Scheme 1. Synthesis of KEAP1 BRD4 PROTAC.
Reagent and conditions: (a) BnBr, K₂CO₃, EtOH, 70 ^oC, 81%; (b) Br₂, AcONa, AcOH, r.t, 96%; (c) MeI, NaH, DMF, 0 ^oC to r.t, 79%; (d) Zn dust, AcOH, 0 ^oC to 45 ^oC, 59%; (e) NaNO₂, 10% H₂SO₄ (aq.), 87%; (f) tert-Butyl acrylate, Pd(PPh₃)₄, P(O-Tol)₃, DMF, 95 ^oC, 79%; (g) 13, [RhCl(Cod)]₂, Et₃N, Dioxane/H₂O (2:1), 95 ^oC, 53%; (h) 16, DIAD, PPh₃, anhydrous THF, r.t, 75%; (i) H₂, Pd/C, MeOH, r.t, 98%; (j) NaH, Bromo acetic acid, THF, reflux, 95%; (k) (i) 19a-d, HATU, DIPEA, DMF, r.t, 45-60%; (ii) 4N HCl/Dioxane, r.t, 86-95%