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Preparation method of ertapenem and its sodium salt

A technology of ertapenem and sodium salt is applied in the field of preparation of carbapenem compound ertapenem and its sodium salt, and can solve the problems of difficult removal, excessive heavy metals, poor product purity and the like, and achieves improved product purity, Reduce the effect of product degradation

Active Publication Date: 2012-10-17
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The former deprotection method needs to be carried out under argon and no light conditions, and the reaction conditions are harsh; although the latter deprotection method has relatively mild reaction conditions, it has the following defects: 1) it needs to use tetrakis (triphenylphosphine) palladium and palladium-carbon catalysts, and tetrakis (triphenylphosphine) palladium is sensitive to air, so it needs to be stored in a dark place and refrigerated; 2) the catalyst is dissolved in the reaction solvent, and it is not easy to remove after post-treatment; 3) the product appears during post-treatment A large amount of degradation will affect the purity of the final product
[0014] Although the method reported in the above literature avoids the use of ertapenem side chain 4 (P is HCl) as raw material and ion-pair reagent extraction technology and / or multi-stage countercurrent centrifugal extraction technology, and attempts to change the reaction solvent or use activated carbon adsorption method to remove the catalyst in the solution, but the effect is not good, and the product is degraded in large quantities, resulting in poor purity of the product and excessive heavy metals

Method used

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  • Preparation method of ertapenem and its sodium salt
  • Preparation method of ertapenem and its sodium salt
  • Preparation method of ertapenem and its sodium salt

Examples

Experimental program
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preparation example 1

[0037] Preparation Example 1P 1 ,P 2 Both are PNB, P 3 ,P 4 Preparation of compound 2a for H

[0038] Compound 3(P 1 PNB) 36.0g was dissolved in 300ml DMF, compound 4 (P 2 PNB) 26.7g, 7.3g of diisopropylethylamine was slowly added dropwise at -35°C, and reacted under stirring. After completion of the reaction, the reaction solution was added to the acid aqueous solution of pH 2~6 to obtain 46.6g of compound 2a (P 1 ,P 2 Both are PNB, P 3 is H) solid.

[0039] P 1 ,P 2 For other carboxyl protecting groups (including P is HCl), P 3 The preparation of compound 2a which is H can refer to the method described in Preparation Example 1.

preparation example 2

[0040] Preparation Example 2P 1 ,P 2 Both are PNB, P 3 for Na + ,P 4 Preparation of compound 2a for H

[0041] Compound 3(P 1 is PNB) 100g and compound 4 (P 2 for PNB, P 3 Dissolve 73.8g of H) in DMF, add 60mL of DBU solution in DMF at -50°C, stir, after the reaction is complete, pour the reaction solution into ethyl acetate and buffer solution (175g potassium dihydrogen phosphate dissolved in water or hydrogen phosphate In the mixed solution of dipotassium buffer solution), adjust the pH value of the two-phase system to 4.5, separate the liquids, add the ethyl acetate solution of sodium isooctanoate (32g) to the organic phase, obtain a pasty substance, and slowly pour out the organic phase layer, the paste substance was dissolved in methanol, and isopropyl ether was added to the methanol solution to obtain 110g of compound 2a (P 1 ,P 2 Both are PNB, P 3 for Na + )solid.

[0042] P 1 ,P 2 For other carboxyl protecting groups (including P is HCl) and P 3 The prep...

preparation example 3

[0043] Preparation Example 3P 1 ,P 2 ,P 3 Both are PNB, P 4 Preparation of compound 2a for H

[0044] Add 2L of anhydrous acetonitrile into the reaction flask, cool to -20°C under the protection of dry nitrogen, add compound 3(P 1 is PNB) 59.5g, compound 4 (P 2 ,P 3 Both are PNB) 69.7g and diisopropylamine 12.1g, react at -15°C for 4h, pour the reaction solution into 2.5L ice water, extract with dichloromethane (1L×3), combine the organic phases, and use Saturated brine (1L×3), dried over anhydrous sodium sulfate, filtered, and concentrated to give 64.5g of compound 2a (P 1 ,P 2 ,P 3 Both are PNB) solids.

[0045] P 1 ,P 2 ,P 3 The preparation of compound 2a, which are all other carboxyl protecting groups, can refer to the method described in Preparation Example 3.

[0046] The present invention will be further described below in conjunction with examples, but these examples do not constitute any limitation to the present invention.

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Abstract

The invention relates to a preparation method of ertapenem as shown in the formula 1 and its sodium salt. According to the method, water is used as a reaction solvent, an ertapenem intermediate as shown in the formula 2a undergoes a hydrogenated deprotection reaction in the presence of alkali and a catalyst, so as to generate ertapenem as shown in the formula 1 or its sodium salt. The single solvent water is used as a reaction solvent in the method provided by the invention, thus solving the problem of dissolving the catalyst by the reaction solvent, simplifying post-treatment operational step, reducing product degradation and raising product purity. In addition, the preparation method is economical, safe and environmentally friendly, and is more suitable for industrial operation at large scale.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to an improved preparation method of a carbapenem compound ertapenem and its sodium salt. Background technique [0002] Ertapenem (Ertapenem, structural formula as formula 1), chemical name [4R, 5S, 6S]-3-[[(3S, 5S)-5-[[(3-carboxyphenyl)amino]carbonyl]- 3-pyrrolyl]mercapto-6-[(1R)-1-hydroxyethyl]-4-methyl-7-carbonyl-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid , a new broad-spectrum carbapenem antibiotic jointly developed by Merck and AstraZeneca, has good antibacterial activity against Gram-positive bacteria and negative aerobic and anaerobic bacteria. [0003] [0004] Chinese patent CN93101472.7 discloses the compound ertapenem and its disodium salt and their preparation methods for the first time, and the disclosed synthetic route is shown in Scheme 1. Due to the difference in the protecting groups of the raw material compound 2 used, different deprotection meth...

Claims

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Application Information

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IPC IPC(8): C07D477/20C07D477/06
CPCY02P20/55
Inventor 史颖李坤赵学斌谢赞吕健
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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