CS200464B2 - Process for preparing sulphides - Google Patents

Description

The invention relates to a process for the preparation of sulfides of the general formula I

where

R @ ₁ is hydrogen or alkyl of up to 12 carbon atoms, is hydrogen, hydroxyl or acyloxy of up to 4 carbon atoms, R @ 4 is alkyl of up to 12 carbon atoms optionally substituted by fluorine, hydroxyl, acyloxy of up to 4 carbon atoms, phenyl or p-tolyl,

A is alkylene of up to 8 carbon atoms, optionally at least once substituted by fluorine, one of R 2 and R 5g is either hydrogen and the other is hydroxyl or acyloxy of up to 4 carbon atoms or R p and R g together are = O and the bond marked -the ¢ (.- or β-configuration, and their physiologically acceptable salts).

It has been found that the compounds of the formula I have, in addition to a blood pressure lowering effect, a prostaglandin-like effect in good tolerability. They have vasodilating, anti-inflammatory, diuretic, bronchospasmolytic, gastric secretion, platelet aggregation, lipid degradation, and noradrenaline release inhibiting properties and effects affecting nasal mucosal collapse. In addition, they affect the function of the corpus luteum, the transport of the egg of the fallopian tube, the nidation and fertility of the male. The compounds of formula I can therefore be used as medicaments as well as intermediates for the preparation of other medicaments.

200464.

AND

The compounds of formula I contain at least 2 asymmetric carbon atoms in the five-membered ring. When one of the radicals R @ ₂ and R @ 6 is hydrogen, the other a hydroxy or acyloxy group having up to 4 carbon atoms, or R @ 1 is not hydrogen, the third ring carbon atom is asymmetric; if one of the radicals R ₂ and R g is hydrogen, hydroxy or acyloxy second up to 4 carbon atoms and R is not hydrogen in the ring are four asymmetric centers. If one of A or R 4 is substituted alkylene or alkyl, other asymmetric centers may exist in both side chains.

The compounds of the formula I can therefore exist in various stereoisomeric forms and, as a rule, as mixtures of racemates.

The products of the invention also include optically active compounds of formula I and their racemates. Particularly preferred are the optically active stereoisomers of formulas Ia to Ih, their optical antipodes and racemates:

(L ») (lb) 0 ')

(id) (Ie) (lf)

wherein R 13 is hydrogen or acyl of up to 4 carbon atoms.

The present invention provides a process for the preparation of compounds of formula (I), characterized in that a compound of formula (I) wherein R ₂ and R 1g together represent an oxygen atom of a carbonyl group is reacted with a reducing agent and / or by reaction with esterifying or solvolyzing agents to another compound of formula X, and / or the compound of formula X is resolved into its racemates and / or optical antipodes, and / or the compound of formula I is converted into a physiologically acceptable salt by treatment with base; salts.

In the above formulas, R, in addition to hydrogen, is preferably an alkyl radical of up to 12 carbon atoms. In particular, they are straight-chain alkyl, in particular of up to 6 carbon atoms, for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl; but also an isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-pentyl, 3-pentyl, tert-pentyl, neopentyl, 2-hexyl, 3-hexyl or isohexyl radical or, for example, also n-heptyl, an n-octyl, n-nonyl, n-decyl, n-undecyl or n-dodecyl residue.

The radicals R @ ₂ and R @ ₁₆ together represent = O or one of the radicals R @ 2 and R @ 1 g represents hydrogen; the other represents hydroxyl or acyloxy of up to 4 carbon atoms, the hydroxyl or acyloxy radical being in the i or β position.

If one of the radicals R @ ₂ and R @ 8 is acyloxy, the acid residues are preferably derived from carboxylic acids, in particular aliphatic carboxylic acids. It is preferably a formyloxy-, acetoxy-, propionyloxy- or butyryloxy group. However, acid residues can also be derived, for example, from sulfonic acids or inorganic acids. The acyloxy group is, for example, a methylsulfonyloxy-, ethylsulfonyloxy-, 2-hydroxyethylsulfonyloxy-, HOSO ₂ O- or (HO) ₂ P (O) -O- group.

In addition to hydrogen or hydroxyl, R 3 is also acyloxy of up to 4 carbon atoms. The hydroxyl or acyloxy group may be in the fi or (i) position. Suitable acyloxy groups are, in particular, those mentioned for R ₂ and R 6. When one of R ₂ and R ₁₈ is hydrogen, the other is acyloxy of up to 4 carbon atoms and R3 is acyloxy of up to 4 carbon atoms, the acyloxy groups are preferably the same.

R 4 represents straight or branched alkyl of up to 12 carbon atoms optionally substituted by fluorine, hydroxy, acyloxy of up to 4 carbon atoms, phenyl or p-tolyl. Suitable alkyl radicals are preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl; 2,2-dimethylpropyl, 3,3-dimethylbutyl, 4,4-dimethylpentyl, 5,5-dimethylhexyl, 6,6-dimethylheptyl, 7,7-dimethyloctyl, 8,8-dimethylnonyl, 9,9-dimethyldecyl; but also isopropyl, isobutyl, isopentyl, isohexyl, isoheptyl, isooctyl, 2-butyl, 2-pentyl, 2-hexyl, 2-heptyl, or 2-octyl. Particularly preferred are 3,3-dimethylpentyl, 3,3-dimethylhexyl, 3,3-dimethylheptyl, 3,3-dimethyloctyl or 3,3-dimethylnonyl.

Especially preferred are also alkyl groups which are substituted in the 2-position by a hydroxy or acyloxy group having up to 4 carbon atoms, such as 2-hydroxypropyl, 2-hydroxybutyl, 2-hydroxypentyl, 2-hydroxyhexyl, 2-hydroxyheptyl, 2-hydroxyoctyl, 2 -hydroxy-6,6-dimethyl * heptyl, 2-hydroxy-2-methylheptyl, 2-hydroxy-7,7-dimethyloctyl, 2-formyloxypropyl, 2-formyloxyheptyl, 2-acetoxyheptyl, 2-acetoxy-6,6-dimethylheptyl , 2-acetoxy-7,7-dimethyloctyl, 2-hydroxynonyl, 2-hydroxy-2-methylnonyl, 2-hydroxy-3,3-dimethylnonyl, 2-hydroxy-8,8-dimethylnonyl and, if not already mentioned, above said OH-substituted alkyl groups at the 2-position.

R 4 may also be F substituted with up to 12 carbon atoms, preferably terminal trifluoroalkyl such as 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, 7,7,7-trifluorheptyl or 8,8,8-trifluoroctyl. When R4 is a phenyl-substituted alkyl radical, it is preferably a N-phenylalkyl group such as a 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 7-phenylheptyl or 8-phenyloctyl group. R 4 can also be an alkyl radical substituted with p-tolyl, preferably an α-p-tolylalkyl radical, such as 2-p-tolylethyl, 3-p-tolylpropyl or 4-p-tolylbutyl.

Of course, R 4 may also be an alkyl radical of up to 12 carbon atoms, which has my more different substituents. Preferred examples of such R4 radicals are:

2-hydroxy-7,7,7-trifluorheptyl, 2-hydroxy-8,8,8-trifluoroctyl, 2-acetoxy-7,7,7-trifluorheptyl, 2-acetoxy-8,8,8-trifluoroctyl group: 2 -hydroxy-9,9,9-trifluoronyl, 2-hydroxy-2-methyl-9,9,9-trifluoronyl, 2-hydroxy-3,3-dimethyl-9,9,9-trifluoronyl.

A is preferably unsubstituted alkylene of up to 8 carbon atoms, such as a methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene or octamethylene radical. When A is substituted with alkylene of up to 8 carbon atoms, these are fluoroalkylene groups such as:

-CHgCHF-, -CH ₂ CF ₂ -, -CH ₂ CH ₂ CHFCH ₂ -, -CH ₂ CH ₂ CH ₂ CF ₂ -, -CH ₂ CH ₂ CH ₂ CHFCHF-, -CH ₂ CH ₂ CF ₂ -, -CH ₂ CH ₂ CH ₂ CF ₂ CH ₂ -, -CH ₂ CH ₂ CF ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CF ₂ CH ₂ CH ₂ -, - (CH ₂ ) 5 CF ₂ - or - ( CH ₂ ) ₄ CHFCHF.

Compounds of formula I in which R ₂ R _t g together are an oxygen atom of the carbonyl group is converted by treatment with a reducing agent to the compound of formula 1 wherein one of the radicals R ₂ and RJG represents hydrogen, the other is a hydroxyl group and R3 is hydrogen, or one of the radicals R ₂ and R g is hydrogen, one hydroxyl group, and hj is a hydroxyl group. Only those reducing agents are suitable which leave the carboxyl group or the carboalkoxy group unchanged, preferably also complex metal hydrides, in particular NaBH4, optionally in the presence of AlCl3 or LiBr or LiBH4. It is preferably carried out in the presence of an inert solvent, for example in a low alcohol; in an ether such as tetrahydrofuran or ethylene glycol dimethyl ether. The reaction is preferably terminated by boiling the reaction mixture. The decomposition of the metal complex formed can be carried out in a conventional manner, for example with aqueous ammonium chloride solution. However, chemically activated hydrogen can also be used under suitable reaction conditions. Selective reduction of the carbonyl group is possible, for example, by stirring with zinc dust at 0 ° C in 50% acetic acid; suitable reducing agents are also aluminum alcoholates such as aluminum isopropylate (according to Meerwein-Ponndorfs; for example in benzene or toluene at a temperature in the range of 20 to 110 ° C).

Compounds of formula I wherein R ₂ and R g together are carbonyl oxygen, may be prepared also by reacting a compound of formula II

D Ro

D (II),

X is chlorine, bromine, iodine, alkylsulfonyloxy of up to 4 carbon atoms or arylsulfonyloxy of up to 10 carbon atoms and R 1, R ₂ , R 3, R 6 and A are as defined above with a compound of formula III

W-S-R 4 (III) wherein

W is hydrogen or an alkali or alkaline earth metal equivalent and R 4 is as defined above.

D represents either a straight N -hydroxycarbonyl-2-alkylene- (1,2) - or a n-alkoxycarbonyl-2-alkenylene- (1,2) - residue optionally substituted with fluorine; or direct N-hydroxycarbonyl-1-haloalkylene- (1,2) - N -alkoxycarbonyl-1-haloalkylene- (1H-residue, optionally at least once substituted with fluorine and the corresponding 1-alkylsulfonyloxy- or 1-arylsulfonyloxy groups). consider the following residues:

7-hydroxycarbonyl-1-heptenylene- (1,2) -,

8-hydroxycarbonyl-1-octenylene- (1,2) -,

9-hydroxycarbonyl-1-nonenylene- (1,2) -,

7-ethoxycarbonyl-1-heptenylene- (1,2) -,

8-ethoxycarbonyl-1-octenylene- (1,2) -,

9-ethoxycarbonyl-1-nonenylene- (1,2) -,

1-chloro-8-hydroxycarbonyl-octylene- (1,2) -,

1-bromo-8-hydroxycarbonyl-octylene- (1,2) -,

- iodo-8-hydroxycarbonyl-octylene- (1,2) -,

1-chloro-8-methoxycarbonyl-octylene- (1,2) -,

1-bromo-8-methoxycarbonyl-octylene- (1,2) -,

- iodo-8-methoxycarbonyl-octylene- (1,2) -,

1-Methylsulfonyloxy-8-ethoxycarbonyl-octylene- (1,2) -,

1-ethylsulfonyloxy-8-ethoxycarbonyl-octylene- (1,2) -,

1-p-tolylsulfonyloxy-8-ethoxycarbonyl-octylene- (1,2) -,

1- (4-bromophenyl) -sulfonyloxy-8-ethoxycarbonyl-octylene- (1,2) -,

-t-naphthylsulfonyloxy-8-ethoxycarbonyl-octylene- (1,2)-residue.

X is in addition to chlorine, bromine or iodine also an alkylsulfonyloxy group having up to 4 carbon atoms, preferably methylsulfonyloxy or ethylsulfonyloxy, but also 2-hydroxyethylsulfonyloxy or butylsulfonyloxy; or arylsulfonyloxy having up to 10 carbon atoms, such as p-tolylsulfonyloxy, p-bromophenylsulfonyloxy, 1-naphthylsulfonyloxy or 2-naphthylsulfonyloxy.

W represents, in addition to hydrogen, an alkali metal or alkaline earth metal equivalent, preferably Na, K or 0.5 Ca.

Compounds of formula II are therefore substituted cyclopentanones, 2-cyclopentenones, cyclopentanols or 2-cyclopentenols; preferably 3-halocyclopentanones, 3-alkylsulfonyloxycyclopentanones or 3-arylsulfonyloxycyclopentanones, in particular 3'-chloro-2-carboxyalkyl, 3-bromo-2-carboxyalkyl, 3-iodo-2-carboxylic acid, -carboxyalkyl-, 3-methylsulfonyl-2-carboxyalkyl-, 3-p-tolylsulfonyloxy-2- N -carboxyalkyl-, 3-bromo-4 (K'-hydroxy-2 H- carboxyalkyl-, 3 bromo-4? -hydroxy-2-N-carboxyalkyl-cyclopentanones; 2-carboxyalkyl- or 2-carbalkoxyalkyl-2-cyclopentanones, in particular 2-n-carboxyalkyl-, 2-n-carbalkoxyalkyl-, 4α-hydroxy-2? 4'-carboxyalkyl-, 4o (-hydroxy-2-yl-carbalkoxyalkyl-), 4'-acyloxy-2'-carboxyalkyl-, 4'-acyloxy-2'-carbalkoxyalkyl- 4- (3-hydroxy-2-N-carboxyalkyl), 4 (3-hydroxy-2-N-carbalkoxy alkyl), 4 (1-acyloxy-2-N-carboxyalkyl-, 4'-ayloxy-2- 3-halocyclopentanols, 3-alkylsulfonyloxycyclopentanols or 3-arylsulfonyloxycyclopentanols, in particular 3-chloro-2-N-carboxyalkyl-, 3-bromo-2-N-carboxyalkyl- iodo-2- (N-carboxyalkyl-, 3-methyls) 3-p-tolylsulfonyloxy-2-N-carboxyalkyl-, 3-bromo-4-hydroxy-2-N-carboxyalkyl-, 3-iodo-4-hydroxy-2- N - carboxyalkylcyclopentanols; o 2-carboxyalkyl- or 2-carbalkoxyalkyl-2-cyclopentenols, in particular 2-carboxyalkyl-,

2'-carbalkoxyalkyl-, 4'-hydroxy-2'-carboxyalkyl-, 4o (-hydroxy-2'-carbalkoxyalkyl-, 4'-acyloxy-2'-carboxyalkyl-, 4'-acyloxy -2- N -carbalkoxyalkyl-, 4 H -hydroxy-2 - N -carboxyalkyl-, 4 H -carboxycarbalkoxyalkyl-, 4,5-acyloxy-2 H -carboxyalkyl-, 4 H -acyloxy-2- -carbalkoxyalkyl-2-pentenols.

The compounds of formula III are optionally substituted alkali metal or alkaline earth thiols or thiolates, preferably n-alkyl or 2-hydroxy-n-alkylthiols or their alkali salts, in particular optionally substituted n-propyl, η-hexyl n-heptyl-, η-octyl-, 2-hydroxy-n-hexyl-, 2-hydroxy-n-heptyl-, 2-hydroxy-n-octylthiols or corresponding to sodium thiolates. The compounds of formula II are known or can be prepared from known compounds by known methods.

For example, diethyl acetal can be prepared from 2-bromo-2-cyclopentenone by treatment with ethanol, which is reacted with lithium in ether in a known manner and reacted with (CH 2 Cl 2) / CuCl and the organic compound obtained is reacted with tert. butoxycarbonyl alkyl iodides.

This reaction is preferably carried out in the range of -50 to + 5 ° C, preferably in particular -30 to -10 ° C and under an inert gas atmosphere, for example under argon. However, it is also possible, for example, to react the cyclopentanone-2-carboxylic acid ethyl ester in a known manner with ** alkoxycarbonyl or n-cyanalkyl bromides or i-iodides in the presence of an alkali metal alcoholate such as NaOC3H3. as CCl 4, Br _2, and then reacted with H ₂ SO 4 · It is formed according to yet still unexplained mechanism of the reaction of compound of formula II.

*

The compounds of formula III are known or can be prepared according to known methods, for example as described by Houben-Weyl in Methoden der organischen Chemie, Vol. IX, p. 3 et seq.

(Stuttgart, 1955). It is preferred to start from compounds which otherwise correspond to formula III, but in which W is X and especially is Br, and reacted with an acidic alkali metal sulfide, preferably KHS or NaHS. The reaction is usually carried out using a solvent, preferably an alcohol such as methanol, ethanol or isopropanol, optionally also in the presence of water or an aprotic dipolar solvent such as acetone, dimethylformamide, dimethylsulfoxide, tetramethylurea, hexyaethylphosphoric triamide, tetrahydrothiophene-S, S-dioxide. or propylene carbonate or mixtures of these solvents. When the reaction mixture is treated under acidic conditions, usually free thiols of formula III are obtained, which can be converted into thiolates of formula III by reaction with bases, preferably alkali metal or alkaline earth metal hydroxides, in particular sodium hydroxide or potassium hydroxide.

If the compounds of formula (III) are 2-hydroxyalkantiols, they can be advantageously prepared from the corresponding 1,2-epoxyalkanes and hydrogen sulfide in the presence of a basic catalyst.

The reaction of a compound of formula II (D = -CH = 1-A-COOR) with a compound of formula III is generally carried out in the presence of a basic catalyst and using a suitable solvent, preferably an alcohol such as methanol or ethanol; however, for example, a hydrocarbon such as benzene or toluene may also be used; water or liquid ammonia is also suitable. It is also possible to work without solvent.

Suitable base catalysts are preferably metal hydroxides, in particular alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or calcium hydroxide; alkali metal alcoholates such as sodium ethylate, sodium ethylate or potassium tert-butylate; basic salts, preferably carbonates or acetates, such as potassium carbonate or NaOCOCH 3; ammonia; amines such as trimethylamine, triethylamine, isopropylamine, tert-butylamine or ethylenediamine; alicyclic amines such as cyclohexylamine, dicyclohexylamine or dimethylaniline; or heterocyclic amines such as piperidine, pyrrolidine, pyridine, quinoline, diazabicyclo [2.2.2] octane or diazabicyclo [3.4.0] non-ene; or quaternary ammonium hydroxides such as tetramethylammonium hydroxide or benzyltrimethylammonium hydroxide.

The presence of a basic catalyst is particularly favorable when a compound of formula III wherein W is H. is used. When a compound of formula III where W is equivalent to an alkali metal or alkaline earth metal is used, the reaction mixture is generally alkaline and addition of a basic catalyst is not necessary. It is of course also possible to use a suitable basic catalyst as a solvent (especially liquid ammonia). The reaction is carried out in the range of -40 to 120 ° C, preferably between room temperature and the boiling point of the reaction mixture; the reaction time is, depending on the reaction conditions, between 3 hours and 7 days.

The reaction of a compound of formula II (D = -CHX-CH-A-COOR,) with a compound of formula III (W = alkali metal or alkaline earth metal equivalent) is carried out in a manner known per se and described in the literature. The reaction is preferably carried out in an inert solvent, in particular one of the abovementioned solvents. The reaction temperature is in the range of 0 to 120 ° C, especially in the range between room temperature and the boiling point of the reaction mixture; the reaction time is, depending on the reaction conditions, between 3 hours and 7 days.

From other compounds of formula I, esters of formula I (R 1 = alkyl of up to 12 carbon atoms) can be prepared according to methods described in the literature. For example, an acid of formula I (R, - H) may be reacted with an appropriate alcohol in the presence of an inorganic or organic acid such as hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, trifluoroacetic acid, sulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid. an acid or an acidic ion exchanger optionally in the presence of an inert solvent such as benzene, toluene or xylene at a temperature between 0 ° C and boiling point. The alcohol is preferably used in excess.

Preferred alcohols have the formula R 7 OH wherein R 7 is alkyl of up to 12 carbon atoms.

In particular, they are straight-chain primary alcohols having up to 12 carbon atoms, such as methanol ethanol, propanol, butanol, hexanol, octanol, decanol or dodecanol; however, it may also be, for example, isopropyl alcohol, sec-butyl alcohol or a target. Butyl alcohol.

Further, it is possible to work in the presence of water-binding agents, for example anhydrous heavy metal sulphates or molecular sieves. The reaction water can also be removed azeotropically, preferably using hydrocarbons (e.g. benzene or toluene) or chlorinated hydrocarbons (e.g. chloroform or 1,2-dichloroethane).

Esterification takes place under mild conditions when the reaction water is chemically bound by the addition of carbodiimides (for example Ν, Ν'-dicyclohexylcarbodiimide) using inert solvents such as ether, dioxane, 1,2-dimethoxyethane, benzene, CH 2 Cl 2 or CHCl 3 and bases may be added. like pyridine. Methyl or ethyl esters may also be prepared by reacting the free acids with diazomethane or diazoethane in an inert solvent such as ether, benzene or methanol.

Esters of formula I (R, not H) are also obtained by the addition of carboxylic acids (I, R = H) to olefins (e.g. isobutylene, cyclohexane), preferably in the presence of catalysts (e.g. ZnCl2, BF3, H2SO4, arylsulfonic acids) pyrophosphoric acid, boric acid, oxalic acid), at a temperature in the range of 0 to 200 ° C, at a pressure in the range of 0.1 to 300 MPa, and in an internal solvent such as ether, tetrahydrofur; . dioxane, methylene chloride, benzene, toluene or xylene.

Furthermore, esters of formula I (R, not H) may be prepared by reaction of metal salts of carbon acids of formula I (R, = H), preferably alkali metal, lead or silver salts, with alkyl halides, for example R7Cl, optionally in an inert solvent , for example ether, benzene, dimethylformamide or petroleum ether, or with alkyl chlorosulfites, for example of the formula R7-OSOCI and subsequent thermolysis of the adduct obtained.

Further, it is possible to prepare esters of formula I (R, not H) by re-esterifying other esters of formula I with an excess of the corresponding alcohol or by reacting the carboxylic acids of formula I (R, = H) with any other esters of the corresponding alcohol surplus. Analogously, esters of formula I are obtained by re-esterification of alcohols of formula I (one of R 1 and R 1 g is hydrogen, the other is hydroxyl and R 3 = H, or one of R 2 and R 1 g is hydrogen, the other hydroxyl group and R 3 = OH ) by an excess of a low alkyl ester or by re-esterification of other esters which otherwise correspond to formula I, but in which R2, R3 and R, g have the following meanings:

One of R 12 and R 18 is hydrogen, the other is esterified hydroxyl and R 3 = hydrogen; one of R 2 and R 18 is hydrogen, the other is esterified hydroxyl and R 3 = OH; one of R2 and R1, g is hydrogen, the other is esterified hydroxyl and S3 is esterified hydroxyl; one of R 2 and R 16 is hydrogen, the other a hydroxyl group, and R 3 is an esterified hydroxyl group, with an excess of esterified carboxylic acids. The esterification processes described in the literature are carried out, in particular in the presence of basic or acidic catalysts, for example sodium ethylate or sulfuric acid, at a temperature between 0 ° C and boiling point. Preferably, after equilibration, one reactant is removed by distillation.

Alcohols of formula I (one of the radicals R 2 and R g is hydrogen, one hydroxyl group and R 3 = hydrogen or one of the radicals R ₂ represents hydrogen, hydroxyl group, and the second

R 3 = OH) can be reacted with halides or anhydrides of esterified acids or their alkali metal alcoholates without or with the addition of acid-binding agents such as sodium or potassium hydroxide, sodium or potassium carbonate or pyridine.

Suitable solvents are inert organic solvents such as ether, tetrahydrofuran or benzene. Excess halide or anhydride may also be used as solvent. In the preferred embodiment, yields an alcohol of formula I (one of the radicals R ₂ and R g is hydrogen, one hydroxyl group and R 3 = hydrogen or one of radicals R 2 and R | 6 is hydrogen, a second hydroxyl group and R3 is equal to the hydroxyl group ) together with a halide or anhydride of an esterified acid into a pyridine solution.

It is further possible to esterify alcohols of formula I with ketenes. The reaction is preferably carried out in an inert solvent such as ether, benzene or toluene and with the addition of acid catalysts such as sulfuric acid or p-toluenesulfonic acid.

Furthermore, esters of formula I can be hydrolyzed to acids of formula I, wherein R 1 = H, preferably in the presence of an acid catalyst, especially sulfuric or hydrochloric acid. The reaction takes place in the range of -10 to 100 ° C. Preferably, the reaction mixture is first allowed to stand for up to 6 days at room temperature and then generally boiled for up to 6 hours.

If a basic catalyst is used, preferably an alkali metal or alkaline earth metal hydroxide such as sodium, potassium or barium hydroxide or a basic salt such as potassium or sodium carbonate is suitable. The reaction is carried out in water or a water / alcohol mixture at elevated temperature, preferably at the boiling point of the reaction mixture, optionally also in an autoclave at elevated pressure.

The acids of the formula I are also obtained by dry heating of in particular the tertiary alkyl esters of the formula I (R R = COO-t-alkyl) to a temperature in the range of 50 to 350 ° C. Thermolysis can also be carried out in an inert solvent such as benzene, water, dimethylformamide, ethylene glycol, glycerin, dimethylsulfoxide, cyclohexanol, preferably with the addition of a catalytic amount of an acid, such as p-toluenesulfonic acid.

The compounds of formula I have, as already explained, more asymmetric centers, however always at least two. Therefore, they are generally formed as mixtures of different stereoisomeric forms, i.e. as racemates or, as a rule, as mixtures of racemates. Because the different racemates are diastereomeric, they can be isolated from the mixtures due to their different physical properties and obtained pure, for example by recrystallization from suitable solvents (in particular, well-crystalline derivatives may be used instead of the compounds themselves), by distillation. both adsorption chromatography or partition chromatography methods as well as mixed forms are suitable.

Racemates can be resolved in their optical antipodes according to various known methods reported in the literature. Chemical cleavage methods are preferred. Diastereomers are then formed from the racemic mixture by reaction with an optically auxiliary. Optionally, the optically active base can be reacted with a carboxyl group of a compound of formula I (R 1 = H). For example, diastereomeric salts of the compounds of formula I with optically active amines such as quinine, quinchonidine, brucine, cinchonine, hydroxyhydrindamine, morphine, 1-phenylethylamine, 1-naphthylethylamine, phenyloxynaphthylmethylamine, quinidine, strychnine, lysine arginine, lysine amino acids can be obtained. amino acids. In a similar manner, ester diastereomers can be prepared by esterifying compounds of formula I (R 1 = H) with optically active alcohols such as borneol, menthol, 2-octanol. The difference in solubility of the resulting diastereomeric salts or esters allows selective crystallization of one of the forms and recovery of optically active compounds from the mixture.

Hydroxy acids and hydroxy esters of formula I (one of the radicals R ₂ and R 6 is hydrogen, the other is hydroxy group and R 3 = hydrogen; one of the radicals R ₂ and R 6 is hydrogen, the other hydroxy group and R3 = OH) can be further converted by esterification with an optically active acid as well as (+) - and (-) - tartaric acid, dibenzoyl - (+) - and - (-) - tartaric acid, diacetyl - (+) - a

- (-) - tartaric acid, camphoric acid, β-camphorsulfonic acid, (+) - and (-) - mandelic acid, (+) - and (-) - malic acid, (+) - and (-) - 2 phenylbutyric acid, (+) - dinitrodiphenic acid or (+) - and (-) - lactic acid into suitable diastereomeric esters which can be cleaved due to their different solubilities. The optically active compounds of formula I are then obtained by saponification of the pure diastereomers. However, the acid esters of phthalic or succinic acid can also be prepared first by reaction with phthalic or succinic anhydride and the thus obtained compounds are converted into one of the above-mentioned optically active bases into diastereomeric salts and the pure enantiomers are obtained from these.

Particular preference is given to resolving the racemates or mixtures of racemates by means of chromatographic methods. Either can be used to resolved into pure enantiomers of an optically active carrier such as tartaric acid, starch, cane sugar, cellulose or acetylated cellulose and an optically inactive and / or optically active solvent or an optically inactive carrier such as silica gel or alumina in combination with an optically active solvent. Optical antipodes can also be resolved biochemically using selective, enzymatic reactions. Racemic acids of formula I (R 1 = H) can be treated with an oxidase or optionally a decarboxylase which, by oxidation or decarboxylation, disrupts one form while the other form remains unchanged. Furthermore, a hydrolase can be used to advantageously form an optically active form in a functional acid derivative of a racemic mixture. Thus, esters or amides of acids of formula I (R 1 = H) can be exposed to a hydrolase which selectively saponates one enantiomer and leaves the other unchanged.

Furthermore, it is naturally possible to obtain optically active compounds according to the described processes by using starting materials which are already optically active. When compounds are prepared by reacting a compound of formula II (D = -CH = 6-A-COOR;) with a compound of formula III (W = H), the residues -A-COOR 1 and -S-R 4 are generally in the trans-position, i.e. when the alkylthio group is in the β-position, the -carboxy- or carbalkoxyalkyl group is in the ω-position and vice versa.

When a compound of formula I or a precursor with a certain spherical ratio of one or more carbon atoms is converted to a compound of formula I or another compound of formula I to form a new asymmetric center, appropriate control of the reaction may result in this carbon atom having some, preferably desired configuration.

For example, when adding a compound of formula III (W = H) to a compound of formula XI (D = CH = O-A * -COOR ₁ , R 3 = α-acyloxy of up to 4 carbon atoms), the alkylthio group preferably enters the β-position. The corresponding 4 H -hydroxy-2- (-carboxyalkyl) -3 H -alkylthiocyclopentanone is obtained, for example, from 4α-bromo-2- (ω-carboxyalkyl) -2-cyclopentenes by addition of a compound of formula III (W = H) and subsequent hydrolysis when the configuration is reversed to 4-position.

The compounds of formula I (R 1 = H) can be converted by treatment with a base into physiologically acceptable metal or ammonium salts. Suitable salts are, in particular, the sodium, potassium, magnesium, calcium and ammonium salts, further substituted ammonium salts, such as dimethyl and diethyl200464 ammonium salts, monoethanol, diethanol and triethanolammonium salts, oyclohexylammonium salts, dicyclohexylammonium salts and dibenzylethylenediamethylenediamethylenediamethylenediamethylenediamines.

Conversely, the compounds of formula I may be liberated from metal and ammonium salts by reaction with acids, in particular mineral acids, such as hydrochloric or sulfuric acid.

The novel compounds can be used in admixture with solid, liquid and / or semi-liquid carriers as medicaments in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for parenteral, enteral or topical application and do not react with the novel compounds, such as water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, lactose, starch, magnesium stearate, talc , petrolatum, cholesterin. For parenteral administration, in particular solutions, preferably oily or aqueous solutions, and suspensions, emulsions or implants, are used. For enteral administration are tablets, dragees, syrups, slave, or suppositories, for topical application of ointments, creams, powders not _t bo. Said preparations may optionally be sterilized or adjuvants such as glidants, preservatives, stabilizers or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffers, coloring agents, flavoring and / or flavoring substances and / or other active substances, e.g. . vitamins. «

The substances may preferably be administered in a dosage of 0.1 to 2000 mg per dosage unit.

The following infra-red spectra were recorded using a Perkin Elmer 6 instrument as a film and the magnetic resonance spectra were measured using Varian HA 100 or A 60 in CDCl 3 relative to tetramethylsilane as an internal standard.

He did

To 3.4 g of 2- (6-carboxyhexyl) -3-heptylthiocyclopentanone dissolved in 30 ml of methanol is added 2.0 g of NaBH4, stirred at 20 DEG C. for 2 hours, poured into 100 ml of a saturated aqueous solution after cooling. The organic phase was washed with water, dried over Na2SO4, the solvent was distilled off, and after chromatographic purification of the residue (silica gel / chloroform), 2- (6-carboxyhexyl) -3-heptylthiocyclopantanol was obtained.

It is obtained analogously from: 2- (6-carboxyhexyl) -3- (2-hydroxy-2-methylheptylthio) -cyclopentanone, 2- (6-carboxyhexyl) -3- (2-hydroxy-2-methylheptythio) -cyclopentanol, for which calculated: 64.13% C, 10.23% H, 8.56% S;

Found:% C, 63.00;% H, 10.18;% S, 8.3%.

Infrared spectrum: bands at 1,710 and 3,400 cm -1;

Magnetic Resonance Spectrum: signals at 0.9 ppm, 1.21 ppm, 2.31 ppm, 3.88 ppm and 5.84 ppm.

Example 2

A mixture of 2- (6-carboxyhexyl) -2-cyclopentenone (6 g), propylthiol (10 ml) and piperidine (7.2 ml) was allowed to stand at room temperature for 5 days, diluted with ether (150 ml). ml of concentrated hydrochloric acid and then saturated aqueous NaCl solution, dried over sodium sulfate, the solvent is distilled off and after chromatographic purification of the residue (silica gel) CH3OH: CHCl3 = 1: 9), 2- (6-carboxyhexyl) -3-propylthiocyclopentanone is obtained as an oil Rf = 0.3 (silica gel) chloroform: methanol > 95: 5 for which

1 calculated: 62.9% C, 9.15% Η, 11.19% S;

Found:% C, 61.5;% H, 9.4;% S, 10.95.

IR spectrum: bands at 1695, 1730, 2860 and 2940 cm ^-1 broad band between 3000 cm ^- 'and 3400 cm ^-'.

Magnetic Resonance Spectrum: signals at 0.86 ppm, 3.0 ppm, and 9.75 ppm.

It is obtained analogously from heptantiol, 2-hydroxyheptantiol, 2-hydroxy-2-methylheptantiol, by reaction with 2- (6-carboxyhexyl) -2-cyclopentenonene; 2- (6-carboxyhexyl) -3-heptythiocyclopenta-

non, Rf = 0.3 (silica gel / chloroform: methanol = 95: 5, for which calculated: 66.62% C, 10.01% H, 9.36% S; Found: C 65.6, H 9.71, 9.8% S. Infrared spectrum: bands at 1700 , 1,730, 2,860 and 2 94Ο cm ”', wide strips between 3,000 cm " and 3 400 cm ''.

*

Magnetic Resonance Spectrum: signals at 0.86 ppm, 3.0 ppm, and 9.75 ppm.

2- (6-carboxyhexyl) -3- (2-hydroxyheptylthio) cyclopentanone, Rf = 0.2 (silica gel / chloroform: methanol = 95: 5), calculated for: 63.65% C, 9.56% H, 8.94% S;

Found: C 62.7, H 9.5, S 8.3%.

IR spectrum: bands at 1700, 1730, 2880 and 2950 cm ^- ', broad band between 3000 cm "' and 3500 cm ''.

Magnetic Resonance Spectrum: signals at 0.9 ppm, 3.1 ppm, 3.75 ppm and 6.8 ppm.

2- (6-carboxyhexyl) -3- (2-hydroxy-2-methylheptylthio) cyclopentanone,

R f = 0.25 (silica gel / chloroform: methanol = 95: 5) calculated for: 64.48% C, 9.74% H, 8.61% S;

Found: 65.6% C, 10.7% H, 7.9% S.

Infrared spectrum: strips at 1,740, 2,850, 2,920 and 3,400 cm ”', wide strips between

000 cm '' and 3 300 cm ''.

Magnetic Resonance Spectrum: signals at 0.9 ppm, 2.75 ppm, 3.0 ppm and 6.4 ppm.

Example3

To a mixture of 3.1 g of 2- (6-carboxyhexyl) -2-cyclopentenone and 1.5 g of 2-hydroxyheptantiol dissolved in 30 ml of dry ethanol is added 5 g of dry triethylamine, boiled for 8 hours, the reaction mixture is added to 150 ml of ice-water and 10 ml of concentrated HCl, extracted with 200 ml of ether, the organic phase is washed with saturated aqueous NaCl solution, dried over sodium sulphate, the solvent is evaporated and the residue is purified by chromatography (silica gel / CH3OH:

CHCl 3 = 1: 9) gives 2- (6-carboxyhexyl) -3- (2-hydroxyheptylthio) cyclopentanone as an oil; R _f = 0.2 (silica gel / chloroform: methanol = 95: 5); for which calculated: 63.65% C, 9.56% H, 8.94% S;

Found: C 62.7, H 9.5, S 8.3%.

IR spectrum: bands at 1700, 1730, 2880 and 2950 cm ^- ', broad band between 3000 cm "' and 3500 cm '.

Magnetic Resonance Spectrum: signals at 0.9 ppm, 3.1 ppm, 3.75 ppm and 6.8 ppm.

It is obtained analogously from 2-heptantiol by reaction with 2- (6-carbethoxyhexyl) -2-cyclopentenone,

2- (6-carbethoxyhexyl) -3-heptylthiocyclopentanone, R f = 0.7 (silica gel / chloroform), calculated for: 68.07% C, 10.33% H, 8.65% S;

Found:% C, 67.8;% H, 10.4;

IR spectrum: bands at 1730, 2870 and 2950 cm ^1st

Magnetic Resonance Spectrum: signals at 0.9 ppm and 3.0 ppm. Signals between 3.95 ppm * and 4.3 ppm (quartet).

Example 4 «

3.2 g of 2- (6-carbethoxyhexyl) -2-cyclopentenone, dissolved in 20 ml of dry ethanol, is added to a solution of sodium heptantiolate (prepared by dissolving 0.24 g of sodium in 30 ml of dry ethanol and adding 1.3 g of heptylthiol) , stirred under nitrogen at 40 ° C for 24 hours.

The reaction mixture was diluted with 150 mL of ice water and 10 mL of concentrated HCl, extracted with CH 2 Cl 2, washed with saturated aqueous NaCl, dried with sodium sulfate, the solvent was distilled off and the residue was chromatographed to give 2- (6-carbethoxyhexyl) -3-heptylthio- cyclopentanone; _Rf = 0.7 (silica gel / chloroform); for which calculated: 68.07% C, 10.33% H, 8.65% S;

Found: C 67.8%, H 10.4%, S 8.6%.

Infrared spectrum: bands at 1,730, 2,870 and 2,950 cm ';

Magnetic resonance spectrum: signals at 0.9 ppm and 3.0 ppm, signal between 3.95 ppm and 4.3 ppm (quartet).

Example 5

A mixture of 6 g of 2- (6-carbethoxyhexyl) -2-cyclopentenone, 10 ml of propantiol and 7.2 ml of piperidine is allowed to stand for 5 days at room temperature, diluted with 150 ml of ether, and the ether phase is first washed with 60 ml of ice water. ml of concentrated hydrochloric acid and then saturated aqueous NaCl solution, dried over sodium sulfate, the solvent is distilled off and after chromatographic purification of the residue (silica gel / chloroform), N - (carbetoxyhexyl) -3-propylthiocyclopentanone is obtained as an oil; R f = 0.7 (silica gel / chloroform); for which calculated: 64.93% C, 9.61% H, 10.2% S;

found: 65.6% C, 9.7% H, 9.8% S _t

Infrared spectrum: bands at 1,730, 2,870 and 2,950 cm ';

Magnetic resonance ^spectrum! signals at 1.0 ppm, 3.0 ppm, and 4.0 to 4.22 ppm (quartet).

'3

Example 6

4.0 g of 2- (6-tert-butoxycarbonylhexyl) -3-heptylthioeyclopentanone (obtainable by introducing isobutylene into a dry ethereal solution of 2- (6-carboxyhexyl) -3-heptylthiocyclopentanone in the presence of BF-j) is boiled in dry for 5 hours of p-xylene, the solvent was distilled off and after chromatographic purification of the residue (silica gel / chloroform), 2- (6-carboxyhexyl) -3-heptylthiocyclopentanone was obtained; Rf = 0.3 (silica gel / chloroform: methanol = 95: 5) J calculated for: 66.62% C, 10.0% H, 9.36% Found: 65.5% C, 9.71 % H, 9.8% S.

Infrared spectrum: bands at 1,700, 1,730, 2,860 and 2,940 cm ^-1 , wide bands between

000 cm -1 and 3 400 cm ^- ·.

»

Magnetic Resonance Spectrum: signals at 0.86 ppm, 3.0 ppm, and 9.75 ppm.

> Example 7

To a solution of 3.4 g of N- (6-carboxyhexyl) -3-heptylthiocyclopentanone in 25 ml of dry ethanol is added at room temperature 70 ml of a 0.2 N solution of diazoethane in ether, the reaction mixture is poured into 100 ml of ice water containing 5 ml. concentrated hydrochloric acid, stirred, the organic phase was separated, the aqueous phase was extracted three times with 30 ml of chloroform, the combined organic phases were washed with water, dried with sodium sulfate, the solvent was distilled off and the residue was purified by chromatography (silica gel / chloroform). (6-Carbethoxyhexyl) -3-heptylthiocyclopentanone; R f = 0.7 (silica gel / chloroform); for which calculated: 68.07% C, 10.33% H, 8.65% S;

found: 67.8% C. 0.4% H, 8.6% S.

Infrared spectrum: bands at 1,730, 2,870 and 2950 cm @ -1; ·

Magnetic Resonance Spectrum: signals at 0.9 ppm, 3.0 ppm and between 3.95 ppm and 4.3 ppm (quartet).

Example 8

To a solution of 3.9 g of 2- (6-carbethoxyhexyl) -3- (2-hydroxyheptylthio) -cyclopentanone in 20 ml of benzene is added dropwise, with stirring at room temperature, 10 ml of a solution of 0.8 g of acetyl chloride in 20 ml of benzene, after 10 minutes 10 ml of a 0.5 N aqueous solution of NaOH is added, then the remaining 10 ml of benzene solution of acetyl chloride is added dropwise, and after a further 20 minutes 10 ml of a 0.5 N aqueous solution of NaOH is again added, stirred for 30 minutes, the organic phase is separated. Wash with water, dry over sodium sulphate, distill off the solvent and chromatographically purify (silica gel / chloroform) to give 2- (6-carbetoxyhexyl) -3- (2-acetoxyheptylthio) cyclopentanone, Rf = 0.5.

Example 9 ΐ ·

To a solution of 3.9 g of 2- (6-carbethoxyhexyl) -3- (2-hydroxyheptylthio) cyclopentanone in 30 ml of pyridine was added 2.0 g of acetic anhydride dissolved in 20 ml of pyridine, stirred at 25 ° C for 14 hours. the mixture is poured into 100 ml of water, saturated with NaCl, extracted three times with 40 ml of ether, the organic phase is washed with water, dried over sodium sulphate, the solvent is distilled off and the residue is purified by chromatography (silica gel / chloroform). carbetoxyhexyl) -3- (β-acetoxyheptylthio) cyclopentanone, R f = 0.5.

Example 10

4.3 B 2- (6-Carbethoxyhexyl) -3- (2-acetoxyheptylthio) cyclopentanone was stirred for 2 hours at room temperature in 30 ml of 1% KOH solution in dioxane-water (1: 1), poured while cooling into 60 ml of 2 N aqueous HCl solution, extracted three times with 30 ml of CH 9 ClO, the organic phase is washed with water, dried over sodium sulfate, the solvent is distilled off and the residue is chromatographed (silica gel / chloroform) to give 2- (2-carboxyhexyl) -3 - (2-hydroxyheptyltio) cyclopentanone, R _f = 0.2 (silica gel / chloroform: methanol = 95: 5); for which calculated: 63.65% C, 9.56% H, 8.94% S;

Found: C, 62.7; H, 9.5; S, 8.3.

Infrared spectrum: bands at 1,700, 1,730, 2,880 and 2,950 cm ^-1 , wide bands between

000 cm ^-1 and 3500 cm ^-1 ; *

Magnetic Resonance Spectrum: signals at 0.9 ppm, 3.1 ppm, 3.75 ppm and 6.8 ppm.

Example 11

Dissolve 0.24 g of sodium in 20 ml of dry ethanol, add dropwise a solution of 3,4 g of 2- (6-carboxyhexyl) -2-heptylthiocyclopentanone in 20 ml of dry ethanol, dilute with 60 ml of dry ether and the precipitated sodium salt of 2- ( 6-Carboxyhexyl) -2-heptylthiocyclopentanone was filtered off.

Example 2

To a solution of 3.7 g of 2- (6-carboxyhexyl) -2-heptylthiocyclopentanone sodium salt in a mixture of 30 ml of water and 30 ml of ethanol is added 10 ml of 1 N aqueous HCl, the reaction mixture is saturated with NaCl,

It is extracted three times with 20 ml of benzene, the organic phase is washed with water, dried over Na2SO4, the solvent is distilled off and after chromatographic purification of the residue (silica gel / chloroform), 2- (6-carboxyhexyl) -3-heptylthiocyclopentanone is obtained; R f = 0.3 (silica gel / chloroform: methanol = 95: 5); for which calculated: 66.62% C, H 10.01%, 9.36% 5;

Found: C 65.5, H 9.71, S 9.8.

Infrared spectrum: bands at 1,700, 1,730, 2,860 and 2,940 cm ^-1 , wide bands between

000 cnr 'and 3400 cm'.

Magnetic Resonance Spectrum: signals at 0.86 ppm, 3.0 ppm and 9.75 ppm.

Example 13

a) analogously to Example 2, from 2- (6-carboxyhexyl) -2-cyclopentenone, by reaction with 2-hydroxy-2-p-tolyletanethiol (obtained from 4-methylbenzaldehyde), 2- (6-carboxyhexyl) -3 - (2-hydroxy-2-p-tolylethylthio) cyclopentanone as an oil.

Infrared spectrum: bands at 1,500, 1,620, 1,700 and 1,735 cm -1, wide bands at 3,500 cm -1

Magnetic Resonance Spectrum: signals at 2.3 ppm (singulet), 2.88 ppm, 4.79 ppm (triplet) and between 7.2 and 7.35 ppm (multiplet);

and by reaction with 2-hydroxy-2-methyl-2-p-tolyl-etantiol (obtainable from 4-methylacetophenone), 2- (6-carboxyhexyl) -3- (2-hydroxy-2-methyl-2-p-tolyl) -ethylthi-o) cyclopentanone as an oil.

Infrared spectrum: bands at 1,500, 1,620, 1,700 and 1,740 cm ^-1 , wide bands at

400 cm ^-1 .

Magnetic Resonance Spectrum: signals at 1.55 ppm (singulet), 2.3 ppm (singulet) and between 7.0 and 7.3 ppm (multiplet).

b) analogously to Example 2, from 2- (6-carboxyhexyl) -4-hydroxy-2-cyclopentenone by reaction with 2-hydroxy-2-methylheptanthiol 2- (6-carboxyhexyl) -3- (2-hydroxy-2-) methyl-heptylthio) -4-hydroxy-cyclopentanone as an oil.

Infrared spectrum: bands at 1,710 and 1,740 cm wide bands at 3,450 cm Magnetic Resonance Spectrum: signals at 0.85 ppm, 1.2 ppm, 2.3 ppm (triplet), 4.2 ppm and 5.8 ppm (multiplet), and a stereoisomer as an oil.

IR spectrum: bands at 1710 and 1740 cm ^-1, a broad band at 3500 cm ^- '.

Magnetic Resonance Spectrum: signals at 0.86 ppm, 1.2 ppm, 2.31 ppm (triplet), 4.2 ppm ** and 5.75 ppm (multiplet);

by treatment with 2-hydroxy-3-methylheptantiol 2- (6-carboxyhexyl) -3- (2-hydroxy-3-methylheptylthio) -4-hydroxy-cyclopentanone as an oil.

- 1 -1

Infrared spectrum: bands at 1,700 and 1,720 cm, wide bands at 3,350 cm.

Magnetic Resonance Spectrum: signals at 0.94 ppm, 3.68 ppm, 4.27 ppm and 5.88 ppm (multiplet); , by reaction with 2-hydroxy-4-ethylheptantiol 2- (6-carboxyhexyl) -3- (2-hydroxy-4-ethylheptylthio) -4-hydroxycyclopentanone as an oil.

IR spectrum: bands at 1720 and 1740 cm ^- ', broad band at 3450 cm ^-'.

Magnetic Resonance Spectrum: signals at 3.9 ppm, 4.29 ppm and 5.86 ppm;

by reaction with 2-hydroxy-2,3-dimethylheptantiol 2- (6-carboxyhexyl) -3- (2-hydroxy-2,3-dimethylheptylthio) -4-hydroxycyclopentanone as an oil.

IR spectrum: bands at 1710 and 1740 cm ^- ', broad band at 3400 cm ^-'.

Magnetic Resonance Spectrum: signals at 0.88 ppm, 0.97 ppm, 1.2 ppm, 4.3 ppm and 6.0 ppm (multiplet);

by reaction with 2-hydroxy-2-methyl-2-p-tolyletanethiol 2- (6-carboxyhexyl) -3- (2-hydroxy-2-methyl-2-p-tolylethylthio) -4-hydroxycyclopentanone as an oil.

IR spectrum: bands at 1510, 1707 and 1740 cm ^- ', broad band at 3400 cm ^-'. Magnetic Resonance Spectrum: signals at 1.6 ppm (singulet), 2.3 ppm (singulet), 4.2 ppm and between 7.1 and 7.5 ppm (multiplet), and the stereoisomer of this compound (as an oil).

IR spectrum: bands at 1506, 1705 and 1740 cm ^- ', broad band at 3420 cm ^-'. Magnetic Resonance Spectrum: signals at 1.6 ppm (singulet), 2.32 ppm (singulet),

J 4.25 ppm and between 7.1 and 7.5 ppm (multiplet);

by reaction with 2-hydroxy-2-p-tolylethanethiol 2- (6-carboxyhexyl) -3- (2-hydroxy-2-p-tolylethylthio) -4-hydroxycyclopentanone as an oil.

«·

IR spectrum: bands at 1710, 1740 and 3400 cm ^- '.

Magnetic Resonance Spectrum: signals at 2.3 ppm, 4.21 ppm and 7.15 to 7.4 ppm;

by reaction with 2-hydroxy-2-methyl-3-phenyl-propantiol 2- (6-carboxyhexyl) -3- (2-hydroxy-2-methyl-3-phenyl-propylthio) -4-hydroxycyclopentanone as an oil;

Infrared spectrum: bands at 1,500, 1,715 and 1,745 om ^-1 , wide breasts at 3,450 cm -1. Magnetic Resonance Spectrum: signals at 1.2 ppm, 2.35 ppm (triplet), 5 ppm (Wide Multiplet) and 7.3 ppm, and the stereoisomer of this compound as an oil.

Infrared spectrum: bands at 1,600, 1,745, 1,750 cm -1, wide bands at 3,400 cm -1. Magnetic Resonance Spectrum: signals at 1.2 ppm, 2.25 ppm (triplet), 4.25 ppm, 5.2 pian (Wide Multiplet) and 7.3 ppm;

by reaction with 2-hydroxy-2-methyl-4-phenylbutantiol 2- (6-carboxyhexyl) -3- (2-hydroxy-2-methyl-4-phenylbutylthio) -4-hydroxycyclopentanone as an oil.

Infrared spectrum: bands at 1,710 and 1,730 cm @ -1, wide bands at 3,400 cm @ -1.

Magnetic Resonance Spectrum: signals at 1.35 ppm, 5.3 ppm and 7.25 ppm.

Example 14 g of 2- (6-carboxyhexyl) -3- (2-hydroxy-2-methyl-2-p-tolylethylthio) -4-hydroxycyclopentanone is dissolved in 50 ml of methanol, 2 drops of water are added, while cooling with ice and stirring 1.5 g of NaBH4 are added over two hours, 50 ml of ice-water are added, acidified with hydrochloric acid, extracted with 3x50 ml of diethyl ether, the combined organic phases are washed with 3x20 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered , the solvent was distilled off and chromatographic purification (silica gel / chloroform / methanol = 9: 1) gave 2- (6-carboxyhexyl) -3- (2-hydroxy-2-methyl-2-p-tolylethylthio) -1,4-cyclopentanediol as oil.

Infrared spectrum: bands at 1,505 and 1,705 cm -1, wide bands at 3,350 cm -1.

Magnetic Resonance Spectrum: signals at 1.23 ppm, 2.3 ppm, 4.21 ppm (quartet), 4.6 ppm (wide multiplet), and between 7.0 and 7.3 ppm.

It is obtained analogously from 2- (6-carboxyhexyl) -3- (2-hydroxy-2-methyl-4-phenylbutylthio) -4-hydroxycyclopentanone by reduction of NaBH4- 2- (6-carboxyhexyl) -3- (2-hydroxy-2). methyl-4-phenylbutylthio) -1,4-cyclopentanediol as an oil.

Infrared spectrum: bands at 1,700 and 3,400 cm -1.

Magnetic Resonance Spectrum: signals at 1.33 ppm, 4.4 ppm and 7.25 ppm and the stereoisomer of this compound as an oil.

Infrared spectrum: bands at 1,700 and 3,400 cm -1.

Magnetic Resonance Spectrum: signals at 1.33 ppm, 5.62 ppm (wide multiplet) and in between

7.12 and 7.30 ppm.

It is obtained analogously from 2- (6-carboxyhexyl) -3- (2-hydroxy-2-methylheptyltlo) -4-hydroxycyclopentanone by reduction of NaBH4- 2- (6-carboxyhexyl) -3- (2-hydroxy-2-methylheptylthio) - 1,4-cyclopentanediol as an oil.

Infrared spectrum: bands at 1,705, 2,680 and 3,340 cm -1.

Magnetic Resonance Spectrum: signals at 0.89 ppm, 1.22 ppm, 2.3 ppm, 4.18 ppm and

5.03 ppm and the stereoisomer as an oil.

Infrared spectrum: bands at 1,705, 2,680 and 3,340 cm -1.

Magnetic Resonance Spectrum: signals at 0.9 ppm, 1.28 ppm, 2.3 ppm, 4.0 ppm,

4.1 ppm and 4.8 ppm.

Example 15

Analogously to Example 2, it is obtained by reaction of 2- (6-carboxyhexyl) -2-cyclopentenone a

3,3-dimethyl-2-hydroxy-4-phenylbutantiol (obtainable from 2- / 2-methyl-3-phenyl-2-propyl oxirane and 2- (6-carboxyhexyl) -3- (3,3-dimethyl) -2-hydroxy-4-phenylbutylthio) cyclopentanone.

Infrared spectrum: bands at 1,710, 1,740 and 3,500 cm -1:

Magnetic Resonance Spectrum: signals at 0.81 ppm, 0.91 ppm, 2.31 ppm, 3.32 ppm and

7.22 ppm.

Example 16

Analogously to Example 13b, 2- (6-carbomethoxyhexyl) -3- (2-hydroxy-2-methyl-) is obtained from 2- (6-carbomethoxyhexyl) -4-hydroxy-2-cyclopentenone by reaction with 2-hydroxy-2-methylheptantiol. heptythio) -4-hydroxycyclopentanone.

IR spectrum: bands at 1740 and 3420 cm ^- '.

Magnetic Resonance Spectrum: signals at 0.86 ppm, 1.21 ppm, 2.25 ppm, 3.61 ppm and

4.22 ppm.

Example 17

Analogously to Example 14, 2- (6-carbomethoxyhexyl) -3- (2-hydroxy-2-methylheptylthio) -4-hydroxycyclopentanone was obtained by reduction of NaBH 4 - (6-carbomethoxyhexyl) -3- (2-hydroxy-2- methylhepylthio) -1,4-cyclopentanediol.

Infrared spectrum: bands at 1,740 and 3,490 cm -1.

Magnetic Resonance Spectrum: signals at 0.90 ppm, 1.22 ppm, 2.31 ppm, 3.61 ppm and

4.18 ppm.

Example 18

Analogously to Example 2, it is obtained from 2- (β-carbomethoxyhexyl) -4 (R) -hydroxy-2-cyclopentenone ([alpha] D = + 16.8 ° (CHCl3)) obtainable by reaction with 2 (R) -aminoxy -4-methylvaleric acid, chromatographic separation of diastereomeric oximes (silicic acid / chloroform: ethanol - 99: 1), oxime cleavage of TiCl 2) by reaction with 2 (S) -hydroxy-2-methylheptylthiol ([alpha] ³ g 3, 3), 8 ° (CH 2 OH), obtainable from 2 (S) -methyl-2-pentyloxirane ([alpha] 1 D ^{= +} 14.5 °, (CH 3 OH) and hydrogen sulfide in the presence of di isopropylamine) 2 (R) - (6-carbomethoxyhexyl) -3 (R) - (2 (E) -hydroxy-2-methylheptylthio) -4 (R) -hydroxy-cyclopentanone [.alpha.] D @ 20 = -64 DEG (CHCl3).

Infrared spectrum: bands at 1175, 1445, 1460, 1740, 2950 and 3420 cm -1.

Magnetic Resonance Spectrum: signals at 0.89 ppm (triplet), 1.25 ppm (singulet),

2.27 ppm (triplet), 3.62 ppm (singulet) and 4.23 ppm;

by reaction with 2 (R) -hydroxy-2-metylheptyltiolem (/ * alpha /? 9 _fi = + 2.8 ° (CH ^ OH) obtainable from 2 (R) PQ Q «°° 3« 5

(2-R) - (6-carbomethoxyhexyl) -3 (R) - (2 (R) -methyl-2-pentyloxirane ([alpha] / gg = -12.6 (CH3 OH)) and hydrogen sulfide in the presence of diisopropylamine) -hydroxy-2-methyl-heptylthio) -4 (R) -hydroxy-cyclopentanone [α] D = -38.7 ° (CHCl 3).

IR spectrum: bands at 1170, 1440, 1460, 1740, 2930 and 3400 cm ^- '.

Magnetic Resonance Spectrum: signals at 0.89 ppm (triplet), 1.27 ppm (singlet), 2.28 ppm (triplet), 3.63 ppm (singlet) and 4.23 ppm.

The following Examples A and B describe the preparation of some of the starting materials used in the process of the invention.

Example A g of a 20% dispersion of sodium hydride in paraffin oil is washed 3 times with 30 ml of dry n-pentane, the solvent is removed, 33 g of trimethylsulfoxonium iodide are added, then 100 ml of dimethylsulfoxide is added dropwise, stirred at room temperature for 20 min. , a solution of 14.2 g of 2-heptanone in 15 ml of dimethylsulfoxide is added dropwise, stirred for another 2 hours, 500 ml of water are added under ice-cooling, extracted 3 times with 250 ml of ether, the combined ether extracts are washed with water, dried with sodium sulfate. distilling off and fractionating the residue gave 2-methyl-2-pentyloxirane as a colorless liquid; mp = 55 ° C (2666 Pa).

Hydrogen sulfide was added to 150 ml of methanol under ice-cooling until a weight gain of 3.2 g was reached, a solution of 370 mg of diethylamine in 11 ml of methanol was added, followed by 4.8 g of 2-methyl-2-pentyloxirane in 18 ml of methanol. Sulfurous gaseous gas was added to the solution for 15 minutes, allowed to stand for 2 hours at room temperature, the solvent was distilled off, the residue was dissolved in 50 ml of petroleum ether (t = 50-70 ° C), washed with water, dried with sodium sulfate, solvent distillation and 2-hydroxy-2-methylheptantiol as a colorless liquid is obtained as a residue, calculated for: 59.2% C, 11.18% H, 19.76%, found: 60.1% C, 11.1, 60.H, 20.20% S.

IR spectrum: bands at 920, 1140, 1380, 1465, 2570 and 3450 cm ^- '.

Magnetic Resonance Spectrum: signals at 0.96 ppm, 1.26 ppm, 2.27 ppm and 2.67 ppm.

Analogously, other 2-hydroxy-2-methyl-R 1 -sulfides of formula (II), in particular in Examples 1 and 2, can also be prepared from the corresponding ketones.

Example B

To a boiling solution of 550 g of 7-bromoenanthonic acid ethyl ester in 6 L of toluene is added 500 g of potassium 2-oxocyclopentanecarboxylic acid potassium salt with stirring, boiling further, after 1 hour 250 g of 2-oxocyclopentanecarboxylic acid ethyl ester are added. The reaction mixture was diluted with 3 L of ether, washed with water, dried over Na 2 SO 4, the solvent was distilled off and the residue was fractionated to give 2-carbethoxy-2- (6-carbethoxyhexyl) -cyclopentanone. as a colorless oil, mp = 165 ° C (40 Pa).

To a solution of 100 g of 2-carbethoxy-2- (6-carbethoxyhexyl) -cyclopentanone in 1 liter of CHCl3 was added dropwise with stirring over 2 hours at 20 DEG C. 48 g of Br2 dissolved in 500 ml of CHCl3, the solvent was distilled off. is dissolved in a mixture of 4 liters of ethanol, 1 kg of H 2 SO 4 (density = 1.84 g / cm 2) and 100 ml of H 2 O, boiled under N 3 for 18 hours, poured on 10 kg of ice after cooling, extracted 3 times with 5 L of ether The combined ether extracts were dried over sodium sulfate, the solvent was distilled off, and after chromatographic purification of the residue (silica gel / petroleum ether: ether = 1: 1), 2- (6-carboethoxyhexyl) -2-cyclopentenone was obtained.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of sulfides of formula I wherein R ₁ represents hydrogen or alkyl with up to 12 carbon atoms, R1 is hydrogen, hydroxyl or acyloxy of up to 4 carbon atoms, R1 represents alkyl of up to 12 carbon atoms, optionally substituted by fluorine, a hydroxyl group full, aoyloxy of up to 4 carbon atoms, phenyl or p-tolyl, A is alkylene of up to 8 carbon atoms, optionally at least once substituted by fluorine, one of Rg and b is hydrogen and the other is hydroxy or acyloxy of up to 4 carbon atoms, or Rg and Rg together are = O and va2ba denoted by - alpha or beta configuration, and their physiologically acceptable salts, characterized in that the compound represented by the general formula I, wherein R 8 and R 8 together together represent an oxygen atom of a carbonyl group, is reacted with a reducing agent and / or the obtained compound of formula I is reacted with an esterifying or solvolysing agent to another compound of formula I, and / or the compound of formula 1 is resolved into its racemates and / or optical antipodes, and / or the compound of formula 1 is converted into a physiologically acceptable salt by treatment with base; from salt.