A process for the preparation of an intermediate for kinase inhibitors

Abstract

The present disclosure relates to a process for the preparation of an intermediate for kinase inhibitors. Particularly, the present disclosure relates to a process for the preparation of 1-5 BOC-4-(6-amino-3-pyridyl) piperazine. The process of the present disclosure is simple, cost- effective, commercially scalable and environment friendly. Further, the process of the present disclosure provides the intermediate for kinase inhibitors with high purity and high yield.

Description

[0001] A PROCESS FOR THE PREPARATION OF AN INTERMEDIATE FOR KINASE INHIBITORS

[0002] FIELD

[0003] The present disclosure relates to a process for the preparation of an intermediate for kinase inhibitors.

[0004] BACKGROUND

[0005] The background information herein below relates to the present disclosure but is not necessarily prior art.

[0006] Kinase inhibitors are a class of medicines which act as cyclin-dependent kinase inhibitors that are used to treat certain types of hormone receptor positive HER2 -negative breast cancer. These medicines interrupt the process through which breast cancer cells divide and multiply by targeting the specific proteins known as the cyclin-dependent kinases 4 and 6, abbreviated as CDK4 / 6. l-BOC-4-(6-amino-3-pyridyl) piperazine is used as a key intermediate for the synthesis of CDK4 / 6 inhibitors such as Palbociclib and Ribociclib. The structure of l-BOC-4-(6-amino-3- pyridyl) piperazine is represented as:

[0007] Formula I

[0008] Conventional processes for the preparation of l-BOC-4-(6-amino-3-pyridyl) piperazine are associated with the drawbacks such as tedious work up steps, use of solvents which are not environment friendly, expensive reagents as well as formation of impurities which affects the purity of final product. Therefore, there is felt a need to provide a process for the preparation of l-BOC-4-(6-amino- 3 -pyridyl) piperazine that mitigates the afo restated drawbacks or at least provide an alternative solution.

[0009] OBJECTS

[0010] Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:

[0011] 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.

[0012] Another object of the present disclosure is to provide a process for the preparation of an intermediate for cyclin-dependent kinase (CDK4 / 6) inhibitors.

[0013] Still another object of the present disclosure is to provide a process for the preparation of 1- BOC-4-(6-amino-3-pyridyl) piperazine.

[0014] Yet another object of the present disclosure is to provide a process for the preparation of 1- BOC-4-(6-amino-3-pyridyl) piperazine with a comparatively high purity and better yield.

[0015] Still another object of the present disclosure is to provide a simple and cost-effective process for the preparation of l-BOC-4-(6-amino-3-pyridyl) piperazine.

[0016] Yet another object of the present disclosure is to provide an environment-friendly and commercially scalable process for the preparation of l-BOC-4-(6-amino-3-pyridyl) piperazine.

[0017] Still another object of the present disclosure is to provide di-tert-butyl 4,4'-(diazene-l,2- diylbis(pyridine-5 ,2-diyl))-bis(piperazine- 1 -carboxylate) (Dimer-I) .

[0018] Yet another object of the present disclosure is to provide l,2-bis(6-(4-(tert- butoxycarbonyljpiperazin- 1 -yl)pyridin-3 -yljdiazene- 1 -oxide (Dimer-II) .

[0019] Still another object of the present disclosure is to provide l,2-bis(6-piperazin-l-yl)pyridin-3- yl)diazene (Dimer-III).

[0020] Yet another object of the present disclosure is to provide l,2-bis(6-piperazin-l-yl)pyridin-3- yl)diazene-l -oxide (Dimer-IV). 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 l-BOC-4-(6-amino-3- pyridyl) piperazine having a structure of formula I,

[0023] Formula I

[0024] The process for the preparation of l-BOC-4-(6-amino-3-pyridyl) piperazine comprises the following steps: i. reacting 5-bromo-2-nitro pyridine and tert-butyl piperazine- 1 -carboxylate by using a base in a first fluid medium at a first predetermined temperature for a first predetermined time period under stirring followed by cooling to a temperature in the range of -5 °C to 20 °C and filtering to obtain solids of l-BOC-4-(6-nitro-3 -pyridyl) piperazine; ii. reducing l-BOC-4-(6-nitro-3 -pyridyl) piperazine by using a reducing agent in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain a first product mass comprising l-BOC-4-(6- amino-3 -pyridyl) piperazine, diazo compounds and its N-oxides; and iii. hydrogenating the first product mass by using a hydrogenating agent in the second fluid medium under stirring at a third predetermined temperature for a third predetermined time period to obtain a second product mass comprising l-BOC-4-(6- amino-3 -pyridyl) piperazine.

[0025] The base is selected from an inorganic base and an organic base.

[0026] The inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate and potassium bicarbonate. The organic base is selected from the group consisting of triethylamine, diisopropylethylamine and N,N-dimethylethylamine.

[0027] The reducing agent is selected from the group consisting of sodium sulfide, sodium dithionite, tin chloride, iron / HCl, zinc / HCl, titanium(III) chloride and metal catalysts.

[0028] The hydrogenating agent is selected from the group consisting of tT / Pd / C. tT / Rancy Ni, H2 / Pd(OH)2 / C and H2 / Pd(OAc)2.

[0029] The first fluid medium is water.

[0030] The second fluid medium is a polar solvent selected from the group consisting of methanol, ethanol, isopropanol and n-butanol.

[0031] The molar ratio of 5-bromo-2-nitro pyridine to tert-butyl piperazine- 1 -carboxylate is in the range of 1: 1 to 1: 1.5.

[0032] The molar ratio of 5-bromo-2-nitro pyridine to the base is in the range of 1 : 1 to 1:2.

[0033] The molar ratio of l-BOC-4-(6-nitro-3 -pyridyl) piperazine to the reducing agent is in the range of 1:2 to 1:6.

[0034] The mass ratio of the first product mass to the hydrogenating agent is in the range of 15: 1 to 25: 1.

[0035] The first predetermined temperature is in the range of 80 °C to 120 °C.

[0036] The first predetermined time period is in the range of 5 hours to 20 hours.

[0037] The second predetermined temperature is in the range of 40 °C to 65 °C.

[0038] The second predetermined time period is in the range of 1 hour to 5 hours.

[0039] The third predetermined temperature is in the range of 30 °C to 70 °C.

[0040] The third predetermined time period is in the range of 2 hours to 10 hours.

[0041] The yield of l-BOC-4-(6-amino-3-pyridyl) piperazine is in the range of 85% to 95%. The diazo compound formed during the process is di-tert-butyl 4,4'-(diazene-l,2- diylbis(pyridine-5,2-diyl))-bis(piperazine-l -carboxylate) (Dimer-I) and the diazo N-oxide compound is l,2-bis(6-(4-(tert-butoxycarbonyl)piperazin-l-yl)pyridin-3-yl)diazene 1-oxide (Dimer-II) and having the following structures: Dimer-I Dimer ■■■ II.

[0042] Di-tert-butyl 4,4'-(diazene-l,2-diylbis(pyridine-5,2-diyl))-bis(piperazine-l-carboxylate) (Dimer-I) and l,2-bis(6-(4-(tert-butoxycarbonyl)piperazin-l-yl)pyridin-3-yl)diazene 1 -oxide (Dimer-II) undergoes deprotection to result l,2-bis(6-piperazin-l-yl)pyridin-3-yl)diazene (Dimer-III) and l,2-bis(6-piperazin-l-yl)pyridin-3-yl)diazene-l-oxide (Dimer-IV) respectively having the following structures:

[0043] Dimer - III Dimer - IV.

[0044] The Dimer I, the Dimer II, the Dimer III and the Dimer IV are in an amount less than 0.1%. l-BOC-4-(6-amino-3-pyridyl) piperazine prepared by the process of the present disclosure having the structure of formula I,

[0045] Formula I l-BOC-4-(6-amino-3-pyridyl) piperazine is having a purity greater than 99%. l-BOC-4-(6-amino-3-pyridyl) piperazine is having the purity is in the range of 99.50% to 99.99%.

[0046] BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWING

[0047] The present disclosure will now be described with the help of the accompanying drawing, in which:

[0048] Figure 1 illustrates a mass spectrum for di-tert-butyl 4,4'-(diazene-l,2-diylbis(pyridine-5,2- diyl))-bis(piperazine-l -carboxylate) (Dimer-I) in accordance with the present disclosure; and

[0049] Figure 2 illustrates a mass spectrum for l,2-bis(6-(4-(tert-butoxycarbonyl)piperazin-l- yl)pyridin-3-yl)diazene-l -oxide (Dimer-II) in accordance with the present disclosure.

[0050] DETAILED DESCRIPTION

[0051] The present disclosure relates to a process for the preparation of an intermediate for kinase inhibitors.

[0052] Embodiments, of the present disclosure, will now be described with reference to the accompanying drawing.

[0053] 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.

[0054] 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.

[0055] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed elements.

[0056] 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.

[0057] Conventional processes for the preparation of l-BOC-4-(6-amino-3-pyridyl) piperazine are associated with the drawbacks such as tedious work up steps, use of solvents which are not environment friendly, expensive reagents as well as formation of impurities which affects the purity of the final product.

[0058] The present disclosure provides a process for the preparation of an intermediate for kinase inhibitors. Particularly, the present disclosure provides intermediate for cyclin-dependent kinase (CDK4 / 6) inhibitors such as Palbociclib and Ribociclib. More particularly, the present disclosure provides a process for the preparation of l-BOC-4-(6-amino-3-pyridyl)piperazine with a comparatively high purity and high yield.

[0059] The process of the present disclosure is simple, environment friendly and economical.

[0060] In a first aspect, the present disclosure provides a process for the preparation of l-BOC-4-(6- amino-3 -pyridyl) piperazine having a structure of formula I, The process comprises the following steps: i. reacting 5-bromo-2-nitro pyridine and tert-butyl piperazine- 1 -carboxylate by using a base in a first fluid medium at a first predetermined temperature for a first predetermined time period under stirring followed by cooling to a temperature in the range of -5 °C to 20 °C and filtering to obtain solids of 1- BOC-4-(6-nitro-3-pyridyl) piperazine; ii. reducing l-BOC-4-(6-nitro-3 -pyridyl) piperazine by using a reducing agent in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain a first product mass comprising l-BOC-4- (6-amino-3 -pyridyl) piperazine, diazo compounds and its N-oxides; and iii. hydrogenating the first product mass by using a hydrogenating agent in the second fluid medium under stirring at a third predetermined temperature for a third predetermined time period to obtain a second product mass comprising 1- BOC-4-(6-amino-3-pyridyl) piperazine.

[0061] The process is described in detail below.

[0062] In a first step, 5-bromo-2-nitro pyridine and tert-butyl piperazine -1 -carboxylate are reacted by using a base in a first fluid medium at a first predetermined temperature for a first predetermined time period under stirring followed by cooling to a temperature in the range of -5 °C to 20 °C and filtering to obtain solids of crude l-BOC-4-(6-nitro-3-pyridyl) piperazine.

[0063] The crude l-BOC-4-(6-nitro-3 -pyridyl) piperazine is further purified by crystallization by using alcohol preferably isopropyl alcohol (IPA) to obtain l-BOC-4-(6-nitro-3-pyridyl) piperazine with a purity >95%.

[0064] In an embodiment of the present disclosure, a molar ratio of 5-bromo-2-nitro pyridine to tertbutyl piperazine-l-carboxylate is in the range of 1: 1 to 1: 1.5. In an exemplary embodiment of the present disclosure, the molar ratio of 5-bromo-2-nitro pyridine to tert-butyl piperazine-l- carboxylate is 1: 1.2.

[0065] In an embodiment of the present disclosure, the base is selected from an inorganic base and an organic base. In an embodiment of the present disclosure, the inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate and potassium bicarbonate.

[0066] In an embodiment of the present disclosure, the organic base is selected from the group consisting of triethylamine, diisopropylethylamine and N,N-dimethylethylamine. In an exemplary embodiment of the present disclosure, the base is an inorganic base and is potassium carbonate.

[0067] In an embodiment of the present disclosure, a molar ratio of 5-bromo-2-nitro pyridine to the base is in the range of 1: 1 to 1:2. In an exemplary embodiment of the present disclosure, the molar ratio of 5-bromo-2-nitro pyridine to the base is 1: 1.5.

[0068] In an embodiment of the present disclosure, the first fluid medium is water.

[0069] In accordance with the present disclosure, the use of aqueous media (water) for the preparation of l-BOC-4-(6-nitro-3-pyridyl) piperazine involves simple isolation process, reduces the operation cost and reduces the cost of manufacturing, thereby making the process economical.

[0070] In an embodiment of the present disclosure, the first predetermined temperature is in the range of 80 °C to 120 °C. In an exemplary embodiment of the present disclosure, the first predetermined temperature is 100 °C (reflux temperature).

[0071] In an embodiment of the present disclosure, the first predetermined time period is in the range of 5 hours to 20 hours. In an exemplary embodiment of the present disclosure, the first predetermined time period is 13 hours.

[0072] In a second step, l-BOC-4-(6-nitro-3-pyridyl) piperazine is reduced by using reducing agent in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain a first product mass comprising l-BOC-4-(6-amino-3- pyridyl)piperazine, diazo compounds and its N-oxides.

[0073] In an embodiment of the present disclosure, the reducing agent is selected from the group consisting of sodium sulfide, sodium dithionite, tin chloride, iron / HCl, zinc / HCl, titanium(III) chloride and metal catalysts. In an exemplary embodiment of the present disclosure, the reducing agent is sodium sulfide. In an embodiment of the present disclosure, the reducing agent is used in the form of an aqueous solution. Further, water present in the solution serves as a source of hydrogen for the reduction.

[0074] In accordance with an embodiment of the present disclosure, the reducing agent such as sodium sulfide is easy to separate as well as cost effective.

[0075] In an embodiment of the present disclosure, a molar ratio of l-BOC-4-(6-nitro-3-pyridyl) piperazine to the reducing agent is in the range of 1:2 to 1:6. In an exemplary embodiment of the present disclosure, the molar ratio of l-BOC-4-(6-nitro-3 -pyridyl) piperazine to the reducing agent is 1:4.4.

[0076] In an embodiment of the present disclosure, the second fluid medium is a polar solvent selected from the group consisting of methanol, ethanol, isopropanol and n-butanol. In an exemplary embodiment of the present disclosure, the second fluid medium is methanol.

[0077] In an embodiment of the present disclosure, the second predetermined temperature is in the range of 40 °C to 65 °C. In an exemplary embodiment of the present disclosure, the second predetermined temperature is in the range of 50 °C to 55 °C.

[0078] In an embodiment of the present disclosure, the second predetermined time period is in the range of 1 hour to 5 hours. In an exemplary embodiment of the present disclosure, the second predetermined time period is 2 hours.

[0079] In an embodiment of the present disclosure, the di -tert-butyl 4,4'-(diazene-l,2- diylbis(pyridine-5,2-diyl))-bis(piperazine-l -carboxylate) (Dimer-I) and l,2-bis(6-(4-(tert- butoxycarbonyl)-piperazin-l-yl) pyridin-3-yl)diazene 1-oxide (Dimer-II) are formed as impurities during the reduction of l-BOC-4-(6-nitro-3 -pyridyl) piperazine.

[0080] In an embodiment of the present disclosure, the first product mass is purified by using a fluid medium to obtain 83.5 to 91.5% of l-BOC-4-(6-amino-3-pyridyl) piperazine; 0.5 % to 1.5 % of di-tert-butyl 4,4'-(diazene-l,2-diylbis(pyridine-5,2-diyl))-bis(piperazine-l-carboxylate) (Dimer-I); and 8% to 15 % of l,2-bis(6-(4-(tert-butoxycarbonyl)-piperazin-l-yl) pyridin-3- yl)diazene 1-oxide (Dimer-II) by HPLC.

[0081] In an exemplary embodiment of the present disclosure, the first product mass is purified by using a fluid medium to obtain 87% of l-BOC-4-(6-amino-3-pyridyl) piperazine, 0.75 % of di-tert-butyl 4,4'-(diazene-l,2-diylbis(pyridine-5,2-diyl))-bis(piperazine-l-carboxylate) (Dimer-I) and 12 % of l,2-bis(6-(4-(tert-butoxycarbonyl)-piperazin-l-yl)pyridin-3-yl)diazene 1 -oxide (Dimer-II) by HPLC.

[0082] In an embodiment of the present disclosure, the fluid medium is a mixture of dichloromethane, water and toluene.

[0083] In a third step, the first product mass is hydrogenated by using a hydrogenating agent in the second fluid medium under stirring at a third predetermined temperature for a third predetermined time period to obtain a second product mass comprising l-BOC-4-(6-amino-3- pyridyl) piperazine.

[0084] In an embodiment of the present disclosure, the hydrogenating agent is selected from the group consisting of FF / Pd / C. FF / Rancy Ni, H2 / Pd(OH)2 / C and H2 / Pd(OAc)2. In an exemplary embodiment of the present disclosure, the hydrogenating agent is FF / Rancy Ni. Hydrogenation is carried out in the presence of hydrogen gas.

[0085] In an embodiment of the present disclosure, the mass ratio of the first product mass to the hydrogenating agent is in the range of 15: 1 to 25: 1. In an exemplary embodiment of the present disclosure, the mass ratio of the first product mass to the hydrogenating agent is 20: 1.

[0086] In an embodiment of the present disclosure, the third predetermined temperature is in the range of 30 °C to 70 °C. In an exemplary embodiment of the present disclosure, the third predetermined temperature is 60 °C.

[0087] In an embodiment of the present disclosure, the third predetermined time period is in the range of 2 hours to 10 hours. In an exemplary embodiment of the present disclosure, the third predetermined time period is 5 hours.

[0088] In an embodiment of the present disclosure, the second product mass comprising l-BOC-4- (6-amino-3 -pyridyl) piperazine is filtered through a hyflo bed and washed with methanol to obtain a filtrate. Methanol from the filtrate is evaporated to obtain solids. The solids are washed with water to obtain l-BOC-4-(6-amino-3-pyridyl) piperazine.

[0089] The step of hydrogenation during the process of the present disclosure is necessary to hydrogenate / breakdown of N=N of Dimer-I and Dimer-II if present, that leads to the formation of l-BOC-4-(6-amino-3-pyridyl) piperazine, thereby reducing the impurity from 12.75% to less than 0.07% in step III and increasing the yield of l-BOC-4-(6-amino-3- pyridyl) piperazine (i.e., increased from 87% to 93.4%).

[0090] In an embodiment of the present disclosure, the yield of l-BOC-4-(6-amino-3-pyridyl) piperazine is in the range of 85% to 95%. In an exemplary embodiment of the present disclosure, the yield of l-BOC-4-(6-amino-3-pyridyl) piperazine is 93.4%.

[0091] In accordance with an exemplary embodiment of the present disclosure, the schematic representation for the preparation of l-BOC-4-(6-amino-3-pyridyl) piperazine is illustrated as

[0092] Scheme A below:

[0093] Scheme-A

[0094] The present disclosure provides a process for the preparation of l-BOC-4-(6-amino-3- pyridyl) piperazine which is free from dimer impurities or any other unknown impurities. Even if the dimer impurities and any other unknown impurities are present in the final product (l-BOC-4-(6-amino-3-pyridyl) piperazine) that is not more than 0.10%. In an exemplary embodiment of the present disclosure, the impurities are less than 0.07%. Due to the process of the present disclosure, the impurities are drastically reduced.

[0095] The present disclosure provides a simple, environment friendly and economic process for the preparation of l-BOC-4-(6-amino-3 -pyridyl) piperazine with a comparatively better yield and high purity.

[0096] In an embodiment of the present disclosure, the diazo compound formed during the process is di-tert-butyl 4,4'-(diazene-l,2-diylbis(pyridine-5,2-diyl))-bis(piperazine-l-carboxylate) (Dimer-I) and the diazo N-oxide compound is l,2-bis(6-(4-(tert-butoxycarbonyl)piperazin-l- yl)pyridin-3-yl)diazene 1 -oxide (Dimer-II) and having the following structures:

[0097] Dimer-I. Dimer - IL

[0098] In an embodiment of the present disclosure, di-tert-butyl 4,4'-(diazene-l,2-diylbis(pyridine- 5,2-diyl))-bis(piperazine-l-carboxylate) (Dimer-I) and l,2-bis(6-(4-(tert- butoxycarbonyl)piperazin-l-yl)pyridin-3-yl)diazene 1 -oxide (Dimer-II) undergoes deprotection to result into l,2-bis(6-piperazin-l-yl)pyridin-3-yl)diazene (Dimer-III) and 1,2- bis(6-piperazin-l-yl)pyridin-3-yl)diazene-l -oxide (Dimer-IV) respectively having the following structures:

[0099] Di er-III Dimer -IV.

[0100] In another embodiment of the present disclosure, di -tert-butyl 4,4'-(diazene-l,2- diylbis(pyridine-5,2-diyl))-bis(piperazine-l -carboxylate) (Dimer-I) is converted into 1,2- bis(6-(piperazin-l-yl)pyridin-3-yl)diazene (Dimer-III) by deprotection of BOC as illustrated in Scheme B below.

[0101] Scheme-B In an embodiment of the present disclosure, l,2-bis(6-(4-(tert-butoxycarbonyl)-piperazin-l- yl)pyridin-3-yl)diazene 1 -oxide (Dimer-II) is converted into l,2-bis(6-(piperazin-l- yl)pyridin-3-yl)diazene 1 -oxide (Dimer-IV) by deprotection of BOC as illustrated in Scheme C below.

[0102] Scheme-C

[0103] In an embodiment of the present disclosure, the Dimer I, the Dimer II, the Dimer III and the Dimer IV are in an amount less than 0.1%.

[0104] In an embodiment of the present disclosure, Dimer-I and Dimer-II if present in the first product mass ((i.e.,l-boc-4-(6-amino-3-pyridyl) piperazine) leads to formation of Dimer-III and Dimer-IV respectively in downstream process during the preparation of Palbociclib or Ribociclib API. These structurally related dimer impurities pose challenges during purification and contribute to decrease in the final API yield. Consequently, it is essential to control and minimize the levels of Dimer-I and Dimer-II in the intermediate to maintain both the efficiency of the process and the quality of the final product. Due to the hydrogenation, Dimer-I and Dimer-II impurities are removed thereby preventing the formation of Dimer-III and Dimer-IV impurities during the preparation of Palbociclib or Ribociclib API.

[0105] In an embodiment of the present disclosure, l-BOC-4-(6-amino-3-pyridyl) piperazine prepared by the process of the present disclosure having structure of formula I,

[0106] Formula I

[0107] In an embodiment of the present disclosure, l-BOC-4-(6-amino-3 -pyridyl) piperazine of the present disclosure having a purity greater than 99%. In an embodiment of the present disclosure, l-BOC-4-(6-amino-3-pyridyl) piperazine of the present disclosure has a purity in the range of 99.50% to 99.99%. In an exemplary embodiment of the present disclosure, the purity of l-BOC-4-(6-amino-3 -pyridyl) piperazine is 99.90%

[0108] 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.

[0109] 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.

[0110] EXPERIMENTAL DETAILS

[0111] EXAMPLE 1: Preparation of l-BOC-4-(6-amino-3-pyridyl) piperazine (BAPP) in accordance with the present disclosure

[0112] Step I: Preparation of l-BOC-4-(6-nitro-3-Dyridyl) piperazine (BNPP)

[0113] 100 g of 5-bromo-2-nitro pyridine and 110 g of tert-butyl piperazine- 1 -carboxylate were added in a reactor followed by adding 100 g of potassium carbonate (base) and 500 ml of water (first fluid medium) and heated at 100 °C (reflux temperature) (first predetermined temperature) for 13 hours (first predetermined time period) under stirring followed by cooling to a temperature in the range of 0 °C to 5 °C and filtering to obtain solids comprising crude 1 - BOC-4-(6-nitro-3-pyridyl) piperazine.

[0114] The crude l-BOC-4-(6-nitro-3-pyridyl) piperazine was further purified by crystallization by using isopropyl alcohol (IP A) to obtain l-BOC-4-(6-nitro-3-pyridyl) piperazine with a purity >95%.

[0115] Step II: Preparation of l-BOC-4-(6-amino-3-pyridyl) piperazine with di-tert-butyl 4,4l-(diazene-l,2-diylbis(pyridine-5,2-diyl))-bis(piperazine-l-carboxylate) (Dimer-I) and l,2-bis(6-(4-(tert-butoxycarbonyl)-piperazin-l-yl)pyridin-3-yl)diazene 1-oxide (Dimer-II) as impurities

[0116] 100 g of l-BOC-4-(6-nitro-3-pyridyl) piperazine was added in a reactor followed by adding sodium sulfide solution (111 g of sodium sulfide dissolved in 300 ml of water) (reducing agent) in 300 ml of aqueous methanol (second fluid medium) and heated to a temperature in the range of 50 °C to 55 °C (second predetermined temperature) for 2 hours (second predetermined time period) to obtain a first product mass comprising a crude l-BOC-4-(6- amino-3 -pyridyl) piperazine, di-tert-butyl 4,4'-(diazene-l,2-diylbis(pyridine-5,2-diyl))- bis(piperazine- 1 -carboxylate) (Dimer-I) and l,2-bis(6-(4-(tert-butoxycarbonyl)-piperazin-l- yl)pyridin-3-yl)diazene 1-oxide (Dimer-II).

[0117] The first product mass was purified by using dichloromethane (DCM), water and toluene to obtain 87% of l-BOC-4-(6-amino-3-pyridyl) piperazine, 0.75 % of di-tert-butyl 4,4'- (diazene-l,2-diylbis(pyridine-5,2-diyl))-bis(piperazine-l -carboxylate) (Dimer-I) and 12 % of

[0118] 1.2-bis(6-(4-(tert-butoxycarbonyl)-piperazin- 1 -yl)pyridin-3-yl)diazene- 1 -oxide (Dimer-II) by HPLC. The Dimer-I and Dimer-II were isolated by column chromatography and characterized by mass analysis. Figure 1 illustrates the mass spectrum of Dimer-I and Figure 2 illustrates the mass spectrum of Dimer-II.

[0119] Step III: Hydrogenation of the first product mass comprising, di-tert-butyl 4,4'- (diazene-l,2-diylbis(pyridine-5,2-diyl))-bis(piperazine-l-carboxylate) (Dimer-I) and

[0120] 1.2-bis(6-(4-(tert-butoxycarbonyl)-piperazin-l-yl)pyridin-3-yl)diazene 1-oxide

[0121] (Dimer-II) as impurities in l-BOC-4-(6-amino-3-pyridyl) piperazine.

[0122] 100 g of the first product mass comprising l-BOC-4-(6-amino-3 -pyridyl) piperazine, di- tert-butyl 4,4'-(diazene- 1 ,2-diylbis(pyridine-5,2-diyl))-bis(piperazine- 1 -carboxylate) (Dimer-I) and l,2-bis(6-(4-(tert-butoxycarbonyl)-piperazin-l-yl)pyridin-3-yl) diazene-1- oxide (Dimer-II) (without purified) was charged in a reactor followed by adding 5 g (5.0 % w / w) Raney Ni in methanol and a hydrogen gas was introduced with 5 kg / cm2pressure under stirring at 60 °C (third predetermined temperature) for 5 hours (third predetermined time period) to obtain a second product mass comprising l-BOC-4-(6-amino-3-pyridyl) piperazine. The reaction was carried out till the impurities are less than 0.10%.

[0123] The second product mass was filtered through hyflo bed and washed with methanol to obtain a filtrate. Methanol in the filtrate was distilled off to obtain solids. The obtained solids were washed with water to obtain 93.4 gm (93.4%) of l-BOC-4-(6-amino-3-pyridyl) piperazine with a purity 99.90%. Maximum impurity observed was less than 0.07%.

[0124] Comparative example 1: Preparation of l-BOC-4-(6-amino-3-pyridyl) piperazine (BAPP) by direct hydrogenation l-BOC-4-(6-nitro-3-pyridyl) piperazine was prepared in a similar manner to step I of Example 1 of the present disclosure.

[0125] 100 gm of l-BOC-4-(6-nitro-3 -pyridyl) piperazine was added in the hydrogenator followed by adding 1.2 litre of methanol and 10 gm of Raney Ni at ambient temperature to obtain a mixture. 5 kg / cm2of hydrogen pressure was applied in the reaction mixture followed by heating to a temperature in the range of 45 °C to 50 °C and maintained till reaction completes to obtain a reaction mixture.

[0126] The reaction mixture was cooled to 25 °C to 27 °C followed by releasing the pressure and unloading to obtain a product mixture. The so obtained product mixture was fdtered through celite and washed with 100 ml of methanol to obtain a wet mass and a fdtrate. Methanol in the filtrate was distilled off followed by adding 300 ml toluene and heated to a temperature in the range of 70 °C to 80 °C for 60 minutes to obtain a product mass. The product mass was cooled to 0 °C to 10 °C for 60 minutes followed by filtering and drying to obtain l-BOC-4-(6- amino-3 -pyridyl) piperazine (BAPP). The observed purity of l-BOC-4-(6-amino-3-pyridyl) piperazine (BAPP) was 76.8% (HPLC).

[0127] From Example 1 and Comparative Example 1, it is observed that the process of the present disclosure for the preparation of l-BOC-4-(6-amino-3-pyridyl) piperazine involves an initial reduction of l-BOC-4-(6-nitro-3-pyridyl) piperazine using a mild reducing agent, followed by hydrogenation results in a final product (l-BOC-4-(6-amino-3 -pyridyl) piperazine) of higher purity with negligible impurities formation. Whereas, the conventional process provides less pure product.

[0128] TECHNICAL ADVANCEMENT

[0129] The present disclosure described hereinabove has several technical advantages including, but not limited to, the realization of a process for the preparation of an intermediate for kinase inhibitors that

[0130] • is simple, cost effective and environment friendly; • reduces dimer impurities; and

[0131] • provides l-BOC-4-(6-amino-3-pyridyl) piperazine with a comparatively high purity and better yield.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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 l-BOC-4-(6-amino-3 -pyridyl) piperazine having a structure of formula I,Formula I said process comprising the following steps: i. reacting 5-bromo-2-nitro pyridine and tert-butyl piperazine- 1 -carboxylate by using a base in a first fluid medium at a first predetermined temperature for a first predetermined time period under stirring followed by cooling to a temperature in the range of -5 °C to 20 °C and filtering to obtain solids of 1- BOC-4-(6-nitro-3-pyridyl) piperazine; ii. reducing l-BOC-4-(6-nitro-3 -pyridyl) piperazine by using a reducing agent in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain a first product mass comprising l-BOC-4- (6-amino-3 -pyridyl) piperazine, diazo compounds and its N-oxides; and iii. hydrogenating said first product mass by using a hydrogenating agent in said second fluid medium under stirring at a third predetermined temperature for a third predetermined time period to obtain a second product mass comprising 1- BOC-4-(6-amino-3-pyridyl) piperazine.

2. The process as claimed in claim 1, wherein said base is selected from an inorganic base and an organic base.

3. The process as claimed in claim 2, wherein• said inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate and potassium bicarbonate; andsaid organic base is selected from the group consisting of triethylamine, diisopropylethylamine and N,N-dimethylethylamine.

4. The process as claimed in claim 1, wherein said reducing agent is selected from the group consisting of sodium sulfide, sodium dithionite, tin chloride, iron / HCl, zinc / HCl, titanium(III) chloride and metal catalysts.

5. The process as claimed in claim 1, wherein said hydrogenating agent is selected from the group consisting of IT / Pd / C. Fh / Rancy Ni, H2 / Pd(OH)2 / C and H2 / Pd(OAc)2.

6. The process as claimed in claim 1, wherein• said first fluid medium is water; and• said second fluid medium is a polar solvent selected from the group consisting of methanol, ethanol, isopropanol and n-butanol.

7. The process as claimed in claim 1, wherein a molar ratio of 5-bromo-2-nitro pyridine to tert-butyl piperazine -1 -carboxylate is in the range of 1: 1 to 1: 1.5.

8. The process as claimed in claim 1, wherein a molar ratio of 5-bromo-2-nitro pyridine to said base is in the range of 1 : 1 to 1:2.

9. The process as claimed in claim 1, wherein a molar ratio of l-BOC-4-(6-nitro-3- pyridyl) piperazine to said reducing agent is in the range of 1:2 to 1:6.

10. The process as claimed in claim 1, wherein a mass ratio of said first product mass to said hydrogenating agent is in the range of 15: 1 to 25: 1.

11. The process as claimed in claim 1, wherein• said first predetermined temperature is in the range of 80 °C to 120 °C; and• said first predetermined time period is in the range of 5 hours to 20 hours.

12. The process as claimed in claim 1, wherein• said second predetermined temperature is in the range of 40 °C to 65 °C; and• said second predetermined time period is in the range of 1 hour to 5 hours.

13. The process as claimed in claim 1, wherein• said third predetermined temperature is in the range of 30 °C to 70 °C; and• said third predetermined time period is in the range of 2 hours to 10 hours.

14. The process as claimed in claim 1, wherein the yield of l-BOC-4-(6-amino-3-pyridyl) piperazine is in the range of 85% to 95%.

15. The process as claimed in claim 1, wherein said diazo compound formed during the process is di-tert-butyl 4,4'-(diazene-l,2-diylbis(pyridine-5,2-diyl))-bis(piperazine-l- carboxylate) (Dimer-I) and said diazo N-oxide compound is l,2-bis(6-(4-(tert- butoxycarbonyl)piperazin-l-yl)pyridin-3-yl)diazene 1 -oxide (Dimer-II) and having the following structures:Dimer I Dimer ~ II.

16. The process as claimed in claim 15, wherein said di-tert-butyl 4,4'-(diazene-l,2- diylbis(pyridine-5,2-diyl))-bis(piperazine-l-carboxylate) (Dimer-I) and said l,2-bis(6- (4-(tert-butoxycarbonyl)piperazin- 1 -yl)pyridin-3 -yl)diazene 1 -oxide (Dimer-II) undergoes deprotection to result l,2-bis(6-piperazin-l-yl)pyridin-3-yl)diazene (Dimer-III) and l,2-bis(6-piperazin-l-yl)pyridin-3-yl)diazene-l -oxide (Dimer-IV) respectively having the following structures:Dimer - III Dmier ~ I .

17. The process as claimed in claim 16, wherein said Dimer I, said Dimer II, said DimerIII and said Dimer IV are in an amount less than 0.1%.

18. l-BOC-4-(6-amino-3-pyridyl) piperazine prepared by the process as claimed in claim 1 having the structure of formula I,Formula I19. l-BOC-4-(6-amino-3 -pyridyl) piperazine as claimed in claim 18 having a purity greater than 99%.

20. l-BOC-4-(6-amino-3 -pyridyl) piperazine as claimed in claim 19, wherein said purity is in the range of 99.50% to 99.99%.

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