1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 1-(3-{1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-methanoyl}-4-methoxy-phenoxy)-propan-2-one

HRID 2230730Notes

Reaction equation

HRID 2230730 reaction equation
Cl.Cl.[CH2:3]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C@:26]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][NH:28][CH2:27]2)[CH2:19][CH2:18]1)[CH3:4].[CH3:37][O:38][C:39]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50](=[O:52])[CH3:51])=[CH:44][C:40]=1[C:41](O)=[O:42].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:3]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C@:26]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][N:28]([C:41]([C:40]3[CH:44]=[C:45]([CH:46]=[CH:47][C:39]=3[O:38][CH3:37])[O:48][CH2:49][C:50](=[O:52])[CH3:51])=[O:42])[CH2:27]2)[CH2:19][CH2:18]1)[CH3:4]

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 81531DiisopropylethylamineHCID 27960291-Hydroxybenzotriazole hydrateHCID 184645202-Methoxy-5-(2-oxo-propoxy)-benzoic acidHCID 701481071-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole dihydrochloride

Product 1

HCID 599022651-(3-{1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-methanoyl}-4-methoxy-phenoxy)-propan-2-oneYield 85.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Stir a mixture of 1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole dihydrochloride (0.33 g, 0.61 mmol, Preparation 12.1), 2-methoxy-5-(2-oxo-propoxy)-benzoic acid (0.14 g, 0.61 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.14 g, 0.73 mmol), 1-hydroxybenzotriazole hydrate (0.099 g, 0.73 mmol), diisopropylethylamine (0.25 mL, 1.2 mmol) and dichloromethane (10 mL) overnight at room temperature. Dilute the reaction mixture with dichloromethane, wash with saturated brine, dry (MgSO4) the organic phase, filter and concentrate the filtrate in vacuo. Purify the residue by column chromatography on silica gel eluting sequentially with ethyl acetate, 3% methanol in dichloromethane and 5% methanol in dichloromethane. Concentrate the appropriate fractions to afford 0.35 g of the title compound, Rf=0.48 (silica gel, 10% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.

Workup

  1. washwash with saturated brine
  2. dry with materialdry (MgSO4) the organic phase
  3. filtrationfilter
  4. concentrationconcentrate the filtrate in vacuo
  5. customPurify the residue by column chromatography on silica gel eluting sequentially with ethyl acetate, 3% methanol in dichloromethane and 5% methanol in dichloromethane
  6. concentrationConcentrate the appropriate fractions

Sources & evidence

ORD record
ord-f5ed9fd8be6442c8b119d08ce20c9036
Source dataset
uspto-grants-2002_07
Patent number
US06423704B1

Reaction notes

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