Sodium hydride → chloromethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate

HRID 1518666Notes

Reaction equation

HRID 1518666 reaction equation
[CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.[H-].[Na+].Cl[C:34]([O:36][CH2:37][Cl:38])=[O:35]>CC1CCCO1.C(OCC)(=O)C>[Cl:8][C:4]1[C:5]([Cl:7])=[CH:6][CH:1]=[CH:2][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[C:24]3[C:23]([CH2:30][CH2:29][C:27](=[O:28])[N:26]3[C:34]([O:36][CH2:37][Cl:38])=[O:35])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1

Participants

6

Reactant 3

HCID 24758Sodium hydride2×HCID 60795AripiprazoleHCID 62754Chloromethyl chloroformate

Product 1

HCID 66810238chloromethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate

Reagents, catalysts & solvents 2

HCID 73012-MethyltetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a suspension of aripiprazole (1 g, 2.23 mmol) in 2-methyltetrahydrofuran (20 mL) was added NaH (178 mg, 4.46 mmol). After 1 hour, a further of NaH (178 mg) was added. The reaction was stirred at ambient temperature overnight then heated to reflux for 3 hours. The reaction was cooled to room temperature and chloromethyl chloroformate (0.60 mL, 6.69 mmol) was then added and the reaction stirred for 2 hours. The reaction was cooled to 0° C., diluted with ethyl acetate (20 mL) and quenched with aqueous saturated NaHCO3 solution (20 mL). The reaction was extracted with ethyl acetate (3×20 mL) and the combined organics washed with brine (50 mL), then dried (MgSO4) and concentrated to give chloromethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (crude yield 1.54 g) as a 2:1 mixture of product/aripiprazole. The product was taken onto the next step crude.

Workup

  1. temperaturethen heated
  2. temperatureto reflux for 3 hours
  3. temperatureThe reaction was cooled to room temperature
  4. stirringthe reaction stirred for 2 hours
  5. temperatureThe reaction was cooled to 0° C.
  6. customquenched with aqueous saturated NaHCO3 solution (20 mL)
  7. extractionThe reaction was extracted with ethyl acetate (3×20 mL)
  8. washthe combined organics washed with brine (50 mL)
  9. dry with materialdried (MgSO4)
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-b639c3cb5aaa4855bfd44bfce8b2eaf7
Source dataset
uspto-grants-2015_07
Patent number
US09072788B2

Reaction notes

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