Iodine chloride → (S)-(3,5-Bis-trifluoromethyl-benzyl)-(11-methyl-2,3,4,5,7,8,9,10-octahydro-1H-naphtho[2,3-b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine

HRID 507125Notes

Reaction equation

HRID 507125 reaction equation
[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[CH:15]=[C:16]3[C:21](=[CH:22][C:9]1=2)[CH2:20][CH2:19][CH2:18][CH2:17]3.[C:38](=O)(O)[O-].[Na+].ICl.[F-].[Cs+].CB(O)O>ClCCl.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].CO>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[CH2:6][N:7]([C@H:8]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[C:15]([CH3:38])=[C:16]3[C:21](=[CH:22][C:9]1=2)[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1

Participants

11

Reactant 5

HCID 24640Iodine chlorideHCID 25953Cesium fluorideHCID 139377Methylboronic AcidHCID 516892Sodium BicarbonateHCID 59432294(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(2,3,4,5,7,8,9,10-octahydro-1H-naphtho[2,3-b]azepin-5-yl)-amine

Product 1

HCID 59432451(S)-(3,5-Bis-trifluoromethyl-benzyl)-(11-methyl-2,3,4,5,7,8,9,10-octahydro-1H-naphtho[2,3-b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine

Reagents, catalysts & solvents 5

HCID 167845palladium(II) acetateCatalystHCID 15826098Cyclopenta-1,3-diene;cyclopenta-2,4-dien-1-yl(diphenyl)phosphane;iron(2+)CatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent3×

Procedure

To a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(2,3,4,5,7,8,9,10-octahydro-1H-naphtho[2,3-b]azepin-5-yl)-amine (Example 77, Step 3) (0.19 mmol) in dichloromethane (5 mL), add sodium bicarbonate (0.28 mmol) and methanol (2 mL). Add a 1.0 M solution of iodine monochloride (0.28 mmol) in dichloromethane dropwise. After stirring for 1 h at room temperature, quench the reaction with concentrated aqueous sodium metabisulfite. Dilute with dichloromethane (20 mL) and water (20 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum. Dissolve the crude intermediate in dioxane (5 mL) and purge with nitrogen. To this solution add palladium acetate (0.04 mmol), diphenylphosphinoferrocene (0.04 mmol), cesium fluoride (0.76 mmol), and methylboronic acid (0.76 mmol). Heat the mixture at 60° C. for 4 h, then cool to room temperature and remove the solvent under vacuum. Chromatograph the product over silica gel eluting with ethyl acetate/hexane (5-25%) to afford the title compound. MS (ES+): 539 (M+H).

Workup

  1. customquench
  2. customthe reaction with concentrated aqueous sodium metabisulfite
  3. customSeparate the organic phase
  4. washwash the aqueous with dichloromethane (2×10 mL)
  5. dry with materialDry the combined organics over sodium sulfate
  6. filtrationfilter
  7. customremove solvent under vacuum
  8. dissolutionDissolve the crude intermediate in dioxane (5 mL)
  9. custompurge with nitrogen
  10. temperatureHeat the mixture at 60° C. for 4 h
  11. temperaturecool to room temperature
  12. customremove the solvent under vacuum

Sources & evidence

ORD record
ord-6451b8462d294e4d96a9a08e17c7024e
Source dataset
uspto-grants-2010_08
Patent number
US07786108B2

Reaction notes

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