Potassium Carbonate → HCID 86640819, compound

Participants

Reaction Conditions

Reaction Steps

N-(2-(methoxymethyl)-1H-benzo[d]imidazol-6-yl)-5-((tetrahydro-2H-pyran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine. To a mixture of tris(dibenzylideneacetone)dipalladium(0) (0.077 g, 0.084 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.098 g, 0.169 mmol) in 1,4-dioxane (10 mL) was added 2-(methoxymethyl)-1-tosyl-1H-benzo[d]imidazol-5-amine (0.280 g, 0.844 mmol), 2-bromo-5-((tetrahydro-2H-pyran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine (0.25 g, 0.844 mmol) and finely ground potassium carbonate (0.35 g, 2.53 mmol) in a sealable vessel with a stir bar. Nitrogen was blown in to blow out air. The resulting mixture was sealed, stirred, and heated at 120° C. LCMS after 3 h shows complete conversion to desired product. The resulting mixture was filtered. Saturated aqueous sodium bicarbonate was added and extracted with ethyl acetate (2×100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator to dryness and purified using reverse-phase preparatory HPLC (eluting with 20-70% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 39 min). Fractions containing the desired product were concentrated on a rotary evaporator and aqueous hydrochloric acid (25 mL, 6M) was added and heated to 70° C. overnight. The solvent was removed on a rotary evaporator and purified using reverse-phase semi-preparatory HPLC (eluting with 5-40% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 39 min). Fractions containing the desired product were loaded onto a Strata X—C ion exchange column from Phenomenex. The column was washed successively with water, acetonitrile, methanol, and then hot 10% ammonium hydroxide in methanol. The product eluted with the 10% ammonium hydroxide in methanol and was concentrated on a rotary evaporator to dryness. This material was crystallized from 20% ethyl acetate in hexane and dried under high vacuum at 40° C. to give the desired product as a white solid (0.130 g, 0.331 mmol, 39.2% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.30 (br s, 1H), 9.56 (br s, 1H), 8.14 (s, 1H), 7.30-7.55 (m, 4H), 6.89 (d, J=5.86 Hz, 1H), 4.58 (s, 2H), 3.84 (dd, J=11.32, 2.73 Hz, 2H), 3.36 (s, 3H), 3.26 (t, J=10.93 Hz, 2H), 3.06 (d, J=7.03 Hz, 2H), 2.19-2.36 (m, 1H), 1.54 (d, J=11.32 Hz, 2H), 1.29-1.45 (m, 2H); MS (ESI) m/z 393.2 [M+1]+.

Provenance & Evidence