Potassium Phosphate, Tribasic → (R)-N-(4-(Chlorodifluoromethoxy)phenyl)-5-(5-cyano-2-fluorophenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

HRID 924156Notes

Reaction equation

HRID 924156 reaction equation
[C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7](B(O)O)[CH:8]=1)#[N:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:22]1[C:23]([N:42]2[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]2)=[N:24][CH:25]=[C:26]([CH:41]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([Cl:40])([F:39])[F:38])=[CH:32][CH:31]=1)=[O:28]>O1CCOCC1>[Cl:40][C:37]([F:38])([F:39])[O:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27](=[O:28])[C:26]2[CH:41]=[C:22]([C:7]3[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[F:12])[C:23]([N:42]3[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]3)=[N:24][CH:25]=2)=[CH:31][CH:32]=1

Participants

5

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27833615-Cyano-2-fluorobenzeneboronic acidHCID 72545856(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Product 1

HCID 89908251(R)-N-(4-(Chlorodifluoromethoxy)phenyl)-5-(5-cyano-2-fluorophenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
130 °C

Procedure

5-Cyano-2-fluorophenylboronic acid (53.5 mg, 0.324 mmol), K3PO4 (138 mg, 0.648 mmol) and PdCl2(dppf)-(CH2Cl2) (17.65 mg, 0.022 mmol) were added to (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1,) in dioxane (1.5 mL) in a vial at RT. The vial was evacuated/purged with argon, sealed and stirred at 130° C. for 2.5 h. The RM was diluted with EtOAc (60 mL), washed with an aq. sat. solution of NaHCO3 (20 mL) and brine (2×20 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated off under reduced pressure. The residue was dissolved in MeOH (3 mL), filtered through a SPE PL-Thiol cartridge (StratoSpheres™, 500 mg, nominal:1.5 mmol), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 18% to 23% in 6 min) to afford the title product as a white solid. HPLC (Condition 10) tR=6.31 min, UPLC-MS (Condition 3) tR=1.12 min, m/z=503.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-2.01 (m, 2H) 2.93 (br. s, 1H) 3.19 (dd, J=11.14, 4.11 Hz, 1H) 3.23-3.43 (m, 2H) 4.21 (br. s, 1H) 4.84 (br. s, 1H) 7.34 (d, J=8.99 Hz, 3H) 7.57 (br. s, 1H) 7.80-7.91 (m, 3H) 7.94-8.24 (m, 4H) 8.79 (d, J=1.96 Hz, 1H) 10.16 (s, 1H).

Workup

  1. customThe vial was evacuated/purged with argon
  2. customsealed
  3. additionThe RM was diluted with EtOAc (60 mL)
  4. washwashed with an aq. sat. solution of NaHCO3 (20 mL) and brine (2×20 mL)
  5. dry with materialThe organic phase was dried over Na2SO4
  6. filtrationfiltered
  7. customthe solvent was evaporated off under reduced pressure
  8. dissolutionThe residue was dissolved in MeOH (3 mL)
  9. filtrationfiltered through a SPE PL-Thiol cartridge (StratoSpheres™, 500 mg, nominal:1.5 mmol)
  10. washthe cartridge was washed with MeOH
  11. customthe solvent was evaporated off under reduced pressure
  12. customto give a residue which
  13. customwas purified by preparative SFC (Column 2-EP, from 18% to 23% in 6 min)

Sources & evidence

ORD record
ord-31dd039bf43347f5b972930d7639405f
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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