Hydrochloric Acid → (1-{6-[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]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

HRID 79822Notes

Reaction equation

HRID 79822 reaction equation
Cl.C(OC([N:9]1[CH:14]([C:15]2[NH:19][C:18]3[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[CH:35]=[CH:34][C:33]([C:36]6[NH:37][C:38]([CH:41]7[CH2:47][C:44]8([CH2:46][CH2:45]8)[CH2:43][N:42]7[C:48](OC(C)(C)C)=[O:49])=[N:39][CH:40]=6)=[CH:32][CH:31]=5)=[CH:26][CH:25]=4)[CH:22]=[CH:23][C:17]=3[N:16]=2)[CH:13]2[CH2:55][CH:10]1[CH2:11][CH2:12]2)=O)(C)(C)C.[CH3:56][O:57][C:58]([NH:60][CH:61]([CH:65]([CH3:67])[CH3:66])[C:62]([OH:64])=O)=[O:59].[CH3:68]N1CCOCC1.CN(C(ON1N=NC2[CH:86]=[CH:87][CH:88]=[N:89]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:99]([O:102][CH2:103]C)(=[O:101])C>O1CCOCC1.C(Cl)Cl>[CH3:103][O:102][C:99](=[O:101])[NH:89][CH:88]([C:48]([N:42]1[CH:41]([C:38]2[NH:37][C:36]([C:33]3[CH:32]=[CH:31][C:30]([C:27]4[CH:26]=[CH:25][C:24]([C:21]5[CH:22]=[CH:23][C:17]6[N:16]=[C:15]([CH:14]7[CH:12]8[CH2:11][CH:10]([CH2:55][CH2:13]8)[N:9]7[C:62](=[O:64])[CH:61]([NH:60][C:58]([O:57][CH3:56])=[O:59])[CH:65]([CH3:67])[CH3:66])[NH:19][C:18]=6[CH:20]=5)=[CH:29][CH:28]=4)=[CH:35][CH:34]=3)=[CH:40][N:39]=2)[CH2:47][C:44]2([CH2:45][CH2:46]2)[CH2:43]1)=[O:49])[CH:87]([CH3:68])[CH3:86]

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 79724-MethylmorpholineHCID 8857Ethyl AcetateHCID 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 666204783-(6-{4'-[2-(5-tert-Butoxycarbonyl-5-aza-spiro[2.4]hept-6-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

Product 1

HCID 66620373(1-{6-[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]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterYield 53%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

4N HCl in dioxane (2 mL)was added to 3-(6-{4′-[2-(5-tert-Butoxycarbonyl-5-aza-spiro[2.4]hept-6-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 (53 mg, 0.073 mmol) in 2 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 (1 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (2.1 eq., 26.6 mg), 4-methylmorpholine (6 eq., 0.048 mL), followed by HATU (2 eq., 56 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% ACN/H2O+0.1% TFA). Product was lyophilized to give (1-{6-[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]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DH) (41.6 mg, 53%).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customdried overnight under vacuum
  3. dissolutionThe residue was dissolved in DMF (1 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% ACN/H2O+0.1% TFA)

Sources & evidence

ORD record
ord-92f40cb1e55341bca429af9dd65683d7
Source dataset
uspto-grants-2014_09
Patent number
US08841278B2

Reaction notes

Loading…