2,2,2-Trifluoroethyl trifluoromethanesulfonate → HCID 54761505, compound

HRID 929970Notes

Reaction equation

HRID 929970 reaction equation
Cl.[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:26][N:25]=3)=[CH:18][CH:17]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6].CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:54][C:55]([F:58])([F:57])[F:56])(=O)=O>CC#N>[F:2][CH2:3][C:4]([C:8]1[O:12][N:11]=[C:10]([NH:13][C:14](=[O:38])[NH:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:32][CH2:33][N:34]([CH2:54][C:55]([F:58])([F:57])[F:56])[CH2:35][CH2:36]4)=[CH:26][N:25]=3)=[CH:20][CH:21]=2)[CH:9]=1)([CH3:7])[CH2:5][F:6]

Participants

5

Reactant 3

HCID 803662,2,2-Trifluoroethyl trifluoromethanesulfonate2×HCID 81531Diisopropylethylamine2×HCID 67125929HCID 67125929, compound

Product 1

HCID 54761505HCID 54761505, compoundYield 74%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a stirred solution of N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride (50 mg, 0.091 mmol) from Step 4 of Example 17 in 3 mL of CH3CN was added DIEA (32 mL, 0.18 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (21 mg, 0.18 mmol). The resulting mixture was then stirred at rt for 1 h, heated at 85° C. for 1 h. CH3CN was then evaporated under reduced pressure and the residue was taken up in 2 mL of DMF. To the reaction mixture was then added DIEA (32 μL, 0.18 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (21 mg, 0.18 mmol), and heated at 85° C. for 2 h. LC-MS indicated that the reaction was complete. Purification by reverse phase HPLC yielded N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yloxy)picolinamide (40 mg, 74%) as a white solid. LC-MS (ESI) m/z 597 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.59 (s, 1H), 8.77 (s, 1H), 8.36 (d, J=2.83 Hz, 1H), 8.08 (d, J=8.85 Hz, 1H), 7.81 (d, J=8.85 Hz, 2H), 7.67 (dd, J=2.83, 8.85 Hz, 1H), 7.42 (d, J=8.85 Hz, 2H), 6.79 (s, 1H), 4.73 (s, 2H), 4.65 (td, J=3.93, 8.15 Hz, 1H), 4.57 (s, 2H), 3.23 (q, J=10.24 Hz, 2H), 2.80-2.96 (m, 2H), 2.62 (t, J=9.42 Hz, 2H), 1.97 (br. s., 2H), 1.60-1.76 (m, 2H), 1.34 (s, 3H).

Workup

  1. temperatureheated at 85° C. for 1 h
  2. customCH3CN was then evaporated under reduced pressure
  3. customPurification by reverse phase HPLC

Sources & evidence

ORD record
ord-877edef58f1643ed973b300e1fefd2e4
Source dataset
uspto-grants-2016_03
Patent number
US09296722B2

Reaction notes

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