Dichloromethane → (4aS,5S,7aS)-7a-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

HRID 68380Notes

Reaction equation

HRID 68380 reaction equation
Br[C:2]1[C:3]([F:28])=[CH:4][C:5]([F:27])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:19]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl.C(O)(C(F)(F)F)=O>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.CCO>[F:27][C:5]1[CH:4]=[C:3]([F:28])[C:2]([C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)=[CH:7][C:6]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH2:19])=[N:9]2

Participants

10

Reactant 5

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 10796Cesium carbonateHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 86707819tert-Butyl ((4aS,5S,7aS)-7a-(5-bromo-2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate

Product 1

HCID 57415617(4aS,5S,7aS)-7a-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

Reagents, catalysts & solvents 4

HCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
100 °C

Procedure

tert-Butyl ((4aS,5S,7aS)-7a-(5-bromo-2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (100 mg, 0.21 mmol) was dissolved in DME (1.5 mL), EtOH (0.7 mL) and water (0.5 mL). The solution was heated to 100° C. Pyrimidin-5-ylboronic acid (51.5 mg, 0.416 mmol), bis(triphenylphosphine)palladium (II) chloride (29.2 mg, 0.042 mmol) and cesium carbonate (406 mg, 1.25 mmol) were added and the reaction was stirred at 100° C. for 45 minutes. The reaction was cooled to room temperature and partitioned between DCM and saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with DCM (×2). The organic layers were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (Biotage SNAP 10 g, 12 mL/min eluting with 20-80% EtOAc in n-hexane). The material was stirred in DCM (2 mL, 31.08 mmol) and TFA (2 mL) for 1 hour at room temperature. The solvents were removed in vacuo. The residue was passed over a 5 g SCX cartridge, washing with MeOH then 2N NH3/MeOH. The basic fractions were concentrated in vacuo and the residue was purified by column chromatography (Biotage SNAP 10 g, 12 mL/min gradient 0-20% MeOH in EtOAc) to leave the title compound as a white solid.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. custompartitioned between DCM and saturated aqueous NaHCO3
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with DCM (×2)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by column chromatography (Biotage SNAP 10 g, 12 mL/min eluting with 20-80% EtOAc in n-hexane)
  8. customThe solvents were removed in vacuo
  9. washwashing with MeOH
  10. concentrationThe basic fractions were concentrated in vacuo
  11. customthe residue was purified by column chromatography (Biotage SNAP 10 g, 12 mL/min gradient 0-20% MeOH in EtOAc)

Sources & evidence

ORD record
ord-0e899d999aaf4afeb40170a2ad1d28b4
Source dataset
uspto-grants-2014_09
Patent number
US08822455B2

Reaction notes

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