Ammonia → Methyl [7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate

HRID 572506Notes

Reaction equation

HRID 572506 reaction equation
[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1)#[N:2].N>C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[C:16]([O:18][CH3:19])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1

Participants

5

Reactant 2

HCID 222AmmoniaHCID 68352905Methyl [7-cyano-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate

Product 1

HCID 68295579Methyl [7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetateYield 78.3%

Reagents, catalysts & solvents 2

HCID 935NickelCatalystHCID 702EthanolSolvent

Procedure

A solution of methyl [7-cyano-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate (30 mg, 0.069 mmol) in Ethanol (3.5 mL), saturated with ammonia gas, was treated with Raney 2800 Nickel (0.5 mL, 0.069 mmol), purged and filled with N2 3×, H2 3×, and stirred under H2 at 40 psi overnight. The mixture was filtered through Celite, washed with MeOH, and concentrated. The residue was purified by column chromatography (0-20% MeOH/DCM) to afford methyl [7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate (23.7 mg, 0.054 mmol, 78% yield) as a colorless oil. The methyl ester was hydrolyzed in a manner similar to that described in Example 165 Step C and purified by reverse phase HPLC to afford [7-(aminomethyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetic acid-TFA salt (18.8 mg, 0.033 mmol, 76% yield) as off white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.42 (s, 1 H), 7.61 (d, J=8.4 Hz, 1 H), 7.36-7.15 (m, 3 H), 7.11-6.99 (m, 1 H), 5.23 (s, 1 H), 4.23 (s, 2 H), 3.70 (s, 3 H), 2.36 (s, 3 H), 2.31 (s, 3 H), 0.98 (s, 9 H); LCMS (m/z) ES+=423 (M+1).

Workup

  1. custompurged
  2. additionfilled with N2 3×, H2 3×
  3. filtrationThe mixture was filtered through Celite
  4. washwashed with MeOH
  5. concentrationconcentrated
  6. customThe residue was purified by column chromatography (0-20% MeOH/DCM)

Sources & evidence

ORD record
ord-1460a427d5fe4cc28f572c84561dea88
Source dataset
uspto-grants-2015_05
Patent number
US09029391B2

Reaction notes

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