Hydrochloric Acid → methyl {(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

HRID 1751624Notes

Reaction equation

HRID 1751624 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[C:17]1[NH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]3[C:54]4[C:30](=[C:31]5[C:51](=[CH:52][CH:53]=4)[C:35]4[N:36]=[C:37]([C@@H:39]6[CH2:43][CH2:42][CH2:41][N:40]6C(OC(C)(C)C)=O)[NH:38][C:34]=4[CH:33]=[CH:32]5)[O:29][CH2:28][C:26]=3[CH:27]=2)=[CH:20][N:21]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[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]([OH:64])=O)=[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:38][C:34]2[CH:33]=[CH:32][C:31]3[C:51](=[CH:52][CH:53]=[C:54]4[C:25]5[CH:24]=[CH:23][C:22]([C:19]6[NH:18][C:17]([C@H:13]7[CH2:14][CH2:15][CH2:16][N:12]7[C:10](=[O:11])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])=[N:21][CH:20]=6)=[CH:27][C:26]=5[CH2:28][O:29][C:30]4=3)[C:35]=2[N:36]=1)=[O:64])=[O:59]

Participants

11

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphateHCID 86688818tert-butyl (2S)-2-[9-(2-{(2R)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate

Product 1

HCID 86688820methyl {(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamateYield 51%

Reagents, catalysts & solvents 5

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

Conditions

Temperature
60 °C

Procedure

A mixture of tert-butyl (2S)-2-[9-(2-{(2R)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (270 mg, 0.37 mmol), concentrated HCl (1.5 mL) and ethanol (8 mL) was heated to 60° C. for 1 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 two more times. The crude material was dissolved in 5:1 dichloromethane/dimethylformamide (3.8 mL). To this solution was added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (96 mg, 0.46 mmol), COMU (190 mg, 0.44 mmol) and diisopropylethylamine (0.20 mL, 1.1 mmol). The reaction was stirred at 0° C. for 30 minutes then warmed to room temperature. Upon completion, 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 reverse phase HPLC (Gemini, 15 to 45% ACN/H2O+0.1% TFA) to yield methyl {(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (155 mg, 51% yield over 2 steps). LCMS-ESI+: calculated for C46H48N8O7: 824.92; observed [M+1]+: 825.67.

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 two more times
  7. dissolutionThe crude material was dissolved in 5:1 dichloromethane/dimethylformamide (3.8 mL)
  8. temperaturethen warmed to room temperature
  9. stirringstirring
  10. waitwas continued for 30 minutes
  11. washthe organic layer was washed with water and brine
  12. extractionThe combined aqueous washings were extracted three times with ethyl acetate
  13. dry with materialthe combined organic layers were dried (MgSO4)
  14. concentrationconcentrated
  15. customThe crude material was purified by reverse phase HPLC (Gemini, 15 to 45% ACN/H2O+0.1% TFA)

Sources & evidence

ORD record
ord-d3c091c819c8454bb96a1c2a6bed8306
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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