Lithium Hydroxide → 2-Tert-butoxy-2-[4-(3,4-dimethylphenyl)-7-[(4-methoxyphenyl)methyl]-2-methyl-1-oxo-3-isoquinolyl]acetic acid

HRID 572502Notes

Reaction equation

HRID 572502 reaction equation
Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)=[C:7]([CH:14]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([O:17]C)=[O:16])[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.[Br-].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][Zn+])=[CH:37][CH:36]=1.[OH-].[Li+]>CN(C)C=O.C(OCC)(=O)C.O1CCCC1.CO.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>[CH3:23][C:20]([O:19][CH:14]([C:7]1[N:8]([CH3:13])[C:9](=[O:12])[C:10]2[C:5]([C:6]=1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1)=[CH:4][CH:3]=[C:2]([CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)[CH:11]=2)[C:15]([OH:17])=[O:16])([CH3:21])[CH3:22]

Participants

9

Reactant 3

HCID 3939Lithium Hydroxide2×HCID 68295047Methyl [7-bromo-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetateHCID 178490611HCID 178490611, compound

Product 1

HCID 682957702-Tert-butoxy-2-[4-(3,4-dimethylphenyl)-7-[(4-methoxyphenyl)methyl]-2-methyl-1-oxo-3-isoquinolyl]acetic acidYield 31%

Reagents, catalysts & solvents 5

HCID 178418397HCID 178418397, compoundCatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of methyl [7-bromo-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate (34.0 mg, 0.070 mmol) and (4-methoxybenzyl)zinc(II) bromide (0.280 mL, 0.140 mmol) in N,N-Dimethylformamide (DMF) (1.2 mL) was degassed with nitrogen for 5 minutes. Pd(PPh3)4 (8.08 mg, 6.99 μmol) was added and the mixture was irradiated in the microwave at 120° C. for 20 minutes. The mixture was diluted with ethyl acetate, washed with water, followed by brine, dried over sodium sulfate, filtered and then concentrated to give a dark residue. The crude residue was treated with 2M lithium hydroxide (0.140 mL, 0.280 mmol) in Tetrahydrofuran (THF) (0.8 mL) and Methanol (0.8 mL) and then stirred at 70° C. for 30 minutes. Additional 2 M lithium hydroxide (0.200 mL, 0.400 mmol) was added and the mixture was stirred at 70° C. for 2 additional hours. The mixture was concentrated and the residue was purified by reverse phase chromatography to afford the title compound as a white solid (11 mg, 31%). 1H NMR (400 MHz, CHLOROFORM-d) δ=8.39-8.30 (m, 1 H), 7.41-7.29 (m, 2 H), 7.29-7.18 (m, 1 H), 7.17-7.09 (m, 2 H), 7.09-6.96 (m, 2 H), 6.81 (dd, J=2.0, 8.6 Hz, 2 H), 5.34 (s, 1 H), 4.04 (s, 2 H), 3.77 (s, 3 H), 3.68 (s, 3 H), 2.35 (m, 3 H), 2.30 (m, 3 H), 1.06 (m, 9 H); LC/MS (m/z) ES+=514 (M+1).

Workup

  1. customwas degassed with nitrogen for 5 minutes
  2. customthe mixture was irradiated in the microwave at 120° C. for 20 minutes
  3. washwashed with water
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give a dark residue
  8. stirringthe mixture was stirred at 70° C. for 2 additional hours
  9. concentrationThe mixture was concentrated
  10. customthe residue was purified by reverse phase chromatography

Sources & evidence

ORD record
ord-5584f9b491314629bd9bc0d4faa677f7
Source dataset
uspto-grants-2015_05
Patent number
US09029391B2

Reaction notes

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