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Current Radiopharmaceuticals

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ISSN (Print): 1874-4710
ISSN (Online): 1874-4729

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Research Article

Synthesis of Deuterium Labeled 5, 5-Dimethyl-3-(α, α, α-trifluoro-4-nitro-m-tolyl) Hydantoin

Author(s): Ratna Sekhar Bolla*, Narasimha Murthy Gandikota and Ivaturi Venkata Kasi Viswanath*

Volume 12, Issue 1, 2019

Page: [82 - 87] Pages: 6

DOI: 10.2174/1874471012666181130162731

Price: $65

Abstract

Objective: Stable and non-radioactive isotope labeled compounds gained significance in recent drug discovery and other various applications such as bio-analytical studies. The modern bioanalytical techniques can study the adverse therapeutic effects of drugs by comparing isotopically labeled internal standards. A well-designed labeled compound can provide high-quality information about the identity and quantification of drug-related compounds in biological samples. This information can be very useful at key decision points in drug development. In this study, we tried to synthesize Nilutamide- d6 which can be useful to study the adverse effects of Nilutamide, and based on these can modify or widen the new drug derivatives. Nilutamide is a nonsteroidal antiandrogen which is used in the treatment of prostate cancer. The aim of this study was to develop a synthetic approach to prepare deuterium labeled [2H6]-5, 5-dimethylimidazolidine-2, 4-dione and [2H6]-nilutamide.

Methods: Since nilutamide is a derivative of hydantoin, it involves the synthesis of Dimethylhydantoin via Bucherer-Bergs hydantoin synthesis, followed by oxidative N-arylation with 4-iodo-1-nitro-2- (trifluoromethyl) benzene.

Conclusion: We successfully synthesized [2H6]-nilutamide and [2H6]-dimethylhydantoin with good isotopic purity, measured to be of adequate quality for use as internal standards in bio-analytical studies. A brief mechanistic study of Bucherer-Bergs hydantoin reaction was carried and the reason for possible H/D exchange was explained.

Keywords: Bucherer-Bergs hydantoin synthesis, [2H6]- 5, 5-dimethyl imidazolidine-2, 4-dione, [2H6]-nilutamide, antineoplastic, non-steroidal antiandrogen, prostate cancer, deuterium labeling.

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[1]
(a)Dhanawat, M.; Banerjee, A.G. Design, Synthesis and anticonvulsant screening of some substituted piperazine and aniline derivatives of 5-phenyl oxazolidin-2,4-diones and 5,5-diphenylimidazolidin-2,4 diones. Med. Chem. Res., 2012, 21, 2807.
(b)Thenmozhiyal, J.C.; Wong, P.T-H.; Chui, W.K. Anticonvulsant activity of phenylmethylenehydantoins: A structure-activity relationship study. J. Med. Chem., 2004, 47, 1527-1535.
[2]
(a)Dinesh, D. Rishipathak, S.C.Pal, Microwave assisted synthesis and biological evaluation of hydantoin derivatives. Asian J. Chem., 2007, 19(7), 5450-5458.
(b)Michel Bourin, Eric Dailly, Martine Hascoet, Preclinical and clinical pharmacology of cyamemazine: Anxiolytic effects and prevention of alcohol and benzodiazepine withdrawal syndrome. CNS Drug Rev., 2004, 10(3), 219-229.
[3]
(a)Ask, K.; Dijols, S.; Giroud, C.; Casse, L. Frapart, Y.-M.; Sari, M.-A.; Kim, K.-S.; Stuehr, D. J.; Mansuy, D.; Camus, P.; Boucher, J.-L. Comparison of in vitro Bioactivation of flutamide and Its cyano analogue. Chem. Res. Toxicol., 2003, 16, 1547-1554.
(b)Lanter, J.C.; Fiordeliso, J.J.; Jiang, W.; Allan, G.F.; Lai, M.T.; Linton, O. Hahn, do W.; Lundeen, SG.; Sui, Z. The discovery of a potent orally efficacious indole androgen receptor antagonist through in vivo screening. Bioorg. Med. Chem. Lett., 2007, 17, 123-126.
[4]
(a)Keck, P.E.; McElroy, S.L. Bipolar disorder, obesity, and pharmacotherapy-associated weight gain. J. Clin. Psychiatry, 2003, 64(12), 1426-1435.
(b)Rogawski, Michael A; Losher, Wolfgand; The neurobiology of antiepileptic drugs. Nat. Rev. Neuroscience., 2004, 5(7), 553-564.
[5]
(a)Nique, F.; Hebbe, S.; Peixoto, C.; Annoot, D.; Lefrancois, J-M.; Duval, E.; Michoux, L. Triballeau; Discovery of diarylhydantoins as new selective androgen receptor modulators. J. Med. Chem., 2012, 55, 8225.
(b)Nique, F.; Hebbe, S.; Triballeau, N.; Peixoto, C.; Lefrancois, J-M.; Jary, H.; Alvey, L.; Manioc, M.; Housseman, C.; Klaassen, H.; Van der Aar, E.; Feyen, J.; Fletcher, S.; Blanqué, R.; Robin-Jagerschmidt, C.; Deprez, P. Identification of a 4-(hydroxymethyl)diarylhydantoin as a selective androgen receptor modulator. J. Med. Chem., 2012, 55, 8236.
[6]
Atzrodt, J.; Derdau, V.; Fey, T.; Zimmerman, J. The renaissance of H/D exchange. J. Angew. Chem. Int. Ed., 2007, 46, 7744-7765.
[7]
(a)Kerr, W.J.; Mudd, R.J.; Owens, P.K.; Reid, M.; Brown, J.A.; Campos, S. Hydrogen isotope exchange with highly active iridium(i) NHC/phosphine complexes: A comparative counter-ion study. J. Labelled Comp. Radiopharm., 2016, 59(14), 601-603.
(b)Kerr, W.J.; Brown, J.A.; Cochrane, A.R.; Irvine, S.; Mondal, B.; Parkinson, J.A. The Synthesis of Highly Active Iridium(I) Complexes and their Application in Catalytic Hydrogen Isotope Exchange. Adv. Synth. Cat., 2014, 356(17), 3551-3562.
(c)Goran. N. Nilsson, Kerr, J.K. The development and use of novel iridium complexes as catalysts for ortho-directed hydrogen isotope exchange reactions. J. Labelled Comp. Radiopharm., 2010, 53(11-12), 662-667.
[8]
Lynch, J.E. Side chain synthesis for an antiarrythmic compound, U.K. Patent, GB 2,328,942, Mar 10 1999.
[9]
(a)Kreipl, A.; Boege, N.; Thiel, W.R. Method for coupling halogen- substituted aromatic compounds with organic compounds comprising trialkylsilyl substituted heteroatoms. WO2010106078, Sep 23 2010.
(b)Li, Qian; Wu, Weizhong; Synthesis of nilutamide and Its analogue. Zhongguo Yiyao Gongye Zazhi, 2004, 35(8), 455-456.
(c)Rishipathak, D.D.; Pal, S.C.; Belsare, D.P. Microwave assisted synthesis and biological evaluation of hydantoin derivatives. Asian J. Chem., 2007, 19(7), 5450-5458.
(d)Seuron, P. Process for 1-Phenyl-imidazoline-2,5-diones.U.S. Patent 5,166,358, Nov 24 1992.
(e)Perronnet, J. 1-(3’-Trifluoromethyl-4’-nitrophenyl)- 4,4-dimethylimidazolidines U.S. Patent 4,097,578, Jun 27 1978.
[10]
Cox, R.F.B.; Stormont, R.T. Acetonecyanohydrin. Org. Synth. coll. 1943, 2, 7; (b) Wagner, E.C.; Baizer, M. 5-dimethyhydantoin. Org. Synth. Coll, 1940, 20, 42.
[11]
(a)Ali, M.Y.; Johannes, D.; Kirsten, T. Bi- and tricyclic products from tetra- and penta-peptides of alpha-methylalanine. Acta Chem. Scand., 1973, 27, 1509-1518.
(b)Chiarelli, R. Rassat, A. Nitroxydes-LVI: Syntheses de radicaux nitroxydes deuteries. Tetrahedron, 1973, 29, 3639-3647.
(c)obert Chiarelli et Andre Rassat; Deuterated nitroxide radical - tetra methyl 2,2,5,5-aza -1-cyclopentane oxa-3-oxyl-1. FR2154857, May 18. 1973.
[12]
Monteiro, J.L. Bartholomaus. P.; Corra, A.G.; Kappe, C.O. Continuous Synthesis of Hydantoins: Intensifying the Bucherer–Bergs Reaction. Synlett, 2016, 27, 83-87; (b) Bucherer and steiner. preparation of hydantoin from carbonyl compounds by reaction with potassium cyanide and ammonium carbonate, or from the corresponding cyanohydrin and ammonium carbonate. J. Prakt. Chem., 1934, 140, 291; (c) Elinor W. The Chemistry of the Hydantoins. Chem. Rev., 1950, 46(3), 403-470; (d) Worman, J.J.; Uhrich, K.; Olson, E.; Diehl, J.; Famum, S. Hawthome; Mechanism of formation of hydantoins. Sci. Tech. Connect, 1985, 10(01), 12.
[13]
Jyotirmayee, D.; Kalyan, D.; Ganesh, C.M. A Diversity-oriented Approach to spirocyclic and fused hydantoins via olefin metathesis. J. Org. Chem., 2012, 77, 8071-8082.
[14]
(a)Jack. H, Ramon. A. Evangelista; Iminium-ion formation and deuterium exchange by acetone in the presence of pyrrolidine, pyrazolidine, Isoxazolidine, and their acyclic analogs. J. Am. Chem. Soc., 1980, 102(5), 1649.
(b)Hammons, G.; Westheimer, F.H.; Nakaoka, K.; Kluger, R. Proton-exchange reactions of acetone and butanone. Resolution of steps in catalysis by acetoacetate decarboxylase. J. Am. Chem. Soc., 1975, 97(6), 1568-1572.
(c)Juan, C. Ana, R.; Enrique, R.; John, P.R. Glycine Enolates: The effect of formation of iminium ions to simple ketones on α-amino carbon acidity and a comparison with pyridoxal iminium ions. J. Am. Chem. Soc., 2008, 130,6, 2041-2050.
[15]
Li, Q.; Wu, W. Synthesis of nilutamide and its analogue. Zhongguo Yiyao Gongye Zazhi, 2004, 35(8), 455-456.

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