Formaldehyde → (S)-N-((methylthio)methyl)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine

Participants

Reaction Conditions

Reaction Steps

A 350 mL pressure vessel was charged with (S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine (Intermediate 3, 10 g, 32.3 mmol) and sodium methanethiolate (4.53 g, 64.7 mmol), which were dissolved in a mixture of THF (64.7 mL) and water (43.1 mL). Aqueous 37% formaldehyde (5.25 mL, 64.7 mmol) was added and the reaction mixture was heated to 90° C. for 2 hours. Another 2 eq. of aqueous 37% formaldehyde were added and the reaction mixture was heated for an additional 2 hours. The reaction mixture was then cooled to 25° C. The layers were separated in the separatory funnel and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified using silica gel chromatography, eluting with EtOAc:Hex (30:70) to yield 9 g (24.36 mmol, 75%) of the title product as an oil; 1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 2H), 7.56-7.43 (m, 1H), 7.41 (t, J=6.6 Hz, 1H), 7.13 (d, J=7.3 Hz, 1H), 6.51 (d, J=8.2 Hz, 1H), 5.18-4.98 (m, 1H), 4.59 (d, J=6.7 Hz, 2H), 3.69 (dd, J=10.3, 4.9 Hz, 2H), 2.21-2.0 (m, 4H), 2.12 (s, 3H); m/z found [M+H]+=370.35.

Provenance & Evidence