Potassium Carbonate → (S)-1-isopropyl-4-(piperidine4-carbonyl)-2-methyl piperazine

Participants

Reaction Steps

(S)-1-Isopropyl-4-(piperidine-4-carbonyl)-2-methylpiperazine dihydrochloride (D29) (1.5 g) in water 5 ml was treated with solid K2CO3. The resulting oil was extracted with EtOAc (25 ml), dried (MgSO4) and evaporated to give (S)-1-isopropyl-4-(piperidine4-carbonyl)-2-methyl piperazine as the free base (1 g). 5-Bromo-2-trifluoromethylpyridine (F. Cottet and M. Schlosser, Eur. J. Org. Chem., 2002, 327-330)(0.13 g) in degassed dry dioxan (3 ml) was charged with tris(dibenzylideneacetone) dipalladium(0)(30mg) and 2-dicyclohexylphosphino-2′-(N,N-dimrethylamino)biphenyl (60 mg). The dark suspension was stirred at rt for 20 min under a blanket of argon. To this reaction a solution of (S)-1-isopropyl-4-(piperidine-4-carbonyl)-2-methyl piperazine (0.15 g) in degassed dioxan (2 ml) was added followed by sodium tert-butoxide (0.11 g). The reaction mixture was stirred at 90° C. for 2 h. After allowing the reaction to cool to rt MeOH (20 ml) was added and the crude reaction mixture was poured onto a 10 g isolute SCX column which was washed with MeOH (50 ml) and then eluted with 10% ammonia in MeOH (50 ml). The product was further purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.88 ammonia solution) in DCM]. Fractions containing the required product were evaporated to give the free base which was dissolved in DCM (10 ml) and treated with 1N HCl in diethyl ether to give the title compound (E79) as a solid (150 mg). LCMS electrospray (+ve) 399 (MH+). 1H NMR [DMSO-d6]δ: 1.09 (3H, d, J=6.4 Hz), 1.33-1.35 (6H, m), 1.54-1.74 (4H, m), 2.98-3.16 (5H, m), 3.23-3.68 (3H, m), 3.83-4.45 (5H, m) 7.44 (1H, dd, J=8.8 Hz), 7.63 (1H, d, J=8.8 Hz), 8.4 (1H, d, J=2.8 Hz), 10.55 (1H, bs).

Provenance & Evidence