DK163918B - CYCLOPROPANCARBOXYLIC ACID DERIVATIVES, PROCEDURES FOR THEIR PREPARATION AND PESTICIDE PREPARATIONS WITH CONTENTS - Google Patents

Abstract

1. Claims (for the contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE) In all the possible isomer forms, the compounds with the formula (I') : see diagramm : EP0041021,P51,F1 in which the double bond has Z geometry, the cyclopropane copula is of 1R cis structure and A' represents : either an alkyl radical containing 1-18 carbon atoms, or a benzyl radical possibly substituted by one or more radicals chosen from the group constituted by alkyl radicals containing 1-4 carbon atoms, alkenyl radicals containing 2-6 carbon atoms, alkenyloxy radicals containing 2-6 carbon atoms, alkadienyl radicals containing 4-8 carbon atoms, the methylenedioxy residue, and the halogen atoms, or a see diagramm : EP0041021,P51,F2 group, in which the substituent R1 represents a hydrogen atom or a methyl radical and the substituent R2 represents a monocyclic aryl or a -CH2 -C -= CH group and notably a 5-benzyl-3-furylmethyl group, or a see diagramm : EP0041021,P51,F3 group in which R3 represents an aliphatic organic radical containing 2-6 carbon atoms and one or more carbon-carbon unsaturations and notably the radicals -CH2 -CH=CH2 , -CH2 -CH=CH-CH3 , -CH2 -CH=CH-C2 H5 , -CH2 -CH=CH-CH=CH2 , or a see diagramm : EP0041021,P51,F4 group, in which R3 retains the same significance as previously, each of R'1 and R'2 , identical or different, represents a hydrogen atom, a halogen atom, an alkyl radical containing 1-6 carbon atoms, an aryl radical containing 6-10 carbon atoms, an alkyloxycarbonyl group containing 2-5 carbon atoms, or a cyano group, or a see diagramm : EP0041021,P51,F5 group, in which B represents a CH2 group, or a C=O group, or a hetero element chosen from oxygen and sulphur, R4 represents a hydrogen atom, a methyl radical, a -CONH2 radical, a -CSNH2 radical or a -C -= CH radical R5 represents a halogen atom or a methyl radical and n represents a numeral 0, 1 or 2, and notably the 3-phenoxybenzyl, alpha-ethynyl-3-phenoxybenzyl, 3-benzoylbenzyl, 1-(3-phenoxyphenyl) ethyl or alpha-thioamido-3-phenoxybenzyl groups, or a see diagramm : EP0041021,P52,F1 group, or a see diagramm : EP0041021,P52,F2 group, in which each of the substituents R6 , R7 , R8 , R9 represents a hydrogen atom, a chlorine atom, or a methyl radical and in which S/I signifies an aromatic ring or a similar dihydro or tetrahydro ring, or a see diagramm : EP0041021,P52,F3 group, or a see diagramm : EP0041021,P52,F4 group, in which R10 represents a hydrogen atom or a CN radical, R12 represents a -CH2 - radical or an oxygen atom, R11 represents a thiazolyl or thiadiazolyl radical of which the bond with see diagramm : EP0041021,P52,F5 may be found at any one of the available positions, R12 being linked to R11 by the carbon atom situated between the sulphur atom and a nitrogen atom, or a see diagramm : EP0041021,P52,F6 group, or a see diagramm : EP0041021,P53,F1 group in which R13 represents a hydrogen atom or a CN radical, or a see diagramm : EP0041021,P53,F2 group, in which R13 is defined as above and the benzoyl radical is in position 3 or 4, or a see diagramm : EP0041021,P53,F3 group, in which R14 represents a hydrogen atom, a methyl, ethynyl or cyano radical and R15 and R16 , which are different from one another, represents a hydrogen, fluorine or bromine atom, or a see diagramm : EP0041021,P53,F4 group in which R14 is defined as above, each of the R17 's represents, independently, an alkyl group containing 1-4 carbon atoms, an alkoxy group containing 1-4 carbon atoms, an alkylthio group containing 1-4 carbon atoms, an alkylsulphonyl group containing 1-4 carbon atoms, or a trifluoromethyl, 3,4-methylenedioxy, chloro, fluoro, or bromo group, p represents a numeral 0, 1 or 2 and B' represents an oxygen atom or a sulphur atom, and R represents an alkyl radical, linear, branched or cyclic, saturated or unsaturated, containing 1-18 carbon atoms, as well as the mixtures of these isomers. 1. Claims (for the contracting State AT) Preparation process for all the possible isomer forms, of compounds with the formula (I') : see diagramm : EP0041021,P57,F2 in which the double bond has Z geometry, A' represents : either an alkyl radical containing 1-18 carbon atoms, or a benzyl radical possibly substituted by one or more radicals chosen from the group constituted by the alkyl radicals containing 1-4 carbon atoms, the alkenyl radicals containing 2-6 carbon atoms, the alkenyloxy radicals containing 2-6 carbon atoms, the alkadienyl radicals containing 4-8 carbon atoms, the methylene dioxy residue, and the halogen atoms, or a see diagramm : EP0041021,P58,F1 group, in which the substituent R1 represents a hydrogen atom or a methyl radical and the substituent R2 represents a monocyclic aryl or a -CH2 -C -= CH group and notably a 5-benzyl-3-furylmethyl group, or a see diagramm : EP0041021,P58,F2 group, in which R3 represents an aliphatic organic radical containing 2-6 carbon atoms and or more carbon-carbon unsaturations and notably the -CH2 -CH=CH2 , -CH2 CH=CH-CH3 , -CH2 CH=CH-C2 H5 , -CH2 -CH=CH-CH=CH2 radicals, or a see diagramm : EP0041021,P58,F3 group, in which R3 retains the same significance as previously, R'1 and R'2 identical or different, each represent a hydrogen atom, a halogen atom, an alkyl radical containing 1-6 carbons atoms, an aryl radical containing 6-10 carbon atoms, an alkyloxycarbonyl group containing 2-5 carbon atoms, or a cyano group, or a see diagramm : EP0041021,P58,F4 group, in which B represents a CH2 or C=O group, or a hetero element chosen from oxygen and sulphur, R4 represents a hydrogen atom, a methyl radical, a -CONH2 radical, a -CSNH2 radical or a -C -= CH radical, R5 represents a halogen atom or a methyl radical and n represents a numerical 0, 1 or 2, and notably the 3-phenoxybenzyl, alpha-ethynyl-3-phenoxybenzyl, 3-benzoylbenzyl, 1-(3-phenoxyphenyl)ethyl or alpha-thiomado-3-phenoxybenzyl group, or a see diagramm : EP0041021,P58,F5 group or a see diagramm : EP0041021,P59,F1 group, in which each of the substituents R6 , R7 , R8 , R9 , represents a hydrogen atom, a chlorine atom or a methyl radical and in which S/I signifies an aromatic ring or a similar dihydro or tetrahydro ring, or a see diagramm : EP0041021,P59,F2 group, or a see diagramm : EP0041021,P59,F3 group in which R10 represents a hydrogen atom or a CN radical, R12 represents a -CH2 - radical or an oxygen atom, R11 represents a thiazolyl or thiadiazolyl radical of which the bond with see diagramm : EP0041021,P59,F4 may be found in any of the available positions, R12 being linked to R11 by the carbon atom situated between the sulphur atom and a nitrogen atom, or a see diagramm : EP0041021,P59,F5 group, or a see diagramm : EP0041021,P59,F6 group, in which R13 represents a hydrogen atom or a CN radical, or a see diagramm : EP0041021,P60,F1 group, in which R13 is defined as above and the benzoyl radical is in position 3 or 4, or a see diagramm : EP0041021,P60,F2 group, in which R14 represents a hydrogen atom, a methyl, ethynyl or cyano radical, and each of R15 and R16 , which are different, represents a hydrogen, fluorine or bromine atom, or a see diagramm : EP0041021,P60,F3 group, in which R14 is defined as above, each of the R17 's represents, independently, an alkyl group containing 1-4 carbon atoms, an alkoxy group containing 1-4 carbon atoms, an alkylthio group containing 1-4 carbon atoms, an alkylsulphonyl group containing 1-4 carbon atoms, or a trifluoromethyl, 3,4-methylenedioxy, chloro, fluoro or bromo group, p represents a numeral 0, 1 or 2 and B' represents an oxygen atom or a sulphur atom, and R represents an alkyl radical, linear branched or cyclic, saturated or unsaturated, containing 1-18 carbon atoms, as well as the mixtures of these isomers, characterized in that an acid with the formula (II) : see diagramm : EP0041021,P60,F4 in which the double bond has Z geometry, R being defined as previously, or a functional derivative of this acid, is submitted to the action of an alcohol with the formula (III) : A'OH in which A' retains the same significance as previously, and in this way the corresponding compound with the formula (I') is obtained.

Description

in

DK 163918B

The invention relates to novel cyclopropane carboxylic acid derivatives of the formula I as defined in claim 1, their preparation and pesticidal compositions containing them.

The invention relates to cyclopropane carboxylic acid derivatives having at the 3-position an unsaturated side-chain of Z-geometry and of the structure H - C

Cyclopropane carboxylic acid derivatives were already known to have, at the 3-position, a chain of structure H.

15 \ / g ------- —o / \ R02c η but whose geometry is essentially E. For example. may be mentioned 20 French Patent No. 2,185,612 and the journal J. Chem.

Soc. Perkin I, pages 2470, 1974 and Pest. Sci. 1, page 499, 1976. However, the side chain geometry of these compounds is predominantly E. In fact, the synthetic methods used to prepare these derivatives lead almost exclusively to the E geometry {see Agr. Biol. Chem. 34, page 1119 1970). For these compounds, whose geometry in the side chain is E, no remarkable property has been demonstrated.

It has now been found that the compounds of formula 30 I, whose side chain has Z structure, exhibit very good in-secticidal properties, cf. comparative examples in the experimental part below.

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The invention relates in particular to the compounds whose preparation is set forth in the experimental part. In particular, among these 10 compounds are mentioned: - (1R, cis) -2,2-dimethyl-3 - ((Z) -3-methoxy-3-oxo-1-propenyl) - cyclopropane carboxylic acid = (1S) -2 - with thy 1-4-oxo-3- (2-prope-nyl) -2-cyclopenten-1-yl ester, - (1R, cis) -2,2-dimethyl-3 - ((Z) -3-tert. -butoxy-3-oxo-1-propanyl) -cyclopropane carboxylic acid 1- (3-propargyl-2,5-dioxoimide-azolidinyl) methyl ester, (IR, cis) -2,2-dimethyl-3- ( (Z) -2-cyclopropylmethoxycarbonyl-ethenyl) -cyclopropane carboxylic acid 1- (3 * -propargyl-2,5-dioxo-imidazolidinyl) methyl ester, 20 - (1R, cis) -2,2-dimethyl-3 - (( Z) -2-isopropoxycarbonylethenyl) - cyclopropane carboxylic acid 1- (R) -3-phenoxyphenylethyl ester, - (1R, cis) -2,2-dimethyl-3 - ((Z) -2-isopropoxycarbonylethenyl) -, cyclopropane carboxylic acid 1- (3-propargyl-2,5-dioxoimidazolidinyl) methyl ester and 25 - (IR, trans) -2,2-dimethyl-3 - ((Z) -2-isopropoxycarbonylethenyl) -cyclopropane-1- R) -3-phenoxyphenylethylester.

The compounds of formula I have interesting properties which enable their use in the control of parasites. It can for example. These include the control of plants' parasites, domestic parasites and parasites on warm-blooded animals. Thus, the compounds of the invention can be used to control insects, nematodes and acarides which are parasites on plants and animals.

The invention enables the use of the compounds of formula I as defined above to control parasites on plants, domestic parasites and parasites on warm-blooded animals.

The compounds of formula I can thus be used for

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3, in particular, the control of insects in agriculture, for the control of e.g. aphids, lepidopterous and coleopteric larvae.

They are used in doses of 10-300 g of active substance per day. ha.

The compounds of formula I can also be used to control domestic insects, especially flies, mosquitoes and cockroaches.

In particular, some of the compounds of formula I have an excellent knock-down effect.

The compound of Example 1 is particularly noteworthy.

In addition, the compound of formula I is light stable and is not toxic to mammals.

The combination of these properties makes the compounds of formula I into compounds which fully meet the requirements of 15 in the modern agrochemical industry. They enable the crops to be protected while preserving the environment.

The compounds of formula I can also be used to control acarides and nematodes which are parasites on plants.

The compound of formula I can further be used to control acarides which are parasites on animals, to control e.g. blood mites and in particular blood mites of the species Boophilus, the species Hyalomnia, the species Imblyomnia and the species Rhipi-cephalus or to combat all kinds of enclosures and in particular 25 sarcoptic, psoroptic and chorioptic enclosures.

The invention thus also relates to the provision of compositions intended for the control of parasites on warm-blooded animals, domestic parasites and parasites on plants and containing at least one of the above-mentioned binding claims.

In particular, insecticidal compositions with at least one of the compounds of this invention are designated as active ingredient.

Specifically, compositions containing as active ingredient are disclosed: 35 - (1R, cis) -2,2 * -dimethyl-3 - ((Z) -3-methoxy-3-oxo-1-propenyl) -cyelopropanecarboxylic acid (1S) ) -2-methyl-4-oxo-3- (2-propenyl) -2-cyclopenten-1-ylster, - (1R, cis) -2,2-dimethyl-3 - ((Z) -3-tert .-butoxy-3-oxo-l-propenyl) ~

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4-Cyclopropane carboxylic acid 1- (3-propargyl-2,5-dioxoimidazolidinyl) methyl ester, - (IR, cis) -2,2-dimethyl-3- ((2) -2-cyclopropylmethoxycarboxy-1-thenyl ) -cyclopropane carboxylic acid 1- (3-propargyl-2,5-dioxo-imidazolidinyl) ethyl ester, - (IR, cis) -2,2-dimethyl-3- ((2) -2-isopropyloxycarbonylethenyl) cyclopropane carboxylic acid -1- (R) -3-phenoxyphenylethyl ester, - (IR, cis) -2,2-dimethyl-3- ((2) -2-isopropoxycarbonylethenyl) cyclopropanecarboxylic acid 1- (3-propargyl-2,5- dioxoimidazolidinyl) methyl ester and - (IR, trans) -2,2-dimethyl-3- ((Z) -2-isopropoxycarbonylethenyl) cyclopropane carboxylic acid 1- (R) -3-phenoxyphenylethyl ester.

The compositions of the invention are prepared according to the usual processes used in the agrochemical, veterinary or animal feed industries.

In these preparations for use in agriculture and household, the active ingredient (s) may optionally be added to one or more other pesticides. These compositions may be in the form of powders, granules, suspensions, emulsions, solutions, aerosol solutions, combustible strips or baits or other preparations normally used in such compounds.

In addition to the active ingredient, these preparations usually contain a binder or carrier and / or a nonionic surfactant which further ensures a uniform distribution of the constituents of the mixture. The binder or carrier used may be a liquid such as water, ethanol, hydrocarbons or other organic solvents, a mineral, animal or vegetable oil, a powder such as talc, clay, silicates, diatomaceous earth or a solid combustible substance.

The insecticidal compositions of the invention preferably contain 0.005 $ -10 $ active weight by weight.

According to an advantageous embodiment, the compositions of the invention are used in the form of smoke preparations for domestic use.

The compositions according to the invention can then, for the benefit of the inactive part, be constituted by an insecticidal smoke

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5 or a fibrous non-combustible substrate. In this latter case, after the incorporation of the active substance into the heated apparatus such as an electric mosquito extermination apparatus, the smoke preparation is applied. In the case of using an insecticide spray, the inert carrier may e.g. be of pyrethrum or tabu powder (powder of leaves of Machilus thumbergii), pyrethrum style powder, cedar leaf powder, sawdust, e.g. of pine, starch and coconut shell powder.

The dose of active substance is then e.g. 0.03-1% by weight.

In the case where a non-combustible fibrous support is used, the dose of active substance may then be e.g. 0.03-95% by weight.

The compositions of the invention for domestic use 15 may also be obtained by producing an active ingredient sprayable oil which soaks up the wall of a lamp which is then ignited.

The concentration of active ingredient in the oil is then preferably 0.03-95% by weight.

The insecticidal compositions of the invention, like the acaricidal and nematodicidal preparations, may be optionally added to one or more other pesticidal agents. In particular, the acaricidal and nematodicidal compositions may be present in forums of powders, granules, suspensions, emulsions or solutions.

For acaricidal debris, wettable powders are preferably used for spraying the r-o leaf and containing 1-80 $, or liquids for spraying, on the leaf containing 1-500 g / liter of active ingredient. Powder can also be used for powdering the foliage and containing 0.05-3 $ active ingredient.

For nematodic use, liquids are preferably used for treating the soil and containing 300-500 g / liter of active ingredient.

The acaricidal and nematodicidal compositions of the invention are preferably used in doses of 1-100 g of active ingredient per hectare.

To enhance the biological activity of the compound of the invention, one may add classic synthetic compounds to them.

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6 gaseous agents used in such cases as 1- (2,5,8-trioxadodecyl) -2-propyl-4,5-methylenedioxybenzene (or piperonylbutoxide) or 1β- (2-ethylheptyl) - bicyclo (2,2-1) -5-heptene - 2,3-dicarboximide or piperonyl-bis-2- (2'-n-butoxyethoxy) -5-ethylacetal (or tropital).

When it comes to fighting acarides as parasites on animals, the compounds of the invention are very often incorporated into nutritional preparations in conjunction with a food intended for animals. The mixture in question may vary according to the species of animal, it may contain cereals, sugar and cereals, soy press, peanuts and sunflower seeds, flour of animal origin, e.g. fish meal, synthetic amino acids, mineral salts, vitamins and antioxidants.

Thus, the invention also relates to the aforementioned nutrient preparations.

The compounds of formula I have an excellent general tolerance and can be used in warm-blooded animals to combat, in particular, disorders caused by mites and creatures, and to combat lice as a preventive or curative measure.

The compounds of formula I according to the invention can be administered by external route, by spraying, in the form of bath or by application.

The compounds of formula I according to the invention may also be administered by application to the backbone of animals by the so-called pouring method. They can also be administered by the digestive route or parenterally.

It should also be stated that the products of the invention can be used as biocides and as growth regulating agents.

The invention also relates to a process for the preparation of the compounds of formula I, and this process is characterized by the characterizing part of claim 2.

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The esterification reaction can be carried out by other methods. One can, for example. reacting the acid of formula II with alcohol of formula III in the presence of dicyclohexylcarbo diimide or diisopropylcarbodiimide.

The compounds of formula II are novel to compounds for which manufacturing experiments have been given in the experimental section below.

The compounds of formula II can be prepared by a process by reacting a compound of formula IV

Half \ == co2aic (IV)

Hal represents a halogen atom, and alc represents an alkyl group of 1-20 carbon atoms, in a first step with an alkaline agent capable of detaching the halogen atoms, and a second step,

either with an agent capable of introducing the carboxyl group to obtain the compound of formula V

H09CSC \ / \ \ / \ (V) 25

which is subjected to the action of an esterifying agent to obtain a compound of formula VI

30 X \, N

R02C-C1 CL / X2 CO2alc (VI) wherein R has the same meaning as above, or with an alkyl chloroformate of the formula V * R-O-C0-01 (V ')

wherein R has the same meaning as above for directly obtaining the compound of formula VI

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8 R02C-Csg3c (VI)

5, then subjecting the compound of formula VI to the effect of a gentle hydrogenation agent to obtain the compound of formula VII

10 M 'm in (VII) R02C-C = C / \ CO2alc

wherein the group COgR is in the Z-position subjected to the action of an acid hydrolysis agent capable of selectively cleaving the branched ester group at the carbon atom at the 1-position to obtain a corresponding compound of formula II

V- ^ X

/ X / 8 (II) ro2c

A Method for Preparing the Compounds · "

Formula I may consist of subjecting a compound of Formula VIII

HjC CHj f f X * / (7111) 30 ho2c - 0 == σ co-a. · Where A 'is defined as above, the action of an esterifying agent to give the compound of formula I corresponding thereto «

The compound of formula VIII is prepared by subjecting a compound of formula IX

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9 H-tGL / CH-t 5 C13C-CH2-02C-CE c N> Vn \ ^^^ CQ25 (12)

effect of a compound of formula III

A'-OH (III)

10 where A * has the same meaning as above to give a compound of formula X

H-C \ / CH, O \ / 15 CX)

Cl5C-CE2-02C-C £ C * / wC02 A '

* I

subjecting to the action of an agent for cleavage of the ester group carried by the acetylenic carbon atom to give a compound of formula XI

E3 \ / ^ 3 25 / \ CH) eo2c-esc. The effect of a gentle hydrogenation agent is obtained to obtain the compound of formula VIII.

In a preferred embodiment of the process, the following applies: - The esterification of compound IX occurs by reacting compound IX with the alcohol III in the presence of dieyclo-35-hexylcarbodiimide or diisopropylcarbodiimide.

The cleavage of the ester X occurs by using a metal powder, e.g. zinc powder in acidic environment.

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10 - The gentle hydrogenation agent is hydrogen in the presence of a catalyst such as palladium in the presence of traces of quinoline.

The above process comprises an obvious variant 5, which involves the exchange of hydrogenation and esterification steps.

Thus, such a process consists in subjecting a compound of formula XI

10 EXCX. CE2 / m H02 C-C = Cv / c02 A '15 \ Z__

wherein A 'is as defined above, the action of an esterifying agent to give a compound of formula III

Where R and A 'have the same meaning as above subjected to the action of a gentle hydrogenation agent to obtain the compound with formula I.

The preferred compounds for carrying out the above method are identical to those defined above for the analog operations.

The compound of formula IX can be prepared by subjecting an acid of formula XIII

E-, C / CE

3 \ Y 5 35 / \> (2111) H02 C02 al c

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11 where alc represents an alkyl group of 1-8 carbon atoms, the action of 2,2,2-trichloroethanol, upon which the resulting ester is subjected to an acidic hydrolysis.

An example of preparing a compound of Formula IX is described below in the experimental part.

The alcohols of formula III used in the process of the invention are generally known compounds. However, some of these alcohols, namely, the compounds of formula 10, CH 3 0 O, 1,011 15 wherein R 1 and R 2 g have the same meaning as above, are novel and lead to esters which are quite remarkable from a biological point of view.

Among these alcohols may be mentioned especially 3-phenoxy-4-fluoro-alpha-methylbenzyl alcohol. These alcohols can be prepared as set forth below in the experimental part by the action of an organometal compound, e.g. a methyl magnesium halide, on aldehydes corresponding to the alcohols to be prepared.

The following examples illustrate the method 25 of the invention.

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Example 1, (IR, cis, Z) -2,2-Dimethyl-5- (5-methoxy-5-oxo-1-propenyl) -oyolo-propanecarboxylic acid (IS) -2-methyl-4-oxo 3- (2-propenyl) -2-cycle penten-ly ter.

Step A: (1R „o, ΖΖ) -2,2-Dimethyl 1-3- (5-methoxy-5-oxo-1-propenyl) cyclopropane carboxylic acid chloride,

1 ml of thionyl chloride is introduced into a mixture of 1.8 g (1R, cis, AZ) -2,2-dimethyl-3- (2-methoxy-3-oxo-1-propanol) cyclopropane carboxylic acid prepared as set out below 10 in Preparation I and 10 ml of isoprene. Stir for 30 minutes at 0 ° C and then at 20 ° C for 4 hours. Evaporates to dryness under reduced pressure at 50 ° C. A compound is obtained which is used immediately in the next step.

Step B: (IR, cis, Δζ) -2,2-Dimethyl-3- (3-methoxy-5-oxo-1-propenyl) -15-cyclopropanecarboxylic acid (IS) -2-methyl-4-oxo -3- (2-propenyl) 2-cyclopenten-1-viester.

761 mg of (4S) -hydroxy-3-methyl-2- (2-propenyl) -2-cyclopenten-1-one, 5 ml of benzene and 0.4 ml of pyridine are mixed. The solution is cooled to 10 ° C and 888 g (IR, cis, AZ) -20 -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclopropanecarboxylic acid chloride are added in solution ml of benzene. The reaction mixture is kept under stirring for 16 hours. You pour into water, decant the organic phase and wash it with water. Dry, filter and evaporate to dryness. 1.9 g of a compound are obtained which are chromatographed on silio gel eluting with benzene and ethyl acetate (95 * 5). Thus 1.06 g of the expected compound is obtained, <Xjj = + 71.5 ° + 2.5 ° (c = 0.5 $ »ceci5).

IMR, CDC15, ppm: 1.3 and 1.32, hydrogen in the methyl groups at the 2-position, 1.9-2.05, H at the 1-position in cyciopropane, 3.1-3.3-3.4 , H at the 3-position in cyciopropane, 6.5 to 6.8, E at the carbon atom at the 1-position in ethenyl, 5.8-6.04, H at the carbon at the 2-position in ethenyl, 3.7, H in the methoxy group, 5.6 to 5.8, E at the carbon atom at the 4-position of (4S) -3-methyl-1-oxocyclopent-2-en-4-yl,

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13 2.95 to 3. K at the carbon atom at the 1-position in propenyl, 5.5 to 6.2, E at the carbon atom at the 2-position in propenyl, 4.8 to 5.2, E at the carbon atom at the 3-position in propenyl.

Example 2 «(1H, cis.AZ) -2,2-dimethyl-5- (5-ethoxy-3-oxo-1-propenyl) -cyclo-propane carboxylic acid (1S) -2-methyl-4-oxo-3 - (2-propenyl) -2-cy-clopenten-I ylater.

1 g of cyclohexylcarbodiimide, 6 mg of 4-dimethylaminopyridine and 12 ml of methylene chloride are introduced into a flask containing 1.1 g (1R, cis, AZ) -2,2-dimethyl-3- (3-ethoxy-3-cxo) -1-propenyl) -cyclopropanecarboxylic acid prepared as set forth below in Preparation 2. 900 mg (4S) -4-hydroxy-3-methyl-2- (2-propenyl) -2-cyclopent-1-one is then dissolved. in 1 ml of methylene chloride. The reaction mixture is kept under stirring for 16 hours. The filtrate is filtered and evaporated to dryness under reduced pressure to give 2.4 g of a compound which is purified by chromatography on silica gel. Eluant: n-hexane and isopropyl ether (6: 4). 1.3 g of 20 of the expected compound are obtained, (Xjj = + 34 ° + 2 ° (c = 0.6 $, benzene).

EMR, CDCl3 ppm: 1.27, H in the methyl groups at the 2-position, 3.1-3.4, E at the carbon atom at the 3-position in cyclopropane, 6.4 to 6.8, H at the carbon atom at 1- the position in ethenyl, 5.8-6, H at the carbon atom at the 2-position in ethenyl, 1.17, 1.28, 1.4 and 4 to 4.4, H in ethoxy, 4.7 to 5.2 , E at the carbon atom at the 3-position of propenyl.

Example 3

(IR. Cis. ΔΖ) - 2,2-Dimethyl-3- (3-oxo-3-propoxy-1-propenyl) -cvolo-propane carboxylic acid (1S) -2-methyl-4-oxo-5- ( 2-propenyl) -2-c yclo-penten-l-yl ester.

Working as in Example 2 from 1.5 g (IR, cis, ΔΖ) -2,2-dimethyl-3- (3-oxo-3-propoxy-1-propenyl) -cyclopropane-carboxylic acid and 1, 1 g (4S) -4-hydroxy-3-ethyl-2- (2-propenyl) -2-cyclopenten-1-one gives 3.1 g of the expected compound which is purified by chromatography on silica gel; eluent: hexane and isopropyl ether (7: 3). You evaporate to

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ISLAND

dryness to give 1.7 g of the expected compound, α + = + 39.5 + 2.5 ° (c = 0.5 $, benzene).

EMR, CDCl3, ppm: 1.5 and 1.31, H in methyl at the 2-position in cyclopropane, 3.1 to 3.42, H at the carbon atom at the 3-position in cyclopropane, 6.4 to 6, 8, H at the carbon atom at the 1-position in ethenyl, 5.8-6, E at the carbon atom at the 2-position in ethenyl, 4-4.08-4.2, H in the propoxy at the α position relative to GO2, 0.83-0.95-1.06, H in propoxy at γ position relative to CO 2, 5.6 to 5.7, H at the carbon atom at the 4-position in (4S) -3- -methyl-. 2- (2-propenyl) -1-oxocyclopent-2-en-4-yl, 2, H in methyl at the 3-position of (4S) -5-methyl-2- (2-propenyl) -1 oxocyclopent-2-ene-4-yl, 4.7 to 5.2, H at the carbon atom at the 5-position of propenyl.

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Example 4

(IR. Ois.ΔΖ) -2,2-dimethyl-3- (5- (1-methylethoxyl) -5-ozo-1-propenyl) -cyclopropanecarboxylic acid (1S) -2-methyl-4-oxo- 3- (2-propenyl) -2-cyclopenten-ly ester.

Step A: (IR.cis → ΔΖ) -2,2-dimethyl 1-5- (3-1- (1-methylethoxy) -5-oxo-1-propenyl) -cyclopropane carboxylic acid chloride.

A mixture of 900 mg (1E, cis, AZ) -2,2-dimethyl-5- (3- (1-methylethoxy) -3-oxo-1-propenyl) -cyclopropanecarboxylic acid, 9 ml is stirred for 4 hours at room temperature. isoprene and 1 ml of thionyl chloride. Evaporate to dryness and obtain 1.4 g of a compound which is used immediately in the next step.

Step B: (1E.cis.AZ) -2,2-Dimethyl-5- (5- (1-methylethoxy) -5-oxo-1-propenyl) -cyclopropanecarboxylic acid (1S) -2-methyl-4 -oxo-5- (2-propenyl) -cvolopenten-l-yl ester.

1.5 ml of pyridine are introduced into a mixture containing 1.4 g of the compound prepared in step A, 10 ml of benzene and 750 mg (4S) -4-hydroxy-5-methyl-2- (2-propenyl) - cyclopent-2 - en-l-one. The reaction mixture is kept under stirring for 3 hours and poured into a mixture of ice water and. 2 UT hydrochloric acid (100 ml 35 and 20 ml). The aqueous suspension is extracted with ethyl acetate. The organic phases are washed with water until neutrality, dried, filtered and evaporated to dryness.

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15 which reduced pressure. 2.3 g of a compound are obtained which are chromatographed on silica gel; eluant: cyclohexane and ethyl acetate (8: 2), thus obtaining 486 mg of the expected compound, - + 26 ° + 2 ° (c = 0.5 $, benzene), 5 UMR ,, CDCl3, ppm: 1 , 28 and 1.32, the Hi methyl groups at the 2-position in cyclopropane, 1.88-2, H at the carbon atom at the 1-position in cyclopropane, 3.11 to 3.4, H at the carbon atom at the 3-position in cyclopropane, 1 ° 6.4 to 6.8, H at the carbon atom at the 1-position in ethenyl, 5.8-6, H at the carbon atom at the 2-position in ethenyl, 5, H at the carbon atom in isopropyl at the α-position in ratio of C = 0, 1.3, H at the carbon atoms of isopropyl at the β-position relative to CO, 4.8 to 5.2, H at the carbon atom at the 3-position at propenyl, 5.7, H at the carbon atom at the 4-position at (4S) -3-methyl-2- (2-propenyl) -1-oxocyclopent-2-en-4-yl, 2, H at the carbon atom at the 3-position at (4S) - 3-methyl-2- (2-20-propenyl) -1-oxocyclopent-2-en-4-yl.

Example 5, (IR, cis.A1) -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclo-propane carboxylic acid (1S) -cyan- (6- phenoxy-2-pyridinylmethyl methyl ester.

4.96 g of (IR, cis, AZ) -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclopropane carboxylic acid are introduced into 75 ml of methylene chloride. 2 ml of pyridine and 5.2 g of dicyclohexylcarbodiimide are then added.

Stir for a few minutes and introduce 5.9 g of (RS) -α-hydroxy-6-phenoxy-2-pyridinacetonitrile and then 0.1 g of 4-dimethylaminopyridine. The reaction mixture is kept under stirring for 1 hour and then filtered. The filtrate is evaporated under reduced pressure. Chromatograph the residue on a column and use as the eluent cyclohexane and ethyl acetate (85:15). In this way 7.7 g of the expected compound is obtained, Ojj = 59 ° + 2.5 ° (c = 0.5 $>, CHOlj).

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16 Ν, Μ, Ε., CDCl ^, ppm: 6.3 H carried by the carbon atom bearing the C $ group, 1 * 22 - 1.27 and 1.3 H in the methyl groups at the 2-position in cyclopropane, 3.17 to 3.5 H v. The carbon atom at the 3-position in cyclopropane, 3.7 H in the methoxv group, 5.8 to 6.0 ethylenic H at the α position relative to the carboxyl group, 6.3 to 6.6 ethylenically H at the β position relative to the carboxyl group, 6.9-7 H carried by the carbon atoms in the 3- and 5-position of pyridine, 7.7-7.8-7.9 H carried by the carbon atom of The 4-position in pyridine.

15

Example 6

(IR. Cis. ΔΖ) -2,2-dimethyl-3- (5-methoxy-5-oxo-1-propenyl) -oyolo-propanecarboxylic acid (1.3 <4> 5.6 «7-hexahydro-1, 3-dioxo-2H-iso indol-2-yl) -meth.vlester.

Working as in Example 1, Step B, from 1.5 g (1R, cis, AZ) -2,2-dimethyl-3- (methoxycarbonylethenyl) cyclopropane carboxylic acid chloride and 1.4 g 1.3, 4,5,6,7-hexahydro-2-hydroxymethyl-1H-isoindole-1,3 (2H) -dione gives 3 g of a compound which is chromatographed on silica gel eluting with cyclohexane and ethyl acetate (8: 2). Evaporate to dryness to give 1.86 g of the expected compound.

IMR, CDCl3, ppm: 1.27 and 1.3 H in the methyl groups at the 2-position in cyclopropane, 1.78-1.93 H carried by the carbon atom at the 1-position in cyclopropane, 3.06 -3.53 H carried by the carbon atom at the 3-position in cyclopropane, 5.8-6) H carried by the carbon atom at 2-still-6.4 to 6.8) gene in the ethenyl group, 3.7 H in the methyl group in the methoxy group, 1.6 to 2 H v. 4-, 5-, 6- and 7-carbon atoms in indole, 5.5 H in the methylene group at the α-position relative to CO2 associated with the carbon atom at the 1-position in cyclopropane.

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Example 7

(IR, C 1-6 Z 2 tg-dimethyl-5-thymethoxy) -oxo-1-propenyl] -cyclopropanecarboxylic acid (5- (phenylmethyl) -3-furanyl) methyl ester.

Working as in Example 1 from 3.22 g (IR, 5 cis, ΔΖ) -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclo-propane carboxylic acid chloride and 2, 8 g of 5- (phenylmethyl) -3-furanyl-methanol give 6.3 g of a compound which is chromatographed on silica gel eluting with cyclohexane and ethyl acetate (8: 2). Thus, 2.33 g of the expected compound is obtained, a-p = + 48 ° + 1.5 ° (c = 0.1%, CHCl 3).

JST.MR, CDCl3, ppm: 1.26-1.28 H in the methyl groups at the 2-position in cyclopropane, 1.86-2.02 H r, the carbon atom at the 1-position in cyclopropane 3.0 to 3.3 H at the carbon atom at the 3-position in cyclopropane, 6.4 to 6.8 H at the carbon atom at the 1-position in ethenyl, 5.8-5.9 H at the carbon atom at the 2-position in ethenyl, 3.7 H in the methoxy group 4.9 H in the CH 2 group at α position relative to CO, which is linked to the carbon atom at the 1 position of the cyclopropane group, 7.3 H at the carbon atom at the 2 position of the furanyl group, 6 H at the carbon atom at the 4-position in the furanyl group, 7.2 aromatic hydrogen atoms.

Example 8.

(IR. Cis. ΔΖ) -2,2-dimethyl-3- (3-propoxyl-3-oxo-1-propenyl) -cyclo-propanecarboxylic acid (1- (2-propenyl) -2.4) -dioxoimide azolidine-3-yl) methyl ester.

1.2 g (1R, cis, ÅZ) -2,2-dimethyl-3- (3-prop-oxy-3-oxo-1-propenyl) -cyclopropane carboxylic acid, 20 ml of methylene chloride and 100 ml of 4 -dimethylaminopyridine. 1 g of dicyclohexylcarbodiimide is then introduced into the solution thus obtained. 900 mg of 3-hydroxymethyl-1- (2-propynyl) -2,4-imidazolidinedione are added with stirring.

35 Stir for 16 hours at 20 ° C and filter. The filtrate was treated with Hi hydrochloric acid and then steamed to neutrality, dried and evaporated to dryness under reduced pressure.

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18

An oil is obtained which is chromatographed on silica gel eluting with benzene and ethyl acetate (8: 2). 1.2 g of the expected compound is obtained, ccjj = + 2 ° + 1 ° (c = 0.5 $, benzene).

EMR, CDOlj, ppm: 5 1.25 and 1.28 H in the methyl groups at the 2-position, 1.83-1.97 E at the carbon atom at the 1-position in cyclopropane, 3.0 to 3.4 Ξ at the carbon atom at the 3-position in cyclopropane, 6.4 to 6.7 H at the carbon atom at the 1-position in etbenyl, 5.6-5.8 E at the carbon atom at the 2-position in ethylene, 10-4.1-4, 2 Ξ in propoxy at α position relative to C = 0, 0.83-0.95-1.07 H in propoxy at α position relative to C = 0, 2.33-2.37-2, 41 H at the carbon atom at the 3-position in propynyl, 4 H at the carbon atom at the 3-position in 2,5-dioxoimidazolidinyl, 4.2-4.3 E in the methylene group at the α-position relative to the triple bond.

Example 9

(1 E, cis, ΔΖ) -2,2-dimethyl-5- (3-oxo-3-methoxy-1-propenyl) cyclopropane-1-carboxylic acid m-phenoxybenzyl ester.

20 g of methylene chloride are charged with 2 g of (ΐΕ, οϊε, Δ -) -2,2-dimethyl-3- (3-oxo-3-methoxy-1-propenyl) -cyclopropane-1-carboxylic acid, , 9 ml of pyridine and 2.5 g of dicyclohexylcarbodiimide. Stir for 10 minutes, add 2.4 g of m-phenoxybenzyl alcohol and stir for 1 hour 30 minutes, add 40 mg of dimethylaminopyridine, stir for 2 hours 30 minutes, eliminate the insoluble material formed by filtration, evaporate the filtrate to dryness under reduced pressure. pressure, chromatograph the residue on silica gel eluting with a mixture of cyclohexane and ethyl acetate (9: 1) to give 3 g (1R, cis, AZ) -2,2-dimethyl-3- (3-oxo- 3-methoxy-1-propenyl) -cyclopropane-1-carboxylic acid - m-phenoxybenzyl ester, α + + 48 ° + 1.2 ° (c = 1 $, chloroform).

Analysis: C23H24 ° 5 = 380.444 calculated: C $ 72.61 Ξ $ 6.36 found: 72.7 6.4 35 In analogy to Example 9, the following compounds can be prepared from the appropriate acids and alcohols:

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19

Example 10.

(IR) cis.AZ) -2. 2-dimethyl-1-3- (3-methoxy-3-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid-g- (ES) -cyan- (3- (4-bromophenoxy) -phenyl) - Methyl ester, 5 Analysis: 02/1 ^ 22 ^^^ 5 ~ 484 »342 Calcd: C $ 59.51 H $ 4.58 Br $ 16.50 11 $ 2.89 Found: 59.7 4.6 16.2 2.8 CDCl 3: - peaks from 1.26 to 1.34 ppm, which are added to the hydrogen atoms 10 in the twin methyl groups, - peaks at 1.97-2.06 and from 3.22 to 3.48 ppm, which are attributed to the urban drug atoms at the 1 and 3 positions in cyclopropyl, - peaks at 3.7-3.73 ppm, which are attributed to the hydrogen atoms in CO 2 -CH3, 15 peaks at 5.85-5.98 and 5.9-6, 03 ppm attributed to the ethylenic hydrogen atoms (ester side), - peak at 6.33 ppm attributed to the hydrogen atom in -CH-CN, - peaks of 6.43 to 6.67 ppm attributed to the ethylenic hydrogen atoms (cyclopropyl side), 20 - peaks from 6.85 to 7.52 ppm attributed to the hydrogen atoms in bromophenyl, - peaks from 6.94 to 7.55 ppm attributed to the hydrogen atoms in the second aromatic ring.

Example 11.

(IB. Cis.AZ) -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid ~ 4-oxo-4- (H) -pyranic acid 3-yl ester. mp. 106 ° C, ocD = + 153 ° ++ 2.5 ° (c * = 0.8 $, benzene) Example 12.

(IR.cis, ΔΖ) -2,2-dimethyl-3- (3-isopropoxy-3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid 1- (R) - (3-phenoxyphenyl) -eth .vlester. ocp = + 140 ° + 2.5 ° (c = 1 $, benzene) Example 13.

(1R.cis.AZ) -2,2-dimethyl-3- (5-ethoxy-5-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid -1- (R) - (3-phenoxyphenyl) - e th.vles ter.

At = + 145 ° ± 2.5 ° (c = 1 $, benzene)

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20

Example 14.

(IR, cis, Δ2) -2,2-dimethyl- (3- (5-methoxy-5-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid 1- (R) - (3-phenoxyphenyl) ethyl ester, ajj = + 130.5 ° + 2.5 ° (c = 1 $, chloroform)

Example 15

(1R.cis.AZ) -2.2-dimethyl-5- (5-methoxy-3-oxo-1-propenyl) -cyolo-propane-1-carboxylic acid (RS) -α-cyano- (5- benzoylphenyl) methyl ester. aD = + 43 ° i · * · 0 (° = toluene) 10

Example 16, (IR, cis, Δ Z) -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyolo-propane-1-carboxylic acid (5-benzoylphenyl) methyl ester, αE = + 5 ° ± 1.5 ° (c = 1 $, chloroform) 15

Example 17, (IR, cis, ΔΖ) -2,2-dimethyl-3-yl-5-methoxy-3-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid (2,5,4,5, 6-pentafluorpheny1) methyl ester.

+ = 29.5 ° + 2 ° (c = 0.8 °, chloroform) 20

Example 18.

(IR, cis, Z) -2,2-dimethyl-3- (3-methoxy-3-oxo-l-propenyl) -cyclo-propane-l-carboxylic acid (RS) -cyano (2,5,4 5,6-Pentafluorophenyl) methyl ester, Analysis: = 403.31 calculated: C $ 53.61 H # 3.50 1 $ 3.47 Ή 23.55 Found: 53.9 3.5 3.4 23.7

Example 19.

(IR, ois, Δ2) -2,2-dimethyl-5- (5-oxo-3-n-propoxyl-propenyl) -cyclo-propane-1-carboxylic acid (RS) -cyanamide 2- (6-Phenoxypyridyl) -me thyl ester, ot

Example 20

(IR, cis, ΔΖ) -2,2-dimethyl-3- (3-propoxy-3-oxo-1-propenyl) -ovolo-propane-1-carboxylic acid-11M [5-phenoxyphenyl) ethyl ester.

Ojj = + 123 ° + 2 ° (c = 0.9 / 3, chloroform)

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21

Example 21, (1H, cis <AZ) -2,2'-Dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid 1- (R) -5 -phenox.vphenyl) -2-propyn-l-yleEter.

= + 55.5 ° + 1.5 ° (c = Vfo, chloroform) 5

Example 22, (1R.cis + AZ) -2,2-dimethyl-3- (3-isopropoxy-5-oxo-1-propenyl) -cyclo-propane-1- (carboxylic acid) 1- (R) - (3 -phenoxyphenyl) -2-propynyl ester, m.p. 66UC.

= + 47 ° + i ° (c * 1.256, chloroform)

Example 23

(R 'cis.AZ) -2,2-dimethyl-3- (3-p-propoxy-3 ~ oxo ~ l ~ propenyl) ~ oyclo-propane ~ L-' ca.rboxyls.yre ~ R ~ (, 3 ~ pheGoxyphenyl) -2 ~ propyn ~ l-yles ter.

= + 48 ° + 2 ° (c = 156, chloroform).

Example 24.

(1R, cis.AZ) -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid ~ (4-benzoylphenyl) methyl ester.

20 = 46 ° + 2 ° (c = I56, chloroform)

Example 25

(IR, cis. AZ) -2,2-Dimethyl-3- (3-oxo-3-tert-butoxy-1-propenyl) -ylopropane-1-carboxylic acid (RS) -cyan-2- (6- phenoxypyridyl) -25 methyl ester.

= 68 ° + 1.5 ° (c = 156, chloroform)

Example 26

(IR.cis.ΔΖ) -2. 2-dimethyl-5- (3-methoxy-3-oxo-1-propenyl) -cyclo-, propane-1-carboxylic acid (RS) -oyan- (4-benzoylphenyl) methyl ester. Analysis: G25 ^ 23 ^ 5 ^ = 417.446 Calc'd: C $ 71.93 H $ 5.85 t0 3.35 Found: 71.9 5.8 3.2 35 Example 27.

(IR. Cis.AZ) -2- 2-dimethyl-3- (3-oxo-3-tert-butoxy-1-propenyl) oyclopropane-1-carboxylic acid ~ (5-propynyl-2 -yl-2,3-dioxolmidazoli-dinyl] -methyl ester.

= + 1 ° + 2 ° (c = 0.556. chloroform).

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22

Example 28 "(1R.cis" AZ) -2,2-Dimethyl-5- (5-isopropoxy-5-oxo-1-propenyl) cyclopropane-1-carboxylic acid (5-propyn-2-yl-2 (5-Dioxoimide azole-idinyl) methyl ester. SNP. 78 ° C.

Ajj = + 15 »5 ° + 1 ° (c = Ifo, chloroform)

Example 29 "(IR" cis "Ag) -2" 2-Dimethyl-3- (5-oclobutoxy-3-oxo-1-propenyl) oyclopropane-1-carboxylic acid (3-propyn-2-y (2- (5-Dioxoimidazole-idinyl) methyl ester.

α-Q = + 18 ° + 1 ° (c = 1.2 $, chloroform)

Example 50 "(IR" cis "ΔΖ) -2" 2-Dimethyl-5- (5-isobutoxy-5-oxo-1-propenyl) -15-cyclopropane-1-carboxylic acid 3-propyn-2-yl 2- (5-Dioxoimidazole-idinyl) methyl ester. α-Q = + 20.5 ° + 1.5 ° (c = 1 $, chloroform)

EXAMPLE 51 (20Roisoaz) -2,2-Dimethyl-5- (5-oxo-3-ethoxy-1-propenyl) oyclo-propane-1-carboxylic acid (5-propyn-2-yl) -2 '5-dioxoimidazolidinyl) -, methyl ester.

α-β = + 10 ° + 4 ° (c = 0.2 $, chloroform) Example 52.

(1R.cis.AZ) - 2,2-Dimethyl-5- (5-ethoxy-5-oxo-1-propenylcyolopropane-1-carboxylic acid-1- (R) - (5-phenoxyphenyl) -2-prop .yn-l-yl ester.

Ojj = + 48.5 ° + 2 ° (chloroform) Example 35 "(IR" cis "ΔΖ) -2,2-Dimethyl-3 ~ (3 ~ oxo-5-isopropoxy-1-propenyl) -ylo-clopropane -1-carboxylic acid (5-benzyl-5-furyl) methyl ester. ccjj = + 44 ° + 2 ° (c = 0.4 $, chloroform) Example 34.

(IR c cis ΔΖ) -2 «-dimethyl-1-3- (3-oxo-3-isopropoxy-propenyl) -cyclo-propane-1-carboxylic acid m-phenoxybenzyl ester.

ctjj = + 42 ° + 2 ° (c = 0.5 $, chloroform).

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23

Example 55 (& R.ois.ΔΖ) - 2,2-Dimethyl-3- (3-chloro-3-cyclopropylmethoxy) -propenyl) -ocyclopropane-1-carboxylic acid (RS) -cyan-2- ( 6-phenox.yp.yri-dyl) methyl ester.

5 = + 53 ° + 2 ° (c = 0.5 $, chloroform)

Example 56

(IR (cis.ΔΖ) -2,2-dimethylchyl-3- (5-oxo-5-n-propoxypropenyl) -cyclopropane-1-carboxylic acid γ-5-benzyl-5-furyl) methyl ester , Α-rj = + 41 ° + 2 ° (c = 0.5 $, chloroform)

Example 57.

(Ia.cis' AZ) -2,2-aimeth.yl-5- (3-oxo-5-isopropoxypropenyl) -c.yclo-propan-l-carboxylic acid 1.5.4.5 '6' 7-hexahydro-1,5- dioxo-2H-iso-15 * (3ol-2-yl) methyl ester. mp 94 ° C.

Or) - -22.5 ° + 2 ° (o = o, $ 5, chloroform).

Example 58

(ljR.cis.AZ) -2,2 ~ d ime th, yl -5- (3-oxo-5-n-pr opoxy-1-propenyl) py clo-20 Propane-1-carboxylic acid - (1.5.4 "5" 6 "7-Hexahydro-1,3-dioxo-2H-iso-indol-2-yl) -methyl ester" m.p. 76 ° C.

(15 = -15 ° (c = 0.15 $, carbon tetrachloride)

Example 59.

(IR) cis. ΔΖ) -2,2-dimethyl-5- (5-oxo-5'-n-propoxy-1-propepyl) -cyclopropane-1-carboxylic acid m-pheaoxybenzyl ester. = + 40 ° + 2 ° (c = 0.5 $, chloroform)

Example 40.

(1R.cis.AZ) -3- (5-oxo-5-cyclopropylmethoxy-1-propenyl) -cyolo-propane-1-carboxylic acid m-phenoxybenzyl ester.

(¾ = + 46.5 ° + 2 ° (c = 0.6 $, chloroform)

Example 41.

(1R-cis.AZ) -2,2-dimethyl-5- (5-cyclobutoxy-5-oxo-1-propenyl) -cyclopropane-1-carboxylic acid 1- (R) - (5-phenoxyphenyl) ethyl te r. (¾ = + 125.5 ° + 2 ° (c = 1 $, chloroform)

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24

Example 42

(IR, cis, AZ) -2,2-Dimethyl-3- (3-oxo-5- (cyclopropylmethoxy) -1-propenyl) -cyclopropane-1-carboxylic acid (1.5 7-Hexahydro-1,3-dioxo-2H-isoindol-2-yl) methyl ester, m.p. 102 ° C, 5 = + 6.5 ° + 2 ° (c = 0.3 $, chloroform)

Example 45

(IR, cis, Z) -2.2-dimethyl-3- (3-oxo-5- (cyclopropylmethoxy) -l-propenyl) -cyclopropane-l-carboxylic acid (5-benzyl-3-furyl) methyl ester. Ajj = + 42 ° + 2 ° (c = 0.7 $, chloroform)

Example 44

(IR, cis, ΔΖ) -2,2-dimethyl-3- (3-oxo-3- (cyclopropylmethoxy) -1-propenyl) -cyclopropane-1-oreboxylic acid (S) -2-methyl-4 oxo-3- (2-propenyl) -2-cyolopentenyl ester <oj = + 64.5 ° + 2.5 ° (c = 1

Example 45

(IR. Cis. ΔΖ) -2,2-dimethyl-3- (5-cyclopentyloxy-3-oxo-1-propenyl) -20-cyclopropane-1-carboxylic acid (3-propyn-2-yl-2) 5-dioxoimidazole-idinyl) methyl ester, α D = + 15.5 ° + 1.5 ° (c = 1 $, chloroform)

Example 46

(IR, cis, ΔΖ) -2,2-dimethyl-3- (5-oxo-5-oyolopentyloxy-1-propenyl) cyclopropane-1-carboxylic acid (RS) -cyan-2- (6-phenoxy) -6-pyriainyl) -, methyl ester.

Oj) = + 42 ° + 1 ° (c = 0.9 $, benzene) Example 47 + (IR, cis, ΔΖ) -2,2-dimethyl-5- (5-methoxy-5-oxo-1 propenyl) oyclo-propane-1-carboxylic acid (5-propyn-2-yl-2,5-dioxoimidazolidinyl) methyl ester, an = ca. + 1 ° (c = 0.5 $, benzene)

Xj 99 35

Example 48 ((IR, cis, ΔΖ) -2,2-dimethyl-5- (5-se c, -butoxy-3-oxo-1-propenyl) -cyclopropane-1-oreboxylic acid (3-propyn) -2-yl-2,5-dioxoimide azolidinedyl) methyl ester, n + 16.5 µl + 1 ° (c = 0, S $, chloroform)

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Example 49.

(IR, cis, ΔΖ) -2,2-Dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid (S) -cyan-3-phenoxy-4- fluorophenylmethyl ester, 5 dj = + 66.5 ° + 2.5 ° (c = 0.5 $, benzene)

Example 50

(IR. Cis, ΔΖ) -2,2-dime thyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclo-propane-1-yl acid - (RS) -1 - (4-fluoro-3-phenoxyphenyl) -2-pro-10 Pvn-1-yl ester.

EME, CEC15: - peaks from 1.22 to 1.32 ppm attributed to the hydrogen atoms in the twin methyl groups, - peaks at 1.09 - 2.05 and from 3.1 to 3.43 ppm attributed to the hydrogen atoms in 1- and the 3-position in cyclopropyl, - peaks from 2.62 to 2.66 ppm, which are attributed to the hydrogen i = CH, - peaks at 3.72 to 3.73 ppm, which are attributed to the hydrogen atoms in CO2-CH3, - peaks from 5 , 8 to 6 ppm attributed to the ethylenic hydrogen (ester side), - peaks of 6.38 to 6.83 ppm attributed to the ethylenic hydrogen (cyciopropyl side), and the hydrogen of 002-0Ε2 - peaks of 6.9 to 7.55 ppm, which is attributed to the hydrogen atoms in the aromatic rings.

25

Example 51.

(1R.cis.AZ) -2,2-dimethyl-3- (3- (11-dimethylethoxy) -3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid (ES) -1- (4- fluoro-3-phen ~ ocyphenyl) -2-prop.yn-l-yl ester.

30 N.M.R., CECl *:

S

- peaks from 1.22 to 1.31 ppm attributed to the hydrogen atoms in the twin methyl groups, - peaks at 1.47-1.5 ppm attributed to the hydrogen atoms in tert-butyl, 35 - peaks veo 1.87 to 2.01 and from 3.12 to 3.43 ppm attributed to the hydrogen atoms at the 1- and 3-position in cyclopropyl, - peaks from 2.6 to 2.65 ppm attributed to the hydrogen i = CH,

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26 - peaks at 5.7-5.9 ppm attributed to the ethylenic hydrogen (ester side), - peaks from 6.28 to 6.72 ppm attributed to the ethylenic hydrogen (cyclopropyl side) and the hydrogen in C 5 - peaks from 6.91 to 7.55 ppm attributed to the hydrogen atoms in the aromatic rings.

Example 52

(IR «cis.ΔZ) -2,2-dimethyl-3- (5-methoxy-5-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid (SS) -1- ( 6-phenyl-2-pyridinyl-2-propyn-1-yl ester.

EMR, CBC +: - peaks from 1.23 to 1.31 ppm attributed to the hydrogen atoms in the twin methyl groups, 15 peaks at 1.96-2.1 and from 3.13 to 3.47 ppm attributed to the hydrogen atoms in 1 - and 3-position in cyclopropyl, - peaks from 2.59 to 2.63 ppm attributed to the hydrogen ice = CH, - peak at 3.73 ppm attributed to the hydrogen atoms in COgCH 2, - peaks from 5.78 to 6 , 02 ppm attributed to the ethylenic hydrogen (ester side), - peaks at 6.3-6.34 ppm attributed to the hydrogen in CO 2 -CH, - peaks from 6.43 to 6.88 ppm attributed to the ethylenic hydrogen (the cyclopropyl side), - peaks from 6.75 to 7.9 ppm, attributed to the hydrogen atoms 25 in the aromatic rings.

Example 53.

(IR. Cis «ΔΖ) -2« 2-ηmethyl 1-5- (3- (1 «1- <3imethylethoxy) -3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid (BS) - (6-Phenoxy-2-pyridinyl) -2-propyn-1-yl ester.

RMR, CDC15: - peaks from 1.24 to 1.32 ppm attributed to the hydrogen atoms in the twin methyl groups, - peak at 1.5 ppm attributed to the hydrogen atoms in tert-butyl, - peaks at 1.93- 2.07 and from 3.13 to 3.46 ppm attributed to the hydrogen atoms at the 1- and 3-position in cyclopropyl,

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27 - peaks from 2.59 to 2.63 ppm attributed to the hydrogen in 2 CH, - peaks from 5.68 to 5.90 ppm attributed to the ethylenic hydrogen (ester side), - peaks at 6.3-6, 34 ppm attributed to the hydrogen in C1 -C1W, 5 - peaks from 6.47 to 6.86 ppm attributed to the ethylenic hydrogen (cyclopropyl side), - peaks from 6.75 to 7.9 ppm attributed to the hydrogen atoms in the aromatic rings, 10

Example 54, (1R.cis <gAZ) -2,2-dimethyl-5- (5- (1'-dimethylethoxy) -3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid phenyl - peaks at 1.28 to 1.32 ppm attributed to the hydrogen atoms of the twin methyl groups, - peak at 1.5 ppm attributed to the hydrogen atoms in tert-butyl, - peaks at 1, 9-2.04 and from 3.08 to 3.41 ppm attributed to the hydrogen atoms in the 1- and 3-position in cyclopropyl, 20 - peak at 5.15 ppm attributed to the hydrogen atoms in COg-CE 2 - c6h5, - peaks at 5.72-5.92 ppm attributed to the ethylenic hydrogen (ester side), 25 - peaks from 6.38 to 6.75 ppm attributed to the ethylenic hydrogen (cyclopropyl side), - peak at 7.4 ppm , which is attributed to the hydrogen atoms in the aromatic ring, 3Q Example 55 '(1R.cis, AZ) -2,2-dimethyl-5- (3- (1'-dimethylethoxy) -3-oxo-1-propenyl) cyclopropane 1-carboxylic acid (6-phenoxy-2-pyridinyl) methyl ester.

N.M.R., CDCl3: 35 - peaks at 1.3-1.32 ppm attributed to the hydrogen atoms in the twin methyl groups, - peak at 1.51 ppm attributed to the hydrogen atoms in tert-butyl,

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28 - peaks at 1.96-2.11 and from 3.13 to 3.47 ppm attributed to the hydrogen atoms in the 1- and 3-position in cyclopropyl, - peak at 5.13 ppm attributed to the hydrogen atoms in CC CEg - peaks at 5.73-5.92 ppm attributed to the ethylenic hydrogen (ester side), - peaks from 6.37 to 6.73 ppm attributed to the ethylenic hydrogen (cyclopropyl side), - peaks at 7.58-7.72-7.85 ppm attributed to the hydrogen atoms in the pyridyl ring, 10

Example 56 «(1E, cis.AZ) -2,2-Dimethyl-5- (5-methoxy-3-oxo-1-propenyl) -cvolo-propane-1-carboxylic acid (6-phenoxy) 2-pyridinyl) methyl ester.

CDC13: 15 - peak at 1.3 ppm attributed to the hydrogen atoms in the twin methyl groups, - peaks at 1.98-2.13 and from 3.13 to 3.45 ppm attributed to the hydrogen atoms at the 1 and 3 positions in cyclopropyl, - peak at 3.74 ppm, which is attributed to the hydrogen atoms in COg-CE ^, 20 - peak at 5.12 ppm, which is attributed to the hydrogen atoms in COg-C2 -, - peaks at 5.82-6.02 and from 6.5 to 6.87 ppm attributed to the ethylenic hydrogen atoms; peaks from 7 to 7.85 ppm attributed to the hydrogen atoms in the aromatic rings.

25

Example 57.

(IB, cis, ΔΖ) -2,2-dimethyl-5- (3- (1,1-dimethylethoxy) -3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid (RS) - (6) -phenoxyl-2-pyridinyl) ethyl ester.

30 R.M.R., CEC15: - peaks from 1.25 to 1.32 ppm attributed to the hydrogen atoms in the twin methyl groups, - peaks at 1.47-1.57 ppm attributed to hydrogen atoms in COP-CH - ** »% 35

DK 163918 B

29 - peak at 1.5 ppm »attributed to the hydrogen atoms in tert-butyl, - peaks at 1.95-2.09 and from 5.12 to 5.43 ppm attributed to the hydrogen atoms in 1- and 3- the position in cyclopropyl, 5 - peaks from 5.63 to 5.97 ppm attributed to the hydrogen in CO 2 -CHm, - peaks from 5.67 to 5.92 and from 6.32 to 6.75 ppm attributed to the ethylenic hydrogen atoms, - peaks from 6.67 to 7.5 ppm attributed to the hydrogen atoms 10 in the aromatic rings, - peaks from 7.55 to 7.83 ppm attributed to the hydrogen atoms in the pyridyl ring.

Example 58

(IR) cis, Δ2) -2 '2-Dimethyl-5- (5-methoxy-5-oxo-1-propyl) -cyclopropane-1-carboxylic acid (HS) -1- (6- phenoxy-2-pyridinyl) -ethyl ester. CEC1: - peaks from 1.25 to 1.3 ppm attributed to the hydrogen atoms in the twin methyl groups, 20 - peaks from 1.43 to 1.57 ppm attributed to the hydrogen atoms in CO 2 -CH-c »i% - peaks at 1 , 97-2.11 and from 3.1 to 3.42 ppm attributed to the hydrogen atoms at the 1- and 3-position in cyclopropyl, - peaks from 5.63 to 6.08 ppm attributed to the hydrogen in OOp -CH 2, - peaks from 5.78 to 6.02 and from 6.45 to 6.87 ppm, are attributed to the ethylenic hydrogen atoms, - peaks from 6.67 to 6.8 and from 7 to 7.67 ppm attributed to the hydrogen atoms in the aromatic rings, - peaks from 7.55 to 7.83 ppm, attributed to the hydrogen atoms in pyridyl.

35

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30

Example 59 «(IR. Cis« ΔΖ) -2. 2-dimethyl-3- (3- (1'-dimethylethoxy) -3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid (3- (phenylcarbonyl) -phenyl) -methyl ester.

Analysis: C27K30 ° 5 = 434.537 calculated: C% 74.63 H% 6.96 found: 74.60 7.00

Example 60

(IS, cis. ΔΖ) -2,2-dimethyl-3- (3-tert-butoxy-3-oxo-1-propenyl) -1-cyclopropane-1-carboxylic acid 1-R (5-Phenox.yphenyl) -2-prop.yn - 1-ylestsr.

Oq = + 58 ° + 1.5 ° (c = 1.2%, chloroform) Example 61.

(1H.cis.-AZ) -2,2-dimethyl-3- (3-oyclopropylmethoxy-3-oxo-1-pi, o-penyl) -cyolopropanecarboxylic acid (1L) - (3-Phenox, yphenyl methyl) -ester, - + 121 ° + 3 ° (c = 0.6%, chloroform) 20

Example 62

(IR, cis.ΔΖ) -2,2-dimetby1-3- (3-cyclopropyImethoxy-3-oxo-1 - propenyl) -c.yclopropanoarboxyls.vre- (5-PXQP.yn-2-yl-2.5- dioxo-imidazolidinyl) methyl ester.

Ajj = + 14 ° + 2 ° (c = 0.5%, chloroform)

Example 63 "(IR. Cis. ΔΖ) -2,2-Dimethyl-5- (3-cyclopropylmethoxy) -3-oxo-1-propenyl) cyclopropanecarboxylic acid - (IB) - (3-phenoxyphenyl) ) -2 -pr o-30 P.yn-ly lester.

α-Q = + 46 ° + 2 ° (c = 0.5%, chloroform)

Example 64 "(IR, cis, ΔΖ) -2" 2-Dimethyl 1-3- (3-n-butoxyl-3-oxo-1-propenyl) -35-cyclopropanecarboxyl acid (3-propyn-2-yl-2 <5-dloxoimidazole-> idinyl) methyl ester, α-rj = + 17 ° + 1 ° (c = 1%, chloroform)

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31

Example 65 (IR, αis) ΔΖ) -2,2-Dimethyl-3- (3-thoxy-3-oxo-1-propenyl) cyclo-propane carboxylic acid ~ (S) -c. yan- (5 ~ Pheno3: y - 4-i'luorghen.vl) methyl ester.

+ 47.5 ° + 2 ° (c = 0.5 $, chloroform)

Example 66, (1R.cis.AZ) -2,2-dimethyl-5-yl-isopropoxy-3-oxo-1-propenyl) oyclopropane carboxylic acid (S) -cyan- (3-phenoxy-4-fluorophenyl) -10-methyl ester, <Xp = + 50 ° + 2 ° (c = 0.3 $, chloroform)

Example 67

(IR. Cis.ΔΖ) -2,2-dimethyl, 3- (3-cyclopropylmethoxy-3-oxo-1-prop-phenyl) -cyclopropanecarboxylic acid (S) -cyan- (3-phenoxy) -4-fluoro-phenyl) -methyl ester. ou = + 53 ° (c - 0.25 $, chloroform)

Example 68.

(1H, cis.ΔΖ) -2,2-dimethyl-3- (3-tert-butoxy-3-oxo-1-propenyl) -cyclopropane carboxylic acid (2.3.4.5.6-pentafluorophenyl) -me th.vl-sister.

aD. = + 37.5 ° + 1.5 ° (c = 1 $, chloroform) Example 69.

C IR.cis.ΔΖ) -2,2-Dimethyl-3- (3-tert-butoxy-3-oxo-1-propenyl) -cyclo-propanecarboxylic acid (3-Phenoxy-4-fluorophenyl) methyl ester. αΰ = + 55.5 ° + 2.5 ° (c = 0.5 $, chloroform) Example 70.

(LR.cis.AZ) -2.2-dimetfcyl-5- (3-methoxy-3-oxo-l-propenyl) -eyclo-propapcarboxylsyre- (5-Phenoxy-4-fluorophenyl) methyl ester. α-β = + 50.5 ° + 2.5 ° (c = 0.55 $, chloroform) 1

Example 71.

(LR.cis.AZ) -2.2-dimethyl-3- (3-tert-butoxy-3-oxo-l-propenyl) - cyclopropanecarboxylic acid (LR S) - (3-phenoxy-4-fluorophenyl) eth. yl ester.

TT TiT * D Λ * ΠΠΊ ·

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32 - peaks from 1.19 to 1.28 ppm attributed to the hydrogen atoms in the twin methyl groups, - peaks at 1.48-1.5 ppm attributed to the hydrogen atoms in tert-butyl, 5 - peaks from 1.41 to 1, 53 ppm, which is attributed to the hydrogen atoms in CO 9 -CH 2 qe 3 - peaks at 1.85-1.99 and from 3.07 to 3.38 ppm attributed to the hydrogen atoms at the 1- and 3-position in cyclopropyl, - peaks from 5.58 to 6 and from 6.27 to 6.7 ppm attributed to the ethylenic hydrogen atoms, peaks from 6.27 to 6.7 ppm attributed to the hydrogen atom in COp-OHn

b I

15 - peaks from 6.92 to 7.53 ppm, which are attributed to hydrogen atoms in the aromatic rings.

Example 72

(IR.cis.AZ) -2,2-Diaethyl-5- (5-methoxy-5-oxo-1-propenyl) -cyclopropanecarboxylic acid (1BS) - (3-Phenoxy-4-fluorophenyl) ethyl ester . CSC13: - peaks from 1.19 to 1.29 ppm attributed to the hydrogen atoms in the twin methyl groups, - peaks from 1.41 to 1.54 ppm attributed to the hydrogen atoms 25 in CO / p-GH-, tc% - peaks at 1.87-2.02 and from 3.07 to 3.22 ppm attributed to the hydrogen atoms at the 1- and 3-position in cyclopropyl, 30 peaks from 5.82 to 6.17 attributed to the hydrogen atom in CO -CHr "c" - peaks from 5.93 to 6.2 and from 6.58 to 7 ppm attributed to the ethylenic hydrogen atoms, 35 peaks from 7.03 to 7.72 ppm attributed to the hydrogen atoms in the aromatic rings .

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33

Example 73 (IR, cis. ΔΖ) -2,2-dimethyl-3- (3-tert-butoxy-5-oxo-1-propenyl) -cyclopropane carboxylic acid 5-benzyl-5-furyl methyl ester.

aD = + 54.5 ° + 1.5 ° (c - 1 $, chloroform) 5

Example 74 "(IR. Cis. ΔΖ) - 2" 2-Dimethyl-3- (3-tert-butoxy-3-oxo- (1-propenyl) -cyclopropanecarboxylic acid (1S) -2-methyl) 4-oxo-3- (2-propenyl) - cyclopenten-l-yl ester.

+ 73 ° (c = 0.25 $, chloroform)

Example 75

(IR. Cis. ΔΖ) -2,2-3-dimethyl-5- (3-methoxy-5-oxo-1-propenyl) -cyclopropanecarboxylic acid (2-henoxy-5-thiazolyl) methyl ester.

Mp 62 ° C, α-β = + 60.5 ° + 1.5 ° (c = 1.5 $, benzene)

Example 76

(IR.cis.ΔΖ) -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -oyclo-propanecarboxylic acid ~ (RS) -thioamidophenoxyphenylmethyl ester.

IR spectrum: - absorptions at 1652 cm -1 (C = C) 3475-3365 cm -1 (0 = 3) t m0 25 in 1713-1736 cm -1 (0 = 0) HMR, CEClj: - peaks at 1 , 25-1.27-1.30 ppm attributed to the hydrogen atoms in the twin ethyl groups, 30 - peaks at 1.97-2.11 ppm attributed to the hydrogen atom at the 1-position in cyclopropyl, - peaks at 3.08-3, 43 ppm attributed to the hydrogen atom at the 3-position in cyclopropyl, - peaks at 3.69-3.72 ppm attributed to the hydrogen atoms in the methyl group in methoxycarbonyl, - peaks at 5.73-5.92 ppm and 5.8- 5.99 ppm, which is attributed to the ethylenic hydrogen atom at the α position of CO 2 ~ CH 2,

DK 163918 B

34 - peaks at β, 32-6.66 ppm attributed to the ethylenic hydrogen atom at the 1-position of -CC

“Peak at 6.42 ppm, which is attributed to the hydrogen bonded to the carbon atom bearing the group -C-HH

5 'i

Example 77

(IR) cis ΔΖ) -2 "2-Dimethyl-3- (3-tert" -butoxy-5-oxo-1-propenyl) -cyclopropane carboxylic acid (2-phenyl-5-thiazolyl) methyl ester. α-jj = + 68 ° + 1.5 ° (c = 1 $, chloroform)

Example 78

(1R.cis.AZ) -2,2-dimethyl-5- (5-methoxy-3-oxo-1-propenyl) -cyclo-propanecarboxylic acid (IRS) -oyan- (2-phenoxy-5-thiazolyl) -methyl-methyl j.

ester «oc-j-j = + 60 ° + 2 ° (c = 1 $, chloroform)

Example 79

(1 E "cis" Δ -2) -2 "2-Dimethyl-3- (3-tert-butoxy-3-oxo-1-propenyl) cyclopropanecarboxylic acid (RS) -oyan- (2-phenoxy) -5-thiazolyl) -, methyl ester.

ojj = + 65 ° + 2 ° (c = 0.5 $, chloroform)

Example 80 «(IR- [alpha] az) -2 + 2-dimethyl-5- (5-isopropoxy-5-oxo-1-propenyl) cyclopropane carboxylic acid (1R) -3-Phenoxyphenylethyl ester. α-β = + 59 ° + 1.5 ° (c = 1 $, chloroform)

Example 81.

2 Q ~ (IR. Cis. ΔΖ) -2,2-Dimethyl-3- (3-allyloxy-5-cxo-1-propenyl) -cyclopropanecarboxylic acid 1- (R) - (3-Phenoxyphenyl) ethyl ester. Step A: (IR) cis -2-2-Dimethyl-3- (3.3,3-trichloroethoxy-3-oxo-propynyl) -cyclopropanecarboxylic acid tert -butyls.

6.2 g of dicyclohexylcarbodiimide is introduced into a solution containing 7.15 g (IR, cis) -2,2-dimethyl-3- (3-hydroxy-3-oxopropynyl) cyclopropanecarboxylic acid tea rt.-butyl ester, prepared as set forth in Preparation 2A, and 80 mg of dimethylamino amine in 35 ml of methylene chloride. The reaction mixture is stirred for 1 minute and 4.5 g of 2,2,2-trichloroethanol are added. Stir under stirring for 1 hour and eliminate the formed precipitate by filtration. The filtrate is washed with 5 L hydrochloric acid and then with water until neutrality, dried and evaporated to dryness. 14 g of an oil is obtained which is chromatographed on silica gel eluting with a mixture of benzene and ethyl acetate (97 * 5). Thus, 9 g of the expected compound are isolated, m.p. 7C-71 ° C.

Step B: (IR. Cis) -2,2-dimethyl-5- (5.5,5-trichloro-thoxy-3-o: xo-propynyl) -cyclopropane carboxylic acid.

Can reflux for 1 hour a mixture containing 11.4 g of the compound prepared according to step A, 120 ml of toluene and 300 mg of p-toluenesulfonic acid. Can recharge room temperature and wash the reaction mixture with water, dry it and evaporate to dryness. Thus, 9.5 g of the expected compound is obtained, which is used immediately in the following step.

Step C: (15.cis) -2,2-Dimeth.71-5- (5.5.5-Trichloroethoxy-5-oxo-propypyl) ocyclopropanecarboxylic acid () - (5-Pheaoxyphenyl) ethyl ester .

6 g of the compound obtained in step B are mixed, 30 ml of methylene chloride and 600 mg of 4-dimethylaminopyridine.

Then, slowly, in the solution thus obtained at 0 ° C, stir in 3.95 g of dicyclohexylcarbodiimide, stir for an additional 30 minutes, still at 0 ° C, and add dropwise a solution of 4.1 g of 1- (R) - (3-phenoxyphenyl) ethanol in 12 ml of methylene chloride.

May stir the reaction mixture for 17 hours at room temperature and filter. The filtrate is evaporated to dryness under reduced pressure. An oil is obtained which is chromatographed on silica gel eluting with cyclohexane and ethyl acetate (8: 2). 4.4 g of the desired compound are obtained.

Step D: (IR.cis) -2,2-Dimethyl-5- (5-hydroxy-3-oxopropynyl) -35-cyclopropanoarboxylic acid -1β- (5-phenoxyphenyl) ethyl ester.

0.53 g of zinc powder is introduced into a solution with stirring.

DK 163918B

36 solution of 4.16 g of the compound prepared in step C in 4 ml of methylene chloride and 45 ml of acetic acid. The mixture is stirred for 30 minutes at room temperature and then 0.53 g of zinc powder is added again. This operation is repeated two more times 5 and then, by filtration, the remaining zinc which is rinsed with 40 ml of water and 100 ml of methylene chloride is eliminated.

Extract with methylene chloride. Wash, dry and evaporate to dryness under reduced pressure. Thus, 3.05 g of the expected compound are obtained.

Step Bt (1R.ois.AZ) -2,2-dimethyl-3- (5-hydroxy-3-oxo-1-propenyl) -cyciopropanoarboxylic acid 1- (R) - (3-Phenoxyphenyl) ethyl ester.

Hydrogenation of 3 g of the compound of the previous step is carried out in the presence of 80 ml of ethyl acetate in the presence of 500 mg of palladium hydroxide ($ 10 on barium sulfate) and 0.9 ml of quinoline. The filtrate is filtered and washed with hydrochloric acid and then with water. Dry and evaporate to dryness under reduced pressure. Thus, 2.9 g of the expected compound, 20 Step Pi (1R.cis.AZ) -2,2-dimethyl-3- (5-allyloxy-5-oxo-1-prope-nyl) -oyolopronanecarboxylic acid 1- ( R) - (3-phenoxyphenyl) -, ethyl ester.

1.4 g (1R, cis, AZ) -2,2-dimethyl-3 * - (3-hydroxy-3-oxo-1-propenyl) -cyclopropanecarboxylic acid 1- (R) - (3- 25-phenoxyphenyl) ethyl ester (prepared in step E), 7 ml of methylene chloride and 0.14 g of 4-dimethylaminopyridine. 760 mg of dicyclohexylcarbodiimide is stirred at 0 ° C, stirred for an additional 20 minutes at 0 ° C, and at this temperature 0.26 ml of allyl alcohol is then added to 2 ml of methylene en chloride. The mixture is stirred at room temperature for 1 hour and then the reaction mixture is filtered. The filtrate is evaporated to dryness under reduced pressure to give an oil which is ehromatographed on silica gel eluting with hexane and isopropyl ether (8: 2). 570 mg of the expected compound are obtained, = + 109.5 ° 35 + 2 ° (c = 1 $, chloroform).

37

Example 82, (1R + cis, AZ) -2,2-Dimethyl-3- (3-tert-butoxy-3-oxo-1-propenyl) -cyclopropane carboxylic acid 1- (R) - (3-Phenoxyphenyl) ethyl ester.

While stirring at room temperature, 1.4 g of 5-tert.-butyl-1TjIT'-diisopropylurea are introduced into a solution of 1,74 g (1R, cis, AZ) -2,2-dimethyl-3- (3- hydroxy-3-oxo-1-propanyl) -cyclopropane carboxylic acid 1- (R) - (3-phenoxyphenyl) ethyl ester (prepared according to the procedure of step S of Example 81) in 8 'ml of ethyl acetate. Lian stirs another 4 hours and then filters. The filtrate is evaporated to dryness under reduced pressure. Pure obtained compound is chromatographed on silica gel eluting with hexane and ether (| 3: 2). Thus, 930 mg of the expected compound is obtained with m.p. 80 ° C,

At + 125 ° + 2 ° (c = Ifo, chloroform), 15

Example 83.

(IR, cis, ΔΖ) -2,2-dimethyl-3- (3-tert-butoxy-3-oxo-1-propenyl) cyclopropane carboxylic acid m-phenoxybenzyl ester.

Step A: (IR.cis) -2,2-dimethyl-3- (3.3,3-trichloroethoxy-3-oxo-propynyl) -oyolopropane carboxylic acid m-phenoxybenzyl ester.

6.7 g (1R, cis) -2,2-dimethyl-3- (3,3,3-trichloroethoxy-3-oxopropynyl) -cyclopropane carboxylic acid (prepared according to step B of Example 81), 67 ml of methylene chloride are mixed. and 200 mg of 4-dimethylaminopyridine are then added at 0 ° and with stirring 4.5 g of m-phenoxybenzyl alcohol in 5 ml of methylene chloride and then a solution of 4.4 g of dicyclohexylcarbodiimide in 5 ml of methylene chloride. The reaction mixture is stirred for 3 hours at room temperature and filtered. The filtrate is evaporated to dryness under reduced pressure to give II, 5 g of an oil which is chromatographed on silica gel, eluting with cyclohexane and ethyl acetate (85 * 15). Rer is available 7.1 g of the expected compound.

Step B: (1R.cis) -2,2-Dimethyl-3- (5-hydroxy-3-oxopropynyl) -35-cyclopropane carboxylic acid m-phenoxybenzyl ester.

While stirring, 5 g of zinc powder is introduced into a solution of 5 g of the substance of step A in 18 ml.

DK 163918 B

38 acetic acid and 2 ml of water. The mixture is stirred for 2 hours at room temperature and then, by filtration, the residual zinc which is rinsed with water and then with methylene chloride is removed. The organic phase is washed with water, dried 5 and evaporated to dryness under reduced pressure. The resulting residue is taken up in toluene which is evaporated to dryness under reduced pressure. This last operation is performed 3 times. Thus, 3.6 g of compound is obtained, which is used immediately in the next step.

Step G: (IR, cis) -2,2-dimethyl-3- (3-tert-butoxy-3-oxo-propynyl) -cyclopropanecarboxylic acid m-phenoxybenzyl ester.

4 ml of o-tert.-butyl-U, .alpha.-diisopropylurea are added dropwise with stirring at room temperature in 2 g of the compound obtained in the previous step. Then 25 ml of ethyl acetate is added and stirred for 1 hour. The excess reagent is destroyed by the addition of 2 ml of acetic acid and further stirred for 15 minutes. Filter, rinse with ethyl acetate and evaporate the filtrate to dryness. 2.8 g of an oil is obtained which is purified by chromatography on silica gel eluting with 20 cyclohexane and ethyl acetate (8: 2). 1.4 g of the expected compound is thus obtained.

Step D: (1R.cis.AZ) -2> 2-H 3 -methyl-3- (5-tert-butoxy-5-oxo-1-propenyl) -cyclopropane carboxylic acid m-phenoxy-benzyl ester hydrogenation of 1.4 g of the compound prepared in rich steps in 30 ml of ethyl acetate in the presence of 500 mg of palladium hydroxide ($ 10 on barium sulfate) and 0.7 ml of quinoline. Filter, wash the filtrate with 2 vas hydrochloric acid and with water, dry it and evaporate to dryness under reduced pressure. Thus, an oil is obtained which is purified by double chromatography on silica gel eluting with cyclohexane and ethyl acetate (9: 1 the first time and 95: 5 the second time).

Thus, 1 g of the expected compound is obtained, = + 38.5 ° + 2.5 ° (c = 0.5 $, benzene).

35 39

Example 84

(1E.cis.AZ) -2,2-Dimethyl-3- (3-oxo-5-ethoxyl-propenyl) -oycio-propanecarboxylic acid - (5S) -cyan-2- (6-ph an oxy pv ridy 1) -mg thyle ste r Step A; (ia.cis) -2,2-dimethyl-5- (5-03CO-5-methoxypropynyl) -5-cyclopropane carboxylic acid.

A solution containing 2.6 g of (1B, cis) -2,2-dimethyl-3- (3-oxo-3-methoxy-propynyl) -cyclopropane carboxylic acid tert-butyl ester prepared according to step A is refluxed for 1 hour 30 minutes. in preparation 1, 25 ml of toluene and 100 mg of 10β-toluenesulfonic acid. Can allow to re-enter room temperature, keep the reaction mixture under stirring for 20 hours and then evaporate to dryness under reduced pressure. Dec is obtained 1.95 g of the expected compound.

Step B: (IB. Cis) -2,2-cimethyl-3- (3-oxo-3-methoxy-propynyl) -cyclo-propanecarboxylic acid (55) -2- (6-phenoxypyridyl) methyl ester .

A solution of 1S, 9 g (BS) -cyan-2- (6-phenoxypyridyl) -methanol in 75 ml of methylene chloride is mixed with a solution of 21.6 g (15, 20 cis) under stirring and under nitrogen atmosphere. 2,2-dimethyl-3- (3-oxo-3-methoxypropynyl) -cyclopropane-carboxylic acid (prepared after the previous step) in 75 ml of methylene chloride. 1 g of 4-dimethylamino-pyridine is then introduced at 5 ° C and after dissolution 21 g of dicyclohexylcarbodiimide. Stir for 4 hours at room temperature. The filtrate is filtered and evaporated under reduced pressure at 40 ° C. Chromatograph the residue obtained on silica gel eluting with cyciohexane and ethyl acetate (7: 3). Thus, 35.4 g of the expected compound are obtained.

Step C; (1b.cis) -2,2-dimethyl-5- (3-oxo-3-hydroxypropynyl) -cyclopropanecarboxylic acid (H3) -cyan-2- (6-phenoxypyridyl) methyl ester

A mixture of 35.4 g of the compound obtained in the previous step, 175 ml of dioran, 35 ml of water and 5 g of p-toluenesulfonic acid, was refluxed for 24 hours. The solution is evaporated under reduced pressure and the residue is taken up in 250 ml of methylene chloride and 100 ml of water. The organic phase is washed with water, dried and evaporated under reduced pressure. Male chromatic

DK 163918 B

40 trains the resulting substance on silio gel eluting with cyclohexane and ethyl acetate (6: 4) with 0.1 # acetic acid, thus obtaining 17.7 g of the expected compound.

Step D: (1S.cis.AZ) -2,2-Dimethyl-3- (5-oxo-3-hyaroxy-1-propenyl) -cyclopropanecarboxylic acid (SS) -cyan-2- (6-phenoxypy) r id y 1) -me thy le ste r.

Hydrogenation of 17.7 g of the compound prepared in the previous step is carried out in 200 ml of ethyl acetate in the presence of 2.5 g of palladium hydroxide (10 # on barium sulfate) and 10 2.5 ml of quinoline at 20 ° C. Filter, dry, evaporate to remove the solvent under reduced pressure and chromatograph on silica gel eluting with cyclohexane, ethyl acetate and acetic acid (6: 4: 0.1). Thus, 15 g of the expected compound are obtained.

Step E: (1R.cis.AZ) -2β-dimethyl-5- (5-oxo-3-ethoxy-1-propenyl) -cyclopropanecarboxylic acid (SS) -cyan-2- (6-phenoxypyric acid) dyl) methyl ester.

70 mg of 4-dimethylaminopyridine is added with stirring and under nitrogen, and then 1.13 g of dicyclohexylcarbodiimide in a solution of 1.95 g (1R, cis, AZ) cooled to 2,2-dimethyl-2 3- (3-oxo-3-hydroxy-1-propenyl) -cyclopropanecarboxylic acid (SS) -cyan-2- (6-phenoxypyridyl) methyls (prepared as in previous steps) in 10 ml of methylene chloride and 2 ml of ethanol.

25 Stir for an additional 1 hour 30 minutes at room temperature, filter, rinse, wash the insoluble material with methylene chloride and evaporate to dryness under reduced pressure. The residue is chromatographed on silio gel twice eluting with cyclohexane and ethyl acetate (8: 2 the first time and 85:15 the second time) to give 1.4 g of the expected compound, ap = + 48® + 2 ° (c = 0.5 #, chloroform).

Example 85.

(IR.cis.ΔΖ) -2,2-Dimethyl-3- (3-OXO-3-isopropyloxy-1-propenyl) -35-cyclopropanecarboxylic acid (SS) -cyan-2- (6-phenoxypyridyl) methyl ester .

Working as in Example 84 from 1.95 g of 41 (IR, cis, ΔΖ) ~ 2,2-dimethyl-3- (3-oxo-5-hydroxy-1-propenyl) -cyclopropane carboxylic acid (RS) -cyan-2- (6-phenoxypyridyl) methyl ester prepared as indicated in step D of Example 84 and 2 ml of isopropanol gives an oil which is chromatographed on 5 silicages! eluting with cyelohexane and ethyl acetate (Sil). Thus, 1.7 g of the expected compound is obtained, = + 53 ° + 2 ° (c = 0.75 $, chloroform).

Example 86

(IR, cis, ΔΖ) -2- 2-dimethyl-3- (3-oxo-3-cyclobutoxyl-propenyl) cyclopropanecarboxylic acid (RS) -cyan-2- ( 6-phenoxypyridyl) methyl ester.

Working as in Example 84 from 2.1 g (IR, cis, ΔΖ) ~ 2,2-dimethyl-3- (3-oxo-3-hydroxy-1-propenyl) -cyclo-propane carboxylic acid (RS) ) -cyan-2- (6-phenoxypyridyl) methyl ester prepared as indicated in Step D of Example 84 and 1 ml of cyclobutanol gives an oil which is chromatographed on silica gel eluting with hexane and ethyl acetate (8: 2). Thus, 1.6 g of the expected compound is obtained, = 44.5 ° + 2 ° 20 (c = 0.5 $, benzene).

Example 87

(1H4cis / AZ) -2,2-dimethyl-3- (5-oxo-3-n-butoxy-1-propenyl) -cyclopropanearboxylic acid (ES) -cyan-2- (6-phenoxypyridyl) methyl 25 ester.

Working as in Example 84 from 2.1 g of (IR, cis, ΔΖ) -2,2-dime thyl -3- (3-oxo-3-hydroxy-1-propenyl) -cyclo-propane carboxylic acid ( RS) -cyan-2- (6-phenoxypyridyl) methyl ester prepared as indicated in step D of Example 84 and 1 ml of n-butanol gives an oil which is chromatographed on silica gel eluting with n-hexane and ethyl acetate (9 * 1). Thus 1.55 g of the expected compound is obtained, cc-q = + 52 ° + 2.5 ° (c = 0.5 $, chloroform). 1

Example 88.

(IR. Cis. ΔΖ) -2,2-dimethyl-3- (5-oxo-5-allyloxy-1-propenyl) -cyclopropanecarboxylic acid (RS) -e, 2- ( 6-phenoxypyridyl) -Me-dimethylester.

Working as in Example 84 from 2.1 g (IR,

DK 163918B

42 cis, ΔΖ) -2,2-dimethyl-3- (3-oxo-3-hydroxy-1-propenyl) -cyclo-propane carboxylic acid (RS) -cyan-2- (6-phenoxypyridyl) -methyl ester prepared as indicated in step D of Example 84 and 0.8 ml of allyl alcohol, an oil is obtained which is chromatographed on silica gel eluting with n-hexane and ethyl acetate (85 * 15).

Thus 1.55 g of the expected compound is obtained, = + 53 ° + 3 ° (c = 0.3 $, chloroform).

Example 89

(IR, cis.ÅZ) -2,2-dimethyl-3- (3-oxo-3- (1,1-dimethylpropoxy) -propenyl) -cyclopropane carboxylic acid 3-phenoxyphenylmethyl ester. Step A: (IR.cis «ΔΖ) -2. 2-dimethyl-3- (3-oxo-3- (1,1-dimethylpropoxy) propynyl) cyclopropane carboxylic acid 3-Phenoxyphenylmethyl ester.

15 ml mix 3 g of the compound prepared in step B of Example 83, 3 ml of methylene chloride, 1 ml of tert-amyl alcohol and 0.1 g of dimethylaninopyridine. In stirring and at 5 ° C, ilan adds 1.75 g of dicyolohexylcarbodiimide in 1 ml of methylene chloride, recharge at room temperature and stir for 4 to 30 minutes, filter, evaporate the filtrate to dryness under reduced pressure and chromatograph the residue on silica gel. eluting with hexane and ethyl acetate (S: 2), 1.05 g of the expected compound are obtained.

Step 3: (1R.cis.AZ) -2.2-6imethyl-3- (3-oxo-3- (1,1-dimethyl-propoxy) -propenyl) -cyclopropane-arboxylic acid-3-phenoxy-phenyl-ethyl ester.

Hydrogenation of 1.05 g of the compound of the previous step is carried out in 20 ml of ethyl acetate in the presence of 0.2 g of palladium hydroxide ($ 10 on barium sulfate) and 0.2 ml of quinoline. Filter, wash the filtrate with 0.1 L

hydrochloric acid and then with water, dry it and evaporate to dryness under reduced pressure, chromatograph the residue on silica gel eluting with hexane and ethyl acetate (95 * 5) to obtain 0.756 g of the expected compound, = + 56.5 ° 35 + 2 , 5 ° (c = 1 $, chloroform).

43

UIS. ΙΟ ^ ΰ ΙΟ D

Preparation 1 «(IR« cis, Δ2) -2 »2-Dimethyl 1-5- (3- ae thoxy-3-oxo-1-propenyl) - Cyclopropane carboxylic acid,

Step A: (1H, cis) -2,2-dimethyl-5- (5-methoxy-5-oxo-1-propynyl) -5-cyclopropane carboxylic acid tert.-butyl ester.

Lian introduces 55 g (1H, cis) -2,2-dimethyl-3- (2,2-di-bromovinyl) cyclopropane carboxylic acid tert. -buty reads in 550 ml of tetrahydrofuran. The uranium cools to -70 ° C and, in 40 minutes, adds 132 ml of a solution of butyllithium in cyclohexane (20%) and stirs for 30 minutes at -65 ° C, then 12.5 ml of methyl chloroformate is added. After 2 hours reaction at -70 ° C, the temperature is allowed to rise to -20 ° C and the reaction mixture obtained is poured into an aqueous monosodium phosphate solution and extracted with ether. Wash, dry and evaporate to dryness under reduced pressure. Thus, 38.3 g of a compound are obtained which is chromatographed on silica gel eluting with cyclohexane and ethyl acetate (8: 2) to give 17.2 g of the expected compound. Step 3: (1P, cis, ΔΖ) -2,2-Dimethyl-5- (3-methoxy-3-oxo-1-propane-nip-cyclopropanecarboxylic acid tert-butyl ester.

Hydrogenation of 12 g of the compound of step A is performed in 240 ml of ethyl acetate in the presence of 2.4 g of palladium hydroxide ($ 10 on barium sulfate) and 2.4 ml of quinoline. Filter and dry. Thus, 11 g of the 25 expected compound are obtained.

Step C; (IR, cis "ΔΖ) -2,2-dimethyl-3- (5-methox.v-5-oxo-l-propenyl-IFF) ~ cyclopropane carboxylic acid.

A solution was refluxed for 3 hours containing 13.5 g of the compound prepared in Step B, 100 ml of toluene and 400 mg of hydrated p-toluenesulfonic acid. Evaporate to dryness under reduced pressure to give 11.2 g of a compound which is chromatographed on silica gel eluting with cyclohexane, ethyl acetate and acetic acid (60: 39si). Evaporate to dryness under reduced pressure to obtain 9 * 6 g of the 35 expected bond index with m.p. 110 ° 0, = + 75.5 ° + 2 ° (c = 1%, chCl 5).

DK 163918 B

44

If. Μ. R., CDCIU, ppm: 1.3: protons in the methyl groups in the 2-position in cyclopropane, 1.86-2 in protons in the 1-position in cyclopropane, 3.1 - 3.28 - 3.43: proton at the 3-position in cyclopropane, 5 5.8-5.99 in ethylenic proton in α-position relative to the group COgCH ^, 6.42 - 6.58 j: ethylenic proton in β-position in -6, 61-6.77 5 in the group for the group CC ^ CH ^ 8.63: proton in the group COgH, 10 3.71: protons in methoxy «

Preparation 2, (1E, c is, ΔΖ) -2,2-dimethyl-3- (3-8 thoxy-3-oxo-1-propenyl) -cyclopropanecarboxylic acid · Prin Ai (15.cis) - 2,2-dimethyl-3- (3-hydroxy-5-oxo-l-propynyl) - syclopropancarboxylsyre tert-butyl ester.

26 g of (1H, ois) -2,2-dimethyl-3- (2,2-dibromo-vinyl) -cyclopropanecarboxylic acid tert-butyl ester are introduced into 175 ml of anhydrous tetrahydrofuran, then added at -65 ° C 60 ml 20 20 $ fs solution of butyllithium in cyclohexane. The mixture is stirred for 1 hour at -60 ° 0 and a stream of carbon dioxide is bubbled for 1 hour 30 minutes and the reaction mixture is poured into ice-cold water added with 1 µl sodium hydroxide solution. Wash with ether. The aqueous alkaline phase is simulated to a pH of 4 and extracted with ether. The organic phases are dried and evaporated to dryness under reduced pressure. A compound is then obtained which is recrystallized from petroleum ether (bp 60-80 ° 0). 8.3 g of the expected compound are obtained with m.p. 144 ° 0th

, Ppm: 1.22 and 1.37 m · protons in the methyl groups at the 2-position in cyclopropane, 1.78: protons at the 1 and 3-position in cyclopropane, 1.47: protons in tert-butyl,

8.25: proton in the -C-OE group

ir o 45 DK itttsnts b

Step B: (1R.cis) -2,2-dimethyl-3- (3-ethoxyl-3-oxo-1-propynyl) oyclopropane carboxylic acid tert.-butyl ester.

4 g of the compound prepared in step A, 3.4 g of dicyclohexylcarbodiimide and 6 mg of 4-dimethylamino-pyridine in 30 ml of methylene chloride are added, then 1.5 ml of ethanol is added and stirred for 16 hours at 20 ° 0. Uian filters and evaporates the filtrate under reduced pressure. There is thus obtained 5.5 g of a compound which is purified by chromatography on silica gel eluting with cyelohexane and ethyl acetate (9: 1) # 10 4.25 g of the expected compound are thus obtained.

UMR, CDCl3, ppm: 1.18 - 1.21 and 1.36 - 1.47: protons at the 2-position in cyclopropane, 1.73 and 1.82: protons at the 1 and 3 positions in cyclopropane, 1.47: protons in tert-butyl, 1 »27 - 1.38 - 1.5 u protons in ethyl.

4.0 - 4.13 - 4.25 - 4.36)

Step C: (iR.cis.AZ) -2,2-dimethyl-3- (3-ethoxy-5-oxo-1-prope-20-nyl) -cyclopropane carboxylic acid tert-butyl ester.

Hydrogenation of 4.3 g of the substance prepared in the previous step is carried out in 100 ml of ethyl acetate in the presence of 800 mg of palladium hydroxide on barium sulfate and 0.8 ml of quinoline. Filtering, brings the filtrate to a pH below 7 with 2 3? hydrochloric acid and wash with water. Dry and evaporate to dryness under reduced pressure. 4.6 g of a compound are obtained which are chromatographed on silica gel eluting with cyelohexane and ethyl acetate (95: 5). Thus, 2.5 g of the expected compound are obtained:.

NMR, ODCL₂, ppm: 1.25 and 1.28: protons in the methyl groups at the 2-position in cyclopropane, 1.78 - 1.93: proton at the 1-position in cyclopropane, 2.98-3.1 -5 , 2: proton at the 3-position in cyclopropane, 6.4 - 6.6 - 6.8: proton v. Ethylenic carbon in the o-position relative to cyclopropane,

DK 163918B

46 5.7 - 5> 9: proton at ethylenic carton atom bearing the ethoxycarbonyl group, 4.0 - 4.15 - 4.25 - 4.36: proton in the methylene group 1 ethoxy. Step D; (IR.cis.ΔΖ) -2,2-dimethyl-5- (5-ethoxy-5-oxo-1-propenyl) -5-cyolopropanoarboxylic acid.

He introduces 2.5 g of the compound prepared in step C and 20 mg of hydrated p-toluenesulfonic acid in 20 ml of toluene. Lian heats to reflux for 40 minutes, evaporates to dryness under reduced pressure, and thus obtains 2.1 g of a residue which is chromatographed on silica gel eluting with cyclohexane, ethyl acetate and acetic acid (60: 39: 1). He isolates 1.7 g of compound which is recrystallized from cyclohexane. Thus 1.5 g of the expected compound are obtained with m.p. 96 ° C.

Ϊ! .M. R, CD Cl 2, ppm: 1.3 and 1.32: protons in the methyl groups at the 2-position in cyclopropane, 1.86 - 2.02: proton at the carbon atom at the 1-position in cyclopropane, 3.15 3.28 I. proton at the carbon atom at the 3-position of 3.3 - 3.45) cyclopropane 6.38-6.53) proton at the ethylenic carbon atom 6.55-6 *, 73}: branched on cyclopropane, 5.78- 5.96: proton at the ethylenic carbon atom bearing the ethoxycarbonyl group, 1.18 - 1.3 - 1.41: protons in the methyl group of the ethoxycarbonyl group, 4.0-4.13 j. protons in the methyl group of the ethoxycar- 4,25-4,36) bonyl group, Preparation 5.

(1β-cis. ΔΖ) -2,2-dime thyl-5- (5-propoxo-5-oxo-1-propenyl) -ylo-propanecarboxylic acid.

Step A: (1R.cis) -2,2-dimethyl-5-propoxy-5-oxo-1-propynyl-cyclopropane arboxyl acid tert.-butyls.

Lian introduces 22.8 g (1R, cis) -2,2-dimethyl-3 * - (2,2-dibromovinyl) -cyclopropane carboxylic acid tert.-butyl ester and 250 ml of tetrahydrofuran and then at -60 ° C 55 ml of 20 $ butyllithium. 47 υκ itjjyio d solution in cyclohexane. He maintains at -65 ° C for 1 hour and introduces at -65 ° C over 15 minutes S ml of n-propyl chloro formate. He continues stirring for 1 hour at -65 ° C, allowing the temperature to rise to room temperature over 1 hour and again stirring for 1 hour at room temperature. Lian pours on a saturated aqueous monosodium phosphate solution, stirring, extracting with ether and washing with water. Lian dries and evaporates to dryness under reduced pressure. Teres are thus obtained 19.5 g of an oil which is purified by ehromatography on silica gel eluting with cyclohexane and ethyl acetate (3 * 1). # Ter is thus obtained 11.5 g of the expected compound, CTC1X, ppm: 1.17 and 1.37 * protons in the methyl groups at the 2-position in cyclopropane, 1.72: protons at the 1- and 3-position in cyclo propane, 1.44: protons in tert, -butyl, 4, 0-4.12-4.23: proton in the methylene group at the 1-position in propoxycarbonyl, 0.83 - 0.95 - 1.06; protons in the methyl group of propoxycar bonyl.

Step 5: (IR, ois, ΔΖ) -2,2-dimethyl-5- (3-propoxy-3-ox: o-1-propenyl) -cyclopropane carboxylic acid tert -butyl ester.

He hydrogenates 7 g (1H, cis) -2,2-dimethyl-3- (n-prop-oxy-3-oxo-1-propynyl) -cyclopropanecarboxylic acid tert -butyl ester in 140 ml of ethyl acetate in the presence of 1.4 g of palladium hydroxide (10 µl on barium sulfate) and 1.4 ml of quinoline. He wash the filtrate with 2 Ή hydrochloric acid and then wash with water, dry and evaporate to dryness under reduced pressure. Thus, ter 30 is obtained 7.2 g of a compound which is chromatographed on silica gel eluting with cyclohexane and ethyl acetate (95 * 5). Thus, Lian gets 6.1 g of the expected compound. Hi.LI.R., CTCl 2, ppm: 1.25 and 1.29: proton in the methyl groups at 2-position 35 in cyclopropane, 1.5 to 2.03 * proton at the carbon atom at 1-position in cyclopropane,

DK 163918 B

48 5 05 to 5.35: proton, at about :: the bon atom at the 3-position of oyclopropane, 6.5-6.66 | s proton at the ethylenic carbonatone, 6.69-6.85): associated with oyclopropane, 5.82-6.0: proton at the ethylenic carbon atom bearing the propoxycarbonyl group, 4.02-4.12-4 , 23: proton in the methylene group at the 1-position in the propoxycarbonyl group, 0.86 - 0.98 - 1.1: proton in the methyl group in the propoxycarbonyl group, laugh 0: (IR «cis .ΔΖ) -2,2-dimethyl 1-5- (5-propoxy-3-oxo-1-prope-nyl) -cyclopropane carboxylic acid.

He refluxes for 1 hour a mixture of 5.8 g of the substance prepared in step 3, 200 mg of hydrated p-toluene-15 sulfonic acid and 60 ml of toluene · Lian evaporates to dryness under reduced pressure to obtain 5 g of a compound which chromatography on silica gel eluting with cyclohexane, ethyl acetate and acetic acid (70: 29: 1). 4.2 g of the expected compound are obtained.

CDCl3, ppm: 1.27 and 1.29: H in methyl grouperae at the 2-position in oyclopropane, 1.86-2: H at the 1-position in oyclopropane, 5.15 to 5.45: H in 3- the position in oyclopropane, 5.8-6: H at the ethylenic carbon atom bearing the group CO2CHgCE2CH2, 6.4 - 6.56 - 6.59 '· Η at the ethylenic carbon atom attached to oyclopropane, 3.98 - 4.08 - 4.18: The H 1 methylene group at the 1-position in the propoxycarbonyl group, 0.83 - 0.95 - 1.06 s H in the methyl groups in the propoxycarbonyl group.

35 49 DK 163318 b

Preparation 4.

(IR, cis, ΔΖ) -212-dimethyl-3- (5- (1-methylethoxy) -3-oxo-1-prope-nyl) -cyclopropane carboxylic acid.

Grin A: (1R. ci s. ΔΖ) -2,2 -d ime th y 1 -3 - (5 -hydroxy-3-oxo-1-pr o pe -5 'n.yl) - oyclopropane carboxyls.vre-tert «-but, dirty ter.

Lian hydrogenates 2 g (1R, cis) -2,2-dimethyl-3- (3-hydroxy-3-oxo-1-propynyl) -cyclopropanic acid-tert-butyl ester in 40 ml of ethyl acetate in the presence of 0.38 g of palladium hydroxide (105¾ on barium sulfate) and 0.4 ml of quinoline. Lian filters, the filtrate was washed with 0.5 H hydrochloric acid and then with water until neutrality, dried, evaporated to dryness under reduced pressure and obtained 2 g of the expected compound, m.p. 94 ° C.

grin B; (IR, αisΖ) -2,2-dimethyl-3- (3- (1-methylethoxy) -5-oxo-15-1-propenyl) cyclopropane carboxylic acid tert-butyl ester.

lian mixes 2.7 g (1R, cis) -2,2-dimethyl-3 - ((Z) -3-hydroxy-3-oxo-1-propenyl) -cyclopropane carboxylic acid tert, butyl ester in 2 ml of ethyl acetate, then add 2 g of 0-isopropyl-1? II-diisopropylpyric acid and stir for 1 hour at room temperature. Lian heats to reflux for 1 hour 30 minutes, returns to 20 ° C, filters insoluble material and evaporates the filtrate to dryness under reduced pressure. Per 3, 5 g of an oil is obtained which is chromatographed on silica gel eluting with benzene and cyclohexane 25 (7: 3). Thus, 1 g of the expected compound is obtained, which is used immediately in the following step.

Step C: (IR.cis, ΔΖ) -2,2-dimethyl 1-3- (3- (1-methylethoxy) -3-oxo-1-propenyl) -cvolonropanecarboxylic acid.

Lian heats to 120 ° with stirring for 2 hours 30 ml-50 nuts a mixture containing 1.4 g (1E, cis, ÅZ) -2,2-dimethyl-3- (3- (1-methylethoxy) -3 -oxo-1-propenyl) -cyclopropanecarboxylic acid tert-butyl ester, 100 mg of p-toluenesulfonic acid and 14 ml of toluene. Lian evaporates to dryness under reduced pressure. Per is obtained a residue which is recrystallized from isopropyl ether. lian 35 ice-cooler, sucks, dries and thus receives 500 mg of the expected compound with m.p. 98 ° G.

DK 163918B

50

Preparation 5.

(1β-cis.AZ) -2,2-dimethyl-5- (3-cyolobutyloxy-5-oxo-1-propylene-yl) -cyclopropane carboxylic acid.

lane A: (IR, cis. ΔΖ) -2,2-dimethyl-3- (3-cyclobutyloxy-5-oxo-5-1-propenyl) -cyclopropanecarboxylic acid tert-butyl ester

Lian dissolves 4 g (1E, cis, AZ) -2,2-dimethyl-3- (3-hydroxy-3-oxo-1-propenyl) -cyclopropane carboxylML-tert.-butyl ester in methylene chloride and then adds 1.7 mg cyelobuta-ncl. Lian lowers the temperature to between 0 and 5 ° C and adds 10 3.45 g of dicyclohexylcarbodiimide and 28 mg of dimethylaminopyridine in 20 mg of methylene chloride and continues stirring for 2 hours at approx. 5 ° C and 2 hours at room temperature. Lian eliminates the dicyclohexylurea formed, evaporates the filtrate to dryness and chromatographs on silica gel eluting with a mixture of n-hexane and isopropyl ether (9il). Per 2.3 g of the expected compound is obtained.

Step B; (15, ois.ΔΖ) -2'-2-dimethyl-3- (3-cyclobutyloxy-3-oxo-1-propenyl) -cyclopropanoarboxylic acid.

For 15 minutes, Lian refluxes 2.3 g of 20 of the above compound, 25 ml of toluene and 250 mg of p-toluenesulfonic acid, cools and stirs for 2 hours at a temperature between 0 and 45 ° C. The insoluble material is filtered off and the filtrate is evaporated to dryness to give 1.8 g of the expected compound.

25 I «Β. spectrum: -0Ξ: acid 3500 cm ”* 1 · -0 = 0: acid 1733 cm” 1 + ester approx. 1702 cm ”1 twin-di-Ke 1390 cm” 1 30 1380 cm ”1

Preparation 6.

(1β-cis.AZ) -2,2-dimethyl-3- (3- (PS) -1-methylpropyloxy-3-oxo-1-propsnyl) -cyolopropane carboxylic acid.

Step A: (1E.cis) -2,2-Dimethyl-3- (3- (3S) -1-methylpropyloxy-3--oxo-1-pro-pynyl) -cyclo-propanoic acid, tert-butyl ester .

Mix 4 g of (IPI, cis) -2,2-dimethyl 1-3- (3-hydroxy)

L / IV 1009 ΙΟ D

51 -3-oxo-1-p (opynyl) -cyclopropane carboxylic acid tert.-butyl ester, 40 ml of methylene chloride and 6 mg of 4-dimethylaminopyridine, and then 3.4 g of dicyclohexylcarbodiimide are added. After stirring for 30 minutes under inert atmosphere and in 2 ml of methylene chloride, 2 ml of 1-methylpropanol and 2 ml of methylene chloride are added over 5 minutes and stirring is continued for 3 hours at room temperature. The resulting dicyclohexylurea is filtered off, the filtrate is evaporated to dryness under reduced pressure and the residue is chromatographed on silica gel eluting with a mixture of n-hexane and isopropyl ether (8: 2). 3.5 g of the expected compound are obtained.

Step B: (IR.cis.ΔΖ) -2,2-dimethyl-3- (3- (BS) -1-methylpropyloxy-3-oxo-1-propenyl) oyclopropane carboxylic acid. --butylester.

Hydrogenate 3 g of the compound prepared as above in Preparation 4. Chromatograph on silica gel eluting with a mixture of n-hexane and isopropyl ether (9: 1) to give 2.5 g of the expected compound .

Jrin C: (1R, cis.AZ) -2- 2-dimethyl-3- (3- (RS) -1-methylpropyloxy-3 * oxo-1-propenyl) -oyclopropanoarboxylic acid.

3 g of the compound prepared above are stirred with 250 mg of p-toluenesulfonic acid in 25 ml of toluene. Reflux is heated until gas evolution ceases. Evaporate to dryness under reduced pressure and chromatograph the residue on silica gel eluting with a mixture of cyclohexane, ethyl acetate and acetic acid (70: 30: 1). 1.85 g of the expected compound are obtained.

I.R. Spectrum (CHO1): 30 OH: acid 3510 cm -1 = 0: acid 1735 cm -1 ester 1170 cm 1 con}. C = C 1637 cm 1 twin, di-Me 1381 cm -1 35

DK 163918B

52

Preparation 7 · (IR.cis, ΔΖ) -2,2-dimethyl-3- (3-oxo-5- (cyclopropylmethoxy)) -propenyloclopropane-1-carboxylic acid.

Step A: (IR.iso ΔΖ) -2 "2-Dimethyl-3- (3-oxo-3-oyclopropyl-methoxy) -propenylcyclopropane-1-carboxylic acid tert-butyl ester.

Into 150 ml of methylene chloride are introduced 20 g (1R, cis, AZ) - 2,2-dimethyl-3- (3-hydroxy-3-oxo-1-propenyl) cyclopropane-1-carboxylic acid tert-butyl ester and 6.2 g of eyclopropylearbinol, adding 2 g of dimethylaminopyridine and 17.5 g of di-cyclohexylcarbodiimide dissolved in 60 ml of methylene chloride and stirring for 2 hours at 20 ° C, eliminating the insoluble material formed, evaporating to dryness by distillation. under reduced pressure and chromatograph the residue on silica gel eluting with a mixture of hexane and isopropyl ether (9: 1) · Rer is obtained 12.32 g (l, e, * AZ) -2,2-dimethyl-5- (3-oxo-3-cyelopro-pylmethoxy) -propenylcyclopropan earboxylsyre-l-tert-butyl ester.

Step B: (IR.cis.ΔΖ) -2,2-dimethyl-5- (5-oxo-3-cyclopropylmethoxy) propenylcyclopropane-1-carboxylic acid.

Into 120 ml of toluene are added 12.32 g (1R, cis, AZ) -2,2-dimethyl-3- (3-oxo-3-cyclopropylmethoxy) propenylcyclopropane - 1-carboxylic acid tert-butyl ester and 0.6 g of p-toluenesulfonic acid and heated to reflux, the reflux maintained for 45 minutes, cooled, evaporated to dryness under reduced pressure, chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (7: 3) added 1 # acetic acid to give 8.94 g (IR, cis, ΔΖ) -2,2-dimethyl-3- (3-oxo-3-cyclopropylmethoxy) propenyley-clopropane-1-carboxylic acid, m.p. 106 ° C.

RMR, ODC1, ppm: 1.29-1.31: protons in the twin methyl groups, 1.13: proton in -CH_7 1.85-2: 2 protons in the 1-position in cyclopropane, 3.9-4: proton in 0-0¾ - <5.82-6.01 and from 6.42 to 6.77: ethylenic cis protons.

UK Ί633Ίΰ Ο 53

Preparation 8 (IR) cis ΔΖ) -2,2-d imethyl-3- (3-oxo-3-tert-but oxypropenyl 1) -cyelopropane carboxylic acid.

Step A: (1R.cis) -2,2-dimethyl-3- (3-oxo-3-hydroxypropynyl) -5-oyclopropane-1-carboxylic acid methyl ester.

Into 360 ml of tetrahydrofuran 36.5 g (1R, cis) - 2,2-d imethyl-3- (2,2-dibromoethenyl) cyclopropane-1-carboxylic acid methyl ester are added at -70 ° C. 20 # suspension of butyl lithium in cyclohexane, stirring for 10 minutes, bubbling 10 carbon dioxide for 30 minutes, raising the temperature to 20 ° C, pouring the reaction mixture into a mixture of water, ice and sodium bierbonate, extracting with ethyl ether, washing with water, acidifying the organic phases, extracting them with ether, washing the combined organic phases with water, evaporating them to dryness under reduced pressure, chromatographing the residue on silica gel eluting with a mixture of cyclohexane and ethyl acetate (6: 4 ) added 1 # acetic acid and obtained 6.8 g (1R, cis) -2,2-dimethyl-3- (3-oxo-3-hydroxypropynyl) -cyclopropane-1-earboxylic acid methyl ester.

Step B: (IR, cis) -2,2-Dimethyl 1-3- (3-oxo-3-tert.-butoxypropynyl) 1-cyclopropane-1-carboxylic acid methyl ester.

6.8 g of (IR, ois) -2,2 - dimethyl-3- (3'-Oxo-3-hydroxypropynyl) -cyclopropane-1-carboxylic acid methyl ester are added to 10ml of ethyl acetate and added at 15 ° C. 13.5 g of O-tert.-butyl-25-N, JP-diisopropylurea, stir for 2 hours, eliminate by filtration the insoluble material formed, evaporate the filtrate to dryness, chromatograph the residue on silica gel eluting with a mixture of cyclohexane and ethyl acetate (85ί15) to give 7 g (1R, cis) -2,2-dimethyl-3- (3-oxo-3-tert, -butoxypropynyl) -cyclopropane-1-carboxylic acid methyl ester.

Step C: (1R.ois.AZ) -2,2-dimethyl-3- (5-oxo-3-tert.-butoxy-1-propenyl) -cyclopropan-1-carboxylic acid ethyl ester.

Hydrogenation at 20 ° C in the presence of 10 # palladium hydroxide on barium sulfate and 1.4 ml of quinoline 7g (1R, cis) -35 -2,2-dimethyl-3- (3-oxo-3-tert-butoxypropynyl) ) -cyclopropane-1-carboxylic acid methyl ester in 149 ml of ethyl acetate. Filtrate, wash the filtrate with 1 µL hydrochloric acid and then with water, dry

DK 163918B

54 stirred and evaporated to dryness by distillation under reduced pressure to give 5.8 g (1R, cis, AZ) -2,2-dimethyl-3- (3-oxo-3-tert-butoxy-1- propenyl) -cyclopropane-1-carboxylic acid methyl ester.

Step D: (IR.cis.AZ) -2,2-dimethyl-3- (3-oxo-5-tert-butoxy-1-propenyl) -cyclopropane-1-carboxylic acid.

To a mixture of 25 ml of methanol and 9.8 ml of 1 R aqueous sodium hydroxide solution is added 2.5 g (IR, cis, ΔΖ) -2,2 - dimethyl-3- (3-oxo-3-tert-butoxy) -l-propenyl) -cyclopropane-Ι-ΙΟ-carboxylic acid methyl ester, stir for 3 hours at 50 ° C, cool to -75 ° C, pour the reaction mixture into water, extract with ethyl ether, simmer the aqueous phase to a pH of 1 with hydrochloric acid, extract with ether, evaporate the organic extracts to dryness by distillation under reduced pressure, chromatograph the residue on silica gel eluting with a mixture of cyclohexane and ethyl acetate (7 * 3) with 1 $ acetic acid and sheep 1.576 g (1R, cis, AZ) -2,2-dimethyl-3- (3-oxo-3-tert-butoxypropenyl) -cyclopropane-1-carboxylic acid.

I.R. Spectrum (CHCl3) s Absorption at 3500 cm attributed to acid OH (monomer + dimer)

Absorbances at 1730 cm 2 and 1695 cm 2, attributed to acid and ester C = 0

Absorption at 1628 cm 2, attributed to conjugated C = C 25 Absorptions at 1390 cm 2 and 1377 cm 2, attributed to the twin methyl groups

Absorption at 1368 cm 2, attributed to tert-butyl. Preparation 9.

(IR. Cis-ΔΖ) -2,2-dimethyl-3- (3-isobutyloxy-5-oxo-1-propenyl) -cyclopropane-1-oreboxylic acid.

Step A: (IR.cis.ΔΖ) -2- [2-dimethyl-3- (3-isobutoxy-5-oxo-1-propenyl) -cyclopropane-1-carboxylic acid tept.-butyl ester.

Into 10 ml of methylene chloride and 1 g of isobutanol are introduced 4 g of (1R, cis, AZ) -2,2-dimethyl-3- (3-hydroxy-3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid -tert.-butyl ester prepared after Preparation 4, Step A, and then 2.8 g of dicyclohexylcarbodiimide and 30 mg of dimethylamino-UK-pyridine dissolved in 10 ml of methylene chloride are added at 0 ° C. Stir for 17 hours at 20 ° G, eliminate the insoluble material by filtration, evaporate to dryness under reduced pressure, chromatograph the residue on silica gel eluting with a mixture of cyclohexane and isopropyl ether (9: 1) to give 2.1 g (1E, cis, AZ) -2,2-dimethyl-3- (3-isobutoxy-3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid tert-butyl ester.

Step B: (IB. Cl s sΔΖ) -2,2-dimethyl-3- (3-isobutoxy-3-oxo-1-propenyl) -cyolopropane-1-carboxylic acid.

2.1 g of (1B, cis, AZ) -2,2-dimethyl-3- (3-isobutoxy-3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid tert are introduced into 20 ml of toluene. -butyl ester and 0.1 g of p-toluenesulfonic acid, heated to reflux and maintained for 15 minutes, evaporated to dryness under reduced pressure, chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (7: 3) added 1 # acetic acid and obtained 1.53 g (1E, cis, AZ) -2,2-dimethyl-3- (3-butoxy-3-oxo-1-propenyl) -eyclopropane-1-carboxylic acid.

B. spectrum (chloroform):

Absorption at 3300 cm ”', attributed to acid-0H Absorption at 1730 cm *", 1, 1706 cm "*, 1 and 1694 cm *" 1, attributed to acid C = 0, and conjugated ester Absorption at 1630 cm cm ** 1, which is attributed to C = C (ΔΖ) 25 Absorption at 1390 cm ”1 and 1380 cm” 1, which is attributed to twin methyl groups.

Preparation 10, (IB. Cis. ΔΖ) -2,2-dimethyl-3- (3-n-butoxy-3-oxo-1-propenyl) -30-cyclopropane carboxylic acid.

Step A: (1B) cis -2,2-Dimethyl-3- (3-n-butoxy-3-oxo-1-propynyl) -cyclopropane carboxylic acid tert. -but.vles ter.

4 g of (1E, cis) -2,2-dimethyl-3- (3-hydroxy-3-oxo-1-propynyl) -cyclopropane carboxylic acid tert-butyl ester, 40 ml of methylene chloride and 6 mg of 4-diethylaminopyridine are mixed. and 3.4 g of dicyclohexyl arbodiimide are added. After stirring for 30 minutes under inert atmosphere, add

DK 163918 B

56 over 5 minutes 4 ml of a mixture of n-butanol and methylene chloride (1: 1) and continue stirring for 3 hours at room temperature. The resulting dieyclohexyl urea is filtered off, the filtrate is evaporated to dryness under reduced pressure and the residue is chromatographed on silica gel eluting with a mixture of cyclohexane and ethyl acetate (9 * 1). 4.7 g of the expected compound are obtained.

Step B: (IR. Cis. ΔΖ) -2,2-Dimethyl-3- (3-n-butoxy-5-oxo-1-propenyl) oyclopropane carboxylic acid tert-butyl Butter.

Hydrogen atmosphere is stirred for 15 minutes under 800 mg of palladium hydroxide on barium sulfate in 20 ml of ethyl acetate and then 4.7 g of the above compound is added in 50 ml of ethyl acetate and 0.8 ml of quinoline and left under hydrogen atmosphere for 30 minutes. The filtrate is washed, washed with 1 Bf hydrochloric acid and then with water, dried, evaporated to dryness under reduced pressure and chromatographed on silica gel eluting with a mixture of cyclohexane and ethyl acetate (95 * 5). 3.4 g of the expected compound are obtained.

Step C: (IR, cis.ΔΖ) -2,2-dimethyl-3- (3-n-butoxy-3-oxo-1-propene-nyl) -cyclopropane carboxylic acid.

3.3 g of the above-prepared compound are stirred with 350 mg of p-toluenesulfonic acid in 40 ml of toluene. It is heated to reflux until the gas evolution of iso-butylene is stopped, which lasts for example. 40 minutes. Evaporate to dryness under reduced pressure, ehromatograph the residue on silica gel eluting with a mixture of cyclohexane, ethyl acetate and acetic acid (75 * 25 * 1) to obtain 2 g of the expected compound.

NMR, CPC15, ppm: 1.26 and 1.3: protons in the methyl groups at the 2-position in cyclopropane 1.85-1.99 * proton at the 1-position in cyclopropane 3.13 to 3.47: proton in 3 position in cyclopropane 35 6.4-6.57 and 6.59-6.75 * proton at the 1-position in the allyl chain 5.8-5.99 * proton at the 2-position in the allyl chain

DK 163918 B

57

Preparation 11.

(LR.cis.AZ) -2,2-dimethyl-3- (3-cyclopento: xy-5-oxo-l-propenyl) - cvclopropan-l-oarboxylsyre.

Step A: (IR) [α] -2 -2,2-Dimethyl-3- (3-cyclopentoxy-3-oxo-1-5-propenyl) -cyclopropane-1-carboxylic acid tert-butyl ester.

Into 15 ml of methylene chloride are introduced 4 g (1R, cis, AZ) - 2,2-dimethyl-3- (3-hydroxy-3-oxo-1-propenyl) -eyclopropane-1-carboxylic acid tert. -butyl ester and 1.43 g of cyclopentanol, and 10 ml of 3.43 g of cyclohexylcarbodiimide and 40 mg of dimethylaminopyridine dissolved in 10 ml of methylene chloride are added, stirring the suspension at 20 ° C for 17 hours, eliminating the insoluble material by filtration, evaporating the filtrate to dryness under reduced pressure, chromatograph the residue 15 on silica gel eluting with a mixture of cyclohexane and isopropyl ether (0: 1) to give 1.38 g (IR, cis, ΔΖ) -2,2-dimethyl-3 - (3-cyclopentoxy-3-oxo-1-propenyl) -eyclopropane-1-carboxylic acid tert-butyl ester, m.p. 57 ° C.

Step B: (IR. Ois. ΔΖ) -2,2-dimethyl-3- (3-cyclopentoxy-3-oxo-1-20-propenyl) -cyclopropane-1-carboxylic acid.

2.54 g (IR, cis, ΔΖ) -2,2-dimethyl-3- (3-cyclopentoxy-3-oxo-1-propenyl) -eyclopropane-1-carboxylic acid are added in 25 ml of toluene. tert, -butyl ester and 0.1 g of p-toluenesulfonic acid, heating to reflux and maintaining the reflux for 20 minutes, evaporating to dryness under reduced pressure, chromatographing the residue on silica gel eluting with a mixture of hexane and ethyl acetate. (7: 3) added 1 # acetic acid to give 1.82 g (IR, cis, ΔΖ) -2,2-dimethyl-3- (3-cyclopentoxy-3-oxo-1-propenyl) -cyclopropane-1- carboxylic acid.

I.R. spectrum (chloroform):

Absorption at 3510 cm -1 attributed to acid OH Absorbances at 1735 cm -1 and 1702 cm 1 attributed to acid C: = 0 and conjugated ester

Absorption at 1632 cm -1, attributed to conjugated Cf = C

-1

Absorption at 1380 cm, which is attributed to the twin methyl groups

DK 163918B

58

Preparation 12.

(IR «trans «ΔΖ) -2,2-dimethyl-3- (3- (1-methylthoxy) -3-oxo-1-propenyl) -ocyclopropane carboxylic acid.

Step A: (IR. Trans) -2,2-Dimethyl 1-5- (5-hydroxy-3-oxo-1-propynyl) -oyolopropane carboxylic acid tert-butyl ester.

As in Step A of Preparation 2, 40 g of (1E, trans) -2,2-dimethyl-3- (2,2-dibromovinyl) -cyclopropane-carboxylic acid tert-butyl ester is used. After ehrornatography on silica gel of the crude product eluting with cyclohexane, ethyl acetate and acetic acid (6: 4: 0.2), 19.2 g of the expected compound are obtained.

Step B: (1R.t.R.) -2,2-D ime tb y 1-3 - (3- (1-methylthoxy) -3-oxo-1-propynyl) oyclopropane carboxylic acid tert-butyl ester. 3.6 g of the compound obtained in the previous ttin are mixed with 20 ml of ethyl acetate, 3 g of 0-isopropyl diisopropylamine is added and the mixture is stirred at reflux for 16 hours. After cooling to room temperature, the filtrate is dried and evaporated to dryness under reduced pressure to give 2.7 g of the expected compound.

Step C: (1R.trans.AZ) -2,2-dimethyl-3- (3- (1-methylethoxy) -5-oxo-1-propenyl) -oyolopropane carboxylic acid tert.-butyl ester.

2.7 g of the compound prepared in the previous step is hydrogenated in 50 ml of ethyl acetate in the presence of 0.55 g of palladium hydroxide ($ 10) on barium sulfate and 0.55 ml of quinoline. The filtrate is washed, the filtrate is washed with 1 liter of hydrochloric acid and then with water until neutrality, dried and evaporated to dryness under reduced pressure. 2.18 g of the expected compound are obtained per.

Step P: (IR.trans.AZ) -2,2-dimethyl-3- (3- (1-methylethoxy) -3-oxo-1-propenyl) -cyclopropane carboxylic acid.

2.18 g of the substance prepared in the previous step is refluxed with 20 ml of toluene and 0.2 g of p-toluenesulfonic acid. After cooling to room temperature, the organic phase is washed, dried and evaporated to dryness under reduced pressure. 1.6 g of the expected compound are obtained.

59

Liis. 1009 IO D

Preparation 13 «3-Phenoxy-g-hydroxybenzenethethioamide« In a solution of 200 g of α-cyan-3-phenoxybenzyl alcohol in 200 ml of toluene and 4.5 ml of triethylamine, 5 bubbles of city-drug sulphide are allowed to react for 22 hours. do not mix in an aqueous 1N hydrochloric acid, separate the organic phase by decantation, wash it with water, dry it, evaporate it to dryness under reduced pressure, chromatograph the residue on silica gel eluting with a mixture of benzene and ethyl acetate (8: 2), crystallizes from isopropyl ether to give 18.5 g of 3-phenoxy-oc-hydroxy-benzenethethioamide, m.p. 70 ° C, I.R. Spectrum (chloroform):

Absorption at 3600 cm ”1, which is freely attributed and associated

OH

Absorbances at 3478 and 3360 cm ”1, attributed to -JTH9 -i

Absorbances at 1670, 1578 and 1477 cm attributed to the aromatic rings and -CS-NHg spectrum (deuterochloroform): 20 peaks at 3.97-4.03 ppm attributed to the hydrogen in hydroxyl peaks at 5.18-5.25 ppm attributed to the hydrogen carried at the carbon atom in the α position to -CS- peaks from 6.92 to 7.58 ppm attributed to hydrogenate carvings 25 in the aromatic rings at 7.5 ppm attributed to hydrogenated carbons me i-STHg

Preparation 14 '(2-phenoxy-4-thiadiazolyl) -methanol.

Step A: 2-Phenoxythiazole-4-carboxylic acid ethyl ester

2 g of 2-chlorothiazole-4-carboxylic acid ethyl ester, 50 ml of dimethylformamide, 2.5 ml of hexamethylphosphoric triamide and 1.5 g of sodium iodide are heated, the reaction mixture is heated to 100 ° C, kept at this temperature for 1 hour, cooled to 35 20 ° G, introduces portionwise 1.32 g of potassium phenate, heats the reaction mixture to ten lb. of cooling for 1 hour 30 minutes, adds 0.66 g of potassium phenate, maintains the reflux for 1 hour.

DK 163918 B

60 ml for 30 minutes, cool, add water and ethyl acetate, extract with ethyl acetate, wash the organic phases with water and evaporate to dryness, chromatograph and evaporate the residue on silica gel eluting with a mixture of hexane, isopropyl ether and triethylamine (7: 3: 1) to give 1.08 g of 2-phenoxythiazole-4-carboxylic acid ethyl ester, m.p. 67 ° C.

Step B: (2-Phenox-V-4-thiazolyl) -methanol.

To a solution of 12 g of 2-phenoxythiazole-4-carboxylic acid ethyl ester in 60 ml of toluene is slowly introduced at -10 ° C 54 ml of toluene solution of diethyl sodium aluminum hydride at a concentration of 2 moles per ml. liter, stirring for 1 hour at -5 ° C, introducing at -20 ° C 80 ml of 2 L hydrochloric acid and then water, eliminating the insoluble material formed by filtration, decanting the filtrate, washing the organic solution with water, 15 with 2 IT sodium hydroxide solution and then again with water, evaporating to dryness, chromatographing the residue on silica gel eluting with a mixture of methylene chloride and ethyl acetate (8: 2) to give 8.15 g (2-phenoxy-4-thiazolyl) -methanol.

I.R. spectrum (chloroform): Absorption at 3590 cm -1, attributed to hydroxyl

Absorbances at 1551, 1530, 1503 and I486 cm "1, attributed to the aromatic ring and thiazole Absorption at 690 cm" 1, attributed to phenyl (deformation).

HMR spectrum (deuterochloroform): peak at 4.5 ppm, which is attributed to the hydrogenators in GHg-O peak at 3 * 5 ppm, which is attributed to the hydrogen in -OH peak at 6.66 ppm, which is attributed to the thiazolic hydrogen peaks from 7, 10 to 7.50 ppm, which is attributed to the hydrogen atoms 30 in the aromatic ring

Preparation 15.

(BS) -tt-cyano- (2-phenoxy-4-thiazolyl) methanol.

Step A: (2-Phenoxy-4-thiazolyl) -methanal.

In a solution of 4.6 g of (2-phenoxy-4-thiazolyl) methanol, 19.1 g of manganese dioxide is introduced, stirred for 17 hours at 40 ° C and then for 3 hours at 60 ° C, eliminating the - 61

UK Ί63 Ίΰ B

soluble residue by filtration, evaporating to dryness under reduced pressure, chromatographing the residue on silica gel eluting with a mixture of methylene chloride and ethyl acetate (8: 2) to give 2.6 g (2-phenoxy-4-thiazolyl) -methanal, m.p.

63 ° C.

Step B: (RS) -q-Cyan- (2-phenoxy-4-thiazolyl) -methanol.

In a solution of 0.85 g of sodium cyanide in 5 ml of water, 2.4 g of (2-phenoxy-4-thiazolyl) -methanal dissolved in 10 ml of ether is added at 10 ° C, stirred for 10 minutes, introduced dropwise. at 0 ° C a mixture of 2 ml of concentrated aqueous sulfuric acid solution and 3 ml of water, stirring for 2 hours at 0 ° C, separating the organic phase by decantation, washing with water, drying, evaporating to dryness under reduced pressure, adding isopropyl ether to the residue, sucks the precipitate, dries it and gives 2.28 g (RS) -q-cyano- (2-phenoxy-4-thiazolyl) -methanol.

I, R. spectrum (chloroform):

Absorption at 3580 cm "1, which is attributed to the hydroxyl group Absorption at 3550 cm" 1, which is attributed to the associated hydroxyl group 20 Absorption at 1590, 1504 and 1487 cm "1, which is attributed to the aromatic ring and thiazole.

li.M.R. Spectrum (deuterochloroform): peak at 4.08 ppm attributed to the hydrogen in -OH

peak at 5.41 ppm, which is attributed to the hydrogen in 0Ξ-0Η 25 peak at 7.33 ppm, which is attributed to the hydrogen atoms in phenyl peak at 7.0 ppm, which is attributed to the thiazolic hydrogen.

Preparation 16.

3-phenoxy-4-fluoro-g-methylbenz.vlalkohol.

At 20 ° C, 15.8 ml of a 2.6 M solution of methyl magnesium iodide in ether are added to a mixture containing 8 g of 3- (4-fluorophenoxy) benzaldehyde in 50 ml of ethyl ether. Allow to stand for 1 hour at room temperature, pour the mixture into an aqueous ammonium chloride solution, decant, extract with 35 ether and obtain the expected compound crystallized from isopropyl ether. Mp. 64 ° C.

DK 163918B

62

Examples of preparations «

Example A: Preparation of a soluble concentrate.

A homogeneous mixture of:

The compound of Example 1 is 0.25 g of piperonyl butoxide 1 g

Tween 80 0.25 g

Topanol A 0.1 g

Water 98.4 g Example B: Preparation of an emulsifiable concentrate.

You mix thoroughly:

The compound of Example 1 is 0.015 g of pipe ronyl but oxide 0.5 g

Topanol A 0.1 g rylene 95.885 g

Tween 80 3.5 g

Example C: Preparation of an emulsifiable concentrate:

A homogeneous mixture of:

The compound of Example 1 1.5 g 20 Tween 80 20 g

Topanol A 0.1 g xylene 78.4 g

Example 3): Preparation of a smoke preparation.

Homogeneously mixed: 25 The compound of Example 1 0.25 g taboo (pyrethrum quas) 25 g cedar leaf powder 40 g pine sawdust 33.75 g brilliant green 0.5 g 30 p-nitrophenol 0.5 g 35 63

UN 1009 ΙΟ D

Investigation of the activity of compounds of the invention on parasites.

Example I. Examination of the lethal effect of the compounds of Examples 1-8 on housefly 5 The test insects are female flies of a pyrethrenoid sensitive strain reared at 22-23 ° C and 60-65% relative humidity and is 4-5 days old. Topical application of 1 μΐ acetone solution to the insect's dorsal thorax is performed using Arnold's micromanipulator. 10 50 individuals are used for each dose of the compound studied.

Mortality is checked 24 hours after treatment.

It is found that the compounds in the sample used have a good lethal / twitching.

Example II. Examination of the lethal activity of the compounds of Examples 1-8 on larvae of Spodoptera littoralis.

The assays are performed by topically applying an acetone solution using Arnold's micromanipulator on the dorsal thorax of the larvae. 15 larvae are used for each dose of the compound studied. The larvae used are larvae in the fourth larval stage, ie. ca. 10 days old when raised at 24 ° C and 65 # humidity. After treatment, the individuals are placed in an artificial nutritional environment (Poitout's environment).

25 Mortality is checked 48 hours after treatment.

It is found that the compounds of the sample used have a good lethal effect.

Example III. Investigation of the activity of compounds 30 of Examples 1-8 on larvae of Epilachna varivestris.

The tests are performed by topical application in the same way as the flies and larvae of Spodoptera. Larvae are used in the penultimate larval stage and after treatment, the larvae are nourished on bean plants. Mortality is checked 72 hours after treatment.

It is found that the compounds in the sample used have a good lethal effect.

DK 163918B

64

Example IV, Investigation of the shock effect on housefly`

The test insects are female flies of 4-5 days # Work by direct atomization in Keamå 'and MarchJ's cylinder, using as a solvent a mixture of acetone 5 (5 #) and Isopar L (mineral oil solvent) (solvent used 2 ml per # second ). 50 insects are used per dose. Control is performed every minute until 10 minutes and then at 15 minutes, and KT50 is determined by the usual methods.

It is found that the compounds have a good activity and one of them, namely the compound of Example 1, has a remarkable activity, its KT50 being 0.4 minutes, 0.26 minutes and 2.02 minutes at concentrations of 1g, respectively. / liter, 0.5 g / liter and 0.25 g / liter.

Example Y. Effect on Tetran.vchus urticae.

Adulticide trial.

Two-leaf bean plants are used, which are treated with Pisher's gun in various doses of the compounds investigated. After drying, these planks are infected with 25 20 females of Tetranychus urticae per year. leaf and kept constant at 22-23 ° C and 60-65 # relative humidity. The count of live and dead acarides is done 24 hours and 48 hours after treatment #

The pore compounds of Examples 1-8 have a good adulticidal effect in this experiment.

Example VI. Investigation of the insecticidal effect on mosquitoes of the species Cules pipiens of the compound of Example 1 used in the form of smoke coil.

Neutral supports for smoke coils are impregnated with active substance in acetone solution. In a closed glass cylinder of 13.50 dm ^, 20 female mosquitoes are released in 4-5 days, and within 2 minutes a spiral of smoke which is ignited at one end is introduced. The knock-down check is performed every minute and the test is stopped, 5 minutes after all the insects have been killed.

The results are as follows: - At a dose of $ 0.60 of active material relative to the weight of the coil, EC50 = 5.42 minutes, and - at this dose, the lethal effect is $ 98.3.

5 Comparative experiment A. Shock effect on housefly

Proceed as in Example IV, the concentration being 0.25 g / liter.

The results are expressed as relative strength: 10 Compound according to relative strength, for example, to bioalletrine 1 6,271 2 2,794 3 1,369 4 3,455 5 2,828 15 6 1,065 7 2,655 8 9,223 9 1,666 14 1,289 17 4,261 21 1,786 2f) 27 4,210 28 13,266 29 7,900 30 2,898 31 10,081 37 2,034 38 2,608 42 2,883 25 44 1,351 47 7,354 48 6,635 50 2,825 58 3,271 62 13,280 64 2,096 65 5,157 66 2,298 70 4,932 75 2,332 35 66 DK 163918j ^ \ B. Lethal activity of larvae of

Epilachna varivestris

Proceed as in Example II.

The results are expressed as relative strength: 5 Compound according to relative strength in relation to, for example, _to deltamethrin_ 4 9,362 9 1,712 21 2,024 67 1,175 10 15 20! i 25 30 35

Claims (3)

1. Cyclopropane carboxylic acid derivatives in the isomeric form IR / cis and of the formula I H-C CH H \ 1 x C = C / \ COOA '/ X / 3 l \ 2 ro2c where the double bond has the geometric form Z, A' is a benzyl group or the group -CHO -1-1 X3-C j) or the group CH-, Jv CH_CH = CH_ ti. Or the group H c- where R 1 is a hydrogen atom or a methyl group, the group CSNH 2 or the group C = CH, or the group wherein R 1 is a hydrogen atom or the group CN and the benzoyl group is in the 3 or 4 position, or the group or the group 20 -CH, - / N ~ CH D - ^ γ · 3 Y o I- N '- where R 2 g is a hydrogen atom or the group CN, or the group 15 0 _A or the group (1 J R, FF ao F \ where represents a hydrogen atom or the group CN, or the group 25. R14 = R15 where R4 is an ethynyl or cyano group and R4, and R4, which are different, represent a hydrogen, fluorine or bromine atom, or the group DK 163918 B where R - is a hydrogen atom or a methyl, ethynyl or cyano group, and R is a linear branched or cyclic, saturated or unsaturated alkyl group having 1-18 carbon atoms. • 2nd Process for Preparation of Compounds 5 in the Isomeric Form IR, cis, Z and of Formula I H-jC CH-, ti J \ y J N 1 x C-C / \ CO_A '/ \ / 3 l \ ^ 2 R02C wherein the double bond has the geometric form Z, and A 'and R have the meaning given in claim 1, characterized in that an acid in the isomeric form IR, cis, Z and of the formula 15 in HC C1I, H \ / 3 "\ _J / 2 \ 11 / C c \ z £ _X / u" 0H Wherein the double bond has the geometric form Z and R is as defined in claim 1, or a functional derivative of this acid is reacted with an alcohol of the formula III A1OH III wherein A 'is as defined in claim 1 to give a corresponding compound of formula I. 3. Pesticidal compositions containing compound 2Q seme I according to claim 1. 35