DE1954587A1 - 2',3',5'-tri-o-acetyl-6-azanridine prepn - Google Patents

Abstract

A new process for prepg. 2',3',5'-tri-O-acetyl-6-azauridine consists of reacting 6-azauridine with acetic acid in the presence of a catalyst e.g. acetyl halide, H2SO4, p-toluenesulphonic acid, ZnCl2 or an H-form cation exchanger at temps up to b.p. with azeotropic removal of water. The starting material may be pure 6-azauridine or the impure material obtained by the fermentation process. Has less side effects than 6-azauridine.

Description

"Process for the preparation of 2, 3 *, 5 'Tri-O-acetyl-6-azauridine" The invention relates to a process for the preparation of 2 ', 3', 5'-tri-O-acetyl-6-azauridine.

The basic compound, the unsubstituted 6-azauridine, has its use as a medicinal product has some disadvantages.

One of the main drawbacks is that it is when administered per os is accompanied by neurotic side effects. Therefore it is necessary the drug to be administered intravenously, but this is sometimes the case with larger doses must be administered, is cumbersome and uncomfortable.

Another disadvantage of this substance is that it is the Body excretes soon after administration and thus its healing effect is not fully is exploited. There have therefore been sought such derivatives of 6-azauridine which eliminate the aforementioned disadvantages of 6-azauridine. From links this Type were 2 ', 3', 5'-Tri-O-acyl derivatives of 6-azauridine, 2 ', 3 -Di-O-acyl derivatives of 6-azauridine and 2 '3' -Di-O-acyl derivatives of 6-azauridine-5'-phosphate will, The present invention deals with a completely new one Process for the preparation of the triacetyl derivative of 6-azauridine, which is not only is in principle completely new and in the field of nucleosides - in which area belongs to the chemistry of azauridine - has not yet been used, but that is essential is simpler and therefore cheaper to produce than the previously known ones Preparation: ings method of these substances 0 The subject invention of a method for the preparation of 2,3 ', 5'-tri-O-acetyl-6-azauridine is characterized by 6-azauridine with acetic acid in the presence of a catalyst, e.g. in the presence of an acetyl halide, of sulfuric acid, of pwtoluenesulfonic acid, of zinc chloride or a cation exchanger in the H + cycle, is acetylated, the reaction possibly accelerated by increasing the temperature or even at the boiling point the reaction mixture is carried out; the water produced by the reaction is removed from the reaction solution, advantageously by azeotropic distillation.

By reaction of an organic acid with 6-azauridine in the presence A catalyst initially produces the monoacetyl derivative of 6-azauridine. By Lengthening the reaction time increases the amount of the diacyl derivative in the reaction mixture at.

Less substituted derivatives of 6-azauridine can be extracted from the reaction mixture zOBo by chromatography on cellulose, silica gel, aluminum oxide and the like. are isolated0 The fully acylated derivatives of 6-azauridine result from the reaction of an organic acid with 6-azauridine in the presence of a catalyst and with the simultaneous removal of the water formed during the reaction. The water of reaction is removed either by adding substances that bind the water formed in the reaction mixture (e.g. Molecular sieves, anhydrous sodium sulfate) or form an azeotropic mixture with the water (e.g. toluene, carbon tetrachloride). In the second case, the water of reaction is advantageously removed from the reaction mixture by azeotropic distillation.

Fully acylated derivatives of 6-azauridine can also be obtained from derivatives of 6-azauridine with a lower degree of acylation (from the mono- and di-acyl derivatives) by the action of an equivalent amount of an acylating agent, i.e. one Acid halide or an anhydride of an organic acid in the presence of a Catalyst are prepared and this either directly in the reaction mixture or after isolation of the lower acylated derivatives.

Instead of pure 6-azauridine, unpurified 6-azauridine can also be used as the starting substance 6-azauridine can be used from a suitable production phase of 6-azauridine (e.g. the product from fermentation production, the additional 6-azauridine or the 6-azauracil, uracil, hypoxanthine, orotic acid and other compounds).

Below is the process for preparing 2 ', 3', 5'-Tri-O-acetyl # 6 # azauridine according to the present invention explained in more detail on implementation examples, without wishing to be limited to these in any way.

Example 1 6-Azauridine (4.9 g) is heated in acetic acid (40 ml) dissolved. The cooled solution is added sulfuric acid (0.2 ml) and toluene (30 ml) added. This solution is then heated to the boiling point and that is water forming in the reaction mixture distilled off azeotropically0 The course of the reaction is followed by chromatography. After three to four hours of heating to the boiling point the reaction solution is cooled and, with stirring, becomes a sodium hydrogen carbonate solution (2g in 10 ml of water) added. The reaction solution is distilled in vacuo. The residue is dissolved in ethyl acetate (10 ml), and toluene (10 ml) is added and the solvents are then distilled off in vacuo.

This process is repeated twice more4 The residue is in Dissolved ethyl acetate (200 ml), filtered the solution with activated charcoal and the filtrate evaporated in vacuo.

The residue is crystallized from ethanol in the usual way. 4.45 g of 2 ', 3', 5'-tri-O-acetyl-6-azauridine with a melting point of 100 to 1O20C are obtained, that has the same physical constants as an authentic sample. By processing the mother liquors, a further proportion of the same Substance (1.48 g, m.p. = 100 to 102 ° C). Processing of the mother liquors done by chromatography on a silica gel column.

Example 2 A mixture of acetic acid (30 ml) and acetyl chloride (0.5 ml) is added 6-azauridine (5 g). The reaction mixture is placed on a vibrating shaker Shaken at Ziamertemperature until the starting substance has dissolved.

After standing for four days, the reaction solution is evaporated off in vacuo The residue is codistilled twice with a dioxane / benzene mixture (1 t 1). The residue is then dissolved in 15 ml of acetic acid and the solution is acetic anhydride (2ml) and acetyl chloride (0.4ml) added. After standing at room temperature for 24 hours the solution is distilled in vacuo and the residue twice with an ethanol-benzene mixture and codistilled once with ethanol.

The residue is then recrystallized from ethanol (96%). the Substance is left in the refrigerator overnight for crystallization, then Sucked off, washed on the filter with 96% ethanol and dried in vacuo.

6.96 g of the 2 ', 3', 5'-tri-O-acetyl-6-azauridine are obtained.

Claims (1)

P a t e n t a n s p r ü c h e Method for the preparation of 2 ', 3', 5'-tri-O-acetyl-6-azauridine, gekennreichnet dadruch that 6-azauridine with acetic acid in the presence of a catalyst such as zoBo acetyl halide, sulfuric acid, p-toluenesulfonic acid, zinc chloride, a cation exchanger is acetylated in cycle 1, the reaction optionally by increasing the Accelerated temperature, possibly carried out at the boiling point of the O-emic and the water produced by the reaction from the reaction solution - with advantage by azeotropic distillation - is removed.