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Potassium Hydroxide → 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-(difluoromethoxy)-3,4-dihydroisoquinolin-1(2H)-one

HRID 577478
Notes
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Reaction equation

HRID 577478 reaction equation
[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:27])[C:20]([OH:26])=[CH:21][CH:22]=3)[C:17]2=[O:28])=[C:13]([CH3:29])[CH:12]=[C:11]([CH3:30])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[C:34](P(=O)(OCC)OCC)([F:36])[F:35]>CC#N.O.CCOC(C)=O.O>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:27])[C:20]([O:26][CH:34]([F:36])[F:35])=[CH:21][CH:22]=3)[C:17]2=[O:28])=[C:13]([CH3:29])[CH:12]=[C:11]([CH3:30])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 14797Potassium HydroxideHCID 144101Bromodifluoromethyl diethylphosphonateHCID 867237042-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one

Product 1

HCID 867237052-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-(difluoromethoxy)-3,4-dihydroisoquinolin-1(2H)-oneYield 72%

Reagents, catalysts & solvents 3

HCID 962
Water
Solvent
HCID 8857Ethyl AcetateSolvent
HCID 18373917Acetonitrile--water (1/1)Solvent

Procedure

To a solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1h, 0.1 g, 0.237 mmol) and KOH (0.265 g, 4.74 mmol) in CH3CN/H2O (10 mL/1 mL) was added diethyl [bromo(difluoro)methyl]phosphonate (0.126 g, 0.474 mmol) at −78° C. under N2 atmosphere. The resulting mixture was allowed to warm to room temperature and stirred for 30 minutes. The mixture was diluted with EtOAc (20 mL) and H2O (5 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep. TLC (petroleum ether/EtOAc, 4:1) to obtain 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-(difluoromethoxy)-3,4-dihydroisoquinolin-1(2H)-one (1i, 0.08 g, 72%) as a yellow oil.

Workup

  1. customThe organic layer was separated
  2. extractionthe aqueous layer was extracted with EtOAc (2×10 mL)
  3. washwashed with brine (10 mL)
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated under vacuum
  6. customThe residue was purified by prep

Sources & evidence

ORD record
ord-610e96a60d7f4cba9a1d75ede5034e86
Source dataset
uspto-grants-2015_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09040515B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes