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Method of preparing vilazodone and intermediate thereof

A compound and selected technology, applied in the direction of organic chemistry, can solve the problems of harsh Buchwald reaction conditions, not suitable for large-scale industrial production, and low reaction yield

Active Publication Date: 2014-03-26
JIANGSU SIMCERE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 of preparing vilazodone and intermediate thereof
  • Method of preparing vilazodone and intermediate thereof
  • Method of preparing vilazodone and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097]

[0098] (1) Preparation of 5-(4-(3-butynyl)piperazin-1-yl)benzofuran-2-carboxamide

[0099] Add 24.5g (100mmol) of 5-(piperazin-1-yl)benzofuran-2-carboxamide, 57.1g (150mmol) of sodium phosphate dodecahydrate, 500ml tetrahydrofuran, and 125ml water in the reaction flask, and add dropwise at room temperature 4-Bromo-1-butyne 33.0g (250mmol), then heated to 65°C and stirred for 18h. The heat was turned off and the aqueous layer was separated while hot. The organic phase was evaporated to dryness under reduced pressure, and the solid was beaten with 500 ml of ethanol at room temperature, and filtered after two hours to obtain 25.6 g of a yellow solid, with a yield of 86.2%. MS-ESI[M+H] + :298

[0100] 1 H NMR: (400MHz, d 6 -DMSO)δ8.03(s,1H),7.61(s,1H),7.48(d,J=9.6Hz,1H),7.42(s,1H),7.16~7.18(m,2H),3.11(t ,J=4.8Hz,4H),2.79(s,1H),2.58(t,J=4.8Hz,4H),2.54(t,J=7.6Hz,2H),2.37(t,J=7.6Hz,2H ).

[0101] (2) 3-(4-(4-(2-carbamoylbenzofuran-5-yl)piperazin-1-yl)-1-butynyl)-5...

Embodiment 2

[0112]

[0113] (1) Preparation of 5-(4-(3-butynyl)piperazin-1-yl)benzofuran-2-carboxamide

[0114]Add 24.5g (100mmol) of 5-(piperazin-1-yl)benzofuran-2-carboxamide, 27.6g (200mmol) of sodium carbonate, 300ml tetrahydrofuran, and 200ml water into the reaction flask, and add 4-iodine dropwise at room temperature -1-butyne 36.0g (200mmol), then heated to 65°C and stirred for 18h. The heat was turned off and the aqueous layer was separated while hot. The organic phase was evaporated to dryness under reduced pressure, and the solid was beaten with 500 ml of ethanol at room temperature, and filtered after two hours to obtain 24.2 g of a yellow solid, with a yield of 81.5%.

[0115] (2) 5-(4-(4-(1-benzyl-5-cyanindol-3-yl)-3-but-ynyl)piperazin-1-yl)benzofuran-2-methyl Preparation of amides

[0116] Add 24.2 g (81.5 mmol) of 5-(4-(3-butynyl) piperazin-1-yl) benzofuran-2-carboxamide, 1-benzyl-3-iodoindole- 29.2g (81.5mmol) of 5-formonitrile, (1,1'-bis(diphenylphosphinoferrocene)...

Embodiment 3

[0120]

[0121] (1) Preparation of 5-(4-(3-butynyl)piperazin-1-yl)benzofuran-2-carboxamide

[0122] Add 24.5g (100mmol) of 5-(piperazin-1-yl)benzofuran-2-carboxamide, 30.3g (300mmol) of triethylamine, 300ml tetrahydrofuran, and 100ml water into the reaction flask, and add 4- Iodo-1-butyne 45.0g (250mmol), then heated to 80°C and stirred for 12h. The heat was turned off and the aqueous layer was separated while hot. The organic phase was evaporated to dryness under reduced pressure, and the solid was beaten with 500 ml of ethanol at room temperature, and filtered after one hour to obtain 22.9 g of a yellow solid, with a yield of 77.1%.

[0123] (2) 5-(4-(4-(5-cyano-1-(4-methoxybenzyl)indol-3-yl)-3-butynyl)piperazin-1-yl)benzene Preparation of furan-2-carboxamide

[0124] Add 22.9 g (77.1 mmol) of 5-(4-(3-butynyl) piperazin-1-yl) benzofuran-2-carboxamide in the reaction flask, 1-(4-methoxybenzyl) -3-bromoindole-5-carbonitrile 30.6g (90mmol), palladium acetate 0.224g (1mmo...

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Abstract

The invention provides a method of preparing vilazodone and an intermediate thereof. The method comprises the following steps: obtaining the intermediate shown as a formula (V) through a coupling reaction; and obtaining vilazodone by reducing an acetylenic bond and removing an N protective radical for the intermediate shown as the formula (V); or further converting to obtain vilazodone. The method provided by the invention overcomes the deficiencies in existing preparation of vilazodone and the intermediate thereof. The raw material is easy to obtain, the reaction yield is high, and the method is suitable for industrialized production and has a greater application value.

Description

technical field [0001] The invention relates to a method for preparing vilazodone and its intermediate through metal-catalyzed coupling reaction. Background technique [0002] Vilazodone (Vilazodone), chemical name 5-(-4-(4-(5-cyanindol-3-yl) butyl) piperazin-1-yl) benzofuran-2-carboxamide, Its structure is shown in formula (I). On January 21, 2011, the vilazodone hydrochloride (biibryd) tablets developed by Trovis were approved by the US FDA for the treatment of major depressive disorder (MDD) in adults. It is the first new type of indolealkylamine antidepressant . This medicine is indicated for the treatment or prevention of depression, anxiety, bipolar disorder, mania, dementia, psychoactive substance-related disorders, sexual dysfunction, eating disorders, obesity, fibromyalgia, sleep disorders, psychotic-like Mental disorders, cerebral infarction, stress, side effects of hypertension treatment, brain disorders, chronic pain, acromegaly, hypogonadism, secondary amenor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12C07D209/14
CPCC07D209/14C07D295/205C07D307/85C07D405/12
Inventor 廖明毅朱溪陈琪朱玉成陈伟张连第丁磊
Owner JIANGSU SIMCERE PHARMA
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