Process for producing dioxolane nucleoside analogues
The present invention relates to a process conducted in a single reaction vessel for producing a dioxolane nucleoside analogue of formula I or a pharmaceutically acceptable salt thereof; the process comprising the steps of adding a Lewis acid, a silylating agent and a non-silylated purine or pyrimidine base or an analogue thereof to a dioxolane of formula II. The invention also provides a process for producing a dioxolane compound of formula III; by reacting a dioxolane compound of formula IV in a suitable solvent in the presence of DIB and I 2 , using a suitable source of energy.
1. A process for producing a dioxolane compound of formula III
said process comprising:
reacting a dioxolane compound of formula IV in a solvent;
in the presence of diacetoxy iodobenzene and I 2 , wherein said process is conducted using a source of energy; and wherein R 10 is a hydroxyl protecting group.
2. The process according to claim 1 , wherein the dioxolane compound of formula IV is added to a mixture of diacetoxy iodobenzene and I 2 .
3. The process according to claim 1 , further comprising reacting said dioxolane compound of formula IV in the presence acetic acid, wherein the dioxolane compound of formula IV is added to a mixture of diacetoxy iodobenzene, I 2 and acetic acid.
4. The process according to claim 1 , wherein R 10 is C 1-6 alkyl, C 6-12 aryl, C 6-12 arylalkyl, CO—C 1-6 alkyl, CO—C 1-6 alkoxy, CO—C 6-12 aryloxy, or CO—C 6-12 arylalkyl.
5. The process according to claim 4 , wherein R 10 is acetyl, pivaloyl, benzoyl, isopropyloxycarbonyl, or benzyl.
6. The process according to claim 4 , wherein R 10 is benzoyl.
7. The process according to claim 1 , wherein the solvent is toluene or dichloromethane.
8. The process according to claim 7 , wherein the solvent is dichloromethane.
9. The process according to claim 1 , wherein diacetoxy iodobenzene is used in a molar ratio of about 1.0 equivalent to about 2.5 equivalents with respect to the dioxolane compound of formula III.
10. The process according to claim 9 , wherein diacetoxy iodobenzene is used in a molar ratio of about 1.1 equivalent to about 1.5 equivalents with respect to the dioxolane compound of formula III.
11. The process according to claim 1 , wherein I 2 is used in a molar ratio of about 0.1 equivalent to about 1.0 equivalent with respect to the dioxolane compound of formula III.
12. The process according to claim 11 , wherein I 2 is used in a molar ratio of about 0.3 equivalent to about 0.5 equivalent with respect to the dioxolane compound of formula III.
13. The process according to claim 1 , wherein the source of energy is light.
14. The process according to claim 13 , wherein the source of energy is tungsten lamp light.
15. The process according to claim 13 , wherein the source of energy is daylight.
16. The process according to claim 1 , wherein the source of energy is heat.
17. A process for producing a dioxolane compound of formula III:
said process comprising:
reacting a dioxolane compound of formula IV in a solvent in the presence of diacetoxy iodobenzene and I 2 ;
wherein R 10 is acetyl, pivaloyl, benzoyl, benzyl, or isopropyloxycarbonyl, and
said dioxolane compound of formula IV is added to a mixture of diacetoxy iodobenzene and I 2 , and said process is conducted using a source of energy.
18. A process according to claim 17 , wherein diacetoxy iodobenzene is used in a molar ratio of about 1.0 equivalent to about 2.5 equivalents with respect to the dioxolane compound of formula III.
19. A process according to claim 17 , wherein diacetoxy iodobenzene is used in a molar ratio of about 1.1 equivalent to about 1.5 equivalents with respect to the dioxolane compound of formula III.
20. A process according to claim 17 , wherein I 2 is used in a molar ratio of about 0.1 equivalent to about 1.0 equivalent with respect to the dioxolane compound of formula III.
21. A process according to claim 17 , wherein I 2 is used in a molar ratio of about 0.3 equivalent to about 0.5 equivalent with respect to the dioxolane compound of formula III.
22. A process for producing a dioxolane compound of formula III:
said process comprising:
reacting a dioxolane compound of formula IV in a solvent in the presence of diacetoxy iodobenzene and I 2 ;
wherein
the dioxolane compound of formula IV is added to a mixture of diacetoxy iodobenzene, I 2 and acetic acid,
R 10 is acetyl, pivaloyl, benzoyl, benzyl, or isopropyloxycarbonyl; and
said process is conducted using a source of energy.
23. A process according to claim 22 , wherein diacetoxy iodobenzene is used in a molar ratio of about 1.0 equivalent to about 2.5 equivalents with respect to the dioxolane compound of formula III.
24. A process according to claim 22 , wherein diacetoxy iodobenzene is used in a molar ratio of about 1.1 equivalent to about 1.5 equivalents with respect to the dioxolane compound of formula III.
25. A process according to claim 22 , wherein I 2 is used in a molar ratio of about 0.1 equivalent to about 1.0 equivalent with respect to the dioxolane compound of formula III.
26. A process according to claim 22 , wherein I 2 is used in a molar ratio of about 0.3 equivalent to about 0.5 equivalent with respect to the dioxolane compound of formula III.