ABSTRACT
We have established practical synthetic methods for penciclovir (PCV, 1) and famciclovir (FCV, 2) from N2-acetyl-7-benzylguanine (NAc7BnG, 3) and 6,6-dimethyl-5, 7-dioxaspiro[2.5]octane-4,8-dione (4)--the latter being a more easily prepared cyclic precursor of the diacetate side chain (5) used in the conventional process. The coupling of 4 with 3 proceeded regioselectively at the N9 position of guanine in good yield. The coupling product was then successfully transformed into the known antiviral agents in a short number of steps.
Subject(s)
2-Aminopurine/analogs & derivatives , Acyclovir/analogs & derivatives , Antiviral Agents/chemical synthesis , Guanine/analogs & derivatives , 2-Aminopurine/chemical synthesis , 2-Aminopurine/chemistry , Acyclovir/chemical synthesis , Acyclovir/chemistry , Antiviral Agents/chemistry , Famciclovir , Guanine/chemistry , Molecular Structure , Prodrugs/chemical synthesis , Prodrugs/chemistryABSTRACT
Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors (Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from l-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to l-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.
Subject(s)
HIV Protease Inhibitors/chemical synthesis , Organophosphates/chemical synthesis , Sulfonamides/chemical synthesis , Carbamates , Furans/chemical synthesis , Furans/chemistry , Molecular Conformation , Molecular StructureABSTRACT
A simple and versatile method was developed for the synthesis of alpha-aminoalkyl alpha'-halomethyl ketone derivatives, which are useful intermediates of protease inhibitors. It involves selective halogenation of the alpha-position on a beta-ketoester, which is prepared by cross-Claisen condensation using N-protected amino acid ester. The title compound is obtained in high yield after decarboxylation of the alpha-halo-beta-ketoester.
