Description:

FORM 2

THE PATENTS ACT, 1970
(39 of 1970)

&

THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
[See section 10, Rule 13]

PROCESS FOR PREPARATION OF PURE CLOMAZONE;

RALLIS INDIA LIMITED, A COMPANY ORGANIZED UNDER THE LAWS OF INDIA WHOSE ADDRESS IS 23RD FLOOR, VIOS TOWER, NEW CUFFE PARADE, OFF EASTERN FREEWAY, WADALA, MUMBAI - 400037, MAHARASHTRA, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED
 
FIELD OF THE INVENTION
[001] The present disclosure relates to an improved process for the preparation of pure clomazone. The present disclosure further relates to an improved process for purification of crude clomazone.

BACKGROUND OF THE INVENTION
[002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[003] Clomazone chemically known as 2-[(2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone is an isoxazolidinone herbicide. It is a selective herbicide, and it acts by inhibiting the enzyme 1-deoxy-D-xylulose-5-phosphate synthase (Doxp Synthase). Clomazone has the structural formula as given below:

[004] The known processes for preparation of clomazone involve the use of ether catalysts along with bases such as sodium hydroxide and potassium hydroxide and single solvent system during the process to prepare 3-chloro-N-hydroxy-2,2-dimethylpropanamide by reacting 3-chloro-2,2-dimethylpropionyl chloride with hydroxylamine hydrochloride. Also, the known processes involve the usage of phase transfer catalysts such as methyl tricaprylylammonium chloride, and tetrabutylammonium bromide during the reaction of 3-chloro-N-hydroxy-2,2-dimethylpropanamide with 2-chlorobenzyl chloride to prepare clomazone which in turn renders the processes less eco-friendly and costly. Thus, the processes are not suitable for commercial scale up. Also, the known clomazone purification process involves tedious purification steps.
[005] Therefore, there remains an unmet need in the art to provide a process for preparation and/or purification of clomazone that can overcome one or more disadvantage(s) of the process(es) known in the art. There is thus a need in the art to provide an improved, efficient, and easy process for preparation of clomazone. Also, there remains a need for simpler and efficient process for purification of clomazone.
[006] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

OBJECTS OF THE INVENTION
[007] It is an object of the present disclosure to provide a process for preparation of pure clomazone of formula (I).
[008] It is an object of the present disclosure to provide a process for the purification of crude clomazone of formula (Ia).

SUMMARY OF THE INVENTION
[009] In general aspects the present disclosure provides an improved process for preparing pure clomazone of formula (I).
[0010] In an aspect the present disclosure is directed to provide a process for preparing 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) comprising reacting 3-chloro-2,2-dimethylpropionyl chloride of formula (V) with hydroxylamine hydrochloride of formula (IV) in presence of a base and biphasic solvent system
.
[0011] In another aspect, the present disclosure provides a process for preparing crude clomazone of formula (Ia) comprising reacting 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) with 2-chlorobenzyl chloride of formula (II) in presence of a base and a solvent and in absence of a phase transfer catalyst
.
[0012] In yet another aspect, the present disclosure provides a process for purification of crude clomazone of formula (Ia) comprising treating the crude clomazone of formula (Ia) with concentrated H2SO4 to obtain pure clomazone of formula (I)

.
[0013] In yet another aspect, the present disclosure provides a process for preparing pure clomazone of formula (I), comprising the steps of:
(i) reacting 3-chloro-2,2-dimethylpropionyl chloride of formula (V) with hydroxylamine hydrochloride of formula (IV) in presence of a base and biphasic solvent system to produce 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III)
;
(ii) reacting 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) with 2-chlorobenzyl chloride of formula (II) in presence of a base and a solvent and in absence of a phase transfer catalyst to produce crude clomazone of formula (Ia)
; and
(iii) treating the crude clomazone of formula (Ia) with concentrated H2SO4, to obtain the pure clomazone of formula (I)
.
[0014] Various objects, features, aspects, and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

DETAILED DESCRIPTION OF THE INVENTION
[0015] The following is a detailed description of embodiments of the present disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0016] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[0017] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0018] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
[0019] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” The term “about” may refer to + 5 of the specific figure preceding the term “about”. Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
[0020] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it is individually recited herein.
[0021] All processes described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0022] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0023] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus, if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[0024] It should also be appreciated that the present invention can be implemented in numerous ways, including as a system, a method or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
[0025] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0026] The compound of formula (I), referred to as clomazone, chemically known as 2-[(2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone has a structural formula (I) as given below:
.
[0027] The present disclosure provides an improved process for preparing pure clomazone of Formula (I).
[0028] In one embodiment, there is provided a process for preparing 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) comprising reacting 3-chloro-2,2-dimethylpropionyl chloride of formula (V) with hydroxylamine hydrochloride of formula (IV) in presence of a base and biphasic solvent system.
[0029] The base can be selected from the group comprising of but not limiting to carbonates and tertiary amines.
[0030] In one embodiment, the base is selected from the group comprising of carbonates selected from potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate, or the like or mixture thereof.
[0031] In one embodiment, preferably, the base is potassium carbonate.
[0032] The tertiary amines are selected from the group consisting of but not limited to triethyl amine, N,N-diisopropylethylamine, or the like or mixture thereof.
[0033] The known processes use hydroxides such as sodium hydroxide and potassium hydroxide as base during the process for the preparation of 3-chloro-N-hydroxy-2,2-dimethylpropanamide by reacting 3-chloro-2,2-dimethylpropionyl chloride with hydroxylamine hydrochloride.
[0034] However, in the present invention it has been surprisingly found that, the use of the base potassium carbonate has significant advantage over the use of other bases such as sodium hydroxide and potassium hydroxide during the process for the preparation of 3-chloro-N-hydroxy-2,2-dimethylpropanamide by reacting 3-chloro-2,2-dimethylpropionyl chloride with hydroxylamine hydrochloride. The addition of strong bases such as sodium hydroxide and potassium hydroxide additionally require pH control devices and continuous monitoring to control the desired pH in the range of 7.5 to 8.5 throughout the reaction. Whereas, by adding the week bases such as potassium carbonate and sodium carbonate in accordance with the process of the present invention, unexpectedly the pH is automatically maintained at the pH range of 6.5 to 8.5 throughout the reaction without any need for the use of any additional pH control devices and continuous monitoring to control the pH in the range of 6.5 to 8.5. Thereby making the process easy and avoiding the variation of pH which leads to the formation of impurities that result into the lower yield of the product.
[0035] The biphasic solvent system used during the preparation of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) consists of organic solvent and water.
[0036] The organic solvent is selected from the group consisting of ethyl acetate, toluene, dichloromethane, 1,2-dichloroethane, methyl tertiary-butyl ether (MTBE), diethyl ether, ethyl methyl ether or the like or mixture thereof.
[0037] In the biphasic solvent system, the volume ratio of the organic solvent to the water is in the range of from about 1 to 3: to about 2 to 4 by volume. Preferably, the ratio of organic solvent to the water is 1: 2 by volume.
[0038] The biphasic solvent system is selected from the group consisting of combination comprising ethyl acetate: water, toluene: water, dichloromethane: water, 1,2-dichloroethane: water, methyl tertiary-butyl ether (MTBE): water, diethyl ether: water, ethyl methyl ether: water or the like or mixtures thereof. Preferably, the biphasic solvent system comprises ethyl acetate: water.
[0039] In the biphasic solvent system, the volume ratio of the ethyl acetate: water is in the range from about 1-3: to about 2-4 by volume. Preferably, the ratio of ethyl acetate to the water is 1: 2 by volume.
[0040] The processes known in the art use single solvents such as water, methanol and dimethylformamide during the process for the preparation of 3-chloro-N-hydroxy-2,2-dimethylpropanamide by reacting 3-chloro-2,2-dimethylpropionyl chloride with hydroxylamine hydrochloride.
[0041] However, in the present invention it has been surprisingly found that the use of the biphasic solvent system has significant advantage over the use of single solvents such as water. When water alone is used as solvent during the preparation of 3-chloro-N-hydroxy-2,2-dimethylpropanamide, the product obtained is of less purity. Therefore, an additional purification step such as crystallization or wash with organic solvents such as acetone, ethylene dichloride (EDC) and methylene dichloride (MDC) is required to be carried out to obtain the pure product for using it in further steps. But the additional purification step results in lower yield of the desired product 3-chloro-N-hydroxy-2,2-dimethylpropanamide.
[0042] However, by using the biphasic solvent system of the present invention such as ethyl acetate: water, the additional purification step is avoided, because the ethyl acetate solvent present in the biphasic solvent system is surprisingly found to help both in the dissolution of 3-chloro-2,2-dimethylpropionyl chloride of formula (V) and even for purification of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III). That is, the impurities formed along with the 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) are easily dissolved in ethyl acetate and removed during filtration, thereby avoiding the requirement of additional purification of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) making the process more efficient.
[0043] The known processes also use catalysts such as ether catalysts or phase transfer catalysts such as ethyl xanthic acid potassium salt during the preparation of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III). However, the present invention does not use any ether catalysts or phase transfer catalysts during the preparation of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) making the process eco-friendly and economical.
[0044] In a preferred embodiment, there is provided a process for preparing 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) comprising reacting 3-chloro-2,2-dimethylpropionyl chloride of formula (V) with hydroxylamine hydrochloride of formula (IV) in presence of a base K2CO3 and biphasic solvent system ethyl acetate: water.
[0045] The reaction scheme in accordance with an embodiment of the present disclosure is as follows:
.

[0046] The reaction of 3-chloro-2,2-dimethylpropionyl chloride of formula (V) with hydroxylamine hydrochloride of formula (IV) is carried out at a temperature range of 5 to 10 °C.
[0047] The reaction of 3-chloro-2,2-dimethylpropionyl chloride of formula (V) with hydroxylamine hydrochloride of formula (IV) is carried out at a pH range of 6.5 to 8.5.
[0048] In an embodiment, there is provided a process to prepare crude clomazone of formula (Ia) by reacting 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) with 2-chlorobenzyl chloride of formula (II) in presence of a base and a solvent and in the absence of a phase transfer catalyst.
[0049] The base can be selected from carbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate or a mixture thereof. Preferably, the base is potassium carbonate.
[0050] The processes known in the art uses the combination of two different bases such as hydroxides and carbonates during the reaction of 3-chloro-N-hydroxy-2,2-dimethylpropanamide with 2-chlorobenzyl chloride to prepare the crude clomazone.
[0051] However, in the present invention it has been surprisingly found that, the use of single base such as potassium carbonate is sufficient for the reaction of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) with 2-chlorobenzyl chloride of formula (II) to prepare the crude clomazone of formula (Ia), thereby avoiding the use of multiple bases.
[0052] In an embodiment, the solvent used during the preparation of crude clomazone of formula (Ia) is water.
[0053] Further, the processes known in the art use phase transfer catalysts such as methyl tricaprylylammonium chloride, tetrabutylammonium bromide, methyltributylammonium chloride, tetrabutylammonium chloride or benzyltriethylammonium chloride along with the multiple bases and the solvent for increasing the rate of reaction of 3-chloro-N-hydroxy-2,2-dimethylpropanamide with 2-chlorobenzyl chloride rendering the processes less eco-friendly, costly, and not suitable for commercial scale up. Also, such processes require tedious purification steps.
[0054] However, in the present invention reaction of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) with 2-chlorobenzyl chloride of formula (II) is surprisingly carried out in the absence of a phase transfer catalyst thereby making the process eco-friendly, efficient requiring less purification step and economical.
[0055] In a specific embodiment, the present invention discloses reaction of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) with 2-chlorobenzyl chloride of formula (II) in presence of a base K2CO3 and a solvent water and in the absence of a phase transfer catalyst to produce crude clomazone of formula (Ia).
[0056] The crude clomazone of formula (Ia) has two impurities, Impurity A (1-(2-chlorophenyl) methoxy-3,3-dimethyl-2-azetidinone) and Impurity B (3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole).
[0057] The crude clomazone of formula (Ia) along with the Impurities A and B is collected in the ethylene dichloride (EDC) solvent layer.
[0058] The reaction scheme as per one of embodiments is as follows:
.
[0059] In yet another embodiment, the present invention provides a process for purification of crude Clomazone of formula (Ia) comprising the steps of treating the crude clomazone of formula (Ia) with concentrated H2SO4 to obtain the pure clomazone of formula (I).
[0060] The reaction scheme as per one of the embodiments is as follows:
.
[0061] The clomazone purification methods known in the art are tedious. Particularly, one of the known processes involves distilling out the solvent carrying the crude clomazone and then purging of hydrochloric acid (HCl) gas under anhydrous conditions at 45 °C into the crude clomazone. This process helps in the removal of only one isomeric impurity, 1-(2-chlorophenyl)methoxy-3,3-dimethyl-2-azetidinone (Impurity A) and not the other impurity 3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole (Impurity B) of clomazone.
[0062] However, in the present invention it has been surprisingly found that, the use of concentrated H2SO4 has significant advantage over the use of HCl gas during the process for the purification of crude clomazone. That is by using concentrated H2SO4 both the impurities Impurity A (1-(2-chlorophenyl) methoxy-3,3-dimethyl-2-azetidinone) and Impurity B (3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole) are removed to obtain pure clomazone of formula (I) in an acidic medium. Further, the acidic medium containing pure clomazone of formula (I) is then washed with cold water and then with 10% aqueous solution of Na2CO3, followed by brine solution to remove the traces of H2SO4 and distilled under high vacuum distillation to obtain 98% pure Clomazone of formula (I).
[0063] The method of the present disclosure for preparation of clomazone and method for purification of clomazone provides several advantages over the processes known in the art and thereby satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.
[0064] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
[0065] The present invention is further explained in the form of the following examples. However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.

EXAMPLES
Example 1: Synthesis of Pure Clomazone of Formula (I).
Step 1: Preparation of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) from 3-chloro-2,2-dimethylpropionyl chloride of formula (V) and hydroxylamine hydrochloride of formula (IV).

Part A:
[0066] 89.6 g (1.29 mol) of hydroxylamine hydrochloride of formula (IV), 400 ml (2V) of water (solvent) were charged into a 2 L round bottom flask equipped with mechanical stirrer, addition funnel, reflux condenser and temperature indicator to obtain a solution A. The solution A was cooled to 5 to 10 °C and 213.9 g (1.55 mol) of solid potassium carbonate was added to the solution A in an equal portion over a period of half an hour to 1 hour, with the temperature maintained at 5 to 10 °C to avoid any exothermic reactions.
Part B:
[0067] 200.0 g (1.29 mol) of 3-chloro-2,2-dimethylpropionyl chloride of formula (V) and 200 ml (1V) of ethyl acetate (solvent) were charged into the conical flask and mixed to obtain solution B.
Part C:
[0068] Solution B was added drop wise to the solution A (biphasic solvent layer of ethyl acetate and water was observed) over a period of 5-6 hrs. with continuous stirring while maintaining the temperature of the reaction mixture at 5 to 10 °C.
[0069] The reaction mixture was stirred while maintaining the pH at the range of from 6.5 to 8.5 till the reaction was complete. The reaction mixture was then cooled to 0 to 3 °C and was filtered under vacuum to obtain the white solid containing 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III). Yield: 180.0 g, 92%; GC purity >98%.
Step 2: Preparation of crude clomazone of formula (Ia) from 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) and 2-chlorobenzyl chloride of formula (II).

[0070] 100.0 g (0.66 mol) of white solid containing 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) obtained from step 1 and 100 mL (1V) water were charged into a 2 L round bottom flask equipped with mechanical stirrer, addition funnel, reflux condenser and temperature indicator and were mixed to obtain a slurry. The slurry was heated to 40-50 °C and a potassium carbonate solution (182.4 g, 1.31 mol of potassium carbonate in 300 ml of water (3V)) was added to the slurry. The slurry was heated to 80 to 85°C.
[0071] 106.2 g (0.66 mol) of 2-chlorobenzyl chloride of formula (II) was added drop wise to the above slurry over a period of about 2-3 hrs. at 80 to 85 °C, with continuous stirring to obtain the reaction mass. The reaction mass was heated to 90 to 95 °C for about 12-14 hrs. till the completion of the reaction. The reaction mass was further cooled to 25 to 30 °C and diluted with ethylene dichloride (EDC, 200 mL), filtered under vacuum to remove the inorganic salts and to obtain the filtrate EDC solvent layer containing crude clomazone of formula (Ia) along with Impurity A (1-(2-chlorophenyl)methoxy-3,3-dimethyl-2-azetidinone) and Impurity B (3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole).
Step 3: Purification of crude clomazone of formula (Ia) to obtain pure clomazone of formula (I).

[0072] The filtrate EDC solvent layer containing crude clomazone of formula (Ia) along with Impurity A (1-(2-chlorophenyl)methoxy-3,3-dimethyl-2-azetidinone) and Impurity B (3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole) was charged into a 2 L round bottom flask and heated to 45 to 50 °C. 22.6 g (0.23 mol) of the concentrated H2SO4 was added drop wise to the EDC layer over a period of about half an hour to one hour with continuous stirring while maintaining the temperature at 50 to 55 °C to obtain a solution. The solution was stirred at 50 to 55 °C for about 2-3 hrs. Then, the solution was allowed to cool to 25 to 30 °C.
[0073] The above solution was washed with 100.0 mL of cold water, followed by 100.0 mL of 10% aqueous solution of Na2CO3 which was followed by 100.0 mL of brine solution to remove the traces of H2SO4 in the solution. Further, the solution was distilled out to obtain the organic mass without any isomeric impurities. Further, the organic mass was distilled under high vacuum distillation to obtain pure clomazone of formula (I). Yield: 66% (102.8g), HPLC purity >98%.

Example 2: Synthesis of Pure Clomazone of Formula (I).
Step 1: Preparation of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) from 3-chloro-2,2-dimethylpropionyl chloride of formula (V) and hydroxylamine hydrochloride of formula (IV).

Part A:
[0074] 89.6 g (1.29 mol) of hydroxylamine hydrochloride of formula (IV), 400 ml (2V) of water (solvent) were charged into a 2 L round bottom flask equipped with mechanical stirrer, addition funnel, reflux condenser and temperature indicator to obtain a solution A. The solution A was cooled to 5 to 10 °C and 164.3 g (1.55 mol) of solid sodium carbonate was added to the solution A in an equal portion over a period of half an hour to 1 hour, with the temperature maintained at 5 to 10 °C to avoid any exothermic reactions.
Part B:
[0075] 200.0 g (1.29 mol) of 3-chloro-2,2-dimethylpropionyl chloride of formula (V) and 200 ml (1V) of ethyl acetate (solvent) were charged into the conical flask and mixed to obtain the solution B.
Part C:
[0076] Solution B was added drop wise to the solution A (biphasic solvent layer of ethyl acetate and water was observed) over a period of 5-6 hrs. with continuous stirring while maintaining the temperature of the reaction mixture at 5 to 10 °C.
[0077] The reaction mixture was stirred while maintaining the pH at the range of from 6.5 to 8.5 till the reaction was complete. The reaction mixture was then cooled to 0 to 3 °C and was filtered under vacuum to obtain the white solid containing 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III). Yield: 180.0 g, 92%; GC purity >98%.

Step 2: Preparation of crude clomazone of formula (Ia) from 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) and 2-chlorobenzyl chloride of formula (II).

[0078] 100.0 g (0.66 mol) of white solid containing 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) obtained from step 1 and 100 mL (1V) water were charged into a 2 L round bottom flask equipped with mechanical stirrer, addition funnel, reflux condenser and temperature indicator and were mixed to obtain a slurry. The slurry was heated to 40-50 °C and a sodium carbonate solution (138.16 g, 1.31 mol of sodium carbonate in 300 ml of water (3V)) was added to the slurry. The slurry was heated to 80 to 85°C.
[0079] 106.2 g (0.66 mol) of 2-chlorobenzyl chloride of formula (II) was added drop wise to the above slurry over a period of about 2-3 hrs. at 80 to 85 °C, with continuous stirring to obtain the reaction mass. The reaction mass was heated to 90 to 95 °C for about 12-14 hrs. till the completion of the reaction. The reaction mass was further cooled to 25 to 30 °C and diluted with ethylene dichloride (EDC, 200 mL), filtered under vacuum to remove the inorganic salts and to obtain the filtrate EDC solvent layer containing crude clomazone of formula (Ia) along with Impurity A (1-(2-chlorophenyl)methoxy-3,3-dimethyl-2-azetidinone) and Impurity B (3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole).
Step 3: Purification of crude clomazone of formula (Ia) to obtain pure clomazone of formula (I).

[0080] The filtrate EDC solvent layer containing crude clomazone of formula (Ia) along with Impurity A (1-(2-chlorophenyl)methoxy-3,3-dimethyl-2-azetidinone) and Impurity B (3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole) was charged into a 2 L round bottom flask and heated to 45 to 50 °C. 22.6 g (0.23 mol) of concentrated H2SO4 was added drop wise to the EDC layer over a period of about half an hour to one hour with continues stirring while maintaining the temperature at 50 to 55 °C to obtain a solution. The solution was stirred at 50 to 55 °C for about 2-3 hrs. Then, the solution was allowed to cool to 25 to 30 °C.
[0081] The above solution was washed with 100.0 mL of cold water, followed by 100.0 mL of 10% aqueous solution of Na2CO3 which was followed by 100.0 mL of brine solution to remove the traces of H2SO4 in the solution. Further, the solution was distilled out to obtain the organic mass without any isomeric impurities. Further, the organic mass was distilled under high vacuum distillation to obtain pure clomazone of formula (I). Yield 65% (102 g) and HPLC purity: 99% purity.

COMPARITIVE EXAMPLES
Comparative Example 1A: Synthesis of Clomazone by a conventional process.
Step 1

[0082] 8.96 g (0.129mol) of hydroxylamine hydrochloride of formula (IV), 40 ml (2V) of water (solvent) were charged into a 250 mL round bottom flask equipped with mechanical stirrer, addition funnel, reflux condenser and temperature indicator to obtain solution A. Solution A was cooled to 5 to 10 °C and 6.2 g (0.155 mol) solid base NaOH was added to solution A in an equal portion over a period of half an hour to 1 hour, with the temperature maintained at 5 to 10 °C to avoid any exothermic reactions.
[0083] 2g of phase transfer catalyst PEG 400 was added to solution A and 20 g (0.129 mol) of 3-chloro-2,2-dimethylpropionyl chloride was added drop wise over a period of 1-1.5 hours with continuous stirring while maintaining the temperature of the reaction mixture at5 to 10 °C.
[0084] The reaction mixture was stirred for 5-6 hours for completion. The reaction mixture was then cooled to 0 to 3 °C and was filtered under vacuum to obtain the white solid containing 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III). Yield: 65% (12.8 g), GC purity: 78%.
Step 2

[0085] 20.0 g (0.132 mol) of white solid containing 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) obtained from step 1 and 40 mL (2V) water were charged into a 250 ml round bottom flask equipped with mechanical stirrer, addition funnel, reflux condenser and temperature indicator and were mixed to obtain a slurry. The slurry was heated to 40-50 °C and a sodium hydroxide solution (6.3g, 0.158 mol in 13 ml of water) was added to the slurry and stirred for 1 to 2 hours. The slurry was heated to 80 to 85 0C, further the base sodium carbonate (16.7g, 0.158 mol) and the PTC 2g of TBAB was added to the slurry.
[0086] 21.3 g (0.132 mol) of 2-chlorobenzyl chloride of formula (II) was added drop wise to the above slurry over a period of about 1-1.5 hrs. at 80 to 85 °C, with continuous stirring to obtain the reaction mass. The temperature of the reaction mass was maintained at 80 to 85 °C for about 12-14 hrs. till the completion of the reaction. The reaction mass was further cooled to 25 to 30 °C and diluted with ethylene dichloride (EDC, 20 mL), filtered under vacuum to remove the inorganic salts and to obtain the filtrate EDC solvent layer which was distilled under vacuum to obtain crude clomazone of formula (Ia) (45 to 50%) along with Impurity A (1-(2-chlorophenyl)methoxy-3,3-dimethyl-2-azetidinone) (3 to 5%) and Impurity B (3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole) (5 to 8%).

Step 3

[0087] Crude clomazone of formula (Ia) along with Impurity A ( 1-(2-chlorophenyl)methoxy-3,3-dimethyl-2-azetidinone) and Impurity B (3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole) was charged into a 250 ml round bottom flask and dry HCl was purged at 45 to 50 °C. 22.6 g (0.627 mol) for 3 to 4 hours to obtain a reaction mass. The reaction mass was cooled to 10 to 15 °C. The above reaction mass pH was adjusted 8 to 9 by adding to 50 ml 10% NaOH solution which was further washed with EDC (2 * 50 ml) to obtain EDC organic layer. Further, the EDC organic layer was distilled under high vacuum distillation to obtain clomazone Yield 35 % (11g) and HPLC purity: 92% purity with and Impurity B (3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole) (1 to 3%).

Comparative Example 2A: Synthesis of Clomazone
Step 1

[0088] 8.96 g (0.129mol) of hydroxylamine hydrochloride of formula (IV), 40 ml (2V) of water (solvent) were charged into a 250 mL round bottom flask equipped with mechanical stirrer, addition funnel, reflux condenser and temperature indicator to obtain a solution A. Solution A was cooled to 5 to 10 °C and 6.2 g (0.155 mol) base solid NaOH was added to solution A in an equal portion over a period of half an hour to 1 hour, with the temperature maintained at 5 to 10 °C to avoid any exothermic reactions.
[0089] 2g of phase transfer catalyst TBAB was added to the solution A and 20 g (0.129 mol) of 3-chloro-2,2-dimethylpropionyl chloride was added drop wise over a period of 1-1.5 hours with continuous stirring while maintaining the temperature of the reaction mixture at 5 to 10 °C .
Step 2

[0090] 20.0 g (0.132 mol) of white solid containing 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) obtained from step 1 and 40 mL (2V) water were charged into a 250 ml round bottom flask equipped with mechanical stirrer, addition funnel, reflux condenser and temperature indicator and were mixed to obtain a slurry. The slurry was heated to 40-50 °C and sodium hydroxide solution (6.3g, 0.158 mol in 13 ml of water) was added to the slurry and stirred for 1 to 2 hours. The slurry was heated to 80 to 85°C, further the base sodium carbonate (16.7g, 0.158 mol) and 2g of the phase transfer catalyst PEG-400 was added to the slurry.
[0091] 21.3 g (0.132 mol) of 2-chlorobenzyl chloride of formula (II) was added drop wise to the above slurry over a period of about 1-1.5 hrs. at 80 to 85 °C, with continuous stirring. The temperature of the reaction mass was maintained at 80 to 85 °C for about 12-14 hrs. till the completion of the reaction. The reaction mass was further cooled to 25 to 30 °C and diluted with ethylene dichloride (EDC, 20 mL), filtered under vacuum to remove the inorganic salts and to obtain the filtrate EDC solvent layer which was distilled under vacuum to obtain crude clomazone of formula (Ia) ( 45 to 50% ) along with Impurity A (1-(2-chlorophenyl)methoxy-3,3-dimethyl-2-azetidinone) (3 to 5%) and Impurity B (3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole) (5 to 8%).
Step 3

[0092] Crude clomazone of formula (Ia) along with Impurity A ( 1-(2-chlorophenyl)methoxy-3,3-dimethyl-2-azetidinone) and Impurity B (3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole) was charged into a 250 ml round bottom flask and the dry HCl was purged at 45 to 50 °C. 22.6 g (0.627 mol) for 3 to 4 hours to obtain a reaction mass. The reaction mass was cooled to 10 to 15 °C. The above reaction mass pH was adjusted to 8 to 9 by adding 50 ml 10% NaOH solution which was further washed with EDC (2 * 50 ml) to obtain EDC organic layer. Further, the EDC organic layer was distilled under high vacuum distillation to obtain clomazone Yield 32 % (10g) and HPLC purity: 92% purity with and Impurity B (3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole) (1 to 3%).

Table 1: Comparison of the Present invention with conventional processes to prepare Clomazone.

Examples Process to prepare Formula (III)
Step 1 Process to prepare pure clomazone of formula (I)
Step 2 and 3
Base Solvent PTC* Purity Yield Bases Solvent PTC* Acid Purity
Yield
Present Invention
1 K2CO3 Ethyl acetate+ Water Absent >98% 92% K2CO3 water Absent H2SO4 >98% 66%
2 Na2CO3 Ethyl acetate+ Water Absent 98% 92% Na2CO3 water Absent H2SO4 99% 65%
Comparative Examples
1A NaOH water PEG-400 78% 65% NaOH+
Na2CO3 water TBAB Dry HCl 92% 35%
2A NaOH water TBAB 80% 68% NaOH+
Na2CO3 water PEG-400 Dry HCl 92% 32%

PTC*: Phase transfer catalyst
[0093] Accordingly, from the test results shown above, it is evident that the process of the present invention provides unexpected and surprising results i.e., the yield and purity of clomazone prepared in accordance with the process of the present invention are improved and are greater.
[0094] The yield of Clomazone obtained with the process as per the present invention Examples 1 and 2 is greater (65%) than the yield of Clomazone prepared by the conventional processes as shown in the Comparative Examples 1A and 2A (below 32%).
[0095] The Comparative Examples 1A and 2A use single solvent such as water during the preparation of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) which lead to the formation of the 3-chloro-N-hydroxy-2,2-dimethylpropanamide with less purity because of which the additional purification step such as wash with the organic solvent methylene dichloride (MDC) was required to be carried out to obtain the pure product for use in further steps. But the additional purification step resulted in the lower yield of the desired product 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) (less than 68%). In contrast, the process of the present invention carried out with biphasic solvent system ethyl acetate: water avoided the additional purification step as the ethyl acetate solvent present in the biphasic solvent system surprisingly helped both for dissolution of 3-chloro-2,2-dimethylpropionyl chloride of formula (V) and even for purification of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III). That is the impurities formed along with the 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) were easily dissolved in ethyl acetate and removed during filtration, thereby avoiding the requirement of additional purification of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) but resulted in the high yield of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) (higher than 92% and purity of >98% hence making the process more efficient.
[0096] Additionally, the Comparative Examples 1A and 2A use phase transfer catalysts such as PEG-400 and TBAB during the preparation of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) and crude clomazone of formula (I)a. However, the present invention does not require such phase transfer catalysts during the preparation of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) and crude clomazone of formula (I)a, and hence makes the process eco-friendly and economical. Also, the comparative Examples 1A and 2A use multiple bases such as NaOH and Na2CO3 during the preparation of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) and crude clomazone of formula (I)a. In contrast Examples 1 and 2 of the present invention use a single base such as potassium carbonate during the entire reaction thereby avoiding the use of multiple bases.
[0097] Finally, the comparative Examples 1A and 2A use HCl gas for the purification of crude clomazone of formula (Ia) which helped in removal of only one isomeric impurity, 1-(2-chlorophenyl)methoxy-3,3-dimethyl-2-azetidinone (Impurity A) and not the other impurity 3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole (Impurity B) of Clomazone which resulted in obtaining Clomazone with less yield of 32 % and lower purity of only 92%, whereas the process of the present invention which uses concentrated H2SO4 has significant advantage over the use of HCl gas during the process for the purification of crude clomazone. That is by using concentrated H2SO4 both the impurities Impurity A (1-(2-chlorophenyl) methoxy-3,3-dimethyl-2-azetidinone) and Impurity B (3-(2-chlorophenyl)methoxy-4,5-dihydro-4,4-dimethylisoxazole) were removed to obtain the Clomazone of formula (I) with much higher purity 99% and yield 66%.
[0098] The foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. A skilled artisan will appreciate that the quantity and type of each ingredient can be used in different combinations or singly.
Such changes and modifications may be made without departing from the scope of the invention. All such variations and combinations would be falling within the scope of present disclosure.
, Claims:

1. A process for preparing pure clomazone of formula (I), comprising the steps of:
(i) reacting 3-chloro-2,2-dimethylpropionyl chloride of formula (V) with hydroxylamine hydrochloride of formula (IV) in presence of a base and biphasic solvent system to produce 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III)
;
(ii) reacting 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) with 2-chlorobenzyl chloride of formula (II) in presence of a base and a solvent and in the absence of a phase transfer catalyst to produce crude clomazone of formula (Ia); and

(iii) treating crude clomazone of formula (Ia) with concentrated H2SO4, to obtain pure clomazone of formula (I)
.
2. The process for preparing pure clomazone as claimed in claim 1, wherein the reaction of 3-chloro-2,2-dimethylpropanoyl chloride of formula (V) with hydroxylamine hydrochloride of formula (IV) is carried out in the presence of base selected from the group comprising of carbonates selected from potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate and tertiary amines selected from triethyl amine, and N,N-diisopropylethylamine.

3. The process for preparing pure clomazone as claimed in claim 1 or 2, wherein the reaction of 3-chloro-2,2-dimethylpropanoyl chloride of formula (V) with hydroxylamine hydrochloride of formula(IV) is carried out in the presence of the base potassium carbonate.

4. The process for preparing pure clomazone as claimed in claim 1, wherein the reaction of 3-chloro-2,2-dimethylpropanoyl chloride of formula (V) with hydroxylamine hydrochloride of formula(IV) is carried out in the presence of the biphasic solvent system comprising of ethyl acetate: water, toluene: water, dichloromethane: water, 1,2-dichloroethane:water, methyl tertiary-butyl ether (MTBE): water, diethyl ether: water, and ethyl methyl ether: water.

5. The process for preparing pure clomazone as claimed in claim 1 or 5, wherein the reaction of 3-chloro-2,2-dimethylpropanoyl chloride of formula (V) with hydroxylamine hydrochloride of formula(IV) is carried out in the presence of the biphasic solvent system comprising ethyl acetate: water.

6. The process for preparing pure clomazone as claimed in claim 5, wherein the volume ratio of ethyl acetate to water is in the range selected from 1- 3 : 2-4 by volume.

7. The process for preparing pure clomazone as claimed in claim 6, wherein the ethyl acetate to water is in the ratio of 1:2.

8. The process for preparing pure clomazone as claimed in claim 1, wherein the reaction of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) with 2-chlorobenzyl chloride of the formula (II) is carried out in the presence of base selected from the group comprising of carbonates selected from potassium carbonate, sodium carbonate, sodium bicarbonate and cesium carbonate.

9. The process for preparing pure clomazone as claimed in claim 8, wherein the reaction of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) with 2-chlorobenzyl chloride of the formula (II) is carried out in the presence of base potassium carbonate.

10. The process for preparing pure clomazone as claimed in claim 1, wherein the reaction of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) with 2-chlorobenzyl chloride of the formula (II) is carried out in the presence of a solvent water.

11. The process for preparing pure clomazone as claimed in claim 8, wherein the reaction of 3-chloro-N-hydroxy-2,2-dimethylpropanamide of formula (III) with 2-chlorobenzyl chloride of the formula (II) is carried out in the absence of phase transfer catalyst.

12. A process for purification of crude clomazone of formula (Ia) comprising the steps of treating the crude clomazone of formula (Ia) with conc. H2SO4 to obtain the pure clomazone of formula (I).