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

HRID 2230710Notes

Reaction equation

HRID 2230710 reaction equation
I.I.[CH:3]1([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[N:16]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:5][CH2:4]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[N:34][N:33]=[N:32]2)=[CH:27][C:26]=1[C:36]([N:38]1[CH2:42][CH2:41][C@:40]([CH2:49][CH2:50]OS(C)(=O)=O)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:39]1)=[O:37].C(N(CC)CC)C.C(#N)C>ClCCl>[OH-:24].[NH4+:7].[CH:3]1([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[N:16]2[CH2:22][CH2:21][CH2:20][N:19]([CH2:50][CH2:49][C@:40]3([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:41][CH2:42][N:38]([C:36]([C:26]4[CH:27]=[C:28]([N:31]5[CH:35]=[N:34][N:33]=[N:32]5)[CH:29]=[CH:30][C:25]=4[O:24][CH3:23])=[O:37])[CH2:39]3)[CH2:18][CH2:17]2)[CH2:4][CH2:5]1

Participants

7

Reactant 4

HCID 6342AcetonitrileHCID 8471TriethylamineHCID 184646651-cyclopropylmethyl-2-[1,4]diazepan-1-yl-1H-benzoimidazole dihydroiodideHCID 86583904HCID 86583904, compound

Product 2

HCID 14923Ammonium HydroxideYield 30%HCID 599022641-((R)-3-{2-[4-(1-Cyclopropylmethyl-1H-benzoimidazol-2-yl)-[1,4]diazepan-1-yl]-ethyl}-3-phenyl-pyrrolidin-1-yl)-1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoneYield 130%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Reflux a mixture of 1-cyclopropylmethyl-2-[1,4]diazepan-1-yl-1H-benzoimidazole dihydroiodide (0.60 g, 1.14 mmol), methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.53 g, 1.12 mmol, example 47.2), triethylamine (0.65 mL, 4.66 mmol) and acetonitrile (10 mL) for 8 hours. Cool and dilute with dichloromethane (150 mL), wash the organic phase with NaHCO3 (30 mL) and saturated brine solution (30 mL), dry (MgSO4) the organic phase, filter and evaporate. Purify the residue by silica gel chromatography (4×41 cm) eluting with dichloromethane:methanol:30% ammonium hydroxide (95:5:0.05} to afford 0.47 g of the title compound, Rf=0.32 (silica gel, dichloromethane:methanol:30% ammonium hydroxide solution. The compound may be converted to the dihydrochloride salt by methods well known in the art.

Workup

  1. temperatureReflux
  2. temperatureCool
  3. washwash the organic phase with NaHCO3 (30 mL) and saturated brine solution (30 mL)
  4. dry with materialdry (MgSO4) the organic phase
  5. filtrationfilter
  6. customevaporate
  7. customPurify the residue by silica gel chromatography (4×41 cm)
  8. washeluting with dichloromethane

Sources & evidence

ORD record
ord-9cc1ed271fde4b80b7a45f002cc3e9f6
Source dataset
uspto-grants-2002_07
Patent number
US06423704B1

Reaction notes

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