DES0041461MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Registration date: May 15, 1952. Advertised on February 9, 1956

GERMAN PATENT OFFICE

PA TENTAN REGISTRATION UNG

CLASS 12o GROUP 25 S 41461 IVb / 12 ο

The inventor has requested not to be named

Merck & Co., Inc., Rahway, N.J. (V. St. A.)

Representative: Dr. ML Eule, patent attorney, Munich 13

Process for the preparation of p-cyclohexylbenzyl methyl ketones

The priority of registration in the V. St. v. America of May 17, 19131 is claimed

The invention relates to a process for the preparation of new p-cyclohexylbenzyl methyl ketones the general formula

X "

-GH, - CO-

CH ₂ Z

in which X is O, OH, an acyl or alkoxy group and Z is chlorine, bromine, Jbd, OH or acetoxy means.

These connections can enjoy the in Fig. Ι . the illustrated reaction scheme; It is z. B. p- (Äcet oxy cyclohexyl) -benzyldiazomethylketone (IV) with bromine or hydrogen chloride in ethereal solution to p- (Acetoxycyclöhexyl) -behzylhalogenmethylketon (V), in which halogen is chlorine or bromine, reacted. When Halogen should be iodine, then the corresponding chlorine or bromine compound with sodium iodide be reacted in a suitable organic solvent. Obtained by hydrolysis of V. the p- (Oxycyclohexyl) -benzylharogerimethylketon (VI), which in the oxidation, with chromium (VI) oxide p- (Ketocyclöhexyl) -benzylhalogenmethylketön in acetic acid solution (VII) delivers.

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The ρ - (acetoxycyclohexyl) benzylacetoxymethyl ketone (VIII) is obtained by reacting the compound IV with potassium acetate in the presence of

: Acetic acid. The p- (oxycyclohexyl) -benzylacetoxyr methyl ketone (IX) is obtained from compound VI by treatment with potassium acetate in the presence of acetic acid. Oxidation of compound IX gives p- (ketocyclohexyl) benzyl acetoxymethyl ketone (X).

ίο The ρ - (acetoxycyclohexyl) - benzyloxymethyl ketone (XI) is obtained by hydrolysis of the compound IV in the presence of a strong acid, e.g. B. Sulfuric acid. By treating compounds IX and X with potassium bicarbonate in the presence of aqueous methanol gives 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 Morpholine is oxidized, then hydrolyzed with aqueous sodium hydroxide, acidified with acid and the p- (Oxycyclohexyl) phenylacetic acid (II) is obtained, which when reacted with acetic anhydride ρ- (Acetoxycyclohexyl) phenylacetic acid (III) results in the diazoketone (IV) according to known processes is converted.

The preparation of the various compounds is shown in the examples below described.

The compounds which can be prepared by the process according to the invention are physiologically active; In particular, the chloromethyl and oxymethyl ketones have one obtained from the adrenal cortex Hormones similar effectiveness. The chloromethyl ketones are particularly valuable. Furthermore let the various ketones as intermediates for the production of other chemical compounds use.

p-Cyclohexylbenzyl methyl ketones Adrenal hormone-like effects

connection 35 p- (4-acetoxycyclohexyl) benzyl acetoxymethyl ketone Test used dosage
mg per kg inhibition
% ³⁰ p- (4-oxycyclohexyl) benzylchloromethyl ketone p- (4-Acetoxycyclohexyl) benzylchloromethyl ketone mustard 25.0 53 p- (4-acetoxycyclohexyl) benzyloxymethyl ketone the same 25.0 36 p- (4-Ketocyclohexyl) benzylchloromethyl ketone the same 25.0 40 the same delay the sodium 2.0 50 chloride from divorce the same 0.15 30th . the same 0.15 30th

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 injection, both groups received an injection of 0.1 cm ^{3 of} a 10% mustard suspension, which was produced according to the US Pharmacopoeia, specifically under the plantar aponeurosis of the right hind foot. On 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 experimental inhibition =
in %

Average volume difference between the right and left hind legs of the control animals.

animals and the swelling inhibition in ° / ₀ calculated as follows:

Average volume under-. ■ "■ · differentiated between right and left

Hind leg of the control animals (mean volume difference between the right and left hind legs of the one with the test substance treated animals).

2. Delay in excretion of sodium chloride. Rats weighing 100 to 200 g will become the adrenal glands removed; 24 hours after the operation, the animals are given the oil solution at midnight dissolved test substance. At 1:00 am, the animals are given a small amount of radioactive sodium Sodium chloride. The urine is collected from the first to the seventh hour and left to dry

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evaporated. The sodium concentration is determined by measuring the amount of radioactive sodium in the Urine residue determined. The test results are expressed as the percentage of the during the test duration of excreted sodium in the ver. equal to the amount of sodium excreted control animals observed simultaneously.

Example ι

a) p- (4-Acetoxycyclohexyl) -benzyldiazomethylketone (IV)

48 g (0.185 mol) of 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 cm ^{3 of} freshly distilled morpholine were refluxed for about 7 hours and evaporated to dryness in vacuo. The residue was then about 7 hours in a mixture of 400 cm ³ 5o ° / ₀ aqueous ethanol and 300 cm ³ heated 4o ° / ₀ aqueous sodium hydroxide solution under reflux. The solution was concentrated to approximately 350 cm ³ and then cooled, whereupon the crystalline sodium salt of p- (4 "oxycyclohexyl) phenylacetic acid precipitated. Recrystallization of the salt from water and subsequent acidification gave the pure p- (4-oxycyclohexyl) -phenylacetic acid (II) with a m.p. == 228.9 to 229.7 °; Yield 15 ° / _O. 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 slowly under good Stirring was added. Everything was dissolved in about 45 minutes. The reaction mixture then remained ^{at room temperature for I 1} Z ₄ hours and, after briefly heating on the steam bath, was ^{poured into 120 cm 3 of} cold water Was filtered off, washed thoroughly with water and dried in vacuo Repeated recrystallization from methanol-water gave pure p - ^ - acetoxycyclohexyl) phenylacetic acid (III), F . = 115 to 6.2 °; Yield 84%.

2.7 g (0.01 mol) of compound III were dissolved in 30 cm ^{3 of} dry benzene containing one drop of pyridine, and 5.5 cm ^{3 of} purified thionyl chloride were added. After standing at room temperature for 4 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 cm ^{3 of} dry benzene and evaporated to dryness in vacuo at 50 °. The acid chloride obtained was dissolved in 25 cm ^{3 of} absolute ether and added to a cold solution (approximately 0 °) of diazomethane in 60 cm ^{3 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 the p- (4 ~ acet- ¹ oxycyclohexyl) - benzyldiazomethyl ketone F. = 104 to 105.5 °; Yield 44%.

Similarly, the p- (2- and 3-acetoxycyclohexyl) benzyldiazomethyl ketone will be obtained.

b) ρ - (4 - Aceto xycyclohexyl) - benzylchloromethyl ketone

(V)

3 g of the diazoketone (IV) were dissolved in 50 cm ^{3 of} absolute ether, cooled in ice and then treated with dry hydrogen chloride until the vigorous evolution of nitrogen ceased (about 10 minutes). The solvent was distilled off, the dark red residue was dried in vacuo on a steam bath and then recrystallized from ether-petroleum ether. This gave p- (4-acetoxycyclohexyl) benzylchloromethyl ketone, mp = 89.1 to 89.8 °; Yield 83%.

The p- (2- and 3-acetoxycyclohexyl) benzylchloromethyl ketones can be prepared in a corresponding manner will.

If hydrogen bromide is used instead of hydrogen chloride, the p - ^ - acetoxycyclohexyl) benzyl bromomethyl ketone is obtained in this way. The iodine methyl ketone was obtained by using an acetone solution of the chloromethyl ketone treated with sodium iodide.

c) p- (4-oxycyclohexyl) benzylchloromethyl ketone
(VI)

2.8 g (0.091 mol) of p- (4-Acetoxycyclohexyl) -benzylchlormethylketons (V) dissolved in 70 cm ³ of alcoholic hydrochloric acid (18: 1), were I ¹ Z heated for ₂ hours under reflux and evaporated to dryness in vacuo . After recrystallization from ether - petroleum ether, the residue yielded p- (4-oxycyclohexyl) benzylchloromethyl ketone (VI), mp = 125.2 to 126.4 °; Yield 15%.

The corresponding bromine and iodine derivatives can be used in the same manner as described in example b) are prepared, as are the p- (2- and 3-acetoxycyclohexylj-benzylhalomethyl ketones.

d) p- (4-Ketocyclohexyl) -benzylchloromethylketone
(VII).

ι g (0.0038 mol) of p- (4-Oxycyclöhexyl) -benzylchloromethylketon (VI) was dissolved in 5 cm ^{3 of} glacial acetic acid, and the solution was cooled to about 15 °. A solution of 0.25 g of chromium oxide in 4 cm ^{3 of} water and 26 cm ^{3 of} glacial acetic acid was added to this mixture over the course of 2 hours. After standing for about 20 hours at 10 °, the solution was evaporated to dryness in vacuo, the residue was ^{mixed with 25 cm 3 of} water, extracted with 50 cm ^{3 of} ether, the ethereal solution was ^{washed twice with 25 cm 3 of} water each time, dried over sodium sulfate, on about 10 cm ³ concentrated and diluted with enough petroleum ether to precipitate the ρ - (4 - ketocyclohexyl) - benzylchloromethyl ketone (VII), which was filtered off and recrystallized from ether-petroleum ether or acetone-petroleum ether, F. = 91.2 to 92, 1 °; Yield 50%

In the same way as described in example b) can the bromine and iodine derivatives, likewise the

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ρ- (2- and s-Ketocyclöhexy ^ -benzylchloromethylketone getting produced.

Example 2
5

a) p- (4-Oxycyclohexyl) benzyl acetoxymethyl ketone

(ix) '

16 g (0.061 mol) of p- (4-oxycyclohexyl) benzylchloromethyl ketone (VI), 9.8 g of freshly melted potassium acetate and 300 cm ^{3 of} glacial acetic acid were refluxed for about one day and then evaporated to dryness in vacuo. The residue was 50 cm ³

Waters mixed, ^{extracted with 200 cm 3 of} ether, the ether layer washed twice with 50 crii ^{3 of} water each time, dried over sodium sulfate and evaporated to dryness. After distillation in vacuo, the residue gave the p- (4-oxycyclohexyl) -behzylaCetoxymethylketoii (IX), b.p. _{0> 6} = 182 to 183 °; Yield 69%.

III the p- (2- and 3-Oxycyclohexyl) -benzyläcetoxymethylketone produced will.

^a 5 b) p- (4-KetocyClohexyl) -benzyl acetoxymethyl ketone

(X)

In the same way as described in the example id), was obtained from p- (4-oxycyclohexyl) -benzyl acetoxymethyl ketone (IX) with chromium oxide-glacial acetic acid the p- (4-ketocyclohexyl) -benzyl acetoxymethyl ketone (X), m.p. = 82.5 to 84.5 °; Yield 50%.

The p- (2- and 3-ketocyclohexyl) -benzylacetoxymethyl ketones can be obtained in a corresponding manner Will.

Example 3

p- (4-Öxycyclohexyl) -benzyloxymethylketon (XII)
40

0.0037 mol of p- (4-oxycyclohexyl) benzyl acetoxymethyl ketone (IX) in 50 cm ^{3 of} methanol were mixed with 1 g of potassium bicarbonate, dissolved in 10 cm ^{3 of} water and 25 cm ^{3 of} methanol. After about 2 days of standing at room temperature the solution was evaporated to dryness in vacuo, the residue treated with 25 a ³ dilute hydrochloric acid, treated with 200 cm ^{3 of} ether extracted, separated, the ethereal solution, first with 25 cm ^{3 of} 5 ° / _o sodium carbonate solution and then washed with 50 cm ^{3 of} water each time, dried over potassium carbonate, concentrated to about 10 cm ³ and treated with enough petroleum ether to precipitate the p- (4-oxycyclohexyl) benzyloxymethyl ketone (XII). M.p. = 122 to 123.5 °; Yield 25%.

The p- (2- and 3 ^: oxycyclohexyl) -benzyloxymethyl ketones were prepared in a similar manner.

Example 4
p- (4-Ketocyclohexyl) -benzyloxymethyiketone (XIH)

In the same way as in Example 3, the ρ - (4 - ketocyclohexyl) benzyloxymethyl ketone (XIII) could be prepared from the p- (4-ketocyclohexyl) benzyl acetoxymethyl ketone (X) by treating with potassium bicarbonate in methanol, F. = 128 to 129 ⁰ ; Yield 32%.

The p- (2- and 3-ketocyclohexyl) -benzyloxymethyl ketones were obtained in a corresponding manner.

Example 5 p- (4-Acetoxycyclohexyl) -benzyloxymethylketone (XI)

ι g (0.003 mol) of p- (4-acetoxycyclohexyl) -benzyldiazomethylketone (IV) were dissolved in 10 cm ^{3 of} dioxane and treated with 10 cm ^{3 of} 2 η-sulfuric acid at room temperature. A slow evolution of nitrogen began immediately. After standing at room temperature and standing for about ^x / ₂ hours at 40 °, the mixture was ^{diluted with 25 cm 3 of} water and ^{extracted with 100 cm 3 of} ether, the ether layer was separated, twice with 25 cm ^{3 of} water each time, then Washed once with 25 cm ^{3 of} saturated sodium bicarbonate solution and finally with 25 cm ^{3 of} water, dried over sodium sulphate, the sodium sulphate was filtered off and the solution was then evaporated to dryness in vacuo. The residue would be crystallized from ether - petroleum ether, and sometimes the p- (4-acetoxycyclohexyl) benzyloxymethyl ketone (XI), m.p. 93.4 to 95.9 °; Yield 37 ° / ₀ .

In a corresponding way, the. p- (2- and 3 - acetoxycyclohexyl) - benzyloxymethyl ketones will.

Example 6

p- ^ -Acetoxycyclohexyl) benzyl acetoxymethyl ketone

(VIII) "ο

2.7 g (0.01 mol) of p- (4-acetoxycyclohexyl) benzyldiazomethyl ketone (IV) were dissolved in 10 cm ^{3 of} glacial acetic acid and heated on a steam bath for about ¹ Z ₂ hours until the evolution of gas ceased. A few crystals of molten potassium acetate were then added to the reaction mixture and the mixture was heated for about 1 hour, then the solution was cooled, poured into 50 cm ^{3 of} water and extracted with 200 cm ^{3 of} ether. The ethereal solution was separated off, ^{washed twice with 50 cm 3 of} water each time, dried over anhydrous sodium sulfate, concentrated to approximately 10 cm ³ and diluted with sufficient petroleum ether to precipitate the p- (4-acetoxycyclohexyl) benzylacetoxymethyl ketone (VIII). The precipitate was filtered off and purified by vacuum distillation. Repeated recrystallization from ether-petroleum ether gives glittering, colorless platelets with a F. = 106.7 to 107.8 °; Yield 50%.

The p- (2- and 3-acetoxycyclohexyl) -benzylacetoxymethyl ketones were made in a similar manner manufactured.

In the preceding examples, the acetoxy group in Cyclohexyhing can also be replaced by others Residues which can be converted into an oxy group by hydrolysis are replaced, e.g. B.

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by the benzoxy and low molecular weight acyloxy groups or by low molecular weight alkoxy groups.

Claims (4)

PATENT CLAIMS: i. Process for the preparation of p-cyclohexylbenzyl methyl ketones. the general formula -CH ₂ -CO-CH ₂ Z in which X is O, OH, an acyloxy or alkoxy group and Z is bromine, iodine, OH or acetoxy, characterized in that a compound the formula CHN, IV OAc in which OAc denotes an acyl or alkoxy radical, either with hydrogen halide to form p- (acetoxycyclohexyl) benzyl halomethyl ketone (V) reacted, then with a mineral acid to form p- (oxycyclohexyl) -benzylhalomethyl ketone (VI) hydrolyzed, which then either with 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 in the p- (oxycyclohexyl) -benzylacetoxymethylketone (IX) and this finally to either the p- (oxycyclohexyl) -benzyloxymethyl ketone (XII) hydrolyzed or first with chromium oxide and acetic acid to the corresponding one p- (Ketocyclohexyl) -benzylacetoxymethylketone (X) oxidized and then to the p- (Ketocyclohexyl) -benzyloxymethylketone (ΧΠΙ) hydrolyzed or with an alkali acetate in the presence a low molecular weight fatty acid in p- (acetoxycyclohexylj-benzyl acetoxymethyl ketone (VIII) converted or in the presence of a strong acid to p- (Acetoxycyclohexyl) -benzyloxymethylketon (XI) is hydrolyzed. 2. The method according to claim 1, characterized in that that a p- (acetoxycyclohexyl) benzyldiazomethyl ketone (IV) is used as the starting material, by reacting 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 under Formation of p- (acetoxycyclohexyl) phenylacetic acid (III) and treatment of the latter Reaction product (III) was prepared with thionyl chloride and diazomethane. 3. The method according to claim 1, characterized in that the alkali metal acetate is potassium acetate, as a low molecular weight fatty acid acetic acid, for the hydrolysis of the compounds IX and X Potassium bicarbonate in aqueous methanol and, as hydrogen halide, hydrogen chloride or hydrogen bromide is used. 4. The method according to claim 1, characterized in that that p- (4 ~ acetoxycyclohexyl) - benzyldiazomethylketone used as the starting material will. 1 sheet of drawings