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Synthetic method for 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid

A synthetic method, the technology of propylene glycol monomethyl ether, applied in the direction of organic chemistry, etc., can solve the problems of incomplete reaction of raw materials, long time, poor purity of compound I, etc., and achieve the effects of shortening the reaction time, increasing the yield, and high purity

Inactive Publication Date: 2016-02-03
SHANGHAI FAMO BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Finally, compound I is hydrolyzed with methyl ester and acetyl group in one step to obtain compound III, but there are many problems in the final hydrolysis reaction, for example: 1. The hydrolysis reaction of this step takes a long time, requiring more than 15 hours, and the reaction of raw materials is not complete; 2. The compound I prepared according to the literature method has poor purity. If the two protecting groups are directly hydrolyzed without purification, a lot of impurities will be produced, which makes it difficult to guarantee the product quality of compound III, and increases the difficulty of purification of compound III, which in turn affects the final product. Purification of Pharmaceutical Standards

Method used

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  • Synthetic method for 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid
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  • Synthetic method for 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Preparation of 4-acetylamino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (compound of formula II)

[0037] Formula I compound (100g, purity 80%) obtained above in the mixed solvent of water (400ml) and propylene glycol monomethyl ether (80ml), add 40% sodium hydroxide aqueous solution (100g), react at 70 ℃ for 2 hours , TLC monitors that the reaction is complete. The temperature of the reaction solution was lowered, filtered with suction, the filter cake was washed once with water, and dried to obtain the sodium salt of the compound of formula II (63 g), with a purity of 98.2%.

[0038] Salts of the compound of formula II such as potassium salt, lithium salt and ammonium salt can be synthesized by a method similar to Example 1.

[0039] MS(m / z): 256.1[M+H] +

[0040] 1 H-NMR (DMSO-d6, 400MHz)

[0041] δ: 2.07(3H, s), 3.05(2H, t), 4.65(2H, t), 7.61(1H, s), 9.89(1H, s), 12.89(1H, s)

Embodiment 2

[0043] Preparation of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (compound of formula III)

[0044] The sodium salt of the compound of formula II (63g, 0.227mol) was added to a reaction flask, 3mol / L NaOH aqueous solution (250ml) and propylene glycol monomethyl ether (40ml), and reacted at 100° C. for 3 hours, and TLC monitored that the reaction was complete. Cool down to 35°C, filter with suction, wash the filter cake with water, put the obtained filter cake into a reaction flask, add water (500ml) and propylene glycol monomethyl ether (50ml), heat to 85°C, heat filter, add 6mol / L hydrochloric acid aqueous solution dropwise to the filtrate to adjust When the pH reached 2, a large amount of solids were precipitated, cooled, filtered with suction, washed the filter cake with water, and dried to obtain the compound of formula III (47 g), yield: 97%, purity: 99.5%.

[0045] MS(m / z): 214.6[M+H] +

[0046] 1 H-NMR (DMSO-d6, 400MHz)

[0047] δ: 2.97 (2H, t), 4.60 (...

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Abstract

The present invention relates to a drug intermediate synthetic method, in particular to a synthetic method for 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid of Prucalopride Succinate intermediate. The method comprises performing hydrolysis adopting a two-step method. According to the synthetic method disclosed by the invention, the raw material can be reacted adequately; the reaction time can be shortened; the obtained product is high in purity; and the yield is improved.

Description

technical field [0001] The invention relates to a synthesis method of a pharmaceutical intermediate, in particular to a synthesis method of prucalopride succinate intermediate 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid. Background technique [0002] Prucalopride succinate (formula IV), chemical name: N-[1-(3-methoxypropyl)-4-piperidinyl]-4-amino-5-chloro-2,3-di Hydrobenzofuran-7-carboxamide succinate, the structural formula is as follows: [0003] [0004] Prucalopride succinate is a highly selective 5-HT4 receptor agonist developed by the Belgian company Janssen and launched in the UK in 2010 for the treatment of female constipation that cannot be relieved by laxatives. [0005] CN1164233 reports that the compound of formula IV is synthesized mainly by the condensation of key intermediate 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (formula III) and side chain (formula V) to form succinate Salt made: [0006] [0007] Wherein the synthesi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/79
Inventor 唐家邓
Owner SHANGHAI FAMO BIOTECH CO LTD
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