Lithium Hydroxide → HCID 178463390, compound

HRID 1620264Notes

Reaction equation

HRID 1620264 reaction equation
Cl.Cl[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH3:18])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.ClCC1C(NCC)=NC2C(C=1)=CC(OC)=CC=2.[CH3:36][O:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][C:47]=1[O:48][CH3:49])[C:44]([CH2:50][O:51][CH3:52])=[N:43][C:42]([OH:53])=[CH:41]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[CH2:17]([NH:16][C:5]1[C:4]([CH2:3][C:41]2[C:40]3[C:45](=[CH:46][C:47]([O:48][CH3:49])=[C:38]([O:37][CH3:36])[CH:39]=3)[C:44]([CH2:50][O:51][CH3:52])=[N:43][C:42]=2[OH:53])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]=1)[CH3:18]

Participants

7

Reactant 4

HCID 3939Lithium HydroxideHCID 681822213-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amineHCID 681824593-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochlorideHCID 178494696HCID 178494696, compound2×

Product 1

HCID 178463390HCID 178463390, compound

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
160 °C

Procedure

To a stirred solution of 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride SLA 28166 (84 mg, 0.29 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-(methoxymethyl)isoquinolin-3-ol SMA 44012 (73 mg, 0.29 mmol) followed by a 2 N aq. LiOH solution (0.29 mL, 0.58 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 new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-(methoxymethyl)isoquinolin-3-ol. 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) and the mixture was stirred for 5 min at room temperature and concentrated at 40° C. under vacuum to afford 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-(methoxymethyl)isoquinolin-3-ol dihydrochloride 67 as a yellow solid (9 mg, 6% 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 new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5)

Sources & evidence

ORD record
ord-20d0709eee3343b58fbaf926d93f5d00
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

Loading…