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Method for preparing vilazodone and intermediate thereof

A compound, selected technology, applied in the direction of organic chemistry, bulk chemical production, etc., can solve the problems of harsh Buchwald reaction conditions, not suitable for mass industrial production, and low reaction yield

Active Publication Date: 2014-02-12
JIANGSU SIMCERE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] In this method, the Buchwald reaction conditions are relatively harsh, the reaction yield is not high, and it is not suitable for large-scale industrial production

Method used

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  • Method for preparing vilazodone and intermediate thereof
  • Method for preparing vilazodone and intermediate thereof
  • Method for preparing vilazodone and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099]

[0100] (1) Preparation of 5-(4-(3-butenyl)piperazin-1-yl)benzofuran-2-carboxamide

[0101] Add 24.5g (100mmol) of 5-(piperazin-1-yl)benzofuran-2-carboxamide, 41.4g (300mmol) of potassium carbonate, and 400ml of N,N-dimethylformamide in the reaction flask, at room temperature 16.2g (120mmol) of 4-bromo-1-butene was added dropwise, and then heated to 60°C and stirred for 12h. Stop heating, cool to room temperature, filter, add the filtrate to 800 ml of water, stir for 0.5 h, filter, dry, and recrystallize with ethyl acetate to obtain 25.6 g of a brown solid with a yield of 86%.

[0102] MS-ESI(M+1): 300

[0103] 1 H NMR: (400MHz, d-DMSO) δ: 8.05 (s, 1H), 7.63 (s, 1H), 7.47 (d, J=9.6 Hz, 1H), 7.41 (s, 1H), 5.83 (m, 1H) ), 5.08(dd, J=17.2, 1.6Hz, 1H), 5.00(d, J=8.0Hz, 1H), 3.11(t, J=4.8Hz, 4H), 2.55(t, J=4.8Hz, 4H ), 2.41(t, J=7.2Hz, 2H), 2.35(m, 2H)

[0104] (2) 5-(4-(4-(1-benzyl-5-cyanoindol-3-yl)-3-but-enyl)piperazin-1-yl)benzofuran-2-methyl Preparation of amide

[0105] Ad...

Embodiment 2

[0113]

[0114] (1) Preparation of 5-(4-(3-butenyl)piperazin-1-yl)benzofuran-2-carboxamide

[0115] Add 24.5g (100mmol) of 5-(piperazin-1-yl)benzofuran-2-carboxamide, 42.4g (200mmol) of potassium phosphate, and 400ml of tetrahydrofuran into the reaction flask, and add 4-iodine-1 dropwise at room temperature. -Butene 18.2g (120mmol), then heated to 70°C and stirred for 36h. Stop heating, cool to room temperature, filter, add the filtrate to 1000 ml of water, stir for 1 h, filter, dry, and recrystallize with ethyl acetate to obtain 22.8 g of brown solid with a yield of 76.3%.

[0116] (2) 3-(4-(4-(2-carbamoylbenzofuran-5-yl)piperazin-1-yl)-1-butenyl)-5-cyanoindole-1-carboxylic acid Preparation of tert-butyl ester

[0117] Add 22.8g (76.8mmol) of 5-(4-(3-butenyl)piperazin-1-yl)benzofuran-2-carboxamide, 5-cyano-3-iodoindole- 23.4g (63.5mmol) of tert-butyl 1-formate, 0.58g (0.5mmol) of tetrakis(triphenylphosphine)palladium and 150ml of N,N-dimethylformamide, replaced with argon for thr...

Embodiment 3

[0126]

[0127] (1) Preparation of 5-(4-(3-butenyl)piperazin-1-yl)benzofuran-2-carboxamide

[0128] Add 24.5g (100mmol) of 5-(piperazin-1-yl)benzofuran-2-carboxamide, 20.2g (200mmol) of triethylamine, and 400ml of N,N-dimethylformamide into the reaction flask, 27.3g (150mmol) of 4-bromo-1-butene was added dropwise at room temperature, and then heated to 60°C and stirred for 6h. Stop heating, cool to room temperature, filter, add the filtrate to 800 ml of water, stir for 0.5 h, filter, dry, and recrystallize with ethyl acetate to obtain 24.1 g of a brown solid with a yield of 80.6%.

[0129] (2) Preparation of 5-(4-(4-(5-cyanoindol-3-yl)-3-butenyl)-piperazin-1-yl)benzofuran-2-carboxamide

[0130] Add 24.0g (80.1mmol) of 5-(4-(3-butenyl)piperazin-1-yl)benzofuran-2-carboxamide and 18.0 of 3-bromoindole-5-carbonitrile to the reaction flask. g (81.4mmol), triethylamine 24.3g (240.3mmol), bis(triphenylphosphine) palladium dichloride 0.701g (1mmol) and tris(o-methylphenyl)phosphine 0.6g, ...

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Abstract

The invention provides a method for preparing vilazodone and an intermediate thereof. According to the method, an intermediate shown in formula (V) can be obtained by virtue of a coupling reaction, and vilazodone can be obtained from the intermediate shown in formula (V) by virtue of olefinic bond reduction and N protecting group removal; or vilazodone can be obtained by virtue of further transformation. The method provided by the invention overcomes defects in the existing preparation method for vilazodone and an intermediate thereof, as well as is easy to get raw materials, high in reaction yield, suitable for industrialized production, and high in application value.

Description

Technical field [0001] The invention relates to a method for preparing vilazolone and its intermediates through a metal-catalyzed coupling reaction. Background technique [0002] Vilazodone, chemical name 5-(-4-(4-(5-cyanoindol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxamide, Its structure is shown in formula (I). On January 21, 2011, the biibryd tablet developed by Trovis was approved by the US FDA for the treatment of adult major depressive disorder (MDD). It is the first new indole alkylamine antidepressant. . The drug is used to treat or prevent depression, anxiety, bipolar disorder, mania, dementia, mental disorders related to psychoactive substances, sexual dysfunction, eating disorders, obesity, fibromyalgia, sleep disorders, psychotic-like disorders Mental disorders, cerebral infarction, tension, side effects in the treatment of hypertension, brain disorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome, and unwanted postpartum...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D307/85C07D209/14C07D295/205
CPCY02P20/55C07D405/12C07D209/14C07D295/205C07D307/85
Inventor 朱溪陈琪韩伟黄常康廖明毅
Owner JIANGSU SIMCERE PHARMA
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