1,4-Dioxane → 1-cyclopropyl-6-{4-[(dimethylamino)methyl]phenyl}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide

HRID 85476Notes

Reaction equation

HRID 85476 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:27][N:28]([CH3:45])[CH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:33]4[CH:34]=[CH:35][C:30]([CH2:29][N:28]([CH3:45])[CH3:27])=[CH:31][CH:32]=4)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]4[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=4[CH3:24])=[O:15])[C:5]=3[CH:6]=[N:7]2)[CH2:13][CH2:12]1

Participants

8

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 34604594-((N,N-Dimethylamino)methyl)phenylboronic acid pinacol esterHCID 545962186-bromo-1-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide

Product 1

HCID 545962201-cyclopropyl-6-{4-[(dimethylamino)methyl]phenyl}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To a 20 mL microwave vial containing a mixture of 6-bromo-1-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.070 g, 0.169 mmol), N,N-dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (0.060 g, 0.202 mmol), and potassium phosphate (tribasic) (0.107 g, 0.506 mmol) were added 1,4-dioxane (2.0 mL) and water (0.5 mL). The suspension was stirred with degassing under N2 for 10 min. (emulsion), and then PdCl2(dppf)-CH2Cl2 adduct (0.021 g, 0.025 mmol) was added. The contents were sealed and heated at 100° C. (heat block) for 2 h. After cooling to RT, the reaction mixture was diluted with EtOAc. Silica gel was added the mixture was concentrated in vacuo to dryness. The contents were purified by silica gel chromatography (dry loaded, eluent: 8-95% gradient chloroform (containing 10% 2M Ammonia in Methanol) and DCM). The collected product was concentrated from MTBE and dried in a vacuum oven for 2 h. The title compound was collected as a white solid (67 mg, 81%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.20 (m, 4H), 2.12 (s, 3H), 2.15-2.24 (m, 9H), 3.44 (s, 2H), 3.87 (t, J=5.31 Hz, 1H), 4.38 (d, J=4.80 Hz, 2H), 5.88 (s, 1H), 7.42 (m, J=8.34 Hz, 2H), 7.80 (m, J=8.08 Hz, 2H), 7.90 (s, 1H), 8.04 (s, 1H), 8.31 (s, 1H), 8.67 (t, J=4.93 Hz, 1H), 11.53 (s, 1H); LC-MS(ES) m/z=470.3 [M+H].

Workup

  1. additionTo a 20 mL microwave vial containing
  2. customwith degassing under N2 for 10 min. (emulsion)
  3. customThe contents were sealed
  4. temperature(heat block) for 2 h
  5. temperatureAfter cooling to RT
  6. additionSilica gel was added the mixture
  7. concentrationwas concentrated in vacuo to dryness
  8. customThe contents were purified by silica gel chromatography (dry loaded, eluent: 8-95% gradient chloroform (containing 10% 2M Ammonia in Methanol) and DCM)
  9. concentrationThe collected product was concentrated from MTBE
  10. customdried in a vacuum oven for 2 h
  11. customThe title compound was collected as a white solid (67 mg, 81%)

Sources & evidence

ORD record
ord-68385521ff1145b496ffe26a814bd686
Source dataset
uspto-grants-2014_09
Patent number
US08846935B2

Reaction notes

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