Method for synthesizing anti-cancer drug vorinostat

A technology for vorinostat and anticancer drugs, applied in the field of drug synthesis, can solve problems such as long time consumption, difficulty in vorinostat, and non-production operation, and achieve the effects of good yield, high purity and few impurities

Active Publication Date: 2015-01-21
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 was 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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  • Method for synthesizing anti-cancer drug vorinostat
  • Method for synthesizing anti-cancer drug vorinostat
  • Method for synthesizing anti-cancer 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 anti-cancer drug vorinostat and belongs to the field of drug synthesis technology. The method comprises the steps of: reacting octanedioic acid with aniline in the presence of perfluorinated sulfonic acid resin to obtain suberanilic acid; reacting the suberanilic acid with hydroxylamine in the presence of a condensation agent 1,3-dicyclohexyl carbodiimide; separating the product vorinostat. The intermediate product suberanilic acid prepared by the method is high in purity, good in yield, low in impurity content and is safe and environment-friendly, and therefore 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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IPC IPC(8): C07C259/06
Inventor 刘学键
Owner NANTONG FINC PHARMA CHEM
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