22% |
Stage #1: 3-propoxyazetidine hydrochloride; (S)-3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione With N-ethyl-N,N-diisopropylamine In acetonitrile at 20 - 50℃; for 3.5h;
Stage #2: With hydrogenchloride In water |
5.96
5.96 3-(1-OXO-4-((4-((3-PROPOXYAZETIDIN-1-YL)METHYL)BENZYL) OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE HYDROCHLORIDE To a solution of (S)-3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 0.451 mmol) in dry MeCN (5 mL), was added 3-propoxyazetidine hydrochloride (75 mg, 0.496 mmol) and DIEA (0.276 mL, 1.579 mmol). The mixture was stirred at room temperature for 3 h and LCMS indicated benzyl bromide starting material was consumed. The mixture was heated to 50° C. for ~30 min, cooled slowly to rt, and then stored at 4° C. overnight. The mixture containing the crude product was concentrated in vacuo and the residue was dissolved in minimal DMF (~5 mL) for Prep HPLC purification. The product was eluted with an acetonitrile/water gradient (0.1% formic acid in both mobile phases, 5% to 60% MeCN over 20 minutes) and fractions were collected by mass trigger. The desired fractions were combined and concentrated in vacuo to give a clear glass residue. 1N HCl (2-3 mL) was added and the mixture was concentrated in vacuo to dryness. This process was repeated twice to obtain HCl salt. To the clear residue, MeCN and Et2O were added in small portions and the mixture was sonicated until a white solid was obtained. The slurry was concentrated in vacuo to dryness and twice evaporated from Et2O (3-4 mL portions) until a free flowing white solid was obtained. The solid was dried in a vacuum oven overnight to give 3-(1-oxo-4-((4-((3-propoxyazetidin-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dione hydrochloride as a white solid (52 mg, 22%): HPLC: Waters Symmetry C18, 5 μm, 3.9*150 mm, 1 ml/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 6.60 min (99.8%); mp: 142-144° C.; 1H NMR (DMSO-d6) δ 0.87 (t, J=7.4 Hz, 3H, CH3), 1.40-1.59 (m, 2H, CH2), 1.91-2.06 (m, 1H, CHH), 2.35-2.47 (m, 1H, CHH), 2.53-2.65 (m, 1H, CHH), 2.84-3.01 (m, 1H, CHH), 3.28-3.39 (m, 2H, CH2O, overlapped with DMSO), 3.89 (br. s., 2H, CH2), 4.06-4.23 (m, 2H, CH2), 4.23-4.32 (m, 2H, CHH, CHH), 4.36 (s, 2H, CH2), 4.44 (d, J=17.6 Hz, 1H, CHH), 5.12 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.28 (s, 2H, CH2), 7.27-7.38 (m, 2H, Ar), 7.44-7.53 (m, 1H, Ar), 7.55 (s, 4H, Ar), 10.97 (s, 1H, NH), 11.09 (br. s., 1H, HCl); 13C NMR (DMSO-d6) δ -0.01, 12.34, 24.22, 32.97, 47.32, 53.70, 62.70, 63.30, 69.33, 71.21, 71.67, 117.13, 117.29, 129.67, 130.77, 131.82, 131.96, 134.99, 137.66, 138.23, 155.27, 170.35, 172.81, 174.98; LCMS: MH=478; Anal Calcd for C27H31N3O5.+3.2 H2O+1.3 HCl: C, 55.66; H, 6.70; N, 7.21; Cl, 7.91; H2O, 9.89; Found: C, 53.73; H, 6.33; N, 6.90; Cl, 7.63; H2O, 9.62. |