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A method for preparing anticancer drug vorinostat

A technology of vorinostat and anticancer drugs, applied in the field of drug synthesis, can solve the problems of short reaction time, low yield, poor selectivity, etc., and achieve the effects of reduced reaction time, good selectivity, and increased yield

Inactive Publication Date: 2017-12-08
THE AFFILIATED HOSPITAL OF QINGDAO UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The object of the present invention is to overcome the defects of long reaction time, poor selectivity and low product yield in the existing method for preparing vorinostat, and provide a kind of preparation vorinostat suitable for short reaction time, good selectivity and high yield. Nota's method
[0008] In the preparation of vorinostat, the yield is low due to the lack of selectivity in the reaction of suberic acid. In the prior art, the reaction of the monocarboxyl group of suberic acid is controlled by adjusting the reaction conditions or using a special coupling agent. By modifying a carboxyl group in suberic acid, the problem of reaction selectivity can be fundamentally solved.

Method used

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  • A method for preparing anticancer drug vorinostat

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Experimental program
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Effect test

Embodiment 1

[0026] Preparation of suberic acid-substrate self-assembled film

[0027] Hydrophilic treatment of quartz sheet: place the cut substrate (quartz sheet, 10cm×10cm) in a strong acid mixed solution (H 2 SO 4 / HNO 3 , volume ratio 1:1), boiled at 90°C for 1 hour, then stood at room temperature, cleaned with deionized water and ultrasonicated for 15 minutes to obtain a hydrophilic substrate, which was stored in deionized water until use.

[0028] The specific process of self-assembly includes: adding the hydrophilic substrate to the solution of suberic acid in anhydrous toluene, keeping it warm at 50°C for 10 hours, then taking out the substrate and washing it with water to obtain the suberic acid-substrate self-assembled film . The solution concentration of suberic acid in anhydrous toluene is 1×10 -3 mol / L.

Embodiment 2

[0030] Preparation of suberic acid-substrate self-assembled film

[0031] Hydrophilic treatment of quartz wafers: place the cut substrate (silicon wafer, 10cm×10cm) in a strong acid mixed solution (H 2 SO 4 / HNO 3 , volume ratio 1:1), boiled at 90°C for 1 hour, then stood at room temperature, cleaned with deionized water and ultrasonicated for 15 minutes to obtain a hydrophilic substrate, which was stored in deionized water until use.

[0032] The specific process of self-assembly includes: adding the hydrophilic substrate to the solution of suberic acid in anhydrous toluene, keeping it warm at 60°C for 8 hours, then taking out the substrate and washing it with water to obtain the suberic acid-substrate self-assembled film . The solution concentration of suberic acid in anhydrous toluene is 1×10 -4 mol / L.

Embodiment 3

[0034] Preparation of suberic acid-substrate self-assembled film

[0035] Hydrophilic treatment of quartz sheet: place the cut substrate (glass sheet, 10cm×10cm) in a strong acid mixed solution (H 2 SO 4 / HNO 3 , volume ratio 1:1), boiled at 90°C for 1 hour, then stood at room temperature, cleaned with deionized water and ultrasonicated for 15 minutes to obtain a hydrophilic substrate, which was stored in deionized water until use.

[0036] The specific process of self-assembly includes: adding the hydrophilic substrate to the solution of suberic acid in anhydrous toluene, keeping it warm at 45°C for 10 hours, then taking out the substrate and washing it with water to obtain the suberic acid-substrate self-assembled film . The solution concentration of suberic acid in anhydrous toluene is 1×10 -3 mol / L.

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Abstract

The invention discloses a method for preparing an anticancer drug--Vorinostat. The method comprises the following steps: 1) subjecting a hydrophilic substrate and octanedioic acid to contacting and carrying out self-assembling so as to obtain an octanedioic acid-substrate self-assembled film; 2) in the presence of 1,3-dicyclohexylcarbodiimide, subjecting the octanedioic acid-substrate self-assembled film to contacting with aniline in THF, after a reaction is completed, adding a 4M HCl solution and carrying out a reaction under stirring, and carrying out extraction with dichloromethane so as to obtain octanedioic acid monoanilide; and 3) subjecting octanedioic acid monoanilide and hydroxylamine hydrochloride to a reaction so as to obtain Vorinostat. The preparation method for Vorinostat provided by the invention provides a novel synthetic route for Vorinostat. By adopting the method for preparing Vorinostat provided by the invention, mild conditions and good selectivity are achieved; the time of the reaction, specifically the time of the aniline amidation reaction, is greatly reduced; meanwhile, the yield of Vorinostat is greatly improved.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for preparing vorinostat. Background technique [0002] Vorinostat, launched in the United States in October 2006, is the first new anticancer drug that inhibits protein deacetylase, and it can play a role by inducing cell differentiation, blocking cell cycle, and inducing cell regulation . The specific structural formula is as follows: [0003] [0004] At present, there are many synthetic methods for vorinostat, most of which use suberic anhydride or suberic acid and aniline ring-opening amidation to obtain suberic acid monoanilide, and then esterification and hydroxylamine hydrochloride aminolysis to obtain. However, there are problems such as low yield and long reaction time in these methods, and the reaction conditions are quite harsh. For example J.Med.Chem., 1995,38 (9): the method for 1411-1413 report, first dioic acid and aniline, KOH react at 190...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C259/06C07C231/02C07C233/07
CPCC07C231/02C07C259/06C07C233/07
Inventor 刘美新吕映频
Owner THE AFFILIATED HOSPITAL OF QINGDAO UNIV
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