Preparation method of N, N-dimethylacetamide

A technology of dimethylacetamide and methylpyrimidine, which is applied in the field of preparation of 2--N,N-dimethylacetamide, can solve the problems of complicated post-treatment process, poor atom economy and high reaction cost, and achieve the goal of reaction And the effect of simple post-processing, low cost and high atom economy

Active Publication Date: 2021-09-03
SHANGHAI RECORD PHARM CO LTD
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Problems solved by technology

[0009] As can be seen from the above reaction process, the compound 2-(2-n-butyl-4-hydroxyl-6-methylpyrimidin-5-yl)-N,N-dimethylacetamide of formula 1 is Fimasartan An important intermediate in the preparation process, but the above method needs to use a condensing agent to activate the carboxyl group in the compound of formula 6 in the preparation of the compound of formula 1. The condensing agent is relatively expensive and will produce by-product urea, thus causing the reaction and post-treatment process More complex, poor atom economy, relatively high reaction cost

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  • Preparation method of N, N-dimethylacetamide

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[0029] The invention provides a preparation method of 2-(2-n-butyl-4-hydroxyl-6-methylpyrimidin-5-yl)-N,N-dimethylacetamide, comprising the following steps:

[0030] 1) Make pentamidine hydrochloride and dimethyl acetylsuccinate react under the effect of organic amine to obtain 2-(2-n-butyl-4-hydroxyl-6-methylpyrimidin-5-yl)-acetic acid methyl Esters, wherein the pKa of the organic amine is 8-11.5;

[0031] 2) Reaction of 2-(2-n-butyl-4-hydroxyl-6-methylpyrimidin-5-yl)-acetic acid methyl ester with dimethylamine to obtain 2-(2-n-butyl-4-hydroxyl -6-methylpyrimidin-5-yl)-N,N-dimethylacetamide.

[0032] Above-mentioned preparation method can be represented by following chemical reaction formula:

[0033]

[0034] In the reaction of pentamidine hydrochloride and dimethyl acetylsuccinate, it is necessary to use alkali to neutralize the HCl in pentamidine hydrochloride, so that the nitrogen atom in the carbon-nitrogen double bond in pentamidine hydrochloride It has nucleophil...

Embodiment 1

[0052] The preparation method of the present embodiment 2-(2-n-butyl-4-hydroxyl-6-methylpyrimidin-5-yl)-N,N-dimethylacetamide is as follows:

[0053] 1) Preparation of 2-(2-n-butyl-4-hydroxyl-6-methylpyrimidin-5-yl)-acetic acid methyl ester

[0054] At room temperature, 13.7 g (0.1 mol) of pentamidine hydrochloride and 20.7 g (0.11 mol, 1.1 equiv) of dimethyl acetylsuccinate were added to a 250 mL four-necked flask, and 70 mL of methanol was added to dissolve the reactant completely. Under stirring state, use the constant pressure dropping funnel to add dropwise N,N-diisopropylethylamine 25.8g (0.2mol, 2.0equiv, pKa value is 10.98), control dropping time to be 0.5h, dropwise add The system was heated to reflux for 4 hours.

[0055] After cooling the reaction system to room temperature, concentrate under reduced pressure to remove methanol to obtain a concentrate, add 100 mL of water to the concentrate, add 13 g of concentrated hydrochloric acid under stirring to adjust the pH...

Embodiment 2

[0063] The preparation method of the present embodiment 2-(2-n-butyl-4-hydroxyl-6-methylpyrimidin-5-yl)-N,N-dimethylacetamide is as follows:

[0064] 1) Preparation of 2-(2-n-butyl-4-hydroxyl-6-methylpyrimidin-5-yl)-acetic acid methyl ester

[0065] At room temperature, add 27.4g (0.2mol) of pentamidine hydrochloride and 41.4g (0.22mol, 1.1equiv) of dimethyl acetylsuccinate into a 500mL four-neck flask, add 70mL of methanol to completely dissolve the reactants, and stir 51.6g (0.4mol, 2.0equiv) of N, N-diisopropylethylamine was added dropwise using a constant pressure dropping funnel, and the dropping time was controlled to be 1h. After the dropping was completed, the system was heated to reflux for 4 hours .

[0066] After cooling the reaction system to room temperature, concentrate under reduced pressure to remove methanol to obtain a concentrate, add 200 mL of water to the concentrate, add 26 g of concentrated hydrochloric acid under stirring to adjust the pH to 3, and use...

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Abstract

The invention provides a preparation method of N, N-dimethylacetamide, which comprises the following steps: 1) enabling pentamidine hydrochloride and dimethyl acetylsuccinate to react under the action of organic amine to obtain 2-(2-n-butyl-4-hydroxy-6-methylpyrimidine-5-yl)-methyl acetate, wherein the pKa of the organic amine is 8-11.5; 2) enabling the 2-(2-n-butyl-4-hydroxy-6-methylpyrimidine-5-yl)-methyl acetate to react with dimethylamine, so as to obtain the 2-(2-n-butyl-4-hydroxy-6-methylpyrimidine-5-yl)-N, N-dimethylacetamide. The preparation method provided by the invention has the advantages of simple reaction and post-treatment process, high atom economy and low cost.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a preparation method of N,N-dimethylacetamide, in particular to a 2-(2-n-butyl-4-hydroxyl-6-methylpyrimidin-5-yl) The preparation method of -N,N-dimethylacetamide. Background technique [0002] Fimasartan (Fimasartan), developed by South Korea Boryeong Pharmaceutical Co., Ltd., is a new type of non-peptide angiotensin II receptor antagonist, which has the effect of selectively blocking AT1 receptors. It shows rapid and effective antihypertensive effects in various types of hypertension, is very safe and has good tolerance, and is superior to other drugs of the same type. Fimasartan was first launched in South Korea in 2011, and in the United States, Australia, and Russia in 2013. [0003] The structural formula of Fimasartan is as follows: [0004] [0005] Boryeong Pharmaceutical Co., Ltd. discloses a preparation method for Fimasartan in Korean Patent No. 10-521980. The prepara...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/36C07D403/10
CPCC07D239/36C07D403/10Y02P20/55
Inventor 黄志
Owner SHANGHAI RECORD PHARM CO LTD
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