Lithium Hydroxide → HCID 178488006, compound

HRID 1620230Notes

Reaction equation

HRID 1620230 reaction equation
[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH:7]=[C:6]([OH:18])[N:5]=1)([CH3:3])[CH3:2].[ClH:19].[Cl:20][CH2:21][C:22]1[C:23]([NH:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:20].[ClH:19].[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([CH2:21][C:22]2[C:23]([NH:34][CH2:35][C:36]([F:39])([F:37])[F:38])=[N:24][C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=3)=[C:6]([OH:18])[N:5]=1)([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 3939Lithium HydroxideHCID 681821763-(Chloromethyl)-6-methoxy-N-(2,2,2-trifluoroethyl)quinolin-2-amine hydrochloride2×HCID 178486705HCID 178486705, compound2×

Product 1

HCID 178488006HCID 178488006, compoundYield 15%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
160 °C

Procedure

To a stirred solution of 1-isopropyl-6,7-dimethoxyisoquinolin-3-ol SIL 32164 (362 mg, 1.46 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-(2,2,2-trifluoroethyl)quinolin-2-amine hydrochloride SLA 41070 (500 mg, 1.47 mmol) at RT followed by a 2 N aq. solution of LiOH (1.47 mL, 2.94 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 EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided, after evaporation, 161 mg of 1-isopropyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-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 (1.5 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-isopropyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 51 as a yellow solid (130 mg, 15% 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 CH2Cl2:MeOH=100:0 to 97:3)
  8. customprovided
  9. customafter evaporation, 161 mg of 1-isopropyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol as a brown solid
  10. dissolutionThis free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask
  11. customequipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.5 mL)
  12. stirringThe reaction mixture was stirred for 5 min at RT
  13. concentrationthen concentrated at 40° C. under vacuum

Sources & evidence

ORD record
ord-9d066c81d9b24df1b7ca578d05f9a342
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

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