Hydrochloric Acid → (1-{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-dibenzothiophen-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

HRID 417566Notes

Reaction equation

HRID 417566 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:25]=[CH:26][C:27]5[C:31]6[CH:32]=[CH:33][C:34]([C:36]7[NH:37][C:38]([CH:41]8[CH2:45][CH2:44][CH2:43][N:42]8C(OC(C)(C)C)=O)=[N:39][CH:40]=7)=[CH:35][C:30]=6[S:29][C:28]=5[CH:53]=4)[CH:22]=[CH:23][C:17]=3[N:16]=2)[CH:13]2[CH2:54][CH:10]1[CH2:11][CH2:12]2)=O)(C)(C)C.[CH3:55][O:56][C:57]([NH:59][CH:60]([CH:64]([CH3:66])[CH3:65])[C:61](O)=[O:62])=[O:58].C[N:68]1[CH2:73][CH2:72][O:71]CC1.CN(C(ON1N=N[C:84]2[CH:85]=CC=N[C:83]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:98]([O:101][CH2:102]C)(=[O:100])C>O1CCOCC1.C(Cl)Cl>[CH3:102][O:101][C:98](=[O:100])[NH:68][CH:73]([C:72]([N:42]1[CH2:43][CH2:44][CH2:45][CH:41]1[C:38]1[NH:37][C:36]([C:34]2[CH:33]=[CH:32][C:31]3[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:13]8[CH2:54][CH:10]([CH2:11][CH2:12]8)[N:9]7[C:61](=[O:62])[CH:60]([NH:59][C:57]([O:56][CH3:55])=[O:58])[CH:64]([CH3:66])[CH3:65])[NH:19][C:18]=6[CH:20]=5)=[CH:53][C:28]=4[S:29][C:30]=3[CH:35]=2)=[CH:40][N:39]=1)=[O:71])[CH:84]([CH3:85])[CH3:83]

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 666211943-(6-{7-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-dibenzothiophen-3-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

Product 1

HCID 66620995(1-{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-dibenzothiophen-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterYield 59%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

4N HCl in dioxane (3 mL) was added to 3-(6-{7-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-dibenzothiophen-3-yl}-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (141 mg, 0.194 mmol) in 3 mL DCM. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and dried overnight under vacuum. The residue was dissolved in DMF (4 mL) and to this solution was added 2-Methoxycarbonylamino-3-methyl-butyric acid (2.08 eq., 71 mg), 4-methylmorpholine (6 eq., 0.12 mL), followed by HATU (2.04 eq., 150 mg). Reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was diluted in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 20% MeOH/ethyl acetate), followed by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H2O+0.1% TFA). Product was lyophilized to give (1-{2-[5-(7-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-dibenzothiophen-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DE) (121 mg, 59%). 1H-NMR: 300 MHz, (DMSO-d6) δ: 8.60-8.40 (m, 4H), 8.16 (m, 1H), 8.01 (m, 1H), 7.90 (m, 2H), 7.76 (m, 1H), 7.33 (m, 2H), 5.15 (m, 1H), 4.76 (m, 1H), 4.56 (d, 1H), 4.22-4.08 (m, 3H), 3.85 (m, 2H), 3.55 (d, 6H), 2.76 (m, 1H), 2.30-1.50 (m, 9H), 0.96-0.75 (m, 12H). 19F-NMR: 300 MHz, (CD3OD-d4) δ: −112.88. LCMS-ESI+: calc'd for C46H52N8O6S: 845.02. Found: 845.4 (M+H+).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customdried overnight under vacuum
  3. dissolutionThe residue was dissolved in DMF (4 mL) and to this solution
  4. customReaction mixture
  5. stirringwas stirred at 0° C. for 30 minutes
  6. washwashed with saturated sodium bicarbonate solution
  7. dry with materialThe organic layer was dried (MgSO4)
  8. concentrationconcentrated
  9. custompurified by flash column chromatography (silica gel, 0 to 20% MeOH/ethyl acetate)

Sources & evidence

ORD record
ord-e8272159125b4251b314732b48f67386
Source dataset
uspto-grants-2012_01
Patent number
US08088368B2

Reaction notes

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