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A kind of preparation method of imipenem

A technology of imipenem and diisopropylethylamine, applied in organic chemistry and other directions, can solve the problems of yield impact, many impurities, complicated operation, etc., and achieve creative effects

Active Publication Date: 2022-08-05
浙江瑞博制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example: the control of pH is very strict, the operation is cumbersome, there are too many impurities after hydrogenation, which is not conducive to the subsequent purification, and there is an extra step of solvent washing to remove the solvent in the clathrate, and the yield is affected

Method used

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  • A kind of preparation method of imipenem
  • A kind of preparation method of imipenem
  • A kind of preparation method of imipenem

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027]

[0028] After adding 180L of methylene chloride and 120L of methanol to 20kg of the compound of formula I, the temperature was lowered to -25°C. 4.8kg of diisopropylethylamine was added, and 6.3kg of benzyl imide was added after dissolving, and the reaction was completed at -25°C. The pH value was adjusted to 5.4 with hydrochloric acid, and after the product was extracted with water, the aqueous phase was cooled to -25° C. and stirred for 12 to 36 hours, and filtered to obtain 18.04 kg of a white solid compound of formula II, the HPLC purity was greater than 97%, and the yield was greater than 85%.

Embodiment 2

[0030]

[0031] Add 200ml of isopropanol and 10.9kg of N-methylmorpholine to 18.04kg of the compound of formula II, adjust the pH to 7.4 with hydrochloric acid, add 10kg of 5% palladium on carbon, hydrogenate at 25°C and 1.5Mpa for 50min, and filter to obtain imipeptide. Nan solution, the liquid phase purity was 99%, the external standard measured imipenem containing 11.55kg, and the yield was 95%.

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Abstract

The invention provides a preparation method of imipenem. The compound of formula I is included in a solvent, and after adding dichloromethane and methanol, the temperature is lowered to ‑25°C. After adding diisopropylethylamine, adding benzyl imide after dissolving, the reaction is complete at -25°C, adding hydrochloric acid to adjust the pH value to 5.4, after extracting the product with water, cooling the aqueous phase to -25°C, stirring, and filtering to obtain The white solid compound of formula II is then prepared through catalytic hydrogenation to obtain imipenem. In the present invention, because the purity of the white solid imipenem intermediate of formula II is relatively high, through catalytic hydrogenation, a higher purity can be finally prepared. The product of imipenem. In addition, the intermediate in the solid state provided by the present invention solves the technical problem that the solid state cannot be obtained in the prior art. Compared with the prior art, the one-pot method is preferred. The present invention has remarkable effects and creativity. .

Description

technical field [0001] The invention relates to a preparation method of carbapenem compounds, in particular to a preparation method of imipenem. Background technique [0002] Imipenem (Imipenem, I) is a carbapenem extended-spectrum beta-lactam antibiotic developed by Merck Company, which has antibacterial effect on Gram-positive and negative aerobic and anaerobic bacteria. Its complex preparation with organic ion transport inhibitor cilastatin sodium (trade name: Taineng) is the first carbapenem beta-lactam antibiotic on the market. [0003] Imipenem has attracted much attention due to its excellent antibacterial properties, and there are many reports on its synthesis process, mainly including the following schemes: [0004] Route 1: US4374772 discloses a method for directly preparing imipenem by reacting thiomycin (II) with imidobenzyl ether. This method seems to have simple steps, but it is very demanding on reaction conditions, especially the control of pH. The requirem...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D477/20C07D477/06
CPCC07D477/20C07D477/06
Inventor 潘晨王池雅刘丽
Owner 浙江瑞博制药有限公司