Scheme 2
From: Synthesis, biological evaluation and clinical trials of Cereblon-based PROTACs
Chemical synthesis of pomalidomide-based PROTACs from 3-nitrophtalic anhydride. Reagents and conditions: a Acetic anhydride, reflux, 2 h; b tert-butyl-(2,6-dioxopiperidin-3-yl)carbamate 3, sodium acetate, acetic acid, reflux, 6 h; b1 3-aminopiperidine-2,6-dionehydrochloride, sodium acetate, acetic acid, 130 °C, 48 h; b2 3-aminopiperidine-2,6-dionetrifluoroacetate, triethylamine, THF, 80 °C, 6 h; b3 3-aminopiperidine 2,6-dionehydrochloride, sodium acetate, acetic acid, 80 °C, 12 h; c1 Palladium on Carbon (Pd/C), H2, DMF, rt, 24 h; c2 Fe, ammonium chloride, ethanol/water mixture, rt, overnight; c3 Ammonium formate, Pd/C, methanol, rt, 2 h; d 3-aminopiperidine-2,6-dionehydrochloride, triethylamine, THF, ≤20 °C, 30 min; e Pd/C, H2, 145 psi, methanol, rt, 30 min, quant.; f Methanol, reflux, 2 h; g glutamine, DMF, 80 to 87 °C, 8 h; h Pd/C, H2, 50 psi, metanol, 3 h; i CDI, acetonitrile, reflux, 4.5 h.
