Process for the preparation of D-ribavirin
View Patent ↗A process for the preparation of ribavirin on an industrial scale is described which comprises the reaction of glycosylation of 3-substituted triazoles in the presence of a Lewis acid. Said process comprises: a) the reaction of a triazole of the formula with a protected ribofuranose of the formula b) the removal of the Pg groups and, optionally, the conversion into a carboxyamide group of the R 2 group of the compound obtained of the formula DD/mac—01.07.02.
1. A process for the preparation of a compound of formula (IV)
which consists of:
a) the reaction of a triazole of the formula
wherein R 2 represents a C 1 -C 4 alkoxycarbonyl, arylalkoxycarbonyl, carboxyl, cyano, carboxyamide group
with a protected ribofuranose of the formula
wherein Pg represents a group protecting the hydroxyl function and R 1 represents a leaving group selected from among C 1 -C 4 acyloxy, aryloxy and halogen;
in the presence of from 1 to 1.5 moles of a Lewis acid for every mole of (II) and
a solvent selected from the group consisting of a halogenated hydrocarbon, an ether, an aromatic hydrocarbon, and mixtures thereof, said solvent having a reflux temperature,
said reaction step a) performed at a reaction temperature between −10° C. and the reflux temperature of the solvent; and
b) the removal of the Pg groups and the conversion of the R 2 group of the compound obtained of the formula
wherein Pg and R 2 have the meanings given above, into a carboxyamide group, to give the compound of formula (IV),
wherein the triazole (I), ribofuranose (II), and solvent are provided to the reaction step a) as a pre-cooled suspension and the Lewis acid is added to the pre-cooled suspension while maintaining a temperature below 20° C.
2. A process according to claim 1 , wherein R 2 represents a C 1 -C 4 alkoxycarbonyl group.
3. A process according to claim 1 , wherein Pg represents acetyl, benzoyl or benzyl.
4. A process according to claim 1 , wherein R 1 represents a group selected from group consisting of chlorine, bromine C 1 -C 4 acyloxy, and mixtures thereof.
5. A process according to claim 1 , wherein Pg represents acetyl, R 2 represents a carbomethoxy group and R 1 represents an acetoxy group.
6. A process according to claim 1 , wherein the Lewis acid is selected from the group consisting of AlCl 3 , SbCl 5 , BF 3 , SnCl 4 , FeCl 3 , and mixtures thereof.
7. A process according to claim 1 , wherein the reagents in stage a) are used in a molar ratio of 1-2 moles of I and 1-1.5 moles of Lewis acid to every mole of II.
8. A process according to claim 1 , wherein the compound of formula (IV) is isolated by crystallisation from aqueous methanol.
9. A process according to claim 7 , wherein said crystallisation is cried out at a temperature below 50° C. and using from 2 to 5 volumes of methanol per volume of water.
10. A process according to claim 2 , wherein R 2 represents a carbomethoxy group.
11. A process according to claim 3 , wherein Pg represents acetyl.
12. A process according to claim 4 , wherein R 1 represents an acetoxy group.
13. A process according to claim 6 , wherein the Lewis acid is SnCl 4 .
14. A process according to claim 7 , wherein the reagents in stage a) are used in a molar ratio of 1-1.2 moles of I and 1-1.1 moles of Lewis acid to every mole of II.
15. A process for the preparation of a compound of the formula (IV)
which consists of:
a) the reaction of a triazole of the formula
wherein R 2 represents a C 1 -C 4 alkoxycarbonyl, arylalkoxycarbonyl, carboxyl, cyano, carboxyamide group
with a protected ribofuranose of the formula
wherein Pg represents a group protecting the hydroxyl function and R 1 represents a leaving group selected from among C 1 -C 4 acyloxy, aryloxy and halogen;
in the presence of a Lewis acid selected from the group consisting of AlCl 3 , SbCl 5 , BF 3 , SnCl 4 FeCl 3 , and mixtures thereof and
a solvent consisting of a halogenated hydrocarbon, said solvent having a reflux temperature,
said reaction step a) performed at a reaction temperature between −10° C. and the reflux temperature of the solvent; and
b) the removal of the Pg groups and the conversion of the R 2 group of the compound obtained of the formula
wherein Pg and R 2 have the meanings given above, into a carboxyamide group, to give the compound of formula (IV).
16. A process according to claim 15 , wherein said halogenated hydrocarbon is selected from the group consisting of dichloromethane, chloroform, trichloroethane, and mixtures thereof.
17. A process according to claim 16 , wherein said halogenated hydrocarbon is dichloromethane.