PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE OR RACEMIC CYCLOPROPANE-CARBOXYLIC-ACID CHLORIDES

Abstract: The present invention relates to a new process for the preparation of cyclopropane carboxylic acid chlorides of formula (I), wherein A is a halogen atom or a C1-4 alkyl group, line SIMILAR is indicating an alpha or beta space position compared to the plane of the cyclopropane ring. The compounds of formula (I) are intermediates of the pyrethroide synthesis.

Description: PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE OR RACEMIC CYCLOPROPANE-CARBOXYLIC-ACID CHLORIDES The present invention relates to a new process for the preparation of cyclopropaπe-carboxylic acid chlorides which are intermediates of the pyrethroide synthesis. The synthetic pyrethroides are wide-spread insec- ticides of the present days. Several processes are known to their preparation (e.g. Hungarian Application No. 55/85 and Hungarian Patent Specification No. 197,292 1, etc.). In the course of the most wide-spread industrial processes the cyclopropaπe-carboxylic-acid derivatives were esterificated - taking in consideration the sensi- vity of these compounds - under very mild conditions by the activation of the alcohol and the acide component respectively. Between these methods the application of cyclopropane-carboxylic-acid chlorides is the most obvious (e.g. Hungarian Patent Specification No. 170,866). Between the known methods to the preparation of carbonic-acid chlorides coming in consideration most of them have many disadvantages. The application of these processes is very much limited by the mentioned sensi¬ tivity and inclination to isomerizatioπ and decomposi¬ tion of the compounds. E.g. at the conventional prepara¬ tion of cis-permetrine-acid chloride with thionylchloride even under the most mild conditions a 5-10 % cis-traπs isomerisation can be observed, which means a great dis¬ advantage because of the great difference in the bio¬ logical efficacy of the individual isomeres (British Applaication No. 1,540,632, Pestic. Sci. (1978), _9, 112-16; Pestic. Sci., (1980), _U, 169-179, European Application No. 067,461). The product thus obtained can be applied only very circumstantially without further purification because of the decomposition products and traces of acid being present. The above statement can be generalized as chemical property of the cyclopropane-carboxylic-acids. To th preparation of pyrethroides of a good quality amongst the methods co ing in consideration industrially only the fine vacuum distillation can be used for purifi¬ cation. On the other hand because of the high sensibility of the product the highly acidic distillation circum¬ stances are causing great losses. In the case of optically active compounds the decomposition is unambiguously cleared and it can be explained with the catalytic effect of the strong acids formed in the course of the reaction or being present. These properties can be generalized for the cyclopropane- -carboxylic acids (Tetrahedron Letters, Vol. 25, No. 15, 1595-1598, 1984). A further step was the process according to which as an activated derivative of cyclopropaπe-carboxylic- -acid the dimethyl-(acyloxy-methylenedieπe)-ammonium salt of the general formula (IV) was applied (Hungarian Patent Specification No. 444). According to the examples the dimethylforma ide was reacted in anhydrous acetonitrile or toluene at tempera¬ tures between -20 °C and 0 °C with oxalylchloride or phosgene respectively and the suspension obtained was further reacted at -15 C with cyclopropane-carboxylic- -acid components and to the mixture thus obtained at -20 C th suitable alcohol components were added. This method resulted in a very simple way the tetrametrine, per etrine or ciπneriπe respectively formed as a product of the starting material without decomposition or iso¬ merisation respectively of the activated acid derivative. The activated acid derivative can't be stored because of in the presence of certain - firstly in the presence of metallic - contaminations it can undergo to self catalyzed decomposition, which can cause even at room temperature an explosion. The reaction mixture - as the waste acide formed from the reagent in the course of activation is always present in the system as a complex - is not harm¬ less. A further disadvantage is, that according to the patent examples in the esterification step a great excess of organic base (e.g. pyridine) is needed to neutralize the waste acid set free, this increases the costs and even the processing is made more difficult. The direct use of the reaction mixture to the esterifica- tion, because of the lack of the purifying step the formed contaminations and the accompanying byproducts can directly get into the pyrethroide eπdproduct. In the case of this activated acid derivative the unfavour¬ able effect of the DMF set free at the esterification step can lead to side reactions too, mainly in the case when in the alpha position of the alcohol cyan substi¬ tuted pyrethroides are prepared by reacting water, water soluble cyanides and suitable substituted aldehydes (e.g. according to the method of GFR Of enleguπgsschrift No. 2,231,312). The present invention relates to the preparation of optically active and/or racemic cyclopropaπe-carboxylic- -acid chlorides of the general formula (I) by the reaction of cyclopropane-carbonic acids of the general formula (II) with a complex of the general formula (III) in a way, that dimethyl- ormamide is reacted with phos¬ gene, thionyl- j phosphoryl-, oxaly- or phosphorchloride at 0 - 30 °C in a molar ratio of 1:1 - 1:0.25 in the presence of an organic aprotic solvent as diluent or without the same and reacting the complex obtained of the general formula (III) without isolation in the presence of an apolar aprotic organic solvent as diluent or without the same at 0 - 30 °C with cyclopropane- carboxylic acid of the general formula (II) and in given case the emulsion obtained is precipitated, and the pure acid halogenide of the general formula (I) or its apolar aprotic solvent solution is selectively separated from the by-product formed, the complex of the general formula (V) separated as a precipitated liquid phase and from the impurities dissolved in it based on the specific weight difference of the phases. In the specification the substitueπts of variable meaning are always as follows: A = halogen atom or a C, * alkyl group, Y = chlorine atom, or a -0S0C1-, -0P0C1 2 , or a -0PC1 2 group, ^ - the line indicating an o or ( space position compared to the plain of the cyclopropane ring, Y 1 - an -OH, -0S0 2 H, -OPOCl(OH), -0P0(0H) 2 , -OPCl(OH), 0P(0H) 2 or -0P0C1 2 group. The present is based on the recognition, that under suitable conditions the cyclopropane-carboxy- lic acid is present above 0 °C in a total extent in the form of a chloride of the general formula (I). Reacting 2,2-dichloro-vinyl-3,3-dimethyl-cyclopropane-carboxylic- -acid the characteristic IR zone of the product isolated o, ^ c n ,„„ ._ __-l at 0 U C V C = 0 1779-1781 cm "1 and this is identical with the wave zone characteristic for acid chlorides. The infrared spectrum of the acid chloride prepared according to the standard method was quite identic with the spectrum of the product. The NMR picture taken at 0 C from the compound showed only the presence of the acid chloride, too. The molecular weight calculated from the weight of the sample and its esterification has unanimously given the molecular weight of the acid chloride. We recognized further, that the waste acid formed in the reaction as by-product is complexated immediately with the dimethyl-formamide present and this way choosing the right quantity of dimethyl-formamide the waste acid can be totally precipitated, separated. The contaminating decomposition products formed in a small quantity are dissolved in the strongly polar DMF-complex phase and they can be separated together with the same, thus a quite pure acid chloride can be obtained. This is so far important as this way a product of 98 w% purity can be safely obtained, the further purifying of which e.g. distillation is superfluous. Carrying out the reaction with differently substitu¬ ted cyclopropane-carbonic acids no significant difference can be observed related to the run out of the reaction or the possibility of separation. This is surprising, because in the case of other carbonic-acids the formed acid halogenides are forming a homogenous solution with the formed waste acid complex and thus it can't be separated. The question is explained by the surprising apolarity of the formed acid chloride of the general formula (I) and by the particularly bad solubility and complex forming properties of the same. The present in¬ vention is based on the recognition and aimed application of these properties. Amongst the solutions according to the present in¬ vention .we have found very advantageous that, according to which dimethyl-formamide is reacted in a molar ratio of 1 : 1 - 0.9 with phosphoryl-chloride or in a molar ratio of 1 : 1-0.4 with thioπyl-chlαride . One can proceed in a way, that to the reaction as diluent dimethyl-formamide is applied. In this case the quantity of the dimethyl-formamide applied as reagent and diluent is expediently at most 4 moles calculated on the moles of the starting cyclopropane-carboxylic acid of the general formula (II). Th iπcrease of the dimethyl-formamide quantity is transforming gradually the emulsion to a homogenous solution. Parallel to this the quantity and purity of the acid chloride to be obtained is decreasing. General¬ ly oreas the equivalent dimethyl-formamide quantity can be hardly applied, because the dissolvent effect of the dimethyl-formamide not co plexated for both phases becomes effective. 0 Although the application of a further solvent quantity is generally not needed, the separation of the phases can be improved by the addition of strongly apolar aprotic solvents, which are dissolving only the acid halogenide phase. As diluents one or more C,_, 2 - carbohydrates in given case halogeπated carbohydrates can be applied in a 0.1 - 5 fold quantity calculated on the mass of the acid halogenide of the general formula (I). Such solvents are e.g. hexane, heptane, petrolether, cyclohexane, carboπtetrachloride etc. The increase of 0 the polarity is disadvantageous in this case, too. To the reaction with cyclopropane-carboxylic-acid the complex of the general formula (III) is applied in such a quantity, that the ratio of the halogen atoms of the group calculated on the moles of the cyclopropane- -carboxylic-acid of the general formula (II) should be 1:1, 5:1. The most significant advantages of the present process are: The size of the reaction can be easily increased and it can be carried out in an industrial scale with reagents of industrial quality. The reagents must be not totally relieved of water and applying the halogeπat- ing agent in a small excess the question can be solved in a simple way. Applying polyvalent halogenatiπg agents 5 the active halogen content can be exploited in a full extent according to the usual stochiometric proportions of the reagents of this type used to the preparation of conventional acid chlorides. The carbonic acid activating reaction is very quick and it is slightly endotherm, it is expedient to carry out this reaction at room tempera¬ ture. At a higher temperature of 10 - 20 °C firtsly the instability of the waste acid-complex formed from the reagent and the strongly acidic medium are causing a decompositoπ. The reaction results the product with a yield of 95 mass %, moreover after the hydrolysis of the waste acid at the separation the lost 1 - 5 mass% of the cyclo- propane-carboxylic-acid can be obtained in a simple way from the hydrolysate and it can be recyclized. The yield of the method is practically quantitative. The product is sited generally depending on the halogenating agent in the upper phase and thus after the separation of the waste acid in the same reaction vessel it can be esteri- ficated by the addition of one equivalent of organic amine and the alcohol component solution. According to its quality it can be applied immediately to the known one step preparation of yrethroides containing in the alcohol part (.σ{ position) a cyan substitueπt as e.g. cypermethrine. deltametrine, cyhalotrine, cypheπotrine , etc. The position is especially favourable in the case of the preparation of optically active acid halogenides, because the compounds are not suffering any iso βxiza- tion. According to its purity the product can be stored for years without the smallest sign of decomposition. The process developed by us can be carried out in a simple way even in a size of several kilomoles. The quality of the product obtained is above 98 - 99 mass% even in such a size. To the illustration of the process the following examples are described without limiting the scope of protection. The purity values in the examples are determined by argentometric methods, poteπtiometric titration and HPLC measurement after methanolic esterification (Perkin Elmer, column: 250 x 4.6 mm, Spherisorb ODS, 10 ,um elueπt: 60 % methaπol 40 % aqueous buffer (pH = 2.5), (detector LC-75, (225 nm). Example 1 95 g (100 ml, 1.3 moles, 1.3 equivalents) of di¬ methyl-formamide are weighed at room temperature into a mixing apparatus, by strong cooling it is cooled to -10 °C and while intensive stirring and cooling 160 g (96 ml, 1.04 moles, 1.04 equiv.) of phosphoryl-chloride are added in a tempo, that at the end of the dosage the temperature of the mixture is gradually increased to 20 °C. The mixture is stirred for 30 minutes ; then 210 g/1 mol, 1 equiv.) of cis-2,2-dimethyl-3-(2 ' ,2 ' - -dichloro-vinyl)—cyclopropane-carboxylic-acid are added. During the dosage the temperature of the reaction mixture does not change. At room temperature the mixture is stirred for 2 hours and the emulsion obtained is settled for 1 hour and the lower phase is let to flow on crushed ice. The upper colourless phase is separated. 218 g of isomer-free cis-2 ,2-dimethyl-3-(2 ' ,2 ' - -dichlorovinyl)-cyclopropaπe-carboxylic-acid chloride of 99 > absolute purity are obtained. CgH 9 Cl 3 0 Mw 227.52 Calculated: C % = 42.23, H % = 3.98, Cl H = 46.74; Found: C % = 42.02, H % = 3.95, Cl % = 46.82. The isorner purity, the active ingredient content respectively is determined by HPLC measurement and by argentometric and potentiometric titration. Yield: 95 %. The hydrolizes waste acid phase is filtered after cool¬ ing. The recovered target compound is dried. The 8 g of the crystalline pale yellow coloured material can be used again in the next reaction after crystallization. Thus the total yield makes 99 %. Example 2 One proceeds according to the process of example 1 with the difference, that 300 g (1.00 mol) of cis-2,2- -dimethyl-3-(2 ! ,2'-dibromo-vinyl)-cyclopropane-carboxylie acid and 100 ml of n-hexane are weighed in the apparatus. 368 g of a colourless viscous acid-chloride - n-hexane solution is obtained. According to the titrations de¬ scribed above and according to the HPLC measurement the solution contains 82 % of cis-2,2-dimethyl-3-(2' ,2'- -dibromo-vinyl)-cyclopropane-carboxylic-acid chloride and 18 h of n-hexane. Yield: 95 %. A small portion of the product obtained is evaporated in vacuo and analysed. CgH 9 Br 2 C10 Mw: 316.54 Calculated: C % = 30.35, H % = 2.86, Cl % = 11.20; Found: C % = 30.00, H % = 2.92, Cl % = 11.28. Example 3 One proceeds according to process of example 1 with the difference, that 210 g (1 mol) of (+)-cis- -2,2-dimethyl-3-(2' ,2'-dichloro-vinyl)-cyclopropane- -carboxylic acid (/ " °^_7 Q 5 = 31.3°, c = 1, CHC1 3 ) is weighed in the apparatus. Thus 219 g of (+)-cis-2,2- -dimethyl-3-(2',2'-dichloro-vinyl)-cyclopropane-carboxy- lic acid chloride of 99 % purity are obtained. CgH 9 Cl 3 0 Mw: 227.52 Calculated: C % = 42.33, H % = 3.98, Cl % = 46.74; Found C % = 42.15, H % = 4.06, Cl % = 46.81. A small part of the acid chloride is hydrolysed with water and the optical rotation of the obtained (+)-cis-2,2-dimethyl-3-(2' ,2'-dichloro- inyl-cyclopropane- -carboxylic acid is measured fol r , = 31.3 (c = 1, CHC1,), that is no isomeratioπ occured in the course of the transformation. Yield = 95 %. Example 4 One proceeds according to example 1 with the diffe- rence, that 170 g (1.00 mol) of trans chrysanthemic acid are weighed into the apparatus. Thus 180 g of trans chrysanthemic acid chloride of 98 % purity are obtained. Yield = 95 %. C 10 H 15 C10 Mw> 186 - 68 - Calculated: C % = 64.33, Found C = 64.28, Example 5 Into a mixing apparatus 10 ml of carbon-tetra- chloride, 170 ml (160.5 g, 2.18 moles, 2.19 equiv.) of dimethyl-formamide are weighed and while strong cool¬ ing and intensive stirring the mixture is cooled to -10 °C. Keeping the temperature, 80.2 ml (131.5 g, 1.10 moles, 1.10 equiv.) of thionyl-chloride are added. The mixture is stirred for further 30 minutes where- after 210 g (1 mol, 1 equiv.) of trans-2 ,2-dimethyl- -(2 ' ,2 '-dichloro- iπyD-cyclopropaπe-carboxylie-acid are added. After stirring for 2 hours and settling for 2 hours the lower phase is separated. Thus 2.28 g of trans-2,2-dimethyl-(2 ' ,2 '-dichloro-viπyl)-cyclopro- pane-carboxylic-acid chloride are obtained, which is a colourless oil containing 7 % of carbon-tetrachloride. Purity = 93 %. CgH 9 Cl 3 0 Mw. = 227.52 Analysis of the evaporated sample: Calculated: C h = 42.23, H % = 3.98, Cl % = 46.74; Found C % = 42.18 H 3.94, Cl % = 46.92. NMR (C0C1 3 ) (ppm) = 1.30 (d (6H)2CH 2.20, d(lH), Cl; 2.40 g (1H)C3; 5.60, d(lH); 3 χ 3 = 5.2 Hz, J CH 3H = 7.7 Hz. Yield = 95 . Example 6 Into a mixing apparatus 85 ml (80.25 g, 1.1 moles, 1.1 equiv.) of dimethyl-formamide are weighed. According to the previous examples 131.5 g (80.2 ml, 1.10 moles, 1-1 eαuiv.) of thionyl-chloride are added, whereafter the solution is stirred at room temperature in vacuo for 3 hours, while the mixture is transformed to a dense suspension. While vigorously stirring 210 g (1 mol, 1 equiv.) of cis-2,2-dimethyl-3-(2' ,2 ' -dichloro-viπyl)- -cyclopropaπe-carboxylic-acid are added and the mixture is reacted at room temperatur for 2 hours, after settling the lower phase is separated. 215 g of colourless cis- -2,2-dimethyl-3-(2' ,2' -dichloro- inyl-cyclopropane- -carboxylic-acid chloride (an oil) are obtained. Yield = 94 %, purity = 98 %. Analysis: CgH^l j O Mw. = 227.52 Calculated: C % = 42.23, H % = 3.98, Cl % = 46.74; - Found C % = 42.19, H % = 4.05, Cl % = 46.81. Example 7 To a mixture of 85 ml (80.25 g, 1.1 mol, 1.1 equiv.) dimethyl-formamide and 200 ml of n-hexane at -10 C while vigorous stirring 140 g (1.10 mol, 1.10 equiv.) of oxalyl-chloride are added-. The suspension is stirred for 30 minutes at -10 °C, whereafter at room temperature 210 g (1.0 mol, 1.0 equiv.) of trans-2,2-dimethyl-3- -(2' ,2' -dichloro-vinyl)-cyclopropane-carboxylic-acid are added stirring at room temperature for 3 hours. Mean¬ while the suspension gradually becomes transformed into an emulsion. The mixture is se.ttled and the upper phase is separated. 344 g of the colourless trans-2,2- -dimethyl-3-(2',2'-dichloro-vinyl)-cyclopropane-carboxy- lic acid chloride are obtained. Acid chloride content 61.1 %. The IR and NMR spectrum of the acid chloride obtained is identic with that of the product of example 5. Yield = 93 %. Example 8 While vigorous stirring 20 ml (19 g, 0.26 moles, 2.6 equiv.) of dimethyl-formamide are cooled to -10 °C and 5.9 ml (9.3 g, 6.7 mmoles, 0.67 equiv.) of phosphor- -trichloride are dropwise added in a tempo, that at the end of addition the temperature of the reaction mixture should be 20 °C. The mixture is stirred for 30 minutes, thereafter 16.8 g (0.1 mol, 0.1 equiv.) of chrysanthemic acid are added. After 2 hours of stirring and 1 hour of settling the upper phase is separated. 18.2 g of colour¬ less chrysanthe ic-acid chloride are obtained (oil). Yield: 97.5 %. Analysis: C ln H 15 C10, Mw = 186.68. Calculated: C % = 64.33, H % = 8.09, Cl % = 18.99; Found C % = 64.29, H % = 8.12, Cl % = 19.05. Active ingredient content: 97 %. Example 9 To 95 g (100 ml, 1.3 moles, 1.3 equiv.) of dimethyl- -formamide at -10 °C 108.3 g (0.52 moles, 0.52 equiv.) of phosphor-pentachloride are added. The mixture is stirred for 30 minutes at 20 °C, whereafter 210 g (1 mol, 1 equiv.) of cis-2,2-dimethyl-3-(2 ' ,2 '-dichloro-vinyl)- -cyclopropaπe-carboxylic-acid are added. The mixture is stirred for 2 hours and the emulsion is settled for 2 hours and the lower phase is allowed to flow on crushed ice. The upper colourless phase is separated. The product obtained is 215 g of isomerfree cis-2,2- -dimethyl-3-(2 * ,2 ' -dichloro-viπyl)-cyclopropaπe-carboxy- lic-acid chloride. Analysis: Calculated: C % = 42.23, H % = 3.98, Cl % = 46.74; Found C % = 42.12, H % = 3.90, Cl % = 47.05. Yield = 93.7 % .

Claims: What we cla im is : 1 A process f or the preparation of optically active and/or racemic cyclopropane-carboxylic-acid chlorides of the general f ormula ( I ) wherein line r is indicating an ti or p space position compared to the plane of the cyclopropane ring, A is a halogen atom or a C, * alkyl group, reacting cyclopropane-carboxylic-acid of the general formula (II) with a complex of the general formula (III) - A has the same meaning as mentioned above, while Y is a chlorine atom or a -0S0C1, -0P0C1 2 or -0PC1 2 group, c h ar a ct er i ze d b y , that dimethyl-formamide is reacted at 0 - 30 °C with thionyl-, phosphoryl-, oxa- lyl-, or phosphor-chloride in a molar ratio of 1:1 - - 1:0.25 in a given case in the presence of a diluent, thereafter the complex of the general formula (III) obtained - Y has the same meaning as eπtiπed above - is reacted without isolation in given case in the presence of an apolar, aprotic organic solvent as diluent at a temperature of 0 - 30 °C with cyclopropaπe-carboxylic- -acid of the general formula (II) - A has the same meaning as mentioned above - in a given case the emulsion obtained is precipitated, and the pure acid chloride of the general formula (I) or its apolar, aprotic solvent solution is separated from the complex of the general formula (V) wherein Y ,1 x is an -OH, -0S0 2 H, -OPOCl(OH), -0P0(0H) 2 , -OPCl(OH), -0P(0H) 2 or -0P0C1 2 group, formed as a by-product in a form of an extra liquid phase and from the contaminations dissolved in the sa e^based on the speci¬ fic weight difference. 2. Process according to claim 1, ch ara c t er i ze d by, that dimethyl-formamide is reacted with phosphoryl- -chloride in a molar ratio of 1:1-0.9 or with thioπyl- -chloride in a molar ratio of 1:1-0.4. 3. Process according to claim 1, char act er i zed by, that in the case applying as diluent dimethyl-form- amide.the quantity of dimethyl- ormamide applied as reagent and diluent is at most 4 moles calculated on the starting cyclopropane-carboxylic-acid 4. Process according to any of claims 1-2, c h ar a c t er i z e d by, that as diluent an organic, aprotic solvent, advantageously a C, , n , in given case a haloge- nated hydrocarbon is applied in a 0.1 - 5 fold quantity calculated on the mass of the acid chloride of the general formula (I). 5. Process according to claims 1-3, c ha r a c t e ¬ r i z e d by, that to the reaction with cyclopropane- -carboxylic-acid the complex of the general formula (III) - the meaning of Y is the same as mentioned above - is applied in a quantity that the ratio of the number of halogen atoms in the Y group calculated on the moles of the cyclopropane-carboxylic-acid of the general formula (II) - the meaning of A is the same as mentioned above - should be 1-1.5:1.

Inventors: BERTOK BELA, HIDASL GYOERGY, IMREI LAJOS, LAK ISTVAN, NAGY LAJOS, SOMFAI EVA, SZEKELY ISTVAN, THURNER ANGELIKA, ZOLTAN SANDOR, BERTOK, BELA, HIDASL, GYOERGY, IMREI, LAJOS, LAK, ISTVAN, NAGY, LAJOS, SOMFAI, EVA, SZEKELY, ISTVAN, THURNER, ANGELIKA, ZOLTAN, SANDOR
Applicants: CHINOIN GYOGYSZER ES VEGYESZET, CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT.
Application year: 1990
Main classification: C07C51
IPC codes: C07C51, C07C61, C07C69