Lithium Hydroxide → HCID 178440228, compound

HRID 1620283Notes

Reaction equation

HRID 1620283 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:33][CH2:34][CH2:35][O:36][CH3:37])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.[Li+].[OH-].[CH2:40]1COCC1>>[CH3:16][O:15][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[O:13][CH3:14])[C:3]([CH2:1][CH2:2][CH3:40])=[N:4][C:5]([OH:17])=[C:6]2[CH2:20][C:21]1[C:22]([NH:33][CH2:34][CH2:35][O:36][CH3:37])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2

Participants

5

Reactant 4

HCID 3939Lithium HydroxideHCID 8028TetrahydrofuranHCID 681822733-(chloromethyl)-6-methoxy-N-(2-methoxyethyl)quinolin-2-amine hydrochloride2×HCID 178437769HCID 178437769, compound

Product 1

HCID 178440228HCID 178440228, compound

Procedure

To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 47022 (215 mg, 0.92 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 3-(chloromethyl)-6-methoxy-N-(2-methoxyethyl)quinolin-2-amine hydrochloride SLA 47064B (292 mg, 0.92 mmol) and a 2 N aq. LiOH solution (0.92 mL, 1.84 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to room temperature, THF was then removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (RP 18, eluent CH3CN:H2O:TFA=100:0:0.05 to 50:50:0.05) followed by a new purification by column chromatography (RP 18, eluent CH3CN:H2O:TFA=100:0:0.05 to 66:34:0.05) gave 6,7-dimethoxy-4-((6-methoxy-2-(2-methoxyethylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol (mg). This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((6-methoxy-2-(2-methoxyethylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 77 as a brown solid (61 mg, 12% yield).

Workup

  1. customTHF was then removed at 40° C. under vacuum
  2. extractionthe solution was extracted with CH2Cl2 (50 mL)
  3. washwashed with brine (10 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customPurification by column chromatography (RP 18, eluent CH3CN:H2O:TFA=100:0:0.05 to 50:50:0.05)
  8. customfollowed by a new purification by column chromatography (RP 18, eluent CH3CN:H2O:TFA=100:0:0.05 to 66:34:0.05)

Sources & evidence

ORD record
ord-80be2a1f24f44e3d9ae17a4046d8227f
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

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