Synthetic method of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid

A technique for the synthesis of aminothiaxamic acid, which is applied in the direction of organic chemistry, can solve the problems of adverse effects on the health of operators and environmental safety, difficult control of the reaction, slow reaction speed, etc., and achieves easy control of process operation, shortened production cycle, and safe and convenient use Effect

Active Publication Date: 2010-08-18
YIYUAN XINQUAN CHEM
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AI Technical Summary

Problems solved by technology

[0007] 1. The process of nitrosation reaction is a heterogeneous reaction, not only the slow reaction speed leads to a long period, but also the yield is low
[0008] 2. Chlorine gas is used as the chlorination...

Method used

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  • Synthetic method of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0043] ①. Homogeneous oximation reaction: preparation of ethyl 2-hydroxime acetoacetate

[0044] Add 60mL of ethanol aqueous solution (volume ratio 1:2), 20mL of ethyl acetoacetate, and 10g of sodium nitrite into the three-necked flask, stir, and add 30g of glacial acetic acid dropwise at a temperature of 0-5°C for 1 hour. After the addition, continue The reaction was stirred for 2 h, extracted with 25 mL of chloroform, separated, and the organic phase was directly used for the next reaction.

[0045] ②.Methylation reaction: Preparation of ethyl 2-methoxyiminoacetoacetate

[0046] Transfer the organic phase of ethyl 2-hydroxime acetoacetate prepared in step ① into a flask, and add 110 mL of 20% sodium carbonate solution and 0.4 g of polyethylene glycol. Then, start to add 19 mL of dimethyl sulfate dropwise, control the reaction temperature at 10°C to 14°C, and the pH value at 8 to 10, complete the dropwise addition in 1 hour, and keep warm for 3 hours after the addition. Chl...

Embodiment 2

[0056] ①. Homogeneous oximation reaction: preparation of ethyl 2-hydroxime acetoacetate

[0057] Add 60mL of ethanol aqueous solution (volume ratio 1:2), 20mL of ethyl acetoacetate, and 10g of sodium nitrite into the three-neck flask, stir, and add 40g of glacial acetic acid dropwise at a temperature of 0-5°C, and finish adding in 1 hour. The reaction was stirred for 2 h, extracted with 25 mL of chloroform, separated, and the organic phase was directly used for the next reaction.

[0058] ②.Methylation reaction: Preparation of ethyl 2-methoxyiminoacetoacetate

[0059] Transfer the organic phase of ethyl 2-hydroxime acetoacetate prepared in step ① into a flask, add 110 mL of 20% sodium carbonate solution and 0.4 g of tetrabutylammonium bromide. Then, start to add 19 mL of dimethyl sulfate dropwise, control the reaction temperature at 10°C to 14°C, and the pH value at 8 to 10, complete the dropwise addition in 1 hour, and keep warm for 3 hours after the addition. Chloroform 20...

Embodiment 3

[0069] ①. Homogeneous oximation reaction: preparation of ethyl 2-hydroxime acetoacetate

[0070] Add 60mL of ethanol aqueous solution (volume ratio 1:2), 20mL of ethyl acetoacetate, and 10g of sodium nitrite into the three-neck flask, stir, and add 50g of glacial acetic acid dropwise at a temperature of 0-5°C for 1 hour. After the addition, continue The reaction was stirred for 2 h, extracted with 25 mL of chloroform, separated, and the organic phase was directly used for the next reaction.

[0071] ②.Methylation reaction: Preparation of ethyl 2-methoxyiminoacetoacetate

[0072] Transfer the organic phase of ethyl 2-hydroxime acetoacetate prepared in step ① into a flask, add 110 mL of 20% sodium carbonate solution and 0.5 g of benzyltrimethylammonium chloride. Then, start to add 19 mL of dimethyl sulfate dropwise, control the reaction temperature at 10°C to 14°C, and the pH value at 8 to 10, complete the dropwise addition in 1 hour, and keep warm for 3 hours after the additio...

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Abstract

The invention relates to a synthetic method of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid, which belongs to the synthetic methods of heterocyclic compounds containing 1,3-thiazole ring. The synthetic method is characterized by comprising the following operation steps: 1) homogeneous oximation reaction: preparing 2-hydroxamic ethyl acetoacetate; 2) methylation reaction: preparing 2-methoxyimino ethyl acetoacetate; 3) triphosgene chlorination reaction: preparing 4-chloro-2-methoxyimino ethyl acetoacetate; 4) cyclization reaction: preparing 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid ethyl ester; 5) hydrolysis: preparing a crude product of the 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid; and 6) refining: preparing a product of the 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid. The invention provides an oximating agent system which is applicable to homogeneous nitrosification reaction. The invention provides a triphosgene chlorinating agent which has the advantages of small toxicity, safe and convenient storage, transportation and use, easy control of process operation and high yield. The yield of the 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid ethyl ester is not less than 95.4%; the yield of the crude product of the 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid is not less than 94.4%; and the yield of the finished product of the 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid is not less than 90.5%. The purity of the finished product of the 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid is not less than 99.06%, and the melting point is 182.1 DEG C-183.9 DEG C. The synthetic method is used for synthesizing raw materials of the third generation of cephalosporins.

Description

technical field [0001] The invention is a method for synthesizing aminothiaxamic acid. The invention belongs to a method for synthesizing a heterocyclic compound containing a 1,3-thiazole ring, in particular to a method for preparing a heterocyclic compound with two double bonds between ring atoms without other condensed rings. Background technique [0002] The chemical name of aminothiaxamic acid is 2-(2-amino-4-thiazolyl)-2-methoxyimine acetic acid or 2-aminothiazole-4-methylhydroxamic acid, and its English name is 2-(2-Amino-4- Thiazolyl)-2-methoxyiminoacetic acid, the structural formula is: [0003] [0004] Amthioxamic acid is a raw material for the synthesis of third-generation cephalosporins. Amthioxamic acid cephalosporin antibiotics have good curative effects on infections caused by some drug-resistant bacteria and difficult-to-control pathogens, and have low toxicity and broad-spectrum long-acting effects. The curative effect is dozens of times higher than tha...

Claims

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Application Information

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IPC IPC(8): C07D277/593
Inventor 王孟周磊吕光海
Owner YIYUAN XINQUAN CHEM
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