Lithium Hydroxide → HCID 178440221, compound

HRID 1620262Notes

Reaction equation

HRID 1620262 reaction equation
[ClH:1].[Cl:2][CH2:3][C:4]1[C:5]([CH2:16][CH3:17])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C:26]([CH2:32][CH2:33][CH3:34])=[N:25][C:24]([OH:35])=[CH:23]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:2].[ClH:1].[CH2:16]([C:5]1[C:4]([CH2:3][C:23]2[C:22]3[C:27](=[CH:28][C:29]([O:30][CH3:31])=[C:20]([O:19][CH3:18])[CH:21]=3)[C:26]([CH2:32][CH2:33][CH3:34])=[N:25][C:24]=2[OH:35])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]=1)[CH3:17]

Participants

6

Reactant 3

HCID 3939Lithium HydroxideHCID 68182181HCID 68182181, compound2×HCID 178440211HCID 178440211, compound

Product 1

HCID 178440221HCID 178440221, compoundYield 5%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
160 °C

Procedure

To a stirred solution of 3-(chloromethyl)-2-ethyl-6-methoxyquinoline hydrochloride SMA 44014 (183 mg, 0.67 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (166 mg, 0.67 mmol) followed by a 2 N aq. LiOH solution (0.67 mL, 1.34 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to room temperature, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided after evaporation 4-((2-ethyl-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-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 (0.32 mL) and the mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-ethyl-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 66 as a yellow solid (17 mg, 5% yield).

Workup

  1. temperatureAfter cooling to room temperature
  2. washMeOH=9:1 (150 mL), washed with brine (20 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated at 40° C. under vacuum
  6. customPurification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5)
  7. customfollowed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5)
  8. customprovided
  9. customafter evaporation 4-((2-ethyl-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol
  10. dissolutionThis free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask
  11. customequipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.32 mL)
  12. stirringthe mixture was stirred for 5 min at RT
  13. concentrationthen concentrated at 40° C. under vacuum

Sources & evidence

ORD record
ord-687ca75fa97e4c5ebd0be8611e371731
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

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