Description:PROCESS FOR THE PREPARATION OF MESOTRIONE WITH HIGH PURITY AND HIGH YIELD
FIELD OF INVENTION
[0001] The present disclosure relates to technical field of organic synthesis. In particular, the present disclosure relates to an improved process for the preparation of mesotrione of technical grade which has several advantages like low cost, high purity and high yield.
BACKGROUND OF THE INVENTION
[0002] Mesotrione is an aromatic ketone that is cyclohexa-1,3-dione in which one of the hydrogens at position 2 is substituted by a 4-(methane sulfonyl)-2-nitrobenzoyl group. Mesotrione has the following chemical structure (Formula I):

(Formula I)
[0003] Mesotrione is used as a selective herbicide for the pre-emergence and post-emergence control of a wide range of broad-leaved and grass weeds in maize. It is used for controlling crabgrass, goosegrass, barnyard grass, and yellow foxtail. This herbicide can also control several species of broadleaf weeds, as well as creeping bent grass, nimble will, and nutsedge in turf.

[0004] EP granted patent viz. EP0805792B1 discloses a process for the preparation of 2-(substituted benzoyl)-1,3 cyclohexanediones. The process employs a rearrangement reaction to form the desired 2-(substituted benzoyl)-1,3 cyclohexanediones, in the presence of a non-polar solvent, a cyanide source, an alkali or alkaline earth metal carbonate, a phase transfer catalyst and water.

[0005] Similarly, PCT Publication viz. WO 2005/035487 discloses a process for purifying mesotrione. The process comprises the steps of forming an aqueous mesotrione enolate solution, performing one or more purification processes on the solution, and thereafter, crystallizing purified mesotrione from the aqueous solution.

[0006] US Granted Patent viz 10421714 discloses that the preparation of mesotrione is carried out in three stages from the starting material 2-nitro-4-methylsulphonyl benzoic acid. After acid chloride formation with thionyl chloride, condensation with 1,3 cyclohexanedione and rearrangement in the presence of cyanide ion, they claim the overall yield is 51.7% from these three stages. Further, all three stages of the preparation of mesotrione are carried out separately.

[0007] In US Publication No. 2020031767A1, the preparation of mesotrione is carried out from 4-toluene sulphonyl chloride in five stages. But the overall yield from last three stages that includes acid chloride formation, condensation and rearrangement is 77.5%.

[0008] However, none of the cited references or any existing prior arts provides the process for the preparation of mesotrione of technical grade in high yields and at the same time having high purity.

[0009] There is a need for an improved process for the preparation of mesotrione in a “single pot” in high yields and purity, with only low amounts of impurities present. An improved process scheme for the preparation of mesotrione has now been found. The process scheme is carried out, all three stages in a “Single pot” to reduce the time of production, handling waste. This process has been found as safe and easy to handle in commercial scale.

[00010] Therefore, this process provides an efficient, economical yet simple process for the preparation of mesotrione of technical grade in higher yield and with higher purity.

OBJECTS OF THE INVENTION

[00011] An object of the present disclosure is to provide an improved process for the synthesis of mesotrione in a “Single-Pot” having high purity.

[00012] Another object of the present disclosure is to provide an improved process for the synthesis of mesotrione having high yield.

[00013] Yet another object of the present disclosure is to provide an improved process for the synthesis of mesotrione employing fewer unit operations in a single reactor.

[00014] Another object of the present disclosure is to provide an improved process for the synthesis of mesotrione which is rapid, economic and environment friendly.

[00015] It is further object of the present disclosure is to provide an improved process for the synthesis of mesotrione which is feasible at commercial scale.

SUMMARY OF THE INVENTION
[00016] The present invention addresses this need and have developed an improved process which does not involve the use of any toxic and/or costly solvents, catalysts or reagents. Moreover, the process does not require additional purification steps and critical workup procedures. Accordingly, the present invention provides an improved process for the preparation of mesotrione, which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations.

[00017] This and other features and aspects of the present invention will be better understood with reference to the following description and appended claims. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.

DETAILED DESCRIPTION OF THE INVENTION
[00018] Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications.

[00019] Definitions

[00020] For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.

[00021] The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

[00022] The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.

[00023] Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.

[00024] A principal embodiment of the present invention provides the process for the preparation of mesotrione technical having the chemical formula:
,
wherein the process comprises the following steps:
a) Synthesis of 2-nitro-4-(methylsulfonyl) benzoyl chloride

[00025] In an embodiment, 2- nitro-4-methylsulphonyl benzoyl chloride (III) is prepared by reaction of 2-nitro-4-methylsulphonyl benzoic acid (IV) with thionyl chloride in the presence of dimethyl formamide and a solvent and heating them to reflux.

[00026] Examples of solvent include dichloromethane, 1,2-dichloroethane, dichloropropane, and mixtures thereof.

[00027] Preferably, the solvent is 1,2-dichloroethane.

[00028] In one embodiment, the yield of 2- nitro-4-methylsulphonyl benzoyl chloride of formula (III) obtained using this process is between 95 – 98%.

[00029] In another embodiment, purity of 2- nitro-4-methylsulphonyl benzoyl chloride of formula (III) obtained is between 95 – 98%.

b) Synthesis of Mesotrione

[0030] In certain embodiment, there is provided a process for preparation of an enol ester of formula (II) by reaction of 2- nitro-4-methylsulphonyl benzoyl chloride of formula (III) with 1,3-cyclohexanedione.

[0031] In at least one embodiment, the enol ester of formula (II) is prepared by the reaction of 2- nitro-4-methylsulphonyl benzoyl chloride of formula (III) with 1,3-cyclohexanedione in the presence of a solvent.

[0032] Examples of solvent include dichloromethane, 1,2-dichloroethane, dichloropropane, and mixtures thereof. Preferably, the solvent is dichloromethane and 1,2-dichloroethane.

[0033] In one preferred embodiment, the enol ester of formula (II) is converted into mesotrione by reacting the enol ester of formula (II) with acetone cyanohydrin in presence of a base.

[0034] The base that can be used for this purpose includes organic or inorganic base. Preferably, the base may be an organic base such as triethylamine, diethanolamine, triethanolamine or N-methylglucamine.

[0035] In one preferred embodiment, the base can be triethylamine.

[0036] The resulting solution of mesotrione of formula (I) may be washed with an aqueous solution of an acid. Suitable acids for use in this step are known in the art. Inorganic acids are suitable and include mineral acids, especially sulphuric acid, nitric acid and hydrochloric acid. A preferred acid is hydrochloric acid.

[0037] In a certain embodiment, the resulting solution of mesotrione of formula (I) is acidified to pH 1 by using 5% hydrochloric acid and layer with dichloromethane and the organic layer is distilled to recover solvent dichloromethane.

[0038] In some embodiments, mesotrione of formula (I) produced according to the process of the present disclosure may be optionally subjected to purification. Purification of mesotrione may include a conventional procedure known to a person skilled in the art.

[0039] In a certain embodiment, purification of mesotrione of formula (I) may be done by using methanol.

[0040] In one embodiment, the disclosed process produces mesotrione of formula (I) in high yields i.e., between 81 – 85%.

[0041] In another embodiment, purity of mesotrione of formula (I) obtained using the process of the present invention is between 95 – 98%.

[0042] In another embodiment of the present disclosure, the total time taken for the completion of step one of the process is between 11-15 hours, more preferably 12 hours.

[0043] In yet another embodiment of the present disclosure, the total time taken for the completion of step two of the process for the preparation of mesotrione is 30-35 hours.

[0044] In an embodiment, the total time taken for both the step one and step two is between 41 -50 hours.

[0045] In another embodiment of the present disclosure, reaction mixture in step one of the process is refluxed at temperature between 82-85C for 4 hours to 6 hours or 60-650C for 7 - 9 hours.

[0046] In yet another embodiment of the present disclosure, a reaction mixture in step two is kept on reacting for 6-8 hours at 40C.

[0047] In a preferred embodiment of the present disclosure, the yield of 2-nitro -4-(methylsulfonyl)- benzoyl chloride obtained is between 95- 98% and wherein the purity of 2-nitro -4-(methylsulfonyl)- benzoyl chloride is between 95- 98%.

[0048] In another embodiment of the present disclosure, the yield of mesotrione obtained is between 81-85% and the purity of mesotrione obtained is between 95- 98%.

[0049] The present invention is further illustrated by the following examples, which should not be construed as limiting in any way. The following is a description of the examples.
Examples:
A) Synthesis of 2-nitro-4- (methyl sulfonyl) benzoyl chloride

[0050] A mixture of 459.2 g 98% 2-nitro-4-(methylsulfonyl) benzoic acid, 229.5 g thionyl chloride, 4.0 g Dimethylformamide and 2000 ml 1,2-dichloroethane was heated to reflux at 82-85C for 6 hours or 60-65C for 8 hours. The solution was then concentrated under reduced pressure to give 484 g 2-nitro -4-(methylsulfonyl)- benzoyl chloride. The yield is 98.0% and the content is 98.0%.
b) Synthesis of Mesotrione

[0051] A mixture of 1600 ml dichloromethane, 484 g 98% 2-nitro-4-(methylsulfonyl)-benzoyl chloride and 204.5 g 1,3-cyclohexanedione was added with 24.0 g acetone cyanohydrin dropwise over 1 hour at 30 – 35oC and thereafter addition of 440.0 g triethylamine started at 30 – 35oC over 1 hour. The mixture was kept on reacting for 6-8 hours at 40oC. Lastly the reaction mixture was with 400 g 5% hydrochloric acid to adjust to pH 1 and was separated and extract aqueous layer with dichloromethane and the organic layer was distilled to recover solvent dichloromethane. The Residual mass was crystallized with 1400 ml methanol. Reaction mass was filtrated and dried to get 528.6 g mesotrione in 22-25 hours in work up operation. The yield is 83.0% and the content is 98.0 %

[0052] The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds compositions or biological systems, which can, of course, vary. 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 be limiting.

[0053] While various aspects and illustrative embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.
, Claims:We Claim:
1. A process for the preparation of mesotrione of formula (I):

(I)
wherein the process comprises the following steps:
a) reacting 2-nitro-4-methylsulphonyl benzoic acid of formula (IV) with thionyl chloride to obtain 2-nitro-4-methylsulfonylbenzoyl chloride of formula (III);

b) reacting 2-nitro-4-methylsulfonylbenzoyl chloride of formula (III) with 1,3-cyclohexanedione and acetone cyanohydrin to obtain 3-(2-nitro-4-methyl sulfonyl benzoyloxy) cyclohexen-1-one of formula (II) and converting the enol ester of formula (II) to mesotrione of formula (I).

2. The process for preparation of mesotrione as claimed in claim 1, wherein the time taken for the completion of step a) is between 11 to15 hours and step b) is 30-35 hours.
3. The process for preparation of mesotrione as claimed in claim 1, wherein the reaction of 2-nitro-4-methylsulphonyl benzoic acid of formula (IV) with thionyl chloride is carried out in the presence of dimethyl formamide and a solvent.
4. The process for preparation of mesotrione as claimed in claim 4, wherein the solvent is selected from dichloromethane, 1,2-dichloroethane, dichloropropane, and their mixtures thereof.
5. The process for preparation of mesotrione as claimed in claim 1, wherein the conversion of the enol ester of formula (II) to mesotrione of formula (I) is carried out in presence of a base and solvent to produce mesotrione of formula (I).
6. The process for preparation of mesotrione as claimed in claim 4, wherein the base is selected from triethylamine, diethanolamine, triethanolamine or N-methylglucamine.
7. The process for preparation of mesotrione as claimed in claim 6, wherein the solvent is selected from dichloromethane, 1,2-dichloroethane, dichloropropane, and their mixtures thereof.
8. The process for preparation of mesotrione as claimed in claim 1, wherein the solution of mesotrione of formula (I) is washed with an aqueous solution of an acid.
9. The process for preparation of mesotrione as claimed in claim 1, wherein the yield of 2-nitro -4-(methylsulfonyl)- benzoyl chloride of formula (III) is between 95-98% and the purity of 2-nitro -4-(methylsulfonyl)- benzoyl chloride is between 95-98%.
10. The process for preparation of mesotrione as claimed in claim 1, wherein the yield of mesotrione of formula (I) is between 81-85% and the purity of mesotrione is between 95-98%.