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Preparation method of enzalutamide of formula (VIII)

A kind of enzalutamide, generative technology, applied in the field of chemical drug synthesis, can solve the problems of large environmental pollution, unstable intermediates, high cost, etc., to avoid the production of isothiocyanate intermediates, reagents are cheap and easy to obtain , the effect of mild reaction conditions

Pending Publication Date: 2019-04-19
SHANGHAI UNIV OF MEDICINE & HEALTH SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] In view of the above-mentioned shortcoming of prior art, the object of the present invention is to provide a kind of preparation method of enzalutamide of formula (VIII), be used to overcome the low yield of target product of the method for preparing enzalutamide in the prior art , high cost, high environmental pollution, unstable intermediates, not suitable for mass production and other defects

Method used

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  • Preparation method of enzalutamide of formula (VIII)
  • Preparation method of enzalutamide of formula (VIII)
  • Preparation method of enzalutamide of formula (VIII)

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Under nitrogen protection, compound I (50.0 g, 0.267 mol) and compound N-tert-butoxycarbonyl-2-methylalanine (60.1 g, 0.295 mol) were added to a 1 L three-necked flask, and 150 mL of anhydrous THF was added at room temperature Stir until the solid is completely dissolved, add DIPEA (38.2g, 0.295mol) and control the reaction temperature at 10-30°C, then add 50mL of anhydrous THF, stir at room temperature for 10-15min, add CDI (52.3g, 0.322mol) in batches, The internal temperature was raised to 50-60°C and stirred for 30 minutes. Add DBU (61.3 g, 0.403 mol) and react at 55-65° C. for 3-4 h to stop the reaction. Add 150 mL of citric acid aqueous solution at 60°C and stir for 30 min, separate the liquid, concentrate the organic phase, and replace the solvent with ethanol, recrystallize with ethanol, filter with suction, and dry to obtain 45.8 g of white solid, with a yield of 49.5%. 1 H-NMR (400M, DMSO-d6):

[0039] δ10.292(s,1H),8.372(s,1H),8.176-8.154(d,1H,J=8.8Hz),8.07...

Embodiment 2

[0041]Under the protection of nitrogen, the amino protecting group PG is tert-butoxycarbonyl compound III (100g, 0.269mol) into a 500mL three-neck flask, add 300mL of 4M HCl isopropanol solution, and heat to 55-65°C for 2h. Stop the reaction, concentrate to 100mL, add 100mL of isopropanol, concentrate again to 100mL, add 300mL of ammonia solution in an ice-water bath, stir for 30min, filter with suction, wash the filter cake with 100mL of water, filter with suction to dryness, and dry at 60°C to obtain a white color Solid compound (IV) 68.1g, yield 93.33%. 1 H-NMR (400M, DMSO-d6):

[0042] δ8.463-8.458(d,1H,J=2.0Hz),8.216-8.189(dd,1H,J=8.4Hz,2.0Hz),8.097-8.071(dt,1H,J=8.4Hz,1.0Hz), 5.062(brs,3H),1.303(s,6H)

Embodiment 3

[0044] Under the protection of nitrogen, put the amino protecting group PG as tert-butoxycarbonyl compound III (100g, 0.269mol) into a 500mL three-neck flask, add 300mL of 4M HCl methanol solution, heat to 50-60°C for 1h, and stop the reaction , concentrated to 100mL, added 100mL of methanol, concentrated again to 100mL, added 300mL of ammonia solution in an ice-water bath, and stirred for 30min, filtered with suction, washed the filter cake with 100mL of water, filtered with suction to dryness, and dried at 55°C to obtain a white solid compound (IV )67.0g, yield 91.78%.

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Abstract

The invention discloses a preparation method of enzalutamide of formula (VIII). The method comprises the following steps: carrying out a condensation reaction on a compound of formula (I) and an aminoprotecting group PG-containing compound of formula (II) to produce a compound of formula (III); carrying out a protecting group PG removal reaction on the compound of formula (III) to form a compoundof formula (IV); carrying out a coupling reaction on the compound of formula (IV) and a compound of formula (V) at 25-160 DEG C to form a compound of formula (VI); and converting the compound of formula(VI-a) into a compound of formula (VII) when W is a C1-8 alkoxy group, and converting the compound of formula (VI-b) into into the compound of the formula (VIII) when the W is a methylamino group.The method has the advantages of high yield, omitting of the production of an intermediate isothiocyanate with poor stability, mild reaction conditions, simplicity in operation, and cheap and easily available reagents, is suitable for small-scale preparation in the laboratory, and is also suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical drug synthesis, and in particular relates to an androgen receptor antagonist, in particular to a preparation method of enzalutamide of formula (VIII). Background technique [0002] Enzalutamide (MDV3100) is a new generation of androgen receptor antagonist jointly developed by Medivation and Astellas. Translocation and coactivator recruitment. Enzalutamide was shown to induce tumor cell apoptosis without agonist activity. On August 31, 2012, it was approved by the US Food and Drug Administration (FDA) for the treatment of advanced male castration-resistant prostate cancer (castration-resistant prostate cancer) that has spread or recurred. The trade name is Xtandi, and the chemical formula is 4-[3- [4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thione-1-imidazolidinyl]-2-fluoro-N-methyl phenylbenzamide, which is an oral preparation. [0003] Enzalutamide (enzalutamide, MDV3100), the s...

Claims

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Application Information

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IPC IPC(8): C07D233/86
CPCC07D233/86Y02P20/55
Inventor 孟祥国邵雷黄钢周兆丽吴锴田佩川徐晨钦姜智腾熊亮斌
Owner SHANGHAI UNIV OF MEDICINE & HEALTH SCI
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