FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of an antiviral agent namely Ribavirin of Formula I,

from an intermediate β -D-ribofuranose derivative of Formula II,

wherein R1 represents protecting groups and R represents alkyl groups
which in turn is prepared from triazole derivative of Formula III wherein R2 is as described above
and ribofuranose compound of Formula IV R!0.
V°?
V I Formula IV
R^ OR1
wherein R1 is as described above
using catalytic amount of trifluoromethane sulfonic acid in the presence or absence of a solvent.
BACKGROUND OF THE INVENTION
Ribavirin of Formula I is a useful antiviral agent.
o
II
HO. N
1 o i Formula I
P
HO OH
The process for the preparation of Ribavirin was first disclosed in J. Med. Chem. 1972, Vol. 15 (11), 1150-54 and US Patent 3,798,209 which describe the activation of triazole nucleus with silylating agent such as hexamethyldisilazane and subsequently coupling with protected ribofuranose derivative in acetonitrile to prepare compound of formula V. The protecting groups were removed using sodium methoxide in methanol and subsequently the ester group was converted to amide group to prepare Ribavirin as shown in Scheme-I. f

wherein PG represents benzoyl group Further in the exemplified process, the coupling reaction takes about 3 days for completion and the end product is difficult to purify. Additional isolation processes like recrystallization and / or column chromatography were used which makes this process unattractive from commercial point of view.
Alternatively, Ribavirin is prepared by the fusion reaction of a mixture of 3- carbomethoxytriazole and tetraacetyl-p-D-ribofuranose at higher temperature such as 160-165°C in the presence of bis(p-nitrophenyl)phosphate. The above process suffers from drawbacks like critical reaction conditions, such as heating at high temperature, which leads to degradation and makes it difficult to isolate and purify the end product. Moreover, the compound of Formula V prepared is of grey colour and hence additional purification is required to produce highly pure Ribavirin.
European Patent EP 1 281 715 discloses the preparation of Ribavirin by treating triazole compound of Formula VI
R3
I V Formula VI
N' H
wherein R3 represents C1-C4 alkoxycarbonyl, carboxyl, cyano and carboxyamide
with protected ribofuranose of Formula VII PGO.
\of
\ J Formula VII
PGO OPG
wherein PG represents protecting groups and R4 represents a leaving group selected from C1-C4 acyloxy, aryloxy and halogen
in the presence of lewis acids, removing protecting groups and optionally converting R3 group of the triazole ring to the carboxylamide group.
US Patent 6,660,854 discloses the process for the preparation of P-D-ribofuranose derivatives of Formula II
o
11
R'O (N
^ O ? Formula II
P
R'O OR1
by reacting compound of Formula VIII

wherein R1 represents protecting group for hydroxyl group with compound of Formula IX

wherein R2 represents C1-C4 alkyl group
at 90-100°C in the presence of catalyst such as methanesulfonic acid, benzene- sulfonic acid and p-toluenesulfonic acid. Thereafter, the compound of Formula II is converted to Ribavirin by subjecting to ammonolysis and further purified by recrystallization.
This patent is an improvement over prior art processes. In the exemplified processes the preparation of compound of Formula II, which is a key intermediate for Ribavirin, is carried out by the coupling reaction between triazole derivative] of Fomula IX and (3 anomer of D-ribofuranose of Formula VIII. However no |. process is exemplified for the preparation of Ribavirin from the compound of ' Formula II.
Therefore, it is an object of the present invention to provide an industrially advantageous process for the preparation of Ribavirin in high purity and high yield under mild conditions. The process avoids the critical reaction conditions and additional purification steps.
SUMMARY OF THE INVENTION
The present invention relates to an industrially advantageous process for the preparation of Ribavirin of Formula I
O
ii
N-Y^nh,
HO. £ N
I o i Formula I
P
HO OH
which comprises,
a) reacting a triazole compound of Formula III
? rU^v
OR2 Formula III
I N N' H
wherein R2 represents alkyl group with protected ribofuranose of Formula IV
r!O.
n Formula IV
R'O OR1
wherein R1 represents protecting groups
using catalytic amount of trifluoromethane sulfonic acid, in the presence or absence of solvent, at a temperature of 60°C to 140°C to prepare an intermediate
β-D-ribofiiranose derivative of Formula II,

wherein R1 and R2 are as defined above
b) deprotecting the intermediate of Formula II using conventional methods and preferably in the presence of sodium methoxide in methanol to prepare a compound of Formula IX,

c) ammonolysis of compound of Formula IX using ammonia in the presence of methanol, to prepare Ribavirin.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly the present invention relates to an improved process for the preparation of pure Ribavirin of Formula I from triazole derivative of Formula III and ribofuranose derivative of Formula IV.
The starting materials of Formula III and Formula IV can be prepared by the methods reported in the prior art.
According to the present invention the R1 group in ribofuranose of Formula IV represents a group, which is capable of protecting the hydroxyl function. Suitable protecting groups are acyl groups and preferably acyl groups used are acetyl and benzoyl.
The R2 group of triazole compound of Formula III is alkyl group and preferably C1-C4 alkyl.
According to the present invention the ribofuranose derivative of Formula IV can be used as p anomer of D-ribofuranose of Formula IV and a mixture of a and P anomers of D-ribofuranose of Formula IV in the coupling reaction to prepare the intermediate P-D-ribofuranose derivative of Formula II,
In one of the embodiments of the present invention, p anomer of D-ribofuranose of Formula IV is used in the coupling reaction to prepare the intermediate β-D- ribofuranose derivative of Formula II,
In another embodiments of the present invention, a mixture of α and β anomers of D-ribofuranose of Formula IV has also been used in the coupling reaction, thus avoiding the additional step to separate P anomer from the mixture of a and P anomers.
The solvents used in the present coupling reaction can be selected from hydrocarbons, halogenated hydrocarbons, esters, ethers, ketones, nitriles and the like. Preferably toluene is used.
In one of the embodiments of the present reaction, coupling reaction can be carried out in the absence of solvent.
Usually coupling reaction is conducted at a temperature between 60°C to 140°C and preferably 80° to 130°C. When the reaction is carried out in the presence of solvent, preferably it is carried out at reflux temperature of the solvent.
The product of the coupling reaction is isolated by known processes such as concentration of the reaction mass and subsequently the resulting product is crystallized from alcoholic solvents and preferably methanol is used to isolate pure intermediate of Formula II.
The above intermediate of formula II is converted to Ribavirin by removal of protecting groups and subsequently converting ester group of the triazole ring into carboxylamide group.
The removal of protecting group is carried out using conventional methods as described by T. Green and P. Wuts in 'Protective Groups In Organic Synthesis'. Particularly, when protecting group is acetyl group, the removal of acetyl groups is performed using sodium methoxide in methanol. Thereafter, the conversion of ester group to carboxylamide group is carried out using ammonia and methanol.
Major advantage realized in the present invention is the use of trifluoromethane sulfonic acid in catalytic amount as the coupling agent in the presence or absence of solvent. A mixture of α and β anomers of D-ribofuranose of Formula IV can also be used to prepare the intermediate β-D-ribofuranose derivative of Formula II,
Further the invention is more fully described with reference to the following examples, which are only illustrative and not to be construed as any limitation thereof.
Example-1
PREPARATION OF l-(2,3,5-TRI-0-ACETYL-fi-D-RIB0FURAN0SYL)-lH-l,2,4- TRIAZOLE-3-CARBOXYLICACID METHYL ESTER
A mixture of methyl l,2,4-triazole-3-carboxylate (9.5 g, 0.0748 mole), 1,2,3,5- tetra-O-acetyl-P-D-ribofiiranose (25 g; 0.0785 mole) and toluene (50 ml) was heated to 80-85°C. To the reaction mixture trifluoromethane sulfonic acid (0.34 g) was added and maintained for 5 hours at reflux. Toluene was distilled off under vacuum and the reaction mass was dissolved in hot methanol (75 ml) and crystallized to give 23 g of the title compound.
Example-2
PREPARATION OF l-(2,3,5-TRI-0-ACETYL-P-D-RIB0FURAN0SYL)-lH-l,2,4- TRIAZOLE-3-CARBOXYLIC ACID METHYL ESTER
A mixture of methyl l,2,4-triazole-3-carboxylate (19 g, 0.1496 mole), 1,2,3,5- tetra-O-acetyl-β-D-ribofuranose (50 g; 0.157 mole) and toluene (100 ml) was heated to 80-85°C. To the reaction mixture trifluoromethane sulfonic acid (0.7 g) was added and maintained for 5 hours at 95-100°C. Toluene was distilled off under vacuum and the reaction mass was dissolved in hot methanol (75 ml) and crystallized to give 48 g of the title compound.
Example-3
PREPARATION OF I-(2,3,5-TRI-0-ACETYL-p-D-RIB0FURAN0SYL)-lH-l,2,4- TRIAZOLE-3-CARBOXYLIC ACID METHYL ESTER
Trifluoromethane sulfonic acid (0.34 g) is added to the mixture of methyl 1,2,4- triazole-3 -carboxylate (9.5 g, 0.0748 mole), 1,2,3,5-tetra-O-acetyl-p-D- ribofiiranose (25 g; 0.0785 mole) and toluene (50 ml) at 20-30°C. The reaction mixture was maintained for 5 hours at reflux. Toluene was distilled off under vacuum and the reaction mass was dissolved in hot methanol (75 ml) and crystallized to give 22 g of the title compound.
Example-4
PREPARATION OF l-(2rJ,5-TRI-0-ACETYL-p-D-RIB0FURAN0SYL)-lH-l,2,4- TRIAZOLE-3-CARBOXYLIC ACID METHYL ESTER
A mixture of methyl l,2,4-triazole-3-carboxylate (9.5 g, 0.0748 mole), 1,2,3,5- tetra-O-acetyl-β-D-ribofuranose (25 g; 0.0785 mole) and xylene (50 ml) was heated to 80-90°C. To the reaction mixture trifluoromethane sulfonic acid (0.34 g) was added and maintained for 3 hours at reflux. Xylene was distilled off under vacuum and the reaction mass was dissolved in hot methanol (75 ml) and crystallized to give 19.50 g of the title compound.
Example-5
PREPARATION OF l-(2,3,5-TRI-0-ACETYL-(3-D-RIB0FURAN0SYL)-lH-l,2,4- TRIAZOLE-3-CARBOXYLIC ACID METHYL ESTER
A mixture of methyl 1,2,4-triazole-3-carboxylate (19 g, 0.1496 mole) and 1,2,3,5- tetra-O-acetyl-β-D-ribofiiranose (50 g; 0.157 mole) was heated to melt. To the molten reaction mixture trifluoromethane sulfonic acid (0.7 g) was added and maintained for 5 hours at 95-100°C. The reaction mass was dissolved in hot methanol (150 ml) and crystallized to give 48 g of the title compound.
Example-6
PREPARATION OF l-(2,3,5-TRI-0-ACETYL-p-D-RIB0FURAN0SYL)-lH-i,2,4- TRIAZOLE-3-CARBOXYLIC ACID METHYL ESTER
A mixture of methyl l,2,4-triazole-3-carboxylate (19 g, 0.1496 mole) and 1,2,3,5- tetra-O-acetyl-β-D-ribofuranose (50 g; 0.157 mole) was heated to melt. To the molten reaction mixture trifluoromethane sulfonic acid (0.7 g) was added and maintained for 5 hours at 80-85°C. The reaction mass was dissolved in hot methanol (150 ml) and crystallized to give 46 g of the title compound.
Example-7
PREPARATION OF l-(2,3,5-TRIO-ACETYL-P-D-RIBOFURANOSYL)-lH-l,2,4- TRIAZOLE-3-CARBOXYLIC ACID METHYL ESTER
A mixture of methyl l,2,4-triazole-3-carboxylate (9.5 g, 0.0748 mole) and 1,2,3,5- tetra-O-acetyl-β-D-ribofiiranose (25 g; 0.0785 mole) was heated to melt. To the molten reaction mixture trifluoromethane sulfonic acid (0.34 g) was added and maintained for 2 hours at 120-130°C. The reaction mass was dissolved in hot methanol (75 ml) and crystallized to give 20 g of the title compound.
Example-8
PREPARATION OF l-(2,3,5-TRI-O ACETYL-(J-D-RIBOFURANOSYL)-lH-l,2,4- TRIAZOLE-3-CARBOXYLIC ACID METHYL ESTER
A mixture of methyl l,2,4-triazole-3-carboxylate (19 g, 0.1496 mole) and 1,2,3,5- tetra-O-acetyl-D-ribofuranose (50 g; 0.157 mole) was heated to melt. To the molten reaction mixture trifluoromethane sulfonic acid (0.7 g) was added and maintained for 5 hours at 95-100°C. The reaction mass was dissolved in hot methanol (150 ml) and crystallized to give 34 g of the title compound.
Example-9
PREPARATION OF RIBAVIRIN
To the l-(2,3,5-tri-0-acetyl-P-D-ribofuranosyl)-lH-l,2,4-triazole-3-carboxylic acid methyl ester (50 g; 0.1298 moles), 30% sodium methoxide solution (1.99 g; 0.011 moles) was added at 5-10°C and maintained for 3 hours. The reaction mass was neutralized with acetic acid and distilled off methanol under reduced pressure to residue. To the residue added 22.8% w/v methanolic ammonia solution (35.8 g; 3.7 m.eq.) and stirred for 8 hours. The slurry was concentrated to half of the volume and then added water (25 ml). The slurry was heated to 65-70°C for distillation of product and diluted with methanol (50 ml). The reaction mass was cooled to 0-5°C to crystallize l-p-D-ribofuranosyl-lH-l,2,4-triazole-3- carboxamide. The product was filtered and washed with methanol (100 ml). The wet product (34.8 g) was dissolved in DM water (25 ml) at 60-70°C. To the solution methanol (60 ml) was added at 60-70°C. The resulting solution was cooled to 30-40°C and stirred for 30 min for crystallization of product. The slurry was cooled to 0-5°C and maintained for 2 h. The product is filtered and washed with methanol (25 ml). The wet product is dried at 50-60°C to obtain Ribavirin.

WE CLAIM:
1. A process for the preparation of Ribavirin of Formula I,
I
which comprises,
a) reacting a triazole compound of formula III,
Formula III
wherein R2 represents alkyl group with protected ribofuranose compound of formula IV,
Formula IV
wherein R1 represents protecting groups using catalytic amount of trifluoromethane sulfonic acid, in the presence or absence of solvent, at a temperature of 60°C to 140°C to prepare an intermediate P-D- ribofuranose of formula II,
Formula II
wherein R1 and R2 are as defined above
b) deprotecting the ribofuranose intermediate of formula II using
conventional methods and preferably in the presence of sodium
methoxide in methanol to prepare a compound of formula IX, o
II
n__-/^OR2 Formula IX
HO OH
c) ammonolysis of compound of formula IX using ammonia in the presence of methanol to prepare Ribavarin.
2. The process as claimed in claim 1 wherein the solvent is selected from hydrocarbons, halogenated hydrocarbons, esters, ethers, ketones, nitriles and the like and preferably toluene is used.
3. The process as claimed in claim 1 wherein the reaction is carried out at a temperature of 60°C to 140°C and preferably between 80°C to 130°C.