Preparation method of 2-aminopyrimidine-6-aryl compound

Abstract

The present invention provides a method for preparing a 2-aminopyrimidine-6-aryl compound. The preparation method comprises: subjecting a dispersion liquid containing a β-ketoester compound, guanidine carbonate and a 4A molecular sieve to a condensation reaction to obtain a 2-aminopyrimidine-6-aryl compound. The present invention introduces a 4A molecular sieve in the process of preparing a 2-aminopyrimidine-6-aryl compound. On the one hand, the 4A molecular sieve can remove the byproduct water from the reaction system, thereby more effectively suppressing the side reaction and thus improving the product yield. On the other hand, it can also promote a better forward progress of the reaction, thereby further improving the yield of the product.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a method for preparing a 2-aminopyrimidine-6-aryl compound. Background Art

[0002] 2-aminopyrimidine derivatives are a type of structural unit commonly found in anti-tumor, cardiovascular disease treatment and anti-inflammatory drugs. Introducing different substituted phenyl groups at the ortho position of the 4th position of 2-aminopyrimidine can construct a new structural unit to obtain a 2-aminopyrimidine-6-aryl compound. Currently, there are two common methods for constructing this structural unit. One synthesis method is to obtain the target compound by Suzuki-Miyaura reaction of substituted 2-amino-4-halopyrimidine and aryl borate. For this type of compound, the synthesis method has a low yield (28-48%), a low catalyst recovery rate, and a high production cost. Another synthesis method is to obtain the target compound by condensation reaction of β-ketoester compounds and guanidine carbonate, with a yield of 59-75%. However, both of the above reactions have the problem of low yield. Therefore, it is necessary to provide a new preparation method for 2-aminopyrimidine-6-aryl compounds to make the product yield higher and the purity higher. Summary of the invention

[0003] The main purpose of the present invention is to provide a method for preparing a 2-aminopyrimidine-6-aryl compound to solve the problem of low product yield in the prior art when preparing the 2-aminopyrimidine-6-aryl compound.

[0004] In order to achieve the above object, according to one aspect of the present invention, a method for preparing a 2-aminopyrimidine-6-aryl compound is provided. The 2-aminopyrimidine-6-aryl compound has a structure shown in Formula I:

[0005]

[0006] The preparation method comprises: subjecting a dispersion liquid containing a β-ketoester compound, guanidine carbonate and 4A molecular sieve to a condensation reaction to obtain a 2-aminopyrimidine-6-aryl compound; the β-ketoester compound has a structure shown in formula II:

[0007]

[0008]

[0009] wherein R1, R2, and R3 each independently represent hydrogen, alkyl, nitro, cyano, fluoroalkyl, methoxy, fluorine, chlorine, bromine, or hydroxyl.

[0010] Furthermore, R1, R2, and R3 each independently represent hydrogen, C1-C6 alkyl, nitro, or cyano.

[0011] Furthermore, the 4A molecular sieve is in powder form, and the average particle size of the 4A molecular sieve is ≥42μm, preferably 42-96μm; or the 4A molecular sieve is in spherical form, and the diameter of the 4A molecular sieve is 0.5-1.0mm; or the 4A molecular sieve is in strip form, and the length of the 4A molecular sieve is 1.6-5mm.

[0012] Furthermore, the 4A molecular sieve is in powder form, the LOD of the 4A molecular sieve is ≤2.5%, the static water adsorption is ≥24.5%, the sieve residue is ≤0.3%, and the bulk density is 450-600 g / cm 3 .

[0013] Furthermore, the dispersion liquid also includes a solvent, and preferably the solvent is trifluoroethanol.

[0014] Furthermore, the weight ratio of the β-ketoester compound, guanidine carbonate and 4A molecular sieve is 1:(0.6-1.5):(0.3-3.0).

[0015] Furthermore, based on the total weight of the β-ketoester compound, guanidine carbonate and 4A molecular sieve per gram, the amount of the solvent used is 2.4 to 7.2 mL.

[0016] Furthermore, during the condensation reaction, the reaction temperature is 60 to 80° C., and the reaction time is 12 to 36 hours.

[0017] Furthermore, the preparation method includes: replacing the reaction kettle with inert gas for 2 to 5 times, adding β-ketoester compounds, guanidine carbonate, 4A molecular sieve and solvent into the reaction kettle for premixing to form a dispersion; after premixing, continuing to replace the reaction kettle with inert gas for 2 to 5 times, and then allowing the dispersion to undergo condensation reaction at a stirring speed of 30 to 180 r / min.

[0018] Furthermore, after the condensation reaction, the preparation method further comprises the step of purifying the material after the condensation reaction; preferably, the purification step comprises: adjusting the temperature of the material after the condensation reaction to 15-35°C and then performing a first filtration treatment on it to obtain a first filter cake and a first filtrate; extracting the first filtrate with an organic solvent to obtain an aqueous phase and an organic phase; adjusting the pH value of the aqueous phase to 0.5-1 with an acid and then performing a second filtration treatment on it to obtain a second filter cake; drying the second filter cake to obtain a 2-aminopyrimidine-6-aryl compound; preferably, the acid is one or more of hydrochloric acid, sulfuric acid or hydrobromic acid.

[0019] The present invention introduces 4A molecular sieves in the process of preparing 2-aminopyrimidine-6-aryl compounds. First, it can remove the byproduct water from the reaction system, thereby more effectively inhibiting the side reaction and thus improving the product yield. Secondly, the addition of 4A molecular sieves can also promote better forward progress of the reaction, thereby further improving the product yield. Furthermore, the addition of 4A molecular sieves has no negative impact on the overall reaction system, and on the basis of reaction stability, can further efficiently improve the product yield and purity. DETAILED DESCRIPTION

[0020] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application can be combined with each other. The present invention will be described in detail below in conjunction with the embodiments.

[0021] The applicant of the present invention unexpectedly found that in the process of preparing 2-aminopyrimidine-6-aryl compounds (R1, R2, R3 each independently represent hydrogen, alkyl, nitro, cyano, fluoroalkyl, methoxy, fluorine, chlorine, bromine or hydroxyl) by condensing β-ketoester compounds with guanidine carbonate, by-products such as alcohol and water were generated during the reaction process when β-ketoester compounds and guanidine carbonate were refluxed in a polar protic solvent. This part of the by-product water will cause the raw material β-ketoester to undergo an alkaline hydrolysis side reaction of the ester group, thereby promoting the generated carboxylic acid to further decarboxylate to generate aryl ethyl ketone impurities, which in turn leads to a low yield of the reaction. The synthetic route involved in the above reaction process is as follows (wherein Et represents ethyl):

[0022]

[0023] Based on this discovery, the applicant of the present invention further provides a method for preparing a 2-aminopyrimidine-6-aryl compound, the preparation method comprising: subjecting a dispersion containing a β-ketoester compound, guanidine carbonate and a 4A molecular sieve to a condensation reaction to obtain a 2-aminopyrimidine-6-aryl compound. The present invention introduces a 4A molecular sieve in the above-mentioned condensation reaction process. First, it can remove the byproduct water from the reaction system, thereby more effectively suppressing the side reaction and thereby improving the product yield. Secondly, the addition of the 4A molecular sieve can also promote better forward progress of the reaction, thereby further improving the yield of the product. Furthermore, the addition of the 4A molecular sieve has no negative impact on the overall reaction system, and on the basis of reaction stability, can further efficiently improve the product yield and purity.

[0024] In a preferred embodiment, R1, R2, and R3 each independently represent hydrogen, C1-C6 alkyl, nitro, or cyano. Based on this, the above preparation method has better applicability, and the obtained product has higher yield and higher purity. More preferably, R1, R2, and R3 each independently represent hydrogen, C1-C3 alkyl, nitro, or cyano.

[0025] In a preferred embodiment, the 4A molecular sieve is in powder form, and the average particle size of the 4A molecular sieve is ≥42μm, preferably 42-96μm, for example, it can be 48μm (300 mesh) specification. Alternatively, the 4A molecular sieve is spherical, and the diameter of the 4A molecular sieve is 0.5-1.0mm, for example, it can be 0.5-0.8mm specification; or, the 4A molecular sieve is strip-shaped, and the length of the 4A molecular sieve is 1.6-5mm, for example, it can be 1.6-2.5mm or 3-5mm. Based on this, the dehydration efficiency in the reaction system is higher, the by-products are less, the product yield is higher, and the purity is higher. Further preferably, the 4A molecular sieve is in powder form, the LOD of the 4A molecular sieve is ≤2.5%, the static water adsorption is ≥24.5%, the sieve residue is ≤0.3% (>42μm), and the bulk density is 450-600g / cm 3 The above LOD (Loss on Drying) is the ratio of the weight loss of the material during the drying process to the initial weight. The above 4A molecular sieves of the present invention can be prepared according to conventional molecular sieve preparation methods, or can be directly purchased commercially.

[0026] In a preferred embodiment, the dispersion also includes a solvent, and the solvent is trifluoroethanol. Compared with conventional solvents such as ethanol and methanol in the prior art, the present invention uses trifluoroethanol as the condensation reaction solvent, which can further effectively inhibit side reactions, thereby greatly improving the product yield and reducing production costs.

[0027] In order to further balance the product yield and reaction stability, in a preferred embodiment, the weight ratio of the β-ketoester compound, guanidine carbonate and 4A molecular sieve is 1:(0.6-1.5):(0.3-3.0), for example, it can be 1:0.78:0.3, 1:0.78:1.4, 1:0.76:1.4, 1:0.94:1.4.

[0028] In a preferred embodiment, the amount of solvent used is 2.4 to 7.2 mL per gram of the total weight of the β-ketoester compound, guanidine carbonate and 4A molecular sieve. Based on this, on the one hand, the dispersion of each reaction raw material in the dispersion is better, thereby promoting higher reaction efficiency in the subsequent reaction system. On the other hand, the side reaction can be further effectively suppressed, thereby further improving the product yield and purity on the basis of reducing production costs.

[0029] In order to further improve the stability of the condensation reaction and the product conversion rate, in a preferred embodiment, during the condensation reaction, the reaction temperature is 60 to 80° C. and the reaction time is 12 to 36 hours.

[0030] In a preferred embodiment, the preparation method comprises: after replacing the reactor with an inert gas for 2 to 5 times, adding a β-ketoester compound, guanidine carbonate, 4A molecular sieve and a solvent into the reactor for premixing; after premixing, continuing to replace the reactor with an inert gas for 2 to 5 times, and performing a condensation reaction at a stirring speed of 30 to 180 r / min. Based on this, the reaction safety is better, the stability is better, the product yield is higher, and the purity is higher. Preferably, the above-mentioned inert gas can be nitrogen.

[0031] In order to further improve the purity of the product, in a preferred embodiment, after the condensation reaction, the preparation method further includes the step of purifying the material after the condensation reaction. Preferably, the purification includes: adjusting the temperature of the material after the condensation reaction to 15-35°C, and then performing a first filtration treatment on it to obtain a first filter cake and a first filtrate; extracting the first filtrate with an organic solvent to obtain an aqueous phase and an organic phase; adjusting the pH value of the aqueous phase to 0.5-1.0 with an acid, and then performing a second filtration treatment on it to obtain a second filter cake; drying the second filter cake to obtain a 2-aminopyrimidine-6-aryl compound. Preferably, the first filtrate can also be concentrated to a small volume system, and then a small amount of water is added thereto to stir and dissolve the trace solid matter, and then it is extracted with an organic solvent. Preferably, the above-mentioned organic solvent can be selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran or methyl tert-butyl ether, and the above-mentioned acid can be selected from one or more of hydrochloric acid, sulfuric acid or hydrobromic acid. Preferably, the above-mentioned filtration can be carried out by suction filtration, and the temperature during the drying process is 50-55°C. Preferably, the yield of the 2-aminopyrimidine-6-aryl compound is 80-90%, and the purity is 90-99%.

[0032] The present application is further described in detail below in conjunction with specific embodiments. These embodiments should not be construed as limiting the scope of protection claimed in the present application.

[0033] Example 1

[0034]

[0035] Replace the nitrogen atmosphere in a 25mL three-necked flask three times, add 1a (1.0g, 1.0eq), trifluoroethanol (5.4mL, 5.4V), guanidine carbonate (0.78g, 1.0eq) and 4A molecular sieve (0.3g, 0.3w / w), replace the nitrogen atmosphere three times. After stirring, control the temperature at 70-75℃ and stir for 16h. Take samples for HPLC control, raw material: 0.2%, product: 67%.

[0036] Among them, 4A molecular sieve is in powder form, with an average particle size of 48μm (300 mesh), LOD of 4A molecular sieve is 1.10%, static water adsorption is 25.50%, sieve residue is 0.20%, and bulk density is 520g / cm 3 .

[0037] Post-treatment: Cool the system temperature to 30-35°C, filter with suction, and wash the filter cake with trifluoroethanol. Concentrate the filtrate under reduced pressure to a small volume, add water and stir to dissolve. Wash the aqueous phase with dichloromethane. Separate the liquids, and adjust the pH value of the aqueous phase to 1 with hydrochloric acid. Filter with suction, wash the filter cake with water, drain, and dry in a forced air drying oven at 50-55°C to constant weight to obtain 0.64 g of an off-white solid product with a product purity of 98% and a yield of 66%.

[0038] NMR is as follows: 1H NMR (400MHz, DMSO) δ11.15 (s, 1H), 7.83-7.81 (d, J = 8.8 Hz, 1H), 7.63-7.61 (d, J = 8.8 Hz, 1H), 7.46-7.42 (t, J = 7.6 Hz, 1H), 6.81 (s, 1H), 6.64 (s, 2H), 2.50 (s, 3H).

[0039] Example 2

[0040]

[0041] Replace the nitrogen atmosphere in a 100mL three-necked flask three times, add 1a (6.0g, 1.0eq), trifluoroethanol (32.4mL, 5.4V), guanidine carbonate (4.67g, 1.0eq) and 4A molecular sieve (8.4g, 1.4w / w), replace the nitrogen atmosphere three times. After stirring, control the temperature at 70-75℃ and stir for 16h. Take a sample and control it in HPLC, raw material: 1.0%, product: 87%.

[0042] Among them, 4A molecular sieve is in powder form, with an average particle size of 48μm (300 mesh), LOD of 4A molecular sieve is 1.10%, static water adsorption is 25.50%, sieve residue is 0.20%, and bulk density is 520g / cm 3 .

[0043] Post-treatment: Cool the system temperature to 30-35°C, filter with suction, and wash the filter cake with trifluoroethanol. Concentrate the filtrate under reduced pressure to a small volume, add water and stir to dissolve. Wash the aqueous phase with dichloromethane. Separate the liquids, and adjust the pH value of the aqueous phase to 1 with hydrochloric acid. Filter with suction, wash the filter cake with water, drain, and dry in a forced air drying oven at 50-55°C to constant weight to obtain 5.0 g of an off-white solid product with a product purity of 98% and a yield of 85%.

[0044] NMR is as follows: 1H NMR (400MHz, DMSO) δ11.15 (s, 1H), 7.83-7.81 (d, J = 8.8 Hz, 1H), 7.63-7.61 (d, J = 8.8 Hz, 1H), 7.46-7.42 (t, J = 7.6 Hz, 1H), 6.81 (s, 1H), 6.64 (s, 2H), 2.50 (s, 3H).

[0045] Example 3

[0046]

[0047] Replace the nitrogen atmosphere in a 25mL three-necked flask three times, add 1a (1.0g, 1.0eq), trifluoroethanol (5.4mL, 5.4V), guanidine carbonate (0.78g, 1.0eq) and 4A molecular sieve (0.3g, 0.3w / w), replace the nitrogen atmosphere three times. After stirring, control the temperature at 70-75℃ and stir for 16h. Take samples for HPLC control, raw material: 0.2%, product: 60%.

[0048] Among them, the 4A molecular sieve is spherical with a diameter of 0.5-0.8 mm. The LOD of the 4A molecular sieve is 1.10%, the static water adsorption is 25.5%, the sieve residue is 0.15%, and the bulk density is 500 g / cm 3 .

[0049] Post-treatment: Cool the system temperature to 30-35°C, filter with suction, and wash the filter cake with trifluoroethanol. Concentrate the filtrate under reduced pressure to a small volume, add water and stir to dissolve. Wash the aqueous phase with dichloromethane. Separate the liquids, and adjust the pH value of the aqueous phase to 1 with hydrochloric acid. Filter with suction, wash the filter cake with water, drain, and dry in a forced air drying oven at 50-55°C to constant weight to obtain 0.59 g of an off-white solid product with a product purity of 81% and a yield of 60%.

[0050] NMR is as follows: 1H NMR (400MHz, DMSO) δ11.15 (s, 1H), 7.83-7.81 (d, J = 8.8 Hz, 1H), 7.63-7.61 (d, J = 8.8 Hz, 1H), 7.46-7.42 (t, J = 7.6 Hz, 1H), 6.81 (s, 1H), 6.64 (s, 2H), 2.50 (s, 3H).

[0051] Example 4

[0052]

[0053] Replace the nitrogen atmosphere in a 25mL three-necked flask three times, add 1a (1.0g, 1.0eq), trifluoroethanol (5.4mL, 5.4V), guanidine carbonate (0.78g, 1.0eq) and 4A molecular sieve (3.0g, 3.0w / w), and replace the nitrogen atmosphere three times. After stirring, control the temperature at 70-75℃ and stir for 16h. Take samples for HPLC control, raw material: 0.2%, product: 60%.

[0054] Among them, the 4A molecular sieve is in strip shape with a diameter of 0.5-0.8 mm. The LOD of the 4A molecular sieve is 1.10%, the static water adsorption is 18.50%, the sieve residue is 0.15%, and the bulk density is 500 g / cm 3 .

[0055] Post-treatment: Cool the system temperature to 25-35°C, filter with suction, and wash the filter cake with trifluoroethanol. Concentrate the filtrate under reduced pressure to a small volume, add water and stir to dissolve. Wash the aqueous phase with dichloromethane. Separate the liquids, and adjust the pH value of the aqueous phase to 1 with hydrochloric acid. Filter with suction, wash the filter cake with water, drain, and dry in a forced air drying oven at 50-55°C to constant weight to obtain 0.60 g of an off-white solid product with a product purity of 98% and a yield of 61%.

[0056] NMR is as follows: 1H NMR (400MHz, DMSO) δ11.15 (s, 1H), 7.83-7.81 (d, J = 8.8 Hz, 1H), 7.63-7.61 (d, J = 8.8 Hz, 1H), 7.46-7.42 (t, J = 7.6 Hz, 1H), 6.81 (s, 1H), 6.64 (s, 2H), 2.50 (s, 3H).

[0057] Example 5

[0058]

[0059] The 25mL three-necked flask was replaced with nitrogen three times, and 1c (2.0g, 1.0eq), ethanol (10.8mL, 5.4V), guanidine carbonate (1.52g, 1.0eq) and 4A molecular sieve (2.8g, 1.4w / w) were added, and the nitrogen was replaced three times. After stirring, the temperature was controlled at 70-75℃ and stirred for 16h. Samples were taken for HPLC control, raw material: 24%, product: 64%.

[0060] Among them, 4A molecular sieve is in powder form, with an average particle size of 48μm (300 mesh), LOD of 4A molecular sieve is 1.10%, static water adsorption is 25.50%, sieve residue is 0.20%, and bulk density is 520g / cm 3 .

[0061] Post-treatment: Cool the system temperature to 30-35°C, filter with suction, and wash the filter cake with ethanol. Concentrate the filtrate under reduced pressure to a small volume, add water and stir to dissolve. Wash the aqueous phase with dichloromethane. Separate the liquids, and adjust the pH value of the aqueous phase to 1 with hydrochloric acid. Filter with suction, wash the filter cake with water, drain, and dry it in a forced air drying oven at 50-55°C to constant weight to obtain 0.9 g of an orange solid product with a product purity of 87% and a yield of 46%.

[0062] NMR is as follows: 1H NMR (400MHz, DMSO) δ11.05 (s, 1H), 8.32-8.28 (m, 2H), 8.22-8.13 (m, 2H), 6.79 (s, 2H), 6.31 (s, 1H).

[0063] Example 6

[0064]

[0065] Replace the nitrogen in a 25mL three-necked flask three times, add 1c (2.0g, 1.0eq), trifluoroethanol (10.8mL, 5.4V), guanidine carbonate (1.52g, 1.0eq) and 4A molecular sieve (2.8g, 1.4w / w). Replace the nitrogen three times, start stirring, control the temperature at 70-75℃, and stir for 16h. Take a sample and HPLC control, raw material: 2.6%, product: 89%.

[0066] Among them, 4A molecular sieve is in powder form, with an average particle size of 48μm (300 mesh), LOD of 4A molecular sieve is 1.10%, static water adsorption is 25.50%, sieve residue is 0.20%, and bulk density is 520g / cm 3 .

[0067] Post-treatment: Cool the system temperature to 25-35°C, filter with suction, and wash the filter cake with trifluoroethanol. Concentrate the filtrate under reduced pressure to a small volume, add water and stir to dissolve. Wash the aqueous phase with dichloromethane. Separate the liquids, and adjust the pH value of the aqueous phase to 1 with hydrochloric acid. Filter with suction, wash the filter cake with water, drain, and dry in a forced air drying oven at 50-55°C to constant weight to obtain 1.3 g of orange-yellow solid, with a product purity of 92% and a yield of 66%.

[0068] NMR is as follows: 1H NMR (400MHz, DMSO) δ11.05 (s, 1H), 8.32-8.28 (m, 2H), 8.22-8.13 (m, 2H), 6.79 (s, 2H), 6.31 (s, 1H).

[0069] Example 7

[0070]

[0071] Replace the 100mL three-necked flask with N2 three times, add 1b (10.0g, 1.0eq), trifluoroethanol (54.0mL, 5.4V), guanidine carbonate (9.37g, 1.0eq) and 4A molecular sieve (14.0g, 1.4w / w). Replace the flask with nitrogen three times, start mechanical stirring, control the temperature at 70-75℃, and stir for 16h. Sampling control, raw material: 2.3%, product: 95%.

[0072] Among them, 4A molecular sieve is in powder form, with an average particle size of 48μm (300 mesh), LOD of 4A molecular sieve is 1.10%, static water adsorption is 25.50%, sieve residue is 0.20%, and bulk density is 520g / cm 3 .

[0073] Post-treatment: Cool the system temperature to 25-30°C, filter with suction, and wash the filter cake with trifluoroethanol. Concentrate the filtrate under reduced pressure to a small volume, add water and stir to dissolve. Wash the aqueous phase with dichloromethane. Separate the liquids, and adjust the pH value of the aqueous phase to 1 with hydrochloric acid. Filter with suction, wash the filter cake with water, drain, and dry in a forced air drying oven at 50-55°C to constant weight to obtain 8.3 g of a white solid with a product purity of 100% and a yield of 85%.

[0074] NMR is as follows: 1H NMR (400MHz, DMSO) δ7.93-7.92 (d, J = 2.8 Hz, 1H), 7.92-7.91 (d, J = 4 Hz, 1H), 7.55-7.53 (t, J = 3.2 Hz, 1H), 7.52-7.50 (t, J = 3.8 Hz, 1H), 7.49-7.48 (t, J = 1.6 Hz, 1H), 7.44 (s, 1H), 6.23 (s, 1H).

[0075] Comparative Example 1

[0076]

[0077] The 25mL three-necked flask was replaced with nitrogen three times, and compound 1a (2.5g, 1.0eq), trifluoroethanol (13.5mL, 5.4V) and guanidine carbonate (1.95g, 1.0eq) were added, and the nitrogen was replaced three times. After stirring, the temperature was controlled at 70-75℃ and stirred for 16h. Samples were taken for HPLC control, raw material: 0.9%, product: 60%.

[0078] Post-treatment: The reaction solution was cooled to 25-35°C, concentrated under reduced pressure to a small volume, dissolved in water, and the aqueous phase was washed with dichloromethane. The liquid was separated, and the pH value of the aqueous phase was adjusted to 1 with hydrochloric acid. The filter cake was washed with water, dried, and dried in a forced air drying oven at 50-55°C to constant weight to obtain 1.4 g of an off-white solid product with a purity of 98% and a yield of 58%.

[0079] Comparative Example 2

[0080]

[0081] The 25mL three-necked flask was replaced with nitrogen three times, and compound 1c (2.0g, 1.0eq), ethanol (10.8mL, 5.4V) and guanidine carbonate (1.52g, 1.0eq) were added, and the nitrogen was replaced three times. After stirring, the temperature was controlled at 70-75℃ and stirred for 16h. Samples were taken for HPLC control, raw material: 54%, product: 34%.

[0082] Post-treatment: The reaction solution was cooled to 25-35°C, concentrated under reduced pressure to a small volume, dissolved in water, and the aqueous phase was washed with dichloromethane. The liquid was separated, and the pH value of the aqueous phase was adjusted to 1 with hydrochloric acid. The filter cake was washed with water, dried, and dried in a forced air drying oven at 50-55°C to constant weight to obtain 0.4 g of an orange solid product with a purity of 81% and a yield of 20%.

[0083] NMR is as follows: 1H NMR (400MHz, DMSO) δ11.05 (s, 1H), 8.32-8.28 (m, 2H), 8.22-8.13 (m, 2H), 6.79 (s, 2H), 6.31 (s, 1H).

[0084] Comparative Example 3

[0085]

[0086] Replace the nitrogen atmosphere in a 100mL three-necked flask three times, add 1c (2.0g, 1.0eq), trifluoroethanol (10.8mL, 5.4V) and guanidine carbonate (1.52g, 1.0eq), replace the nitrogen atmosphere three times. After stirring, control the temperature at 70-75℃ and stir for 16h. Take a sample and perform HPLC control. Raw material: 38%, product: 52%.

[0087] Post-treatment: the system temperature was cooled to 25-35°C, the reaction solution was concentrated to a small volume under reduced pressure, and the aqueous phase was washed with dichloromethane. The liquid was separated, and the pH value of the aqueous phase was adjusted to 1 with hydrochloric acid. The filter cake was washed with water, dried, and dried in a forced air drying oven at 50-55°C to constant weight to obtain 0.78 g of an orange-yellow solid, with a product purity of 83% and a yield of 31%.

[0088] NMR is as follows: 1H NMR (400MHz, DMSO) δ11.05 (s, 1H), 8.32-8.28 (m, 2H), 8.22-8.13 (m, 2H), 6.79 (s, 2H), 6.31 (s, 1H).

[0089] Comparative Example 4

[0090]

[0091] Replace the 100mL three-necked flask with N2 three times, add 1b (10.0g, 1.0eq), trifluoroethanol (54.0mL, 5.4V) and guanidine carbonate (9.37g, 1.0eq). Replace the flask with nitrogen three times, start mechanical stirring, control the temperature at 70-75℃, and stir for 16h. Sampling control, raw material: 15%, product: 82%.

[0092] Post-treatment: Cool the system temperature to 25-35°C, concentrate the filtrate under reduced pressure to a small volume, add water and stir to dissolve. Wash the aqueous phase with dichloromethane. Separate the liquids, and adjust the pH value of the aqueous phase to 1 with hydrochloric acid. Filter by suction, wash the filter cake with water, drain it, and dry it in a forced air drying oven at 50-55°C to constant weight to obtain 6.1 g of white solid, with a product purity of 99% and a yield of 63%.

[0093] NMR is as follows: 1H NMR (400MHz, DMSO) δ7.93-7.92 (d, J = 2.8 Hz, 1H), 7.92-7.91 (d, J = 4 Hz, 1H), 7.55-7.53 (t, J = 3.2 Hz, 1H), 7.52-7.50 (t, J = 3.8 Hz, 1H), 7.49-7.48 (t, J = 1.6 Hz, 1H), 7.44 (s, 1H), 6.23 (s, 1H).

[0094] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a 2-aminopyrimidine-6-aryl compound, characterized in that: The 2-aminopyrimidine-6-aryl compound has a structure shown in Formula I: Formula I The preparation method comprises: subjecting a dispersion liquid containing a β-ketoester compound, guanidine carbonate and 4A molecular sieve to a condensation reaction to obtain the 2-aminopyrimidine-6-aryl compound; the β-ketoester compound has a structure shown in Formula II: Formula II Wherein, R1 represents hydrogen or methyl, R2 represents hydrogen or cyano, and R3 represents hydrogen or nitro; The dispersion also includes a solvent, which is trifluoroethanol; during the condensation reaction, the reaction temperature is 60-80° C., and the reaction time is 12-36 hours; The 4A molecular sieve is in powder form, with an average particle size of 42-96 μm, LOD ≤ 2.5%, static water adsorption ≥ 24.5%, sieve residue ≤ 0.3%, and a bulk density of 450-600 g / cm 3 ;or, The 4A molecular sieve is spherical, and the diameter of the 4A molecular sieve is 0.5-1.0 mm; or, The 4A molecular sieve is in strip shape, and the length of the 4A molecular sieve is 1.6-5 mm; The weight ratio of the β-ketoester compound, the guanidine carbonate and the 4A molecular sieve is 1:(0.6-1.5):(0.3-3.0).

2. The method for preparing a 2-aminopyrimidine-6-aryl compound according to claim 1, characterized in that: The amount of the solvent used is 2.4-7.2 mL per gram of the total weight of the β-ketoester compound, the guanidine carbonate and the 4A molecular sieve.

3. The method for preparing the 2-aminopyrimidine-6-aryl compound according to claim 1, characterized in that: The preparation method comprises: After replacing the reaction kettle with inert gas for 2 to 5 times, adding the β-ketoester compound, the guanidine carbonate, the 4A molecular sieve and the solvent into the reaction kettle for premixing to form the dispersion; After the premixing, the reaction kettle is continuously replaced with the inert gas for 2 to 5 times, and then the dispersion is stirred at a speed of 30 to 180 r / min to perform the condensation reaction.

4. The method for preparing the 2-aminopyrimidine-6-aryl compound according to claim 3, characterized in that: After the condensation reaction, the preparation method further comprises a step of purifying the material after the condensation reaction.

5. The method for preparing the 2-aminopyrimidine-6-aryl compound according to claim 4, characterized in that: The purification step comprises: The temperature of the material after the condensation reaction is adjusted to 15-35° C., and then the material is subjected to a first filtration treatment to obtain a first filter cake and a first filtrate; Extracting the first filtrate with an organic solvent to obtain an aqueous phase and an organic phase; The aqueous phase is subjected to a second filtration treatment after adjusting the pH value of the aqueous phase to 0.5-1 using an acid to obtain a second filter cake; The second filter cake is dried to obtain the 2-aminopyrimidine-6-aryl compound.

6. The method for preparing the 2-aminopyrimidine-6-aryl compound according to claim 5, characterized in that: The acid is one or more of hydrochloric acid, sulfuric acid or hydrobromic acid.

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