Methyl morpholine oxide → Tert-butyl (3-((5-acetyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate

HRID 527398Notes

Reaction equation

HRID 527398 reaction equation
[OH:1][CH:2]([C:4]1[C:5]([NH:12][C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=[CH:17][CH:18]=2)=[N:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1)[CH3:3].C[N+]1([O-])CCOCC1.CO.CCOC(C)=O>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:2]([C:4]1[C:5]([NH:12][C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=[CH:17][CH:18]=2)=[N:6][C:7]([S:10][CH3:11])=[N:8][CH:9]=1)(=[O:1])[CH3:3]

Participants

6

Reactant 3

HCID 82029Methyl morpholine oxideHCID 21584119Ethylacetate methanolHCID 86732008Tert-butyl (3-((5-(1-hydroxyethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate

Product 1

HCID 86732010Tert-butyl (3-((5-acetyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamateYield 56.5%

Reagents, catalysts & solvents 2

HCID 178419074HCID 178419074, compoundCatalystHCID 6344DichloromethaneSolvent

Procedure

Tetrapropylammonium perruthenate (1.05 g, 2.99 mmol) was added to a heterogenous mixture of tert-butyl (3-((5-(1-hydroxyethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (22.5 g, 59.8 mmol) and 4-methylmorpholine N-oxide (8.75 g, 74.7 mmol) in DCM (460 mL) at RT. The mixture was stirred at RT for 3 h and concentrated under reduced pressure. The dark solid was dissolved in 10% MeOH in DCM and the material was adsorbed on to silica gel. The material was purified by silica gel pad (2-L sintered medium frit filled halfway with silica gel) eluted with 10% EtOAc in DCM (2 L) followed by 20% EtOAc in DCM (2 L). The fractions containing the desired product was concentrated to afford a white solid. 1.2 L of 1/1 MeOH/EtOAc was added to the solid and the mixture was heated to reflux and cooled to RT slowly. The mixture sat at RT overnight. The white fluffy needles were collected by filtration and washed with EtOAc to afford tert-butyl (3-((5-acetyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (53) (12.66 g, 33.8 mmol, 56% yield). The filtrate was concentrated and the residue was absorbed on to silica gel and the material was purified by silica gel pad (2 L sintered medium frit filled halfway with silica gel) eluted with 10% EtOAc in DCM (2 L) followed by 15% EtOAc in DCM (2 L) followed by 20% EtOAc in DCM. The fractions containing the desired product was concentrated to afford a white solid. 600 mL of 1/1 MeOH/EtOAc was added to the solid and the mixture was heated to reflux and cooled to RT slowly. The mixture was seeded with a small amount of the desired product when the mixture was at 60° C. The mixture sat at RT overnight. The white fluffy needles were collected by filtration and washed with EtOAc to afford additional tert-butyl (3-((5-acetyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (53) (4.20 g, 11.22 mmol, 18% yield). m/z (ESI, +ve ion) 374.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 11.30 (1H, s), 8.68-8.73 (1H, m), 7.91 (1H, s), 7.30-7.35 (1H, m), 7.05 (1H, dd, J=8.0, 1.0 Hz), 6.46 (1H, br. s.), 2.59 (3H, s), 2.56 (3H, s), 1.52 (9H, s).

Workup

  1. concentrationconcentrated under reduced pressure
  2. dissolutionThe dark solid was dissolved in 10% MeOH in DCM
  3. customThe material was purified by silica gel pad (2-L sintered medium frit filled halfway with silica gel)
  4. washeluted with 10% EtOAc in DCM (2 L)
  5. additionThe fractions containing the desired product
  6. concentrationwas concentrated
  7. customto afford a white solid
  8. temperaturethe mixture was heated
  9. temperatureto reflux
  10. temperaturecooled to RT slowly
  11. waitThe mixture sat at RT overnight
  12. filtrationThe white fluffy needles were collected by filtration
  13. washwashed with EtOAc

Sources & evidence

ORD record
ord-d75efdc853dd46c8bf8f991de1caa15a
Source dataset
uspto-grants-2016_05
Patent number
US09346801B2

Reaction notes

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