Trifluoroacetic acid → (R)-N-(4-(Chlorodifluoromethoxy)phenyl)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

HRID 73794Notes

Reaction equation

HRID 73794 reaction equation
C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[C:9]([N:28]2[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]2)=[N:10][CH:11]=[C:12]([CH:27]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([Cl:26])([F:25])[F:24])=[CH:18][CH:17]=1)=[O:14].O1CCCCC1[O:40][CH2:41][CH2:42][N:43]1[CH:47]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:45]=[N:44]1.C(O)(C(F)(F)F)=O>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:26][C:23]([F:25])([F:24])[O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:27]=[C:8]([C:46]3[CH:45]=[N:44][N:43]([CH2:42][CH2:41][OH:40])[CH:47]=3)[C:9]([N:28]3[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29]3)=[N:10][CH:11]=2)=[CH:17][CH:18]=1

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 10340Sodium Carbonate2×HCID 593418191-[2-(oxan-2-yloxy)ethyl]-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 72545856(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Product 1

HCID 86702627(R)-N-(4-(Chlorodifluoromethoxy)phenyl)-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

2M Na2CO3 (0.375 mL, 0.75 mmol) was added to a solution of (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 9.2, 116 mg, 0.25 mmol) and 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (161 mg, 0.5 mmol) in DME (1.0 mL). under an argon atmosphere. PdCl2(dppf) (9.15 mg, 0.013 mmol) was then added and the RM mixture was stirred at 100° C. for 2 h. After cooling at RT, the RM was dissolved in EtOAc and washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude product was dissolved in DCM (1.4 mL) cooled to 0° C., then treated with TFA (0.77 mL, 10 mmol) and stirred at RT for 3 h. The RM was poured into aq. Na2CO3 10% (15 mL) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH, from 2% to 10% MeOH) to afford an off-white powder. HPLC (Condition 4) tR=4.33 min, UPLC-MS (Condition 3) tR=0.88 min, m/z=494 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.88 (m, 2H) 2.96 (d, J=11.73 Hz, 0H) 3.24-3.37 (m, 2H) 3.41-3.53 (m, 1H) 3.75 (q, J=5.73 Hz, 2H) 4.04-4.25 (m, 4H) 4.81 (d, J=3.52 Hz, 1H) 4.86-4.94 (m, 1H) 7.31 (d, J=8.21 Hz, 2H) 7.53-7.59 (m, 1H) 7.79-7.89 (m, 3H) 7.93 (d, J=2.35 Hz, 1H) 8.65 (dd, J=2.35, 0.78 Hz, 1H) 10.15 (s, 1H).

Workup

  1. temperatureAfter cooling at RT
  2. washwashed with brine
  3. dry with materialdried over Na2SO4
  4. customthe solvent was evaporated off under reduced pressure
  5. dissolutionThe crude product was dissolved in DCM (1.4 mL)
  6. temperaturecooled to 0° C.
  7. stirringstirred at RT for 3 h
  8. extractionextracted with EtOAc
  9. dry with materialThe combined extracts were dried over Na2SO4
  10. customthe solvent was evaporated off under reduced pressure

Sources & evidence

ORD record
ord-53b61a100a984d2e9e664d48bbd9ba93
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Reaction notes

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