Trifluoroacetic acid → 6-(1-Amino-3-azabicyclo[3.1.0]hexan-3-yl)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 525694Notes

Reaction equation

HRID 525694 reaction equation
CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[N:35](C3CCCCO3)[N:34]=[CH:33][CH:32]=2)=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.[C:42]12([NH:48]C(=O)OC(C)(C)C)[CH2:47][CH:46]1[CH2:45][NH:44][CH2:43]2.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.CCOC(C)=O.C(Cl)Cl>[NH2:48][C:42]12[CH2:47][CH:46]1[CH2:45][N:44]([C:11]1[C:30]([C:31]3[NH:35][N:34]=[CH:33][CH:32]=3)=[CH:29][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=3)=[O:16])=[CH:13][N:12]=1)[CH2:43]2

Participants

9

Reactant 5

HCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 81531DiisopropylethylamineHCID 21256582Carbamic acid, 3-azabicyclo[3.1.0]hex-1-YL-, 1,1-dimethylethyl esterHCID 899080896-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 1180449656-(1-Amino-3-azabicyclo[3.1.0]hexan-3-yl)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 3

HCID 3776IsopropanolSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
140 °C

Procedure

DIPEA (96 μL, 0.55 mmol) was added to a mixture of 6-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 32.1, 117 mg, 0.25 mmol) and (tert-butyl 3-azabicyclo[3.1.0]hexan-1-ylcarbamate, 59.2 mg, 1.2 mmol) in iPrOH (250 μL) in a vial, which was sealed and the RM mixture was stirred at 140° C. for 18 h. After cooling at RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in DCM (1 mL), cooled to 0° C., treated with TFA (0.45 mL, 5.85 mmol) and was stirred at RT for 3 h. The RM was poured into 10% aq. Na2CO3 (10 mL) and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC (Column 2-EP, from 22% to 27% in 6 min) to afford the title compound as an amorphous white powder. HPLC (Condition 4) tR=4.2 min, UPLC-MS (Condition 3) tR=0.76 min, m/z=445.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.56-0.71 (m, 1H) 0.96-1.10 (m, 1H) 1.61-1.79 (m, 1H) 2.26 (s, 1H) 3.22-3.37 (m, 1H) 3.44 (d, J=1.00 Hz, 1H) 3.70 (d, J=1.00 Hz, 1H) 6.40 (d, J=1.56 Hz, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.84 (d, J=8.99 Hz, 3H) 8.07 (d, J=2.35 Hz, 1H) 8.71 (br. s, 1H) 10.24 (s, 1H) 13.00 (br. s, 1H).

Workup

  1. customwas sealed
  2. temperatureAfter cooling at RT
  3. washwashed with brine
  4. dry with materialdried over Na2SO4
  5. customthe solvent was evaporated off under reduced pressure
  6. customto give a residue which
  7. temperaturecooled to 0° C.
  8. stirringwas stirred at RT for 3 h
  9. extractionextracted with EtOAc
  10. dry with materialThe combined extracts were dried over Na2SO4
  11. customthe solvent was evaporated off under reduced pressure
  12. customto give a crude product which
  13. customwas purified by preparative SFC (Column 2-EP, from 22% to 27% in 6 min)

Sources & evidence

ORD record
ord-8c179f7d2cbd43dfabb826abc7267b34
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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