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Preparation method of biapenem

A biapenem and molar ratio technology, applied in the field of drug synthesis, can solve the problems of unfavorable production safety, low product yield and purity, long synthesis route and the like in the hydrogen absorption reaction, so as to improve the yield of the ring-closing reaction and improve the product quality. Yield and purity, effect of reducing reaction time

Active Publication Date: 2019-10-18
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the large hydrophobic groups in the raw material molecules, the solubility in water is also small, so all the methods that use the mixture of water and organic solvents as the reaction medium and remove the protective groups through catalytic hydrogenation require a large amount of organic solvents. And water, the system is too large for the hydrogen absorption reaction is not conducive to production safety
[0015] In summary, in the prior art methods for synthesizing biapenem, there are problems such as long synthetic route, easy degradation during the reaction process, low product yield and purity, etc.

Method used

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  • Preparation method of biapenem
  • Preparation method of biapenem

Examples

Experimental program
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Effect test

Embodiment 1

[0034] The preparation of embodiment 1 compound III

[0035] Add 80mL of acetonitrile to a 500mL reaction flask, add 9.24g of 4-mercapto-N,N-bis(p-nitrobenzyloxycarbonyl)pyrazolidine (compound II), add 2.07g of N,N-diisopropylethylamine and Tetraisopropyl titanate 2.27g. Blow nitrogen gas, cool down to -5~0°C, add 11.89g of compound I in batches, complete the addition within 15 minutes, continue to stir and react at -5~0°C for 90 minutes, after the reaction, add 240mL of purified water to crystallize for 2h, suction filter, 40 After vacuum drying at °C for 3 h, 14.17 g of compound III was obtained, with a yield of 87.9%, and a purity of 99.2% by HPLC.

Embodiment 2

[0036] The preparation of embodiment 2 compound III

[0037] Add 80mL of acetonitrile to a 500mL reaction flask, add 9.24g of 4-mercapto-N,N-bis(p-nitrobenzyloxycarbonyl)pyrazolidine (compound II), add 2.33g of N,N-diisopropylethylamine and Tetraisopropyl titanate 2.84g. Blow nitrogen gas, cool down to -5~0°C, add 11.89g of compound I in batches, complete the addition within 15 minutes, continue to stir and react at -5~0°C for 90 minutes, after the reaction, add 240mL of purified water to crystallize for 2h, suction filter, 40 It was dried in vacuo at °C for 3 h to obtain 14.60 g of compound III. The yield was 90.6%, and the purity by HPLC was 99.1%.

Embodiment 3

[0038] The preparation of embodiment 3 compound III

[0039] Add 80mL of acetonitrile to a 500mL reaction flask, add 9.24g of 4-mercapto-N,N-bis(p-nitrobenzyloxycarbonyl)pyrazolidine (compound II), add 2.69g of N,N-diisopropylethylamine and Tetraisopropyl titanate 3.41g. Blow nitrogen gas, cool down to -5~0°C, add 11.89g of compound I in batches, complete the addition within 15 minutes, continue to stir and react at -5~0°C for 90 minutes, after the reaction, add 240mL of purified water to crystallize for 2h, suction filter, 40 It was dried in vacuo at °C for 3 h to obtain 14.89 g of compound III. The yield was 92.4%, and the purity by HPLC was 99.2%.

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Abstract

The invention belongs to the technical field of medicines, and discloses a preparation method of biapenem. The method comprises the following steps: p-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[(diphenylphosphono)oxy]-1-methylcarboxyl pen-2-em-3-carboxylate and 4-sulfydryl-N,N-bis(p-nitrobenzyloxycarbonyl)pyrazolidine are used as raw materials, substitution is performed, hydrogenation is performed and cyclization is performed to synthesize the biapenem. The method provided by the invention overcomes the defects of a long reaction route, easy degradation of raw materials in the reactionprocess, a low yield and the like in the prior art, and is more suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of biapenem Background technique [0002] Carbapenem antibiotics are the atypical β-lactam antibiotics with the broadest antibacterial spectrum and the strongest antibacterial activity. Because of their stability to β-lactamase and low toxicity, they have become the most important treatment for severe bacterial infections. One of the antibacterial drugs. Since the discovery of thiamycin in 1976, pharmacologists around the world have successively discovered and developed a series of new carbapenem antibiotics, such as imipenem, panipenem, meropenem, faropenem, Apenem, Ritipenem Etc. The most important feature of this kind of antibiotics is that they not only have strong antibacterial activity and broad antibacterial spectrum, but also are highly stable to various β-lactamases, and can still exert a strong antibacterial effect on cephalosporin-resistant bacteria...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/06
CPCC07D519/06
Inventor 孙松郑建伟李呈龙
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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