CN115108985B - Synthesis method of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione - Google Patents
Synthesis method of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione Download PDFInfo
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Abstract
The invention discloses a synthetic method of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione, which comprises the following steps: adding the acryloylbenzamide shown in the formula I and the acryloylbenzamide shown in the formula II into a reaction containerShown in the specification, cyclohexyl formic acid, solvent, photocatalyst 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile and oxidant K 2 S 2 O 8 And inorganic base, under the protection of nitrogen, carrying out addition reaction under the condition of illumination of a 5W blue LED lamp and stirring, and separating and purifying after the reaction is finished to obtain a 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione product shown in a formula III. The synthesis method provided by the invention has the advantages of easy control of reaction process, mild condition, simple post-treatment and high yield.
Description
Technical Field
The invention relates to the technical field of organic chemical synthesis, in particular to a method for synthesizing 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione.
Background
Isoquinoline diketones and derivatives thereof are important N-heterocyclic compounds, and are widely used in natural products, drug molecules and organic functional materials. The research shows that the compounds have obvious physiological activities, such as anti-tumor, anti-pain, anti-disease, anti-arrhythmia, anti-thrombus and the like, and the synthesis and development of the compounds are important subjects in the research fields of synthetic chemistry, pharmaceutical chemistry and material chemistry. In recent years, the research field has been rapidly developed, and a series of isoquinoline dione synthesis methods with important practical values are reported successively.
Among the methods developed, the radical tandem reaction of acryl benzamide has proved to be an attractive method for synthesizing isoquinolinedione due to its simplicity and high atomic efficiency.
In 1975, moore.D.W reported a synthetic method for obtaining isoquinoline-1, 3, 4-trione by oxidizing isoquinolinone under the condition of sodium dichromate acetate at room temperature.
In 1980, vekemans.J developed the synthesis of isoquinoline-1.3 (2H.4H) -dione from N-substituted benzamides and oxalyl chloride at high temperature.
In 2008, yadav.J.S. et al disclose the synthesis of isoquinoline-1, 3, 4-diones using azido reagents to insert amino groups in the ortho position of the ketone under the catalysis of an iron salt.
However, some of the reported methods require high reaction temperatures and suffer from the disadvantage of low yields, and due to the potential effect of 4-alkylated isoquinolinediones, it remains critical to develop more efficient and convenient methods of constructing such compounds under mild reaction conditions.
The publication CN107805220-a discloses that 4-substituted isoquinoline-1.3 (2h.4h) -dione is obtained by reaction in the presence of a palladium catalyst, a ligand and a base, and the method uses expensive solvents and raw materials, and is difficult to control the reaction, severe in conditions and difficult to post-treat.
The present invention developed a metal-free and mild series reaction of acryl benzamide with carboxylic acid and alpha-iminooxy acid. The method is characterized in that 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione is synthesized with moderate to good yield through decarboxylation, free radical addition and intramolecular cyclization under the existence of visible light, the reaction process is easy to control, the condition is mild, the post-treatment is simple, the yield is high, and the environmental pollution is reduced.
Disclosure of Invention
The invention aims to provide a method for synthesizing 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione by metal-free series reaction of acryloylbenzamide, carboxylic acid and alpha-iminooxy acid in the presence of visible light, wherein the reaction process of the method is easy to control, the condition is mild, the post-treatment is simple, and the yield is high.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a method for synthesizing 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2 h,4 h) -dione of the formula III comprising the steps of:
adding acryl benzamide shown in a formula I, cyclohexyl formic acid shown in a formula II, a solvent, a photocatalyst 2,4,5, 6-tetra (9-carbazolyl) -m-phthalonitrile (4 CzIPN) and an oxidant K into a reaction container 2 S 2 O 8 And inorganic base, under the protection of nitrogen, carrying out addition reaction under the condition of illumination and stirring of a 5W blue LED lamp, and separating and purifying after the reaction is finished to obtain a 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione product shown in a formula III;
preferably, the inorganic base is at least one of sodium hydroxide, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, potassium carbonate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate, and more preferably cesium carbonate.
Preferably, the solvent is at least one of dimethyl sulfoxide, methanol, tetrahydrofuran, dichloromethane, dioxane, acetonitrile, a mixture of dimethyl sulfoxide and water, and more preferably dimethyl sulfoxide.
Preferably, the acryloylbenzamide is mixed with cyclohexylformic acid, K 2 S 2 O 8 The feeding mole ratio of the inorganic base to the 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile (4 CzIPN) is 1:1.5-2.5:2.5-3.5:2.5-3.5: 0.01-0.03; more preferably 1:2:3:3:0.02.
preferably, the reaction conditions are specifically as follows: the reaction mixture was placed at a distance of 2-3 cm from a 5W blue LED lamp and stirred at room temperature for 12-15 hours. It is further preferred that the room temperature is 20-30 ℃, more preferably 25 ℃.
Preferably, the separation and purification are performed by the following steps: by saturated KHCO 3 The reaction was quenched, the aqueous layer extracted with ethyl acetate and the combined organic layers were sequentially washed with saturated NaHCO 3 、H 2 O and saturated brine and washed with Na 2 SO 4 Drying; then the organic solution is decompressed and concentrated, the obtained solvent is recycled, and the concentrated product is purified by column chromatography on silica gel with petroleum ether/ethyl acetate as eluent.
As a further preference, the silica gel has a particle size of 200 to 300 mesh.
As a further preferable mode, ethyl acetate of petroleum ether in the eluent is v Petroleum ether ：v Acetic acid ethyl ester ＝5： 1。
Compared with the prior art, the invention has the following excellent beneficial effects:
the invention provides a rapid synthesis method of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -diketone, which can realize the improvement of the overall yield of a target product in the whole production route process, has good product quality, simple and convenient operation and mild reaction conditions, and has low price of raw materials and solvents used in the whole process, thereby being beneficial to control of cost.
Drawings
FIG. 1 shows the target product 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione synthesized in example 1 of the invention 1 HNMR spectra.
FIG. 2 is a schematic diagram of the target product 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione synthesized in example 1 of the invention 13 CNMR spectra.
Detailed Description
The technical features of the technical solution provided in the present invention will be further clearly and completely described in connection with the detailed description below, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the examples of the present invention, the acryl benzamide is described in reference [ Y.—L.Deng, S.Tang, G.Ding, M.—W.Wang, J.Li, Z.—Z.Li, L.Yuan, R.— L.Sheng, org.Biomol.Chem.2016,14,9348-9353; Y.Su, R.Zhang, W.Xue, X.Liu, Y.Zhao, K.Wang, D.Huang, C.Huo, Y.Hu, org.Biomol.Chem.2020,18,1940-1948] by Takara Shuzo.
Example 1
Synthesis of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione
25mL Schlenk tube was equipped with a stirrer, and acryl benzamide (5 mmol), cyclohexylformic acid (10 mmol,2 equivalents), K were added 2 S 2 O 8 (15 mol,3 eq.) Cs 2 CO 3 (15 mmol,3 eq.) and 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile (4 CzIPN) (0.1 mmol,2 mol%). Dry DMSO (20 mL) was injected into the reaction tube under nitrogen protection. The reaction mixture was then placed at a distance of about 2 cm from a 5W blue LED lampAnd stirred at 25 ℃. After stirring for 12 hours, saturated KHCO was used 3 (50 mL) quench the reaction. The aqueous layer was extracted with ethyl acetate (4X 30 mL). The combined organic layers were washed with saturated NaHCO 3 (50mL)、H 2 O (5X 12 mL) and saturated brine (50 mL) and washed with Na 2 SO 4 And (5) drying. Concentrating the organic solution under reduced pressure, recovering the solvent, and concentrating the concentrated product on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v) Petroleum ether ：v Acetic acid ethyl ester =5: 1) Column chromatography purification was performed on the eluent to give 1.20g of the target product. Fig. 1 and 2 show the hydrogen and carbon spectra of the product, respectively.
Example 2
Synthesis of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione
25mL Schlenk tube was equipped with a stirrer, and acryl benzamide (5 mmol), cyclohexylformic acid (10 mmol,2 equivalents), K were added 2 S 2 O 8 (15 mol,3 eq.) Cs 2 CO 3 (15 mmol,3 eq.) and 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile (4 CzIPN) (0.1 mmol,2 mol%). Dry DMSO (20 mL) was injected into the reaction tube under nitrogen protection. The reaction mixture was then placed at a distance of about 2 cm from a 5W blue LED lamp and stirred at 30 ℃. After stirring for 12 hours, saturated KHCO was used 3 (50 mL) quench the reaction. The aqueous layer was extracted with ethyl acetate (4X 30 mL). The combined organic layers were washed with saturated NaHCO 3 (50mL)、H 2 O (5X 12 mL) and saturated brine (50 mL) and washed with Na 2 SO 4 And (5) drying. Concentrating the organic solution under reduced pressure, recovering the solvent, and concentrating the concentrated product on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v) Petroleum ether ：v Acetic acid ethyl ester =5: 1) Column chromatography purification was performed on the eluent to give 1.15g of the target product.
Example 3
Synthesis of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione
25mL Schlenk tube was equipped with a stirrer, and acryl benzamide (5 mmol), cyclohexylformic acid (10 mmol,2 equivalents), K were added 2 S 2 O 8 (15 mol,3 eq.) Cs 2 CO 3 (15 mmol,3 eq.) and 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile (4 CzIPN) (0.1 mmol,2 mol%). Dry DMSO (20 mL) was injected into the reaction tube under nitrogen protection. The reaction mixture was then placed at a distance of about 2 cm from a 5W blue LED lamp and stirred at 25 ℃. After stirring for 12 hours, saturated NaHCO was used 3 (50 mL) quench the reaction mixture. The aqueous layer was extracted with ethyl acetate (4X 30 mL). The combined organic layers were washed with saturated NaHCO 3 (50mL)，H 2 O (5X 12 mL) and saturated brine (50 mL) and washed with Na 2 SO 4 And (5) drying. Concentrating the organic solution under reduced pressure, recovering the solvent, and concentrating the concentrated product on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v) Petroleum ether ：v Acetic acid ethyl ester =5: 1) Column chromatography purification was performed on the eluent to give the target product 1.11g.
Example 4
Synthesis of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione
25mL Schlenk tube was equipped with a stirrer, and acryl benzamide (5 mmol), cyclohexylformic acid (10 mmol,2 equivalents), K were added 2 S 2 O 8 (15 mol,3 eq.) Cs 2 CO 3 (15 mmol,3 eq.) and 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile (4 CzIPN) (0.1 mmol,2 mol%). Dry methanol (20 mL) was injected into the reaction tube under nitrogen blanket. The reaction mixture was then placed at a distance of about 2 cm from a 5W blue LED lamp and stirred at 25 ℃. After 12 hours, saturated K is used 2 CO 3 (50 mL) quench the reaction mixture. The aqueous layer was extracted with ethyl acetate (4X 30 mL). The combined organic layers were washed with saturated NaHCO 3 (50mL)，H 2 O (5X 12 mL) and saturated brine (50 mL) and washed with Na 2 SO 4 And (5) drying. Concentrating under reduced pressure to obtain solvent, recovering the solvent, and concentrating the concentrated product on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (PE-EtOAc, v) Petroleum ether ：v Acetic acid ethyl ester =5: 1) Column chromatography purification was performed on the eluent to give the target product 0.96g.
Example 5
Synthesis of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione
25mL Schlenk tube was equipped with a stirrer, and acryl benzamide (5 mmol), cyclohexylformic acid (10 mmol,2 equivalents), K were added 2 S 2 O 8 (15 mol,3 eq.) Cs 2 CO 3 (15 mmol,3 eq.) and Ir [ dF (CF 3) ppy2](dtbbpy) PF6 (0.1 mmol,2 mol%). Dry DMSO (20 mL) was injected into the reaction tube under nitrogen protection. The reaction mixture was then placed at a distance of about 2 cm from a 5W blue LED lamp and stirred at 25 ℃. After 12 hours, saturated NaHCO was used 3 (50 mL) quench the reaction mixture. The aqueous layer was extracted with ethyl acetate (4X 30 mL). The combined organic layers were washed with saturated NaHCO 3 (50mL)、H 2 O (5X 12 mL) and saturated brine (50 mL) and washed with Na 2 SO 4 And (5) drying. Concentrating the organic solution under reduced pressure, recovering the solvent, and concentrating the concentrated product on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v) Petroleum ether ：v Acetic acid ethyl ester =5: 1) Column chromatography purification was performed on the eluent to give the target product 0.84g.
Example 6
Synthesis of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione
A25 mL Schlenk tube was fitted with a stirrer and was charged with acryl benzamide (5 mmol), cyclohexyl formic acid (10 mmol,2 eq), DTBP (15 mol,3 eq), cs 2 CO 3 (15 mmol,3 eq.) and 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile (4 CzIPN) (0.1 mmol,2 mol%). Dry DMSO (20 mL) was injected into the reaction tube under nitrogen protection. The reaction mixture was then placed at a distance of about 2 cm from a 5W blue LED lamp and stirred at 25 ℃. After 12 hours, saturated KHCO was used 3 (50 mL) quench the reaction mixture. The aqueous layer was extracted with ethyl acetate (4X 30 mL). The combined organic layers were washed with saturated NaHCO 3 (50mL)，H 2 O (5X 12 mL) and saturated brine (50 mL) and washed with Na 2 SO 4 And (5) drying. Concentrating the organic solution under reduced pressure to obtain solvent, recycling, concentrating to obtain the final productThe product was purified on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v) Petroleum ether ：v Acetic acid ethyl ester =5: 1) Column chromatography purification was performed on the eluent to give 0.81g of the target product.
Example 7
Synthesis of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione
A25 mL Schlenk tube was fitted with a stirrer and was charged with acryl benzamide (5 mmol), cyclohexyl formic acid (10 mmol,2 eq), TBHP (15 mol,3 eq), cs 2 CO 3 (15 mmol,3 eq.) and 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile (4 CzIPN) (0.1 mmol,2 mol%). Dry DMSO (20 mL) was injected into the reaction tube under nitrogen protection. The reaction mixture was then placed at a distance of about 2 cm from the 5W blue LED and stirred at 25 ℃. After 12 hours, saturated KH was used 2 PO 3 (50 mL) quench the reaction mixture. The aqueous layer was extracted with ethyl acetate (4X 30 mL). The combined organic layers were washed with saturated NaHCO 3 (50mL)，H 2 O (5X 12 mL) and saturated brine (50 mL) and washed with Na 2 SO 4 And (5) drying. Concentrating the organic solution under reduced pressure, recovering the solvent, and concentrating the concentrated product on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v) Petroleum ether ：v Acetic acid ethyl ester =5: 1) Column chromatography purification was performed on the eluent to give 0.61g of the target product.
Comparative example 1: synthesis of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione using 4CzIPN as photocatalyst, a mixture of dimethyl sulfoxide and water as solvent
25mL Schlenk tube was equipped with a stirrer, and acryl benzamide (5 mmol), cyclohexylformic acid (10 mmol,2 equivalents), K were added 2 S 2 O 8 (15 mol,3 eq.) Cs 2 CO 3 (15 mmol,3 eq.) and 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile (4 CzIPN) (0.1 mmol,2 mol%). Dry DMSO/H under nitrogen blanket 2 O(20mL，v DMSO ：v H2O =4: 1) Injected into the reaction tube. The reaction mixture was then placed at a distance of about 2 cm from the 5W blue LED and stirred at 25 ℃. After the time period of 12 hours, the mixture was stirred,by saturated KHCO 3 (50 mL) quench the reaction mixture. The aqueous layer was extracted with ethyl acetate (4X 30 mL). The combined organic layers were washed with saturated NaHCO 3 (50mL)，H 2 O (5X 12 mL) and saturated brine (50 mL) and washed with Na 2 SO 4 And (5) drying. The organic solution was then concentrated under reduced pressure on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v Petroleum ether ：v Acetic acid ethyl ester =5: 1) Column chromatography purification was performed on the eluent to give the target product 0.77g.
Comparative example 2: eosin Y is used as photocatalyst and dimethyl sulfoxide is used as solvent
Synthesis of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione
25mL Schlenk tube was equipped with a stirrer, and acryl benzamide (5 mmol), cyclohexylformic acid (10 mmol,2 equivalents), K were added 2 S 2 O 8 (15 mol,3 eq.) Cs 2 CO 3 (15 mmol,3 eq.) and Eosin Y (0.1 mmol,2 mol%). Dry DMSO (20 mL) was injected into the reaction tube under nitrogen protection. The reaction mixture was then placed at a distance of about 2 cm from the 5W blue LED and stirred at 25 ℃. After 12 hours, saturated Na was used 2 CO 3 (50 mL) quench the reaction mixture. The aqueous layer was extracted with ethyl acetate (4X 30 mL). The combined organic layers were washed with saturated NaHCO 3 (50mL)，H 2 O (5X 12 mL) and saturated brine (50 mL) and washed with Na 2 SO 4 And (5) drying. The organic solution was then concentrated under reduced pressure on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v Petroleum ether ：v Acetic acid ethyl ester =5: 1) Column chromatography purification was performed on the eluent to give 0.18g of the target product.
Comparative example 3: ru (bpy) is used 3 (PF 6 ) 2 As photocatalyst and tetrahydrofuran as solvent
Synthesis of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione
25mL Schlenk tube was equipped with a stirrer, and acryl benzamide (5 mmol), cyclohexylformic acid (10 mmol,2 equivalents), K were added 2 S 2 O 8 (15 mol,3 eq.) Cs 2 CO 3 (15 mmol,3 eq.) and Ru (bpy) 3 (PF 6 ) 2 (0.1 mmol,2 mol%). Dry tetrahydrofuran (20 mL) was injected into the reaction tube under nitrogen blanket. The reaction mixture was then placed at a distance of about 2 cm from the 5W blue LED and stirred at 25 ℃. After 12 hours, saturated Na was used 2 CO 3 (50 mL) quench the reaction mixture. The aqueous layer was extracted with ethyl acetate (4X 30 mL). The combined organic layers were washed with saturated NaHCO 3 (50mL)，H 2 O (5X 12 mL) and saturated brine (50 mL) and washed with Na 2 SO 4 And (5) drying. The organic solution was then concentrated under reduced pressure on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v Petroleum ether ：v Acetic acid ethyl ester =5: 1) Column chromatography purification was performed on the eluate to give 0.34g of pure product.
Claims (9)
1. A method for synthesizing 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2 h,4 h) -dione of the formula III comprising the steps of:
adding acryl benzamide shown in a formula I, cyclohexyl formic acid shown in a formula II, a solvent and a photocatalyst 2,4,5, 6-tetra (9-carbazolyl) -m-phthalonitrile and an oxidant K into a reaction container 2 S 2 O 8 The inorganic base is cesium carbonate, and undergoes addition reaction under the condition of illumination of a 5W blue LED lamp and stirring at room temperature under the protection of nitrogen, and after the reaction is finished, 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione products shown in a formula III are obtained through separation and purification;
2. the synthesis method according to claim 1, wherein: the solvent is at least one of dimethyl sulfoxide, methanol, tetrahydrofuran, dichloromethane, dioxane, acetonitrile, dimethyl sulfoxide and water.
3. The synthesis method according to claim 1, wherein: the acryl benzamide and the cyclohexyl formic acid, K 2 S 2 O 8 The feeding mole ratio of the inorganic base to the 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile is 1:1.5-2.5:2.5-3.5:2.5-3.5:0.01-0.03.
4. The synthesis method according to claim 1, wherein: the acryl benzamide and the cyclohexyl formic acid, K 2 S 2 O 8 The feeding mole ratio of the inorganic base to the 2,4,5, 6-tetra (9-carbazolyl) -isophthalonitrile is 1:2:3:3:0.02.
5. the synthesis method according to claim 1, wherein: the reaction conditions are specifically as follows: the reaction mixture was placed at a distance of 2-3 cm from a 5W blue LED lamp and stirred at room temperature for 12-15 hours.
6. The synthesis method according to claim 5, wherein: the room temperature is 20-30 ℃.
7. The synthesis method according to claim 6, wherein: the room temperature was 25 ℃.
8. The synthesis method according to claim 1, wherein: the separation and purification adopts the following operations: by saturated KHCO 3 The reaction was quenched, the aqueous layer extracted with ethyl acetate and the combined organic layers were sequentially washed with saturated NaHCO 3 、H 2 O and saturated brine and washed with Na 2 SO 4 Drying; then the organic solution is decompressed and concentrated, the obtained solvent is recycled, and the concentrated product is purified by column chromatography on silica gel with petroleum ether/ethyl acetate as eluent.
9. The method of synthesis according to claim 8, wherein: the particle size of the silica gel is 200-300 meshes, and the volume ratio of petroleum ether to ethyl acetate in the eluent is v Petroleum ether ：v Acetic acid ethyl ester ＝5：1。
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