Potassium Carbonate → methyl (R)-2-((S)-2-(5-(4'-(2-((S)-1-((R)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

HRID 1751374Notes

Reaction equation

HRID 1751374 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@H:6]([CH:55]([CH3:57])[CH3:56])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[CH:19]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[NH:39][C:38]([C@@H:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](OCC6C=CC=CC=6)=[O:46])=[N:37][CH:36]=5)=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH:21]=[CH:22][C:16]=2[N:15]=1)=[O:8])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:64][O:65][C:66]([NH:68][C@H:69]([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)C(O)=O)=[O:67].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>O.C(O)C.[Pd].C(#N)C.CO.[OH-].[Na+].C(OCC)(=O)C>[CH3:1][O:2][C:3]([NH:5][C@H:6]([CH:55]([CH3:57])[CH3:56])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[CH:19]=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[NH:39][C:38]([C@@H:40]6[CH2:44][CH2:43][CH2:42][N:41]6[C:45](=[O:46])[C@H:69]([NH:68][C:66](=[O:67])[O:65][CH3:64])[C:73]6[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=6)=[N:37][CH:36]=5)=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH:21]=[CH:22][C:16]=2[N:15]=1)=[O:8])=[O:4]

Participants

12

Reactant 4

HCID 11430Potassium CarbonateHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphateHCID 86708717HCID 86708717, compound

Product 1

HCID 86708718methyl (R)-2-((S)-2-(5-(4'-(2-((S)-1-((R)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamateYield 55%

Reagents, catalysts & solvents 7

HCID 962WaterCatalystHCID 14798Sodium HydroxideCatalystHCID 23938PalladiumCatalystHCID 702EthanolSolventHCID 887MethanolSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of (S)-benzyl 2-(5-(4′-(2-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.28 g, 0.37 mmol), potassium carbonate (105 mg, 0.75 mmol) and water (1 drop) in ethanol (5 mL) was added 10% palladium on carbon (200 mg). The reaction flask was flushed with argon for 2 minutes. Hydrogen gas was bubbled through the reaction mixture for 10 minutes. The reaction was stirred under hydrogen gas for 18 hours, and then flushed with argon. The mixture was diluted with methanol and filtered through Celite. The filtrate was concentrated and used without purification in the next step. This residue was dissolved in a 5:1 mixture of dichloromethane:dimethylformamide (4.3 mL) and cooled to 0° C. To the solution were sequentially added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (98 mg, 0.47 mmol) and COMU (202 mg, 0.47 mmol). After one hour, the reaction was diluted with acetonitrile (2 mL) and methanol (2 mL). To this solution was added ten drops of 5M aqueous NaOH solution and stirring was continued for 30 minutes. The reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined aqueous washings were extracted three times with ethyl acetate, and the combined organic layers were dried (MgSO4) and concentrated. The crude material was purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H), followed by flash column chromatography to yield methyl (R)-2-((S)-2-(5-(4′-(2-((S)-1-((R)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (165 mg, 55%). LCMS-ESI+: calculated for C47H50N8O6: 822.95; observed [M+1]+: 823.87.

Workup

  1. customThe reaction flask was flushed with argon for 2 minutes
  2. customHydrogen gas was bubbled through the reaction mixture for 10 minutes
  3. customflushed with argon
  4. additionThe mixture was diluted with methanol
  5. filtrationfiltered through Celite
  6. concentrationThe filtrate was concentrated
  7. customused without purification in the next step
  8. dissolutionThis residue was dissolved in a 5:1 mixture of dichloromethane
  9. waitAfter one hour
  10. stirringstirring
  11. waitwas continued for 30 minutes
  12. washthe organic layer was washed with water and brine
  13. extractionThe combined aqueous washings were extracted three times with ethyl acetate
  14. dry with materialthe combined organic layers were dried (MgSO4)
  15. concentrationconcentrated
  16. customThe crude material was purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H)

Sources & evidence

ORD record
ord-ab26f11cf33c4a648fad958b149b2a44
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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