CS205086B2 - Method of producing hydroxyderivatives of aryloxy and arylthio-perhydro-aza-heterocycles - Google Patents

Description

The invention relates to a process for the preparation of hydroxy derivatives of aryloxy and arylthioperhydroazaheterocycles and their salts.

The compounds produced according to the invention correspond to the general formula I

in which

R 1 represents hydrogen or an alkyl radical of up to 4 carbon atoms,

R2 is a primary aliphatic hydrocarbon radical having up to 4 carbon atoms,

Y means oxygen or sulfur, ni and n? each having a value of 1 to 3, the sum of n1 - nz being at most 4, and Ar being optionally alkyl or alkoxy having at most 4 carbon atoms, halogen having an atomic number of up to 35 and / or a phenyl or naphthyl substituted trifluoromethyl or methylenedioxy group or a 5,6,7,8-tetrahydronaphthyl residue.

The aliphatic hydrocarbon radicals R2 are preferably lower alkyl, but may also be lower alkenyl or lower alkynyl.

In phenyl Ar residues, said residues may be present one, two or three times and are either the same or different.

The general terms used in connection with the present invention have the following meanings, for example:

The primary alkyl radical R2 is, for example, methyl, ethyl, propyl, butyl or 1-butyl, the alkyl radical R1 and the alkyl radical Ar may furthermore also be isopropyl, isobutyl, sec-butyl or tert-butyl .

The primary lower alkenyl radical R2 is, for example, the allyl or 2-methylallyl radical, while the primary lower alkynyl radical R2 is, for example, the propargyl radical.

A defined alkoxy substituent Ar is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy or tert-butyloxy.

Halogen with atomic number up to 35 is chlorine, bromine or fluorine.

Salts of the compounds of the formula I are acid addition salts, in particular pharmaceutically acceptable non-toxic addition salts with suitable inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid or with suitable organic, such as aliphatic, cycloaliphatic, aromatic, araliphatic or Heterocyclic carboxylic or sulfonic acids, for example with formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, pyruvic acid, benzoic acid , anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, phenylacetic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, acids ethylene sulfonic acid, 4-chlorobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylamine sulfonic acid.

Due to the close relationship between the novel compounds in the free form and in the form of their salts, the free compounds and the salts according to the purpose and purpose are also to be understood as correspondingly corresponding salts or free compounds.

The compounds of the invention may be in the form of isomeric mixtures, for example mixtures of compounds with the cis- and trans-configuration, or uniform isomers, for example of the cis- or trans-configuration, further in the form of a racemate or optical antipodes.

The novel compounds of the formula I have valuable pharmacological properties and, in particular, have antidepressant activity, as can be shown by appropriate pharmacological tests. Thus, these agents suppress norepinephrine uptake, as exemplified by suppressing noradrenaline secretion caused by 3-hydroxy-4-methyl-N-methylphenethylamine in rat brain [A. Carlsson, H. Corrodi, K, Fuxe and T. Hoekfelt, Europ. J. Pharmacol. 5, 367 (1969)] after oral administration at 100 mg / kg. They further potentiate the serotonin effect, as evidenced by potentiating the efficacy of 5-hydroxytryptophan-induced head tremor in mice after intraperitoneal administration of 3 to

100 mg / kg. In particular, these compounds are inherently suppressed by serotonin uptake, as can be shown by suppressing serotonin secretion caused by 2-hydroxy-4-methyl-os-ethylphenethylamine [A. Carlson et al., Europ. J. Pharmacol. 5, 357 (1969) in rat brain following oral administration of a dose of 3 to 100 mg / kg.

These pharmacological properties are characterized by the novel compounds and their pharmacologically acceptable acid addition salts as antidepressants, which can be used in the form of pharmaceutical preparations for the treatment of depression of various kinds.

In particular, the invention relates to the preparation of compounds of the formula I in which R1 represents hydrogen or an alkyl group having at most 4 carbon atoms, R2 represents a primary aliphatic hydrocarbon radical having at most 4 carbon atoms, for example methyl or ethyl, further propargyl; phenyl, naphthyl or 5,6,7,8-tetrahydronaphthyl, wherein the phenyl radical is optionally at most twice substituted by an alkyl radical or alkoxy of not more than 4 carbon atoms, or by a halogen atom having an atomic number of up to 35, or substituted by trifluoromethyl; the substituents may be the same or different from each other, and Y, ni, n2 and ni + Π2 are as defined above, but Y is preferably oxygen and ni + 112 is preferably together 3, as well as their acid addition salts, particularly pharmaceutically of useful acid addition salts.

In particular, the invention relates to the preparation of compounds of the formula I in which R1 represents an alkyl group having up to 4 carbon atoms, in particular methyl or preferably hydrogen, R2 represents a primary alkyl group having up to 4 carbon atoms, in particular methyl and Ar represents phenyl, naphthyl or a 5,6,7,8-tetrahydronaphthyl group, wherein the phenyl group is preferably twice substituted by an alkyl or alkoxy group having up to 4 carbon atoms, in particular a methyl or methoxy group, or a halogen atom having an atomic number of up to 35, said substituents may be the same or different from each other, and Y, ni, n2 and ni + · m are as defined above, however, Y preferably represents oxygen, ni and 112 together represent 3, and ni represents in particular 1 am 2, and their addition salts with acids, especially pharmaceutically usable acid addition salts.

In particular, the invention relates to an advantage of the following compounds of the above formula I:

trans-3-hydroxy-4- (1-naphthyloxy) -1-methylpepridine, trans-3-liydroxy-4-phenylthio-1-methylpiperidine, trans-3-hydroxy-4- (3,4-dimethylphenoxy) -1- methylpiperidine, trans-4-hydroxy-3- (3,4-dimethylphenoxy) 1-methylpiperidine, trans-3-methoxy-4- (3,4-dimethylphenoxy) -1-methylpiperidine, trans-3-hydroxy-4 - (3,4-dimethylphenoxy) -1-propargylpiperidine, trans-3-hydroxy-4- (2,3-dimethylphenoxy) -1-methylpiperidine, trans-3-methoxy-4- (2,3-dimethylphenoxy) -1 -methylpiperidine, trans-3-hydroxy-4- (5,6,7,8-tetrahydro-1-naphthyloxy) -1-methylpiperidine, trans-3-hydroxy-4- (p-fluorophenoxy) -1-methylpiperidine, trans -3-hydroxy-4- (2-bromo-4-methoxyphenoxy) -1-methylpiperidine, trans-3-hydroxy-4- (p-trifluoromethylphenoxy) -1-methylpiperidine, trans-4-hydroxy-5 - (3,4-dimethylphenoxy) hexahydro-1-methyl-1H-azepine, trans -4-hydroxy-5- (p-trifluoromethylphenoxy) hexahydro-1-methyl-1H-azepine, cis-3-hydroxy-4- (3,4-dimethylphenoxy) -1-methylpiperidine, cis-3-hydroxy-4- (3,4-dimethylphenoxy) -1-methylpiperidine, cis-3-methox γ-4- (2,3-diethylphenoxy) -1-methylpiperidine, cis-3-methoxy-4- (2,3-dimethylphenoxy) -1-methylpiperidine, cis-3-hydroxy-4- (m-chlorophenoxy) -1-methylpiperidine, cis-3-hydroxy-4- (1-naphthyloxy) -1-methylpiperidine, cis-3-hydroxy-4- (5,6,7,8-tetrahydro-1-naphthyloxy) -1 methylpiperidine, cis-3-hydroxy-4- (p-fluorophenoxy) -1-methylpiperidine, as well as their acid addition salts, in particular pharmaceutically usable acid addition salts.

The novel compounds of the formula I according to the invention are prepared by the preparation of a compound of the formula II

O ~ R '

Ar-Y

c 'Λ (ii) (Ctyk-N-CO-R wherein

R ^2c represents hydrogen, an alkoxy group having a maximum of 4 carbon atoms or an aliphatic hydrocarbon radical having a maximum of 3 carbon atoms, and

R1, Ar, Y, ni, Π2, as well as nt + n2 having the meaning given in formula I, reduce the carbonyl group or the alkoxycarbonyl group.

Suitable reducing agents are, for example, metal hydrides, such as diisobutylaluminum hydride, or complex metal hydrides, such as lithium aluminum hydride, or hydrogen boron compounds, in particular diborane.

The reducing medium used is an inert solvent, for example of an etheric nature, such as diethyl ether, di-n-butyl ether, tetrahydrofuran or dioxane, operating in the temperature range from -20 to -J-100 ° C, in an open or optionally closed vessel. and under a shielding gas such as nitrogen.

The starting materials of the formula II can be prepared in a manner known per se.

For example, a compound of formula IIa can be used

(l &&) in which

RZ ^c and ni are as defined above, oxidized with an oxidizing agent such as peroxide compounds, such as hydrogen peroxide in methylene chloride in the presence of trifluoroacetic anhydride to give the corresponding 3,4-epoxide derivative and this is then treated součeninou IIb

Ar-Y-Hb) in which

Ar and Y are as defined in Formula I.

Further, the starting materials of formula II can also be prepared from analogs of the reaction products of formula I in which R 2 is hydrogen by conventional acylation methods, taking care not to select either the acylating agent, the amount thereof and the reaction conditions. or optionally acylated and the O-acyl group can then be removed by slight hydrolysis, or cleaved also in situ, i.e. during the reduction. Particularly suitable for the selective N-acylation are lower alkyl esters such as methyl and ethyl esters and carboxylic acids corresponding to the radicals R @ 2. However, other carboxylic acid derivatives customary as acylating agents such as anhydrides, halides and mixed anhydrides, e.g. (lower) alkyl esters of carbonic acid.

Analogues of compounds of formula I with hydrogen instead of R2 are obtained, for example, by employing, in the above reaction sequence, after 205086, instead of compounds of formula IIa analogues with easily cleavable groups such as benzyloxycarbonyl and reacting with a compound of formula IIb, cleaves, for example, by hydrogenolysis or solvolysis.

Further, the starting materials of formula ΪΙ may be obtained by isomerization of analogs of compounds of formula I which contain an acyl group instead of R 1 and a hydrogen site instead of R 2. This isomerization, known as Ο, Ν-acyl migration, is carried out in a manner known per se, for example by treatment with an alkali such as an alkali metal hydroxide, an alkali metal carbonate or an alkali metal acid carbonate such as sodium hydroxide, potassium carbonate or sodium bicarbonate, or an amine , such as ammonia or benzylamine, in a lower alkanol such as methanol or water, operating at a temperature of about + 10 ° to - 100 ° C, preferably with stirring. This isornerization can also be carried out in an anhydrous solvent, for example benzene or toluene, at an elevated temperature.

Depending on the process conditions and starting materials, the novel compounds are obtained in free form or in the form of their salts, which are also within the scope of the invention, and the novel compounds or their salts may also be present in the form of hemihydrates, monohydrates, sesquihydrates or polyhydrates. The acid addition salts of the novel compounds can be converted into free compounds in a manner known per se, for example by treatment with basic agents such as alkali metal hydroxides, carbonates or acid carbonates or ion exchangers, and these can be converted again if they contain acidic substituents such as phenolic hydroxyl groups. or carboxyl groups, can be converted into base salts by treatment with suitable strong bases. On the other hand, the free bases obtained can form acid addition salts with organic or inorganic acids, for example with the abovementioned acids. In particular, acids and bases suitable for the preparation of pharmaceutically usable salts are used in the preparation of acid addition salts and base salts.

These or other salts, especially acid addition salts of novel compounds, such as picrates or perchlorates, can also be used to purify the free bases obtained by converting the free bases into salts, separating and purifying them, and releasing them from the salts again. base.

Depending on the choice of starting materials and processes, the novel compounds can be present as optical antipodes or racemates or, if they contain at least two asymmetric carbon atoms, also as mixtures of racemates.

The racemate mixtures obtained can be separated into the two stereoisomeric (diastereomeric) racemates in a known manner, for example by chroimatography and / or fractional crystallization, based on the physicochemical differences of the diastereoisomers.

The racemates obtained can be decomposed into antipodes by known methods, for example by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reaction with an optically active substance which forms salts with a racemic compound, in particular an acid, and on the basis of various solubilities, to diastereoisomeric salts from which the antipodes can be released by treatment with suitable agents. Particularly suitable optically active acids are, for example, the D- and L-forms of tartaric acid, O, O-di-p-toluyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Preferably, the more effective of both antipodes is isolated.

Depending on the reaction conditions and the starting materials, the reaction products of formula I are obtained as pure isomers or as mixtures of isomers. Such mixtures may be represented, for example, by mixtures of cis- and trans-configuration compounds.

Mixtures of isomers of the above type are separated in the customary manner, for example by crystallization and / or chromatographic methods, such as by silica gel column chromatography using conventional solvent mixtures as eluents, into the pure isomers.

The invention relates to those embodiments of the process in which the starting material is formed under the reaction conditions or in which the reactants are optionally present in the form of their derivatives as salts.

Suitably, after carrying out the reaction according to the invention, starting materials are used which lead to the groups of final substances mentioned especially at the beginning, and in particular to the particularly described or emphasized reaction products. Thus, for example, the starting materials may be present in the cis- or trans-configuration.

The novel compounds can be used, for example, in the form of pharmaceutical preparations which are suitable for enteral, for example oral or rectal, or for parenteral administration, and contain a therapeutically effective amount of the substance optionally together with pharmaceutically acceptable carriers. or liquid. Thus, tablets or gelatin capsules containing the active compound, i.e. a compound of formula I or a pharmaceutically acceptable salt thereof, are used together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and / or glidants. substances such as silica gel, talc, stearic acid or salts thereof, such as magnesium or calcium stearic acid, and / or poly (ethylene glycol). The tablets may also contain binders, for example magnesium aluminum silicate, starches such as corn, wheat, rice or marzipan starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or optionally disintegrating tablets such as starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent agents, or adsorbents, colorants, flavors, and sweeteners. Furthermore, the new ^farmako'og: cally active compound used in the form of parenterally administrable compositions or infusníoh solutions. Such solutions are preferably isotonic aqueous solutions or suspensions which may be prepared before use, for example in the case of lyophilized preparations which contain the active ingredient alone or together with a suitable material, for example mannitol.

The pharmaceutical preparations may be sterilized and / or may contain adjuvants such as preservatives, stabilizers, wetting agents and / or emulsifiers, co-solvents, salts for regulating the osmotic pressure and / or buffers.

Said pharmaceutical compositions, which may optionally contain other pharmacologically active substances, are produced in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving and lyophilizing processes, and contain about 0.1 to 100%, in particular about 1 to 50 percent active ingredients, lyophilisates up to 100% active ingredient.

The dosage may be dependent on various factors such as the mode of administration, the species, the age or / and the individual condition. Daily dosages for oral administration are between about 0.5 mg / kg and about 50 mg / kg for a warm-blooded weight of about 70 kg, especially between about 0.05 and about 3.0 g.

The following examples serve to illustrate the invention.

Example 1

6.64 g (0.03 mol) of trans-3-hydroxy-4- (2,3-dimethylphenoxy) piperidine described in (d) below are dissolved in 100 ml of ethyl formate and the solution is boiled for 1.5 hours under reflux. The solution obtained is evaporated to dryness in a water-jet vacuum, the white solid obtained is dissolved in 100 ml of methyl chloride, this solution and the organic phase are washed with 50 ml of 1 N hydrochloric acid solution, dried over sodium sulphate and evaporated in a water-jet vacuum. to give trans-3-hydroxy-4- (2,3-dimethylphenoxy) -1-formylpiperidine, m.p. 140-141 ° C.

Analogously using 7.06 g (0.03 mol) of 4-trans-hydroxy-5- (2,3-dimethylphenoxy) hexahydro-1H-azepine described in the following paragraph hj, 4-trans-hydroxy-5 is obtained. - (2,3-dimethylphenoxy) -1-formylhexahydro-1H-azepine.

7.5 g (0.03 mol) of the above 1-formyiderivative are dissolved in 100 ml of absolute tetrahydrofuran and this solution is added dropwise under a inert atmosphere of nitrogen at 0 ° C to a suspension of 2.0 g of lithium aluminum hydride in 150 ml of absolute tetrahydrofuran. The reaction mixture was stirred for 5 hours at room temperature, then cooled in an ice bath to 0 ° C and treated sequentially with 2 mL of water, 2 mL of 2 N sodium hydroxide solution and 6 mL of water. The precipitated salts are filtered off and the filtrate is evaporated to dryness in a water pump bag.

The colorless oily residue was dissolved in 20 mL of chloroform and filtered through a pad of silica gel, eluting with additional chloroform. The combined filtrates were evaporated in a water pump vacuum to give crystalline trans-3-hydroxy-4- (2,3-dimethylphenoxy) -1-methylpiperidine, m.p. 105-107 ° C. The acid fumarate prepared from the base by treatment with fumaric acid crystallizes from a mixture of methanol and ether and has a melting point of 150-152 ° C.

In an analogous manner, from 4-hydroxy-5- (2,3-dimethyl-4-hydroxy-5- (2,3-dimethylphenoxy) -1-formylhexahydro-1H-azepine) (7.9 g, 0.03 mol) is obtained. dimethylphenoxy] -1-methylhexahydro-1H-azepine.

The trans-3-hydroxy-4- (2,3-d'methylphenoxy) piperidine used as the first starting material can be prepared as follows:

a) 83.1 g (1 mol) of 1,2,5,6-tetrahydropyridine are dissolved in 300 ml of benzene. 83 g of sodium bicarbonate are added to this solution, the mixture is cooled to 0 DEG C. under nitrogen and 332 ml of a 50% solution of benzyl chloroformate in toluene (1 mol) are added dropwise at 0 DEG C. over 1 hour.

The reaction mixture was stirred at 0 ° C for 2.5 h and then poured into 1.5 L of ice water. The benzene phase is separated, the aqueous phase is shaken three times with 250 ml of methylene chloride. Then, the combined organic phases are washed with 1 N hydrochloric acid solution and then with saturated sodium chloride solution, dried over sodium sulfate and evaporated in a water pump vacuum. The oily residue was distilled under high vacuum to give 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine, bp 102-113 ° C / 1 mbar.

(b) 108.5 g (0.5 mol) of 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine are dissolved in 1000 ml of dichloroethane and 182 g (0.9 mol) of 85% m- chloroperbenzoic acid. The slightly exothermic reaction is maintained in a water bath at room temperature. After completion of the preparation, the reaction mixture which forms a white suspension is stirred for 48 hours at room temperature, the precipitated m-chlorobenzoic acid is filtered off, the filtrate is washed successively with a saturated solution of sodium carbonate, then with a solution of ferrous sulfate, then 0.1 N sodium hydroxide solution and finally water, the organic phase is dried over sodium sulphate and evaporated in a water pump vacuum. 3,4-epoxy-1-benzyloxycarbonylpiperidine, which remains as a yellowish oil, is a uniform product by spectroscopy and thin layer chromatography and can be used for the following reactions without further purification. Distillation of this compound under high vacuum at a boiling point of 145-146 DEG C./53 mbar produces partial decomposition.

cj 50.0 g (0.21 mol) of 3,4-epoxy-1-benzyloxycarbonylpiperidine together with 53.8 g (0.42 mol) of 2,3-dimethylphenol and 210 ml of 2 N sodium hydroxide solution (0.42 mol) mol) was dissolved in 800 ml of acetonitrile. The reaction mixture is heated at reflux for 7 hours, then cooled to room temperature and concentrated in a water pump vacuum to about 1/3 of the original volume. It is then shaken three times using 200 ml of methylene chloride each time ^. The phases are washed with 2N sodium hydroxide solution, then with water, dried over sodium sulphate and evaporated in a water pump vacuum. Trans-3-hydroxy-4- (2,3-dimethylphenoxy) -1-benzyloxycarbonyl is obtained as a brownish oil.

d) 50.8 g (0.143 mol) of trans-3-hydroxy-4- (2,3-dimethylphenoxy) -1-benzyloxycarbonylpiperidine are dissolved in 1000 ml of methanol and this solution is hydrogenated in the presence of 5.0 g of 5% palladium on After the hydrogen uptake is complete, the catalyst is filtered off with diatomaceous earth and the filtrate is evaporated in a water-jet vacuum.The crude base crystallizes from a mixture of methanol and ether and provides trans-3-hydroxy-4- (2). 127 DEG-129 DEG C. The neutral fumarate prepared from this compound by fumaric acid crystallizes from a mixture of methanol and ether, m.p.

The second starting material can be produced as follows:

e) 15.9 g (0.05 mol) of endo-4- (p-toluenesulfonyloxy-1-azabicyclo [3.2.1] octane hydrochloride, m.p. 146-148 ° C, obtainable according to W Kunze, Dissertation der Universitat Basel 1973, 6349, p. 92, by the reaction there and in J. Org. Chem., 33, 4376-438 (1968), described the endo-1-azabicyclo [3.2.1] octane-4- of ol with about 1.2 times molar amount of p-toluenesulfonyl chloride in absolute chloroform at room temperature at about 48 hours reaction time, precipitating the crude product with pentane and recrystallizing from chloroform, and 23.0 g (0.2 mol) of methanesulfonyl chloride are stirred in 1400 mL of 0 75 N sodium hydroxide solution at room temperature for 4 hours and then the reaction mixture is heated to 90 ° C for 20 minutes with stirring.

After cooling, the reaction mixture was extracted four times with methylene chloride. The combined extracts were washed with 0.1 N hydrochloric acid solution, dried over potassium carbonate and evaporated to give 1-methylsulfonyl-2,3,6,7-tetrahydro-1H-azepine, m.p. mixture of ethyl acetate and benzene).

f) 1-Methanesulfonyl-2,3,3,7,7-tetrahydro-1H-azepine (11.7 g, 0.067 mol) was dissolved in methylene chloride (230 ml) and 23 g (0.13 mol) was added portionwise. m-chloroperbenzoic acid. A white suspension soon formed which was further stirred for 24 hours at room temperature. The precipitated m-chlorobenzoic acid is filtered off, the filtrate is washed with a saturated aqueous solution of sodium carbonate, then with an aqueous solution of ferrous sulfate, then with a 0.1 N sodium hydroxide solution and finally with water and dried over sodium sulfate.

Concentration of the solution in a water pump vacuum resulted in the formation of white crystals of 1-methanesulfonylhexahydro-3,4-epoxy-1H-azepine, which were isolated by filtration. M.p. 133-134 ° C.

g) 7.0 g (0.036 mol) of 1-methylsulfonylhexahydro-3,4-epoxy-1H-azepine together with 8.9 g (0.073 mol) of 2,3-dimethylphenol and 36.6 ml of 2 N sodium hydroxide solution ( 0.013 mol) was dissolved in 200 ml acetonitrile. The reaction mixture was heated to reflux for 5 days, then cooled and concentrated in a water pump vacuum. The residue is dissolved in 200 ml of methylene chloride, the organic phase is washed three times with 100 ml of 2N sodium hydroxide solution each, then with water, dried over sodium sulphate and evaporated in a water-jet vacuum. The crude product obtained was purified by preparative thin layer chromatography (100 X 20 cm silica gel plates, 1.5 mm layer thickness). Elution with ethyl acetate-toluene (3: 1) gave trans-4-hydroxy-5- (2,3-dimethylphenoxy) -1-methanesulfonylhexahydro-1H-azepine, m.p. 112-115 ° C.

(h) 3.45 g (0.011 mol) of trans-4-hydroxy-5- (2,3-dimethylphenoxy) -1-methylsulfonyltetrahydro-1H-azepine are dissolved in 75 ml of absolute benzene and 15 ml of this solution are added under a nitrogen atmosphere. 70% solution of sodium bis-2-methoxyethoxyaluminium hydride in benzene. The reaction mixture is heated to reflux for 15 hours, then cooled to 0 ° C in an ice-water bath and 15 ml of water are added dropwise. The precipitated aluminum salt was filtered off and washed with benzene. The filtrate was evaporated to dryness in a water pump vacuum. The crude trans-4-hydroxy-5- (2,3-dimethylphenoxy) hexahydro-1H-azepine obtained is converted into the hydrochloride by treatment with a 6N solution of hydrochloric acid in ether, which crystallizes from a mixture of ether and ethyl acetate. Melting point 113-115 ° C.

Example 2

In an analogous manner to that described in Example 1, cis-3-hydroxy-4- (2,3-dimethylphenoxy) -piperidine is obtained from 5.5 g (0.25 mol) of cis-3-hydroxy-4- (2,3-dimethylphenoxy) piperidine described below. 4- (2,3-dimethylphenoxy) -1-formylpiperidine as a pale yellow oil.

Reduction with 3 g of lithium aluminum hydride in 100 ml of tetrahydrofuran, carried out analogously to Example 1, gave cis-3-hydroxy-4- (2,3-dimethylphenoxy) -1-methylpiperidine as a colorless oil which crystallized from methylene chloride. Melting point 80-82 ° C. The neutral fumarate prepared from the base by the action of filmic acid crystallizes from a mixture of methanol and ether. M.p. 159-161 ° C.

The starting material can be prepared as follows:

a) 13.8 g (0.038 mol) of trans-3-hydroxy-4- (2,3-dimethylphenoxy) -1-benzyloxycarbonylpiperidine described above together with 27.4 g of dicyclohexyclarbodiimide and 3.5 ml of pyridine are dissolved in 90 ml of absolute dimethylsulfoxide. The mixture was cooled to 0 ° C with an ice-water bath and then 1.9 ml of trifluoroacetic acid was added. The cooling bath was removed again and the reaction mixture was further stirred for 4 hours under a nitrogen atmosphere. The white suspension was diluted with 250 mL of ethyl acetate and a solution was added dropwise

12.3 g (0.13 mol) of oxalic acid in 200 ml of methanol. After gas evolution had ceased, the reaction mixture was cooled to 0 ° C in an ice-water bath, diluted with 400 ml of water and the precipitated dicyclohexylurea was separated. The aqueous phase of the filtrate is extracted with 250 ml of ethyl acetate, the combined organic phases are dried over sodium sulphate and evaporated to dryness in a water-jet vacuum. The crude product obtained was dissolved in benzene and this solution was filtered through a pad of silica gel. Elution with a 95: 5 mixture of benzene and ethyl acetate gave colorless product 4- (2,3-dimethylphenoxy) -1-benzyloxycarbonyl-3-piperidone, which can crystallize from ethyl acetate. Melting point 108-111 ° C.

b1 In analogy to Example 3c), 4- (2,3-dimethylphenoxy) -1-benzyloxycarbonyl-3-piperidone (8.0 g, 0.022 mol) was obtained by selective reduction of cis-3 potassium tri-sec-butylborohydride. -hydroxy-4- (2,3-dimethylphenoxy) -1-benzyloxycarbonylpiperidine as a yellowish oil.

c) By analogy to Example 3d), by hydrogenation of 3.7 g (0.01 mol) of this product cis-3-hydroxy-4- (2,3-dimethylphenoxy) piperidine is obtained as a colorless oil. Fumaric acid crystallized from methanol / ether, m.p. 188-189 ° C.

Example 3

In an analogous manner to that described in Example 1, cis-3-hydroxy- is obtained from 5.2 g (0.023 mol) of cis-3-hydroxy-4- (3,4-dimethylphenoxy) piperidine by reaction in 100 ml of ethyl formate. 4- (3,4-Dimethyl-phenoxy) -1-formyl-piperidine as a yellowish oil.

Reduction of this product (0.023 mol), carried out analogously to Example 1, with 3 g of lithium aluminum hydride in 150 ml of tetrahydrofuran affords cis-3-hydroxy-4- (3,4-dimethylphenoxy) -1-methylpiperidine, which crystallizes from methylene chloride. 127 DEG-129 DEG. The fumarate prepared from the base by treatment with fumaric acid crystallizes from a mixture of ether and ethanol. M.p. 157-159 ° C.

The starting material can be prepared as follows:

aj In an analogous manner to that described in Example 1c), 3,4-epoxy-1-benzyloxycarbonylpiperidine is obtained from 116.5 g (0.5 mol) and 122 g (1 mol) of 3,4-dimethylphenol gives a mixture of trans-3 hydroxy-4- (3,4-dimethoxyphenoxy) -1-benzyloxycarbonylpiperidine and trans-4-hydroxy-3- (3,4-dimethoxyphenoxy) -1-benzyloxycarbonylpiperidine as a yellowish oil. The two isomers were separated by column chromatography on silica gel using benzene with a gradually increasing addition of ethyl acetate as the eluent, and trans-3-hydroxy-4- (3,4-dimethylphenoxy) -1-benzyloxycarbonylpiperidine was isolated as the first major fraction and the main product and finally pure trans-4-hydroxy-3- (3,4-dimethylphenoxy) -1-benzyloxycarbonylpiperidine is isolated after the mixed fraction and both isomers are separated as a pale yellow oil.

b) Using an analogous procedure to that described in Example 2a), from 20.0 g (0.056 mol) of trans-3-hydroxy-4- (3,4-dimethylphenoxy) -1-benzyloxycarbonylpiperidine, 40.0 g (0.19) mol) of dicyclohexylcarbodiimide, 5.2 ml of pyridine and 4.2 g of trifluoroacetic acid in 130 ml of absolute dimethyl sulfoxide gave 4- (-3,4-dimethylphenoxy) -1-benzyloxycarbonyl-3-piperidone as a yellow oil.

c) 10.0 g (0.028 mol) of 4- (3,4-dimethylphenoxy) -1-benzyloxycarbonyl-3-piperidone are dissolved in 60 ml of absolute tetrahydrofuran and 112 ml of a 0.5 M solution are added dropwise at room temperature under a nitrogen atmosphere. potassium tri-sec-butylborohydride (0.056 mol) in tetrahydrofuran.

After the addition was complete, the reaction mixture was further stirred at room temperature for 3 hours and then concentrated in a water pump vacuum to about 1/3 of the original volume. This solution is cooled to 0 DEG C. in an ice-water bath, 130 ml of water are added dropwise and extracted twice with 150 ml of methylene chloride each time. The combined organic phases are washed with 0.1 N hydrochloric acid solution, then with 0.1 N sodium hydroxide solution and finally with water, dried over sodium sulfate and evaporated to dryness in a water-jet vacuum. The oily crude product was dissolved in toluene and the resulting solution was filtered through a pad of silica gel. Elution with toluene / ethyl acetate (5: 1) gave cis-3-hydroxy-4- (3,4-dimethylphenoxy) -1-benzyloxycarbonylpiperidine as a pale yellow oil.

d) 6.0 g (0.0163 mol) of this product was dissolved in 120 ml of methanol and hydrogenated. The hydrogenation is carried out in the presence of 0.6 g of 5% palladium on carbon catalyst at atmospheric pressure and at room temperature. After completion of the hydrogen uptake, the catalyst was filtered off through diatomaceous earth and the filtrate was evaporated in a water pump vacuum. The crude base obtained, ie cis-3-hydroxy-4- (3,4-dimethylphenoxy) piperidine, crystallizes from a mixture of methanol and ether. Melting point 140-143 ° C.

The neutral fumarate prepared from this base by fumaric acid crystallizes from a mixture of methanol and ether. Melting point 186-190 ° C.

Example 4

In analogy to Example 1, 6.1 g (0.025 mol) of trans-3-hydroxy-4- (1-naphthyloxy) piperidine and 100 ml of ethyl formate were obtained trans-3-hydroxy-4- (naphthyloxy). 1-formylpiperidine, and reduction of this product (0.025 mol) with 3 g of lithium aluminum hydride in 150 ml of tetrahydrofuran gave trans-3-hydroxy-4- (1-naphthyloxy) -1-methylpiperidine as a pale yellow oil. The hydrochloride prepared from this base by treatment with hydrogen chloride in ether is an amorphous substance.

The starting material can be prepared as follows:

(a) In an analogous manner to that described in Example 1c), from 17.5 carbonylpiperidine and 21.6 g (0.15 mol) of 1-gram (0.075 mol) 3,4-epoxy-1-benzyloxycarbonylpiperidine and 21.6 g ( 0.15 mol) of trans-3-hydroxy-4- (1-naphthyloxy) -1-benzyloxycarbonylpiperldine 1-naphthol as a reddish oil. Hydrogenation of 0.05 mol of this compound, carried out analogously to Example 1d), provides trans-3-hydroxy-4- (1-naphthyloxy) piperidine as a crude base. The acid fumarate prepared from this base by the action of fumaric acid crystallizes from a mixture of methanol and ether. Mp 242-244 ° C.

Example 5

Using analogous procedure to that described in Example 1, using trans-4-hydroxy-3- (3,4-dimethylphenoxy) piperidine (5.53 g, 0.025 mol) and 100 ml of formic acid ethyl ester gave trans-4-hydroxy-3. - (3,4-dimethylphenoxy) -1-foranylpiperidine, and reduction of this product (0.025 mol) with 3 grams of lithium aluminum hydride in 150 mL of tetrahydrofuran affords trans-4-hydroxy-3- (3,4-dimethylphenoxy) -1-methylpiperidine mp 98-99 ° C. The hydrochloride prepared from this base by treatment with ethereal hydrogen chloride is an amorphous substance.

The starting material is obtained by hydrogenation of 7.5 g (0.022 mol) of trans-4-hydroxy-3- (3,4-dimethylphenoxy) -1-benzyloxycarbonylpiperidine [cf. Example 3a)], which is carried out analogously to Example 1d). Crystallization from methanol / ether gave trans-4-hydroxy-3- (3,4-dimethylphenoxy) piperidine, m.p. 93-95 ° C.

Example 6

Using the same procedure as in Example 1, using 5.88 g (0.025 mol) of trans-3-methoxy-4- (3,4-dimethylphenoxy) piperidine and 100 ml of ethyl formate, the corresponding 1-formyl derivative is obtained, and the product is reduced (0.025 mol). (3 g) of lithium aluminum hydride in 150 ml of tetrahydrofuran gave trans-3-methoxy-4- (3,4-dimethyiphenoxy) -1-methylpiperidine as a pale yellow oil. The acid fumarate obtained from this base by fumaric acid crystallizes from a mixture of methanol and ether, m.p. 151-153 ° C.

The starting material was prepared as follows:

a) To a suspension of 8.15 g (0.18 mol) of a 55% oil dispersion of sodium hydride in 100 ml of dimethylformamide is added a solution of 45 g (0.12 mol) of trans-3-hydrothoxy over 30 minutes at 30-35 ° C. -4- (3,4-dimethylphenoxy) -1-benzyloxycarbodaylpiperidine [cf. Example 3a]] in 100 ml dimethylformamide. The mixture is then heated to 50 ° C and 22.5 g (0.15 mol) of methyl iodide are added dropwise. The reaction mixture was stirred at 60-70 ° C for 3 hours and at room temperature for 15 hours, then poured into 600 ml of ice-water and extracted three times with 150 ml of ethyl acetate each time. The combined organic phases are washed once with water, dried over sodium sulphate and evaporated first under vacuum of a water pump and then under high vacuum to dryness. There was thus obtained trans-3-methoxy-4- (3,4-dimethylphenoxy) -1-benzyloxycarbonylpiperidine as a pale yellow oil.

b) 36.9 g (0.1 mol) of trans-3-methoxy-4- (3,4-dimethylphenoxy) -1-benzyloxycarbonylpiperidine are dissolved in 800 ml of methanol and hydrogenated in the presence of 6 g of 5% palladium on carbon as a catalyst at atmospheric pressure and room temperature. After completion of the hydrogen demand, the catalyst was filtered through a pad of diatomaceous earth and the filtrate was evaporated in vacuo. There was thus obtained trans-3-methoxy-4- (3,4-dimethylphenoxy) piperidine as a yellowish oil, and the acid fumarate prepared from this base was crystallized from a mixture of methanol and ether, m.p.

Example 7

Using an analogous procedure to that described in Example 1, using 5.53 g (0.025 mol) of trans-3-hydroxy-4- (3,4-dimethylphenoxy) piperidine as described in Example 4 and 100 ml of ethyl formate, a trans was obtained. -3-hydroxy-4- (3,4-dimethylphenoxy) -1-formylpiperidine, and reduction of this product (0.025 mol) with 3 g of lithium aluminum hydride in 150 ml of tetrahydrofuran affords trans-3-hydroxy-4- (3,4) Dimethylphenoxy-1-methylpiperidine as a pale yellow oil The hydrochloride prepared from this base by treatment with ethanolic hydrogen chloride and precipitation with ether is an amorphous substance.

The starting material can be obtained by hydrogenation of 71.8 g (0.2 mol) of trans-3-hydroxy-4- (3,4-dimethylphenoxy) -1-benzyloxycarbonylpiperidine (cf. Example 3a)], performed analogously to Example 1d), wherein: 125 DEG -127 DEG C. The fumarate acid obtained from this base is crystallized from ethanol / ether with a mixture of ethanol and ether to give trans-3-hydroxy-4- (3,4-dimethylphenoxy) piperidine. mp 175-177 ° C.

Example 8

Analogously to Example 1, using trans-3-hydroxy-4- (phenylthio) piperidine (5.23 g, 0.025 mol) and 100 ml of ethyl formate gave trans-3-hydroxy-4- (phenylthio) -1-phenylpiperidine. and reduction of this product (0.025 mol) with 3 g of lithium aluminum hydride in 150 ml of tetrahydrofuran gave trans-3-hydroxy-4-) phenylthio) -1-methylpiperidine as a yellow oil. The acid fumarate prepared from this base by the action of fumaric acid crystallizes from a mixture of methanol and ether. M.p. 150-152 ° C.

The starting material can be prepared as follows:

and 124.5 g (1.5 mol) of 1,2,5,6-tetrahydropyridine are dissolved in 1200 ml of benzene. To this solution was added 124 g of sodium bicarbonate, then the mixture was cooled to 0 ° C under nitrogen and a solution of 316 g (1.5 mol) of 2,2,2-trichloroethyl ester was slowly added dropwise over 3.5 hours at this temperature. chloroformic acid in 250 ml benzene. The resulting white suspension was stirred for 15 hours at 0 ° C and then poured onto 2000 ml of ice water. The benzene phase is separated and the aqueous phase is extracted twice with 1000 ml of methylene chloride each time. The combined organic phases were washed with 1 N hydrochloric acid solution, then with saturated sodium chloride solution, dried over sodium sulfate and evaporated in a water-jet vacuum to give 1- (3, 3, 3, 3-trichloroethoxycarbonyl) as a slightly reddish oil. -1,2,5,6-tetrahydropyridine.

bj 100 g (0,38 mol of 1 - ([S ₍ 1S, 1'-trichloroethoxycarbonyl) -1,2,5,6-tetrahydropyridine) is dissolved in 1200 ml methylene chloride and 157 g (0, 77 mol% 85% m-chloroperbenzoic acid The slightly exothermic reaction is maintained at room temperature with an aqueous bath After the addition (about 2 hours) is complete, the reaction mixture, which forms a white suspension, is further stirred for 15 hours at room temperature. The precipitated m-chlorobenzoic acid is filtered off, the filtrate is washed with a saturated aqueous solution of sodium bicarbonate, then with an aqueous solution of ferrous sulphate, then with a 0.1N sodium hydroxide solution and finally with water, dried over sodium sulphate and evaporated in a water pump vacuum. The residual oil was dissolved in 100 ml of benzene and filtered through a pad of silica gel, eluting with 1: 1 benzene / ethyl acetate and evaporating the solvent to give a slightly orange oil. certain 3,4-epoxy-l- (J3 / 3 "E-trichloroethoxycarbonyl) piperidine.

c) Dissolve 40 g (0.146 mol) of N-epoxy-1- (1,1,1-trichloroethoxycarbonyl) piperidine together with 32 g (0.29 mol) of thiophenol and 146 ml (0.29 mol) of a 2 N solution sodium hydroxide in 300 ml of acetonitrile. The reaction mixture is heated at reflux for 4 hours, then cooled to room temperature and concentrated in a water pump vacuum to about 1/3 of the original volume. This solution is then diluted with 900 ml of water and extracted three times with 1000 ml of methylene chloride each time. The combined organic phases were washed twice with 0.1 N sodium hydroxide solution and then with water, dried over sodium sulfate and evaporated in a water-jet vacuum. The residual oil was dissolved in 50 ml of benzene and this solution was filtered through a pad of silica gel. Eluting with benzene / ethyl acetate (4: 1), trans-3-hydroxy-4-phenylthio-1- (R, R, R) - trichloroethoxycarbonyl) piperidine was isolated as a slightly orange oil.

d) 14.0 g (0.036 mol) of trans-3-hydroxy-4-phenylthio-1- (3R, 3-trichloroethoxycarbonyl) piperidine are dissolved in 140 ml of 90% acetic acid and to this solution portionwise 9.5 g (0.14 mol) of zinc powder are added. The reaction mixture was then stirred for 1 hour at room temperature and then filtered through a pad of diatomaceous earth. The filtrate is evaporated under high vacuum, the residue is taken up in 500 ml of water, the solution is cooled to 0 ° C in an ice-water bath and at this temperature is strongly alkalized with concentrated sodium hydroxide solution and extracted twice with 200 ml of methylene chloride. The combined organic phases were washed once with water, dried over sodium sulphate and evaporated in a water-jet vacuum, whereupon the crude trans-3-hydroxy-4-phenylthiopiperidine was obtained as a crystalline base, which was recrystallized from methanol-ether. Melting point 135-136 ° C.

The neutral fumarate produced from this base by fumaric acid crystallizes from a mixture of methanol and ether. Melting point 171 - 173 ° C.

Example 1 9

In analogy to Example 1, using 5.7 g (0.025 mol) of trans-3-hydroxy-4- (m-chlorophenoxy) piperidine and 100 ml of formic acid ethyl ester, trans-3-hydroxy-4- (m-chlorophenoxy) was obtained. -1-formylpiperidine, and reduction of this product (0.025 mol) with 3 g of lithium aluminum hydride in 150 ml of tetrahydrofuran affords trans-3-hydroxy-4- (m-chlorophenoxy) -1-methylpiperidine as a pale yellow oil and from this compound with ether hydrochloride.

The starting material is prepared as follows:

a) In analogy to Example 1c) from 15.0 g (0.064 mol) of 3,4-epoxy-1-benzyloxycarbonylpiperidine and

16.5 g (0.12 mol) of m-chlorophenol gave an oily crude product, which was dissolved in benzene, filtered through silica gel, and the solvent was evaporated to give trans-3-hydroxy-4- (m-chlorophenoxy) -1 -benzyloxycarbonylpiperidine. Analogous to that described in Example 1dj, hydrogenation of 0.39 mol of this compound yielded crystalline trans-3-hydroxy-4- (m-chlorophenoxy) piperidine, m.p. 109-111 ° C. The acid fumarate produced from this compound by fumaric acid crystallizes from a mixture of methanol and acetone. Melting point 138-140 ° C.

Example 10

Analogous to that described in Example 1, using 6.2 g (0.025 mol) of trans-3-hydroxy-4- (5,6,7,8-tetrahydro-1-naphthyloxy) piperidine and 100 ml of ethyl formate, a trans was obtained. -3-hydroxy-4- (5,6,7,8-tetrahydro-1-naphthyloxy) -1-formylpiperidine, and reduction of this product (0.025 mol) with 3 g of lithium aluminum hydride in 150 ml of tetrahydrofuran affords trans-3-hydroxy -4- (5,6,7,8-tetrahydro-1-naphthyloxy) -1-methylpiperidine as a pale yellow oil, and hydrochloride was obtained therefrom by treatment with ethereal hydrogen chloride.

The starting material is prepared as follows:

(a) In an analogous manner to that described in Example 1cj, from 23,3 g (0,1 mol) 3,4-epoxy-1-benzyloxycarbonylpiperidine and 28,9 g (0,195 mol) 5,6,7,8-tetrahydro-1 -naphthol gives trans-3-hydroxy-4- (5,6,7,8-tetrahydro-1-naphthyloxy) -1-benzyloxycarbonylpiperidine as an oily product. Analogous to that described in Example 1d) by hydrogenation of 26.6 g ( 0.07 mol) of this product gave trans-3-hydroxy-4- (5,6,7,8-tetrahydro-1-naphthyloxy) piperidine, which was recrystallized from methanol-ether, m.p. 168-169 ° C. This product with fumaric acid yields a neutral fumarate crystallizing from a mixture of methanol and ether, m.p. 208-210 ° C.

Example 11

Analogous to Example 1, 6.33 g (0.025 mol) of trans-3-hydroxy-4- (3,4-dimethoxyphenoxy) piperidine and 100 ml of ethyl formic acid tr-3-hydroxy-4- are obtained. (3,4-dimethoxyphenoxy) -1-formylpiperidine, and reduction of this product (0.025 mol with 3 g lithium aluminum hydride in 150 ml tetrahydrofuran) affords trans-3-hydroxy-4- (3,4-dimethoxyphenoxy) -1-methylpiperidine in pale yellow oil and the corresponding hydrochloride was treated with ethereal hydrogen chloride.

The starting material is prepared as follows:

a) In analogy to Example 1cj, from 9.3 g (0.04 mol) of 3,4-epoxy-1-benzyloxycarbonylpiperidine and

12.3 g (0.03 mol) of 3,4-dimethoxyphenol yield an oily crude product which is dissolved in a small amount of benzene and this solution is purified over a silica gel column using a 4: 1 mixture of benzene and ethyl acetate as eluent, then pure trans-3-hydroxy-4- (3,4-dimethoxyphenoxy) -1-benzyloxycarbonylpiperidine is obtained. Analogously to Example 1d) with 0.014 mol of this compound by hydrogenation to give trans-3-hydroxy-4- {3 (4-dimethoxyphenoxy) piperidine. The neutral fumarate prepared from this compound by fumaric acid crystallizes from a mixture of methanol and ether. Melting point 173-175 ° C.

Claims (5)

SUBJECT A process for the preparation of hydroxy derivatives of aryloxy- and arylthio-perhydroazaheterocycles, wherein: R 1 represents hydrogen or an alkyl radical of up to 4 carbon atoms, R2 is a primary aliphatic hydrocarbon radical having up to 4 carbon atoms, Y is oxygen or sulfur, n1 and n2 are in each case 1 to 3, the sum of n1 + n2 being at most 4, and Ar is optionally alkyl or alkoxy having at most 4 carbon atoms, halogen having an atomic number of up to 35 and / or trifluoromethyl or a methylenedioxy-substituted phenyl or naphthyl or 5,6,7,8-tetrahydronaphthyl radical, and their acid addition salts, characterized in that in a compound of the formula II or ₄ (II): R ^c represents hydrogen, an alkoxy group having a maximum of 4 carbon atoms or an aliphatic hydrocarbon radical having a maximum of 3 carbon atoms, 3 R1, Ar, Y, ni, Π2 as well as ni + 112 have the meanings given in formula I, reduce the carbonyl group or the alkoxycarbomyl group, and then optionally obtain the mixture of isomers into the pure isomers and / or obtain the mixture of cis and trans isomers is optionally resolved into cis- and trans-configuration compounds, and / or the racemate obtained is optionally resolved into optical antipodes, as the free compound of formula I obtained is optionally converted into a salt or the resulting salt is optionally converted into a free compound of formula I. 2. A process according to claim 1, wherein the compound is of the formula YNALEZU II ^C wherein R2 is hydrogen or an aliphatic hydrocarbon radical with maximum 3 carbon atoms and R, Ar, Y, Ni, Π2 and ni + n2 4 are defined as in point 1, the carbonyl group is reduced and then optionally the obtained the mixture of isomers is separated into the pure isomers, and / or the mixture of cis- and trans-isomers obtained is optionally separated into compounds having a cis- and trans-configuration, or / and the racemate obtained is optionally resolved into optical antipodes, and / or the free compound obtained I is optionally converted into a salt or the resulting salt is optionally converted into a free compound of formula I. 3. The method according to claim 1, characterized in that in a compound of formula II wherein Ri, R 2 ^C, Y, ni, nz and ni + m are defined as in point 1, and Ar is optionally not more than twice a phenyl group having a maximum of 4 carbon atoms or an alkoxy group having a maximum of 4 carbon atoms or a halogen atom having an atomic number of up to 35, or a naphthyl residue or a 5,6,7,8-tetrahydronaphthyl residue, reduces the carbonyl or alkoxycarbonyl group; the optionally obtained mixture of isomers is separated into the pure isomers, and / or the obtained mixture of cis and trans isomers is optionally separated into compounds with the cis and trans configuration, and / or the resulting racemate is optionally resolved into optical antipodes, and / or the compound of formula I is optionally converted into a salt or the resulting salt is optionally converted into a free compound of formula I. 4. A method according to claim 1, characterized in that in a compound of formula II wherein R2 represents hydrogen or a ^C aliphatic hydrocarbon radical with maximum 3 carbon atoms and Ar is optionally not more than two alkyl or alkoxy each having up to 4 carbon atoms, or a halogen atom having an atomic number of up to 35 substituted phenyl, or naphthyl or 5,6,7,8-tetrahydronaphthyl, and R 1, Y, n 1, n 2 as well as n 1 + 112 are as defined in point 1, reduces the carbonyl group whereupon the optionally obtained mixture of isomers is separated into the pure isomers, and / or the obtained mixture of cis and trans isomers is optionally separated into compounds having a cis and trans configuration, and / or the resulting racemate is optionally resolved into optical antipodes; and optionally recovering the free compound of formula I into a salt or converting the obtained salt into the free compound of formula I. 5. A method according to claim 1, characterized in that in a compound of formula II wherein R is hydrogen, ^R2C is hydrogen or alkoxy having up to 4 carbon atoms, Ar is 2,3-dimethylphenyl or 3,4- dimethylphenyl, Y is oxygen, n1 is 1 and liz is 2, reduces the carbonyl or alkoxycarbonyl group, whereupon the optionally obtained free compound is converted into a salt or the obtained salt is optionally converted into a free compound.