Preparation method of 3-(4-chlorobutyl)-5-cyanoindole

A cyanoindole and chlorobutyl technology, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of high cost, unsuitable for scale-up production, complicated post-processing operations and the like, and achieves convenient industrial production, stable and controllable quality, and high product quality. good purity

Active Publication Date: 2013-01-16
CHIRAL QUEST (SUZHOU) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The technical problem to be solved by the present invention is to overcome the disadvantages of the existing 3-(4-chlorobutyl)-5-cyanindole preparation method, such as high cost, cumbersome post-processing operation, and unsuitable scale-up production. , and a preparation method of 3-(4-chlorobutyl)-5-cyanindole is provided

Method used

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  • Preparation method of 3-(4-chlorobutyl)-5-cyanoindole
  • Preparation method of 3-(4-chlorobutyl)-5-cyanoindole

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Experimental program
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Effect test

Embodiment 13-（4

[0068] The preparation of embodiment 13-(4-chlorobutyl)-5-cyanindole

[0069] Aluminum trichloride (43.2g, 0.32mol, 2.3eq) was added to a mixed solvent of nitromethane (50g) and dichloromethane (150g), and stirred. Add 4-chlorobutyryl chloride (25g, 0.177mol, 1.25eq) dropwise at 0-10°C, and then add dropwise the solution of the compound shown in formula (I) (20g (0.141mol, 1.0eq) of compound of formula I dissolved in 50g nitromethane and 150g dichloromethane). After reacting for about 2 hours, TLC showed that the reaction was complete. Add anhydrous tetrahydrofuran (400g) dropwise at 0-10°C. After dropping, add anhydrous aluminum trichloride (38g, 0.282mol, 2eq.) in batches at a temperature of -5-5°C; Add sodium borohydride (25g, 0.66mol, 4.68eq) at ~5°C. After the addition, keep stirring at -5~5°C. After the reaction is complete, add the reaction solution dropwise into ice water. The liquid was extracted and separated, and the organic phase was washed with saturated brine,...

Embodiment 23-（4

[0072] Preparation of Example 23-(4-chlorobutyl)-5-cyanindole

[0073] Aluminum trichloride (90g, 0.675mol, 2.3eq.) was added to a mixed solvent of nitromethane (100g) and dichloromethane (300g), and stirred. 4-Chlorobutyryl chloride (48.1g, 0.341mol, 1.18eq) was added dropwise at 0-10°C, and the addition was completed. Add dropwise the solution of the compound shown in formula (I) (the compound of formula I (41g, 0.288mol, 1.0eq) is dissolved in 100g nitromethane and 300g dichloromethane), dropwise at 0-10°C, after the reaction is complete, Anhydrous tetrahydrofuran (800 g) was added dropwise at 0-10° C., and the drop was completed. Add anhydrous aluminum trichloride (67.7g, 0.51mol, 1.8eq) in batches at 0-10°C; after adding, add sodium borohydride (32.7g, 0.864mol, 3eq.) at 0-10°C, Keep the temperature at 0-10°C. After the reaction was complete, the reaction solution was added dropwise to ice water. The liquid was extracted and separated, and the organic phase was washed...

Embodiment 33-（4

[0074] Preparation of Example 33-(4-chlorobutyl)-5-cyanindole

[0075] Aluminum trichloride (44g, 0.33mol, 2.3eq) was added to a mixed solvent of nitromethane (24g) and dichloromethane (96g), and stirred. 4-Chlorobutyryl chloride (23g, 0.163mol, 1.15eq) was added dropwise at 0-10°C, and the addition was completed. Add dropwise the solution of the compound shown in formula (I) (the compound of formula I (20g, 0.141mol, 1.0eq) is dissolved in 24g nitromethane and 96g dichloromethane), dropwise at 0~10°C, after the reaction is completed, Add anhydrous tetrahydrofuran (200g) dropwise to the reaction solution at 0-10°C. After the drop is complete, add anhydrous aluminum trichloride (37.5g, 0.282mol, 2.0eq) in batches at -5-5°C; after the addition, Sodium borohydride (16g, 0.423mol, 3.0eq) was added at -5~5°C, maintaining the temperature at -5~5°C. After the reaction was complete, the reaction solution was added dropwise to ice water. The liquid was extracted and separated, and t...

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Abstract

The invention discloses a preparation method of 3-(4-chlorobutyl)-5-cyanoindole which is shown as the formula IV. The preparation method comprises the steps as follows: carrying out following carbonyl reduction reaction on a compound III and a hydroboron reducing agent in the solvent under the catalyzing of Lewis acid to obtain the product, wherein Lewis acid is one or more of aluminium trichloride, magnesium chloride, zinc chloride and ferric chloride; and the hydroboron reducing agent is one or more of sodium borohydride, potassium borohydride, lithium borohydride and borane. The preparation method disclosed by the invention is safe in operation, low in requirement on equipment, low in cost, simple in post-processing steps, high in yield of product, high in purity, and is suitable for industrialization.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of 3-(4-chlorobutyl)-5-cyanindole. Background technique [0002] Vilazodone hydrochloride, the chemical name is 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-methan Amide hydrochloride is a new antidepressant drug developed by Clinical Data. In January 2011, it was approved by the US Food and Drug Administration (FDA) for the treatment of depression in adults. Its chemical structural formula is as follows: [0003] [0004] Vilazodone Hydrochloride [0005] (A) [0006] Vilazodone hydrochloride is a 5-HT 1A Compared with the existing antidepressants in clinical practice, the novel antidepressants with dual effects of partial receptor agonism and 5-HT reuptake inhibition have the characteristics of rapid onset of action and no side effects of sexual dysfunction for patients. [0007] Patent WO2000035872 discloses ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/10
Inventor 吴生文
Owner CHIRAL QUEST (SUZHOU) CO LTD
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