Water → (4aS,5R,7aS)-5-Methyl-7a-(2',4,5'-trifluoro-[1,1'-biphenyl]-3-yl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

HRID 68367Notes

Reaction equation

HRID 68367 reaction equation
C(OC([N:8]([C:12]1[S:13][CH2:14][C@@H:15]2[C@@H:20]([CH3:21])[O:19][CH2:18][C@:16]2([C:22]2[CH:27]=[C:26](Br)[CH:25]=[CH:24][C:23]=2[F:29])[N:17]=1)C([O-])=O)=O)(C)(C)C.O.[F:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C([O-])(O)=O.[Na+].Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[CH3:21][C@@H:20]1[C@@H:15]2[C@@:16]([C:22]3[CH:27]=[C:26]([C:36]4[CH:37]=[C:32]([F:31])[CH:33]=[CH:34][C:35]=4[F:38])[CH:25]=[CH:24][C:23]=3[F:29])([N:17]=[C:12]([NH2:8])[S:13][CH2:14]2)[CH2:18][O:19]1

Participants

9

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 2734335(2,5-Difluorophenyl)boronic acidHCID 86707808tert-Butyl[(4aS,5R,7aS)-7a-(5-bromo-2-fluorophenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]imidodicarbonate

Product 1

HCID 57415376(4aS,5R,7aS)-5-Methyl-7a-(2',4,5'-trifluoro-[1,1'-biphenyl]-3-yl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amineYield 14%

Reagents, catalysts & solvents 4

HCID 13169693Triphenylphosphine palladium dichlorideCatalystHCID 702EthanolSolventHCID 80711,2-DimethoxyethaneSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
100 °C

Procedure

tert-Butyl[(4aS,5R,7aS)-7a-(5-bromo-2-fluorophenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]imidodicarbonate (0.15 g, 0.34 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 (2,5-difluorophenyl)boronic acid (0.11 g, 0.67 mmol), cesium carbonate (0.659 g, 2.02 mmol) and dichloropalladium-triphenylphosphane (0.047 g, 0.067 mmol) and the reaction was stirred at 100° C. After 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 dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL). After 1 hour, the solvents were removed in vacuo. The residue was neutralised with saturated aqueous NaHCO3 and extracted with DCM (×2). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified using column chromatography (gradient 0-15% MeOH in EtOAc) to give the title compound (18 mg, colourless solid). 1H NMR (400 MHz, CDCl3) δ ppm: 7.50-7.58 (m, 2 H), 7.09-7.2 (m, 3 H), 6.97-7.06 (m, 1 H), 4.61 (d, J=10.1 Hz, 1 H), 4.35-4.47 (m, 1 H), 4.21 (dd, J=10.0, 1.6 Hz, 1 H), 3.28 (dd, J=13.5, 3.7 Hz, 1 H), 3.03 (dt, J=8.1, 4.0 Hz, 1 H), 2.91 (dd, J=13.6, 4.0 Hz, 1 H), 1.44 (d, J=6.1 Hz, 3 H)

Workup

  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. dissolutionThe residue was dissolved in DCM (2 mL)
  7. waitAfter 1 hour
  8. customthe solvents were removed in vacuo
  9. extractionextracted with DCM (×2)
  10. dry with materialThe combined organic layers were dried (MgSO4)
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe residue was purified

Sources & evidence

ORD record
ord-85d84f8cc9fe4a068f2de9825942d775
Source dataset
uspto-grants-2014_09
Patent number
US08822455B2

Reaction notes

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