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Synthetic method of carbapenem antibiotic drug intermediate

A technology for carbapenems and synthesis methods, which is applied in chemical instruments and methods, compounds of Group 4/14 elements of the periodic table, organic chemistry, etc., can solve the problems of heavy metal pollution, low yield and the like, and achieves low cost , the reaction is simple, the raw materials are cheap and easy to obtain

Active Publication Date: 2018-09-28
ZHEJIANG GONGSHANG UNIVERSITY +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] For overcoming above-mentioned shortcoming, especially heavy metal pollution, the deficiency of low productive rate, the present invention proposes a kind of synthetic method of carbapenem antibiotic drug intermediate, this synthetic method has raw material easy to get, each step reaction condition is stable and gentle, and the advantage of avoiding the use of chiral reducing agents

Method used

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  • Synthetic method of carbapenem antibiotic drug intermediate
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  • Synthetic method of carbapenem antibiotic drug intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] A carbapenem antibiotic drug intermediate (3R,4R)-3-(R)-1-tert-butyldimethylsiloxyethyl]-4-acetoxy-2-azetidinone (abbreviation: 4-AA) new synthetic method, this method has the following steps to form:

[0066] (1) Synthesis of Intermediate A

[0067] Add 5.9kg (R)-methyl 3-hydroxybutyrate, 7.1L DMF-DMA and 10L methyltetrahydrofuran (MTHF) into the reactor, stir, and reflux at 90°C for 3h. After completion, cool the reactor to room temperature. Add 10L of distilled water to wash 3 times. Liquid separation, the upper organic layer was recovered under reduced pressure at 70°C to recover MTHF, the recovered MTHF could be recycled, and the obtained foam was Intermediate A, which was directly used in the next step without treatment. The reaction yield of this step is 95%.

[0068] use 1 H-NMR, 13 C-NMR, FT-IR detection, the data are as follows: 1 H-NMR:1.18(m,3H,CH 3 ),3.25(m,6H,N(CH 3 ) 2 ), 3.31(q, J=2.4, 1H, CH), 3.71(s, 3H, CH 3 ), 4.90(m, 1H, OC-CH=), 5.14(m, ...

Embodiment 2

[0093] A carbapenem antibiotic drug intermediate (3R,4R)-3-(R)-1-tert-butyldimethylsiloxyethyl]-4-acetoxy-2-azetidinone (abbreviation: 4-AA) new synthetic method, this method has the following steps to form:

[0094] (1) Synthesis of Intermediate A

[0095] Add 5.9kg (R)-methyl 3-hydroxybutyrate, 8L DMF-DMA and 8kg toluene into the reactor, stir, and reflux at 110°C for 3h. After completion, cool the reactor to room temperature. The resulting mixture was concentrated under reduced pressure at 70°C to recover toluene, and the resulting concentrated solution was purified by silica gel column chromatography using methanol / petroleum ether (20:80) as the mobile phase to obtain Intermediate A. The reaction yield of this step was 85%.

[0096] (2) Synthesis of Intermediate B

[0097] Take 3kg of intermediate A and 0.15kg of Pd / C in the reaction kettle, and add 5L of ethanol as a solvent. Charge 3MPa of hydrogen, react at 70°C for 8h, after completion, cool the reactor to room tem...

Embodiment 3

[0113] A carbapenem antibiotic drug intermediate (3R,4R)-3-(R)-1-tert-butyldimethylsiloxyethyl]-4-acetoxy-2-azetidinone (abbreviation: 4-AA) new synthetic method, this method has the following steps to form:

[0114] (1) Synthesis of Intermediate A

[0115] Add 5.9kg (R)-methyl 3-hydroxybutyrate, 8L DMF-DMA and 15L dichloromethane into the reactor, stir, and reflux at 90°C for 4h. After completion, cool the reactor to room temperature. Add 10L of distilled water to wash 3 times. Liquid separation, the organic layer was recovered under reduced pressure at 60°C to recover dichloromethane, the recovered dichloromethane could be recycled, and the obtained foam was Intermediate A, which was directly used in the next step without treatment. The reaction yield of this step is 76%.

[0116] (2) Synthesis of Intermediate B

[0117] Take 3kg of intermediate A and 0.45kg of Raney Ni in the reaction kettle, and add 5L of ethanol as a solvent. Charge 3MPa of hydrogen, react at 60°C fo...

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Abstract

The invention discloses a synthetic method of a carbapenem antibiotic drug intermediate. By using (R)-3-hydroxybutyrate as the raw material, the carbapenem antibiotic drug intermediate 4-AA is prepared. Raw materials for the process are cheap and easily-available and can be purchased in quantity. The synthetic method has simple steps, yield of each step is high, and reactions are simple. By usinga chiral column as the split chiral center, use of a precious metals chiral reducing catalyst is avoided. the synthetic method of the invention has the following advantages: cost is low; yield is high; and reaction conditions are easily available.

Description

technical field [0001] The invention relates to a method for synthesizing an intermediate in the technical field of medicine, in particular to a method for synthesizing a carbapenem antibiotic drug intermediate. Background technique [0002] Penems and carbapenems are new atypical β-lactam antibiotics successfully developed in the 1980s. The listed varieties include imipenem, panipenem, and meropenem ( meropenem), faropenem (faropenem), ertapenem (ertapenem), biapenem (biapenem), doripenem (doripenem), etc., are effective against Gram-negative and positive bacteria, aerobic bacteria, and anaerobic bacteria. It has broad-spectrum and powerful antibacterial effect, is stable to β-lactamase, and has good antibacterial effect on cephalosporin-resistant bacteria. . [0003] (3R,4R)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-acetoxy-2-azetidinone (4-AA) is a synthetic penem And the key intermediate of carbapenem antibiotics, there are 3 chiral carbon atoms in its structure, so t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
CPCC07F7/1892
Inventor 熊春华张玉红韩晓祥刘占祥赵国标徐旋杨伟强徐建忠
Owner ZHEJIANG GONGSHANG UNIVERSITY
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