A method for separation of CIS and trans isomers of hydantoin-containing spiro-compound from an isomeric mixture

Abstract

A method for separation of cis and trans isomers of hydantoin-containing spiro- compound from an isomeric mixture, including contacting the isomeric mixture with a medium comprising a polar aprotic solvent, and separating the cis isomer and / or trans isomer.

Description

[0001] A METHOD FOR SEPARATION OF CIS AND TRANS ISOMERS OF HYDANTOIN- CONTAINING SPIRO-COMPOUND FROM AN ISOMERIC MIXTURE

[0002] TECHNICAL FIELD

[0003] The present invention relates to a separation method of cis and trans isomers of a hydantoin-containing spiro-compound comprising an effective solvent system and additives.

[0004] BACKGROUND

[0005] Spirotetramat is a systemic insecticide that acts by inhibiting lipid biosynthesis. A biologically active isomer of the Spirotetramat is specifically the cis isomer of the structure, and its isomeric identity is predefined at an earlier synthesis of cis-8-Methoxy-l,3- diazaspiro[4.5]decane-2, 4-dione intermediate, an isomer of hydantoin-containing spiro- compound. The synthesis of this intermediate usually results in both cis and trans isomers, hence a subsequent workup step is a key to an efficient production of the active Spirotetramat.

[0006] Normally, the synthesized isomeric mixture of hydantoin-containing spiro-compound, as obtained from a Bucherer-Bergs reaction results in an isomeric ratio of cis / trans of about 60 / 40 - 80 / 20. Therefore, it is necessary to further develop an efficient and cost-effective workup step to separate the cis hydantoin-containing spiro-compound from the as-synthesized isomeric mixture to further improve the cis / trans ratio. Nevertheless, it is still challenging to separate the isomers and obtain a ratio of above 95 / 5 (cis / trans) while maintaining an overall yield of above 55%. Such an optimized separation method is essential for increasing the isomeric purity and yield of the Spirotetramat final product.

[0007] In addition, to increase cost-efficiency, it would be beneficial to implement steps to recycle materials left after workup, such as undesired isomers and / or used solvents, towards the production of additional hydantoin-containing spiro-compound. SUMMARY

[0008] This disclosure is directed to methods comprising the separation of cis and trans isomers of a hydantoin-containing spiro-compound by using optimized parameters of solvent system, additives, and additional physical parameters. Advantageously, the method results in a high cis / trans ratio of above 95 / 5, while achieving an overall yield of above 55%; preferably, a ratio of 99 / 1 (cis / trans) and an overall yield of 58%. Moreover, the method requires a minimum amount of solvent which is an advantage in terms of production and cost.

[0009] In addition, the disclosure relates to an agriculture composition comprising Spirotetramat synthesized from the separated cis hydantoin-containing spiro-compound obtained by the method of this invention.

[0010] According to some embodiments, provided is a method for separation of cis and trans isomers of hydantoin-containing spiro-compound from an isomeric mixture, the method including: contacting said isomeric mixture with a medium comprising a polar aprotic solvent, and separating said cis isomer and / or trans isomer.

[0011] According to some embodiments, the cis isomer remains in an essentially solid form and the trans isomer is solubilized.

[0012] According to some embodiments, the medium further comprises water.

[0013] According to some embodiments, the ratio between the polar aprotic solvent and water is of about 1 / 0.1 to about 1 / 1.

[0014] According to some embodiments, the method includes heating the mixture to about 20- 80°C. According to some embodiments, the method includes heating the mixture to about 60- 70°C.

[0015] According to some embodiments, the separating is performed by a separation technique selected from a group consisting of filtration, chromatography, centrifugation, crystallization, precipitation, and any combination thereof. Each possibility is a separate embodiment.

[0016] According to some embodiments, the overall yield of the method is at least 55% and the cis / trans ratio at least 95 / 5. According to some embodiments, the cis and trans hydantoin-containing spirocompound comprises a structure of formula (1):

[0017] According to some embodiments, R represents alky, alkenyl, arylalkyl, acyl, or aryl. Each possibility is a separate embodiment.

[0018] According to some embodiments, R represents C1-C4 alkyl. Each possibility is a separate embodiment.

[0019] According to some embodiments, R represents methyl. Each possibility is a separate embodiment.

[0020] According to some embodiments, the isomeric mixture includes 1,4-cis and 1,4-trans isomers of the hydantoin-containing spiro-compound.

[0021] According to some embodiments, the isomeric mixture is obtained via Bucherer-Bergs reaction comprises 4-alkoxy cyclohexanone as a starting material, which includes a structure of the formula (2):

[0022] According to some embodiments, R represents alky, alkenyl, arylalkyl, acyl, or aryl. Each possibility is a separate embodiment.

[0023] According to some embodiments, R represents C1-C4 alkyl. Each possibility is a separate embodiment.

[0024] According to some embodiments, R represents methyl. According to some embodiments, the method further includes admixing an amine base additive. According to some embodiments, the amine base additive is selected from a group consisting of triethylamine, tert-butyl amine, N-methyl piperazine, diisopropylamine, isopropylamine, morpholine, their derivatives, and any combination thereof. Each possibility is a separate embodiment. According to some embodiments, the ratio between the 4-alkoxy- cyclohexanone starting material, the polar aprotic solvent, and the additive is from 1 / 9 / 0.1 to 1 / 2 / 1.0 (w / v / v). According to some embodiments, the ratio between the 4-alkoxy- cyclohexanone starting material, the polar aprotic solvent N,N-dimethylacetamide, and the amine base additive is from 1 / 1 / 0. 1 to 1 / 5 / 1.5 (w / v / v).

[0025] According to some embodiments, the Bucherer-Bergs reaction reagents include Ammonium carbonate and Sodium cyanide in water.

[0026] According to some embodiments, the polar aprotic solvent includes a structure of any of the formulas (3,4):

[0027] According to some embodiments, Ri, R2, and R3 each represent any of C1-C10 alkyls. Each possibility is a separate embodiment.

[0028] According to some embodiments, the polar aprotic solvent is selected from a group consisting of N,N-dimethylacetamide, N,N-diethylacetamide, N,N-dipropylacetamide, N,N- dibutylacetamide, N,N-dimethylformamide, N,N-diethylformamide, N,N- Diisopropylformamide, N,N-Dimethyldecanamide their derivatives, and any combination of thereof. Each possibility is a separate embodiment. According to some embodiments, the polar aprotic solvent is N,N-dimethylacetamide.

[0029] According to some embodiments, the polar aprotic solvent is acetonitrile.

[0030] According to some embodiments, the ratio between the volume of the medium to the weight of the isomeric mixture of the hydantoin-containing spiro-compound is from 0.5 / 1 to 12 / 1 (v / w). According to some embodiments, the ratio between the volume of a N,N- dimethylacetamide-based medium to the weight of the isomeric mixture of the hydantoin- containing spiro-compound is from 0.5 / 1 to 5 / 1 (v / w).

[0031] According to some embodiments, there is provided a method for separation of cis and trans isomers of hydantoin-containing spiro-compound from an isomeric mixture, the method including: contacting said isomeric mixture with a medium comprising a polar protic solvent comprising methanol, and separating said cis isomer and / or said trans isomer.

[0032] According to some embodiments, the cis isomer remains in an essentially solid form and the trans isomer is solubilized

[0033] According to some embodiments, the medium further comprises water.

[0034] According to some embodiments, the ratio between the polar protic solvent and the water is of about 1 / 0.1 to 1 / 0.5.

[0035] According to some embodiments, the method includes heating the mixture to about 20- 80°C. According to some embodiments, the method includes heating the mixture to about 60- 70°C.

[0036] According to some embodiments, the separating is performed by a separation technique selected from a group consisting of filtration, chromatography, centrifugation, crystallization, precipitation, and any combination thereof.

[0037] According to some embodiments, the method providing an overall yield of at least 55% and a cis / trans ratio of at least 95 / 5.

[0038] According to some embodiments, the cis and trans hydantoin-containing spiro- compound includes a structure of formula (1):

[0039]

[0040] According to some embodiments, R represents H, alky, alkenyl, arylalkyl, acyl, or aryl. Each possibility is a separate embodiment.

[0041] According to some embodiments, R represents C1-C4 alkyl. Each possibility is a separate embodiment.

[0042] According to some embodiments, R represents methyl.

[0043] According to some embodiments, the isomeric mixture includes 1,4-cis and 1,4-trans isomers of the hydantoin-containing spiro-compound.

[0044] According to some embodiments, the isomeric mixture is obtained via Bucherer-Bergs reaction comprises 4-alkoxy cyclohexanone as a starting material, which comprises a structure of the formula (2):

[0045] According to some embodiments, R represents alky, alkenyl, arylalkyl, acyl, or aryl. Each possibility is a separate embodiment.

[0046] According to some embodiments, preferably, R represents C1-C4 alkyl Each possibility is a separate embodiment.

[0047] According to some embodiments, particularly preferably, R represents methyl.

[0048] According to some embodiments, the Bucherer-Bergs reaction reagents include ammonium carbonate and sodium cyanide in water. According to some embodiments, the method further includes admixing an amine base additive. According to some embodiments, the amine base additive is selected from a group consisting of triethylamine, tert-butyl amine, N-methyl piperazine, diisopropylamine, Isopropyl amine, Morpholine, their derivatives, and any combination thereof. Each possibility is a separate embodiment. According to some embodiments, the ratio between the 4-alkoxy- cyclohexanone starting material, the polar protic solvent, and the additive is from 1 / 10 / 0.1 to 1 / 20 / 2.0 (w / v / v). According to some embodiments, the ratio between the 4-alkoxy- cyclohexanone starting material, the polar protic solvent methanol, and the additive is from 1 / 5 / 0.1 to 1 / 20 / 2.0 (w / v / v).

[0049] According to some embodiments, the ratio between the volume of the medium to the weight of the isomeric mixture of the hydantoin-containing spiro-compound is from 5 / 1 to 20 / 1 (v / w). According to some embodiments, the ratio between the volume of a methanol-based medium to the weight of the isomeric mixture of the hydantoin-containing spiro-compound is from 5 / 1 to 15 / 1 (v / w).

[0050] According to some embodiments, there is provided a process for preparation of spirotetramat compound, the process including obtaining the cis hydantoin-containing spiro- compound separated according to the herein disclosed method, hydrolysis of hydantoin, esterification of amino acid, amide formation, cyclization, and ethoxycarbonylation to obtain spirotetramat.

[0051] According to some embodiments, there is provided an agricultural composition including the spirotetramat obtained according to the herein disclosed process.

[0052] According to some embodiments, the agricultural composition further includes one or more additives selected from a group consisting of emulsifiers, adjuvants, dispersants, stabilizers, anti-foam agents, rheology modifiers, surfactants, pH regulators, thickeners, spreading agents, anti-freeze agents, and any combination thereof Each possibility is a separate embodiment.

[0053] Certain embodiments of the present disclosure may include some, all, or none of the above advantages. One or more technical advantages may be readily apparent to those skilled in the art from the figures, descriptions and claims included herein. Moreover, while specific advantages have been enumerated above, various embodiments may include all, some or none of the enumerated advantages. In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the figures and by study of the following detailed descriptions.

[0054] BRIEF DESCRIPTION OF THE FIGURES

[0055] The invention will now be described in relation to certain examples and embodiments with reference to the following illustrative figures.

[0056] FIG. 1 is an exemplary HPLC chromatogram of a crude isomeric mixture of 8- methoxy-1, 3 -diazaspiro[4.5] decane-2, 4-dione, according to some embodiments. HPLC analysis was performed under isocratic conditions of acetonitrile with ammonium bicarbonate 0.0 IM with a flow rate of 1 mL / min run through an Eclipse XDB - C18 (250 nm X 4.6 mm X 5 pm) column. A UV-vis detector was used to detect the compound at a wavelength of 200 nm.

[0057] FIG. 2 is an exemplary HPLC chromatogram of a separated cis-8-methoxy-l,3- diazaspiro[4.5]decane-2, 4-dione, according to some embodiments.

[0058] FIG. 3A is an exemplary LC-MS chromatogram of a separated cis-8-methoxy-l,3- diazaspiro[4.5]decane-2, 4-dione, according to some embodiments.

[0059] FIG. 3B is an exemplary LC-MS spectrum of a separated cis-8-methoxy-l,3- diazaspiro[4.5]decane-2, 4-dione, according to some embodiments.

[0060] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0061] In the following description, various aspects of the disclosure will be described. For the purpose of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the different aspects of the disclosure. However, it will also be apparent to one skilled in the art that the disclosure may be practiced without specific details being presented herein. Furthermore, well-known features may be omitted or simplified in order not to obscure the disclosure.

[0062] Prior to setting forth the present subject matter in detail, it may be helpful to provide definitions of certain terms to be used herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this subject matter pertains. The following definitions are provided for clarity.

[0063] The term "a" or "an" as used herein includes the singular and the plural, unless specifically stated otherwise. Therefore, the terms "a," "an," or "at least one" can be used interchangeably in this application.

[0064] As used herein, the verb "comprise" as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.

[0065] As used herein, the term "about" when used in connection with a numerical value includes ±10% from the indicated value. In addition, all ranges directed to the same component or property herein are inclusive of the endpoints, are independently combinable, and include all intermediate points and ranges. It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention.

[0066] As used herein, the term "overall yield" refers to a mole percentage of the desired hydantoin-containing spiro-compound relative to a calculated theoretical amount of the obtained product. The calculations are based on the amount of the starting material used initially in a synthetic step, whereas the starting material is assumed to be fully converted into the hydantoin-containing spiro-compound.

[0067] As used herein, the term "polar aprotic solvent" refers to an organic solvent that lacks an acidic proton and is polar. The solvent lacks hydroxyl and amine groups. Examples of such solvents include but are not limited to, acetonitrile, N,N-dimethylacetamide, N,N- dimethylformamide, l-methyl-2-pyrrolidone, dimethyl sulfoxide, and their derivatives.

[0068] As used herein, the term "polar protic solvent" refers to water or an organic solvent that comprises a relatively labile atom of hydrogen bound to oxygen or nitrogen. Examples of such organic solvents include but are not limited to, methanol, isopropanol, butanol, tert-butanol, and their derivatives. According to some embodiments, the polar protic solvent is not ethanol.

[0069] As used herein, the term "amine base" refers to Lewis base organic compounds comprising at least one nitrogen having non-pairing electrons available for proton binding, such as, but not limited to, triethylamine, tert-butyl amine, N-methyl piperazine, diisopropylamine, isopropylamine, morpholine, and their derivatives

[0070] As used herein, the term “essentially solid form” refers to a (cis) isomer that is mostly insoluble in the applied solvent system and remains in a solid form, however, a small portion of about 10-15% of the said isomer is soluble in the solvent system.

[0071] It has surprisingly been found that a separation method of cis and trans isomers of hydantoin-containing spiro-compound from an isomeric mixture can advantageously be performed by using a medium comprising an aprotic polar solvent. This method takes advantage of the different solubility levels of the cis vs. the trans isomers of the compound

[0072] According to some embodiments, the isomeric mixture of the said compound is contacted (mixed) with the medium for about 2-6 hours; preference is given to a period of about 2 hours.

[0073] Advantageously, according to some embodiments, the cis isomer remains in an essentially solid form due to better intermolecular interactions with itself, whereas the trans isomer is solubilized in the medium The unique chemical properties allow the two isomers to be essentially divided into two separable media: solid (cis isomer) and liquid (solubilized trans isomer).

[0074] According to some embodiments, the medium further comprises water.

[0075] According to some embodiments, the ratio between the aprotic polar solvent and the water is about 1 / 0.1 - 1 / 1 (v / v). According to some embodiments, the ratio between the polar aprotic solvent N,N-dimethylacetamide and the water is about 1 / 0.01 - 1 / 0.3 (v / v). According to some embodiments, the ratio between the polar aprotic solvent N,N-dimethylacetamide and the water is about 1 / 0.01 (v / v).

[0076] According to some embodiments, the temperature used in the method of the invention is from about 20-80 °C; preference is given to a temperature range of about 60-70 °C.

[0077] According to some embodiments, the heating of the reaction mixture is followed by an incubation at a temperature of 22-25 °C. According to some embodiments, the separation method comprises a separation technique selected from a group consisting of fdtration, chromatography, centrifugation, crystallization, precipitation, and any combination thereof. Each possibility is a separate embodiment. According to some embodiments, preference is given to the fdtration technique.

[0078] According to some embodiments, the reaction mixture is then fdtered, followed by washing the undissolved cis isomer of the hydantoin-containing spiro-compound with an additional polar solvent in an amount of 10-30% of the volume used at the first separation step.

[0079] According to some embodiments, the purified cis isomer of the hydantoin-containing spiro-compound is vacuum-dried for a period of about 15-100 minutes. According to some embodiments, the purified isomer is vacuum-dried for about 15-30 min, 15-45 min, 30-60 min, 45-100 min. Each embodiment is a separate embodiment. Preference is given to a time range of 15-45 minutes.

[0080] According to some embodiments, the purified cis isomer of the hydantoin-containing spiro-compound is subsequently dried in a vacuum oven under low pressure of 600-700 mm / Hg at a temperature of 60-65 °C for 2-12 hours until a constant weight is achieved. According to some embodiments, the purified isomer is dried in a vacuum oven for 2-4, 4-6, 6-8, 8-10, or 10-12 hours. Each embodiment is a separate embodiment. Preference is given to a period of 8- 10 hours.

[0081] According to some embodiments, a pure cis isomer of hydantoin-containing spiro- compound is obtained in an overall yield of at least 55% and a cis / trans ratio of at least 95 / 5. According to some embodiments, a pure cis hydantoin-containing spiro-compound is obtained in an overall yield of at least 60%, and a cis / trans ratio of at least 98 / 2.

[0082] According to some embodiments, the hydantoin-containing spiro-compound comprises but is not limited to, at least 2 rings, wherein one of them is a hydantoin ring, and the other one is a cyclohexane ring. Preference is given to a spiro compound with two rings.

[0083] According to some embodiments, an isomer is characterized by, but not limited to, at least 2 substituents at the cyclohexane ring. Preference is given to 2 substituents. According to some embodiments, the characterizing positions are, but are not limited to, positions 1 and 4, hence, resulting in at least 2 isomeric options of cis-1,4 and trans-1,4 isomers of the said hydantoin-containing spiro-compound.

[0084] According to some embodiments, the hydantoin-containing spiro-compound comprises a structure of formula (1): wherein

[0085] - R represents alky, alkenyl, arylalkyl, acyl, or aryl Each possibility is a separate embodiment.

[0086] - Preferably, R represents C1-C4 alkyl. Each possibility is a separate embodiment.

[0087] - Particularly preferably, R represents methyl, ethyl, n-propyl, n-butyl, i-propyl, or i- butyl. Each possibility is a separate embodiment.

[0088] -Most preferably, R represents methyl

[0089] According to some embodiments, the isomeric mixture is obtained via but not limited to a Bucherer-Bergs reaction. Specifically, and according to some embodiments, a starting material of 4-alkoxy-cyclohexanone is converted to the hydantoin-containing spiro-compound by using alkaline metal cyanides such as sodium cyanide or potassium cyanide, or by using trimethylsilyl cyanide (TMSCN), together with ammonium carbonate. Each possibility is a separate embodiment Preference is given, but not limited to, sodium cyanide and ammonium carbonate reagents. According to some embodiments, the solvent used for the synthesis is selected from a group consisting of water, N,N-dimethylformamide, dimethyl sulfoxide, 1- methyl-2-pyrolidone, methanol, ethanol, dimethylacetamide, their derivatives, or any combination thereof. Each possibility is a separate embodiment. According to some embodiments, preference is given to water. According to some embodiment, the 4-alkoxy -cyclohexanone comprises a structure of the formula (2): wherein

[0090] - R represents alky, alkenyl, arylalkyl, acyl, or aryl. Each possibility is a separate embodiment.

[0091] - Preferably, R represents C1-C4 alkyl. Each possibility is a separate embodiment.

[0092] - Particularly preferably, R represents methyl, ethyl, n-propyl, n-butyl, i-propyl, or i- butyl. Each possibility is a separate embodiment.

[0093] -Very particularly preferably, R represents methyl.

[0094] According to some embodiments, the Bucherer-Bergs reaction towards the formation of the isomeric mixture of hydantoin-containing spiro-compound is carried out as described in scheme (1): wherein

[0095] - R represents alky, alkenyl, arylalkyl, acyl, or aryl. Each possibility is a separate embodiment.

[0096] - Preferably, R represents C1-C4 alkyl. Each possibility is a separate embodiment.

[0097] - Particularly preferably, R represents methyl, ethyl, n-propyl, n-butyl, i-propyl, or i- butyl. Each possibility is a separate embodiment. -Most preferably, R represents methyl.

[0098] According to some embodiment, upon stepwise addition of the reagents, the reaction mixture is held at 50-50 °C for about 6 hours. According to some embodiments, the reaction mixture is oxidized with an oxidizing agent such as, but not limited to, sodium hypochlorite and a pH adjustment agent such as chloric acid. The reaction results in a mixture of cis and trans isomers of the hydantoin-containing spiro-compound with a cis / trans ratio of about 70 / 30.

[0099] According to some embodiments, the polar aprotic solvent comprises, but is not limited to, a structure of any of the formulas (3,4): wherein

[0100] - Ri, R2, and R3 each represent any of C1-C10 alkyls. Each possibility is a separate embodiment.

[0101] - Preferably, Ri, R2, and R3 each represent methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decanyl. Each possibility is a separate embodiment.

[0102] - Particularly preferably, Ri, R2, and R3 each represent methyl.

[0103] According to some embodiments, the polar aprotic solvent is selected from, but not limited to, a group consisting of N,N-dimethylacetamide, N,N-di ethyl acetamide, N,N- dipropyl acetamide, N,N-dibutylacetamide, N,N-dimethylformamide, N,N-diethylformamide, N,N-Diisopropylformamide, their derivatives, and any combination thereof. Each possibility is a separate embodiment.

[0104] Specifically, and according to some embodiments, the polar aprotic solvent is N,N- dimethylacetamide According to some embodiments, the polar aprotic solvent is selected from a group consisting of, but not limited to, l-methyl-2-pyrrolidone, dimethyl sulfoxide, acetonitrile, and their derivatives. Each possibility is a separate embodiment.

[0105] According to some embodiments, the medium further comprises admixing an amine base additive.

[0106] According to some embodiments, the amine base additive is selected from a group consisting of triethylamine, tert-butyl amine, N-methyl piperazine, diisopropylamine, isopropylamine, morpholine, their derivatives, and any combination thereof. Each possibility is a separate embodiment. Preference is given to triethylamine.

[0107] According to some embodiments, the ratio between the 4-alkoxy-cyclohexanone starting material, the polar aprotic solvent, and the additive is from about 1 / 9 / 0.1 to 1 / 2 / 1.0, respectively (gr / ml / ml, w / v / v). According to some embodiments, the ratio between the 4- alkoxy-cyclohexanone starting material, the polar aprotic solvent N,N-dimethylacetamide, and the additive is from about 1 / 3.5 / 0.1 to 1 / 3.5 / 1.0, or from about 1 / 1.5 / 0.1 to 1 / 1.5 / 1.0, respectively (gr / ml / ml, w / v / v). According to some embodiments, the ratio between the 4- alkoxy-cyclohexanone starting material, the polar aprotic solvent N,N-dimethylacetamide, and the additive is from about 1 / 1 / 0.1 to 1 / 5 / 1.5, respectively (gr / ml / ml, w / v / v).

[0108] Advantageously, a low volume of the medium can be used with respect to the weight of the isomeric mixture. According to some embodiments, a relationship between an absolute volume of a medium comprising an aprotic solvent and an absolute weight of the isomeric mixture of the said compound is from about 100 mL / 146g to 900 mL / 146g, respectively. According to some embodiments, a relationship between a medium comprising an aprotic solvent N,N-dimethylacetamide and the isomeric mixture of the said compound is from about 100 mL / 146gr to 350 mL / 146gr, respectively.

[0109] According to some embodiments, the relationship between the volume of the medium and the weight of the isomeric mixture is selected from a group consisting of about 100 mL / 146 gr, 270 mL / 146 gr, 450 mL / 146 gr, 700 mL / 146 gr, and 900 mL / 146gr. Each possibility is a separate embodiment. Preference is given to the volume-weight relationship of about 270 mL / 146 gr for medium comprising a polar aprotic solvent N,N-dimethylacetamide Advantageously, according to some embodiments, a ratio between the volume of a medium comprising an aprotic polar solvent to the weight of the isomeric mixture is as low as from about 0.5 / 1 to 12 / 1 (mL / gr, v / w). According to some embodiments, a ratio between the volume of a medium comprising an aprotic polar solvent, N,N-dimethylacetamide, to the weight of the isomeric mixture is as low as from about 0.6 / 1 to 5 / 1 (mL / gr, v / w).

[0110] According to some embodiments, the ratio between the volume of the aprotic solventbased medium to the weight of the isomeric mixture of the said compound is about 0.6 / 1, 1 / 1, 2.5 / 1, 5 / 1, 7 / 1, 10 / 1, or 12 / 1 (mL / gr, v / w). Each possibility is a separate embodiment. Preference is given to a ratio of about 0.6 / 1 - 2.5 / 1 (mL / gr, v / w) for medium comprising N,N- dimethylacetamide aprotic solvent.

[0111] It has surprisingly been found that a separation method of cis and trans isomers of hydantoin-containing spiro-compound from an isomeric mixture can advantageously be performed by using a medium comprising some specific protic solvent. This method takes advantage of the different solubility levels of the cis vs. the trans isomers of the compound.

[0112] According to some embodiment, the polar protic solvent is selected from a group consisting of, but not limited to, water, methanol, isopropanol, butanol, their derivatives, and any combination thereof. Each possibility is a separate embodiment. Preference is given to methanol. According to some embodiments, the polar protic solvent is not ethanol.

[0113] According to some embodiments, the isomeric mixture of the said compound is contacted (mixed) with the medium for about 2-6 hours; preference is given to a period of about 2 hours.

[0114] Advantageously, according to some embodiments, the cis isomer remains in an essentially solid form due to better intermolecular interactions with itself, whereas the trans isomer is solubilized in the medium. The unique chemical properties allow the two isomers to be essentially divided into two separable media: solid (cis isomer) and liquid (solubilized trans isomer).

[0115] According to some embodiments, the medium further comprises water. According to some embodiments, the ratio between the protic polar solvent and the water is about 2 / 1 to 4 / 1. According to some embodiments, the ratio between methanol and water is about 3 / 1.

[0116] According to some embodiments, the temperature used in the method of the invention is from about 20-80 °C; preference is given to a temperature range of about 60-70 °C.

[0117] According to some embodiments, the heating of the reaction mixture is followed by an incubation at a temperature of 22-25 °C.

[0118] According to some embodiments, the separation method comprises a separation technique selected from a group consisting of fdtration, chromatography, centrifugation, crystallization, precipitation, and any combination thereof. Each possibility is a separate embodiment. According to some embodiments, preference is given to the filtration technique.

[0119] According to some embodiments, the reaction mixture is then filtered, followed by washing the undissolved cis isomer of the hydantoin-containing spiro-compound with an additional polar solvent in an amount of 10-30% of the volume used at the first separation step.

[0120] According to some embodiments, the purified cis isomer of the hydantoin-containing spiro-compound is vacuum-dried for a period of about 15-100 minutes. According to some embodiments, the purified isomer is vacuum-dried for about 15-30 min, 15-45 min, 30-60 min, 45-100 min. Each embodiment is a separate embodiment. Preference is given to a time range of about 15-45 minutes.

[0121] According to some embodiments, the purified cis isomer of the hydantoin-containing spiro-compound is subsequently dried in a vacuum oven under low pressure of 600-700 mm / Hg at a temperature of 60-65°C for 2-12 hours until a constant weight is achieved. According to some embodiments, the purified isomer is dried in a vacuum oven for about 2-4, 4-6, 6-8, 8- 10, or 10-12 hours. Each embodiment is a separate embodiment Preference is given for a period of about 8-10 hours

[0122] According to some embodiments, a pure cis isomer of hydantoin-containing spiro- compound is obtained in an overall yield of at least 55% and a cis / trans ratio of at least 95 / 5. According to some embodiments, a pure cis hydantoin-containing spiro-compound is obtained in an overall yield of at least 60%, and a cis / trans ratio of at least 98 / 2 According to some embodiments, the hydantoin-containing spiro-compound comprises but is not limited to, at least 2 rings, wherein one of them is a hydantoin ring, and the other one is a cyclohexane ring. Preference is given to a spiro compound with two rings.

[0123] According to some embodiments, an isomer is characterized by, but not limited to, at least 2 substituents at the cyclohexane ring. Preference is given to 2 substituents.

[0124] According to some embodiments, the characterizing positions are, but are not limited to, positions 1 and 4, hence, resulting in at least 2 isomeric options of cis-1,4 and trans-1,4 isomers of the said hydantoin-containing spiro-compound.

[0125] According to some embodiments, the hydantoin-containing spiro-compound comprises a structure of formula (1): wherein

[0126] - R represents alky, alkenyl, arylalkyl, acyl, or aryl. Each possibility is a separate embodiment.

[0127] - Preferably, R represents C1-C4 alkyl. Each possibility is a separate embodiment.

[0128] - Particularly preferably, R represents methyl, ethyl, n-propyl, n-butyl, i-propyl, or i- butyl. Each possibility is a separate embodiment.

[0129] -Most preferably, R represents methyl.

[0130] According to some embodiments, the isomeric mixture is obtained via but not limited to a Bucherer-Bergs reaction. Specifically, and according to some embodiments, a starting material of 4-alkoxy-cyclohexanone is converted to the hydantoin-containing spiro-compound by using alkaline metal cyanides such as sodium cyanide or potassium cyanide, or by using trimethylsilyl cyanide (TMSCN), together with ammonium carbonate. Each possibility is a separate embodiment Preference is given, but not limited to, sodium cyanide and ammonium carbonate reagents. According to some embodiments, the solvent used for the synthesis is selected from a group consisting of water, N,N-dimethylformamide, dimethyl sulfoxide, 1- methyl-2-pyrolidone, methanol, ethanol, dimethylacetamide, their derivatives, or any combination thereof. Each possibility is a separate embodiment. According to some embodiments, preference is given to water.

[0131] According to some embodiment, the 4-alkoxy -cyclohexanone comprises a structure of the formula (2): wherein

[0132] - R represents alky, alkenyl, arylalkyl, acyl, or aryl. Each possibility is a separate embodiment.

[0133] - Preferably, R represents C1-C4 alkyl. Each possibility is a separate embodiment.

[0134] - Particularly preferably, R represents methyl, ethyl, n-propyl, n-butyl, i-propyl, or i- butyl. Each possibility is a separate embodiment.

[0135] -Very particularly preferably, R represents methyl.

[0136] According to some embodiments, the Bucherer-Bergs reaction towards the formation of the isomeric mixture of hydantoin-containing spiro-compound is carried out as described in scheme (1): cis trans wherein

[0137] - R represents alky, alkenyl, arylalkyl, acyl, or aryl. Each possibility is a separate embodiment.

[0138] - Preferably, R represents C1-C4 alkyl. Each possibility is a separate embodiment.

[0139] - Particularly preferably, R represents methyl, ethyl, n-propyl, n-butyl, i-propyl, or i- butyl. Each possibility is a separate embodiment.

[0140] -Most preferably, R represents methyl.

[0141] According to some embodiment, upon stepwise addition of the reagents, the reaction mixture is held at 50-50 °C for about 6 hours. According to some embodiments, the reaction mixture is oxidized with an oxidizing agent such as, but not limited to, sodium hypochlorite and a pH adjustment agent such as chloric acid. The reaction results in a mixture of cis and trans isomers of the hydantoin-containing spiro-compound with a cis / trans ratio of about 70 / 30.

[0142] According to some embodiments, the medium further comprises admixing an amine base additive.

[0143] According to some embodiments, the amine base additive is selected from a group consisting of triethylamine, tert-butylamine, N-methyl piperazine, diisopropylamine, isopropylamine, morpholine, their derivatives, and any combination thereof. Each possibility is a separate embodiment. Preference is given to triethylamine.

[0144] According to some embodiments, the ratio between the 4-alkoxy-cyclohexanone starting material, the polar protic solvent, and the additive is from about 1 / 10 / 0.1 to 1 / 20 / 2.0, respectively (gr / ml / ml, w / v / v). According to some embodiments, the ratio between the 4- alkoxy-cyclohexanone starting material, the polar protic solvent methanol, and the additive is from about 1 / 10 / 0.5 to 1 / 20 / 0.5, respectively (gr / mL / mL, w / v / v). According to some embodiments, the ratio between the 4-alkoxy-cyclohexanone starting material, the polar protic solvent methanol, and the additive is from about 1 / 12 / 0.5 - 1 / 15 / 0.5, respectively (gr / mL / mL, vi / v / ).

[0145] According to some embodiments, a relationship between an absolute volume of a medium comprising a protic solvent and an absolute weight of the isomeric mixture of the said compound is from about 1200 mL / 146 gr - 1500 mL / 146 gr, respectively. According to some embodiments, the relationship between the volume of the medium and the weight of the isomeric mixture is selected from a group consisting of about 1200 mL / 146 gr, 1300 mL / 146gr, 1400 mL / 146 gr, and 1500 mL / 146 gr. Each possibility is a separate embodiment.

[0146] According to some embodiments, a ratio between the volume of a medium comprising a protic polar solvent to the weight of the isomeric mixture is from about 5 / 1 to 20 / 1 (ml / gr, v / w) According to some embodiments, the ratio between the volume of a medium comprising a protic polar solvent methanol to the weight of the isomeric mixture is from about 5 / 1 to 15 / 1 (ml / gr, v / w).

[0147] According to some embodiments, the ratio between the volume of the protic solventbased medium to the weight of the isomeric mixture of the said compound is about 5 / 1, 7 / 1, 10 / 1, 15 / 1, 17 / 1, or 20 / 1 (mL / gr, v / w). Each possibility is a separate embodiment. Preference is given to a ratio of about 8 / 1-10 / 1 (ml / gr, v / w) for medium comprising methanol solvent.

[0148] According to some embodiments, a process for the preparation of spirotetramat compound is provided, the method comprising obtaining the cis hydantoin-containing spirocompound separated according to the method of the invention, followed by hydrolysis of hydantoin, esterification of amino acid, amide formation, cyclization, and ethoxycarbonylation to obtain the Spirotetramat.

[0149] According to some embodiments, an agricultural composition comprising the spirotetramat is obtained according to the preparation process.

[0150] According to some embodiments, the agricultural composition further comprises one or more additives selected from a group consisting of emulsifiers, adjuvants, dispersants, stabilizers, anti-foam agents, rheology modifiers, surfactants, pH regulators, thickeners, spreading agents, anti-freeze agents, and any combination thereof

[0151] The following examples are presented in order to more fully illustrate some embodiments of the invention. They should, in no way be construed, however, as limiting the broad scope of the invention. One skilled in the art can readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the invention. EXAMPLES

[0152] Example 1 - Synthesis of cis-8-Methoxy-l,3-diazaspiro[4.5]decane-2, 4-dione

[0153] An amount of 129 1 gr of ammonium carbonate (1 23 mol, 1 6 eq) is initially added to 500 mL of water (500 mL) until a clear solution is obtained. At a temperature of 25-30 °C, 39.6 gr of sodium cyanide (0.77 mol, 1.0 eq) is added followed by a slow dropwise addition of 100 gr of 4-methoxy cyclohexanone (0.77 mol, 1.0 eq) over a period of 15-20 min until a hazy solution is observed. The resulting reaction mixture is heated to 50-55 °C until a white slurry mass is observed. The reaction mass is maintained at 50-55 °C for 6 h and its progress is monitored by HPLC. After a full conversion is obtained, the reaction is cooled down to 22-25 °C, followed by further cooling to 0-10 °C. The reaction is then quenched by the addition of 7.5 gr of sodium hypochlorite (0.01 mol) followed by heating the reaction mass to 22-25 °C for 1 h The pH of the reaction mass is then adjusted to 6.5-7.0 (from 10.5-11.5) with 220 mL of concentrated hydrochloric acid and stirred for 1-2 h. The reaction mass is heated to 40-45 °C for 1 h followed by cooling to 22-25 °C for 30 min while keeping pH at 6.5-7 0 with hydrochloric acid, if required. The crude solid is fdtered by using a Buchner funnel and washed with 75 mL of water. Finally, the crude solid product is vacuum dried for 1 h at 22-25 °C. The resulting cis / trans ratio of the crude product is about 70 / 30. The crude weight yield is 96-97%. As seen in FIG. 1, according to HPLC results, cis and trans isomers were eluted in the corresponding ratio.

[0154] Example 2 - purification of cis-8-Methoxy-I,3-diazaspiro[4.5]decane-2, 4-dione from an isomeric mixture of cis and trans isomers by using N,N-dimethylacetamide

[0155] An amount of 165 gr of the isomeric mixture is added to 290 mL of dimethylacetamide at a temperature of 22-25 °C, followed by heating the mixture to 60-65 °C for 2 h, and then cooling it to 22-25 °C. After 1 h the solid is filtered by using a Buchner funnel and washed with 29 mL of dimethylacetamide Finally, the solid product is vacuum dried for 30 min at 22-25 °C followed by additional drying in a vacuum oven (600-700 mm / Hg, 60-65 °C) for 8-10 h until a constant weight of 89.3 gr of the purified cis isomer is obtained resulting in an overall yield of 58 %, purity of 96 % (w / w), and a cis / trans isomer ratio of 99 / 1 . The obtained filtrate is kept aside for a later regeneration of the starting material 4-methoxy cyclohexanone from the trans isomer, as well as a recovery of the used N,N-dimethylacetamide solvent. As seen in FIG. 2, according to the HPLC results, cis and trans isomers were eluted in the corresponding isomer ratio. As seen in FIG. 3A and FIG 3B, according to LC-MS results, the main eluted peak was at 199.1 m / z, corresponding to the expected mass (M+H).

[0156] Example 3 - purification of cis-8-Methoxy-l,3-diazaspiro[4.5]decane-2, 4-dione from an isomeric mixture of cis and trans isomers by using methanol

[0157] An amount of 20.0 gr of the isomeric mixture is added to 300 mL of methanol at a temperature of 22-25 °C, followed by heating the mixture to 60-65 °C for 5 h, and then cooling it to 22-25 °C. After 1 h the solid is filtered by using a Buchner funnel and washed with 20 mL of methanol. Finally, the solid product is vacuum dried for 30 min at 22-25 °C followed by additional drying in a vacuum oven (600-700 mm / Hg, 60-65 °C) for 8-10 h until a constant weight of 11.6 gr of the purified cis isomer is obtained resulting in an overall yield of 55 %, purity of 99.7 %, and a cis / trans isomer ratio of 98 / 2. The obtained filtrate is kept aside for a later regeneration of the starting material 4-methoxy cyclohexanone from the trans isomer, as well as a recovery of the used methanol solvent.

[0158] Example 4 - purification of cis-8-Methoxy-l,3-diazaspiro[4.5]decane-2, 4-dione from an isomeric mixture of cis and trans isomers by using acetonitrile and water

[0159] An amount of 10.0 gr of the isomeric mixture is added to 90 mL of acetonitrile and 90 mL of water at a temperature of 22-25 °C. After mixing for 2 h the solid is filtered by using a Buchner funnel, and vacuum dried for 30 min at 22-25 °C, followed by additional drying in a vacuum oven (600-700 mm / Hg, 60-65 °C) for 8-10 h until a constant weight of 4.5 gr of the purified cis isomer is obtained resulting in an overall yield of 41 %, purity of 99.98 %, and a cis / trans isomer ratio of 99 / 1. The obtained filtrate is kept aside for a later regeneration of the starting material 4-methoxy cyclohexanone from the trans isomer, as well as a recovery of the used methanol solvent.

[0160] Example 5 - purification of cis-8-Methoxy-l,3-diazaspiro[4.5]decane-2, 4-dione from an isomeric mixture of cis and trans isomers by using isopropanol and water An amount of 10.0 gr of the isomeric mixture is added to 70 mL of isopropanol and 30 mL of water at a temperature of 22-25 °C, followed by heating the mixture to 65 °C for 2 h, and then cooling it to 22-25 °C. After 1 h the solid is filtered by using a Buchner funnel, vacuum dried for 30 min at 22-25 °C, and finally dried in a vacuum oven (600-700 mm / Hg, 60-65 °C) for 8-10 h until a constant weight of 5.4 gr of the purified cis isomer is obtained resulting in an overall yield of 52 %, purity of 99 48 %, and a cis / trans isomer ratio of 97 / 3. The obtained filtrate is kept aside for a later regeneration of the starting material 4-methoxy cyclohexanone from the trans isomer, as well as a recovery of the used methanol solvent.

[0161] Example 6 - purification of cis-8-Methoxy-l,3-diazaspiro[4.5]decane-2, 4-dione from an isomeric mixture of cis and trans isomers by using butanol and water

[0162] An amount of 10.0 gr of the isomeric mixture is added to 70 mL of butanol and 30 mL of water at a temperature of 22-25 °C, followed by heating the mixture to 65 °C for 2 h, and then cooling it to 22-25 °C. After 1 h the solid is filtered by using a Buchner funnel, vacuum dried for 30 min at 22-25 °C, and finally dried in a vacuum oven (600-700 mm / Hg, 60-65 °C) for 8-10 h until a constant weight of 5.5 gr of the purified cis isomer is obtained resulting in an overall yield of 53 %, purity of 99.71 %, and a cis / trans isomer ratio of 97 / 3. The obtained filtrate is kept aside for a later regeneration of the starting material 4-methoxy cyclohexanone from the trans isomer, as well as a recovery of the used methanol solvent.

[0163] Example 7 - purification of cis-8-Methoxy-l,3-diazaspiro[4.5]decane-2, 4-dione from an isomeric mixture of cis and trans isomers by using N,N-dimethylformamide and triethylamine

[0164] An amount of 31.4 gr of the isomeric mixture is added to 50 mL of N,N- dimethylformamide and 6 4 gr of triethylamine at a temperature of 22-25 °C, followed by heating the mixture to 65 °C for 2 h, and then cooling it to 22-25 °C. After 1 h the solid is filtered by using a Buchner funnel, washed with 25 mL of methanol, vacuum dried for 30 min at 22-25 °C, and finally dried in a vacuum oven (600-700 mm / Hg, 60-65 °C) for 8-10 h until a constant weight of 24.9 gr of the purified cis isomer is obtained resulting in an overall yield of 61 %, purity of 99.9 %, and a cis / trans isomer ratio of 99 / 1. The obtained filtrate is kept aside for a later regeneration of the starting material 4-methoxy cyclohexanone from the trans isomer, as well as a recovery of the used methanol solvent.

[0165] Example 8 - purification of cis-8-Methoxy-l,3-diazaspiro[4.5]decane-2, 4-dione from an isomeric mixture of cis and trans isomers by using l-methyl-2-pyrrolidine and triethylamine

[0166] An amount of 32.5 gr of the isomeric mixture is added to 37.5 mL of l-methyl-2- pyrrolidine and 6.6 gr of triethylamine at a temperature of 22-25 °C, followed by heating the mixture to 65 °C for 2 h, and then cooling it to 22-25 °C. After 1 h the solid is filtered by using a Buchner funnel, vacuum dried for 30 min at 22-25 °C, and finally dried in a vacuum oven (600-700 mm / Hg, 60-65 °C) for 8-10 h until a constant weight of 15.2 gr of the purified cis isomer is obtained resulting in an overall yield of 60 %, purity of 99.79 %, and a cis / trans isomer ratio of 99 / 1. The obtained filtrate is kept aside for a later regeneration of the starting material 4-methoxy cyclohexanone from the trans isomer, as well as a recovery of the used methanol solvent.

[0167] Example 9 - purification of cis-8-Methoxy-l,3-diazaspiro[4.5]decane-2, 4-dione from an isomeric mixture of cis and trans isomers by using methanol and triethylamine

[0168] An amount of 25.5 gr of the isomeric mixture is added to 250 mL of methanol and 6.9 gr of tri ethylamine at a temperature of 22-25 °C, followed by heating the mixture to 65 °C for 2 h, and then cooling it to 22-25 °C. After 1 h the solid is filtered by using a Buchner funnel, washed with 25 mL of methanol, vacuum dried for 30 min at 22-25 °C, and finally dried in a vacuum oven (600-700 mm / Hg, 60-65 °C) for 8-10 h until a constant weight of 15.2 gr of the purified cis isomer is obtained resulting in an overall yield of 57 %, purity of 99.9 %, and a cis / trans isomer ratio of 99 / 1. The obtained filtrate is kept aside for a later regeneration of the starting material 4-methoxy cyclohexanone from the trans isomer, as well as a recovery of the used methanol solvent. Example 10 - purification of cis-8-Methoxy-l,3-diazaspiro[4.5]decane-2, 4-dione from an isomeric mixture of cis and trans isomers by using N,N-dimethylacetamide and triethylamine

[0169] An amount of 65.0 gr of the isomeric mixture is added to 100 mL of N,N- dimethylacetamide and 13.2 gr of triethylamine at a temperature of 22-25 °C, followed by heating the mixture to 65 °C for 2 h, and then cooling it to 22-25 °C. After 1 h the solid is filtered by using a Buchner funnel, washed with 33 mL of methanol, vacuum dried for 30 min at 22-25 °C, and finally dried in a vacuum oven (600-700 mm / Hg, 60-65 °C) for 8-10 h until a constant weight of 29.8 gr of the purified cis isomer is obtained resulting in an overall yield of 58 %, and a cis / trans isomer ratio of 99 / 1. The obtained filtrate is kept aside for a later regeneration of the starting material 4-methoxy cyclohexanone from the trans isomer, as well as a recovery of the used methanol solvent.

[0170] Example 11 - purification of cis-8-Methoxy-l,3-diazaspiro[4.5]decane-2, 4-dione from an isomeric mixture of cis and trans isomers by using water and triethylamine

[0171] An amount of 30.47 gr of the isomeric mixture is added to 50 mL of water and 20. 13gr of triethylamine at a temperature of 22-25 °C, followed by heating the mixture to 65 °C for 2 h, and then cooling it to 22-25 °C. After 1 h the solid is filtered by using a Buchner funnel, washed with 25 mL of methanol, vacuum dried for 30 min at 22-25 °C, and finally dried in a vacuum oven (600-700 mm / Hg, 60-65 °C) for 8-10 h until a constant weight of 12.8 gr of the purified cis isomer is obtained resulting in an overall yield of 51.20 %, purity of 99.9 %, and a cis / trans isomer ratio of 97 / 3

[0172] The descriptions of the various embodiments of the present invention have been presented for purposes of illustration, but are not intended to be exhaustive or limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The terminology used herein was chosen to best explain the principles of the embodiments, the practical application or technical improvement over technologies found in the marketplace, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.

[0173] While certain embodiments of the invention have been illustrated and described, it will be clear that the invention is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions and equivalents will be apparent to those skilled in the art without departing from the spirit and scope of the present invention as described by the claims, which follow.

Claims

CLAIMS1. A method for separation of cis and trans isomers of hydantoin-containing spirocompound from an isomeric mixture, the method comprising; a. contacting said isomeric mixture with a medium comprising a polar aprotic solvent, and; b. separating said cis isomer and / or trans isomer.2 The method according to claim 1, wherein in step 'a', the cis isomer remains in an essentially solid form and the trans isomer is solubilized.

3. The method according to claim 1 or 2, wherein said medium further comprises water.4 The method according to claim 3, wherein the ratio between the polar aprotic solvent and water is of about 1 / 0. 1 to 1 / 1.

5. The method of any one of claims 1-4, wherein step 'a' comprises heating the mixture to about 20-80°C.

6. The method of claim 5, wherein step 'a' comprises heating the mixture to about 60- 70°C.

7. The method of any one of claims 1-6, wherein the separation of step 'b' is performed by a separation technique selected from a group consisting of fdtration, chromatography, centrifugation, crystallization, precipitation, and any combination thereof.

8. The method of any one of claims 1-7, providing an overall yield of at least 55% and a cis / trans ratio of at least 95 / 5.

9. The method of any one of claims 1-8, wherein the cis and trans hydantoin-containing spiro-compound comprises a structure of formula (1):wherein- R represents alky, alkenyl, arylalkyl, acyl, or aryl.

10. The method according to claim 9, wherein R represents C1-C4 alkyl.

11. The method according to claim 10, wherein R represents methyl.

12. The method of any one of claims 1-11, wherein the isomeric mixture comprises 1,4-cis and 1,4-trans isomers of the hydantoin-containing spiro-compound.

13. The method of claim 12, wherein the isomeric mixture is obtained via Bucherer-Bergs reaction comprises 4-alkoxy cyclohexanone as a starting material, which comprises a structure of the formula (2):wherein- R represents alky, alkenyl, arylalkyl, acyl, or aryl. Preferably, R represents C1-C4 alkyl.- Particularly preferably, R represents methyl.

14. The method of claim 13, wherein step 'a' further comprises admixing an amine base additive.

15. The method of claim 14, wherein the amine base additive is selected from a group consisting of triethylamine, tert-butylamine, N-methyl piperazine, diisopropylamine, isopropylamine, morpholine, their derivatives, and any combination thereof.

16. The method of claim 15, wherein the ratio between the 4-alkoxy -cyclohexanone starting material, the polar aprotic solvent, and the additive is from 1 / 9 / 0. 1 to 1 / 2 / 1.0 (w / v / v).

17. The method of claim 16, wherein the ratio between the 4-alkoxy -cyclohexanone starting material, the polar aprotic solvent N,N-dimethylacetamide, and the amine base additive is from 1 / 1 / 0.1 to 1 / 5 / 1.5 (w / v / v).

18. The method of any one of claims 13-17, wherein Bucherer-Bergs reaction reagents comprise Ammonium carbonate and Sodium cyanide in water.

19. The method of any one of claims 1-18, wherein the polar aprotic solvent comprises a structure of any of the formulas (3,4):whereinRi, R2, and R3 each represent any of C1-C10 alkyls.

20. The method of any one of claims 1-19, wherein the polar aprotic solvent is selected from a group consisting of N,N-dimethylacetamide, N,N-diethylacetamide, N,N- dipropylacetamide, N,N-dibutylacetamide, N,N-dimethylformamide, N,N- diethylformamide, N,N-Diisopropylformamide, N,N-Dimethyldecanamide their derivatives, and any combination of thereof.

21. The method of claim 20, wherein the polar aprotic solvent is N,N-dimethylacetamide.

22. The method of any one of claims 1-21, wherein the polar aprotic solvent is Acetonitrile.

23. The method of any one of claims 1-22, wherein the ratio between the volume of the medium to the weight of the isomeric mixture of the hydantoin-containing spirocompound is from 0.5 / 1 to 12 / 1 (v / w).

24. The method of claim 23, wherein the ratio between the volume of a N,N- dimethylacetamide-based medium to the weight of the isomeric mixture of the hydantoin-containing spiro-compound is from 0.5 / 1 to 5 / 1 (v / w).

25. A method for separation of cis and trans isomers of hydantoin-containing spiro- compound from an isomeric mixture, the method comprising; a. contacting said isomeric mixture with a medium comprising a polar protic solvent comprising methanol, and; b. separating said cis isomer and / or said trans isomer.

26. The method according to claim 25, wherein in step 'a', the cis isomer remains in an essentially solid form and the trans isomer is solubilized27. The method according to claims 25 and 26, wherein said medium further comprises water.

28. The method according to claim 27, wherein the ratio between the polar protic solvent and the water is of about 2 / 1 to 4 / 1 .

29. The method of any one of claims 25-28, wherein step 'a' comprises heating the mixture to about 20-80°C30. The method of claim 29, wherein step 'a' comprises heating the mixture to about 60- 70°C.

31. The method of any one of claims 25-30, wherein the separation of step 'b' is performed by a separation technique selected from a group consisting of filtration, chromatography, centrifugation, crystallization, precipitation, and any combination thereof.

32. The method of any one of claims 25-31, providing an overall yield of at least 55% and a cis / trans ratio of at least 95 / 5.

33. The method of any one of claims 25-32, wherein the cis and trans hydantoin-containing spiro-compound comprises a structure of formula (1):wherein- R represents H, alky, alkenyl, arylalkyl, acyl, or aryl.

34. The method according to claim 33, wherein R represents C1-C4 alkyl.

35. The method according to claim 34, wherein R represents methyl.

36. The method of any one of claims 25-35, wherein the isomeric mixture comprises 1,4- cis and 1,4-trans isomers of the hydantoin-containing spiro-compound.

37. The method of claim 36, wherein the isomeric mixture is obtained via Bucherer-Bergs reaction comprises 4-alkoxy cyclohexanone as a starting material, which comprises a structure of the formula (2):wherein- R represents alky, alkenyl, arylalkyl, acyl, or aryl.- Preferably, R represents C1-C4 alkyl.- Particularly preferably, R represents methyl.

38. The method of claim 37, wherein Bucherer-Bergs reaction reagents comprise ammonium carbonate and sodium cyanide in water.

39. The method of any one of claims 37-38, wherein step 'a' further comprises admixing an amine base additive.

40. The method of claim 39, wherein the amine base additive is selected from a group consisting of triethylamine, tert-butyl amine, N-methyl piperazine, diisopropylamine, Isopropylamine, Morpholine, their derivatives, and any combination thereof.

41. The method of claim 40, wherein the ratio between the 4-alkoxy -cyclohexanone starting material, the polar protic solvent, and the additive is from 1 / 10 / 0. 1 to 1 / 20 / 2.0 (w / v / v).

42. The method of claim 41, wherein the ratio between the 4-alkoxy-cyclohexanone starting material, the polar protic solvent methanol, and the additive is from 1 / 5 / 0.1 to 1 / 20 / 2.0 (w / v / v).

43. The method of any one of claims 25-42, wherein the ratio between the volume of the medium to the weight of the isomeric mixture of the hydantoin-containing spirocompound is from 5 / 1 to 20 / 1 (v / w).

44. The method of claim 43, wherein the ratio between the volume of a methanol-based medium to the weight of the isomeric mixture of the hydantoin-containing spirocompound is from 5 / 1 to 15 / 1 (v / w).

45. A process for preparation of spirotetramat compound, the process comprising obtaining the cis hydantoin-containing spiro-compound separated according to the method of any one of claims 1-44, hydrolysis of hydantoin, esterification of amino acid, amide formation, cyclization, and ethoxycarbonylation to obtain Spirotetramat.

46. An agricultural composition comprising the spirotetramat obtained according to claim 45.

47. The agricultural composition of claim 46, further comprising one or more additives selected from a group consisting of emulsifiers, adjuvants, dispersants, stabilizers, antifoam agents, rheology modifiers, surfactants, pH regulators, thickeners, spreading agents, anti-freeze agents, and any combination thereof.

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