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A kind of preparation method of vilazodone intermediate

A technology of vilazodone and intermediates, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of unsuitability for industrial production, difficult operation of red aluminum, low yield and the like, and achieves short synthesis route, low cost and high yield. high effect

Active Publication Date: 2017-10-13
北京启嘉医疗器械有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the Friedel-Crafts acylation step of this route, the rare Lewis acid isobutyl aluminum chloride is also used as a catalyst. In the reduction step, red aluminum is used as a selective reducing agent, but the weight of red aluminum And feeding is not easy to operate in the workshop, the yield is low, only 27%, and it needs to be purified by column chromatography, which is not suitable for industrial production

Method used

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  • A kind of preparation method of vilazodone intermediate
  • A kind of preparation method of vilazodone intermediate
  • A kind of preparation method of vilazodone intermediate

Examples

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Effect test

Embodiment 1

[0028] Synthesis of 6-chlorohexanal-4-cyanophenylhydrazone

[0029] Take 21.40g (0.126mol) of 4-cyanophenylhydrazine hydrochloride and add it to a 250mL three-necked bottle, 2 Under protection, add 140mL methanol, 13.40g Et 3 N (0.133mol) was stirred into a solution, cooled in an ice bath, and 6-chlorohexanal (23.30g, 0.174mol) was added dropwise at 0-5°C, after the addition was complete, stirred at this temperature for about 15 minutes, TLC showed a reaction Complete (petroleum ether: ethyl acetate = 1: 1), stop the reaction. The reaction liquid was poured into ice water, kept stirring at -10-0°C, and a solid was precipitated, filtered, and vacuum-dried to obtain 26.6 g of hydrazone, with a yield of 84%. The obtained hydrazone is a mixture of Shuangjian Shun and trans isomers, the ratio of the two is 1:4, and the identification data of the cis structure is as follows:

[0030] 1 H-NMR, (400MHz CDCl 3 ppm) 7.48 (d, J = 8.6Hz 2H), 7.13 (t, J = 5.1Hz, 1H), 6.99 (d, J = 8.6H...

Embodiment 2

[0034] Synthesis of 3-(4-chlorobutyl)-5-cyanindole

[0035] Put 10.00 g of hydrazone (40 mmol) in a 500 mL flask, add 150 mL of acetonitrile and 14.80 g (44 mmol) of polyphosphoric acid, and heat until the acetonitrile refluxes. After reacting for about one hour, HPLC showed that the reaction was complete (acetonitrile:water=80:20). Cool the reaction solution to room temperature, distill off acetonitrile under reduced pressure, add water (200 mL) and ethyl acetate (200 mL) to dissolve the residue, separate the water layer, extract the water layer with ethyl acetate (3×150 mL), combine the organic layers, and use Wash with water (2×200 mL), wash with saturated sodium chloride solution (200 mL), dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a yellow solid. Add 1:1 (V / W) methanol to the product, heat to reflux to dissolve, cool to room temperature to precipitate a solid, filter and dry in vacuo to obtain 5.59 g of indole comp...

Embodiment 3

[0038] Synthesis of Vilazodone

[0039] Add 3-(4-chlorobutyl)-5-cyanindole 36.10g (155mmol), 5-(piperazin-1-yl)benzofuran-2-carboxamide 36.00g (147mmol ), 25.50g of sodium acetate (310mmol), dissolved in 500mL of DMAC under stirring, reacted at 90°C (external temperature) for 18 hours, cooled the reaction solution to room temperature, added 1L of water, extracted with ethyl acetate (3 × 400mL), combined organic The organic layer was washed with water (2×300 mL), washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a yellow solid. Using a mixed solvent for purification, first dissolve the solid in THF, add acetone and methanol under stirring, stir to precipitate the solid, filter, vacuum dry and weigh to obtain vilazodone.

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Abstract

The invention provides a preparation method of a vilazodone intermediate. In this method, hexanal compounds are used as starting materials to react with phenylhydrazine or aniline compounds, and the obtained compounds are ring-closed under acid catalysis to obtain 3-(4-chlorobutyl)-5-cyanoindol This method avoids the acylation reaction of acyl chloride under the catalysis of Lewis acid in the literature, and also avoids the step of red aluminum reduction of carbonyl to obtain methylene in the literature, which is not easy to achieve in the workshop. This compound is a key intermediate in the synthesis of vilazodone. The method has easy-to-obtain raw materials, mild reaction conditions, simple operation, easy process control, low cost and easy industrial production.

Description

technical field [0001] The invention relates to a preparation method of a drug intermediate, in particular to a preparation method of an antidepressant drug vilazodone hydrochloride intermediate. Background technique [0002] Depression is an attack form of manic depression, with low emotion, slow thinking, and decreased speech and movement, slowness as typical symptoms. Depression seriously plagues the life and work of patients, and brings a heavy burden to families and society. About 15% of patients with depression die by suicide. A joint study by the World Health Organization, World Bank and Harvard University shows that depression has become the second leading cause of disease burden in China. [0003] Vilazodone hydrochloride, the chemical name is 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-2-benzofurancarboxamide Hydrochloride is a new drug jointly developed by American Trovis Pharma LLC and Merck for the treatment of severe depression in adults. Its chemica...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C253/30C07C255/66C07C255/61C07D405/12
Inventor 刘素云孙长安
Owner 北京启嘉医疗器械有限公司
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