Lithium Hydroxide → HCID 178437773, compound

HRID 1620221Notes

Reaction equation

HRID 1620221 reaction equation
[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[ClH:18].[CH2:19]([NH:26][C:27]1[C:36]([CH2:37][Cl:38])=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:39][CH3:40])[CH:33]=2)[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:38].[ClH:18].[CH2:19]([NH:26][C:27]1[C:36]([CH2:37][C:6]2[C:7]3[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=3)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=2[OH:17])=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:39][CH3:40])[CH:33]=2)[N:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1

Participants

6

Reactant 3

HCID 3939Lithium HydroxideHCID 68182200HCID 68182200, compound2×HCID 178437769HCID 178437769, compound2×

Product 1

HCID 178437773HCID 178437773, compoundYield 9%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
160 °C

Procedure

To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (70 mg, 0.30 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added N-benzyl-3-(chloromethyl)-6-methoxyquinolin-2-amine hydrochloride SLA 41008 (105 mg, 0.30 mmol) followed by a 2 N aq. LiOH (0.30 mL, 0.60 mmol) and the mixture was stirred at 160° 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 CH2Cl2:MeOH=100:0 to 97:3) provided, after evaporation, 17.3 mg of 4-((2-(benzylamino)-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-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 (0.28 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-(benzylamino)-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 44 as a yellow solid (16 mg, 9% 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 CH2Cl2:MeOH=100:0 to 97:3)
  7. customprovided
  8. customafter evaporation, 17.3 mg of 4-((2-(benzylamino)-6-methoxyquinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol as a brown solid
  9. dissolutionThis free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask
  10. customequipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.28 mL)
  11. stirringThe reaction mixture was stirred for 5 min at RT
  12. concentrationthen concentrated at 40° C. under vacuum

Sources & evidence

ORD record
ord-c2ee1ec34f8e4efb90bc937e71ee0bfe
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

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