One-pot preparation process of monosodium ertapenem

A preparation process, the technology of ertapenem, which is applied in the preparation of ertapenem monosodium salt and in the field of pharmaceutical synthesis, can solve the problems of poor product purity and excessive heavy metals

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

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Problems solved by technology

[0013] Chinese patent application CN102731506A reports that the product of this method will also be degraded in large quantities, and the resulting product has poor purity and heavy metals exceeding the standard

Method used

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  • One-pot preparation process of monosodium ertapenem
  • One-pot preparation process of monosodium ertapenem

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1: Preparation of double-protected ertapenem crystal form

[0057] In a dry four-neck flask, put carbapenem core (40.0g, 0.067mol), 60ml of dimethylformamide,

[0058] Under the protection of nitrogen, stir to dissolve and clarify. Cool to -40~-30°C, add diisopropylethylamine (17.4g, 0.135mol) dropwise, and control the temperature at -40~-30°C. After the dropping, ertapenem side chain (31.60 g, 0.071 mol) dissolved in 120 ml of dimethylformamide was added dropwise at -40 to -30°C. After dropping, keep warm at -40~-30°C until the reaction is complete, add 400ml of dichloromethane to the reaction solution, and then wash with potassium dihydrogen phosphate buffer solution with a pH value of 2-10, and the organic layer obtained at -5~-10 Stir and crystallize at ℃ overnight, filter, wash the filter cake with a small amount of dichloromethane, filter dry, and send it to 25 ℃ for vacuum drying to obtain 49.9g of double-protected ertapenem crystal form, the yield is 9...

Embodiment 2

[0059] Example 2: Preparation of Ertapenem Monosodium Salt

[0060] In a dry four-neck flask, add carbapenem nucleus (36.2 g, 0.061 mol) and 110 ml of dimethylformamide, stir to dissolve and clarify under nitrogen protection. Cool to -40~-30°C, add diisopropylethylamine (15.74g, 0.122mol) dropwise, and control the temperature at -40~-30°C. After the dropping, ertapenem side chain (29.0 g, 0.065 mol) dissolved in 110 ml of dimethylformamide was added dropwise at -40 to -30°C. After dropping, keep warm at -40~-30°C until the reaction is complete, add 400ml of dichloromethane to the reaction solution, then wash with potassium dihydrogen phosphate buffer solution with a pH value of 2-10, concentrate the obtained organic layer to dryness, add 300ml THF was stirred to dissolve and clarified, then cooled to about 0-5°C, and 160ml of 5% sodium bicarbonate solution was added dropwise. After dropping, the mixture was poured into a 2000L autoclave, and then 12.0g of 10% palladium carbon...

Embodiment 3

[0061] Example 3: Preparation of Ertapenem Monosodium Salt

[0062] In a dry four-neck flask, add carbapenem nucleus (36.2 g, 0.061 mol) and 60 ml of dimethylformamide, stir to dissolve and clarify under nitrogen protection. Cool to -40~-30°C, add diisopropylethylamine (15.74g, 0.122mol) dropwise, and control the temperature at -40~-30°C. After the dropping, ertapenem side chain (27.16 g, 0.061 mol) dissolved in 60 ml of dimethylformamide was added dropwise at -40 to -30°C. After dropping, keep warm at -40~-30°C until the reaction is complete. Add 350ml of dichloromethane and 50ml of methanol to the reaction solution, then wash with potassium dihydrogen phosphate buffer solution with a pH value of 2-10, and concentrate the obtained organic layer to dryness. , add 300ml THF, stir to dissolve and clarify, then cool to about 0-5°C, add 400ml of 2% sodium bicarbonate solution dropwise. The kettle was replaced with nitrogen, and then replaced with hydrogen. After the replacement,...

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Abstract

The present invention relates to the technical field of medicine synthesis, especially to the technical field of monosodium ertapenem preparation, specifically to a one-pot preparation process of monosodium ertapenem. The one-pot preparation process comprises: i) carrying out a condensation reaction of a compound represented by a formula (a) and a compound represented by a formula (b) in the presence of an organic alkali, pouring the reaction solution into a halogenated alkane solvent, washing with a buffer solution, and concentrating the organic layer to obtain a compound represented by a formula (c); and ii) adding tetrahydrofuran to dissolve the concentrated compound represented by the formula (c), cooling to a temperature of -5-10 DEG C, adding a sodium bicarbonate solution with a mass fraction of 0.5-5% in a dropwise manner, adding palladium carbon, introducing hydrogen gas, filtering after completing the reaction, rinsing the filter cake with water, adjusting the pH value of the filtrate with acetic acid/methanol to 5-6, adding an alcoholic solvent/dichloromethane, carrying out stirring layering, adding a solvent A to the obtained water layer, adding a methanol/n-propanol mixed solution in a dropwise manner at a temperature of 0-5 DEG C, filtering, and rinsing the filter cake with acetone to obtain the monosodium ertapenem.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to the technical field of preparation of ertapenem monosodium salt. 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-ene-2-carboxylic acid sodium salt, its structural formula is as follows: [0003] [0004] The application number is CN93101472.7 Example 12 discloses the preparation method of ertapenem. The method uses compound 1 as raw material, under the action of tetrakis(triphenylphosphine) palladium and 10% palladium carbon catalyst, tetrahydrofuran, The mixed solution of ethyl acetate and water is used as the reaction solvent, undergoes hydrogenation deprotection reaction, the reaction is completed, filtered, th...

Claims

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Application Information

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