FI56371C - FREQUENCY REQUIREMENT FOR THERAPEUTIC USE OF THERAPEUTIC BENSOYLESTRAR AV 1,8,9-TRIHYDROXIANTRACEN - Google Patents

Description

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Patent · och ragitt «r« tyralten Anaekan uttagd eeh utl.akrffUn published 28.09.79 (32) (33) (31) Pyydetty «Tuoikeui — Bajlrd prlorltut 26.11.71

England-England (GB) 54927/71 (71) Sterwin AG, Zeughausgasse 9 * Zug, Switzerland-Switzerland (CH) (72) Andrew Robertson, West Danton, Newcastle-upon-Tyne, England-England (GB) (74) Oy Kolster Ab (54) The present invention relates to a process for the preparation of therapeutically useful 1,8,9-trihydroxyanthracene benzoyl esters. with a general formula

R R R

* t t 0 0 0

T1 (i) which compounds may also exist as 9-anthrone tautomers, wherein each R is independently hydrogen or a Χ, Υ-substituted benzoyl group, wherein at least one of the symbols R is a Χ, Υ-substituted benzoyl group, X and Y represent 2,563? 1 is independently a chlorine atom, a hydroxy, nitromethyl, methoxy or acetoxy group, and Y may further represent hydrogen, and R 1 is a hydrogen atom or a methyl group. The 1,8,9-trihydroxyanthracene derivatives prepared according to the invention are novel compounds and can be used in human or veterinary medicine.

The process according to the invention is characterized in that the corresponding 1,8,9 ° trihydroxyanthracene is reacted with a substituted benzoic acid chloride of the formula CO 2 (II) in the presence of a catalyst in an inert solvent, an inert gas.

1,8,9-trihydroxyanthracene, known in its tautomeric form as .1,8-dihydroxy-9-anthrone - known as ditranol (see the British Pharmaceutical. Codex, 1968), has for many years been one of the most successful drugs in the treatment of dermatological conditions such as dandruff, as well as the related substance 1,8,9-trihydroxy-3-methyl-anthracene (commonly known as "chrysarobin" described in the Merck Index for 1,8,9-trihydroxy-3-methyl-anthracene and its tautomer, 1,8-dihydro -roxy-3-methyl-9-anthrone). Unfortunately, however, the use of ditranol or kry-sarobin has a number of very serious disadvantages, not the least of which is that both can cause severe patching and irritation of the skin. It has now been found that certain ester derivatives of these compounds have no or very little such coloring and irritating properties, although the desired pharmaceutical activity remains.

The esters of formula I may be mono-, di- or tri (substituted-benzoyloxy) anthracenes and the anthracene moiety itself may have a methyl substituent in the 3-position. These esters may also exist as 9-anthrone tautomers.

Preferred compounds of general formula I are those in which each R represents a Χ, Υ-substituted benzoyl group and R 1 is a hydrogen atom, i.e. tribenzyl esters of ditranol. The X and Y substituents may be at any position on the phenyl ring of the benzoyl group.

The process according to the invention is a conventional process for the esterification of phenols.

When preparing the triester, the benzoyl chloride starting material is preferably used in excess of the 3 stoichiometrically required molar equivalents; at least 1.25 times the required amount, ie 3 * 75 molar equivalents, is required, and a little more is used (to take into account the amount spent on side reactions). When preparing a mono- or diester, benzoyl chloride should be used in approximately the amount required stoichiometrically - i. about one or two molar equivalents as needed. In these cases, the formation of product mixtures (unreacted starting material, monoester, diester and triester) cannot be avoided, and the various compounds can be separated by conventional separation methods (e.g., chromatographic methods). The preferred preparation method uses about 2 molar equivalents of benzoyl chloride, and the mono diesters formed are separated from the resulting reaction mixture.

The inert solvent may be an aromatic hydrocarbon, for example benzene, toluene or xylene (preferably the latter two are used), or it may be an alkyl fatty acid ester, for example ethyl acetate or (preferably) isopropyl acetate.

The basic catalyst is preferably medium strong. Nitrogen bases are generally suitable, especially heterocyclic compounds (such as pyridine) and tertiary amines (such as trimethylamine or triethylamine).

The reaction must be carried out in an inert atmosphere to prevent the formation of oxidation by-products. A suitable atmosphere is nitrogen, although other inert gases such as argon may be used.

The rate of the reaction depends, of course, on the temperature. The reaction is preferably carried out at 15-60 ° C, below this temperature the reaction is very slow, while at higher temperatures there are more side reactions which affect the purity of the product.

Certain substituted benzoyloxy derivatives can be converted to other substituted benzoyloxy derivatives by further reactions. For example, 1,8,9-tri (2-methoxy-benzoyloxy) anthracene can be dealkylated to give 1,8,9-tri (2-hydroxybenzoyloxy) anthracene. The advantage of this preparation method is that the intermediate, the 2-methoxy compound, is easily crystallized and recrystallized (and can thus be purified relatively easily), whereby a purer 2-hydroxy compound can be obtained as a final product.

The benzoyl chloride reagent used must be as pure as possible. Impurities cause side reactions which result in a very impure product. A particularly harmful impurity is thionyl chloride (used in the preparation of benzoyl chloride), which forms complexes with a basic catalyst.

k 56371

The product obtained by the process of the invention can generally be isolated from the reaction mixture and purified by conventional methods. For isolation and purification, crystallization from a suitable solvent or precipitation from solution using petroleum ether or another hydrocarbon such as n-hexane can be used. A suitable crystallization solvent is a mixture of toluene and dimethylformamide (90:10 to 50:50 ratios are suitable), and suitable solvents for the precipitation separation are either aliphatic esters (such as isopropyl acetate) or arenes (such as benzene, toluene or xylene).

The anthracene derivatives prepared according to the invention can be used for the treatment of inflammatory conditions of the skin, especially in the treatment of dandruff.

Experimental Results 1) Cream and paste preparations containing either ditranol or triacetoxybenzoylditranol were prepared. The preparations each contained either 0% by weight of ditranol (w / w) or an equivalent amount of triacetoxybenzoyltitranol. A sample of each ointment and paste was applied to four fabrics, namely wool, nylon, cotton, and rayon, kept in daylight for 1 week. Each fabric was washed with detergent using the normal method.

Fabrics treated with ditranol had very many stains (brown color), whereas fabrics treated with triacetoxybenzoylditranol had virtually no stains.

The next experiment using trisalyloylditranol showed slightly more stain formation than acetoxybenzoylditranol, but the result was much better than with ditranol.

2) Clinical trials (comprising both pharmaceutical trials and staining trials)

Clinical trials were performed to determine pharmaceutical activity and tendency to stain or stain by comparing triacetoxybenzoyl-ditranol, hereinafter referred to as T.A.D., and ditranol.

Experimental Procedure

Twelve patients were used for the experiment. Each patient acted as their own observer by applying T.A.D. paste to one side and ditrano litita paste to the other side.

The experiments were performed on small areas of psoriasis on both sides of the patient, and the T.A.D. paste and control substance were lubricated on the inflamed area, while the surrounding normal skin was protected with zinc paste. The results from both sides were compared at the end of the experiment and during the experiment, and evaluated using an effect scale showing "healing" (therapeutic effect), skin irritation, and skin discoloration.

It should also be noted that two patients were discontinued after one week due to severe irritation due to ditranol, whereas one patient was discontinued after one week of recovery, and 5 56371 patients were discontinued three weeks after recovery, and one patient was discontinued after two weeks of recovery. due to vesicular rash. The results of the experiments showed the following: 1) T.A.D paste is an effective preparation for the treatment of psoriasis.

2) T.A.D. has a therapeutic effect that lasts, compared to ditranol.

3) The effect of T.A.D. starts slightly slower than that of ditranol.

1+) Staining or stain formation is hardly observed at all when using T.A.D. paste.

5) Patients are very happy to receive T.A.D. paste due to its non-coloring as well as cosmetic properties.

The compounds according to the invention are used as pharmaceutical preparations which may contain 0.05 to 10%, in particular 0.1 to 10% by weight, of the active anthracene derivative.

Preparations for external use are preferably in the form of a paste or ointment and may also contain other active ingredients which are important in the external treatment of skin diseases.

The following examples illustrate the invention. The 1,8,9-trihydroxyanthracenes used in these examples were in fact mostly in the 1,8-dihydroxy-9-anthrone tautomeric form.

Example 1 Preparation of 1.8.9-tri (2-acetoxy-benzoyloxy) anthracene 1.8.9-Trihydroxyanthracene (113 g), triethylamine (151-5 g) and isopropyl acetate (1 liter) were stirred together at room temperature under nitrogen. 2-Acetoxybenzoyl chloride (1 + 00 g) was added dropwise over 1 + 5 minutes, and the mixture was stirred for another 30 minutes and then filtered. The filtrate was slowly added with vigorous stirring to petroleum ether (b.p. U0 ° / 60 ° C, 8 liters) and the precipitated solid was washed well with petroleum ether (b.p. 1 + 0 ° / 60 ° C) and then dissolved in boiling isopropyl acetate (1 liter). The solution was clarified (with charcoal, filtered through a pad of Celite 2, allowed to cool, the cold solution filtered and added slowly with vigorous stirring to petroleum ether (b.p. 1 + 0 ° / 60 ° C, 8 liters). g) was treated a second time in the same manner to give 1,8,9-tri (2-acetoxy-benzoyloxy) -anthracene (158 g, 1 + 1 +%), mp 105-120 ° C (dec.).

The following details are important for good yields.

1. Precipitation must be done slowly to avoid the formation of oily lumps.

2. The precipitated solid must be washed well with petroleum ether (b.p. i + 0 ° / 60 ° C) to prevent spontaneous decomposition.

3. It is important to add the precipitated solid to boiling isopropyl acetate to prevent tar formation.

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Example 2 Preparation of 1,8,9-tri (2-acetoxybenzoyloxy) anthracene 1,8,9-Trihydroxyanthracene (120 g) was heated in xylene (1200 g) and pyridine (300 g) for 10 minutes at 60 ° C under a continuous stream of nitrogen. 675 g of 2-acetoxybenzoyl chloride (acetylsalicyloyl chloride) were added dropwise over 15 minutes with vigorous stirring, maintaining the temperature at 60 ° C throughout. The mixture was allowed to stand for 10 minutes at 60 ° C, the dark green solution was poured into a large excess of petroleum ether (5 liters, b.p. i + 0/60 ° C) with rapid stirring, whereupon a yellow-green solid precipitated.

The precipitate was washed well with diethyl ether and dried at room temperature to give 320 g of crude product (85% yield) which decomposed above 15 ° C.

The crude product was added in 50 g portions to boiling xylene (300 mL) and activated carbon. The solution was filtered through a pad of diatomaceous earth (Celite '-' ') to give a dark yellow solution; this was added cold to petroleum ether (500 ml, b.p. It0 ° / 60 ° C). Filtration gave the purified product as a pale yellow amorphous solid (30 g - 60% yield) which decomposed at 152 ° C. The overall production yield was 50%.

The product was characterized by the following methods: 1. Microanalysis Clt1H2Ö ° 12 = ^ 12

Calculated: C JS 69.10 H ^ 3.95

Obtained 69.25 U, 10 2. Mass spectrometry

The molecular ion was found to be M = 712 3. Chromatography

Thin layer chromatography using different solvent systems (chloroform / methanol - 90/10; toluene; and ethyl acetate / ethanol - 75/25) showed the product to be a single substance.

k. Infrared spectrum (KBr tablet) 1750 cm-C = O (from aromatic ester and acetylated phenol) 1610 cm-C = C (aromatic) 1370 cm-CH (from acetyl-C-CH) _ 1 * 12 ^ 5 cm - C-0 (from aromatic ester) 1200 cm - C-0 (from acetylated phenol) 5 · NMR spectrum (deuterochloroform)

Tau values were: 7.0-7.7 (9H, s, 3 x COCH 2) 3, -1-1 (19H, m, aromatic) 7 56371

The following details are important to achieve high yields.

a) Acetylsalicylyl chloride (2-acetoxybenzoyl chloride) was obtained by reacting acetylsalicylic acid (2-acetoxybenzoic acid) and thionyl chloride in chloroform in the presence of aluminum chloride. It was found essential that this product was completely purified (in vacuo) to remove all thionyl chloride (which forms a complex with pyridine, causing a large decrease in yield).

b) The reaction was carried out under a nitrogen atmosphere to prevent the formation of a purple oxidation product which decomposed on standing.

c) The reaction product had to be treated immediately.

d) During the initial reaction and subsequent precipitation, vigorous stirring was essential to prevent the formation of difficult-to-handle tar.

e) Thorough washing of the precipitated material with diethyl ether was essential to remove pyridine and / or xylene and prevent tar formation.

Note The determination of the melting point of this compound is not of great importance because the product begins to disperse well below the melting point and it was generally found that the higher the dose, the wider the dispersion / melting range of the product.

Example 3 Preparation of 1,8,9-tri (2-hydroxy-benzoyloxy) anthracene 1,8,9-trihydroxyanthracene (72 g) was suspended in toluene (800 ml) and the mixture was heated to 50 ° C under nitrogen while pyridine ( 180 ml). After the phenol was dissolved, the temperature was lowered to 30 ° C, and salicylyl chloride (200 g, 1+ equiv.) Was added dropwise to the mixture. The pyridinium salt (hydrochloride) precipitated immediately, the mixture was stirred for another 5 minutes and the pyridinium salt was filtered off.

The remaining toluene solution was slowly added to petroleum ether (9 liters, b.p. U0 ° / 60 ° C) to precipitate the crude ester product, the product was filtered and partially suction dried.

The crude ester was dissolved in toluene (500 mL), activated carbon was added, and the (R) mixture was filtered through a pad of diatomaceous earth (Celite®). The ester was reprecipitated by adding the solution to petroleum ether (9 liters, b.p. U0 ° / 60 ° C). Further precipitation from toluene (500 ml) or isopropyl acetate in petroleum ether (9 liters, b.p. 1 + 0 ° / 60 ° C) was necessary to obtain a purer product. The ester was collected and air-dried on filter paper.

8 56371

The purified product was a pale yellow amorphous solid (60 g, 32%), m.p. 107 ° -122 ° C (dec.).

Purification was best performed on a small scale (use of large amounts gave a dark green tar which gradually became a brittle green amorphous solid).

1. Microanalysis = 586

Calculated: C% 71.7 H% 3.8

Obtained: 71 Λ 3 »* + 2. Mass spectrometry With careful adjustment of the operating conditions, the molecular ion was identified as - = 586. e 3. Chromatography

Thin layer chromatography using different solvents (chloroform / methanol - 90/10; toluene; and ethyl acetate / ethanol - 75/25) showed the product to be pure.

h. Infrared spectrum (KBr tablet) 3250 cm 1 - OH (salicyloyl) 1750 cm - C = 0 (ester) 1610 cm - C = C (aromatic) 12U5 cm 1 - C-0 (ester) 750, 695 cm - CH (aromatic) The salicylyl chloride required in this synthesis was obtained by reacting salicylic acid and thionyl chloride in petroleum ether (b.p. 1 + 0 ° / 60 ° C) in the presence of pyridine (100% yield).

Example U

Preparation of 1.8.9-tri (U-chloro-benzoyloxy) anthracene 1.8.9-Trihydroxyanthracene (8 g), benzene (250 ml) and pyridine (2k g) were stirred together at room temperature under a stream of nitrogen until a clear solution was obtained. Lt-Chloro-benzoyl chloride (25 g) was added over 15 minutes, and the resulting solution was heated under reflux for 3 hours. The solvent was then removed under reduced pressure, ethanol (200 ml) was added, and the resulting pale yellow precipitate was heated in a refluxing vessel in ethanol (500 ml), filtered hot and the residue was washed with ethanol and dried. Crystallization from toluene / dimethylformamide (80/20) gave the ester as pale yellow needles (12.8 g, 56%) m.p. 311 + ° C (dec.).

9 S63s 1

Example 5 Preparation of 1,8,9-tri (3-chloro-benzoyloxy) anthracene This ester was prepared in the same manner as in the preparation of 1,8,9-tri (U-chloro-benzoyloxy) anthracene in Example U.

Crystallization from toluene / dimethylformaride (75/25) gave the ester as pale yellow needles (9 g>> 0%) m.p. 276 ° -277 ° 0.

Example 6 Preparation of 1.8.9-tri (2-chloro-benzoyloxy) anthracene This ester was prepared in the same manner as 1,8,9-tri (1 + -chlorobenzoyloxy) anthracene in Example U.

Crystallization from toluene / dimethylformamide (90/10) gave the ester as pale yellow needles (13 g, 57%) m.p. 272-273 ° C.

Example 7 Preparation of 1.8.9-tri (4-methyl-benzoyloxy) anthracene 1.8.9-Trihydroxyanthracene (8 g), benzene (250 ml) and pyridine (2k g) were stirred together at room temperature under a stream of nitrogen until a clear solution was obtained. U-Methyl-benzoyl chloride (25 g) was added over 1 minute and the solution was heated at reflux for 3 hours.

The solvent was then removed under reduced pressure, ethanol (200 ml) was added and the resulting pale yellow precipitate was heated to reflux in ethanol (500 ml), filtered hot and the residue was washed with ethanol and dried. Crystallization from toluene / dimethylformamide (90/10) gave the ester as pale yellow needles (3 g, 15%) m.p. 269 ° C (dec.).

Example 8 Preparation of 1,8,9-tri (3-methylbenzoyloxy) anthracene This ester was prepared in the same manner as 1,8,9-tri (U-methylbenzoyloxy) anthracene in Example 7 ·

Crystallization from toluene / dimethylformamide (80/20) gave the ester as pale yellow needles (13 g, 60%) m.p. 258-260 ° C.

Example 9 Preparation of 1.8.9-tri (L-nitro-benzoyloxy) anthracene 1.8.9-Trihydroxyanthracene (8 g), benzene (250 ml) and pyridine (2 g) were heated at reflux under a stream of nitrogen until a clear solution was obtained (ca. 5 minutes). Lt-Nitrobenzoyl chloride (25 g) was added over 10 minutes and refluxing was continued for a further 2 hours. The solvent was then removed under reduced pressure, ethanol (200 ml) was added and the resulting tan precipitate was heated to reflux with ethanol (500 ml), filtered hot and the residue washed with ethanol. Crystallization from dimethylformamide / toluene (50/50) gave the ester as straw-colored needles (1.5 g »6%) m.p. 165 ° C (dec.).

10 b S J / 1

Example 10 Preparation of 1,8,9-tri (3-nitro-benzoyloxy) anthracene 1,8,9-trihydroxyanthracene (8 g), benzene (250 ml) and pyridine (2h g) were heated at reflux under a stream of nitrogen until a clear solution was obtained ( about 5 minutes). 3-Nitrobenzoyl chloride (25 g) was added over 10 minutes and refluxing was continued for a further 6 hours.

The solvent was then removed under reduced pressure, ethanol (200 ml) was added and the resulting brown precipitate was heated to reflux in ethanol (500 ml), filtered hot and the residue washed with ethanol. Crystallization from toluene / dimethylformamide (90/10) gave the ester as a light brown amorphous solid (3.5 g, 11%) m.p. 265 ° C (dec.).

Example 11 Preparation of 1,8,9-tri (H-methoxy-benzoyloxy) anthracene 1.8.9-Trihydroxyanthracene (8 g), benzene (250 ml) and pyridine (2b g) were stirred together at room temperature under a stream of nitrogen until a clear solution was obtained. U-Methoxy-benzoyl chloride (25 g) was added over 5 minutes and the solution was heated at reflux for 3 hours. The solvent was then removed under reduced pressure, ethanol (200 ml) was added and the resulting pale yellow precipitate was heated in a reflux flask with ethanol (500 ml), filtered hot and the residue was washed with ethanol and dried. Crystallization from toluene / dimethylformamide (90/10) gave the ester as pale yellow needles (11 g, 50%), m.p. 260 ° C (dec.).

Example 12 Preparation of 1.8.9-tri (U-hydroxy-benzoyloxy) anthracene 1,8,9 'Trihydroxyanthracene (8 g), benzene (250 ml) and pyridine (2h g) were stirred together at room temperature under a stream of nitrogen until a clear solution was obtained. U-hydroxy-benzoyl chloride (25 g - obtained from 4-hydroxy-benzoic acid and thionyl chloride) was added over 15 minutes and stirring was continued for 1 hour. A dark brown tar-like substance was obtained, which was washed well with ethanol and dissolved in boiling toluene / dimethylformamide (90/10). On cooling, a light green / brown solid was obtained which was crystallized from toluene / dimethylformamide (90/10) to give the ester as light green needles (0.5 g, 2%) m.p. 22 ° C (dec.).

Example 13 Preparation of 3-methyl-1,8,9-tri (2-hydroxy-benzoyloxy) anthracene 1.8.9-Trihydroxy-3-methyl-anthracene (8 g of chrysarobin) was suspended in water (200 ml) and heated to 50 ° C. in a water bath in a continuous stream of nitrogen.

11 S63? 1

Pyridine (20 ml) was added and the mixture was stirred until all the phenol had dissolved. The temperature was then lowered to 30 ° C and salicyloyl chloride (25 g) was added dropwise over 10 minutes. The mixture was heated at reflux for 3 hours and then concentrated under reduced pressure. Addition of ethanol gave a tan powder which was washed with boiling ethanol, dissolved in boiling toluene, clarified with charcoal and filtered. The filtrate was added dropwise to petroleum ether (U0 / 60 ° C) with vigorous stirring and the precipitate was filtered off to give the purified ester as a pale yellow solid (12 g, 60%), m.p. 160 ° C (dec.).

Example 14 Preparation of 1,8,9-trihydroxyanthracene mono- / di (2-acetoxybenzoyl) esters 1) Preparation of ester mixture 1,8,9-trihydroxyanthracene (6 g), xylene (60 g) and pyridine (5 g) were mixed under nitrogen for 10 minutes at 60 ° C. 2-Acetoxybenzoyl chloride (10.5 g, 2 molar equivalents) was added dropwise over 5 minutes, and after heating for an additional 10 minutes, heating was stopped. Activated carbon (1?) (R) and Celite® were added and stirring was continued for 10 minutes. The mixture was filtered through Celite, and the filtrate was added dropwise to stirred petroleum ether, (b.p. U0 / 60 ° C, 750 mL). The product was isolated as a light green amorphous solid (k g).

Examination of the product by thin layer chromatography showed that only a small amount of free 1,8,9-trihydroxyanthracene was present. In addition to the spot corresponding to the triester site, spots indicating the presence of lower esters were observed.

A similar synthesis was performed using only 1 molar equivalent of 2-acetoxy-benzoyl chloride and pyridine per equivalent of 1,8,9-trihydroxy-anthracene. In this case, the tan product was found to contain a relatively high proportion of free 1,8,9-trihydroxyanthracene and was considered less suitable for subsequent separation steps than the product described above.

2) Separation of esters by dry column chromatography

The separation was performed using 1 g of material dissolved in chloroform (50 ml), added to silica gel (Woelm, dry column chromatography, 15 g), and the solvent was evaporated under reduced pressure. The resulting dispersion of mixed esters on silica gel was applied to a dry column (3 x 50 cm) and eluted with toluene.

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The resulting seven clear colored bands were physically separated, eluted with chloroform through sintered glass, and the resulting solutions were examined by thin layer chromatography. The solutions were numbered 1-7 according to the R 1 values in the descending direction. Samples 5 »6 and 7 were master samples, evaporated to dryness, and the solid products obtained from these samples were examined by mass spectrometry, which turned out to be monoester, diester and triester, respectively.

The esters had the following mass spectrometric values: Sample Ester m / e (calculated) m / e (obtained) 5 mono- 380 388 (one fraction 550) 6 di- 550 550 7 tri- 712 712 (one fraction 550 and less 388)

Example 15 Preparation of 1,8-di (U-methylbenzoyloxy) -9-anthrone C18-8- (1 + -methylbenzyloxy) -9-hydroxyanthracene tautomer 7 1.8.9-Trihydroxyanthracene (8 g), benzene (250 ml) and pyridine (2 L + g) was stirred together at room temperature under a stream of nitrogen until a clear solution was obtained.

To this solution was added 1 + -methylbenzoyl chloride (25 g) over 5 minutes and the mixture was heated to reflux for 1 hour. The solvent was evaporated under reduced pressure, and ethanol (200 ml) was added to the residue. The resulting yellow precipitate was filtered, washed well with ethanol and ether and dried (50 ° C / 0.1 mm Hg, 2l + hours). Crystallization from toluene / dimethylformamide (80/20) gave the title compound as yellow crystals (10.9 g, 67%), m.p. 252 ° C.

Example 16 Preparation of 1.8.9-tri (2,1 + -dichlorobenzoyloxy) anthracene 1,8,9-trihydroxyanthracene (8 g), benzene (250 ml) and pyridine (1 + 8 g) were stirred together at room temperature under a stream of nitrogen until a clear solution.

To this solution was added 1,1 + -dichlorobenzoyl chloride (25 g) over 15 minutes, and the mixture was refluxed for 9 hours. The solvent was removed under reduced pressure, ethanol (250 ml) was added to the residue, and the yellow precipitate formed was filtered. The precipitate was washed well with water, ethanol and finally ether and dried at room temperature under reduced pressure to give the title compound (15.7 g 59 → 5%). · Crystallization from toluene / dimethylformamide (75/25) gave the triester as yellowish green crystals (10.3 g). g, 39%)> m.p. 305 ° C.

Formula: C ^ H ^ gClgOg = 7 ^ 5

Analysis calculated: C 56.1 + 0% t H 2.15%, Cl 28.55%

Found: C 56.1 + 0%, H 2.20%, Cl 28.25% ·

Claims (1)

A process for the preparation of therapeutically useful substituted benzoyl esters of 1,8,9-trihydroxyanthracene having the general formula RRR • «oop, j Jf jf / (χ) which compounds may also exist as 9-anthrone tautomers, wherein each R is independently hydrogen or a Χ, Υ-substituted benzoyl group, wherein at least one of the symbols R is a Χ, Υ-substituted benzoyl group, X and Y independently represent a chlorine atom, a hydroxy, nitro, methyl, methoxy or acetoxy group, and Y may further denote a hydrogen, and R1 is a hydrogen atom or a methyl group, characterized in that the corresponding 1,8,9-trihydroxyanthracene is reacted with a substituted benzoic acid chloride of the formula (Vcoci (II)) in the presence of a catalyst in an inert solvent, in an inert gas.