Water → HCID 178448979, compound

Participants

Reaction Steps

Methylene chloride (4.0 mL) and trifluoroacetic acid (4.0 mL, 52 mmol) were added to the {1-(cis-4-{[6-[(tert-butylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, stirred for 1 hour, and then concentrated to remove TFA. LCMS showed clean conversion to the hydroxymethyl intermediate (M+2H 320) and no loss of tert-butyl group. To the residue was added methanol (7.0 mL), followed by 1,2-propanediamine (30 μL, 0.35 mmol), followed by 15.0 M ammonium hydroxide in water (1.8 mL, 27 mmol). The solution was stirred 2.5 hours. LCMS showed complete reaction with no loss of tert-butyl group and no primary amine detected. The product was isolated by preparative LCMS using a Waters Fraction-Linx instrument and a 30 mm×100 mm Sunfire C18 column; 5% CH3CN—H2O (0.1% TFA), 4.0 minutes; 8.0 minute gradient to 30%; 60 mL/min; 8 runs; retention time 11.0 min. The eluent was concentrated by 50%, then freeze-dried to give white solid. Yield 238 mg. NMR showed it to be the tetra-TFA salt. 1H NMR (300 MHz, DMSO-D6): δ 12.5 (s, 1H, NH); 11.0 (s, 1H, NH); 9.13 (t, 2H, NH2); 9.08 (s, 1H); 8.77 (s, 1H); 8.56 (s, 1H); 7.71 (m, 1H); 7.29 (s, 1H); 7.13 (m, 1H); 5.34 (s, 1H, OCH); 4.98 & 4.7 (m, 4H, azetidine); 4.33 (t, 2H, CH2); 3.75 (s, 2H, CH2CN); 3.48 (s, 1H, NCH); 2.08 (m, 2H); 1.90 (m, 21-1); 1.71 (m, 2H); 1.50 (m, 2H); 1.33 (s, 9H). LCMS calculated for C30H36F3N10O (M+H)+: m/z=609.67.

Provenance & Evidence