Diisopropylamine → HCID 58579110, compound

HRID 2046148Notes

Reaction equation

HRID 2046148 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.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>O1CCCC1>[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:43](=[O:47])[CH:44]([CH3:46])[CH3:45])=[CH:34][CH:33]=2)[CH2:23][CH2:22]1

Participants

6

Reactant 4

HCID 7912DiisopropylamineHCID 60795AripiprazoleHCID 62325Isobutyryl chlorideHCID 178418339Butyllithium

Product 1

HCID 58579110HCID 58579110, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of diisopropylamine (1.3 mL, 8.9 mmol) in tetrahydrofuran (25 mL) at 78° C. was added n-BuLi (2.2M in hexanes, 4.1 mL, 8.9 mmol). The reaction mixture was warmed to 0° C. and after 10 min was re-cooled to 78° C. and aripiprazole (2.0 g, 4.5 mmol) added. The reaction mixture was stirred for 30 min and then isobutyryl chloride (0.7 mL, 6.7 mmol) added. After 2 h the reaction mixture was warmed to room temperature and stirred for 1 h. A second reaction was carried out under exactly the same conditions and the two reactions were combined. This mixture was washed with water, dried over MgSO4, filtered and evaporated. The residue was dissolved in diethyl ether and 4M HCl in diethyl ether added to form a precipitate. The mother liquor was decanted and the residual gum was washed with diethyl ether. The gum was then partitioned between ethyl acetate and saturated sodium bicarbonate, and the organic layer separated. After drying over MgSO4 and evaporation, the residue was further purified on silica eluting with 1:1:0.1 dichloromethane/ethyl acetate/methanol to give Compound-16 (1.3 g) as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ 7.16-7.13 (m, 2H), 7.08 (d, 1H), 6.98-6.92 (m, 1H), 6.65-6.59 (m, 2H), 3.93 (t, 2H), 3.48 (dt, 1H), 3.12-3.01 (m, 4H), 2.86 (dd, 1H), 2.72-2.59 (m, 6H), 2.47 (t, 2H), 1.84-1.64 (m, 4H), 1.25 (d, 6H). [M+H]+=518.2.

Workup

  1. temperaturewas re-cooled to 78° C.
  2. temperatureAfter 2 h the reaction mixture was warmed to room temperature
  3. stirringstirred for 1 h
  4. customA second reaction
  5. washThis mixture was washed with water
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customevaporated
  9. dissolutionThe residue was dissolved in diethyl ether
  10. addition4M HCl in diethyl ether added
  11. customto form a precipitate
  12. customThe mother liquor was decanted
  13. washthe residual gum was washed with diethyl ether
  14. customThe gum was then partitioned between ethyl acetate and saturated sodium bicarbonate
  15. customthe organic layer separated
  16. dry with materialAfter drying over MgSO4 and evaporation
  17. customthe residue was further purified on silica eluting with 1:1:0.1 dichloromethane/ethyl acetate/methanol
  18. customto give Compound-16 (1.3 g) as a yellow solid

Sources & evidence

ORD record
ord-9477ade9e82c4e0d9c0c5b8f4b59eaeb
Source dataset
uspto-grants-2013_11
Patent number
US08592427B2

Reaction notes

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