Stereoselective synthesis of nucleoside analogues using bicyclic

Details Stereoselective synthesis of nucleoside analogues using bicyclic Stereoselective synthesis of nucleoside analogues using bicyclic

1995-02-02

1998-06-09

Berch, Mark L.

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

Organic compounds

Pteroyl per se or having -c-, wherein x is chalcogen, bonded...

544265, 544309, 544317, C07D47300, C07D23902

Patent

active

057636060

DESCRIPTION:

BRIEF SUMMARY
FIELD OF INVENTION

The present invention relates to a stereoselective process for preparing nucleoside analogues and derivatives. Particularly, the invention relates to a process for preparing nucleoside analogues and derivatives that are predominantly in their cis-isomer configuration.


BACKGROUND OF THE INVENTION

Nucleoside analogues and derivatives are an important class of therapeutic agents. For example, a number of nucleoside analogues have shown antiviral activity against retroviruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and human T-lymphotropic virus (HTLV) (PCT publication WO 89/04662 and European Patent publication 0349242 A2). Among the nucleoside analogues shown to have antiviral activity are 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxy-cytidine (ddC) and 2'-deoxy-3'-thiacytidine Patent publication 0382526 A2).
Most nucleoside analogues and derivatives contain at least two chiral centers (shown as * in formula (A)), and each isomer can exist in two pairs of optical isomers (enantiomers) (i.e., two in the cis-configuration and two in the trans-configuration). However, generally the cis-isomers exhibit useful biological activity. ##STR2##
Many of the known processes for producing nucleoside analogues and derivatives rely on conventional glycosylation procedures to add the sugar to the purine or pyrimidine base. These procedures invariably give diastereomeric mixtures of cis- and trans- isomers which require tedious separation and result in lower yields of the desired biologically active cis-nucleoside analogues. Improved glycosylation methods designed to yield only the cis-nucleoside require addition of an aryl or an acyl substituent to the sugar preferably in the 2'- position. Because the 2'-substituent is only useful in controlling cis-nucleoside synthesis in one configuration (when the 2'-substituent is trans- to the 4'-substituent), multiple steps are required to introduce this substituent in the proper configuration. The 2'-substituent must be removed after glycosylation, requiring controlling stereochemistry in the synthesis of 2'-deoxyribose nucleoside", Tetrahedron Lett.31, pp, 1815-1818 (1990).!
Therefore, a general and economically attractive stereoselective synthesis of the biologically active cis-nucleoside analogues is an important goal.
The process of this invention has the advantages of allowing preparation of cis-nucleoside analogues and derivatives in fewer steps, using inexpensive and available starting materials and avoiding tedious protection and deprotection steps. Furthermore the process of this invention affords good yields of the desired cis-nucleoside analogues and derivatives.


SUMMARY OF THE INVENTION

The present invention seeks to provide an improved process for producing predominantly cis-nucleoside analogues and derivatives of formula (I) and pharmaceutically acceptable salts or esters thereof: ##STR3## wherein; X is S, or O; thereof.
The process of this invention comprises the following steps: ##STR4## with a mild dehydrating agent; step 2); pyrimidine base (R.sub.2) or analogue or derivative thereof with a novel bicyclic intermediate of formula (III): ##STR5## wherein X and Y are as defined above and Z is S or O, the coupling is achieved using an appropriate Lewis acid in a suitable solvent; formula (II): ##STR6## and step 3): suitable reducing reagent in a suitable solvent.


DETAILED DESCRIPTION OF THE INVENTION

Scheme 1 depicts the preferred process as it applies to any nucleoside analogue in general, particularly 1,3-oxathiolane, 1,3-dioxolane, 1,3-dithiolane, 3'-azido-3'-deoxy or 2',3'-dideoxy nucleoside analogues. ##STR7## wherein X is S, or O; thereof.
The novel process of this invention is carried out preferably with a compound of formula (II) wherein X is O, Y is S and Z is O.
The various steps as illustrated in scheme 1 may be briefly described as follows:
Step 1 The 2-carboxylic or thiocarboxylic acid of the sugar derivative of formula (IV) can be prepared by any method known in the art (e.g., PCT publication WO92/

REFERENCES:
patent: 5332814 (1994-07-01), Moser

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