Potassium Carbonate → tert-butyl 4-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl)methyl]piperidine-1-carboxylate

HRID 1520080Notes

Reaction equation

HRID 1520080 reaction equation
[C:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[BH:15]1C2CCCC1CCC2.Br[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[C:28]2[C:34]1[N:35]=[N:36][N:37]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[O:46])=[CH:41][CH:40]=2)[CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CN(C=O)C.O>[BH3:15].[N:47]1([C:45]([C:42]2[CH:41]=[CH:40][C:39]([N:37]3[CH:38]=[C:34]([C:28]4[C:27]5[C:31](=[CH:32][CH:33]=[C:25]([CH2:14][CH:11]6[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]6)[CH:26]=5)[NH:30][N:29]=4)[N:35]=[N:36]3)=[CH:44][CH:43]=2)=[O:46])[CH2:48][CH2:49][O:50][CH2:51][CH2:52]1

Participants

9

Reactant 4

HCID 11430Potassium CarbonateHCID 789669-Borabicyclo(3.3.1)nonaneHCID 27568081-Boc-4-Methylenepiperidine2×HCID 574046585-bromo-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

Product 2

HCID 6331BoraneHCID 67981478tert-butyl 4-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl)methyl]piperidine-1-carboxylateYield 87%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

A degassed solution of 1-N-Boc-4-methylene-piperidine (48 mg; 0.24 mmol; 1.1 eq.) and 9-BBN (0.5 M 0.44 mL of a 0.5 M solution in THF; 0.22 mmol; 1.0 eq.) in THF (0.5 mL) was heated at 800 for 1 h in a sealed tube. This solution was allowed to cool to RT and cannulated to a degassed mixture of 5-bromo-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole (100 mg; 0.22 mmol; 1.0 eq.), PdCl2dppf (1 mg; 0.001 mmol; 0.01 eq.) and potassium carbonate (76 mg; 0.55 mmol; 2.5 eq.) in DMF (1 mL) and water (0.1 mL). The resulting mixture was heated at 65° C. O/N. As the reaction was not complete, a second solution of borane was prepared (from 0.24 mmol of 1-N-Boc-4-methylene-piperidine) and added to the reaction mixture which was heated at 65° C. for one more night. The reaction mixture was poured into water and extracted twice with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 90:10) gave the title compound as a yellow powder (110 mg, 87%). 1H NMR (300 MHz, DMSO-d6) δ 13.29 (brs, 1H), 9.36 (s, 1H), 8.21-8.08 (m, 3H), 7.74-7.65 (m, 2H), 7.56-7.48 (m, 1H), 7.32-7.23 (m, 1H), 4.04-3.81 (m, 2H), 3.79-3.36 (m, 8H), 2.83-2.56 (m, 3H), 1.84-1.50 (m, 3H), 1.49-1.39 (m, 1H), 1.37 (s, 9H), 1.21-0.91 (m, 2H). HPLC (max plot) 86.0%; Rt 4.36 min. UPLC/MS: (MS−) 470.2 (M-tBuOCO).

Workup

  1. temperatureThe resulting mixture was heated at 65° C
  2. additionadded to the reaction mixture which
  3. temperaturewas heated at 65° C. for one more night
  4. extractionextracted twice with EtOAc
  5. washCombined organic phases were washed with brine
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 90:10)

Sources & evidence

ORD record
ord-257db6f62f984566b028b2833f1ca78b
Source dataset
uspto-grants-2015_07
Patent number
US09073892B2

Reaction notes

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