Water → (R)-2-(3-Hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-5'-(trifluoromethyl)-[3,3'-bipyridine]-5-carboxamide

HRID 924107Notes

Reaction equation

HRID 924107 reaction equation
Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][CH:35]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1

Participants

6

Reactant 4

HCID 962Water2×HCID 10796Cesium carbonateHCID 45158900[5-(Trifluoromethyl)pyridin-3-yl]boronic acidHCID 86702593(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 118195307(R)-2-(3-Hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-5'-(trifluoromethyl)-[3,3'-bipyridine]-5-carboxamide

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
65 °C

Procedure

A mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 112 mg, 0.25 mmol), (5-(trifluoromethyl)pyridin-3-yl)boronic acid (71.6 mg, 0.375 mmol) and Cs2CO3 (163 mg, 0.5 mmol) in degassed dioxane (3 mL) in a MW vial was evacuated/purged with argon. PdCl2(dppf)-(CH2Cl2) (20.42 mg, 0.025 mmol) was added and the vial sealed. Water (0.6 mL) was added and the RM was stirred at 65° C. for 3.5 h. The solvent was evaporated off under reduced pressure to give a residue that was treated with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over MgSO4/charcoal, filtered and the filtrate was evaporated off under reduced pressure to give a residue that was purified by flash chromatography (Silica gel column, 25 g, EtOAc). Palladium was removed using a SPE PL-Thiol MP cartridge (StratoSpheres™). The residue was dissolved in EtOAc and n-heptane was added. The solution was concentrated under reduced and the resulting suspension was stirred and filtered. The solid was washed with n-hexane then dried under HV at 45° C. to afford the title product as an amorphous white powder. UPLC-MS (Condition 3), tR=1.09 min, m/z=513.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.69-1.78 (m, 1H) 1.80-1.89 (m, 1H) 2.85 (d, J=10.92 Hz, 1H) 3.13-3.26 (m, 2H) 3.27-3.40 (m, 1H) 4.20 (br. s, 1H) 4.88 (br. s, 1H) 7.36 (d, J=8.66 Hz, 2H) 7.85 (d, J=8.85 Hz, 2H) 8.11 (s, 1H) 8.27 (br. s, 1H) 8.79 (s, 1H) 8.93 (s, 1H) 8.99 (s, 1H) 10.19 (s, 1H).

Workup

  1. customwas evacuated/purged with argon
  2. customThe solvent was evaporated off under reduced pressure
  3. customto give a residue that
  4. extractionextracted with EtOAc
  5. washThe combined extracts were washed with water and brine
  6. dry with materialdried over MgSO4/charcoal
  7. filtrationfiltered
  8. customthe filtrate was evaporated off under reduced pressure
  9. customto give a residue that
  10. customwas purified by flash chromatography (Silica gel column, 25 g, EtOAc)
  11. customPalladium was removed
  12. dissolutionThe residue was dissolved in EtOAc
  13. additionn-heptane was added
  14. concentrationThe solution was concentrated
  15. stirringthe resulting suspension was stirred
  16. filtrationfiltered
  17. washThe solid was washed with n-hexane
  18. customthen dried under HV at 45° C.

Sources & evidence

ORD record
ord-17b4e0acd07d4886af54957fe9047b32
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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