Hydrochloric Acid → HCID 57891190, compound

Participants

Reaction Conditions

Reaction Steps

At −78° C., CH3CN in THF (1505 uL, 28.82 mmoL) was added dropwise to n-BuLi (2.5 M in hexane, 11.52 mL) in THF (40 mL). After stirring at −78° C. for 1 h, tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (Int-12a, 3708 mg, 14.41 mmoL) in THF (10 mL) was added dropwise in 5 min. The mixture was stirred at −78° C. for 1 h and −45° C. for 1 h. At 0° C., 1N HCl was added carefully to adjust the pH to about 7. The mixture was then extracted with ethyl acetate (x2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation afforded tert-butyl-4-(3-cyano-2-oxopropyl)piperidine-1-carboxylate (Int-12b) which was then heated at 100° C. overnight with 1H-pyrazol-5-amine (1197 mg, 14.41 mmoL) in HOAc (25 mL). Concentration provided crude tert-butyl 4-((7-aminopyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (Int-12c) which was treated with SEMCl (72.05 mmoL, 12.71 mL) and DIEA (144.4 mmoL, 25.05 mL) in DCE (100 mL) at 50° C. for 1 h. The mixture was diluted with H2O and then extracted with CH2Cl2 (x2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (Int-12d): LCMS tR=3.05 Min (5 min run, UV254nm). Mass calculated for, M+591.3, observed m/z 592.3 (M+H).

Provenance & Evidence