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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.



Synthesis pics



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.
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



J Med Chem 2010, 53(7): 2779
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.


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


From 2-fluoro-4-bromo – benzoic acid s-1, firstly the carboxylic acid is converted to acid chloride with SOCl2 s-2, and then methylamine to give the enamine compound s-3, and s-3 bromide aminoisobutyric acid Ullmann (Goldberg) in CuCl catalyzed reaction to give the compound s-4, followed by reaction of the carboxylic acid and methyl iodide to give the corresponding methyl ester compound s-5.
Aniline compound s-6 in the sulfur phosgene primary amine is converted to the isothiocyanate s-7.
Finally, the nitrogen atom of the compound s-5 attack isothiocyanate s-7, followed by transesterification ring closure to give the final Xtandi (Enzalutamide, uh miscellaneous Lu amine). Scheme: WO2011106570A1



    • seshu says:

      Dear Sir,
      My name is Seshu, Working as a manger R&D API Bulk Drug.

      Dolutegravir key intermediate which is from Maltol. Another two intermediates those are Chiral amine & Difluoro i prepared successfully. Now we want to pepare key intermediate which is from Maltol. completed 3 steps. in 4th step we need to use CO gas with palladium acetate (replace Bromo) at ortho position to get Ester compound.
      I want without CO how to prepare? pl suggest
      We tried NACN, KtertButoxide like… no reactinon

  1. Dr Anthony, Day in and day out you dish out excellent stuff and nowadays some spectroscopy also, How do you get time, may Allah give you all the strenght and will to continue helping all and specially Pakistan chemists

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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