FIELD OF THE INVENTION:

The present invention relates to a novel process for the preparation of 2-chloro-4-methylaniline of formula I. More particularly, the present invention relates to a process for the preparation of 2- chloro-4-methylaniline of formula I from N protected toluidine of formula III.

BACKGROUND OF THE INVENTION:

2-chloro-4-methylaniline is used as an intermediate in the production of dyes, organic pigments, optical brighteners, printing inks and pesticides. 2-chloro-4-methylaniline is used in determination of aniline derivatives in environmental water samples using an on-line combination of supported liquid membrane extraction and liquid or gas chromatography.

There are several synthetic methods reported in the literature to prepare 2-chloro-4-methylaniline of formula I by aromatic ring chlorination.

Journal of Applied Chemistry, Vol 4, Iss. 1, PP 38-43 by Satyadev et. al., discloses the chlorination of p-toluidine of formula IV to prepare 2-chloro-4-methylaniline of formula I. Satyadev et. al., merely studies the kinetics of the chlorination reaction.

The process for the preparation of 2-chloro-4-methylaniline of formula I disclosed in Satyadev et. al., is depicted in scheme-I herein below: Though the Satyadev et. al. studies the kinetics of chlorination of p-toluidine to prepare 2-chloro- 4-methylaniline of formula I, it does not provide details pertaining to procedure such as chlorinating agent, temperature, time, yield and purity.

Motivated by Satyadev et. al. the inventors of the present invention prepared 2-chloro-4- methylaniline of formula I from p-toluidine using chlorine as a chlorinating agent. The selectivity in favor of 2-chloro-4-methylaniline of Formula I is far inferior (10%) for this process to be industrially feasible and promising.

The other approach for preparing 2-chloro-4-methylaniline of formula I from p-toluidine include steps of protecting, chlorination and deprotecting.

One of such processes is referred to in Chemische Berichte, 1900, vol. 33, Pg. 2505 by Reverdin et. al., in which 2-chloro-4-methylaniline of formula I is referred to be synthesized by chlorinating p -acetoluidine to obtain an intermediate A-(2-chloro-4-methylphenyl)acetamide followed by a saponification reaction. However, Reverdin et. al., also does not provide details pertaining to procedure such as chlorinating agent, reagents for saponification (acid or basic saponification), temperature, time, yield and purity of the product.

Another process for chlorinating p -acetoluidine is reported in European Journal of Organic Chemistry, 2018, Iss. 34, Pg. 4748-4753 by Ghosh et. al. The process of Ghosh et. aL, discloses the synthesis of A-(2-chloro-4-methylphenyl)acetamide by chlorination of p -acetoluidine using N- chlorosuccinimide as a chlorinating agent and Cu-MnO as a catalyst in acetonitrile solvent under irradiation with light to provide A-(2-chloro-4-methylphenyl)acetamide.

However, Ghosh et. al., fails to disclose the further hydrolysis of N-(2-chloro-4- methylphenyl)acetamide to obtain 2-chloro-4-methylaniline of formula I.

Further, Ghosh et. al. discloses the use of N-chlorosuccinimide as a chlorinating agent and use of Cu-MnO as a catalyst which makes the process expensive and industrially not viable.

US4327036 discloses a process for the preparation of A-(2-chloro-4-methylphenyl)acetamide by addition of trifluoracetic acid to the solution of p -acetoluidine in methylene dichloride to obtain a reaction mixture. To the reaction mixture a solution of dichlorine monoxide in carbon tetrachloride is added dropwise and the mixture is stirred for 3 hours. The reaction mixture is added to water and neutralized by addition of sodium bicarbonate. The organic layer is washed with sodium bisulfite solution, brine and distilled out to give tan solid. The solid is further recrystallised twice from ether to obtain pure N-(2-chloro-4-methylphenyl)acetamide with 41% yield.

US ’036 process involves the use of dichlorine monoxide as a chlorinating agent which is an expensive material. Dichlorine monoxide when heated above 120°C or heated rapidly at lower temperature may explode and is unusually stored as hydrate in frozen form. Also liquid dichlorine monoxide has been reported to be shock-sensitive. Therefore, the US ’036 process is neither safe nor industrially viable.

The above literature processes fail to provide chlorination of N protected toluidine by using simple and inexpensive chlorinating agents. Also above processes either use expensive catalysts or unsafe/costly chlorinating reagents. Further, the above process fails to disclose the detailed process of hydrolysis of N protected ortho chloro toluidine to obtain 2-chloro-4-methylaniline of formula I.

Therefore, there is a continuous need to develop a process for the preparation of 2-chloro-4- methylaniline of formula I from N protected toluidine obviating the use of unsafe/expensive chlorinating reagents and expensive catalysts to provide N protected ortho chloro toluidine of formula II followed by hydrolysis reaction.

Accordingly, the inventors of the present invention developed a novel process for the preparation of 2-chloro-4-methylaniline of formula I from N protected toluidine having 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 2-chloro-4- methylaniline of formula I from N protected toluidine of formula III which employs inexpensive and safer chlorinating agent. Another object of the present invention is to provide a process for the preparation of 2-chloro-4- methylaniline of formula I from N protected toluidine of formula in which employs inexpensive and easily available catalysts.

Yet another object of the present invention is to provide a process for the preparation of 2-chloro- 4-methylaniline of formula I from N protected toluidine of formula in which is industrially amenable.

Yet another object of the present invention is to provide a process for the preparation of N protected ortho chloro toluidine of formula II from N protected toluidine of formula III.

Further object of the present invention is to provide a process for the preparation of 2-chloro-4- methylaniline of formula I by employing optimized, cost effective and industrially feasible conditions for deprotection of N protected ortho chloro toluidine of formula II.

SUMMARY OF THE INVENTION:

Accordingly, the present invention provides a novel, efficient and industrially advantageous process for the preparation of 2-chloro-4-methylaniline of formula I by chlorination of N protected toluidine of formula III to obtain N protected ortho chloro toluidine of formula II which is further deprotected to 2-chloro-4-methylaniline of formula I.

In an embodiment, the present invention provides a process for the preparation of 2-chloro-4- methylaniline of formula I comprising the steps of: a. chlorinating N protected toluidine of formula III wherein, P ¹ represents -COR ¹ or -COOR ¹ , and

P ² represents H, -COR ¹ or -COOR ¹ ; wherein,

R ¹ is C1-C4 alkyl group, benzyl or phenyl; and P ¹ and P ² are same or different; using chlorine in the presence of a metal catalyst in a suitable organic solvent to obtain N protected ortho chloro toluidine of formula II; wherein P ¹ and P ² are as stated above; b. deprotecting N protected ortho chloro toluidine of formula II to obtain 2-chloro-4- methylaniline of formula I; and c. optionally purifying 2-chloro-4-methylaniline of formula I to obtain pure 2-chloro-4- methylaniline of formula I.

The process for the preparation of 2-chloro-4-methylaniline of formula I as disclosed in the present invention is depicted in scheme II herein below:

Scheme: II

In another embodiment, the present invention provides a process for the preparation of N protected ortho chloro toluidine of formula II, comprising chlorinating N protected toluidine of formula III with chlorine in the presence of metal catalyst in an organic solvent.

The process for the preparation of N protected ortho chloro toluidine of formula II is depicted in scheme-in herein below:

Scheme HI

DETAILED DESCRIPTION OF THE INVENTION:

The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the disclosure to achieve one or more of the desired objects or results. The numerical values mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higher/lower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the disclosure, unless there is a statement in the specification specific to the contrary.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skilled in the art. In case of conflict, the present document, including definitions will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

The terms“comprise(s),”“include(s), ’’“having, ’’“has, ’’“can, ”“contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,”“an” and“the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments“comprising, ’’“consisting of and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

The present invention provides a process for the preparation of 2-chloro-4-methylaniline of formula I.

In accordance with the first aspect of the present invention there is provided a process for the preparation of 2-chloro-4-methylaniline of formula I comprising the steps of: a. chlorinating N protected toluidine of formula III, wherein,

P ¹ represents -COR ¹ or -COOR ¹ , and

P ² represents H, -COR ¹ or -COOR ¹ ; wherein, R ¹ is C1-C4 alkyl group, benzyl or phenyl;

P ¹ and P ² are same or different; using chlorine in the presence of a metal catalyst in a suitable organic solvent to obtain N protected ortho chloro toluidine of formula II; Formula II wherein P ¹ and P ² are as defined above, and b. deprotecting N protected ortho chloro toluidine of formula II of step (a) to obtain 2-chloro-4-methylaniline of formula I.

In the first step, N protected toluidine of formula III

Formula III wherein, P ¹ represents -COR ¹ or -COOR ¹ , and

P ² represents H, -COR ¹ or -COOR ¹ ; wherein,

R ¹ is C1-C4 alkyl group, benzyl or phenyl, and

P ¹ and P ² are same or different; is reacted with chlorine in the presence of a metal catalyst in a suitable organic solvent to obtain the N protected ortho chloro toluidine of formula II.

The process for the preparation of N protected ortho chloro toluidine of formula II is depicted in scheme-in herein below:

Scheme III

The starting material of the process, N protected toluidine of formula III can be prepared as per process disclosed in US2337825.

Typically, the molar ratio of N protected toluidine of formula III to chlorine ranges from 1: 1.5 to 1:2.

Non-limiting examples of the metal catalyst useful for the chlorination reaction is selected from Aluminium powder, Aluminium chloride (AICI3), Iron(III) chloride (FeCh), Fe powder, Iron(II) oxide (FeO) or mixture thereof.

Typically, the weight of the catalyst with respect to the weight of N protected toluidine of formula III ranges from 1% to 5%. Non-limiting examples of the organic solvent useful for the chlorination reaction is selected from carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, ethyl acetate or mixtures thereof.

Though the higher volumes of the organic solvent can be used for carrying out the chlorination reaction, the organic solvent in the range of 2 to 6 volumes with respect to the weight of N protected toluidine of formula III is expected to provide considerable reaction feasibility.

Though the chlorination reaction can be quenched by any chlorination reaction quenching media, a sodium thiosulphate solution is used to quench the chlorination reaction.

In the second step, N protected ortho chloro toluidine of formula II

Formula II wherein,

P ¹ represents -COR ¹ or -COOR ¹ , and

P ² represents H -COR ¹ or -COOR ¹ ; wherein,

R ¹ is C1-C4 alkyl group, benzyl or phenyl, and

P ¹ and P ² are same or different; is deprotected to obtain the 2-chloro-4-methylaniline of formula I.

Typically, the N protected ortho chloro toluidine of formula II wherein either of P ¹ and P ² is -COR ¹ or -COOR ¹ is deprotected by hydrolysis using a base to obtain 2-chloro-4-methylaniline of formula I. In one embodiment, P ¹ in formula II and III represents -COR ¹ ; wherein R ¹ is C1-C4 alkyl group; and P ² in formula II and III represents H.

Non-limiting examples of the base useful for the hydrolysis reaction are sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate or mixtures thereof.

Typically, the molar ratio of N protected ortho chloro toluidine of formula II to the base ranges from 1: 1 to 1:5.

In one embodiment, the yield of crude 2-chloro-4-methylaniline of formula I is more than 45 %.

In the third step, 2-chloro-4-methylaniline of formula I may be purified to obtain pure 2-chloro-4- methylaniline of formula I.

In one embodiment, 2-chloro-4-methylaniline of Formula I is purified by distillation.

In one embodiment, the purity of 2-chloro-4-methylaniline of formula I prepared by using the process of the instant invention is in the range from 97 to 99.9 %.

In one embodiment, N protected ortho chloro toluidine of formula II is isolated.

In another embodiment, N protected ortho chloro toluidine of formula II is not isolated.

In accordance with the second aspect of the present invention there is provided a process for the preparation of N protected ortho chloro toluidine of formula II

Formula II wherein,

P ¹ represents -COR ¹ or -COOR ¹ , and P ² represents H, -COR ¹ or -COOR ¹ ; wherein,

R ¹ is C1-C4 alkyl group, benzyl or phenyl, and

P ¹ and P ² are same or different; in which N protected toluidine of formula III

Formula III wherein,

P ¹ represents -COR ¹ or -COOR ¹ , and P ² represents H, -COR ¹ or -COOR ¹ ; wherein,

R ¹ is C1-C4 alkyl group, benzyl or phenyl, and

P ¹ and P ² are same or different; is reacted with chlorine in the presence of a metal catalyst in a suitable organic solvent. Typically, the molar ratio of N protected toluidine of formula III to chlorine ranges from 1 : 1.5 to 1:2.

Non-limiting examples of the metal catalyst useful for the chlorination reaction is selected from Aluminium powder, Aluminium chloride (AICI3), Iron(III) chloride (FeCh), Fe powder, Iron(II) oxide (FeO) or mixture thereof. Typically, the weight of the catalyst with respect to the weight of N protected toluidine of formula III ranges from 1 % to 5 %.

Non-limiting examples of the organic solvent useful for the chlorination reaction is selected from carbon tetrachloride, chloroform, dichloromethane, ethylene dichloride, ethyl acetate or mixtures thereof.

Though the higher volumes of the organic solvent can be used for carrying out the chlorination reaction, the organic solvent in the range of 2 to 6 volumes with respect to the weight of N protected toluidine of formula III is expected to provide considerable reaction feasibility.

Typically, the chlorination reaction is carried out at 30 °C to 100 °C for 3 hours to 15 hours. Typically, the hydrolysis reaction is carried out at 60 °C to 100 °C for 1 hour to 5 hours.

Though the chlorination reaction can be quenched by any chlorination reaction quenching media, a sodium thiosulphate solution is used to quench the chlorination reaction.

In one embodiment, N protected ortho chloro toluidine of formula II is isolated.

In another embodiment, N protected ortho chloro toluidine of formula II is not isolated. In the process of the present invention the compound of formula V and VI might be generated as impurity or a side product. wherein, P ¹ represents -COR ¹ or -COOR ¹ , and

P ² represents H, -COR ¹ or -COOR ¹ ; wherein,

R ¹ is C1-C4 alkyl group, benzyl or phenyl, and

P ¹ and P ² are same or different; n in formula V represents 1 to 3 and m in formula VI represents 1 to 2.

Various features and embodiments of the present invention are illustrated in the following representative examples, which are intended to be illustrative and non-limiting.

EXAMPLES:

Example- 1: Preparation of 2-chloro-4-methylaniline of formula I

In a 2L four-necked flask, ethylene dichloride (1000 mL), p -acetotoluidine (250 g) and Fe catalyst (2.5 g) were added and the reaction mixture was heated. To the reaction mixture chlorine gas was purged till the completion of the reaction. The reaction mixture was cooled to room temperature. After completion of the reaction, the reaction is quenched with sodium thiosulphate solution and worked up to obtain a reaction mixture which was hydrolyzed using aqueous solution of sodium hydroxide (335 g). The reaction mixture was worked up to obtain a crude mass of 2-chloro-4- methylaniline of formula I.

The crude mass of 2-chloro-4-methylaniline of formula I was further purified by distillation (Yield: 47 % on the basis of reacted p -acetotoluidine, Purity: >99.5%).

Example-2: a) Step I: Preparation of the N-(2-chloro-4-methylphenyl)acetamide

In a 2L four-necked flask, ethylene dichloride (400 mL), p -acetotoluidine (250 g) and Fe catalyst (2.5 g) were added and the reaction mixture was heated. To the reaction mixture chlorine gas was purged till the completion of the reaction. The reaction mixture was cooled to room temperature. After completion of the reaction, the reaction is quenched with sodium thiosulphate solution, worked up followed by filtration to obtain solid. The obtained solid was washed with water and dried to obtain N-(2-chloro-4-methylphenyl)acetamide of formula (II). (Purity: 60%). b) Step II: Preparation of 2-chloro-4-methylaniline of formula I

In a 2L four-necked flask, the obtained solid of the compound of formula II and aqueous solution of sodium hydroxide (335 g) were added and reaction mass was heated. The reaction mixture was worked up to obtain crude liquid mass of 2-chloro-4-methylaniline of formula I. (Yield: 69 %; Purity: 67 %). c) Step III: Purification of 2-chloro-4-methylaniline of formula I

The crude mass of 2-chloro-4-methylaniline of formula I was purified by fractional distillation (Yield: 72 %, Purity: >99.5%).

Example-3: Preparation of 2-chloro-4-methylaniline of formula I

In a 2L four-necked flask, ethylene dichloride (1000 mL), p -acetotoluidine (250 g) and AlCh catalyst (7.5 g) were added and the reaction mixture was heated. To the reaction mixture chlorine gas was purged till the completion of the reaction. The reaction mixture was cooled to room temperature. After completion of the reaction, the reaction is quenched with sodium thiosulphate solution and worked up to obtain a reaction mixture which was hydrolyzed using aqueous solution of sodium hydroxide (335 g). The reaction mixture was worked up to obtain a crude mass of 2- chloro-4-methylaniline of formula I.

The crude mass of 2-chloro-4-methylaniline of formula I was further purified by distillation (Yield: 47 % on the basis of reacted p -acetotoluidine, Purity: >99.5%).

Example-4: a) Step I: Preparation of the N-(2-chloro-4-methylphenyl)acetamide

In a 2L four- necked flask, ethylene dichloride (400 mL), p -acetotoluidine (250 g) and Aluminium chloride (AlCh) catalyst (7.5 g) were added and the reaction mixture was heated. To the reaction mixture chlorine gas was purged till the completion of the reaction. The reaction mixture was cooled to room temperature. After completion of the reaction, the reaction is quenched with sodium thiosulphate solution, worked up followed by filtration to obtain solid. The obtained solid was washed with water and dried to obtain N-(2-chloro-4-methylphenyl)acetamide of formula (II). (Purity: 60%). b) Step II: Preparation of 2-chloro-4-methylaniline of formula I

In a 2L four-necked flask, the obtained solid of the compound of formula II and aqueous solution of sodium hydroxide (335 g) were added and reaction mass was heated. The reaction mixture was worked up to obtain crude liquid mass of 2-chloro-4-methylaniline of formula I. (Yield: 69 %; Purity: 67 %). c) Step III: Purification of 2-chloro-4-methylaniline of formula I

The crude mass of 2-chloro-4-methylaniline of formula I was purified by fractional distillation (Yield: 72 %, Purity: >99.5%).

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.