Potassium Iodide → 3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine

HRID 2041605Notes

Reaction equation

HRID 2041605 reaction equation
[OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22]C(=O)N(C)C)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36](=[O:41])[C:35]2([CH3:43])[CH3:42].[I-].[K+]>CO.ClCCl>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH2:29][CH2:30][CH2:31][C:32]3[CH:33]=[C:34]4[C:38](=[CH:39][CH:40]=3)[NH:37][C:36](=[O:41])[C:35]4([CH3:42])[CH3:43])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]

Participants

7

Reactant 4

HCID 4875Potassium IodideHCID 14797Potassium Hydroxide2×HCID 576559793-tert-butoxycarbonyl-7-chloro-6-dimethylaminocarbonylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineHCID 576560325-(3-Chloropropyl)-3,3-dimethyl-1,3-dihydro-indol-2-one

Product 1

HCID 667073103-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineYield 96.3%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 6344DichloromethaneSolvent

Procedure

Under nitrogen atmosphere, add potassium hydroxide (138 mg, 2.46 mmol) to a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (375 mg, 0.97 mmol) in methanol (10 mL). Heat under reflux for 2 h then add further potassium hydroxide (159 mg, 2.83 mmol) and continue heating under reflux for another 6 h. Cool the reaction mixture and add dropwise via cannula a solution of 5-(3-chloropropyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (245 mg, 1.03 mmol) in methanol (10 mL). Stir at ambient temperature overnight then heat at 50° C. for 5 h. Add potassium iodide (186 mg, 1.12 mmol) to the reaction mixture and then heat under reflux for 5 h. Concentrate in vacuo and partition the residue between water (100 mL) and EtOAc (50 mL). Extract the aqueous phase with EtOAc (2×50 mL). Wash the combined extracts with brine (50 mL), dry over MgSO4, filter and concentrate in vacuo to obtain the crude mixture as a yellow oil. Dilute this oil with dichloromethane then re-concentrate in vacuo and repeat until a solid remains. Dry the solid in a vacuum oven to give 3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow solid (481 mg) that was used without further purification. MS (ES+) m/z: 537 (M+Na)÷.

Workup

  1. temperatureHeat
  2. temperatureunder reflux for 2 h
  3. temperaturecontinue heating
  4. temperatureunder reflux for another 6 h
  5. temperatureCool the reaction mixture
  6. temperaturethen heat at 50° C. for 5 h
  7. temperatureunder reflux for 5 h
  8. concentrationConcentrate in vacuo
  9. custompartition the residue between water (100 mL) and EtOAc (50 mL)
  10. extractionExtract the aqueous phase with EtOAc (2×50 mL)
  11. washWash the combined extracts with brine (50 mL)
  12. dry with materialdry over MgSO4
  13. filtrationfilter
  14. concentrationconcentrate in vacuo
  15. customto obtain the crude mixture as a yellow oil
  16. concentrationthen re-concentrate in vacuo and repeat until a solid remains
  17. customDry the solid in a vacuum oven

Sources & evidence

ORD record
ord-5ce860463b384c4e8b702302bbbe169c
Source dataset
uspto-grants-2013_11
Patent number
US08580780B2

Reaction notes

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