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New preparation process of medicinal raw material duloxetine hydrochloride of antidepressant drug

An anti-depression and new technology technology, applied in the direction of organic chemistry and the like, can solve the problems of duloxetine hydrochloride not reaching the therapeutic effect, insufficient optical rotation of chiral compounds, and poor dealkylation reaction effect, etc. The effect of clear process, low production cost and easy operation

Inactive Publication Date: 2013-10-23
李晓红
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the existing synthesis process of duloxetine hydrochloride, Mannich uses dimethylamine hydrochloride, which makes the dealkylation reaction in the subsequent steps not effective; the residual crystallization solvent is harmful to the human body; The optical rotation of the compound is not high enough; so that the final product duloxetine hydrochloride cannot achieve better therapeutic effect

Method used

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  • New preparation process of medicinal raw material duloxetine hydrochloride of antidepressant drug
  • New preparation process of medicinal raw material duloxetine hydrochloride of antidepressant drug
  • New preparation process of medicinal raw material duloxetine hydrochloride of antidepressant drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] In a 1000ml three-necked flask with a reflux device, add 126.0g (1.0mol) of 2-acetylthiophene, 196.9g (1.25mol) of N-methylbenzylamine hydrochloride, and 45.0g (1.5mol) of polyaldehyde, and concentrate 10ml of hydrochloric acid, 300ml of isopropanol, heated to reflux under stirring, reacted for 8 hours, after the reaction of the raw materials was monitored by TCL, cooled to room temperature, filtered, the filter cake was washed twice with 100ml of ethanol, and the obtained solid was vacuum-dried to obtain a white crystal 274.6 g, m.p: 173-176°C, yield 94.2%.

Embodiment 2

[0025] In a 1000ml three-necked flask, 291.5g (1.0mol) of 1-(N-methyl-N-benzyl)amino-3-(2-thienyl)-3-acetone hydrochloride prepared in Example 1 was added, and 300ml Ethanol and 100ml of water to dissolve all the solids, control the temperature below 20°C, slowly add about 40g of 30% sodium hydroxide solution to pH = 11 under stirring, slowly add 37.0g (0.5mol) of sodium borohydride solution dropwise, and stir at room temperature After reacting for 3 hours, 150ml of acetone was added, stirred for 30 minutes, ethanol was distilled off under reduced pressure, and filtered by suction to obtain 231.3g of white solid, with a yield of 90%.

Embodiment 3

[0027] In a 1000ml three-necked flask, add 128.5g (0.5mol) of (RS)-(N-methyl-N-benzyl)-3-hydroxyl-3-(2-thienyl)propylamine prepared in Example 2, DMSO500ml, add Potassium hydroxide 112g (1.0mol), 1-fluoronaphthalene 73g (0.5mol), heated to 110°C and stirred for 2 hours, cooled to 20°C, filtered to obtain 162.8g of solid, yield 85%.

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Abstract

The invention relates to a new preparation process of the medicinal raw material duloxetine hydrochloride of an antidepressant drug and belongs to the technical field of drug synthesis. The new preparation process is characterized in that N-methyl benzylamine hydrochloride but not dimethylamine hydrochloride is used in Mannich reaction; because benzyl is easier to remove as compared with methyl, dealkylation in a subsequent step has better effect and higher yield; an expensive chiral catalyst or a phase-transfer catalyst is not used; a better solvent crystallizing and removing method is adopted, so that the harm of a residual crystallizing solvent to a human body is prevented; the splitting of a chiral compound is carried out after dealkylation, and a mixture obtained after splitting is separated by adopting a unique recrystallization technology to prepare (S)-N-methyl-3-(1-naphthoxy)-3-(2-thienyl) propylamine / tartrate with high purity and high optical activity, so that a finally obtained duloxetine hydrochloride product can achieve better treatment effect. The new preparation process disclosed by the invention has the advantages of mildness in reaction condition, clear process, good easiness and convenience in operation and low production cost and is extremely favorable for industrial production.

Description

1. Technical field [0001] The invention relates to a new preparation process of duloxetine hydrochloride, an antidepressant drug raw material drug, and belongs to the technical field of drug synthesis. 2. Background technology [0002] Duloxetine hydrochloride, the chemical name is (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride, is a selective serotonin and normethyl Dual adrenaline reuptake inhibitors were first launched in the United States and the European Union in 2004, and are mainly used clinically for the treatment of depression, diabetic peripheral neuralgia and moderate to severe stress urinary incontinence in women. [0003] The synthesis of duloxetine hydrochloride has been reported abroad in US20090275760A1, US20100331388A1, WO2011 / 077443A1, US20120029212A1 and other materials. [0004] Domestically, in the document CN102070602A, the inventor Wang Nianjun reported on the synthesis of duloxetine hydrochloride. [0005] In the existing synt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/20
Inventor 李晓红
Owner 李晓红
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