Hydrogen Bromide → methyl (R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

HRID 1751366Notes

Reaction equation

HRID 1751366 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:57]([CH3:59])[CH3:58])[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:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](OCC7C=CC=CC=7)=[O:47])=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:56]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].Br.[CH3:61][O:62][C:63]([NH:65][C@H:66]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)C(O)=O)=[O:64].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(O)(=O)C.ClCCl.C(OCC)(=O)C.CN(C)C=O>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:57]([CH3:59])[CH3:58])[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:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:47])[C@H:66]([NH:65][C:63](=[O:64])[O:62][CH3:61])[C:70]7[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=7)=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:56]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]

Participants

10

Reactant 5

HCID 260Hydrogen BromideHCID 81531DiisopropylethylamineHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 67681922HCID 67681922, compoundHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate

Product 1

HCID 67681424methyl (R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamateYield 26%

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A mixture of (S)-benzyl 2-(5-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (260 mg, 0.33 mmol), 33% HBr in acetic acid (1 mL) and dichloromethane (4 mL) was vigorously stirred at room temperature for 30 minutes and then thoroughly concentrated. The crude material was diluted with dichloromethane and concentrated, letting the resulting residue sit under vacuum overnight. To this residue were sequentially added dichloromethane (2.4 mL), dimethylformamide (0.6 mL), (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (88 mg, 0.42 mmol), and COMU (154 mg, 0.36 mmol) and diisopropylethylamine (0.16 mL, 0.9 mmol). After stirring for 30 minutes at room temperature the reaction was diluted with ethyl acetate and washed sequentially with saturated aqueous NaHCO3 solution, water and brine. The organic layer was dried (MgSO4), then filtered through a freebasing column (Stratospheres™ PL-HCO3MP SPE, Part #: PL3540-C603). The filtrate was concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield methyl (R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate (72 mg, 26%). LCMS-ESI+: calculated for C48H50N8O7: 850.96; observed [M+1]+: 851.93.

Workup

  1. concentrationthoroughly concentrated
  2. additionThe crude material was diluted with dichloromethane
  3. concentrationconcentrated
  4. customsit under vacuum overnight
  5. stirringAfter stirring for 30 minutes at room temperature the reaction
  6. washwashed sequentially with saturated aqueous NaHCO3 solution, water and brine
  7. dry with materialThe organic layer was dried (MgSO4)
  8. filtrationfiltered through a freebasing column (Stratospheres™ PL-HCO3MP SPE, Part #: PL3540-C603)
  9. concentrationThe filtrate was concentrated
  10. custompurified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H)

Sources & evidence

ORD record
ord-1dd3688539804ddb8a70d5779cfc475d
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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