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Synthetic method of cefoperazone acid

A technology of cefoperazone acid and a synthesis method, applied in the field of medicine, can solve the problems of unstable acyl chloride intermediate, unfavorable industrial production, harsh reaction conditions and the like, and achieves the effects of simple preparation method, stable intermediate and improved yield

Active Publication Date: 2016-05-11
HENAN KANGDA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] At present, the synthesis methods of cefoperazone acid mainly include acid chloride method, mixed acid anhydride method, thioester method, and amino substituent distribution condensation method. The existing synthesis methods have high raw material costs, unstable acid chloride intermediates, and low product yields. , harsh reaction conditions, poor product quality and other defects are not conducive to large-scale industrial production

Method used

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  • Synthetic method of cefoperazone acid
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  • Synthetic method of cefoperazone acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] (1) Mix 65g of boron trifluoride acetonitrile and 6.8g of 1-methyl-5-mercaptotetrazolium, stir for 30min, then add 14g of 7-ACA, react at 30°C for 1h, transfer to 100g of purified water for hydrolysis, and At 10°C, add dilute ammonia water until crystals appear, grow crystals for 30 minutes, continue to add dilute ammonia water to adjust the pH to 3.0, grow crystals for 1 hour, filter with suction, wash with 60% acetone aqueous solution, and dry until the water content is ≤1%. To obtain 16.1g of white solid 7-ACT, its purity>99%, mass yield 115%;

[0029] (2) Mix 14g of 7-ACT from step (1), 77ml of acetonitrile, and 14g of N,O-(bis)trimethylsilylacetamide, stir and dissolve until clear at a temperature of 25°C to obtain 7-ACT amino Alkylate solution, cooled to 0°C, set aside;

[0030] (3) Mix 15.5g of HO-EPCP, 45ml of N,N-dimethylacetamide, 25ml of acetonitrile and 8g of trimethylchlorosilane, stir and dissolve, then cool down to -20°C, then add 8.1g of phosphorus oxyc...

Embodiment 2

[0033] (1) Mix 65g of boron trifluoride acetonitrile and 6.8g of 1-methyl-5-mercaptotetrazolium, stir for 30min, then add 14g of 7-ACA, react at 30°C for 1h, transfer to 100g of purified water for hydrolysis, and At 10°C, add dilute ammonia water until crystals appear, grow crystals for 30 minutes, continue to add dilute ammonia water to adjust the pH to 3.0, grow crystals for 1 hour, filter with suction, wash with 60% acetone aqueous solution, and dry until the water content is ≤1%. Get 7-ACT;

[0034] (2) Mix 14g of 7-ACT from step (1), 90ml of acetonitrile, and 14g of N,O-(bis)trimethylsilylacetamide, stir and dissolve until clear at a temperature of 25°C to obtain 7-ACT amino Alkylate solution, cooled to 0°C, set aside;

[0035] (3) Mix 15g of HO-EPCP, 60ml of N,N-dimethylacetamide, 40ml of acetonitrile and 8g of trimethylchlorosilane, stir and dissolve, then cool down to -20°C, then add 8.1g of phosphorus oxychloride, and keep the reaction , HPLC tracking detection reac...

Embodiment 3

[0038] (1) Mix 65g of boron trifluoride acetonitrile and 6.8g of 1-methyl-5-mercaptotetrazolium, stir for 30min, then add 14g of 7-ACA, react at 30°C for 1h, transfer to 100g of purified water for hydrolysis, and At 10°C, add dilute ammonia water until crystals appear, grow crystals for 30 minutes, continue to add dilute ammonia water to adjust the pH to 3.0, grow crystals for 1 hour, filter with suction, wash with 60% acetone aqueous solution, and dry until the water content is ≤1%. Get 7-ACT;

[0039] (2) Mix 13g of 7-ACT from step (1), 70ml of acetonitrile, and 13g of N,O-(bis)trimethylsilylacetamide, stir and dissolve until clear at a temperature of 25°C to obtain 7-ACT amino Alkylate solution, cooled to 0°C, set aside;

[0040](3) Mix 16g HO-EPCP, 60ml N,N-dimethylacetamide, 40ml acetonitrile and 10g trimethylchlorosilane, stir and dissolve, then cool down to -25°C, then add 7.5g phosphorus oxychloride, keep warm for reaction , HPLC tracking detection reaction solution,...

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Abstract

The invention discloses a synthetic method of cefoperazone acid. The method comprises the steps of: reacting raw materials of 7-ACA and 1-methyl-5-mercapto tetrazole under the catalysis of boron trifluoride acetonitrile to obtain 7-ACT; dissolving the 7-ACT in a mixed solution of acetonitrile and N,O-(bis) trimethylsilyl acetamide to obtain a 7-ACT amino alkylate solution; mixing HO-EPCP, an organic solvent and a catalyst, adding phosphorus oxychloride for reaction at the temperature of -25 to -20 DEG C, wherein when the residue amount of HO-EPCP in the reaction solution is no more than 0.5%, the reaction is complete, so as to prepare a HO-EPCP acyl chloride solution; mixing and reacting 7-ACT amino alkylate solution with HO-EPCP acyl chloride solution, adding an aqueous solution of sodium bicarbonate after the reaction, standing foe stratification, filtering a lower layer material, adding water, crystallizing, filtering, washing and drying to obtain the cefoperazone acid. The method has the advantages of simpleness, high yield and stable intermediate.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a method for synthesizing cefoperazone acid. Background technique [0002] Cefoperazone sodium is the third-generation cephalosporin developed and discovered by Japan Toyama Chemical Industry Company. It is used to treat respiratory tract infection, biliary tract infection, obstetrics and gynecology infection, surgical infection, etc. After entering the body, it is hydrolyzed by non-specific esterase into cefoperazone to play a role. [0003] Cefoperazone, the chemical name is 7-(((4-ethyl-2,3-dioxo-1-piperazinyl)formamido)(4-hydroxyphenyl)acetamido)- 3-((1-Methyl-1H-tetrazol-5-yl)thiomethyl)-8-oxo-5-thio-1-azabicyclo(4.2.0)oct-2-ene-2- Formic acid is a raw material for the synthesis of cefoperazone sodium, and its structural formula is: [0004] [0005] At present, the synthesis methods of cefoperazone acid mainly include acid chloride method, mixed acid anhydride method...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36C07D501/06
CPCC07D501/06C07D501/36
Inventor 刘建峰李红德韩新正李志军李文杰高德瀛孙津鸽
Owner HENAN KANGDA PHARMA
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