Preparation method of 2-aminothiophene-3,4-dicarboxylic acid derivative

A technology of dicarboxylic acid derivatives and aminothiophene, applied in the direction of organic chemistry, etc., can solve problems such as inability to realize large-scale production, and achieve the effects of easy large-scale production and simple operation.

Inactive Publication Date: 2019-10-01
上海吉奉生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

ZL201811165670.3 uses cyclic ketones, nitriles and sulfur as raw materials to prepare 2-aminothiophene compounds. The ketones used are limited to cyclic ketones and aromatic ketones; 4486-4489 ) reported the synthesis of 2-aminothiophene-3,4-dicarboxylate methyl ester and 2-aminothiophene-3,4-dicarboxylate ethyl ester; patent US2018 / 170948 and literature Organic Letters (Organic Letters,2011 ,13,38-41) and Journal of Organic Chemistry (Journal of Organic Chemistry, 2012,77,8167-8173) reported the synthesis of 2-aminothiophene-3-carboxylate ethyl-4-carboxylate methyl ester, in these reports , the purification of the final product needs to be completed by column chromatography, which cannot achieve large-scale production
Apart from this, there are no other literature reports

Method used

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  • Preparation method of 2-aminothiophene-3,4-dicarboxylic acid derivative
  • Preparation method of 2-aminothiophene-3,4-dicarboxylic acid derivative
  • Preparation method of 2-aminothiophene-3,4-dicarboxylic acid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021]

[0022] Add 1.0 kg methyl pyruvate, 1.0 kg DMF, 1.5 kg tert-butyl cyanoacetate, 0.38 kg high-purity sulfur powder into the reaction kettle, start stirring, and stir at room temperature for 30 mins. Dissolve 1.1 kg of triethylamine in 1.0 kg of DMF and slowly drop it into the reactor. During the dropwise addition, the temperature of the reaction system was controlled not to exceed 60°C. After the addition, the temperature of the reactor was raised to 70° C., and the reaction was carried out for 12 hours. Cool to room temperature, dilute with 10L ethyl acetate, wash with 10L of 10% citric acid aqueous solution, 10L of 10% sodium chloride aqueous solution, and 10L of water, and dry the organic phase with anhydrous magnesium sulfate for 2 hours ,filter. Control the temperature in the reaction kettle (-20°C), start to feed dry hydrogen chloride gas until no solid is precipitated, continue to stir at -20°C for 1 hour, filter, collect the solid, and dissolve the obtained...

Embodiment 2

[0025]

[0026] The specific operation is the same as in Example 1. The reaction materials are methyl pyruvate and methyl cyanoacetate.

[0027] The yield is 80%. 1 H NMR (CDCl 3 , 400 MHz, ppm): 8.27 (s, 1H), 7.46 (s, 2H), 3.90(s, 6H).

Embodiment 3

[0029]

[0030] The specific operation is the same as in Example 1. The reaction materials are ethyl pyruvate and ethyl cyanoacetate.

[0031] The yield is 85%. 1 H NMR (CDCl 3 , 400 MHz, ppm): 8.27 (s, 1H), 7.46 (s, 2H), 4.35 (m, 4H), 1.30 (t, 6H).

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Abstract

The invention relates to a preparation method of a 2-aminothiophene-3,4-dicarboxylic acid derivative, and mainly solves the technical problem that the purification of the existing preparation method needs column chromatography and cannot be produced on a large scale. The preparation method comprises (1) reacting pyruvate, cyanoacetate and sulfur powder in the presence of an alkali and a solvent toobtain a reaction solution; (2) diluting the obtained reaction solution with ethyl acetate, washing with a citric acid aqueous solution, a sodium chloride aqueous solution and water in sequence to obtain a crude 2-aminothiophene-3,4-dicarboxylic acid derivative solution; (3) cooling the obtained crude 2-aminothiophene-3,4-dicarboxylic acid derivative solution to 0 to -20DEG C, and introducing a dry hydrogen chloride gas until all solids are separated out; (4) using 0 to -20DEG C ethyl acetate to wash filtered filter cake for once, and adjusting the pH to 7-8 with saturated sodium bicarbonate;(5) performing liquid separating, collecting an organic phase, washing the organic phase with an aqueous solution to obtain a pure 2-aminothiophene-3,4-dicarboxylic acid derivative solution; and (6)removing the ethyl acetate to obtain the pure 2-aminothiophene-3,4-dicarboxylic acid derivative.

Description

technical field [0001] The invention relates to a preparation method of 2-aminothiophene-3, 4-dicarboxylic acid derivatives. The method has the characteristics of short synthetic route, simple operation and easy industrial production. Background technique [0002] 2-Aminothiophene-3, 4-dicarboxylic acid derivatives, whose structure is shown in the following formula, are important chemical drug intermediates, mainly used in the synthesis of thienopyrimidine derivatives. [0003] [0004] Thienopyrimidine derivatives are fused heterocyclic compounds with good bactericidal, antifungal, and antitumor activities, especially for inhibiting acetyl-CoA carboxylase (ACC) and for mutating epidermal growth factor receptor tyrosine Kinase (EGFR-TK) inhibitors have important uses in the treatment or prevention of diseases regulated by acetyl-CoA carboxylase (ACC) in mammals, especially humans, and in the treatment of EGFR-related diseases. [0005] The Gewald reaction is an importan...

Claims

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Application Information

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IPC IPC(8): C07D333/38
CPCC07D333/38
Inventor徐红岩卫兵
Owner上海吉奉生物科技有限公司