Hydrochloric Acid → (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

HRID 1751651Notes

Reaction equation

HRID 1751651 reaction equation
C([O:5][C:6]([NH:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:28][C:27]([C@@H:29]4[CH2:33][C@H:32]([CH2:34][O:35][CH3:36])[CH2:31][N:30]4[C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])=[N:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])=O)(C)(C)C.Cl.[CH3:48][O:49][C:50]([NH:52][C@@H:53]([CH:66]([CH3:68])[CH3:67])[C:54]([N:56]1[CH2:60][C@@H:59]([S:61][CH3:62])[CH2:58][C@H:57]1C(O)=O)=[O:55])=[O:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C.CO>[CH3:48][O:49][C:50]([NH:52][C@@H:53]([CH:66]([CH3:68])[CH3:67])[C:54]([N:56]1[CH2:60][C@@H:59]([S:61][CH3:62])[CH2:58][C@H:57]1[C:6]([NH:8][CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:28][C:27]([C@@H:29]4[CH2:33][C@H:32]([CH2:34][O:35][CH3:36])[CH2:31][N:30]4[C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:38])=[N:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:11])=[O:5])=[O:55])=[O:51]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67682555HCID 67682555, compoundHCID 69671862(2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxylic acid

Product 1

HCID 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-carboxylateYield 58%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

(2S,4S)-benzyl 2-(5-(4′-(2-(tert-butoxycarbonylamino)acetyl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (640 mg, 1.02 mmol) was dissolved in DCM (8 mL), MeOH (2 mL) and HCl (4 M in dioxane, 2 mL) was added. The reaction mixture was stirred for 14 h and then concentrated under reduced pressure. The crude residue was treated with (2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxylic acid (324 mg, 1.02 mmol), HATU (388 mg, 1.02 mmol) and DMF (10 mL), then DIPEA (0.9 mL, 5.12 mmol) was added dropwise. After 1 h, the mixture was diluted with EtOAc and washed successively with 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)pyrrolidine-2-carboxamido)acetyl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (487 mg, 58%).

Workup

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

Sources & evidence

ORD record
ord-3a24ab97abb947a1bfa4195a714c69b5
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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