Method of preparation of antiviral compounds and useful intermediates thereof

摘要

The invention is directed to processes for synthesizing bicyclic nucleoside antiviral compounds and for synthesizing the intermediates used in the process. The invention is also directed to novel intermediate compounds useful in the process. The antiviral compounds are useful in the treatment of herpes zoster (i.e., varicella zoster virus, VZV, shingles) and for the prevention of post herpetic neuralgia (PHN) resulting from this viral infection.

主权项

1. A process for the synthesis of a compound of Formula (IV) from a compound of Formula (IIIa):wherein:
R1 is C1-C6 alkyl; and R4 and R5 are each independently H or C1-C2 alkyl,or a pharmaceutically acceptable salt thereof,comprising the steps of
(1) protecting the primary hydroxyl group in a compound of Formula (IIIa) to form a compound of Formula (V), comprising reacting the primary hydroxyl group in a compound of Formula (IIIa) with R10X in the optional presence of a base, wherein:
R10 is trityl, 4,4′-dimethoxytrityl, tert-butyldimethylsilyl, diphenylmethylsilyl, or tert-butyldiphenylsilyl; andX is a leaving group; (2) protecting the secondary hydroxyl group in a compound of Formula (V) to form a compound of Formula (VI), comprising reacting a compound of Formula (V) with R11X in the optional presence of a base, wherein:
R11 is C1-C6 alkanoyl, halogen substituted alkanoyl, optionally substituted aroyl, optionally substituted benzyl, carboxylbenzyl, or diphenylmethyl; andX is a leaving group; (3) deprotecting the primary hydroxyl group in a compound of Formula (VI) to form a compound of Formula (VII), comprising reacting a compound of Formula (VI) with an acid; (4) esterifying the primary hydroxyl group in a compound of Formula (VII) with a compound of Formula (X) to form a compound of Formula (VIII), comprising esterifying the primary hydroxyl group in a compound of Formula (VII) with a compound of Formula (X), optionally in the presence of a coupling or dehydrating agent and/or a base, to form a compound of Formula (VIII), wherein:
R6 is tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or carboxybenzyl; (5) deprotecting the secondary hydroxyl group and amino acid group in a compound of Formula (VIII) to form a compound of Formula (IV), comprising deprotecting R11 and R6 in a compound of Formula (VIII), to provide a compound of Formula (IV); and (6) optionally converting a compound of Formula (IV) to a pharmaceutically acceptable salt thereof.