Carbon Dioxide → 3-fluoro-4-((5R,7S)-7-hydroxy-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile

HRID 2036033노트

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HRID 2036033 반응식
[Li]CCCC.CCCCCC.C(=O)=O.Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[C@@H:36]1[N:40]2[CH:41]=[N:42][CH:43]=[C:39]2[C:38](=[O:44])[CH2:37]1)[C:31]#[N:32]>C1COCC1.CC(C)=O>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[C@@H:36]1[N:40]2[CH:41]=[N:42][CH:43]=[C:39]2[C@@:38]([OH:44])([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[CH2:37]1)[C:31]#[N:32]

참가 물질

8

반응물 5

HCID 280Carbon DioxideHCID 8058HexaneHCID 5210081-Bromo-4-(trifluoromethoxy)benzeneHCID 67216150(R)-3-fluoro-4-(7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrileHCID 178418339Butyllithium

생성물 1

HCID 532366653-fluoro-4-((5R,7S)-7-hydroxy-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile수율 15.8%

시약·촉매·용매 2

HCID 180Acetone용매HCID 8028Tetrahydrofuran용매2회

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온도
-78 °C

실험 절차

To a solution of a 1.6 M n-BuLi solution in hexane (0.428 ml, 0.684 mmol) cooled in a dry ice and acetone bath was added a solution of 1-bromo-4-(trifluoromethoxy)benzene (0.046 ml, 0.311 mmol) in 1 mL THF. The yellow crude was stirred at −78° C. for 1 hr. This crude was cannulated to a solution of 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (75 mg, 0.311 mmol) in THF (1 mL) cooled to −78° C. The crude was slowly warmed to room temperature over 5 hrs. The crude was quenched with NH4Cl and diluted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was first purified via preparation plate using 5% (2M NH3 in MeOH)/CH2Cl2. The product was further purified using HPLC to give 19.8 mg of the entitled product as the major diastereomer. MS 404.2 (M+H); LCMS condition A, retention time 1.38 min. 1H NMR (400 MHz, CDCl3) δ ppm 2.94 (d, 1H), 3.26 (dd, 1H), 5.71 (d, 1H), 6.72 (br. s., 1H), 7.03-7.17 (m, 3H), 7.27-7.39 (m, 3H), 7.40-7.52 (m, 2H).

후처리

  1. temperaturecooled to −78° C
  2. temperatureThe crude was slowly warmed to room temperature over 5 hrs
  3. customThe crude was quenched with NH4Cl
  4. additiondiluted with EtOAc
  5. washThe organic layer was washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude was first purified via preparation plate
  10. customThe product was further purified

출처 및 근거

ORD 기록
ord-de9cee6187c349bd85c0925e228b5c41
출처 데이터셋
uspto-grants-2013_11
특허 번호
US08575160B2

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