DE2530823A1 - Nucleosides cleavage - by reacting with acyl halides to eliminate fully acylated sugar residues - Google Patents

Abstract

Nucleosides are cleaved by subjecting nucleosides or their acyl derivs. ("acyl" being 2-8C acyl) to the action of acyl halides of the formula RCOX (where R is 1-3C alkyl and X is Cl or Br) so as to bring about elimination of the halide of the fully acylated sugar component. The reaction is pref. carried out at -10 degrees to +50 degrees C (esp. 20 degrees C) in the presence of an anhydrous organic solvent, esp. acetic acid, acetronitrile or benzene. In an example, inosine is reacted with acetyl bromide in acetic acid at room temp. and the reaction product is reacted with silylated uracil in the presence of mercury (II) bromide to give 2',3',5'-tri-O-acetyl-uridine. Production of peracylated sugar halides useful as intermediates for e.g. the prod. of analogues of nucleoside antibiotics or other biologically active substances derived from the sugar components of nucelosides. The reaction is carried out under mild conditions and yields products that are difficult to obtain by conventional procedures.

Description

Title: Nucleoside Cleavage Method =========================================== =========================== The invention relates to a method for cleaving nucleosides.

So far, the cleavage of nucleosides by acid hydrolysis (Chargaff E., Davidson J.N .: The Nucleic Acids, Vol. 1., S.192-193) or acetolysis with higher Temperature (Robins M.J., Robins R.K .: J. Am. Chem. Sec. 87, 4934 (1965)). The disadvantage of the previously known methods is that they are in an acidic environment or works at a higher temperature; decomposition can occur under these conditions the sensitive sugar components occur. None of the previously known methods leads directly to halogenosis of the completely acylated sugar component.

The advantage of the method according to the invention is that one the cleavage of nucleoside under very mild conditions, that is, under lower conditions Temperature and with the addition of strong Acid performs, the dissolved sugars at the same time protected by acylation directly in the reaction mixture will. In this way the process enables the production of halogenoses the acylated sugars, which in any other way not at all or only with great difficulty are accessible. The process thus enables all forms of formation that arise from sugar halogenoses go out. Halogenesis produced according to the invention can be used directly for the subsequent Use nucleoside conversion. This is the way to make analogues of nucleoside antibiotics or of other active biological sugar components of nucleoside-derived substances. Halogenosis can easily be found in convert a number of sugar derivatives that are used for the production of sugar derivatives and analogs are important in sugar chemistry or in the pharmaceutical industry and which in some cases could not be made at all, or theirs total production would be very expensive and difficult.

The invention relates to a method for the cleavage of nucleosides, in which one uses nucleosides, free or their acyl derivatives, with the acyl 2 - 8 carbon atoms contains, by the action of the acyl halide of the general formula RCOK, where R is alkyl with 1 - 3 carbon atoms and X denotes Bt or Ct under formation the halogenosis of completely acylated sugar component spoltet. Another hallmark the invention consists in the fact that the reaction at a temperature of -100 to +500 C, advantageously carried out at 200 C, the reaction in the presence of an anhydrous aerobic solvent, especially acetic acid, acetonitrile or benzene is carried out.

Example 1 The mixture of inosine (267 mg), acetyl bromide (2 ml) and Acetic acid (2 ml) is stirred at room temperature for 1.5 hours.

Thereafter, toluene (4 ml) is added, the mixture at a temperature left to stand at 30 C within 3 hours, the insoluble fraction is filtered off, Washed through with dry toluene and the combined filtrates are in vacuo evaporated. The dry residue is codistilled with toluene (3 x 5 ml) and in acetonitrile (5 ml) dissolved. The solution becomes the silylated uracil (which is produced by silylation was prepared from 140 mg uracil) was added. The molecular sieves become the mixture Potasit 3 (0.5 g) and mercury (II) bromide (100 mg) were added. After its dissolution the mixture is left to stand at room temperature for 3 hours.

The molecular sieves were then filtered off and washed with acetinitrile washed through. The dry residue of the combined filtrates is dissolved in chloroform (20 ml) dissolved. The chloroform solution is mixed with 10% solution of potassium iodide (3 x 4 ml) washed through with water (2 x 4 ml), dried out with magnesium sulfate and evaporated in vacuo. The dry residue is placed on the column of silica gel (30 g, 30-60, i) chromatographed in the benzene-acetone (3: 1) system.

After crystallization from ethanol, 150 mg (41%) 2 'are obtained, 3 ', 5'-tri-O-acetyluridine.

Example 2 The mixture of inosine (516 mg), acetyl chloride (3 ml) and acetic acid (3 ml) is shaken until dissolved (30 minutes). After twelve hours Let it stand, it is evaporated in vacuo, the dry residue with toluene (3 x 5 ml) code-distilled and stirred with toluene (5 d). The solid portion is filtered off and washed through with toluene. The combined toluene filtrates are made with silver acetate (334 mg) stirred at room temperature within 12 hours, filtered off and in vacuo drained. After the dry residue has crystallized from ethanol, mon wins 307 mg (48%) tetra-0-acetylribose.

The solid portion that remains insoluble in toluene is mixed with chloroform extracted (10 ml). Evaporation of the extract gives 340 mg (43 to 2 ', 3 ', 5'-tri-O-acetylinosine. The portion which is insoluble in chloroform is dissolved in water (5th ml) dissolved, the solution neutralized to pH 6 and the excreted Nicderschlag filtered off from hyponynthin, washed through with ethanol and dried out (110 mg, 41%).

Example 3 The mixture of inosine (268 mg), acetyl chloride (3 ml) and Benzene (3 ml) is shaken at room temperature for 20 hours.

The solid fraction is filtered off and washed through with benzene.

The combined filtrates are evaporated and the dry residue with Benzene (3 x 5 ml) codistilled. The dry residue is dissolved in benzene to make the solution silver acetate (168 mg) is added and the mixture is at room temperature within stirred for 12 hours, filtered off and the filtrate evaporated in vacuo. By Crystallization from ethanol gives 120 mg (38 Sc;) of tetra-O-acetylribofuranose. By processing the excreted insoluble portion in the previous one If a similar procedure is used, 197 mg 450%) 2 ', 3', 5'-ri-0-acetylinosine are obtained and 46 mg (34 to Hypoxonthin.

Example 4 Tetrabenzoyladenosine (684 mg) is dissolved in a mixture of acetyl chloride (5 ml) and acetic acid (5 ml). The solution is dissolved at room temperature 2 Days stand. The mixture is evaporated in vacuo and the dry residue with toluene (3 x 2 ml) codistilled. The dry residue is dissolved in a mixture of toluene (9 ml) and ethanol (1 ml) stirred. The solid (benzoyladenine) 117 mg) is filtered off and washed through with toluene. The combined filtrates are evaporated in vacuo and the dry residue is on the column of silica gel (30 g, 30-60 p) in the system Benzene-ethyl acetate (4: 1) chromatographed, 123 mg (18%) of starting material are obtained and 293 mg (58 to product with a melting point of 130.5-131.50C without depression with l-0-acetyl-2,3,5-tri-0-benzoyl-dwribofurenose.

Claims (2)

PATENT CLAIMS Process for the cleavage of nucleosides, thereby g e k e n n -z e i c h n e t that nucleosides - free or their acyl derivatives, where acyl 2 - 8 Contains carbon atoms - by action of acyl halide of the general formula RCOX, where R is alkyl with 1-3 carbon atoms and X is Br or Cl, under Formation of halogenises of the completely asylated sugar component splits. 2. A method for producing according to claim 1, characterized in that g e k It is noted that the reaction can be carried out at a temperature of -100 to + 500 C, preferably at 200 C, and in the presence of anhydrous organic solvent, with the advantage of acetic acid, acetonitrile or benzene.