Hydrochloric Acid → 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)acetic acid

HRID 2278688Notes

Reaction equation

HRID 2278688 reaction equation
Cl.CO.C[O:5][C:6]([CH3:8])=[O:7].[Cl:9][C:10]1[C:11]([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH:35](CC#N)[CH:34]([CH2:39][CH3:40])[C:33]([C:41]([F:44])([F:43])[F:42])=[N:32]4)=[CH:27][CH:26]=3)[CH:20]([CH3:45])[CH2:19]2)=[CH:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=1.[Li+].[OH-].I>C(#N)C.O>[Cl:9][C:10]1[C:11]([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH:35]([CH2:8][C:6]([OH:5])=[O:7])[CH:34]([CH2:39][CH3:40])[C:33]([C:41]([F:44])([F:42])[F:43])=[N:32]4)=[CH:27][CH:26]=3)[CH:20]([CH3:45])[CH2:19]2)=[CH:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=1

Participants

8

Reactant 5

HCID 313Hydrochloric Acid2×HCID 3939Lithium HydroxideHCID 24841Hydrogen iodide3×HCID 11389366Methyl acetate methanolHCID 867194262-(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

Product 1

HCID 901516572-(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)acetic acid

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-5087d2e0abe34efd823fe259c13e14bb
Source dataset
uspto-grants-2015_09
Patent number
US09133163B2

Reaction notes

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