Stereoselective fusion glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides
AssigneeEli Lilly and Company
InventorTa-Sen Chou
Life of this patent
Estimating the term…
Abstract
A stereoselective fusion glycosylation process for prearing beta-anomer enriched 2'-deoxy-2',2'-difluoronucleotides and 2'-deoxy-2'-fluoronucleosides by reacting an alpha-anomer enriched 2-deoxy-2,2-difluorocarbohydrate or 2-deoxy-2-fluorcarbohydrate with at least a 3 molar equivalent of a nucleobase derivative at a temperature sufficient to melt the carbohydrate and nucleobase derivative.
Claims18
A stereoselective fusion glycosylation process for preparing a beta-anomer enriched nucleoside of the formula ##STR16## wherein each X is independently selected from hydroxy protecting groups and R' is a nucleobase selected from the group consisting of ##STR17## wherein R.sub.1 is selected from the group consisting of hydrogen C.sub.1 -C.sub.7 alkyl arid halo;
- R.sub.2 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.7 alkyl and halo;
- Z is a hydroxy protecting group and W is an amino protecting group;
- comprising reacting alpha-anomer 2,2-difluorocarbohydrate in a anomer ratio of greater than 1:1 alpha to beta of the formula ##STR18## wherein Y is selected from the group consisting of C.sub.1 -C.sub.7 alkylsulfonyloxy, arylsulfonyloxy, substituted C.sub.1 -C.sub.7 alkylsulfonyloxy and substituted arylsulfonyloxy and X is as defined above;
- with at least 3 molar equivalents;
- of a nucleobase derivative R" selected from the group consisting of ##STR19## wherein R.sub.1, R.sub.2, Z and W are as defined above;
- at a temperature ranging from about 100.degree. C. to about 160.degree. C. in the absence of a catalyst and a solvent.
A stereoselective glycosylation process for preparing a beta-anomer enriched nucleoside of the formula ##STR21## wherein each X is independently selected from hydroxy protecting groups and R' is a nucleobase selected from the group consisting of ##STR22## wherein R.sub.1 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.7 alkyl and halo;
- R.sub.2 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.7 alkyl and halo;
- Z is a hydroxy protecting group and W is an amine protecting group;
- comprising reacting alpha-anomer 2-fluorocarbohydrate in a anomer ratio of greater than 1:1 alpha to beta of the formula ##STR23## wherein Y i8 selected from the group consisting of C.sub.1 -C.sub.7 alkylsulfonyloxy, arylsulfonyloxy, substituted C.sub.1 -C.sub.7 alkylsulfonyloxy and substituted arylsulfonyloxy and X is as defined above;
- with at least 3 molar equivalents of a nucleobase derivative, R" selected from the group consisting of ##STR24## wherein R.sub.1, R.sub.2, Z and W are as defined above;
- at a temperature ranging from about 100.degree. C. to about 160.degree. C. in the absence of a catalyst and a solvent.
Dependencies are inferred from the claim text.