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Method for preparing anticarcinogen vorinostat

A technology of vorinostat and anticancer drugs, which is applied in the field of drug synthesis, can solve the problems of low product yield and cumbersome steps, and achieve the effects of good selectivity, simple operation steps and good catalytic effect

Inactive Publication Date: 2016-07-20
QINGDAO MUNICIPAL HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The object of the present invention is to overcome the defects of cumbersome steps and low product yield in the existing method for preparing vorinostat, and provide a method suitable for high yield and simple preparation of vorinostat

Method used

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  • Method for preparing anticarcinogen vorinostat

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] A method for preparing anticancer drug vorinostat, comprising the following steps:

[0025] 1) 15.6g (100mmol) of suberic anhydride, CuI3.8g (20mmol) and 8.8g (95mmol) of aniline were carried out in water and 1,4-dioxane (50ml mixed solvent) for contact reaction, after the reaction ended, Filtrate, adjust the pH of the filtrate to 6, filter with suction, wash the obtained filter cake with water, and dry to obtain 23.3 g of suberoyl anilide, with a yield of 93.6% and a purity of 97.25%. The temperature of the contact reaction is 8°C , the volume ratio of water and 1,4-dioxane is 1:8;

[0026] 2) Dissolve suberoyl anilide in methanol, add cation exchange resin 5.8g and ZnCl 2 1.3g (9.4mmol), heated at 50°C for 3 hours, concentrated, poured into water, extracted with ethyl acetate, concentrated, washed with petroleum ether, dried to obtain 23.4g of methyl octanoanilide, yield 95.1%, purity 98.70 %;

[0027] 3) Stir and react 6.5g (100mmol) of hydroxylamine hydrochloride...

Embodiment 2

[0029] A method for preparing anticancer drug vorinostat, comprising the following steps:

[0030] 1) Suberic anhydride 15.6g (100mmol), CuI7.6g (40mmol) and aniline 9.3g (100mmol) are carried out contact reaction in water and 1,4-dioxane (50ml mixed solvent), after reaction finishes, Filtrate, adjust the pH of the filtrate to 5, filter with suction, wash the obtained filter cake with water, and dry to obtain 22.8 g of suberoylanilide, with a yield of 91.7% and a purity of 99.82%. The temperature of the contact reaction is 5°C , the volume ratio of water and 1,4-dioxane is 1:5;

[0031] 2) Dissolve suberic acid monoanilide in methanol, add cation exchange resin 6.8g and ZnCl 2 1.9g (13.7mmol), heated at 50°C for 3 hours, concentrated, poured into water, extracted with ethyl acetate, concentrated, washed with petroleum ether, and dried to obtain 21.9g of methyl octanoanilide, with a yield of 90.6% and a purity of 97.12 %;

[0032] 3) Stir and react 6.5g (100mmol) of hydroxyl...

Embodiment 3

[0034] A method for preparing anticancer drug vorinostat, comprising the following steps:

[0035] 1) Suberic anhydride 15.6g (100mmol), CuI5.7g (30mmol) and aniline 8.4g (90mmol) were carried out in water and 1,4-dioxane (60ml mixed solvent) for contact reaction, after the reaction ended, Filtrate, adjust the pH of the filtrate to 6, filter with suction, wash the obtained filter cake with water, and dry to obtain 22.7 g of suberoyl monoanilide, with a yield of 91.0% and a purity of 95.96%. The temperature of the contact reaction is 10°C , the volume ratio of water and 1,4-dioxane is 1:10;

[0036] 2) Dissolve suberoyl anilide in methanol, add cation exchange resin 11.3g and ZnCl 2 1.8g (13.6mmol), heated at 55°C for 3 hours, concentrated, poured into water, extracted with ethyl acetate, concentrated, washed with petroleum ether, dried to obtain 21.7g of methyl octanoanilide, yield 90.8%, purity 96.43 %;

[0037] 3) Stir and react 6.5g (100mmol) of hydroxylamine hydrochlori...

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Abstract

The invention discloses a method for preparing anticarcinogen vorinostat. The method includes: (1) subjecting suberic anhydride and aniline to contact reaction in water and 1,4-dioxane at the temperature of 5-10 DEG C in the presence of CuI, performing filtering after reaction is finished, regulating the pH of filtrate to 5-6, performing suction filtration, washing filter cake obtained after suction filtration, and drying to obtain 7-phenylcarbamoylheptanoic acid; (2) dissolving the 7-phenylcarbamoylheptanoic acid in methanol, adding cation exchange resin and ZnCl2, heating to 50-55 DEG C for reaction for 3 hours, concentrating, extracting with ethyl acetate, concentrating, washing with petroleum ether, and drying to obtain suberanilic acid methyl ester; (3) subjecting hydroxylamine hydrochloride and sodium methoxide to stirring reaction in absolute methanol for 0.5-1h, filtering prior to adding the suberanilic acid methyl ester into filtrate for reaction at the temperature of 40 DEG C for 3-5 hours, cooling to room temperature, regulating the pH to 7, performing suction filtration, washing filter cake, and performing recrystallization with ethyl alcohol to obtain the vorinostat. The method is high in yield, quick in reaction and simple to operate.

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 Applications(China)
IPC IPC(8): C07C259/06
CPCC07C259/06
Inventor 陈令浩
Owner QINGDAO MUNICIPAL HOSPITAL
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