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Substituted piperazine compound and preparation method for intermediate of vilazodone

A compound and piperazine technology, applied in the field of medicine, can solve the problems of environmental hazards, high preparation cost, long reaction route, etc., and achieve the effects of environmental protection route, simple operation and outstanding yield

Active Publication Date: 2014-09-17
天津泰普制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The shortcoming of this method is: reaction route is longer, and two (2-chloroethyl) amine hydrochloride used in the reaction is a kind of chemical that can be used as chemical weapon, and the used diethanolamine of synthesis it is a kind of to Environmentally harmful compounds, so as our country pays more and more attention to environmental protection, this synthetic route at the expense of the environment will also be eliminated
[0010] Although the route is short in steps, expensive transition metal palladium catalysts and tri-tert-butylphosphine ligands are used, and the catalysts cannot be recycled and used mechanically, and the preparation cost is high
And wherein intermediate 5-(4-Boc-piperazinyl-1-yl)-benzofuran-2-carboxylic acid ethyl ester is difficult to separate, needs to adopt the method for column chromatography, is not suitable for large-scale industrial production

Method used

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  • Substituted piperazine compound and preparation method for intermediate of vilazodone
  • Substituted piperazine compound and preparation method for intermediate of vilazodone
  • Substituted piperazine compound and preparation method for intermediate of vilazodone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Preparation of 5-(4-acetylpiperazin-1-yl)-2-hydroxybenzaldehyde

[0037] Add 269g (2.8mol) of methanesulfonic acid, 88g (0.4mol) of 4-(4-acetylpiperazin-1-yl)phenol and 56g (0.4mol) of urotropine into a 2L four-necked flask, stir and heat, The temperature was raised to 110° C., and the reaction was carried out for 3 hours. After the reaction is complete, keep stirring, add 1L of water, add 1L of ethyl acetate after the addition, then pour into a separation funnel, separate the ethyl ester layer, wash with water, add anhydrous magnesium sulfate to dry, filter, recover the ethyl acetate under reduced pressure, evaporate Dry to get 50g of oil. The yield is 50%. NMR(DMSO)δ2.0(S,3H), 3.30-3.60(d,4H), 3.81(s,4H), 6.87-7.13(d,1H), 7.65-7.76(d,2H), 10.26(s , 1H, -CHO)

[0038] The resulting solid can be isolated by dissolving in ethanol, adding hydrochloric acid ethanol solution dropwise, and drying the corresponding hydrochloride sample.

Embodiment 2

[0040] Preparation of 5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde

[0041] Add 947g (2.8mol) of polyphosphoric acid, 78g (0.28mol) of 4-(4-tert-butoxycarbonylpiperazin-1-yl)phenol and 78g (0.56mol) of urotropine into a 2L four-neck flask , stirred and heated, the temperature was raised to 90°C, and the reaction was carried out for 1 hour. After the reaction is complete, keep stirring, add 1L of water, add 1L of ethyl acetate after the addition, then pour into a separation funnel, separate the ethyl ester layer, wash with water, add anhydrous magnesium sulfate to dry, filter, recover the ethyl acetate under reduced pressure, evaporate Dry to get 38g of oil. The yield is 45%. mp84-86°C; MS306 (M+), 250 (100%), 233, 176, 164.

Embodiment 3

[0043] Preparation of 5-(4-benzylpiperazin-1-yl)-2-hydroxybenzaldehyde

[0044] Add 319g (2.8mol) of trifluoroacetic acid, 150g (0.56mol) of 4-(4-benzylpiperazin-1-yl)phenol and 78g (0.56mol) of urotropine into a 2L four-neck flask, stir and heat , heated up to 100°C, and reacted for 2 hours. After the reaction is complete, keep stirring, add 1L of water, add 1L of ethyl acetate after the addition, then pour into a separation funnel, separate the ethyl ester layer, wash with water, add anhydrous magnesium sulfate to dry, filter, recover the ethyl acetate under reduced pressure, evaporate 69g of oil was obtained after drying. The yield is 42%. mp 101-103°C; MS 296 (M+), 205, 119, 91 (100%).

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Abstract

The invention belongs to the technical field of medicine and relates to a substituted piperazine compound and a preparation method for an intermediate of vilazodone. Substituted piperazine phenol is employed as a raw material and is subjected to a hydroformylation reaction, a cyclization reaction and a formylation reaction to obtain 5-(1-piperazine)-benzofuran-2-methanamide of a salt thereof. Finally vilazodone is prepared. The preparation method overcomes defects in a preparation method in the prior art, is simple in operation, is environment-friendly in processes and is free of any expensive catalysts. The intermediate is convenient to separate, is outstanding in yield, is low in cost and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a preparation method of an important intermediate, in particular to a substituted piperazine compound and a method for preparing a vilazodone intermediate. Background technique [0002] Vilazodone (Vilazodone) is a new type of drug for the treatment of severe depression, the structural formula is as follows: [0003] [0004] 5-(1-piperazinyl)-benzofuran-2-carboxamide or its acid addition salt is a key intermediate in the synthesis of vilazodone. [0005] Patent CN1181067C describes a method for preparing 5-(1-piperazinyl)-benzofuran-2-carboxamide, see the following formula. [0006] [0007] The shortcoming of this method is: reaction route is longer, and two (2-chloroethyl) amine hydrochloride used in the reaction is a kind of chemical that can be used as chemical weapon, and the used diethanolamine of synthesis it is a kind of to Environmentally harmful compounds, so as ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/185C07D295/205C07D295/116C07D307/85
CPCC07D295/116C07D295/185C07D295/205C07D307/85
Inventor 陈蔚潘毅康江鹏陶勇
Owner 天津泰普制药有限公司
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