Pyridine → (S)-2-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridin-2-yl)propanamide

Participants

Reaction Conditions

Reaction Steps

A flask was charged with (S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine (Intermediate 3, 5.44 g, 17.59 mmol) and (S)-2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propanoic acid (Intermediate 8, 5.10 g, 20.23 mmol, ee: 99%), CH2Cl2 (58.6 mL) and the resulting mixture was stirred at 25° C. for 5 minutes. To the resulting yellow heterogeneous mixture was added HOAt (2.394 g, 17.59 mmol) and DCC (6.90 g, 33.4 mmol). The reaction mixture was cooled to 0° C. and pyridine (2.85 mL, 35.2 mmol) was added slowly around the edges of the flask. The reaction mixture was kept at 0° C. for 5 minutes before it was removed from the ice bath, and was then stirred at 25° C. for 3 hours. The reaction mixture was diluted with CH2Cl2 and filtered over Celite® to remove urea byproduct. The filtrate was then quickly concentrated to an oil, taken up in minimal CH2Cl2 and added dropwise to stirring hexanes to precipitate out crude (S,S)-product which was dried overnight. The product was recrystallized from CH2Cl2:MeOH (4:1) to obtain the title product (4.78 g, 8.79 mmol, 50%, de>99%); 1H NMR; 1H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.12 (s, 2H), 8.34 (s, 1H), 7.88 (dt, J=15.7, 8.1 Hz, 2H), 7.68 (d, J=8.2 Hz, 1H), 5.84 (d, J=6.7 Hz, 1H), 5.11 (p, J=7.4, 7.0 Hz, 1H), 3.83-3.61 (m, 2H), 3.46 (s, 3H), 3.19 (s, 3H), 2.33-1.96 (m, 4H), 1.87 (d, J=7.3 Hz, 3H); m/z [M+H]+=544.20.

Provenance & Evidence