WO2011005127A1

WO2011005127A1 - Stable crystalline polymorph of 2-(2-chloro-4-mesyl- benzoyl)-cyclohexane/-1,3-dione and process for preparing the same

Info

Publication number: WO2011005127A1
Application number: PCT/PT2010/000028
Authority: WO
Inventors: José NEVES; Luis Teixeira; Surendra Bhatia; Martin Ermrich
Original assignee: Sapec-Agro, Sa
Priority date: 2009-07-07
Filing date: 2010-07-06
Publication date: 2011-01-13
Also published as: PT104664A; EP2451778A1

Abstract

The present invention relates to a new stable crystalline polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-1,3-dione and to a process for preparing the same. More particularly, it relates to compositions having said polymorph for controlling unwanted plants. The process for preparing crystalline polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-1,3-dione comprising the following steps of: 1) preparation of 4-sulfomethyl-2-chloro benzoyl chloride; 2)preparation of enol ester derivative; 3)rearrangement of enol ester derivative to 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-1,3-dione; and 4) purification of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-1,3-dione. The polymorphic structure is assessed using infra-red and Raman spectra and X-ray crystallography data. The polymorph has a powder X-Ray diffraction spectrum with characteristic peaks at 2? = 17.2°, 17.6°, 19.1°, 21.0°, 26.0° and 28.7°. A stable formulation of the above mentioned polymorph is used as herbicide.

Description

"STABLE CRYSTALLINE POLYMORPH OF 2-(2-CHLORO-4-MESYL- BENZOYL)-CYCLOHEXANE-1 ,3-DIONE AND PROCESS FOR PREPARING

THE SAME"

FIELD OF THE INVENTION

The present invention relates to a new stable crystalline polymorph of 2-(2-cbloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione and to a process for preparing the same. More particularly, it relates to compositions having said polymorph for controlling unwanted plants.

BACKGROUND OF THE INVENTION

The manufacture of biologically active compounds like pharmaceuticals, agrochemicals and other fine chemicals involves synthesis, purification, isolation and recovery by re crystallisation. Many of these biologically active compounds exhibit polymorphism: the ability of a substance to exist in two or more solid forms with different arrangement of atoms or molecules. Different polymorphs of a biologically active compound can have different physical properties, which can be advantageously used to select a specific polymorph for a specific application. There has been an increasingly demand in the development of biologically active compounds with specific crystal polymorphism.

In the agrochemical field, 1 ,3-cyclohexanedione based molecules have gained importance due to their good efficacy as herbicides in maize, particularly against broad range of monocotyledon and dicotyledon weeds. These compounds were first reported by Stauffer Chemical, U.S. Patent No. 4775411 (1988). The process disclosed therein involves the rearrangement of an enol ester derivative using triethylamine as base, and acetone cyanohydrins as catalyst. One of the derivative thus produced, namely 2-(2-chloro-4-mesyl-benzoyi)- cyclohexane-l,3-dione was of commercial importance.

Although the product could exist in two or more different polymorphs, no study or report was available to define specific crystal polymorphs.

Subsequent patent documents, namely US 4775411; (1988) and EP 249150; (1991), disclose process improvements. The resulting product was characterized by melting point. Crystal polymorph studies of 2-(2-cUoro-4-mesyl-benzoyl)-cyclohexane- 1 ,3-dione were first reported in 2003, describing the existence of 2-(2-chloro-4-mesyl- benzoyl)-cyclohexane-l,3-dione in two forms, a metastable form I and a thermodynamically stable form II.

A procedure to recrystallize 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione form π using isopropanol as solvent was also described in European Patent EP 1517731 (2003).

SUMMARY OF THE INVENTION The present invention relates to a new stable crystalline polymorph of

2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione (so called Form III in the following description) and to a process for preparing the same. Resulting products from this Form III are efficient when applied as weed controlling agents. The new stable crystalline polymorph of 2-(2-chloro-4-mesyl-benzoyl)- cyclohexane-l,3-dione has a powder X-Ray diffraction spectrum with characteristic peaks at 2Θ = 17.2°, 17.6°, 19.1°, 21.0°, 26.0° and 28.7° (± 0.10° in each case). In one aspect, the crystalline polymorph of the invention has the following Lattice parameters: a = 10.326(6) A; b = 11.875(5) A; c = 12.130(5) A; β = 95.00(3)°; V = 1,481.7(18) A³. In another aspect, the crystalline polymorph of the invention has a density of about 1.474 g/cm³.

In another aspect, the crystalline polymorph of the invention has a molecular weight of about 328.78 and a volume per atom of about 17.6 A³.

The present invention also relates to a composition comprising a crystalline polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione as defined above.

In one aspect, the composition of the invention comprises at least one form of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione which differs from the polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l ,3-dione of the invention.

In another aspect, said composition comprises less than about 20% by weight of the at least one form of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-<lione which differs from the polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione of the invention.

Preferably the composition comprises less than about 5% by weight of the at least one form of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione which differs from the polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l ,3-dione of the invention.

In another aspect, said composition further comprising other herbicides.

Preferably said herbicides are selected from the group comprising sulfonylureas, chloroacetamides, dinitroanilines, triazines, isoxazoles, oxyacetamides and combinations thereof. The invention further relates to the use of the above composition for controlling unwanted plants, namely for controlling weeds selected from the group comprising Cyperus esculentus, Cyperus rotundas, Chenopodium spp., Amaranthus spp.. Datura stramonium, Polygonum aviculare and Solatium nigrum.

The present invention also relates to a process for preparing a crystalline polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l ,3-dione as defined in claim 1, comprising the steps of: 1) preparation of 4-sulfomethyl-2-chloro benzoyl chloride; 2) preparation of enol ester derivative; 3) rearrangement of enol ester derivative to 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione; and 4) purification of 2-(2-chloro- 4-mesyl-benzoyl)-cyclohexane-l,3-dione; wherein in step 1, a reaction of benzoic acid derivative with thionyl chloride in the presence of a catalyst is carried out to produce the benzoyl chloride derivative; in step 2, the benzoyl chloride derivative produced in step 1 is condensed with 1,3-cyclohexane-dione in the presence of a catalyst and a solvent to obtain an enol ester derivative; in step 3, the enol ester derivative of step 2 dissolved in a solvent is rearranged using catalytic amount of CN^"; and in step 4, the 2-(2-chloro-4- mesyl-benzoyl)-cyclohexane-l,3-dione is purified by dissolving it in mild alkaline conditions using an alkali solution; extracting using an organochloride solvent; and acidifying the resulting aqueous layer using an acid solution.

In one aspect, the catalyst of step 1 is DMF, the catalyst of step 2 is piperidine, the solvent of step 2 is acetonitrile and the solvent of step 3 is acetonitrile.

In another aspect, the concentration of the alkali solution is in the range of about 5%-20%.

Further, in another aspect, the alkali solution is selected from the group comprising sodium, potassium, alkaline earth metal salts and combinations thereof. In another aspect of the invention, said concentration of the acid solution is in the range of about 10-20% . In still another aspect, of the invention, in step 4 of the above process, the alkali solution is sodium hydroxide, the organochloride solvent is dichloroethane and the acid solution is hydrochloric acid.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows the powder X-Ray diffraction spectrum of Form III of 2-(2-chloro- 4-mesyl-benzoyl)-cyclohexane-l,3-dione. The strongest reflections are marked with arrows.

Fig. 2 shows the IR spectrum of Form UI of 2-(2-chloro-4-mesyl-benzoyl)- cyclohexane-l,3-dione in the range of 4000-700 cm^"1. Fig 3, 4 and 5 shows the Raman spectrum of Form III of 2-(2-chloro-4-mesyl- benzoyl)-cyclohexane-l,3-dione at Raman's shifts of 3150-2800 cm^'1, 1750-1000 cm ¹ and 950-200 cm ¹.

DETAILED DESCRIPTION OF THE INVENTION

In order to prepare a pure form of the new crystalline polymorph of 2-(2-chloro- 4-mesyl-benzoyl)-cyclohexane-l,3-dione, it is necessary to produce and control the purity of raw materials and intermediates. The key raw materials are 1,3-cyclohexane-dione and 4-sulfomethyl benzoic acid, which are commercially available in pure form.

The process for preparation of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3- dione of Form III Polymorph of the invention comprises the following steps: Step 1: Preparation of 4-sulfomethyl-2-chloro benzoyl chloride

The reaction of benzoic acid derivative with thionyl chloride in the presence of a catalyst, like DMF, is carried out to produce the respective benzoyl chloride derivative.

Step 2: Preparation of enol ester derivative

The benzoyl chloride derivative produced in step 1 is condensed with 1,3-cyclohexane-dione in the presence of piperidine as catalyst, and acetonitrile as solvent. The reaction is carefully monitored for the absence of starting materials, and the product thus obtained is an enol ester derivative.

Step 3: Rearrangement of enol ester derivative to 2-(2-chloro-4-mesyl-benzoyl)- cyclohexane-1 ,3-dione.

Enol ester dissolved in acetonitrile solvent is rearranged using catalytic amount of CN^". The CN^' can be provided by the use of KCN or Acetone cyanohydrin.

Step 4: Purification of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione to produce the specific Form III Polymorph of the invention.

2-(2-chloro-4-mesyl-benzoyl)-cyciohexane-l ,3-dione thus produced is further purified by dissolving it in mild alkaline conditions using an aqueous alkali solution at low concentration (5%-20%). The alkali solution may be any suitable solution. Preferably the alkali solution is selected from the group comprising sodium, potassium and alkaline earth metal salts and combinations thereof, which salts are, for example, hydroxides and carbonates. Unwanted by-products which cause instability, are extracted using an organochloride solvent, for example, dichlorethane. The resulting aqueous layer is acidified using a diluted acid solution, for example of hydrochloric acid, with a concentration in the range of about 10-20% , to produce 2-(2-chloro-4-mesyl-benzoyl)- cyclohexane-1 ,3-dione in pure form of specific Form HI crystal polymorph. The process of the invention provides a stable specific Form III of 2-(2-chloro-4- mesyl-benzoyl)-cyclohexane-l,3-dione having a powder X-Ray diffraction spectrum shown in Fig. 1 , with the relative intensities of the reflections versus 2Θ depicted in the following Table 1. Accordingly, Form III has characteristic peaks at 2θ = 17.2°, 17.6°, 19.1°, 21.0°, 26.0° and 28.7°, (± 0.10° in each case).

Table 1

Table 2 shows the crystallographic data of Form III of 2-(2-chloro-4-mesyl- benzoyl)-cyclohexane-l ,3-dione. Table 2

The X-Ray powder diffraction analysis was carried out using a STOE θ/θ- Diffractometer, Cu- Ka- radiation (λ= 1.5418 A); U = 40 kV, I = 40 mA; secondary beam monochromator: plane Graphite (002); scintillation counter; slits: 0,75 mm, 0,35 mm, 2 x 8 mm; angle region, step width, time/step: 2Θ= 4.0° - 35.0°, Δ2Θ = 0.04°, 5s. The analysis was carried out by filling the sample holder and the surface of the sample is carefully smoothed and adjusted against a knife edge.

The stable specific Form HI of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane- 1,3-dione according to the invention may be further characterized by IR and Raman spectroscopy. Accordingly, the invention further provides a stable specific Form III of

2-(2-cbloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione having an IR spectrum with the bands depicted in Table 3 and signals shown in Fig. 2. Table 3

[cm¹]

1667.0

1554.1

1405,0

1317.0

1159.7

1147.8

1092.7

966.1

934.3

890.4

790.3

777.4

756.5

FT-IR spectra were obtained using a B-Optics spectrometer, ALPHA-P model, from Broker. The analysis was carried out by placing the sample into the sample holder and taking the measure.

Form in of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione has a Raman spectrum with the bands depicted in Table 4 and the signals shown in Fig. 3 to Fig. 5.

Table 4

Raman spectra were acquired on a FT-Raman 960 spectrometer (Thermo Nicolet) equipped with an indium gallium arsenide (InGaAs) detector. Wavelength verification was performed using sulfur and cyclohexane. Each sample for analysis was prepared by placing the sample into a glass tube and positioning the tube in a gold-coated tube holder. Approximately 0.5 W of Nd: YVCU laser power (1064 nm excitation wavelength) was used to irradiate the sample. Each spectrum represents 256 co-added scans collected at a spectral resolution of 4 cm ¹. The stable crystal polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3- dione of the invention has physicochemical properties such that enable easy handling in formulations.

The stable crystal Form in polymorph of 2-(2-chloro-4-mesyl-benzoyl)- cyclohexane-1 ,3-dione of the present invention is particularly suitable for preparing solid and liquid formulations. Examples of said formulations are: granules, encapsulated granules, tablets, water-dispersible granules, water-dispersible powders, water- dispersible powders, dust formulations, suspension concentrates, oil-based suspension concentrates, suspoemulsions, or suspension concentrates for plant protection. Due to its stability, the stable crystal Form III polymorph of 2-(2-chloro-4-mesyl-benzoyl)- cyclohexane-l,3-dione is highly suitable for preparing compositions for controlling unwanted plants, alone or together with auxiliaries, carriers, and other active compounds.

The invention also relates to compositions comprising the stable Form III polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l ,3-dione and at least one form of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione which differs from Form HI polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione. Compositions comprising less than about 20% by weight of at least one form of 2-(2-chloro-4-mesyl- benzoyl)-cyclohexane-l,3-dione which differs from Form III polymorph of 2-(2-chloro-4- mesyl-benzoyl)-cyclohexane-l,3-dione are preferred. Preferably, compositions comprising less than about 15%, much preferably less than about 10%, and most preferably less than about 5%, by weight of at least one form of 2-(2-chloro-4-mesyl- benzoyl)-cyclohexane-l ,3-dione which differs from stable crystal Form III polymorph of 2-(2-chioro-4-mesyl-benzoyl)-cyclohexane-l,3-dione.

The stable crystal Form IH polymorph of 2-(2-chloro-4-mesyl-benzoyl)- cyclohexane-l,3-dione of the invention can be preferably employed as a plant protection agent, by controlling a wide range of Dicotyledonous and Monocotyledonous weeds selected from the group comprising Cyperus esculentus, Cyperus rotundus, Chenopodium spp. , Amaranthus spp. , Datura stramonium, Polygonum aviculare and Solarium nigrum.

The above compositions may comprise other herbicides in order to extend the range of weeds to be controlled, particularly some grasses. The herbicides are selected from the group comprising sulfonylureas, chloroacetamides, dinitroanilines, triazines, isoxazoles, oxyacetamides and combinations thereof.

The active compound can be formulated into granules, encapsulated granules, tablets, water-dispersible granules, water-dispersible tablets, water-dispersible powders, dust formulations, suspension concentrates, oil-based suspension concentrates, suspoemulsions, suspension concentrates or any other suitable formulations. These formulations are produced in a known manner, for example, by mixing the active compounds liquid solvents and/or solid carriers, optionally with the use of surfactants.

The following examples further illustrate some aspects of the invention but are not intended to limit its scope.

EXAMPLES Example 1:

Production of stable crystal structure of 2-(2-chloro-4-mesyl-benzoyl)- cydohexane-l ,3-dione a) Conversion of acid to acid chloride.

In a reactor fitted with an agitator, condenser, and scrubber with 10% sodium hydroxide solution, toluene (500ml) was charged followed by the 2-chloro-4- sulfomethylbenzoic acid (10Og) and catalytic amount of DMF (2ml). The reaction mixture was cooled to 0 ⁰C and thionyl chloride (5Og) was added slowly over a period of 3 hours keeping the temperature below 5 ⁰C. The reaction mixture was slowly heated to 50 ⁰C allowing the HCl and SCh formed to escape into the scrubber.

The end of the reaction was determined by absence of acid. The solvent was distilled off along with the excess thionyl chloride used for the reactor. The residue thus obtained (105 g) was used directly for the next step. b) Condensation for acid chloride with cyclohexanedione.

In a reactor fitted with an agitator, cyclohexanedione (6g), acid chloride (12g), acetonitrile (3SmI) and piperidine (ImI) were mixed at room temperature and the agitation was continued for 5 hours. The end of the reaction was checked by the absence of cyclohexanedione and the enol ester thus formed was obtained by the recovery of the acetonitrile followed by filtration of solid mass thus obtained. The purity of enol ester thus obtained was 97% . Enol ester was further purified by use of isopropanol.

c) Rearrangement of enol ester to 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3- dione.

5g of enol ester was taken up in a solvent acetonitrile, along with acetone cyanohydrin (0.1Sg) and triethylamine (2.Og) and reaction mixture was stirred at the room temperature for 10 hours. The solvent was distilled off. Ethylenedichloride (25ml) was added and the organic layer was washed with sodium bicarbonate solution (5%) to remove the hydrolyzed acid. The crude 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione was obtained by the distillation of EDC and it was recrystallized from methylene dichloride. The purity of crude 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione was 96% and 3.85g of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione was obtained.

d) Purification to obtain the Form III of 2-(2-chloro-4-mesyl-benzoyl)- cyclohexane-1 ,3-dione.

Crude 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l ,3-dione (2g) obtained above was dissolved in 5% sodium hydroxide (50 ml) and dichloroetnane (30ml) was added to remove the by-products. After agitating the reaction mixture for 30 minutes, the agitation was stopped and two layers were allowed to separate. The bottom organic layer was removed and the aqueous layer was acidified using 15% HCl solution to pH3-3.5.

The product thus obtained was filtered and dried to obtain 1.6 g of pure 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione and its characteristics were determined by use of XPRD.

Example 2:

Liquid Formulation of 2-(2<hloro-4-mesyl-benzoyl)-cycIohexane-l,3-dione (Form πi)

A pre-mix of water (45.3 g), MPG (9.Og), Atlox 4913 (3.4 g), Atlox 4894 (2.3 g), Brij-96 (9.9g) and AF9030 (0.1 g) was prepared. 30.5 g of Form HI polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-<lione, obtained in Example 1 was added and mixed until homogeneity. The formulation was milled twice in a Dyno-mill, maintaining the temperature of the product below 20 ⁰C. Then, AF9030 (0.1 g) and thickening agent (9.9 g) was added with gentle stirring.

Example 3:

Storage Properties The shelf life of the liquid formulation from Example 2 was determined by using the method described in QPAC Handbook, Volume J, MT46.3, pag. 128; Editors W Dobrat and A Martijn; Collaborative International Pesticides Analytical Council Limited, 2000. Samples obtained in the Example 2 were stored at 54 ⁰C for 14 days. After storage, the samples were brought to room temperature and compared to those freshly prepared. It was observed a slight phase separation but it was readily dispersed. The formulation properties of the formulation did not change after storage.

Claims

1. A crystalline polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione having a powder X-Ray diffraction spectrum with characteristic peaks at

2Θ = 17.2°, 17.6°, 19.1°, 21.0°, 26.0° and 28.7° (± 0.10° in each case).

2. The crystalline polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3- dione according to claim 1 having the following Lattice parameters: a = 10.326(6) A;

b = 11.875(5) A;

c = 12.130(5) A;

β = 95.00(3)°;

V = 1,481.7(18) A³.

3. The crystalline polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3- dione according to claim 1 or 2 having a density of about 1.474 g/cm³.

4. The crystalline polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3- dione according to any of preceding claims having a molecular weight of about 328.78 and a volume per atom of about 17.6 A³.

5. A composition comprising a crystalline polymorph of 2-(2-chloro-4-mesyl- benzoyl)-cyclohexane-l ,3-dione as defined in any of the preceding claims.

6. The composition according to claim 5, further comprising at least one form of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione which differs from the polymorph of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione of any of claims 1-4.

7. The composition according to preceding claim, comprising less than about 20% by weight of the at least one form of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane- 1,3-dione which differs from the polymorph of 2-(2-chloro-4-mesyl-benzoyl)- cyclohexane-l,3-dione of any of claims 1-4.

8. The composition according to preceding claim, comprising less than about 5% by weight of the at least one form of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3- dione which differs from the polymorph of 2-(2-chloro-4-mesyl-benzoyl)- cyclohexane-1 ,3-dione of any of claims 1-4.

9. The composition according to any of claims 5 to 8, further comprising other herbicides.

10. The composition according to preceding claim, wherein the other herbicides are selected from the group comprising sulfonylureas, chloroacetamides, dinitroanilines, triazines, isoxazoles, oxyacetamides and combinations thereof.

11. Use of the composition according to any of claims S to 10, for controlling unwanted plants.

12. The use according to preceding claim, for controlling weeds selected from the group comprising Cyperus esculentus, Cyperus rotundus, Chenopodium spp., Amaranthus spp. , Datura stramonium, Polygonum aviculare and Solarium nigrum.

13. A process for preparing crystalline polymorph of 2-(2-chloro-4-mesyl-benzoyl)- cyclohexane-1 ,3-dione as defined in claim 1, comprising the steps of:

1- preparation of 4-sulfomethyl-2-chloro benzoyl chloride;

2- preparation of enol ester derivative; 3- rearrangement of enol ester derivative to 2-(2-chloro-4-mesyl-benzoyl)- cyclohexane-1 ,3-dione; and

4- purification of 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l ,3-dione; wherein in step 1, a reaction of benzoic acid derivative with thionyl chloride in the presence of a catalyst is carried out to produce the benzoyl chloride derivative; in step 2, the benzoyl chloride derivative produced in step 1 is condensed with

1 ,3-cyclohexane-dione in the presence of a catalyst and a solvent to obtain an enol ester derivative; in step 3, the enol ester derivative of step 2 dissolved in a solvent is rearranged using catalytic amount of CN^"; and in step 4, the 2-(2-chloro-4-mesyl-benzoyl)-cyclohexane-l,3-dione is purified by:

- dissolving it in mild alkaline conditions using an alkali solution;

- extracting using an organochloride solvent; and

- acidifying the resulting aqueous layer using an acid solution.

14. The process of claim 13, wherein the catalyst of step 1 is DMF; the catalyst of step 2 is piperidine; the solvent of step 2 and 3 is acetonitrile.

15. The process of claim 13, wherein the concentration of the alkali solution is in the range of about 5% -20% .

16. The process of preceding claim, wherein the alkali solution is selected from the group comprising sodium, potassium, alkaline earth metal salts and combinations thereof.

17. The process of claim 13, wherein the concentration of the acid solution is in the range of about 10-20% .

18. The process of claim 13, wherein in step 4 the alkali solution is sodium hydroxide, the organochloride solvent is dichloroethane and the acid solution is hydrochloric acid.