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New monosodium ertapenem crystal form and preparation process thereof

A technology for the preparation of ertapenem, applied in the direction of organic chemistry, organic chemistry methods, etc., can solve the problems of affecting crystal form stability, small particle size of activated carbon, and degradation of ertapenem, so as to reduce moisture absorption and Degradation risk, low risk of product degradation, easy to filter effect

Inactive Publication Date: 2015-07-22
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this preparation process needs to add an activated carbon decolorization step at low temperature. The small size of activated carbon will prolong the filtration time. Long-term filtration will lead to moisture absorption of the crystal form and degradation of ertapenem, which will affect the stability of the crystal form. have an impact

Method used

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  • New monosodium ertapenem crystal form and preparation process thereof
  • New monosodium ertapenem crystal form and preparation process thereof
  • New monosodium ertapenem crystal form and preparation process thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1: Preparation of ertapenem monosodium salt crystal form

[0060]Put the double-protected base ertapenem (48g, 0.061mol) into a three-necked flask, add 300ml THF, stir to dissolve and clarify, then cool to about 0-5°C, add 600ml of 1% sodium bicarbonate solution dropwise, after dropping, put Pour the mixed solution into a 2000L autoclave, then add 12.0g of 10% palladium carbon, replace the reaction kettle with nitrogen, and then replace with hydrogen. After 5 hours, TLC detection was completed and the reaction was filtered, the filter cake was rinsed with 5ml of pure water, the filtrate was adjusted to PH=5-6 with acetic acid / methanol, then 500ml of isopropanol and 500ml of dichloromethane were added, and the layers were stirred for 10 minutes and separated. Add 300ml of n-butanol to the aqueous layer, stir and separate the layers, separate the aqueous layer and add methanol / n-propanol (200 / 100ml) mixture dropwise after filtration. After dropping, add ertapenem ...

Embodiment 2

[0061] Example 2: Preparation of ertapenem monosodium salt crystal form

[0062] Put the double-protected base ertapenem (48g, 0.061mol) into a three-neck flask, add 350ml THF, stir to dissolve and clarify, then cool to about 0-5°C, add 160ml of 5% sodium bicarbonate solution dropwise, after the drop is completed, put The mixture was poured into a 2000L autoclave, and then 10.0g of 10% palladium carbon was added. The reactor was replaced with nitrogen, and then replaced with hydrogen. After 5 hours, the TLC detection reaction was completed and filtered, the filter cake was rinsed with 5ml of pure water, the filtrate was adjusted to PH=5-6 with acetic acid / methanol, then 600ml of n-propanol and 700ml of dichloromethane were added, and the layers were stirred for 10 minutes and separated. Add 300ml of n-butanol to the aqueous layer, stir and separate the layers, separate the aqueous layer and add methanol / n-propanol (250 / 125ml) mixture dropwise after filtration. After dropping, ...

Embodiment 3

[0063] Example 3: Preparation of ertapenem monosodium salt crystal form

[0064] Put the double-protected base ertapenem (48g, 0.061mol) into a three-necked flask, add 350ml THF, stir to dissolve and clarify, then cool to about 0-5°C, add 250ml of 3% sodium bicarbonate solution dropwise, after dropping, put Pour the mixed liquid into a 2000L autoclave, then add 13.0g of 10% palladium carbon, replace the reaction kettle with nitrogen, and then replace with hydrogen. After 5 hours, after TLC detection, the reaction was completed and the filter cake was rinsed with 5ml of pure water. The filtrate was adjusted to PH=5-6 with acetic acid / methanol, then 600ml of n-propanol and 500ml of dichloromethane were added, and the layers were stirred for 10 minutes and separated. Add 300ml of n-butanol to the obtained water layer, stir and separate layers, separate the obtained water layer and drop into methanol / n-propanol (400 / 400ml) mixed solution after filtering. After dropping, add ertape...

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Abstract

The present invention relates to the technical field of pharmaceutical intermediate synthesis, particularly to a new monosodium ertapenem crystal form and a preparation process thereof, wherein the characteristic peaks exist when the 2[theta] angle is 4.63+ / -0.1 DEG, 5.51+ / -0.1 DEG, 7.32+ / -0.1 DEG, 7.74+ / -0.1 DEG, 8.19+ / -0.1 DEG, 10.99+ / -0.1 DEG, and 12.99+ / -0.1 DEG.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a new crystal form of ertapenem monosodium salt and the technical field of preparation thereof. Background technique [0002] Ertapenem sodium is a new type of broad-spectrum carbapenem antibiotic developed by Merck Pharmaceuticals, the chemical name is (4R,5S,6S)-3-[[(3S,5S)-5-[[(3 -Carboxyphenyl)carbamoyl]pyrrolidin-3-yl]thio-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]heptyl- 2-alkene-2-carboxylic acid sodium salt, its structural formula is as follows: [0003] [0004] Patent application document WO2008062279 discloses amorphous ertapenem monosodium salt, which is unstable, easily discolored and has low purity. [0005] Patent application document WO2003026572 discloses type A and type B crystals of ertapenem monosodium salt. The method for preparing type A crystals is to first add part of n-propanol to an aqueous solution of er...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/06
CPCC07D477/20C07B2200/13C07D477/06
Inventor 蔡亚祥方健张怀宝林荆鑫
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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