Synthesis of (2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-yl-1H-imidazol-1-yl}ethyl)dimethylamine

Abstract

An efficient eight-step synthesis of the title compound, starting from oxoacetic acid monohydrate, was developed. Condensation of oxoacetic acid monohydrate with N,N-dimethylethanamine followed by reductive amination and protection gave N-(tert-butoxycarbonyl)-N-[2-(dimethylamino)ethyl]glycine. Activation of this intermediate with 1,1′-carbonylbis-1H-imidazole followed by treatment with (methoxyamino)methane gave tert-butyl [2-(dimethylamino)ethyl]{2-[methoxy(methyl)amino]-2-oxoethyl}carba­mate, which upon reaction with [4-fluoro-3-(trifluoromethyl)phenyl]magnesium bromide, generated in situ, and subsequent deprotection gave 2-{[2-(dimethylamino)ethyl]amino}-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone dihydrochloride. Coupling of this diamine with an activated carboxylic acid gave tert-butyl 4-{1-[2-(dimethylamino)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidine-1-carboxylate, which on treatment with sodium acetate in ethanol followed by deprotection in situ and neutralization gave the title compound in good yield.

Key words

alkylation - heterocycles - imidazoles

• References

• 1 Fromtling RA. Clin. Microbiol. Rev. 1988; 1: 187
• 2 Sharpe TR, Cherfolsky SC, Hewes WE, Smith DH, Gregory WA, Haber SB, Leadbetter MR, Whitney JG. J. Med. Chem. 1985; 28: 1188
• 3 Uçucu O, Karaburun NG, Işikdağ I. Farmaco 2001; 56: 285
• 4 Graczyk PP, Khan A, Bhatia GS, Palmer V, Medland D, Numata H, Oinuma H, Catchick J, Dunne A, Ellis M, Smales C, Whitfield J, Neame SJ, Shah B, Whilton D, Morgan l, Patel T, Chung R, Desmond D, Staddon JM, Sato N, Inoue A. Bioorg. Med. Chem. Lett. 2005; 15: 4666
• 5 Laufer SA, Zimmermann W, Ruff KJ. J. Med. Chem. 2004; 47: 6311
• 6 Black JW, Durant GI, Emmett JC, Ganellin CR. Nature (London) 1974; 248: 65
• 7 Srinivas N, Palne S, Nishi Gupta S, Bhandari K. Bioorg. Med. Chem. Lett. 2009; 19: 324
• 8 Kiselyov AS, Semenova M, Semenov VV. Bioorg. Med. Chem. Lett. 2006; 16: 1440
• 9 Blum CA, Zheng X, De Lombaert S. J. Med. Chem. 2004; 47: 2318

For leading references, see:
• 10a Jin Z. Nat. Prod. Rep. 2009; 26: 382
• 10b Jin Z. Nat. Prod. Rep. 2006; 23: 464
• 10c Jin Z. Nat. Prod. Rep. 2005; 22: 196
• 10d Cui B, Zheng BL, He K, Zheng QY. J. Nat. Prod. 2003; 66: 1101
• 11 Dally RD, Joseph S, Shepherd TA. US 2010120801, 2010
• 12 Vaid RK, Spitler J, Boini S, Henry K, Jiansheng X, Gao B, Lu X. Synthesis 2012; 44: 2231
• 13 Blackaby WP, Goodacre SC, Hallett DJ, Jennings A, Lewis RT, Street LJ, Wilson K. US 2004192692, 2004
• 14 Gajda T, Zwierzak A. Synthesis 1981; 1005
• 15 Brehme R. Synthesis 1976; 1005
• 16 Koziara A, Zawadzki S, Zwierzak A. Synthesis 1979; 527
• 17 Emmons GT, Kongsamut S, Karson CN, Legoff CM. US 2008138413, 2008
• 18 Guillemont JE. G, Motte MM. S, Andries KJ. L, Koul A. WO 200868269, 2008
• 19 May SA, Johnson MD, Braden TM, Calvin JR, Haeberle BD, Jines AR, Miller RD, Plocharczyk E, Rener GA, Richey RN, Schmid CR, Vaid RK, Yu H. Org. Process Res. Dev. 2012; 16: 982