FI66585B - FOERFARANDE FOER FRAMSTAELLNING AV SAERSKILT VID BEHANDLING AVSORIASIS ANVAENDBARA 1,8-DIHYDROXI-10-ACYL-9-ANTRONER - Google Patents

Description

1 66585

The present invention relates to a process for the preparation of 1,1'-dihydroxy-10-acyl-59-anthrones. 10-Substituted 1,8-dihydroxy-9-anthrons have been used for several years to replace ditranol, which has been known since 1916 for the treatment of psoriasis and is a strong skin and clothing dye and highly inflamed skin.

The structural formula of 1,8-dihydroxy-10-acyl-9-anthrone is as follows:

CO-R

20 wherein R is an alkyl group having 2 to 4 carbon atoms. The compounds have been prepared according to Finnish patent publication FI 57743 by reacting anthralin in boiling Bentene with an acid chloride, in which case pyridine is also present. An excess of 20% of acid chloride is used. The reaction mixture is refluxed for 10 hours and the product is crystallized from acetic acid. The yield in the method in question is, for example, only 25.5% of theory.

It is an object of the present invention to provide a method by which considerable advantages can be obtained. The reaction temperature can be reduced to as low as -10 ° C, and in any case, rather low reaction temperatures, for example room temperature, can be used. In addition, highly carcinogenic benzene can be avoided and less harmful toluene, for example, can be used. The yield is further increased 2-3 times compared to the method of the Finnish patent FI 57743.

2 66585

The above advantages are achieved by a method, the characteristic features of which are given in the appended claim 1.

The invention is based on the fact that the replacement of pyridine with 2,6-dimethylpyridine makes it possible to lower the reaction temperature, to use toluene, xylene or chlorinated hydrocarbons such as dichloromethane or tetrachlorethylene instead of benzene and to even triple the yield compared to the known process. In addition, if 100% excess of acid chloride is used, the reaction is completed in two hours.

It follows from the above-mentioned low reaction temperature, which may be, for example, -10 ° C to + 20 ° C, that the amount of impurities entering the finished 1,8-dihydroxy-10-acyl-9-anthrone is small. Thus, the purification is a simple operation as compared with the corresponding operation of the known method. Suitable recrystallization solvents are acetonitrile or 2-propanol in addition to or instead of acetic acid.

The compounds according to the invention can be used, for example, in petrolatum or paraffin-based skin creams in concentrations of 0.5 to 5% sn, in skin care needles, for example in concentrations of 2 to Θ%, and in gels and film-forming solutions.

The following examples illustrate the invention in more detail.

30

Example 1

To a mixture of 2500 ml of toluene, 225 g (1.0 mol) of 1,2-dihydroxy-9-anthrone and 232 ml (214 g, 2.0 mol) of 2,6-dimethylpyridine were added below 0 ° C. 3,66585 207 mL (213 g, 2.0 mol) of butyric chloride over 2 hours. The mixture was stirred at a temperature below 0 ° C after the addition for a further two hours.

The mixture was then warmed to + 40 ° C, the 2,6-dimethylpyridine hydrochloride was filtered off and most of the toluene was evaporated off under reduced pressure. 2300 ml of isopropanol were added to the residue, the mixture was cooled to -10 ° C and the precipitate was collected by filtration. Recrystallization from acetonitrile was carried out to give 222 g of 1,8-dihydroxy-10-butyryl-9-anthrone. This was 75% of theory.

Example 2 15

The procedure was completely analogous to Example 1, but xylene was used instead of toluene. The yield was the same as in Example 1, i.e. 75%.

20 Example 3

To a mixture of 1200 mL of toluene, 113 g (0.5 mol) of 1,8-dihydroxy-9-anthrone and 116 mL (107 g, 1 mol) of 2,6-dimethylpyridine was added below 0 ° C over about 2 hours 86 , 9 mL (92.5 g, 1 mol) of propionyl chloride.

Stirring was continued for another two hours after the addition.

Separation of the resulting 1,2β-dihydroxy-10-propionyl-9-anthrone 30 was performed as described in Example 1. The yield (120 g) was 82% of theory.

Example 4 Starting from 1,8-dihydroxy-9-anthrone and valeryl chloride and using 100% excess valeryl chloride, and proceeding otherwise as in Example 1, 1,8-dihydroxy-10-valeryl-9-anthrone was obtained in 53% yield. .

Claims (3)

66585 A method of using 1,8-dihydroxy-10-acyl-9-anthrone of the formula 5 HO 0 OH, in particular for the treatment of psoriasis 10 COR wherein R is an aryl group having 2 to 4 carbon atoms, starting from 1,8-dihydroxy-9-anthrone of the formula 15 HO 0 OH [Q 2 ^ Jo] 2 O and an acid chloride of the formula RCOCl, wherein R is same as above, characterized in that the reaction is carried out in toluene, xylene or a chlorinated hydrocarbon at a temperature of -10 to + 20 ° C, in which case 2,6-dimethylpyridine is also used in the reaction mixture. Process according to Claim 1, characterized in that a 100% excess of acid chloride is used. Process according to Claim 1, characterized in that the acid chloride is added over a period of two hours and the stirring is continued for a further two hours.