Process for the diastereoselective synthesis of nucleoside...

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

1999-06-23

2001-12-11

Shah, Mukund J. (Department: 1611)

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

Organic compounds

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

C544S317000, C544S318000

Reexamination Certificate

active

06329522

ABSTRACT:

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:
(also known as 3TC™ or lamivudine) and its pharmaceutically acceptable derivatives, disclosed in International application PCT/GB9100706, 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.
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. W092/20669 discloses a diastereoselective process for producing optically active cis-nucleoside analogues and derivatives of formula (I).
wherein
W is S, S═O, SO
2
, or O;
X is S, S═O, SO
2
or O;
R
1
is hydrogen or acyl; and
R
2
is a desired purine or pyrimidine base or an analogue or derivative thereof; the process comprising the step of reacting the desired purine or pyrimidine base or analogue thereof with an intermediate of formula (IIa) or (IIb)
wherein
R
3
is a substituted carbonyl or carbonyl derivative; and
L is a leaving group;
using a Lewis acid of the formula (III)
wherein
R
5
, R6 and R
7
are independently selected from the group consisting of hydrogen; C
1-20
alkyl optionally substituted by fluoro, bromo, chloro, iodo, C
1-6
alkoxy or C
6-20
aryloxy; C
7-20
aralkyl optionally substituted by halogen, C
1-20
alkyl or C
1-20
alkoxy C
6-20
aryl optionally substituted by fluoro, bromo, chloro, iodo, C
1-20
alkyl or C
1-20
alkoxy; trialkylsilyl; fluoro; bromo; chloro and iodo; and
R
8
is selected from the group consisting of fluoro; bromo; chloro; iodo; C
1-20
sulphonate esters, optionally substituted by fluoro, bromo, chloro or iodo; C
1-20
alkyl esters optionally substituted by fluoro, bromo, chloro or iodo, polyvalent halides; trisubstituted silyl groups of the general formula (R
5
) (R
6
) (R
7
) Si (wherein R
5
, R
6
and R
7
are as defined above); saturated or unsaturated selenenyl C
6-20
aryl; substituted or unsubstituted C
6-20
arylsulphenyl; substituted or unsubstituted C
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 W092/20669 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 relation to the large-scale production of nucleoside analogues in factory processes.
We have now found that, by judicious selection of the leaving group L in intermediates (IIa) and (IIb), the reaction with the purine or pyrimidine base, or analogue thereof, can be successfully effected without the addition of a Lewis acid catalyst, and in particular, without the addition of a Lewis acid of formula (III).
The present invention accordingly provides a stereoselective process for producing cis-nucleoside analogues and derivatives of formula (I)
wherein
W is S, S═O, SO
2
, or O;
X is S, S═O, SO
2
, or O;
R
1
is hydrogen or acyl; and
R
2
is a purine or pyrimidine base or an analogue thereof; the process comprising the step of glycosylating the purine or pyrimidine base or analogue or derivative thereof with an intermediate of formula (IVa) or (IVb)
wherein R
3
is a substituted carbonyl or carbonyl derivative; and
G represents halo, cyano or R
9
SO
2
; where R
9
represents alkyl optionally substituted by one or more halo, or optionally substituted phenyl;
characterised in that the glycosylation reaction is effected without the addition of a Lewis acid catalyst.
In a preferred embodiment, the present invention provides a stereoselective process for producing cis-nucleoside analogues and derivatives of formula (I) as previously defined, which process comprises the step of glycosylating the purine or pyrimidine base or analogue or derivative thereof with an intermediate of formula (IVa) or (IVb) as previously defined, characterised in that the glycosylation reaction is effected without the addition of a Lewis acid of formula (III)
wherein
R
5
, R
6
and R
7
are independently selected from the group consisting of hydrogen; C
1-20
alkyl optionally substituted by fluoro, bromo, chloro, iodo, C
1-6
alkoxy or C
6-20
aryloxy; C
7-20
aralkyl optionally substituted by halogen, C
1-20
alkyl or C
1-20
alkoxy; C
6-20
aryl optionally substituted by fluoro, bromo, chloro, iodo, C
1-20
alkyl or C
1-20
alkoxy; trialkylsilyl; fluoro; bromo; chloro and iodo; and
R
8
is selected from the group consisting of fluoro; bromo; chloro; iodo; C
1-20
sulphonate esters, optionally substituted by fluoro, bromo, chloro or iodo; C
1-20
alkyl esters optionally substituted by fluoro, bromo, chloro or iodo, polyvalent halides; trisubstituted silyl groups of the general formula (R
5
) (R
6
) (R
7
) Si (wherein R
5
, R
6
, and R
7
are as defined above); saturated or unsaturated selenenyl C
6-20
aryl; substituted or unsubstituted C
6-20
arylsulphenyl; substituted or unsubstituted C
6-20
alkoxyalkyl; and trialkylsiloxy.
It will be appreciated that, if the glycosylation step is carried out using an equimolar mixture of intermediates (IVa) and (IVb), a racemic mixture of cis-nucleoside analogues will be obtained. However, it is preferred that glycosylation is effected using an optically pure compound of formula (IVa) or (IVb), thereby producing the desired cis-nucleoside analogue in high optical purity.
A “nucleoside” is defined as any compound which consists of a purine or pyrimidine base linked to a pentose sugar.
As used herein, a “nucleoside analogue or derivative” is a compound containing a 1,3-oxathiolane, 1,3-dioxolane or 1,3-dithiolane linked to a purine or pyrimidine base or an analogue thereof which may be modified in any of the following or combinations of the following ways: base modifications, such as addition of a substituent (e.g., 5-fluorocytosine) or replacement of one group by an isosteric group (e.g., 7-deazaadenine); sugar modifications, such as substitution of hydroxyl groups by any substituent or alteration of the site of attachment of the sugar to the base (e.g., pyrimidine bases usually attached to the sugar at the N-1 site may be, for exampl

Affiliated with

Also associated with

Rating

Process for the diastereoselective synthesis of nucleoside... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the diastereoselective synthesis of nucleoside..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the diastereoselective synthesis of nucleoside... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2583601