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METHOD FOR MANUFACTURING 7alpha-ALKOXYOXACEPHEM INTERMEDIATE COMPOUND

A technology for alkoxy cephem and intermediates, which is applied in the field of preparation of 7α-alkoxy cephem intermediates, can solve problems such as unfavorable, expensive photoreaction equipment, low yield and the like, and achieves easy mass production , excellent yield, simple preparation process

Active Publication Date: 2019-03-19
DONGDO +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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

Method used

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  • METHOD FOR MANUFACTURING 7alpha-ALKOXYOXACEPHEM INTERMEDIATE COMPOUND
  • METHOD FOR MANUFACTURING 7alpha-ALKOXYOXACEPHEM INTERMEDIATE COMPOUND
  • METHOD FOR MANUFACTURING 7alpha-ALKOXYOXACEPHEM INTERMEDIATE COMPOUND

Examples

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Embodiment 1

[0084] 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

[0085] As starting material, 50.0 g (0.13 mol) of 7-amino-3-chloromethyl-1-oxa-3-cephem-4-carboxylic acid diphenyl ester were injected with 450 g of dichloromethane, and After cooling to -20°C, 29.0 g (0.4 moles) 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 methoxy) was dropped at a temperature of -40°C to -50°C. Then, after stirring for 5 minutes at the same temperature, 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 above reaction solution. After stirring for 30 minutes, the dichloromethane layer was separated and washed with dilute sodium bicarbonate. After adding 50 g of anhydrous magnesium sulfate to ...

Embodiment 2

[0089] 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

[0090] As starting material, 50.0 g (0.13 mol) of 7-amino-3-chloromethyl-1-oxa-3-cephem-4-carboxylic acid diphenyl ester were injected with 450 g of dichloromethane, and After cooling to -20°C, 29.0 g (0.4 moles) 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 methoxy) was dropped at a temperature of -40°C to -50°C. Then, after stirring for 5 minutes at the same temperature, 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 above reaction solution. After stirring for 30 minutes, the dichloromethane layer was separated and washed with dilute sodium bicarbonate. After adding 50 g of anhydrous magnesium sulfate t...

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Abstract

The invention discloses a method for manufacturing a 7alpha-alkoxyoxacephem intermediate compound and the intermediate compound. The method and the intermediate compound are characterized in that themethod includes, after a step S1 of reacting a compound represented by a following chemical formula 1 with a halogen compound, metal alkoxide and a reducing agent in an organic solvent, a step S2 or astep S3 of performing a continuous reaction with an acetamido gasifying agent or a thioalcohol agent to generate a compound shown as following chemical formula 3 or chemical formula 5; and a simple preparation process, easy batch production and a high yield are achieved. The formulae are shown in the description, wherein R is Cl, Br, I and halogen derivatives; R1 is a carboxyl protecting group including diphenylmethyl, p-methoxybenzyl, p-nitrobenzyl or hydrogen (H); and R2 is an alkyl group having 1 to 4 carbon atoms.

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 Applications(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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