FI66584C - ANALOGIFICATION OF THERAPEUTIC ACTIVATION OF THERAPEUTIC ACTIVATED 3-PHENYLCYCLOALKAN-ELLER -CYCLOALKEN-1-OLER - Google Patents

Description

r_, ANNOUNCEMENT

j & A W (11) UTLAGGNINGSSKMFT Oo5 8 4 • 3® c (45) Patent ui eyFr.r.c Lty 12 11 I 'll (si) K * .niik * .a? c 07 C 39/17, 39/23, 43/23 FINLAND — FINLAND (21) p »wi> ttih« k «r ^ —p *****» ötan * 782794 (22) Hakwnisptlvt — Amöteningadag 12.09.78 (23) AHcupewt — GlltifhaC * d * g 12.09.78 (41) TufletfulklMkfi - Blivtcoffandlf 14.03.79

Jj *** "*** · i * • ^ kbtwIhalUtu · (44) ΜΜΜΙβΙ ^ μοιι l» IrnnHiiWiihn yw.- 31 q7 fit oeh AmMun uth | d oeh vdjkrfftw pAlMfid (32) (33) (31)? Rri « * r * wHaw »« »wp ^ oth * 13-09.77 25.07.78 USA 833IO2, 926687 <7l) Pfizer Inc., 235 East 42nd Street, New York, New York, USA (72) Charles Armon Herbert, Waterford, Connecticut,

Michael Ross Johnson, Gales Ferry, Connecticut,

Lawrence Sherman Melvin Jr., Gales Ferry, Connecticut, USA (74) Oy Kolster Ab (54) Analog method for the preparation of therapeutically active 3 "phenylcycloalkane or cycloalken-1-ols - Analogiför-farande för framstälIning av therapeutiskt active 3-phenylcycloalkan-cycloalken-1-ol

The present invention relates to an analogous process for the preparation of therapeutically active 3-phenylcycloalkane or cycloalken-1-ols of the formula I

OR.

Ά

Z-W

wherein R is a saturated or unsaturated cycloalkyl moiety of formula I-A, I-B, I-C or I-D 2, «> <“ *

H ^ 0H M / L · I

v / hi ** \ - \ 3

V — Λ-— 3 R ·? ** 3 S. m A O

>% Ru ^ 3> 'd ^ d κ2 \ 4 R2 k K2 k R2

I-A I-B I ~ c I_D

2 66584 in which one of the dotted lines in each ring may indicate a double bond; is hydrogen or benzyl; R 2 is hydrogen, alkyl of 1 to 6 carbon atoms, or alkenyl of 3 to 6 carbon atoms; R 1 is hydrogen or methyl; is hydrogen or alkyl of 1 to 6 carbon atoms; Z is alkylene of 1-13 carbon atoms or -O-alk2-, wherein alk2 is alkylene of 1-13 carbon atoms; and W is hydrogen or phenyl; and pharmaceutically acceptable acid addition salts thereof.

The compounds of formula I are useful as central nervous system agents, in particular as analgesic, sedative, sedative and anxiolytic agents in mammals, including man, and / or as anticonvulsants, urinary excretors, diarrhea agents and diarrhea agents.

Despite the large number of commonly available analgesic agents, the search for new and better agents continues, thus emphasizing that there is a shortage of a substance that is useful over a very wide range of pain and with minimal side effects. The most commonly used substance, aspirin, has no practical value in controlling severe pain and is known to have a variety of unwanted side effects. Other analgesic agents such as d-propoxyphene, codeine, and morphine tend to be addictive. The need for better and more effective analgesics is therefore obvious.

U.S. Patent 3,576,887 discloses 1- (1'-hydroxy) alkyl-2-o-hydroxyphenylcyclohexanes and hexenes used as intermediates in the preparation of 6,6-dialkyltetrahydro- and hexahydro-dibenzo (b, d) pyrans , which can be used as central nervous system depressants.

It has now been found that the 3-phenylcycloalkan or cycloalken-1-ols of the formula I are effective as central nervous system agents, in particular as analgesic, sedative, sedative and anxiolytic agents in mammals, and in humans, including humans, 3 66584 as anticonvulsants, diuretics and antidiarrheals in mammals, including humans. Examples of pharmaceutically acceptable acid addition salts include mineral acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate; salts of organic acids such as citrate, acetate, sulfosalicylate, tartrate, glycolate, malate, malonate, maleate, pamoate, salicylate, stearate, phthalate, succinate, gluconate, 2-hydroxy-3-naphthoate, lactate, and mandelate; methanesulfonate.

The compounds of formula I have asymmetric centers in the 1-, 3- and 4-positions of the cycloalkyl moiety and, when the cycloalkyl group is 6-8-membered, in the 5-position and may, of course, additionally have asymmetric centers in the 4- and 5-position substituents and in the phenyl ring. CZW). It is preferred that the 1-position substituent of the cycloalkyl moiety is in the cis position relative to the phenolic or substituted phenol moiety in the 3-position, and that the 3- and 4-substituents and the 4- and 5-substituents of the cycloalkyl moiety are in the trans position relative to each other because the biological activity is then higher (quantitatively).

For convenience, the above formulas represent racemic compounds. However, the above formulas are considered to be general formulas and include within their scope racemic modifications of the compounds of this invention, mixtures of their diastereomers, pure entantiomers, and diastereomers. The utility of a racemic mixture, a mixture of diastereomers, as well as pure enantiomers and diastereomers is determined by the biological evaluation methods described below.

Due to the higher biological activity compared to the activity of the other compounds described herein, compounds of formula I wherein R 2 is hydrogen or alkyl are preferred; R 1 is hydrogen and Z and W have the meanings given below: -Z-_W-alkylene of 8-11 hydrogen carbon atoms alkylene of 4-7 phenyl carbon atoms -O-alk-phenyl-O-alk-hydrogen * 4 665 84

Preferred compounds of formula I, and in particular saturated cycloalkyl compounds of formula I, are Preferred compounds wherein: each and R 1 is hydrogen; Z is -C (CH3) 2 (CH2) g and W is hydrogen; Z is C 1 -C 4 alkylene and W is phenyl; Z is -O-alkylene of 7-9 carbon atoms and W is hydrogen; Z is -O-alkylene of 4 to 5 carbon atoms and W is phenyl; R 2 = hydrogen, methyl, propyl or propenyl; R 3 = hydrogen and R 2 = hydrogen or methyl.

Particularly preferred are saturated cycloalkyl compounds of formula I, wherein R 1, R 2, R 2, R 2, Z and W are as defined above in connection with the preferred compounds and R has the formula I-B or I-C.

In view of the analgesic activity, a particularly preferred group of compounds are also the above-mentioned primary compounds in which R 2 is methyl, propyl or propenyl and R 1 and R 2 are each hydrogen.

The process according to the invention for the preparation of the compounds of the formula I is characterized by the reduction of a substituted cycloalkanone or a cycloalkenone of the formula I *

Z-W

wherein R 'is a saturated or unsaturated cycloalkanoyl moiety of formula I'-A, I'-B, I'-C or I'-D

0 0 _λΟ 0 iv '"' C Ar 1 RH 5 R3 1% r3} i R3 R2 R3 R2 N R2 Rt R2

I '-A would-B be-C I-D

66584 wherein the dotted lines, R 1, R 2, R 3, R 2, Z and W are as defined above, and if desired the benzyl group R 1 is removed, preferably hydrogenolytically, and if desired the compound obtained is converted into an acid addition salt.

The saturated cycloalkyl compounds of formula I of this invention wherein R 3 is hydrogen are prepared from the appropriate 2-bromo-5- (Z-W-substituted) phenol by a series of reactions involving, as a first step, protection of the phenol group. Suitable protecting groups include groups which are not harmful in subsequent reactions and which can be removed under conditions which do not cause undesired reactions at other positions in said compounds or products thereof. Exemplary such protecting groups include methyl, ethyl, benzyl, or substituted benzyl substituted with, for example, alkyl of 1 to 4 carbon atoms, halogen (Cl, Br, F, I), and alkoxy of 1 to 4 carbon atoms. Ether protecting groups, or blocking groups, can be removed using a solution of hydrogen bromide in acetic acid or a 48% aqueous solution of hydrogen bromide. The reaction is carried out at higher than normal temperatures, most preferably at boiling temperature. However, when Z is -O-alk2 ", e.g. polyphosphoric acid or trifluoroacetic acid must be used in order to prevent the breaking of the ether bond. Other reagents such as hydroiodic acid, pyridine hydrochloride or hydrobromide may be used to remove ether protecting groups such as methyl or ethyl groups. When the protecting groups are benzyl or substituted and benzyl groups, they can be removed by hydrogenation from the catalytic. Suitable catalysts are palladium or platinum, especially on a carbon support. Alternatively, they can be removed by solvolysis using trifluoroacetic acid. Another method involves treatment with n-butyllithium in a reaction-neutral solvent at room temperature.

For the present invention, the precise chemical structure of the protecting group is not critical, as its importance depends on its ability to perform its function as described above. One skilled in the art can easily and quickly select and identify suitable protecting groups. The suitability and effectiveness of a group as a hydroxy protecting group is determined using such an amount of 6,66584 in the series of reactions described herein. Therefore, there must be a group that is easily removable to release the hydroxy groups. Methyl and benzyl are preferred protecting groups because they are easily removed.

The protected 2-bromo-5- (ZW-substituted) phenol is then reacted with magnesium in a reaction-neutral solvent and generally in the presence of a catalyst activator, e.g. copper salts such as chloride, bromide and iodide (to promote 1,4-addition) to a suitable 4- With R 2-2-cycloalken-1-one (e.g. 4-1β-2-cyclohexen-1-one). Suitable reaction-neutral solvents include cyclic and acyclic ethers such as, for example, tetrahydrofuran, dioxane and ethylene glycol dimethyl ether (diglyme). The Grignard reagent is formed in a known manner, such as, for example, by boiling a mixture of one molar part of bromine reagent and two molar parts of magnesium in a reaction-neutral solvent, e.g. tetrahydrofuran. The resulting mixture is then cooled to about 0 ° C to 20 ° C, and cuproiodide is added followed by the appropriate 2-cycloalken-1-one at a temperature of about 0 ° C to 20 ° C. The amount of cuproiodide used is not critical but can vary within wide limits. With molar ratios in the range of about 0.2 to about 0.02 moles per mole of bromine reagent, cycloalkanone in which the phenolic hydroxy group is protected is obtained in satisfactory yields (formula I ', = protecting group; = H).

The protected cycloalkanone is then treated with a suitable reagent to remove the protecting group. The benzyl group is conveniently removed by the method described above.

When R2 is an alkenyl group, the cycloalkenones thus prepared act as intermediates in the preparation of the corresponding cycloalkenones (IA-ID) in which R2 is alkyl.

The cycloalkanol compounds of formula I are prepared by reduction from protected cycloalkanones. Sodium borohydride is preferred as a reducing agent at this stage because it preserves not only the satisfactory yield of the desired product but also the protecting group of the phenolic hydroxy group and reacts slowly enough with hydroxyl-containing solvents (methanol, ethanol, water) to allow their use as solvents. The temperatures used are generally between about -40 ° C and about 30 ° C. To improve the selectivity of the reduction, lower temperatures, even about -70 ° C, can be used. Higher temperatures cause a reaction between sodium borohydride and hydroxyl-containing solvents. If higher temperatures are desirable, or necessary to effect the desired reduction, isopropyl alcohol or diethylene glycol dimethyl ether is used as the solvent. Potassium tri-sec-butyl borohydride is sometimes preferred as a reducing agent because it stereoelectively promotes the formation of trans-1,3-phenylcycloalkanol. The reduction is performed in dry tetrahydrofuran at a temperature below about -50 ° C using an equimolar amount of a ketone compound and a reducing agent.

Reducing agents such as lithium borohydride, diisobutylaluminum hydride or lithium aluminum hydride, which can also be used, require the use of dry conditions and ethylene-ethyl, ethylene-ethylene-solvents, non-hydroxyl-containing solvents such as 1,2-dimethoxyethane, tetrahydrofuran and diethyl ether.

The cycloalkanols of the formula I in which OR 1 is hydroxy can, of course, be obtained directly by reducing the catalytically protected cycloalkanone with palladium on carbon or by reducing the catalytically or chemically unprotected cycloalkanone (formula I ', OR 1 = OH) using the reducing agents described above.

In practice, it is recommended that unprotected cycloalkanols of formula I (OR 2 = OH) be prepared by reduction of benzyl-protected cycloalkanones (formula Γ, OR 2 = benzyloxy) as described above, as this allows stereochemical control of the reduction and facilitation of the formation of the cis-hydroxy epimer. separation and purification.

Compounds of formula I having a double bond at the 2,3-position are prepared according to the Grignard reaction from appropriately protected 2-bromo-5- (ZW-substituted) phenol by reacting it with 3-alkoxy-2-cycloalken-1-one (which the alkoxy group has 8,66584 1-4 carbon atoms) in a reaction-neutral solvent at a temperature of about -30 ° C to + 10 ° C. The protected cycloalkenone compound thus prepared is then deprotected as described above and the resulting compound is reduced to the corresponding cycloalkenol. Alternatively, the protected cycloalkenone is chemically reduced, e.g. using sodium borohydride, to the protected cycloalkenol, which is then deprotected to liberate the phenolic hydroxy group.

Compounds of formula I having a double bond at the 3,4-position are prepared from compounds of formula 1 'having a double bond at the 2,3-position. The process involves the ketalization of suitable 2,3-unsaturated compounds of formula 1 'with an alkylene glycol having 2 to 4 carbon atoms in the presence of a dehydrating agent such as p-toluenesulfonic acid in a solvent such as benzene, allowing the by-product water to be removed as an azeotropic mixture. The isomerization of the double bond to the 3,4-unsaturated ketal derivative takes place. Detection by treatment with dilute acid gives 3,4-unsaturated compounds of formula 1 '. Reduction of the oxo group as described above gives the corresponding alcohol.

Protected cycloalk-2-enones (formula I ', = protecting group) are also suitable as intermediates in the preparation of methyl compounds of formula I. The R 1 substituent is placed by performing a conjugated addition of dimethyl copper-lithium to the appropriate cycloalk-2-enone. The process involves the reaction of a suitably protected cycloalkenone with dimethyl copper lithium in a reaction-neutral solvent such as cyclic and acyclic ethers and especially tetrahydrofuran at a temperature of about 0 ° C to -20 ° C. The organometallic reagent causes 1,4-addition to the protected cycloalkenone to form tertiary carbon. The R 1 -substituted protected cycloalkanone is then deprotected and reduced, or the reduction is performed first and then the protecting group is removed according to the methods described above. In this case, a 1,2-adduct is also formed.

a 66584

Compounds of formula I wherein R is a saturated cycloalkyl moiety of formula IB and other than hydrogen are prepared by administering the appropriate 2-bromo-5- (ZW-substituted) phenol in which the phenolic group is as described above. suitably protected, react with magnesium to form the Grignard reagent as described above. The resulting Grignard reagent is then treated, without isolation, at reduced temperature, e.g., about + 10 ° C to about -20 ° C, with N, N-dimethylformamide. The reaction mixture is then allowed to warm to room temperature and the product, protected 2-hydroxy-4- (Z-W-substituted) benzaldehyde, is recovered by known methods. The benzaldehyde derivative is then converted to the β- / 5-hydroxy-U- (ZW-substituted) phenyl-β-3-alkenone via a Witting reaction with the appropriate 1-triphenylphosphoranylidene-2-alkanone in a reaction-neutral solvent at a temperature of about room temperature. and the boiling point of the solvent. The above-mentioned 2-propanone derivative makes it possible to form a cyclohexyl moiety. The arylalkenone thus prepared is then reacted to cyclize the Alkenone with a dialkyl malonate, mainly one having 1 to * + carbon atoms in the alkyl groups. The reaction is carried out in a reaction-neutral solvent such as an alcohol having 1 to 4 carbon atoms at a temperature between about 25 ° C and about the boiling point of the solvent.

The resulting carbalkoxy-substituted cycloalkanedione compound is then decarboxylated by treatment with aqueous sodium or potassium hydroxide at a higher than normal temperature, i. at about 50 ° C to 100 ° C, and the cycloalkanedione derivative is isolated by conventional, known methods. It is then ketalized by reaction with methanol, or another alcohol having up to 4 carbon atoms, or alkylene glycol having 2 to 4 carbon atoms in the presence of a dehydrating acid such as p-toluenesulfonic acid.

In the case of a cyclohexyl derivative, the 3-methoxy-2-cyclohexen-1-one derivative is then reacted with lithium aluminum hydride in a reaction-neutral solvent such as diethyl ether, dioxane, tetrahydrofuran or diglyme at a temperature of about -10 ° C. and thereafter 10 66584 is further treated with dilute inorganic acid. The aryl-substituted-2-cyclohexen-1-ones formed are then treated with the appropriate dialkyl copper paryllithium in a suitable reaction-neutral solvent such as hexane, diethyl ether, or mixtures of these solvents or cyclic ethers such as tetrahydrofuran at a temperature of about -2 ° C to about 0 ° C. . The protected 3 - [- (Z-W -) -substituted-2-hydroxyphenyl] -5-R 4 -cycloalkanone is then deprotected and reduced, or first reduced and then deprotected, according to the methods previously described.

Alternatively, when 5-ZT2-benzyloxy-4- (ZW) -phenyl] -3-alkoxy-2-cyclohexen-1-ones is reacted with the appropriate Grignard reagent R1 MgBr and subsequently hydrolyzed with acid, the corresponding 5-Z2-benzyloxy is formed. -4- (ZW) phenyl] -3-R, -2-cyclohexen-1-ones, which are then catalytically reduced to the corresponding cyclohexanones. Cleavage of benzyl, as described above, affords 5-ε-hydroxy-4- (Z-W) phenylT7-3-R4-cyclohexanones, which are then reduced to the corresponding cyclohexanols as described above.

Compounds of formula I in which R is a saturated cycloalkyl moiety of formula I-C and in which R 1 is other than hydrogen are prepared by extending the ring of the cyclohexyl derivative. Reaction of the appropriate 5-Z2-benzyloxy-4- (ZW) -phenyl-7-3-R4-cyclohexanone with lithium dibromomethane in a reaction neutral solvent such as diethyl ether gives 1-dibromomethyl-5-Z2-benzyloxy-U- (ZW). ) -fenyyli7-3-R cyclohexanol.

Further reaction of 1-dibromomethyl-cyclohexanol in a reaction-neutral solvent such as tetrahydrofuran with n-butyllithium gives 3-Z2-hydroxy-4- (ZW) -phenyl] -Rβ-cycloheptanones, which are then deprotected and reduced, or first reduced and then deprotecting by the methods previously described.

Compounds of formula I wherein R is a saturated cycloalkyl moiety of formula I-D and wherein R 1 is other than hydrogen are prepared by extending the ring of the cycloheptyl derivative according to the methods previously described.

11 66584

When IA-IC is hydrogen in the structures, according to the methods previously described, the ring of these structures can be expanded to a ring that is larger than methylene; i. correspondingly to structures IB-ID. 2-Bromo-5- (Z-W substituted) phenol reagents are prepared by bromination of the appropriate 3- (Z-W substituted) phenol by conventional methods, for example, by treatment with bromine in carbon tetrachloride at a temperature of about 20 ° C to 30 ° C. The required 3- (Z-W substituted) phenols, unless known compounds, are prepared by the methods described herein. A suitable method for preparing reagents in which the Z moiety is alkylene or -O-alk 4 - involves the use of a Witting reaction with a suitable aldehyde such as 2- (3-hydroxyphenyl) -2-methylpropionaldehyde, the hydroxy group of which is protected by the formation of bentsyylieette-ri. Said aldehyde is then treated with the appropriate alkyltriphenylphosphonium bromide, the alkyl group of which expands the propionaldehyde group to the desired length. In a typical process, the aldehyde reagent is added to a slurry of sodium dimethyl and alkyl triphenylphosphonium bromide in dimethyl sulfoxide at a temperature below 30 ° C, e.g., about 10 ° to 30 ° C. Upon completion of the reaction, the alkene-substituted protected phenol is recovered by known methods. Hydrogenation of the alkene with palladium on carbon then affords the desired 3-CZ-W substituted phenol-benzyl ether. By judiciously selecting the (3-hydroxyphenyl) -substituted-aldehyde and alkyl-triphenylphosphonium bromide reagents to be used as starting materials, the desired 3- (Z-W-substituted) phenol reagents are obtained.

The preparation of the appropriate 4-R 2 '2-cycloalken-1-one allows the synthesis of structures of formulas IA-D wherein R 1 is hydrogen by the methods previously described. By reacting the appropriate 1,3-cycloalkanedione with an alcohol having 1 to 4 carbon atoms and an acid catalyst such as p-toluenesulfonic acid in a reaction-neutral solvent such as benzene or toluene, and using an apparatus capable of separating water at temperatures where the reaction solvent boils, 3-alkoxy-2-cycloalken-1-ones are obtained. By reacting the appropriate 3-alkoxy-2-cycloalken-12,665 8,4'-one with lithium diisopropylamide in a reaction-neutral solvent such as tetrahydrofuran, hexamethylphosphoramide and the appropriate I-Xrn, where X is bromine or iodine or some other suitable leaving group, in the presence of 4-R2-3-alkoxy-2-cycloalken-1-ones, 4-R2-3-alkoxy-2-cycloalken-1-one is then reacted with lithium aluminum hydride in a reaction-neutral solvent such as diethyl ether at temperatures of about -10 ° C to 10 ° C and then further treated with dilute inorganic acid. The resulting 4-R 2 '2-cycloalken-1-one is then further modified by the methods already described.

Compounds of formula I wherein R is a saturated cycloalkyl moiety of formula IBID and wherein R 2 and are each other than hydrogen are prepared by administering the appropriate 5-ZT 2 -benzyloxy-4- (ZW) phenylx 7-3-methoxy- React 2-cyclohexen-1-one with lithium diisopropylamide in a reaction-neutral solvent at low temperature, e.g. -50 ° C to -78 ° C. Hexamethylphosphoramide and the appropriate R 2 'iodide (wherein R 2 is other than hydrogen) are then added to give 5-Z 2 -benzyloxy-4- (Z-W) -phenyl] -3-methoxy-6-R 2 -2-cyclohexen-1-one. Further reaction of said compound with the appropriate Grignard reagent R 1 'MgX (wherein R 1' is alkyl) under standard Grignard reaction conditions gives 3- [2-benzyloxy-4- (ZW) phenylx / -4-R 2 -5- R '- 5-cyclohexen-l-one. Removal of the benzyl group and reduction of said compound by the methods described above gives the desired 3- [2-hydroxy-4- (Z-W) -phenyl] -N-R5-5-R'-cyclohexanol. Reduction of the double bond of 3-β2-benzyl-U- (Z-W) -phenyl-7- [2- [2- [5- (5-R) 1-5-cyclohexen-1-one with Pd / C gives the corresponding saturated cyclohexanone derivative. " These latter derivatives are suitable as intermediates in the preparation of the corresponding cycloheptanone and cyclooctanone derivatives by the ring expansion method described above.

A suitable process for the selective alkylation of 3- (2, H-dihydroxyphenyl) cycloalkanones at the H-hydroxy group involves, as a first step, the conversion of 3- (2, H-dihydroxyphenyl) cycloalkanone to a ketal. The conversion is carried out according to well-known ketalization methods, such as by reacting 3- (2,4-dihydroxyphenyl) cycloalkanone with an alcohol, in particular an alcohol having one to four carbon atoms, an acid such as sulfuric acid, p-toluenesulfonic acid, in the presence of hydrogen chloride under conditions in which the by-product water is removed. A suitable process involves the reaction of 3- (2,4-dihydroxyphenyl) cycloalkanone with an orthomuric acid ester dissolved in an alcohol corresponding to the alcohol moiety of the orthomuric acid ester. Suitable reagents include trimethyl orthoformate and methanol with concentrated sulfuric acid, anhydrous hydrogen chloride or ammonium chloride as catalyst.

The ketal thus prepared is then alkylated by reacting it with a suitable alkylating agent such as WZX wherein W and Z are as defined above and X is selected from the group consisting of chlorine, bromine, mesyloxy (CH 2 -SC 2 -O) and tosyloxy (p- CH 2 -C 6 H 2 -SC 2 -O-) acid scavenger, e.g. in the presence of sodium or potassium carbonate. The alkylated ketal is then decalcified according to known methods by treatment with an aqueous acid solution.

A further process for the preparation of 3- (ZW-substituted) phenols in which Z is alkylene or -O-alk2-»involves the application of a Witting reaction with a suitable phenolic aldehyde or ketone, e.g. 3-hydroxybenzaldehyde or 3- (hydroxyphenyl) alkyl ketone. , the phenolic hydroxy group of which is protected, for example, by conversion to benzyl, methyl or ethyl ether. By selecting suitable reagents, compounds having straight or side chain alkylene groups (Z) can be prepared. When a ketone, e.g. 3-hydroxyacetophenone, is used as the reagent, compounds are obtained in which the methyl group in Z is on the carbon atom adjacent to the phenyl group.

Substitution of the methyl or ethyl group at other sites, e.g., the β-carbon atom of the alkylene group, is accomplished by selecting the appropriate carboalkoxyalkylidene-triphenylphosphorane, e.g., (ChHc) -P = C (R ') - C00CoH_. The unsaturated es-b o o o ether thus prepared is reduced to the corresponding alcohol by reacting it with lithium aluminum hydride. Alternatively, with a phenolic protecting group other than benzyl (e.g. methyl), the alcohol is prepared by reduction of the catalytic unsaturated ester m 66584 using palladium on carbon, followed by treatment of the thus prepared saturated ester with lithium aluminum hydride. By converting the alcohol thus prepared to the corresponding tosylate or mesylate and then alkylating the tosylate or mesylate with the alkali metal salt of the appropriate H0- (alk2) -W reagent and finally deprotecting, the desired 3- (Z-W substituted) -phenol is obtained.

A variation of the above reaction sequence involves the bromination of an alcohol rather than its conversion to a tosylate or mesylate. A suitable brominating agent is phosphorus tribromide. The bromine derivative is then reacted with the appropriate HQ (alk2) -W in the presence of a suitable base (Williamso ether synthesis).

Bromine compounds are also valuable intermediates in increasing the chain length of the alkylene moiety in the above reaction sequence to give compounds where Z is -alkylene-W. The process involves treating the bromine derivative with triphenylphosphine to give the corresponding triphenylphosphonium bromide. Reaction of triphenylphosphonium bromide with a suitable aldehyde or ketone in the presence of a base such as sodium hydride or n-butyllithium gives an unsaturated derivative which is then catalytically hydrogenated to the corresponding saturated compound.

An alternative method of attaching an alkyl or aralkyl group to an aromatic ring, and specifically a group in which the carbon atom adjacent to the aromatic ring is a tertiary carbon atom, includes an acid-catalyzed electrophilic aromatics substituted with a tertiary alcohol of guaiacol in the presence of an acid, e.g. In accordance with the general procedure, a mixture of methanesulfonic acid and an equimolar amount of guaiacol and a tertiary alcohol is allowed to react at temperatures of about 30 to about 80 ° C until the reaction is substantially complete. The product is isolated by pouring the reaction mixture onto ice, followed by extraction with a suitable solvent such as methylene chloride. The 2-methoxy-4-alkylphenol is then converted to the desired 3-alkylphenol by removal of the phenolic hydroxy group. The process involves the conversion of a hydroxy group to a dialkyl phosphate group by reacting it with a dialkyl chlorophosphonate, e.g. diethyl chlorophosphonate, or diethyl phosphonate and triethylamine. Treatment of the dialkyl phosphate with lithium / ammonia and subsequent cleavage of the resulting alkylated methyl ether with boron tribromide or pyridine hydrochloride or other known methyl cleavage agents affords the desired 3-alkylphenol.

A suitable method of preparing the compounds of this invention wherein -Z-W is -O-alk2-W involves the use of 4-bromoresorcinol as a starting material. The process involves the protection of both hydroxy groups of resorcinol by benzylation by standard methods. The benzyl group is preferred as a protecting group in this process because it is easily removed from the catalytic group by hydrogenation without cleavage to the ether group -O-alk-W. Of course, other protecting groups such as alkyl (e.g. methyl or ethyl) may also be used. However, the benzyl protecting group is preferred because it causes fewer side reactions. The protected 4-bromoresorcinol is then treated according to the Grignard reaction and reacted with the appropriate cycloalkenone in a reaction-neutral solvent as described above. The 3- (2, H-dibenzyloxyphenyl) -cycloalkanone thus prepared is then hydrogenated from the catalytic palladium carbon to give the corresponding 3- (2, 4-dihydroxyphenyl) -cycloalkanone in equilibrium with its hemiketal. The hemi-ketal is then converted to the corresponding C 1-4 alkyl, e.g. methyl ketal by reaction with, for example, a trialkyl orthoformate such as trimethyl orthoformate in a suitable solvent such as a C 1-4 alcohol, e.g. methanol in the presence of concentrated sulfuric acid. The alkyl ketal thus prepared is then alkylated with a suitable alkyl or aralkyl methanesulfonate or tosylate in the presence of dry sodium or potassium carbonate in a suitable reaction neutral solvent such as Ν, Ν-dimethylformamide at a temperature of about 75 ° C to 100 ° C. The advantage of this method is that simpler compounds can be used throughout the reaction sequence. The O-alkylated or aralkylated ketal is then decetalized by reacting it with, for example, hydrochloric acid to give the corresponding 16,66584 3- (2-hydroxy-4-O- (alk2) -phenyl) cycloalkanone in equilibrium with its whey ketal, which is reduced to the corresponding compound of formula I.

The analgesic properties of the compounds of this invention are determined by experiments using pain stimuli.

Experiments Using Heat-Induced Pain Stimuli a) Hot Plate Testing of Analgesic Effect Using Mice The method used has been modified according to Woolfe and MacDonald1, J. Pharmacol. Exp. Ther, 80 (1944) 300-307. A controlled thermal stimulus is applied to the soles of the mice with a 3.2 mm (1/8 inch) thick aluminum plate. A 250 watt inf crab heat lamp reflector is placed below the aluminum plate base. A temperature controller connected to the plate surface thermistors is programmed by the heat lamp to maintain a constant temperature of 57 ° C. Each mouse is dropped into a glass cylinder on a hot plate (diameter 16.5 cm) and the counting of time is started when the paws of the animals touch the plate. After 0.5 and 2 hours of dosing with the test compound, signs of the first "oscillating" movements of one or both hind legs of the mouse are observed or until 10 seconds have elapsed without such movements Morphine = 4-5.6 mg / kg (sc) .

b) Testing for analgesic effect based on mouse tail vibration

The mouse tail vibration test has been modified according to D'Amour and Smith, J. Pharmacol. Exp. Ther. 72 (1941) 74-79 using controlled high-intensity tail-directed heating. Each mouse is placed in a tight-fitting metal cylinder with the tail emerging through the other end. This cylinder is placed in such a position that it rests evenly above the hidden heat lamp. At the start of the test, the aluminum lamp on top of the lamp is pulled back, allowing the light beam to pass through the gap and focus on the end of the tail. At the same time, the timer starts. A sudden oscillation of the tail is noted. An untreated mouse usually responds within 3-4 seconds of exposure to lamp light. The duration of the security test is 10 seconds. Each mouse is tested 0.5 and 2 hours after administration of 17,66584 morphine and test compound. The MPE value of morphine is 3.2-5.6 mg / kg (s.c.).

(c) Tail dipping method

The method is a variation of the vessel method developed by Benbasset et al., Arch. int. Pharmacodyn. 122 (1959) 122. Charles River CD-I albino male mice (19-21 g) are weighed and labeled for identification. Five animals are usually used in each drug treatment group, with each animal acting as its own control. For general protection, new test substances are first administered at a dose of 56 mg / kg intraperitoneally or subcutaneously in 10 ml / kg. Before drug treatment and 0.5 and 2 hours after drug administration, each animal is placed in a cylinder. Each cylinder is provided with adequate ventilation of the hole and closed with a round nylon plug through which the tail of the animal protrudes. The cylinder is held upright and is completely immersed in a constant temperature water bath (56 ° C). The end point of each experiment is a vigorous jerk or vibration of the tail associated with a motor reaction. In some cases, the endpoint may be less stressful after drug administration. To prevent unnecessary damage to the tissue, the experiment is stopped and removed from the water bath within 10 seconds. The reaction time is recorded in seconds to the nearest 0.5 second. The medium control and a standard substance of known potency are tested in parallel with the substances to be screened. If the activity of the test substance has not returned to baseline at the 2-hour test site, reaction times are determined at 4 and 6 hours. The last measurement is performed at 24 hours if the activity is equally detectable at the end of the test day.

Experiment using chemical pain stimuli Prevention of phenylbenzoquinone-induced writhing

Groups of five Carworth Farms CF-1 mice are pretreated by subcutaneous or oral administration of saline, morphine, codeine, or a test compound. After twenty minutes (if treated subcutaneously) or fifteen minutes (if treated orally 18 66584), each group is treated by intraperitoneal injection of phenylbenzoquinone, a stimulus known to cause abdominal contractions. Mice are observed for 5 minutes to determine whether or not writhing occurs 5 minutes after stimulus injection. MPE ^ 0 values indicating the prevention of writhing of drug pretreatments are noted.

Experiments using pressure-induced pain stimuli

Effect on the Haffner tail stabbing method In order to determine the effects of the test compound on the aggressive reaction elicited using the tail stabbing stimulus, a variant of the Haffner method, Experimentelle Priifung Schemerzstillender, is used. Deutsch Med. Wscher.

55 (1929) 731-732. An Charles River (Sprague-Dawley) CD albino male rat (50-60 g) is used in the experiment. Prior to drug treatment and again 0.5, 1, 2, and 3 hours after treatment, a Johns Hopkins 2.5-inch "bulldog" clamp is attached to the root of the rat's tail. The end point of each experiment is a clear offensive and bite-seeking attitude to a repulsive stimulus, with the time spent on the attack being recorded in seconds. The clamp is removed within 30 minutes if no attack has yet occurred, and the reaction delay time is recorded as 30 seconds. Morphine is active at a dose of 17.8 mg / kg (i.p.).

Experiments using electrically induced pain pulses' 'Flinch-Jump' test

A variation of Tenen’s flick-jump method is used to determine pain thresholds. Psychopharmacologia 12 (1968) 278-285. The Charles River (Sprague-Dawley) CD albino male rat (175-200 g) is used in the experiment. Prior to drug administration, the feet of each rat are immersed in a 20% glycerol / saline solution. The animals are then placed in a tray and given a series of 1-second electric shocks to their feet as the current increases every 30 seconds. These currents 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 in terms of (a) flick, (b) wagging, and (c) jumping or rapid forward movement when the shock is given. Each rat is given an electric shock of 19,66584 and in a separate ascending series just before drug treatment and 0.5, 2, 4, and 24 hours after drug treatment.

The results of the above experiments are expressed as a percentage of the maximum possible effect (MPE-%). The MPE% of each group is statistically compared to the MPE% of the standard test and pre-drug control values. The MPE% is calculated as follows: ..tv- a test time - control time x 10 0.

MPE -% = - interrupt time - control time

When used orally or parenterally as analgesic agents, the compounds of this invention are most conveniently administered in admixture. Such compositions contain a pharmaceutical carrier selected on the basis of the chosen route of administration and normal pharmaceutical practice. They can be administered, for example, as tablets, pills, powders, or granules containing excipients such as starch, milk sugar, certain types of clay paints, etc. They can be administered as capsules, mixtures with similar or similar excipients. They may also be administered in the form of oral suspensions, solutions, emulsions, syrups and elixirs, which may contain flavoring and coloring agents. For oral administration of the therapeutic agents of this invention, tablets or capsules containing from about 0.01 to about 100 mg are suitable in most cases.

The physician will determine the dosage which will be most suitable for an individual patient and it will vary with the age, weight and route of administration and the route of administration for each patient. Generally, however, the initial dose of analgesic for adults may be from about 0.1 to about 750 mg per day in a single dose or in divided doses. In many cases, it is not necessary to exceed a daily dose of 100 mg. The recommended oral dose is about 1.0 to 300 mg per day; the preferred dose is about 1.0 to about 50 mg / day. The recommended parenteral dose is from about 0.1 to about 100 mg / day; the preferred amount is about 0.1 to about 20 mg / day.

The analgesic activity of several compounds of this invention is determined by the methods described above. The compounds have the formula below: 20 66584

H β ^> <OH

] ^ ΐαι R ^^ Z-W R2

The following abbreviations are used in Table I: PBQ = phenylbenzoquinone-induced distortion; TF = tail twitch; HP = hot plate; RTC = rat tail pinching; and FJ = flicker-jump.

The individual values in the table are ED5Q values. The number followed by the second number in parentheses indicates the% protection observed at a given dose. Thus, 31 (56) indicates protection at 31% at a dose of 56 mg per kilogram of body weight.

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Their activity as diuretics is determined by the method of Lipschitz1 et al., J. Pharmacol. 197 (1943) 97, in which rats are used as experimental animals. The dosage range used for this purpose is the same as mentioned above when using the compounds described herein as analgesic agents.

Use as an antidiarrheal drug is determined by the modified method of Neimegeers et al., Modern Pharmacology-Toxicology, Willem van Bever and Harbans Lal, Eds. 7 (1976) 68-73. Charles River CD-1 rats (170-200 g) are housed in group booths for 18 hours prior to the experiment. The animals are fasted overnight, freely given water, before castor oil is administered. The test drug is administered subcutaneously or orally in constant volumes of 5 ml per kg body weight in a medium containing 5% ethanol, 5% Emulphor EL-620 (polyoxyethylated vegetable oil emulsifier supplied by Antara Chemicals, New York, NY), and 90% saline, followed by one hour later by castor oil (one ml, oral). The animals are housed in small separate booths (20.5 x 16 x 21 cm) with hanging wire mesh floors. A removable cardboard plate is placed under the wire floors and examined for the presence or absence of diarrhea one hour after castor oil administration. For each day of the experiment, a group of animals treated with a medium / castor oil mixture is used as a control group. Results are expressed as the number of animals protected one hour after dosing. In general, the dosage amounts at which these compounds are used as antidiarrheal drugs are comparable to their use as analgesic agents.

The sedative effect of the compounds of this invention is determined by administering them orally to rats at doses of about 0.1 to about 50 mg per kilogram of body weight and observing a consequent reduction in spontaneous exercise activity. The daily dose range in mammals is from about 0.01 to about 100 mg.

The anticonvulsant effect is determined by subcutaneous administration of the test compound to Swiss male mice (Charles River) weighing 14-23 g in the same type of medium used to study its usefulness as an antidiarrheal drug. Groups of five mice are used in the experiment. The day before the experiment, the mice are fasted overnight, but are given free access to water. The treatments are performed by administering the drug with a 10 ml / kg 25-caliber subcutaneous needle. Experimental animals are treated with the test compound and, one hour after drug administration, are given an electroconvulsive shock, 50 mA / 60 Hz, transcorneally. At the same time, control experiments are performed in which the mice are given only the medium as a control treatment. Electroconvulsive treatment causes intensified flexor muscle spasms in all control mice with a residence time of 1.5-3 seconds. The protective effect is reported when the mouse does not experience intensified flexor muscle spasms within 10 seconds of electric shock.

The anticonvulsant effect is otherwise determined in the same manner as in the evaluation of the anticonvulsant effect, but the stimulant administered is pentylenetetrazole administered 120 mg / kg intraperitoneally. This treatment causes jerky seizures at the latest after one minute in more than 95% of the treated control mice. The protective effect is reported when the time taken to detect the seizure has at least doubled due to the pretreatment with the drug.

The sedative / paralytic effect is determined by treating groups of six mice by subcutaneous injection of different doses of test substances. At 30 and 60 minutes after treatment, mice are placed on a rotating rod for one minute and their performance on the rotating rod is evaluated. The inability of the mouse to remain on the rotating rod is considered evidence of a sedative / paralytic effect.

Example 1 3- [2-Benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -cyclohexanone (starting material) A. A solution of 75.0 g (0.193 mol) of 2- (3-benzyloxy-4-bromophenyl) ) -2-methyloctane in 200 ml of tetrahydrofuran was slowly added to 9.25 grams (0.386 moles) of 70-80 mesh magnesium metal. The resulting mixture was boiled for 20 minutes and then cooled to -18 ° C. Coproiodide (1.84 g, 9.7 mmol) was added and stirring was continued for 10 minutes. To the resulting mixture was slowly added a solution of 18.5 g (0.193 mol) of 2-cyclohexen-1-one in 40 ml of tetrahydrofuran at such a rate that the reaction temperature was kept below -3 ° C under cooling with a salt-ice mixture. The reaction mixture was stirred for a further 30 ml - 2.1 66584 minutes (t <0 ° C) and then added to 500 ml of 2N hydrochloric acid and 2 liters of ice water. The reaction mixture was extracted three times with 500 ml portions of ether. The combined extracts were washed twice with 100 ml portions of water, twice with 100 ml portions of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil, the oil was purified by column chromatography on 1.6 kg of silica gel, eluting with 20% ether-cyclo to give 62.5 g (79.7%) of product as an oil.

IR: (CHCl 3 1709, 1613 and 1575 cm-1).

3 + MS: m / e 406 (M), 362, 321, 315 and 91.

B. From the appropriate 2-benzyloxy-4-ZW-bromobenzenes and the appropriate cycloalkenones, the following compounds (starting materials) were prepared according to the above procedure: 3- [2-Benzyloxy-4- [2- (5-phenylpentyloxy] phenyl] cyclohexanone as an oil (3 , 6 g, 87%) of 2-benzyloxy-4- [2- (5-phenylpentyloxy)] 7-bromobenzene (4.0 g, 9.4 mmol), IR: (CHCl 3) 1712, 1616 and 1592 cm -1. 1, MS; m / e 422 (M +), 315, 323, 296, 278, 253, 205 and 91; trans-3-Z2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -4-methylcyclohexanone as an oil (5.11 g, 61%) from 2-benzyloxy-4- (1,1-dimethylheptyl) bromobenzene (7.83 g, 0.0201 mol) and 4-methylcyclohex-2-enone (2.21 g, 0, 0201 moles), IR: (CHCl 3) 1712, 1613 and 1575 cm -1, MS: m / e 420 (M +), 363, 335, 329, 273, 271 and 91; 3-Z 2-benzyloxy-4- (1 , 1-dimethylheptyl) phenyl-7-cyclopentanone as an oil (3.5 g, 58%) from 2-benzyloxy-4- (1,1-dimethylheptyl) bromobenzene (6.00 g, 15.4 mmol); 0.43 (0.25 mm silica gel, life ether / hexane 1: 1); 3- (2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl) -7-cycloheptanone as an oil (2.94 g; 46%) from 2-benzyloxy-4- (1,1-dimethylheptyl) bromobenzene ( 6.00 g, 15.4 mmol) and cycloheptenone (1.69 g, 15.4 mmol); 3- (2,4-dibenzyloxyphenyl) cyclohexanone as a solid (17.9 g, 40%), m.p. 108-109 ° C; from 1-bromo-2,4-dibenzyloxybenzene (43 g, 0.116 mol) and cyclohex-2-enone (11.1 g, 0.116 mol), the product was recrystallized from ether / pentane, 66584 TR: (CHCl 3) 1709, 1618 and 1595 cm-1, MS: m / e 295, 181 and 91, analysis: calculated for C 18 H 18 N 2 O 2: C, 80.80; H, 6.78%, Found: C, 80.88; H, 6.80%; 3- [2-Benzyloxy-4- (1,1-dimethyloctyl) phenyl] cyclohexanone as an oil (5.0 g, 46%) from 2- [3-benzyloxy-4-bromophenyl] -2-methylnonane (10, 4 g, 0.0258 mol) and 2-cyclohexen-1-one (2.48 g, 0.0258 mol), IR: (CHCl 3) 1715, 1618 and 1577 cm -1, MS: m / e 420 (M + ), 377, 329 and 321; 3- [2-Benzyloxy-4-t-butylphenyl] -cyclohexanone as an oil (27.6 g, 58%) from 2- (3-benzyloxy-4-bromophenyl) -2-methylpropane (45.4 g, 0.142 mol) and 2-cyclohexen-1-one (13.9 g, 0.145 mol), IR: (CHCl 3) 1724, 1623, and 1582 cm -1, MS: 336 (M +), 321, 293, 245 and 91; 3- [2-Benzyloxy-4- (1,1-dimethylpropyl) phenyl] -cyclohexanone as an oil (15.8 g, 63%) from 2- (3-benzyloxy-4-bromophenyl) -2-methylbutane ( 24.0 g, 0.0721 mol) and 2-cyclohexen-1-one (7.06 g, 0.0735 mol), IR: (CHCl 3) 1718, 1618 and 1575 cm -1, MS: m / e 350 (M +), 335, 321, 307, 259 and 91; 3- [2-Benzyloxy-4- (1,1-dimethylbutyl] phenyl] -cyclohexanone as an oil (15.1 g, 42%) from 2- (3-benzyloxy-4-bromophenyl) -2-methylpentane (34.8 g , 0.100 mol) and 2-cyclohexen-1-one (10.5 g, 0.110 mol), IR: (CHCl 3) 1736, 1631 and 1592 cm -1, MS: m / e 364 (M +), 321, 273, and 91: trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4-propenyl) cyclohexanone as an oil (58.3 g, 70%) 1-bromo-2-benzyloxy -4- (1,1-dimethylheptyl) bromobenzene (73.0 g, 0.188 mol) and 4- (2-propenyl-2-cyclohexen-1-one (25.5 g, 0.188 mol)), IR: (CHCl 3) 1712, 1645, 1613 and 1575 cm -1, MS: m / e 446 (M +), 360, 354 and 91; 3- [2-benzyloxy-4- (1,1-dimethylpentyl) phenyl] cyclohexanone as an oil (11.5 g, 37%) from 2- (3-benzyloxy-4-bromophenyl) -2-methylhexane (29.6 g, 0.0818 mol) and 2-cyclohexen-1-one (8, 63 g, 0.09 mol), 26 6 65 8 4 IR: (CHCl 3) 1730, 1629 and 1592 cm -1, MS: m / e 378 (M +), 335, 321, 287 and 91; 3- / 2 ~ benzyloxy-4- (1,1-dimethyl-hexyl) f enyl 4-cyclohexanone as an oil (11.0 g, 35%) from 2- (3-benzyloxy-4-bromophenyl) -2-methylheptane (30.2 g, 0.0806 mol) and 2-cyclohexen-1-one (8.5 g, 0.0886 mol), IR: (CHCl 3) 1715, 1623 and 1585 cm -1, MS: m / e 392 (M +), 348, 321, 301, 259 and 91; 3- (2-benzyloxy-4- (1,1-dimethylnonyl) phenyl) cyclohexanone as an oil (13.5 g, 43%) from 2- (3-benzyloxy-4-bromophenyl) -2-methyldecane (30.5 g, 0.073 mol) and from 2-cyclohexen-1-one (7.71 g, 0.0803 mol), IR: (CHCl 3) 1715, 1623, and 1582 cm -1, MS: m / e 434 (M +), 342, 321 and 91; 3- (2-Benzyloxy-4- (1,1-dimethyl-decyl) -phenyl) -cyclohexanone as an oil (7.0 g, 17%) 2- (3-benzyloxy-4-bromo-phenyl) -2 -methylundecane (40.0 g, 0.0928 mol) and 2-cyclohexen-1-one (9.8 g, 0.102 mol), IR: (CHCl 3) 1715, 1623 and 1585 cm -1, MS: m / e 448 (M +), 321 and 91; 3- (2-Benzyloxy-4- (1,1-dimethylundecyl) phenyl) -cyclohexanone as an oil (11.5 g, 40%) from 2- (3-benzyloxy-4-bromo-phenyl) -2-methyldodecane (27.5 g). g, 0.062 mol) and 2-cyclohexen-1-one (6.68 g, 0.0682 mol), IR: (CHCl 3) 1718, 1623 and 1585 cm -1, MS: m / e 462 (M +) , 417, 371, 321 and 91; 3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclooctanone as an oil (10.6 g, 63%) from 2- (3-benzyloxy-4-bromophenyl) -2-methyloctane (15.0 g, 38.6 mmol) and 2-cycloocten-1-one (4.78 g, 38.6 mmol), IR: (CHCl 3) 1715, 1629 and 1587 cm -1, MS: m / e 434 ( M +), 477, 363, 349, 343, 326 and 91.

2 ’66584

Example 2 (starting material) 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclohexanone A. A mixture of 19.5 g (0.0468 moles) of 3- [2-benzyloxy-4- ( 1,1-Dimethylheptyl) phenylcyclohexanone, 12.3 g of sodium bicarbonate, 3.00 g of 10% palladium on carbon and 250 ml of ethanol were stirred under a single atmosphere of hydrogen for 1.5 hours, then the reaction mixture was filtered through diatomaceous earth with ethyl acetate. and the filtrate was evaporated to a solid The crude solid was purified by column chromatography on 280 g of silica gel eluting with 20% ether / cyclohexane to give a solid which was recrystallised from aqueous methanol to give 9.1 g (62%) of a solid. ), mp 87 ° C, mainly in hemiketal form.

IR: (KBr) 3226, 1629 and 1580 cm -1 (CHCl 3) 3571, 3289, 1704, 1623 and 1575 cm -1, MS: m / e 316 (M +), 298, 273 and 231, analysis: calculated for 21 ^ 32 ^ 2: ^ 5 7 ^, 70; H, 10.19, found: C, 79.69; H, 9.89.

B. However, the above procedure was repeated using the appropriate reagents of Example 1 to give the following starting materials: 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-methylcyclohexanone as an oil (54 mg, 86%) of 80 mg (0.19 mmol) of 3- [2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -4-methyl-cyclohexanone, IR: (CHCl3) 3597, 3390, 1623 and 1572 cm -1, MS: m / e 330 (M +), 315, 287 and 245; trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -4-methylcyclohexanone (825 mg, 99% ), mp 62-64 ° C, (recrystallized from pentane) trans-3- [2-benzyloxy-4- (1,1-dimethyl-heptyl) -phenyl] -4-methyl-cyclohexanone (1.05 g, 2.50 mmol), IR: (CHCl 3) 3571, 3333, 1721 (weak), 1626 and 1577 cm -1, MS: m / e 330 (M +), 312, 288, 273, 245, 203 and 161, analysis: calculated for 22-34 ° 2: C, 79.97; H, 10.37; Found: C, 80.33; H, 10.30; 28 6658 4 3-Z- [1- (1-dimethylheptyl) -2-hydroxyphenyl] cyclohepta -nonia (0.54 g, 47%), mp 61-62 ° C (pentane from 3-E-2-benzyloxy-4- (1,1-dimethylheptyl) phenyl-7-cyclopentanone (1.50 g, 3.83 mmol), IR: (KBr) 3279, 1739, 1621 and 1577 cm-1 MS: m / e 302 (M +), 283, 217, 189, 175 and 161, analysis: calculated for C 20 H 30 O 2: C '79> 42i 10.00, found: C, 79.65; H, 10.03; 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cycloheptanone (795 mg, 63%), m.p. 78-79 ° C (from pentane) 3-Q-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cycloheptanone (1.60 g, 3.80 mmol), IR: (CHCl 3) 3571, 3289, 1701, 1621, 1605 and 1577 cm -1, MS: m / e 330 (M +) and 245, Analysis: Calculated for C 22 H 24 N 3 79.95; H, 10.37, Found: C, 79.60; H, 10 33; in quantitative yields of 3- [2-hydroxy-4- (2- (5-phenyl-pentyloxy-phenyl) -cyclohexanone as an oil from 3- (2-benzyloxy-4- (2- (5-phenyl-pentyloxy)) -phenyl] -cyclohexanone (1 .0 g, 2.26 mmol), IR: (CHCl 3) 3571, 3333, 1709, 1623 and 1587 cm -1, MS: m / e 352 (M +), 206, 188 and 91; 3- / 4- ( 1,1-dimethyloctyl) -2-hydroxyphenyl] cyclohexanone (0.75 g, 48%) from 2.00 g (4.76 mmol) of 3- [2-benzyloxy-4- (1,1-dimethyloctyl) phenyl-cyclohexanone, m.p .: 78-80 ° C (from pentane), IR: (CHCl 3) 3571, 3333, 1709 (weak), 1620 and 1577 cm -1, MS: m / e 330 (M +), 314, 312, 287 and 231, Analysis: Calculated for N, 79.95; H, 10.37%, Found: C, 79.97; H, 9.99%; 3- (4-t-butyl-2-hydroxyphenyl) cyclohexanone (4.22 g, 58%) from 3- (2-benzyloxy-4-t-butylphenyl) cyclohexanone (10.0 g, 0.0298 mol), 29 66584 mp: 177-178 ° C (from isopropyl ether), IR : (KBr) 3279, 1639 and 1592 cm-1, MS: m / e 246 (M +), 231, 228, 215, 213, 203, 189, 176 and 161; 3- [4- (1,1-dimethylpropyl) -2-hydroxyphenyl] cyclohexanone (2.52 g, 45%) from 3- [2-benzyloxy-4- (1,1-dimethylpropyl) phenyl] cyclohexanone ( 7.50 g, 0.0214 mol), m.p .: 165-166 ° C (from isopropyl ether), IR: (CHCl 3) 3636, 340.1, 1724 (weak), 1634 and 1587 cm MS: m / e 260 ( M +), 242, 231, 217, 213 and 161, analysis: calculated for 78.42; K, 9.29%, Found: C, 78.17; H, 9.22%; 3- [4- (1,1-Dimethylbutyl) -2-hydroxyphenyl] cyclohexanone (0.6 g, 11%) from 3- [2-benzyloxy-4- (1,1-dimethylbutyl) phenyl] cyclohexanone (7.00 g, 0.0192 mol), m.p .: 101-102 ° C (from isopropyl ether), IR: (CHCl 3) 3636, 3401, 1724 (weak), 1634 and 1585 cm -1, MS: m / e 274 (M +) , 256, 231 and 213, analysis: calculated for C 18 H 28 O 2: C, 78.79; H, 9.55%, found: C, 78.78; H, 9.21%; trans-3- / 4- (1 1,1-Dimethylheptyl-N-hydroxyphenyl-N-propyl-cyclohexanone (1.0 g, 76%) as an oil trans-3- (2-benzyloxy-4- (1,1-dimethylheptyl) phenyl) -4- (2- propenyl) cyclohexanone (1.65 g, 3.69 mmol), IR: (CHCl 3) 3610, 3390, 1718 (weak), 1629 and 1577 cm -1, MS: m / e 358 (M +), 340, 288, 273, 255, 203 and 161. 3- [4- (1,1-dimethylpentyl) -2-hydroxyphenyl] -cyclohexanone (4.0 g, 95%) 3- [2-benzyloxy-4- ( 1-dimethylpentyl) phenyl-4-cyclohexanone (5.5 g, 0.0146 mol), m.p .: 124.5-125.5 ° C (from pentane), IR: (CHCl 3) 3623, 3378, 1718 (weak), 1634 and 1587 cm -1, MS: m / e 288 (M +), 245 and 231, analysis: calculated for C2.q ^ 28 ^ 2: 79.12; H, 9.79%, Found: C, 79.32; H, 9.53%; 3- [1 + - (1,1-dimethylhexyl) -2-hydroxyphenyl] cyclohexanone (quantitative) from 3- [2-benzyloxy-4- (1,1-dimethylhexyl) phenyl] cyclohexanone (2.0 g, 5.1 mmol) , m.p .: 82-83 ° C, 66584 IR: (CHCl 3) 3636, 1734, 1616 and 1585 cm -1, MS: m / 3 302 (M +), 284, 259 and 231, analysis: calculated for ^ 20 ^ 30 ^ 21 79.42; H, 10.00%; Found: C, 79.16; H, 9.75%; 3 - ["4- (1,1-dimethylinonyl) -2-hydroxyphenyl] cyclohexanone (2.4 g, 61%) from 3- [2-benzyloxy-4- (1,1-dimethylinonyl) phenyl] -7-cyclohexanone (5, 0 g, 11.5 mmol), m.p .: 72-73 ° C, IR: (CHCl 3) 3650, 3413, 1721 (weak), 1639 and 1595 cm -1, HRMS: m / e 344.2691, (M + , 326.2570 and 301.2168; 3-, 4- (1,1-dimethyldecyl) -2-hydroxyphenylcyclohexanone (88 mg, 55%) 3- [2-benzyloxy-3- (1 , 1-dimethyldecyl) phenyl] cyclohexanone (2.0 g, 4.46 mmol), m.p .: 78-79 ° C, IR: (CHCl 3) 3623, 1629, 1616 and 1587 cm -1, HRMS: m / e 358.2836 (M +, C 24 H 39 O 2); 3- [4- (1,1-dimethylundecyl) -2-hydroxyphenyl] cyclohexanone (1.49 g, 46%) 3- [2-benzyloxy-4- (1,1- dimethylundecyl) phenyl-cyclohexanone (4.00 g, 8.66 mmol), m.p .: 72-73 ° C, IR: (KBr) 3268, 1629 and 1580 cm -1, MS: m / e 372 (M + ), 354, 329 and 231, analysis: calculated for C 25 H 40 O 2: C '80> 59? H> 10) 82%, found: C, 80.70; H, 10.84%; 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclooctanone (1.92 g, 81%) 3- (2-benzyloxy-4- (1,1-dimethylheptyl) phenyl) from n-cyclooctanone (3.02 g, 6.95 mmol), m.p .: 118 ° C, IR: (CHCl 3) 3623, 3356, 1709, 1629 and 1587 cm -1, MS: m / e 344 (M + ), 329, 326, 283, 273, 259 and 241, analysis: calculated for C 23 H 36 O 2: C, 80.18; H, 10.53%, found: C, 79.92; H, 10.37%; 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl) -4-methyl-2-cyclohexen-1-one (1.15 g, 70%) 3 - [/ 2-benzyloxy-4 - (1,1-dimethylheptyl) phenyl-4-methyl-2-cyclohexen-1-one (2.10 g, 5.02 mmol), m.p .: 111 ° C. (from diisopropyl ether-petroleum ether), 316 65 8 4 IR: (CHCl 3) 3534, 3279, 1667, 1623 and 1567 cm -1, MS: m / e 328 (M +), 313 and 243, analysis: calculated for C22H32O2: C, 80.44; H, 9.83%; Found: C, 80.35; H, 9.67%.

Example 3 cis-3- [2-Benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -'-cyclohexanol and the trans isomer (final product) A. To a solution of 43.0 g (-40 ° C) ( 0.106 moles) of 3- (2-benzyloxy-4- (1,1-dimethylheptyl) phenyl) cyclohexanone in 500 ml of methanol and 15 ml of tetrahydrofuran were added in three portions to 8.05 g (0.212 moles) of sodium borohydride. The reaction mixture was stirred for 1 hour at -40 ° C, allowed to warm to -10 ° C and quenched by the addition of 100 mL of saturated sodium chloride solution. The reaction mixture was added to 1500 ml of water and extracted three times with 450 ml portions of ether. The combined ether extracts were washed with three 100 mL portions of water and two 200 mL portions of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil, the oil was purified by column chromatography on 400 g of silica gel eluting with 20% ether / cyclohexane to give in the order of elution, 5.0 g (12%) of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl] -phenyl) -cyclohexanol, IR: (CHCl3) 3636, 3497, 1629 and 1587 cm-1, MS: m / e 408 (M +), 393, 390, 323 and 91, analysis: calculated for C 28 H 40 O 2: 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, m.p .: 75.5-76.5 ° C.

IR: (CHCl 3) 3636, 3497, 1629 and 1587 cm -1, MS: m / e 408 (M +), 393, 390, 323 and 91, analysis: calculated for C 29 H 40 O 2: C, 82.30; H, 9, 87%, found: C, 81.95, H, 9.74%.

B. The following final product compounds were prepared in a similar manner from the appropriate ketones of Example 1: in quantitative yields Z-3-Z2-benzyloxy-4- (1,1-dimethyl-heptyl) -phenyl-3-methylcyclohexanol as an oil as 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl-3-methylcyclohexanone (200 mg, 0.476 mmol), 32 66584 IR: (CHCl 3) 3546, 3378, 1603 and 1555 cm -1, MS: m / e 422 (M +), 337, 314, 299, 271 and 229. trans, trans-3- (2-berylloxy-4- (1,1-dimethylheptyl) phenyl) -4-methylcyclohexanol (0.225 g, 14%) as an oil and 1.19 g ( 74%) of the cis, trans isomer of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -4-methylcyclohexanone (1.6 g, 3.8 mmol); trans, trans: PMR : 0.80 (m, terminal side chain methyl and C-4-methyl), ^ 1.27 (s, gem dimethyl), 3.12 (m, benzylmethine), 4.20 (m, carbinol methine), 5.13 (s, benzyl ether-methylene), 6.95 (m, aryl-H), 7.15 (d, J = 8Hz, aryl-H) and 7.48 (bs, phenyl-H), XR: (CHCl 3) 3413, 1616 and 1575 cm -1,

MS: m / e 422 (M &lt; + &gt;), 407, 337, 314, 272, 229 and 91; cis, trans: r TMS

PMR: 0.70 (d, J = 6Hz, C-4-methyl), 0.85 (m, terminal side chain methyl), 1.29 (s, gem dimethyl), 2.81 (m, benzyl methine), 3.75 (m, carbinol-methine), 5.13 (s, benzyl ether-methylene), 6.93 (m, aryl-H), 7.15 (d, J = 8 Hz, aryl-H ) and 7.43 (bs, phenyl-H), IR: (CHCl 3) 3571, 3390, 1618 and 1577 cm -1, MS: m / e 422, 337, 314, 272, 229 and 91; cis and trans 3- (2-Benzyl-oxy-4- (1,1-dimethyl-heptyl) -phenyl) -cyclopentanol (1.1 g, 85%) as an oil 3- (2-benzyloxy-4- (1,1-dimethyl-heptyl)) phenyl-4-cyclopentanone (1.32 g, 3.37 mmol), MS: m / e 394 (M +), 379, 376, 309 and 91; trans-3- (2-benzyloxy-4- (1,1- dimethylheptyl) phenyl-N-cycloheptanol (695 mg, 49%) and 380 mg (27%) of the cis-isomer as oils from 3- (2-benzyloxy-4- (1-dimethylheptyl) phenyl) cycloheptanone (1.40 g , 3.33 mmol);

Cis: PMR: 0.85 (m, side chain methyl), 1.3Q (s, gem dimethyl), 3.15 (m, benzylmethine), 3.90 (m, carbinolmethine), 5, 15 (s, benzyl ether-methylene), 6.8-7.4 (m, aryl-H) and 7.45 (bs, phenyl-H), IR: (CHCl 3) 3571, 3448, 1613 and 1572 cm -1 MS: m / e 422 (M +), 337, 314, 229 and 91; 33 66584 trans:

OTMS

PMR: σ 0 »86 (m, terminal methyl), 1.26 (s, gem dimethyl), 3.41 (m, benzylmethine), 4.10 (m, carbinolmethine), 5, 17 (s, benzylmethylene), 6.7-7.2 (m, aryl-H), 7.18 (d, J = 8Hz, aryl-H), and 7.45 (bs, phenyl-H) IR: (CHCl 3) 3534, 3390, 1613 and 1572 cm -1, MS: m / e 422 (M +), 337, 331, 314, 246, 229 and 91; cis-3-12-benzyloxy-4- ( 2- (5-phenylpentyloxy)) phenyl] cyclohexanol (1.51 g, 76%) and the trans isomer (0.379 g, 19%) as oils 3- (2-benzyloxy-4- (2- (5-phenylpentyloxy)) - phenyl-cyclohexanone (2.0 g, 4.52 mmol)); trans: PMR: ^ 1 ^ ^ 1.28 (d, J = 6Hz, methyl), 2.68 (m, benzylmethylene); ), 3.45 (m, benzylmethine), 4.22 (m, carbinolmethine), 4.30 (m, side chain methine), 5.09 (s, benzyl ether-methylene), 6.45 ( dd, J = 8 and 2Hz, aryl-H), 6.55 (bs, aryl-H), 7.10 (d, J = 8Hz, aryl-H), 7.25 (s, phenyl-H) and 7.45 (bs, phenyl-H), IR: (CHCl 3) 3571, 3448, 1613 and 1590 cm -1, MS: m / e 444 (M +), 298, 280, 190 and 91; Λ ^ 1.25 (d, J = 6Hz, methyl), 3.0 (m, benzylmethine), 3.77 (m, carbinolmethine), 4.38 (m, side chain methine), 5.10 (s, benzyl ether-methine), 6.50 ( dd, J = 8 and 2Hz, aryl-H), 6.58 (bs, aryl-H), 7.12 (d, J = 8Hz, aryl-H), 7.32 (s, phenyl-H) and 7.43 (s, phenyl-H), IR: (CHCl 3) 3571, 3390, 1613 and 1587 cm -1, MS: m / e 444 (M +), 298, 190 and 91; cis-3- [2-benzyloxy-4- (1H-dimethyloctyl) phenyl] -cyclohexanol (1.35 g, 45%) and the trans isomer (0.34 g, 11%) 3.00 g (7.14 mmol) of 3- [2-benzyloxy-4- (1,1-dimethyloctyl) phenyl) -cyclohexanone and 0.90 g (30%) of a cis-trans mixture, trans: PMR: 0 .87 (m, terminal side chain methyl), 1.25 (s, gem dimethyl), 3.50 (m, benzylmethine), 4.22 (m, carbinolmethine), 5.15 (s, benzyl ether) -methylene) and 6.8-7.6 (m, aryl-H and phenyl-H, IR: (CHCl 3) 3497, 1623 and 1582 cm -1, MS: m / e 422 (M +) and 323; 3 * 66584 cis: 0.85 (m, terminal side chain methyl), 1.2 5 (s, gem dimethyl), 3.10 (m, benzylmethine), 3.75 (m, carbinolmethine), 5, 12 (s, benzyl ether-methylene), 6.91 (dd, J = 8 and 2 Hz, aryl-H), 6.91 (d, J = 2Hz, aryl-H), 7.17 (d, J = 8Hz, aryl-H) and 7.42 (bs, phenyl-H), IR: (CHCl 3) 3571, 3425, 1618 and 1577 cm -1, MS: m / e 422 (M +) and 323; cis-3- (2-benzyloxy-4-t-butylphenyl) cyclohexanol (7.18 g, 59%) and the trans isomer (1.33 g , 11%), and 1.5 g (12%) of a mixture of cis and trans isomers from 12.0 grams (0.0357 moles) of 3- (2-benzyloxy-4-t-butylphenyl) cyclohexanone; cis: m.p .: 78-79 ° C (from hexane) PMR: 1.30 (s, t-butyl), 3.10 (m, benzylmethine), 3.72 (m, carbinolmethine), 5, 12 (s, benzyl ether-methylene), 6.97 (d, J = 2Hz, aryl-H), 6.97 (dd, J = 8 and 2 Hz, aryl-H), 7.17 (d, J = 8Hz, aryl-H) and 7.40 (bs, phenyl-H), IR: (CHCl 3) 3636, 3472, 1621 and 1582 cm -1, MS: m / e 338 (M +), 323, 320, 230, 215 and 91, Analysis: Calculated for C 23 H 30 O 2: C, 81.61; H, 8.93%; Found: C, 81.79; H, 7.77%;

r TMS

PMR: dCDCl 1.23 (s, t-butyl), 3.50 (m, benzylmethine), 4.20 (m, carbinolmethine), 5.02 (s, benzyl ether-methylene) and 6.8 -7.4 (m, aryl-H and phenyl-H), IR: (CHCl 3 3650, 3472, 1626 and 1587 cm -1, MS: m / e 338 (M +), 323, 320, 230 and 91; cis -3- [2-benzyloxy-4- (1,1-dimethylpropyl) phenyl] cyclohexanol (6.3 g, 78%) and the trans isomer (1.0 g, 12%) as oils 8, 0 grams (0.0229 moles) of 3- [2-benzyloxy-4- (1,1-dimethylpropyl) phenyl] cyclohexanone; cis: mp PMR: 0.67 (t, J = 7Hz, terminal methyl), 1.26 ( s, gem dimethyl), 3.05 (m, benzylmethine), 3.75 (m, carbinolmethine), 5.15 (s, benzyl ether-methylene), 6.92 (d, J = 2, aryl -H), 6.92 (dd, J = 8 and 2H, aryl-H), aryl-H) and 7.42 (bs, phenyl-H), IR: (CHCl 3) 3636, 3344, 1626 and 1587 cm MS: m / e 352 (M +), 337, 334, 323, 244, 215 and 91; 35 66584 trans: IR: (CHCl 3) 3636, 1626 and 1587 cm -1, HS: m / e 352 ( M +), 337, 33%, 323, 244, 215 and 91; cis-3- [2-benzyloxy-4- (1,1-dimethylbutyl) phenyl] -cyclohexanol (4.16 g, 52%) and the trans isomer (0.88 g, 11%), and 0, 49 g (6.1%) of a mixture of cis and trans isomers as oils from 8.0 g (0.022 mol) of 3- [2-benzyloxy-4- (1,1-dimethylbutyl) phenyl] -cyclohexone; cis: PMR: 0.80 (m, terminal methyl), 1.23 (s, gem dimethyl), 3.05 (m, benzylmethine), 3.70 (m, carbinolmethine), 5.08 (s , benzyl ether-methylene), 6.86 (d, J = 2Hz, aryl-H), 6.86 (dd, J = 8 and 2 Hz, aryl-H), 7.11 (d, J = 8Hz, aryl -H) and 7.35 (bs, phenyl-H), IR: (CHCl 3) 3623, 3448, 1621 and 5182 cm -1, MS: m / e 366 (M +), 351, 348, 323, 258, 215 and 91, trans:

r TMS

PMR: <d 0.83 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.40 (m, benzylmethine), 4.18 (m, carbinolmethine), 5.09 (s , benzyl ether-methylene), 6.86 (d, J = 2Hz, aryl-H), 6.86 (dd, J = 8 and 2Hz, aryl-H), 7.11 (d, J = 8Hz, aryl-H), H) and 7.39 (m, phenyl-H), IR: (CHCl 3) 3623, 3472, 1623 and 1585 cm -1, MS: m / e 366 (M +), 351, 348, 323, 258, 215 and 91: trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -cis-4- (2-propenyl) cyclohexanol (1.9 g, 13%) and cis-3, trans-4 isomer (7.3 g, 51%) as oils from trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4- (2-propenyl) cyclohexanone (14.3 g, 32, 1 mmol), eluting from silica gel with pentane / ether 2: 1 gave first the title compound as an oil and then the cis-3, trans-4 isomer, trans-3, cis-4 isomer: IR: (CHCl 3) 3559, 3401 , 1639, 1608 and 1567 cm "1 '

MS: m / e 448 (M +), 433, 430, 363, 406 and 91, rTMS

PMR: c? Gdc °> 82 terminal methyl), 1.25 (s, gem dimethyl), 3.30 (m, benzylmethine), 412 (m, carbinolmethine), 4.6-5.0 (m , vinyl-H), 5.06 (s, benzylmethylene), 5.2-6.1 (m, vinyl-H), 6.82 (d, J = 2Hz, aryl-H), 6.82 (dd, J = 8 and 2Hz, aryl-H), 7.07 (d, J = 8Hz, aryl-H) and 7.38 (bs, phenyl); 36 66584 s »cis-3, trans-4 isomer: IR: (CHCl 3) 3571, 3401, 1639, 1610 and 1572 cm -1, MS: m / e 448 (M +), 406, 363 and 91, PMR: Λ max 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 2.90 (m, benzylmethine), 3.73 (m, carbinolmethine), 4.6-5, 1 (m, vinyl-H), 5.02 (s, benzylmethylene), 5.3-6.3 (m, vinyl-H), 6.75 (d, J = 2Hz, aryl-H), 6.75 (dd, J = 8 and 2Hz, aryl-H), 6.99 (d, J = 8Hz, aryl-H) and 7.25 (bs, phenyl); Syloxy-4- (1,1-dimethylheptyl) phenyl-trans-4- (2-butenyl) cyclohexanol (495 mg, 82%) and the trans-3,4-cis-4 isomer (105 mg, 18%) from trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] - (2-butenyl) -cyclohexanone (600 mg, 1.30 mmol), trans-3, cis-4 isomer eluted first, trans-3, cis-4 isomer: MS: m / e 462 (M +), 447, 444, 377 and 91, cis-3, trans-4 isomer: IR: (CHCl 3) 3610, 3448, 1618 and 1577 cm -1, MS: m / e 462 (M +), 447, 444, 377 and 91; cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl) -trans-4- (2-pentenyl) cyclohexanol and the trans-3,4-cis-4 isomer trans-3- (2-benzyloxy) 4- (1,1-dimethylheptyl) phenyl) -4- (2-pentenyl) -cyclohexanone (497 mg, 1.04 mmol); elution first gave 84 mg (17%) of the trans-3, cis-4 isomer (Rf = 0.26, silica gel, 33% ether / pentane) and then 363 mg (73%) of cis-3, trans-4 isomer (Rf = 0.13, silica gel 33% ether / pentane); cis-3- [2-benzyloxy-4- (1,1-dimethylpentyl) phenyl] -cyclohexanol (5.0 g, 83%) and the trans isomer (0.60 g, 10%) as oils 3- * 2-Benzyloxy-4- (1,1-dimethylpentyl) phenyl} cyclohexanone (6.0 g, 58 mmol); trans: IR: (CHCl 3) 3636, 3497, 1623 and 1582 cm -1, MS: m / e 380 (M +),

ETC

PMR: cdci (m, terminal methyl), 1.24 (s, gem dimethyl), 3.5 (m, benzylmethine), 4.20 (m, carbinolmethine), 5.09 (s, benzylmethylene) ) and 6.8-7.6 (m, aryl-H); cis: IR: (CHCl 3) 3636, 1621 and 1580 cm -1, MS: m / e 380 (M +), PMR: 0.7 δ (m, terminal methyl), 1.14 (s, gem dimethyl), 2, 9 0 3 37 66584 (m, benzylmethine), 3.52 (m, carbinolmethine), 4.80 (s, Benzylmethylene), 6.49 (dd, J = 8 and 2Hz, aryl-H ), 6.49 (d, J = 2Hz, aryl-H), 6.72 (d, J = 8Hz, aryl-H) and 6.96 (bs, phenyl); cis-3- / 2-benzyloxy- 4- (1,1-Dimethylhexyl) phenyl} cyclohexanol (3.0 g, 43%) and the trans isomer (660 mg, 9%) as oils 3- (2-benzyloxy-4- (1,1-dimethylhexyl) ) phenyl-cyclohexanone (7.0 g, 17.9 mmol); cis: IR: (CHCl 3) 3623, 3448, 1618 and 1575 cm -1,

MS: m / e 394 (M &lt; + &gt;), r-TMS

PMR: ci D (31 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.07 (m, benzylmethine), 3.70 (m, carbinolmethine), 5, 08 (s, benzylmethylene), 6.88 (d, J = 2Hz, aryl-H), 7.12 (d, J = 8Hz, aryl-H) and 7.37 (bs, phenyl); IR: (CHCl 3) 3623, 3448, 1618 and 1577 cm -1, MS: m / e 394 (M +), PMR: δ 0.80 (m, terminal methyl), 1.27 (s, gem dimethyl), 3, 42 (m, benzylmethine), 4.12 (m, carbinolmethine), 5.02 (s, benzylmethylene), 6.83 (m, aryl-H), 7.04 (d, J = 8Hz, aryl-H) and 7.34 (bs, aryl-H), cis-3 - {(2-benzyloxy-4- (1,1-dimethylnonyl) phenyl) -cyclohexanol (5.0 g, 59%) and trans isomer (1.0 g, 12%) as oils from 3-benzyloxy-4- (1,1-dimethylnonyl) -phenyl] -cyclohexanone (8.5 g, 19.6 mmol); cis: IR: (CHCl 3); ) 3623, 3448, 1618 and 1577 cm -1, MS: m / e 436 (M +),

r TMS

PMR CDCl 3 0.83 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.04 (m, benzylmethine), 3.67 (m, carbinolmethine), 5.08 (s , benzylmethylene), 6.87 (dd, J = 8 and 2Hz, aryl-H), 6.87 (d, J = 2Hz, aryl-H) and 7.05-7.45 (m, aryl- H and phenyl); trans: IR: (CHCl 3) 3610, 3448, 1618 and 1575 cm -1,

MS: m / e 436 (M &lt; + &gt;), aTMS

PMR: <3cdc10> 82 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.43 (m-benzylmethine), 4.16 (m, carbinolmethine), 5.02 (2 , benzylmethylene) and 6.7-7.5 (m, aryl-H and phenyl); 3,66584 cis-3- [2-Benzyloxy-4- (1,1-dimethylundecyl) phenyl] cyclohexanol (3.5 g, 50%) and the trans isomer (1.0 g, 14%) as oils 3- [2- benzyloxy-4- (1,1-dimethylundecyl) phenyl) cyclohexanone (7.00 g, 15.0 mmol); cis: IR: (CHCl 3) 3636, 3448, 1621 and 1582 cm -1, HS: m / e 464 (M +),

r TMS

PMR: <? 0.95 (m, terminal methyl), 1.33 (s, gem dimethyl), 3.09 (m, benzylmethine), 3.70 (m, carbinolmethine), 5.20 (s, benzylmethylene), 6.99 (dd, J = 8 and 2Hz, aryl-H), 7.22 (d, J = 8Hz, aryl-H) and 7.50 (bs, phenyl-H); trans: IR: (CHCl 3) 3534 (broad), 1618 and 1577 cm -1, MS: m / e 464 (M +), PMR: ^ ^ ^ 0.85 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.48 (m, benzylmethine), 4.17 (m, benzylmethine), 5.08 (s, benzylmethylene) and 6.75-7.55 (m, aryl-H and phenyl) ; cis-3- [2-benzyloxy-4- (1,1-dimethyldecyl) phenyl] -cyclohexanol (2.66 g, 59%) and the trans isomer (0.36 g, 8%) as oils 3- 2-benzyloxy-4- (1,1-dimethyldecyl) phenyl] cyclohexanone (4.5 g, 10.0 mmol); cis: IR: (CHCl 3) 3704, 3571, 1639 and 1597 cm -1, MS: m / e 450 (M +),

ETC

PMR: cod (m, terminal methyl), 1.25 (s, gem dimethyl), 3.08 (m, benzylmethine), 3.74 (m, carbinolmethine), 508 (s, benzylmethylene), 6.88 (dd, J = 8 and 2Hz, aryl-H), 6.88 (d, J = 2Hz, aryl-H), 7.12 (d, J = 8Hz, aryl-H) and 7.37 (bs, phenyl); trans: IR: (CHCl 3) 3623, 3448, 1616 and 1577 cm -1, MS: m / e 450 (M +), PMR: CDCl 3 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.53 (m, benzylmethine), 4.22 (m, carbinolmethine), 5.02 (s, benzylmethylene) and 6.8-7.6 (m, aryl-H and phenyl); N- [benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclooctanol (13.6 g, 19%) and the trans isomer (4.12 g, 59%) as oils 3-E-2-benzyloxy-4- (1,1-dimethylheptyl) phenyl-cyclooctanone (7.0 g, 16.1 mmol), 39 6 6 5 8 4 IR: (CHCl 3), MS: m / e 436 (M +), 421, 418, 351, 328, 300, 243 and 91,

ETC

PMR: <££ D £ - ^ 0.83 (m, terminal methyl), 1.28 (s, gem dimethyl), 3.19 (bm, benzylmethine), 3.89 (bm, carbinolmethine), 5.10 (s, benzylmethylene), 6.83 (m, aryl-H), 7.08 (d, J = 8Hz, aryl-H) and 7.38 (m, phenyl); trans: IR: (CHCl 3), MS: m / e 436 (M +), 421, 418, 351, 328, 243 and 91,

r TMS

PMR: λ max 0.83 (m, terminal methyl), 1.28 (s, gem dimethyl), 3.4 (bm, benzylmethine), 3.9 (m, carbinolmethine), 5, 10 (s, benzylmethylene), 6.85 (m, aryl-H), 7.08 (d, J = 8Hz, aryl-H) and 7.36 (m, phenyl).

Example 4 cis-3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] cyclohexanol (final product) A. A mixture of 22.0 g (0.0539 moles) of cis-S-N-benzyloxy -4- (1,1-Dimethylheptyl) phenyl-cyclohexanol, 12.0 g of sodium hydrogencarbonate and 2.0 g of 10% palladium on carbon were stirred under one atmosphere of hydrogen pressure for 2 hours. The reaction mixture was filtered through diatomaceous earth with ethyl acetate and the filtrate was evaporated to a solid. The solid was recrystallized from hexane to give 13.2 g (77%) of the title product, m.p. 109-110 ° C, IR: (CHCl 3), 3610, 3356, 1626 and 1582 cm -1, MS: m / e 318 (M +), 300, 233 and 215, analysis: calculated for C 21 H 34 O 2: 79, 19, H, 10.76, found: C, 78.96, H, 10.59.

B. Following the procedure described above, the following end products were prepared from the appropriate reagents of Example 3: trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cyclohexanol (2.47 g, 71%), m.p. 124-125 ° C (from pentane) trans-3-ZT2-benzyloxy-4- (1,1-dimethylheptyl) phenyl? 7 cyclohexanol (4.50 g, 0.011 mol), IR: (CHCl 3> 3610, 3390, 1626 and 1575 cm -1 MS: m / e 318 (M +), 300, 233 and 215, Analysis: Calculated for C 21 H 21 Cl 2, 79 and 10576; Found: C, 78.82; H, 10.43; "° 66584 in quantitative yields of Z-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -S-methylcyclohexanol], mp 90-91 ° C (recrystallized from petroleum ether) Z-3 -? - benzyloxy From 4- (1,1-dimethyl-heptyl) -phenyl-O-S-methylcyclohexanol (180 mg, 0.246 mmol), IR: (CHCl 3) 3597, 3333, 1605 and 1570 cm -1, MS: m / e 332 (M +), 314, 299, 286, 271, 247 and 229, Analysis: Calculated for C 18 H 19 N 2 O: C, 79.45; H, 10.92; Found: C, 79.24; H, 10; 64, in quantitative yields trans, trans-3-N- (1,1-dimethylheptyl) -2-hydroxyphenyl--4-methylcyclohexanol, mp 134-135 ° C (from pentane) trans, trans-3- [2- benzyloxy-4- (1,1-dimethylheptyl) -phenyl} -4-methylcyclohexanol (190 mg, 0.450 mmol), IR: (CHCl 3) 3571, 3333, 1626 and 1575 cm -1, MS: m / e 332 (M +), 317, 314, 247, 233 and 229, Analysis: Calculated for C, 79.46; H, 10.92%, Found: C, 79.13; H, 10.68%; in quantitative terms cis, trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -4-methylcyclohexanol, m.p. 150-151 ° C (from pentane), cis, trans-3- (4-benzyloxy-4- (1,1-dimethylheptyl) -phenyl) -4-methylcyclohexanol (1.15 g, 2.72 mmol), IR: (CHCl 3) 3571, 3333, 1621, 1605 and 1580 cm -1, MS: m / e 332 (M +), 314, 272, 247, 233 and 229, analysis: calculated for? 79.46; H, 10.92, found: C, 79.15; H, 10.72; cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cyclopentanol (464 mg, 55%) and 227 mg (27%) of the trans isomer as oils from a mixture of cis- and trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl} cyclopentanols (1.10 g, 2.79 mmol); cis:

C TMS

PMR: ^ cod °> 33 side chain terminal methyl), 1.24 (s, gem dimethyl), 3.2 ^ (m, benzylmethine), 4.52 (m, carbinolmethine), 6.75 ( dd, J = 8 and 2Hz, aryl-H), 6.81 (bs, covers? 6.75 aryl-H) and 6.97 (d, J = 8Hz, aryl-H), IR: ( CHCl 3) 3571, 3300, 1623 and 1567 cm -1, MS: m / e 304 (M +), 286, 219, 201 and 159; 41 66584 trans: PMR: λ max 0.83 (m, side chain terminal methyl), 1.27 (s, gem dimethyl), §, 60 (m, benzylmethine), 4.55 (m, carbinol-methyl), 6.78 (bs, covers <^ 6.88: η , aryl-H), 6.88 (dd, J = 8 and 2Hz, aryl-H) and 7.10 (d, J = 8Hz, aryl-H), IR: (CHCl 3) 3571, 3333, 1621 and 1575 cm -1, HS: m / e 304 (M +), 286, 219 and 201; in quantitative yields trans-3- [trans- (1,1-dimethylheptyl) -2-hydroxyphenyl] cycloheptanol, m.p. 55-57 ° C, from trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cycloheptanol (695 mg, 1.64 mmol), IR: (CHCl 3) 3333, 1621 and 1570 cm -1, MS: m / e 332 (M +), 314, 247 and 229, analysis: calculated for λ 22 ^ 36 ^ 2:? 9.46; H, 10.92, Found: C, 79.68; H, 10.62; in quantitative yields cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cycloheptanol, m.p. 103-104 ° C (recrystallized from pentane) cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cycloheptanol (380 mg, 0.900 mmol), IR: (CHCl 3) 3571, 3311 , 1621, 1605 and 1580 cm -1, MS: m / e 332 (M +), 314, 247 and 229, analysis: calculated for δ 9.46; H, 10.92; Found: C, 79.39; H, 10.72; in quantitative yields cis-3- [4-hydroxy-4- (2- (5-phenylpentyloxy)) phenyl] cyclohexanol, m.p. 80-84 ° C (from pentane) cis-3- {2-benzyloxy-4- (2- (5-phenylpentyloxy)) phenyl] cyclohexanoate (1.45 g, 3.27 mmol).

IR: (CHCl 3) 3597, 3333, 1623 and 1597 cm -1, MS: m / e 354 (M +), 336, 208, 190 and 91, analysis: calculated for C 19 H 18 N 2 O 2: C, 77.93; H , 8.53%, found: C, 77.95; H, 8.31%; trans-3- / 2-hydroxy-4- (2- (5-phenylpentyloxy)) phenyl] cyclohexanol (241 mg, 90%), mp 65-70 ° C (from pentane) trans-3- [2-Benzyloxy-4- (2- (5-phenylpentyloxy) phenyl] cyclohexanol (0.355 g, 0.754 mmol), IR: (CHCl 3) 3597, 3378, 1629 and 1587 cm -1, MS: m / e 354 (M +), 336, 208, 190 and 91; Analysis: Calculated for C 23 H 3 QO 3: C, 77.93; H, 8.53% Found: C, 77.53; H, 8.40%; 42,66584 cis-3- [9- (1,1-dimethyloctyl) -2-hydroxyphenyl] -4-cyclohexanol (0.725 g, 68%) , 36 grams (3.32 mmol) of cis-3- [2-benzyloxy-9- (1,1-dimethyloctyl) phenyl] cyclohexanol, m.p .: 100-101 ° C (recrystallized from hexane), IR: (CHCl 3) 3571, 3333, 1626 and 1582 cm -1, MS: m / e 332 (M +), 3m, 233 and 215, analysis: calculated for C 22 H 23 N 2: 7, 96; 10.92%, Found: C, 79.85; H, 11.03%; Trans-3- [9- (1,1-dimethyloctyl) -2-hydroxyphenyl] -cyclohexanol (0.195 g, 100%) as an oil from 296 mg (0.582 mmol) of trans-3- [2-benzyloxy-9- (1,1-dimethyloctyl) phenyl-cyclohexanol, m.p .: 99-95 ° C (from petroleum ether), IR: (CHCl 3) 3650, 39.36, 1639 and 1582 cm -1, MS: m / e 332 (M +) , 319, 233 and 215, analysis: calculated for C 22 H 23 N 2: 79.96, H, 10.92%, found: C, 79.39, H, 10.55%, cis-3- (9 t-butyl-2-hydroxyphenyl) cyclohexanol (3.99 g, 77%) from cis-3- (2-benzyloxy-9-t-butylphenyl) -cyclohexanol (7.1 g, 0.021 mol), m.p .: 177 -178 ° C (from isopropyl ether), IR: (KBr) 3989, 3268, 1639 and 1592 cm -1, MS: m / e 298 (M +), 233, 230, 215, 187, 176, 173 and 161. Analysis: Calculated for C, 77.37; H, 9.79%, Found: C, 77.00; H, 9.59%; trans-3- (9-t-butyl-2-hydroxyphenyl) cyclohexanol (0.725 g, 99%) from trans-3- (2-benzyloxy-9-t-butylphenyl) cyclohexanol (1.25 g, 2.96) mmol), m.p .: 136-137 ° C (from isopropyl ether), IR: (CHCl 3) 3623, 3901, 1626 and 1575 cm -1, MS: m / e 298 (M +), 233, 230, 215, 187 and 173 , analysis: calculated for cpeH29 ° 2: 77.37; H, 9.79%, found: C, 77.39; H, 9.99%; cis-3- [9- (1,1-dimethylpropyl) 2-Hydroxyphenyl-7-cyclohexanol (1.95 g, 32%) from cis-3- [2-benzyloxy-9- (1,1-dimethylpropyl) -phenyl] -cyclohexanol (6.1 g) , 0.0173 mol), m.p .: 166-167 ° C (from isopropyl ether), IR: (KBr) 3509, 3279, 1629 and 1592 cm -1, MS: m / e 262 (M +), 297, 299, 233 and 215; 4s 66584 trans-3- (1,1-dimethylpropyl) -2-hydroxyphenyl-4-cyclohexanol (0S50 g, 68%) from trans-S-N-benzyloxy-Ud, 1-dimethylpropyl) -phenylcyclohexanol (1, 00 g, 2.84 mmol), m.p .: 124-125 ° C (from isopropyl ether), IR: (CHCl 3) 3636, 3413, 1639 and 1585 cm -1 MS: m / e 262 (M +), 247, 244, 233 and 215, Anal yysi: calculated for C '77 »82; H, 9.99%, Found: C, 77.51; H, 9.87%; cis-3- [4- (1,1-dimethylbutyl) -2-hydroxyphenyl] -cyclohexanol (1.9 g, 74%) cis-3- {5-benzyloxy-4- (1,1-dimethylbutyl) -phenyl from methyl cyclohexanol (3.39 g, 9.26 mmol), m.p .: 138-139 ° C (pentane), IR: (KBr) 3509, 3279, 1629 and 1592 cm -1, MS: m / e 276 ( M +), 261, 258, 233 and 215; trans-3- [4- (1,1-dimethylbutyl) -2-hydroxyphenyl] -cyclohexanol (0.45 g, 87%) as an oil trans-3- From 2-benzyloxy-4- (1,1-dimethylbutyl) phenyl} cyclohexanol (0.700 g, 1.91 mmol), IR: (CHCl 3) 3636, 3390, 1629 and 1575 cm -1, MS: m / e 276 (M +), 261, 258, 233 and 215; Trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cis-4-propylcyclohexanol (620 mg, 78%) trans-3- [2-benzyloxy-4- (1,1 -dimethylheptyl) phenyl-cis-4- (2-propenyl) cyclohexano-list (1.0 g, 2.23 mmol), m.p .: 92-94 ° C, IR: (CHCl 3) 3623, 3390, 1629 and 1578 cm -1, analysis: calculated for C 24 H 24 O 2 C, 79.94; H, 11.18%, found: C, 80.10; H, 10.89%; cis-3- / 4- (1,1-Dimethylheptyl) -2-hydroxyphenyl-7-trans-4-propylcyclohexanol (550 mg, 74%) cis-3- [4-benzyloxy-4- (1,1-dimethylheptyl) phenyl] trans-4- (2-propenyl) cyclohexanol (930 mg, 2.07 mmol), m.p .: 126 ° C (pentane), IR: (CHCl 3 3597, 3390, 1629 and 1575 cm -1, MS: m / e 360 (M +) , 345, 342, 275 and 257, analysis: calculated for δ 24 ^ 40 ^ 2 '5 H, 11.18%, found: C, 79.85; H, 10.95%; ^ 66584 tpans-4-butyl -cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cyclohexanol (322 mg, 80%) cis-3- [12-benzyloxy-4- (1,1-dimethylheptyl) phenyl] - from trans-4- (2-butenyl) cyclohexanol (500 m g, 1.08 mmol), m.p .: 131 ° C (from pentane), IR: (CHCl 3) 3636, 3356, 1629 and 1587 cm -1, MS: m / e 374 (M +), 356, 302, 289, 272, 271, 257, 247, 233, 217, 187 and 161; Trans-4-pentyl-cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cyclohexanol (225 mg, 76%) cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) ) phenyl 7-trans-4- (2-pentenyl) cyclohexanol (363 mg, 0.762 mmol), m.p .: 13-136 ° C; cis-3- [4- (1,1-dimethylpentyl) -2-hydroxyphenyl] cyclohexanol (2.5 g, 60%) cis-3- [2-benzyloxy-4- (1,1-dimethylpentyl) phenyl] from cyclohexanol (5.5 g, 0.0144 mol), m.p .: 112-113 ° C. (from pentane, isopropyl ether), IR: (CHCl 3) 3636, 3390, 1631 and 1592 cm -1, MS: m / e 290 (M +), 272, 233 and 215, analysis: calculated for? H, 10.41%, found: C, 78.76; H, 10.11%; trans-3- [N- (1,1-dimethylpentyl) -2-hydroxyphenyl]), cyclohexanol (385 mg , 78%) from trans-3- [2-benzyloxy-4- (1,1-dimethylpentyl) -phenyl] -cyclohexanol (640 mg, 1.68 mmol), m.p .: 114-115 ° C (from pentane), IR: (CHCl 3) 3636, 3390, 1631 and 1577 cm -1, MS: m / e 290 (M +), 272, 233 and 215, analysis: calculated for C 18 H 30 O 2: C '78.57; H, 10.41%, Found: C, 78.38; H, 10.10%; cis-3- [N- (1,1-dimethylhexyl) -2-hydroxyphenyl] cyclohexanol (2.3 g, 99%) cis-3- [2-benzyloxy-4- (1,1-dimethylhexyl) phenyl] from cyclohexanol (3.00 g, 7.61 mmol), m.p .: 98-10 ° C (from pentane), IR: (CHCl 3) 3636, 3367, 1626 and 1587 cm -1, MS: m / e 304 (M +) , '286, 233 and 215, analysis: calculated for C 20 H 21 O 3: C' 78.89; H, 10.59%, found: C, 78.57; H, 10.46%; 45 66584 trans-3 Trans-3- (1,1-dimethylhexyl-2-hydroxyphenyl) cycloanole (440 mg, 86%) trans-3- (2-benzyloxy-4- (1,1-dimethylhexyl) phenyl) from cyclohexanol (660 mg, 1.68 mmol), m.p .: 113-114 ° C (from pentane), IR: (CHCl 3) 365, 3390, 1631, 1616 and 1580 cm -1, MS: m / e 304 (M +) , 286, 233 and 215, HRMS: 304.2419 (C20H3202); cis-3- [4- (1,1-dimethylnonyl] -2-hydroxyphenyl] -7-cyclohexanol (4.0 g, 100%) cis-3- 2-benzyloxy-4- (1,1-dimethylnonyl) -phenylcyclohexanol (5.0 g, 1.15 mmol), m.p .: 82-83 ° C (from pentane), IR: (CHCl 3) 3650, 3390, 1637 and 1597 cm-1, MS: m / e 346 (M +), 328, 23 3 and 215, Analysis: Calculated for C 23 H 39 O 2: C, 79.71; H, 11.05%, Found: C, 79.71; H, 11.14%; Trans-3- [4- (1,1-dimethylnonyl) -2-hydroxyphenyl] cyclohexanol (709 mg, 89%) trans-3- [2-benzyloxy-4- (1,1-dimethylnonyl) phenyl] -N -cyclohexanol (1.00 g, 2.29 mmol), m.p .: 69-70 ° C (pentane), IR: (CHCl 3) 3636, 3413, 1631, 1618 and 1582 cm -1, MS: m / e 346 (M +), 328, 233 and 215, analysis: calculated for C 19 H 19 O 3 C, 79.71; H, 11.05%, found: C, 79.11; H, 10.86%; cis-3- [4- (1,1-Dimethyldecyl) -2-hydroxyphenyl] cyclohexane (2.02 g, 98%) of cis-3- (2-benzyloxy-4- (1,1-dimethyldecyl)) methyl) from cyclohexanol (2.6 g, 5.78 mmol), m.p .: 93-94 ° C (from pentane), IR: (CHCl 3) 3636, 3390, 1629 and 1587 cm -1, MS: m / e 360 ( M +), 342, 288, 233 and 215, Analysis: Calculated: C, 79.94; H, 11.18%, Found: C, 80.12; H, 11.39%; Trans-3- {β- (1,1-dimethyldecyl) -2-hydroxyphenyl] -cyclohexanol (130 mg, 45%) trans-3 - [(2-benzyloxy-4- (1,1-dimethyldecyl) phenyl) from cyclohexanol (360 mg, 0.80 mmol), m.p .: 76-77 ° C, IR: (CHCl 3 3636, 3425, 1631, 1616 and 1580 cm -1, MS: m / e 360 (M +), 342, 233 and 215, analysis: calculated for C 24 H 40 O 2: C> 79> 91 *; H> 1] L> 18 found: C, 80.20; H, 11.27%; ε 66584 cis-3- / 4 - (1,1-dimethylundecyl) -2-hydroxyphenyl-cyclohexanol (2.39 g, 85%) from cis-3- [2-benzyloxy-4- (1,1-dimethylundecyl) -phenyl] -cyclohexanol (3.5 g) , 7.54 mmol), m.p .: 85-86 ° C> IR: (CHCl 3) 3636, 3390, 1634 and 1592 cm -1, MS: m / e 374 (M +), 356, 233 and 215, analysis : calculated for C 25 H 42 O 2: C> 8011.30%, found: C, 80.00; H, 11.48%; trans-3- [4- (1,1-dimethylundecyl) -2-hydroxyphenyl] cyclohexanol (487 mg , 60%) from trans-3- [2-benzyloxy-4- (1,1-dimethylundecyl) -phenyl] -cyclohexanol (1.00 g, 2.16 mmol), m.p .: 73-74 ° C, IR: (CHCl 3) 3636, 3413, 1637 and 1585 cm -1, MS: m / e 374 (M +), 356, 233 and 215, analysis: calculated for C 25 H 42 O 2: C> 80> 15J H, 11.30%, found: C, 80.11; H, 11.16%; cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclooctanol 0.793 g, 73%) cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl] cyclooctanol; from octanol (1.36 g, 3.11 mmol), m.p .: 89-90 ° C (from pentane), MS: m / e 346 (M +), 328, 261 and 243, analysis: calculated for £ 23-38 ° 2: C, 79.71; H, 11.05%; Found: C, 79.90; H, 10.89%; Trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] cyclooctanol (2 , 62 g, 83%) of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl] cyclooctanol (4.0 g, 9.17 mmol), m.p .: 76-77 ° C, MS: m / e 346 (M +), 328, 261 and 243, analysis: calculated for C 23 H 38 O 2: C, 79.71; H, 11.05%, Found: C, 79.81; H, 10.86%.

47 6 6584

Example 5 3- [2-Benzyloxy-4- (1,1-dimethylheptyl) -phenyl] cyclohex-2-enone (starting material) A. A solution of 3.89 g (10 mmol) of 2- (3- benzyloxy-4-bromophenyl) -2-methyloctane in 10 ml of tetrahydrofuran was slowly added to 360 milligrams (14.4 mmol) of 70-80 mesh magnesium metal. The resulting mixture was boiled for 30 minutes and then cooled to 0 ° C. To this solution was slowly added a solution of 1.40 g (10 mmol) of 3-ethoxy-2-cyclohexen-1-one in 3 ml of tetrahydrofuran, and the reaction mixture was stirred for 30 minutes at 0 ° C, followed by the addition of 20 ml of 1N. sulfuric acid and heated on a water bath for 30 minutes, then the mixture was cooled and added to a mixture of 200 ml of ether and 200 ml of water, the organic extract was washed successively with 200 ml of saturated sodium hydrogen carbonate solution and 200 ml of saturated sodium chloride solution, dried over magnesium sulfate The crude product was purified by chromatography on oil in a bath of 170 g of silica gel eluting with ether / pentane 1: 1 to give 2.5 g (54%) of the title compound as an oil.

IR: (CHCl 3) 1667, 1610 and 1558 cm -1, MS: m / e 404 (M +), 319, 313 and 91.

B. In a similar manner, 3- (2-benzyloxy-4- (1,1-dimethylheptyl) phenyl) -4-methylcyclohex-2-enone was prepared as an oil (4.12 g, 77%) using 3-ethoxy-6- methyl 2-cyclohexen-1-one (1.98 g, 12.9 mmol), magnesium (0.61 g, 25.7 mmol) and 12.9 mmol (5.0 g) of 2- (3 benzyloxy-4-bromophenyl) -2-metyylioktaania.

IR: (CHCl 3 1667, 1613 and 1565 cm -1, MS: m / e 418 (M +), 400, 385, 333, 299, 291 and 91.

Example 6 3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methylcyclohexanone (starting material)

To a solution of -10 ° C to -5 ° C containing 4.17 mmol of dimethyl copper parlithium in 10 ml of tetrahydrofuran was slowly added 5.60 mg (1.39 mmol) of 3- (2-benzyloxy). 4- (1,1-dimethylheptyl) phenyl} -cyclohex-2-enone in 5 ml of tetrahydrofuran. The reaction mixture was stirred for a further 30 minutes and then added to 100 ml of saturated ammonium chloride solution, so-called 66584, and to 100 ml of ether. After stirring for 10 minutes, the reaction mixture was extracted with 200 ml of ether. The ether extract was washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil. The oil was preparatively purified by chromatography on three silica gel plates 20 cm x 20 cm x 2 mm and eluting with cyclohexane / ether 2: 1 to give 282 mg (48%) (higher Rf) of the title compound as an oil, and 211 mg (36 %) (lower Rf value) 3- [2-Benzyloxy-4- (1,1-dimethylbenzyl) phenyl] -1-methylcyclohex-2-en-1-ol as an oil.

Title compound: IR: (CHCl 3) 1704, 1610, 1565 cm -1.

MS: m / e 420 (M &lt; + &gt;), 405, 377, 337 and 329.

3-N-Benzyloxy-4- (1,1'-dimethylheptyl) phenyl] -7-ethylcyclohex-2-en-1-ol: IR: (CHCl 3) 3571, 3401, 1661, 1608 and 1585 cm -1 1.

MS: m / e 420 (M &lt; + &gt;), 402, 335 and 317.

Example 7 3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] cyclohex-2-enone (starting material)

A mixture of 400 mg (0.988 mmol) of 3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclohex-2-enone and 20 mg of 5% palladium on carbon was stirred under one atmosphere of hydrogen pressure. minutes.

The reaction mixture was then filtered through diatomaceous earth with ether and the filtrate evaporated to a solid. The crude solid was recrystallized from petroleum ether to give 110 mg (35%) of the title compound, m.p. 122-123 ° C.

IR: (KBr) 3448, 1634, 1608 and 1565 cm -1.

MS: m / e 314 (M &lt; + &gt;), 299 and 229.

Analysis: Calculated for C, 80.21; H, 9.62%, found C, 80.23; H, 9.46%.

Example 8 (starting material) 3- (2,4-dihydroxyphenyl) cyclohexanonimethyl ketal in a solution of 0.0 g (33.0 mmol) of 3- (2,4-dihydroxyphenyl) cyclohexanone in 100 ml in methanol and 15 ml of trimethyl orthoformate, 10 drops of concentrated 49 66584 sulfuric acid were added. The reaction mixture was then stirred for 3 hours without cooling by allowing the temperature to rise to room temperature, after which the reaction was quenched by the addition of excess solid sodium bicarbonate. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in a mixture of 200 ml of water and 200 ml of ether. The ether extract was washed once with 150 ml of saturated sodium hydrogen carbonate solution, dried over magnesium sulphate and evaporated to dryness, the oily residue crystallized from ether / pentane to give 5.74 g (77%) of the title compound, m.p. 12 9-13 ° C.

IR: (KBr) 3289, 1629, 1613 and 1597 cm -1.

MS: 220 (M +), 205, 203, 188, 177, 161 and 136.

Analysis: Calculated for C 19 H 18 N 2 O 2: C, 70.89; H, 7.32%, Found: C, 70.79; H, 7.34%.

Example 9 3- [2-Hydroxy-4- (4-phenylbutyloxy) phenyl] cyclohexanone methyl ketal (starting material) A. A mixture of 5.03 g (22.8 mmol) of 3- (2,4-dihydroxyphenyl) ) cyclohexanone methyl ketal, 10.1 g (73.2 mmol) of dry potassium carbonate and 6.12 g (26.8 mmol) of 4-phenylbutyl methanesulfonate in 25 ml of Ν, Ν-dimethylformamide, were heated to 85-100 ° C: in 4 hours. The reaction mixture was cooled and added to a mixture of 200 ml of water and 200 ml of ether. The ether extract was washed twice with 200 ml of water, dried over magnesium sulphate and evaporated to an oil. The oil was purified by column chromatography on 400 g of silica gel eluting with pentane / ether 2: 1 to give 7.4 g (92%) of the title compound as an oil.

IR: (CHCl 3) 1623 and 1590 cm -1.

MS: m / e 352 (M &lt; + &gt;) and 91.

Analysis: Calculated for C 9 H 8 O 2: C, 78.37; H, 8.01%, Found: C, 78.34; H, 8.07%.

B. The following compounds were prepared in a similar manner but using the appropriate mesylate derivative instead of 4-phenylbutyl methanesulfonate: 3- [4-hydroxy-4- (2-heptyloxy) phenyl] cyclohexanone methyl ketal (6.13 g, 75%) as an oil 5.7 grams (25.9 mmol) * 3- (2,4-dihydroxyphenyl) cyclohexanone methyl ketal and (2-heptyl) methanesulfonate (6.2 g, 32.3 mmol), 50 6 6 5 Δ 4 IR: (CIIC13) 1637 and 1600 cm-1, MS: m / e 318 (M +), 286, 274, 220, 204 and 178; 3- [2-Hydroxy-4- (2-octyloxy) phenyl] cyclohexanone methyl ketal as an oil (5.03 g, 58%) from 3- (2,4-dihydroxyphenyl) cyclohexanone methyl ketal (5.7 g, 25.9 mmol) and (2-octyl) methanesulfonate (7.3 g, 35.1 mmol), IR: (CHCl 3) 1639 and 1600 cm -1, MS: m / e 332 (M +), 300, 289, 272 and 220; 3- (4-hydroxy-4- (2-noyloxy) phenyl) cyclohexanone methyl ketal (5.23 g, 59%) as an oil from 3- (2,4-dihydroxyphenyl) cyclohexanone methyl ketal (5.7 g, 25.9 mmol) and (2-nonyl) methanesulfonate (7.9 g, 35.5 mmol), IR: (CHCl 3) 1634 and 1590 cm -1, MS: m / e 346 (M +), 314, 220, 188 and 161; 3- [2-Hydroxy-4- (2- (4-phenyl) butoxy) phenyl] cyclohexanone methyl ketal as an oil (5.1 g, 56%) from 3- (2,4-dihydroxyphenyl) cyclohexanone methyl ketal (5, 7 g, 25.9 mmol) and 2- (4-phenylbutyl) methanesulfonate (8.0 g, 35.0 mmol), IR: (CHCl 3) 1639 and 1603 cm -1, MS: m / e 352 ( M +), 320, 220 and 188. S - N - hydroxy - N- (2- (6-phenyl) hexyloxy) phenyl] cyclohexanone methyl ketal (5.3 g, 54%) as an oil 3- (2,4-dihydroxyphenyl) cyclohexanone methyl ketal (5.7 g, 25.9 mmol) and 2- (6-phenylhexyl) methanesulfonate (9.0 g, 35.5 mmol), IR: (CHCl 3) 1634 and 1597 cm -1, MS : m / e 380.2342 (M +, C25H3203), 220.1088, 188.0986 and 177.0550.

Example 10 (starting material) 3-Z2-hydroxy-4- (4-phenylbutyloxy) phenyl) cyclohexanone A. A mixture of 6.8 g (19.3 mmol) of 3- [2-hydroxy-4- (4- phenylbutyloxy) phenyl) cyclohexanone methyl ketal, 100 ml of 2N hydrochloric acid and 60 ml of dioxane were heated at reflux for 1 hour. The reaction mixture was cooled and added to a mixture of 300 ml of ether and 500 ml of saturated sodium chloride solution. The ether extract was washed once with 500 ml of saturated sodium chloride solution and 500 ml of saturated sodium hydrogen carbonate solution, dried over magnesium sulphate and evaporated to an oil. g (98%) of the title compound as an oil.

IR: (CHCl 3) 3571, 3333, 1718 (weak), 1626 and 1595 cm -1.

MS: m / e 388 (M &lt; + &gt;), 320, 310, 295, 268 and 91.

In a similar manner, the following starting materials were prepared from the appropriate ketals of Example 9. _______________________ 3- [4- (2-Heptyloxy) -2-hydroxyphenyl} -β 3 -hexanone (4.7 g, 82%) as an oil from 6.0 grams (18.8 mmol) of the corresponding methyl ketal, XR: <CHCl 3) 3636, 3390, 1724 (weak), 1639 and 1600 cm -1, MS: m / e 304 (M +), 206, 188, 171, 1063 and 137; 3- [4- (2-octyloxy) -2-hydroxyphenyl] cyclohexanone (4 , 1 g, 85%) as an oil from 5.0 g (15.0 mmol) of the corresponding methyl ketal, IR: (CHCl 3) 3636, 3378, 1721 (weak), 1631 and 1595 cm -1, MS: m / e 318 (M + ), 206, 188, 178 and 163; 3- [trans- (2-Nonyloxy) -2-hydroxyphenyl] cyclohexanone (4.35 g, 89%) as an oil from 5.1 g (14.7 mmol) of the corresponding methyl ketal, IR: (CHCl 3) 3584, 3367, 1709 ( weak), 1626 and 1587 cm-1, MS: m / e 332 (M +), 206, 187 and 171; 3- [trans- (2- (4-phenyl) butyloxy) -2-hydroxyphenyl] cyclohexanone (3.8 g, 79%) from 5.0 g (14.2 mmol) of the corresponding methyl ketal, as an oil, IR: (CHCl 3) 3636, 3425, 1724 (weak), 1637 and 1600 cm -1, MS: m / e 338 (M +), 206, 188, 132, 117 and 91; 3- / 4- (2- (6-phenyl) hexyl] ) -2-hydroxyphenyl-5'-chlorohexanone (4.45 g, 89%) as an oil from 5.2 g (13.6 mmol) of the corresponding methyl ketal, IR: (CHCl 3) 3636, 3390, 1718, 1637 and 1600 cm -1, MS; m / e 366 (M +), 206, 188 and 91.

Example 11 cis-3- [2-Hydroxy-4- (4-phenylbutyloxy) phenyl] cyclohexanol and trans isomer (final product) A. To a solution of 4.8 g (14, 2 mmol) 3- [2-hydroxy-4- (4-phenylbutyloxy) phenyl] cyclohexanone In 25 ml of methanol was added 0.539 g (14.2 mmol) of sodium borohydride. 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 ether extract was washed once with 150 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to an oil, the oil was purified by column chromatography on 400 g of silica gel eluting with dichloromethane / ether 2.5: 1 to give 3.37 g (70%) of cis- isomer, crystallized from cyclohexane, and 0.68 g (14%) of the trans isomer, crystallized from cyclohexane, and 0.69 g (14%) of a mixture of substances.

cis-isomer:

M.p .: 79-80 ° C.

1 H-NMR: 2.70 (m, benzylmethylene), 3.26 (m, benzylmethine), 3.34 (bt, J = 6Hz, -OCH 2 -), 4.28 (m, OH, carbinol-methine with D 2 O 4.25, M, carbinol-methine), 6.42 (dd, J = 8 and 2Hz, aryl-H), 6.45 (d, J = 2Hz, aryl-H), 7.03 (d, J = 8 Hz, aryl-H) and 7.22 (s, phenyl-H).

IR: (CHCl 3) 3610, 3333, 1631 and 1603 cm -1.

MS: m / e 340 (M &lt; + &gt;), 322, 190 and 91.

Analysis: Calculated for δ 22-28 ° 3: 7 <7> 6-L »H, 8.29%, Found: C, 77.46; H, 8.25%.

trans isomer: mp: 112-114 ° C.

PMR: λmax 2.68 (m, benzylmethylene), 3.80 (m, OH, -OC 3 O-, carbinolmethine with D 2 O ci 3.63, m, carbinolmethine and λmax); 90, bt, J = 6Hz, -OCH 2 -), 6.32 (bs, masks ci6.40; n), 6.40 (dd, J = 8 and 2Hz, aryl-H), 7.00 (d, J = 8 Hz, aryl-H) and 7.20 (s, phenyl-H).

IR: (CHCl 3) 3610, 3390, 1631 and 1595 cm -1.

MS: m / e 340 (M &lt; + &gt;), 322, 190 and 91.

Analysis: Calculated for C 22 H 22 N 2 O 3: 77, 1 H, 8.29%, Found: C, 77.40; H, 8.31.

B. In a similar manner the following final products were prepared: cis-3- [4- (2-heptyloxy) -2-hydroxyphenyl] cyclohexanol and the trans isomer as oils from 3- [4- (4-heptyloxy) -hydroxyphenyl] -cyclohexanone (5.2 g, 13.6 mmol); in the order of elution, 854 mg (36%) of the cis-3 and then 107 mg (3%) of the trans-3 isomers are obtained on silica gel; cis: IR: (CHCl 3) 3597, 3333, 1629 and 1600 cm -1, MS: m / e 306 (M +), 208, 190, 173 and 162, PMR: 0.82 (m, methyl), 2.8 (m, benzylmethine), 3.7 (m, carbinolmethine and OH), 4.1 (m, methine), 6.38 (m, aryl-H) and 6.93 (d, J = 8Hz , aryl-H); 53 66584 trans: MS: m / e 306 (M +), 208 and 190,

ETC

PMR: & qpq-1 0.82 (m, methyl), 3.25 (m, benzylmethine), 4.3 (m, carbinolmethine and OH), 6.33 (m, aryl-H) and 6 .94 (d, J = 8Hz, aryl-H); cis-3- [4- (2-octyl) cyclo-2-hydroxyphenyl] cyclohexane and the trans isomer of 3- [4- (2-octyloxy) -2-hydroxyphenyl] cyclohexanone (2.92 g, 9.18 mmol) ); in the order of elution, 1.58 g (54%) of cis-3 and then 0.57 g (19%) of trans-3 isomers are obtained first from the silica gel; cis: IR: (CHCl 3) 3663, 3390, 1637 and 1608 cm -1, MS: m / e 320 (M +), 319, 208 and 190,

r TMS

PMR cdci (m, methyl), 2.81 (m, benzylmethine), 3.8 (m, carbinolmethine), 4.1 (m, side chain methine and OH), 6.35 (m, aryl -H) and 6.96 (d, J = 8Hz, aryl-H); trans: IR: (CHCl 3) 3636, 3390, 1634 and 1595 cm -1, MS: m / e 320 (M +), 235, 208, 190 and 173, PMR: <0.82 (m, methyl), δ , 25 (m, benzylmethine), 4.1-4.9 (m, carbinol and side chain methines and OH), 6.35 (m, aryl-H) and 6.96 (d, J = 8Hz , aryl-H); cis-3-N- (2-nonyloxy) -2-hydroxyphenylcyclohexanol and the trans isomer of 3- (4- (2-nonyloxy) -2-hydroxyphenyl] cyclohexanone (31.5 g, 19.48 mmol); in the order of elution from silica gel, first 2.11 g (67%) of cis-3 and then 0.32 g (10%) of trans-3 isomers are obtained as oils; cis: IR: (CHCl 3> 3663, 3390, 1639 and 1610 cm -1, MS: m / e 334 (M +), 316, 208 and 190,

C TMS

PMR: 0.88 (m, methyl), 2.85 (m, benzylmethine), 3.5-4.1 (m, carbinolmethine and OH), 4.22 (m, side chain methine), 6.38 (m, aryl-H) and 6.97 (d, J = 8Hz, aryl-H); trans: IR: (CHCl 3) 3636, 3413, 1637 and 1592 cm -1, MS: m / e 334 (M +), 316, 208, 206 and 190, PMR: L 1 '"methyl), 3.23 (m, benzylmethine), 3.9-4.6 (m, carbinyl and side chain methines and OH), 6.36 (m, aryl-H) and 6.96 (d, J = 8Hz, aryl- B); cis-3-N- (2- (4-phenyl) butyl) cyclohexanol 546,68484 and the trans isomer 3- {4- (2- (4-phenyl) butyloxy) - 2-hydroxy-phenyl-cyclohexanone (2.9 g, 8.23 mmol); in the order of elution from silica gel, first 1.29 g (44%) of cis-3 and then 241 mg (8%) of trans-3 isomers are obtained; cis: m.p .: 96-105 ° C (from pentane), IR: (CHCl 3) 3636, 3390, 1634 and 1608 cm -1, MS: m / e 340 (M +), 322, 208, 190, 162, 147, 136 and 91, PMR: 1.30 (d, J = 6Hz, methyl), 3.75 (m, carbinol-methine), 4.23 (m, side chain -methine), 6.21 (d, J = 2Hz, aryl) -H), 6.38 (dd, J = 8 and 2Hz, aryl-H), 6.98 (d, J = 8Hz, aryl-H) and 7.20 (s, phenyl), analysis: calculated for 22 DEG-28 DEG C., 77.61; H, 8.29%, found: C, 77.59; H, 8.18%; trans: IR: (CHCl3) 3623, 3390, 1637 and 1595 cm-1 MS: m / e 340 (M +), 342, 208, 190, 162, 147, 136 and 91,

r TMS

PMR: <4 qdci ^ -> 30 (d, J = 6Hz, methyl), 3.3 (m, benzylmethine), 4.23 (m, carbinol and side chain methines), 6.38 (m, aryl- H), 6.94 (d, J = 8 Hz, aryl-H) and 7.18 (s, phenyl); cis-3- [4- (2- (6-phenyl) hexyloxy) -2-hydroxyphenyl] cyclohexanol and the trans isomer 3- (4- (2- (6-phenyl) hexyloxy) -2- hydroxyphenyl-cyclohexanol (3.3 g, 9.01 mmol); in the order of elution from silica gel, first 1.54 g (46%) of cis-3 and then 274 mg (8%) of trans-3 isomers are obtained; cis: mp: 99-113 ° C (from pentane), IR: (CHCl 3) 3636, 3367, 1631 and 1592 cm -1, MS: m / e 368 (M +), 350, 208, 190, 162, 147, 136 and 91,

c TMO

PMR:? CpCl 2 N 2 O (d, J = 6Hz, methyl), 3.6 (m, carbinolmethine), 4.2 (m, side chain methine), 6.37 (m, aryl-H) , 6.98 (d, J = 8 Hz, aryl-H) and 7.18 (s, phenyl-H), analysis: calculated for C 22 H 22 N 2 O 2: C '78.22; H, 8.75%, Found: C, 78.05; H, 8.56%; trans: IR: (CHCl 3) 3636, 3413, 1634 and 1597 cm -1, MS: m / e 368 (M +), 350, 208, 190, 162, 147, 136 and 91, PMR: c (d, J = 6Hz, methyl), 4.21 (m, carbinol and side chains), 6.37 (m, aryl-H), 6.95 (d, J = 8Hz, aryl-H) 66584 and 7.15 (s, phenyl-H).

Example 12 3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] -2-cyclohexenol (final product) in a solution at -30 ° C with 1.00 g (3.18 mmol) ) 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -2-cyclohexenone in 60 ml of ether was added dropwise 6.3 ml of a 1 mol (in toluene) solution of diisobutylaluminum hydride. The reaction mixture was stirred for an additional 30 minutes at -30 ° C and then added to 1.5 liters of water. The solution was extracted three times with 400 ml portions of ether and the combined extracts were washed twice with 12 ml of saturated sodium chloride solution and dried over magnesium sulfate. After evaporation to dryness, the crude product was purified by chromatography on a column of 50 g of Florial eluting with ether to give an oil. Crystallization of the oil from pentane gave 256 mg (25%) of the title product. M.p .: 87-88 ° C.

HS: m / e 316 (M +), 298, 231 and 213.

Analysis: Calculated for ^ 2 ^ 32 ^ 2: C, 79.70; H, 10.19%, Found: C, 79.68; H, 9.96%.

Example 13 3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] -3-3-cyclohexenone ethylene ketal (starting material)

A solution of 500 mg (1.59 mmol) of 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -2-cyclohexenone, 7.8 g (127 mmol) of ethylene glycol, 375 mg (3, 18 mmol) of hydroquinone and 50 mg (0.263 mmol) of p-toluenesulfonic acid monohydrate in 50 mL of Bentene were heated at reflux for 12 hours using a Dean-Stark condenser filled with 3A molecular sieves. The reaction mixture was cooled and added to 500 ml of saturated sodium hydrogen carbonate solution. The mixture was extracted three times with 150 ml portions of ether, dried over magnesium sulphate and evaporated to a solid. This solid was purified by column chromatography on 50 g of silica gel eluting with 50% ether / Petro-ether to give (after refluxing from pentane) 393 mg (69%) of the title product.

M.p .: 97-98 ° C.

MS: m / e 358 (M &lt; + &gt;), 297, 273, 245 and 229.

56 6 6 5 8 4 Analysis: Calculated for C, 77.05; H, 9.56%, Found: C, 76.9.8; H, 9.4 2%.

Example 14 3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] -4-methylcyclohex-3-enone (starting material)

A mixture of 4.08 g (0.1 mol) of 3- [4- (1,1-dimethyl-neptyl) -2-hydroxyphenyl] -4-methyl-cyclohex-3-enone-ethylene ketal, 50 ml 2N Oxalic acid and 50 ml of methanol were stirred at 25 ° C for 6 hours. The reaction mixture was added to a mixture of 500 ml of water and 250 ml of ether. The ether extract was washed once with 250 ml of saturated sodium hydrogen carbonate solution, once with 250 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. The residue was purified by column chromatography on 400 g of silica gel eluting with 50% ether / pentane to give the title compound.

Example 15 3-N- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cyclohex-3-en-1-ol (final product) in a solution at -18 ° C with 17.5 g (50 mmol) ) 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cyclohex-3-enone in 50 ml of methanol, 1.9 g (50 mmol) of sodium borohydride were added. The reaction mixture is stirred for 30 minutes and then added to a mixture of 250 ml of saturated sodium chloride solution and 250 ml of ether. The ether extract is washed once with 250 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of 400 g of silica gel, eluting with a 50% ether / pentane mixture, to give the title compound.

Example 16 3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] -cyclohex-2-en-1-ol (final product) in a solution at -18 ° C with 70.0 g (0, 20 moles) 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl) -cyclohex-2-enone In 200 ml of methanol is added 7.6 g (0.20 moles) of sodium borohydride. The reaction mixture is stirred for 30 minutes and then added to a mixture of one liter of saturated sodium chloride solution and one liter of ether. The ether extract is washed once with 500 ml of 576 65 84 saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of 500 g of silica gel eluting with 50% ether / pentane to give the title compound.

Example 17 Trans-4 -, (β-Benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -5-buten-4-one (starting material)

A solution of 2-benzyloxy-4- (1,1-dimethylheptyl) -benzaldehyde (65.2 g, 0.193 mol} and 1-triphenylphosphoranylidene-2-propanone (62.0 g, 0.195 mol} in dichloromethane) (195 ml} was heated at reflux for 20 hours. A second batch of 15.5 g (15.5 g, 0.047 mol) was added and heating was continued at reflux for 24 hours. The reaction mixture was cooled, evaporated to dryness and diluted with ether. The triphenylphosphine oxide formed The precipitate was removed by filtration The crude oil was purified by column chromatography on 1.5 kg of silica gel eluting with 20% ether / hexane to give 53.9 g (74%) of the title compound as an oil.

IR: (CHCl 3) 1681, 1621 and 1575 cm -1.

MS: (m / e) 378 (M +}, 364, 337, 293, 271, 251 and 91.

Example 18 5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4-carbomethoxy-1,3-cyclohexanedione (starting material)

To a solution of sodium methylate (0.67 g, 12.4 mmol) and dimethyl malonate (1.86 g, 14.1 mmol) in methanol (4.75 mL) was slowly added a solution of trans-4 - [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-buten-2-one (3.75 g, 9.92 mmol) in methanol (4 mL). The reaction mixture was heated at reflux for 3 hours, then cooled and evaporated to dryness in vacuo. The residue was diluted with ether and saturated sodium chloride solution and acidified with 1N hydrochloric acid. The ether extract was washed twice with 500 ml of saturated sodium chloride solution (500 ml), dried over magnesium sulphate and evaporated to dryness to give 4.71 g (99%) of the title compound. M.p .: 108-109 ° C (from petroleum ether / ether).

IR: (CHCl 3) 1742, 1709, 1612 and 1577 cm -1.

MS; (m / e) 478 (M +), 446, 419, 393, 387 and 91.

Analysis: Calculated for C 18 H 18 N 2 O 2: C, 75.28; H, 8.00%, found: C, 75.05; H, 7.97%.

58 6 6 5 8 4

Example 19 5- [4-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -1,3-cyclohexanedione (starting material)

A mixture of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4-carbomethoxy-1,3-cyclohexanedione (20.8 g, 43.5 mmol), dioxane (40 mL ) and 20% sodium hydroxide (40 mL) was heated at 100 ° C for 2.5 h. The mixture was cooled in an ice bath and acidified with concentrated hydrochloric acid. This mixture was heated at 100 ° C for 1 h, cooled to 10 ° C and then neutralized with sodium bicarbonate. The resulting mixture was added to a solution of saturated sodium hydrogencarbonate solution and ether. The ether extract was dried over magnesium sulfate and evaporated to an oil. Purification of this oil by chromatography on a column of one kilogram of silica gel eluting with 10% acetone / ether gave 10.9 g (60%) of the title compound.

M.p .: 102-103 ° C (pentane / ether mixture).

IR: (CHCl 3) 3636-2222 (broad), 1739, 1712, 1613 (broad) and 1577 (shoulder).

MS: m / e 420 (M &lt; + &gt;), 335, 329 and 91.

Analysis: Calculated for δ 28-36 ° C, 79.96; H, 8.63%, Found: C, 79.87; H, 8.54%.

Example 2Q

5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methoxy-2-cyclohexen-1-one (starting material)

A solution of (5.0 g, 11.9 mmol) of 5- [4-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -1,3-cyclohexanedione and p-toluenesulfonic acid (200 mg) in methanol ( 250 ml) in a flask connected to a Soxhlet condenser with 3A molecular sieves was heated at reflux for 30 minutes. The reaction mixture was cooled, concentrated in vacuo and the residue was diluted with a mixture of saturated sodium bicarbonate solution and ether. The ether extract was washed successively with saturated sodium hydrogen carbonate solution, saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness to give 5.15 g (99%) of the title compound as an oil.

1R: (CHCl 3) 1644, 1612, 15Q 3, 1460 and 1379. cm -1.

MS: (m / e) 434 (M +), 349, 343 and 91.

59 6 6584

Example 21 5- [1-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -2-cyclohexen-1-one (starting material) to a solution of the title compound of Example 20 at 0 ° C. - 1-Benzyloxy-4- (1,1-dimethylheptyl) phenyl) -1-3-methoxy-2-cyclohexen-1-one (500 mg, 1.15 mmol), lithium aluminum hydride (20 mg) was added in ether (20 mL). , 0.53 mmol). The reaction mixture was stirred for 30 minutes at 0 ° C, acidified with 1N salt and stirred for 2 hours at room temperature. The ether phase was removed, washed successively with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. The crude oil was purified by chromatography on a column of 100 g of silica gel eluting with 50% ether / pentane to give 353 mg (76%) of the title compound as an oil.

IR: (CHCl 3) 1681, 1672, 1613, 1575 and 1479 cm -1.

MS: (m / e) 404 (M +), 319, 313 and 91.

Example 22 5 -, / 2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl, β-3-methyl-2-cyclohexen-1-one (starting material) A. To a solution at 0 ° C in which was methylmagnesium iodide (11 ml of 2.9 mol in ether) and tetrahydrofuran (10 ml) was added dropwise a solution of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methoxy-2- cyclohexen-1-one (3.45 g, 7.95 mmol) in tetrahydrofuran (10 mL). The reaction mixture was then warmed and stirred at room temperature for 2 hours, after which it was added to ice-cold 1N hydrochloric acid. After stirring for 20 minutes, the hydrolysis mixture was extracted with ether. The ether extract was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by column chromatography on 100 g of silica gel eluting with 25% ether / pentane to give 3.08 g (93%) of the title compound.

M.p .: 60-61 ° C (from pentane) MS: (m / e) 418 (M +), 333, 327 and 91.

60 66584 B. In a similar manner, the following compounds were prepared from suitable reagents: 5-E-2-benzyloxy-4- (1,1-dimethylhexyl) phenyl, 7-3-ethyl-9-cyclohexen-1-one (2 , 83 g, 82%) as an oil from 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methoxy-2-cyclohexen-1-one (3.46 g, 7.97 mmol) and 10.8 ml of 2.94 molar ethylmagnesium bromide (in ether), IR: (CHCl 3) 1698, 1666, 1623 and 1582 cm -1, MS: (m / e) 432 (M +), 341 and 91 ; 5- [2-Benzyloxy-4- (1,1-dimethylphenyl) phenyl] -3-n-propyl-9-cyclohexen-1-one (3.48 g, 85%) as an oil 5- [2-benzyloxy From 4- (1,1-dimethylheptyl) phenyl] -3-methoxy-2-cyclohexen-1-one (4.00 g, 9.21 mmol) and n-propylmagnesium bromide (36.8 mmol), IR: ( CHCl 3) 1661, 1631, 1612 and 1575 cm -1, MS: (m / e) 446 (M +), 355 and 91; 5- [1-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-n-hexyl] -2-cyclohexen-1-one (4.11 g, 92%) as an oil 5 - [2-benzyloxy From 4- (1,1-dimethylheptyl) phenyl] -3-methoxy-2-cyclohexen-1-one (4.00 g, 9.21 mmol) and 7.37 mL of 2.5-mole of n-hexylmagnesium. sodium bromide (in ether), IR: (CHCl 3) 1678, 1661, 1633, 1618 and 1582 cm -1, MS: (m / e 488 (M +), 403, 397 and 91.

Example 23 cis-3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -5-methylcyclohexanone (starting material)

A mixture of 5- [N-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methyl-2-cyclohexen-1-one (1.00 g, 2.39 mmol) and 500 mg % palladium on carbon - 50% water, stirred under one atmosphere of hydrogen pressure for one hour. Another 500 mg portion of catalyst was added and stirring was continued for 30 minutes. A third portion of 500 mg of catalyst was added and stirring was continued for 13 minutes. The reaction mixture was then filtered through sodium bicarbonate and magnesium sulfate and the filtrate was evaporated to dryness. The residue was purified by chromatography on a column of 140 g of silica gel eluting with 10% ether / petroleum ether to give 323 mg (32%) of the title compound as an oil.

61 66584 MS: (m / e) 420 (M +), 402, 363, 335, 329 and 91.

Example 24 'cis-3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl: R-5-methylcyclohexanone (starting material) A. A mixture of 5- [2-benzyloxy-4- ( 1,1-dimethylheptyl) phenyl-3-methyl-2-cyclohexen-1-one (2.83 g, 6.77 mmol), 1.5 g of 5% palladium on carbon -50% water, and sodium hydrogen carbonate (2.8 g) in methanol (30 ml), stirred under one atmosphere of hydrogen pressure for 45 minutes. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in ether, dried over magnesium sulphate and evaporated to dryness. Crystallization of the residue from pentane gave 1.15 g (52%) of the title compound. M.p .: 95-98 ° C.

Analysis: Calculated for ^ 22 ^ 34 ^ 2 '9 a 9 5; H, 10.37, Found: C, 80.22; H, 10.28%.

B. Following the above procedure, the compounds listed below were prepared from the appropriate reagents of Examples 21 and 22.

cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-ethyl-methyl] hexanone (1.34 g, 60%) 5-E-2-benzyloxy-4- (1.1 -dimethylheptyl) phenyl-3-ethyl-2-cyclohexen-1-one (2.83 g, 6.55 mmol), m.p .: 106-107 ° C.

IR: (CHCl 3) 3597, 3333, 1709, 1626 and 1585 cm -1, MS: (m / e) 344 (M +), 326, 315, 297, 273 and 259, analysis: calculated for C, 80.18 H, 10.53%, found: C, 80.27; H, 10.39%; cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-propylcyclohexanone ( 1.66 g, 61%) of 5- [2-benzyloxy-4- (1,1-dimethyl-heptyl) -phenyl] -3-propyl-2-cyclohexen-1-one (3.40 g, 7.62 mmol) mp: 86.5-90.5 ° C, IR: (CHCl 3) 3533, 3289, 1700, 1618 and 1577 cm -1, MS: (m / e) 358 (M +), 340, 315, 297 and 273, Analysis: Calculated for C 24 H 38 O 2: C '80.39; H, 10.68%, Found: C, 80.16; H, 10.57%; 62 66584 cis-3- / 4- (1, 1-Dimethylheptyl) -2-hydroxyphenyl-5-hexyl-cyclohexanone (3.06 g, 93%) 5- (5-benzyloxy-4- (1,1-dimethyl-heptyl) phenyl) -3-hexyl-2- from cyclohexen-1-one (4.00 g, 8.2 mmol), mp: 84-85 ° C (from pentane), IR: (CHCl 3) 3571, 3333, 1703, 1623 and 1582 cm -1, MS : (m / e) 400 (M +), 382 and 315, analysis: calculated for C 12 H 14 O 2 C, 80.94; H, 11.07%, found: C, 80.97; H, 10, 94%.

Example 25 To a solution of trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -5-methyl-cyclohexanone (starting material) at 0 ° C in dimethyl copper lithium (2.47 mmol) ) in ether (3 mL) and hexane (2 mL) was added dropwise a solution of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -2-cyclohexen-1-one (500 mg, 1 , 24 mmol) in ether (1.5 mL). The reaction mixture was stirred for 15 minutes and then poured into saturated aqueous ammonium chloride solution (300 ml). The reaction mixture was extracted with three 50 ml portions of ether, the combined ether extracts were washed with water, brine, dried over magnesium sulfate and evaporated to dryness to give 475 mg (92%) of the title compound as an oil.

IR: (CHCl 3) 1704, 1613 and 1577 cm -1.

MS: (m / e) 420 (M &lt; + &gt;), 402, 363, 335 and 329.

Example 26 trans-3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] -5-methylcyclohexanone (starting material)

A mixture of trans-3- [2-benzyloxy-4- (1,1-dimethyl-heptyl) -phenyl] -5-methyl-cyclohexanone (175 mg, 0.417 mmol) and 175 mg of 5% palladium on carbon in 50% water in methanol (8 mL), stirred under one atmosphere of hydrogen pressure until hydrogen uptake was complete. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated to dryness in vacuo. Crystallization of the residue from pentane gave 89 mg (64%) of the title compound.

M.p .: 99-102 ° C.

MS: m / e 330 (M &lt; + &gt;), 312, 273 and 245.

63 66584

Example 27 '(final product) cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -trans-5-methylcyclohexanol and the trans-cis isomer in a solution of trans at -78 ° C with trans -3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -5-methylcyclohexanone (300 mg, 10.714 mmol) in methanol (15 mL) and tetrahydrofuran (5 mL) was added over 1 hour. sodium borohydride (216 mg, 5.68 mmol). The reaction mixture was stirred for a further 2 hours at -78 ° C, warmed to room temperature and evaporated to dryness in vacuo. The residue was acidified with dilute hydrochloric acid and extracted with ether. The extract was dried over magnesium sulfate, evaporated to dryness and the residue was purified by column chromatography on 50 g of silica gel eluting with 30% ether / pentane to give 232 mg (77%) of the trans, cis isomer and 45.9 mg (15%) of ) cis, trans isomerism. trans, cis: MS: (m / e) 422 (M +), 337, 314, 229 and 91.

ETC

PMR: cdci (n, terminal methyl), 1.05 (d, J = 7 Hz, C-5-methyl), 1.26 ^ (s, gem dimethyl), 3.70 (n, benzylmethine), 4 .05 (n, carbinolmethine), 5.13 (s, benzylmethylene), 6.8-8.0 (n, aryl-H) and 7.1-7.6 (n, aryl- H and phenyl). cis, trans: MS: (m / e) 422 (M +), 337, 314, 229, 206 and 91.

ETC

PMR: CDCl (n, p-methyl), 1.05 (d, J = 7 Hz, C-5-methyl), 3.1-5.3 (n, benzyl and carbinol methines), 5.13 (s, benzylmethylene), 5.40 (s, OH) and 6.8-7.7 (n, phenyl and aryl-H).

Example 28 (final product) cis-3- (2-benzyloxy-4- (1,1-dimethylheptyl) phenyl) -cis-5-methylcyclohexanol and the trans, trans isomer in a solution of -78 ° C containing cis -3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -5-methylcyclohexanone (228 mg, 0.543 mmol) in methanol (10 mL) was added sodium borohydride (160 mg, 4 , 21 mmol) within 2 hours. The reaction mixture was allowed to warm to room temperature and then added to a mixture of ether and saturated sodium chloride solution. The ether extract was dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was preparatively purified chromatographically on five silica gel plates, 20 cm x 20 cm x 0.5 mm, eluting with 50% ether / pentane to give 3S mg (16%) of the trans, trans isomer ( Rf 0.25, silica gel, 33% ether / petroleum ether) and 168 mg (Rf 0.17, silica gel, 33% ether / petroleum ether) cis, cis isomer.

Example 29 cis-3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] -cis-5-methylcyclohexanol (final product) A. To a solution of cis-3- (4- (1 (1-dimethylheptyl) -2-hydroxyphenyl) -5-methylcyclohexanone (898 mg, 2.13 mmol) in methanol (30 mL) is added sodium borohydride (805 mg, 21.8 mmol). The reaction mixture was stirred for 1 hour at -78 ° C, warmed to room temperature and added to a mixture of ether and saturated sodium chloride solution. The ether extract was dried over magnesium sulfate and evaporated to dryness to give an oil. Crystallization from pentane gives 589 mg (65%) of the title compound. M.p .: 113-114 ° C.

IR: (CHCl 3) 3636, 3390, 1631 and 1592 cm -1.

MS: (m / e) 332 (M +), 314, 247, 229 and 95.

Analysis: Calculated for ^ 22 ^ 36 ^ 2 'C, 79.46; H, 10.91%.

Found: C, 79.79; H, 10.62%.

B. In a similar manner, the following final products were prepared from the appropriate reagents: cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cis-5-ethyl-cyclohexanol (0.74 g, 74%) cis- 3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -5-ethylcyclohexanone (1.00 g, 2.30 mmol), m.p .: 110-111 ° C, IR: (CHCl 3) 3636, 3367 , 1631 and 1587 cm -1, analysis: calculated for C 23 H 38 O 2: C, 79.71; H, 11.05%, found: C, 79.41; H, 10.71%; cis-3- / 4 - (1,1-dimethylheptyl) -2-hydroxyphenyl] -L) -cis-5-n-propylcyclohexanol (0.954 g, 71%) cis-3- [4- (1,1-dimethylheptyl) -2 -hydroxyphenyl--5-n-propylcyclohexanone (1.34 g, 3.74 mmol), m.p .: 10-10-10 ° C (from pentane), IR: (CHCl 3) 3636, 3378, 1626 and 1587 cm -1, MS : (m / e) 360 (M +), 342, 275, 275 and 161, analysis: calculated for C 21 H 4 qO 2: C, 79.94; H, 11.18%, Found: C, 79.88; H, 11.22%, 65 6 6 5 8 4 cis-3- [4- (1,1-dimethylheptyl] -2-hydroxyphenyl] -N-cis: -5-n-methylcyclohexanol, with 120 g of silica gel After purification by elution with a% ether / pentane mixture, cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] was obtained in quantitative yields as an oil with traces of the trans-trans isomer. From η 5 -5-n-hexylcyclohexanone (1.20 g, 3.00 mmol), IR: (CHCl 3) 3623, 3355, 1626 and 1585 cm -1, HS: (m / e) 402 (M +), 384, 317 and 290.

Example 30 trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cis-5-methylcyclohexanol (final product) A. A mixture of trans-3- [2-benzyloxy-4- (1,1 1-Dimethyl-heptyl) phenyl-7-cis-5-methylcyclohexanol (220 mg, 0.521 mmol) and 220 mg of 5% palladium on carbon in 50% water in methanol (8 mL) were stirred under one atmosphere of hydrogen pressure for 3 hours. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated to dryness. Crystallization of the residue from petroleum ether gave 91 mg (53%) of the title compound.

M.p .: 111-112 ° C.

IR: (CHCl 3) 3571, 3333, 1629 and 1572 cm -1.

HS: (m / e) 332 (M +), 314, 246 and 229.

B. The following final compounds were prepared in a similar manner from the appropriate reagents: cis-3- (1,1-dimethylheptyl) -2-hydroxyphenyl-10-trans-5-methylcyclohexanol (20.0 mg, 56%) as an oil cis-3- from oxyloxy-4- (1,1-dimethylheptyl) phenyl-4-trans-5-methylcyclohexanol (45 mg, 0.107 mmol), highly resolved MS: (m / e) 332.2698 (M +, C 22 H 36 ° 2 + 314, 2635, 247, 1657 and 229,1600, trans-3- [5- (1,1-dimethylheptyl) -2-hydroxyphenyl] -trans-5-methylcyclohexanol (28 mg, quantitative yield) trans-3-A-benzyloxy From 4- (1,1-dimethylheptyl) phenyl-O-trans-5-methyl-cyclohexanol (36 mg, 0.085 mmol) to give the product as an oil, Rf = 0.35 (silica gel, 50% ether / pentane cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cis-5-methyl-cyclohexanol in quantitative yields cis-3- [2-benzyloxy-4- (1,1-dimethylheptyl) ) from phenyl 7-cis-5-methylcyclohexanol 66584 66 (168 mg, 0.398 mmol), which was identical to the product of Example 29.

Example 31 Trans-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cis- 4- (2-propenyl) cyclohexanol (final product) A. A solution of trans-3- [2-benzyloxy-4 - (1,1-dimethylheptyl) -phenyl-7-cis-4- (2-propenyl) cyclohexanol (900 mg, 2.01 mmol) and 2.74 ml of 2.2 mol mol of n-butyllithium (in hexane) in ether (3 ml). ) was stirred for 2 days at room temperature. A second portion of 2.0 mmol of n-butyllithium was added and the reaction mixture was stirred for another 2 days. The reaction mixture was added to saturated ammonium chloride solution (250 ml), and the mixture was extracted with ether. The ether extract was dried over magnesium sulfate and evaporated to dryness. The residue was purified by column chromatography on 20 g of silica gel eluting with 50% ether / pentane to give 631 mg (8%) of the title compound.

M.p .: 85-91 ° C.

IR: (CHCl 3) 3311, 1639, 1618 and 1567 cm -1.

MS: (m / e) 358 (M +), 343, 340, 316, 299, 273 and 255.

B. Using this method, the final product compound is prepared: cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -trans-4- (2-propenyl) cyclohexanol (241 mg, 60%) cis-3- 2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -7-trans-4- (2-propenyl) cyclohexanoate (500 mg, 1.12 mmol).

M.p .: 124-125 ° C (from pentane).

IR: (CHCl 3) 3571, 3333, 1642, 1618 and 1580.

MS: (m / e) 358 (M +), 340, 298, 286, 273 and 255.

Analysis: Calculated for O 2 O 2 • O 2: C, 80.39; H, 10.68%.

Found: C, 80.52; H, 10.57%.

Example 32 Trans-3-N- (1,1-dimethylheptyl) -2-hydroxyphenyl-4- (2-propenyl) cyclohexanone (starting material)

To a solution of 3- [4- (1,1-dimethylheptyl) -2-hydroxy-phenyl] -4- (2-propenyl) cyclohexanol (2.15 g, 6.03 mmol) (mixture of isomers) in dichloromethane (15 mL ) pyridine chlorochromate (2.59 g, 12.1 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature, diluted with ether, 57 66584 diatomaceous earth was added and the mixture was filtered through magnesium sulfate. The filtrate evaporated to dryness was purified by chromatography on a column of 200 g of silica gel eluting with 20% ether / pentane to give 250 mg of the crude title compound. This was further purified by preparative chromatography on two silica gel plates, 20 cm x 20 cm x 2 mm, eluting twice with 20% ether / pentane to give 200 mg (9.3%) of the title compound as an oil.

IR: (CHCl 3) 3571, 3390, 1718, 1650, 1626 and 1577 cm -1.

MS: (m / e) 356 (M +), 341, 338, 314, 288, 271, 257, 253 and 229.

Analysis: Calculated for C 21 H 19 N 2 O 2 · 8 → 8 5; H, 10.18%.

Found: C, 80.92; H, 9.86%.

Example 33 Trans-3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl,} - 4- (2- (propenyl) -cyclohexanone-ethylene ketal (starting material) A mixture of trans-3- -benzyloxy-4- (1,1-dimethyl-heptyl) -phenyl} -4- (2-propenyl) -cyclohexanone (17.0 g, 38.1 mmol), ethylene glycol (47.2 g, 0.762 mol) ) and p-toluenesulfonic acid monohydrate (250 mg) in benzene (200 ml) were heated at reflux for 3 hours using a Dean-Stark separator The reaction mixture was cooled and added to a mixture of 1N sodium hydroxide (200 ml), ether (100 ml) ml) and pentane (100 ml) The organic extract was washed twice with 200 ml portions of water, twice with 200 ml portions of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness to give the title compound in quantitative yields.

IR: (CHCl 3) 1656, 1626 and 1587 cm -1.

MS: (m / e) 490 (M +), 475, 450, 449, 448, 446, 407, 405, 399, 383 and 91.

Example 34 Trans-3- [N-Benzyloxy-4- (1,1-dimethylheptyl) -phenyl, 7-4- (2-butenyl) -cyclohexanone (starting material) A. A mixture of trans-3- -benzyloxy-4- (1,1-dimethylheptyl) -phenyl] -4- (2-butenyl) cyclohexanone-ethylene ketal (700 mg, 1.38 mmol), dioxane (20 mL) and 2N hydrochloric acid (20 mL ) was heated at reflux for 1.5 hours. The reaction mixture was cooled, poured into ice water (500 ml) and extracted with ether (300 ml).

6 8 «584

The ether extract was washed with two 20.0. 1 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness to give the title compound in quantitative yield as an oil.

IR: (CHCl 3) 1715, 1616 and 1575 cm -1.

MS: (m / e) 460 (M +), 403, 375, 369, 363, 313, 273, 271 and 91.

Rf: 0.43 (silica gel, 25% ether / pentane).

B. In a similar manner there was prepared: trans-benzyloxy-4- (1,1-dimethylheptyl) phenyl-7-4- (2-pentenyl) cyclohexanone in quantitative yields as an oil trans-3- (2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -1 + - (2-Pentenyl) cyclohexanone-ethylene ketal (540 mg, 1.04 mmol).

Rf: 0.57 (silica gel, 33% ether / pentane).

Example 35 cis-3- [4- (1,1-Dimethylheptyl) -2-hydroxyphenyl] -cis-4-methyl-cyclohexanol and cis-3-N- (1,1-dimethylheptyl) -2-hydroxyphenyl] -7- 4-Methylcyclohexanone A mixture of 3 - [(4-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4-methylcyclohex-2-enone and 391 mg of 5% Pd / carbon-50% water in methanol (15 ml) was stirred under one atmosphere of hydrogen pressure until gas absorption ceased. The reaction mixture was filtered through diatomaceous earth using ethyl acetate and evaporated to dryness. The residue was purified by column chromatography on silica gel (200 g) eluting with 50% ether / hexane to give 758 mg of a mixture of ketones and 820 mg (53%) of the title alcohol, which was crystallized from cyclohexane. The ketone mixture was further preparatively purified by chromatography on five silica gel plates, 20 cm x 20 cm x 2 mm, eluting four times with dichloromethane to give 112 mg (7.2%) of the title ketone as an oil.

Title alcohol M.p .: 134-13 5 ° C.

XR: (CHCl 3) 3623, 3333, 1626 and 1585 cm -1.

MS: (m / e) 332 (M &lt; + &gt;), 314, 247 and 229.

Analysis: Calculated for C 22 H 36 O 2: C> 79 »+ 6i H, 10.92%.

Found: C, 79.40; H, 10.72%.

69 6 6 5 8 4

IR of the title ketone: (CHCl 3) 3623, 3390, 1634 and 1582 cm -1.

MS: (m / e) 330 (M &lt; + &gt;), 315, 312, 288, 273, 271 and 245.

Example 36 5- (2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl-3-methoxy-6-methyl-2-cyclohexen-1-one (starting material) to a solution at -78 ° C in which 0.5 mol of lithium diisopropylamide in 500 ml of tetrahydrofuran (50.5 g, 0.5 mol of diisopropylamine and 417 ml of 1.2 mol of n-butyllithium in hexane) is added dropwise (30 mm ) a solution of 217 g (0.5 mol) of 5- (2-benzyloxy-4- (1,1-dimethyl-heptyl) phenyl) -3-methoxy-2-cyclohexen-1-one in 250 ml of tetra The reaction mixture is stirred for a further 30 minutes at -78 [deg.] C., after which 179 g (1.0 mol) of hexamethylphosphoramide and 78.1 g (0.55 mol) of methyl iodide are added, and the reaction mixture is allowed to slowly warm to room temperature. The reaction mixture is evaporated to dryness in vacuo to remove tetrahydrofuran and added to a mixture of one liter of ice water and one liter of ether. The ether extract is washed three times with one liter of water, dried magnetically. with sodium sulfate and evaporated to dryness to give the title compound in almost pure form. The title compound is purified by chromatography on a column of 2 kg of silica gel, eluting with an ether / pentane mixture.

Example 37 5- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3,4-dimethyl-2-cyclohexen-1-one (starting material

Following the procedure of Example 1, 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-methoxy-6-methyl-2-cyclohexen-1-one is reacted according to the Grignard reaction with methylmagnesium iodide to give the title compound is obtained. Cleavage of benzyl from the product according to the method of Example 2 gives the corresponding phenol.

Example 38 3- [2-Hydroxy-4- (1,1-dimethylheptyl) phenyl] -4,5-dimethylcyclohexanol (final product)

The debenzylated compound of Example 37 is reduced with sodium borohydride according to the procedure of Example 11 to give the title compound.

70 66584

Example 39 3- [2-Benzyloxy-4- (1,1-dimethylheptyl) phenyl] -4,5-dimethylcycloheptanone (starting material) to a solution of 17.4 g (0.10 mol) at -78 ° C dibromomethane and 21.7 g (0.050 mol) of 3-E-2-benzyloxy-4- (1,1-dimethylheptyl) phenyl-E-4-4,5-dimethylcyclohexanone in 100 ml of tetrahydrofuran are added dropwise over 2 hours to a solution of is lithium dicyclohexylamide (0.10 mol) in 100 ml of tetrahydrofuran. The reaction mixture is stirred for a further hour at -78 ° C and 2 ml (0.11 mol) of water are added. The reaction mixture is added to a mixture of 300 ml of ether and 200 ml of water. The ether extract is dried over magnesium sulfate and evaporated to dryness. The crude product is purified by chromatography on a column of 500 g of silica gel eluting with ether / pentane to give pure 3-N, N-benzyloxy-4- (1,1-dimethylheptyl) phenylx7-1-dibromomethyl-4,5-dimethylcyclohexanol.

To a solution of 30.4 g (0.050 moles) of 3-Z-2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -1-dibromomethyl-4,5-dimethylcyclohexanol at -78 ° C In 150 ml of tetrahydrofuran, 47.7 ml (0.105 mol) of n-butyllithium (2.2 mol of hexane) are slowly added over 2 hours. The reaction solution is stirred for a further 2 hours at -78 ° C and for 10 minutes at 0 ° C and then the reaction is stopped by pouring into 300 ml of ice-cold 1-norm. hydrochloric acid. The reaction mixture is extracted with two 250 ml portions of ether, the combined ether extracts are washed with 250 ml of saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of 500 g of silica gel, eluting with an ether / pentane mixture to give the title compound.

Example 40 Sodium salt of cis-3-2H- (1,1-dimethylheptyl) -2-hydroxyphenyl-7-cyclohexanol-21-O-hemisuccinate ester in a solution at 0 ° C with 1.00 g (3, 14 mmol) of cis-3-Z4- (1,1-dimethylheptyl-2-hydroxyphenyl) cyclohexanol in 3 ml of dichloromethane are added 0.383 g (3.14 mmol) of 4-N, N-dimethylaminopyridine. (3.14 mmol) succinic anhydride in ml 7i 66584 Dichloromethane The reaction mixture is stirred * for 1 hour at 0 [deg.] C. and then 3.14 ml of 1N hydrochloric acid are slowly added, the reaction mixture is stirred for a further 5 minutes and then added to the mixture. with 100 ml of water and 100 ml of dichloromethane The dichloromethane extract is dried over magnesium sulphate and evaporated to dryness, the residue is dissolved in 5 ml of ethanol and 3.14 ml of 1N ethanolic sodium hydroxide solution are added. The title compound is obtained from the mixture.

Example 41 cis-3-114- (1,1-dimethylheptyl) -2-hydroxyphenyl-7-cyclohexanol-21-O-phosphate ester monosodium salt in a slurry at 0 ° C with 0.126 g (3.14 mmol) of potassium hydride In 3 ml of dimethylformamide, a solution of 1.00 g (3.14 mmol) of cis-3- [4- (1,1-dimethylheptyl) -2-hydroxyphenyl] -cyclohexanol in 3 ml of dimethylformamide is added. At the end of gas evolution (^ 10 minutes), 0.932 g (3.14 mmol) of dibenzyl phosphorus chloride are added slowly. The reaction mixture is stirred for one hour and then added to a mixture of 200 ml of ether and 100 ml of water. The ether extract is washed with two 100 ml portions of water, dried over magnesium sulphate and evaporated to a residue. The residue is mixed with 1.0 g of 5% platinum on carbon and 25 ml of ethanol, and the mixture is stirred under one atmosphere of hydrogen pressure for 3 hours. The reaction mixture is filtered through diatomaceous earth and 3.14 ml of 1-norm is slowly added to the filtrate. ethanolic sodium hydroxide solution. Addition of ether causes the product to crystallize. Recrystallization from ethanol then gives the title compound.

Claims (3)

72 66584 Patents An analogous process for the preparation of therapeutically active 3-phenyl-cycloalkane or cycloalken-1-ols of formula I OR, * · & zW wherein R is a saturated or unsaturated cycloalkyl moiety of formula IA, IB, IC or ID HH OH H ^ OH \ OH H OH / \ ö Ö * C_ar / V "R4} R3} \ R3 I \ R3 R2 R3 r2 Ri * R2 Ri * R2 IA IB IC ID where one of the dotted lines in each ring may indicate a double bond ; R 1 is hydrogen or benzyl; is hydrogen, alkyl of 1 to 6 carbon atoms or alkenyl of 3 to 6 carbon atoms; R 3 is hydrogen or methyl; R 1 is hydrogen or alkyl of 1 to 6 carbon atoms; is alkylene of 1-13 carbon atoms or -O-alk2_j wherein alk2 is alkylene of 1-13 carbon atoms, and W is hydrogen or phenyl, and pharmaceutically acceptable acid addition salts thereof, characterized in that a substituted cycloalkanone is reduced or cycloalkenone of formula 1 'ZW 73 6 6 5 8 4 wherein R' is saturated or an unsaturated cycloalkanoyl moiety of the formula I'-A, I'-B, I'-C or I'-D 0 0 0 Λ ά. r \ r \ H- · ', 1' Vv «, R2 R3 R2 RH R2 R ^ R2 I '-A I'-B I'-Cl' -D where dotted lines, R- ^, R2, Rg, Z and W is as defined above, and if desired, the benzyl group R 1 is removed, preferably hydrogenolytically, and if desired, the compound obtained is converted into an acid addition salt. i ”66584 Analogite for the preparation of therapeutically active 3-phenylcycloalkan-eller -cycloalken-1-ol with formulas I ° R Z-W color 2. Rq r "π π" 3. R4 R2 Rj. R9 ^ I-A I-B I-C I-D are derived from the same ring and are double-bonded; R 2 is hydrogen or benzyl; R 2 is alkyl, 1-6 chol atoms or alkenyl from 3-6 chol-atoms; Rg is possible or methyl; R 1 is an alkyl or 1-6 cholate atom; Z is alkyl of 1-13 cholera or -O-alk2 »color alk2 is alkyl of 1-13 cholera; och W är väte eller phenyl; and pharmacologically active compounds of the form a cycloalkanone or a cycloalkenone with a formula I * 0R1 R 'JL 1 1¾ Z-W