反应详情

A round bottom flask was charged with (S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-amine (5.097 g, 16.43 mmol) and (S)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoic acid (Intermediate 8) (4.97 g, 19.71 mmol). The reagents were suspended in DCM (Volume: 36.5 ml, Ratio: 4), sonicated and allowed to stir for 5 minutes. To the yellow heterogenous mixture was added DCC (5.76 g, 27.9 mmol) and finally pyridine (Volume: 18.25 ml, Ratio: 2) was added and the mixture was allowed to stir for 3 hours. The reaction mixture was diluted with CH2Cl2 and filtered over Celite®. The filtrate was then concentrated and redissolved in a minimal amount of and added dropwise to stirring hexanes to precipitate out crude 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-yl)propanamide, which was dried overnight. The mixture of diasteromers was resolved using SFC purification to give the (S,S)-isomer in 2.58 g (retention time: 2.5 min, de: 98%); and the (R,S)-isomer in 0.208 g (retention time: 2.2 min, de: 99%); 1H NMR, (S,S)-isomer (300 MHz, DMSO-d6) δ 11.40 (s, 1H), 9.16 (d, J=3.5 Hz, 3H), 8.97 (s, 1H), 8.36 (s, 1H), 5.86 (d, J=7.3 Hz, 1H), 5.20-5.03 (m, 1H), 3.73 (t, J=6.5 Hz, 2H), 3.46 (s, 3H), 3.19 (s, 3H), 2.29-2.04 (m, 4H), 1.89 (d, J=7.3 Hz, 3H); m/z found [M+H]+=545.19

1. customsonicated
2. additionwas added
3. stirringto stir for 3 hours
4. filtrationfiltered over Celite®
5. concentrationThe filtrate was then concentrated
6. dissolutionredissolved in a minimal amount of and
7. additionadded dropwise
8. stirringto stirring hexanes
9. customto precipitate out crude 2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-yl)propanamide, which
10. customwas dried overnight
11. additionThe mixture of diasteromers
12. customSFC purification
13. customto give the (S,S)-isomer in 2.58 g (retention time: 2.5 min, de: 98%)