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.

2′,3′-Dideoxy-3′-fluoro-5-O-[(S)-(+)-2-(l-valyloxy)-propionyl] guanosine (lagociclovir valactate) is a prodrug of 3′-fluoro-2′,3′-dideoxyguanosine with high oral bioavailability in humans and potent activity against hepatitis B virus (HBV). A five-step synthesis of lagocyclovir valactate starting from 2-amino-6-chloropurine is described. The synthesis was performed at kilogram scale, and the target nucleoside prodrug was isolated as the hemisulphate salt with an overall yield of 23%. The major challenges were N-glycosylation of a 2-deoxyfluorosugar, which required separation of α- and β-anomers, and deprotection of the penultimate intermediate by hydrogenation.

Melflufen is a novel cytostatic currently in phase III clinical trials for treatment of multiple myeloma. Development of a process suitable for production is described. The two key features of the novel method are late introduction of the alkylating pharmacophore and an improved method for formation of the bis-chloroethyl group.