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A kind of method utilizing modified mesoporous material to catalyze preparation vorinostat

A technology of vorinostat and mesoporous silica is used in the synthesis of pharmaceutical compounds and the synthesis of suberoylanilide hydroxamic acid, which can solve the problems of harsh reaction temperature and conditions, long reaction time, and many steps.

Active Publication Date: 2021-05-25
新昌县勤勉生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method route is long, and step is many, and needs severe reaction temperature and condition, and total yield is low, less than 25%
But low reaction efficiency and more steps are still insurmountable shortcomings
[0014] Specifically, for example, in the presence of a coupling agent (for example, 1,3-dicyclohexylcarbodiimide (DCC), 1,1′-carbonyldiimidazole (CDI), 1-ethyl-3-(3- In the case of dimethylaminopropyl) carbodiimide hydrochloride, 1,3-diisopropylcarbodiimide (DIC, etc.), the modified suberic acid can be combined with Aniline or hydroxylamine reaction, in which the coupling agent is used to selectively control the carboxyl functional group in suberic acid. Although this method can increase the yield by improving the reaction selectivity, the reaction efficiency is not improved, and the reaction time is longer

Method used

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  • A kind of method utilizing modified mesoporous material to catalyze preparation vorinostat

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Experimental program
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Effect test

Embodiment 1

[0049] Preparation of suberic anhydride / coupling agent modified mesoporous silica:

[0050] (1) Add 0.5 mol of suberic anhydride and 0.5 mol of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride to 100 ml of silane coupling agent KH-550, under ice bath condition Stir the reaction for 5 min, cool to room temperature, filter, and dry in vacuo to obtain solid A;

[0051] (2) Weigh 50 grams of 30 nm mesoporous silica particles and disperse them in 300 ml of 95% methanol, adjust the pH to 9.5 with ammonia water, and stir evenly to obtain a mesoporous silica dispersion;

[0052] (3) Take 2.5 grams of the above solid A and disperse it in 30 ml of ethanol, slowly add it to the above mesoporous silica dispersion, keep warm at 30°C and slowly stir for 6 h, after the reaction, centrifuge and wash with absolute ethanol After solids, disperse them in 120ml methanol-hydrochloric acid mixed solution system (methanol: 30wt% hydrochloric acid volume ratio = 5:1), reflux at 50°C for 5 ...

Embodiment 2

[0054] Preparation of caprylanid:

[0055] Add 0.1 mol (17.4 g) of suberic acid to 350 ml of THF solvent, then add 80 g of the modified mesoporous silica particles prepared above, and stir and pretreat at 40 °C for 2 h to fully modify the suberic acid monolayer Carboxyl group: after pretreatment with suberic acid, add 0.1mol of aniline, raise the temperature to 55°C and continue to stir for 5 hours. After the reaction is completed, filter to remove by-product impurities and silica particles, and wash with THF and absolute ethanol respectively , recovered for later use; vacuum-concentrate the obtained filtrate to one-fifth of the original volume at 60°C, then adjust the pH of the concentrated solution to 10.5 with 1.5 mol / l potassium hydroxide solution, stir at 35°C for 10 min, and Filtrate, add hydrochloric acid solution to the filtrate to adjust the pH to 2, stir for 5 minutes, cool to separate the solid, wash with water, and dry in vacuo to obtain about 23 g of caprylanilic ...

Embodiment 3

[0057] Preparation of Octanoanilic Acid in the Presence of Accelerator

[0058] Add 17.4 g of suberic acid into 300 ml of THF solvent, then add 50 g of the above-mentioned modified mesoporous silica particles, stir at 35°C for 1 h, add 0.1 mol of aniline and 0.05 mol of B- Chlorophthalic borane, heated up to 45°C and stirred for 3.5 h, cooled to room temperature, adjusted the pH value to 11 with 10% sodium hydroxide solution, filtered by suction to remove by-product impurities and silica particles, and used 1 mol / L hydrochloric acid was adjusted to a pH value of 1, stirred for 5 min, cooled and suction filtered, and the filter cake was washed with water and dried to obtain a white solid caprylanilic acid with a purity of 99.3% and a yield of 93.3% as measured by HPLC.

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Abstract

The invention provides a method for preparing vorinostat under the mesoporous silica coupling / catalysis system modified by suberic anhydride and coupling agent, the method comprises the following steps: preparing suberic anhydride and coupling agent Modified mesoporous silica; pretreat the suberic acid reactant with the hydrophilic modified mesoporous silica for 1-2 h, and then react with aniline or its salt to form the intermediate octanoylanilide acid; in the presence of modified mesoporous silica, the obtained caprylanilic acid is reacted with hydroxylamine or its salt to prepare vorinostat. The method of the invention has high selectivity and yield, short amidation reaction time, and the obtained vorinostat has a purity of over 99%.

Description

technical field [0001] The invention relates to a method for synthesizing pharmaceutical compounds, in particular to a method for synthesizing suberoylanilide hydroxamic acid, and belongs to the fields of organic synthesis and medicinal chemical synthesis. Background technique [0002] Suberoylanilide hydroxamic acid (suberoylanilide hydroxamic acid), also known as N-hydroxy-N'-phenylsuberamide, trade name Vorinostat (Vorinostat), is listed in the United States in 2006 to inhibit protein deacetylation It is a new type of anticancer drug based on enzymes, which can play a role by inducing cell differentiation, blocking cell cycle, and inducing cell regulation. Since histone deacetylase inhibitors (HDI) have broad-spectrum epigenetic activity, It is indicated for the treatment of a type of skin cancer called cutaneous cell lymphoma (CTCL). The specific structural formula is as follows: [0003] [0004] For the preparation method of suberoylanilide hydroxamic acid (herein...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C259/06C07C233/07C07C231/02B01J31/02
CPCB01J31/0274C07C231/02C07C259/06C07C233/07
Inventor 陈国妃
Owner 新昌县勤勉生物医药科技有限公司
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