DESC:FIELD OF THE INVENTION
The present invention relates to the process for preparation of a herbicidal benzoyl cyclohexanedione compound. More particularly, the present invention relates to an alternative and an improved process for preparation of Tembotrione of Formula (I). The alternative process in relation to the present invention is a consistently reproducible process, which results in high yield and purity of Tembotrione.
BACKGROUND OF THE INVENTION
Tembotrione (I), belongs to the benzoyl cyclohexanedione class of compound, chemically known as 2-{2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]benzoyl} cyclohexane-1,3-dione, is a herbicide, developed by Bayer in 2007. Tembotrione has the structural formula as follows:

Structure of Tembotrione of Formula (I)
It successfully prevents the genus of weeds Trianthema, Echinochloa sp., Bracheria sp., and others. It has a strong killing impact on a variety of weeds, no residual activity, strong anti-raining ability, and a wide range of weeding.
Tembotrione (I) is a herbicide that is applied after the crop has emerged to suppress a wide range of grassy and broad-leaved weeds in maize and other crops. This benzoyl cyclohexanedione compound is primarily used for corn, but it can also be used for lawns, sugarcane, rice, onions, sorghum, and other small crops. It also has a flexible application period, can be compounded with different products, and is safe for crops, the environment, and subsequent crops. It can also effectively prevent and remove annual broadleaf weeds and some gramineous weeds. It targets a variety of broad-leaved and gramineous weeds in the middle and late stages of a corn field's germination. It has great control effects on thistle, field bindweed, speedwell, pepper weed, weasel flower, cleavers, and other weeds. Its broad weeding spectrum and lengthy weeding appropriateness.
There are number of processes reported in prior art for preparing benzoyl cyclohexanedione derivatives mainly Tembotrione. Reference in this regard is made to the following:
Patent application no. CN1323292A of Bayer Cropscience AG reports that when 2, 6-dichlorotoluene is used as a starting material to synthesize 2-[2-chloro-4-mesyl-a-(2,2,2-trifluoroethoxy)-m-toluoyl]cyclohexane-1,3-dione, , however, in the process of the said application, a large amount of solid waste is generated, and hence the yield is low.
Reference can also be made with respect to patent application no. CN105601548A of University of Heilongjiang, which reports that when 3-chloro-2-methylaniline is used as a starting material to synthesize 2-[2-chloro-4-mesyl-a-(2,2,2-trifluoroethoxy)-m-toluoyl]cyclohexane-1,3-dione, expensive brominating agents are used when 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid methyl ester is prepared, wherein, a large amount of solid waste is generated, and the yield is low.
Thus, the prior art processes for preparation of Tembotrione (I), are often complicated, and/or are time- consuming resulting in lesser yield and purity of the final compound Tembotrione. Further, the prior art processes sometimes result in unstable form of Tembotrione (I). Additionally, many of the published process do not produce high yields, purity of the active ingredient/final product.
Accordingly, there is an ongoing and long felt need for an improved process for preparing Tembotrione (I) with an improved yield, purity and selectivity.
Thus, it is the objective of the present invention to provide an alternative and improved process for preparing Tembotrione under basic conditions in which the yield, purity and selectivity are improved. A need still remains for simple, cost effective, consistently reproducible and environmentally friendly process for preparing highly pure, stable Tembotrione (I).
Hence, there is a need for an alternative and improved process for preparation of Tembotrione which overcomes the drawbacks of prior arts. Therefore, the present invention conceived a novel, inventive and industrially useful process for the preparation of Tembotrione of formula (I).
The present invention satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the prior arts.
OBJECTIVE AND ADVANTAGES OF THE INVENTION
The main objective of the present invention is to provide an alternative, improved, simple, economically advantageous and cost-effective process for the preparation of Tembotrione of Formula (I), with high purity and yield of Tembotrione on a commercial scale.
Another objective of the present invention is to provide a novel and effective alternative and improved process for preparation of Tembotrione of formula (I), with reduced or minimal waste generation.
Another objective of the present invention is to provide an alternative and improved process for the preparation of Tembotrione of Formula (I), with an improved reaction rate and minimized side reaction and/or formation of by-products.
Another objective of the present invention is to provide an alternative and improved process for the preparation of Tembotrione of formula (I), that involves less expensive and readily available reagents and solvents.
Another objective of the present invention is to provide an alternative and improved process for the preparation of Tembotrione of formula (I), which is industrially and economically robust process with safe operations.
Another objective of the present invention is to provide an alternative and improved process for the preparation of Tembotrione of formula (I), which results in improved yield and purity of the final product.
Another objective of the present invention is to provide an alternative and improved process for the preparation of Tembotrione of formula (I), wherein, less effluent is generated.
A further objective of this invention is to obtain a compound-(2), i.e., 2-bromo-5-chloro-4-methylphenol by reacting a compound-(1), i.e., 3-chloro-4-methylphenol with a halogenating agent, in the presence of suitable Lewis acid and a suitable solvent.
A further objective of this invention is to obtain a compound-(3), i.e., 6-bromo-3-chloro-2-(chloromethyl)-4-methylphenol by halomethylation of the compound-(2) in the presence of a formylating agent and a Lewis acid.
A further objective of this invention is to obtain a compound-(4), i.e., 6-bromo-3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl]phenol by reacting the compound-(3) with 2,2,2-trifluoroethan-1-ol in the presence of base.
A further objective of this invention is to obtain a compound-(5), i.e., 3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl] phenol by reacting the compound-(4) in the presence of a dehalogenating agent.
A further objective of this invention is to obtain a compound-(9), i.e., 2-Chloro-4-methanesulfonyl-1-methyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene, by reacting the compound-(5), i.e., 3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl] phenol, with tosyl chloride in the presence of base followed by the reaction with methyl thiol and subsequent oxidation with mild oxidizing agents.
A further objective of this invention is to obtain a compound (10), i.e., 1-(bromomethyl)-2-chloro-4-methanesulfonyl-3-[(2,2,2-trifluoroethoxy)methyl]benzene, by halogenating the compound (9), at benzylic position by halogenating agents in presence of radical initiator.
A further objective of this invention is to obtain a compound-(11), i.e., 2-[2-Chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzyl]-cyclohexane-1,3-dione, by reacting the compound (10) with 1,3-Cyclohexadione using the suitable solvent and in the presence of base.
A further objective of this invention is to oxidize the compound (11) in the presence of an oxidizing agents to furnish a target compound, i.e., Tembotrione of Formula (I).
Some or all these and other objects of the invention can be achieved by way of the invention described hereinafter.
SUMMARY OF THE INVENTION
Accordingly, the main aspect of the present invention is to provide an alternative and improved process for the preparation of Tembotrione of Formula (I). Provided herein is simple, cost effective and consistently reproducible process for the preparation of highly pure and stable form of Tembotrione.
In an aspect, the present invention provides an alternative and improved process for the preparation of Tembotrione of Formula (I), using cost effective and readily available reagents.
In another aspect, the present invention provides an alternative and improved process for the preparation of a Tembotrione of formula (I), comprising:
a) reacting a compound-(1), i.e., 3-chloro-4-methylphenol with a halogenating agent, in the presence of suitable Lewis acid and a suitable solvent, to obtain a compound-(2), i.e., 2-bromo-5-chloro-4-methylphenol;
b) halomethylation of the compound-(2) in the presence of a formylating agent and a Lewis acid, to obtain a compound-(3), i.e., 6-bromo-3-chloro-2-(chloromethyl)-4-methylphenol;
c) reacting the compound-(3) with 2,2,2-trifluoroethan-1-ol in the presence of base, to obtain a compound-(4), i.e., 6-bromo-3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl]phenol;
d) reacting the compound-(4) in the presence of a dehalogenating agent, to obtain a compound-(5), i.e., 3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl] phenol;
e) reacting the compound-(5) with tosyl chloride in the presence of base to obtain the corresponding tosylate followed by reaction with methyl thiol in presence of base and subsequent oxidation with a mild oxidizing agent, to obtain a compound-(9), i.e., 2-Chloro-4-methanesulfonyl-1-methyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene;
f) reacting the compound-(9), at benzylic position using halogenating reagents in presence of radical initiator to obtain a compound-(10), i.e., 1-(bromomethyl)-2-chloro-4-methanesulfonyl-3-[(2,2,2-trifluoroethoxy)methyl]benzene;
g) reacting the compound (10) with 1,3-Cyclohexadione in a suitable solvent, and in the presence of base to obtain a compound-(11), i.e., 2-[2-Chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzyl]-cyclohexane-1,3-dione;
h) oxidizing the compound-(11) in the presence of an oxidizing agents to furnish the target compound, i.e., Tembotrione of Formula (I).
In another aspect, the present invention provides an alternative and improved process for the preparation of Tembotrione of Formula (I), which comprises reacting a compound 3-chloro-4-methylphenol (1), i.e.,

with brominating agent including but not limited to hydrogen bromide & hydrogen peroxide or N-Bromosuccinimide (NBS) in the presence of suitable Lewis acid and ethylene dichloride (EDC) as a solvent, to obtain a compound 2-bromo-5-chloro-4-methylphenol (2), i.e.,

followed by chloromethylation of the compound-(2), in the presence of formaldehyde and zinc chloride, to obtain a compound 6-bromo-3-chloro-2-(chloromethyl)-4-methylphenol (3), i.e.,

The compound (3), on reacting further with 2,2,2-trifluoroethan-1-ol in the presence of base, obtains a compound 6-bromo-3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy)methyl]phenol (4), i.e.,

The compound (4), then undergoes debromination to obtain a compound 3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl] phenol (5), i.e.,

wherein hydroxy group of the compound (5) is converted to the corresponding tosylate followed by nucleophilic displacement reaction of tosylate with methane thiol in the presence of the base or with sodium thiomethoxide to get the thioether intermediate. The thioether intermediate is oxidized under controlled conditions to obtain a compound 2-Chloro-4-methanesulfonyl-1-methyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene (9), i.e.,

Further, the compound 2-Chloro-4-methanesulfonyl-1-methyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene (9) is brominated in the presence of hydrogen bromide (47-49%) and Hydrogen peroxide (H2O2) or N-Bromosuccinimide (NBS) in the presence of free radical initiator to obtain a compound 1-(bromomethyl)-2-chloro-4-methanesulfonyl-3-[(2,2,2-trifluoroethoxy)methyl]benzene (10), i.e.,

The compound (10), is then condensed with 1,3-Cyclohexadione using suitable solvent and, in the presence of base to furnish a compound 2-[2-Chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzyl]-cyclohexane-1,3-dione (11), i.e.,

The compound (11), is oxidized with oxidizing agents like tert-butyl hydroperoxide, Selenium dioxide, 2-Iodoxybenzoic acid (IBX) and alike to yield the target compound, i.e., Tembotrione of Formula (I).

Formula (I).
The reaction scheme of the present invention is represented as following Scheme-1:
Scheme 1:

In another aspect, the present invention obtains a compound-(2), i.e., 2-bromo-5-chloro-4-methylphenol by reacting a compound-(1), i.e., 3-chloro-4-methylphenol with a halogenating agent, in the presence of suitable Lewis acid and a suitable solvent.
In another aspect, the present invention obtains a compound-(3), i.e., 6-bromo-3-chloro-2-(chloromethyl)-4-methylphenol by halomethylation of the compound-(2) in the presence of a formylating agent and a Lewis acid.
In another aspect, the present invention obtains a compound-(4), i.e., 6-bromo-3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl]phenol by reacting the compound-(3) with 2,2,2-trifluoroethan-1-ol in the presence of base.
In another aspect, the present invention obtains a compound-(5), i.e., 3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl] phenol by reacting the compound-(4) in the presence of a dehalogenating agent.
In an aspect, the present invention obtains a compound-(9), i.e., 2-Chloro-4-methanesulfonyl-1-methyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene, by reacting the compound-(5), i.e., 3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl] phenol, with tosyl chloride in the presence of base to obtain the tosylate followed by reacting it with methyl thiol and subsequent oxidation with mild oxidizing agents.
In an aspect, the present invention obtains a compound (10), i.e., 1-(bromomethyl)-2-chloro-4-methanesulfonyl-3-[(2,2,2-trifluoroethoxy)methyl]benzene, by halogenating the compound (9), at benzylic position by halogenating reagents in presence of radical initiator.
In an aspect, the present invention obtains a compound (11), i.e., 2-[2-Chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzyl]-cyclohexane-1,3-dione, by reacting the compound (10) with 1,3-Cyclohexadione in presence of base followed by rearrangement in the presence of an acetone cyanohydrin.
In an aspect, the present invention oxidizes the compound-(11) in the presence of an oxidizing agents to furnish the target compound, i.e., Tembotrione of Formula (I).
DETAILED DESCRIPTION OF THE INVENTION
At the very outset of the detailed description, it may be understood that the ensuing description only illustrates a particular form of this invention. However, such a particular form is only exemplary embodiment, and without intending to imply any limitation on the scope of this invention. Accordingly, the description is to be understood as an exemplary embodiment and teaching of the invention and not intended to be taken restrictively.
It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the present disclosure.
Certain ranges are presented herein with numerical values being preceded by the term “about”. The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximately unrecited number may be a number which in the context in which it is presented, provides the substantial equivalent of the specifically recited number. In an embodiment, “about” can mean within one or more standard deviations, or within ±30%, 25%, 20%, 15%, 10%, or 5% of the stated value.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any process and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred process is described. For the purposes of the present invention, the following terms are defined below:
The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.
As used herein, the terms, “including”, “includes”, “comprising”, and comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items.
Each embodiment is provided by way of explanation of the invention and not by way of limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the process described herein without departing from the scope of the invention. For instance, features illustrated or described as part of one embodiment can be applied to another embodiment to yield a still further embodiment.
In an embodiment, the present invention provides an alternative and improved process for the preparation of Tembotrione of Formula (I).
In one of the embodiments, the present invention provides an alternative and improved process for the preparation of Tembotrione of Formula (I), using cost effective and readily available reagents.
In another embodiment, the present invention provides an alternative and improved process for the preparation of a Tembotrione of formula (I), comprising:
a) reacting a compound-(1), i.e., 3-chloro-4-methylphenol with a halogenating agent, in the presence of suitable Lewis acid and a suitable solvent, to obtain a compound-(2), i.e., 2-bromo-5-chloro-4-methylphenol;
b) halomethylation of the compound-(2) in the presence of a formylating agent and a Lewis acid, to obtain a compound-(3), i.e., 6-bromo-3-chloro-2-(chloromethyl)-4-methylphenol;
c) reacting the compound-(3) with 2,2,2-trifluoroethan-1-ol in the presence of base, to obtain a compound-(4), i.e., 6-bromo-3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy)methyl]phenol;
d) reacting the compound-(4) in the presence of a dehalogenating agent, to obtain a compound-(5), i.e., 3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl] phenol;
e) reacting the compound-(5) with tosyl chloride in the presence of base to obtain the corresponding tosylate followed by reacting it with methyl thiol in presence of base and subsequent oxidation with a mild oxidizing agent, to obtain a compound-(9), i.e., 2-Chloro-4-methanesulfonyl-1-methyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene;
f) reacting the compound-(9), at benzylic position using halogenating reagents in presence of radical initiator to obtain a compound-(10), i.e., 1-(bromomethyl)-2-chloro-4-methanesulfonyl-3-[(2,2,2-trifluoroethoxy)methyl]benzene;
g) reacting the compound (10) with 1,3-Cyclohexadione in a suitable solvent and, in the presence of base to obtain a compound-(11), i.e., 2-[2-Chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzyl]-cyclohexane-1,3-dione;
h) oxidizing the compound-(11) in the presence of an oxidizing agents to furnish the target compound, i.e., Tembotrione of Formula (I).

In one of the embodiments, the halogenating agent is selected from the group comprising bromine, N-Bromosuccinimide, hydrogen bromide (HBr), chlorine, fluorine, iodine wherein the halogenating agent is combined with acetic acid, water, hydrogen, and/or H2O2 or combination thereof. In a preferred embodiment, the halogenating agent is a brominating agent.
In one of the embodiments, the radical initiator is selected from the group comprising azobisisobutyronitrile (AIBN), benzoyl peroxide or combination thereof.
In one embodiment, the base is selected from the group comprising diisopropylamine, diisopropylethylamine, triethylamine, dimethylamine, trimethyl amine, pyridine, N-methylmorpholine, 3-picoline, 2-picoline, 4-picoline, sodium carbonate, potassium carbonate, calcium hydroxide or combination thereof.
In one of the embodiments, the suitable solvent is selected from the group comprising N-dimethylformamide, benzene, dichloromethane, isopropanol, 1,2-dichloroethane, chloroform, 1, 4-dioxane, diethyl ether, acetic acid, hydrogen peroxide, o-dichlorobenzene ethylene dichloride, carbon tetrachloride, chlorobenzene, dichlorobenzene, tetrahydrofuran and acetonitrile, ethyl acetate, Acetone, dimethylsulfoxide. cyclohexane, hexane, heptane, toluene, xylene, etc or combination thereof.
In one of the embodiments, the formylating agent is selected from the group comprising para-formaldehyde, formalin, formic acid, methyl formate, N,N-dimethylformamide, diazomethane, cyanogen bromide, hydrogen cyanide etc or combination thereof.
In one of the embodiments, the dehalogenating agent used is selected from the group comprising Zinc, Iron (Fe), sodium, hydrogen gas, Tin (II) chloride, sodium borohydride, sodium amalgam (Na/Hg) etc or combination thereof. In a preferred embodiment, the dehalogenating agent is a debrominating agent.
In one of the embodiments, the oxidizing agent is selected from the group comprising hydrogen peroxide, potassium permanganate, potassium dichromate, chlorine, sodium dichromate, chromium trioxide, nitric acid, perchloric acid, osmium tetraoxide, etc or combination thereof.
In one of the embodiments, the Lewis acid in the reaction of the present invention is selected from the group comprising Zinc chloride (ZnCl2), Aluminium Chloride (AlCl3), Ferric Chloride (FeCl3), Boron Trifluoride (BF3), Boron Trichloride (BCl3), Titanium tetrachloride (TiCl4), Antimony Pentafluoride (SbF5), etc or combination thereof.
In one of the embodiments, the catalyst is selected from palladium (II) acetate, triphenyl phosphine, sodium tungstate, dihydrate, Pd/C or Raney Nickel, Pt/C, PtO2/C, Na2WO4.2H2O, (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl or (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO), Cobalt(II) acetate, Co-napthenate etc. or combination thereof.
In another embodiment, the present invention obtains a compound-(2), i.e., 2-bromo-5-chloro-4-methylphenol by reacting a compound-(1), i.e., 3-chloro-4-methylphenol with a halogenating agent, in the presence of suitable Lewis acid and a suitable solvent.
In an aspect, the present invention provides that the compound (2), i.e., 2-Bromo-5-chloro-4-methylphenol (2) is prepared by two methods, i.e., method A and method B.
In another embodiment, a method A for the preparation of a compound (2), i.e., 2-Bromo-5-chloro-4-methylphenol (2) comprises the step of charging a reactor with ethylene dichloride (EDC), followed by addition of compound (1), i.e., 3-Chloro-4-methylphenol and mandelic acid to obtain a mixture. The mixture is stirred for suitable period of around 25 minutes to 30 minutes followed by portion-wise addition of N-Bromosuccinimide to obtain a reaction mass.
The reaction mass as obtained is slowly warmed at a temperature range of 55oC to 60oC. The reaction is monitored by TLC and HPLC and after completion, the reaction mass is filtered, wherein, the residue is washed with ethylene dichloride (EDC). Further, the combined organic layer is washed with water, brine and dried over anhydrous Sodium sulfate, filtered, concentrated to furnish a compound (2), i.e., 2-Bromo-5-chloro-4-methylphenol, after purification, HPLC purity (area): 95%, Yield: 173 g, 78%.
In another embodiment, a method B for the preparation of a compound (2), i.e., 2-Bromo-5-chloro-4-methylphenol (2) comprises the step of charging a reactor with ethyl acetate, followed by addition of compound (1), i.e., 3-Chloro-4-methylphenol and dimethylsulfoxide (DMSO) to obtain a mixture. The mixture is stirred for suitable period of around 25 minutes to 30 minutes. Further, aqueous solution of Hydrogen Bromide (HBr) is added portion-wise to the mixture at a temperature range of 55oC to 60oC to. The reaction is monitored by TLC and HPLC and after completion, the organic layer is separated. The aqueous layer is washed with ethyl acetate. The combined organic layer is further washed with water, brine and dried over anhydrous Sodium sulfate, filtered, concentrated to furnish to furnish a compound (2), i.e., 2-Bromo-5-chloro-4-methylphenol, after purification, HPLC purity (Area): 98%, Yield: 168.8 g, 76%.
In another embodiment, the present invention obtains a compound-(3), i.e., 6-bromo-3-chloro-2-(chloromethyl)-4-methylphenol by halomethylation of the compound-(2) in the presence of a formylating agent and a Lewis acid.
In an embodiment, the present invention provides a method for preparing a compound-(3), i.e., 6-Bromo-3-chloro-2-chloromethyl-4-methylphenol, wherein, the method comprises adding the compound-(2), i.e., 2-Bromo-5-chloro-4-methylphenol in a charged concentrated HCl followed by addition of Lewis acid such as ZnCl2, to obtain a reaction mixture. The reaction mixture is stirred for a period of 15 to 20 minutes, followed by addition of paraformaldehyde in one lot to obtain a reaction mass and then the reaction mass is saturated with HCl gas. The reaction is stirred at room temperature and then warmed up to a temperature of 55oC to 60oC. The reaction is monitored by TLC and HPLC. After completion, the reaction mass is cooled to room temperature and extracted with a solvent such as ethylene dichloride. The combined organic layer is then washed with water, brine and dried over anhydrous Sodium sulphate, filtered, concentrated to furnish crude product, i.e., a compound-(3), 6-Bromo-3-chloro-2-chloromethyl-4-methylphenol. After purification, HPLC purity (area): 98%, Yield: 237.7 g, 83%.
In another embodiment, the present invention obtains a compound-(4), i.e., 6-bromo-3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl]phenol by reacting the compound-(3) with 2,2,2-trifluoroethan-1-ol in the presence of base.
In an embodiment, the present invention provides a method for preparing a compound-(4), 6-Bromo-3-chloro-4-methyl-2-(2,2,2-trifluoro-ethoxymethyl)-phenol, wherein, the method comprises charging the reactor with ethylene dichloride (EDC) followed by trifluoroethanol and potassium carbonate to obtain a reaction mixture. The reaction mixture is stirred for a period of 3 to 4 hours, wherein, tetrabutyl ammonium bromide is added followed by addition of the compound-(3), i.e., 6-Bromo-3-chloro-2-chloromethyl-4-methylphenol and a solvent such as ethylene dichloride (EDC) to obtain a reaction mass. The reaction mass is refluxed. The reaction is monitored by TLC and HPLC. After completion, the reaction mass is cooled to room temperature and filtered using filtration aid to obtain a solid cake. The solid cake is washed with ethylene dichloride (EDC). The combined organic layer is then washed with water, brine and dried over anhydrous Sodium sulphate, filtered, concentrated to furnish crude product, a compound-(4), i.e., 6-Bromo-3-chloro-4-methyl-2-(2,2,2-trifluoro-ethoxymethyl)-phenol, after purification, HPLC purity (area): 93%, Yield: 189.8 g, 80%.
In another embodiment, the present invention obtains a compound-(5), i.e., 3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl] phenol by reacting the compound-(4) in the presence of a dehalogenating agent.
In an embodiment, the present invention provides a method for preparing a compound-(5), i.e., 3-Chloro-4-methyl-2-(2,2,2-trifluoro-ethoxymethyl)-phenol (5), wherein, the method comprises charging a reactor with freshly distilled solvent such as isopropanol followed by addition of palladium (II) acetate, triphenyl phosphine, potassium hydroxide, and the compound-(4), i.e., 6-Bromo-3-chloro-4-methyl-2-(2,2,2-trifluoro-ethoxymethyl)-phenol and then refluxing to obtain a reaction mass. The reaction is monitored by TLC and HPLC. After completion, the solvent such as isopropanol is removed under reduced pressure to obtain a residue. The residue is diluted with ice cold water and extracted with ethyl acetate twice. The combined organic layer is then washed with brine and dried over anhydrous Sodium sulphate, filtered, concentrated to furnish crude product, compound-(5), i.e., 3-Chloro-4-methyl-2-(2,2,2-trifluoro-ethoxymethyl)-phenol. After purification, HPLC purity (area): 95%, Yield: 115.9 g, 94%.
In one of the embodiments, a compound-(9), i.e., 2-Chloro-4-methanesulfonyl-1-methyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene, is obtained by reacting the compound-(5), i.e., 3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl] phenol, with tosyl chloride in the presence of base to obtain the corresponding tosylate followed by its reaction with methyl thiol and subsequent oxidation with mild oxidizing agents.
In another embodiment, the method for preparing a compound-(9), i.e., 2-Chloro-4-methanesulfonyl-1-methyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene comprises a step of:
Step 5A: wherein, a reactor is charged with a solvent such as ethylene dichloride (EDC) followed by addition of a compound-(5), i.e., 3-chloro-4-methyl-2-(2,2,2-trifluoroethoxymethyl)-phenol under Nitrogen atmosphere, to obtain a reaction mixture. The reaction mixture is stirred for a period of 20 minutes and then Triethylamine is added and the mixture is again stirred for a period of 20 minutes, followed by addition of p-toluenesulfonyl chloride. The reaction is monitored by TLC and HPLC. After completion, the reaction mass is washed with water, brine and organic layer was dried over anhydrous Sodium sulphate, filtered, concentrated to furnish crude tosylate. HPLC purity (area): 95%, Yield: 153.7 g, 96 %.
Step 5B: wherein, an autoclave reactor is charged with a solvent such as ethylene dichloride (EDC) followed by addition of Tosylate as obtained in Step 5A, wherein, tetrabutyl ammonium bromide is further added to obtain a reaction mass. The reaction mixture is stirred for a period of 20 minutes followed by addition of a catalyst. Methane thiol is then purged. The reaction mixture is heated to a temperature of 80oC. The reaction is monitored by TLC and HPLC by drawing the samples at regular time interval. After completion, the reaction mass is diluted with a solvent such as ethylene dichloride, washed with Aqueous NaOH (20%), water, brine and organic layer is dried over anhydrous Sodium sulphate, filtered, concentrated to furnish crude product, 2-Chloro-1-methyl-4-methylsulfanyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene. After purification, HPLC purity (area): 95%, Yield: 74.4 g, 75 %.
Step 5C: charging a reactor with a solvent such as methanol followed by the addition of product obtained in step 5B along with sodium tungstate, dihydrate to obtain a reaction mixture. The reaction mixture is stirred for a period of 20 minutes followed by dropwise addition of hydrogen peroxide (30% Aqueous solution) at room temperature. After complete addition of hydrogen peroxide, the reaction mass is stirred at room temperature. The reaction is monitored by TLC and HPLC. After completion, the solid material is filtered and treated as first crop. The filtrate is quenched with sodium thiosulfate and concentrated in vacuo to obtain residue. The residue is dissolved in solvent such as ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to furnish second crop. After purification, HPLC purity (Area): 95%, Yield: 140.6 g, 95 %.
In an embodiment, the compound (5) i.e., 3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl] phenol, after tosylation followed by treatment with MeSH/Base, is oxidized using a mild oxidising agent which will oxidize Sulfide to the corresponding sulfone group, furnishing compound (9).
In one of the embodiments, a compound (10), i.e., 1-(bromomethyl)-2-chloro-4-methanesulfonyl-3-[(2,2,2-trifluoroethoxy)methyl]benzene, is obtained by reacting the compound (9), at benzylic position by halogenating reagents in presence of radical initiator.
In another embodiment, the present invention provides that a compound-(10), i.e., 1-Bromomethyl-2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene is prepared by method A and method B.
In an embodiment, the method A for preparing a compound-(10), i.e., 1-Bromomethyl-2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene, comprises charging a reactor with a solvent such as ethylene dichloride (EDC) followed by addition of a compound-(9), i.e., 2-Chloro-4-methanesulfonyl-1-methyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene and azobisisobutyronitrile (AIBN), to obtain a reaction mixture. The reaction mixture is stirred for a period of 10 minutes and then hydrogen bromide (HBr) and hydrogen peroxide (H2O2) are added dropwise simultaneously at a temperature of 50oC to 55oC to obtain a reaction mass. The reaction is monitored by TLC and HPLC. After completion, the reaction mass is diluted with ethylene dichloride (EDC), washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to furnish a compound-(10), i.e., 1-Bromomethyl-2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene. After purification, HPLC purity (Area): 95%, Yield: 118.6 g, 74 %.
In an embodiment, the method B for preparing a compound-(10), i.e., 1-Bromomethyl-2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene, comprises charging a reactor with acetonitrile followed by addition of the compound-(9), i.e., 2-Chloro-4-methanesulfonyl-1-methyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene an azobisisobutyronitrile (AIBN), to obtain a reaction mixture.
The reaction mixture is stirred for a period of 10 minutes and then N-Bromo succinimide is added portion wise at a temperature of 50oC to 55oC, to obtain a reaction mass. The reaction is monitored by TLC and HPLC. After completion, the reaction mass is filtered. The filtrate is concentrated under reduced pressure, to obtain a residue. The residue is extracted with ethylene dichloride (EDC). The organic layer is washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to furnish a compound-(10), i.e., 1-Bromomethyl-2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene. After purification, HPLC purity (Area): 95%, Yield: 71.6 g, 67 %.
In one of the embodiments, a compound-(11), i.e., 2-[2-Chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzyl]-cyclohexane-1,3-dione, is obtained by reacting the compound (10) with 1,3-Cyclohexadione in presence of base followed by rearrangement in the presence of an acetone cyanohydrin.
In an embodiment, the present invention provides a method for preparing a compound-(11), i.e., 2-[2-Chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl) benzyl]-cyclohexane-1,3-dione (11), wherein, the method comprises charging a reactor with N,N-dimethylformamide followed by addition of tetrabutyl ammonium bromide, 1,3-Cyclohexadione and potassium carbonate to obtain a reaction mixture. The reaction mixture is stirred for a period of 10 minutes, and then heated to a temperature of 90oC to obtain a reaction mass. The reaction mass is stirred at this temperature for a period of 45 minutes. Further, the compound-(10), i.e., 1-Bromomethyl-2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene in dimethylformamide (DMF) are added dropwise to the reaction mass at the same temperature. The reaction is monitored by TLC and HPLC. After completion, the reaction mass is filtered. The filtrate is concentrated under reduced pressure to obtain a residue. The residue is extracted with ethylene dichloride (EDC). The organic layer is washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to furnish a compound-(11), i.e., 2-[2-Chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl) benzyl]-cyclohexane-1,3-dione. After purification, HPLC purity (Area): 95%, Yield: 64.8 g, 79 %.
In one of the embodiments, the compound-(11) is oxidized in the presence of an oxidizing agents to furnish the target compound, i.e., Tembotrione of Formula (I).
The process for preparing Tembotrione of formula (I) disclosed according to the present invention yields Tembotrione with purity of around 95% and a yield of above 80%.
In an embodiment, the present invention provides an alternative and improved method for preparing Tembotrione of formula (I), wherein, the method comprises charging a reactor with fluorobenzene and Dimethyl sulfoxide (DMSO) followed by addition of a compound-(11), i.e., 2-[2-Chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)benzyl]-cyclohexane-1,3-dione and 2-Iodoxybenzoic acid (IBX) in a single portion to obtain a reaction mixture. The reaction mixture is stirred at room temperature for a period of 15 minutes and then refluxed for 12 hours, to obtain a reaction mass. The reaction is monitored by TLC and HPLC. After completion, the reaction mass is filtered. The filtrate is diluted with ethyl acetate. The organic layer is washed with water, saturated solution of NaHCO3, water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to furnish Tembotrione (I). After purification, HPLC purity (Area): 95%, Yield: 41.8 g, 85%.
In an embodiment, the reactions mentioned herein were carried out at a temperature of from 0? to 200? for a period of about 1 hour to about 24 hours and at a pressure of from an atmospheric pressure to 50 bar.
In an embodiment, the purity is determined by high-performance liquid chromatography (HPLC) analysis or thin layer chromatography (TLC).
According to another aspect, there is provided a process for preparing agrochemical composition comprising highly pure and stable Tembotrione obtained as per the process disclosed herein. Yet in another embodiment, agrochemical compositions comprise at least a bio-active effective amount of highly pure and stable Tembotrione obtained by the processes disclosed herein. The agrochemical compositions further contain one or more agrochemically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
While preferred embodiments and examples have been shown and described, it is to be understood that various further modifications will be apparent to those skilled in the art.
TECHNICAL ADVANCEMENT /ADVANTAGES
The present disclosure described hereinabove has several technical advantages including, but not limited to, the realization of an alternative and improved process for the preparation of a Tembotrione of formula (I), that:
1. the process of the present invention is economically advantageous and cost-effective process, with high purity and yield of Tembotrione of formula (I) on a commercial scale;
2. the process of the present invention is processed with reduced or minimal waste generation and shows to have an improved reaction rate, minimized side reaction and/or formation of by-products;
3. the process of the present invention involves less expensive and readily available reagents and solvents and thus, is industrially and economically robust process with safe operations;
4. the process of the present invention generates less effluents, short residence time of the material, high selectivity and involves less equipment investment, manufacturing cost savings;
5. the process of the present invention involves reduced material consumption, and the amounts of by-products in the final product is also reduced and environment friendly;
6. the process of the present invention employs less toxic and easily available reagents;
7. the process of the present invention is fast, highly efficient and easily operable and involves mild reaction conditions;
8. the process of the present invention involves simple filtration method and zero effluents and requires no further purification and recover and reuse all the solvents used in the process.
The present invention has the advantage of short residence time of the material, high selectivity, high yield, less equipment investment, manufacturing cost savings, reduced material consumption, reducing the amount of by-products in the final product.
Accordingly, the entire process is technically advanced over the conventional process, continuous, low energy consumption, an efficient and feasible continuous synthesis of Tembotrione. Thus, present process is rapid and industrially viable. Therefore, the present invention involves technical advance as compared to the existing knowledge or having economic significance or both and that makes the invention not obvious to a person skilled in the art.
EXAMPLES
Although the content of the present invention is further specifically explained using examples, the present invention is not limited to the following examples as long as the gist of the present invention is not exceeded. The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the invention.
Tembotrione (Formula I) is synthesized by sequential reactions starting from a compound (1). The compound (1) is subjected to the bromination using brominating agents like but not limited to Bromine in acetic acid, Bromine in water, HBr and H2O2, and alike either neat or using solvents including but not limited to ethylene dichloride, acetonitrile, carbon tetrachloride, chlorobenzene, o-dichlorobenzene to furnish a compound (2), wherein, the said bromination is carried out at a temperature of from 0oC to 180oC for a period of 1 hour to 24 hours. The more preferred temperature range is from 25oC to 180oC and at pressure of from an atmospheric pressure to 50 bar.
The compound (2) is then chloromethylated using formylating agents like para-formaldehyde or formalin or alike in presence of Lewis acid like but not limited to zinc chloride, aluminium chloride or ferric chloride to furnish a compound (3) which is alkylated with Trifluoroethyl alcohol using bases known to the skilled in the art to obtain a compound (4). The said reaction of chloromethylation is carried out at a temperature of from 0oC to 200oC for a period of 1 hour to 24 hours. The more preferred temperature range is from 25oC to 200oC and at pressure of from an atmospheric pressure to 10 bar. The compound (4) is debrominated to give a compound (5) at a temperature of from 0oC to 200oC for a period of 1 hour to 24 hours. The more preferred temperature range is from 25oC to 200oC and at pressure of from an atmospheric pressure to 10 bar.
The compound (5) is subjected to tosylation, followed by nucleophilic substitution and oxidation using the reaction conditions known to the skilled in the art to provide a compound (9), which on bromination provides a compound (10) which is then treated with 1,3-Cyclohexadione in the presence of base followed by rearrangement in the presence of acetone cyanohydrin to obtain a compound (11). The compound (11) is oxidized in the presence of an oxidizing agents to furnish the target compound, i.e., Tembotrione of Formula (I).
The selected starting material is optimally substituted to get desired selectivity and improved yield for the proposed scheme.
The following is the reaction scheme of the present invention:

Scheme-1
Example 1: Preparation of 2-Bromo-5-chloro-4-methylphenol (2)

Method A: N-Bromosuccinimide (NBS), Mandelic acid, Acetonitrile or Methyl cyanide (MeCN), H2O, room temperature, Overnight
Method B: Hydrogen Bromide (HBr) (48%), Dimethyl sulfoxide (DMSO), Ethyl acetate (EtOAc), 60oC, 8 hours
Method A:
A four necked glass reactor (2 Lit) fitted with condenser, thermometer pocket, thermometer, mechanical stirrer was charged with ethylene dichloride (EDC) (460 mL) followed by 3-Chloro-4-methylphenol (147.4 g). Mandelic acid (31.14 g) was added to this. The mixture was stirred for 30 minutes. N-Bromosuccinimide (210 g) was added portion-wise. The reaction mass was slowly warmed to 55oC – 60oC. The reaction was monitored by TLC and HPLC. After completion, the reaction mass was filtered. The residue was washed with ethylene dichloride (EDC). The combined organic layer was washed with water, brine and dried over anhydrous sodium sulfate, filtered, concentrated to furnish a compound-(2), i.e., 2-Bromo-5-chloro-4-methylphenol. After purification, HPLC purity (area): 95%, Yield: 173 g, 78%.
Method B:
A four necked glass reactor (2 Lit) fitted with condenser, thermometer pocket, thermometer, mechanical stirrer was charged with Ethyl acetate (500 mL) followed by 3-Chloro-4-methylphenol (146 g). Dimethyl sulfoxide (DMSO) (40 g) was added to this. The mixture was stirred for 30 minutes. Hydrogen Bromide (HBr) (48% Aqueous solution, 308 g) was added portion-wise at 60oC. The reaction was monitored by TLC and HPLC. After completion, the organic layer was separated. The Aqueous layer was washed with ethyl acetate. The combined organic layer was washed with water, brine and dried over anhydrous Sodium sulfate, filtered, concentrated to furnish a compound-(2), i.e., 2-Bromo-5-chloro-4-methylphenol. After purification, HPLC purity (Area): 98%, Yield: 168.8 g, 76%.

Example 2: Preparation of 6-Bromo-3-chloro-2-chloromethyl-4-methylphenol (3)

A four necked glass reactor (2 Lit) fitted with condenser, thermometer pocket, thermometer, mechanical stirrer was charged with Concentrated HCl (192.3 g). 2-Bromo-5-chloro-4-methylphenol (255.1 g) was suspended in the reactor followed by addition of Lewis acid such as ZnCl2 (47.1 g). The reaction mixture was stirred for 15-20 minutes. Paraformaldehyde (46.31 g) was added in one lot and then the reaction mass was saturated with HCl gas. The reaction was stirred at room temperature and then warmed up to 55o C. The reaction was monitored by TLC and HPLC. After completion, the reaction mass was cooled to room temperature and extracted with ethylene dichloride. The combined organic layer was washed with water, brine and dried over anhydrous Sodium sulphate, filtered, concentrated to furnish crude product, 6-Bromo-3-chloro-2-chloromethyl-4-methylphenol. After purification, HPLC purity (area): 98%, Yield: 237.7 g, 83%
Example 3: Preparation of 6-Bromo-3-chloro-4-methyl-2-(2,2,2-trifluoro-ethoxymethyl)-phenol (4)

A four necked glass reactor (2 Lit) fitted with condenser, thermometer pocket, thermometer, mechanical stirrer was charged with ethylene dichloride (EDC) (250 mL) followed by Trifluoroethanol (78.7 g). Potassium carbonate (229.5 g) was charged in a single lot. The reaction mixture was stirred for 3-4 hours. Tetrabutyl ammonium bromide (12.6 g) was added followed by 6-Bromo-3-chloro-2-chloromethyl-4-methylphenol (210.5 g) in ethylene dichloride (EDC) (500 mL) was added. The reaction mass was refluxed. The reaction was monitored by TLC and HPLC. After completion, the reaction mass was cooled to room temperature and filtered using filtration aid. The solid cake was washed with ethylene dichloride (EDC) (2 X 100 mL). The combined organic layer was washed with water, brine and dried over anhydrous Sodium sulphate, filtered, concentrated to furnish crude product, 6-Bromo-3-chloro-4-methyl-2-(2,2,2-trifluoro-ethoxymethyl)-phenol, After purification, HPLC purity (area): 93%, Yield: 189.8 g, 80%.
Example 4: Preparation of 3-Chloro-4-methyl-2-(2,2,2-trifluoro-ethoxymethyl)-phenol (5)

A four necked glass reactor (1 Lit) fitted with condenser, thermometer pocket, thermometer, mechanical stirrer was charged with freshly distilled Isopropanol (510 mL) followed by Palladium (II) acetate (0.120 g), Triphenyl phosphine (0.55 g), Potassium hydroxide (67.2 g), Compound (4) (182.2 g) and refluxed. The reaction was monitored by TLC and HPLC. After completion, isopropanol was removed under reduced pressure to obtain a residue. The residue was diluted with ice cold water and extracted with ethyl acetate twice. The combined organic layer was washed with brine and dried over anhydrous Sodium sulphate, filtered, concentrated to furnish crude product, 3-Chloro-4-methyl-2-(2,2,2-trifluoro-ethoxymethyl)-phenol. After purification, HPLC purity (area): 95%, Yield: 115.9 g, 94%.
Example 5: Preparation of 2-Chloro-4-methanesulfonyl-1-methyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene (9)

Step 5A:
A four necked glass reactor (1 Lit) fitted with condenser, thermometer pocket, thermometer, mechanical stirrer was charged with Ethylene dichloride (EDC) (350 mL) followed by 3-chloro-4-methyl-2-(2,2,2-trifluoroethoxymethyl)-phenol (114.1 g) under Nitrogen atmosphere. The reaction mixture was stirred for 20 minutes. Triethylamine (93.5 g) was added and the mixture is stirred for 20 minutes, followed by addition of p-toluenesulfonyl chloride (84.2 g). The reaction was monitored by TLC and HPLC. After completion, the reaction mass was washed with water, brine and organic layer was dried over anhydrous Sodium sulphate, filtered, concentrated to furnish crude tosylate. HPLC purity (area): 95%, Yield: 153.7 g, 96 %.
Step 5B:
In an autoclave reactor (2 Lit) fitted with condenser, thermometer pocket, thermometer, mechanical stirrer was charged with Ethylene dichloride (EDC) (350 mL) followed by Tosylate obtained in Step 5A (153.7 g). Tetrabutyl ammonium bromide (5.84 g) was added. The reaction mixture was stirred for 20 minutes. A catalyst (5 mol%) was added. Methane thiol was purged. The reaction mixture was heated to 80 oC. The reaction was monitored by TLC and HPLC by drawing the samples at regular time interval. After completion, the reaction mass was diluted with Ethylene dichloride (200 mL), washed with Aqueous NaOH (20%), water, brine and organic layer was dried over anhydrous Sodium sulphate, filtered, concentrated to furnish crude product. After purification, HPLC purity (area): 95%, Yield: 74.4 g, 75 %.
Step 5C:
A four necked glass reactor (1 Lit) fitted with condenser, thermometer pocket, thermometer, mechanical stirrer was charged with Methanol (410 mL) followed by the Step 5B product (147.37 g). Sodium tungstate, dihydrate (8.3 g) was added. The reaction mixture was stirred for 20 mins. Hydrogen peroxide (245.8 g, 30% Aqueous solution) was added dropwise at room temperature. After complete addition of hydrogen peroxide, the reaction mass was stirred at room temperature. The reaction was monitored by TLC and HPLC. After completion, the solid material was filtered and treated as first crop. The filtrate was quenched with sodium thiosulfate and concentrated in vacuo to obtain residue. The residue was dissolved in Ethyl acetate (300 mL), washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to furnish second crop. After purification, HPLC purity (Area): 95%, Yield: 140.6 g, 95 %
Example 6: Preparation of 1-Bromomethyl-2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene

Method A: Hydrogen Bromide (HBr), Hydrogen peroxide (H2O2), Azobisisobutyronitrile (AIBN), Ethylene Dichloride (EDC), 10oC to reflux
Method B: N-Bromosuccinimide (NBS), Acetonitrile (can), 10oC to reflux
Method A: A four necked glass reactor (1 Lit) fitted with condenser, thermometer pocket, thermometer, mechanical stirrer was charged with ethylene dichloride (EDC) (450 mL) followed by 2-Chloro-4-methanesulfonyl-1-methyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene (139.2 g) followed by azobisisobutyronitrile (AIBN) (3.29 g). The reaction mixture was stirred for 10 minutes. HBr (48%, 81.7 g), H2O2 (30%, 53.14 g) were added dropwise simultaneously at 50oC to55oC. The reaction was monitored by TLC and HPLC. After completion, the reaction mass was diluted with ethylene dichloride (EDC), washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to furnish 1-Bromomethyl-2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene. After purification, HPLC purity (Area): 95%, Yield: 118.6 g, 74 %.
Method B: A four necked glass reactor (1 Lit) fitted with condenser, thermometer pocket, thermometer, mechanical stirrer was charged with Acetonitrile (250 mL) followed by 2-Chloro-4-methanesulfonyl-1-methyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene (92.8 g) followed by azobisisobutyronitrile (AIBN) (1.9 g). The reaction mixture was stirred for 10 minutes. N-Bromo succinimide (60.5 g) was added portion wise at 50 oC to55oC. The reaction was monitored by TLC and HPLC. After completion, the reaction mass was filtered. The filtrate was concentrated under reduced pressure. The residue was extracted with ethylene dichloride (EDC). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to furnish 1-Bromomethyl-2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene. After purification, HPLC purity (Area): 95%, Yield: 71.6 g, 67 %.
Example 7: Preparation of 2-[2-Chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl) benzyl]-cyclohexane-1,3-dione (11)

A three necked RB flask (250 mL) along with condenser, thermometer pocket, thermometer, mechanical stirrer was charged with N,N-dimethylformamide (150 mL) followed by Tetrabutyl ammonium bromide (3.25 g), 1,3-Cyclohexadione (25.1 g) and potassium carbonate (62.6 g) The reaction mixture was stirred for 10 minutes, and then heated to 90oC. The reaction mass was stirred at this temperature for 45 minutes. The compound-(10), i.e., 1-Bromomethyl-2-chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene (82.5 g) in dimethylformamide (DMF) was added dropwise at the same temperature. The reaction was monitored by TLC and HPLC. After completion, the reaction mass was filtered. The filtrate was concentrated under reduced pressure. The residue was extracted with ethylene dichloride (EDC). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to furnish a compound-(11), i.e., 2-[2-Chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl) benzyl]-cyclohexane-1,3-dione. After purification, HPLC purity (Area): 95%, Yield: 64.8 g, 79 %.
Example 8: Preparation of Tembotrione (I)

A three necked RB flask (500 mL) along with condenser, thermometer pocket, thermometer, mechanical stirrer was charged with fluorobenzene and DMSO (2:1) (150 mL) followed by compound-(11), i.e., 2-[2-Chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)benzyl]-cyclohexane-1,3-dione (51.55 g). 2-Iodoxybenzoic acid (IBX) (103.6 g) was added in a single portion. The reaction mixture was stirred at room temperature for 15 minutes and then refluxed for 12 hours. The reaction was monitored by TLC and HPLC. After completion, the reaction mass was filtered. The filtrate was diluted with ethyl acetate. The organic layer was washed with water, saturated solution of NaHCO3, water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to furnish Tembotrione (I). After purification, HPLC purity (Area): 95 %, Yield: 41.8 g, 85 %.
The present invention is more specifically explained by examples given above. However, it should be understood that the scope of the present invention is not limited by the examples in any manner. It will be appreciated by any person skilled in this art that the present invention includes the given examples and further can be modified and altered without departing from the novel teachings and advantages of the invention which are intended to be included within the scope of the invention.
,CLAIMS:I/WE CLAIM:

1. An alternative and improved process for the preparation of a Tembotrione of formula (I), comprising:
a) reacting a compound-(1), i.e., 3-chloro-4-methylphenol with a halogenating agent, in the presence of suitable Lewis acid and a suitable solvent, to obtain a compound-(2), i.e., 2-bromo-5-chloro-4-methylphenol;
b) halomethylation of the compound-(2) in the presence of a formylating agent and a Lewis acid, to obtain a compound-(3), i.e., 6-bromo-3-chloro-2-(chloromethyl)-4-methylphenol;
c) reacting the compound-(3) with 2,2,2-trifluoroethan-1-ol in the presence of base, to obtain a compound-(4), i.e., 6-bromo-3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl]phenol;
d) reacting the compound-(4) in the presence of a dehalogenating agent and a catalyst, to obtain a compound-(5), i.e., 3-chloro-4-methyl-2-[2,2,2-trifluoroethoxy) methyl] phenol;
e) reacting the compound-(5) with tosyl chloride in the presence of base followed by methyl thiol in presence of base and a catalyst and subsequent oxidation with a mild oxidizing agent, to obtain a compound-(9), i.e., 2-Chloro-4-methanesulfonyl-1-methyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzene;
f) reacting the compound-(9), at benzylic position using halogenating reagents in presence of radical initiator to obtain a compound-(10), i.e., 1-(bromomethyl)-2-chloro-4-methanesulfonyl-3-[(2,2,2-trifluoroethoxy)methyl]benzene;
g) reacting the compound (10) with 1,3-Cyclohexadione in a suitable solvent, and in the presence of base to obtain a compound-(11), i.e., 2-[2-Chloro-4-methanesulfonyl-3-(2,2,2-trifluoro-ethoxymethyl)-benzyl]-cyclohexane-1,3-dione;
h) oxidizing the compound-(11) in the presence of an oxidizing agents to furnish the target compound, i.e., Tembotrione of Formula (I).

2. The process according to claim 1, wherein, the halogenating agent is selected from the group comprising bromine, chlorine, fluorine, iodine, or combination thereof.

3. The process according to claims 1-2, wherein the halogenating agent is combined with acetic acid, water, hydrogen, and/or H2O2 or combination thereof.

4. The process according to claim 1, wherein, the radical initiator is selected from the group comprising azobisisobutyronitrile (AIBN), benzoyl peroxide or combination thereof.

5. The process according to claim 1, wherein, the base is selected from the group comprising diisopropylamine, diisopropylethylamine, triethylamine, dimethylamine, trimethyl amine, pyridine, N-methylmorpholine, 3-picoline, 2-picoline, 4-picoline, sodium carbonate, potassium carbonate, calcium hydroxide or combination thereof.

6. The process according to claim 1, wherein, the suitable solvent is selected from the group comprising N-dimethylformamide, isopropanol, benzene, dichloromethane, 1,2-dichloroethane, chloroform, 1, 4-dioxane, diethyl ether, acetic acid, hydrogen peroxide, o-dichlorobenzene ethylene dichloride, carbon tetrachloride, chlorobenzene, dichlorobenzene, tetrahydrofuran and acetonitrile, ethyl acetate, acetone, dimethylsulfoxide, Dimethyl sulfoxide (DMSO), cyclohexane, hexane, heptane, toluene, xylene, etc. or combination thereof.

7. The process according to claim 1, wherein, the formylating agent is selected from the group comprising para-formaldehyde, formalin, formic acid, methyl formate, N,N-dimethylformamide, diazomethane, cyanogen bromide, hydrogen cyanide etc or combination thereof.

8. The process according to claim 1, wherein, the dehalogenating agent used is selected from the group comprising Zinc, Iron (Fe), sodium, hydrogen gas, Tin (II) chloride, sodium borohydride, sodium amalgam (Na/Hg) etc or combination thereof.

9. The process according to claim 1, wherein, the oxidizing agent is selected from the group comprising hydrogen peroxide, potassium permanganate, potassium dichromate, chlorine, sodium dichromate, chromium trioxide, nitric acid, perchloric acid, osmium tetraoxide, iodine, fluorine etc. or combination thereof.

10. The process according to claim 1, wherein, the Lewis acid is selected from the group comprising Zinc chloride (ZnCl2), Aluminium Chloride (AlCl3), Ferric Chloride (FeCl3), Boron Trifluoride (BF3), Boron Trichloride (BCl3), Titanium tetrachloride (TiCl4), Antimony Pentafluoride (SbF5), Thionyl chloride (SOCl2), Copper Chloride (CuCl2) etc, or combination thereof.

11. The process according to claim 1, wherein, the catalyst is selected from palladium (II) acetate, triphenyl phosphine, sodium tungstate, dihydrate, Pd/C or Raney Nickel, Pt/C, PtO2/C, Na2WO4.2H2O, (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl or (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO), Cobalt(II) acetate, Co-napthenate etc. or combination thereof.

12. The process according to claim 1 where the reaction is carried out at a temperature in the range from 0? to 200?, preferably 55°C to 60°C.

13. The process according to claim 1, wherein the reaction is carried out for a period of about 1 hour to about 24 hours.

14. The process according to claim 1, wherein the reaction is carried out at a pressure of from an atmospheric pressure to 50 bar.

15. The process as claimed in claim 1, wherein yield of Tembotrione of formula (I) is in the range of 70% to 85% and purity is 95%.

16. An agrochemical composition, wherein the composition comprises at least a bio-active effective amount of Tembotrione of formula (I) as obtained by the process claimed in claims 1-15.

17. The agrochemical composition as claimed in claim 16, wherein the composition further comprises one or more agrochemically acceptable excipients.

18. A process for preparing the agrochemical composition comprising Tembotrione of formula (I) as claimed in claims 16-17.