Water → 3-tert-butoxycarbonyl-7-chloro-6-(2,2-difluoro-2-phenyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

HRID 911739Notes

Reaction equation

HRID 911739 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].C(N(CC)CC)C.FC(F)(F)S(O[CH2:34][C:35]([F:43])([F:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=O)=O.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:34][C:35]([F:43])([F:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[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 8471TriethylamineHCID 22138897HCID 22138897, compoundHCID 66706900HCID 66706900, compound

Product 1

HCID 667072233-tert-butoxycarbonyl-7-chloro-6-(2,2-difluoro-2-phenyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineYield 56%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
40 °C

Procedure

Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.52 mmol) in methanol (10 mL) and add potassium hydroxide (0.934 g, 16.64 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 (0.163 g). Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.163 g, 0.52 mmol) in anhydrous DMSO (5 mL) and add triethylamine (0.43 mL, 3.12 mmol) and 2,2-difluoro-2-phenylethyl trifluoromethanesulfonate (151 mg, 0.52 mmol). Heat the solution at 40° 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, 9:1 and 4:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(2,2-difluoro-2-phenyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (132 mg, 56%).

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, 9:1 and 4:1)

Sources & evidence

ORD record
ord-14ebbff8aa8e4054be91be0e93fea5f9
Source dataset
uspto-grants-2011_09
Patent number
US08022062B2

Reaction notes

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