Improved process for the preparation of aminopyrimidine derivatives

Abstract

The present invention provides an improved process for the preparation of an aminopyrimidine derivative or a pharmaceutically acceptable salt thereof having selective inhibitory activity against protein kinases, in particular against mutant epidermal growth factor receptor. And additionally, the present invention provides novel intermediates useful in said process and a process for their preparation.

Description

[0001] This application is a divisional application of the patent application with application number 201880048638.9, filed on July 25, 2018, and titled “Improved process for preparing aminopyrimidine derivatives”. TECHNICAL FIELD

[0002] The present invention relates to an improved process for preparing aminopyrimidine derivatives or pharmaceutically acceptable salts thereof. And additionally, the present invention relates to novel intermediates useful in the process and a process for preparing the same. BACKGROUND

[0003] WO 2016 / 060443 has disclosed aminopyrimidine derivatives or pharmaceutically acceptable salts thereof having selective inhibitory activity against protein kinases, especially against mutant epidermal growth factor receptors. The aminopyrimidine derivatives or pharmaceutically acceptable salts thereof can provide effective and safe treatment for non-small cell lung cancer. WO 2016 / 060443 has disclosed N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholino- phenyl)acrylamide of Formula 1 below, as an aminopyrimidine derivative, and a process for preparing the same.

[0004] <Formula 1>

[0005]

[0006] WO 2016 / 060443 has also disclosed a process for preparing aminopyrimidine derivatives of Formula (I), for example, a process according to the following reaction scheme. In the following reaction scheme, R1may be methoxy, R2may be hydrogen, R3may be morpholinyl, R4may be hydrogen, R5may be phenyl, R6may be hydrogen, and R7may be dimethylamino.

[0007] <Reaction Scheme>

[0008]

[0009] Specifically, the process for preparing the compound of Formula (I) according to the above reaction scheme includes reacting a compound of Formula (a) with a compound of Formula (b) by using sodium hydride to obtain a compound of Formula (c); reacting the compound of Formula (c) with a compound of Formula (d) by using sodium hydride to obtain a compound of Formula (e); performing reductive amination of the compound of Formula (e) to obtain a compound of Formula (f); reducing the compound of Formula (f) by using iron and ammonium chloride to obtain a compound of Formula (g); and reacting the compound of Formula (g) with acryloyl chloride to obtain the compound of Formula (I).

[0010] The method includes a reaction using sodium hydride in order to prepare the compound of formula (c) and the compound of formula (e). However, since sodium hydride has a high fire and explosion possibility, there is a problem in that it is difficult to use in industrial mass production.

[0011] And in addition, the method includes using iron in a step of reducing a nitro group of the compound of formula (f) to an amino group thereof. However, the use of iron can cause corrosion and contamination in the reactor, which makes it difficult to apply it to mass production. Furthermore, during reduction using iron and ammonium chloride to obtain the compound of formula (g), unknown color tones and degradation products are produced; and the product, i.e., the compound of formula (g), is obtained in black. Therefore, in order to obtain the final product, the compound of formula (I) having a suitable purity needs to perform a purification method by column chromatography, which is difficult to apply to mass production. In addition, the yield of the step of preparing the compound of formula (g) is only about 60%.

[0012] Furthermore, since acryloyl chloride used in the final step of preparing the compound of formula (I) has low stability, it is difficult to handle at a production site. And in addition, since various degradation products are produced during the reaction of the compound of formula (g) with acryloyl chloride, it is difficult to prepare the compound of formula (I) having a suitable purity. SUMMARY

[0013] Technical problem

[0014] The present application provides an improved method which is suitable for industrial mass production, and which is capable of producing N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholino- phenyl)acrylamide (compound of formula 1) or a pharmaceutically acceptable salt thereof having high purity and yield.

[0015] And in addition, the present application provides a new intermediate usable in the method and a method of preparing the same.

[0016] Solution to the problem

[0017] According to an aspect of the present application, there is provided a process for preparing N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholino- phenyl)acrylamide (a compound of Formula 1) or a pharmaceutically acceptable salt thereof, the process comprising (a) reacting N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholino-benzene-1,3-diamine (a compound of Formula 3) with a compound of Formula 4 to obtain a compound of Formula 2; and (b) reacting the compound of Formula 2 with a base to obtain N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholino-phenyl)acrylamide:

[0018] <Formula 2>

[0019]

[0020] <Formula 4>

[0021]

[0022] wherein X is halogen.

[0023] In one embodiment, the N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholino-benzene-1,3-diamine (a compound of Formula 3) used in step (a) can be obtained by a process comprising the steps of: (i) reacting 4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (a compound of Formula 6) with tin chloride in the presence of hydrochloric acid to obtain a complex of Formula 5, and (ii) reacting the complex of Formula 5 with a base to obtain N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholino-benzene-1,3-diamine:

[0024] <Formula 5>

[0025]

[0026] In another embodiment, 4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2- methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (compound of Formula 6) used in step (i) can be obtained by reacting 1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3- phenyl-1H-pyrazole-4-carbaldehyde (compound of Formula 7) with dimethylamine or a salt thereof.

[0027] In another embodiment, 1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3- phenyl-1H-pyrazole-4-carbaldehyde (compound of Formula 7) can be obtained by reacting 4-chloro-N-(2- methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (compound of Formula 9) with 3-phenyl-1H- pyrazole-4-carbaldehyde (compound of Formula 10). 4-Chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (compound of Formula 9) can be obtained by reacting N-(2-methoxy-4- morpholino-5-nitrophenyl)formamide (compound of Formula 11) with 4-chloro-2-(methylsulfonyl)pyrimidine (compound of Formula 12). And further, N-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (compound of Formula 11) can be obtained by performing formylation of 2-methoxy-4-morpholino-5-nitroaniline (compound of Formula 13). 4-Chloro-2-(methylsulfonyl)pyrimidine (compound of Formula 12) can be obtained by performing oxidation of 4-chloro-2-(methylthio)pyrimidine (compound of Formula 18). 2-Methoxy-4-morpholino-5-nitroaniline (compound of Formula 13) can be obtained by reacting 4-fluoro-2-methoxy-5-nitroaniline (compound of Formula 14) with morpholine (compound of Formula 15).

[0028] In another embodiment, 1 -(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl- 1 H-pyrazole-4-carbaldehyde (the compound of Formula 7) can be obtained by reacting N-(2-methoxy-4-morpholino-5-nitrophenyl)formaldehyde (the compound of Formula 11) with 1 -(2-(methylsulfonyl)pyrimidin-4-yl)-3-phenyl- 1 H-pyrazole-4-carbaldehyde (the compound of Formula 16). 1 -(2-(methylsulfonyl)pyrimidin-4-yl)-3-phenyl- 1 H-pyrazole-4-carbaldehyde (the compound of Formula 16) can be obtained by reacting 1 -(2-(methylthio)pyrimidin-4-yl)-3-phenyl- 1 H-pyrazole-4-carbaldehyde (the compound of Formula 17) with an oxidizing agent. 1 -(2-(methylthio)pyrimidin-4-yl)-3-phenyl- 1 H-pyrazole-4-carbaldehyde (the compound of Formula 17) can be obtained by reacting 4-chloro-2-(methylthio)pyrimidine (the compound of Formula 18) with 3-phenyl- 1 H-pyrazole-4-carbaldehyde (the compound of Formula 10).

[0029] According to another aspect of the present application, there is provided a compound of Formula 2 or a salt thereof:

[0030] <Formula 2>

[0031]

[0032] wherein X is halogen.

[0033] According to another aspect of the present application, there is provided a complex of Formula 5:

[0034] <Formula 5>

[0035]

[0036] According to another aspect of the present application, there is provided 1 -(2-(methylsulfonyl)pyrimidin-4-yl)-3-phenyl- 1 H-pyrazole-4-carbaldehyde (the compound of Formula 16).

[0037] According to another aspect of the present application, there is provided 1 -(2-(methylthio)pyrimidin-4-yl)-3-phenyl- 1 H-pyrazole-4-carbaldehyde (the compound of Formula 17).

[0038] Advantages of the invention

[0039] The process of the present application avoids the use of acryloyl chloride in the step of converting N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinophen-1,3-diamine (the compound of Formula 3, i.e. the compound corresponding to Formula (g) in WO 2016 / 060443) to N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide (the compound of Formula 1, i.e. the compound corresponding to Formula (I) in WO 2016 / 060443). That is, the process of the present application comprises reacting the compound of Formula 3 with 3-halopropionyl chloride to obtain the compound of Formula 2 (which is a novel intermediate), and reacting the compound of Formula 2 with a base to obtain the compound of Formula 1, which process minimizes the production of degradation products, thereby enabling the preparation of the compound of Formula 1 in high purity and yield.

[0040] And further, the improved process of the present application can avoid the use of ferric chloride and ammonium chloride in the step of converting 4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (the compound of Formula 6, i.e. the compound corresponding to Formula (f) in WO 2016 / 060443) to N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinophen-1,3-diamine (the compound of Formula 3, i.e. the compound corresponding to Formula (g) in WO 2016 / 060443). That is, the process of the present application comprises reacting the compound of Formula 6 with tin chloride in the presence of an acid to obtain a complex of the compound of Formula 6 and tin chloride; and reacting the complex with a base to obtain the compound of Formula 3, which process makes it possible to prepare the compound of Formula 3 in high yield (e.g. 75% or more) and in high purity. And further, the process is able to solve the problem of corrosion and contamination in the reactor caused by the use of iron. In addition, the process can avoid the production of unknown color tones and degradation products; and thereby avoid performing the purification process by column chromatography which is unsuitable for industrial batch production.

[0041] Further, the improved process of the present application is capable of eliminating the use of sodium hydride having high fire and explosion potential in the preparation of key intermediates, i.e. 4-chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (compound of Formula 9, i.e. corresponding to compound of Formula (c) in WO 2016 / 060443) and l-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3- phenyl-lH-pyrazole-4-carbaldehyde (compound of Formula 7, i.e. corresponding to compound of Formula (e) in WO 2016 / 060443) in the steps. Thus, the process of the present application is suitable for industrial bulk production.

[0042] Best mode for carrying out the invention

[0043] The present application provides an improved process for preparing N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-lH-pyrazol-l-yl)pyrimidin-2-yl)amino)-4- methoxy-2-morpholino phenyl)acrylamide or a pharmaceutically acceptable salt thereof. The overall reaction scheme of the process of the present application is represented as the following Reaction Scheme 1 or 2.

[0044] <Reaction Scheme 1>

[0045]

[0046] <Reaction Scheme 2>

[0047]

[0048] Hereinafter, the process of the present application will be described in detail with reference to the corresponding steps of Reaction Schemes 1 and 2.

[0049] The present application provides a process for preparing N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-lH-pyrazol-l-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholino phenyl)acrylamide (compound of Formula 1) or a pharmaceutically acceptable salt thereof, the process comprising (a) reacting N1-(4-(4-((dimethylamino)methyl)-3-phenyl-lH-pyrazol-l-yl)pyrimidin-2-yl)-6-methoxy-4-morpholino benzene-l,3-diamine (compound of Formula 3) with a compound of Formula 4 to obtain a compound of Formula 2; and (b) reacting the compound of Formula 2 with a base to obtain N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-lH-pyrazol-l-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholino phenyl)acrylamide:

[0050] <Formula 2>

[0051]

[0052] <Formula 4>

[0053]

[0054] wherein X is halogen.

[0055] In the process of the present application, X is preferably chlorine or bromine.

[0056] In the process of the present application, the reaction of step (a) can be carried out in the presence of one or more bases selected from the group consisting of potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate (including monopotassium phosphate, dipotassium phosphate and tripotassium phosphate), sodium phosphate (including monosodium phosphate, disodium phosphate and trisodium phosphate), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, triethylamine, diisopropylamine and diisopropylethylamine. Preferably, the base can be sodium bicarbonate. The base can be used in an amount ranging from 1.0 equivalent to 5.0 equivalents, preferably 1.0 equivalent to 3.0 equivalents, per 1 equivalent of the compound of formula 3. The reaction of step (a) can be carried out in the presence of a solvent selected from the group consisting of acetonitrile, methyl ethyl ketone, acetone, methyl isobutyl ketone, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, C1-C5 alcohol, toluene, ethyl acetate, isopropyl acetate, diethyl ether, water and a mixture thereof. Preferably, the solvent can be selected from the group consisting of acetonitrile, tetrahydrofuran, methyl ethyl ketone, acetone, dichloromethane, water and a mixture thereof. More preferably, the solvent can be a mixed solvent of acetonitrile and water, a mixed solvent of methyl ethyl ketone and water or a mixed solvent of tetrahydrofuran and water. The reaction of the compound of formula 3 with the compound of formula 4 can be carried out at a temperature ranging from 0°C to 50°C, preferably 0°C to 30°C. The compound of formula 2 can be isolated according to conventional methods such as concentration (e.g., concentration under reduced pressure, etc.), filtration, drying, and the like.

[0057] The base used in step (b) can be one or more selected from the group consisting of potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphates (including monopotassium phosphate, dipotassium phosphate and tripotassium phosphate), sodium phosphates (including monosodium phosphate, disodium phosphate and trisodium phosphate), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, triethylamine, diisopropylamine and diisopropylethylamine. Preferably, the base can be one or more selected from the group consisting of sodium hydroxide, triethylamine and diisopropylamine. More preferably, the base can be triethylamine. The base can be used in an amount ranging from 1.0 equivalent to 20.0 equivalents, preferably 5.0 equivalents to 10.0 equivalents, per 1 equivalent of the compound of formula 2. The reaction of step (b) can be carried out in the presence of a solvent selected from the group consisting of acetonitrile, methyl ethyl ketone, acetone, methyl isobutyl ketone, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, C1-C5 alcohols, toluene, ethyl acetate, isopropyl acetate, diethyl ether, water and mixtures thereof. Preferably, the solvent can be selected from the group consisting of acetonitrile, tetrahydrofuran, methyl ethyl ketone, acetone, dichloromethane, water and mixtures thereof. More preferably, the solvent can be a mixed solvent of acetonitrile and water, a mixed solvent of methyl ethyl ketone and water or a mixed solvent of tetrahydrofuran and water. The reaction of the compound of formula 2 with the base can be carried out at a temperature ranging from 40°C to 150°C, preferably at a temperature ranging from 60°C to 100°C, more preferably at a temperature of the reflux temperature of the solvent used. The compound of formula 1 produced from the reaction can be isolated in the form of a free base or in the form of an organic or inorganic salt (for example, in the form of a mesylate salt) according to a conventional method.

[0058] In one embodiment of the process of the present application, step (a) and step (b) can be carried out in a one-pot reaction without isolating the compound of formula 2. Thus, the process of the present application is suitable for industrial batch production.

[0059] In the method of the present invention, the N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinophenyl-1,3-diamine (the compound of formula 3) used in step (a) can be obtained by a method comprising the following steps: (i) reacting 4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (the compound of formula 6) with tin chloride in the presence of hydrochloric acid to obtain the complex of formula 5, and (ii) reacting the complex of formula 5 with a base to obtain N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinophenyl-1,3-diamine):

[0060] <Formula 5>

[0061]

[0062] In step (i), the tin chloride may be used in the form of anhydrite or a hydrate (e.g., dihydrate). Tin chloride may be used in amounts ranging from 2.0 to 10.0 equivalents, preferably from 3.0 to 5.0 equivalents, per equivalent of the compound of formula 6. An acid may be used in amounts ranging from 2.0 to 10.0 equivalents, per equivalent of the compound of formula 6. Furthermore, the reaction in step (i) may be carried out at temperatures ranging from 0°C to 100°C, preferably from 40°C to 85°C. Therefore, the reaction can be carried out under mild conditions; and is thus suitable for industrial mass production. The reaction may be carried out in the presence of one or more solvents selected from water, C1-C644, C1-C14 ... 10 Alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, etc.), dichloromethane, tetrahydrofuran, acetonitrile, and ethyl acetate. In one embodiment, the solvent may be ethanol or a mixture of ethanol and dichloromethane. The complex of formula 5 obtained in step (i) can be subjected to subsequent steps [i.e., step (ii)] without separation. Furthermore, the complex of formula 5 obtained in step (i) can be separated from the reaction mixture itself or by crystallization with an antisolvent. The antisolvent may be one or more selected from: dichloromethane, ethyl acetate, C1-C5 alcohols (e.g., methanol, ethanol, isopropanol, butanol, etc.), acetone, acetonitrile, methyl ethyl ketone, tetrahydrofuran, hexamethylphosphoramide, dimethyl ether, diethyl ether, diisopropyl ether, ethyl acetate, dimethoxyethane, and toluene. Preferably, the antisolvent may be dichloromethane. Although there is no specific limitation on the amount of antisolvent to be used, based on the complex of Formula 5, the antisolvent can be used in a weight ratio ranging from 2 to 20 times, preferably 3 to 10 times. Crystallization can also be carried out at temperatures ranging from 0°C to 40°C, preferably from 0°C to 25°C.

[0063] Step (ii) provides N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinophen-1,3-diamine (a compound of Formula 3) by reacting the complex of Formula 5 with a base. The base can be one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphates (including monopotassium phosphate, dipotassium phosphate and tripotassium phosphate) and sodium phosphates (including monosodium phosphate, disodium phosphate and trisodium phosphate). Preferably, the base can be sodium hydroxide.

[0064] In the process of the present application, the 4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (a compound of Formula 6) used in step (i) can be obtained by reacting 1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde (a compound of Formula 7) with dimethylamine or a salt thereof. The reaction can be carried out in the presence of one or more reducing agents selected from the group consisting of sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride, preferably sodium triacetoxyborohydride. The reducing agent can be used in an amount ranging from 1.0 equivalent to 5.0 equivalents, preferably 1.0 equivalent to 2.0 equivalents, per 1 equivalent of the compound of Formula 7, although the amount thereof can vary depending on the reducing agent. The reaction can be carried out in the presence of one or more bases selected from the group consisting of diisopropylethylamine and triethylamine. Also, the reaction can be carried out in the presence of one or more solvents selected from the group consisting of C1-C5 alcohols (e.g. methanol, ethanol, propanol, isopropanol, butanol, etc.), dimethylacetamide, dimethylformamide, dichloromethane, tetrahydrofuran, acetonitrile and ethyl acetate. The reaction can be carried out at a temperature ranging from 0°C to 50°C, preferably 20°C to 30°C. Thus, the reaction can be carried out under mild conditions; and thus is suitable for industrial batch production. The compound of Formula 6 produced from the reaction can be isolated from the reaction mixture as it is, or by crystallization with an anti-solvent. The anti-solvent can be C1-C5 alcohols (e.g. methanol, ethanol, isopropanol, butanol, etc.), water, or a mixture thereof, preferably water. Although the amount of the anti-solvent to be used is not particularly limited, the anti-solvent can be used in a weight ratio ranging from 2 to 20 times, preferably 3 to 10 times, based on the complex of Formula 7. The crystallization can also be carried out at a temperature ranging from 0°C to 40°C, preferably 20°C to 30°C. 10 alcohols (e.g. methanol, ethanol, isopropanol, butanol, etc.), water, or a mixture thereof, preferably water. Although the amount of the anti-solvent to be used is not particularly limited, the anti-solvent can be used in a weight ratio ranging from 2 to 20 times, preferably 3 to 10 times, based on the complex of Formula 7. The crystallization can also be carried out at a temperature ranging from 0°C to 40°C, preferably 20°C to 30°C.

[0065] In one embodiment, 1 -(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)- 3-phenyl-1 H-pyrazole-4-carbaldehyde (compound of Formula 7) can be obtained by reacting 4-chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (compound of Formula 9) with 3-phenyl-1 H-pyrazole-4-carbaldehyde (compound of Formula 10) (see Reaction Scheme 1). The reaction of compound of Formula 9 with compound of Formula 10 can be carried out in the presence of one or more bases selected from potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, potassium phosphate (including monopotassium phosphate, dipotassium phosphate and tripotassium phosphate), sodium phosphate (including monosodium phosphate, disodium phosphate and trisodium phosphate), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, triethylamine, diisopropylamine and diisopropylethylamine. Preferably, the base can be one or more selected from sodium carbonate, potassium carbonate and potassium phosphate. Also, the reaction can be carried out in the presence of one or more solvents selected from dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, C1-C5 alcohols, ethyl acetate, acetone, methyl ethyl ketone, acetonitrile and toluene. Preferably, the solvent can be selected from dichloromethane, dimethylformamide and dimethylacetamide. More preferably, the solvent can be dimethylformamide. Also, the reaction can be carried out at a temperature in the range of 0 °C to 100 °C, preferably 40 °C to 60 °C.

[0066] In the process of the present application, 4-chloro-N-(2-methoxy-4-morpholino-5- nitrophenyl)pyrimidin-2-amine (compound of Formula 9) can be obtained by reacting N-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (compound of Formula 11) with 4-chloro-2-(methylsulfonyl)pyrimidine (compound of Formula 12) (see Reaction Scheme 1). The reaction of compound of Formula 11 with compound of Formula 12 can be carried out in the presence of one or more bases selected from sodium C1-C6 alcohol, potassium C1-C6 alcohol, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, dimethylaminopyridine, and triethylamine. Preferably, the base can be sodium C1-C6 alcohol or potassium C1-C6 alcohol. And further, the reaction can be carried out in the presence of an inert solvent, for example, in the presence of one or more solvents selected from dimethylformamide, dimethylacetamide, dichloromethane, dimethylsulfoxide, tetrahydrofuran, hexamethylphosphoramide, C1-C5 alcohol, diethyl ether, ethyl acetate, acetonitrile, and acetone. Preferably, the solvent can be dimethylformamide, dimethylacetamide, tetrahydrofuran, or a mixture thereof. And further, the reaction can be carried out at a temperature in the range of 0 °C to 50 °C, preferably 0 °C to 10 °C.

[0067] In the process of the present application, N-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (compound of Formula 11) can be obtained by performing formylation of 2-methoxy-4-morpholino-5-nitroaniline (compound of Formula 13) (see Reaction Scheme 1). The formylation can be carried out with a mixture of acetic acid (e.g. anhydrous acetic acid) and formic acid. The amount of each of acetic acid and formic acid to be used can be in the range of 2 moles to 5 moles, preferably 2.5 moles to 3.5 moles, per 1 mole of compound of Formula 13. And further, the formylation can be carried out in the presence of an inert solvent, for example, in the presence of one or more solvents selected from dimethylformamide, dimethylacetamide, dichloromethane, dimethylsulfoxide, tetrahydrofuran, hexamethylphosphoramide, C1-C5 alcohol, diethyl ether, ethyl acetate, acetonitrile, and acetone. Preferably, the solvent can be dimethylformamide, dimethylacetamide, tetrahydrofuran, or a mixture thereof. And further, the reaction can be carried out at a temperature in the range of 0 °C to 70 °C, preferably 20 °C to 50 °C.

[0068] In the process of the present application, 4-chloro-2-(methylsulfonyl)pyrimidine (compound of formula 12) can be obtained by performing oxidation of 4-chloro-2-(methylthio)pyrimidine (compound of formula 18). The oxidation can be performed with one or more oxidizing agents selected from the group consisting of potassium permanganate, chromic acid, oxygen, hydrogen peroxide and 3-chloroperbenzoic acid. Preferably, the oxidizing agent can be hydrogen peroxide. The amount of oxidizing agent to be used can range from 1.8 moles to 10.0 moles, preferably from 2.0 moles to 5.0 moles per 1 mole of compound of formula 18. And further, the reaction rate can be increased by performing the oxidation in the presence of a catalyst such as ammonium molybdate tetrahydrate. Further, the reaction can be performed in the presence of one or more solvents selected from the group consisting of C1-C5 alcohols, carbon tetrachloride, chloroform, dichloromethane, acetone, methylethyl ketone, methyl isobutyl ketone, cyclohexanone, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, cyclohexane, petroleum ether, kerosene, toluene, xylene, mesitylene and benzene. Preferably, the solvent can be a C1-C5 alcohol.

[0069] In the process of the present application, 2-methoxy-4-morpholino-5-nitroaniline (compound of formula 13) can be obtained by reacting 4-fluoro-2-methoxy-5-nitroaniline (compound of formula 14) with morpholine (compound of formula 15). The reaction can be performed in the presence of one or more bases selected from the group consisting of C1-C6 sodium alkoxide, C1-C6 potassium alkoxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, dimethylaminopyridine, triethylamine and diisopropylethylamine. Preferably, the base can be triethylamine or diisopropylethylamine. The reaction can be performed in the presence of an inert solvent, for example in the presence of one or more solvents selected from the group consisting of dimethylformamide, dimethylacetamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, hexamethylphosphoramide, C1-C5 alcohol, diethyl ether, ethyl acetate, acetonitrile and acetone. Preferably, the solvent can be selected from the group consisting of acetonitrile, dimethylformamide and dimethylacetamide. And further, the reaction can be performed at a temperature ranging from 0 °C to 100 °C, preferably from 70 °C to 80 °C.

[0070] In another embodiment, 1 -(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1 H-pyrazole-4-carbaldehyde (compound of Formula 7) can be obtained by reacting N-(2-methoxy-4-morpholino-5-nitrophenyl)formaldehyde (compound of Formula 11) with 1 -(2-(methylsulfonyl)pyrimidin-4-yl)-3-phenyl-1 H-pyrazole-4- carbaldehyde (compound of Formula 16) (see Reaction Scheme 2). The reaction of the compound of Formula 11 with the compound of Formula 16 can be carried out in the presence of one or more bases selected from the group consisting of sodium C1-C6 alcoholates, potassium C1-C6 alcoholates, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, dimethylaminopyridine, and triethylamine. Preferably, the base can be one or more selected from the group consisting of sodium C1-C6 alcoholates, potassium C1-C6 alcoholates, sodium carbonate, potassium carbonate, and potassium phosphate. If the compound of Formula 7 is prepared according to Reaction Scheme 2, it is possible to avoid the use of sodium hydride. Also, further, the reaction can be carried out in the presence of an inert solvent, for example in the presence of one or more solvents selected from the group consisting of dimethylformamide, dimethylacetamide, dichloromethane, dimethylsulfoxide, tetrahydrofuran, hexamethylphosphoramide, C1-C5 alcohols, diethyl ether, ethyl acetate, acetonitrile, and acetone. Preferably, the solvent can be dimethylformamide, dimethylacetamide, tetrahydrofuran, or mixtures thereof. Also, further, the reaction can be carried out at a temperature in the range of 0 °C to 50 °C, preferably 0 °C to 10 °C.

[0071] In the method of the present invention, 1-(2-(methanesulfonyl)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carboxaldehyde (the compound of formula 16) can be obtained by reacting 1-(2-(methylthio)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carboxaldehyde (the compound of formula 17) with an oxidizing agent (see reaction scheme 2). The oxidation can be carried out with one or more oxidizing agents selected from potassium permanganate, chromic acid, oxygen, hydrogen peroxide, and 3-chloroperbenzoic acid. Preferably, the oxidizing agent can be hydrogen peroxide. The amount of oxidizing agent used per mole of the compound of formula 17 can range from 1.8 moles to 10.0 moles, preferably from 2.0 moles to 5.0 moles. Furthermore, the reaction rate can be increased by performing the oxidation in the presence of a catalyst such as ammonium molybdate tetrahydrate. Furthermore, the reaction can be carried out in the presence of one or more solvents selected from C1-C5 alcohols, carbon tetrachloride, chloroform, dichloromethane, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, cyclohexane, petroleum ether, kerosene, toluene, xylene, mesitylene, and benzene.

[0072] In the method of the present invention, 1-(2-(methylthio)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carboxaldehyde (the compound of formula 17) can be obtained by reacting 4-chloro-2-(methylthio)pyrimidine (the compound of formula 18) with 3-phenyl-1H-pyrazole-4-carboxaldehyde (the compound of formula 10). The reaction of the compound of Formula 18 with the compound of Formula 10 can be carried out in the presence of one or more bases selected from potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, potassium phosphate (including potassium monohydrogen phosphate, potassium dihydrogen phosphate, and potassium trihydrogen phosphate), sodium phosphate (including sodium monohydrogen phosphate, sodium dihydrogen phosphate, and sodium trihydrogen phosphate), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, triethylamine, diisopropylamine, and diisopropylethylamine. Preferably, the base may be selected from sodium carbonate, potassium carbonate, and potassium phosphate. The reaction can be carried out in the presence of one or more solvents selected from dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, C1-C5 alcohols, ethyl acetate, acetone, methyl ethyl ketone, acetonitrile, and toluene. Preferably, the solvent can be selected from dichloromethane, dimethylformamide, and dimethylacetamide. More preferably, the solvent can be dimethylformamide. Furthermore, the reaction can be carried out at a temperature ranging from 0°C to 100°C, preferably from 40°C to 60°C.

[0073] The present invention includes novel intermediates that can be used in the improved methods.

[0074] That is, the present application provides a compound of Formula 2 or a salt thereof:

[0075] <Formula 2>

[0076]

[0077] wherein X is halogen.

[0078] Further, the present application provides a complex of Formula 5:

[0079] <Formula 5>

[0080]

[0081] Further, the present application provides 1-(2-(methylthio)pyrimidin-4-yl)-3-phenyl- 1H-pyrazole-4-carbaldehyde (a compound of Formula 17).

[0082] Further, the present application provides 1-(2-(methylthio)pyrimidin-4-yl)-3-phenyl- 1H-pyrazole-4-carbaldehyde (a compound of Formula 17).

[0083] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present application.

[0084] Example 1: Preparation of 2-methoxy-4-morpholino-5-nitroaniline (compound 13)

[0085] A mixture of 4-fluoro-2-methoxy-5-nitroaniline (60.0 g, 0.322 mol), acetonitrile (600.0 mL), diisopropylethylamine (83.3 g, 0.645 mol) and morpholine (84.2 g, 0.967 mol) was refluxed under stirring for 4 hours. Purified water (1.8 L) was added to the reaction mixture. The resulting solid was filtered and then dried under vacuum to obtain 78.0 g of the title compound. (Yield: 95.5%)

[0086] 1 H-NMR (400 MHz, DMSO) δ 7.21 (s, 1H), 6.76 (s, 1H), 5.03 (s, 2H), 3.89 (s, 3H), 3.69 (t, 4H), 2.92 (t, 4H)

[0087] Example 2: Preparation of N-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (compound 11)

[0088] A mixture of anhydrous acetic acid (254.0 g, 2.487 mol) and formic acid (137.4 g, 2.984 mol) was stirred at 50 °C for 30 minutes. 2-Methoxy-4-morpholino-5-nitroaniline (210.0 g, 0.829 mol) and tetrahydrofuran (219.0 mL) were added to the reaction mixture, which was then stirred at 20 °C to 25 °C for 1 hour. Methyl tert-butyl ether (2.1 L) was added to the reaction mixture. The resulting solid was filtered and then dried under vacuum to obtain 211.0 g of the title compound. (Yield: 90.5%)

[0089] 1 H-NMR (400 MHz, DMSO) δ 9.88 (s, 1H), 8.85 (s, 1H), 8.29 (d, 1H), 6.83 (s, 1H), 3.99 (s, 1H), 3.72-3.74 (t, 4H), 3.03-3.05 (t, 4H)

[0090] Example 3: Preparation of 4-chloro-2-(methylsulfonyl)pyrimidine (compound 12)

[0091] A 35% hydrogen peroxide solution (90.7 g, 0.933 mol) and ammonium molybdate tetrahydrate (11.5 g, 0.01 mol) were added to a solution of 4-chloro-2-(methylthio)pyrimidine (50.0 g, 0.311 mol) in ethanol (250.0 mL). The reaction mixture was stirred for 2 hours, and then extracted with dichloromethane (200.0 mL) and purified water (250.0 mL). The separated organic layer was washed with a 10% sodium sulfite solution and purified water, and then concentrated under reduced pressure. The resulting residue was crystallized by adding isopropyl alcohol thereto. The resulting solid was filtered and then dried under vacuum to obtain 51.2 g of the title compound. (Yield: 85.4%)

[0092] 1 H-NMR (400 MHz, DMSO) δ 9.05 (d, 1H), 8.06 (d, 1H), 3.42 (s, 3H)

[0093] Example 4: Preparation of 4-chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (compound 9)

[0094] A mixture of N-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (15.0 g, 0.05 mol), tetrahydrofuran (40.0 mL) and dimethylacetamide (60.0 mL) was cooled to 0-5 °C. Sodium tert-butoxide (5.6 g, 0.06 mol) and 4-chloro-2-(methylsulfonyl)pyrimidine (11.3 g, 0.06 mol) were added to the mixture, which was then stirred at 0-10 °C for 1 hour. A 2 N NaOH solution (75.0 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour, and then purified water (150.0 mL) was added thereto. The resulting solid was filtered and then dried under vacuum to obtain 16.1 g of the title compound. (Yield: 82.6%)

[0095] 1 H-NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.38-8.40 (t, 2H), 6.95 (d, 1H), 6.83 (s, 1H), 6.95 (d, 1H), 6.83 (s, 1H), 3.94 (s, 3H), 3.73-3.75 (t, 4H), 3.06-3.08 (t, 4H)

[0096] Example 5: Preparation of l-(2-(methylthio)pyrimidin-4-yl)-3-phenyl-lH-pyrazole-4-carbaldehyde (compound 17)

[0097] A mixture of 4-chloro-2-(methylthio)pyrimidine (102.6 g, 0.639 mol), 3-phenyl-1H-pyrazole-4-carbaldehyde (100.0 g, 0.581 mol), potassium carbonate (160.5 g, 1.162 mol) and dimethylformamide (700.0 mL) was stirred at 40-50 °C for 2 hours. Purified water (1.6 L) was slowly added to the reaction mixture, which was then stirred at room temperature for 2 hours. The resulting solid was filtered and then dried under vacuum to obtain 154.0 g of the title compound. (Yield: 81.4%)

[0098] 1 H-NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 9.20 (s, 1H), 8.65 (d, 1H), 7.84-7.86 (m, 2H), 7.67-7.71 (m, 3H), 2.65 (s, 3H)

[0099] Example 6: Preparation of l-(2-(methylsulfonyl)pyrimidin-4-yl)-3-phenyl-lH-pyrazole-4-carbaldehyde (compound 16)

[0100] A mixture of 4-chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2- amine (3.2 g, 0.009 mol), dimethylformamide (22.4 mL), potassium carbonate (2.4 g, 0.017 mol) and 3-phenyl-lH-pyrazole-4-carboxaldehyde (1.7 g, 0.010 mol) was stirred at 40-50 °C for 12 h. To the reaction mixture was added purified water (32.0 mL). The resulting solid was filtered and then dried under vacuum to obtain 4.3 g of the title compound. (Yield: 98.0 %)

[0101] 1 H-NMR (400 MHz, DMSO) 8.94 (s, 1H), 8.38 (d, 1H), 8.38 (s, 1H), 6.96 (d, 1H), 6.83 (s, 1H), 3.94 (s, 3H), 3.73-3.75 (t, 4H), 3.06-3.09 (t, 4H)

[0102] Example 7: Preparation of l-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-lH-pyrazole-4-carbaldehyde (compound 7) Example 8: Preparation of l-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-lH-pyrazole-4-carbaldehyde (compound 7)

[0103] A mixture of 4-chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2- amine (3.2 g, 0.009 mol), dimethylformamide (22.4 mL), potassium carbonate (2.4 g, 0.017 mol) and 3-phenyl-lH-pyrazole-4-carboxaldehyde (1.7 g, 0.010 mol) was stirred at 40-50 °C for 12 h. To the reaction mixture was added purified water (32.0 mL). The resulting solid was filtered and then dried under vacuum to obtain 4.3 g of the title compound. (Yield: 98.0 %)

[0104] 1 H-NMR (400 MHz, DMSO) 8.94 (s, 1H), 8.38 (d, 1H), 8.38 (s, 1H), 6.96 (d, 1H), 6.83 (s, 1H), 3.94 (s, 3H), 3.73-3.75 (t, 4H), 3.06-3.09 (t, 4H)

[0105] Example 9: Preparation of 4-(4-((dimethylamino)methyl)-3-phenyl-lH-pyrazol-l-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (compound 6) Example 10: Preparation of N1-(4-(4-((dimethylamino)methyl)-3-phenyl-lH-pyrazol-l-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinophen-l,3-diamine tin complex (compound 5)

[0106] A mixture of N-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (0.4 g, 1.4 mmol), tetrahydrofuran (2.6 mL), dimethylacetamide (1.8 mL) and sodium tert-butoxide (0.2 g, 2.0 mmol) was stirred at 10 °C for 2 hours. After adjusting the temperature of the reaction mixture to room temperature, 1-(2-(methylsulfonyl)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde (0.5 g, 1.5 mmol) was added thereto. The resulting reaction mixture was stirred at room temperature for 1 hour. 2N NaOH solution (2.1 mL) was added to the reaction mixture, which was then stirred for about 1 hour. The resulting solid was filtered and then dried under vacuum to obtain 0.67 g of the title compound. (Yield: 93.9%)

[0107] 1 H-NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.57-8.61 (q, 3H), 7.98 (d, 2H), 7.52 (d, 2H), 7.50 (s, 1H), 7.36 (s, 1H), 6.88 (s, 1H), 4.01 (s, 3H), 3.75-3.77 (t, 4H), 3.41 (s, 2H), 3.07-3.10 (t, 4H), 2.24 (s, 6H)

[0108] Example 11: Preparation of N1-(4-(4-((dimethylamino)methyl)-3-phenyl-lH-pyrazol-l-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinophen-l,3-diamine tin complex (compound 5) Example 12: Preparation of N1-(4-(4-((dimethylamino)methyl)-3-phenyl-lH-pyrazol-l-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinophen-l,3-diamine (compound 3)

[0109] Dimethylamine hydrochloride (39.0 g, 0.479 mol) and triethylamine (161.4 g, 1.595 mol) were added to a solution of 1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde (160.0 g, 0.319 mol) in dimethylformamide (1,120 mL). The reaction mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (121.7 g, 0.574 mol) was added to the reaction mixture, which was then stirred at room temperature for 3 hours. Purified water (2,240 mL) was added to the reaction mixture, which was then stirred for 1 hour. The resulting solid was filtered under reduced pressure and then dried under vacuum to obtain 164.0 g of the title compound. (Yield: 96.9%)

[0110] 1 H-NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.57-8.61 (q, 3H), 7.98 (d, 2H), 7.52 (d, 2H), 7.50 (s, 1H), 7.36 (s, 1H), 6.88 (s, 1H), 4.01 (s, 3H), 3.75-3.77 (t, 4H), 3.41 (s, 2H), 3.07-3.10 (t, 4H), 2.24 (s, 6H)

[0111] Example 13: Preparation of 3-chloro-N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-lH-pyrazol-l-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)propanamide (compound 2, X = Cl) Example 14: Preparation of 3-bromo-N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-lH-pyrazol-l-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)propanamide (compound 2, X = Br)

[0112] A mixture of 4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy- 4-morpholino-5-nitrophenyl)pyrimidin-2-amine (10 g, 0.019 mol), tin chloride dihydrate (21.3 g, 0.094 mol), ethanol (200.0 mL), and 35% hydrochloric acid solution (13.1 mL, 0.151 mol) was refluxed with stirring for 2 hours. The reaction mixture was cooled to 20°C to 30°C. Dichloromethane (100.0 mL) was slowly added to the reaction mixture, which was then stirred for 2 hours. The resulting solid was filtered under reduced pressure and then vacuum dried to obtain 21.6 g of the title compound.

[0113] 1 H-NMR (400 MHz, DMSO) δ 10.07 (br, 1H), 10.01 (br, 1H), 9.24 (s, 1H), 8.62-8.63 (d, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 7.73-7.74 (d, 2H), 7.51-7.58 (m, 3H), 7.39-7.40 (d, 1H), 7.13 (s, 1H), 4.54 (s, 2H), 3.92 (s, 3H), 3.81 (s, 4H), 2.91 (s, 4H), 2.70 (s, 6H)

[0114] Example 15: Preparation of N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-lH-pyrazol-l-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide (compound 1) ​

[0115] A mixture of 4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy- 4-morpholino-5-nitrophenyl)pyrimidin-2-amine (20 g, 0.038 mol), ethanol (400.0 mL), dichloromethane (200.0 mL), and 35% hydrochloric acid solution (26.2 mL, 0.302 mol) was stirred for 30 minutes. Tin chloride dihydrate (42.5 g, 0.189 mol) was added to the reaction mixture, which was then refluxed with stirring for 2 hours. The reaction mixture was cooled to room temperature and then stirred for 2 hours. The resulting solid was filtered under reduced pressure and then vacuum dried to obtain 40.6 g of the title compound. (Yield: 82.1%)

[0116] 1H-NMR (400 MHz, DMSO) δ 10.07 (br, IH), 10.01 (br, IH), 9.24 (s, IH), 8.62-8.63 (d, IH), 8.55 (s, IH), 8.18 (s, IH), 7.73-7.74 (d, 2H), 7.51-7.58 (m, 3H), 7.39-7.40 (d, IH), 7.13 (s, IH), 4.54 (s, 2H), 3.92 (s, 3H), 3.81 (s, 4H), 2.91 (s, 4H), 2.70 (s, 6H)

[0117] ​ ​

[0118] A mixture of N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinophthalazine-1,3-diamine tin complex (40.6 g), dichloromethane (200.0 mL) and 2N NaOH solution (200.0 mL) was stirred at room temperature for 1 hour and then filtered. After the resulting filtrate was allowed to stand, the separated organic layer was treated with activated carbon and then concentrated under reduced pressure. Ethanol (100.0 mL) was added to the mixture, which was then stirred. The resulting solid was filtered and then dried in vacuum to obtain 14.2 g of the title compound. (Yield: 75.2%)

[0119] 1 H-NMR (400 MHz, DMSO) δ 8.57 (s, IH), 8.48 (d, IH), 8.16 (s, IH), 7.95 (d, 2H), 7.41-7.49 (m, 4H), 7.28 (s, IH), 6.72 (s, IH), 4.53 (s, 2H), 3.75-3.77 (t, 7H), 3.42 (s, 2H), 2.83 (t, 3H), 2.22 (s, 6H)

[0120] ​ ​

[0121] To a mixture of N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinophthalazine-1,3-diamine (0.5 g, 0.99 mmol), sodium bicarbonate (0.25 g, 2.99 mmol) and acetonitrile (5.0 mL) was added 3-chloropropanoyl chloride (0.16 g, 1.30 mmol). The reaction mixture was stirred at 20 to 30 °C for 3 hours. Purified water (5.0 mL) was added to the reaction mixture, which was stirred for 1 hour and then filtered under reduced pressure. The resulting solid was dried under vacuum to obtain 0.50 g of the title compound. (Yield: 85.0 %)

[0122] 1 H-NMR (400 MHz, DMSO) δ 9.09 (s, 1H), 9.06 (s, 1H), 8.79 (s, 1H), 8.50-8.51 (d, 1H), 8.17 (s, 1H), 8.02 (d, 2H), 7.45-7.48 (t, 2H), 7.39-7.42 (t, 1H), 7.31 (d, 1H), 6.89 (s, 1H), 3.98-3.99 (t, 2H), 3.88 (s, 3H), 3.78-3.80 (t, 4H), 3.43 (s, 2H), 2.85-2.86 (t, 4H), 2.21 (s, 6H)

[0123] ​ ​

[0124] To a mixture of N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinophthalazine-1,3-diamine (0.5 g, 0.99 mmol), sodium bicarbonate (0.25 g, 2.99 mmol) and acetonitrile (5.0 mL) was added 3-chloropropanoyl chloride (0.16 g, 1.30 mmol). The reaction mixture was stirred at 20 to 30 °C for 3 hours. Purified water (5.0 mL) was added to the reaction mixture, which was stirred for 1 hour and then filtered under reduced pressure. The resulting solid was dried under vacuum to obtain 0.50 g of the title compound. (Yield: 85.0 %)

[0125] 1H-NMR (400 MHz, DMSO) δ 9.08 (s, 2H), 8.80 (s, 1H), 8.50 (d, 1H), 8.16 (s, 1H), 8.02 (d, 2H), 7.45-7.48 (t, 2H), 7.39-7.42 (t, 1H), 7.31 (s, 1H), 3.88 (s, 3H), 3.83-3.85 (t, 2H), 3.79-3.81 (t, 4H), 3.43 (s, 2H), 3.09-3.12 (t, 2H), 2.85-2.87 (t, 4H), 2.19 (s, 6H)

[0126] ​ ​

[0127] A mixture of 3-bromo-N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)propanamide (10.0 g, 16.9 mmol), acetonitrile (200.0 mL) and triethylamine (17.1 g, 169.2 mmol) was refluxed under stirring for 16 hours. The reaction mixture was cooled to 20-30 °C and then concentrated under reduced pressure to remove the solvent. Dichloromethane (100.0 mL) and purified water (100.0 mL) were added to the reaction mixture, which was then stirred. The separated organic layer was concentrated under reduced pressure and then n-propanol (200.0 mL) was added thereto, followed by refluxing under stirring. The reaction mixture was slowly cooled to 20-30 °C and then stirred for 2 hours. The resulting solid was filtered under reduced pressure and then vacuum dried to obtain 8.0 g of the title compound. (Yield: 85.0%)

[0128] 1 H-NMR (400 MHz, DMSO) δ 9.15 (s, 2H), 9.08 (s, 1H), 8.53-8.55 (d, 1H), 8.18 (s, 1H), 8.04-8.06 (d, 2H), 7.47-7.50 (m. 2H), 7.34-7.36 (m, 1H), 7.34 (d, 1H), 6.96 (s, 1H), 6.71-6.78 (q, 1H), 6.43-6.44 (d, 1H), 5.84-5.85 (d, 1H), 3.91 (s, 3H), 3.82 (s, 4H), 3.46 (1s, 1H), 2.86 (s, 4H), 2.21 (s, 6H)

[0129] Example 16: Preparation of N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H- pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholino- phenyl)acrylamide (Compound 1) Example 16: Preparation of N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H- pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholino- phenyl)acrylamide (Compound 1)

[0130] To a mixture of 3-chloropropanoyl chloride (0.3 g, 2.60 mmol) was added N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinophen-1,3-diamine (1.0 g, 1.99 mmol), acetonitrile (20.0 mL) and sodium bicarbonate (0.5 g, 5.99 mmol). The reaction mixture was stirred at 20-30 °C for 2 h. Triethylamine (2.0 g, 19.9 mmol) was added to the reaction mixture, which was then refluxed with stirring for 16 h. The reaction mixture was cooled to 20-30 °C and then concentrated under reduced pressure to remove the solvent. Dichloromethane (15.0 mL) and purified water (10.0 mL) were added to the reaction mixture, which was then stirred. The separated organic layer was concentrated under reduced pressure, and then n-propanol (20.0 mL) was added to it, followed by refluxing with stirring. The reaction mixture was slowly cooled to 20-30 °C and then stirred for 2 h. The resulting solid was filtered under reduced pressure and then dried under vacuum to obtain 0.83 g of the title compound. (Yield: 75.0%)

[0131] 1 H-NMR (400 MHz, DMSO) δ 9.15 (s, 2H), 9.08 (s, 1H), 8.53-8.55 (d, 1H), 8.18 (s, 1H), 8.04-8.06 (d, 2H), 7.47-7.50 (m. 2H), 7.34-7.36 (m, 1H), 7.34 (d, 1H), 6.96 (s, 1H), 6.71-6.78 (q, 1H), 6.43-6.44 (d, 1H), 5.84-5.85 (d, 1H), 3.91 (s, 3H), 3.82 (s, 4H), 3.46 (1s, 1H), 2.86 (s, 4H), 2.21 (s, 6H)

[0132] Example 16: Preparation of N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H- pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholino- phenyl)acrylamide (Compound 1) Example 16: Preparation of N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H- pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholino- phenyl)acrylamide (Compound 1)

[0133] To a mixture of N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinophthalazine-1,3-diamine (1.0 g, 1.99 mmol), tetrahydrofuran (17.0 mL), purified water (1.7 mL) and sodium bicarbonate (1.1 g, 5.99 mmol) was added 3-chloropropanoyl chloride (0.3 g, 2.60 mmol). The reaction mixture was stirred at 20 to 30 °C for 2 hours. Triethylamine (2.0 g, 19.9 mmol) was added to the reaction mixture, which was then refluxed with stirring for 16 hours. The reaction mixture was cooled to 20 to 30 °C and then concentrated under reduced pressure to remove the solvent. Dichloromethane (10.0 mL) and purified water (10.0 mL) were added to the reaction mixture, which was then stirred. The separated organic layer was concentrated under reduced pressure, and then n-propanol (20.0 mL) was added thereto, followed by refluxing with stirring. The reaction mixture was slowly cooled to 20 to 30 °C and then stirred for 2 hours. The resulting solid was filtered under reduced pressure and then vacuum dried to obtain 0.88 g of the title compound. (Yield: 79.5%)

[0134] 1 H-NMR (400 MHz, DMSO) δ 9.15 (s, 2H), 9.08 (s, 1H), 8.53-8.55 (d, 1H), 8.18 (s, 1H), 8.04-8.06 (d, 2H), 7.47-7.50 (m. 2H), 7.34-7.36 (m, 1H), 7.34 (d, 1H), 6.96 (s, 1H), 6.71-6.78 (q, 1H), 6.43-6.44 (d, 1H), 5.84-5.85 (d, 1H), 3.91 (s, 3H), 3.82 (s, 4H), 3.46 (1s, 1H), 2.86 (s, 4H), 2.21 (s, 6H)

[0135] Example 16: Preparation of N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H- pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholino- phenyl)acrylamide (Compound 1) ​

[0136] To a mixture of N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinophen-1,3-diamine (20.0 g, 0.039 mol), methyl ethyl ketone (160.0 mL) and sodium bicarbonate (10.1 g, 0.120 mol) was added 3-chloropropanoyl chloride (6.6 g, 0.052 mol). The reaction mixture was stirred at 20 °C to 30 °C for 2 hours. Dichloromethane (10.0 mL) and purified water (10.0 mL) were added to the reaction mixture, which was then stirred. The separated organic layer was concentrated under reduced pressure, and then to this was added methyl ethyl ketone (300.0 mL) and triethylamine (40.4 g, 0.400 mol) followed by refluxing for 10 hours with stirring. The reaction mixture was cooled to 0 °C to 5 °C and then stirred for 2 hours. The resulting solid was filtered under reduced pressure and then dried under vacuum to obtain 17.7 g of the title compound. (Yield: 79.9%)

[0137] 1 H-NMR (400 MHz, DMSO) δ 9.15 (s, 2H), 9.08 (s, 1H), 8.53-8.55 (d, 1H), 8.18 (s, 1H), 8.04-8.06 (d, 2H), 7.47-7.50 (m. 2H), 7.34-7.36 (m, 1H), 7.34 (d, 1H), 6.96 (s, 1H), 6.71-6.78 (q, 1H), 6.43-6.44 (d, 1H), 5.84-5.85 (d, 1H), 3.91 (s, 3H), 3.82 (s, 4H), 3.46 (1s, 1H), 2.86 (s, 4H), 2.21 (s, 6H).

Claims

1. A complex of formula 5: ###0001### <formula 5> ​

Images