RU2095351C1 - Cyclopropanecarboxylic acid pyrazolides in the form mixture of diastereomers as intermediate compounds for preparation pypetroids - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: present invention describes cyclopropanecarboxylic acid pyrazolides of formula I:

wherein R¹ is Cl, CF₃. Said compounds are used as intermediate compounds for preparation of optically active pyrethroid compounds. Compound I is prepared with yield of 93 % from pyrazole II:

and racemic cyclopropane carboxylic acid III:

Description

где Ia R¹ Cl
Ib R¹ CF₃
в качестве промежуточных соединений при получении пиретроидов.The invention relates to new chemical compounds, in particular pyrazolidides of cyclopropanecarboxylic acids of the formula I

where Ia R ¹ Cl
Ib R ¹ CF ₃
as intermediates in the preparation of pyrethroids.

 The objective of the invention is to improve the method of producing pyrethroids in terms of the choice of intermediate compounds, which will allow to obtain optically active pyrethroid compounds (with a purity of not less than 90 95%) according to a simpler and more technological scheme.

Ранее пиратроиды получали по схеме [1]

где индекс (r) обозначает рацемическая смесь соответствующих соединений.The described compounds I were used under the conditions found to obtain 1R-cis acids (II) with a purity of 90 95% and esters of 1R-cis acids and lower alcohols, from which optically active pyrethroid compounds are obtained

Previously, pirateroids were obtained according to the scheme [1]

where the index (r) denotes a racemic mixture of the corresponding compounds.

Racemic acids II (r) were converted to acid chlorides by the action of thionyl chloride, and the obtained chlorides were used to acylate the alcohol components of R ² OH. In this case, pyrethroid compounds III (r) were obtained as a mixture of enantiomers.

 Racemic ethyl esters of V (r) pyrethroid acids were alkylated with pyrethroid alcohol components in the presence of bases (sodium methylate) to give the pyrethroid compounds III (r) as a mixture of enantiomers.

 The presented scheme has several disadvantages.

По этой схеме рацемические кислоты II(r) обрабатывают оптически активным амином с образованием смеси диастереомерных солей аминов, которые разделяют перекристаллизацией и выделяют диастереомерную соль, содержащую 1R-кислоту. Действием минеральной кислоты полученную соль разлагают и выделяют оптически активную кислоту, которую переводят в хлорангидрид и получают оптически активный пиретроид III.Pyrethroid III (r) contains 50% of the 15 ballast isomer having an activity 2 3 orders of magnitude lower than the corresponding value for the 1R isomer. Given this fact, the activity of the drug is reduced by 2 times, and for the defeat of arthropods, 2 times higher norms of pyrethroid are required in comparison with the pure 1R-isomer. This, in turn, inevitably leads to the accumulation of toxic substances, residues of pyrethroids and their metabolites in the natural environment. In addition, the consumption of pyrethroid alcohol components for the production of the drug with the same specific activity is 2 times higher than that of the 1R drug. Also known is the antagonism of pyrethroid isomers when the presence of the 1S isomer decreases the activity of the 1R isomer [2]
It is also possible to obtain pyrethroids according to the scheme [3]

In this scheme, racemic acids II (r) are treated with an optically active amine to form a mixture of diastereomeric amine salts, which are separated by recrystallization and the diastereomeric salt containing 1R acid is isolated. By the action of a mineral acid, the resulting salt is decomposed and an optically active acid is isolated, which is converted to the acid chloride and the optically active pyrethroid III is obtained.

 The disadvantage of this method is the instability of the amines used to the action of atmospheric oxygen, as well as, as a rule, the high solubility of free amines in water. These facts make it difficult to regenerate expensive optically active amines for reuse.

По этой схеме рацемические кислоты II(r) через хлорангидриды переводят в смесь диастереомерных эфиров оптически активного ментола IX. Разделение диастереомеров осуществляют перекристаллизацией с отделением менее растворимого изомера. Щелочным гидролизом полученного диастереомера выделяют оптически активную кислоту II, которую используют в виде хлорангидрида в синтезе оптически активного пиретроида.It is also possible to obtain pyrethroids according to the scheme [4]

According to this scheme, racemic acids II (r) are transferred via acid chlorides to a mixture of diastereomeric esters of optically active menthol IX. The separation of diastereomers is carried out by recrystallization with the separation of the less soluble isomer. By alkaline hydrolysis of the resulting diastereomer, the optically active acid II is isolated, which is used as the acid chloride in the synthesis of the optically active pyrethroid.

The disadvantages of this method are the high cost of D - (+) - menthol X, used for the separation of racemic mixtures of 1R-acids, the resistance of menthol esters to hydrolysis. In connection with the latter fact, hydrolysis is carried out by autoclaving in methanol solutions of alkali at 120 ^o C for 6 hours, which implies the need for sophisticated technological equipment and significant energy costs. In addition, long-term treatment of compounds containing a halogen vinyl fragment with bases at elevated temperature can lead to the elimination of hydrogen chloride and the appearance of an impurity of acetylene compounds [5], which reduces the quality of cyclopropanecarboxylic acid II.

Раствор пиразола IV и рацемической циклопропанкарбоновой кислоты II(r) в эфире в присутствии триэтиламина обрабатывают хлористым тионилом и выделяют пиразолид I с выходом 93% в расчете на кислоту.New intermediate compounds receive according to the scheme

A solution of pyrazole IV and racemic cyclopropanecarboxylic acid II (r) in ether in the presence of triethylamine is treated with thionyl chloride and pyrazolid I is isolated in 93% yield based on acid.

 The use of the claimed compounds I allows one to separate racemic cyclopropanecarboxylic acids and obtain 1R-cis acid with a purity of 90-95% by hydrolysis of diastereomeric compounds II in aqueous-alcoholic solutions of alkali; the use of the claimed compounds I after separation of the diastereomers allows to obtain alcoholically in the environment of lower alcohols in the presence of dry hydrogen chloride optically active esters of cyclopropanoic acids V, which are intermediate compounds in the preparation of pyrethroids.

где индекс (d) здесь и далее по тексту обозначает единственный диастереомер, а именно (2'R, 4'S).

where the index (d) hereinafter denotes the only diastereomer, namely (2'R, 4'S).

Таким образом, предлагаемая новая общая схема синтеза пиретроидов через соединения I имеют вид

Преимущества пиразолидов I по сравнению с известными соединениями заключаются в следующем.The use of the claimed compounds I after separation of diastereomers makes it possible to obtain optically active pyrethroid preparations permethrin III (a) and bifentrin III (b) with a purity of 90-95% by alcoholysis in the environment of pyrethroid alcohol components in the presence of dry hydrogen chloride

Thus, the proposed new general scheme for the synthesis of pyrethroids through compounds I have the form

The advantages of pyrazolides I in comparison with the known compounds are as follows.

1. The high availability of intermediate compound I. Pyrazole IV, used in the synthesis of pyrazolides I, is an available compound. Pyrazole IV is synthesized from (+) - 3 karen, which is a large-capacity product of the chemical industry, using inexpensive reagents with a yield of 76% [6-7]
2. Technological advantages in the preparation of intermediates. The chemical stability of pyrazole IV with respect to most oxidizing agents is significantly higher than that of the known amines used to break down racemic acids. In addition, pyrazole IV has very low solubility in water, which also distinguishes compound IV from most amines of cleavage agents. The chemical stability of pyrazole IV and its low solubility in water facilitates its regeneration for reuse. The preparation of intermediates I is carried out in one step with a yield of 93% by treating a mixture of pyrazole IV and cyclopropanecarboxylic acid with thionyl chloride in the presence of triethylamine (examples 1, 2), in contrast to the two-stage synthesis of menthol esters IX.

 3. Advantages in obtaining isomeric intermediates of pyrethroids. The use of pyrazolides of cyclopropanecarboxylic acids Ia, b allows after recrystallization and saponification to obtain 1R-cis acid with a purity of 90-95% (examples 5, 6). The hydrolysis of pyrazolides I (d) is carried out under much milder conditions than the hydrolysis of the known menthol esters IX and does not require complex technological equipment. The alcoholysis of pyrazolides I (d) in lower alcohols is also easily feasible and makes it possible to obtain, under mild conditions, the corresponding optically active esters of 1R-cis cyclopropanecarboxylic acids Va, b with a purity of 90-95% (examples 7, 8), which are intermediate compounds for the preparation of pyrethroids . Both as a result of hydrolysis and as a result of alcoholysis of pyrazolides I (d), it is possible to regenerate pyrazole IV used in the synthesis of pyrazolides.

 4. Advantages in obtaining pyrethroid drugs (examples 9, 10). Alcoholysis of pyrazolides I (d) in the environment of pyrethroid alcohol components - alcohols VI and VII is carried out in high yield and at the same time regeneration of the pyrazole cleavage agent. Moreover, instead of the three stages 1) saponification of the diastereomeric compound to obtain cyclopropanecarboxylic acid; 2) obtaining acid chloride; 3) the acylation of the pyrethroid alcohol component and the production of the pyrethroid are used only stage: alcoholysis of pyrazolid I (d).

 The invention is demonstrated by the following examples.

Example 1. Obtaining a mixture of diastereomers of the pyrazolide cis-Z-cygalothrinic acid Ib To a solution of 24.3 g of racemic cis-Z-cygalothrinoic acid IIb (r) and 17 g of pyrazole IV in 100 ml of benzene and 11 ml of triethylamine at 10 ^° C. was added 6.54 g of thionyl chloride with stirring. The mixture was stirred at room temperature for 3 hours, washed with 1M HCl solution (50 ml), 0.5 M Na ₂ CO ₃ solution (30 ml), dried with anhydrous sodium sulfate and, after evaporation, 36.0 g (93%) of the mixture was obtained diastereomers of pyrazolid cis-Z-cyhalothrinic acid Ib.

Example 2. Obtaining a mixture of diastereomers of pyrazolid cis-permethric acid Ia. To a solution of 20.9 g of racemic cis-permethric acid IIa (r) and 17 g of pyrazole IV in 100 ml of benzene and 11 ml of triethylamine at 10 ^° C., 6.54 g of thionyl chloride are added with stirring. The mixture was stirred at room temperature for 3 hours, washed with 1 M HCl solution (50 ml), 0.5 M Na ₂ CO ₃ solution (30 ml), dried with anhydrous sodium sulfate and an evaporation field gave 33.0 g (93.5 %) mixtures of diastereomers of pyrazolide cis-permethric acid Ia.

Example 3. Obtaining the diastereomer of the pyrazolide 1R-cis-Z-cygalothrinic acid Ib (d), 100 ml of a benzene solution containing 36.0 g of the diastereomeric mixture of the pyrazolide of cis-Z-cygalothrinic acid Ib obtained according to example 1, after the stage of drying with anhydrous sulfate sodium, diluted with 100 ml of methanol and cooled to -5 ^° C and 16.7 g (92.7%) of a light yellow viscous oil were separated, which contained, according to NMR spectra, at least 90% of the pyrazolid 1R-cis-cygalotrinic acid diastereomer Ib d) The resulting product has the following characteristics:
[α] $\genfrac{}{}{0ex}{}{\text{19}}{\text{578}}$ + 190 ^o (s 9.9, CHCl ₃ )
¹ H NMR (200 MHz, δ ppm): 2.21 s (3H-1); 2.733 ddd (a 5); 3.013 ddd (b H 5); 1.75 m (H 5, H -6); 1.07 s (3H 9); 0.673 s (3H - 10); 3.424 d (H 2); 2.358 dd (H 4 '); 6.921 dq (H 5 '); 1.325 s (3H - 7 '); 1.370 s (3H 8 '). NMR ¹³ C 'd ppm 50.32 MHz) 12.8 sq. 148.19 p. 131.20 s; 152.27 t; 27.13 t; 34.91 d; 25.63 d; 21.89 s; 26.19 sq; 13.59 sq; 167.86 s; 32.83 d; 30.87 s; 31.13 d; 129.94 d; 121.69 s; 28.33 sq; 14.66 sq; 120.36 sec

Example 4. Obtaining pyrazolid 1-R-cis-permethric acid Ia (d). 100 ml of a benzene solution containing 33.0 g of a diastereomeric mixture of pyrazolide cis-permethric acid Ia, obtained according to example 2, after the drying step with anhydrous sodium sulfate, diluted with 100 ml of methanol, cooled to -5 ^o C and separated 15.2 g (92 , 0%) light yellow crystals containing, according to NMR spectra, at least 95% of the pyrazolid diastereomer of 1R-cis-cygalothrinic acid.

 The resulting product has the following characteristics.

[α] $\genfrac{}{}{0ex}{}{\text{22}}{\text{578}}$ + 184 ^o (s 11, CHCl ₃ ); t _square 89-90 ^o C.

¹ H NMR (200 MHz, CHCl ₃ , δ m.); 2719 s (3H 1); 2.775 ddd (a 5-); 3.00 ddd (b 5); 1.74 m (H 6, H 7); 1.06 m (3H 9); 0.67 s (3H 10); 3.280 d (H 2 '); 2.192 (H 4 '); 6.304 d (H 5 '); 1.288 s (3H 7 '); 1.313 s (3H 8 ') ¹³ C NMR (d ppm 50.32 MHz); 12.78 sq; 147.86 s; 130.92 s; 152.15 t; 27.14 t; 34.89 d; 25.64 d; 217.5 s; 26.21 sq; 13.59 sq; 168.11 s; 30.08 s; 29.89 s; 34.77 d; 124.68 d; 120.65 s; 28.34 sq; 14.68 sq. M.

 Example 5. Obtaining 1-R-cis-Z-cyhalothrinic acid IIb. To a solution of 3.86 g of pyrazolid 1-R-cis-Z-cyhalothrinoic acid Ib (d) in 50 ml of methanol is added a solution of 0.7 g of KOH in 10 ml of methanol and after 5 minutes 50 ml of water are added with stirring. The resulting mixture was boiled for 3 hours with stirring. Methanol was evaporated under reduced pressure, and the cooled mixture was diluted with water (100 ml) and extracted with methylene chloride (2x30 ml). After drying with anhydrous sodium sulfate and evaporation of the solvent under reduced pressure, 1.38 g (85.2%) of pyrazole IV are obtained in the form of yellowish crystals. The aqueous phase was acidified with concentrated hydrochloric acid (5 ml), saturated with sodium chloride and extracted with chloroform (2x30 ml). After drying with anhydrous sodium sulfate and evaporating the solvent under reduced pressure, 2.21 g (91%) of 1-R-cis-Z-cyhalothrinic acid IIb are obtained in the form of white crystals.

[α] $\genfrac{}{}{0ex}{}{\text{twenty}}{\text{578}}$ +39.5 (s 2.8, CHCl ₃ ).

 Example 6. Obtaining 1-R-cis-permethric acid IIa. To a solution of 3.5 g of pyrazolid 1-R-cis-permethric acid Ia (d) in 50 ml of methanol, a solution of 0.7 g of KOH in 10 ml of methanol is added and after 5 minutes 50 ml of water are added with stirring. The resulting mixture was boiled for 3 hours with stirring. Methanol was evaporated under reduced pressure, and the cooled mixture was diluted with water (100 ml) and extracted with methylene chloride (2x30 ml). After drying with anhydrous sodium sulfate and evaporation of the solvent under reduced pressure, 1.35 g (83.3%) of pyrazole IV are obtained in the form of yellowish crystals. The aqueous phase was acidified with concentrated hydrochloric acid (5 ml), saturated with sodium chloride and extracted with chloroform (2 • 30 ml). After drying with anhydrous sodium sulfate and evaporation of the solvent under reduced pressure, 1.95 g (93%) of 1-R-cis-permethric acid IIa are obtained in the form of white crystals.

[α] $\genfrac{}{}{0ex}{}{\text{21}}{\text{578}}$ +29.0 (s 8.8, CHCl ₃ ).

 Example 7. Obtaining ethyl ester of 1-R-cis-Z-cygalothrinic acid Vb. Dry gaseous hydrogen chloride was blown into 50 ml of ethanol in a solution of 3.86 g of pyrazolid 1-R-cis-Z-cyhalothrinic acid IIb (d) for 1.5 hours. The reaction mixture was evaporated in vacuo, diluted with 150 ml of 1M hydrochloric acid and extracted with diethyl ether (2x30 ml). The organic extract was dried with anhydrous sodium sulfate and, after evaporation of the solvent, 2.30 g (85.3%) of 1-R-cis-Z-cyhalothrinic acid Vb ethyl ester were obtained as a slightly colored oil. 30 ml of concentrated aqueous ammonia was added to the acidic pharesis and the resulting mixture was extracted with chloroform (2x20 ml). The organic extract was dried with anhydrous sodium sulfate and, after evaporation of the solvent, 1.35 g (83.3%) of pyrazole IV were obtained in the form of yellowish crystals.

 Example 8. Obtaining ethyl ester of 1-R-cis-permethric acid Va. Dry gaseous hydrogen chloride was blown into a solution of 3.5 g of pyrazoline 1-R-cis-permethric acid Ia (d) in 50 ml of ethanol for 1.5 hours. The reaction mixture was evaporated in vacuo, diluted with 150 ml of 1M hydrochloric acid and extracted with diethyl ether (2x30 ml). The organic extract was dried with anhydrous sodium sulfate and, after evaporation of the solvent, 2.05 g (86.4%) of 1-R-cis-permethric acid ethyl ester Va was obtained as a slightly colored oil. 30 ml of concentrated aqueous ammonia was added to the acidic aqueous phase, and the resulting mixture was extracted with chloroform (2x20 ml). The organic extract was dried with anhydrous sodium sulfate, and after evaporation of the solvent, 1.4 g (87.5%) of pyrazole IV were obtained as yellowish crystals.

Example 9. Obtaining 1R-cis-bifentrin IIIb. In a solution of 3.9 g of pyrazolid 1-R-cis-Z-cyhalothrinoic acid Ib (d) and 3.0 g of 2-methyl-3-phenylbenzyl alcohol VI in 15 ml of chloroform, dry hydrogen chloride is blown for 1.5 hours. The reaction mixture was evaporated under reduced pressure, 1M hydrochloric acid (100 ml) was added to the residue, and extracted with benzene (2x75 ml). The organic extracts were combined, washed with saturated NaCl (100 ml), dried with anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude product was purified by silica gel chromatography (eluent pentane-benzo 10: 1) and 3.28 g (75%) of 1-R-cis bifentrin IIIb were obtained after evaporation in the form of yellowish crystals with a melting point of 70-71 ^° C. After extraction, 1 ml of concentrated aqueous ammonia was added to the acidic aqueous phase and the resulting mixture was extracted with chloroform (2x20 ml). The organic extract was dried with anhydrous sodium sulfate and, after evaporation of the solvent, 1.34 g (83%) of pyrazole IV were obtained in the form of yellowish crystals.

Example 10. Obtaining 1R-cis-permethrin IIIa. In a solution of 3.5 g of pyrazolid 1-R-cis-permethric acid Ia (d) and 3.0 g of 3-phenoxybenzyl alcohol VII in 15 ml of chloroform, dry hydrogen chloride was blown for 1.5 hours. The reaction mixture was evaporated under reduced pressure , 1 M hydrochloric acid (100 ml) was added to the residue and extracted with benzene (2x75 ml). The organic extracts were combined, washed with saturated NaCl (100 ml), dried with anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude product was purified by silica gel chromatography (eluent-pentane-benzene 10: 1), and, after evaporation, 3.20 g (76%) of 1-R-cis permethrin IIIa were obtained as a white crystalline mass with a melting point of 64-65 ^° C.

 After extraction, 30 ml of concentrated aqueous ammonia are added to the acidic aqueous phase and the resulting mixture is extracted with chloroform (2x20 ml). The organic extract was dried with anhydrous sodium sulfate and, after evaporation of the solvent, 1.34 g (83%) of pyrazole IV were obtained in the form of yellowish crystals.

Claims (1)

Cyclopropanecarboxylic pyrazolides as a mixture of diastereomers

where R ¹ chlorine or R ¹ CF ₃ ,
as intermediates in the preparation of pyrethroids.