1,2-Dimethoxyethane → N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-[(1R)-1-methylpropyl]-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide

HRID 42407Notes

Reaction equation

HRID 42407 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.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[N:41][CH:42]=2)O1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:26][C:25]1[CH:24]=[C:23]([CH3:27])[NH:22][C:21](=[O:28])[C:20]=1[CH2:19][NH:18][C:16]([C:4]1[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([C@H:11]([CH3:12])[CH2:13][CH3:14])[C:9]=2[CH:10]=[C:2]([C:37]2[CH:42]=[N:41][C:40]([N:43]3[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]3)=[CH:39][CH:38]=2)[CH:3]=1)=[O:17]

Participants

7

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 162179462-(Piperazin-1-yl)pyridine-5-boronic acid, pinacol esterHCID 67465306(R)-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 67469073N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-[(1R)-1-methylpropyl]-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamideYield 75.9%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolvent

Procedure

To a 30 mL microwave vial were added (R)-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, 0.225 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCl2(dppf)-CH2Cl2 adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140° C. for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25% ACN/H2O, 0.1% NH4OH to 60% ACN/H2O, 0.1% NH4OH) to give 90 mg of product as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (m, 3H), 1.41 (d, J=6.57 Hz, 3H), 1.81 (td, J=7.14, 2.91 Hz, 2H), 2.11 (s, 3H), 2.15-2.20 (m, 3H), 2.24 (s, 3H), 2.77-2.83 (m, 4H), 3.41-3.49 (m, 4H), 4.35 (d, J=5.05 Hz, 2H), 4.54-4.68 (m, 1H), 5.87 (s, 1H), 6.88 (d, J=8.84 Hz, 1H), 7.17 (d, J=1.52 Hz, 1H), 7.26 (s, 1H), 7.73 (d, J=1.26 Hz, 1H), 7.91 (dd, J=8.84, 2.53 Hz, 1H), 8.16 (t, J=5.05 Hz, 1H), 8.50 (d, J=2.27 Hz, 1H); LCMS: 527.7 (MH+).

Workup

  1. customthe mixture was degassed for 5 min
  2. customby bubbling nitrogen
  3. customthe tube was sealed
  4. customThe mixture was irradiated (microwave) at 140° C. for 10 min
  5. concentrationThe mixture was concentrated
  6. filtrationfiltered
  7. customThe filtrate was purified

Sources & evidence

ORD record
ord-def9790131b84a3e845a19252e8167d5
Source dataset
uspto-grants-2013_09
Patent number
US08536179B2

Reaction notes

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