Preparation method of cefprozil

A technology of cefprozil and 7-ACA, which is applied in the field of medicine, can solve the problems of affecting the ability of enzymes to catalyze synthesis, cannot achieve industrial production, and the product purity is not high, and achieve the effect of mild conditions, easy scale-up, and high product purity

Active Publication Date: 2019-03-26
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Sun Baihu (Master's Thesis of Tianjin University, 2012), CN104928340, CN 105368910 A, etc. reported a method for enzymatically synthesizing cefprozil, using water as the reaction medium, the product is easy to accumulate around the enzyme, affecting the ability of the enzyme to catalyze the synthesis, and penicillin Acylase has obvious hydrolysis in aqueous medium, which will lead to the inevitable decomposition of cefprozil and the side chain activated by ester or amide into β-lactam core and corresponding side chain acid, resulting in There are many impurities, the product purity is not high, and the reaction cycle is long. If the reaction cycle is shortened, the conversion rate will be greatly reduced, which cannot meet the requirements of industrial production.

Method used

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  • Preparation method of cefprozil

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Experimental program
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Effect test

Embodiment 1

[0018] Embodiment 1: the synthesis of compound 2

[0019] Under nitrogen protection, 100mL of benzene, 40mmol of 7-ACA, 48mmol of hexamethyldisilazane, and 0.5mmol of pyridine were successively added to the reaction flask, stirred and heated to reflux for 2 hours, cooled to 0°C, and three Methyl iodosilane (TMSI) 44mmol, keep warm for 1h, add 38mmol of trifluoroethoxy phosphate, continue the reaction for 1h, add 36mmol of sodium hexamethyldisilazide, 60mmol of 15-crown-5, heat and reflux for 30min, cool to At room temperature, 36 mmol of acetaldehyde was added and reacted at room temperature for 6 h. After the reaction is complete, add 50mL of water to the reaction solution, stir, collect the organic phase, extract with 25mL of 3mol / L hydrochloric acid in 3 times, combine the water layers, wash with 50mL of dichloromethane, separate the organic layer, and wash the obtained aqueous solution with 20% sodium hydroxide The pH of the solution was adjusted to 2.5, and a solid preci...

Embodiment 2

[0020] Embodiment 2: the synthesis of compound 2

[0021] Under the protection of nitrogen, add 100mL of benzene, 40mmol of 7-ACA, 40mmol of hexamethyldisilazane and 0.5mmol of pyridine in turn to the reaction flask, stir and heat up to reflux for 2h, cool the reaction solution to 0°C, drop three Methyl iodosilane (TMSI) 40mmol, keep warm for 1h, add 32mmol of trifluoroethoxy phosphate, continue the reaction for 1h, add 32mmol of sodium hexamethyldisilazide, 40mmol of 15-crown-5, heat and reflux for 30min, cool to At room temperature, 32 mmol of acetaldehyde was added and reacted at room temperature for 6 h. After the reaction is complete, add 50mL of water to the reaction solution, stir, collect the organic phase, extract with 25mL of 3mol / L hydrochloric acid in 3 times, combine the water layers, wash with 50mL of dichloromethane, separate the organic layer, and wash the obtained aqueous solution with 20% sodium hydroxide The pH of the solution was adjusted to 2.5, a solid w...

Embodiment 3

[0022] Embodiment 3: the synthesis of compound 2

[0023] Under the protection of nitrogen, add 100mL of benzene, 40mmol of 7-ACA, 56mmol of hexamethyldisilazane, and 0.5mmol of pyridine in sequence in the reaction flask, stir and raise the temperature to reflux for 2h, cool the reaction solution to 0°C, dropwise add three Methyl iodosilane (TMSI) 48mmol, keep warm for 1h, add 44mmol of trifluoroethoxy phosphate, continue the reaction for 1h, add 40mmol of sodium hexamethyldisilazide, 80mmol of 15-crown-5, heat and reflux for 30min, cool to At room temperature, 40 mmol of acetaldehyde was added and reacted at room temperature for 6 h. After the reaction is complete, add 50mL of water to the reaction solution, stir, collect the organic phase, extract with 25mL of 3mol / L hydrochloric acid in 3 times, combine the water layers, wash with 50mL of dichloromethane, separate the organic layer, and wash the obtained aqueous solution with 20% sodium hydroxide The pH of the solution was...

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Abstract

The invention relates to a preparation method of cefprozil. A synthesis method comprises the following steps: taking 7-ACA (7-aminocephalosporanic acid) as a starting raw material; after carrying outsilylation protection, carrying out a series of reactions including iodination and the like to generate a compound 2; taking the compound 2 to react with methyl D-(-)-4-hydroxy-phenylglycinate under the catalysis of immobilized penicillin acylase to generate a compound 1, so as to obtain a target product cefprozil. The preparation method provided by the invention has the advantages of moderate reaction conditions, environmental friendliness, high conversion ratio, simple technology and high cis-isomer content.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a preparation method of cefprozil. Background technique [0002] Cefprozil (Cefprozil), chemical name: (6R,7R)-7-[(2R)-amino(4-hydroxyphenyl)acetamido]-8-oxo-3-(1-propenyl)-5 - Thio-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, a second-generation cephalosporin antibiotic, is a cephalosporin spectrum developed by Bristol-Myers Squibb Antibacterial drug, with strong antibacterial activity against G+, G- bacteria and anaerobic bacteria, especially against G+ bacteria, clinically used for mild and moderate infections caused by sensitive bacteria, including upper and lower respiratory tract infections, as well as skin and skin Soft tissue infection. Its structural formula is as follows formula I: [0003] [0004] At present, there are chemical methods and enzymatic methods for the production of cefprozil at home and abroad. In China, chemical methods are mainly used to syn...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/22C07D501/06
CPCC07D501/06C07D501/22
Inventor 李明杰武玉梅李成彬
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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