Process for the diastereoselective synthesis of nucleoside analo

Details Process for the diastereoselective synthesis of nucleoside analo Process for the diastereoselective synthesis of nucleoside analo

1996-12-24

2000-04-18

Ford, John M.

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

Organic compounds

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

544318, 544317, C07D40704, C07D40904, C07D41104

Patent

active

060517093

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a diastereoselective process for the preparation of optically active cis-nucleoside analogues and derivatives.
Nucleosides and their 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).
In particular, 4-Amino-1-(2R-hydroxymethyl-[1,3]oxathiolan-5S-yl)-1H-pyrimidin-2-one, which may be represented by the following formula: ##STR2## (also known as 3TC.TM. or lamivudine) and its pharmaceutically acceptable derivatives, disclosed in International application PCT/GB91/00706, publication no. WO91/17159, has been described as having antiviral activity, in particular against retroviruses such as the human immunodeficiency viruses (HIV's), the causative agents of AIDS (WO91/17159) and hepatitis B virus (HBV) (European Patent Application Publication no. 0474119).
Most nucleosides and nucleoside analogues and derivatives contain at least two chiral centres (shown as * in formula (A)), and exist in the form of two pairs of optical isomers (i.e., two in the cis-configuration and two in the trans-configuration). However, generally only the cis-isomers exhibit useful biological activity. Therefore a general stereoselective synthesis of cis nucleoside analogues is an important goal. ##STR3## Different enantiomeric forms of the same cis-nucleoside analogue may, however, have very different antiviral activities. M M Mansuri et al., "Preparation of The Geometric Isomers of DDC, DDA, D4C and D4T As Potential Anti-HIV Agents", Bioorg. Med. Chem. Lett., 1 (1), pp. 65-68 (1991). Therefore, a general and economically attractive stereoselective synthesis of the enantiomers of the biologically active cis-nucleoside analogues is an important goal.
International patent application publication no. WO92/20669 discloses a diastereoselective process for producing optically active cis-nucleoside analogues and derivatives of formula (I). ##STR4## wherein W is S, S.dbd.O, SO.sub.2, or O; thereof; pyrimidine base or analogue thereof with an intermediate of formula (IIa) or (IIb) ##STR5## wherein R.sub.3 is a substituted carbonyl or carbonyl derivative; and ##STR6## wherein R.sub.5, R.sub.6 and R.sub.7 are independently selected from the group consisting of hydrogen; C.sub.1-20 alkyl optionally substituted by fluoro, bromo, chloro, iodo, C.sub.1-6 alkoxy or C.sub.6-20 aryloxy; C.sub.7-20 aralkyl optionally substituted by halogen, C.sub.1-20 alkyl or C.sub.1-20 alkoxy C.sub.6-20 aryl optionally substituted by fluoro, bromo, chloro, iodo, C.sub.1-20 alkyl or C.sub.1-20 alkoxy; trialkylsilyl; fluoro; bromo; chloro and iodo; and iodo; C.sub.1-20 sulphonate esters, optionally substituted by fluoro, bromo, chloro or iodo; C.sub.1-20 alkyl esters optionally substituted by fluoro, bromo, chloro or iodo, polyvalent halides; trisubstituted silyl groups of the general formula (R.sub.5) (R.sub.6) (R.sub.7) Si (wherein R.sub.5, R.sub.6, and R.sub.7 are as defined above); saturated or unsaturated selenenyl C.sub.6-20 aryl; substituted or unsubstituted C.sub.6-20 arylsulphenyl; substituted or unsubstituted C.sub.6-20 alkoxyalkyl; and trialkylsiloxy.
The process of WO92/20669 allows the stereo-controlled synthesis of a racemic cis-nucleoside analogue from an equimolar mixture of (IIa) and (IIb), and of a given enantiomer of a desired cis-nucleoside analogue in high optical purity if the starting material is optically pure (IIa) or (IIb). However, the WO92/20669 process relies on the use of a Lewis acid of formula (III).
There are a number of disadvantages associated with the use of such Lewis acids. In particular, they are highly reactive and unstable compounds and there are therefore hazards associated with their use. Furthermore, they are expensive and have significant toxic effects. These disadvantages are of particular importance in

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