Sodium Iodide → (R)-6,6-difluoro-5-(2-fluoro-5-iodo-phenyl)-5,7,7-trimethyl-[1,4]oxazepan-3-one

HRID 331132Notes

Reaction equation

HRID 331132 reaction equation
Br[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](=[O:19])[NH:9]2)[CH:7]=1.CN[C@@H]1CCCC[C@H]1NC.[I-:32].[Na+]>O1CCOCC1.[Cu]I>[F:15][C:14]1([F:16])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9][C@@:8]1([C:6]1[CH:7]=[C:2]([I:32])[CH:3]=[CH:4][C:5]=1[F:21])[CH3:20]

Participants

6

Reactant 3

HCID 5238Sodium Iodide2×HCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamine2×HCID 58562968(R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one

Product 1

HCID 68380642(R)-6,6-difluoro-5-(2-fluoro-5-iodo-phenyl)-5,7,7-trimethyl-[1,4]oxazepan-3-oneYield 96.2%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

A solution of (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate B6.1) (200 mg, 546 μmol) in dioxane (2 ml) was treated consecutively with trans-N,N′-dimethyl-1,2-cyclohexanediamine (16.0 mg, 109 μmol), copper(I)iodide (10.6 mg, 54.6 μmol), and sodium iodide (165 mg, 1.09 mmol). The reaction mixture was stirred at 110° C. for 15 hours. Following TLC the reaction was incomplete. Another amount of copper(I)iodide (10.6 mg, 54.6 μmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (16.0 mg, 109 μmol), and sodium iodide (165 mg, 1.09 mmol) was added. Stirring was continued at 110° C. during the weekend. For the workup, the reaction mixture was evaporated at reduced pressure and the residue was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 90:60 as the eluent. The (R)-6,6-difluoro-5-(2-fluoro-5-iodo-phenyl)-5,7,7-trimethyl-[1,4]oxazepan-3-one (217 mg, 96% yield) was obtained as light yellow viscous oil. MS (ISP): m/z=414.1 [M+H]+.

Workup

  1. stirringStirring
  2. customwas continued at 110° C. during the weekend
  3. customFor the workup, the reaction mixture was evaporated at reduced pressure
  4. customthe residue was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 90:60 as the eluent

Sources & evidence

ORD record
ord-c8228707a438413f93f220d125ba013f
Source dataset
uspto-grants-2014_11
Patent number
US08877744B2

Reaction notes

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