AU2004321853B2

AU2004321853B2 - Process for preparing (S)-alpha-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)-isovalerate

Info

Publication number: AU2004321853B2
Application number: AU2004321853A
Authority: AU
Inventors: Ishratullah Khwaja; Mahesh Masna; Venkata Krishnam Raju Penumatcha; Chappeta Venkateswara Reddy; Vaddu Venkata Narayana Reddy; Ramesh Babu Tella
Original assignee: Council of Scientific and Industrial Research CSIR
Current assignee: Council of Scientific and Industrial Research CSIR
Priority date: 2004-07-20
Filing date: 2004-07-20
Publication date: 2011-03-17
Anticipated expiration: 2024-07-20
Also published as: AU2004321853A1; WO2006010994A1

Description

WO 2006/010994 PCT/IB2004/002473 1 PROCESS FOR PREPARING (S)- a-CYANO-3-PHENOXYBENZYL-(S)-2-(4 CHLOROPHENYL)-ISOVALERATE Field of Invention: The present invention relates to an environmentally benign process for the preparation 5 of (S)-a-cyano-3-phenoxybenzyl-(S)- 2-(4-chlorophenyl)isovalerate from its diastereomeric mixture (RS)-a-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl) isovalerate. More particularly, the present invention deals with the method for preparation of diastereomeric mixture of (RS)-a-cyano-3-phenoxybenzyl-(S)-2-(4 chlorophenyl)isovalerate (herein after referred as diastereomer-A) and its subsequent 10 conversion to (S)-a-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate (hereinafter referred as S,S isomer), the most biologically active isomer of racemic fenvalerate via the crystallization induced dynamic kinetic resolution. The method provides a process for preparation of S,S isomer besides effectively converting the undesired isomer (R)-a-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate 15 (hereinafter referred as SR isomer) via epimerization of the alcohol moiety using inexpensive catalyst to a desired diastereomeric mixture. Thus the method provides a simpler and efficient process for the industrial preparation of the biologically active SS isomer obviating the use of costly reagents such as cyclic dipeptides, enzymes as described in the prior art. This method also provides a route to green process in the 20 sense that the undesired SR isomer is converted to a useful entity within the process parameters thus reducing chemical burden on environment Background of the Invention As regards of SS isomer of general formula (I) C1 0 -- P I NI 0 25 Where the * indicate asymmetric carbon atom having "S" configuration on both acid and alcohol moieties is of great interest, as the resolved isomer, esfenvalerate (SS) is biologically most active and has fourfold higher insecticidal activity than that of racemic fenvalerate a commercially important synthetic pyrethroid. An economically WO 2006/010994 PCT/IB2004/002473 2 viable process for its preparation (SS isomer) is of great utility as it eliminates use of large quantity of a.i., thereby reducing chemical burden on environment. Reference is made to EP Patent application 0,040,991 wherein a method for preparation of an enantiomeric pair (SS-RR) having insecticidal activity is described. The main 5 draw-back of this process is that. it yields a pair of enantiomers (SS-RR) instead of a single stereo isomer (SS). Reference is made to the Patent application DE 2830031 wherein the process for preparation of esfenvalerate from its diastereomeric mixture is described. It describes a method for crystallization of SS isomer with or without using catalyst by four different 10 processes. The method A describes a process wherein SS isomer is crystallized without using a catalyst. The method B describes a process where in epimerisation at asymmetric carbon atom of alcohol moiety is effected by using a protic solvent or /and base catalyst. The method C describes a process wherein mother liquor after separating SS 15 isomer is subjected to epimerisation with or without a catalyst. The method D performs the same procedure as in method C using a catalyst. The main draw back of this process is that it employs protic solvents like methanol, ethanol with bases viz triethylamine, ammonia at temperature OC .to - 5'C. At this temperature decomposition of the product, along with side reactions is observed. 20 Another draw back is that the experimental conditions described are not completely reproducible albeit the procedure described is strictly followed. EP patent 0050521, by Sumitomo Chemical Company Ltd. Japan, claims a method for preparation of SS isomer starting from a super saturated solution of diastereomeric mixture having respectively S configuration on acid moiety and (S), (R) configuration 25 on Alcohol moiety using pure seed crystal solution of S-S isomer in presence or absence of basic catalyst. However the method could not be reproduced with consistency albeit the experimental conditions are followed as described in the patent. Another drawback of this method is that when base catalyst like ammonia, triethylamine is used as described in experimental procedure of the patent, many a time 30 product degeneration is observed in contrast to the crystallization of SS - isomer. Preparation of (S)- c-cyano-3-phenoxy benzylalcohol by different methods viz. cyclic dipeptide, enzymes are known in prior art, reference is made to US patent application 4,526,727 wherein a process is described for synthesis of (S)- a-cyano-3- WO 2006/010994 PCT/IB2004/002473 3 phenoxy benzylalcohol using cyclic dipeptide, cyclo (D-phenylalanyl-D-histidine) and its subsequent esterification with (RS)- 2-(4-chlorophenyl)isovaleric acid or its reactive derivatives to form a diastereomeric ester, followed by crystallization in a protic solvent to obtain SS isomer. The draw back of this process is that though cyclic 5 dipeptide catalyst is used to synthesise the desired (S)-alcohol, the scale up operations for these processes are not yet commercially viable. Yet another draw back is that the process described for synthesis of the di peptide depend upon many physical characteristics like non-crystallinity, cohesiveness of the cyclic dipeptide which require stringent controls in preparation of the cyclic di peptide and are difficult to 10 attain on scale up process leading to restriction of process parameters on a multi kilo scale preparation. Reference is made to US patent application 5,177,242 where in a method to prepare optically active (S)-cyano-3-phenoxybenzylalcohol by reacting corresponding aldehyde with hydrocynic acid using an enzyme S-oxynitrilase immobilized on a membrane is 15 described. The draw back of this method is that though it may be performed with reasonable success on a laboratory scale, it is difficult to obtain the enzyme of desired activity level on a multi scale operations as the enzyme activity is variant w.r.t. source of its isolation. 20 Another disadvantage of this method is the stringent physical parameters to be maintained for immobilization of enzyme on the membrane with out effecting denaturation may practically pose problems on a commercial process. Objects of the invention: The main object of the present invention is to develop a process for production of SS 25 isomer [(S)-a-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate]. It is another object of the invention to provide a process for preparation of diastereomeric mixture of (RS)-a-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl) isovalerate (hereinafter referred as diastereomer-A) in an effective manner which consistently yields the desired isomer on crystallization. 30 It is another objective of the invention to utilize an inexpensive catalyst to convert the undesired isomer (R)-c-cyano-3 -phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate (hereinafter referred as SR Isomer) via epimerisation of the alcohol moiety to useful entity.

4 A further objective of the invention is to provide an environmentally benign process for production of biologically active SS isomer avoiding costly reagents known in prior art. A further object of the invention is to provide a process for conversion of undesired 5 isomer into useful entity with in the process parameters and recycle it to the processes of crystallization, thus reducing chemical burden on environment resulting in enhancing cost effectiveness of the process. Summary of the invention: The present invention relates to an environmentally benign process for the 10 preparation of (S)-a-cyano-3-phenoxybenzyl-(S)- 2-(4-chlorophenyl)isovalerate from its diastereomeric mixture (RS)-a-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl) isovalerate. In one specific embodiment, there is provided a process for preparation of (S)-a cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl) isovalerate (SS isomer), said process 15 comprising the steps of; a. crystallizing (RS)-a-cyano-3-phenoxybenzyl-(S)-2-(4-chloro phenyl)isovalerate (diastereomer-A), in presence of crystals or slurry of SS isomer of a purity of 99% or greater, in a solvent that is a saturated solution or of 1,2-dichloroethane to obtain crystals of SS isomer from 20 mother liquor; b. epimerizing the mother liquor enriched with RS isomers, and c. recycling for further batches of crystallization. Detailed description of the invention: Accordingly the present invention provides a process for manufacture of (S)-X-cyano-3 25 phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate which comprises preparation of a diastereomeric ester (RS)-a-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate (diastereomer-A), a supersaturated solution of which in a hydrophilic organic solvent like alcohol having 1-5 carbon atoms in presence of pure SS seed crystals on controlled crystallization yields the desired SS isomer which was separated and the mother liquor 30 enriched with unwanted SR isomer was epimerised and recycled into further batches of crystallization. 25242651 (GHMatters) 60111I 4a In one embodiment of the invention, the diastereomeric ester (Diastereomer-A) is prepared either by addition of (S)-2-(4-chlorophenyl) isovaleroyl chloride to aqueous solution (RS)-c-cyano 3-phenoxybenzylalcohol or addition of a premixed solution of 5 (RS)-3-phenoxybenzaldehyde and (S)-2-(4-chlorophenyl) isovaleroyl chloride to aqueous solution of sodium cyanide under PTC conditions, more preferably by addition of (S)-2-(4-chlorophenyl)isovaleroylchloride to aqueous solution of (RS)-c-cyano3 phenoxybenzylalcohol under PTC conditions. In another embodiment of the invention the choice of solvent is selected from the 10 group consisting of aromatic hydrocarbon, chlorinated hydrocarbons like toluene, benzene, hexane, chloroform, 1,2-dichloroethane, dichloromethane respectively, more preferably 1,2-dichloroethane. 25242651 (GHMatters) 6101/11 WO 2006/010994 PCT/IB2004/002473 5 In another embodiment of the invention the phase transfer catalyst is quarternary ammonium salt selected from the group consisting of tertabutylammoniumbromide (TBAB), tertiarybutylammoniumhydrogensulphate (TBAHS), Benzyltriethylammonium chloride (TEBA) benzyltributylammoniumchloride, N-butyl 5 N,N-dimethyl-ca-phenylethylammoniumbromide. In yet another embodiment of the invention, the quaternary ammonium salt is tetrabutylammoniumbromide. In yet another embodiment of the invention, sodium cyanide is used in amount of 1.0 to 1.60 mole per mole of 3-phenoxybenzaldehyde. 10 In further embodiment of the invention, (S)-2-(4-chlorophenyl). isovaleroylchloride is used in amount of 1.0 to 1.03 mole per mole of 3-phenoxybenzaldehyde. In yet another embodiment of the invention, the (S)-2-(4-chlorophenyl) isovaleroyl chloride is added over a period of time ranging from 100-120 minutes. In yet another embodiment of the invention, the (S)-2-(4-chlorophenyl) 15 isovaleroylchloride is added to an aqueous solution of (RS)-a-cyano-3-phenoxy benzylalcohol at a temp. ranging from -2'C to -4'C. In another embodiment of the invention the course of the esterification reaction is followed by HPLC analysis drawing samples at intervals of time ranging from 30-90 minutes. 20 In a further embodiment of the invention, the reaction is continued after addition of acid chloride for a further period of time ranging from 60-120 minutes. In a further embodiment of the invention, the diastereomeric ester formed (dilute diastereomer-A) is concentrated under pressure ranging from 80-60 mm Hg to obtain diastereomer-A. 25 In another embodiment of the invention, the solvent recovered from distillation of dilute diastereomer-A is recycled for further batches of diastereomer-A formation. In another embodiment of the invention, the diastereomeric ester (diastereomer-A) is subjected to the process of crystallization either by equilibration at a temperature range of 200'-220'C under vacuum ranging from 100-50 mm Hg or without such operation 30 more preferably without equilibration, by preparing a saturated solution in an organic solvent or solvent mixtures thereof and cooling the solution in such a manner that when seed/slurry of SS isomer is introduced, the added crystals remain thereafter in solution, WO 2006/010994 PCT/IB2004/002473 6 in undissolved state and only crystals of required isomer (SS) alone crystallizes from the solution. In yet another embodiment of the invention, the process of crystallization is controlled by predetermined rate of cooling the solution to a temperature range and 5 maintaining the solution at that temperature range for sufficient period such that the rate of crystallization of SS isomer is conspicuous and the process is continued for sufficient period of time, till the crystallization of desired SS isomer is completed as indicated by enrichment of SR isomer in supernatant liquid. In yet another embodiment of the invention, the progress of crystallization is 10 monitored by chiral HPLC analysis, drawing samples at regular intervals of time to find the enrichment of SR isomer. In yet another embodiment of the invention, the process of crystallization is stopped when the analysis of SR isomer is in the range of 50-55%. In a further embodiment of the invention, the process of crystallization is preferably 15 increased either by stirring or shaking the solution more preferably by stirring. In another embodiment of the invention, the process of crystallization can be carried out at a temperature range +10 0 C to -15"C and most advantageously at a range of +2 0 C to - 8 0 C. In another embodiment of the invention, the reaction time is such that it should be 20 adequate to ensure that desired product (SS-isomer) of sufficient purity is obtained, generally in the range of 24-80 hrs more preferably 30-60 hrs. In yet another embodiment of the invention, the organic solvent selected is from the group comprising of lower alcohols and/or aromatic aliphatic hydrocarbons or mixtures thereof. 25 In another embodiment of the invention, the solvent is selected from alcohols consisting of methanol, ethanol, isopropanol and hydrocarbon solvents like Hexane, Toluene, Heptane. In another embodiment of the invention, the solvent is more preferably lower alkanol like methanol. 30 In another embodiment of the invention, the concentration of the diastereomer-A in solution is preferably in the range of 12-40% w/w w.r.t. solvent and more preferably in the range of 12-30%.

WO 2006/010994 PCT/IB2004/002473 7 In further embodiment of the invention, the mother liquor enriched with SR isomer obtained after separation of the desired SS isomer is concentrated under reduced pressure to remove the solvent and then heated to a temperature of 50'-90' more preferably at 60'-70"C under vacuum for a period of 1-4 hrs more preferably 2-3 hrs, 5 cooled to room temperature and subjected to process of crystallization to obtain further quantity of the desired isomer (SS)-isomer. In another embodiment of the invention, the mother liquor enriched with SR isomer is treated with a catalyst to effect equilibration of the isomers thus conveniently avoiding the tedious process of concentration of the mother liquor and subsequent 10 heating thus reducing reaction times. The equilibrated mother liquor having almost equal ratio's of both isomers (SS:SR) is further subjected to process of crystallization of desired (SS) isomer. In another embodiment of the invention, the mother liquor equilibrated is replenished with an amount of diastereomer-A equivalent to the weight of SS isomer 15 obtained from process of crystallization and further subjected to process of crystallization maintaining the same concentration of the solution. This process is iterative and continued till crystals of SS isomer is obtained, thus, quite advantageous from the commercial point of view. In another embodiment of the invention the catalyst employed for equilibration can 20 either be organic or inorganic bases like alkali and alkaline earth metal hydroxides and carbonates like sodium hydroxide, potassium hydroxide, sodium carbonates and nitrogen containing bases like ammonia, dimethylamine, triethylamine, quaternary ammonium hydroxide like tetrabutylammoniumhydroxide, triethylbenzyl ammonium chloride or optically amines like (-) phenylethylamine or halides of alkali metals or 25 ammonium halides. The more preferred base being fluorides of alkali metals or ammonium halides most preferably potassiumfluoride. In yet another embodiment of the invention, with regard to the quantity of catalyst used it can be employed in the range of 2-10 mole%, more preferably in the range of 4-6 mole% w.r.t. the SR enriched mother liquor. 30 The process of the invention involves the preparation of diastereomeric mixture (diastereomer-A) in such a manner when it is subjected to process of crystallization, only crystals of SS isomer precipitates out and the mother liquor enriched with undesired isomer (SR isomer) is epimerised using an inexpensive catalyst and recycled WO 2006/010994 PCT/IB2004/002473 8 to the process of crystallization in an iterative manner till crystals of SS isomer is obtained. In this quest for development of a suitable technology, a comprehensive search for solvent system and catalyst was undertaken to circumvent the problems encountered in referred EP 0,050,521. The results are tabulated in Table-1. 5 Despite many methods known in literature for the preparation of (S)- o-cyano-3 phenoxy benzylalcohol-(S)-2-(4-chlorophenyl)isovalerate, they have not yet been developed to the level where they can be carried out in an economic manner. In the present method of crystallization induced dynamic kinetic resolution (CIDKR), the SR isomer enriched mother liquor is epimerised at the benzyllic carbon atom using 10 inexpensive catalyst and iteratively subjected to the process of crystallization by replenishing with fresh diastereomer-A equal to the quantity of SS isomer obtained. This approach is more practicable and quite appealing for small preparations (m+ g) to pilot and process scale production (kg tonnes). Many a time the results obtained from crystallization experiments as performed 15 following the procedure described in EPO 0,050,521 are not reproducible albeit the conditions described therein are adhered to without deviation. Several modifications like varying of concentration of diastereomer-A, solvents, addition of additives like FeO, H 3

PO

3 , glacial acetic acid, process impurities like methyl ester of (S)-2-(4 chlorophenyl)isovalericacid, PTC catalyst, mother liquor were incorporated to the 20 crystallizing solution of diastereomer-A as described in experimental part without any success in obtaining the required SS isomer in a consistent manner. Physical parameters like heating the diastereomer-A at temperatures ranging from 60 -120'C and subsequent crystallization showed improved measure of success, though not to the manner where it can be useful entity on an industrial scale. Hence, a re-visit to the 25 preparation of diastereomer-A (Table-2) was resorted to, and attempts were directed to modify the procedure of diastereomer-A preparation. In the present process a solution of (S)-2-(4-chlorophenyl)isovaleroylchloride in dichloroethane was added to a preformed solution of (RS)-a-cyano-3-phenoxybenzylalcohol, and after usual work up, this diastereomer-A was subjected to crystallization induced dynamic kinetic resolution 30 (CIDKR) as such without resorting to any further operations like heating under vacuum etc., thus more importantly saving energy. The crystallization process can be performed at relatively high temperature than described in prior art.

WO 2006/010994 PCT/IB2004/002473 9 In an embodiment of the invention, the process of crystallization of diastereomeric mixture (diastereomer-A) is performed via a phenomena known as crystallization induced dynamic kinetic resolution. It is known that enantiomers / diastereomers of compounds possessing acidic hydrogen atom on an asymmetric carbon atom can be 5 epimerized with bases. In this process they pass briefly through the flat state. [P. Sykes; Explanations of reactions - methods and criteria of organic reaction mechanisms ; verlag chemie 1973, page 133, and D.J.. Cram. Fundamentals in Carbanion Chemistry, page 85-105, [Academic Press 1965] which is also observed in the case of the readily base catalyzed epimerisation of optically active mandelic acid 10 nitrile (a) and of the corresponding methylether (b) to the racemic compounds. CN CN OUH OCH3 HH a b It is also known that formation of inter convertible diastereomers may lead to the preferential and possibly even to sole crystallization of one of the two isomers. The necessary instability of the compounds (species) involved in this special type of 15 crystallization process may however, also make the isolation of pure enantiomer or diastereomers difficult. In spite of this potential draw back, the use of crystallization induced asymmetric transformation is very appealing, particularly when separations are attempted on industrial scale. It is observed that when two diastereomers in a mixture which are related as epimers in a super saturated solution are in equilibrium (Fig. 1) the 20 presence of base catalyst causes epimerisation of a diastereomer at chiral carbon which has acidic hydrogen as in the case of synthetic pyrethroid esters bearing cyano group on chiral carbon, the diastereomeric equilibrium is continually displaced by slow crystallization of one of the two species upon addition of homochiral crystals of an isomer. The species which crystallizes is not necessarily that which predominates at 25 equilibrium. This phenomena is described as crystallization induced asymmetric disequilibration in which the rate of crystallization of less soluble diastereomer is slower than the rate of equilibration of the two species in solution. This phenomena known as crystallization induced asymmetric transformation of second order even WO 2006/010994 PCT/IB2004/002473 10 though the work "order" is improperly used, the correct meaning in context is kind as asymmetric transformation of second kind. The diastereomeric ester (diastereomer-A) is prepared either by reaction of aqueous sodium cyanide with a premixed solution of 3-phenoxybenzaldehyde and (S)-(+)-2-(4 5 chlorophenyl)-isovaleroylchloride or by reaction of the acid chloride with a preformed c-cyano-3-phenoxybenzylalcohol under PTC conditions more preferably by latter method to obtain a diastereomeric ester which consistently yields the crystals of desired isomer (SS) on crystallization. The esterification is carried out in a solvent system selected from the group 10 consisting of chlorinated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons like chloroform, dichloromethane 1,2-Dichloroethane, hexane, heptanc, octane, toluene, benzene respectively more preferably, 1,2-Dichloroethane using PTC catalyst belonging to quaternary ammonium salt selected from the group consisting of tetrabutyl ammoniumbromide (TBAB), tetrabutylammoniumhydrogensulphate (TBAHS), 15 Benzyltriethylammoniumchloride (TEBA), Benzyltributylammoniumchloride, N-butyl N,N, dimethylphenylethylammoniumbromide, more preferably tetrabutylammonium bromide by addition of 3-phenoxybenzaldehyde to an aqueous solution of sodium cyanide at ambient or low temperature followed by the addition of (S)-2-(4 chlorophenyl) isovaleroyl chloride over a period of time ranging from 60-180 minutes 20 more preferably from 90-120 minutes at a temperature range of -60 to + 4'C, more preferably -3 to 0C under stirring, preferably maintaining the temperature of reaction for a further period of time ranging from 60-120 minutes after reaction, following the course of the reaction by HPLC analysis, drawing samples at intervals of time ranging from 30-120 minutes. The diastereomeric ester (diasteromer-A) formed is recovered 25 from its dilute solution by stripping of the solvent under vacuum (80-60 mm Hg) and purging Nitrogen gas to ensure complete removal of the last traces of the solvent. The diastereomeric ester (diastereomer-A) thus obtained is subjected to crystallization in a saturated solution containing solvent/solvent mixtures selected from the group comprising of lower alcohols and/or aromatic, aliphatic hydrocarbons and 30 mixed solvents thereof, preferably alcohols containing 1 to 5 carbon atoms such as methanol, ethanol, isopropanol, aromatic hydrocarbons benzene, toluene, aliphatic hydrocarbons, hexane, heptane, octane, more preferably methanol in a concentration in the range of 12-40% w/w more preferably in the range of 12-30% WO 2006/010994 PCT/IB2004/002473 11 w/w by following a programmed rate of cooling viz stepwise decreasing the temperature to 20'C from ambient temperature, thereby cooling to 10"C at intervals of time preferably 2-8"C per hour more preferably 4-6'C per hour. At this temperature (10 0 C) pure crystals of SS isomer or slurry more preferably pure crystals (SS isomer) is 5 introduced, wherein the added crystals/slurry remain in solution in undissolved state, decrease in temperature is continued to reach the onset temperature of crystallization at the rate of 2-1 0 C per hour preferably 1C per hour and maintained around the onset of crystallization (2-5'C) wherein the crystallization of SS isomer is conspicuous. Further decrease in temperature is effected by maintaining the solution at a 10 temperature range of +2 to 18'C for a sufficient time ranging from 24-72 hrs, preferably 24-36 hrs by shaking or stirring the solution preferably stirring until crystallization is substantially completed as indicated by chiral HPLC analysis wherein samples of supernatant liquid indicate enrichment of undesired SR isomer. The crystallization process is stopped when SR isomer is in the range of 50-55% separating 15 the crystals of SS isomer from solution either by filtration, decantation, or centrifugation, more preferably by filtration. The mother liquor separated from the desired SS isomer is either concentrated under reduced pressure and heated to 60 0 -70'C under vacuum for 2-3 hrs and subjected to process of crystallization or the mother liquor is epimerised using either an organic or 20 inorganic base catalyst, which is stable under reaction conditions, examples include nitrogen containing bases like Ammonia, Triethylamine, 1-naphthylamine, quinoline, quaternary ammonium hydroxides like TEBA, TBAH also useful are inorganic bases like alkali and alkaline earth metal hydroxides carbonates, halides more preferably potassium fluoride in 2-10 mole % by heating generally for 4-6 hrs preferably 3-5 hrs 25 till the ratio of two isomers is almost equal as indicated by chiral HPLC analysis. The contents are cooled and subjected to the process of crystallization or more conveniently the equilibrated mother liquor is -eplenished with an amount of diastereomer-A equal to the wt. of crystals of SS isomer obtained in earlier cycle and subjected to process of crystallization as described above. This step is iterative and continued by addition of 30 diastereomer-A each time till crystals of SS isomer is obtained. Thus consecutively using the equilibrated mother liquor of one cycle in another cycle as such avoids many process steps and enriching mother liquor with diastereomer-A to the extent of crystals (SS isomer ) obtained maintains the saturated WO 2006/010994 PCT/IB2004/002473 12 state of solution as also the catalyst is reused more often, with out isolation. By the use of combined enrichment and crystallization process, all the desired isomer (SS ) may be effectively recovered from the diastereomeric mixture (diastereomer-A). BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWING: 5 Fig.1: shows second order asymmetric transformation The following examples are given by way of examples and therefore should not construed to limit the scope of the present invention. EXPERIMENTAL PART-A 10 EXAMPLE-1 Preparation of (RS)-a-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl) isovalerate (diastereomer-A): 81.37gms of NaCN and 815.5gms of water is charged into a suitable reactor equipped with cooling system, mechanical stirrer, dropping funnel and thermometer. 15 The contents are mixed well and 49.6g of dichloroethane and 10.2 gms of tetrabutylammonium bromide is charged into the reactor under stirring and cooled to +5'C. 246.98g of (S)-(+)2-4(-chlorophenyl)isovaleroyl chloride and 205.4gms of metaphenoxybenzaldehyde was mixed with 803 ml of dichloroethane and added over a period of 90 mts. through a dropping funnel under vigorous stirring. The temperature 20 of the reaction inixture was maintained at +4'C for a further period of 4 hrs and brought to room temperature. The organic layer (DCE) is separated out and washed with distilled water (3x200ml) till pH of aqueous layer is neutral. The dilute organic layer (DCE) is concentrated to obtain crude ester (diastereomer-A) of composition of SS:SR ratio 46:48 in 95% yield. 25 Wt. of ester = 441.5 Ratio of SS:SR = 46:48 This material is used for preferential crystallization of esfenvalerate. EXAMPLE -2 10 gms of diastereomer-A of having SS/SR ratio 46.1/48.4 is dissolved in 13.13gms 30 of Heptane, toluene mixture containing 10% of toluene by heating and transferred to a suitable R.B flask provided with thermovel, and stirrer. At room temperature the solution was turbid to which 7.Og of methanol was added and cooled to -16C under stirring for about 65 hrs. by adding a seed crystal (99.3) of SS-isomer at -13 0 C at the WO 2006/010994 PCT/IB2004/002473 13 end of which a viscous mass was observed . No preferential crystallization was noticed. Wt. of crude = 1O.Ogms % purity of SS isomer = 46.1 5 EXAMPLE - 3 To 9.84 of liquid diastereomer-A was added 17.76gms of methanol to form a 35% w/w solution of diastereomer-A which was refluxed for 1 hr at 65 0 C and cooled to room temperature. The resulting solution was subjected to crystallization by cooling in a cryogenic bath to +6'C. A seed crystal of SS isomer of 99.9% purity was added to the 10 solution at 15'C and process of crystallization was continued for 18 hrs. at 6'C. The crystals obtained were filtered off. Wt. of crystals = 8.86 % purity of SS-isomer = 46.57 Wt. of ML = 16.31gms 15 EXAMPLE-3A The mother liquor obtained (16.3 g) in the above example-3 was further subjected to the crystallization by adding a seed crystal at 2"C and the process of crystallization was continued for 22 hrs. at +6 0 C. At the end of which the crystals obtained were filtered off and analyzed. 20 Wt. of crystals = 0.51g % purity of SS-isomer = 95 EXAMPLE.- 4 52.2gms of liquid diastereomer-A of Fenvalerate was dissolved in 1 lOg of Methanol to obtain a solution of 32% w/w diastereomer-A which was refluxed for 1 hr and 25 cooled to room temperature. The solution was filtered off and cooled under stirring form 23'C to -15'C. A seed crystal of pure SS-Isomer of 99% purity was introduced into the system at -14'C. The process of crystallization is continued for a period of 170hrs at the end of which the crystals obtained were separated and filtered off. Wt. of crystals = 20.Og 30 % purity of SS-isomer = 42.89 Wt. of ML = 115.86gms WO 2006/010994 PCT/IB2004/002473 14 EXAMPLE - 4A The ML of example 4 (115.88g) is concentrated and divided into two parts. TolO.7gms of Diasdtereomer-A was added 14.6 gms of heptane toluene mixture of composition as described in example-2 and refluxed for 2 hrs. The contents were 5 cooled to room temperature and 7.7g of methanol was added and cooled to -10 C in a cryogenic bath. A scoop of seed crystals of SS isomer of 99.9% was added at -10 0 C. The solution was cooled to -14'C and maintained at that temperature for 144 hrs. The precipitated crystals were removed by filtration and ML was separated out. Wt. of crystals = 0.9g 10 % purity of SS isomer = 98 EXAMPLE -5 To 19.96 gms of liquid diastereomer-A obtained from ex- 1 was added 61 ml of MeOH heated to reflux, cooled to room temperature and filtered off. The solution was cooled in a cryogenic bath under stirring by setting the temperature to -15'C seed crystals of 15 SS-Isomer (99.3%) was introduced after temperature reached to -15'C and further cooling was continued for 96 hrs. At the end of which the precipitated crystals were separated out. Wt. of crystals = 9.22g % purity of SS-isomer = 45.2% 20 Wt. of ML = 87.20gms EXAMPLE - 5A The ML obtained from the above example-5 was further subjected to crystallization by cooling to -15'C. At -1 VC a slurry of seed crystals (0.07248g; 99%) of SS-isomer was introduced. The solution is stirred at -1 5.5'C for a period of 96 hrs. The separated 25 out crystals were weighed and air dried. Wt. of crystals = 6.80g % purity of SS-isomer = 57.1 EXAMPLE -6 20.Og of Mother liquor obtained from experiments where no preferential 30 crystallization has not occurred was dissolved in 143gms of Methanol to obtain a 12% w/w solution of diastereomer-A and subjected to process of crystallization by cooling to -8'C under stirring in a reactor with a provision for temperature recording and addition of seed crystals. A seed crystal of 99.3% of SS-Isomer was introduced at -8'C, WO 2006/010994 PCT/IB2004/002473 15 followed by 4m] of (6% w/w) methonolic ammonia. The cooling at -8 0 C was continued for 87 hrs and solids obtained were analyzed for SS-isomeric content. Wt. of crystals = 7.40g % purity of SS-isomer = 97.45% 5 Wt. of ML = 155.88g EXAMPLE-7 The mother liquor obtained from above example-6 was subjected to preferential crystallization as described below: 7.36g of diastereomer-A obtained after concentration of Mother liquor(155.8g) from 10 above example-6 was dissolved in MeOH to obtain a 12% solution of diastereomer-A which was cooled under stirring in a cryogenic bath from +4'C to -15'C. 2.3 ml of methonolic ammonia of 6% (w/w) was introduced into the system at -4'C followed by SS-isomer seed crystal (99%). The process of cooling is continued for a period of 42 hrs and the crystals obtained were separated out. 15 Wt. of crystals = 2 .95g % purity of SS-isomer = 98.4% EXAMPLE-8 16.07g of solids of isomeric ratio of SS:SR (1:1) obtained from experiments 30, 33, 34 (Table-1) was dissolved in MeOH to get a solution of 12% and subjected to 20 crystallization in a cryogenic bath by cooling from room temperature to -5 0 C. A pure seed crystal of SS-isomer (99%) was introduced at 0C followed by 3.2ml of 6% w/w methanolic ammonia. The solids obtained were filtered off at the end of 94 hrs and analyzed. Wt. of crystals = 8.86k 25 % purity of SS-isomer = 43.2% Wt. of ML = 116.4gms EXAMPLE-9 5.14g of diastereomer-A was dissolved in MeOH to obtain 12% solution. To the above solution 0.06g (2 mol%) of TBAOH (tetrabutylammoniumhydroxide) was added 30 and cooled to -5 0 C. At that temperature a seed crystal of SS-isomer (99.3%) was introduced into the system and further cooling was subjected in a stepwise manner to 17'C (-5"C for 18hr; -10 0 C for 24hrs, -15'C for 29 hrs and -17'C for 40 hr) at the end of which the crystals obtained were filtered off and analyzed.

WO 2006/010994 PCT/IB2004/002473 16 Wt. of crystals = 0.81g % purity of SS-isomer = 96.38% EXAMPLE-10 5.03g of diastereomer-A was dissolved in MeOH to obtain 17.4% solution which 5 was subjected to crystallization in a cryogenic bath at -1 5oC to -1 8'C for a period of 81 hrs by adding 2.0ml of 6% methonolic ammonia and seed crystal (99.3%) at -15 0 C. The crystals obtained were separated. Wt. of crystals = 1.28g % purity of SS-isomer = 92.9% 10 EXAMPLE-11 23.25 gins of diastereomer-A whose composition consists of 5.Og liquid diastereomer-A and the rest obtained from mother liquor of KR-92 (Table-1) was dissolved in 97.45 gins of MeOH to obtain 19.26 w/v solution which was subjected to cooling in a cryogenic bath from room temperature to -8.6'C in 48 hrs. A seed of pure 15 SS isomer (99.3%) was introduced at -8'C followed by 10ml of MeOH/NH 3 of 6% w/w. At the end of reaction time (48 hrs) 2.Oml of acetic acid was added and the crystals obtained were separated out. Wt. of crystals = 1.16g % purity of SS-isomer = 97.6% 20 EXAMPLE-12 2.0 gms of diastereomer-A having SS:SR 45:46 ratio was mixed with 0.5gms of SS isomer and 22.5 g of MeOH was added to obtain 10% w/w solution of diastereomer-A which was enriched with 20% of SS isomer. This solution was subjected to crystallization under at a stepwise cooling from +5'C to -3'C by adding a seed crystal 25 at 0 0 C. The process of crystallization was continued for a period of 147 hrs, at the end of which the crystals obtained gave a purity of 70% of SS-isomer. Wt. of crystals = 1.43g % purity of SS-isomer = 69% Wt. of ML = 21.09 30 EXAMPLE-13 a. In a suitable reactor provided with a provision for measurement of temperature was added 8.Og of diastereomer-A and 12g of heptane, toluene mixture (Hep:Tol = 1:1) to obtain 40% w/w solution. The solution was cooled to -5 0 C, a seed crystal of SS isomer WO 2006/010994 PCT/IB2004/002473 17 (99%) was introduced and further cooling at that temperature was continued for 90 hrs. the crystals were separated out and analyzed for their SS-isomer content. Wt. of crystals = 0.11 g % purity of SS-isomer = 77.2% 5 Wt. of ML = 20.46 b. The mother liquor (40%) was further subjected to crystallization following the procedure described above except that the solution was cooled to -13'C for 240 hrs. the crystals obtained were separated out by filtration. Wt. of crystals = 2 .85g 10 % purity of SS-isomer = 54.2% EXAMPLE -14 In a suitable reactor was placed diastereomer-A (36.33g) obtained form the experiments where the preferential crystallization has not been achieved and methanol (2.38g), and stirred well to obtain a 13% w/w solution of diastereomer-A. This solution 15 was cooled in a cryogenic bath under stirring from +5'C to -10 C at the rate of one degree per hour. Seed crystal of SS-isomer (99.3%) was introduced into the system at -1 0 C and further cooling after reaching -10'C was continued for 36 hrs. The solids obtained were separated out by filtration and analyzed. Wt. of crystals = 13.31 g 20 % purity of SS-isomer = 96.5 EXAMPLE -15 In a 250ml round bottom flask was placed 10.08gms of diastereomer-A and 67.0gms of a mixture of IPA and hexane (45:55) heated to reflux (90'C) for lhr. The solution was cooled to room temperature, filtered into a 250ml round bottom flask, having 25 provision for temperature measurement, stirrer and cooled to 5'C in a cryogenic programmed temperature bath. Further cooling from +5 to -0 OC was effected in such a manner that there was a decrease of one degree for every 60 minutes. A seed crystal of SS-isomer was added to the solution at +1'C and cooling is continued till -10C. After remaining at -1 OC for 24 hrs. The solids obtained were separated out and analyzed. 30 Wt. of solids = 6.43 g % purity of SS-isomer = 49.83 WO 2006/010994 PCT/IB2004/002473 18 EXAMPLE -16 Tol7.69gms of concentrated, mother liquor obtained from experiments after separating the solids (SS:SR 1:1) was added 0.llg of methyl ester, of (S)-2-(4 chlorophenyl)isovaleric acid, and 116gms of methanol to obtain 13.3% w/w 5 homogeneous solution of diastereomer-A and refluxed for lhr; The contents were cooled to room temperature and subjected to crystallization in a cryogenic bath by cooling in a stepwise manner from RT to +3'C in 4 hrs. Further cooling was effected to -4'C at the rate of 1C for 60 minutes. A seed crystal of SS-isomer (99.3%) was introduced at -2 0 C. The solution was held at -3'C for a further period of 72 hrs at the 10 end of which solids obtained were separated and analyzed. Wt. of crystals = 7.84 g % purity of SS-isomer = 44.5 EXAMPLE-17 8.82g of diastereomer-A (SS:SR 1:1) was mixed with 1.5gm of mother liquor of earlier 15 experiments and dissolved in methanol (55g), heated to reflux for one hr to obtain 13.9% solution of diastereomer-A which was cooled to room temperature and. transferred to a suitable reactor provided with thermovel to measure temperature and a stirrer. The stirred solution was cooled in a cryogenic bath at a stepwise rate of cooling of one degree centigrade for one hour from +50 to -7'C. Pure SS isomer (99.3%) was 20 added to the cooling solution at +1VC. After keeping the solution at -7 0 C for 1 hrs the solids obtained were filtered and separated. Wt. of Solids = 5.63 g % purity of SS-isomer = 45.23 EXAMPLE-18 25 15.05gms of diastereomer-A having ratio of SS:SR 45:48 obtained from unsuccessful experiment of preferential crystallization was dissolved in 101 gms of methanol to obtain a 13% solution of diastereomer-A to which 0.Olg of iron rust was added. This solution was subjected to crystallization in a 250ml round bottom flask having provision for temperature recording and stirring by placing in a cryogenic bath 30 and decreasing the temperature at the rate of +1 0 C/hr from +12'C to -5"C. A slurry of seed crystals crystallized from pet ether was introduced into the system at +1 0 C and further cooling is effected till temperature was reached to -5'C. The solution was held WO 2006/010994 PCT/IB2004/002473 19 at -5'C for a further period of 10 hrs. The crystals obtained at -5'C were dissolved while filtering. Wt. of crystals = 0.63 g % purity of SS-isomer = 43.62 5 Wt. of ML = 110.68 EXAMPLE-19 15.04g of diastereomer-A was equilibrated at 120'C under vacuum for 2 hrs, cooled to room temperature and 95 gms of methanol was added to obtain 13.6% solution of diastereomer-A. This solution was subjected to crystallization, in a 250ml round 10 bottom flask fitted with a stirrer, a thermovel and an arrangement to add a slurry of seed crystals, by cooling the solution at a programmed rate from +100 C to -13'C at the rate of 1"C/3hrs. When the temperature reached +10'C, slurry of seed crystals in hexane obtained by fresh crystallization of 200mg of SS-isomer of 99.3% was added at once. After reaching -13'C the solution was continued to be kept at that temperature 15 for 48 hrs and the solids obtained were filtered off. Wt. of crystals = 2.13 g % purity of SS-isomer = 94.7 Wt. of ML = 106.29 EXAMPLE-20 20 Diastereomer-A having SS:SR in the ratio of 1:1 obtained from crystallization experiments wherein preferential crystallization has not taken place was pooled together and 13.0g of that material was equilibrated at 120'C for 2 hrs under vacuum (200-3'00mm) and cooled to room temperature and was dissolved in 85gm of MeOH to obtain a 13.0% solution of diastereomer-A. This solution was filtered off and 25 transferred to a suitable reactor having provision for stirring, temperature measurement and introduction of slurry seed of crystals. This solution was gently stirred from +1 OC to -13'C in a cryogenic bath following a rate of cooling of 1 C/3hr after addition of about 200mg of slurry of seed crystals (SS-isomer) and 100mg iron rust at +10C. After reaching -1 3 0 C the solution was continued to be at that temperature for a further 30 period of 52 hrs and crystals were separated out by filtration. Wt. of crystals = 2.13 g % purity of SS-isomer = 94.7 WO 2006/010994 PCT/IB2004/002473 20 EXAMPLE-21 60.0g of diastereomer-A was equilibrated at 1 10 C for 12 hrs and cooled to room temperature. To the above liquid diastereomer-A was added 400g of MeOH to obtain 13.0% solution. This solution was subjected to programmed rate of cooling l 0 C/5hr 5 from +10 0 C to +2'C while introducing a seed crystal of SS-isomer (99.3%) at +10 0 C under gentle stirring in a 500ml round bottom flask by keeping in a temperature programmed cryogenic bath. After attaining the temperature of +2'C the solution was further held at that temperature for 40hrs. and crystals obtained were separated by filtration. 10 Wt. of crystals = 1.67 g % purity of SS-isomer = 98.2 EXAMPLE-22 10.Og of diastereomer-A having a ratio of SS:SR in 1:1 was dissolved in 66g of methanol to obtain 13.0% solution of diastereomer-A. This solution was subjected to 15 crystallization by addition of slurry seed crystals in hexane at +10 0 C and cooling the solution from that temperature to 4"C in a phased manner while introducing 0.Olg of quinide at 6'C and further cooling the reaction mass to 4 0 C and holding the solution at that temperature for 36 hrs. At the end of which the crystals obtained were analyzed. Wt. of crystals = 0.95 g 20 % purity of SS-isomer = 42.0 EXAMPLE-23 10.0g of diastereomer-A was equilibrated at 120'C for 2 hrs and cooled to room temperature. To the liquid isomer-A was added 67.Og of methanol to obtain 12.8% solution of diastereomer-A which was subjected to crystallization by addition of 0.33g 25 of glacial acetic acid and cooling the solution from +18'C to +3 0 C under stirring at a rate of cooling of 2 0 C/hr by addition of a slurry of seed of crystals (200mg) at 14C. After reaching +7'C the solution was cooled to +3'C at the rate of 1 C per every 3 hrs. and held at that temperature for 48 hrs and the crystals were separated by filtration. Wt. of crystals = 3.46 g 30 % purity of SS-isomer = 47.02 EXAMPLE-24 99.5 gins of liquid isomer prepared on a 3.0kg batch scale as described in example-l was heated at 120'C for 3 hrs and cooled to RT. Thus obtained material was dissolved WO 2006/010994 PCT/IB2004/002473 21 in 618 gms of methanol to obtain 13.8 solution of diastereomer-A which was cooled at a programmed rate of 1*C/hr from -10 0 C to -8"C in a suitable reactor having provision for stirring, introduction of slurry seed and measurement of temperature slurry seed of crystals freshly crystallized in hexane of SS isomer were introduced at +8 0 C. Further 5 cooling to -12 0 C from -8"C was affected at the rate of 1VC/3 hrs, after reaching -12'C the solution was held at that temperature for 48 hrs and solids obtained were filtered off and analyzed. Wt. of solids = 1.39g % of SS-isomer = 94.0 10 Wt. of ML = 704.68 EXAMPLE-25 The mother liquor of example-24 (704.68g) after separating the 1.39g of crystals was concentrated and made to a solution of 19.8% in methanol. 140.Og of heptane was added to -the solution and the programmed rate of cooling from +6 0 to -13'C was 15 continued by introduction of slurry seed of SS isomer at 5'C as described in above example. The reaction mixture was kept at -1 3 0 C for a period of 90 hrs. the separated crystals were analyzed for SS-isomer content by HPLC. Wt. of solid: 9.54 % purity of SS isomer = 97.5 20 EXAMPLE-26 17.36g of liquid isomer-A melted at 120'C was dissolved in 90.3g in methanol-toluene mixture (87:3.2) to obtain a 16.87 % diastereomer-A solution. This solution was cooled from +20'C to 14C at a programmed rate of cooling of 2 0 C/hr in a cryogenic bath while stirring and seeded with a crystal of 99.9% SS-isomer at +14 0 C. Further 25 cooling from +14'C to +2'C was performed at the rate of +1 0 C/90 minutes. - After reaching the temperature of +2'C the solution was held at that temperature for a period of 12 hrs under gentle stirring. The crystals obtained are filtered and analyzed for SS isomer content by HPLC. Wt. of solids - 7.05g 30 % of SS-isomer = 43.3g EXAMPLE-27 20.Og of diastereomer-A was equilibrated at 120C for 4 hr cooled to RT and made to 11.5% diastereomer-A solution in methanol-toluene mixture containing 3% of WO 2006/010994 PCT/IB2004/002473 22 toluene. This solution was cooled from +15 "C to -6'C in a suitable reactor provided with a stirrer, thermovel, and provision for introduction of seed crystals by placing in a cryogenic bath having programmed temperature cooling facility. A seed crystal of 99.3% of SS-isomer was added at +9"C and cooling is continued from -6'C at 1 0 C/hr. 5 1.0 ml of 9% w/w methonolic ammonia was added at -3'C. The solution was held at 6'C for a period of 16 hrs and crystals were separated out and analyzed for SS isomer content. Wt. of solids = 6.7g % of SS-Isomer = 42.27 10 EXAMPLE-28 40.02 gms of diastereomer-A prepared on a 3.0kg scale batch prepared according to procedure described in example-1 was dissolved in a mixture of Heptane (65g), N,N DEA ( 2 8.0g) and hexane (18.9g) to obtain 30% solution. Prior to this, the diastereomer-A was equilibrated at 120 0 C for 4 hr as described in above examples. 15 Thus obtained solution was cooled in an appropriate reactor having provision for seed crystal addition, thermovel and stirrer following a programmed cooling in a cryogenic bath at the rate of 1 0 C/hr from --10 *C to -10 C. A seed crystal of 99.3% of SS isomer was added at +6 C. After reaching -10 C, the reaction mixture was held at that temperature for a further period of 24 hrs, at the end of which solids were separated 20 by filtration. Wt. of solids - 2.54g % of SS-isomer = 81.35 EXAMPLE-29 10.26g of diastereomer-A was dissolved in 31.26gms of methanol to obtain a 25% w/w 25 solution which was cooled in a reactor provided with a provision for seed crystal addition, thermovel and stirrer 0.03g of tetrabutylammoniumbromide (TEBA) and 4.Oml of glacial acetic acid was added at 21 C followed by addition of pure SS-isomer crystals of 99.3%. Further cooling was followed by a temperature programme designated at the rate of I 0 C/4 hr to +15 0 C. The solution was kept at that temperature 30 for 19 hrs wherein growth of crystals was conspicuous and started increasing. At the end of 19 hrs at 15 0 C, the crystals were separated by filtration. Wt. of solids - 4.75g % of SS-Isomer = 47.02 WO 2006/010994 PCT/IB2004/002473 23 EXAMPLE-30 10.04gms of diastereomer-A was dissolved in 30gms of MeOH to obtain 25.0%w/w solution. To which was added 0.520g of fenvaleric acid and 0.018g of PTC catalyst (TBAB) and refluxed for 2/2hrs. This solution was transferred to a suitable reactor 5 provided with a stirrer, thermovel, provision for seed crystal addition and kept in a cryogenic bath for cooling from +25 0 C to +19'C at 1*C/2 hrs. A seed crystal was introduced at +19'C. After reaching +19 0 C the solution was held at that temperature for 20 hrs. The crystals obtained were separated and analyzed for SS-isomer content. Wt. of solids = 4.4g 10 % of SS-Isomer = 46.88 EXAMPLE-31 7.Og of diastereomer-A recovered from earlier experiments having SS:SR (46:47) was equilibrated at 1 15'C for 4 hrs and cooled to RT. This material was dissolved in 41.5 4 g of IPA:MeOH (10:30) mixture to obtain a 14.5% w/w solution of diastereomer-A 15 which was subjected to preferential crystallization in a 250ml round bottom flask fitted with a stirrer, thermovel to measure temperature and provision for addition of seed crystals. This solution was cooled in a cryogenic bath from +23 0 C, by decreasing temperature at the rate of 2'C for every 3 hrs. A seed crystal of 99% purity of SS isomer was introduced into the system at 20'C and temperature was decreased hereafter 20 at V C for 2 hrs. It was observed that crystal was dissolved at 18C. A fresh seed crystal was added to the solution at that temperature and process of crystallization was continued by decreasing temperature to 14C, where in the increase of crystals was conspicuous and the solution was held at that temperature for 10 hrs and solids obtained were filtered off and analyzed for SS isomer content by HPLC. 25 Wt. of solids = 2.8g % of SS-isomer = 44.7 EXAMPLE-32 2 79.Og of diastereomer-A having SS:SR ratio 432:435 was equilibrated at 120'C under vacuum (200-100mmof Hg) for 2 hrs, cooled to room temperature and made to 30 29.9% w/w solution of diastereomer-A in methanol. This solution was transferred to a 2.0 lit round bottom flask equipped with a stirrer, thermovel and a provision for addition of slurry of seed crystals. This solution is cooled in a cryogenic bath under stirring at a temperature programme such that the rate of crystallization is conspicuous WO 2006/010994 PCT/IB2004/002473 24 and continuous without getting abrupt crystallization, from +20'C to +5'C at the rate of 1 0 C/hr upto +12'C wherein slurry of seed crystals of SS-isomer obtained from crystallization of SS-isomer in hexane was added together with mother liquor. After keeping the solution at 12 0 C for 1 hr, further cooling is continued by decreasing the 5 temperature at the rate of 1C while observing the process of crystallization once in 2 or 3 hrs. Thus after reaching 5"C the solution was held at that temperature (5"C) for 34 hrs and crystals were separated out and analyzed for SS-isomer content. Wt. of crystals = 49.44 g % purity of SS-isomer = 95.67 10 Wt. of ML = 857.1Og EXAMPLE-33 To the mother liquor obtained (857g) from example example-32 was added 610mg of KF and heated at 49'C for 60 hrs and concentrated to 30% w/w solution and 15 subjected to process of crystallization from +20'C to 0 0 C as described in above example and holding the solution for a further period of 72 hrs at 0 0 C. The crystals obtained were filtered off and analyzed for SS-isomer content by chiral HPLC. Wt. of crystals = 64.3 g % purity of SS-isomer = 65.23 20 Wt. of ML = 670.84 g EXAMPLE-34 The mother liquor (670.0g) of example 33 was heated under stirring at 55 0 C for 20 hrs, concentrated the solution to 30% w/w and kept for cooling in an appropriate reactor as used in above example following a temperature programme from +1 5'C to 25 6 0 C at the rate of 2 0 C/hr. initially i.e. from +15'C to +12'C, where upon a slurry of seed crystals of SS-isomer (99.3%) prepared as described in above example was introduced into the system. The process of cooling was continued till the onset of cooling at the rate of 1 0 C/hr i.e. upto +4'C. Further cooling was continued to -6'C by observing the rate of crystallization and decrease of temperature is performed in such a 30 manner that it does not initiate abrupt crystallization. After keeping the solution at 6'C for 24'C hrs, the crystals obtained were found to form a lump which was dissociated by raising the temperature to +4'C where in it was broken and the crystals were separated by usual manner as described in above examples.

WO 2006/010994 PCT/IB2004/002473 25 Wt. of crystals = 14.03 g % purity of SS-isomer = 89.79 Wt. of ML = 518.2 g EXAMPLE-35 5 - The ML (518g) obtained from example 34 was heated at 55C for 20 hrs and concentrated to 30% w/w solution of diastereomer-A and filtered before subjecting to the process of crystallization in a reactor as described in ex. KR-301 under programmed cooling from +15C to -10*C following the procedure described in ex. KR-308. After attaining the temperature of -10*C, the solution was maintained at that temperature for 10 20 hrs. The solids were separated and analyzed for SS-isomer content by chiral HPLC analysis. Wt. of solids = 10.22g % purity of SS-isomer = 95.63 Wt. of ML = 857.1Og 15 EXAMPLE-36 The ML (857g) obtained from example 35 was equilibrated at 55 0 C for 4 hrs cooled, filtered and used for process of crystallization in a 1.0 lit round bottom flask provided with a thermovel, stirrer and provision for addition seed slurry. The reactor was cooled in a cryogenic bath, at a programmed rate of cooling from +22C to -10"C by adding 20 slurry a seed as prepared as described in ex. 301 was introduced at 8C. Further cooling is done by decreasing the temperature while observing rate of crystallization at the rate of 1C for every 5 hrs till temperature is reached to -10C and holding the solution at that temperature for a further period of 50 hrs. At the end of which crystals were separated out, and analyzed for SS-isomer content. 25 Wt. of crystals = 3.94 g % purity of SS-isomer = 93.9 Wt. of ML = 429.06 Table Expt. No. Wt. of Crystals % purity 30 (in gms) (SS isomer) 32 49.44 95.67 33 64.3 65.23 34 14.03 89.79 WO 2006/010994 PCT/IB2004/002473 26 35 10.02 93.63 36 3.94 93.9 PART B Preparation of diastereomer-A 5 EXAMPLE -37 8.32g of NaCN and 78.8 gms of H 2 0 was charged simultaneously into a 500ml reactor equipped with a provision for cooling the reaction mass to -4 C to -5 0 C, a mechanical stirrer, thermovel, dropping funnel and a vent tube. The contents are stirred well. Dichloromethane (80g) and tetrabutylammonium bromide (1.08g) was added to 10 the solution while stirring after which metaphenoxybenzaldehyde (21.7g) was added to the solution under stirring through a droping funnel over a period of 15 minutes at 20 25*C and stirred well for 30 minutes. This solution was cooled to -4'C and 25.54 gms of (S)-(2)-(4-chlorophenyl)isovaleroylchloride diluted with 40ml of dichloroethane was added, keeping the temperature between -1 to -4'C in two hrs. the temperature of 15 reaction mass was further maintained at that temperature for another two hrs during which period the reaction was monitored by chiral HPLC after which the reaction temperature was brought to room temperature and layers were allowed to separated out. The lower organic layer (DCE) was separated and washed thrice with (3 x 2000 ml) distilled water, each time checking the pH of aqueous layer, and continued washings if 20 pH is not neutral. The upper aqueous layer (NaCN) is detoxified separately. The DCE layer is concentrated at 40 0 C - 50"C at 35-40 mm of Hg and purged with nitrogen intermittently to yield 48.18 gm of diastereomer-A of composition SS:SR 43:87:46.44. EXAMPLE-38 20.2g of the liquid diastereomer-A (SS/SR 45.2/45.5) prepared as described in the 25 above example-37 is used as such without any further modifications by dissolving in 60.Ogms of methanol to obtain a 25% w/w solution of diastereomer-A. This solution was cooled in a suitable reactor equipped with a provision for seed crystal addition, thermovel and stirrer; by placing in a temperature programmed cryogenic bath in a stepwise manner from +20'C to +15 C at 2 0 C/hr. A slurry of seed crystals of SS isomer 30 was added at +15'C and solution was held at that temperature for 12 hrs. Further cooling was effected by decreasing temperature @ 1 C/hr till temperature reached to +7'C. The solution was held at 7 0 C for 24 hrs and the crystals obtained were filtered off, analyzed for SS-isomer content by chiral HPLC.

WO 2006/010994 PCT/IB2004/002473 27 Wt. of crystals = 2.58 90% purity of SS-isomer = 96.4 EXAMPLE-39 106.79gms of liquid diastereomer-A obtained following the procedure described in 5 example 37 wherein a new PTC catalyst was used instead of TEBA. This material was dissolved in 430 gms of methanol in a 1000 ml round bottomed flask equipped with a stirrer, thermovel and provision for addition of seed crystal to obtain a into 32.35 (w/w) solution of diastereomer-A. This solution was cooled in a cryogenic bath under stirring following a programmed rate of cooling (from +20'C to 16C in 2 hrs 10 (2 0 C/hr) at the end of which temperature was decreased in one step to 7C and a seed crystals of SS-isomer (99.3%) was introduced into the reactor. Further cooling was effected from +7'C to -7'C at the rate of 1 0 C/hr and the solution was kept at -7'C for 60 hrs at the end of which the crystals obtained were separated by filtration, dried and analyzed for SS-isomer content. 15 Wt. of crystals = 16.5g % purity of SS-isomer = 95.2% Wt. of ML = 506.Ogms EXAMPLE-40 The mother liquor obtained in the above experiment (example 39) was equilibrated 20 with 0.37g of potassium thioxide at 63*C for 18 hrs. cooled to room temperature and was replenished with 16.Ogms of liquid isomer-A as used in example above and made up to 19.7% w/w solution by adding 20.Ogms of methanol. The process of crystallization was repeated as described in above example except that instead of decreasing temperature from 16'C to 7C at once it was effected at the rate of 4 0 C per 25 hr. and further cooling is done as described in above example upto -6'C and the solution was held at that temperature (-6*) for 2 hrs. After separating the crystals, and ML, the crystals were analyzed by chiral HPLC for SS-isomers content. Wt. of crystals = 12.16 % purity = 96.7% 30 Wt. of ML = 515.84g EXAMPLE-41 The ML (515.84 gms) of example 40 was equilibrated at 60'C for 18 hrs at 65'C, cooled to room temperature and replenished with 16.0 gms of liquid diastereomer as WO 2006/010994 PCT/IB2004/002473 28 used in above example and made upto 20% w/w solution by addition of 21 gms of methanol. This solution was subjected to crystallization by decreasing the temperature from 18' to 5"C at the rate of 3*C/hr. and introducing SS-isomer (99.3%) seed crystal at 5'C. Further cooling to -8'C was effected at the rate of 1 or 2'C while observing the 5 rate of crystallization. The solution was held at -8 0 C for 24 hrs. The crystals obtained were separated out by filtration, dried and analyzed for SS-isomer content. Wt. of crystals = 11 .Og % purity of SS-isomer = 97.5 Wt. of ML = 530.06g. 10 EXAMPLE-42 The mother liquor 530.06 gms obtained in above example-41 was equilibrated at 60"C for 6 hrs cooled to room temperature and replenished with 15.8 gms of liquid diastereomer as used in above example and replenished with 23.Og of methanol respectively to obtain 20% w/w solution of liquid diastereomer A. This solution was 15 subjected to stepwise cooling following the method described in above example from +16 to +3 0 C, at which temperature (3C) seed crystals of SS-isomer (99%) was added and further cooling to -8'C was continued by decreasing the temperature while observing the rate of crystallization in such a manner at the rate" of 1 0 C/5h upto -2'C from +3'C and there after at the rate of 1C for 90 minutes and holding the solution at 20 8 0 C for 12 hrs at the end of which the crystals obtained were separated and analyzed by chiral HPLC for their SS-isomer content. Wt. of crystals = 11.33g % purity of SS = 98.55 Wt. of ML = 552.29g 25 EXAMPLE-43 i The ML (552.9) obtained in above example-42 was equilibrated for 10 hrs at 65 0 C, cooled and replenished with 15.07 g of liquid isomer as used for the above example and 15.Og ofmethanol respectively to obtain a 20% w/w solution of diastereomer-A, which was subjected to step-wise cooling following the temperature programme as described 30 in above example except that cooling was continued upto -11 C and holding the solution between -10*C to -11 C for 48 hrs. The crystals obtained were separated by filtration and analyzed for SS-isomer content by chiral HPLC.

WO 2006/010994 PCT/IB2004/002473 29 Wt. of crystals = 6.91 % purity = 95.9 wt. of ML 567.54g Table: 5 Expt. No. Wt. of SS isomer % purity (gms) 39 16.5 96.5 40 12.16 96.7 41 11.0 97.58 10 42 11.33 98.5 43 6.91 95.9 EXPT-39 M.L. 506.Og + 16g (liqdiastereomer-A) 16.8 (96%) EXPT-40 Cryst 12.16 (967) ML 518.8 +16 g liq.dia EXPT-41 ML 530.06g + 16g liq. dia Crystal 11.0 (97.5%) EXPT-42 Crystal 11.83 (98.55%) ML 552.29 + 15.07 g liq. dia EXPT-43 I F 567.37 ML 6.99 crystals (95.91) WO 2006/010994 PCT/IB2004/002473 30 EXAMPLE-44 51.4g of liquid diastereomer-A prepared as described in example-37 except that instead of tetrabutylammonium bromide (TBAB) a new phase transfer catalyst N-butyl N,N dimethyl-a-(S)-phenyl ethylammoniumbromide, was used and dissolved in 5 104.45g of MeOH to obtain a 33% w/w solution of diastereomer-A. This solution was transferred to a 500 ml round bottom flask equipped with a thermovel, stirrer and provision for addition of slurry seed and cooled in a cryogenic bath from +20 to +8'C at the rate 2 0 C/hr till temperature is reached to +13 0 C, at which a slurry seed crystals of SS-isomer (99.3%) crystallized from SS-isomer in hexane together with mother liquor 10 was introduced into the system. Further cooling to +8'C is effected at the rate 1 0 C/4 hrs and the solution was held at that temperature for 20 hrs and filtered. The crystals obtained were analyzed for SS-isomer content. Wt. of crystals= 11.2g % purity of SS-isomer = 95.3 15 wt. of ML = 140.45g EXAMPLE-45 The mother liquor 140.45gms obtained from above example-44 was equilibrated with KF (250mg) at 60'C for 5 hrs, cooled to room temperature and replenished with 11.23g of diastereomer-A, and subjected for crystallization by cooling the solution 20 from +20' to +90 in a suitable reactor as described in above example-40 following the same procedure and the solution was held at +9'C for 20 hrs and filtered. The crystals were analyzed for SS-isomer content. Wt. of solid = 9.65g %Purity of crystals = 96.5 25 Wt. of ML = 144.04gms EXAMPLE-46 Preparation of diastereomer - A 0.66kg of Sodium cyanide and 6.24kg of distilled water is charged simultaneously into a 20.0 lit. glass stirred reactor, equipped with a provision to cooling the reaction 30 mass to -4'C, a mechanical stirrer, thermovel, dropping funnel and a vent tube. The contents are stirred well till a clear solution is obtained. 4.4kg Dichloroethane, and 0.084kg of tetrabutylammonium bromide (PTC) are charged in to the reactor under stirring, after which 1.75kg of metaphenoxybenzaldehyde (MPBA) is added through a WO 2006/010994 PCT/IB2004/002473 31 dropping funnel over a period of 25-30 mnts. at a temp. of 20-25C. The reaction mixture is cooled to -3* to -5'C, 2.15kg of (S)-fenvaleroylchloride is diluted with 2.2 kg of dichloroethane (DCE) and added over a period of 1/ 2 to 2 hrs. through a dropping funnel maintaining the temperature between -3 to -4'C under vigorous stirring. The 5 temperature of reaction mass is maintained at this temperature for a further period of 2 hrs. The reaction is monitored by HPLC analysis (conversion of MPBA). The reaction mixture is brought to room temperature and the layers were allowed to separate out. The lower DCE layer is discharged weighed (11.19kg) and kept aside. The upper aqueous layer (7.75 kg) containing sodium cyanide is discharged weighed and 10 detoxified separately. The DCE layer(1 1.19kg) is washed with (3 x 3.0 kg) distilled water, each time checking the pH of aqueous layer. The washings of DCE layer is continued till the pH of aqueous layer is neutral. The dilute DCE layer (11.19kg) is taken for recovery of diastereomer-A. The dilute DCE layer (11.19kg) is weighed and fed into a Rotary evaporator 15 equipped with a condenser provision for circulating cold water, vacuum system and a heater. The solvent DCE is removed at 40*-50'C at 35-40 mm of Hg. After removing the last traces of DCE, nitrogen is purged into the system intermittently by applying vacuum to ensure the complete removal of solvent for a further period of 1 hr. The contents are cooled to room temperature, weighed (3.89kg) and discharged into 20 storage tank. Wt. of diastereomer-A = 3.89kg Ratio of SR:SS = 45.2:43.5 EXAMPLE-47 The material obtained from example 46 is used for preferential crystallization of 25 esfenvalarate in an iterative manner as described below: 2.878 kg of Diastereomer-A (1:1 diastereomeric mixture) is charged into a crystallizer having provision for mechanical stirrer, thermovel, a calcium chloride guard tube and external cooling system. 8.684kg of methanol is charged into the reactor to obtain about 25% solution and the contents are mixed well to obtain a 30 homogeneous solution. The solution is initially cooled to 22'C under stirring from room temperature, thereafter cooling is effected to 10C by decreasing the temperature at the rate of 4*C per hour, at this temperature (10'C) pure crystals of esfenvalerate (99.5 %) is introduced into the system. Further cooling is effected carefully to reach WO 2006/010994 PCT/IB2004/002473 32 the temperature (5-2C) at the rate of 1C per hour wherein the onset of crystallization is conspicuous. The solution is maintained around the onset of crystallization and the progress of crystallization is monitored by HPLC analysis wherein the concentration of SR-isomer in supernatant liquid is in the range of 55-60%. At this stage the solution is 5 filtered off (ML-1) and the crystals obtained are weighed and air dried. This step is iterative and continued till esfenvalerate is obtained by crystallization process (5 cycles). Wt. of crystals = 0.516kg %Purity of crystals = 96.5 10 Wt. of ML = 10.67kg EXAMPLE-47A The filtrate enriched with SR-isomer ML-1 (10.67kg) is charged into all glass jacketed stirred reactor provided with provision for temperature recording and heating system and the contents are heated to 62-65 0 C for 5 hrs. The process of epimerization 15 is monitored by HPLC analysis, drawing samples at regular intervals of time and the reaction is stopped when the sample showed a ratio of 1:1 with respect to SR:SS isomers. The solution is cooled to 30'C and diastereomer-A (0.558kg)equivalent to esfenvalerate obtained in earlier cycle is added and the solution is made up to 25% by adding methanol (0.424kg). The process of crystallization is repeated by following the 20 process of cooling from 30 to 3'C as per the procedure described in example 47 for a period of 60 hrs. at the end of which the crystals obtained were separated weighed and. dried Wt. of crystals = 0.432kg %Purity of crystals = 97.2 25 Wt. of ML = 10.887kgs EXAMPLE-47B The filtrate enriched with SR-isomer ML-2 (10.88kg) obtained from example 47A is charged into all glass jacketed stirred reactor provided with provision for temperature recording and heating system and the contents are heated to 62-65'C for 5 hrs. The 30 process of epimerization is monitored by HPLC analysis, drawing samples at regular intervals of time and the reaction is stopped when the sample showed a ratio of 1:1 with respect to SR:SS isomers. The solution is cooled to 30*C and diastereomer-A (0.452kg) equivalent to esfenvalerate obtained in earlier cycle is added, solution is made up to WO 2006/010994 PCT/IB2004/002473 33 25% by adding methanol (0.504kg). The process of crystallization is repeated by following the process of cooling from 24 tol*C as per the procedure described in example 47 for a period of 64 hrs. at the end of which the crystals obtained were separated weighed and dried. 5 Wt. of crystals = 0.408kg %Purity of crystals = 97.5 Wt. of ML = 11.122kgs EXAMPLE-47C The filtrate enriched with SR-isomer ML-3 (11.12kg) obtained from 47B is charged 10 into all glass jacketed stirred reactor provided with provision for temperature recording and heating system and the contents are heated to 62-65*C for 5% his. The process of epimerization is monitored by HPLC analysis, drawing samples at regular intervals of time and the reaction is stopped when the sample showed a ratio of 1:1 with respect to SR:SS isomers. The solution is cooled to 30'C and diastereomer-A (0.436kg) 15 equivalent to esfenvalerate obtained in earlier cycle is added, solution is made up to 25%. The process of crystallization is repeated by following the process of cooling from 26 tol C as per the procedure described in example 47 for a period of 64 hrs. at the end of which the crystals obtained were separated weighed and dried. Wt. of crystals = 0.384kg 20 %Purity of crystals = 96.8 Wt. of ML = 10.89kgs EXAMPLE-47D The filtrate enriched with SR-isomer ML-4 (10.89kg) obtained from example 47C is charged into all glass jacketed stirred reactor provided with provision for temperature 25 recording and heating system and the contents are heated to 62-65'C for 5% hrs. The process of epimerization is monitored by HPLC analysis, drawing samples at regular intervals of time and the reaction is stopped when the sample showed a ratio of 1:1 with respect to SR:SS isomers. The solution is cooled to 30 0 C and diastereomer-A (0.398kg) equivalent to esfenvalerate obtained in earlier cycle is added, solution is made up to 30 25%. The process of crystallization is repeated by following the process of cooling from 25 to -1*C as per the procedure described in example 47 for a period of 65 hrs. at the end of which the crystals obtained were separated weighed and dried.

WO 2006/010994 PCT/IB2004/002473 34 Wt. of crystals = 0.184kg %Purity of crystals = 92.4 Wt. of ML = 10.826kgs EXAMPLE-47E 5 The filtrate enriched with SR-isomer ML-5 (10.826kg) obtained from example 47D is charged into all glass jacketed stirred reactor provided with provision for temperature recording and heating system and the contents are heated to 62-65"C for 6% hrs. The process of epimerization is monitored by HPLC analysis, drawing samples at regular intervals of time and the reaction is stopped when the sample 10 showed a ratio of 1:1 with respect to SR:SS isomers. The solution is cooled to 30C and diastereomer-A (0.280kg) equivalent to esfenvalerate obtained in earlier cycle is added, solution is-made up to 25%. The process of crystallization is repeated by following the process of cooling from 29 to -5"C as per the procedure described in example 47 for a period of 75 hrs. at the end of which the crystals obtained were separated weighed 15 and dried. Wt. of crystals = 0.256kg %Purity of crystals = 94.5 Wt. of ML = 10.520kgs Table: 20 Expt. No. Wt. of Crystals % purity (SS Isomer) 47 0.516 96.5 47A 0.432 97.2 47B 0.408 97.5 25 47C 0.384 96.8 47D 0.184 92.4 47E 0.256 95.4 The main advantages of the of the present invention are: 1. The present invention makes it possible to obtain high optically pure (>95%) 30 SS isomer in an iterative manner 2. The another advantage of the invention is the effective use of the unwanted SR isomer from the ML by epimerisation process using.catalyst and recycling the same iteratively as such 3. Another advantage is consecutively using thus equilibrated ML of one cycle in 35 another cycle as such avoids many process steps. Replenishing the ML with WO 2006/010994 PCT/IB2004/002473 35 fresh diastereomer-A to the extent of crystals of SS isomer obtained maintains the saturated state of the solution. 4. Yet another advantage is the catalyst used for epimerisation is reused without isolation for further batches. 5 5. Yet another advantage is that the method effectively combines the enrichment and crystallization process without isolation of the catalyst and thereof all the desired isomer (SS isomer) can be effectively obtained from diastereomer-A.

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WO 2006/010994 PCT/1B2004/002473 46 o 0 0 0 .. o to.2' 40. to W ) -00~I~0 t)' . o Cc (UC4 (Z o ( 0,0 0 U) 0. 0) t d 0 .o b o 0 rn .4 o- 0A w 0 > 4-n 0 m 0 'fl- 0 Lf = I z t n0 00t C5 c ON C 00 0. 0 00 00 >-. 00 t 00 00 0 0 0 0 0 0 0 a) . a) a) aU o- "R. C'4~ C a4 00 W0n w 4o 0 44 0 0 0 04,0 C4.4U o C> It 0 00 0? *?O ? 0 00 0 WO 2006/010994 PCT/1B2004/002473 47 ON C> 004 o6 5 0 v) CN Cd 0 00 ed u.a a)) U) "o P0u 0) E ::1 o0 Q) C2 0 ~ c 00Io i00 U 0c (D "? r-- ~ ~ 0 +, o-:: C, - 0 - -n 00 0 M0 4) I a c C 44t P0 3~ * - 00 0 00 + 00 0 a) 00 o' o a " 0n 0 00 0 0 0 0 00 00 ~0 - 0 0m -0 %n m00 C', P 01! Nn C 0R 00 l4~ 0> C4 C) C14 Z >.0 0 0 0 0 0 VI)4 4)s.4 Q) 0000 00 00 00 a WO 2006/010994 PCT/1B2004/002473 48 vO 0d N Cl)) u C>4 0l 0Co ~0 0i 0 0n U C) -. Cl) 0 asC-c 00 00 a) 0 06 Eu0 9 0)aaO C C C C C CL iO' ci 00 'Cl4 C- Cl) Cl4 N CAI~ * am NC a 00~ ( -z tn 00 - - 00 O 0 (N! 00 C14 7% \0 Cl00 (N 00 4 6 , 00 00 N 00 a CNC CN( C-4 Nl wi cn en) 00 'I rN00 M M \-O. 00 00 N O'. en~)~00e -'-z 0 0 0 00 00 0 r4 1'-l0 .0 \0 m 00 m~~1 00 (N ( - l (N N( re k 00 C4 ( 000 I S 00- - 0 0 0 0 ~ 00 0 - - - --- - 00 00 000 - 0) iR 0) 0= 0= 00:00 00 t F-4 t. ~ - ' I - 00 Ca (N 0) 'n (N 0 0) 0 000000 000 0 0 0 0 00 NNt ON 0 - 00 'tf0 0 a*,N C>~ ON Cs' I ON~ (N r- C- ( N ( N-o -: (N en O W)~0 W):N- t rn( r~I tn 10 N- 00 0) t 'I)r 00 a.% 00 000 0D 0) 0 0)C < (ON ON ON-4 (ON4 - - - - WO 2006/010994 PCT/1B2004/002473 49 0 00 C) 0 d u 0 . C- 0 0 a 0 00 "~ 0 Ei 0 0 0 0 0~ 't co W 0 n 0 00Z , 00 0 00 0~~C <D 00'0 ,-I 01 0 rnC Cfl Cn e el N- r4 c4 -n en en en .

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Oo0 000 ct W 0 0. 0 0 0 00 0 00 r5,0- 0 (D 00- 0 '10 1 -~ 00 CN C) C>\ c C 10 o 0 0C0 en cq0 W)- 0n 0 0 0 00 00 en 0000a 0~k oko o o 6 WO 2006/010994 PCT/1B2004/002473 53 4d) > 0~ 6g -- ' C> 0 CD 4! -0 Qn Lf 0 Cli N C14 O0LJ 000 C) fn00f Nn -NC14 00 W) 00 C) 0 00 C14 0> 000 0 (D ( Cn ' n r -N '~\0'C t ,O r - \0 ' -- O M I-. - ' Cic CiNr- r N 0 1~ 200 0 Ci 1~\ 0r 1 - 22000, 0 0 .2 0~0 0 0 00C +i +ic 0100 +1 ci2 ' + + wU 0-0 0 ~0 00 0 0 00 c0 2 W 002 0600 cn 00 2 t 000.ll00 \0 en 00 000 en~ t- ~ ON\ en N.- \ r0 00) C14 M eq i- nenC14C14 cii C14 n C z~O0 Ontnt I 0 0 \0 c 10 o01. -~~~w W) - . - - - WO 2006/010994 PCT/1B2004/002473 54 - 00 cci 02 00 r 00 .00 r-~ ~ ~ 00a C- WO 2006/010994 PCT/1B2004/002473 55 C) I- ~ X x 72 -"-o 1. -oo 1.0 N0 40. E ) 0 0.) a a 0 ) 0) a)0 a)~~Q -0aa a a) a ~ ) P.4 tn~ tn t I~ 00 'f) C) 0r m = c GOf~f~ n- C. O 00 r %.4~~ ~ ~ \ )W n Ne nC4c C 1 0 N 00N w U tN 0 7 ,C 0 , 7% Cl %ItO -h ~ C 't 'IT e.T It Cl 00 00 N-N en 'I C -) -. en -- 4 - m ~ m 'I 0 n '/ 0 0> 0 00 "~ -k-- - - - -C CN il n ~ ~a 20 0 0 0 -00000 0 0 0 00 0- 0000 0 0 00000 0 0 0 (U 0a 00 0 00 0 00 0) 0 00 - -- 4 -! 1,O el-i Ci en ONen a, N- 'rn 0C ON a C> C000 0) en 00 0) ON as 0 C, 00C m c ;5 C 0 0 tr ON - M 4 Cfn4 -n It~ e Ifn IC r00 O C 0q en C C'~ N)0 r 00 ON 0 NN N NN 00 00 000000000 00w 00 w ON WO 2006/010994 PCT/1B2004/002473 56 -e . > C c U Q ). C> 01 UU U) 0)t ) n C* 0u0 0Z3 -~0N 4. -o, o 5u W -6 '.0) m00 0oO'C 'I' .14~ 0-. Q> M Nd 0 0 0 0 0 a - W) c t- l '0 rA CU 00 0 %0c )00 00 00 000C4 q 00C ~ \0 -00 0 ie'0 .2 0 ~ 0ce 0%. 0~ 0 ~ O0 000 00 00000 tn -1 - - tn~~c m'e 00'C WO 2006/010994 PCT/1B2004/002473 57 00, 0 00> 0 0 00 0 ci, ~ 0 CNU 0- 0 a) . -H CU F- C)C O -- 4 I4 1 604N 00C> ep 0%. cc~ C 0C C 05 ~ ~ > 00d n l W 0o 0 00 N ~E 0N -o u fe4~' ~ G~ 00 0P 00 5 0 00 00 0 000 - C)C) C) 0 0N C 1 N 0 - - cn -4- - - 00 0 004 0 0 00 00 0 000 40 M_ _ _ _ _ _ _ _ _ _ _ i n_ WO 2006/010994 PCT/1B2004/002473 58 00 rA u 0 C42 0 c~CCU c~~~C r-nj O 00 'r 00 cJ. -0'- IF c A *d0 0 0~ 0 CIS) 4-b ciN\0 e 004 G >e 00 00 0 rz rA00 If)9 -~ 0 0 o 9 00 0-00 cn c Ci e _ _ _0 -1i WO 2006/010994 PCT/1B2004/002473 59 v) - 0 0 u0 0 n 15 C) b 0e C14 -o -d1 0 0 CU CU 0 co -D -o 73~ Cd Q C 0 o m - d 9 C> 00 0 NM I- m oC M \ 00 CM r. 00 Mf 00DC rq I' 00 _0 0n \ 0 00 0 0 0 0 0 0 0 0 00 o (D 0 00 ~ ~ ~ C (O >eq Mt cq~ -1 -n en en-m e '4-4 q eqc WO 2006/010994 PCT/1B2004/002473 60 '0 0< 0 rn 0 C) 0 ell -0 Q 2' m ~ 03 02 00 00 C9 U) r tn 0cC>'~ C) VON ++ 0 0 + en 0 0 0 0 00 t- 00 0 000e M ~ ~ ~ en( T I TI oq eq N -c - 1 WO 2006/010994 PCT/1B2004/002473 61 0 &:- u o - = 00 C)-0 0 0) CpC N ~ C4 0 Cd a Z-d 0 t, > Cc C> C)d 0 eI 0 1:1 Nc Z - to -t , - "c c, C) C4-4 0 0 0 Ne 0 ca r C 0 0 N 0 cq 00 0 00~ 04 0 C14 IT 00 r e'q C14- * ON ~ r m .2 M~e en6 C4.4 GO) ct i \6 ( ~ ( 16 _ ~ j WO 2006/010994 PCT/1B2004/002473 62 oo 4-;0 dC edN > 0 u 0 C 0 0 00 u 0 co~ coi W Zo ) CU 0 - 0 0 U in0 0>' 0'. 0'. .0 C) 0 0 e'~cc 0 e'n in:ni ON C') ± - +) kn wl CD C> 1 00k Na Z 000, 0 r 0 C- C0 (' i i -d Z u 0- t- -N (O - n n 9- W -n ON ON a\ ~'o 0 0 0 0 040 0 0 in 0 o0 6 8' w' ' - -' ') 0' 0' 0 0n '300 ' in &0n in i i n 3 '3 ~ii iii 00 WO 2006/010994 PCT/1B2004/002473 63 4)' cr cco. 0 t4- 4) 0Z 0 o0E El 0I 0'C0- 0 4V - V 0 tn I- 0 . 00 04 \0M m .4) = N 00c V 1 0'N C eC CN aa q V o Z ~ V ooCl- C 4 - -- +- ~-N O N 0( 0 00 N =,.0 r4 C) +) 4) 4 QN 6 v U' 00V 00 0(1 ON C> -0 N- ~ 0 V w' rz u al . P, w0 C) 0~ + C) on O O ' 0 0 0l 00 C~ C 1 ClN Cl r- t 00 r-)C ON C4 lt r l WO 2006/010994 PCT/1B2004/002473 64 0 i -0 C3 1.0 U 0.f 00Od 000 ri0. Ir 0q 0 0 0U C1 0 -0 . . 0 00 Q 0d 0 N- C'1 0 0 0 r0 o0 0. ~ ~ ~ ~ o cONO a*a\2*a, o oN0 riF ~ N 0 t -- . a,%r -c; 0 0n 00 01 00000\ o) C 0 A-' 00 e0 LO C;\- :t 0 t ~ rq 00 Z u Nn 00 1(' 00 - i 0 t) 0 ~ 0 0 C) 00 C11 ci) C> - 'r N \0 -) C0t)C> C 9 V- 00 - 0 --- N ~ ~ c N 0 0 0 -c 0r 0 0t 0 N 0 N N N) 00 00 00000 00 00 Wi c i c ~ ii c ic 1. tn 00 If I'D i, W)I WO 2006/010994 PCT/1B2004/002473 65 0 -YU -0 0 - Iu V)) C to~~~ ~~ A2 4 .C L)UC~. 00 cz U V~~ - UCUdei m CU0 "- z 00 'R 0 0 d hbo0 rA CUq 0 0 S~' 0 CU- 0Cd 2 El 0 ~H ~ cjO CUE 0 z V 0 ONV (7 00N * U O ON 0 t tn C> 6 6l q0 ItC4 C> C> C C4 C4r 0 0 0. 0 0 0 0 0 .

4-CU t q \\0 0 00 Cl Cl-l . Cl C; 06 0 0 0 (Y) VnC C) 0t 00 ~ (7 00 "r " l N6 o 0> -C M 't to V0 ON ONON rA (7 ON ON ON O COA C4N C e q e Nl~ C C4 WO 2006/010994 PCT/1B2004/002473 66 0 0 M to~ 00 ~c oa co wo ~ I d C .) -~ o 0 Cd 0 o ~ ~ $..- ef1(S 0~ eC0 C) c00 0 C? 0 w 00 e~0 0e0 O I.w m 0 0- 00 0 01- .~e ~ 0 4w 0000r- en0 00e~ r-- r - 4 t-- 4- -- &i - c r;t; - N c Cictt (O o N 00 \ (Aef 0% 00c C)0 rf 'Z: . cli C) w~ C> 0 C 00 000 00 004 oo000)00 m\0 -L ~ '0 cq C140 -1 ena C. 0 00-00 et0- 0.0 0 - Ci).' -. 0 -- C)WI * q 1 1 0-C en cq C14 000. 0 000 00 000 00 -0 -0 M ~ ~ ~ ~ cccc 00 r-00 \ 00 ( 10 0 C1 WO 2006/010994 PCT/1B2004/002473 67 En*4 Cd U - -o0 ol o > Go ta- o 4 .- - -4 C44U 4 ~-. 0C ch ~ ~ V)0C tuc wim ,;oor- r < I r-~ cl U N- rfte en It mOo .- \0iC C6 CN 00~ - - ~ - C>- M 0 0 0 00 00 00 0 - 0 0 C~ -0eIWo C, eqC, e -o 00 0 0000000 0 Cc0 r- knUtn e~oo 00 CoO)~0 en~ 00 0 0I 0 e lN eq eq ej 6 6 C C Jo 0 0t e'C ~0 0 0 -. - 0 WO 2006/010994 PCT/1B2004/002473 68 C)) 4) 0 cm C-o 00 >~4 '0J4 CU 0 l m) CU 0 u n~ ?= - Cl 00 C ION 00s 0 N 3I00 C .4-o W ~ Cl vi tn W)0 11 0 .I00 N Nq C>( 00 00 I tON W) V- (D ON \ lN ON ON \0 c7N ~ NT'T10 cl 00 C% O ON ON In tn C t Nr tn " C - - - -- - ONl ON 0 0 0 0 0 .0 0 0 0 000 0 r- ~ ~ I - In W n \10 \D r OC C14" n 00 N C14 C14 C C4 C4 C%4C C C4 U ON 00 CN m ON ON . -00 r- n n 00 >0 0 00 0 0 0 00 0000 0 '.0 NONa \0 00 ON \0 \ '.C4 n (ON 0s C> -n en W) i n 0 NTN -'0- 'IT 0 -i I in 00 l00~ Cl C C) C> C> C)~ V) l-- C; 0 ~ C14 ON 'C1 er'0 -Nn l S00 ON) 0- It ~n \0Nr-00O 0l C C4 Cl4 me n e eneM m rn en NT cn en e n n e ne en e I I C, 1 I I l i I I WO 2006/010994 PCT/1B2004/002473 69 0u 0 00*0 -Cd o Z u r. 0 z ~0 d C * o + "C; bb "C as M 0d 's &. U ~ Q U.. tfl0 0~~ N) N W) 00 c' a.% m u u% cn 00 en~\ 0 m 'f W -1 N 2 0 0 C6 W 0 O~O 0 C7 0 0 0o0 c

U

0 U C.) (A U C) n(Dnu 40 Nn CN00 0 C; vi 0 f fOL ~ ~ ui c-i \6 mi vi r- r ce 0 0 0 0 c c1 i0% 0 N '0 00 - ci o 0 0I' 00 kn i > 0 C C >C 6) C6 00 o C, C40 C4 14 C1 cq cq N ~ ~ 0 r4C1 -4C* 00 > -0 0i 0r 0 0 N0000 00 en en 4 4en Mr 4n I > C -e 4C, 0 WO 2006/010994 PCT/1B2004/002473 70 Q 0 crs 0 0 Uc0 )d1 M) D o0 0 z - - .7; Cd z U>, Cd C4 ~~~~ 0 0 ~ 0e V L.0 1f" c n )kn C Ct4\ 4 4N-004 trtri m on ~ C)a C? C? ? 00 00 C> 00 Cf) N n0 nt 06 n ' 00 00 1 n 0 n W) *1- ON 00 0 * 00t (O O NO O 7,cl O 00 N O 00 n( r 1 e'e rl i C 0 00 0> 00 0000000004 ) -\ C) \. 0000C . 0 T 0 00 N 1 1 1 00 0 00 o~~e o oo oo C) N) C>~ C C> ) \0 00 0td I'D f (D < >w 0~ 00 0 0%0 00-0~00000 Id, 00Id 101 liriim\DC)C WO 2006/010994 PCT/1B2004/002473 71 >0 0~ 00 WO 2006/010994 PCT/1B2004/002473 72 0 0 ui i U)U CU~CUCUCd mC ~ + . a U 7;t( -d c zN. C'o M 1-06C' 0 00 0 o too 00 0 o o - C 0

C

0 Cd cd 0 U U~ 0~ Z 0-~ 'o QD -C~ QD . 0 U @ I d Ii ca U C>, Ei< WO 2006/010994 PCT/1B2004/002473 73 00 C- I 0 0 u Km 0 0 0 z COO CO C)O ) - Cd d * .= o I Uo44+ >~ 0 0, = 0 0 zo .4 0.- . wo 4.. U)4 U < b z r, 00 I i I4 n _ _ _ _ WO 2006/010994 PCT/1B2004/002473 74 o -3 INS oz 0 0. 00 0 o -0 0 0 0 0 0 0 0 0 r. 0 U u U " .U < -0 00 0 00 U.0 0 0 C CA 0 c'd 0-4 C U0 ElQ 5 U u U0U 0 '. 0 ~cjc> 74a It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country. 5 In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention. 26242651 (GHMatters) 6101111

Claims

1. A process for preparation of (S)-a-cyano-3-phenoxybenzyl-(S)-2-(4 chlorophenyl) isovalerate (SS isomer), said process comprising the steps of; 5 a. crystallizing (RS)-a-cyano-3-phenoxybenzyl-(S)-2-(4-chloro phenyl)isovalerate (diastereomer-A), in presence of crystals or slurry of SS isomer of a purity of 99% or greater, in a solvent that is a saturated solution or of 1,2-dichloroethane to obtain crystals of SS isomer from mother liquor; 10 b. epimerizing the mother liquor enriched with RS isomers, and c. recycling for further batches of crystallization.

2. The process as claimed in claim 1, wherein the diastereomer-A is prepared by addition of (S)-(+)-2-(4-chlorophenyl)isovaleroyl chloride to an aqueous solution of (RS)-at-cyano-3-phenoxybenzylalcohol in a two phase system using 15 a phase transfer catalyst to form a solution.

3. The process as claimed in claim 2, wherein the phase transfer catalyst is a quaternary ammonium salt selected from a group consisting tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium hydrogen sulphate (TBAHS), triethyl benzyl ammonium chloride (TEBA), 20 benzyltributylammonium chloride, and N-butyl-N,N-dimethyl-at-(S) phenylethylammonium bromide.

4. The process as claimed in claim 2 or claim 3, wherein the Phase Transfer Catalyst is tetrabutyl ammonium bromide.

5. The process as claimed in any one of claims 2 to 4, wherein (S)-(+)-2-(4 25 chlorophenyl)isovaleroyl chloride is added to the aqueous solution of (RS)-a cyano-3-phenoxybenzyl alcohol over a period of time ranging from 60-240 minutes, or from 100-120 minutes.

6. The process as claimed in any one of claims 2 to 5, wherein (S)-(+)-2-(4 chlorophenyl) isovaleroyl chloride is added to aqueous solution of (RS)-a 30 cyano-3-phenoxybenzylalcohol at a temperature ranging from -8'C to +50'C, or from -4'C to -2'C. 25242651 (GHMatters) 6/01/11 76

7. The process as claimed in any one of claims 2 to 6, wherein after addition of the (S)-(+)-2-(4-chlorophenyl)isovaleroyl chloride the solution is maintained for a period 30-180 minutes, or for a period of 60-120 minutes. 5 8. The process as claimed in any one of claims 1 to 7, wherein the crystallisation is monitored by HPLC analysis, wherein samples are withdrawn at intervals of 60 120 minutes.

9. The process as claimed in any one of claims 1 to 8, wherein the solution of diastereomer-A is concentrated from the solvent under reduced pressure from 10 80-60 mm Hg.

10. The process as claimed in claim 9, wherein the solvent recovered after concentration is recycled and use to prepare additional of diastereomer-A.

11. The process as claimed in any one of claims 1 to 10, wherein the SS isomer is crystallized from a saturated solution of diastereomer-A by seeding with pure 15 crystals or slurry of SS isomer of a purity of 99% or greater optionally in presence of base catalyst.

12. The process as claimed in any one of claims I to 11, wherein the concentration of diastereomer-A in solution is in the range of 10-40% w/w, or in the range of

25-30%. 20 13. The process as claimed in any one of claims I to 12, wherein the process of crystallization is controlled by cooling the solution to a temperature for a time sufficient to increase the amount of SR isomer in supernatant liquid. 14. The process as claimed in claim 13, wherein the crystals of SS isomer remain undissolved in the solution when the temperature is cooled from ambient 25 temperature. 15. The process as claimed in claim 13 or 14, wherein the crystallization of the SS isomer is conspicuous. 16. The process as claims in any one of claims 13 to 15, wherein the SS isomer crystallizes when the temperature is decreased. 30 17. The process as claimed in claim 16, wherein only the SS isomer crystallizes. 25242651 (GHMatters) 6/01/11 77 18. The process as claimed in any one of claims 13 to 17, wherein the temperature of solution is monitored by analyzing samples of supernatant liquid by HPLC analysis at intervals of time ranging from 4-8 hrs. 5 19. The process as claimed in claim 18, wherein the process of crystallization is terminated when concentration of the SR isomer in supernatant liquid is in the range of 55-60% w/w. 20. The process as claimed in claim any one of claims I to 19, wherein the crystals obtained are separated by centrifugation, decantation or filtration. 10 21. The process as claimed in any one of claims I to 20, wherein crystallization is increased by stirring or shaking the solution. 22. The process as claimed in any one of claims I to 21, wherein the process of crystallization is carried out at a temperature in the range of -1 8*C to +10 C. 23. The process as claimed in any one of claims I to 22, wherein crystallization 15 occurs in from 24 to 80 hrs or in from 30 to 72 hrs. 24. The process as claimed in any one of claims I to 23, wherein after removing SS isomer crystals, the mother liquor containing the SR isomer is equilibrated either by concentration and heating; or with a base to obtain 1:1 ratio of SS:SR isomer and subjected to further crystallization. 20 25. The process as claimed in claim 24, wherein the process of crystallization is continued by addition of diastereomer-A in each cycle iteratively until crystals of SS isomer are obtained.

26. The process as claimed in claim 24 to 25, wherein the mother liquor is equilibrated with either inorganic or organic base, or wherein the mother liquor 25 is equilibrated by selecting a base that does not catalyze the formation of side products from diastereomer-A.

27. The process as claimed in any one of claims 24 to 26, wherein the base is selected from the group consisting earth metal hydroxides, earth metal carbonates, nitrogen containing bases, organic bases, quarternary ammonium 30 salts, halides of alkali metals and ammonium halides or a mixture thereof. 25242651 (GHMatters) 6101/11 78

28. The process as claimed in any one of claims 24 to 27, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, dimethylamine, trimethylamine, triethylamine, 5 N,N-dimethylaniline, tetrabutylammonium bromide, triethylbenzyl ammonium chloride, triethylbenzylammonium bromide, benzyl tributyl ammonium chloride, and N-butyl-N,N-dimethyl-a-(S)-phenyl ethylamine or a mixture thereof.

29. The process as claimed in any one of claims 24 to 28, wherein the base 10 potassium fluoride is used in the range 2-10 mole percent or in the range 4-6 mole percent.

30. (S)-a-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate produced by the process according to any one of claims I to 29.

31. A process for the preparation of (S)-c-cyano-3-phenoxy-benzyl-(S)-2-(4 15 chlorophenyl) isovalerate, or (S)-a-cyano-3-phenoxy-benzyl-(S)-2-(4 chlorophenyl) isovalerate produced by the process, substantially as herein described with reference to the Examples and/or Figures. 25242651 (GHMatters) 9/02J11