Lithium Hexamethyldisilazide → Methyl 1-[(1,1-dimethylethoxy)carbonyl]-beta-(4-fluorophenyl)-alpha-(2-methyl-1-oxopropyl)-2-oxo-3-piperidinepropanoate

HRID 29093

Reaction equation

HRID 29093 reaction equation
[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[C:33]([C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C:34]([O:36][CH3:37])=[O:35])=[CH:28][CH:27]=1>C1COCC1>[CH3:12][C:11]([CH3:14])([O:10][C:8]([N:3]1[CH2:4][CH2:5][CH2:6][CH:7]([CH:32]([C:29]2[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=2)[CH:33]([C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C:34]([O:36][CH3:37])=[O:35])[C:2]1=[O:1])=[O:9])[CH3:13]

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 7577838tert-Butyl 2-oxopiperidine-1-carboxylateHCID 54501938Methyl 2-[(4-fluorophenyl)methylidene]-4-methyl-3-oxopentanoate

Product 1

HCID 11419535Methyl 1-[(1,1-dimethylethoxy)carbonyl]-beta-(4-fluorophenyl)-alpha-(2-methyl-1-oxopropyl)-2-oxo-3-piperidinepropanoateYield 77.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-30 °C

Procedure

To a stirred solution of 1,1-dimethylethyl 2-oxo-1-piperidinecarboxylate (10 g, 50 mmole) in anhydrous THF (50 mL) which had been cooled to −20 to −30° C. was added LiHMDS in THF (55 mL, 1M, 55 mmol) solution, maintaining the temperature between −25 to −35° C. The reaction mixture was stirred for 20-30 minutes then transferred via cannula to a cooled solution (−20° C.) of methyl 3-(4-fluorophenyl)-2-isobutyrylacrylate (12.5 g, 50 mmol) in 75 mL anhydrous THF. When the reaction was complete as judged by TLC monitoring, the reaction was quenched with 100 mL of saturated ammonium chloride and extracted with ethyl acetate (2×200 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to provide an off white solid. Recrystallization from ethyl acetate/hexanes afforded 17.4 g (77% yield) of methyl 1-[(1,1-dimethylethoxy)carbonyl]-β-(4-fluorophenyl)-α-(2-methyl-1-oxopropyl)-2-oxo-3-piperidinepropanoate in as a white crystalline solid. NMR clearly shows a mixture of isomers: IR (KBr) cm−1 2979, 1758, 1755, 1745, 1714, 1671; 1H NMR (CDCl3, 400 MHz) δ 7.21-7.20 (m, 4H), 6.93-6.92 (m, 4H), 4.40 (dd, 2H), 4.09 (m, 2H), 3.66 (s, 3H), 3.58-3.33 (m, 4H), 3.32 (s, 3H), 2.80-2.48 (m, 4H), 2.02-1.60 (m, 6H), 1.47 (s, 18H), 1.43-1.51 (m, 2H), 1.08 (d, J=4 Hz, 3H), 1.05 (d, J=8 Hz, 3H), 0.85 (d, J=4 Hz, 3H), 0.71 (d, J=8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 206.9, 206.8, 171.7, 171.6, 168.4, 168.2, 162.6, 160.2, 151.9, 134.5, 134.3, 131.1, 130.0, 130.8, 130.7, 115.2, 115.1, 115, 114.9, 82.9, 61.5, 60.8, 53.0, 52.6, 48.2, 48.0, 46.3, 45.9, 45.6, 44.9, 41.9, 40.9, 28.63, 24.2, 24.0, 21.9, 21.3, 19.5, 19.0, 18.8, 18.7; HRMS (ES) calcd. for C24H32FNNaO6 (M+Na): 472.2111; found: 472.2100.

Workup

  1. customthe reaction was quenched with 100 mL of saturated ammonium chloride
  2. extractionextracted with ethyl acetate (2×200 mL)
  3. dry with materialThe combined organic phases were dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto provide an off white solid
  7. customRecrystallization from ethyl acetate/hexanes

Sources & evidence

ORD record
ord-9fad3c27966e48db8790c435435d15c8
Source dataset
uspto-grants-2008_09
Patent number
US07420059B2

Linked notes

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