Potassium Hydroxide → 1-methylethyl ((2S,4R)-1-acetyl-6-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate

HRID 2366979Notes

Reaction equation

HRID 2366979 reaction equation
[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[OH-].[K+].[CH3:25][N:26]([CH3:43])[CH2:27][CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>C(O)C.CC(C1C=CC=C(C(C)C)C=1N1[CH-]N(C2C(C(C)C)=CC=CC=2C(C)C)CC1)C.C1C=NC=C(Cl)C=1.Cl[Pd]Cl>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:32]3[CH:31]=[N:30][N:29]([CH2:28][CH2:27][N:26]([CH3:43])[CH3:25])[CH:33]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]

Participants

6

Reactant 3

HCID 14797Potassium HydroxideHCID 529350201-Methylethyl((cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamateHCID 57722832N,N-Dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-amine

Product 1

HCID 529333851-methylethyl ((2S,4R)-1-acetyl-6-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamateYield 49.3%

Reagents, catalysts & solvents 2

HCID 588388791,3-Bis[2,6-di(propan-2-yl)phenyl]imidazolidin-2-ide;3-chloropyridine;dichloropalladiumCatalystHCID 702EthanolSolvent

Procedure

1-Methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (0.24 g, 0.650 mmol), potassium hydroxide (1.300 mL, 1.300 mmol), N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanamine (for a preparation see Intermediate 115) (0.190 g, 0.715 mmol) and (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride (0.03 g, 0.044 mmol) were dissolved in ethanol (10 mL) and 1,2-dimethoxyethane (DME) (10.00 mL) and the resulting mixture was degassed under house vacuum with several quenches with nitrogen then refluxed for three hours, cooled to room temperature, allowed to stand for 16 h then concentrated in vacuo. The residue was partitioned between water (30 mL) and EtOAc (30 mL) and the layer were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. Purification of this residue by SP4 using a 25 G silica cartridge (gradient: 0 to 10% (2M NH3 in MeOH) in DCM) gave 1-methylethyl((2S,4R)-1-acetyl-6-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (137 mg, 0.320 mmol, 49.3% yield) as an amber oil.

Workup

  1. custom1,2-dimethoxyethane (DME) (10.00 mL) and the resulting mixture was degassed under house vacuum with several quenches with nitrogen
  2. temperaturethen refluxed for three hours
  3. concentrationthen concentrated in vacuo
  4. customThe residue was partitioned between water (30 mL) and EtOAc (30 mL)
  5. customthe layer were separated
  6. dry with materialThe organic phase was dried over MgSO4
  7. concentrationconcentrated in vacuo
  8. customPurification of this residue by SP4

Sources & evidence

ORD record
ord-0844087616344e708f03404b6a1e1991
Source dataset
uspto-grants-2014_04
Patent number
US08697725B2

Reaction notes

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