Method for preparing piperacillin acid

A technology of piperacillin acid and ampicillin, which is applied in the field of drug preparation, can solve the problems of ampicillin degradation and increase the difficulty of impurity removal, and achieve the effects of improved purity, wide market promotion value, and reduced side effects

Active Publication Date: 2015-09-16
NORTH CHINA PHARM GRP SEMISYNTECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The present invention provides a preparation method of piperacillin acid to solve the problem that the use of organic solvents in the acylation process of the existing piperacillin production process increases the difficulty of subsequent impurity removal, and the addition of acid chlorides leads to the degradation of ampicillin products.

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  • Method for preparing piperacillin acid
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  • Method for preparing piperacillin acid

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preparation example Construction

[0026] A kind of preparation method of piperacillin acid disclosed by the invention comprises the following steps:

[0027] a, add raw materials: add ampicillin, water, buffer solution of pH=6.0~9.0 in the reactor; Wherein the mass ratio of ampicillin and water added is 1:3~1:10, the added water and buffer solution The volume ratio is 4:1~10:1, and the buffer solution is boric acid-borax buffer solution, citric acid-disodium hydrogen phosphate buffer solution, glycine-sodium hydroxide buffer solution, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution or One of the ammonia-ammonium chloride buffer solutions.

[0028] Wherein, the ampicillin adopted in the present invention is a commercially available product, and the quality of ampicillin should meet the Pharmacopoeia standard. The pH of the boric acid-borax buffer solution is 7.5-9.0, and its preparation method is referred to the preparation of common buffer solutions. The pH of the citric acid-disodium...

Embodiment 1

[0035] A preparation method of piperacillin acid, comprising the following steps:

[0036] a, add raw materials: add raw materials in the reactor according to the mass ratio of ampicillin and water as 1:5, and the volume ratio of water and buffer solution as 4:1, add 8g ampicillin, 40mL water, 10mL pH in this embodiment =7.5-9.0 boric acid-borax buffer solution;

[0037] B, acylation reaction: in the reaction vessel of step a, continue to add raw materials by the mass ratio of EDPC and ampicillin as 1:2, add 4g EDPC in the present embodiment, add sodium hydroxide solution simultaneously, control pH to be 7.0-8.5 , after adding EDPC, insulate and react for 30 minutes at a temperature of 8°C;

[0038]c. Crystallization and purification: continue to add 50 mL of water to the reaction vessel of step a according to the volume ratio of the solvent to the water added in step a as 1.25:1, and crystallize. Control the crystallization temperature to 15° C. The pH at the end point was ...

Embodiment 2

[0040] A preparation method of piperacillin acid, comprising the following steps:

[0041] a, add raw materials: in the reactor, the mass ratio of ampicillin and water is 1:6, and the volume ratio of water and buffer solution is 9.6:1. Add raw materials, add 16g ampicillin, 96mL water, 10mL pH in the present embodiment =6.0-8.0 citric acid-disodium hydrogen phosphate buffer solution;

[0042] B, acylation reaction: in the reaction vessel of step a, press EDPC and the mass ratio of ampicillin is 1:4 to continue to add raw material, add 4g EDPC in the present embodiment, add sodium carbonate solution simultaneously, control pH to be 6.0-8.0, After adding EDPC, insulate and react for 45 minutes at a temperature of 3°C;

[0043] c. Crystallization and purification: continue to add 96mL of ethyl acetate to the reaction vessel of step a according to the volume ratio of the solvent and the water added in step a as 1:1 for crystallization, control the crystallization temperature to 1...

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Abstract

The invention discloses a method for preparing piperacillin acid. The method comprises the following steps: adding ampicillin, water and a buffer solution with the pH of 6.0-9.0 into a reactor; adding EDPC into the reactor, meanwhile, adding an alkaline regulator to control the pH to be 6.0-9.0, and reacting for 30-60 minutes in the temperature range of 0 to 10 DEG C while carrying out heat preservation; and adding a solvent to crystallize, controlling the crystallizing point to be 15+/-2 DEG C, dropwise adding an acidic regulator to regulate the end pH to be 1.5-2.0, carrying out crystal growing for 1 hour in the temperature range of 0 to 10 DEG C, and then, filtrating, washing and drying crystals, thereby obtaining the piperacillin acid finished product. According to the method, during acylation, water is used as a solvent, and the buffer solution is added, so that synthetic reaction for piperacillin acid is inhibited from going towards a reverse reaction direction, the yield of piperacillin acid is increased, and the purity of the product is improved.

Description

technical field [0001] The invention relates to a preparation method of medicine, in particular to a preparation method of piperacillin acid. Background technique [0002] The chemical name of piperacillin is (2S,5R,6R)-6-[2-(2R)-4-(4-ethyl-2,3-dioxo-1-piperazinyl)formamide Base-2-phenylacetamido]penicillanic acid is a semi-synthetic penicillin antibiotic with a white or off-white powder appearance, developed by Japan Toyama Chemical Industry Co., Ltd. The effect of piperacillin on gram-positive bacteria is similar to that of ampicillin, and it has a good antibacterial effect on enterococci, and it also has certain effects on some bacteroides and clostridia, and has a broad-spectrum antibacterial effect. Its structural formula is shown below. [0003] [0004] The structural formula of piperacillin [0005] In the synthesis process of piperacillin acid, ampicillin and 4-ethyl-2,3-dioxopiperazinocarbonyl chloride (EDPC for short) are usually used for acylation reaction ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/04C07D499/68
CPCC07D499/04C07D499/68
Inventor 左丽华严正人高任龙朱军魏士倩郝瑞霞刘慧勤王利杰刘丹
Owner NORTH CHINA PHARM GRP SEMISYNTECH CO LTD
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