DE1088950B - Process for the preparation of hydrogenated anthracene derivatives - Google Patents

Description

GERMAN

General formula antibiotics

N (CH ₃ ),

OH O

Method of manufacture
of hydrogenated anthracene derivatives

Applicant:

Farbwerke Hoechst Aktiengesellschaft

formerly Master Lucius & Brüning,

Frankfurt / M., Brüningstr. 45

Dr. Hans Muxfeldt, Braunschweig,
has been named as the inventor

saponified to free carboxy groups, optionally the dicarboxylic acid by decarboxylation in monocarboxylic acids transferred and optionally to free the alkoxy groups present by treatment with acid Splitting oxy groups.

It has now been found that anthracene derivatives of the formula

, -CH ₉ -COOH

in which X is hydrogen or chlorine, A is halogen, in particular chlorine or bromine, or an O-alkyl group and Alk is a

lower alkyl groups, in particular methyl groups, are 35 in which X is hydrogen or halogen and alk is lower

indicates, by reduction in alcohols of the formula alkyl radical, in particular a methyl group, means,

X CH,

in which X is hydrogen or chlorine, Y is hydrogen or, if X is hydrogen, also stand for the hydroxyl group, have gained great importance in pharmacy. The connections are up today obtained organically. The total synthesis of such tetracyclic compounds or such Degradation products which have the tetracyclic ring system have not yet been described.

Subject of the patent application F 27Ö96 IIb / 12o is a process for the production of anthracene derivatives, being compounds of the general formula

CH,

r - CO - A

Alk Alk

-CH ₉ OH

can win if you have compounds of the formula
X CH ₃

- COOH

converted, this converts into the corresponding hydrohalic acid or p-toluenesulfonic acid ester, the obtained Compounds with sodium carbethoxy succinic acid dialkyl esters or carbethoxymethylmalonic acid dialkyl esters condensed, the compounds obtained cyclized by treatment with polyphosphoric acid, if appropriate esterified carboxyl groups still present

Alk Alk

in which X and Alk have the meanings given above, initially in a manner known per se via the Stage of the acid halide with diazomethane converted into the diazoketone and this by thermal decomposition in cyclohexanol or benzyl alcohol and subsequent saponification of the resulting cyclohexyl or

009 607/424

Benzyl ester into the carboxylic acid of the general formula

CH.

CH ₂ -COOH

Alk Alk

transferred and optionally the compounds obtained for the purpose of cleavage of the alkoxy groups of the action Subjected by hydrohalic acids.

Serving in the process of the present invention as starting material 1 ^ S. ^ tetrahydro-S-carboxy-9-methyl-8,10-dialkoxyanthracen-1-one or the 5-position chlorinated derivative of this compound is according to the The process of the present invention is first converted into the corresponding acid halide in the manner customary for monocarboxylic acids. Suitable agents for this are above all phosphorus halides, such as phosphorus tri- or pentabromide, phosphorus oxychloride or phosphorus pentachloride. Oxalyl chloride can also be used to make the acid chloride. The reaction is carried out in the presence of solvents. Hydrocarbons such as gasoline, benzene, ethers such as diethyl ether, dioxane, tetrahydrofuran and, above all, low molecular weight chlorinated aliphatic hydrocarbons are suitable for this purpose. It is expedient to carry out the reaction at temperatures below ⁰ ° C. The acid halide obtained in this way is then converted into the corresponding diazoketone in the usual way with the aid of diazomethane. Here you can enter the acid chloride in an ethereal diazomethane solution while stirring and cooling with ice. However, in order to avoid having to keep large amounts of diazomethane in stock, it has proven to be expedient to dissolve the acid chloride in ether and to distill diazomethane, which is continuously produced in a separate vessel from nitrosomethylurea, and to continuously add it with the acid chloride unite. In this way it is possible without difficulty to convert large amounts of the acid chloride into the diazoketone. The obtained diazoketone of the formula

be transferred. The diazoketone is suspended in pure benzyl alcohol or cyclohexanol and the mixture is heated to higher temperatures with stirring. Advantageously carried out at temperatures between 170 and 18O ⁰ C, but they also lower temperatures may apply, but must thereby assume a yield deterioration in buying. The esters obtained in this way can be saponified without difficulty, the free acid being obtained. The benzyl ester can also

ίο by careful hydrogenation with Raney nickel under Normal pressure at room temperature in the 3-carboxymethylene-8,9-dialkoxy -10-methyl -1,2,3,4-tetrahydroanthracen-1-one or the corresponding 5-chloro compound can be converted. The dialkoxy groups contained in the 8,9-position can by ether cleavage using hydrohalic acids, in particular Hydrochloric acid, easily converted into oxy groups.

The compounds obtained by the process are of particular interest as intermediates for Synthesis of pharmaceutically valuable compounds such as tetracyclines.

example

a)

8, lQ-dimethoxy-l-one are suspended in 600 cc of absolute chloroform and the suspension was cooled with stirring to 0 ⁰ C. 10 g of finely powdered pure phosphorus pentachloride are added in portions to the mixture and the mixture is stirred until complete dissolution has occurred. The temperature is ^{kept below 0} ° C. during the reaction. Thereafter, the solvent at a bath temperature of 40 ° C is distilled off completely suspended the remaining crystalline residue in a mixture of 50 cc of absolute ether and 30 cc of absolute petroleum ether (boiling point 40 to 60 ⁰ C) and the solvent is filtered off. The filter residue is washed with absolute ether and dried in a vacuum. 16.7 g of the compound are obtained in this way

Cl CH,

COCl

i — CO —CHN ₉

Alk Alk

can by thermal decomposition in benzyl alcohol or cyclohexanol and subsequent saponification of the esters obtained in carboxylic acids of the formula
X CH ₃

, -CH ₉ -COOH

OCH ₃ OCH ₃ 0

which melts at 163 to 165 ^{° C.}

b) The acid chloride obtained in the manner described under a) in an amount of 16.7 g is in the course one hour in part while stirring and cooling with ice in an ethereal diazomethane solution (made from 30 g nitrosomethylurea) entered. The mixture is then left for 2 hours at room temperature stirred and the mother liquor separated by suction. The filter residue is washed with ether. The yield of finely crystalline light yellow diazoketone of the formula

Cl CH ₃

CO-CHN ₉

OCH ₃ OCH ₃ O

is 14.2 g (= 79% of theory). The connection

melts at 155 to 157 ° C with evolution of nitrogen and decomposition.

c) 14.2 gl ^ A ^ etrahydro-S-diazoacetyl-S-chloro-Q-methyl-8,10-dimethoxyanthracen-l-one is suspended in 50 ecm of the purest benzyl alcohol and the mixture is heated to 170 bis with stirring 180 ⁰ C preheated oil bath. After the evolution of nitrogen has ceased, the benzyl alcohol is completely removed by steam distillation, the residue remaining after the benzyl alcohol is driven off is dissolved in benzene and the benzene solution is adsorbed on acidic silica gel. When washing with benzene, a yellow zone migrates through the column, which is eluted with benzene. After the solvent has been removed, 11.9 g of a yellow oil remain from the eluate, which is the benzyl ester of l ^ .S ^ -Tetrahydro-S-carboxymethylene-S-chloro ^ -methyl-8,10-dimethoxyanthracen-l-one . The oil is dissolved without further purification in 300 cc of hot ethanol, and 200 cc of 10 ° / ₀ strength potassium hydroxide solution containing 1 g of sodium dithionite is added together ao cooked flußkühler the rear. The yellow solution is then diluted with water, the aqueous solution is acidified and extracted with chloroform. The chloroform extract, washed with water and dried over sodium sulfate, is diluted with 200 ecm benzene and the mixture is concentrated to 50 ecm. After standing for 12 hours, the crystals which have separated out are suctioned off and washed well with ether. 7.05 g (= 48% of theory) are obtained in this way C. A sample purified by re-adsorption on silica gel and recrystallization from chloroform-petroleum ether melts at 188 to 189 ° C.

d) 87 mg l ^ .S ^ -Tetrahydro-S-carboxymethylene-S-chloro ^ -methyl-S ^ O-dimethyloxyanthracen-l-one if you dissolve in 5 ecm glacial acetic acid, the cold solution is diluted with 20 ecm concentrated hydrochloric acid and the mixture is allowed to stand for 5 hours at room temperature. During this time changes the color of the initially red solution to yellow. The 1,2,3,4-tetrahydro-S-carboxymethylene-S-chloro-methyl-S.lO-dioxyanthracen-1-one formed separates crystalline. The mother liquor is filtered off with suction, the residue is dissolved in chloroform and the adsorbed Chloroform solution on acidic silica gel. When washing with chloroform, a yellow zone runs very quickly through the column, the eluate of which is discarded. This is followed by a slowly migrating deep yellow zone, the eluate of which is concentrated and petroleum ether is added. It separates 47 mg (= 57% of theory) of the above Compound in crystalline form. The compound melts at 191 to 193 ° C.

The Arndt-Eistert synthesis is a well-known reaction for the chain extension of carboxylic acids, however, those known for the conversion of diazoketones into carboxylic acids or their derivatives lead Reaction conditions, d. H. Heating with water, alcohols or amines in the presence of silver powder, Copper oxide, palladium black or a silver benzoate triethylamine complex compound, in the compounds used according to the process according to the invention, this is not the aim. With the thermal Only the keto ether is formed when a mixture of dimethylaniline and benzyl alcohol decomposes

Cl

CH,

CH ₉ -O-CH,

OCH

It was therefore surprising that thermal decomposition of the diazoketones in benzyl alcohol or cyclohexanol results in the corresponding benzyl or cyclohexanol esters lengthened _{in the chain by one CH 2 group in satisfactory yield.}

Claims (1)

PATENT CLAIM: Process for the preparation of hydrogenated anthracene derivatives, characterized in that compounds of the general formula CH, , —COOH in which X is hydrogen or chlorine and Alk is a low molecular weight Alkyl group, in particular a methyl group, means in a manner known per se into the corresponding carboxylic acid halides transferred, this by reaction with diazomethane in itself known manner converts them into the corresponding diazoketones by heating in benzyl alcohol or cyclohexanol into the benzyl or cyclohexyl esters of compounds of the general formula CH CH, -COOH Alk Alk in which X and Alk have the abovementioned meaning, converts the esters formed in the customary manner saponified and optionally the alkoxy groups present to form hydroxyl groups by acid cleavage convicted. Considered publications:
Houben - Weyl, methods of organ. Chemie, Vol. 8, 1952, pp. 456 to 458. © 009 607/424 9.60