Preparation method of enzalutamide

A technology of enzalutamide and diisopropylcarbodiimide, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of unsuitability for industrial production, unsuitability for scale-up, low reaction yield, etc., to achieve suitable industrial production and reduce impurities The effect of producing and improving the purity

Inactive Publication Date: 2016-04-06
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disadvantages of this method: ①The reaction uses microwave radiation, which is not suitable for amplification; ②The post-treatment uses column chromatography, which is not suitable for industrial production; ③The reaction yield is low, the yield is only 25%, and the cost is high
The reaction is carried out in a sealed tube, which is not suitable for scale-up, and the reaction yield is low, only 4%.

Method used

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  • Preparation method of enzalutamide
  • Preparation method of enzalutamide
  • Preparation method of enzalutamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1: 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine-1 Preparation of -yl)-2-fluoro-N-methylbenzamide

[0041] 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoic acid (500g, 2.0mol, 1eq), 3-buten-1-ol (140g, 2.0mol, 1.0eq), dimethylaminopyridine (24g, 0.2mol), 1,3-diisopropylcarbodiimide (500g, 4.0mol) and dichloromethane (2L) were sequentially added to a 10L reaction flask, The internal temperature was controlled at 20-30°C, and the reaction was stirred for 12 hours. Add 2L of water into the reaction flask, extract, extract the aqueous phase with dichloromethane 2L×3, combine the dichloromethane layers, wash twice with 2L of saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure. Add 4L of acetone and stir, filter, add 10L of n-hexane to the solution, stir and crystallize for 2h to obtain the crude intermediate 1 (480g, 1.6mol).

[0042] Dis...

Embodiment 2

[0045] Example 2: 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine-1 Preparation of -yl)-2-fluoro-N-methylbenzamide

[0046] 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoic acid (500g, 2.0mol, 1eq), 2-propen-1-ol (116g, 2.0 mol, 1.0eq), dimethylaminopyridine (24g, 0.2mol), 1,3-diisopropylcarbodiimide (500g, 4.0mol) and dichloromethane (2L) were added to the 10L reaction flask in turn, and the control The internal temperature is 20-30°C, and the reaction is stirred for 12 hours. Add 2L of water into the reaction flask, extract, extract the aqueous phase with dichloromethane 2L×3, combine the dichloromethane layers, wash twice with 2L of saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure. Add 4L of acetone, stir, filter, add 10L of n-hexane to the solution, stir and crystallize for 2h, and obtain the crude intermediate 1 (441g, 1.5mol).

[0047] Disso...

Embodiment 3

[0050] Example 3: 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine-1 Preparation of -yl)-2-fluoro-N-methylbenzamide

[0051] 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoic acid (500g, 2.0mol, 1eq), 4-penten-1-ol (172g, 2.0mol, 1.0eq), dimethylaminopyridine (24g, 0.2mol), 1,3-diisopropylcarbodiimide (500g, 4.0mol) and dichloromethane (2L) were sequentially added to a 10L reaction flask, The internal temperature was controlled at 20-30°C, and the reaction was stirred for 12 hours. Add 2L of water into the reaction flask, extract, extract the aqueous phase with dichloromethane 2L×3, combine the dichloromethane layers, wash twice with 2L of saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure. Add 4L of acetone, stir, filter, add 10L of n-hexane to the solution, stir and crystallize for 2h, and obtain the crude product of Intermediate 1 (451g, 1.4mol).

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Abstract

The invention provides a preparation method of enzalutamide. The method comprises the following steps: condensing an initial raw material 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropioric acid and enol to obtain an intermediate I, and reacting the intermediate I with The method has the advantages of simple operation, suitableness for industrial production, high yield and high purity.

Description

technical field [0001] The invention relates to the field of chemical synthesis of medicines, in particular to a preparation method of enzalutamide. Background technique [0002] Enzalutamide, chemical name: 4-(3-fluoro-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thio Oxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, CAS: 915087-33-1, structure: [0003] [0004] Enzalutamide is an androgen receptor (AR) antagonist jointly developed and marketed by Medivation and AstellasPharma under the license of the University of California. For the treatment of metastatic castration-resistant prostate cancer previously treated with docetaxel. [0005] At present, the preparation methods of enzalutamide disclosed in the literature include the following: [0006] Charles L. Sawyers et al. (CN101222922) reported the preparation method of enzalutamide: N-methyl-2-fluoro-4-(1,1-dimethyl-cyanomethyl)-aminobenzene Formamide and 4-isothiocyanato-2-trifluoromethylbenzonitrile ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/86
Inventor 武华周王永恒毕方超李孝壁戚郜飞
Owner JIANGSU HANSOH PHARMA CO LTD
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