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The synthetic method of ethyl demethylthiaxamate

A technique for the synthesis of ethyl demethylaminothiaxamate and its synthetic method, which is applied in the field of preparation of antibiotic drug intermediates, can solve the problems of increased impurities in cyclization products, poor product color, and difficulties in separation and purification, and achieves high industrial application value and is easy to use. Effect of large-scale production and improvement of reaction yield

Active Publication Date: 2020-03-20
YIYUAN XINQUAN CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] ①Ethyl acetoacetate is used as raw material, first oximed, then halogenated, and then cyclized with thiourea under the action of a conventional catalyst. The process is cumbersome to operate, difficult to separate and purify, and the product has poor color and medium yield
[0005] ②Ethyl acetoacetate is used as raw material, firstly halogenated, then oximated, and then cyclized with thiourea. This process is prone to 2-position, 4-position and multi-halogenation competition reactions, so that the cyclization The impurities in the product increased significantly, the appearance color was darker, and the yield was low
The process has high energy consumption, many unit operations, long production cycle, and troublesome post-processing

Method used

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  • The synthetic method of ethyl demethylthiaxamate
  • The synthetic method of ethyl demethylthiaxamate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] (1) Oximation reaction: Preparation of ethyl 2-hydroxyiminoacetoacetate (Ⅱ)

[0032] Add 52.5g of sodium nitrite and 450g of purified water into the three-neck flask, stir for 25min, after fully dissolving, cool down to 10-15°C, add 90g of ethyl acetoacetate, then slowly drop 74.5g of 50% concentrated sulfuric acid solution to control the reaction The temperature of the system is 10-15° C., the time for the dropwise addition is 4 hours, and the reaction is continued for 3 hours after the dropwise addition is completed. Stand still for 15min, layered, add 65g chloroform to the aqueous phase, stir for 15min, stand still for 15min, layered, add 45g chloroform again for the aqueous phase, stir for 15min, stand for 15min, layered, combine the organic phases, and distill under reduced pressure, The obtained reaction solution was used for bromination reaction.

[0033] (2) Bromination reaction: Preparation of ethyl 4-bromo-2-hydroxyiminoacetoacetate (Ⅲ)

[0034] At 30-40°C, ...

Embodiment 2

[0038] (1) Oximation reaction: Preparation of ethyl 2-hydroxyiminoacetoacetate (Ⅱ)

[0039] Add 52.5g of sodium nitrite and 435g of purified water into the three-necked flask, stir for 30min, after fully dissolving, cool down to 10-15°C, add 90g of ethyl acetoacetate, then slowly dropwise add 74.5g of 50% concentrated sulfuric acid solution to control the reaction The temperature of the system is 10-15° C., the dropwise addition time is 3 hours, and the reaction is continued for 5 hours after the dropwise addition is completed. Stand still for 15min, layered, add 55g of chloroform to the water phase, stir for 15min, stand for 15min, layered, add 55g of chloroform to the water phase, stir for 15min, stand for 15min, layered, combine the organic phases, and distill under reduced pressure, The obtained reaction solution was used for bromination reaction.

[0040] (2) Bromination reaction: Preparation of ethyl 4-bromo-2-hydroxyiminoacetoacetate (Ⅲ)

[0041] At 30-40°C, slowly ad...

Embodiment 3

[0045] (1) Oximation reaction: Preparation of ethyl 2-hydroxyiminoacetoacetate (Ⅱ)

[0046] Add 52.5g of sodium nitrite and 465g of purified water into the three-neck flask, stir for 20min, after fully dissolving, cool down to 10-15°C, add 90g of ethyl acetoacetate, then slowly add 74.5g of 50% concentrated sulfuric acid solution dropwise to control the reaction The temperature of the system is 10-15° C., the dropwise addition time is 5 hours, and the reaction is continued for 3 hours after the dropwise addition is completed. Stand still for 15min, layered, add 60g chloroform to the aqueous phase, stir for 15min, stand still for 15min, layered, add 50g chloroform for the aqueous phase, stir for 15min, stand for 15min, layered, combine the organic phases, and distill under reduced pressure, The obtained reaction solution was used for bromination reaction.

[0047] (2) Bromination reaction: Preparation of ethyl 4-bromo-2-hydroxyiminoacetoacetate (Ⅲ)

[0048] At 30-40°C, slowly...

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Abstract

The invention relates to a method for synthesizing ethyl 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate, and belongs to the technical field of the preparation of antibiotic drug intermediates. The method provided by the invention comprises the following steps: using ethyl acetoacetate, sodium nitrite and concentrated sulfuric acid as raw materials; using purified water as a solvent; performing oximation reaction first, and then performing halogenation reaction; then adding thiourea; using 12-ammonium phosphomolybdate (AMP) as the catalyst, and using methanol as a solvent to perform cyclization reaction, thereby obtaining ethyl2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetate. The method provided by the invention is simple in process, shortens the reaction cycle, increases the reaction yield, and reduces corrosion to equipment; the used catalyst is separated from the product easily and can be reused, thereby reducing the production cost, greatly reducing the 'three wastes' pollution, and having an extremely high industrial application value.

Description

technical field [0001] The invention relates to a method for synthesizing ethyl demethylaminothiaxamic acid, and belongs to the technical field of preparation of antibiotic intermediates. Background technique [0002] (Z)-2-(2-Amino-4-thiazole)-2-Hydroxyiminoacetic acid ethyl ester (referred to as demethylaminothiaxamic acid ethyl ester) is a synthetic β-lactam antibiotics ceftazidime, cefotaxime, ceftriaxone The important side chain intermediates of , cefixime, cefpirome, etc. These drugs have broad-spectrum antibacterial activity, and have significant curative effect on severe infections such as sepsis, meningitis, pneumonia, etc., and are basically non-toxic to the kidney. Important antibiotics for the treatment of infectious diseases. [0003] The common method of synthesizing ethyl demethylthiaxate in the prior art at present has: [0004] ①Ethyl acetoacetate is used as a raw material, firstly oximated, then halogenated, and then cyclized with thiourea under the actio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/40
CPCC07D277/40
Inventor 周浩张立明朱海昌
Owner YIYUAN XINQUAN CHEM
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