IE45486B1 - Allethrolone esters - Google Patents

Abstract

An optically active (R)- or (S)-allethrolone X-sulphonate is reacted with a salt of 2,2-dimethyl-3-(2'-R1-2'-R2-vinyl)cyclopropanecarboxylic acid, in an organic solvent. X above represents a C1-C3 alkyl or a phenyl optionally substituted at the para position by a methyl or a fluorine, chlorine or bromine atom and R1 and R2 are defined in Claim 1. Esters of formula: are obtained in which the allethrolone has the antipode configuration, (S) or (R), of that of the sulfonate used. The process makes it possible to reuse (R)-allethrolone produced by resolution of racemic allethrolone. The esters (I) have an insecticidal action; they can be used, especially, in the form of an insecticidal composition.

Description

This invention relates to a process for preparing optically active allethrolone esters of cyclopropane carboxylic acids.

It has previously been shown that in general the 5 esterification of cyclopropane carboxylic acids with (S)~ allethrolone leads to compounds having a much higher insecticidal activity than compounds formed using (R)allethrolone or racemic allethrolone. However, the methods t . for obtaining such (S)-allethrolone esters described 10 hitherto, all involve esterifying the cyclopropane carboxylic acid or a functional derivative thereof with (S)-allethrolone In order to obtain the desired (S)-allethrolone, a resolution process such as that described in French Patent Specification No. 2,166,503 has been used. However, such processes lead to the obtention not only of the desired (s) isomer but also of the (R) isomer and therefore the yield of the desired (S) isomer is low.

We have recently found methods for converting the (R) isomer into the more preferred (s) isomer thereby obtaining increased yields of the (S) isomer.

One such method is described in our Patent Specification No. 45008 However, the method described therein involves racemisation of the (R)-allethrolone followed by a further resolution step and thus is relatively complex to carry out whilst still leading intermediately to a mixture of the (R) and (S) isomers which inevitably leads to low yields unless the procedure is repeated several times.

Further methods of converting the (R) isomer into the (S) isomer are described in Irish Patent Specification No. 45008 and British Patent Specification No. 1,543,474, which methods allow the direct conversion of(R)-allethrolone into (S)-allethro10 lone by formation of an (R)-allethrolone sulphonate, in the latter case followed by conversion to a carboxylate, and subsequent hydrolysis thereof.

We have now found, however, that i.l; ii; po;;:;i.hI< Lo convert (R)-allethroI one or indeed (S)-allethrolone sulphonates directly into an allethrolone cyclopropane carboxylic acid ester wherein the allethrolone has the configuration antipodal to that of the sulphonate, in a single reaction step and in high yields.

Thus according to one feature of the present invention there is provided a process for the preparation of compounds of general formula 1, •. ¢5488 (wherein the allethrolone ring is optically active and either (1) and Rg, which may be the same or different, each represents an alkyl radical containing from 1 to 3 carbon atoms; (2) R^ and R2, being the same, each represents a fluorine, chlorine, or bromine atom; (3) R^ represents an alkyl radical containing 1 or 2 carbon atoms and R^ represents an acetyl or methoxymethyl radical; or (4) and R^, together with the carbon atom to which they are attached, form a carbocyclic ring containing from 3 to 6 carbon atoms or a group of formula in .......«ι X which X represents an oxygen or sulphur atom) which comprises reacting an optically active compound of formula II, .. 4 4 S 4 8 3 H3C rso2o (II) (wherein R represents an alkyl radical containing from I to 3 carbon atoms or a phenyl radical optionally substituted in the para position by a methyl radical or a fluorine, chlorine or bromine atom) of appropriate configuration with a salt of a compound of formula III, (III.) (wherein R^ and are as defined above), in the presence of an organic solvent, the reaction proceeding with in10 version of configuration in the allethrolone ring.

The compound of formula II may be in the form of a single isomer, e.g. the (R) isomer or in the form of a mixture of isomers in which one isomer, e.g. the (R) isomer, predominates. Similarly the salt of the compound of formula HI may be in the form of a single optically active isomer or of a mixture thereof, e.g. a racemate, depending on the product which it is desired to obtain.

The. salt of the compound of formula HI is preferably 4 3 18 8 an alkali metal , iilkaline earth metal or an ammonium -.-it or a salt formed with a tertiary base, particularly preferred being an alkali metal salt especially the sodium and potassium salts.

The compound of formula 111 may, for example, be a 2j 2-dimethyl-3-(2’-methylprop-l'-enyl)-cyclopropane-lcarboxylic acid; a 2,2-dimethyl-3-(2,,2,-dichlorovinyl)cyclopropane-l-carboxylic acid; a 2,2-dimethy 1-3-(2', /dibromovinyl)-cyclopropane-l-carboxylic acid; a 2,2-dimethyl10 3-(2*, 2*-difluorovinyl)-cyclopropane-l-carboxylic acid; a 2.2- dimethyl-3-(21-methyl-3’-methoxy-(E)-prop-15-enyl)eyclopropane-l-carboxylic acid; a 2,2-dimethyl-3-(2*-.cthyl3'-oxo-but-1'-enyD-cyclopropanc-I-carboxylic acid; a 2,2diriietbyl-3-(cyclopentylidene-methyl)-cyclopropane-l15 carboxylic acid; a 2,2-dimethyl-3-(2*-oxo-3’-oxa-cyclopentylidene-methyl)-cyclopropane-i-carboxylic acid; or a 2.2- dimethyl-3-(2loxo-3’-thia-cyclopentylidene-methyl)cyclopropane-l-carboxylic acid.

Particularly preferred compounds of general formula HI are 2,2-dimethyl-3^(2 *-methylprop-l '-cnyl)-cycl opropaneJ.R-carboxylit acid; 2,2-dimethyl-3S-(2’-methylprop-l ’-r.nyl)cy clopropane-'lR-carboxylic acid: 2,2-dimethyl-3R- (cyclopentylidene-methyl)-eyclopropane-lR“carboxylic acid; 2,26 dimethyl-3S-(2* ,2’-dichlorovinyl )-cycloprop,-ine-lR-carboxylic acid; 2,2-dimethyl-3S-(2’,2’-difluorovinyl)-cyclopropaneIR-carboxylic acid; and 2,2-dimethyl-3R-(2,,2‘-difluorovinyl )-cyclopropane-lR-carboxylic acid.

The organic solvent used in the reaction between the compound of formula II and the salt of the compound of formula III preferably comprises dimethylformamide, hexamethylphosphorotriamide, dimethylsulphoxide, dimethoxyethane, acetonitrile, an aliphatic ketone containing from 3 to 6 carbon atoms, an alkanol, a monocyclic aromatic hydrocarbon or a mixture thereof. Particularly preferred solvents are hexamethylphophorotriami.de, dimethylsulphoxide, dimethylformamide, a mixture of toluene and dimethylsulphoxide and a mixture of toluene and a secondary or tertiary alkanol containing from 4 to 6 carbon atoms, especially tertiary butanol, The comppunds of general formula II are described and claimed in Irish Patent Specification No. 45008 as well as processes for their preparation. Thus, for example, they may be obtained by reaction of optically active allethrolone of appropriate configuration with a compound of formula IV, R S02 Cl (IV) (wherein R is as hereinbefore defined) in the presence of an - 7 •a S 4 8 s organic solvent and of a basic agent, the reaction proceeding with retention of configuration in the allethrolone ring. The basic agent is preferably a tertiary base, particularly triethyl/unine and preferred organic solvenLu comprise an aliphatic ketone containing from 3 to 6 carbon atoms, a monocyclic aromatic hydrocarbon, an ether oxide, a chlorinated solvent or a mixture thereof. Particularly preferred solvents comprise acetone and toluene.

Of the compounds of general formula II, especially 10 preferred are those wherein R represents a methyl or p-tolyl radical. Preferably the compound of formula II is used in the reaction with the salt of the compound of formula III without isolation from the reaction mixture in which it was formed, in which case the solvent used in 15 its preparation preferably comprises a monocyclic aromatic hydrocarbon.

The salt of the compound of formula III is also desirably used in the reaction with the compound of formula II without isolation from the reaction mixture in which it was formed. Formation of the salt of the compound of formula III may, for example, be effected by reaction of a compound of formula III as hereinbefore defined with ati appropriate base in the presence of an organic solvent, which solvent 43483 preferably comprises dimethylformamide, dimethylsulphoxide, hexamethylphosphorotriamide, dimethoxyethane, acetonitrile, an aliphatic ketone containing from 3 to 6 carbon atoms, an alkanol, a monocyclic aromatic hydrocarbon or a mixture thereof.

Thus, as mentioned above, the process according to the present invention enables an (R)-allethrolone sulphonate to be converted directly, in one stage, into an (S)-allethrolone cyclopropane carboxylic acid ester hence avoiding the necessity of isolating (s)-allethrolone and subsequently using this to esterify an appropriate cyclopropane carboxylic acid chloride. The process of the present invention is also of advantage in that it may be used not only on a single allethrolone sulphonate isomer but also on a mixture of isomers in which one isomer predominates since, such mixtures are almost invariably obtained after a particular isomer has been isolated during a resolution process.

The process according to the present invention is surprising and could not have been predicted from the literature. Thus, although a few examples of the inversion of optically active alcohols by the action of an acetate on their tosylates have previously been described, this method has not hitherto been applied to allethrolone. The α 3 4 8 6 preparation of allethrolone sulphonates Is known to give rise to difficulties and indeed the LreaLinent of alk-Uirolone with methanesulphonyl chloride in the presence ol a weak base such as pyridine to give a chlorinated derivative rather than the sulphonate has previously been described.

The allethrolone sulphonates such as are used in the present invention are also unstable, being sensitive to heat and to the presence of mineral and organic bases which cause them to lose their sulphonyl group and thus lead to dimerisation by a Diels .Alder ’reaction as follows.

These sulphonates are also sensitive to the presence of hydrochlorides of bases such as e.g. triethylamine which induce the formation of chlorinated derivatives.

We have fopnd, as described in our Irish Patent Specification wo. 1283/77, that using certain conditions described therein as mentioned above, these sulphonates may be prepared in good yields, thus enabling their preparation for use in the present invention to be effected.

The reaction of these sulphonates with a cyclopropane carboxylic acid salt might also be expected to give rise to difficulties not only due to the alkaline nature of Iii.·;» ;..'dtf! wiiich i.f might, be expr-cl ι .1 would lend io b-ad Lo dimerj sation of the sulphonates but also due Lo incomplete epimerization in the allethrolone ring leading to at least partial racemization.

However we have found that the process according to the present invention leads, with very high yields, to a remarkably pure product both from the chemical and optical point of view, undesirable side reactions being substantially avoided or reduced.

Of the compounds of general formula I which may, for example, be prepared according to the present invention, the following are novel compounds constituting a further feature of the. present Invention. - 11 5 4 S S (S)-allethrolone 2,2-dimethyl-3R-(cyclopentylidenemethyl)-cyclopropane-lR-carboxylate (compound A), (S)-allethrolone 2,2-dimethyl-3S-(2*,2’-dichlorovlnyl) cyclopropane-lR-carboxylate (compound B), (S)-allethrolone 2,2-dimethyl-3S-(2',2'-difluorovinyl) cyclopropane-IR-carboxylate (compound C) and (S)-allethrolone 2,2-dimethyl-3R-(2*,2'-difluorovinyl) cyclopropane-lR-carboxylate (compound D).

We have found that the above four compounds A, B, C 10 and D possess good insecticidal activity including an extremely high knock-down power (i.e. power to paralyse insects) as illustrated hereinafter.

They are of particular use in the domestic field but are also applicable in agriculture in which case, in particular,·they may optionally he combined with other pyrethrin compounds.

Thus, for example, the knock-down activity and lethal activity of the compounds A, B, C and D was tested on houseflies and on Aedes Acgypti: A) Study of the knock-down effect on the housefly The test insects are female houseflies, aged 3 days. Spraying is direct in a Kearns and March chamber, using, as solvent for the test compound, a mixture, in equal volumes, “ of acetone and kerosene (quantity of solution used: 500 mg). About 50 insects are used per treatment. Checks are made every minute up to 15 minutes.

The result is expressed as the K.T. 50 which is the time necessary to paralyse 50% of the insects. Thus this time decreases as the activity of the test compound increases.

The experimental results obtained are summarized in' the following Table: - · KT 50 3 minutes! 2.6 r- co CO 2.9 4.3 in r- rH V kO r-{ r—! 1.7 1.7 Γχ rH in CM CO kO 0 Pi «ri 0 kO 0 1 0 0 O 0 0 0 O g 0 ch σ» 0 co 0 O 0 0 0 0 m r-i r-4 r-i lH rH rH rH rH rH · CO ΰ •rl 2 CO r* co 0 Ch O O O O O O kO CN 0 0 co O O O O O O a l rH ch CO ch Ch kO rH r-i »—i rH rH rH a o CO .5 CO co O 0 co O O O O O O g co Ch O 0 r—i O Q O O O O 00 ch p-*. ch r-i 00 in rH r-i rH rH rH r-i ό , £4 W Ci co co co O w 3 •ri « O O CO O O Fi co Ch co Ch co in O O Ch O O O Ch 00 co kD ¢0 r—i r-l t-i rH rH ε w o CO pi P4 β CO in ω in •ri 2 co 00 ω 0 kO co co kO O co m St r- r-1 Ch ch co CO P*- w fj O co r- J O co 0 CM CM in CM St CM CM 0 O CM co rH co r-i Ch ch in kD kO CO * TJ O •ri o r 0 O O 0 0 0 in 0 0 O O 0 0 0) O O in O in CM 0 0 m O 0 m Uj ϋ O m CM in CM r—1 0 in CM O m CM o h r-l r-i rH o e •U co Φ 4J PQ a ¢3 Ό T3 τί Ό ϋ a s 6 3 3 3 3 o 0 0 0 a CL 0. e ε B1 fcs s 0 c 0 0 Cl 0 0 ϋ Conclusion: Compounds A, B, C and D are endowed with a good knock-down activity with respect to the housefly * For compounds C and D, the KT 50 were determined by graphic estimation. Β) Study of the lethal effect on the housefly The test insects are houseflies of both sexes. 1 μΐ of an acetonic solution of the test compound is topically applied on the dorsal thorax of the insects. 50 individual flies are used per dosage. A check on mortality is made twenty four hours after treatment.

The compound to be tested is synergized by piperonyl butoxide (10 parts by weight of piperonyl butoxide for 1 part of the compound to be tested).

Dose in ng of test compound per fly % mortality after 24 hours 1 LD 50 in ng per insect Compound 50 70. 9 Λ 25 12. 5 72. 5 28.2 17. 5 Compound 250 100 13 • 100 50 8b. 7 65. 6 33. 0 Compound Z5 100 C 12. 5 6. 25 53. 3 16. 7 10.1 Compound 175 100 D 50 25 90 46.6 25. 4 Conclusion: The compounds are endowed with a good lethal activity on the housefly. - 15 / α ΰ 4 8 3 C) Study of the insecticidal activity of compounds C and D in the form of fumigant composition; on Aedes Aegypti The knock-down effect and the lethal effect of the compound to be tested are studied on females of the species 5 Aedes Aegypti.

The method of the Dainippon closed cylinder is used.

A fumigenic coil containing the compound to be tested is burnt for one minute at one end of a closed cylinder of 20 cm diameter and 43 cm height containing 20 female Aedes Aegypti. iO The knock-down effect is observed every thirty seconds for five minutes. The results are expressed in KT 50 (i.e. the time necessary to paralyse 50 percent of the insects) ' for each dose. This time decreases as the activity of the test I compound increases.

The individual dead Aedes Aegypti are also counted after 24 hours and the results of lethal activity are expressed in percentage mortality. series of successive tests were made and the averages of these tests were determined.

The tests are made in parallel with a test using a comparison compound known for its high knock-down activity ((S)-allethrolone d-trans-chrysanthemate [or compound E]).

The experimental results obtained are summarized in the following table: 4δυ According to a yet further feature of the present invention there are provided insecticideL compositions comprising, as active ingredient, at least one of the four compounds A, B, C andD mentioned above in association with an insecticidal carrier or excipient.

The insecticidal compositions may be in the form of any conventional insecticidal preparation and may optionally include one or more further pesticidal agents and/or synergistic agents such as, for example piperonyl butoxide or N-(ethyl-2-heptyl)-bicyclo(2,2,J.)-5-hepten-2,3-dicarboximide. Preferred forms Include powders, pellets, suspensions, emulsions, solutions, aerosols, combustible strips and baits.

The active ingredient may be incorporated in carriers and excipient' customarily employed in insecticidal compositions such as, for example, water, alcohols, hydrocarbons and other organic solvents, animal, vegetable and mineral oils, powders e.g. talc, clay, silicates and kieselguhr, and combustible solids e.g. Tabu powder or Pyrethrum marc. Advantageously the compositions may contain surface-active agents, preferably non-ionic surface-active agents, to aid uniform dispersion of the constituents of the composition.

Preferably the compositions will contain from 0.01 to 95'X by weight of active ingredient. - 18 - A particularly preferred form of the insecticidal composition:; according to the invention are insecticidal coils, especially those containing from 0.01 to 10% by weight of active ingredient, in association with a combustible inert support composed, for example, of Pyrethrum marc, Tabu powder, powdered Machilus Thumbergii leaves, cedar leaf powder, wood dust (e.g. pine sawdust), starch, coconut shell powder or Pyrethrum stem powder.

The active ingredient may alternatively be incorporated, preferably in a concentration of 0.01 to 95% by weight, in an incombustible fibrous substrate and the fumigent thus obtained may then be placed on a heating apparatus e.g. of the type known as electro mosquito destroyer whereby the active ingredient may be vapourized at a controlled rate. Further forms include incorporating the active ingredient in a pulvei-izable oil, preferably in a concentration of O.Oi to 95% by weight, which oil may then be used to impregnate the wick of a lamp whereby combustion of the oil and thus vapourization of the active ingredient takes place.

(S)-aliethrolono 2,2-dimetliyl-3S-(2',2’-difluorovinyl)cyclopropane-lR-carboxylate and (S)-allethrolone 2,2-dimethyl1))-(2', 2' “di.fluorovinyl)-cyclopropane-lR-carboxylate show particularly advantageous activity when used in the form of a fumigent composition.

The following Examples illustrate the invention. - 19 ά S 4 8' 3 ' Example 1 (4R)-2~Allyl-3-methyl-cyclopent-2-en-l-one-4-yl 2,2-dimethyl1 I 3R-(2 -methylprop-1 -enyl)-cyclopropane-lR-carboxylate [or (R)-allethrolone d-trans-chrysanthemate] starting from (S)allethrolone-methane sulphonate Into 33 cm of hexamethylphosphorotriamide are introduced 12.5 g of (S)-allethrolone-mcthane sulphonate and 9.65 g of sodium d-trans-chrysanthemate are added thereto. The mixture obtained is stirred for ten minutes, then a mixture of IN sodium hydroxide, water and n-heptane is added thereto. The resultant mixture is stirred and the organic phase is separated off by decantation. The aqueous phase is extracted with heptane and the organic phases are combined, washed and dried. 12.94 g of (R)-allethrolone d-trans-chrysanthemate are obtained.

Circular dichroism (dioxan) Infl. 345 nm Ac = “ 1.18 Max. 332 nm Ae = - 2.41 Max. 321 nm Ae = - 2.73 Infl. 310 nm Ae = - 2.08 Max. 230 nm Ae = + 15.9 - 20 415 48 3 The (S)-allethrolone-methane sulphonate used may be prepared in the following way: 7.35 g of (S)-aU.cthrolono are dissolved in 7.5 cm of acetone. The solution obtained is cooled to -1.50C and 3 then 8.4 cm of triethylamine,followed slowly by 4.3 cm of methanesulphonyl chloride in solution in 11 cm of acetone,are added thereto. The resultant mixture is stirred for fifteen minutes and then poured into a mixture ..3 of 23 cm of IN hydrochloric acid, 56 cm of water and 3 23 cm of methylene chloride. The mixture thus obtained is stirred for fifteen minutes and then the organic phase i s separated off by decantation. Tho aqueous phase is extracted with methylene chloride and the organic phase are combined, washed, dried and concentrated to dryness. 12.5 g of crude (S)-allethrolone-methane sulphonate are obtained which are used in the above condensation without further purification.

The sodium chrysanthemate used above may be prepared · in the following manner: Into a solution of 16.8 of 2,2-dimethyl-3R-(2'-methyl~ prop-1*-enyl)-cyclopropane-lR-carboxylic acid in 50 cm of acetone, is introduced the quantity of a ION aqueous solution of sodium hydroxide necessary to obtain the turning of - 21 phenolphthalein. The precipitate thus formed is isolated by centrifugation and is washed and dried. 18.6 g of sodium 2,2-dimethyl-3R-(2,-methylprop-l'-enyl)-cyc.l.opropane 1Rcarboxylate are obtained and are used for the condensation without further purification.

Example 2 (S)-Allethrolone 2,2-dimethyl-3R-(2' -me thyIprop-11-enyl)cyclopropane-IR-carboxylate starting from (R)-allethrolonemethane sulphonate JO Operating in a manner analogous to that of Example 1, starting with (R)-allethrolone-methane sulphonate, (S)allethrolone 2,2-dimethyl-3R-(2’-methyIprop-1’-enyl^cyclopropane- lR-carboxylate [αΐ^θ ~ 50° (c = 5%, toluene) is obtained with the same yield. £5 Example 3 (R)-allethrolone 2,2-dimethy1-3R-(21-methyIprop-1*-enyl)cyclopropane-IR-carboxylate starting from (S)-a.llethrolonemethane sulphonate To a solution of potassium d-trans-chrysanthemate (obtained as described hereinafter starting with 110 g of d-trans chrysantliemic acid) is rapidly added, at + 15°C, a - 22 solution of 165 g of (s)-allethrolone-methane sulphonate in 3 350 cm of dimethylsulphoxide. The mixture obtained is stirred at 20°C for 24 hours and then 100 cm3 of heptane 3 and 500 cm of water are added thereto. The resultant mixture is stirred and the organic phase is separated off by decantation. The aqueous phase is extracted with heptane and' the heptane phases are combined, washed in an aqueous IN solution of sodium hydroxide and then in water. The aqueous washings are extracted with heptane and the heptane fractions are combined, dried and concentrated to dryness by distillation 169 g of (R)-allethrolone 2,2-dimethyl-3R-(2*-methylprop-1'20 o enyl)“cyclopropane-lR-carboxylate are obtained = + 11 (c = 1%, ethanol).

U.V. spectrum (ethanol) Maximum at 225 nm, E^ » 600; Maximum at 295 nm, E^ = 3.

Circular dichroism (dioxan) Max. Infl. 230 nm 310 nm Δε =* + 15 Δε = - 2.15 Max. 320 nm Δε * - 2.70 Infl. 330 nm Δε = - 2.43 l'nfl. 345 nm Δε at - 1.14 . 23 άΰ-lbo ' The (S)-allethrolone-me thane sulphonate used at the beginning of Example 3 may be prepared in the following manner: In 20p cin of acetone are dissolved 100 g of (S)5 allethrolone [Β.Ρ.θ 6 mm/Hg = 3-i5°C’ = + 14° (c = 1.3%, chloroform), U.V. absorption (ethanol): maximum at 229 nm, E^ = 180] and 114.5 cmJ of triethylamine are added thereto at -15°C. The mixture obtained is stirred and a solution qf 86.5 g of methanesulphonyl chloride in 180 cm of anhydrous acetone is introduced therein at a temperature of between 0 and +5°C over a period of about 20 minutes.

Stirring of the mixture is effected for 20 minutes at -10°C 3 and then 200 cm of methylene chloride are introduced therein at -15°C, followed by a mixture of 50 cm3 of an 11.8N aqueous solution of hydrochloric acid. The resultant mixture is stirred and the organic phase is separated off by decantation. The aqueous phase Is extracted with methylene chi oriel· and the organic phases are combined and washed with water. The aqueous washings are extracted with methylene chloride and the chloromethylenic phases are combined, washed, dried and concentrated to dryness under reduced pressure. 165 g of crude (S)-allethrolone-methane sulphonate are obtained which _ 24 are used in the condensation with the potassium d-Lrans chrysanthemate without further purification.

The solution of potassium d-trans-chrysanthemate used above may be prepared in the following manner: Into a mixture of 100 cm of dimethylsulphoxide and cm of water, are introduced 110 g of 2,2-dimethyl-3R(2'-methylprop-l '-enyl) -cyclopropane-IR-carboxylic acid [ [α]2θ ~ j. 36.7° (dimethylformamide)J and 2 drops of an alcoholic solution of phenolphthalein are added thereto.

!.O The quantity of an aqueous solution of potash (50° Be) necessary to turn the phenolphthalein pink (about 49.5 cm ) is then added at + 15°C. 0.7 cm^ of water are then added to the resultant mixture and a solution is obtained which contains potassium 2,2-dimethyl-3R-(2’-methylprop-l'-enyl)15 cyclopropane-lR-carboxylate.

Example 4 (4S)-2-Allyl-3-itiethyl-cyclopent-2-en-l-pne-4-yl 2,2-dimethyl· 3R-(2*-methylprop-l'-enyl) -cyclopropanc-lR-carboxylate [or (S)-allethrolone d-trans chrysanthemate] starting from (R)20 allethrolone-methane sulphonate To a solution of potassium d-trans-chrysanthemate (obtained as described hereinafter starting from 11 g of 25ft ΰ 18 ο d-trans chrysanthemic acid) is added, at -)- 15 C, a solution s a I , of 16 g of (R)-allethrolone-methane sulphonate in 35 cm'} of dimethylsulphoxide. The mixture obtained is stirred for 24 hours at 20°C and then water and heptane are added thereto. The resultant mixture is stirred and the organic phase is separated off by decantation. The aqueous phase is re-extracted with heptane and the organic phases are combined, washed with IN sodium hydroxide, then with water, dried and concentrated to dryness. 16.1 g of (S)-allethrolone 2,2-dimethyl-3R-(2'-methylprop-l’-enyl)cyclopropane-lR-carboxylate are obtained.

U.V. spectrum: (ethanol) Max. 227-228nm e = 17 400 Indicates a chemical purity of 94% for the allethrolone chrysanthemate.

Circular dichroism- (dioxan) Max. 227.5 nm Δε = - 24.5 Infl. 310 nm Δε = + 1.87 Max. 320 nm Δε = + 2.40 Max. 332 nm Δε = + 2.16 Infl. 345 nm Δε = + 1.02 This dichroism corresponds to : 90% of the (S)-allethrolone ester : 4% of the (R)-allethrolone ester _ 26 . plus : 6% of impurities (according to the U.V. titer) not affecting the D.C.

The optical purity of the ester is therefore 90 ^95.8% 90+4 The rate of stereoconversion of (R)-allethrolone—the (S)-allethrolone ester is therefore quantitative (95.8) 95.5 The (R)-allpthrolone-methane sulphonate used at the beginning of Example 4, may be prepared in the following manner: (R)-allethrolone of = -15° - 1° (c = 1%, chloroform) is used which, according to its circular dichroism, contains 95.5% of isomer (R) and 4.5% isomer (S). j g of (R)-allethrolone are dissolved in 20 cm acetone.

The solution obtained is cooled to -15°C and 11.4 cm3 of triethylamine are added thereto, followed,, maintaining the temperature below 0°C, by a mixture of 18 cm^ of acetone 3 and 5.8 cm of methanesulphonyl chloride. The resultant mixture is stirred for twenty minutes at -10°C and methylene chloride is introduced therein. The mixture thus obtained is acidified by the addition of an aqueous IN solution of hydrochloric acid and the mixture obtained is stirred. The organic phase-is separated off by decantation and the aqueous phase is again extracted with methylene chloride. The chloromethylenic phases are combined, washed with water, dried - 27 486 and concentrated under reduced pressure. 16 g of crude (R) -alleth.rolone-methane sulphonate are obtained which are used without further purification.

The solution of potassium d-trans-chrysanthemate used above may be prepared in the following manner: g of d-trans-chrysanthemic acid (IR, 3R) are 3 dissolved in 10 cm of dimethylsulphoxide and 3 cm of water are added thereto followed by a drop of an alcoholic solution of phenolphthalein. Potash lye is then introduced until the phenolphthalein turns colour.

Example 5 (S) -Allethrolone 2,2-dimethyl-3R-(21-methyIprop-1'-eny1)cyclopropane-lR-carboxylate starting from (R)-allethrolonemethane sulphonate (without isolation of the intermediate methane sulphonate) At 20°C, a. solution of (R)-allethrolono-methane sulphonate (obtained as described hereinafter from 250 g of (R)-nllethrolone) is introduced rapidly into a solution of potassium d-trans-chrysanthemate (obtained also as described hereinafter starting from 293 g of d-trans-chrysanthemic acid), The mixture obtained is stirred at 20°C for 24 hours and then 750 cm of water are added thereto over a period of about - 28 10 minutes at 20°G. The resultant mixture is stirred and the organic phase· is separated off by decantation. The aqueous phase is extracted with toluene and the combined organic phasep are washed in water with a IN aqueous solution of sodium hydroxide, dried over magnesium sulphate and filtered. 250 g of alumina are added to the filtrate and the mixture obtained is stirred, filtered and concentrated to dryness under reduced pressure. 400.7 g of (S)allethrolone 2,2-dimethyl-3R-(2’-methylprop-1’-enyl)10 cyclopropane-lR-carboxylate are obtained. = _ 49° (c = toluene).

The solution of (R)-allethrolone-methane sulphonate used above is prepared in the following manner: 250 g of (R)-allethrolone, [α]3θ e 10.5°(c = 10%, chloroform) are dissolved in 750 cm toluene and 225 g of methanesulphonyl chloride are introduced therein over 10 minutes at - 13°C, followed, over about two hours at - 8°C, 3 by a solution of 217.5 g of triethylamine in 200 cm of toluene. The mixture obtained is stirred for 15 minutes and then 1000 cm3 of water are added thereto at - 5°C over about 30 minutes. The resultant mixture is stirred and the organic phase is separated off by decantation. The aqueous phase i.s extracted with toluene and the toluenic phases are _ 29 _ S 4 8 β > combined and washed with water. The aqueous washings are extracted with toluene and the toluenic phases are combined and dried to give the toluenic solution of (R)-allethrolonemethane sulphonate used above.

The solution of potassium d-trans-chrysanthemate used above may be prepared in the following manner: In 500 cm of dimethylsulphoxide are dissolved 293 g of 2,2-dimethyl-3R-(2’-methylprop-l’-enyl) -cyclopropane-1Rcarboxylic acid and 184.2 g of an aqueous solution of potash (50°Be) are introduced therein at 40°C over about 30 minutes.

The mixture obtained is stirred for 30 minutes at 40°C and l a solution of potassium 2,2-dimethyl-3R-(2,-mothylprop-I enyl)-cyclopropane-IR-carboxylate is obtained.

Example 6 (R)-Allethrolone 2,2-dimethyl-3R-(2'-methylprop-11-enyl) cyclopropane-IR-carboxylate starting from (S)-allethrolonemethane sulphonate (without isolation of the intermediate methane sulphonate) Starting with 250 g of (S)-allethrolone, ~ + 14° (c = 1.3%, chloroform), a toluenic solution of (S)-allethrolone-methanc sulphonate is prepared operating in a manner analagous to that of Example 5 and, after condensation with potassium d-trans-chrysanthemate, used in solution, according _ to a modus operands similar to that of Example 5, 397 g of (R) -allethrolone ,2,2-dimethyl-3R-(2'-methylprop-1’-enyl)cyclopropane-lR-carboxylate are obtained [α]^θ = -4° (c = 5%, toluene).

Example 7 (S) -Allethrolone 2,2-dlmathyl-3R-(2'-methylprop-1'-enyl)cyclopropane-lR-carboxylate starting from (R)-allethroJ.onemethane sulphonate (without isolation of the intermediate methane sulphonate).

Into a solution of potassium d-trans-chrysanthemate (obtained as described hereinafter starting from 82.8 g of d-fcrans-chrysanthemic acid) is introduced at 18 - 20°C, over a few minutes, a solution of (R)-allethrolone-methane sulphonate (obtained as described hereinafter starting with 50 g of (R)-all'ethrolone). The obtained mixture is stirred vigorously for 35 hours at 18 - 20°C and then 150 cm^ of water are added thereto. The toluenic phase thus obtained is separated off by decantation and the aqueous phase is extracted with toluene. The toluenic phases are combined, washed with water, washed free of chrysantbemic acid using an aqueous solution containing 5% sodium bicarbonate and 5% sodium carbonate, then again with water until neutral, dried and finally filtered. Ϊ, S: ‘1 δ d 0.1 g of hydroquinone are added to the filtrate and the mixture ’ ' obtained is’ concentrated to'dryness by distillation under reduced pressure. 92.9 g of (S)-allethrolone 2,2-dimethyl3R-(2'-methylprop-l’-;enyl) -cyclopropane-lR-carboxylate are obtained. [α]2θ = 50.5° (c = 5%, toluene).

The solution of (R)-allethrolone-methane sulphonate used above is prepared in the following manner: Into 150 cm of toluene are introduced 50 g of (R)allethrolone followed, over about 10 minutes at 0°C, by 45 g of methanesulphonyl chloride. A solution of 43.5 g of triethylamine in 40 cm of toluene is then added to the mixture obtained, over about one hour at 0°C. The resultant mixture is stirred for 30 minutes at 0°C and then 200 cm^ of water are introduced therein at 0°C over about 30 minutes.

The mixture thus obtained is stirred and the toluenic phase is separated off by decantation. The toluene phase is washed with water until free of chloride, operating at a temperature lower than + 5°C and is then dried and filtered. A solution of (R)-allethrolone-methane sulphonate is obtained which is used in the condensation with the potassium chrysanthemate without further purification.

The solution of potassium d-trans-chrysanthemate used above may be prepared in the following manner: 3 Into a mixture of 100 cm of tertiary butanol and 100 cm^ of toluene, are introduced, at 20°C, 24.9 g of potash (titrating 90-8%) followed by 82.8 g of 2,2-dimethyl-. 3R-(2’-methylprop-I’-enyl) -cyclopropane-lR-carboxylic acid over about 30 minutes at 25-30°C. The mixture obtained is stirred for 2¼ hours at 25-30°G and then cooled to 20°C.

A solution of potassium 2,2-dimethyl-3R-(2’-methylprop-l’enyl)-cyclopropane-lR-carboxylate is obtained whichis used without further purification.

Example 8 (S)-Allcthrolone 2,2-dimethyl-3S-(2’-methylprop-1 '-enyl)cyclopropsne-lR-carboxylate starting from (R)-allethrolonemethane sulphonate (without Isolation of the intermediate methane sulphonate) 3 Into a mixture of 20 cm of toluene and 20 cm of tertiary butanol are introduced 10 g of sodium 2,2-dimethyl3S- (2'-methylprop-1'-e.nyl) -cyclopropane-IR-carboxylate [sodium cis-chrysanthematej followed, rapidly, by 31.8 cm of a toluenic solution containing 1.1 mole/1 of (R)-allethrolone-methane 'sulphonate. The mixture obtained is stirred 3 3 for 2 hours and then 30 cm of toluene and 20 cm of tertiary butanol are added thereto. The resultant mixture is stirred - 33 _ for 65 hours and then water is added thereto. The mixture thus formed’ is extracted with ether and the ethereal extracts are washed with water and with a dilute aqueous solution of ammonia, dried and concentrated to dryness by distillation under reduced pressure. 9.94 g of the crude ester are obtained which are purified by chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9 : 1). 7.38 g of (S)-allethrolone 2,2-dimethyl-3S-(2'methylprop-l’-enyl) -cyclopropane-lR-carboxylate are obtained. [α]2θ = + 39.5° (c = 0.8%, chloroform).

Circular dichroism (dioxan) = - 9.85 at 231 ran = + 2.68 at 320 ran = + 2.38 at 332 ran The sodium cis-chrysanthemate used above is prepared in the following manner: Into 200 cm of ethanol are introduced 20 g of 2,2dimethyl-3S-(2’-methylprop-l’-enyl).-cyclopropane-IR-carboxylic » t acid and a few crystals of phenolphthalein. To the mixture obtained is slowly added. concentrated soda lye until Lhc mixture turns pink, the solvents are then eliminated by distillation under reduced pressure. 22 g of sodium 2,2-dimethyl-3S(2'-methylprop-l’-enyl) -cyclopropane-lR-carboxylic acid are i S 4 8 6 obtained.

The toluenic solution of (R)-allethrolone-methane sulphonate used above is prepared in the following manner: Into 105 cm of toluene are introduced 35 g of freshly rectified (R)-allethrolone (B.P. = 97°G under 0.2 mm of mercury). The mixture obtained is stirred and then cooled to + 2°C. 22 cin of methanesulphonyl chloride are added thereto over 15 minutes at + 2 °C, followed by a mixture of 3 3 cm of toluene and 42 cm of triethylamine over one hour at + 2°C. The resultant mixture is stirred for 30 minutes at 0°C and then 35 cin of ice-water are added thereto over 10 minutes at 0°C, followed by a single addition of 100 cm of ice-water. The mixture thus formed is stirred and the aqueous phase is separated from the organic phase by decantation. The organic phase is washed in water at 0°C and the toluenic phas,e is dried and filtered. The solution obtained, which is maintained at 0°C, contains 1.13 mole of allethrolone-methane sulphonate per litre.

Example 9 (S)-Allethrolone 2,2-dimethyl-3S-(2*-methylprop-l*-enyl)cyclopropane-lR-carboxylate starting from (R)-allethrolone-ptoluene sulphonate Into a mixture of 20 cm of dimethylsulphoxide and _ 35 _ ^45486 - 2 cm of water arc introduced.2,28. g of sodium 2,2-dimelby13S- ( 21 -mothyliirop-1'-eny1) - cyclopropane- IR-ca rboxylat e [sodium cis-chrysanthemate] followed by 3.4 g of (R)allcthrolone-p-toluene sulphonate. The mixture obtained is stirred for 2 hours at ambient temperature and then poured into an aqueous solution of hydrochloric acid. The resultant mixture is stirred and the aqueous phase is separated and extracted with petroleum ether (B.P. 35-75°G). The organic extracts are washed in water, dried and concentrated to dryness. 2.4 g of a residue are obtained which are chromatographed on silica gel, eluting with a mixture of benzene and tthyl acetate (9 :l). 2.06 g of (S)-allethrolone 2,2-dimethyl-3S- (2-methylprop-l’-enyl)-cyclopropane-lRcarboxylate are obtained.

Circular dichroism (dioxan) Δε = - 7.8 at 233 nm t Δε = + 2.4 at 320 nm Δε = + 2.1 at 332 nm The sodium cis-chrysanthemate used above is prepared in the same manner as in Example 8.

The (R)-allethrolone-g-toluene sulphonate used above is prepared in the fallowing manner: Into 100 cm of tetrahydrofuran containing 11.6 <· of (R) - 364 S 4 8 3 allethrolone, are introduced 11.6 g of trieLhylaminc, at - 50°C under an inert atmosphere, followed by 21.9 of ptoluenesulphonyl chloride. The mixture obtained is stirred for 48 hours at + 5°C and then poured into an 0.1N aqueous solution of hydrochloric acid. The resultant mixture is stirred and the aqueous phase is separated and extracted with chloroform. The organic extracts are washed with water, dried and concentrated to dryness. Tlie residue (29 g) is chromatographed on silica gel, eluting with a mixture of benaene and ethyl acetate (95 : 5). 6.8 g of (R)-allethrolonep-toluene sulphonate are obtained.

Example 10 (S)-Allethrolone 2.2-dlmethvl-3S-(2'-metbvlprop-l'-enyl)cyclopropane-lR-carboxylate starting from (R)-allethrolone15 p-bromobenzene sulphonate Into a mixture of 38 cm of dimethylsulphoxide and 3 3.8 cm of water, are introduced 3.8 g of sodium 2,2-dimethyl3S-(2'-methylprop-1*-enyl)-cyclopropane-lR-carboxylate [sodium cis-chrysanthematej followed by 3.77 g of (R)-allethrolone3 bromobenzene sulphonate and 5 cm of dimethylsulphoxide.

The mixture obtained is stirred for 30 minutes and then left for 15 hours. Λ IN aqueous solution of hydrochloric acid - 37 . -iSliio ,, J ; ' . Ϊ : is then added, thereto and the aqueous phase thus obtained is •separated and extracted with petroleum ether (B.P. = 35-75°C). The organic phases are washed with IN sodium hydroxide and water, dried and concentrated to dryness. 1.02 g of a · residue are obtained which are chromatographed on silica gel, eluting with a mixture of petroleum ether (B.P. = 35-75°C). and diethyl ether (7 : 3). 0.422 g of (S)-allethrolone 2,2dimethyl-3S-(2’-methyIprop-1*-enyl) -cyclopropane-1Rcarboxylate are obtained.

Circular dichroism (dioxan) Δε =- 3.4 at 233 nm Δε =+ 1.5 at 321 nm Δε = + 1.7 at 332 nm The sodium cis-chrysanthemate used above is prepared in 15 the same manner as that prepared in Example 8.

The(R)-allethrolone-g-bromohenzene sulphonate used is , prepared in the following manner: Into 25 cm of tetrahydrofuran are introduced 2.5 g of (R)-allethrolone. The mixture obtained is cooled to 0°C and 2.5 g of triethylamine are added thereto followed by 6.3 g of g-bromobenzenesulphonyl chloride. The resultant mixture is stirred for 6 hours at + 5°C and then a dilute aqueous solution of hydrochloric acid is added thereto. The mixture thus formed - 38 _ ·-« 5 J & J is stirred and extracted with methylene chloride. The combined phases are washed with water, dried and concentrated to dryness. 7.47 g of crude (R)-allethrolonep-bromobenzene sulphonate are obtained, which are used without further purification.

Example 11 (4S)-2-Allyl-3-methyl-cyclopent-2-en~l-one-4-yi [(S)allethrolone] 2,2-dimethyl-3R-(eyclopentylidene-methyl)cyclopropane-lR-carboxylate starting from (R)-allethrolonemethane sulphonate 0.530 g of (R)-allethrolone-methane sulphonate (obtained as described hereinafter from 0.362 g of (R)-allethrolone) are 3 dissolved in 10 cm of dimethylformamide. The solution obtained is cooled to + 5°C and 0.576 g of potassium 2,2dimethyl-3P.-(cyclopentylidene-methyl)-IR-carboxylate (obtained as described hereinafter) arc added thereto. The mixture obtained is stirred at + 5 °C for one hour and then poured into water. The resultant mixture is acidified to pH 4 hy addition of dilute hydrochloric acid and then extracted with petroleum ether. The organic phase is dried and concentrated. Tbe residue is chromatographed on silica gel, eluting with a mixture of benzene and ethyl acetate (95 : 5). 0.443 g of 39«3483 (S)-allethrolone 2,2-dimethy1-3R-(cyclopentylidenc-metbyl)cyclopropane-lR-carboxylate are Isolated having“the following characteristics [α]ρθ = “ 38° +-2.5° (c = 0.6%, chloroform) Circular dichroism (dioxan) Infl. at 345 nm Δε = + 1.09 Max. at 332 nm Δε = + 2.32 Max. at 320 nm Δε =+2.60 Infl. at.310 nm Δε = + 1.97 Max. at 230 nm Δε = - 26.7 The (R)-a.llethrolone-methane sulphonate used above may be prepared in the following manner: 0.362 g of (R)-allethrolone (which, according to its circular dichroism has an optical purity of 97 - 98%) are : t dissolved in 4 cm of a mixture of benzene and ether (50 : 50) The solution obtained is cooled to -6°C and 0.46 cm^ of ’ I triethylamine are added thereto followed slowly by 0.2 cm of 3 i methanesulphonyl chloride in solution in 2.7 cm. of a mixture of benzene and ether (50 : 50). The resultant mixture is stirred for 2 hours at -10°C then poured into a dilute solution of hydrochloric·acid. The organic phase thus formed is separated off by decantation. The.aqueous phase is extracted withether and the organic phases aro combined, washed with water, dried and concentrated to dryness by distillation under reduced piessure. 0.530 % of. crude (1/)allethrolone-methane sulphonate are obtained ane. are used without further purification.

The potassium 2,2--dimethyl-3R- ' cyclopant','.'.idene-methyl) 5 cyclopropane-IR-carboxylate usee above may be prepared as fellows: 0.576 g of porassium. 2,2-dimefchyl-3R-(cyclopantylideneTi!tthyl)-cy.ilopropane-lR-carbji:yIate are prepared by neutralisation of a methanolic solution of 2,2-uimetb.yl-38.-(cyclo10 pentylii Example 12 (S>-Allethrolone 2,2rdimethyl-3S-(,21,,2 Michloroyinyl>-cycl,opropaae-lR-carboxylate [or (S)-allethrolone (lR,tyans)-2.9.diaethyl-3-(2 *,2 ’ -dlchlorovinyl)-cyclop,rppane-l»;carboxylafce1 starting from „(R)-allothrolcne-methane sulphonate (without isolation of the intermediate.methane,sulphonate) 3 Into a mixture of 20 cm of toluene ano 20 cm of tertiary butanol are introduced 10 g c-f sodium Oil,trans>2,2« dimethyl-3-(2!,2 ‘-dichlyrc-viayl)-cyclopropane-1-carboxylic . 41. «0·* acid, followed by 26.2 cm of a toluenic solution of (R): ' alia thro lone-me thane sulphonate (titrating 1,3 niole/li Lre).

·.. . The mixture obtained is stirred for 2 hours and then 30 cm'' ‘ . 3 of toluene and 20 cm of tertiary butanol are added thereto.

The resultant mixture is stirred for 65 hours and then treated analagously to Example 8. 9.26 g of crude ester are obtained which are chromatographed on silica gel,'eluting with a mixture of cyclohexane and ethyl acetate (9 : 1). 7.91 g of (S)-allethrolone (lR,trans)2.2-dimethyl-3-(2l.2t10 dichlorovinyl)-cyclopropane-l-carboxylate are obtained. [α]^θ = -26° (c = 0.5%, chloroform).

Circular dichroism (dioxan) Δε --23.6 at 228 nm Δε - + 2.62 at 321 Uftl Δε = + 2.32 at 332 nm The sodium (lR,trans)-2s2-dimethyl-3-(2’,2'-diclilorovinyl)-cyclopropane-1-carboxylate used above is obtained in .the following manner: Into 200 cm of ethanol are introduced 20 g of (IR,trans)20 2P 2-dimethyl-*3-(2’,2'-dichlorovinyl)-cyclopropane-l-carboxylic acid and a few crystals of phenolphthalein. To the mixture obtained is slowly added soda lye until the colour turns pi.nk» The mixture thus formed is concentrated to dryness by distillation under reduced pressure. Benzene is added to the residue and the resultant mixture is concentrated to dryness. This operation is then carried out a second time. 22.6 g sodium (IR,trans)-2,2-dimethyl-3-(2’,2'-dichlorovinyl)-cyclopropane-l-carboxylate are obtained.

The toluenic solution of (R)-allethrolone-methane sulphonate used above is prepared in the same manner as that used in Example 8.

Example 13 (S)-Allethrolone 2,2-dimethyi-3S-(2 ',2'-dichlorovinyl)eyclopropiine-IR-carboxylate [or (S)-allethrolone (IR,trans) 2,2-dimethyl-3-(2 ’,2 ’-dlchlorovinyl)-cyclopropane-I-carboxylate] starting from (R)-allethrolone-p-toluene sulphonate.

Into a mixture of 20 cm of dimethylsulphoxide and 2 cm of water are introduced 2.78 g of sodium (IR.trans)2,2-dimethyl-3-(2 ’,2 ’-dichlorovinyl)-cyclopropane-l-carboxylate followed by 3.4 g of (R)-allethrolone-g-toluene sulphonate.

The mixture obtained is stirred for two hours at ambient temperature, then acidified and extracted with petroleum ether (B.P. => 35 - 75°C). The organic phases are washed with IN sodium hydroxide, then with water, dried and concentrated to dryness. .3 g of residue are obtained which are chromato. 43 graphed on silica, gel, eluting with a mixture of benzene and ethyl acetate (9 : 1). 2.3l g of (S)-allethrolone (IR, trans)-2,2-dimethyl-3-(2', 2’'-dichlorovinyl)-cyclopropane1-carboxylate are obtained.

The sodium (IR,trans)-2,2-dimethyl-3-(2’.2'-dich1orovinyl)-cyclopropane-1-carboxylate is obtained in the same manner as in Example 12.

The (R)-allethrolone-g-toluene sulphonate used above is obtained in the same way as that of Example 9.

Example 14 (S)-Allethrolone 2,2-dlniethyl-3S-(2',2'-difiuorovinyl)cycIopropane-lR-carboxylate [or (S)-allethrolone (lR,trans)2.2- dimethyl-3-(2 *,21-difluorovinyl)-cyclopropane-l-carboxylate] starting from (R)-allethrolone-methane sulphonate (without isolation of the intermediate methane sulphonate) 3 Into a mixture of 36 cm of toluene and 36 cm of tertiary butanol are introduced 18.26 g of sodium (IR.trans)2.2- dimethyl-3-(21,21-difluorovinyl)-cyclopropane-l-carboxyl3 ate followed, over one minute by 54.5 cm of a toluenic solution of (R)-allethrolone-methane sulphonate (titrating 1.13 mole/litre). The mixture obtained is stirred for 76 hours at 20°C and then treated in the same manner as that of .- 44 .

Example 8. 18.69 g of crude ester are obtained which are chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9 : l). 15.1 g of (S)allethrolone (IR.trans)-2.2-dimethyl-3-(2'.Z’-difluorovinyl)5 cyclopropane-l-carboxylate are obtained. [α]2θ = . 24.5° (c = 1%, chloroform) Circular dichroism (dioxan) Δε = - 22.6 at 225 nm Δε = + 2.51 at 320 nm Δε =+2.23 at 332 nm U.V. spectrum (ethanol) Max. at 228 nm ε = 15 300 The sodium salt used in Example 14 is prepared in an annlagous manner to that used for preparing the sodium salt of Example 8. Starting with 17 g of (lR.trans)-2.2-dimethvl3-(2’,2’-difluorovinyl)-cyclopropane-1-carboxylic acid, 18.27 g of the sodium salt are obtained.

The toluenic solution of (R)-allethrolone-methane sulphonate used in Example 14 is obtained in the same manner as that used in Example 8.

Example 15 (S)-Allethrolone 2,2-dimethyl-3R-(2 1,2 ,-di.fluorovinyl)-cycl_o. 45 propane-lR-carboxylate |or (s)-allethrolone (lR,ci.s)-2,2dimethyl-3-(2 ',2 -difluorovinyl)-cyclopropane-l-carboxylate] starting from (R)-allethrolone-methane sulphonate (without isolation of the intermediate methane sulphonate) 3 Into a mixture of 23 cm of toluene and 23 cm of tertiary butanol, are introduced 11.5 g of sodium (lR.cis)-2,2dimcthyl -3-(2 2*-difluorovinyl)-cyclopropane-l-carboxyiate, followed, over one minute, by 35 cm of a toluenic solution of allethrolone-methane sulphonate (titrating 1.13 mole/litre).

The mixture obtained is stirred for 76 hours at 20°C and then treated in the same manner as in Example 8. 12.25 g of crude ester are obtained which are purified by chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9 : 1). 9.61 g of (S)-allethrolone (IR.cis) 2,2-dimethyl-3-(2 2 '-difluorovinyl)-cyclopropane-l-carboxylate o are obtained. [α]^ =+5 (c = 0.8%, chloroform).

Circular dichroism (dioxan) Δε =- 18.1 at 226 nm Δε = + 2.6 at 321 nm Δε = + 2.3 at 332 nm U.V. spectrum (ethanol) Max- at 228 nm ε = 15 200 - 46 .

The sodium salt used above is prepared in the same way as that used for preparing the sodium salt of Example 8. Starting from 10.57 g of (IR.cis)-2,2-dimethyl-3-(2',21difluorovinyl)-cyclopropane-l-carboxylic acid, 11.65 g of the sodium salt are obtained.

The toluenic solution of (R)-allethrolone-methane sulphonate used above is identical to that prepared in Example 8.

Example 16 j.0 Preparation of an emulsifiable concentrate The following are intimately mixed: (S)-allethrolone (IR transl·2,2-dimethyl-3-(2’,2’-difluorovinyl )-cyclopropane-l-carboxylate ...................... 0.3 g piperonyl butoxide .................................... 3 g topanol A ............................................. 0.1 g xylene................................................96.6 g Example 17 Preparation of a fumigcnic coil A solution of 0,1 g of (S)-allethrolone. (IR, trans>-2,220 dimethyl-3-(2 *,2 ’-difiuorovinyl)-cyelopropane-l-carboxyl.ate in 5 cm of methanol is carefully incorporated into a mixture - 47 0.4 cm and a diameter of about 12 cm.

Example 18 Preparation of a fumigenic coil A solution of 0.15 g of (S)-allethrolone 0-R, cish2.2dimethyl-3-(22*-difluorovinyl)-cyclopropane-1-carboxylate 3 in 5 cm of methanol is carefully incorporated into a mixture constituted by 43 g of Pyrethrum stem powder, 52 g of coconut shell powder and 4.4 g of soluble starch. The powder obtained is mixed with about 100 g of water, dried and shaped as a coil, with a thickness of about 0.4 cm and a diameter of about 12 cm.

Example 19 Preparation of a composition intended to be electrically heated A solution of 0.2 g of (S)-allethroIone (LR, trans)-2.220 dimethy1-3-(2 2 ’-difluorovinyl)-cyclopropane-l-carhoxylate .in 5 cm of toluene is adsorbed onto the surface of a par;.!1.1.el - 48 _ 6 466 epipedic piece of asbestos measuring 2 x 2 x 0.8 cm. A second piece of asbestos having the same dimensions is fixed to the first. In this way, a fuinigcnic composition is obtained which is used by being heated on a plate provided with an electric resistance.

Claims (19)

1. A process for the preparation of compounds of general (wherein the allethrolone ring is optically active and 5 either (1) and R 2 , which may be the same or different, each represents an alkyl radical containing from 1 to .3 carbon atoms;

2. (2) R^ and R 2 , being the same, each represents a 10 fluorine, chlorine or bromine atom;

3. (3) R^ represents an alkyl radical containing 1 or 2 carbon atoms and R 2 represents an acetyl or methoxymethyl radical; or (4) Rj, and R 2> together with the carbon atom to 15 which they are attached., form a carbocyclic ring containing from 3 to 6 carbon atoms or a group of formula in which X represents an oxygen or sulphur atom) •which comprises reacting an optically active compound of - 50 •S S 4 8 3 formula II, h 3 c rso 2 i (II) (wherein R represents an alkyl radical containing from 1 to 3 carbon atoms or a phenyl radical optionally substituted in the para position by a methyl radical or a fluorine, chlorine or bromine atom) of appropriate configuration with a salt of a compound of formula III, (in) (wherein R^ and R 2 are as defined above), in the presence of an organic solvent, the reaction proceeding with inversion of configuration in the allethrolone ring.

2. A process as claimed in claim 1 wherein the salt of the compound of formula III is an alkali metal, alkaline earth metal or ammonium salt or a salt formed with a tertiary base. - 51 3. A process as claimed in claim 2 therein the salt of the compound of formula III is a sodium or potassium salt.

4. A process as claimed in any of the preceding claims wherein the compound of formula III is a 2,2-dimethyl3-(2’-methylprop-l’-enyl)-cyclopropane-1-carboxylic acid; a 2,2-dimethyl-3-(2*,2-dichlorovinyl)-cyclopropane-lcarboxylic acid; a 2,2-dimethyl-3-(2*,2’-dibromovinyl)cyclopropane-l-carboxylic acid; a 2,2-dimethyl-3-(2,2difluorovinyl)-cyclopropane-1-carboxylic acid; a 2,2dimethyl-3-(2‘-methyl-3 1 -methoxy-(E)-prop-1'-enyl)cyclopropane-l-carboxylic acid; a 2,2-dimethyl-3-(2’ethyl-3'-oxo-but-l-enyl)-cyclopropane-1-carboxylie acid; a 2,2-dimethyl-3-(cyclopentylidene-methyl)-cyclopropane1-carboxylic acid; a 2,2-dimethy1-3-(2 1 -oxo-3'-oxacyciopentylidene-methyl)-cyclopropane-1-carboxylic acid; or a2,2-dimethyl-3-(2’-oxo-3’-thia-cyclopentylidene-methyl)cyclopropane-l-carboxylic acid.

5. A process as claimed in claim 4 wherein the compound of formula III is 2,2-dimethy1-3R-(2'-methylprop-l'-enyl)cyclopropane-IR-carboxylic acid; 2,2-dimethyl-3S—(2’ — methylprop-l’-enyl)-cyclopropane-IR-carboxylic acid; 2,2dimcLhyl-3R~(eyeiQperitylidcne-methylJ-cyelopropnne-IRcarboxylic acid; 2,2-dimethyi-3S-(2*,2’-dichlorovinyl)- 52„ cyclopropane-lR-carboxylic acid; 2,2-dimethyl-3S-(2',2'difluorovinyl)-cyclopropane-lR-carboxylic acid; or 2,2-dimethyl-3R-(2* ,2’-difluorovinyl)-cyclopropane-lRcarboxylic acid.

6. A process as claimed in any of the preceding claims wherein the organic solvent comprises dimethylformamide, hexamethylphosphorotriamide, dimethylsulphoxide, dimethoxyethane, acetonitrile, an aliphatic ketone containing from 3 to 6 carbon atoms, an alkanol, a monocyclic aromatic hydrocarbon or a mixture thereof.

7. A process as claimed in claim 6 vherein the solvent is hexamethylphosphorotriamide, dimethylsulphoxide, dimethylformamide, a mixture of toluene and dimethylsulphoxide or a mixture of toluene and a secondary or tertiary alkanol containing from 4 to 6 carbon atoms.

8. A process as claimed in claim 7 wherein the solvent is a mixture of toluene and tertiary butanol.

9. A process as claimed in any of the preceding claims wherein, in the compound of formula II, R represents a methyl or £-tolyl radical.

10. A process as claimed in any of the preceding claims wherein, in the compound of formula II, the allethrolone ring has the (R) configuration. - 53 -i S 4 8 3

11. A process as claimed in any of claims 1 to 8 wherein the compound of formula II is in the form of a mixture of (R) and (S) isomers in which the (R) isomer predominates. 5

12. A process as claimed in any of the preceding claims wherein the compound of formula II is obtained by reaction of optically active allethrolone of appropriate configuration with a compound of formula IV, rso 2 Cl (IV) (wherein R is as defined in claim 1) in the presence of an organic solvent and of a basic agent, the reaction proceeding with retention of configuration in the allethrolone ring.

13. A process as claimed in claim 12 wherein the com15 pound of formula II is not isolated.

14. A process as claimed in claim 12 or claim 13 wherein, in the reaction of allethrolone with the compound of formula IV, the solvent comprises a monocyclic aromatic hydro carbon. 20 15.

A process as claimed in any of the preceeding claims wherein the salt of the compound of formula III is obtained by reacting a compound of formula III with an appropriate base in the presence of an organic solvent. -5416.

A process as claimed in claim 15 wherein the salt of the compound of formula III is not isolated.

17. A process as claimed in claim 15 or claim 16 wherein, in the reaction of the compound of formula III 5 with the base, the solvent comprises dimethylformamide, dimethylsulphoxide, hexamethylphosphorotrianide, dimethoxyethane, acetonitrile, an aliphatic ketone containing from 3 to 6 carbon atoms , an alkanol, a monocyclic aromatic hydrocarbon or a mixture thereof. ]0

18. A process for the preparation of compounds of general formula I as claimed in claim 1 substantially as herein described.

19. A process for the preparation of compounds of general formula I as defined in claim 1 substantially as 15 herein described in any one of Examples 1 to 15.

20. Compounds of general formula I as defined in claim 1 whenever prepared by a process as claimed in jury one of claims 1 to 19. 4 3 -18 6

21. (S)-Allethrolone 2,2-dimethyl-3R-(cyclopentylidenemethyl)- cyclopropane-IR-carboxylate.

22. (S)-Allethrolone 2,2-dimethyl-3S-(2',2'-dichlorovinyl)-cyclopropane-IR-carboxylate. 5 23. (S)-Allethrolone 2,2-dimethyl-3S-(2’,2’-difluorovinyl)-cyclopropane-IR-carboxylate.

24. (S)-Allethrolone 2,2-dimethyl-3R-(2’,2'-difluorovinyl)-cyclopropane-IR-carboxylate.

25. Insecticidal compositions comprising, as active 10 ingredient, at least one compound as claimed in any one of claims 21 to 24 in association with an insecticidal carrier or excipient.

26. Insecticidal compositions as claimed in claim 25 substantially as herein described.

27. · Insecticidal compositions substantially as herein described in any one of Examples 16 to 19. Dated this the 9th day of September, 1977