阅读说明：本技术 3-甲氧基喹啉-5胺的合成方法 (Synthetic method of 3-methoxyquinoline-5 amine ) 是由 王治国 李文龙 郦荣浩 罗春艳 于 2021-07-09 设计创作，主要内容包括：本发明实施例公开一种3-甲氧基喹啉-5胺的合成方法,涉及杂环化合物合成技术领域,以有效合成3-甲氧基喹啉-5胺。该合成方法包括以5-溴-3-甲氧基喹啉和二苯甲酮亚胺为原料,于45℃～120℃进行偶联反应,获得中间化合物,在碱性条件下,利用盐酸羟胺在25℃～30℃处理所述中间化合物,获得3-甲氧基喹啉-5胺。本发明实施例提供的合成方法用于合成喹啉类化合物。(The embodiment of the invention discloses a method for synthesizing 3-methoxyquinoline-5 amine, which relates to the technical field of heterocyclic compound synthesis and aims to effectively synthesize the 3-methoxyquinoline-5 amine. The synthesis method comprises the steps of taking 5-bromo-3-methoxyquinoline and benzophenone imine as raw materials, carrying out coupling reaction at 45-120 ℃ to obtain an intermediate compound, and treating the intermediate compound by using hydroxylamine hydrochloride at 25-30 ℃ under an alkaline condition to obtain 3-methoxyquinoline-5 amine. The synthesis method provided by the embodiment of the invention is used for synthesizing the quinoline compound.)

1. A method for synthesizing 3-methoxyquinoline-5 amine is characterized by comprising the following steps:

(1) taking 5-bromo-3-methoxyquinoline and benzophenone imine as raw materials, and carrying out coupling reaction at 45-120 ℃ to obtain an intermediate compound, wherein the structural formula of the intermediate compound is as follows:

(2) under the alkaline condition, hydroxylamine hydrochloride is used to react with the intermediate compound at the temperature of 25-30 ℃ to obtain the 3-methoxyquinoline-5 amine.

2. The method for synthesizing 3-methoxyquinoline-5 amine as claimed in claim 1, wherein the reaction solvent of the coupling reaction comprises one or more of 1, 4-dioxane, tetrahydrofuran and toluene.

3. The method of claim 1, wherein the catalyst for the coupling reaction comprises a palladium catalyst and a ligand.

4. The method of claim 3, wherein the palladium catalyst comprises palladium acetate and/or palladium dichloride, and the ligand comprises 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene and/or triphenylphosphine and/or 1,1' -bis (diphenylphosphino) ferrocene.

5. The method of claim 3, wherein the basic material of the coupling reaction comprises cesium carbonate and/or sodium tert-butoxide.

6. The method for synthesizing 3-methoxyquinoline-5 amine according to claim 3, wherein the molar ratio of the 5-bromo-3-methoxyquinoline to the benzophenone imine is 1 (1.5 to 3), the molar ratio of the 5-bromo-3-methoxyquinoline to the palladium catalyst is 1 (0.03 to 0.04), the molar ratio of the 5-bromo-3-methoxyquinoline to the ligand is 1 (1 to 1.1), and the molar ratio of the 5-bromo-3-methoxyquinoline to the basic substance is 1 (3 to 4).

7. The method for synthesizing 3-methoxyquinoline-5 amine according to any one of claims 1 to 6, wherein the substance for forming the basic condition comprises anhydrous sodium acetate and/or sodium carbonate and/or potassium carbonate.

8. The method for synthesizing 3-methoxyquinolin-5 amine according to claim 7, wherein the molar ratio of the hydroxylamine hydrochloride to the intermediate compound is (1.5 to 2):1, and the molar ratio of the substance that forms the basic condition to the hydroxylamine hydrochloride is (2.5 to 3): 2.

9. the method for synthesizing 3-methoxyquinolin-5 amine according to any one of claims 1 to 6, wherein the method further comprises, before step (1):

brominating 3-methoxyquinoline by a brominating agent in concentrated sulfuric acid at the temperature of-5 ℃ to obtain 5-bromo-3-methoxyquinoline.

10. The method for synthesizing 3-methoxyquinoline-5 amine according to claim 9, wherein the molar ratio of the 3-methoxyquinoline to the brominating agent is 1 (0.8-1.1), and the brominating agent comprises N-bromosuccinimide and/or tetrabutylammonium tribromide.

Technical Field

The embodiment of the invention relates to the technical field of heterocyclic compound synthesis, and particularly relates to a synthesis method of 3-methoxyquinoline-5-amine.

Background

The quinoline compound is an organic heterocyclic compound and can be used for preparing medicines, dyes, photosensitive materials, rubbers, solvents, chemical reagents and the like. The quinoline compound is mainly used for preparing three major drugs of nicotinic acid series, 8-hydroxyquinoline series and quinine series in medicine, and has wide application prospect.

In the related literature reports, a quinoline compound is related, the chemical name of the quinoline compound is 3-methoxyquinoline-5 amine, and the structural formula is shown as follows:

however, the synthesis method of 3-methoxyquinoline-5 amine is not reported in the related documents, and therefore, a synthesis method of 3-methoxyquinoline-5 amine is required.

Disclosure of Invention

The embodiment of the invention aims to provide a method for synthesizing 3-methoxyquinoline-5 amine so as to effectively synthesize the 3-methoxyquinoline-5 amine.

In order to achieve the above object, the present invention provides a method for synthesizing 3-methoxyquinoline-5 amine, comprising:

5-bromo-3-methoxyquinoline and benzophenone imine are taken as raw materials, a coupling reaction is carried out at 45-120 ℃ to obtain an intermediate compound, and hydroxylamine hydrochloride is used for reacting with the intermediate compound at 25-30 ℃ under an alkaline condition to obtain 3-methoxyquinoline-5 amine. The intermediate compound has the structural formula:

the application provides a preparation method of 3-methoxyquinoline-5 amine for the first time, and is expected to promote the compound to generate further economic benefit in the medical field. In addition, the invention adopts 5-bromo-3-methoxyquinoline as a raw material, forms an N-C bond under the action of a good halogen-amine conversion reagent benzophenone imine, and obtains the 3-methoxyquinoline-5-amine through Buchwald-Hartwig cross coupling reaction by one step. In the synthesis method of 3-methoxyquinoline-5 amine provided by the embodiment, the reaction temperature is controlled, so that the C-O bond in the structural formula of the reaction substrate is not broken in the coupling reaction process, the occurrence probability of side reaction is reduced, and the yield of the synthesized 3-methoxyquinoline-5 amine is effectively improved. In addition, the pH value of the intermediate compound is limited, so that the intermediate compound is in proper alkaline conditions, the leaving of the intermediate benzophenone in an oxime form can be accelerated, and the reaction speed is accelerated. The whole synthesis process is simple and short in steps, simple and convenient to operate and beneficial to industrial popularization.

Detailed Description

In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

The embodiment of the invention provides a method for synthesizing 3-methoxyquinoline-5 amine, which comprises the following steps:

step 101: 5-bromo-3-methoxyquinoline and benzophenone imine are taken as raw materials to carry out coupling reaction at 45-120 ℃ to obtain an intermediate compound. When the coupling reaction is carried out at 45-120 ℃, the methoxyl can be ensured not to fall off from the 5-bromo-3-methoxyquinoline, and the occurrence rate of side reaction is further reduced. For example: when the reaction solvent of the coupling reaction comprises one or more of 1, 4-dioxane, tetrahydrofuran and toluene, the temperature of the coupling reaction can be maintained between 66 ℃ and 110 ℃ when the reaction system is refluxed.

The structure of the intermediate compound is shown as follows:

the synthetic route of the above intermediate compound is shown below:

as can be seen from the synthetic route for the intermediate compounds: the molar ratio of the 5-bromo-3-methoxyquinoline to the benzophenone imine is theoretically 1:1, and then the intermediate compound can be synthesized. However, in consideration of chemical reaction kinetics, ease of removal of excess raw materials, and the like, an intermediate compound may be synthesized in the presence of an excess of benzophenone imine. For example: the molar ratio of the 5-bromo-3-methoxyquinoline to the benzophenone imine can be 1 (1.5-3).

The coupling reaction may be a Buchwald-Hartwig coupling reaction, which may be catalyzed by a catalyst comprising a palladium catalyst and an electron-withdrawing ligand, and simultaneously, an alkaline substance is used to assist the reaction. The molar ratio of the 5-bromo-3-methoxyquinoline to the palladium catalyst is 1 (0.03-0.04), the molar ratio of the 5-bromo-3-methoxyquinoline to the ligand is 1 (1-1.1), and the molar ratio of the 5-bromo-3-methoxyquinoline to the basic substance is 1 (3-4).

Illustratively, the palladium catalyst comprises palladium acetate and/or palladium dichloride, and the ligand comprises 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene and/or triphenylphosphine. The alkaline substance may include cesium carbonate and/or sodium tert-butyl alkoxide.

In practical application, the 5-bromo-3-methoxyquinoline can be a self-synthesized raw material or a purchased raw material. When 5-bromo-3-methoxyquinoline is a raw material for self synthesis, before the 5-bromo-3-methoxyquinoline and benzophenone imine are used as raw materials and undergo a coupling reaction at a reflux temperature of 45 ℃ to 120 ℃ to obtain an intermediate compound, the method for synthesizing 3-methoxyquinoline-5 amine provided by the embodiment of the present invention further comprises: brominating 3-methoxyquinoline by a brominating agent in concentrated sulfuric acid at the temperature of-5 ℃ to obtain 5-bromo-3-methoxyquinoline. The time of the bromination reaction is 30 min-120min to ensure the completeness of the bromination reaction. The molar ratio of the 3-methoxyquinoline to the brominating agent is 1 (0.8-1.1), and the brominating agent comprises N-bromosuccinimide and/or tetrabutylammonium tribromide.

Illustratively, concentrated sulfuric acid can be added into a reaction kettle, the temperature is controlled to be 0-10 ℃, 3-methoxyquinoline is added, then a brominating agent is added at-5 ℃, the temperature is kept at-5 ℃, and the stirring reaction is carried out until the Thin Layer Chromatography (TLC) detection reaches the reaction end point, so as to obtain a first reaction system. The developing solvent used for the thin-layer chromatography can be a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (10-20): 1. Because the reaction is carried out at-5 ℃ to 5 ℃, the side reaction that the methoxyl group falls off can not occur.

Experiments show that when the molar ratio of the 3-methoxyquinoline to the brominating agent is 1 (0.8-1.1), the time for reaching the reaction end point is 30-120 min. When the reaction end point is reached, adding the first reaction system into ice water, adjusting the pH value with an alkaline solution (such as a sodium hydroxide solution) until a solid is separated out in the reaction kettle (the pH value is 8-9), separating the solid, washing the solid with water, and separating the 5-bromo-3-methoxyquinoline from the solid by adopting a column chromatography elution mode.

And then adding 5-bromo-3-methoxyquinoline into the reaction solvent, controlling the temperature to be 20-30 ℃, adding benzophenone imine, an alkaline substance, a ligand and a palladium catalyst, and then refluxing and stirring overnight under the protection of argon to obtain a second reaction system. When the TLC detects the end of the reaction, water and ethyl acetate (volume ratio 2:1) are added to the second reaction system, and the mixture is stirred until the layers are separated. After separation, the aqueous layer was extracted with ethyl acetate, all organic layers were combined, washed with saturated brine, dried over sodium sulfate, and eluted by column chromatography to give an intermediate reaction.

Step 102: under the alkaline condition, hydroxylamine hydrochloride reacts with an intermediate compound at the temperature of between 25 and 30 ℃ to obtain 3-methoxyquinoline-5 amine, and the synthetic route of the step is as follows:

when the intermediate compound is processed at 25-30 ℃, the methoxyl group on the intermediate compound is protected, and under the alkaline condition, the intermediate compound benzophenone can be separated in the form of oxime, thereby accelerating the reaction speed.

Exemplary, from a chemical reaction kinetics point of view, the species that create the alkaline condition include anhydrous sodium acetate and/or sodium carbonate and/or potassium carbonate. Wherein the molar ratio of the hydroxylamine hydrochloride to the intermediate compound is (1.5-2): 1, and the molar ratio of the substance forming the alkaline condition to the hydroxylamine hydrochloride is (2.5-3): 2.

in order to more clearly describe the synthesis method of 3-methoxyquinolin-5 amine provided in the examples of the present invention, the following examples are given.

Example one

The synthesis method of 3-methoxyquinoline-5 amine provided by the embodiment of the invention comprises the following steps:

step one, synthesizing 5-bromo-3-methoxyquinoline by the following synthetic route:

the synthesis method of the 5-bromo-3-methoxyquinoline comprises the following steps: adding 200mL of concentrated sulfuric acid with the mass fraction of 95% into a reaction kettle, controlling the temperature to be 0-3 ℃ (the temperature fluctuates between 0 ℃ and 3 ℃), adding 3-methoxyquinoline (50g, 314mmol, 1eq), then adding N-bromosuccinimide (55.9g, 314mmol, 1eq) at-5 ℃, preserving the temperature, stirring and reacting at-5 ℃ until the thin-layer chromatography (TLC) detection reaches the reaction end point, and obtaining a first reaction system. The developing solvent used for the thin-layer chromatography can be a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate is 10:1, and the reaction time is 90-120 min.

When the reaction end point is reached, adding the first reaction system into ice water, adjusting the pH value by using a 5% sodium hydroxide aqueous solution by mass until a solid is separated out in the reaction kettle (the pH value is 8 at the moment), washing the solid by using water after the solid is separated out, and separating out 30g of 5-bromo-3-methoxyquinoline with the purity of 98% from the solid by adopting a column chromatography elution mode, wherein the yield is 40%, and an eluent used for the column chromatography is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50: 1.

The second step, the synthesis of intermediate compound, the synthetic route is as follows:

the synthesis method of the intermediate compound comprises the following steps: 5-bromo-3-methoxyquinoline (30g, 126mmol, 1eq) was added to 600ml of 1, 4-dioxane, benzophenone imine (57g, 315mmol, 2.5eq), cesium carbonate (143.7g, 441mmol, 3.5eq), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (72.9g, 126mmol, 1eq) and palladium acetate (1.13g, 5mmol, 0.04eq) were added, the mixture was refluxed (103 ℃) under argon protection and stirred overnight to obtain a second reaction system. When TLC detects the end point of the reaction, go toThe reaction system was added with 1.4L of water and 700ml of ethyl acetate (volume ratio 2:1), and stirred for 10min until the layers were separated. After the layers were separated, the aqueous layer was extracted 2 times with 700ml of ethyl acetate each time; all organic layers (ethyl acetate extracts) were combined, washed with 500ml of saturated brine, dried over 200g of sodium sulfate and chromatographed (eluent petroleum ether: ethyl acetate in a volume ratio of 30: 1) to give 20g of intermediate product of 97% purity in 47% yield, M/z (EI) of mass spectrum 338.9 (M + H)⁺。

Step three, synthesizing 3-methoxyquinoline-5 amine, wherein the synthetic route is as follows:

the synthesis method of the 3-methoxyquinoline-5 amine comprises the following steps: dissolving the intermediate compound (20g, 59.9mmol, 1eq) in 200ml of methanol, adding anhydrous sodium acetate (14.5g, 177.3mmol, 3eq) and hydroxylamine hydrochloride (8.2g, 118.2mmol, 2eq) to the solution, then reacting at 25 ℃, when TLC detection reaches the reaction end point, the reaction time is 1h, obtaining a third reaction system, pouring the third reaction system into 600ml of ice water to obtain an ice water mixed system, adjusting the pH of the ice water mixed system to 8 at 10 ℃ by using sodium bicarbonate, extracting the ice water mixed system for three times by using 500ml of ethyl acetate each time, combining all organic layers, washing by using 500ml of saturated saline water, and drying by using 100g of anhydrous sodium sulfate; column layer wash (eluent is petroleum ether and ethyl acetate in a volume ratio of 2:1) to obtain 8.7g of solid compound 3-methoxyquinoline-5-amine, yield 83.5%, purity 98%, mass spectrum: m/z (EI) 175.1(M + H)⁺，¹H NMR(600MHz,Chloroform-d)δ8.67(d,J＝2.7Hz, 1H,Ar-H),7.57(d,J＝8.4Hz,1H,Ar-H),7.41–7.33(m,2H,Ar-H),6.85(d, J＝7.4Hz,1H,Ar-H),4.16–4.02(m,2H,NH₂),3.97(s,3H,OCH₃). As can be seen from nuclear magnetic and mass spectrum data of the 3-methoxyquinoline-5 amine, the synthesis method provided by the embodiment of the invention can effectively synthesize the 3-methoxyquinoline-5 amine.

Example two

The synthesis method of 3-methoxyquinoline-5 amine provided by the embodiment of the invention comprises the following steps:

step one, synthesizing 5-bromo-3-methoxyquinoline by the following synthetic route:

the synthesis method of the 5-bromo-3-methoxyquinoline comprises the following steps: adding 200mL of 75% concentrated sulfuric acid into a reaction kettle, controlling the temperature to be 5-10 ℃ (the temperature fluctuates between 0 ℃ and 3 ℃), adding 3-methoxyquinoline (50g, 314mmol, 1eq), then adding tetrabutylammonium tribromide (166.54g, 345.4mmol, 1.1eq) at 0 ℃, keeping the temperature at 0 ℃ and stirring for reaction until the Thin Layer Chromatography (TLC) detection reaches the reaction end point, thus obtaining a first reaction system. The developing solvent used for the thin-layer chromatography can be a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate is 10:1, and the reaction time is 100 min.

When the reaction end point is reached, adding the first reaction system into ice water, adjusting the pH value by using a 7% sodium hydroxide aqueous solution until a solid is separated out in the reaction kettle (the pH value is 9), separating the solid, washing the solid by using water, and separating 29.3g of 5-bromo-3-methoxyquinoline with the purity of 97.5% from the solid by adopting a column chromatography elution mode, wherein an eluent used for the column chromatography is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50: 1.

The second step, the synthesis of intermediate compound, the synthetic route is as follows:

the synthesis method of the intermediate compound comprises the following steps: 5-bromo-3-methoxyquinoline (30g, 126mmol, 1eq) is added to 500ml of tetrahydrofuran, benzophenone imine (34.2g, 189mmol, 1.5eq), sodium tert-butoxide (12.1g, 123mmol, 1.0eq), triphenylphosphine (36.4g, 138.6mmol, 1.1eq) and palladium dichloride (0.67g, 3.78mmol, 0.03eq) are added, the mixture is refluxed (66 ℃) under the protection of argon and stirred overnight, and a second reaction system is obtained. When TLC detects the reaction end point, adding 1.6L water and 800ml ethyl acetate (volume ratio 2:1) into the second reaction system, stirring for 10min until delamination, and after delamination, extracting the water layer with ethyl acetate for 3 times, wherein the amount of ethyl acetate used is 800ml each time; all organic layers (ethyl acetate extracts) were combined, washed with 450ml of saturated brine, dried over 180g of sodium sulfate and eluted by column chromatography (eluent petroleum ether: ethyl acetate in a volume ratio of 30: 1) to give 12g of intermediate reaction product with a purity of 95%.

Step three, synthesizing 3-methoxyquinoline-5 amine, wherein the synthetic route is as follows:

the synthesis method of the 3-methoxyquinoline-5 amine comprises the following steps: dissolving the intermediate compound (20g, 59.9mmol, 1eq) in 200ml of methanol, adding sodium carbonate (15.87g, 149.75mmol, 2.5eq) and hydroxylamine hydrochloride (6.24g, 89.85mmol, 1.5eq) thereto, then reacting at 30 ℃, when the TLC detection reaches the reaction end point, the reaction time is 1.2h, obtaining a third reaction system, pouring the third reaction system into 550ml of ice water, obtaining an ice water mixed system, adjusting the pH of the ice water mixed system to 8 with sodium bicarbonate at 16 ℃, extracting the three ice water mixed systems with 500ml of ethyl acetate each time, combining all organic layers, washing with 500ml of saturated saline water, and drying with 100g of anhydrous sodium sulfate; eluting by column chromatography (eluent is petroleum ether and ethyl acetate with volume ratio of 2:1) to obtain 7.1g of solid compound 3-methoxyquinoline-5-amine.

EXAMPLE III

The synthesis method of 3-methoxyquinoline-5 amine provided by the embodiment of the invention comprises the following steps:

step one, synthesizing 5-bromo-3-methoxyquinoline by the following synthetic route:

the synthesis method of the 5-bromo-3-methoxyquinoline comprises the following steps: adding 200mL of 90 mass percent concentrated sulfuric acid into a reaction kettle, controlling the temperature to be 5-10 ℃ (the temperature fluctuates between 0 ℃ and 3 ℃), adding 3-methoxyquinoline (50g, 314mmol, 1eq), then adding N-bromosuccinimide (27.94g, 157mmol, 0.5eq) and tetrabutylammonium tribromide (75.70g, 157mmol, 0.5eq) at 5 ℃, keeping the temperature at 5 ℃ and stirring for reaction until the Thin Layer Chromatography (TLC) detection reaches the reaction end point, thereby obtaining a first reaction system. The developing solvent used for the thin layer chromatography can be a mixed solvent of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate is 10:1, and the reaction time is 120 min.

When the reaction end point is reached, adding the first reaction system into ice water, adjusting the pH value by using a 10% sodium hydroxide aqueous solution by mass until a solid is separated out in the reaction kettle (the pH value is 8.5), separating the solid, washing the solid with water, and separating 25g of 5-bromo-3-methoxyquinoline with the purity of 97.5% from the solid by adopting a column chromatography elution mode, wherein an eluant used for the column chromatography is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50: 1.

The second step, the synthesis of intermediate compound, the synthetic route is as follows:

the synthesis method of the intermediate compound comprises the following steps: 5-bromo-3-methoxyquinoline (30g, 126mmol, 1eq) is added to 600ml toluene, benzophenone imine (68.5g, 378mmol, 3eq) and cesium carbonate (143.7g, 441mmol, 3.5eq), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (72.9g, 126mmol, 1eq) and palladium acetate (1.13g, 5mmol, 0.04eq) are added with temperature controlled at 26 ℃, and then stirred under reflux (111 ℃) overnight under the protection of argon to obtain a second reaction system. When TLC detects the reaction end point, adding 1.6L water and 800ml ethyl acetate (volume ratio 2:1) into the second reaction system, stirring for 10min until delamination, and after delamination, extracting the water layer with ethyl acetate for 3 times, wherein the amount of ethyl acetate used is 800ml each time; all organic layers (ethyl acetate extracts) were combined, washed with 450ml of saturated brine, dried over 180g of sodium sulfate and eluted by column chromatography (eluent petroleum ether: ethyl acetate in a volume ratio of 30: 1) to give 17.6g of intermediate reaction product having a purity of 97%.

Step three, synthesizing 3-methoxyquinoline-5 amine, wherein the synthetic route is as follows:

the synthesis method of the 3-methoxyquinoline-5 amine comprises the following steps: dissolving the intermediate compound (20g, 59.9mmol, 1eq) in 200ml of methanol, adding potassium carbonate (20.70g, 149.75mmol, 2.5eq) and hydroxylamine hydrochloride (7.49g, 107.82mmol, 1.8eq) thereto, then reacting at 26 ℃, when the TLC detects that the reaction end point is reached, the reaction time is 0.9h, obtaining a third reaction system, pouring the third reaction system into 550ml of ice water, obtaining an ice water mixed system, adjusting the pH of the ice water mixed system to 8 with sodium bicarbonate at 10 ℃, extracting the three ice water mixed systems with 500ml of ethyl acetate each time, combining all organic layers, washing with 500ml of saturated saline water, and drying with 100g of anhydrous sodium sulfate; eluting by column chromatography (eluent is petroleum ether and ethyl acetate with volume ratio of 2:1) to obtain solid compound 3-methoxyquinoline-5-amine 7.3 g.

The application provides a preparation method of 3-methoxyquinoline-5 amine for the first time, and is expected to promote the compound to generate further economic benefit in the medical field. In addition, the invention adopts 5-bromo-3-methoxyquinoline as a raw material, forms an N-C bond under the action of a good halogen-amine conversion reagent benzophenone imine, and obtains the 3-methoxyquinoline-5-amine through Buchwald-Hartwig cross coupling reaction by one step. In the synthesis method of 3-methoxyquinoline-5 amine provided by the embodiment, the reaction temperature is controlled, so that the C-O bond in the structural formula of the reaction substrate is not broken in the coupling reaction process, the occurrence probability of side reaction is reduced, and the yield of the synthesized 3-methoxyquinoline-5 amine is effectively improved. In addition, the pH value of the intermediate compound is limited, so that the intermediate compound is in proper alkaline conditions, the leaving of the intermediate benzophenone in an oxime form can be accelerated, and the reaction speed is accelerated. The whole synthesis process is simple and short in steps, simple and convenient to operate and beneficial to industrial popularization.

In the foregoing description of embodiments, the particular features, structures, materials, or characteristics may be combined in any suitable manner in any one or more embodiments or examples.

The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.