ENZALUTAMIDE

Enzalutamide, MDV-3100

MDV3100 is an orally bioavailable, organic, non-steroidal small molecule targeting the androgen receptor (AR) with potential antineoplastic activity. MDV3100 (Enzalutamide) blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Early preclinical studies also suggest that MDV3100 inhibits breast cancer cell growth.

1H NMR FROM THE NET

1H NMR PREDICT AND 13 C NMR PREDICT BELOW

COSY PREDICT

Synthesis pics

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PATENT
http://www.google.com/patents/WO2015063720A1?cl=en

Enzalutamide is chemically described as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl] -5 ,5 -dimethyl-4-oxo-2-sulfanylideneimidazolidin- 1 -yl } -2-fluoro-N-methylbenzamide of Formula I.

FORMULA I

Processes for the preparation of enzalutamide are described in U.S. Publication Nos. 2007/0004753 and 2007/0254933 and PCT Publication Nos. WO 2007/127010, WO 2006/124118, and WO 2011/106570.

PCT Publication No. WO 2011/106570 discloses that the processes described in U.S. Publication Nos. 2007/0004753 and 2007/0254933 result in a 25% yield of enzalutamide in the final step, which accounts for a 15% overall yield. PCT Publication No. WO 2011/106570 further discloses that the known processes for preparing enzalutamide involve the use of extremely toxic reagents, for example, acetone cyanohydrin.

Acetone cyanohydrin is toxic and therefore its use as a reagent should be avoided for industrial production of a pharmaceutical ingredient. Thus, there is a need in the art to develop a process for the preparation of enzalutamide that avoids the use of acetone cyanohydrin as a reagent

Example 6: Process for the preparation of Enzalutamide (Formula I)

Ethyl N-[3-fluoro-4-(methylcarbamoyl)-phenyl]-2-methylalaninate (Formula IV; 0.2 g) and 4-isothiocyanato 2-(triflouromethyl)-benzonitrile (Formula V; 0.33 g) were added to dimethyl sulfoxide (0.2 mL) and isopropyl acetate (0.4 mL) and heated to 90°C to 95°C. The reaction mixture was cooled to 70°C followed by the addition of methanol (0.4 mL). The reaction mixture was stirred for 2 hours. Isopropyl acetate (4 mL) was added to the reaction mixture followed by washing with water (4 mL). The organic layer was concentrated at 35°C under vacuum to obtain an oily residue which was further purified using silica gel column to obtain the title compound.

Yield: 0.2 g

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PAPER

J Med Chem 2010, 53(7): 2779

http://pubs.acs.org/doi/full/10.1021/jm901488g
A structure−activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.

N-Methyl-4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]-2-fluorobenzamide, 92

………………………..and concentrated and the residue was purified with SiO2 column chromatography (dichloromethane/acetone, 95:5) to give92 (30 mg, 51%) as colorless crystals.

1H NMR (CDCl3, 400 MHz) δ 1.61 (s, 6H), 3.07 (d, 3H, J= 4.1 Hz), 6.71 (m, 1 H), 7.15 (dd, 1H, J = 11.7, 2.0 Hz), 7.24 (dd, 1H, J = 8.4, 2.0 Hz), 7.83 (dd, 1H, J = 8.2, 2.1 Hz), 7.95 (d, 1H, J = 2.1 Hz), 7.99 (d, 1H, J = 8.2 Hz), 8.28 (dd, 1H, J = 8.4, 8.4 Hz).

13C NMR (CDCl3, 125 MHz) δ 23.8, 26.9, 66.5, 110.3, 114.6, 117.7, 117.9, 121.7 (q, J = 272.3 Hz), 126.1, 126.9 (q, J = 4.6 Hz), 132.0, 133.3, 133.6 (q, J = 33.4 Hz), 135.2, 136.7, 138.9 (d, J = 10.8 Hz), 160.3 (d, J = 248.6 Hz), 162.6 (d, J = 3.3 Hz), 174.3, 179.6.

19F NMR (CDCl3, 100 MHz) δ −111.13, −62.58.

HRMS: found 465.1023 [M + H]+, calculated for [C21H16F4N4O2S + H]+ 465.1003.

COMPARISON OF 1H NMR KNOWN VALUES WITH PREDICTED —-KNOWN IN RED

REF

MEDIVATION PROSTATE THERAPEUTICS, INC.; JAIN, Rajendra, Parasmal; ANGELAUD, Remy; THOMPSON, Andrew; LAMBERSON, Carol; GREENFIELD, Scott Patent: WO2011/106570 A1, 2011 ; Location in patent: Page/Page column 46

Regents of the University of California Patent: US2007/254933 A1, 2007 ; Location in patent: Page/Page column 7 ;

WO2011/106570 A1,

J Med Chem 2010, 53(7): 2779

WO2013067151A1 *	Nov 1, 2012	May 10, 2013	Medivation Prostate Therapeutics, Inc.	Treatment methods using diarylthiohydantoin derivatives
WO2014041487A2 *	Sep 11, 2013	Mar 20, 2014	Dr. Reddy’s Laboratories Limited	Enzalutamide polymorphic forms and its preparation
WO2014066799A2 *	Oct 25, 2013	May 1, 2014	Memorial Sloan-Kettering Cancer Center	Modulators of resistant androgen receptor
WO2014167428A3 *	Mar 5, 2014	Feb 19, 2015	Shilpa Medicare Limited	Amorphous 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-n-methylbenzamide
EP2536708A2 *	Feb 16, 2011	Dec 26, 2012	Aragon Pharmaceuticals, Inc.	Androgen receptor modulators and uses thereof