A PROCESS FOR THE PREPARATION OF PURE 2-NITRO-4-METHYLSULFONYL

BENZOIC ACID

FIELD OF THE INVENTION:

The present invention relates to a novel process for the preparation of a key intermediate, 2-nitro- 4-methylsulfonyl benzoic acid.

The present invention also relates to a process for the preparation of pure 2-nitro-4-methylsulfonyl benzoic acid.

BACKGROUND

2-nitro-4-methylsulfonyl benzoic acid (Formula I) is a key intermediate for the synthesis of a herbicide, Mesotrione. Formula I

Mesotrione is used as a selective herbicide, especially in maize and is sold under brand names such as Callisto and Tenacity. It was first marketed by Syngenta in 2001. Mesotrione is hereinafter referred to as the following compound of Formula II. Formula II.

Several synthetic methods have been reported in the literature to prepare the compound of Formula Generally, the compound of Formula II can be manufactured by reacting the compound of Formula I with phosgene in the presence of an organic solvent to provide the corresponding acid chloride, the acid chloride intermediate can then be reacted with 1,3-cyclohexanedione in the presence of a cyanide catalyst and triethylamine to form crude compound of Formula II. The solvents can be removed via distillation and the compound of Formula II is precipitated from the remaining reaction mixture through a series of pH adjustment steps and isolated by filtration or centrifugation. The crude compound of Formula II prepared by this process contains a lot of impurities, the said impurities not resulting from the above reaction but in fact resulting from impurities in the starting material, from the compound of Formula I. Due to the impurities in the starting material, the resulting compound of Formula II does not meet the relevant standards.

The impurities, for example, nitro and dinitro impurities present in the final product for any reason are undesirable. The regulatory agencies require the content of impurities to the minimum possible extent to ensure maximum safety and avoid toxicity including genotoxicity because of such impurities.

It is usually required that the content of an individual impurity in the final product should not exceed a certain limit. As per regulatory guidance for manufacturers the process impurities should be maintained below set limits. The specific limit may be achieved by using pure raw materials, controlling process parameters, such as temperature, pressure, time and stoichiometric ratio, and purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.

It is always advantageous to use an intermediate of high purity which is free from the undesired impurities or such impurities should be present in acceptable amounts. The purity of the chemical compounds can be measured by chromatographic techniques such as high pressure liquid chromatography (HPLC) or by gas chromatography (GC).

In order to overcome the above problems, it is necessary to develop a process for the preparation of a pure key intermediate compound of Formula I for the synthesis of the compound of Formula II.

There are several methods disclosed in the prior art for preparation of the compound of Formula I. US5424481 discloses the preparation of the compound of Formula I involving the reaction of p- toluenesulfonyl chloride with chloroacetic acid in the presence of sodium sulfite and sodium bicarbonate to obtain 4-methylsulfonyltoluene, which is further converted to 4-methylsulfonyl-2- nitrotoluene (hereinafter referred to as the compound of Formula V) by nitration reaction. The compound of Formula V is further converted to the compound of Formula I by oxidation reaction using sulfuric acid and vanadium pentoxide as a catalyst. However, the yield of the compound Formula I obtained by using this method is only 81%.

Bioorganic & Medicinal Chemistry 10 (2002) 1841-1854 discloses the preparation of the compound of Formula IV involving the reaction of the compound of formula III with chlorosulfonic acid at 0-5°C using chloroform as a solvent to obtain the compound of Formula IV with yield of only 83.54%. The said journal reference does not disclose the further conversion of the compound of Formula IV to the compound of Formula I.

However there are limited uses of the chloroform as a solvent on a large scale due to its anesthetic properties and its other health hazards.

US7285678 discloses a purification method of the compound of Formula I which involves the dissolution of the compound of Formula I by adjusting the pH 2-10, followed by contacting an aqueous solution of the compound of Formula I with activated carbon, treating an aqueous solution of the compound of Formula I with sufficient base to hydrolyze undesired nitro and dinitro substituted impurities; followed by maintaining the resulting aqueous solution comprising the compound of Formula I at a temperature of up to about 95°C, and adjusting the pH of said solution to about a pH which is sufficient to affect crystallization of the compound of Formula I upon cooling.

Thus, the process disclosed in the US’678 is economically not viable as it involves the use of high temperature and involves the use of acid-base purification which makes the process more tedious.

CN106699616 discloses a process for purification of the compound of Formula I by dissolving the compound of Formula I in an appropriate amount of solvent and the resulting reaction mixture is heated to 30-150°C under stirring for 0-2 h. The compound of Formula I is precipitated by the addition or without addition of solvent. However, the CN’616 discloses a lengthy list of the solvents such as alcohol solvents selected from methanol, ethanol, propanol, butanol, pentanol, hexanol, cyclohexanol, ethylene glycol, propylene glycol, 2-methoxyethanol, 2-ethoxyethanol, benzyl alcohol, ether solvents selected from diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane, dioxane, anisole; alkane solvents selected from petroleum ether, pentane, n- hexane, cyclohexane, octane, heptane, 1,2,3,4-tetralin, chlorine-containing solvents selected from methyl chloride, dichloromethane, chloroform, carbon tetrachloride, 1 ,2-dichloroethane, 1,1- dichloroethane, and chlorobenzene, benzene ring- containing solvent selected from group consisting of benzene, toluene, phenol, and methylphenol, acetonitrile, pyrrolidone.

Further CN’616 specifically demonstrates the purification of the compound of Formula I by using solvents such as methanol, ethanol, dichloromethane and toluene. CN’616 fails to provide the compound of Formula I with an acceptable level of impurities.

There is a continuous need to develop a simple, economically advantageous and industrially viable process for preparation of the pure compound of Formula I having acceptable levels of impurities.

The inventors of the present invention provide the process for the preparation of the compound of the Formula I with improved yield and purity.

OBJECTS OF THE INVENTION

The objects of the present invention are described herein below:

An object of the present invention is to provide a process for the preparation of the compound of Formula I with improved purity.

Another object of the present invention is to provide a novel intermediate of a compound of Formula IVc which can be used for the synthesis of the compound of Formula I.

Yet another object of the present invention is to provide a process for the preparation of the pure compound of Formula I which employs industrially feasible solvent suitable for large scale batch production. Further object of the present invention is to provide the process for the preparation of the compound of Formula I with acceptable levels of impurities.

Other objects and advantages of the present invention will be more apparent from the following description which is not intended to limit the scope of the present invention. SUMMARY OF THE INVENTION

The present invention relates to a novel, efficient and industrially advantageous process for the preparation of the compound of Formula I.

A first aspect of the present invention is to provide a process for the preparation of the compound of Formula I comprising reacting the compound of Formula III with chlorosulfonic acid in the presence of a reagent selected from thionyl chloride, phosgene or oxalyl chloride and ethylene dichloride as a solvent to obtain a compound Formula IV. The compound of Formula IV is reacted with alkali metal sulfite and carboxylic acid or salts thereof in the presence of inorganic base to obtain the compound of Formula IVc. The compound of Formula IVc is converted to a compound of Formula V, which is then oxidized by using a catalyst to obtain the crude compound of Formula I.

The crude compound of Formula I obtained is purified.

The process for preparation of pure compound of Formula I is depicted in scheme-I herein below:

Scheme-I

A second aspect of the present invention is to provide a novel intermediate of the compound of Formula IVc which can be further converted into the compound of Formula I wherein A is H or Na or K.

A third aspect of the present invention is to provide a process for the purification of the compound of Formula I using ether as a solvent. The process for the purification of compound of Formula I is depicted in scheme-II herein below

Scheme-II DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses a process for the preparation of a compound of Formula I with improved purity.

The starting material of the process, the compound of Formula III, can be prepared as per process disclosed in US4804792. In accordance with the first aspect of the present invention there is provided a process for the preparation of the compound of formula I as depicted in Scheme-I.

Scheme-I

The process is described herein after:

In step (a) a compound of Formula III is reacted with chlorosulfonic acid in the presence of a reagent selected from thionyl chloride, phosgene or oxalyl chloride and using ethylene dichloride as a solvent to obtain a compound Formula IV.

The process of the step (a) wherein volume of the ethylene dichloride solvent with respect to weight of the compound of Formula III ranges from 2 to 10.

The process of the step (a) wherein the molar ratio of the compound of Formula IP to chlorosulfonic acid ranges from 1:1 to 1:8.

The process of the step (a) wherein the molar ratio of the compound of Formula III to thionyl chloride, phosgene or oxalyl chloride ranges from 1:0.5 to 1:5.

The process of the step (a) is carried out at a temperature ranging between 25°C and 90°C. In step (b) the compound of Formula IV obtained in step (a) is reacted with alkali metal sulfite and carboxylic acid or salts thereof in the presence of inorganic base to obtain a compound of Formula IVc followed by conversion to a compound of Formula V. wherein A is H or Na or K.

The process of step (b) is carried out at a temperature of 0°C -105°C.

The process of the step (b), wherein the alkali metal sulfite includes sodium sulfite, potassium sulfite and the combination thereof. The process of step (b) wherein the molar ratio of the compound of Formula IV to alkali metal sulfite ranges from 1:1 to 1:3.

The process of step (b) wherein inorganic base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate and combinations thereof. The process of step (b) wherein the molar ratio of the compound of Formula IV to inorganic base ranges from 1:1 to 1:10.

The process of step (b) wherein carboxylic acid is selected from chloroacetic acid, trichloroacetic acid, acetic acid and alkali metal salts thereof, preferably sodium and potassium salt.

The process of step (b) wherein the molar ratio of the compound of Formula IV to the carboxylic acid or alkali metal salt of the carboxylic acid ranges from 1:1 to 1:5. In one embodiment the compound of Formula IVc can be isolated.

In another embodiment the compound of Formula IVc can be converted in-situ to the compound of Formula V.

The compound of Formula IVc is converted to the compound of Formula V by heating at 70°C- 100°C.

The process of step (c) wherein the oxidation is carried out using nitric acid as an oxidising agent and sulphuric acid as a reaction media in the presence of a catalyst.

The process of step (c) wherein nitric acid is used from 30% to 70% strength by weight.

The process of step (c) the molar ratio of the compound of Formula V to nitric acid ranges from 1:1 to 1:15.

The process of step (c) wherein sulphuric acid used is from 50% to 98% strength by weight.

The process of step (c) wherein the molar ratio of the compound of Formula V to sulphuric acid ranges from 1:1 to 1:6.

The process of step (c) wherein the catalyst used is vanadium catalyst preferably vanadium pentoxide (V2O5) or ammonium metavanadate (NH4VO3).

The process of step (c) wherein the weight of the catalyst with respect to the weight of the compound of Formula V ranges from 0.5% to 25%.

In step (d) the compound of Formula I as obtained in step (c) is purified using ether.

The process of step (d) wherein volume of the ether solvent with respect to weight of the compound of Formula I ranges from 1 to 10.

The process of step (d) wherein the ether solvent is selected from group consisting of dimethyl ether, ethyl methyl ether, diethyl ether, 1,4-dioxane, diglyme, ethylene glycol, tetrahydrofuran, methyl-/c/7-butyl ether, 1 ,2-dim ethoxy ethane, anisole and combinations thereof. The process of step (d) wherein the purification of the compound of Formula I is carried out at a temperature ranging from 30°C to 110°C by employing a technique selected from crystallization, recrystallization and filtration.

In accordance with the second aspect of the present invention there is provided an intermediate of the compound of Formula IVc. wherein A is H or Na or K.

In accordance with the third aspect of the present invention there is provided a process for the purification of the compound of formula I. The purification is as described in step (d) of the first aspect.

The compound of Formula I can be purified by using ether or combinations thereof as described above.

An embodiment of the invention relates to a process for purification of the compound of Formula I on treating with ether or combinations thereof results in pure compound of Formula I having acceptable or negligible impurities.

The inventors of the present invention have observed that the process for the purification of the compound of Formula I when carried out by using ether as solvent, provides the compound of Formula I with improved purity and acceptable levels of impurities. The said compound of Formula I can be used for the synthesis of the compound of Formula II. EXAMPLES:

Example 1:

Step-a: Synthesis of the compound of Formula IV (3-nitro-4-methylbenzenesulfonyl chloride)

In a 2L four-necked flask, chlorosulfonic acid (340 g), ethylene dichloride (1L) and o-nitrotoluene (200 g) were added and the reaction mixture was heated to 80°C-85°C. The reaction mixture was stirred for ~3 hours and cooled to 60°C-65°C. To the reaction mixture, thionyl chloride (191 g) was added and the reaction mixture was stirred. After completion of the reaction, the reaction mass was cooled to 25°C-30°C and poured into chilled water (200 ml). The organic layers were separated and washed with water (100 ml). The organic layer was further concentrated to obtain the compound of Formula IV. (Purity: 95%, Yield: 99%).

Step-b: Synthesis of the compound of Formula IVc and Formula V (2-nitro-4-methylsulfonyl toluene)

In a 3L four-necked flask, sodium sulfite (184 g), sodium bicarbonate (478 g) and water (1.72L) were charged and the reaction mixture was cooled to 0°C-5°C. To the reaction mixture, the compound of Formula IV (as obtained in step-1) was added at 0°C-30°C and stirred for 1-3 h. A solution of chloroacetic acid (262 g) in water (262 ml) was added at 40°C-45°C and the reaction temperature was raised to 65°C and stirred. The compound of Formula IVc (wherein A is Na) was formed.

The compound of Formula IVc (wherein A is Na) is identified by using 1H NMR.

1H NMR :(300 MHz, DMSO): 8.444-8.439 (d, 1H); 8.006-7.979 (dd, 1H); 7.450-7.423 (dd, 1H); 4.080 (s, 2H); 2.592 (s, 3H)

The reaction mass heated to 70°C-100°C. After completion of the reaction, the reaction mixture was cooled to 20°C-35°C to precipitate solids. The precipitated solids were filtered and washed with water (500 ml) to obtain wet material. To the wet material, methanol (800 ml) was charged, refluxed to 60°C-65°C and cooled to 0°C-5°C to precipitate solids. The precipitated solids were filtered and dried to obtain the compound of Formula V (Purity: 99.0% , Yield: 80%). Step-c: Synthesis of the compound of Formula I (2-nitro-4-methylsulfonyl benzoic acid (Crude))

In a 1L flask fitted with a stirrer, 70% sulfuric acid (300 g), the compound of Formula V (100 g) and V2O5 (8 g) were charged and temperature of the reaction mixture was increased to 130°C- 140°C. To the reaction mixture 55% nitric acid (620 ml) was added in 12-20 hours. The reaction mixture was stirred for ~3hrs. After completion of the reaction, water (300 ml) was charged to the reaction mass to precipitate solids. The precipitated solids were filtered and washed with 2% sulphuric acid (100 ml) followed by water (100 ml). The filtered solids were dried to give the compound of Formula I. ( Purity: > 92% , Yield: 92%).

Step-d: Purification of the compound of Formula I

In a 1L flask fitted with a stirrer, 1,4-dioxane and crude compound of Formula I (100g) was charged at 25°C and the mixture was heated to 50°C-100°C, stirred and filtered to obtain a filtrate. The filtrate was cooled and stirred to precipitate solids. The precipitated solids were filtered and washed by 1,4-dioxane. The wet cake was dried to obtain the compound of Formula I. (purity > 99%).

Example 2:

Step-d: Purification of the compound of Formula I

In a 1L flask fitted with a stirrer, tetrahydrofuran and crude compound of Formula I (100g) was charged at 25°C and the mixture was heated to 50-65°C, stirred and filtered to obtain a filtrate. The filtrate was cooled and stirred to precipitate solids. The precipitated solids were filtered and washed by tetrahydrofuran. The wet cake was dried to obtain the compound of Formula I. (purity > 99%).

Example 3:

In a 1L flask fitted with a stirrer, MTBE and crude compound of Formula I (100g) was charged at 25°C and the mixture was heated to 50-65°C, stirred, cooled to RT and washed by MTBE. The wet cake was dried to obtain the compound of Formula I. (purity > 99%). Example 4:

In a 1L flask fitted with a stirrer, mixture of THF and MTBE and crude compound of Formula I (lOOg) was charged at 25°C and the mixture was heated to 50-65°C, stirred, cooled to RT and washed by MTBE. The wet cake was dried to obtain the compound of Formula I. (purity > 99%).

Example 5:

In a 1L flask fitted with a stirrer, diglyme (200 ml) and crude compound of Formula I (100g) was charged at 25 °C and the mixture was heated to 90-100°C, stirred, cooled to RT and washed by diglyme. The wet cake was dried to obtain the compound of Formula I. (purity > 99%).

The effect of the various organic solvent for purification of the compound of Formula I as disclosed in CN106699616 is depicted in Table No. 1.

Table No. 1:

However, when the purification of the compound of Formula I is carried out using 1,4 dioxane (ether) as a solvent, the impurity level in the compound of I is reduced drastically to acceptable level of impurities which is seen in Table No. 2.

Table No.2:

Conclusion: It has been observed from Table No. 2 that when purification of the compound of Formula I is carried out using 1,4 dioxane as a solvent, the purity of the compound of Formula I increases by at least 4.5%. None of the examples disclosed in CN106699616 provides the purification method which increases the purity of the compound of Formula I by more than 4.0%. Further, when purification of the compound of Formula I is carried out using 1,4 dioxane as a solvent, nitro and dinitro substituted impurity level reduces upto 0%. However, none of the examples disclosed in CN106699616 provides the compound of Formula I with 0% nitro and dinitro substituted impurity.

Also, it has been observed that when purification of the compound of Formula I is carried out using 4 vol of 1,4 dioxane the purity of the compound of Formula I increases by 7.75%.

Thus, when the compound of Formula I is purified by using the process of the present invention used for the synthesis of the compound of Formula II provides the compound of Formula II with desired purity. The inventors of the present invention have also carried out the experiments disclosed in example 1, 2, 3 and 4 of the CN 106699616 and solvent of present invention and provided the comparative data in Table No. 3.

Table No. 3

As per data provided in the Table No. 3, it has been observed that when purification of the compound of Formula I is carried out using 1,4-dioxane as a solvent, the purity increases upto 99.76%. None of the solvent disclosed in the CN106699616 provided the product with purity more than 98%. The other impurities level by using 1,4-dioxane is reduced to 0.16% in comparison to the impurities obtained in the presence of other solvents. Further, when the purification is carried out using ethyl alcohol as a solvent the percentage of total other impurity increases. However, when purification is carried out using 1,4-dioxane as a solvent, there is no increase in other impurity levels.

The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

The description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.

While considerable emphasis has been placed herein on the particular features of this invention, it will be appreciated that various modifications can be made, and that many changes can be made in the preferred embodiments without departing from the principles of the invention. These and other modifications in the nature of the invention or the preferred embodiments will be apparent to those skilled in the art from the invention herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.