Diisopropylamine → Hexyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate

HRID 2046142Notes

Reaction equation

HRID 2046142 reaction equation
C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[CH:14]=[C:15]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]4[CH2:42][CH2:41][C:39](=[O:40])[NH:38][C:36]=4[CH:37]=3)[CH2:23][CH2:22]2)[C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=1.[CH2:43]([O:49][C:50](Cl)=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>CC1CCCO1>[Cl:20][C:16]1[C:17]([Cl:19])=[CH:18][CH:13]=[CH:14][C:15]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[C:36]3[C:35]([CH2:42][CH2:41][C:39](=[O:40])[N:38]3[C:50]([O:49][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:51])=[CH:34][CH:33]=2)[CH2:23][CH2:22]1

Participants

6

Reactant 4

HCID 7912DiisopropylamineHCID 22466Hexyl chloroformateHCID 60795AripiprazoleHCID 178418339Butyllithium

Product 1

HCID 56596929Hexyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate

Reagents, catalysts & solvents 1

HCID 73012-MethyltetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of diisopropylamine (1.11 mL, 7.87 mmol) in 2-methyltetrahydrofuran (37 mL) at −5° C. was added n-BuLi (3.0 mL, 2.5 M in hexanes, 7.49 mmol) slowly. After 20 minutes, the reaction was cooled to −78° C. and Aripiprazole (1.68 g, 3.74 mmol) was added. After a further 10 minutes, hexylchloroformate (1.53 mL, 9.37 mmol) was added. The reaction was held at −78° C. for 2 hours before allowing to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica eluting with 0 to 3% tetrahydrofuran in ethyl acetate. The product was triturated in heptane to remove aliphatic impurities and then filtered and dried to afford Compound-59 (0.487 g) as a colorless solid. 1H-NMR (300 MHz, CDCl3) δ 7.14 (2H, m), 7.07 (1H, d), 6.95 (1H, m), 6.62 (1H, dd), 6.54 (1H, d), 4.38 (2H, t), 3.95 (2H, t), 3.06 (4H, m), 2.89 (2H, t), 2.66 (6H, m), 2.47 (2H, t), 1.90-1.65 (6H, m), 1.49-1.30 (6H, m), 0.88 (3H, t). [M+H]+=576.2.

Workup

  1. waitAfter a further 10 minutes
  2. waitThe reaction was held at −78° C. for 2 hours
  3. temperatureto warm to room temperature overnight
  4. customThe reaction was quenched with saturated aqueous ammonium chloride solution (30 mL)
  5. extractionextracted with ethyl acetate (2×30 mL)
  6. washwashed with saturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL)
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated
  9. customThe crude product was purified by column chromatography on silica eluting with 0 to 3% tetrahydrofuran in ethyl acetate
  10. customThe product was triturated in heptane
  11. customto remove aliphatic impurities
  12. filtrationfiltered
  13. customdried
  14. customto afford Compound-59 (0.487 g) as a colorless solid

Sources & evidence

ORD record
ord-03a75048aea4498098d2aa76d09a669a
Source dataset
uspto-grants-2013_11
Patent number
US08592427B2

Reaction notes

Loading…