Crystalline pair of enantiomers of phenylacetate and preparation of a pair of énanciomère pesticide.

The present invention relates to a process for the preparation⁵ phenylacetate pesticidal rich in a pair of enantiomers and a novel intermediate which is a pair of enantiomers have different crystalline properties are important for the ease of carrying out the method.

The novel intermediate is the crystalline form of a pair of enantiomers cyanobenzyl phenylacetate of formula I

wherein R¹ is a hydrogen atom, a halo atom - ' gene group or an alkyl group containing 1 to 4 carbon atoms or a methoxy or ethoxy group, each optional -

ard substituted with one or more halogen J.

THE O *

Wherein R " is a hydrogen atom or a methyl group; X is

2

a phenoxy group, benzyl or phényIthio; X is a halogen atom Eu is a methyl group and n is 0, 1 or 2 * which comprises an R-alpha isopropylphénylacétate of s-α-cyanobenzyl and s-alpha isopropylphénylacétate R-α-cyanobenzyl corresponding (hereinafter referred to as the pair¹ x-enantiomers) substantially free of other stereoisomers "

The pair of enantiomers crystalline X-I^O can be prepared hr from R, O-alpha isopropylphénylacétate of RjS-to-alphâ-cyanobenzyl corresponding racemic by passing the racemate through a chromatography column containing an appropriate filling material, for example silica gel, using a liquid eluent, for example 1 % ethyl oxide in 1' normal hexane. The pair of enantiomers X is collected as being the first to leave the two pairs of enantiomers. The pair of enantiomers crystalline X according to the invention can then be obtained by cooling the-pair of enantiomers of X resulted from the chromatographic separation. The cooling (for crystallization) is carried out at any temperature at which crystals die X form, e.g. between

About 20 °c - 5ô °C and preferably between about " 15®C. and about 5 °c. The pair of enantiomers having the crystalline X - trading interest contains R-α-isopropyl p chlorophénylacétate s-alpha-cyano 3 a-phénoxybenzyle and s-α-isopropyl p chlorophénylacétate R-alpha-cyano 3 a-phénoxybenzyle. This material is usually collected to a purity of greater than 60% /, typically of about 64%; additional recystallizations resulted in a product having a purity of at least 75% and usually above at least 80 T or even more than 90 sec. crystals enriched with the pair of enantiomers of X (it is to say containing crystals of the enantiomeric pair X and other crystalline forms of the a or 1' other diastereomers of X) are formed also during in situ cooling of the racemate described above in a solvent,, for example methanol, from which the desired X-enriched crystals spontaneously crystallize the-preferentially without adding seed crystals of X, for example as described below in the example 1 (has). One derivatives repeated recrystallization of crude crystals, as in the example I in (d) below, gives the enantiomeric pair X in a crystalline form of high purity and a melting point of 68 °c.

The other enantiomeric pair comprises a s-alpha isopropylphénylacétate s-àlpha-cyanobenzyl and the R alpha isopropylphénylacétate R-alphà-cyanobenzyl - corresponded and is referred to hereinafter as a pair of enantiomers Ÿ " crystals:

the pair of enantiomers ii have an interval of fusioft " T and - appear to be dice mixtures' crystals of each of the two isomers that constitute this pair of enantiomers. The crystals of the pair¹ enantiomers X have unique properties significantly different from those of the pair crystal therein. These unique properties and different comprise a higher melting point and clearer than that of the pair therein crystalline, indicating that the crystalline X pair of enantiomers racemic crystalline dice two enantiomers which constitute the pairs X rather than a mixture of crystals of each of the two enantiomers in the pair as crystal therein. In addition, it has been found that the solubility of the pair there is 2 to 4 crystalline times larger than that of the pair of enantiomers crystalline X or crystals enriched pair X and that the pair of enantiomers X has a much greater crystallization rate that the enantiomeric pair Y these properties of the pair of enantiomers crystalline X crystals and enriched pair X for a pair of enantiomers enriched product Y is prepared by the process according to the present invention.

According to its appearance method, the present invention provides a process for the preparation of unisopropylphénylacétate cyanobenzyl of formula I defined above which is rich in the enantiomeric pair 1 therein as defined above), which is precipitated crystals enriched enantiomer pair of X in the presence of crystals of enantiomeric pair X from a solution of the R, O-alpha isopropy1-to-phenylacetate of R, O-α-cyanobenzyl corresponding racemic, is separated from the mother liquor enriched such crystals at X, then redissolved in a solvent and the resulting solution is treated with a base to epimerize the enantiomeric pair X-dissolved by forming the corresponding racemic mixture, is recycled to the racemic mixture th the precipitation step, and the mother liquor is collected enriched enantiomeric pair therein.

The Patent of n * 4 238,406 E.U.A. describes a process for the preparation of the pair of enantiomers by crystallization from therein of the thereof in the presence

- '^5: .■07040

seed of the pair of Cl⁶ the liquors lead® Y enantiomers enriched in the peers erffective powerU" enantiomers X are not crystallized, but rather are epimerized to form a recycle stream substantially racemic. Thus₀ the method according to the present invention is very different #, and is substantially the inverse of that described in the Patent of e "U-, has" above I. One derivatives after the pair of enantiomer e X initial or crystals of enriched X have been foriaés, it has been found that it is very difficult to obtain crystals of the pair of enantiomers therein, the present method avoids this problem by eliminating the need for the d * crystals with the pair⁸ enantiomers " therein, and derives advantages different properties and previously unknown of the pair of crystals and crystal S enantiomers enriched 1, further # the much greater rate of crystallization of the pair of enantiomers enriched crystals X or X permits the use of a shout ' stalusor continuous, multi-stage, if desired, instead of very large crystallizers discontinuous. A continuous operation is often preferred to the batch operation for reasons both technical UG ' economic.

The method according to the invention is of interest

particular marketing in the preparation of phenyl -

1' cyanobensyla acetates of formula I wherein s is a halogen atom or. an alkyl - or-alkoxy optionally halogenated" for example chlorine © U

fluorine, or SU methyl, ethyl, isopropyls, terfc-to-butvle,

" 2 methoxy, ethoxy, ûiiiuorométhoxy or ' trifluoromethoxy R is hydrogen the i x ^ is. a substituent 3-phenoxy and n is Giro d.., the R... is located preferably at the position mita or, more.... willwill spécialementpara, relative to the carbon atom of the group. bengyi.® cians ^ the potion. acid .•.

Because of products. pesticidal properties, the present method is particularly advantageous for the preparation of a form enriched in su_F. * a phény. lace of Ta Te of formula I wherein is hard chlorine LTO UT " group;

Z 11

c_iluoarr-to-meohinxy,, B.. * æh MU sétzmæ. 42' ^ hycSrsœ fiàræfiàræ.f, 2K is uœ group 3-phenoxy and n is zero; and especially the compound alpha isopropy1 P-chlorophénylacétate 4 'alpha-to-cyaho and 3 a-phénoxybenzyle.

The solvent used in the method can be any material inert liquid wherein the phenylacetate is at least partially soluble to the ambient temperature. Examples of suitable for classes of solvents include chlorinated hydroearbures "ethers" nitriles, esters, amides, hydroxylated solvents SEA, like solvents suitable hyérexyléseèmprennent lower alkanols containing 1 I to 4 carbon atoms as 1' of isopropanol, butanol, ethanol and the inéthanol, and preferably containing 1 to 2 carbon atoms, specially the roéthamol. Other solvents which can be used are alkanes containing 5 to 10 carbon atoms such as n-pentane, n-hexane, n-heptane, m octane, n-nonane, n-decane and isomers thereof. Petroleum fractions rich alkanes are also usable, for example a gasoline of a distillation range at atmospheric pressure between 4i and 65 * c, between 60 and 80 °c or between 10 and t10 * c. Thru petroleum ether can also be used. Cyclohexane and méthylcyclohexanes are examples of cycloalkanes useful " beginning of 6 to 8 carbon atoms. Aromatic hydrocarbon type solvents may contain from 6 to 10 carbon atoms, for example benzene, toluene, O -, 1 * m - and p-xylene, trimethylbenzenes, P-ethyltolnene " like chlorinated hydrocarbons of 1 to 4 usable contiemnemt chlorine atoms in combination cMA a chain of 1 to 4 aleans containing carbon atoms or with a noymbeazéniqué, e.g. carbon tetrachloride, chloroform, dichloromethane, the 1.3-dichloroethane "trichloroethane, the hexachloroethane, 1" 3 * 1 * 2 or chlorobenzene and 1.3-dichlorobenzene. The ethers can be those containing 4 to 6 carbon atoms such as ethyl oxide, oxide of methyl tert-butyl and isopropyl oxide. Tetrahydrofuran and dioxane are also useful. The nitriles usable usually contains 2 to 6 also of carbon atoms, for example 1' nitriles are acetonitrile and the like. The esters can be those lower alcohols and acids containing each of, 2 to 6 carbon atoms, for example ethyl acetate. Amides can be those of alcoylamines and acids each comprising from 1 to lower 6 carbon atoms, for example dimethylformamide.

Although different solvents can be used in the steps of crystallization and epimerization, it is often convenient to use the same solvent in both steps, alkanes and alkanols are preferred. Alkanols containing 1 to 4 carbon atoms are particularly useful, especially the inéthanol.

The epimerization catalyst can be any basic agent, e.g. inorganic or organic in nature, mistletoe does not form itself stable reaction products with the ester of cyanohydrin, and preferably has a pK of less ^ 6. Examples of inorganic compounds usable include hydroxides, carbonates, hydrides and metal cyanides of alkali and alkaline earth metals, as well as oxides of metals, such as sodium cyanide, 1' sodium hydroxide, barium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, calcium oxide, alumina, zinc oxide, andc.

Organic bases that can be used are alkali metal salts or alkaline earth metal salts of weak organic acids or organic nitrogen bases, alkali metal alcoholates and alkali metal amides. The useful salts include sodium acetate, magnesium formate, potassium tert, 1' isopropy ETL. sodium, etc nitrogenous bases may be ammonia, ammonium hydroxide or any nitrogenous base alkyl, aryl or heterocyclic, including mono - or polyamines, and the like preferably, the organic nitrogen base is uneune.amine wherein all alkyl groups contain from 1 to 10 carbon atoms, aryl or aralkyl groups all contain from 6 to 20 carbon atoms and 1 to 2 rings hydrocarbyl, . and any heterocyclic amines contain at least one nitrogen atom in a five or six-membered heterocyclic ring optionally containing a sulfur or oxygen atom or another nitrogen atom, such as trimethylamine, diethylamine, triethylamine, piperidine, 1 'isoamylamine, benzylamine, the 1 naphthylamine, diethylamine, tri-n-propylamine hydrochloride, ephedrine, tert-butylamine, 1' ethanolamine, triethylenediamine, tetramethylenediamine, pyrrolidine, quinoline, pyridine, morpholine or tetrabutylammonium hydroxide. The amines are preferably secondary amines and tertiary amines containing especially a combination ' any groups described above. When the amine is a tertiary amine, it advantageously contains three alkyl groups of 1 to 4 carbon atoms, for example trimethylamine, tri-n-propylamine and especially triethylamine.

Other suitable basic agents are ion exchange resins having a strongly basic character -.

Such resins include ion exchange resins containing quaternary ammonium and amine types. Resins of these types are often sold under the commercial names - Dowex and Amberlite, for example those derived from trimethy laminate (as the products known as commercial "Amberlite ARDS and 400", "will-to-40l Amberlite", "Amberlite SRI and 402", "Amberlite dioleyldimethyl above 900", "Duolite-101 a-d", "Duolite AE-to-111", "Dowex 1", "Dowex 11", "Dowex 21k", and

" Ionae iv=450®ii _I and those derived from '" DFEs dimethylethanolamine Icomme products known as commercial

⁵³ At Amber lifce&-410 ir "," Amberlite "," will-to-911 Dowex 2 "," © 11 - 102 of the tee Α Ο%="Ionac-542" and "Ionax-550"). It was achieved very good results with those derived from triaéthylamine "when these catalysts are available in a neutralized form, for example in the chloride form, they must be activated to form hydroxyl by treatment with an aqueous alkali metal hydroxide, e.g. 1" sodium hydroxide, and washed with water to remove the anions before use. Are also useful as basic agents, liquid amines of high molecular weight which are insoluble in water such as " Amberlites liquids^{THE CT} which are commercially available under the designations i°amberlites la2 ATIA and liquid types.

Of databases. containing phosphorus are also usable, as aIcoylphosphines ' lower such as tripfeényl phosphine and tri-n-butyl-phosphine oxide.

preferred base for the Te 1' epimerization is ammonia or a tertiary sleoylamine wherein each alkyl group contains from 1 to 4 carbon atoms, as the fcriéthylamine "

the Te catalyst concentration 'Û' épifrtérisatiori may vary to 100 mole % dka 0.0111 and 0.01 to 50 is conveniently of δ moles with respect to the ' amount of racemate, preferably 0.05 to 20 mole %, . and. especially 0.1 I-

15 hearths % of O Normally, uses about 1 moles

0

If © has desired, a stabilizing amount of an acid may be added to the solution prior to crystallization of racemic mixture to neutralize the catalyst or other basic materials and ' to prevent epimerization of the enantiomeric pair. - Y in the mother liquor during the crystallized ©!®subsequent® crystal enriched in the pair confectioneries⁸ k-enantiomers,

J

Although the precise amount of acid required is dependent upon the amount of basic catalyst used or any other basic material present, use can be made of 0,001 to 5%, preferably 0.01 to 0.5% by weight of acid with respect to the charge of phenylacetate.

Any inorganic or organic acid or any acid-active material which will not adversely affect the desired product can be used to stabilize the solution, for example mineral acids, such as hydrochloric acid or sulfuric acid, sulfonic acids, as toluene sulfonic acid, or organic acids, including acids alcanoîques lower, such as acetic acid, propionic acid or butyric acid. Acetic acid is preferred.•

The precipitation, for example crystallization, is conducted by forming a mixture of the racéraate in a suitable solvent as defined above. The method may be conducted at any temperature at which crystal formation occurs in the pair of enantiomers enriched the X, conveniently between -50 and 60 °c, preferably between -35 and 5 °c and especially between 5 and -15^I C..

It is often advantageous to add significant amounts of seed crystals for increasing the rate of crystallization ^. It is usually very practical to use crystals of the pair of enantiomers X substantially pure or enriched crystals as seed crystals pairs X, but can be used crystals of one or the other of the diastereoisomers isolated from " the pair of enantiomers X or a crystal mixture of the two diastereoisomers of the pair of enantiomers.. the X-use of seed crystals of the pair of enantiomers X in a state of purity would lead to higher yields in the enantiomeric pair Y in the filtrate. Other nucleating agents known can be used when it is desired seed crystals # sprayed e.g. silica, potassium acetate, andc, the amount CTEs geins® e crystalline used is not critical₇ but the crystallization is faster with high quaBfcifeé seed crystals, the amount of seed crystals may range from 0.05 to 10% relative to the phenylacetate in solution and is preferably from about 1%. Of course, as the process progresses, the crystals of the pair of enantiomers X which are formed serve as additional quantities of seed " crystals enriched enantiomer pair of radiation produced during the L^T operation can be separated and collected; after crystallization by methods such as filtration,, centrifugation or decanting the liquor " mother, andc.

The choice of the method of separation will depend in part on the fact that the crystals must be epimerized in the same container in which they were formed or that they should be transferred to another container, as appropriate in a batch process, continuous or semi-continuous.

Carried conveniently epimerization th " dissolving the enantiomeric pair X in a suitable solvent comae defined above and adding to the solution the desired amount of catalyst epimerization. The method may ftre implemented at any temperature at which the epimerization occurs without substantial decomposition of the phenylacetate. The epimerization is much faster at higher temperatures. Conveniently, 1' epimerization is conducted at temperatures between -50 °c and the reflux temperature of the solvent, preferably between 150 c and -20®^I C., and especially between 0 °c and 50 °c.

The product of 1' epimerization is essentially a solution of racemic phenylacetate. The product may then are combined with fresh amounts of racemic or phenylacetate solution with the mother liquor rich Y and the resultant mixture is subjected of qouveau has a precipitation (crystallization) under the conditions described previously above.

The neutralization is effected or catalyst removal of residual epimerization by known methods. In some cases, catalysts which are insoluble in the solvents of the method are advantageous, for example a catalyst which is a basic ion exchange resin, while in other cases there may be added a small amount of acidic material, for example acetic acid, when using a basic catalyst such as ammonia.

As stated above, the mother liquor enriched enantiomer pair of Y is separated from the pair of enantiomers enriched crystals X or X by known methods, for example by removing by centrifuging the crystals of X or enriched in X. the enantiomeric pair Y may then be concentrated or separate ' of the solvent, e.g. by evaporation while expelling a lighter solvent such as methanol. Other light impurities may be removed, for example, in a thin film evaporator scraped surface.

The ordinarily skilled artisan will understand that the present method can be carried out batchwise, continuous or continuous using one or more processing containers as appropriate.

In its operation particularly preferred, the present invention provides a process for the preparation of the pair of enantiomers consisting of s-α-isopropyl p chlorophénylacétate s-alpha-cyano 3 a-phénoxybenzyle and R-α-isopropyl p chlorophénylacétate R-alpha-cyano 3 a-phénoxybenzyle corresponding (so-called hereinafter fenvalératé therein), in which precipitated crystals of a pair of enantiomers formed R-α-isopropyl p chlorophénylacétate s-alpha-cyano 3 a-phénoxybenzyle and s-α-isopropyl p chlorophénylacétate of R "aIpha" EY as anogenital 3 a-phénoxybenzy1e (rívetted^O following named fenvalerate OA is the X) in the presence of crystals based on Senvalérate X from a solution of R, s alphâ~iaôprop: of Fx "P chlorophénylacéfcate of R, the s-alpha-cyano 3 a-phén ©3 £ybeasy! I * is separated from the crystals of fenvalerate X of the liquor -" era * redissolved crystals of fenvalerate X in a * solvent solution is processed of fenvalerate X with a base so as th épisiériser fenvalerate X into corresponding racemic fenvalerate, recycled mixture raceaic to 1" precipitation step and collecting the fenvalerate Y from the mother liquor.

Although which can be used various catalysts * reaction conditions and solvents previously described above for preparing the fenvalerate THEREIN, it is preferable to use as solvent an alkanol containing 1 to FISs ee carbon atoms and as catalyst or a 1° ammoniaque alcoylaaine tertiary containing 1 to 4 carbon atoms in each alkyl group. The use of mémé.ih&nol with triethylamine or specially with ammonia is preferred.

The crystals of fenvalerate X have a point of 68 °c fusts®_S about 20 °C above crystals in 'that were' previously obtained for fenvalerate THEREIN,

The invention is illustrated by the following examples * in which the identity of the products, including that take still intermediates, was confirmed by gas chromatography GSC) and by spectral analyses based on nuclear magnetic resonance (NMR -) as needed " Example 1

One derivatives solution containing 240 g of fenvalerate technical substantially racemic, . 4, 49 g of potassium acetate UCN optional nucleating agent), 0.6 g of water and 520 grams based on methanol stream is cooled below 0^I C. coameneent crystals to grow rapidly, and there is soon a thick cake of crystals at the bottom of the container with a supernatant solution above the cake. Dropping this mixture at room temperature for several hours.

Then the mixture is shaken so as to fragment pieces of solid matter and filtering a small portion.

The white solid collected, after successive flushes iced methanol, is analyzed by the GC and found that it contains 74.2% of fenvalerate X a portion of the solid is recrystallized once from methanol to give 81.3% of X-fenvalerate.

The filtrate from the first filtration is cooled to 0 °c is isolated in other crystals. These crystals are recrystallized seven times from acidified methanol to acetic acid, by analyzing each time the product by the GC. The standard analysis of the final product is of 3.7 g of fenvalerate Y of a purity of 99.8% and a melting point of 68 °c.

A solution containing 400 g of fenvalerate raceraic technology (ratio of fenvalerate therein " at fenvalerate X 4, 7.1 for 52.9), 405 g of methanol ' and 0.2 g of acetic acid is combined and heated to form a homogeneous solution. The mixture is cooled and stirred to 23 °c and added 5.0 g of crystals of fenvalerate the X (prepared commeen 1 (has) above) finely powdered * the temperature of the slurry is slowly lowered to 0 * c in 5 hours and a sample of 45.9 g of the slurry is taken and stored Dato ' ns in the refrigerator to provide seeds later in the experiment. Is allowed to settle out of the slurry and the remainder is discharged 360.7 g of the mother liquor by a glass filter tube. The crystal bed is rinsed twice with residual portions of cold methanol (124.1 grams in total) and discharged also by the filter tube. The invention collects a total of 152.6 grams. One derivatives of GC analysis of the filtrate indicates that the ratio of Y to X-fenvalerate fenvalerate has been heated to 77/23.

1

Mainly in bone balloon'd © 500 eïa, © were introduced 355.6 g of filtrate © crystallization results from above and © has performs © distillation of this charge to the traders a column Isolated Older shat? 10 to plateaus, the DS 2,s4 centimeters, ; jmsçm⁰ at a temperature of 105 °c balloon to recover methanol for recyclageo collected a total of 237 g of distillate and the product fenvalerate crude rich ee " 1 remaining weighs 106 grams, 1⁹ analysis by THE GC indicates that the ratio of fenvalerate yen at fenvalerate X in, the rest product is

of 79/21.

Has 3s8 g of wet crystals remaining after removal of the filtrate and washing liquids from the previous crystallization, © 140 g of methanol was added to the recovered by distillation " 5ô °C the mixture is heated to dissolve the solids and © has maintains the solution at that temperature, and is added 0,375 cm of aqueous solution concentrated® ammonia, in three portions,, EDD 137 min, for catalyzing 1⁹ epimerization. After the total 25®FISs

min, © quenches the reaction mixture per se I-de^O the addition of Tl

0,265 cSAs "acetic acid" the ratio of fenvalerate? at fenvalerate CS mixture has - been carried - D.^O "aEs initial value of 36/64 more than 44/56 (based on ' îsi sample taken after 205 minutes!" ^

The reaction mixture resulting from the epimerization 4s4 grams above is cooled to room temperature and added " has complement of 106 g of fenvalerate raeemic, in © lRi®₍ time that the 151 - g washing fluids methanolic crystals of the crystallization and 149 g of methane preceding! of complement from the distillation. 765 - G homogenized mixture is placed into a bath to 25®C. adds the 45.2 g of slurry seed retained after the previous crystallization, © has agitated mixture and cooled during 3 hours * q°g confectioneries and maintaining the mixture at this temperature for 15 additional hours, whereafter bone iôtraitf in the manner described above. The invention collects a total of 337 g of filtrate, and 1' analysis by the GC indicates that it has a ratio of Y to X fenvalerate fenvalerate 85/15.

The filtrate is distilled, coarse above, obtain 83.6 g of residue, which according to the analysis by the GC has a ratio of Y to X fenvalerate fenvalerate 77/23.

Examples II-V.

According to procedures similar to those of the example I-, forms rich phenylacetates Y of following are prepared by crystallization of the pair of enantiomers corresponding X, epimerization and recycling: α-isopropyl P-phenylacetate (difluorométhôxy) - alpha-cyano 3 a-phénoxybenzyle (ll), α-isopropyl pméthylphénylacétate alpha-cyano 3 a-phénoxybenzyle (lll), α-isopropyl p fluorophénylacétate alpha-cyano Sphénoxybenzyle (VI) and alpha-isoproyl - (p-tert butyl) phenylacetate alpha-cyano 3 a-phénoxyb'phénoxyb' enzÿle (volts).