Water → HCID 178488755, compound

HRID 1620159Notes

Reaction equation

HRID 1620159 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH3:23])=[N:11][C:10]=2[OH:24])[CH:5]=[N:6][CH:7]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O>CCO.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(COC)OC>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[C:12]([CH3:23])=[N:11][C:10]([OH:24])=[C:9]2[CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH:3]=1

Participants

9

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 201262(4-Methoxyphenyl)boronic acidHCID 178486672HCID 178486672, compound2×

Product 1

HCID 178488755HCID 178488755, compound

Reagents, catalysts & solvents 4

HCID 178418476HCID 178418476, compoundCatalystHCID 702EthanolSolventHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred solution of 4-((5-bromopyridin-3-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 34166 (53 mg, 136 μmol) in absolute EtOH (0.9 mL) in a 20 mL microwave vial equipped with a magnetic stirrer were added 4-methoxyphenylboronic acid (41 mg, 270 μmol), Pd(PPh3)2Cl2 (10 mg, 14 μmol), a 2 N aq. Na2CO3 solution (0.30 mL, 0.60 mmol), H2O (2.7 mL) and dimethoxyethane (3.5 mL) and the resulting mixture was stirred at 140° C. for 25 min. After cooling to RT, the mixture was diluted with EtOAc (30 mL) and this solution was filtered through a celite plug, then washed with brine (10 mL). The organic phase was isolated and the celite plug was then further washed with CH2Cl2 (50 mL) and the organic layer was washed with brine (20 mL). The organic layers were then combined, dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) provided 32 mg of 6,7-dimethoxy-4-((5-(4-methoxyphenyl)pyridin-3-yl)methyl)-1-methylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.5 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to give 6,7-dimethoxy-4-((5-(4-methoxyphenyl)pyridin-3-yl)methyl)-1-methylisoquinolin-3-ol dihydrochloride 16 as a pale brown solid (37 mg, 56% yield).

Workup

  1. filtrationthis solution was filtered through a celite plug
  2. washwashed with brine (10 mL)
  3. customThe organic phase was isolated
  4. washthe celite plug was then further washed with CH2Cl2 (50 mL)
  5. washthe organic layer was washed with brine (20 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated at 40° C. under vacuum
  9. customPurification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6)

Sources & evidence

ORD record
ord-2a7e397175f24b228f3dae5a038ebdef
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

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