Method for synthesizing biapenem medicine intermediates

A synthesis method and technology for intermediates, which are applied in the field of synthesis of intermediates, can solve the problems of heavy metal pollution, low yield and the like, and achieve the effects of low cost, simple reaction and simple steps.

Active Publication Date: 2018-05-25
ZHEJIANG GONGSHANG UNIVERSITY +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] In order to overcome the above-mentioned shortcomings, especially heavy metal pollution and low yield, the present invention proposes a synthetic method for penem drug intermediates. Compared with other routes, the synthetic route has the advantages of easy-to-obtain raw materials and low reaction conditions in each step. Stable and mild, avoiding the use of chiral reagents

Method used

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  • Method for synthesizing biapenem medicine intermediates
  • Method for synthesizing biapenem medicine intermediates
  • Method for synthesizing biapenem medicine intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] A penem 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:

[0064] (1) Synthesis of Intermediate A

[0065] 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%.

[0066] 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, 1H, OH), 7.62(m,...

Embodiment 2

[0089] A penem 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:

[0090] (1) Synthesis of Intermediate A

[0091] 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%.

[0092] (2) Synthesis of Intermediate B

[0093] Add 3 kg of intermediate A to the reaction kettle, add 5 L of acetonitrile as a solvent, add 2 L of p-methoxyaniline acetonitrile solution with a concentration of 0.5 mol / L dropwise at room temperature, complete the ...

Embodiment 3

[0107] A penem 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:

[0108] (1) Synthesis of Intermediate A

[0109] 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%.

[0110] (2) Synthesis of Intermediate B

[0111] Add 2.78kg of intermediate A to the reaction kettle, add 7.5L of solvent methanol, add 2L of p-methoxyaniline methanol solution with a concentration of 0.5mol / L dropwise ...

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Abstract

The invention discloses a method for synthesizing biapenem medicine intermediates. The method has the advantages that the biapenem medicine intermediates 4-AA are prepared from (R)-3-polyhydroxybutyrate which is a raw material, and the raw material in the routes is inexpensive, is easily available and can be substantially purchased; the method includes simple steps, the various steps are high in yield, and reaction is simple; chiral reagents and chiral resolution are omitted, accordingly, the method is low in cost and high in yield, 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 penem drug intermediate. Background technique [0002] 4-AA, or (3R,4R)-3-[(R)-1-tert-butyldimethylsiloxyethyl]-4-acetoxy-2-azetidinone, is a synthetic imine Imipenem, panipenem, meropenem, faropenem, ertapenem, biapenem, doripenem, etc. An important intermediate of penem and carbapenem antibiotics. Penems and carbapenems are new atypical β-lactam antibiotics successfully developed in the 1980s. They have broad-spectrum and potent antibacterial effects on Gram-negative and positive bacteria, aerobic bacteria, and anaerobic bacteria. It is stable to β-lactamase and has a good antibacterial effect on cephalosporin-resistant bacteria. It has become the drug of choice for the treatment of severe infections and multiple infections, and is one of the hot spots in the development of antibacterial drugs. [0003...

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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