A process for the preparation of a triaminopyrimidine compound and novel intermediates thereof

Abstract

The present invention relates to a process for the preparation of a triaminopyrimidine compound of Formula I. Further, the present invention relates to the novel intermediate compounds and process for preparation thereof. More particularly, the present invention relates to the use of the novel intermediate compounds for the preparation of the triaminopyrimidine compound of Formula I.

Description

[0001] A PROCESS FOR THE PREPARATION OF A TRIAMINOPYRIMIDINE COMPOUND AND NOVEL INTERMEDIATES THEREOF

[0002] RELATED APPLICATION

[0003] This application claims priority to Indian Provisional Patent Application No. 20232101260, filed on Nov 30, 2023, the contents of which are incorporated herein in its entirety by reference.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to a process for the preparation of a triaminopyrimidine compound of Formula I. Further, the present invention relates to the novel intermediate compounds and process for preparation thereof. In particular, the present invention relates to the use of the novel intermediate compounds for the preparation of the triaminopyrimidine compound of Formula I.

[0006] BACKGROUND OF THE INVENTION

[0007] The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

[0008] International (PCT) Publication No. WO 2015 / 165660 Al (the WO '660) discloses triaminopyrimidine compounds, intermediates, pharmaceutical compositions and methods for use for preventing or treating malaria, wherein one of the triaminopyrimidine compound disclosed is a compound of Formula I as represented below: The WO '660 discloses a process for the preparation of compound of Formula I and intermediates thereof.

[0009] The journal article: Nature Communications, 6(1) (2015): 6715, also discloses a process for the preparation of a triaminopyrimidine compound of Formula I, and its use for treating malaria.

[0010] International (PCT) Publication No. WO 2019 / 049021 Al (WO ‘021) discloses a process for the preparation of compound of Formula I and crystalline Form I and Form II of the compound of Formula I.

[0011] Still there is need to develop an alternative process that is economically viable and industrially scalable for preparing the triaminopyrimidine compound of Formula I.

[0012] SUMMARY OF THE INVENTION

[0013] In one general aspect, the present invention provides a compound selected from a compound of Formula VI, a compound of Formula V, or a compound of Formula III, or a salt thereof, wherein X is halogen selected from chloro, bromo, or iodo.

[0014] In another general aspect, the present invention provides a process for the preparation of a compound of Formula I,

[0015] the process comprising:

[0016] (a) reacting a compound of Formula V, or a salt thereof,

[0017] Formula V wherein X is halogen, with a compound of Formula IV, or a salt thereof,

[0018] Formula IV to obtain a compound of Formula III, or a salt thereof, wherein X is halogen; and

[0019] (b) reacting the compound of Formula III, or a salt thereof, with a compound of Formula II, or a salt, or a hydrate thereof, to obtain the compound of Formula I.

[0020] In another general aspect, the present invention provides a process for the preparation of the compound of Formula V, or a salt thereof, the process comprising:

[0021] (a) reacting a compound of Formula VII,

[0022] Formula VII with phosphoryl halide, to obtain a compound of Formula VI, or a salt thereof,

[0023] Formula VI wherein X is halogen; and

[0024] (b) reacting the compound of Formula VI, or a salt thereof, with a methylating agent, optionally in the presence of a reducing agent, in one or more solvents, to obtain the compound of Formula V, or a salt thereof.

[0025] In another general aspect, the present invention provides a process for the preparation of a compound of Formula I,

[0026] the process comprising: reacting a compound of Formula III, or a salt thereof, wherein X is halogen, with a compound of Formula II, or a salt, or a hydrate thereof,

[0027] Formula II to obtain the compound of Formula I. The process of the present invention is a better alternative process that is economically viable and industrially scalable for preparing the triaminopyrimidine compound of Formula I. Also, the present invention provides the novel intermediate compounds, which gives advantage by providing a product with better quality for final drug substance in terms of purity and yield.

[0028] DETAILED DESCRIPTION OF THE INVENTION The aforementioned general and further specific aspects of the invention are fulfilled by the description of the invention provided herein after. The invention can further be understood in light of the description of the embodiments provided herein after. It is to be understood that the description, in no way, is intended to limit the scope of the invention to the expressly specified embodiments only. The equivalents and variants thereof or trivial modifications thereof which are apparently obvious to those skilled in the art, are also intended to be included within the scope of the present invention.

[0029] Detailed description of routine and conventional unit operations, which are easily understood by the skilled artisan, are not included herein. Such routine unit operations are to be construed as ordinarily understood and as routinely practiced by the person skilled in the field of the invention, unless otherwise specifically described.

[0030] The following definitions are used in connection with present application, unless it is indicated otherwise.

[0031] In general, the term "reacting ’ is used in its ordinary meaning as they are used in the field of the invention, unless defined specifically otherwise.

[0032] The term "optionally’ is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

[0033] The term "alkyl ’ as used herein, unless otherwise specifically described, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, one or more of which may be substituted with hetero atom(s) independently selected from nitrogen, oxygen, and sulfur. The non-limiting examples of alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, etc.

[0034] The numerical in phrases like ""Ci- 6 alkyl”, refers that there are 1 to 6 carbon atoms in the alkyl chain.

[0035] The term "halogen ’ denotes fluorine, chlorine, bromine, or iodine. The product(s) obtained may further be purified to obtain them in purer form. The product(s) obtained may further be dried additionally to achieve desired level of moisture and / or residual solvents.

[0036] The product(s) obtained may further be converted to any other physical forms thereof which includes but not specifically limited to polymorph(s), salt(s), solvate(s), or hydrate(s); and crystalline or amorphous forms thereof.

[0037] The product(s) obtained may further be subjected to physical processing which includes, but not limited to, pressing, crushing, triturating, milling, or grinding to adjust the particle size of the product(s) to desired levels.

[0038] Thus, in one general aspect, the present invention provides a compound selected from a compound of Formula VI, a compound of Formula V, or a compound of Formula III, or a salt thereof, wherein X is halogen selected from chloro, bromo or iodo.

[0039] In one embodiment, X in the compound of Formula VI is chloro.

[0040] In another embodiment, X in the compound of Formula V is chloro.

[0041] In another embodiment, X in the compound of Formula III is chloro.

[0042] In another embodiment, the present invention provides a compound selected from a compound of Formula VI, a compound of Formula V, or a compound of Formula III, or a salt thereof as an intermediate for the synthesis of triaminopyrimidine compound of Formula I. In another embodiment, the present invention provides the use of a compound selected from a compound of Formula VI, a compound of Formula V, or a compound of Formula III, or a salt thereof, for the synthesis of the triaminopyrimidine compound of Formula I. In another embodiment, the present invention provides a compound selected from a compound of Formula Via, a compound of Formula Va, or a compound of Formula Illa, or a salt thereof, as an intermediate for the synthesis of triaminopyrimidine compound of Formula I.

[0043] In another general aspect, the present invention provides a process for the preparation of a compound of Formula I, the process comprising: (a) reacting a compound of Formula V, or a salt thereof, wherein X is halogen, with a compound of Formula IV, or a salt thereof,

[0044] Formula IV to obtain a compound of Formula III, or a salt thereof,

[0045] Formula III wherein X is halogen; and

[0046] (b) reacting the compound of Formula III, or a salt thereof, with a compound of Formula II, or a salt, or a hydrate thereof,

[0047] Formula II to obtain the compound of Formula I.

[0048] In one embodiment, X in the compound of Formula V and compound of Formula III is chloro.

[0049] In general, the reaction at step (a) is carried out

[0050] (i) in the presence of one or more bases optionally in one or more solvents; or

[0051] (ii) in the presence of a transition metal catalyst, one or more bases, and optionally a ligand in one or more solvents.

[0052] In one embodiment, the reaction at step (a) is carried out in the presence of one or more bases optionally in one or more solvents; wherein the one or more bases are selected from diisopropylethylamine, triethylamine, and l,8-diazabicyclo(5.4.0)undec-7-ene; and one or more solvents are selected from toluene, tetrahydrofuran, 1,4-dioxane, xylene, dimethylsulfoxide and dimethylacetamide. In particular, the base is diisopropylethylamine.

[0053] In another embodiment, the reaction at step (a) is carried out in the presence of one or more bases and in absence of any other solvents, wherein the one or more bases are selected from diisopropylethylamine, triethylamine, and l,8-diazabicyclo(5.4.0)undec-7-ene. In particular, the base is diisopropylethylamine.

[0054] In another embodiment, the reaction at step (a) is carried out in the presence of a transition metal catalyst, one or more bases, and optionally a ligand in one or more solvents, wherein the transition metal catalyst is a palladium catalyst selected from PdCh, Pd(OAc)2, Pd(PPh3)4. PdCl2(CH3CN)2, PdCl2(PPh3)2, Pd2(dba)3, Pd(dba)2, [(Allyl)PdCl]2, and [PdCl(crotyl)]2; the ligand is a phosphine ligand selected from Josiphos SL-J009-1, Josiphos SL-J009-2, Joshiphos SL-J002-1, Josiphos SL-J002-2, Josiphos SL-J003 and Josiphos SL-J004, XPhos, DPEphos, Xantphos, l,l'-bis(diphenylphosphino)ferrocene (DPPF), DCyPF, BINAP, triphenylphosphine, tributylphosphine, or derivatives thereof; the base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, sodium phosphate, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5- diazabicyclo(4.3.0)non-5-ene (DBN), 1,1, 3, 3 -tetramethyl guanidine (TMG), or mixtures thereof; and the solvent is selected from one or more of toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, xylene, or mixtures thereof. In particular, the transition metal catalyst is Pd(PPh3)4, the base is cesium carbonate, and the solvent is toluene.

[0055] In general, the reaction at step (a) can be carried out at a temperature ranging from 50 °C to the reflux temperature of the solvent used. Particularly, the reaction may be carried out at a temperature ranging from 50 °C to 120 °C. More particularly, the reaction may be carried out at a temperature ranging from 80 °C to 110 °C. The reaction may be carried out for a time sufficient for the completion of reaction, for example 10-18 hours. After completion of the reaction, the reaction mixture may be cooled and the compound of Formula III may be isolated from the reaction mixture by any of the processes under common knowledge of a person skilled in the art.

[0056] In general, the reaction at step (b) is carried out (i) in the presence of a Grignard reagent in one or more solvents; or

[0057] (ii) in the presence of a transition metal catalyst, one or more bases, and optionally a ligand in one or more solvents.

[0058] In one embodiment, the reaction at step (b) is carried out in the presence of a Grignard reagent in one or more solvents; wherein the Grignard reagent is selected from alkyl-magnesium halides having General Formula (VIII),

[0059] Ri-Mg-Xi (VIII) wherein Ri is a linear or branched Ci-6 alkyl or C3-6 cycloalkyl, and Xi is a halogen selected from chloro, bromo, and iodo.

[0060] In general, the Grignard reagent is selected from isopropyl magnesium chloride, cyclohexyl magnesium chloride, tert-butyl magnesium chloride, -tolyl magnesium chloride, hexyl magnesium chloride, isopentyl magnesium chloride, cyclohexyl magnesium chloride, and cyclohexyl magnesium bromide; and the solvent is selected from one or more of tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether, di-isopropyl ether, toluene, xylene and 1,4-dioxane. In particular, the Grignard reagent is isopropyl magnesium chloride, and the solvent is tetrahydrofuran, toluene, or a mixture thereof.

[0061] In general, the reaction of the compound of Formula III or salt thereof, with the compound of Formula II, or salt thereof, or a hydrate thereof in presence of a Grignard reagent may be carried out at a temperature of ranging from 0 °C to the reflux temperature of the solvent used. Particularly, the reaction may be carried out at a temperature ranging from 0 °C to 40 °C. More particularly, the reaction may be carried out at room temperature. The reaction may be carried out for a time sufficient for the completion of reaction, for example 1-4 hours. After completion, the compound of Formula I may be isolated from the reaction mixture by any of the processes under common knowledge of a person skilled in the art.

[0062] In another embodiment, the reaction at step (b) is carried out in the presence of a transition metal catalyst, one or more bases, and optionally a ligand in one or more solvents, wherein the transition metal catalyst is a palladium catalyst selected from PdCh, Pd(OAc)2, Pd(PPh3)4, PdC12(CH3CN)2, PdC12(PPh3)2, Pd2(dba)3, Pd(dba)2, [(Allyl)PdCl]2, and [PdCl(crotyl)]2; the ligand is a phosphine ligand selected from Josiphos SL-J009-1, Josiphos SL-J009-2, Joshiphos SL-J002-1, Josiphos SL-J002-2, Josiphos SL-J003 and Josiphos SL-J004, XPhos, DPEphos, Xantphos, l,l'-bis(diphenylphosphino)ferrocene (DPPF), DCyPF, BINAP, triphenylphosphine, tributylphosphine, or derivatives thereof; the base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, sodium phosphate, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5- diazabicyclo(4.3.0)non-5-ene (DBN), 1,1,3,3-tetramethyl- guanidine (TMG), or mixtures thereof; and the solvent is selected from toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2- methyltetrahydrofuran, xylene, or mixtures thereof. In particular, the transition metal catalyst is Pd(OAc)2, the base is cesium carbonate, ligand is BINAP, and the solvent is toluene.

[0063] In general, the reaction of the compound of Formula III or salt thereof, with the compound of Formula II, or salt thereof, or a hydrate thereof in presence of a transition metal catalyst may be carried out at a temperature of ranging from 50 °C to the reflux temperature of the solvent used. Particularly, the reaction may be carried out at a temperature ranging from 80 °C to 120 °C. More particularly, the reaction may be carried out at a temperature ranging from 80 °C to 110 °C. The reaction may be carried out for a time sufficient for the completion of reaction, for example 10-16 hours. After completion, the compound of Formula I may be isolated from the reaction mixture by any of the processes under common knowledge of a person skilled in the art.

[0064] In another embodiment, the compound Formula II used at step (b) is in the form of monohydrochloride monohydrate.

[0065] In another general aspect, the present invention provides a process for the preparation of a compound of Formula V, or a salt thereof, the process comprising:

[0066] (a) reacting a compound of Formula VII,

[0067] Formula VII with phosphoryl halide, to obtain a compound of Formula VI, or a salt thereof,

[0068] Formula VI wherein X is halogen; and

[0069] (b) reacting the compound of Formula VI, or a salt thereof, with a methylating agent, optionally in the presence of a reducing agent, in one or more solvents, to obtain the compound of Formula V, or a salt thereof.

[0070] In general, the phosphoryl halide is POCI3 or POBn. In particular, the phosphoryl halide is POCh. In general, the reaction of compound of Formula VII with phosphoryl halide is optionally carried out in the presence of a catalyst. The catalyst for this purpose can be selected from pyridine, W-dimcthyl aniline, '. '-dicthyl aniline, and A'.A'-diisopropylcthylaminc. In particular, the catalyst is pyridine. In one embodiment, X in the compound of Formula VI is chloro or bromo. In another embodiment, X in the compound of Formula VI is chloro.

[0071] In another embodiment, the present invention provides a process for the preparation of the compound of Formula V, or a salt thereof, wherein the compound of Formula VI is not isolated.

[0072] In general, the methylating agent at step (b) is selected from diazomethane, 2,2- dimethoxypropane, dimethyl carbonate, dimethyl sulfate, dimethyl zinc, methyl flourosulfonate, methyl iodide, methyl bromide, methyl trifluoromethanesulfonate, trimethoxonium tetraflouroborate, formaldehyde, and a mixture of formic acid and formaldehyde. In particular, the methylating agent is formaldehyde, for example aqueous formaldehyde. In general, the reducing agent at step (b) is selected from sodium triacetoxyborohydride, sodium borohydride, and sodium cyanoborohydride. In particular, the reducing agent is sodium triacetoxyborohydride .

[0073] In general, the one or more solvents at step (b) is selected from ethyl acetate, dichloromethane, methanol, ethanol, tetrahydrofuran and 1,4-dioxane. In particular, the solvent is ethyl acetate.

[0074] In another embodiment, the reaction of compound of Formula VI, or a salt thereof, with a methylating agent as per step (b) is carried out in presence of a reducing agent, wherein the methylating agent is formaldehyde and the reducing agent is selected from sodium triacetoxyborohydride, sodium borohydride, and sodium cyanoborohydride. In particular, the reducing agent is sodium triacetoxyborohydride.

[0075] In general, the reaction at step (b) can be carried out at a temperature ranging from 0 °C to 50 °C, particularly at a temperature of 0 °C to room temperature. The reaction can be carried out for the time sufficient for the completion of reaction, for example, for 1 to 6 hours. After completion of reaction, the compound of Formula V or salt thereof can be isolated from the reaction mixture by any of the processes under common knowledge of a person skilled in the art. Alternatively, the compound of Formula V or a salt thereof, is not isolated and reacted with the compound of Formula IV, or a salt thereof as per the process of the present invention.

[0076] In general, the compound of Formula VII or a salt thereof is reacted with phosphoryl halide, particularly POCh in the presence of catalytic amount of pyridine at 100 °C to 110 °C to obtain the intermediate compound of Formula VI, which is not isolated and reacted with formaldehyde in the presence sodium triacetoxyborohydride to obtain the compound of Formula V. The reaction mixture may be basified and extracted with one or more solvents to obtain the compound of Formula V. The compound of Formula V may be obtained by removal of solvent after extraction. The reaction mixture may be basified using one or more bases selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate. In particular, sodium carbonate may be used. In another general aspect, the present invention provides a process for the preparation of a compound of Formula I, the process comprising: reacting a compound of Formula III, or a salt thereof, wherein X is halogen, with a compound of Formula II, or a salt, or a hydrate thereof,

[0077] Formula II to obtain the compound of Formula I.

[0078] The reaction of compound of Formula III or a salt thereof, with the compound of Formula II, or a salt, or a hydrate thereof can be carried out in a manner as described supra. In another general aspect, the present invention provides a process for the preparation of a compound of Formula I,

[0079] the process comprising:

[0080] (a) reacting a compound of Formula VII, Formula VII with phosphoryl halide, to obtain a compound of Formula VI, or a salt thereof,

[0081] Formula VI wherein X is halogen;

[0082] (b) reacting the compound of Formula VI, or a salt thereof, with a methylating agent, optionally in the presence of a reducing agent, in one or more solvents, to obtain the compound of Formula V, or a salt thereof;

[0083] (c) reacting the compound of Formula V, or a salt thereof, wherein X is halogen, with a compound of Formula IV, or a salt thereof,

[0084] Formula IV to obtain a compound of Formula III, or a salt thereof,

[0085] Formula III wherein X is halogen; and

[0086] (d) reacting the compound of Formula III, or a salt thereof, with a compound of Formula II, or a salt, or a hydrate thereof,

[0087] Formula II to obtain the compound of Formula I.

[0088] The reaction of compound of Formula VII with phosphoryl halide as per step (a) of the above process, reaction of compound of Formula VI, or a salt thereof, with a methylating agent as per step (b) of the above process, reaction of the compound of Formula V, or a salt thereof, with a compound of Formula IV, or a salt thereof as per step (c) of the above process, and the reaction of compound of Formula III, or a salt thereof, with the compound of Formula II, or a salt, or a hydrate thereof as per step (d) of the above process can be carried out in a manner as described earlier in the specification.

[0089] In another embodiment, the compound of Formula VI or salt thereof, and the compound of Formula V or salt thereof, are not isolated. The product(s) obtained by the process of the present invention may further be purified to obtain them in purer forms. The product(s) obtained may further be dried additionally to achieve the desired level of moisture and / or residual solvents.

[0090] The product(s) obtained may further be converted to any other physical forms thereof which includes but not specifically limited to polymorph(s), salt(s), solvate(s), or hydrate(s); and crystalline or amorphous forms thereof.

[0091] The complete process for the preparation of triaminopyrimidine compounds of the present invention can be depicted by the Scheme below:

[0092] The present invention is further illustrated by the following examples which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in various publications.

[0093] NMR spectra were recorded using Bruker Avance 400 MHz FT NMR spectrometer. Mass was determined using mass spectrometer Qtrap-4500 from Applied Biosciences (ABSciex).

[0094] Examples:

[0095] Example 1: Preparation of tert-butyl (7?)-4-(2,4-dioxo-l,2,3,4-tetrahydro- pyrimidin-5-yl)- 2-methylpiperazine-l-carboxylate (VII) :

[0096] Formula VII

[0097] In 2 L four neck round bottom flask, 5 -bromouracil (1.25 Kg, 6.545 mol), tert-butyl (R)-2- methylpiperazine-1 -carboxylate (1.32 Kg, 6.545 mol) and pyridine (4V, 5L) were added at 25 °C to 35 °C. The reaction mass was stirred for 15 hours at 115 °C to 120 °C. After completion, the reaction mass was cooled to 25 °C to 35 °C and water (10V) was added and stirred for 1 hour. The reaction mass was filtered, washed with 2.5 L water (2V) and dried to obtain 1.37 Kg (67.4%) of the title compound.

[0098] Example 2: Preparation of tert-butyl (7?)-4-(2,4-dioxo-l,2,3,4-tetrahydro- pyrimidin-5-yl)- 2-methylpiperazine-l-carboxylate (VII):

[0099] In 2 L four neck round bottom flask, 5-bromouracil (286.06 g, 1.49 mol), tert-butyl (7 )-2- methylpiperazine-l-carboxylate (100 g, 0.74 mol), DIPEA (193.60 g,1.49 mol) and pyridine (4V, 400 ml) were added at 25 °C to 35 °C. The reaction mass was stirred for 16 hours at 115 °C to 120 °C. After completion, the reaction mass was cooled to 25 °C to 35 °C and water (12V) was added and stirred for 1 hour. The reaction mass was filtered, washed with 2L water (2V) and dried to obtain 120 g (77.4%) of the title compound.

[0100] Example 3: Preparation of (R)-2,4-dichloro-5-(3,4-dimethylpiperazin-l-yl)pyrimidine (Compound of Formula V, wherein X is Chloro):

[0101] Formula VII Formula Via Formula Va

[0102] To a 250 ml 4 neck RBF, compound of Formula VII (25 g, 0.08 mol), phosphorus oxychloride (5V) and pyridine (0.5 g, 0.0063 mol) were added. The temperature of the reaction was raised to 105 °C to 110 °C and stirred for 6H at 105 °C to 110 °C. After completion of reaction, phosphorus oxychloride (~3 to 3.5V) was distilled out and the reaction was cooled to 50 °C to 60 °C. To this mixture, ethyl acetate (6V) was added and stirred, followed by distillation of ethyl acetate (~3V) and the reaction mass was allowed to cool at 25 °C to 35 °C. In another 1 liter 4 neck RBF water (3V) was added and cooled to 0 °C to 5 °C and the above reaction mass was quenched in water at 0 °C to 10 °C. Further temperature of reaction mass was raised to 15 °C to 25 °C and the pH was adjusted to 6 to 7 by using 20% aqueous sodium carbonate solution at 15 °C to 25 °C. To this reaction mass 13.1 g of 37% Aq. formaldehyde (13.1 g, 0.44 mol) was added and stirred for 10 minutes at 15 °C to 25 °C. The reaction mass was cooled to 15 °C to 20 °C followed by addition of sodium triacetoxyborohydride (34.15 g, 0. 16 mol) and stirred for 2 hours at this temperature. After completion of reaction, the pH was adjusted to 7 to 9 by using 20% aqueous sodium carbonate solution and stirred for 30 minutes. The layers were separated, and the product were back extracted from aqueous layer using ethyl acetate (5 V). The product containing organic layer was distilled off to get crude desired product which was further used without purification in the next step.

[0103] 1H NMR (400 MHz, CDC13) 5 8.19 (s, 1H), 3.37-3.25 (m, 2H), 3.06-2.88 (m, 2H), 2.68-2.46 (m, 2H), 2.39-2.34 (m, 4H), 1.13 (d, J = 6.4 Hz, 3H).13C NMR (100 MHz, CDCh) 5 156.1, 152.3, 149.9, 142.3, 57.3, 54.9, 50.5, 42.4, 16.7. ESIMS m / z: 261.1 [M+H]+for C10H14C12N4

[0104] Example 4: Preparation of (R)-2-chloro-N-(l,5-dimethyl-lH-pyrazol-3-yl)-5-(3,4- dimethylpiperazin-l-yl)pyrimidin-4-amine (Compound of Formula III, wherein X is chloro):

[0105] To a 250 ml 4 neck RBF, compound of Formula Va, 'A'-diisopropylcthylaminc (4V) and 1,5- dimethyl-lH-pyrazol-3-amine (DMPA) (11.16 g, 0.10 mol) were added at 25 °C to 35 °C. The temperature of the reaction mass was raised to 95 °C to 105 °C and stirred for 16 hours. After completion of reaction, the reaction mixture was cooled to 50 °C to 80 °C, followed by the addition of toluene (7V) and further cooled to 45 °C to 60 °C. To this mixture, water (2V) was added and stirred for 30 minutes at 45 °C to 60 °C. The layers were allowed to settle and the organic layer was separated. The aqueous layer was again extracted with toluene (2V). The combined organic layer was distilled out to remove traces of solvent. The obtained residue was crystallized in acetonitrile (3V) and filtered off followed by drying to obtain pure compound of formula Illa 15.0 g (Yield: 55 %, Purity: 98.0%).

[0106] ‘H NMR (400 MHz, DMSO-d6) 5 8.45 (s, 1H), 8.02 (d, J = 0.8 Hz, 1H), 6.4 (s, 1H), 3.66 (s, 3H), 2.92-2.76 (m, 4H), 2.47-2.37 (m, 2H), 2.30-2.27 (m, 4H), 2.22 (s, 3H), 0.99 (d, J = 6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) 5 156.3, 154.3, 147.6, 144.7, 139.5, 131.2, 97.9, 57.5, 58.0, 55.3, 51.4, 42.6, 35.9, 17.0, 11.3. ESIMS m / z: 336.2 [M+H]+ for C15H22CIN7.

[0107] Example 5: Preparation of (R)-2-chloro-N-(l,5-dimethyl-lH-pyrazol-3-yl)-5-(3,4- dimethylpiperazin-l-yl)pyrimidin-4-amine (Compound of Formula III, wherein X is chloro):

[0108] To a 4-Neck 100 ml RBF, a compound of Formula Va (2.0 g) and subsequently toluene (19V) were added under continuous purging of nitrogen. After 5 min, DMPA (1.1 mol) was added and the reaction mixture was stirred continuously for 10 min., followed by the addition of freshly dried cesium carbonate (2.0 mol) into the reaction mixture under nitrogen atmosphere. Further, Pd (PPh3)4 (0.03 mole equivalent) was added into the reaction mixture and rinsed with toluene (IV) with continuous nitrogen supply and the reaction mixture temperature was raised up to 110 °C. The reaction mixture was stirred at this temperature till the complete conversion of compound of Formula Va. After completion of reaction, the reaction mixture was filtered over celite under vacuum and the celite pad was washed with toluene (5 V).

[0109] Toluene layer was washed with water and layer was separated. Water was added to the toluene layer and the pH was adjusted to 1 using dilute HC1 and stirred. Layers were separated and product containing aqueous layer was basified with aq. sodium carbonate solution and stirred. The, obtained solid was filtered and dried to obtain of the compound of Formula Illa (1.7g) which was taken as such for next step.

[0110] 'H NMR (400 MHz, DMSO-d6) 5 8.45 (s, 1H), 8.02 (d, J = 0.8 Hz, 1H), 6.4 (s, 1H), 3.66 (s, 3H), 2.92-2.76 (m, 4H), 2.47-2.37 (m, 2H), 2.30-2.27 (m, 4H), 2.22 (s, 3H), 0.99 (d, J = 6 Hz, 3H);13C NMR (100 MHz, DMSO-d6) 5 156.3, 154.3, 147.6, 144.7, 139.5, 131.2, 97.9, 57.5, 58.0, 55.3, 51.4, 42.6, 35.9, 17.0, 11.3. ESIMS m / z: 336.2 [M+H]+for C15H22CIN7.

[0111] Example 6: Preparation of (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(l,5- dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-l-yl)pyrimidine-2,4-diamine (compound of Formula I):

[0112] To a 250 ml 4 neck round bottom flask, a compound of Formula Illa (5 g, 0.015 mol), 4- cyclopropyl-5-fluoro-6-methylpyridin-2-amine hydrochloride monohydrate (compound of Formula II.HCl.H2O; 3.45 g, 0.016 mol) and toluene (5V) at 25 °C to 35 °C were added. To this mixture 2M solution of isopropylmagnesium chloride (iPrMgCl) in THF (41 ml, 0.083 mol) were added at 20 °C to 30 °C. The resulting reaction mixture was agitated for a minimum of 4 hours. The resulting slurry was quenched into previously cooled dil. HC1 solution (15 ml Con. HC1 + 15 ml Water) at 15 °C to 35°C and flushed RBF with toluene(3V) and stirred for 30 minutes. To this 20% aqueous solution of sodium carbonate was added and pH adjusted to 8 to 10 . The temperature of reaction mass was raised to 40 °C to 50 °C and stirred for 1 hour. The obtained slurry was filtered through celite bed and filtrate were collected. The layers were separated, and the aqueous layer was again extracted with using toluene (5 V). The combined organic layer was distilled out under vacuum to obtain the crude material. Crystallization of this crude material in ethyl acetate (12V) followed by vacuum drying afforded the compound of Formula I, 4.0 g (Yield: 73%, Purity: 99.7%).

[0113] Example 7: Preparation of (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(l,5- dimethyl-lH-pyrazol-3-yl)-5-(3,4-dimethylpiperazin-l-yl)pyrimidine-2,4-diamine (compound of Formula I):

[0114] Formula I

[0115] To a 100 ml 4 neck round bottom flask, a compound of Formula Illa (400 mg, 1.2 mmol), toluene (15V), and subsequently 4-cyclopropyl-5-fluoro-6-methylpyridin-2 -amine hydrochloride monohydrate (compound of Formula II.HCl.H2O; 0.29 g, 1.3 mmol) and cesium carbonate (0.81 g, 2.5 mmol) were added under nitrogen atmosphere. After that, Pd(OAc)2 (8 mg, 0.036 mmol) and Rac -BINAP (0.022 g, 0.0035 mmol) were added. The temperature of the reaction mixture was raised up to 110 °C and stirred for 16 hours. After completion of the reaction, the reaction mixture was filtered over hyflo under vacuum. Toluene layer was washed with water (7V) and pH was adjusted to 1-3 with 20% aqueous solution of hydrochloric acid and stirred. The layers were separated, and the aqueous layer was basified with 20% aqueous solution of sodium carbonate and pH was adjusted around 9-10. A brownish thick slurry of compound of Formula I was observed which was extracted with dichloromethane (10V). Dichloromethane layer was distilled out under vacuum below 40 °C. Crude residue was used for the crystallization in acetonitrile (3V), the mixture was filtered to get the pure compound of Formula 1 (130 mg) .

[0116] While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

Claims:

1. A compound selected from a compound of Formula VI, a compound of Formula V, or a compound of Formula III,or a salt thereof, wherein X is halogen selected from chloro, bromo, or iodo.

2. The compound according to claim 1, wherein the compound is a compound of Formula VI, wherein X is chloro.

3. The compound according to claim 1 , wherein the compound is a compound of Formula V, wherein X is chloro.

4. The compound according to claim 1, wherein the compound is a compound of FormulaIll, wherein X is chloro.

5. A process for the preparation of a compound of Formula I,the process comprising:(a) reacting a compound of Formula V, or a salt thereof,wherein X is halogen,with a compound of Formula IV, or a salt thereof,Formula IV to obtain a compound of Formula III, or a salt thereof,wherein X is halogen; and(b) reacting the compound of Formula III, or a salt thereof, with a compound of Formula II, or a salt, or a hydrate thereof,to obtain the compound of Formula I.

6. The process according to claim 5, wherein X in the compound of Formula V and compound of Formula III is chloro.

7. The process according to claim 5, wherein the reaction at step (a) is carried out(i) in the presence of one or more bases, optionally in one or more solvents; or(ii) in the presence of a transition metal catalyst, one or more bases, and optionally a ligand in one or more solvents.

8. The process according to claim 7, wherein the one or more bases at (i) are selected from diisopropylethylamine, triethylamine, and l,8-diazabicyclo(5.4.0)undec-7-ene; and one or more solvents at (i) are selected from toluene, tetrahydrofuran, 1,4-di oxane, xylene, dimethylsulfoxide, and dimethylacetamide.

9. The process according to claim 7, wherein the transition metal catalyst at (ii) is a palladium catalyst selected from PdCh, Pd(OAc)2, Pd(PPh3)4, PdChCCFFCbfh, PdChCPPh ,Pd2(dba)3, Pd(dba)2, [(Allyl)PdCl]2, and [PdCl(crotyl)]2; the ligand is a phosphine ligand selected from Josiphos SL-J009-1, Josiphos SL-J009-2, Joshiphos SL-J002-1, Josiphos SL-J002-2, Josiphos SL-J003 and Josiphos SL-J004, XPhos, DPEphos, Xantphos, 1,1'- bis(diphenylphosphino)ferrocene (DPPF), DCyPF, BINAP, triphenylphosphine, tributylphosphine, or derivatives thereof; the base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, sodium phosphate, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,1,3,3-tetramethyl guanidine (TMG), or mixtures thereof; and the solvent is selected from one or more of toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2- methyltetrahydrofuran, xylene, or mixtures thereof.

10. The process according to claim 5, wherein the reaction at step (b) is carried out(i) in the presence of a Grignard reagent in one or more solvents; or(ii) in the presence of a transition metal catalyst, one or more bases, and optionally a ligand in one or more solvents.

11. The process according to claim 10, wherein the Grignard reagent at (i) is selected from alkyl-magnesium halides having General Formula (VIII),Ri-Mg-Xi (VIII) wherein Ri is a linear or branched Ci-6 alkyl or C3-6 cycloalkyl, and Xi is a halogen selected from chloro, bromo, and iodo.

12. The process according to claim 11, wherein the Grignard reagent is selected from isopropyl magnesium chloride, cyclohexyl magnesium chloride, tert-butyl magnesium chloride, p- tolyl magnesium chloride, hexyl magnesium chloride, isopentyl magnesium chloride, cyclohexyl magnesium chloride, and cyclohexyl magnesium bromide; and the solvent is selected from one or more of tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether, di -isopropyl ether, and 1,4-dioxane.

13. The process according to claim 10, wherein the transition metal catalyst at (ii) is a palladium catalyst selected from PdCh, Pd(OAc)2, Pd(PPh3)4, PdC12(CH3CN)2, PdCh(PPh3)2, Pd2(dba)3, Pd(dba)2, [(Allyl)PdCl]2, and [PdCl(crotyl)]2; the ligand is a phosphine ligand selected from Josiphos SL-J009-1, Josiphos SL-J009-2, Joshiphos SL- J002-1, Josiphos SL-J002-2, Josiphos SL-J003 and Josiphos SL-J004, XPhos, DPEphos, Xantphos, l,l'-bis(diphenylphosphino)ferrocene (DPPF), DCyPF, BINAP, triphenylphosphine, tributylphosphine, or derivatives thereof; the base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassiumphosphate, sodium phosphate, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5- diazabicyclo(4.3.0)non-5-ene (DBN), 1,1,3,3-tetramethyl- guanidine (TMG), or mixtures thereof; and the solvent is selected from toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, xylene, or mixtures thereof.

14. The process according to claim 5, wherein the compound of Formula V, or a salt thereof, is prepared by a process comprising:(a) reacting a compound of Formula VII,Formula VII with phosphoryl halide, to obtain a compound of Formula VI, or a salt thereof,Formula VI wherein X is halogen; and(b) reacting the compound of Formula VI, or a salt thereof, with a methylating agent, optionally in the presence of a reducing agent, in one or more solvents, to obtain the compound of Formula V, or a salt thereof.

15. The process according to claim 14, wherein the phosphoryl halide is POCh or POBn.

16. The process according to claim 14, wherein the methylating agent at step (b) is selected from diazomethane, 2,2-dimethoxypropane, dimethyl carbonate, dimethyl sulfide, dimethyl zinc, methyl flourosulfonate, methyl iodide, methyl bromide, methyl trifluoromethanesulfonate, trimethoxonium tetraflouroborate, formaldehyde, and a mixture of formic acid and formaldehyde.

17. The process according to claim 14, wherein the reducing agent at step (b) is selected from sodium triacetoxyborohydride, sodium borohydride, and sodium cyanoborohydride.

18. The process according to claim 5, wherein the compound Formula II used at step (b) is in the form of monohydrochloride monohydrate.

19. A process for the preparation of a compound of Formula I,the process comprising: reacting a compound of Formula III, or a salt thereof,wherein X is halogen, with a compound of Formula II, or a salt, or a hydrate thereof,Formula II to obtain the compound of Formula I.

20. The process according to claim 19, wherein X in the compound of Formula III is chloro.

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