JPS6360737B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to cyclopropanecarboxylic acid ester derivatives, their preparation and their use as toxic pesticides.

general formula [wherein R ¹ and R ² are independently selected from chlorine, bromine and methyl. ] The cyclopropanecarboxylic acid ester derivative is
is a known compound with toxic pesticide activity (e.g. British Patent Specification No. 1413491 or US Patent No.
(See No. 4024163). These derivatives are members of a group of toxic pesticide compounds commonly referred to in the art as "pyrethroid insecticides." The compound of formula contains two asymmetric centers in the cyclopropane ring of the acid moiety and a third asymmetric center in the alcohol moiety;
However, this leads to the existence of eight possible isomers. In general, “Synthetic Pyrethroids”,
As disclosed by Itaya et al. in ACS Symposium Series 42, pages 45-54, superior toxic pesticide activity resides in compounds with a cis-configuration about the cyclopropane ring, and
Nature, Vol. 248, pages 710 and 711 (1974)
As described by Elliott et al., the isomer with the greatest toxic pesticide activity is generally
It is an isomer called the 1R cis S-isomer, where 1R cis refers to the configuration of the acid moiety and S refers to the configuration of the alcohol moiety.

The project to create the 1R cis S-single isomer is exclusively
either a synthetic route that inherently creates an intermediate containing a cyclopropane carboxylic acid moiety in the 1R cis configuration, or a route that involves an optical resolution step to separate the 1R cis-compound from the 1S cis-compound. . 1R cis- to make the derivative of the above formula
Esterification of the intermediate leads to the production of a mixture of 1R cis R- and 1R cis S- final products. Separation of these final products is probably accomplished by physical methods, at least in theory, since the 1RcisR- and 1RcisS-compounds are not enantiomers. However, 1R cisR- and
Although ^it has been established that such separation of 1R cisS-compounds can be achieved relatively easily when R ¹ and R ² are both bromine atoms, in other cases e.g.
It has proven to be relatively difficult and relatively expensive when both R 2 and R ² are chlorine atoms.

Surprisingly, in a compound of the formula as a compound containing all eight isomers of the formula in equal weight, it contains up to four times the most toxic pesticide active (1R cis S-) isomer, weight to weight. A new compound has been discovered. This new compound has the advantage that it can be easily and relatively inexpensively produced by a route that does not involve asymmetric synthesis or optical resolution steps.

The present invention provides 1R cisS- and 1S cisR
- formula in the form of a 1:1 mixture of isomers; [wherein R ¹ and R ² are each independently selected from chlorine, bromine and methyl. ] provides a compound.

Compounds of the present invention in which R ¹ and R ² are both halogen atoms are preferred, and R ¹ and R ² are preferably both chlorine atoms.

According to a preferred embodiment of the invention, at least
1R cis S- and 1S of α-cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate in the form of a crystalline solid with a melting point of 75°C cisR-
Compounds are provided that include a 1:1 mixture of isomers. Advantageously, the melting point is at least 80°C, preferably in the range 84 to 87°C.

Compounds of the invention are compounds of the formula 1RcisS
-, 1S cisS-, 1RcisR- and 1ScisR-isomers are treated with a solvent and 1ScisS
1 of the 1R cis S- and 1S cis R-isomers, substantially free of the 1R cis R- and 1S cis S-isomers, from a solution of a compound of the formula containing - and 1R cis R- isomers: A mixture can be prepared by a method that includes separating the mixture as a crystalline solid.

The process may conveniently be carried out by cooling a solution of a mixture of 1R cisS-, 1S cisS-, 1RcisR- and 1S cisR-isomers.

Instead, the method, in at least some cases, comprises preparing a mixture of 1R cis S-, 1S cis S-, 1R cis R- and 1S cis R- isomers with a solvent at or below ambient temperature. contact at temperature,
and from the resulting solution containing the 1S cisS- and 1R cisR-isomers, the 1R cisS- and 1S cisR
- Can be accomplished by separating the remaining solid crystalline 1:1 mixture of isomers.

The solvent used should be such that the 1RcisS-/1ScisR-enantiomer pair is substantially less soluble than the 1ScisS-/1RcisR-enantiomer pair.

Suitable solvents are lower liquid alkanes having up to 8 carbon atoms, such as pentane or petroleum ethers from 30/50 petroleum ether to 100/120 petroleum ether, preferably 40/60 or 60/80 petroleum ether; and isopropanol. liquid C _1-4 alkanols such as

The crystallization of the 1R cis S-/1S cis R-enantiomeric pair is
Depending on the concentrations of the various isomers present, it may be carried out at temperatures ranging from -50°C to 20°C, preferably from 0°C to 10°C.

Separation and recovery of the crystalline compound of the present invention from the supernatant containing the 1S cis S- and 1R cis R-isomers can be accomplished by methods such as filtration, centrifugation, or decantation.

Solutions of compounds of formula containing the 1S cis S- and 1R cis R-isomers are useful starting materials for the preparation of additional quantities of the compounds according to the invention. By treatment with an appropriate base under appropriate conditions, racemization can occur at the α-carbon atom of the alcohol moiety of the compound of formula, thus eliminating some of the 1S cis S- and 1R cis R-isomers in solution. It has further been found that can be converted into the 1S cis R- and 1R cis S-isomers, respectively, and additional amounts of the compound according to the invention can be isolated as described above.

Therefore, the preferred method of the present invention is
A solution of a compound of formula containing the - and 1R cisR- isomers is treated with a base, and during or after treatment with base, a 1:1 ratio of the 1R cisS- and 1S cisR-isomers is removed from the solution. Further including separating the mixture.

In a preferred method of the invention, 1R cis S-,
When a mixture of 1S cis S-, 1R cis R- and 1S cis R-isomers is completely dissolved in a solvent and the resulting solution contains equal amounts of all four cis-isomers, 1R cis S- - and at least some of the 1S cis R- isomer before or during treatment with base,
As a crystalline solid, 1R cis R- and 1S cis S-
A 1:1 mixture of 1R cis S- and 1S cis R-isomers, substantially free of isomers, is separated from the solution.

Suitable bases for use in the method of the invention are:
Includes ammonia, primary, secondary and tertiary amines, alkali metal hydroxides, alkali metal carbonates, alkali metal alkoxides, and basic ion exchange resins. Preferred amine bases are 1
Alkylene diamines containing 5 or more C _1-4 alkyl and/or benzyl groups, or having up to 4 carbon atoms, such as ethylenediamine, or having 5 or 6 ring atoms and ring Heterocyclic amine bases having a nitrogen atom bonded to a carbon atom and optionally oxygen, sulfur or an additional nitrogen atom, such as pyrrolidine, morpholine or piperidine.

If desired, the preferred method of the invention can be carried out in two separate steps, optionally at two different locations. For example, treatment with a base can be carried out at elevated temperatures, e.g. 20°C to 100°C, to achieve rapid racemization.
Preferably it may be carried out at a temperature in the range of 20 DEG C. to 60 DEG C., followed by cooling to effectuate crystallization of a 1:1 mixture of 1R cis S- and 1S cis R-isomers, as described above. If the base is in solution, both steps of the process can be carried out in a single reaction zone, or the temperature raising step can be carried out in one reaction zone and the crystallization step in the other reaction zone.

However, the base may be in a solid phase, for example on a basic ion exchange resin (e.g. Dowex
AGIX8, Amberlite IRA400 or Amberlite
(sold under the trade names Dowex and Amberlite, such as IR45) or solid potassium carbonate, and the process may be carried out under anhydrous conditions for the heating step, optionally in the presence of a C _1-4 alkanol such as methanol. The following can be carried out with the base in one reaction zone, for example in a packed column, and a solution of the isomer of the compound of formula is removed to another reaction zone for the crystallization step.

When the base is present in solution in the preferred process of the invention and both steps of the process are carried out in a single reaction zone, treatment with base and
Crystallization of a 1:1 mixture of cis R-isomers is -50
C. to 20.degree. C., preferably 0.degree. C. to 20.degree. C. may be carried out at the same time. In this method of simultaneous base treatment and crystallization, 1RcisS
The - and 1S cisR- isomers are continuously removed from the solution by crystallization, so that the supernatant solution is always enriched in the 1S cisS- and 1R cisR-isomers, and racemization can always occur. Thus, in such a process, the starting material may be a racemic mixture of all four cis-isomers of a compound of formula which is introduced directly into the reaction zone. The 1S cis S- and 1R cis R-isomers dissolve relatively easily, producing solutions enriched in those isomers. Racemization then occurs and one of the 1R cisS- and 1S cisR-isomers is dissolved until substantially all of the 1S cisS- and 1R cisR-isomers are dissolved and a final equilibrium is achieved. :1 mixture crystallizes continuously from solution.
Additional amounts of the racemic mixture consisting of all four cis-isomers are added during the performance of such a process, either continuously or in portions.
discreet portions) may be added.

If the preferred process of the invention is not carried out using a solid phase base, the base may include ammonia, a primary, secondary or tertiary amine or an alkali metal carbonate, preferably sodium or potassium carbonate, in aqueous solution. is preferred.

It has been found that when a solution of the 1S cis S- and 1R cis R-isomers of a compound of formula is treated with a base in the presence of a C _1-4 alkanol such as methanol, the rate of racemization can be enhanced. . The rate of racemization can also be increased if the solution is treated with a base in the presence of a phase transfer catalyst. The phase transfer catalyst is preferably a quaternary ammonium halide. The substituent in the quaternary ammonium halide is, for example, a C _1-4 alkyl group and/or a benzyl group. Preferred quaternary ammonium halides are the chlorides and bromides of tetrabutylammonium and benzyltriethylammonium.

The compounds of the invention contain a high proportion of the most toxic pesticidally active isomer of the compound of formula. Therefore,
The invention also provides a toxic pesticide composition comprising a compound of the formula according to the invention as defined above together with a suitable carrier therefor, which composition comprises a compound of the formula 1S cis S- and 1R cis R- Substantially free of isomers. The invention further provides a method for controlling pests, such as insects or mites, characterized in that a compound of the formula according to the invention or a composition according to the invention is applied to a habitat.

The carrier in the above compositions may be solid or liquid (including substances that are normally gaseous but are compressed to form a liquid) and may be of synthetic or natural origin, inorganic or organic. The active ingredients are suitably formulated with at least one carrier in order to facilitate application to the site to be treated, such as plants, seeds or soil, or to facilitate storage, transport or handling.

Preferably, the above composition contains at least two carriers, at least one of which is a surfactant. Surfactants can be emulsifiers, dispersants or wetting agents. It can be non-ionic or ionic. Toxic pesticide compositions are generally formulated and shipped in concentrated form and are subsequently diluted by the farmer or other user prior to application. Surfactants facilitate this dilution process.

Any carrier commonly used in the formulation of toxic pesticides may be used in the above compositions, suitable examples of which are described, for example, in British Patent Specification No.
Seen in issue 1232930.

The above compositions can be used, for example, as wettable powders, microcapsules, dusts, granules, solutions, emulsions, emulsions,
It may be formulated as a suspension concentrate or as an aerosol. The composition may have controlled release properties or may be adapted for use as a dietary supplement.

Wettable powders usually contain 25, 50 or 75% by weight of active ingredient and, in addition to inert solid substances, 3 to 10% by weight of dispersants and if necessary 0 to 10% by weight of stabilizers, penetrants. and/or may contain a fixing agent. Dusting agents are usually formulated as dust concentrates with a composition similar to wettable powders but without a dispersion medium, and are further diluted with a solid carrier at the site of use, usually from 1/2 to 10% by weight. % of the active ingredient.

Granules usually have a size in the range of 10 to 100 BS mesh (1.676 to 0.152 mm) and may be manufactured by agglomeration or impregnation methods. Generally, granules contain 1/2 to 25% active ingredient and 0 to 10% by weight of active ingredient.
% by weight of additives such as stabilizers, slow-release modifiers and/or binders.

Emulsions usually contain 10-50% w/v active ingredient, 2-20% w/v in addition to solvent and co-solvents if necessary.
emulsifier and 0-20% w/v of other additives such as stabilizers, penetrants and/or corrosion inhibitors. Suspension concentrates are stable, non-settling, flowable products, usually containing 10-75% by weight of active ingredient, 0.5-15% by weight of dispersing agents, 0.1-10% by weight of suspending agents such as protective colloids and thixotropes. and 0 to 10% by weight of other additives such as antifoaming agents, corrosion inhibitors, stabilizers, penetrants and/or sticking agents, and as a dispersion medium water or an organic liquid in which the active ingredient is substantially insoluble. Contains. Certain organic additives and/or inorganic salts may be dissolved in the dispersion medium to help prevent settling or as antifreeze agents for water.

Aqueous dispersions or emulsions made by diluting the above wettable powders or emulsions with water can be water-in-oil or oil-in-water and have a thick "mayonnaise"-like consistency. may have.

The above composition may also contain other ingredients such as killing insects,
It may contain one or more other compounds with herbicidal or fungicidal properties, or attractants such as pheromones or dietary ingredients for use in bait and trap preparations.

The invention will be better understood from the following examples.

Example 1 α by crystallization method using isopropanol
-cyano-3-phenoxybenzyl 3-(2,
1:1 mixture of 1R cis S- and 1S cis R-isomers of α-cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate
5.0 g of a racemic mixture of cis-isomers of 2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate were dissolved in 30 ml isopropanol with gentle warming. The resulting solution was cooled to 10°C and left at that temperature for 20 hours.
A precipitate settles out and the precipitate is separated by filtration to give a solid product in the form of colorless crystals with a melting point of 77-81°C.
1.4g was obtained. High performance liquid chromatography analysis revealed that the product was separated from the starting 1R cis S- and
It was shown to be a 90% pure 1:1 mixture of 1S cis R-isomers.

3.2 g of the solid product obtained above was recrystallized from pentane to obtain 2.0 g of a colorless crystalline solid with a melting point of 84-86°C. This product is determined by high performance liquid chromatography analysis of the starting material.
It was shown to be a 1:1 mixture of 1R cis S- and 1S cis R-isomers with approximately 99% purity.

Example 2 By crystallization method using 40/60 petroleum ether,
α-cyano-3-phenoxybenzyl 3-(2,
1:1 mixture of 1R cis S- and 1S cis R-isomers of α-cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate
10 g of a racemic mixture of cis-isomers of 2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate were dissolved in 150 ml of 40/60 petroleum ether with gentle warming. The resulting solution is 20
℃ and left at that temperature for 3 days. A colorless crystalline precipitate settled out and was isolated by filtration. The yield obtained was 3.3 g, with a melting point of 79-81°C, and the starting materials 1RcisS- and 1S
A 1:1 mixture of >90% purity of the cis R-isomer was shown.

A part of the product obtained by the above method was divided into 40/60
Recrystallized once, twice and three times from petroleum ether. The resulting products were all colorless crystalline solids with melting points of 83-86 °C, 84-86 °C, and 86 °C, respectively.
˜87° C. and high performance liquid chromatography showed samples to be 99% pure, >99.9% pure, and 100% pure of the desired isomer pair.

Example 3 α-Cyano-3-phenoxybenzyl 3 by treatment of the solid racemate with 40/60 petroleum ether
-1:1 mixture of 1R cis S- and 1S cis R- isomers of -(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate α-cyano-3-phenoxybenzyl 3-(2 ，
10 g of a racemic mixture of cis-isomers of 2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate were stirred with 75 ml of 40/60 petroleum ether at ambient temperature (20 DEG C.) for 5 days.
By filtration, 4.1g of colorless crystals with a melting point of 81.5-83℃ were obtained.
was obtained and shown by high performance liquid chromatography to be a 1:1 mixture of the 1R cis S- and 1S cis R-isomers of the starting material with approximately 97% purity.

Compared to the products of Examples 1 to 3 above, 1R
cisS-α-cyano-3-phenoxybenzyl 3
It should be noted that both -(2,2-dichlorovinyl)-2,2-cyclopropanecarboxylate and the 1S cisR-enantiomer have melting points of 53-54°C.

Example 4 By crystallization method using 60/80 petroleum ether,
α-cyano-3-phenoxybenzyl 3-(2,
1:1 mixture of 1R cis S- and 1S cis R-isomers of α-cyano-3-phenoxybenzyl 3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate
10.0 g of a racemic mixture of cis-isomers of 2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate were treated in a manner similar to that of Examples 1 and 2 using 60/80 petroleum ether as solvent. did. By recrystallizing the initial product, 3.8 g of colorless crystals with a melting point of 93-97 °C were obtained.
High performance liquid chromatography showed the sample to be approximately 80% pure of the desired pair of isomers. This product was recrystallized twice more to give 3.15 g and
2.7 g of colorless crystals were obtained, and each desired pair of isomers was isolated by high-performance liquid chromatography.
It was shown to contain more than 95% and more than 99%.

Example 5 By crystallization method using 40/60 petroleum ether,
α-cyano-3-phenoxybenzyl 3-(2
1:1 mixture of 1R cis S- and 1S cis R-isomers of α-cyano-3-phenoxybenzyl 3-(-methylpropenyl)-2,2-dimethylcyclopropanecarboxylate in the form of a colorless oil. 2-Methylpropenyl)-2,2-dimethylcyclopropanecarboxylate cis-
15.3 g of a racemic mixture of isomers was added as a solvent to 40/
The procedure was similar to that of Examples 1 and 2 using 60 petroleum ether. 5.75 g of the initial colorless crystalline product has a melting point of 60-66°C and NMR analysis at 360MHz reveals that the starting material is 1RcisS-
It was shown to be a 90% pure 1:1 mixture of the and 1S cis R-isomers. This initial product is 40/
60 recrystallized three times from petroleum ether, each
With melting point 65-70℃, 69-72℃ and 70-72℃
4.7g, 4.3g and 4.0g of product were obtained. These products were determined by NMR analysis at 360MHz.
95% purity, 98% purity and 99.5% of desired isomer pair
It was shown to be a 1:1 mixture of greater purity.

Example 6 α-cyano-3-phenoxybenzyl 3- by the method using isopropanol as solvent
1R cis S of (2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate
- and 1S cis R-isomers α-cyano-3-phenoxybenzyl 3-(2,
12.9 g of a racemic mixture of cis-isomers of 2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate are dissolved in 52 ml of isopropanol at 20°C and 2.0 ml of a 0.880 solution of ammonia in water are added. 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 an additional 4 hours. Separate the settled precipitate and add 5 ml of isopropanol and 15 ml of 60/ml at 5°C.
Washing with 80 petroleum ether gave 5.1 g of a solid product in the form of colorless crystals with a melting point of 77-81°C. High performance liquid chromatography showed the product to be a 90% pure 1:1 mixture of the 1R cisS- and 1S cisR-isomers of the starting material. A similar analysis of the solution revealed that 1S cis S- and 1R cis R-
The ratio of the concentration of the isomers to the concentration of the 1R cis S- and 1S cis R-isomers was shown to be approximately 3:2.

Concentrate the liquor and washings obtained from the above process series, dissolve the resulting material in 30 ml isopropanol, add with stirring 2.0 ml of 0.880 ammonia solution in water, and repeat the above process steps. Repeat, melting point 74-79℃
An additional 2.1 g of colorless crystals were obtained, which by high performance liquid chromatography showed a 1:1 concentration of 85% purity of the 1R cis S- and 1S cis R-isomers of the starting material.
It was shown that it was a mixture. A similar analysis of the fluid showed that the ratio of the concentration of 1S cis S- and 1R cis R-isomers to the concentration of 1R cis S- and 1S cis S-isomers was about 4:1.

Example 7 α-Cyano-3-phenoxybenzyl 3 by method using 40/60 petroleum ether as solvent
-1:1 mixture of 1R cis S- and 1S cis R- isomers of -(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate α-cyano-3-phenoxybenzyl 3-(2 ，
10 g of a racemic mixture of cis-isomers of 2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate were mixed with 75 ml of 40/60 petroleum ether, and
Stirred with 1 ml of a 0.5 molar solution of sodium carbonate in a 1:1 v/v mixture of water and methanol containing 10% w/v tetrabutylammonium bromide. The reaction mixture was stirred at ambient temperature (20°C) for 5 days. melting point due to
5.6 g of colorless crystals at 80-82° C. were obtained, which by high performance liquid chromatography showed 96% purity of the 1R cis S- and 1S cis R-isomers of the starting material.
1 mixture. A similar analysis of the fluid showed that the ratio of the concentration of 1S cis S- and 1R cisR-isomers to the concentration of 1R cisS- and 1S cisR-isomers was 3.4:1.

Claims (1)

[Claims] 1 Formula in the form of a 1:1 mixture of 1R cis S- and 1S cis R-isomers, substantially free of 1S cis S- and 1R cis R-isomers [wherein R ¹ and R ² are each independently selected from chlorine, bromine and methyl. ] compound. 2. The compound according to claim 1, wherein R ¹ and R ² are both chlorine atoms. 3 α-Cyano-3-phenoxybenzyl 3- in the form of a crystalline solid with a melting point of at least 75°C.
consisting of a 1:1 mixture of 1R cis S- and 1S cis R-isomers of (2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate,
A compound according to claim 1. 4 Formula in the form of a 1:1 mixture of 1R cis S- and 1S cis R-isomers, substantially free of 1S cis S- and 1R cis R- isomers [wherein R ¹ and R ² are each independently selected from chlorine, bromine and methyl. ] In the method for producing a compound of the formula, 1RcisS-, 1S-cisS-, 1RcisR- and
A mixture of 1S cis R-isomers is treated with a solvent and from a solution of a compound of formula containing 1S cis S- and 1R cis R-isomers, 1R cis R- and 1S
1R cisS, substantially free of cisS-isomer
- and 1S cisR- isomers are separated as a crystalline solid. 5. The method of claim 4, comprising cooling the solution of the mixture of 5 1R cis S-, 1 S-cis S-, 1 R cis R- and 1 S cis R- isomers. 6 contacting the mixture of 1R cis S-, 1S-cis S-, 1R cis R- and 1S cis R- isomers with a solvent at or below ambient temperature;
and from the resulting solution enriched in 1S-cisS- and 1RcisR-isomers, 1RcisS- and 1ScisR-
5. The method of claim 4 comprising separating the remaining solid crystalline 1:1 mixture of isomers. 7 A solution of a compound of formula containing the 1S-cisS- and 1RcisR-isomers is treated with a base, and during or after treatment with base, the 1RcisR- and 1ScisS- Substantially free of isomers, 1:1 of 1R cis S- and 1S cis R-isomers
7. The method of claim 4, 5 or 6, further comprising separating the mixture. 8. A process according to claim 7, wherein the solution of the isomer of the compound of formula 8 contains as solvent a lower liquid alkane or a liquid C _1-4 alkanol having up to 8 carbon atoms. 9. The method of claim 8, wherein the base comprises ammonia, a primary, secondary or tertiary amine or an alkali metal carbonate in aqueous solution. 10. The method of claim 9, wherein the solution is treated with the base in the presence of a _C1-4 alkanol. 11. The method of claim 9 or 10, wherein the solution is treated with the base in the presence of a phase transfer catalyst.