Lithium Hydroxide → HCID 178463395, compound

HRID 1620291Notes

Reaction equation

HRID 1620291 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].Cl.Cl[CH2:20][C:21]1[C:22]([NH:34][CH2:35][CH3:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[C:26]([F:33])[CH:25]=2.[Li+].[OH-]>C1COCC1>[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)[C:6]([CH2:20][C:21]2[C:22]([NH:34][CH2:35][CH3:36])=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[C:26]([F:33])[CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]

Participants

5

Reactant 3

HCID 3939Lithium HydroxideHCID 68182173HCID 68182173, compound2×HCID 178437769HCID 178437769, compound2×

Product 1

HCID 178463395HCID 178463395, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
155 °C

Procedure

To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (114 mg, 0.49 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-N-ethyl-7-fluoro-6-methoxyquinolin-2-amine hydrochloride SMA 44096 (149 mg, 0.49 mmol) at RT followed by a 2 N aq. LiOH solution (0.49 mL, 0.98 mmol) and the mixture was stirred at 155° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL). The organic solution was washed with brine (10 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) gave 16 mg of 1-ethyl-4-((2-(ethylamino)-7-fluoro-6-methoxyquinolin-3-yl)methyl)-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 (0.5 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-ethyl-4-((2-(ethylamino)-7-fluoro-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 82 as a yellow solid (19 mg, 7% yield).

Workup

  1. temperatureAfter cooling to RT
  2. customTHF was removed at 40° C. under vacuum
  3. washThe organic solution was washed with brine (10 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated at 40° C. under vacuum
  7. customPurification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5)

Sources & evidence

ORD record
ord-e7000b29cf82451fbd1a256fbec3f93c
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

Loading…