Hydrochloric Acid → (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-aminopropanoate hydrochloride

To a solution of (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-((tert-butoxycarbonyl)amino)propanoate (0.032 g, 0.058 mmol) in DCM (2 mL) at −20° C. was added HCl in diethyl ether (2.0 ml, 2.0 mmol, 1.0 M). The reaction mixture was slowly warmed to rt over 10 min and then allowed to stir at rt for 19 h. The solvent was then removed in vacuo to provide a pale yellow semisolid. The crude product was then purified by RP-HPLC on a Kinetex C18 (250×20 mm) 5 μm column using a gradient of 10% solvent B to 40% solvent B over 7 minutes at 15 mL/min where solvent A=0.05% HCl in water and solvent B=acetonitrile. Active fractions were concentrated by lyophilization to provide 4.7 mg (16%) of (S)-4-((3S,4S)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl 2-aminopropanoate hydrochloride, the titled compound of example 4 as an off-white solid. LC-MS (Method A) RT=1.762 min, (M+H)+=454. 1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, J=9.0 Hz, 2H), 7.24-7.10 (m, 6H), 5.10-4.85 (m, 1H), 4.45-4.22 (m, 4H), 4.04-3.94 (m, 1H), 3.34-3.18 (m, 4H), 3.06 (d, J=12.0 Hz, 2H), 2.43-2.31 (m, 1H), 2.27 (s, 3H), 2.24-2.14 (m, 1H), 2.13-2.01 (m, 1H), 2.01-1.85 (m, 1H), 1.58 (d, J=7.0 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ −183.778.

1. customThe solvent was then removed in vacuo
2. customto provide a pale yellow semisolid
3. customThe crude product was then purified by RP-HPLC on a Kinetex C18 (250×20 mm) 5 μm column
4. customover 7 minutes
5. concentrationActive fractions were concentrated by lyophilization

ORD-Eintrag

ord-4cd368c54ddd468fa4aef587cf663455

Quelldatensatz

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09187506B2