CS216506B2 - Method of making the derivatives of the 3-+l 2-hydroxy-4-subst.phenyl+p cycloalcanols - Google Patents

Abstract

The invention relates to a process for producing derivatives 3- (2-hydroxy-4-substitutedphenyl) cycloalkanols general formula by reacting the corresponding ketone with a hydride metal.

Description

The present invention relates to a process for the preparation of certain cycloalkanols having 5 to 8 carbon atoms in the cycloalkyl ring containing in the 3-position 2-hydroxy-4- (ZW-substituted) phenyl lovene, wherein Z represents a C 1 -C 13 alkylene group or a residue of the formula - (alk- _m- O- (alk2) _n - in which each of the symbols man has a value of ΰ or 1 and each of the symbols falki) and (alkz) represents an alkylene group having 1 to 13 carbon atoms, with the sum the carbon atoms in the (a-1k1) + (alk2) radicals are not higher than 13, and W represents a hydrogen atom, a phenyl, chlorophenyl, fluorophenyl or pyridyl group.

The above products are useful as central nervous system affecting agents, 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.

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 pain conditions, which at the same time has minimal side effects. The most commonly used substance, aspirin, has no practical significance for the treatment of major pain and is also known to exhibit various undesirable side effects. Other analgesics such as d-propoxyphene, codeine and morphine are addictive. This clearly implies a need for a better and more effective analgesic.

U.S. Patent 3,576,887 (Apr 27, 71) discloses a series of 1- ((-hydroxy-alkyl-2-o-hydroxyphenylcyclohexane and -cyclohexane derivatives as intermediates for the preparation of 6,6-dialkyltetrahydro- and hexahydrodibenzo [b] , d] pyranes, which can be used as central nervous system depressants.

It has now been found that certain cycloalkanones containing a 2-hydroxy-4-substenyl group at the 3-position (see general formula 1j below) are effective as agents for influencing the central nervous system, in particular as analgesics, tranquilizers, sedatives and anti anxiety in mammals, including humans, and / or as anticonvulsants, diuretics, and antidiarrheal agents for mammals, including humans, The invention also discloses various derivatives of these compounds useful as dosage forms thereof, as well as intermediates for the preparation of compounds of Formula I , including the method of their manufacture.

The compounds produced by the process of the invention corresponding to the general formula (I) in which:

R represents a saturated or unsaturated cycloalkyl radical selected from the group consisting of radicals of formulas I-A, I-B, I-C and

I-D,

in which the dashed line represents an optionally present double bond at any of the indicated positions, and in the case of the presence of a double bond, a residue as defined by R3 may not be present,

R1 represents a hydrogen atom, a C1-C5 alkanoyl group, a benzyl group, a -P (Oj (OH) 2 group and its mono-sodium and potassium salts, a -CO2CH2zCOOH group and its sodium and potassium salts, or - CO- [CH 2] _p -NR 5 R 6, where p is a number of 1 to 4, R 5 and R 6 are each independently hydrogen or. C 1 -C 4 alkyl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperidine, pyrrole, pyrrolidine, morpholine and N-alkylpiperazine (C 1 -C 4) -alkyl,

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,

R3 represents a hydrogen atom or a methyl group,

R a represents a hydrogen atom or a C 1 -C 6 alkyl group, provided that when R 3 represents a methyl group, R 4 represents a hydrogen atom,

Z represents an alkylene group having 1 to 13 carbon atoms or the remainder of the formula - (alki) _m -O- (alkzine), wherein (alkij and (alkjj each represent an alkylene group having 1 to 13 carbon atoms) with the sum of the carbon atoms in groups (alki) + (alkz) is not higher than 13, the amine is always 0 or 1, and

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

- @ - «1 1 where

Wi represents a hydrogen, fluorine or chlorine atom.

The invention also includes pharmaceutically acceptable acid addition salts of those compounds of formula I that contain basic groups. As. typical examples of such compounds are those in which W represents a pyridyl group and / or OR 1 represents a basic ester residue. 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, malic acid salts, malonates, maleates, pomoates, salicylates, stearates, phthalates, succinates, gluconates, 2-hydroxy-3-naphthoates, lactates, mandelic acid salts and methanesulfonates.

Compounds of the invention which have the radicals I-A to I-D in the meaning of R have a center of asymmetry at positions 1, 3 and 4 and, in the case where the cycloalkyl radical is six to eight, at the 5-position of the cycloalkyl. and, of course, may contain other centers of asymmetry in the substituents at positions 4 and 5, and in the —Z — W group on the phenyl ring. Due to the quantitatively higher biological activity, the cis-arrangement between the substituent at the 1-position of the cycloalkyl ring and the phenolic or substituted phenolic residue at the 3-position and the trans-arrangement between the substituents at the 3-position and 4 and the 4-position at the cycloalkyl ring are preferred.

For the sake of simplicity, the above formulas refer to racemic compounds, but it is to be understood that racemic mixtures of the respective compounds, mixtures of diastereomers as well as pure enantiomers and diiastereontomers are meant by these formulas. The use of racemic mixtures, mixtures of diastereomers, as well as pure enantiomers and diastereomers is determined by their biological activity as determined by the procedures described below.

Because of their greater biological activity over the other compounds described herein, those compounds wherein R is one of the groups of the above formulas I-A to I-D are preferred, R 2 is hydrogen or alkyl as defined above, R 1 is hydrogen or above R 3 represents a hydrogen atom or a methyl group, R 4 represents a hydrogen atom or an alkyl group as defined above, and Z and W have the following meanings:

215 5 0 6

8

Z m is C 8 -C 6 alkylene - C 7 alkylene - (alki) m -O- (alk 2) _n O hydrogen

(alki) _m -O- (alk ₂ ) _n O

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

R 1 and R 5 are hydrogen atoms,

Z is —C (CH3) 2 (CH2) 6 and W is hydrogen,

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

R 2 represents a hydrogen atom, a methyl, propyl or propenyl group,

R 3 represents a hydrogen atom and

R a represents a hydrogen atom or a methyl group.

With respect to analgesic activity, particularly preferred compounds from the group of the above-mentioned preferred compounds are those wherein R2 is methyl, propyl. or a propenyl group and R 3 and R 4 represent hydrogen atoms.

The compounds of general formula (I) are used as starting materials in the preparation of the compounds of the formula I according to the invention as described below

wherein n is 0, 1, 2 or 3 and

R1, R2, R3, R4, Z and W are as defined above.

These starting materials can be prepared as described in our related Czechoslovak patents 216,502, 216,503, 216,505.

The cycloalkanol derivatives of the above general formula (I) according to the invention are prepared by reduction of the corresponding protected cycloalkanones. The preferred reducing agent in this case is sodium borohydride, which not only provides satisfactory yields of the desired product, but retains the pyridyl 1 hydrogen also protecting group on phenolic hydroxyl function and reacts so slowly with solvents containing hydroxyl groups (methanol, ethanol, water) to allow their use In general, the reaction is carried out at a temperature of from about -40 DEG C. to about 30 DEG C., but lower temperatures of up to about -70 DEG C. can be used to increase the selectivity of the reduction. It is desirable or desirable to carry out the reduction at a higher temperature, using isopropyl alcohol or dimethyl ether of diethylene glycol as the solvent, and occasionally potassium tri-sec-butylborohydride is preferred as a reducing agent because it aids the stereoselective formation of trans-1,3-phenylcyclic. The reduction is carried out in dry tetrahydrofuran at a temperature below about -50 ° C, using equimolar amounts of ketoderivatives and a reducing agent.

Other reducing agents, such as lithium borohydride, diisobutylaluminum hydride or lithium aluminum hydride, which can also be used, require working under anhydrous conditions and using solvents free of hydroxyl groups such as 1,2-dimethoxyethane, tetrahydrofuran, diethyl ether or ethylene glycol dimethyl ether.

Of course, the cycloalkanols of formula I in which OR 1 is a hydroxyl group can be obtained directly by catalytic reduction of protected cycloalkanones in the presence of palladium on carbon, or by catalytic or chemical reduction of unprotected cycloalkanones (OR 1 = OH) using the reducing agents described above.

In practice, it is preferable to produce unprotected cycloalkanols of formula I by reducing the above benzyl-protected cycloalkanones, since this procedure allows stereochemical reduction control and formation of the cis-hydroxyepimer as the major; product, thereby facilitating the separation and purification of epimeric alcohols.

Alternatively, the corresponding cycloalkenone or protected cycloalkenone may be chemically reduced, for example using sodium borohydride, to the cycloalkenol, from which the protecting group is then cleaved off, if necessary, to regenerate the phenolic hydroxy group.

Esters of the invention wherein R 1 is an alkanoyl group as defined above or a radical of the formula -CO- (CH 2) _p NR 5 R 6 are readily prepared by reacting the corresponding compounds in which R 1 is hydrogen with the corresponding alkanoic acids or acids of formula HOOC- (CFfejpNiRsRe) Alternatively, these esters are prepared by reacting the above hydroxy derivatives with the chlorides or anhydrides of the corresponding alkanoic acids, for example acetyl chloride or acetic anhydride, in the presence of a base such as pyridine.

Thus, the esters of the above compounds in which OR 1 is a hydroxyl group are prepared by acylation according to the procedures described above. Compounds in which only the R radical is acylated are obtained by mild hydrolysis of the corresponding diacyl derivatives, with the advantage of facilitating the hydrolysis of the phenolic acyl group. The thus formed compounds can then be further acylated with a different acylating agent to form a diesterified compound containing different ester groups.

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

Tests using thermal stimuli

(a) Hot plate analgesic efficacy test

A modification of the procedure described by Woolfe and MacDonald [J. Pharmaool. Exp. Ther. 89, 300-307 (1944)]. The test mice are placed on a 0.3 cm thick aluminum plate, which is heated in a controlled manner to irritate the mouse paws with heat. Under the aluminum plate there is an infrared radiator with a power input of 2.50 W. The radiator operation is controlled by a thermal regulator coupled to thermistors on the surface of the plate so that the plate temperature 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 as soon as the animal's paw touches the plate. Experimental mice are observed at 0.5 and 2 hours after administration of the test compound to detect the first jerky movements of one or both hindpaws, or for 10 seconds in the absence of such movements. Morphine has an MPE 50 of -4-5.6 mg / kg (subcutaneous) in this test.

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

This test is a modification of the procedure described by D‘Amour and Schmith [J. Pharmaool. 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 MPE 50 value of 3.2 to 5.6 mg / kg (subcutaneous administration).

cj Tests in submerged tail mice

The method used is a modification of the procedure developed by Benbasset et al. [Sheet. int. Pharmacoiyn. 122, 434 (1959)]. Male white mice (Charles River CD-I strain, weighing 19-21 g) were weighed and labeled. Each substance is tested per group of 5 animals, each animal serving as its own control. For general efficacy, the new test substance is first administered intraperitoneally or subcutaneously at a dose of 56 mg / kg administered in a volume of 10 ml / kg. Prior to and at 0.5 and 2 hours after drug administration, each animal is placed in a cylinder having 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 protruding tail of the animal 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 seconds, rounded to 0.5 seconds. In parallel, the test is carried out after application of the vehicle and standard of known efficacy only, if the efficacy of the test substance does not fall to baseline within 2 hours after drug administration, the latency of the test day is determined. final measurement 24 hours after administration.

Test using chemical stimuli

Suppression of painful convulsions (writhing) induced by phenylbenzoquinone

Groups of 5 mice (Carworth Farms CF-1) are each pre-treated by subcutaneous or oral administration of saline, morphine, codeine or test compound. Phenylbenzoquinone, known to induce ahdominal contraction, is then administered intraperitoneally at 20 minutes (for subcutaneous or oral administration) or 50 minutes (for oral administration). Observe for 5 minutes to determine whether or not there are painful cramps, and MPE50 values are determined for each test substance to prevent painful cramps when pretreated.

Tests using pressure stimuli

Efficiency in the Haffner test

A modification of the procedure described by Haffner (Experimentelle Pfufung Schmerzstillendor. Deutsch. Med. Wschr., 55, 731-732 (1929)) is used to determine the efficacy of a test compound on an aggressive tail-induced response.

Male white rats (150 to 60 g) of the Charles River (Sprague-Dawley) CD strain are used for the assay. Prior to administration of the test substance and again at 0.5, 1, 2, and 3 hours after drug administration, the rat's tail is clamped (John-Hopkins, 6.35 cm bulldog) clampj. The endpoint of each experiment is the pronounced offensive behavior and biting towards the pain-stimulating tool, recording the latency time of the response in seconds If no attack occurs within 30 seconds, the clamp is removed and the latency of the response is recorded as 30 seconds Morfin is the time of interruption at this η / measured time

When administered orally or parenterally as analgesics, the compounds of the invention 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 compounds described herein 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. 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 flavorings and a test effective for intraperitoneal administration at a dose of 17.8 mg / kg.

Tests using electrical stimuli

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

A modification of the method described by Tenen [Psycbopharmacologia, 12, 278-285 (1968)] is used to determine the pain threshold. Male white rats (175-200 g) of the Charles River strain (Sprague-Dawley) CD are used for testing, and paws of all rats are immersed in a 20% solution of glycerin in saline prior to administration of the test substance. paws, at thirty second intervals, give one second electric shocks at increasing current intensity, and these increasing intensities are 0.26, 0.39, 0.52, 0.78, 1.05, 1.31, 1.58, 1.86 , 2.13, 2.42, 2.7.2, and 3.04 mA The behavior of each animal is recorded to see if an electric shock occurs

a rebound, bj to screech, and / or

(c) jump or fast 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:

check time „ί -; —— ^{x 100} dye check time. 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.

The most appropriate dosage for a particular patient, which will vary depending on the age, weight, response and route of administration, will be determined by the attending physician. 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 about 1.0

300 mg / day, preferably from about 1.0 to 50 mg / day. A suitable dosage 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 the applications described below. These dosage forms may be formulated as single or multiple doses, as described above, in order to achieve a daily dosage effective for each use.

The compounds of the invention may be formulated for administration as solid or liquid preparations for oral or parenteral administration. The active ingredient capsules of the present invention can be prepared by mixing 1 part by weight of the active ingredient 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 by weight 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 0.10 to 100 milligrams of active ingredient.

Suspensions and solutions of the compounds of the invention, particularly those in which R 1 is hydrogen, are often prepared just prior to use in order to avoid storage stability problems of the active ingredient suspension or solution (e.g., precipitation of active ingredient J.

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

The analgesic activity of several compounds of the present invention was determined by the methods described above. These compounds correspond to the general formula

The following abbreviations are used in the table for each test:

FBCH - painful cramps caused by phenylbenzoquinone,

DO = heat irritation of tail,

HD = hot plate,

SO = tail clamping (Haffnerj,

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 in% at the given batch. Thus, a value of 31 (56) means that a dose of 56 mg / kg body weight gives 31% protection.

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The diuretic activity of the compounds of the present invention is illustrated by the assay performed by Lipschitz et al. [J. Pharmacol., 1S7, 97 (1943)], using rats as test animals. The dosage range for this use corresponds to the dosage given above for the use of the compounds of the invention as analgesics.

Antidiarrheal efficacy is exacerbated using the procedure described by Neimegeers et al. [Modern Pharmacology-Toxicology, Willem van Bever and Harbans Bal, Eds., 7, 68-73 (1976)]. Charles River CD-I (170-209 g) rats were housed in cages 18 hours prior to the start of the test. 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% emulsifiers based on polyoxyethylated vegetable oil and 99% saline, and after one hour is orally administered with a provocative dose (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 is administered, it is determined whether or not diarrhea has occurred. For all tests performed within 1 day, a control group of animals given only vehicle and castor oil always serves as a control. Results are recorded as the number of animals protected from diarrhea for 1 hour after castor oil administration. In general, the dosages for use of the disclosed compounds as antidiarrheal agents correspond to those used for the administration of these compounds as analgesics.

The transquilizing activity of the compounds of the invention is determined by orally administering the 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 mg.

Anticonvulsive efficacy was determined by subcutaneously administering the test compound to male mice (Charles Riverj weighing 14-23 g in a vehicle of the same type as used in the diarrheal efficacy test). Experiments were performed on groups of 5 mice each. mice are fasted overnight without being restricted in water intake Test compound is administered at a volume of 10 ml / kg using a subcutaneous syringe # 25. 1 hour after administration of the test substance, the animals are transcutaneously shocked with 50 mA (60 mA). The electroconvulsive shock elicits tonic stretcher stretchers with a latency of 1.5 to seconds in all control mice, and the test substance is considered to be effective if the treated mice are treated with an electroconvulsive shock. for 10 seconds after electroconvulsive shock did not goes to no tonic cramps, stretchers.

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

Sedative / depressant efficacy was determined by administering to groups of 6 mice each subcutaneously various doses of the test compound. 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 spinning rod indicates sedative / depressive activity of the test substance.

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

Example 1 cis-3- [2-Benzyloxy-4- (1,1d ^: methylheptyl) phenyl] cyclohexanol and the corresponding trans-isomer

To a solution of 43.0 g (0.106 mole) of 3- [benzyloxy-4- (1,1-dimethylheptyl) phenyl 1] cyclohexanone in 500 ml of methanol and 15 ml of tetrahydrofuran, cooled to -40 ^Q C was added in three portions 8.05 g (0.212 mol) of sodium borohydride. The reaction mixture was stirred at -40 ° C for 1 hour, then allowed to warm to -10 ° C and was quenched by addition. 103 ml of saturated sodium chloride solution. The reaction mixture is added to 1500 ml of water and extracted three times with 450 ml of ether each time. The combined ether extracts were washed three times with 10 ml of water each time and twice with 200 ml of saturated sodium chloride solution each time, dried over magnesium sulfate and evaporated. The oily residue was purified by column chromatography (400 g silica gel, 20% ether in cyclohexane).

5.0 g (12% of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclohexanol) are successively eluted from the column.

PMR (deuterochloroform, tetramethylsilane, values <5):

0.85 (multiplet, terminal methyl),

1.26 (singlet, germinal dimethyl),

3.51 (multiplet, meth group of the benzyl · residue),

4.24 (multiplet, methine grouping of carbinol residue),

5.15 (singlet, benzyl · methylene group),

6.85 to 7.26 (multiplet, proton of aryl residue and

7.47 (multiplet, proton of the phenyl moiety);

IR (chloroform): 3636, 3497, 1629, and 1587 cm ^-1 ;

Mass spectrum (m / e): 408 (M ^& lt ^{; +} & gt ^; ), 393, 390, 323 and 91;

Analysis calculated for C28H40O2:

% C, 82.30;% H, 9.87;

found:

% C, 81.98;% H, 9.82;

and 22.2 g (51%) of cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclohexanol

PMR (deuterochloroform, tetramethylsilane, values of 5):

0.85 (multiplet, terminal methyl),

1.28 (singleite, geminal dimethyl),

3.1 (multiplet, meth group of benzyl residue),

3.79 (multiplet, meth group of carbine lead residues)

5.12 (singlet, benzyl methylene group),

0.83 to 7.22 (multiplet, proton of aryl residue);

7.42 (singlet, phenyl proton); mp 75.5-76.5 ° C;

IR (chloroform):

3636, 3497, 1629 and 1587 cm ^-1 ;

Mass spectrum (m / e):

408 (M &lt; + &gt;), 393, 390, 323 and 91;

For C28H40O2 calculated:

82.30%, 9.87% H; found:

% C, 81.95;% H, 9.74.

In an analogous manner, the following compounds are prepared from the corresponding ketones:

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

This product was prepared in quantitative yield as an oil from 200 mg (0.476 mmol) of 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methylcyclohexanone.

PMR (deuterochloroform, tetramethylsilane, δ '):

0.81 (multiplet, terminal methyl in side chain),

1.23 (singlet, geminal dimethyl),

1.30 (singlet, methyl on C3),

3.65 (multiplet, methine grouping of carbinol residue),

5.00 (singlet, benzyletheir methylene) ,.

6.61 to 7.3 (proton of the aryl residue);

7.25 (multiplet, proton of the phenyl residue). IR (chloroform):

3546, 3378, 1603 and 1555 cm ^-1 .

Mass spectrum (m / e):

422 (M &lt; + &gt;), 337, 314, 299, 271 and 229.

Trans, tr, ans-3- [2-Beinzyloxy-4- (1,1-dimethylheptyl) phenyl] -4-methylcyclohexanol and the corresponding cis, trans-isomer

These isomers are prepared from trans-3- [2-benzyloxy-4- (1,1-dimethylhepyl) phenyl] -4-methylcyclohexanone. The trans, trans-isomer resulted in an oily form in 14% yield, the cis, trans-isomer in 74% yield.

Cis-3- [2-Benzyloxy-4- (2- (5-phenylpentyloxy) phenyl) cyclohexanoil and the corresponding trans-isomer

These isomers are prepared from 2.0 g (4.52 mmol) of 3- [2-benzyloxy-4- (2- (5-phenylpentyloxy) -phenyl] cyclohexanone), both of which result in the oily form of the cis-isomer in the yield 1.51 g (76%) and the trans-isomer in 0.379 g (19%).

trans-isomer:

PMR (deuterochloroform, tetramethylsilane, hodnoty values):

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

2.68 (multiplet, methylene group of the benzyl residue),

3.45 (multiplet, meth group of the benzyl residue),

4.22 (multiplet, methine grouping of carbinol residue),

4.30 (multiplet, methine grouping in side chain),

5.09 (singlet, methylene group of the beinzylether group),

6.45 (double doublet, J = 8 Hz and J = 2 Hz, proton of the airyl residue),

6.55 (broad singlet, proton of the aryl residue),

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

7.25 (singlet, proton of phenyl);

7.45 (broad singlet, phenyl proton).

IR (chloroform):

3571, 3448, 1590 and 161.3 cm ^1st

ia

Mass spectrum (m / e):

444 (M ^& lt ^{; +} & gt ^; ), 298, 280, 190 and 91.

cis-Isomer:

PMR (deuterochloroform, tetramethylsilane, δ '):

1.2 (δ (doublet, J = 6 Hz, methyl))

3.0 (multiplet, meth group of the benzyl residue),

3.77 (multiplet, methine grouping of carbinol residue),

4.38 (multiplet, methine group in side chain),

5.10 (singlet, methine of the benzyl ether moiety),

6.59 (double doublet, J = 8 Hz and J = 2 Hz, aryl residue breakthrough),

58 (broad singlet, proton of aryl residue),

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

7.32 (singlet, proton of the phenyl group) and 7.43 (singlet, proton of the phenyl group).

IR (chloroform):

3571, 3390, 1613 and 1587 cm ^-1 .

Mass spectrum (m / e):

444 (M ^& lt ^{; +} & gt ^; ), 298, 190 and 91.

cis-3 - [, 2-Benzyloxy-4- (1,1-dimethyloctyl) phenyl] cyclohexanol and the corresponding trans-isomer

These isomeric products were prepared from 3.00 g (7.14 mmol) of 3- [2-benzyloxy-4- (1,1-dimethyhyloctyl) phenyl] cyclohexanone. The cis-isomer resulted in a yield of 1.35 g (45%) and trams-isomeir in a yield of 0.34 g (11%). Further, a mixture of cis and trans isomers was obtained in a yield of 0.90 g (30%).

trsins-isomeir:

PMR (deuterochloroform, tetramethylsilane, δ '):

0.87 (multiplet, terminal methyl in side chain),

1.25 (singlet, geminal dimethyl),

3.50 (multiplet, meth group of the benzyl residue),

4.22 (me Carbinol residue clay grouping),

5.15 (singlet, benzylether methylene group); and

6.8 to 7.6 (multiplet, proton of aryl residue and proton of femyl residue).

IR (chloroform):

3497, 162 (3 and 1582 cm ¹⁾ .

Mass spectrum (m / e):

422 (M ⁺ ) and 323.

cis-Isomer:

PMR (deuterochloroform, tetramethylsilane, hodnoty values):

0.85 (multiplet, terminal methyl in side chain),

1.25 (singlet, geminal dimethyl),

3.10 (multiplet, meth group of the benzyl · residue),

3.75 (multiplet, methine grouping of carbinol residue),

5.12 (singlet, beinzylether methylene group or moiety),

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

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

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

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

IR (chloroform):

3571, 34215, 1618 and 1577 cm ^-1 .

Mass spectrum (m / e):

422 (M &lt; + &gt;) and 323.

cis-3- (2-Benzyloxy-4-tert-butylphenyl) cyclohexainol, the corresponding trans-isomer and a mixture of cis- and trans-isomers

These products were prepared from 12.0 g (0.0357 mol) of 3- (2-benzyloxy-4-tert-butylphenyl) cyclohexanone. The cis-isomer results in yield

7.18 g (59%), trans-isomer in 1.33 g (11%), and mixture of cis- and trans-isomers in 1.5 g (12%).

cis-Isomer:

Mp 78-79 ° C (after crystallization from hexane).

PMR (deuterochloroform, tetramiethylsilane, S-values):

1.30 (singlet, t-butyl),

3.10 (multiplet, methincent benzyl group)

3.72 (multiplet, methine grouping of the kairbinoi residue),

5.12 (singlet, benzyl ether methylene group),

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

6.97 (double doublet, J = 8 Hz and J - 2 Hz, proton, aryl residue),

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

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

IR (chloroform):

3636, 3472, 1621 and 1582 cm ^-1 .

Mass spectrum (m / e):

338 (M ^& lt ^{; +} & gt ^; ), 323, 320, 230, 215, and 91.

Analysis calculated for C23H30O2:

% C, 81.61;% H, 8.93;

found:

81.79% C, 8.77% H. trans-Isomeir:

PMR (deuterochloroform, tetramethylsilane, 'δ values'):

1.2 (3 (singlet, t-butyl),

3.50 (multiplet, meth group of the benzyl residue),

4.20 (multiplet, methine grouping of carbinol or residue),

5.02 (singlet, benzyl ether methylene group);

6.8 to 7.4 (multiplet, proton of the aryl radical and also the proton of the phenyl radical).

IR (chloroform):

3650, 3472, 1626 and 1587 ^cm-first

Mass spectrum (m / e):

338 (M &lt; + &gt;), 323, 320, 230 and 91.

cis-3 - [, 2-Benzyloxy-4- (1,1-dimethylpropyl) phenyl] cyclohexanol and the corresponding trans-isoimer

These products are prepared in oily form from 8.0 g (0.0229 mol) of 3- [2-benzyloxy-4- (1,1-dimethylpyrropyl) phenyl] cyclohexanone. The cis-isomeir resulted in 6.3 g (78%), the trans-isomer in 1.0 g (12%).

cis-Isomer:

PMR (deuterochloroform, tetramethylsilane, (values <$):

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

1.26 (singlet, geminal dimethyl),

3.05 (multiplet, meth group of benzylic residue),

3.75 (multiplet, methine grouping of carhinol residue),

5.15 (single, methylene group of the benzyl ether moiety),

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

6,9,2 (double doublet, J = 8 Hz and J = 2 Hz, proton air or residue),

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

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

IR (chloroform):

3636, 3344, 1626 and 1587 cm ^-1 .

Mass spectrum (m / e):

352 (M &lt; + &gt;), 337, 334, 323, 244, 215, and 91.

Trans-Isomeir:

IR (chloroform):

3636, 1626 and 1587 cm ^-1 .

Mass spectrum (m / e):

352 (M ^& lt ^{; +} & gt ^; ), 337, 334, 323, 244, 215, and 91.

cis-3- [2-Benzyloxy-4- (1,1-dimethylbutyl) phenyl] cyclohexanol, the corresponding trans-isomer and a mixture of cis- and transisomers

These products, obtained in oily form, are prepared from 8.0 g (0.022 mol) of 3- [2-benzyloxy-4- (1,1-dimethylbutyl) phenyl] cyclohexanone. The cis-isomer yield was 4.16 g (52%), the trans-isomer yield was 0.88 g (11%), and the cis-trans isomer yield was 0.49 g (6.1%).

cis-Isomer:

PMR (deuterochloroform, tetramethylsilane, S-values):

0.80 (multiplet, terminal methyl,

1.23 (singlet, geminal dimethyl),

3.05 (multiplet, methine group of benzyl residue),

3.70 (multiplet, methine grouping of carbinol residue),

5.08 (singlet, henzyl ether methylene group or moiety),

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

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

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

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

IR (chloroform):

'3623, 3448, and 1582 cm 16.21 ¹ -.

Mass spectrum (m / e):

366 (M &lt; + &gt;), 351, 348, 323, 258, 215, and 91.

trans-isomer:

PMR (deuterochloroform, tetramethylsilane, hodnoty values):

0.83 (multiplet, terminal methyl),

1.22 (singlet, geminal dimethyl),

3.40 (multiplet, methine grouping of the beinzyl residue),

4.18 (mulitiplet, methine grouping of carbinol residue),

5.09 (singlet, benzylether methylene group),

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

1 β 5 O 6

6.86 (double doublet, J = 8 Hz and J = 2 Hz, aryl residue protein,

7.11 (doublet, J = 8 Hz, proton of aryl residue and.

7.30 (multiplet, proton of the phenyl residue).

IR (chloroform):

3623, 3472, 16.23 and 1585 cm ^-1 .

Mass spectrum (m / ej):

366 (M ^& lt ^{; +} & gt ^; ), 351, 348, 323, 258, 215, and 91.

trans-3- [2-Beuzyl-γ-4- (1,1-dimethylheptyl) phenyl] -Cs-4- (2-propenyl) cyclohexanol and the corresponding cis-3-, trans, ns-4-isomer

These products were prepared in an oily form from 14.3 g (32.1 mmol) of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-propenyl) -cyclohexanoin. of cis-4-isomeir was 1.9 g (13%), yield of cis-3, trans-4-isomer 7.3 g (51%). From a silica gel column using pentane / ether (2: 1). The eluent was eluted first with the oily trams-3, eis-4-isoroer (title compound) and then with the corresponding cis-3, trans-4-isomer.

trans-3, cis-4-isomer

IR (chloroform):

3559, 3401, 1639, 1608 and 1567 cm ^-1 .

Mass spectrum (m / ej):

448 (M ^& lt ^{; +} & gt ^; ), 433, 430, 363, 406, and 91.

PMR (deuterochloroform, tetramethylsilane, δ values):

0.82 (multiplet, terminal methyl),

1.25 (singlet, geminal dimethyl),

3,, 30 (multiplet, meth group of benzyl · residue j,

4.12 (multiplet, methine grouping of carbinol residue,

4.6 to 5.0 (multiplet, vinyl group proton),

5.06 (singlet, benzyl methylene group),

5.2 to 6.1 (multiplet, vinyl group proton),

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

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

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

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

cls-3, tranis-4-isomeir:

IR (chloroform):

3571, 3401, 1639, 1610 and 1.572 cm ¹ .

Mass spectrum (m / e):

448 (M ^& lt ^{; +} & gt ^; ), 406, 363 and 91.

PMR (deuterochloroform, tetramethylsilane, hodnoty values):

0.8.2 (multiplet, terminal methyl),

1.22 (singlet, geminal dimethyl),

2.90 (multiplet, meth group of benzyl residue,

3.73 (multiplet, methine grouping of carbinol residue),

4.6 to 5.1 (multiplet, vinyl group proton),

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

5.3 to 6.3 (multiplet, vinyl group proton),

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

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

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

7.25 (broad singlet, femyl).

cis-3- [2-Benzyl-ox-4- (1,1-dimethylheptyl) phenyl] -trans-4- (2-butenyl) cyclohexanol and the corresponding trans-3, cis-4-isomer

These products were prepared from 600 mg (1.30 mmol) of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -2-butenyl] cyclohexainone to yield cis-3, trans-4-isomeir. 495 mg (82%), the yield of trans-3, cis-4-isomer was 105 mg (18%), and the trans-3, cis-4-isomer, trans-3, cis- 4-Isomer:

Mass spectrum (m / ej):

462 (M + j, 447, 444, 377 and 91. cis-3, trans -4-isomer:

IR (chloroform):

3610, .3448, 1618 and 1577 cm ^-1 .

Mass spectrum (m / ej):

462 (M &lt; + &gt;), 447, 444, 377 and 91.

cis-3- [2-Beinzyloxy-4- (1,1-dimethylheptyl) phenyl] -trans-4- (2-pentyl) cyclohexanol and the corresponding trans-3, cis-4-isomer

These products were prepared from 497 mg (1.04 mmol) of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-pentenyl) cyclohexanone. The column was eluted first with 84 mg (17%) of the trans-3, cis-4-isomer of Rf = 0.26 (silica gel, 33% ether in pentane) and then with 363 mg (73% cis- _; 3, tra.ns). -4-isomer of Rf = 0.13 (silica gel, 33% ether in pentane).

cis-3- [2-Benzyloxy-4- (1,1-dimethylpentyl) phenyl] cyclohexanol and the corresponding trams-isomer

These products were prepared from 6.0 g (58 m; mol of 3- [2-benzyloxy-4- (1,1-dimethylpentyl) phenyl] cyclobexanone) to yield 5.0 g (83%) of the cis-isomer. , the yield of trans-isomeir

0.60 g (10%).

trans-isomer:

IR (chloroform):

3633, 3497, 1623 and 1582 Tsar ¹ .

Mass spectrum (m / e):

380 (M ^& lt ^{; +} & gt ^; ).

PMR (deuterochlor: crni, tetramethylsilane, 5):

0.83 (multiplet, terminal methyl),

1.24 (singlet, geminal dimethyl),

3.5 (multiplet, methine group of benzyl residue), 4.20 (multiplet, methine group of icarbinol residue),

5.09 (singlet, methylene group of the benzylene moiety);

6.8 to 7.6 (multiplet, proton of the aryl residue).

cls-isomer:

IR (chloroform):

3636, 1621 and 1580 cm ^-1 .

Mass spectrum (m / e):

380! (M +).

PMR (deuterochloroform, tetramethylsilane, δ values):

0.75 (multiple-methyl, terminal methyl), 1,14 (singlet, geminal dimethyl),

2.90 (multiplet, meth group of the benzyl residue),

3.52 (multiplet, methine grouping of carbinol residue),

4.80 singlet, methylene group of the benzyl residue),

6.49 (double doublet, J = 8 Hz a) = 2 Hz, proton of the arthritic residue),

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

6.72 (doublet, J = 8 Hz, aryl residue proton);

6.96 (broad singlet, phenyl).

cis-3- [2-Benzyloxy-4- (1,1-dimethylhexyl) phenyl] cyclohexanol and the corresponding trans-isomer

These products are prepared in oily form from 7.0 g (17.9 mmol) of 3- [2-beinzyloxy-4- (1,1-dimethylmethylhexyl) phenyl] cyclohexane. The cis-isomer yield was 3.0 g (43%), the trans-isomer yield 630 mg (9%).

cis-isomer:

IR (chloroform):

3623, 3448, 1618 and 1575 cm ^-1 .

Mass spectrum (m / e):

394 (M &lt; + &gt;).

PMR (deuterochloroform, tetramethylsilane, δ values):

0.82 (multiplet, terminal methyl),

1.22 (singlet, geminal dimethyl),

3.07 (multiplet, meth group of the benzyl residue,

3.70 (multiplet, meth group of the benzyl residue),

3.70 (multiplet, methine grouping of carbinot residue), 5.08 (singlet, methylene group of benzyl residue),

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

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

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

7.37 (broad singlet, phenyl).

trans-isomer:

IR (chloroform):

3623, 3448, 1618 and 1577 cm -1.

Mass spectrum (m / e):

394 (M &lt; + &gt;).

PMR (deuterochloroform, tetramethylsilane, values <S):

0.80 (multiplet, terminal methyl),

1.27 (singlet, geminal dimethyl),

3.42 (multiplet, meth group of benzyl residue),

4.12 (multiplet, methine grouping of carbinol residue),

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

6.83 (multiplet, aryl residue proton), 7.04 (doublet, J = 8 Hz, aryl residue proton) and

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

cis-3- [2-Benzyloxy-4- (1,1-dimethylnonyl) phenyl] cyclohexamol and the corresponding trans-isomer

These products were prepared from 8.5 g (19.6 mmol) of 3- [2-benzyloxy-4- (1,1-dimethylnonyl) phenyl] cyclohexanone. Both isomeirs result in an oily form, the cis-isomer in 5.9 g (59%) and the trans-isomer in 1.0 g (12%).

cis-isomer:

IR (chloroform):

3623, 3448, 1618 and 1577 cm -1.

Mass spectrum (m / e):

436 (M &lt; + &gt;).

PMR (deuterochloroform, tetramethylsilane, δ values):

0.83 (multiplet, terminal methyl),

1.22 (singlet, geminal dimethyl),

3.04 (multiplet, meth group of the benzyl residue),

3.67 (multiplet, methine grouping of carbinol residue),

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

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

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

7.06 to 7.45 (multiplet, aryl residue proton and phenyl).

Trans-Isomeir:

IR (chloroform):

3610, 3,448, 1618 and 1575 cm ^-1 .

Mass spectrum (m / e):

436 (M ^& lt ^{; +} & gt ^; ).

PMR (deuterochloroform, tetramethylsilane, δ values):

0.82 (multiplet, terminal methyl),

1.22 (singlet, geminal dimethyl),

3.42 (multiplet, meth group of benzyl, residue),

4.16 (multiplet, methine grouping of carbinol residue),

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

6.7 to 7.5 (multiplet, aryl proton and phenyl).

cis-3- [2-Benzyloxy-4- (1,1-diethylenedecyl) phenyl] cyclohexanol and the corresponding thornomer;

These products were prepared from 7.00 g (16.0 mmol) of 3- [2-benzyloxy-4- (1,1-dimethylundecyl) phenyl] cyclohexanone. Both isomers resulted in an oily form, cis-isomeir in 3.5 g (50%) and trans-isomer in 1.0 g (14%).

cis-Isomer:

IR (chloroform):

36 (36, 3448, 1621 and. 1582 cm ¹⁾ .

Mass spectrum (m / e):

464 (M ^& lt ^{; +} & gt ^; ).

PMR (deuterochloroform, tetramethylsilane, δ values):

0.95 (multiplet, terminal methyl),

1.33 (singlet, geminal dimethyl),

3.09 (multiplet, meth group of the benzyl residue),

3.70 (multiplet, methine grouping of carbinol residue),

5.20 (singlet, benzyl methylene group),

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

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

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

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

Trans-Isomeir:

IR (chloroform):

3534 (wide band), 1618 and 1577 cm ^-1 .

Mass spectrum (m / ej):

464 (M &lt; + &gt;).

PMR (deuterochloroform, tetramethylsilane, δ values):

0.85 (multiplet, terminal methyl),

1,2'2 (singlet, geminal dimethyl),

3.48 (multiplet, meth group of benzyl residue),

4.17 (multiplet, meth group of the benzyl residue),

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

6.75 to 7.55 (multiplet, proton of aryl residue and phenyl).

cis-3- [2-Benzyloxy-4- (1,1-dimethyldecyl) phenyl] cyclohexanol and the corresponding trans-isomer

These products are prepared in oily form from 4.5 g (10.0 mmol) of 3- [2-benzyloxy-4- (1,1-dimethyldecyl) phenyl] cyclohexanone. The yield of cis -isomer is 2.66 g (59%), the yield of the trans -isomer is 0.36 g (8%). cis-Isomer:

IR (chloroform):

3704, 3571, 1639 and 1597 cm ^-1 .

Mass spectrum (m / e):

450 (M &lt; + &gt;).

PMR (deuterochloroform, tetramethylsilane, δ values):

0.86 (multiplet, terminal methyl),

1.25 (singlet, geminal dimethyl),

3.03 (multiplet, meth group of benzyl residue),

3.74 (multiplet, methine grouping of carbiinol · residue),

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

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

6 ', 88 (doublet, J = 2 Hz, proton of aryl residue),

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

7.37 (broad singlet, phenyl).

trans-Isomer:

IR (chloroform):

3623, 3448, 1616 and 1577 cm ^"1 ·.

Mass spectrum (m / e):

430 (M &lt; + &gt;).

PMR (deuterochlorotorm, tetramethylsilane, hodnoty values):

0.82 (multiplet, terminal methyl),

1.22 (singlet, geminal dimethyl),

3.53 (multiplet, meth group of the benzyl residue),

4.22 (multiplet, methine grouping of carbinol residue),

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

6.8 to 7.6 (multiplet, aryl residue proton and phenyl).

cis-3- [2, -Benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclooctanol and the corresponding trans-isomer

These products were prepared in oily form from 7.0 g (16.1 mmol) of 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclooctanone to yield 1.36 g of the cis-isomer (m.p. 19%), trans-isomer yield 4.12 g (59%).

cis-Isomer:

Mass spectrum (m / e):

436 (M &lt; + &gt;), 421, 418, 351, 328, 300, 243, and 91.

PMR (deotorochloroform, totramethylsilane,'j values:

0.83 (multiplet, terminal methyl),

1.28 (singlet, geminal dimethyl),

3.19 (wide multiplet, methine se, buy of benzylic residue),

3.89 (broad multiplet, methine group k = rb'not residue),

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

6.83 (multiplet, proton of aryl residue), 7.08 (doublet, 18 Hz, proton of aryl residue) and

7.38 (multiplet, phenyl).

trans-Iscmeter:

Mass spectrum (m / e):

436 (M &lt; + &gt;), 421, 418, 351, 328, 243, and 91.

PMR (deuterochlorcrime, tetramethylsilane, throw-, ty δ j:

0.83 (multiplet, terminal methyl),

1.28 (singlet, geminal dimethyl),

3.4 (broad multiplet, meth group of the benzyl residue),

3.9 (multiplet, methine grouping of carbinol 'residue),

5.10 (singlet, benzyl · methylene group),

6.85 (multiplet, aryl residue proton), 7.08 (doublet, J = 8 Hz, aryl residue proton) and

7.36 (multiplet, phenyl).

Example 2, cis-3- [2-Hydroxy-4- (4-phenylbutyloxy) phenyl] cyclohexanol and the corresponding trans-isomer

To a solution of 4.8 g (14.2 mmol) of 3- [2-hydroxy-4- (4-phenylbutyloxy) phenyl] cyclothexanone in 25 ml of methanol cooled to -18 ° C was added 0.539 g (14.2 mmol) of The reaction mixture was stirred for 40 minutes and then added to a mixture of 250 ml of saturated sodium chloride solution and 250 ml of ether. The resulting oil was purified by column chromatography (430 g silica gel, dichloromethane / ether 2.5: 1) to give 3.37 g (70%) of the cis-isomer, which was crystallized from cyclohexane. 68 g (14%) of the trans-isomer crystallized from cyclohexane and 0.69 g (14%) of a mixture of these isomers.

Melting point 79-80 ° C.

PMR (deuterochlorcrime, tetramethylsilane, values <5):

2.70 (multiplet, benzyl · methylene group),

3.26 (multiplet, meth group of the benzyl residue),

3.93 (broad triplet, J = 6 Hz, - OCH 2 -),

4.28 (multiplet, hydroxyl, methine grouping of carbinol residue, with D2O signal at 4.25, multiplet, methine grouping of carbinol residue),

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

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

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

7.22! (singlet, proton of phenyl).

IR (chloroform):

3610, 3333, 1631 and 1603 cm ^-1 .

Mass spectrum (m / e):

340 (M &lt; + &gt;), 322, 190 and 91.

216596

Analysis calculated for: C 22 H 28 O 3

% C, 77.61;% H, 8.29; found ·:

% C, 77.46;% H, 8.25.

trans-isomer:

Melting point 112-114 ° C.

PMR (deuterochloroform, tetramethylsilane, values of 5):

2.68 (multiplet, methylene group of the benzyl residue),

3.80 (multiplet, hydroxyl, - OCH 2 -, methine grouping of the carbinol ¹ residue, with a D ² O signal at 3.63, multiplet, methine grouping of the carbinol or residue, and at

3.90, broad triplet, J = 6 Hz, —OCH2—), 6.32 (broad singlet, overlapping signal at

6.40),

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

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

7.20 (singlet, phenyl proton).

IR (chloroform):

3610, 3390, 1631 and 1595 cm ^-1 .

Mass spectrum (m / e):

340 (M &lt; + &gt;), 322, 190 and 91.

Calcd for C22H2 & O3:

% C, 77.61;% H, 8.29;

found:

% C, 77.40;% H, 8.31.

The following compounds are also prepared in an analogous manner:

cis-3- [4- (2-Heptyloxy) -2-hydroxyphenyl] cyclohexanol and the corresponding trans-isomer

These products were prepared as an oil from 5.2 g (13.6 mmol) of 3- [4- (2-; heptyloxy) -2-hydroxyphenyl] cyclohexanone, which was eluted first with 854 mg (36%) of cis isomer followed by 107 mg (3% of the trans isomer).

cis-Isomer:

IR (chloroform):

3597, 3333, 1629 and 1600 cm ^-1 .

Mass spectrum (m / e):

306 (M + 1, 208, 190, 173 and 162).

PMR (deuterochloroform, tetramethylsilane, values of 5):

0.82 '(multiplet, methyl)

2.8 (multiplet, meth group of benzyl residue),

3.7 (multiplet, methine grouping of carbinol residue and hydroxyl),

4.1 (multiplet, meth group),

6.38 (multiplet, proton of aryl residue);

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

trans-isomer:

Mass spectrum (m / e):

306 (M + 1, 208 and 190.

PMR (deuterochloroform, tetramethylsilane, values <S):

0.82 (multiplet, methyl)

3.25 (multiplet, meth group of the benzyl residue).

4.3 (multiplet, methine grouping of carbinol residue and hydroxyl) ,,

6.33 (multiplet, aryl residue proton);

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

cis-3- [4- (2-octyloxy) -2-hydroxyphenyl] cyclohexanol and the corresponding trans-isomer

These products were prepared from 2.92 g (9.18 mmol) of 3- (4- (2-octyloxy) -2-hydroxyphenyl) cyclohexanone.

1.58 g (54%) of the cis-isomer are eluted first from the chromium atographic silica gel column and then 0.57 g (19% of the trans-isomer).

cis-Isomer:

IR (chloroform):

3663, 3390, 1637 and 1608 cm ^-1 .

Mass spectrum (m / ej):

320 (M + 1, 319, 208 and 190.

PMR (deuterochloroform, tetramethylsilane, ó 'values:

0.83 (multiplet, methyl)

2.81 (multiplet, meth group of the benzyl residue),

3.8 (mulitiple, methine grouping of carbinol residue),

4.1 (multiplet, methine side chain group and hydroxyl),

6.35 (multiplet, aryl residue proton) and

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

trans-isomer:

IR (chloroform):

3636, 3390, 1634 and 1595 om ' ¹ .

Mass spectrum (m / ej):

320 (M + 1, 235, 208, 190 and 173).

218506

PMR (deuterochloroform, tetramethylsflam, ó):

0, 82 (multiplet, methyl)

3.25 (multiplet, meth group of the benzyl residue),

4.1 to 4.9 (multiplet, methine groupings in carbinol residue and side chain, and hydroxyl),

6.35 (multiplet, proton of aryl residue); and

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

cis-3- [4- (2-Nonyloxy) -2-hydroxyphenyl] cyclohexanol and the corresponding trans-isomer

These products were prepared from 3.15 g (19.48 mmol) of 3- [4- (2-nonyloxy) -2-hydroxyphenyl] -cyclohexanone, and 2.11 g (67 percent) was eluted from the silica gel column first. of the vitreous, cis-isomer and then 0.32 grams (19%) of the oily trans-isomer.

IR (chloroform):

3663, 3399, 1639 and 1610 cm ^-1 .

Mass spectrum (m / e):

334 (M ^& lt ^{; +} & gt ^; ), 316, 208 and 190.

PMR (deuterochloroform, tetramethylsilane, hodnoty values):

0.88 (multiplet, methyl)

2.85 (multiplet, meth group of the benzyl residue),

3.5 to 4.1 (multiplet, methine carbinol moiety and hydroxyl),

4.22 (multiplet, side chain methine grouping),

6.38 (multiplet, proton of aryl residue);

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

trans-isomer:

IR (chloroform):

3636, 3413, 1637 and 1592 cm ^-1 .

Mass spectrum (m / e):

334 (M &lt; + &gt;), 316, 208, 206 and 190.

PMR (deuterochloroform, tetramethylsilane, ό values):

0.88 (multiplet, methyl)

3.23 (multiplet, meth group of the benzyl · residue),

3.9-4.6 (multiplet, meth group in carbinol residue and side chain, and hydroxyl),

6.36 (multiplet, proton aryl residue) and 6.96 (doublet, J = 8 Hz, proton aryl residue).

cis-3- [4- (2- / 4-Phenyl / butyloxy) -2-hydroxyphenyl] cyclohexanol and the corresponding trans-isomer

These products were prepared from 2.9 g (8.23 mmol) of 3- [4- (2- (4-phenyl) butyloxy] -2-hydroxyphenyl] cyclohexanone, eluting first with 1.29 g of silica gel column. (44%) of the cis -isomer followed by 241 mg (8%) of the trans -isomer.

cis-Isomer:

Melting point 96-105 ° C (after crystallization from pentane i.

IR (chloroform):

3636, 3390, 1634 and 1608 cm ^-1 .

Mass spectrum (m / e):

340 (M + H, 322, 208, 190, 162, 147, 136, and 91).

PMR (deuterochloroform, tetraroethylsflan, a value):

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

3.7i5 (multiplet, methine grouping of carbinol residue),

4.23 (multiplet, methine grouping in side chain),

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

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

6.98 (doublet, J = 8 Hz, proton aryl residue) and 7.20 (singlet, phenyl).

For C22H28O3 calculated:

% C, 77.61;% H, 8.29; found:

77.59% C, 8.18% H. trans-isomer:

IR (chloroform):

3623, 3390, 1637 and 1595 cm ^-1 .

Mass spectrum (m / e):

340 (M ^& lt ^{; +} & gt ^; ), 342, 208, 190, 162, 147, 136, and 91.

PMR (deuterochloroform, tetramethylsilane, values 0):

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

3.3 (multiplet, meth group of benzyl residue,

4.23 (multiplet, methine groupings in carbinol residue and side chain),

6.38 (multiplet, aryl residue proton),

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

7.18 (singlet, phenyl).

216500 cis-3- [4- (2- (6-Phenyl) hexyloxy) -2-hydroxyphenyl] cyclohexanol and the corresponding trans-isomer

These products were prepared from 3.3 g (9.01 mmol) of 3- [4- (2- / 6-phenyl / hexyloxy) -2-hydroxyphenyl] cyclohexanone. %) of the cis isomer followed by 274 mg (8%) of the trans isomer.

cis-Isomer:

The temperature is 99-113 ° C (from pentane).

IR (chloroform):

3636, 3367, 1631 and 1592 cm ^-1 .

Mass spectrum (m / e):

36 | 8 (M ^& lt ^{; +} & gt ^; ), 350, 208, 190, 162, 147, 136, and 91.

PMR (deuterium chloride, tetramethylsilane, <S):

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

3.6 (miultiplet, methine grouping of carbinol residue),

4.2 (multiplet, methine grouping in side chain),

6.37 (multiplet, proton of aryl residue),

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

7.18 (single, proton of the phenyl moiety).

For C24H32O3 calculated:

78.22% C, 8.75% H;

found:

% C, 78.05;% H, 8.56.

trans-Isomer:

IR (chloroform):

3636, 3413, 1634 and 1597 cm ^-1 .

Mass spectrum (m / e):

368 (M &lt; + &gt;), 350, 208, 190, 162, 147, 136, and 91.

PMR (deuterium chloride, tetramethylsilane, δ '):

1.26 (doublet, J = 61 Hz, methyl),

4.21 (multiplet, methine grouping of carbiinol residue and side chain),

6.37 (multiplet, aryl residue proton), 6.915 (doublet, J = 8 Hz, aryl residue proton) and

7.15 (singlet, phenyl proton).

Example 3

3- (4- (1,1-Dimethylheptyl) -2-hydroxyphenyl) -2-cyclohexenol

To a solution of 1.00 g (3.18 mmol) of 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -2-cyclohexenone in 60 mL of ether cooled to -30 ° C was added dropwise 6, 3 ml of 1M diisobutylaluminum hydride toluene solution. The reaction mixture was stirred at -30 ° C for 30 minutes and then added to 1.5 L of water. The resulting solution was extracted with ether (3.times.400 ml), the combined extracts washed with brine (2.times 125 ml) and dried (MgSO4). After evaporation of the solvent, the crude product was purified by silica gel column chromatography eluting with ether. The oily product is obtained after crystallization from pentane. 256 mg (25%) of the title compound.

Mp 87-88 ° C.

Mass spectrum (m / e):

316 (M &lt; + &gt;), 298, 231 and 213.

PMR (deutercyl chloride, tetramethylsilane, δ values):

• 0.83 (multiplet, terminal methyl),

4.37 (multiplet, methine grouping of carbinol residue),

5.93 (multiplet, vinyl residue proton),

6, .37 (broad signal, hydroxyl);

6.87 (multiplet, proton of aryl residue).

Analysis calculated for: C 31 H 32 O 2

% C, 79.70;% H, 10.19; found:

% C, 79.68;% H, 9.96.

Example 4

3- (4- (1,1-Dimethylhephyl) -2-hydroxyphenyl] cyclohex-3-en-1-ol

To a solution of 17.5 g (50 mmol) of 3- (4- (1,1-dimethylheptyl) -2-hydroxyphenyl) cyclohex-3-enone in 50 ml of methanol cooled to -18 ° C was added The reaction mixture was stirred for 30 minutes, then poured into 2:50 mL of saturated sodium chloride solution and 250 mL of ether, and the ether extract was washed once with 250 mL of saturated sodium chloride solution, dried over sulfate. The residue was purified by column chromatography (400 g silica gel, eluting with 50% ether in pentane) to give the title compound.

Example 5

3- [4- (1,1-Dimethylhepyl) -2-hydroxyphenyl] cyclohex-2-en-1-ol

To a solution of 70.0 g (0.20 mol) of 3- (4- (1,1-di2163Q methylheptyl) -2-hydroxy-phenyl) -cyclohex-2-emone in 203 mL of methanol at -18 ° C is added 7, 6 g (0.20 mol) of sodium borohydride was stirred for 30 minutes and then added to 1 liter of saturated sodium chloride solution and 1 liter of ether, and the ethereal extract was washed once with 500 ml of saturated sodium chloride solution, dried over magnesium sulfate and dried. The residue was purified by column chromatography on 500 g of silica gel using 50% ether in pentane as eluent to give the title compound.

Example 1 a d 6

3- [2-Hydroxy-4- (1,1-dimethylheptyl) phenyl] -1-methylenecyclohexane

To a 50% suspension of sodium hydride in mineral oil (2.28 g, 48 mmol), washed three times with 25 mL of pentane each, 90 mL of dry dimethyl sulfoxide was added and the mixture was heated at 70 ° C for 3/4 hours. 17.79 g (51 mmol) of methyl-triphenylphosphonium bromide are added in one portion. The resulting yellow solution is stirred at 25 ° C for 30 minutes, then a solution of 2.2-6 grams (6.3 mmol) of 3- [2- of acetoxy-4- (1,1-dimethylheptyl) -phenyl] cyclohexanone in 90 ml of dimethylsulfoxide, the reaction mixture is stirred at 63 DEG-66 DEG C. for a further 1.5 hours and then poured into 150 ml of ice-water containing 25 ml. g of sodium bicarbonate, and extracted three times with 50 ml of ether each time. The combined ether extracts were dried over magnesium sulfate, decolorized with charcoal and filtered through a pad of silica gel. Evaporation gave a colorless oily material which was chromatographed on 75 g of silica gel using cyclohexane / i-k-o eluent. First, the non-polar impurities are eluted, then the title compound, as a colorless oil, is eluted by increasing the polarity of the eluent (ether-cyclohexane 1: 10).

Example 7 cis-3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -rans-5-methylcyclohexanol and the corresponding trans, cis-isomer

To a solution of 3'CO mg (10.714 mmol) of t-rans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -5-methylcyclohexainoin in a mixture of 15 mL of methanol and 5 mL of tetrahydrofuran , cooled to -78 ^DEG C., 216 mg (5.68 mmol) of sodium borohydride are added over 1 hour. The reaction mixture was stirred at -78 ° C for 2 hours, then warmed to room temperature and evaporated in vacuo. The residue was acidified with dilute hydrochloric acid and extracted with ether. The extract was dried over magnesium sulfate, evaporated and the residue purified by column chromatography (50 g silica gel, 30% ether in pentane). The column was eluted first with 232 mg (77%) of the trans-cis-isomerTU and then with 45.9 mg (15%) of the cis, trans-isomer. trans, cis-isomer:

Mass spectrum (m / e):

422 (M + 1, 337, 314, 229 and 91).

0.86 (multiplet, terminal methyl),

1.06 (doublet, J = 7 Hz, methyl at C 6,

1.26 (singlet, geminal dimethyl),

3.70 (multiplet, meth group of the benzyl residue),

4.05 (multiplet, methine grouping of carbin-ol residue),

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

6.8 to 7.0 (multiplet, propyl of aryl) and 7.1 to 7.6 (multiplet, proton of aryl and phenyl J.

cis.trans-Isomer:

Mass spectrum (m / e):

422 (M &lt; + &gt;), 337, 314, 229, 2-06 and 91.

PMR (deuteircchloroform, tetramethylsiliain, δ):

0.9 (multiplet, terminal methyl),

1.05 (doublet, J = 7 Hz, methyl per Cs),

3.1 to 4.3 (multiplet, methine grouping of benzyl and carbinol residues),

5.13 (singlet, benzyl methylene group),

5.40 (singlet, hydroxy) a

6.8 to 7.7 (multiplet, proton of phenyl and aryl radical).

Example 8 icis-3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -cis-5-methylcyclohexanol and the corresponding trans, tr-isomer

To a solution of 228 mg (0.543 mmol) of cis -3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -5-m-ethyl-cyclohexane in 10 ml of methanol, cooled to -78 ° C, during 160 mg (4.21 mmol) of sodium borohydride are added over 2 hours, the reaction mixture is allowed to warm to room temperature and then poured into a mixture of ether and saturated sodium chloride solution, and the ethereal extract is dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (5 plates 20 cm X 20 cm X 0.5 mm) using 50% ether in pentane as the solvent system to give 36 mg (16%) of trans, m.p. trans-isomer (R _f = 0.25, silica gel, 33% ether in petroleth-eiru) -a 168 mg of cis, cis-isomer (R _f = 0.17, silica gel, 33% ether in petr-oletheru).

Example 9 cis-3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] -cis-5-methylcyclohexanol

To a solution of 896 mg (2.13 mmol) of cis-3- [4- (1,1-dimethylheptyl-2-hydroxyphenyl) -5-methyl-cyclohexainone in 30 mL of methanol cooled to -78 ° C was added 805 mg (21.8 mmol) of sodium borohydride The reaction mixture was stirred at -78 ° C for 1 hour, then warmed to room temperature and added to a mixture of ether and saturated sodium chloride solution. oily residue which crystallized from pentane gave 589 mg (65%) of the title compound.

Melting point 113-114 ° C.

IR (chloroform):

3636, 3390, 1631 and 1592 ^cm-first

Mass spectrum (m / e):

332 (M + 1, 314, 247, 229 and 95).

PMR (deiuteiro-chloroform, tetramethylsilane, δ 'values:

1.21 (singlet, geminal dimethyl),

2.95 (multiplet, methine group of the beinzyl residue j,

3.82 (multiplet, methine grouping of carbinol residue), 5.62 (singlet, ihydroxy),

6.82 (multiplet, aryl residue proton); and

7.12 (doublet, J = 8 Hz, aryl residue proton).

For C22H36O2 calculated:

79.46% C, 10.91% ₂ found:

79.79%, 10.62% H.

The following compounds are obtained in an analogous manner from the appropriate starting materials:

cis-3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] - cis-5-ethylcyclohexanol

This product was prepared in a yield of 0.74 graim (74%) from 1.00 g (2.30 mmol) of cis -3- [4- (1,1-dimethylmethylheptyl) -2-hydroxyphenyl] -5- ethylhexainone.

Melting point 110-111 ° C.

IR (chloroform):

3636, 3367, 1631 and 1587 ^cm-first

PMR (deuteinochloroform, tetramethylsilane, áj values:

0.90 (multiplet, thyminal methyls),

1.22 (singlet, geminal dimethyl),

2.95 (multiplet, methine grouping of benzyl residue),

3.85 (multiplet, methine grouping of carbinol residue),

5.59 (singlet, hydroxyl),

6.85 (multiplet, aryl residue proton); and

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

Analysis calculated for: C25H38O2:

% C, 79.71;% H, 11.05; found:

% C, 79.41;% H, 10.71.

cis-3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl) -cis-5-n-propylcyclohexanol

This product was prepared in a yield of 0.954 g (71%) from 1.34 g (3.74 mmol) of cis -3- (4- (1,1-dimethylheptyl) -2-hydroxyphenyl) -5-n-. propylcyclohexanone.

Melting point 103-104 ° C (from pentane).

IR (chloroform):

3636, 3378, 1626 and 1587 cm ^-1 .

Mass spectrum (m / e):

360 (M + 1, 342, 275, 257 and 161).

PMR (deuterochloroform, tetramethylsilane)

0.90 (multiplet, thyminal methyls),

1.22 (singlet, geminal dimethyl),

2.95 (multiplet, methine grouping of the beinzyl residue),

3.82 (multiplet, methine grouping of carbinol residue),

5.42. (singlet, hydroxyl),

6.85 (multiplet, proton aryl residue) and 7.06 (doublet, J = 8 Hz, proton aryl residue).

Analysis: C24H40O2 calculated:

79.94% C, 11.19% IT;

found:

% C, 79.88;% H, 11.22.

cis-3- [4- (1,1-Dimethylheptyl-2-hydroxyphenyl) -eis-5-n-hexylcyclohexanol

This product was prepared from 1.20 g (3.00 mmol) of cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-n-hexylcyclohexamone. After purification on a 120 g silica gel column with 5.0% ether in pentane as eluent, the above product was obtained in quantitative yield as an oil containing traces of the corresponding trans, trans-isoimer.

IR (chloroform):

3623, 3355, 16-26 and 1585 cm @ -1

Mass spectrum (m / e):

402 (M + 1, 384, 317 and 209).

PMR (de-uterochlorcíorm, tetramethylsilane, δ '):

0.90 (multiplet, terminal methyls),

1.22 (singlet, geminal dimethyl),

2.97 (multiplet, meth group of the benzyl group),

3.85 (multipl-et, methine grouping of the carbinino residue),

4.32 (multiplet, meth group of the k-arbinol moiety in the trans.trans-isomer),

5.5-8 (broad siglet, hydroxy), 6.85 (multiplet, aryl-proton) and

7.0-9 (doublet, J = 8 Hz, proton of the aryl residue).

Claims (4)

SUBJECT A process for the preparation of 3- (2-hydroxy-4-substituted-phenyl) -cycloalkanol derivatives of the general formula: R1 is hydrogen, C1 -C5 alkanoyl, benzyl, - P (O) (OH) 2 and its mono-sodium and potassium salts, -OO (CH2) 2COOH and its sodium and potassium salt, or: —CO— (CH2) _{p —} NR5R6, where p is an integer of 1 to 4, R5 and R6 are each independently hydrogen or C1-C4alkyl; or R 5 and R 6 together with the nitrogen atom to which they are attached form a five or six membered heterocyclic ring selected from the group consisting of piperidine, pyrrole, pyrrolidine, morpholine and N-alkylpiperazine containing alkyl moieties of 1 to 4 carbon atoms, 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, R3, if present, represents a hydrogen atom, R1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, Z represents an alkylene group having from 1 to 13 carbon atoms or a radical of formula YNOLEZ - (alki) _m -O- (alkzine), where (alki) and (alk2) are in each case an alkylene group having 1 to 13 carbon atoms, with the sum of the carbon atoms in the (alki) + (alka) groups is not higher than 13, aman is always -0 or -1, W represents a hydrogen atom, a pyridyl group or a radical of the formula VZ, wherein W 1 is hydrogen, fluorine or chlorine, and n is 0, 1, 2 or 3, provided that when n is 0, R 4 represents a hydrogen atom, characterized in that - formulas in which R 1, R 2, R 3, R 4, Z, W, n and the dotted line are as defined above, reacted with a metal hydride. 2. The process according to claim 1, wherein the borohydride is sodium borohydride, potassium tri-sec-butyl borohydride, lithium borohydride, diisobutyial aluminum hydride or lithium aluminum hydride, and the reduction is carried out at a temperature of from -70 to +30 ° C. . 3. A process according to claim 2, wherein the reducing agent is n-atrium borohydride and the reaction is carried out at a temperature of from -40 DEG to +30 DEG C. using methanol, ethanol or water as the solvent. 4. A method according to claim 2, characterized in that as reducing agent a tri-sek.ibutylboro hydride and the reaction is carried out at a temperature below -50 C in a dry ^{Q-tetrahydrofuran} in a solvent.