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Meropenem intermediate and preparation method thereof

A technology of meropenem and intermediates, which is applied in the field of medicine, can solve the problems of unfriendly water body and ecological environment, increase the cost of solid-liquid waste liquid treatment, and the inability to recover phosphorus-containing reagents, and achieves increased treatment costs, short preparation time, and high efficiency. Beneficial to industrial production

Active Publication Date: 2022-01-14
SHENZHEN HAIBIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In view of this, the application provides a meropenem intermediate and its preparation method, which can effectively solve the problem that the phosphorus-containing reagents cannot be recovered in the synthesis process of the existing meropenem, which is unfriendly to water bodies and the ecological environment, pollutes the environment, and increases solid-liquid Technical Deficiencies of Waste Liquid Treatment Fees

Method used

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  • Meropenem intermediate and preparation method thereof
  • Meropenem intermediate and preparation method thereof
  • Meropenem intermediate and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0067] The embodiment of the present application provides a meropenem intermediate represented by formula I, and the specific preparation method includes:

[0068] According to the following synthesis route, add 50ml of dichloromethane, 10g of azabicyclic compounds represented by formula II, and 3.3g of ethyl chloroformate (1.1eq) into a four-necked flask, and cool down to -25°C; Ethylamine (1.2eq) 3.35g, reacted at -25°C for 0.5h, and the product was ready for use, which was the intermediate of meropenem represented by formula I. Mass spectrometry data of the reaction solution, MS (M+1: 435.13).

[0069] The name of the meropenem intermediate shown in formula I is (4R, 5R, 6S)-3-(ethoxycarboxy)-6-((R)-1-hydroxyethyl)-4-methyl-7-oxo Dio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid-(4-nitro)benzyl ester.

[0070] .

[0071] Detect the mass spectrum of the meropenem intermediate shown in the formula I of the embodiment of the present application, and the results are as f...

Embodiment 2

[0073] The embodiment of the present application provides undeprotected meropenem represented by formula V, and the specific preparation method includes:

[0074] According to the following synthetic route, add 50ml of acetonitrile and 9.75g of meropenem side chain (1.0eq) shown in formula IV to the product in Example 1, cool down to -15°C; start adding tetramethylguanidine (1.2eq) dropwise 3.82g, reacted at -15°C for 1h. After the reaction was completed, 50 ml of saturated brine was added for washing, and the layers were separated. The aqueous phase was extracted three times with 150 ml of ethyl acetate, and the organic phases were combined. Concentrate the organic phase at 45°C to an oily substance, add 50ml of ethyl acetate and stir to dissolve, then cool down to 0°C and stir for crystallization for 2h, filter, and dry at 35°C to obtain 17.66g of undeprotected meropenem represented by formula V , the molar yield of the two-step method was 92%, and the purity by HPLC was 98...

Embodiment 3

[0078] The embodiment of the present application provides a meropenem intermediate represented by formula I, and the specific preparation method includes:

[0079] According to the following synthetic route, add 50ml of dichloromethane, 10g of azabicyclic compounds represented by formula II, and 3.74g of isopropyl chloroformate (1.1eq) into a four-necked flask, and cool down to -20°C; start to add dropwise Triethylamine (1.2eq) 3.35g, reacted at -20°C for 0.5h, and the product was ready for use, which was the intermediate of meropenem represented by formula I. Mass spectrometry data of the reaction solution, MS (M+1: 449.15).

[0080] The meropenem intermediate represented by formula I is (4R, 5R, 6S)-3-(isopropyloxycarboxy)-6-((R)-1-hydroxyethyl)-4-methyl-7- Oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid-(4-nitro)benzyl ester.

[0081] .

[0082] Detect the mass spectrum of the meropenem intermediate shown in the formula I of the embodiment of the present applicatio...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a meropenem intermediate and a preparation method thereof. The meropenem intermediate provided by the invention has a structure as shown in a formula I which is described in the specification. In the formula, R is selected from C1-C6 alkyl groups, optionally substituted phenyl groups or optionally substituted benzyl groups. The preparation method of the meropenem intermediate comprises the following step: mixing an azabicyclo compound, a chloroformate compound, a first organic base and an organic solvent for a reaction to obtain the meropenem intermediate, wherein the azabicyclo compound has a structure as shown in a formula II, the chloroformate compound has a structure as shown in a formula III, and the meropenem intermediate has a structure as shown in the formula I. The meropenem intermediate and the preparation method thereof provided by the invention can effectively overcome the technical defects that in an existing meropenem synthesis process, a phosphorus-containing reagent cannot be recycled, is not friendly to a water body and the ecological environment and pollutes the environment, and solid-liquid waste liquid treatment cost is increased.

Description

technical field [0001] The application belongs to the field of medical technology, and in particular relates to a meropenem intermediate and a preparation method thereof. Background technique [0002] Meropenem, chemical name: (-)-(4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl); Meropenem; 3-[[5 -[(Dimethylamino)carbonyl]-3-pyrrolidinyl]thio]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3,2, 0] Hept-2-ene-2-carboxylic acid is a carbapenem antibiotic with broad antibacterial spectrum and strong antibacterial activity. It is used to treat many different infections, including meningitis and pneumonia. It is currently one of the important drugs for the treatment of severe and multi-drug resistant bacterial infections, and it has been more and more widely used in clinical practice. Therefore, transforming the traditional process of the medicine has good economic and social benefits. [0003] In recent years, with the increasing pressure of environmental protection and the wides...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/18C07D477/20C07D477/06C07D477/08
CPCC07D477/18C07D477/20C07D477/06C07D477/08
Inventor 罗文军欧军林笃安王东邢祖阁林楠棋幸志伟孙万鹏
Owner SHENZHEN HAIBIN PHARMA
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