CH634843A5 - Process for the preparation of substituted purine derivatives. - Google Patents

Description

The invention relates to a process for the preparation of the 9- (2-hydroxyethoxymethyl) derivatives of the purines 2-amino-adenine and guanine. 20 The 9- (2-hydroxyethoxymethyl) derivatives of the purines show an activity against viruses, in particular against the classes of the DNA and RNA viruses, in both in vitro and in vivo experiments. In particular, these compounds act against the adenovirus, for example against 2s, the adenovirus 5 and the rhinovirus. They are particularly effective against cowpox and herpes viruses, including against herpes simplex, herpes zoster and chickenpox viruses in mammals, which cause diseases such as keratitis herpetica in rabbits and Encepha-30 litis herpetica in mice.

Examples of 9- (2-hydroxyethoxymethyl) derivatives of the purines which show a particularly good activity against viruses are 9- (2-hydroxyethoxymethyl) guanine and 2-amino-9- (2-hydroxyethoxymethyl) adenine. 35 A whole series of production processes for the 9- (2-hydroxyethoxymethyl) derivatives of purine are already known. For example, they can be made by removing a protecting group from the 2-position in the side chain. On the other hand, they can be prepared by converting the 40 2- and / or 6-substituent on the purine ring into another substituent (see main patent).

It has now been found that some 9- (2-hydroxy-ethoxymethyl) derivatives of the purines can be prepared in a new and advantageous synthetic way. 45 The process according to the invention for the preparation of the purine derivatives of the formula I

O

mean, provided that R2 means hydrogen, if R1 means hydroxy, hydrolyzes.

2. The method according to claim 1, characterized in that hydrolyzing a compound of formula II, wherein X1 and X2 are alkyl groups having 1 to 4 carbon atoms.

3. Process according to claims 1 or 2, characterized in that a compound of formula II, wherein X1 and X2 are the same and each represents a methyl group, is hydrolyzed.

4. The method according to any one of claims 1 to 3, characterized in that the base used is a primary or secondary aliphatic amine in aqueous or alcoholic solution, an alkoxide in alcoholic solution or a hydroxide in aqueous or alcoholic solution.

5. Application of the method according to claim 1 to compounds of formula II, which are prepared by the guanine or 2-aminoadenine, wherein the 2- and

>

ch2.o.ch2.ch2.oh where R is amino or hydroxy is characterized in that in the presence of a base a compound of formula II

55

n

N

H0N

n-

■ n

60

3rd

634 843

0

x -c-n r

(II)

0

ch20ch2ch2-0-c-x '

where R1 is hydroxy or - NR2.CX \

II

O

X1 and X-, which may be the same or different, each represent an alkyl or phenyl group, and R2 is hydrogen or

CX1,

II

O

mean, provided that R2 means hydrogen, when R 'means hydroxy, hydrolyzes.

If X1 and X2 are alkyl groups, they preferably have 1 to 4 carbon atoms, they are preferably the same and each represents a methyl group.

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

A compound of formula II, wherein R1 NR2CX '

II

O

and R2

CX1

O

mean can be completely hydrolyzed in one step, for example using aqueous methylamine. On the other hand, and even more preferred is the process in which the compound of formula II is deacylated in two steps. In the first step, a single

CX'-

II

O

Group from the 2 and 6 positions on the purine ring through mild

20th

30th

35

40

50

60

65

Hydrolysis can be removed at room temperature using, for example, butylamine in a lower alcohol. The second stage of hydrolysis, in which the rest

CX1-

O

Groups are to be removed, is usually carried out using a stronger base, such as aqueous methylamine.

The starting materials of Formula II are new. According to the invention, these compounds are reacted with guanine or 2-aminoadenin, in which the 2- and 9-, or the 2-, 6- and 9-positions are acylated, with a diester of 2-oxa-1,4-butanedioI in the presence a catalytic amount of a strong acid such as sulfuric acid, sulfonic acids such as p-toluenesulfonic acid, methane sulfonic 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, for example, acetic anhydride, or other acylating agents, such as, for example, an acid halide.

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

The preparation of the starting materials and exemplary embodiments of the invention are described in more detail below with the aid of the examples:

Example 1 9- (2-Hydroxyethoxymethyl) guanine To a mixture of 102 g of acetic anhydride, 15 g of acetic acid and 5.0 g of p-toluenesulfonic acid, which had cooled to 10 ° C., 70 g of dioxolane were added with stirring and cooled in such a way that the temperature of the vessel never rose above 40 ° C. The mixture was cooled to room temperature and 300 ml of toluene and 50 g of diacetylguanine were added. The reaction mixture was then heated at reflux temperature with stirring for 16 hours. The mixture was then cooled to room temperature, 50 ml of chloroform were added and the solid product was removed by filtration. The filter cake was carefully washed out with chloroform and dried. The dried filter cake was added to 350 ml of 40% aqueous methylamine and the mixture was heated at reflux temperature with stirring for 40 minutes, then cooled and filtered. The filtrate was evaporated to a thick slurry under reduced pressure. The slurry was cooled and filtered and the filter cake washed with ethanol and dried. The result was 27 g of 9- (2-hydroxyethoxy-methyl) guanine (more than 90% pure), melting point 255 to 257 ° C.

Example 2 9- (2-Hydroxyethoxymethyl) guanine A mixture of 50 g diacetylguanine, 59.8 g 2-oxa-1,4-butanediol diacetate and 1.2 g p-toluenesulfonic acid in 350 ml toluene became 16 with stirring at the reflux temperature Heated for hours. The mixture was cooled to room temperature, filtered and the filter cake was washed thoroughly with toluene. The filter cake was dried and added to 350 ml of 40% aqueous methylamine. The mixture was stirred at reflux temperature

634 843

4th

Heated for 40 minutes, cooled to room temperature and filtered. The filtrate was evaporated to a thick slurry under reduced pressure. 200 ml of ethanol was then added to the slurry, which was then cooled, filtered and washed with ethanol and dried. 36 g of 9- (2-hydroxyethoxy-methyljguanine (more than 90% pure) resulted.

Example 3

2-Acetamido-9- (2-acetyloxyethoxymethyl) hypoxanthine A mixture of 1.0 g diacetylguanine, 0.82 g 2-oxa-1,4-butanediol diacetate and 23 mg p-toluenesulfonic acid in 4 g mineral oil was added with stirring reduced pressure heated to 115 ° C overnight. The mineral oil was then poured off. The residue was triturated with chloroform and then extracted with boiling methanol. The methanol extract was concentrated to 50 ml, quenched and filtered. The filtrate was evaporated to dryness to give 0.43 g of a solid residue. The solid was purified by column chromatography (10 g of silica gel in chloroform, eul with chloroform: acetone (1: 1)), and then recrystallized from ethanol. 0.14 g of 2-acetamido-9- (2-acetyloxyethoxymethyl) hypoxanthine resulted, melting point 202.5 to 204.5 ° C.

Example 4

2-Amino-9- (2-hydroxyethoxymethyl) adenine a) 89.0 g of 2-formamido-adenine were placed in a 5 liter flask which was equipped with a hollow stirrer (air-stirrer) and with a reflux condenser and a CaCh- Drying tube was provided, and 41 acetic anhydride were added. The mixture was brought to reflux temperature and held there for 60 hours. At the end of this time, excess anhydride was stirred by temperature for 3 hours and then left in a cold room overnight. The product was removed by filtration to give a creamy mass which was slurried with 500 ml of acetone once and filtered again. Then it was dried in vacuo at 65 ° C for 3 hours and then at room temperature overnight and gave 154.2 g (91.7%) of a light brown, hard solid. The product was purified by dissolving in 10 ml / g of hot dimethylformamide at 100 to 110 ° C and gave an opaque brown solution. After cooling overnight at 5 ° C., the reaction product was separated off by filtration, washed out once with 250 ml of acetone and air-dried. The result was 121.7 g (78.8%) of 2,6-diacetamido-9- (2-acetoxyethoxymethyl) purine.

Is d) This 121.7 g2,6-diacetamido-9- (2-acetoxyethoxy-methyl) purine was added to a stirred solution of 608.5 ml of a 40% aqueous methylamine solution over a period of 5 minutes. The addition was accompanied by a weakly exothermic reaction which raised the temperature of the mixture to 35 ° C. All solids were dissolved within a few minutes. After stirring for 2.5 hours, thin layer chromatography of the mixture indicated the completion of the reaction. The mixture was then concentrated in vacuo on a water bath at 45 to 50 ° C and gave a thick mass of brown crystals. This was then slurried with 545 ml (7 ml / g) for 15 minutes to remove the N-methylacetamide and then filtered in vacuo. The filter cake was washed once with 200 ml of acetone and air-dried to give 74.7 g (96.0%) of crude hydrated 2-amino-9- (2-hydroxyethoxymethyl) adenine as light brown crystals. These were dried in vacuo at 80 ° C for 18 hours and gave 69.3 g (89.0%) of dry product.

B

Claims (3)

634843 2nd PATENT CLAIMS 1. Process for the preparation of purine derivatives of the formula I (I) 0 X -C-N (ii) 0 9-, or the 2-, 6- and 9-position are acylated, with a diester of 2-oxa-1,4-butanediol in the presence of a catalytic amount of a strong acid. 6. Application according to claim 5 of the method; one of claims 2 to 4. 7. Use according to claim 5 or 6, characterized in that p-toluenesulfonic acid is used as the acid catalyst. o.chn.ch “.oh in which R denotes amino or hydroxy, characterized in that a compound of the formula II ch2och2ch? ro-c-x2 wherein R1 Hydroxy or - NR2.C.X! ; ii O X1 and X2, which may be the same or different, each represent an alkyl or phenyl group; and R2 is hydrogen or -CX1