Potassium Carbonate → N-(4-(Chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)-6-((tetrahydro-2 h-pyran-4-yl)oxy)nicotinamide

HRID 629110Notes

Reaction equation

[O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.Cl[C:9]1[C:28]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[CH:27][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([Cl:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[O:14])=[CH:11][N:10]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:26][C:23]([F:24])([F:25])[O:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:27]=[C:28]([C:29]3[CH:34]=[N:33][CH:32]=[N:31][CH:30]=3)[C:9]([O:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[N:10][CH:11]=2)=[CH:21][CH:20]=1

Participants

Conditions

Temperature: 120 °C

Procedure

Tetrahydro-2H-pyran-4-ol (0.105 mL, 1.095 mmol) was added to a stirred mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide (Example 76, 100 mg, 0.243 mmol) and K2CO3 (201.6 mg, 1.458 mmol) in MeCN (1 mL) and the RM was stirred at 110-130° C. for 26 h. The solvent was evaporated off under reduced pressure and the crude product was purified by SFC (Column 2-EP; gradient 9% to 19% in 6 min.) and lyophilized in water/MeCN (minimum volume) to give the title compound. UPLC-MS (Condition 2) tR=1.09 min, m/z=477.0/479.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.76 (m, 2H) 1.98-2.11 (m, 2H) 3.48-3.60 (m, 2H) 3.70-3.82 (m, 2H) 5.37-5.49 (m, 1H) 7.38 (d, J=9.16 Hz, 2H) 7.88 (d, J=9.00 Hz, 2H) 8.50 (d, J=2.38 Hz, 1H) 8.83 (d, J=2.51 Hz, 1H) 9.16 (s, 2H) 9.23 (s, 1H) 10.45 (s, 1H).

Workup

customThe solvent was evaporated off under reduced pressure
customthe crude product was purified by SFC (Column 2-EP; gradient 9% to 19% in 6 min.)

Sources & evidence

ORD record: ord-a8323be6be7542a794bd034585ee8db7
Source dataset: uspto-grants-2016_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09315489B2

Reaction notes

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