CN114560854A - Synthetic method of aromatic amino pyrimidine azole compound - Google Patents

Abstract

The present application relates to the technical field of synthetic chemistry, in particular to a method for synthesizing aromatic aminopyrimidine azole compounds. The method for synthesizing the aromatic aminopyrimidine azole compound includes: mixing the chloropyrimidine compound represented by the formula II1 or the formula II2 with the aromatic amine R ₅ -NH ₂ , and carrying out an amination reaction to obtain the compound represented by the formula I1 or the formula I2 Aromatic aminopyrimidine azole compounds; the substrate in this reaction process has good applicability, and no palladium catalyst is required, the reaction conditions are mild, there is no side reaction, and the yield is high, so it can be suitable for large-scale synthesis.

Description

Synthetic method of aromatic aminopyrimidine azoles

technical field

The application belongs to the technical field of synthetic chemistry, and in particular relates to a method for synthesizing aromatic aminopyrimidine azole compounds.

Background technique

Pyrimidine amine derivatives can be used in the research of various enzyme inhibitors. For example, it has been reported that pyrimidine amine derivatives can be used as photokinase inhibitors, or as inhibitors of nuclear tyrosine kinase Wee-1. Pyrimidine amine skeletons can be used as excellent hydrogen bond acceptors and hydrogen bond donors, so the introduction of pyrimidine amine skeletons is of great help to enhance the activity of enzyme inhibitors. The amination technology of pyrimidine derivatives has been reported many times, but the existing synthetic methods are relatively complicated, and there are relatively high reaction temperatures (such as up to 150 ° C), harsh conditions (such as the need to use catalysts), and subsequent processing is relatively trivial, etc. Many deficiencies.

The azole-containing compounds can be widely used in the field of medical research and have broad prospects. For example, Pemafibrate, a drug used to treat hyperlipidemia, and Acebilustat, a respiratory drug, and benzothiazoles also have a good inhibitory effect on Hepatitis C Virus (HCV). However, the amination synthesis technology of related compounds is not suitable for substrates, and it takes a long time and the reaction conditions are harsh. When the aromatic substrate contains groups such as cyano groups, it is easily destroyed, which is not conducive to large-scale synthesis. .

SUMMARY OF THE INVENTION

The purpose of this application is to provide a method for synthesizing aromatic aminopyrimidineazole compounds, aiming to solve the technical problem of how to prepare aromatic aminopyrimidineazole compounds simply and at low cost.

In order to realize the above-mentioned application purpose, the technical scheme adopted in this application is as follows:

The application provides a method for synthesizing an aromatic aminopyrimidine azole compound, comprising the following steps:

Mixing the chloropyrimidine compound represented by the formula II1 or the formula II2 with the aromatic amine R ₅ -NH ₂ to carry out an amination reaction to obtain the aromatic aminopyrimidine azole compound represented by the formula I1 or the formula I2;

When the general structural formula of the chloropyrimidine compound is formula III1, the general structural formula of the aromatic aminopyrimidineazole compound is formula I1; when the general structural formula of the chloropyrimidine compound is formula II2, the The general structural formula of the aromatic aminopyrimidine azole compounds is formula I2;

in,

R ₁ is selected from at least one of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₁ -C ₂₀ alkoxy;

R ₂ is selected from hydrogen, halogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₁ -C ₂₀ alkoxy, substituted or unsubstituted C At least one of ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted polyaliphatic heterocyclic group, substituted or unsubstituted C ₆ -C ₂₀ aryl group;

R ₃ is selected from at least one of hydrogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl;

R ₄ is selected from at least one of hydrogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl;

R ₅ is selected from at least one of substituted or unsubstituted C ₆ -C ₂₀ aryl, substituted or unsubstituted aromatic heterocyclic group;

X is oxygen or sulfur.

In the method for synthesizing aromatic aminopyrimidine azole compounds provided in this application, the chloropyrimidine compound represented by formula II1 or formula II2 is mixed with aromatic amine R ₅ -NH ₂ to carry out amination reaction to obtain the corresponding aromatic amino pyrimidine azoles The reaction process has good substrate applicability, and does not need a palladium catalyst, the reaction conditions are mild, there is no side reaction, and the yield is high, so it can be suitable for large-scale synthesis.

Detailed ways

In order to make the technical problems, technical solutions and beneficial effects to be solved by the present application more clear, the present application will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application, but not to limit the present application.

In this application, the term "and/or", which describes the relationship between related objects, means that there can be three relationships, for example, A and/or B, which can mean that A exists alone, A and B exist at the same time, and B exists alone Happening. where A and B can be singular or plural. The character "/" generally indicates that the associated objects are an "or" relationship.

In this application, "at least one" refers to one or more, and "multiple" refers to two or more. "At least one item(s) below" or similar expressions thereof refer to any combination of these items, including any combination of single item(s) or plural items(s).

It should be understood that, in various embodiments of the present application, the size of the sequence numbers of the above-mentioned processes does not imply the sequence of execution, some or all of the steps may be executed in parallel or sequentially, and the execution sequence of each process should be based on its functions and It is determined by the internal logic and should not constitute any limitation on the implementation process of the embodiments of the present application.

The terms used in the embodiments of the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. As used in the embodiments of this application and the appended claims, the singular forms "a," "the," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

The weight of the relevant components mentioned in the description of the examples of the present application can not only refer to the specific content of each component, but also can represent the proportional relationship between the weights of the components. It is within the scope disclosed in the description of the embodiments of the present application that the content of the ingredients is scaled up or down. Specifically, the mass described in the description of the embodiment of the present application may be a mass unit known in the chemical field, such as μg, mg, g, kg, etc.

The compounds and their derivatives involved in the examples of the present application are all named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, Ohio) nomenclature system. Therefore, the compound groups specifically involved in the examples of this application are described and explained as follows:

"Alkyl" means a straight or branched, monovalent, saturated aliphatic chain including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, Isopentyl, hexyl and other similar groups.

"Alkoxy" refers to a straight or branched saturated aliphatic chain bonded to an oxygen atom, including but not limited to, for example, methoxy, ethoxy, propoxy, butoxy, isobutoxy group, tert-butoxy, and other similar groups. (C _a -C _b )Alkoxy refers to any straight or branched, monovalent, saturated aliphatic chain of any alkyl group containing "a" to "b" carbon atoms bonded to an oxygen atom.

"Cycloalkyl" refers to a saturated monocyclic or polycyclic alkyl group. Cycloalkyl groups include, but are not limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and other similar groups.

A "polyaliphatic heterocyclyl" refers to a heterocyclyl group without aromatic character, meaning that one or more carbon atoms in the cycloalkyl group have been substituted with a heteroatom such as nitrogen, oxygen, or sulfur. It may be a three-membered heterocyclic group such as an oxiranyl group, a four-membered heterocyclic group such as a propiolactone group, a five-membered heterocyclic group, and the like.

"Aryl" refers to a cyclic aromatic hydrocarbon, which may be a monocyclic or polycyclic or fused ring aromatic hydrocarbon, including, but not limited to, groups such as phenyl, naphthyl, anthracenyl, phenanthryl and other similar groups.

"Aromatic heterocyclyl", also known as heteroaryl, refers to a monocyclic or polycyclic or fused-ring aromatic hydrocarbon in which one or more carbon atoms have been replaced by heteroatoms such as nitrogen, oxygen or sulfur. If the heteroaryl group contains more than one heteroatom, these may or may not be the same. Heteroaryl groups include, but are not limited to, groups such as benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyranyl, furyl, imidazolyl, indazolyl, Indolyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, Phthalazinyl, pteridyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrido[3,4-b]indolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazine group, quinolinyl, quinoxalinyl, thiadiazolyl, thitriazolyl, thiazolyl, thienyl, triazinyl, triazolyl, xanthyl and other similar groups.

The above-mentioned hetero atoms may be oxygen atoms, nitrogen atoms, sulfur atoms and the like. Halogen may include fluorine, chlorine, bromine, iodine.

Unsubstituted refers to the groups in which the hydrogens on the carbon atoms of the above-mentioned alkyl groups, alkoxy groups, cycloalkyl groups, polybasic alicyclic groups, aryl groups, aromatic heterocyclic groups and other groups are not substituted; Substituted refers to the group in which some hydrogens on the carbon atoms of the above-mentioned alkyl group, alkoxy group, cycloalkyl group, polybasic alicyclic group, aryl group and aromatic heterocyclic group are substituted; the substituent can be halogen , C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, hydroxyl, mercapto, nitro, etc.

The embodiment of the present application provides a method for synthesizing an aromatic aminopyrimidine azole compound, and the method for synthesizing comprises the following steps:

The chloropyrimidine compound represented by the formula II1 is mixed with the aromatic amine R ₅ -NH ₂ to carry out an amination reaction to obtain the aromatic aminopyrimidine azole compound represented by the formula I1; or,

The chloropyrimidine compound shown in formula II2 is mixed with aromatic amine R ₅ -NH ₂ to carry out amination reaction to obtain the aromatic aminopyrimidine azole compound shown in formula I2;

in,

R ₁ is selected from at least one of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₁ -C ₂₀ alkoxy;

R ₂ is selected from hydrogen, halogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted C ₁ -C ₂₀ alkoxy, substituted or unsubstituted C At least one of ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted polyaliphatic heterocyclic group, substituted or unsubstituted C ₆ -C ₂₀ aryl group;

R ₃ is selected from at least one of hydrogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl;

R ₄ is selected from at least one of hydrogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl;

R ₅ is selected from at least one of substituted or unsubstituted C ₆ -C ₂₀ aryl, substituted or unsubstituted aromatic heterocyclic group;

X is oxygen or sulfur.

In the synthesis method of aromatic aminopyrimidine azole compounds provided in the examples of this application, the chloropyrimidine compound represented by formula II1 or formula II2 is mixed with aromatic amine R ₅ -NH ₂ to carry out amination reaction to obtain the corresponding aromatic amino group The pyrimidine azole compounds have good substrate applicability in the reaction process, and do not need a palladium catalyst, the reaction conditions are mild, there is no side reaction, and the yield is high, so it can be suitable for large-scale synthesis.

In some embodiments, in the chloropyrimidine compounds represented by formula III1 or formula II2, R ₁ is selected from hydrogen, halogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted At least one of the substituted C ₁ -C ₂₀ alkoxy groups; wherein, the substituted or unsubstituted C ₁ -C ₂₀ alkyl group may be a straight chain or branched chain containing 1-20 carbon atoms The alkyl, substituted or unsubstituted C ₁ -C ₂₀ alkoxy group may be a straight-chain or branched-chain alkoxy group containing 1 to 20 carbon atoms. Specifically, R ₁ is selected from at least one of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, and substituted or unsubstituted C ₁ -C ₁₀ alkoxy. In some embodiments of the present application, R ₁ is selected from hydrogen, halogen, unsubstituted C ₁ -C ₆ alkyl or unsubstituted C ₁ -C ₆ alkoxy.

In some embodiments, in the chloropyrimidine compound represented by formula III1 or formula II2, R ₂ is selected from hydrogen, halogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl, substituted or unsubstituted Substituted C ₁ -C ₂₀ alkoxy, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl, substituted or unsubstituted polyaliphatic heterocyclyl, substituted or unsubstituted At least one of C ₆ -C ₂₀ aryl groups; wherein, substituted or unsubstituted C ₃ -C ₂₀ cycloalkyl groups may be monocyclic or polycyclic alkyl groups containing 3-20 carbon atoms, which are The substituted or unsubstituted polyaliphatic heterocyclic group may be a heterocyclic group containing heteroatoms and 2-20 carbon atoms, and the substituted or unsubstituted _C6 - _C20 aryl group may be a heterocyclic group containing 6-20 carbon atoms. Aromatic hydrocarbons with carbon atoms. Specifically, R ₂ is selected from hydrogen, halogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ alkoxy, substituted or unsubstituted C 1 -C 10 alkoxy At least one of substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted polyaliphatic heterocyclic group, and substituted or unsubstituted C ₆ -C ₁₄ aryl group. In some embodiments of the present application, R ₂ is selected from hydrogen, halogen, unsubstituted C ₁ -C ₆ alkyl, unsubstituted C ₁ -C ₆ alkoxy, unsubstituted C ₃ -C ₆ Cycloalkyl, unsubstituted three- to seven-membered alicyclic heterocyclic group or unsubstituted C ₆ -C ₁₄ aryl.

In some embodiments, in the chloropyrimidine compound represented by formula III1 or formula II2, R ₃ is selected from at least one of hydrogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl; R ₄ is selected from From at least one of hydrogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl; R ₃ and R ₄ may be the same or different. Specifically, R ₃ is selected from at least one of hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl; R ₄ is selected from hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkane at least one of the bases. In some embodiments of the present application, R ₃ is selected from hydrogen or unsubstituted C ₁ -C ₆ alkyl, and R ₄ is selected from hydrogen or unsubstituted C ₁ -C ₆ alkyl.

In some embodiments, the aromatic amine R ₅ -NH ₂ is at least one selected from substituted or unsubstituted C ₆ -C ₂₀ aryl, substituted or unsubstituted aromatic heterocyclic group ; Wherein, the substituted or unsubstituted aromatic heterocyclic group can be a heteroaryl group containing heteroatoms and 3-20 carbon atoms, such as five- or six-membered heteroaryl, benzoheterocycle, heterocyclic Heterocycle. Specifically, R ₅ is selected from at least one of substituted or unsubstituted C ₆ -C ₁₄ aryl, substituted or unsubstituted aromatic heterocyclic group. In some embodiments of the present application, R ₅ is selected from phenyl, naphthyl, anthracenyl or phenanthryl.

In some embodiments, the chloropyrimidine compound represented by the formula III1 or the formula II2 is mixed with the aromatic amine R ₅ -NH ₂ in a molar ratio of 1:0.6-0.8 to carry out the amination reaction. Through the excess of chloropyrimidines, aromatic aminopyrimidineazoles can be better generated.

In some embodiments, the chloropyrimidine compound represented by the formula III1 or the formula II2 and the aromatic amine R ₅ -NH ₂ are dissolved in a solvent to carry out an amination reaction. Wherein, the solvent includes 1,4-dioxane. Further, the solvent includes 1,4-dioxane and acetic acid; the solvent formed by mixing 1,4-dioxane and acetic acid can better promote the amination reaction of chloropyrimidine compounds and aromatic amines. Specifically, 1,4-dioxane and acetic acid are mixed in a volume ratio of 1-10:1 to form a reaction solvent. More specifically, the volume ratio of 1,4-dioxane to acetic acid is preferably 1 to 5:1.

In some embodiments, the chloropyrimidine compound represented by the formula II1 or the formula II2 is mixed with the aromatic amine R ₅ -NH ₂ to carry out the amination reaction at a temperature of 50-100° C. and a time of 1-10 h. Further, the temperature is 60-100°C, and the time is 2-4h. The amination reaction can be better carried out under the above temperature and time conditions.

In some embodiments, the chloropyrimidine compound represented by formula III1 or formula II2 is obtained by chlorination of the corresponding thiomethylpyrimidine compound and a chlorine-containing compound.

Specifically, the above-mentioned chlorine-containing compound is selected from at least one of sulfonyl chloride, thionyl chloride and phosphorus oxychloride; the temperature of the above-mentioned chlorination reaction is 0 to room temperature (25° C.), and the time is 0.5 to 24 hours. is 2 to 4 hours. The thiomethylpyrimidine compound and the chlorine-containing compound can be chlorinated in a solvent, and specifically, the solvent used for the thiomethyl chlorination can be dichloromethane (DCM), acetic acid, and the like.

Specifically, the synthesis of the aromatic aminopyrimidine azole compounds in the embodiments of the present application may include: (1) the reaction of a thiomethylpyrimidine compound with a chlorine-containing compound such as sulfonyl chloride to obtain a product: a chlorine compound represented by formula II1 or formula II2 A pyrimidine compound; (2) the above-mentioned chloropyrimidine compound is reacted with a corresponding aromatic amine R ₅ -NH ₂ to obtain the target compound: an aromatic aminopyrimidine azole compound represented by formula I1 or formula I2. The specific process is as follows:

The method for synthesizing the aromatic aminopyrimidineazole compounds represented by the above-mentioned formula I1 or formula I2 in the embodiments of the present application can use the thiomethylpyrimidineazole compound to obtain the corresponding chloropyrimidineazole compound through the reaction, and then react with the aromatic amine compound to obtain the corresponding chloropyrimidineazole compound. These compounds can be obtained by amination reaction. This process can avoid the use of palladium catalyst, the reagents and raw materials used are easy to obtain, the substrate applicability is good, and it has many advantages such as short and mild reaction time, no side reactions, and simple post-treatment. Large-scale synthesis of aromatic aminopyrimidine azoles, namely aromatic aminopyrimidine ox(thi)azoles.

The following description will be given in conjunction with specific embodiments.

For the synthesis of thiomethylpyrimidine compounds in the examples, please refer to (J.Med.Chem.2009,52,1081-1099), (Chem.Eur.J.2011,17,9385-9394), (Bioorg.Med Chem. 2015, 23, 5725-5733), (J. Med. Chem. 2012, 55, 2846-2857), US 9133178 B2 and WO 2012055942.

Example 1

A kind of synthesis of aromatic aminopyrimidine azoles:

In formula I1, X is O, R ₁ is H, R ₂ is methoxy, R ₃ and R ₄ are both H, and R ₅ is 1-naphthyl. The specific synthesis steps are as follows:

(1) Synthesis of 5-(2-chloro-4-methoxypyrimidin-5-yl)isoxazole

500 mg of 5-(2-methylthio-4-methoxypyrimidin-5-yl)isoxazole was added to a 100 mL round-bottomed flask, 50 mL of dichloromethane was added, and 0.5 mL of sulfonyl chloride was slowly added dropwise at 0°C. After the addition, the reaction was naturally raised to room temperature for 2 hours. The reaction was completed, and the product was 450 mg of 5-(2-chloro-4-methoxypyrimidin-5-yl)isoxazole with a yield of 95.0%. for the next step of amination reaction.

(2) Amination reaction

Into a 5mL round-bottomed flask was added 1-naphthylamine (20mg, 0.14mmol), 5-(2-chloro-4-methoxypyrimidin-5-yl)isoxazole (44mg, 0.21mmol), 1,4- 2 mL of dioxane, 1 mL of glacial acetic acid, replaced the system with argon for 3 times, reacted at 90 °C for 2 h, cooled to room temperature (25 °C), extracted with ethyl acetate, and subjected to column chromatography (PE:EA=5:1) to obtain 5-(Isoxazol-5-yl)-4-methoxy-N-(naphthalen-1-yl)pyrimidin-2-amine 30 mg, yield 68.0%, purity 95%.

The structure of the obtained product was confirmed by mass spectrometry and nuclear magnetic resonance, and the results were: 1H NMR (300MHz, CDCl3)δ(ppm): 8.72(s, 1H), 8.18(d, J=3Hz, 1H), 8.12(d, J ＝3Hz,1H),7.80(d,J＝3Hz,1H),7.69(d,J＝3Hz,1H),7.54-7.59(m,1H),7.50-7.53(m,1H),7.47-7.48( m,1H),7.45(d,J=3Hz,1H),6.87(d,J=3Hz,1H),4.00(s,3H).MS(ESI):[M+H+]:319.

Example 2

A kind of synthesis of aromatic aminopyrimidine azoles:

In formula I1, X is O, R ₁ is H, R ₂ is methoxy, R ₃ and R ₄ are both H, and R ₅ is 2-anthracenyl. The specific synthesis steps are as follows:

(1) Synthesis of 5-(2-chloro-4-methoxypyrimidin-5-yl)isoxazole

Refer to Example 1.

(2) Amination reaction

2-Anthracenylamine (20 mg, 0.10 mmol), 5-(2-chloro-4-methoxypyrimidin-5-yl)isoxazole (33 mg, 0.16 mmol), 1,4 was added to a 5 mL round-bottomed flask - 2 mL of dioxane, 1 mL of glacial acetic acid, replaced the system with argon for 3 times, reacted at 90°C for 2 h, cooled to room temperature, extracted with ethyl acetate, and subjected to column chromatography (PE:EA=5:1) to obtain 5-( Isoxazol-5-yl)-4-methoxy-N-(2-anthryl)pyrimidin-2-amine 30 mg, yield 78.9%, purity 95%.

The structure of the obtained product was confirmed by mass spectrometry and nuclear magnetic resonance, and the results were: 1H NMR (500MHz, CDCl3)δ(ppm): 8.82(s,1H), 8.72(s,1H), 8.34(s,1H), 8.30( s,1H),8.18(d,J＝5Hz,1H),8.01(d,J＝5Hz,1H),7.99(d,J＝5Hz,1H),7.86(d,J＝10Hz,1H),7.56 (d,J＝5Hz,1H),7.52-7.55(m,1H),7.50-7.52(m,1H),6.87(d,J＝5Hz,1H),4.00(s,3H).MS(ESI) :[M+H+]:367.

Example 3

A kind of synthesis of aromatic aminopyrimidine azoles:

In formula I1, X is O, R ₁ is H, R ₂ is methoxy, R ₃ is methyl, R ₄ is H, and R ₅ is 1-naphthyl. The specific synthesis steps are as follows:

(1) Synthesis of 5-(2-chloro-4-methoxypyrimidin-5-yl)4-methylisoxazole

500 mg of 5-(2-methylthio-4-methoxypyrimidin-5-yl) 4-methylisoxazole was added to a 100 mL round-bottomed flask, 50 mL of dichloromethane was added, and sulfonic acid was slowly added dropwise at 0°C. Acid chloride 0.4mL, after the addition, the reaction was naturally raised to room temperature for 2h. The reaction was completed, and the product 5-(2-chloro-4-methoxypyrimidin-5-yl)4-methylisoxazole 460mg was obtained by spin drying, Yield 97.0%. for the next step of amination reaction.

(2) Amination reaction

In a 5mL round-bottomed flask, 1-naphthylamine (20mg, 0.14mmol), 5-(2-chloro-4-methoxypyrimidin-5-yl)4-methylisoxazole (47mg, 0.21mmol) were added, 2 mL of 1,4-dioxane, 1 mL of glacial acetic acid, replaced the system with argon three times, reacted at 90°C for 2 h, cooled to room temperature, extracted with ethyl acetate, and subjected to column chromatography (PE:EA=5:1) to obtain 5-(4-Methylisoxazol-5-yl)-4-methoxy-N-(naphthalen-1-yl)pyrimidin-2-amine 30 mg, yield 64.7%, purity 95%.

The structure of the obtained product was confirmed by mass spectrometry and nuclear magnetic resonance, and the results were: 1H NMR (400MHz, CDCl3)δ(ppm): 8.70(s, 1H), 8.45(s, 1H), 8.12(d, J=8Hz, 1H ),7.79(d,J＝4Hz,1H),7.69(d,J＝4Hz,1H),7.56-7.58(m,1H),7.50-7.52(m,1H),7.47-7.48(m,1H) ,7.45(d,J＝4Hz,1H),3.99(s,3H),2.32(s,3H).MS(ESI):[M+H+]:333.

Example 4

A kind of synthesis of aromatic aminopyrimidine azoles:

In formula I1, X is O, R ₁ is H, R ₂ is methoxy, R ₃ is methyl, R ₄ is H, R ₅ is 2-naphthyl, and the specific synthesis steps are as follows:

(1) Synthesis of 5-(2-chloro-4-methoxypyrimidin-5-yl)4-methylisoxazole

Refer to Example 3.

(2) Amination reaction

2-naphthylamine (20mg, 0.14mmol), 5-(2-chloro-4-methoxypyrimidin-5-yl)4-methylisoxazole (47mg, 0.21mmol) were added to a 5mL round bottom flask, 2 mL of 1,4-dioxane, 1 mL of glacial acetic acid, replaced the system with argon three times, reacted at 90°C for 2 h, cooled to room temperature, extracted with ethyl acetate, and subjected to column chromatography (PE:EA=5:1) to obtain 5-(4-Methylisoxazol-5-yl)-4-methoxy-N-(naphthalen-2-yl)pyrimidin-2-amine 32 mg, yield 69.6%, purity 95%.

The structure of the obtained product was confirmed by mass spectrometry and nuclear magnetic resonance, and the results were: 1H NMR (400MHz, CDCl3)δ(ppm): 8.70(s,1H), 8.52(s,1H), 8.45(s,1H), 7.82( d,J＝4Hz,1H),7.77(d,J＝4Hz,1H),7.74(d,J＝4Hz,1H),7.59(d,J＝8Hz,1H),7.47-7.49(m,1H) ,7.44-7.46(m,1H),4.00(s,3H),2.31(s,3H).MS(ESI):[M+H+]:333.

The above descriptions are only preferred embodiments of the present application and are not intended to limit the present application. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present application shall be included in the protection of the present application. within the range.

Claims (10)

1. A synthetic method of an aromatic aminopyrimidine azole compound is characterized by comprising the following steps:

the chloropyrimidine compound shown as a formula II1 or a formula II2 and aromatic amine R₅-NH₂Mixing, and carrying out amination reaction to obtain aromatic aminopyrimidine azole compounds shown as formula I1 or formula I2;

when the structural general formula of the chloropyrimidine compounds is formula II1, the structural general formula of the aromatic aminopyrimidine azole compounds is formula I1; when the structural general formula of the chloropyrimidine compounds is formula II2, the structural general formula of the aromatic aminopyrimidine azole compounds is formula I2;

wherein,

R₁selected from hydrogen, halogen, substituted or unsubstituted C₁-C₂₀Alkyl, substituted or unsubstituted C₁-C₂₀At least one of alkoxy groups;

R₂selected from hydrogen, halogen, substituted or unsubstituted C₁-C₂₀Alkyl, substituted or unsubstituted C₁-C₂₀Alkoxy, substituted or unsubstituted C₃-C₂₀Cycloalkyl, substituted or unsubstituted polyhydric aliphatic heterocyclic group, substituted or unsubstituted C₆-C₂₀At least one of aryl groups;

R₃selected from hydrogen, substituted or unsubstituted C₁-C₂₀At least one of alkyl groups;

R₄selected from hydrogen, substituted or unsubstituted C₁-C₂₀At least one of alkyl groups;

R₅selected from substituted or unsubstituted C₆-C₂₀At least one of an aryl group, a substituted or unsubstituted aromatic heterocyclic group;

x is oxygen or sulfur.

2. The synthetic method of claim 1 wherein R is₁Selected from hydrogen, halogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₁-C₁₀At least one of alkoxy groups; r₂Selected from hydrogen, halogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₁-C₁₀Alkoxy, substituted or unsubstituted C₃-C₁₀Cycloalkyl, substituted or unsubstituted polyhydric aliphatic heterocyclic group, substituted or unsubstituted C₆-C₁₄At least one of aryl groups; r₃Selected from hydrogen, substituted or unsubstituted C₁-C₁₀At least one of alkyl groups; r₄Selected from hydrogen, substituted or unsubstituted C₁-C₁₀At least one of alkyl groups; r₅Selected from substituted or unsubstituted C₆-C₁₄Aryl, substituted or unsubstituted heteroaromaticAt least one of the ring groups.

3. The method of synthesis of claim 2, wherein R is₁Selected from hydrogen, halogen, unsubstituted C₁-C₆Alkyl or unsubstituted C₁-C₆An alkoxy group.

4. The method of synthesis of claim 2, wherein R is₂Selected from hydrogen, halogen, unsubstituted C₁-C₆Alkyl, unsubstituted C₁-C₆Alkoxy, unsubstituted C₃-C₆Cycloalkyl, unsubstituted three-to seven-membered aliphatic heterocyclic group or unsubstituted C₆-C₁₄And (4) an aryl group.

5. The method of synthesis of claim 2, wherein R is₃Selected from hydrogen or unsubstituted C₁-C₆Alkyl radical, R₄Selected from hydrogen or unsubstituted C₁-C₆An alkyl group.

6. The method of synthesis of claim 2, wherein R is₅Selected from phenyl, naphthyl, anthryl or phenanthryl.

7. The method of synthesis according to any one of claims 1 to 6, wherein the chloropyrimidine compound and the aromatic amine are present in a molar ratio of 1: 0.6 to 0.8, and mixing the above components to carry out the amination reaction.

8. The synthesis process according to any one of claims 1 to 6, wherein in the amination reaction the solvent comprises 1, 4-dioxane or the solvent comprises 1, 4-dioxane and acetic acid;

and/or in the amination reaction, the temperature is 50-100 ℃, and the time is 1-10 h.

9. The method of any one of claims 1 to 6, wherein the chloropyrimidines are obtained by chlorination of the corresponding thiomethylpyrimidines and the chlorine-containing compound.

10. The method of synthesis according to claim 9, wherein the chlorine-containing compound is selected from at least one of sulfuryl chloride, thionyl chloride and phosphorus oxychloride;

and/or the temperature of the chlorination reaction is 0-25 ℃ and the time is 0.5-24 h.