Triethylamine → (R)-5-[5-(3-chloro-phenylethynyl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one

HRID 331146Notes

Reaction equation

HRID 331146 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.C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[CH:37])[CH:31]=1>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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[Cl:29][C:30]1[CH:31]=[C:32]([C:36]#[C:37][C:2]2[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]3([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]3)[CH:7]=2)[CH:33]=[CH:34][CH:35]=1

Participants

8

Reactant 3

HCID 8471TriethylamineHCID 1230861-Chloro-3-ethynylbenzeneHCID 58562968(R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one

Product 1

HCID 68380411(R)-5-[5-(3-chloro-phenylethynyl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-oneYield 90%

Reagents, catalysts & solvents 4

HCID 11776TriphenylphosphineCatalystHCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 6228DimethylformamideSolvent

Procedure

A dried pressure tube was charged with (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate B6.1) (250 mg, 622 μmol) and dimethylformamide (2 ml). The solution was flushed with argon, thereafter, successively bis(triphenylphosphin)palladium(II)chloride (31.2 mg, 43.5 μmol), triphenylphoshine (3.26 mg, 12.4 μmol), triethylamine (126 mg, 1.24 mmol), 1-chloro-3-ethynylbenzene (175 mg, 1.24 mmol), and copper(i) iodide (3.6 mg, 18.7 μmol) were added. The tube was sealed and the reaction mixture stirred at room temperature for 10 minutes, then it was heated at 60° C. for 16 hours. For the workup, the reaction mixture was cooled and evaporated at reduced pressure. The residue was directly purified by chromatography on an amine-silica phase using a gradient of heptane/ethyl acetate=100:0 to 60:10 as the eluent. The (R)-5-[5-(3-chloro-phenylethynyl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (235 mg, 90% yield) was obtained as a green foam. MS (ISP): m/z=422.1 [M+2+H]+ and 424.2 [M+H]+.

Workup

  1. customThe solution was flushed with argon
  2. customThe tube was sealed
  3. temperatureit was heated at 60° C. for 16 hours
  4. temperatureFor the workup, the reaction mixture was cooled
  5. customevaporated at reduced pressure
  6. customThe residue was directly purified by chromatography on an amine-silica phase

Sources & evidence

ORD record
ord-2c5c6ddc7ff049b6ba271b847991c3d4
Source dataset
uspto-grants-2014_11
Patent number
US08877744B2

Reaction notes

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