Hydrochloric Acid → [2-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-phenyl-ethyl]-carbamic acid methyl ester

HRID 79956Notes

Reaction equation

HRID 79956 reaction equation
C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6C(OC(C)(C)C)=O)=[N:37][CH:38]=5)=[CH:30][CH:29]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.[OH-].[Na+].[CH3:54][O:55][C:56]([NH:58][C@H:59]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:60]([OH:62])=O)=[O:57].CCOP(O[N:78]1N=N[C:82]2[CH:83]=[CH:84][CH:85]=[CH:86][C:81]=2[C:79]1=O)(OCC)=O.[C:89]([O-:92])(O)=[O:90].[Na+].[CH3:94]O>CN(C=O)C>[CH3:54][O:55][C:56](=[O:57])[NH:58][CH:59]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:60]([N:40]1[CH2:41][CH2:42][CH2:43][CH:39]1[C:36]1[NH:35][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:23]3[CH:22]=[CH:21][C:20]4[C:25](=[CH:26][CH:27]=[C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[C:6](=[O:5])[CH:79]([NH:78][C:89]([O:92][CH3:94])=[O:90])[C:81]6[CH:82]=[CH:83][CH:84]=[CH:85][CH:86]=6)=[N:17][CH:16]=5)[CH:19]=4)[CH:24]=3)=[CH:29][CH:30]=2)=[CH:38][N:37]=1)=[O:62]

Participants

9

Reactant 7

HCID 313Hydrochloric AcidHCID 887MethanolHCID 14798Sodium HydroxideHCID 516892Sodium BicarbonateHCID 42939953-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-oneHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 666200632-[5-(6-{4-[2-(1-tert-butyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 66620407[2-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-phenyl-ethyl]-carbamic acid methyl esterYield 49%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a slurry of 2-[5-(6-{4-[2-(1-tert-butyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.07 g, 0.09 mmol) in MeOH (0.1 mL) was added HCl in dioxanes (4 M, 1.5 mL). The resulting solution was stirred at room temperature for 2 hour and basified with NaOH (2 N). The crude product was extracted with CH2Cl2. The organic extracts were combined, dried over Na2SO4 and concentrated. (R)-Methoxycarbonylamino-phenyl-acetic acid (0.08 g, 0.4 mmol, 4.4 equiv.) and DMF (1.0 mL) were then added, followed by DEPBT (0.12 g, 0.4, 4 equiv.) and NaHCO3 (0.04 g, 0.43 mmol, 4 equiv.). The resulting slurry was stirred at room temperature for 7 days. The reaction mixture was purified by preparative HPLC (Gemini, 15→40% McCN in H2O (0.1% formic acid)) and lyophilized to provide [2-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-phenyl-ethyl]-carbamic acid methyl ester (0.04 g, 49%) as a white powder. LCMS-ESI+: calc'd for C50H48N8O6: 856.4 (M+). Found: 858.1 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: (Mixture of rotomers) 10.32-10.45 (m, 2H), 8.26 (s, 1H), 8.00 (s, 1H), 7.72-7.98 (m, 8H), 7.19-7.50 (m, 12H), 6.07 (m, 2H), 5.28-5.55 (m, 4H), 3.73 (m, 2H), 3.66 (s, 3H), 3.65 (s, 3H), 3.22 (m, 2H), 2.86-2.96 (m, 2H), 2.22 (m, 2H), 2.04 (m, 2H), 1.92 (m, 2H).

Workup

  1. extractionThe crude product was extracted with CH2Cl2
  2. dry with materialdried over Na2SO4
  3. concentrationconcentrated
  4. stirringThe resulting slurry was stirred at room temperature for 7 days
  5. customThe reaction mixture was purified by preparative HPLC (Gemini, 15→40% McCN in H2O (0.1% formic acid))

Sources & evidence

ORD record
ord-58216f40bed64189b8dac3bd79584f43
Source dataset
uspto-grants-2014_09
Patent number
US08841278B2

Reaction notes

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