Process for preparing purine nucleosides

Details Process for preparing purine nucleosides Process for preparing purine nucleosides

2002-08-01

2004-01-20

Barts, Samuel (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S024100, C536S026110, C536S027100, C536S027300, C536S027400, C536S027630, C536S028100, C514S045000, C514S046000

Reexamination Certificate

active

06680382

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to the chemical preparation of purine nucleosides. More specifically, the invention relates to the coupling of an adenine derivative with a blocked arabinofuranosyl to form a &bgr;-D-adenine nucleoside. Such nucleosides are valuable compounds in the field of cancer therapy and as anti-viral agents.
BACKGROUND OF THE INVENTION
A number of &bgr;-D-purine nucleosides derived from adenine are useful as antitumor and antiviral agents. An important step in the synthesis of such agents is the formation of the N-glycoside bond between the adenine nucleobase and an arabinofuranosyl derivative. The coupling reactions used to form the N-glycoside bond of 2′-deoxynucleosides have typically resulted in the formation of a mixture of &agr; and &bgr;-anomers.
Nucleosides have been synthesized by fusion glycosylation, wherein the reaction is carried out in the absence of solvent at a temperature sufficient to convert the reactants to a molten phase. E.g., 2,6-dichloropurine has been coupled under fusion conditions with 5-O-benzyl-2-deoxy-1,3-di-O-acetyl-2-fluroarabinose to form a 2′-fluoroarabinonucleoside in 27% yield (Wright et al., J. Org. Chem. 34:2632, 1969). Another synthetic method utilizes silylated nucleobase derivatives, e.g., a silylated nucleobase has been coupled with a peracetylated deoxy-sugar in the presence of a solvent and a Friedel Crafts catalyst (Vorbruggen et al., J. Org. Chem. 41:, 2084, 1976). This method has been modified by incorporating a sulfonate leaving group in the deoxy-sugar in the synthesis of 2′-deoxy-2′-difluoronucleosides (U.S. Pat. No. 4,526,988; U.S. Pat. No. 4,965,374).
High yields of 2′-deoxy-2′-fluoro-pyrimidine nucleosides were obtained from refluxing pyrimidines with 2-deoxy-2-fluoro-3,5-di-O-benzoyl-&agr;-O-arabinofuranosyl bromide. (Howell et al., J. Org. Chem. 53:85-88, 1988). It was found that use of solvents with lower dielectric constants produced have higher &bgr;:&agr; anomer ratios. It was postulated that such solvents favored an S
N
2 reaction, whereas solvents with higher dielectric constants favored production of &agr;-anomers via an ionic S
N
1 pathway.
Anion glycosylation procedures have also been used to prepare 2′-deoxy-2′-fluoropurine nucleosides. EP 428109 discloses the coupling of the sodium salt of 6-chloropurine, formed by sodium hydride, with 3,5-dibenzyl-&agr;-D-arabinofuranosyl bromide using conditions that favor S
N
2 displacement. Use of 1:1 acetonitrile/methylene chloride resulted in a nucleoside product with a &bgr;:&agr; anomer ratio 10:1, as opposed to a ratio of 3.4:1 observed when using a silylated purine reactant. In regard to the use of adenine salts, the amino substituent at the C-6 position was protected as a benzoyl derivative during the coupling reaction. Protecting the exocyclic amino group precludes the formation of arabinofuranosyl adducts which otherwise may be expected to be produced (e.g., Ubukata et al., Tetrahedron Lett., 27:3907-3908, 1986; Ubukata et al., Agric. Biol. Chem., 52: 1117-1122, 1988; Searle et al., J. Org. Chem., 60:4296-4298, 1995; Baraldi et al., J. Med. Chem., 41:3174-3185, 1998). The preparation of &agr; and &bgr; anomers of 2′-deoxy-2′-fluoropurine and 2′-difluoropurine nucleosides by anion glycosylation are disclosed by U.S. Pat. No. 5,744,597 and U.S. Pat. No. 5,281,357, with &bgr;-anomer enriched nucleosides prepared in a &bgr;:&agr; anomer ratio of greater than 1:1 to about 10:1 and from greater that 1:1 to about 7:1 respectively. In regard to purines substituted with exocyclic amino groups, both patents again disclose protecting such groups during coupling to an appropriate sugar moiety. U.S. Pat. No. 5,281,357 also discloses the effect of solvents on the &bgr;:&agr; anomer ratio of 9-[1-(2′-deoxy-2′, 2′-difluoro-3′,5′-di-O-benzoyl-D-ribofuranosyl)]-2,6-dipivalamidopurine prepared by coupling the potassium salt of 2,6-dipivalamidopurine with an &agr; anomer enriched preparation of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-dibenzoyl-1-trifluoromethanesulfonate. There was no correlation between the dielectric constant of the six solvents used and the &bgr;:&agr; anomer ratio, e.g. ethyl acetate and acetonitrile both gave the same ratio of 1.6:1. t-Butyl alcohol gave the highest &bgr;:&agr; anomer ratio of 3.5:1.
Despite the preparative methods for purine nucleosides known in the art, there is still a need for economically preferable, effective and efficient process for the preparation of these compounds. The object of the present invention is to provide such a process. Further objects are to minimize the number of process reaction steps and to provide a process that is readily scalable for the production of commercial-scale quantities. Other objects and advantages will become apparent to persons skilled in the art and familiar with the background references from a careful reading of this specification.
SUMMARY OF THE INVENTION
In its most general terms, one aspect of the present invention provides for the preparation of &bgr;-adenine nucleosides by coupling an adenine derivative containing an unprotected exocyclic amino group at the C-6 position, and a blocked arabinofuranosyl derivative. In preferred embodiments, this reaction can be depicted as:
R
1
is hydrogen, halogen or —OR
6
, wherein R
6
is a hydroxy protecting group. In a preferred embodiment R
1
is fluoro. R
2
and R
3
are hydroxy-protecting groups. In preferred embodiments R
2
, R
3
and R
6
are independently benzoyl or acetyl. R
4
is a leaving group. Suitable leaving groups include, halo, fluorosulfonyl, alkylsulfonyloxy, trifluoroalkylsulfonyloxy and arylsulfonyloxy. In a preferred embodiment, R
4
is bromo. R
5
is hydrogen, halogen or —NH
2
. In preferred embodiments, R
5
is chloro or fluoro.
Surprisingly, this reaction proceeds without substantial production of adducts resulting from addition of the blocked arabinofuranosyl (1) with the exocyclic amino group at the C-6 position of compound (2) (hereinafter termed “C-6 exocyclic amino group”), which remains unprotected during the reaction, and/or the nitrogen at the N-7 position of the adenine ring. An example of an undesired C-6 exocyclic amino group by-product adduct is represented by the following formula:
For the purposes of the present invention, and in light of the objective to provide an economically preferable, effective and efficient process, “substantial formation” means conversion of about 40% of the adenine derivative of formula (2) to a by-product adduct or adducts resulting from addition of the blocked arabinofuranosyl of formula (1) to the unprotected C-6 exocyclic amino group and/or N-7 position of compound (2). In embodiments wherein R
5
is —NH
2
(hereinafter termed “R
5
—NH
2
group”), “substantial formation” means conversion of about 40% of the adenine derivative of formula (2) to by-product adduct(s) resulting from addition of the blocked arabinofuranosyl of formula (1) to the unprotected C-6 exocyclic amino group and/or N-7 position and/or the R
5
—NH
2
group of compound (2).
Even more surprising is that the reaction can proceed without even a significant production of adducts resulting from addition of the blocked arabinofuranosyl (1) with the C-6 exocyclic amino group and/or N-7 position of compound (2). For the purposes of the present invention, “significant production” means conversion of about 5% of the adenine derivative of formula (2) to a by-product adduct or adducts resulting from addition of the blocked arabinofuranosyl (1) to the unprotected C-6 exocyclic amino group and/or N-7 position of compound (2). In embodiments wherein R
5
is —NH
2
, “significant production” means conversion of about 5% of the adenine derivative of formula (2) to a by-product adduct(s) resulting from addition of the blocked arabinofuranosyl of formula (1) to the unprotected C-6 exocyclic amino group and/or N-7 position and/or the R
5
—NH
2
group of compound (2).
Useful bases are gen

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