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Preparation method of 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester

A technology of acetamido and methyl carboxylate, applied in organic chemistry, bulk chemical production, etc., to achieve the effects of high yield and purity, shortened reaction route, and safe operation

Pending Publication Date: 2022-06-07
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0041] 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 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester
  • Preparation method of 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester
  • Preparation method of 4-acetamido-5-chloro-2, 3-dihydrobenzofuran-7-carboxylic acid methyl ester

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Effect test

Embodiment 1

[0065] Methyl 4-acetamido-5-chlorosalicylate (methyl 4-acetamido-2-hydroxy-5-chlorobenzoate, 24.36 g, 0.1 mol), potassium carbonate (17.97 g, 0.13 mol) were added In N,N-dimethylformamide (250ml), add ethylene carbonate (15.85g, 0.18mol) under temperature control at 10~15℃, and after the addition, control temperature at 100~105℃ to react. The reaction solution was cooled to room temperature for filtration, dichloromethane (150ml) was added to the filtrate, the organic phase was separated and the organic phase was washed with saturated brine (150ml×2), dried, filtered, and the filtrate was concentrated under reduced pressure to dryness to be the intermediate I-1, yield 93.7%.

Embodiment 2

[0067] Methyl 4-acetamido-5-chlorosalicylate (methyl 4-acetamido-2-hydroxy-5-chlorobenzoate, 24.34g, 0.1mol), sodium bicarbonate (10.92g, 0.13mol) Add N,N-dimethylacetamide (250ml), control the temperature at 10~15℃, add ethylene carbonate (11.45g, 0.13mol), and after the addition, control the temperature at 100~105℃ to react, after testing the reaction is completed , the reaction solution was cooled to room temperature and filtered, dichloromethane (150ml) was added to the filtrate, the organic phase was separated and the organic phase was washed with saturated brine (150ml×2), dried, filtered, and the filtrate was concentrated under reduced pressure to dryness. Body I-1, yield 90.6%.

Embodiment 3

[0069] Methyl 4-acetamido-5-chlorosalicylate (methyl 4-acetamido-2-hydroxy-5-chlorobenzoate, 24.38g, 0.1mol), triethylamine (13.16g, 0.13mol) Add dimethyl sulfoxide (250ml), add ethylene carbonate (10.57g, 0.12mol) under temperature control at 10-15°C, and complete the addition, control temperature at 110-115°C for reaction, and after the reaction is detected, reduce the reaction solution to a lower temperature. Filter to room temperature, add dichloromethane (150ml) to the filtrate, separate the organic phase, wash the organic phase with saturated brine (150ml×2), dry, filter, and concentrate the filtrate to dryness under reduced pressure to obtain Intermediate I-1, Yield 87.2%.

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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, 4-acetamido-5-methyl chlorosalicylate is taken as a reaction raw material, ethoxyl is introduced by ethylene carbonate, then a benzotetrahydrofuran ring is directly constructed through an intramolecular alkylation reaction, a compound I is prepared, and the reaction equation is shown in the specification. According to the preparation method, the reaction route can be effectively shortened, the operation is safe, simple and convenient, the prepared target product is high in yield and purity, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of prucalopride intermediate 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester. Background technique [0002] Prucalopride Succinate, chemical name is 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl ]-7-benzofurancarboxamide succinate, is a new generation of high-selectivity, high-affinity serotonin 4(5-HT developed by Belgian Movetis Company 4 ) receptor agonists, which restore impaired intestinal motility by direct action on the intestinal wall. It was approved by the European Union for the treatment of chronic constipation in October 2009, launched in Germany in January 2010, in the UK in March of the same year, and 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 constipation. . Its chemical structure...

Claims

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Application Information

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IPC IPC(8): C07D307/79
CPCC07D307/79Y02P20/55
Inventor 鲍广龙张乃华
Owner LUNAN PHARMA GROUP CORPORATION
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