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Preparation process of Mezlocillin

A technology of mezlocillin and ampicillin trihydrate, applied in the direction of organic chemistry, etc., can solve the problems of high solvent residue in ethyl acetate and unreported solvent residue in ethyl acetate, etc., and achieve the reduction of solvent residue, obvious economic benefits and Social benefit, quality improvement effect

Active Publication Date: 2009-11-25
ZHEJIANG JINHUA CONBA BIO PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this preparation process does not report the solvent residue of ethyl acetate in the mezlocillin product, the solvent residue of ethyl acetate in the mezlocillin product obtained by our experiment according to this method is high, higher than the ICH international standard (≤0.5%) , by the mezzlocillin that this method gained by experiment, the solvent residue of the ethyl acetate in the mezzlocillin sodium product that obtains by traditional method salting in aqueous phase, lyophilization is still higher than ICH international standard (≤ 0.5%) (little removal of ethyl acetate in lyophilization)

Method used

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  • Preparation process of Mezlocillin
  • Preparation process of Mezlocillin
  • Preparation process of Mezlocillin

Examples

Experimental program
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Effect test

Embodiment 1

[0054] Add 10kg of ampicillin trihydrate (II), 150L of purified water to the cleaned reactor, stir, cool to 0-5°C, add 4% sodium hydroxide solution dropwise until all ampicillin trihydrate is dissolved, add slowly 5.9kg 1-chloroformyl-3-methanesulfonyl-2-imidazolidinone (III) was subjected to condensation reaction, and the reaction temperature was kept at 0-5°C, while 4% sodium hydroxide solution was added dropwise to control the pH of the solution. Between 7.0-7.5; the condensation reaction is over, the reaction product is filtered, 40L of acetone is added to the filtrate, the temperature is controlled at 20-25℃, 1N hydrochloric acid is added dropwise, and solids are precipitated. When the pH value is 2.0, stop adding 1N hydrochloric acid and continue Stir for about 30 minutes; the crystalline product is separated by filtration, and the solid is washed three times with a 20% acetone aqueous solution (volume ratio, acetone:water=1:4) in a conventional amount, filtered to dryness, ...

Embodiment 2

[0057] Add 10kg of ampicillin trihydrate (II), 150L of purified water to the cleaned reactor, stir, cool to 0-5°C, add 4% sodium hydroxide solution dropwise until all ampicillin trihydrate is dissolved, add slowly 5.9kg 1-chloroformyl-3-methanesulfonyl-2-imidazolidinone (III), continue to maintain the reaction temperature at 0-5 ℃, while adding 4% sodium hydroxide solution to control the pH of the solution at 7.0-7.5 Between; the reaction product was filtered, 60L of acetone was added to the filtered filtrate, the temperature was controlled at 20-25 ℃, 1N hydrochloric acid was added dropwise to precipitate solids, when the pH value was 2.0, stop adding 1N hydrochloric acid, and continue to stir for about 30 minutes The crystalline product was separated by filtration, and the solid was washed three times with 20% acetone aqueous solution (volume ratio, acetone:water=1:4), filtered to dryness, and dried to obtain (I). The quality situation is as follows:

[0058]

Embodiment 3

[0060] Add 10kg of ampicillin trihydrate (II), 150L of purified water to the cleaned reactor, stir, cool to 0-5°C, add 4% sodium hydroxide solution dropwise until all ampicillin trihydrate is dissolved, add slowly 5.9kg 1-chloroformyl-3-methanesulfonyl-2-imidazolidinone (III), continue to maintain the reaction temperature at 0-5 ℃, while adding 4% sodium hydroxide solution to control the pH of the solution at 7.0-7.5 Between; the reaction product is filtered, 55L ethanol is added to the filtered filtrate, the temperature is controlled at 20-25 ℃, 1N hydrochloric acid is added dropwise to precipitate solids, when the pH value is 2.0, stop adding 1N hydrochloric acid, continue to stir for about 30 minutes The crystalline product is separated by filtration, and the solid is washed three times with a conventional 20% ethanol aqueous solution (volume ratio, ethanol: water=1:4), filtered to dryness, and dried to obtain (I). The quality situation is as follows:

[0061]

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Abstract

The invention relates to a preparation process of Mezlocillin, which reacts Ampicillin trihydrate with 1-chlorocarbonyl-3-methylsulfonyl-2-imidazolidinone in water phase under alkaline condition and then proceeds acidified crystallization, filtration, washing and drying in acetone / water, or alcohol / water, or isopropanol / water system to obtain Mezlocillin. The Mezlocillin prepared by the inventive method can reach 95%-97% of molar yield, 0.06%-0.4% of organic residual quantity, more than 98.5% of dry basis content, less than 0.4% of single impurity, less than 1.5% of total related substances and good quality, is particularly suitable for direct lyophilization in water-phase salt formation to obtain high-quality Mezlocillin sodium for injection of medicinal product, and has prominent economical and social benefits.

Description

(1) Technical field: [0001] The invention belongs to the field of drug synthesis, and specifically relates to a method for preparing mezlocillin. (2) Background technology: [0002] Mezlocillin, its chemical name is (2S, 5R, 6R)-3,3-dimethyl-6-[(R)-2-{3-(methylsulfonyl-2-oxo-1-imidazolidine Carboxamide)-2-phenylacetamido}-7-oxo-4-thia-1-azabicyclo[3.2.O]heptane-2-carboxylic acid. Has the following structure of formula I: [0003] [0004] Mezlocillin (I) is the precursor of a new semi-synthetic penicillin and mezlocillin sodium (IV). Its medicinal manifestation is mezlocillin sodium for injection. It is generally salted by mezlocillin in an aqueous solution, lyophilized or passed through a solvent. It is obtained by crystallization and is a semi-synthetic ureide penicillin, first developed and marketed in Germany. It has been included in the American, Japanese and European Pharmacopoeias. Mezlocillin sodium has broad-spectrum antibacterial activity, and has good antibacterial a...

Claims

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Application Information

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IPC IPC(8): C07D499/68C07D499/04
Inventor 金庆平赖月琴李文辉宋旭莹黄卫莲贾红妹余斌
Owner ZHEJIANG JINHUA CONBA BIO PHARM CO LTD
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