Hydrochloric Acid → methyl {(2S,3S)-1-[(2S,5S)-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-2-[(methoxycarbonyl)amino]acetyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate

Temperature

40 °C

To a solution of tert-butyl (2S,5S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-isoleucyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-5-methylpyrrolidine-1-carboxylate (0.30 g, 0.39 mmol) in a mixture of dichloromethane (4 mL) and methanol (0.5 mL) was added HCl (4M in dioxanes, 1.45 mL, 5.80 mmol). The solution was heated to 40° C. for 1 h and cooled to room temperature. The solution was then concentrated in vacuo. The resulting solid was dissolved in DMF (3 mL), followed by the addition of (S)-2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonylamino)acetic acid (0.11 g, 0.46 mmol), HATU (0.18 g, 0.48 mmol), and diisopropylethylamine (0.3 mL, 1.72 mmol). The resulting solution was stirred at room temperature for 3 h. Aqueous HCl (6M, 4 drops) was added and the solution was purified by reverse phase HPLC (Gemini column, 10-53% MeCN/H2O/0.1% TFA). The desired fractions were combined, and the organics were concentrated in vacuo. The resulting aqueous solution was basified with saturated NaHCO3 to provide a white precipitate. The solid was filtered and dried to provide methyl {(2S,3S)-1-[(2S,5S)-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl]-2-[(methoxycarbonyl)amino]acetyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate (0.082 g, 23%) as a white powder. LCMS-ESI+: calc'd for C50H62N8O9: 903.08 (M+). Found: 903.84 (M+H+). 1H NMR (400 MHz, Methanol-d4) δ 8.36-8.22 (m, 1H), 7.98-7.82 (m, 1H), 7.69-7.20 (m, 8H), 5.22-5.07 (m, 3H), 5.02 (d, 1H), 4.73-4.64 (m, 1H), 4.49 (s, 3H), 4.26-3.97 (m, 4H), 3.79 (d, 1H), 3.72 (s, 1H), 3.63-3.52 (m, 4H), 3.47-3.32 (m, 1H), 2.61-2.43 (m, 1H), 2.32-1.98 (m, 4H), 1.95-1.78 (m, 1H), 1.79-1.65 (m, 1H), 1.54 (s, 4H), 1.41 (d, 2H), 1.28-1.09 (m, 3H), 1.04 (dd, 6H), 0.90 (d, 1H), 0.88-0.59 (m, 10H).

1. temperaturecooled to room temperature
2. concentrationThe solution was then concentrated in vacuo
3. dissolutionThe resulting solid was dissolved in DMF (3 mL)
4. customthe solution was purified by reverse phase HPLC (Gemini column, 10-53% MeCN/H2O/0.1% TFA)
5. concentrationthe organics were concentrated in vacuo
6. customto provide a white precipitate
7. filtrationThe solid was filtered
8. customdried

ORD record

ord-433f382ad2334a3fa7999e1e1c3340a6

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09233974B2