FR2541681A1 - Process for the preparation of acycloguanosine - Google Patents

Abstract

Process for the preparation of acycloguanosine of formula: from guanine, consisting in protecting the amine and hydroxyl groups, in reacting 1-acetoxy-2-(chloromethyloxy)ethane, and in removing the protecting groups by hydrolysis.

Description

Process for the preparation of acycloguanosine
The present invention relates to a new process for the preparation of acycloguanosine of formula

Unlike the processes known to date, the process according to the invention consists in transforming a guanine in which the functional groups amine in position 2 and hydroxyl in position 6 are protected by means of suitable reagents into a protected acycloguanosine, which easily converts to acycloguanosine.

The advantages of the process are higher overall yields, the use of inexpensive reagents, easy to obtain commercially and not dangerous, and finally the possibility of carrying out different operations in two distinct phases or directly in a single phase.

Guanine (1), in a solution of dimethylformamide containing an organic or inorganic base, is treated with benzaldehyde in order to obtain Schiff base (2), and the latter with acetic anhydride or daacetyl chloride in order to transform the Schiff base (2) into its acetylated derivative (3).

Compound (3), in the presence of a tertiary amine and 1-acetoxy-2-chloromethyloxyethane (4), provides the derivative (5) which, by hydrolysis with ammonia and acetic acid, turns into acycloguanosine .

The above transformations are shown by the following reaction scheme

Each of the reactions described can be carried out by separating the intermediate products obtained, or, as described later in the example, the process can be carried out in a single phase or in several successive times.

In the first reaction, the guanine is dissolved in an appropriate solvent (for example dimethylformamide or similar solvents: if it is desired to conduct the process in a single phase, it is necessary to use aprotic, but polar, solvents, because of the low solubility of guanine in non-polar solvents), a base (preferably a tertiary amine in equimolecular amount), benzaldehyde in equimolecular amount is added, and, if it is desired to operate in a single phase, a dehydrating agent, by example of anhydrous sodium sulfate or molecular resins.

In the second reaction, the mixture obtained by the first reaction is directly treated with acetic anhydride or acetyl chloride in an amount which can vary from 1 to 2 moles per mole in order to acetylate the hydroxyl group.

The third reaction can be carried out directly on the mixture obtained by the second reaction; To this mixture is added another basic molecule (preferably a tertiary amine, the same as that used in the first reaction) and the reagent (4) in molecular quantity.

The last reaction consists in removing the protective groups by treatment with ammonia, in order to hydrolyze the acetyl group and, in part, the Schiff base; the complete hydrolysis of the latter is obtained by the addition of acetic acid and by gentle heating.

The reagent (4) is easily prepared from ethylene glycol monoacetate, using formaldehyde and hydrochloric acid.

An exemplary embodiment of the present invention is described below by way of illustration and not limitation.

EXAMPLE
15.1 g of guanine are dissolved in the minimum quantity of dimethylformamide, containing 10.1 g of anhydrous triethylamine and 10.6 g of benzaldehyde.

By gently heating the mixture, molecular resins are added to remove the water that forms in the reaction and stirred until the reaction is complete.

The resins are separated from the solution by decantation and 11 g of acetic anhydride are added, then the mixture is heated until complete reaction.

Finally, it is allowed to cool, 15 g of anhydrous triethylamine and 16 g of 1-acetoxy-2-chloromethyloxyethane are added, and finally the solution is further heated with stirring at 50-800C until the substitution in position 9 is finished.

Then diluted with 50 ml of methanol saturated with gaseous ammonia. The mixture is transferred to an autoclave and heated to 50-800C until complete hydrolysis.

Finally, it is allowed to cool, the volatile substances are evaporated under vacuum, 95% acetic acid is added to obtain a clearly acidic reaction, and the mixture is stirred at room temperature until complete hydrolysis of the Schiff base.

At the end of the reaction, the volatile substances are evaporated under vacuum, the residue is diluted with water, the pH is adjusted so as to obtain the maximum precipitation of acycloguanosine; the latter, after filtration and washing with hexane, is recrystallized to the constant melting point of 2560C.

Claims (5)

Claims 1.- Process for the preparation of acvcloquanosine of formula:

 characterized in that the guanine of formula is reacted:

 with benzaldehyde in dimethylformamide in the presence of a base to obtain the corresponding Schiff base, which is reacted with a reactive derivative of acetic acid to obtain the acetylated derivative of formula:

 which is reacted with 1-acetoxy-2-chloromethyloxyethane in the presence of a tertiary amine to obtain the derivative of formula

 and that the latter is finally hydrolyzed to produce the desired acycloguanosine. 2.- Method according to claim 1, characterized in that the acetic acid derivative is anhydride or acid chloride. 3.- Method according to one of claims 1 and 2, characterized in that the final hydrolysis is carried out with ammonia and acetic acid. 4.- Method according to one of the preceding claims, characterized in that the different operations are carried out in two different phases. 5.- Method according to one of claims i to 3, characterized in that the process is carried out in a single phase in the presence of a dehydrating agent.