Cesium carbonate → 6-{3-[(Dimethylamino)methyl]phenyl}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-[(1S)-1-methylpropyl]-1H-indole-4-carboxamide

HRID 873360Notes

Reaction equation

HRID 873360 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([C@H:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:35][N:36]([CH:38]=O)[CH3:37].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][N:36]([CH2:38][C:2]1[CH:10]=[C:9]([C:2]2[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:17])[C:5]3[C:6]([CH3:15])=[CH:7][N:8]([C@@H:11]([CH3:12])[CH2:13][CH3:14])[C:9]=3[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:37]

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 21962138N,N-Dimethylformamide--water (1/1)HCID 67467218(S)-6-bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-1H-indole-4-carboxamide

Product 1

HCID 682099656-{3-[(Dimethylamino)methyl]phenyl}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-[(1S)-1-methylpropyl]-1H-indole-4-carboxamide

Reagents, catalysts & solvents 1

HCID 178418397HCID 178418397, compoundCatalyst

Procedure

(S)-6-bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-1H-indole-4-carboxamide (100 mg, 0.23 mmol), N,N-dimethyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine, HCl (100 mg, 0.34 mmol) and Palladium Tetrakis (26 mg, 0.023 mmol) in DMF/water (3 ml:1 ml) were stirred for 10 min under nitrogen. Cesium carbonate (220 mg, 0.68 mmol) was added and the insoluble mixture was irradiated (microwave) at 150° C. for 15 min. The contents were evaporated, dissolved in DCM/MeOH (1:1), and pre-absorbed on silica gel and purified using silica gel chromatography (eluent: DCM/MeOH/NH4OH, gradient 0 to 80:20:2 in DCM). The isolated product was first treated with EtOAc along with some hexanes. The product was then dissolved in MeOH and purified by reverse-phase HPLC (30×100 Varian Polaris C18 column, eluent: 10-80% gradient of MeCN in water with 0.1% TFA). The product fractions were combined, most of the solvent was evaporated, and a sat. solution of NaHCO3 was added. Solids that crashed out were filtered, air-dried for 15 min, and dried in vacuum-oven overnight. The solid product was collected as 87 mg (75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (br. s., 1 H), 8.23 (t, J=4.67 Hz, 1 H), 7.77 (d, J=1.01 Hz, 1 H), 7.60-7.64 (m, 2 H), 7.40 (t, J=7.58 Hz, 1 H), 7.30 (s, 1 H), 7.20-7.26 (m, 2 H), 5.87 (s, 1 H), 4.59-4.68 (m, 1 H), 4.36 (s, 1 H), 4.35 (s, 1 H), 3.46 (s, 2 H), 2.24 (s, 3 H), 2.18 (s, 9 H), 2.11 (s, 3 H), 1.76-1.88 (m, 2 H), 1.41 (d, J=6.57 Hz, 3 H), 0.74 (t, J=7.33 Hz, 3 H); LCMS: 499.4 (MH+).

Workup

  1. customthe insoluble mixture was irradiated (microwave) at 150° C. for 15 min
  2. customThe contents were evaporated
  3. dissolutiondissolved in DCM/MeOH (1:1)
  4. custompre-absorbed on silica gel
  5. custompurified
  6. additionThe isolated product was first treated with EtOAc along with some hexanes
  7. dissolutionThe product was then dissolved in MeOH
  8. custompurified by reverse-phase HPLC (30×100 Varian Polaris C18 column, eluent: 10-80% gradient of MeCN in water with 0.1% TFA)
  9. customwas evaporated
  10. additiona sat. solution of NaHCO3 was added
  11. filtrationSolids that crashed out were filtered
  12. customair-dried for 15 min
  13. customdried in vacuum-oven overnight
  14. customThe solid product was collected as 87 mg (75%)

Sources & evidence

ORD record
ord-831c43da55bb430cbbc0a48323dee601
Source dataset
uspto-grants-2015_03
Patent number
US08975291B2

Reaction notes

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