GB1604682A - Derivatives of cyclopropanecarboxylic acids - Google Patents

Description

(54) IMPROVEMENTS RELATING TO DERIVATIVES OF CYCLOPROPANE-CARBOXYLIC ACID (71) We, NATIONAL RESEARCH DEVELOPMENT CORPORATION, a British Corporation established by Statute of Kingsgate House, 66/74, Victoria Street, London SW1, do hereby declare the invention for which we pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to new derivatives of cyclopropanecarboxylic acids, useful as pesticides, and particularly as insecticides, to processes for their preparation, to compositions containing them and to their use as pesticides.

U.K. Patent Specification No. 1,413,491 describes and claims, inter alia, cl-cyano-3- phenoxybenzyl esters of 2,2-dimethyl 3-dihalovinyl-cyclopropanecarboxylic acids. These esters have the general formula

in which R2 and R3 which may be the same or different, each represent halogen.

Compounds of formula I can exist in the form of geometrical isomers depending upon whether the hydrogen atoms carried at C1 and C3 of the cyclopropane ring are in the cis or trans relationship. Because of the unsymmetrical substitution at C1 and C3 on the cyclopropane ring, each cis isomer can exist in one of two optically active forms and each trans isomer can exist in one of two optically active forms. When the absolute configuration at C1 of compounds of formula I is the same as that at C1 in (+)-trans chrysanthemic acid, the absolute configuration of C1 in compound I is designated 1R. The absolute configuration of C3 in compounds of formula I cannot vary independently of the C1 configuration in a compound having specified geometrical configuration and, for a compound having trans configuration and R configuration at Cl, strict application of the sequence rule (Cahn, R.S. Ingold C. and Prelog V. Angew. Chem. Int. Ed. 5,385 (1966)) requires the designation S to be applied at C3. However, application of the same sequence rule to the same C3 centre in (+)-trans chrysanthemic acid requires that centre to be designated R, even though it is directly related in absolute configuration to the configuration designed S in compounds of formula I. This is because the nature of the substitution at C3 is different in (+)trans chrysanthemic acid from that of compounds of formula I. However, because the specification of the geometrical configuration and the absolute configuration at C1 fixes the C3 configuration absolutely, and to avoid possible confusion arising from the fact that different compounds of the same series may otherwise require sometimes R, sometimes S designations of the configuration at C3, we have proposed the nomenclature 1R trans for such compounds as this provides sufficient information to determine the absolute configuration of the whole molecule.

Similar considerations have resulted in our designating compounds having the same absolute configuration as (+)-cis chrysanthemic acid as 1R cis compounds. In cases where we have dealt with compounds having the same configuration as (-) trans or (-) cis chrysanthemic acid, we are applying the designations 1S trans and 1S cis respectively.

There is one further site of asymmetry in compounds of formula I which is at the a-carbon atom carrying the cyano substituent. Compounds of formula I can exist in forms having the absolute R or in forms having the absolute S configuration at this a-carbon atom.

In the Specification of our U.K. Patent No. 1,413,491, we describe esters of formula I which are mixtures containing both the cis and the trans isomer and which contain compounds having R configuration and compounds having S configuration at C1. These mixtures are racemic mixtures at the asymmetric centres of the cyclopropane ring and can be designated (+)-cis-trans or RS-cis-trans. Specification No. 1,413,491 also describes the preparation of esters of formula I which are substantially pure cis or substantially pure trans isomers and having R configuration at C1. All of the esters of formula I described in Specification No. 1,413,491 are mixtures of compounds having R configuration at the a-carbon atom with compounds having S configuration at the a-carbon atom.

The Specification of British Patent No. 1,448,228 which is a Patent of Addition to Patent No. 1.413,491, describes further esters of formula I which are substantially pure cis isomers or substantially pure trans isomers, which have R configuration at C1 and which are mixtures of compounds having R configuration at the a-carbon atom with compounds having S configuration at the a-carbon atom. Example 1 in Specification No. 1,448,228 describes the resolution of RS-a-cyano-3-phenoxybenzyl [1R, cis]-2,2-dimethyl-3-(2,2dibromovinyl)-cyclopropanecarboxylate which enabled a crystalline isomer having S configuration at the a-carbon atom to be separated from a residue rich in the isomer having R configuration at the a-carbon atom. The RS mixture was designated compound P29B in Specification No. 1,448,228 and the crystalline S isomer which we isolated has subsequently been called decamethrin.

We have now been able to prepare individual isomers from many of the isomeric mixtures of compounds of formula I described in our earlier Patent Specifications Nos.

1,413,491 and 1,448,228.

Accordingly, the present invention provides an individual isomer of the formula

wherein R2 and R3, which may be the same or different, are each halogen, in which the hydrogen atoms at C1 and C3 of the cyclopropane ring are substantially completely in the cis configuration or substantially completely in the trans configuration, in which C1 of the cyclopropane ring is substantially completely in the absolute R configuration and in which the a-carbon atom is substantially completely in the R configuration or substantially completely in the S configuration, with the proviso that, when the ester has 1R,cis configuration, R2 and R3 do not both represent bromine and do not both represent chlorine; and, when the ester has lR,trans configuration, R2 and R3 do not both represent chlorine.

In the isomers of the present invention, it is preferred that R2 and R3 both represent the same halogen and isomers of the invention include those wherein R2 and R3 both represent fluorine or both represent bromine.

Specific isomers of the present invention include: S-a-cyano-3-phenoxybenzyl [1 R, cis]-2,2-dimethyl-3-(2,2-difluorovinyl)- cyclopropanecarboxylate; S-a-cyano-3-phenoxybenzyl [lR,trans]-2,2-dimethyl-3-(2,2-difluorovinyl)- cyclopropanecarboxylate; S-a-cyano-3-phenoxybenzyl [lR,trans]-2,2-dimethyl-3-(2,2-dibromovinyl)- cyclopropanecarboxylate.

Isomer mixtures with compounds having R configuration at the a-carbon atom with compounds having S configuration at the a-carbon atom, but which are substantially pure cis or trans isomers with respect to the hydrogen atoms at C1 and C3 of the cyclopropane ring and which are substantially pure R configuration at Cl of the cyclopropane ring, are described in our earlier Specifications Nos. 1,413,491 and 1,448,228. These isomer mixtures are obtainable by esterifying RS-a-cyano-3-phenoxybenzyl alcohol or an esterifiable derivative thereof with the desired geometrical and optical isomer of the cyclopropanecarboxylic acid or esterifiable derivative thereof and our above-mentioned earlier Specifications describe the preparation of the isomer mixtures by reacting the RS-a-cyano-3phenoxybenzyl alcohol with the appropriate carboxylic acid chloride in dry benzene in the presence of pyridine. Example 1 of Specification No. 1,448,228 describes the separation of the mixture in which R2 and R3 both represent bromine and the cyclopropane ring has lR,cis configuration by dissolving the RS mixture in hexane and maintaining the hexane solution at -200C until precipitation of the crystals of the S isomer occurs.

We have found that RS mixtures can be separated into individual isomers of the invention and additionally into isomers of formula I in which, when the ester has 1R cis configuration, R2 and R3 may each be chlorine or may each be bromine, and when the ester has 1R trans configuration, R2 and R3 may each be chlorine, by thin layer chromatography.

By this procedure, the RS mixture may be eluted for example on preparative chromoplates of silica gel using a 6:1 by volume mixture of hexane and diethylether for developing. The upper and lower portions of the resulting ester band can be separately removed and extracted with diethylether. This separation gives the individual isomers of approximately 75% purity and by rechromatographing, it is possible to isolate the individual R or S isomer in approximately 97 to 99% purity.

A still further technique available for separation of the RS mixtures is by high pressure liquid chromatography, which again enable the individual R and S isomers to be recovered in approximately 99% purity.

Like the RS mixtures described in our above-mentioned Patent Specifications, the individual isomers of the represent invention including the 1R cis R2=R3=Cl, 1R trans R2=R3=Cl and 1R cis R =R =Br isomers obtainable by the process of the present invention are also particularly active pesticides and find particular application as insecticides against a wide variety of species. The S isomer of formula in which R2 and R3 both represent bromine and the cyclopropane ring has lR,cis configuration (decamethrin) described in our earlier Specification No. 1,448,228 is approximately 28 times more toxic to houseflies than bioresmethrin (5-benzyl-3-furylmethyl(+)-trans chrysanthemate) and decamethrin is still the most toxic compound to houseflies yet discovered of any class of insecticide. We have now found that many of the isomers of the present invention have exceptionally high toxicities to houseflies, compared to bioresmethrin.

One or more of the individual isomers of the present invention including the 1R cis R2=R3=Cl, 1R trans R2=R3=Cl and 1R cis R2= R = Br isomers obtainable by the present invention may be formulated with an inert carrier or diluent to give a pesticidal composition and these may be prepared for example, for insecticidal use, in the form of dusts and granular solids, wettable powders, mosquito coils and other solid preparations and as emulsions, emulsifiable concentrates, sprays, aerosols and other liquid preparations after the addition of the appropriate solvents, diluents and surface active agents.

Synergists may be added to the compositions. The compositions may also include other pesticidal compounds, for example to improve insecticidal toxicity or knock-down.

The following Examples are given to illustrate the invention: Example 1 RS-a-cyano-3-phenoxybenzyl [1R,cis] 2,2-dimethyl-3-(2,2-difluorovinyl) cyclopropanecaroboxylate was prepared as described in Example 2 of U.K. Specification No. 1,448,228.

Samples of this RS mixture of approximately 150mg were separated by thin layer chromatography. The sample was applied on Merck Silicagel 60 F254 chromatoplates (2mm thick) and developed twice in hexane:diethylether (6:1). The upper and lower portions of the resulting ester band were scraped separately and extracted with diethylether. Each fraction (approximately 75% pure) was rechromatographed on several 0.25mm plates (10 to 15mg per plate) once for the upper fraction or twice for the lower fraction to give the R isomer or S isomer in 20 to 25 mg yield and approximately 97 to 99% pure. The apparent RF values (analytical conditions, as component mobility relative to the solvent front after two developments) are given in Table I below.

Example 2 This Example describes the separation of the RS mixture of Example 1 by high pressure liquid chromatography. The RS mixture (10 to 20mg) was injected onto a Zorbax SIL column (Dupont, 250mm x 7.9mm internal diameter) which was eluted with 2% (v/v) ethylacetate in hexane at 700 pounds per square inch monitoring with a Cecil model 212 U.V. detector at 292nm. Separate fractions were collected, concentrated and rechromatographed as necessary to give 50 to 75mg of the R isomer and S isomer of approximately 99% purity in 4 to 5 hours. The HPLC retention volumes (analytical conditions, detector at 254nm) and retention volume ratios are given in Table I below.

Example 3 The procedure described in Example 1 and Example 2 was applied to the separation of the following RS mixtures: Stereochemistry about cyclo- R2 & R3 propane ring lR,trans F Prepared as described in Example 2 of Specification No. 1,448,228 1R,cis Cl Prepared by a method analogous to that of Example 27 of Specification No. 1,413,491 using the appropriate isomer of the acid chloride.

1R,trans Cl Prepared as described in Example 28 of Specification No. 1,413,491 lR,cis Br Prepared as described in Example 27 of Specification No. 1,413,491 lR,trans Br Prepared as described in Example 28 of pecification No. 1,413,491 TABLE 1 Physical properties of compounds separated chromatographically Compound Stereochemistry Stereochemistry T.l.c. H.p.l.c.d retention No. about cyclo- in alcohol R=R [α]Db Rfc retention volume propane ring volume ratio (ml) 1 1R,cis R F -5.2 0.50 27.0 1.14 2 1R,cis S F +7.6 0.46 30.6 3 1R,cis R Cl -13.6 0.48 28.4 1.16 4 1R,cis S Cl +16.1 0.43 32.8 5 1R,cis R Br -21.3 0.44 29.0 1.17 6 1R,cis S Br +10.6 0.40 33.9 7 1R,trans R F -6.8 0.44 36.5 1.10 8 1R,trans S F -20.9 0.41 40.0 9 1R,trans R Cl -2.4 0.42 33.6 1.12 10 1R,trans S Cl -9.4 0.39 37.8 11 1R,trans R Br +4.6 0.40 36.2 1.15 12 1R,trans S Br -2.9 0.37 41.4 a) Shifts in CCl4 differ significantly from those in CDCl3 b) In acetone c) After 2 developments d) Measured after thorough equilibration, under standard conditions (solvent composition and pressure constant throughout) Nmr peaks (ppm downfield of Me4Si) in CDCl3a Alcohol Acid Purity Aromatics CHCN 1-H 3-H vinyl H Methyls on C-2 (%) (m) (s) (d) (q) (d) 1(s) 2(s) > 99 6.9-7.5 6.33 m m 4.56 1.25 1.25 > 99 " 6.35 m m 4.59 1.21 1.16 > 99 " 6.32 1.89 2.10 6.26 1.28 1.28 > 97 6.37 1.89 2.16 6.30 1.24 , 1.19 > 99 " 6.33 m m 6.69 1.31 1.29 > 97 " 6.38 m m 6.70 1.25 1.20 > 99 " 6.37 1.52 2.05 4.03 1.30 1.19 > 99 " 6.39 1.54 2.08 4.05 1.21 1.14 > 99 " 6.37 1.65 2.28 5.59 1.33 1.22 > 97 " 6.39 1.67 2.28 5.61 1.23 1.18 > 99 " 6.38 1.69 2.19 6.15 1.33 1.24 > 97 6.39 1.70 2.25 6.17 1.24 1.20 The insecticidal activity of the isomers of the invention was assessed against houseflies and mustard beetles using the following techniques: Houseflies (Musca domestica) Female flies were treated on the thorax with a one microlitre drop of insecticide dissolved in acetone. Two replicates of 15 flies were used at each dose rate and 6 dose rates were used per compound under test. After treatment, the flies were maintained at a temperature of 20 C+1 and kill was assessed 24 and 48 hours after treatment. LD50 values were calculated in micrograms of insecticide per fly and relative toxicities were calculated from the inverse ratios of the LIDS, values. (See Sawicki et al, Bulletin of the World Health Organisation, 35,893, (1966) and Sawicki et al, Entomologia and Exp. Appl.10,253 (1967)).

Mustard Beetles (Phaedon cochleariae Fab) Acetone solutions of the test compound were applied ventrally to adult mustard beetles using a micro drop applicator. The treated insects were maintained for 48 hours after which time kill is assessed. Two replicates of 20 to 30 mustard beetles were used at each dose level and 3 to 4 dose levels were used for each compound. Again, LD50 values were calculated and relative toxicities were calculated on a weight for weight basis from the inverse ratios of LDso (see Elliott et al, J.Sci. Food Agric.20,561 (1969)).

Relative toxicities were calculated by comparison with 5-benzyl-3-furylmethyl (+)-transchrysanthemate which is one of the most toxic chrysanthemate esters known to houseflies and mustard beetles, its toxicity being about 24 times that of allethrin to houseflies and 65 times that of allethrin to mustard beetles.

The following relative toxicities were obtained.

Claims (21)

1. Relative Toxicity Weight for Weight Compound Houseflies Mustard Beetles

   5-benzyl-3-furylmethyl (+)-trans-chrysanthemate 100 100 (bioresmethrin) 1 3 97 2 310 1800 3 67 140 4 2000 4500 5 32 270 6 1900 3700 7 7 19 8 150 310 9 66 89 10 1100 1800 11 26 14 12 760 1600 WHAT WE CLAIM IS: 1. An individual isomer of the formula

   wherein R2 and R3, which may be the same or different, are each halogen, in which the hydrogen atoms at C1 and C3 of the cyclopropane ring are substantially completely in the cis configuration or substantially completely in the trans configuration, in which Cl of the cyclopropane ring is substantially completely in the absolute R configuration and in which the a-carbon atom is substantially completely in the R configuration or substantially completely in the S configuration, with the proviso that, when the ester has lR,cis configuration, R2 and R3 do not both represent bromine and do not both represent chlorine; and, when the ester has lR,trans configuration R2 and R3 do not both represent chlorine.
2. 2. An isomer according to claim 1 wherein R2 and R3 represent the same halogen.
3. 3. An isomer according to claim 1 or 2 wherein the halogen is fluorine or chlorine or hromine.
4. 4. An isomer according to any one of the preceding claims having [S] configuration at .
5. 5. An isomer according to any one of the preceding claims wherein the hydrogens at C1 and C3 are in the cis relationship to each other.
6. 6. l R l-a-cyano-3-phenoxybenzyl [1R,cis]-2,2-dimethyl-3-(2,2-difluorovinyl)- cyclopropane carboxylate.
7. 7. [S j-a-cyano-3-phenoxybenzyl [I R,cisj-2,2-dimethyl-3-(2,2-difluorovinyl)- cyclopropane carboxylate.
8. 8. Rj-a-cyano-3-phenoxybenzyl [1 R ,trans] -2,2-dimethyl-3-(2,2-difluorovinyl)- cyclopropane carboxylate.
9. 9. [S4-a-cyano-3-phenoxybenzyl [1 R,trans].2,2-dimethyl-3-(2,2-difluorovinyl)- cyclopropane carboxylate.
10. 10. [R]-a-cyano-3-phenoxybenzyl [lR,trans]-2,2-dimethyl-3-(2,2-dibromovinyl)- cyclopropane carboxylate.
11. 11. [S]-a-cyano-3-phenoxybenzyl [1 R,trans]-2,2-dimethyl-3-(2,2-dibromovinyl)- cyclopropane carboxylate.
12. 12. A method of isolating an individual isomer of the formula

    wherein R2 and R3, which may be the same or different, are each halogen, in which the hydrogen atoms at C1 and C3 of the cyclopropane ring are substantially completely in the cis configuration or substantially completely in the trans configuration, in which C1 of the cyclopropane ring is substantially completely in the absolute R configuration and in which the a-carbon atom is substantially completely in the R configuration or substantially completely in the S configuration, which method comprises subjecting an isomer mixture having RS configuration at Ca and the desired configuration at C1 and C3, to thin layer chromatography.
13. 13. A method according to claim 12 which comprises absorbing the mixture onto preparative chromatoplates of silica gel, eluting the plate with a mixture of hexane and diethyl ether, separatmg the resulting ester bands and subjecting them to rechromatography to give substantially pure S isomer and substantially pure R isomer.
14. 14. A method of isolating an individual isomer of formula II as defined in claim 12 which comprises subjecting an isomer mixture having RS configuration at Ca and the desired configuration at C1 and C3 to high pressure liquid chromatography.
15. 15. A method according to any one of claims 12-14 substantially as hereinbefore described with reference to any one of the Examples.
16. 16. An individual isomer obtained by a process according to any one of claims 12-15.
17. 17. A composition for combatting pest infestation which comprises an individual isomer according to any one of claims 1-11 or 16 together with an inert diluent or carrier.
18. 18. A composition according to claim 17 including natural pyrethrin, another synthetic pyrethroid or another pesticidal compound.
19. 19. A composition according to claims 17 or 18 including a compound capable of synergising natural pyrethrin or a synthetic pyrethroid.
20. 20. A composition according to claim 17 substantially as hereinbefore described.
21. 21. A method of combatting pest infestation which comprises applying to a pest or to an environment susceptible to pest infestation a compound according to any one of claims 1-11 or 16 or a composition according to any one of claims 17-20.