CS257175B1 - Process for preparing 9-(2-acetoxymethyl)-n2-acetylguanine - Google Patents

Abstract

The solution relates to a method of preparation 9- (2-acetoxyethoxymethyl) -N 2 -acetylguanine by reacting the sodium salt of N 2 -acetylguanine a Of 2-acetoxyethoxymethylbromide, whereby the obtained mixture of 7- and 9-isomers is separated by the bud column chromatography, or fractional chromatography by precipitation of the isomeric solution with diethyl ether. There is an increase in the way described the yield of the desired substance which serves as a an intermediate for antiviral preparation acyclovir drugs.

Description

The invention relates to a process for the preparation of 9- (2-acetoxyethoxymethyl) -N-acetylguanine.

It is a preferred intermediate for the preparation of the antiviral drug acyclovir (Japanese Patent JP 5,980,685). This patent describes the preparation of 9- (2-acetoxyethoxy-2-methyl) -N-acetylguanine by heating N-acetylguanine and 1- (acetoxymethoxy) -2-acetoxyethane with an acid catalyst. Chromatographic separation of the mixture yielded 2

9- (2-acetoxyethoxymethyl) -N-acetylguanine in 26% yield, furthermore, 52% of the undesired 7-isomer was obtained. The title compound was also obtained in 11% yield in a similar manner using diacetylguanine instead of N-acetylguanine (Czechoslovak Patent No. 196,384).

These disadvantages, mainly due to the low yields, are avoided by the method of preparation

9- (2-acetoxyethoxymethyl) -N-acetylguanine by reaction of N-acetylguanine and 2-acetoxyethoxymethyl2 bromide according to the invention, characterized in that N-acetylguanine is deprotonated with sodium hydride in an aprotic solvent, preferably dimethylformamide, and the sodium salt thus formed is stirred with 2-acetoxyethoxymethyl bromide, preferably at room temperature. The process according to the invention is preferably carried out by separating the reaction mixture on a silica gel column (0.063-0.200 mm) and washing the column first with chloroform and then with chloroform / 2% methanol. After working up and chromatographic separation of the mixture, 9- (2-acetoxyethoxymethyl) -N-acetylguanine was obtained in 48% yield, followed by 2 undesired 7-isomer in 26% yield. 9- (2-acetoxyethoxymethyl) -N-acetylguanine can also be obtained from the reaction mixture according to the invention also by fractional precipitation of a methanolic, ethanolic or chloroform solution of the reaction mixture with ether.

v 2

In the process for preparing 9- (2-acetoxyethoxymethyl) -N-acetylguanine according to the invention, the yield of the desired compound is significantly increased (from 26 Ϊ to 48%) and the amount of unwanted isomer of 7- (2-acetoxyethoxymethyl) -N-acetylguanine ( from 52% to 26%). Thus, the starting materials are much better utilized in the process according to the invention.

Out! N-acetylguanine can be advantageously prepared according to U.S. Pat. AO 252 622 2-acetoxyethoxymethyl bromide can be easily prepared from 1,3-dioxolane and acetyl bromide (Robins M. J., Hatfield P. W.

Can. J. Chem. 60, 547 (1982).

• 2

The process for preparing 9- (2-acetoxyethoxymethyl) -N-acetylguanine according to the invention is simple and provides the desired compound in higher yield.

Further details are given in the following examples. The examples given are merely illustrative and not limiting.

He did

9- (2-acetoxyethoxymethyl) -N-acetylguanine

To a stirred suspension of N-acetylguanine (3.84 g, 20 mmol) in dimethylformamide (75 mL) was added 80% sodium hydride (0.7 g, 23 mmol) and the mixture was stirred at room temperature for 8 hours.

After cooling to 0 ° C, a solution of 2-acetoxyethoxymethyl bromide (5.76 g, 30 mmol) in dimethylformamide (5 mL) was added, the reaction mixture was stirred at 5 ° C for 1 h and at room temperature for 6 h and then left overnight. state. After evaporation to dryness, the residue was boiled with chloroform (500 mL), cooled and the insoluble material was filtered off with suction. The filtrate was evaporated to dryness and the residue was chromatographed on a silica gel column (250 g, 0.063-0.200 mm), first washed with chloroform (2 L) and then with chloroform / 2% methanol.

2.95 g of 9- (2-acetoxyethoxymethyl) - N -acetylguanine (48%) of m.p. 199 DEG-201 DEG C., and 1.61 g of the 7-isomer (26%), m.p. Mp 185-187.5 ° C.

Example 2

9- (2-acetoxyethoxymethyl) -N-acetylguanine

The reaction mixture obtained as described in Example 1 was dissolved in ethanol (25 ml) after evaporation of the chloroform and the solution was slowly precipitated with ether (total 50 ml), cooled, the insoluble material was filtered off with suction and recrystallized from ethanol. 2.1 g (34%) of m.p. 198.5 - 201 ° C.

Claims (2)

A process for the preparation of 9- (2-acetoxyethoxymethyl) -N-acetylguanine by reacting N-acetylguanine and 2-acetoxyethoxymethyl bromide, characterized in that a solution of the sodium salt of N 'acetylguanine and 2-acetoxyethoxymethyl bromide in an aprotic solvent, preferably dimethylformamide, is stirred. preferably at room temperature, whereupon a mixture of the 7- and 9- (2-acetoxyethoxymethyl) 2 isomers The N-acetylguanine is separated by column chromatography, or by fractional precipitation of an ethanolic, methanolic or chloroform solution of the isomer mixture with diethyl ether. 2. The process of claim 1 wherein the column chromatography is a mixture of 7- and a 9- (2-acetoxyethoxymethyl) -N-acetylguanine is carried out on a silica gel column and the column is washed first with chloroform and then with a mixture of chloroform and methanol.