Water → HCID 178437786, compound

HRID 1620151Notes

Reaction equation

HRID 1620151 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][CH3:21])=[N:8][C:7]=1[OH:22].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=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>[CH2:20]([C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[C:6]([CH2:5][C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[C:7]([OH:22])[N:8]=1)[CH3:21]

Participants

9

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 201262(4-Methoxyphenyl)boronic acidHCID 178437783HCID 178437783, compound2×

Product 1

HCID 178437786HCID 178437786, compound

Reagents, catalysts & solvents 4

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

Procedure

To a stirred solution of 4-(3-bromobenzyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28138 (79 mg, 0.196 mmol) in EtOH (0.9 mL) in a 20 mL microwave vial equipped with a magnetic stirrer were added 4-methoxyphenylboronic acid (60 mg, 0.393 mmol), Pd(PPh3)2Cl2 (10.0 mg), a 2 N aq. Na2CO3 solution (0.3 mL), 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 the organic solution was passed through a celite plug, then washed with brine (10 mL). The celite plug was then further washed with CH2Cl2 (50 mL) and the organic layer was washed with brine (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 98:2) gave 1-ethyl-6,7-dimethoxy-4-((4′-methoxy-[1,1′-biphenyl]-3-yl)methyl)isoquinolin-3-ol. This free base was dissolved in CH2Cl2 (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 (3 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-((4′-methoxy-[1,1-biphenyl]-3-yl)methyl)isoquinolin-3-ol hydrochloride 9 as a yellow solid (55 mg, 60% yield).

Workup

  1. washwashed with brine (10 mL)
  2. washThe celite plug was then further washed with CH2Cl2 (50 mL)
  3. washthe organic layer was washed with brine (20 mL)
  4. dry with materialThe combined organic layers were dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated at 40° C. under vacuum
  7. customPurification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 98:2)

Sources & evidence

ORD record
ord-ed563fd86dbc42c19c76ac7368ae049c
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

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