Acetic Acid → HCID 86709786, compound

HRID 1529399Notes

Reaction equation

HRID 1529399 reaction equation
[N+](=[CH2:3])=[N-].[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20])=[CH:16][CH:17]=2)[C:12]([C:25]2[N:30]=[C:29]([O:31][C@H:32]3[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37][CH2:36][C:33]43[CH2:35][CH2:34]4)[CH:28]=[N:27][CH:26]=2)=[N:11]1.CC(O)=O>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3([C:21]([F:24])([F:22])[F:23])[CH2:3][CH2:20]3)=[CH:16][CH:17]=2)[C:12]([C:25]2[N:30]=[C:29]([O:31][C@H:32]3[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37][CH2:36][C:33]43[CH2:35][CH2:34]4)[CH:28]=[N:27][CH:26]=2)=[N:11]1

Participants

6

Reactant 3

HCID 176Acetic AcidHCID 9550Diazomethane4×HCID 67959857HCID 67959857, compound

Product 1

HCID 86709786HCID 86709786, compoundYield 59%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Diazomethane (˜0.25M in Et2O (prepared according to Aldrich Technical Bulletin AL-180, Aldrich, St. Louis, Mo.); 1.0 mL, 0.250 mmol) was added (dropwise) to a solution of (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(3,3,3-trifluoroprop-1-en-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (41.8 mg, 0.070 mmol) and palladium(II) acetate (1.565 mg, 6.97 μmol) in DCM (1.0 mL) at 0° C., and the resulting solution was stirred at 0° C. for 30 min. Additional diazomethane (˜0.25M in Et2O; 2.0 mL, 0.500 mmol) was added, and the resulting solution was stirred at 0° C. for 30 min. Additional palladium(II) acetate (4.54 mg, 0.020 mmol) and diazomethane (˜0.25M in Et2O; 2×2.0 mL, 2×0.500 mmol) were sequentially added, and the reaction was stirred at 0° C. for 5 min. Additional diazomethane (˜0.25M in Et2O; 2.0 mL, 0.500 mmol) was added, the reaction was stirred at 0° C. for 5 min. HOAc (0.160 mL, 2.79 mmol) was added to quench excess diazomethane, and the resulting mixture was stirred at 25° C. for 12 h. The mixture was concentrated onto silica gel and chromatographically purified (ISCO, 12 g silica gel column, 0-60% EtOAc/hexanes, 15 min, 254 nm) to provide (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (25.2 mg, 0.041 mmol, 59% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 9.03 (1 H, s), 8.52 (1 H, s), 8.21 (1 H, br. s.), 7.63 (1 H, s), 7.53 (1 H, d, J=8.8 Hz), 5.80 (1 H, d, J=9.0 Hz), 4.69 (1 H, d, J=11.5 Hz), 4.44 (1 H, br. s.), 4.24-4.36 (1 H, m), 4.03 (1 H, d, J=11.5 Hz), 3.71-3.84 (1 H, m), 3.24 (1 H, d, J=14.7 Hz), 2.88-3.03 (1 H, m), 2.56-2.71 (1 H, m), 2.42-2.55 (1 H, m), 2.17-2.29 (1 H, m), 2.12 (1 H, d, J=7.8 Hz), 1.65-1.88 (5 H, m), 1.37-1.55 (9 H, m), 0.81-0.92 (2 H, m), 0.72 (1 H, br. s.), 0.48-0.63 (4 H, m). 19F NMR (377 MHz, CDCl3) δ ppm −70.26 (3 F, br. s.). MS (ESI, pos. ion) m/z: 614.3 (M+1).

Workup

  1. stirringthe resulting solution was stirred at 0° C. for 30 min
  2. stirringthe reaction was stirred at 0° C. for 5 min
  3. stirringthe reaction was stirred at 0° C. for 5 min
  4. customto quench excess diazomethane
  5. stirringthe resulting mixture was stirred at 25° C. for 12 h
  6. concentrationThe mixture was concentrated onto silica gel
  7. customchromatographically purified (ISCO, 12 g silica gel column, 0-60% EtOAc/hexanes, 15 min, 254 nm)

Sources & evidence

ORD record
ord-dfc2f9c6893d4574957bce1763d05fd4
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

Loading…