The preparation method of 7α-alkoxycephem intermediate

一种烷基、对甲氧基苄基的技术，应用在7α-烷氧基氧头孢烯中间体的制备领域，能够解决不有利、昂贵光反应设备、收率低等问题

Active Publication Date: 2021-09-10
DONGDO +1
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  • Abstract
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Problems solved by technology

[0003] As important intermediates for the industrially efficient production of such 1-oxasporines such as latamoxef or fluoxefef, 7α-methoxy-1-oxasporine derivatives are disclosed as Its preparation method is well known, by adding Cl 2 Finally, the method of carrying out 7α-methoxylation, but photoirradiation generally requires expensive photoreaction equipment, so there is a problem of being industrially unfavorable
[0004] And, in this method, in order to obtain 7α-methoxy-1-oxasporin compound from 3-exomethylene-1-oxasporine compound, by synthesizing intermediates, temporarily It is isolated and synthesized by reacting chlorine in the presence of pyridine as a base, but there is still a limitation of low yield

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  • The preparation method of 7α-alkoxycephem intermediate
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  • The preparation method of 7α-alkoxycephem intermediate

Examples

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Embodiment 1

[0080] Example 1. (6R, 7R)-diphenylmethyl-7-(difluoromethylthio)acetamido)-3-(chloromethyl)-7-methoxy-8-oxo-5 Preparation of oxa-1-aza-bicyclo[4,2,0]oct-2-ene-2-carboxylate

[0081] As starting material, 450 g of dichloromethane were injected into 50.0 g (0.13 mol) of 7-amino-3-chloromethyl-1-oxa-3-cephem-4-carboxylic acid diphenyl ester, and After cooling to -20°C, 29.0 g (0.4 mol) of chlorine was injected for 60 minutes. After stirring for 10 minutes at the same temperature, 174.7 g (0.46 mol) of a methanol solution of 10% LiOMe (lithium methoxide) was dropped at a temperature of -40°C to -50°C. Then, after stirring at the same temperature for 5 minutes, 6.4 g (0.11 mol) of acetic acid was added. 428.5 g of 10% sodium sulfite and 400 g of purified water were sequentially added to the reaction liquid. After stirring for 30 minutes, the dichloromethane layer was separated and washed with dilute sodium bicarbonate. 50 g of anhydrous magnesium sulfate was added to the organi...

Embodiment 2

[0085] Example 2. (6R, 7R)-diphenylmethyl-7-amino-7-methoxy-3-((1-methyl-1H-tetrazol-5-ylthio)methyl)-8 Preparation of -oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate

[0086] As starting material, 450 g of dichloromethane were injected into 50.0 g (0.13 mol) of 7-amino-3-chloromethyl-1-oxa-3-cephem-4-carboxylic acid diphenyl ester, and After cooling to -20°C, 29.0 g (0.4 mol) of chlorine was injected for 60 minutes. After stirring for 10 minutes at the same temperature, 174.7 g (0.46 mol) of a methanol solution of 10% LiOMe (lithium methoxide) was dropped at a temperature of -40°C to -50°C. Then, after stirring at the same temperature for 5 minutes, 6.4 g (0.11 mol) of acetic acid was added. 428.5 g of 10% sodium sulfite and 400 g of purified water were sequentially added to the reaction liquid. After stirring for 30 minutes, the dichloromethane layer was separated and washed with dilute sodium bicarbonate. 50 g of anhydrous magnesium sulfate was added to the organ...

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Abstract

The invention discloses a preparation method and an intermediate compound of a 7α-alkoxycephem intermediate. The preparation method and the intermediate compound of the 7α-alkoxycephem intermediate of the present invention are characterized in that, comprising step S2 or step S3, in an organic solvent, the compound represented by chemical formula 1 is mixed with a halogen compound or a metal alkoxide After reacting with reducing agent (step S1), acetamidating agent or mercaptanizing agent are reacted continuously to generate the compound represented by the following chemical formula 3 or chemical formula 5. According to the above presentation, the preparation process is simple, and the mass production is easy and the yield Excellent effect. (R is Cl, Br, I and halogen derivatives, R1, as a carboxyl protecting group, is diphenylmethyl, p-methoxybenzyl, p-nitrobenzyl or hydrogen, R2 is a carbon number of 1 to 4 alkyl).

Description

technical field [0001] The invention relates to a preparation method of a 7α-alkoxycephem intermediate, and in more detail relates to a preparation method of a 7α-alkoxycephem intermediate with simple and continuous preparation process, easy batch production and excellent yield. Background technique [0002] Flumoxef sodium or latamoxef sodium, as oxocefem antibiotics, is one of the main antibiotics leading the antibiotic market. The above-mentioned flumoxef sodium is used as the main raw material of flumoxef acid (Flomoxef acid). Sodium bicarbonate (sodium bicarbonate) is used as a salt-modifying substance to adjust the pH of the solution by freeze-drying the solution. The above-mentioned latamoxef sodium uses latamoxef acid (latamoxef acid) as the main raw material and uses sodium bicarbonate (sodium bicarbonate) A preparation obtained by freeze-drying a solution to adjust the pH of the solution as a salt-modifying substance. [0003] As important intermediates for the in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D505/06C07D505/16C07D505/20
CPCC07D505/06C07D505/16C07D505/20C07D505/10Y02P20/55C07D505/12A61K31/5365C07D498/04
Inventor 金东灿
Owner DONGDO
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