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A novel process for preparing enzalutamide

A technology of impurities and primary amines, applied in the new field of preparation of enzalutamide, can solve problems such as limited synthesis methods

Active Publication Date: 2018-02-13
SCINOPHARM TAIWAN LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since acetone cyanohydrin 2 has been identified as an extremely hazardous chemical, this synthetic method has very limited industrial applications

Method used

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  • A novel process for preparing enzalutamide
  • A novel process for preparing enzalutamide
  • A novel process for preparing enzalutamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] Preparation of diamide 14

[0108]

[0109] A four-neck round bottom flask was equipped with a mechanical stirrer and a thermometer. At 20-30°C, under nitrogen, add compound 8 (10g, 39.39mmol, 1 equivalent), EDCI (7.33g, 47.2mmol, 1.2 equivalents), HOBt (7.20g, 47.3mmol, 1.2 equivalents) and DMF (50 mL, 5 vol). The mixture was stirred at 20-30 °C for 5 min, then the EtNH 2 (2M in THF, 49 mL, 98 mmol, 2.5 eq) was added to the reaction flask. The reaction mixture was stirred at 20-30°C for 15 hours. After the reaction was complete, EtOAc (100 mL, 10 vol) and saturated NH 4 Cl(aq) (100 mL, 10 vol), stirring was continued for 5 minutes. The resulting mixture was filtered and the filtrate was added to H 2 O (50mL). The organic portion was withdrawn and the aqueous layer was washed with EtOAc (3 x 50 mL, 5 vol). The combined organic fractions were concentrated to dryness to afford about 7 g of crude compound 14 as a yellow oil. To the yellow oil was added EtOAc (5...

Embodiment 2

[0111] Cyclization reaction: amide method

[0112]

[0113] A four-neck round bottom flask was equipped with a mechanical stirrer and a thermometer. At 20-30°C, in nitrogen, compound 14 (0.5g, 2mmol, 1 equivalent), compound 4 (0.89g, 3.9mmol, 2.2 equivalents) were added to the flask, Molecular sieves (0.5 g, 1 wt) and MeCN (2 mL, 4 vol). The reaction mixture was stirred at 20-30°C to remove water. After 16 hours, the reaction mixture was heated to 60-70°C for 24 hours. Another amount of compound 4 (1.29 g, 5.66 mmol, 3.2 equiv, twice) was added, and stirring was continued for 24 hours. After the reaction was complete, EtOAc (10 mL, 20 vol) was added to the reaction mixture, H 2 O (10 mL, 20 vol) and saturated NaCl(aq) (5 mL, 10 vol), stirring was continued for 5 minutes. The mixture was filtered and the phases were separated. The separated aqueous layer was extracted with EtOAc (50 mL, 5 vol). The combined organic fractions were concentrated to near dryness to afford ...

Embodiment 3

[0115] Cyclization Reaction: The Acid Method

[0116]

[0117] A four-neck round bottom flask was equipped with a mechanical stirrer and a thermometer. Compound 8 (5 g, 19.66 mmol, 1 eq), THF (25 mL, 5 vol) and 2N NaOH(aq) (14.8 mL, 29.6 mmol, 1.5 eq) were added to the flask under nitrogen at 20-30 °C. The mixture was stirred at 20-30°C for 30 minutes. Compound 4 (13.5 g, 58.98 mmol, 3.6 equiv) was added at 20-30°C in three equal portions every 5-6 hours. After the reaction was complete, EtOAc (25 mL, 5 vol) and H 2 O (10 mL, 2 vol). The mixture was stirred for 5 minutes, then the phases were separated. The separated aqueous portion was extracted with EtOAc (25 mL, 5 vol). The combined organic fractions were concentrated to near dryness to afford 10.5 g of crude enzalutamide as a yellow oil. IPA (50 mL, 10 vol) was added to the yellow oil, and the mixture was heated to 50-60 °C to obtain a homogeneous solution. The mixture was cooled to 20-30°C and stirred for 1 hour...

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Abstract

The present invention provides a process for the efficient preparation of enzalutamide of the following formula I:

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Patent Application No. 62,173,814, filed June 10, 2015, under Section 35, Section 119(e) of the US Patent Code, the disclosure of which is incorporated herein by reference. [0003] Statement Regarding Invention Rights Under Federally Sponsored Research and Development [0004] Not applicable [0005] Reference "Sequence Listing", table or computer program listing appendix submitted on a compact diskette [0006] Not applicable Background technique [0007] The present invention relates to a preparation chemically named 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazole A new method of alk-1-yl)-2-fluoro-N-methylbenzamide, which is represented by the following structure: [0008] [0009] Enzalutamide (with marketed) as an agent for the treatment of castration-resistant prostate cancer, and was approved by the U.S. Food and Drug Admin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/86
CPCC07D233/86A61P13/08A61P35/00A61K31/4164
Inventor 廖苑秀郭俊徹施雯莉陈尚鸿
Owner SCINOPHARM TAIWAN LTD
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