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Preparation method of cefoperazone acid

A technology of cefoperazone acid and dichloromethane, which is applied in the field of preparation of cefoperazone acid, can solve the problems of high residual solvent in the product, poor product fluidity and high S-isomer, and achieves difficult to encapsulate impurities and low fluidity. , the effect of low S-isomer

Inactive Publication Date: 2018-11-30
东瑞(南通)医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the high reaction temperature, this process has the disadvantage of high S-isomer. At the same time, water is used to separate the product from acetonitrile and DMA. The solvent recovery is difficult and the residual solvent of the product is high.
[0007] Han Xinzheng et al used dichloromethane as solvent to silylate 7-TMCA with N, O-(bis)trimethylsilyl acetamide; dichloromethane and DMA as solvents, dissolved HO-EPCP, added dropwise trichloroxy Phosphorus is chlorinated, combined for condensation reaction, sodium bicarbonate and water are added at the end of the reaction, layered, and the water phase adjusts the pH to crystallize to obtain cefoperazone acid. This process solvent recovery is simple, but the crystallization is directly crystallized from the water phase. During the crystallization process It is easy to wrap impurities, and the resulting product has poor fluidity
[0008] JPS57118588A discloses a synthetic method, the hydrochloride of 7-MPCA is the starting material, HO-EPCP and pivaloyl chloride are used to prepare anhydride, mixed and condensed to obtain cefoperazone acid, but the product yield is low

Method used

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  • Preparation method of cefoperazone acid
  • Preparation method of cefoperazone acid
  • Preparation method of cefoperazone acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] (1) Add 20g of 7-TMCA to 40mL of dichloromethane, add 7.86g of hexamethyldisilazane, 5.29g of trimethylchlorosilane, react at 45°C for 4 hours, cool and set aside.

[0026] (2) 80mL of dichloromethane and 20mL of DMA, add 22.46g of HO-EPCP, dropwise add 6.85g of triethylamine, cool down to -50°C, add 0.04g of pyridine, dropwise add 7.95g of ethyl chloroformate, and react for 2h.

[0027] (3) Add (1) into (2), control the temperature at -40~-45°C, and react for 2 hours.

[0028] (4) After the reaction, add 120 mL of water, adjust the pH to 6.5 with triethylamine, add 20 mL of acetone, adjust the pH to 2.0 with acid to crystallize, filter and dry to obtain 35.33 g of cefoperazone acid, and the weight yield is 176.65%.

Embodiment 2

[0030] (1) Add 20g of 7-TMCA to 40mL of dichloromethane, add 18g of N,O-(bis)trimethylsilylacetamide, react at 35°C for 1 hour, cool down, and set aside.

[0031] (2) 80mL of dichloromethane and 20mL of DMA, add 22.85g of HO-EPCP sodium salt, cool to -40°C, add 0.05g of lutidine, dropwise add 8.3g of ethyl chloroformate, and react for 2h.

[0032] (3) Add (1) into (2), control the temperature at -35~-40°C, and react for 2 hours.

[0033] (4) After the reaction, add 120 mL of water, adjust the pH to 7.0 with sodium carbonate, add 20 mL of acetonitrile, adjust the pH to 1.8 with acid to crystallize, filter and dry to obtain 35.40 g of cefoperazone acid, and the weight yield is 177%.

Embodiment 3

[0035] (1) Add 20g of 7-TMCA to 40mL of dichloromethane, add 13.76g of hexamethyldisilazane, react at 35°C for 1 hour, cool down, and set aside.

[0036] (2) 80mL of dichloromethane and 20mL of DMA, add 22.85g of HO-EPCP potassium salt, cool down to -50°C, add 0.06g of N-methylmorpholine, dropwise add 7.3g of ethyl chloroformate, and react for 2h.

[0037] (3) Add (1) into (2), control the temperature at -45~-50°C, and react for 2 hours.

[0038] (4) After the reaction, add 120 mL of water, adjust the pH to 6.0 with sodium bicarbonate, add 20 mL of methanol, adjust the pH to 2.2 with acid to crystallize, filter and dry to obtain 35.10 g of cefoperazone acid, and the weight yield is 175.5%.

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Abstract

The invention relates to a preparation method of cefoperazone acid. The preparation method comprises the following steps: (1) in a dichloromethane system, allowing 7-TMCA to react with a silanizationreagent at 20-70 DEG C, and carrying out silanization protection on the amino group and the carboxyl group; (2) in a dichloromethane body and a DMA system, allowing HO-EPCP salt to react with ethyl chloroformate at the reaction temperature of 20-70 DEG C under the action of a catalyst to prepare mixed anhydride; (3) adding the 7-TMCA after silanization protection into the mixed anhydride, reactingat 20-70 DEG C to obtain a reaction solution; (4) hydrolyzing the reaction solution, adding alkali to adjust the pH to be 5.5-7.5, layering, adding solvent into the water phase, adding acid to adjustthe pH to be 1.5-2.5, crystalizing and filtering to obtain cefoperazone acid. The method disclosed by the invention has the advantages that the product yield can be improved, S-isomer can be reduced,the residual solvent is reduced, the solvent is easy to recycle, the wastewater does not contain phosphorus and is easy to process.

Description

technical field [0001] The invention relates to a preparation method of an antibiotic intermediate, in particular to a preparation method of cefoperazone acid. Background technique [0002] 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 [0003] [0004] The synthetic techniques of cefoperazone acid include mixed anhydride method, acid chloride method, two-step synthesis method, etc. Currently, the acid chloride method is more commonly used. [0005] Jin Shi and others dissolved HO-EPCP in DMA as a solvent, and added phosphorus oxychloride dropwise to prepare HO-EPCP chloride. At the same time, using DMA as a solvent, dissolve the hydrochloride of 7-TMCA, stir evenly, and add trimethylchlorosilane to remove the water con...

Claims

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Application Information

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IPC IPC(8): C07D501/06C07D501/12C07D501/36
CPCC07D501/06C07D501/12C07D501/36
Inventor 陈永生高飞周永泉张楚天杨军田
Owner 东瑞(南通)医药科技有限公司
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