Processes for preparing 1,3-dioxolane nucleosides

1. A process for preparing a D- or L-dioxolane nucleoside of formulae III-VI:

wherein

R is H, halogen, OH, OR′, SH, SR′, NH 2 , NHR′, NR′ 2 , lower alkyl of C 1 -C 4 , CH═CH 2 , N 3 C═CH 2 , CO 2 H, CO 2 R′, CONH 2 , CN, CONHR′, CH 2 OH, CH 2 CN, CH 2 CH 2 OH, CF 3 , CH 2 CH 2 F, CH═CHCO 2 H, CH═CHCO 2 R′, CH═CHCl, CH═CHBr, or CH═CHI;

R′ is lower alkyl (C 1 -C 4 );

each X and Y is independently H, halogen, OH, OCH 3 , SH, SCH 3 , NH 2 , NHR′, NR′ 2 , or CH 3 ; and

Z is CH, or C—X;

comprising the steps of:

1) preparing compounds of formula VII or VIII:

by:

a) oxidation of 1,2-O-protected-glycerol to an acid salt, or hydrolysis of methyl (R)- or (S)-1,2-O-protected-glycerate to form intermediate 1:

b) alkylation of intermediate 1 with a compound of formula X′CH 2 CH(OR 6 ) 2 , wherein X′ is halogen or pseudohalogen, and R 6 is alkyl or aralkyl (C 1-20 );

c) cyclization with an acid catalyst optionally with hydrolysis of the acetal;

2) hydrolyzing the ester group of the compound of formula VII or VIII followed by protection of the resulting alcohol under basic conditions to form a compound of formula 6 (including D- and L-isomers):

wherein R 7 is a protecting group;

3) decarboxylating the carboxylic group of compound 6; and

4) coupling with a purine or pyrimidine base or its derivative, followed by deprotection to form a D- and L-dioxolane nucleoside of formulae III-VI.

2. The process according to claim 1 , wherein the basic conditions used for hydrolysis of the ester of formula VII and VIII in step 2 include a base that is an organic or inorganic base or combination thereof.

3. The process of claim 2 wherein the base is an aqueous alkali or alkali earth metal base.

4. The process of claim 3 , wherein the base is aqueous NaOH or aqueous KOH.

5. The process of claim 1 , wherein the oxidation in step 1 is conducted using an oxidizing agent selected from the group consisting of NaIO 4 /RuCl 3 hydrate, NaOCl/RuCl 3 hydrate, KMnO 4 , NaIO 4 and KIO 4 and combinations thereof.

6. The process of claim 1 , wherein decarboxylation in step 3 is carded out at from about −10° C. to 100° C., in an aprotic solvent or water, or combination thereof.

7. The process of claim 6 , wherein the solvent is an aprotic solvent.

8. The process of claim 7 , wherein the solvent is hexane, cyclohexane, toluene, ethyl acetate, THF, dioxane, acetonitrile, dichloromethane, dichloroethane, diethyl ether, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide, or a combination thereof.

9. The process of claim 1 , wherein the acid catalyst in step 1 is a Lewis acid.

10. The process of claim 1 , wherein the acid catalyst in step 1 is BF 3 etherate.

11. The process of claim 1 , comprising coupling the purine or pyrimidine base or its derivative by:

silylation of the purine or pyrimidine base or its derivative; and

coupling of the silylated purine or pyrimidine base or its derivative to the compound of Formula 6 in the presence of a Lewis acid.

12. The process of claim 11 , wherein the Lewis acid is selected from the group consisting of tin tetrachloride, titanium tetrachloride or trimethylsilyl triflate.

13. The process of claim 11 , wherein the purine or pyrimidine base or its derivative is silylated with hexamethyldisilazane (HMDS).

14. The process of claim 1 , further comprising isolating the nucleoside of formula II-VI in optically active form.

15. The process of claim 14 , wherein the optically active form is isolated by resolution of a racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.

16. The process of claim 1 , wherein the purine or pyrimidine base is selected from the group consisting of adenine, N 6 -alkyl-purines, N 6 -acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -thioalkyl purine, N 2 -alkylpurines, N 2 -alkyl-6-thiopurines, thymine, cytosine, 5-fluoro-cytosine, 5-methylcytosine, 6-azapyrimidine, including 6-aza-cytosine, 2- and/or 4-mercapto-pyrimidine, uracil, 5-halouracil, including 5-fluorouracil, C 5 -alkylpyrimidines, C 5 -benzyl-pyrimidines, C 5 -halopyrimidines, C 5 -vinylpyrimidine, C 5 -acetylenic pyrimidine, C 5 -acyl pyrimidine, C 5 -hydroxyalkyl purine, C 5 -amido-pyrimidine, C 5 -cyanopyrimidine, C 5 -nitro-pyrimidine, C 5 -aminopyrimidine, N 2 -alkyl-purines, N 2 -alkyl-6-thiopurines, 5-azacytidinyl, 5-aza-uracilyl, triazolopyridinyl, imidazolo-pyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl.

17. The process of claim 1 , wherein R 7 is acyl, silyl, alkyl or an aralkyl group (C 1-20 ).