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Preparation method of prucalopride intermediate

A technology of prucalopride and intermediates, applied in the field of drug synthesis, to achieve the effects of high yield and purity, shortened reaction route, and safe operation

Pending Publication Date: 2022-05-06
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0032] Aiming at the many problems existing in the preparation of prucalopride related intermediate 4-acetylamino-5-chloro-2,3-dihydrobenzofuran-7-carboxylate, the present invention provides a 4- Preparation method of acetylamino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester

Method used

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  • Preparation method of prucalopride intermediate
  • Preparation method of prucalopride intermediate
  • Preparation method of prucalopride intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0055] 1,2-dibromoethane (31.94g, 0.17mol), Na 2 CO 3 (12.72g, 0.12mol) was added to N,N-dimethylformamide (200ml), and after stirring at a temperature of 50-55°C, slowly added 4-acetylamino-5-chlorosalicylic acid methyl ester (4 -Acetamido-2-hydroxyl-5-chlorobenzoic acid methyl ester, SM-1, 24.36g, 0.10mol) in N,N-dimethylformamide (50ml) solution, continue to react until TLC detects that the reaction is complete, The reaction solution was poured into warm water (600ml) at 45-50°C and stirred, and cooled naturally to room temperature, stirred and crystallized, filtered, and the filter cake was recrystallized from toluene to obtain intermediate I-1 with a yield of 95.7% and a purity of 99.0 %.

Embodiment 2

[0057] 1,2-dibromoethane (41.33g, 0.22mol), KHCO 3 (12.01g, 0.12mol) was added into N,N-dimethylformamide (200ml), and the temperature was controlled at 50-55°C and stirred evenly, then slowly added dropwise methyl 4-acetylamino-5-chlorosalicylate (24.35 g, 0.10mol) of N,N-dimethylformamide (50ml) solution, continue to react until TLC detects that the reaction is complete, pour the reaction solution into warm water (600ml) at 45-50°C, stir and naturally cool to room temperature, Stir and crystallize, filter, and the filter cake is recrystallized from toluene to obtain intermediate I-1, with a yield of 94.4% and a purity of 97.3%.

Embodiment 3

[0059] 1,2-dibromoethane (43.21g, 0.23mol), K 2 CO 3 (16.58g, 0.12mol) was added into N,N-dimethylformamide (200ml), and after the temperature was controlled at 50-55°C and stirred evenly, slowly added dropwise methyl 4-acetylamino-5-chlorosalicylate (24.38 g, 0.10mol) of N,N-dimethylformamide (50ml) solution, continue to react until TLC detects that the reaction is complete, pour the reaction solution into warm water (600ml) at 45-50°C, stir and naturally cool to room temperature, Stir and crystallize, filter, and the filter cake is recrystallized from toluene to obtain intermediate I-1, with a yield of 90.1% and a purity of 97.1%.

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a prucalopride intermediate 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester. According to the method, methyl 4-acetamido-5-chlorosalicylate is taken as a starting raw material and firstly reacts with 1, 2-dibromoethane, then a benzotetrahydrofuran ring is directly constructed through an alkylation reaction on a benzene ring under the action of a catalyst, a compound I is prepared, and the reaction equation is as follows. According to the preparation method, the reaction route can be effectively shortened, the operation safety is improved, and the target product prepared by the method is relatively high in yield and purity.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of prucalopride intermediate 4-acetylamino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester. Background technique [0002] Prucalopride Succinate, chemical name 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl ]-7-benzofuran carboxamide succinate is a new generation of highly selective and high-affinity 5-hydroxytryptamine 4 (5-HT) developed by Belgium Movetis Company 4 ) receptor agonists, which restore impaired intestinal motility through direct action on the intestinal wall. In October 2009, the European Union approved it for the treatment of chronic constipation. It was launched in Germany in January 2010, and in the UK in March of the same year. It was approved by the FDA in October 2012. Clinical studies have shown that the drug has a constant and safe effect on patients with severe chronic constipat...

Claims

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Application Information

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IPC IPC(8): C07D307/84
CPCC07D307/84
Inventor 张乃华鲍广龙刘忠
Owner LUNAN PHARMA GROUP CORPORATION
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