Water → HCID 66706660, compound

HRID 911726Notes

Reaction equation

HRID 911726 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([SH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30](Br)[CH3:31])=[CH:26][CH:25]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH:30]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH3:31])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 133890301-(1-Bromoethyl)-4-fluorobenzeneHCID 66706900HCID 66706900, compound

Product 1

HCID 66706660HCID 66706660, compoundYield 84%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
45 °C

Procedure

Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (415 mg, 1.08 mmol) in methanol (20 mL) and add potassium hydroxide (1.938 g, 34.53 mmol). Heat at 60° C. for 4 h. Cool the reaction mixture to ambient temperature, add aqueous saturated ammonium chloride and concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic phase over anhydrous Na2SO4 and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.34 g, 1.086 mmol). Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.34 g, 1.086 mmol) in anhydrous DMF (10 mL), add sodium hydride (65 mg, 1.63 mmol, 60% in mineral oil) and stir the mixture for 5 min. Add a solution of (±)-1-(4-fluorophenyl)ethyl bromide (332 mg, 1.63 mmol) in anhydrous DMF (5 mL) and heat the solution at 45° C. overnight. Cool to ambient temperature, add water and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over anhydrous Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1 and 9:1) to give (±)-3-tert-butoxycarbonyl-7-chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (397 mg, 84%). MS (ES+) m/z: 336 (M+H−Boc)+.

Workup

  1. temperatureCool to ambient temperature
  2. extractionextract the aqueous phase twice with EtOAc
  3. dry with materialDry the combined organic extracts over anhydrous Na2SO4
  4. filtrationfilter
  5. concentrationconcentrate in vacuo
  6. customPurify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1 and 9:1)

Sources & evidence

ORD record
ord-c279fc4ee9a24bd89db09d6cf2786206
Source dataset
uspto-grants-2011_09
Patent number
US08022062B2

Reaction notes

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