Lithium Hexamethyldisilazide → (2S,3R)-Diisopropyl 2-((6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)methyl)-3-hydroxysuccinate

HRID 73482

반응식

HRID 73482 반응식
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:22][CH:23]([CH3:25])[CH3:24])(=[O:21])[C@@H:12]([CH2:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[OH:13].Br[CH2:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([N:35]2[C:39]([CH3:40])=[CH:38][CH:37]=[C:36]2[CH3:41])[N:29]=1>C1COCC1>[CH3:40][C:39]1[N:35]([C:30]2[N:29]=[C:28]([CH2:27][C@@H:14]([C@@H:12]([OH:13])[C:11]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH:33]=[C:32]([CH3:34])[CH:31]=2)[C:36]([CH3:41])=[CH:37][CH:38]=1

참가 물질

5

반응물 3

HCID 2733832Lithium HexamethyldisilazideHCID 10921962Diisopropyl (R)-(+)-malateHCID 445431562-(Bromomethyl)-6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridine

생성물 1

HCID 44543304(2S,3R)-Diisopropyl 2-((6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-2-yl)methyl)-3-hydroxysuccinate수율 70%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매3회

반응 조건

온도
-78 °C

실험 절차

To a dry flask containing THF (20 mL) at −78° C. was added fresh LHMDS (1.0 M in THF, 10 mL, 10 mmol). After 10 min, a solution of diisopropyl (R)-(+)-malate (5b, 1008 μL, 4.88 mmol) was added dropwise as a solution in THF (5 mL) through a cannula. The reaction was stirred at the same temperature for 10 min then transferred to an ice-bath (0° C.) for 30 min. The reaction was cooled to −78° C. again and 6 (1017 mg, 3.66 mmol) was added slowly (1 drop/sec) as a solution in THF (5 mL) through a cannula. The color of the reaction mixture turned light purple. The reaction was maintained at −78° C. for an additional 30 min then transferred to an ice-bath and slowly warm to room temperature. After 2 h, the reaction was quenched with NH4Cl (1 mL) then partitioned between EtOAc (200 mL) and saturated NH4Cl (150 mL). The inorganic layer was extracted with EtOAc (150 mL). The combined organic layer was washed by H2O (100 mL), brine (100 mL), dried over Na2SO4, and concentrated. The crude yellow oil was purified by flash column chromatography (EtOAc/hexanes, 1:9-1:4) to give 4b (1.76 g, 2.56 mmol, 70%) as a pale yellow oil (without detection of any cis-isomer): 1H NMR (500 MHz, CDCl3) δ 1.14-1.15 (d, J=6.5 Hz, 3H), 1.17-1.18 (d, J=6.0 Hz, 3H), 1.25-1.26 (d, J=6.5 Hz, 3H), 1.29-1.30 (d, J=6.0 Hz, 3H), 2.13 (s, 6H), 2.41 (s, 3H), 3.10-3.15 (dd, J=8.5, 14.0 Hz, 1H), 3.34-3.40 (m, 2H), 3.72-3.76 (dt, J=2.5, 8.0 Hz, 1H), 4.07-4.09 (dd, J=2.5, 7.0 Hz, 1H), 4.96-5.01 (m, 1H), 5.09-5.15 (m, 1H), 5.90 (s, 2H), 6.89 (s, 1H), 7.10 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.5, 21.2, 21.8, 21.9, 22.0, 36.1, 48.0, 68.8, 70.1, 70.6, 107.0, 120.7, 124.1, 128.7, 150.1, 158.7, 171.5, 173.4; LCQ-MS (M+H+) calcd for C23H33N2O5 417. found 417; LC-TOF-MS (M+H+) calcd for C23H33N2O5 417.23895. found 417.23834.

후처리

  1. customthen transferred to an ice-bath
  2. wait(0° C.) for 30 min
  3. temperatureThe reaction was maintained at −78° C. for an additional 30 min
  4. customthen transferred to an ice-bath
  5. temperatureslowly warm to room temperature
  6. waitAfter 2 h
  7. customthe reaction was quenched with NH4Cl (1 mL)
  8. customthen partitioned between EtOAc (200 mL) and saturated NH4Cl (150 mL)
  9. extractionThe inorganic layer was extracted with EtOAc (150 mL)
  10. washThe combined organic layer was washed by H2O (100 mL), brine (100 mL)
  11. dry with materialdried over Na2SO4
  12. concentrationconcentrated
  13. customThe crude yellow oil was purified by flash column chromatography (EtOAc/hexanes, 1:9-1:4)

출처 및 근거

ORD 기록
ord-a85301cefa144f6ead5244ece6da9c95
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08829187B1

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