-EPCP chloride
[0037] Add 138.0mL DMAC, 146.0mL CH 2 Cl 2, 27.2g HO-EPCP, stirred until dissolved. Cool down to -20...
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Abstract
The invention relates to a synthesis method of cefoperazone acid, and belongs to the technical field of medicines. The method comprises the following steps: (1) adopting 7-ACA (7-aminocephalosporanic acid) and 1-methyl-5-mercapto-1,2,3,4-tetrazole as raw materials, allowing reaction between the two raw materials in the catalysis of a boron trifluoride-acetonitrile solution to obtain 7-TMCA (7-amino-3-methyl tetrazolyl cephalosporanic acid) hydrochloride, and performing the protection of carboxyl group and amino group on 7-TMCA hydrochloride with trimethylchlorosilane; (2) allowing reaction of HO-EPCP (2-[(4-ethyl-2,3-dioxopiperazinyl)carbonylamino]-2-(4-hydroxyphenyl)acetic acid) and phosphorus oxychloride in a DMAC (dimethylacetamide) and dichloromethane solution in the protection of nitrogen gas to obtain HO-EPCP chloride; and (3) allowing N-acylation reaction of the 7-TMCA hydrochloride subjected to the protection of carboxyl group and amino group obtained by the step (1) and HO-EPCP chloride obtained by the step (2) with polyethylene glycol 800 as a phase transfer catalyst in a dichloromethane-water mixed solution, regulating pH with a hydrochloric acid solution, and crystallizing to obtain cefoperazone acid. In the invention, the yield of 7-TMCA hydrochloride under the catalysis of boron trifluoride is improved by 3%. The addition of the phase transfer catalyst reduces occurrence of side reaction, improves the reaction yield by 5%, makes the final product yield reach above 69.0%, and improves purity to above 99%.
Description
technical field [0001] The invention relates to a method for synthesizing cefoperazone acid, which belongs to the technical field of medicine. Background technique [0002] Cefoperazone sodium is the third-generation cephalosporin developed and discovered by Japan Toyama Chemical Industry Co., Ltd., which went on the market in 1981: sold abroad through Pfizer. This product has strong antibacterial activity against Gram-negative bacteria including Pseudomonas aeruginosa, also has antibacterial activity against Gram-positive bacteria and Bacteroides, has strong tolerance to β-lactamase, and induces β-lactam The enzyme production ability is extremely low, so it is not easy to induce bacterial resistance; this product is effective and safe for various infectious diseases such as respiratory tract infection, biliary tract infection, obstetrics and gynecology infection, and surgical infection. This product has high stability, and its aqueous solution degradation follows first-ord...
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