NO131343B - - Google Patents

Description

Analogy methods of manufacture

of new pharmacologically active a-phenyl-

fatty acid compounds.

The invention relates to analogous methods for the production of new pharmacologically active α-phenyl fatty acids with it

general formula

in which R means an optionally lower alkyl, lower alkoxy or oxo-substituted 1-cycloalkenyl residue with 4-8 ring members, Ph means an optionally lower alkyl, lower alkoxy, trifluoromethyl or halogen substituted p-phenylene residue and R-^ and R£ each means a hydrogen -

atom or an alkyl group,

as well as their esters with lower alkanols, which optionally contain more hydroxyl groups, or with lower dialkylaminoalkanols, their amides, which are optionally N-substituted with lower alkyl, dilower alkyl amino alkyl or hydroxy, and their pharmaceutically usable salts.

The 1-cycloalkenyl residue may be substituted one or more times. These are residues with 4-8, preferably 5-7 ring members, such as 1-cyclobuteny1- or 1-cyclooctenyl residues and especially 1-cyclopentenyl-, 1-cyclohexenyl-' or 1-cycloheptenyl residues, which optionally have one or more substituted times.

The phenylene residue Ph can be unsubstituted or have one, two or more substituents. As substituents, the below-mentioned lower alkyl or alkoxy acid residues, trifluoromethyl and halogen atoms come into consideration.

As lower alkyl radicals R 1 and/or R 2 come into consideration those which have a maximum of 6 carbon atoms.

Lower alkyl residues are e.g. methyl, ethyl, propyl or isopropyl residues or straight or branched, butyl, pentyl or hexyl residues which are attached in any position.

Lower carboxylic acid residues are, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy or amyloxy groups and as halogen atoms, fluorine, chlorine or bromine atoms are preferably considered.

Examples of ester-forming lower alkanols include methanol, ethanol, propanol, butanol or hexanol.

Other ester-forming lower alkanols are those containing dilower alkylamino groups, e.g. dimethylamino or diethylamino groups.

In the amidated carboxyl groups (carbamyl groups), the amide nitrogen atom can be unsubstituted, mono- or disubstituted, preferably with lower alkyl residues or dilower alkyl, amino-lower alkyl group or also with hydroxy.

The new compounds have valuable pharmacological properties, above all analgesic as well as antinociceptive and anti-inflammatory effects. Thus, in the Writhing test on mice, when administered orally from 1 to 200, especially 10 to 200 mg/kg, they show a clear antinociceptive effect. In the kaolin edema test on rat paws when administered orally in a dose from 1 to 200 mg/kg, they show

clear anti-inflammatory effect.

Admittedly, there is already e.g. from French patent no. 3-124 M known in the p-position with an alkyl, alkenyl or cycloalkyl residue substituted a-phenylacetic acids and their esters with anti-inflammatory action, which have partly already been introduced into medical practice. Thus, e.g. the a-(isobutylphenyl)propionic acid mentioned there has received the widest recognition as an anti-inflammatory (E.F. Davis, G.S. Avery, Drugy 2, 4l6 (1972)). The basis for the present invention is the surprising discovery that the a-/_ p-(1-cyclohexenyl)-phenyl/-propionic acids obtainable according to the invention show more favorable values for the ratio between therapeutically effective and toxic doses than the known a-(isobutyl -phenyl)-propionic acid. Thus, in comparative experiments -- carried out on rats, the anti-inflammatory effect of the a-/<_> p-(l-c<y>chlorohexene<y>l)-phenyl/- propionic acids I-XX as well as the aforementioned d-(isobutyl-phenyl)-propionic acid (XXI)

in the kaolin leg edema standard test and in the adjuvant arthritis test (Pharmacology 2, 288-294 (1969)) obtained the following values for the effective dose ED-jq_jjq, the acute toxicity and the therapeutic width.

For comparison, the following compounds were used: α-/_ p-(1-cyclohexenyl)-phenyl_l/-propionic acid amide I N-(2-dimethylamino)ethyl-α-7 p-(1-cyclohexenyl)-phenylT-propionic acid amide, hydrochloride II a-/_ p-(6-methyl-1-cyclohexenyl)-phenyl_1/-propionic acid III a-/_ p-(4-methyl-1-cyclohexenyl)-phenyl/-propionic acid IV Sodium-a-_/ p- (4-methyl-1-cyclohexenyl)-phenyl propionate V a-/_ p-(1-cyclopentenyl)-phenyl-1/-propionic acid VI a-/_ p-(1-cycloheptenyl)-phenyl/ -propionic acid VII a-_/—p -(1-cyclohexenyl)-phenyl_1/-propionhydroxamic acid VIII a-/<->p-(1-cyclohexenyl)-phenyl7-butyric acid IX a-/-p-(1-cyclohexenyl) - p eny _l/-prop ionic acid-l-glycero le ste r X Sodium p-(l-cyclohexenyl)-phenylacetate XI a-/_ p-(l-cyclooctenyl)-pheny2-/-propionic acid XII a- /~p-(1-cyclohexenyl)-phenyl_1/-a-methyl-pentanoic acid XIII a-/_ 3-methyl-4-(1-cyclohexenyl)-phenyl_1/-propionic acid XIV a-/_ 3-methyl-4 -(1-cyclohexenyl)-phenyl/-propionic acid amide XV a-_/ p-(6-oxo-1-cyclohexenyl)-phenyl/-propionic acid XVI a-/~4-(1-cyclohexenyl)-3-methoxy- pheny^/-propionic acid and XVII a.- £~ 4-(1-cyclohexenyl)-3-methoxy-pheny 1/-propionic acid amide XVIII a-/_ p-(1-cyclohexenyl)-pheny_l/- propionic acid XIX α-/_ 3-Chloro-4-(1-cyclohexenyl)-phenyl_1/-propionic acid. XX

In the following table, the α-(isobutylphenyl)-propionic acid known from French patent No. 3*124 M is denoted by XXI. ;Particularly to be highlighted because of their good anti-inflammatory and analgesic (antinociceptive) effect are the compounds of' formula IV in which R' means one with a lower alkoxy group or especially lower alkyl group substituted or preferably unsubstituted 1-cycloalkenyl residue with 5, 6 or 7 ring members, Ph ' means one with a lower alkoxy group, lower alkyl group or a halogen atom substituted or preferably unsubstituted p-phenylene residue, Rj' and R2' means lower alkyl residues or hydrogen atoms and Rx means a lower alkoxy group, such as a methoxy or ethoxy group or a free amino group, a amino group or above all a hydroxyl group Of particular importance due to their good anti-inflammatory effect are compounds of formula V in which R" means an optionally lower alkylated 1-cyclopentenyl-, 1-cyclohexeny 1- or 1-cycloheptenyl residue, R-^" means a methyl residue or a hydrogen atom and R means a hydroxyl group or otherwise a lower alkoxy group with a maximum of 4 ka rbonatorries or a free amino group and especially a-/p(1-cyclohexenyl)-phenyl_l/-propionic acid of formula VI ;a-/_ p-(1-cyclopentenyl)-phenyl7-propionic acid as well as ;a-/_ p-(l -cycloheptenyl)-phenyl]/-propionic acid; The new compounds are obtained by methods known per se. Preferably, one proceeds in such a way that one reacts a compound of formula VII or VIII in which R, Ph, and R^ have the previous meanings, and Y means a cyano group or an acid halide or thioamide group, with water, alcohol, ammonia or with a amine containing at least one hydrogen atom bonded to nitrogen. A cyano group can in the usual way, e.g. by hydrolysis or alcoholysis is converted into a free, esterified or amidated carboxyl group. ;The hydrolysis to amidated resp. free carboxyl groups takes place in a known manner, for example in the presence of a strong base such as an alkali hydroxide, e.g. sodium or potassium hydroxide or in the presence of a strong acid, e.g. a mineral acid, such as hydrochloric acid and optionally by hydrolysis to free carboxyl groups by the addition of an oxidizing agent, such as nitric acid. The alcoholysis of an esterified carboxyl group takes place in the usual way, e.g. by reaction with a corresponding alcohol, e.g. in the presence of a mineral acid which. sulfuric acid, and preferably in the presence of ammonium chloride. ;An acid halide, such as acid chloride or thioamide grouping can be reacted with water, alcohols, ammonia, an amine containing at least one hydrogen atom bonded to nitrogen or hydroxylamine in the usual way, if desired, in the presence of acid binding agents, such as organic or inorganic bases, or possibly of catalysts and/or oxidizing agents, possibly in an acidic or neutral environment. However, one can also react with a compound of formula X, in which R, Ph, R-^ and Rg have the indicated meanings, and Y^ means a lithium or sodium atom or a group of formula -Mg-Hal, in which Hal means chlorine, bromine or iodine, with carbonic acid. The reaction takes place in the usual way, preferably in an inert solvent such as an ether, e.g. diethyl or dibutyl ether or tetrahydrofuran. Furthermore, in a compound of formula XI, in which R, Ph, R-j^ and R 2 have the indicated meanings, and means an optionally functionally modified formyl residue, Y 2 can be oxidized to a carboxyl group. A functionally modified formyl group is e.g. a hydrate thereof. For oxidation of a formyl group, for example, silver oxide in alkali comes into consideration, e.g. in caustic soda or other common oxidizing agents. However, it is also possible to rearrange a ketoxime of formula ;, in which R, Ph, R 1 and R 2 have the indicated meanings, and R' denotes an alkyl residue. The relocation can take place in the usual way, e.g. by means of a Beckmann rearrangement, the carbonyl group being oxidized by means of an intramolecular disproportionation to a carbamoyl group, i.e. to a carboxyl group alkyl-substituted-amidated at the amino nitrogen atom^; One rearranges the oxime with formula XII in the usual way, e.g. with acidic agents, such as sulfuric acid or phosphorus pentachloride. ;The new compounds in which the residue R2 means hydrogen can also be obtained by using in a compound of formula XIII ;;in which R, Ph and R^ have the indicated meanings, and means an acyl residue or a carboxyl group, or one of the above defined esters, amides or salts thereof, cleave off the remainder Y^. The residue Y^ is preferably a free carboxyl group or a lower alkanoyl residue. - The removal of a free carboxyl group can be carried out in the usual way by decarboxylation, e.g. by heating; or heating. The cleavage of a lower alkanoyl residue, especially an acetyl residue, can take place in a known manner, e.g. known for cleavage of ;g-ketoesters, especially under the influence of strong bases, e.g. alkali hydroxide, e.g. sodium or potassium hydroxide, or alkali alcoholate, e.g. sodium ethylate, preferably at elevated temperature and in an inert solvent. The new compounds can also be obtained starting from a compound of formula XIV, in which Ph, R-^ and R2 have the indicated meanings, and RQ means a cycloalkyl residue corresponding to the residue R, in which at the carbon atoms in 1- and 2 -position is bound cleavable residues, or one of the above-mentioned defined esters, amides or salts thereof, cleaves the said residues while forming a 1,2-double bond. ;The cleavable residues can be the same or different. Equally cleavable residues are thereby particularly halogen atoms, such as chlorine, bromine or iodine. If the cleavable residues are different, then one, especially the one in the 2-position, is preferably a hydrogen atom and the other, especially the one in the 1-position, is preferably a free or reactive esterified or etherified hydroxyl group, a quaternized ammonium group, e.g. a trimethylammonium group, an alkylsulfonyl group, e.g. a methylsulfonyl group, a tertiary sulfonium group, e.g. a dimethylsulfonium group or a dialkylamine oxide group, e.g. a diethylamine oxide group. The separation takes place in the usual way. If a residue is a free or etherified hydroxyl group, the cleavage is carried out e.g. in the presence of strong acids, such as mineral acid, e.g. sulfuric acid, or hydrohalic acid, such as chloric or hydrobromic acid. A reactive esterified hydroxyl group is e.g. a hydroxyl group esterified with a strong organic or inorganic acid, e.g. a halogen atom, such as chlorine, bromine or iodine, or an arylsulfonyloxy group, such as p-toluenesulfonyloxy, or a xanthogenyl group, further also an acyloxy group, especially an acetoxy group. An etherified hydroxyl group is e.g. a lower alkoxy group, e.g. a methoxy group. If a residue is a reactive esterified hydroxyl group, then one preferably works in a basic environment, for example in the presence of inorganic bases, such as metal hydroxides, e.g. sodium or potassium hydroxide or carbonates, such as sodium or potassium carbonate or organic amines, such as e.g. pyridine and possibly at elevated temperature. If a residue is a xanthogenyl group, the cleavage can above all be carried out without a solvent or in a high-boiling solvent such as di- or triethylene glycol dimethyl ether, and at elevated temperature, preferably under reduced pressure. If a residue is a quaternized ammonium group, especially a trimethylammonium group, an alkylsulfonyl, ternary sulfonium or dialkylamine oxide group, the cleavage can preferably be carried out thermally, for example by heating without a solvent, preferably under reduced pressure, or in a high-boiling solvent, e.g. eg, di- or triethylene glycol dimethyl ether, preferably under reduced pressure. ;Is in the 1- and 2-position together two identical residues, especially two halogen atoms, e.g. two bromine atoms, present, cleavage can preferably be carried out by means of metallic reduction. The reducing agent is preferably zinc and acid, e.g. acetic acid, or zinc and water or alcohol, e.g. ethanol. The cleavage can further be carried out with sodium iodide and alcohol, e.g. ethanol. Formed esters and amides can in the usual way, e.g. by hydrolysis, preferably in the presence of strong bases or strong acids, e.g. the above, transfer into free acids. If desired, during the hydrolysis of primary amides, an oxidizing agent such as nitric acid can be added. Formed esters or acids can also be converted into amides in the usual way, for example by reaction with ammonia or with amines that contain at least one hydrogen atom bound to nitrogen. possibly dehydration of the intermediately formed ammonium salt. Free acids can be esterified in the usual way, e.g. by reaction with a corresponding alcohol, preferably in the presence of an acid', such as a mineral acid, e.g. sulfuric acid or hydrochloric acid or in the presence of a water-binding agent, such as dicyclohexylcarbodiimide, or by reaction with a corresponding diazo compound, e.g. a diazoalkane. The esterification can also be carried out by reacting a salt of an acid, e.g. of the sodium salt with a reactive esterified alcohol, e.g. a halide;- as a chloride. Free acids can e.g. also transferred in the usual way; in acid halides or -anhydrides, e.g. by reaction with halides of phosphorus or sulphur, such as thionyl chloride, phosphorus pentachloride or phosphorus tribromide, or with acid halides such as chloroformate esters. The acid anhydrides or halides can then be converted in the usual way by reaction with corresponding alcohols, if desired, in the presence of acid-binding agents, such as organic or inorganic bases or with ammonia, into esters or amides. ;Furthermore, in formed compounds, in which and/or R2 means hydrogen atoms, lower alkyl, R1 or R2. For example, one can transfer a corresponding compound, above all an ester or an amide, in the α-metal salt, e.g. by reacting with strong bases, such as alkali metal amides, -hydrides or -hydrocarbon compounds such as sodium amide, -hydride or phenyl- or butyllithium, and then reacting this, preferably without isolation, with a reactive ester of a lower alkanol of the formula R-^OH resp. R 2 OH. Reactive esters are especially those with strong inorganic or organic acids, preferably with hydrohalic acids, such as hydrochloric, bromic or hydroiodic acids, sulfuric acid or with arylsulphonic acids, such as benzene, p-bromobenzene or p-toluenesulphonic acid. Depending on the process conditions and starting material, acidic end products are obtained, i.e. those in which there is a free carboxyl group, in free form or in the form of their salts with bases. Formed free acids can in the usual way, e.g. by reaction with corresponding basic agents, is transferred into the salts with bases, especially in therapeutically applicable salts with bases, e.g. salts with organic amines or metal salts. As metal salts, alkali metal salts or alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts, come into consideration above all. From the salts, the free acids are released in the usual way, e.g. in the case of turnover with acidic means. End substances with a basic character can also be obtained in free form, or in the form of their salts. The salts of the basic final substances can be prepared in a manner known per se, e.g. with alkalis or ion exchangers are transferred in the free bases. From the latter, salts can be prepared by reaction with organic or inorganic acids, especially those which are suitable for the formation of therapeutically applicable salts. Examples of such acids include halogenated acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, priopionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid , maleic acid, hydroxymaleic or pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or sulfanilic acid, methionine or tryptophan, lysine or arginine. The salts can also be used to purify the new compounds, e.g. as one transfers the free compounds, their salts, isolates these and again transfers them to free compounds. Due to the narrow relationship between the new compounds in free form and in the form of their salts, in the preceding and following free compounds are also understood to mean the corresponding salts. The new compounds can, depending on the choice of starting materials and working methods and depending on the number of asymmetric carbon atoms, exist as optical antipodes, racemates or isomeric mixtures (e.g. racemate mixtures). 'Formed' isomer mixtures (racemate mixtures) can, due to the physico-chemical differences of the component, be divided into the two stereoisomers (diastereomers), pure isomers, e.g. racemates, for example by chromatography and/or fractional crystallization. "Formed racemates can be obtained by known methods, for example by recrystallization from an optically active solvent, with the help of microorganisms or by reacting one free carboxylic acid with an optically active base that forms salts with the racemic compound and separating the salts formed in this way," for example, because of their different solubilities, separate into the diastereomers from which the antipodes can be released by the action of a suitable agent. A particularly common optically active base is, for example, the D and L forms of cinchonine. Preferably, one isolates the most active of the two antipodes. ;Formed racemates of basic compounds can be further separated by reaction with an optically active acid that forms salts with the racemic compound and separation of salts formed in this way, e.g. due to their different solubilities in diastereomers from which the antipodes can be released by the action of a suitable agent. Particularly common optically active acids are, for example, the D and L forms of v inic acid, di-o-toluyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid. The invention also relates to the embodiments of the method according to which one starts from one or other step of the method as an intermediate formed compound and carries out the missing method steps or interrupts the method at one or other step, or where a starting substance is formed in the reaction conditions or where a reaction component is optionally present in the form of its salt. Thus, the new compounds can be obtained when one oxidizes the compounds of the type with formula XI in which Y2 means an oxymethyl group, e.g. with a suitable oxidizing agent. Thereby, intermediate compounds of formula XI are formed, in which Y2 means a formyl group which is then, as stated above, further oxidized, e.g. the hydroxymethyl group can primarily be transferred in a formyl group, e.g. with finely divided manganese dioxide, preferably in an inert, neutral, organic solvent, such as e.g. petroleum ether, chloroform, acetone or ether, and then, e.g. as indicated above, in a carboxyl group. ;One can also convert a corresponding diazoketone instead of a ketene with formula VIII, e.g. according to the method of Arndt-Eistert with water, alcohol, ammonia, primary or secondary amines. Thereby, a ketene of formula VIII is intermediately formed, which is then further reacted as indicated. Preferably, a diazoketone of formula ;; in which R and Ph have the indicated meanings is reacted in the presence of a catalyst, such as a metal catalyst, especially colloidal silver, and at an elevated temperature. However, the reaction can also be carried out in an alcoholic solution, further in an aqueous and ammoniacal (or amine-basic) environment, especially at an elevated temperature. ;Appropriately, for carrying out the reaction according to the invention, starting materials are used, which lead to the groups of end materials specifically mentioned at the beginning and especially to the end materials specifically mentioned and produced. The starting materials are known and, if they are new, can be produced according to known methods. ;The nitriles used as preferred starting materials ;with formula ;which are advantageously used as starting materials, can e.g. is produced when one transfers a compound of formula ; where Hal means a halogen atom such as chlorine or bromine, to a corresponding ketal or acetal, e.g. an ethylene ketal, transfers the prepared compound with magnesium to the corresponding Grignard reagent and reacts this with a corresponding cycloalkanone. In the 1-hydroxycycloalkyl compound produced, the hydroxyl group is split off, preferably in the presence of an acid, forming a 1,2-double bond, and in the thus produced compound of formula ;; the oxo group is reduced in the usual way to a hydroxyl group. The hydroxyl group is transferred in a known manner, e.g. by reaction with halides of phosphorus or sulfur as well as phosphorus oxychloride or thionyl chloride or similar bromides to a corresponding halogen atom which can then be transferred to the cyan group by reaction with a salt of hydrocyanic acid, such as sodium cyanide. Compounds where R2 does not denote hydrogen can be prepared by introducing the residue R2, e.g. in the nitrile, for example in a similar way as described above for ester and amide, via the α-metal salt, and reacts this with a reactive ester of a corresponding alcohol. The new connections can e.g. find application in the form of pharmaceutical preparations and contain the active compounds in free form or possibly in the form of salts, especially the therapeutically usable alkali metal salts, in a mixture with pharmaceutical organic or inorganic, solid or liquid carriers, suitable for enteral, parenteral or topical application. For the preparation of the preparations, substances are used that do not react with the compounds, e.g. water, gelatin, lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oil, benzyl alcohols, rubber, propylene glycols, petroleum jelly or other known pharmaceutical carriers. The pharmaceutical preparations can be made in the form of tablets, dragees, capsules, suppositories, creams, ointments or in liquid form as solutions (e.g. elixirs or syrups), suspensions or emulsions. Optionally, the preparations are sterilized and/or auxiliary substances are added, such as preservatives, stabilisers, wetting or emulsifying agents, dissolution agents or salts to change the osmotic pressure or buffers. They can also be added to other therapeutically valuable substances. The pharmaceutical preparations are produced in a known manner: The invention will be described in more detail in the following with the help of examples, where the temperatures are indicated in degrees Celsius.' Example 1. A solution of 50.3 g α-β-(1-cycloheptenyl)-phenyl 1/propionic acid nitrile and 26 g potassium hydroxide in 400 ml ethanol and 80 ml water is boiled for 36 hours at reflux. After evaporation of the ethanol in a vacuum, the residue is taken up in water. The aqueous solution is first shaken out with ether, acidified with concentrated hydrochloric acid and extracted again with ether. These ether extracts, which are washed with water, give after drying over sodium sulfate, evaporation in vacuo and recrystallization from ether-petroleum ether the compound α-/_—p-(1-cycloheptenyl)-phenyl7-propionic acid with the formula; in the form of colorless crystals with m.p. . 105 - 107°C. ;The sodium salt is produced by dissolving the carboxylic acid in the calculated amount of ethanolic caustic soda and evaporation in a vacuum. It has a decomposition point of 229-233°C. ;Starting material fatty α-_/— p-(1-cyclohepteny 1)-phenyl l/-propionic acid nitrile can be prepared as follows: A well-stirred suspension of 14.6 g of magnesium shavings, which has been washed with chloroform and activated with iodine, in 150 ml of absolute tetrahydrofuran, a solution of 97.6 g of 2-(p-bromophenyl)-2-methyl-1,3-dioxolane in 500 ml of tetrahydrofuran is added dropwise at 60°C. The dripping is regulated so that the temperature does not exceed 60°C. At the end of the reaction, the mixture is heated for 30 minutes at 60°C, cooled to 20°C and 67 g of cycloheptanone are now added dropwise while stirring. After heating for one hour at 50 - 60°C, the reaction mixture is evaporated. Ice and 200 ml of saturated aqueous ammonium chloride solution are added to the residue. It is extracted with ether, dried over sodium sulphate and evaporated. The residue is recrystallized from ether-petroleum ether, whereby 2-/_-p-(1'-hydroxy-cycloheptyl)-phenyl7-2-methyl-1,3-dioxolane is obtained as colorless crystalline compounds with m.p. 78 - 80°C. A solution of 43 g of this compound in 240 ml of glacial acetic acid and 90 ml of 2-N hydrochloric acid is heated for 1 hour at 100°C. After cooling, add 300 ml of water, extract with ether, wash with 2-N sodium bicarbonate solution and evaporate the ether extract dried over sodium sulphate. The oil residue is distilled under high vacuum and yields p-(1-cycloheptenyl)-acetophenone as a viscous oil with a boiling point of 140°/0.004 mm Hg. ;A solution of 49 g of this ketone in 100 ml of methanol is added dropwise with stirring to a solution of 11 g of sodium borohydride in 500 ml of methanol and 100 ml of water, cooled to 0°C. The reaction solution is further stirred for 1 hour at 5 - 10° and allowed to stand for 16 hours at room temperature. 600 ml of water are then added, extracted with methylene chloride, dried over sodium sulphate and evaporated. One thus obtains as an oily colorless residue 1-hydroxy-1-1_p-(1-cycloheptenyl)"-phenyl7-ethane. 49 g of this hydroxy compound is dissolved in 400 ml of absolute benzene, 28 ml of thionyl chloride is added and it is left in 2 hours at room temperature. After evaporation in a vacuum, a solution of the prepared 1-chloro-1-(p-(1-cycloheptenyl)-phenyl-17-ethane in 100 ml of dimethyl sulphoxide is added to a suspension of 26 g of sodium cyanide in 150 ml of dimethyl sulphoxide at 50 - 60°C with stirring. The mixture is left to react for 1 hour at this temperature, cooled, 150 ml of water are added and extracted with ether-acetic acid 1:1. The organic ether extracts are washed with water, dried over sodium sulfate, evaporated and gives the crude α-/_ p-(1-cycloheptenyl)-phenyl7-propionic acid nitrile usable for the above hydrolysis, in the form of a viscous, brown oil. ;Example 2. ;A solution of 27.5 g of a-/ p -(1-cyclopentenyl)-phenyl1/-propionic acid nitrile and 16.5 g of potassium hydroxide in 200 ml of ethanol and 40 ml of water are boiled for 30 hours under backflow. It is evaporated in vacuo, the residue is taken up in water and extracted with ether. The clear, aqueous solution is acidified with 5-n hydrochloric acid and extracted with ether. The ether extracts are dried and evaporated over sodium sulfate, the solid residue is recrystallized from ether-petroleum ether. In this way α-/<_> p-(l-c<y>chloro<p>enten<y>l)-phen<yl>7-propionic acid with the formula is obtained in the form of colorless crystals with mp 137 - 140°C. ;The sodium salt is recovered by dissolving the carboxylic acid ;in the calculated amount of ethanolic caustic soda and precipitation with ether. ;Starting material fatty 2-/_ p-(l-c<y>chloro<p>entene<y>l)-phenyl/-propionic acid nitrile can be prepared as follows: A carefully stirred suspension of 7.3 g of magnesium shavings, washed with chloroform and activated with iodine, in 150 ml of absolute tetrahydrofuran, is added dropwise at 60°C a solution of 48.6 g of 2-(p-bromophenyl )-2-methyl-1,3-dioxolane in 100 ml of tetrahydrofuran. The dropwise addition is regulated so that the reaction temperature does not exceed 60° C. At the end, it is heated for a further 30 minutes d 60°C, cooled to 20°C, and 21.6 g of cyclopentanone are added dropwise. After heating for one hour to 50-60°C, the reaction mixture is evaporated and ice and 200 ml of saturated aqueous ammonium chloride solution are added to the residue. It is extracted with ether, dried over sodium sulphate and evaporated. The residue is recrystallized from ether-petroleum ether, and 2-_/—p-(1'-hydroxy-cyclopentyl)-phenyl 17-2-methyl-1,3-dioxolane with a melting point of 90 - 91°C is obtained. A solution of 15 g of this compound in 80 ml of glacial acetic acid and 30 ml of 2-n hydrochloric acid is heated for 1 hour at 100°C. After cooling, dilute with 200 ml of water and extract with ether. The ether layers are washed with 2-n sodium bicarbonate solution, dried over sodium sulfate and evaporated. The residue gives after recrystallization from ether-petroleum ether p-(1-cyclopentenyl)-acetophenone with a melting point of 100-102°C. A solution of 30 g of this ketone in 200 ml of methanol is added dropwise with stirring to a solution of 7.8 g of sodium borohydride in 300 ml of methanol and 60 ml of water, cooled to 0°C, and 60 ml of water added. The mixture is stirred for 1.5 hours at 5-10°C, allowed to stand for 16 hours, water is added and the mixture is extracted with methylene chloride. The methylene chloride extracts. dried over sodium sulfate, evaporated and the residue recrystallized from ether-petroleum ether, to produce l-hydroxy-l-/_~p-(l-cyclopentenyl)-phenyl7-ethane with melting point 90 - 92°C. ;A solution of 35.5 g of this hydroxy compound in 350 ml abs. benzene, 21 ml of thionyl chloride is added and stirred for 2 hours at room temperature. It is then evaporated in vacuo, the crude oil produced from 1-chloro-1-[p-(1-cyclopentenyl)-phenyl-7-ethane is dissolved in 50 ml of dimethylsulfoxide and this mixture is added with stirring to a suspension of 23 g sodium cyanide in 400 ml of dimethylsulfoxide, at 50 - 60°C. After standing for one hour at this temperature, it is cooled, it is diluted with 300 ml of water and extracted with ether-acetic acid (1:1). The organic extracts are washed with water, dried over sodium sulfate and evaporated to give α-/~ p-(1-cyclopentenyl)-phenyl-17-propionic acid nitrile, as a crude oil which can be used directly for the above hydrolysis. Example 3. A solution of 24 g of a mixture of α-β-(6-methyl-1-cyclohexenyl)-phenyl-17-propionic acid nitrile and α-β-(2-methyl-1-cyclohexenyl) -phenyl7-propionic acid nitrile and 11 g of potassium hydroxide in 200 ml of ethanol and 70 ml of water are boiled for 15 hours under reflux. After evaporation of the ethanol in vacuum, the residue is dissolved in water and extracted. The aqueous solution is acidified with 5-n hydrochloric acid and extracted with ether. The oily ether residue is dissolved in ether and a solution of sodium ethanolate in ethanol is added. A mixture of α-/_~p-(6-methyl-1-cyclohexenyl)-phenyl7-propionic acid sodium salt and α-/<->p-(2-methyl-1-cyclohexenyl)-phenylV-propionic acid sodium salt is precipitated with the ;formulas ;;which is isolated by filtration, washing with acetone-ether and drying in vacuum at 60°C. ;The starting material a-/p-(1-methyl-1-cyclohexenyl)-phenyl7-propionic acid nitrile mixture can be prepared as follows: ;A well-stirred suspension of 8.8 g of magnesium shavings, ;washed with chloroform and activated with iodine, suspended in 150 ml abs. tetrahydrofuran, a solution of 23 g of 2-(p-bromophenyl)-2-methyl-1,3-dioxolane in 450 ml abs. is added dropwise at 60°C. tetrahydrofuran. The dripping is regulated so that the temperature does not exceed 60°C. After the addition, the mixture is further heated for 30 minutes at 60°C, cooled to 5°C and added dropwise with stirring hl g 2-methylcyclohexanone. After heating at 50 - 60°C for one hour, the reaction mixture is filtered off and evaporated in a rotary evaporator. The residue is added to ice and saturated aqueous ammonium chloride solution. It is extracted with ether, dried over sodium sulphate and evaporated. The residue is recrystallized from ether-petroleum ether, whereby 2-[p-(2'-methyl-1'-hydroxy-cyclohexyl)-phenyl]-2-methyl-1,3-dioxolane with a melting point of 77 - 80°C is obtained. A solution of 33 g of this compound in 150 ml of glacial acetic acid is added to 80 ml of 2-n hydrochloric acid and heated for 1 hour at 100°C. Cool, add 700 ml of water, extract twice with 300 ml of petroleum ether, dry over sodium sulphate and evaporate. The residue is distilled under high vacuum, whereby a 7:3 mixture of p-(6-methyl-1-cyclohexenyl)-acetophenone and p-(2-methyl-1-cyclohexenyl)-acetophenone emerges as a pale yellow oil, boiling point 130 - 140 °C/0.2 mm Hg. To a solution of h g of sodium borohydride in 200 ml of methanol and h0 ml of water cooled to 5°C, a solution of 23 g of the above-described ketone mixture is added dropwise while stirring. One continues to stir for 1| hour at 5-10°C, leave for 16 hours, add 600 ml of water, extract with methylene chloride, dry over sodium sulphate and evaporate in vacuo. The residue is distilled in high vacuum, and a mixture of 1-hydroxy-l-/<->p-(6-methyl-1-cyclohexenyl)-phenyl7-ethane and 1-hydroxy-l-/_—p- (2-methyl-1-cyclohexenyl 1)-phenyl3.7-ethane as a colorless oil with a boiling point of 120 - 140°C/0.1 mm Hg. ;A solution of 23 g of this mixture in 200 ml abs. benzene is allowed to stand in the presence of 11.5 ml of thionyl chloride for 16 hours at room temperature. Evaporation in vacuo dissolves the crude, oily mixture of 1-chloro-1-[p-(6-methyl-1-cyclohexenyl)-phenyl]-ethane and 1-chloro-1-/<->p -(2-methyl-1-cyclohexenyl)-phenyl-7-ethane in 30 ml of dimethyl sulphoxide and add dropwise with stirring o v «i rice'' mixture to a suspension of 18 g of sodium cyanide in 120 ml of dimethyl sulphoxide, heated to 50° C. The mixture is allowed to react further for 2 hours at 70 - 80°C, cooled and 300 ml of water are added. The residue of the evaporated ether extract is a mixture of α-£~p-(6-methyl-1-cyclohexenyl)- phenyl7-propionic acid nitrile and α-/~p-(2-methyl-1-cyclohexenyl)-phenyl7-propionic acid nitrile in the ratio 7:3, which can be used directly for the above hydrolysis. ;Example 4. ;A solution of 18 g of α-/ ~p-(4-methyl-1-cyclohexenyl)-phenyl7-propionic acid nitrile and 9.2 g of potassium hydroxide in 120 ml of ethanol and 70 ml of water are boiled for 24 hours under reflux. After evaporation of the ethanol in a rotary evaporator under vacuum, the residue is added to 400 ml of water and extracted with ether. The aqueous solution is acidified with 2N hydrochloric acid and shaken out with ether. This is dried over magnesium sulfate and the evaporated ethereal solution is recrystallized from ether-petroleum ether and gives a- <£>~p-(4-meth<y>l-l-cyclohexenyl)-phenyl.7-propionic acid with the formula ;;in the form of pale yellow crystals , melting point 100 - 104°C. The sodium salt is prepared by dissolving this carboxylic acid in the calculated amount of ethanolic caustic soda and precipitation with ether. ;Starting material for an α-/-p-(4-methyl-1-cyclohexenyl)-phenyl 3,7-propionic acid nitrile can be prepared as follows: A well-stirred suspension of 7.3 g of magnesium shavings, washed with chloroform and activated with iodine, in 150 ml of absolute tetrahydrofuran, a solution of 48.6 g of 2-(p-bromophenyl)-2-methyl-1,3-dioxolane in 100 ml of tetrahydrofuran is added dropwise at 60°C. After the reaction has started, the rest of the solution is added dropwise, taking care that the temperature does not exceed 60°C. At the end of the reaction, the mixture is heated for a further hour at 50 - 60°C, then cooled to 20°C and 34 g of 4-methyl-cyclohexanebn are added dropwise. The reaction is then carried out for 1 hour at 50 - 60°C, the residue is evaporated and ice and a saturated aqueous ammonium chloride solution are added. It is extracted with ether, dried over magnesium sulphate and evaporated. The residue is recrystallized from ether-pentane, and 2-[p-(4'-methyl-1'-hydroxy-cyclohexyl)-phenyl-17-2-methyl-1,3-dioxolane'' with a melting point of 125 - 127°C is obtained. A solution of 15 g of this compound in 80 ml of glacial acetic acid is added to 30 ml of 2-n hydrochloric acid and heated for one hour at 100°C. After adding water, extract with ether. The ether solution is washed with 2-n bicarbonate solution and water, dried over magnesium sulphate and evaporated. The solid residue, which is recrystallized from ether-petroleum ether, gives the compound p-(4-methyl-1-cyclohexenyl)-acetophenone with a melting point of 50 - 52°C. ;To a solution of 1.8 g of sodium borohydride in 80 ml of methanol and 15 ml of water cooled to 0°C, 8.8 g of p-(4-methyl-1-cyclohexenyl)-acetophenone are added in portions while stirring. The mixture is stirred for 11 hours at 5 - 10°C and 4 hours at room temperature, 200 ml of water are added and extracted three times with 100 ml of methylene chloride each time. The methylene chloride residue is recrystallized from petroleum ether and gives 1-hydroxy-1-[p-(4-methyl-1-cyclohexenyl)-phenyl]-ethane with a melting point of 65-67°C. A solution of 4.3 g of this compound in 60 ml of absolute benzene is stirred in the presence of 2.5 ml of thionyl chloride for 2 hours at room temperature. It is evaporated in vacuo, the crude, oily 1-chloro-1-(p-(4-methyl-1-cyclohexenyl)-phenyl-1/-ethane is taken up in 20 ml of absolute dimethylsulfoxide, and this solution is added dropwise with stirring to a suspension of 2.3 g of sodium cyanide in 30 ml of absolute dimethyl sulfoxide. Heat for 2 hours at 50 - 60°C, cool, add 150 ml of water and extract with a mixture of ether-acetic acid (1:1). The extract is washed with water, dried over magnesium sulphate and evaporated. The brown oil residue consists predominantly of ot-/-p-(4-methyl-1-cyclohexenyl)-phenyl-17-propionic acid nitrile and can be directly used for the above hydrolysis. ;Example 5- ;A solution of 24 g of ot-[<->p-(4-methoxy-1-cyclohexenyl)-phenyl_17-propionic acid nitrile and 10 g of potassium hydroxide in 200 ml of ethanol and 70 ml of water is boiled for 24 hours under reflux. It is then evaporated in vacuo, the residue dissolved in water, extracted with ether, the aqueous phase acidified with 5-n hydrochloric acid and the precipitated oil extracted with ether. The oily ether residue is dissolved in ether, a solution of sodium ethanolate in ethanol is added and the α-/<->p-(4-methoxy-1-cyclohexenyl)-phenyl7-propionic acid sodium salt with formula is obtained which after precipitation is filtered, washed with acetone -ether and dried in vacuum at 60°C. ;Starting material f a ct-/~p-(4-methoxy-1-cyclohexenyl)-phenyl7-propionic acid nitrile can be prepared in the following way: ;A well-stirred suspension of 14.5 g of magnesium shavings, ;washed with chloroform and activated with iodine, suspended in 150 ml abs. tetrahydrofuran, a solution of 121 g of 2-(p-bromophenyl)-2-methyl-1,3-dioxolane in 500 ml of absolute tetrahydrofuran is added dropwise at 60°C. The addition is adjusted so that the reaction temperature does not exceed 60°C. After the addition is finished, the mixture is heated for 30 minutes at 60°C, cooled to 5°C and 77 g of 4-methoxycyclohexanone are now added dropwise while stirring. After heating for 1 hour at 50 - 60°C, the reaction mixture is filtered off and evaporated in a rotary evaporator. The residue is added to a saturated aqueous ammonium chloride solution. The whole is extracted with ether, dried over sodium sulphate and evaporated. The residue is recrystallized from ether-petroleum ether to give 2-(4-methoxy-1-hydroxy-cyclohexyl)-phenyl7-2-methyl-1,3-dioxolane with a melting point of 137-140°C. ;To a solution of 55 g of this compound in 120 ml of glacial acetic acid, 20 ml of concentrated hydrochloric acid and 40 ml of water are added. It is heated for 2 hours at 80 - 90°C, cooled, 2000 ml of water are added and extracted with ether. The ether residue is distilled in high vacuum at 160-170 C/0.1 mm Hg, and then recrystallized from petroleum ether, which gives the product p-(4-methoxy-1-cyclohexenyl)-acetophenone with a melting point of 40 - 42°C. ;To a solution of 4.5 g of sodium borohydride in 200 ml of methanol and 40 ml of water, 24 g of the above ketone is added, stirred for 2 hours at 5 - 10°C, 500 ml of water is added, extracted with methylene chloride and evaporated. The oil residue is distilled in high vacuum at l60 l80°C (0.1 mm Hg). A solution of 24 g of this oily 1-hydroxy-1-(4-methoxy-1-cyclohexenyl)-phenyl-7-ethane in 250 ml of absolute benzene is added to 12 ml of thionyl chloride and stirred for 3 hours at room temperature. After evaporation in vacuo, the crude, oily 1-chloro-1-(4-methoxy-1-cyclohexenyl)-phenyl-7-ethane is added to a suspension of 18 g of sodium cyanide in 100 ml of dimethylsulfoxide at 50°C. The mixture is allowed to react for a further 1 hour at 65°C, cooled, 400 ml of water is added and extracted with ether. The ether residue constitutes the crude β-(4-methoxy-1-cyclohexenyl)-phenyl7-propionic acid nitrile and can be used directly for the above hydrolysis. Example 6. A solution of 9.5 g of α-β-(1-cyclohexenyl)-phenyl-17-propionic acid nitrile in a solution of 5 g of potassium hydroxide in 150 ml of ethanol and 50 ml of water is boiled for 24 hours under reflux. After evaporation of the ethanol in vacuum, 200 ml of water are added to the residue. The insoluble components are removed by filtration, activated carbon is added and filtered. The clear, aqueous solution is acidified with 2-N hydrochloric acid and extracted with methylene chloride. The residue of the methylene chloride solution, which is dried over magnesium sulfate and evaporated, is recrystallized from ether-petroleum ether and gives a-/_ p-(1-cyclohexenyl)-phenyl/-propionic acid of the formula ;;as colorless crystals with a melting point of 106 - 108° C. ;The sodium salt is obtained by dissolving the carboxylic acid in the calculated amount of ethanolic caustic soda and by evaporation in a vacuum, decomposition point (245°C) 248-250°C. 'Starting substance f et in this example', α-/-p-(1-cyclohexenyl)-phenyl-1/-propionic acid nitrile is prepared as follows: A carefully stirred suspension of 9.8 g of magnesium shavings, washed with chloroform and activated with iodine, in 150 ml of absolute tetrahydrofuran is added dropwise at 60°C to a solution of 96 g of 2-(p-bromophenyl)-2-methyl-1,3-dioxolane in 150 ml of tetrahydrofuran. The addition is regulated so that the reaction temperature does not exceed 60°C. At the end of the reaction, heat is continued for 30 minutes at 60°C, it is cooled to 5°C and, with continued stirring, 35 g of cyclohexanone are added dropwise. After further heating at 50 - 60°C for one hour, the reaction mixture is filtered off and evaporated in a rotary evaporator. The residue is added to ice and a saturated aqueous ammonium chloride solution. It is extracted with ether, dried over magnesium sulphate and evaporated. The residue is recrystallized from ether-petroleum ether, and gives 2-[p-(1'-hydroxy-1'-cyclohexyl)-phenyl 17-2-methyl-1,3-dioxolane with a melting point of 117 - 118°C. ;To a solution of 80 g of this compound in 200 ml of glacial acetic acid, 30 ml of concentrated hydrochloric acid and 50 ml of water are added. It is heated in a water bath for 3 hours to 80°C. After water has been added until no more flocculation forms, the crystals are filtered off. These give after drying and recrystallization from petroleum ether p-(1-cyclohexenyl)-acetophenone with a melting point of 76 - 77°C. ;To a solution of 7 g of sodium borohydride in 300 ml of methanol and 80 ml of water cooled to 5°C, 50 g of p-(1-cyclohexenyl)-acetophenone are added in portions while stirring. Stirring continues for 2 hours at room temperature, evaporating and reducing the solution to half in a rotary evaporator, adding 1000 ml of water and extracting three times with 500 ml of methylene chloride each time. The methylene chloride residue is recrystallized from petroleum ether and gives 1-hydroxy-1-/-p-(1-cyclohexenyl)-phenyl-17-ethane with a melting point of 60 - 62°C. A solution of 20 g of 1-hydroxy-1-(p-(1-cyclohexenyl)-phenyl-7-ethane in 300 ml of absolute benzene is stirred in the presence of 10 ml of thionyl chloride at room temperature. After evaporation in vacuo, the crude, oily 1-chloro-1-_/~p-(1-cyclohexenyl)-phenyl 17-ethane is dissolved in 50 ml of dimethylsulfoxide and added with stirring and dropwise to a suspension of 15 g of sodium cyanide in 300 ml of dimethyl sulfoxide. After stirring for 15 hours at 70°C, cool, add 400 ml of water and extract with a mixture of ether-acetic acid (1:1). The extract is dried over magnesium sulphate, filtered off and evaporated in vacuo. After distillation of the residue in high vacuum, the product α-/~P_(1-cyclohexenyl)-phenyl7-propionic acid nitrile is obtained as a yellow oil, boiling point 125 - 130 (0.1 torr). ;Example 7. ;To a solution of 10 ml of pyridine in 25 ml of ethanol cooled to 10°C, 7 g of a-/_-p-(1-cyclohexenyl)-phenyl-7-propionic acid chloride are added dropwise. The mixture is allowed to stand for 3 hours at room temperature, evaporated in vacuo, the residue taken up in ether and washed with water. Then wash with 2N hydrochloric acid, saturated sodium bicarbonate solution and once more with water. The ether extracts are dried over sodium sulfate and evaporated, distilled under high vacuum to give α-/_ p-(l-cyclohexenyl)-phenyl]/-propionic acid ethyl ester with the formula in the form of a colorless oil with a boiling point of 130 - 140°C (0.1 mm Hg). The starting material for a-/~p-(1-cyclohexenyl)-phenyl-17-propionic acid chloride can be prepared as follows: A solution of 17 g of a-_/— p-(1-cyclohexenyl-phenyl/-propionic acid in 100 ml of absolute benzene is added 8 ml of thionyl chloride and heated for one hour at 80 - 90°C. One evaporates in vacuum, dissolves the residue in 3 times 50 ml of absolute benzene and evaporates each time in vacuum. One obtains as residue a-/~p-(1- cyclohexenyl)-phenyl/- propionic acid chloride, which can be used directly further for the preparation of the above ester. ;Example 8. ;In a solution of 7 g of a-/~p-(1-c<y>clohexene<y>l) -phen<y> 1/propionic acid chloride in 100 ml of absolute benzene is introduced with stirring and at room temperature ammonia gas until saturation. It is then evaporated to dryness, 100 ml of water is added and extracted with methylene chloride. The solid residue of evaporated methylene chloride extract is recrystallized from ethyl acetate-petroleum ether and gives a-/~p-(1-cyclohexenyl)-phenyl_l/-propionic acid amide of the formula ;;Example 9. ;A hot solution of 50 g of a-/_ p-(1-cyclohexenyl)-phenyl/-propionic acid in 1850 ml of ethanol is added to a hot solution of 63.9 g of chinchonidine in 1850 ml of ethanol. It is cooled slowly and after 16 hours the precipitated crystals of the chinchonidine salt of the enriched (+ )-α-β-(1-cyclohexenyl)-phenyl-1/-propionic acid are filtered off. By repeated fractional distillation according to the usual triangular scheme, the pure chinchonidine salt of dextrorotatory acid is obtained. Crystals are constantly recrystallized in h% ethanolic solution, while the mother liquor, which predominantly contains the chinchonidine salt of left-rotating acids, is crystallized by evaporation to 2/3 volume. The medium fractions are separated by hot dissolution and slow cooling. The pure chinchonidine salt of dextrorotatory acid is suspended in ether and shaken with 2-n hydrochloric acid until both phases are clear. The ether layer is washed with water, dried over sodium sulphate and evaporated. ( + )-α-_/ p-(1-cyclohexenyl)-phenyl7-propionic acid is obtained, melting point-101-102°C, /~a7^° = +53°C (ethanol, c = 1). ;In an analogous way, dextrorotatory acid can be prepared with ;(-)-α-phenylethylamine instead of chichonidine. ;Fractions containing practically pure chinchonidine salts of levorotatory acid are suspended in ether and shaken with 2-n hydrochloric acid until both phases are clear. The ether layer is washed with water, dried over sodium sulphate and evaporated. The residue is reacted in hot ethanol with the calculated amount of (+)-α-phenylethylamine and the formed salt is fractionally crystallized. From the pure fractions one can isolate (-)-ct-/~p-(1-cyclohexenyl)-phenyl7-propionic acid, melting point 101 - 102°C, l~ a7^ °= -53°C. By heating a 1% solution of the antipodes in 2-n sodium hydroxide solution for 16 hours to 100°C, a partial racemization is obtained. The optical rotation of the (-)-antipodes thus falls from -53°C to -24°C. propionic acid in 50 ml of ethanol and 20 ml of dimethylformamide are added to 3 g of 3-dimethylaminoethyl chloride and allowed to stand for 3 hours. Evaporate in vacuo, make the residue alkaline with ammonia and extract with ether. The ether residue is dissolved in a little ethanol and ethanolic hydrochloric acid and ether are added, whereby the hydrochloride of the 3-dimethylamino-ethyl ester of α-/~p-(1-cyclohexenyl)-phenyl_l7-propionic acid with the formula ;;precipitates as colorless crystals with a melting point of 132 - 134°C. Example 11. A solution of 6 g of g-dimethylaminoethylamine in 40 ml of toluene is added dropwise with stirring at room temperature to a solution of 6 g of a-/_p-(1-cyclohexenyl)-phenylV-propionic acid chloride in 10 ml of toluene. The mixture is stirred for 2 hours, extracted with 2-n hydrochloric acid, the hydrochloric acid aqueous solution is washed with vinegar and the mixture is made alkaline with 4-n caustic soda. It is extracted with acetic acid, washed with water, dried over sodium sulphate and evaporated in a vacuum. The solid residue is recrystallized from methylene chloride petroleum ether and the product N-(B-dimethylamino)-ethyl-α-/_—p-(1-cyclohexenyl)-phenyl7-propionic acid amide with the formula is obtained as colorless crystals with a melting point of 77 - 78° C. The hydrochloride melts at 123 - 126°C. ;Example 12. ;To a solution of 7.1 g of a-/_ p-(1-cyclohexenyl)-phenyl/- propionaldehyde in 70 ml of ethanol is added a solution of 17 g of silver nitrate in 35 ml of water, and dropwise while stirring a solution of 10 g of sodium hydroxide in 25 ml of water, thereby preventing the mixture temperature from rising above 45°C, by suitable cooling. Stirring continues for 2 hours at room temperature, filtering through celite, rinsing with ethanol and evaporating the filtrate to 70 ml. , The aqueous alkaline solution is extracted with ether, acidified with 2-n hydrochloric acid, and the precipitated acid is taken up in methylene chloride. The residue from the methylene chloride solution, which was dried over magnesium sulfate and evaporated, is recrystallized from ether and gives α-_/ p-(1-cyclohexenyl)-phenyl_l/-propionic acid as colorless crystals with a melting point of 106 - 108°C. The compound is identical to the acid from example 6. The fatty starting material used in this example, a-/_ p-(1-cyclohexenyl)-phenyl_17-propionaldehyde can be prepared in the following way: A solution of 38 g of chloroacetic acid ethyl ester and 19.^ g of p -(1-cyclohexenyl)-acetophenone in 200 ml of absolute toluene is added with stirring at 0 - 5°C dropwise over 45 minutes to a solution of sodium ethanolate in ethanol (7.2 g of sodium in 200 ml of ethanol). After stirring for 16 hours at room temperature, most of the ethanol is evaporated in a rotary evaporator under vacuum, the reaction mixture is diluted with toluene and shaken out with ice water. The toluene layer is dried over sodium sulphate and evaporated under vacuum to give a brown oil which is distilled under high vacuum. O-methyl-g-/_ p-(1-cyclohexenyl)-phenyl7-glycidic acid ethyl ester is obtained as a pale yellow oil with a boiling point of 150 - 155°C (0.15 mm Hg). 9.6 g of this ester are dissolved in 40 ml of ethanol and a solution of 0.78 g of sodium in 60 ml of ethanol is added. Another 0.72 ml of water is added and the mixture is allowed to stand for 20 hours at room temperature. The precipitated sodium salt is filtered off, dissolved in 400 ml of water, adjusted to pH 3 with 2-n hydrochloric acid and boiled for 6 hours at reflux under a nitrogen atmosphere. Moon cools, extracts with chloroform, dries over NaSO, evaporates and fractionates the oil residue in high vacuum. In this way, a-/_-p-(1-cyclohexenyl)-phenylZ-propionaldehyde with a boiling point of 178 - 190°C (0.14 mm Hg) is obtained. Example 13. A solution of 23 g of α-β-(1-cyclohexenyl)-phenyl7-butyric acid nitrile and 10 g of potassium hydroxide in 200 ml of ethanol and 80 ml of water is boiled for 36 hours under reflux. After the ethanol has evaporated, it is mixed with 100 ml of water, resulting in a precipitate which, after filtration, is recrystallized from ether-petroleum ether and gives ct-/_~p-(1-cyclohexenyl)-phenyl]/-butyric acid amide with the formula; as white crystals with melting point 148 - 149°C. The filtered alkaline solution is acidified with 2-N hydrochloric acid, extracted with ether and the ether extracts dried over sodium sulphate are evaporated in vacuo. The residue recrystallized from petroleum ether gives as the main product a-/-p-(1-cyclohexenyl)-phenyl7-butyric acid of the formula ;; as white crystals with a melting point of 101 - 103°C. The a-/_ p-(1-cyclohexenyl)-phenyl/-butyric acid nitrile used as starting material can be prepared in the following way: A solution of 119 g of p-bromo-propiophenone and 100 g of ethylene glycol in 1000 ml of benzene is mixed with 1 ml of concentrated sulfuric acid and boil while separating the water that forms for 10 hours under reflux. The excess ethylene glycol is separated in a separatory funnel and the benzene solution is washed with soda solution and water. After the benzene solution has been dried over sodium sulphate, it is evaporated in a vacuum to constant weight. The oily residue is the pure 2-(p-bromophenyl)-2-ethyl-1,3-dioxolane, which in the IR spectrum no longer has any carbonyl bands. A well-stirred suspension of 5.3 g of magnesium shavings that has been washed with chloroform and activated with iodine in 150 ml of absolute tetrahydrofuran is mixed at 65°C dropwise with a solution of 51.4 g of 2-(p-bromophenyl)-2- ethyl-1,3-dioxolane in 100 ml of absolute tetrahydrofuran. The dripping is regulated so that after the start of the reaction the temperature does not exceed 65°C. Finally, 50 ml of absolute tetrahydrofuran is also added and finally heated for 1 hour at 70°C. It is cooled to 20°C, mixed dropwise with stirring with 20 g of cyclohexanone and stirred for 3 hours at 35 - 40°C. Evaporate in vacuum on a rotary evaporator, mix with ice and saturated ammonium chloride solution and extract with ether. The ethereal extracts are dried over sodium sulphate and evaporated in vacuo. The solid residue gives after recrystallization from ether-petroleum ether 2-7 p-(1-hydroxy-cyclohexyl)-phenyl]V-2-ethyl-1,3-dioxolane as a colorless crystalline compound with a melting point of 92-93°C. A solution of 25 g of this compound in 200 ml of glacial acetic acid, 12 ml of concentrated hydrochloric acid and 20 ml of water is heated for 1.5 hours at 60 - 70°C. After cooling, mix with 250 ml of water as a solid white precipitate falls out. It is filtered off, washed with water, the crystals are taken up in methylene chloride and dried over sodium sulphate. After evaporation in a vacuum, the residue is recrystallized from petroleum ether and p-(1-cyclohexenyl)-propiophenone is obtained as white crystals with a melting point of 78 - 79°C. A solution of 25 g of this ketone in 10 ml of methanol is added dropwise with stirring to a solution of 5 g of sodium borohydride in 300 ml of methanol and 40 ml of water cooled to 0°C. The reaction solution is left for 16 hours at room temperature, evaporated to half and mixed with 100 ml of water. One extracts with methylene chloride, washes the methylene chloride extract with water, dries it over sodium sulphate and evaporates in a vacuum. The oily residue solidifies on standing and is 1-hydroxy-1-/_ p-(1-cyclohexenyl)-phenyl 1/propane with a melting point of 46 - 47°C. 20 g of this hydroxy compound are dissolved in 200 ml of benzene, mixed with 10 ml of thionyl chloride and allowed to stand for 2 hours at room temperature. After evaporation in a vacuum, a solution of the 1-chloro-1-/p-(1-cyclohexenyl)-phenyl/-propane thus formed in 100 ml of dimethylsulfoxide is added to a suspension of 10 g of sodium cyanide in 100 ml of dimethylsulfoxide and heated for 4 hours at 60°C. After cooling, it is mixed with water and extracted twice with each time 500 ml of a mixture of ether and vinegar in the ratio 1:1. The organic extracts are dried over sodium sulfate and evaporated, obtaining the crude α-/β-(1-cyclohexenyl)-phenyl/-butyric acid nitrile as a pale brown oil. ;Example 14. ;A solution of 20 g of eth-/p-(1-cyclohexenyl)-phenyl/-propionic acid in 150 ml of absolute methanol is mixed with 8 ml of concentrated sulfuric acid and boiled for 2 hours under reflux. Evaporate in vacuum on a rotary evaporator, mix with ice and water, make it carefully alkaline with saturated soda solution and extract with ether. The ether extracts dried over sodium sulfate and evaporated in vacuum give, after distillation in high vacuum, a-/_ p-(1-cyclohexenyl)-phenyl! L/-propionic acid methyl ester of formula ;; with boiling point 140 - 145°C (0.1 mm Hg). In an analogous way, /_—a-/-p-(1-cyclohexenyl) phenylZ-propionic acid/butyl ester is obtained with a boiling point of approx. l40°C (0.01 mm Hg) and /_ et-/ p-(1-cyclohexenyl)-phenyl7-propionic acid/tert-butyl ester, boiling point l60-163°C (0.06 mm Hg). ;Example 1 15 ;A solution of 4.7 g of hydroxylamine hydrochloride in 50 ml of absolute methanol is mixed with a solution of 2.3 g of sodium in 50 ml of absolute methanol, cooled to 0°C and filtered from separated sodium chloride. To the filtrate is added 8.13 g of ct-/_ p-(1-cyclohexenyl)-phenyl/-propionic acid methyl ester and the reaction solution is allowed to stand for 16 hours. It is then evaporated in vacuo, the solid residue is taken up in 1000 ml of water, mixed with 2-n hydrochloric acid to an acidic reaction and extracted with ether. The ether extract dried over sodium sulfate and evaporated in vacuum gives a solid residue from which, by recrystallization from ether-petroleum ether, eth-/, p-(1-cyclohexenyl)-phenylZ-propionhydroxamic acid with the formula; as a white, crystalline substance with a melting point of 145 - 146 °C. ;Example 16. ;Into a 750 ml three-necked flask cooled with an acetone-dry ice bath, which is equipped with a stirrer and a dry ice cooler, as much ammonia is introduced over a KOH tower until 200 ml of liquid ammonia has accumulated. One then mixes in small portions lj53 g of sodium and adds to the dark blue colored solution 50 mg of Fe (NO^) .j. 9H20. After 15 minutes, the color of the reaction solution turns grey-brown. A solution of 14.64 g of ct-_lp-(1-cyclohexenyl)-phenyl/-propionic acid methyl ester in 20 ml of ether is now added dropwise and stirred for half an hour. After this time, a solution of 8.52 g of methyl iodide in 50 ml of ether is mixed dropwise and allowed to react for 1.5 hours. After adding 355 g of ammonium chloride, the ammonia is evaporated, the residue is taken up in methylene chloride and washed with water. The methylene chloride extracts, dried over sodium sulfate and evaporated in a vacuum, give after distillation in a high vacuum a-/_ p-(1-cyclohexenyl)-phenyl]V-isobutyric acid methyl ester of the formula ;; with a boiling point of 150 - 155°C (0.05 mm Hg ). ;Exe mpe117. A solution of 11 g of a-/_ p-(1-cyclohexenyl)-phenyl/- isobutyric acid methyl ester in 100 ml of ethanol is mixed with 20 ml of 10-n caustic soda and heated for 2 hours at 60 - 70°C. After evaporation in vacuum, take up in water, wash with ether and acidify the aqueous alkaline phase with 2-N hydrochloric acid. Extract with ether, wash the ether extracts with water, dry them over sodium sulphate and evaporate. The solid residue gives, after recrystallization from ligroin et-/, p-(1-cyclohexenyl)-phenyl/-isobutyric acid of the formula; as white crystals with a melting point of 142 - 144°C. ;Example 18. ;A solution of 21.2 g of 1,2-0-isopropylidene-glycerol in ;70 ml of absolute pyridine is mixed at 5°C dropwise with stirring with a solution of 40 g of ct-/_ p-(1- cyclohexenyl)-phenyl L/-propionic acid chloride in 30 ml of absolute benzene and allowed to stand for 16 hours at room temperature. Evaporate under vacuum on a rotary evaporator, mix the residue with ice, extract with ether and wash the ethereal phase in sequence three times with each time 100 ml of 2-n hydrochloric acid, twice with each time 100 ml of water and once with 100 ml of saturated sodium bicarbonate solution. After drying over sodium sulfate, evaporation in a vacuum and distillation in a high vacuum, one obtains eth-/.-p-(1-cyclohexenyl)-phenyl 17-propionic acid-1,2-0-isopropylidene-3-glycerol ester of the formula ;;as a oil with boiling point 170 - 175°C (0.01 mm Hg). A solution of 28 g of a-(1-cyclohexenyl)-phenyl-1/-propionic acid-1,2-0-isopropylidene-3-glycerine ester in 1500 ml of 60% acetic acid is heated for 1 hour at 60°C. It is then evaporated under vacuum on a rotary evaporator, mixed with ice, made alkaline with a saturated sodium bicarbonate solution and extracted with ether. The ether extracts washed with water and dried over sodium sulphate are evaporated in vacuo. Distillation in high vacuum gives a -/. p-(l-cyclohexenyl)-phenyl].7-propionic acid-l-glycerol ester of the formula ;;as a viscous oil with a boiling point of 150°C (0.04 mm Hg), which solidifies on standing to a solid product with a melting point of 50 - 52°C. Example 19. A solution of 34 g of a-f~ p-(1-cyclooctenyl)-phenyl7-propionic acid nitrile in 300 ml of ethanol is mixed with a solution of 16 g of potassium hydroxide in 60 ml of water and boiled for 36 hours under reflux. After evaporation of the ethanol in a vacuum, the residue is taken up in 350 ml of water. The aqueous solution is first shaken with ether, then acidified with concentrated hydrochloric acid and extracted again with ether. The water-washed ether extracts give, after drying over sodium sulfate and evaporation in vacuo, a yellow oil. Distillation in high vacuum gives ct-/_ p-(1-cyclooctenyl)-phenyl7-propionic acid with the formula ;; as a viscous oil with a boiling point of 190 - 195°C (0.1 mm Hg). The solid sodium salt with a melting point of 136 - 140°C is obtained by dissolving this carboxylic acid in ether, mixing with the calculated amount of ethanolic caustic soda, evaporating and extracting the residue with acetone. The α-/_ p-(1-cyclooctenyl)-phenyl]/-propionic acid nitrile used as starting material can be prepared as follows: A well-stirred suspension of 31 g of magnesium shavings which was washed with chloroform and activated with iodine in 400 ml of absolute tetrahydrofuran is mixed dropwise at 60°C with a solution of 244 g of 2-(p-bromo-phenyl)-2-methyl-1,3-dioxolane in 600 ml of tetrahydrofuran. The addition is regulated so that after the start of the reaction the temperature does not exceed 60°C. Finally, it is heated for a further 1 hour at 60°C, then cooled to 15°C and mixed dropwise with 164 g of cyclooctanone while stirring. After it has been left to react for 1 hour at room temperature, the reaction mixture is evaporated in vacuo. The residue is mixed with ice and -450 ml of a saturated aqueous ammonium chloride solution. Extract with ether, wash the ether phase with water, dry it over sodium sulphate and evaporate it in a vacuum. After the fractional distillation in high vacuum, 2-l_p-(1-hydroxy-cyclooctenyl)-phenyl/-2-methyl-1,3-dioxolane is obtained as a colorless viscous oil with a boiling point of 150 - 162°C (0.05 mm Hg ). A solution of 85 g of this compound in 480 ml of glacial acetic acid and 150 ml of 2-N hydrochloric acid is heated for 1 hour at 100°C. After cooling, the maa is evaporated in vacuo, mixed with water and extracted with ether. The ether extracts washed with 2-n sodium bicarbonate solution are dried over sodium sulphate and evaporated in vacuo. Distillation in high vacuum gives p-(1-cyclooctenyl)-acetophenone sonv viscous pale yellow oil with boiling point 134-136°C (0.15 mm Hg). A cooled to 5 C solution of 14 g of sodium borohydride in 500 ml of methanol and 120 ml of water is mixed with stirring with a solution of 70 g of p-(1-cyclooctenyl)-acetophenone in 200 ml of methanol, stirred for 2 hours at 5 - 10°C and left for 2 hours at room temperature. Evaporate in vacuum approx. 500 ml of methanol, mix with 500 ml of water and extract with methylene chloride. The methylene chloride extracts are washed with water, dried over sodium sulphate and evaporated in vacuo. The practically colorless oily residue is the crude 1-hydroxy-1-/<->p-(1-cyclooctenyl)-phenyl7-ethane which is processed directly further. A solution of 69.2 g of this hydroxy compound in 700 ml of absolute benzene is mixed with 50 ml of thionyl chloride and 5 drops of dimethylformamide and allowed to stand for 3 hours at room temperature. After evaporation in a vacuum, the 1-chloro-1-β-p-(1-cyclooctenyl)-phenyl-7-ethane thus formed is dissolved in 150 ml of dimethylsulfoxide and the solution is stirred into a suspension heated to 50 - 60°C of 34.5 g of sodium cyanide in 200 ml of dimethylsulfoxide. It is left to react for a further 1 hour at this temperature, then cooled, mixed with 300 ml of water and extracted with a 1:1 mixture of ether and acetic acid. The organic extracts are washed with water, dried over sodium sulphate and evaporated. The residue gives after distillation in high vacuum a-/~p-(1-cyclooctenyl)-pheny3/7-propionic acid nitrile in the form of a yellow oil with a boiling point of 165 - 172°C (0.15 mm Hg). ;Example 20. ;A solution of 5 g of p-(1-cyclohexenyl)-phenyl-acetonitrile in 100 ml of absolute ethanol is cooled to -10°C. Dry HCl gas is introduced while stirring for 1 hour and allowed to stand for 16 hours. One now evaporates on a rotary evaporator in vacuum to a volume of 30 ml, pouring the reddish alcoholic solution into 100 ml of saturated soda solution which was mixed with 100 g of ice and extracting twice with 150 ml of ether each time. The ethereal solution is first washed with saturated sodium chloride solution, then extracted with 100 ml of ice-cold 2-n H2SOi(. The sulfuric acid extract is heated on a water bath for 30 minutes at 60°C, as a colorless oil separates. It is shaken out with ether, washed with water, dried over sodium sulfate, filtered and evaporated. The residue is distilled under high vacuum and one obtains p-(1-cyclohexenyl)-phenyl-acetic acid ethyl ester with the formula: as a colorless oil and boiling point 130 - 135°C (0.5 mm Hg). The p-(1-cyclohexenyl)-phenyl-acetonitrile used as starting material in this example can be prepared as follows: ;A solution of 7 g of p-(1-cyclohexenyl)-phenyl bromide in ;100 ml of absolute ether is mixed with stirring and under a nitrogen atmosphere at 5°C with 50 ml of a solution of 4.3 g of n-butyllithium in absolute ether.It is allowed to come to room temperature, stirred for 30 minutes at 30°C, then cooled to 20°C and mixed dropwise - ;show with a solution of 4 g. N-methyl-N-formyl-aniline in 50 ml absolute ether, as the internal temperature rises to 30°C. After it has been allowed to react for 30 minutes at room temperature, the reaction solution is poured into 100 ml of ice-cold 2 N hydrochloric acid and extracted with ether. The ether layers are washed with water, dried over sodium sulphate and evaporated in vacuo. The residue is distilled under high vacuum and gives p-(1-cyclohexenyl)-benzaldehyde with a boiling point of 110 - 120°C (0.2 mm Hg). A cooled to 0°C solution of 5 g of this aldehyde in 30 ml of methanol and 10 ml of water. mixed with stirring with 1 g of sodium borohydride. The mixture is stirred for a further 15 minutes at 5°C, mixed with 150 ml of water and extracted with methylene chloride. The methylene chloride residue is distilled under high vacuum to obtain the solid p-(1-cyclohexenyl)-benzyl alcohol with a boiling point of 120 - 125°C (0.1 mm Hg), which after recrystallization from ether-petroleum ether melts at 70 - 71°C. A solution of 4 g of this alcohol in 50 ml of toluene is mixed with 1 ml of thionyl chloride and heated for 10 minutes at 80°C. It is evaporated in vacuo, the oily p-(1-cyclohexenyl)-benzyl chloride is taken up in 30 ml of dimethylsulfoxide and added to a heated to 50°C and stirred suspension of 2 g of powdered dry sodium cyanide in 50 ml of dimethylsulfoxide. After it has been allowed to react for 2 hours at 70°C, it is poured into 150 ml of water, extracted with ether and the residue distilled under high vacuum. The solid o-(1-cyclohexenyl)-phenyl-acetonitrile with a boiling point of 145°C (0.15 mm Hg) is thus obtained, which after recrystallization from petroleum ether melts at 71 - 73°C. The p-(1-cyclohexenyl)-benzaldehyde mentioned in this example as an intermediate can also be prepared in the following way: A well-stirred suspension of 2.65 g of magnesium shavings, which was washed with chloroform and activated with iodine, in 100 ml of absolute tetrahydrofuran is mixed at 60°C dropwise with a solution of 22.9 g of 2-(p-bromophenyl)-1,3-dioxolane in 100 ml of tetrahydrofuran. The addition is regulated so that after the start of the reaction the temperature does not exceed 60°C. Finally, it is heated for a further 60 minutes at 60°C, then cooled to 30°C and mixed with 11 g of cyclohexanone dropwise while stirring. After heating for 1 hour at 50°C, the reaction mixture is evaporated on a rotary evaporator in vacuum, and the residue is mixed with ice and a saturated aqueous ammonium chloride solution. It is extracted with ether, dried over sodium sulphate and evaporated. The residue is distilled under high vacuum and gives 2-_ lp-(1-hydroxy-cyclohexyl)-phenylZ-1,3-dioxolane with a boiling point of 160 - 170°C (0.05 mm Hg), which becomes solid on standing and after recrystallization from ether-petroleum ether melts at 95 - 97°C. "A solution of 10 g of this compound" in 30 ml of glacial acetic acid is mixed with 3 ml of concentrated hydrochloric acid and 5 ml of water and heated for 1 hour in a nitrogen atmosphere at 100°C. After cooling to room temperature, mix with ice and extract with ether. The ethereal extracts are washed with saturated sodium bicarbonate solution and with water, dried over sodium sulphate and evaporated. The residue gives after distillation in high vacuum p-(1-cyclohexenyl)-benzaldehyde with boiling point 110 - 120°C (0.2 mm Hg). ;Example 21. ;A solution of 2 g of p-(1-cyclohexenyl)-phenyl-acetic acid ethyl ester in 50 ml of ethanol is mixed with 15 ml of 2 N NaOH and heated for 2 hours at 60°C. After the main amount of ethanol has been distilled off in a vacuum, it is mixed with 20 ml of water, acidified with 2 N hydrochloric acid and extracted with ether. The ether layers are dried over sodium sulphate, filtered off and evaporated. The solid residue is recrystallized from petroleum ether and gives p-(1-cyclohexenyl)-phenyl-acetic acid of formula ;; as colorless crystals with a melting point of 120 - 121°C. Example 22. In a 750 ml three-necked flask cooled with an acetone-dry ice bath, which is equipped with a stirrer and a dry ice cooler, as much ammonia is fed over a KOH tower until 200 ml of liquid ammonia has accumulated . It is then mixed in small portions with 1.7 g of sodium and 50 mg of iron (III) nitrate nonahydrate (Pe (NO.,, . 9Ho0)) is added to the dark blue solution. After 15 minutes, the color of the reaction solution turns grey-brown. A solution of 12.2 g of p-(1-cyclohexenyl)-phenylacetic acid ethyl ether in 20 ml of absolute ether is now added dropwise and stirred for another half hour. After this time, a solution of 7.1 g of methyl iodide in 40 ml of absolute ether is mixed drop by drop and allowed to react for 1.5 hours. After adding 3.9 g of ammonium chloride, the ammonia is evaporated, the residue is taken up with methylene chloride and washed with water. The methylene chloride extracts dried over sodium sulfate and evaporated in vacuum give, after distillation in high vacuum, ot-</> p-(l-c<y>chlorohexene<y>l)-phen<y>l<7->propionic acid ethyl ester of formula ;; with boiling point 140 - 145°C (0.05 mm Hg). Example 23. A solution of 15 g of a-/_~~p-(1-cyclohexenyl)-phenyl]L/- propionic acid ethyl ester in 200 ml of ethanol is mixed with 20 ml of 4 N caustic soda and heated for 2 hours in a water bath at 60°C. After evaporation of the ethanol in a vacuum, the residue is mixed with 100 ml of water, the clear aqueous solution is acidified with 2 N hydrochloric acid and extracted with methylene chloride. The residue of the methylene chloride solution dried over sodium sulfate and evaporated is recrystallized from ether-petroleum ether, obtaining a-/_ p-(1-cyclohexenyl)-phenyl]L/-propionic acid with a melting point of 106 - 10 8°C which is identical to that in example 6 formed compound. ;Example 24. ;5.2 g of α-/_ p-(1,2-epoxy-cyclohexyl)-phenyl]L/-propionic acid methyl ester is hydrogenated with 1.5 g of Raney nickel in 50 ml of absolute ethanol at room temperature and normal pressure. Thereby, 448 ml of hydrogen is absorbed within 52 minutes. The catalyst is filtered off, evaporated in a vacuum and the residue distilled. At 14 0-145°C/0 .1 mm Hg, a mixture of a-v et-(p-cyclohexyl-phenyl)-propionic acid methyl ester and ot-/ p-(l-cyclohexenyl)-phenyl/-propionic acid methyl ester of the formula distils ;which is formed by dewatering the intermediately formed et-/-p-(1-hydroxycyclohexyl)-phenyl/-propionic acid methyl ester. The desired unsaturated compound can be separated for impurities by preparative gas chromatography. It is identical to the compound formed according to example 14. ;Example 25. ;A solution of 15 g of ct-/~p-(1-cyclohexenyl)-phenyl7-ct-methyl-malonic acid diethyl ester in 200 ml of ethanol is heated with 60 ml of 4 N caustic soda in a water bath at 70°C for 4 hours. The main amount of ethanol is evaporated in a vacuum, mixed with 100 ml of water, acidified with 5 N hydrochloric acid and extracted with methylene chloride. The methylene chloride extracts are dried over sodium sulphate, filtered off and evaporated. The crude, solid residue is heated for 1 hour in an oil bath at 170°C until carbon dioxide no longer evolves. After cooling to room temperature, the solid residue is crystallized from ether and petroleum ether and ct-/_ p-(1-cyclohexenyl) is obtained -phenyl/-propionic acid with a melting point of 106 - 108°C, which is identical to the compound formed in example 6. The ct-/_—p-(1-cyclohexenyl)-phenyl/-ct- mentioned in this example as starting material Methylmalonic acid diethyl ester can be prepared in the following way: A solution of 2.3 g of sodium in 150 ml of absolute ethanol is mixed dropwise at room temperature with stirring with a mixture of 24.4 g of p-(1-cyclohexenyl)-phenylacetic acid ethyl ester and 14, 6 g of oxalic acid diethyl ester. It is heated for 2 hours at 70°C and allowed to stand overnight at room temperature as a yellowish-brown precipitate forms. This is filtered off, dried and suspended as a powder in ether and shaken with approx. 10 ml of concentrated hydrochloric acid and 50 g of ice. The ethereal phase is also washed with ice water, dried over sodium sulfate and evaporated in vacuo. The residue consisting of crude p-(1-cyclohexenyl)-phenyl-ct-ethoxalyl-acetic acid ethyl ester is distilled in high vacuum, turning into a viscous oil at 180 - 200°C (0.1 mm Hg). 15 g of the [_ p-(1-cyclohexenyl)-phenyl/-malonic acid diethyl ester thus formed are dissolved in 100 ml of absolute dimethylformamide and mixed with stirring at room temperature with 1.3 g of sodium hydride. The mixture is now heated to 30°C and a solution of 8 g of methyl iodide in 20 ml of benzene is added dropwise. The mixture is stirred for a further 4 hours at 40°C, then evaporated in vacuo, mixed with ice water and extracted with methylene chloride. The water-washed methylene chloride extracts are dried over sodium sulphate and evaporated in vacuo. The residue gives, after distillation in high vacuum, eth-/ p-(1-cyclohexenyl)-phenyl/- ct-methyl-malonic acid diethyl ester with a boiling point of 180 - 185°C (0.05 mm Hg). Example 26. A solution of 13 g of p-(1-cyclohexenyl)-phenyl-thio-acetomorpholide in 30 ml of glacial acetic acid is mixed with 5 ml of concentrated sulfuric acid and 6 ml of water and heated for 4 hours at 100°C. It is then cooled to 0°C, adjusted with 4 N caustic soda to pH 8, evaporated in vacuum on a rotary evaporator, mixed with water and animal charcoal, filtered off and acidified with 4 N hydrochloric acid. It is then extracted with ether, dried over sodium sulphate, filtered and evaporated in vacuo. The solid residue is recrystallized from ether-petroleum ether and p-(1-cyclohexenyl)-phenylacetic acid with a melting point of 118 - 120°C is obtained, which is identical to the compound formed in example 21. The p-(1-cyclohexenyl)-phenyl-thioacetomorpholide used as a starting material in this example can be prepared in the following way: A mixture of 20 g of p-(1-cyclohexenyl)-acetophenone, 9 g of morpholine and 3.5 g sulfur is heated for 1 hour at 100°C and 15 minutes at 150°C. It is then cooled, mixed with ethanol and the separated crystals are filtered off. After recrystallization twice from ethanol-petroleum ether, p-(1-cyclohexenyl)-phenyl-thioacetomorpholide with formula ;; is obtained as crystals with a melting point of 154 - 156°C. ;Example 27- ;To a well-stirred suspension of 3 g of magnesium shavings in 100 ml of absolute tetrahydrofuran, 0.3 ml of ethyl bromide is added while stirring. When the Grignard reaction has started, a solution of 26.5 g of 1-bromo-1-[~p-(1-cyclohexenyl)-phenyl-7-ethane in 50 ml of absolute tetrahydrofuran is mixed and it is ensured that the temperature does not exceed 60 °C. The reaction is allowed to continue for a further 1 hour, cooled to room temperature and the reaction solution poured into a solution of dry ice in ether. The reaction mixture is allowed to come to room temperature, acidified with 4 N hydrochloric acid, and the organic phase is separated from the aqueous solution. The organic phase is now shaken three times with 1 N sodium bicarbonate solution, the alkaline aqueous solution is separated and extracted with ether after acidification with 2 N hydrochloric acid. The ether extracts are washed with water, dried over sodium sulphate and evaporated in vacuo. After recrystallization of the residue from ether-petroleum ether, a-/~p-(1-cyclohexenyl)-phenyl7-propionic acid with a melting point of 106 - 108°C is obtained, which is identical to the compound formed in example 6. ;The 1-bromo-1-/ p-(1-cyclohexenyl)-phenylV-ethane used as starting material in this example can be prepared in the following way: A solution of 20.2 g of 1-hydroxy-1-/_ p-( 1-cyclohexenyl)-phenyl/-ethane in 200 ml of absolute benzene is mixed with stirring with 43 g of phosphorus pentabromide. After 4 hours, evaporate in vacuum on a rotary evaporator, mix three times with absolute toluene and evaporate each time in vacuum. The bromide thus formed can be used directly for the above-mentioned Grignard reaction. ;Example 28. ;To 360 ml of 0.7 N diazomethane solution in ether, a solution of 21 g of p-(1-cyclohexenyl)-benzoic acid chloride in 100 ml of absolute ether is dripped under stirring at 0°C and allowed to heat up during 1 hour to room temperature. After distilling off excess diazomethane and the solvent in vacuo, the crude diazoketone is mixed with 70 ml of benzyl alcohol and 70 ml of N,N-dimethylaniline and heated for 1.5 hours with stirring at 180 - 190°C. The cooled reaction mixture is then mixed with 300 ml of water, acidified with hydrochloric acid and extracted with ether. The organic extract is washed with 2 N hydrochloric acid and then with water, dried over sodium sulfate and then evaporated in vacuo. The crude benzyl ester formed as a residue is dissolved in 200 ml of ethanol, mixed with 100 ml of 5 N caustic soda and allowed to stand at room temperature for 48 hours. The main amount of ethanol is distilled off in a vacuum, acidified with 5 N hydrochloric acid and extracted with ether. The ether extracts are washed neutrally, dried over sodium sulphate and evaporated in vacuo. The solid residue is recrystallized from petroleum ether, obtaining the pure p-(1-cyclohexenyl)phenylacetic acid with a melting point of 120 - 121°C, which is identical to the compound prepared in example 23. The p-(1-cyclohexenyl)benzoic acid chloride used as starting material in this example is prepared as follows: To a well-stirred suspension of 15 g of earth-activated magnesium shavings in 300 ml of absolute tetrahydrofuran, a solution of 120 g of p-( 1-cyclohexenyl)-bromobenzene in 300 ml of absolute tetrahydrofuran. The reaction solution is then boiled for 1.5 hours under reflux. It is cooled to -5°C and a dry CC^ current is introduced through the Grignard solution for one hour. One evaporates in a vacuum, mixes with water and filters off solid matter. After recrystallization from ethanol, p-(1-cyclohexenyl)-benzoic acid is obtained with a melting point of 190 - 1-93°C. A solution of 20 g of this carboxylic acid in 200 ml of ethanol is mixed with a solution of 2.3 g of sodium in 100 ml of ethanol. It is then evaporated in vacuo to dryness, the sodium salt thus formed is suspended in 200 ml of absolute benzene and mixed at 5°C with stirring with 25 g of oxalyl chloride. After the reaction mixture has been allowed to stand for 16 hours, it is filtered from the sodium chloride formed, evaporated to dryness and thus the crude p-(1-cyclohexenyl)-benzoic acid chloride is obtained, which can be used directly for the above-mentioned "reaction" with diazomethane. Example 29. A solution of 5 g of a-/_ 3-chloro-4-(1-cyclohexenyl)-phenyl/-propionic acid nitrile and 5 g of potassium hydroxide in 200 ml of ethanol and 50 ml of water is boiled for 15 hours under reflux. After evaporation of the ethanol in vacuum, the aqueous residue is extracted with ether. After the ethereal phase has been dried over sodium sulfate and evaporated in vacuum, the solid residue is recrystallized from ether-petroleum ether, obtaining a-_ /3_chloro-4-(l- cyclohexenyl)-phenyl]1/-propionic acid amide ;with formula ;;as colorless crystals of melting point 125 - 126°C. ;The aqueous alkaline phase is clearly filtered through diatomaceous earth (Hyflo), acidified with 2 N hydrochloric acid and extracted with ether. The ether extract washed with water, dried over sodium sulfate and evaporated in vacuo the oily residue is dissolved in petroleum ether, treated with activated carbon, filtered off and concentrated in a vacuum. If allowed to stand, crystallization occurs. One filters off and thus obtains ot-/3-chloro-4-(1-cyclohexenyl)-phenyl/-propionic acid with formula ;; as colorless crystals of melting point 97 - 99°C. The sodium salt is obtained by dissolving this carboxylic acid in the calculated amount of ethanolic caustic soda and by evaporation in a vacuum. The ct-/_~3-chloro-4-(1-cyclohexenyl)-phenyl-/-propionic acid nitrile used as starting material in this example can be prepared in the following way: A mixture of 19.8 g of 4-bromo-3 -chloroacetophenone, 18.5 g ethylene glycol, 500 ml toluene and 0.2 ml concentrated sulfuric acid are boiled in an apparatus equipped with a water separator for 2 hours under reflux, ensuring that the water formed is periodically separated. After cooling to room temperature, the toluene solution is treated with saturated sodium bicarbonate solution and with water, dried over sodium sulfate and evaporated in vacuo. The oily residue is distilled under high vacuum and thus 2-(4-bromo~3-chloro-phenyl)-2-methyl-1,3-dioxolane of boiling point 85-93°C (0.03 mm Hg) is obtained as a faint yellow oil e. To a cooled to -70°C solution of 27.7 g of 2-(4-bromo-3-chloro-phenyl)-2-methyl-1,3-dioxolane in 500 ml of absolute ether, while stirring and under a nitrogen atmosphere dropwise over 60 minutes 65 ml of a 1.5 N ethereal butyllithium solution. After it has been allowed to react for 30 minutes at -70°C, 9.8 g of cyclohexanone are mixed dropwise over 15 minutes. The reaction mixture is brought to room temperature and stirred for a further 30 minutes at 30°C. It is then mixed with ice, with saturated ammonium chloride solution and the ether layer is washed with ice-cold 2 N hydrochloric acid. The ether extract dried over sodium sulfate and evaporated in vacuum is fractionated in high vacuum. The fraction distilling in the range .190-210°C; (0.1 mm Hg) is the crude 2-/_— 3~chloro-4-(1-hydroxy-1-cyclohexyl)-phenyl7-2-methyl-1 ,3-dioxolane. ;9 g of this compound is boiled with 150 ml of glacial acetic acid and ;50 ml of concentrated hydrochloric acid for one hour under reflux. After cooling to room temperature, dilute with 200 ml of water and extract with ether. The ether extracts are dried over sodium sulphate and evaporated in vacuo. The oily residue is fractionated in high vacuum. The fraction distilling at 140-145°C (0.1 mm Hg) is 3-chloro-4-(1-cyclohexenyl)-acetophenone. ;To a cooled to 0°C solution of 1 g of sodium borohydride in 100 ml of methanol and 20 ml of water, 7 g of 3-chloro-4-(1-cyclohexenyl)-acetophenone are added in portions while stirring. The mixture is stirred for a further 2 hours at 10°C, mixed with ice and water and extracted with methylene chloride. The methylene chloride extracts washed with water and dried over sodium sulphate are evaporated in vacuo. The residue is the crude 1-hydroxy-1-(3-chloro-4-(1-cyclohexenyl)-phenyl)-ethane. A solution of 7 g of this hydroxy compound in 150 ml of absolute benzene is mixed with 2 ml of thionyl chloride and boiled under reflux for 5 min. It is left for 2 hours at room temperature and then evaporated in a vacuum. The residue consists of 1-chloro-1-./3-chloro-4-(cyclohexenyl)-phenyl_17-ethane. A solution of 8 g of this compound in 20 ml of dimethyl sulphoxide is added dropwise with stirring to a suspension of 2 g of sodium cyanide in 30 ml of dimethyl sulphoxide heated to 70°C. After it has been left to react for 30 min. at 110°C, the reaction mixture is poured into 300 ml of ice water and extracted with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in vacuo. After evaporation in a vacuum, the crude α-[3-chloro-4-(1-cyclohexenyl)-phenyl]-propionic acid nitrile is obtained, which can be directly used for the above-mentioned hydrolysis. Example 30. 14 g of methylamine are added to 24.4 g of α-β-(1-cyclohexenyl)-phenyl-7-propionic acid methyl ester in 100 ml of absolute ethanol and the mixture is heated in an autoclave for 30 hours at 140°C. It is then evaporated to dryness in vacuo, the residue is dissolved in 200 ml of methylene chloride and extracted with 100 ml of normal hydrochloric acid. The organic phase is washed with water until the reaction is neutral, dried over sodium sulphate and evaporated in vacuo. One thus obtains ct-/ p-(1-cyclohexenyl)-phenyl/- propionic acid methylamide with the formula ; which crystallizes from methanol-water in the form of mica-like small plates of m.p. 118 - 120°C. ;Example 31. ;To 10.0 g of p-toluenesulfonic acid chloride in 100 ml of absolute pyridine, 12.2 g ~b-l_ p-(1-cyclohexenyl)-phenyl7-2-butanone oxime in 20 ml of pyridine are added slowly while stirring. It is left overnight at room temperature. It is then mixed with 1 ml of water and heated for 10 hours at 80°C. For processing, divide between 3 times 500 ml of water and 500 ml of methylene chloride. The organic phases are washed with 2 N hydrochloric acid and water, dried over sodium sulphate and evaporated to dryness in vacuo. From methanol-water, ot-/_ p-(1-cyclohexenyl)-phenyl7-propionic acid methylamide of formula ;; crystallizes in mica-like small plates of m.p. 119 - 121°C. The p-(1-cyclohexenyl)-phenyl7-2-butanone-oxime used as starting material can be obtained in the following way: 29 g of 1-chloro-3-/ are dissolved. p-(1-cyclohexenyl)-phenyl 17-2-butanone (m.p. 66-67°C) and 20 g of powdered potassium iodide in 250 ml of glacial acetic acid. Add 100 g of zinc dust to this mixture in portions while stirring. The mixture is stirred overnight at room temperature, then the reaction mixture is filtered. The filtrate is evaporated under high vacuum and the residue is distributed between 3 times 500 ml of methylene chloride and 500 ml of water. The evaporation residue of the neutral washed and dried methylene chloride phases is distilled at 95-98°C/0.05 mm Hg. Thus, 3-[p-(1-cyclohexenyl)-phenyl7-2-butanone is obtained as an oil. 18 g of this ketone, 18 g of hydroxylamine hydrochloride and 18 g of sodium acetate are heated in 100 ml of ethanol to boiling. Add water to the warm solution until everything is dissolved. An additional 10 min is set aside. at 80°C and mixing with water until cloudy. On cooling, 3-/_—p-(1-cyclohexenyl)-phenyl7-2-butanone-oxime crystallizes in long needles and melting point 128-130°C. ;Example 32. ;Under nitrogen and water exclusion, 8.4 g of l-^<_>p-(l-cycloheptenyl)-phenyl7-ethyl bromide in 30 ml of absolute ether is slowly added dropwise with stirring to 300 mg of lithium in 10 ml of absolute ether. Stir until all the lithium has dissolved. The reaction solution is then transferred under nitrogen into a dropping funnel and slowly dripped into a well-mixed suspension of 10 g of finely powdered carbon dioxide in 20 ml of absolute ether. It is allowed to slowly warm to room temperature and left overnight at room temperature. The reaction solution is divided between 3 times 50 ml of ether and 50 ml of 1 N caustic soda. The aqueous phases are acidified at 10°C with concentrated hydrochloric acid and extracted with 3 times 50 ml of methylene chloride. The organic phases are washed neutrally, dried over sodium sulphate and evaporated in vacuo to dryness. From ether-petroleum ether one obtains ct-1_ p-(1-cycloheptenyl)-pheny ^./-propionic acid of formula ;;of m.p. 105 - 107°C. The sodium salt produced in the usual way has a m.p. ;229 - 233°C. The 1-/_~p-(1-c<y>chloroheptenyl)-phenyl/-ethyl bromide used as starting material can be prepared as follows': A well-stirred suspension of 14.6 g of magnesium shavings which was washed with chloroform , activated with iodine in 150 ml of absolute tetrahydrofuran, is mixed at 60°C dropwise with a solution of 97.6 g of 2-(p-bromophenyl)-2-methylene-3-dioxolane in 500 ml of tetrahydrofuran. The addition is regulated so that the temperature does not exceed 60°C at the beginning of the reaction. Finally, you still heat up for 30 min. at 60°C, then cool to 20°C and now mix with stirring dropwise with 67 g of cycloheptanone. After heating at 50-60°C for 1 hour, the reaction mixture is evaporated. The residue is mixed with ice and 200 ml of a saturated aqueous ammonium chloride solution. It is extracted with ether, dried over sodium sulphate and evaporated. The residue is recrystallized from ether-petroleum ether, obtaining 2-/_ p-(11-hydroxy-cycloheptyl)-pheny 3./-2-methyl 1-1, 3-dioxolane as a colorless crystalline compound m.p. 7-8-80°C. A solution of 43 g of this compound in 240 ml of glacial acetic acid and 90 ml of 2 N hydrochloric acid is heated for 1 hour at 100°C. After cooling, mix with 300 ml of water, extract with ether, wash with 2 N sodium bicarbonate solution and evaporate the ether extracts dried over sodium sulphate. The oily residue is distilled under high vacuum and gives p-(1-cycloheptenyl)-acetophenone as a viscous oil of boiling point 140°C70.04 mm Hg. A solution of 49 g of this ketone in 100 ml of methanol is brought dropwise to 0°C with stirring. cooled solution and 11 g of sodium borohydride in 500 ml of methanol and 100 ml of water. The reaction solution is stirred for a further 1 hour at 5-10°C and is then allowed to stand for 16 hours at room temperature. It is then mixed with 600 ml of water, extracted with methylene chloride, dried over sodium sulphate and evaporated. Thus, 1-hydroxy-1-(1-cycloheptenyl)-phenyl-7-ethane is obtained as an oily, colorless residue. 49 g of this hydroxy compound are dissolved in 400 ml of absolute benzene, mixed with 28 ml of thionyl chloride and allowed to stand for 2 hours at room temperature. By evaporation, the crude l-/~p-(1-cycloheptenyl)-phenyl/-ethyl chloride is obtained which can be further processed without further purification. 6.8 g of p-(1,1-cycloheptenyl)-phenyl.1/-ethylene chloride in 100 ml of acetone is boiled with a solution of 10.3 g of sodium bromide in a little water with stirring overnight under reflux. As much water is added to the hot solution at the start of boiling until the solution homogenizes. For preparation, divide between 3 times 100 ml of methylene chloride and 100 ml of water. The organic phases are dried over sodium sulfate and evaporated in vacuo to dryness. The crude 1-[p-(1-cycloheptenyl)-phenyl]-ethyl bromide contained in the evaporation residue is dried under high vacuum and used directly. Example 33. To a solution of 5 g of diisopropylamine in 35 ml of absolute tetrahydrofuran, 16.9 ml of a 2.9 N butyllithium solution in hexane is slowly added dropwise under nitrogen and stirring at -10°C to -5°C and then 5 *3 g ct-/_ 4-(1-cyclohexenyl)-phenyl/-propionic acid in 20 ml of absolute tetrahydrofuran. Stir for 10 min. at -5°C and then immediately add 8.5 g of propyl iodide. Thereby, the temperature of the reaction mixture is increased to approx. 20°C. It is allowed to stand overnight at room temperature and then distributed between methylene chloride and water. The aqueous phase is acidified with concentrated hydrochloric acid and

extracted with methylene chloride. The organic extract is decolorized with a slightly diluted sodium bisulphite solution, washed with water and dried over sodium sulphate. Cold ct-/_ -4-(1-cyclohexenyl)-phenyl/-ct-methylpentanoic acid of the formula crystallizes from pentane

with m.p. 80-82 C.

Example el 34j_

75 g of sodium iodide and 85 g of n-propyl iodide are added to 26 g of a-/~4-(1,2-epoxy-1-cyclohexyl)-phenyl7-propionic acid methyl ester in 500 ml of absolute dimethylsulfoxide and heated with stirring for 3 hours at 85°C. The mixture is then partitioned between water and methylene chloride, decolorized with sodium bisulphite, the organic phase is dried over sodium sulphate and evaporated in vacuo to dryness.

The evaporation residue is chromatographed on 500 g of silica gel with ether-methylene chloride = 1:20 as eluent. Fractions (a 100 ml) 8 to 14 contain a mixture of a-/<->4-(6-oxo-1-cyclohexenyl)-phenyl/-propionic acid methyl ester and a-/<->4-(2-oxo -1-cyclohexyl)-phenyl/-propionic acid methyl ester, from which the latter can be crystallized with pentane/ether. The in the mother liquor repeat living α-/_ 4-(6-oxo-1-cyclohexenyl)-phenyl)-propionic acid methyl ester of formula

was further purified by distillation. Boiling point 130-135°C (0.005 mm Hg).

Example 35.

50 ml of 0.5 N caustic soda is added to 6 g of α-/_ 4-(6-oxo-1-cyclohexenyl)-phenyl//-propionic acid methyl ester in 50 ml of ethanol and allowed to stand at room temperature for 12 hours. The mixture is then acidified with concentrated hydrochloric acid at 0°C and extracted with methylene chloride. The organic phase is washed neutrally, dried over sodium sulphate and evaporated to dryness in a vacuum. From ether/petroleum ether, a-/_ 4-(6-oxo-1-cyclohexenyl)-phenyl 3N-propionic acid crystallizes with the formula

which after 3 times of recrystallization melts at 111-112°C. Example 36. To 17 g of α-/_ 4-(1-cyclohexenyl-3-methoxy-phenyl-7-propionitrile in 300 ml of ethanol, 9 g of potassium hydroxide are added in 100 ml of water and the mixture is boiled for 20 hours under reflux. Then it is evaporated to dryness in vacuo and dissolve the residue in 500 ml of water and extract with 3 times 150 ml of ether. The ether phase is washed neutral, dried over sodium sulfate and evaporated in vacuo. From ether-petroleum ether crystallizes a-/_ 4-(1-cyclohexenyl)-3- methoxy-phenyl/-propionic acid amide of formula

of m.p. 128-130°C.

The α-/_ 4-(1-cyclohexenyl)-3-methoxy-phenyl/-propionitrile used as starting material can be obtained in the following way: 70 g of 3-methoxy-4-bromo-benzene acid (Beilstein: 10,11,83) in 1 liter of benzene is mixed with 300 ml of thionyl chloride and boiled for 2 hours with exclusion of water under reflux. The reaction solution is now evaporated to dryness in vacuo. From ether crystallizes after treatment with activated carbon ("Norit") 3-methoxy-4-bromo-benzene acid chloride of m.p. 88-90°C.

To 16 g of magnesium shavings (activated with iodine) in 400 ml of absolute ether, a stream of methyl bromide is introduced until all the magnesium is dissolved. The gas flow is regulated so that the ether solution boils slowly. It is then cooled to 20°C and, while cooling, is mixed in portions with 60 g of dry cadmium chloride and is then boiled for 1 hour under reflux. The resulting reaction mixture is stirred and ice-cooled slowly to 75 g of 3-methoxy-4-bromo-benzene acid chloride in 250 ml of absolute benzene, so that the temperature does not rise above 28° C. It is then stirred for 1 hour at 30° C. The reaction mixture is now poured onto 1 kg of ice, acidified with 150 ml of concentrated hydrochloric acid and extracted with .1 liter of ether. The ether phase washed with 2 times 200 ml of 1 N caustic soda, washed neutrally, dried over sodium sulfate and evaporated in vacuo.The crude 3-methoxy-4-bromoacetophenone formed is further processed directly.

60 g crude 3-methoxy-4-bromoacetophenone. boil with 57 g ethylene glycol, 900 ml benzene and 1 ml concentrated sulfuric acid for 6

hours on water separator. It is then allowed to cool to room temperature and the solution is extracted with 2 times 200 ml of 2 N sodium carbonate solution. The organic phase is washed off neutrally, dried over sodium sulphate and evaporated to dryness in a vacuum. From petroleum ether crystallizes 3~methoxy-4-bromoacetophenone, ethylene dioxide, m.p. 62-65°C (after recrystallization twice, m.p. 65-67°C).

For 3.8 g of magnesium shavings (activated with iodine) you have

20 ml of absolute tetrahydrofuran and then drip slowly with stirring to 37 g of the above-mentioned dioxyketal dissolved in 200 ml of absolute tetrahydrofuran, so that the temperature does not exceed 40°C. It is then cooled to room temperature and, under ice-cooling, 13.5 g of cyclohexanone are added dropwise. It is then heated for 1 hour at 40°C. The solvent is then removed in vacuo, the residue is mixed with 500 g of ice and 50 ml of saturated ammonium chloride solution and the mixture is extracted with 3 times 500 ml of ether. The organic phase is washed neutrally, dried over sodium sulphate and evaporated in vacuo. From ether-petroleum ether, the crude 4-(1-hydroxy-cyclohexyl)-3-methoxy-acetophenone-dioxyketal of m.p. 90-100°C.

To 32 g of this ketal in 500 ml of glacial acetic acid, add 20 ml of concentrated hydrochloric acid and heat for 1 hour at 100°C. It is then evaporated in a vacuum to 30 ml and the residue diluted with water and petroleum ether. The organic phase is washed neutrally, dried over sodium sulphate and evaporated in vacuo. The residue is fractionally distilled in vacuum. The fraction boiling at 120-130°C (0.05 mm Hg) contains 3-methoxy-4-(1-cyclohexenyl)-acetophenone.

To 22. g 3-methoxy-4-(1-cyclohexenyl)-acetophenone in

180 ml of methanol and 40 ml of water are mixed with 5 g of sodium borohydride in portions while stirring at 5°C. Continue stirring for 30 min. at 10°C and 1 hour at room temperature. The reaction solution is then evaporated in vacuo. The residue is distributed between water and

methylene chloride. The organic phase is dried over sodium sulfate and evaporated in vacuo. The oily 1-[3-methoxy-4-(1-cyclohexenyl)-phenyl]-ethanol thus formed is further processed directly.

To 22 g of this carbinol in 400 ml of absolute benzene, 8.2 ml of thionyl chloride are added at 10°C and left to stand at 5°C under exclusion of water for 2 hours. The reaction mixture is then evaporated to dryness at room temperature in a vacuum. The thus formed crude oily 1-(3-methoxy-4-(1-cyclohexenyl)-phenyl)-1-chloroethane is further processed directly without further purification.

To 13 g of sodium cyanide in 250 ml of absolute dimethyl sulphoxide, 23 g of the above-mentioned chlorine compound are added and the mixture is stirred for 10 hours at 90°C under exclusion of water. It is then cooled to room temperature and the reaction solution is divided between 1 liter of ice water and 3 times 250 ml of ether. The organic phases are washed

with saturated soda solution, with 1 N hydrochloric acid and with water, dried

over sodium sulfate and evaporated to dryness in vacuo. The residue is taken up in 500 ml of petroleum ether. One decants from undissolved material and evaporates to dryness in a vacuum. The residue contains the crude α-β-3-methoxy-4-(1-cyclohexenyl)-phenyl-7-propionitrile which is used without further purification directly for the above-mentioned hydrolysis. Example .37•

The aqueous phase formed in example 36 is acidified with concentrated hydrochloric acid and extracted with petroleum ether. The organic phase is washed neutrally, dried over sodium sulfate and filtered over activated carbon ("Norit") and evaporated in vacuo. From petroleum ether et-/ 4-(1- c<y>clohexene<y>l)-3-methoxy-phenyl/-propionic acid crystallizes with. formula

with m.p. 128-131°C.

E xample l 38.

To 11 g of crude α-β-3-methyl-4-(1-cyclohexenyl)-phenyl7-propionitrile in 200 ml of ethanol and 70 ml of water, 6 g of potassium hydroxide are added and heated for 24 hours under reflux. It is then allowed to cool to room temperature and the reaction mixture between ether (2 times 150 ml) and water (2 times 100 ml) is improved. The organic phase is washed neutrally, dried over sodium sulphate and evaporated in vacuo. The evaporation residue contains β-[3-methyl-4-(J-cyclohexenyl)-phenyl]1/-propionamide of the formula

of m.p. 125-127°C (after 2 times crystallization from ether-petroleum ether).

The a-f~ 3-methyl-4-(1-cyclohexenyl)-phenyl]V-propionitrile used as starting material can be obtained in the following way: To 46.4 g of 3-methyl-4-bromo-acetophenone ( A.F. Dokukina et al., Zhur. Obscheher, Khim. 26, 1651 (1956)) in 700 ml of absolute benzene and 40.8 g of ethylene glycol, 1 ml of concentrated sulfuric acid is added and boiled for 6 hours under exclusion of water with a water separator. The reaction mixture is then separated to room temperature and distributed between 200 ml of benzene and 500 ml of 2 N soda solution.

The organic phase is washed neutrally, dried over sodium sulphate and evaporated to dryness in a vacuum. The residue is distilled under high vacuum. The fraction boiling at 84-85°C/0.07 mm Hg contains 3-methyl-4-bromo-acetophenone-ethylene ketal.

To 14.4 g of magnesium shavings, one drips at approx. 50°C 138 g of the above ketal in 150 ml of absolute tetrahydrofuran and keep it at this temperature until all the magnesium is dissolved. 52.5 g of cyclohexanone are then added dropwise to this solution in 100 ml of absolute tetrahydrofuran and then allowed to stand for 1 hour at 40°C. It is then cooled to room temperature, the largest part of the solvent is removed in vacuo and the residue is mixed with 1000 g of a mixture of saturated ammonium chloride solution and ice. The reaction mixture is now extracted 3 times with 500 ml of petroleum ether. The organic phases are washed neutrally, dried over sodium sulphate and evaporated to dryness in a vacuum. The evaporation residue is taken up in 700 ml of glacial acetic acid and 200 ml of concentrated hydrochloric acid, and boiled for 3 hours. It is then evaporated to dryness in a vacuum and the residue is distributed between 3 times 500 ml of petroleum ether and 200 ml of 2 N caustic soda. The organic phases are washed neutrally, dried over sodium sulphate and evaporated in vacuo. The distillation of the residue in high vacuum gives the fraction boiling at 108-110°C70.04 mm Hg 3-methyl-4-(1-cyclohexenyl)-acetophenone.

To 18 g of this acetophenone in 150 ml of methanol and

30 ml of water are mixed with 5 g of sodium borohydride while stirring at 0°C. The mixture is stirred for 1 hour at 0°C and 1 hour at room temperature. It is then evaporated in a vacuum to a volume of approx. 30 ml and distribute the residue between water and methylene chloride. The organic phase is washed neutrally, dried over sodium sulphate and evaporated in vacuo. The crude 3-methyl-4-(1-cyclohexen-1-yl)-phenylmethyl-carbinol contained in the oily residue is dissolved in 300 ml of absolute benzene and mixed at 10°C with 11 g of thionyl chloride. After 3 hours under moisture exclusion at 10°C, the solvent is removed in vacuum at room temperature. The crude 3-methyl-4-(1-cyclohexenyl)-phenylmethylcarbinyl chloride recurring in the oily residue is dissolved in 150 ml of absolute dimethyl sulphoxide, mixed with 7 g of sodium cyanide and heated for 2 hours under exclusion of water at 100°C with stirring . It is then cooled to room temperature and the reaction mixture is distributed between 3 times 300 ml of water and 3 times 200 ml of ether. The organic phases are dried over the residue in high vacuum at 90-120°C boiling fraction (0.2 mm Hg) contains ct-/_ 3-methyl-4-(1-cyclohexenyl)-phenyl/-propionitrile which is further processed directly without further purification .

E xample 39-

The aqueous phase formed in example 38 is adjusted with concentrated hydrochloric acid to pH 2 and extracted with petroleum ether. The organic phase is washed neutrally, dried over sodium sulphate and evaporated in vacuo to dryness. From the evaporation residue crystallizes with ether-pentane α-/_ 3-methyl-4-(1-cyclohexenyl)-phenyl//-propionic acid of the formula

with m.p. 96-98°C.

Example 40.

To 17.2 g of ct-methyl-ct-/p-(1-cycloheptenyl)-phenylZ-malonic acid diethyl ester in 200 ml of ethanol, 100 ml of 2 N caustic soda is added and allowed to stand for 24 hours. The largest part of ethanol is then removed in vacuo and extracted with 100 ml of ether. The aqueous phase is acidified at 0°C with concentrated hydrochloric acid and extracted with 200 ml of methylene chloride. The organic phase is evaporated, the residue is dissolved in 100 ml of pyridine and boiled under reflux until the formation of carbon dioxide has ended. Pyridine is removed in vacuo, the residue is taken up in 200 ml of water, made acidic with concentrated hydrochloric acid and extracted twice with 200 ml of methylene chloride. The neutral-washed and dried over sodium sulphate organic phases are evaporated in vacuo. From ether-petroleum ether ct-/~p-(1-cycloheptenyl)-phenyl/-propionic acid crystallizes with the formula

of m.p. 105-107°C.

The sodium salt is obtained by dissolving this carboxylic acid in the calculated amount of ethanolic caustic soda and by evaporating

ning in a vacuum. It has a decomposition point of 229-233°C.

Example 41.

To a solution of 13.4 g of eth-/p-(1-cyclopentenyl)-phenyl-1/-propionaldehyde in 140 ml of ethanol, a solution of 34 g of silver nitrate in 70 ml of water is added dropwise, while stirring, a solution of 20 g of sodium hydroxide in 70 ml of water. During the addition, the temperature is kept below 40°C. The mixture is then stirred for 2 hours at room temperature, filtered through diatomaceous earth ("Celite"), rinsed with ethanol and the filtrate evaporated to 70 ml. The aqueous alkaline solution is extracted with ether, acidified with 2 N hydrochloric acid and extracted with methylene chloride. From the residue, of the neutral-washed methylene chloride phase dried over sodium sulfate, crystallises from ether-petroleum ether a-/_ p-(1-cyclopenteny 1)-phenyl ^/-propionic acid

with formula

with m.p. 137-140°C.

The α-£β-(1-cyclopentenyl)-phenyl-1/-propionaldehyde used as starting material can be prepared in the following way: A well-stirred suspension of 7.3 g of magnesium shavings that has been washed with chloroform and activated with iodine in 150 ml of absolute tetrahydrofuran is mixed dropwise at 60°C. Finally, you heat up still for 30 min. at 60°C, then cool to 20°C and now mix with stirring dropwise with 21.6 g of cyclopentanone. After heating for 1 hour at 50-60°C, the reaction mixture is evaporated and the residue is mixed with ice and 200 ml of saturated aqueous ammonium chloride solution. It is extracted with ether, dried over sodium sulphate and evaporated. The residue is recrystallized from ether-petroleum ether, obtaining 2-/_ p-(1-hydroxy-cyclopentyl)-phenyl]7-2-methylene-3-dioxolane of m.p. 90-91°C.

A solution of 15 g of this compound in 80 ml of glacial acetic acid and 30 ml of 2 N hydrochloric acid is heated for 1 hour at 100°C. After cooling, dilute with 200 ml of water and extract with ether. The ether layers are washed with 2 N sodium bicarbonate solution, dried

over sodium sulfate and evaporate. The residue gives after recrystallization from ether-petroleum ether p-(1-cyclopentenyl)-acetophenone of m.p. 100-102°C.

A solution of 76 g of chloroacetic acid ethyl ester and

6.0 g of p-(1-cyclopentenyl)-acetophenone in 400 ml of absolute toluene are mixed with stirring at 0°C dropwise with a solution of 14.4 g of sodium in 400 ml of absolute ethanol. The addition lasts approximately 1 hour. It is then stirred for 20 hours at room temperature. After removal of the main amount of ethanol in vacuum, extraction is carried out in ice water. The toluene layer dried over sodium sulfate is evaporated in vacuum to dryness and dried in high vacuum.

18.4. g of the crude g-methyl-g-[p-(1-cyclopentenyl)-phenyl]-glycidyl acid ethyl ester thus prepared is mixed with a solution of 1.56 g of sodium in 80 ml of absolute ethanol. After adding 1.42 ml of water, it is allowed to stand for a day at room temperature and the sodium salt is filtered off. The sodium salt is dissolved in 800 ml of water, adjusted with concentrated hydrochloric acid to pH 3 and boiled overnight under reflux under nitrogen. The reaction mixture is extracted with methylene chloride. After drying over sodium sulphate, it is evaporated to dryness under vacuum. The crude α-/_β-(1-cyclopentenyl)-phenyl7-propionaldehyde contained in the evaporation residue is used directly without further purification.

Example 42.

A solution of 10.0 g of ct-methyl-ct-/p-(1-cyclohexenyl)-phenyl-17-malonic acid monomethyl ester is dissolved in 100 ml of pyridine and heated to boiling until complete cessation of carbon dioxide evolution. The pyridine is then distilled off under reduced pressure and the evaporation residue is distilled under high vacuum. This gives you a -/. p-(1-Cyclohexenyl)-phenyl7-propionic acid methyl ester of formula

of boiling.point0jl mm Rg 1<4>0-145°C.

The ct-methyl-ct-/p-(1-cyclohexenyl)-phenyl/-malonic acid monomethyl ester used as starting product can be prepared in a manner known per se by α-methylation of et-/p-(1-cyclohexenyl)- phenyl 1/-malonic acid monomethyl ester or by α-carboxylation of ct-1_ p-(1-cyclohexenyl)-phenyl]/-propionic acid methyl ester.

Example 43»

To 17.2 g of a-/_ p-(1-cyclohexenyl)-phenyl/-malonic acid monomethyl ester in 200 ml of ethanol, 100 ml of 2 N caustic soda is added and allowed to stand for 24 hours. The largest part of ethanol is then removed in vacuo and extracted with 100 ml of ether. The aqueous phase is acidified at 0°C with concentrated hydrochloric acid and extracted with 200 ml of methylene chloride. The organic phase is evaporated. The residue is dissolved in 100 ml of pyridine and boiled under reflux until the formation of carbon dioxide has ended. Pyridine is removed in vacuo, the residue is taken up in 200 ml of water, acidified with concentrated hydrochloric acid and extracted twice with 200 ml of methylene chloride. The organic phases washed neutrally and dried over sodium sulfate are evaporated in vacuo. From ether-petroleum ether, et-/ p-(1-cyclohexenyl)-phenyl_1/- acetic acid crystallizes with the formula

with m.p. 120-121°C.

The starting product eth-/ p-(1-cyclohexenyl)-phenyl/-malonic acid monomethyl ester can be obtained in a manner known per se by partial esterification of eth-/, p-(1-cyclohexenyl)-phenyl_/ -malonic acid or by α-carboxylation of α-/_ p-(1-cyclohexenyl)-phenyl JL/-acetic acid methyl ester.

Example 45.

A solution of 10 g of eth-/p-(2-hydroxy-1-cyclohepty 1)-phenyl 1/-propionic acid methyl ester in 50 ml of glacial acetic acid is mixed with 15 ml of concentrated hydrochloric acid and heated for 3 hours at 80°C. Evaporate in a vacuum, mix with ice and make alkaline with 2 N caustic soda. The alkaline aqueous solution is extracted with ether, then acidified with 2 N hydrochloric acid and shaken again with ether. This ether extract is dried over sodium sulfate and evaporated in vacuo. After recrystallization of the thus formed residue from ether-petroleum ether, ct-7 p-(1-cycloheptyl)-phenyl7-propionic acid is obtained with the formula

as colorless crystals of m.p. 105-107°C.

The sodium salt is obtained by dissolving this carboxylic acid

in the calculated amount of ethanolic caustic soda and by evaporation in a vacuum.

The ct-l<_>p-(2-hydroxy-l-c<y>chlorohe<p>t<y>l)-phenyl7-propionic acid methyl ester used in this example as starting material can be prepared in the following way: A solution of 12 g of a-/_-p-(1,2-epoxy-1-cycloheptyl)-phenyl-1/-propionic acid methyl ester in 150 ml of ethanol is hydrogenated in the presence of 1 g of palladium charcoal to consume one equivalent of hydrogen. The catalyst is filtered off, evaporated in vacuo and the crude α-/_p-(2-hydroxy-1-cycloheptyl)-phenyl7-propionic acid methyl ester is obtained, which can be directly used for the above-mentioned reaction.

Claims (4)

1. Analogous methods for the production of new pharmacologically active ct-phenyl fatty acids of the general formula I in which R means an optionally lower alkyl1-, lower alkoxy- or oxo-substituted 1-cycloalkenyl residue with 4-8 ring members, Ph means an optionally lower alkyl-, lower alkoxy-, trifluoromethyl- or halogen-substituted p-phenylene residue, and R-^ and R^ each mean hydrogen or lower alkyl , as well as their esters with lower alkanols, which optionally contain several hydroxyl groups, or with lower dialkylaminoalkanols, their amides, which are optionally N-substituted with lower alkyl, dilower alkylaminoalky1 or hydroxy, and their pharmaceutically usable salts, characterized in that either a) a compound with formula VII or VIII in which R, Ph, R^ and R 2 have the meanings given above, and Y means a cyano group, or an acid halide or thioamide group, reacted with water, alcohol, ammonia or an amine containing at least one hydrogen atom bound to nitrogen, being a ketene with formula VIII is optionally formed in situ by rearrangement of a diazoketone with formula or b) a compound of formula X in which R, Ph, R^ and R 2 have the indicated meanings, and Y-^ means a lithium or sodium atom, or a group of the formula -Mg-Hal, in which Hal means chlorine, bromine or iodine, is reacted with carbonic acid, or c ) in a compound of formula XI in which R, Ph, R-^ and R 2 have the meanings given above, and Y 2 means an optionally functionally modified formyl residue, Y 2 is oxidized to a carboxyl group, with a compound of formula XI possibly being formed ■ in situ under the reaction conditions by oxidation of the corresponding hydroxymethyl compound, or d) -a ketoxime of formula XII in which R, Ph, R1 and R2 have the indicated meanings, and R' means an alkyl residue, is rearranged, or e) splits off the residue Y- , in a compound of formula XIII in which R, Ph and R^ have the indicated meanings, and Y^ means an acyl residue or a carboxy group or an above-defined ester, amide or salt thereof, or f) in a compound of formula XIV in which Ph . after which, if desired, compounds formed in which R-^ and/or R2 are hydrogen are alkylated, and/or free acids formed are converted into esters or amides, or esters formed into amides or into the free acids, and/or amides formed into the free acids, and/or formed racemates are split in the optical antipodes, and/or formed acids are transferred into their salts. 2. Process according to claim 1 for the production of α-β-(l-cyclohexenyl)-phenyl β-propionic acid and salts thereof, characterized by that as starting material a compound of formula VII - XI, XIII or XIV is used, in which R means 1-cyclohexenyl, Ph means p-phenylene, R^ means methyl and R2 means hydrogen and Y, Y-^, Y2 and Yj have the meanings set out in claim 1.' 3. Method according to claim 1 for the production of α-£~ p-(1-cycloh-heptenyl)-phenyl7-propionic acid and salts thereof, characterized in that a compound with the formulas VII - XI., XIII or XIV is used as starting material, in which R-^ means 1-cycloheptenyl, Ph means p-phenylene, R^ means methyl and R2 means hydrogen and Y, Y^, Y2 and Yj have the meanings given in claim 1. 4. Process according to claim 1 for the production of ct-_lp-(l-cyclopentenyl)-phenyl-l/-propionic acid and salts thereof, characterized in that a compound of formula XII - XI, XI, XIII or XIV is used as starting material, wherein means 1-cyclopenteny 1, Ph means p-phenylene, R-^ means methyl and R2 means hydrogen and Y, Y^, Y2 and Y^ have the meanings given in claim 1.