DE1900668A1 - New, substituted cyclohexenecarboxylic acids, cyclohexanoic acids, their derivatives and processes for their preparation - Google Patents

Description

D R. w. Schalk dipl.-ing. p. Wirth dipl.-ing. G. Dan ν en β erg DR. V.SCHMIED-KOWARZIK · DR. P. WEI NHOLD

6 FRANKFURT AM MAIN

OR. ESCHENHEIMER STR. 39 SK / SK

PA-3Ü3

ayntex Corporation
Apartado Postal 7386
Panama / Panama

New, substituted cyclohexenecarboxylic acids, cyclohexanoic acids, their derivatives and processes for their preparation

The present invention relates to a new method of manufacture substituted cyclohexenecarboxylic acids and new, substituted cyclohexenecarboxylic acids and their derivatives. The present invention relates refer in particular to a process for the preparation of cyclohexenecarboxylic acids and their derivatives with the following formula:

(A)

it says:

R stands for hydrogen, methyl or ethyl;
R ^{2 represents} methyl or ethyl;

R stands for hydrogen, methyl, ethyl or isopropyl; R represents hydrogen, lower alkoxy, hydroxy and the hydrolyzable, carbxylic esters thereof, cyclopentyloxy, cyclohexyl oxy, tetrahydropyran-2 ¹ yloxy, tetrahydrofuran-2'-yloxy, the group OSOgOX or the group OPO (OX) ₂ , where X is hydrogen or represents an alkali metal; R * for hydrogen, lower alkyl, lower alkoxy, hydroxy and the hydrolyzable, carboxylic esters thereof, cyclopentyloxy, cyclohexyloxy, tetrahydropyran-2 ¹ -yloxy, tetrahydrofuran ^ '- yloxy, the group OSO-OX or

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the group OFO (OX) ₂ , where X is hydrogen or an alkali metal; and Z and Z ¹ are each a carbon-carbon single bond or double bond, provided that at least one of the symbols Z and Z ^{1 is} a carbon-carbon single bond.

As used herein, the term "lower alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group having from 1 to about 6 carbon atoms. The term "lower alkoxy" as used herein refers to the group -Oalkyl in which alkyl is a lower k alkyl group as defined above. The wavy line (c) in the 2-position means ad, - and / or ß-configuration, ie the cis and trans isomers.

As used herein, "hydrolyzable carboxylic esters" refer to based on the commonly used in the art of synthetic hormones, derived from hydrocarbon carboxylic acids, hydrolyzable carboxylic ester groups. The term "hydrocarbon carboxylic acid" used here refers to both substituted and unsubstituted hydrocarbyl carboxylic acids. These acids can be completely be saturated or contain varying degrees of unsaturation (including aromatic bonds); you can just branched chain or cyclic and preferably containing 1-12 carbon atoms. Furthermore, they can be replaced by functional groups, e.g. hydroxyl groups, Alkoxy groups with up to 6 carbon atoms, acyloxy groups with up to 12 carbon atoms, nitro, amino, halogen groups, etc. substituted be bound to the hydrocarbon backbone. Typical customary hydrolyzable esters thus include according to the present definition the acetate, propionate, butyrate, valerate, caproate, unanthate, caprylate, Pelargonate, acrylate, undecenoate, phenoxyacetate, benzoate, phenyl acetate, Diphenyl acetate, diethyl acetate, trimethyl acetate, tert-butyl acetate, tri-

909835/1533

methylhexanoate, methylneopentyl acetate, cyclohexyl acetate, cyclopentyl propionate, Adamantoate, glycolate, methoxyacetate, hemisuccinate, hemiadipate, Hemi-ß.ß-dimethylglutarate, acetoxyacetate, 2-ChIOr - ^ - nitrobenzoate, aminoacetate, Diethylaminoacetate, piperidinoacetate, 13-chloropropionate, trichloroacetate, 13-chlorobutyrate, etc.

The compounds of the above formula A can be as shown below Process are produced:

^ o f.

(VII)

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1 3 ¹ V 5 In the above formulas, R, R, R and R have the already given B «German

2 ¹
tung, and R stands for hydrogen octar methyl,

When carrying out the above process, a compound of the formula I with a tetronic acid of the formula II Ln an aqueous solution of a water-miscible, organic solvent, such as methanol, ethanol, monoglyme, diglyme, tetrhaydrofuran, etc., at about room temperature up to about 75 C. for the duration of about 1-40 hours to form the Λ -substituted tetronic acid (III). In this reaction, temperatures above room temperature are preferred if the phenyl ring of the isothouronium acetate (I) contains a free hydroxyl group or is unsubstituted. Although this is not necessary, this reaction can be carried out in the presence of an alkaline catalyst, for example organic tertiary amines such as triethylamine, or inorganic alkalis such as sodium or potassium hydroxide. The reaction is usually completed in about 1 ¹ V hours. A compound of formula III is then treated with an acid, preferably a strong acid, alone or in an organic solvent inert to the reaction, such as benzene, xylene, methanol, dioxane, etc., at a temperature from about room temperature to the reflux temperature of the solvent brought into contact for a period of about 1-2 ^ hours to form an enol lactone of the formula IV. Examples of the inorganic and organic acids suitable for this reaction are p-toluenesulfonic acid, sulfosalicylic acid, anhydrous orthophosphoric acid, sulfuric acid, formic acid, hydrochloric acid, etc. This ring cyclization is preferably carried out by treatment with p-toluenesulfonic acid in benzene, xylene or toluene at reflux for about k hours . If the phenyl ring of compound III is unsubstituted or has a free hydroxyl group, the solvent is preferably xylene or toluene.

9 0 9 8 3 5/1533

An enol lactone of the formula IV is then treated with an aqueous solution of a base, such as the alkali metal hydroxides, etc., in a water-miscible, organic Solvent treated at about room temperature for a period of about one to a few hours, whereupon the reaction mixture to form a Equilibrium mixture of a tautomeric cis-keto acid of the formula VA and des cis-lactols of the formula VB is acidified. This equilibrium mixture is predominantly the cis-lactol, and for the sake of clarity and avoidance In the following, unnecessary verbosity includes the cis-lactol

also the cis-keto acid, i.e. the equilibrium mixture.

15in cis-lactol is then subjected to a carbonyl reduction to form a cis-oleic acid of the formula VI. The cis-lactol can also be obtained first by treatment with a lower alkyl halide, preferably an alkyl bromide or iodide having up to 6 carbon atoms, in an organic solvent such as dimethylacetamine or dimethylformamide, at about room temperature for a period of about 1 hour the corresponding cii-ketoester (VI ¹ ) are converted; then the cis-ketoester is subjected to carbonyl reduction to form the acid ester (VI "), whereupon the latter is converted to the free acid (VI) by alkaline hydrolysis. Although the following description refers to the carbonyl reduction of the above cis-lactol, it is equally applicable or suitable for the carbonyl reduction of the keto ester.

909835/1 533

... (XX) alkyl

.. .COOalkyl .. .CH ₂ -R

(VI ')

(VI ")

A cis-lactol (VA and VB) is used to form the cis-acid (VI) in a carbonyl reduction subject. This can be done electrolytically in a divided electrolysis cell. When performing the carbonyl reduction according to electrochemical process, the reduction takes place at the cathode of a split electrolysis cells in an electrolytic medium consisting of a mineral acid electrolyte, Water and an inert organic material that is miscible with water Solvent at a current density of about 0.01-0.2 amps / cm and at a temperature of about Θ-70 C. for a period of about 1-16 hours. Mineral acids suitable for the electrolytic medium are sulfuric acid, hydrochloric acid, perchloric acid, hydrobromic acid, phosphoric acid, etc., where Sulfuric acid or perchloric acid is preferred. Organic, mixable with water Solvents which are inert to the electrolysis reaction and which are suitable for the electrolytic medium are ethers, such as dioxane and tetrahydrofuran etc., lower monohydric alcohols such as methanol, ethanol, etc., lower alkylene glycols such as ethylene glycol, propylene glycol, etc., and mixtures the above solvents, etc. in which the cis-lactol is soluble or substantially soluble.

The amount of solvent present in the electrolyte medium can vary from the amount sufficient to dissolve or substantially dissolve the cis-lactol up to about 9% by weight, preferably from about 20-85% by weight, of the total

-7a -

90983 5/153 3

electrolytic medium. The amount of acid in the medium can be from about 1-20% by weight, preferably from about 2-15% by weight, of the total electrolytic medium. The amount of water in the medium should be at least 5% by weight, preferably about 10-75% by weight, of the total electrolytic medium. A preferred medium consists of an equal volume of the inert organic solvent and an equal volume of 10 to 50% by weight aqueous sulfuric acid.

The cathode materials suitable for el ektroclmmi see reduction include high tension materials such as lead, Cadmium, mercury u:; v ?. The cathode can have various physical properties • Have shapes, but should be anticipated in a shape with a high surface area before, for example as a foil or hashed} aJit, for the purpose of use as a guide Ausre3cliend hard ir-t. The anode materials suitable for this reduction are conductors that are difficult to oxidize, many carbon, platinum, kison, Lead, etc. In general, the anode material can be any conductor which is not attacked by the electrolytic medium in a way that would convert it to a soluble state within a short period of time.

ο A current density of about 0.01-0.2 Amp./cm, preferably about 0.02-0.1, can be applied. Reduction times of about 1-10 hours are usually used, depending mainly on the current efficiency of the system, tis we ·.! sine'i'r-itiperpr.;: · -? wiscl; cn t-ti; a 5- ^ 0 ° Cr bc-f, r: /. agt.

Eiri <; 2-ΑΊ Kylfvclohfix-3 --en- '»■ cai'Va-iö"' · '"V-. ^: . · R; i; zvr Piliiun ;; d <.; r on ⁴ r: j> 3 (-r'i'mden 3, ^ί \ -ϋϊΐι \ &'ον& ι \ -Τι.γ> - · ~'->.<ί" VIII): '■ • ■■■ ie:, iiir.s'i Ked '', - tion

i Min kai <'·.], ν1'irr:] ;, -., B ₁ uii- ■■.' V r:> ~ nd \ ■ -. -. j.adi ^: - i. '·: ■ -: -. ^ Jyaaioi -κ, · '-.'- Υ ·· Λ j sriäui: - α'ΐί ¹ - Tin) Ι ο) ^1:;! ... \, · "iVolgf-.

9 0 9 8 3 5 /

BAD ORIQiNAL

iSine 2-alkylcyclohex-A-en-1-carboxylic acid (VII) can be prepared by treating a 2-alkyleyclohex-3-ene-1-carbnni>: iure (VI) with hydrogen chloride etc. in an organic solvent, such as benzol, toluene etc., according to the procedure of UÜ patent specification 2 ^r > 82 253.

Liln, particularly suitable for the preparation of the trins isomers of the formula V * Method · consists in treating an iSnollaeton (IV) with an aqueous one Solution of an alkali metal hydroxide, such as sodium or potassium hydroxide, in a water-miscible organic solvent at about room temperature for a period of a few hours or at higher temperatures, e.g. reflux temperature, for a shorter period of time; so you get one trans-keto acid of the formula V together with a smaller amount of an equilibrium mixture of the cis isomers (VA and VB) < The trans-keto acid can at this point by conventional methods, e.g. fractional crystallization, to be isolated.

(V)

The keto acid (V ¹ ) is subjected to the electrochemical reduction processes described above to form the corresponding acid.

909835 / 15'J'J

When opening Knollactons (IV) by treatment with alkali hydroxide provide reaction times of around 1-3 hours, predominantly the cis isomer '» during reaction times of more than about 3 hours for the formation of the trans-. Lead isomers. This means that the formation of the trans-Xsomer is prolonged Reaction times faster than about 3 hours.

When carrying out the above process, acid-labile groups in a compound of the formula III and V, ie when R and / or R are tetrahydrop.yran-2 ¹ -yloxy or tetrahydrofuran-2'-yloxy, usually become free hydroxyl groups in the course of the reaction hydrolyzed. The free hydroxyl group (ri) is then etherified, optionally again by treatment with dihydropyran or dihydrofuran and an ijäurekatal, ysator such as p-toluenesulfonic acid, alone or in a co-solvent such as benzene. Base-labile (Irupiieri in a compound of Formula IV, ie if R and / or R stand for a hangover group, are usually hydrolyzed to free hydroxyl groups in the course of the reaction, which can then be re-esterified using conventional esterification processes, if necessary.

The cyclohexenecarboxylic acids of the above formula VI and. VII and the cyclohexanecarboxylic acids of the above formula VIII and the acids derived from compounds of the formula V can be converted into valuable acid derivatives of the following formula B to be converted:

R ¹

(B)

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- .ter -

in which

R for hydroxymethyl or the. That is, hydrolyzable, earboxylic underneath it, Fonnyl, -COtH, -COF, -OwIJhV, c ki · dir. Group -GOIr sees., Where R is lower alkyl or an Al i i.länetaJl; and R to R ", Z and Z ¹ have the Iiodoutting given above, with the proviso that none of the irrational R or R for the group

iiiri ·· OPO (C ¹ '' .. «lei-tw-nn Ii""" - ("X) CJ or -COF means«

OSO ₀ C / odf ϊ

Tu ' iire <"li] <rii ·,' (! .H = - {'■■''·) -ueivVn by reha'vi \\ mr dor dor free .'.-- aure (VI, VIl (Hi ( ! J IJV) nit TriΓ: (- rylphosphin riiitoff iVti'G.rh'Jorkohlc-in or by treatment mil thionyl 'l.irrid or 0> nly] ehlnj * id in cin ^ m inert (i), h. \ ^jnpenit: rl <: n Lö: ϋ: υ _'s medium viv chloroform or lietlr, J'iir'hlorid, egg-v ^ Y TI / imnertcii-IIci ^ structure for a period of about 1-12 Standen it.!. ) ialtpn _c üa'ure.- · - IaLi J ν. \ Jrvp \ nn k <: πι <:> wahrei '.' J dioser reaction completed: iJ th four; ast one

/ 4. 5

Compound of the formula 1 B, in v; Icher R and / or R for Te1.rahydropyran ~ P'-yloxy or Pei.rah.vdrofuran-; · '-, γίοχ, ν. Are desired, it is therefore necessary to the free hydroxyl compound:; - ..?., etherified by V ».; jv; ending of the etherification process described above.

6 "

The compounds of formula Ii in which R is -C-F are by Treatment of the free acid leads to N- (2-chloro-l, l, 2-trifluoroethyl) "diet; vlai'-in in an inert solvent such as jither, acetonitrile or methylene chloride? id, at a Tenpi r * w of etv '' '·' :, lir; oiva for the return to JuPtcmperatur fir · -./t Iiauer from j - 1C,: .->:. u cmV "! -.-: ..

or: u in

• j · t: .ii ι j i. :. J "i-. ·.

'. " Iv-i. ]>: I Rüc

ί Ί i?

BAD CmiQtHAL

6 "7 7

The compounds of the formula B in which R is -C-OR, where R means an alkali metal can be obtained by treating the free acid with a dilute alkali metal hydroxide solution or a dilute alkali metal bicarbonate solution in a lower alcohol solvent such as ethanol at around room temperature. The alkali metal salt can then by treatment with a lower alkyl odide or bromide in dimethyl acetamide or dimethylformamide into the acid ester (B;

6 "7 7
R means -C-OR, where R is lower alkyl).

The compounds of formula B, in which R is hydroxymethyl, are produced by treating the ester (B ;; R stands for

"7 7
-C-OR ι where R is lower alkyl), for example with lithium aluminum tert-butoxyl in an inert solvent such as tetrahydrofuran. The hydroxymethyl compound can then be subjected to conventional esterification processes to form the corresponding hydrolyzable carboxylic esters; or it can also be converted into the corresponding aldehyde (Bi R stands for formyl) by treatment, for example with chromium trioxide in pyridine.

The compounds according to the invention with the group OPO (OX) _? can eg from the corresponding free, hydroxy-substituted compounds by treatment

with ß-cyanoethyl phosphate and a condensing agent and then

by reaction with hydrolysis of the reaction product or / a functional derivative of phosphoric acid, such as dibenzyl phosphate halide and catalytic hydrogenation. The phosphoric acid ester can be converted into the corresponding alkali metal salts by treatment with a base, for example sodium ethylate, sodium or potassium bicarbonate, etc. By regulating the amount of base, both monoals and disalts can be obtained. Suitable processes are, for example, in US patents 2,936,313, 3 2 * f8 408, 3 Z ^ k 100,

909835/1533

3 257 385, 3 268 562 and 3 3 ^ 5 259 as well as in Chem. & Ind, page 117 ^ -1175 I ₁ S. July 1967).

The compounds according to the invention with the group OSO 2 ^ can be obtained from the corresponding free hydroxy compounds by treatment, for example, with a sulfur trioxide / pyridine complex at low temperature ^ see British patent specification 926 4-72 (1963), Journ "Am. Chem. Soc, 6j3, 1259 (19 ² H), J.Biol. Chera., JL15_, 381 (1937) and "Steriods" 10, No. 3, 310 (September 1967).

The cyclohexenecarboxylic acids and their derivatives according to formulas A and B above are excellent anti-fertility agents. They can be used and administered in the same way as the known cyclohexenecarboxylic acids which come under the formulas A and B (cf., for example, US Pat. No. 2,582,253 and 3,344 Wf). Because of their excellent anti-fertility properties, the compounds of the above formulas A and B are suitable for combating pests, for example, of rodents such as rats, mice, nutria, etc. For this purpose, the compounds are mixed with a suitable bait, such as grain, salmon, etc., and placed in an area accessible to rodents. The amount of anti-fertility agent incorporated into the bait is not critical as long as it does not exceed the limit above which the rodent will detect the presence of the agent. The mixture of anti-fertility agent and bait is preferably made available to the pest on alternate days, for example, in an amount which, from past experience, can be expected to be completely eaten in two days.

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Swallowable bait carriers include liquids, solids, and mixtures thereof such as water, milk, molasses, corn oil, srdnufi oil, cottonseed oil, sugar, peanut butter, fried chicken feed, holker mixes, corn, oats, wheat, bran, meat, fish, tallow, sliced Grass or hay, cheese, salt, etc. Furthermore, conventional agents for luring the pests and other additives conventionally used in bait can be added. Anti-fertility and bait preparations kcnr.er. aB alo granular mixture, as a paste, syrup, in the form of a tablet »? etc. ariii- le-daughter application r _{4 be} ergesöeilen. Other carriers can also be used, for example by forming a solution, for example a salt solution octet * mixture, which contains a small amount of the anti-fertility agent. I / r.impregnlern a suitable carrier, such as cellulose-containing materials, win HoIa, with the solution.

The following examples illustrate the present invention to restrict »

Example 1

To a solution of 16.8 g of ethyl - ^ - propionylpropionate in 100. g bromine was added dropwise with such a gel, so that the solution remained clear all the time. The mixture was stirred for a further 2 hours. After the reaction time, the ether was evaporated off under reduced pressure and the resulting oil was then dissolved in 6% xylene and the xylene mixture obtained was 1? Reflux for hours. The vinyl mixture was allowed to cool and then concentrated to a smaller volume; on cooling, a precipitate of dimethyl tetronic acid separated out, which was filtered off and urocrystallized from benzene / hexane.

According to the above procedure using ethyl - ^ - propionyl butyrate as a starting material, o \, -ethyl-methyltetronic acid was obtained.

909835/1533

example

In the above method of preparing the starting material, R represents Hydrogen, methyl, ethyl or isopropyl, R means hydrogen, hydroxy or ester, lower alkoxy, cyclopentyl ray, cyclohexyloxy, tetrahydropyran

5 "

2'-yloxy or tetrahydrofuran-2 ^l -yloxyi R is lower alkyl, hydrogen, hydroxy or ester, lower alkoxy, cyclopentyloxy, cyclohexyloxy, tetrahydropyran-2-yloxy or ¹ tetrahydrofuran-2-yloxy ^l; and X represents chlorine or bromine .

To a freshly prepared solution of 3/4 g of methyl magnesium bromide in 20 ecm of tetrahydrofuran, a solution of 1 molar equivalent of benzaldehyde in 25 ecm of tetrahydrofuran and 15 ecm of ether was added. The resulting mixture was kept at room temperature for 2k hours and then refluxed for 2 hours. Then it was cooled and diluted with water. This mixture was acidified with HCl and stirred to destroy the excess Grignard reagent. The organic phase was separated and the aqueous layer was extracted several times with ether. The combined ether extracts and organic phase were washed with water, dried and evaporated to give 2-phenyl-2-hydroxy-ethane (3; R = R ~ R ^ "= hydrogen). 2 g

909835/1533

2 ~ phenyl-2-hydroxyethane in 50 ecm pyridine were added to a mixture of 1 g chromium trioxide in 10 ecm pyridine. This mixture was left to stand at room temperature for 15 hours and then diluted with ethyl acetate and filtered. The filtrate was washed with water, dried and evaporated to give methyl phenyl ketone (k \ BT = R = R ^ = hydrogen).

A freshly prepared solution of 3 g of vinyl bromide in 3 ecm of tetrahydrofuran was added to 0.5 g of magnesium in 5 ecm of tetrahydrofuran to produce a V inylmagnesium Grignard reagent ζ. A solution of 1 g of methyl phenyl ketone in 25 ecm of tetrahydrofuran and 10 ecm of ether was then added to this mixture, and the mixture obtained was kept at room temperature for 2k hours, then heated to reflux for 1 hour and cooled. The reaction mixture was then poured into water, acidified with hydrochloric acid, and vigorously stirred to decompose any excess Grignard reagent. The organic phase was separated off and the aqueous layer was extracted several times with ether. The combined ether extracts were washed neutral with water, dried over sodium sulfate and evaporated to give 2-phenyl-2-hydroxybut-3-ene (5; R ³ * R ^ "= R ⁵ " = hydrogen).

By repeating this procedure using substituted benzaldehyde, for example 4-methoxybenzaldehyde, 4,6-bimethoxybenzaldehyde, 4-methoxy-omethylbenzaldehyde, 6-methoxybenzaldehyde, 4,6-di-hydroxybenzaldehyde and 6-methylbenzaldehyde instead of benzaldehyde, the corresponding Obtained substituted 3-butene compounds, ie 2- (4'-methoxyphenyl) -2-hydroxybut-3-ene, 2, - (^ f ', 6'-dimethoxyphenyl) -2-hydroxybut-3-ene , 2 - (^ ¹ -Methoxy-6 ¹ -methylphenyl) -2-hydroxybut-3-ene, 2- (6'-methoxyphenyl) -2-hydroxybut-3-ene, 2- {k ^} , o'-dihydroxyphenylJ ^ -hydroxybut-3-ene and 2- (6'-44ethylphenyl) -2-hydroxybut-3-ene. '

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By repeating the above procedure using ethyl magnesium bromide, n-propyl magnesium bromide and isobutyl magnesium bromide instead of Methylraagnesium bromide contained the corresponding compounds of the formula

3
5, in which R stands for methyl, ethyl or isopropyl.

Example 3

A mixture of 11.8 g of thiourea and 100 ecm of acetic acid was added heated in a steam bath until the mixture was homogeneous. The solution was then cooled to room temperature and then 1 molar equivalent of 2-phenyl-2-hydroxy-but-3-ene added. The resulting mixture was stirred until it was homogeneous. Then the acetic acid was reduced by heating under Pressure (5o-60 ° C.) Removed. The residue was stirred in 70 ecm ether poured. The resulting precipitate was collected and dried

/ 3 ^ 5 net and gave 3-phenyl-but-2-enylisothiouronium acetate (I; R = R = R = Hydrogen).

By repeating the above process using other compounds of formula 5 prepared according to Example 2 as starting material, such as 2 - (^ ¹ -methoxyphenyl) -2-hydroxy-but-3-ene, 3, - (^ ¹ -methoxyphenyl) - 3-hydroxypent - ^ - en, ^, - (^ ¹ -Methoxyphenyl) -4-hydroxyhex-5-en, 4 - (^ ¹ -Methoxyphenyl) -dihydroxy-2-methylhex-5-en, ^ -phenyl- ^ -hydroxy-2-methylhex-5-ene, k- (k ^f , 6'-dimethoxyphenyl) -4-hydroxy-2-methylhex "-5-ene, 3 - (^ ¹ t ^ '-dimethoxyphenyl) -3 -hydroxypent-4-ene and 4 - (^ ¹ -Methoxy-6 ¹ -methylphenyl) -4-hydroxyhex-5-ene, the corresponding isothiouronium acetates were obtained.

Example 4

^S To a solution of 12.5 g of 3-yl Ph ^You t-2-enylisothiouroniumacetat in a mixture of 80 cc of ethanol and 100 cc of water, a solution of 1 molar equivalent ^, / ^ Dimethyltetronsäure in 20 cc of ethanol was added. the

909835/15 3 3

The mixture was immediately diluted by adding a further 80 ecm of water, stirred and left to stand at room temperature for two hours. Then it was heated to about 60 ° C. for 10 hours and cooled to 5 ° C. for 2 hours; the precipitate formed in this way was filtered off and yielded Oi - (3-phenylbut-2-enyD - ^. ^ dimethyltetronic acid (III; B ^ = R ² '= C1L ·; RW * = R ⁵ = hydrogen).

Example 5

A solution of 1 molar equivalent of C \ , ^ - dimethyltetronic acid in 20 ecm of ethanol added. The mixture was immediately diluted with 80 ecm of water and then stirred and left to stand at room temperature for Zh hours. Then it was cooled to 5 g for 2 hours; the precipitate thus formed was filtered off and gave oC- / 3 - (^ ^l - ^ i ^e th ° ^x yphen _r yl) -5-methylhex-2-enyi / -o (', jf ^ -dimethyltetronic acid (III; R ^{1 -} = R ² ^ CH-; R ³ = isopropyl; R ^ = OCH ₃ ; R ⁵ = hydrogen).

By using other isothiouronium acetates prepared according to Example 3 in this process, such as 3 - (^ ¹ t6'-dimethoxyphenyl) -hex-2-enyl isothioruoniuraacetat, 3 - (^ · '-jlethoxy-6' -methylphenyl) -hex- 2-enylisothiouroniujnacetat, 3- ( ² ^ ¹ , 6 '-Dimethoxyphenyl) ^ - methylhex - ^ - enylisothiouroniumacetat, 3 - (^' - Metboxy-6 ¹ -methylphenyl) -5-niethylhex-2-enylisothiouroniuTnacotat or

3- (4 ', 6'-Dimethoxyphenyl) -pent-2-enylisothiouronium acetate, the corresponding products were obtained, ie o £ - ^ - (4 · _f 6'-Dimethoxyphenyl) -hex-2-ehy] J-

909835/15 3 3

c ^ ', Γ-dimethy! tetronic acid, οί- / 3 - (^' -Methoxy-6 ¹ -methylphenyl) -hex-2-enyl / - <£} , ^ - dimethy! tetronic acid, <Κ- / 3- (^ ', 6'-Dimethoxyphenyl) -5-methylhex-2-eny] J- • λ', ^ - dimethyltetronic acid, dL-ß> - {^ -Methoxy-6 ¹ -methy! Phenyl) -5-raethylhex- 2-enenyl7-o (i / * - dimethyltetronic acid and <^ - / 3- (4 ', 6' -dimethoxyphenyl) -pent-2-enyl / - ^ ¹ , / '- dimethy! Tetronic acid.
Example 6

9 gi> (- (3-i ^J henylbut-2-enyl) - </ $, / '- dimethy tetronic and ^ O mg of p-toluenesulfonic acid in 120 cc of toluene was refluxed for k h, wherein continuously the water from the reaction mixture was removed by a Dean-Stark trap. After cooling, the reaction mixture was filtered through a short column of silica gel and evaporated under reduced pressure to give 5-Pheryl-3 | 8 ~ dimethyl6,7,8,9-tetrahydroisobenzofuran-1- on (IV; R ¹ ^ R ² '= CH ,,; R ^ R = R ^ = hydrogen).

Example 7

To a solution of 1 g q ( -0 - (^ ¹ , 6 '-Dir
methyltetronic acid in 20 ecm was added 1 ecm of 15% by weight hydrochloric acid. The resulting mixture was stirred and allowed to stand at room temperature for 17 hours. Then it was extracted with ether for a few quays. The ether extracts were combined, washed well with water, dried and evaporated to give 5 - (^ ¹ to ¹ -Dimethoxyphenyli ^ fS-dimethyl-o ^ te, ⁰ -

1 2 ¹ 3 J ^

tetrahydroisobenzofuran-1-one (IV; R = R = CH ~; R = hydrogen; R = R ⁵ = OCH «).

909835 / ibJ,

QD

-GH,

By repeating this process using other, substituted tetronic acids (see, for example, Example 5) as starting material, the corresponding products were obtained, ie 5 - (^ ¹ -4 ^ ethoxyphenyl) - ^ isopropyl-3,8-dimethyΙό, 7,8, 9-tetrahydroisobenzofuran-l-one, 5 - (^ ¹ f6 '-Dimetho-xyphenyl) - ^ - ethyl-3,8-dimethyl-6,7,8,9-tetrahydroiaobenzofuron-l-one, 5 - (^' -Methoxy-6 ¹ -rae-thylphenyl) - ⁱ J-ethyl-3,8-dimethyl-6,7,8,9-tetrahydroisobenzofuran-1-one _t 5 - (^ ¹ * 6 ¹ -Dimethoxyphenyl) -4- isopropyl-318-dimethyl-6,718,9-tetrahydroisoben zofuran-1-one, 5_ (k '-methoxy-6'-methylphenyl) -4-isopropyl-3' 8-dimethyl6,7,8,9-tetrahydroisobenzofuran-1- one or 5 - (^ ', 6 · -Dimethoxyphenyl) -3,4,8-trimethyl-6,7,8,9-tetrahydroisobenzofuran-1-one.

Example 8

A mixture of 0.5 g of 5-phenyl ~ 3 _{t of} 8-dimethyl-6,7 »8,9-tetrahydroisobenzofuran-1-one in 60 ecm of ethanol and 2u ecm of aqueous IN sodium hydroxide solution was left to stand for 2 hours at room temperature. Then this reaction mixture was acidified by adding aqueous Q, IN hydrochloric acid. The acidic mixture obtained was extracted a few times with ether, the ether extracts combined, dried and evaporated under reduced pressure; they gave cis-5-phenyl-3 $, 8-dimethyl-3 ^ -hydroxy-3,9 »6,7> 8,9 -hexahydroisobenzof uran-1- one, as follows:

909835/1533

-2Θ- -

19006B8

.. .COOH
• · »C — GH

Example 9

A mixture of 307 mg of cis-5-P ^h enyl-3 $, ß-dime-thyl-Sjf-hydroxy ^, 9,6,7,8,9-hexahydroisobenzofuran-1-in, 1 cc of methyl iodide and 7 cc Di me thy lac et amid was stirred in the dark for 5 hours. D-mn the excess methyl iodide was removed by evaporation under reduced pressure. The reaction mixture was then poured into water and the mixture extracted several times with ether. The ether extracts were combined, washed with water and then with dilute aqueous sodium thiosulfate solution, dried and evaporated to give the methyl ester of cis - ^ - phenyl-1-methyl-2-acetylcyclohex-3-ene-carboxylic acid, which was recrystallized from benzene / hexane (VI ¹ SR ¹ = !! ² '= CH ₃ ; R ³ = R = R ⁵ = hydrogen; alkyl =' CH ^).

By repeating the above procedure using a different one, lower Alkyl iodides "or bromides, e.g., ethyl iodide, etc., instead of methyl iodide the corresponding lower allyl esters were obtained.

Example lü

In the cathode part of a divided electrolysis cell, which is equipped with a cellulose dialysis membrane, Lead electrodes (each electrode mai3 2 cm 5 cm 1.6 mm) and a stirrer was provided, 20 mg of the methyl ester of cis - ^ - phenyl-1-methyl'v-acetylcyclohex-3-ene carboxylic acid and a mixture of 15 ecm dioxane and 15 ecm 10 wt .- ^ iger sulfuric acid added. Another lot of one Mixture of 15 ecm dioxane and 15 ecm 10% aqueous sulfuric acid was used

909835/153 3

put in the cell. A current density of 0.02 amps / cm was applied for 5 hours. The reaction mixture was then removed from the cell and concentrated under reduced pressure to a small volume, which was extracted several times with ether. The ether extracts were combined, washed with water and a 5% aqueous sodium bicarbonate solution, dried and evaporated to dryness; the methyl ester of cis-4-phenyl-imethyl-ethylcyclohex-O-ene carboxylic acid (VI "; R ^{1 =} R ^ CH-i R ^ = R = R ^ = hydrogen; alkyl = CH ₃ ) was obtained in this way.

By repeating this procedure using the cis-lactol of Example 8 as a starting material was obtained the cis-Λ-phenyl-l-methyl-2-

12 '3 ^ p

ethylcyclohex-3-ene carboxylic acid (VI; R = R = CHo; R -R = R -hydrogen).

Example 11

A solution of 1 g of cis - ^ - phenyl-1-methyL-a-ethylcyclohex ^ -encarboxylic acid in dry benzene was cooled in an ice bath and then saturated with dry hydrogen chloride. This reaction mixture was allowed to stand at room temperature for k hours. After evaporation of the solvent, the cis-4-phenyl-1-4nethyl-2-ethylcyclohex- ^ - en-carboxylic acid (VII; r ¹ - ^ ² '= CH ₃ ; R ^ R ^ R ^ hydrogen) was obtained.
Example 12

A suspension of 0.3 g of 5- ^ ig ^e ni palladium-on-carbon catalyst in 50 cc of methanol was hydrogenated for 30 minutes. A solution of 2 g of cis - ^ - phenyl-1-methyl-2-ethylcyclohex-3-ene-carboxylic acid in 150 ecm of methanol was added and hydrogenated with stirring until the hydrogen ceased to take up. The catalyst was filtered off and the filtrate was evaporated; so one got

■ 1 2 ¹

the cis - ^ - phenyl-l-methyl ^ '- ethylcyclohexanecarboxylic acid (VIII; R = R = 0Ηοί

909835/1533

- zz -

Example 13

nine mixture of 67O mg 5 - (^ ¹ # 6 '-Diraethoxyphenyl) -3,8-din: ethyl-6,7,8,9-tetrahydroisobenzofuran-1-one in 70 ecm dioxane and 45 ecm aqueous 0.1N- Sodium hydroxide became JS hours at -20 ° C. ditched. Then the solvents were removed by evaporation under reduced pressure. The residue obtained was diluted with water and acidified by adding dilute hydrochloric acid. This aqueous mixture was extracted several times with ether. The ether extracts were combined and evaporated to dryness and gave a mixture of trans-4- (4 ', 6' -dimethoxyphenyl) -1-methyl-2-acetylcyclohex-3-ene carboxylic acid and cis ~ 5- (4 ', 6'- Dimethoxyphenyl) 3 <, 8-dimethyl-3 s-hydroxy-3,9 ₁ 6,7,8,9 -hexahydro i soben zofuran-1 -one, which was separated by fractional crystallization using benzene / hexane and the trans - ^ - Cf ¹ , 6 '-Dimethoxyphenyl) -l-methyl ^ -acetylcyclohex ^ -encarboxylic acid (V ¹ ; R ^1- = R ² ' = CHo; ^ = hydrogen; R = R ^ = OCH.J.

When the above-prepared trans-keto acid was subjected to the reduction procedure of Example 10, trans-4- ( k ^x , 6'-dimethoxyphenyl) -1-methyl-1-2-ethylcyclohex-3-en-carboxylic acid was obtained.
Example lh

A mixture of 1 g of 5-Pheny1-3,8-dimethyl-3t ^ -dehydroisobenzofuran-1-one, 0.4 g of potassium carbonate and 100 ecm of aqueous ethanol (1: 1) was added for 4 hours Heated to reflux, then cooled to room temperature, concentrated to dryness under reduced pressure and the residue chromatographed on silica gel; so one got the potassium salt of the trans ^ -Phenyl-l-methyl ^ - acetylcyclohex-3-ene-carboxylic acid, according to Example 9 to the corresponding Methyl ester was implemented. Using the procedure of Example 10 the methyl ester thus obtained was converted into the ethyl ester of trans-4-phenyl-imethyl-2-ethylcyclohex-3-ene-carboxylic acid converted.

909835/153 L <

- 29 -

Example 15 - _ -

ttine hybrid of 3UO mg of the methyl ester of cis-4-phenyl-1-methyl-2-ethylcyclohex-3-ene-carboxylic acid, 3 »! S potassium hydroxide, 7 ecm ethanol and 7 ecm Water in a sealed tube was heated to about .180 C for about 45 minutes, allowed to cool, and then poured into water. The mixture obtained was acidified by adding dilute aqueous hydrochloric acid and some Extracted times with / \ thylacetate. The ethyl acetate extracts were combined, -. dried and evaporated and gave the cis-Λ-phenyl-1-methyl-2-ethylcyclohex-3-en-carboxylic acid.

Using this procedure, the methyl ester of Example 14 was converted into trans-4-phenyl-1-methyl-2-ethylcyclohex-3-ene-carboxylic acid converted.

example l6_

A solution of 1 g of cis-4- (4 ', 6' -dimethoxyphenylJ-l-methyl- ^ - ethylcyclohex-3-ene-carboxylic acid in 20 ecm CCl ^ was allowed to react with 2 g of triphenylphosphine. The reaction mixture was allowed to react for 12 hours at Held at 25 ° C., then poured into ice water, filtered and the filtrate extracted with ether. The ether extracts were dried and evaporated to give the cxs-k- {k ^x , 6'-dimethoxyphenyl) -l-methyl-2-ethylcyclohex- 3-ene-carboxylic acid chloride.

Example 17

A solution of 1 g of cis-4 - (^ - ', 6'-Dimethoxyphenyl) -l-methyl-2-ethylcyclohex- ■ 3-ene-carboxylic acid in 30 ecm of anhydrous methylene chloride xiurde with 1 g of N- (2-chloro-1, l, 2-trifluoroethyl) diethylamine ditched. The reaction mixture was refluxed for 5 hours, then poured into ice water and filtered and extracted with ether. The ether extracts were combined, dried and evaporated to give the cis-4- (4 ', 6' -dimethoxyphenyO-1-methyl - ^ - ethylcyclohex-3-ene-carboxylic acid fluoride.

909835/15 2 o-

- 2 * F -

Example 18

Its hybrid of 1 g of the methyl ester of the cis - ^ - Phenyl-l-methyl ^ -äthyl-ί cyclohex-3-ene-carboxylic acid in 20 ecm anhydrous tetrahydrofuran was in a dry ice-acetone bath cooled to -75 C. and with a pre-cooled Solution of 0.6 g of lithium aluminum hydride in 20 ecm of anhydrous tetrahydrofuran treated. The reaction mixture was allowed to warm to room temperature and then refluxed for 15 hours. Then she became cooled, poured into ice water and extracted a few times with ethyl acetate. The ethyl acetate extracts were combined, washed neutral with water and dried and evaporated to dryness and gave the cis - ^ - phenyl-l-methyl-l-hydroxy-methyl-2-ethylcyclohex-3-ene, which can be increased further by recrystallization from acetone / hexane.

According to the above procedure, the methyl ester of cis- ^ J - (^ ¹ , 6'-Dimethoxy-DhenylJ-l-methyl ^ -äthylcyclohex ^ -en-carboxylic acid in cis - ^ - (^ ', 6' -Dimethoxyphenyl) - 1-methyl-1-hydroxymethyl-2-ethylcyclohex-3-ene converted.

Example 19

To a solution of 1 g of ice - *) · -Phenyl-1-methyl-1-hydroxymethyl-2-ethylcyclohex-3-ene in 25 ecm of pyridine, which was previously heated to 0 ° C. had been cooled, a cooled solution (0 ° C.) of 1 g of chromium trioxide in 25 ecm of pyridine was added dropwise. The reaction mixture obtained was at 0 ° C. for 2k hours. held, diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate was washed with water, dried and evaporated to give cis - ^ - phenyl-1-methyl-l-formyl-2-äthylcyclohex-3-en _f can be umkristalüsiert from acetone / hexane.

909835/153 3

By repeating the above procedure using cis- ^ J- (^ J- ¹ , 6 '- Whore thoxyphenyl) -1 -methyl-1-hydroxymetnyl ^ -äthylcyclohex ^ -en as starting material, ice - * »- ( ² J- ¹ , 6 '-Dirnethoxyphenyl) -! - methyl-1-formyl-2-ethylcyclohex-3-en.
Example 20

A solution of 1 g of cis - ^ - (4 ', o'-DimethoxyphenylJ-l-methyl ^ -äthylcyclohex-3-en-carboxylic acid, 2 ecm thionyl chloride in 20 ecm benzene was refluxed for 2 hours, cooled and evaporated residue was dissolved in anhydrous dioxane and the solution was saturated with a stream of anhydrous ammonia Then, water was added after 24 hours and the \ product filtered off so there was obtained cis ^ J- ^(4-1, 6'-dimethoxyphenyl) -. l-methyl-2-ethylcyclohex-3-ene-carboxamide.

By repeating the above procedure using cis - ^ - phenylmethyl-2-ethylcyclohex-3-ene-carboxylic acid as the starting material, the cis - ^ - phenyl-i -methyl ^ -äthylcyclohex ^ -en-carboxamide was obtained. Example 21

A mixture of 5 g cis - ^ - (4'-MethoxyphenylJ-l ^ -dimethyl ^ -äthylcyclohex- ^ -en-carboxylic acid, 15 g ^ 8- ^ ige aqueous hydrobromic acid and 30 ecm glacial acetic acid was heated to reflux for 2 hours, cooled, neutralized by addition of dilute aqueous sodium bicarbonate and extracted with methylene chloride, the methylene chloride extracts were combined, washed with water, dried and evaporated to give cis - ^ - C ^ - ¹ -hydroxyphenyl) -1,2-dimethyl-3-ethylcyclohex-4 -en-carboxylic acid.

909835/1533

- 26 * -

Example 22

By adding 1 g of liquid sulfur trioxide to 35 ecm of dry pyridine under a nitrogen atmosphere at about -1O ° C. up to -5 C. a pyridine / sulfur trioxide adduct was produced. To the adduct in pyridine, 5 g of 4- (4'-hydroxyphenyl) -1, 2-dimethyl-3-ethylcyclohex - ^ - en-carboxylic acid in 30 ecm of pyridine were added with constant cooling. The reaction mixture was left at OC for about 1.5 hours. and then stirred for another 2-3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the concentrate digested with dry ether until crystals formed which were then covered with dry ether and allowed to stand for a few hours. The reaction product was filtered, then dissolved in methanol and titrated to a pH of about 9 with N-sodium methylate. The mixture was filtered and the resulting filtrate was concentrated under reduced pressure. The concentrated solution was ^{cooled to about -W 3} ° C. to -50 ° C. and added to ether with stirring. The reaction product was filtered and gave the disodium salt of ^ - (^ '- HydroxyphenylsulfatJ-l ^ -dimethyl ^ - ethylcyclohex-4-en-carboxylic acid.

The disodium salt of ^ - (^ ¹ -Hydroxyphenylsulfat) -1,2-dimethy1-3-äthylcyclohex- ⁱ 4-en-carboxylic acid was dissolved in methanol and on a

Cast column containing the free acid form of an ion exchange resin. The column was washed with methanol and the collected filtrate was evaporated to dryness under reduced pressure; in this way the * 4 ~ (A · ¹ -hydroxyphenylsulfate) -1, E-diinethyl-1-ethylcyclohex- ^ - en-carboxylic acid was obtained. Example 23

A mixture of 2 g of cis- ^ i- {h- ^f -hydroxyphenyl) -1,2-dimethyl-3-ethylcyclohex- ^ t-en-carboxylic acid and 2 molar equivalents of β-cyanoethyl phosphate in pyridine was with a pyridine solution of 8 molar Equivalents N ₁ N ¹ -

90983b / ■ 1 b 3 c

Dicyclohexylcarbodiiraid combined and the reaction mixture left to stand for 24 hours at room temperature. Then it was diluted with about 10 ecm of water and left to stand at about 5 ° C for 2 days. The mixture was then evaporated to dryness under reduced pressure and the residue was taken up in about 35 ecm aqueous methanol (1: 1). This mixture was treated with about 12 cc 5- $ ig ^e ** N aqueous atriumhydroxyd solution and after about one hour at room temperature, concentrated under reduced pressure, diluted with 30 cc of aqueous methanol, concentrated, and mixed with 75 cc water. This mixture was filtered and the filtrate was treated batchwise and then in columns with an excess of a sulfonic acid ion exchange resin (H form); the cis-4- (4 ¹ -hydroxy ph enyl-4 ¹ -dihydrogen phosphate) -1,2-dimethyl-3-eth, ylcyclohex-4-ene carboxylic acid was obtained in this way.

Example 24

By repeating the procedure of Example 8 using others Enollactones of the following formula:

(IV)

as starting material, the corresponding cis-lactols were obtained. In

1 ·· 2 '

of the above formula, R represents hydrogen, methyl or ethyl; R be

3
indicates hydrogen or methyl; R stands for hydrogen, methyl, ethyl

4 "
or isopropyl; R is hydrogen, hydroxy and the hydrolyzable, carb-

oxylic ester of the same, lower alkoxy, cyclopentyloxy, cyclohexyloxy,

909835/153 3

1v900668

5 " Tetrahydropyran-2 ¹ -yloxy or Tetrahydrofuran-2 ¹ -yloxy; iind R stands for hydrogen, lower alkyl, hydroxy and the hydrolyzable, carboxylic chain of the same, lower alkoxy, cyclopentyloxy, glyclohexyloxy, tetrahydropyran-2'-yloxy or tetrahydrofuran 2 ¹ -yloxy.

Representative finollactones (IV ¹ ) are those of Example 7 which were converted to the corresponding cis -lactol by the method of Example 8, ie cis-5 (^ ' _f 6'-diinethoxyphenyl) -3f, 8-dimethyl-3 $ - hydroxy-3,9,6,7,8,9-hexahydro-isobenzofuran-l-one _f cis-5 - (^ '- methoxyphenyl) -4-isopropyl-3 ^, 8-dimethyl-3 £ -hydroxy- 3,9,6,7,8,9-hexaohydroisobenzofuran-1-one, cis-5 - (^ ', 6'-dimethoxyphenyl) -4-ethyl-3i, 8-dimethyl-3j-hydroxy-3,9, 6,7,8,9-hexahydroisobenzofuran-1-one, cis -5 - (^ '- methoxy-6 ¹ -nethylphenyl) - ^ - ethyl-3 ^, 8-dimethyl-3,9,6,7,8 , 9-hexahydrq-isobenzof uran-1-one, cis-5 - (^ ', 6'-diraethoxyphenyl) - ^ - isopropyl-3?> Ö-diinethyl-33-hydroxy-3,9,6,7,8 , 9-hexahydroisobenzofuran-1-one, cis-5 - (^ '- methoxy-6 ¹ -methylphenyl) -4-isopropyl-3 \ , 8-dimEbhyl-3 jh, ydroxy-3,916,7,8,9- hexahydro isoben zofuran-1-one and cis-5 - (^ ', 6' -DiraethoxyphenylJ ^ fj ^ -iS-trimethyl ^ i-hydroxy-3,9,6,7,8,9-hexahydroisobenzofuran-1-one.

The enol lactones (IV) were obtained from the substituted tetronic acids (III ¹ ) by following the procedure of Example 7.

R ¹
0

Il

R-

(ΙΙΓ)

1 2 ¹ 3 Ψ ¹ S "In Formula III ¹ above, R ₁ R, R, R and R ^ already have those

meaning given above.

90983B / 1533

If the cis-lactols of this example were subjected to the procedure of Example 10, cis - ^ - C ^ ¹ , 6 '-dimethoxyphenyl) -1-metry1-2-ethylcyclohex-3-ene-carboxylic acid, cis-4- ( 4 '4iethoxyphenyl) -l- ~ et.hTl-2-ethyi-3-isopropyleyclohex-3-ene-carboxylic acid, cis-4- (4', 6'-dimetnoxyphenyl) -! - methyl-2,3-diethylcyclohex- 3-ene-carboxylic acid, cis-4 - (^ - '-Metnoxy-6 ¹ -m - ..:. I - Tlphenyl) -l-methyl-2,3-diethyleyelohex-3-ene-carboxylic acid, cis- A- ( h ^x , 6 ^: -Di = methoxyphenyl) -l-methyl-2-ethyl-3-isopropylcyclohex-3-ene-carboxylic acid _i cis - ^ - i ^ ^1- methoxy-6 ¹ -methylphenyl) -i -niethyl - ^ - ethyl ^ -isopropylGyGlche; '- 3-ene-carboxylic acid and CiS - ^ - ( ¹ I- ¹ _f 6 ^t -dimethoxyphenyl) -i, 3-diraethyl-2-ethjicyclohex-3-ene-carboxylic acid.
In spi el 25

A) D:.? H Wi ^: <"" .. Carrying out the process of Example 9 using the cis-lactols from Example Zh as the starting material, the ^ methyl ester of the cis - ^ - C ^ ¹ , 6 'was obtained -Dimethoxyphenyl) -l-methjl-2-aoetylcyclGhex-3-ene carboxylic acid, the methyl ester of cis - ^ - (4 '-Metho;:; - · phenyl) -l-methyl-2-acetyl-3-isopropylcyclohex-3- en-carboxylic acid, the methyl ester of cis - ^ - (^ ', 6' -dimethoxyphenyl) -l-methyl ^ -acetyl ^ -äthylqyclohex-3-en-carrionic acid, the methyl ester of CiS - ^ - ( ¹ J- ¹ - ^ ö ^letiocy-1 -methylpheny; '; - 1 -iiiethyl-2-acetyl-3-äthylcyclohex-3-ene-carboxylic acid, the Methylester of cis ^ fC ^ ^1, 6'-dimethoxyphenyl) -1-methyl -2-acetyl-3-isopropylcyclohex-3-ene-carboxylic acid, the methyl ester of c ± sk - (^ ¹ -i-lethoxy-o ¹ -methylphenyl) -l-methyl ^ -acetyl-S-isopropylcyclohex-3-en -carboxylic acid and the methyl ester of cis-4 - (^ - ^J , 6 'dimethoxyphenyl) -1,3 ~ dimethyl-2-acetylcyclohex-3-ene-carboxylic acid.

B) The methyl esters obtained above were subjected to the procedure of Example 10. This gave the methyl ester of ice- ¹ ! - (^ ¹ , 6 '-dimethoxyphenyl) -l-methyl ^ -äthylcyclhex ^ -en-carboxylic acid, the methyl ester of egg cis-4- ( k ^x -Methoxyphenyl) -1- methy 1-2-ätliyl-3-isopropylcyclohex-3-en-oarboxylic acid,

909835/1533

the methyl ester of cis-Λ- (4 ¹ , 6'-Diiaethoxyphenyli-l-methyl-Z ^ -diäthylcyclohex-3-en-carboxylic acid, the methyl ester of cis-Λ - (^ t- ¹ -Methoxy-6 ¹ methylp- j enyl) -l-methyl-2,3-diethylcyclohex ~ 3-ene-carboxylic acid, the methyl ester of cis ~ ^ - (4 ', 6' -dimethoxyphenyl) -l-raethyl-2-ethyl-3-isopropylc5 ₍ rclohex -3-ene-carboxylic acid, the methyl ester of cis-Λ- (4 '-Methoxy-6 ¹ -methylphenyl) -1-methyl-2-ethyl-3-isopropylcyclohex-3-ene-carboxylic acid and the methyl ester of ei s - ^ - ('4- ¹ , 6' -Dimethoxyphenyl) -1,3-diraethyl-2-ethylcyclohex-3-ene-carboxylic acid.

By repeating the procedure of Example 15, the above methyl esters were obtained converted into the corresponding free acids.

Example 26

A solution of 1 g of cis - ^ - (4- ¹ , 6 '-DimethoisphenylJ-l-methyl-E-ethylcyclohex-3-ene-carboxylic acid in dry benzene was cooled in an ice bath and then saturated with dry hydrogen chloride. This mixture was saturated about k hours at room temperature then allowed to stand, the solvent was evaporated to obtain the cis-4 -. (^ ^1, 6'-dimethoxyphenyl ·) -1-methyl-Z-äthylcyclohex - ^ - en-carboxylic acid "

By the above procedure, the other cyclohex-3-ene compounds of the present invention, such as the cyclohex-3-ene-carboxylic acid of Example Z ¹ ^ _{1, can be converted} into cyclohex-^ - ene compounds such as cis- ^ -i ^ ¹ -Jylethoxyphenyl) -l-methyl ^ -äthyl ^ -isopropylcyclohex - ^ - en-carboxylic acid, cis - ^ - (4- ¹ , 6 '-Dimethoxyphenyl) -l-methyl-Z ^ -diethylcyclohex - ^ - enecarboxylic acid, cis-5 - (^ '-iiethoxy-ό ¹ -methylphenyl) -l-methyl-2,3-diethylcyclohex - ^ - en-carboxylic acid, cis - ^ - C ^ ¹ , 6' -dimethoxyphenyl) -l- methyl ^ -äthyl ^ - isooropylc ^ '- clohex - ^ - en-car'-bonsäure, cis - ^ - (A-' -Methoxy-6 ¹ -methylphenyl) -1-piethyi-2-etnyl-3-isopropylcyclohex- ^z 4- en-carboxylic acid and cis - ^ + - (^ ¹ , 6'-dimethoxyphenyl) -1,3-dimethyl-2-ethylcyclohex-4-ene-carboxylic acid.

909835/1533

Example 27

Repeating the procedure of Example 12 with the cyclohex-3-ene carboxylic acids from Example 24 as starting materials gave cis-4- (V, 6'-dimethoxyphenyl) -l-methyl ^ -ethylcyclohexanecarboxylic acid, cis-4- (V methoxyphenyl) -l-methyl ^ -ethyl ^ -isopropylcyclohexanecarboxylic acid, is-4- (V, 6 ^! -Dimethoxyphenyl) -l-methyl ^^ - diethylcyclohexanecarboxylic acid, cis-4- (V 4Iethoxy-6'-methylphenyl) -l-methyl ~ 2,3-diethylcyclohexanecarboxylic acid, cis-4- (V, 6'-dimethoxyphenyl) -l-methyL - ^ - ethyl-S-isopropylcyclohexanecarboxylic acid, cis-4- (V-methoxy-6 ¹ -methylphenyl) -l- methyl-2-ethyl-3-isopropylcyclohexanecarboxylic acid and cis-4- (V, 6 · -dimethoxyphenyl) -1,3-dimethyl-2-ethylcyclohexanecarboxylic acid.
Example 28

Repeating the procedure of Example 13 with the other enol lactones from Example 7 as starting material gave trans-4- (V-methoxyphenyl) -l-methyl-2-ethyl-3-isopropylcyclohex-3-ene-carboxylic acid, trans-4 - (4 ', 6' -Dimethoxyphenyl) -l-methyl ^^ - diethylcyclohex ^ -en-carboxylic acid, trans-4- (V -ilethoxy-6 ¹ -methylphenyl) -l-methyl ^^ - diethyleyclohex ^ -encarboxylic acid, trans-4- (V, 6 '-Diraethoxyphenyl) ^{-l-methyl-2-ethyl-3-isopropylcyclohex-3-car} eri-' t ^{| ons} äure, trans-4- (V methoxy-6-methylphenyl ¹⁾ -l-methyl-2-ethyl-3-isopropylcyclohex-3-ene-carboxylic acid and trans-4- (V, 6'-dimethoxyphenyl) -1,3-dimethyl-2-ethylcyclohex-3-ene-carboxylic acid. ·

Using the procedures of Examples 11 and 12, the trans- Cyclohex-3-ene-carboxylic acids 4.n the corresponding trans-C.yclohex-4-ene-carboxylic acid and trans-cyclohexanecarboxylic acids are converted.

909835/1533

Example 29

1 molar equivalent of potassium bicarbonate was added with stirring to a solution of 1 g of cis - ^ - (^ ' _f 6'-D: methoxyphenyl) -l-methyl-2,3-diethylcyclohex-3-ene-carboxylic acid in 25 ecm of benzene. This mixture was stirred until the development of carbon dioxide ceased, then it was evaporated and yielded the potassium salt of cis - ^ - (4 · ', 6' -DimethoxyphenylJ-l-methyl ^^ - diethylcyclohex-3-ene-carboxylic acid.

By using the above method, the others can be made according to the invention Acids are converted into the potassium salt.

By using sodium bicarbonate in the above procedure instead of Potassium bicarbonate, the sodium salts are obtained.

Acid salts can also be obtained by titrating a solution of the free acid with an alcohol solution of an alkali metal alkoxide, for example potassium or sodium methoxide, until neutral. Example 30

A) A solution of 1 molar equivalent of 4-methoxybenzaldehyde in 25 ecm tetrahydrofuran and 15 ecm ether was added to a freshly prepared solution of ^ g n-propylmagnesium bromide in 30 ecm tetrahydrofuran. The resulting mixture was kept at room temperature for 2k hours and then heated to reflux for 2 hours, cooled, diluted with water and acidified with hydrochloric acid and stirred to decompose excess Grignard reagent. The organic phase was washed with water, dried and evaporated and gave 4 - (^ ¹ -methoxyphenyl) - ^ t-hydroxybutane (3; R = ethyl;

JLlH en.

R = OCKo; R = hydrogen). 2 g 4 ~ (^ '-Methoxypheny ^ l - ^ - hydroxybutane in 50 ecm of pyridine were added to a mixture of 1 g of chromium trioxide in 10 ecm Pyridine was added to the mixture at room temperature for about 15 hours

909835/153 3

1-3Ü0668

- ys -

left to stand and then diluted with ethyl acetate and filtered. hs.z the filtrate was washed with water, dried and evaporated to give

3 V ¹ 5 "

n-ProFöL - ^ - methoxyphenyl ketone (k \ R = ethyl; R = OCH ₃ ; R = hydrogen). This compound, after treatment according to the procedure of Example 21, provided n-ProFßi-^ t-hydroxyphenyl ketone (^; B? = Ethyl; R "= OH, R ⁵ " = hydrogen).

By repeating the above procedure using ^ ₁ 6 ^ TMethoxy-dimethoxybenzaldehyde and-o-methylbenzaldehyde as a starting material instead of ^ -Methoxybenzaldehyd obtain n-Propjl- ^ jo-dihydroxyphenyl

3 ·· 4 "5"

ketone (4; Br = ethyl; R = BT = hydroxy) and n-propyl - ^ - hydroxy-6-methyl-

phenyl ketone (4; B? = ethyl = R ⁴ "= hydroxy; R ⁵ " = CH ₃ ).

B) The mixture of Ig n-ProRyl - ^ - hydroxyphenyl ketone, 3 ecm pyridine and 1.5 g acetic anhydride was left to stand for 15 hours at room temperature, then poured into ice water and the precipitate formed was filtered off, washed with water and dried; This gave nJ ropyl-if_ _ace toxyphenyl ketone, which can be further purified by urocrystallization.

By using other carboxylic acid anhydrides instead of acetic acid anhydride, such as propionic anhydride, n-butyric anhydride, n-caproic anhydride, Trimethyl acetic anhydride, the corresponding esters were obtained.

By repeating the above procedure using n-propyl-4,6-dihydroxyphenyl ketone and n-propyl-4-hydroxy-6-methylphenyl ketone as a starting material, n-propyl 1-4-, 6-diacetoxyphenyl ketone and n-propyl-4-acetoxy-6-methylphenyl ketone, respectively, were obtained.

909835/1533

C) A freshly prepared solution of 3 g of vinyl bromide in 3 ecm of tetrahydrofuran was added to 0.5 g of magnesium in 5 ecm of tetrahydrofuran to produce a vinyl mae; nesium Gri2: Jiard-Heagenz. A solution of 1 g was then added to this mixture n-Propyi-4-acetoxyphenyl ketone in 25 ecm tetrahydrofuran and 10 ecm ether was added. The resulting mixture was kept at room temperature for 2 1/2 hours, then heated to reflux for 1 hour, cooled, poured into water, acidified with hydrochloric acid and stirred to decompose excess Grignard reagent. The organic phase was separated off and the aqueous layer was extracted several times with ether. The combined ether phases were washed neutral with water, dried over sodium sulfate and evaporated and gave 4 - (^ t- ¹ -acetoxyphenyl) - ⁱ t-hydroxyhex-5-en (5; B? = Ethyl; R = A _o etoxy; R ^ "= Hydrogen f).

Repeating the above procedure with n-PropyL- ^ jo-diacetoxyphenyl ketone and ^ -acetoxy-o-methylphenyl ketone as starting material gave k ~ (k ' , 6 · - DiacetoxyphenylJ - ^ - hydroxy-hex-S-ene bz-r, ^ - (^ '- Acetoxy-o ¹ -methylphenyl) -4-hydroxyhex-5-ene.

Example 3_1

diine solution of 1 chemical equivalent of n-propyl - ^ - hydroxyphenyl ketone in 25 ecm of benzene was heated to reflux, and about 2 ecm were distilled off, to eliminate moisture. The mixture was cooled to room temperature, 2 chemical equivalents of sodium hydride were added, then there were 2 chemical equivalents of cyclopentyl bromide in 10 ecm benzene within dropped in from 20 minutes. The mixture was refluxed for 20 hours heated, whereupon the precipitate of sodium bromide is filtered off and the organic Phase was dried and evaporated; so one got n-propyl - ^ - cyclo-

909835/1533

3 ·· 4 "5"

pentyloxyphenyl ketone (k \ R = ethyl; R = cyclopentyloxy; R = hydrogen).

By repeating the above procedure using an equivalent Amount of cyclohexyl bromide instead of cyclopentyl bromide was obtained n-Propyte-4-cy clohexyloxyphenylketon.

When other hydroxy compounds from Example 30 (A) used, so one got n-Propjl - ^. o-dicyclopentyloxyphenylketon or-, n -P ropyi-cyclopentyloxy-δ-phenyl ketone.

W When the above cyclopentyl and cyclohexyl ethers were subjected to the procedure of Example 30 (C), 4- (4'-Glylopentyloxyphenyl) -4-hydroxyhex-5-ene, 4- (4'-Gyclohexyloxyphenyl) -4- hydroxyhex-5-ene, 4- (4 ', 6 ^r -Dicyclopentyloxyphenyl) -4-hydroxyhex-5-ene, k- ( k ¹ , 6 ■ -Dicyclohexyloxypheny 1) -H- hydroxyhex-5-ene, 4- ( 4- '-Cyclopentyloxy-6'-methylphenyl) -4-hydroxyhex-5-ene or 4 - (^ ¹ -cyclohexyloxy-o-methylphenyl) -4-hydroxyhex-5-ene.

Example 32

1.5 ecm of dihydropyran became a solution! g n-propyl- ^ f-hydroxyphenyl ketone in 10 ecm benzene was added. To eliminate moisture, about 1 ecm was distilled off; 0.3 g of p-toluenesulfonic acid was added to the cooled solution. This mixture was left to stand at room temperature for k days, washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue was chromatographed on neutral clay and gave n-propyl-4- (tetrahydropyran-2 ¹ -yloxy} -

3 ·· 4 "5"

phenyl ketone (k \ R = ethyl; R = tetrahydropyran-2 ¹ -yloxy; R = hydrogen).

909835/1533

A freshly prepared solution of 3 g vinyl bromide in 3 ecm tetrahydrofuran was added to 0.5 g magnesium in 5 ecm tetrahydrofuran to produce a vinyl magnesium Grignard reagent. To this mixture was then added a solution of 1 g nP ro ρν1-4 - (- tetrahydropyrans ^1-yloxy) -phenylketon added in 25 cc of tetrahydrofuran and 10 cc of ether and the resulting mixture maintained at room temperature 2h hours, then under reflux for an hour! heated and cooled. The reaction mixture was then poured into water and hydrochloric acid was added to decompose excess Grignard reagent. The organic phase was separated off and the aqueous layer was extracted several times with ether. The combined ether phases were washed neutral with water, dried over sodium sulfate and evaporated; thus obtained 4 - / V ¹ - (T6trahydropyran-2 "-yloxy) -pheny] J- ² i-hydroxy-

3 4 "5"

hex-5-en (5; R ^ ethyl; R = tetrahydropyran-2 ¹ -yloxy; R = hydrogen).

By using dihydrofuran in the above procedure instead of dihydropyran was obtained the corresponding tetrahydrofuran-2 ^1-yl ether. Using this procedure, other hydroxy compounds of Formula K can be converted to the tetrahydropyranyl and tetrahydrofuranyl ethers. Example 33

Example 3 was made using K- {K ^X -acetoxyphenyl) -4-hydroxyhex-5-ene, k- (k ^l , 6'-diacetoxyphenyl) -4-hydroxyhex-5-ene, and 4 - (^ ¹ -acetoxy -6 ¹ -methylphenyl) -A-hydroxyhex-5-ene is repeated as starting material, whereby 3 - (^ ¹ -acetoxyphenyl) -hex-2-enyl-isothiouronium acetate, 3 - (^ ¹ »6'-diacetoxyphenyl) -hex -2-enyl-isothiouronium acetate or ^3-1 J- '-acetoxy-6'-methylphenyl) hex-2-enyl-isothiouronium acetate.

909835/1533

Treatment of the above obtained isothiournoium acetates according to the procedure of Example 5 gave o £ - ^ 3- (4'-acetoxyphenyl) -hex-2-enyl / -0C ' Jt dimethyltetronic acid, ö (- / 3 - (^ ¹ »6 ¹ -Diace _i toxyphenyl) -hex-2-enyl7-o ('J * "- dimethy! Tetronic acid or c <- ^ - (^' - Acetoxy-o'-methyiphenylJ-hex ^ -enyl / -n (', jT-dimethyltetronic acid, which can be treated according to the method of Example 7 to form the corresponding enol lactones, ie 5 - (^ ¹ -acetoxyphenyl) - ^ - ethyl-3,8-dimethyl-6,7,8,9-tetrahydrolsobenzofuran-1 -one, 5- (4x, 6x Diace toxyphenyl) -4-ethyl-3,8-dimethyl-6,7,8,9-tetrhaydro-isobenzofuran-1-one or 5 - (^ '- acetoxy -6 · -methylphenyl) - ^ - äthyl-3 _f S-dimethyl-o ^ fS ^ -tetrahydrois obe nzof uran-1-one.

Example 3Jj;

Instead of making the isothiouronium acetate of the compounds of Formula 5 before reacting with a tetronic acid to form the compounds of formula III can also be a tetronic acid directly with a compound of formula 5 in the presence of an alkaline catalyst in one aromatic hydrocarbon solvents are reacted at elevated temperatures; such as.

To a solution of 1 g of ^ - (^ '- CyclopentyloxyphenylJ - ^ - hydroxyhex ^ -en in 20 ecm of toluene was added 0.5 g of triethylamine and 0.5 g of "I" -dimethyltetronic acid. The resulting reaction mixture was stirred under a nitrogen atmosphere Heated to reflux for about k hours, during which time the water of reaction was removed, then the reaction mixture was partially concentrated by distillation, cooled, and diluted with benzene. This mixture was washed with 5% aqueous bicarbonate and water, dried over sodium sulfate and under evaporated to dryness under reduced pressure} so one obtained ^ f - / ^ - (^ '- CyclopentyloxyphenylJ-hex ^ -enylJ-o ^', Jj ^ - dimethy! tetronic acid.

909835/1533

Example 3yy

Example Jk was repeated using ^ - (4'-methoxyphenyl) - * 4-hydroxyhex-5-ene and at. -Methyltetronic acid, whereby C (-j \ - {h ^x -Methoxyphenyl) -hex ^ -enyl / '- ^' - methyletronic acid received. This was treated according to the procedures of Examples 7, 8, 10 and 11 to give 5 - (^ ¹ -methoxyphenyl) - ^ - ethyl-S-methyl-o, 7,8,9-tetrahydro-isobenzofuran-1 - ^^ cis-Si ^ ¹ -Methoxyphenyl) -8-methyl-3-hydroxy-3 »9 , 6 _f 7,8,9-hexahydro-isobenzofuran-1-one,

-Methoxyphenyl) - ^ 3-ethy 1-1,2-dimethylcyclohex-3-ene-carboxylic acid and * -Methoxyphenyl) -3-ethyl-1,2-dimethylcyclohex- ⁱ »-en-carboxylic acid.

Treatment of 5 - {^ -Methoxyphenyl) - ^ - - ethyl-e-methyl-o, 7,8,9-tetrahydro-isobenzofuran-1-one according to the procedure of Example 13 gave trans-4 - (^ ¹ -methoxyphenyl ) -3-ethyl-1,2-dimethylcyclohex-3-ene-carboxylic acid.

Example 3J>

The compound containing free hydroxyl groups was subjected to the formula

7 "... COOR ^r

HO-

Following the procedures of Examples 22 and 23, compounds of formula

909835/15 3

ΊΟ

.. .coor ⁷

12 3 7 '

in which R, R ', R, Z and Z ^{1 have} the meaning given above; R.

7 "means hydrogen, lower alkyl or an alkali metal; R stands for hydrogen or lower alkyl; and Ϊ ¹ is the group OSO ₂ OX or OPO (OX) ₂ , where X stands for hydrogen or an alkali metal.

The free hydroxy compounds of Formula IX can also be converted to ethers according to the method of Example 30 (B) ήχ valuable carboxylic acid esters and according to the methods of Examples 31 and 32.

The compounds of the formula IX originate - using the method of Example 21 - from the ^ Mlethoxyphenylverbindungeni. or they can also be made from a compound of the formula I or III, in which R stands for hydroxy _? after the one described above! Process are produced.

if§ / i

Claims (1)

P atent claims 1, - compounds of the formula: 5 » in which R represents hydrogen, methyl or ethyl; 2 'R is hydrogen or methyl; 3 R ^ represents hydrogen, methyl, ethyl or isropyl; ! μι R is hydrogen, hydroxy and the hydrolyzable carboxylic acid esters of the same, low alkoxy, cyclopentyloxy, cyclohexyloxy, tetrhydropyran-2 ¹ -yloxy or tetrahydrofuran-2 ¹ -yloxy; and R is hydrogen, lower alkyl, hydroxy, and the hydrolyzable Carbonsäureester thereof, lower alkoxy, cyclopentyloxy, cyclohexyloxy, tetrahydropyran-2-yloxy or ¹ tetrahydrofuran-2-yloxy means. ¹ 2.- Compounds according to claim 1, characterized in that daJ3 R water 3 ·· k ⁿ 5 " Means substance or methyl, R stands for ethyl and R and R each Mean methoxy. Compounds according to claim 1, characterized in that R stands for hydrogen or methyl, R 1 stands for ethyl, R is methoxy and Br stands for methyl. k, - enollactones of the following formula: 909835/1533 r5 " f ^ O
j R * "- O * ■ III! I. in which i ^ l 2 « R represents hydrogen, methyl or ethyl; R is hydrogen or methyl; "- 3 R- ^ represents hydrogen, methyl, ethyl or isopropyl; R denotes hydrogen, hydroxy and the hydrolyzable carboxylic acid esters thereof, lower alkoxy, cyclopentyloxy, cyclohexyloxy, tetrahydropyran-2 ¹ -yloxy or tetrahydrofuran-2 ¹ -yloxy; and 5 "R stands for lower alkyl, hydrogen, hydroxy and the hydrolyzable carboxylic acid esters thereof, lower alkoxy, cyclopentyloxy, cyclohexyloxy, tetahydropyran-2'-yloxy or tetrahydrofuran-2 ¹ -yloxy. 5 · - enol lactones according to claim 4, characterized in that R is for 3 - V ¹ *> ™ Is hydrogen or methyl, R is ethyl and R and R are each Mean methoxy. 6, - enollactones according to claim k, characterized in that R is for 3 - 2j.ii 5 » Is hydrogen or methyl, R * ^ is ethyl, R is methoxy and R Means methyl. 7.- Compounds of the formula 2 « in which 1 R is hydrogen, methyl or - &thyl; 2 ¹ 'R is hydrogen or methyl; 3 R is hydrogen, methyl, ethyl or isopropyl; R "denotes hydrogen, hydroxy and the hydrolyzable carboxylic acid esters thereof, lower alkoxy, cyclopentylojiy, cyelohexyloxy, tetrahydropyran-2'-yloxy or tetrahydrofuran-2 ¹ -yloxy; 5 "Br hydrogen, lower alkyl, hydroxy, and the same hydrolyzable Garbonsäureester, lower alkoxy, Ccylopentyloxy, cyclohexyloxy, tetrahydropyran-2-yloxy or tetrahydrofuran-2 ^{1 1-yloxy} group; and K is ^[hydrogen or lower alkyl. 8, - Compounds according to claim 7, characterized in that R and R jes? e3J} -§ stand for methpxy. ψ! 9 compounds according to claim 7, characterized in that R fmr methoxy sjbeh |. and R is methyl. dgr the following formulas C and Ö § / 1633 in which R represents hydrogen, methyl or ethyl; 2
R is methyl or ethyl; 3
R represents hydrogen, methyl, ethyl or isopropyl; R denotes hydrogen, lower alkoxy, hydroxy and the hydrolyzable carboxylic acid esters thereof, cyclopentyloxy, cyclohexyloxy, tetrahydropyran-2 ¹ -yloxy or tetrahydrofuran-2 ¹ -yloxy; 6 »
R for the group _Qder stands; and 8 ■ .411 R is hydrogen or lower alkyl, provided that R is a 6 » has a meaning other than hydrogen when R represents the group U •• U stands, 11, - compounds of formula E. R ⁶ ' • * Hit ο rwvR which represents hydrogen, methyl or ethyl; Methyl Qdpr is ethyl; Wai§ei »itoff f methyl, ethyl or isopropyl means j for hydrogen »lower alkoxy, hydroxy and the hydrolyzable The same, Gyelqpentylqxy, Gyelqhexylq.xy _f Tetrahy '-yioxy,' Petrahydrofupan ^ Uylqxy, which stands Qmpm © SOgOX or clig QFO (OX) 1, wqbej % Waterski _§ ^ _r ^ Alk # liflj§tail bgde.} ittt $ 'Ed ti? for lower alkyl, hydrogen, lower alkoxy, hydroxy and the hydrolyzable carboxylic acid esters thereof, cyclopentyloxy, cyclohexyloxy, tetrahydropyran-2'-yloxy, tetrahydrofuran-2'-yloxy _f the group OSO2OX or the group OPO (OX) ₂ , where X is hydrogen or represents an alkali metal; R for hydroxymethyl or the hydrolyzable carboxylic acid esters thereof, 71 71 Formyl, -COCl, -COF, -CONH ₂ or the group -COOR, in which R is hydrogen, lower alkyl or an alkali metal, provided since R and R each have a meaning other than the group OSO ₂ OX or the group OPO (OX) ₂ when R stands for -COCl or -COF. 12.- Compounds of formulas F and G other (F) . .R in which R for hydroxy and the hydrolyzable carboxylic acid esters thereof, low Alkoxy, cyclopentyloxy, cyclohexyloxy, tetrahydropyran-2'-yloxy, tetrahydrofuran-2'-yloxy or the group OSO ₂ OX or OPO (OX) ₂ , where X is hydrogen or an alkali metal; 909835/163 R represents hydrogen, methyl or ethyl; 2
R is methyl or ethyl; R is hydrogen, methyl, ethyl or isopropyl; R is hydrogen, lower alkoxy, hydroxy and the hydrolyzable carboxylic acid esters thereof, Gyclopentyloay, Cyclohexyloxy, Tetrahydropyran-2 · -yloxy, Tetrahydrofuran-2'-ylo35y _t the group 030 OX or the group OPO (OX) ₂ , where X is hydrogen or represents an alkali metal; and R for hydroxymethyl or the hydrolyzable carboxylic acid esters thereof, 71 71 Formyl, -COCl, -COF, -CONH ₂ or the group -COOR ', where R ^{f is} hydrogen, lower alkyl or an alkali metal, provided that R and R ^ each have a meaning other than the group OSOpOX or OPO (OX ) _{Have 2} when R is -COCl or -COF. 3 13 · - Compounds according to claim 12, characterized in that R for Isoprpyl stands. k 14.- Compounds according to claim 12 _f, characterized in that R and R each represent cyclopentyloxy. 6 · 15.- Compounds according to claim 12, characterized in that R is for 7 7 the group -COOR, where R is hydrogen or an alkali metal. if 16.- Compounds according to claim I5 »characterized in that R and R 3 - each represent hydroxy and R- denotes ethyl or isopropyl. 17'- compounds according to claim 15, characterized in that R and R 3 - each represent methoxy and Br means ethyl or isopropyl. - if 18. Compounds according to claim 15, characterized in that R and R each stand for acetoxy and Br stands for ethyl or isopropyl. 19.- Compounds of the following formulas H and J: ... C
2 ... C-OR ' (H) (J) in which R represents hydrogen, methyl or ethyl; 2
R is methyl or ethyl; R ^ is hydrogen, methyl, ethyl or isopropyl; 7 ¹
R represents hydrogen, lower alkyl or an alkali metal; and Y is hydroxy and the hydrolyzable carboxylic acid esters thereof, cyclopentyloxy, cyclohexyloxy, tetrahydropyran-2 ¹ -ylo3Qf, tetrahydrofuran - ^ '- yloxy, the group OSO ₂ OX or OPO (OX) ₂ , where X stands for hydrogen or an alkali metal. 20, - Compounds according to claim 19, characterized in that Ϊ for hydroxy 7 '
and R is hydrogen or lower alkyl; 21, ** Compounds according to claim 19, characterized in that Ϊ for the Group QSQpOX stands. 22,, β Compounds according to claim 19, characterized in that J stands for the group QPO (OX) g. % 3 "compounds of the following formula; 9098.36 / 1 * 3? in which 3
R represents hydrogen, methyl, ethyl or isopropyl; R represents hydrogen, hydroxy and the hydrolyzable carboxylic acid esters thereof, lower alkoxy, cyclopentyloxy, cyclohexyloxy, tetrahydropyran-2 ¹ -yloxy or tetrahydrofuran-2 ¹ -yloxy; and R is hydrogen, lower alkyl, hydroxy and the hydrolyzable carboxylic acid esters the same, lower alkoxy, cyclopentyloxy, cyclohexyloxy, tetrahydropyran-2'-yloxy or tetrahydrofuran-i-2'-yloxy means, 2j.ii cn 2k, - Compounds according to claim 23, characterized in that R and R each represent methoxy, 25. Compounds according to claim 23, characterized in that R stands for cn
Is methoxy and Vr is methyl. ♦ β - 26, - Process for the production of substituted cyclohex-3-ene-carboxylic acids, characterized in that a compound of the formula: .5 " CH = CH,
C-OH CH ₂ or the corresponding isothiouronium acetate thereof with a tetronic acid the formula: O = in an aqueous solution of a water-miscible organic solvent reacted and then with an inorganic or organic acid to obtain an enol lactone of the formula: .1 R- R- " treated the Knollacton with an aqueous solution of an alkali metal hydroxide treated in an organic, water-miscible solvent and then in a divided electrolysis cell in an electrolytic Medium consisting essentially of a mineral acid electrolyte, water and an inert, water-miscible organic solvent, -JG- at a high hydrogen overvoltage cathode at a current density of about 0.01-0.2 amps / cm to obtain a substituted cyelohex-3-ene carboxylic acid Subjected to the following formula to a carbonyl reduction: R ¹ where in the above formulas R represents hydrogen, methyl or ethyl; 2 *
R is hydrogen or methyl ; 3
R is hydrogen, methyl, ethyl or isopropyl; R represents hydrogen, hydroxy, lower alkoxy, cyclopentyloxy or cyclohexyloxy; R is lower than alkyl, hydrogen, hydroxy, lower alkoxy, gyclopentyloxy or Cyelohexyloxy means ;, R represents hydrogen, hydroxy and the hydrolyzable carboxylic acid esters thereof, lower alkoxy, cyelopentyloxy, cyelohexjlDxy, tetrahydrojgrran-2 · -yloxy or tetrahydrofuran-2 ¹ -yloxy; and R denotes hydrogen, lower alkyl, hydroxy and the hydrolyzable carboxylic acid esters thereof, lower alkoxy, cyelopentyloxy, cyelohexyloxy, tetrahydropyran-2 ¹ -yloxy or tetrahydrofuran -2 ¹ -yloxy . 90 98 * 35/1 5 3 ^^ ' 27. Process according to Claim 26, characterized in that the cyclohex-3-ene-carboxylic acid obtained in this way is subjected to catalytic hydrogenation to form the corresponding 3, k- dihydro compound. 28. Process according to Claim 26, characterized in that the cyclohex-3-ene-carboxylic acid thus obtained is treated with hydrogen chloride in an organic solvent to form the corresponding cyclohex-4-ene-carboxylic acid. The patent attorney: IÖ9835 / 1533