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Preparation method of vilazodone or its hydrochloride

A technology of vilazodone hydrochloride and vilazodone, which is applied in the field of preparing vilazodone or its hydrochloride, can solve the problems of being unsuitable for mass industrialized preparation, high preparation cost, expensive and the like

Active Publication Date: 2011-12-07
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method adopts expensive metal palladium complex catalyst and tri-tert-butyl phosphorus ligand, not only the preparation cost is high, but also the preparation method of intermediate 3-(4-piperazine butyl) indole-5-carbonitrile has not been seen report, so it is not suitable for large-scale industrialized preparation of vilazodone hydrochloride

Method used

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  • Preparation method of vilazodone or its hydrochloride
  • Preparation method of vilazodone or its hydrochloride
  • Preparation method of vilazodone or its hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Preparation of 3-(4-Hydroxybutyl)indole-5-cyanocyanide(III)

[0067] At room temperature, dissolve 3-(4-chlorobutyryl)indole-5-cyanide (0.4mol, 99g) in 2000ml of isopropanol, stir for 5min, add sodium borohydride (1mol, 38g), and heat up to reflux React for 6 hours, slowly pour the reaction solution into 500ml of 1N ice-diluted hydrochloric acid, stir for 30min, and rotate the reaction solution under reduced pressure until there are basically only water and solids, dissolve the solids with 1000ml ethyl acetate, separate the liquid, and The phases were extracted with 250ml of ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and evaporated to dryness to obtain 86g of a yellow oily crude product, which was washed with 1L of petroleum ether to obtain 83g, which was directly used in the next reaction .

[0068] ESI-MS[M+H] + : 215.12

[0069] 1 H-NMR (CDCl 3 ): δ1.63-1.70(m, 2H), 1.74-1.83(m,...

Embodiment 2

[0071] Preparation of 4-(5-cyanindol-3-yl)butyl p-toluenesulfonate (I)

[0072] The crude 3-(4-hydroxybutyl)indole-5-cyanide (83g) prepared in the previous step reaction was dissolved in 1200ml of methylene chloride, the temperature was controlled in an ice-water bath at 0-5°C, stirred for 5min, and pyridine (68g ), and p-toluenesulfonyl chloride (0.436mol, 83g) was added after stirring for 10min. Raise the temperature to 15-20°C and react for 2 hours, pour the reaction solution into 500ml of water, stir for 0.5 hours, separate the liquids, extract the water phase with 30ml of dichloromethane, combine the organic phases, wash with saturated saline, evaporate to dryness, and place the obtained solid in 700ml of ethanol Stir at 40° C. for 2 h, cool to room temperature, filter and dry to obtain 88 g of white powder, the two-step yield is 60%.

[0073] ESI-MS[M+Na] + : 391.09

[0074] 1 H-NMR (DMSO-d6): δ1.60-1.64 (m, 4H), 2.40 (s, 3H), 2.66 (t, 2H, J=7.8Hz), 4.08 (t, 2H, J=5....

Embodiment 3

[0076] Preparation of 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide (compound 1, vilazodone)

[0077] Dissolve 4-(5-cyanindol-3-yl)butyl p-toluenesulfonate (0.12mol, 44.2g) in 800ml acetonitrile, add 5-(1-piperazinyl)-benzofuran -2-Carboxamide (0.1mol, 24.5g), diisopropylethylamine (0.3mol, 38g) was then heated to reflux for 3 hours, the solvent was evaporated under reduced pressure, and the residue was added with 200ml of water and 400ml of ethyl acetate, After stirring for 1 h, the insoluble matter was collected by filtration to obtain 42 g of a light yellow solid crude product, which was recrystallized in 150 ml of methanol to obtain 35 g of a white powder with a yield of 79%.

[0078] ESI-MS[M+H] + : 442.22.

[0079] 1 H-NMR (DMSO-d6): δ1.49-1.51 (m, 2H), 1.62-1.67 (m, 2H), 2.30-2.34 (m, 2H), 2.47-2.50 (m, 4H), 2.72 (t , 2H, J=7.2Hz), 3.04-3.09(m, 4H), 7.09-7.12(m, 2H), 7.32(s, 1H), 7.38-7.51(m, 4H), 7.60(br.s, 1H ,D 2 O heavy water exchang...

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Abstract

The invention discloses a preparation method of vilazodone or its hydrochloride, which comprises the following steps: the compound of formula (I) is mixed with the compound of formula (II) 5-(1 -piperazinyl)-benzofuran-2-formamide reaction, then collect vilazodone shown in formula 1 from the reaction product; Gained vilazodone 1 is in a solvent, and hydrochloric acid is salified to prepare formula (A ) shown vilazodone hydrochloride. The present invention overcomes the defects and deficiencies in the existing preparation methods of vilazodone and its intermediates, is more suitable for the large-scale industrial preparation of vilazodone hydrochloride, has obvious creativity, and has a relatively large positive progress effect and practical application value. The reaction formula is as follows:

Description

technical field [0001] The invention relates to a method for preparing vilazodone or its hydrochloride. technical background [0002] Vilazodone hydrochloride (Vilazodone hydrochloride), the chemical name is 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-methyl Amide hydrochloride is a new antidepressant drug developed by Clinical Data. In January 2011, it was approved by the US Food and Drug Administration (FDA) for the treatment of depression in adults. Its chemical structure is as shown in formula (A): [0003] [0004] Vilazodone hydrochloride is a 5-HT 1A Compared with the existing clinical antidepressants, the new antidepressant has dual effects of partial receptor agonism and 5-HT reuptake inhibition, and has the characteristics of rapid onset of action and no side effects of sexual dysfunction for patients. [0005] At present, the following methods have been disclosed at home and abroad to prepare vilazodone hydrochloride: [0006] 1) The prepa...

Claims

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Application Information

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IPC IPC(8): C07D405/12
Inventor 李建其王冠王超黄雷
Owner SHANGHAI INST OF PHARMA IND
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