2-TRIFLUOROMETHYL-PYRIMIDINE-5-CARBALDEHYDE

Intermediate B4-2-Trifluoromethyl-5-formylpyrimidine At -78 deg.] C in was added 1mol / L toluene solution of diisobutylaluminum hydride to the compound of Reference Example 77 (50.0mg, 0.227mmol) of toluene (0.8 mL of) solution (0.25mL, 0.25 mmol), for 15 minutes stirring. Thereafter, the reaction solution was added saturated Rocher ear saline solution, stirred for 1 hour. The mixture was extracted with ethyl acetate for use organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Utilizing silica column chromatography (hexane / ethyl acetate) The residue obtained was purified, thereby obtaining the title compound (30.0mg, 75percent).2-Trifluoromethyl-pyrimidine-5-carbaldehyde Step B: Intermediate B4-2-Trifluoromethyl-5-formylpyrimidine To a solution of ethyl 2-trifluoromethylpyrimidine-5-carboxylate (5.17 g) in toluene (120 ml) cooled in dry ice/acetone was added a solution of diisobutylaluminium hydride (25 wt %, 31 ml) over 15 min.The mixture was stirred at -78 C. for 45 min, then dilute HCl (2M, 120 ml) was added cautiously.After allowing the mixture to warm to room temperature diethyl ether was added.The organic phase was separated, washed with water, then brine, dried (MgSO4) and evaporated to give the title compound as a colourless solid (3.46 g, 84%).1H-NMR (CDCl3) delta 10.29 (1H, s), 9.37 (2H, s); 13C-NMR (CDCl3) delta 187.7, 159.6 (q, J=38 Hz), 159.1 (2C) 129.6, 119.2 (q, J=276 Hz).At -78 deg.] C in was added 1mol / L toluene solution of diisobutylaluminum hydride to the compound of Reference Example 77 (50.0mg, 0.227mmol) of toluene (0.8 mL of) solution (0.25mL, 0.25 mmol), for 15 minutes stirring. Thereafter, the reaction solution was added saturated Rocher ear saline solution, stirred for 1 hour. The mixture was extracted with ethyl acetate for use organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Utilizing silica column chromatography (hexane / ethyl acetate) The residue obtained was purified, thereby obtaining the title compound (30.0mg, 75%).2-Trifluoromethyl-pyrimidine-5-carbaldehyde To a solution of ethyl 2-trifluoromethyl-pyrimidine-5-carboxylate (1 g, 5 mmol) in DCM (23 mL) at -78 C. was added DIBAL-H (6 ml, 6 mmol, 1.0 M solution in toluene) slowly and stirred at the same temperature for 3 h. The mixture was quenched with slow addition of 2M hydrochloric acid and warmed to room temperature. The mixture was extracted with EtOAc (3*20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound (572 mg, yield: 71.5%). 1H NMR (CDCl3 400 MHz): deltappm 10.27 (s, 1H), 9.35 (s, 2H).To a solution of ethyl 2-(trifluoromethyl)pyrimidine-5-carboxy.ate (25.5 g, 1 16.0 mmol) in dichloromelhane (580 mL) at -78 0C was slowly added DEBAL-H (1.0 M; 130.0 mL, 130.0 mmol). The mixture was stirred at -78 0C. After 2 h, the mixture was quenched via slow addition of HCl (2.0 M in water). The mixture was allowed to warm to ambient temperature. The mixture was extracted with diethyl ether (3x). The combined organic extracts was dried over Na2SO4, filtered and concentrated to give the title compound (28.2 g).To a solution of ethyl 2-(trifluoromethyl)pyrimidine-5~carboxylate (25.5 g, 116.0 mmol) in dichloromethane (580 mL) at -78 0C was slowly added DIBAL-H (1.0 M; 130.0 mL, 130.0 mmol). The mixture was stirred at -78 0C. After 2 h, the mixture was quenched via slow addition of HCl (2.0 M in water). The mixture was allowed to warm to ambient temperature. The mixture was extracted with diethyl ether (3x). The combined organic extracts was dried over Na2SO4, filtered and concentrated to give the title compound (28.2 g).To a solution of ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate (0.750 g, 2.73 mmol) in toluene (13.6 mL) at about -78 C. was added DIBAL-H (1M in cyclohexane, 3.30 mL, 3.30 mmol) over about 15 min and the reaction was left stirring at about -78 C. for about 1 h. The reaction was quenched with the slow addition of 2N aqueous HCl (13.6 mL) and the reaction was warmed to ambient temperature. The reaction mixture was extracted with ether (3×15 mL) and the combined organics were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give crude 2-(trifluoromethyl)pyrimidine-5-carbaldehyde. To a mixture of (1S, 3S, 4R)-3-(3H-imidazo[1, 2-a]pyrrolo[2, 3-e]pyrazin-8-yl)-4-methylcyclopentylamine (0.112 g, 0.437 mmol, Example No.1, Step D) and 2-(trifluoromethyl)pyrimidine-5-carbaldehyde (0.100 g, 0.568 mmol) in DCE (1.00 mL) and MeOH (1.00 mL) was added acetic acid (0.038 mL, 0.655 mmol) and sodium triacetoxyborohydride (0.139 g, 0.655 mmol). The reaction was left stirring at ambient temperature for about 3 h. The reaction was concentrated under reduced pressure and the residue was taken up in DCM and saturated aqueous NaHCO3 (10 mL each). The layers were separated and the aqueous phase was extracted with DCM (2×10 mL) and EtOAc (10 mL). The combined organics were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give (1S, 3S, 4R)-3-(3H-imidazo[1, 2-a]pyrrolo[2, 3-e]pyrazin-8-yl)-4-methyl-N-((2-(trifluoromethyl)pyrimidin-5-yl)methyl)cyclopentylamine (0.035 g, 19%) as an off-white solid;Step B: 2-(Trifluoromethyl)pyrimidine-5-carbaldehyde To a solution of ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate (25.5 g, 116.0 mmol) in dichloromethane (580 mL) at -78 C was slowly added diisobutylaluminium hydride (1.0 M; 130.0 mL, 130.0 mmol). The mixture was stirred at -78 C. After 2 h, the mixture was quenched via slow addition of hydrochloric acid (2.0 M). The mixture was allowed to warm to ambient temperature. The mixture was extracted with diethyl ether (3x). The combined organic extracts was dried over sodium sulfate, filtered and concentrated to give the title compound (28.2 g).