反应详情

To a round bottom flask charged with N-(pyrimidin-4-yl)-5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide (EXAMPLE 48, 167.0 mg, 0.327 mmol) was added MeOH (3271 μl), then formaldehyde (265 μl, 3.27 mmol). The solution was maintained at rt for 15 min, then sodium triacetoxyhydroborate (693 mg, 3.27 mmol) was added portionwise. After 10 min, the reaction mixture was partitioned between ice and saturated NaHCO3 and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (1×25 mL). The combined organic extracts were washed with brine (1×20 mL) and dried over Na2SO4 and concentrated under a vacuum. The residue was taken up in minimal MeOH and purified by reverse phase preparative HPLC (20 to 80% CH3CN:H2O (1% TFA modifier) over 15 min). Clean fractions were combined and concentrated to afford 5-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide 2,2,2-trifluoroacetate (190 mg, 0.298 mmol) as a off-white amorphous solid. 1H NMR (400 MHz, MeOH) δ ppm 1.98-2.47 (m, 2H) 2.49-2.90 (m, 4H) 3.08-3.28 (m, 1H) 3.37-3.58 (m, 1H) 3.64-3.90 (m, 1H) 5.68 (d, J=8.51 Hz, 1H) 7.16 (dd, J=6.36, 0.98 Hz, 1H) 7.54 (d, J=8.02 Hz, 1H) 7.58-7.69 (m, 2H) 7.70-7.85 (m, 3H) 7.94 (d, J=8.61 Hz, 1H) 8.18 (d, J=8.31 Hz, 1H) 8.30 (d, J=6.36 Hz, 1H) 8.60 (s, 1H) 8.72 (d, J=1.37 Hz, 1H); m/z (ESI, +ve ion) 525.2 (M+H)+.

1. customthe reaction mixture was partitioned between ice and saturated NaHCO3 and EtOAc
2. customThe layers were separated
3. extractionthe aqueous layer was extracted with EtOAc (1×25 mL)
4. washThe combined organic extracts were washed with brine (1×20 mL)
5. dry with materialdried over Na2SO4
6. concentrationconcentrated under a vacuum
7. custompurified by reverse phase preparative HPLC (20 to 80% CH3CN:H2O (1% TFA modifier) over 15 min)
8. concentrationconcentrated