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

HRID 29093

반응식

HRID 29093 반응식
[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]

참가 물질

5

반응물 3

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

생성물 1

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

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매3회

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온도
-30 °C

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-9fad3c27966e48db8790c435435d15c8
출처 데이터셋
uspto-grants-2008_09
특허 번호
US07420059B2

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