Potassium Carbonate → methyl (R)-2-((S)-2-(5-(7-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

HRID 1751380Notes

Reaction equation

HRID 1751380 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:56]([CH3:58])[CH3:57])[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:55]=[CH:54][C:26]4[C:27]5[CH:33]=[CH:32][C:31]([C:34]6[NH:38][C:37]([C@@H:39]7[CH2:43][CH2:42][CH2:41][N:40]7C(OCC7C=CC=CC=7)=O)=[N:36][CH:35]=6)=[CH:30][C:28]=5[S:29][C:25]=4[CH:24]=3)[CH:21]=[CH:22][C:16]=2[N:15]=1)=[O:8])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:65][O:66][C:67]([NH:69][C@H:70]([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[C:71](O)=[O:72])=[O:68].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>O.C(O)C.[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:56]([CH3:58])[CH3:57])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:22]2[CH:21]=[C:20]([C:23]3[CH:55]=[CH:54][C:26]4[C:27]5[CH:33]=[CH:32][C:31]([C:34]6[NH:38][C:37]([C@@H:39]7[CH2:43][CH2:42][CH2:41][N:40]7[C:71](=[O:72])[C@H:70]([NH:69][C:67](=[O:68])[O:66][CH3:65])[C:74]7[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=7)=[N:36][CH:35]=6)=[CH:30][C:28]=5[S:29][C:25]=4[CH:24]=3)[CH:19]=[CH:17][C:16]=2[N:15]=1)=[O:8])=[O:4]

Participants

9

Reactant 4

HCID 11430Potassium CarbonateHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 67681969HCID 67681969, compoundHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate

Product 1

HCID 86708719methyl (R)-2-((S)-2-(5-(7-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamateYield 47%

Reagents, catalysts & solvents 4

HCID 962WaterCatalystHCID 23938PalladiumCatalystHCID 702EthanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of (S)-benzyl 2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.19 g, 0.24 mmol), potassium carbonate (70 mg, 0.50 mmol) and water (1 drop) in ethanol (3.5 mL) was added 10% palladium on carbon (175 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 (3.0 mL) and cooled to 0° C. To the solution were sequentially added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (76 mg, 0.36 mmol) and COMU (150 mg, 0.35 mmol). After one hour, 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% TFA) to yield methyl (R)-2-((S)-2-(5-(7-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (95 mg, 47%). LCMS-ESI+: calculated for C47H48N8O6S: 853.00; observed [M+1]+: 853.85.

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. washthe organic layer was washed with water and brine
  11. extractionThe combined aqueous washings were extracted three times with ethyl acetate
  12. dry with materialthe combined organic layers were dried (MgSO4)
  13. concentrationconcentrated
  14. customThe crude material was purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% TFA)

Sources & evidence

ORD record
ord-ad2e064a506e4f3abddc5c196ae62ae7
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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