IE50479B1 - Cyclopropane carboxylic acid ester derivatives - Google Patents

Abstract

There is provided a compound of formula wherein R<1> and R<2> are each independently selected from chlorine, bromine and methyl, in the form of a 1:1 mixture of the 1RcisS- and 1ScisR- isomers substantially free of 1ScisS- and 1RcisR-isomers, processes for preparing such compounds, and their use as pesticides. Compounds according to the invention contain up to four times as much of the most active isomer of the compound of formula I as a compound containing equal amounts of all eight possible isomers, and they are readily prepared by routes which do not involve any stereospecific synthesis or optical resolution steps.

Description

This invention relates to cyclopropane carboxylic acid, ester derivatives, their preparation and their use as pesticides.

Cyclopropane carboxylic acid ester derivatives of general formula 2 wherein R and R are independently selected from chlorine, bromine and methyl, are known compounds having pesticidal activity, see for example Patent Specification No. 37581 or US Patent No. 4,024,103. These derivatives are members of a class of pesticidal compounds commonly referred to in the art as pyrethroid insecticides. Compounds of formula I contain two centres of asymmetry in the cyclopropane ring of the acid, moiety and a third centre of asymmetry in the alcohol moiety, leading to the existence of eight possible isomers. In general, superior pesticidal activity resides among the compounds having cis-configuration about the cyclopropane ring, as disclosed by Itaya et al in Synthetic Pyrethroids, ACS Symposium Series 42, Pages 45 to 54, and the isomer which has the greatest pesticidal activity is generally that isomer which is conveniently designated the IReisS-isomer, IRois- designating configuration tte acid moiety and S-designating configuration in the alcohol moiety, as described by Elliott et al in Nature, Vox- 2U8, Psge,; T10 and 711 (1974).

Attempts to produce IReisS- single isomers rest either on synthesis routes which inherently produce intermediates containing the cyclopropane carboxylic acid moiety in exclusively lRcisconfiguration or on a route which involves an optical resolution step to separate lRcis- compounds from lSci_s- compounds. Esterification of a lRcis- intermediate to produce a derivative of formula I above leads to production of a mixture of IReisR- and IReisS- end products. Separation of these end products is possible by physical methods, at least in theory, since the IReisR- and IReisS- compounds are not enantiomers. However, although such separation of IReisR and IReisS- compounds has 1 2 proved to be relatively readily attainable when R and R are both bromine atoms, it has proved to be more difficult and more 1 2 costly in other cases, for example when R and R are both chlorine atoms.

There has now surprisingly been discovered a novel compound which contains weight for weight, up to four times as much of the most pesticidally active (IReisS-) isomer of a conpound of formula I as a oompound containing equal weights of all eight isomers of formula I. This novel compound has the advantage that it may be readily and relatively cheaply prepared, by a route which does not involve any asymmetric synthesis or optical resolution step.

This invention provides a compound of formula 50478 2 wherein R and. R are each independently selected from chlorine, bromine and methyl, in the form of a 1:1 mixture of the lRcisSand IScisR- isomers substantially free of IScisS- and lRcisRisomers. 2 Compounds of the invention wherein R and R are both halo1 2 gen atoms are preferred and R and R are preferably both chlorine atoms.

According to a preferred embodiment of the invention there is provided a compound which comprises a 1:1 mixture of IRcisS10 and IScisR- isomers of Οζ-cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate in the form of a crystalline solid having a melting point of at least 75°C. Advantageously the melting point is at least 80°C and is preferably in the range 84 to 87°C.

Compounds of the invention may be prepared by a process which comprises treating a mixture of the IReisS-. lS-cisS-, IReisR- and IScisR- isomers of a compound of formula I with a solvent, and separating off a 1:1 mixture of the IReisS- and IScisR-isomers Bubatant.-ial ly free of IReisR- and IScisS- isomers as a crystalline solid from a solution of the compound of formula I which contains IScisS- and IReisR- isomers.

The process may conveniently be effected by cooling a solution of the mixture of IReisS-, lS-cisS-, IReisR- and lScisRisomers.

Alternatively, the process may in at least some cases be effected by contacting the mixture of IReisS-, IScisS-, IRcisRand IScisR- isomers with the solvent at or below ambient temperature and separating the residual solid crystalline 1:1 mixture of IReisS- and IScisR- isomers from the resulting solution which contains IScisS- and IReisR- isomers.

The solvent used should be one in which the lRcisS-ZlScisRenantiomer pair is substantially less soluble than the IScisS-/ IReisR- enantiomer pair.

Suitable solvents include the lower liquid alkanes of up to 8 carbon atoms, for example pentane or the petroleum ethers from 3C/5O petroleum etbei to 100/120 petroleum ether, preferably 1*0/60 or 60/80 petroleum ether; and the liquid alkanols such as isopropanol.

Crystallisation of the IRcisS-ZlScisR- enantiomer pair maybe effected at a temperature in the range -50° C to 20°C, preferably 0°C to 10°C, depending on the concentrations of the various present isomers.

Separation and recovery of the crystalline compound of the invention from the supernatant solution, which contains lSeisSand IReisR- isomers, may be effected by methods such as filtration, centrifugation or decantation.

The solution of the compound of formula I which contains IScisS- and IReisR- isomers is a useful raw material for the preparation of additional amounts of compound according to the invention. It has been further discovered that, on treatment with a suitable base, under appropriate conditions racemisation may take place at the 0( -carbon atom of the alcohol moiety in the compound of formula I, so that a proportion of the IScisS- and IReisR- isomers in the solution may be converted into IScisR- and IRcisS- isomers respectively, and additional amounts of compound according to the invention may be isolated as described above.

Accordingly, the preferred process of the invention further canprises treating the solution of the ccmpound of formula I which contains IScisS- and IReisR- isomers with a base, and separating off from the solution a 1:1 mixture of the IRcisS- and IScisR- isomers, during or after the treatment with the base.

If in the preferred process of the invention the mixture of the IRcisS-, IScisS-. IReisR- and IScisR- isomers is completely dissolved in the solvent, and the resulting solution contains equal quantities of all four cis-isomers, at least sane of the IRcisS- and IScisR-isomers are separated fran the solution in the form of a 1:1 mixture of the IRcisS- and IScisR- isomers substantially free of IReisR- and IScisS- isomers as a crystalline solid before or during the treatment with the base.

I 50470 Suitable bases for use in tbe process of tbe invention include anmcnia, primary, secondary and tertiary amines, alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, and basic icn exchange resins. Preferred amine bases contain cne or more alkyl and/or bensyl groups, or are alkylene diamines of cp to 4 carbon atoms, for exanple ethylenediamine, or are heterocyclic amine bases having 5 or 6- ring atoms and containing the nitrogen atom and optionally an osygen, a sulphur or an additional nitrogen atom attached to carbon atoms in the ring, for exanple pyrrolidine, morpholine or piperidine.

If desired, the preferred process of the invention mey ba effected in two separate steps, optionally in two different locations. For exanple the treatment vzith the base nay be effected at an elevated tenperature, for exanple a tenperature in the range of from 20°C to 100°C, preferably 20°C to 60°C, for fast racemisation, followed by cooling to effect crystallisation of the 1:1 mixture of the IRcisS- and IScisR- iscmers as described above. If the base is present in solution, both steps of the process may be effected in a single reaction zone, or the elevated tenperature step may be effected in one reaction zone and the crystallisation step msy be effected in another reaction zone.

However, the base may be in the solid phase, e.g. a basic icn exchange resin, for exanple those sold under the trade names Dcwex (Registered Trade Mark) and Anberlite (Registered Trade Mark) such as Dowex AGEX 8, Anberlite IRA 400 or Amberlite IR 45, or solid potassium carbonate, and the process may be effected under anhydrous conditions, optimally in the presence of a alkanol such as methanol, with the base in cne reaction zone, for example a packed column, fear the elevated tenperature step, the solution of isomers of the compound of formula I being renoved to another reaction zone for the crystal1i saticn step.

When the base is present in solution in the preferred process of the invention and both steps of the process are effected in a single reaction zone, the treatment with the base 50473 and crystallisation of the 1:1 rarcture of the IRcisS- and IScisRisomers may be effected simultaneously at a temperature in the range -50°C to 20°C, preferably 0°C to 2o'"C, In such a simultaneous base treatment and crystallisation process, the lRcisS5 and IScisR-isomers are continuously removed from solution by crystallisation so that the supernatant solution is always rich in IScisS- and IReisR- isomers and racemisation is always able to occur. Accordingly, in such a process the starting material may be a racemic mixture of all four cis- isomers of the compound of formula I which is introduced directly into the reaction zone.

The IScisS- and IReisR- isomers will dissolve more readily to give a solution which is rich in those isomers. Racemisation then occurs and the 1:1 mixture of IRcisS- and ISaisR- isomers crystallises out of solution continuously until substantially all of the IScisS- and IReisR- isomers have dissolved and a final equilibrium has been reached. Additional quantities of the racemic mixture of all four ci3- isomers may be added continuously or in discreet portions throughout the time span of such a process.

When the preferred process of the invention is not being effected with a base in the solid phase, it is preferred for the base to comprise ammonia, a primary, secondary or tertiary amine, or an alkali metal carbonate,, preferably sodium or potassium carbonate, in aqueous solution.

It has been found that the rate of racemisation may be enhanced when the solution of the IScisS- and IReisR- isomers of the compound of formula I is treated with the base in the presence of a alkanol, for example methanol. The rate of racemisation may also be enhanced when the solution is treated with the base in the presence of a phase-transfer catalyst. The phase-transfer catalyst is preferably a quaternary ammonium halide. The substituents in the quaternary ammonium halide are for example alkyl groups and/or benzyl groups. Preferred quaternary ammonium halides are tetrabutyl ammonium and benzyl triethyl ammonium chlorides and bromides.

The compounds of the invention contain a high proportion of the most pesticidally-active isomer of the relevant compound of formula I. The invention therefore also provides a pesticidal composition which comprises a compound of formula I in accordance with the invention as defined above in association with a suitable carrier therefor, the composition heing substantially free of IScisS- and lBcisR- isomers of the compound of formula I. The invention further provides a method of combating pests, e.g. insect or acarid pests, at a locus which comprises applying to the locus a compound of formula I in accordance with the invention or a composition in accordance with the invention.

A carrier in a composition of the invention may he a solid or a liquid, including a material which is normally gaseous hut which has been compressed to form a liquid, inorganic or organic, and of synthetic or natural origin. The active ingredient is suitably formulated with at least one carrier to facilitate its application to the locus, for example plants, seeds or soil, to he treated, or to facilitate storage, transport or handling.

Preferably a composition of the invention contains at least two carriers, at least one of which is a surface-active agent.

The surface-active agent may he an emulsifier, a dispersing agent or a wetting agent. It may he non-ionic or ionic. Pesticidal compositions are generally formulated and transported in a concentrated form which is subsequently diluted hy the farmer or other user before application. A surface-active agent facilitates this process of dilution.

Any of the carriers commonly used in the formulation of pesticides may he used in the compositions of the invention, and suitable examples of these are to he found, for example, in British Patent Specification No. 1,232,930.

The composition of the invention may for example he formulated as a wettahle powder,. microcapsules, a dust, granules, a solution, an emulsifiahle concentrate, an emulsion, a suspension concentrate or an aerosol. The composition may have controlled release properties, or may he suitable for use as a hait.

Wettable powders usually contain 25, 30 cr 75% w of active ingredient and may contain, in addition to inert solid material; 3-10% v of a dispersing agent and, where necessary, 0-10% w of a stabiliser, a penetrant and/or a sticker. A dust is usually formulated as a dust concentrate having a composition similar to that of a wettable powder but without a dispersant, and is diluted in the field with further solid carrier to give a composition usually containing £-10% w of active ingredient.

Granules usually have a size in the range of from 10 to 100 BS mesh (1.676-0.152 mm) and may be manufactured by agglomeration or impregnation techniques. Generally, granules will contain 25% w active ingredient and 0-10% w of additives, for example a stabiliser, slow release modifier and/or a binding agent.

Emulsifiable concentrates usually contain, in addition to a solvent, and, when necessary, co-solvent, 10-50% w/v active ingredient, 2-20% w/v emulsifier and 0-20% w/v of other additives, for example a stabiliser, a penetrant and/or a corrosion inhibitor. A suspension concentrate is a stable, nonsedimenting, flowable product and usually contains 10-75% w active ingredient, 0.5-15% w of dispersing agent, 0.1-10% w of suspending agent, for example protective colloid and for a thixotropic agent, and 0-10% w of other additives including, for example, a defoamer, a corrosion inhibitor, a stabiliser, a penetrant and/or a sticker, and as dispersant, water or an organic liquid in which the active ingredient is substantially insoluble; certain organic additives and/or inorganic salts may be dissolved in the dispersant to assist in preventing sedimentation or as anti-freeze for water: The aqueous dispersions and emulsions formed by diluting a wettable powder or an emulsifiable concentrate of the invention with water, also lie within the scope of the present invention. Such dispersions and emulsions may be of the water-in-oil or of the oil-in-water type, and may have a thick mayonnaise™like consistency.

A composition of the invention may also contain other ingredients, for example, one or more other compounds possessing pesticidal, herbicidal or fungicidal properties, or attractants, for example pheromones or food ingredients, for use in baits and trap formulations.

The invention will be better understood from the following Examples.

Example 1 1:1 mixture of IRcisS- and IScisR- isomers of O< -cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate by crystallisation process using isopropanol .0 g of a racemic mixture of cis-isomers o£o(,-cya.tiO-3phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate was dissolved in 30 ml isopropanol with gentle warming. The resulting solution was cooled to 10°C and allowed to stand at that temperature for 20 hours. A precipitate settled out and was separated off by filtration to give I.U g of a solid product in the fonn of colourless crystals, m.p. 7T-8l°C. Highperformance liquid chromatography analysis showed the product to be a 90$ pure 1:1 mixture of IRcisS- and IScisR- isomers of the starting material. 3.2 g of solid product obtained as above was recrystallised from pentane, yielding 2.0 g of a colourless crystalline solid, mp 8U-86°C. This product was shown by high-performance liquid chromatography analysis to be about 99$ pure 1:1 mixture of the IRcisS- and IScisR- isomers of the starting material.

Example 2 1:1 mixture of IRcisS- and IScisR- isomers of c(-cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyolopropane carboxylate by crystallisation process using Uo/6o petroleum ether g of a racemic mixture of cis-isomers of oA-cyano-330 phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethyicyclopropane carboxylate was dissolved in 150 ml Uo/6o petroleum ether with gentle warming. The resulting solution was cooled to 20°C and allowed to stand at that temperature for 3 days. A colourless crystalline precipitate settled out and was isolated by filt35 ration. The yield obtained was 3.3 g, had mp 79-θ1°0 and was shown hy high perioimaace liquid chromatography to be a greater than 90/ pure 1:1 mixture of IReisS- and IScisR- isomers of the starting material.

Portions of the product obtained in the above process were recrystallised once, twice and three times from U0/60 petroleum ether. The resulting products, which were all colourless crystalline solids had mp 83-86°C, 8L-86°C and 86-87°C, respectively and were shown by high performance liquid chromatography to he 99/ pure, greater than 99.9/ pure and 100/ pure samples of the desired pair of isomers.

Example 3 1:1 mixture of IReisS- and IScisR- isomers of -cyano-3-phenoxybenzyl 3-(2,2-diehlorovinyl)-2,2-dimethylcyclopropane carboxylate hy treatment of solid racemate with k0/60 petroleum ether g of a racemic mixture of cis-isomer3 of Oi -cyano-3phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethyloyclopropane carboxylate was stirred with 75 ml L0/60 petroleum ether for 5 days at ambient temperature (20°C). Filtration gave U.l g of colourless crystals, mp 8l.5-83°C, which were shown hy high performance liquid chromatography to he about 97/ pure 1:1 mixture of IReisS- and IScisR- isomers of the starting material.

By comparison with the products of Examples 1 to 3 above, it should be noted that IReisS- pt.-eyano-3-phenoxybenzyl 3-(2,2dichlorovinyl)-2,2-cyclopropane carboxylate and the lScisRenantiomer both have mp 53-5^°C.

Example U 1:1 mixture of IReisS- and IScisR- isomers of o4.-cyano-3-phenoxybenzyl 3-(2,2-dibramovinyl)-2,2-dimethylcyclopropane carboxylate hy crystallisation process using 60/80 petroleum ether. .0 g of a racemic mixture of cis-isomers of oC-cyano-3phenoxyhenzyl 3-(2,2-dibromovinyl)-2,2-dimethyloyclopropane carboxylate was treated by a process similar to those of Examples 1 and 2 using 60/80 petroleum ether as solvent. Reerystallisation of the initial product yielded 3.8 g of colourless crystals, m.p. 93-97°C, which were shown by high performance liquid chroma50479 tography to be an about 80% pure sample of the desired pair of isomers. A further two recrystallisations of this product yielded respectively 3.15 g and 2.7 g of colourless crystals, of m.p. 99-101°C and 100-101°C, which were shown by high performance liquid chromatography to contain greater than 95% and 99% respectively of the desired pair of isomers.

Example 5 1:1 mixture of IScisS- and IScisR- isomers of o( -cyano-3phenoxybenzyl 3-(2-methylpropenyl)-2,2-dimethylcyclopropane carboxylate by crystallisation process using 4θ/6θ petroleum ether .3 g of a racemic mixture of cis-isomers of oi -cyano-3phenoxybenzyl 3-( 2-methylpropenyl )-2,2-dimethylcyclopropane carboxylate in the form of a colourless oil was treated by a process similar to those of Examples 1 and 2, using 40/60 petrol15 eum ether as solvent. 5.75 g of initial colourless crystalline product had mp 6O-66°C and was shown by HMR analysis at 360 MHz to be a 90% pure 1:1 mixture of IReisS- and IScisR- isomers of the starting material. This initial product was reerystallised three times from 40/60 petroleum ether, yielding respectively 4.7 g, 4.3 g and 4.0 g of product having mp 65-70°C, 69-72°C and 70-72°C. These products were shown by HMR analysis at 360 MHz to be 95% pure, 98% pure and greater than 99.5% pure 1:1 mixtures of the desired pair of isomers.

Example 6 1:1 mixture of IReisS- and IScisR- isomers of ej -cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate by process using isopropanol as solvent 12.9 g of a racemic mixture of cis-isomers of c( -cyano-3phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate was dissolved in 52 ml isopropanol at 20°C, and 2.0 ml of .880 solution of ammonia in water was added with stirring. After stirring at 20°C for 21 hours, the reaction mixture was cooled and stirred at 0°C to 5°C for a further 4 hours. The precipitate which settled out was filtered off, washed with 5 nil of isopropanol at 5°C and with 15 ml of 60/80 petroleum ether to give 5-1 g of solid product in the form of colourless crystals, mp 77-81°C. High-performance liquid chromatography showed the product to he a 90? pure 1:1 mixture of IHcisS- and lScisH-isonsers of the starting material.. Similar analysis of the filtrate showed the ratio of the concentrations of the IScisS-aad IReisR- isomers to those of the IRcisS- and IScisR- isomers to he about 3:2.

The filtrate and the washings from the above process sequence were concentrated, the resulting material was dissolved in 30 ml isopropanol and 2.0 ml of .880 solution of ammonia in water was added with stirring and the above process steps were repeated to yield a further 2.1 g of colourless crystals, mp 74-79°C, which were shown by high-performance liquid chromatography to be a 85? pure 1:1 mixture of IRcisS- and IScisR- isomers of the starting material. Similar analysis of the filtrate showed the ratio of the concentrations of the IScisS- and IReisR- isomers to those of the IRcisS- and IScisR- isomers to be about 4:1.

Example 7 1:1 mixture of IRcisS- and IScisR- isomers of Q< -cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate by process using 4o/6o petroleum ether as solvent g of a racemic mixture of cis- isomers of

Claims (15)

CLAIMS 5 chlorine, bromine and methyl, in the form of a 1:1 mixture of the IRcisS- and IScisR- isomers substantially .free of IScisS- and IReisR- isomers.

1.2

2. A compound of Claim 1 wherein R and R are both chlorine atoms. 10

3. A compound which comprises a 1:1 mixture of IRcisS- and IScisR-isomers of ©4 -cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate in the form of acrystalline solid having a melting point of at least 75°C.

4. A compound according to Claim 1 substantially as herein25 before described with particular reference to. any one of the

5.Examples . 5 · A process for preparing a compound according to any one of Claims 1 to 3 which comprises treating .a mixture of the. IRcisS-, lS-cisS-, IReisR- and IScisR- isomers of a compound 2o of formula I with a solvent, and. separating off a 1:1 mixture of the IReisS- and lScisft- isomers substantially free of IReisR- and locisS- isomers as a crystalline solid from a solution of the compound of formula I which contains IScisS- and IReisR- isomers.

6. A process according to Claim 5 which comprises cooling a solution of the mixture of IReisS-. lS-cisS-, IReisR- and IScisR-isomers.

7. A process according to Claim 5 which comprises contacting the mixture of IReisS-. IScisS-, IReisR- and IScisR- isomers with the solvent at or below ambient temperature and separating the residual solid crystalline 1:1 mixture of the IReisS- and IScisR- isomers from the resulting solution which is rich in the IScisS- and IReisR- isomers.

8. A process according to Claim 5, 6 or 7 which further comprises treating the solution of the compound of formula I which contains IScisS- and IReisR- isomers with a base, and separating off from the solution a 1:1 mixture of the IReisS- and IScisR- isomers substantially free of lRcisRand IScisS- isomers, during or after the treatment with the base.

9. A process according to Claim 8 wherein the solution of the isomers of the compound of formula I contains a lower liquid alkane of up to 8 carbon atoms or a liquid alkanol as solvent.

10. A process according to Claim 9 wherein the base comprises ammonia, a primary, secondary or tertiary amine, or an alkali metal carbonate, in aqueous solution.

11. A process according to Claim 10 wherein the solution is treated with the base in the presence of a C.^ alkanol.

12. A process according to Claim 10 or 11 wherein the solution is treated with the base in the presence of a phase-transfer catalyst.

13. A process according to Claim 5 substantially as hereinbefore described with particular reference to any one of the Examples. S0479

14. A pesticidal composition which comprises a compound, according to any one of Claims 1 to 4 in association with a suitable carrier therefor, the composition being substantially free of IScisS- and IReisR- isomers of the compound of 5. Formula I.

15. A method of combating pests at a locus which comprises applying to the locus a confound according to any one of Claims 1 to 4 or a composition according to Claim lh.