FIELD

The present disclosure relates to a process for the direct synthesis of Fedratinib intermediate. Particularly, the present disclosure relates to a process for the direct synthesis of 3-amino-N- (tert-butyl)benzene sulfonamide.

DEFINITION:

As used in the present disclosure, the following term is generally intended to have the meaning as set forth below, except to the extent that the context in which it is used indicates otherwise. Direct synthesis- The term ‘direct synthesis’ also known as a ‘synthesis reaction’ or ‘direct combination reaction’, refers to a type of chemical reaction in which two or more simple substances combine to form a more complex product.

BACKGROUND

The background information herein below relates to the present disclosure but is not necessarily prior art.

3-amino-N-(tert-butyl)benzene sulfonamide is a useful intermediate in the preparation of Fedratinib. Fedratinib belongs to a class of drugs known as kinase inhibitors. Fedratinib works by slowing or stopping the growth of cancer cells. The structural representation of Fedratinib is as given below:

Fedratinib

Various methods for the preparation of 3-amino-N-(tert-butyl)benzene sulfonamide are reported in the prior art. Conventionally, the preparation of 3-amino-N-(tert-butyl)benzene sulfonamide is carried out by using highly toxic chemicals, which are dangerous during operation as they are difficult to recover and hazardous to the environment. Generally, 3- amino-N-(tert-butyl)benzene sulfonamide is prepared by reducing N-(tert-butyl)-3- nitrobenzenesulfonamide in the presence of zinc. The disadvantages of this method are the use of zinc which leads to the formation of more sludge during the reaction and it becomes very difficult to remove sludge from the final product and thus, resulting in poor product quality, low yield of the product, high production costs and hence, industrially not feasible.

Moreover, the conventional process for the synthesis of 3-amino-N-(tert-butyl)benzene sulfonamide is carried out by using costly reagents like N, N-di-isopropyl ethylene amine (DIPEA). The literature is replete with various other methods for the synthesis of 3-amino-N- (tert-butyl)benzene sulfonamide by various other routes. However, these methods are associated with drawbacks such as low yield and / or low purity of 3-amino-N-(tert- butyl)benzene sulfonamide and thus, not suitable for commercial scale. Further, these methods require tedious purification steps, thereby resulting in an expensive process.

Therefore, there is felt a need to provide an alternative process for direct synthesis of 3- amino-N-(tert-butyl)benzene sulfonamide that mitigates the drawbacks mentioned hereinabove or at least provides a useful alternative.

OBJECTS

Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows: It is an object of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative.

An object of the present disclosure is to provide a process for the direct synthesis of 3-amino- N-(tert-butyl)benzene sulfonamide.

Another object of the present disclosure is to provide a process for the direct synthesis of 3- amino-N-(tert-butyl)benzene sulfonamide with a comparatively high yield and high purity.

Still another object of the present disclosure is to provide a process for the direct synthesis of 3-amino-N-(tert-butyl)benzene sulfonamide that is simple, efficient, environmental friendly and economical. Yet another object of the present disclosure is to provide a process for the direct synthesis of 3-amino-N-(tert-butyl)benzene sulfonamide that involves in situ reaction.

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

The present disclosure relates to a process for the direct synthesis of 3-amino-N-(tert- butyljbenzene sulfonamide represented by formula (I):

Formula (I) The process for the direct synthesis of 3-amino-N-(tert-butyl)benzene sulfonamide comprises reacting nitrobenzene with a sulfonating agent followed by reacting with a chlorinating agent under stirring for a first predetermined time period to obtain 3-nitrobenzenesulfonyl chloride. The so obtained 3-nitrobenzenesulfonyl chloride is reacted with tert-butyl amine under stirring for a second predetermined time period to obtain N-(tert-butyl)-3- nitrobenzenesulfonamide. Further, N-(tert-butyl)-3-nitrobenzenesulfonamide is reduced in the presence of a reducing agent to obtain a product mass comprising a crude 3-amino-N-(tert- butyl) benzene sulphonamide. The so obtained crude 3-amino-N-(tert-butyl) benzene sulfonamide is isolated and recrystallized to obtain a pure 3-amino-N-(tert-butyl) benzene sulfonamide. DETAILED DESCRIPTION

Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, known processes or well-known apparatus or structures, and well-known techniques are not described in detail.

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. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open-ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.

The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.

3-amino-N-(tert-butyl)benzene sulfonamide is a useful intermediate in the preparation of Fedratinib. Fedratinib belongs to a class of drugs known as kinase inhibitors. Fedratinib works by slowing or stopping the growth of cancer cells.

Various conventional methods for the preparation of 3-amino-N-(tert-butyl)benzene sulfonamide are known in the prior art. Flowever, the product obtained by using the conventional methods has a comparatively low yield and low purity. Further, the conventional methods of preparing 3-amino-N-(tert-butyl)benzene sulfonamide require costly and highly toxic reagents such as N, N-di-isopropyl ethylene amine (DIPEA) and zinc, resulting in operational inconveniences and unsuitability for the large-scale production.

The present disclosure provided a simple, economic and environmental friendly process for the direct synthesis of 3-amino-N-(tert-butyl)benzene sulfonamide. 3-amino-N-(tert- butyl)benzene sulfonamide is represented by Formula I:

Formula I

The process for direct synthesis of 3-amino-N-(tert-butyl)benzene sulfonamide comprises the following steps: (i) reacting nitrobenzene with a sulfonating agent followed by reacting with a chlorinating agent under stirring for a first predetermined time period to obtain 3- nitrobenzenesulfonyl chloride;

(ii) reacting 3-nitrobenzenesulfonyl chloride with tert-butyl amine under stirring for a second predetermined time period to obtain N-(tert-butyl)-3- nitrobenzenesulfonamide;

(iii) reducing N-(tert-butyl)-3-nitrobenzenesulfonamide in the presence of a reducing agent to obtain a product mass comprising crude 3-amino-N-(tert-butyl) benzene sulfonamide; and

(iv) isolating and recrystallizing the crude 3-amino-N-(tert-butyl) benzene sulfonamide to obtain a pure 3-amino-N-(tert-butyl) benzene sulfonamide.

In accordance with the present disclosure, the process for the direct synthesis of 3-amino-N- (tert-butyl)benzene sulfonamide (Fedratinib intermediate) is described in detail.

In a first step, nitrobenzene is reacted with a sulfonating agent followed by reacting with a chlorinating agent under stirring for a first predetermined time period to obtain 3- nitrobenzenesulfonyl chloride.

In accordance with the embodiment of the present disclosure, the reaction is monitored by using a thin layer chromatography (TLC).

In accordance with the embodiment of the present disclosure, the sulfonating agent is at least one selected from the group consisting of chlorosulfonic acid, bromo sulfonic acid and fluoro sulphonic acid. In an exemplary embodiment of the present disclosure, the sulfonating agent is chlorosulfonic acid.

In accordance with the embodiment of the present disclosure, the chlorinating agent is at least one selected from the group consisting of thionyl chloride, sulfuryl chloride, phosphorous oxychloride, phosphorous trichloride and phosphorous pentachloride. In an exemplary embodiment of the present disclosure, the chlorinating agent is thionyl chloride.

In accordance with the embodiment of the present disclosure, the nitrobenzene is reacted with a sulfonating agent at a temperature in the range of 100°C to 150°C. In an exemplary embodiment of the present disclosure, the temperature is 110 °C.

In accordance with the present disclosure, a reaction mixture of nitrobenzene and the sulfonating agent is cooled to a temperature in the range of 40°C to 70°C followed by adding a chlorinating agent.

In accordance with the embodiment of the present disclosure, the nitrobenzene is reacted with a chlorinating agent at a temperature in the range of 40°C to 70°C. In an exemplary embodiment of the present disclosure, the temperature is 45 °C.

In accordance with the embodiment of the present disclosure, the first predetermined time period is in the range of 8 to 14 hours. In an exemplary embodiment of the present disclosure, the first predetermined time period is 10 hours.

In accordance with the embodiment of the present disclosure, 3-nitrobenzenesulfonyl chloride so obtained is quenched in water having a temperature is in the range of 0 to 5 °C followed by the addition of a first fluid medium to obtain a biphasic mixture containing an aqueous layer and an organic layer comprising 3-nitrobenzenesulfonyl chloride.

In accordance with the embodiment of the present disclosure, the organic layer comprising 3- nitrobenzenesulfonyl chloride is separated and used for the next step.

In accordance with the embodiment of the present disclosure, the first fluid medium is at least one selected from the group consisting of ethyl acetate, butyl acetate, dichloromethane, chloroform (CHCI ₃ ), carbon tetrachloride (CCI ₄ ) and ethylene dichloride (EDC). In an exemplary embodiment of the present disclosure, the first fluid medium is ethyl acetate. In another exemplary embodiment of the present disclosure, the first fluid medium is dichloromethane. In accordance with the embodiment of the present disclosure, a mass ratio of nitrobenzene to the tert-butyl amine is in the range of 0.1:1 to 1:1. In an exemplary embodiment of the present disclosure, the mass ratio of the nitrobenzene to the tert-butyl amine is 0.4:1.

In a second step, 3-nitrobenzenesulfonyl chloride is reacted with tert-butyl amine under stirring for a second predetermined time period to obtain N-(tert-butyl)-3- nitrobenzenesulfonamide.

In accordance with the embodiment of the present disclosure, the reaction is monitored by using high-performance liquid chromatography and/or a thin layer chromatography (HPLC/TLC). In accordance with the embodiment of the present disclosure, the second predetermined time period is in the range of 8 to 14 hours. In an exemplary embodiment of the present disclosure, the second predetermined time period is 12 hours.

In accordance with the embodiment of the present disclosure, the tert-butyl amine is added to the organic layer comprising 3-nitrobenzenesulfonyl chloride, at a temperature in the range of 0 to 10 °C to obtain a reaction mass comprising N-(tert-butyl)-3-nitrobenzenesulfonamide.

In accordance with the embodiment of the present disclosure, 3-nitrobenzenesulfonyl chloride is reacted with tert-butyl amine by maintaining a temperature in the range of 25 °C to 35°C. In an exemplary embodiment of the present disclosure, the temperature is 30 °C.

In accordance with the embodiment of the present disclosure, water is added to the reaction mass comprising N-(tert-butyl)-3-nitrobenzenesulfonamide to obtain a slurry followed by extracting N-(tert-butyl)-3-nitrobenzenesulfonamide from the slurry in a second fluid medium to obtain N-(tert-butyl)-3-nitrobenzenesulfonamide.

In accordance with the embodiment of the present disclosure, the second fluid is at least one selected from ethyl acetate and dichloromethane. In an exemplary embodiment of the present disclosure, the second fluid medium is ethyl acetate. In another exemplary embodiment of the present disclosure, the second fluid medium is dichloromethane.

In accordance with the present disclosure, the first fluid medium and the second fluid medium can be the same or different. In a third step, N-(tert-butyI)-3-nitrobenzenesuIfonamide is reduced in the presence of a reducing agent to obtain a product mass comprising a crude 3-amino-N-(tert-butyl) benzene sulfonamide.

In accordance with the embodiment of the present disclosure, the reaction is monitored by using a thin layer chromatography (TLC).

In accordance with the present disclosure, the reducing agent is at least one selected from Pd/C (palladium on carbon) and Raney Nickel (Raney Ni). In an exemplary embodiment of the present disclosure, the reducing agent is Pd/C. In another exemplary embodiment of the present disclosure, the reducing agent is Raney Ni. In accordance with the embodiment of the present disclosure, (tert-butyl)-3- nitrobenzenesulfonamide is reduced in the presence of a reducing agent at a temperature in the range of 25°C to 35°C. In an exemplary embodiment of the present disclosure, the temperature is 30°C.

In accordance with the embodiment of the present disclosure, the mass ratio of the reducing agent to the N-(tert-butyl)-3-nitrobenzenesulfonamide is in the range of 1:5 to 1:15. In an exemplary embodiment of the present disclosure, the mass ratio of the reducing agent to the N-(tert-butyl)-3-nitrobenzenesulfonamide is 1:10.

In accordance with the present disclosure, the N-(tert-butyl)-3-nitrobenzenesulfonamide is reduced in a third fluid medium in the presence of a reducing agent to obtain a product mass comprising a crude 3-amino-N-(tert-butyl) benzene sulfonamide.

In accordance with the present disclosure, the third fluid medium is at least one selected from the group consisting of ethyl acetate, methanol, isopropyl alcohol (IP A) and ethanol. In an exemplary embodiment of the present disclosure, the third fluid medium is ethyl acetate. In another exemplary embodiment of the present disclosure, the third fluid medium is ethanol. In a fourth step, the so obtained crude 3-amino-N-(tert-butyl) benzene sulfonamide is isolated followed by recrystallization to obtain a pure 3-amino-N-(tert-butyl) benzene sulfonamide.

In accordance with the present disclosure, the crude 3-amino-N-(tert-butyl) benzene sulfonamide is isolated from the product mass by distilling the third fluid medium followed by adding a fourth fluid medium and recrystallizing the crude 3-amino-N-(tert-butyl) benzene sulfonamide in the fourth fluid medium to obtain a pure 3-amino-N-(tert-butyl) benzene sulfonamide.

In accordance with the present disclosure, the fourth fluid medium is at least one selected from the group consisting of isopropyl alcohol (IP A), ethanol and butanol. The schematic representation of the process for the direct synthesis of 3-amino-N-(tert-butyl) benzene sulfonamide is as given below: nit ut l) enzene sup onamide chloride sulfonamide

In accordance with the present disclosure, the purity of the product (3-amino-N-(tert-butyl) benzene sulfonamide) is 99%. In accordance with the present disclosure, the yield of the product (3-amino-N-(tert-butyl) benzene sulfonamide) is 80%.

The present disclosure provides an alternative process for the direct synthesis of 3-amino-N- (tert-butyl) benzene sulfonamide by using non-toxic and cheap reagents.

The process for the direct synthesis of 3-amino-N-(tert-butyl) benzene sulfonamide in accordance with the present disclosure, has various advantages such as convenient operation conditions, time-saving process, easy purification, low operation costs, good yield and efficiency hence the process is industrially feasible.

As a result of using non-toxic, inexpensive and easily available reagents, the process of the present disclosure is cost-efficient, economic and environmental friendly. The foregoing description of the embodiments has been provided for purposes of illustration and is not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but, are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure. The present disclosure is further illustrated herein below with the help of the following experiments. The experiments used herein are intended merely to facilitate an understanding of the ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the experiments should not be construed as limiting the scope of embodiments herein. These laboratory-scale experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to industrial/commercial scale.

EXPERIMENTAL DETAILS

Direct synthesis of 3-amino-N-(tert-butyl) benzene sulfonamide in accordance with the present disclosure:

EXAMPLE: 1

Step (i ): 212 g of chlorosulfonic acid was charged into a first reactor under stirring and heated at 11 CPC and 50 g of nitrobenzene was added to obtain a mixture. The reactor containing the mixture was then cooled to 45 °C and 48 g of thionyl chloride was added to the mixture under stirring for 10 hours to obtain a first reaction mass comprising 3-nitrobenzenesulfonyl chloride. The completion of the reaction was monitored by using TLC and after reaction completion, the first reaction mass was quenched in ice water having a temperature below 5°C followed by the addition of 250 ml ethyl acetate to obtain a biphasic mixture containing an aqueous layer and an organic layer (ethyl acetate layer). The organic layer (ethyl acetate layer) comprising 3-nitrobenzenesulfonyl chloride was separated and was used for the next step.

Step (ii): Ethyl acetate layer containing 3-nitrobenzenesulfonyl chloride was charged in a second reactor and 118 g of tert-butyl amine was added to the reactor at a temperature below 10°C to obtain a second reaction mass. The second reaction mass was maintained at 30°C under stirring for 12 hours to obtain a third reaction mass comprising N-(tert-butyl)-3- nitrobenzenesulfonamide. The completion of the reaction was monitored by using TLC and after reaction completion, 250 ml of water was added to the second reaction mass to obtain a slurry. 250 ml of ethyl acetate was added to the slurry and N-(tert-butyl)-3- nitrobenzenesulfonamide was extracted from the slurry in ethyl acetate. Ethyl acetate containing N-(tert-butyl)-3-nitrobenzenesulfonamide was used for the next step. Step (in ^' ): Ethyl acetate containing N-(tert-butyl)-3-nitrobenzenesulfonamide was charged into a clean and dry autoclave and 5 g of Pd/C as a reducing reagent was added to the autoclave at 30°C to obtain a product mass comprising crude 3-amino-N-(tert-butyl) benzene sulfonamide. The completion of the reaction is monitored by using TLC.

Step (iv): After reaction completion, the reducing agent, Pd/C was removed by filtration and ethyl acetate was removed by distillation and then 200 ml of isopropyl alcohol (IP A) was added to the product mass to isolate a crude 3-amino-N-(tert-butyl) benzene sulfonamide. The crude 3-amino-N-(tert-butyl) benzene sulfonamide was recrystallized in IPA to obtain a pure 3-amino-N-(tert-butyl) benzene sulfonamide having a purity of 99% and a yield of 80%.

EXAMPLE 2:

Step (G): 212 g of chlorosulfonic acid was charged into a first reactor under stirring and heated at 110°C and 50 g of nitrobenzene was added to obtain a mixture. The reactor containing the mixture was then cooled to 50°C and 48 g of thionyl chloride was added to the mixture under stirring for 10 hours to obtain a first reaction mass comprising 3-nitrobenzenesulfonyl chloride. The completion of the reaction was monitored by using TLC and after reaction completion, the first reaction mass was quenched in ice water having a temperature below 5°C followed by the addition of 250 ml dichloromethane (DCM) to obtain a biphasic mixture containing an aqueous layer and an organic layer (DCM layer). The organic layer (DCM layer) comprising 3-nitrobenzenesulfonyl chloride was separated and was used for the next step.

Step (ii): DCM layer containing 3-nitrobenzenesulfonyl chloride was charged in a second reactor and 118.5 g of tert-butyl amine was added to the reactor at a temperature below 10°C to obtain a second reaction mass. The second reaction mass was maintained at 30°C under stirring for 10 hours to obtain a third reaction mass comprising N-(tert-butyl)-3- nitrobenzenesulfonamide. The completion of the reaction was monitored by using TLC and after reaction completion, 250 ml of water was added to the second reaction mass to obtain a slurry. 250 ml of DCM was added to the slurry and N-(tert-butyl)-3-nitrobenzenesulfonamide was extracted from the slurry in DCM. DCM was distilled out and the remaining residue comprising N-(tert-butyl)-3-nitrobenzenesulfonamide was dissolved in ethanol.

Step (iii): Ethanol containing N-(tert-butyl)-3-nitrobenzenesulfonamide was charged into a clean and dry autoclave and 12 g of Raney Ni as a reducing reagent was added to the autoclave at 30°C to obtain a product mass comprising crude 3-amino-N-(tert-butyl) benzene sulfonamide. The completion of the reaction is monitored by using TLC.

Step (iv): After reaction completion, the reducing agent, Raney Ni was removed by filtration and ethanol was removed by distillation and then 200 ml of isopropyl alcohol (IP A) was added to the product mass to isolate a crude 3-amino-N-(tert-butyl) benzene sulfonamide. The crude 3-amino-N-(tert-butyl) benzene sulfonamide was recrystallized in IPA to obtain a pure 3-amino-N-(tert-butyl) benzene sulfonamide having a purity of 99% and a yield of 80%.

The present disclosure thus provides a simple, efficient and environment friendly process for the direct synthesis of 3-amino-N-(tert-butyl) benzene sulfonamide.

Inference :

• From examples 1 and 2, it was observed that the reaction time to complete the reaction was less.

• Easy recycling of solvent was observed when Pd/C was used as a reducing agent and ethyl acetate was used as a solvent in step-I to step III as compared to MDC (methylene chloride) as a solvent.

• A greater yield of 3-amino-N-(tert-butyl) benzene sulfonamide was obtained (80%) in comparison to the conventional process (64%) with isolating steps.

TECHNICAL ADVANCES AND ECONOMICAL SIGNIFICANCE

The present disclosure described herein above has several technical advantages including, but not limited to, the realization of a process for the direct synthesis of 3-amino-N-(tert-butyl) benzene sulfonamide, which:

• is feasible for commercial scale-up;

• is simple, economical and environment-friendly; and

• provides high yield and high purity of 3-amino-N-(tert-butyl) benzene sulfonamide. The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following 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 herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

The foregoing description of the specific embodiments so fully reveals 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.

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.

Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.

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. While considerable emphasis has been placed herein on the components and component parts of the preferred embodiments, it will be appreciated that many embodiments can be made and that many changes can be made in the preferred embodiments without departing from the principles of the disclosure. These and other changes in the preferred embodiment, as well as other embodiments of the disclosure, will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.