Generated: May 30, 2017
|Title:||Method of synthesis of 1,3-dioxolane nucleosides|
|Abstract:||A synthesis of 1,3-dioxolane nucleosides that includes condensing a 2-0-protected-5-0-acylated-1,3-dioxolane with a purine or pyrimidine base in the presence of a titanium containing Lewis acid to provide predominately the desired .beta.-isomer in the C1'-position of a 1,3-dioxolane nucleoside. A process for the resolution of a racemic mixture of 1,3-dioxolane nucleoside enantiomers is also disclosed that includes the step of exposing the racemic mixture to an enzyme that preferentially catalyzes a reaction in one of the enantiomers.|
|Inventor(s):||Liotta; Dennis C. (Stone Mountain, GA)|
|Assignee:||Emory University (Atlanta, GA)|
|Filing Date:||Dec 06, 1991|
|Claims:||1. A process for the preparation of 1,3-dioxolane nucleosides comprising reacting a 2-0-protected-5-0-acylated-1,3-dioxolane with an oxygen or nitrogen protected purine or pyrimidine base in the presence of a titanium catalyst of the formula: |
wherein m=4; n=2, 3, or 4; Ti=titanium; X=Cl, Br, or I; and Y is alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, and mixtures thereof, or a bifunctional molecule that contains both an alkoxy and an amino bifunctional group and that is bound to the titanium molecule by both the alkoxy and amino moieties, to provide predominately the desired .beta.-isomer in the C1'-position of the 1,3-dioxolane nucleoside.
2. The method of claim 1, wherein the titanium catalyst is selected from the group consisting of TiCl.sub.4, TiCl.sub.2 (OiPr).sub.2, and TiCl.sub.3 (OiPr).
3. The method of claim 1, wherein the 1,3-dioxolane nucleoside is 2-hydroxymethyl-5-(thymidin-1-yl)-1,3-dioxolane.
4. The method of claim 1, wherein the purine of pyrimidine base is selected form the group consisting of cytosine, thymine, uracil, adenine, and guanine.
5. The method of claim 1, wherein the alkoxy group is lower alkoxy (C.sub.5 or less).
6. The method of claim 1, wherein the alkyl moiety in the alkylamino group has one to five carbon atoms.
7. The method of claim 1, wherein the bifunctional molecule is selected from the group consisting of 2-aminoethanol, 3-aminopropanol, and 1-substituted and 2-substituted derivatives thereof in which the substituents are lower alkyl (C.sub.5 or less) or aryl groups.
8. The method of claim 1, wherein the titanium catalyst is TiCl.sub.4.
9. The method of claim 1, wherein the alkyl group contains one to five carbon atoms.
10. The method of claim 1, wherein the 1,3-dioxolane nucleoside is 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-dioxolane.
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