SE447113B - INTERMEDIATE PRODUCTS FOR THE PREPARATION OF 2-AMINO-9- (2-HYDROXYETHOXIMETHYL) ADENINE AND 9- (2-HYDROXYETHOXIMETHYL) -GUANIN - Google Patents

Description

According to patent application 7709606-3, it has been found that certain 9- (2-hydroxyethoxymethyl) derivatives of purines can be prepared via a new and advantageous synthetic route. The said patent application 7709606-3 thus relates to a process for the preparation of compounds of formula (I) (CH2.0.CH2.Ch2.0H wherein R represents amino or hydroxy; wherein a compound of formula (II) 2 CHZOCHZCHZ- OCX 2 -CX1 and X1 and X2 are the same or II 0 different and each represents a lower alkyl group, and R2 represents hydrogen or -Cx1 provided that R2 represents hydrogen when R1 represents hydroxy, hydrolyzed in the presence of a base. preferably has 1-4 carbon atoms and most preferably X 1 and X are identical and each represents a methyl group.

The intermediates of formula (II) are novel and the present invention provides, as intermediates, compounds of formula (II) as above. These compounds can be prepared by reacting with guanine or 2-aminoadenine in which R1 represents hydroxy or -NR, wherein the 2- and 9-, respectively 2-, 6- and 9-positions are acylated, to react with a diester of 2-oxa -1,4-butanediol in the presence of a catalytic amount of a strong acid such as sulfuric acid, sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, sulfamic acid, bis- (p-nitrophenyl) phosphate or polyphosphoric acid. The acylated purine can in turn be prepared by reacting the corresponding purine with an acid anhydride, such as acetic anhydride, or other acylating agent, for example acid halide.

To prepare the diester of 2-oxa-1,4-butanediol, dioxolane is reacted with an acid anhydride in the presence of a catalytic amount of a strong acid, for example one of those listed above.

The invention, the characteristics of which appear from the appended claims, will now be illustrated with reference to the following examples, which illustrate the preparation of the intermediates according to the invention and their use for the preparation of compounds of formula (I).

EXAMPLE 1 9- (2-Hydroxyethoxymethyl) guanine A mixture of acetic anhydride (102 g), acetic acid (15 g) and p-toluenesulfonic acid (5.0 g), cooled to 10 ° C, was added with dioxolane (70 g) with stirring. and cooling to such an extent that the temperature in the reaction vessel never exceeded 40 ° C. The mixture was then cooled to room temperature and toluene (300 ml) and diacetylguane (50 g) were added. The reaction mixture was then heated to reflux with stirring for 16 hours. It was then cooled to room temperature, chloroform (50 ml) was added and the solid product was removed by filtration. The filter cake was washed thoroughly with chloroform and dried to give 2-acetamido-9- * (2'-CetOXietloxymethyl) -hypoxanthine. The dried filter cake was added to 40% aqueous methylamine (350 ml), and the mixture was heated to reflux with stirring for 40 minutes, cooled and filtered. The filtrate was evaporated under reduced pressure to a slurry. The slurry was cooled and filtered, and the filter cake was washed with ethanol and dried to give 9- (2-hydroxyethoxymethyl) guanine (27 g, greater than 90% purity) mp 255-257 ° C, yield = 56%.

EXAMPLE 2 2: Streets A mixture of diacetylguanine (50 g), 2-oxa-1,4-butanediol diacetate (59.8 g), and p-toluenesulfonic acid (1.2 g) in toluene (350 ml) was heated under stirring to reflux for 16 hours. The mixture was cooled to room temperature, filtered and the filter cake was washed thoroughly with toluene to give 2-acetamido-9 - (2-acetoxytoxymethyl) -hypoxanthine. The filter cake was dried and 447 g / l 4 was added to 40% aqueous methylamine (350 ml). The mixture was heated under reflux and stirring for 40 minutes, cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure to give a thick slurry. Ethanol (200 ml) was added to the slurry, which was then cooled, filtered, washed with ethanol and dried to give 9- (2-hydroxyethoxymethyl) guanine (36 g, more than 90% purity), yield = 75 %.

EXAMPLE 3 2: Acetamido-9- (2-acetyloxyethoxymethyl) hypoxanthine A mixture of diacetylguanine (1.0 g) 2-oxa-1,4-butanediol-diacetate (0.82 g) and p-toluenesulfonic acid (23 mg) in mineral oil (4 g) was heated at 115 ° C with stirring under reduced pressure overnight. The mineral oil was decanted. The residue was triturated with chloroform and extracted with boiling methanol. The methanol extract was concentrated to 50 ml, cooled and filtered.

The filtrate was evaporated to dryness to give a solid residue (0.43 g). The solid residue was purified by column chromatography (silica gel, 10 g, in chloroform, eluting with 1: 1 chloroform: acetone), followed by recrystallization from ethanol to give 2-acetamido-9- (2-acetyloxyethoxymethyl) hypoxanthine ( o, 14 g), mp 2o2, s-2o4,5 ° c.

EXAMPLE 4 2: Amino-9- (2-hydrogietoxymethyl) adenine (a) 2-formamidoadenine (89.0 g) was placed in a 5 liter flask equipped with an air stirrer and reflux condenser (CaCl 2 - drying tube), to which was added acetic anhydride ( 4 liters).

The mixture was refluxed for 60 hours. At the end of this time, the excess anhydride was removed by distillation at atmospheric pressure until about 3.5 liters of distillate were obtained.

Distillation was continued under reduced pressure to remove most of the remaining anhydride. A dark brown residue in the reaction vessel became a viscous gummy mass on cooling to room temperature and this mass was then dissolved in dichloromethane, filtered to remove suspended solids, and the solvent removed in vacuo to give 211.0 g (* 100%) 2. 6-bis- (diacetylamino) -9-acetylpurine. The analyzed yield was 96.7% based on NMR and the rest of the material was acetic anhydride. 5,447,113 (b) Pentaacetylpurine (174 g) was combined with 1,4-diacetoxy-2-oxabutane (26.8 g) in a flask equipped with air agitator and drying tube. The mixture was then placed in an oil bath at 130 ° C and stirred for a few minutes to homogenize the batch. The acid catalyst, the paratoluenesulfonic acid (2.74 g), was then added in one portion and heating was continued in vacuo for 4 hours, during which time an almost quantitative conversion to products was observed. The reaction mixture was then cooled to room temperature and stored in dry nitrogen. (c) The fusion product (208.5 g) was dissolved in ethanol (5 ml / g) at room temperature and transferred to a cheat equipped with a dropping funnel, air stirrer and thermometer. n-Butylamine (140.4 g) was then added dropwise over a period of 2 hours and the exothermic reaction nx fl e flfi bsneí help of a water bath. The highest temperature that the reaction mixture was allowed to assume was only 30 ° C. The product began to separate from the reaction mixture during the addition process. After completion of the addition, the mixture was stirred at room temperature for 3 hours, after which it was placed in a cold room overnight.

The product was removed by filtration to give a paste-like mass which was slurried with acetone (1 x 500 ml) and re-filtered. This mass was dried in vacuo at 65 ° C for 3 hours and then at room temperature overnight to give 155.2 g (91, 7%) of a light brown hard substance. The product was purified by dissolving it in hot dimethylformamide (10 ml / g) at 100-110 ° C to give an opaque brown solution. After cooling overnight at 5 ° C, the product was removed by filtration, washed with acetone (1 x 250 ml) and air dried to give 121.7 g (78.8%) of 2,6-diacetamido-9- (2-acetoxyethoxymethyl). purin. (d) 2,6-Diacetamido-9- (2-acetoxyethoxymethyl) purine (121.7 g) was added to a stirred solution of aqueous methylamine (608.5 ml of 40% solution) over a 5 minute period. The addition was accompanied by a slight exothermic reaction which raised the temperature of the mixture to 35 ° C and all solids dissolved in a few minutes. After stirring for 2 l / 2 h, thin layer chromatography of the mixture showed that the reaction was complete. The mixture was then concentrated in vacuo on a water bath at 45-5000 to give a thick mass of brown crystals. This mass was then slurried with acetone (545 ml, 7 ml / g) for 15 minutes to remove 447,113 N-methylacetamide and vacuum filtered. The cake was rinsed with (1 x 200 ml) and air dried to give 74.7 g of crude, hydrated 2-amino-9- (2-hydroxyethoxymethyl) adenine light brown crystals. These were dried in vacuo at 80 ° C to give 69.3 g (89.0%) of dry product.

EXAMPLE 5 6.19 g of 2-acetamido-9- (2-acetyloxyethoxymethyl) hypoxanthine was suspended in 40 ml of sodium hydroxide and heated under reflux for 1 hour. The mixture was cooled, neutralized with 6N hydrochloric acid and the product was filtered off. The solid was washed with 10 ml. ice water and with 15 ml of acetone and dried overnight under vacuum. 4.13 g (91, 8%) of 9- (2-hydroxyethoxymethyl) guanine were obtained, m.p. 255-257 ° C; EXAMPLE 6 6.19 g of 2-acetamido-9- (2-acetyloxyethoxymethyl) hypoxanthine were slurried in a solution of 3.24 g of sodium methylate in 40 ml of methanol.

The mixture was heated under reflux for 1 hour and allowed to cool. 3.96 g of glacial acetic acid were added and the mixture was poured into 40 ml of water.

After cooling, 0 ° C, the resulting precipitate was filtered, washed with 15 ml of cold water and with 15 ml of acetone and dried under vacuum to give 4.03 g (89.6%) of 9- (2-hydroxyethoxymethyl) guanine. melting point 255-25700.

EXAMPLE 7 6.19 g of 2-acetamido-9- (2-acetyloxyethoxymethyl) hypoxanthine was added to a solution of 3.96 g of potassium hydroxide in 40 ml of ethanol and heated under reflux for 1 hour. The mixture was allowed to cool and 3.96 g of glacial acetic acid was added. The mixture was poured into 40 ml of water and 50 ml of water was added. The pH was adjusted to 7.0 with aqueous sodium hydroxide and the mixture was cooled with ice water and filtered. The solid was washed with 20 ml of cold water and with 20 ml of acetone and dried under vacuum to give 4.0 g (88.9%) of 9- (2-hydroxyethoxymethyl) guanine, m.p. 255-257 ° C.

EXAMPLE 8 6.19 g of 2-acetamido-9- (2-acetyloxyethoxymethyl) hypoxanthine were slurried with 5 mg of triethylamine and 40 ml of water and the mixture was heated under reflux for 2 hours. The mixture was allowed to cool to 0 ° C and filtered. The solid was washed with 15 ml of water and with 15 ml of acetone and dried under vacuum to give 4.34 g (96%) of 9- (2-hydroxyethoxymethyl) guanine, m.p. 255-257 ° C.

Claims (2)

1. Intermediate claims 1. Intermediates for use in the process for the preparation of compounds of formula (I) R N in N / \. Wherein R represents amino or hydroxy, characterized in that they are compounds of the formula (II) 1 2 N \ i '(ï | cm. \ _, Xl- ( Wherein R 1 represents hydroxy or -NR 2 -C-X 1, and X 1 and X 2 are the same 8 or different and each represents a lower alkyl group, and R2 represents hydrogen or -CX1, where R2 represents hydrogen, when R1 represents hydroxy. Intermediates according to Claim 1, characterized in that X 1 and X 2 are the same and each represents a methyl group.