Diisopropylamine → 4-[4-Hydroxy-1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidyl]-1-(3-pyridyl)butane-1,3-dione

HRID 1478435Notes

Reaction equation

HRID 1478435 reaction equation
C(NC(C)C)(C)C.[Li]CCCC.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22])[CH:14]=1.[CH:25]([O:28][C:29]1[CH:43]=[CH:42][C:32]([C:33]([N:35]2[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]2)=[O:34])=[CH:31][C:30]=1[CH3:44])([CH3:27])[CH3:26]>CCCCCC.C1COCC1>[OH:41][C:38]1([CH2:22][C:21](=[O:23])[CH2:20][C:19]([C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[O:24])[CH2:39][CH2:40][N:35]([C:33](=[O:34])[C:32]2[CH:42]=[CH:43][C:29]([O:28][CH:25]([CH3:26])[CH3:27])=[C:30]([CH3:44])[CH:31]=2)[CH2:36][CH2:37]1

Participants

7

Reactant 4

HCID 7912DiisopropylamineHCID 3001601-(Pyridin-3-yl)butane-1,3-dioneHCID 897045931-(4-Isopropoxy-3-methyl-benzoyl)piperidin-4-oneHCID 178418339Butyllithium

Product 1

HCID 897045014-[4-Hydroxy-1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidyl]-1-(3-pyridyl)butane-1,3-dioneYield 64.1%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 8058HexaneSolvent

Conditions

Temperature
-78 °C

Procedure

To an oven-dried round bottom flask was added diisopropylamine (6.4 mL, 46 mmol) and THF (125 mL). It was cooled to −78° C., and a solution of nBuLi (18 mL of 2.5 M, 46 mmol) in hexane was added. It was stirred at 0° C. for 30 minutes and again cooled to −78° C. 1-(3-pyridyl)butane-1,3-dione (3.40 g, 21.0 mmol) in a solution of THF (25 mL) was added dropwise. After 30 minutes at −78° C., a solution of 1-(4-isopropoxy-3-methyl-benzoyl)piperidin-4-one (5.74 g, 20.8 mmol) in THF (25 mL) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride (100 mL). Volatiles were removed under reduced pressure to one-third volume. It was extracted with ethyl acetate (2×75 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude brown oil was purified by column chromatography (100% ethyl acetate) to provide 4-[4-hydroxy-1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidyl]-1-(3-pyridyl)butane-1,3-dione (5.85 g) as a yellow foaming solid. 1H NMR (400 MHz, CDCl3) δ 15.81 (s, 1H), 9.08 (d, J=1.9 Hz, 1H), 8.76 (dd, J=4.8, 1.5 Hz, 1H), 8.19 (dd, J=8.0, 1.6 Hz, 1H), 7.49-7.42 (m, 1H), 7.24-7.17 (m, 2H), 6.80 (d, J=8.2 Hz, 1H), 6.20 (s, 1H), 4.55 (m, 1H), 4.51-4.25 (br s, 1H), 3.52-3.26 (m, 4H), 2.68 (s, 2H), 2.20 (s, 3H), 1.75-1.51 (m, 4H), 1.34 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 438.22, found 439.5 (M+1)+; Retention time: 1.37 minutes (3 min run).

Workup

  1. temperatureagain cooled to −78° C
  2. waitAfter 30 minutes at −78° C.
  3. temperatureto slowly warm to room temperature
  4. stirringstirred overnight
  5. customThe reaction mixture was quenched with saturated ammonium chloride (100 mL)
  6. customVolatiles were removed under reduced pressure to one-third volume
  7. extractionIt was extracted with ethyl acetate (2×75 mL)
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe crude brown oil was purified by column chromatography (100% ethyl acetate)

Sources & evidence

ORD record
ord-84dd5f9789ec4fbdabd22119cc56a33a
Source dataset
uspto-grants-2016_08
Patent number
US09403839B2

Reaction notes

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