Hydrochloric Acid → (1-{2-[5-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

HRID 79810Notes

Reaction equation

HRID 79810 reaction equation
[CH3:1][O:2][C:3](=[O:60])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:59]=[CH:58][C:36]5[N:37]=[C:38]([CH:40]6[CH:45]7[CH2:46][CH:42]([CH2:43][CH2:44]7)[N:41]6[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])[NH:39][C:35]=5[CH:34]=4)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(=O)NC(C([N:71]1[CH:76]([C:77]2[NH:81][C:80]3[CH:82]=[C:83]([C:86]4[CH:91]=[CH:90][C:89]([C:92]5[CH:97]=[CH:96][C:95](C6C=CC7N=C(C8C9CC(CC9)N8C(=O)C(NC(OC)=O)C(C)C)NC=7C=6)=[CH:94][CH:93]=5)=[CH:88][CH:87]=4)[CH:84]=[CH:85][C:79]=3[N:78]=2)[CH:75]2[CH2:125][CH:72]1[CH2:73][CH2:74]2)=O)C(C)C.Cl.[C:128]([O:132][C:133]([N:135]1[CH:140]([C:141]2NC3C=C(C4C=CC(C5C=CC(C6NC(C7CCCN7C(OC(C)(C)C)=O)=NC=6)=CC=5)=CC=4)C=CC=3N=2)[CH:139]2[CH2:179]C1C[CH2:138]2)=[O:134])(C)(C)C.C[O:181]C(NC(C(C)C)C(O)=O)=O.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:60])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]4[CH:59]=[CH:58][C:36]5[N:37]=[C:38]([CH:40]6[CH:45]7[CH2:46][CH:42]([CH2:43][CH2:44]7)[N:41]6[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])[NH:39][C:35]=5[CH:34]=4)=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8].[CH3:56][O:55][C:53](=[O:54])[NH:52][CH:48]([C:47]([N:41]1[CH:40]([C:38]2[NH:39][C:35]3[CH:34]=[C:33]([C:95]4[CH:96]=[CH:97][C:92]([C:89]5[CH:90]=[CH:91][C:86]([C:83]6[CH:84]=[CH:85][C:79]7[N:78]=[C:77]([CH:76]8[CH:75]9[CH2:125][C:72]([C:141](=[O:181])[CH:140]([NH:135][C:133]([O:132][CH3:128])=[O:134])[CH:139]([CH3:179])[CH3:138])([CH2:73][CH2:74]9)[NH:71]8)[NH:81][C:80]=7[CH:82]=6)=[CH:87][CH:88]=5)=[CH:93][CH:94]=4)[CH:59]=[CH:58][C:36]=3[N:37]=2)[CH:45]2[CH2:46][CH:42]1[CH2:43][CH2:44]2)=[O:57])[CH:49]([CH3:50])[CH3:51]

Participants

12

Reactant 8

HCID 313Hydrochloric AcidHCID 79724-MethylmorpholineHCID 312751,4-DioxaneHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 138211012-((Methoxycarbonyl)amino)-3-methylbutanoic acidHCID 66620703(1-{2-[5-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterHCID 666209833-(6-{4'-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterHCID 66620992(1-{3-[6-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

Product 2

HCID 66620703(1-{2-[5-(4'-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterHCID 86762794(1-{3-[6-(4'-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

(1-{2-[5-(4′-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DA) and (1-{3-[6-(4′-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DB): 4N HCl in dioxane (3 mL)was added to 3-(6-{4′-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester and 3-(6-{4′-[2-(2-Boc-2-aza-bicyclo[2.2.1]hept-3-yl)-3H-benzoimidazol-5-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester mixture (163 mg, 0.233 mmol) in 3 mL DCM and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (3 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (2.1 eq., 85 mg), 4-methylmorpholine (6 eq., 0.15 mL), followed by HATU (2 eq., 181 mg). Reaction mixture was stirred at 0° C. for 50 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% MeCN/H2O+0.1% TFA). Product was lyophilized to give (1-{2-[5-(4′-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DA) (102 mg) and byproduct (1-{3-[6-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-biphenyl-4-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DB) (10.6 mg).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customdried overnight under vacuum
  3. dissolutionThe residue was dissolved in DMF (3 mL) and to this solution
  4. customReaction mixture
  5. stirringwas stirred at 0° C. for 50 minutes
  6. washwashed with dilute sodium bicarbonate solution
  7. dry with materialThe organic layer was dried (MgSO4)
  8. concentrationconcentrated
  9. custompurified by preparative reverse phase HPLC (GEMINI, 5 to 100% MeCN/H2O+0.1% TFA)

Sources & evidence

ORD record
ord-0ca7b46453654acca472e6bfbab7eabf
Source dataset
uspto-grants-2014_09
Patent number
US08841278B2

Reaction notes

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