Oxalyl chloride → HCID 46200930, compound

Participants

Reaction Conditions

Reaction Steps

To a solution of 1,1-dimethylethyl(2S)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate D2 (0.140 g, 0.44 mmol) in DMF (2 ml) was added 3,5-dimethyl-2-pyrazinamine (0.054 g, 0.44 mmol) and the mixture was stirred at 150° C. for 30 min. The reaction mixture was charged into a SCX column and was eluted with methanol and ammonia 2 M in methanol. Collected fractions gave 0.115 g of a crude containing the desired 6,8-dimethyl-2-[(2S)-2-piperidinylmethyl]imidazo[1,2-a]pyrazine. UPLC: rt=0.34, peak observed: 245 (M+1). C14H20N4 requires 244. Into a 7 ml screw capped vial 2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (0.114 g, 0.52 mmol) was dissolved in DCM (1 ml), Oxalyl chloride (0.100 ml, 1.14 mmol) then DMF (0.036 ml, 0.47 mmol) were added and the resulting mixture was stirred for 30 min at rt. The solvent was removed under reduced pressure and the resulting yellow solid dissolved in DCM (1 ml) and added dropwise to the solution containing the crude (0.115 g) 6,8-dimethyl-2-[(2S)-2-piperidinylmethyl]imidazo[1,2-a]pyrazine and TEA (0.197 ml, 0.47 mmol) in DCM (1 ml) cooled at 0° C. The ice-bath was removed and the reaction mixture left under stirring at rt for 1 h. DCM was added and the mixture washed with a saturated NaHCO3 aqueous solution, the organic phase was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (Biotage 25 M, DCM/MeOH, 90/01) and by fraction lynx (basic method). The free base of the title compound was obtained (0.039 g, 0.079 mmol, 20% yield from D2, three steps) as a yellow solid. UPLC: rt=0.58, peak observed: 446 (M+1). C25H27N5OS requires 445. 1H NMR [the product is present as a mixture of conformers (ratio c.ca 60/40)] (500 MHz, DMSO-d6). The free base (0.037 g, 0.08 mmol) was transferred into a 7 ml screw capped vial with anhydrous DCM (1 ml) and the solution cooled to 0° C. HCl (0.125 ml of a 1 M solution in Et2O, 0.13 mmol) was added dropwise and the mixture stirred for 15 min. The solvent was removed under reduced pressure and the resulting solid triturated with anhydrous Et2O. The title compound was obtained (0.041 g, 0.08 mmol, 98% yield) as a white solid. UPLC: rt=0.58, peak observed: 446 (M+1-HCl). C25H28ClN5OS requires 482.

Provenance & Evidence