Patent EA-000844-B1 (EA)
Title: METHOD FOR THE SYNTHESIS OF DIOXOLANE NUCLEOSIDES WITH beta-CONFIGURATION
Inventor: MANSOUR TAREK
IPC: C07H/
Filed: 1996-12-13
Abstract: 1. A process for producing a β-nucieoside analogue compound of formula (III):   and salts thereof, wherein R1 is a hydroxyl protecting group; and R2 is a purine or pyrimidine base or an analogue or derivative thereof, the process comprising glycosylating said purine or pyrimidine base at a temperature below about -10 degree C, with an intermediate of formula (II):   wherein L is halogen. 2. The process according to claim 1, wherein L is iodo. 3. The process according to claim 2, wherein R1 is benzyl. 4. The process according to claim 1, wherein R2 is selected from the group consisting of   wherein R3 is selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C6 acyl groups; R4 and R5 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, bromine, chlorine, fluorine, and iodine; R6 is selected from the group of hydrogen, halo cyano, carboxy, C1-C6 alkyl, C1-C6 alkoxycarbonyl, C1-C6 acyl, C1-C6 acyloxy, carbamoyl, and thiocarbamoyl; and X and Y are independently selected from the group of hydrogen, bromine, chlorine, fluorine, iodine, amino, and hydroxyl groups. 5. The process according to claim 1, wherein R2 is   wherein R3 is selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C6 acyl groups; and  R4 is selected from the group consisting of hydrogen, C1-C6 alkyl, bromine, chlorine, fluorine, and iodine. 6. The process according to claim 5, wherein R3 is H or acetyl and R4 is H or F. 7. The process according to claim 1, wherein the glycosylation reaction occurs at a temperature below about -15 degree C. 8. The process according to claim 1, wherein the glycosylation reaction occurs at a temperature below about -20 degree C. 9. The process according to claim 1, wherein the glycosylation reaction occurs at a temperature below about -50 degree C. 10. The process according to claim 1, wherein the glycosylation reaction occurs at about -78 degree C. 11. The process according to any one of claims 7 to 10 wherein L is iodo-. 12. The process according to claim 11 wherein R1 is benzyl. 13. The process according to claim 1, wherein the compound of formula (III) is subsequently deprotected to give a compound of formula (I)   wherein R2 is a purine or pyrimidine base or an analogue or derivative thereof. 14. The process according to claim 1, wherein the intermediate of formula (II) is prepared by reacting an intermediate of formula (II')   wherein L' is a leaving group; with a Lewis acid of formula (IV)   wherein R3<'> R4<'> and R5<'> are independently selected from the group consisting of hydrogen; C1-C20 alkyl, optionally substituted by halogens, C6-C20 alkoxy or C6-C20 aryloxy; C7-C20 aralkyl, optionally substituted by halogen, C1-C20 alkyl or C1-C20 alkoxy; C6-C20, optionally substituted by halogens, C1-C20 alkyl or C1-C20 alkoxy; trialkylsilyl; fluoro; bromo; chloro and iodo; and R6<'> is selected from the group consisting of halogen C1-C20 sulphonate esters, optionally substituted by halogens; C1-C20 alkyl esters, optionally substituted by halogen; polyvalent halides; trisubstituted silyl groups of the general formula (R3<'>)(R4<'>)(R5<'>)Si, wherein R3<'> R4<'> R5<'> are as defined above; saturated or unsaturated selenenyl C6-C20 aryl; substituted or unsubstituted C6-C20 arylsulphenyl; substituted or unsubstituted C1-C20 alkoxyalkyl and trialkylsiloxy. 15. The process according to claim 14, wherein the Lewis acid is selected from TMSI and SiH2I2. 16. The process according to claim 15, wherein the Lewis acid is TMSI. 17. The process according to claim 14, wherein L is iodo-. 18. The process according to claim 17, wherein R1 is benzyl. 19. The process according to any one of claims 14 to 18, wherein the compound of formula (III) is subsequently deprotected to give a compound of formula (I)   wherein R2 is a purine or pyrimidine base or an analogue or derivative thereof. 20. The process according to claim 19, wherein the glycosylation reaction occurs at a temperature below about -15 degree C. 21. The process according to claim 19, wherein the glycosylation reaction occurs at a temperature below about -20 degree C. 22. The process according to claim 19, wherein the glycosylation reaction occurs at a temperature below about -50 degree C. 23. The process according to claim 19, wherein the glycosylation reaction occurs at about -78 degree C.