CN117794567A

CN117794567A - Method for producing pure 2-nitro-4-methylsulfonylbenzoic acid

Info

Publication number: CN117794567A
Application number: CN202280054627.8A
Authority: CN
Inventors: P·波特尼斯; S·迪因格拉; S·K·辛格
Original assignee: Aldi Industries Ltd
Current assignee: Aldi Industries Ltd
Priority date: 2021-07-09
Filing date: 2022-07-08
Publication date: 2024-03-29
Also published as: EP4366771A1; WO2023281536A1

Abstract

The present invention relates to a process for the preparation of 2-nitro-4-methylsulfonylbenzoic acid of formula I. The invention also relates to a process for purifying 2-nitro-4-methylsulfonylbenzoic acid of formula I.

Description

Method for producing pure 2-nitro-4-methylsulfonylbenzoic acid

Technical Field

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

The invention also relates to a method for preparing pure 2-nitro-4-methylsulfonylbenzoic acid.

Background

2-nitro-4-methylsulfonylbenzoic acid (formula I) is a key intermediate for synthesizing herbicide mesotrione.

Mesotrione is used as a selective herbicide, especially in corn, and is sold under the brand names Calisto and Tenacity, among others. It was first sold by syngeneta in 2001. Mesotrione is hereinafter referred to as a compound of formula II below.

Several synthetic methods for preparing compounds of formula II have been reported in the literature.

In general, compounds of formula II can be made by reacting a compound of formula I with phosgene in the presence of an organic solvent to provide the corresponding acid chloride, and then the acid chloride intermediate can be reacted with 1, 3-cyclohexanedione in the presence of a cyanide catalyst and triethylamine to form the crude compound of formula II. The solvent may be removed by distillation and the compound of formula II precipitated from the remaining reaction mixture by a series of pH adjustment steps and separated by filtration or centrifugation. The crude compound of formula II produced by this process contains a large amount of impurities which are not produced by the above reaction but are actually impurities from the starting material compound of formula I. The resulting compounds of formula II do not meet the relevant standards due to impurities in the starting materials.

Impurities present in the final product, such as nitro and dinitro impurities, for any reason are undesirable. Regulatory authorities require the impurity levels to be as low as possible to ensure maximum safety and to avoid toxicity, including genotoxicity, due to such impurities.

It is generally desirable that the individual impurities in the final product should not exceed certain limits. The process impurities should remain below the set limits according to manufacturer regulatory guidelines. Specific limitations can be achieved by using pure starting materials in the manufacturing process, controlling process parameters such as temperature, pressure, time and stoichiometry, and purification steps such as crystallization, distillation and liquid-liquid extraction.

It is always advantageous to use high purity intermediates that are free of undesired impurities, or such impurities should be present in acceptable amounts. The purity of a chemical compound 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 preparing pure key intermediate compounds of formula I to synthesize compounds of formula II.

Several methods for preparing compounds of formula I are disclosed in the prior art.

US5424481 discloses the preparation of compounds of formula I, which involves the reaction of p-toluenesulfonyl chloride with chloroacetic acid in the presence of sodium sulfite and sodium bicarbonate to obtain 4-methylsulfonyltoluenes, which are further converted to 4-methylsulfonyl-2-nitrotoluene (hereinafter referred to as compounds of formula V) by nitration. The compound of formula V is further converted to the compound of formula I by oxidation using sulfuric acid and vanadium pentoxide as catalysts. However, the yield of the compound of formula I obtained by using this method is only 81%.

Bioorganic & Medicinal Chemistry 10 (2002) 1841-1854 discloses the preparation of compounds of formula IV involving reaction of a compound of formula III with chlorosulfonic acid at 0-5 ℃ using chloroform as solvent to give compounds of formula IV in yields of only 83.54%. Said journal reference does not disclose further conversion of the compound of formula IV to the compound of formula I.

However, the large-scale use of chloroform as a solvent is limited due to the anesthetic nature of chloroform and other health hazards.

US7285678 discloses a process for the purification of a compound of formula I which involves dissolving the compound of formula I by adjusting the pH2-10, followed by contacting the aqueous solution of the compound of formula I with activated carbon, treating the aqueous solution of the compound of formula I with sufficient base to hydrolyze the undesired nitro and dinitro substituted impurities; the resulting aqueous solution comprising the compound of formula I is then maintained at a temperature of up to about 95 ℃ and the pH of the solution is adjusted to a pH about sufficient to effect crystallization of the compound of formula I upon cooling.

Thus, the method disclosed in US'678 is not economically viable as it involves the use of high temperatures and involves the use of acid-base purification, which makes the method more cumbersome.

CN106699616 discloses a process for purifying a compound of formula I by dissolving the compound of formula I in a suitable amount of solvent and heating the resulting reaction mixture to 30-150 ℃ with stirring for 0-2 hours. The compound of formula I is precipitated with or without the addition of a solvent.

However, CN'616 discloses a long list of 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-tetrahydronaphthalene, chlorine-containing solvents selected from methyl chloride, methylene chloride, chloroform, carbon tetrachloride, 1, 2-dichloroethane, 1-dichloroethane and chlorobenzene, benzene-ring-containing solvents selected from benzene, toluene, phenol and methylphenol, acetonitrile, pyrrolidone.

CN'616 also specifically illustrates the purification of the compound of formula I by using solvents such as methanol, ethanol, dichloromethane and toluene. CN'616 fails to provide compounds of formula I with acceptable impurity levels.

There is a continuing need to develop a simple, economically advantageous and industrially viable process to prepare pure compounds of formula I with acceptable impurity levels.

The present inventors have provided a process for preparing compounds of formula I in improved yields and purity.

Object of the Invention

The purpose of the invention is described below:

it is an object of the present invention to provide a process for preparing compounds of formula I with improved purity.

It is another object of the present invention to provide a novel compound intermediate of formula IVc which is useful for the synthesis of compounds of formula I.

It is yet another object of the present invention to provide a process for preparing pure compounds of formula I using industrially viable solvents suitable for large scale mass production.

It is a further object of the present invention to provide a process for preparing a compound of formula I at acceptable impurity levels.

Other objects and advantages of the present invention will become more apparent from the following description, which is not intended to limit the scope of the present invention.

Disclosure of Invention

The present invention relates to a novel, efficient and industrially advantageous process for preparing a compound of formula I.

In a first aspect the present invention provides a process for the preparation of a compound of formula I comprising reacting a compound of formula III with chlorosulphonic acid in the presence of a reagent selected from thionyl chloride, phosgene or oxalyl chloride with 1, 2-dichloroethane as solvent to give a compound of formula IV. Reacting a compound of formula IV with an alkali metal sulfite and a carboxylic acid or salt thereof in the presence of an inorganic base to obtain a compound of formula IVc. The compound of formula IVc is converted to the compound of formula V, which is then oxidized by using a catalyst to give the crude compound of formula I.

The resulting crude compound of formula I is purified.

The process for preparing pure compounds of formula I is depicted in scheme-I below:

in a second aspect, the present invention provides a novel compound intermediate of formula IVc which can be further converted into a compound of formula I.

Wherein A is H or Na or K.

In a third aspect, the present invention provides a process for purifying a compound of formula I using an ether as solvent.

The process for purifying the compound of formula I is depicted in scheme-II below

Detailed Description

The present invention discloses a process for preparing compounds of formula I with improved purity.

The starting material for the process, i.e. the compound of formula III, can be prepared according to the process disclosed in US 4804792.

According to a first aspect of the present invention there is provided a process for the preparation of a compound of formula I as depicted in scheme-I.

The method is described below:

in step (a), the 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 1, 2-dichloroethane as a solvent to give the compound of formula IV.

The process of step (a) wherein the volume of 1, 2-dichloroethane solvent relative to the weight of the compound of formula III is in the range from 2 to 10.

The process of step (a) wherein the molar ratio of the compound of formula III to chlorosulfonic acid is in the range of 1:1 to 1:8.

The process of step (a) wherein the molar ratio of the compound of formula III to thionyl chloride, phosgene or oxalyl chloride is in the range of 1:0.5 to 1:5.

The process of step (a) is carried out at a temperature in the range between 25 ℃ and 90 ℃.

In step (b), the compound of formula IV obtained in step (a) is reacted with an alkali metal sulfite and a carboxylic acid or a salt thereof in the presence of an inorganic base to obtain a compound of formula IVc, which is then converted into 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 from 0℃to 105 ℃.

The process of step (b), wherein the alkali metal sulfite comprises sodium sulfite, potassium sulfite, and combinations thereof.

The process of step (b) wherein the molar ratio of the compound of formula IV to alkali metal sulfite is in the range of 1:1 to 1:3.

The process of step (b), wherein the inorganic base is selected from the group consisting of 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 the inorganic base is in the range of 1:1 to 1:10.

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

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 is in the range of 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℃to 100 ℃.

The process of step (c) wherein the oxidation is carried out in the presence of a catalyst using nitric acid as the oxidant and sulfuric acid as the reaction medium.

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

During step (c), the molar ratio of the compound of formula V to nitric acid is in the range of 1:1 to 1:15.

The process of step (c) wherein sulfuric acid is used at a strength of 50 wt.% to 98 wt.%.

The process of step (c) wherein the molar ratio of the compound of formula V to sulfuric acid is in the range of 1:1 to 1:6.

The process of step (c) wherein the catalyst used is a vanadium catalyst, preferably vanadium pentoxide (V ₂ O ₅ ) Or ammonium metavanadate (NH) ₄ VO ₃ )。

The process of step (c) wherein the weight of the catalyst is in the range of 0.5% to 25% relative to the weight of the compound of formula V.

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

The process of step (d) wherein the volume of the ether solvent is in the range of 1 to 10 relative to the weight of the compound of formula I.

The process of step (d), wherein the ether solvent is selected from the group consisting of dimethyl ether, ethyl methyl ether, diethyl ether, 1, 4-dioxane, diglyme, ethylene glycol, tetrahydrofuran, methyl-t-butyl ether, 1, 2-dimethoxyethane, anisole, and combinations thereof.

The process of step (d) wherein the purification of the compound of formula I is carried out by employing a technique selected from crystallization, recrystallization and filtration at a temperature in the range of 30 ℃ to 110 ℃.

According to a second aspect of the present invention there is provided a compound intermediate of formula IVc.

Wherein A is H or Na or K.

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

The compounds of formula I may be purified as described above by using ethers or combinations thereof.

One embodiment of the present invention relates to a process for purifying a compound of formula I by treatment with an ether or a combination thereof, to obtain a pure compound of formula I with acceptable or negligible impurities.

The inventors of the present invention have observed that when the purification process of the compound of formula I is performed by using an ether as solvent, the compound of formula I is provided with improved purity and acceptable impurity levels. The compounds of formula I are useful in the synthesis of compounds of formula II.

Examples:

example 1:

step-a: synthesis of Compound (3-nitro-4-methylbenzenesulfonyl chloride) of formula IV

In a 2L four-necked flask, chlorosulfonic acid (340 g), 1, 2-dichloroethane (1L) and o-nitrotoluene (200 g) were added and the reaction mixture was heated to 80℃to 85 ℃. The reaction mixture was stirred for 3 hours and cooled to 60 ℃ to 65 ℃. Thionyl chloride (191 g) was added to the reaction mixture and the reaction mixture was stirred. After the reaction was completed, the reaction mass was cooled to 25℃to 30℃and poured into chilled water (200 ml). The organic layer was separated and washed with water (100 ml). The organic layer was further concentrated to give the compound of formula IV. (purity: 95%, yield: 99%).

Step-b: synthesis of Compounds of formulas IVc and V (2-nitro-4-methylsulfonylmethyltoluene) in a 3L four-necked flask sodium sulfite (184 g), sodium bicarbonate (478 g) and water (1.72L) were added and the reaction mixture was cooled to 0℃to 5 ℃. The compound of formula IV (as obtained in step-1) is added to the reaction mixture at 0-30 ℃ and stirred for 1-3 hours. A solution of chloroacetic acid (262 g) in water (262 ml) was added at 40℃to 45℃and the reaction temperature was raised to 65℃and stirred. A compound of formula IVc (wherein a is Na) is formed.

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

1H NMR:(300MHz,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 was heated to 70 ℃ to 100 ℃. After the reaction was completed, the reaction mixture was cooled to 20 ℃ to 35 ℃ to precipitate a solid. The precipitated solid was filtered and washed with water (500 ml) to obtain a wet material. Methanol (800 ml) was added to the wet material, refluxed to 60-65 ℃ and cooled to 0-5 ℃ to precipitate a solid. The precipitated solid was filtered and dried to give the compound of formula V (purity: 99.0%, yield: 80%).

Step-c: synthesis of Compound of formula I (2-nitro-4-methylsulfonylbenzoic acid (crude))

In a 1L flask equipped with a stirrer, 70% sulfuric acid (300 g), a compound of formula V (100 g) and V were added ₂ O ₅ (8g) And the temperature of the reaction mixture was increased to 130 ℃ to 140 ℃. 55% nitric acid (620 ml) was added to the reaction mixture over 12-20 hours. The reaction mixture was stirred for 3 hours. After the reaction was completed, water (300 ml) was added to the reaction mass to precipitate a solid. The precipitated solid was filtered and washed with 2% sulfuric acid (100 ml) and then with water (100 ml). The filtered solid was dried to give the compound of formula I (purity:>92%, yield: 92%).

Step-d: purification of the Compounds of formula I

In a 1L flask equipped with a stirrer, 1, 4-dioxane and crude compound of formula I (100 g) were added at 25℃and the mixture was heated to 50℃to 100℃with stirring and filtered to give a filtrate. The filtrate was cooled and stirred to precipitate a solid. The precipitated solid was filtered and washed with 1, 4-dioxane. The wet cake is dried to give the compound of formula I (purity > 99%).

Example 2:

step-d: purification of the Compounds of formula I

Tetrahydrofuran and crude compound of formula I (100 g) were added at 25 ℃ and the mixture was heated to 50-65 ℃, stirred and filtered to give a filtrate in a 1L flask equipped with a stirrer. The filtrate was cooled and stirred to precipitate a solid. The precipitated solid was filtered and washed with tetrahydrofuran. The wet cake is dried to give the compound of formula I (purity > 99%).

Example 3:

in a 1L flask equipped with a stirrer, MTBE and crude compound of formula I (100 g) were added at 25℃and the mixture was heated to 50-65℃with stirring, cooled to room temperature and washed with MTBE. The wet cake is dried to give the compound of formula I (purity > 99%).

Example 4:

in a 1L flask equipped with a stirrer, a mixture of THF and MTBE and the crude compound of formula I (100 g) were added at 25℃and the mixture was heated to 50-65℃with stirring, cooled to room temperature and washed with MTBE. The wet cake is dried to give the compound of formula I (purity > 99%).

Example 5:

in a 1L flask equipped with a stirrer, diglyme (200 ml) and crude compound of formula I (100 g) were added at 25℃and the mixture was heated to 90-100℃with stirring, cooled to room temperature and washed with diglyme. The wet cake is dried to give the compound of formula I (purity > 99%).

The effect of various organic solvents for purifying the compounds of formula I as disclosed in CN106699616 is depicted in table 1.

Table 1:

however, when the purification of the compound of formula I was performed using 1, 4-dioxane (ether) as solvent, the impurity level in the compound of I was drastically reduced to acceptable impurity levels, as can be seen in table 2.

Table 2:

conclusion: from table 2 it has been observed that the purity of the compound of formula I increases by at least 4.5% when the purification of the compound of formula I is performed using 1, 4-dioxane as solvent. None of the examples disclosed in CN106699616 provide a purification method that increases the purity of the compound of formula I by more than 4.0%.

Furthermore, when the purification of the compound of formula I is carried out using 1, 4-dioxane as solvent, the nitro and dinitro substituted impurity levels are reduced up to 0%. However, none of the examples disclosed in CN106699616 provides the compound of formula I with 0% nitro and dinitro substituted impurities.

It has also been observed that the purity of the compound of formula I increases by 7.75% when purification of the compound of formula I is performed using 4 volumes of 1, 4-dioxane.

Thus, when the compound of formula I purified by using the method of the present invention is used in the synthesis of the compound of formula II, the compound of formula II is provided in the desired purity.

The inventors of the present invention also conducted the experiments disclosed in examples 1,2,3 and 4 of CN106699616 and the solvents of the present invention and provided comparative data in table 3.

TABLE 3 Table 3

From the data provided in table 3, it has been observed that when purification of the compound of formula I is performed using 1, 4-dioxane as solvent, the purity increases up to 99.76%. None of the solvents disclosed in CN106699616 provided the product in more than 98% purity. The other impurity level using 1, 4-dioxane was reduced to 0.16% compared to the impurities obtained in the presence of the other solvents. Furthermore, when purification is performed using ethanol as a solvent, the percentage of the total amount of other impurities increases. However, when purification is performed using 1, 4-dioxane as a solvent, the other impurity levels are not increased.

The embodiments herein and the various features and advantageous details thereof are explained with reference to non-limiting embodiments in the specification. 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. Thus, 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 a particular feature of the invention may have been fairly emphasized herein, it should be understood that various modifications may be made and that numerous changes may be made in the preferred embodiment without departing from the principles of the invention. These and other modifications of the invention or the preferred embodiments will be apparent to those skilled in the art from the herein-described invention, whereby it is to be clearly understood that the foregoing description is to be interpreted merely as illustrative of the invention and not as a limitation.

Claims

1. A process for preparing a compound of formula I;

the method comprises the following steps:

a) The compound of formula III is reacted with 1, 2-dichloroethane as solvent in the presence of a reagent selected from thionyl chloride, phosgene or oxalyl chloride,

with chlorosulfonic acid to give a compound of formula IV,

b) Reacting the compound of formula IV with an alkali metal sulfite and a carboxylic acid or a salt thereof in the presence of an inorganic base to give a compound of formula IVc, which is then converted to a compound of formula V,

c) Oxidizing said compound of formula V in the presence of a catalyst to obtain a crude compound of formula I, and

d) Purifying the compound of formula I obtained in step (c) with an ether.

2. A process for purifying the compound of formula I, the process comprising: treating the crude compound of formula I with an ether or a combination thereof to yield the pure compound of formula I.

3. The process according to claim 1, wherein the volume of the 1, 2-dichloroethane solvent relative to the weight of the compound of formula III is in the range from 2 to 10.

4. The process of claim 1, wherein the molar ratio of the compound of formula III to chlorosulfonic acid is in the range of 1:1 to 1:8.

5. The method of claim 1, wherein the molar ratio of the compound of formula III to thionyl chloride, phosgene or oxalyl chloride is in the range of 1:0.5 to 1:5.

6. The method of claim 1, wherein the temperature of step (a) is in the range of 25 ℃ to 90 ℃.

7. The method of claim 1, wherein

i. The inorganic base is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, and combinations thereof, and

the molar ratio of the compound of formula IV to inorganic base is in the range of 1:1 to 1:10.

8. The method of claim 1, wherein the temperature of step (b) is in the range of 0 ℃ to 105 ℃.

9. The method of claim 1, wherein

i. The alkali metal sulfite is selected from sodium sulfite, potassium sulfite, and combinations thereof, and

the molar ratio of the compound of formula IV to alkali metal sulfite is in the range of 1:1 to 1:3.

10. The method of claim 1, wherein

a. The carboxylic acid is selected from chloroacetic acid, trichloroacetic acid or acetic acid, and

b. the salt of the carboxylic acid is an alkali metal salt selected from sodium or potassium salts.

11. The process of claim 1, wherein the molar ratio of the compound of formula IV to the carboxylic acid or salt thereof is in the range of 1:1 to 1:5.

12. The process of claim 1, wherein the compound of formula IVc is isolated and heated at 70 ℃ to 100 ℃ to obtain the compound of formula V.

13. The process of claim 1, wherein the compound of formula IVc is converted in situ by heating at 70 ℃ to 100 ℃ to obtain the compound of formula V.

14. The process of claim 1, wherein the oxidation of the compound of formula V is performed using nitric acid in the presence of sulfuric acid.

15. The method of claim 14, wherein

i. The strength of sulfuric acid is in the range of 50 to 98 wt%, and

the molar ratio of the compound of formula V to sulfuric acid is in the range of 1:1 to 1:6.

16. The method of claim 14, wherein

i. The strength of nitric acid is in the range of 30 to 70 wt%, and

the molar ratio of the compound of formula V to nitric acid is in the range of 1:1 to 1:15.

17. The method of claim 1, wherein

i. The catalyst is selected from vanadium pentoxide (V) ₂ O ₅ ) Or ammonium metavanadate (NH) ₄ VO ₃ ) Vanadium catalyst of (2), and

the weight of the catalyst is in the range of 0.5% to 25% relative to the weight of the compound of formula V.

18. The method according to claims 1 and 2, wherein

i. The ether solvent is selected from the group consisting of dimethyl ether, ethyl methyl ether, diethyl ether, 1, 4-dioxane, ethylene glycol, tetrahydrofuran, diglyme, methyl-t-butyl ether, 1, 2-dimethoxyethane, anisole, and combinations thereof, and

wherein the volume of the ether solvent is in the range of 1 to 10 relative to the weight of the compound of formula V.

19. The method according to claims 1 and 2, wherein the purification is performed at a temperature in the range of 30 ℃ to 110 ℃.

20. Compound of formula IVc

Wherein A is H or Na or K.