Acetic Acid → Ammonia methanol

Participants

Reaction Steps

Combine N-(6-amino-pyridin-2-yl)-2,4,6-trifluoro-benzamide (Preparation 43, 668 mg, 2.5 mmol), 1-methyl-4-piperidone (566 mg, 5.0 mmol), acetic acid (450 mg, 0.43 mL, 7.5 mmol), molecular sieves 4 Å (1 g) and 1,2-dichloroethane, stir for 30 min at room temperature, then add sodium triacetoxyborohydride (1.325 g, 6.25 mmol) portionwise. Add another batch of 1-methyl-piperidone (566 mg, 5.0 mmol) and sodium triacetoxyborohydride (1.325 g, 6.25 mmol) if starting benzamide is still present after overnight reaction. Quench the reaction with 0.1N NaOH solution. Extract the mixture with ethylacetate three times. Combine organic layers, dry over Na2SO4, filter and concentrate to afford a residue. Chromatography (silica gel, 4% 2M NH3-methanol in CH2Cl2) provides 571 mg (63%) of the free base of the title compound. Dilute the free base in CH2Cl2 (1 mL), add 1M HCl/Et2O (5.6 mL, 5.6 mmol), remove the supernatant, wash the white solid with ether four times and dry in vacuum oven to afford 600 mg (88%) of the free base of the title compound. Using a salt formation method similar to that described in Example 53 gives the title compound: Free base: mass spectrum (ion spray): m/z=365.0 (M+1); 1H NMR (CDCl3, ppm): 8.50 (1H, s), 7.49 (m, 2H), 6.70 (m, 2H), 6.14 (d, 1H), 4.38 (d, 1H), 3.48 (m, 1H), 2.78 (m, 2H), 2.28 (s, 3H), 2.05 (m, 4H), 1.51 (m, 2H). Di-hydrochloride salt: Anal calc'd for C18H19F3N4O.2HCl: C, 49.44; H, 4.84; N, 12.81. Found: C, 49.31; H, 4.96; N, 12.49.

Provenance & Evidence