Process for the preparation of purine derivatives

Details Process for the preparation of purine derivatives Process for the preparation of purine derivatives

1999-01-27

2001-02-13

Berch, Mark L. (Department: 1611)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

Reexamination Certificate

active

06187922

ABSTRACT:

The present invention relates to a process for the preparation of novel compounds, which are of potential use as antiviral agents, to a process for their reparation and to their use as pharmaceuticals.
U.S. Pat. Nos. 5,075,445 and 5,246,937, the subject matter of which is incorporated herein by reference, disclose antiviral compounds penciclovir (Example 4 of '445) and famciclovir (Example 2 of '937) and methods for their preparation. 2-Amino-6-chloropurine (ACP) is 9-substituted with an appropriate side chain precursor, followed by conversion of the 6-chloro moiety to a hydroxy moiety (i.e. to form a guanine) or hydrogen (a 2-aminopurine).
In particular, beginning column 4 of '445, and column 3 of '937, a process is described for the preparation of such purine derivatives wherein the hydroxy groups in the 9-(4-hydroxy-3-hydroxymethylbut-1-yl) substituent are in acylated form, i.e. the ACP is reacted with 2-acyloxymethyl-4-(leaving group)-but-1-yl acylate. The leaving group may be halo, such as chloro, bromo or iodo although alternative leaving groups, such as tosylate or methanesulphonate may be employed. The acyl groups have advantages over the alternative protecting groups already described in acyclonucleoside chemistry in providing a good yield of 9-substitution and avoiding by-products which are difficult to isolate.
The following examples illustrate the process of the invention to form 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-amino-6-chloropurine, (DACP). The following descriptions illustrate the preparation of side chain intermediates. Penciclovir is prepared from DACP according to the method described in '445 column 14, lines 4-16 and famciclovir is prepared from DACP according to the method described in Example 2 of '937.


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