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US 5,696,254 AGranted
Processes for the diastereoselective synthesis of nucleoside analogues
AssigneeBioChem Pharma Inc.
InventorsTarek Mansour, Haolun Jin, Allan H. L. Tse, M. Arshad Siddiqui
Life of this patent
Estimating the term…
Abstract
The present invention relates to highly diastereoselective processes for production of cis-nucleosides and nucleoside analogues and derivatives in high optical purity, and intermediates useful in those processes.
Claims25
A diastereoselective process for producing optically active cis-nucleoside and nucleoside analogues and derivatives of formula (I) ##STR67## wherein W is S, S.dbd.O, SO.sub.2, or 0;
- X is S, S.dbd.O, SO.sub.2, or 0;
- R.sub.1 is hydrogen or acyl;
- and
- R.sub.2 is a desired purine or pyrimidine base or an analogue or derivative thereof
- the process comprising the step of glycosylating the desired purine or pyrimidine base or analogue or derivative thereof with an intermediate of formula (IIa) or (IIb) ##STR68## wherein R.sub.3 is a substituted carbonyl or carbonyl derivative;
- and
- L is a leaving group,
- using a Lewis acid of the formula (III) ##STR69## 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
- R.sub.8 is selected from the group consisting of fluoro;
- bromo;
- chloro;
- 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 arylsulfenyl;
- substituted or unsubstituted C.sub.6-20 alkoxyalkyl;
- and trialkylsiloxy.
25 more elements
A diastereoselective process for producing optically active cis-nucleoside and nucleoside analogues and derivatives of formula (I) ##STR71## wherein W is S, S.dbd.O, SO.sub.2, or 0;
- X is S, S.dbd.O, SO.sub.2, or 0;
- R.sub.1 is hydrogen or acyl;
- and
- R.sub.2 is a desired purine or pyrimidine base or an analogue or derivative thereof
- the process comprising the step of glycosylating the desired purine or pyrimidine base or analogue or derivative thereof with a single enantiomer of a compound of formula (II) ##STR72## wherein R.sub.3 is a substituted carbonyl or carbonyl derivative;
- and
- L is a leaving group,
- using a Lewis acid of the formula (III) ##STR73## 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
- R.sub.8 is selected from the group consisting of fluoro;
- bromo;
- chloro;
- 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 arylsulfenyl;
- substituted or unsubstituted C.sub.6-20 alkoxyalkyl;
- and trialkylsiloxy.
25 more elements
A diastereoselective process for producing optically active cis-oxathiolane and analoguss and derivatives of formula (Ia) ##STR77## wherein R.sub.1 is hydrogen or acyl;
- and
- R.sub.2 is a desired purine or pyrimidine base or
- an analogue or derivative thereof comprising the step of glycosylating the desired purine or pyrimidine base or analogue or derivative thereof with a single enantiomer of a resolved ester derived from the compound of formula (IX) ##STR78## using a Lewis acid of the formula (III) ##STR79## 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
- R.sub.8 is selected from the group consisting of fluoro;
- bromo;
- chloro;
- 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 arylsulfenyl;
- substituted or unsubstituted C.sub.6-20 alkoxyalkyl;
- and trialkylsiloxy.
20 more elements
Dependencies are inferred from the claim text.