CS252483B2 - Method of crystalline material production - Google Patents

Description

The present invention relates to a process for preparing crystalline material.

Compound alpha-cyano-3-phenoxybenzyl cis-3- (Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2-dimethylcyclopropanecarboxylate, also known as cyhalothrin, preparation of this compound the compound and its use as an insecticidal agent is described, inter alia, in U.S. Patent No. 4,183,948. This product is a mixture of four isomers that can be described as follows:

Isomer A - ester derived from Isomer B - ester derived from Isomer C - ester derived from Isomer D - ester derived from (+) - cis-acid (-) - cis-acid (+) - cis-acid (-) - cis -acids and alpha- (S) -alcohol and alpha- (R) -alcohol and alpha- (R) -alcohol and alpha- (S) -alcohol

Cyhalothrin alone normally contains from 40 to 60 wt. % of isomers A and B and 60 to 40 wt. isomers C and D and form a viscous liquid at room temperature. Cooling does not cause crystallization in this mixture.

Isomer A and isomer B have identical physical properties, such as solubility, melting point and the like, but differ only in directions in which they rotate the plane of polarized light and as such represent a pair of enantiomers. Similarly, isomer C and isomer D represent the other pair of enantiomers.

P.D.Bentley et al., Pestic. Sci., 11 (2) 156-164 (1980), it is known that isomer A is the most active of the four isomers and that isomers B and D are inactive in tests on flies (Musea domestica). In this test, isomer A is in fact 25 times more active. than the known insecticide permethrin and is the most effective synthetic insecticide ever reported. While it would be desirable to use isomer A alone as the active ingredient of the insecticidal compositions, this is not readily accomplished for economic reasons. For this purpose, it would be desirable that parts of the isomer molecule, both acid and alcohol, be prepared by chiral synthesis and then reacted together in a manner that ensures that the chirality is not altered.

These techniques have not yet been developed to the extent that the synthesis is carried out economically without simultaneously producing undesired isomeric products requiring separation using expensive reagents.

Recently, a method has been found in which a pair of enantiomers consisting of isomer A and isomer B can be readily separated from isomers C and isomers D in a physical manner not requiring chiral synthesis or chemical resolution, and by which insecticidal products of acceptable efficacy can be prepared economically.

It is an object of the present invention to provide a process for preparing a crystalline material consisting of at least 90 wt. an enantiomeric pair of isomers represented by (S) -alpha-cyano-3-phenoxybenzyl (IR, cis) -3- (Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2 -dimethylcyclopropanecarboxylate and (R) -α-cyano-3-phenoxybenzyl (1S, cis) -3- (Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2- % dimethyl cyclopropanecarboxylate in racemic ratios and not more than 10 wt. of any other alpha-cyano-3-phenoxybenzyl 3- (2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2-dimethylcyclopropanecarboxylate isomer, characterized in that a concentrated solution of the mixture is % isomers of alpha-cyano-3-phenoxybenzyl cis-3- (2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2-dimethylcyclopropanecarboxylate consisting of 40 to 60 wt. an enantiomeric pair of isomers represented by (S) -α-cyano-3-phenoxybenzyl (1R, cis) -3- (Z-2-chloro-3,3,3-trifluoroprop-1-1-en-1-yl) -2 , 2-dimethylcyclopropanecarboxylate and (R) -α-cyano-3-phenoxybenzyl (1S, cis) -3- (Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2, % From 2-dimethylcyclopropanecarboxylate and from 60 to 40 wt. an enantiomeric pair of isomers represented by (R) -alpha-cyano-3-phenoxybenzyl (IR, cis) -3- (Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2 -dimethylcyclopropanecarboxylate and (S) -α-cyano-3-phenoxybenzyl (1S, cis) -3- (Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2- dimethyl cyclopropanecarboxylate in an organic solvent selected from lower alkanols containing up to 6 carbon atoms and liquid alkanes containing up to 8 carbon atoms, cooled to a temperature between -20 ° C and +10 ° C, crystals of an enantiomeric pair of isomers remaining to the cooled solution then in solid undissolved state and the solution is maintained at the temperature range for 16 hours to 33 days, whereupon the precipitated crystalline material is separated from the solution and optionally recrystallized to less than 10% by weight. any of the isomers of alpha-cyano-3-phenoxybenzyl 3- (2-chloro-3,3,3-trifluoroprop-1-enyl) -2,2-dimethylcyclopropanecarboxylate.

Preferred alcoholic solvents are ethanol, isopropanol, butan-1-ol, butan-2-ol, pentan-1-ol, isopropanol / t-butanol (1: 1), isopropanol / 1,2-ethanediol (2: 1) . A particularly preferred solvent is isopropanol. Preferred liquid alkane solvents are n-hexane and n-heptane.

The term concentrated solution is preferably one that comprises from 2: 1 to 1: 5, most preferably 1: 1 parts by weight of cyhalothrin to the solvent.

The cyhalothrin used in this process can be contaminated up to 10% by weight of the corresponding trans-isomers and (E) -isomers. Preferably, the cyhalothrin is at least 95% pure because such a preparation usually provides a product of higher yield and purity.

If the process is carried out using the addition of a certain amount of crystals of a pair of enantiomers of isomers, then the time required to precipitate the product from solution is usually shortened.

(An amount of enantiomeric pair of isomers of sufficient quality for addition can be obtained by separating cyhalothrin by high pressure liquid chromatography into the desired pair of isomers separated from the other isomers present).

The process is preferably carried out by preparing a solution, optionally with gentle heating, and then cooling the solution to a temperature in the range of 0 to 10 ° C for an initial period during which a substantial amount of product crystallizes, followed by further cooling the solution to -15. ° C to -5 ° C for the second part of the time, substantially complete crystallization occurs prior to separation of the precipitated product.

If recrystallization is required to separate the product from other isomers that may precipitate with the product during crystallization, it may be carried out in any suitable recrystallization solvent, for example in the solvent mentioned above as a solvent useful in the product preparation process.

The product may be secreted in one or two different forms of the product referred to as product I and product II. Typically, product I is only slowly excreted and the time required to achieve a sufficient yield is preferably at least 7 to 15 days or more. Product II is eliminated more rapidly and a good yield can be obtained over a period of from 1 to 6 days.

Where crystals of an enantiomeric pair of isomers prepared by high pressure liquid chromatography are added, then excretion is usually carried out in the form of product I. If this precipitated material is recrystallized several times and then used to inoculate further crystallizations, then the likelihood of obtaining product II is increased. it may be necessary to carry out a series of crystallizations before the TI product actually precipitates. Once product II is formed and used to inoculate further crystallizations, it always causes product to precipitate as product II.

The product I precipitated in the above manner is a white crystalline material, m.p. 36-42 ° C. If it is free from contamination of the remaining amounts of isomer C and isomer D by recrystallization, then product I melts at 41-42 ° C. Infrared spectral analysis shows that it consists of a mixed crystal conglomerate wherein each individual crystal is composed of molecules of one isomer, either isomer A or isomer B, and that there is approximately the same amount of crystals of each isomer. Product I is therefore a racemic mixture. These crystals are fine needles which, as mentioned above, are slowly secreted from concentrated cyhalothrin solutions. Separation of the product by filtration is also slow due to the tendency of fine needles to plug the filter.

Product II is characterized by a melting point above 47 ° C, typically 48 to 50 ° C. This form crystallizes faster and covers the appearance of rhomboids, although in fact they are monoclinic. This makes it easier to filter because the crystals of this form do not tend to clog the filter like the needles of the low melting form described above.

Infrared spectroscopy and X-ray crystallographic analysis of the above melting form show that each individual crystal is composed of equal amounts of isomer A and isomer B arranged regularly in a crystal lattice. This form is thus a racemic compound.

Data relating to the crystalline form of product II was obtained by studying X-ray diffraction characteristics of the crystal of about 0.13 x 0.13 x 0.12 mm using a Philips PW 1100 four circle X-ray diffractometer with Mo-K _A radiation from a graphite monochromator . A 0 to 20 scanning method was used with a scan speed of 0.5 seconds. Chem.,

1980, 29th »2 956. The data obtained for Product II are summarized as follows: Crystal form: monoclinic space group: C2 / c = 34.764 (5) b = 7.023 (2) c = 18.624 (3) ^_1 x 10 nm beta = 101.95 (3),

U = 4,448.46 x 10 ^-1 nm,

Z = 8 density = 1,343 g / cm \

F (000) = 1856.

(Mo-K 2) = 1.77 cm -1, (δ-Κ _χ ) = 0.710 69 x 10 ^-1 nm.

The crystal lattice consists of regularly arranged alternating molecules of the two isomers A and B, each containing trifluoromethyl groups in trans order to the cyclopropane group via a double bond (Z-configuration). The unit cell contains 4 molecules of each of the enantiomeric isomers.

The crystalline material of the invention may be used in an insecticidal composition useful for controlling insect pests. Except for the active ingredient, the compositions and methods of use are identical to those disclosed in U.S. Patent No. 4,183,948, supra, the claims of which are incorporated herein by reference.

The invention is illustrated by the following examples.

In the examples, the isomer A is referred to herein as the IR, cis-S-isomer, that is, the isomer with the R-configuration at the carbon atom of the cyclopropane ring attached to the carboxylate group. on a cyano-bearing carbon atom. Isomer B is referred to as the 1S, cis-R-isomer, isomer C as the 1R, cis-R-isomer, and isomer D as the 1S, cis-S-isomer.

Example 1

This example illustrates the separation of alpha-cyano-3-phenoxybenzyl cis-3- (Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2-dimethylcyclopropanecarboxylate into pairs of enantiomeric isomers.

The material to be separated was characterized by thin-layer chromatography on 0.25 mm (analytical purity) silica gel using various mixtures of eluents.

The material was slightly divided into two components corresponding to the two pairs of enantiomers present.

The average Rf values for the two components were as follows:

Elution agent Diethyl ether: n-hexane Rf (diameter) ARf 10:90 0.22 0,025 15:85 0.28 0.030 20:80 0.33

Separation of this material was performed by high pressure liquid chromatography on a Waters Associates System 500 apparatus with a PrePAk-500 silica gel column. Charge 0.5 g oyhalothrin consisting of a 55:45 mixture of 1S, cis-S / 1R, cis-R: 1R, cis-S / 1S, cis-R enantiomers. A 1: 9 mixture of diethyl ether and petroleum ether (b.p. 40-60 ° C) was used as eluent at a flow rate of 0.2 liters per minute.

Fractions were collected after four recycling operations. The first fraction was identified by proton magnetic resonance spectroscopy as IR, ois-R / 1S, cis-S enantiomeric pair, and the second fraction as 1R, ois-S / 1S, cis-R enentiomeric pair. Each fraction had a purity of about 98% and together corresponded to about 60% of the indicated amount. PMR data are summarized in the following table (delta values in CDCl3):

1R, cis-S / 1S, cis-R 1S, cis-S / 1R, cis-R

1,213 1,30 J (dl 1.34 (s) 1,98Λ 1.98 2.07 (m) 2.07 1 (m) 2.19 1 2,19> 2.29 ( 2,29 1 2.38 J 2.38 J 6.38 (with) 6.32 (with) 6.77 χ (d) 6,771 (d) 6,87 / 6,87 / 6,97-7, 50 (m) 6.97-7.50 (m)

Example 2

This example illustrates the crystallization of the 1R-cis-S / 1S, cis-R-isomeric pair from a cyhalothrin solution. The crystals used for seeding were prepared as in Example 1.

455.6 g of a mixture of cis-isomers of alpha-cyano-3-phenoxymenzyl 3- (Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2-dimethylcyclopropanecarboxylate containing 43, 2 wt. 1R, cis-S and 1S, cis-R isomers and 56.8% wt. The 1S, cis-S and 1R, cis-R isomers were dissolved in 460 ml of isopropanol, which had been previously dried by distillation from calcium hydride. Dissolution was accomplished by heating the mixture to about 50 ° C. The solution was cooled to 3 ° C with stirring with magnet coated with polytetrafluoroethylene. Several crystals of a mixture of 1R, cis-S and 1S, cis-R isomers of alpha-cyano-3-phenoxybenzyl 3- (Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl) are then added. -2,2-dimethylcyclopropanecarboxylate. Stirring was continued at this temperature for 9 days, then the suspension was cooled to -10 ° C and the mixture was vigorously stirred with a polytetrafluoroethylene stirrer for 7 days.

The precipitated solid is filtered at 3 ° C to dryness, washed once with 100 ml of petroleum ether 40 to 60 ° C cooled to 3 ° C and then dried to constant weight in a vacuum desiccator over phosphorus pentoxide. 97.6 g of white crystals are obtained. This product contains 86.9% by weight of capillary gas chromatography. mixtures of 1: 1 1R, cis-S and 1S, cis-R-isomers of the starting material. The solid was dissolved in 300 mL of anhydrous 40-50 ° petroleum ether, cooled to 3 ° C with stirring, and several crystals of a mixture of 1R, cis-S and 1S, cis-R isomers of alpha-cyano-3-phenoxybenzyl were added as seed. 3- (z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2-dimethylcyclopropanecarboxylate. After 2 hours, the resulting white suspension was filtered at 3 ° C and the solid was filtered off with suction. Further drying in a vacuum desiccator over phosphorus pentoxide gave 73.6 g of a white solid containing 92 wt. mixtures of 1R, cis-S and 1S, cis-isomers of alpha-cyano-3-phenoxybenzyl 3- (Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2- 36-42 ° C, dimethyl cyclopropanecarboxylate;

Example 3

A mixture of cyhalothrin isomers containing 6.4 g of the 1R, cis-S isomers, 6.4 g of the 1S, cis-R isomers,

3.2 g of the 1S, cis-S isomers and 3.2 g of the 1R, cis-R isomers were dissolved in n-hexane (20 mL) and stirred under a nitrogen atmosphere at -5 ° C. After dissolution and cooling, a few milligrams of the racemic mixture (obtained according to Example 2) are added and further purified by crystallization until the melting point is 41.5 to 42.0 ° C). Stirring was then continued at -5 ° C for 16 hours. The precipitated solid is filtered on a sintered glass funnel cooled to 0 ° C and then washed twice with haxane cooled to -5 ° C. 9.30 g of material, m.p. 48 to 49.5 ° C of at least 99% purity with respect to cyhlaothrin isomers and containing at least 96.3% of the 1R, cis-S and 1S, cis-R-isomers in equal proportions.

According to infrared spectroscopy analysis, this product is different from the product of Example 2. The crystalline form is also different (rhomboid rather than needle-like) and, together with a higher melting point, shows that it is a racemic compound where individual crystals contain equal amounts of 1R, cis -S and 1S, cis-R-isomers, both molecules being regularly arranged in a crystal lattice.

Infrared (Liquid Paraffin Suspension): 1050, 1030, 1 010, 990, 970 (inflex), 963, 95Q, 935, 920, 908, 904, 895, 888, 873, 838, 830 (inflex), 820 , 805,

795, 785, 760, 748, 725, 702, 695, 650 cm ^1st

Figures 1 and 2 show the infrared spectra of the product of this example and of the product of Example 2. Figure 3 shows the infrared spectrometer of the IR, cis-S-isomer alone. It can be seen that the spectra of the product of Example 2 and the IR, cis-S-isomer alone are identical, indicating that the product of Example 2 is a conglomerate of the racemic mixture, while the different spectrometer of the product of Example 3 shows that it is a racemic compound.

Example 4

A mixture of cyhalothrin isomers containing 20.61 g of isomer A, 20.61 g of isomer-B / 4.04 g of isomer C and 4.04 g of isomer D is dissolved in hot hexane (100 mL), cooled to 5 ° C and A small amount of the product of Example 3. the mixture is then cooled slowly with vigorous stirring at --5 ° C _D

The precipitate was filtered off, washed on the filter with cold hexane and air dried. There was thus obtained the racemic compound 1R, cis-S- and 1S, cis-R-isomers (28.6 g) m.p. Mp 49-50 ° C.

Example 5

This example illustrates the effect of various solvents, solvent ratios on cyhalothrin, time and temperature on yield and product quality in the form of a racemic mixture (Product I). The cyhalothrin used as starting material contained 42% (+1%) of the 1R-cis-S / 1S, cis-R enantiomeric pair of isomers. In each experiment, several milligrams of crystals of the racemic mixture were added after cooling to the desired temperature as seeds on the crystallizer. The results are summarized in Table I.

Example 6

This example illustrates the precipitation of the racemic compound of the product (Product II). A mixture of technical cyhalothrin (200 g, 95.8% pure) and isopropanol (20 ml) was placed in a round glass flask containing a series of glass beads, cooled to -5 ° C and crystals of the racemic compound (4.0 g) added. ). The cooled mixture was stirred at -5 ° C for 23 hours while turning the flask. The precipitate is filtered off by pouring the mixture into a sintered suction funnel pre-cooled to -5 ° C and the filter cake is washed by trituration with pre-cooled n-hexane (one volume) to give the .alpha.-dried (racemic) compound and 1S, cis-R-isomers of cyhalothrin (39.5 g), m.p. 49.5-50 ° C.

Tab u 1 k and I Try C. Mass Cyhalothrin (G) Solvent / volume (ml) temperature ° C / time (days) Mass precipitates (G) % content 1R, cis-S / 1S, cis-R isomeric pair

1. 5.0 ethanol / , 3/8 0.26 84.3 5.0 2 10.0 n-propanol 3/11 1.03 86.7 10.0 3 50.0 n-propanol 3/12 50.0 and then -10/4 8.7 91.9 4 5.0 n-butanol 3/33 0.14 86.9 5.0 ^: 5 5.0 sec-butanol 3/8 0.41 82.6 5.0 6 10.0 isobutanol 10.0 3/11 1.18 79.0 7 5.0 t-butanol / isopropanol (1: 1) 10.0 3/14 0.64 88.3 8 5.0 n-pentanol 3/33 0.64 68.8 5.0 9 10.0 isopropanol 3/11 0.97 79.1 5.0 10 10.5 n-hexane 0/9 0.61 99.1 .10.0 11 10.0 n-heptane 3/22 0.48 98.6 10.0 12 9.6 n-heptane 3/11 0.73 96.5 10.0 13 10.0 2,2,4-tri- 3/8 1.17 80.3 methylpentane 10.0 14 2 000 n-hexane 0/18 then 406 93,3 ^X - 2 000 -5/7 15+ 200.0 isopropanol 0/7 26,5 ^XX 92.0 200 16+ 204.0 isopropanol 5/7 9,6 ^XX 97.0 200 x After crystallization from petroleum ether (40-60 ° C) weight 281 g.

xx Excluding seed crystal weight + 4.0 g additional seed crystals

Claims (3)

A process for producing a crystalline material consisting of at least 90 wt. an enantiomeric pair of isomers represented by (S) -alpha-cyano-3-phenoxybenzyl (1R, cis) -3- (Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2 -dimethylcyclopropanecarboxylate and (R) -α-cyano-3-phenoxybenzyl (1S, cis) -3- (Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2- % dimethyl cyclopropanecarboxylate in racemic ratios and not more than 10 wt. of any other alpha-cyano-3-phenoxybenzyl-3- (2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2-dimethylcyclopropanecarboxylate isomer, characterized by a concentrated solution of a mixture of isomers % alpha-cyano-3-phenoxybenzyl cis -3- (2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2-dimethylcyclopropanecarboxylate consisting of 40 to 60 wt. an enantiomeric pair of isomers represented by (S) -alpha-cyano -3-Phenoxybenzyl (1R, cis) -3- (Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl) 2,2-dimethylcyclopropane-arbo carboxylate and (R) -alpha- cyano-3-phenoxybenzyl (1S, cis) -3- (Z-2-chloro-3,3,3, -trifluoroprop-1-en-1-yl) -2,2-dimethylcyclopropanecarboxylate and from 60 to 40% by weight . an enantiomeric pair of isomers represented by (R) -alpha-cyano-3-phenoxybenzyl (1R, cis) -3- (Z-2-chloro-3,3,3-trifluoro-1-en-1-yl) -2,2 -dimethylcyclopropanecarboxylate and (S) -α-cyano-3-phenoxybenzyl (1S, cis) -3- (Z-2-chloro-3,3,3, -trifluoroprop-1-en-1-yl) -2,2 -dimethylcyclopropanecarboxylate in an organic solvent selected from lower alkanols containing up to 6 carbon atoms and liquid alkanes containing up to 8 carbon atoms, cooled to a temperature between -20 ° C and +10 ° C, to the cooled solution is added crystals of an enantiomeric pair of isomers, which remain in the solid undissolved state and the solution is maintained at the temperature range for 16 hours to 33 days, whereupon the precipitated crystalline material is separated from the solution and optionally recrystallized until it contains less than 10% by weight. any other isomer of .alpha.-.alpha.-cyano-3-phenoxybenzyl 3- (2-chloro-3,3,3-trifluoroprop-1-en-1-yl) -2,2-dimethylcyclopropanecarboxylate. 2. The method of claim 1 wherein the solution is prepared from a mixture of alpha-cyano-3-phenoxybenzyl cis-3- (2-chloro-3,3,3-trifluoroprop-1-en-1-yl) isomers - 2,2-dimethylcyclopropanecarboxylate and solvent in a ratio of 2: 1 to 1: 6 parts by weight. 3. The process of claim 1 wherein the solvent is isopropanol.