CS216502B2 - Method of making thederivatives of the 3-+l2-hydroxy-4-subst-phenyl+p-cycloalkanons - Google Patents

Description

The present invention relates to a process for the preparation of certain cycloalkanones and their unsaturated derivatives of 5 to 8 carbon atoms in the cycloalkyl ring containing at the 3-position a 2-hydroxy-4- (ZW-substituted) phenyl group wherein Z represents an alkylene group having 1 to 13 carbon atoms or a radical of the formula - [alk] _n - O - (alk ₂ ) _n - in which each of m and n is 0 or 1 and each of (alki) and (alkz) represents an alkylene group having 1 to 13 carbon atoms, provided that the sum of the carbon atoms in the (alki) and (alkz) radicals is not more than 13 and W represents a hydrogen atom, a phenyl, a chlorophenyl, a fluorophenyl or a pyridyl group.

The above products are useful as central nervous system agents, particularly as analgesics, tranquilizing agents, sedatives and anti-anxiety agents in mammals, including humans, and / or as anticonvulsants, diuretics, and antidiarrheal agents for mammals, including humans.

Although a number of analgesics are currently available, there is a continuing search for new and better formulations, as there is no agent suitable for the treatment of a wide range of painful conditions, which at the same time has minimal side effects. The most commonly used substance, aspirin, is of no practical significance for the treatment of major pain and, moreover, is known to exhibit various undesirable side effects. Other morphine are addictive. This clearly implies a need for a better and more effective analgesic.

U.S. Patent 3,576,887 (April 27, 71) discloses a series of 1- [beta] -hydroxyalkyl-2-o-hydroxyphenylcyclohexane and -cyclohexene derivatives as intermediates for the preparation of 6,6-dialkyltetrahydr o- and -hexahydrodibenzoate [b, d] pyranes, which can be used as central nervous system depressants.

It has now been found that certain cycloalkanones and their unsaturated derivatives containing a 2-hydroxy-4-substituted phenyl group at the 3-position (see general formula I below) are effective as agents for influencing the central nervous system, in particular as analgesics, tranquilizing agents, sedatives, and anti-anxiety agents in mammals, including humans, and / or as anticonvulsants, diuretics, and antidiarrheal agents for mammals, including humans. The invention also provides various derivatives of these compounds which are useful as dosage forms of these compounds, as well as intermediates for the preparation of compounds of formula I, including processes for their preparation.

218502

The compounds produced by the process according to the invention correspond in general. 'formula I,

However, it is to be understood that racemic mixtures of the respective compounds, mixtures of diastereomers, as well as pure enantiomers and diastereomers are meant by this formula. The applicability of racemic mixtures, mixtures of diastereomers as well as pure enantiomers and diastereomers is given by their biological activity as determined by the procedures described below.

Various intermediates useful for the preparation of the compounds of formula (I) include those of formulas (II) to (IV) wherein the dotted line represents an optional double bond,

Q is a protecting group of the phenolic hydroxyl function, n is -O, 1, 2 or 3,

R 2 represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 alkenyl group, a phenyl group or a C 1 -C 4 phenylalkyl group in the alkyl moiety,

Z denotes an alkylene group having 1 to 13 carbon atoms or a radical of the formula - (alk ₁ ) _m -O- (alk ₂ ) _n -, wherein (alkij and (alka) each denote an alkylene group having 1 to 13 carbon atoms, with that the sum of the carbon atoms in the (alki) + (alka) groups is not more than 13 amines are always 0 or 1, and

W represents a hydrogen atom, a pyridyl group or a radical of the formula

(lil)

wherein W 1 represents a hydrogen, fluorine or chlorine atom.

The invention also includes pharmaceutically acceptable acid addition salts of those compounds of formula I which contain basic groups. Typical examples of such compounds are those in which W represents a pyridyl group. Of course, in the case of compounds containing two basic groups, acid addition salts with several acids are possible. Representative examples of the above-mentioned pharmaceutically acceptable acid addition salts include salts with mineral acids such as hydrochlorides, hydrobromides, sulfates, phosphates and nitrates, salts with organic acids such as citrates, acetates, sulfosalicylates, tartrates, glycolates, salts with malic acid, malonates, maleates, pamoates, - salicylates, stearates, phthalates, succinates, glyconates, 2-hydroxy-3-naphthoates, lactates, salts of mandelic acid and methanesulfonates.

For the sake of simplicity,

which do not show any stereochemistry, and their possible cis- and trans-isomers, in which:

Z, - W, - R 2 and - Из are as defined above,

Y ‘represents a cyano group or a formyl group, t - is a number of values from 1 to 8,

R 7 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, and

A represents a group

-CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -CH 2 -.

Compounds of formula IV are ketal and hemiketal forms of saturated cycloalkyl derivatives of formula I from which the protecting group of the phenolic hydroxyl function of Q is cleaved.

Of the alkylene group having 8-11 carbon atoms, j is an alkylene group of 4-7 carbon atoms (ALK _m -O- (alk _{2) n} (Alk -O- (alk _{2) n}

Because of their higher biological activity over the other compounds described herein, those compounds in which R 2 represents a hydrogen atom or an alkyl group as defined above are preferred and Z and W have the following meanings:

mn W, -hydrogen ^{1- (1} -pyridyl)

( ₇ ) pyridyl ( ₇ ) pyridyl ()

1 hydrogen

Particularly preferred compounds of the formula I, in particular the saturated cycloalkyl derivatives of the formula I, are those mentioned above, in which they represent:

Z is - С (СНз) 2 (СН2) б and W represents a hydrogen atom,

Z is (C 4 -C 7) alkylene and W is phenyl,

Z is -O-alkylene of 7 to 9 carbon atoms and W is hydrogen,

Z is -O-C 4 -C 5 alkylene and W is phenyl,

R @ 2 is hydrogen, methyl, propyl or propenyl.

With respect to analgesic activity, particularly preferred compounds from the group of the above-mentioned preferred compounds are those in which R 2 is a methyl, propyl or propenyl group.

The saturated cycloalkyl derivatives of the formula I according to the invention are prepared from the corresponding 2-bromo-5- (Z-W-substituted) phenol by a series of reactions comprising, as a first step, the protection of phenolic hydroxyl by introducing a protecting group Q.

Suitable protecting groups are those which do not interfere with the subsequent reactions and which can be removed under conditions which do not lead to undesired reactions at other sites of the above compounds or products thereof. Representative examples of such Q-protecting groups include methyl, ethyl, benzyl, or substituted benzyl, with, for example, C1-C4alkyl, halogen (fluoro, chloro, bromo, or iodo) or alkoxy; 1-4 carbon atoms.

The ether protecting groups can be removed by using hydrobromic acid in acetic acid or by treatment with 48% aqueous hydrobromic acid. The reaction is carried out at an elevated temperature, preferably at reflux. However, when Z is a residue, such acids as the acid should be used; polyphosphoric or trifluoroacetate to avoid cleavage of the ether bond. Other reagents such as hydroiodic acid, hydrochloride or pyridine hydrobromide can also be used to remove ether protecting groups such as methyl or ethyl groups. If the protecting groups are benzyl or substituted benzyl groups, such groups may be cleaved by catalytic hydrogenolysis. Suitable catalysts are palladium or platinum, especially on charcoal carriers. Alternatively, such groups may be cleaved by solvolysis using trifluoroacetic acid. Another procedure consists in treating n-butyllithium in an inert solvent at room temperature.

The precise chemical structure of the protecting group does not play a decisive role, only its ability to meet the above requirements is important. Choosing and identifying suitable protecting groups will not be a problem for those skilled in the art. The suitability and effectiveness of a given hydroxyl protecting group is determined by its utility in the reactions described herein. Thus, the protecting group should be one that can be easily removed by regenerating the hydroxyl group. Because of their easy cleavability, methyl and benzyl groups are preferred protecting groups.

The protected 2-bromo-5- (ZW-substituted) phenol is then reacted with magnesium in an inert solvent and generally in the presence of a reaction promoter, for example, a monovalent copper salt such as copper (I) chloride, bromide or iodide (to promote 1,4-addition). ) and the corresponding 4-R 2 -cycloalken-1-one (for example, 4-R 2 -cyclohexen-1-one).

Suitable inert solvents are cyclic and acyclic ethers such as tetrahydrofuran, dioxane and ethylene glycol dimethyl ether. The Grignard reagent is prepared in a known manner, for example by boiling a mixture of 1 mole of the bromo derivative with 2 moles of magnesium in an inert solvent such as tetrahydrofuran. The resulting mixture was cooled to about 0 ° C to -20 ° C, at which temperature copper (I) iodide and then the appropriate 2-cycloalken-1-one were added thereto. The amount of cuprous iodide used is not critical and may vary within wide limits. Satisfactory yields of the protected phenolic hydroxyl function cycloalkanones are achieved using about 0.2 to 0.02 moles of copper (I) iodide for each mole of starting bromo derivative.

The resulting product of formula (I) can be deprotected by treatment with a suitable reagent (Q). The benzyl group is conveniently cleaved as described above. When the protecting group is an alkyl (methyl or ethyl) group, it is cleaved by the above methods or by treatment with, for example, pyridine hydrochloride.

The cycloalkanones thus obtained, in which R2 represents an alkenyl group, serve as intermediates for the preparation of the corresponding cycloalkanones having an alkyl group as R2.

Compounds of the invention containing a double bond at the 2,3-position are prepared by Grignard reaction of an appropriately protected 2-bromo-5- (ZW-substituted) phenol with 3-alkoxy-2-cycloalken-1-one (containing 1-4 atoms in the alkoxy moiety) carbon) in an inert solvent at a temperature of about -30 ° C to + 10 ° C. The cycloalkenone derivative thus obtained can then optionally be deprotected as described above and possibly further reduced to the corresponding cycloalkenol. Alternatively, the protected cycloalkenone may optionally be reduced chemically, for example using sodium hydride, to the protected cycloalkenol, which is then deprotected to regenerate the free phenolic hydroxyl function.

The analgesic properties of the compounds of the invention are determined by the tests described below using irritant stimuli.

J

Tests using thermal stimuli

a) Tsst analgesic йСти ^ и on mice on a hot plate

A modification of the procedure described by Woolfe and MacDonald [J. Pharmacol. Exp. Ther. 80, 300-307 (1944)]. The test mice are placed on a 0.3 cm thick aluminum plate, which is heated in a controlled manner so as to irritate the mouse paws with heat. Below the aluminum plate is an infrared radiator with a power input of 250 W. The radiator operation is controlled by a thermal regulator coupled to thermistors on the surface of the plate so that the temperature of the plate is maintained at a constant value of 57 ° C. Each test mouse is placed in a glass cylinder (16.5 cm diameter) seated on a hot plate, and the time is counted when the animal's paw touches the plate. Experimental mice are observed at 0.5 and 2 hours after t administration of the test compound to detect the first twitching movements of one or both hindpaws, or for 10 seconds in the absence of such movements. Morphine has an MPE50 value of 4 to 5.6 mg / kg (subcutaneous administration) in this assay.

(b) Mouse anaggetic efficacy test, in which animals abruptly remove the tail from the site of thermal irritation

This test is a modification of the procedure described by D’Amour and Smith []. Pharmacol. Exp. Ther. 72, 74-79 (1941)], and utilizes thermal irritation of the tail of a controlled intensity mouse. Each mouse is placed in a sliding metal cylinder such that its tail protrudes at one end of the cylinder. The cylinder is arranged such that the protruding tail of the animal is in a horizontal position above the covered heat emitter. At the beginning of the test, the aluminum screen is removed from the emitter and the beam of light with the slit and focus is directed to the end of the animal's tail. At the same time the clocks start. An increase in the time required for the mouse to respond to thermal irritation by tail twitching is observed. Untreated mice usually respond to thermal irritation in 3 to 4 seconds. The endpoint of protection provided by the test substance is 10 seconds. Each mouse is tested at 0.5 to 2 hours after administration of morphine or test compound. Morphine has an MPE50 value of 3.2 to 5.6 mg / kg (subcutaneous administration).

c) Tests in submerged tail mice

The method used is a modification of the procedure developed by Benbasset et al. [Sheet. int. Phnrmacodya. 122, 434 (1959)]. Male white mice (Charles River CD-1 strain, weighing 19-21 g) were weighed and labeled. Each substance is tested on a group of 5 animals, each serving as its own control. For general assessment of efficacy, the new test substance is first administered by intraperitoneal or subcutaneous administration at a dose of 56 mg / kg administered in a volume of 10 ml / kg. Before administration of the drug and at 0.5 and 2 hours after drug administration, each animal is placed in a cylinder provided with adequate ventilation openings and closed with a circular nylon closure through which the animal's tail protrudes from the cylinder. The cylinder is held in an upright position, with the animal's protruding tail fully immersed in a water bath heated to a constant temperature of 56 ° C. The experiment always ends with a vigorous twitch or tail pull associated with a motor response. In some cases, this may be less vigorous after administration of the test substance. To prevent unwanted tissue damage, the experiment is terminated and the animal's tail is removed from the bath after 10 seconds. The latency of the response is recorded in 165050 in seconds, rounded to 0.5 seconds. In parallel, the test is performed after application of only the vehicle and standard of known efficacy. If the efficacy of the test substance does not decrease to baseline within 2 hours after administration, the latency of the response is determined at 4 and 6 hours after administration. If, at the end of the test day, the test compound still shows efficacy, a final measurement is made 24 hours after administration.

Test using chemical stimuli

Suppression of painful cramps [writhing]. induced by phenylbenzoquinone

Groups of 5 mice each (Carworth Farms CF-1) are premedicated by subcutaneous or oral administration of saline, morphine,. codeine or test compounds. Phenylbenzoquinone, which is known to induce abdominal contractions, is then injected intraperitoneally into all groups of test animals after 20 minutes (for subcutaneous administration) or 50 minutes (for oral administration). Five minutes after injection of the compound, mice are observed for 5 minutes to determine whether or not they experience painful convulsions. MPE 50 values are determined for each test substance to prevent painful convulsions when pre-administered.

Tests using pressure irritants. stimuli

Efficiency in the Haffner test

A modification of the procedure described by Haffner [Experimentelle Prüfung Schmerzstillender] is used to determine the efficacy of a test compound on an aggressive tail-induced response. Deutsch. Copper. Wschr., 55, 731-732 (19219)].

Male white rats (50-60 g) of the Charles River (Sprague-Dawley) CD strain are used for the assay. Prior to administration of the test compound and again at 0.5, 1, 2 and 3 hours after drug administration, the tail of the rat is boiled with a clamp (John-Hopkins, 6.35 cm bulldog clamp). The end point of each experiment is the explicitly offensive behavior and biting towards the pain-inducing tool, recording the latency time of the response in seconds. If no attack occurs within 30 seconds, the clip is removed and the latency of the response is recorded as 30 seconds. Morphine is effective in this test when administered intraperitoneally at a dose of 17.8 mg / kg.

Tests using electrical stimuli

A test in which test animals bounce from the site of an electrical irritant stimulus

A modification of the procedure described by Tenen [Psychopharmacologia, 12, 278-285 (19613)] is used to determine the pain threshold. Male white rats (175-200 g) of the Charles River (Sprague-Dawley) CD strain are used for the assay. Prior to administration of the test substance, the paws of all rats are immersed in a 20% solution of glycerin in saline. The animals are then placed in a cage and one-second electric shocks are delivered to their paws at 30 second intervals with increasing current intensity. These increasing intensities are 0.26, 0.39, 0.52, 0.78, 1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3, 04 mA. The behavior of each animal is recorded as to whether an electric shock occurs

(b) for screaming; and / or

(c) to jump or move forward.

One rat of shocks at increasing current intensity is given to each rat just prior to administration of the test substance and at 0.5, 2, 4 and 24 hours after administration of the test substance.

The results of the above tests are recorded as the maximum possible effect in% (% MPE). The% MPE values for each group are statistically compared to the% MPE values for the standard and the control values observed prior to drug administration. The% MPE values are calculated using the following formula:

_{n / К <тчтп} Measured Time - Check Time ""% MPE = - = ----— V —------—______------- x 100 Interrupt Time - Check Time

When the compounds of the invention are administered orally or parenterally as analgesics, they are conveniently administered in the form of compositions comprising a pharmaceutical carrier selected on the basis of the chosen route of administration and having regard to standard pharmaceutical practice. For example, the disclosed compounds may be administered in the form of tablets, pills, powders or granules containing, for example, starch, milk sugar, certain types of clay, as carriers, and the like. The compounds of the invention may also be administered in capsules containing the same. or with equivalent carriers. The disclosed compounds may also be administered in the form of suspensions, solutions, emulsions, syrups or elixirs for oral administration, which dosage forms may contain flavoring and coloring agents. For most oral applications of the therapeutic agents of the invention, tablets or capsules containing from about 0.01 to 100 mg of active ingredient are suitable.

2'165 0 2

The physician will determine the most appropriate dosage for the particular patient, which will vary depending on the patient's age, weight, response and route of administration. In general, however, the initial analgesically effective dose for adult patients may range from about 0.1 to 750 mg / day, the total dose being administered in single or multiple doses. In many cases it is not necessary to exceed the daily dose of 100 mg. A suitable dosage range for oral administration is from about 1.0 to 300 mg / day, a preferred range from about 1.0 to 50 mg / day. A preferred dose range for parenteral administration is from about 0.1 to 100 mg / day, a preferred range from about 0.1 to 20 mg / day.

The invention also provides pharmaceutical compositions comprising unit dosage forms suitable for use as the analgesics described above and for other applications described herein. These dosage forms may be formulated as single or multiple doses, as described above, so that the daily dosages effective for each use can be increased.

The compounds of the invention may be formulated for administration as solid or liquid preparations for oral or parenteral administration. Capsules containing the active compounds according to the invention can be prepared by mixing 1 part by weight of the active compound with 9 parts by weight of a carrier, such as starch or milk sugar, and filling the insertable gelatin capsules so that each capsule contains 100 parts of the mixture . Tablets containing the above-described compounds as active ingredients are prepared using suitable mixtures of the active ingredient and standard carriers and excipients used in the preparation of tablets, such as starch, binding agents and glidants, such that each tablet contains, from the 0.10 to 100 mg of active ingredient.

Suspensions and solutions of the compounds of the invention are often formulated just prior to use in order to avoid storage-related stability problems of the active ingredient suspension or solution [e.g.

Formulations suitable for such use are generally dry solid preparations which are then suitably formulated for injection.

Using the procedures described above, the analgesic activity of several compounds corresponding to the compounds according to the invention was determined, from which the Q-protecting group was cleaved to regenerate the free phenolic hydroxyl function.

The results of these tests are shown in the following table, using the following abbreviations for each test:

FBCH · = painful cramps caused by phenylbenzoquinone,

DO = heat irritation of the tail, HD = hot plate,

SO = tail clamping [Haffner], OD = electric shock.

The table shows the ED 50 values (if only one number is given). The figure followed by the second number in parentheses refers to the% protection for the given batch. Thus, a value of 20 (56) means that a dose of 56 mg / kg body weight gives 20% protection.

TABLE

Analgesic efficacy of ED 50 [mg / kg] or protection in% (mg / kg) for subcutaneous administration

• tešou-. · N Rž OF w FBCH HD TO 1 H C (CH 3) 0 (CH 2) 6 H 4,5 15.3 H C (CH 5) 2 (CH 2) 6 H 20 (55) 1 H OCH (CH3) (CH2) 3 C6H5 56 jjb) H C (CH 5) 2 (CH 2) 6 H 20 (55) 2 H C (CH 5) 2 (CH 2) 6 H 2.15 33 (10) 58 ₍ 9) 0 H C (CH 5) 2 (CH 2) 6 H 15 (56) 1 H O H 32 (55) 1 (c) H O H 43 (55) 1 cis-CHs C (CH 5) 2 (CH 2) 6 H 1.51

the use corresponds to the dosage given above in the description of the use of the compounds of the invention as analgesics.

Antidiarrheal efficacy is determined using a modification of the procedure they have described

Neimegeers et al. [Modern Pharmacology-Toxicology, Willem van Bever and Harbans Lal, Eds., 7, 68-73 (197 (5)]. Charles River CD-1 rats (170-200 g) are placed in an 18-hour period prior to the test.

Legend:

^(a> = phenol hydroxyl benzyl ether ( ^b) = 2-analogue ( ^c) · = methyl ketal derivative

The diuretic activity of the compounds of the present invention is illustrated by the assay performed by Lipschitz et al. [J. Pharmacol., 197, 97 (1943)], using rats as test animals. The dosage range for this common cage. Before castor oil administration, the animals are fasted overnight, without limiting water intake. The test substance is administered subcutaneously or orally in a constant volume of 5 ml / kg body weight, in a mixture of 5% ethanol, 5% emulsifier based on polyoxyethylated vegetable oil and 90 ¹ % saline, and then orally administered a challenge dose after one hour. (1 mL) of castor oil. Animals are housed in small individual cages (20.5 X 16 X 21 cm) with suspended wire trays. A strip of cardboard is placed under the wire mat and one hour after the castor oil has been administered, it is determined whether or not there has been a deterioration. For all tests performed within 1 day, they always serve as a control group of animals receiving only vehicle and castor oil. Results are recorded as the number of animals protected from diarrhea within 1 hour of castor oil administration. In general, dosages when using the disclosed compounds as antidiarrheal agents correspond to those used when administering the compounds as analgesics.

The transquilizing activity of the compounds of the invention is determined by orally administering test compounds to rats at doses of about 0.01 to 50 mg / kg body weight and observing the following decrease in spontaneous motor activity. The daily dosage for mammals ranges from about 0.01 to 100 milligrams.

Anticonvulsive activity was determined by subcutaneously administering the test compound to male mice (Charles River) weighing 14 to 23 g in a vehicle of the same type as used in the anti-diarrheal activity test. Experiments were performed on groups of 5 mice each. The day before the test, the mice are fasted overnight, without limiting water intake. The test compound is administered in a volume of 10 ml / / kg using a subcutaneous syringe # 25. 1 hour after administration of the test substance, the animal is transcorally administered with an electroconvulsive shock at a current of 50 mA (60 Hz). In parallel, a control experiment was performed in which mice were given vehicle only. Electroconvulsive shock elicits tonic stretcher stretchers with latency time in all control mice

1.5 to 3 seconds. The test substance is considered to be effective if no tonic convulsions of the stretcher occur in the treated mouse for 10 seconds after electroconvulsive shock.

Efficacy against anxiety is determined in a manner similar to anticonvulsant, except that pentylentetrazole administered intraperitoneally at a dose of 120 mg / kg is used as a seizure agent. Administration of this agent induces clonic convulsions in more than 95% of control mice within less than 1 minute. A test substance is considered to be effective if the latency time of convulsions is at least doubled when premedicated with the substance.

Sedative / depressant efficacy was determined by administering subcutaneously different doses of the test compound to groups of 6 mice each. 30 and 60 minutes after application, mice are placed on a rotating rod for 1 minute and evaluated for their ability to remain on the rod. The inability of the treated mouse to stick to the rotating rod indicates the sedative / depressive efficacy of the test substance.

The invention is illustrated by the following non-limiting examples.

Example 1

3--2-Benzyloyy-4- (1,1-dimethylheyl) phenyl] cyclohexanone

To 9.25 g (0.368 mol) of magnesium metal (70-80 mesh) was slowly added 75.0 g (0.193 mol) of 2- (3-benzylooy-4-bromophenyl) -2-methyloctane in 200 ml of tetrahydrofuran. The resulting mixture was refluxed for 20 minutes, then cooled to -18 ° C, treated with 1.84 g (9.7 mmol) of copper (I) iodide and stirring was continued for 10 minutes. A solution of 18.5 g (0.193 mol) of 2-cyclohixen-1-one in b of 40 ml of tetrahydrofuran was slowly added to the reaction mixture at such a rate as to maintain the reaction temperature below -3 ^° C with cooling with ice / salt mixtures. The mixture was stirred for 30 minutes while maintaining the temperature below 0 [deg.] C. and then added to 500 ml of 2N hydrochloric acid and 2 liters of ice water. The aqueous mixture was extracted with ether (3.times.500 ml), the combined extracts washed with water (2.times.100 ml), brine (2.times.100 ml), dried (MgSO4) and evaporated to an oil. The oily material afforded 62.5 g (79.7%) of the desired product as an oil after chromatography on a column of 1.6 kg of silica gel, eluting with 20% ether in cyclohixane.

PMR (diuterochloroform, tetram butyl, a value):

0.84 (multiplet, thirminal methyl),

1.27 (singlet, geminal dimithyl),

3.32 (broad multiplet, binhyl methine group),

5.06 (singlit, benzyl methylene group),

6.7 - 7.3 (multiplet, aryl residue proton) and

7.32 (singlit, proton of the finyl residue).

IR (chloroform) 1709, 1613 and 1575 cm · ^ ^1.

Mass Spectrum: m / e = 406 (M &lt; + &gt;), 362,

321, 315 and 91.

The following compounds were prepared from the corresponding 2-benzyloxy-3-Z-N-bromobenzenes, and cycloalkenones using the above procedure:

3- [2-Benzyloxy-4- (2- (5-phenylpentyloxy)) phenyl] cyclohexanone

This product was obtained as an oil from 4.0 g (9.4 mmol) of 2-benzyloxy-4- [2- (5-phenylpentyloxy)] bromobenzene. Yield 3.6 g (87%).

PMR (deuterochloroform, tetramethylsilane, hodnoty values):

1.10 (doublet, J = 6 Hz, methyl),

3.30 (multiplet, methine group of the benzyl residue),

4.25 (multiplet, methine side chain group),

4.93 (singlet, benzyl ether methylene group),

6.30 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

6.37 (broad singlet, proton of aryl residue),

6.88 (doublet, J = 8 Hz, aryl residue proton),

7.23 (singlet, proton of phenyl);

7.38 (broad singlet, proton of the phenyl moiety),

IR, (chloroform): 1712, 1616 and 1592 cm -1,

Mass Spectrum: m / e = 422 (M &lt; + &gt;), 351,

323, 296, 278, 253, 205 and 91

Trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4-methylcyclohexanone

This product is obtained as an oil from 7.83 g (0.0201 mol) of 2-benzyloxy-4-1,1-dimethylheptylbromobenzene and 2.21 g (0.0201 mol) of 4-methylcyclohex-2-enone, Yield: 5.11 g (61%).

PMR (deuterochloroform, tetramethylsilane, <):

AND

0.81 (doublet, J = 7 Hz, methyl on Cl),

1.28 (singlet, geminal dimethyl),

5.06 (singlet, benzyl ether methylene group),

6.8 - 7.2 (multiplet, proton of the aryl residue);

7.35 (singlet, phenyl proton),

IR (chloroform): 1712, 1613 and 1575 ^cm-1

Mass Spectrum: m / e = 420 (M &lt; + &gt;), 363, 335, 329, 273, 271 and 91,

3- [2-Benzyloxy-4- (1,1-dimethylphenyl) phenyl] cyclopentanone

This product is obtained as an oil from

6.00 g (15.4 mmol) of 2-bis (1, 2-dimethylheptylbromobenzene); Yield 3.5 g (58%); Thin layer silica gel chromatography (0.25 mm) in a mixture of equal parts of ether and hexane gave Rf = 0.43,

3- [2-Benzyloxy-4- (1,1-dimethylethyl) phenyl] cycloheptanone

This product was obtained as an oil from 2.00 g of 2.00 g (15.4 mmol) of 2-benzyloxy-4- (1,1-dimethylheptylbromobenzene) and 1.69 g (15.4 mmol) of cycloheptenone. (46 percent)

3- (2,4-Dibenzyloxyphenyl) cyclohexanone

This product was obtained as a solid, m.p. 108 DEG-109 DEG C., from 43 g (0.116 mol) of 1-bromo-2,4-dibenzyloxybenzene and 11.1 g (0.116 mol) of cyclohex-2-enone. a mixture of ether and pentane,

PMR (depterochloroform, tetramethylsilane, hodnoty values):

1.47 - 2.8 (multiplet, methylene groups),

3.37 (broad multipeet, methine group of the benzyl residue),

4.98 (singlet, benzyl ether methylene groups),

6.47 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

6.53, (broad singlet, overlapping signal at 6.47, proton aryl residue),

6.99 (doublet, J = 8 Hz, proton of aryl residue) a

7.31 (singlet, phenyl proton),

IR (chloroform): 1709, 1618 and 1595 cm ^{@ 3} ,

Mass spectrum: m / e = 295, 181 and 91, Anal. Calcd. For C 26 H 26 O 3:

% C, 80.80;% H, 6.78.

80.88 ° C, 6.80% H,

3- [2-Benzyloxy-4- (1,1-pentyl) phenyl] cyclohexanone .....

This product is obtained as an oil from

10.4 g (0.0258 mol) of 2- (3-benzyloxy-4-bromophenyl) -2-methylnonane and 2.48 g (0.0258 mol)

2-cyclohexen-1-one, yield 5.0 g (46 percent),

PMR (depterochloroform, lelramelhylsilane, values of 5):

0.83 (multiplet, terminal methyl side chain j,

1.23 (singlet, geminal dimethyl),

3,4 (muttiptet, methinc group of the phenyl residue),

5.11 (single methylene group of the ether),

6.92 (doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

6.92 (doublet, λ = 2 Hz, proton of the aryl residue),

7.17 (doublet, J = 8 Hz, proton of the aryl residue) and

7.42 (broad singlet, proton of the phenyl residue).

IR (chloroform): 1715, 1618 and 1577 cm @ 4

Mass spectrum: m / e = 420 (M +), 377, 329 and 321.

3- (2-Benzyloxy-4-tert-butylphenyl) cyclohexanone

This product is obtained as an oil from

45.4 g (0.142 mol) of 2- (3-benzyloxy-4-bromophenyl) methylmethylpropane and 13.9 g (0.145 mol) of 2-cyclohexanedione. Yield 27.6 g (58%).

PMR (depterochloroform, tetramethylsilane, values of 5):

1.31 (singlet, t-butyl) ·,

5.10 (singlbt, ben zylephher mehrylene group) a

6.8-7.4, multiipet, prooon aryl residue and proton phenyl residue).

IR (chloroform: 1724, 1623 and 1582 cm @ -1 ⁾ .

Mass spectrum: m / e = 336 (M &lt; + &gt;), 321, 293, 245, and 91.

3- [2tBenzylooy-4- (1] 1-dimethylethyl) phenyl] cyclohexanone

This product was obtained as an oil from 24.0 g (0.0721 mol) of 2t (3-benzylnxrt4-tetramethyl) t-methylbuian and 7.06 g (0.0735 mol)

2-cyclohexen-1-one. Yield: 15.8 g (63%).

PMR (deuterochloroform, tbiramethrtsitae, values 5):

0.67 (triplet, J = 7 Hz, terminal methyl),

1.23 (singlet, geminal dimethyl),

5,10, methylene group of benzyl ether),

6.92 (doublet: J = 2 Hz, proton of the aryl residue),

6.92 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

7.17 (doublet, J = 8 Hz, proton of the aryl residue) and

7.42 (broad singlet, proton of the phenyl residue).

IR (chloroform); 1718, 1618 and 1575 ^cm-first

Mass spectrum: m / e = 350 (M &lt; + &gt;), 335, 321, 307, 259, and 91.

3- [2tBenzylnxyt4t (1,1-dimethylbutyl) phenyl] cyclohexanone

This product is obtained as an oil from

34.8 g (0.100 mol) of 2- (3-benzyloxy-4-bromophenyl) methylmethylpentaeu and 10.5 g (0.110 mol) of 2-cyclohexylphenone yield 15.1 g (42 percent).

PMR (deuterochloroform, tetramethylsilane, <] values:

0.80 (multiplet, terminal methyl),

1.22 (singlet, geminal dimethyl),

5.07 (singlet, benzene ether,

6.86 (doublet, J = 2 Hz, aloe residue proton),

6.86 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

7.08 (doublet, J = 8 Hz, proton of the aryl residue) and

7.34 (broad width, t of residue).

IR (chloroform): 1736, 1631 and 1592 cm ^-1 .

Mass spectrum: m / e = 364 (M &lt; + &gt;), 321, 273 and 91.

trans-3- [2tBeesterine-4t (1,1-dimethylheptylphenyl) -4- (2-propenyl) cyclohexanone

The product was obtained as -oleate 73.0 g (0.188 mol] Уtbrnm 2-bbezrloxr ^г T4T (У, ldimlbthylhtφtrl] bгrmbeezeeu and 25.5 g (0.188 mol) of 4- (2-rгopeeyl) t2 crktnhbxbet - The yield was 58.3 g (70%).

IR (chloroform): 1712, 1645, 1613 and 1575 µm ¹ .

Mass Spectrum: m / e = 446 (M +), 360, 354 and 91.

PMR (deuterrchlorΌfrrm, tbirambthylsitae, ó values):

0.82 (multiplet, terminal methyl),

1.23 (singlet, gemic dimethyl),

4.7 - 5.1 (multiplet, wavelet proton),

5.02 (singlet, methine of the benzyl residue),

5.3 - 6.1 (multsrlet, vinyl proton),

6.79 [doublet, J = 2 Hz, aryl residue proton),

6.82 (doublet of doublets, J = 8 Hz and 2 Hz, proton of the ar residue);

7.0 (doublet, J = 8 Hz, proton of the aryl residue).

3- [2-Benzyloxy-4- (1,1-dimethylpentyl) phenyl] cyclohexanone

This product was obtained as an oil from 29.6 g (0.0818 mol) of 2- (3-benzyloxy-4-bromophenyl) -2-methylhexane and 8.63 (0.09 mol) of 2-cyclohexen-1-one . Yield: 11.5 g (37 percent).

IC (chloroform): 1730, 1629 and 1592 cm ^-1 .

Mass spectrum: m / e = 378 (M ⁺ ), 335, 321, 287, and 91.

PMR (deuterochloroform, tetramethylsilane, δ values):

0.82 (multiplet, terminal methyl),

1.23 (singlet, geminal dimethyl),

3.35 (multiplet, methine group of the benzyl residue),

5.10 (singlet, methylene group of the benzyl residue),

6.90 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

6.90 (doublet, J = 2 Hz, proton of aryl residue),

7.13 (doublet, J = 8 Hz, proton of the aryl residue);

7.38 (broad singlet, phenyl).

3- [2-Benzyloxy-4- (1,1-dimethylhexyl) phenyl] cyclohexanone

This product is obtained as an oil from

30.2 g (0.0806 mol) of 2- (3-benzyloxy-4-bromophenyl) -2-methylheptane and 8.5 g (0.0886 mol)

2-cyclohexen-1-one. Yield: 11.0 g (35%).

IR (chloroform): 1715, 1623 and 1585 ст.

Mass spectrum: m / e = 392 (M ⁺ ), 348, 321, 301, 259, and 91.

PMR (deuterochloroform, tetramethylsilane, values of 5):

0.81 (multiplet, terminal methyl),

1.22 (singlet, geminal dimethyl),

3.4 (multiplet, methine group of the benzyl residue),

5.08 (singlet, methylene group of the benzyl residue),

6.88 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

6.88 (doublet, J = 2 Hz, aryl residue proton),

7.10 (doublet, J = 8 Hz, proton of aryl residue) and

7.37 (broad singlet, proton of the aryl residue).

3- [2-Benzyloxy-4- (1,1-dimethylnonyl) phenyl] cyclohexanone

This product is obtained as an oil from

30.5 g (0.073 mol) 2- (3-benzyloxy-4-bromophenyl) -2-methyldecane and 7.71 g (0.0803 mol)

2-cyclohexen-1-one. The yield was 13.5 g (43 percent).

IC (chloroform): 1715, 1623 and 1582 cm ^-1 .

Mass spectrum: m / e = 434 (M ⁺ ), 342, 321 and 91.

PMR (deuterochloroform, tetramethylsilane, δ values):

0.85 (multiplet, terminal methyl),

1.24 (singlet, geminal dimethyl),

3.4 (multiplet, methine group of the benzyl residue),

5.09 (singlet, methylene group of the benzyl residue),

6.88 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

6.88 (doublet, J = 2 Hz, aryl residue proton),

7.11 (doublet, J = 8 Hz, proton of the aryl residue);

7.37 (broad singlet, phenyl).

3- [2-Benzyloxy-4- (1,1-dimethyldecyl) phenyl] cyclohexanone

This product was obtained as an oil from 40.0 g (0.0928 mol) of 2- (3-benzyloxy-4-bromophenyl) -2-methylenedecane and 9.8 g (0.102 mol)

2-cyclohexen-1-one. The yield was 7.0 g (17 percent).

IC (chloroform): 1715, 1623 and 1585 cm ^-1 .

Mass spectrum: m / e = 448 (M ⁺ ), 321 and 91.

PMR (deuterochloroform, tetramethylsilane, δ values):

0.84 (multiplet, terminal methyl),

1.23 (singlet, geminal dimethyl),

3.5 (methine group of the benzyl residue),

5.02 (singlet, methylene group of the benzyl residue),

6.77 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

6.77 (doublet, J = 2 Hz, aryl residue proton),

7.13 (doublet, J = 8 Hz, proton of the aryl residue);

7.38 (broad singlet, phenyl).

3- [2-Benzyloxy-4- (1,1-dimethylundecyl) phenyl] cyclohexanone

This product is obtained as an oil from

27.5 g (0.062 mol) of 2- (3-benzylOxy-4-bromophenyl) -2-methyldodecane and 6.68 g (0.0682 mol) of 2-cyclohexen-1-one. Yield: 11.5 g (40%).

IR. (Chloroform): 1718, 1623, 1585 cm ^1st

Mass spectrum: m / e = 462 (M +), 417, 371, 321, and 91.

PMR (deuterochloroform, tetramethylsilane, <):

0.89 (multiplet, terminal methyl),

1.26 (singlet, geminal dimethyl),

3.4 (multiplet, methine group of the benzyl residue),

5.11 (singlet, methylene group of the benzyl residue), 6.89 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

6.89 (doublet, J = 2 Hz, aryl residue proton),

7.12 (doublet, J = 8 Hz, proton of the aryl residue) a

7.37 (broad singlet, phenyl).

3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclooctanone

This product was obtained from 15.0 g (38.6 mmol) of 2- (3-benzyloxy-4-bromophenyl) -2-methyloctane and 4.78 g (38.6 mmol) of 2-cyclooctenten-1-one. Yield: 10.6 g (63%).

IC (chloroform): 1715, 1629 and 1587 cm -1.

Mass Spectrum: m / e = 434 (M +), 477, 363, 349, 343, and 91.

PMR (deuterochloroform, tetramethylsilane, <):

0.83 (multiplet, terminal methyl),

3.7 [broad multiplet, methine group of the benzyl residue),

5.06 (singlet, benzyl methylene group);

6.7 - 7.5 (multiplet, proton of the aryl residue).

Example 2

3- [2-Benzyloxy-4- [1,1-dimethylheptyl] phenyl] cyclohex-2-enone

To 360 mg (14.4 mmol) of magnesium metal (70-80 mesh) was slowly added a solution of 3.89 g (10 mmol) of 2- (3-benzyloxy-4-bromophenyl) -2-methyloctane in 10 mL of tetrahydrofuran. The mixture was heated to reflux for 30 minutes, then cooled to 0 ° C and a solution of 1.40 g (10 mmol) of 3-ethoxy-2-cyclohexen-1-one in 3 mL of tetrahydrofuran was slowly added. The reaction mixture was stirred at 0 ° C for 30 minutes, then 20 ml of 1N sulfuric acid was added, the resulting mixture was heated on a steam bath for 30 minutes, cooled and added to a mixture of 200 ml of ether and 200 ml of water. The organic extract is washed successively with 200 ml of saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated to an oily residue. The crude product was purified by column chromatography on 170 g of silica gel using a mixture of equal parts of ether and pentane as eluent. 2.5 g (54%) of the title compound are obtained as an oil.

PMR (deuterochloroform, tetramethylsilane, values <5:

0.87 (multiplet, terminal methyl side chain),

1.30 (singlet, geminal dimethyl),

2.05 (double triplet, J = 6 and 6 Hz, methylene group on Cs),

5.19 [singlet, benzyl ether methylene group),

6.30 (triplet, J = 1 Hz, vinyl proton), 7.00 (double doublet, J = 8 and 2 Hz, aryl residue proton),

7.02 (doublet, J = 2 Hz, aryl residue proton),

7.25 (doublet, J = 8 Hz, proton of the aryl residue) a

7.45 (singlet, phenyl proton).

IC (chloroform): 1667, 1610, and 1558 cm -1.

Mass spectrum: m / e = 404 (M &lt; + &gt;), 319, 313 and 91.

In an analogous manner, a yield of 4.12 g (77%) was prepared using 1.98 g (12.9 mmol) of 3-ethoxy-6-methyl-2-cyclohexen-1-one, 0.61 g (25%). , 7 mmol) of magnesium and

12.9 mmol of 2- [3-benzyloxy-4-bromophenyl) -2-methyloctane oily 3- [2-benzyloxy-4- (1-methyl-4-bromophenyl) -2-methyloctane] phenyl] - 4-Methylcyclohex-2-enone.

IC (chloroform): 1667, 1613, and 1565 cm 4

Mass spectrum: m / e = 418 (M &lt; + &gt;), 400, 385, 333, 327, 299, 291 and 91.

PMR (deuterochloroform, tetramethylsilane, values of 5):

0.85 (multiplet, terminal methyl),

1.02 (doublet, J = 7 Hz, methyl),

2.45 (multiplet, methylene),

3.2 (mellietet, mttt, ii, a, yy type),

5.10 (s, methylene group of the benzyl residue),

6.01 (doublet, J = 1 Hz, vinyl proton),

6.90 (multiplet, aryl proton) and

7.37 (singlet, proton of the phenyl residue).

Preparation

2- (4-Bromo-3-hydroxyphenyl) -2-methyl-octane

To a solution of 110 g (0.50 mol) of 2- (3-hydroxyphenyl) -2-methyloctane in 200 ml of carbon tetrachloride at 0 ° C was added dropwise a solution of g (0.50 mol) of bromine in 90 ml of carbon tetrachloride, dropwise. The reaction mixture was stirred for an additional 15 minutes and then evaporated to give 150 g (100%) of the desired product as an oil.

PMR (deuterochloroform, tetramethylsilane, values of 5):

0.85 (wide triplet, terminal methyl),

0.8 - 1.9 (multiplet, methylene groups),

1.28 (singlet, geminal dimethyl),

5.4 (broad singlet, phenolic proton),

6.78 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

7.02 (doublet, J = 2 Hz, proton at C 2 aryl residue);

7.37 (doublet, J = 8 Hz, proton on C 5 aryl residue).

IR (chloroform): 3559, 3289, and 1585 cm ^-1 .

Mass spectrum: m / e = 300, 289 (M &lt; + &gt;), 215, 213, 201, 199, 187, and 185.

The following compounds were prepared in an analogous manner:

2- (4-Bromo-3-hydroxyphenyl) -2-methylnonane

This product was obtained as an oil from 7.8 g (0.033 mol) of 2- (3-hydroxyphenyl) -2-methylnonane. Yield: 82% (8.5 g).

PMR (deuterochloroform, tetramethylsilane, values of 5):

0.86 (multiplet, terminal methyl),

1.27 (singlet, geminal dimethyl),

5.50 (broad singlet, hydroxyl group),

6.83 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

7.08 doublets, J = 2 Hz, proton of aryl residue),

7.43 (doublet, J = 8 Hz, proton of the aryl residue).

IR (chloroform): 3279, 1613 and 1587 cm ^-1 .

Mass spectrum: m / e = 314, 312 (M &lt; + &gt;), 212, 210, 185 and 187,

2- (4-Bromo-3-hydroxyphenyl) -2-methylbutane

This product was obtained in oily form from 9.50 g (0.0579 mol) of 2- (3-hydroxyphenyl) -2-methylbutane. Yield: 12.7 g (98%).

PMR (deuterochloroform, tetramethylsilane, values of 5):

0.67 (triplet, J = 7 Hz, terminal methyl),

1.23 (singlet, geminal dimethyl),

1.56 (quartet, J = 7 Hz, methylene group),

5.2 (broad singlet, hydroxyl group),

6.84 (double doublet, J = 8 Hz, proton of the aryl residue).

IR (chloroform): 3521, 3279, 1608, 1600 and 1577 cm @ -1.

Mass spectrum: m / e = 244, 242 (M &lt; + &gt;), 229, 227, 215, 213, 187 and 185.

2- (4-bromo-3-hydroxyphenyl) -2-methylpentane

This product was obtained as an oil from 21.0 g (0.118 mol) of 2- (3-hydroxyphenyl) -2-methylpentane. Yield: 29.9 g (99%).

PMR (deuterochloroform, tetramethylsilane, <):

0.83 (multiplet, terminal methyl),

1.22 (singlet, geminal dimethyl),

5.42 (broad singlet, hydroxyl group),

6.75 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

6.98 (doublet, J = 2 Hz, proton aryl residue,

7.32 (doublet, J = 8 Hz, proton of the aryl residue). ,

IR (chloroform): 3610, 3333, 1618, and 1600 mc ^-1 .

Mass spectrum: m / e = 258, 256 (M ^& lt ^{; +} & gt ^; ), 243, 241, 215, 213, 201, 199, 187, and 185.

2- (4-bromo-3-hydroxyphenyl) -2-methylhexane

This product was obtained as an oil from 16.0 g (0.0833 mol) of 2- (3-hydroxyphenyl) -2-methylhexane. The yield was 22.8 g (100 percent).

IR (chloroform): 3610, 3333 and 1600 ^cm-first

Mass spectrum: m / e = 272 and 270 (M +), 215, 213, 187.

2- (4-bromo-3-hydroxyphenyl) -2-methylheptane

This product was obtained as an oil from 20.0 g (0.971 mol) of 2- (3-hydroxyphenyl) -2-methylheptane. Yield. is quantitative. IC (chloroform): 3584, 3333, and 1600 cm -1.

Mass Spectrum: m / e = 286 and 284 (M &lt; + &gt;), 215, 213, 187 and 185.

PMR (deuterochloroform, tetramethylsilane, hodnoty values):

0.87 (multiplet, terminal methyl),

1.30 (singlet, geminal dimethyl),

5.49 (broad singlet, hydroxyl group),

6.83 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

7.07 (doublet, J = 2 Hz, proton of aryl residue,

7.42 (doublet, J = 8 Hz, proton of the aryl residue).

2- (4-Bromo-3-hydroxyphenyl) -2-methyldecane

This product was obtained as an oil from 20.6 g (0.0831 mol) of 2- (3-hydroxyphenyl) -2-methyldecane. Yield: 23.2 g (85 percent).

IR (chloroform): 3571, 3333 and 1661 cm ¹ ".

Mass spectrum: m / e = 328 and 326 (M &lt; + &gt;), 313, 311, 215 and 213.

PMR (deuterochloroform, tetramethylsilane, δ values):

0.82 (multiplet, terminal methyl),

1.30 (singlet, geminal dlmethyl),

5.49 (singlet, hydroxyl group),

6.82 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

7.07 Duplicate, J = 2 Hz, proton of aryl residue,

7.41 (doublet, J = 8 Hz, proton of the aryl residue).

2- (4-Bromo-3-hydroxyphenyl) -2-methylenedecane

This product was obtained as an oil from 21.0 g (0.0802 mol) of 2- (3-hydroxyphenyl) -2-methylenedecane. The yield is quantitative.

IR (chloroform): 3571, 3333 and 1600 (broad band) cm ^-1 .

Mass Spectrum: m / e = 342 and 340 (M ^& lt ^{; +} & gt ^; ), 215, 213, 187 and 185.

PMR (deuterochloroform, tetramethylsilane, δ values):

0.86 (multiplet, terminal methyls),

1.22 (singlet, geminal dimethyl),

5.45 (broad singlet, hydroxyl group),

6.74 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

6.99 (doublet, J = 2 Hz, proton aryl residue,

7.33 (doublet, J = 8 Hz, proton of the aryl residue).

2- (4-Bromo-3-hydroxyphenyl) -2-methyldodecane

This product was obtained as an oil from 21.0 g (0.0761 mol) of 2- (3-hydroxyphenyl) -2-methyldodecane. The yield was 22.0 g (81 percent).

IR (chloroform): 3597, 3333, 1613 and 1592 cm ^-1 .

Mass spectrum: m / e = 356 and 354 (M &lt; + &gt;), 340, 338, 215 and 213.

PMR (deuterochloroform, tetramethylsilane, δ values):

0.92 (multiplet, terminal methyl),

1.29 (singlet, geminal dimethyl),

5.47 (broad singlet, hydroxyl group),

6.81 (double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

7.06 (doublet, J = 2 Hz, proton of aryl residue),

7.41 (doublet, J = 8 Hz, proton of the aryl residue).

Preparation В

2- (3-Benzyloxy-4-bromophenyl) -2-methyloctane

To a suspension of 23.0 g (0.575 mol) of potassium hydride in 400 ml of N, N-dimethylformamide cooled to -18 ° C, a solution of 150 g (0.5 mol) was added over 45 minutes while maintaining the reaction temperature below -15 ° C. 2- (4-bromo-3-hydroxyphenyl) -2-methyloctane in 400 ml of N, N-dimethylformamide. After stirring for 15 minutes, a solution of 98.3 g (0.575 mol) of benzyl bromide in 200 ml of Ν, Ν-dimethylformamide was added. The resulting mixture was warmed to room temperature, stirred for 30 minutes, then added to 6 L of ice water. The aqueous mixture was extracted six times with 500 ml of ether each time, the combined extracts were washed twice with 1 liter of water and once with 1 liter of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give the title compound in quantitative yield.

PMR (deuterochloroform, tetramethylsilane, δ values):

0.85 (wide triplet, terminal methyl),

0.8 - 2.0 (multiplet, methylenes),

1.22 (singlet, geminal dimethyl),

5.17 (singlet, methylene group of the benzyl residue),

6.7 - 7.6 (two multiplets, the proton of the aryl residue and the proton of the phenyl residue).

IR (chloroform) 1592 and 1575 cm ^1st

Mass spectrum: m / e = 390, 388 (M +), 375, 373, 354, 352, 305, 303, and 91.

The following compounds are also prepared in an analogous manner:

2- (3-Benzyloxy-4-bromophenyl) -2-methylnonane

This product was obtained in oily form from 8.5 g (0.027 mol) of 2- (3-hydroxy-4-bromophenyl) -2-methylnonane, 0.744 g (0.031 mol) of sodium hydride and 5.3 g (0.031 mol) of benzyl bromide. Yield: 10.4 g (95%).

PMR (deuterochloroform, tetramethylsilane, δ values):

0.87 (terminal methyl),

1.23 (singlet, geminal dimethyl),

5.18 (singlet, benzyl ether methylene group),

6.8 '(double doublet, J = 8 Hz and 2 Hz, proton of the aryl residue),

6.97 (doublet, J = 2 Hz, aryl residue proton,

7.43 (multiplet, proton of the aryl residue and proton of the phenyl residue).

IR (chloroform): 1600 and 1575 cm ^-1 .

Mass spectrum: m / e = 404, 402 (M +), 305, 303, and 91.

2- (3-Benzyloxy-4-bromophenyl) -2-methylpropane

This product was obtained from 38.0 g (0.166 mol) of 2- (4-bromo-3-hydroxyphenyl) -2-methylpropane in a yield of 46.5 g (88%). The crystalline melting point of pentane is 52-54 ° C.

PMR (deuterochloroform, 'tetramethylsilane, δ values):

1.25 (singlet, t-butyl), 5.18 (singlet, benzyl ether methylene group),

6.7 - 7.0 (multiplet, two protons of the aryl residue),

7.2 - 7.6 (multiplet, one proton of the aryl residue and proton of the phenyl residue).

IR (chloroform): 1600 and 1585 cmA

Mass spectrum: m / e = 320, 318 (M &lt; + &gt;), 305, 303, 239 and 223.

2- (3-Benzyloxy-4-bromophenyl) -2-methylbutane

This product was obtained as an oil from 17.3 g (0.0777 mol) of 2- (4-bromo-3-hydroxyphenyl) -2-methylbutane. Yield 24.9 g (99%).

i _

IR (chloroform): 1600 and 1585 cm ^-1 .

Mass spectrum: m / e = 334, 332 (M &lt; + &gt;), 319, 317, 309, 303, 253, 223 and 91.

2- (3-Benzyloxy-4-bromophenyl) -2-methylpentane

This product was obtained as an oil from 25.7 g (0.100 mol) of 2- (4-bromo-3-hydroxyphenyl) -2-methylpentane. Yield 34.3 g (99%).

PMR (deuterochloroform, tetramethylsilane, values of 5):

0.80 (multiplet, terminal methyl),

1.23 (singlet, geminal dimethyl),

5.12 (singlet, benzyl ether methylene group),

6.6 - 6.9 (multiplet, two aryl protons),

7.1 - 7.5 (multiplet, aryl proton and phenyl proton).

IR (chloroform): 1610 and 1595 cm -1.

Mass spectrum: m / e = 348, 346 (M &lt; + &gt;), 333, 331, 305, 303 and 91.

2- (3-Benzyloxy-4-bromophenyl) -2-methylhexane

This product was obtained as an oil from 22.7 g (0.0831 mol) of 2- (4-bromo-3-hydroxyphenyl) -2-methylhexane. Yield: 30 g (98%).

IR (chloroform): 1605 and 1592 cm ^-1 .

Mass spectrum: m / e = 363, 361 (M +), 305 and 303.

PMR (deuterochloroform, tetramethylsilane, values of 5):

0.78 (multiplet, terminal methyl),

1.18 (singlet, geminal dimethyl),

5.12 (singlet, benzyl methylene group),

6.65 - 6.9 (multiplet, proton of aryl residue),

7.15 - 7.6 (multiplet, proton of the aryl and phenyl moieties).

2- (3-Benzyloxy-4-bromophenyl) -2-methylheptane

This product was obtained as an oil from 23.0 g (0.0806 mol) of 2- (4-bromo-3-hydroxyphenyl) -2-methylheptane. The yield is quantitative.

IR (chloroform): 1600 and 1582 cm ^-1 .

Mass Spectrum: m / e = 376, 374 (M &lt; + &gt;), 305, 303, 215, and 213.

PMR (deuterochloroform, tetramethylsilane, hodnoty values):

0.80 (multiplet, terminal methyl),

1.19 (singlet, geminal dimethyl),

5.12 (singlet, benzyl methylene group),

6.65 - 6.95 (multiplet, proton of aryl residue),

7.15 - 7.6 (multiplet, proton of aryl radical and phenyl).

2- (3-Benzyloxy-4-bromophenyl) -2-methyldecane

This product was obtained as an oil from 23.2 g (0.0712 mol) of 2- (4-bromo-3-hydroxyphenyl) -2-methyldecane. The yield is quantitative.

IR (chloroform): 1600 and 1585 cm ^-1 .

Mass Spectrum: m / e = 418 and 416 (M &lt; + &gt;), 305, 303, 215 and 213.

PMR (deuterochloroform, tetramethylsilane, δ values):

0.91 (multiplet, terminal methyl),

1.26 (singlet, geminal dimethyl),

5.19 (singlet, methylene group of the benzyl residue),

6.7 - 7.0 (multiplet, aryl residue proton),

7.25 - 7.65 (multiplet, proton of the aryl radical and phenyl).

2- (3-Benzyloxy-4-bromophenyl) -2-methylenedecane

This product was obtained as an oil from 27.3 g (0.113 mol) of 2- (4-bromo-3-hydroxyphenyl) -2-methylenedecane. Yield: 40.0 g (82%).

IR (chloroform): 1605 and 1587 cm ^-1 .

Mass spectrum: m / e = 432, 430 (M ⁺ ), 305, 303, 215, and 213.

PMR (deuterochloroform, tetramethylsilane, δ values):

0.90 (multiplet, terminal methyl),

1.24 (singlet, geminal dimethyl),

5.18 (singlet, methylene group of the benzyl residue),

6.7 - 7.0 (multiplet, aryl residue proton),

7.2 - 7.6 (multiplet, aryl proton and phenyl).

2- (3-Benzyloxy-4-bromophenyl) -2-methyldodecane

This product was obtained as an oil from 22.0 g (0.0620 mol) of 2- (4-bromo-3-hydroxyphenyl) -2-methyldodecane. The yield is

27.5 g (100%).

IR (chloroform): 1605 and 1592 cm ^-1 .

Mass spectrum: m / e = 446 and 444 (M ⁺ ), 305 and 303.

PMR (deuterochloroform, tetramethylsilane, values of 5):

0.86 (multiplet, terminal methyl),

1.21 (singlet, geminal dimethyl),

5.13 (singlet, benzyl methylene group),

6.7 - 6.95 (multiplet, proton of aryl residue),

7.2 - 7.55 (multiplet, proton of the aryl radical and phenyl).

Claims (4)

A process for the preparation of 3- (2-hydroxy-4-substituted-phenyl) -cycloalkanone derivatives of the general formula I, in which: Q is a protecting group of the phenolic hydroxyl function, n is 0, 1, 2 or 3, R 2 represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 alkenyl group, a phenyl group or a C 1 -C 4 phenylalkyl group in the alkyl moiety, Z is C 1 -C 13 alkylene or a radical of formula - (alk ', -O' (alk ₂ ) '-, BACKGROUND OF THE INVENTION wherein (alki) and (alka) are in each case an alkylene group having 1 to 13 carbon atoms, provided that the sum of the carbon atoms in the (alki) + (alkz) groups is not greater than 13 and m and n are each 0 or 1; W represents a hydrogen atom, a pyridyl group or a radical of formula wherein W 1 represents a hydrogen, fluorine or chlorine atom, characterized in that the compound of the general formula III, Q, Z and W, as defined above, are subjected to a Grignard reaction with a compound of formula IV wherein: Y is hydrogen or C 1 -C 4 alkoxy, and n and R 2 are as defined above, with at least one of R 2 and Y being hydrogen. 2. A process according to claim 1, wherein the starting material is a compound of formula IV, wherein R2 and n are as defined above and Y is hydrogen, and the Grignard reaction is carried out at a temperature in the range of -20 ° C. to 0 ° C. 3. The process according to claim 1, wherein the Grignard reaction is carried out in the presence of cuprous iodide. 4. The process of claim 1 wherein the starting material is a compound of formula (IV) wherein R2 and n are as defined above and Y is C1-C4 alkoxy and the Grignard reaction is carried out at a temperature of from -30 to 4-10 ° C.