Process for synthesis of nucleoside analogues

Details Process for synthesis of nucleoside analogues Process for synthesis of nucleoside analogues

1997-09-30

2000-11-07

Wilson, James O.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514 49, 514 50, 514274, 536 41, 544242, 544245, 544253, 544255, 544285, 544293, C07D41104, A61K 31505

Patent

active

061437484

DESCRIPTION:

BRIEF SUMMARY
The present invention is concerned with a process for the preparation of anti-viral 1,3-oxathiolane nucleosides, which employs an intramolecular glycosylation to produce exclusively the .beta.-diastereomer. The invention also relates to novel intermediates obtained by the process.
1,3-Oxathiolane nucleosides possess two chiral centres (at the C1'- and C4'-positions according to the furanose numbering system) and typically exist as diastereomeric pairs of the .alpha.- and .beta.-forms, each form comprising two enantiomers. The .alpha.- and .beta.-diastereoisomers tend to have different anti-viral activities, the .beta.-form typically being the more potent. Similarly, the enantiomeric pairs of each diastereomer tend to have different properties.
.beta.-Diastereomers have traditionally been obtained by preparation of the diastereomeric mixture followed by laborious separation of the .beta.-form by physical means such as differential solubility or chromatography. It follows that the overall yield of .beta.-isomer is typically less than 50%.
International Patent Application No. WO91/11186 (U.S. Pat. No. 5,204,466) describes a process whereby 1,3-oxathiolane nucleosides may be obtained with high .beta.-diastereoselectivity by condensing a carbohydrate or carbohydrate-like moiety with a heterocyclic base in the presence of a specific Lewis acid, typically stannic chloride. The process is further exemplified in International Patent Application No. WO92/14743.
Further diastereoselective processes for the preparation of nucleoside analogues involving condensation of a carbohydrate or like moiety with a purine or pyrimidine base are described in WO92/20669 (U.S. Pat. No. 5,756,706) and WO95/29174.
We have now developed an efficient new process which provides exclusively the .beta.-diastereomer of a 1,3-oxathiolane pyrimidine nucleoside with no .alpha.-contamination. The critical steps involved in the synthesis are cyclisation of an appropriate heterocyclic acetaldehyde with 1,4-dithiane-2,5-diol to give a "5'-tethered" 1,3-oxathiolane nucleoside analogue which then undergoes an intramolecular glycosylation on the same face of the carbohydrate ring to give exclusively the (1'-tethered) .beta.-diastereomer. The intramolecular glycosylation of 5'-tethered furanose nucleosides is known from, inter alia, Japanese Patent No. 06263792-A, but the prior art comprises no reports of applying such methodology to the preparation of anti-viral 1,3-oxathiolane nucleosides. The resulting .beta.-diastereomer may be hydrolysed to the corresponding cytidine analogue or may be resolved by any suitable technique known to a skilled person, for example, by esterification followed by selective enzymatic hydrolysis, removal of the `unwanted` enantiomer and hydrolysis of the ester of desired enantiomeric configuration. Alternatively, it may be possible, for example, by use of a chiral auxiliary, to obtain intermediates substantially enantiomerically pure which intermediates can be carried forward to yield the desired enantiomerically pure product.
According to one aspect of the present invention, there is provided a process for the preparation of compounds of formula (I) ##STR1## wherein R is hydrogen, C.sub.1-6 alkyl, or halogen and Y is hydroxy, amino, C.sub.1-6 alkoxy or OR.sup.1, where R.sup.1 is a chiral auxiliary, which process comprises treating a compound of formula (II) ##STR2## wherein R and Y are as hereinbefore defined and R.sup.2 represents hydrogen, C.sub.1-6 acyl, C.sub.1-6 alkyl or halogen with a suitable Lewis acid or a reagent apt to convert the group OR.sup.2 to a leaving group.
Suitable Lewis acids include, for example, stannic chloride or trimethylsilyl triflate. Reaction with a Lewis acid is suitably conducted at reduced temperature (e.g. 0.degree. C. to -20.degree. C.) in a polar aprotic solvent followed by treatment with base.
Where R.sup.2 is H, the group OR.sup.2 may conveniently be converted to a leaving group by reaction with a halogenating agent such as a thionyl halide or an oxalyl halide, or a tosyl or mesyl hal

REFERENCES:
patent: 5538975 (1996-07-01), Dionne
Jung, M.E. et al., New Approach to the Synthesis of .beta.-2'-Deoxyribonucleosides; Intramolecular Vorbruggen Coupling, Journal of Organic Chemistry, vol. 58, pp. 807-808, 1993.

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