Trifluoroacetic acid → (4aS,5R,7aS)-7a-(2-fluoro-5-(1H-imidazol-2-yl)phenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

HRID 68363

반응식

HRID 68363 반응식
C(OC([N:8]([C:16]1[S:17][CH2:18][C@@H:19]2[C@@H:24]([CH3:25])[O:23][CH2:22][C@:20]2([C:26]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[CH:28][C:27]=2[F:41])[N:21]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.I[C:43]1[N:44](COCC[Si](C)(C)C)[CH:45]=[CH:46][N:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>COCCOC.C([O-])(O)=O.[Na+].C(Cl)Cl.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C.O>[F:41][C:27]1[CH:28]=[CH:29][C:30]([C:43]2[NH:44][CH:45]=[CH:46][N:47]=2)=[CH:31][C:26]=1[C@:20]12[CH2:22][O:23][C@H:24]([CH3:25])[C@H:19]1[CH2:18][S:17][C:16]([NH2:8])=[N:21]2

참가 물질

11

반응물 4

HCID 6422Trifluoroacetic acidHCID 10796Cesium carbonateHCID 103588652-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazoleHCID 86707804di-tert-Butyl{(4aS,5R,7aS)-7a-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl}imidodicarbonate

생성물 1

HCID 57415242(4aS,5R,7aS)-7a-(2-fluoro-5-(1H-imidazol-2-yl)phenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine수율 84.9%

시약·촉매·용매 6

HCID 13169693Triphenylphosphine palladium dichloride촉매HCID 702Ethanol용매HCID 962Water용매HCID 6344Dichloromethane용매HCID 80711,2-Dimethoxyethane용매HCID 516892Sodium Bicarbonate용매

반응 조건

온도
100 °C

실험 절차

di-tert-Butyl{(4aS,5R,7aS)-7a-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl}imidodicarbonate (0.1 g, 0.17 mmol) was dissolved in 1,2-dimethoxyethane (1.5 mL), water (0.7 mL) and ethanol (0.5 mL). The resulting solution was heated to 100° C. and to it was added 2-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (0.1 g, 0.31 mmol), cesium carbonate (0.33 g, 1.0 mmol) and dichloropalladium-triphenylphosphane (0.02 g, 0.03 mmol) and the reaction was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with saturated aqueous NaHCO3 and extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified using column chromatography (gradient 0-100% EtOAc in hexane) to give a mixture of mono and bis BOC products. 1H NMRs consistent with desired structures. The residues were combined and dissolved in DCM (2 mL). Trifluoroacetic acid (1 mL) was added and the solution stirred at room temperature for 1 hour. The solvents were removed in vacuo and saturated aqueous NaHCO3 added. The solution was extracted with DCM (×3). The combined organics were dried (MgSO4), filtered and concentrated to give the title compound (48 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 7.76-7.89 (m, 2 H), 7.06-7.13 (m, 3 H), 4.57 (d, J=9.1 Hz, 1 H), 4.32-4.40 (m, 1 H), 3.81 (dd, J=8.8, 1.8 Hz, 1 H), 3.07 (dd, J=13.4, 3.5 Hz, 1 H), 2.71 (dd, J=13.3, 3.9 Hz, 1 H), 2.57-2.64 (m, 1 H), 1.37 (d. J=6.1 Hz, 3 H)

후처리

  1. temperatureThe reaction mixture was cooled to room temperature
  2. extractionextracted with EtOAc (×3)
  3. dry with materialThe combined organic layers were dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified
  7. customto give
  8. stirringthe solution stirred at room temperature for 1 hour
  9. customThe solvents were removed in vacuo and saturated aqueous NaHCO3
  10. additionadded
  11. extractionThe solution was extracted with DCM (×3)
  12. dry with materialThe combined organics were dried (MgSO4)
  13. filtrationfiltered
  14. concentrationconcentrated

출처 및 근거

ORD 기록
ord-6482be790bac44298a4f2ee490d04bfe
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08822455B2

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