3-(chloromethyl)-6-methoxy-N-propylquinolin-2-amine → HCID 178456828, compound

HRID 1620231Notes

Reaction equation

HRID 1620231 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:19][CH2:20][C:21]1[C:22]([NH:33][CH2:34][CH2:35][CH3:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.Cl.[Cl:38]CC1C(NCCC)=NC2C(C=1)=CC(OC)=CC=2>C1COCC1.CCCCCC.C(Cl)Cl>[ClH:19].[ClH:38].[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])=[C:6]2[CH2:20][C:21]1[C:22]([NH:33][CH2:34][CH2:35][CH3:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2

Participants

7

Reactant 3

HCID 681821123-(chloromethyl)-6-methoxy-N-propylquinolin-2-amineHCID 681822053-(Chloromethyl)-6-methoxy-N-propylquinolin-2-amine hydrochlorideHCID 178440211HCID 178440211, compound

Product 1

HCID 178456828HCID 178456828, compoundYield 5%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8058HexaneSolvent

Conditions

Temperature
150 °C

Procedure

To a stirred solution of 6,7-dimethoxy-1-propyl-isoquinolin-3-ol RBO 35134 (250 mg, 1.01 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-propylquinolin-2-amine free base SLA 28178 (269 mg, 1.01 mmol) followed by a dropwise addition of n-Buli (1.6 M in hexane, 0.65 mL, 1.04 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and 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 92:8) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation, 70 mg of 6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)-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 (0.40 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 52 as a yellow solid (26.6 mg, 5% yield).

Workup

  1. temperatureAfter cooling to RT
  2. washMeOH=9:1 (150 mL) and 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 92:8)
  7. customfollowed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5)
  8. customprovided
  9. customafter evaporation, 70 mg of 6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-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 (0.40 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-14dca34390c642a8b512d309c84be0f0
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

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