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A process for producing enzalutamide

A kind of enzalutamide, suitable technology, be applied in the field of preparation medicine enzalutamide

Inactive Publication Date: 2016-11-23
ZENTIVA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this reaction only achieved a negligible yield of 2 wt%

Method used

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  • A process for producing enzalutamide
  • A process for producing enzalutamide
  • A process for producing enzalutamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 2-fluoro-4-nitro-N-methylbenzamide of formula IV.

[0037]

[0038] Add 2000 ml of isopropyl acetate, 10 ml of DMF to 250 g (1.35 mol) of 2-fluoro-4-nitrobenzoic acid of formula III in a 5000-ml reactor, heat the mixture to 60° C., and place the container with Flush well with nitrogen. Then, 193 g (1.62 mol) of thionyl chloride were added dropwise within 50 minutes, and the mixture was further stirred at 60° C. overnight. The next day, the mixture was cooled to -10 °C, the turbidity was filtered through a folded filter, and the obtained clear solution of 2-fluoro-4-nitrobenzoyl chloride was transferred to a bottle and kept under an inert nitrogen atmosphere .

[0039] 500 ml of isopropyl acetate, 524 g of 40% aqueous methylamine solution were charged into the reaction vessel, and the mixture was cooled to 0°C. To this mixture was added dropwise a solution of 2-fluoro-4-nitrobenzoyl chloride over 4 hours, and the resulting mixture was stirred for a further 1 hour. ...

Embodiment 2

[0042] 4-Amino-2-fluoro-N-methylbenzamide hydrochloride of formula V.

[0043]

[0044] 40.0 g (0.202 mol) of 2-fluoro-4-nitro-N-methylbenzamide of the formula IV were charged into a 1500 ml autoclave, and 500 ml of methanol and 0.50 g of 10% by weight palladium on activated carbon were added. The mixture was hydrogenated at a pressure of 600 kPa and a temperature of 50° C. for 1 hour, then the catalyst was removed by filtration through a bed of celite and the solvent was evaporated to dryness. The evaporated product (35.6 g) was dissolved in 180 ml of hot ethanol and 21 g of concentrated (35%) hydrochloric acid (0.202 mmol) were added. After inoculation and cooling, the solid product that separated was aspirated and washed with ethanol. 29.3 g (71% by weight) of the product of the formula V are obtained in the form of white crystals with a melting point of 222° C. to 228° C. (dec.). HPLC purity: 99.89%. 1 H NMR (DMSO): δ (ppm): 2.75 (d, 3H), 6.80 (m, 2H), 7.57 (t, 1H), ...

Embodiment 3

[0046] 2-[3-fluoro-4-(methylcarbamoyl)phenylamino]-2-methylpropionic acid of formula XI.

[0047]

[0048] 50.0 g (0.244 mol) of 4-amino-2-fluoro-N-methylbenzamide hydrochloride of formula V were charged into a 500 ml container equipped with an anchor stirrer, 50 ml of dimethylacetamide was added, and The mixture was heated to 70°C. Then, 68.0 g (0.672 mol) of triethylamine was added, and the mixture was stirred for 60 minutes. Thereafter, the temperature was raised to 100° C., and a preheated solution of 54.3 g (0.325 mol) of 2-bromo-2-methylpropionic acid in 25 ml of dimethylacetamide was added dropwise to the mixture during 10 minutes . The mixture was stirred at 100°C for a further 1 1 / 2 hours, then it was cooled to 40°C and 125ml of water and a solution of 40g of citric acid in 100ml of water were added. The mixture was seeded with product, cooled to 20°C, and stirred overnight. The isolated product was suctioned on a Buchner funnel, washed with a considerable amou...

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Abstract

This invention provides a new process for producing enzalutamide of formula I, starting from the intermediate of formula XI, which cyclizes with the isothiocyanate of formula VIII in the presence of a base, an alcohol of the general formula R-OH as an additive, in a suitable solvent, wherein R is an alkyl with the number of carbon atoms C1C20, or a substituted alkyl with the number of carbon atoms C1C20, an aryl with the number of carbon atoms C6-C16, or a substituted aryl with the number of carbon atoms C6-C16.

Description

technical field [0001] The present invention relates to the new method for preparing drug enzalutamide (I), [0002] [0003] The drug enzalutamide is used for the treatment of prostate cancer. Enzalutamide (formerly known as MDV3100) is a novel drug that acts as an inhibitor of Androgen Receptor (AR) signaling and unlike other currently available antiandrogens, it prevents AR translocation to the nucleus , binding of AR to DNA, and uptake of other transcriptional activators; it is also characterized by a higher affinity for AR. Its ability to induce tumor shrinkage was also demonstrated in preclinical studies. Background technique [0004] The synthesis of enzalutamide (Scheme 1) was first described in a basic patent application in 2006 (WO2006 / 124118). The key step is the final cyclization of the isothiocyanate VIII and nitrile IX, which however gives very low yields. [0005] [0006] plan 1. [0007] A new method from the company Medivation Prostate Therapeuti...

Claims

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Application Information

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IPC IPC(8): C07D233/86
CPCC07D233/86
Inventor J·施塔赫O·克莱坎P·莱纳特J·莱姆丝
Owner ZENTIVA AS
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