HU199386B - Process for producing optically active or raceme chlorides of cyclopropane-carboxylic acid - Google Patents

Abstract

The present invention relates to the preparation of cyclopropanecarboxylic acid chlorides of formula (I), wherein the line represents the α or β spacing relative to the cyclopropane ring plane, A represents a halogen atom, or a C 1-4 alkyl group such that dimethylformamide is 0; -30 * C is reacted with thionyl, phosphoryl, oxalyl or phosphorus chloride in a molar ratio of 1: 1 to 1: 0.25. then, without isolation, the resulting complex is reacted at 0-30 ° C with the appropriate cyclopropanecarboxylic acid and the pure acid halide or its (apolar aprotic) solvent solution selectively separated from the separated liquid phase and contaminated with it by the difference in phase specific gravity between the phases; to separate. Scope of the description: 5 pages, Figure 2 COCl HU 199 386 A -1-

Description

The present invention relates to a novel process for the preparation of cyclopropane carboxylic acid chlorides which are intermediates in pyrethroid synthesis.

Synthetic pyrethroids are a common insecticide these days. Several processes are known for their preparation (e.g., Hungarian Patent Application T / 39077, Hungarian Patent Publication No. 197,292, etc.) In the most common processes, cyclopropanecarboxylic acid derivatives have been esterified, under mild conditions, to alcohol or by activating the acid component. The most obvious of these methods is the use of cyclopropanecarboxylic acid chlorides (eg Hungarian Patent No. 170,866).

However, known methods for preparing carboxylic acid chlorides have several disadvantages. The aforementioned sensitivity of the compounds, their high propensity for isomerization and decomposition, severely limit the applicability of these processes, e.g., 5-10% of cis-trans isomerization is observed under the mildest conditions in conventional thionyl chloride production. because of the very large differences in the biological potency of the isomers. (British Patent Application 1,540,632, Pestic.Sci, 1978, 9,112-116; Pestic Sci (1980), 11,169-179, 067,461).

The product thus obtained, without purification, due to the presence of decomposition products and traces of acid, can only be used to a great extent in the preparation of pure, high-quality piertroids. Of the methods available for purification, only fine vacuum distillation is industrially applicable, but due to the sensitivity of the product, highly acidic distillation conditions cause great losses.

The decomposition of optically active compounds is clearly explained by the catalytic action of the strong acids formed or present in the reaction. The above statement can be generalized as the chemical property of cyclopropanecarboxylic acids. (Tetrahedron Letters, Vol 25, No 15, 15951598,1984).

A further step was the use of dimethyl- (acyloxymethylidene-diene) -ammonium-5O (IV) as an activated derivative of cyclopropanecarboxylic acid (Hungarian Patent No. 180,444). In the examples, dimethylformamide is reacted with oxalyl chloride or phosgene in anhydrous acetonitrile or toluene at -20 ° C to 0 ° C, and the resulting slurry is further reacted with the cyclopropanecarboxylic acid components at -15 ° C to give a mixture of -20 ° C. This process provided tetramethrin, permethrin and cinnerin in a very simple manner without degradation or isomerization of the starting material or the activated acid derivatives formed as the product. However, the reaction mixture, since the "waste acid" produced by the reagent is always present in the system in a complex form during activation, is not harmless. Activated acid derivatives should not be stored as they may undergo self-catalyzed decomposition in the presence of certain contaminants, primarily metal, which may cause an explosion even at room temperature. A further disadvantage is that the patent examples show that the esterification step requires a large excess of organic base (e.g. pyridine) to neutralize the "waste acid" liberated, which increases the cost and complicates the processing. Due to the direct use of the reaction mixture for esterification, the lack of a purification step, the impurities formed and accompanying by-products can be incorporated directly into the pyrethroid end product. For this activated acid derivative, the unfavorable effect of DMF liberated in the esterification step can also lead to side reactions, especially when the alcohol moiety is prepared by pyrethroids containing a cyano substituent by reaction with water, water soluble cyanides, and appropriately substituted aldehydes (e.g. method).

The present invention relates to a process for the preparation of optically active or racemic cyclopropanecarboxylic acid chlorides of formula (I) by reacting cyclopropanecarboxylic acids of formula (Π) with a complex of formula (módon) by reacting dimethylformamide with 0-30 ° C. onion, thionyl, phosphoryl, oxalyl or phosphorus chloride in a 1: 1 to 1: 0.25 molar ratio, in the presence or absence of a diluent in an organic aprotic solvent, followed by isolation of the resulting complex of formula (ap) with apolar aprotic organic diluent in the presence or absence of a solvent at 0 to 30 ° C with cyclopropanecarboxylic acid (Π), optionally settling the resulting emulsion and separating the pure acid halide (I) or apolar polar aprotic solvent solution as a separate liquid phase Formula (V) is selectively separated from the complex and the impurities dissolved therein by the difference in weight between the phases

In the patent, the variable substituents are always the following:

A - halogen or C 1-4 alkyl,

Y is chlorine, or -OSOC1, -OPOC12, or OPCl2

- _ represents the α or B position relative to the plane of the cyclopropane ring,

Y ^r - OH, OSO2H, -OPOCl (OH), -OPO (OH) 2, OPC1 (OH), -OP (OH) 2 or -OPOCl2 group.

The present invention is based on the discovery that, under appropriate conditions, the cyclopropanecarboxylic acid is completely present as chloride of formula (I) above 0 ° C. In the reaction of 2,2-dichloro-vinyl-3,3-dimethyl-cyclopropanecarboxylic acid, the characteristic IR band of the product isolated at 0 ° C is vC-0 0 1779-1781 cm- ¹ and is identical to that of the acid chlorides. The infrared spectrum of acid chloride prepared in a standard manner was completely identical to that of the product. NMR of the compound at 0 ° C also showed the presence of acid chloride only. The molecular weight calculated from the weight of the sample and its esterification clearly gave the molecular weight of the acid chloride.

It has also been found that the waste acid formed as a by-product of the reaction is immediately complexed with the dimethylformamide present,

With the correct choice of the amount of -2-dimethylformamide, it can be completely sedimented and separated.

Small amounts of contaminating decomposition products are soluble in the highly polar DMF complex phase and can also be separated together to obtain a completely pure acid chloride. This is all the more important as it safely yields a product of absolute purity above 98% which is further purified e.g. its distillation is redundant.

By carrying out the reaction with several differently substituted cyclopropanecarboxylic acids, no significant difference was observed either in the course of the reaction or in its separability. This is surprising because, in the case of other carboxylic acids, the acid halides formed form a homogeneous solution with the resulting waste acid complex and thus cannot be prepared. This issue is explained by the surprising apolarity of the acid chloride (I) formed in the reaction, which is special because of its expected "poor" solubility and complexation properties. The present invention is based on the recognition and targeted use of these properties.

It has been found very advantageous of the present invention to react dimethylformamide with phosphoryl chloride in a 1: 1-0.9 molar ratio or thionyl chloride in a 1: 1-0.4 molar ratio.

The reaction may be carried out using dimethylformamide as the diluent. The amount of dimethylformamide used as reagent and diluent is preferably not more than 4 moles per mole of the starting cyclopropanecarboxylic acid of formula (Π).

Increasing the amount of dimethylformamide gradually changes the emulsion into a homogeneous solution. In parallel, the amount and purity of the acid halide that can be recovered is reduced. Generally, more than 4 equivalents of dimethylformamide are difficult to use because of the solubilizing action of both phases by uncomplexed dimethylformamide.

Although no additional solvent is generally required, phase separation can be improved by the addition of highly apolar aprotic solvents which dissolve only the acid-halide phase. The diluent may be one or more halogenated hydrocarbons having from 1 to 12 carbon atoms, optionally halogenated. -5 hairs. Hyen solvents e.g. hexane, heptane, petroleum ether, cyclohexane, carbon tetrachloride, etc. Again, increasing polarity is disadvantageous.

For the reaction with cyclopropanecarboxylic acid, the complex of formula (ΙΠ) is used in an amount such that the ratio of the number of halogen atoms in the Y group is 1 to 1.5: 1 per mole of cyclopropanecarboxylic acid of formula (Π).

The main advantages of our procedure:

The reaction can be easily scaled and commercialized using industrial grade reagents. There is no need for complete dehydration of the reagents, and using a small excess of halogenating agent can easily solve the problem. When using polyvalent halogenating agents, the active halogen content can be fully utilized, in accordance with the stoichiometric ratios of these types of reagents used in the "conventional" acid chloride production. The carboxylic acid activation reaction is very fast and poorly endothermic, preferably at room temperature. At temperatures above 10-20 ° C, decomposition is already detectable, mainly due to the instability of the waste acid complex of the reagent and the highly acidic medium. The reaction yields the product in about 95% yield, and even after the hydrolysis of the waste acid, the 1-5% cyclopropanecarboxylic acid lost in the separation can be easily recovered from the hydrolyzate and recycled. The yield of the method is thus practically quantitative. Depending on the halogenating agent, the product is generally in the upper phase so that, after separation of the waste acid, it can be esterified in the same reaction vessel by the addition of a solution of 1 equivalent of an organic amine and alcohol component. Due to its quality, pyrethroids containing a cyano substituent at the α-position of the alcohol moiety, e.g. cypermethrin, deltamethrin, cyhalothrin, cyphenothrin, etc. also known in the production of one step.

The situation is particularly favorable for the preparation of optically active acid halides, since the compounds do not undergo any isomerization. Due to its purity, the product obtained can be stored for many years without the slightest sign of degradation.

The process we have developed in this way is easy to carry out in several kilos. The product quality obtained is very much above 98-99%.

Without limiting the scope of our patent, the following examples illustrate the process.

The purity values reported in the Examples were argentometric, potentiometric titration, and after methanol esterification by HPLC (Perkin Elmer, Colonna: 250 x 4.6 mm Spherisorb ODS, 10 μ eluent: 60% methanol in 40% aqueous buffer (ph 25), (detector LC-75, (225nm).

Example 1

Dimethylformamide (95 g, 100 mL, 1.3 mol, 1.3 eq.) Was added to a stirred apparatus at room temperature, cooled to -10 ° C with vigorous external cooling, and 160 g (96 mL, 1 mL) was added with vigorous stirring and cooling. 04 moles, 1.04 eq.) Of phosphorus chloride at a rate such that the temperature of the mixture gradually rises to 20 ° C by the end of the addition. After stirring for 30 min, 210 g (1 mol, 1 eq) of cis-2,2-O11 -11- [3- (2-dichloro-vinyl) -cyclopropanecarboxylic acid are added. After addition, the reaction mixture remains stable at room temperature for 2 hours, then the resulting emulsion is settled for 1 hour and the lower phase is left on 1 kg of crushed ice. The upper colorless phase is separated off.

218 g of 99% absolute purity of isomerically pure cis -2,2-dimethyl-3- (2 ', 2'-dichloro-vinyl) -cyclopropanecarboxylic acid chloride are obtained.

Found: C, 42.02; H, 3.95; Q, 46.82. C8H9d3OMe227J2 requires C, 42.23; H, 3.98; Cl, 46.74.

-3The isomeric purity or. The drug content was determined by HPLC and argentometric and potentiometric titration.

Yield: 95%. The hydrolyzed waste acid phase was filtered off after cooling. The resulting target stock was dried. The 8 g pale yellow crystalline material was recrystallized from the next reaction in 99% yield.

Example 2 10

In the same manner as in Example 1, 300 g (1.00 moles) of cis 2,2-dimethyl-3- (2 ', 2'-dibromovinyl) cyclopropanecarboxylic acid and 100 ml of n- of hexane. 368 g of a colorless viscous acid chloride-hexane solution are obtained. Titration and HPLC as described above give 82% by weight of cis-2,2-dimethyl-3- (2 ', 2'-dibromo-vinyl) -cyclopropanecarboxylic acid. chloride and 18% n-hexane. Yield 95%. A small portion of the resulting material was evaporated in vacuo and analyzed

CeHgBrcClO.Ms 316.54 theory: C: 30.35%, H: 2.86%, Cl: 11.20% found: G 30.00%, H: 2.92%, Cl: 11.28%.

Example 3

The procedure of Example 1 was followed, except that 210 g (1 mol) of (+) - cis-2,2-dimethyl-3-1,2 ', 2'-dichloro-methyl) -cyclopropanecarboxylate ( [α] D = 31.3 ', c-1, CHCl 3). 30.219 g of 99% pure (+) - cis-2,2-dimethyl-3- (2 ', 2-dichloro-vinyl) -cyclopropanecarboxylic acid chloride are obtained.

H, 3.98; Cl, 46.74; 35 Found: C, 42.15; H, 4.06; Cl, 46.81.

A small amount of the acid chloride is hydrolyzed with water and the resulting optical rotation is measured [α] ²⁵ D - 31.3 (c-1,

CHCb) i.e. no isomerization during the conversion. Yield 95%. 40

Example 4

The procedure of Example 1 was followed, except that 170 g (1.00 mol) of trans-chrysanthemic acid was added. 180 g of 98% pure trans-chrysanthemic acid chloride are obtained in 95% yield.

CioHisCIO.Ms 186.68.

H, 8.09; Cl, 18.99; Found: C, 64.28; H, 8.06; Cl, 19.02. 50

Example 5

10 ml of carbon tetrachloride, 170 ml (160.5 g2.19 moles, 2.19 eq.) Of dimethylformamide are added to a stirred apparatus, and then cooled to -10 ° C with vigorous cooling and vigorous stirring. ml (131.5 g,

1.10 mol, 1.10 equiv.) Of thionyl chloride. The mixture was stirred for an additional 30 minutes and 210 g (1 mol, 1 quart) of trans-2,2-dinyl-ethyl (2 ', 2'-dichloro-60-vinyl) -cyclopropanecarboxylic acid were added. After stirring at room temperature for 2 hours and settling for 2 hours, the lower phase was separated to give 2.28 g of trans-2,2-dimethyl- (2 ', 2'-dichloro-vinyl) -cyclopropanecarboxylic acid chloride, containing 7% carbon tetrachloride. winter oil. Purity: 931%.

CgHgCbO.Ms 227.52

Elemental analysis of evaporated sample: C, 42.23%, H, 3.98%, Cl: 46.74%, Found: G 42.18%, H: 3.94%, Cl: 46.92%.

IR (CCl4) v C-01 781 cm ^r

NMR (CDCl3) δ (ppm) -1, 30, d (6H) 2CH3,2,20, d (1H)

Cl; 2.40 g (1H) C3; 5.60, d (1H) -CH; Ji.3-5.2Hz, Jch.3H-7.7Hz

Yield: 95%.

Example 6

85 ml (80.25 g 1.1 mol, 1.1 eq.) Of dimethylformamide were added to the stirring apparatus, followed by the addition of 131, Sg (80.2 ml, 1.1 mol, 1.1 eq.) Thionyl chloride and the solution is stirred at room temperature under vacuum for 3 hours to give a thick slurry. 210 g (1 mol, 1 eq) of cis-2,2-dimethyl-3- (2 ', 2'-dichloro-vinyl) -cyclopropanecarboxylic acid are added with good stirring and the mixture is reacted for 2 hours at room temperature and then separated after settling. lower phase. Colorless cis-2,2-dimethyl-3- (2 ', 2'-dichloro-vinyl) -cyclopropanecarboxylic acid chloride (oil) (215 g, 94%) was obtained. Purity 98%.

Found: C, 42.19; H, 4.05; Cl, 46.81. Found: C, 42.13; H, 3.98; Cl, 46.74;

Example 7 A mixture of 140 g (1.10 moles, , 10 eq) oxalyl chloride. The suspension is stirred for 30 minutes at -10'C and 210 g (1.0 mole, 1.0 eq) of trans-2,2-dimethyl-3- (2 ', 2'-dildorovinyl) -cyclopropanecarboxylic acid are added at room temperature and stirring at room temperature for 3 hours. During this time, the suspension gradually becomes an emulsion. The mixture was allowed to settle and the upper layer elválasztjuk344g colorless trans-2,2-dimethyl-3- ^{(2, 2-dichloro-vinyl)} cyclopropanecarboxylic acid chloride as acid chloride tar CONTENTS 61.6%. The resulting acid chloride has the same IR and NMR spectra as in Example 5.

Yield: 93%.

Example 8 Dimethylformamide (19 g, 0.26 mol, 2.6 eq.) Was cooled to -10 ° C with vigorous stirring.

Phosphorus trichloride (5.9 mL, 9.3 g, 67 mmol, 0.67 eq.) Was added dropwise to bring the reaction temperature to 20 ° C at the end of the addition. After stirring for 30 minutes, 16.8 g (0.1 mol, 1 eq) of chrysanthemic acid are added. After stirring for 2 hours and then settling for 1 hour, the upper phase was separated to give 18.2 g of a colorless oil of chrysanthemic acid chloride (97.5%).

Analysis: Calculated for C 10 H 18 GO, MS-186.68, G 64.33%, H: 8.09%, Cl: 18.99%, Found: C: 64.29%, H: 8.12%, Cl: 19 05%.

Active ingredient content: 971%.

Example 9

To 95 g (100 ml, 1.3 mol, 1.3 eq) of dimethylformamide-48 was added 108.3 g (0.52 mol, 052 eq) of phosphorus pentachloride at -10 ° C. After stirring for 30 min at 20 ° C, 210 g (1 mol, 1 eq) of dis-2,2-dimethyl-342 ', 2'-dichloro-vinyl) -cyclopropanecarboxylic acid are added. After stirring for 2 hours, the emulsion is settled for 1 hour and the lower phase is left on 1 kg of crushed ice. The upper colorless phase is separated off 215 g of this product were 991% absolute purity, isomerically pure cis-2,2-dimethyl-3- (2 ^', 2'-dichlorovinyl) cyclopropane carboxylic acid chloride.

Analysis: Found: C: 42.23%, H: 3.98%, Cl: 46.74% Found: C: 42.12%, H: 3.90%, Cl: 47.05%.

Yield: 93.7%.

Claims (5)

A process for the preparation of optically active or racemic cUdopropane carboxylic acid chlorides of the formula I: - a line representing a space or a β relative to the plane of the cildopropane ring, A is halogen or alkyl having 1 to 4 carbon atoms, by reaction of a cyclopropanecarboxylic acid of formula (szel) with a complex of formula (ΠΙ) -A has the meaning given above while Y is chlorine or -OSOC1, -OPOC12. or -OPCl 2, wherein the dimethylformamide is reacted at 030 ° C with thionyl, phosphoryl, oxalyl, or phosphorus chloride in a 1: 1 to 1: 0.25 molar ratio, optionally in the presence of a diluent, and The compound of formula (lex) - A represents the above complex without isolation, optionally in the presence of a non-polar aprotic organic solvent as the diluent at a temperature of 0-30 ° C with cyclopropanecarboxylic acid of formula () - A is the above-mentioned optional emulsion, then the pure acid chloride of the formula I is precipitated -A represents a solution of the above or its polar aprotic solvent from the complex formed by the by-product, which is separated into a separate liquid phase - - ^Y1 is pursuant -OH -OSO2H, -OPOCl (OH) OPO (OH) 2, -OPC1 (OH), -OP (OH) 2 or -OPOCfccsoport and the dissolved contaminants in specific gravity difference between the phases selectively separated. 2. A process according to claim 1 wherein the dimethylformamide is reacted with phosphoryl chloride in a molar ratio of 1: 1 to 1: 0.9 or thionyl chloride in a molar ratio of 1: 1 to 1: 0.4. 3. A process according to claim 1 wherein the diluent used is dimethylformamide and the total amount of dimethylformamide used as diluent is up to 4 moles of the starting compound of formula (Π). -A is based on the above moles of cyclopropanecarboxylic acid. Process according to claim 1 or 2, characterized in that the diluent is an organic aprotic solvent, preferably in the range of 0.1 to 5 times by weight based on the weight of the acid halide of formula (I), optionally halogenated hydrocarbon. 5. A process according to any one of claims 1 to 3, wherein the complex of formula (ΠΙ) is reacted with cyclopropanecarboxylic acid - Y is used in an amount such that the ratio of the number of halogens in the Y to the cyclopropanecarboxylic acid of formula (Π) A is 1-1.5: 1, based on the moles above.