反应详情

Example 86 (Isomers 1, 2 and 3): To a solution of 3.6 M HCl in MeOH/MeOAc (326 μL, 1.174 mmol) was added to 2-(1-(4-((1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-ethyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile (37 mg, 0.069 mmol) and the reaction stirred at rt for 48 h. The reaction mixture was diluted with acetonitrile and was evaporated to remove methanol and acetonitrile. The residue was dissolved in ethyl acetate and washed with a saturated aqueous NaHCO3 (2×100 mL), water, and brine. The organic layer was then dried (Na2SO4), filtered, and concentrated. The residue was dissolved in THF (124 μl) and water (13 μl) at rt was added 2M LiOH (345 μl, 0.69 mmol). The reaction mixture was stirred at rt for 1 h and LCMS showed no starting material. Then, 3N HCl (0.4 mL) was added at 0° C. and warmed up to rt. The solvent was evaporated and the residue was dissolved in CH3CN, filtered. Purification by RP-Prep HPLC afforded a diastereomeric mixture. The diastereomers were separated by chiral Prep. SFC to provide Example 86, Isomers 1, 2 and 3 as single stereoisomers, prepared following the procedure for Example 81. Example 86, Isomer 1 (off-white solid, 5 mg): LC-MS Anal. Calc'd for C26H30ClF3N4O4 554.19. found [M+H] 555.1. 1H NMR (400 MHz, CD3CN) δ ppm 8.00 (s, 1H), 7.13-7.06 (m, 2H), 7.02-6.94 (m, 2H), 6.38 (s, 1H), 4.60 (d, J=9.3 Hz, 1H), 4.01 (td, J=8.9, 4.3 Hz, 1H), 3.87 (s, 3H), 3.59-3.50 (m, 2H), 3.31 (dd, J=3.5, 2.3 Hz, 1H), 2.97-2.87 (m, 1H), 2.76-2.66 (m, 2H), 2.52 (dd, J=16.2, 9.4 Hz, 1H), 2.25-2.16 (m, 1H), 2.10-2.02 (m, 1H), 1.79-1.58 (m, 4H), 1.12 (d, J=6.8 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H). HPLC (Orthogonal method, 30% Solvent B start): RT=12.5 min, HI: 98%. hGPR40 EC50=73 nM. Example 86, Isomer 2 (off-white solid, 5 mg): LC-MS Anal. Calc'd for C26H30ClF3N4O4 554.19. found [M+H] 555.1. 1H NMR (400 MHz, CD3CN) δ ppm 7.89 (s, 1H), 7.01-6.94 (m, 2H), 6.91-6.83 (m, 2H), 6.27 (s, 1H), 4.49 (d, J=9.3 Hz, 1H), 3.89 (td, J=8.9, 4.2 Hz, 1H), 3.76 (s, 3H), 3.51-3.39 (m, 2H), 3.20 (dd, J=3.7, 2.1 Hz, 1H), 2.86-2.78 (m, 1H), 2.64-2.54 (m, 2H), 2.41 (dd, J=16.3, 9.5 Hz, 1H), 2.14-2.06 (m, 1H), 1.96 (dd, J=12.4, 5.8 Hz, 1H), 1.71-1.48 (m, 3H), 1.01 (d, J=6.6 Hz, 3H), 0.87-0.80 (m, 3H). HPLC (Orthogonal method, 30% Solvent B start): RT=12.5 min, HI: 96%. hGPR40 EC50=599 nM. Example 86, Isomer 3 (off-white solid, 5 mg): LC-MS Anal. Calc'd for C26H30ClF3N4O4 554.19. found [M+H] 555.1. 1H NMR (400 MHz, CD3CN) δ ppm 8.00 (s, 1H), 7.13-7.06 (m, 2H), 7.01-6.92 (m, 2H), 6.38 (s, 1H), 4.60 (d, J=9.8 Hz, 1H), 4.01 (td, J=8.8, 4.1 Hz, 1H), 3.87 (s, 3H), 3.60-3.50 (m, 2H), 3.31 (dd, J=3.5, 2.0 Hz, 1H), 2.97-2.86 (m, 1H), 2.75-2.65 (m, 2H), 2.52 (dd, J=16.3, 9.3 Hz, 1H), 2.25-2.17 (m, 1H), 2.07 (d, J=6.5 Hz, 1H), 1.81-1.59 (m, 3H), 1.12 (d, J=6.5 Hz, 3H), 0.95 (t, J=7.5 Hz, 3H). HPLC (Orthogonal method, 30% Solvent B start): RT=12.5 min, HI: 95%. hGPR40 EC50=1932 nM.

1. customwas evaporated
2. customto remove methanol and acetonitrile
3. dissolutionThe residue was dissolved in ethyl acetate
4. washwashed with a saturated aqueous NaHCO3 (2×100 mL), water, and brine
5. dry with materialThe organic layer was then dried (Na2SO4)
6. filtrationfiltered
7. concentrationconcentrated
8. dissolutionThe residue was dissolved in THF (124 μl)
9. stirringThe reaction mixture was stirred at rt for 1 h
10. temperaturewarmed up to rt
11. customThe solvent was evaporated
12. dissolutionthe residue was dissolved in CH3CN
13. filtrationfiltered
14. customPurification by RP-Prep HPLC
15. customafforded a diastereomeric mixture
16. customThe diastereomers were separated by chiral Prep
17. customSFC to provide Example 86, Isomers 1, 2 and 3 as single stereoisomers
18. customprepared