Water → tert-butyl (2S,4S)-2-[4-[2-[4-[2-[(2S,4S)-1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]ethynyl]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylate

HRID 1625516Notes

Reaction equation

HRID 1625516 reaction equation
I[C:2]1[N:3]=[C:4]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:5][CH:6]=1.[CH3:20][C@@H:21]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:23]([C:33]2[NH:37][C:36]3C=C[C:40]([C:42]4[CH:47]=[CH:46][C:45]([C:48]#[C:49][Si](C)(C)C)=[CH:44][CH:43]=4)=[CH:41][C:35]=3[N:34]=2)[CH2:22]1.C(Cl)Cl.[CH2:57]1CCN2C(=NCCC2)C[CH2:58]1.O>CN(C=O)C.[Cu]I>[C:16]([O:15][C:13]([N:8]1[CH2:9][C@@H:10]([CH3:12])[CH2:11][C@H:7]1[C:4]1[NH:5][C:6]2[CH:57]=[CH:58][C:48]([C:45]3[CH:46]=[CH:47][C:42]([C:40]#[C:41][C:35]4[N:34]=[C:33]([C@@H:23]5[CH2:22][C@H:21]([CH3:20])[CH2:25][N:24]5[C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[NH:37][CH:36]=4)=[CH:43][CH:44]=3)=[CH:49][C:2]=2[N:3]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]

Participants

8

Reactant 5

HCID 962WaterHCID 6344DichloromethaneHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 53261949(2S,4S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylateHCID 178461440tert-butyl (2S,4S)-4-methyl-2-[5-[4-(2-trimethylsilylethynyl)phenyl]-1H-benzimidazol-2-yl]pyrrolidine-1-carboxylate

Product 1

HCID 178461457tert-butyl (2S,4S)-2-[4-[2-[4-[2-[(2S,4S)-1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]ethynyl]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylateYield 61.9%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6228DimethylformamideSolvent

Procedure

The well-degassed solution of tert-butyl (2S,4S)-2-(4-iodo-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (38.21 mg, 0.1013 mmol), tert-butyl (2S,4S)-4-methyl-2-[5-[4-(2-trimethylsilylethynyl)phenyl]-1H-benzimidazol-2-yl]pyrrolidine-1-carboxylate (40 mg, 0.08444 mmol), Pd(DPPF)(Cl)2.CH2Cl2 (6.896 mg, 0.008444 mmol), CuI (3.217 mg, 0.01689 mmol), DBU (128.5 mg, 126.2 μL, 0.8444 mmol), and water (4.563 mg, 4.563 μL, 0.2533 mmol) in DMF (3 mL) is stirred at 70° C. under N2 overnight. After removal of the solvent under reduced pressure, the residue is purified by flash column chromatography on silica gel using methanol/CH2Cl2 (0-6%) to provide the desired tert-butyl (2S,4S)-2-[4-[2-[4-[2-[(2S,4S)-1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]ethynyl]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylate (34 mg, 61.8% yield). LC/MS: m/z=651.42 (M+H+).

Workup

  1. customAfter removal of the solvent under reduced pressure
  2. customthe residue is purified by flash column chromatography on silica gel

Sources & evidence

ORD record
ord-df585b1fe12d4c27a310eefe30b3be77
Source dataset
uspto-grants-2014_07
Patent number
US08779156B2

Reaction notes

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