Hydrochloric Acid → methyl (S)-1-((S)-2-(5-(4'-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

HRID 1751376Notes

Reaction equation

HRID 1751376 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:32]=[CH:33][C:34]5[N:38]=[C:37]([C@@H:39]6[CH2:43][CH2:42][CH2:41][N:40]6C(OC(C)(C)C)=O)[NH:36][C:35]=5[CH:51]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].Cl.[CH3:56][O:57][C:58]([NH:60][C@H:61]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:62](O)=[O:63])=[O:59].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(#N)C.CO.[OH-].[Na+].C(OCC)(=O)C.C(O)C>[CH3:56][O:57][C:58]([NH:60][C@H:61]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:62]([N:40]1[CH2:41][CH2:42][CH2:43][C@H:39]1[C:37]1[NH:36][C:35]2[CH:51]=[C:31]([C:28]3[CH:29]=[CH:30][C:25]([C:22]4[CH:23]=[CH:24][C:19]([C:16]5[NH:15][C:14]([C@@H:10]6[CH2:11][CH2:12][CH2:13][N:9]6[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:52]([CH3:54])[CH3:53])=[N:18][CH:17]=5)=[CH:20][CH:21]=4)=[CH:26][CH:27]=3)[CH:32]=[CH:33][C:34]=2[N:38]=1)=[O:63])=[O:59]

Participants

11

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 69675309HCID 69675309, compoundHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate

Product 1

HCID 67681766methyl (S)-1-((S)-2-(5-(4'-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateYield 66%

Reagents, catalysts & solvents 5

HCID 14798Sodium HydroxideCatalystHCID 702EthanolSolventHCID 887MethanolSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

A solution of (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, 0.50 mmol), concentrated HCl (1 mL) and ethanol (6 mL) was heated to 60° C. for one hour. The reaction was concentrated and redissolved in a minimal amount of methanol. An equal volume of dichloromethane was added and the solution was again concentrated. Dichloromethane was added to the resulting residue and concentrated off three more times, until the crude material was a yellow powder. The crude material was dissolved in a 5:1 mixture of dichloromethane:dimethylformamide (4.9 mL) and cooled to 0° C. To the solution are sequentially added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (119 mg, 0.57 mmol), COMU (232 mg, 0.54 mmol) and diisopropylethylamine (0.26 mL, 1.5 mmol). After one hour, the reaction is 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 (S)-1-((S)-2-(5-(4′-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (270 mg, 66%). LCMS-ESI+: calculated for C47H50N8O6: 822.95; observed [M+1]+: 823.90.

Workup

  1. concentrationThe reaction was concentrated
  2. dissolutionredissolved in a minimal amount of methanol
  3. additionAn equal volume of dichloromethane was added
  4. concentrationthe solution was again concentrated
  5. additionDichloromethane was added to the resulting residue
  6. concentrationconcentrated off three more times
  7. dissolutionThe crude material was dissolved in a 5:1 mixture of dichloromethane
  8. waitwas continued for 30 minutes
  9. washthe organic layer was washed with water and brine
  10. extractionThe combined aqueous washings were extracted three times with ethyl acetate
  11. dry with materialthe combined organic layers were dried (MgSO4)
  12. concentrationconcentrated
  13. customThe crude material was purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H)

Sources & evidence

ORD record
ord-d813e45b363949fb95de2a161cd33ef0
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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