A Large Scale Process for the Preparation of Thymitaq

Abstract

The large scale manufacturing of the anticancer agent 2-amino-6-methyl-5-(pyridin-4-ylsulfanyl)-3H-quinazolin-4-one dihydrochloride (thymitaq) from 6-bromo-5-methylanthranilic acid is described. The chemical route consists of two chemical steps: formation of a bromoquinazolinone and a copper-mediated Ullman-like coupling between 4-mercaptopyridine and the bromoquinazolinone. During process development, sodium hydride was replaced with sodium hydroxide and a method for removal of copper, based on 2,4,6-trimercapto-s-triazine, was developed. A number of purification operations were performed to ensure a product of pharmaceutical quality.

Cu/Fe-Catalyzed Carbon-Carbon and Carbon-Heteroatom Cross-Coupling Reactions

“…This method has been employed successfully for the synthesis of promazine drugs like chlorpromazine, triflupromazine and acepromazine in good yield. Wennerberg et al [190] prepared the anticancer agent thymatiq in large scale by copper-mediated coupling between halide and 4-mercaptopyridine (Scheme 62b). Bagley et al reported a copper mediated methodology for the synthesis of P38α MAPK Clinical Candidate VX-745 by C-S coupling reaction (Scheme 62c) [191].…”

Novel Annulation of Cyanuric Chloride with 2‐Aminobenzamides: A New Approach to 2‐Amino‐3‐substituted Quinazolin‐4(3H)‐ones

“…Quinazolin-4(3H)-ones are important class of naturally occurring nitrogen heterocycles [1] among them 2-amino functionalized quinazolin-4(3H)-ones were extensively studied in medicinal chemistry for a variety of pharmacological properties, which include anti-cancer, [2,3,4] anti-hypertensive, [5] anti-hepatitis C, [6] anti-viral, [7] anti-hyperglycemic, [8] anti-malarial, [9,10] antiinflammatory, [11] anti-microbial [12] and anti-bacterial activity. [13] Some of the important bioactive molecules, with 2-amino quinazolin-4(3H)-one pharmacophore, are shown in (Figure 1).…”

Pd-Catalyzed Regioselective Mono-Arylation: Quinazolinone as the Inherent Directing Group for C(sp2)–H Activation

“…Quinazolinones are one of the important nitrogen-containing heterocyclic motifs; it is found in more than 200 natural products as well as in several drugs (Figure ). , The quinazolinone derivatives possess a wide range of pharmacological activities such as antimalarial, anticancer, antimicrobial, antidiabetic, anti-inflammatory, antihypertensive, anticonvulsant, diuretic, among others. − The synthesis of various natural and synthetic derivatives of quinazolinones has acquired immense attention by the scientific community because of their wide range of biological properties. − …”