CS196384B2 - Method of preparing substituted purines - Google Patents

Abstract

9-(2-Hydroxyethoxymethyl) derivatives of 2-amino-adenine and guanine of formula I are prepared by hydrolysis from compounds of formula II. The reaction is carried out in the presence of a base. The symbols in formula I and II have the meanings given in Patent Claim 1. The novel compounds of formula II are prepared by reacting the guanine or 2-aminoadenine, wherein the 2- and 9-positions, or the 2-, 6- and 9-positions, are acylated, with a diester of 2-oxa-1,4-butanediol. This reaction is carried out in the presence of a catalytic amount of an acid. The 9-(2-hydroxyethoxymethyl) derivatives of 2-aminoadenine and guanine are novel and exhibit an antiviral action, especially against the classes of the DNA- and RNA-viruses. <IMAGE>

Description

SÓHAEFFER HOWARD JOHN, RALEIGH (Sp. St. A.)

THE WELLCOME FOUNDATION LIMITED, LONDON (United Kingdom) (54) Process for the preparation of substituted purines

The invention relates to a process for the preparation of 9-substituted purines, in particular 9- (2-hydroxylethoxymethyl) purine derivatives, in particular 2-aminoadenine and guanine.

9- (2-Hydroxyethoxymethyl) purine derivatives have antiviral activity against various classes of DNA and RNA viruses in both in vitro and in vivo assays. These compounds are particularly active as antiviral agents against adenovirus such as adenovirus 5 and rhinovirus. They are particularly effective as anti-viral agents against vaccinia and herpes viruses, including simplex, zoster and varicella in mammals, which cause diseases such as herpes keratitis in rabbits and herpes encephalitis in mice.

Examples of 9- (2-hydroxyethoxymethyl) purine derivatives having particularly good antiviral activity include 9- (2-hydroxyethoxymethyl) guanine and 2-amino-9- (2-hydroxyethoxymethyl) adenine.

Numerous methods are known for the preparation of 9- (2-hydroxyethoxymethyl) derivatives of purine, for example they can be prepared by removing the protecting group from position 2 of the side chain. Alternatively, a Conversion of 2 and / or 6 Substituent on the Core, Purine to Various Substituents can be prepared (see British Patent Specification No. 1,523,865.)

It has now been found that certain 9- (2-hydroxymethyl) purine derivatives can be prepared by a new and advantageous synthetic route in good yield and in particular in a more pure form. Accordingly, the present invention provides a process for the preparation of 9 substituted purines of formula (I),

R

wherein R is an amino or hydroxy group, characterized in that a compound of formula (II) is hydrolyzed in the presence of a base,

where

R @ ¹ 'represents a hydroxy group. or a group of formula

-NR 2 -CX 1

II

O

X 1 and X ² have the same or different meanings and each represents an alkyl group of from 1 to 2. 4 carbon atoms or a phenyl group,

R ² 'is hydrogen or a group of' the formula

-CX1

II o

with the proviso that in the case where R 1 represents a hydroxyl group, it means:. R2 'is hydrogen.

When X 1 and Q 2 are C 1 -C 4 alkyl groups, they are most preferably the same and are methyl.

The base used in the hydrolysis may be an aqueous or alcoholic primary or secondary aliphatic amine, an alkoxide in an alcohol, or an aqueous or alcoholic hydroxide such as sodium alkoxide or sodium hydroxide, the preferred base being an aqueous primary aliphatic amine such as aqueous methylamine. Depending on the base used, the hydrolysis can be carried out at room temperature up to the temperature of the steam bath. In general, the lower the reaction temperature, the longer the reaction time, but the fewer side reactions.

The starting material of formula (II) in which R @ 1 is --NRGX @ 1

II

O and R &lt; 2 &gt;

II

O can be perfectly hydrolyzed in one step using, for example, aqueous methylamine. Or, more preferably, the starting material of formula (II) is deacylated in two steps: In the first step, one group of formula (CXi • II) is removed.

from positions 2 and 6 of the purine core by mild hydrolysis at room temperature using, for example, butylamine in a lower alcohol. Second hydrolysis step to remove the remaining group of formula —CX ^x ·

II.

O is performed using a stronger base than aqueous methylamine.

The starting materials of the formula II are new. They can be prepared by reacting guanine or 2-aminoadenine in which the 2 'and 9 or 2, 6 and 9 positions are acylated with 2-oxal, 4-butanediol diesters in the presence of a catalytic amount of a strong acid, such as sulfuric acid, sulfonic acids , as . is para-toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, amidosulfonic acids, bis- (para-nitrophenyl) phosphate or polyphosphoric acid.

The acylated purine can be prepared by reacting a suitable purine with an acid anhydride such as acetic anhydride or an acid. with another acylating agent, such as an acid halide.

To prepare the 2-oxa-1,4-butanediol diester, dioxolane is reacted with an acid anhydride in the presence of a catalytic amount of a strong acid such as the above.

The following examples illustrate the process according to the invention.

Example 1 '

9- (2-Hydroxyethoxymethyl) guanine

To a mixture of acetic anhydride (102 g), acetic acid (15 g) and para-toluenesulfonic acid (5.0 g), cooled to 10 ° C, was added with stirring and cooling dioxolene (70 g) at such a rate so that the temperature does not exceed 40 ° C. The mixture was then cooled to room temperature and toluene (300 mL) and diacetylguanine (50 g) were added. The 'reaction' mixture was then refluxed for 16 hours, with stirring. After cooling 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. The dried filter cake was added to 40% aqueous methylamine (350 ml) and the mixture was refluxed with stirring for 40 minutes, cooled, filtered. The filtrate was evaporated to a thick solid under reduced pressure. sludge. The slurry was cooled and filtered, the filter cake was washed with ethanol and dried to give 9- (2-hydroxyethoxymethyl) guanine. (27 g, purity &gt; 90%), m.p. 255-257 ° C and 56% yield.

Example 2

9- (2-НуЬгохуеП1охутеи1у1) guanine

A mixture of diacetylguanine (50 g), 2-oxa-1,4-butanediol diacetate (59.8 g) and para-toluenesulfonic acid (1.2 g) in toluene (350 ml) with

se. cooks under. with stirring for 16 hours. The mixture was then cooled to room temperature, filtered and the filter cake was washed thoroughly with toluene. The filter cake was dried and added to 40% aqueous methylamine (350 mL). The mixture was refluxed with stirring for 40 minutes, cooled to room temperature and filtered. se. The filtrate was evaporated to a residue. under reduced pressure to give a thick sludge. Ethanol (200 ml) was added to the slurry and cooled. filtered, washed with ethanol. and dried to give 9- (2-hydroxyethoxymethyl) guanine (36 g, purity &gt; 90%), m.p. 255-257 ° C, and. is 75%. '? '. ..

Example. 3. . . ...

2-Acetamido-9- (2-acetyloxy) -buthoxyl). hypoxanthin

Mixture. diacetylguanine (1.0 g),. . Of 2-oxa-1,4-butanediol diacetate (0.82 g). a. para-toluenesulfonic acid (23 mg) v. mineral. The oil (4 g) was kept at 115 ° C with stirring under reduced pressure overnight The mineral oil was then decanted off, the residue was triturated with chloroform and then extracted with boiling methanol. The volume of 50 ml was cooled rapidly and filtered, and the filtrate was evaporated to dryness to give a residue (0.43 g) .The solid residue was purified by column chromatography (silica gel, 10 g in chloroform). eluent (1: 1 chloroform / acetone) and recrystallized from ethanol to give 2-acetamido-9- (2-acetyloxy-L-hexon-1-yl) hypoxanthine (0.14 g), m.p. 204.5 ° C ..

Ex. 1 to d 4

2-Amino-9- (2-hydroxyethoxymethyl) adenine

a) 2-Formamldoadenine (89.0 g) was added. add to a 5 liter flask,. equipped with an air mixer and a reflux condenser (calcium chloride drying tube) to which it is added. acetic anhydride (4 liters). The mixture was refluxed for 60 hours. At the end of this time, the excess acetic anhydride is removed by distillation at atmospheric pressure while distillation. until about 3.5 liters of distillate is obtained. It is then further distilled under reduced pressure to remove most of the acetic anhydride. Dark brown residue. after cooling to room temperature. to a viscous gum, dissolved in dichloromethane, filtered to remove any suspended solids, and then the solvent was removed in vacuo to give 211.0 g (&gt; 100 percent) 2,6-bis- (diacetylamino) -9- acetylpurine. The yield obtained is 95.7% and is reduced to the calculated yield, the remainder being acetic anhydride.

b) penta-Acetylpurine (174 g) was mixed with. 1,4-diacetoxy-2-oxabutane (126.8 g) in a flask equipped with an air stirrer and drying tube. The mixture was then placed in a 130 ° C oil bath. Stir for several minutes to homogenize. Then para-fluorenesulfone was added in one portion. acid (2.74 g) as a catalyst and heating is continued under vacuum for 4 hours; . after this time, an almost quantitative observation was observed. conversion to the prepared product. The reaction mixture was then cooled to room temperature and stored. se pod. dry nitrogen.

c). The molten product (208.5 g) was dissolved in ethanol (5 ml / g) at grease temperature and transferred to a flask equipped with a dropping funnel, an air stirrer and a thermometer; rem. T-Butylamine is then added dropwise over two hours. (140.4 g) and the exothermic reaction is controlled using a water bath. The maximum temperature allowed in the reaction is only 30 ° C. During . dropwise the product began to separate from the reaction mixture. Mon. After the dropwise addition, the mixture was stirred at room temperature for three hours and then. on. place the night in a cool room. The product was collected by filtration as. a pasty mass which is suspended in acetone (1 X 500 mL). and filtered again. Dry under vacuum at temperature. 65 degrees Celsius for three. hours and then at room temperature overnight to yield

The product was then purified by dissolving it in hot dimethylformamide (10 ml / g) at a temperature of 100-110 ° C to an opaque brown solution. overnight at 5 ° C, the product was filtered off, washed with acetone (1 x 250 mL) and air dried to give 121.7 g (78.8%) of 2,6-diacetamido- 9- (2-acetoxyethoxyethoxy) purine.

d) 2,6-Diacetamido-9- (2-acetoxyethoxymethyl) purine (121.7 g) was added to a stirred solution of aqueous methylamine (608.5 mL of a 40% solution) over five. minutes. The addition is associated with a slight heat evolution, thereby raising the temperature of the mixture to 35 ° C and all the solid being in several. minutes dissolve. Stir for two and a half hours; At this time, the mixture reacts perfectly. Concentrate the mixture in a water bath bag at 45-50 ° C to form. A dense mass of brown crystals is obtained. The mass was suspended in acetone (545 mL, 7 mL / g) for 15 minutes to 'remove'. N-methylacetamide and vacuum filtered. Rinse the filter cake with acetone (1 X 200 ml) and air dry. to yield 74.7 g (96.0 percent) of crude, hydrated 2-amino-9- (2-hydroxyethoxymethyl) adenium as brown crystals. Crystals. is dried under vacuum at 80 ° C. Mon 18 hours to give 69.3 g (89.0%) of dry product, mp 183-184 ° C.

188384

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pRedmet vynalezu

Claims (5)

1. A process for the preparation of substituted purines of formula (I): R * C-jio-CU _£ CH-OH (I) wherein R is amino or hydroxyl, "characterized in that. At this moment . base hydrolyzes a compound of formula II wherein R 1 is hydroxy or a group of the formula —NR2 —C — X1 II. O X 1 and X ² have the same or different meanings and each represents a C 1 -C 4 alkyl group or a phenyl group, R2 represents a hydrogen atom or a group of the formula —C # Provided that when R 1 is hydroxy, R ² is hydrogen. 2. The method of item. 1, characterized in that in the presence of a base, a compound of formula (II) in which X 1 and χ 2 is a methyl group and R ¹ and R 2 are as defined in point 1 is hydrolyzed. 3. A process as claimed in claim 1, wherein the base used is an aqueous or alcoholic primary or secondary aliphatic amine, an alkoxide in the alcohol or an aqueous or alcoholic hydroxide. 4. A method according to claim 1 · · for the preparation of substituted purines of formula I wherein R is OH, characterized · in that in the presence of base hydrolyzing a compound of formula II wherein Ri is hydroxy, R2 is hydrogen and X 1 and X ² are same or different and each represents a C 1 -C 4 alkyl group or a phenyl group. 5. The process of item 1 for preparing substituted. purines of formula I, where R 'represents hydroxy, · characterized in that in the presence of a base · hydrolyzing a compound of formula II wherein R1 is hydroxy and R2 atom- atom and X1 · ^X2 are each a methyl group.