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The preparation method of cefoperazone acid

A technology of cefoperazone acid and hydrochloride, which is applied in the field of medicine, can solve problems such as complex operation, harsh reaction conditions, and difficult control of conditions, and achieve the effects of high purity, simple reaction steps, and cost reduction

Active Publication Date: 2016-04-20
YIYUAN XINQUAN CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Patent CN102532168A reports a synthesis method of cefoperazone acid, which needs to react HO-EPCP with phosphorus oxychloride to obtain chloride, and then react, the operation is complicated, the conditions are difficult to control, and the cost is high
For the synthetic methods reported so far, there are disadvantages such as high cost of raw materials, low product yield, poor quality and harsh reaction conditions, long reaction time, and many reaction steps.

Method used

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  • The preparation method of cefoperazone acid
  • The preparation method of cefoperazone acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] (1) Dissolve 1.1 mol of 1-methyl-5-mercaptotetrazolium in 180 mL of boron trifluoride acetonitrile under nitrogen gas, keep the reaction for 1 hour, add 1 mol of 7-ACA in three times, stir at 28°C for 2 hours, and then Add 80mL of concentrated hydrochloric acid dropwise within 0.5h, add 80mL of water, keep warm at 15°C and stir for 2h, stir at 5°C for 1h, filter with suction, wash the filter cake three times with 40mL of acetonitrile-acetone solution with a volume ratio of 1:1, and dry in vacuo to obtain 7 - TMCA hydrochloride 46.21 g. 7-TMCA hydrochloride and 34 mL of N,N-dimethylacetamide were stirred and dissolved, and 10 mL of trimethylchlorosilane was added dropwise in an ice bath, and stirred at 18°C ​​for 1 hour to obtain 7-TMCA with protected groups Hydrochloride.

[0022] (2) Add 1.0 mol of 7-TMCA hydrochloride, 1.1 mol of HO-EPCP and 0.27 mol of diethyl benzotriazolyl phosphate obtained in step (1) into 490 mL of DMF solution, stir and add three 20 mL of eth...

Embodiment 2

[0024] (1) Dissolve 1.15mol of 1-methyl-5-mercaptotetrazolium in 170mL of boron trifluoride acetonitrile under nitrogen gas, keep the reaction for 1h, add 1mol of 7-ACA in three times, stir at 29°C for 2.6h, Then add 80 mL of concentrated hydrochloric acid dropwise within 0.5 h, add 90 mL of water, keep warm at 15°C and stir for 1.5 h, then stir at 5°C for 1.5 h, filter with suction, wash the filter cake three times with 40 mL of acetonitrile-acetone solution with a volume ratio of 1:1, vacuum After drying, 46.70 g of 7-TMCA hydrochloride was obtained. 7-TMCA hydrochloride and 36 mL of N,N-dimethylacetamide were stirred and dissolved, and 5 mL of trimethylchlorosilane was added dropwise in an ice bath, and stirred at 18°C ​​for 1.5 h to obtain the group-protected 7- TMCA hydrochloride.

[0025] (2) Add 1.0 mol of 7-TMCA hydrochloride, 1.0 mol of HO-EPCP and 0.38 mol of diethyl benzotriazolyl phosphate, which were prepared in step (1), and add 520 mL of DMF solution, stir and ...

Embodiment 3

[0027] (1) Dissolve 1.2 mol of 1-methyl-5-mercaptotetrazolium in 140 mL of boron trifluoride acetonitrile under nitrogen gas, keep the reaction for 1 hour, add 1 mol of 7-ACA in three times, and stir at 29°C for 2.6 hours. Then add 80 mL of concentrated hydrochloric acid dropwise within 0.5 h, add 90 mL of water, keep warm at 15°C and stir for 1.5 h, then stir at 5°C for 1.5 h, filter with suction, wash the filter cake three times with 40 mL of acetonitrile-acetone solution with a volume ratio of 1:1, vacuum After drying, 46.70 g of 7-TMCA hydrochloride was obtained. 7-TMCA hydrochloride and 38 mL of N,N-dimethylacetamide were stirred and dissolved, and 7 mL of trimethylchlorosilane was added dropwise in an ice bath, and stirred at 18°C ​​for 1.5 h to obtain the group-protected 7- TMCA hydrochloride.

[0028] (2) Add 1.0 mol of 7-TMCA hydrochloride, 1.5 mol of HO-EPCP and 0.53 mol of benzotriazolyl diethyl phosphate prepared in step (1) into 560 mL of DMF solution, stir and a...

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Abstract

The invention belongs to the field of medicine, and particularly relates to a preparation method of cefoperazone acid. The method comprises the following steps: with 7-ACA (amin-oeephalosporanic acid) and 1-methyl-5-tetrazole-thione as raw materials under catalysis of boron trifluoride acetonitrile, reacting to prepare 7-TMCA (7-Amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-3-cephem-4-carboxylicacid)hydrochloride; carrying out carboxyl and amino group protection on the 7-TMCA hydrochloride by using trimethylchlorosilane; and with the group-protected 7-TMCA hydrochloride prepared in the step (1), HO-EPCP ((2R)-2-[(4-Ethyl-2,3-dioxopiperazinyl)carbonyllamino]-2-(4-hydroxyphenyl)acetic acid) and benzotriazole diethyl phosphonate as raw materials, carrying out N-acylation reaction in a DMF (Dimethyl Formamide) solution under catalysis of triethylamine, so as to obtain the cefoperazone acid, wherein acyl chloride is prepared by reaction in absence of the HO-EPCP, the benzotriazole diethyl phosphonate is directly added to directly carry out acylation reaction on the HO-EPCP and the group-protected 7-TMCA hydrochloride. Thus, the preparation method is simple in reaction step, low in cost and high in purity.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of cefoperazone acid. Background technique [0002] Cefoperazone acid is a third-generation cephalosporin antibiotic with a broad antibacterial spectrum and is the first-line drug against Pseudomonas aeruginosa. It 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 the production of β-lactamase Its ability is extremely low, and it is not easy to induce bacterial resistance. It has good therapeutic effect and safety on various infection symptoms such as respiratory tract, biliary tract, obstetrics and gynecology, and surgery. It has high stability, and its degradation in aqueous solution follows first-order kinetics. Domestic production of raw materials began in 1985, and clinical ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/36C07D501/04
CPCY02P20/55
Inventor 薛颖张立明
Owner YIYUAN XINQUAN CHEM
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