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Method for preparing prucalopride

A technology of methylacetanilide and reaction, which is applied in the field of preparation of prucalopride, can solve problems such as inconvenient operation, and achieve the effects of less by-products, improved purity and yield, and mild reaction conditions

Active Publication Date: 2019-01-18
IANGSU COLLEGE OF ENG & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This route uses butyllithium twice, which requires a low temperature of -78°C, and the isomers produced by chlorination need to be separated by column chromatography, which is inconvenient to operate

Method used

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  • Method for preparing prucalopride
  • Method for preparing prucalopride
  • Method for preparing prucalopride

Examples

Experimental program
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Effect test

Embodiment 1

[0047] Step 1, the preparation of 3-chloro-4-methylacetanilide: Take 141g of 3-chloro-4-methylaniline, dissolve it in 200mL ethyl acetate, add 102g of acetic anhydride dropwise under ice bath, after the dropwise addition, The temperature was raised to room temperature, and the reaction was continued for 12 hours. After the reaction, the reaction solution was washed with water until neutral, dried and filtered, and the filtrate was distilled under reduced pressure to obtain 175 g of a white solid.

[0048] Step 2, the preparation of 3-(2-hydroxyethoxy)-4-methylacetanilide: take 183g of 3-chloro-4-methylacetanilide, dissolve it in 400mL dimethyl carbonate, add ethylene glycol 62g , potassium hydroxide 100g, heated to reflux for 12h, after the reaction, filtered to remove the solid, the filtrate was washed with water, the organic layer was dried and filtered, the filtrate was decompressed to recover the solvent, and the residual solid petroleum ether:ethyl acetate=2:1 was recrysta...

Embodiment 2

[0057] Step 1, the preparation of 3-chloro-4-methylacetanilide: take 141g of 3-chloro-4-methylaniline, dissolve it in 200mL ethyl acetate, add 110g of acetic anhydride dropwise under ice bath, after the dropwise addition, The temperature was raised to room temperature, and the reaction was continued for 12 hours. After the reaction, the reaction solution was washed with water until neutral, dried and filtered, and the filtrate was distilled under reduced pressure to obtain 181 g of a white solid.

[0058] Step 2, the preparation of 3-(2-hydroxyethoxy)-4-methylacetanilide: take 183g of 3-chloro-4-methylacetanilide, dissolve it in 400mL dimethyl carbonate, add ethylene glycol 70g , potassium hydroxide 100g, heated to reflux for 12h, after the reaction, filtered to remove the solid, the filtrate was washed with water, the organic layer was dried and filtered, the filtrate was decompressed to recover the solvent, and the residual solid petroleum ether:ethyl acetate=2:1 was recrysta...

Embodiment 3

[0067] Step 1, the preparation of 3-chloro-4-methylacetanilide: Take 141g of 3-chloro-4-methylaniline, dissolve it in 200mL ethyl acetate, add 120g of acetic anhydride dropwise under ice bath, after the dropwise addition, The temperature was raised to room temperature, and the reaction was continued for 12 hours. After the reaction, the reaction solution was washed with water until neutral, dried and filtered, and the filtrate was distilled under reduced pressure to obtain 185 g of a white solid.

[0068] Step 2, the preparation of 3-(2-hydroxyethoxy)-4-methylacetanilide: Take 183g of 3-chloro-4-methylacetanilide, dissolve it in 400mL dimethyl carbonate, add ethylene glycol 76g , potassium hydroxide 100g, heated to reflux for 12h, after the reaction, filtered to remove the solid, the filtrate was washed with water, the organic layer was dried and filtered, the filtrate was decompressed to recover the solvent, and the residual solid petroleum ether:ethyl acetate=2:1 was recrysta...

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Abstract

The invention provides a method for preparing prucalopride. The method comprises the following steps: taking 3-chloro-4-methylaniline as an initial raw material, performing amino protection, nucleophilic substitution, hydroxy protection, aromatic hydrocarbon chlorination, free radical bromination, hydrolysis, molecular Friedel-Crafts alkylation reaction ring closure, amino deprotection and oxidative amidation, thereby obtaining the prucalopride. According to the scheme, a dangerous process is not adopted, any highly toxic reagent is not used, the method is safe, green and environmental-friendly, the amount of by-products produced in the reaction is small, and the yield is improved.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of prucalopride. Background technique [0002] Prucalopride, the chemical name is 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7- Benzofuran carboxamide is a selective 5-HT developed by Belgium Movetis NV company 4 Receptor agonist. In October 2009, the European Medicines Agency approved its monosuccinate for marketing. It is clinically used to treat female constipation that cannot be relieved by laxatives. The trade name is Resolor. This product is the first new type of dihydrobenzofuran carboxylic acid derivatives to promote intestinal motility agent, which can efficiently and selectively stimulate 5-HT 4a and 5-HT 4b Receptors, increase gastrointestinal motility, improve constipation symptoms. [0003] The synthetic scheme of prucalopride mainly contains following three kinds: [0004] Scheme 1, Yuan Youzhi and othe...

Claims

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Application Information

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IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 冯成亮严宾张民
Owner IANGSU COLLEGE OF ENG & TECH
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