Potassium Phosphate, Tribasic → HCID 67959665, compound

HRID 1529391Notes

Reaction equation

Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[CH3:39][N:40]1[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH:42]=[N:41]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:39][N:40]1[C:44]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]2[N:22]=[C:21]([O:23][C@H:24]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]43[CH2:27][CH2:26]4)[CH:20]=[N:19][CH:18]=2)=[CH:43][CH:42]=[N:41]1

Participants

Conditions

Temperature: 150 °C

Procedure

(4R)-tert-Butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (158 mg, 0.270 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Aldrich, St. Louis, Mo.; 84 mg, 0.405 mmol), PdCl2(Amphos) (Aldrich, St. Louis, Mo.; 19.14 mg, 0.027 mmol), and potassium phosphate (172 mg, 0.811 mmol) in a mixture of dioxane (2.5 mL) and water (0.250 mL) was heated by microwave at 150° C. for 5 min. The resulting mixture was heated at 100° C. for 3 h. The mixture was subsequently concentrated onto silica gel and chromatographically purified (ISCO, 12 g silica gel column, 0-80% EtOAc/hexanes, 15 min, 254 nm) to provide (4R)-tert-butyl 4-(6-(5-(1-methyl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (158 mg, 0.270 mmol, 100% yield) as a light-yellow oil: 1H NMR (400 MHz, CDCl3) δ ppm 9.06 (1 H, s), 8.43 (1 H, s), 8.21 (1H, br. s.), 7.76 (1 H, d, J=8.6 Hz), 7.58 (1 H, s), 7.49 (1 H, d, J=8.4 Hz), 6.33 (1H, s), 5.86 (1 H, d, J=7.6 Hz), 4.57 (1 H, br. s.), 4.31-4.40 (1 H, m), 4.19-4.29 (1 H, m), 4.06 (1 H, d, J=11.0 Hz), 3.93 (3 H, s), 3.75-3.87 (1 H, m), 3.15 (1 H, d, J=14.1 Hz), 2.92 (1 H, br. s.), 2.60-2.74 (1 H, m), 2.43 (1 H, br. s.), 2.25 (1 H, m, J=9.0, 4.1 Hz), 2.17 (1 H, d, J=14.9 Hz), 1.76-1.91 (2 H, m), 1.74 (2 H, br. s.), 1.13 (9 H, br. s.), 0.78-0.88 (2 H, m), 0.62-0.73 (2 H, m). MS (ESI, pos. ion) m/z: 586.4 (M+1).

Workup

temperatureThe resulting mixture was heated at 100° C. for 3 h
concentrationThe mixture was subsequently concentrated onto silica gel
customchromatographically purified (ISCO, 12 g silica gel column, 0-80% EtOAc/hexanes, 15 min, 254 nm)

Sources & evidence

ORD record: ord-8f1a49cedea94621aa947260fd41e552
Source dataset: uspto-grants-2015_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09090593B2

Reaction notes

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