DESC:FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of 2-chloro-4-(methylsulfonyl)benzoic acid. More particularly, the present invention relates to a simple, efficient, cost effective and improved process for the synthesis of 2-chloro-4-(methylsulfonyl)benzoic acid.
BACKGROUND OF THE INVENTION:
2-Chloro-4-(methylsulfonyl)benzoic acid is an important precursor for the synthesis of pesticides and herbicides (U.S. Pat. No. US4704467, EP0203428). It is also an important intermediate which is also widely used in dyes and pharmaceutical industries. Further, it is an important intermediate for the synthesis of cornfield herbicide 2-(2-chloro-4-methylsulfonylbenzoyl)-1,3-cyclohexanedione. It is also used as an intermediate for the synthesis of the drug Vismodegib which is a therapeutic drug for symptomatic metastatic Basal Cell Carcinoma (BCC).

There are several methods available in the prior art for the synthesis 2-chloro-4-(methylsulfonyl) benzoic acid. Some of the prior art processes are as follows:
CN113735745 discloses a process for the synthesis of 2-chloro-4-methylsulfonylbenzoic acid, wherein said process comprises adjusting the temperature of the microchannel reactor within the range of 100-110?; the microchannel reactor is loaded with a heterogeneous catalyst, which is prepared by dissolving chitosan in water, adding cobalt acetate and manganese acetate, under stirring followed by washing and drying. The microchannel reactor was preheated with air followed by the addition of a preheated solution of 2-chloro-1-methyl-4- (methylsulfonyl) benzene in glacial acetic acid to obtain 2-chloro-4-methylsulfonylbenzoic acid. The yield of the 2-chloro-4-methylsulfonylbenzoic acid is 97.2 %.
CN105017101 discloses a process for the synthesis of 2-chloro-4-(methylsulfonyl)benzoic acid, wherein said process comprises the steps of adding 2-chloro-4-methylsulfonyl toluene, nitric acid and catalysts into an autoclave, injecting oxygen with pressure intensity of 0 MPa to 3.0 MPa into the autoclave. The autoclave was heated to a temperature within the range of 140°C to 200°C and maintained at the same temperature for 1 h under stirring to afford 2-chloro-4-(methylsulfonyl)benzoic acid. The yield of the 2-chloro-4-methylsulfonylbenzoic acid is 77.6 %.
CN102627591 discloses a process for the synthesis of 2-chloro-4-methylsulfonylbenzoic acid, wherein said process comprises the reaction of 4-methylsulfonyltoluene and chlorine in the presence of an iron catalyst and at least one low-polarity solvent at a temperature within the range of 85 to 95°C to obtain 2-chloro-4-methylsulfonyltoluene. 2-Chloro-4-methylsulfonyltoluene was oxidised with nitric acid at a temperature within the range of 175 to 195°C to obtain 2-chloro-4-methylsulfonylbenzoic acid. The preparation method optimizes the two-step reaction conditions and the yield of the 2-chloro-4-methylsulfonylbenzoic acid is 85 %.
The methods known from the prior art are sometimes not suitable for the efficient synthesis of 2-chloro-4-(methylsulfonyl)benzoic acid because the yield or purity is not sufficient and/or the reaction conditions and parameters such as temperature or pressure are not optimal because they lead to unwanted side products and/or less yields. Few of the prior art document uses excess amount of nitric acid as an oxidizing agent for the oxidation of 2-chloro-4-(methylsulfonyl)toluene produce the large amount of NOx which causes huge environmental pollution.
Also, some of the prior art processes has widely used transition metals (such as organic acid salts of cobalt, manganese and the like) and oxidation promoters (bromides) as catalysts., These production methods and the catalytic systems need to be carried out under high temperature and high pressure there by leading to higher energy consumption, corrosion of equipment as well as environment pollution to a certain extent. Also the few prior art used the homogenous catalyst which is further difficult to separate from the product.
A further disadvantage of such procedures results from the fact that the desired reaction product can only be separated from the reaction mixture by complicated extraction with an organic solvent which in the case of industrial implementation leads to additional expenses. In addition, the processes involve consumption of solvents in huge quantities, thereby making them costly and inappropriate for industrial production.
There is therefore a need for a simple, cost-effective process which allows for the preparation of 2-chloro-4-(methylsulfonyl)benzoic acid from cheap starting materials and under easily controllable reaction conditions, that should solve the aforesaid problems associated with processes described in the prior art, which will be suitable for large-scale preparation, in terms of simplicity, yield and purity of the product.
Accordingly, the inventors of the present invention have developed a process for the synthesis of 2-chloro-4-(methylsulfonyl)benzoic acid that addresses the problem associated with the processes reported in the prior art. The present invention provides a one step process for the synthesis of 2-chloro-4-(methylsulfonyl)benzoic acid. The process of the present invention does not involve use of any toxic and/or costly solvents and reagents. Moreover, the process does not require any additional purification steps and critical workup procedure.
OBJECTIVE OF THE INVENTION:
The main objective of the present invention is to provide an improved process for the synthesis of 2-chloro-4-(methylsulfonyl)benzoic acid.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides an improved process for the preparation of 2-chloro-4-(methylsulfonyl)benzoic acid comprising the step of reacting 2-chloro-1-methyl-4-(methylsulfonyl) benzene with a suitable oxidizing agent in the presence of a suitable acid and optionally in the presence of a suitable solvent.
In one embodiment, said suitable oxidizing agent is selected from manganese dioxide or chromium trioxide.
In another embodiment, said suitable acid is selected from sulphuric acid, acetic acid, or mixture thereof.
DETAILED DESCRIPTION OF THE INVENTION:
The definitions provided herein for the terminologies used in the present disclosure are for illustrative purpose only and in no manner limit the scope of the present invention disclosed in the present disclosure.
As used herein, the terms “comprises”, “comprising”, “includes”, “including”, “has”, “having”, “contains”, “containing”, “characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process or method.
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
In line with the above objectives defined, the present invention provides a process for the preparation of 2-chloro-4-(methylsulfonyl)benzoic acid which comprises reacting 2-chloro-1-methyl-4-(methylsulfonyl) benzene with a suitable oxidizing agent in the presence of suitable acid and optionally in the presence of a suitable solvent.
In one embodiment, said suitable oxidizing agent is selected from manganese dioxide or chromium trioxide.
In another embodiment, said suitable acid is are selected from, but is not limited to, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethane sulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g. hydrobromic acid, sulfuric acid, phosphoric acid, and the like.
The suitable solvents as used in any of the process steps of the present invention are selected from, but are not limited to aliphatic, alicyclic or aromatic halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane or trichloroethane; ethers such as diethylether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxyethane or anisole; nitriles such as acetonitrile, propionitrile, n- or iso-butyronitrile or benzonitrile; amides such as N,N-dimethylformamide, ?,?-dimethylacetamide, N-methyl formanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide or sulfones such as sulfolane; alcohols such as methanol, ethanol, isopropanol, polyethylene glycols; water or mixtures thereof.
The process for the synthesis of 2-chloro-4-(methylsulfonyl)benzoic acid as disclosed in the present invention is as depicted in scheme 1 below:
Scheme: 1

In a preferred embodiment, the present invention provide a process for the preparation of 2-chloro-4-(methylsulfonyl)benzoic acid which comprises, reacting 2-chloro-1-methyl-4-(methylsulfonyl) benzene with a suitable oxidizing agent in the presence of suitable acid, wherein said suitable oxidizing agent is chromium trioxide and said suitable acid is a mixture of sulphuric acid and acetic acid, and the reaction is carried out at a temperature in the range of 10 to 50 ? for a period in the range of 1 to 5 h.
In another preferred embodiment, the present invention provide a process for the preparation of 2-chloro-4-(methylsulfonyl)benzoic acid which comprises, reacting 2-chloro-1-methyl-4-(methylsulfonyl) benzene with a suitable oxidizing agent in the presence of suitable acid, wherein said suitable oxidizing agent is manganese dioxide and said suitable acid is sulphuric acid and the reaction is carried out at a temperature in the range of 70 to120 ? for a period in the range of 8 to16 h.
The solvent can likewise be separated off by means of conventional techniques, for example by distillation, and can, if desired, be recycled. The product can be purified in a manner known per se, for instance by distillation or crystallization.
Following completion of the reaction, typical post-processing operations or product purification may be performed. There are no particular limitations on the purification method used, and conventional methods such as distillation, recrystallization or column chromatography may be used.
The invention is further illustrated with reference to the following examples. It is apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. The starting materials according to the present invention are known compounds that are commercially available or can be prepared in a known manner.
Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.
Examples:
Example 1: Synthesis of 2-chloro-4-(methylsulfonyl)benzoic acid

50% Sulphuric acid (100 g) was charged to a mixture of 2-chloro-1-methyl-4-(methylsulfonyl) benzene (10 g) and manganese dioxide (25 g). The reaction mass was heated at 95 ? for 10 h After completion of the reaction, the reaction mass was cooled to 25 ?, and basified by 10 % sodium hydroxide up to pH 9.0 and filtered. The filtrate was acidified with 20% aqueous sulphuric acid to obtain a solid mass which was filtered. Solid compound purified in methanol to obtain 2-chloro-4-(methylsulfonyl)benzoic acid as a solid with purity 99 % and yield 90 %. M/Z 233[M-1]; 1HNMR (400 MHz, DMSO-d6): d 13.0 (bs, 1H), 8.07 d (J =1.5 Hz, 1H), 7.99 d (J = 8.4 Hz, 1H), 7.95 dd (J = 9.9, 4.0 Hz, 1H), 3.33(s, 1H); 13C NMR (100 MHz,DMSO-d6): d 166.15, 143.91, 136.60, 132.37, 131.59, 129.05, 125.91, 43.28; IR: 3005 (-O-H), 2547 (-C-H), 1697 (-C=O), 1596 ( -C=C), 1308 (-S-O), 1145 ( -C-O), 966 (-C-O), 766 (-C-H), 743 (-C-Cl).IR: 3005 (-O-H), 2547 (-C-H), 1697 (-C=O), 1596 (-C=C), 1308 (-S-O), 1145 ( -C-O), 966 (-C-O), 766 (-C-H), 743 (-C-Cl).
Example 2: Synthesis of 2-chloro-4-(methylsulfonyl)benzoic acid

98% Sulphuric acid (50g) was charged to a mixture of acetic acid (50 g), 2-chloro-1-methyl-4-(methylsulfonyl) benzene (10 g ) and 50% aqueous solution of chromium trioxide (29 g). The reaction mass was stirred at 25 ? for 3 h. After completion of the reaction, the reaction mass was diluted with water (100 mL); the precipitate obtained was filtered and washed with water (10 mL) to obtain 2-chloro-4-(methylsulfonyl)benzoic acid as a solid with purity 99 % and yield 95 % w.r.t. 2-chloro-1-methyl-4-(methylsulfonyl) benzene. M/Z 233[M-1]; 1HNMR (400 MHz, DMSO-d6): d 13.0 (bs, 1H), 8.07 d (J =1.5 Hz, 1H), 7.99 d (J = 8.4 Hz, 1H), 7.95 dd (J = 9.9, 4.0 Hz, 1H), 3.33(s, 1H); 13C NMR (100 MHz,DMSO-d6): d 166.15, 143.91, 136.60, 132.37, 131.59, 129.05, 125.91, 43.28; IR: 3005 (-O-H), 2547 (-C-H), 1697 (-C=O), 1596 ( -C=C), 1308 (-S-O), 1145 ( -C-O), 966 (-C-O), 766 (-C-H), 743 (-C-Cl).
Advantages of the present invention:
1) Batch process developed at atmospheric pressure i.e. energy saving and safe process by using cheaper reagent CrO3-acetic acid-H2SO4
2) Catalyst free process
3) In-situ process from previous step in same sulphuric acid i.e. recycled the reaction mass of previous step to oxidation step.
4) Easy workup procedure
,CLAIMS:WE CLAIM:
1. A process for preparing 2-chloro-4-(methylsulfonyl)benzoic acid comprising the step of:
a) reacting 2-chloro-1-methyl-4-(methylsulfonyl) benzene with a suitable oxidizing agent in the presence of a suitable acid and optionally in the presence of a suitable solvent,
wherein oxidizing agent is selected from manganese dioxide or chromium trioxide.

2. The process as claimed in claim 1, wherein said acid is selected from sulphuric acid, acetic acid, or mixture thereof.

3. The process as claimed in claim 1, wherein said solvent is selected from chlorobenzene, dichlorobenzene, tetrachloromethane, dichloroethane, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxyethane, anisole, acetonitrile, propionitrile, n- or iso-butyronitrile, benzonitrile, N,N-dimethylformamide, ?,?-dimethylacetamide, N-methyl formanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, dimethyl sulfoxide, sulfolane, methanol, ethanol, isopropanol, polyethylene glycols, water or mixtures thereof.

4. The process as claimed in claim 3, wherein said solvent is water.

5. The process as claimed in claim 1, wherein the temperature during the reaction step a) is in the range of 10 to 120 ?.

6. The process as claimed in claim 1, wherein the purity of 2-chloro-4-(methylsulfonyl)benzoic acid is more than 99 %.

7. The process as claimed in claim 1, wherein said process comprises, reacting 2-chloro-1-methyl-4-(methylsulfonyl) benzene with a suitable oxidizing agent in the presence of suitable acid, wherein said oxidizing agent is chromium trioxide and said acid is a mixture of sulphuric acid and acetic acid, and the reaction is carried out at a temperature in the range of 10 to 50 ? for a period in the range of 1 to 5 h.

8. The process as claimed in claim 1, wherein said process comprises, reacting 2-chloro-1-methyl-4-(methylsulfonyl) benzene with a suitable oxidizing agent in the presence of suitable acid, wherein said oxidizing agent is manganese dioxide and said acid is sulphuric acid and the reaction is carried out at a temperature in the range of 70 to120 ? for a period in the range of 8 to16 h.