Lithium Hydroxide → HCID 178440231, compound

HRID 1620302Notes

Reaction equation

HRID 1620302 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[CH2:21][C:22]1[C:23]([NH:36][CH2:37][CH3:38])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH2:33][CH3:34])=[C:27]([F:35])[CH:26]=2.[Li+].[OH-]>C1COCC1.CO>[CH2:33]([O:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[F:35])[N:24]=[C:23]([NH:36][CH2:37][CH3:38])[C:22]([CH2:21][C:6]1[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]=1[OH:18])=[CH:31]2)[CH3:34]

Participants

6

Reactant 3

HCID 3939Lithium HydroxideHCID 68182263HCID 68182263, compound2×HCID 178440211HCID 178440211, compound2×

Product 1

HCID 178440231HCID 178440231, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
155 °C

Procedure

To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (55 mg, 222 μmol) in THF (5 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added a solution of 3-(chloromethyl)-6-ethoxy-N-ethyl-7-fluoroquinolin-2-amine hydrochloride SMA 44106 (76 mg, 238 μmol) in MeOH (0.5 mL) at RT followed by a 2 N aq. LiOH solution (240 μL, 480 μmol) and the mixture was stirred at 155° C. for 1.5 h under microwave irradiation. After cooling to RT, THF and MeOH were 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) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 96:4) gave 4-((6-ethoxy-2-(ethylamino)-7-fluoroquinolin-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 (0.5 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((6-ethoxy-2-(ethylamino)-7-fluoroquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol 86 as a brown solid (15 mg, 12% yield).

Workup

  1. temperatureAfter cooling to RT
  2. customTHF and MeOH were 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)
  8. customfollowed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 96:4)

Sources & evidence

ORD record
ord-c81620ad8f7b42579460179661879fd7
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

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