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Preparation method of trans-4-dimethylaminocrotonic acid hydrochloride

A technology of dimethylamino crotonate hydrochloride and dimethylamine is applied in the field of preparation of trans-4-dimethylamino crotonate hydrochloride, and can solve the problems of low yield, high cost and unfavorable Industrial production and other problems, to achieve the effect of high yield, low cost and convenient operation

Inactive Publication Date: 2015-09-23
JIANGSU HANSOH PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But the yield in the reported method is low (the general mass yield is 18% based on the dosage of 4-bromocrotonate methyl ester), and the cost is high (most documents use the tetrahydrofuran solution of dimethylamine as the reaction reagent, 2M 100ml of dimethylamine tetrahydrofuran solution is priced at 567 yuan), which is not conducive to industrial production

Method used

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  • Preparation method of trans-4-dimethylaminocrotonic acid hydrochloride
  • Preparation method of trans-4-dimethylaminocrotonic acid hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Add dimethylamine hydrochloride (182.3g) and THF (1000ml) into the reaction flask, cool down to -10~0°C, add triethylamine (310ml) dropwise and react for 0.5h at -10~0°C, then -10 Add 4-bromocrotonate methyl (200g)-THF (500ml) solution dropwise at ~0°C, after dropping, react at -10 ~ 0°C for 16 hours, TLC detects that 4-bromocrotonate methyl is basically completely reacted, filter , the filter cake was washed with a small amount of THF, the filtrate was dried under reduced pressure, IPA (100ml of isopropanol) was added, and the pH was adjusted to 1-2 with 2N hydrochloric acid, after the adjustment was completed, 150g of oil was obtained;

Embodiment 2

[0027] Cool the above oil to -10~0°C, add NaOH (133g)-water (1250ml) solution dropwise under stirring, after the drop is complete, raise the temperature to 50°C for 1 hour, and detect trans-4-dimethylaminocroton by TLC The acid methyl ester basically reacted completely, cooled to -10°C ~ 0°C, adjusted pH = 1 ~ 2 with 2N HCl, after adjustment, reduced pressure to dryness, added 800ml of ethanol and stirred at room temperature for 10min, filtered, filter cake NaCl with a small amount of ethanol After washing, the filtrate was dried under reduced pressure, and IPA (100ml isopropanol)-acetone (200ml) was added to stir and crystallize overnight, and filtered to obtain 92.5g of white solid, with a mass yield of 50.7%.

[0028] 1 H-NMR(DMSO-d6)δ:2.70(s,6H),3.88(d,J=6.8Hz,2H),6.18(d,J=15.6Hz,1H),6.84(m,1H),11.39( br,1H),12.71(br,1H).

Embodiment 3

[0030] In the first step, refer to Example 1 (conditions are the same), in the second step, add the oily substance into methanol (1500ml), cool down to -10~0°C, add NaOH (133g)-water (1250ml) solution dropwise under stirring, and finish the dropping , rise to 50°C and react for 1h, TLC detects that the reaction of trans-4-dimethylaminocrotonate methyl ester is basically complete, cool to -10°C ~ 0°C, adjust the pH to 1 ~ 2 with 2N HCl, after the adjustment is completed, Reduced pressure to dryness, added 800ml of ethanol and stirred at room temperature for 10min, filtered, washed the filter cake NaCl with a small amount of ethanol, reduced the filtrate to dryness, added IPA (100ml)-acetone (200ml) and stirred and crystallized overnight, filtered to obtain 40.6g of white solid , The mass yield is 22.3%.

[0031] The structure confirmed that the obtained white solid was the same as the product in Example 2.

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Abstract

The invention relates to a preparation method of trans-4-dimethylaminocrotonic acid hydrochloride, wherein the preparation method is a preparation process of the important pharmaceutical intermediate represented by the formula (I), methyl 4-bromocrotonate and a dimethylamine compound are subjected to substitution, salt formation, hydrolysis and salt formation to prepare the compound trans-4-dimethylaminocrotonic acid hydrochloride represented by the formula (I). The preparation method is concise in process, high in yield, and suitable for industrialized amplification requirements.

Description

technical field [0001] The invention relates to the fields of organic chemical synthesis and medicinal chemistry, in particular to a preparation method of trans-4-dimethylaminocroton hydrochloride. Background technique [0002] The invention relates to a preparation method of trans-4-dimethylaminocroton hydrochloride. Trans-4-dimethylaminocroton hydrochloride is a very important pharmaceutical intermediate. It is an important component in the structure of antineoplastic drugs afatinib and neratinib. There are many literature reports on the synthesis of trans-4-dimethylaminocroton hydrochloride, such as US2003050222A1, WO2004066919, WO2009033581, WO2010151710A2, WO2011099764, etc. But the yield in the reported method is low (the general mass yield is 18% based on the dosage of 4-bromocrotonate methyl ester), and the cost is high (most documents use the tetrahydrofuran solution of dimethylamine as the reaction reagent, 2M The price of 100ml of dimethylamine tetrahydrofuran s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/18C07C229/30
Inventor 张亮杨勇陈安丰周炳城陈亭亭
Owner JIANGSU HANSOH PHARMA CO LTD
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