Process for preparing 5′-acetylstavudine

Details Process for preparing 5′-acetylstavudine Process for preparing 5′-acetylstavudine

2001-04-12

2002-02-26

Shah, Mukund J. (Department: 1624)

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

Organic compounds

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

Reexamination Certificate

active

06350873

ABSTRACT:

The present invention relates to a process for preparing 5′-acetylstavudine, an intermediate which is useful in the preparation of 2′,3′-didehydro-3′-deoxythymidine, an active principle with antiviral action which is commonly known as stavudine (D4T).
TECHNICAL FIELD OF THE INVENTION
Many processes for preparing stavudine have been described in the literature, such as, for example, those reported in: EP-A-0 340 778, EP-A-0 493 602, EP-A-0 501 511, WO 92/09599, EP-A-0 334 368, EP-A-0 519 464, EP-A-0 653 435, EP-A-0 653 436, EP-A-0 735 044, in Mansuri et al., J. Org. Chem. 1989, 54, 4780-4785 and in Classon et al., Acta Chem. Scand., B36, 1982, 251. Among these, EP-A-0 334 368, Mansuri et al. and Classon et al. describe the preparation of stavudine by deacetylation of 5′-acetylstavudine; in greater detail, both EP-A-0 334 368 and Mansuri et al. describe a process for preparing 5′-acetylstavudine (B) by reductive elimination of 2′-deoxy-2′-bromo-3′,5′-diacetyl-5-methyluridine (A) in the presence of zinc as reducing agent and copper as activating agent, according to the reaction scheme given below.
5′-Acetylstavudine is then converted into the final product by hydrolysis with sodium methoxide in methanol. The synthetic scheme described in Classon et al. is substantially identical, the only difference being that the reductive elimination reaction is carried out in the presence of zinc as reducing agent and acetic acid as activating agent.
However, the two synthetic processes described above are relatively unsatisfactory, in particular on account of the reductive elimination reaction which gives only moderate yields and, thus, is difficult to apply at the industrial level; the purpose of the present invention is thus to find a process which allows the reductive elimination of 2′-deoxy-2′-bromo-3′,5′-diacetyl-5-methyluridine in yields greater than those of the processes known in the art.
DESCRIPTION OF THE INVENTION
A process has now been found, and this constitutes the subject of the present invention, which makes it possible to prepare 5′-acetylstavudine in yields that are substantially greater than those of the processes described above; according to this process, 2′-deoxy-2′-bromo-3′,5′-diacetyl-5-methyluridine is converted into 5′-acetylstavudine by reductive elimination in the presence of zinc as reducing agent combined with an ammonium salt or a phosphonium salt as activating agent.
Among the various ammonium salts, the ones that are particularly preferred are the halides and sulphates; among the halides, those that are most indicated for carrying out the invention are selected from tributylamine hydrochloride, triethylamine hydrochloride, ammonium chloride, tributylamine hydrobromide, triethylamine hydrobromide and/or ammonium bromide.
Among the phosphonium salts, the ones that are preferred are the halides, in particular the bromides, for example such as triphenylphosphine hydrobromide.
As will be seen from the examples which follow, and which should be considered as purely illustrative of and non-limiting on the invention, zinc is generally used in an amount of between 1 and 4 equivalents and preferably between 1.5 and 2.4 equivalents, while the ammonium salt is used in an amount of between 0.2 and 2 equivalents and preferably between 0.5 and 1.5 equivalents.
The process according to the present invention may be carried out in the usual organic solvents used in reductive eliminations, such as alcohols, ethers, esters or dipolar aprotic solvents; among these, the preferred solvents are dipolar aprotic solvents such as, for example, DMF or DMSO and ethereal solvents such as, for example, THF, or mixtures thereof.
In the preferred embodiment of the invention, 1.5-2.4 equivalents of zinc powder are added to a solution at 20° C. of 2′-deoxy-2′-bromo-3′,5′-diacetyl-5-methyluridine in DMF, DMSO or THF, or mixtures thereof. The reaction mixture is left stirring for about 10 minutes and 0.5-1.5 equivalents of the ammonium salt, preferably tributylamine hydrochloride, triethylamine hydrochloride, ammonium chloride, tributylamine hydrobromide, triethylamine hydrobromide or ammonium bromide, are then added; the system is then left to react at 30° C. for about 2 hours, until the reaction is complete.
As may be appreciated from the examples attached, the process according to the present invention allows the production of 5′-acetylstavudine in particularly high yields when compared those of processes known in the prior art; specifically, 5′-acetyl-10 stavudine may be obtained in yields of 56-67% working with 86-90 g of 2′-deoxy-2′-bromo-3′,5′-diacetyl-5-methyluridine and in yields of greater than 70% by working with about 10 g of starting material; in contrast, the processes described in EP-A-0 334 368, Mansuri et al. and Classon et al. give yields of 44-52% by working using substantially smaller starting amounts of 2′-deoxy-2′-bromo-3′,5′-diacetyl-5-methyluridine, that is to say more or less of the order of 1.6-2 g.
The 5′-acetylstavudine obtained according to the process of the present invention may then be converted into stavudine according to the various processes known in the art, such as, for example, those disclosed in EP-A-0 334 368, Mansuri et al. and Classon et al., which should thus be considered as included in the present description also as regards the preparation of 2′-deoxy-2′-bromo-3′,5′-diacetyl-5-methyluridine.


REFERENCES:
Amino, Y et al, Chem. Pharm. Bull., 39, 1991, 622-625.*
Talekar, R.R. et al, Synthesis, 1993, 303-306.

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