Hydrochloric Acid → methyl (2S,3R)-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-(difluoromethoxy)-1-oxobutan-2-ylcarbamate

HRID 1751360Notes

Reaction equation

HRID 1751360 reaction equation
[F:1][CH:2]([F:57])[O:3][C@H:4]([CH3:56])[C@H:5]([NH:51][C:52]([O:54][CH3:55])=[O:53])[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]4[NH:38][C:37]([C@@H:39]5[CH2:43][CH2:42][CH2:41][N:40]5[C:44](OC(C)(C)C)=[O:45])=[N:36]C=4)=[CH:30][CH:29]=2)[CH:22]=[CH:21]3)=[CH:16][N:17]=1)=[O:7].Cl.O1CCOC[CH2:60]1.[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(O)=O)=[O:68].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>CN(C)C=O.C(OCC)(=O)C.ClCCl>[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:44]([N:40]1[CH2:41][CH2:42][CH2:43][C@H:39]1[C:37]1[NH:38][C:34]([C:31]2[CH:30]=[CH:29][C:28]([C:23]3[CH:24]=[C:25]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C:15]3[NH:14][C:13]([C@@H:9]5[CH2:10][CH2:11][CH2:12][N:8]5[C:6](=[O:7])[C@@H:5]([NH:51][C:52](=[O:53])[O:54][CH3:55])[C@H:4]([O:3][CH:2]([F:57])[F:1])[CH3:56])=[N:17][CH:16]=3)[CH:27]=[CH:26]4)=[CH:33][CH:32]=2)=[CH:60][N:36]=1)=[O:45])=[O:68]

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphateHCID 86708711HCID 86708711, compound

Product 1

HCID 86708712methyl (2S,3R)-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-(difluoromethoxy)-1-oxobutan-2-ylcarbamateYield 45%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

A solution of (S)-tert-butyl 2-(5-(4-(6-(2-((S)-1-((2S,3R)-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (68 mg, 0.09 mmol), dichloromethane (1 mL), 4M HCl in dioxane (0.07 mL, 0.28 mmol) and dimethylformamide (0.1 mL) was stirred at room temperature for one hour. Dichloromethane (5 mL) was added to the reaction and then concentrated to a solid. Dilution with dichloromethane and concentration was repeated a total of three times. The resulting solid was dissolved in methanol and filtered through a freebasing column (Stratospheres™ PL-HCO3MP SPE, Part #: PL3540-C603). The filtrate was concentrated and used without further purification. The crude material was dissolved in a 4:1 dichloromethane:dimethylformamide solution (0.8 mL). To this solution was added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (25 mg, 0.12 mmol) and COMU (41 mg, 0.1 mmol) and the reaction was cooled to 0° C. Diisopropylethylamine (0.045 mL, 0.24 mmol) was added and the reaction was stirred at 0° C. for one hour. The reaction was diluted with ethyl acetate and the organic layer was washed with water and brine, dried (MgSO4) and concentrated. The resulting residue was purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield methyl (2S,3R)-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-(difluoromethoxy)-1-oxobutan-2-ylcarbamate (34 mg, 45% over 2 steps). LCMS-ESI+: calculated for C47H48F2N8O7: 874.93; observed [M+1]+: 875.78.

Workup

  1. concentrationconcentrated to a solid
  2. concentrationDilution with dichloromethane and concentration
  3. dissolutionThe resulting solid was dissolved in methanol
  4. filtrationfiltered through a freebasing column (Stratospheres™ PL-HCO3MP SPE, Part #: PL3540-C603)
  5. concentrationThe filtrate was concentrated
  6. customused without further purification
  7. dissolutionThe crude material was dissolved in a 4:1 dichloromethane
  8. washthe organic layer was washed with water and brine
  9. dry with materialdried (MgSO4)
  10. concentrationconcentrated
  11. customThe resulting residue was purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H)

Sources & evidence

ORD record
ord-ab369926ca214bbca92b40650dce680b
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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