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Synthetic technology for 4-acetamido-2,3-dihydrobenzofuran-7-methyl formate

A technology of acetamido and methyl formate, applied in directions such as organic chemistry, can solve problems such as being unsuitable for industrial large-scale production

Inactive Publication Date: 2013-04-03
芷威(上海)化学科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These reagents and processes are also not suitable for large-scale industrial production.

Method used

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  • Synthetic technology for 4-acetamido-2,3-dihydrobenzofuran-7-methyl formate
  • Synthetic technology for 4-acetamido-2,3-dihydrobenzofuran-7-methyl formate
  • Synthetic technology for 4-acetamido-2,3-dihydrobenzofuran-7-methyl formate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] Add 0.5kg of compound 3 (self-made, see Chem.Pharm.Bull46(1)42-52(1998)) and 5L of methanol into a 10L flask, cool down to -20°C, and start to pass through the 0 produced by the ozone generator. 3 , the ozone concentration was 41.23 mg / L, and the temperature was maintained for 8 hours to complete the reaction. Add 0.1 kg of sodium borohydride after the reaction ends, and the reaction ends in about 2-3 hours. After the end, glacial acetic acid was added to adjust the pH to neutral. Methanol was concentrated under reduced pressure to obtain off-white product Compound 5 (0.3kg), melting point: 170-175°C; 1HNMR (DMSO): δ2.089 (3H, s), 2.846 (2H, t), 3.580 (2H, t) , 3.898(3H,s), 5.242(1H,s), 7.385(1H,d), 7.651(1H,d), 9.628(1H,s), 11.104(1H,s).

Embodiment 2

[0185]Compound 5 (0.3kg) obtained in Example 1, 300ml of dichloromethane, and 30ml of pyridine were added to a 5L bottle, the temperature was lowered to -10°C, 100ml of methanesulfonyl chloride was added, and the reaction was maintained at -10°C for 8-10 hours. After the reaction, dichloromethane was concentrated under reduced pressure to obtain a pink product, which was filtered, washed with water, and dried. Compound 9 (0.32 kg) was obtained. Melting point: 134.6-136.3°C; 1H NMR (CDCl 3 ): δ2.223 (3H, s), 2.992 (3H, s), 3.160 (2H, t), 3.944 (3H, s), 4.520 (2H, t) , 7.614(1H,d), 7.760(1H,d), 7.999(1H,s), 11.274(1H,s).

Embodiment 3

[0187] Compound 9 (0.3kg) obtained in Example 2, 100ml of triethylamine and 3L of ethyl acetate were refluxed for 10 hours. After the end of the reaction, the triethylamine was concentrated under reduced pressure to obtain an off-white solid. Recrystallized from ethyl acetate to obtain 0.18 kg of compound 6. Melting point: 125.8-128.9°C; 1H NMR (CDCl 3 ): δ2.216 (3H, s), 3.138 (2H, t), 3.889 (3H, s), 4.771 (2H, t), 6.997 (1H, s) , 7.489(1H,d), 7.264(1H,d).

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Abstract

The invention discloses a synthetic technology for 4-acetamido-2,3-dihydrobenzofuran-7-methyl formate. The invention provides a method for synthesizing 4-acetamido-2,3dihydrobenzofuran-7-methyl formate, which comprises Steps (a), (b) and (c) as described in the specification, wherein Step (a) is executed under an ozone condition, and / or Step (c) is executed as described in the specification.

Description

technical field [0001] The invention relates to a synthesis process of 4-acetylamino-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester. 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-HT4 receptor agonist, and its monosuccinate is clinically used to treat female constipation that cannot be relieved by laxatives. The trade name is Resolor. [0003] 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid is an important intermediate for the synthesis of prucalopride, [0004] US5374637 (CN1045781, EP389037)) and J.Het.Chem, 1980,17(6):1333-5. reported its synthetic method. Its synthetic route is as follows: [0005] [0006] Both steps of this method need to use butyllithium reagent, and its hexane solution is flammable and expensive. Not suitable for mass production. [0007] Chem.Pharm.Bull 46(1), 42-52(1998) and Pharmacy and Clinical Res...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/79C07D405/12
Inventor 付开勇李华许仓
Owner 芷威(上海)化学科技有限公司