CS264455B1 - 5,6-Dihydro-S-azauridine and a process for its preparation - Google Patents

Abstract

The solution concerns a new 5,6-dihydro-5-azauridine and a method for its production. The substance can be used in the pharmaceutical industry.

Description

(57) The present invention relates to a novel 5,6-dihydro-5-azauridine and to a process for its preparation. The substance can be used in the pharmaceutical industry.

The invention relates to a 5,6-dihydro-5-azauridine of formula I

O

The object of the present invention is also a process for the preparation of 5,6-dihydro-5-azauridine of formula I, which is a new analog of uridine.

The 5,6-dihydro-5-azauridine of formula I is a novel uridine analog from which it can be formally derived by substituting the CH group at the 5-pyrimidine nucleus position with an isoelectronic nitrogen atom and then adding hydrogen to the double bond at the 5,6-triazine ring position. The dihydronucleoside of formula I belongs to the group of nucleosides of 5,6-dihydro-5-azauracil. The most prominent of this group is the nucleoside antibiotic 5,6-dihydro-5-azathymidine (DHAdT), which was isolated from culture filtrates of S. platensis var. customs duties. ensis (DeBoer, Bannisters US Pat.

907,643 (1975)). and shows activity against DNA viruses and gram-negative bacteria. A putative intermediate of DHAdT biosynthesis is 5'-phosphate-5,6-dihydro-5-azauridine. Alone

5,6-Dihydro-5-azauracil is also a known selectively acting antiphytoviral agent and its predicted active metabolite is also said 5'-phosphate-5,6-dihydro-5-azauridine.

For this reason, 5,6-dihydro-5-azauridine of formula I can also be expected to have antiviral or antibacterial activity.

Unlike 5-azauridine, the 5,6-dihydro-5-azuridine of formula I is stable in aqueous solutions over a wide pH range and is also substantially better soluble in water.

A process for the preparation of 5,6-dihydro-5-azauridine of formula I is characterized in that the free or blocked 5-azauridine of formula II

(II) wherein R is hydrogen or acyl, optionally a covalent alcoholate of a compound of formula (II) wherein R is acyl, is reduced by zinc powder in anhydrous C 1 -C 4 carboxylic acid, and when a compound of formula (II) wherein R is acyl , the resulting 2 ', 3', 5'-tri-O-acyl-5,6-dihydro-5-azauridine of formula III

(III),

RO OR where R is acyl, undergoes alcoholysis or ammonolysis.

The reduction proceeds very well already at room temperature using five to ten times the theoretical amount of powder recovery. Commercially available acetic acid has proved to be a carboxylic acid. The reduction of the less stable blocked 5-azauridine is preferably carried out in a mixture of carboxylic acid and 2,2-dimethoxypropane, which guarantees the anhydrous nature of the reaction medium. The alcoholysis of the 2 ', 3', 5'-tri-O-acyl-5,6-dihydro-5-azauridine of formula III is carried out with a solution of an alkali metal alkoxide in C 1 -C 4 alkanol, preferably sodium methoxide in methanol. Ammonolysis of compounds of formula III ₍ is carried out with a solution of ammonia in C 1 -C 4 alkanol, preferably in methanol.

The invention is further illustrated by the following non-limiting examples.

He did

Preparation of 2 ', 3', 5'-tri-O-benzoyl-5,6-dihydro-5-azauridine

A mixture of acetic acid (5 ml) and 2,2-dimethoxypropane (2 ml) was allowed to stand at room temperature in a sealed flask for 24 hours. Zinc powder (0.65 g) and the covalent adduct of 2 ', 3', 5'-tri-O-benzoyl-5-azauridine with methanol (0.590 g; 1 mmol) were then added sequentially. The mixture was stirred vigorously magnetically at room temperature for 7 hours and the insoluble material was filtered off with suction through a frit. The frit material was washed sequentially with acetic acid, methanol and richly chloroform-methanol (9: 1). The combined filtrates were shaken with water and 5% sodium bicarbonate solution. After drying (MgSO4), the organic layer was evaporated in vacuo. Crystallization residue from chloroform-methanol-petroleum ether yielded a total of 0.515 g (92%) after treatment of the mother liquors and drying of the product obtained at 100 ° C under water pump vacuum.

2 ', 3', 5'-tri-O-benzoyl-5,6-dihydro-5-azauridine; m.p. Mp 219-221 ° C (dec.).

Example 2

Preparation of 5,6-dihydro-5-azauridine

A mixture of 5-azauridine (0.245 g; 1 mmol), acetic acid (5 mL), and zinc powder (0.65 g) was magnetically stirred at room temperature for 24 hours. The insoluble material is filtered off with suction and washed successively with acetic acid and rich methanol. The combined filtrates were evaporated in vacuo, the residue was dissolved in water and applied to a weakly acidic cation exchange column (50 mL) in H ⁺ form, which was prepared in water. The product was washed with water and the eluate evaporated in vacuo. Crystallization of the residue from methanol-water (9: 1) afforded a total of 0.210 g (85%) of 5,6-dihydro-5-azauridine for the mother liquors; mp 189-190 ° C (dec.).

Example 3

Preparation of 5,6-dihydro-5-azauridine

A mixture of 2 ', 3', 5'-trans-O-benzoyl-5,6-dihydro-5-azauridine (0.560; 1 mmol), methanol (5 mL) and methanolic 1M-NaOCH ₃ (2 mL) was stirred magnetically. in a sealed flask for 24 hours. The starting material initially goes into solution and then a gel-like precipitate is formed. After acidification of the mixture with acetic acid (0.2 ml), the gel-like precipitate was dissolved and the product immediately began to precipitate. 0.223 g (90%) of 5,6-dihydro-5-azauridine is obtained; mp 189-190 ° C (dec.).

Claims (6)

1. 5,6-dihydro-*5-azauridine of the formula T _H HN^NH boy ₂ HO OH 2. A process for the production of 5,6-dihydro-5-azauridine according to point 1 of formula I, characterized in that free or blocked 5-azauridine of general formula II is N NH roch ₂ .0. RO OR (II) where R is hydrogen or acyl, or a covalent alcoholate of the compound of general formula II, where R is acyl, is reduced with zinc powder in anhydrous carboxylic acid with 1 to 4 carbon atoms and in the case of using a compound of general formula II, where R is acyl, the resulting 2',3',5'-tri-O-acyl-5-azauridine of general formula III O H^HN NH roch ₂ ¹ .0 Tf RO OR where R is acyl, undergoes alcoholysis or ammonolysis. (III) 3. The method according to item 2, characterized in that the reduction of the compound of general formula II is carried out with five to ten times the theoretical amount of zinc powder in an anhydrous acetic acid environment at room temperature. 4. The method according to item 2, characterized in that the reduction of the compound of general formula II, where R is acyl, is carried out in the presence of an excess of 2,2-dimethoxypropane. 5. The method according to item 2, characterized in that the alcoholysis of the compound of general formula III is carried out by dissolving an alkali metal alkoxide in an alkanol with 1 to 4 carbon atoms, preferably sodium methoxide in methanol. 6. The method according to item 2, characterized in that the aranolysis of the compound of general formula III is carried out with a solution of ammonia in an alkanol with 1 to 4 carbon atoms, preferably in methanol.