Triethylamine → 1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-phenyl-3-(2-{4-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-pyrrolidin-1-yl]-methanone

HRID 2230736Notes

Reaction equation

HRID 2230736 reaction equation
I.I.[N:3]1([C:10]2[N:14]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@:41]([CH2:50][CH2:51]OS(C)(=O)=O)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:38].C(N(CC)CC)C>C(#N)C>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[CH:28][C:27]=1[C:37]([N:39]1[CH2:43][CH2:42][C@@:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH2:50][CH2:51][N:6]2[CH2:7][CH2:8][CH2:9][N:3]([C:10]3[N:14]([CH2:15][C:16]([F:19])([F:17])[F:18])[C:13]4[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=4[N:11]=3)[CH2:4][CH2:5]2)[CH2:40]1)=[O:38]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 184650772-[1,4]diazepan-1-yl-1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole dihydroiodideHCID 86583904HCID 86583904, compound

Product 1

HCID 599022751-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-phenyl-3-(2-{4-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-pyrrolidin-1-yl]-methanoneYield 77%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

Reflux a stirred solution of 2-[1,4]diazepan-1-yl-1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole dihydroiodide (0.44 g, 0.79 mmol), methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.38 g, 0.79 mmol, example 47.2), triethylamine (2.54 mmol) and acetonitrile (11 mL) under argon for 20 hours. Cool and concentrate in vacuo. Dilute with dichloromethane (100 mL), wash the organic phase with NaHCO3 solution (2×20 mL), dry (Na2SO4) the organic phase, filter and evaporate in vacuo. Purify the residue by flash chromatography (silica gel, 7×15 cm) eluting with 10% methanol/0.1% ammonium hydroxide solution in dichloromethane, concentrate the appropriate fractions, and dry the resultant material in vacuo (0.2 Torr) for 2 hours to afford 0.41 g of the title compound as a beige colored foam, Rf=0.39 (silica gel, 10% methanol/0.1% ammonium hydroxide solution in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.

Workup

  1. temperatureCool
  2. concentrationconcentrate in vacuo
  3. additionDilute with dichloromethane (100 mL)
  4. washwash the organic phase with NaHCO3 solution (2×20 mL)
  5. dry with materialdry (Na2SO4) the organic phase
  6. filtrationfilter
  7. customevaporate in vacuo
  8. customPurify the residue by flash chromatography (silica gel, 7×15 cm)
  9. washeluting with 10% methanol/0.1% ammonium hydroxide solution in dichloromethane
  10. concentrationconcentrate the appropriate fractions
  11. dry with materialdry the resultant material in vacuo (0.2 Torr) for 2 hours

Sources & evidence

ORD record
ord-da25c54b3e9347e5b37628fa1402206d
Source dataset
uspto-grants-2002_07
Patent number
US06423704B1

Reaction notes

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