EP0000506A2 - Substituted phenyl O- or S- etherified cycloalkanols, a process for their preparation and their application as hypolipidemia, their esters with cyclopropanecarboxylic acids and the application of these esters as insecticides - Google Patents
Substituted phenyl O- or S- etherified cycloalkanols, a process for their preparation and their application as hypolipidemia, their esters with cyclopropanecarboxylic acids and the application of these esters as insecticides Download PDFInfo
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- EP0000506A2 EP0000506A2 EP78100374A EP78100374A EP0000506A2 EP 0000506 A2 EP0000506 A2 EP 0000506A2 EP 78100374 A EP78100374 A EP 78100374A EP 78100374 A EP78100374 A EP 78100374A EP 0000506 A2 EP0000506 A2 EP 0000506A2
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- phenoxy
- oxygen
- etherified
- cycloalkanols
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N53/00—Biocides, pest repellants or attractants, or plant growth regulators containing cyclopropane carboxylic acids or derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
Definitions
- the invention relates to new etherified cycloalkanols, in particular those of the formula (I) in which X 1 is oxygen, sulfur or methylene, X 2 oxygen or sulfur, A is an optionally substituted phenyl radical and n is an integer from 1 to 10, and processes for their preparation, and also pharmaceutical preparations containing these compounds and their use preferably in the form of pharmaceutical preparations.
- radicals and compounds designated "lower" in connection with the present description preferably contain up to and with 7 and primarily up to and with 4 carbon atoms.
- a substituted phenyl radical A is a mono-, di- or poly-substituted phenyl radical.
- the following may be mentioned in particular as substituents: halogen to atomic number 35, lower alkyl, lower alkoxy or trifluoromethyl.
- Halogen represents fluorine or bromine, but preferably chlorine.
- X 2 and the hydroxyl group are preferably trans to one another.
- the new compounds have valuable pharmacological properties. So they cause a reduction in lipid content in the - serum, as for example on the male rat, which in each case mg, a dose of 10 to 200 for 3 days / kg of the test substances and at 4 days two such doses is obtained and subsequently determining the cholesterol and Triglyceride concentration in the serum, can be shown. They can thus be used as hypolipidaemics for the treatment of lipid metabolism disorders.
- cyclopropanecarboxylic acid esters which are suitable for combating various animal and vegetable pests, in particular for combating representatives of the Akarina family: Ixodidae, Argasidae, Tetranychidae, Dermanyssidae and insects of the families : Acrididae, Blattidae, Gryllidae, Gryllotalpidae, Tettigoniidae, Cimicidae, Pyrrhocoridae, Reduviidae, Aphididae, Delphaci- dae, Diaphididae, Pseudococcidae, Chrysomilidae, Coccinellidae, Bruchidae, Scarabaide, Noir , Culicidae, Tipulidae, Stomoxydae, Muscidae, Calliphoridae, Trypertidae or Pul
- the invention relates to 1- (4-phenoxy-phenoxy) cyclopentan-2-ol.
- the invention also preferably relates to the compounds of the formula where R is hydrogen or chlorine and n represents the integers 3, 4 or 5 or the compounds of the formula wherein R represents hydrogen or chlorine and n represents the integers 3, 4 or 5.
- the invention particularly relates to the new compounds described in the examples.
- the new compounds are obtained in a manner known per se; for example, a compound of formula (IV) or a salt thereof, with a compound of formula (V) or represent a carbonyldioxy group of the formula -OC. (0) 0-, and split off any protective group which may be present in the compounds obtained, and, if desired, separate an isomer mixture obtainable according to the process into the individual isomers.
- Salts of compounds of formula (IV) are primarily metal, especially alkali metal e.g. Sodium or potassium salts, which are usually prepared in situ.
- a reactive esterified hydroxyl group is in particular one which is esterified with a strong acid, such as a strong inorganic or organic acid.
- a strong acid such as a strong inorganic or organic acid.
- Particularly strong inorganic acids are hydrohalic acids, such as hydrochloric or hydrobromic acid, or sulfuric acid, and organic acids, primarily sulfonic acids, such as a benzenesulfonic acid optionally substituted by halogen, lower alkyl or lower alkoxy; e.g. p-toluenesulfonic acid or p-methoxybenzenesulfonic acid, or an alkanesulfonic acid e.g. Methane or ethanesulfonic acid.
- a protected hydroxy group is especially an esterified hydroxy group, e.g. an acyloxy group such as a lower alkanoyloxy, e.g. Acetoxy or a benzoyloxy group or an etherified hydroxy group, e.g. a tetrahydropyranyloxy or an aralkoxy group such as the benzyloxy group.
- an esterified hydroxy group e.g. an acyloxy group such as a lower alkanoyloxy, e.g. Acetoxy or a benzoyloxy group or an etherified hydroxy group, e.g. a tetrahydropyranyloxy or an aralkoxy group such as the benzyloxy group.
- the reaction is carried out in a manner known per se. It is preferably carried out in the presence of a base, in particular an inorganic base, such as an alkali or alkaline earth metal hydroxide, carbonate or hydride, for example sodium or potassium hydroxide, hydride or carbonate or an organic base, such as piperidine, pyridine, Quinoline or a tri-lower alkylamine, e.g. Trimethylamine, triethylamine or dimethylisopropylamine.
- a carbodiimide such as dicyclohexylcarbodiimide in the presence of copper chloride. It can work in an inert solvent such as acetone or dimethyl sulfoxide.
- the reaction can also be carried out in a high-boiling solvent such as xylene, toluene or quinoline at an elevated temperature, for example 80-200 °, or in the absence of a solvent.
- a protected hydroxy group can be used in a manner known per se, e.g. set free by hydrolysis or hydrogenolysis.
- the starting materials to be used for this reaction are known or can be obtained in a manner known per se.
- the new compounds can, however, also be obtained if a compound of the formula (VI) the keto group is reduced to the carbinol group in a manner known per se and, if desired, a mixture of isomers obtainable according to the process is separated into the individual isomers.
- the reduction can usually be e.g. with catalytically activated hydrogen, e.g. in the presence of Raney nickel or a palladium catalyst such as Pd / C or with metal hydrides such as sodium borohydride, lithium aluminum hydride or diborane, in the presence of an inert solvent such as water, alcohols e.g. Carry out methanol or ethanol, or ethers such as diethyl ether or tetrahydrofuran.
- catalytically activated hydrogen e.g. in the presence of Raney nickel or a palladium catalyst such as Pd / C or with metal hydrides such as sodium borohydride, lithium aluminum hydride or diborane
- an inert solvent such as water, alcohols e.g. Carry out methanol or ethanol, or ethers such as diethyl ether or tetrahydrofuran.
- the starting material used in this process method is obtained in a manner known per se, e.g. by reacting a keto-cycloalkanol or a reactive ester thereof with a compound of formula IV in the manner shown above, or by reacting a compound of formula IV with a reactive ester of 3-hydroxy-cycloalkene and subsequent oxidation of the double bond, e.g. with mercury II nitrate or acetate in water, or a peracid such as peracetic acid.
- the starting material of formula (VI) thus obtained can, if desired, be reduced without isolation.
- the new compounds can be present as isomer mixtures, such as racemates or diastereoisomer mixtures, or in the form of the pure isomers, such as the optically active components.
- the separation of isomer mixtures obtained into the individual isomers can be carried out by known methods. Mixtures of diastereoisomers can be e.g. due to physico-chemical differences, such as those of solubility, e.g. by fractional crystallization or distillation, or by chromatography into the individual isomers.
- Racemates can be obtained, for example, by esterifying the alcohol racemate with an optically active acid, for example optically active camphorsulfonic acid, separating the ester / diastereoisomer mixture thus obtainable and saponifying the ester, or by esterifying the alcohol racemate with a dicarboxylic acid, only one carboxyl group being esterified, Forming a salt of the monoester acid racemate thus obtainable with a suitable optically active base, for example optically active brucine, a-phenylethylamine or ephedrine, splitting the salt diastereoisomer
- an optically active acid for example optically active camphorsulfonic acid
- separating the ester / diastereoisomer mixture thus obtainable and saponifying the ester
- a dicarboxylic acid only one carboxyl group being esterified
- Forming a salt of the monoester acid racemate thus obtainable with a suitable optically active base, for example optically active
- the invention also relates to those embodiments of the process in which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing process steps, or terminates the process at any stage, or forms a starting material under the reaction conditions or in the form of a reactive one Derivative or salt used.
- the starting materials used are preferably those which, according to the process, lead to the compounds described above as being particularly valuable.
- the present invention also relates to pharmaceutical preparations which contain compounds of the formula I.
- the pharmaceutical preparations according to the invention are those for enteral, such as oral or rectal, and parenteral administration to warm-blooded animals which use the pharmacological active ingredient alone or together with a pharmaceutically applicable agent - Contain their carrier material.
- the dosage of the active ingredient depends on the WarmblUter species, the age and the individual condition, as well as on the mode of administration.
- Suitable carriers are, in particular, fillers, such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, and also binders, such as starch paste using, for example, corn, wheat, rice or potato starch, gelatin , Tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulope and / or polyvinyl pyrrolidone, and / or if desired.
- fillers such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate
- binders such as starch paste using, for example, corn, wheat, rice or potato starch, gelatin , Tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxy
- Disintegrants such as the above-mentioned starches, carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.
- Auxiliaries are primarily flow regulators and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol.
- Dragee kernels are provided with suitable, if appropriate gastric juice-resistant, coatings, including concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrodidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic see solvents or solvent mixtures Production of gastric juice-resistant surges, solutions of suitable cellulose preparations, such as acetyl cellulose or hydroxypropyl methyl cellulose phthalate. Dyes or pigments can be added to the tablets or dragée coatings, for example for identification or for labeling different doses of active ingredient.
- the pharmaceutical preparations containing from about 0.1% to 100%, in particular from about 1% to about 50% of the active ingredient.
- the single dose for a warm-blooded animal weighing approximately 70 kg is between 0.1 and 0.75 g, the daily dose between 0.2 and 1 g
- the invention also relates to new cyclopropane carboxylic acid esters of the formula (VII) R 1 wherein A, X 1 , X 2 and n have the meaning given above and R 1 , R 2 , R 3 and R 4 each represent hydrogen, methyl or chlorine, their preparation and their use in pest control.
- esters are suitable for combating various types of animal and vegetable pests.
- the compounds of the formula VII are prepared by methods known per se, for example as follows: Hal stands for halogen, especially for chlorine or bromine.
- tertiary amines such as trialkylamines, e.g. Ethyl diiscpropylamine; Pyridine; Dialkylanilines; also inorganic bases, such as hydrides, hydroxides, alkoxides and carbonates of alkali and alkaline earth metals.
- the process is generally carried out at a temperature of about 10 ° C. to 100 ° C., with acid halides mostly at 0 ° C. to 30 ° C. and with acid anhydrides mostly at 70 ° C. to 100 ° C., under normal pressure and in an inert solution -or diluents performed.
- Suitable solvents or diluents are e.g. Benzene, toluene, xylene; Paraffin hydrocarbons such as hexane or heptane; Ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane; also esters, such as ethyl acetate.
- insecticidal effect can be broadened considerably by adding other insecticides and / or acaricides and can be adapted to the given circumstances.
- the compounds of formula VII can be used alone or together with suitable carriers and / or additives.
- suitable carriers and additives can be solid or liquid and correspond to the substances commonly used in formulation technology, e.g. natural or regenerated substances, solvents, dispersants, wetting agents, adhesives, thickeners, binders and / or fertilizers.
- the compounds of the formula VII can be processed with dusts, emulsion concentrates, granules, dispersions, sprays, into solutions or slurries in customary formulations which are common knowledge in application technology.
- Agents according to the invention are prepared in a manner known per se by intimately mixing and / or grinding active ingredients of the formula VII with the suitable carriers, optionally with the addition of dispersing agents or solvents which are inert to the active ingredients.
- the active ingredients can be present and used in the following processing forms.
- the content of active ingredients in the agents described above is between 0.1 to 95% by weight.
- the 2- (4-phenoxy-phenoxy) -cyclohexan-l-ol is obtained in an analogous manner, which melts at 62-65 ° after recrystallization from hexane and the 2- (4-benzylphenoxy) -cyclohexan-l-ol that after recrystallization from isopropanol melts at 78-80 °.
- a solution of 12.6 g of 3- (4-phenoxyphenoxy) cyclopent-l-ene in 25 ml is added dropwise to a mixture of 15.9 g of mercury (II) acetate, 35 ml of water and 50 ml of tetrahydrofuran over the course of an hour Tetra.hydrofuran and stirred for about 15 hours at room temperature.
- 50 ml of 3N sodium hydroxide solution are added dropwise within 1 1/2 hours and then 50 ml of a 0.5N solution of sodium borohydride in 3N sodium hydroxide solution within 1 hour.
- the reaction mixture is stirred for 2 hours at room temperature and filtered off from the precipitated mercury. It is poured. Filtrate on ice water, extracted with ether, the organic phase washed with saturated sodium chloride solution, dry
- the compound of formula IV is obtained with a refraction of n 20 D : 1.5542.
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Abstract
Verätherte Cycloalkanole der Formel <IMAGE> worin X1 Sauerstoff, Schwefel oder Methylen, X2 Sauerstoff oder Schwefel, A einen gegebenenfalls substituierten Phenylrest und n eine ganze Zahl von 1 bis und mit 10 darstellen sowie Verfahren zu deren Herstellung. Diese Verbindungen, insbesondere das 2-(4-Phenoxy-phenoxy)-cyclopentan-1-ol, besitzen eine Lipidsenkende Wirksamkeit. Ferner sind sie Zwischenprodukte zur Herstellung der insektiziden Cyclopropansäureester der Formel <IMAGE> worin A, X1, X2, und n die oben gegebene Bedeutung besitzen und R¹, R², R³ und R<4> je Wasserstoff, Methyl oder Chlor bedeuten.Etherified cycloalkanols of the formula <IMAGE> in which X1 is oxygen, sulfur or methylene, X2 oxygen or sulfur, A is an optionally substituted phenyl radical and n is an integer from 1 to 10 and methods for their preparation. These compounds, especially 2- (4-phenoxy-phenoxy) -cyclopentan-1-ol, have a lipid-lowering activity. Furthermore, they are intermediates for the preparation of the insecticidal cyclopropanoic acid esters of the formula <IMAGE> in which A, X1, X2, and n have the meaning given above and R¹, R², R³ and R <4> are each hydrogen, methyl or chlorine.
Description
Die Erfindung betrifft neue verätherte Cycloalkanole, insbesondere solche der Formel (I) -
Die im Zusammenhang mit der vorliegenden Beschreibung mit "nieder" bezeichneten Reste und Verbindungen enthalten vorzugsweise bis und mit 7 und in erster Linie bis und mit 4 Kohlenstoffatome.The radicals and compounds designated "lower" in connection with the present description preferably contain up to and with 7 and primarily up to and with 4 carbon atoms.
Ein substituierter Phenylrest A ist ein mono-, di- oder polysuLstituierter Phenylrest. Als Substituenten seien insbesondere genannt: Halogen bis eihschliesslich Atomnummer 35, Niederalkyl, Niederalkoxy oder Trifluormethyl.A substituted phenyl radical A is a mono-, di- or poly-substituted phenyl radical. The following may be mentioned in particular as substituents: halogen to atomic number 35, lower alkyl, lower alkoxy or trifluoromethyl.
Die Allgemeinbegriffe können folgende Bedeutung haben:
- Niederalkyl ist z.B. n-Propyl Isopropyl, n-Butyl, Isobutyl, sek.-Butyl, tert.-Butyl, n-Pentyl, Isopentyl,.n-Hexyl, Isohexyl oder n-Heptyl, aber vor allem Methyl oder Aethyl.
- Niederalkoxy ist z.B. n-Propoxy', Isopropoxy oder n-Butyloxy, besonders aber Methoxy oder Aethoxy.
- Lower alkyl is, for example, n-propyl isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, .n-hexyl, isohexyl or n-heptyl, but especially methyl or ethyl.
- Lower alkoxy is, for example, n-propoxy ', isopropoxy or n-butyloxy, but especially methoxy or ethoxy.
Halogen steht fUr Fluor oder Brom, vorzugsweise jedoch fUr Chlor.Halogen represents fluorine or bromine, but preferably chlorine.
Vorzugsweise stehen X2 und die Hydroxygruppe in trans-Stellung zu einander.X 2 and the hydroxyl group are preferably trans to one another.
Die neuen Verbindungen besitzen wertvolle pharmakologische Eigenschaften. So bewirken sie eine Senkung des Lipidgehaltes im-Serum, wie das z.B. an der männlichen Ratte, welche während 3 Tagen jeweils eine Dosis von 10 bis 200 mg/kg der Testsubstanzen und am 4 Tage zwei solche Dosen erhält und anschliessend Bestimmung der Cholesterin-und Triglycerid-Konzentration im Serum, gezeigt werden kann. Sie können somit als Hypolipidaemika zur Behandlung von Lipidstoffwechselstörungen verwendet werden.The new compounds have valuable pharmacological properties. So they cause a reduction in lipid content in the - serum, as for example on the male rat, which in each case mg, a dose of 10 to 200 for 3 days / kg of the test substances and at 4 days two such doses is obtained and subsequently determining the cholesterol and Triglyceride concentration in the serum, can be shown. They can thus be used as hypolipidaemics for the treatment of lipid metabolism disorders.
Sie können aber auch als Zwischenprodukte dienen, insbesondere zur Herstellung von Cyclopropancarbonsäureestern, welche sich zur Bekämpfung von verschiedenartigen tierischen und pflanzlichen Schädlingen, insbesondere.zur Bekämpfung von Vertretern der Ordnung Akarina der Familien: Ixodidae, Argasidae, Tetranychidae, Dermanyssidae, sowie von Insekten der Familien: Acrididae, Blattidae, Gryllidae, Gryllotalpidae, Tettigoniidae, Cimicidae, Pyrrhocoridae, Reduviidae, Aphididae, Delphaci- dae, Diaphididae, Pseudococcidae, Chrysomilidae, Coccinellidae, Bruchidae, Scarabaidae, Dermestidae, Tenebrionidae, Curculionidae, Tincidae, Noctuidae, Lymantriidae, Pyralidae, Galleridae, Culicidae, Tipulidae, Stomoxydae, Muscidae, Calliphoridae, Trypertidae oder Pulicidae.
In allererster Linie betrifft die Erfindung das 1-(4-Phenoxy-phenoxy)-cyclopentan-2-ol.First and foremost, the invention relates to 1- (4-phenoxy-phenoxy) cyclopentan-2-ol.
Die Erfindung betrifft auch vorzugsweise die Ver--bindungen der Formel
Die Erfindung begrifft ganz besonders die in den Beispielen beschriebenen, neuen Verbindungen.The invention particularly relates to the new compounds described in the examples.
Die neuen Verbindungen werden in an sich bekannter Weise erhalten; so kann man z.B. eine Verbindung der Formel (IV)
Salze von Verbindungen der Formel (IV) sind in erster Linie Metall-, insbesondere Alkalimetall- z.B. Natrium- oder Kaliumsalze, die Ublicherweise in situ hergestellt werden.Salts of compounds of formula (IV) are primarily metal, especially alkali metal e.g. Sodium or potassium salts, which are usually prepared in situ.
Eine reaktionsfähig veresterte Hydroxygruppe ist insbesondere eine solche die mit einer starken Säure, wie einer starken anorganischen oder organischen Säure verestert ist. Als starke anorganische Säuren seien insbesondere Halogenwasserstoffsäuren, wie Chlor-oder Bromwasserstoffsäure, oder Schwefelsäure genannt und als organische Säuren, in erster Linie Sulfonsäuren, wie eine gegebenenfalls durch Halogen, Niederalkyl oder Niederalkoxy substituierte Benzolsulfonsäure; z.B, p-Toluolsulfonsäure oder p-Methoxybenzolsulfonsäure, oder eine Alkansulfonsäure, z.B. Methan- oder Aethansulfonsäure.A reactive esterified hydroxyl group is in particular one which is esterified with a strong acid, such as a strong inorganic or organic acid. Particularly strong inorganic acids are hydrohalic acids, such as hydrochloric or hydrobromic acid, or sulfuric acid, and organic acids, primarily sulfonic acids, such as a benzenesulfonic acid optionally substituted by halogen, lower alkyl or lower alkoxy; e.g. p-toluenesulfonic acid or p-methoxybenzenesulfonic acid, or an alkanesulfonic acid e.g. Methane or ethanesulfonic acid.
Eine geschützte Hydroxygruppe ist insbesondere eine veresterte Hydroxygruppe, z.B. eine Acyloxygruppe, wie eine Niederalkanoyloxy-, z.B. Acetoxy- oder eine Benzoyloxygruppe oder eine verätherte Hydroxygruppe, z.B. eine Tetrahydropyranyloxy- oder eine Aralkoxygruppe, wie die Benzyloxygruppe.A protected hydroxy group is especially an esterified hydroxy group, e.g. an acyloxy group such as a lower alkanoyloxy, e.g. Acetoxy or a benzoyloxy group or an etherified hydroxy group, e.g. a tetrahydropyranyloxy or an aralkoxy group such as the benzyloxy group.
Die Reaktion wird in an sich bekannter Weise vor- genommen. Dabei arbeitet man vorzugsweise in Gegenwart einer Base, insbesondere einer anorganischen Base, we einem Alkali- oder Erdalkali-hydroxyd, -carbonat oder -hydrid, z.B. Natrium- oder Kaliumhydroxyd, -hydrid oder -carbonat oder einer organischen Base, wie Piperidin, Pyridin, Chinolin oder einem Triniederalkylamin, z,B. Trimethylamin, Triäthylamin oder Dimethylisopropylamin. Man kann sie aber auch in Gegenwart eines Carbodiimids, wie Dicyclohexylcarbodiimid in Gegenwart von Kupferchlorid, durchführen. Dabei kann in einem inerten Lösungsmittel, wie Aceton oder Dimethylsulfoxyd arbeiten. Die Reaktion kann aber auch in einem hoher siedenden Lösungsmittel, wie Xylol, Toluol oder Chinolin bei erhöhter Temperatur, z.B. 80-200°, oder in Abwesenheit eines Lösungsmittels erfolgen.The reaction is carried out in a manner known per se. It is preferably carried out in the presence of a base, in particular an inorganic base, such as an alkali or alkaline earth metal hydroxide, carbonate or hydride, for example sodium or potassium hydroxide, hydride or carbonate or an organic base, such as piperidine, pyridine, Quinoline or a tri-lower alkylamine, e.g. Trimethylamine, triethylamine or dimethylisopropylamine. But you can also in the presence of a carbodiimide such as dicyclohexylcarbodiimide in the presence of copper chloride. It can work in an inert solvent such as acetone or dimethyl sulfoxide. However, the reaction can also be carried out in a high-boiling solvent such as xylene, toluene or quinoline at an elevated temperature, for example 80-200 °, or in the absence of a solvent.
Eine geschützte Hydroxygruppe lässt sich in an sich bekannter Weise, z.B. durch Hydrolyse oder Hydrogenolyse in Freiheit setzen.A protected hydroxy group can be used in a manner known per se, e.g. set free by hydrolysis or hydrogenolysis.
Die zu dieser Reaktion zu verwendenden Ausgangsstoffe sind bekannt, oder lassen sich auf an sich bekannte Weise erhalten.The starting materials to be used for this reaction are known or can be obtained in a manner known per se.
Die neuen Verbindungen lassen sich aber auch erhalten, wenn man in einer Verbindung der Formel (VI)
Die Reduktion lässt sich in Ublicher Weise z.B. mit katalytisch aktiviertem Wasserstoff, z.B. in Gegenwart von Raney-Nickel oder eines Palladiumkatalysators wie Pd/C oder mit Metallhydriden, wie Natriumborhydrid, Lithiumaluminiumhydrid oder Diboran, in Gegenwart eines inerten Lösungsmittels, wie Wasser, Alkoholen, z.B. Methanol oder .Aethanol, oder Aethern, wie Diäthyläther oder Tetrahydrofuran durchfUhren.The reduction can usually be e.g. with catalytically activated hydrogen, e.g. in the presence of Raney nickel or a palladium catalyst such as Pd / C or with metal hydrides such as sodium borohydride, lithium aluminum hydride or diborane, in the presence of an inert solvent such as water, alcohols e.g. Carry out methanol or ethanol, or ethers such as diethyl ether or tetrahydrofuran.
Das in dieser Verfahrensmethode verwendete Ausgangsmaterial wird in an sich bekannter Weise erhalten, z.B. durch Umsetzen eines Keto-cycloalkanols oder eines reaktionsfähigen Esters davon mit einer Verbindung der Formel IV in der oben gezeigten Art, oder durch Umsetzen einer Verbindung der Formel IV mit einem reaktionsfähigen Ester eines 3-Hydroxy-cycloalkens und anschliessender Oxydation der Doppelbindung, z.B. mit Quecksilber-II-nitrat oder acetat in Wasser, oder einer Persäure wie Peressigsäure. Das so erhaltene Ausgangsmaterial der Formel (VI) lässt sich, wenn erwünscht, ohne Isolierung reduzieren.The starting material used in this process method is obtained in a manner known per se, e.g. by reacting a keto-cycloalkanol or a reactive ester thereof with a compound of formula IV in the manner shown above, or by reacting a compound of formula IV with a reactive ester of 3-hydroxy-cycloalkene and subsequent oxidation of the double bond, e.g. with mercury II nitrate or acetate in water, or a peracid such as peracetic acid. The starting material of formula (VI) thus obtained can, if desired, be reduced without isolation.
Die neuen Verbindungen können als Isomerengemische, wie Racemate oder Diastereoisomerengemische, oder in Form der reinen Isomeren, wie der optisch aktiven Komponenten, vorliegen. Die Auftrennung von erhaltenen Isomerengemischen in die individuellen Isomeren kann nach bekannten Methoden geschehen. Diastereoisomerengemische lassen sich z.B. auf Grund physikalisch-chemischer Unterschiede, wie solchen der Löslichkeit, z.B. durch fraktioniertes Kristallisieren oder Destillieren, oder durch Chromatographie in die einzelnen Isomeren auftrennen.The new compounds can be present as isomer mixtures, such as racemates or diastereoisomer mixtures, or in the form of the pure isomers, such as the optically active components. The separation of isomer mixtures obtained into the individual isomers can be carried out by known methods. Mixtures of diastereoisomers can be e.g. due to physico-chemical differences, such as those of solubility, e.g. by fractional crystallization or distillation, or by chromatography into the individual isomers.
Racemate kann man z.B. durch Verestern des Alkohol-racemates mit einer optisch aktiven Säure, z.B. optisch aktiver Camphersulfonsäure, Trennen des so erhältlichen Ester-Diastereoisomerengemisches und Verseifen des Esters oder durch Verestern des Alkohol-racemates mit einer Dicarbonsäure, wobei nur eine Carboxylgruppe verestert wird, Bilden eines Salzes des so erhältlichen Monoester-säureracemates mit einer geeigneten optisch aktiven Base, z.B. optisch aktives Brucin, a-Phenyläthylamin oder Ephedrin, Aufspalten des so erhältlichen Salz-Diastereoisomerenge- Racemates can be obtained, for example, by esterifying the alcohol racemate with an optically active acid, for example optically active camphorsulfonic acid, separating the ester / diastereoisomer mixture thus obtainable and saponifying the ester, or by esterifying the alcohol racemate with a dicarboxylic acid, only one carboxyl group being esterified, Forming a salt of the monoester acid racemate thus obtainable with a suitable optically active base, for example optically active brucine, a-phenylethylamine or ephedrine, splitting the salt diastereoisomer
Die oben beschriebenen Verfahren werden nach an sich bekannten Methoden durchgeführt, in Abwesenheit oder vorzugsweise in Anwesenheit von VerdUnnungs- oder Lösungsmitteln, wenn notwendig, unter Kühlen oder Erwärmen, unter erhöhtem Druck und/oder in einer Inertgas-, wie Stickstoffatmosphäre..The processes described above are carried out according to methods known per se, in the absence or preferably in the presence of diluents or solvents, if necessary, with cooling or heating, under elevated pressure and / or in an inert gas, such as nitrogen atmosphere.
Die Erfindung betrifft auch diejenigen Ausführungsformen des Verfahrens, bei denen man von einer auf irgendeiner Stufe des Verfahrens als Zwischenprodukt erhältlichen Verbindung ausgeht und die fehlenden Verfahrensschritte durchfuhrt, oder das Verfahren auf irgendeiner Stufe abbrichc, oder einen Ausgangsstoff unter den Reaktionsbedingungen bildet oder in Form eines reaktionsfähigen Derivats oder Salzes verwendet. Dabei geht man vorzugsweise von solchen Ausgangsstoffen aus, die Verfahrensgemäss zu den oben als besonders wertvoll beschriebenen Verbindungen führen.The invention also relates to those embodiments of the process in which one starts from a compound obtainable as an intermediate at any stage of the process and carries out the missing process steps, or terminates the process at any stage, or forms a starting material under the reaction conditions or in the form of a reactive one Derivative or salt used. The starting materials used are preferably those which, according to the process, lead to the compounds described above as being particularly valuable.
Die vorliegende Erfindung betrifft ebenfalls pharmazeutische präprate, welche Verbindungen der Formel l enthalten, Bei den erfindungsgemässen pharmazeutischen Präparaten handelt es sich um solche zur enteralen, wie oralen oder rektalen, sowie parenteralen Verabreichung an Warmblüter, welche den pharmakologischen Wirkstoff allein oder zusammen mit einem pharmazeutisch anwendba- ren Trägermaterial enthalten. Die Dosierung des Wirkstoffes hängt von der WarmblUter-Spezies, dem Alter und dem individuellen Zustand, sowie von der Applikationsweise ab.The present invention also relates to pharmaceutical preparations which contain compounds of the formula I. The pharmaceutical preparations according to the invention are those for enteral, such as oral or rectal, and parenteral administration to warm-blooded animals which use the pharmacological active ingredient alone or together with a pharmaceutically applicable agent - Contain their carrier material. The dosage of the active ingredient depends on the WarmblUter species, the age and the individual condition, as well as on the mode of administration.
Geeignate Trägerstoffen sind insbesondere FUllstoffe, wie Zucker, z.B. Lactose, Saccharose, Mannit oder Sorbit, Cellulosepräparate und/oder Calciumphosphate, z.B. Tricalciumphosphat oder Calciumhydrogenphosphat, ferner Bindemittel, wie Stärkekleister unter Verwendung z.B. von Mais-, Weizen-, Reis- oder Kartoffelstärke, Gelatine, Traganth, Methylcellulose, Hydroxypropyl-methylcellulose, Natriumcarboxymethylcellulope und/oder Polyvinylpyrrolidon, und/oder, wenn erwünscht. Sprengmittel, wie die obgenannten Starken, ferner Carboxymethylstärke, quervernetztes Polyvinyipyrrolidon, Agar, Alginsäure oder ein Salz davon, wie Natriumalginat. Hilfsmittel sind in erster Linie Fliessregulier- und Schmiermittel, z.B. Kieselsäure, Talk, Stearinsäure oder Salze davon, wie Magnesium- oder Calciumstearat, und/oder Polyäthyienglykol. Dragee-Kerne werden mit geeigneten, gegebenenfalls Magensaft-resistenten UeberzUgen versehen, wobei man u.a. konzentrierte zuckerlösungen, welche gegebenenfalls arabischen Gummi, Talk, Polyvinylpyrrodidon, Polyäthylenglycol und/oder Titandioxid enthalten, Lacklösungen in geeigneten organisehen Lösungsmitteln oder LösungsmittelgemischenHerstellung von Magensaft-resistenten UebersUgen, Lösungen von geeigneten Cellulosepräparaten, wie Acetylcellulo- sephthalat oder Hydroxypropylmethylcellulosephthalat, verwendet. Den Tabletten oder Dragée-Ueberzügen können Farbstoffe oder Pigmente, z.B. zur Identifizierung oder zur Kennzeichnung verschiedener Wirkstoffdosen, beigefügt werden.Suitable carriers are, in particular, fillers, such as sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, and also binders, such as starch paste using, for example, corn, wheat, rice or potato starch, gelatin , Tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulope and / or polyvinyl pyrrolidone, and / or if desired. Disintegrants such as the above-mentioned starches, carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily flow regulators and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee kernels are provided with suitable, if appropriate gastric juice-resistant, coatings, including concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrodidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic see solvents or solvent mixtures Production of gastric juice-resistant surges, solutions of suitable cellulose preparations, such as acetyl cellulose or hydroxypropyl methyl cellulose phthalate. Dyes or pigments can be added to the tablets or dragée coatings, for example for identification or for labeling different doses of active ingredient.
Die pharmazeutischen Präparate enthaltend von etwa 0,1 % bis 100%, inbesondere von etwa 1% bis etwa 50 % des Aktivstoffes. Die Einzeldosis für einen Warmblüter von etwa 70 kg Gewicht beträgt zwischen 0,1 und 0,75 g, die Tagesdosis zwischen 0,2 und 1 gThe pharmaceutical preparations containing from about 0.1% to 100%, in particular from about 1% to about 50% of the active ingredient. The single dose for a warm-blooded animal weighing approximately 70 kg is between 0.1 and 0.75 g, the daily dose between 0.2 and 1 g
Die Erfindung betrifft auch neue Cyclopropancarbonsäureester der Formel (VII) R1
Wegen ihrer Wirkung bevorzugt man Verbindungen der Formel VII,worin A Phenyl, X1 und X2 Sauerstoff bedeuten. Weiterhin bevorzugt sind Verbindungen der Formel VII, worin R1, R2, R3 und R4 entweder Wasserstoff oder Methyl bedeüten. Hervorzuheben sind ferner Verbindung der Formel VII worin R1und R2 Chlor und R3 und R4 Methyl bedeuten.Because of their action, preference is given to compounds of the formula VII in which A is phenyl, X 1 and X 2 are oxygen. Also preferred are compounds of formula VII, wherein R 1 , R 2 , R 3 and R 4 mean either hydrogen or methyl. Also to be emphasized are compounds of the formula VII in which R 1 and R 2 are chlorine and R 3 and R 4 are methyl.
Wie uben bereits bemerkt eignen sich diese Ester assgozeichnet zur Bekämpfung von verschiedenartigen tierischer- und pflanzlichen Schädlingen.As already noted, these esters are suitable for combating various types of animal and vegetable pests.
Die Verbindungen der Formel VII werden nach an sich bekannten Methoden, z.B. wie folgt hergestellt:
Als basische Säureacceptoren kommen z.B. in Frage: tertiäre Amine, wie Trialkylamine, z.B. Aethyl-diiscpropylamin; Pyridin; Dialkylaniline; ferner anorganische Basen,wie Hydride, Hydroxide, Alkoxide und Karbonate von Alkali- und Erdalkalimetallen.As basic acid acceptors come e.g. in question: tertiary amines, such as trialkylamines, e.g. Ethyl diiscpropylamine; Pyridine; Dialkylanilines; also inorganic bases, such as hydrides, hydroxides, alkoxides and carbonates of alkali and alkaline earth metals.
Das Verfahren wird im allgemeinen bei einer Tamperatur von etwa 10°C bis 100°C, mit Säurehalogeniden meist bei 0°C bis 30°C und mit Säureanhydriden meist bei 70°C bis 100°C, bei normalem Druck und in einem inerten Lösungs-oder Verdünnungsmittel durchgeführt. Als Lösungs- oder Verdünnungsmittel eignen sich z.B. Benzol, Toluol, Xylol; Paraffinkohlenwasserstoffe wie Hexan oder Heptan; Aether wie Diäthyläther, Tetrahydrcfuran, Dioxan, Dimethoxyäthan; ferner Ester, wie Essigsäureäthylester.The process is generally carried out at a temperature of about 10 ° C. to 100 ° C., with acid halides mostly at 0 ° C. to 30 ° C. and with acid anhydrides mostly at 70 ° C. to 100 ° C., under normal pressure and in an inert solution -or diluents performed. Suitable solvents or diluents are e.g. Benzene, toluene, xylene; Paraffin hydrocarbons such as hexane or heptane; Ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane; also esters, such as ethyl acetate.
Die insektizide Wirkung lässt sich durch Zusatz von anderen Insektiziden und/oder Akariziden wesentlich verbreitern und an gegebene Umstände anpassan.The insecticidal effect can be broadened considerably by adding other insecticides and / or acaricides and can be adapted to the given circumstances.
Als Zusätze eignen sich z.B.:
- - organische Phosphorverbindungen,
- - Nitrophenole und Derivate,
- - Formamidine, Harnstoffe, Carbamate,
- - Chrysanthemumsäure-Derivate oder
- - chlorierte Kohlenwasserstoffreste.
- - organic phosphorus compounds,
- - nitrophenols and derivatives,
- - formamidines, ureas, carbamates,
- - Chrysanthemic acid derivatives or
- - chlorinated hydrocarbon residues.
Die Verbindungen der Formel VII können für sich allein oder zusammen mit geeigneten Trägern und/oder Zuschlagstoffen eingesetzt werden. Geeignete Träger und Zuschlagstoffe können fest oder flüssig sein und entsprechen den in der Formulierungstechnik üblichen Stoffen, wie z.B. natürlichen oder regenerierten Stoffe, Lösungs-, Dispergier-, Netz-, Haft-, Verdickungs-, Binde- und/oder Düngemitteln. Zur Applikation können die Verbindungen der Formel VII mit Stäubemitteln, Emulsionskonzentraten, Granulate, Disperionen, Sprays, zu Lösungen oder Aufschlämmungen in üblicher Formulierung, die in der Applikationstechnik zum Allgemeinwissen gehören, verarbeitet werden.The compounds of formula VII can be used alone or together with suitable carriers and / or additives. Suitable carriers and additives can be solid or liquid and correspond to the substances commonly used in formulation technology, e.g. natural or regenerated substances, solvents, dispersants, wetting agents, adhesives, thickeners, binders and / or fertilizers. For application, the compounds of the formula VII can be processed with dusts, emulsion concentrates, granules, dispersions, sprays, into solutions or slurries in customary formulations which are common knowledge in application technology.
Die Herstellung erfindungsgemässer Mittel erfolgt in an sich bekannter Weise durch inniges Vermischen und/oder Vermahlen von Wirkstoffen der Formel VII mit den geeigneten Trägerstoffen, gegebenenfalls unter Zusatz von gegenüber den Wirkstoffen inerten Dispergier- oder Lösungsmitteln. Die Wirkstoffe können in den folgenden Aufarbeitungsformen vorliegen und angewendet werden.
Der Gehalt an Wirkstoffen in den oben beschriepenen Mitteln liegt zwischen 0,1 bis 95 Gew - %The content of active ingredients in the agents described above is between 0.1 to 95% by weight.
Die folgenden Beispiele dienen zur Illustration der Erfindung. Temperaturen sind in Celsiusgraden angegeben.The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius.
Zu dieser Schmelze wird innerhalb 25 Minuten, 6, 7 g 90%- iges Kaliumhydroxydpulver zugegeben und das Ganze während einer Stunde bei 130° gerührt. Nach dem Abkühlen nimmt man das Reaktionsgemisch in Aether:Hexan (1:1) auf und wäscht die organische Lösung viermal mit 10%-iger Kaliumhydroxydlösung und dreimal mit gesättigter Kochsalzlösung. Die organische Phase wird über Natriumsulfat getrocknet .und am Rotationsvaporisator bei vermindertem Druck-eingeengt. Man destilliert das Rohprodukt und erhält das 2-(4-Phenoxyphenoxy)-cyclopentan-l-ol als farbloses-Oel vom Siedepunkt Kp0.001 181-185° und dem Brechungsindex n20 D=1.5812.6.7 g of 90% potassium hydroxide powder are added to this melt within 25 minutes and the whole is stirred at 130 ° for one hour. After cooling, the reaction mixture is taken up in ether: hexane (1: 1) and the organic solution is washed four times with 10% potassium hydroxide solution and three times with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator under reduced pressure. The crude product is distilled and the 2- (4-phenoxyphenoxy) -cyclopentan-l-ol is obtained as a colorless oil with a boiling point of Kp 0.001 181-185 ° and a refractive index n 20 D = 1.5812.
In analoger Weise erhält man das 2-(4-Phenoxy- phenoxy)-cyclohexan-l-ol, das nach dem Umkristallisieren aus Hexan bei 62-65° schmilzt und das 2-(4-Benzylphenoxy)-cyclohexan-l-ol das nach dem Umkristallisieren aus lsopro- panol bei 78-80° schmilzt.The 2- (4-phenoxy-phenoxy) -cyclohexan-l-ol is obtained in an analogous manner, which melts at 62-65 ° after recrystallization from hexane and the 2- (4-benzylphenoxy) -cyclohexan-l-ol that after recrystallization from isopropanol melts at 78-80 °.
In analoger Weise zu dem im Beispiel 1 beschriebenen Verfahren erhält man, ausgehend von den entsprechenden Ausgangsstoffen,
- das 2-(4-Phenylmercaptophenoxy)-cyclopentan-1-ol als farbloses Oel vom Brechungsindex n20 D = 1,6217;
- das 2-Benzylphenoxy)cyclopenta-l-ol als Oel vom Bre- chungsindex n20 D = 1,5794;
- das 2-[4-(4-Chlor-phenoxy)-phenoxy]-cyclopentan-l-ol vom F. = 53-55°;
- das 2-[4-(4-Chlor-phenoxy)-phenoxy]-cyclohexan-l-ol vom F. 82-83°;
- das 2-(4-Phenylmercaptophenoxy)-cyclohexan-1-ol vom F. 79-81°;
- das 2-[4-(2, 4-Dichlor-phenoxy) -phenoxy]-cytlohexan-l-ol vom F. 84-86°;
- das 2-[4-(2,4-Dichlor-phenoxy)-phenoxyl-cyclopentan-l-ol als Oel vom Brechungsindex n20 D= 1,5946;
- das 2-[4-(2-Methyl-phenoxy)-phenoxyl-cyclohexan=l-ol vom F. 73-75°;
- das 2-(4-(4-Chlor-phenylmercapto)-phenoxyl-cyclohexan-1-ol vom F. 90-92°;
- das 2-(4-Phenoxy-phenylmercapto)-cyclohexan-l-ol als Oel vom Brechungsindex n20 D = 1,6051;
- das 2-(4-Phenoxy-phenylmercapto)-cyclopentan-l-ol, als Oel vom Brechungsindex n20 D = 1,6101;
- das 2-[4-(2-Methyl-phenoxy)-phenoxy]-cyclopentan-l-ol, als Oel vom Brechungsindex n20 D = 1,5757 oder
- das 2-[4-(4-Chlor-phenylmercapto)-phenoxy]-cyclopentan-l-ol, als Oel vom Brechungsindex n20 D = 1,6212.
- the 2- (4-phenylmercaptophenoxy) cyclopentan-1-ol as a colorless oil with a refractive index n 20 D = 1.6217;
- the 2-benzylphenoxy) cyclopenta-l-ol as an oil with the refractive index n 20 D = 1.5794;
- the 2- [4- (4-chlorophenoxy) phenoxy] cyclopentan-l-ol of mp = 53-55 °;
- the 2- [4- (4-chlorophenoxy) phenoxy] cyclohexan-l-ol of mp 82-83 °;
- the 2- (4-phenylmercaptophenoxy) cyclohexan-1-ol, mp 79-81 °;
- the 2- [4- (2,4-dichlorophenoxy) phenoxy] cytlohexan-l-ol of mp 84-86 °;
- the 2- [4- (2,4-dichlorophenoxy) phenoxyl-cyclopentan-l-ol as an oil with a refractive index n 20 D = 1.5946;
- the 2- [4- (2-methylphenoxy) phenoxylcyclohexan = 1-ol of mp 73-75 °;
- the 2- (4- (4-chlorophenylmercapto) phenoxylcyclohexan-1-ol, mp 90-92 °;
- the 2- (4-phenoxy-phenylmercapto) cyclohexan-l-ol as an oil with a refractive index n 20 D = 1.6051;
- the 2- (4-phenoxy-phenylmercapto) cyclopentan-l-ol, as an oil of refractive index n 20 D = 1.6101;
- the 2- [4- (2-methylphenoxy) phenoxy] cyclopentan-l-ol, as an oil of refractive index n 20 D = 1.5757 or
- the 2- [4- (4-chlorophenylmercapto) phenoxy] cyclopentan-l-ol, as an oil of refractive index n 20 D = 1.6212.
Zu einer Lösung von 8,04 g 2-(4-Phenoxyphenoxy)-cyclopentan-1-on in 60 ml Methanol gibt man bei Raumtemperatur eine Lösung von 3;78 g Natriumborhydrid in 10 ml Wasser. Das Reaktionsgemisch wird noch 15 Stunden bei Raumtemperatur gerührt und anschliessend unter vermindertem Druck eingeengt. Man giesst den Rückstand auf Eiswasser und extrahiert mit Aether. Die organische Phase wird zweimal mit gesättigter Kochsalzlösung gewaschen, über-Natriumsulfat getrocknet und am Rotationsvaporisator einge-.Oel vom KP0.001 181-1850°.A solution of 3-78 g of sodium borohydride in 10 ml of water is added to a solution of 8.04 g of 2- (4-phenoxyphenoxy) cyclopentan-1-one in 60 ml of methanol at room temperature. The reaction mixture is stirred for a further 15 hours at room temperature and then concentrated under reduced pressure. The residue is poured onto ice water and extracted with ether. The organic phase is washed twice with saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. .Oil from K P0.001 181-1850 °.
Das Ausgangsmaterial lässt sicherhalten:
- Zu einer Lösung von 18,6 g 4-Phenoxypher.cl in 80 ml Aceton werden 15,2 g,wasserfreies Kaliumcarbonat gegeben und das Reaktionsgemisch eine Stunde am Rückfluss gekocht, Man tropft dann 17,3 g 2-Brom-cyclopentanon zu und kocht während 20 Stunden am Rückfluss. Man kühlt das Reaktionsgemisch ab, filtriert und engt das Filtrat am Rotationsvaporisator ein. Man nimmt das erhaltene 0el in Aether auf, wäscht die Lösung viermal mit 10%-iger Kaliumhydroxydlösung und zweimal mit gesättigter Kochsalzlösung, trocknet über Natriumsulfat und engt am Rotationsvaporisator ein. Das erhaltene rohe 2-(4-Phenoxyphenoxy)- cyclopentan-l-on wird ohne weitere Reinigung für die oben beschriebene Um- Setzung verwendet.
- 15.2 g of anhydrous potassium carbonate are added to a solution of 18.6 g of 4-phenoxypher.cl in 80 ml of acetone and the reaction mixture is refluxed for one hour. Then 17.3 g of 2-bromo-cyclopentanone are added dropwise and the mixture is boiled at reflux for 20 hours. The reaction mixture is cooled, filtered and the filtrate is concentrated on a rotary evaporator. The oil obtained is taken up in ether, the solution is washed four times with 10% potassium hydroxide solution and twice with saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The crude 2- (4-phenoxyphenoxy) cyclopentan-1-one obtained is used for the reaction described above without further purification.
In analoger Weise zum vorstehenden Beispiel 3 erhält man ausgehend von den entsprechenden Ausgangsstof- fen das 2-(4-Phenoxyphenoxy)-cyclohexa -l-on vom F. - 103-105°, das wie oben beschrieben zum entsprechenden 2-(4- Phenoxyphenoxy)-cyclohexan-l-ol vom F. - 62-65° reduziert wird.Analogously to Example 3 above, starting from the corresponding starting materials, the 2- (4-phenoxyphenoxy) cyclohexa-l-one of F. -103-105 ° is obtained, which, as described above, gives the corresponding 2- (4- Phenoxyphenoxy) cyclohexan-l-ol is reduced from F. - 62-65 °.
Zu einer Lösung von 18,6 g 4-Phenoxyphenol in 120 ml Dimethylsulfoxyd werden unter Eiskühlung 6,7 g 90%- iger Kaliumhydroxydpulver zugegeben und das Ganze 1/2 Stunde bei Raumtemperatur gerührt. Man gibt dann 16,3 g 2-Acetoxy-cyclopentylchlorid im Laufe von 20.Minuten zu, rührt dann das Reaktionsgemisch bei 50° ca . 18. 'Stunden. Man giesst auf Eiswasser, extrahiert mit Aether, wäscht die organische Phase nochmals mit Wasser und einmal mit gesättigter Kochsalzlösung, trocknet über Natriumsulfat und engt ein. Das erhaltene 1-Acetoxy-2-(4-phenoxyphenoxy)-cyclopentan liegt nach fraktionierter Destillation als farbloses Oel mit einem Brechungsindex von n20 D= 1.5560 vor.6.7 g of 90% strength potassium hydroxide powder are added to a solution of 18.6 g of 4-phenoxyphenol in 120 ml of dimethyl sulfoxide with ice cooling and the whole is stirred at room temperature for 1/2 hour. 16.3 g of 2-acetoxy-cyclopentyl chloride are then added over the course of 20 minutes and the mixture is stirred then the reaction mixture at 50 ° approx. 18 hours. It is poured onto ice water, extracted with ether, the organic phase is washed again with water and once with saturated sodium chloride solution, dried over sodium sulfate and concentrated. After fractional distillation, the 1-acetoxy-2- (4-phenoxyphenoxy) cyclopentane obtained is present as a colorless oil with a refractive index of n 20 D = 1.5560.
Zu einer Lösung von 6,24 g 1-Acetoxy-2-(4-phen- oxyphenoxy)-cyclopentan in 50 ml Aethanol tropft man bei Raumtemperatur eine Lösung von 1,68 g Kaliumhydroxyd gelöst in 20 ml Wasser zu, kocht dann 3 Stunde am RUck- fluss und dampft nach dem Abkühlen am Rotationsvaporisator auf 1/3 des ursprünglichen Volumens ein. Man giesst den Rückstand auf Eiswasser, extrahiert mit Aether, wäscht die organische Phase dreimal mit gesättigter Kochsalzlö- sung, trocknet über Natriumsulfat und engt am Rotations- vaporisator ein. Destillation des Rückstandes gibt das 2-(4-Phenoxyphenoxy)-cyclopentan-l-ol als farbloses 0el vom kP0.001 181-I85°.A solution of 1.68 g of potassium hydroxide dissolved in 20 ml of water is added dropwise to a solution of 6.24 g of 1-acetoxy-2- (4-phenoxyphenoxy) cyclopentane in 50 ml of ethanol at room temperature, and the mixture is then boiled for 3 hours on the reflux and evaporates after cooling on the rotary evaporator to 1/3 of the original volume. The residue is poured onto ice water, extracted with ether, the organic phase is washed three times with saturated sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. Distillation of the residue gives the 2- (4-phenoxyphenoxy) -cyclopentan-l-ol as a colorless oil of k P0.001 181-I85 °.
Zu einem Gemisch von 15.9 g Quecksilber(II)acetat, 35 ml Wasser und 50 ml Tetrahydrofuran tropft man im Laufe einer Stunde eine Lösung von 12,6 g 3-(4-Phenoxy- phenoxy)-cyclopent-l-en in 25 ml Tetra.hydrofuran zu und rührt ca. 15 Stunden bei Raumtemperatur. Dann tropft man 50 ml 3N-Natronlauge innerhalb 1 1/2 Stunden zu und anschliessend innerhalb 1 Stunde 50 ml einer 0,5N-Lösung von Natriumborhydrid in 3N-Natronlauge. Man rührt das Reaktionsgemisch 2 Stunden bei Raumtemperatur und fil- .triert vom ausgefallenen Quecksilber.ab. Man giesst das. Filtrat auf Eiswasser, extrahiert mit Aether, wäscht die organische Phase mit gesättigter-Kochsalzlösung, trock- A solution of 12.6 g of 3- (4-phenoxyphenoxy) cyclopent-l-ene in 25 ml is added dropwise to a mixture of 15.9 g of mercury (II) acetate, 35 ml of water and 50 ml of tetrahydrofuran over the course of an hour Tetra.hydrofuran and stirred for about 15 hours at room temperature. Then 50 ml of 3N sodium hydroxide solution are added dropwise within 1 1/2 hours and then 50 ml of a 0.5N solution of sodium borohydride in 3N sodium hydroxide solution within 1 hour. The reaction mixture is stirred for 2 hours at room temperature and filtered off from the precipitated mercury. It is poured. Filtrate on ice water, extracted with ether, the organic phase washed with saturated sodium chloride solution, dry
Herstellung der Verbindung der Formel
Zu einer Lösung von 28,3 g 2-(4-Phenoxy)-phenoxy- cyclohexanol in 150 ml wasserfreiem Benzol fügt man 12,1 g Triäthylamin hinzu und tropft anschliessend unter Rühren innerhalb einer Stunde bei 15-20° 11,5 g Cyclopropancarbonsaurechlorid zu. Das Reaktionsgemisch wird 24 Stunden bei Rauntemperatur weiter gerührt, hierauf nacheinander und wiederholt mit Wasser, verdünnter Salzsäure, 10%-iger Na- triumcarbonatlösung und schliesslich mit gesättigter Kochsalzlösung neutral gewaschen. Die organische Phase wird adgetrennt. Über Natriumsulfat getrocknet und im Vakuum vom Lösungsmittel befreit. Der ölige Rückstand wird an Kieselgel chromatographisch weiter gereinigt (Eluiermittel: Methylacetat-Hexan 1:4).12.1 g of triethylamine are added to a solution of 28.3 g of 2- (4-phenoxy) -phenoxy-cyclohexanol in 150 ml of anhydrous benzene, and 11.5 g of cyclopropanecarboxylic acid chloride are then added dropwise with stirring at 15-20.degree to. The reaction mixture is stirred for a further 24 hours at room temperature, then successively and repeatedly washed neutral with water, dilute hydrochloric acid, 10% sodium carbonate solution and finally with saturated sodium chloride solution. The organic phase is separated. Dried over sodium sulfate and freed from solvent in vacuo. The oily residue is further purified by chromatography on silica gel (eluent: methyl acetate-hexane 1: 4).
Man erhält die Verbindung der Formel IV mit einer Refraktion von n20 D: 1,5542.The compound of formula IV is obtained with a refraction of n 20 D : 1.5542.
Auf analoge Weise werden auch die folgenden Verbindungen hergestellt:
Claims (19)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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CH900277 | 1977-07-20 | ||
CH9002/77 | 1977-07-20 |
Publications (2)
Publication Number | Publication Date |
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EP0000506A2 true EP0000506A2 (en) | 1979-02-07 |
EP0000506A3 EP0000506A3 (en) | 1979-06-27 |
Family
ID=4347259
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78100374A Withdrawn EP0000506A3 (en) | 1977-07-20 | 1978-07-12 | Substituted phenyl o- or s- etherified cycloalkanols, a process for their preparation and their application as hypolipidemia, their esters with cyclopropanecarboxylic acids and the application of these esters as insecticides |
Country Status (11)
Country | Link |
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US (1) | US4175137A (en) |
EP (1) | EP0000506A3 (en) |
JP (1) | JPS5422343A (en) |
DD (1) | DD138202A5 (en) |
DK (1) | DK322678A (en) |
ES (2) | ES471829A1 (en) |
FI (1) | FI782253A (en) |
IL (1) | IL55163A0 (en) |
IT (1) | IT7850347A0 (en) |
NO (1) | NO782492L (en) |
ZA (1) | ZA784104B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0031023A2 (en) * | 1979-12-22 | 1981-07-01 | Degussa Aktiengesellschaft | Cyclopropane-carboxylic acid esters, process for their preparation and their use |
US4282388A (en) * | 1977-12-01 | 1981-08-04 | Bayer Aktiengesellschaft | Cyclic 1,2-diol benzyl ether compounds |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1981002892A1 (en) * | 1980-04-10 | 1981-10-15 | Dainippon Jochugiku Kk | Cyclopropanecarboxylic acid ester derivatives,process for their preparation,and insecticidal and acaricidal composition containing such as effective ingredients |
JPS5958067A (en) * | 1982-09-28 | 1984-04-03 | Nippon Steel Corp | Writing material |
DE3812967A1 (en) * | 1987-06-24 | 1989-01-05 | Bayer Ag | AZOLYL METHYL CYCLOPROPYL DERIVATIVES |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH372293A (en) * | 1957-03-01 | 1963-10-15 | Bayer Ag | Process for the production of thiomethylalen |
NL7504534A (en) * | 1974-04-18 | 1975-10-21 | Ciba Geigy | PROCEDURE FOR PREPARING PHENOXY-PHENYL ETHERS AND PROCEDURE FOR APPLYING THEM IN CONTROL OF HARMFUL ORGANISMS. |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
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US3098105A (en) * | 1962-06-27 | 1963-07-16 | Dow Chemical Co | Alkanol phenoxy thioethers |
US3272854A (en) * | 1963-07-18 | 1966-09-13 | Us Rubber Co | Cycloaliphatic sulfite esters |
US3379752A (en) * | 1964-05-20 | 1968-04-23 | Merck & Co Inc | Phenoxy substituted 3-hydroxyalkanoic acids and a method for their preparation |
US3506682A (en) * | 1966-08-25 | 1970-04-14 | Syntex Corp | Phenylcyclopropyl carbinols and process for their preparation |
US3715401A (en) * | 1970-05-01 | 1973-02-06 | Gen Electric | Process for producing 3-hydroxyalkyl ethers |
US3962459A (en) * | 1973-09-04 | 1976-06-08 | Sandoz, Inc. | Lipidemia treatment with p-phenoxy-alkylphenone compositions |
US4051173A (en) * | 1974-04-02 | 1977-09-27 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Phenoxyalkanol derivatives |
NL7504667A (en) * | 1974-04-26 | 1975-10-28 | Ciba Geigy | PROCEDURE FOR PREPARING NEW ETHERS. |
US4065503A (en) * | 1974-09-30 | 1977-12-27 | Sandoz, Inc. | P-Phenoxy-alkylphenones and corresponding alcohols |
US4017549A (en) * | 1974-10-24 | 1977-04-12 | Ciba-Geigy Corporation | Diphenylmethane ether derivatives |
DK451175A (en) * | 1974-10-24 | 1976-04-25 | Ciba Geigy Ag | PEST CONTROL |
US4080474A (en) * | 1975-02-19 | 1978-03-21 | Beecham Group Limited | Hypolipidaemic compositions |
-
1978
- 1978-07-12 EP EP78100374A patent/EP0000506A3/en not_active Withdrawn
- 1978-07-13 US US05/924,315 patent/US4175137A/en not_active Expired - Lifetime
- 1978-07-17 DD DD78206764A patent/DD138202A5/en unknown
- 1978-07-17 FI FI782253A patent/FI782253A/en not_active Application Discontinuation
- 1978-07-18 IT IT7850347A patent/IT7850347A0/en unknown
- 1978-07-18 ES ES471829A patent/ES471829A1/en not_active Expired
- 1978-07-18 IL IL55163A patent/IL55163A0/en unknown
- 1978-07-19 DK DK322678A patent/DK322678A/en unknown
- 1978-07-19 ZA ZA00784104A patent/ZA784104B/en unknown
- 1978-07-19 NO NO782492A patent/NO782492L/en unknown
- 1978-07-20 JP JP8778178A patent/JPS5422343A/en active Pending
-
1979
- 1979-03-22 ES ES478880A patent/ES478880A1/en not_active Expired
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH372293A (en) * | 1957-03-01 | 1963-10-15 | Bayer Ag | Process for the production of thiomethylalen |
NL7504534A (en) * | 1974-04-18 | 1975-10-21 | Ciba Geigy | PROCEDURE FOR PREPARING PHENOXY-PHENYL ETHERS AND PROCEDURE FOR APPLYING THEM IN CONTROL OF HARMFUL ORGANISMS. |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4282388A (en) * | 1977-12-01 | 1981-08-04 | Bayer Aktiengesellschaft | Cyclic 1,2-diol benzyl ether compounds |
EP0031023A2 (en) * | 1979-12-22 | 1981-07-01 | Degussa Aktiengesellschaft | Cyclopropane-carboxylic acid esters, process for their preparation and their use |
EP0031023A3 (en) * | 1979-12-22 | 1981-09-09 | Degussa Aktiengesellschaft | Cyclopropane-carboxylic acid esters, process for their preparation and their use |
Also Published As
Publication number | Publication date |
---|---|
IL55163A0 (en) | 1978-09-29 |
JPS5422343A (en) | 1979-02-20 |
EP0000506A3 (en) | 1979-06-27 |
DK322678A (en) | 1979-01-21 |
ES471829A1 (en) | 1979-10-01 |
IT7850347A0 (en) | 1978-07-18 |
ZA784104B (en) | 1979-07-25 |
FI782253A (en) | 1979-01-21 |
DD138202A5 (en) | 1979-10-17 |
US4175137A (en) | 1979-11-20 |
NO782492L (en) | 1979-01-23 |
ES478880A1 (en) | 1979-07-01 |
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