JPS605579B2 - Novel cycloalkanol compound and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a specific cyclohexanol (formula 1 below) and a method for producing the same.

The product can be used as a CNS agent, particularly as an analgesic, tranquilizer, sedative and anxiolytic in mammals, including humans, and/or as a locksmith, diuretic, and in mammals, including humans. and is useful as an anaerobic agent. Despite the large number of analgesics currently available, the search for new and improved analgesics continues to demonstrate the need to find effective analgesics to control varying degrees of pain with minimal side effects. It is pointed out that there is a shortage of drugs.

Aspirin, the most commonly used analgesic, has no practical value in controlling severe pain and is known to exhibit a variety of undesirable side effects. d-propoki 4
Other analgesics such as Codine and Morphine have an addictive tendency.Therefore, there is a clear need for improved and more potent analgesics.U.S. Pat. No. 3,576,887 (
(Published April 27, 1971) contains a series of 11(1'- hydroxy)alkyl-2-
-Hydroxyphenylcyclohexane or -ene compounds are described.

According to the invention, 2-hydroxy-4-(substituted)-
Certain cyclohexanols having a phenyl group (formula 1 below) are effective as CNS agents, particularly as analgesics in mammals, including humans, as tranquilizers, sedatives and anxiolytics, and as anxiolytics in mammals. It has been discovered to be useful as a drug, diuretic, and stimulant.

The compound has the formula [wherein R is hydrogen or pendyl and Z is -○-
(alk)-, (alk) is alkylene having 1 to 13 carbon atoms, and W is selected from the group consisting of hydrogen and.

However, the above formula is general and is meant to encompass racemic variants of the compounds of the invention, diastereomeric mixtures thereof, pure enantiomers and diastereomers thereof.

The utility of racemic mixtures, diastereomeric mixtures and pure enantiomers and diastereomers is determined by the biological value method described below. Intermediates useful in the preparation of compounds of Formula 1 have the formula Rho W below.

(cis and trans isomers) (Stereochemistry is not shown here.

) (wherein Z and W have the same meanings as above, Y is selected from the group consisting of cyano and formyl, t is an integer of 1 to 8, and R7 is hydrogen and 1 to 4 carbon atoms Compounds of formula W (selected from the group consisting of alkyl) represent the hemiketal and ketal forms of saturated cycloalkyl compounds of formula 1.

Preferred compounds of formula 1 are those in which each substituent has the following definitions. Z is 10-alkylene with 7 to 9 carbon atoms, and W is hydrogen;
Z is -0-alkylene having 4 to 5 carbon atoms and W is phenyl.

The present invention will be explained in more detail below.

The saturated cycloalkyl compounds of the present invention are prepared from the appropriate 2-bromo-5-(Z-W-substituted)phenol by a series of reactions that include protection of the phenol group as a first step.

'Suitable protecting groups are those that can be removed under conditions that do not inhibit subsequent reactions and do not cause undesired reactions elsewhere in the compound or in products prepared therefrom. Representative examples of such protecting groups are methyl, ethyl, benzyl or substituents such as alkyl of 1 to 4 carbon atoms,
Halo (CI, Br, F, 1) and substituted pennzyl, which is alkyl of 1 to 4 carbon atoms. Ether protection or blocking groups are removed by the use of bromic acid in acetic acid or 48% aqueous hydrobromic acid. The reaction is carried out at an elevated temperature, preferably at reflux temperature. When the protecting groups are penzyl or substituted penzyl groups, they can be removed by catalytic hydrogenolysis. Suitable catalysts are palladium or platinum, especially those supported on carbon. Alternatively, they can be removed by solvolysis using trifluoroacetic acid. Yet another method consists of treatment with n-butyllithium in a reactive inert solvent at room temperature. The precise chemical structure of the protecting group is not important to the invention. This is because the importance of the protecting group lies in its ability to act in the manner described above. Selection and identification of appropriate protecting groups is readily within the skill of those skilled in the art. The suitability and effectiveness of a group as a hydroxyl protecting group can be determined by using such groups in the reaction sequences exemplified herein. Therefore, it must be a group that can be easily removed to regenerate the hydroxyl group. Methyl and pendyl are preferred protecting groups because they are easily removed. The protected 2-bromo-5-(Z-W-substituted)phenol is then reacted with magnesium in an inert solvent and usually with promoters such as cuprous chloride, bromide and It is reacted with 4-R.12-cyclohexen-1-one in the presence of a cuprous salt such as chloride. Suitable reaction-inert solvents are, for example, cyclic or acyclic solvents such as tetrahydrofuran, dioxane and dimethylbutal (diglyme) of ethylene glycol. For example, Grignard reagent is 1
It can be produced in a known manner, such as by refluxing a mixture of molar proportions of bromine reactant and 2 molar proportions of magnesium in a reaction-inert solvent, such as tetrahydrofuran. The resulting mixture is then cooled to about 0-120 o'clock,
The cuprous iodide is added followed by the appropriate 2-cyclohexen-1-one at a temperature of about 0 to 120 degrees. The amount of cuprous iodide used is not critical and can vary widely. A molar ratio of about 0.2 to 0.02 moles per mole of bromine reactant provides sufficient yields of cyclohexanone (formula lr, R,=penzyl) in which the phenolic hydroxyl group is protected. The protected cyclohexanone is then treated with a suitable reagent to remove the protecting group.

Penzyl groups can be conveniently removed by the methods described above. Cyclohexanol compounds of formula 1 are prepared from protected cyclohexanone of formula 1' by reduction.

[In the formula, R, , Z and W are as defined above.

] Sodium borohydride is preferred as the reducing agent in this step. This is because it not only gives the desired product in a satisfactory yield, but also preserves the protecting group of the phenolic hydroxyl group and allows it to be used as a solvent with hydroxyl-containing solvents (methanol, ethanol, water). This is because it reacts as slowly as possible. Approximately 140 to 3
A temperature of 0 qo is commonly used. Lower temperature, about 170q
Even temperatures as low as 300 ml can be used to increase the selectivity of the reduction. Higher temperatures cause a reaction between the sodium borohydride and the hydroxyl-containing solvent. If higher temperatures are desired or required for a given reduction, inpropyl alcohol or the dimethyl ether of glycol is used as the solvent. A sometimes preferred reducing agent is tri-sec-butylpotassium borohydride. The reason for this is that the stereoselective production of trans-1,3-phenylcycloalkanol is advantageously carried out. The reduction is carried out in dry tetrahydrofuran at a temperature below about 150 pm using equimolar amounts of the ketone compound and reducing agent. Reducing agents such as lithium borohydride, disoptylaluminium hydride, or lithium aluminum hydride can also be used, but these are suitable under anhydrous conditions and non-hydride conditions.

Requires a xyl solvent such as 112-dimethoxyethane, tetrahydrofuran, diethyl ether, dimethyl ether of ethylene glycol.
Cycloalkanols in which R, is hydroxyl can of course be prepared by catalytic reduction of protected cycloalkanes on palladium-supported carbon, or by catalytic reduction of unprotected cycloalkanones (formula 1', OR, =OH) using the above-mentioned reducing agents or It can be obtained directly by chemical reduction.

When actually implementing it, benzyl-protected cyclohexanone (
Formula 1(
Preferably, the unprotected cyclohexanol of OR,=OH) is prepared. The reason is that stereochemical control of the reduction and formation of cis-hydroxyepimer as the main product is enabled, facilitating separation and purification of the epimer alcohol. As one of the methods for producing the compound of the present invention, 3
-methoxy 2-cyclohexen-1-one derivative is then treated with lithium aluminum hydride and diethyl ether,
The reaction is carried out in a reaction inert solvent such as dioxane, tetrahydrofuran or diglyme at a temperature of about -10 DEG to 10 DEG C. and worked up with a dilute mineral acid.

The resulting aryl-substituted 2-cycloalken-1-one can be prepared by dissolving the resulting aryl-substituted 2-cycloalken-1-one in a suitable dialkyl steel lithium in a suitable reactive inert solvent such as hexane, diethyl ether or mixtures of these solvents, or in a reduced ether such as tetrahydrofuran. Processed at temperatures between 0°C and -2000°C. The protected 3-[4-(Z-W)-substituted-2-hydroxyphenyl]-cyclohexanone is then deprotected and reduced or reduced and then deprotected by the method described above. . A convenient method of preparing the compounds of the invention consists in the use of 4-fromresorcinol as starting material.

The method consists in protecting the two hydroxyl groups of sorcinol by pendylation by standard methods. Penzyl groups are preferred as protecting groups in this method. This is because this is the ether group 1○-(alk)'W
This is because it can be removed by catalytic hydrogenation without cleavage. Other protecting groups such as al takyl (eg methyl or ethyl) can of course be used. However, penzyl protecting groups are preferred because they cause fewer side reactions. The protected 4-bromoresorcinol is then converted into Grignard (Gr
ig order rd) reaction with the appropriate cyclohexenone in a reaction inert solvent according to the method described above.
The 3-(2,4-dibenzyloxyphenyl)cyclohexanone thus produced was catalytically hydrogenated over palladium on carbon to give the corresponding 3-(2,4-dihydroxyphenyl)cyclohexanone, which Exists in equilibrium with the hemiketal form. The hemiketal is then prepared by reacting with a trialkyl orthoformate, such as trimethyl orthoformate, in the presence of concentrated sulfuric acid in a suitable solvent such as a C,~4 alcohol (e.g. methanol). 4 alkyl (eg methyl) ketal. The alkyl ketal thus obtained is then combined with a suitable alkyl or aralkyl methanesulfonate or tosylate and anhydrous sodium carbonate or
is alkylated with potassium and a suitable reactive inert solvent such as N.N-dimethylformamide at a temperature of about 75 to 20,000°C. This method has the advantage of allowing the use of simpler compounds throughout the entire reaction process. The 0-alkylated or a3-alkylated ketal is then reacted with, for example, hydrochloric acid to produce the corresponding 3-(2-hydroxy-4-[0-(alk)]phenyl)cyclohexanone, which is in equilibrium with the hemiketal. exists in 3 formula 1'
A compound represented by , where R is hydrogen, exists as a solution in equilibrium with the hemiketal form, and some exist substantially completely in the hemiketal form in the crystalline state, so the formula 1'
A compound represented by R, where R is hydrogen, is meant to include hemiketal and keto forms. The analgesic properties of the present invention can be determined by testing with nociceptive stimuli.

Tests Using Thermal Nociceptive Stimuli'a} Mouse Hot Plate Analgesia Test The method used was described by Woofe and MacDonaid, J.;
Pharmacol. Exp. mer. , 8 300
This method is a partial modification of the method of No. 307 (1944).

A controlled thermal stimulus is applied to the mouse paw on a 3.2 sided (1/8 inch) thick aluminum ramp. A 250 watt reflective infrared heat lamp is placed under the aluminum plate flooring.

A heat regulator connected to a thermistor on the plate surface is programmed to maintain the heat lamp at a constant temperature of 57q0. Each mouse is dropped into a glass cylinder (165 skins (6 inches) in diameter) placed on a hot plate and the time is measured from when the animal's paw touches the plate. 0.5 after treatment with test compound.
and at the second hour, the first “bounce” of one or both hind legs.
Observe the state of interlocking (Hicking), or observe until a period of one inkstone passes without such movement. Morphine is 9'kg of M circle E5o = 4-5.6 (
s. c. ). {b} Mouse tail wag analgesic test The tail wag test in mice uses controlled high-intensity heat applied to the tail Amour and Smith, J.
．． Pharmaco. Exp. Ther. , 72, 74
79 (1941) with some modifications.

Each mouse is placed in a metal cylinder that can be fitted with a sliding iron, with the tail protruding from one end. The cylinder is placed so that the tail lies flat on the recessed heat lamp. At the start of the test, pull back the aluminum flag on the lamp so that the light beam focuses through the slit and onto the end of the tail. Run the timers at the same time. Check the incubation period for sudden tail flipping. Untreated mice are usually exposed to lamps for 3
Reacts after ~4 seconds. The end point of protection is 1 sand.
Each mouse was tested 0.5 and 2 hours after treatment with morphine and test compound. Morphine has an MPE5o of 9/k9 (s.c.) of 3.2 to 5.6. 'c}
Tail immersion method This method is described by Ben Sset, et al., Arch.
lnt. To the enemy of Pharmacod 122, 434 (1
This is a modified method of the receiver method developed by (959).

Charles River C
D-1 female white mice (19 to 21) were weighed,
Attach a tag for individual identification. Typically five animals are used for each drug treatment group, one of which serves as its own control. For routine screening purposes, the new test agent is first injected intraperitoneally or subcutaneously at a volume of 10 skins/k9;
A dosage of 56 females/kg is given. Each animal is placed in a cylinder before and 0.5 and 2 hours after drug treatment. Each cylinder is perforated to allow adequate ventilation and closed with a circular nylon plug that allows the animal's tail to protrude. Stand the cylinder vertically and place the tail in a warm water tank (56℃).
) completely immersed in the liquid. The end point of each test was a forceful twitch of the tail accompanied by a motor response. In some cases, the end point decreases in intensity after drug treatment. To prevent excessive tissue destruction, the test is stopped within 1 sand and the tails are removed from the water bath. Reaction latencies are expressed in seconds to the nearest 0.9 increments. Vehicle controls and known potency standards are tested simultaneously in screening subjects. If pretest activity does not return to baseline values at the 2 hour test time point, response latencies are measured at 4 and 6 hours. A final measurement is taken at 24 hours if activity is still observed at the end of the test day. Testing with Chemical Nociceptive Stimuli Phenylbenzoquinone Stimulant-induced Suppression of Agony Groups of 5 CawomhFa dishes CF-1 mice were administered subcutaneously or orally with saline, morphine, codine or the test compound. Pre-process.

After 20 minutes (for subcutaneous treatment) and 5 minutes (for oral treatment), each group is treated by intraperitoneal injection with phenylbenzoquinone, an irritant known to cause abdominal floppy.

Mice showed signs of distress starting 5 minutes after injection of the stimulant.
Observe for minutes. M-yen E5 in preventing the agony of drug pretreatment
Check o. Test using pressure nociceptive stimulation Haffner tail pinch method Haffner Experimentell
e Pr heartung Schmerzstillende
r. Due to h Med. WSChr. , 55, 731
A modification of the method of 1732 (1929) is used to determine the effect of the test compound on the aggressive response elicited by tail-pinching stimulation.

Charles River (Sprague Dawlay)
Male white rats (50-60 yen) of the CD breed are used. 0 before and after drug treatment. Johns Hopkins 6.35 at 1st, 2nd and 3rd hour
A (2.5 inch) "bulldog" clamp was placed at the base of the rat's tail. The end point of each test was overt attack and coughing behavior in response to the unpleasant stimulus, and the attack latency was recorded in seconds. If no attack occurs with sand 3, remove the clamp and record the reaction latency as 3 sand.

Morphine is active at 9/kg (jp) of 17.8. 0 Test using electrical nociceptive stimulation "Frinchy jump" test
, Psychopharmacologia, 12, 2
78-285 (1968) is used to determine the pain threshold.

Charles River
Sprague Dawley
] Female albino rats (175-200 yen) of the CD species are used.
Before drug administration, each rat's paw was soaked with 20% glycerol/
Soak in saline solution. The animal is then brought into the room and given 10 seconds of electric shocks to the legs, increasing in intensity in steps of 3 steps. This strength is 0.200.39 0
．． 52, 0.78" 1.05 1.31, 1.58,
1.86, 2.13, 2.42, 2.72 and 3.04
This is A. The behavior of each animal is assessed by the presence of (a) flinching, (b) circling, and (c) jumping or rapid forward movements at the onset of the shock. before drug treatment, and 0.5 2,
4, and 24 hours later. The results of the above tests indicate the maximum possible effect rate [%MP
E)].

The %MPE for each group is statistically compared to standard and pre-drug control values. %MPE is calculated as follows. When used as an analgesic for oral or parenteral administration, the compounds of the present invention are conveniently administered in the form of compositions.

Such compositions contain a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice. For example, these are tablets, pills, powders or granules containing excipients such as starch, lactose, certain types of clay, etc. These may be mixed with the same or equivalent excipients and administered as capsules. They may also be administered in the form of oral suspensions, solutions, emulsions, syrups and elixirs, which may contain flavoring and coloring agents. For oral administration of the therapeutic agents of the invention, tablets or capsules containing about 0.01 to 100 9 are suitable for most uses. The physician will determine the dosage that works best for the individual patient, which will vary depending on the age, weight, and response of the particular patient as well as the route of administration.

However, in general, the initial analgesic dose for adults is 1
It varies from about 0.1 to 750 9 per day and is administered in single or divided doses. In most cases there is no need to exceed 100 females per day. An advantageous oral dosage range is from about 1.0 to 300 9/day, with a preferred dosage from about 1.0 to 50 9/day. An advantageous parenteral dosage is about 1.0 to 50 9/day, a preferred dosage is about 0.1 to 20 9/day.
The present invention also provides pharmaceutical compositions containing the compounds of the present invention as analgesics and in single dosage forms that have value for other uses disclosed herein.

Dosage forms may be presented in single or multiple doses as described above to achieve a daily dosage as effective for a particular application. The compounds (medicaments) herein can be formulated to be administered in solid or liquid dosage forms for oral or parenteral administration.

Capsules containing the drug of the invention are prepared by mixing 1 part by weight of the drug with 9 parts by weight of an excipient, such as starch or lactose, and then placing the capsules in nested gelatin capsules so that each capsule contains 9 parts by weight of the mixture. It is manufactured by filling the Tablets containing the compound are prepared in such a way that each tablet contains a suitable mixture of medicaments and standard ingredients used in the manufacture of tablets, such as starch, binders and lubricants at 0.1% per tablet.
It is manufactured by blending to contain 0 to 100 2 drugs. These drugs, especially R, (formulas 1 and 0
) is hydroxyl are prepared immediately prior to use to avoid stability problems (eg, precipitation) of the drug suspension or solution during storage.

Compositions suitable for this purpose are usually dry solid compositions, which are reconstituted to their original liquid state for administration by injection. The method described above determines the analgesic activity of several compounds of the invention.

The compound has the formula shown below. G ‘ ○ days ○ ZW Table 1: G = (day, OH) In the table, the following abbreviations were used.

P80 = phenylbenzoquinone yielding agony, TF = tail cramp, HP = hot plate, RTC = rat tail pinch, and FJ = fright - jump The single value in the table is ED5.

belongs to. The second number with the number in parentheses is the protection rate observed at a given dose.

Therefore, for example, 31 (56) is 9'k9 of 56.
One body weight dose represents 31% protection. Table 1 Analgesic active ED phosphorus bata) or polyprotectant small subcutaneous injection G
Z W PBQ
H'tranS-.

H). CH<. Day 3) CH2) 3 C
6th 5 28ku56>kuH'CiS-. H＞
. CHkuCH3)kuCH2>3C
6th 5 38ku H'tranS-. H＞
. kuCH2)4 C6day5
>56kuH'CiS-. H)
. kuCH2)4 C6day5
>56 notes) cls-OH=cis-OHtr
ans-○H=trans-○ The activity of the Japanese invention compound as a diuretic was determined by Lipschitz et al. using rats as test animals. , J.
Pharmacol. , 197, 97 (1943).

The dosage range for this use is the same as described for the use of the compounds of the invention as analgesics. Its usefulness as an antisolvent is demonstrated by Neime Hoko ersetal. ,Modern
Phannacology-Toxicology. W
Mr. illem van ver and Harbans La
l, Eds. , 7, 68 Ichinne (1976).

Charles River CD
-1 rat (170-200 ft) is placed in the group pen one chick hour before testing. Animals are fasted overnight before administration of castor oil and given free access to water. The test drug was 5% ethanol;
5% Em phor EL-620 [A
ntara Chemicals, New York, N.
Y. Polyoxyethylated vegetable oil emulsifier available from
and administered subcutaneously or orally at a constant volume of 5 kg9 body weight in 90% saline vehicle, and 1 hour later challenged with castor oil (
1, orally). Animals are housed in small individual Yuzu Z (20.5 x 16 x 21, cage) with suspended wire mesh floor. Disposable base paper was placed under a wire mesh to test for diarrhea 1 hour after the castor oil challenge. The vehicle/castor oil treated group served as the control for daily testing. Results were expressed as the number of animals rescued 1 hour after challenge. Generally, dosage levels when using these compounds as antidepressants are similar to those for use as analgesics. The tranquilizer activity of the compounds of this invention is determined by oral administration to rats at a dose of about 0.01 to 50 female'k9 monomers and observing a decrease in locomotor activity.

The daily dosage range in mammals is approximately 0.01 to 10
It is 9 of 0.

Analgesic activity is determined by administering the test compound subcutaneously to male Swiss mice (Charles River) weighing 14-23 mm using the type of vehicle used for anti-lagata efficacy. .

Mice are used in groups of five. One day before serving, mice are fasted overnight but provided with water ad libitum. Treatments are given through a 25 gauge hypodermic needle in a volume of 10''k9. Subjects are treated with test compound and 1 hour later challenged with an electric shock, 50 A at 60 days 2, delivered via the cornea. A control experiment is performed at the same time and mice are given vehicle only as a control treatment. Electroshock treatment produces tonic extensor shock with a latency of 1.5-3 seconds in all control mice. Protection is recorded when the mouse does not show any tonic extensor movements for one hour after receiving the electrical shock. The anti-destabilizing agent activity was 9/k of 120 when the active agent was administered intraperitoneally.
It is determined in the same manner as in the evaluation of mirror dust agent activity, except that it is Bentilenetetrazole (No. 9).

This treatment produces clonic episodes within 1 minute in over 95% of treated control mice. When the incubation period of Keiren is delayed by at least two times due to drug pretreatment,
Protection is recorded. Sedative/depressant activity is determined by subcutaneously injecting groups of six animals with various doses of the test agent. One mouse was placed in one eye at 30 and 6 after treatment.
Place them on the rotating twill for a minute and evaluate their behavior on the rotating twill. If the mouse is unable to turn the spindle, this is considered evidence of sedative-depressant activity. Reference example 13-[2
-penzyloxy-4-(1'1-dimethylheptyl)
-Phenyl]cyclohexanone 75.0 (0.193
A solution of 2-(3-benzyloxy-4-bromphenyl)-12-methyloctane dissolved in 200% tetrahydrofuran was added for 9.25 hours (0.388 hours).
l) was added to 70-80 mesh metal magnesium.

The resulting mixture was refluxed for 20 minutes and then cooled to 100 ml. Copper steel (1) (1.84 hours, 9.7 mmole
) was added and the ritual was continued for 10 minutes. A solution of 18.5 holes (0.193 holes) of 2-cyclohexene-1-one dissolved in 40 points of tetrahydrofuraso was gradually added to the resulting mixture until the reaction temperature was brought to -3 by cooling with salt and ice.
Addition was made at a rate such that it remained below 0.00. The reaction mixture was heated for an additional 30 min (t<000), then 50 min.
Hydrochloric acid was added for 1 hour and then added to ice water. The stopped reaction was extracted three times with 500M each of ether. The extracts were combined, washed twice with 100 parts of water, twice with 100 parts of saturated sodium chloride, dried over magnesium sulfate, and concentrated to give an oil. This oily substance 1.
Purified by column chromatography on 6k9 silica gel, eluting with 20% ether cyclohexane;
2.5 hours (79.7%) of product was obtained as an oil. 51R: (CHC13) 1709 1613 and 15
75 enemy - IMS; m/e406 (M ten), 362, 32
The compounds listed below were prepared from the appropriate 2-penzyloxy-4-ZW-bromobenzene and the appropriate cycloalkenone by the methods described above.

0 3-[2-penzyloxy-4-(2-(5-phenylbentyloxy))phenyl]cyclohexanone.

Obtained as an oily substance. (3.6 min., 87%) Raw material: 2-benzyloxy-4-[2-(5-phenylbentyloxy)]bromobenzene (4.0 min., 9.4 mm.le)
. IR: (CHC13) 1712, 1616 and 159
2 Skin-IMSmnoe422 (M10), 351・323・
29, 278, ``253, 205 and 91.

Reference example 2 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cyclohexanone 19.5 units (0.04
68 hole) of 3-[2-benzyloxy-4-(1
・1-dimethylheptyl)phenyl] cyclohexanone, 12.3 evening sodium bicarbonate, 3.00 evening 10
A mixture of 1% palladium on carbon and 250% ethanol was heated under 1 atm of hydrogen. I worshiped the bug time.

The reaction mixture was then passed through diatomaceous earth with ethyl acetate and the filtrate was evaporated to a solid. The crude solid was purified by column chromatography on 280 ml of silica gel, eluting with 20% ether-cyclohexane. By recrystallizing this solid from an aqueous methanol solution, the melting point was 8.
70 in principle Hemiketal type 9.1 night (62%)
The title compound was obtained. IR: (KBr)3220 16
29 and 1580 skin-1 (CHC13) 3571, 32
81, 1704, 1623 and 1575 skin - IMS: m
Noe316 (M+), 29 pieces 273 and 231.

Elemental analysis Calculated value as C2, day 3202: C, 79
．． 70; Sun “10.19.

Experimental value: C, 79.69: day, 9.89. The following compound was prepared by repeating the above method using the appropriate reactants of Reference Example 1.

3-[2-Hydroxy-4-(2-(5-phenylbentyloxy))phenyl]cyclohexanone.

Obtained quantitatively as an oily substance. Raw materials: 3-[2-benzyloxy-4-(2-(5-phenylbentyloxy)
) phenyl] cyclohexanone (1.0 molar, 2.26 skin mole). IR: (CHC13) 3571, 3333
, 1709 1623 and 1587C 10MS:m
/e352(M10), 200188 and 91.

Reference example 3cis-3-[2-benzyloxy-4-(1
・1-dimethylheptyl)phenyl]cyclohexanol and its trans isomer 43.0 mo (0.106 mo
le) 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohexanone at 500
A solution dissolved in methanol and 15 liters of tetrahydrofuran was cooled to -40°C and heated at 8.05 pm (0.
．． 212 holes) of sodium borohydride was added in three portions.

The reaction mixture was stirred for 1 hour at −4°C, returned to 110°C, and then quenched by adding 100°C of saturated sodium chloride. 150% of the stopped reactant
The solution was added to 0.0 m of water and extracted 3 times with 450 g of ether. The ether extracts were combined, washed three times with 100% water and then twice with 200% saturated brine, dried over magnesium sulfate, and evaporated to give an oil. The oil was purified by column chromatography on 400 ml of silica gel eluting with 20% ether-cyclohexane to give 50 ml (12%) of the trans isomer and 22.2% of the trans isomer as detailed below.
The cis isomer (51%) was obtained with this elution order. Trans-3-[2-benzyloxy-4-(111-dimethylheptyl)-phenyl]cyclohexanol: IR
:(CHC13) 36303497, 1629 and 15
87-1.

MS: m/e408 (M+), 39u 390, 323
and 91. Elemental analysis: Calculated value as C28 day 4.02: C, 82.30; day, 9.87% Experimental value: C,
81.98: day, 9.82% and cis-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohexanol.

Melting point: 75.5-76.500 1R: (CHC13) 3630 3497, 1629 and 1587 Ka-1.

MS: m/e 408 (M+), 39 in 390, 323 and 91. Elemental analysis. : Calculated value as C28th 4o02: C, 82.30; day, 9.87% Experimental value: C, 81.
95; day, 9.74% Example 1 The following compound was prepared from the appropriate ketone of Reference Example 1 in the same manner as in Reference Example 3.

cis-[2-penzyloxy-4-(2-(5-phenylbentyloxy))phenyl]cyclohexanol (1.51, 76%) and the trans isomer (0.3
79 evening, 19%) obtained as an oily substance.

Raw materials: 3-[2-penzyloxy-4-(2-(5-phenylbentyloxy)) phenyl] cyclohexanone (2.0 min, 4.52 skin mole). For transformers:
PMR: 6 stages 1.28 (d, J=6Hz, methyl) L
2.68 (m, benzylic methylene), 3.45 (m,
(penzyl methine), 4.22 (m, carbinol methine), 4.30 (m, side chain methine), 5,09 (S, benzyl ether methylene), 6.45 (dd, J=
8 and 2HZ "ArH), 6.55 (bs, ~H),
7.10 (d, J = 8 days 2, ~H), 7.25 (S, P
hH) and 7.45 (bs, PhH).

IR: (CHC13) 3571, 344 & 1613 and 1590 - IMS: m/s444 (M+), 298
, 280, 190 and 91. In the case of cis: PMR: 1.25 (d, J = 6Hz, methyl) "3.0 (m
, benzylic methine), 3.

77 (m, carbinol methine), 4.38 (m, side chain methine), 5.10 (S, benzyl, ether methine) 6.50 (dd, J:8 and 2HZ, AH)
6.58 (bs, ~H), 7.12 (d, J=8HZ
, needle), 7.32 (S, PhH) and 7.43 (S, P
hH).

IR: (CHC13) 3571, 3390, 1613 and 1587 - IMS: m/e444 (M+), 298
190 and 91.

Reference example 4cis-3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cyclohexanol 22.0 holes (0.0539 holes) of cis-3-[2
-benzyloxy-4-(1,1-dimethylheptyl)
phenyl]cyclohexanol, 12.0 hours of sodium bicarbonate and 2.0 hours of 10% palladium on charcoal. The raw mixture was heated under 1 atmosphere of hydrogen for 2 hours.

The reaction mixture was passed through a diaphragm with ethyl acetate, and the filtrate was evaporated to obtain a solid. The solid was recrystallized from hexane to give 13.2 min (77%) of the title compound, mp 10.
9-110qo was obtained. IR; (CDC13) 3610
3350 1626 and 1582c-IMS:m
/e318(M+), 300, 233 and 215.

Elemental analysis: C2, calculated value as day 3402: C, 79
．． 19:day, 10.76% Example 2 Following the method of Reference Example 4, the following compounds were prepared from the appropriate reactants of Reference Example 3.

Cis-3-[2-hydroxy-4-(2-(5-phenylbentyloxy))phenyl]cyclohexanol.

Obtained quantitatively. Melting point: 80-8400. (Bentan).
Raw material customer cis-31 [2-penzyloxy-41 (21 (
5-phenylbentyloxy)) phenyl]cyclohexanol (1.45 m, 3.27 m. Ie). IR:
(CHC13) 3597, 33331623 and 159
7th arc-1.

MS: mno e354 (M ten 33020 & 190 and 91. Elemental analysis: Calculated value as C23 day 3.03: C '77.93; day, 8.53% Experimental value: C,
77.95; day, 8.31%.

trans-131[2-hydroxy-4-(2-(5-phenylbentyloxy))phenyl]cyclohexanol (9 of 241, 90%). Melting point: 65-70q0 (from bentane). Raw materials: trans-3-[2-penzyloxy-4-(2-(5-phenylbentyloxy))phenyl]cyclohexanol (0.355, 0.75
4mmole). IR: (CHC13) 3597, 33
7 & 1629 and 1587 skin-1. MS; m/e35
4 (M 10 pieces 33020 & 190 and 91. Elemental analysis:
Calculated value as C23 day 3.03: C, 77.93: day, 8.53% Experimental value: C
77.53; day, 8.40%.

Reference example 53-[2-hydroxy-4-(4-phenyl phthyloxy)phenyl]cyclohexanone methyl ketal 5.03 moles (22.8 moles) of 3-(204
-dihydroxyphenyl)cyclohexanone methyl ketal, 10.1 moles (73.2 moles) of anhydrous potassium carbonate and 6.21 moles (26.8 mmoles) of 4-phenylbutyl tansulfonate to 25M N.N-dimethyl Mixture with formamide added to 85-1000
0 for 4 hours.

The reaction mixture was cooled and added to 200 °C of water and 200 °C of ether. The ether extract was washed twice with 200ml of water, dried over magnesium sulfate and evaporated to give an oil. The oil was purified by column chromatography on 2:1 pentane:ether on silica gel for 400 min.
%) of the title compound as an oily material. IR:(C
DC13) 1623 and 1590c -1.

MS: mnos352 (M10) and 91. Elemental analysis: C2
Calculated value as 3 days 2803: C, 78.37; day, 8.01% Experimental value: C,
78.34: Sun, 8.07%.

The following compounds were similarly prepared using the appropriate mesylate derivative in place of 4-phenylbutyl methanesulfonate.

3-[2-Hydroxy-4-(2-heptyloxy)phenyl] hexanone methyl ketal (6.13 pm, 75%).

Obtained as an oily substance. Raw materials: 5.7 evenings (25.9 mmo
le) 3-(2,4-dihydroxyphenyl)cyclohexanone methyl ketal and (2-heptyl) methanesulfonate (6,2 moles, 32,3 moles). IR
: (CHC13) 1637 and 1600 Ka-1.

MS: m/e318 (M+), 280 274, 220
, 204 skin 178.3-[2-hydroxy-4-(2
-octyloxy)phenyl]cyclohexanone methyl ketal.

Obtained as an oily substance. (5.03 evening, 58%). material:
3-(2,4-dihydroxyphenyl)cyclohexanone methyl ketal (5.7 nights, 25.9 mmol18) and (2-octyl) methanesulfonate (7,3 nights, 3
5.1 m. Ie). IR: (CHC13) 1639 and 1600 skin-1.

MS: mnoe332 (M 300, 289, 272
and 220.3-[2-hydroxy-4-(2-(4-phenyl)butoxy)phenyl]cyclohexanone methyl ketal.

Obtained as an oily substance. (5.1 evening, 56%). Raw materials: 3
-(2,4-dihydroxyphenyl)cyclohexanone methyl ketal (5.7 min, 25.9 mole) and 2-(4-phenylbutyl) methanesulfonate (8.7 min, 25.9 mole).
0 evening, 35.0 mmole). IR: (CHC13)1
639 and 1603 arc-1. MS: m/e352 (M+
), 320, 220 and 188. 3-[2-hydroxy-4-(2-(6-phenyl)hexyloxy)phenyl]cyclohexamenmethyl ketal (5.3 evening, 54
%).

Obtained as an oily substance. Raw material: 3-(2,4-dihydroxyphenyl)cyclohexanone methyl ketal (5.7
25.9 mmole) and 2-(6-phenylhexyl) methanesulfonate (9.0 mmole, 35.5 mmole)
le). IR: (CHC13) 1634 skin 1597 skin-1. MS: m/e380.2342 (M+, C25
day 3203), 220.1088, 188.0986 and 177.0550. Reference example 63-[2-hydroxy-4-(4-phenylbutyloxy)phenyl]cyclohexanone 6.8 female (19.3 mmole) of 3-[2
A mixture of -hydroxy-4-(4-phenylbutyloxy)phenylcyclohexanone methyl ketal, 100% of 2N hydrochloric acid and 60% of dioxane was heated under reflux for 1 hour.

Cool the reaction mixture, add 300' of ether and 500' of
of saturated sodium chloride. The ether extract was washed once each with 500' of saturated sodium chloride and 500' of saturated sodium bicarbonate, dried over magnesium sulfate, and evaporated to give an oil. The oil was purified by column chromatography on silica gel eluting with 1:1 ether:cyclohexane for 400 min to give 6.4 min (98%) of the title compound as an oil. IR: (CHC13) 3571, 333 included
1718 (of), 1626 and 1595 arc-1.

MS: m/e388 (M+), 320, 310, 295
, 268 and 91.

The following compound was obtained from the appropriate ketal of Reference Example 5 in a similar manner.

3-[4-(2-heptyloxy)-2-hydroxyphenyl]cyclohexanone (4.7 min, 82%).

Obtained as an oily substance. Raw materials: 6.0 evenings (18.8 mmo
le) corresponding methyl ketal. IR: (CHC13
) 3630 3390, 1724 (of), 1639 and 1600 Ka-1.

MS: m/e304 (M+), 200 18 & 171,
163 and 137.

3-[4-octyloxy)-2-hydroxyphenyl]cyclohexanone (4.1 min., 85%).

Obtained as an oily substance. Ingredients: 5.0 yen (15.0 skin mo
le) corresponding methyl ketal. IR: (CHC13
) 3630 3378 1721 (of), 1631 and 1595 cm-1.

MS: m/e318 (M+), 200 188 178
and 163.

3-[4-(2nonyloxy)-2-hydroxyphenyl]cyclohexanone (4.35 hours, 89%).

Obtained as an oily substance. Raw materials: 5.1 evenings (14.7 mmo
le) corresponding methyl ketal. IR: (CHC13
) 3584 3367, 1709 (of), 1626 and 1587 enemy-1.

MS: m/e332 (M ten), 20mm 187 and 17
1.

3-[4-(2-(4-phnyl)butyloxy)-2-
Hydroxyphenyl] cyclohexanone (3.8 evening, 7
9%).

Raw material: 5.0 moles (14.2 moles) of the corresponding methyl ketal. Obtained as an oily substance. IR: (CHC13
) 3630 342 Australia 1724 (of), 1637 and 1
600 skin-1.

MS: m/e338 (M ten), 20018 & 132, 1
17 and 91.

3-[4-(2-(6-phenyl)hexyloxy)-
2-Hydroxyphenyl]cyclohexanone (4.45
evening, 89%).

Obtained as an oily substance. Raw materials: 5.2 evenings (13.6 mmo
The corresponding methylketer'le of le). IR: (CHC1
3) 36303390 "171 & 1637 and 1600
Cm-10MS: m/e366 (M+), 200 18
8 and 91.

Example 3 Cis-3-[2-hydroxy-4-(4-benyloxy)phenyl]cyclohexanol and its trans isomer 4.8 mmoles (14.2 mmole) of 3-
[2-hydroxy-4-(4-phenylbutyloxy)
Phenyl] cyclohexanone was dissolved in 25 volumes of methanol and cooled to -18°C.
mmole) of sodium borohydride was added.

The reaction mixture was allowed to stand for 40 minutes and then added to 250 g of saturated sodium chloride and 250 g of ether. The ether extract was washed once with 150' of saturated sodium chloride, dried over magnesium sulfate and evaporated to give an oil. This oil was coated on silica gel for 400 min.
The cis isomer (crystallized from cyclohexane) was purified by column chromatography eluting with 5:1 dichloromethane:ether (70%).
and 0.68 (14%) trans isomer (crystallized from cyclohexane) and 0.69 (14%) mixed material were obtained. For cis isomer: Melting point: 79-8000 PMR: 6 sickle neck 32.70 (m, benzylic methylene)
3.26 (m, benzylic methine), 3.93 (bt,
J: 6HZ, -OC ratio -), 4.28 (m, OH, carbinolmethine, D20 used 64.25, M, Calbi/
lumetine), 6.42 (dd, Jko8 and 2HZ, ~
H), 6.45 (d, J=2HZ, MH), 7.03 (
d, J=8HZ, ~H) and 7-22 (S, PMH) melon: (CHC13) 3610, 33301631 and 16
03 skin-1.

MS: m/e340 (M+), 322, 190 and 91
. Elemental analysis: Calculated value as C22nd 2803: C, 7
7.

61: Sun, 8.29% Experimental value: C, 77.46:day, 8.25%.

For trans isomer; melting point: 112-114°C PMR: 6 sheaths 2.68 (m, benzylic methylene),
o 3.80 (m, OH, 1OCH2, 83.63 m, carbinolmethine and 63.90, bt, J6HZ, 1OCH2), 6.32 (戊, 66 .40), 6.40 (d
d, J = 8 and 2 days 2, ArH), 7.00 (d" J
= 8th 2, ArH) and evening 7.20 (S, PhH).

IR: (CHC13) 3610, 3390 1631 and 1595 skin-1. MS: m/e340 (M+), 32
2, 190 and 91. Elemental Analysis: Calculated as C22 Day 2803: C, 77.61; Day, 8.29% 0 Experimental Value: C, 77.40; Day, 8.31%.

The following compounds were produced in a similar manner. cis-3
1[4-(2-heptyloxy)-2-hydroxyphenyl]cyclohexanol and its trans isomer. Obtained as an oily substance. Raw materials: 3-[4-(2-heptyloxy)-2-hydroxyphenyl]cyclohexanone (5.2 hours, 13.6 mmole). In order of elution from silica gel, 9 (36%) cis-3 isomers of 854 and 9 (3%) trans-3 isomers of 107 were obtained.
For cis: IR: (CHC13) 3597, 3333 1629 and 1600 skin-1.

MS: m/e306 (M ten), 20 & 190, 173
and 162. PWR: 65 units, 30.82 (m, methyl), 2.8 (m, benzyl methine), 3.7 (m,
carbinolmethine and OH), 4.1 (m, methine)
, 6.38 (m, ~H) and 6.93 (d, Jko8HZ
,~H). For transformers: MS: m/e306 (M10), 208 and 190.

PMR: 6 isoki, 30.82 (m" methyl), 3.2
5 (m, benzylic methine), 4.3 (m, carbinolmethine and OH), 6.33 (m, ArH) and 6.
94 (d, J=8HZ, ~H). cis-31 [4-(2
-octyloxy)-2-hydroxyphenyl]cyclohexanol and its trans isomer.

Raw materials: 3-[4-(2-octyloxy)-2-hydroxyphenyl]cyclohexanone (2.92 pm, 9.1
8mmole). The order of elution from silica gel is 1. The cis-3 isomer of Uta (54%) and 0.57 U (19%)
) was obtained. For cis: IR: (CHC13) 366 included 3390, 1637 and 1608 enemy-1.

MS: m/e320 (M+), 319, 208 and 19
0. PMR: 6 total 30.83 (m, methyl), 2.8
1 (m, benzylic methine), 3.8 (m, carbinolmethine), 4.1 (m, side chain methine and OH), 6.
35 (m, ~H) and 6.96 (d, J=8HZ, ~H
). For transformer: IR: (CHC13), 3636
, 3390, 1634 and 1595 skin 10MS: m/
e320 (M 10), 23fu 208 190 and 17fuP
MR: 65 units & 0.82 (m, methyl), 3.25 (m
, benzylic methine) 4.1-4.9 (m, carbyl/- and side chain methine and OH), 6.35 (m, Ar
H) and 6.96 (d, J=8HZ, ArH).

Cis-3-[4-(2-/nyloxy)-2-hydroxyphenyl]cyclohexanol and its trans isomer. Raw materials: 3-[4-(2-nonyloxy)-2-hydroxyphenyl]cycloto2xanone (3.15 evening, 1
9.48 mmole). In order of elution from silica gel, 2
．． 11 (67%) of the cis-3 isomer and 0.32 (67%) of the cis-3 isomer.
10%) of the trans-3 isomer was obtained as an oil.
IR: (CHC13) 3663, 3390, 1639 and 1610ka-1.

3MS: m/e334 (M+), 316, 208 and 1
90.

PMR: 30.88 (m, methyl), 2.85
(m, benzylmethine), 3.5-4.1 (m, rubinolmethine and OH), 4.22 (m, side chain methine)
, 6.38 (m, ArH), and 6.97 (d, J=8
HZ, 3-H). For trans: IR: (CHC13) 3636, 34131637 and 1592 skin-1.

MS: m/e334 (M10), 310208206 and 190. PMR: 130.88 (m, methyl) with 6 dia.
, 3.23 (m, benzylic methine), 3.9-4.
6 (m, carbinol and side chain methine and OH), 6.
36 (m"ArH) and 6.96 (d, J=8HZ, A
rH). Cis-3-[4-(2-(4-phenyl)butyloxy)-2-hydroxyphenyl]cyclohexanol and its trans isomer. Raw materials: 3-[4-(2-(4-phenyl)butyloxy)-2-hydroxyphenyl]cyclohexanone (2.9 hours, 8.23 mmol
e). 1.29 days (44%) in order of elution from silica gel
cis-3 isomer and 241 (8%) trans-3 isomer
The isomer was obtained. For cis: Melting point: 96-105°C (from bentane) IR: (CHC13) 36303390 1634 skin 1608 skin-1.

MS: m/e340 (M10), 322, 208, 190
, 162, 147, 136 and 91. PMR: 6 sheaths in 1
．． 30 (d, J = 6 Hz, methyl), 3.75 (m, force rubinolmethine) ÷ 4.23 (m, side chain methine), 6
．． 21 (d, J = 2HZ, ~H), 6.38 (dd, J
=8 and 2HZ, ArH), 6.98(d, J=8HZ
, ~H) and 7.20 (S, ph). Elemental analysis: C22
Calculated value for day 2803: C, 77.61: day, 8.
29% experimental value: C, 77.59; day, 8.18%.

For transformer: IR: (CHC13) 362 in 339
-1 of 0, 1637 and 1595c.

MS: m/e340 (M+), 342, 208, 190
, 162, 147, 136 and 91. PMR: 6 three units 1.30 (d, J = 6 Hz, methyl), 3.3 (m, benzylic methine), 4.23 (m, carbinol and side chain methine), 6.38 (m, ArH), 6.94(d,
J = 8 days 2, ~H) and 7.18 (S, ph).

For cis: cis-3-[4-(2-(6-phenyl)
hexyloxy)-2-hydroxyphenyl)cyclohexanone and its trans isomer.

Raw materials: 3-[4-(2-(6-phenyl)hexyloxy)-2-hydroxyphenyl]cyclohexanol (
3.3 min, 9.01 mole), 1.54 min (46%) of the cis-3 isomer and 27 in order of elution from silica gel.
9 of 4 (8%) trans-3 isomers were obtained. For the cis isomer: Melting point: 99-113 0 (from bentane) IR: (CHC13) 3630 3367, 1631
and 1592 skin-1.

MS: m/e368 (M+), 350, 208, 190
, 162, 147, 136 and 91. PMR: 65 units, 31.30 (d, J=6Hz, methyl), 3.6 (m
, carbinolmethine), 4.2 (m, side chain terminaline),
6.37 (m, ArH), 6.98 (d, Jko8HZ,
~H) and 7.18 (S, PNH).

Elemental analysis: Calculated value as C24th 3203: C, 78
．． 22: day, 8.75% experimental value: C, 78.05: day,
8.56%.

For trans isomer; IR: (CHC13)3630
3413163 rainbow skin 1597 skin-1.

MS: m/e368 (M 10), 350, 208, 190
, 162, 147, 136 and 91. PMR: 6 stages & 1
．． 25 (d, J=6Hz, methyl), 4.21 (m, carbinol and side chain methine), 6.37 (m, ArH)
, 6.95 (d, J=8HZ, ~H) and 7.15 (S
, PNH).

Claims (1)

[Claims] 1 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is hydrogen or benzyl, and Z is -O
-(alk)-, (alk) is alkylene having 1 to 13 carbon atoms, and W is hydrogen or a compound represented by ▲Numerical formula, chemical formula, table, etc. ▼]. 2. The compound according to claim 1, wherein R_1 is hydrogen and W is ▲a mathematical formula, a chemical formula, a table, etc.▼. 3. The compound according to claim 2, wherein Z is -O-(alk)-, and (alk) is alkylene having 4 to 5 carbon atoms. 4. The compound according to claim 3, wherein Z is -O-CH(CH_3)(CH_2)_3-, that is, 3-
[2-Hydroxy-4-(2-(5-phenylpentyloxy)phenyl)]cyclohexanol. 5 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is hydrogen or benzyl, and Z is -O
-(alk)-, where (alk) is a carbon atom of 1 to 13
A method for producing a compound represented by the formula ▲ where W is hydrogen or ▲ mathematical formula, chemical formula, table, etc. ▼
There are mathematical formulas, chemical formulas, tables, etc. ▼ A manufacturing method characterized by reducing the compound [in the formula, R_1, Z and W have the same meanings as above].