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Method for preparing highly pure trans-4-dimethylaminocrotonic acid hydrochloride through one-pot technology

A technology of dimethylamino crotonate hydrochloride and dimethylamino crotonate is applied in the field of preparing high-purity trans-4-dimethylamino crotonate hydrochloride by one-pot method, which can Solve the problems of complex process and low product purity, and achieve the effect of simple operation steps, good product purity and simple operation

Active Publication Date: 2016-06-15
CHONGQING WEIPENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The purpose of the present invention is to provide a one-pot method for preparing high-purity trans-4-dimethylamino croton with wide sources of materials, low cost and high product purity for the problems of complex process and low product purity in the prior art. hydrochloride method

Method used

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  • Method for preparing highly pure trans-4-dimethylaminocrotonic acid hydrochloride through one-pot technology
  • Method for preparing highly pure trans-4-dimethylaminocrotonic acid hydrochloride through one-pot technology
  • Method for preparing highly pure trans-4-dimethylaminocrotonic acid hydrochloride through one-pot technology

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] To prepare trans-dimethylaminocroton hydrochloride, follow the steps below:

[0030] 1. Preparation of trans-4-bromocrotonate

[0031] At room temperature, 50.0g (0.4995mol) trans-methyl crotonate, 89.3g (0.50mol) bromosuccinimide, 3.5g (0.01mol) benzoyl peroxide were successively put into a 1000ml four-necked reaction flask and 250.0ml chloroform. After feeding, start stirring until reflux for 10.0 hr, then cool down to room temperature to obtain trans-4-bromocrotonate methyl chloroform solution.

[0032] 2. Preparation of trans-4-dimethylaminocrotonic acid

[0033] At room temperature, slowly add 100.0 g of 33% dimethylamine aqueous solution (0.7320 mol) dropwise into the four-necked reaction flask in step 1, the dropping temperature is -10-25°C, the dropping time is 0.5 h, after the dropping is completed, stir and react for 0.5 hr, to obtain trans-4-dimethylamino crotonate methyl chloroform solution.

[0034] 3. Preparation of trans-4-dimethylaminocroton hydrochl...

Embodiment 2

[0037] To prepare trans-dimethylaminocroton hydrochloride, follow the steps below:

[0038] 1. Preparation of trans-4-bromocrotonate

[0039] At room temperature, 11.4g (0.1mol) trans-ethyl crotonate, 26.7g (0.15mol) bromosuccinimide, 0.93g (0.004mol) benzoyl peroxide were successively put into a 500ml four-necked reaction flask and 114.0 ml ethyl acetate. After feeding, start stirring until reflux for 15.0 hr, then cool down to room temperature to obtain trans-4-bromocrotonate ethyl chloroform solution.

[0040] 2. Preparation of trans-4-dimethylaminocrotonic acid

[0041] At room temperature, slowly add 40.8g of 33% dimethylamine aqueous solution (0.30mol) dropwise to the four-necked reaction flask in step 1, after the drop is completed, stir and react for 1.0hr to obtain trans-4-dimethylaminocrotonate ethyl ester Chloroform solution.

[0042] 3. Preparation of trans-4-dimethylaminocroton hydrochloride

[0043] At room temperature, slowly add 200ml of 1mol / L potassium h...

Embodiment 3

[0045] To prepare trans-dimethylaminocroton hydrochloride, follow the steps below:

[0046] 1. Preparation of trans-4-bromocrotonate

[0047] At room temperature, 20.0g (0.1560mol) trans isopropyl crotonate, 40.0g (0.2248mol) bromosuccinimide, 1.4g (0.0058mol) benzyl peroxide were successively put into a 1000ml four-necked reaction flask Acyl and 100.0ml carbon tetrachloride. After feeding, start stirring until reflux for 12.0 hr, then cool down to room temperature to obtain trans-4-bromocrotonate methyl chloroform solution.

[0048] 2. Preparation of trans-4-dimethylaminocrotonic acid

[0049] At room temperature, slowly drop 40.0 g of 33% dimethylamine aqueous solution (0.2928 mol) into the four-necked reaction flask in step 1, after the dropping, stir and react for 1.5 hr to obtain trans-4-dimethylaminocrotonate methyl ester Chloroform solution.

[0050] 3. Preparation of trans-4-dimethylaminocroton hydrochloride

[0051]At room temperature, slowly add 160ml of 1mol / L ...

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PUM

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Abstract

The invention discloses a method for preparing highly pure trans-4-dimethylaminocrotonic acid hydrochloride through a one-pot technology. The method comprises the following steps: reacting trans-crotonate with bromosuccinimide to generate trans-4-bromocrotonate, adding dimethylamine, carrying out a condensation reaction to generate trans-4-dimethylaminocrotonate, adding an alkali, and hydrolyzing to obtain the product. The method adopting the one-pot technology to prepare the product has simple operating steps, and allows the highly pure product to be obtained. The method has the advantages of wide sources of materials, low cost, environmental protection, high total yield, good product purity, simple operation, and suitableness for industrial production.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for preparing high-purity trans-4-dimethylaminocroton hydrochloride in one pot. Background technique [0002] Trans-4-dimethylaminocrotonic acid is an important intermediate of antineoplastic drugs Neratinib and Afatinib. Since trans-4-dimethylaminocrotonic acid contains an α, β-unsaturated carbonyl structure, as a Michael acceptor, it reacts with the nucleophilic group on the corresponding protease to form a covalent bond to produce biological effects. The structural formula of trans-4-dimethylaminocroton hydrochloride is as follows: [0003] [0004] The existing synthetic route of trans-4-dimethylaminocrotonic acid is mainly based on crotonic acid as the starting material: select different protecting groups (methoxyl or trimethylchlorosilane) to form esters with carboxyl groups, and then introduce Dimethylamino, deprotected to obtain the target compound. [0005...

Claims

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Application Information

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IPC IPC(8): C07C227/18C07C229/30
CPCC07C67/307C07C227/08C07C227/18C07C229/30C07C69/65
Inventor 刘泽燕冯强邹晓川周兴国韩公超向永陈露龚雪
Owner CHONGQING WEIPENG PHARMA
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