HU199390B - Process for producing mixture of cipermetrin's enantiomeres - Google Patents

Abstract

1. Technical Result Increase in stability of the composition. 2. Essence A stable arthropodicidal composition containing stabilizer and as active ingredient cypermethrine of the formula (I) CH O Cl CO2 CH Cl  wherein carbon atoms indicated by 1,3 and  stand a chiral carbon atom and the wavy line indicates cis or trans configuration related to the cyclopropane ring – which contains at least 95% of 1R trans S and 1S trans R (Ib) isomer pair, or mixture of 1R cis S and 1S cis R (Ia) and the isomer pair (Ib) of the ratio (Ia):(Ib) = 55:45-25:75, or the isomer pair Ia or Ib and as a stabilizer non-volatile carboxylic acids of pK1=1-5 such as phtalic acid, succinic acid, tetraric acid, maleic acid, fumaric acid, malonic acid or once or several times substituted alkylated derivatives thereof and/or oxalic acid. 3. Field of Application Organic chemistry. 5 Tables.

Description

The present invention relates to a defined isomeric ratio of [o-Cyano-3-phenoxybenzyl) -3- (2,2-dichloro-vinyl) -2,2-dimethylcyclopropanecarboxylate (cypermethrine free or R-ISO) hereinafter referred to as cypermethrin) as an asymmetric transformation.

As used herein, the substituents are characterized by the positions S and R with respect to the chiral carbon atom represented by oC. The cis 10 and trans are denoted by the position of the substituents on the 3 carbon atoms of the cyclopropane ring, the absolute position of the 1 carbon substituent being given by the IR or IS prefix, respectively. 15

The following abbreviations are used to designate the various enantiomers or pairs of enantiomers as used herein:

la Mixture of iris and lyscisR 20 (Fastac) lb IRtrans and IStransR (Transmix)

Ic A mixture of IRcisR and lIScisS

Id IRtransR and IStransS mixture 25

If iris lg IRtrans

Ih lSciszR

IItransR 1a + 1b Asymmetryin (Chinmix) 30% by weight in the present specification always means by weight.

It is known that enantiomeric mixtures of cypermethrin la and lb in a ratio of 55: 45 to 25: 75, known as asymmetrine under the trademark Chinmix, are very valuable active ingredients against various arthropods (Hungarian Patent Application No. 158/85). They have a higher pest control effect and a lower mammalian toxicity than mixtures of cypermethrin containing the 8 possible isomers together. Several methods for the preparation of the active ingredient are known, but do not include asymmetric transformation 45 starting from mixtures containing all 8 isomers. Since the chemical synthesis of cypermethrin in the most feasible commercial production generally results in a product 50 containing the 8 isomers, a solution which can be reproduced easily from the 8 isomeric mixture by a simple method is desirable among the aims of economical asymmetryin production. directly yields an active ingredient containing the desired enantiomers in appropriate proportions.

According to the known method of preparation, cytermethrin of sufficient purity can be selectively crystallized under suitable conditions under suitable conditions of solvent, temperature, use of pure seed crystals and very slow crystallization, such that the starting cypermethrin (la) and (lb) yields a mixture of (la) and (lb). The disadvantage of this process is that the remaining, biologically inert, stereoisomers of cypermethrin remain unused. (Hungarian Patent Application No. 158/85).

SUMMARY OF THE INVENTION It is an object of the present invention to provide Chinmix from a mixture of 8 isomers by a second type of asymmetric transformation.

The application of the principle of second-order asymmetric transformation (Mislow, Introduction to Stereochemistry, 1966, p. 122) was first described among pyrethroids in the synthesis of two cis isomers of (If) lRcisS-dibromo-vinyl (Chemistry and Industry). 1984, p. 200). In this case, the product is a single stereoisomeric chiral molecule with a melting point of 120 ° C. Thus, it represents a relatively simple system since only two stereoisomers are present in the equilibrium mixture and only one stereoisomeric molecule crystallizes.

One of the cis-enantiomeric pairs of cypermethrin, which contains the 1: 1 ratio of the cis-enantiomeric pair of la (IrisS-IScisR) cypermethrin, is known as alphamethrin. Alphamethrin was prepared by a second type of asymmetric transformation starting from the cis-cypermethrin (la + Ic) consisting essentially of the four cis isomers which did not contain the trans isomers. In this process, alpha-amethrin was isolated from the epimerizable equilibrium mixture of cis-cypermethrin in a secondary or tertiary amine (without solvent) at 70-0 ° C, and the other enantiomeric pair was continuously epiralized (U.S. Patent Nos. 186,406 and 186,407). ).

On a similar principle, starting from a mixture of four trans stereoisomers of cypermethrin (Ib-Id), the preparation of the lb (IRtransS and IStransR) enantiomeric pair was described with trialkylamines or inorganic bases in a solvent or solvent. (e.g. petroleum ether) by epimerization in the presence of 2,6-di-tert-butyl-4-methylphenol at 30-60 ° C.

To date, there is no published literature in which a second type of asymmetric transformation has been performed starting from a mixture of all steric and optical isomeric strengths of cypermethrin (la + lb + Ic + Id). In the literature, rather than the reaction starting from cis isomers, reference is made to the difficult feasibility, such as that described in U.S. Patent No. 6,7461. According to the European patent, which describes the preparation of the la 'isomeric pair (page 6, lines 29-48), the presence of 6 or 10% trans isomeric impurity in the starting material can be recovered when transforming the mixture of (la + Ic) isomers in triethylamine. l reduced its yield to 63% and 36%, respectively. Higher

Thus, for the trans isomer content, no crystallization of the la material was expected, and even less the (la '+ lb) mixture could be recovered.

The present invention relates to a process for the preparation of an isomeric mixture of a synthetic pyrethroid of formula (I) having an enantiomeric pair of irisS and lScisR (1a) and an enantiomeric pair of IRtransS and IStransR (lb): (lb) = 55:45 - 25:75. containing at least 95% by weight of an isomeric or crystalline mixture of isomers of formula (I) having a purity of at least 90 tX in a ratio of 65:35 to 15:85 at a temperature of 0-25 ° C. 0.1-0.5 by weight of the mixture. parts by weight of triethylamine or 0.0005 to 0.01 parts by weight of 1,5-diazabicyclo (4.3.0) non-5-ene or 1,5-diazabicyclo (5.4.0) undeo-7-ene and , 2-0.5 parts by weight of propanol is vigorously stirred for 4-10 days at the saturation point of the desired mixture of isomers, while additional propanol is added to the mixture at a ratio of 0.5 to 2 parts by weight of cypermethrin at the end of the reaction. , optionally after gradual cooling, the precipitated crystalline product is isolated and then washed with solvent to remove base traces and other impurities.

The basis of our procedure is the recognition that the fusion epimerization is extremely critical for the successful implementation of the second type of asymmetric transformation. and to maintain the rate of crystallization not only by selecting the appropriate base but also by adding a certain amount of propanol in parallel with the epimerization reaction at the appropriate temperature. It has been observed that when the oil-like cypermethrin isomeric mixture is a solvent suitable for crystallization, e.g. isopropanol is added, then to a certain extent cypermethrin dissolves the solvent, and at one point the so-called. saturation or equilibrium value - the mixture suddenly becomes an emulsion. With further addition of the solvent, the resulting emulsion is gradually converted to a true solution. The same phenomenon is observed when the solvent for crystallization also contains a base. Asymmetric transformation is observed to be most advantageously performed at this saturation or equilibrium value. To our knowledge, this observation has not yet been published in relation to other asymmetric transformations.

The equil. however, the saturation state is a narrow interval and, as a result, even a small difference affects the composition of the resulting product.

Raising the temperature from 13-15 ° C to 20 ° C to produce a mixture of Ia: Ib = 4: 6 isomerization results in a significant decrease in yield instead of the thermodynamically expected higher melting point (86 ° C) of the Ia enantiomeric pair. lb enantiomeric pair. The same can be achieved by increasing the amount of solvent. All this allows the cis: trans composition of the starting cypermethrin to be varied up to 30 tX and the desired isomer ratio of product is isolated.

In addition to the above, it is more preferable to start with an asymmetric transformation with a slurry of solid crystalline cypermethrin rather than a homogenous solution. In this case, since some of the material is not in solution, the solvent (+ base) -cypermethrin ratio in the liquid phase is favorable at all stages of the transformation. For a successful asymmetric transformation, the rate of epimerization and crystallization must be comparable. This can only be achieved with a relatively high base concentration since the crystallization rate is given for the solvent used.

On the other hand, in the case of suspension transformation techniques, the so-called saturation or equilibrium state is formed in a self-regulating manner with a smaller volume of solvent. Compared to .emulsion * techniques, although dissolution must occur in addition to crystallization, the process can be accelerated. A particular advantage of the suspension technique is that the cis / trans ratio does not change with time for the precipitated Xa + 1b.

Of the other two enantiomeric pairs present in (la + lb) and cypermethrin, the solubility of (Ic + ld) is better in Iris trans and lScisS (Ic) plus IRtransR and IStransR (ld), and these are mainly solubilized by the suspension technique. . This also explains why this technique allows for faster asymmetric transformation.

The following is a description of the process of the present invention for providing some particularly important (Ia: Ib) isomer ratios.

For the preparation of a mixture of isomeric ratios, the isomeric weight ratio of Ia: Ib = = 40:60 is based on a mixture of cypermethrin in the ratio (la + Ic) = 35-45, (lb + ld) = 50-60 tX and the reaction is continued (depending on the amount) for 4 to 10 days at 3 to 16 ° C, then for 1 to 5 days at 0, with a weight ratio of cypermethrin: triethylamine: propanol of 1: 0.2- 0.3: 1-1.5. Propanol addition should be started from day 2 and continued until day 5. la:

Preparation of the isomeric mixture of lb = 50:50 tX was carried out as starting material (la + Ic) = 40-55, (lb + ld) = 45-55 tX and isomerization continued for 1-10 days.

la: lb = 25 - 30:75 - 70 tX for the preparation of an isomer mixture as starting material

-3 '

HU 199:

(la + Ic) = 35-45, (Ib + Id) = 50-60 tX. Asymmetric transformation and isolation were performed at 25 ° C for 1-5 days. As propanes, normal or preferably isopropanol can be used.

When starting with oily cypermethrin as starting material, it is preferable to cool the reaction mixture below 0 ° C and to recrystallize it before the asymmetric transformation.

Washing of the filtered crystalline product can further reduce the amount of (Ic + Id) isomeric pairs present in the isolated product. Such solvents may be used, e.g. hexane, heptane, petroleum ether, ethanol and / or isopropanol. It is also very important, due to the stability of the material, to completely remove the base traces adhering to the surface of the crystals of the product. Accordingly, it is preferable to include a wash in which the solvent contains a small amount of inorganic or organic acids, for example 0.5 tX acetic acid.

The following examples illustrate the invention. 25

Materials used or recovered

Analyzed by HPLC (see Analythical Methods for Pesticides and Plant Growth Regulators: XIII, Ed. By G. Zweig and J.

Sherma, Academic Press 1984.) '. 30

Example 1

Preparation of a 40:60 (w / w) mixture of iris and lScisR enantiomeric pair (la) 35 and IRtransS and lStrisR enantiomeric pair (Ib):

In a magnetic stirrer, 100 g of crystalline cypermethrin of 40 99 tX purity (m.p. 38-43 ° C. Isomer ratio: la = 18.1 tX, Ib = 23.1 tX, Ic = 23.5 tX, Id = 34.3 tX). It is suspended in a mixture of 21.7 g of triethylamine and 23.5 g of isopropanol and stirred for 24 hours at 16 [deg.] C. The gradually thickening suspension is diluted 4 times with 31.5 g of isopropanol each twenty-four hours and then at 0 [deg.] C. After stirring for a further 24 hours, the dense slurry was filtered, washed with 39.3 g of 50 isopropanol, 31.5 g of 0.25 tX acetic acid in isopropanol and then 23.5 g of isopropanol and dried under vacuum at room temperature to give 87 g of an off-white crystalline solid. .

Mp 62-63 ° C, Isomeric Structure: la = 38.0 tX, Ib = 59.3 tX, Ic = 1.2 tX, Id = 0.4 tX. Purity: 98.9 tX.

The mother liquor was evaporated and the above procedure was carried out with 13.5 g of the product, 3.0 g of isopropanol and 2.8 g. starting with a mixture of triethylamine (g) was repeated to give the second generation an additional 7 g of snow-white crystals. 62-65 ° C, Isomeric Structure:

6

Ia: 48X Ib: 48.2X Ic: lX Id: 0.4X) Honesty:

97.6 tX.

Example 2

IrisIS and lIScISR (la) and IRtransS and

IStransR (Ib) Preparation of a 40:60 w / w mixture of cypermethrin:

The same procedure as in the first example was used, except that crystalline cypermethrin was replaced by 100 g. dense oil consistency cypermethrin purity:

95.6% by weight of isomeric composition: Ia: 17.6tx Ib: 22.6t% Ic: 22.9tX Id: 32.4tX) and the reaction is run at + 11 ° C. Combining the first and second generations gives 91 g (91X) of an off-white crystalline material. (M.p. 62-64 ° C, Isomeric Composition Ia: 38, 1xX Ib: 58, 1xX Ic: 1xXX Id: 0.7x) Purity 98x.

Example 3

IrisIS and lIScISR (la) and IRtransS and

Preparation of IStransR (Ib) 50:50 by weight from cypermethrin:

In the same manner as in the first example, the starting material was crystalline cypermethrin (100 g of 98 tX purity Ia: 22.3 tX Ib: 20.4 tX Ic: 26.6 tX Id: 28.7 tX). The combined first and second generations yielded 95 g of an off-white crystalline solid. (Mp: 64.5-65.5 ° C, Isomeric composition Ia: 48.2 tX Ib: 48.4% Ic: 1.1 tX Id: 0.6 tX) Purity: 98.3 tX.

Example 4

IrisIS and lIScISR (la) and IRtransS and

Preparation of IStransR (Ib) from cypermethrin at ° C,

In the same manner as in the first example, the same starting mixture was epimerized at 25 ° C

52.1 g of an off-white crystalline solid are obtained. (M.p. 65-68 ° C, isomer composition Ia: 28.8 tX Ib: 67.3 tX Ic: 0.8 tX Id: 0.3 t%> Purity:

97.2%.

Example 5

IrisIS and lIScISR (la) and IRtransS and

Preparation of ItransR (Ib) from Cypermethrin with 60 DBN.

Using the same starting mixture as in the first example, but using 0.1 S [1,0,5] diazabicyclone-5 (DBN) al65 instead of triethylamine, the combined first and second

HU 199390 In the ration 95 g of a white crystalline substance are obtained. (M.p. 62-64 ° C, Isomeric Composition Ia: 39.4tX Ib: 57.4tX Ic: 1.2tX Id: 0.8tX) Purity: 98.8tX.

fi. example

IRISIS and ISISISR (la) and IRtransS and

Preparation of a 40:60 mixture of trans (lb) transfected from cypermethrin with n-propanol:

100 g of cypermethrin oil (purity: 91.4 tX, la: 16.6 tX Ib: 21.5 tX Ic: 21.8 tX Id: 31.5 tX) was charged into a two-tube thermometer magnetic stirrer. The material

Stir in a mixture of 14.5 g of triethylamine and 24.1 g of n-propanol at 10-12 ° C for 4 days. Meanwhile, after 24 hours, the suspension is diluted with a mixture of 14.5 g of triethylamine and 16 g of n-propanol, and the dilution is repeated 3 times with 24.1 g of npropanol every 24 hours.

After addition of the last portion of solvent, the mixture was cooled to 5-0 ° C and stirred for an additional 24 hours.

The precipitated crystals are filtered off and washed as described in the first example, decontaminated and dried, to give 82 g of a snow-white crystalline material in the first generation. 30 (m.p. 62-63 ° C, Isomer Strength Ia: 38.0 tX Ib: 60.0 tX Ic: 1.0 tX Id: 0.5 tX). Tiszteság:

99.5 tX. After evaporation, the mother liquor is recrystallized as in the first example. 35

Example 7

In a propeller mixer duplicator with 3000 liters steam-heated, controlled cooling, 600 kg of cypermethrin oil / purity:

tX, composition: (la + Ic) = 42 tX, (lb + ld) = 50 tX, 180 kg of anhydrous isopropanol (water content: max 0.2 tX) and 180 kg of 45 anhydrous triethylamine (water content: max.

0.2 tX) with stirring. Optionally, at 25 ° C, 4 kg of inoculum crystal of cytermethrin la = 38 tX, 1b = 58 tX are inoculated. To carry out the asymmetric transformation, the solution was stirred at 3-7 ° C for 18 hours, then 228 kg anhydrous isopropanol was added to the crystallization mixture, again stirred at 3-7 ° C for 24 hours, and 96 kg anhydrous isopropanol was added. After stirring for 24 hours at 3-7 ° C, 96 kg of anhydrous isopropanol were finally aspirated and stirred at 3-7 ° C for an additional 168 hours. The reaction mixture was then cooled to 0 - (-5) ° C and stirred for 96 hours. The resulting crystal slurry 60 was filtered through four equal portions of a nitrogen filter. The 120 kg crystal mass was washed per filter cake with anhydrous isopropanol, filtered, slurried with 4TX acetic acid in isopropanol, and then filtered under nitrogen pressure. The resulting crystals were dried in a strip-belt vacuum dryer at 40-45 ° C under vacuum for 12 hours with stirring.

500 kg of asymmetryin are obtained, its composition

According to GC analysis: (la) = 38.2 tX, (lb) = 58.3 tX, (Ic) = 0.6 tX, (ld) = 0.8 tX. Purity: 97.9 tX.

fi. example

In the same manner as in the first example, the stirring cap was used with the aid of a friction disk stirrer and after dilution 3, dilution 4 was carried out after 48 hours, the mixture was stirred at 48C for 48 hours and the material was stirred for another 40 ml. (31.5 g) is diluted with isopropanol. The mixture was further cooled and then stirred at -5 ° C for 48 hours and at -10 ° C for 72 hours. In the same manner as in the first example, 90 g of an off-white crystalline solid were obtained: m.p. 62.5 ° C. Isomer composition: la: 39.0 tX, lb: 59.5 t%, Ic: 0.6 tX, ld: 0.2 t%.

Example 9

100 g of crystalline cypermethrin (m.p. 38-43 ° C, la: 18.1 tX, lb: 23.1 tX, Ic: 23.5 tX, ld: 34.3 tX, purity 99 tX) in 30 mL (21 (7 g) was suspended in a mixture of triethylamine and 30 ml (23.5 g) of isopropanol and stirred at 16 ° C for 24 hours. The gradually thickening slurry was diluted with 40 ml (31.5 g) of isopropanol and stirred for 12 hours. The suspension was diluted with another 40 mL (31.5 g) of isopropanol and filtered. The filtrate was washed with cold isopropanol (50 mL, 39.3 g), isopropanol (40 mL, 31.5 mL) containing 0.5% acetic acid, and then with cold hexane (50 mL). The first generation gave 70 g of an off-white crystalline solid, m.p. 62-64 ° C. Isomer composition: la: 36.0 tX, lb: 59.1 tX, Ic: 3.1 tX, lb:

1.6 tX. Purity: 99.8 tX.

Example 10

The procedure of Example 1 is followed except that 0.1 g of 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU) is used in place of triethylamine. The combined first and second generations gave 94 g of white crystals. 62.5-64 ° C, isomer composition: la: 39.6 tX, lb: 57.2 tX, Ic:

1.2 tX, ld: 0.9 tX. Purity: 98.9 tX.

Claims (8)

A process for the preparation of a synthetic pyrethroid of formula (I) wherein the atoms designated by alpha 1,3 and a2 represent a chiral carbon atom, the wavy line representing a cis or trans position relative to the cyclopropane ring to produce an isomeric mixture of (la) the enantiomeric pair and the IRtransS and IStransR (Ib) enantiomeric pairs of at least 95 tX by weight in the range of Ia: lb = 55:45 to 25:75, characterized in that the cis is in the form of an oil or crystalline solid of at least 90 tX: a mixture of isomers of formula (I) containing trans isomers in a ratio of 65:35 to 15:85 at a temperature of 0-25 ° C with 0.1-0.5 parts by weight of triethylamine or 0.0005-0.01 parts by weight based on the starting mixture, 5-diazabicyclo [4.3.0] non-5-ene or 1,5-diazabicyclo [5.4.0] undec-7-ene and 0.2-0.5 parts of propanol are stirred vigorously for 4-10 days. saturates the desired mixture of isomers si, while additional propanol is added to the mixture as the reaction proceeds, with a ratio of 0.5 to 2 parts by weight of cypermethrin at the end of the reaction, optionally after gradual cooling, isolating the crystalline product and optionally washing with solvent. base traces and other impurities are removed. The process according to claim 1, wherein the asymmetric transformation is carried out in the presence of isopropanol. Process according to claim 1, characterized in that during the last third of the reaction time, the reaction mixture is gradually cooled to below 0 ° C, preferably to -10 to -25 ° C. 4. Process according to any one of claims 1 to 3, characterized in that the washing solvent is petroleum ether, heptane, hexane, ethanol and / or isopropanol or mixtures of the above with inorganic or organic acids, preferably acetic acid. Process for the preparation of a mixture of isomers according to Claim 1: Ia: Ib = 40:60, characterized in that the starting material is IrisS + lScisR + IrisR + + lScisS (la + Ic) = 35-45 tX, IRtransS + + IStransR + The mixture is trans + IRtransR (Ib + + Id) = 50-65 tX and the reaction is continued for 4-10 days at 3-16 ° C, then for 1-5 days at 0 ° C while The weight ratio of pyrethroid to triethylamine risopropanol of formula I is from 1: 0.2 to 0.3: 1 to 1.5. 20 6. A process according to claim 4 for the preparation of an isomer mixture of la: Ib = 50:50 by weight, characterized in that (la + Ic) = 45-55 tX, (Ib + Id) = = 45-55 tX is used as starting material. us. The process according to claim 1 for the preparation of a mixture of isomers of la: lb = 25-30: 75-70, characterized in that starting material (la + Ic) = 35-45 tX, A mixture of isomers of 30 (Ib + Id) = 50-55 tX was used and the reaction was conducted and isolated at 25 ° C. 8. A process according to any one of claims 1 to 5, characterized in that it is an initial process The material is a mixture of oily isomers which are pre-crystallized at 0 ° C.