DE946446C - Process for the preparation of p-cyclohexylphenyl methyl ketones - Google Patents

Description

Process for the preparation of p-cyclohexylbenzyl methyl ketones The invention relates to a process for the preparation of new p-cyclohexylbenzyl methyl ketones of the general formula in which X is O, OH, an acyl or alkoxy group and Z is chlorine, bromine, iodine, OH or acetoxy.

These compounds can be prepared according to the reaction scheme illustrated in Figure r. It is z. B. p- (Acetoxycyclohexyl) -benzyldiazomethylketone (IV) with bromine or hydrogen chloride in ethereal solution to p- (Acetoxycyclohexyl) -benzylhalogenomethylketone (V), in which halogen is chlorine or bromine is reacted. If halogen is the same If iodine is supposed to be, then the corresponding chlorine or bromine compound can be mixed with sodium iodide in a suitable organic "solvent. By hydrolysis p- (Oxycyclohexyl) -benzylhalogenmethylketon (VI) is obtained from V, which at the oxidation with Ch2om- (VI) -oxide in acetic acid solution the p- (ketocyclohexyl) -benzylhalomethylketone (VII) delivers. The p - (acetoxycyclohexyl) benzyl acetoxymethyl ketone (VIII) is obtained through implementation of the compound IV with potassium acetate in the presence of acetic acid. The p- (oxycyclohexyl) -benzylacetoxymethylketone (IX) is obtained from of compound VI by treatment with potassium acetate in the presence of acetic acid. Oxidation of compound IX gives p- (ketocyclohexyl) benzyl acetoxymethyl ketone (X).

The p - (acetoxycyclohexyl) benzyloxymethyl ketone (XI) is obtained by hydrolysis of compound IV in the presence of a strong acid, e.g. $ Sulfuric acid. By treating the compounds IX and X with potassium bicarbonate in the presence of aqueous methanol gives the p- (oxycyclohexyl) -benzyloxymethyl ketone (XII) or the p- (ketocyclohexyl) -benzyloxymethyl ketone (XIII).

The starting compound IV is prepared by converting from the p- (acetoxycyclohexyl) phenyl methyl ketone (I) goes out, this according to Willgerodt by heating under reflux with sulfur in Oxidized morpholine, then hydrolyzed with aqueous sodium hydroxide, acidified and the p- (oxycyclohexyl) phenylacetic acid (II) obtained, which in the reaction with acetic anhydride gives p - (acetoxycyclohexyl) phenylacetic acid (III), which is converted into the diazoketone (IV) by known processes.

The preparation of the various compounds is described in the examples given below. The compounds which can be prepared by the process according to the invention are physiologically active; In particular, the chloromethyl and oxymethyl ketones have a similar effectiveness to hormones obtained from the adrenal cortex. The chloromethyl ketones are particularly valuable. Furthermore, the various ketones can be used as intermediates for the production of other chemical compounds. p-Cyclohexylbenzylmethylketone Adrenal cortex hormone-like effects Compound Test Used Dosage Inhibition g mg per kg p- (4-Oxycyclohexyl) benzylchloromethyl ketone mustard 25.0 53 p- (4-Acetoxycyclohexyl) benzyloxymethyl ketone like 25.0 36 p- (4-Ketocyclohexyl) -benzylchloromethyl ketone likewise 25.0 40 same delay . the sodium 2.0 50 chloride ex- divorce p- (4-Acetoxycyclohexyl) -benzyl acetoxymethyl ketone also 0, = 5 30 p- (4-Acetoxycyclohexyl) benzylchloromethyl acetone desgl. 0.15 30 Description of the test procedures used i. Mustard test (anti-arthritic effect). Sexually mature, male, white rats weighing about 100 g are divided into two groups of five animals each. One group receives subcutaneous injections on three consecutive days with the compound to be tested for effects similar to adrenal cortex hormones. After the third syringe, both groups receive an injection of 0.1 cm3 of a 100% mustard suspension, which was prepared according to the US Pharmacopoeia, under the plantar aponeurosis of the right hind foot. The day after the mustard injection, the results are recorded as follows: The left and right hind feet of the control animals as well as the test animals are immersed in a calibrated tube filled with mercury to the same depth, whereupon the difference in displacement in mm is recorded. The average volume difference between the feet of the control animals is compared with that of the test animals and the degree of swelling inhibition is calculated as follows 2. Delay in excretion of sodium chloride. Rats weighing from 100 to zoo g have their adrenal glands removed; 24 hours after the operation, the animals are given the test substance dissolved in the oil solution at midnight. At one o'clock the animals are given a small amount of sodium chloride containing radioactive sodium. The urine is collected from the first to the seventh hour and evaporated to dryness. The sodium concentration is determined by measuring the amount of radioactive sodium in the urine residue. The test results are expressed as the percentage of sodium excreted during the test period compared to the amount of sodium excreted by control animals observed at the same time. Example 1 a) p- (4-Acetoxycyclohexyl) -benzyldiazomethylketone (IV) 48 g (0.185 mol) p- (4-Acetoxycyclohexyl) -acetophenone (I) [prepared according to Friedel-Crafts from p- (4-Acetoxycyclohexyl) benzene and acetyl chloride], 10 g of powdered sulfur and 100 cm3 of freshly distilled morpholine were refluxed for about 7 hours and evaporated to dryness in vacuo. The residue was then refluxed for about 7 hours in a mixture of 400 cm3 50% aqueous ethanol and 300 cm3 40% aqueous sodium hydroxide solution. The solution was concentrated to approximately 350 cm3 and then cooled, whereupon the crystalline sodium salt of p- (4-oxycyclohexyl) phenylacetic acid precipitated. When the salt was recrystallized from water and then acidified, pure p- (4-oxycyclohexyl) phenylacetic acid (II) was obtained with a mp = 228.9 to 22 g, 7 °; Yield 15%. 3 g of this acid were suspended in 12 cm 3 of acetic anhydride, cooled in an ice bath, and six drops of concentrated sulfuric acid were slowly added with thorough stirring. Everything was resolved in about 45 minutes. The reaction mixture was then left to stand for ½ hours at room temperature and, after briefly heating on the steam bath, was poured into 120 cm3 of cold water. The reaction product, which solidified on standing in the cold for a long time, was filtered off, washed thoroughly with water and dried in vacuo. Repeated recrystallization from methanol-water gave pure p- (4-acetoxycyclohexyl) phenylacetic acid (III), mp = 115 ° to 116.2 °; Yield 840/0.

2.7 g (0.1 mol) of the compound III were dissolved in dry benzene containing 30 cm # of a drop of pyridine, and 5.5 cm 3 of purified thionyl chloride were added. After standing at room temperature for 40 minutes and at 50 ° for about 5 minutes, the excess solvent and the thionyl chloride were removed in vacuo at 50 °. The residue was dissolved in 5 cm3 of dry benzene and evaporated to dryness in vacuo at 50 °. The acid chloride obtained was dissolved in 25 cm3 of absolute ether and added to a cold solution (approximately 0 °) of diazomethane in 60 cm3 of absolute ether. After standing for about 1 hour at room temperature, the evolution of gas had ceased and the solvent and the excess diazomethane were removed in vacuo at room temperature. Recrystallization of the residue from ether-petroleum ether gave p- (4-acetoxycyclohexyl) benzyldiazomethyl ketone (IV), m.p. 104 to 1o5.5 °; Yield 44%. The p- (2- and 3-acetoxycyclohexyl) benzyldiazomethyl ketones can be obtained in a corresponding manner.

b) p- (4-Acetoxycyclohexyl) -benzylchloromethylketone (V) 3 g of the diazoketone (IV) were dissolved in 50 cm3 of absolute ether, cooled in ice and then treated with dry hydrogen chloride until the vigorous evolution of nitrogen ceased (about xo minutes ). The solvent was distilled off, the dark red residue .getrocknet in vacuo on a steam bath and then recrystallized from ether-petroleum ether. This gave p- (4-acetoxycyclohexyl) benzylchloromethyl ketone, m.p. = 99.1 to 8g, 8 °; Yield 83%.

The p- (2- and 3-acetoxycyclohexyl) benzylchloromethyl ketones can be used in a corresponding manner getting produced.

If hydrogen bromide is used instead of hydrogen chloride, one obtains the p- (4-acetoxycyclohexyl) benzyl bromomethyl ketone. The iodine methyl ketone was obtained when treating an acetone solution of chloromethyl ketone with sodium iodide. c) p- (4-Oxycyclohexyl) -benzylchloromethyl ketone (VI) 2.8 g (0.08 mol) of the p- (4-acetoxycyclohexyl) -benzylchloromethyl ketone (V), dissolved in 70 cm3 of alcoholic hydrochloric acid (18: i), were taken for 1½ hours Heated to reflux and evaporated to dryness in vacuo. The residue delivered recrystallization from ether-petroleum ether, the p- (4-Oxycyclöhe, xyl) benzylchlorriiethylketon (VI), m.p. = 125.2 to 126.4 °; Yield 15o / ..

The corresponding bromine and iodine derivatives can be prepared in the same manner as described in example b), as can the p- (2- and 3-acetoxycyclohexyl) benzyl halomethyl ketones. d) p- (4-Ketocyclohexyl) -benzylchloromethylketone (VII) ig (0.0038 mol) p- (4-Oxycyclohexyl) -benzylchloromethylketone (VI) was dissolved in 5 cm3 of glacial acetic acid, and the solution was cooled to about 15 °. A solution of 0.25 g of chromium oxide in 4 cm3 of water and 26 cm3 of glacial acetic acid was added to this mixture over the course of 2 hours. After standing at 10 ° for about 20 hours, the solution was evaporated to dryness in vacuo, the residue was mixed with 25 cm3 of water, extracted with 50 cm3 of ether, the ethereal solution was washed twice with 25 cm3 of water each time, dried over sodium sulfate, and concentrated to about 10 cm3 and diluted with enough petroleum ether to precipitate the p- (4-ketocyclohexyl) -benzylchloromethyl ketone (VII), which was filtered off and recrystallized from ether-petroleum ether or acetone-petroleum ether, F. = g1.2 to g2.1 °; Yield 50 ° / 0.

In the same manner described in example b), the bromine and iodine derivatives, likewise the p- (2- and 3-ketocyclohexyl) benzylchloromethyl ketones getting produced.

Example 2 a) p- (4-Oxycyclohexyl) -benzyl acetoxymethyl ketone (IX) 16 g (0.061 mol) of p- (q-oxycyclohexyl) -benzylchloromethyl ketone (VI), 9.8 g of freshly melted potassium acetate and 300 cm3 of glacial acetic acid were about Heated under reflux i day and then evaporated to dryness in vacuo. The residue was mixed with 50 cm3 of water, extracted with 200 cm3 of ether, the ether layer was washed twice with 50 cm3 of water each time, dried over sodium sulfate and evaporated to dryness. After distillation in vacuo, the residue gave p- (4-oxycyclohexyl) benzyl acetoxymethyl ketone (IX), b.p.a, e = 182 to 183 °; Yield 690 / ,.

The p- (2- and 3-oxycyclohexyl) benzyl acetoxymethyl ketones can be used in a corresponding manner getting produced.

b) p- (4-Ketocyclohexyl) -benzylacetoxymethylketone (X) In the same way as described in Example id), the p- (4-oxycyclohexyl) -benzylacetoxymethylketone (IX) with chromium oxide-glacial acetic acid was given the p- ( 4-ketocyclohexyl) benzyl acetoxymethyl ketone (X), m.p. = 82.5 to 84.5 °; Yield 50 o / o. The p- (2- and 3-ketocyclohexyl) -benzylacetoxymethyl ketones can be obtained in a corresponding manner.

- Example 3 p- (4-oxycyclohexyl) -benzyloxymethyl ketone (XII) 0.037 moles of p- (4-oxycyclohexyl) -benzylacetoxymethyl ketone (IX) were dissolved in 50 cm3 of methanol with xg potassium bicarbonate, 'dissolved in 10 cm3 of water and 25 cm3 of methanol , offset. After standing for about 2 days at room temperature, the solution was evaporated to dryness in vacuo, the residue treated with 25 cm3 of dilute hydrochloric acid, extracted with zoo cm3 of ether, the ethereal solution separated, first with 25 cm3 of 5% sodium carbonate solution and then with 50 cm3 each 'Washed with water, dried over potassium carbonate, concentrated to about 10 cm3 and treated with enough petroleum ether to precipitate the p- (4-oxycyclohexyl) benzyloxymethyl ketone (XII). M.p. = 122 to x23.5 °; Yield 25%.

The p- (2- and 3-oxycyclohexyl) -benzyloxymethyl ketones were in corresponding Way made. Example 4 p- (4-Ketocyclohexyl) -benzyloxymethylketone (XIII) In in the same manner as in Example 3, the p- (4-ketocyclohexyl) benzyloxymethyl ketone (XIII) from the p- (4-ketocyclohexyl) benzyl acetoxymethyl ketone (X) by treating with potassium bicarbonate in. Methanol can be produced, m.p. = 128 _ to r29 °; yield 32 0 / a.

The p- (2- and 3 - ketocyclohexyl) - Benzyloxymethylketone obtained.

Example s p- (4-Acetoxycyclohexyl) -benzyloxymethylketone (XI) = g (0.003 MOI) p- (4-Acetoxycyclohexyl) -benzyldiazomethylketone (IV) were in 10 cm3 of dioxane dissolved and treated with 10 cm3 of 2N sulfuric acid at room temperature. It began immediately a slow evolution of nitrogen. - After standing for 1/4 hour at room temperature and standing at 40 ° for about 1/2 hour, the mixture was diluted with 25 cm3 of water and extracted with 100 cm3 of ether, the ether layer separated, twice with 25 cm3 of water, then once with 25 cm3 of saturated sodium bicarbonate solution and finally Washed with 25 cm3 of water, dried over sodium sulfate, and the sodium sulfate was filtered off and the solution was then evaporated to dryness in vacuo. The residue was removed Ether-petroleum ether crystallized out, and the p- (4-acetoxycyclohexyl) benzyloxymethyl ketone was obtained (XI), m.p. = 93.4 to 95.9 °; Yield 37%.

The p- (2- and 3-acetoxycyclohexyl) benzyloxymethyl ketones were able to work in a corresponding manner getting produced.

Example 6 p- (4-Acetoxycyclohexyl) -benzyl acetoxymethyl ketone (VIII) 2.7 g (0.1 mol) of p- (4-acetoxycyclohexyl) benzyldiazomethyl ketone (IV) were dissolved in 10 cm3 of glacial acetic acid and put on a steam bath about 1/2 Heated hour until the gas evolution ceases. Then a few crystals of molten potassium acetate were added to the reaction mixture and heated for about an hour, then the solution was cooled, poured into 50 cm3 of water and extracted with zoo cm3 of ether. The ethereal solution was separated off, washed twice with 50 cm3 of water each time, dried over anhydrous sodium sulfate, concentrated to approximately 10 cm3 and diluted with sufficient petroleum ether to precipitate the p- (4-acetoxycyclohexyl) benzyl acetoxymethyl ketone (VIII). The precipitate was filtered off and purified by vacuum distillation. Repeated recrystallization from ether-petroleum ether gives glittering, colorless platelets with a temperature of 10.6.7 to 10.7.8 °; Yield 50%.

The p- (2- and 3-acetoxycyclohexyl) - produced benzylacetoxyinethyl ketones.

In the previous examples, the acetoxy group. im Cyclohexyh7ng also by other radicals which are converted into an oxy group by hydrolysis can be replaced, e.g. B. by the benzoxy and low molecular weight Acyloxy groups or by low molecular weight alkoxy groups.

Claims (3)

PATENT CLAIMS: i. Process for the preparation of p-cyclohexylbenzyl methyl ketones of the general formula , in which X is 0, OH, an acyloxy or alkoxy group and Z is bromine, iodine, 0 is H or acetoxy, characterized in that a compound of the formula in which OAc denotes an acyl or alkoxy radical, either reacted with hydrogen halide to give p- (acetoxycyclohexyl) benzyl halomethyl ketone (V), then with a mineral acid to give p- (oxycyclohexyl) benzyl halomethyl acetone (VI), which is then hydrolyzed with either chromium (VI ) oxide and acetic acid to p- (ketocyclohexyl) -benzyl halomethyl ketone. (VII) is oxidized or with alkali acetate in the presence of a low molecular weight fatty acid to p- (oxycyclohexyl) -benzyl acetoxymethyl ketone (IX) and this finally to either p- (oxycyclohexyl ) -benzyloxymethyl ketone (XII) or first oxidized with chromium oxide and acetic acid to the corresponding p- (ketocycrlohexyl) -benzyl acetoxymethyl ketone (X) and then to the p- (ketocyclohexyl) -benzyloxymethyl ketone (XIII) hydrolysed in the presence of an alkali acetate Fatty acid converted into p- (acetoxycyclohexyl) -benzylacetoxymethyl ketone (VIII) or in the presence of a strong acid to p- (acetoxycyclohexyl) -benzyloxym ethyl ketone (XI) is hydrolyzed. 2. The method according to claim i, characterized in that a p- (acetoxycyclohexyl) benzyldiazomethyl ketone (IV) is used as the starting material, This is done by converting p- (acetoxycyclohexyl) acetophenone (I) according to Willgerodt Oxidation with sulfur in morpholine, hydrolysis with aqueous alkali and acidification with formation of p- (oxycyclohexyl) phenylacetic acid (II), reacting the same with Acetic anhydride with formation of p- (acetoxycyclohexyl) phenylacetic acid (III) and treating the last-mentioned reaction product (III) with thionyl chloride and diazomethane was produced. 3. The method according to claim i, characterized in that that as alkali metal acetate potassium acetate, as low molecular weight fatty acid acetic acid, for the hydrolysis of compounds IX and X potassium bicarbonate in aqueous methanol and hydrogen chloride or hydrogen bromide is used as hydrogen halide. q .. procedure according to claim i, characterized in that p- (q.-acetoxycyclohexyl) benzyldiazomethyl ketone is used as the starting material is used.