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Novel ultrasonic synthesis method for Entinostat

A technology of entinostat and ultrasonic synthesis, applied in organic chemistry and other directions, can solve the problems of affecting product purity, easy generation of impurities, long reaction time, etc., and achieve the effects of long reaction time, improved purity, and short production cycle.

Inactive Publication Date: 2016-11-09
石家庄海瑞药物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Add 4-aminomethylbenzoic acid, 1,8-diazabicycloundec-7-ene (DBU) and triethylamine suspension in tetrahydrofuran to the reaction solution, stir at room temperature for 5 h, and react Remove THF by liquid rotary evaporation, dissolve in water, acidify the solution with hydrochloric acid to precipitate a solid, filter, and wash the filter cake with water and methanol respectively to obtain purified compound 1; Step 2: Compound 1 and CDI were stirred in THF at 60 °C for 3 h , after the acyl imidazolyl group was formed, the clear solution was cooled to room temperature, 1,2-phenylenediamine and trifluoroacetic acid were added to the solution, and the stirring was continued for 16 h; the reaction mixture was rotary evaporated to remove tetrahydrofuran, and the crude product was dissolved in hexane and water Stir in the mixed solution for 1 h and then filter and dry. The filter cake is ground and washed twice in dichloromethane to obtain purified entinostat; step 1 of the method requires organic base catalysis, which is easy to cause residue and affects the purity of the product. The reaction between Compound 1 and CDI needs to be heated for 3 hours to complete, and the further reaction with o-phenylenediamine takes 16 hours. The reaction time is longer and impurities are easy to form

Method used

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  • Novel ultrasonic synthesis method for Entinostat
  • Novel ultrasonic synthesis method for Entinostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Entinostat is prepared as follows:

[0034] (1) Preparation of 4-[N-(pyridine-3-methoxycarbonyl)aminomethyl]benzoic acid (compound Ⅰ)

[0035] Add N,N'-carbonyldiimidazole (CDI) (4.86g, 30mmol) into 48ml tetrahydrofuran, put the solution in an ultrasonic cleaner, turn on the ultrasonic wave, control the temperature at 10~20°C, and add pyridinemethanol to the solution (3.27g, 30mmol), reacted 30min, TLC monitoring reaction was complete, added 4-aminomethylbenzoic acid (4.53g, 30mmol) in the reaction solution, controlled temperature 20~40 ℃, continued reaction 1h, TLC monitoring reaction ended, The solvent was evaporated under reduced pressure, 100ml of water was added to the residue, and a large amount of solid was precipitated, filtered, and dried to obtain 4-[N-(pyridine-3-methoxycarbonyl)aminomethyl]benzoic acid (6.74g, harvested rate of 78.5%).

[0036] (2) Preparation of N-(2-aminobenzene)-4-[N-(pyridine-3-methoxycarbonyl)aminomethyl]benzamide (crude entinostat) ...

Embodiment 2

[0041] Entinostat is prepared as follows:

[0042] (1) Preparation of 4-[N-(pyridine-3-methoxycarbonyl)aminomethyl]benzoic acid (compound Ⅰ)

[0043]Add N,N'-carbonyldiimidazole (CDI) (6.32g, 39mmol) into 65ml of tetrahydrofuran, place the solution in an ultrasonic cleaner, turn on the ultrasonic wave, control the temperature at 10~20°C, and add pyridinemethanol to the solution (3.27g, 30mmol), reacted 15min, TLC monitoring reaction was complete, added 4-aminomethylbenzoic acid (6.05g, 40mmol) in the reaction solution, controlled temperature 20~40 ℃, continued reaction 1h, TLC monitoring reaction ended, The solvent was evaporated under reduced pressure, 130ml of water was added to the residue, and a large amount of solid was precipitated, filtered, and dried to obtain 4-[N-(pyridine-3-methoxycarbonyl)aminomethyl]benzoic acid (6.79g, harvested rate of 79.1%).

[0044] (2) Preparation of N-(2-aminobenzene)-4-[N-(pyridine-3-methoxycarbonyl)aminomethyl]benzamide (crude entinosta...

Embodiment 3

[0049] Prepare entinostat as follows:

[0050] (1) Preparation of 4-[N-(pyridine-3-methoxycarbonyl)aminomethyl]benzoic acid (compound Ⅰ)

[0051] Add N,N'-carbonyldiimidazole (CDI) (7.30g, 45mmol) to 73ml of tetrahydrofuran, place the solution in an ultrasonic cleaner, turn on the ultrasonic wave, control the temperature at 10~20°C, and add pyridinemethanol to the solution (3.27g, 30mmol), reacted 15min, TLC monitoring reaction was complete, added 4-aminomethylbenzoic acid (6.80g, 45mmol) in the reaction solution, controlled temperature 20~40 ℃, continued reaction 1h, TLC monitoring reaction ended, The solvent was evaporated under reduced pressure, 140ml of water was added to the residue, and a large amount of solid was precipitated by ultrasonication for 30min, which was filtered and dried to obtain 4-[N-(pyridine-3-methoxycarbonyl)aminomethyl]benzoic acid (6.76g, harvested rate of 78.7%).

[0052] (2) Preparation of N-(2-aminobenzene)-4-[N-(pyridine-3-methoxycarbonyl)amino...

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Abstract

The invention relates to a novel ultrasonic synthesis method for Entinostat. The method comprises the following steps: (1) 4-[N-(pyridine-3-methoxycarbonyl)aminomethyl]benzoic acid is prepared under an ultrasonic condition; (2) the compound is subjected to condensation with o-phenylenediamine under an ultrasonic condition in presence of a condensing agent and a catalyst, and a crude Entinostat product is obtained; (3) the crude Entinostat product is subjected to backflow beating in ethyl alcohol, and the final Entinostat product is prepared. The method has the advantages that the production cycle is short, the process is simple, the yield is high, and the product purity is high.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for ultrasonically synthesizing entinostat. Background technique [0002] Breast cancer is one of the most common malignant tumors in women. The incidence rate accounts for 7% to 10% of all kinds of malignant tumors in the whole body. It is second only to uterine cancer and has become the main cause of threat to women's health. Its incidence is often related to genetics. And women aged 40 to 60 before and after menopause have a higher incidence rate. It is one of the malignant tumors that usually occurs in the glandular epithelial tissue of the breast, seriously affecting women's physical and mental health and even threatening their lives. [0003] Entinostat is an investigational histone deacetylase (HDAC) inhibitor developed by Syndax Pharmaceuticals in the United States. Its structural formula is shown in Formula II and it is used for advanced breast cancer (...

Claims

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Application Information

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IPC IPC(8): C07D213/30
CPCC07D213/30
Inventor 武倩倩胡永亮范丽佳
Owner 石家庄海瑞药物科技有限公司