Patent Description:
As used in the present disclosure, the following terms are generally intended to have the meaning as set forth below, except to the extent that the context in which they are used indicate otherwise.

Equilibration refers to a process of allowing an enantiomeric mass under stirring to attain equilibrium, for obtaining a specific enantiomeric ratio.

Crude Indoxacarb refers to Indoxacarb obtained from a manufacturing unit, comprising optically active isomer of Indoxacarb (S-isomer) and optically inactive isomer of Indoxacarb (R-isomer) along with impurities. Crude Indoxacarb is either amorphous or crystalline in nature. The impurities are inert in nature comprising compounds such as oxadiazine precursor, oil and the like. The amount of impurities present in crude Indoxacarb is in the range of <NUM> wt. % to <NUM> wt.

The background information herein below relates to the present disclosure but is not necessarily prior art.

Indoxacarb is known to have pesticidal activity and is especially effective against lepidopteran larvae. Indoxacarb is an oxadiazine compound exhibiting stereoisomerism, wherein (+)-S-isomer has insecticidal activity whereas the R-isomer is inactive. However, the isolation process to obtain the S-isomer crystals of Indoxacarb with high purity is tedious and expensive.

Therefore, there is felt a need, for an efficient process for isolating S-isomer crystals of Indoxacarb, which mitigates the drawbacks mentioned hereinabove.

Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows.

It is an object of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative.

Another object of the present disclosure is to isolate S-isomer crystals of Indoxacarb having comparatively high purity.

Still another object of the present disclosure is to provide an efficient process for isolating S-isomer crystals of Indoxacarb having comparatively high purity.

Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.

The present disclosure provides a process for isolating S-isomer crystals of Indoxacarb having purity in the range of <NUM>% to <NUM>%. The process comprises mixing crude Indoxacarb with a solvent to obtain a slurry, wherein the crude Indoxacarb comprises impurities in an amount in the range of <NUM> wt. % to <NUM> wt. The slurry is heated to a temperature in the range of <NUM> to <NUM> to obtain a heated slurry. The heated slurry is cooled to a temperature in the range of <NUM> to <NUM> to allow crystallization of racemic Indoxacarb and obtain a warm slurry comprising crystals of the racemic Indoxacarb. The warm slurry is filtered at a temperature in the range of <NUM> to <NUM> to isolate a mass comprising racemic Indoxacarb crystals and obtain a filtrate. The filtrate is cooled to a temperature in the range of <NUM> to <NUM> to initiate crystallization followed by equilibrating under stirring for a time period in the range of <NUM> hours to <NUM> hours to allow complete crystallization to obtain a mixture comprising S-isomer crystals of Indoxacarb. The mixture is filtered to isolate the S-isomer crystals of Indoxacarb. The crystals are washed and dried to obtain S-isomer crystals of Indoxacarb having purity in the range of <NUM>% to <NUM>%.

The present disclosure will now be described with the help of the accompanying drawing, in which:.

Embodiments, of the present disclosure, will now be described with reference to the accompanying drawing.

Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details, are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.

The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a," "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," "including," and "having," are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated.

The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.

Indoxacarb is a substituted oxadiazine compound having a single chiral center as shown in the structure (I) below. Indoxacarb is an important pesticidal compound showing improved properties in its crystalline form than in the amorphous form.

The insecticidal activity of Indoxacarb is mainly attributed to the (+)-S-isomer whereas the R-isomer is inactive. Conventional processes of obtaining S-isomer crystals of Indoxacarb is tedious and expensive.

The present disclosure provides a simple and cost effective process for isolating S-isomer crystals of Indoxacarb having comparatively high purity.

Particularly, the present disclosure provides a process for isolating S-isomer crystals of Indoxacarb having purity in the range of <NUM>% to <NUM>%. The process is described in detail herein below.

Crude Indoxacarb is mixed with a solvent to obtain a slurry. The crude Indoxacarb comprises impurities in an amount in the range of <NUM> wt. % to <NUM> wt.

The crude Indoxacarb, obtained from a manufacturing unit, comprises optically active isomer of Indoxacarb (S-isomer) and optically inactive isomer of Indoxacarb (R-isomer) along with impurities. The impurities are inert in nature comprising compounds such as oxadiazine precursor, solvent, oil and the like. The amount of impurities in crude Indoxacarb are in the range of <NUM> wt. % to <NUM> wt. Crude Indoxacarb is either amorphous or crystalline in nature.

Crude Indoxacarb comprises an enantiomeric mixture having S-isomer in an amount in the range of <NUM>% to <NUM>%. In an embodiment, crude Indoxacarb contains S-isomer in an amount of <NUM>% of the enantiomeric mixture.

In an embodiment, crude Indoxacarb is obtained in an amorphous lump form.

In an exemplary embodiment, crude Indoxacarb has total impurities of <NUM> wt. % to <NUM> wt.

In accordance with the present disclosure, the solvent is selected from the group consisting of aliphatic alcohols with C<NUM> to C<NUM> carbon atoms and cyclic alcohols.

Typically, the solvent is selected from the group consisting of methanol, ethanol, <NUM>-propanol, <NUM>-butanol and cyclohexanol. In an exemplary embodiment, the solvent is <NUM>-propanol.

The weight-volume ratio of crude Indoxacarb and the solvent in the mixing step is in the range of <NUM>:<NUM> to <NUM>:<NUM>. In an embodiment, the weight-volume ratio of crude Indoxacarb and the solvent is <NUM>:<NUM>.

The weight-volume ratio lesser than <NUM>:<NUM> would lead to insufficient solubility whereas a ratio greater than <NUM>:<NUM> would lead to the use of excess solvent which not only leads to wastage but also affects the recrystallization of S-isomer during equilibration resulting in comparatively lesser recovery.

In an embodiment, the impurities are mainly inert impurities that get dissolved by the solvent at room temperature.

Further, the slurry is heated to a temperature in the range of <NUM> to <NUM> to obtain a heated slurry. Typically, the slurry is heated to a temperature in the range of <NUM> to <NUM>. In an exemplary embodiment, the solvent used is <NUM>-propanol and the slurry is heated to <NUM>.

The heating of the slurry in the temperature range of <NUM> to <NUM> ensures better solubilization of S-isomer of Indoxacarb in the heated slurry. This range of temperature is important because below <NUM>, solubilization will be ineffective and above <NUM>, there might be loss of solvent in the slurry due to evaporation, depending upon the solvent used.

In the next step, the heated slurry is cooled to a temperature in the range of <NUM> to <NUM> to allow crystallization of racemic Indoxacarb and obtain a warm slurry comprising crystals of the racemic Indoxacarb.

The racemic Indoxacarb has lower solubility than the enantiomeric Indoxacarb and hence crystallizes out preferentially in the cooling step. The removal of racemic Indoxacarb ensures that the inactive R-isomer is completely removed thereby leading to isolation of the S-isomer.

Typically, the heated slurry is cooled to a temperature in the range of <NUM> to <NUM>. In an embodiment, the heated slurry is cooled to <NUM>.

In the next step, the warm slurry is filtered at a temperature in the range of <NUM> to <NUM> to isolate a mass comprising the racemic Indoxacarb crystals and obtain a filtrate.

In an exemplary embodiment, the heated slurry is cooled to <NUM> and the filtration is done at <NUM> to isolate a mass comprising the racemic Indoxacarb crystals.

Further, the filtrate is cooled to a temperature in the range of <NUM> to <NUM> to initiate crystallization followed by equilibrating under stirring for a time period in the range of <NUM> hours to <NUM> hours at a temperature in the range of <NUM> to <NUM> to allow complete crystallization to obtain a mixture containing S-isomer crystals of Indoxacarb.

The cooling of the filtrate is done by using external source of cooling. The step of cooling the filtrate initiates crystallization of the S-isomer of Indoxacarb. Further, equilibration is the process of allowing a solution to attain equilibrium for obtaining complete crystallization. In accordance with the present disclosure, the equilibration step is very important for allowing complete crystallization of the S-isomer crystals, while the impurities and some amount of S-isomer stay in the filtrate.

Typically, the cooling of the filtrate and the equilibration of the first mixture is done at a temperature in the range of <NUM> to <NUM>.

In an embodiment, the filtrate is cooled to <NUM> and the equilibration of the first mixture is done at <NUM>.

Typically, the equilibration is done for a time period in the range of <NUM> hours to <NUM> hours. In an embodiment, the equilibration is done for <NUM> hours.

In the next step, the mixture is filtered to isolate S-isomer crystals of Indoxacarb. The crystals are washed and dried to obtain the S-isomer crystals of Indoxacarb having purity in the range of <NUM>% to <NUM>%.

The step of washing the crystals is done using a fluid medium selected from the group consisting of methanol, ethanol, <NUM>-propanol, t-butanol, <NUM>-butanol and cyclohexanol. The washing of the crystals with the fluid medium ensures complete removal of the impurities in the filtrate, thereby leading to higher purity. In an embodiment, the crystals are washed using <NUM>-propanol.

The step of drying the mass is done under vacuum at a temperature in the range of <NUM> to <NUM>. The temperature range of drying ensures the removal of the fluid medium from the crystals. In an embodiment, the drying is done at <NUM>.

In one embodiment, the S-isomer crystals of Indoxacarb obtained by the process of the present disclosure has a purity of <NUM>%. In another embodiment, S-isomer crystals of Indoxacarb obtained by the process of the present disclosure has a purity of <NUM>%.

In an exemplary embodiment, crude Indoxacarb is mixed with <NUM>-propanol to obtain a slurry, wherein the crude Indoxacarb comprises impurities in an amount of <NUM> wt. The slurry is heated to <NUM> to obtain a heated slurry. The heated slurry is cooled to <NUM> to allow crystallization of racemic Indoxacarb and obtain a warm slurry comprising crystals of racemic Indoxacarb. The warm slurry is filtered at <NUM>, to isolate a mass comprising the racemic Indoxacarb crystals and obtain a filtrate. The filtrate is cooled to <NUM> to initiate crystallization followed by equilibration under stirring for <NUM> hours at <NUM> to allow complete crystallization to obtain S-isomer crystals of Indoxacarb. The mixture is filtered to isolate the S-isomer crystals of Indoxacarb. The crystals are washed with <NUM>-propanol and dried at <NUM> under vacuum, to obtain S-isomer crystals of Indoxacarb having purity of <NUM>%.

The commercial sample of Indoxacarb comprises <NUM>:<NUM> ratio of R:S isomers. The conventional process for isolating S-isomer is tedious and expensive. The process of the present disclosure provides a simple and economical process for isolation of the S-isomer crystals of Indoxacarb.

The foregoing description of the embodiments has been provided for purposes of illustration and not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but, are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.

The present disclosure is further described in light of the following laboratory scale experiments which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. These laboratory scale experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to industrial/commercial scale.

Crude Indoxacarb (<NUM>) having purity of <NUM>% (impurities of <NUM> wt. %) and R: S isomer ratio= <NUM>:<NUM>, was placed in a vessel equipped with stirrer and mixed with Isopropyl alcohol (<NUM>) to obtain a slurry. The slurry was heated to <NUM> to obtain a heated slurry, which was then cooled to <NUM> to allow complete crystallization of racemic Indoxacarb and obtain a warm slurry comprising crystals of the racemic Indoxacarb. The warm slurry was then filtered at <NUM> to isolate crystals of racemic Indoxacarb and obtain a filtrate. The racemic Indoxacarb crystals were dried (<NUM>) and used for further analysis (Sample 1A). The filtrate was cooled to <NUM> to initiate crystallization followed by equilibrating under stirring for <NUM> hours to allow complete crystallization to obtain a mixture comprising S-isomer crystals of Indoxacarb. The mixture was filtered at <NUM> to isolate the S-isomer crystals of Indoxacarb. The crystals were washed with isopropyl alcohol and then dried under vacuum at <NUM> to get S-isomer crystals of Indoxacarb (Sample 2A) (<NUM>) with purity of <NUM>%.

Crude Indoxacarb (<NUM>) having purity of <NUM>% (impurities of <NUM> wt. %) and R: S isomer ratio=<NUM>:<NUM>, was placed in a vessel equipped with stirrer and mixed with methanol (<NUM>) to obtain a slurry. The slurry was heated to <NUM> to obtain a heated slurry, which was then cooled to <NUM> to allow complete crystallization of racemic Indoxacarb and obtain a warm slurry comprising crystals of the racemic Indoxacarb. The warm slurry was then filtered at <NUM> to isolate racemic Indoxacarb and obtain a filtrate. The racemic Indoxacarb crystals were dried (<NUM>) and used for further analysis (Sample 1B). The filtrate was cooled to <NUM> to initiate crystallization followed by equilibrating under stirring for <NUM> hours to allow complete crystallization to obtain a mixture comprising S-isomer crystals of Indoxacarb. The mixture was filtered at <NUM> to isolate the S-isomer crystals of Indoxacarb. The crystals were washed with isopropyl alcohol (<NUM>) and then dried under vacuum at <NUM> to get S-isomer crystals of Indoxacarb (Sample 2B) (<NUM>) with purity of <NUM>%.

Crude Indoxacarb (<NUM>) having purity of <NUM> % (impurities of <NUM> wt. %) and R: S isomer ratio=<NUM>:<NUM>, was placed in a vessel equipped with stirrer and mixed with ethanol (<NUM>) to obtain a slurry. The slurry was heated to <NUM> to obtain a heated slurry, which was then cooled to <NUM> to allow complete crystallization of racemic Indoxacarb and obtain a warm slurry comprising crystals of the racemic Indoxacarb. The warm slurry was then filtered at <NUM> to isolate racemic Indoxacarb and obtain a filtrate. The racemic Indoxacarb crystals were dried (<NUM>) and used for further analysis (Sample 1C). The filtrate was cooled to <NUM> to initiate crystallization followed by equilibrating under stirring for <NUM> hours to allow complete crystallization to obtain a mixture comprising S-isomer crystals of Indoxacarb. The mixture was filtered at <NUM> to isolate the S-isomer crystals of Indoxacarb. The crystals were washed with cold ethanol (<NUM>) and then dried under vacuum at <NUM> to get S-isomer crystals of Indoxacarb (Sample 2C) (<NUM>) with purity of <NUM> %.

Crude Indoxacarb (<NUM>) having purity of <NUM> % (impurities of <NUM> wt. %) and R: S isomer ratio=<NUM>:<NUM>, was placed in a vessel equipped with stirrer and mixed with t-butanol (<NUM>) to obtain a slurry. The slurry was heated to <NUM> to obtain a heated slurry, which was then cooled to <NUM> to allow complete crystallization of racemic Indoxacarb and obtain a warm slurry comprising crystals of the racemic Indoxacarb. The warm slurry was then filtered at <NUM> to isolate racemic Indoxacarb and obtain a filtrate. The racemic Indoxacarb crystals were dried (<NUM>) and used for further analysis (Sample 1D). The filtrate was cooled to <NUM> to initiate crystallization followed by equilibrating under stirring for <NUM> hours to allow complete crystallization to obtain a mixture comprising S-isomer crystals of Indoxacarb. The mixture was filtered at <NUM> to isolate the S-isomer crystals of Indoxacarb. The crystals were washed with cold t-butanol (<NUM>) and then dried under vacuum at <NUM> to get S-isomer crystals of Indoxacarb (Sample 2D) (<NUM>) with purity of <NUM> %.

Crude Indoxacarb (<NUM>) having purity of <NUM> % (impurities of <NUM> wt. %) and R: S isomer ratio=<NUM>:<NUM>, was placed in a vessel equipped with stirrer and mixed with <NUM>-propanol (<NUM>) to obtain a slurry. The slurry was heated to <NUM> to obtain a heated slurry, which was then cooled to <NUM> to allow complete crystallization of racemic Indoxacarb and obtain a warm slurry comprising crystals of the racemic Indoxacarb. The warm slurry was then filtered at <NUM> to isolate racemic Indoxacarb and obtain a filtrate. The racemic Indoxacarb crystals were dried (<NUM>) and used for further analysis (Sample 1E). The filtrate was cooled to <NUM> to initiate crystallization followed by equilibrating under stirring for <NUM> hours to allow complete crystallization to obtain a mixture comprising S-isomer crystals of Indoxacarb. The mixture was filtered at <NUM> to isolate the S-isomer crystals of Indoxacarb. The crystals were washed with cold <NUM>-propanol (<NUM>) and then dried under vacuum at <NUM> to get S-isomer crystals of Indoxacarb (Sample 2E) (<NUM>) with purity of <NUM> %.

Crude Indoxacarb (<NUM>) having purity of <NUM> % (impurities of <NUM> wt. %) and R: S isomer ratio=<NUM>:<NUM>, was placed in a vessel equipped with stirrer and mixed with <NUM>-propanol (<NUM>) to obtain a slurry. The slurry was heated to <NUM> to obtain a heated slurry, which was then cooled to <NUM> to allow complete crystallization of racemic Indoxacarb and obtain a warm slurry comprising crystals of the racemic Indoxacarb. The warm slurry was then filtered at <NUM> to isolate racemic Indoxacarb and obtain a filtrate. The racemic Indoxacarb crystals were dried (<NUM>) and used for further analysis (Sample 1F). The filtrate was cooled to <NUM> to initiate crystallization followed by equilibrating under stirring for <NUM> hours to allow complete crystallization to obtain a mixture comprising S-isomer crystals of Indoxacarb. The mixture was filtered at <NUM> to isolate the S-isomer crystals of Indoxacarb. The crystals were washed with cold <NUM>-propanol (<NUM>) and then dried under vacuum at <NUM> to get S-isomer crystals of Indoxacarb (Sample 2F) (<NUM>) with purity of <NUM> %.

The crude Indoxacarb sample (R:S as <NUM>:<NUM>) used in Example a, and the samples 1A (racemic mixture) and 2A (S-isomer of Indoxacarb), as obtained from Example a were subjected to Differential scanning calorimetry (DSC) analysis as shown in <FIG>, <FIG> and <FIG> respectively.

The crude Indoxacarb as used in Example a (R:S as <NUM>:<NUM>) shows two different peaks in DSC analysis wherein one peak in the range of <NUM> to <NUM> corresponds to melting temperature of S-Indoxacarb and another peak in the range of <NUM> to <NUM> corresponds to melting temperature of racemic Indoxacarb. The sample 1A (racemic Indoxacarb) shows a single peak in DSC corresponding to the melting temperature range of <NUM> to <NUM>. The sample 2A (S-isomer of Indoxacarb) shows a single peak in DSC corresponding to the melting temperature range of <NUM> to <NUM>.

The crude Indoxacarb sample used in Example a (R:S as <NUM>:<NUM>), and samples 1A (racemic mixture), 2A (S-isomer of Indoxacarb), as obtained from Example a was subjected to X-Ray Diffraction (XRD) analysis to obtain data as shown in <FIG>, <FIG> and <FIG> respectively.

The significant peaks in XRD for the crude Indoxacarb sample used in Experiment <NUM> (R:S as <NUM>:<NUM>), sample 1A and sample 2A, as obtained from Experiment <NUM> are as summarized in Table <NUM>, Table <NUM> and Table <NUM> respectively.

As observed in <FIG>, <FIG> and Tables <NUM>, <NUM>, the significant peaks in <FIG> having 2Θ values of <NUM>, <NUM>, <NUM> and <NUM> are also observed in <FIG>, confirming the isolation of racemic Indoxacarb (sample 1A).

As observed in <FIG>, <FIG> and Tables <NUM>, <NUM>, the significant peaks in <FIG> having 2Θ values of <NUM>, <NUM>, <NUM>, <NUM> are also observed in <FIG>, confirming the presence of S-isomer of Indoxacarb in the sample 2A.

The process of the present disclosure is simple and cost effective, wherein S-isomer crystals of Indoxacarb are isolated in comparatively high purity.

The present disclosure described herein above has several technical advantages including but not limited to the realization of a process for isolating S-isomer crystals of Indoxacarb that:.

Claim 1:
A process for isolating S-isomer crystals of Indoxacarb having purity in the range of <NUM>% to <NUM>%, said process comprising the following steps:
a) mixing crude Indoxacarb with a solvent to obtain a slurry, wherein the crude Indoxacarb comprises impurities in an amount in the range of <NUM> wt.% to <NUM> wt.%;
b) heating said slurry to a temperature in the range of <NUM> to <NUM> to obtain a heated slurry;
c) cooling said heated slurry to a temperature in the range of <NUM> to <NUM> to allow complete crystallization of racemic Indoxacarb and obtain a warm slurry comprising crystals of the racemic Indoxacarb;
d) filtering said warm slurry at a temperature in the range of <NUM> to <NUM> to isolate a mass comprising racemic Indoxacarb crystals and obtain a filtrate;
e) cooling said filtrate to a temperature in the range of <NUM> to <NUM> to initiate crystallization followed by equilibrating under stirring for a time period in the range of <NUM> hours to <NUM> hours to allow complete crystallization to obtain a mixture comprising S-isomer crystals of Indoxacarb;
f) filtering said mixture to isolate said S-isomer crystals of Indoxacarb; and
g) washing and drying said crystals to obtain S-isomer crystals of Indoxacarb having purity in the range of <NUM>% to <NUM>%.