Lithium Hydroxide → HCID 178440223, compound

HRID 1620229Notes

Reaction equation

HRID 1620229 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.[Cl:20][CH2:21][C:22]1[C:23]([NH:34][CH2:35][CH3:36])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Cl:37]CC1C(NCC)=NC2C(C=1)=CC(OC)=CC=2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[ClH:20].[ClH:37].[CH2:35]([NH:34][C:23]1[C:22]([CH2:21][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=2[OH:18])=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:32][CH3:33])[CH:29]=2)[N:24]=1)[CH3:36]

Participants

7

Reactant 4

HCID 3939Lithium HydroxideHCID 681822213-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amineHCID 681824593-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochlorideHCID 178440211HCID 178440211, compound2×

Product 1

HCID 178440223HCID 178440223, compoundYield 6%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
150 °C

Procedure

To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (250 mg, 1.01 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride SLA 28166 (290 mg, 1.01 mmol) followed by a 2 N aq. LiOH solution (1.01 mL, 2.02 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, 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 second purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 92:8) provided, after evaporation and drying, 25 mg of 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. 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 (0.45 mL). The reaction mixture was stirred for 5 min at RT, concentrated at 40° C. under vacuum, to afford 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 50 as a yellow solid (30 mg, 6% yield).

Workup

  1. temperatureAfter cooling to RT
  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 second purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 92:8)
  8. customprovided
  9. customafter evaporation
  10. customdrying
  11. dissolutionThis free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask
  12. customequipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.45 mL)
  13. stirringThe reaction mixture was stirred for 5 min at RT
  14. concentrationconcentrated at 40° C. under vacuum

Sources & evidence

ORD record
ord-262c22fc593f499c92faa957b574b62d
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

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