Methyl iodide → HCID 68774665, compound

HRID 2191095Notes

Reaction equation

HRID 2191095 reaction equation
FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[C:17]([C:19]3[C:23]4[CH2:24][C:25]([CH3:30])([CH3:29])[CH2:26][C:27](=[O:28])[C:22]=4[S:21][C:20]=3[N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:16]=[CH:15][N:14]=2)[CH:8]=1)(=O)=O.C(O[C:44](=O)[NH:45][CH:46]1[CH2:49][NH:48][CH2:47]1)(C)(C)C.CC(C)([O-])C.[K+].[H-].[Na+].CI>O1CCOCC1.CN(C=O)C.CC(O)=O.CC(P(C(C)(C)C)C1C(C2[C-]=CC=CC=2)=CC=CC=1)(C)C.[Pd]>[CH3:29][C:25]1([CH3:30])[CH2:24][C:23]2[C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:9]4[CH:8]=[CH:7][CH:12]=[C:11]([N:48]5[CH2:47][CH:46]([NH:45][CH3:44])[CH2:49]5)[CH:10]=4)[CH:18]=3)=[C:20]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[S:21][C:22]=2[C:27](=[O:28])[CH2:26]1

Participants

9

Reactant 5

HCID 6328Methyl iodideHCID 24758Sodium hydride2×HCID 15194053-Aminoazetidine, 3-BOC protectedHCID 23665647Potassium tert-butoxideHCID 87571193HCID 87571193, compound

Product 1

HCID 68774665HCID 68774665, compoundYield 31%

Reagents, catalysts & solvents 3

HCID 119822622-(2'-Di-tert-butylphosphine)biphenylpalladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of Example 360 (200 mg, 0.35 mmol), azetidin-3-ylcarbamic acid tert-butyl ester (125 mg, 0.71 mmol), potassium tert-butoxide (60 mg, 0.49 mmol) and acetato(2′-di-tert-butylphosphino-1,1′-biphenyl-2-yl)palladium(II) (10 mg, 0.02 mmol) in 1,4-dioxane (3.0 mL) was heated in a sealed tube at 100° C., under microwave irradiation, for 30 minutes. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 0-100% EtOAc/heptane). To a solution of the obtained solid in DMF (10 mL) was added sodium hydride (60% dispersion in oil, 10 mg, 0.24 mmol) and the reaction was stirred at room temperature for 30 minutes. Methyl iodide (18 μL, 0.29 mmol) was added and stirring was continued at room temperature for 18 h. Further sodium hydride (60% dispersion in oil, 10 mg, 0.24 mmol) was added and stirring was continued for 2 h at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 0-100% EtOAc/heptane). To a solution of the obtained solid in DCM (8 mL) was added TFA (2 mL) and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was partitioned between DCM (20 mL) and saturated aqueous sodium hydrogencarbonate solution (20 mL). The organic phase was concentrated in vacuo and was purified by column chromatography (SiO2, 0-20% MeOH/DCM) to give the title compound (5 mg, 31%) as a clear glass. δH(CD3OD) 8.68 (1H, d, J 5.1 Hz), 7.91 (1H, s), 7.44 (1H, dd, J 5.3, 1.7 Hz), 7.39-7.29 (2H, m), 7.14-7.08 (1H, m), 6.68-6.60 (1H, m), 4.29-4.17 (2H, m), 4.02-3.91 (1H, m), 3.74-3.56 (6H, m), 3.15-3.01 (4H, m), 2.64 (2H, s), 2.47 (2H, m), 1.05 (6H, s). LCMS (ES+) 503.3 (M+H)+.

Workup

  1. customThe solvent was removed in vacuo
  2. customthe residue was purified by column chromatography (SiO2, 0-100% EtOAc/heptane)
  3. stirringstirring
  4. waitwas continued at room temperature for 18 h
  5. stirringstirring
  6. waitwas continued for 2 h at room temperature
  7. customThe solvent was removed in vacuo
  8. customthe residue was purified by column chromatography (SiO2, 0-100% EtOAc/heptane)
  9. additionTo a solution of the obtained solid in DCM (8 mL) was added TFA (2 mL)
  10. stirringthe reaction mixture was stirred at room temperature for 2 h
  11. customThe solvent was removed in vacuo
  12. customthe residue was partitioned between DCM (20 mL) and saturated aqueous sodium hydrogencarbonate solution (20 mL)
  13. concentrationThe organic phase was concentrated in vacuo
  14. customwas purified by column chromatography (SiO2, 0-20% MeOH/DCM)

Sources & evidence

ORD record
ord-4fb1801fa7804bceb9cdd4e35588b010
Source dataset
uspto-grants-2012_12
Patent number
US08324204B2

Reaction notes

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