18-Crown-6 → 2-Chloro-6-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-4-pyridinecarbonitrile

HRID 1874918노트

반응식

HRID 1874918 반응식
[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[Cl:35][C:36]1[CH:41]=[C:40]([C:42]#[N:43])[CH:39]=[C:38](Cl)[N:37]=1>C1COCC1>[Cl:35][C:36]1[CH:41]=[C:40]([C:42]#[N:43])[CH:39]=[C:38]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([CH3:10])[C:6]=2[F:9])[N:37]=1

참가 물질

6

반응물 4

HCID 2855718-Crown-6HCID 7359062,6-DichloroisonicotinonitrileHCID 27736846-Chloro-2-fluoro-3-methylphenolHCID 23665647Potassium tert-butoxide

생성물 1

HCID 866448942-Chloro-6-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-4-pyridinecarbonitrile수율 44.3%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매2회

실험 절차

6-chloro-2-fluoro-3-methylphenol (4.73 g, 29.5 mmol) and 18-crown-6 (1.558 g, 5.90 mmol) were combined and treated with 20% potassium t-butoxide in THF (16.54 g, 29.5 mmol) in THF at 25° C. and stirred 15 min. 2,6-dichloro-4-pyridinecarbonitrile (5.1 g, 29.5 mmol) was added to the reaction mixture and stirred at ambient temperature for 4 days. A fine white precipitate was filtered off from the reaction mixture and washed with a small amount of DMSO. This material was partitioned between EtOAc and saturated aqueous NaHCO3, the phases separated, and the aqueous phase extracted twice with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated to dryness to give 2-chloro-6-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-4-pyridinecarbonitrile (3.88 g, 13.06 mmol, 44.3% yield) as a white solid. The DMSO filtrate was treated with water and saturated aqueous NaHCO3 to give a purple precipitate that was filtered off, washed with water and air dried. This material was dissolved in DCM, dried over MgSO4, filtered and concentrated to dryness to give a purple solid. The residue was trituarated with EtOH, cooled in an ice bath, filtered and air dried to give a second batch of the desired product (3.65 g, 12.28 mmol, 41.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (d, J=0.82 Hz, 1H), 7.93 (d, J=0.73 Hz, 1H), 7.28-7.43 (m, 2H), 2.28 (d, J=1.74 Hz, 3H). LC-MS (ES+) m/z 296.95, 298.88 [M+H].

후처리

  1. stirringstirred at ambient temperature for 4 days
  2. filtrationA fine white precipitate was filtered off from the reaction mixture
  3. washwashed with a small amount of DMSO
  4. customThis material was partitioned between EtOAc and saturated aqueous NaHCO3
  5. customthe phases separated
  6. extractionthe aqueous phase extracted twice with EtOAc
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated to dryness

출처 및 근거

ORD 기록
ord-df558e7aafc2451c91fc0cb62a0ffdce
출처 데이터셋
uspto-grants-2012_11
특허 번호
US08304419B2

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