A process for the preparation of 5-((4-ethylpiperazin-1-YL)methyl)pyridin-2-amine

Abstract

The present disclosure relates to a process for the preparation of 5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-amine. The process of the present disclosure is simple, cost-effective, commercially scalable and environment friendly. The process of the present disclosure provides comparatively high purity and high conversion of the product.

Description

[0001] A PROCESS FOR THE PREPARATION OF 5-((4-ETHYLPIPERAZIN-l-

[0002] YL)METHYL)PYRIDIN-2-AMINE

[0003] FIELD

[0004] The present disclosure relates to a process for the preparation of Abemaciclib intermediate. Particularly, the present disclosure relates to a process for the preparation of 5-((4- ethylpiperazin- 1 -yl)methyl)pyridin-2 -amine .

[0005] BACKGROUND

[0006] The background information herein below relates to the present disclosure but is not necessarily prior art.

[0007] 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine is a key pharmaceutical intermediate used in the synthesis of Abemaciclib. Abemaciclib is a selective cyclin-dependent kinase (CDK)4 / 6 inhibitor used in the treatment of advanced or metastatic breast cancers. 5-((4-ethylpiperazin- l-yl)methyl)pyridin-2-amine is represented as formula (I) below:

[0008] Formula (I)

[0009] Conventional methods for the preparation of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2- amine are associated with certain drawbacks such as formation of impurities and a low conversion of the final product. Further, the conventional processes require expensive reactants and reagents thereby making the process not economical. Furthermore, these conventional processes require severe reaction conditions, involve complex post-treatment and having difficulties in product purification due to which the conventional processes are not operation friendly. Still further, the conventional processes involve multi-step reaction which are time consuming and energy intensive. Therefore, there is felt a need to provide a process for the preparation of 5-((4-ethylpiperazin-

[0010] 1-yl)methyl)pyridin-2-amine that mitigates the aforestated drawbacks or at least provides a useful alternative.

[0011] OBJECTS

[0012] Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:

[0013] It is an object of the present disclosure to ameliorate one or more problems of the background or to at least provide a useful alternative.

[0014] Another object of the present disclosure is to provide a process for the preparation of Abemaciclib intermediate.

[0015] Yet another object of the present disclosure is to provide a process for the preparation of 5-((4- ethylpiperazin- 1 -yl)methyl)pyridin-2 -amine (Abemaciclib intermediate) .

[0016] Still another object of the present disclosure is to provide a process for the preparation of 5- ((4-ethylpiperazin-l-yl)methyl)pyridin-2 -amine that provides comparatively high purity and high conversion of the product.

[0017] Yet another object of the present disclosure is to provide a simple, cost-effective and environment friendly process for the preparation of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-

[0018] 2 -amine.

[0019] Still another object of the present disclosure is to provide a process for the preparation of 5- ((4-ethylpiperazin-l-yl)methyl)pyridin-2 -amine that is commercially scalable.

[0020] 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.

[0021] SUMMARY

[0022] The present disclosure relates to a process for the preparation of 5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-amine . The process comprises the following steps: i. reacting 2-chloro-5-chloromethylpyridine with 1 -ethylpiperazine by using a first base in a first fluid medium at a first predetermined temperature for a first predetermined time period followed by cooling to a second predetermined temperature to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer; ii. separating the first organic layer from the first biphasic mixture followed by distilling under vacuum to obtain an intermediate comprising l-((6-chloropyridin-3-yl)methyl)- 4-ethylpiperazine; iii. reacting the intermediate and a second base in the presence of a catalyst in an autoclave at a third predetermined temperature for a second predetermined time period to obtain a reaction mixture comprising 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine and piperazinyl methyl pyridine derivatives; and iv. cooling the reaction mixture to a fourth predetermined temperature followed by adding an alkali and a second fluid medium and heating to a fifth predetermined temperature for a third predetermined time period to obtain a product mixture comprising 5 -((4- ethylpiperazin-l-yl)methyl)pyridin-2 -amine having a purity in the range of 80% to 85%.

[0023] 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine having a purity in the range of 80% to 85% is purified by using the following sub-steps:

[0024] • separating the product mixture to obtain a separated second organic layer and a separated second aqueous layer; and

[0025] • distilling the separated second organic layer to obtain slurry, filtering the slurry to obtain solids and drying the solids to obtain 5-((4-ethylpiperazin-l-yl)methyl)pyridin- 2-amine having a purity greater than 99%.

[0026] The purity of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine is greater than 99.4%.

[0027] The first base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.

[0028] The second base is selected from an aqueous ammonia solution and an anhydrous ammonia gas.

[0029] The alkali is selected from sodium hydroxide and potassium hydroxide. The catalyst is selected from copper bromide and copper iodide.

[0030] The first fluid medium is at least one selected from the group consisting of toluene, water, o- xylene, m- xylene and p-xylene.

[0031] The second fluid medium is at least one selected from the group consisting of toluene, ethyl acetate, isopropyl acetate, o-xylene, m- xylene and p-xylene.

[0032] The molar ratio of 2-chloro-5 -chloromethylpyridine to 1 -ethylpiperazine is in the range of 1 : 1 to 1: 1.5.

[0033] The molar ratio of 2-chloro-5-chloromethylpyridine to the first base is in the range of 1: 1 to 1: 1.5.

[0034] The molar ratio of 2-chloro-5 -chloromethylpyridine to the catalyst is in the range of 1:0.1 to 1:0.5.

[0035] The first predetermined temperature is in the range of 75 °C to 100 °C.

[0036] The second predetermined temperature is in the range of 20 °C to 30 °C.

[0037] The third predetermined temperature is in the range of 110 °C to 140 °C.

[0038] The fourth predetermined temperature is in the range of 20 °C to 30 °C.

[0039] The fifth predetermined temperature is in the range of 40 °C to 70 °C.

[0040] The first predetermined time period is in the range of 1 hour to 3 hours.

[0041] The second predetermined time period is in the range of 20 hours to 28 hours.

[0042] The third predetermined time period is in the range of 30 minutes to 120 minutes.

[0043] The percentage conversion of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine is in the range of 60% to 70%.

[0044] The piperazinyl methyl pyridine derivatives formed during the process are 5-((4- ethylpiperazin-l-yl)methyl)pyridin-2-ol (Hydroxy derivative) and 4,4'-((oxybis(pyridine-6,3- diyl))bis(methylene))bis(l -ethylpiperazine) (Dimer derivative) and having the following structures:

[0045] Hydroxy derivative Dimer derivative

[0046] The hydroxy derivative and the dimer derivative are present in an amount less than 0.3%.

[0047] 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine is prepared by the process of the present disclosure having a purity greater than 99%.

[0048] BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWING

[0049] The present disclosure will now be described with the help of the accompanying drawing, in which:

[0050] Figure 1 illustrates a mass spectrum for 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-ol (Hydroxy derivative) in accordance with the present disclosure; and

[0051] Figure 2 illustrates a mass spectrum for 4,4'-((oxybis(pyridine-6,3-diyl))bis(methylene))bis(l- ethylpiperazine) (Dimer derivative) in accordance with the present disclosure.

[0052] DETAILED DESCRIPTION

[0053] The present disclosure relates to a process for the preparation of Abemaciclib intermediate. Particularly, the present disclosure relates to a process for the preparation of 5-((4- ethylpiperazin- 1 -yl)methyl)pyridin-2 -amine .

[0054] Embodiments, of the present disclosure, will now be described with reference to the accompanying drawing.

[0055] 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, well-known processes, well-known apparatus 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.

[0056] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed elements.

[0057] 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.

[0058] Conventional methods for the preparation of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2- amine are associated with certain drawbacks such as formation of impurities and a low conversion of the final product. Further, the conventional processes require expensive reactants and reagents thereby making the process not economical. Furthermore, these conventional processes require severe reaction conditions, involve complex post-treatment and having difficulties in product purification due to which the conventional processes are not operation friendly. Still further, the conventional processes involve multi-step reaction which are time consuming and energy intensive.

[0059] The present disclosure provides a process for the preparation of Abemaciclib intermediate. Particularly, the present disclosure provides a process for the preparation of 5 -((4- ethylpiperazin- 1 -yl)methyl)pyridin-2 -amine .

[0060] The process of the present disclosure is simple, environment friendly, economical, and results in high conversion and higher purity of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine. In an aspect, the present disclosure provides a process for the preparation of 5-((4- ethylpiperazin- 1 -yl)methyl)pyridin-2 -amine .

[0061] The process for the preparation of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine comprises the following steps: i. reacting 2-chloro-5-chloromethylpyridine with 1 -ethylpiperazine by using a first base in a first fluid medium at a first predetermined temperature for a first predetermined time period followed by cooling to a second predetermined temperature to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer; ii. separating the first organic layer from the first biphasic mixture followed by distilling under vacuum to obtain an intermediate comprising l-((6-chloropyridin-3-yl)methyl)- 4-ethylpiperazine; iii. reacting the intermediate and a second base in the presence of a catalyst in an autoclave at a third predetermined temperature for a second predetermined time period to obtain a reaction mixture comprising 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine and piperazinyl methyl pyridine derivatives; and iv. cooling the reaction mixture to a fourth predetermined temperature followed by adding an alkali and a second fluid medium and heating to a fifth predetermined temperature for a third predetermined time period to obtain a product mixture comprising 5-((4- ethylpiperazin-l-yl)methyl)pyridin-2 -amine having a purity in the range of 80% to 85%.

[0062] The process is described in detail below.

[0063] In a first step, 2-chloro-5 -chloromethylpyridine is reacted with 1 -ethylpiperazine by using a first base in a first fluid medium at a first predetermined temperature for a first predetermined time period followed by cooling to a second predetermined temperature to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer.

[0064] In an embodiment of the present disclosure, the first base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate. In an exemplary embodiment of the present disclosure, the first base is potassium carbonate.

[0065] In an embodiment of the present disclosure, the first fluid medium is at least one selected from the group consisting of toluene, water, o-xylene, m-xylene and p-xylene. In an exemplary embodiment of the present disclosure, the first fluid medium is a mixture of toluene and water in a volume ratio of 1 : 1.

[0066] In an embodiment of the present disclosure, a molar ratio of 2-chloro-5 -chloromethylpyridine to 1 -ethylpiperazine is in the range of 1 : 1 to 1 : 1.5. In an exemplary embodiment of the present disclosure, the molar ratio of 2-chloro-5 -chloromethylpyridine to 1 -ethylpiperazine is 1: 1.2.

[0067] In an embodiment of the present disclosure, a molar ratio of 2-chloro-5 -chloromethylpyridine to the first base is in the range of 1: 1 to 1: 1.5. In an exemplary embodiment of the present disclosure, the molar ratio of 2-chloro-5 -chloromethylpyridine to the first base is 1: 1.17.

[0068] In an embodiment of the present disclosure, the first predetermined temperature is in the range of 75 °C to 100 °C. In an embodiment of the present disclosure, the first predetermined temperature is in the range of 85 °C to 90 °C. In an exemplary embodiment of the present disclosure, the first predetermined temperature is 90 °C.

[0069] In an embodiment of the present disclosure, the first predetermined time period is in the range of 1 hour to 3 hours. In an exemplary embodiment of the present disclosure, the first predetermined time period is 2 hours.

[0070] In an embodiment of the present disclosure, the second predetermined temperature is in the range of 20 °C to 30 °C. In an exemplary embodiment of the present disclosure, the first predetermined temperature is 27 °C.

[0071] In a second step, the first organic layer is separated from the first biphasic mixture followed by distilling under vacuum to obtain an intermediate comprising l-((6-chloropyridin-3- yl)methyl)-4-ethylpiperazine .

[0072] In an embodiment of the present disclosure, the distillation is carried out at a temperature in the range of 40 °C to 70 °C. In an embodiment of the present disclosure, the distillation is carried out at a temperature in the range of 50 °C to 60 °C. In an exemplary embodiment of the present disclosure, the distillation is carried out at 60 °C.

[0073] In a third step, the intermediate and a second base are reacted in the presence of a catalyst in an autoclave at a third predetermined temperature for a second predetermined time period to obtain a reaction mixture comprising 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine and piperazinyl methyl pyridine derivatives. In an embodiment of the present disclosure, the catalyst is selected from copper bromide and copper iodide. In an exemplary embodiment of the present disclosure, the catalyst is copper bromide. In another exemplary embodiment of the present disclosure, the catalyst is copper iodide.

[0074] In an embodiment of the present disclosure, a molar ratio of 2-chloro-5 -chloromethylpyridine to the catalyst is in the range of 1:0.1 to 1:0.5. In an exemplary embodiment of the present disclosure, the molar ratio of 2-chloro-5 -chloromethylpyridine to the catalyst is 1:0.18.

[0075] In accordance with the present disclosure, the conversion of l-((6-chloropyridin-3-yl)methyl)- 4-ethylpiperazine to 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine, using copper bromide and copper iodide demonstrate superior catalytic efficiency as compared to copper chloride. This enhanced performance is likely due to the higher nucleophilicity and better leaving group ability of bromide and iodide ions, which facilitate more efficient oxidative addition and reductive elimination steps in the catalytic cycle. Additionally, the softer halide ligands in CuBr and Cui offers a better stabilization of catalytic intermediates, promoting higher conversion rates.

[0076] In an embodiment of the present disclosure, the second base is aqueous ammonia solution and anhydrous ammonia gas. In an exemplary embodiment of the present disclosure, the second base is aqueous ammonia solution.

[0077] In an embodiment of the present disclosure, the third predetermined temperature is in the range of 110 °C to 140 °C. In an embodiment of the present disclosure, the third predetermined temperature is in the range of 120 °C to 130 °C. In an exemplary embodiment of the present disclosure, the third predetermined temperature is 125 °C. In another exemplary embodiment of the present disclosure, the third predetermined temperature is 130 °C.

[0078] In an embodiment of the present disclosure, the second predetermined time period is in the range of 20 hours to 28 hours. In an exemplary embodiment of the present disclosure, the second predetermined time period is 24 hours.

[0079] In an embodiment of the present disclosure, the piperazinyl methyl pyridine derivatives formed during the process are 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-ol (Hydroxy derivative) and 4,4'-((oxybis(pyridine-6,3-diyl))bis(methylene))bis(l-ethylpiperazine) (Dimer derivative) and having the following structures:

[0080] Hydroxy derivative Dimer derivative

[0081] In an embodiment of the present disclosure, the reaction mixture comprises 5 -((4- ethylpiperazin-l-yl)methyl)pyridin-2-ol (Hydroxy derivative) in an amount in the range of 5% to 15% and 4,4'-((oxybis(pyridine-6,3-diyl))bis(methylene)) bis(l -ethylpiperazine) (Dimer derivative) in an amount in the range of 4% to 8%.

[0082] In an exemplary embodiment of the present disclosure, the reaction mixture comprises 5-((4- ethylpiperazin-l-yl)methyl)pyridin-2-ol (Hydroxy derivative) of 8% and 4,4'- ((oxybis(pyridine-6,3-diyl))bis(methylene))bis(l-ethylpiperazine) (Dimer derivative) of 7%. In another exemplary embodiment of the present disclosure, the reaction mixture comprises 5- ((4-ethylpiperazin-l-yl)methyl)pyridin-2-ol (Hydroxy derivative) of 8% and 4,4'- ((oxybis(pyridine-6,3-diyl))bis(methylene)) bis(l -ethylpiperazine) (Dimer derivative) of 5%. In yet another exemplary embodiment of the present disclosure, the reaction mixture comprises 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-ol (Hydroxy derivative) of 12% and 4,4'- ((oxybis(pyridine-6,3-diyl))bis(methylene)) bis(l -ethylpiperazine) (Dimer derivative) of 5%. In still another exemplary embodiment of the present disclosure, the reaction mixture comprises 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-ol (Hydroxy derivative) of 10% and 4,4'-((oxybis(pyridine-6,3-diyl))bis(methylene))bis(l-ethylpiperazine) (Dimer derivative) of C JO / / o.

[0083] In a fourth step, the reaction mixture is cooled to a fourth predetermined temperature followed by adding an alkali and a second fluid medium and heating to a fifth predetermined temperature for a third predetermined time period to obtain a product mixture comprising 5-((4- ethylpiperazin-l-yl)methyl)pyridin-2 -amine having a purity in the range of 80% to 85%.

[0084] In an embodiment of the present disclosure, the fourth predetermined temperature is in the range of 20 °C to 30 °C. In an exemplary embodiment of the present disclosure, the fourth predetermined temperature is 27 °C.

[0085] In an embodiment of the present disclosure, the alkali is selected from sodium hydroxide and potassium hydroxide. In an exemplary embodiment of the present disclosure, the alkali is sodium hydroxide. In an embodiment of the present disclosure, the second fluid medium is at least one selected from the group consisting of toluene, ethyl acetate, isopropyl acetate, o-xylene, m- xylene and p-xylene. In an exemplary embodiment of the present disclosure, the second fluid medium is toluene.

[0086] In accordance with the present disclosure, the reaction mixture comprises 5-((4-ethylpiperazin- 1 -yl)methyl)pyridin-2-amine, 5 -((4-ethylpiperazin- 1 -yl)methyl)pyridin-2-ol (hydroxy derivative) and 4,4'-((oxybis(pyridine-6,3-diyl))bis(methylene))bis(l-ethylpiperazine) (dimer derivative). The incorporation of an alkali in step (iv) facilitates the removal of the hydroxy derivative, while the use of a second fluid medium in step (iv) enables the removal of the dimer derivative. Accordingly, the process of the present disclosure provides crude 5 -((4- ethylpiperazin-l-yl)methyl)pyridin-2 -amine with eliminating impurities such as hydroxy derivative and dimer derivative.

[0087] In an embodiment of the present disclosure, the fifth predetermined temperature is in the range of 40 °C to 70 °C. In an embodiment of the present disclosure, the fifth predetermined temperature is in the range of 50 °C to 60 °C. In an exemplary embodiment of the present disclosure, the fifth predetermined temperature is 60 °C.

[0088] In an embodiment of the present disclosure, the third predetermined time period is in the range of 30 minutes to 120 minutes. In an exemplary embodiment of the present disclosure, the third predetermined time period is 60 minutes.

[0089] In an embodiment of the present disclosure, the product mixture comprising 5 -((4- ethylpiperazin-l-yl)methyl)pyridin-2 -amine having a purity in the range of 80% to 85% is a second biphasic mixture comprising a second organic layer and a second aqueous layer. The second organic layer separated from the second biphasic mixture to obtain a separated second organic layer; distilling the separated second organic layer to obtain slurry, filtering the slurry to obtain solids and drying solids to obtain 5 -((4-ethylpiperazin- l-yl)methyl)pyridin-2 -amine having a purity greater than 99%.

[0090] In an embodiment of the present disclosure, the second organic layer is separated from the second biphasic mixture followed by distilling at a temperature in the range of 40 °C to 70 °C till predetermined amount of volume of a separated second organic layer remains, to obtain a concentrated second organic layer. The concentrated second organic layer is cooled to 10 °C to 25 °C followed by maintaining for a time period in the range of 30 minutes to 90 minutes to obtain a slurry. The slurry is filtered followed by washing with toluene at 10 °C to 25 °C to obtain solids. The so obtained solids are dried at a temperature in the range of 50 °C to 60 °C for a time period in the range of 8 hours to 10 hours to obtain 5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-amine having a purity greater than 99%.

[0091] In an exemplary embodiment of the present disclosure, the second organic layer is separated from the second biphasic mixture followed by distilling at 60 °C till predetermined amount of volume of a separated second organic layer remains, to obtain a concentrated second organic layer. The concentrated second organic layer is cooled to 20 °C followed by maintaining for 60 minutes to obtain a slurry. The slurry is filtered followed by washing with toluene to obtain solids. The so obtained solids are dried at 60 °C for 10 hours to obtain 5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-amine having purity of 99.66%.

[0092] In an exemplary embodiment of the present disclosure, the predetermined amount of volume of the concentrated second organic layer is 2 / 3 amount of the separated second organic layer.

[0093] In an embodiment of the present disclosure, the purity of 5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-amine is greater than 99%.

[0094] In an embodiment of the present disclosure, the purity of 5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-amine is in the range of 99% to 99.99%. In an exemplary embodiment of the present disclosure, the purity of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine is 99.66%. In another exemplary embodiment of the present disclosure, the purity of 5-((4- ethylpiperazin-l-yl)methyl)pyridin-2 -amine is 99.49%. In yet another exemplary embodiment of the present disclosure, the purity of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine is 99.81%. In still another exemplary embodiment of the present disclosure, the purity of 5 -((4- ethylpiperazin-l-yl)methyl)pyridin-2 -amine is 99.59%.

[0095] The process of the present disclosure provides 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2- amine devoid of impurities or piperazinyl methyl pyridine derivatives. Even if the impurities / derivatives and any other unknown impurities are present in the final product (5 -((4- ethylpiperazin-l-yl)methyl)pyridin-2 -amine) that is not more than 0.30% thereby making the process of the present disclosure efficient (since the impurities are drastically reduced). The process for the preparation of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine of the present disclosure is simple, cost-effective, commercially scalable, environment friendly and provides comparatively high purity and high conversion of the product.

[0096] In accordance with an embodiment of the present disclosure, the schematic representation for the preparation of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine is illustrated as Scheme- A below: Scheme-A

[0097] In accordance with the present disclosure, the process of the present disclosure has simple workup step to isolate the 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine with high purity and high conversion of the product.

[0098] 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.

[0099] The present disclosure is further described in light of the following experiments which are set forth for illustration purposes only and not to be construed for limiting the scope of the disclosure. The following experiments are scalable to industrial / commercial processes.

[0100] EXPERIMENTAL DETAILS

[0101] Experiment 1: Preparation of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine in accordance with the present disclosure

[0102] Example 1

[0103] 100 g of 2-chloro-5 -chloromethylpyridine and 100 g of potassium carbonate (first base) were dissolved in a mixture of 400 ml of toluene and 400 ml water (first fluid medium) in a reactor at 27 °C followed by adding 84 g of 1 -ethylpiperazine at 27 °C to obtain a first mixture. The first mixture was heated to 90 °C (first predetermined temperature) and maintained for 2 hours (first predetermined time period) followed by cooling to 27 °C (second predetermined temperature) to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer.

[0104] The first organic layer was separated from the first biphasic mixture followed by distilling a separated first organic layer at 60 °C under vacuum to obtain an intermediate comprising 1 - ((6-chloropyridin-3 -yl)methyl)-4-ethylpiperazine .

[0105] The so obtained intermediate, 700 ml aqueous ammonia solution (second base) and 25 g of copper bromide (catalyst) were charged in an autoclave to obtain a second mixture. The autoclave containing the second mixture was heated to 125 °C (third predetermined temperature) and maintained for 24 hours (second predetermined time period) to obtain a reaction mixture comprising 5-((4-ethylpiperazin-l-yl)methyl) pyridin-2 -amine, 5-((4- ethylpiperazin-l-yl)methyl)pyridin-2-ol (Hydroxy derivative) and 4,4'-((oxybis(pyridine-6,3- diyl))bis(methylene))bis(l -ethylpiperazine) (Dimer derivative).

[0106] The reaction was monitored by HPLC and around 64 % conversion was found for 5-((4- ethylpiperazin-l-yl)methyl)pyridin-2 -amine with around 8 % for 5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-ol (Hydroxy derivative) and around 7 % for 4,4'-((oxybis(pyridine-6,3- diyl))bis(methylene))bis(l -ethylpiperazine) (Dimer derivative). Figure 1 and Figure 2 of the present disclosure provides the mass spectrum of the identified impurities during the preparation of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine.

[0107] The reaction mixture was cooled to 27 °C (fourth predetermined temperature) followed by adding 100 g of sodium hydroxide (alkali) and 1000 ml of toluene (second fluid medium) and heated to 60 °C (fifth predetermined temperature) for 60 minutes (third predetermined time period) to obtain a product mixture comprising 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2- amine having purity of 82%.

[0108] The product mixture comprising 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine having the purity of 82% is a second biphasic mixture comprising a second organic layer and a second aqueous layer. The second organic layer was separated from the second biphasic mixture followed by distilling at 60 °C till 2 / 3 volume of a separated second organic layer remains, to obtain a concentrated second organic layer. The concentrated second organic layer was cooled to 20 °C followed by maintaining for 60 minutes to obtain a slurry. The slurry was filtered followed by washing with 100 ml of toluene to obtain solids. The so obtained solids were dried at 60°C for 10 hours to obtain 58g of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine.

[0109] The purity of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine was 99.66% (HPLC).

[0110] Example 2

[0111] 500 g of 2-chloro-5 -chloromethylpyridine and 500 g of potassium carbonate (first base) were dissolved in a mixture of 2000 ml of toluene and 2000 ml water (first fluid medium) in a reactor at 27 °C followed by adding 420 g of 1 -ethylpiperazine at 27 °C to obtain a first mixture. The first mixture was heated to 90 °C (first predetermined temperature) and maintained for 2 hours (first predetermined time period) followed by cooling to 27 °C (second predetermined temperature) to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer.

[0112] The first organic layer was separated from the first biphasic mixture followed by distilling a separated first organic layer at 60 °C under vacuum to obtain an intermediate comprising 1- ((6-chloropyridin-3 -yl)methyl)-4-ethylpiperazine .

[0113] The so obtained intermediate, 3500 ml aqueous ammonia solution (second base) and 125 g of copper bromide (catalyst) were charged in an autoclave to obtain a second mixture. The autoclave containing the second mixture was heated to 125 °C (third predetermined temperature) and maintained for 24 hours (second predetermined time period) to obtain a reaction mixture comprising 5-((4-ethylpiperazin-l-yl)methyl) pyridin-2 -amine, 5-((4- ethylpiperazin-l-yl)methyl)pyridin-2-ol (Hydroxy derivative) and 4,4'-((oxybis(pyridine-6,3- diyl))bis(methylene))bis(l -ethylpiperazine) (Dimer derivative).

[0114] The reaction was monitored by HPLC and around 60% conversion was found for 5-((4- ethylpiperazin-l-yl)methyl)pyridin-2 -amine with around 8% for 5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-ol (Hydroxy derivative) and around 5% for 4,4'-((oxybis(pyridine-6,3- diyl))bis(methylene))bis(l -ethylpiperazine) (Dimer derivative).

[0115] The reaction mixture was cooled to 27 °C (fourth predetermined temperature) followed by adding 500 g of sodium hydroxide (alkali) and 5000 ml of toluene (second fluid medium) and heated to 60 °C (fifth predetermined temperature) for 60 minutes (third predetermined time period) to obtain a product mixture comprising 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2- amine having purity of 81%.

[0116] The product mixture comprising 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine having the purity of 81% is a second biphasic mixture comprising a second organic layer and a second aqueous layer. The second organic layer was separated from the second biphasic mixture followed by distilling at 60 °C till 2 / 3 volume of a separated second organic layer remains, to obtain a concentrated second organic layer. The concentrated second organic layer was cooled to 20 °C followed by maintaining for 60 minutes to obtain a slurry. The slurry was filtered followed by washing with 500 ml of toluene to obtain solids. The so obtained solids were dried at 60°C for 10 hours to obtain 300g of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine.

[0117] The purity of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine was 99.49% (HPLC).

[0118] Example 3

[0119] 100 g of 2-chloro-5 -chloromethylpyridine and 100 g of potassium carbonate (first base) were dissolved in a mixture of 400 ml of toluene and 400 ml water (first fluid medium) in a reactor at 27 °C followed by adding 84 g of 1 -ethylpiperazine at 27 °C to obtain a first mixture. The first mixture was heated to 90 °C (first predetermined temperature) and maintained for 2 hours (first predetermined time period) followed by cooling to 27 °C (second predetermined temperature) to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer.

[0120] The first organic layer was separated from the first biphasic mixture followed by distilling a separated first organic layer at a temperature in the range of 50 °C to 60 °C under vacuum to obtain an intermediate comprising l-((6-chloropyridin-3-yl)methyl)-4-ethylpiperazine.

[0121] The so obtained intermediate, 700 ml aqueous ammonia solution (second base) and 20 g of copper bromide (catalyst) were charged in an autoclave to obtain a second mixture. The autoclave containing the second mixture was heated to 130 °C (third predetermined temperature) and maintained for 24 hours (second predetermined time period) to obtain a reaction mixture comprising 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine, 5-((4- ethylpiperazin-l-yl)methyl)pyridin-2-ol (Hydroxy derivative) and 4,4'-((oxybis(pyridine-6,3- diyl))bis(methylene))bis(l -ethylpiperazine) (Dimer derivative). The reaction was monitored by HPLC and around 65% conversion was found for 5 -((4- ethylpiperazin-l-yl)methyl)pyridin-2 -amine with around 12% for 5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-ol (Hydroxy derivative) and around 5% for 4,4'-((oxybis(pyridine-6,3- diyl))bis(methylene))bis(l -ethylpiperazine) (Dimer derivative).

[0122] The reaction mixture was cooled to 27 °C (fourth predetermined temperature) followed by adding 100 g of sodium hydroxide (alkali) and 1000 ml of toluene (second fluid medium) and heated to 60 °C (fifth predetermined temperature) for 60 minutes (third predetermined time period) to obtain a product mixture comprising 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2- amine having purity of 84%.

[0123] The product mixture comprising 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine having the purity of 84% is a second biphasic mixture comprising a second organic layer and a second aqueous layer. The second organic layer was separated from the second biphasic mixture followed by distilling at 60 °C till 2 / 3 volume of a separated second organic layer remains, to obtain a concentrated second organic layer. The concentrated second organic layer was cooled to 20 °C followed by maintaining for 60 minutes to obtain a slurry. The slurry was filtered followed by washing with 100 ml of toluene to obtain solids. The so obtained solids were dried at 60°C for 10 hours to obtain 52g of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine.

[0124] The purity of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine was 99.81% (HPLC).

[0125] Example 4

[0126] 100 g of 2-chloro-5 -chloromethylpyridine and 100 g of potassium carbonate (first base) were dissolved in a mixture of 400 ml of toluene and 400 ml water (first fluid medium) in a reactor at 27 °C followed by adding 84 g of 1 -ethylpiperazine at 27 °C to obtain a first mixture. The first mixture was heated to 90 °C (first predetermined temperature) and maintained for 2 hours (first predetermined time period) followed by cooling to 27 °C (second predetermined temperature) to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer.

[0127] The first organic layer was separated from the first biphasic mixture followed by distilling a separated first organic layer at 60 °C under vacuum to obtain an intermediate comprising 1- ((6-chloropyridin-3 -yl)methyl)-4-ethylpiperazine . The so obtained intermediate, 700 ml aqueous ammonia solution (second base) and 20 g of copper iodide (catalyst) were charged in an autoclave to obtain a second mixture. The autoclave containing the second mixture was heated to 130 °C (third predetermined temperature) and maintained for 24 hours (second predetermined time period) to obtain a reaction mixture comprising 5 -((4-ethylpiperazin- 1 -yl)methyl)pyridin-2 -amine, 5 -((4-ethylpiperazin- 1 - yl)methyl)pyridin-2-ol (Hydroxy derivative) and 4,4'-((oxybis(pyridine-6,3- diyl))bis(methylene))bis(l -ethylpiperazine) (Dimer derivative).

[0128] The reaction was monitored by HPLC and around 64 % conversion was found for 5 -((4- ethylpiperazin-l-yl)methyl)pyridin-2 -amine with around 10% for 5 -((4-ethylpiperazin- 1- yl)methyl)pyridin-2-ol (Hydroxy derivative) and around 5% for 4,4'-((oxybis(pyridine-6,3- diyl))bis(methylene))bis(l -ethylpiperazine) (Dimer derivative).

[0129] The reaction mixture was cooled to 27 °C (fourth predetermined temperature) followed by adding 100 g of sodium hydroxide (alkali) and 1000 ml of toluene (second fluid medium) and heated to 60 °C (fifth predetermined temperature) for 60 minutes (third predetermined time period) to obtain a product mixture comprising 5 -((4-ethylpiperazin- l-yl)methyl )pyridin-2- amine having purity of 83%.

[0130] The product mixture comprising 5 -((4-ethylpiperazin- l-yl)methyl)pyridin-2 -amine having the purity of 83% is a second biphasic mixture comprising a second organic layer and a second aqueous layer. The second organic layer was separated from the second biphasic mixture followed by distilling at 60 °C till 2 / 3 volume of a separated second organic layer remains, to obtain a concentrated second organic layer. The concentrated second organic layer was cooled to 20 °C followed by maintaining for 60 minutes to obtain a slurry. The slurry was filtered followed by washing with 100 ml of toluene to obtain solids. The so obtained solids were dried at 60°C for 10 hours to obtain 58g of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine.

[0131] The purity of 5 -((4-ethylpiperazin- l-yl)methyl)pyridin-2 -amine was 99.59% (HPLC).

[0132] Comparative example 1

[0133] 50 g of 2-chloro-5-chloromethylpyridine and 50 g of potassium carbonate were dissolved in a mixture of 200 ml of toluene and 200 ml water in a reactor at 27 °C followed by adding 42 g of 1 -ethylpiperazine at 27 °C to obtain a first mixture. The first mixture was heated to 90 °C and maintained for 2 hours followed by cooling to 27 °C to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer.

[0134] The first organic layer was separated from the first biphasic mixture followed by distilling a separated first organic layer at 60 °C under vacuum to obtain an intermediate comprising 1- ((6-chloropyridin-3 -yl)methyl)-4-ethylpiperazine .

[0135] The so obtained intermediate, 350 ml aqueous ammonia solution and 10 g of copper chloride were charged in an autoclave to obtain a second mixture. The autoclave containing the second mixture was heated to 130 °C and maintained for 24 hours to obtain a reaction mixture.

[0136] Reaction was monitored by HPLC and around 2% conversion found of 5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-amine .

[0137] From Examples 1 to 4 and Comparative Example 1, it is observed that the process of the present disclosure for the preparation of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine is carried out in presence of copper bromide and copper iodide provides maximum conversion of 5 -((4- ethylpiperazin-l-yl)methyl)pyridin-2 -amine upto 65% with maximum purity of greater than 99%. Whereas, the conventional process by using copper chloride provides negligible conversion of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine.

[0138] TECHNICAL ADVANCEMENT

[0139] The present disclosure described hereinabove has several technical advantages including, but not limited to, the realization of a process for the preparation of 5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-amine, that

[0140] • is simple, cost effective and environment friendly; and

[0141] • provides 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine having a comparatively high conversion of the product and high purity.

[0142] 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.

[0143] The foregoing description of the specific embodiments 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.

[0144] 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 invention to achieve one or more of the desired objects or results. While certain embodiments of the inventions have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Variations or modifications to the formulation of this invention, within the scope of the invention, may occur to those skilled in the art upon reviewing the disclosure herein. Such variations or modifications are well within the spirit of this invention.

[0145] 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.

[0146] The numerical values given for various physical parameters, dimensions, and quantities are only approximate values and it is envisaged that the values higher than the numerical value assigned to the physical parameters, dimensions and quantities fall within the scope of the invention unless there is a statement in the specification to the contrary.

[0147] While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment 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.

Claims

CLAIMS:

1. A process for the preparation of 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2 -amine, said process comprising the following steps: i. reacting 2-chloro-5 -chloromethylpyridine with 1 -ethylpiperazine by using a first base in a first fluid medium at a first predetermined temperature for a first predetermined time period followed by cooling to a second predetermined temperature to obtain a first biphasic mixture comprising a first organic layer and a first aqueous layer; ii. separating said first organic layer from said first biphasic mixture followed by distilling under vacuum to obtain an intermediate comprising l-((6-chloropyridin- 3 -yl)methyl)-4-ethylpiperazine ; iii. reacting said intermediate and a second base in the presence of a catalyst in an autoclave at a third predetermined temperature for a second predetermined time period to obtain a reaction mixture comprising 5-((4-ethylpiperazin-l- yl)methyl)pyridin-2 -amine and piperazinyl methyl pyridine derivatives; and iv. cooling said reaction mixture to a fourth predetermined temperature followed by adding an alkali and a second fluid medium and heating to a fifth predetermined temperature for a third predetermined time period to obtain a product mixture comprising 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine having a purity in the range of 80% to 85%.

2. The process as claimed in claim 1, wherein said 5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-amine having a purity in the range of 80% to 85% is purified by using the following sub-steps:• separating said product mixture to obtain a separated second organic layer and a separated second aqueous layer; and• distilling said separated second organic layer to obtain slurry, filtering said slurry to obtain solids and drying said solids to obtain 5-((4-ethylpiperazin-l- yl)methyl)pyridin-2 -amine having a purity greater than 99%.

3. The process as claimed in claim 2, wherein said purity of 5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-amine is greater than 99.4%.

4. The process as claimed in claim 1, wherein said first base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.

5. The process as claimed in claim 1, wherein said second base is selected from an aqueous ammonia solution and an anhydrous ammonia gas.

6. The process as claimed in claim 1, wherein said alkali is selected from sodium hydroxide and potassium hydroxide.

7. The process as claimed in claim 1, wherein said catalyst is selected from copper bromide and copper iodide.

8. The process as claimed in claim 1 , wherein said first fluid medium is at least one selected from the group consisting of toluene, water, o-xylene, m- xylene and p-xylene.

9. The process as claimed in claim 1, wherein said second fluid medium is at least one selected from the group consisting of toluene, ethyl acetate, isopropyl acetate, o-xylene, m- xylene and p-xylene.

10. The process as claimed in claim 1, wherein a molar ratio of 2-chloro-5- chloromethylpyridine to 1 -ethylpiperazine is in the range of 1 : 1 to 1: 1.5.

11. The process as claimed in claim 1, wherein a molar ratio of 2-chloro-5- chloromethylpyridine to said first base is in the range of 1 : 1 to 1: 1.5.

12. The process as claimed in claim 1, wherein a molar ratio of 2-chloro-5- chloromethylpyridine to said catalyst is in the range of 1:0.1 to 1:0.5.

13. The process as claimed in claim 1, wherein• said first predetermined temperature is in the range of 75 °C to 100 °C;• said second predetermined temperature is in the range of 20 °C to 30 °C;• said third predetermined temperature is in the range of 110 °C to 140 °C;• said fourth predetermined temperature is in the range of 20 °C to 30 °C; and• said fifth predetermined temperature is in the range of 40 °C to 70 °C.

14. The process as claimed in claim 1, wherein• said first predetermined time period is in the range of 1 hour to 3 hours;• said second predetermined time period is in the range of 20 hours to 28 hours; and• said third predetermined time period is in the range of 30 minutes to 120 minutes.

15. The process as claimed in claim 1, wherein the percentage conversion of 5 -((4- ethylpiperazin-l-yl)methyl)pyridin-2 -amine is in the range of 60% to 70%.

16. The process as claimed in claim 1, wherein said piperazinyl methyl pyridine derivatives formed during the process are 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-ol (Hydroxy derivative) and 4,4'-((oxybis(pyridine-6,3-diyl))bis(methylene)) bis(l -ethylpiperazine) (Dimer derivative) and having the following structures:Hydroxy derivative Dimer derivative wherein said hydroxy derivative and said dimer derivative are present in an amount less than 0.3%.

17. 5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-amine prepared by the process as claimed in claim 1 having a purity greater than 99%.

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