SYNTHESIS AND PURIFICATION OF VALACYCLOVIR

摘要

N-tert-Butoxycarbonyl-L-valine-2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester (I) is new. Independent claims are included for the following: (1) preparation (P1) of (I) comprising coupling N-t-butoxycarbonyl valine with acyclovir in the presence of a coupling agent; (2) preparation (P2) of valacyclovir (II) or its salt involving (a1) coupling an amine protected valine (preferably N-tert-butoxycarbonyl valine (a) or N-formyl valine (b), especially (a)) with acyclovir (c) in the presence of a coupling agent to form a protected valacyclovir, and (a2) deprotecting the protected valacyclovir; (3) preparation (P3) of valacyclovir hydrochloride (III) involving performing step (a1), and deprotecting the protected valacyclovir with hydrochloric acid; and (4) preparation of (III) in pure form involving either: Process A: forming a slurry of (III) in a lower alkyl alcohol (preferably ethanol), refluxing the slurry, and isolating (III) from the slurry; or Process B: forming a solution of (III) in water, mixing the solution with isopropanol to form a slurry, and isolating (III) from the slurry.