Ethyl Acetate → 4-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholine

HRID 1812370노트

반응식

HRID 1812370 반응식
[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Cl[C:26]1[N:34]=[C:33]([CH3:35])[N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1.C([O-])(=O)C.[K+].CCOC(C)=O>O1CCOCC1.O.CC(O)C.C(Cl)(Cl)Cl>[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH3:9])=[CH:4][C:3]=1[C:26]1[N:34]=[C:33]([CH3:35])[N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1

참가 물질

8

반응물 4

HCID 8857Ethyl AcetateHCID 517044Potassium AcetateHCID 595482686-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purineHCID 666111244-(1-(6-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)ethyl)morpholine

생성물 1

HCID 665998534-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholine수율 55%

시약·촉매·용매 3

HCID 962Water용매HCID 312751,4-Dioxane용매HCID 21906603Chloroform isopropyl alcohol용매

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온도
100 °C

실험 절차

To a 5 mL microwave reaction tube was added 4-(1-(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)ethyl)morpholine (0.523 g, 1.55 mmol), 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Example 3, 0.322 g, 1.28 mmol), Am-Phos (Aldrich, 0.0531 g, 0.075 mmol) and potassium acetate (Aldrich, 0.379 g, 3.87 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL). The mixture was degassed by bubbling argon through for 5 min. The tube was heated in a microwave reactor (Biotage) at 100° C. for 15 min. The reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL). The layers were separated and saturated NH4Cl (30 mL) was added to the aqueous phase. The aqueous phase was extracted with EtOAc (2×40 mL). The combined organic phases were washed with saturated aqueous sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (50 g, eluent: EtOAc in hexanes 20% to 70% then IPA/CHCl3 0% to 12.5%) to afford 4-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholine (0.30 g, 55% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.27-8.37 (m, 3H) 5.86 (d, J=10.37 Hz, 1H) 4.15-4.24 (m, 1H) 3.78-3.88 (m, 1H) 3.64-3.75 (m, 4H) 3.53 (q, J=6.72 Hz, 1H) 2.89 (s, 3H) 2.50-2.60 (m, 2H) 2.38-2.48 (m, 2H) 2.01-2.22 (m, 3H) 1.69-1.91 (m, 3H) 1.43 (d, J=6.65 Hz, 3H). m/z (ESI, positive ion): 427.1 (M+H)+.

후처리

  1. customThe mixture was degassed
  2. customby bubbling argon through for 5 min
  3. customThe reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL)
  4. customThe layers were separated
  5. additionsaturated NH4Cl (30 mL) was added to the aqueous phase
  6. extractionThe aqueous phase was extracted with EtOAc (2×40 mL)
  7. washThe combined organic phases were washed with saturated aqueous sodium chloride (100 mL)
  8. dry with materialThe organic phase was dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe crude product was purified by silica gel column chromatography (50 g, eluent

출처 및 근거

ORD 기록
ord-1e30bdbfd3234bfd8f59a44154be4233
출처 데이터셋
uspto-grants-2013_01
특허 번호
US08362241B2

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