GB2034301A - 3-Phenoxybenzyl 1R, cis-2,2- dimethyl-3-(2-chloro-prop-1- enyl)cyclopropane Carboxylate - Google Patents

Abstract

The novel insecticidal compound 3-phenoxybenzyl 1R, cis-2,2- dimethyl-3-(2-chloro-prop-1-enyl) cyclopropane carboxylate which can be prepared by reacting methyl 1R, cis-2,2-dimethyl-3-(2- oxopropyl)cyclopropane carboxylate with phosphorus pentachloride to produce a mixture of isomers of methyl 1R, cis-2,2-dimethyl-3-(2- chloro-prop-1-enyl)cyclopropane carboxylate, saponifying the isomeric mixture thus obtained with a methanolic potassium compound Voyielic mixture of the corresponding acids and esterifying the potassium salts of the acids with 3- phenoxybenzyl bromide or a derivative thereof.

Description

SPECIFICATION New Pyrethroid The present invention relates to new insecticidal compounds of the synthetic pyrethroid group, a process for their preparation and to insecticidal formulations containing such compounds as active ingredient. More particularly, the invention relates to 3phenoxybenzyl 1 R, cis-2,2-dimethyl-3-(2-chloroprop-1-enyl) cyclopropane carboxylate which is a new insecticide closely related structurally to Permethrin and to a process for the preparation of such new compound in the form of a mixture of isomers thereof. Still further, the invention relates to insecticidal formulations comprising the new compounds of the invention as active ingredient in association with a carrier or diluent therefor.

Natural pyrethrins and cinerins are weii-known for their insecticidal properties and accordingly, it has long been the object of insecticide manufacturers to produce synthetically insecticides possessing the properties of such naturally occurring substances. A number of insecticides structurally related to such natural compounds have been synthetically prepared and employed with success over the last few years in Great Britain, the United States, Japan and other developed countries. These synthetic insecticides possess an advantage over other insecticides by virtue of the fact that they combine high insecticidal activity with low mammalian toxicity.

Furthermore, the synthetically prepared insecticides are in some ways actually superior to natural pyrethrins in that they possess higher photostability and are therefore ideally suited for use in agriculture.

Structura(ly, most synthetic pyrethroids are esters of 2,2-dimethyl-3-vinyl substituted cyclopropane carboxylic acid with an alcohol. An important member of this group employed in commercial use is Permethrin which is identified by the general formula I of the accompanying drawings and comprises an ester of 2,2-dimethyl3-vinyl substituted cyclopropane carboxylic acid with 3-phenoxybenzyl alcohol. Another important synthetic pyrethroid is Resemethrin which is an ester of the above-mentioned acid with 5-benzyl3-furylmethyl alcohol.

Advantageously, it is possible to vary the vinyl substituent in such synthetic pyrethroids at the 3position of the cyclopropane ring without impairing the insecticidal activity of the compounds. Thus, several different 3-vinyl substituted derivatives have been synthesised by other workers and found to have insecticidal activity. For a comprehensive review attention is directed to M. Elliot "Synthetic Pyrethroids", ACS Symposium Series No. 42, 1977, pp. 1 and references cited therein. For instance, the synthesis of the various 3-vinyl substituted analogues was achieved by the reaction of appropriate Wittig reagents with caronaldehyde ester (M. Elliot et al., Nature, 244, 456 (1973); J.

Chem. Soc., Perkin Trans. 1,2470 (1974).

Permethrin has also been synthesised either by a Wittig reaction as described above or from acyclic intermediates involving ring closure of the cyclopropane ring (N. Itaya et al. "Synthetic Pyrethroids", ACS Symposium Series No. 42, 1977, pp. 45).

Regarding the relationship between the stereochemistry of pyrethroid insecticides at positions 1 and 3 of the cyclopropane ring and insecticidal activity, it is well-known that the cisisomers are about twice as active as the transisomers and that absolute configuration 1 R has insecticidal activity whereas 1 S has very low activity (N. Itaya et al. Loc. cit).

Accordingly, a primary object of the present invention is the provision of a new insecticidal compound closely related in structure to Permethrin.

A further object is the provision of such new compound in the form of a mixture of the cisisomers thereof.

Another object of the invention resides in a process for the preparation of the novel insecticidal compound.

Yet another object of the invention is an insecticidal formulation incorporating the novel compound of the invention as active ingredient.

Accordingly, the present invention provides as a new insecticidal compound 3-phenoxy-benzyl 1 R, cis-2 ,2-dimethyl-3-(2-chloro-prop- 1 -enyl) cyclopropane carboxylate.

The preferred forms of the compound of the invention are the double-bond geometrical isomers of the formulae Ila and llb of the drawings taken individually but preferably as a mixture of the two.

According to a preferred embodiment, the invention provides a process for the preparation of the new insecticidal compounds. It is known in the art that the reaction of phosphorus pentachloride (PCI5) with carbonyl compounds gives a mixture of geminal dichloride and vinyl chloride derivatives. This has been studied and described in prior literature [J. Amer. Chem. Soc., 59,2435(1936); ibid. 73,5382(1951)]. Based on this knowledge, the process of the invention employs as starting material methyl 1 R, cis-2,2dimethyl-3-(2-oxopropyl) cyclopropane carboxylate. This ester has the general formula Ill of the accompanying drawings and is preferably obtained from (+)-Car-3-ene which in turn is obtained as a by-product from pine oil.

Accordingly, the present invention also provides a process for the preparation of 3phenoxybenzyl 1 R, cis-2,2-dimethyl-3-(2-chloro prop-i -enyl) cyclopropane carboxylate in the form of a mixture of its double-bond geometrical isomers of the general formulae Ila and llb of the accompanying drawings which comprises reacting methyl 1 R cis-2,2-dimethyl-3-(2oxopropyl) cyclopropane carboxylate of the formula III of the drawings with phosphorus pentachloride to produce a mixture of doublebond isomers of methyl 1 R cis-2,2-dimethyl-3-(2 chloro-prop-1-enyl) cyclopropane carboxylate of the formulae IVa and IVb of the drawings, saponifying the isomeric mixture thus obtained with a methanolic potassium compound to yield a mixture of the corresponding acids of the general formulae Vla and Vlb of the drawings, and esterifying the potassium salts of the acids of formula Vla and Vlb with 3-phenoxy benzyl bromide or a derivative thereof to produce the desired compound.

The reaction of the ester of formula Ill with phosphorus pentachloride is preferably effected with an excess of the latter compound and this has the effect of producing a reaction product in which the predominant component is a mixture of the isomers of formulae IVa and IVb of the drawings. Tests have shown that this reaction product yields the mixture of the isomers of formulae IVa and IVb in an amount of as much as 68.3% by weight based on the total weight of the reaction product. Small quantities of the doublebond isomer of the formula V of the drawings are generally also formed in the course of such reaction.

In accordance with a preferred feature, the reaction of methyl 1 R cis-2,2-dimethyl-3-(2oxopropyl) cyclopropane carboxylate with phosphorus pentachloride is effected at a temperature in the range of from 0 to 250C.

Preferably, methanolic potash prepared by dissolving potassium hydroxide in an aqueous solution of methanol is employed as the methanolic potassium compound in the saponification step.

If desired, the potassium salts of the acids of formula Vla and Vlb from the saponification of the mixture of isomers of the formula IVa and IVb can be employed directly for their esterification with 3-phenoxy benzylbromide or a derivative thereof The preferred derivative of'3-phenoxy benzyl bromide employed in the esterification step is 3phenoxy benzyl triethyl ammonium bromide and the esterification is conveniently carried out in the presence of a polar solvent such as methyl isobutyl ketone. The yield of the novel compound of the invention as a mixture of geometrical isomers of the formulae Ia and llb following the esterification step is exceptionally good i.e. from 56% to 65% by weight.The product of the present invention thus has the advantage over products such as permethrin and resmethrin which contain IR, cis compounds along with other isomers which have little if any activity, in that they can be obtained in good yield without substantial quantities of non-active material, using easily accessible starting materials.

When combined in association with a suitable carrier or diluent therefor, the novel compound of the invention forms a potent insecticidal formulation against pests such as flies, mosquitoes, cockroaches and the like. Tested against the common house-fly (musca domestica), the compound was found to be highly active, with a LD50 for flies by topical application ranging between 0.005 to 0.01 microgram per fly. It was also highly toxic to mosquitoes and cockroaches with an LDso similar to that for the house-fly and falling the range of 0.6 to 1.0 mg/kg of body weight. Typically the compound can be prepared as an emulsion concentrate, for example containing about 25% by weight of active compound, 5 to 10% by weight of emulsifying agent and 65 to 70% by weight of solvent.Suitable emulsifying agents include Swascofix EAS, Noigen NUV and Emulsol EPN (fish oil emulsified with soap). Suitable solvents include Xylene, for example as a Xylene-aromex mixture.

Accordingly, the present invention also provides an insecticidal formulation comprising 3phenoxy benzyl 1 R, cis-2,2-dimethyl-3-(2-chloroprop-1-enyl) cyclopropane carboxylate in combination with a carrier or diluent therefor.

Preferably, the active ingredient in the insecticidal formulations comprises a doublebond geometrical isomer of 3-phenoxy benzyl 1 R cis-2,2-dimethyl-3-(2-chloro-prop- 1 -enyl) cyclopropane carboxylate of the formula Ila or llb or, more preferably, a mixture of these two isomers.

Any conventional carrier of diluent may be employed for the formation of the insecticidal formulations of the invention.

The invention, in particular the preparation of the new insecticidal compounds, will now be described at length in and with reference to the following Examples wherein each of the three main reaction steps in the preparation of the novel compounds is described individually and in detail: Example 1 A. Reaction of methyl 1 R cis-2,2-dimethyl-3 (2-oxopropyl) cyclopropane carboxylate with phosphorus pentachloride 8 g (0.04 mole) methyl 1 R cis-2,2-dimethyl-3 (2-oxopropyl) cyclopropane carboxylate was added dropwise over a period of half an hour to 16 g (0.077 mole) ice-cooled phosphorus pentachloride with shaking, in a 100 ml rb flask.

After the addition was complete, the reaction mixture was allowed to attain room temperature (250C) and left at that temperature for 16 hrs.

The reaction mixture was then diluted with 50 ml benzene and poured on to crushed ice with stirring. The benzene layer was then separated and the aqueous layer extracted twice with benzene (2x50 ml). The combined benzene layer was washed initially with water and then with aqueous sodium bicarbonate to remove mineral acid. It was then washed with water twice and dried (Na2504). Removal of benzene by distillation gave a residue (8.5 g) which was purified by distillation to give a mixture of chloroesters (isomers of the fomulae IVa and IVb) along with small quantihves of double-bond isomer (formula V) also formed in the reaction.

Yield of the distilled material 6 g (68.3%); b.p.

7580 (vapour)/1 .5 mm (G.LC analysis, 3 peaks, on a carbowax column at 140-1 500C approx. in the ratio 42:36:22).

B. Saponification of mixture of chloroesters A cooled solution of 3 g of potassium hydroxide in 25 ml methanol and 2.5 ml water was added in small lots with shaking to 6.0 g of the mixture of esters obtained in Step A and the homogeneous solution thus obtained was allowed to stand at 250C for 1 6 hrs. The solution was then diluted with 30 ml water and most of the methanol was removed under reduced pressure, keeping the temperature below 500C.

The residue was then extracted with ether twice (2x25 ml) to remove the unsaponified ester. The aqueous layer was acidified at 250C with hydrochloric acid, till it was acidic to congo red paper. It was then extracted with ether, thrice (3x30 ml), the ether layer washed with water and dried (Na2504). Evaporation of ether gave a mixture of acids (of formula Vla and Vlb). Yield 4.4 g (80%).

C. Esterification of acid mixture The mixture of acids resulting from Step B was treated with 1.65 g potassium carbonate in 5 ml of water and stirred for 2 hrs at room temperature. To this, 50 ml methyl isobutyl ketone was added and the mixture refluxed in a 1 50 ml rb flask fitted with a Dean Stark unit for azeotropic distillation, till no more water collected. 9 g 3-phenoxy benzyl triethyl ammonium bromide was then added to the reaction flask and the refluxing continued for 3 hrs at 1400. Methyl isobutyl ketone was removed by distillation under reduced pressure and the residue was taken up in ether solution washed with water and dried (Na2504). Evaporation of ether gave a product composed predominantly of esters of the formulae Ila and llb. Yield 7.7 9 (85%).The mixture of esters thus obtained and prior to purification was tested for insecticidal activity. However, since the crude mixture obtained above was contaminated with other more polar impurities (as indicated by TLC, using petroleum ether and benzene in a ratio of 1:1), it was purified by column chromatography on silicic acid (1 :10) and elution with petroleum either and benzene (1:1), when a fraction (6.3 g; 56%) was obtained which consisted predominantly of esters of the formulae Ila and llb. The purified mixture showed better insecticidal activity as compared with the crude mixture.

Example 2 A. Reaction of methyl 1 R cis-2,2-dimethyl-3 (2-oxopropyl) cyclopropane carboxylate with phosphorus pentachloride This step was carried out as in Example 1.

B and C. Saponification and esterification steps A cooled solution of 0.620 g potassium hydroxide in 10 ml methanol and 1 ml water was added dropwise with shaking to 2 g of the mixture of chloroesters of the formulae IVa and IVb obtained from Step A of Example 1. The homogeneous solution thus obtained was allowed to remain at room temperature (250C).

for 1 6 hours. To this reaction mixture, 5 ml water were added and the methanol removed under reduced pressure. The residue was extracted with ether to recover about 1 g of the unsaponified ester and from the aqueous layer was removed by azeotropic distillation employing benzene. After the distillation of benzene, the residue containing the potassium salt was refluxed with 1.8 g 3phenoxy benzyl triethyl ammonium bromide in 20 ml of methyl isobutyl ketone for about 3 hours at 1 400C. The residue was thereafter worked up as stated in Step C of Example 1 to provide a product composed predominantly of a mixture of esters of the formulae Ila and llb. Yield 1.45 g (79.2%).

Example 3 A and B. Reactions of (i) initial ester with phosphorus pentachloride and (ii) saponification These steps were carried out as in Example 1.

C. Esterification of acid mixture 1.2 g of the mixture of acids of formulae Vla and Vlb resulting from Step B were treated with 0.73 g potassium carbonate and 2 ml water and allowed to stand for 2 hours at 250C with occasional shaking. The mixture was then treated with 20 ml methyl isobutyl ketone and 2.63 g 3phenoxy benzene bromide and refluxed for 3 hours at 1 400C using a Dean-Stark azeotropic distillation unit. Methyl isobutyl ketone was removed by distillation under reduced pressure and the residue after dilution with water was extracted with ether. The ether layer was washed twice, dried (Na2S04) and evaporated to give a product composed predominantly of a crude mixture of esters of the formulae Ila and llb. Yield 3.5 g (94.6%). The crude mixture contained a small quantity of unreacted 3-phenoxy benzyl bromide in addition to other more polar impurities (TLC).

It is to be understood the various modifications of the applicants' invention are possible within the scope of what has been described herein.

Claims (21)

Claims

1. As a new insecticidal compound 3phenoxybenzyl 1 R, cis-2,2-dimethyl-3-(2-chloro prop-1 -enyl) cyclopropane carboxylate.

2. A compound of the general formula Ila of the accompanying drawings which is a double-bond geometrical isomer of 3-phenoxybenzyl 1 R, cis2,2-di methyl-3-(2-chloro-prop- 1 -enyl) cyclopropane carboxylate.

3. A compound of the general formula llb of the accompanying drawings which is a doublebond geometrical isomer of 3-phenoxybenzyl 1 R, cis-2 ,2-di methyl-3-(2-chloro-prop- 1 -enyl) cyclopropane carboxylate.

4. A new insecticide comprising a mixture of the double-bond geometrical isomers of formulae Ila and llb of the accompanying drawings.

5. New insecticidal compounds substantially as hereinbefore described.

6. A process for the preparation of 3phenoxybenzyl 1 R, cis-2,2-dimethyl-3-(2-chloro- prop-1-enyl) cyclopropane carboxylate in the form of a mixture of its double-bond geometrical isomers of the general formulae Ila and llb of the accompanying drawings which comprises reacting methyl 1 R, cis-2,2-dimethyl-3-(2oxopropyl) cyclopropane carboxylate of the formula Ill of the drawings with phosphorus pentachloride to produce a mixture of doublebond isomers of methyl 1 R, cis-2,2-dimethyl-3 (2-chloroprop-1-enyl) cyclopropane carboxylate of the formulae IVa and IVb of the drawings, saponifying the isomeric mixture thus obtained with a methanolic potassium compound to yield a mixture of the corresponding acids of the general formulae Vla and Vlb of the drawings, and esterifying the potassium salts of the acids of formula VI and Vlb with 3-phenoxy benzyl bromide or a derivative thereof to produce the desired compound.

7. A process as claimed in Claim 6, wherein the reaction of methyl 1 R cis-2,2-dimethyl-3-(2oxopropyl) cyclopropane carboxylate with phosphorus pentachloride is effected with an excess of PCI5.

8. A process as claimed in Claim 6 or 7, wherein the reaction of methyl 1 R cis-2,2dimethyl-3-(2-oxopropyl) cyclopropane carboxylate with phosphorus pentachloride is effected at a temperature in the range of from 0 to 250C.

9. A process as claimed in any of Claims 6 to 8, wherein the methanolic potassium compound is methanolic potash prepared by dissolving potassium hydroxide in an aqueous solution of methanol.

10. A process as claimed in any of Claims 6 to 9, wherein the potassium salts of the acids of formula Vla and Vlb obtained from the saponification of the mixture of isomers of the formula IVa and IVb are employed directly for their esterification with 3-phenoxy benzyl bromide or a derivative thereof.

11. A process as claimed in any of Claims 6 to 10, wherein the derivative of 3-phenoxy benzyl bromide is 3-phenoxy benzyl triethyl ammonium bromide.

12. A process as claimed in any of Claims 6 to 11, wherein the esterification is carried out in the presence of a polar solvent.

13. A process as claimed in Claim 12, wherein the solvent is methyl isobutyl ketone.

14. A process for the preparation of 3phenoxybenzyl 1 R, cis-2,2-dimethyl-3-(2-chloroprop-1-enyl) cyclopropane carboxylate in the form of a mixture of its double-bond geometrical isomers of the general formulae Ila and llb of the accompanying drawings substantially as hereinbefore described.

1 5. A process for the preparation of 3phenoxybenzyl 1 R, cis-2,2-dimethyl-3-(2-chloro prop-1 -enyl) cyclopropane carboxylate in the form of a mixture of its double-bond geometrical isomers of the general formulae Ila and llb of the accompanying drawings substantially as herein described in any of the foregoing Examples.

16. 3-phenoxybenzyl 1 R, cis-2,2-dimethyl-3 (2-chloro-prop- 1 -enyl) cyclopropane carboxylate in the form of a mixture of its double-bond geometrical isomers of the general formulae Ia and llb of the accompanying drawings whenever prepared by the process claimed in any of Claims 6to 15.

17. An insecticidal formulation comprising 3phenoxybenzyl 1 R, cis-2,2-dimethyl-3-(2-chloro prop-1 -enyl) cyclopropane carboxylate in combination with a carrier or diluent therefor.

1 8. An insecticidal formulation comprising a compound of the general formula Ila of the accompanying drawings in combination with a carrier or diluent therefor.

19. An insecticidal formulation comprising a compound of the general formula llb of the accompanying drawings in combination with a carrier or diluent therefor.

20. An insecticidal formulation comprising a mixture of compounds of the formulae Ia and llb of the accompanying drawings in combination with a carrier or diluent therefor.

21. Insecticidal formulations substantially as herein described.