NO792840L - INTERMEDIATE PRODUCT FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE SUBSTITUTED PHENYL-SUBSTITUTED CYCLOAL CANNON AND CYCLOAL CANOL DERIVATIVES - Google Patents

Description

The invention relates to certain cycloalkanones, cycloalkanols

and unsaturated analogues thereof with from 5 to 8 carbon atoms in the cycloalkyl ring and which in the 3-position have a 2-hydroxy-4-(Z-W-.substituted)-phenyl group where Z is the alkylene with from 1 to 13 carbon atoms or (alk, ) ra -0-(alk_) - where each of m and n is 0

ch 2 n ^

or 1 and each of (alk^ and (alk2) is the alkylene having from 1 to 13 carbon atoms, with the proviso that the sum of carbon atoms in

(alk^) plus (alk2) does not exceed 13; and W is hydrogen, phenyl, chlorophenyl, fluorophenyl or pyridyl, derivatives thereof, intermediates thereof and processes for their preparation.

The products are useful as CNS agents, especially as analgesic, sedative, sedative and sedative agents for. mammal,

including humans, and/or as anticonvulsant, diuretic and antidiarrheal agents for mammals, including humans.

Despite the fact that a large number of analgesic agents are currently available, research continues for new and improved agents, which points to a lack of an agent that is useful for the regulation of wide areas of pain and that is accompanied by a minimum of side effects. The most commonly used agent,

aspirin, has no practical value for the regulation of severe pain and is known to exhibit various undesirable side effects. Other analgesics, such as d-propoxyphene, codeine and morphine,

has habituation properties. The need for improved and powerful analgesic agents is therefore obvious.

U.S. Patent 3,576,887, issued April 27, 1971,

describes a series of 1-(11-hydroxy)-alkyl-2-o-hydroxyphenyl-cyclohexane-or -ene compounds which serve as intermediates for the preparation of 6,6-dialkyl-tetrahydro- and hexahydro-dibenzo-

[d,d]-pyrans for use as sedatives for the central nervous system.

It has now been found that certain cycloalkanones, cycloalkanols and unsaturated analogues thereof which in the 3-position have

a 2-hydroxy-4-(substituted)-phenyl group (formula I below), are effective as CNS agents, particularly as analgesic, sedative, sedative and anxiolytic agents for mammals, including humans, and/or as anticonvulsants, diuretics and antidiarrheals agents for mammals, including humans. Included in this invention are also various derivatives of said compounds which are useful as dosage forms of the compounds, intermediates for the compounds of formula I and methods for their preparation. The compounds have the formula:

where R is selected from the group consisting of saturated and unsaturated cycloalkylenes selected from the group consisting of

where

the dashed lines mean a possible double bond

in one of the specified places, and in this case R. cannot be present;

A is hydrogen when it is alone,

B, when alone, is selected from the group consisting of hydroxy, hydroxymethyl and alkanoyloxy having from 1 to 5 carbon atoms (formula I series of compounds);

A and B together (formula II series of compounds) are selected from the group consisting of oxo, methylene and alkylenedioxy having from 2 to 4 carbon atoms;

R^ is selected from the group consisting of hydrogen, alkanoyl having from 1 to 5 carbon atoms, benzyl, -P (0) (OH)2°9mono- and disodium and potassium salts thereof, -CO(CH2)2C00H and sodium- <p>g the potassium salts thereof, and -C0-(CH~) -NRrR, where p is an integer from 1 to 4, each of R,- and R^ is independently selected from the group consisting of hydrogen and alkyl with from 1 to 4 carbon atoms, or R_ and Rg together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from 1 to 4 carbon atoms in the alkyl group;

R2 is selected from the group consisting of hydrogen, alkyl having from 1 to 6 carbon atoms, alkenyl having from 3 to 6 carbon atoms, phenyl and phenylalkyl having from 1 to 4 carbon atoms in the alkyl portion;

R 1 is selected from the group consisting of hydrogen and methyl;

R 1 is selected from the group consisting of hydrogen and alkyl having from 1 to 6 carbon atoms; with the proviso that when R^ is methyl, R^ is hydrogen;

Z is selected from the group consisting of (a) alkylene having from 1 to 13 carbon atoms, (b) -(alk,) -O-(alk„) - where each of

ch. 2 n

(alk^) and (alk2) are the alkylene having from 1 to 13 carbon atoms, with the proviso that the sum of carbon atoms in (alk^) plus (alk2) does not exceed 13; each of m and n is 0 or 1; and

W is selected from the group consisting of hydrogen, pyridyl,

where W is selected from the group consisting of hydrogen,

fluorine and chlorine.

The dotted lines in the compounds of formula I,

i.e. the formulas IA-ID, means the possible presence of a double bond at one of the specified locations.

Also included in this invention are the pharmaceutically acceptable acid addition salts of such compounds of formula I which contain a basic group. Typical of such compounds are those where the W-variable is pyridyl and/or OR represents a basic ester group. For compounds that have 2 basic groups, polyacid addition salts are of course possible. Representative of such pharmaceutically acceptable acid addition salts are the mineral acid salts, such as the hydrochlorides, hydrobromides, sulfates, phosphates and nitrates; and organic acid salts such as the citrates, acetates, sulfosalicylates, tartrates, glycolates, malates, malonates, maleates, pamoates, salicylates, stearates, phthalates, succinates, gluconates, 2-hydroxy-3-naphthoates, lactates, mandelates and methanesulfonates. . Compounds with the formulas IA-ID where A and B together are oxo and R^ is hydrogen exist in solution in equilibrium with their hemiketal forms. The keto-pg hemiketal forms of these compounds of formula I are included in this invention.

Compounds of formula IA-ID where A is hydrogen and

B is hydroxy contains asymmetric centers in the 11-, 3- and 4-positions and, when the cycloalkyl group is 6- to 8-membered, in the 5-position, in the cycloalkyl part, and can of course contain further asymmetric centers in the substituents in the 4- and 5- position and in (-Z-W) on the phenyl ring. A cis relationship between the substituent in the 1-position of the cycloalkyl part and the phenolic, or substituted phenolic, part in the 3-position is advantageous, and a trans relationship between the 3- and 4-substituents and the 4- and 5-substituents on the cycloalkyl part is advantageous on due to greater (quantitative) biological activity. For the same reason, trans-3,4 relationships are also advantageous in compounds of formula IA-ID where A and B together mean oxo.

For simplicity, the formulas above show the racemic compounds. However, these formulas are to be considered as general formulas and include the racemic modifications of the compounds according to this invention, the diastereomeric mixtures,

the pure enantiomers and diastereomers thereof. The utility of the racemic mixture, the diastereomeric mixture and also the pure ones

enantiomers and diastereomers are determined by the biological assessment processes described below.

In addition to the above formulas, various intermediates useful in the preparation of the compounds of formula I are also included in this invention. The intermediates have the formulas II-IV below:

(in which stereochemistry is not indicated)

where

Z, W, R2 and are as stated above,

Y is selected from the group consisting of cyano and formyl;

t is an integer from 1 to 8;

R_ is selected from the group consisting of hydrogen and alkyl.

having from 1 to 4 carbon atoms; and

Q is selected from the group consisting of -CH,,-, -CH2CH(R4)-,

-CH 2 CH 2 -CH ('R 4 ) - and -CH 2 -CH 2 -CH 2 -CH .(R ) -.

The compounds of formula IV mean the hemiketal and ketal forms of the saturated cycloalkyl compounds of formula I (A-D) where A and B together mean oxo.

Preferred because of their greater biological activity compared to the other compounds described herein are compounds of formulas IA-ID where A and B together are oxo; A and B are each, respectively, hydrogen and hydroxy; R 2 is hydrogen or alkyl;

R 1 is hydrogen or alkanoyl; R 1 is hydrogen or methyl; R 4 is hydrogen or alkyl; and Z and W have the meanings shown below:

Preferred compounds of formula I, and especially the saturated cycloalkyl compounds of formula I, are those advantageous compounds wherein: each of R 1 and R 2 is hydrogen;

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

Z is C 1-7 alkylene and W is phenyl;

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

Z is -O-alkylene having from 4 to 5 carbon atoms and W is phenyl;

A is. hydrogen and B is hydroxy (cis and trans forms);

A and B together are oxo;

R 2 is hydrogen, methyl, propyl or propenyl;

R 3 is hydrogen; and

R 1 is hydrogen or methyl.

Particularly preferred are the saturated cycloalkyl compounds of the formulas IB and IC where R 1 , R 2 , R 2 * / Z and - W

is as indicated for the preferred compounds, and A and B are each hydrogen and hydroxy, respectively.

With regard to analgesic activity, a particularly preferred group of compounds are also the preferred compounds which are

mentioned above where R 2 is methyl, propyl or propenyl and each of R 2 and . R 1 is hydrogen.

The saturated cycloalkyl compounds according to this invention with formula I where R is hydrogen, are prepared from a suitable 2-bromo~5-(Z-W-substituted)phenol by a series of reactions which as a first step includes protection of the phenolic group. Suitable protecting groups are those which do not affect the subsequent reactions and which can be removed under conditions which do not cause unwanted reactions elsewhere in said compounds or on the products formed therefrom. Representative of such protective groups are methyl, ethyl, benzyl or substituted benzyl where the substituent e.g. is alkyl with from 1 to 4 carbon atoms, halogen (Cl, Br, F, I) and alkoxy with from 1 to 4 carbon atoms. The ether-protecting, or blocking, groups can be removed by using hydrobromic acid in acetic acid or 48% aqueous hydrobromic acid. The conversion is carried out at elevated temperatures and preferably at reflux temperature.

When Z is -(alk1 ,) m -O-(alk-2 ) n-, however, acids must be used

such as polyphosphoric acid or trifluoroacetic acid to avoid cleavage of the ether bond. Other reagents, such as hydroiodic acid, pyridine hydrochloride or hydrobromide, can be used to remove ether protecting groups, such as methyl or ethyl groups. When the protecting groups are benzyl or substituted benzyl groups, they can be removed by catalytic hydrogenolysis. Suitable catalysts are palladium or platinum, especially on a carbon support. Alternatively, they can be removed by solvolysis using trifluoroacetic acid. A further method comprises treatment with n-butyllithium in a reaction-inert solvent at room temperature.

The exact chemical structure of the protective

group is not critical of this invention, since its importance lies in its ability to act in the manner described above.

Selection and identification of suitable protecting groups can fast

and easily done by a person skilled in the industry. How suitable and effective a group is as a hydroxy-protecting group is determined by using such a group in the reaction sequences illustrated here. There should therefore be a group that can be easily removed to

regenerate the hydroxy groups. Methyl and benzyl are advantageous protecting groups since they are easy to remove.

The protected 2-bromo-5-(Z-W substituted)phenol is then reacted with magnesium in a reaction-inert solvent and usually

in the presence of a carrier, e.g. copper(I) salts, such as a chloride, bromide or iodide (to promote 1,4-addition) with the appropriate 4-R2_2-cycloalken-1-one (e.g. 4-R2_2-cyclohexene-1- on). Suitable reaction-inert solvents are cyclic and acyclic ethers such as e.g. tetrahydrofuran, dioxane and dimethyl ether of

ethylene glycol (diglym). The Grignard reagent is formed in a known manner, such as e.g. by refluxing a mixture with a ratio of one mole of the bromine reactant to two moles of magnesium in a reaction-inert solvent, e.g. tetrahydrofuran. The reaction mixture is then cooled to approx. 0 to -20°C, and copper(I) iodide is added followed by the appropriate 2-cycloalken-1-one at a temperature of from approx. 0 to -20°C. The amount of copper (I) iodide used is not critical and can be varied greatly. Mol ratio in the range from approx. 0.2 to approx. 0.02 mol per moles of bromine reactant gives satisfactory yields of the cycloalkanone in which the phenolic hydroxy group is protected (formulas IA-ID, R^ = a protecting group;

R 3 = H; A+B = oxo).

The protected cycloalkanone is then treated with an appropriate reagent to remove the protecting group. The benzyl group is conveniently removed in the manner described above. If the protecting group is an alkyl group (methyl or ethyl), it is removed by the above methods or by treatment with e.g. pyridine hydrochloride.

When R2 is an alkenyl group, the cycloalkenones thus formed serve as intermediates for the production of the corresponding cycloalkenones (IA-ID) where R2 is alkyl.

The cycloalkanol compounds of formula.. I are prepared from

the protected cycloalkanones by reduction. Sodium borohydride is advantageous as a reducing agent in this step, since it not only gives satisfactory yields of the desired product, but also preserves the protecting group on the phenolic hydroxy group, and reacts slowly enough with hydroxylic solvents (methanol, ethanol, water) that these can be used as solvents. Temperatures of from approx. -40 to approx. 30°C. Lower temperatures, even down to approx. -70°C, can be used to increase the selectivity of the reduction. Higher temperatures cause reaction of the sodium borohydride with the hydroxylic solvent. If higher temperatures are desired, or necessary for a given reaction, isopropyl alcohol or the dimethyl ether of diethylene glycol is used as solvent. Potassium tri-sec-butyl borohydride is sometimes preferred as the reducing agent since it favors the stereoselective formation of trans-1,3-phenyl-1-cycloalkanol.

The reduction is carried out in dry tetrahydrofuran at a temperature below approx. -50°C using equimolar amounts of the ketone compound and the reducing agent.

Reducing agents such as lithium borohydride, diisobutyl aluminum hydride or lithium aluminum hydride which can also be used require anhydrous conditions and non-hydroxyl solvents,

such as 1,2-dimethoxyethane, tetrahydrofuran, diethyl ether, dimethyl ether of ethylene glycol.

The cycloalkanols of formula I where A is hydrogen and each of B and OR-^ is hydroxy can of course be obtained directly by catalytic reduction of the protected cycloalkanone over palladium-on-carbon or by catalytic reduction or chemical reduction of the unprotected cycloalkanone (formula I , A+B = oxo, 0R1 = OH) by using the reducing agents described above.

In actual practice, it is preferred to form the unprotected cycloalkanols of formula I' (A = H, B = OR^= OH) via reduction of the benzyl-protected cycloalkanones (formula I, A+B = oxo,.

OR^= benzyloxy) as described above, since this allows stereochemical regulation of the reduction and formation of the cis-hydroxy epimer as the main product, thus facilitating the separation and purification of the epimeric alcohols.

Compounds with the formulas IA-ID where the double bond is

in the 2,3-positions is prepared by Grignard reaction of the suitably protected 2-bromo-5-(Z-W-substituted)phenol with a 3-alkoxy-2-cycloalken-1-one (with from 1 to 4 carbon atoms in the alkoxy group) in a reaction-inert solvent at a temperature of from approx. -30 to +10<G>C. The protected cycloalkenone compound thus formed is then deprotected as described above and reduced to the corresponding cycloalkenol. Alternatively, the protected cycloalkenone is reduced chemically, e.g. using sodium borohydride, to the protected cycloalkenol which is then deprotected to regenerate the phenolic hydroxy group.

Compounds with the formulas IA-ID where the double bond

is in the 3/1 position is produced from compounds with the formulas IA-ID where A+B is oxo and the double bond is in the 2,3 position. The process comprises ketalizing an appropriate 2,3-unsaturated compound of formula IA-ID with an alkylene glycol having from 2 to 4 carbon atoms in the presence of a dehydrating agent, such as p-toluenesulfonic acid, in a solvent, such as benzene, allowing azeotropic removal of by-product water. Isomerization of the double bond to 3,4-unsaturated ketal derivative takes place. Decetalization by mild acid treatment gives the 3,4-unsaturated compounds with formulas IA-ID where A+B means oxo. Reduction of the oxo group which

described above, gives the corresponding alcohol.

The protected cycloalk-2-enones (formulas IA-ID,

A+B = oxo, R^= protecting group) also serve as intermediates for compounds of formula I where R^ is methyl.

Introduction of the R 1 -substituent is achieved by concerted addition of dimethyl copper lithium to the appropriate cycloalk-2-enone. The process comprises reacting the suitably protected cycloalkenone with dimethyl copper lithium in a reaction-inert solvent, such as cyclic and acyclic ethers and especially tetrahydrofuran, at from approx. 0 to -20°C. The organometallic reagent provides 1,4-addition to the protected cycloalkenone with formation of tertiary carbon.

The R 1 -substituted protected cycloalkanone is then deprotected and reduced, or reduced and then deprotected according to the method described above. The 1,2-addition product is also formed.

Compounds of formula IB where the cycloalkyl moiety is saturated and where R 2 is different from hydrogen are prepared by reacting the appropriate 2-bromo-5-(Z-W-substituted)phenol,

in which the phenolic group is suitably protected as described above, with magnesium to form the Grignard reagent as previously described. The resulting Grignard reagent is then treated,

without insulation, at a reduced temperature, e.g. about. +10 to -20°C, with N,N-dimethylformamide. The reaction mixture is then allowed to warm to room temperature and the product, a protected 2-hydroxy-4-(Z-W-substituted)-benzaldehyde, is recovered by known methods. The benzaldehyde derivative is then converted to a w-(2-hydroxy-4-(Z-W-substituted)phenyl)-3-alkenone via Wittig reaction with an appropriate 1-triphenylphosphoranylidene-2-alkanone in a reaction-inert solvent at a temperature of from .about. room temperature to the reflux temperature of the solvent. The above-mentioned 2-propanone derivative allows the formation of the cyclohexy1 moiety.

The aryl alkenone thus formed is then reacted with a dialkyl malonate, preferably one in which the alkyl groups have from 1 to 4 carbon atoms, to form the ring of the alkenone. The reaction is carried out in a reaction-inert solvent, such as an alcohol with from 1 to 4 carbon atoms, at a temperature of from approx. 2 5°C to approx. the reflux temperature of the solvent.

It formed the carboxy-substituted cycloalkanedione

is then decarboxylated by treatment with aqueous sodium or potassium hydroxide at an elevated temperature, i.e. from approx. 50 to 100°C, and the cycloalkanedione derivative is isolated by usual standard methods. It is then ketalized by reaction with methanol, or another alcohol with up to 4 carbon atoms, or an alkylene glycol with from 2 to 4 carbon atoms, in the presence of a dehydrating agent such as p-toluenesulfonic acid.

In the case of the cyclohexyl derivative, the 3-methoxy-2-cyclohexen-1-one derivative is then reacted with lithium aluminum hydride in a reaction-inert solvent, such as diethyl ether, dioxane, tetrahydrofuran or diglyme, at a temperature of approx. -10 to 10°C and worked up with diluted mineral acid. The resulting aryl-substituted-2-cyclohexen-1-one is then treated with a suitable dialkyl copper lithium in a suitable reaction-inert solvent, such as hexene, diethyl ether or mixtures of these solvents or in cyclic ethers, such as tetrahydrofuran, at a temperature of from approx. 0 to approx. -20°C. The protected 3-[4-(Z-W-substituted-2-hydroxyphenyl]-5-R 3 -cycloalkanone is then deprotected and reduced, or reduced and then deprotected, according to the methods previously described.

Alternatively, by reacting a 5-[2-benzyloxy-4-(Z-W)phenyl]-3-alkoxy-2-cyclohexen-1-one with an appropriate Grignard reagent R^MgBr followed by acid hydrolysis, the corresponding 5-[ 2-benzyloxy-4-(Z-W)phenyl]-3-R^-2-cyclohexen-1-one which is then catalytically reduced to the corresponding cyclohexanone. Debenzylation, as described above, gives a 5-[2-hydroxy-4-(Z-W)phenyl]-3-R 3 -cyclohexanone which is then reduced to the corresponding cyclohexanol as described above.

Compounds of formula I-C where the cycloalkyl portion is saturated and where R is different from hydrogen, are prepared by ring expansion of the cyclohexyl derivative. Reaction of an appropriate 5-[2-benzyloxy-4-(Z-W)-phenyl]-3-R^-cyclohexanone with lithium dibromomethane in a reaction-inert solvent such as diethyl ether affords a 1-dibromomethyl-5-[2- benzyloxy-4-(Z-W)-phenyl]-3-R^-cyclohexanol. Further reaction of the 1-dibromomethyl-cyclohexanol in a reaction-inert solvent, such as tetrahydrofuran, with n-butyllithium gives a 3-[2-hydroxy-4-(Z-W)-phenyl]-5-R^-cycloheptanone which is then deprotected and is reduced, or reduced and deprived of protection, according to the previously described procedures.

Compounds of formula I-D where the cycloalkyl part is saturated and where is different from hydrogen are prepared by ring expansion. of the cyclohepty1 derivative, according to the previously described methods.

When R^ is hydrogen in structure IA-IC it is possible, according to the previously described methods, to cause ring expansion of these structures to a ring with one methylene group larger, i.e. to IB-ID respectively.

The 2-brdm-5-(Z-W-substituted)phenol reactants are prepared by bromination of an appropriate 3-(Z-W-substituted)phenol according to standard procedures, e.g. when treated with bromine i

carbon tetrachloride at a temperature of from approx. 20 to 30°C. The

, necessary 3-(Z-W-substituted)phenols, if they are not known compounds, are prepared by the methods described here.

A convenient method for the preparation of such reactants where'

The Z moiety is alkylene or (alk,) -O-(alk_) - includes Wittig-

21 m 2 n

reaction with an appropriate aldehyde, such as 2-(3-hydroxyphenyl)-2-methyl-propionaldehyde, whose hydroxy group is protected by benzyl ether formation. This aldehyde is then treated with an appropriate alkyltriphenylphosphonium bromide, the alkyl group of which extends the propionaldehyde group to the desired length. At a typical

method, the aldehyde reactant is added to a slurry of sodium dimsy1 and alkyltriphenylphosphonium bromide in dimethylsulfoxide at a temperature below 30°C, e.g. from approx. 10 to 30°C. When the reaction is complete, the alkene-substituted protected phenol is recovered by known methods. Hydrogenation of the alkene over palladium-on-carbon then gives the desired 3-(Z-W-substituted)-phenol benzyl ether. Judicious choice of the starting reactants, (3-hydroxyphenyl)-substituted aldehyde and alkyltriphenylphosphonium bromide, gives the desired 3-(Z-W-substituted)phenol reactants.

Preparation of the appropriate 4-R2-2-cycloalken-1-one gives rise to the synthesis of the structures with the formulas IA-D where R^ is hydrogen, according to the previously described methods. Reaction of the appropriate 1,3-cycloalkane -dione with an alcohol with from 1 to 4 carbon atoms and an acidic catalyst, such as p-toluenesulfonic acid, in a reaction-inert solvent, such as benzene or toluene, and with an apparatus for water separation at temperatures where reaks. the ionic solvent is at reflux temperature, gives a 3- alkoxy-2-cycloalken-1-one. Reaction of the appropriate 3-alkoxy-2-cycloalken-1-one with lithiodiisopropylamide in a reaction-inert solvent, such as tetrahydrofuran, in the presence of hexamethylphosphoramide and the appropriate R 2X where X is bromide or iodide or another suitable displaceable group gives a 4-R2-3-Alkoxy-2-cycloalken-1-one. The 4-R 2 -3-Alkoxy-2-cycloalken-1-one is then reacted with lithium aluminum hydride in a reaction-inert solvent, such as diethyl ether, at a temperature of approx. -10°C to 10°C and treated with diluted mineral acid. The resulting 4-R2-2-cycloalken-1-one is then converted according to methods already described.

Compounds of formula IB-ID where the cycloalkyl moiety is saturated and where each of R 2 and R 1 is different from hydrogen are prepared by reacting the appropriate 5-[2-benzyloxy-4-(Z-W)-phenyl]-3-methoxy- 2-cyclohexen-1-one with lithiodiisopropylamide in a reaction-inert solvent at a low temperature, e.g. -50

to -78°C. Hexamethylphosphoramide and the appropriate R2 iodide (where R2 is different from hydrogen) are then added to form a 5-[2-benzyloxy-4-(Z-W)phenyl]-3-methoxy-6-R2-2-cyclohexene-1- Wed. Further reaction of this compound with the appropriate Grignard reagent R^'MgX (where R^<1>is alkyl) under usual Grignard reaction conditions gives a 3-[2-benzyloxy-4-(Z-W)phenyl]-4-R2 -5-R^'-5-cyclohexen-1-one. Debenzylation and reduction of said compound, according to the procedures described above, affords the desired 3-[2-hydroxy-4-(Z-W)-phenyl]-4-R2-5-R^V-cyclohexanol. Reduction of the double bond in the 3-[2-benzyloxy-4-(Z-W)phenyl]-4-R2-5-R^1-5-cyclohexen-1-one over Pd/C gives the corresponding saturated cyclohexanone derivative. These latter derivatives serve as intermediates for the preparation of corresponding cycloheptanone and cyclooctanone derivatives by the ring expansion process described above.

A convenient method which allows selective alkylation of 3-(2,4-dihydroxyphenyl)cycloalkanones at the 4-hydroxy group comprises, as the first step, conversion of the 3-(2,4-dihydroxyphenyl)cycloalkanone to a ketal. The conversion is carried out by well-known methods for ketalization, such as reaction of the 3-(2,4-dihydroxyphenyl)cycloalkanone with an alcohol, especially an alcohol having from 1 to 4 carbon atoms, in the presence of an acid, such as sulfuric acid, p -toluenesulfonic acid, hydrogen chloride, under conditions which remove the by-product water. A preferred method

comprises reaction of the 3-(2,4-dihydroxyphenyl)cycloalkanone with

an orthoformic acid ester in solution in an alcohol that corresponds to the alcohol proportion in the pure orthoformic acid ester. Trimethyl orthoformate and methanol are advantageous reactants together with concentrated sulfuric acid, anhydrous hydrogen chloride or ammonium chloride as a catalyst.

The ketal thus formed is then alkylated by reaction with a suitable alkylating agent such as W-Z-X where W and Z are as indicated above, and X is selected from the group consisting of chlorine, bromine, mesyloxy (CH3-SO2-0) and tosyloxy (p- CH3-CgH4-SO2-0-) in the presence of an acid acceptor, e.g. sodium or potassium carbonate. The alkylated ketal is then deketalized according to known methods by treatment with an aqueous acid.

A further method for the formation of 3-(Z-W-substituted)-phenols where Z is alkylene or (alk 2 )-O-(alk 2 )- involves the Wittig reaction with an appropriate phenolic aldehyde or ketone, e.g. 3-hydroxybenzaldehyde or a 3-(hydroxyphenyl)-alkyl ketone, in which the phenolic hydroxy group is protected such as by conversion to benzyl, methyl or ethyl ether. By choosing suitable reactants, compounds can be formed which have linear or branched alkylene groups (Z). When a ketone, e.g. 3-Hydroxyacetophenone is used as reactant, compounds are obtained where Z has a methyl group on the carbon atom adjacent to the phenyl group.

Substitution of a methyl or ethyl group elsewhere, e.g. the beta-carbon atom in the alkylene group, is obtained by choosing the appropriate carbo-alkoxy-alkylidene-triphenylphosphorane, e.g.

(C^Hj-) ^P=C (R1 ) -C00CoH,- . The unsaturated ester thus formed

objZ d

is reduced to the corresponding alcohol by reaction with lithium aluminum hydride. Alternatively, when the phenolic protecting group is different from benzyl (eg methyl), the alcohol is formed by catalytic reduction of the unsaturated ester using palladium-carbon, followed by treatment of the saturated ester thus formed with lithium aluminum hydride. Conversion of the alcohol thus formed to the corresponding tosylate or mesylate followed by alkylation of the tosylate or mesylate with an alkali metal salt of the appropriate HO-(alk2)-W reactant, and finally removal of the protecting group, gives the desired 3-( Z-W-substituted)-phenol.

A variation of the above sequence involves brominating the alcohol rather than converting it to a tosylate or mesylate. Phosphorus tribromide is a convenient brominating agent. The bromine derivative is then reacted with the appropriate K0-(alk^J-W) in the presence of a suitable base (Williamson's ether synthesis).

The bromine compounds also serve as valuable intermediates for increasing the chain length of the alkylene moiety in the above sequence to give compounds where Z is -alkylene-W. The method comprises treating the bromine derivative with triphenylphosphine to

form the corresponding triphenylphosphonium bromide. Reaction of the triphenylphosphohium bromide with an appropriate 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 for introducing an alkyl or aralkyl group into the aromatic nucleus therein, and particularly a group where the carbon atom adjacent to the aromatic nucleus is a tertiary carbon atom, involves acid-catalyzed electrophilic aromatic substitution of guaiacol with a tertiary alcohol in the presence of an acid, e.g. methanesulfonic acid. The general method consists in reacting a mixture of methanesulfonic acid and equimolar amounts of guaiacol and tertiary alcohol at temperatures from approx. 30 to approx. 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-alkyl-phenol is then converted to the desired 3-alkyl-phenol by removal of the phenolic hydroxy group. The method comprises conversion of the hydroxy group to a dialkyl phosphate group by reaction with a dialkyl chlorophosphonate, e.g. diethylchlorophosphonate, or with diethylphosphonate and triethylamine. Treatment of the dialkyl phosphate with lithium/ammonia followed by demethylation of the resulting alkylated methyl ether with brotribromide or pyridine hydrochloride or other known demethylating agents gives the desired 3-alkyl-phenol.

A convenient method for making compounds

according to this invention where -Z-W is -0-(alk2)n~W comprises the use of 4-bromo-resorcinol as starting material. The method comprises protecting the two hydroxy groups in resorcinpl by benzylation according to usual methods. A benzyl group is advantageous as a protecting group in this process, since it can be easily removed by catalytic hydrogenation without cleavage of the ether group -O-(alk2)-W. Other protecting groups,

such as alkyl (e.g. methyl or ethyl), can of course also be used. However, benzyl is preferred as a protecting group since it causes fewer side reactions. The protected 4-bromo-resorcinol is then subjected to the Grignard reaction and reacted with a suitable cycloalkenone in a reaction-inert solvent in the manner described above. The 3-(2,4-dibenzyloxyphenyl)-cycloalkanone thus formed is then subjected to catalytic hydrogenation over palladium-on-carbon to form the corresponding 3-(2,4-dihydroxyphenyl)-cycloalkanone, which exists in equilibrium with its hemiketal. The hemiketal is then converted to the corresponding C, .-alkyl-, e.g. methyl-, ketal by reaction with e.g. a trialkyl orthoformate, such as trimethyl orthoformate, in a suitable solvent such as a C₁₄₄ alcohol, e.g. methanol, in the presence of concentrated sulfuric acid. The alkyl ketal thus formed is then alkylated with a suitable alkyl or aralkyl methane sulphonate or tosylate in the presence of anhydrous sodium or potassium carbonate in a suitable reaction-inert solvent, such as N,N-dimethylformamide, at a temperature of from about 75 to 100°C. The method has the advantage that it allows the use of simpler compounds throughout the reaction sequence. The 0-alkylated or aralkylated ketal is then deketalized by reaction with e.g. hydrochloric acid to form the corresponding 3-(2-hydroxy-4-[O-{ alk^ ) ]phenyl)-cycloalkanone, . which exists in equilibrium with its hemiketal.

Since compounds of formulas IA-ID in which A and B together are oxo and R-^ is hydrogen exist in solution in equilibrium with the hemiketal form and some in the crystalline state exist essentially completely in the hemiketal form, compounds are with formulas IA-ID where A and B together are oxo and R 1 is hydrogen, are intended to include the hemiketal form as well as the keto form.

Compounds according to this invention where A and

B together is the methylene, is easily prepared from the corresponding oxo compounds via the Wittig reaction with methylenetriphenylphosphorane or another suitable methylide. The usual procedure involves development of the Wittig reagent, i.e. the methylide, in situ and, immediately after development of the methylide, reacting it with an appropriate oxo compound. A convenient method for evolution of the methylide comprises reacting sodium hydride with dimethylsulfoxide (sodium dimsy 1) at a temperature of from about 50 to 80°C, usually until evolution of hydrogen ceases, followed by reacting the resulting solution with methylsulfinyl- carbanion (dimsyl) with e.g. methyltriphenylphosphonium bromide at a temperature of from approx. 10 to approx. 80°C. The solution of ylide thus formed is then added to the appropriate oxo compound and the mixture is stirred at a temperature within the range of about room temperature to 80°C. The methylene compound thus formed is isolated by known methods. Hydroboration-oxidation of the methylene compound then gives the hydroxymethyl derivative, which is given as an example here. Borane in tetrahydrofuran is advantageous in the hydroboration step since it is commercially available and gives satisfactory yields of the desired hydroxymethyl compound. The reaction is usually carried out in tetrahydrofuran or diethylene glycol dimethyl ether (diglyme). The borane product is not isolated, but oxidized directly

with alkaline hydrogen peroxide to the hydroxymethyl compound.

There are of course other methods known for developing the methylide, and these can be used instead of the method described above in Typical methods are described by Maercker, Organic Reactions, 1_4, 270 (1965). In the oxo compounds of the formulas IA-ID, the phenolic hydroxy group can be protected if desired, e.g. by conversion to an alkanoyloxy deriv. Other protective groups can of course be used. The hydroxyl group can be converted to ethers, such as e.g. tetrahydropyranyl ethers. However, it is not absolutely necessary to protect the phenolic hydroxy group if sufficient base is present to convert the phenolic hydroxy group to an alkoxide.

Esters of compounds of formulas IA-ID where R^ is alkanoyl or -C0-(CHo)NR..R, are readily prepared by reacting a

2 p 5 6

compound of the formulas IA-ID where R 1 is hydrogen, with a suitable alkanoic acid or an acid of the formula HOOC-(CH-)NR,.R, in the presence of a 2 p 5 6 condensing agent such as dicyclohexylcarbodiimide. Alternatively, they can be prepared by reacting a compound of formulas IA-ID with a suitable alkanoic acid chloride or anhydride, e.g. acetyl chloride or acetic anhydride, in the presence of a base such as pyridine.

Esters of compounds with the formulas IA-ID where A is hydrogen and B is hydroxy or hydroxymethyl and OR-^ is hydroxy are produced by acylation according to the methods described above. Compounds in which only the R group (R=OH, CH2OH) is acylated are obtained by mild hydrolysis of the corresponding diacyl derivative, taking advantage of the greater ease with which the phenolic acyl group is hydrolysed. The thus prepared compounds can then be further acylated with a different acylating agent to form a diesterified compound with different ester groups.

The analgesic properties of the compounds according to this invention are determined by tests using nociceptive stimuli.

Tests where thermal nociceptive stimuli are used

a) Analgesic testing of mice with a hot plate

The method used is modified after Woolfe et

MacDonald, J. Pharmacol. Exp. Ther.,- 80, 300-307 (1944). A regulated heat stimulus is applied to the feet. mouse on an aluminum plate that is 3.175 mm thick. An infrared reflector heat lamp of 250 watts is placed under the bottoms: of the aluminum plate. A thermal regulator, connected to the thermistors on the plate surface, programs the heat lamp to maintain a constant temperature of 57°C. Each mouse is placed into a glass cylinder (16.51 cm diameter) resting on the hot plate, and recording begins when the animal's feet touch the plate. Observations are made for the mouse 1/2 and 2 hours after treatment with the test compound with respect to the first "light strokes" of one foot or both hind feet, or until 10 seconds elapse without such movements. Morphine has an MPE^ = 4-5.6 mg/kg (s.c.).

b) Analgesic test when registering a light stroke of the mouse tail Testing for a light stroke of the tail for mice has been modified

after D'Amour and Smith, J. Pharmacol. Exp. Ther., 12_, 74-79

(1941) using a regulated supply of heat with.high

intensity to the tail. Each mouse is placed in a conveniently fitted metal cylinder, with its tail protruding through one end. This cylinder is placed so that the tail lies flat over a hidden heat lamp. At the start of the test, an aluminum sheet over the lamp is pulled back, allowing a beam of light to pass through the slit and be focused on the end of the tail. A recording device

are simultaneously put into operation. The latency for a sudden light flick of the tail is brought to light. Untreated mice usually respond within 3-4 seconds of being exposed to the lamp. The end point of protection is 10 seconds. Each mouse is tested 1/2 and 2 hours after treatment with morphine and the test compound. Morphine

an MPE[- of 3.2-5.6 mg/kg (s.c).

c) Tail dipping procedure

The procedure is a modification of the recording process

developed by Benbasset et al., Arch. Int. Pharmacodyn., 122, 434

(1959). Male albino mice (19-21 g) of the Charles River CD-1 breed

weighed and marked for identification. Usually 5 animals are used in each drug treatment group, and each animal is compared with itself. For general shielding reasons, new test agents are first administered with a dose of 56 mg/kg intraperitoneally or subcutaneously, and they are given in a volume of 10 ml/kg. Before drug treatment and 1/2 and 2 hours after drug treatment, each animal is placed in the cylinder. Each cylinder is provided with holes to

provide adequate ventilation, and it is closed with a round nylon plug through which the animal's tail protrudes. The cylinder is held in an upright position and the tail is completely immersed in a water bath at a constant temperature (56°C). The endpoint of each trial is an energetic twitch or contraction of the tail coupled with a locomotor response. In some cases, the endpoint may be less severe after drug treatment. To prevent unnecessary tissue damage, the experiment is terminated and the tail is removed from the water bath within 10 seconds. The response latency is recorded in seconds and. rounded to the nearest 1/2 second. An auxiliary comparison and a standard of known power are tested simultaneously with shielded candidates. If the activity of the test agent has not returned to baseline values at the 2-hour test point, response latencies are determined after 4 and 6 hours. A final measurement is carried out after 24 hours if activity is still observed at the end of the test day.

Test using chemical nociceptive stimuli

Attenuation of writhing induced by phenylbenzoquinone stimulant

Groups of 5 Carworth Farms CF-1 mice are treated subcutaneously or orally with saline, morphine, codeine or the test compound. 20 minutes (in the case of subcutaneous treatment) or 50 minutes (in the case of oral treatment) later, each group is treated with an intraperitoneal injection of phenylbenzoquinone, a stimulant known to produce abdominal contractions. The mice are observed for 5 minutes for the presence or absence of writhing, and one begins 5 minutes after the injection of the stimulant. MPE^ values for the drug pretreatments for blocking torsion are determined.

Tests using pressure nociceptive stimuli

Effect of the Haffner Hale clamp process

A modification of the process of Haffner, Experimentalle Prufung Schmerzstillender. Deutch Med. Wschr. , 5_5, 731-732 (1929) is used to ascertain the effects of the test compound on aggressive attack responses produced by a tail pinching stimulus. Male albino rats (50-60 g) of the Charles River (Sprague-Dawley) CD breed are used. Before the drug treatment, and again 1/2, 1, 2 and 3 hours after the treatment, a 6 3.5 mm Johns Hopkins "bulldog" clip is clamped to the root of the rat's tail. At the endpoint of each trial, there is clear attacking and biting behavior directed at the unpleasant stimulus, and the latency to attack is recorded in seconds. The clamp is removed after 30 seconds if no attack has occurred until then, and the latency response is written down as 30 seconds. Morphine is active at 17.8 mg/kg (i.p.).

Tests using electrical nociceptive stimuli - the "Escape jump" test

A modification of the avoidance-jump process of Tenen, Psychopharmacologia, 12_, 278-285 (1968) is used to determine the pain thresholds. Male albino rats (175-200 g) of the Charles River (Sprague-Dawley) CD breed are used. Before receiving the drug, the feet of each rat are immersed in a 20% glycerol/saline solution. The animals are then placed in a chamber and given a series of 1-second shocks to the feet, and these shocks are given with increasing intensity at 30-second intervals. These intensities are 0.26, 0.39, 0.52, 0.78, 1.05, 1.31, 1.58, 1.86, 2.13, 2/12, 2.72, and 3.04 have to. The behavior of each animal is assessed for the presence of (a) avoidance, (b) squealing, and (c) jumping or forward movement when the shock begins. Simple series of increasing shock intensities given to each rat just before and 1/2,

2, 4 and 24 hours after drug treatment.

The results of the above tests are written down as maximum possible power (%MPE). The %MPE values for each group are statistically compared to the %MPE value of the standard and the values of the pre-drug comparisons. The %MPE values are calculated as follows:

The compounds according to this invention, when used as analgesic agents by oral or parenteral administration, are conveniently administered in preparation form. Such preparations include a pharmaceutical carrier selected on the basis of the chosen route of administration and common pharmaceutical practice. They can e.g. administered in the form of tablets, pills, powders or granules containing such inert shaping agents as starch, milk sugar, certain substance types, etc. They can be administered in capsules, in admixture with the same or equivalent inert shaping agents. They can also be administered in the form of oral suspensions, solutions, emulsions, syrups and elixirs which may contain flavorings and colourings. For oral administration of the therapeutic agents according to this invention, tablets or capsules containing from approx. 0.01 to approx. 100 mg, suitable for most applications.

The doctor will determine the dose that will be most suitable for an individual patient, and this will vary with the age, weight and response of the particular patient and with the method of administration. Usually, however, the initial analgesic dose for adults will be in the range from approx. 0.1 to approx. 750 mg per day in a single or divided doses. In many cases, it is not necessary to exceed 100 mg per day. The advantageous oral dose range is from approx. 1.0 to approx. 300 mg/day, and the preferred dose is from approx. 1.0 to approx. 50 mg/day. The advantageous parenteral dose is from approx. 0.1 to approx. 100 mg/day, and the preferred range is from approx. 0.1 to approx. 20 mg/day.

This invention also provides pharmaceutical compositions, including unit dosage forms, which are valuable for the use of the compounds described herein as analgesic agents and other uses disclosed herein. The dosage form may be for a single dose or for multiple doses, as previously noted, to achieve the daily dose effective for a particular application.

The compounds (drugs) described herein may be mixed together for administration in solid or liquid form for oral or parenteral administration. Capsules containing drugs according to this invention, are prepared by mixing one part by weight of drug with 9 parts by weight of inert shaping agent, such as starch or milk sugar, and then introducing the mixture into collapsible gelatin capsules so that each capsule contains 100 parts of the mixture. Tablets containing said compounds are produced by mixing suitable mixtures of drug and common ingredients used in the production of tablets such as starch, binders and lubricants, so that each tablet contains from 0.10 to 100 mg of drug per tablet.

Suspensions and solutions of these drugs, especially those where R, (formulas I and II) is hydroxy, are often prepared just before use, to avoid stability problems with the suspensions or solutions (e.g. precipitation of the drug during storage). Preparations suitable for this are usually dry, solid preparations which are reconstituted for injectable administration.

By means of the above methods, the analgesic activity of several compounds according to this invention is determined. The compounds have the formula shown below:

Table I: A = H, B = OH, Table. II: A+B = oxo

The following abbreviations are used in the tables:

PBQ = phenylbenzoquinone-induced writhing, TF = light tail flick, HP = hot plate, RTC = rat tail clamp, and FJ = avoidance jump.

Single values in the tables are ED5Q values. A number followed by another number in parentheses indicates the % protection observed at a given dose. Thus, 31(56) shows that 31% protection is achieved at a dose of 56 mg/kg body weight.

Their activity as diuretics is determined by the process of Lipschitz et al., J. Pharmacol., 197, 97. (1943)

where rats are used as test animals. The dosage range for this use is the same as that indicated above with respect to the use of the compounds described herein as analgesic agents.

The utility as an antidiarrheal agent is determined by a modification of the method of Neimegeers et al., Modern Pharmacology-Toxicology, Willem van Bever and Harbans Lal, Eds., 1_, 68-73

(1976). Charles River CD-1 rats (170-200 g) are housed in group cages for 18 hours prior to testing. The animals are fasted overnight with water available as desired before administration of castor oil. The test drug is administered subcutaneously or orally with a constant volume of 5 ml/kg body weight. in an adjuvant of 5% ethanol, 5% "Emulphor" EL-620 (a polyoxyethylated vegetable oil emulsifier available from Antara Chemicals, New York, N.Y.) and 90% saline, followed one hour later by a castor oil challenge (1 ml orally). The animals are housed in small individual cages (20.5 x 16 x 21 cm) with mesh floors. A disposable cardboard sheet is placed under the mesh floor and examined one hour after the castor oil provocation for the presence or absence of diarrhoea. A vehicle/castor oil treatment group serves as the comparison for each day of testing. The results are written down as the number of animals that are protected one hour after the challenge. Generally, the dosage amounts of these compounds used as antidiarrheal agents parallel the amounts of them used as analgesic agents.

The sedative activity of the compounds

according to this invention is determined by oral administration

of. them to rats with doses of from approx. 0.01 to approx. 50 mg/kg body weight and observation of the subsequent reduction in spontaneous motor activity. The daily dose range for mammals is from approx. 0.01 to approx. 100 mg.

Anticonvulsant activity is determined by subcutaneous administration of the test compound to male Swiss mice. (Charles River) with a weight of 14-23 g in an adjuvant of the type used in determining the usefulness as an antidiarrheal agent. The mice are divided into groups of 5. The mice are kept fasting overnight before the testing, but are given water ad libitum. The treatments take place with volumes of 10 ml per kg using a 25 calibrated (gauge)

hypodermic needle. The mice are treated with the test compound and,

one hour after exposure, transcorneal electroconvulsive shock, 50 mA at 60 Hz, is administered. At the same time, comparisons are made whereby the mice only receive the aid as a comparison treatment. The electroconvulsive shock treatment produced tonic extensor spasms for all control mice with a latency of 1.5-3 seconds. Protection is noted when a mouse exhibits no tonic extensor muscle contractions for 10 seconds after administration of electroconvulsive shocks.

Neurodepressant activity is determined in a similar way to the assessment of anticonvulsant activity, except for the agent that provokes convulsions, pentylenetetrazole, 120 mg/kg administered intraperitoneally. This treatment produces clonic convulsions in less than 1 minute in over 95% of the treated control mice. Protection is noted when the latency to convulsion is prolonged to at least twice as much by drug pretreatment.

Activity as a sedative and antidepressant is determined by subcutaneous treatment of groups of six mice with different doses of test agents. At 30 and 60 minutes after treatment, the mice are placed on a rotorod for one minute and assessed for their behavior on the rotorod. Inability of the mouse to stay on the rotor is taken as evidence of sedative and antidepressant activity.

Example 1

3-[ 2- benzyloxy- 4-( 1, 1- dimethylhepty1) phenyl] cyclohexanone

A solution of 75.0 g (0.193 mol) of 2-(3-benzyloxy-4-bromo-phenyl)-2-methyloctane in 200 mL of tetrahydrofuran was slowly added to 9.25 g (0.386 mol) of 70-80 mesh magnesium metal . The resulting mixture was refluxed for 20 minutes and then cooled

-18°C. Copper (I) iodide (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 by cooling with brine ice. The reaction mixture was stirred for 30 minutes longer (t<0°C) and then added to 500 ml of 2N hydrochloric acid and 2 liters of ice water. The quenched reaction

mixture was extracted three times with 500 ml portions of

water, twice with 100 ml portions of saturated sodium chloride,

was dried over magnesium sulfate and evaporated to an oil. The oil was purified by column chromatography on 1.6 kg of silica gel, and eluted with 20% ether-cyclohexane to give a product yield of

62.5 g (79.7%) as an oil.

IR: (CHC13) 1709, 1613 and 1575 cm"<1>.

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

The compounds listed below were prepared from the appropriate 2-benzyloxy-4-Z-W-bromobenzenes and the appropriate cycloalkenones in accordance with the above procedure.

3-[ 2- benzyloxy-4-( 2-( 5- phenylpentyloxy)) phenyl]- cyclohexanone as an oil (3.6 g., 87%) from 2-benzyloxy-4- [2-(5-phenyl lpentyloxy) ] - bromobenzene (4.0 g, 9.4 mmol).

IR: (CHC13) 1712, 1616 and 1592 cm"<1>.

MS: m/e 422 (M<+>), 351, 323, 296, 278, 253, 205 and 91.

Trans-3-[2-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 mol).

IR: (CHC13) 1712, 1613 and 1575 cm"<1>

MS: m/e 420 (M<+>), 363, 335, 329, 273, 271 and 91.

3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cyclopentanone as an oil (3.5 g, 58%) from 2-benzyloxy-4-(1,1-dimethylheptyl)-bromobenzene (6 .00 g, 15.4 mmol); Rf = 0.43 (0.25 mm silica gel, eluted with 1:1 ether:hexane).

3-[2-Benzyloxy-4-(1,1-dimethylhepty1)phenyl]cycloheptanone as an oil (2.94 g, 46%) from 2-benzyloxy-4-(1,1-dimethylhepty1)-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.

IR: (CHC13) 1709, 1618 and 1595 cm"1.

MS: m/e 29 5, 181 and 91

Analysis:

Calculated for C„,-H„r0o: C 80.80, H 6.78%

£b/. b5

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: . (CHC13) 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: (CHC13) 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-l-one (7.06 g, 0.0735 mol)..

IR: (CHC13) 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-cyclohexene-1-one (10.5 g, 0.110 mol).

IR: (CHC13) 1736, 1631 and 1592 cm"<1>.

MS: m/e 364 (M+), 321, 273 and 91.

Trans- 3-[ 2- benzyloxy- 4-( 1, 1- dimethylhepty 1) phenyl]- 4-( 2- propenyl)-cyclohexanone

as an oil (58.3 g, 70%) from 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: (CHC13) 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).

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-dimethylhexyl)phenyl]-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: (CHC13) 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 2-cyclohexen-1-one (7.71 g, 0.0803 mol).

IR: (CHC13) 1715, 1623 and 1582 cm"<1>.. MS: m/e 434 (M<+>), 342, 321 and 91.

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

as an oil (7.0 g, 17%) from 2-(3-benzyloxy-4-bromophenyl)-2-methylundecane (40.0 g, 0.0928 mol) and 2-cyclohexen-1-one (9, 8 g, 0.102 mol).

IR: (CHC13) 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-bromophenyl)-2-methyldodecane (27 .5 g, 0.062 mol) and 2-cyclohexen-1-one (6.68 g, 0.0682 mol).

IR: (CHC13) 1718, 1623 and 1585 cm"1.

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

3-[2-Benzyloxy-4-(1,1-dimethylhepty1)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: (CHC13) 1715, 1629 and 1587 cm"<1>.

MS: m/e 434 (M<+>), 477, 363, 349, 343, 326 and 91.

Example 2

3- [ 4-( 1, 1- dimethylhepty1)- 2- hydroxypheny1]- cyclohexanone

A mixture of 19.5 g (0.0468 mol) 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohexanone, 12.3 g sodium bicarbonate, 3.00 g 10% palladium-on- carbon and 250 ml of ethanol were stirred under an atmosphere of hydrogen pressure for 1 1/2 hours. The reaction mixture was then 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 silica gel eluting with 20% ether-cyclohexane to give a solid. Recrystallization of this solid from aqueous methanol gave

9.1 g (62%) of the title product, m.p. 87°C, mainly in the hemiketal form.

IR: (KBr) 3226, 1629 and 1580 cm"<1>.

(CHC13) 3571, 3289, 1704, 1623 and 1575 cm"<1>.

MS: m/e 316 (M<+>), 298, 273 and 231.

Analysis:

Calculated for C2iH32°2: C 79'70'H l0'19-

Found: C 79 , 69, H 9.89.

The above procedure was repeated, but using the appropriate reactants from Example 1, to form the following products.

3- [ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]- 3- methylcyclohexanone as an oil (54 mg, 86%) from .80 mg (0.19 mmol) of 3-[2-benzyloxy-4- (1,1-Dimethylheptyl)phenyl]-3-methylcyclohexanone. . IR: (CHC13) 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%), m.p. 62-64°C (recrystallized from pentane) from trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-methylcyclohexanone (1.05 g, 2.50 mmol).

IR: (CHC13) 3571, 3333 , 1721 (weak), 1626. and 1577 cm"<1>.

MS: m/e 330 (M<+>), 312, 288, 273, 245, 203 and 161.

Analysis:

Calculated for C22H34°2: C 79'97'H 10.37.

Found: C 80.33, H 10.33.

3- [ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]- cyclopentanone (0.54 g, 47%), m.p. 61-62°C (from pentane) from 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-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 c2o<H>30°2<:>C 79'42'H 10'00-

Found: C 79.65, H 10.03.

3- [ 4-( 1, 1- dimethylhepty1)- 2- hydroxyphenyl] cycloheptanone

(795 mg, 63%), m.p. 78-79°C (from pentane), from 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cycloheptanone (1.60 g, 3.80 mmol). IR: (CHC13) 3571, 3289, 1701, 1621, 1605 and 1577 cm"1.

MS: m/e 330 (M+) and 245.

Analysis:

Calculated for C22H34°2: C 79'95'H l0f37-

Found: C 79.60, H 10.33.

Quantitative yield of 3-[ 2- hydroxy- 4-( 2-( 5^ phenyl- pentyloxy))-phenyl] cyclohexanone

as an oil from 3-[2-benzyloxy-4-(2-(5-phenylpentyloxy))phenyl]-cyclohexanone (1.0 g, 2.26 mmol)

IR: (CHC13) 3571, 3333, 1709, 1623 and 1587 cm"<1>.

MS: m/e 352 (M<+>), 206, 188 and 91.

3-(2,4-dihydroxyphenyl)-cyclohexa non

as a solid (8.5 g, 94%), m.p. = 158°C (from isopropyl ether) from 3-(2,4-dibenzyloxyphenyl)cyclohexanone (16.9 g, 43.7 mmol). IR: (KBr) 3195, 1631 and 1603 cm"<1>.

MS: m/e 206 (M<+>), 188, 163, 149 and 136.

Analysis:

Calculated for<C>2.2H14°3<:>C 69'88'H 6.84%

Found: C 69.94, H 6.78%.

3-[4-(1,1-dimethyloctyl)-2-hydroxyphenyl]-cyclohexanone (0.75 g, 48%) from 2.00 g (4.76 mmol) 3-[2-benzyloxy-4-(1 ,1-Dimethyloctyl)phenyl]cyclohexanone. Sm.p. 78-80°C (from pentane). IR: (CHC13) 3571, 3333, 1709 (w), 1626 and 1577 cm"1.,

MS: m/e 330 (M+), 314, 312, 287 and 231.

•Analysis:

Calculated for C22H3'4)2: . C 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). Melting point: 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), mp: 165-166°C (from isopropyl ether).

IR: (CHC13) 3636, 3401, 1724 (w), 1634 and 1587 cm"<1>.

MS: m/e 260 (M<+>), 242, 231, 217, 213 and 161.

Analysis:

Calculated for C17<H>24<0>2<:>C 78.42, H 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).

Melting point: 101-102°C (from isopropyl ether).

IR: (CHC13) 3636, 3401, 1724 (w), 1634 and 1585 cm"<1>.

MS: m/e 274 (M+), 256, 231 and 213.

Analysis: Calculated for C18<H>26°2<:>C 78.79, H 9.55%.

Found: C 78.78, H 9.21%.

Trans-3-[ 4-( 1, 1- dimethylhepty1)- 2- hydroxyphenyl]- 4- propylcyclohexanone (1.0 g, 76%) as an oil from trans-3-[2-benzyloxy-4-(1, 1-Dimethylheptyl)phenyl]-4-(2-propenyl)-cyclohexanone (1.65 g,

3.69 mmol).

IR: (CHC13) 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%) from 3-[2-benzyloxy-4-(1,1-dimethylpentyl)phenyl]-cyclohexanone ( 5.5 g, 0.0146 mol).

Melting point: 124.5-125.5°C (from pentane)

IR: (CHC13) 3623, 3378, 1718 (weak), 1634 and 1587 cm"<1>..

MS: m/e 288 (M<+>), 245 and 231.

Analysis:

Calculated for C19H2g02: C 79.12, H 9.79%

Found: C 79.32, H 9.53%.

3-[ 4-( 1,1-dimethylhexyl)- 2- hydroxyphenyl]- cyclohexanone (quantitative) from 3-[2-benzyloxy-4-(1,1-dimethylhexyl)phenyl]-cyclohexanone (2.0 g, 5 .1 mmol). Melting point: 82-83°C.

IR: (CHC13) 3636, 1634, 1616 and 1585 cm"<1>.

MS: m/e 302 (M<+>), 284, 259 and 231.

Analysis: , Calculated for c2o<H>3o<0>2<:>C 79'42'H l0'00%

Found: C 79.16, H 9.75%.

3-[4-(1,1-dimethylnonyl)-2-hydroxyphenyl)-cyclohexanone (2.4 g, 61%) from 3-[2-benzyloxy-4-(1,1-dimethylnonyl)phenyl]- cyclohexanone (5.0 g, 11.5 mmol). Melting point: 72-73°C.

IR: (CHC13) 3650, 3413, 1721 (weak), 1639 and 1595 cm"<1>.

HRMS: m/e 344.2691, (M<+>), Cn,H,,.0,J, 326.2570 and 301.2168.

3-[ 4-( 1, 1-dimethyldecyl)- 2- hydroxyphenyl]- cyclohexanone (880 mg, 55%) from 3-[2-benzyloxy-3-(1,1-dimethyldecyl)phenyl]- cyclohexanone (2, 0 g, 4.46 mmol). Melting point: 78-79°C.

IR: (CHC13) 3623, 1629, 1616 and 1587 cm"<1>.

HRMS: m/e 358.2836 (<M+,><C>24<H>3<g0>2).

3-[4-(1,1-Dimethylundecyl)-2-hydroxyphenyl]-cyclohexanone (1.49 g, 46%) from 3-[„2-benzyloxy-4-(1,1-dimethylundecyl)phenyl]-cyclohexanone (4.00 g, 8.66 mmol). Melting point: 72-73°C.

IR: (KBr) 3268, 1629 and 1580 cm"<1>.

MS: m/e 372 (M<+>), 354, 329 and 231.

Analysis: Calculated for C25<U>40<0>2<:>' C 80'59' H 10'82%-

Found: C 80.70, H 10.84%.

3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-cyclo. octanone (1.92 g, 81%) from 3-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]-cyclooctanone (3.02 g, 6.95 mmol). Melting point: 118 C.

IR: (CHC13) 3623, 3356, 1709, 1629 and 1587 cm"<1.>

MS: m/e 344 (M+), 329, 326, 283, 273, 259 and 241.

Analysis: Calculated for C23H36°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%) from 3-[2-benzyloxy-4-(1 ,1-dimethylheptyl)phenyl]-4-methyl-2-cyclohexen-1-one (2.10 g, 5.02 mmol).

Melting point: 111°C (from diisopropyl ether-petroleum ether).

IR: (CHC13) 3534, 3279, 1667, 1623 and 1567 cm"<1>.

MS: m/e 328 (M<+>), 313 and 243.

Analysis: Calculated for<C>22H32°2<:>C 80'44'H 9'83%

Found: C 80.35, H 9.67%.

Example 3

cis-3-[2-benzyloxy-4-(1,1-dimethylhepty1)phenyl]cyclohexanol and the trans isomer

to a solution at -40°C of 43.0 g (0.106 mol) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohexanone in 500 ml

methanol and .15 ml of tetrahydrofuran, 8.05 g (0.212 mol) of sodium borohydride were added in 3 portions. The reaction mixture was stirred for 1 hour at -40°C, was allowed to warm to -10°C and was then quenched by the addition of 100 ml of saturated sodium chloride. The quenched reaction mixture was added to 1500 ml of water and extracted with three portions of 450 ml of ether. The combined ether extracts were washed with three 100 mL portions of water and two 200 mL portions of saturated sodium chloride, dried over magnesium sulfate, and evaporated to an oil. The oil was purified by column chromatography on 400 g of silica gel and eluted with 20% ether-cyclohexane, and this gave, in order of elution,

5.0 g (12%) trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cyclohexanol,

IR: (CHC13) 3636, 3497, 1629 and 1587 cm"<1>.

MS: m/e 408 (M<+>), 393, 390, 323 and 91. Analysis: Calculated for C~o<H>.^<0>„<:>C 82.30, H 9.87%

2. o 4UÅ.

Found: C 81.98, H 9.82%,

and 22.2 g (51%) of cis-3-[2-benzyloxy-4-(1,1-dimethylhepty1)phenyl]-cyclohexanol, m.p.: 75.5-76.5°C, IR: ( CHC13) 3636, 3497, 1629 and 1587 cm"<1>.

MS: m/e 408 (M+), 393, 390, 323 and 91.

Analysis: Calculated for C28H40<0>2<:>C 82.30, H 9'87%

Found: C 81.95, H 9.74%.

The following compounds were similarly prepared from the appropriate ketones from Example 1.

A quantitative yield of Z-3-[2-benzyloxy-4-(1,1-dimethylhepty1)-phenyl]-3-methylcyclohexanol as an oil from 3-[2-benzyloxy-4-(1,1-dimethylhepty1) phenyl]-3-methylcyclohexanone (200 mg, 0.476 mmol).

IR: (CHC13) 3546, 3378, 1603 and 1555 cm"<1>.

MS: m/e 422 (M<+>), 337, 314, 299, 271 and 229.

trans, trans- 3-[ 2- benzyloxy- 4-( 1, 1- dimethylhepty1) 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:

TMS

PMR: <5CD£^0.80 (m, terminal side chain methyl and C-4 methyl), 1.27 (s, gem dimethyl), 3.12 (m, benzylic methine), 4.20 (m, carbinol-

methine), 5.13 (s, benzyl ether methylene), 6.95 (m, ArH), 7.15 (d, J=8Hz, ArH) and 7.48 (bs, PhH).

IR: (CHC13> 3413, 1616 and 1575 cm"<1>.

MS: m/e 422 (M<+>), 407, 337, 314, 272, 229 and 91.

cis,trans:

TMS

PMR: 6^^-l 0.70 (d,J=6Hz, C-4 methyl), 0.85 (m, terminal side chain me ty!) , 1.29 (s, gem dimethyl), 2.81 ( m, benzylic methine), 3.75 (m, carbinol methine), 5.13 (s, benzyl ether methylene), 6.93

(m, ArH), 7.15 (d, J=8Hz, ArH) and 7.43 (bs, PhH)..

IR: (CHC13) 3571, 3390, 1618 and 1577 cm"<1>.

MS: m/e 422, 337, 314, 272, 229 and 91.

A mixture of cis- and trans-3-[2-benzyloxy-4-(1,1-dimethylhepty1)-phenyl]-cyclopentanol

(1.1 g, 85%) as an oil from 3-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]-cyclopentanone (1.32 g, 3.37 mmol).

MS: m/e 394 (M<+>), 379, 376, 309 and 91.

Trans-3-[2-benzyloxy-4-(1,1-dimethylhepty1)phenyl]-cycloheptanol

(695 mg, 49%) and 380 mg (27%) of the cis isomer as an oil from 3-[2-benzyloxy-4-(1-dimethylheptyl)phenyl]cycloheptanone (1.40 g,

3.33 mmol).

Cis:

TMS

PMR: 60.85 (m, side chain terminal methyl), 1.30 (s, gem dimethyl), 3.15 (m, benzylic methine), 3.90 (m, carbinol methine), 5.15 (s, benzyl ether methylene), 6.8-7.4 (m, ArH) and 7.45 (bs, PhH).

IR: (CHC13) 3571, 3448, 1613 and 1572 cm"<1>.

MS: m/e 422 (M+), 337, 314, 229 and 91.

Trans:

TMS

PMR: ^CDC^0.86 (m, terminal methyl), 1.26 (s, gem dimethyl), 3.41

(m, benzylic methine), 4.10 (m, carbinol methine), 5.17 (s, benzylic methylene), 6.8-7.2 (m, ArH), 7.18 (d, J=8Hz , ArH)' and 7.45 (bs, PhH). IR: (CHC13) 3534, 3390, 1613 and 1572 cm"<1>.

MS: m/e 422 (M<+>), 337, 331, 314, 246, 229 and 91.

Cis- 3-[ 2- benzyloxy- 4-( 2- 5- phenylpentyloxy) phenyl] cyclohexanol

(1.51 g, 76%) and the trans isomer (0.379 g, 19%) as an oil from 3-[2-benzyloxy-4-(2-(5-phenylpentyloxy))phenyl]cyclohexanone (2.0 g, 4 .52 mmol).

trans:

■ TMS

PMR: fi^c-L 1.28 (d, J=6Hz, methyl), 2.68 (m, benzylic methylene) 3.45 (m, benzylic methyl), 4.22 (m, carbinol-methine), 4, 30 (m, side chain methine), 5.09 (s, benzyl 1-ether-methylene) , 6.4.5 (dd, J=8 and 2Hz, ArH), 6.55 (bs, ArH), 7.10 (d, J=8Hz, ArH), 7.25 (s, PhH) and.

7.4 5 (bs,PhH).

IR: (CHC13) 3571, 3448, 1613 and 1590 cm"<1>.

MS: m/e 444 (M<+>), 298, 280, 190 and 91.

cis :

TMS

PMR: <5CDC11.25 (d, J=6Hz, methyl), 3.0 (m, benzylic methine), 3.77 (m, carbinol methine), 4.38 (m, side chain methine), 5.10 (s, benzylether-methine), 6.50 (dd, J=8 and 2Hz, ArH), 6.58 (bs, ArH), 7.12 (d, J=8Hz, ArH), 7.32 (s, PhH) and 7.43 (s, PhH).

IR: (CHCl 3 ). 3571, 3390, 1613 and 1587 cm"<1>'.

MS: m/e 444 (M<+>), 298, 190 and 91.

cis-3-[2-benzyloxy-4-(1,1-dimethyloctyl)phenyl]-cyclohexanol (1.35 g, 45%) and the trans isomer (0.34 g, 11%) from 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 mixt.

trans:

PMR: <5CDC-i_ 0.87 (m, terminal side chain methyl), 1.25 (s, gem

TMS

dimethyl), 3.50 (m, benzylic methine), 4.22 (m, carbinol methine), 5.15 (s, benzylic ether methylene) and 6.8-7.6 (m, ArH and PhH ).

IR: (CHC13) 3497, 1623 and 1582 cm"<1>.

MS:.m/e 422 (M<+>) and 323.

cis:

TMS

PMR: <5CDC1 0.85 (m, terminal side chain methyl), 1.25 (s, gem dimethyl), .3.10 (m, benzylic methine), 3.75 (m, carbinol methine), 5.12 (s, benzyl ether methylene), 6.91 (dd, J=8 and 2Hz, ArH), 6.91

(d, J=2Hz, ArH), 7.17 (d, J=8Hz, ArH) and 7.42 (bs, PhH).

IR: (CHC13) 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 the cis and trans isomers from 12.0 g (0.0357 mol) 3-(2-benzyloxy-4-t-butylphenyl)cyclohexanone

cis:

Melting point: 78-79°C (from hexane)

■ TMS

PMR: 6cdc-1 1.30 (s, t-butyl), 3.10 (m, benzylic methine), 3.72

(m, carbinyl methine), 5.12 (s, benzyl ether methylene), 6.97 (d,

J=2Hz, ArH), 6.97 (dd, J=8Hz and 2Hz, ArH), 7.17 (d, J=8Hz, ArH)

and 7.40 (bs, PhH).

IR: (CHC13) 3636, 3472, 1621 and 1582 cm"<1>.

MS: m/e 338 (M<+>), 323, 320, 230, 215 and 91.

Analysis: Calculated for c23H3o°2: C 81'61'H 8/93%

Found: C 81.79, H 8.77%

trans:

TMS ■

PMR: 6 ^ 1.23 (s, t-butyl), 3.50 (m, benzylic methine), 4.20

(m, carbinol-methine), 5.02 (s, benzyl ether-methylene). and 6.8-7.4

(m, ArH and PhH).

IR: (CHC13) 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 one oil from 8.0 g (0.0229 mol) 3-[2-benzyloxy-4-(1,1- dimethylpropyl)phenyl]cyclohexanone.

cis :

TMS

PMR: 6CDC^ 0.67 (t,J=7Hz, terminal methyl), 1.26 (s, gem dimethyl), 3.05 (m, benzylic methine), 3.75 (m, carbinol methine), 5 .15 (s, benzyl ether-methylene), 6.92 (d, J=2, ArH), 6.92 (dd, J=8 and 2 Hz, ArH), 7.17 (d, J=8Hz, ArH ) and 7.42 (bs, PhH).

IR: (CHC13) 3636, 3344, 1626 and 1587 cm"<1>.

MS: m/e 352 (M<+>), 337, 334, 323, 244, 215 and 91.

trans:

IR: (CHC13) 3636, 1626 and .1587 cm"1.

MS: m/e 352 (M+), 337, 334, 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 an oil from 8.0 g (0.022 mol) of 3-[2-benzyloxy-4-(1,1-dimethylbutyl)phenyl]-cyclohexanone.

cis:

TMS

PMR: <$CD£^ 0.80 (m, terminal methyl), 1.23 (s, gem dimethyl), 3.05 (m, benzylic methine), 3.70 (m, carbinol methine), 5, 08 (s, benzyl^ether-methylene), 6.86 (d, J=2Hz, ArH), 6.86 (dd, J=8 and 2Hz, ArH),

7.11 (d, J=8Hz, ArH) and 7.35 (bs, PhH).

IR: (CHC13) 3623., 3448, 1621 and 1582 cm"<1>.

MS: m/e 366 (M<+>), 351, 348, 323, 258, 215 and 91.

trans:

TMS

PMR: S^j^ 0.83 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.40

(m, benzylic methine), 4.18 (m, carbinol methine), 5.09 (s, benzyl ether methylene), 6.86 (d, J=2Hz, ArH), 6.86 (dd, J= 8 and 2Hz, ArH), 7.11 (d, J=8Hz, ArH) and 7.39 (m, PhH).

IR: (CHC13) 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- dimethylhepty1) phenyl]- cis- 4-( 2- propenyl)- cyclohexanol

(1.9 g, 13%) and the cis-3,trans-4 isomer (7.3 g, 51%) as an oil from trans-3-[2-benzyloxy-4-(1,1-dimethylhepty1) phenyl]-4-(2-propenyl)-cyclohexanone (14.3 g, 32.1 mmol). The elution order from silica gel with 2:1 pentane:ether was the trans-3,cis-4 isomer of the title compound as an oil followed by the cis-3,trans-4 isomer.

trans-3,cis-4-isomer:

IR: (CHC13) 3559, 3401, 1639, 1608 and 1567 cm"<1>.

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

TMS

PMR: 5cdc-1 0.82 (m, terminal methyl), 1.25 (s, gem dimethyl), 3.30 (m, benzylic methine), 4.12 (m, carbinol methine), 4.6- 5.0 (m, vinyl H), 5.06 (s, benzylic methylene), 5.2-6.1 (m, vinyl H), 6.82 (d, J=2Hz, ArH), 6.82 (dd, J=8 and 2Hz, ArH), 7.07 (d, J=8Hz, ArH) and 7.38

(b.s., Ph.D.).

cis-3,trans-4 isomer:

IR: (CHC13) 3571, 3401,, 1639, 1610 and 1572 cm"<1>.

MS: m/e 448 (M<+>), 406, 363 and 91.

TMS

PMR: <5qDq^ 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl),

2.90 (m, benzylic methine), 3.73 (m, carbinol methine), 4.6-5.1

(m, vinyl H), 5.02 (s, benzylic methylene), 5.3-6.3 (m, vinyl H), 6.75 (d, J=2Hz, ArH), 6.75 (dd, J=8 and 2Hz, ArH), 6.99 (d, J=8Hz, ArH) and .7.25 (bs, Ph) ..

cis- 3-[ 2- benzyloxy- 4-( 1, 1- dimethylhepty1) phenyl]- trans- 4-( 2- butenyl) cyclohexanol

(495 mg, 82%) and the trans-3,cis-4-isomer (105 mg, 18%) from trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-(2-butenyl )-cyclohexanone (600 mg, 1.30 mmol). The trans-3,cis-4 isomer was eluted first.

trans-3,cis-4-isomer:

MS: m/e 462 (M<+>), 447, 444, 377 and 91.

cis-3,trans-4 isomer:

IR: (CHC13) 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,cis-4 isomer from trans-3-(2-benzyloxy-4-(1,1-dimethylheptyl)phenyl)-4-(2-pentenyl)cyclohexanone (497 mg, 1.04 mmol). The elution distribution yielded 84 mg (17%) of the trans-3,-cis-4-isomer (Rf = 0.26, silica gel, 33% ether-pentane) and 363 mg (73%) of the cis- The 3,trans-4-isomer (Rf = 0.13, silica gel, 33% ether-pentane).

cis-3-[2-benzyloxy-4-(1,1-dimethylpenty1)phenyl]-cyclohexanol (5.0 g, 83%) and the trans isomer (0.60 g, 10%) as oils from 3-[ 2-Benzyloxy-4-(1,1-dimethylpentyl)phenyl]cyclohexanone (6.0 g, 58 mmol).

trans:

IR: (CHC13) 3636, 3497, 1623 and 1582 cm"<1>.

MS: m/e 380 (M<+>) .

TMS

PMR: «S^q^tl 0.83 (m, terminal methyl), 1.24 (s, gem dimethyl), 3.5 (m, benzylic methine), 4.20 (m, carbinol methine), 5 .09 (s, benzylic methylene) and 6.8-7.6 (m, ArH).

cis :

IR: (CHC13) 3636 , 1621 and .1580 cm"<1>.

MS: m/e 380 (M<+>).

TMS

PMR: Sqdci 0.75 (m, terminal methyl), 1.14 (s, gem dimethyl),

2.90 (m, benzylic methine), 3.52 (m, carbinol methine), 4.80

(s, benzylic methylene), 6.49 (dd, J=8 and 2Hz, ArH), 6.49

(d, J=2Hz, ArH), 6.72 (d, J=8Hz, ArH) and 6.96 (bs, Ph).

Cis- 3-[ 2- benzyloxy- 4-( 1, 1- dimethylhexyl) phenyl]- cyclohexanol (3.0 g, 43%) and the trans isomer (660 mg, 9%) as oils from 3-[2- benzyloxy-4-(1,1-dimethylhexyl)phenyl]-cyclohexanone

(7.0 g, 17.9 mmol)

cis:

IR: (CHC13) 3623, 3448, 1618 and 1575 cm"<1>.

MS: m/e 394 (M+) .

TMS

PMR: 6CD^ 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.07 (m, benzylic methine), 3.70 (m, carbinol methine), 5.08

(s, benzylic methylene), 6.88 (dd, J=8 and 2Hz, ArH), 6.88

(d, J=2Hz, ArH), 7.12 (d, J=8Hz, ArH) and 7.37 (bs, Ph).

trans:

IR: (CHC13) 3623, 7448, 1618 and 1577 cm"1.

MS: m/e 3 94 (M+)

TMS

PMR: <$cDCl°'80 (m'terminal methyl), 1.27 (s, gem dimethyl), 3.42 (m, benzylic methine), 4.12 (m, carbinol methine), 5.02

(s, benzylic methylene), 6.83 (m, ArH), 7.04 (d, J=8Hz, ArH) and 7.34 (bs, ArH).

Cis- 3-[ 2- benzyloxy- 4-( 1, 1- dimethylnonyl) phenyl]- cyclohexanol (5.0 g, 59%) and the trans isomer (1.0 g, 12%) as oils from 3- [2-Benzyloxy-4-(1,1-dimethylnonyl)phenyl]-cyclohexanone (8.5 g, 19.6 mmol).

cis:

IR: (CHC13) 3623, 3448, 1618 and 1577 cm"<1.>

MS: m/e 4 36 (M<+>).

TMS

PMR: SqqcI 0.83 ^ m' terminal methyl), 1.22 (s, gem dimethyl), 3.04 (m, benzylic methine), 3.67 (m, carbinol methine), 5.08 (s, benzylic methylene), 6.87 (dd, J=8 and 2Hz, ArH), 6.87

(d, J=2Hz, ArH) and 7.05-7.45 (m, ArH and Ph).

trans:

IR: (CHC13) 3610, 3448, 1618 and 1575 cm"<1.>

MS: m/e 4 36 (M<+>)

TMS

PMR: Sqqq-l 0.82 (m, terminal methyl), 1.22 (s, gem dimethyl), 3.42 (m, benzylic methine), 4.16 (m, carbinol methine), 5.02

(s, benzylic methylene) and 6.7-7.5 (m, ArH and Ph).

Cis-3-[2-benzyloxy-4-(1,1-dimethylundecyl)phenyl]-cyclohexanol (3.5 g, 50%) and the trans isomer (1.0 g, 14%) as oils from 3-[ 2-Benzyloxy-4-(1,1-dimethylundecyl)phenyl]cyclohexanone (7.00 g, 15.0 mmol).

cis:

IR: (CHC13) 3636, 3448, 1621 and 1582 cm"<1.>

MS: m/e 464 (M<+>).

TMS

PMR: 6CDC1 0.95 (m, terminal methyl), 1.33 (s, gem dimethyl), 3.09 (m, benzylic methine), 3.70 (m, carbinol methine), 5.20

(s, benzylic methylene), 6.99 (dd, J=8 and 2Hz, arH), 6.99 (dd, J=8 and 2Hz, ArH), 7.22 (d, J=8Hz, ArH) and 7.50 (bs, PhH).

trans:

IR: (CHC13) 3534 (broad), 1618 and 1577 cm"<1.>

MS : m/e 464 . (M+).

TMS

PMR: $DqviQ'85 (m' terminal methyl), 1.22 (s, gem dimethyl), 3.48 (m, benzylic methine), 4.17 (m, benzylic methine), 5.08

(s, benzylic methylene) and 6.75-7.55 (m, ArH and Ph).

cis- 3-[ 2- benzyloxy- 4-( 1, 1- dimethyldecyl) phenyl]- cyclohexanol (2.66 g, 59%) and the trans isomer (0.36 g, 8%) as oils from 3-[ 2-Benzyloxy-4-(1,1-dimethyldecyl)phenyl]-cyclohexanone (4.5 g, 10.0 mmol).

cis:

IR: (CHC13) 3704, 3571, 1639 and 1597 cm"<1.>

MS: m/e 450 (M<+>).

TMS

PMR: 0.86 (m, terminal methyl), 1.25 (s, gem dimethyl), 3.08 (m, benzylic methine), 3.74 (m, carbinol methine), 5.08

(s, benzylic methylene), 6.88 (dd, J=8 and 2Hz, ArH), 6.88

(d, J=2Hz, ArH), 7.12 (d, J=8Hz, ArH) and 7.37 (bs, Ph).

trans:

IR: (CHC13) 3623, 3448, 1616 and 1577 cm"<1.>

MS: m/e 450 (M<+>).

TMS -

PMR:Sqvci 0.82(m, terminal methyl), 1.22 (s, gem dimethyl), 3.53 (m, benzylic methine), 4.22 (m, carbinol methine), 5.02

(s, benzylic methylene) and 6.8-7.6 (m, ArH and Ph).

cis- 3-[ 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl]- cyclooctanol (1.36 g, 19%) and the trans isomer (4.12 g, 59%) as oils from 3- [ 2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cyclooctanone (7.0 g, 16.1 mmol).

MS: m/e 436 (M<+>), 421, 418,.351, 328, 300, 243 and 91.

PMR: <5CDC1 0.83 (m, terminal methyl), 1.28 (s, gem dimethyl),

TMS

3.19 (bm, benzylic methine), 3.89 (bm, carbinol methine), 5.10

(s, benzylic methylene), 6.83 (m, ArH), 7.08 (d, J=8Hz, ArH) and 7.38 (m, Ph).

trans:

MS: m/e 436 (M+), 421, 418, 351,. 328, 2.43 and 91.

TMS

PMR: fiCDC1 0.83 (m, terminal methyl), 1.28 (s, gem dimethyl),

3.4 (bm, benzyl methine), 3.9 (m, carbinol methine, 5.10

(s, benzylic methylene), 6.85 (m, ArH), 7.08 (d, J=8Hz, ArH) and 7.36 (m, Ph).

Example 4

cis- 3-[ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]- cyclohexanol

A mixture of 22.0 g (0.0539 mol) cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cyclohexanol, 12.0 g sodium bicarbonate and 2.0 g 10% palladium -on-carbon was stirred under a hydrogen atmosphere 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: (CHC13) 3610, 3356, 1626 and 1582 cm"<1.>

MS: m/e 318 (M<+>), 300, 233 and 215.

Analysis: Calculated for c2iH34°2: C 79'19'H 10'76

Found: C 78.96, H 10.59.

Following the above procedure, the compounds listed below were prepared from the appropriate reactants of Example 3.

trans- 3-[ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]- cyclohexanol ■

(2.47 g, 71%), m.p. 124-125°C (from pentane) from trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl).phenyl]cyclohexanol (4.50 g, 0.011 mol).

IR: (CHC13) 3610, 3390, 1626 and 1575 cm"<1>.

MS: (m/e 318 (M<+>), 300, 233 and 215.

Analysis: Calculated for<c>2i<K>34°2<:>C 79.19, H 10.76.

Found: C 78.82, H 10.43.

A quantitative yield of Z- 3-[ 4-( 1, 1- dimethylheptyl)- 2-hydroxyphenyl]- 3- methylcyclohexanol,

sm.p. 90-91°C (recrystallized from petroleum ether) from Z-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-methylcyclohexanol (180 mg, 0.246 mmol).

IR: (CHC13( 3597, 3333, 1605 and 1570 cm"<1>).

MS: m/e 332.(M<+>), 314, 299, 286, 271, 247 and 229.

Analysis: Calculated for C22H36°2<:>C 79.45'H 10'92-

Found: C 79.24, H 10.64.

A quantitative yield of trans, trans- 3-[ 4-( 1, 1- dimethylheptyl)-2- hydroxypheny1]- 4- methylcyclohexanol

sm.p. 134-135°C (from pentane) from trans,trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-methylcyclohexanol (19.0 mg, 0.450 mmol). IR: (CHC13) 3571, 3333, 1626 and 1575 cm"<1>.

MS: m/e 332 (M<+>), 317, 314, 247, 233 and 229.

Analysis: Calculated for c22n36°2: C 79'46'H 10'92%

Found: C 79.13, H 10.68%.

A quantitative yield of cis, trans- 3-[ 4-( 1, 1- dimethylheptyl)-2- hydroxyphenyl]- 4- methylcyclohexanol

sm.p. 150-151°C (from pentane) from cis,trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-methylcyclohexanol (.1.15 g, 2.72 mmol). IR: (CHC13) 3571, 3333, 1621, 1605 and 1580 cm"<1>.

MS: m/e 332 (M<+>), 314, 272, 247, 233 and 229.

Analysis: Calculated for C22H36°2<:>C 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 228 mg (27%) of the trans isomer as oils from a mixture of cis- and trans- 3-[2-Benzyloxy-4-(1,1-dimethylheptyl)-phenyl]-cyclopentanol (1.10 g, 2.79 mmol).

cis:

PMR: 6.CDC1 0.83 (m, side chain terminal methyl), 1.2.4 (s, gem

TMS

dimethyl), 3.2 (m, benzylic methine), 4.52 (m, carbinol methine),

6.75 (dd, J=8 and 2Hz, ArH), 6.81 (bs, overlaps 6 6.75, ArH) and 6.97 (d, J=8Hz, ArH).

IR: (CriCl 3 ) 3571, 3300, 1623 and 1567 cm"<1>.

MS: m/e 304 (M<+>), 286, 219, 201 and 159.

trans:

TMS

PMR: 6CDC1 0.83 (m, side chain terminal methyl), 1.27 (s, gem dimethyl), 3.60 (m, benzylic methine), 4.55 (m, carbinol methine),

6.78 (bs, overlaps 6. 6.88, ArH), 6.88 (dd, J=8 and 2Hz, ArH) and 7.10 (d, J=8Hz, ArH).

IR: (CHC13) 3571, .3333, 1621 and 1575 cm"<1>.

MS: m/e 304 (M<+>), 286, 219 and 201.

A quantitative yield of trans-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-cycloheptanol

sm.p. 55-57°C from trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cycloheptanol (695 mg, 1.64 mmol).

IR: (CHC13) 3333, 1621 and 1570 cm"<1>.

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

Analysis: Calculated for C22H36°2<:>C 79'46'H 10'92-

Found: C 79.68, H 10.62.

A quantitative substitution of cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-cycloheptanol

sm.p. 103-104°C (recrystallized from pentane) from cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cycloheptanol (380 mg,.

0.900 mmol).

IR: (CHC13) 3571, 3311, 1621, 1605 and 1580 cm"<1>.

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

Analysis: Calculated for C22H36°2<:>C 79.46, H 10.92

Found: C 79.39, H 10.72.

A quantitative yield of cis-3-[2-hydroxy-4-(2-(5-phenyl-pentyloxy)phenyl]-cyclohexanol,

sm.p. 80-84°C (pentane) from cis-3-[2-benzyloxy-4-(2-(5-phenylpenty1-.oxy))phenyl]-cyclohexanol (1.45 g, 3.27 mmol).

IR: (CHC13) 3597, 3333, 1623 and 1597 cm"1.

MS: m/e 354 (M+), 336, 208, 190 and 91.

Analysis: Calculated for C23H30<0>3<:>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%), m.p. 65-70°C (pentane) from trans-3-[2-benzyloxy-4-(2-(5-phenylpentyloxy)phenyl]cyclohexanol (0.355 g, 0.754 mmol). IR: (CHC13) 3597, 3378, 1629 and 1587 cm"<1>.

MS: m/e 354 (M<+>), 336, 208, 190 and 91

Analysis: Calculated for C23H30<0>3<:>C 77'93'H 8'53%

Found: C 77.53, H 8.40%.

cis-3-[4-(1,1-dimethyloctyl)-2-hydroxyphenyl]-cyclohexanol (0.725 g, 68%) from 1.36 g (3.22 mmol) of cis-3-[2-benzyloxy-4- (1,1-dimethyloctyl)phenyl]cyclohexanol.

Melting point: 100-101°C (recrystallized from hexane)

IR: (CHC13) 3571, 3333, 1626 and 1582 cm"<1>.

MS: m/e 332 (M+), 314, 233 and 215.

Analysis: Calculated for C22H36°2<:>C 79'46, H 10'92%

Found: C 79.85, H 11.03%.

trans-3-[4-(1,1-dimethyloctyl)-2-hydroxyphenyl]-cyclohexanol (0.195 g, 100%) as an oil from 246 mg (0.582 mmol) of trans-3-[2-benzyloxy-4-( 1,1-dimethyloctyl)phenyl]cyclohexanol. Melting point: 94-95°C (from petroleum ether).

IR: (CHC13) 3650, 3436, 1639 and 1582 cm"<1>.

MS: m/e 332 (M<+>), 314, 233 and 215.

Analysis: Calculated for C22H36°2<:>c 79 ' 46> H 10.92%.

Found: ■ C 79.34, H 10.55%.

cis-3-(4-t-butyl-2-hydroxypheny1)cyclohexanol

(3.99 g, 77%) from cis-3-(2-benzyloxy-4-t-butylphenyl)cyclohexanol (7.1 g, 0.021 mol). Melting point: 177-178°C (from isopropyl ether).

IR: (KBr) 3484, 3268, 1634 and 1592 cm"<1.>.

MS: m/e 248 (M<+>), 233, 230, 215, 187, 176, 173 and 161.

Analysis: Calculated for<C>16<H>25°2<:>c 77.37, H 9.74%.

Found: C 77.00, H 9.54%.

trans-3-(4-t-buty1-2-hydroxyphenyl) cyclohexanol

(0.725 g, 99%) from trans-3-(2-benzyloxy-4-t-butylphenyl)cyclohexanol (1.25 g, 2.96 mmol). Melting point: 136-137°C (from isopropyl ether). IR: (CHC13) 3623, 3401, 1626 and 1575 cm"<1>.

MS: m/e 248 (M<+>), 233, 230, 215, 187 and 173. •

Analysis: Calculated for c1gH24°2: c 77.37'H 9.74%.

Found: C 77.34, H 9.49%.

cis-3-(1,1-dimethylpropyl)-2-hydroxyphenyl]-cyclohexanol (1.45 g, 32%) from cis-3-[2-benzyloxy-4-(1,1-dimethylpropyl)phenyl]-cyclohexanol (6.1 g, 0.0173 mol).

Melting point: 166-167°C (from isopropyl ether)

IR: (KBr) 3509, 3279, 1629 and 1592 cm"<1>.

MS: m/e 262 (M<+>), 247, 244, 233 and 215.

trans-3-[4-(1,1-dimethylpropyl)-2-hydroxyphenyl]-cyclohexanol (0.50 g, 68%) from trans-3-[2-benzyloxy-4-(1,1-dimethylpropyl)phenyl ]-cyclohexanol (1.00 g, 2.84 mmol).

Melting point: 124-125°C (from isopropyl ether).

IR: (CHC13) 3636, 3413, 1639 and 1585 cm"<1>.

MS: m/e 262 (M<+>), 247, 244, 233 and 215.

Analysis: Calculated for C17<H>26<0>2<:>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%) from cis-3-[2-benzyloxy-4-(1,1-dimethylbutyl) phenyl]-cyclohexanol (3.39 g, 9.26 mmol). mp: 138-139 (from 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 from trans-3-[2-benzyloxy-4-(1,1- dimethylbutyl)phenyl]cyclohexanol (0.700 g, 1.91 mmol).

IR: (CHC13) 3636, 3390, 1629 and 1575 cm"<1>.

MS: m/e 276 (M<+>), 261, 258, 233 and 215.

trans- 3-[ 4-( 1, 1- dimethylheptyl)- 2- hydroxypheny1]- cis- 4- propy1-cyclohexanol

(626 mg, 78%) from trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]-cis-4-(2-propenyl)-cyclohexanol (1.0 g, 2.23 mmol).

Melting point: 92-94°C.

IR: (CHC13) 3623, 3390, 1629 and 1578 cm"<1>.

Analysis: Calculated for C24H4o°2: C 79.94'H H/18%

Found: C 80.10, H 10.89%.

cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-trans-4-propyl-cyclohexanol (550 mg, 74%) from cis-3-[2-benzyloxy-4-(1,1 -dimethylheptyl)phenyl]-trans-4-(2-propenyl)cyclohexanol (930 mg, 2.07 mmol). Melting point: 126°C (from pentane).

IR: (CHC13) 3597, 3390, 1629 and 1575 cm"<1>.

MS: m/e 360 (M+), 345, 342, 275 and 257.

Analysis: Calculated for c24H4o°2<:>C 79'94'H 11/18%-

Found: C 79.85, H 10.95%.

trans- 4- butyl- cis- 3-[ 4-( 1, 1- dimethylheptyl)- 2- hydroxypheny1]-cyclohexanol

(322 mg, 80%) from cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-butenyl)cyclohexanol (500 mg, 1.08 mmol).

Sm.p.:. 131°C (from pentane).

IR: (CHC13) 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%) from cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-pentenyl)cyclohexanol (363 mg, 0.762 mmol). Melting point: 135-136°C.

cis- 3-[ 4-( 1, 1- dimethylpentyl)- 2- hydroxyphenyl] cyclohexanol

(2.5 g, 60%) from cis-3-[2-benzyloxy-4-(1,1-dimethylpentyl)phenyl]-cyclohexanol (5.5 g, 0.0144 mol).

Melting point: 112-113°C (from pentane, isopropyl ether).

IR: (CHC13) 3636, 3390, 1631 and 1592 cm"<1>.

MS: m/e 290 (M<+>), 272, 233 and 215.

Analysis: Calculated for C19H30°2<:>C 78.57, H 10.41%.

Found: C 78.76, K 10.11%.

trans-3-[4-(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).

Melting point: 114-115°C (from pentane).

IR: (CHC13) 3636, 3390, 1631 and 1577 cm"<1>.

MS: m/e 290 (M<+>), 272, 233 and 215.

Analysis: Calculated for C19H3o<0>2<:>C 78.57 H 10.41%

Found: C 78 , 38, H 10.10%..

cis-3-[4-(1,1-dimethylhexyl)-2-hydroxyphenyl]-cyclohexanol (2.3 g, 99%) from cis-3-[2-benzyloxy-4-(1,1-dimethylhexyl)phenyl ]-cyclohexanol (3.00 g, 7.61 mmol).

Melting point: 98-100°C (pentane).

IR: (CHC13) 3636, 3367, 1626 and 1587 cm"<1>.

MS: m/e 304 (M<+>), 286, 233 and 215.

Analysis: Calculated for<c>2oH32°2<:>C 78'89'H 10'59%-

Found: C.-78.57, H 10.46%.

trans-3-[4-(1,1-dimethylhexyl)-2-hydroxyphenyl]-cyclohexanol (440 mg, 86%) from trans-3-[2-benzyloxy-4-(1,1-dimethylhexyl)-phenyl] -cyclohexanol (660 mg, 1.68 mmol).

Melting point: 113-114°C (pentane).

IR: (CHC13) 3636, 3390, 1631, 1616 and 1580 cm"<1>.

MS: m/e 304 (M<+>), 286, 233 and 215.

HRMS: 304.2419 (C 2 (H 32 O 2 ) ).

cis-3-[4-(1,1-dimethylnonyl)-2-hydroxyphenyl]- cyclohexanol (4.0 g, 100%) from cis-3-[2-benzyloxy-4-(1,1-dimethylnonyl)phenyl ]-cyclohexanol (5.Og, 1.15 mmol).

Melting point: 82-83°C (pentane).

IR: (GHC13) 3650, 3390, 1637 and 1597 cm"<1>.

MS: m/e 346 (M<+>), 328, 233 and 215.

Analysis: Calculated for C23H3Q<0>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%) from trans-3-[2-benzyloxy-4-(1,1-dimethylnonyl)-phenyl] cyclohexanol (1.00 g, 2.29 mmol).

Melting point: 69-70°C (pentane).

IR: (CHC13) 3636, 3413, 1631, 1618 and 1582 cm"<1>.

MS: m/e 346 (M<+>), 328, 233 and 215.

Analysis: Calculated for C23H3g<0>2<:>G 79.71, H 11.05%.

Found: C 7 9.11, H 10.86%.

cis-3-[4-(1,1-dimethyldecyl)^2-hydroxyphenyl]-cyclohexanol (2.02 g, 98%) from cis-3-[2-benzyloxy-4-(1,1-dimethyldecyl)phenyl ]-cyclohexanol (2.6 g, 5.78 mmol).. M.p.: 93-94°C (pentane).

IR: (CHC13) 3636, 3390, 1629 and 1587 cm"1.

MS: m/e 360 (M+), 342, 288, 233 and 215.

Analysis: Calculated for: C24<H>4Q02: C 79.94, H 11.18%

Found: C 80.12, H 11.39%

trans-3-[4-(1,1-dimethyldecyl)-2-hydroxyphenyl]-cyclohexanol (130 mg, 45%) from trans-3-[2-benzyloxy-4-(1,1-dimethyldecyl)-phenyl] cyclohexanol (360 mg, 0.80 mmol). Melting point: 76-77°C. IR: (CHC13) 3636, 3425, 1631, 1616 and 1580 cm"<1>.

MS:, m/e 360 (M+), 342, 233 and 215.

Analysis: Calculated, for c24H4o°2: C 79'94'H 1:L'18%

Found: C 80.20, H 11.27%.

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). Melting point: 85-86°C.

IR: (CHC13) 3636, 3390, 1634 and 1592 cm"<1>.

MS: m/e 374 (M<+>), 356, 233 and 215.

Analysis: Calculated for C25H42°2: C 80'15'H H,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). Melting point: 73-74°C..

IR: (CHC13) 3636, 3413, 1637 and 1585 cm"<1>.'

MS: m/e 374 (M+),

Analysis: Calculated for C25H42°2: c 8°/15'H 11/30%.

Found: C 80.11, H 11.16%.

cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-cyclooctanol (0.793 g, 73%) from cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl] -cyclooctanol (1.36 g, 3.11 mmol).

Melting point: 89-90°C (from pentane).

MS: m/e 346 (M<+>), 328, 261 and 243.

Analysis: Calculated for <C>23H38°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%) from trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)- phenyl]-cyclooctanol (4.0 g, 9.17 mmol).

Melting point: 76-77°C (from pentane).

MS: m/e 346 (M<+>), 328, 261 and 243.

Analysis: Calculated for C23H38°2<:>c 79'7i' H 11.05%.

Found: C 79.81, H 10.86%.

Example 5

3-[ 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl]- cyclohex- 2- enone

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 mg (14.4 mmol) of 70-80 mesh magnesium metal. The resulting mixture was refluxed 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. The reaction mixture was stirred for 30 minutes at 0°C and then quenched by adding 20 ml of IN sulfuric acid and heated on a steam bath in

30 minutes. It was then cooled and added to 200 ml of ether and 200 ml of water. The organic extract was washed successively with 200 ml of saturated sodium bicarbonate and 200 ml of saturated sodium chloride, then dried over magnesium sulfate and evaporated to an oil. The crude product was purified by column chromatography on 170 g silica gel eluting with ether:pentane (1:1) to give 2.5 g (54%)

of the title compound as an oil.

IR: (CHC13) 1667, 1610 and 1558 cm"<1>.

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

In the same way was

3 - [ 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl] - 4- methylcyclohex- 2.- enone

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-methyloctane.

IR: (CHC13) 1667, 1613 and 1565 cm"<1>.

MS: m/e .418 (M+) , 400, 385, 333, 327, 299,. 291 and 91.

Example 6

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

To a solution at -10 to -5°C of 4.17 mmol of dimethyl copper lithium in 10 ml of tetrahydrofuran was slowly added 5.60 g (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 was then added to 100 ml of saturated ammonium chloride and 100 ml of ether. After stirring for 10 minutes, the quenched reaction mixture was extracted with 200 ml of ether. The ether extract was washed with 100 ml saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil was purified by preparative layer chromatography on three 20 cm x 20 cm x 20 mm silica gel plates and eluted with 2:1 cyclohexane:ether, and this

gave 282 mg (48%) (higher Rf) of the title compound as an oil,

and 211 mg (36%) (lower Rf) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1-methylcyclohex-2-en-1-ol as an oil.

Title connection:

IR: (CHC13) 1704, 1610, 1565 cm"<1>

MS: m/e 420 (M<+>), 405, 377, 335 and 329.

3-[2-Benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1-methyl-cyclohex-2-en-1-ol: IR: (CHCl 3 ) 3571, 3401, 1661, 1608 and 1585 cm"1 .

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

Example 7

3- [ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]- cyclohex- 2- enone A mixture of 400 mg (0.988 mmol) 3-[2-benzyloxy-4-(1, 1-dimethylheptyl) phenyl] cyclohex-2-enone and 20 mg of 5% palladium-on-carbon were stirred under an atmosphere of hydrogen pressure for 30 minutes. The reaction mixture was then filtered through diatomaceous earth with ether and the filtrate was 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<+>), 299 and 229.

Analysis: Calculated for c2iH3o°2: C 80'21'H 9.62%-

Found: C 80.23, H 9.461.

Example 8

3-(2,4-dihydroxyphenyl)cyclohexanone-methyl ketal

To a solution at 0°C of 7.0 g (33.0 mmol) of 3-(2,4-dihydroxyphenyl)-cyclohexanone in 100 ml of methanol and 15 ml of trimethyl orthoformate was added 10 drops of concentrated sulfuric acid. The reaction mixture was then stirred for 3 hours without cooling, the temperature was allowed to rise to room temperature, and the reaction mixture was then quenched by adding an excess of solid sodium bicarbonate. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in 200 ml of water and 250 ml of ether. The ether extract was washed once with 150 ml of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated. The oily residue was crystallized from ether-pentane to give 5.74 g (77%) of the title compound, m.p. 129-130°C.

IR: (KBr) 3289, 1629, 1613 and 1597 cm"<1.>

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

Analysis: Calculated for C13H16°3: 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

A mixture of 5.03 g (22.8 mmol) 3-(2,4-dihydroxyphenyl)-cyclohexanone-methyl ketal, 10.1 g (73.2 mmol) anhydrous potassium carbonate and 6.12 g (26.8 mmol) 4-phenylbutyl methanesulfonate in 25 ml of N,N-dimethylformamide was heated at 85-100°C for 4 hours. The reaction mixture was cooled and added to 200 ml of water and 200 ml of ether. The ether extract was washed twice with 200 ml of water, dried over magnesium sulfate and evaporated to an oil. The oil was purified by means of column chromatography on 400 g of silica gel, and

eluted with 2:1 pentane:ether to give 7.4 g (92%) of the title compound as an oil.

IR: (CHC13) 1623 and 1590 cm"<1>

MS: m/e 352 (M<+>) and 91.

Analysis: Calculated for Co_.Hoo0o: C 78.37, H 8.01%

Found: C 78.34, H 8.07%.

The following compounds were prepared in a similar manner, but using the appropriate mesylate derivative instead of 4-phenylbutyl methanesulfonate: 3-[2-hydroxy-4-^(2-heptyloxy)phenyl]-cyclohexanone-methyl ketal (6 .13 g, 75%) as an oil from 5.7 g (25.9 mmol) of 3-(2,4-dihydroxyphenyl)cyclohexanone-methyl ketal and (2-heptyl)methanesulfonate (6.2 g,

32.3 mmol).

IR: (CHC13) 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: (CHC13) 1639 and 1600 cm"<1>.

MS: m/e 332 (M<+>), 300, 289, 272 and 220.

3-[2-hydroxy-4-(2-nonyloxy)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: (CHC13) 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: (CHC13) 1639 and 1603 cm"<1>.

MS: m/e 352 (M<+>), 320, 220 and 188.

3-[ 2- hydroxy- 4-( 2-( 6- phenyl) hexyloxy) phenyl] cyclohexanone methyl ketal (5.3 g, 54%) as an oil from 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: (CHC13) 1634 and 1597 cm"<1>.

MS: m/e 380.2342(<M+,><C>25<H>32°3)'<2>20.1088, 188.0986 and 177.0550.

Example 10

3-[ 2- hydroxy- 4-( 4- phenylbutyloxy) phenyl] cyclohexanone

A mixture of 6.8 g (19.3 mmol) of 3-[2-hydroxy-4-(4-phenylbutyloxy)phenyl]cyclohexanone-methyl ketal, 100 ml. 2N hydrochloric acid and 60 ml of dioxane were heated at reflux for 1 hour. The reaction mixture was cooled and added to 300 ml of ether and 500 ml of saturated sodium chloride. The ether extract was washed once with 500 ml of saturated sodium chloride and once with 500 ml of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to an oil. The oil was purified by column chromatography on 400 g of silica gel eluting with 1:1 ether:cyclohexane to give 6.4 g (98%) of the title compound as an oil.

IR: (CHC13) 3571, 3333, 1718 (w), 1626 and 1595 cm"1.

MS: m/e 388 (M<+>), 320,■310, 295, 268 and 91.

The following compounds were prepared in a similar manner from the appropriate ketals of Example 9:

3- [ 4- ( 2- heptyloxy).- 2- hydroxypheny 1] cyclohexanone

(4.7 g, 82%) as an oil from 6.0 g (18.8 mmol) of the corresponding methyl ketal.

IR: . (CHC13) 3636, 3390, 1724 (weak), 1639 and 1600 cm"<1>.

MS: m/e 304 (M<+>), 206, 188, 171, 163 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: (CHC13) 3636, 3378, 1721 (weak), 1631 and 1595 cm"<1>.

MS: m/e 318 (M<+>), 206, 188, 178 and 163.

3-[ 4-( 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: (CHC13) 3584, 3367, 1709 (weak), 1626 and 1587 cm"<1>.

MS: m/e. 332 (M<+>), 206, 187 and 171.

3-[4-(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: (CHC13) 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)hexyloxy)-2-hydroxyphenyl]cyclohexanone (4.45 g, 89%) as an oil from 5.2 g (13.6 mmol) of the corresponding methyl ketal.

IR: (CHC13) 3636, 3390, 1718, 1637 and 1600 cm"<1>.

MS: m/e 366 (M<+>), 206, 188 and 91.

Oak sample 11

cis- 3- [ 2- hydroxy- 4-( 4- phenylbutyloxy) phenyl] cyclohexanol and the trans isomer

To a solution at -18°C of 4.8 g (14.2 mmol) of 3-[2-hydroxy-4-(4-phenylbutyloxy)phenyl]cyclohexanone in 25 ml of methanol was added 0.539 g (14.2 mmol ) sodium borohydride. The reaction mixture was stirred for 40 minutes and then added to 250 ml of saturated sodium chloride and 250 ml of ether. The ether extract was washed once with 150 ml saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil was purified by column chromatography on 400 g silica gel eluting with 2.5:1 dichloromethane:ether to give 3.37 g (70%) of the cis isomer, crystallized from cyclohexane, and 0.68 g (14 %)

of the trans isomer, crystallized from cyclohexane, and 0.69 g (14%) of mixed material.

cis isomer:

Melting point: 79-80°C.

PMR:. TMS 2.70 (m, benzylic methylene), 3.26 (m, benzylic methine), 3.93 (bt, ]=6Hz, -0CH2~) , 4.28 (m, OH, carbinol methine, with D20 4.25, M, carbinol-methine), 6.42 (dd, J=8 and 2Hz, ArH), 6.45

(d, J=2Hz, ArH), 7.03 (d, J=8Hz, ArH) and 7.22 (s, PhH).

IR: (CHC13) 3610, 3333, 1631 and 1603 cm"<1>.

MS: m/e 340 (M<+>), 322, 190 and 91

Analysis: Calculated for C„„H„o0o: C 77.61, H 8.29%

2.2 2o J

Found: C 77.46, H 8.25%.

trans isomer:

Melting point: 112-114°C

PMR: Sqq^ 2.68 (m, benzylic methylene), 3.80 (m, OH, -0CH2~, carbinol-methine, with D2O 6 3.63, m, carbinol-methine and 6 3.90,

bt, J=6Hz, -0CH2-), 6.32 (bs, overlaps 6 6.40), 6.40 (dd,

J=8 and 2Hz, ArH), 7.00 (d, J=8Hz, ArH) and 7.20 (s, PhH).

IR: (CHC13) 3610, 3390, 1631 and 1595 cm"<1>.

MS: m/e 340 (M<+>), 322, 190 and 91.

Analysis: Calculated for C22H2g03: C 77.61, H 8.29%

Found: C 77.40, H 8.31%.

In a similar manner, the following compounds were prepared: cis-3-[4-(2-heptyloxy)-2-hydroxyphenyl] cyclohexanol and the trans isomer as oils from 3-[4-(2-heptyloxy)-2-hydroxyphenyl] cyclohexanone (5.2 g, 13.6 mmol). In the order of elution from silica gel, 854 mg (36%) of the cis-3 and 107 mg (3%) of the trans-3 isomers were obtained.

cis :

IR: (CHC13) 3597, 3333, 1629 and 1600 cm"<1>.

MS: m/e 306 (M<+>), 208, 190, 173 and 162.

TMS

PMR: <5CDC^ 0.82 (m, methyl), 2.8 (m, benzylic methine), 3.7

(m, carbinol methine and OH), 4.1 (m, methine), 6.38 (m, ArH) and 6.93 (d, J=8Hz, ArH).

trans :■

MS: m/e 306 (M<+>), 208 and 190

PMR: Sqdq! .0.82 (m, methyl), 3.25 (m, benzylic methine), 4.3

(m, carbinol methine and OH), 6.33 (m, ArH) and 6.94 (d, J=8Hz, ArH).

cis-3-[4-(2-octyloxy)-2-hydroxyphenyl]cyclohexanol and the trans isomer from 3-[4-(2-octyloxy)-2-hydroxyphenyl]cyclohexanone (2.92 g, .9.18 mmol). By elution sequence

from silica gel, 1.58 g (54%) of the cis-3 and 0.57 g (19%) of the trans-3 isomers were obtained.

cis:

IR: (CHC13) 3663, 3390, 1637 and 1608 cm"<1>.

MS: m/e 320 (M<+>), 319, 208 and 190.

TMS

PMR: «Sqj^-l 0.8.3 (m, methyl), 2.81 (m, benzylic methine), 3.8

(m, carbinol methine), 4.1 (m, side chain methine and OH), 6.35 (m, ArH) and 6.96. (d, J=8Hz, ArH).

trans:

IR: (CHC13) 3636, 3390, 1634 and 1595 cm"<1>.

MS: m/e 320 (M<+>), 235, 208, 190 and 173

TMS

PMR: Scqq-l 0.82 (m, methyl), 3.25 (m, benzylic methine), 4.1^4.9 (m, carbinol and side chain methines and OH), 6.35 (m, ArH) and 6.96 (•d, J=8Hz, ArH) .

cis-3-[4-(2-nonyloxy)-2-hydroxyphenyl l j-cyclohexanol and the trans-isomer from 3-[4-(2-nonyloxy)-2-hydroxyphenyl]-cyclohexanone (3.15.g, 19 .48 mmol). In order of elution from silica gel, 2.11 g (67%) of the cis-3- and 0.32 g (10%) of the trans-3-isomers are obtained as oils.

cis:

IR: (CHC13) 3663, 3390, 1639 and 1610 cm"<1>.

MS: m/e 334 (M<+>), 316, 208 and 190

TMS

PMR:. <5£dc10.88 (m'metYl) ' 2.85 (m'benzYlic methine), 3.5-4.1 (m, carbinol methine and OH), 4.22 (m, side chain methine), 6 .38 (m, ArH) and 6.97 (d, J=8Hz, ArH).

trans:

IR: (CHC13) 3636, 3413, 1637 and 1592 cm"<1>.

MS:'m/e 334 (M<+>), 316, 208, 206 and 190.

TMS

PMR: Sj^-L 0.88 (m, methyl), 3.23 (m, benzylic methine), 3.9-4.6 (m, carbinol and side chain methines and OH) > 6.36 (m, ArH ) and 6.96 (d, J=8Hz, ArH).

cis-3-[4-(2-(4-phenyl)butyloxy)-2-hydroxyphenyl]cyclohexanol and the trans-isomer from 3-[4-(2-(4-phenyl)butyloxy)-2-hydroxyphenyl]-cyclohexanone (2.9 g, 8.23 mmol). In order of elution from silica gel, 1.29 g (44%) of the c.is-3- and 241 mg (8%) of the trans-3-isomers are obtained.

cis:

Melting point: 96-105°C (from pentane)

IR: (CHC13) 3636, 3390, 1634 and 1608 cm"<1>.

MS: m/e 340 (M<+>), 322, 208, 190, 162, 147, 136 and 91.

TMS

PMR: <5CDC1 1.30 (d, J=6Hz, me ty 1), 3.75 (m, carbinyl methine), 4.23

(m, sidecoil methine), 6.21 (d, J=2Hz, ArH), 6.38 (dd, J=8 and 2Hz, ArH), 6.98 (d, J=8Hz, ArH) and 7 ,20 (s, Ph)..

Analysis: Calculated for<C>22H28°3<:>C 77'61, H 8'29%

Found: C 77.59, H 8.18%.

trans:

IR: (CHC13) 3623, 3390, 1637 and 1595 cm"1.

MS: m/e 340 (M+), 342, 208, 190, 162, 147, 136 and 91.

TMS

PMR: 6CDJ11.30 (d, J=6Hz, methyl), 3.3 (m, benzylic methine), 4.23

(m, carbinol and side chain methine), 6.38 (m, ArH), 6.94 (d, J=8Hz, ArH) and 7.18 (s, Ph).

cis- 3- [ 4- ( 2-.( 6- phenyl) hexyloxy) - 2- hydroxyphenyl) - cyclohexanol and the trans isomer from 3-[4-(2-(6-phenyl) hexyloxy)-2- hydroxyphenyl] -cyclohexanone (3.3 g, 9.01 mmol). In order of elution from silica gel, 1.54 g (46%) of the cis-3 and 274 mg (8%) of the trans-3 isomers are obtained.

cis:

Melting point: 99-113°C (from pentane)

IR: (CHC13) 3636, 3367, 1631 and 1592 cm"<1>.

MS: m/e 368 (M<+>), 350, 208, 190, 162, 147, 136 and 91.

TMS

PMR: 6£Dqil 1.30 (d, J=6Hz, methyl), 3.6 (m, carbinol-methine), 4.2

(m, side chain methine), 6.37 (m,. ArH), 6.98 (d, J=8Hz, ArH) and 7.18

(pp., Ph.D.).

Analysis: Calculated for<C>24H32<0>3<:>Q' 78.22, H 8.75%

Found: C 78.05, H 8.56%.

trans:

IR: (CHC13) 3636, 3413, 1634 and 1597 cm"1.

MS: m/e 368 (M<+>), 350, 208, 190, 162, 147, 136 and 91.

TMS

PMR: <$CDC-]_ 1.25 (d, J=6Hz, methyl), 4.21 (m, carbinol and side chain methine), ^.37 (m, ArH), 6.95 (d, J= 8Hz, ArH) and.7,15. (pp., Ph.D.).

Example 12

3-[ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]- 2- cyclohexenol

To a solution at -30°C of 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 1M' (in toluene) diisobutyl aluminum hydride solution. The reaction mixture was stirred for a further 30 minutes at -30°C and was then added to 1.5 liters of water. The quenched solution was extracted with three 400 ml portions of ether and the combined extracts were washed twice with 125 ml of saturated sodium chloride and dried over magnesium sulfate after evaporation. the crude product was purified by column chromatography. on 50 g of florial and eluted with ether, and this gave an oil. Crystallization of the oil from pentane gave 256 mg (25%) of the title product. Melting point: 87-88°C.

MS: m/e 316 (M<+>), 298, 231 and 213.

Analysis: Calculated for C21H32°2<:>C 79.70, H 10'19%

Found: C 79.68, H 9.96%.

Example 13

3-[ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]^ 3- cyclohexenone-et ylene ketal

A solution of 500 mg (1.59 mmol) 3-[4-(1,1-dimethylheptyl)-2^-hydroxyphenyl]-2-cyclohexenone, 7.8 g (127 mmol) ethylene glycol, 375 mg (3.18 mmol) of hydroquinone and 50 mg (0.263 mmol) of p-toluenesulfonic acid monohydrate in 50 mL of benzene were heated at reflux for 12 hours using a Dean-Stark condenser filled with 3Å molecular sieves. The reaction mixture was cooled and added to 500 ml of saturated sodium bicarbonate. The quenched mixture was extracted with three 150 ml portions of ether, dried over magnesium sulfate and evaporated to a solid. This solid was purified by column chromatography on 50 g silica gel eluting with 50% ether-petroleum ether to give (after crystallization from pentane) 393 mg (69%) of the title product.

Melting point: 97-98°C.

MS: m/e 358 (M<+>), 297, 273, 245 and 229.

Analysis: Calculated for<C>23<H>34°3<:>c 77.05, H 9.56%

Found: C 76.98, H 9.42%.

Example 14

3-[ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]- 4- methylcyclohex- 3- enone

A mixture of 4.08 g (0.1 mol) of 3-[4-(1,1-dimethylhepty1)-2-hydroxyphenyl]-4-methyl-cyclohex-3-enone-ethylene ketal, 50 ml of 2N oxalic acid and. 50 ml of methanol was stirred at 25°C for 6 hours. The reaction mixture was added to 500 ml of water and 250 ml of ether. The ether extract was washed once with 250 ml of saturated sodium bicarbonate and once with 250 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on 400 g of silica gel and eluted with 50% ether-pentane, and this gave the title

the connection.

Example 15

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

Example 16

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

To a solution at -18°C of 70.0 g (0.20 mol) 3-[4-(1,1-dimethylhepty1)-2-hydroxyphenyl]-cyclohex-2-enone in 200 ml methanol is added 7 .6 g (0.20 mol) of sodium borohydride. The reaction mixture is stirred for 30 minutes and then added to 1 liter of saturated sodium chloride and 1 liter of ether. The ether extract is washed once with 500 ml of saturated sodium chloride, dried over magnesium sulphate and evaporated. The residue is purified by column chromatography on 500 g

silica gel and eluted with 50% ether-pentane, and this gives the title compound.

Example 17

3-[ 2- acetoxy- 4-( 1, 1- dimethylheptyl) phenyl] cyclohexanone

A solution of 2.0 g of 3-[2-hydroxy-4-(1,1-dimethylheptyl)-■ phenyl]cyclohexanone in 15 ml of pyridine is treated at 10°C with 10 ml of acetic anhydride and the mixture is stirred for 18 hours under nitrogen. It is then poured onto ice/water and acidified with diluted hydrochloric acid.

The acidified mixture is extracted with ethyl acetate (2 x 100 ml),

the extracts are combined, washed with brine and dried (MgSO 4 ).

Evaporation under reduced pressure gives the title product as an oil.

Example 18

1-a cetoxy-3-[2-acetoxy-4-(2-phenyl)pentyloxy). phenyl] cyclohexane To a solution of 2.0 g of 3-[2-hydroxy-4-(2-(5-phenyl)-pentyloxy)phenyl]cyclohexanol in 20 ml of pyridine at 10°C is added

20 ml of acetic anhydride and the mixture is stirred under nitrogen i

18 hours. It is then poured onto ice water and acidified with diluted

hydrochloric acid. The product is isolated by extraction with ethyl acetate (2 x 100 ml). The combined extracts are washed with brine, dried (MgSO 4 ) and evaporated to give the diacety1 derivative as an oil.

Example 19

3-[ 2-( 4- morpholinobutyryloxy)- 4-( 1, 1- dimethylheptyl) phenyl] - cyclohexanol

To a solution of 3-[2-hydroxy-4-1,1- dimethylheptyl)phenyl]cyclohexanone (0.300 g, 1.0 mmol) in methylene chloride (25 mL) at room temperature. The mixture is stirred for 18 hours and then cooled to 0°C and filtered. Evaporation of the filtrate gives the title product as its hydrochloride salt.

Example 20

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

To 50% sodium hydride/mineral oil (2.28 g, 48 mmol)

(washed with 3 x 25 ml portions of pentane) 90 ml of dry dimethylsulfoxide is added and the mixture is heated at 70°C for 3/4 hour. 17.79 g (51 mmol) of methyltriphenylphosphonium bromide are then added in one portion. The yellow solution is stirred for 30 minutes at 25°C and then 2.26 g (6.3 mmol) of 3-[2-acetoxy-4-(1,1-dimethylhepty1)-phenyl]-cyclohexanone dissolved in 190 ml of dimethylsulfoxide is added , all at once, and the mixture is heated at 63-65°C for an additional 1 1/2 hours. The reaction mixture is then poured into 150 ml of ice water and 25 g of NaHCO 3 , and extracted with 3 x 50 ml of ether. The combined ether extracts are dried over MgSO 4 , decolorized with charcoal and filtered through a pad of silica gel to give a colorless oil which. chromatographed on 75 g of silica gel (elution solvent is cyclohexane). A non-polar impurity is eluted first, then the polarity of the solvent is increased to ether/cyclohexane (1:10) and this gives the title product as a colorless oil.

Example 21

3- [ 2- hydroxy- 4-( 1, 1- dimethylheptyl) phenyl]- 1- hydroxymethyl- cyclohexane

A solution of 1.03 g of 3-[2-hydroxy-4-(1,1-dimethylheptyl)- . phenyl]-1-methylenecyclohexane (3 mmol) dissolved in 25 ml of dry tetrahydrofuran is cooled to 0°C in an ice/water bath. Borane-tetrahydrofuran complex (4.5 ml, 4.5 mmol, IM solution) is added, and the colorless solution is allowed to stir overnight at ambient temperature (18 hours). The mixture is cooled in ice and 8 ml of water added to decompose excess reagent. It is stirred for 15 minutes and then 3 ml (9 mmol) of 3N sodium acetate are added, followed by 3 ml of 30% hydrogen peroxide. It is stirred at 0°C for 15 minutes and then allowed to warm to room temperature and stir overnight (2 4 hours). The reaction mixture is poured onto 100 ml of ice/water and then extracted with 3 x 50 ml of ether. The combined ether extracts are washed with sodium sulphite until the KI test shows negative for starch, dried over MgSO4 and evaporated to dryness, and this gives a pale yellow oil which is chromatographed on 50 g of silica gel (elution solvent is cyclohexane/ether 3:1). to give the product as a colorless foam.

Example 22

trans- 4-[ 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl- 3- buten- 2- one

A solution of 2-benzyloxy-4-(1,1-dimethylhepty1)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. One more portion of ylide (15.5 g, 0.047 mol) was added and heating at reflux was continued for 24 hours. The reaction mixture was cooled, evaporated and diluted with ether. The resulting precipitate of triphenylphosphine oxide was separated by filtration. The crude oil was purified by column chromatography on 1.5 kg silica gel eluting with 20% ether-hexane to give 53.9 g (74%) of the title compound as an oil.

IR: (CHC13) 1681, 1621 and 1575 cm"<1>.

MS: (m/e) 37.8 (M+), 364, 337, 293, 271, 251 and 91.

Example 2 3

5-[ 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl]- 4- carbomethoxy-1, 3- cyclohexanedione

To a solution of sodium methoxide (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, and

was then cooled and evaporated under reduced pressure. The residue was diluted with ether and saturated sodium chloride and acidified with 1N hydrochloric acid. The ether extract was washed twice with saturated sodium chloride (500 mL), dried over magnesium sulfate and evaporated to give 4.71 g (99%) of the title compound.

Melting point: 108-109°C (from petroleum ether-ether).

IR: (CHC13) 1742, 1709, 1612 and 1577.cm"<1>.

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

Analysis: Calculated for C30H3<g0>5<:>C 75.28, H 8.00%

Found: C 75.05, H 7.93%.

Example 24

5-[ 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl]- 1, 3- cyclohexanedione

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 hours. The mixture was cooled in an ice bath and

. acidified with concentrated hydrochloric acid. This mixture was heated

for 1 hour at 10Q°C, cooled to 0°C and then neutralized with sodium bicarbonate. The resulting mixture was added to saturated sodium bicarbonate and ether. The ether extract was dried over magnesium sulfate and evaporated to an oil. Purification of this oil by column chromatography on 1 kg of silica gel and eluting with 10% acetone-ether gave 10.9 g (60%) of the title compound.

Melting point: 102-103°C (from pentane ether).

IR: (CHC13) 3636-2222 (broad), 1739, 1712, 1613 (broad) and 1577

(protrusion)

MS: m/e 420 (M<+>), 335, 329 and 91.

Analysis: Calculated for C28H36<C>)3<:>C 79'96'H 8'63%

Found: C 79.87, H 8.54%.

Example 25

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

A solution of 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1,3-cyclohexadione (5.0 g, 11.9 mmol) and p-toluenesulfonic acid

(200 mg) in methanol (250 mL) in a flask connected to a Soxhlet condenser containing 3Å molecular sieves was heated at reflux for 30 min. The reaction mixture was cooled, concentrated under reduced pressure and the residue was diluted with saturated sodium bicarbonate and ether. The ether extract was washed successively with saturated sodium bicarbonate and saturated sodium chloride,

was dried over magnesium sulfate and evaporated to 5.15 g (99%) of the title compound as an oil.

IR: (CHC13) 1644, 1612, 1503, 1460 and 1379 cm"<1>.

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

Example 26

5-[ 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl]- 2- cyclohexen- 1- one

To a solution at 0°C of the title compound from Example 25, 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-methoxy-2-cyclohexen-1-one (500 mg, 1.15 mmol) in ether (20 mL)

lithium aluminum hydride (20 mg, 0.53 mmol) was added. The reaction mixture was stirred for 30 minutes at 0°C, acidified with 1N hydrochloric acid and stirred for 2 hours at room temperature. The ether phase was separated, washed successively with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate and evaporated.

The crude oil was purified by column chromatography on

100 g of silica gel and eluted with 50% ether-pentane to give 353 mg (76%) of the title compound as an oil.

IR: (CHC13) 1681, 1672, 1613, 1575 and 1479 cm"1.

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

Example 2 7

5-[ 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl]- 3- methyl- 2- cyclohexene- l- or To a solution at 0°C of methylmagnesium iodide (11 ml of 2.9M 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 heated and stirred at room temperature for 2 hours followed by the addition of 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 and saturated sodium chloride, dried over magnesium sulfate and evaporated. The crude product was purified by column chromatography on 100 g silica gel with 25% ether-pentane as eluent, and this gave 3.08 g (93%) of the title compound.

Melting point: 60-61°C. (from pentane).

MS: (m/e) 418 (M+), 333, 327 and 91

In a similar manner, the following compounds were prepared from appropriate reactants: 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-ethyl-2-cyclohexen-1-one (2.83 g, 82 %) as an oil from 5-[2-benzyloxy-4-(1,1-dimethyl-heptyl)phenyl]-3-methoxy-2-cyclohexen-1-one (3.46 g, 7.97 mmol) and 10.8 mL of 2.94 M ethylmagnesium bromide (in ether).

IR: (CHC13) 1698, 1666, 1623 and 1582 cm"<1>.

MS: (m/e) 432 (M<+>), 341 and 91.

5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-n-propyl-2-cyclohexen-1-one.

(3.48 g, 85%) as an oil from 5-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]-3-methoxy-2-cyclohexen-1-one (4.00 g, 9.21 mmol) and n-propyl magnesium bromide (36.8 mmol).

IR: (CHC13) 1661, 1631, 1612 and 1575 cm"<1>.

MS: (m/e) 446 (M<+>), 355 and 91.

5-[2-benzyloxy-4-(1,1-dimethylhepty1)phenyl]-3-n-hexy1-2-cyclohexen-1-one

(4.11 g, 92%) as an oil from 5-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]-3-methoxy-2-cyclohexen-1-one (4.00 g, 9.21 mmol) and 7.37 ml of 2.5 M n-hexylmagnesium bromide (in ether).

IR: (CHC13) 1678, 1661, 1633, 1618 and 1582 cm"<1>.

MS: (m/e) 488 (M<+>), 403, 397 and 91.

Example 28

cis~ 3~ [ 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl]- 5- methyl- cyclohexanone

A mixture of 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-methyl-2-cyclohexen-1-one (1.00 g, 2.39 mmol) and 500 mg of 5% palladium-on-carbon and 50% water was stirred under a hydrogen atmosphere for 1 hour. A further portion of 500 mg of catalyst was added and stirring 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. The residue was purified by column chromatography on 140 g silica gel with 10% ether-petroleum ether as eluent to give 323 mg (32%) of the title compound as an oil.

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

Example 29

cis- 4- [ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]- 5- methyl- cyclohexanone

A mixture of 5-[2-benzyloxy-4-(1,1-dimethyl-heptyl)-phenyl]-3-methyl-2-cyclohexen-1-one (3.83 g, 6.77 mmol), 1 , 5 g

5% palladium-on-carbon and 50% water and sodium bicarbonate (2.8 g) in methanol (30 mL) were stirred under a hydrogen atmosphere for 45 minutes. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated under reduced pressure. The residue was dissolved in ether, . dried with MgSO^ and evaporated. Crystallization of the residue with pentane gave 1.15 g (52%) of the title compound.

Melting point: 95-98°C.

Analysis: Calculated for C22H34°2: C 79'95'H 10'37%

Found: C 80.22, H 10.28%.

Following the above procedure, the compounds listed below were prepared from the appropriate reactants from Examples 2, 7 and 28.

cis- 3- [ 4-( 1,1- dimethylheptyl)-2- hydroxyphenyl]- 5- ethyl1- cyclohexanone (1.34 g, 60%) from 5-[2-benzyloxy-4-(1,1-dimethylheptyl) )phenyl]-3-ethyl-2-cyclohexen-1-one (2.83 g, 6.55 mmol).

Melting point: 106-107°C.

IR: (CHC13) 3597, 3333, 1709, 1626 and 1585 cm"<1>.

MS: (m/e) 344 (M+), 326, 315, 297, 273 and 259.

Analysis: Calculated for C23H3602: 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%) from 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl ]-3-propy1-2-cyclohexen-1-one (3.40 g, 7.62 mmol).

Melting point: 86.5-90.5°C.

IR: (CHC13) 3533, 3289, 1700, 1618 and 1577 cm"<1>.

MS: (m/e) 358 (M<+>), 340, 315, 297 and 273.

Analysis: Calculated for C24H38°2: C 80'39'H 10.68%

Found: C 80.16, H 10.57%.

cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-5-hexylcyclohexanone (3.06 g, 93%) from 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl ]-3-hexyl-2-cyclohexen-1-one (4.00 g, 8.2 mmol).

Melting point: 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 C27H44°2<:>C 80'94'H 11.07%

Found: C 80.97, H 10.94%.

Example 30

trans- 3-[ 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl]- 5- methylcyclohexanone

To a solution at 0°C of 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 sat. aqueous ammonium chloride (300 ml). The quenched reaction mixture was extracted with three 50 mL portions of ether and the combined ether extracts were washed with water and saturated sodium chloride, dried over magnesium sulfate and evaporated to give 475 mg (92%) of the title compound as an oil.

IR: (CHC13) 1704, 1613 and 1577 cm"<1>.

MS: (m/e) 420 (M<+>), 402, 363, 335 and 329.

Example 31

trans- 3- [ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]- 5- methyl- cyclohexanone

A mixture of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-5-methylcyclohexanone (175 mg, 0.417 mmol) and 175 mg of 5% palladium-on-carbon and 50% water in methanol (8 ml) was stirred under a hydrogen atmosphere until hydrogen absorption ceased. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated under reduced pressure. Crystallization of the residue in pentane gave 89 mg (64%) of the title compound.

Melting point: 99-102°C.

MS: m/e 330 (M<+>), 312, 273 and 245.

Example 32

cis- 3-[ 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl]- trans- 5- methyl1-cyclohexanol and the trans, cis- isomer

To a solution at -78°C of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-5-methylcyclohexanone (300 mg, 10.714 mmol) in methanol (15 mL) - tetrahydrofuran (5 ml) sodium borohydride (216 mg, 5.68 mmol) was added in L over a period of 1 hour. The reaction mixture was stirred for 2 more hours at -78°C, was warmed to room temperature and evaporated in vacuo. The residue was acidified with dilute hydrochloric acid and extracted with ether. The extract was dried over magnesium sulfate and evaporated, and the residue was purified by column chromatography on 50 g silica gel with 30% ether-pentane as eluent, and this gave, in the order of elution, 232 mg (77%) of the trans,cis isomer and 45.9 mg ( 15%) of the cis,trans isomer.

trans, cis:

MS: (m/e) 422 (M<+>), 337, 314, 229 and 91.

TMS

PMR: <SCoq-l 0.86 (n, terminal methyl), 1.05 (d, J=7Hz, C-5 methyl), 1.26 (s, gem dimethyl), 3.70 (n, benzylic methine ), 4.05

(n, carbinol-methine), 5.13 (s, benzylic methylene), 6.8-7.0 (n, ArH) and 7.1-7.6 (n, ArH and Ph).

cis,trans:

MS: (m/e) 422 (M<+>), 337, 314, 229, 206 and 91.

TMS

PMR: &^ qq± 0.9 (n, terminal methyl), 1.05 (d, J=7Hz, C-5 methyl), 3.1-4.3 (n<3>benzylic and carbinol methines) , 5.13 (s, benzylic methylene), 5.40 (s, OH) and 6.8-7.7 (n, Ph and ArH).

Example 33

cis- 3- [ 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl]- cis- 5- methyl1-cyclohexanol and trans, the trans isomer

To a solution at -78°C of 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 it was then added to ether and saturated sodium chloride. The ether extract was dried over magnesium sulfate. and evaporated under reduced pressure. The residue was purified by preparative layer chromatography on five silica gel plates (20 cm x 20 cm x 0.5 mm) with

50% ether-pentane as eluent, and this gave 36 mg (16%)

of the trans,trans isomer (R^0.25, silica gel, 33% ether-petroleum ether) and 168 mg (R^0.17, silica gel, 33% ether-petroleum ether) of the cis,cis isomer.

Example 34

cis- 3-[ 4- 1, 1- dimethylheptyl)- 2- hydroxyphenyl- cis- 5- methylcyclohexanol To a solution at -78°C of cis-3-[4-(1, 1-dimethylheptyl)-2-hydroxyphenyl ]-5-methylcyclohexanoh (896 mg, 2.13 mmol)

in methanol (30 ml) was 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 ether and saturated sodium chloride. The ether extract was dried over magnesium sulfate and evaporated to give an oil. Crystallization from pentane gave 589 mg (65%) of the title compound: mp: 113-114°C.

IR: (CHC13) 3636, 3390, 1631 and 1592 cm"<1>.

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

Analysis: Calculated for C22H36°2<:>C 79'46'H ^ 0.91%

Found: C 79.79, H 10.62%.

The following compounds were prepared from appropriate reactants in a similar manner: cis-3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]-cis-5-ethyl-cyclohexanol (0.74 g, 74%) from cis -3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-5-ethylcyclohexanone (1.00 g, 2.30 mmol).

Melting point: 110-111°C.

IR: - (CHC13) 3636, 3367, 1631 and 1587 cm"<1>.

Analysis: Calculated for C23H38<0>2<:>C 79'71'H 11.05%

Found: C 79.41, H 10.71%.

cis- 3-[ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]- cis- 5- n- propy1-cyclohexanol

(0.954 g, 71%) from cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-5-n-propylcyclohexanone (1.34 g, 3.74 mmol).

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

IR: (CHC13) 3636, 3378, 1626 and 1587 cm"<1>.

MS: (m/e) 360 (M<+>), 342, 275, 257 and 161.

Analysis: Calculated for c24H4o°2: C 79.94, H 11.18%

Found: C 79.88, H 11.22%.

cis-3-[4-(1,1-dimethylhepty1)-2-hydroxyphenyl]-cis-5-n-hexyl-cyclohexanol.

after purification on 120 g of silica gel eluted with 50% ether-pentane, a quantitative yield as an oil containing traces of the trans,trans isomer, cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-5 -n-hexylcyclohexanone (1.20 g, 3.00 mmol).

IR: (CHC13) 3623, 3355, 1626. and 1585 cm"<1>.

MS: (m/e) 402 (M<+>), 384, 317 and 299.

Example 35

trans- 3-[ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]- cis- 5- methyl 1-cyclohexanol

A mixture of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cis-5-methylcyclohexanol (220 mg, 0.521 mmol) and 220 mg of 5% palladium-on-carbon and 50 % water in methanol (8 mL) was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated. Crystallization of the residue with petroleum ether gave 91 mg (53%) of the title compound.

Melting point: 111-112°C

IR: (CHC13) 3571, 3333, 1629 and 1572 cm"<1>.

MS: (m/e) 332 (M<+>), 314, 246 and 229.

Similarly, the following compounds were prepared in the same manner from appropriate reactants: cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-trans-5-methylcyclohexanol

(20.0 mg, 56%) as an oil from cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-5-methylcyclohexanol (45 mg, 0.107 mmol) as a oil.

Strong solution MS: (m/e) 332.2698 (<M+,>C22H36°2)' 314'2635' 247.1657 and 229.1600.

trans- 3-[ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]- trans- 5- methylcyclohexanol

(28 mg quantitative yield) from trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-5-methylcyclohexanol (36 mg, 0.0853 mmol) gives the product as an oil.

R^ = 0.35 (silica gel, 50% ether-pentane).

cis-3-[4-( 1, 1- dimethylheptyl)- 2- hydroxypheny1]- cis- 5- methyl1-cyclohexanol

in quantitative yield from cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-cis-5-methylcyclohexanol (168 mg, 0.398 mmol).

It was identical to the product from Example 34.

Example 36

trans-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-cis-4-(2-propenyl)-cyclohexanol.

A solution of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]-cis-4-(2-propenyl)cyclohexanol (900 mg, 2.01 mmol) and 2.74 mL of 2.2M 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 an additional 2 days. The reaction mixture was added to saturated ammonium chloride (250 mL) and the mixture was extracted with ether. The ether extract was dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on 20 g of silica gel with 50% ether-pentane as eluent, and this gave 6 31 mg

(88%) of the title compound:

Melting point: 85-91°C.

IR: (CHC13) 3311, 1639, 1618 and 1567 cm"<1>.

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

Using this method, the following is produced: cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-trans-4-(2-propenyl)-cyclohexanol

(241 mg, 60%) from cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(2-propenyl)-cyclohexanol (500 mg, 1.12 mmol). Melting point: 124-125°C (from pentane).

IR: (CHC13) 3571, 3333, 1642, 1618 and 1580.

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

Analysis: Calculated for <C>24H38°2: C 8o'39'H 10'68%

Found: C 80.52,. H 10.57%.

Example 37

trans- 3-[ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]- 4-( 2- propenyl)-cyclohexanone

To a solution of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-(2-propenyl)cyclohexanol (2.15 g, 6.03 mmol) (mixture of isomers) in dichloromethane (15 ml) was added pyridinium chlorochromate (2.59 g, 12.1 mmol). The reaction mixture was stirred for 2 hours at room temperature and diluted with ether, diatomaceous earth was added and the mixture was filtered through magnesium sulfate.

The evaporated filtrate was purified by column chromatography on 200 g of silica gel with 20% ether-pentane as eluent, and this,

gave 250 mg of the crude title compound. This was further purified by preparative layer 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: (GHC13) 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 C24H36°2<:>C 80.85, H 10.18%

Found: C 80.92, H 9.86%.

Example 38

trans- 3-[ 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl]- 4-( 2- propenyl)- cyclohexanone- ethylene ketal

A mixture of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)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 h with a Dean-Stark trap. The reaction mixture was cooled and added to a mixture of 1N sodium hydroxide (200 mL), ether (100 mL) and pentane (100 mL). The organic extract was washed twice with portions of 200 ml of water and twice with portions of

200 ml of saturated sodium chloride, was dried over magnesium sulfate and evaporated to give a quantitative yield of the title compound.

IR: (CHC13) 1656, 1626 and 1587 cm"<1>.

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

Example 39

trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-5-(2-butenyl).-cyclohexanone

A mixture of trans-3-[2-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). The ether extract was washed with two 200 ml portions of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to give a quantitative yield of the title compound as an oil.

IR: (CHC13) 1715, 1616 and 1575 cm"<1>.

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

R 2 : 0.43 (silica gel, 25% ether-pentane).

In a similar manner was prepared: trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-pentenyl)cyclohexanone in quantitative yield as an oil from trans-3-[2- benzyloxy-4-(1,1-dimethylheptyl)phenyl)-4-(2-pentenyl)-cyclohexanone-ethylene ketal (540 mg, 1.04 mmol).

R 2 : 0.57 (silica gel, 33% ether-pentane).

Oak sample 40

cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-cis-4-methyl1-cyclohexanol and cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4 - methylcyclohexanone

A mixture of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl]-4-methyl-cyclohex-^2-enone and 391 mg of 5% Pd-on-carbon and 50 % water in methanol (15 ml) was stirred under a hydrogen atmosphere until gas absorption had ceased. The reaction mixture was filtered through diatomaceous earth with ethyl acetate and evaporated. The residue was purified by column chromatography on silica gel eluted (200 ml) with 50% ether-hexane to give, in order of elution, 758 mg of a mixture of ketones and 820 mg (53%) of the title alcohol crystallized from cyclohexane. The mixture of ketones was further purified by preparative layer chromatography on five silica gel plates (20 cm x 20 cm x 2 mm) and eluted for 4 h with dichloromethane to give 112 mg (7.2%) of the title ketone as an oil.

Title alcohol:

Melting point: 134-135°C.

IR: (CHC13) 3623, 3333, 1626 and 1585 cm"<1>.

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

Analysis: Calculated for C22H36°2: C 79'46'H 10'92%

Found: C 79.40, H 10.72%.

Title ketcn:

IR: (CHC13) 3623, 3390, 1634 and 1582 cm"<1>.

MS: (m/e) 330 (M<+>), 315, 312, 288, 273, 271 and 245-

Example 41

5-( 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl)- 3- methoxy- 6- methyl 1- 2-cyclohexen- 1- one

To a solution at -78°C of 0.5 mol lithiodiisopropylamide in 500 ml tetrahydrofuran (from 50.5 g, 0.5 mol, diisopropylamine and 417 ml 1.2M n-but<y>lithium in hexane) is added dropwise (30 ml) a solution of 217 g (0.5 mol) of 5'-(2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl)-3-methoxy-2-cyclohexen-1-one in 250 ml of tetrahydrofuran. The reaction mixture is stirred for a further 30 minutes at -78°G, followed by the addition of 179 g (1.0 mol) of hexamethylphosphoramide and 78.1 g (0.55 mol) of methyl iodide. The reaction mixture is allowed to slowly warm to room temperature, it is stirred for 1 hour and quenched by adding 10 ml of water. The reaction mixture is evaporated under reduced pressure to remove the tetrahydrofuran, and it is added to 1 liter of ice water and 1 liter of ether. The ether extract is washed with three portions of 1 liter of water, dried over magnesium sulfate and evaporated to yield the title compound in almost pure form. The title compound is purified by column chromatography on 2 kg of silica gel with ether-pentane as eluent.

Example. 42

5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3,4-dimethyl-2-cyclohexen-1-one

By following the procedure from example 1, 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-methoxy-6-methyl-2-cyclohexen-1-one is reacted by Grignard reaction with methylmagnesium iodide for to provide the title connection.

Debenzylation of the product according to the procedure in example 2 gives the corresponding phenol.

.E xample 4 3

3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4,5-dimethylcyclohexanol

The debenzylated compound from Example 42 is reduced with sodium borohydride according to the procedure in Example 11, and this gives the title compound.

Example 44

3- [ 2- benzyloxy- 4-( 1, 1- dimethylheptyl) phenyl]- 4, 5- dimethylcycloheptanone

To a solution at -78°C of 17.4 g (0.10 mol) of dibromomethane and 21.7 g (0.050 mol) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)-phenyl] -4,5-dimethylcyclohexanone in 100 ml of tetrahydrofuran, a solution of lithium dicyclohexylamide (0.10 mol) in 100 ml of tetrahydrofuran is added dropwise over the course of 2 hours. The reaction mixture is stirred

for a further 1 hour at -78°C and quenched by the addition of 2 ml (0.11 mol) of water. The reaction mixture is added to 300 ml of ether and. 200 ml of water. The ether extract is dried over magnesium sulfate and evaporated. The impure product is purified by column chromatography on 500 g of silica gel with ether-pentane as eluent, and this gives pure 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1-dibromomethyl-4,5-dimethylcyclohexanol .

To a solution at -78°C of 30.4 g (0.050 mol) of 3-[2-benzyloxy-4-(1,1-dimethylhepty1)phenyl]-1-dibromomethyl1-4,5-dimethylcyclohexanol in 150 ml of tetrahydrofuran 47.7 ml (0.105 mol) of n-butyllithium (2.2M in hexane) are added slowly over the course of 2 hours. The reaction mixture is stirred for a further 2 hours at -78°C and 10 minutes at 0°C, and then quenched by pouring into 300 ml of ice-cold 1N hydrochloric acid. The quenched reaction mixture is extracted with two portions of 250 ml with ether, the combined extracts are washed with 250 ml of saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue is purified by column chromatography on 500 g of silica gel with ether-pentane as eluent, and this gives the title compound.

Example 45

General hydrochloride salt formation

Excess hydrogen chloride is introduced into a solution of the appropriate compound of formula IA-ID having a pyridyl group,

and the resulting precipitate is separated and recrystallized from a suitable solvent, e.g. methanol-ether (1:10).

Hydrobromide, sulfate, nitrate, phosphate, acetate, butyrate, citrate, malonate, maleate, fumarate, malate, glycolate, gluconate, lactate, salicylate, sulfosalicylate are produced in a similar way -, succinate, pamoate, tartrate and emboat salts.

Example 4 6

cis- 3-[ 4-( 1, 1- dimethylheptyl)- 2-hydroxypheny1]- cyclohexanol-2'- O- hemisuccinate ester sodium salt

0.383 g (3 .14 mmol) 4-N,N-dimethylamino-pyridine. To the resulting solution is slowly added 0.314 g (3.14 mmol) of succinic anhydride in 1 ml of dichloromethane. The reaction mixture is stirred for 4 hours at 0°C and then 3.14 ml of 1N hydrochloric acid is slowly added. The reaction mixture is stirred for a further ■ 5 minutes and then added to 100 ml of water and 100 ml of dichloromethane. The dichloromethane extract is dried over magnesium sulfate and evaporated. The residue is dissolved in 5 ml of ethanol and 3.14 ml of 1N sodium hydroxide in ethanol is added. Addition of ether causes crystallization. Recrystallization from ethanol-ether gives the title compound.

Example 4 7

cis- 3-[ 4-( 1, 1- dimethylheptyl)- 2- hydroxyphenyl]- cyclohexanol-2'- O- phosphate ester monosodium salt

A solution of 1.00 g (3.14 mmol) cis-3-[4-(1,1-dimethylheptyl) -2-hydroxyphenyl]-cyclohexanol in 3 ml of dimethylformamide. After gas evolution has ceased (110 minutes), 0.932 g (3.14 mmol) of dibenzyl phosphorochloridate is slowly added. The reaction mixture is stirred for 1 hour and then added to 200 ml of ether and 100 ml of water. The ether extract is washed with two 100 ml portions of water, dried over magnesium sulfate and evaporated to a residue. The residue is mixed with 1.0 g of 5% platinum-on-carbon and 25 ml of ethanol and stirred under a hydrogen atmosphere for 3 hours. The reaction mixture is filtered through diatomaceous earth and 3.14 ml of 1N sodium hydroxide in ethanol is slowly added to the filtrate. Addition of ether causes crystallization of the product. Recrystallization from ethanol then gives the title compound.

Example 4 8

100 mg of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-cyclohexanol are mixed and ground thoroughly with 900 mg of starch. The mixture is then placed into telescoping gelatin capsules,

so that each capsule contains 10 mg of the medicinal product and 90 mg of starch.

Oak sample 49

A tablet base is prepared by mixing the ingredients listed below:

Sufficient trans-3-[2-hydroxy-4-(2-(5-phenylpentyloxy))-phenyl]-cyclohexanol is mixed into this base to provide

tablets containing 0.1, 0.5, 1, 5, 10 and 25 mg of drug.

Example 50

Suspensions of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-cyclohexanone are prepared by adding sufficient amounts of drug to 0.5% methylcellulose to provide suspensions with 0.05, 0.1, 0, 5, 1, 5 and 10 mg of drug per ml.

Claims (1)

Intermediate product for the production of therapeutically active substances compounds with the formula e where A is hydrogen and B is hydroxy. or alkanoyloxy with from 1-5 carbon atoms, or A and B together are oxo; is hydrogen, benzyl, alkanoyl with from 1-5 carbon atoms, CO(CH2 )2 COOH and its sodium and potassium salts, P(0)(OH)2 or its mono- and disodium and potassium salts, or -C0(CH») NR,.Rr where p is an integer from 1 to 4, each of 2 p 5 D R^ and Rg individually are hydrogen or alkyl with from 1-4 carbon atoms, or R^ and Rg together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring (piperidino, pyrrolo, pyrrolidino, morpholino or N-alkylpiperazino with from 1-4 carbon atoms in the alkyl group); R2 is hydrogen, alkyl with from 1-6 carbon atoms, alkenyl with from 3-6 carbon atoms, phenyl or phenylalkyl with from 1-4 carbon atoms in the alkyl part; Z is the alkylene with from 1-13 carbon atoms or -(alk,) -0-(alko)-2 1 m 2 n where each of (alk^ ) and (alk2 ) is the alkylene with from 1-13 carbon atoms, with the proviso that the sum of carbon atoms in each of (alk^ ) plus (alk2 ) does not exceed 13; each of m and n is 0 or 1; and W is hydrogen, pyridyl or where is hydrogen, fluorine or chlorine; and the pharmaceutically acceptable acid addition salts of the compounds wherein R 1 is -CO(CH 2 ) NR 2 , R 2 and/or W is pyridyl; the hemiketals of those compounds where A and B together are oxo and R 1 is hydrogen; and the ketals with alkanols with from 1-4 carbon atoms of the compounds where A and B together are oxo and R^ is hydrogen, characterized in that it has