Oxalyl chloride → 7-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yl diethyl phosphate

HRID 2046153Notes

Reaction equation

HRID 2046153 reaction equation
[P:1]([O-])([O:11][CH2:12][C:13]1C=CC=CC=1)([O:3][CH2:4][C:5]1C=CC=CC=1)=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:26]1[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]3[CH:43]=[CH:44][C:45]([NH:47][C:39]=3[CH:38]=2)=[O:46])[CH2:30][CH2:29][N:28]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[CH2:27]1.CC(C)([O-])C.[K+]>ClCCl.CN(C)C=O.CC1CCCO1>[P:1]([O:11][CH2:12][CH3:13])([O:3][CH2:4][CH3:5])([O:46][C:45]1[CH:44]=[CH:43][C:40]2[C:39](=[CH:38][C:37]([O:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]3[CH2:30][CH2:29][N:28]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=4[Cl:55])[CH2:27][CH2:26]3)=[CH:42][CH:41]=2)[N:47]=1)=[O:2]

Participants

8

Reactant 4

HCID 65578Oxalyl chlorideHCID 4193600DibenzylphosphateHCID 10114519DehydroaripiprazoleHCID 23665647Potassium tert-butoxide

Product 1

HCID 575015817-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2-yl diethyl phosphate

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 73012-MethyltetrahydrofuranSolvent

Procedure

To a solution of dibenzyl phosphate (2.48 g, 8.91 mmol) in dichloromethane (25 ml) was added N,N-dimethyl formamide (1 drop) followed by oxalyl chloride (0.75 mL, 8.91 mmol). After 2 hours the reaction mixture was concentrated in vacuo. The residue was dissolved in 2-methyltetrahydrofuran (5 mL) and added to a suspension of dehydro-aripiprazole (1.66 g, 3.71 mmol) and potassium t-butoxide (0.92 g, 8.17 mmol) in 2-methyltetrahydrofuran (35 mL) at 0° C. under argon gas, then allowed to gradually warm to room temperature. After stirring overnight the reaction was quenched with water (25 mL) and 28% aq NH3 (15 mL) and stirred for 10 minutes. The reaction mixture was then extracted with ethyl acetate (2×40 mL). The combined organics were washed with water (50 mL) and brine (50 mL) then dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by column chromatography eluting with 5% methanol (1:1 ethyl acetate/dichloromethane) to give the product. The 1H-NMR showed minor impurities still present (impurities not observed by LCMS). Various further purifications were attempted but failed to remove these impurities.

Workup

  1. concentrationAfter 2 hours the reaction mixture was concentrated in vacuo
  2. dissolutionThe residue was dissolved in 2-methyltetrahydrofuran (5 mL)
  3. customwas quenched with water (25 mL) and 28% aq NH3 (15 mL)
  4. stirringstirred for 10 minutes
  5. extractionThe reaction mixture was then extracted with ethyl acetate (2×40 mL)
  6. washThe combined organics were washed with water (50 mL) and brine (50 mL)
  7. dry with materialthen dried (MgSO4)
  8. concentrationconcentrated in vacuo
  9. customThe crude mixture was purified by column chromatography
  10. washeluting with 5% methanol (1:1 ethyl acetate/dichloromethane)
  11. customto give the product
  12. customto remove these impurities

Sources & evidence

ORD record
ord-1065622161d3414cb8076cb6f5df5583
Source dataset
uspto-grants-2013_11
Patent number
US08592427B2

Reaction notes

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