66% |
With caesium carbonate; In N,N-dimethyl acetamide; at 70℃; |
Compounds 109- 115 were prepared according to the following synthetic scheme:A mixture of l-(5-((4-(((7R,8aS)-5,5-dimethyloctahydroindolizin-7- yl)amino)-5-fluoropyrimidin-2-yl)amino)-4-fluoro-2-hydroxyphenyl)-4-methyl-l,4-dihydro- 5H-tetrazol-5-one (0.16g, l.Oeq, 0.35mmol), iodooxetane (0.2g, 3.0eq, l.OOmmol) and CS2CO3 (0.12g, l.leq, 0.36 mmol) was taken in DMA (lOmL). The reaction mixture was heated at 70C and stirred overnight. After the completion of the reaction the crude mixture was diluted with EtOAc (50 mL) and partitioned with H20 (50 mL). The layers were seperated and the aqueous layer was washed with EtOAc (2 x 50mL). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure to leave a crude oil. The crude mixture was purified by column chromatography on silica gel (ISCO System) using 2M NH3 in MeOH / CH2C12 (gradient system from 0: 1 to 1:9) as eluent to give the product as a solid. [00757] l-(5-((4-(((7/?,8a5)-5,5-dimethyloctahydroindolizin-7-yl)amino)-5- fluoropyrimidin-2-yl)amino)-4-fluoro-2-(((/i)-tetrahydrofuran-3-yl)oxy)phenyl)-4- methyl-l,4-dihydro-5H-tetrazol-5-one (Compound 109): Yield = 66%, 1H NMR (300 MHz, -DMSO) δ 8.41 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 3.8 Hz, 1H), 7.24 (dd, J = 27.0, 9.9 Hz, 2H), 5.07 (s, 1H), 3.96 (s, 1H), 3.83 (dd, J = 10.2, 4.5 Hz, 1H), 3.67 (ddd, J = 18.9, 9.7, 4.4 Hz, 3H), 3.30 (d, J = 0.6 Hz, 3H), 2.81 (s, 1H), 2.30 - 1.99 (m, 3H), 2.02 - 1.76 (m, 2H), 1.76 - 1.45 (m, 5H), 1.38 (t, J = 12.1 Hz, 1H), 1.17 (s, 1H), 1.03 (s, 3H), 0.76 (s, 3H); 19F NMR (282 MHz 6-DMSO) δ -116.0 (s), -166.9 (d); LCMS (m/z): 558 (M+H)+ |