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 1751583Notes

Reaction equation

[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]

Participants

Conditions

Temperature: 0 °C

Procedure

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.

Workup

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

Sources & evidence

ORD record: ord-e940f0b0be7945c6b615b222ac415d77
Source dataset: uspto-grants-2015_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09156823B2

Reaction notes

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