Acetone → HCID 54761506, compound

HRID 929971Notes

Reaction equation

HRID 929971 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].[CH3:39][C:40]([CH3:42])=O.[BH3-]C#N.[Na+]>CO.CC([O-])=O.[Na+]>[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]([CH:40]([CH3:42])[CH3:39])[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 180AcetoneHCID 5003444Sodium cyanoborohydrideHCID 67125929HCID 67125929, compound

Product 1

HCID 54761506HCID 54761506, compoundYield 31%

Reagents, catalysts & solvents 1

HCID 23696304HCID 23696304, compoundSolvent

Conditions

Temperature
80 °C

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 (65 mg, 0.12 mmol) in 2 mL of pH˜4 MeOH/NaOAc buffer was added acetone (0.3 mL, excess) and NaCNBH3 (25 mg, excess). The resulting mixture was reflux at 80° C. for 3 h. LC-MS indicated that the reaction was 50% complete. The reaction was cooled to rt and the crude product was purified by reverse phase HPLC to give N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(1-isopropylpiperidin-4-yloxy)picolinamide as a white solid (20 mg, 31% yield). LC-MS (ESI) m/z 557 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.83 (br. s., 1H), 9.03 (br. s., 1H), 8.35 (d, J=2.83 Hz, 1H), 8.08 (d, J=8.67 Hz, 1H), 7.81 (d, J=9.04 Hz, 2H), 7.65 (dd, J=2.73, 8.76 Hz, 1H), 7.43 (d, J=9.04 Hz, 2H), 6.79 (s, 1H), 4.73 (s, 2H), 4.57 (s, 3H), 2.73 (d, J=6.40 Hz, 3H), 2.23-2.45 (m, 2H), 1.99 (br. s., 2H), 1.53-1.73 (m, 2H), 1.34 (s, 3H), 0.98 (d, J=6.59 Hz, 6H).

Workup

  1. temperatureThe reaction was cooled to rt
  2. customthe crude product was purified by reverse phase HPLC

Sources & evidence

ORD record
ord-4d430c2a69984a7abd3d8cf97e3b4256
Source dataset
uspto-grants-2016_03
Patent number
US09296722B2

Reaction notes

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