METHODE DE PREPARATION DE 1,8-DIHYDROXY-10-ACYL-9- ANTHRONES, PRINCIPALEMENT POUR LE TRAITEMENT DU PSORIASIS

METHOD FOR THE PREPARATION OF 1,8-DIHYDROXY-10-ACYL-9- ANTHRONES, ESPECIALLY FOR USE IN THE TREATMENT OF PSORIASIS

Abrégé anglais

ABSTRACT OF THE DISCLOSURE:
The invention relates to a method for the
preparation of 1,8-dihydroxy-10-acyl-9-anthrone, especially
for use in the treatment of psoriasis, having the formula
< IMG >
where R is an alkyl group having 2-4 carbon atoms, by using
as the initial material 1,8-dihydroxy-9-anthrone and an acid
chloride having the formula RCOC1, where R represents the same
as above. In accordance with the invention, harmful benzene
can be replaced with, for example toluene; this replacing is
possible because pyridine is replaced with 2,6-dimethyl
pyridine.

Revendications

The embodiments of the invention in which an
exclusive property or privilege is claimed are defined as
follows:
1. A method for the preparation of 1,8-dihydroxy-
10-acyl-9-anthrone having the formula
< IMG >
where R is an alkyl group having 2 to 4 carbon atoms,
wherein 1,8-dihydroxy-9-anthrone having the formula
< IMG >
is reacted with an acid chloride having the formula < IMG >
where R is as defined above, in the presence of a solvent
characterized in that the reaction is carried out in the
presence of 2,6-dimethyl pyridine.
2. A method according to claim 1, characterized
in that the solvent is selected from the group consisting of
toluene, xylene and chlorinated hydrocarbons.
3. A method according to claim 2, wherein the
chlorinated hydrocarbons are selected from the group consist-
ing of dichloromethane and tetrachloroethane.
4. A method according to claim 1, characterized
in that the acid chloride is used in an excess of 100 %.
5. A method according to claim 1, characterized
in that the reaction temperature is -10 to +20°C, the acid

chloride is added in the course of two hours, and the
stirring is continued for a further two hours.

Description

The present invention relates to a methGd for
the preparation of 1,8-dihydroxy-10-acyl-9-anthrones,
especially for use in the treatment of psoriasis.
1,8-Dih~droxy-9-anthrones substituted in the 10-
S position have been used for a Eew years to replace dithranol,
which has been known since 1916 and used for the treatment
of psoriasis, and which strongly stains the skin and clothing
in addition to strongly inflaming the skin.
The structural formula of 1,8-dihydroxy-10-acyl-
9-anthrones is as follows:
HO O OH
1~ ~
CO-R
where R is an alkyl group having from 2 to 4 carbon atoms.
Finnish Patent FI 57743 discloses a method for
preparing these compounds, which method consists in causing
anthraline to react in boiling benzene with an acid chloride
in the presence of pyridine. In this method, the acid
chloride is used in an excess of 20%. The reaction mixture
is boiled using return condensation for 10 hours, and the
product is crystallized out from acetic acid. The yield
in the method in question is, for example, only 25.5% of the
theoretical.
The object of the present invention is to provide
an improved method for the preparation of these compounds,
which method has considerable advantages. By way of example,
this new method can be carried out at a reaction temperature
which is as low as -10C. In any case, it makes it possible
to use very low reaction temperatures, for example room
temperature. In addition, this new method makes it possible
to avoid using benzene, which is
,~ - 1 -

~2~ 3
strongly carcinogenic, and to use, for example, toluene,
which is less harmful. Furthermore, the yield can be
incxeased to 2- to 3-fold as compared with the method of
Finnish Patent FI 57743.
The present invention provides a method for the
preparation of l,8-dihydroxy-10-acyl-9-anthrone, especially
for use in the treatment of psoriasis, having the formula
lo ~$
co ~
where R is an alkyl group having 2 to 4 carbon atoms, wherein
1,8-dihydroxy-9-anthrone having the formula
HO O OH
~ O
is reacted with an acid chloride having the formula RCCl,
where R is as defined above, in the presence of a solvent
characterized in that the reaction is carried out in the
presence of 2,6-dimethyl pyridine.
The invention is based on the observation that the
replacement of pyridine with 2,6-dimethyl pyridine makes it
possible to lower the reaction temperature, to use toluene,
xylene or chlorinated hydrocarbons such as dichloromethane
or tetrachloroethene instead o~ benzene, and even to triple
the yield as compared with the known method. If, urther-
more, the acid chloride is used in an excess of 100 ~, thereaction can be completed in two hours.
From the above-mentioned low reaction temperature,
which can be for example ~10C to +20C, it follows that the
amount of impurities passing into the completed 1~8-dihydroxy-
- 2 -

1~ 29~3
10-acyl-9-anthrone is small. Thus the purification is a
simple procedure compared with the respective procedure in
the known method. Acetonitrile or 2-propanol are suitable
for use as the recrystallization solvent along with or
instead of acetic acid.
The compounds prepared in accordance with the
invention can be used in, for example, vaseline- or paraffin-
based skin creams in concentrations of 0.5 - 5 %, in sticks
intended for skin care in concentrations of, for example,
2 - 8 %, and in gels and in film-forming solutions.
The following examples illustrate the invention in
greater detail.
Examp~ 1
Butyryl chloride in an amount of 207 ml (213 g,
2.0 mol) was added in the course of 2 hours at a temperature
below 0C to a mixture which contained 2500 ml toluene, 226 g
(1.0 mol) 1,8-dihydroxy-9-anthrone and 232 ml (214 g, 2.0 mol3
2,6-dimethyl pyridine.
The mixture was stirred at a temperature below 0C
for a further two hours after the addition.
The mixture was thereafter heated to +40C, the
hydrochloride of the 2j6-dimethyl pyridine was filtered off,
and most of the toluene was evaporated at lowered pressure.
2300 ml isopropanol was added to the residue, the mixture
was cooled to -10C, and the precipitate was recovered by
filtration. Recrystallization was carried out from aceto-
nitrile, whereby a yield of 222 g 1,8-dihydroxy-10-butyryl-9-
anthrone was obtained. This was 75 % of the theoretical.
Example 2
39 The procedure was fully analogous to that in
Example 1, except that xylene was used instead of toluene.
The yield was the same as in Example 17 i.e. 75 %.
Example 3
Propionyl chloride in an amount of 86.9 ml (92.5 g,

:~2~L~943
1 mol) was added in the course of about 2 hours at a
temperature below 0C to a mixture which contained 1200 ml
toluene, 113 g ~0.5 mol) 1,8-dihydroxy-9-anthrone and 116 ml
(107 g, 1 mol) 2,6-dimethyl pyridine. Stirring was continued
for a further two hours after the addition.
The 1,8-dihydroxy 10-propionyl-9-anthrone obtained
as the result was separated by the procedure presented in
Example 1. The yield was (120 g3 82 % of the theoretical.
Exa~ple 4
Starting from 1~8-dihydroxy-9-anthrone and valeryl
chloride and using valeryl chloride in an excess of 100 %
and by proceeding otherwise as in Example 1, 1,8-dihydroxy-
10-valeryl-9-anthrone was obtained as the result, the yield
being 53 %.
Example 5
Pharmaceutical compositions were prepared by using
the following constituents and amounts:
liquid paraffin 40 - 60 ~
solid paraffin 40 - 60 %
microcrystalline wax 0~5 - 5 %
In addition, about 2 - 8 % 1,8-dihydroxy-10-butyryl-
9-anthrone was mixed with the carrier composition presented
above. Sticks intended for skin care were molded ~rom the
mixture, and it was observed that the use properties of the
sticks were good and, furthermore, the medication in the
sticks remained unchanged, specifically unoxidized.