HK40032181A - Process for preparing aminopyrimidine derivatives - Google Patents

Description

Improved process for preparing aminopyrimidine derivatives

Technical Field

The present invention relates to improved processes for the preparation of aminopyrimidine derivatives or pharmaceutically acceptable salts thereof. And, in addition, the present invention relates to novel intermediates useful in the process and processes for their preparation.

Background

WO2016/060443 has disclosed aminopyrimidine derivatives or pharmaceutically acceptable salts thereof having selective inhibitory activity on protein kinases, especially protein kinases of mutant epidermal growth factor receptors. The aminopyrimidine derivatives or pharmaceutically acceptable salts thereof can provide effective and safe treatment of non-small cell lung cancer. WO2016/060443 has disclosed as aminopyrimidine derivatives, for example, N- (5- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-ylamino) -4-methoxy-2-morpholinophenyl) acrylamide of the following formula 1 and a process for preparing the same.

< formula 1>

WO2016/060443 has also disclosed a process for the preparation of aminopyrimidine derivatives of formula (I), for example according to the following reaction scheme. In the following reaction scheme, R₁Can be methoxy, R₂Can be hydrogen, R₃May be morpholinyl, R₄Can be hydrogen, R₅Can be phenyl, R₆Can be hydrogen, and R₇May be dimethylamino.

< reaction scheme >

Specifically, the method of preparing the compound of formula (I) according to the above reaction scheme comprises reacting the compound of formula (a) with the compound of formula (b) by using sodium hydride to obtain the compound of formula (c); reacting a compound of formula (c) with a compound of formula (d) by using sodium hydride to obtain a compound of formula (e); performing a 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).

The process comprises a reaction with sodium hydride to produce a compound of formula (c) and a compound of formula (e). However, since sodium hydride has a high possibility of fire and explosion, there is a problem in that it is difficult to use in industrial mass production.

And further, the method comprises using iron in the step of reducing the nitro group of the compound of formula (f) to its amino group. However, the use of iron may cause corrosion and contamination in the reactor, which makes it difficult to apply it to mass production. Furthermore, during the reduction using iron and ammonium chloride to obtain the compound of formula (g), unknown hue and degradation products are produced; and the product (i.e., the compound of formula (g)) was obtained in black. Therefore, in order to obtain the final product, the compound of formula (I) having a suitable purity requires a purification method performed by column chromatography, which is difficult to apply to mass production. Furthermore, the yield of the step of preparing the compound of formula (g) is only about 60%.

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

Disclosure of Invention

Technical problem

The present invention provides an improved process 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-morpholinophenyl) acrylamide (the compound of formula 1) or a pharmaceutically acceptable salt thereof with high purity and yield.

And in addition, the present invention provides novel intermediates useful in the process and processes for their preparation.

Solution to the problem

According to one aspect of the present invention, there is provided a process for the preparation of 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) or a pharmaceutically acceptable salt thereof, which comprises (a) reacting N1- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-yl) -6-methoxy-4-morpholinobenzene-1, 3-diamine (the compound of formula 3) with the 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-morpholinophenyl) acrylamide:

< formula 2>

< formula 4>

Wherein X is halogen.

In one embodiment, N1- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-yl) -6-methoxy-4-morpholinobenzene-1, 3-diamine (the 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 (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-morpholinobenzene-1, 3-diamine:

< formula 5>

In another embodiment, the 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.

In another embodiment, 1- (2- ((2-methoxy-4-morpholino-5-nitrophenyl) amino) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (the compound of formula 7) can be obtained by reacting 4-chloro-N- (2-methoxy-4-morpholino-5-nitrophenyl) pyrimidin-2-amine (the compound of formula 9) with 3-phenyl-1H-pyrazole-4-carbaldehyde (the 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) carboxamide (compound of formula 11) with 4-chloro-2- (methylsulfonyl) pyrimidine (compound of formula 12). And, in addition, N- (2-methoxy-4-morpholino-5-nitrophenyl) carboxamide (compound of formula 11) may 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).

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

According to another aspect of the present invention, there is provided a compound of formula 2:

< formula 2>

Wherein X is halogen.

According to another aspect of the present invention, there is provided a complex of formula 5:

< formula 5>

According to another aspect of the present invention, there is provided 1- (2- (methylsulfonyl) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (a compound of formula 16).

According to another aspect of the present invention, there is provided 1- (2- (methylthio) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (a compound of formula 17).

The invention has the advantages of

The process of the present invention 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-morpholinobenzene-1, 3-diamine (compound of formula 3, i.e. 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 (compound of formula 1, i.e. corresponding to formula (I) in WO 2016/060443). That is, the method of the present invention, which 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, minimizes the generation of degradation products, thereby enabling the preparation of the compound of formula 1 in high purity and yield.

And in addition, the improved process of the present invention may 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-morpholinobenzene-1, 3-diamine (the compound of formula 3, i.e. the compound corresponding to formula (g) in WO 2016/060443). That is, the method of the present invention 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 method makes it possible to prepare the compound of formula 3 in high yield (e.g., 75% or more) and in high purity. And, in addition, the method can solve the problems of corrosion and contamination in the reactor caused by the use of iron. Furthermore, the method can avoid the production of unknown hue and degradation products; and thus avoids performing a purification process by column chromatography, which is not suitable for industrial mass production.

Furthermore, the improved process of the present invention enables to exclude the use of sodium hydride having high fire and explosion potential in the steps of preparing the key intermediates, i.e. 4-chloro-N- (2-methoxy-4-morpholino-5-nitrophenyl) pyrimidin-2-amine (compound of formula 9, i.e. the compound corresponding to formula (c) in WO 2016/060443) and 1- (2- ((2-methoxy-4-morpholino-5-nitrophenyl) amino) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (compound of formula 7, i.e. the compound corresponding to formula (e) in WO 2016/060443). Therefore, the method of the present invention is suitable for industrial mass production.

Best mode for carrying out the invention

The present invention provides an improved process for the preparation of N- (5- ((4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide, or a pharmaceutically acceptable salt thereof. The overall reaction scheme of the process of the present invention is represented as the following reaction scheme 1 or 2.

< reaction scheme 1>

< reaction scheme 2>

Hereinafter, the method of the present invention will be described in detail with reference to the respective steps of reaction schemes 1 and 2.

The invention provides a method for preparing N- (5- ((4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidine-2-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide (a compound of a formula 1) or a pharmaceutically acceptable salt thereof, the process comprises (a) reacting N1- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-yl) -6-methoxy-4-morpholinobenzene-1, 3-diamine (the 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-morpholinophenyl) acrylamide:

< formula 2>

< formula 4>

Wherein X is halogen.

In the process of the present invention, X is preferably chlorine or bromine.

In the process of the present invention, the reaction of step (a) may be carried out in the presence of one or more bases selected from potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphates (including potassium monohydrogen phosphate, potassium dihydrogen phosphate and potassium trihydrogen phosphate), sodium phosphates (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 sodium bicarbonate. The base may be used in an amount ranging from 1.0 equivalent to 5.0 equivalents, preferably from 1.0 equivalent to 3.0 equivalents, per 1 equivalent of the compound of formula 3. The reaction of step (a) may be carried out in the presence of a solvent selected from acetonitrile, methyl ethyl ketone, acetone, methyl isobutyl ketone, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, C₁～C₅Alcohols, toluene, ethyl acetate, isopropyl acetate, diethyl ether, water, and mixtures thereof. Preferably, the solvent may be selected from acetonitrile, tetrahydrofuran, methyl ethyl ketone, acetone, dichloromethane, water, and mixtures thereof. More preferably, the solvent may 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 may be carried out at a temperature ranging from 0 ℃ to 50 ℃, preferably from 0 ℃ to 30 ℃. The compound of formula 2 can be isolated according to a conventional method such as concentration (e.g., concentration under reduced pressure or the like, etc.), filtration, drying, and the like.

The base used in step (b) may 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 phosphate (including potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium hydrogen 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 one or more selected from the group consisting of: sodium hydroxide, triethylamine and diisopropylamine. More preferably, the base may be triethylamine. The base may be used in an amount ranging from 1.0 equivalent to 20.0 equivalents, preferably from 5.0 equivalents to 10.0 equivalents, per 1 equivalent of the compound of formula 2. The reaction of step (b) may be carried out in the presence of a solvent selected from acetonitrile, methyl ethyl ketone, acetone, methyl isobutyl ketone, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, C₁～C₅Alcohols, toluene, ethyl acetate, isopropyl acetate, diethyl ether, water, and mixtures thereof. Preferably, the solvent may be selected from acetonitrile, tetrahydrofuran, methyl ethyl ketone, acetone, dichloromethane, water, and mixtures thereof. More preferably, the solvent may 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 a base may be carried out at a temperature in the range of 40 ℃ to 150 ℃, preferably in the range of 60 ℃ to 100 ℃, more preferably at the reflux temperature of the solvent used. The compound of formula 1 prepared by the reaction may be isolated in the form of a free base or in the form of an organic or inorganic salt (e.g., in the form of a mesylate salt) according to a conventional method.

In one embodiment of the process of the present invention, step (a) and step (b) may be carried out in a one-pot reaction without isolating the compound of formula 2. Therefore, the method of the present invention is suitable for industrial mass production.

In the process of the present invention, N1- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-yl) -6-methoxy-4-morpholinobenzene-1, 3-diamine (the 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 (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-morpholinobenzene-1, 3-diamine:

< formula 5>

In step (i), the tin chloride may be used in the form of anhydrite or a hydrate, such as a dihydrate. Tin chloride may be used in an amount ranging from 2.0 equivalents to 10.0 equivalents, preferably from 3.0 equivalents to 5.0 equivalents, per 1 equivalent of the compound of formula 6. The acid may be used in an amount ranging from 2.0 equivalents to 10.0 equivalents per 1 equivalent of the compound of formula 6. And further, the reaction of step (i) may be carried out at a temperature in the range of 0 ℃ to 100 ℃, preferably 40 ℃ to 85 ℃. Thus, the reaction can be carried out under mild conditions; and is therefore suitable for industrial mass production. The reaction may be carried out in the presence of one or more solvents selected from water, C₁～C₁₀Alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, etc.), dichloromethane, tetrahydrofuran, acetonitrile, and ethyl acetate. In one embodiment, the solvent may be ethanol or a mixed solvent of ethanol and dichloromethane. The complex of formula 5 prepared from step (i) may be subjected to the subsequent step [ i.e., step (ii) ] without isolating it]. And, in addition, the complex of formula 5 prepared from step (i) may be isolated from the reaction mixture itself, or isolated by crystallization with an anti-solvent. The anti-solvent may be one or more selected from the group consisting of: dichloromethane, ethyl acetate, C₁～C₅Alcohols (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 anti-solvent may be dichloromethane. Although the amount of the antisolvent to be used is not particularly limited, the antisolvent may be 2 to 20 times based on the complex of formula 5,preferably in the range of 3 to 10 times by weight. The crystallization can also be carried out at a temperature in the range from 0 ℃ to 40 ℃, preferably from 0 ℃ to 25 ℃.

Step (ii) provides N1- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-yl) -6-methoxy-4-morpholinobenzene-1, 3-diamine (compound of formula 3) by reacting the complex of formula 5 with a base. The base may be one or more selected from the group consisting of: sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate (including potassium monohydrogen phosphate, potassium dihydrogen phosphate, and potassium trihydrogen phosphate), and sodium phosphate (including sodium monohydrogen phosphate, sodium dihydrogen phosphate, and sodium trihydrogen phosphate). Preferably, the base may be sodium hydroxide.

In the method of the present invention, the 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. The reaction may 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 may be used in an amount ranging from 1.0 equivalent to 5.0 equivalents, preferably from 1.0 equivalent to 2.0 equivalents, per 1 equivalent of the compound of formula 7, although the amount thereof may vary depending on the reducing agent. The reaction may be carried out in the presence of one or more bases selected from diisopropylethylamine and triethylamine. And additionally, the reaction may be carried out in the presence of one or more solvents selected from C₁～C₁₀Alcohols (e.g., methanol, ethanol, propanol, isopropanol, butanol, etc.), dimethylacetamide, dimethylformamide, dichloromethane, tetrahydrofuran, acetonitrile, and ethyl acetate. The reaction may be carried out at a temperature in the range of from 0 ℃ to 50 ℃, preferably from 20 ℃ to 30 ℃. Thus, the reaction can be carried out under mild conditions; and is therefore suitable for industrial mass production. The compound of formula 6 produced by the reaction may be isolated from the reaction mixture itself, or byCrystallizing with anti-solvent and separating. The antisolvent may be C₁～C₅Alcohols (e.g., methanol, ethanol, isopropanol, butanol, etc.), water, or mixtures thereof, preferably water. Although the amount of the antisolvent to be used is not particularly limited, the antisolvent may be used in a weight ratio ranging from 2 to 20 times, preferably from 3 to 10 times, based on the complex of formula 7. The crystallization can also be carried out at a temperature in the range from 0 ℃ to 40 ℃, preferably from 20 ℃ to 30 ℃.

In one embodiment, 1- (2- ((2-methoxy-4-morpholino-5-nitrophenyl) amino) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (the compound of formula 7) can be obtained by reacting 4-chloro-N- (2-methoxy-4-morpholino-5-nitrophenyl) pyrimidin-2-amine (the compound of formula 9) with 3-phenyl-1H-pyrazole-4-carbaldehyde (the compound of formula 10) (see reaction scheme 1). The reaction of the compound of formula 9 with the compound of formula 10 may 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 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 one or more selected from the group consisting of: sodium carbonate, potassium carbonate and potassium phosphate. And additionally, the reaction may be carried out in the presence of one or more solvents selected from dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, C₁～C₅Alcohols, ethyl acetate, acetone, methyl ethyl ketone, acetonitrile and toluene. Preferably, the solvent may be selected from dichloromethane, dimethylformamide and dimethylacetamide. More preferably, the solvent may be dimethylformamide. And, in addition, the reaction may be carried out at a temperature ranging from 0 ℃ to 100 ℃, preferably from 40 ℃ to 60 ℃.

In the process of the present invention, 4-chloro-N- (2-methoxy-4-morpholino-5-nitrophenyl) pyrimidin-2-amine (compound of formula 9)Compound) can be obtained by reacting N- (2-methoxy-4-morpholino-5-nitrophenyl) carboxamide (compound of formula 11) with 4-chloro-2- (methylsulfonyl) pyrimidine (compound of formula 12) (see reaction scheme 1). The reaction of the compound of formula 11 with the compound of formula 12 may be carried out in the presence of one or more bases selected from C₁～C₆Sodium alcoholate, C₁～C₆Potassium alkoxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium hydrogen carbonate, 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 may be C₁～C₆Sodium alkoxide or C₁～C₆And (4) potassium alcoholate. And additionally, the reaction may 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, dimethyl sulfoxide, tetrahydrofuran, hexamethylphosphoramide, C₁～C₅Alcohols, diethyl ether, ethyl acetate, acetonitrile and acetone. Preferably, the solvent may be dimethylformamide, dimethylacetamide, tetrahydrofuran, or a mixture thereof. And, in addition, the reaction may be carried out at a temperature ranging from 0 ℃ to 50 ℃, preferably from 0 ℃ to 10 ℃.

In the method of the present invention, N- (2-methoxy-4-morpholino-5-nitrophenyl) carboxamide (compound of formula 11) may be obtained by performing formylation of 2-methoxy-4-morpholino-5-nitroaniline (compound of formula 13) (see reaction scheme 1). The formylation may be carried out using 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 may be in the range of 2 to 5 moles, preferably 2.5 to 3.5 moles, per 1 mole of the compound of formula 13. And in addition, the formylation may 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, dimethyl sulfoxide, tetrahydrofuran, hexamethylphosphoramide, C₁～C₅Alcohols, diethyl ether, ethyl acetate, acetonitrile andacetone. Preferably, the solvent may be dimethylformamide, dimethylacetamide, tetrahydrofuran, or a mixture thereof. And, in addition, the reaction may be carried out at a temperature ranging from 0 ℃ to 70 ℃, preferably from 20 ℃ to 50 ℃.

In the method of the present invention, 4-chloro-2- (methylsulfonyl) pyrimidine (the compound of formula 12) may be obtained by performing oxidation of 4-chloro-2- (methylthio) pyrimidine (the compound of formula 18). The oxidation may 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 may be hydrogen peroxide. The amount of the oxidizing agent to be used may be in the range of 1.8 moles to 10.0 moles, preferably 2.0 moles to 5.0 moles, per 1 mole of the compound of formula 18. And in addition, the reaction rate can be increased by performing the oxidation in the presence of a catalyst such as ammonium molybdate tetrahydrate. Furthermore, the reaction may be carried out in the presence of one or more solvents selected from C₁～C₅Alcohols, 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. Preferably, the solvent may be C₁～C₅An alcohol.

In the method of the present invention, 2-methoxy-4-morpholino-5-nitroaniline (the compound of formula 13) can be obtained by reacting 4-fluoro-2-methoxy-5-nitroaniline (the compound of formula 14) with morpholine (the compound of formula 15). The reaction may be carried out in the presence of one or more bases selected from C₁～C₆Sodium alcoholate, C₁～C₆Potassium alkoxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium hydrogen carbonate, 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 may be triethylamine or diisopropylethylamine. The reaction may be carried out in the presence of an inert solvent, e.g.In the presence of one or more solvents selected from the group consisting of dimethylformamide, dimethylacetamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, hexamethylphosphoramide, C₁～C₅Alcohols, diethyl ether, ethyl acetate, acetonitrile and acetone. Preferably, the solvent may be selected from acetonitrile, dimethylformamide and dimethylacetamide. And, in addition, the reaction may be carried out at a temperature ranging from 0 ℃ to 100 ℃, preferably from 70 ℃ to 80 ℃.

In another embodiment, 1- (2- ((2-methoxy-4-morpholino-5-nitrophenyl) amino) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (the compound of formula 7) can be obtained by reacting N- (2-methoxy-4-morpholino-5-nitrophenyl) carbaldehyde (the compound of formula 11) with 1- (2- (methylsulfonyl) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (the compound of formula 16) (see reaction scheme 2). The reaction of the compound of formula 11 with the compound of formula 16 may be carried out in the presence of one or more bases selected from C₁～C₆Sodium alcoholate, C₁～C₆Potassium alkoxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium hydrogen carbonate, 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 may be one or more selected from the group consisting of: c₁～C₆Sodium alcoholate, C₁～C₆Potassium alkoxides, 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. And additionally, the reaction may 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, dimethyl sulfoxide, tetrahydrofuran, hexamethylphosphoramide, C₁～C₅Alcohols, diethyl ether, ethyl acetate, acetonitrile and acetone. Preferably, the solvent may be dimethylformamide, dimethylacetamide, tetrahydrofuran, or a mixture thereof. And, in addition, the reaction may be carried out at a temperature in the range of from 0 ℃ to 50 ℃, preferably from 0 ℃ to 10 ℃The process is carried out.

In the method of the present invention, 1- (2- (methylsulfonyl) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (the compound of formula 16) can be obtained by reacting 1- (2- (methylthio) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (the compound of formula 17) with an oxidizing agent (see reaction scheme 2). The oxidation may 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 may be hydrogen peroxide. The amount of the oxidizing agent to be used may be in the range of 1.8 moles to 10.0 moles, preferably 2.0 moles to 5.0 moles, per 1 mole of the compound of formula 17. And in addition, the reaction rate can be increased by performing the oxidation in the presence of a catalyst such as ammonium molybdate tetrahydrate. Furthermore, the reaction may be carried out in the presence of one or more solvents selected from C₁～C₅Alcohols, 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.

In the method of the present invention, 1- (2- (methylthio) pyrimidin-4-yl) -3-phenyl-1H-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-1H-pyrazole-4-carbaldehyde (the compound of formula 10). The reaction of the compound of formula 18 with the compound of formula 10 may 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 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 may be carried out in the presence of one or more solvents, the one or more solventsSelected from dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, C₁～C₅Alcohols, ethyl acetate, acetone, methyl ethyl ketone, acetonitrile and toluene. Preferably, the solvent may be selected from dichloromethane, dimethylformamide and dimethylacetamide. More preferably, the solvent may be dimethylformamide. And, in addition, the reaction may be carried out at a temperature ranging from 0 ℃ to 100 ℃, preferably from 40 ℃ to 60 ℃.

The present invention includes within its scope novel intermediates useful in the improved process.

That is, the present invention provides a compound of formula 2:

< formula 2>

Wherein X is halogen.

And further, the present invention provides a complex of formula 5:

< formula 5>

And, in addition, the present invention provides 1- (2- (methylsulfonyl) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (a compound of formula 16).

And, in addition, the present invention provides 1- (2- (methylthio) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (a compound of formula 17).

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1: preparation of 2-methoxy-4-morpholino-5-nitroaniline (Compound 13)

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

¹H-NMR(400MHz，DMSO)δ7.21(s，1H)，6.76(s，1H)，5.03(s，2H)，3.89(s，3H)，3.69(t，4H)，2.92(t，4H)

Example 2: preparation of N- (2-methoxy-4-morpholino-5-nitrophenyl) carboxamide (Compound 11)

A mixture of anhydrous acetic acid (254.0g, 2.487mol) and formic acid (137.4g, 2.984mol) was stirred at 50 ℃ for 30 minutes. 2-methoxy-4-morpholino-5-nitroaniline (210.0g, 0.829mol) and tetrahydrofuran (219.0mL) were added to the reaction mixture, which was then stirred at 20 ℃ to 25 ℃ for 1 hour. To the reaction mixture was added methyl tert-butyl ether (2.1L). The resulting solid was filtered and then dried in vacuo to obtain 211.0g of the title compound. (yield: 90.5%)

¹H-NMR(400MHz，DMSO)δ9.88(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)

Example 3: preparation of 4-chloro-2- (methylsulfonyl) pyrimidine (Compound 12)

A35% hydrogen peroxide solution (90.7g, 0.933mol) and ammonium molybdate tetrahydrate (11.5g, 0.01mol) were added to a solution of 4-chloro-2- (methylthio) pyrimidine (50.0g, 0.311mol) in ethanol (250.0 mL). The reaction mixture was stirred for 2 hours, and then extracted with dichloromethane (200.0mL) 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 thereto isopropyl alcohol. The resulting solid was filtered and then dried in vacuo to obtain 51.2g of the title compound. (yield: 85.4%)

¹H-NMR(400MHz，DMSO)δ9.05(d，1H)，8.06(d，1H)，3.42(s，3H)

Example 4: preparation of 4-chloro-N- (2-methoxy-4-morpholino-5-nitrophenyl) pyrimidin-2-amine (compound 9)

A mixture of N- (2-methoxy-4-morpholino-5-nitrophenyl) formamide (15.0g, 0.05mol), tetrahydrofuran (40.0mL) and dimethylacetamide (60.0mL) was cooled to 0 ℃ to 5 ℃. Sodium tert-butoxide (5.6g, 0.06mol) and 4-chloro-2- (methylsulfonyl) pyrimidine (11.3g, 0.06mol) were added to the mixture, which was then stirred at 0 ℃ to 10 ℃ for 1 hour. A2N NaOH solution (75.0mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour, and then purified water (150.0mL) was added thereto. The resulting solid was filtered and then dried in vacuo to obtain 16.1g of the title compound. (yield: 82.6%)

¹H-NMR(400MHz，DMSO)δ8.94(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)

Example 5: preparation of 1- (2- (methylthio) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (compound 17)

A mixture of 4-chloro-2- (methylthio) pyrimidine (102.6g, 0.639mol), 3-phenyl-1H-pyrazole-4-carbaldehyde (100.0g, 0.581mol), potassium carbonate (160.5g, 1.162mol) and dimethylformamide (700.0mL) was stirred at 40 ℃ to 50 ℃ for 2 hours. Purified water (1.6L) 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 in vacuo to obtain 154.0g of the title compound. (yield: 81.4%)

¹H-NMR(400MHz，CDCl₃)δ10.10(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)

Example 6: preparation of 1- (2- (methylsulfonyl) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (compound 16)

A35% hydrogen peroxide solution (3.4g, 30.3mmol) and ammonium molybdate tetrahydrate (0.4g, 0.3mmol) were added to a solution of 1- (2- (methylthio) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (3.0g, 10.1mmol) in ethanol (21.0 mL). The reaction mixture was stirred for 2 hours, and then extracted with dichloromethane (30.0mL) and purified water (30.0 mL). The separated organic layer was washed with 10% sodium sulfite solution (21.0mL) and purified water, and then concentrated under reduced pressure. The resulting residue was crystallized by adding thereto isopropyl alcohol. The resulting solid was filtered and then dried in vacuo to obtain 2.8g of the title compound. (yield: 84.3%)

¹H-NMR(400MHz，CDCl₃)δ10.12(s，1H)，9.30(s，1H)，9.00(d，1H)，8.27(d，2H)，7.87-7.93(m，2H)，7.48-7.54(m，3H)，3.44(s，3H)

Example 7: preparation of 1- (2- ((2-methoxy-4-morpholino-5-nitrophenyl) amino) pyrimidin-4-yl) -3-benzene 1H-pyrazole-4-carbaldehyde (Compound 7)

A mixture of 4-chloro-N- (2-methoxy-4-morpholino-5-nitrophenyl) pyrimidin-2-amine (3.2g, 0.009mol), dimethylformamide (22.4mL), potassium carbonate (2.4g, 0.017mol) and 3-phenyl-1H-pyrazole-4-carbaldehyde (1.7g, 0.010mol) was stirred at 40 ℃ to 50 ℃ for 12 hours. Purified water (32.0mL) was added to the reaction mixture. The resulting solid was filtered and then dried in vacuo to obtain 4.3g of the title compound. (yield: 98.0%)

¹H-NMR(400MHz，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)

Example 8: preparation of 1- (2- ((2-methoxy-4-morpholino-5-)MirabilitePhenylphenyl) amino) pyrimidin-4-yl) -3-benzenes 1H-pyrazole-4-carbaldehyde (Compound 7)

A mixture of N- (2-methoxy-4-morpholino-5-nitrophenyl) formamide (0.4g, 1.4mmol), tetrahydrofuran (2.6mL), dimethylacetamide (1.8mL) and sodium tert-butoxide (0.2g, 2.0mmol) was stirred at 10 ℃ for 2 hours. After the temperature of the reaction mixture was adjusted to room temperature, 1- (2- (methylsulfonyl) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde (0.5g, 1.5mmol) was added thereto. The resulting reaction mixture was stirred at room temperature for 1 hour. A2N NaOH solution (2.1mL) was added to the reaction mixture, which was then stirred for about 1 hour. The resulting solid was filtered and then dried in vacuo to obtain 0.67g of the title compound. (yield: 93.9%)

¹H-NMR(400MHz，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)

Example 9: preparation of 4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) -N- (2-methoxy-4- Morpholino-5-nitrophenyl) pyrimidin-2-amine (compound 6)

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

¹H-NMR(400MHz，DMSO)δ8.92(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)

Example 10: preparation of N1- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2- 6-methoxy-4-morpholinobenzene-1, 3-diamine tin complex (Compound 5)

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

¹H-NMR(400MHz，DMSO)δ10.07(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)

Example 11: preparation of N1- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2- 6-methoxy-4-morpholinobenzene-1, 3-diamine tin complex (Compound 5)

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

¹H-NMR(400MHz，DMSO)δ10.07(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)

Example 12: preparation of N1- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2- Yl) -6-methoxy-4-morpholinobenzene-1, 3-diamine (Compound 3)

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

¹H-NMR(400MHz，DMSO)δ8.57(s，1H)，8.48(d，1H)，8.16(s，1H)，7.95(d，2H)，7.41-7.49(m，4H)，7.28(s，1H)，6.72(s，1H)，4.53(s，2H)，3.75-3.77(t，7H)，3.42(s，2H)，2.83(t，3H)，2.22(s，6H)

Example 13: preparation of 3-chloro-N- (5- ((4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidine Pyridin-2-yl) amino) -4-methoxy-2-morpholinophenyl) propanamide (compound 2, X ═ Cl)

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

¹H-NMR(400MHz，DMSO)δ9.09(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)

Example 14: preparation of 3-bromo-N- (5- ((4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidine Pyridin-2-yl) amino) -4-methoxy-2-morpholinophenyl) propanamide (compound 2, X ═ Br)

3-Bromopropionyl chloride (0.13mL, 1.297mmol) was added slowly to a mixture of N1- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-yl) -6-methoxy-4-morpholinobenzene-1, 3-diamine (0.5g, 0.998mmol), sodium bicarbonate (0.25g, 3.00mmol), and acetonitrile (5.0 mL). The reaction mixture was stirred at 20 ℃ to 30 ℃ for 3 hours. Purified water (5.0mL) was added to the reaction mixture, which was stirred for 1 hour, and then filtered under reduced pressure. The resulting solid was dried in vacuo to obtain 0.52g of the title compound. (yield: 81.9%)

¹H-NMR(400MHz，DMSO)δ9.08(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)

Example 15: preparation of N- (5- ((4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2- Yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide (Compound 1)

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) propionamide (10.0g, 16.9mmol), acetonitrile (200.0mL), and triethylamine (17.1g, 169.2mmol) was refluxed with stirring for 16 hours. The reaction mixture was cooled to 20 to 30 ℃ and then concentrated under reduced pressure to remove the solvent. Methylene chloride (100.0mL) and purified water (100.0mL) were added to the reaction mixture, which was then stirred. The separated organic layer was concentrated under reduced pressure, and then n-propanol (200.0mL) was added thereto, followed by reflux with stirring. The reaction mixture was slowly cooled to 20 ℃ to 30 ℃ and then stirred for 2 hours. The resulting solid was filtered under reduced pressure and then dried under vacuum to obtain 8.0g of the title compound. (yield: 85.0%)

¹H-NMR(400MHz，DMSO)δ9.15(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)

Example 16: preparation of N- (5- ((4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2- Yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide (Compound 1)

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

¹H-NMR(400MHz，DMSO)δ9.15(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)

Example 17: preparation of N- (5- ((4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2- Yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide (Compound 1)

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

¹H-NMR(400MHz，DMSO)δ9.15(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)

Example 18: preparation of N- (5- ((4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2- Yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide (Compound 1)

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

¹H-NMR(400MHz，DMSO)δ9.15(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 (33)

1. A process for preparing N- (5- ((4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-yl) amino) -4-methoxy-2-morpholinophenyl) acrylamide, or a pharmaceutically acceptable salt thereof, comprising

(a) Reacting N1- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-yl) -6-methoxy-4-morpholinobenzene-1, 3-diamine 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-morpholinophenyl) acrylamide:

< formula 2>

< formula 4>

Wherein X is halogen.

2. The process of claim 1, wherein the reaction of step (a) is carried out in the presence of one or more bases selected from potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, sodium phosphate, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1, 5-diazabicyclo [4.3.0] non-5-ene, pyridine, triethylamine, diisopropylamine, and diisopropylethylamine.

3. The process of claim 1, wherein the reaction of step (a) is carried out in the presence of a solvent selected from acetonitrile, methyl ethyl ketone, acetone, methyl isobutyl ketone, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, C₁～C₅Alcohols, toluene, ethyl acetate, isopropyl acetate, diethyl ether, water, and mixtures thereof.

4. The process of claim 3, wherein the solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, methyl ethyl ketone, acetone, dichloromethane, water, and mixtures thereof.

5. The process of claim 1, wherein the base used in step (b) is 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 phosphate, sodium phosphate, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1, 5-diazabicyclo [4.3.0] non-5-ene, pyridine, triethylamine, diisopropylamine, and diisopropylethylamine.

6. The method of claim 5, wherein the base is one or more selected from the group consisting of: sodium hydroxide, triethylamine and diisopropylamine.

7. The process of claim 1, wherein the reaction of step (b) is carried out in the presence of a solvent selected from acetonitrile, methyl ethyl ketone, acetone, methyl isobutyl ketone, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, C₁～C₅Alcohols, toluene, ethyl acetate, isopropyl acetate, diethyl ether, water, and mixtures thereof.

8. The process of claim 7, wherein the solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, methyl ethyl ketone, acetone, dichloromethane, water, and mixtures thereof.

9. The process of claim 1, wherein steps (a) and (b) are carried out in a one-pot reaction.

10. The process according to any one of claims 1 to 9, wherein the N1- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-yl) -6-methoxy-4-morpholinobenzene-1, 3-diamine in step (a) is 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 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-morpholinobenzene-1, 3-diamine:

< formula 5>

11. The process according to claim 10, wherein the reaction of step (i) is carried out in the presence of one or more solvents selected from water, C₁～C₁₀Alcohols, dichloromethane, tetrahydrofuran, acetonitrile and ethyl acetate.

12. The process of claim 10, wherein the base used in step (ii) is one or more selected from the group consisting of: sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, and sodium phosphate.

13. The method of claim 10, wherein the 4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) -N- (2-methoxy-4-morpholino-5-nitrophenyl) pyrimidin-2-amine is obtained by reacting 1- (2- ((2-methoxy-4-morpholino-5-nitrophenyl) amino) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde with dimethylamine or a salt thereof.

14. The process according to claim 13, wherein the reaction is carried out in the presence of one or more reducing agents selected from the group consisting of sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride.

15. The process of claim 13, wherein the 1- (2- ((2-methoxy-4-morpholino-5-nitrophenyl) amino) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde is obtained by reacting 4-chloro-N- (2-methoxy-4-morpholino-5-nitrophenyl) pyrimidin-2-amine with 3-phenyl-1H-pyrazole-4-carbaldehyde.

16. The process of claim 15, wherein the 4-chloro-N- (2-methoxy-4-morpholino-5-nitrophenyl) pyrimidin-2-amine is obtained by reacting N- (2-methoxy-4-morpholino-5-nitrophenyl) carboxamide with 4-chloro-2- (methylsulfonyl) pyrimidine.

17. The process of claim 16, wherein the N- (2-methoxy-4-morpholino-5-nitrophenyl) carboxamide is obtained by performing formylation of 2-methoxy-4-morpholino-5-nitroaniline.

18. The process of claim 17, wherein the formylation is performed with a mixture of acetic acid and formic acid.

19. The method of claim 16, wherein the 4-chloro-2- (methylsulfonyl) pyrimidine is obtained by performing an oxidation of 4-chloro-2- (methylthio) pyrimidine.

20. The method of claim 19, wherein the oxidizing is performed with one or more oxidizing agents selected from the group consisting of potassium permanganate, chromic acid, oxygen, hydrogen peroxide, and 3-chloroperbenzoic acid.

21. The method of claim 13, wherein the 1- (2- ((2-methoxy-4-morpholino-5-nitrophenyl) amino) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde is obtained by reacting N- (2-methoxy-4-morpholino-5-nitrophenyl) carboxamide with 1- (2- (methylsulfonyl) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde.

22. The method of claim 21, wherein the reaction is in the presence of one or more basesIs carried out under the condition that the one or more bases are selected from C₁～C₆Sodium alcoholate, C₁～C₆Potassium alkoxides, sodium carbonate, potassium carbonate and potassium phosphate.

23. The process of claim 21, wherein the reaction is carried out in the presence of one or more solvents selected from the group consisting of dimethylformamide, dimethylacetamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, hexamethylphosphoramide, C₁～C₅Alcohols, diethyl ether, ethyl acetate, acetonitrile and acetone.

24. The process of claim 21, wherein the 1- (2- (methylsulfonyl) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde is obtained by reacting 1- (2- (methylthio) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde with an oxidizing agent.

25. The method of claim 24, wherein the oxidizing agent is one or more selected from the group consisting of: potassium permanganate, chromic acid, oxygen, hydrogen peroxide and 3-chloroperbenzoic acid.

26. The process of claim 24, wherein the reaction is carried out in the presence of one or more solvents selected from C₁～C₅Alcohols, 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.

27. A process according to claim 24, wherein the 1- (2- (methylthio) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde is obtained by reacting 4-chloro-2- (methylthio) pyrimidine with 3-phenyl-1H-pyrazole-4-carbaldehyde.

28. The process of claim 27, wherein the reaction is carried out in the presence of one or more bases selected from the group consisting of potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, potassium phosphate, sodium phosphate, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1, 5-diazabicyclo [4.3.0] non-5-ene, pyridine, triethylamine, diisopropylamine, and diisopropylethylamine.

29. The process of claim 27, wherein the reaction is carried out in the presence of one or more solvents selected from dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, C₁～C₅Alcohols, ethyl acetate, acetone, methyl ethyl ketone, acetonitrile and toluene.

30. A compound of formula 2 or a salt thereof:

< formula 2>

Wherein X is halogen.

31. A complex of formula 5:

< formula 5>

32.1- (2- (methylsulfonyl) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde.

33.1- (2- (methylthio) pyrimidin-4-yl) -3-phenyl-1H-pyrazole-4-carbaldehyde.