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Method for preparing anti-depression medicine vilazodone

A vilazodone, antidepressant technology, applied in the direction of organic chemistry and the like, can solve the problems of unsuitable industrial production, low synthesis yield, high price, etc., and achieves great application value, high reaction yield, and easily available raw materials. Effect

Inactive Publication Date: 2011-09-14
SCI GENERAL MATERIAL & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But, the part raw material price of this method is more expensive, and the synthetic yield of important intermediate 5-cyano group-3-(4-chlorobutyl) indole is very low, simultaneously, wherein has the purifying means of two-step reaction and all needs column Purified by chromatography, and the total yield of the method is only 3.4%, which is not suitable for industrialized production

Method used

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  • Method for preparing anti-depression medicine vilazodone
  • Method for preparing anti-depression medicine vilazodone
  • Method for preparing anti-depression medicine vilazodone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] (1) Preparation of ethyl 5-aminobenzofuran-2-carboxylate [formula 3 compound]

[0033] 468g (2.0mol) of compound (2), 160g of Raney nickel and 10L of anhydrous methanol were added into a 30L small autoclave, and reacted for 12 hours under the pressure of 5atm and 20°C. The reaction solution was filtered to remove Raney nickel, and methanol was distilled off under reduced pressure. 392 g of crude product of the compound of formula 3 are obtained. The crude product was recrystallized from ethanol to obtain 380 g of the refined product compound of formula 3 as tan crystals. Yield: 93%. Melting point: 61°C.

[0034] (2) Preparation of 5-(bis(2-chloroethyl)amino)benzofuran-2-carboxylic acid ethyl ester [formula 4 compound]

[0035] Mix 40.8g (0.2mol) of the compound of formula 3, 50.5g (0.25mol) of triethylamine and 250ml of DMF, slowly add 38.64g (0.48mol) of 2-chloroethanol dropwise at 20°C, and heat to 90 °C, react for 3 hours. After cooling, the DMF solvent was dis...

Embodiment 2

[0052] Except changing the reaction condition of formula 5 compound, other steps are identical with embodiment 1

[0053]

[0054] Mix 15.83g (0.05mol) of the compound of formula 4, 17.25g (0.125mol) of anhydrous potassium carbonate, and 100ml of DMF, and slowly add a mixed solution of 7.73g (0.075mol) of 4-aminobutyric acid and 25ml of DMF dropwise at 80°C. After the dropwise addition, the reaction was continued for 20 hours to the end of the reaction. The solvent was distilled off under reduced pressure, and 200 ml of dichloroethane was added, followed by washing with 50 ml x 3 times of water and 100 ml x 2 times of saturated brine. The organic layer was dried with anhydrous magnesium sulfate overnight, and the anhydrous magnesium sulfate was removed by suction filtration. 10 ml of thionyl chloride was added dropwise to the dried reaction liquid, and heated to reflux for 2 hours. After the reaction was completed, the remaining thionyl chloride and the solvent were disti...

Embodiment 3

[0056] Except changing the reaction condition of formula 6 compound, other steps are identical with embodiment 1

[0057] First put 4.4g (0.032mol) of anhydrous aluminum trichloride into 200ml of dichloroethane, cool down to 0°C, slowly add 11g (0.029mol) of the compound of formula 5 in 50ml of dichloroethane solution, and control the temperature at 10°C the following. After the dropwise addition was completed, the stirring was continued for 30 minutes, and then a solution of 6.27g (0.032mol) of 5-bromoindole in 30ml of dichloroethane was slowly added. The temperature is controlled between 0-5°C. React for 1.5 hours. The reaction solution was poured into 1L of ice water, and the base layer was separated, dried with anhydrous magnesium sulfate overnight, and the solvent was distilled off under reduced pressure to obtain a brown thick oil, which was recrystallized with isopropanol. 11.49 g of the compound of formula 6 was obtained, yield: 73.9%.

[0058] 1 H-NMR (d 6 -DMSO...

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Abstract

The invention provides a method for preparing an anti-depression medicine vilazodone, which comprises the following steps of: performing nitro reduction on 5-nitrobenzofuran-2-ethyl carboxylate serving as a raw material, conjugating with chlorohydrin, chlorinating by using phosphorus trichloride, cyclizing with 4-aminobutyric acid to generate a piperazine ring, performing acylchlorination, condensing with halogenated indole, performing carbonyl reduction, cyaniding, performing amidation, and the like to obtain the vilazodone. The method overcomes the defects in the prior art, is suitable for industrial production and has high application value, the used raw material is readily available, operating cost is low, and reaction yield is high.

Description

technical field [0001] The invention relates to a medicine preparation method, in particular to an improved preparation method of an antidepressant medicine vilazodone. Background technique [0002] Vilazodone (English name Vilazodone aka: EMD 68843); chemical name 5-(4-(4-(5-cyano-3-indole)-n-butyl)-1-piperazine)benzo Furan-2-amide hydrochloride. It is a new type of antidepressant drug developed by Merck in Germany. GlaxoSmithKline of the United Kingdom obtained the right to market the new drug, and it was approved by the FDA in January 2011. Vilazodone structural formula 1 is as follows: [0003] [0004] Depression is a common mental illness. Its main symptoms are depression, loss of appetite, sleep disturbance, and even attempted suicide. It is clinically chronic and recurrent. According to the annual report released by the World Health Organization in 2009, depression has now ranked fourth among the top ten diseases in the world, and it is expected that by 2020, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12
Inventor 陈牧
Owner SCI GENERAL MATERIAL & CHEM
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