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A kind of preparation method of doripenem

A doripenem and sulfur-based technology, which is applied in the field of preparation of doripenem, can solve problems such as difficult stratification, residual magnesium ions, and difficult crystallization, and achieve simplified post-processing, short crystallization time, and stable sex good effect

Active Publication Date: 2017-11-28
SHANDONG LUOXIN PHARMA GRP CO LTD
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0008] The preparation of doripenem reported in the document Organic Process research&Development 2003, 7, 846-850 is obtained by hydrogen deprotection reaction using 10% palladium carbon as a catalyst. The difference is: ① adding Magnesium chloride hexahydrate instead of using MES buffer; ②The post-reaction treatment process no longer requires column chromatography purification, but it needs to add magnesium chloride hexahydrate multiple times, multiple layers, complicated operation, and serious emulsification during extraction, which is extremely difficult Stratification, and there are magnesium ions remaining, and it is difficult to crystallize without adding seeds

Method used

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  • A kind of preparation method of doripenem

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Embodiment 1

[0029] Preparation of (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-thio-2-(N-sulfamoylamino)methylpyrrolidine

[0030] Dissolve 100.0g (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-acetylthio-2-(N-tert-butoxycarbonylsulfamoylamino)methylpyrrolidine (188mmol) in 500ml methanol , add 28ml of concentrated sulfuric acid dropwise, react at 60°C, after TLC monitors the reaction, cool the solution to below 10°C, adjust the pH to neutral with 10% NaOH solution, then concentrate, extract with ethyl acetate (250ml×3), Extracted and washed with 5% NaCl solution, dried, filtered, and concentrated to obtain an orange oil, which was directly used in the next reaction. MS-ESIm / z:346[M+H] + .

[0031] (1R,5S,6S)-2-[(3S,5S)-1-benzyl p-nitroformate-5-sulfamoylaminomethylpyrrolidine-3-sulfanyl]-6-[(1R) Preparation of -1-hydroxyethyl]-1-methyl-1-carbo-2-penem-3-carboxylic acid p-nitrobenzyl ester alcoholate

[0032] Dissolve (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-sulfanyl-2-(N-sulfamoylamino)methylpyrrolidine, ...

Embodiment 2

[0036] Preparation of (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-thio-2-(N-sulfamoylamino)methylpyrrolidine

[0037] Dissolve 100.0g (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-acetylthio-2-(N-tert-butoxycarbonylsulfamoylamino)methylpyrrolidine (188mmol) in 500ml methanol , add 28ml of concentrated sulfuric acid dropwise, react at 60°C, after TLC monitors the reaction, cool the solution to below 10°C, adjust the pH to neutral with 10% NaOH solution, then concentrate, extract with ethyl acetate (250ml×3), Extracted and washed with 5% NaCl solution, dried, filtered, and concentrated to obtain an orange oil, which was directly used in the next reaction.

[0038] (1R,5S,6S)-2-[(3S,5S)-1-benzyl p-nitroformate-5-sulfamoylaminomethylpyrrolidine-3-sulfanyl]-6-[(1R) Preparation of -1-hydroxyethyl]-1-methyl-1-carbo-2-penem-3-carboxylic acid p-nitrobenzyl ester alcoholate

[0039] Dissolve (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-sulfanyl-2-(N-sulfamoylamino)methylpyrrolidine, 107.2g (180mmol) carbapen...

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Abstract

The invention belongs to the field of medicine synthesis and particularly relates to a doripenem preparation method. The method includes the steps that a compound 5 reacts with concentrated sulfuric acid in methanol to obtain a compound 4; the compound 4 and p-Nitrobenzyl-6-(1-hydroxyethyl)-1-azabicyclo(3.2.0)heptane-3,7-dione-2-carboxylate (a compound 3) are subjected to a condensation reaction under the condition that N,N-diisopropylethylamine exists, water and ethyl acetate are added and stirred after the reaction, an ethyl acetate layer is collected, alcohol is added in ethyl acetate collection liquid, crystallization is carried out, and a compound 2 is obtained; the product is dissolved through ethyl acetate; after a monopotassium phosphate solution and a phase transfer reagent of triethylbenzylammonium chloride are added, zinc powder is added into the ethyl acetate / monopotassium phosphate solution in batches to react and obtain doripenem. According to the method, reaction conditions are moderate, the technology is simple, and the conversion rate and the yield are high. Two-phase reaction is used in deprotection reaction, and the after-treatment process is simplified. The zinc powder which is cheap is used, so that the method is economical, and a new concept and a new method are provided for doripenem preparation.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of doripenem. Background technique [0002] Doripenem, Doripenem, the chemical name is (4R,5S,6S)-3-[((3S,5S)-5-[[(sulfamoyl)amino]methyl]-3-pyrrolidinyl)mercapto -6-[(1R)-1-hydroxyethyl]4-methyl-7-oxyl-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid], molecular formula is C 15 h 24 N 4 o 6 S 2 , and its structural formula is shown in formula 1: [0003] [0004] The antibacterial mechanism of doripenem is the same as that of other β-lactam antibiotics. It inhibits bacterial cell wall synthesis by binding to bacterial penicillin binding proteins (PBPs). It has very high affinity with PBPs of S.aureus, E.coli, P.aeruginosa and other sensitive bacteria. Doripenem is stable to most β-lactamases, including penicillinases, cephalosporins, and extended-spectrum β-lactamases (ESBLs). Doripenem is stable to human dehydropeptidase (DHP-1), will not...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D477/20C07D477/08
CPCC07D477/08C07D477/20
Inventor 李呈龙夏见伟李艳
Owner SHANDONG LUOXIN PHARMA GRP CO LTD
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