CS242880B2 - Method of 3-(2-hydroxy-4(substituted)phenyl-cycloalcanone preparation - Google Patents

Description

The present invention relates to a process for the preparation of novel, pharmacologically active 3- [2-hydroxy-4- (substituted) phenyl] -4 / or 5- (substituted) cycloalkanones or derivatives and intermediates thereof which have analgesic and anti-vomiting properties and are suitable intermediates for the preparation of the corresponding cycloalkanols.

Despite the current availability of numerous analgesic agents, new and improved means are still being sought to reduce the wide range of pain and discomfort associated with minimal side effects. The most commonly used formulation, aspirin, has no practical significance against major pain and is known to have various, unwanted, side effects. Other analgesic agents, such as meperidine, codeine and morphine, show an addictive dependence on their administration. The need for an improved and effective analgesic agent is therefore clearly clear.

Compounds useful as analgesic agents, such as tranquillizers, sedatives, anti-anxiety agents and / or anti-seizure agents, such as diuretics and diarrhea agents, are described in Belgian Patent Specifications 870,404 and 870,402, both issued March 12, 1977. Belgian Patent No. 870,404 discloses 5- [2-hydroxy-4- (substituted) phenyl] cycloalkanones and cycloalkanols which may have an alkyl, alkenyl, phenyl or phenylalkyl radical at the 4-position of the cycloalkanone or cycloalkanol radical; or may have an alkyl substituent at the 5-position. Belgian Patent No. 870,402 discloses certain phenols substituted at the 2-position with acyclic substituents, in particular it describes 2-hydroxyalkyl-4- (substituted) phenols and 2- (oxyalkyl) -4- (substituted) phenols.

U.S. Patent 3,576,887, issued April 27, 1971, discloses a series of 1- (1'-hydroxyalkyl-2-) o-hydroxyphenyl / cyclohexanes having central nervous system depressant properties.

Co-pending D.P.C. (Ph) 6248, entitled Pharmacologically active 4- 2-hydroxy-4- (substituted) phenyl naphthalen-2- (1H) -one and 4- [2-hydroxy-4-substituted / phenyl] naphthalen-2-ol, their derivatives and intermediates, discloses a series of 4- [2-hydroxy-4- (substituted) phenyl] naphthalen-2- (1H) -one and 4- [2-hydroxy-4 (substituted) phenyl] naphthalen-2- (1H) ol , suitable as central nervous system and anti-vomiting agents.

U.S. Pat. No. 3,974,157 discloses 2-phenylcyclohexanones, which may have up to two substituents on the phenyl core of an alkyl, hydroxy or alkoxy substituent, as intermediates for the preparation of 1- (aminoalkyl) -2-phenylcyclohexanol useful as an analgesic as a local anesthetic and as an anti-vomiting agent.

Chemical Abstracts 85, 176952f (1976) refers to numerous 3-phenyl- and 3-phenylalkylcyclohexanones as intermediates for the preparation of 2-aminomethyl-3-phenylcyclohexanones or 2-aminomethyl-3-phenylalkylcyclohexanones having analgesic and sedative effects and can also be used as an antidepressant and antispasmodic agent.

The active ingredients obtainable using intermediates produced by the process of the invention have the general formula I

H R

(I) and are prepared from the compounds of the present invention having the formula (II)

(II) z - w where

R is hydrogen, hydroxy, C 1 -C 5 alkanoylamino, amino or acetamido, hydrogen, benzyl, C 1 -C 5 alkanoyl, P (O) (OH) ₂ and its monosodium salt, disodium salt and a potassium salt, a group of the formula -CO (CH ₂ > ₂ COOH and is a sodium or potassium salt or a group of the formula -CO (CH ₂ ) 4 NR 4 R 6 wherein p represents zero or an integer from 1 to 4,

R @ 1 and R @ 2 are each hydrogen or C1 -C4 alkyl or, together with the nitrogen atom to which they are attached, a 5- or 6-membered piperidine, pyrrole, pyrrolidine, morpholine and N-alkylpiperazine ring having from 1 to 4 atoms carbon in the alkyl moiety, with an integer of 1 or 2,

Y a group of formula

-CH _? -CH / OH or -CH (OH) -CH ₂

W is a hydrogen atom, a pyridyl group or a group of the formula

where it means

W | a hydrogen atom, a chlorine atom or a fluorine atom, provided that when W represents a hydrogen atom, it is a hydrogen atom

(A) an alkylene group of 5 to 13 carbon atoms; or

b) - (alk,) -O- (alk _n ), m 2 n wherein each (alk) and (alk ₂ ) alkylene of 1 to 13 carbon atoms of each man is zero or 1, provided that: the sum of the carbon atoms in (alk 1 J plus (alk ₂ )) is at least 5 and at most 13, and that at least one of man is 1 and provided that when W is not hydrogen, Z is

(a) C 3 to C 8 alkylene; or

b) a group - (alk ^) _m-O- (alk _2), wherein each means (alkp and (alk ₂₎ is alkylene having from 1 to 8 carbon atoms and each of m and n is zero or 1, provided that the sum of carbon atoms v (alk 2 plus (alk ₂ ) is at least 3 and at most 8 and that at least one of m and n is 1.

As mentioned above, pharmaceutically acceptable acid addition salts of compounds of formula I and / or formula II containing one or more basic groups are also effective. Generally, those compounds in which W represents a pyridyl group and / or the group OR ₁ represents a basic ester moiety, R ₂ aminoalkyl group and R amino group are suitable for the preparation of such acid addition salts.

Moreover, the compounds of the formula I or II having more than one basic group are suitable for the preparation of polyaddition salts with acids.

Typical examples of such pharmaceutically acceptable acid addition salts include salts with mineral acids such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate, as well as salts with organic acids such as citrate, acetate, sulfosalicylate, tartrate, glycolate malonate, malate , maleate, panoate, salicylate, stearate, phthalate, succinate gluconate, 2-hydroxy-3-naphthoate, lactate, mandate and methanesulfonate.

Compounds of formula II wherein s, Z, W and Y are as defined above are prepared according to the invention by oxidizing a compound of formula XII

wherein s, R 1, Z and W are as defined above and the corresponding epoxide formed is then reduced with aluminum amalgam or hydrogen on palladium on carbon.

Compounds of formula (II) wherein H is in solution are in equilibrium with their hemiketal forms. The invention also relates to ketophores and hemiketal forms of the compounds of formula II.

The compounds of the formulas I and II contain an asymmetric center at the 3, 4 and 5 positions in the cycloalkyl moiety and may contain a further additional asymmetric center in the (Z-W) portion of the phenyl core. Moreover, the compounds of formula I contain an asymmetric center at the 1-position when R is other than hydrogen. The cis relationship between the substituent at the 1-position of the cycloalkyl moiety and the phenol ring or substituted phenol ring at the 3-position of the compounds of formula I is preferred and the trans relationship between the substituents at the 3 and 4 and 3 and 5 positions on the cycloalkyl moiety is preferred achieves a quantitatively greater biological effect. For the same reason, preference is also given to the relationship of the trans substituents at the 3, 4 and 3,5 position of the compounds of formula II.

In the above formulas, the racemic compounds are indicated. However, Formulas I and II are considered to be general and include racemic modifications of the compounds prepared by the process of the invention, diastereomeric mixtures, pure enanoomers and diastereomers. The usefulness of the racemic mixture, the diastereomeric mixture and the pure enantiomers and diastereomers is determined by the biological evaluation, which is described below.

In view of their greater biological activity relative to the other compounds described, compounds of formula I and II are preferred, wherein each R is hydroxy or acetamido, R R is hydrogen and Z and W are as follows:

OF m n w (C až-C) alkylene group hydrogen atom C 4 -C 7 alkylene a group of the general formula - (alk-O-Calk) 0.1 1 - <O> - ^W1 or a pyridyl group of the general formula

or a pyridyl group, wherein each (alk 1) and (alk ₂ ) that the sum of the carbon atoms in (alk-J represents an alkylene group having 1 to plus (alkp is at least 4 and at most carbon 7),

- ⁽ al ^to l ⁾ nl - ° - ⁽ alk ₂

And each (alk) 3 (alk ₂ ) is an alkylene group having 1 to 11 carbon atoms, provided that the sum of the carbon atoms in (alkp plus (alk)) is at least 7 and at most 11.

Preferred are compounds of formulas I and II wherein:

Z is a group of formula C (CH ₃ ) ₂ (CH ₂ ) ₆ a

W is hydrogen;

Z is (C 4 -C 7) alkylene;

W phenyl;

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

W is hydrogen;

Z is -O-C 4 -C 5 alkylene;

W phenyl;

R in the formula (I) is a hydroxy (cis and trans form) hydrogen atom

Particularly preferred are compounds of formula I and II, wherein R, R1, Z and W are as defined above and are in the 1-form, which is more preferred than the d-form.

Suitable starting materials for the process according to the invention are 5- [2- (hydroxy or substituted hydroxy) -4- (N-substituted) phenyl] -2-cycloalken-1-ones, the preparation of which is described in Belgian patent specification 870,404, published March 12, 1979.

In the process according to the invention, such alkenones are oxidized to the corresponding epoxides which are reduced with aluminum amalgam or hydrogen in the presence of palladium on carbon as a catalyst. The compounds of the formula II prepared by the process according to the invention can then be converted into the compounds of the formula I by the method described in the Czechoslovak patent specification 242 871.

The analgesic properties of the compounds prepared by the process of the invention and the compounds of the formula I are determined by stimulus-based stimulation tests. It is recalled that compounds of formulas I and II, wherein R1 is benzyl, are not pharmacologically active for the purposes described, but are useful as intermediates for compounds of formulas I and II, wherein R1 is hydrogen.

Tests based on stimulus to capture harmful thermal stimuli

a) Analgesic test of the mouse on a hot plate

This method uses the modified tests of Woolf and MacDonald described in J. Pharmacol. Exp. Ther 80, pp. 300-307, 1944. A controlled heat stimulus is applied to a mouse paw on a 3.175 mm thick aluminum plate. A 250-watt infrared heating lamp is placed under the bottom of the aluminum plate. The thermal controller, coupled to the thermistor on the wafer surface, programs to maintain a constant wafer surface temperature of 57 ° C.

Each mouse is dropped into a 165 mm diameter glass cylinder resting on a hot plate and time is measured as the mouse paw touches the plate.

The mice are observed for half an hour and two hours after treatment with the test compound, taking into account the first jerk of one or both hind paws or until 10 seconds have elapsed without such movements. Morphine has an MMU value of 4 to 5.6 mg / kg (s.c.). (MMU always means maximum possible effect.)

(b) Tail flick analgesic test

The modified assays of D'Amour and Smith described in J. Pharmacol are used. Exp. Ther., 22, pp. 74-79, 1941, utilizing the controlled action of intense heat on the mouse tail. Each mouse is placed on the foot of a metal cylinder with the tail extended at one end. The cylinder is adjusted so that the tail lies fully on the shaded heating bulb. At the start of the test, the aluminum plate covering the heating lamp is withdrawn and a light beam is passed through the slit, with the focus on the mouse tail. At the same time the timer will turn on. A sudden tail jerk is detected. Untreated mice generally respond within 3 to 4 seconds after exposure to heat from the bulb. The protection endpoint is 10 seconds. Each mouse is tested half an hour and two hours after treatment with morphine and test substance. Morphine has an MMO of 3.2 to 5.6 mg / kg (s.c.).

(c) Tail immersion test

The modified method described by Bonbasset et al. in Arch. int. Pharmacodyn., 122, 434 (1959). Male Charles River CD-I white mice, weighing 19-21 g, were weighed and labeled for identification. Typically, five mice are used to treat the same substance and control animal. First, each test substance is administered in an amount of 56 mg / kg intraperitoneally or subcutaneously in the form of 10 ml / kg. Prior to treatment with each drug, and half an hour and two hours after administration, each mouse was placed in a roller.

Each cylinder is provided with apertures for adequate ventilation and is closed with a nylon plug through which each mouse is drawn through the tail. The cylinder is held upright and the tail is fully immersed in a water bath at a constant temperature of 56 ° C. The end point of each test is an energetic jerk or tail twitch associated with motor response. In some cases, the endpoint may be less pronounced for drug administration. To prevent unwanted tissue damage, each test is completed within 10 seconds and the tail is removed from the bath.

The response is recorded in seconds to the nearest half second. In parallel with the selected individuals, the carrier and the standard of known efficacy are tested. If the activity of the test drug does not return to baseline in the test after two hours, the response is determined at 4 hours and at 6 hours. The last measurement is made in 24 hours if efficacy is still observed at the end of the test day.

Test based on stimulus to capture harmful chemical stimuli

Suppression of Winding Induced by Phenylbenzoquinone

A group of five Carworth Farms CF-1 mice are pretreated subcutaneously or orally with saline, morphine, codeine, or test drug. In the case of subcutaneous treatment in 20 minutes,

In the case of oral administration at 50 minutes, each group is treated by intraperitoneal injection of phenylbenzoquinone; it is known that this irritation causes abdominal contractions. The mice are observed for 5 minutes with respect to whether or not they are writhing since 5 minutes after the phenylbenzoquinone injection. The value of ΜΜϋ ^ θ is recorded after treatment with the wound blocking agent.

Test based on stimulus to capture harmful pressure stimuli

Influence of Haffner's tail grip

Modified Haffner Tests, described in Experimentelle Prufung Schmerzstillender, Dtsch. Copper. Wschr., 55, 731-732 (1929), is used to determine the effect of a test drug on an aggressive tail-induced response. Male Charles River (Spargue - Dawly) CD male rats are used in this assay.

A 63.5 mm Johns Hopkins clamp is clamped to the root of the rat tail before treatment with the test drug and then half an hour, an hour, two hours and three hours after treatment; the end point of each test is a clear attack and biting of the focus against the cause of the pain, which is recorded in seconds. The clamp is removed after 30 seconds if no response is observed and the response time is recorded in seconds. iMorphine is effective at a dose of 17.8 mg / kg (i.p.).

Test based on stimulus to capture harmful electrical stimuli

Reversing test - rebound

The modified test described by Tenen in Psychopharmacologia,

12, pp. 278-285, 1968 to determine the pain threshold. Male white Charles River (Sprague - Dawley) CD rats weighing 175-200 g are used in this test. Prior to drug administration, the paws of each rat were immersed in a 20% glycerin and brine solution. The rats are placed in the chamber and treated with their paws for one second shocks, which develop 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, 2.42, 2.72 and 3.04. mA.

Observe the behavior of each rat with respect to (a) reversing, (b) squeaking, and (c) bouncing or moving fast forward following an electric shock. A series of shocks of increasing intensity are applied to each rat just before treatment with the test substance and at half an hour, two hours, four hours and 24 hours after treatment with the test drug.

The results of the above tests are recorded as a percentage of the maximum possible effect (% MMU). The percentage of the maximum possible effect of each group is statistically compared to the percentage of the maximum possible effect of the standard and pre-drug values. The percentage of the maximum possible effect is calculated from:

test start time - inspection time% ULS = - x 100 test end time - inspection time

When used as analgesics for oral or parenteral administration, the compounds of the formulas I and II are generally employed in the form of preparations. Such formulations comprise a pharmaceutically acceptable carrier selected with respect to the mode of administration and with respect to conventional pharmaceutical practice. For example, the active ingredient prepared by the method of the invention may be administered in the form of tablets, pills, powder or granules containing excipients such as starch, milk sugar and certain types of clays. They may be administered in the form of capsules in admixture with the same or equivalent excipients. They may also be administered in the form of oral suspensions, solutions, emulsions, syrups and elixirs, which may contain flavoring and coloring agents. For oral administration of the active compounds prepared according to the invention, tablets or capsules containing 0.01 to about 100 mg of the active compound of the formula II or I are suitable. In most cases, such dosages are suitable.

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o in

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P

Λ d

Eh u

EH honors σ

CQ &

r-t ROI i-4 ROI r4 O

CO <N

Γ * CN O ro vo in CN ro Μ * Ή in o t-4 VO O

CN r-4

VO o

WHAT

O <\ o O O O O O O

OS t-3 in cn co m

co o rro o rco σι vo o o CN CN

CNOO ^ OOOCN in vo inu in vo vo

VO in m

VO in

VO O in

AND

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J Μ J ε J J J J 4J -Ρ fl C <0 Φ

The following abbreviations are used in the table:

PBQ phenylbenzoquinone induced writhing

TF Tail Tail

HP hot plate test

RTC tail grip rate

FJ dodging

The methods described above determine the analgesic action of certain compounds of formulas I and XI. The compounds of the general formula:

Table II

^R 3 AND (B) mm0._ 50 PBQ (mg / kg) RTC HIM H OH 5.60 HIM H OH 13.90 39.2 HIM OH H 5.80 56 NC H OH 7.20 hoch ₂ H OH i,, 2! 3.34 NC -0 —-- 2.87

PBQ means phenylbenzoquinone-induced writhing

RTC means the degree of tail grip

The efficacy of the compounds of formulas I and II against vomiting is tested in non-anesthetized, unrestricted cats as described in Proc. Soc. Expl. Biol. and Med., 140, pp. 437-440, 1979.

The compounds of the formulas I and II are effective against vomiting by oral or parenteral administration in the form of pharmaceutical preparations. Such formulations comprise pharmaceutically acceptable carriers selected with respect to the mode of administration and the current pharmaceutical practice. For example, they can be administered in the form of tablets, pills, powders, or granules containing excipients such as starch, milk sugar, certain types of clays, and the like. They may be administered in the form of capsules in admixture with the same or equivalent excipients. They may also be administered in the form of oral suspensions, dispersions, solutions, emulsions, syrups and elixirs, which may contain flavoring and coloring agents. For administration of therapeutic compositions containing a compound of Formula I or II, the tablets or capsules contain from about 0.1 to about 100 mg of the active ingredient; such formulations are suitable for most applications.

The physician will determine the doses that are most appropriate for each patient and will depend on the patient's age, weight and response, and the route of administration. Generally, however, the initial analgesic dose for adults is about 0.1 to about 750 mg per day in single or divided doses.

In many cases it is not necessary to exceed a daily dose of 100 mg. Preferred oral doses are about 1.0 to 300 mg / day. A preferred parenteral dose is about 0.1 to about 100 mg / day; a dosage of about 0.1 to about 20 mg / day is preferred.

The compounds of formulas I and IX may be used to formulate liquid or solid preparations for oral or parenteral administration. Capsules containing an active ingredient of the formula I or IX are prepared by mixing one part by weight of a compound of the formula I or IX with 9 parts of an excipient such as starch or milk sugar and then filling the mixture into gelatin capsules so that each such gelatin capsule contains 100 parts. mixtures. Tablets containing a compound of formula (I) or (II) are prepared by formulating a suitable mixture of the active ingredient and standard ingredients used in the preparation of tablets, such as starch, binding agents and lubricants, so that each tablet contains approximately 0.1 to 100 mg of active ingredient. compounds of formula I or II.

Example 1

7-Oxabicyclo [4.1.0] -4- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -2-heptanone

To a solution of 0 ° C, 3.24 g (8.01 mmol) of 5- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -2-cyclohexen-1-one and 2.3 ml (24 mmol) 30% hydrogen peroxide in 80 ml of methanol was added dropwise with 0.66 ml (3.96 mmol) of 6N sodium hydroxide solution. The reaction mixture was further stirred at 0 ° C for 1 h and then added to 1000 mL of saturated sodium chloride solution. The rapidly cooled reaction mixture was extracted with ether (300 mL), dried (MgSO4) and evaporated to give 3.02 g of crude product. The crude product was purified by column chromatography on 200 g of silica gel, eluting with 20% ether-petroleum ether to give, sequentially, 237 mg (7%) of the cis isomer, 1.72 g (51%) of the mixture and 1.01 g ( 30%) of the trans isomer.

Column chromatography of the mixed fraction on 300 g of silica gel, eluting with 10% ether-petroleum ether, yielded 34 mg (1%) of the cis isomer and 1.56 g (46%) of the trans isomer of the title compound as an oil.

Cis isomer:

IR (CHCl ₃ ) 1718, 1626 and 1582 cm ^-1 .

MS (m / e) 420 (M ^& lt ^{; +} & gt ^; ), 404, 335, 312, 206, and 91.

PMRδ 0.83 (m, terminal methyl), 1.27 (s, gem dimethyl), 2.0 to 2.5 (m), 2.9 to

3.7 (m), 5.15 (s, benzylic methylene), 6.9 (m, ArH), 7.10 (d, J = 8 Hz, ArH) and 7.41 (s, PhH).

Trans isomer:

IR (CHC1 ₃₎ 1718, 1623 and 1577 cm ^'first

MS (m / e) 420 (M ^& lt ^{; +} & gt ^; ), 404, 335, 329, 316, 257, and 91.

PMRj ™ ₃ 0.83 (m, terminal methyl), 1.26 (s, gem dimethyl), 2.0 to 2.8 (m), 3.3 (m)

3.4-4.3 (m), 5.13 (s, benzylic methylene), 6.9 (m, ArH), 7.07 (d, J = 8 Hz, ArH) and 7.41 (s, PhH).

In a similar manner, the cis- and trans-isomers of (5,1-o) -4- [2-benzyloxy-4- (1,1-dimethylheptal) phenyl] -2-cyclooctanone were prepared from 6- [2-benzyloxy-4- (1-benzyloxy) -4- 1,1-dimethylheptyl) phenyl] cyclohept-3-en-1-one.

Example 2

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

To a solution of 267 mg (0.635 mmol) of the cis-isomer of 7-oxabicyclo [4.1.0] -4- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -2-heptanone in 20 mL of 10% aqueous tetrahydrofuran was added 220 mg aluminum amalgam (prepared by washing 1 cm strip of aluminum foil every 15 seconds in 2N sodium hydroxide solution, in water, in 0.5% mercury chloride solution, in water, in 2N sodium hydroxide solution, in water, in 0.5% chloride solution mercuric acid, water, ethanol and ether). The reaction mixture was stirred for 3 hours at 25 ° C and then filtered through diatomaceous earth. The filtrate was evaporated on a rotary evaporator and the residue was dissolved in ether, dried (MgSO4) and evaporated. The residue was purified by preparative chromatography on 2 x 20 cm 2 x 20 cm x 20 cm, eluting with ether to give 156 nig (58 V) of the title compound as an oil.

8, 1 612 and 1 577 cm ¹ .

319, 313 and 310.

0.81 (m, terminal methyl), 1.22 (s, gem dimethyl),

MS (m / e) 422, 404, 337, 331 dm _D ™ 7 ^with

PMRd cdCI,

3.2 (m, benzylic methine),

6.9 (m, ArH); 7.03 (d, J)

Hz, ArH) and 7.38 (s, PhH).

Example

7-Oxabicyclo [4.1.0] -1- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-heptanone ethylene ketal

To a solution of 0 ° C 5.0 g (11.2 mmol) of 3- (2-benzyloxy-4- (1,1-dimethylheptyl) phenyl) cyclohex-3-en-one-ethylene ketal in 15 ml of dichloromethane is added 1 26 g (15 mmol) of sodium bicarbonate and 2.58 g (15 mmol) of m-chloroperoxybenzoic acid. The reaction mixture was stirred overnight at 0 ° C and then filtered. The filtrate was diluted with 200 mL of ether and washed with two 100 mL portions of saturated sodium bicarbonate solution. The organic extract was dried (MgSO4) and evaporated to give the title compound.

Example 4

3- [2-hydroxy-4- (1,1-dimethylheptyl) phenyl] -4-hydroxycyclohexanone ethylene ketal

A mixture of 6,7-oxabicyclo [4.1.o] -1- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] -3-heptanone ethylene ketal and 5% Pd / C / 50% water in 10 mL ethanol The mixture was stirred at 50 psi of hydrogen gas for 45 minutes at room temperature. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated under reduced pressure to give a solid. Recrystallization of the crude solid from diisopropyl ether gave the title compound.

Decetalization yields the corresponding ketone. To this end, a mixture of 3 - [[2-hydroxy-4- (1,1-dimethylheptyl) phenyl] -4-hydroxycyclohexanone ethylene ketal, 50 ml of 2N hydrochloric acid and 100 ml of tetrahydrofuran is maintained at reflux for two hours. The reaction mixture was cooled and added to 500 ml of saturated sodium chloride solution and 250 ml of ether. The ether extract is separated and washed once with 500 ml of saturated sodium chloride solution, once with 500 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to an oil (fume hood). The crude oil was purified by column chromatography on 200 g of silica gel eluting with 80% ether-hexane.

Using the method of Example 3,3- [2-benzyloxy-4- (1,1-dimethylheptyl) phenyl] cyclohept-3-en-1-one, it was converted to 3- [2-hydroxy-4- (1,1-dimethylheptyl) Phenyl] -4-hydroxycycloheptanone.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of 3- (2H-droxy-4 (substituted) phenyl) cycloalkanone of formula XI STEED. (II) where is R is hydrogen, benzyl, C 1 -C 5 alkanoyl, a group of formula P (O) (OH) ₂ and its monosodium salt, disodium salt and potassium salt, a group of formula -CO (ch ₂ ) ₂ cooh and its sodium or potassium salts or a group of formula -CO (CH ₂ ) _p NH ₄ R ₅ wherein p represents zero or an integer from 1 to 4 R @ 1 and R @ 2 are each independently hydrogen or C1 -C4 alkyl or, together with the nitrogen atom to which they are attached, a 5- or 6-membered ring of a pyperidine, pyrrole, pyrrolidine, morpholine and N-alkylpiperazine ring of 1 to 4 atoms carbon in the alkyl moiety, with an integer of 1 or 2, Y a group of formula -CH ₂ -CH (OH) or -CH (OH) -CH ₂ W is a hydrogen atom, a pyridyl group or a group of the formula -X 0 ^ -w, where is W ₁ is a hydrogen atom, a chlorine atom or a fluorine atom, provided that when W is a hydrogen atom, Z is (C 5 -C 13) alkylene or - (alk (R)) - O- (alk ₂ ) wherein each (alkp and (alk ₂ ) C 1 -C 13 alkylene and each man is zero or 1) with the proviso that the sum of the carbon atoms in (alkp plus (alk ₂ ) is at least 5 and at most 13 and that at least one of man is 1 and provided that when W is not hydrogen, Z is an alkylene group with C 3 -C 8 or - (alk? 4 -O- (alk ₂ ) _n , where each (alk?) And (alk ₂ ) is an alkylene group having 1 to 8 carbon atoms and each man zero or 1, provided that wherein the sum of the carbon atoms in (alkp plus (alk ₂ ) is at least 3 and at most 8 and that at least one of man and n is 1, characterized in that the compound of formula III is oxidized; the epoxide is then reduced with aluminum amalgam or hydrogen in the presence of palladium on carbon.