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Preparation method of duloxetine key intermediate

A thienyl and methylamino technology, applied in the field of organic synthesis, can solve the problems of difficult separation and purification, unfavorable long-term use, cumbersome steps, etc., and achieves the effects of fewer reaction steps, economical savings, and simple process route.

Inactive Publication Date: 2014-05-28
ZHANG JIA GANG VINSCE BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, it has been reported that there are many methods for preparing 3-N-methylamino-1-(2-thienyl)-1-acetone hydrochloride, and most of the steps are cumbersome, with high cost and low yield, which is not conducive to long-term use
[0003] Patents CN200480002686.2, WO2004 / 5307 A1, and EP1510517 A1 report a typical Mannich reaction using 2-acetylthiophene, formaldehyde and dimethylamine, and a reverse Michael / Michael reaction from excess methylamine to obtain a monomethylamine ketone compound. The post-treatment of this method is difficult to separate and purify, which affects the yield
[0004] In addition, thiophene and 3-chloropropionyl chloride undergo Friedel-Craft acylation reaction, and then react with methylamine to obtain the product. The first step of this method is easy to acylate at the 5-position, and the purity is low

Method used

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  • Preparation method of duloxetine key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 Preparation of 3-N-methylamino-1-(2-thienyl)-1-acetone hydrochloride

[0021] Put 20ml of 2-acetylthiophene into a three-necked flask, add 160-200ml of methanol, 0.01-0.02g of concentrated hydrochloric acid, 16.2-25.7g of methylamine hydrochloride, and 6.8-8.6g of paraformaldehyde, and heat to reflux for reaction. After 9-10 hours, Crystals were precipitated, filtered, and recrystallized with pure water to obtain 32-33 g.

Embodiment 2

[0022] Example 2 Preparation of 3-N-methylamino-1-(2-thienyl)-1-acetone hydrochloride

[0023] Put 20ml of 2-acetylthiophene into a three-necked flask, add 160-200ml of ethanol, 0.01-0.02g of concentrated hydrochloric acid, 16.2-25.7g of methylamine hydrochloride, and 6.8-8.6g of paraformaldehyde, and heat to reflux for reaction. After 8-9 hours, Crystals were precipitated, filtered, and recrystallized with pure water to obtain 34-35 g.

Embodiment 3

[0024] Example 3 Preparation of 3-N-methylamino-1-(2-thienyl)-1-acetone hydrochloride

[0025] Put 20ml of 2-acetylthiophene in a three-necked flask, add 160-200ml of ethanol, 0.01-0.02g of concentrated sulfuric acid, 16.2-25.7g of methylamine hydrochloride, and 6.8-8.6g of paraformaldehyde, and heat to reflux for 9-10 hours. Crystals were precipitated, filtered, and recrystallized with pure water to obtain 35-36 g.

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Abstract

A preparation method of a duloxetine key intermediate. The invention discloses a preparation method of 3-N-methylamino-1-(2-thienyl)-1-acetonehydrochloride. The preparation method is characterized in that by using 2-acetylthiophene as an initial raw material and using low-carbon alcohol as a solvent, a typical Mannich reaction is carried out between the initial raw material and methylamine hydrochloride and paraformaldehyde in the presence of catalytic amounts of Lewis acid so as to obtain the product. The yield based on the weight reaches 80-85%. The preparation method has advantages of simple operation, high yield, good purity and the like, and is an excellent technology suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a preparation method of 3-N-methylamino-1-(2-thienyl)-1-acetone hydrochloride. Background technique [0002] 3-N-methylamino-1-(2-thienyl)-1-acetone hydrochloride is an important pharmaceutical and chemical intermediate, and it is also a Inhibitors) key intermediates. In recent years, it has been reported that there are many methods for preparing 3-N-methylamino-1-(2-thienyl)-1-acetone hydrochloride, and most of the steps are cumbersome, with high cost and low yield, which is not conducive to long-term use. [0003] Patents CN200480002686.2, WO2004 / 5307 A1, and EP1510517 A1 report a typical Mannich reaction using 2-acetylthiophene, formaldehyde and dimethylamine, and a reverse Michael / Michael reaction from excess methylamine to obtain a monomethylamine ketone compound. The post-treatment of this method is difficult to separate and purify, which affects the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/22
CPCC07D333/22
Inventor 赵金召张梅彭学东王龙
Owner ZHANG JIA GANG VINSCE BIO PHARM
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