Preparation method of meluopeinan

A technology of meropenem and separation method, applied in the field of preparation of meropenem, can solve problems such as affecting product yield

Inactive Publication Date: 2007-04-18
SHENZHEN HAIBIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In hydrogenation deprotection step, generally need to use morpholine propanesulfonic acid (MOPS) buffer solution, and need high molecular resin to purify, will influence the yield of final product (I) like this

Method used

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  • Preparation method of meluopeinan
  • Preparation method of meluopeinan
  • Preparation method of meluopeinan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] [Example 1] (5R, 6S, 8R, 2'S, 4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-1-dimethylaminocarbonyl)pyrrolidine Thio]-6-(1-p-nitrobenzyloxycarbonylethoxy)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (XXIV) Synthesis

[0085] In a bottle equipped with a reflux cooler, add 40 g (0.102 mol) of diazoketone ester (IX) and 200 ml of ethyl acetate, stir and heat the mixture to 60 ° C, add 140 mg of rhodium octanoate, and stir vigorously at the same temperature 30 minutes, until the reaction of the diazoketoester (IX) was completed, a solution of 1-β-methylbicyclic ketoester (X) was obtained. The reaction solution was directly carried on to the next step without separation.

[0086] Take the solution of the above-mentioned 1-β-methylbicyclic ketone ester (X), add 300ml of acetonitrile (dry product), cool in an ice-salt bath to -10~-15°C and protect with nitrogen, then add 14.57g (0.113mol) of Diisopropylethylamine and 27.54 g (0.102 mol) of diphenyl chlorophospha...

Embodiment 2

[0091] [Example 2] (5R, 6S, 8R, 2'S, 4'S)-3-[4-(2-dimethylaminocarbonyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-nitrogen Synthesis of Heterobicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid (I)

[0092](5R, 6S, 8R, 2'S, 4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl)-pyrrolidinylthio] -6-(1-p-nitrobenzyloxycarbonylethoxy)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (XXIV) (ie One-step concentrated oil) 15g (HPLC quantification: 12.5g) was dissolved in 250ml tetrahydrofuran, and 200ml water was added under stirring. The solution was placed in a 1 L autoclave, and then 5.5 g of 2,6-lutidine and 2 g of 10% palladium on carbon were added with stirring. The resulting mixture was hydrogenated for 1 hour under a hydrogen pressure of 1.8 MPa. Remove the catalyst by filtration, dilute the filtrate with 800ml of acetone, then add seed crystals at 5-15°C, after 30 minutes a large amount of crystals will separate out, then add 400ml of acetone dropwise ...

Embodiment 3

[0097] [Example 3] (5R, 6S, 8R, 2'S, 4'S)-3-[4-(2-dimethylaminocarbonyl)pyrrolidinylthio]-6-(1-hydroxyethyl)-1-nitrogen Synthesis of Heterobicyclo[3.2.0]-hept-2-en-7-one-2-carboxylic acid (I)

[0098] (5R, 6S, 8R, 2'S, 4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl)-pyrrolidinylthio] -6-(1-p-nitrobenzyloxycarbonylethoxy)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (XXIV) 10g (crystal matter) was dissolved in 250ml tetrahydrofuran, and 200ml water was added under stirring. The solution was placed in a 1 L autoclave, and then 5.5 g of 2,6-lutidine and 2 g of 10% palladium on carbon were added with stirring. The resulting mixture was hydrogenated for 1 hour under a hydrogen pressure of 1.8 MPa. Remove the catalyst by filtration, dilute the filtrate with 800ml of acetone, then add seed crystals at 5-15°C, after 30 minutes a large amount of crystals will separate out, then add 400ml of acetone dropwise at the same temperature, stir for 30 minut...

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Abstract

The present invention relates to a preparation method of beta-methylcarbapenem antibiotic-meropenem. Said invention provides its chemical structure formula, and concrete steps of its preparation method.

Description

technical field [0001] The invention relates to a preparation method of β-methyl carbapenem antibiotics, in particular to a preparation method of meropenem. Background technique [0002] So far, there have been a large number of natural or synthetic β-lactamase inhibitors reported, which can be divided into oxypenicillane, penem, carbapenem and monocyclic β-lactam oxypenicillin from the chemical structure Alkanes, among which carbapenems, especially β-methyl carbapenems, such as imipenem, meropenem and biapenem have good antibacterial effects on many drug-resistant bacteria, especially on type B enzymes It has a fairly strong inhibitory effect and is a series of unique inhibitors of β-lactamase. Since the discovery of thiamycin's potential antimicrobial activity against Gram-negative and Gram-positive bacteria, research on the synthesis of carbapenem or penem derivatives similar to thiamycin has been extensively developed. [0003] Currently commercialized carbapenem and β...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/02C07D477/20C07D477/18C07D205/08C07D207/00A61P31/04
Inventor 张恒利
Owner SHENZHEN HAIBIN PHARMA
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