Hydrochloric Acid → 4-chloro-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Participants

Reaction Conditions

Reaction Steps

To a solution of 6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol (550 mg, 0.988 mmol) in methanol (5 mL) in a microwave vial, was added potassium hydroxide (554 mg, 9.88 mmol) and then 28% ammonium hydroxide (1 mL, 0.988 mmol). The reaction was heated at 80° C. via microwave irradiation for 45 min. The reaction mixture was poured into iced water, then 4 N aq HCl was added to acidify the reaction mixture to pH=1, then NaHCO3 solid was added to neutralize reaction mixture to pH=7-8. The mixture was extracted twice with a solution of 5% trifluoroethanol in DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was dissolved in dichloroethane (3 mL), and the reaction flask was charged with phosphorus oxychloride (3.67 mL, 39.5 mmol). The reaction flask was capped and then heated to 80° C. for 1 h. The reaction mixture was cooled to r.t. and poured into ice water and diluted with acetone (10 mL). The reaction mixture was stirred for 30 min to provide a clear solution. At that point, NaHCO3 solid was added to neutralize the reaction, and the mixture was extracted twice with DCM. The resulting residue was purified via silica gel FCC (0-100% EtOAc/heptane) to provide 4-chloro-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 421.2 (M+H)+.

Provenance & Evidence