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WO2006010994A1 - Procede de preparation de (s)-alpha-cyano-3-phenoxybenzyl-(s)-2-(4-chlorophenyl)-isovalerate - Google Patents

Procede de preparation de (s)-alpha-cyano-3-phenoxybenzyl-(s)-2-(4-chlorophenyl)-isovalerate Download PDF

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WO2006010994A1
WO2006010994A1 PCT/IB2004/002473 IB2004002473W WO2006010994A1 WO 2006010994 A1 WO2006010994 A1 WO 2006010994A1 IB 2004002473 W IB2004002473 W IB 2004002473W WO 2006010994 A1 WO2006010994 A1 WO 2006010994A1
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isomer
solution
crystallization
crystals
diastereomer
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Inventor
Vaddu Venkata Narayana Reddy
Ishratullah Khwaja
Venkata Krishnam Raju Penumatcha
Ramesh Babu Tella
Mahesh Masna
Chappeta Venkateswara Reddy
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Council of Scientific and Industrial Research CSIR
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Council of Scientific and Industrial Research CSIR
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Priority to PCT/IB2004/002473 priority Critical patent/WO2006010994A1/fr
Priority to AU2004321853A priority patent/AU2004321853B2/en
Publication of WO2006010994A1 publication Critical patent/WO2006010994A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/32—Separation; Purification; Stabilisation; Use of additives
    • C07C253/34—Separation; Purification

Definitions

  • the present invention relates to an environmentally benign process for the preparation of (S)- ⁇ -cyano-3-phenoxybenzyl-(S)- 2-(4-chlorophenyl)isovalerate from its diastereomeric mixture (RS)- ⁇ -cyano-3 -phenoxybenzyl-(S)-2-(4-chlorophenyl) isovalerate.
  • the present invention deals with the method for preparation of diastereomeric mixture of (RS)- ⁇ -cyano-3-phenoxybenzyl-(S)-2-(4- chlorophenyl)isovalerate (herein after referred as diastereomer-A) and its subsequent conversion to (S)- ⁇ -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.
  • diastereomer-A diastereomer-A
  • 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)- ⁇ -cyano-3 -phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate (hereinafter referred as SR isomer) via epimerization of the alcohol moiety using inexpensive catalyst to a desired diastereomeric mixture.
  • SR undesired isomer
  • 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 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
  • SS isomer of general formula (I) As regards of SS isomer of general formula (I)
  • Patent application DE 2830031 wherein the process for preparation of esfen valerate from its diastereomeric mixture is described. It describes a method for crystallization of SS isomer with or without using catalyst by four different 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 isomer is subjected to epimerisation with or without a catalyst.
  • the method D performs the same procedure as in method C using a catalyst.
  • 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 on Alcohol moiety using pure seed crystal solution of S-S isomer in presence or absence of basic catalyst.
  • S acid moiety
  • R configuration on Alcohol moiety
  • the method could not be reproduced with consistency albeit the experimental conditions are followed as described in the patent.
  • the main object of the present invention is to develop a process for production of SS isomer [(S)- ⁇ -cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate] .
  • 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 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.
  • the present invention relates to an environmentally benign process for the preparation of (S)- ⁇ -cyano-3-phenoxybenzyl-(S)- 2-(4-chlorophenyl)isovalerate from its diastereomeric mixture (RS)- ⁇ -cyano-3 -phenoxybenzyl-(S)-2-(4-chlorophenyl) isovalerate.
  • the present invention provides a process for manufacture of (S)- ⁇ -cyano- 3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate which comprises preparation of a diastereomeric ester (RS)- ⁇ -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
  • the diastereomeric ester (Diastereomer-A) is prepared either by addition of (S)-2-(4-chlorophenyl) isovaleroyl chloride to aqueous solution (RS)- ⁇ - cyano 3-phenoxybenzylalcohol or addition of a premixed solution of (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)- ⁇ -cyano3- phenoxybenzylalcohol under PTC conditions.
  • the choice of solvent is selected from the group consisting of aromatic hydrocarbon, chlorinated hydrocarbons like toluene, benzene, hexane, chloroform, 1 ,2-dichloroethane, dichloromethane respectively, more preferably 1 ,2-dichloroethane.
  • the phase transfer catalyst is quarternary ammonium salt selected from the group consisting of tertabutylammoniumbromide
  • TBAB tertiarybutylammoniumhydrogensulphate
  • TAAHS tertiarybutylammoniumhydrogensulphate
  • Benzyltriethylammonium chloride (TEBA) benzyltributylammoniumchloride, N-butyl- N,N-dimethyl- ⁇ -phenylethylammoniumbromide.
  • the quaternary ammonium salt is tetrabutylammoniumbromide.
  • sodium cyanide is used in amount of 1.0 to 1.60 mole per mole of 3-phenoxybenzaldehyde.
  • (S)-2-(4-chlorophenyl). isovaleroylchloride is used in amount of 1.0 to 1.03 mole per mole of 3-phenoxybenzaldehyde.
  • the (S)-2-(4-chlorophenyl) isovaleroyl chloride is added over a period of time ranging from 100-120 minutes.
  • the (S)-2-(4-chlorophenyl) isovaleroylchloride is added to an aqueous solution of (RS)- ⁇ -cyano-3-phenoxy benzylalcohol at a temp, ranging from -2 0 C to -4 0 C.
  • the course of the esterification reaction is followed by HPLC analysis drawing samples at intervals of time ranging from 30-90 minutes.
  • the reaction is continued after addition of acid chloride for a further period of time ranging from 60-120 minutes.
  • the diastereomeric ester formed (dilute- diastereomer-A) is concentrated under pressure ranging from 80-60 mm Hg to obtain diastereomer-A.
  • the solvent recovered from distillation of dilute diastereomer-A is recycled for further batches of diastereomer-A formation.
  • 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 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, in undissolved state and only crystals of required isomer (SS) alone crystallizes from the solution.
  • SS required isomer
  • the process of crystallization is controlled by predetermined rate of cooling the solution to a temperature range and 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.
  • the progress of crystallization is monitored by chiral HPLC analysis, drawing samples at regular intervals of time to find the enrichment of SR isomer.
  • the process of crystallization is stopped when the analysis of SR isomer is in the range of 50-55%.
  • the process of crystallization is preferably increased either by stirring or shaking the solution more preferably by stirring.
  • the process of crystallization can be carried out at a temperature range +1O 0 C to -15°C and most advantageously at a range of +2 0 C to - 8 0 C.
  • reaction time is such that it should be 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.
  • the organic solvent selected is from the group comprising of lower alcohols and/or aromatic aliphatic hydrocarbons or mixtures thereof.
  • the solvent is selected from alcohols consisting of methanol, ethanol, isopropanol and hydrocarbon solvents like Hexane, Toluene, Heptane.
  • the solvent is more preferably lower alkanol like methanol.
  • 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%.
  • 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, cooled to room temperature and subjected to process of crystallization to obtain further quantity of the desired isomer (SS)-isomer.
  • 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 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.
  • the mother liquor equilibrated is replenished with an amount of diastereomer-A equivalent to the weight of SS isomer 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.
  • the catalyst employed for equilibration can 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 ammonium halides.
  • the more preferred base being fluorides of alkali metals or ammonium halides most preferably potassiumfluoride.
  • 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.
  • the process of the invention involves the preparation of diastereomeric mixture
  • 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- chlorophenyl)-isovaleroylchloride or by reaction of the acid chloride with a preformed ⁇ -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 consisting of chlorinated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons like chloroform, dichloromethane 1 ,2-Dichloroethane, hexane, heptane, 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), Benzyltriethylammoniumchloride (TEBA), Benzyltributylammoniumchloride, N-butyl- N,N, dimethylphenylethylammoniumbrornide, more preferably tetrabutylammonium bromide by addition of 3-phenoxybenzaldehyde to an a
  • 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 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% w/w by following a programmed rate of cooling viz stepwise decreasing the temperature to 2O 0 C from ambient temperature, thereby cooling to 10 0 C at intervals of time preferably 2-8 0 C per hour more preferably 4-6 0 C per hour.
  • solvent/solvent mixtures selected from the group comprising of lower alcohols and/
  • Further decrease in temperature is effected by maintaining the solution at a temperature range of +2 to 18 0 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 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°-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 inorganic base catalyst, which is stable under reaction conditions
  • organic or 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 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 replenished 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 diastereomer-A each time till crystals of SS isomer is obtained.
  • This material is used for preferential crystallization of esfenvalerate.
  • the ML obtained from the above example-5 was further subjected to crystallization by cooling to -15 0 C.
  • a slurry of seed crystals (0.07248g; 99%) of SS-isomer was introduced.
  • the solution is stirred at -15.5 0 C for a period of 96 hrs.
  • % purity of SS-isomer 77.2% b.
  • the mother liquor (40%) was further subjected to crystallization following the procedure described above except that the solution was cooled to -13 0 C for 240 hrs. the crystals obtained were separated out by filtration.
  • diastereomer-A (36.33g) obtained form the experiments where the preferential crystallization has not been achieved and methanol
  • the stirred solution was cooled in a cryogenic bath at a stepwise rate of cooling of one degree centigrade for one hour from +5° to -7 0 C.
  • Pure SS isomer 99.3% was added to the cooling solution at +1 0 C.
  • the solids obtained were filtered and separated. Wt.
  • This solution is cooled in a cryogenic bath under stirring at a temperature programme such that the rate of crystallization is conspicuous and continuous without getting abrupt crystallization, from +2O 0 C to +5 0 C at the rate of l°C/hr upto +12 0 C wherein slurry of seed crystals of SS-isomer obtained from crystallization of SS-isomer in hexane was added together with mother liquor.
  • further cooling is continued by decreasing the temperature at the rate of I 0 C while observing the process of crystallization once in 2 or 3 hrs.
  • the mother liquor (670.Og) 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 +15 0 C to - 6 0 C at the rate of 2°C/hr. initially i.e. from +15 0 C to +12 0 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 l°C/hr i.e. upto +4 0 C.
  • 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 upper aqueous layer (NaCN) is detoxified separately.
  • the DCE layer is concentrated at 4O 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 above example-37 is used as such without any further modifications by dissolving in 60.0gms of methanol to obtain a 25% w/w solution of diastereomer-A.
  • the ML (515.84 gms) of example 40 was equilibrated at 6O 0 C for 18 hrs at 65 0 C, cooled to room temperature and replenished with 16.0 gms of liquid diastereomer as 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 0 C at the rate of 3°C/hr. and introducing SS-isomer (99.3%) seed crystal at 5 0 C. Further cooling to -8 0 C was effected at the rate of 1° or 2 0 C while observing the rate of crystallization. The solution was held at -8 0 C for 24 hrs.
  • the mother liquor 530.06 gms obtained in above example-41 was equilibrated at 6O 0 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.
  • 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 15.0g of .methanol respectively to obtain a 20% w/w solution of diastereomer-A, which was subjected to step-wise cooling following the temperature programme as described in above example except that cooling was continued upto -H 0 C and holding the solution between -1O 0 C to -11 0 C for 48 hrs.
  • reaction mixture is cooled to -3° to -5 0 C, 2.15kg of (S)-fenvaleroylchloride is diluted with 2.2 kg of dichloroethane (DCE) and added over a period of VA to 2 hrs. through a dropping funnel maintaining the temperature between -3 to -4 0 C under vigorous stirring. The 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 detoxified separately.
  • DCE dichloroethane
  • the DCE layer(l 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 (1 1.19kg) is taken for recovery of diastereomer-A.
  • the dilute DCE layer (11.19kg) is weighed and fed into a Rotary evaporator 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.
  • 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 storage tank.
  • 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 homogeneous solution.
  • the solution is initially cooled to 22 0 C under stirring from room temperature, thereafter cooling is effected to 1O 0 C by decreasing the temperature at the rate of 4 0 C per hour, at this temperature (1O 0 C) pure crystals of esfen valerate (99.5 %) is introduced into the system.
  • the filtrate enriched with SR-isomer ML-I (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 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 3O 0 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 process of cooling from 30 to 3 0 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
  • 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 0 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 3O 0 C and diastereomer-A (0.452kg) equivalent to esfenvalerate obtained in earlier cycle is added, solution is made up to 25% by adding methanol (0.504kg).
  • the filtrate enriched with SR-isomer ML-3 (1 1.12kg) obtained from 47B 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 Vi 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 3O 0 C and . diastereomer-A (0.436kg) equivalent to esfenvalerate obtained in earlier cycle is added, solution is made up to 25%.
  • 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 recording and heating system and the contents are heated to 62-65 0 C for 5 Vi 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 3O 0 C and diastereomer-A (0.398kg) equivalent to esfenvalerate obtained in earlier cycle is added, solution is made up to 25%.
  • 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 3O 0 C 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 0 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 and dried.
  • the present invention makes it possible to obtain high optically pure (>95%) SS isomer in an iterative manner
  • Another advantage is consecutively using thus equilibrated ML of one cycle in another cycle as such avoids many process steps. Replenishing the ML with 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. 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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Abstract

L'invention concerne un procédé de préparation sans danger pour l'environnement de (S)-a-cyano-3-phénoxybenzyl-(S)-2-(4-chlorophényl)isovalerate à partir de son mélange diaséréomérique (RS)-a-cyano-3-phénoxybenzyl-(S)-2-(4-chlorophényl)isovalerate.
PCT/IB2004/002473 2004-07-20 2004-07-20 Procede de preparation de (s)-alpha-cyano-3-phenoxybenzyl-(s)-2-(4-chlorophenyl)-isovalerate Ceased WO2006010994A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/IB2004/002473 WO2006010994A1 (fr) 2004-07-20 2004-07-20 Procede de preparation de (s)-alpha-cyano-3-phenoxybenzyl-(s)-2-(4-chlorophenyl)-isovalerate
AU2004321853A AU2004321853B2 (en) 2004-07-20 2004-07-20 Process for preparing (S)-alpha-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)-isovalerate

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Cited By (1)

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CN106278944A (zh) * 2016-08-10 2017-01-04 江苏春江润田农化有限公司 一种氰戊菊酯的生产方法

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