FI65229C - MELLANPRODUKT FOER FRAMSTAELLNING AV EN ESTER AV CYKLOPROPANKARBOXYLSYRA ANVAENDNING AV DENNA PRODUKT OCH FOERFARANDE FOERDESS FRAMSTAELLNING - Google Patents

Description

6 5 2 2 9 Intermediate for the preparation of cyclopropanecarboxylic acid ester, use of this intermediate and method for its preparation

The present invention relates to a compound useful as an intermediate in the preparation of a cyclopropanecarboxylic acid ester for use as an insecticide, which ester has the general formula R1

2 3 I

R (R) OC-CH-CH-COOR II

\ /

C

CH 3 CH 3 12 wherein R is hydrogen or a methyl group, R is hydrogen, halogen 3 or an alkyl group, R is hydrogen, halogen or a carboalkoxy group, wherein at least one of R and R is halogen, however, so that when R is hydrogen and the compound is ra-2 3-seed, R and R are not both chlorine atoms, and when 3 2 R is halogen, R is not an alkyl group, and R is a group of the general formula R7

? JRH

-CH-f t- Z'Y III

/ R 887 wherein D is hydrogen or CN, R and R which are the same or different are hydrogen or a -C 1-4 alkyl group, Z is O or CH 2, Y is a C 2 -C 3 alkynyl group or a phenyl group, or R is a group of general formula 2 65229 —-— r9

IV

wherein R is hydrogen or methyl and R is a C 1 -C 4 alkenyl or alkadienyl group or a 2-furyl group, or R is a group of the general formula or dihydro or methyl thereof. tetrahydro analog, or R is a group of the formula

D

1 2 Z n Z n. 3 wherein D is hydrogen or CN, Z is CHO, oxygen, carbonyl or 1.2. * sulfur, Z and Z, which are the same or different, are chlorine or a methyl group, and n is 0, 1 or 2, or R is a group of the formula

- CH2 - C Ξ C-CH2- VIA

or a group of the formula

- och2-c ξ c-ch2- VIB

3 65229

The intermediate of the invention has the general formula R1

R2 (R3) C = C-CH-CH-COE HA

\ /

C

CH 3 CH 3 12 3 wherein R, R and R are as defined above and E is 1 1 halogen or OE where E is hydrogen, a cation or an alkyl group.

Studies have been carried out for several years to find synthetic analogues of pyrethrin which have superior properties to natural products and which could replace them. Synthetic analogs of naturally occurring pyrethrins should ideally be at least as good or preferably significantly better than natural products in terms of their toxicity to both insects and mammals, the extent of the effect and its rate, and in addition they should be easy to prepare.

After naturally occurring pyrethrins were found to be esters of certain substituted cyclopropanecarboxylic acids and substituted cyclopentenolones, the study of synthetic analogs focused first on modifying the ester molecule "alcohol moiety" and later on the ester molecule "acid moiety" or modification. to modify both parts of the ester molecule. Naturally occurring esters are esters of chrysanthemic or pyrethric acids of the formula CH- (X) C * 1 = CH - CH - CH - COOH 3 s / CH3 CHj 4 65229 wherein X is a methyl group (chrysanthemic acid) or a carbomethoxy group (pyrethric acid) . Substituents attached to the carbon atom marked with an asterisk in these acids are thought to produce the toxic effect of pyrethrin insecticides in insects.

The substitution of the 2,2-dimethyl-3-alkenyl-cyclopropanecarboxylic acid esters of the formula II in the 3-alkenyl side chain differs from the corresponding substitution of the previously known pyrethrin-like esters and these esters of the formula II have a strong insecticidal activity and combination of effect.

The activity of the compounds of the formula II as insecticides is surprisingly high, since, for example, (+) - trans-3- (but-1-enyl) and 3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylic acid 5- benzyl 3-furylmethyl esters are about 1.7 and 2.5 times more toxic to houseflies, respectively, than the corresponding (+) - trans chrysanthemate.

The esters of formula II fall into structurally different subgroups depending mainly on the nature of the substituents 2 3 R and R. A very interesting subclass 1 3 ka are those compounds in which R and R are each 2 hydrogen and R is an alkyl group having at least 2 carbon atoms. In this subclass, the highest toxicity to houseflies and mustard beetles is achieved with 5-benzyl-3-furylmethyl esters of 3-β-alkyl-vinyl-2,2-dimethyl-cyclopropanecarboxylic acid when the alkyl group is ethyl.

Other very interesting subclasses are those esters in which R and R are both hydrogen and R is chlorine or bromine, and compounds in which R is methyl and R 2 is hydrogen and R is hydrogen or an alkyl group such as methyl, ethyl or propyl.

65229 5

The most active of the insecticidal esters of formula II are those in which R is hydrogen and R and R are each a halogen group, wherein the various isomeric 2,2-dimethyl-3- (2,2-dichlorovinyl) -cyclopropanecarboxylic acids 5-Benzyl-3-furylmethyl esters are always 2§ times more toxic to houseflies than the corresponding ester of (+) - trans-chrysanthemic acid, which in turn is 50 times more toxic to houseflies than naturally occurring pyrethrin I. These 3-dihalovinyl acids also have specific esters. value because their light stability is higher than that of the corresponding chrysanthemums.

Preferred esters of formula II also include those which are structural esters of 2,2-dimethyl-3-substituted cyclopropanecarboxylic acid in which the 3-substituent is: C «Hc-CH = CH- n-C3H7 ^ CH = CH-Cl -CH = CH-

Br-CH = CH- C1 '' \ C = CH-

Br.

^ C = CH

br

When the ester is one whose structure is derived from furylmethyl alcohol, it is preferred that the furylmethyl alcohol be a 3-furylmethyl alcohol such as that described in British Patent No. 1,168,798. In furylmethyl alcohols and especially 3-furylmethyl alcohol, that R 'and R 0 are each hydrogen or groups containing up to 4 carbon atoms, 6 65229 in particular a methyl group, and that Y is a phenyl group, and Z = CH 2 and D = H. Analogs of these compounds where Z = 0 and D = CN can also be used. Other interesting compounds are those in which Y is an alkynyl group, e.g. a propargyl group.

Specific alcohols in this group from which esters of formula II can be structurally derived include e.g. 5-Benzyl-3-furylmethyl alcohol, 5-benzyl-2-methyl-3-furylmethyl alcohol, 5-benzylfurfuryl alcohol, 4-benzyl-5-methylfurfuryl alcohol, 5-phenoxy-3-furylmethyl alcohol, and α-cyano-5 -benzyl and 5-phenoxy-3-furylmethyl alcohol.

The cyclopentenolones from which the esters of the formula II can be derived structurally are those which are unsubstituted in the 3-position or those which are substituted by a methyl group in the 3-position (R = H or CH2).

Unsubstituted cyclopentenolones at the 3-position are described in British Patent Publication No. 1,305,025. Some of these alcohols are 3-de-methyl analogs of alcohols from which naturally occurring pyrethrins are derived. R10 is a 2-furyl group, or an alkenyl group such as a vinyl, prop-1-enyl or buta-1,3-dienyl group.

When the esters of formula II are structural derivatives of cyclopentenolones having a 3-position substituted by a methyl group (R = methyl), the esters can be derived from alletrolone (R = vinyl), pyretrolone (R10 = buta-1,3-dienyl) , kinerolone (R 10 = prop-1-enyl), jasmolone (R 1 = but-1-enyl) or furetrolone (R * ® = 2-furyl).

When the esters of formula II are phthalimidomethyl esters in which R has the formula V, they may be phthalimido, dihydrophthalimido or tetrahydrophthalimidomethyl esters in which phthalimido, dihydrophthalimido or a tetrahydrophthalimido residue is one described in British Patent Publication Nos. 985,006, 1,052,119 or 1,058,309. 3,4,5,6-Tetrahydrophthalimidomethyl esters are of great interest.

When the esters of formula II are those in which R has the formula VI, it is preferred that they be 3-benzylbenzyl esters, 3-benzoylbenzyl esters or 3-phenoxybenzyl esters, although each ring may be substituted with up to 3 chloro and / or a methyl group. Other very interesting esters when R is of formula VI are 3 where Z is O, or CH 2 and D is -CN, e.g. α-cyano-3-phenoxybenzyl alcohol or α-cyano-3-benzyl- and 3 esters of benzoylbenzyl alcohols.

The compounds of the invention exhibit geometric and optical isomerism and thus can be prepared in optically active forms, which can then be mixed together into racemic mixtures which can then be resolved into optically active forms. In addition, optically active forms or racemic mixtures can be separated into separate geometric isomers. In addition to the geometric isomerism resulting from the spatial structure of the cyclopropane ring substituents relative to each other and with respect to the ring, there is also the possibility of geometric isomerism in the side chain 12 at position 3 when R, R and R are such that the unsaturated side chain is asymmetrically substituted. α-cyano compounds (D = CN) also have the additional potential for optical isomerism, and these compounds include esters of both the racemic mixture and the individual isomers resulting from the asymmetry of the carbon atom to which the D group is attached. The different optical and geometric isomers of the esters of formula II usually have different insect toxicity and different rates of action.

Compounds of the invention having hydrogen atoms at the 1- and 3-positions of the cyclopropane ring in the trans position relative to each other are stereo analogs of (+) - trans-chrysanthemic acid and therefore form a preferred class of compounds of the invention, but are also included in the invention. wherein the two hydrogen atoms in question are in the cis position relative to each other.

According to the invention, intermediates of formula IIA can be used for the preparation of esters of formula II such that the intermediate of formula IIA: R1

R2 (R3) C = C-CH-CH-COE IIA

V

CH 3 CH 3 is reacted with a compound of formula RQ, wherein R, R, R, R and E are as defined above and Q is OH or an esterifying derivative thereof.

Preferably, the acid or acid halide (IIA; E = OH or halogen) is reacted with the alcohol RÖH or the carboxylic acid salt (IIA; E = 0 M +, where M is e.g. a silver or triethylammonium cation) is reacted with the R- with halogen.

For the reason briefly described below, the reactant IIA is initially normally in the form of a lower alkyl ester (E = O-alkyl) in which the alkyl group contains 1 to 6 carbon atoms, and thus a very suitable form for the preparation of insecticidal esters of formula II, except that R is carboalkoxy, is to subject the alkyl ester of formula IIA to a transesterification reaction 9 65229 using the alcohol RÖH, e.g. in the presence of a basic catalyst. When the alkyl ester contains a sensitive base group, e.g.

3 R = carboalkoxy, base-catalyzed transesterification is not preferred and can be avoided by preparing a t-butyl ester which can be converted to the free acid by acid-catalyzed decomposition and the free carboxyl group esterified directly via a salt or halide.

According to the invention, intermediates of formula IIA can be prepared in such a way that a phosphorane of formula R2, z4

= P —z4 X

3-— \ 4

R XZ

is reacted with a carbonyl compound of the formula R1 O = d: - CH - CH - COOE2 \ /

C XIA

Wherein R, R and R are as defined in claim 1, Z represents an organic residue which forms Λ a stable triorganophosphorus oxide, and E represents an alkyl group, and if desired the corresponding alkyl ester is converted into the corresponding ones by methods known per se free carboxylic acid or acid halide or salt.

4

The group Z is preferably a phenyl group.

The phosphorane X and the carbonyl compound XIA are preferably reacted in substantially equimolar amounts, usually in the solvent in which the phosphorane itself is prepared.

As discussed in more detail below, this may be an aromatic hydrocarbon such as benzene, or a polar solvent such as dimethyl sulfoxide, or a chlorinated hydrocarbon such as dichloromethane. The product can be improved if the reaction is carried out in an inert atmosphere, e.g. a nitrogen atmosphere. The reaction between the phosphorane and the aldehyde or 65229 ketone is usually very rapid, and the desired ester can be recovered from the reaction mixture after a reaction time of less than 1 hour, although reaction times of up to 24 hours have also been used. The desired ester can be recovered from the reaction product by extraction as a solvent, e.g. diethyl ether or petroleum ether.

2 3

A phosphorane of formula X wherein neither R nor R is halogen can be prepared from the corresponding phosphonium salt, which in turn can be prepared by reacting an appropriately substituted methyl halide with triorganophosphine according to the following reaction scheme. according to: R3 P74 R3 θ e \ PZ3 \ 4 j, CH halo - ^ CH · PZ * y J hal jehydrohalogenation with base R3 ^ Z4 "^ C = P __z4 R2 / 'Vv'Z4

The flexibility of the synthetic process according to the invention is due to the fact that the starting material is a substituted 3 2 methyl halide, R ~ (R) CH-hal, and the use of a whole series of such substituted halides allows the preparation of a whole series of 2,2-dimethylcyclopropanecarboxylic acids which are substituted In the 3-position with different groups and which have previously been difficult or impossible to prepare. In the above phosphorane synthesis, it is convenient to start with a substituted methyl bromide which is reacted with triphenylphosphine to give the corresponding triphenylphosphonium bromide and then convert the phosphonium salt to a phosphorane or ylide which can be represented by the above formula. Conversion of the phosphonium salt 11 65229 to phosphorane can be accomplished by treating the phosphonium salt with an alkali metal amide or alkali metal methylsulfinylmethyl. For example, sodium amide can be prepared by reacting sodium in liquid ammonia and performing the reaction in the presence of excess ammonia as a liquid medium. At the end of the reaction, the liquid ammonia can be allowed to evaporate and the phosphorane can be dissolved in an organic solvent such as benzene, and the next reaction with the aldehyde or ketone XIA in this organic solvent can be performed. Alternatively, dimethyl sulfoxide can be reacted with sodium hydride to give sodium methylsulfinylmethide, and the phosphonium salt can be prepared using this reagent, and after the formation of phosphoranes, the next reaction with aldehyde or ketone XI can be performed in the same reaction medium.

When R 1 = carboalkoxy, the conversion of the phosphonium salt to phosphorane can be carried out by treating the phosphonium salt with an alkali metal amide in liquid ammonia or an aqueous solution of an alkali metal hydroxide containing e.g.

5% NaOH. The released phosphorane can be separated from the solution by filtration and then reacted with aldehyde XI in a suitable solvent, e.g. Cl 2 Cl 2 · 3 2

Phosphoranes in which R is carboalkoxy and R

is hydrogen or methyl, can be prepared by the above-mentioned methods using a haloacetate or α-halopropionate alkyl ester as a substituted methyl halide, but this synthesis is not entirely satisfactory for such 2

for the preparation of phosphoranes of this type in which R

is an alkyl group having 2 or more carbon atoms.

In the preparation of such higher homologues, a phosphorane in which R is hydrogen and R is a desired alkyl group is first prepared as intermediates using the above methods and starting from an alkyl halide having at least 3 carbon atoms, and this intermediate phosphorane is then reacted with a suitable alkyl chloroformate thiester to attach the desired carboalkoxy group.

2 3

Phosphoranes in which R and / or R are halogen can be prepared by simply modifying the syntheses described above.

2 3

When R and R are each halogen, a carbon tetrahalide can be used instead of a substituted methyl halide, and the reaction proceeds according to the following equation: R 1, Γ * 2 C halogen ^ + 2PZ 3 -> ^ c = P _ z4 r / | r3 / \ Z4 4 + Z ^ P halogen2 whereby the dehydrohalogenation of the quaternary phosphonium halide occurs spontaneously.

Halogenated phosphoranes can also be prepared by halogenating non-halogenated phosphorane, which in turn is obtained by the methods described above according to the following reaction equation Θ ΊΘ Θ dehydrohalogenation of R2CH2 shark + PZ4 - | r2CH2 * PZ4 j shark with a base ^ [r2ch (r3) pz Dehydrohalogenation of ^ ^ R2 - r2ch = p ^ ^ z4 ^ I ^ ^ Z4 I with the base r2 z4 'P —z4 R3 / ^ ^ z4 1 3 65229 3 2 in which formulas hal = halogen, R = halogen and R are as defined above.

It has now been found that it is desirable for the carboxyl group in the reactive aldehyde or ketone XIA to be esterified as the lower alkyl ester in order to obtain the most satisfactory results in the reaction with phosphorane X. Thus, alkyl esters of formula IIA are prepared and since it is possible to convert these alkyl esters into insecticidal esters of formula II, with the exception of those containing a base-sensitive group, e.g.

3 R = carboalkoxy, by a simple base-catalyzed transesterification reaction, it is not necessary to convert the alkyl esters according to the invention into the corresponding acids in order to prepare insecticide esters. However, indirect conversion of these alkyl esters to insecticidal esters is possible, whereby the ester group of the ester of formula IIA is converted to the corresponding free carboxylic acid group by conventional hydrolysis, e.g. via an alkali metal or other salt, and this carboxylic acid can be esterified directly as described above. or alternatively first converted to an acid halide, e.g. chloride, and this acid halide may be converted to an ester by reaction with a suitable alcohol of formula RÖH as described above.

In the case where R is a t-butyl group, the alkyl ester can be converted to the free acid by heating with a small amount of toluene-4-sulfonic acid. This reaction can be carried out in benzene and the resulting carboxylic acid converted to the acid chloride in benzene solution without separation. 1 2 3

Acids of general formula IIA (E = OH) where R = R = H

2 and R = an alkyl group containing at least 2 carbon atoms can be prepared by the reaction of 2-ethynyl-3,3-dimethylcyclopropanecarboxylic acid with a suitable alkyl halide in the presence of an alkali metal followed by catalytic semi-hydrogenation.

65229 14

Alcohols of formula ROH and corresponding halides wherein R is a group of formula IV are described in British Patent Publication No. 1,305,025.

Alcohols of formula ROH where R is a group of formula III or VI and where D is CN can be prepared by conventional methods from the corresponding aldehydes. Thus, furaldehyde or benzaldehyde can be reacted with HCN, suitably prepared in situ from KCN and acid with the addition of HCN to form cyanhydrin.

Alcohols of the formula RÖH in which R is a group of the formula VI in which D is hydrogen can be prepared by reduction of the corresponding acids or esters, e.g. with a hydride, or by conversion of the corresponding halide into an ester, e.g. by reaction with sodium acetate followed by ester hydrolysis, or reacting formaldehyde with a Grignard reagent derived from the corresponding halide. R-halide halides in which R is a group of formula VI wherein D is hydrogen may be prepared by halomethylation of a compound of formula ζΛ z1 n n or by halogenation of a side chain of a compound of formula z1 z1 n n 65229

The following examples illustrate the present invention (temperatures are expressed in degrees C and refractive indices are measured at 20 ° C. Unless otherwise indicated, the hydrogen atoms in the carbon and trans position of the cyclopropane ring are relative to each other).

Example 1 (Preparation of intermediate IIA)

Chloromethylene triphenylphosphonium chloride (2.1 g; 0.006-m) and dry piperidine (0.51 g? 0.006-m) in dry diethyl ether (15 ml) were treated under nitrogen with 8% n-butyllithium in hexane (4.8 ml). 0.388 g; 0.006-m7). The mixture was stirred at room temperature for 1.5 hours and t-butyl trans-caronaldehyde (1.27 g; 0.0064 m) in dry benzene (5 ml) was added. The mixture was then stirred for 3 days, and the solution was filtered and the residue was washed with dry diethyl ether. The filtrate was washed with 10% Na 2 SO 4 and water and the dried (Na 2 SO 4) solvent was evaporated, followed by distillation to give a colorless liquid, b.p. 100 ° / 20 mm (70%). This was determined by NMR spectroscopy to be an ester of formula 3 2 IIA where R = Cl, R = H and E = O-C 4 H 1 and its nD value was found to be 1.4670. The stereochemistry as a double bond at αβ relative to the ring was 20:80 Z: E.

The alkyl ester, the preparation of which is described in Example 1, was then converted to the corresponding 5-benzyl-3-furylmethyl ester by the method described in Example 2.

65229 16

Example 2 (preparation of the final product II)

A mixture of the tertiary butyl ester described in Example 1 (410 mg), toluene-4-sulfonic acid (47.5 mg) and dry benzene (15 ml) was heated at reflux for 2 hours and cooled to give the corresponding carboxylic acid. solution. Pyridine (163 mg) and thionyl chloride (213 mg) were then added and the mixture was allowed to stand for 2 hours to give the acid chloride. A mixture of substantially equimolar amounts of acid chloride, 5-benzyl-3-furylmethyl alcohol and pyridine; was prepared in dry benzene and the mixture was cooled and allowed to stand at room temperature overnight. The mixture was then poured through a column of neutral alumina and eluted with benzene to give a 3 2 L compound of formula II wherein R = Cl, R = H, R = H and R = 5-benzyl-3-furylmethyl. This ester, designated the ester K, had a nf value of 1.5418.

Example 3 (Preparation of intermediate IIA) t-Butyl-trans-caronaldehyde (1.0 g) (obtained by ozone decomposition of (+) - trans-chrysanthemic acid t-butyl ester) and triphenylphosphine (2.65 g) dissolved in dry carbon tetrachloride ( 10 ml) was heated under nitrogen with stirring at 60 ° for 7 hours. The reaction mixture was evaporated under reduced pressure and the residue was extracted with diethyl ether (about 30 ml). The organic extract was washed with water, dried (Na 2 SO 4) and evaporated. The residue was extracted with petroleum ether (40-60 °) and the solution evaporated and distilled to give the crude product (0.77 g) (b.p. 100 ° / 1 mm) which was purified by crystallization to give t-butyl / IR; [-2,2-dimethyl-3- (2,2-dichlorovinyl) cyclopropanecarboxylate, m.p. 52-53 ° (compound P21 / A ').

Example 4 (preparation of intermediate)

Triphenylphosphine (1.32 g) was added to a well-stirred solution of carbon tetrabromide (0.84 g) in dry dichloromethane (15 ml). Then t-butyl - (+) - trans-carbonaldehyde (0.5 g) was added and the solution was stirred overnight at room temperature. After work-up as described in Example 3, the crude product was distilled, 17 65229, to give two fractions (1) b.p. 83-90 ° / 0.7 huti, (0.15 g), ηβ 1.4749, (2) b.p. 90-107 ° / 0.7 Iran (0.24 g), nQ 1.4910. The second fraction was found to contain (glc) about 95% of the desired t-butyl [IR, trane] -2,2-dimethyl-3- (2,2-dibromovinyl) cyclopropanecarboxylate (Compound P21 / B ').

Example 5 (preparation of the final product II)

The t-butyl ester described in Example 3 (280 mg) was heated under reflux with toluene-4-sulfonic acid (55 mg) in dry benzene (10 mL) for 1.5 hours and cooled to give a solution of the corresponding acid.

Pyridine (108.5 mg) and thionyl chloride (126 mg) were then added and the mixture was allowed to stand at room temperature for 2 hours. A solution of pyridine (83.5 mg) and 5-benzyl-3-furylmethyl alcohol (219 mg) in dry benzene (5 ml) was then added and the mixture was allowed to stand overnight. After chromatographic work-up, the solution was evaporated with neutral alumina to give 296 mg of [IR] trans compound of formula II wherein R = C1, R = H 3a R = 5-benzyl-3-furylmethyl. This ester, which was found to be an ester, had a P21 / A n ^ value of 1.5403.

The treatment described above was repeated using the ester P21 / B 'described in Example 4 to give a - - 2 3 / IR, trans / ester P21 / B where R = R = Br, R' = H, R = 5-benzene. silyl-3-furylmethyl, n ^ 1.5462.

Example 6

Conversion of the acid to the acid chloride followed by esterification using 5-benzyl-3-furylmethyl alcohol was repeated as described in Example 5, substituting other isomers of the (+) - trans acid for the acid and using 3-phenoxybenzyl or 3-benzylbenzyl alcohol or (jM-alletrol) in certain experiments. (+) -pyretrolone as an alcohol to give the following esters of formula II.

65229 18

Compound R3 R2 R1 Configuration mp ° nD

P21C Cl Cl H (+) - trans 61 1.5518 P21D Cl Cl H (+) - cis 43 1.5485 P21E Cl Cl H (+) - cis-trans 48.58 1.5445 P21F Cl Cl H (+) -trans 1,5607 P21G Cl Cl H (+) - cis 1,5654 P21H Cl Cl H (+) - cis-trans 1,5694 P21I Cl Cl H (+) - trans 1,5633 P21J Cl Cl H (+) -cis 1,5654 P21K Cl Cl H (+) - trans 1,5701 P21L Cl Cl H (+) - trans 1,5136 P21M Cl Cl H (+) - trans 1,5324

In compounds C, D and ER = 5-benzyl-3-furylmethyl, in compounds F, G and HR = 3-phenoxybenzyl, in compounds I, J and K is R 3 -benzylbenzyl, in compound L is R (+) - alletronyl and in compound M is R (+) - pyrethonyl.

The starting acid was prepared by a conventional modification of chrysanthemic acid synthesis using ethyl diazoacetate, in which case 1,1-dichloro-4-methyl-1,3-pentadiene was reacted with ethyl diazoacetate in the presence of a copper catalyst and the resulting ethyl (+) cis 2,2-Dimethyl-3- (2,2-dichlorovinyl) -cyclopropanecarboxylate was hydrolyzed to the free acid. The cis and trans isomers can be separated by selective crystallization from n-hexane, in which the cis isomer is more soluble. The isomer mixture was dissolved in hexane at room temperature and cooled to 0 ° or -20 ° C as the trans isomer precipitated. The precipitate was triturated, washed with a small volume of hexane at room temperature, and the residue was recrystallized from hexane at 0 ° or -20 ° C to give the trans isomer as a residue. The cis isomer was recovered from the hexane solution.

19 65229

Example 7 a) 5-Benzyl-3-furylaldehyde

Chromium trioxide (3.00 g) was added to a stirred solution of pyridine (4.75 mg) in dry methylene chloride (75 ml) and stirring was continued for 15 minutes. 5-Benzyl-3-furylmethyl alcohol (0.94 g) was then added and the mixture was stirred for 15 minutes. The mixture was filtered and the residue was washed with ether (100 mL). The filtrate and washings were combined and washed with 5% sodium hydroxide solution (3 x 50 mL), 2.5 N hydrochloric acid (50 mL) and 5% sodium carbonate solution (50 mL) and dried (Na 2 SO 4). Yield = (0.53 g), b.p. 116 ° / 0.8 mm Hg, nD = 1.5522.

b) {+) - α-Cyano-5-benzyl-3-furylmethyl alcohol

Aldehyde (1) (0.53 g) was added to a solution of potassium cyanide (0.3 g) in water (3 ml) and dioxane (5 ml) was added to effect dissolution. The solution was stirred for 10 minutes at 15 ° C while 40% sulfuric acid (1 ml) was added dropwise and stirring was continued for another 10 minutes. The mixture was extracted with carbon tetrachloride (50 mL) and dried (Na 2 SO 4). Evaporation gave the product (0.53 g), nD 1.5377. (Structure confirmed by NMR spectrum).

c) (+) - α-Cyano-5-benzyl-3-furyliroethyl - (+) - cis-trans-3- (2 ', 2'-dichlorovinyl) -2,2-dimethyl-cyclopropanecarboxylate (Compound P21 /OF)

A mixture of alcohol (265 mg) prepared as described above and 80 mg of pyridine in 10 ml of dry benzene was added to 227 mg of (+) - cis-trans-3- (2,2-dichlorovinyl) - 2,2-Dimethylcyclopropanecarboxylic acid chloride in 10 ml of dry benzene. The resulting mixture was allowed to stand overnight and the column was then chromatographed on neutral alumina. Evaporation of the solvent gave 0.31 g of P21 / N

Δ 65229 ηβ 1.5428 (structure confirmed by NMR spectrum). Example 8 a) 3-Phenoxybenzaldehyde

Chromium trioxide (3.00 g) was added to a stirred solution of pyridine (4.75 g) in dry methylene chloride (75 ml) and stirring was continued for another 15 minutes. 3-Phenoxybenzyl alcohol (1 g) in methylene chloride (5 ml) was then added and the mixture was stirred for a further 15 minutes, decanted and the residue washed with diethyl ether (100 ml). The filtrate was washed with 5% sodium hydroxide solution (3 x 50 mL), 2.5 N HCl (50 mL) and 5% sodium carbonate solution (50 mL) and dried over Na 2 SO 4 to give 3- phenoxy-benzaldehyde. Yield 0.80 g, b.p. 126 ° / 0.8 mm Hg, nD = 1.5944.

b) (+) - (α-Cyano) -3-phenoxybenzyl alcohol 3-Phenoxybenzaldehyde (0.8 g) was added to a solution of potassium cyanide (0.3 g) in water (1 ml) at 15 °. 40% sulfuric acid was added slowly over 10 minutes dropwise (1 mL) and stirring was continued for another 15 minutes. The mixture was extracted with carbon tetrachloride (40 ml), dried (Na 2 SO 4) and evaporated to give 0.64 g of (+) - α-cyano- (3-phenoxy) -benzyl alcohol. nD = 1.5823 (structure confirmed by NMR spectrum).

c) The α-cyano alcohol (247 mg), pyridine (79 mg) and (+) - cis / trans-2,2-dimethyl-3- (2,2-dichlorovinyl) cyclopropanecarboxylic acid chloride described above (227 mg) mg) was reacted with each other at 20 ° C in benzene solution (20 ml) for 18 hours to give, after chromatographic work-up using neutral alumina and evaporation of the solvent, (+) - α-cyano-3-phenoxybenzyl - (+) - cis-trans -3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylate (Compound P21 / P) (260 mg), ηβ 1.5561. (Structure confirmed by NMR spectrum).

65229

Example 9 a) 3-Benzylbenzaldehyde

Benzylbenzyl alcohol (1 g) was oxidized using the chromium trioxide / pyridine complex as described in Example 8a) to give the aldehyde (0.67 g), b.p. 124 ° C / 0.2 mm, nQ 2 O = 1.6010.

b) (+) - (α-cyano) -3-benzylbenzyl alcohol

The aldehyde prepared (0.67 g) underwent the reactions described in Example 8b) to form the desired cyanohydrin (0.41 g), ηβ20 = 1.5703.

(O- (α-cyano) -3-benzylbenzyl (10-cis / trans- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylate (Compound P21 / Q), ηβ 1,5462, was prepared) from the above-mentioned alcohol b) and acid chloride using the method of Example 8c).

Example 10 (Preparation of Intermediate IIA)

Triphenylphosphine (13 g) was dissolved in dry benzene (60 ml), and methyl bromoacetate (8.3 g) was added dropwise thereto. The solution was heated at 70 ° C for 2 days, then cooled and filtered. The residue was washed with benzene and dried to give about 16 g of (methoxycarbonylmethyl) triphenylphosphonium bromide. The phosphonium salt (10 g) was dissolved in water (250 ml), and 5% aqueous sodium hydroxide solution was added dropwise thereto with stirring until the solution became alkaline as determined by litmus. The resulting precipitate was filtered off, washed with water and dried. Crystallization from ethyl acetate / light benzene gave (methoxycarbonylmethylene) triphenylphosphorane as a colorless solid in about 80% yield.

(Methoxycarbonylmethyl) triphenylphosphorane (3.34 g) in methylene chloride (70 ml) was cooled to -70 ° C and triethylamine (1.01 g) was added with stirring, followed by chlorine (0.077) g) in CCl 4 (11 ml). mL). Stirring was continued at this temperature for 30 minutes and another 1 hour while the reaction mixture was warmed to room temperature. The reaction mixture was washed with water (3 x 50 ml), dried over Na 2 SO 4 and evaporated to give 2.8 g of chlorinated phosphorane / Ph 2 P = C (Cl) COOMe.

A mixture of t-butyl trans-caronaldehyde (obtained from ozone decomposition of (+) - trans-chrysanthemic acid t-butyl ester) (0.7 g) and chlorinated phosphorane (1.3 g) in 10 ml of dry benzene was heated refluxing for 1 hour. After distilling off benzene, the product obtained was distilled under reduced pressure to give t-butyl 2,2-dimethyl-3- (2-chloro-2-carbomethoxyvinyl) chloropropyl carboxylate, b.p. 110 ° C / 0.4 mm, nD 2 O = 1.4749 (yield 0.65 g).

This compound is called compound P24A *.

Example 11 (Preparation of Intermediate IIA)

The procedure described in Example 10 was repeated by replacing methyl bromoacetate with ethyl bromoacetate or propyl bromoacetate and replacing methyl bromoacetate with ethyl bromoacetate and replacing chlorine with bromine in the halogenation of the phosphorane step. The following compounds of formula IIA were obtained.

1 3 2 20

The compound E R R m.p. nD

P24B 't-butyl GOOC ^ Cl 11-10-1 ° C / 0.4 mn 1.4883 P24C t-butyl COO-G ^ Cl 160-180 ° C / 0.8 nm 1.4688 P24D't-butyl COOC Br 120-124 ° C / 0.04 nm 1.4830

Example 12 (Preparation of final product II)

A mixture of Example 10 P24A '(320 mg) and toluene-4-sulfonic acid (50 mg) in dry benzene (10 ml) was heated at reflux for about 2 hours and then cooled. 2,2-Dimethyl-3- (2-chloro-2-carbomethoxyvinyl) -cyclopropanecarboxylic acid was identified in solution by NMR spectrum. Pyrimidine-65529 (111 mg, 114 microliters) and thionyl chloride (132 mg, 80 microliters) were added to the carboxylic acid solution and the mixture was allowed to stand for 3 hours at room temperature.

2,2-Dimethyl-3- (2-chloro-2-carbomethoxyvinyl) -cyclopropanecarboxylic acid chloride was identified in solution by NMR spectrum. A solution of 5-benzyl-3-furylmethyl alcohol (210 mg) and pyridine (88 mg, 90 microliters) in dry benzene (5 mL) was then added and the mixture was allowed to stand overnight at room temperature.

The solution was then passed through a column of neutral alumina and eluted with benzene to give 200 mg of 2,2-dimethyl-3- (2-chloro-2-carbomethoxyvinyl) -cyclopropanecarboxylic acid 5-benzyl-3-furylmethyl ester, m.p. 1 , 5398. This compound is called P24A.

Example 13 (Preparation of final product II)

The treatment described in Example 12 was repeated using the compounds P24B ', P24C and P24D' of Example 11 to give the following compounds of formula II.

3 2 20

Compound R R nQ

P24B COOC2H5 Cl 1.5404 P24C COO -C „H_ Cl 1.5332 n 3 / P24D COOC_Hc Br 1.5366

4. D

The above three compounds are those compounds of formula II wherein R is 5-benzyl-3-furylmethyl.

Example 14 (Preparation of final product II) 3-Phenoxybenzyl (1RS) -trans-2,2-dimethyl-3- (2,2-dichlorovinyl) cyclopropanecarboxylate (1RS) -trans-2,2-dimethyl-3 - (2,2-dichlorovinyl) cyclopropanecarboxylic acid (1.0 g, 0.0048 m), m-phenoxybenzyl alcohol (1.0 g, 0.0050 m) and para-toluenesulfonic acid 24 65229 (0.01 g) ) was heated under reflux in toluene (100 mL) on a Dean and Stark take-off for 36 hours. The solution was cooled and extracted with 5% aqueous sodium bicarbonate (2 x 50 ml), then water (2 x 50 ml), dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was passed through an acid-washed alumina column using petroleum ether (b.p. 80-100 ° C) as eluent. Evaporation of the solvent gave the title compound as a colorless oil which crystallized on standing.

Example 15 (Preparation of final product II) 2-Benzylcyclopent-2-en-1-one (16.0 g) and recrystallized N-bromosuccinimide (16 g) were heated under reflux in CCl 4 (100 ml) until N-bromosuccin imide was completely lost to give 4-bromo-2-benzylcyclopent-2-en-1-one. When the reaction was complete, the product was filtered and heated under reflux in the dark with the silver salt of 2,2-dimethyl-3- (2,2-dichlorovinyl) cyclopropanecarboxylic acid (34.6 g) for five hours. The reaction mixture was filtered through an alumina column and eluted with benzene. Distillation of the eluate gave {+) -2-benzylcyclopent-2-en-1-on-4-yl- (1RS) -cis, trans-3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylate . This ester is called ME8.

Example 16 (Preparation of intermediate IIA) (1R) Trans-3- (2,2-difluorovinyl) -2,2-dimethylcyclopropanecarboxylic acid a) A mixture of freshly distilled dry dimethylformamide (20 ml), triphenylphosphine (7.9 g) ), methyl (1R) -trans-caronaldehyde (3.0 g) and sodium salt of chlorodifluoroacetic acid (3.6 g) were heated at 90 ° C with stirring for 20 hours. Water (60 ml) was then added and the solution was extracted with diethyl ether (2 x 30 ml). The combined ether extracts were washed with water, saturated sodium carbonate solution, saturated sodium chloride solution and then dried over sodium sulfate, and the ether was distilled off to give 2.25 g of methyl (1R) -trans-3- (2,2-difluorovinyl-2, 2-dimethylcyclopropane carboxylate, b.p. 63 ° C / 20 mm, n 1,4209.

b) A basic solution was prepared by dissolving sodium hydroxide (200 mg) in water (1 ml) and to this solution was added ethanol (10 ml). The methyl ester (0.5 g) described above was stirred in the basic solution and the solution was heated to reflux for one hour. The solvents were removed under reduced pressure, and water (30 ml) was added to the residue.

The solution was washed with diethyl ether (2 x 20 mL) and acidified with concentrated hydrochloric acid. The mixture was extracted with diethyl ether (2 x 30 ml), washed with saturated sodium chloride solution, dried over sodium sulphate and the solvents evaporated to give 410 mg of (1R) -trans-3- (2,2-difluorovinyl-2,2-dimethylcyclopropanecarboxylic acid as an oil). with an nD value of 1,440.

Example 17 (Preparation of intermediate IIA) (1R) -cis-3- (2,2-difluorovinyl) -2,2-dimethylcyclopropanecarboxylic acid a) The treatment described in Example 16a was repeated using 1.5 g of methyl (1R) -cis- caronaldehyde, 2.92 g of triphenylphosphine, 1.2 g of sodium chlorodifluoroacetate and 7 ml of dimethylformamide. After evaporation of the last diethyl ether extract, the residue was extracted with petroleum ether (3 x 40 ml) and the petroleum ether evaporated and the residue was distilled to give 440 mg of methyl (1R) -cis-3- (2,2-difluorovinyl) -2,2- dimethylcyclopropanecarboxylate, b.p. 74-78 ° C / 20 mm, nD1.4288.

b) The methyl ester obtained above (380 mg) was added to a solution of sodium hydroxide (200 mg) in water (1 ml) and ethanol (10 ml). The mixture was heated at reflux for one hour with stirring and the solvents were removed under reduced pressure. Water (50 ml) was then added and the solution was washed with 20 ml of diethyl ether, acidified with concentrated hydrochloric acid and extracted with diethyl ether. The ether extracts were washed with brine, dried over sodium sulfate and evaporated to give 290 mg of (1R) -cis-3- (2,2-difluorovinyl) -2,2-dimethylcyclopropanecarboxylic acid, n-1.4456.

Example 18 (Preparation of final product II)

The acids described in Examples 16 and 17 were esterified with 5-benzyl-3-furylmethyl alcohol, 3-phenoxybenzyl alcohol and (aRS) -cyano-3-phenoxybenzyl alcohol following the following procedure. A solution of the acid (110 mg) in benzene (5 ml) was treated with pyridine (50 μl) and thionyl chloride (45 μl) and the mixture was allowed to stand for three hours, at the end of which time the acid had converted to the acid chloride. A solution of 3-phenoxybenzyl alcohol (137 mg) or an equivalent amount of other alcohols and pyridine (50) in benzene (5 ml) was added to the acid chloride and the mixture was allowed to stand overnight. The desired ester was recovered from the solution by passing the solution through a neutral alumina column and eluting the column with benzene. The eluate was evaporated to give the ester as an oil. The following results were obtained.

Compound Acid Alcohol ηβ P31A (1R) -trans 5-Benzyl-3-furyl-1,5142 methyl P31B (1R) -trans 3-phenoxybenzyl 1,5293 P31C (1R) -trans (a-RS) -cyano-3- phenoxy-1,5330 benzyl P31D (1R) -cis 5-benzyl-3-furyl-1,5136 methyl P31E (1R) -cis 3-phenoxybenzyl 1,5349 P31F (1R) -cis (a-RS) -cyano- 3-phenoxy-1,5355 benzyl

The insecticidal activity of the esters of formula II was tested against houseflies and mustard beetles using the following technique: 27 65229

Houseflies (Musca domestica)

Female flies were treated with a 1 microliter drop of venom dissolved in acetone. The experiment was repeated twice using 15 flies in each experiment at each dose level, and 6 different doses were used for each test compound. After treatment, flies were kept at 20 ° C> 1 ° C and mortality was observed 24 and 48 hours after treatment. LD50 values were calculated in micrograms of insecticide per fly and relative toxicities were calculated from the inverse of LD50 values / see Sawicki et al .; Bulletin of the World Health Organization, 35,893 (1966), and Sawicki et al .; Entomology and Exp. Appl. 10, 253 (1967J_7-

Mustard beetles (Phaedon cochleariae Fab)

Acetone solutions of the test compound were administered to adult mustard beetles using a microtip dispenser. Mortality was noted after 48 hours. The experiment was repeated twice using 40-50 mustard peels for each dose amount, and 3-4 different doses of each compound were tested. Also in this case, LD ^ Q values were calculated and also the relative toxicities of the inverse values of LD ^ Q values / see Elliot et al .; J. Sci. Food Agric. 20, 561 (1969 ^ 7-

Relative toxicities were calculated by comparing 5-benzyl-3-furylmethyl - (+) - trans-chrysanthemate, one of the most toxic known Krysan thematic esters to houseflies and mustard beetles, with a toxicity of about 65-fold to allethryl myrtle. in the case of mustard beetles.

The following relative toxicities were obtained.

28 6 5 2 2 9

Relative toxicity

Compound Houseflies Mustard beetles 5-benzyl-3-furylmethyl 1000 1000 (+) - trans-chrysanthemate pyrethrin I 12 1600 bioallethrin 60 20 K 1300 1600 P19A 91 100 P19B 67 320 P19C 24 40 P19D 290 440 P19E 290 500 P19F 130 360 P19G 300 500 P19H 20 50 P21A 2500 2700 P21B 1100 1900 P21C 1000 2200 P21D 1200 1700 P21E 700 1800 P21F 400 790 P21G 680 780 P21H 660 740 P21I 170 420 P21J 360 350 P21K 340 350 P21L 72 73 P21M 19 370 P21N 100 2000 P21P 1300 at least 5000 P24A 82 310 P24B 150 310 P24C 23 120 P24D 450 290 ME8 140 265 P31A 3900 1900 P31B 620 270 P31C 840 730 P31D 2300 1300 P31E 1800 850 P31F 1200 2200 29 6 5 2 2 9 Toxicity to mammals of certain esters of formula II was determined in rats and the results were as follows:

Compound LD5Q (mg / kg in rats

Oral Intravenous

Pyrethrin I 260-420 2-5 5-Benzyl-3-furylmethyl - (+) - trans-chrysanthemate> 8000 340 8000-1000 120 P21E 40 5 P21C> 400 26-33 The synergism of certain esters of formula II was determined in experiments in which the LD50 value of the insecticide was determined in μg of female flies using the methods described above and using untreated flies and flies pretreated with 2 μg / fly from the syntristic "Sesamex" / 2- (3,4-methylene dioxide phenoxy) ) -3,6,9-trioxa-undekaania7. The following results were obtained. Tri LD50

Active only active synergistic compound active compound + coefficient related compound synergistic value substance 5-Benzyl-3-furyl-methyl - (+) - trans-chrysanthemate 0.0054 0.00057 9.4 5-Benzyl-3-furyl-methyl - (+) - cis-trans-chrysanthemate 0.010 0.00079 13 P21C 0.0065 0.00033 19 P21D 0.0058 0.00046 12 P21F 0.013 0.00033 39 P21G 0.0083 0.00037 22

Claims (7)

An intermediate for the preparation of an ester of cyclopropanecarboxylic acid of the general formula R1 R2 (R3) C = C-CH-CH-COOR II V CH3CH3 wherein R is hydrogen or a methyl group, R is hydrogen, halogen an alkyl group, R is hydrogen, halogen or a carboxy group, wherein at least one of the groups R and 3 R is halogen, with the proviso that R is hydrogen and the compound is racemic, R and R are not both chlorine atoms, and where R is halogen, R is not an alkyl group, and R is a group, of the general formula R 7 D -1- -CH ~ T η - -ZY III y R 8 7 8 where D is hydrogen or CN , R and R are the same or different and represent hydrogen or a -C ^ alkyl group, Z is O or CH₂, Y is a C ^-C ^ alkynyl group, or a phenyl group, or R is a group of the general formula Wherein R is hydrogen or methyl and R is a C 2 -C 4 alkenyl or alkadienyl group or a 2-furyl group, or R is a group of the general formula 'c and dih the hydroxy or tetrahydro analog thereof, or R is a group of the general formula Z1n Z2n3 where D is hydrogen or CN, Z is CHO, oxygen, carbonyl or 12H sulfur, Z and Z which are the same or different are chlorine or a methyl group, and n is 0, 1 or 2, or R is a group of formula ^ - CH 2 -C Ξ C-CH 2 - via or a group of formula 65229 - and 2-c = c-ch 2 -vib characterized in that the intermediate the general formula R 1 is R 2 (R 3) C = C-CH-CH-COE IIA \ / c / \ CH 3 CH 3 12 where R, R and R have the above meanings and R is 1 1 halogen or OE where E is hydrogen , a cation or an alkyl group. 2. An intermediate according to claim 1, characterized in that it is 2,2-dimethyl-3- (2-chlorovinyl) -cyclopropanecarboxylic acid, its acid chloride or its alkali metal salt. Intermediate according to claim 1, characterized in that it is 2,2-dimethyl-3- (2,2-dibromovinyl) -cyclopropanecarboxylic acid, these acid chloride or its alkali metal salt. Intermediate according to claim 2 or 3, characterized in that it is in the form of an / IR, cis7 isomer, / IR, trans? Isomer, (+) - trans isomer, (+) - cis isomer or a (+) - cis-trans mixture. Intermediate according to claim 1, characterized in that it is 2,2-dimethyl-3- (2,2-dichloro-vinyl) -cyclopropanecarboxylic acid in the form of an / IR, trans or TR, cis-isomer. Use of the intermediate according to any of claims 1-5 for the preparation of an ester of cyclopropanecarboxylic acid of formula II, characterized in that