Toluene → (2S,4S)-benzyl 2-(5-(4'-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

HRID 1751652Notes

Reaction equation

HRID 1751652 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:57]([CH3:59])[CH3:58])[C:7]([N:9]1[CH2:13][C@@H:12]([S:14][CH3:15])[CH2:11][C@H:10]1[C:16]([NH:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[NH:38][C:37]([C@@H:39]4[CH2:43][C@H:42]([CH2:44][O:45][CH3:46])[CH2:41][N:40]4C(OCC4C=CC=CC=4)=O)=[N:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)=O)=O)=[O:8])=[O:4].[C:60]1(C)C=[CH:64][CH:63]=[CH:62][CH:61]=1.C([O-])(=O)C.[NH4+:71].[CH3:72][CH2:73][O:74][C:75](C)=[O:76]>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:57]([CH3:59])[CH3:58])[C:7]([N:9]1[CH2:13][C@@H:12]([S:14][CH3:15])[CH2:11][C@H:10]1[C:16]1[NH:71][C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4[NH:38][C:37]([C@@H:39]5[CH2:43][C@H:42]([CH2:44][O:45][CH3:46])[CH2:41][N:40]5[C:75]([O:74][CH2:73][C:72]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)=[O:76])=[N:36][CH:35]=4)=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)=[CH:19][N:18]=1)=[O:8])=[O:4]

Participants

5

Reactant 4

HCID 1140TolueneHCID 8857Ethyl AcetateHCID 517165Ammonium AcetateHCID 67682446(2S,4S)-benzyl 2-(5-(4'-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxamido)acetyl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

Product 1

HCID 86708800(2S,4S)-benzyl 2-(5-(4'-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylateYield 58%

Conditions

Temperature
110 °C

Procedure

To (2S,4S)-benzyl 2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxamido)acetyl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (487 mg, 0.59 mmol) was added PhMe (6 mL), MeOEtOH (1 mL), and ammonium acetate (0.91 g, 11.8 mmol) and the solution was heated to 110° C. The solution was stirred for 3 h and then cooled to rt and was diluted with EtOAc and washed successively with water, saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford (2S,4S)-benzyl 2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (276 mg, 58%).

Workup

  1. temperaturecooled to rt
  2. washwashed successively with water, saturated aqueous NaHCO3 and brine
  3. dry with materialThe organics were dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc)

Sources & evidence

ORD record
ord-ad0eeb52b5914788954c7d7278698658
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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