Hydrochloric Acid → HCID 86688334, compound

HRID 1509668Notes

Reaction equation

HRID 1509668 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]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]4[C:37]5[CH:36]=[CH:35][C:34]([C:38]6[NH:42][C:41]([C@H:43]7[CH2:47][CH2:46][CH2:45][N:44]7C(OC(C)(C)C)=O)=[N:40][CH:39]=6)=[CH:33][C:32]=5[CH2:31][O:30][C:26]4=3)[C:20]=2[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]([CH:65]([CH3:67])[CH3:66])[C:62](O)=[O:63])=[O:59].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>CN(C)C=O.C(#N)C.CO.[OH-].[Na+].C(OCC)(=O)C.C(O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:7]([CH3:9])[CH3:8])[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]1[NH:18][C:19]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]4[C:37]5[CH:36]=[CH:35][C:34]([C:38]6[NH:42][C:41]([C@H:43]7[CH2:47][CH2:46][CH2:45][N:44]7[C:62](=[O:63])[C@@H:61]([NH:60][C:58](=[O:59])[O:57][CH3:56])[CH:65]([CH3:67])[CH3:66])=[N:40][CH:39]=6)=[CH:33][C:32]=5[CH2:31][O:30][C:26]4=3)[C:20]=2[N:21]=1)=[O:11])=[O:4]

Participants

12

Reactant 5

HCID 313Hydrochloric AcidHCID 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 86688815HCID 86688815, compound

Product 1

HCID 86688334HCID 86688334, compoundYield 67%

Reagents, catalysts & solvents 6

HCID 14798Sodium HydroxideCatalystHCID 702EthanolSolventHCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of Intermediate tert-butyl (2R)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (390 mg, 0.53 mmol), concentrated HCl (2 mL) and ethanol (10 mL) was heated to 60° C. for 2 hours. 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. One half of the crude material (˜0.27 mmol) was dissolved in dimethylformamide (2.5 mL). To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (66 mg, 0.38 mmol), HATU (140 mg, 0.37 mmol) and diisopropylethylamine (0.48 mL, 2.7 mmol). The reaction was stirred at room temperature for 2 hours, 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 reverse phase HPLC (Gemini, 15 to 45% ACN/H2O+0.1% TFA) to yield methyl {(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}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 (140 mg, 67% yield over 2 steps). LCMS-ESI+: calculated for C43H50N8O7: 790.91; observed [M+1]+: 791.71.

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. stirringstirring
  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 reverse phase HPLC (Gemini, 15 to 45% ACN/H2O+0.1% TFA)

Sources & evidence

ORD record
ord-df4614e656f14fd0b80060701477495d
Source dataset
uspto-grants-2015_12
Patent number
US09221833B2

Reaction notes

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