New synthesis method of 3-(4-chlorobutyl)-5-cyanoindole

A cyanoindole and a synthesis method technology are applied in the synthesis of pharmaceutical intermediates, and the new synthesis field of vilazodone hydrochloride intermediate 3-(4-chlorobutyl)-5-cyanoindole can solve the problem of Human health hazards, strong corrosiveness, easy deliquescence of aluminum, etc., to achieve the effects of good market competitiveness, good quality, and fewer reaction steps

Active Publication Date: 2013-03-13
SUZHOU UUGENE BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The yield of 3-(4-chlorobutyl)-1H-5-cyanindole prepared by the method is low, and in the reduction reaction step, sodium borohydride and anhydrous aluminum chloride are used as reduction catalysts, wherein Sodium borohydride will cause harm to human health. It will cause combustion when it meets water, humid air, high heat and open flame, while anhydrous aluminum trichloride is very easy to deliquescence and is highly corrosive. It will generate heat and cause an explosion when it meets water.

Method used

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  • New synthesis method of 3-(4-chlorobutyl)-5-cyanoindole

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Embodiment 1

[0031] At room temperature, add 500ml of methanol to the reaction bottle, then add 50g of cycloheptene, cool the mixed solution to -30°C, then pass in oxygen-ozone to saturate the reaction solution, then slowly raise the temperature to 40°C, and react After 15 minutes, cool down and replace excess oxygen and ozone in the reaction solution. Add this reaction solution dropwise to the reflux solution of ferric chloride hexahydrate methanol, continue to react for 15 minutes after the dropwise addition, cool to room temperature, extract once with light petroleum ether, dilute the reaction solution with water, and then dichloromethane Extract once. The solution was distilled off to give 1,1-dimethoxy-6-chlorohexane as an oil.

[0032] At room temperature, add 100ml of ethanol to the reaction bottle under the protection of nitrogen, then add 50ml of pure water, then add 18.1g of the 1.1-dimethoxy-6-chlorohexane prepared above, and raise the temperature to 68°C until 1.1-dimethyl Ox...

Embodiment 2

[0035] At room temperature, add 500ml of methanol to the reaction bottle, then add 50g of cycloheptene, cool the mixed solution to -30°C, then pass in oxygen-ozone to saturate the reaction solution, then slowly raise the temperature to 40°C, and react After 15 minutes, cool down and replace excess oxygen and ozone in the reaction solution. Add this reaction solution dropwise to the reflux solution of ferric chloride hexahydrate methanol, continue to react for 15 minutes after the dropwise addition, cool to room temperature, extract once with light petroleum ether, dilute the reaction solution with water, and then dichloromethane Extract once. The solution was distilled off to give 1,1-dimethoxy-6-chlorohexane as an oil.

[0036]At room temperature, add 80ml of methanol to the reaction bottle under the protection of nitrogen, then add 54ml of pure water, then add 20.5g of the 1.1-dimethoxy-6-chlorohexane prepared above, and raise the temperature to 70°C until 1.1-dimethyl Oxy...

Embodiment 3

[0039] At room temperature, add 500ml of methanol to the reaction bottle, then add 50g of cycloheptene, cool the mixed solution to -30°C, then pass in oxygen-ozone to saturate the reaction solution, then slowly raise the temperature to 40°C, and react After 15 minutes, cool down and replace excess oxygen and ozone in the reaction solution. Add this reaction solution dropwise to the reflux solution of ferric chloride hexahydrate methanol, continue to react for 15 minutes after the dropwise addition, cool to room temperature, extract once with light petroleum ether, dilute the reaction solution with water, and then dichloromethane Extract once. The solution was distilled off to give 1,1-dimethoxy-6-chlorohexane as an oil.

[0040] At room temperature, add 158ml of ethanol to the reaction bottle under the protection of nitrogen, then add 70ml of pure water, then add 25.7g of the 1.1-dimethoxy-6-chlorohexane prepared above, and raise the temperature to 69°C until 1.1-dimethyl Ox...

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Abstract

The invention provides a new synthesis method of a vilazodone hydrochloride intermediate 3-(4-chlorobutyl)-5-cyanoindole, belonging to the technical field of medicine synthesis. The invention solves the following problems in the prior art: the synthesis yield of the 3-(4-chlorobutyl)-5-cyanoindole is low, and dangerous sodium borohydride and anhydrous aluminum trichloride are used as reduction catalysts. The synthesis method comprises the following steps: (1) dissolution of alcohol: in a nitrogen or inert gas protective atmosphere, dissolving 1,1-dimethoxy-6-chlorohexane in an alcohol-water mixed solution, and heating to dissolve the 1,1-dimethoxy-6-chlorohexane; and (2) Fischer indole cyclization reaction: slowly and dropwisely adding 4-cyanophenylhydrazine hydrochloride and an alcohol-pure water mixed solvent into the reaction solution in the step (1) to carry out Fischer indole cyclization reaction, carrying out vacuum filtration, and recrystallizing to obtain the 3-(4-chlorobutyl)-5-cyanoindole. The method has the advantage of mild reaction and is simple to operate; and the final product has the advantages of high yield and good quality.

Description

technical field [0001] The invention relates to a synthesis method of a drug intermediate, in particular to a new synthesis method of a vilazodone hydrochloride intermediate 3-(4-chlorobutyl)-5-cyanindole, which belongs to the technical field of drug synthesis. Background technique [0002] Vilazodone hydrochloride is a new antidepressant drug developed by Clinical Data for the treatment of depression in adults. The clinical trial data show that compared with the existing antidepressant drugs in the clinic, vilazodone hydrochloride has the characteristics of rapid onset of action, good tolerance, no sexual dysfunction for patients, and small adverse reactions. Its chemical name is 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide hydrochloride, and its chemical formula is: [0003] [0004] And 3-(4-chlorobutyl)-5-cyanindole is an important intermediate in the synthesis of vilazodone hydrochloride. The literature on the synthesis of 3-(4-chlorobut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/10
Inventor 王伸勇宋丰奎王晓俊胡隽恺
Owner SUZHOU UUGENE BIOPHARMA
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