Evaluation of Kilogram-Scale Sonagashira, Suzuki, and Heck Coupling Routes to Oncology Candidate CP-724,714

Abstract

The synthesis of the anti-cancer compound 2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)phenylamino]quinazolin-6-yl}-E-allyl)acetamide (CP-724,714) (1) on multikilogram scale using several different synthetic routes is described. Application of the Sonogashira, Suzuki, and Heck couplings to this synthesis was investigated to identify a safe, environmentally friendly, and robust process for the production of this drug candidate. A convergent and selective synthesis of the candidate was identified which utilizes a Heck coupling of a protected allylamine to install the critical olefin.

Palladium‐Catalyzed, Highly Efficient, Regiocontrolled Arylation of Electron‐Rich Allylamines with Aryl Halides

“…The beneficial effect of ligand‐free conditions led us to examine the reaction of 1a and 2b without using a ligand. However, when Ripin’s protocol16a was employed, no reaction took place after 20 h (Table 3, entry 2). The catalyst system consisting of Pd 2 (dba) 3 [tris(dibenylideneacetone)dipalladium (0)], NaOAc (sodium acetate) and NEt 3 with EtOH as solvent, reported to be highly effective for the regioselective linear arylation of N ‐allyl‐2‐methoxyacetamide by aryl iodide,16b proved to be ineffective in our case (Table 3, entry 3).…”

Cu‐free Sonogashira Type Cross‐Coupling of 6‐Halo‐2‐cyclopropyl‐3‐(pyridyl‐3‐ylmethyl) Quinazolin‐4(3H)‐ones as Potential Antimicrobial Agents

“…It has also been reported under Pd‐free, amine‐free, ligand‐free, and solvent‐free conditions as well as with tetrabutylammonium salts as additives and in the presence of water as solvent . Despite reports of alkynylation of quinazolinone/quinazolines with terminal acetylenes, very limited information exists in the literature on the Sonogashira cross‐coupling of 6‐halo‐quinazolinones with terminal alkynes to generate 6‐alkynylated‐substituted quinazolinone derivatives . Hence, development of a catalytic system for the alkynylation at the 6‐position of iodoquinazolinones, bromoquinazolinones, or chloroquinazolinones is synthetically an interesting potential.…”

A General Suzuki Cross-Coupling Reaction of Heteroaromatics Catalyzed by Nanopalladium on Amino-Functionalized Siliceous Mesocellular Foam

“…From a patient safety perspective, removal of toxic metal residues in the pharmaceutically active ingredient is very important. 10,11 The acceptable level of the platinoids (Pt, Pd, Ir, Rh, Ru) in a compound for oral administra-tion is less than 10 ppm. 12,13 For this reason, the development of new techniques and supports for immobilization of the catalytic metal species has gained increased attention.…”

“…12,13 For this reason, the development of new techniques and supports for immobilization of the catalytic metal species has gained increased attention. 10,14 Thus, a heterogeneous palladium catalyst where the metal is immobilized to a solid support allows for easier separation of the catalyst from the reaction mixture at the end of the reaction and enables efficient recycling of the catalyst. With ligand-free catalytic systems, the reaction also becomes more environmentally friendly and the workup is further simplified.…”