SU963262A1 - Method of producing amide of 1-beta-d-ribofuranosyl-1,2,4-triazol-3-carboxylic acid - Google Patents

Abstract

METHOD OF OBTAINING AMIDA-1-YB-RIBOFURANOSYL-1, 2,4-TRIAZOL-3-CARBIC ACID by reacting 1,2,4-triazole-Zcarboxylic acid methyl ester with a carbohydrate-containing derivative in the presence of a catalyst, followed by treatment of the 3-carboxylic derivative obtained acids with anhydrous ammonia in methanol, characterized in that, in order to simplify the process, 2,3, 5-tri-0-acetyl uridine is used as a carbohydrate-containing derivative, trifluoromethanesulfonic acid trimethylsilyl ester is used as a catalyst, and e is carried out in an inert organic solvent in the presence of, N, O-bis (trimetnlsilil) trifluoroacetamide at 80-90 sec. o 05 00 (o and 1s

Description

An improved method for producing ами-β-ΰ-ribofuranosyl-1,2,4-triazole-3-carboxylic acid amide (virazole, ribavirin) is proposed, which is widely used in medical practice.

A known method of producing amide 1-0-y-ribofuranosyl-1,2,4-triazole-Zcarboxylic acid by the interaction of methyl ester of 1,2,4-triaeol-

3-carboxylic acid with 1,2,3,5-tetra-O-acetyl-R-ribofuranose fusion in vacuum at 160-165 ° C in the presence of a bis- (i-nitrophenyl) phosphate catalyst, followed by treatment of the obtained 3-car derivative of an acid anhydrous ammonia in methanol. The yield of the target product is 70% based on 1,2,4-triazole-3-carboxylic acid methyl ester.

The disadvantages of this method are the low availability of the initial tetra-0-acyl derivatives of ribofuranose, which are obtained in a multi-stage way, the high temperature of the process, the need to use vacuum in the reaction process and the associated complexity of the technological design of the process of conducting the reaction in the melt.

The aim of the invention is to simplify the process.

This objective is achieved by the described method for producing 1-βτ P-ribofuranosyl-1,2,4-triazole-Zcarboxylic acid amide, which consists in the interaction of 1,2,4-triazole-3-carboxylic acid methyl ester with 2 ', 3, 5 - tri-O-acetyluridine in the presence of N, 0 '(trimethyl silyl) trifluoroacetamide at 80-90 ° С in an inert organic solvent (acetonitrile, dichloroethane) in the presence of a catalyst of trimethylsilyl ether of trifluoromethanesulfonic acid - followed by treatment of the obtained derivative

3-carboxylic acid anhydrous ammonia in methanol. The yield of the target product is 72% based on acetylated uridine and 54% based on 1,2,4-triazole- methyl ester

3-carboxylic acid.

Distinctive features of the method are the use as a carbohydrate derivative of VNIIIL. Order 1166/2 Branch of the RFP

963262 2

2 ', Z ¹ , 5'-tfi-O-acetyluridine, as a catalyst - trimethylsilyl ether of trifluoromethanesulfonic acid, reacting in an inert organic solvent in the presence of N, 0-Bis- (trimethylsilyl) trifluoroacetamide at 80-90 ° С. The starting acetyluridine is obtained by acetylation of uridine with acetic anhydride * ° Reed in pyridine.

Example 1. To a suspension of 1 g of 2,3,5-tri-0-acetyluridine, 0.45 g of methyl ester of 1,2,4-triazole-3-carboxylic acid in 20 ml of anhydrous 15 acetonitrile add 3. ml of 1.0 bis (trimethylsilyl) trifluoroacetamide and the mixture is heated to dissolve (40 ° C). To the solution was added 0.6 ml of trifluoromethanesulfonic acid trimethylsilyl ether and boiled (80-90 ° C). After 4 hours, 0.4 ml of trifluoromethanesulfonic acid trimethylsilyl ether was added and boiled for another 4 hours. The reaction mixture was cooled, a mixture of ethyl acetate and saturated KHCOj solution was stirred in 25 and the mixture was stirred for 1.5 hours. The organic layer was separated, washed with water, dried and evaporated in vacuo. The residue in chloroform is chromatographed 30 on a silica gel column, taking fractions cR _{ 0.5 (TLC on silufol in ethyl acetate, developing with a mixture of anisaldehyde and H ^ SO *,), the eluate is evaporated. The residue was soluble in 35 ml of anhydrous methanol saturated with ammonia at 0 ° C . ^; and kept in a tightly closed flask at 25 ° C for 18 hours

After removal of the solvents, the product was recrystallized from ethanol. Obtain 0.47 g (72%) of 1-p-E-ribofuranosyl-1,2,4-triazole-Zcarboxylic acid amide based on acetylated uridine with a melting point of 17445 176 ° C.

Found,%: C 39.47; H 5.13; N, 22.80.

SDN _1g O 5

Calculated,%: C 39.34; H 4.95; 50 N, 22.94.

Example 2. Proceed analogously to example 1, but carry out the reaction in a mixture of acetonitrile / dichloroethane, get 0.45 g (69%) of amide 1-β-Π55 ribofuranosyl-1,2,4-triazole-3-carboxylic acid.

Claims (1)

METHOD FOR PRODUCING AMIDA-1-βD — Ribofuranosyl-1,2,4-Triazole-3-Carboxylic Acid by Reaction of 1,2,4-Triazole-Zarboxylic Acid Methyl Ether with a Carbohydrate Derivative in the Presence of a Catalyst followed by Treatment of the Derived 3-Carboxylic Derivative acid with anhydrous ammonia in methanol, characterized in that, in order to simplify the process, as a carbohydrate derivative using 2 ', ¹ H, 5'-tri-0atsetiluridin as a catalyst - trifluoromethanesulfonic acid trimethylsilyl ester, and reacting osusches vlyayut in an inert organic solvent in the presence of N, 0-6uc- (the trim tilsilil) trifluoro acetyl tamid at 80-90 ° C.