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Carbapenem bicyclic nucleus preparation and purification method

A carbapenem bicyclic nuclei and purification method technology, applied in the direction of organic chemistry, can solve the problems of excessive heavy metal content, affecting the quality of drugs, and no rhodium removal method, etc., to achieve simple operation, cheap reagents, and environmental friendliness Effect

Inactive Publication Date: 2009-02-11
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Rhodium is a kind of heavy metal. If the product is directly subjected to the next reaction without purification, the heavy metal content of the final drug imipenem and panipenem will exceed the standard, which will affect the quality of the drug
Therefore, it is very important to purify the carbapenem bicyclic mother nucleus and reduce the content of residual rhodium in the product as much as possible, but there are no literature and patent reports so far about the removal method of rhodium in the carbapenem bicyclic mother nucleus

Method used

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  • Carbapenem bicyclic nucleus preparation and purification method
  • Carbapenem bicyclic nucleus preparation and purification method
  • Carbapenem bicyclic nucleus preparation and purification method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] In a 500ml three-necked flask, add 37.6g (0.1mol) (3S, 4R)-3-[(1R)-hydroxyethyl]-4-[3-(4-nitrobenzyloxy)carbonyl-2-oxo Substitute-3-diazopropyl]azetidinyl-2-one, 300ml ethyl acetate, nitrogen gas for 5min, add 0.39g rhodium octanoate, react at 50°C for 3-4 hours, HPLC detection complete reaction, cooling To room temperature, add 300ml of 5% TMT (pH=7.5~8.0) aqueous solution, stir at room temperature for 30min, static layering, ethyl acetate phase was washed with 200ml of water, dried with anhydrous MgSO4, concentrated ethyl acetate under reduced pressure at less than 50°C The ester liquid was about 100ml, cooled to room temperature, added 300ml of isopropyl ether, a white solid was precipitated, filtered, and the filter cake was dried under vacuum and reduced pressure at 30-40°C to obtain 33.0g of carbapenem bicyclic nuclei, yield 94.8% , HPLC normalization method to determine the content of 98.7%, ICP-MS method to determine the rhodium content of 0.6ppm

Embodiment 2

[0027] Except replacing rhodium octanoate with rhodium acetate, the consumption of rhodium acetate is 0.22g, other operating conditions are all the same as Example 1, obtain white solid 30.1g, yield 86.5%, HPLC normalization method determines content 99.1%, ICP-MS Determination of rhodium content 0.4ppm.

Embodiment 3

[0029] Except that the consumption of rhodium octoate is 0.20g, other operating conditions are all the same as in Example 1, and 28.6g of white solid is obtained, and the yield is 82.2%. .

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Abstract

The invention discloses a preparation and purification method of carbapenem bicyclic nuclus shown as formula (I). The preparation method comprises the following steps: cyclization is carried out to (3S, 4R)-3-((1R)-hydroxyethyl]-4-(3-(4-nitro benzyloxy) carbonyl-2-oxo-3-diazo propyl) nitrogen heterocyclic cyclobutyl-2-ketone shown as formula (II) in a reaction solvent under the catalysis of acetic acid rhodium or octanoic acid rhodium and reaction solution is obtained after complete reaction; the reaction solution is added with 2, 4, 6- trithione triazine aqueous solution with the pH value between 7 and 12 and mass concentration between 3 percent and 8 percent to carry out purification, so as to finally obtain the carbapenem bicyclic nuclus product. The method has simple operation, high efficiency of removing residual rhodium in the product and no pollution basically, applies cheap reagent and is environmental friendly.

Description

(1) Technical field [0001] The invention relates to a new method for the preparation and purification of a carbapenem bicyclic nucleus. (2) Background technology [0002] The structure of the carbapenem bicyclic nucleus is shown in formula (I), and it is the key intermediate of synthetic imipenem (imipenem) and panipenem (panipenem), and its chemical name is: (5R, 6S)- p-nitrobenzyl 6-[(1R)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3,2,0]-2-carboxylate. The synthesis of this compound has been reported by patents US4739048 and WO2005021560, that is, through the structure of (3S, 4R)-3-[(1R)-hydroxyethyl]-4-[3-(4-nitrate) as shown in formula (II) Base benzyloxy)carbonyl-2-oxo-3-diazopropyl]azetidinyl-2-one can be prepared by cyclization under the catalysis of rhodium acetate or rhodium octanoate. The reaction equation is as follows: [0003] [0004] The carbapenem bicyclic nucleus obtained by cyclization was crystallized in the reaction solvent to obtain a white to pale ye...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/18C07D477/04
Inventor 孙楠陈伟荣莫卫民胡宝祥胡信全
Owner ZHEJIANG UNIV OF TECH
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