Water → (4aS,5R,7aS)-7a-(5-(5-cyclopropoxypyridin-3-yl)-2-fluorophenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

HRID 68369

Reaction equation

HRID 68369 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[C@:17]12[CH2:25][O:24][C@H:23]([CH3:26])[C@H:22]1[CH2:21][S:20][C:19]([N:27](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:18]2.O.Br[C:44]1[CH:45]=[N:46][CH:47]=[C:48]([O:50][CH:51]2[CH2:53][CH2:52]2)[CH:49]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C([O-])(O)=O.[Na+].C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[CH:51]1([O:50][C:48]2[CH:49]=[C:44]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:17]45[CH2:25][O:24][C@H:23]([CH3:26])[C@H:22]4[CH2:21][S:20][C:19]([NH2:27])=[N:18]5)[CH:4]=3)[CH:45]=[N:46][CH:47]=2)[CH2:53][CH2:52]1

Participants

9

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 682962023-Bromo-5-cyclopropoxypyridineHCID 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

Product 1

HCID 57415497(4aS,5R,7aS)-7a-(5-(5-cyclopropoxypyridin-3-yl)-2-fluorophenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

Reagents, catalysts & solvents 4

HCID 178419050HCID 178419050, compoundCatalystHCID 702EthanolSolventHCID 80711,2-DimethoxyethaneSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
100 °C

Procedure

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 (0.13 g, 0.22 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 3-bromo-5-(cyclopropyloxy)pyridine (0.28 g, 1.32 mmol), cesium carbonate (0.43 g, 1.32 mmol) and bis(triphenylphosphine)palladium (II) dichloride (0.046 g, 0.066 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 purified using column chromatography gradient 0-60% EtOAc in hexane). The purified product was dissolved in DCM (2 mL) and trifluoroacetic acid (1 mL). After 1 hour, the solvents were removed in vacuo. The residue was basified with saturated aqueous NaHCO3 and extracted with DCM (×3). The combined organic layers were dried (MgSO4), filtered and concentrated to leave the title compound. (58 mg)

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. customThe residue was purified
  7. dissolutionThe purified product was dissolved in DCM (2 mL)
  8. waitAfter 1 hour
  9. customthe solvents were removed in vacuo
  10. extractionextracted with DCM (×3)
  11. dry with materialThe combined organic layers were dried (MgSO4)
  12. filtrationfiltered
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-1143e29fa9ba445e8a28c112ed25f61c
Source dataset
uspto-grants-2014_09
Patent number
US08822455B2

Linked notes

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