Water → (R)-tert-butyl 5-(2-(4-fluorophenyl)-6-(4-(4-fluorophenyl)-2-methylpiperazine-1-carbonyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate

HRID 927274Notes

Reaction equation

HRID 927274 reaction equation
[C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:13](=[O:24])[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21](O)=[O:22])=[CH:16][CH:15]=2)([CH3:4])([CH3:3])[CH3:2].[CH:33]1[CH:34]=[CH:35][C:36]2N(O)N=[N:39][C:37]=2[CH:38]=1.O.CCN=C=NCCCN(C)C.[CH3:55][CH2:56][N:57](C(C)C)[CH:58]([CH3:60])[CH3:59].[F:64]C1C=CC(N2CCN[C@H](C)C2)=CC=1.C[C@@H]1CNCCN1C(OC(C)(C)C)=O.FC1C=CC(I)=CC=1.C(O)(C(F)(F)F)=O>ClCCl.[Cu]I>[F:31][C:28]1[CH:29]=[CH:30][C:25]([N:12]2[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:32])=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([N:57]4[CH2:56][CH2:55][N:39]([C:37]5[CH:38]=[CH:33][C:34]([F:64])=[CH:35][CH:36]=5)[CH2:59][C@H:58]4[CH3:60])=[O:22])[CH:18]=3)[C:13]2=[O:24])=[CH:26][CH:27]=1

Participants

12

Reactant 9

HCID 962WaterHCID 6422Trifluoroacetic acidHCID 96054-FluoroiodobenzeneHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 10262201tert-Butyl (2R)-2-methylpiperazine-1-carboxylateHCID 57435413(r)-1-(4-Fluorophenyl)-3-methylpiperazineHCID 900944973-(5-(Tert-butoxy)-5-oxopentyl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxylic acid

Product 1

HCID 90094332(R)-tert-butyl 5-(2-(4-fluorophenyl)-6-(4-(4-fluorophenyl)-2-methylpiperazine-1-carbonyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6344DichloromethaneSolvent2×

Procedure

3-(5-(tert-butoxy)-5-oxopentyl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxylic acid (50 mg, 0.114 mmol)), HOBt.H2O (34.8, 0.228 mmol), EDCI (43.6 mg, 0.228 mmol), Hunig's base (44.1 mg, 0.341 mmol) and (R)-1-(4-fluorophenyl)-3-methylpiperazine (22.1 mg, 0.114 mmol, prepared from the coupling of (R)-tert-butyl 2-methylpiperazine-1-carboxylate and 1-fluoro-4-iodobenzene using CuI followed with deprotection with TFA) were mixed in dichloromethane (1 mL). The mixture was kept stirring at room temperature for 16 hours before it was diluted with dichloromethane (5 mL), washed with aqueous sodium hydrogen carbonate (saturated, 1×3 mL) and hydrochloric acid (0.5 M, 2 mL), dried (MgSO4) and filtered. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane=1:1 to give (R)-tert-butyl 5-(2-(4-fluorophenyl)-6-(4-(4-fluorophenyl)-2-methylpiperazine-1-carbonyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (58 mg, 0.094 mmol) as a yellow foam.

Workup

  1. washwashed with aqueous sodium hydrogen carbonate (saturated, 1×3 mL) and hydrochloric acid (0.5 M, 2 mL)
  2. dry with materialdried (MgSO4)
  3. filtrationfiltered
  4. customThe solvent was evaporated under reduced pressure
  5. customThe residue was purified by column chromatography on silica gel
  6. washeluting with EtOAc/isohexane=1:1

Sources & evidence

ORD record
ord-65c9e10c44ea49368ee1304cc561b6e5
Source dataset
uspto-grants-2016_03
Patent number
US09290454B2

Reaction notes

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