Tetrahydrofuran → 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one

HRID 577502Notes

Reaction equation

HRID 577502 reaction equation
CC(C)([O-])C.[K+].O1CCCC1.[Br:12][C:13]1[C:22]([Cl:23])=[C:21]2[C:16]([CH2:17][CH2:18][NH:19][C:20]2=[O:24])=[C:15]([Cl:25])[CH:14]=1.[CH2:26]([O:33][C:34]1[C:39]([CH2:40]Cl)=[C:38]([CH3:42])[CH:37]=[C:36]([CH3:43])[N:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.C(OC)(C)(C)C.C(O)(=O)C>[CH2:26]([O:33][C:34]1[C:39]([CH2:40][N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[C:22]([Cl:23])[C:13]([Br:12])=[CH:14][C:15]=3[Cl:25])[C:20]2=[O:24])=[C:38]([CH3:42])[CH:37]=[C:36]([CH3:43])[N:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 23665647Potassium tert-butoxideHCID 612578682-(Benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine2×HCID 867237277-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one

Product 1

HCID 867237282-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-oneYield 64.1%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolventHCID 15413tert-Butyl methyl etherSolvent

Procedure

Potassium tert-butoxide solution in tetrahydrofuran (1.0 M, 190 mL, 0.19 mol) was added dropwise to a cooled (0° C.) solution of 7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (253f, 47 g, 0.16 mol) in anhydrous N,N-dimethylformamide (500 mL) under a nitrogen atmosphere. Stirring was continued at 0° C. for 5 minutes, then 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (compound Z, 40.2 g, 0.15 mol) was added in one portion. After stirring for 10 minutes at 0° C., the mixture was treated with concentrated acetic acid (2 mL) and poured into methyl tert-butyl ether (600 mL). The organic solution was washed with water (800 mL) and saturated aqueous sodium chloride solution (800 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 30:1 to 20:1 petroleum ether/ethyl acetate), affording 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (253g, 50 g, 64% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.45-7.43 (m, 2H), 7.32-7.29 (m, 3H), 6.76 (s, 1H), 5.38 (s, 2H), 4.71 (s, 2H), 3.24 (t, J=6 Hz, 2H), 2.72 (t, J=6 Hz, 2H), 2.36 (s, 3H), 2.31 (s, 3H). MS: 521 [M+1].

Workup

  1. stirringAfter stirring for 10 minutes at 0° C.
  2. washThe organic solution was washed with water (800 mL) and saturated aqueous sodium chloride solution (800 mL)
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified by silica gel chromatography (eluting with 30:1 to 20:1 petroleum ether/ethyl acetate)

Sources & evidence

ORD record
ord-b3fa3cb0913549ff9f805fba21d60db4
Source dataset
uspto-grants-2015_05
Patent number
US09040515B2

Reaction notes

Loading…