Potassium Carbonate → (R)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-cyanophenyl)thiazole-4-carboxamide

Participants

Reaction Conditions

Reaction Steps

A mixture of (R)-tert-butyl 2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (122 mg, 0.20 mmol), potassium fluoride dihydrate (62 mg, 0.66 mmol) and 2-cyanophenylboronic acid (88 mg, 0.60 mmol) in THF (3 mL) was degassed by gently bubbling nitrogen through the mixture for 15 min. Tris(dibenzylideneacetone)dipalladium/tri-tert-butyl phosphonium tetrafluoroborate mixture (mole ratio: 1/1.2) (24 mg, 0.020 mmol) was then added and the mixture degassed for a further 10 min before being heated in a microwave at 80° C. for 2 hr. Water was added and the mixture extracted with EtOAc. The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane). The isolated intermediate was dissolved in a mixture of DCM (1.5 mL) and TFA (0.5 mL) and stirred at room temperature for 4 hr. The solvents were removed under reduced pressure and the residue dissolved in MeOH/water (3 mL, 3:1) and K2CO3 (66 mg, 0.48 mmol) added. The mixture was heated at 80° C. for 6 hr. The solvents were removed under reduced pressure and the residue purified by preparative HPLC to yield 355 as an orange solid (36 mg, 51%). 1H NMR (400 MHz, d4-MeOD) δ 7.87 (d, J=7.8 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.68 (s, 1H), 7.55 (t, J=7.8 Hz, 1H), 3.75 (s, 3H), 3.40-3.26 (m, 4H), 3.18-3.10 (m, 1H), 2.05-1.86 (m, 3H), 1.87-1.67 (m, 3H). LCMS (ES+) m/z 437 (M+1).

Provenance & Evidence