DESC:FIELD OF THE INVENTION
[0001] The present disclosure relates to technical field of organic synthesis. In particular, the present disclosure relates to a process for preparation of intermediate of Tembotrione, and preparation of Tembotrione therefrom, which is useful as herbicide.

BACKGROUND OF THE INVENTION
[0002] 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 a prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is a prior art.
[0003] Due to the succession and change of weed populations and the emergence and rapid development of resistance to chemical pesticides, people's awareness of ecological environment protection has been continuously strengthened. The emphasis on the issue of whereabouts continues to increase.
[0004] Tembotrione, a triketone compound, is a potent and highly selective inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD), thereby blocking the pathway of prenylquinone biosynthesis in plants. It has been widely used for the post-emergence control of a wide range of dicotyledonous and monocotyledonous weeds in the field of corn, seed corn, yellow popcorn and sweet corn. Tembotrione is chemically known as 2-[2-chloro-4-(methyl sulfonyl)-3-[(2,2,2-trifluoroethoxy) methyl]benzoyl]-1,3-cyclohexanedione.
[0005] Indian patent application, IN 7377/DN/2014 discloses a process for the preparation of intermediate 2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]-benzoyl chloride (CMTBC) from its acid derivative (CMTBA) by using oxalyl chloride in dichloromethane or ethyl acetate, containing a catalytic amount of DMAP.
[0006] The Chinese patent documents, CN109678767, CN111440099, CN113845451 disclose a process for the preparation of intermediate CMTBC from CMTBA by using thionyl chloride in dichloromethane, followed by preparing triketone herbicide.
[0007] The Chinese patent document, CN110903279 discloses a process for the preparation of intermediate CMTBC from CMTBA by using phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride or phosphorus oxychloride in solvent toluene, 1,2-dichloroethane or petroleum ether, in the presence of catalytic amount of N,N-dimethylformamide.
[0008] However, the processes known in the art for preparing Tembotrione and its intermediate involve tedious procedures, workup and purification steps. This result in excessive production time, which in turn renders the processes more costly and less eco-friendly, thus the processes are not suitable for commercial scale up. The known processes further involve use of high amount of solvents that leads to production of high volume of effluent.
[0009] There is thus a need in the art to provide a new, improved and highly efficient process, which alleviates one or more drawbacks of the conventional processes and gives better conversion, high yield and also leads to formation of low amounts of impurities and by-products. Need is also felt of a process for preparation of intermediate of Tembotrione i.e. CMTBC. The present disclosure satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.
[00010] 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
[00011] It is an object of the present disclosure to provide a new process for preparation of compound 2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]-benzoyl chloride (CMTBC), an intermediate for synthesis of triketone compound Tembotrione.
[00012] It is another object of the present disclosure to provide an economical, efficient and eco-friendly process for preparation of Tembotrione.
[00013] Another object of the present invention is to provide a process which allows to obtain triketone compound Tembotrione in good yield, while minimizing formation of impurities.
[00014] Another object of the present invention is to provide a process for preparing triketone compound Tembotrione, which is simple to operate on a commercial scale, while reducing effluent production.
[00015] Other and further objects of this invention will be apparent from the following detailed description and appended claims which form a part of this specification.

SUMMARY OF THE INVENTION
[00016] The foregoing and other objects are attained by the present disclosure, which in one aspect provides a process for preparation of 2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]-benzoyl chloride (CMTBC) of formula (II) from 2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]-benzoic acid (CMTBA) of formula (I) using phosgene, triphosgene or diphosgene as a chlorinating agent. The reaction is schematically represented below:

[00017] In yet another aspect, there is provided a process for preparation of Tembotrione of formula (IV),

which includes the steps of:
(i) converting CMTBA to CMTBC with a chlorinating agent in presence of a suitable solvent;

(ii) coupling CMTBC with 1,3-cyclohexanedione to produce an enol ester of formula (III); and

(iii) effecting rearrangement of enol ester of formula (III) to tembotrione of formula (IV).

[00018] 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
[00019] The following is a detailed description of embodiments of the invention. The embodiments are in such detail as to clearly communicate the invention. However for a person skilled in the art, 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 invention.
[00020] All numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term "about."
[00021] It should be understood that the terms "a" and "an" as used herein refer to "one or more" of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise. Unless otherwise stated, percentages in the present description are by weight.
[00022] An aspect of the present disclosure relates to a process for preparation of 2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]-benzoyl chloride (CMTBC) of formula (II) from 2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]-benzoic acid (CMTBA) of formula (I) using phosgene, triphosgene or diphosgene as a chlorinating agent. The reaction is schematically represented below:

[00023] In some embodiments, the process is effected in presence of a solvent, optionally in presence of a catalyst.
[00024] In some embodiments, the solvent is selected from a group consisting of: methylene dichloride, ethylene dichloride, dimethyl sulfoxide, N,N-dimethylformamide, carbon tetrachloride, xylene, chloroform, o-dichlorobenzene, chlorobenzene, toluene, tetrahydrofuran, acetone, methyl isobutyl ketone, methyl-t-butylether, acetonitrile, hexane, ethyl acetate, methyl acetate, butyl acetate, cyclohexanone, pyridine, N-methyl-2-pyrrolidone, 1,2-dimethoxyethane, diglyme, 1,4-dioxane, or mixtures thereof.
[00025] In some embodiments, the catalyst is selected from a group consisting of: N,N-dimethylformamide (DMF), PEG-200, PEG-400, quaternary ammonium salts, crown ethers, triphenylphosphine, benzyltriethylammonium chloride, tetrabutylammonium bromide, benzyltributylammonium chloride, dimethylaminopyridine, tetrabutylammonium chloride and phosphonium compounds, preferably DMF or mixtures thereof.
[00026] In some embodiments, the process is conducted at a temperature ranging from 20°C to 80°C, preferably between 50°C to 60°C.
[00027] Another aspect of the present disclosure relates to a process for preparation of Tembotrione of Formula (IV),

which comprises the steps of:
(i) converting CMTBA to CMTBC with a chlorinating agent in presence of a suitable solvent;

(ii) coupling CMTBC with 1,3-cyclohexanedione to produce an enol ester of formula (III); and

(iii) effecting rearrangement of enol ester of formula (III) to tembotrione of formula (IV).

In some embodiments, the process for preparation of Tembotrione of Formula (IV) can be described in following steps 1 to 3, which comprises,
1) converting CMTBA of formula (I) to CMTBC of formula (II) with a chlorinating agent in presence of a first solvent at a first temperature, optionally in presence of a catalyst;

2) coupling of CMTBC of formula (II) with 1,3-cyclohexanedione in presence of a second solvent and a base at a second temperature to produce an enol ester of formula (III);

3) effecting rearrangement of enol ester of formula (III) in presence of a third solvent and a cyanide moiety at a third temperature to obtain tembotrione of formula (IV).

[00028] In one embodiment, above described steps (1), (2) and (3) are effected either in-situ or via isolating the respective products.
[00029] In one embodiment, said steps (1), (2) and (3) are effected in in-situ mode.
[00030] In one embodiment, the chlorinating agent used in step (1) is selected from phosgene, diphosgene or triphosgene, preferably phosgene.
[00031] In one embodiment, the first solvent, second solvent and third solvent used in steps (1), (2) and (3), respectively, are selected independently from the group consisting of methylene dichloride, ethylene dichloride, dimethyl sulfoxide, N,N-dimethylformamide, carbon tetrachloride, xylene, chloroform, o-dichlorobenzene, chlorobenzene, toluene, tetrahydrofuran, acetone, methyl isobutyl ketone, methyl-t-butylether, acetonitrile, hexane, ethyl acetate, methyl acetate, butyl acetate, cyclohexanone, pyridine, N-methyl-2-pyrrolidone, 1,2-dimethoxyethane, diglyme, 1,4-dioxane or mixtures thereof.
[00032] In various embodiments, the first temperature in step (1) ranges from 20°C to 80°C, preferably 50°C to 60°C.
[00033] In one embodiment, the catalyst used in step (1) is selected from the group consisting of N,N-dimethylformamide (DMF), PEG-200, PEG-400, quaternary ammonium salts, crown ethers, triphenylphosphine, benzyltriethylammonium chloride, tetrabutylammonium bromide, benzyltributylammonium chloride, dimethylaminopyridine, tetrabutylammonium chloride and phosphonium compounds, preferably DMF or mixtures thereof.
[00034] In one embodiment, the base used in step (2) is selected from either inorganic or organic base selected from the group consisting of alkali metal or alkaline earth metal hydroxide, carbonates or bicarbonates, ammonium hydroxide, alkylamine like triethylamine or diethylamine, pyridine, 2,6-lutidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or a mixture(s) thereof.
[00035] In various embodiments, the second temperature in step (2) ranges from -10°C to 25°C, preferably between 0°C to 5°C.
[00036] In one embodiment, the cyanide moiety used in step (3) is acetone cyanohydrin.
[00037] In various embodiment, at step (3) the compound of Formula (IV) can be isolated from a reaction mixture by methods known in the art, such as crystallization, extraction or distillation.
[00038] In various embodiments, the third temperature ranges from 10°C to 50°C, preferably between 25°C to 30°C.
[00039] In another aspect, the present invention is directed to a process for preparation of the compound of Formula (II) that can be used as an intermediate for the synthesis of triketone herbicide tembotrione by methods known in the art.
[00040] In various embodiments, the compounds of Formula (II) and (IV), produced in accordance with the process disclosed herein, have a purity of greater than 95% as determined by HPLC.
[00041] The process according to the present invention has a number of advantages over the known processes for the preparation of Tembotrione viz. it afford production of Tembotrione of high purity; in carrying out the process of the present disclosure, the reaction temperature and pressure are not critical; and all the raw materials and reagents are economically viable. The process of the present invention is thus convenient to operate on a commercial scale.
[00042] While the foregoing description discloses various embodiments of the invention, other and further embodiments of the invention may be devised without departing from the basic scope of the invention. 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.
EXAMPLES
[00043] The present invention is further explained in the form of 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.
Example 1
[00044] Conversion of CMTBA of formula (I) to CMTBC of formula (II): CMTBA (25g, 0.072mol), and dichloroethane (100ml, 1.25mol) were charged into a 250ml round bottomed flask and catalytic amount of DMF was added thereto. The mixture was heated to 50-60°C under stirring. Phosgene (10g, 0.10mol) was purged slowly, and the reaction was monitored by HPLC.
[00045] Coupling of CMTBC of formula (II) with 1,3-cyclohexanedione: To a clean and pre-dried 1L round bottomed flask, dichloroethane (50mL), 1,3-cyclohexanedione (8.5g, 0.075mol) and triethylamine (17g, 0.165mol) were added under stirring at the temperature of 25-30°C. To this mixture, reaction mixture of step (a) was added and stirred for about 2 hours at 0-5°C. The reaction mixture was monitored by HPLC.
[00046] Rearrangement of enol ester of formula (III): In the reaction mixture of previous step, 1 ml acetone cyanohydrin was added at 25-30°C and stirred for 1 hr. The reaction mixture was quenched with water (80mL) and the organic layer was separated. Dichloroethane was separated through distillation under reduced pressure at 35-45°C. The aqueous mass obtained was cooled to 5-10°C and acidified to pH<3 using aqueous hydrochloric acid. The precipitated product so obtained was separated through filtration, washed with water (60 mL) and dried under reduced pressure to obtain tembotrione as yellow to tan colored solid. HPLC purity >95%; Yield: 26g (82%).
Example 2
[00047] Conversion of CMTBA of formula (I) to CMTBC of formula (II): CMTBA (50g, 0.144mol), and dichloroethane (200 ml, 2.5mol) were charged into a 500 ml round bottomed flask and catalytic amount of DMF was added thereto. This mixture was heated to 50-60°C temperature under stirring. Phosgene (20g, 0.20mol) was purged slowly, and the reaction was monitored by HPLC.
[00048] Coupling of CMTBC of formula (II) with 1,3-cyclohexanedione: To a clean and pre-dried 1L round bottomed flask, dichloroethane (100mL), 1,3-cyclohexanedione (17g, 0.15mol) and triethylamine (36 g, 0.35mol) were added under stirring at the temperature of 25-30°C. To this mixture, reaction mixture of step (a) was added and stirred for about 2 hours at 0-5°C. The reaction mixture was monitor by HPLC.
[00049] Rearrangement of enol ester of formula (III): In the reaction mixture of previous step, 1 ml acetone cyanohydrin was added at 25-30°C and stirred for 1 hr. The reaction mixture was quenched with water (160mL) and the organic layer was separated. Dichloroethane was separated through distillation under reduced pressure at 35-45°C. The aqueous mass so obtained was cooled to 5-10°C and acidified to pH<3 using aqueous hydrochloric acid. The precipitated product so obtained was separated through filtration, washed with water (60 mL) and dried under reduced pressure to obtain tembotrione as yellow to tan colored solid. HPLC purity >95%; Yield: 54g (84%).
[00050] The numerical values of various parameters given in the specification are at approximations and ±5% variations in these parameters fall within the ambit and the scope of the invention. While considerable emphasis has been placed herein on the specific steps of the preferred process, it will be highly appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the inventions herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.
[00051] The process according to the present invention have various advantages, such as:
i) The present invention provides a process having characteristics of economic and environment friendly with less effluent waste.
ii) The process of the present disclosure involves less expensive and readily available reagents and solvents.
iii) Solvents used in present invention are less expensive and can be recovered and reused.
iv) Product of present invention is directly isolated from the reaction mass without involving any laborious work-up processes. Therefore, the process of the present invention is suitable for implementation at a commercial scale.
v) The present invention provides a new process for preparing Tembotrione, which involves efficient process resulting in competitive yield of the product with optimum purity at commercial scale in comparison to the conventional prior art procedures.
vi) The present invention provides a process for preparing Tembotrione that provides lower impurity profile in final product, as mild reaction condition restricts the formation of undesired impurities.
vii) The present invention provides a process that is simple, safe, time saving and having convenient operational steps at commercial scale.
viii) The present invention provides a process that saves utility at commercial scale because of simple work-up and product isolation procedures.
ix) The present invention provides a process that improves productivity and equipment utilization at commercial scale.
,CLAIMS:1. A process for preparation of 2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]-benzoyl chloride (CMTBC) of formula (II)

(II)
comprising reacting 2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]-benzoic acid (CMTBA) of formula (I)

(I)
with a chlorinating agent which is selected from phosgene, triphosgene and diphosgene.
2. The process as claimed in claim 1, wherein the reaction is effected in presence of a solvent and optionally in presence of a catalyst.
3. The process as claimed in claim 2, wherein the solvent is selected from the group consisting of methylene dichloride, ethylene dichloride, dimethyl sulfoxide, N,N-dimethylformamide, carbon tetrachloride, xylene, chloroform, o-dichlorobenzene, chlorobenzene, toluene, tetrahydrofuran, acetone, methyl isobutyl ketone, methyl-t-butylether, acetonitrile, hexane, ethyl acetate, methyl acetate, butyl acetate, cyclohexanone, pyridine, N-methyl-2-pyrrolidone, 1,2-dimethoxyethane, diglyme, 1,4-dioxane, and mixtures thereof.
4. The process as claimed in claim 2, wherein the catalyst is selected from the group consisting of N,N-dimethylformamide (DMF), PEG-200, PEG-400, quaternary ammonium salts, crown ethers, triphenylphosphine, benzyltriethylammonium chloride, tetrabutylammonium bromide, benzyltributylammonium chloride, dimethylaminopyridine, tetrabutylammonium chloride, phosphonium compounds, and mixtures thereof.
5. The process as claimed in claim 1, wherein the reaction is conducted at a temperature ranging from 20°C to 80°C.
6. The process as claimed in claim 1, further comprises a step of converting the CMTBC of formula (II) to tembotrione of formula (IV)

(IV)
7. A process for preparation of tembotrione of formula (IV),

which comprises the steps of:
(i) converting CMTBA of formula (I) to CMTBC of formula (II) with a chlorinating agent in presence of a solvent

wherein the chlorinating agent is selected from phosgene, triphosgene and diphosgene;
(ii) coupling CMTBC of formula (II) with 1,3-cyclohexanedione to produce an enol ester of formula (III); and

(iii) effecting rearrangement of enol ester of formula (III) to tembotrione of formula (IV).