Hydrochloric Acid → methyl (S)-1-((S)-2-(5-(7-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

HRID 1751583Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1751583
[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:54](C)[CH3:55])[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:32]=[C:31]3[C:22]([C:23]4[CH:24]=[CH:25][C:26]([C:33]5[CH:34]=[CH:35][C:36]6[N:40]=[C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](OC(C)(C)C)=[O:47])[NH:38][C:37]=6[CH:53]=5)=[CH:27][C:28]=4[CH2:29][CH2:30]3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].Cl.O1CCOC[CH2:59]1.[CH3:64][O:65][C:66]([NH:68][C@H:69]([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)C(O)=O)=[O:67].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>CO>[CH3:64][O:65][C:66]([NH:68][C@H:69]([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:46]([N:42]1[CH2:43][CH2:44][CH2:45][C@H:41]1[C:39]1[NH:38][C:37]2[CH:53]=[C:33]([C:26]3[CH:25]=[C:24]4[C:23]([C:22]5[CH:21]=[CH:20][C:19]([C:16]6[NH:15][C:14]([C@@H:10]7[CH2:11][CH2:12][CH2:13][N:9]7[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:54]([CH3:55])[CH3:59])=[N:18][CH:17]=6)=[CH:32][C:31]=5[CH2:30][CH2:29]4)=[CH:28][CH:27]=3)[CH:34]=[CH:35][C:36]=2[N:40]=1)=[O:47])=[O:67]

Komponenten

8

Edukt 6

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 67682236HCID 67682236, VerbindungHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate

Produkt 1

HCID 67682206methyl (S)-1-((S)-2-(5-(7-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateAusbeute 36 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 887MethanolLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

A solution of (S)-tert-butyl 2-(6-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (30 mg, 0.04 mol), methanol (0.5 mL), and 4M HCl in dioxane (1 mL, 4 mmol) was stirred at room temperature. The reaction was thoroughly concentrated after twenty minutes. The resulting residue was dissolved in a 4:1 dichloromethane:dimethylformamide solution (1.0 mL). One half of this solution was removed and used in the subsequent reaction. To this solution (˜0.5 mL) was added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (4.2 mg, 0.02 mmol) and COMU (8.5 mg, 0.02 mmol) and the reaction was cooled to 0° C. Diisopropylethylamine (0.011 mL, 0.06 mmol) was added and the reaction was stirred at 0° C. for twenty minutes. The reaction was quenched by the addition of formic acid (0.05 mL) and thoroughly concentrated. The resulting residue was purified by preparative reverse phase HPLC (Gemini, 10 to 60% ACN/H2O+0.1% HCO2H), followed by a second preparative reverse phase HPLC (Gemini, 10 to 60% ACN/H2O+0.1% TFA) to yield methyl (S)-1-((S)-2-(5-(7-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (6 mg, 36%). LCMS-ESI+: calculated for C49H52N8O6: 848.99; observed [M+1]+: 850.2.

Aufarbeitung

  1. concentrationThe reaction was thoroughly concentrated after twenty minutes
  2. dissolutionThe resulting residue was dissolved in a 4:1 dichloromethane
  3. customOne half of this solution was removed
  4. customused in the subsequent reaction
  5. customThe reaction was quenched by the addition of formic acid (0.05 mL)
  6. concentrationthoroughly concentrated
  7. customThe resulting residue was purified by preparative reverse phase HPLC (Gemini, 10 to 60% ACN/H2O+0.1% HCO2H)

Quellen und Nachweise

ORD-Eintrag
ord-e940f0b0be7945c6b615b222ac415d77
Quelldatensatz
uspto-grants-2015_10
Patentnummer
US09156823B2

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