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Method for synthesizing 4-amino-5-chloro-2,3-dihydro benzofuran-7-carboxylic acid

A synthesis method and technology of dihydrobenzene, applied in the field of medicine, can solve the problems of high corrosiveness and odor of pyridine, and achieve the effects of easy industrial production operation, high total yield, and easy industrial scale production.

Inactive Publication Date: 2014-09-03
TIANJIN WEIJIE TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Although the column chromatography of the intermediate is avoided in this synthetic route, the alkylsulfonyl chloride and pyridine used have relatively high corrosion and odor, and according to the patent report, the reaction needs to be carried out at -20--10°C. Simultaneously yield also only has 60%, so industrialized large-scale production also has various problems

Method used

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  • Method for synthesizing 4-amino-5-chloro-2,3-dihydro benzofuran-7-carboxylic acid
  • Method for synthesizing 4-amino-5-chloro-2,3-dihydro benzofuran-7-carboxylic acid
  • Method for synthesizing 4-amino-5-chloro-2,3-dihydro benzofuran-7-carboxylic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] 1) Add 58.6g (0.23mol) 4-(acetylamino)-2-hydroxyl-3-(2-hydroxyethyl) methyl benzoate and 200ml tetrahydrofuran respectively in a 500ml four-necked flask, 61g (0.23mol ) triphenylphosphine, stirred, added dropwise 40g (0.23mol) diethyl azodicarboxylate, continued to stir for 2 hours, added 90ml n-heptane, stirred for 3 hours, precipitated solid, and suction filtered to obtain 85g of 4-acetyl The crude product of methyl amino-2,3-dihydrobenzofuran-7-carboxylate was directly used in the next step;

[0040] 2) Add 85g (0.36mol) of the crude 4-acetamido-2,3-dihydrobenzofuran-7-carboxylate crude product and 90ml DMF into a 500ml four-neck flask, dissolve the solid, add 22g (0.13mol, 0.36 eq) N-chlorosuccinimide, stir, heat the reaction solution with an oil bath to 80-85°C, continue the reaction for 4 hours, lower the temperature of the reaction solution to room temperature, add 300ml of water, stir for 10 minutes, and precipitate a large amount of light yellow solid , suctio...

Embodiment 2

[0043] 1) Add 5.86g (0.023mol) 4-(acetylamino)-2-hydroxyl-3-(2-hydroxyethyl) methyl benzoate and 30ml tetrahydrofuran to a 100ml four-neck flask, 3.0g (0.012 mol, 0.5eq) triphenylphosphine, stirred, added dropwise 2.0g (0.012mol, 0.5eq) diethyl azodicarboxylate, continued to stir for 2 hours, added 10ml of n-hexane, stirred for 3 hours, precipitated solid, suction filtered , to obtain 6.3 g of crude 4-acetylamino-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester, which was directly used in the next step;

[0044] 2) Add 85g (0.36mol) of the crude 4-acetamido-2,3-dihydrobenzofuran-7-carboxylate crude product and 90ml of acetonitrile into a 500ml four-neck flask, dissolve the solid, add 63g (0.13mol, 1eq ) N-chlorosuccinimide, stirred, heated the reaction solution with an oil bath to 60-70°C, continued the reaction for 4 hours, lowered the temperature of the reaction solution to room temperature, added 300ml of water, stirred for 10 minutes, and precipitated a large amount of...

Embodiment 3

[0047] 1) Add 5.86g (0.023mol) 4-(acetylamino)-2-hydroxyl-3-(2-hydroxyethyl) methyl benzoate and 30ml tetrahydrofuran to a 100ml four-necked flask, 9.15g (0.035mol) mol, 1.5eq) triphenylphosphine, stirred, added dropwise 6g (0.092mol, 1.5eq) diethyl azodicarboxylate, continued to stir for 2 hours, added 10ml of n-pentane, stirred for 3 hours, precipitated solid, suction filtered , to obtain 12g crude product of methyl 4-acetylamino-2,3-dihydrobenzofuran-7-carboxylate, which was directly used in the next step;

[0048] 2) Add 85g (0.36mol) of the crude 4-acetamido-2,3-dihydrobenzofuran-7-carboxylate crude product and 90ml toluene to a 500ml four-neck flask, dissolve the solid, add 63g (0.13mol, 1eq ) N-chlorosuccinimide, stirring, heating the reaction solution with an oil bath to 90-100°C, continuing the reaction for 6 hours, lowering the temperature of the reaction solution to room temperature, stirring for 10 minutes, a large amount of light yellow solid precipitated, suction...

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Abstract

The invention discloses a method for synthesizing a prucalopride midbody 4-amino-5-chloro-2,3-dihydro benzofuran-7-carboxylic acid. The method comprises the following steps: firstly, adding methyl 4-(acetyl amino)-2-hydroxy-3-(2-hydroxy ethyl) benzoate into an organic solvent, adding triphenylphosphine and azo dioctyl phthalate diethyl ester, performing cyclization to obtain a methyl 4-acetamido-2,3-dihydro benzofuran-7-formate rough product, directly chloridizing the rough product by using N-chloro succinimide to obtain a rough product methyl 4-acetamide amino-5-chloro-7-benzofuran formate, and performing hydrolysis and purification to obtain a 4-amino-5-chloro-2,3-dihydro benzofuran-7-carboxylic acid pure product. Compared with a conventional method, the method simplifies the industrial production difficulty and remarkably improves the yield, so that the method disclosed by the invention is easy in industrial production operation, nearly no organic and inorganic waste solvents are used, the total yield is relatively high, and the industrial on-scale production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a synthesis method of 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid. Background technique [0002] Prucalopride is a selective 5-HT4 receptor agonist, and its monosuccinate is clinically used to treat female constipation that cannot be relieved by laxatives, and its trade name is Resolor. 4-Amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid is an important intermediate for the synthesis of prucalopride. [0003] A synthetic method is reported in US5374637 (CN1045781, EP389037) and J.Het.Chem, 1980,17(6):1333-5. Its synthetic route is as follows: [0004] [0005] Both steps of this method require the use of butyllithium reagent. The disadvantage is that its hexane solution is flammable and expensive, so it is not suitable for large-scale production. [0006] Chem.Pharm.Bull46 (1), 42-52 (1998) reported a kind of preparation method of this intermediate, " pha...

Claims

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Application Information

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IPC IPC(8): C07D307/79
CPCC07D307/79
Inventor 宋洪海陈伟黄海平李友峰林松
Owner TIANJIN WEIJIE TECH
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