CN115108985B - Synthesis method of 4- (cyclohexylmethyl) -2, 4-dimethylisoquinoline-1, 3 (2H, 4H) -dione - Google Patents

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

Synthesis of 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione method

technical field

The invention relates to the technical field of organic chemical synthesis, in particular to a synthesis method of 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione.

Background technique

Isoquinoline diones and their derivatives are important N-heterocyclic compounds that widely exist in natural products, drug molecules and organic functional materials. Studies have shown that these compounds have obvious physiological activities, such as anti-tumor, anti-analgesic, anti-disease, anti-arrhythmia, anti-thrombosis, etc. Their synthesis and development are important topics in the research fields of synthetic chemistry, medicinal chemistry and material chemistry. . In recent years, this research field has developed rapidly, and a series of synthetic methods of isoquinolinediones with important practical value have been reported one after another.

Among the developed methods, the radical tandem reaction of acryloylbenzamides proved to be an attractive method for the synthesis of isoquinolinediones due to its simplicity and high atomic efficiency.

In 1975, Moore.D.W reported the synthesis of isoquinolinone-1,3,4-trione by oxidation of isoquinolinone under the condition of sodium dichromate acetic acid at room temperature.

In 1980, Vekemans.J developed the synthesis of isoquinoline-1.3(2H.4H)-dione at high temperature using N-substituted benzamide and oxalyl chloride as raw materials.

In 2008, Yadav.J.S et al disclosed the synthesis of isoquinoline-1,3,4-dione compounds by using an azide reagent to insert an amino group at the ortho position of a ketone under the catalysis of an iron salt.

However, some reported methods require high reaction temperatures and suffer from low yields. Due to the potential effect of 4-alkylated isoquinolinediones, it is more efficient and convenient to develop such compounds under mild reaction conditions. method is still crucial.

The patent of publication number CN107805220-A discloses that in the presence of a palladium catalyst, a ligand and a base, the reaction obtains 4-substituted isoquinoline-1.3(2H.4H)-dione, and the solvent and raw materials used in this method are relatively expensive, and the reaction The control is difficult, the conditions are relatively harsh, and the post-processing is difficult.

The present invention develops a metal-free and mild-conditions tandem reaction of acryloylbenzamide with carboxylic acid and α-iminooxyacid. The synthesis of 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H, 4H)- diketone, the reaction process is easy to control, the conditions are mild, the post-treatment is simple, the yield is high, and environmental pollution is reduced.

Contents of the invention

The object of the present invention is to provide a metal-free series reaction of acryloyl benzamide with carboxylic acid and α-imino oxyacid in the presence of visible light to synthesize 4-(cyclohexylmethyl)-2,4-dimethyl The method of isoquinoline-1,3(2H, 4H)-dione, the reaction process of this method is easy to control, the conditions are mild, the post-treatment is simple, and the yield is high.

To achieve the above object, the present invention adopts the following technical solutions:

A kind of synthetic method of 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H, 4H)-dione shown in formula III, described synthetic method comprises the following steps:

In the reaction vessel, add acryloyl benzamide shown in formula I, cyclohexyl formic acid shown in formula II, solvent, photocatalyst 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN), oxidant K ₂ S ₂ O ₈ and inorganic base, under the protection of nitrogen, addition reaction occurs under the irradiation of 5W blue LED lamp and stirring conditions, after the reaction is completed, the 4-(cyclic compound shown in formula III is obtained by separation and purification. Hexylmethyl)-2,4-dimethylisoquinoline-1,3(2H, 4H)-dione product;

Preferably, the inorganic base is at least one of sodium hydroxide, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, potassium carbonate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, more preferably cesium carbonate.

Preferably, the solvent is at least one of a mixture of dimethyl sulfoxide, methanol, tetrahydrofuran, dichloromethane, dioxane, acetonitrile, dimethyl sulfoxide and water, more preferably dimethyl sulfoxide .

As a preference, the feeding of acryloyl benzamide and cyclohexyl formic acid, K ₂ S ₂ O ₈ , inorganic base, 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN), The molar ratio 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 as follows: place the reaction mixture at a distance of 2-3 cm from a 5W blue LED lamp and stir at room temperature for 12-15 hours. It is further preferred that the room temperature is 20-30°C, more preferably 25°C.

Preferably, the separation and purification are performed as follows: quench the reaction with saturated KHCO ₃ , extract the aqueous layer with ethyl acetate, wash the combined organic layer with saturated NaHCO ₃ , H ₂ O and saturated brine in sequence, and wash with Na ₂ SO ₄ drying; then the organic solution was concentrated under reduced pressure, the obtained solvent was recycled, and the concentrated product was purified by column chromatography on silica gel with petroleum ether/ethyl acetate as eluent.

As a further preference, the particle size of the silica gel is 200-300 mesh.

As a further preference, the ethyl acetate of petroleum ether in the eluent is v _{petroleum ether} : v _{ethyl acetate} = 5:1.

Compared with the prior art, the present invention has the following excellent beneficial effects:

The invention provides a rapid synthesis method of 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione, which can realize the target in the whole production route process The overall yield of the product is improved, the product quality is good, the operation is simple, the reaction conditions are mild, and the raw materials and solvents used in the whole process are low in price, which is beneficial to cost control.

Description of drawings

Figure 1 is the ¹ HNMR spectrum of the target product 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione synthesized in Example 1 of the present invention.

Fig. 2 is the ¹³ CNMR spectrum of the target product 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione synthesized in Example 1 of the present invention.

Detailed ways

The technical features in the technical solutions provided by the present invention will be further clearly and completely described below in conjunction with specific implementation methods. Obviously, the described embodiments are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

In the embodiment of the present invention, the acryloyl benzamide refers to the literature [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] synthesis.

Example 1

Synthesis of 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione

_25mL Schlenk tube equipped with a stir bar, add acryloylbenzamide (5mmol), cyclohexylcarboxylic acid (10mmol, 2eq), _K2S2O8 ( _15mol , 3eq), _Cs2CO3 ( _15mmol , 3eq ) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN) (0.1 mmol, 2 mol%). Under nitrogen protection, dry DMSO (20 mL) was injected into the reaction tube. Then, the reaction mixture was placed at a distance of about 2 cm from a 5W blue LED light and stirred at 25 °C. After stirring for 12 hours, the reaction was quenched with saturated _KHCO3 (50 mL). The aqueous layer was extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with saturated NaHCO ₃ (50 mL), H ₂ O (5×12 mL) and saturated brine (50 mL) and dried over Na ₂ SO ₄ . Then the organic solution was concentrated under reduced pressure, and the obtained solvent was recycled, and the concentrated product was prepared on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v _{petroleum ether} : v _{ethyl acetate} =5:1) as The eluate was purified by column chromatography to obtain 1.20 g of the target product. Figure 1 and Figure 2 are 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 equipped with a stir bar, add acryloylbenzamide (5mmol), cyclohexylcarboxylic acid (10mmol, 2eq), _K2S2O8 ( _15mol , 3eq), _Cs2CO3 ( _15mmol , 3eq ) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN) (0.1 mmol, 2 mol%). Under nitrogen protection, dry DMSO (20 mL) was injected into the reaction tube. Then, the reaction mixture was placed at a distance of about 2 cm from a 5W blue LED light and stirred at 30 °C. After stirring for 12 hours, the reaction was quenched with saturated _KHCO3 (50 mL). The aqueous layer was extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with saturated NaHCO ₃ (50 mL), H ₂ O (5×12 mL) and saturated brine (50 mL) and dried over Na ₂ SO ₄ . Then the organic solution was concentrated under reduced pressure, and the obtained solvent was recycled, and the concentrated product was prepared on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v _{petroleum ether} : v _{ethyl acetate} =5:1) as The eluent was purified by column chromatography to obtain 1.15 g of the target product.

Example 3

Synthesis of 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione

_25mL Schlenk tube equipped with a stir bar, add acryloylbenzamide (5mmol), cyclohexylcarboxylic acid (10mmol, 2eq), _K2S2O8 ( _15mol , 3eq), _Cs2CO3 ( _15mmol , 3eq ) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN) (0.1 mmol, 2 mol%). Under nitrogen protection, dry DMSO (20 mL) was injected into the reaction tube. The reaction mixture was then placed at a distance of approximately 2 cm from a 5W blue LED light and stirred at 25 °C. After stirring for 12 h, the reaction mixture was quenched with saturated NaHCO ₃ (50 mL). The aqueous layer was extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with saturated NaHCO ₃ (50 mL), H ₂ O (5×12 mL) and saturated brine (50 mL) and dried over Na ₂ SO ₄ . Then the organic solution was concentrated under reduced pressure, and the obtained solvent was recycled, and the concentrated product was prepared on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v _{petroleum ether} : v _{ethyl acetate} =5:1) as The eluent was purified by column chromatography to obtain 1.11 g of the target product.

Example 4

Synthesis of 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione

_25mL Schlenk tube equipped with a stir bar, add acryloylbenzamide (5mmol), cyclohexylcarboxylic acid (10mmol, 2eq), _K2S2O8 ( _15mol , 3eq), _Cs2CO3 ( _15mmol , 3eq ) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN) (0.1 mmol, 2 mol%). Under nitrogen protection, dry methanol (20 mL) was injected into the reaction tube. Then, the reaction mixture was placed at a distance of about 2 cm from a 5W blue LED light and stirred at 25 °C. After 12 hours, the reaction mixture was quenched with _{saturated K2CO3} (50 mL). The aqueous layer was extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with saturated NaHCO ₃ (50 mL), H ₂ O (5×12 mL) and saturated brine (50 mL) and dried over Na ₂ SO ₄ . Then the organic solution was concentrated under reduced pressure, and the solvent obtained was recycled, and the concentrated product was separated on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (PE-EtOAc, v _{petroleum ether} : v _{ethyl acetate} =5 : 1) Carry out column chromatography purification as eluent, obtain target product 0.96g.

Example 5

Synthesis of 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione

_25mL Schlenk tube equipped with a stir bar, add acryloylbenzamide (5mmol), cyclohexylcarboxylic acid (10mmol, 2eq), _K2S2O8 ( _15mol , 3eq), _Cs2CO3 ( _15mmol , 3eq ) and Ir[dF(CF3)ppy2](dtbbpy)PF6 (0.1 mmol, 2 mol%). Under nitrogen protection, dry DMSO (20 mL) was injected into the reaction tube. Then, the reaction mixture was placed at a distance of about 2 cm from a 5W blue LED light and stirred at 25 °C. After 12 hours, the reaction mixture was quenched with saturated NaHCO ₃ (50 mL). The aqueous layer was extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with saturated NaHCO ₃ (50 mL), H ₂ O (5×12 mL) and saturated brine (50 mL) and dried over Na ₂ SO ₄ . Then the organic solution was concentrated under reduced pressure, and the obtained solvent was recycled, and the concentrated product was prepared on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v _{petroleum ether} : v _{ethyl acetate} =5:1) as The eluent was purified by column chromatography to obtain 0.84 g of the target product.

Example 6

Synthesis of 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione

To a 25 mL Schlenk tube equipped with a stir bar, add acryloylbenzamide (5 mmol), cyclohexylcarboxylic acid (10 mmol, 2 eq), DTBP (15 mol, 3 eq), _Cs2CO3 (15 _mmol , 3 eq) and 2,4 , 5,6-Tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN) (0.1 mmol, 2 mol%). Under nitrogen protection, dry DMSO (20 mL) was injected into the reaction tube. Then, the reaction mixture was placed at a distance of about 2 cm from a 5W blue LED light and stirred at 25 °C. After 12 hours, the reaction mixture was quenched with saturated _KHCO3 (50 mL). The aqueous layer was extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with saturated NaHCO ₃ (50 mL), H ₂ O (5×12 mL) and saturated brine (50 mL) and dried over Na ₂ SO ₄ . Then the organic solution was concentrated under reduced pressure, and the obtained solvent was recycled, and the concentrated product was prepared on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v _{petroleum ether} : v _{ethyl acetate} =5:1) as The eluent was purified by column chromatography to obtain 0.81 g of the target product.

Example 7

Synthesis of 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione

To a 25 mL Schlenk tube equipped with a stir bar, add acryloylbenzamide (5 mmol), cyclohexylcarboxylic acid (10 mmol, 2 eq), TBHP (15 mol, 3 eq), _Cs2CO3 (15 _mmol , 3 eq) and 2,4 , 5,6-Tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN) (0.1 mmol, 2 mol%). Under nitrogen protection, dry DMSO (20 mL) was injected into the reaction tube. Then, the reaction mixture was placed at a distance of about 2 cm from a 5W blue LED and stirred at 25 °C. After 12 hours, the reaction mixture was quenched with saturated _KH2PO3 (50 _mL ). The aqueous layer was extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with saturated NaHCO ₃ (50 mL), H ₂ O (5×12 mL) and saturated brine (50 mL) and dried over Na ₂ SO ₄ . Then the organic solution was concentrated under reduced pressure, and the obtained solvent was recycled, and the concentrated product was prepared on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v _{petroleum ether} : v _{ethyl acetate} =5:1) as The eluent was purified by column chromatography to obtain 0.61 g of the target product.

Comparative Example 1: Using 4CzIPN as a photocatalyst, a mixture of dimethylsulfoxide and water as a solvent 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)- Synthesis of diketones

_25mL Schlenk tube equipped with a stir bar, add acryloylbenzamide (5mmol), cyclohexylcarboxylic acid (10mmol, 2eq), _K2S2O8 ( _15mol , 3eq), _Cs2CO3 ( _15mmol , 3eq ) and 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (4CzIPN) (0.1 mmol, 2 mol%). Under nitrogen protection, dry DMSO/H ₂ O (20 mL, v _DMSO :v _{H 2 O} =4:1) was injected into the reaction tube. Then, the reaction mixture was placed at a distance of about 2 cm from the 5W blue LED and stirred at 25 °C. After 12 hours, the reaction mixture was quenched with saturated _KHCO3 (50 mL). The aqueous layer was extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with saturated NaHCO ₃ (50 mL), H ₂ O (5×12 mL) and saturated brine (50 mL) and dried over Na ₂ SO ₄ . Then the organic solution was concentrated under reduced pressure, and purified by column chromatography on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v _{petroleum ether} : v _{ethyl acetate} = 5:1) as eluent to obtain the target Product 0.77g.

Comparative Example 2: Using Eosin Y as photocatalyst and dimethyl sulfoxide as solvent

Synthesis of 4-(cyclohexylmethyl)-2,4-dimethylisoquinoline-1,3(2H,4H)-dione

_25mL Schlenk tube equipped with a stir bar, add acryloylbenzamide (5mmol), cyclohexylcarboxylic acid (10mmol, 2eq), _K2S2O8 ( _15mol , 3eq), _Cs2CO3 ( _15mmol , 3eq ) and Eosin Y (0.1 mmol, 2 mol%). Under nitrogen protection, dry DMSO (20 mL) was injected into the reaction tube. Then, the reaction mixture was placed at a distance of about 2 cm from the 5W blue LED and stirred at 25 °C. After 12 hours, the reaction mixture was quenched with _{saturated Na2CO3} (50 mL). The aqueous layer was extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with saturated NaHCO ₃ (50 mL), H ₂ O (5×12 mL) and saturated brine (50 mL) and dried over Na ₂ SO ₄ . Then the organic solution was concentrated under reduced pressure, and purified by column chromatography on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v _{petroleum ether} : v _{ethyl acetate} = 5:1) as eluent to obtain the target Product 0.18g.

Comparative Example 3: Using Ru(bpy) 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 equipped with a stir bar, add acryloylbenzamide (5mmol), cyclohexylcarboxylic acid (10mmol, 2eq), _K2S2O8 ( _15mol , 3eq), _Cs2CO3 ( _15mmol , 3eq ) and Ru(bpy) ₃ (PF ₆ ) ₂ (0.1 mmol, 2 mol%). Under nitrogen protection, dry tetrahydrofuran (20 mL) was injected into the reaction tube. Then, the reaction mixture was placed at a distance of about 2 cm from the 5W blue LED and stirred at 25 °C. After 12 hours, the reaction mixture was quenched with _{saturated Na2CO3} (50 mL). The aqueous layer was extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with saturated NaHCO ₃ (50 mL), H ₂ O (5×12 mL) and saturated brine (50 mL) and dried over Na ₂ SO ₄ . Then the organic solution was concentrated under reduced pressure, and purified by column chromatography on silica gel (200-300 mesh) with petroleum ether/ethyl acetate (v _{petroleum ether} : v _{ethyl acetate} = 5:1) as eluent to obtain pure Product 0.34g.

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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