Acetic Anhydride → 1-(Acetamidomethyl)-4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-yl acetate

HRID 1620244Notes

Reaction equation

HRID 1620244 reaction equation
[CH2:1]([NH:3][C:4]1[C:13]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[C:18]([CH2:29][N:30]3[C:38](=[O:39])[C:37]4C(=CC=CC=4)C3=O)=[N:17][C:16]=2[OH:41])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:42][CH3:43])[CH:10]=2)[N:5]=1)[CH3:2].[OH2:44].NN.[CH3:47][CH:48](N(C(C)C)CC1C=CC=CC=1)C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C(OC(=O)C)(=O)C>CCO.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:47]([O:41][C:16]1[N:17]=[C:18]([CH2:29][NH:30][C:38](=[O:39])[CH3:37])[C:19]2[C:24]([C:15]=1[CH2:14][C:13]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]3[C:11]([CH:12]=1)=[CH:10][C:9]([O:42][CH3:43])=[CH:8][CH:7]=3)=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)(=[O:44])[CH3:48]

Participants

8

Reactant 4

HCID 7918Acetic AnhydrideHCID 24654Hydrazine hydrate (1:1)HCID 16212447N-benzyl-N-propan-2-ylpropan-2-amine;1,4-bis(ethenyl)benzene;styreneHCID 178463388HCID 178463388, compound

Product 1

HCID 601638771-(Acetamidomethyl)-4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-yl acetateYield 72%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 702EthanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
130 °C

Procedure

To a solution of 2-((4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-3-hydroxy-6,7-dimethoxyisoquinolin-1-yl)methyl)isoindoline-1,3-dione CCH 42006-1 (75 mg, 130 μmol) in EtOH (5 mL) in a 10 mL microwave vial equipped with a magnetic stirrer was added hydrazine monohydrate (26 μL, 536 μmol) and the mixture was stirred for 10 min at 130° C. under microwave irradiation. After cooling to RT, the reaction mixture was concentrated to dryness at 40° C. under vacuum. The residue CCH 42006-2 was dissolved in dry CH2Cl2 (4 mL) and half of the solution (around 65 μmol) was transferred in a 5 mL microwave vial equipped with a magnetic stirrer before addition of diisopropylaminomethyl-polystyrene resin (3 mmol/g, 86 mg, 258 μmol), DMAP (2 mg, 16 μmol) and acetic anhydride (34.5 μL, 365 μmol) and the reaction mixture was stirred for 20 min at 100° C. under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2 (30 mL), filtered through cotton wool, then washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) gave 1-(acetamidomethyl)-4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-yl acetate 56 as an off-white solid (25 mg, 72% yield).

Workup

  1. temperatureAfter cooling to RT
  2. concentrationthe reaction mixture was concentrated to dryness at 40° C. under vacuum
  3. dissolutionThe residue CCH 42006-2 was dissolved in dry CH2Cl2 (4 mL)
  4. stirringthe reaction mixture was stirred for 20 min at 100° C. under microwave irradiation
  5. temperatureAfter cooling to RT
  6. filtrationfiltered through cotton wool
  7. washwashed with brine (5 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under vacuum
  11. customPurification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100)

Sources & evidence

ORD record
ord-590f9e5a6fbf4370901391d3dcb947ac
Source dataset
uspto-grants-2014_07
Patent number
US08772316B2

Reaction notes

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