Potassium Carbonate → HCID 69675309, compound

HRID 1751375Notes

Reaction equation

HRID 1751375 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:38][C:37]([C@@H:39]6[CH2:43][CH2:42][CH2:41][N:40]6C(OCC6C=CC=CC=6)=O)=[N:36][CH:35]=5)=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:60][O:61][C:62]([NH:64][C@@H:65]([CH:69]([CH3:71])[CH3:70])[C:66](O)=[O:67])=[O:63].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>O.C(O)C.[Pd].C(#N)C.CO.[OH-].[Na+].C(OCC)(=O)C>[CH3:60][O:61][C:62]([NH:64][C@@H:65]([CH:69]([CH3:71])[CH3:70])[C:66]([N:40]1[CH2:41][CH2:42][CH2:43][C@H:39]1[C:37]1[NH:38][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:25]3[CH:26]=[CH:27][C:22]([C:19]4[CH:20]=[CH:21][C:15]5[N:14]=[C:13]([C@@H:9]6[CH2:10][CH2:11][CH2:12][N:8]6[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[NH:17][C:16]=5[CH:18]=4)=[CH:23][CH:24]=3)=[CH:29][CH:30]=2)=[CH:35][N:36]=1)=[O:67])=[O:63]

Participants

13

Reactant 5

HCID 11430Potassium CarbonateHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 10942966(2S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acidHCID 86708716(S)-benzyl 2-(5-(4'-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Product 1

HCID 69675309HCID 69675309, compoundYield 68%

Reagents, catalysts & solvents 7

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

Procedure

To a solution of (S)-benzyl 2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.65 g, 0.92 mmol), potassium carbonate (200 mg, 1.4 mmol) and water (2 drops) in ethanol (11.6 mL) was added 10% palladium on carbon (260 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. The crude material was dissolved in dimethylformamide (7.4 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (156 mg, 0.9 mmol), HATU (340 mg, 0.9 mmol) and diisopropylethylamine (0.39 mL, 2.2 mmol). The reaction was stirred at room temperature for one hour, and then 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 flash column chromatography to yield (S)-tert-butyl 2-(6-(4′-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (368 mg, 68%). LCMS-ESI+: calculated for C42H49N7O5: 731.88; observed [M+1]+: 732.75.

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. dissolutionThe crude material was dissolved in dimethylformamide (7.4 mL)
  9. stirringThe reaction was stirred at room temperature for 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 flash column chromatography

Sources & evidence

ORD record
ord-47257f21a7834630b9ceb3c05bd173ce
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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