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A kind of synthetic method of anticancer drug vorinostat

A technology of vorinostat and synthetic method, which is applied in the field of drug synthesis, can solve problems such as production operation, time-consuming, and difficulty of vorinostat, and achieve the effect of less impurities, high purity and good yield

Active Publication Date: 2016-06-01
NANTONG FINC PHARMA CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 2. The method reported by J.Med.Chem., 1995, 38(9): 1411-1413: suberic acid is first reacted with aniline and KOH solution at a high temperature of 190°C for 10 minutes to obtain suberic acid monoanilide 22h through ion-exchange resin esterification, obtain suberoylanilide monomethyl ester; then obtain with sodium methylate, hydroxylamine hydrochloride and methyl alcohol reaction 26h, total yield has about 35%, but intermediate reaction contacts high temperature (190 ℃), and the intermediate reaction takes a long time (22h, 26h), which is not very suitable for industrialized production operations;
Therefore, it is very difficult to obtain pure vorinostat from this reaction mixture

Method used

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  • A kind of synthetic method of anticancer drug vorinostat
  • A kind of synthetic method of anticancer drug vorinostat
  • A kind of synthetic method of anticancer drug vorinostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Suberic Acid to Octanoanilide

[0041] Add suberic acid (1.74g, 10mmol) into a 20ml tetrahydrofuran reaction flask, then add 6.7g perfluorosulfonic acid resin, stir for 10-30 minutes, add aniline (0.93g, 10mmol), stir, and heat to 75°C, there is a slight acetonitrile reflux at this time, keep this state for 5 hours, TLC detects the reaction, after the reaction is completed, filter and remove the perfluorosulfonic acid resin, and wash the perfluorosulfonic acid resin with a small amount of acetonitrile 1-2 times, recover spare. Concentrate the filtrate to obtain a concentrate, then add 15ml of 1mol / L aqueous sodium hydroxide solution to the concentrate, stir at 40-50°C for 10-30 minutes, then filter while hot to remove all insolubles, heat the obtained filtrate, and Add HCl solution dropwise to the obtained filtrate, adjust the pH=1-2, then cool to 20°C-25°C, crystallize, filter to obtain a solid, and then wash twice with 20-25°C pure water, 20ml each time , and then d...

Embodiment 2

[0045] Suberic Acid to Octanoanilide

[0046]Add suberic acid (1.74g, 10mmol) into a 20ml acetonitrile reaction flask, then add 5.3g perfluorosulfonic acid resin, stir for 10-30 minutes, add aniline (0.93g, 10mmol), stir, and heat to 80°C, there is slight acetonitrile reflux at this time, keep this state for 5 hours, TLC detects the reaction, after the reaction is completed, filter and remove the perfluorosulfonic acid resin, and wash the perfluorosulfonic acid resin with a small amount of acetonitrile 1-2 times, recover spare. Concentrate the filtrate to obtain a concentrate, then add 15ml of 1mol / L aqueous sodium hydroxide solution to the concentrate, stir at 40-50°C for 10-30 minutes, then filter while hot to remove all insolubles, heat the obtained filtrate, and Add HCl solution dropwise to the obtained filtrate, adjust the pH=1-2, then cool to 20°C-25°C, crystallize, filter to obtain a solid, and then wash twice with 20-25°C pure water, 20ml each time , and then dried i...

Embodiment 3

[0050] Suberic Acid to Octanoanilide

[0051] Add suberic acid (17.4g, 0.1mol) into a 200ml acetonitrile reaction flask, then add 53g perfluorosulfonic acid resin, stir for 10-30 minutes, add aniline (9.3g, 0.1mol), stir, and heat to react To 80°C, there is a slight acetonitrile reflux at this time, keep this state for 5 hours, TLC to detect the reaction, after the reaction is completed, filter out the perfluorosulfonic acid resin, and wash the perfluorosulfonic acid resin with a small amount of acetonitrile 1-2 times, Recycle for spare. Concentrate the filtrate to obtain a concentrate, then add 150ml of 1mol / L aqueous sodium hydroxide solution to the concentrate, stir at 40-50°C for 10-30 minutes, then filter while hot to remove all insolubles, heat the obtained filtrate, and Add HCl solution dropwise to the obtained filtrate, adjust the pH=1-2, then cool to 20°C-25°C, crystallize, filter to obtain a solid, and then wash twice with 20-25°C pure water, 200ml each time , and ...

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Abstract

The invention relates to a method for synthesizing anticancer drug vorinostat, which belongs to the technical field of drug synthesis. It comprises reacting suberic acid and aniline in the presence of perfluorosulfonic acid resin to obtain caprylanilic acid; reacting capryanilic acid and hydroxylamine in the presence of a condensing agent 1,3-dicyclohexylcarbodiimide; isolating the product promise him. The intermediate product caprylanilic acid prepared by the method has high purity, good yield, less impurities, safety and environmental protection, and thus the prepared crude product vorinostat has high purity and good yield.

Description

technical field [0001] The invention relates to a method for synthesizing vorinostat as an active pharmaceutical ingredient, and belongs to the technical field of pharmaceutical synthesis. Background technique [0002] Vorinostat, whose chemical name is "N-hydroxy-N'-phenylsuberamide" or "suberoylanilide hydroxamic acid (SAHA)", is the first histone protein developed by Merck in the United States. Deacetylase (HDAC) inhibitor class antineoplastic drugs. It can play a role by inducing cell differentiation, blocking cell cycle, and inducing cell regulation. It is mainly used clinically for the treatment of cutaneous T-cell lymphoma (CTCL: a type of non-Hodgkin's lymphoma, which is a type of T-cell cancer affecting white blood cells of the skin) that has been exacerbated, persistent, and relapsed, or that has not responded to two systemic drugs. , the trade name is zolinza. The structure is shown in formula (1): [0003] [0004] There are many synthetic routes for vorin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C259/06
Inventor 夏元福
Owner NANTONG FINC PHARMA CHEM