Process for synthesis of nucleoside analogues
AssigneeGlaxo Wellcome Inc.
InventorsMirna C. Samano, Vicente Samano, Michael David Goodyear
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Abstract
The present invention is concerned with a process for the preparation of antiviral 1,3-oxathiolane nucleosides comprising an intramolecular glycosylation reaction to produce exclusively the .beta.-diastereomer, and intermediates useful in the process.
Claims15
A process for the preparation of compounds of formula (I) ##STR11## 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) ##STR12## 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 followed by treating with an aqueous base.
A method for obtaining a compound of formula (IIa) wherein R is H, R.sup.2 is H, C.sub.1-6 acyl, C.sub.1-6 alkyl or halogen and Y is OR.sup.1 wherein R.sup.1 is a chiral auxiliary, from a mixture of isomers by treatment of the mixture of isomers, at least partially in solution, with an agent capable of effecting interconversion of the isomers without complete suppression of the crystallization of the desired single enantiomer (IIa) wherein R is H and Y is OR.sup.1.
A compound of formula (IIa) ##STR15## wherein R represents hydrogen, C.sub.1-6 alkyl or halogen, R.sup.2 represents hydrogen, C.sub.1-6 acyl, C.sub.1-6 alkyl or halogen and Y represents OR.sup.1 wherein R.sup.1 represents (d)-menthyl, (I)-menthyl, (d)-8-phenylmenthyl, (I)-8-phenylmenthyl, (+)-norephedrine or (-)-norephedrine.
A compound selected from the group consisting of (2S*,5R*)-4-ethoxy-5-fluoro-1-[2-(butanoyloxymethyl)-1,3-oxathiolan-5-yl]p yrimidin-2-one and (2S*,5R*)-4-ethoxy-1-[2-(butanoyloxymethyl)-1,3-oxathiolan-5-yl]pyrimidin- 2-one.
A compound selected from the group consisting of (2S,5R)-4-ethoxy-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimid in-2-one and (2S,5R)-4-ethoxy-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one.
A compound selected from the group consisting of (2R,5S)-4-ethoxy-5-fluoro-1-[2-(butanoyloxymethyl)-1,3-oxathiolan-5-yl]pyr imidin-2-one and (2R,5S)-4-ethoxy-1-[2-(butanoyloxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2- one.
A process for the preparation of a compound of formula (Ia) ##STR17## 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 (IIa) ##STR18## wherein R.sup.2 is 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, hydrolyzing the product with an aqueous base and, optionally, where R.sup.1 is not a chiral auxiliary esterifying the racemic .beta.-diasteromer, enzymatically hydrolyzing the racemic ester and recovering the desired enantiomer (IIa).
Dependencies are inferred from the claim text.