Ammonia → HCID 68227446, compound

HRID 331131Notes

Reaction equation

HRID 331131 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=S)[NH:9]2)[CH:7]=1.[NH3:22].C(OO)(C)(C)C>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10]([NH2:22])=[N:9]2)[CH:7]=1

Participants

5

Reactant 3

HCID 222AmmoniaHCID 6410tert-Butyl hydroperoxideHCID 86671874HCID 86671874, compound

Product 1

HCID 68227446HCID 68227446, compound

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

A solution of (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepane-3-thione (intermediate B7.1) (959 mg, 2.51 mmol) in methanol (27 ml) was treated consecutively with ammonia in methanol (7M; 21.5 ml, 151 mmol) and dropwise with tert-butylhydroperoxide (70% in water; 2.07 ml, 15.1 mmol). The reaction mixture was stirred at room temperature overnight. For the workup, the methanol was evaporated at reduced pressure, and the residue partitioned between dichloromethane and water. The organic layer was washed with brine, then the 2 aqueous layers extracted with dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated at reduced pressure. The first purification of the crude product by chromatography on silica-amine phase using a gradient of heptane/ethyl acetate=100:0 to 72:28 was followed by a filtration through a SCX-2 cartridge. The cartridge was washed with a mixture of heptane and ethyl acetate and the product was recovered eluting with a solution of ammonia in methanol (7M). The (R)-5-(5-bromo-2-fluoro-phenyl)-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine was obtained as a light yellow foam (463 mg, 51% yield). MS (ISP): m/z=365.2 [(M+H)+] and 367.1 [(M+2+H)+].

Workup

  1. customFor the workup, the methanol was evaporated at reduced pressure
  2. customthe residue partitioned between dichloromethane and water
  3. washThe organic layer was washed with brine
  4. extractionthe 2 aqueous layers extracted with dichloromethane
  5. dry with materialThe combined organic layers were dried over sodium sulphate
  6. customevaporated at reduced pressure
  7. customThe first purification of the crude product by chromatography on silica-amine phase
  8. filtrationwas followed by a filtration through a SCX-2 cartridge
  9. washThe cartridge was washed with a mixture of heptane and ethyl acetate
  10. customthe product was recovered
  11. washeluting with a solution of ammonia in methanol (7M)

Sources & evidence

ORD record
ord-289a7b39937744b2b4a94f098ee73368
Source dataset
uspto-grants-2014_11
Patent number
US08877744B2

Reaction notes

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