Method for preparing belinostat

A technology of belistat and phenylbenzenesulfonamide, applied in the field of chemical substance preparation, can solve the problems of high corrosiveness, high total cost, long route and the like, avoid strong corrosive substances, reduce potential safety hazards, convenient and simple operation Effect

Inactive Publication Date: 2019-02-15
ANHUI QINGYUN PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The reaction conditions of this route are mild, and recrystallization is mostly used for purification, and the use of sulfuryl chloride and oleum is also avoided, but this route is long, heavy metal salts are used, and the pollution is large, and the total cost is high.
Therefore, it is difficult to achieve large-scale industrial production
[0014] In summary, the current synthesis route of belistat is either because of the use of highly corrosive and polluting reagents, or because of the dangerous and difficult-to-control diazotization reaction in the process route, or because the route is long , the yield is low, the cost is high and it is difficult to realize large-scale industrial production

Method used

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  • Method for preparing belinostat
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  • Method for preparing belinostat

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Experimental program
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Effect test

Embodiment 1

[0045] A kind of preparation method of belistat proposed by the present invention comprises the following steps:

[0046] Synthesis of S1, 3-chloro-N-phenylbenzenesulfonamide: under nitrogen protection, add toluene 2000mL, aniline 183g (1.97mol, 1.0eq) in the 3000mL round-bottomed flask equipped with water trap and mechanical stirring, 300g (2.96mol, 1.5eq) of triethylamine, 456g (2.37mol, 1.2eq) of m-chlorobenzenesulfonic acid, the temperature of the reaction system was controlled at 100°C for 8 hours, the conversion of the raw materials was monitored by TLC, and the reaction solution was washed with saturated sodium carbonate Washing, drying, and concentration gave 492 g of a yellow oily substance, 3-chloro-N-phenylbenzenesulfonamide, with a purity of 97% and a yield of 93%;

[0047] Synthesis of S2, 3-ethyl acrylate-N-phenylbenzenesulfonamide: under nitrogen protection, in a round-bottomed flask equipped with mechanical stirring, add 400 g of 3-chloro-N-phenylbenzenesulfona...

Embodiment 2

[0050] A kind of preparation method of belistat proposed by the present invention comprises the following steps:

[0051] Synthesis of S1, 3-chloro-N-phenylbenzenesulfonamide: under nitrogen protection, add toluene 2000mL, aniline 186.3g (2mol), diethylamine in a 3000mL round bottom flask equipped with a water trap and mechanical stirring 216.5g (2.96mol), 384.8g (2mol) of m-chlorobenzenesulfonic acid, the temperature of the reaction system was controlled at 80°C for 10 hours, and the conversion of raw materials was monitored by TLC. The reaction solution was washed with saturated sodium carbonate, dried, and concentrated to obtain a yellow oil 3-Chloro-N-phenylbenzenesulfonamide;

[0052] Synthesis of S2, 3-ethyl acrylate-N-phenylbenzenesulfonamide: under nitrogen protection, in a round-bottomed flask equipped with mechanical stirring, 267g (1mol ), ethyl acrylate 100g (1mol), triethylamine 101.2g (1mol), palladium acetate 2.24g (0.01mol), 1.4-dioxane 1500mL, heat up to 110°...

Embodiment 3

[0055] A kind of preparation method of belistat proposed by the present invention comprises the following steps:

[0056] Synthesis of S1, 3-chloro-N-phenylbenzenesulfonamide: under nitrogen protection, add toluene 2000mL, aniline 186.3g (2mol), triethylamine in a 3000mL round bottom flask equipped with a water trap and mechanical stirring 151.8g (1.5mol), 138.2g (1mol) of potassium carbonate, 769.6g (4mol) of m-chlorobenzenesulfonic acid, the temperature of the reaction system was controlled at 110°C for 6 hours, the conversion of raw materials was monitored by TLC, and the reaction solution was saturated with sodium carbonate Washing, drying, and concentration gave yellow oil 3-chloro-N-phenylbenzenesulfonamide;

[0057] Synthesis of S2, 3-ethyl acrylate-N-phenylbenzenesulfonamide: under nitrogen protection, in a round-bottomed flask equipped with mechanical stirring, 267g (1mol ), 200g (2mol) of ethyl acrylate, 69g (0.5mol) of potassium carbonate, 76g (0.5mol) of cesium fl...

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Abstract

The invention discloses a method for preparing belinostat. The method comprises the following steps: carrying out an amidation reaction by taking m-chlorobenzene sulfonic acid and phenylamine as raw materials so as to obtain 3-chloro-N-benzenesulfonanilide; carrying out a Heck reaction by taking 3-chloro-N-benzenesulfonanilide and ethyl acrylate as raw material so as to obtain 3-ethyl acrylate-N-benzenesulfonanilide; carrying out a hydroxylation reaction by taking 3-ethyl acrylate-N-benzenesulfonanilide and hydroxylamine hydrochloride as raw materials, thereby obtaining the belinostat. The method for preparing belinostat provided by the invention is cheap and readily available in raw materials, convenient and simple in operation, novel in route, green and environmental-friendly, the yieldis high, and the prepared belinostat is high in purity.

Description

technical field [0001] The invention relates to the technical field of chemical substance preparation, in particular to a preparation method of belistat. Background technique [0002] Belinostat is a new drug developed by Spectrum Biopharmaceuticals for the treatment of T-cell lymphoma (PTCL), chemical name: N-hydroxy-3-(3-phenylaminosulfonylphenyl)propene Belinostat was approved for marketing by the FDA in July 2014. In recent years, Belinostat, as a promising anticancer drug target in the future, has not only become an important drug recognized in the international market for the treatment of T-cell lymphoma, but also for mesothelioma, B -cell lymphoma, soft tissue sarcoma, colorectal cancer, liver cancer, etc. also have a single or combined therapeutic effect, and have huge market potential, so the development of new technology for belistat is of great significance. [0003] [0004] At present, there are mainly the following routes for the synthesis of belistat. [...

Claims

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Application Information

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IPC IPC(8): C07C303/40C07C311/21
CPCC07C303/38C07C303/40C07C311/21
Inventor黄欢黄庆国李凯施亚琴
OwnerANHUI QINGYUN PHARMA & CHEM