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Synthesis method of chidamide

A technology of chidamide and its synthesis method, which is applied in the field of synthesis of chemical drugs, can solve the problems of low purity of chidamide, many impurities, and difficult removal, and achieve the effects of easy control, high product purity, and less impurities

Inactive Publication Date: 2016-09-21
山东川成医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to the patent ZL03139760.3 and US7,244,751, the purity of chidamide is relatively low, only 95%, and there are many impurities, which are not easy to remove

Method used

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  • Synthesis method of chidamide

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Experimental program
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Effect test

Embodiment 1

[0032] (1) Dissolve 14.8g of 3-(3-pyridine)acrylamide in 148g of DMF, stir until dissolved, add 23.7g of 4-(bromomethyl)benzoic acid in small batches under ice bath, and heat up to React at 50°C until dissolved, then stir for 1 hour;

[0033] (2) Adjust the pH to 14 with sodium hydroxide, and control the temperature below 15°C. The reaction solution was poured into ice water, filtered immediately to obtain intermediate 1, and dried at a constant temperature of 70 degrees Celsius for 4 hours to obtain intermediate 1 with a dry weight of 25.1 g and a molar yield of 89%;

[0034] (3) Dissolve 25.1 g of intermediate 1 obtained in the previous step in 201 g of tetrahydrofuran, add tetrahydrofuran hydrochloric acid gas dropwise under ice bath, and adjust the pH to 7.

[0035] (4) Add 25.1 g of trifluoroacetic acid dropwise under ice bath and protect it with nitrogen gas. After stirring for 15 minutes, add 12.4 g of raw material 3,4-diaminofluorobenzene into the reaction system, sti...

Embodiment 2

[0038] (1) Dissolve 14.8g of 3-(3-pyridine)acrylamide in 148g of DMF, stir until dissolved, add 25.8g of 4-(bromomethyl)benzoic acid in small batches under ice bath, and heat up to React at 50°C until dissolved, then stir for 1 hour;

[0039] (2) Adjust the pH to 14 with sodium hydroxide, and control the temperature below 15°C. The reaction solution was poured into ice water, filtered immediately to obtain intermediate 1, and dried at a constant temperature of 70 degrees Celsius for 4 hours to obtain intermediate 1 with a dry weight of 25.2 g and a molar yield of 89.4%;

[0040] (3) Dissolve 25.2g of intermediate 1 obtained in the previous step in 202g of tetrahydrofuran, add tetrahydrofuran hydrochloric acid gas dropwise under ice bath, and adjust the pH to 7;

[0041] (4) 25.2 g of trifluoroacetic acid was added dropwise under ice bath and protected by nitrogen gas. After stirring for 15 minutes, 12.4 g of raw material 3,4-diaminofluorobenzene was added to the reaction syst...

Embodiment 3

[0044] (1) Dissolve 14.8g of 3-(3-pyridine)acrylamide in 148g of DMF, stir until dissolved, add 23.7g of 4-(bromomethyl)benzoic acid in small batches under ice bath, and heat up to React at 50°C until dissolved, then stir for 1 hour;

[0045] (2) Adjust the pH to 14 with sodium hydroxide, and control the temperature below 15°C. The reaction solution was poured into ice water, filtered immediately to obtain intermediate 1, and dried at a constant temperature at 70°C for 4 hours to obtain intermediate 1 with a dry weight of 25.1 g and a molar yield of 89%.

[0046] (3) Dissolve 25.1 g of intermediate 1 obtained in the previous step in 201 g of tetrahydrofuran, add tetrahydrofuran hydrochloric acid gas dropwise under ice bath, and adjust the pH to 7;

[0047] (4) Add 25.1 g of trifluoroacetic acid dropwise under ice bath and protect with nitrogen gas. After stirring for 15 minutes, add 12.4 g of raw material 3,4-diaminofluorobenzene into the reaction system, and stir at 25°C for...

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Abstract

The invention belongs to the technical field of synthesis chemical drugs, and particularly relates to a synthesis method of chidamide. The method comprises the following steps: carrying out reaction on 3-(3-pyridyl)acrylamide and 4-(bromomethyl)benzoic acid to obtain an intermediate N-(methyl-4-benzoic acid)-3-pyridyl acrylamide, and carrying out reaction on the N-(methyl-4-benzoate)-3-pyridylacrylamide and 3,4-diaminofluorobenzene, thereby obtaining the chidamide. The synthesis method overcomes the defects of low product purity and multiple impurities in the prior art. The method has the characteristics of mild conditions, high controllability, high product purity and fewer impurities, and basically satisfies the requirements for green chemistry.

Description

technical field [0001] The invention belongs to the technical field of chemical medicine synthesis, and in particular relates to a synthesis method of chidamide. Background technique [0002] Chidamide (also known as Aipsa) is a new anti-tumor drug independently developed by my country, which has obtained clinical approval from the US Food and Drug Administration. Chidamide is the world's first subtype-selective histone deacetylase oral inhibitor approved for marketing. The first indication is relapsed and refractory peripheral T-cell lymphoma. [0003] According to literature reports, Chidamide has been proven to have a good anti-tumor effect in colon cancer, lung cancer, breast cancer, liver cancer and leukemia, and has significantly improved the quality of life of cancer patients. [0004] Malignant tumors, commonly known as cancer, seriously threaten human life and health. Countless patients die of cancer every year, and its morbidity and mortality have increased signif...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/56
CPCC07D213/56
Inventor 刘怀振马居良关承泰郭明
Owner 山东川成医药有限公司
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