Method for synthesizing pyrrole compound

Abstract

The invention discloses a method for synthesizing a pyrrole compound. The method comprises the following steps: mixing a beta-nitrostyrene compound, an alpha-fluoro-beta-ketone ester compound, cesium carbonate and ethanol, carrying out an addition reaction at 40-60 DEG C, cooling to room temperature after the reaction is finished, adding acetic acid and zinc particles, and carrying out a cyclization reaction at 60-100 DEG C to obtain the pyrrole compound. The method does not need to add a noble metal catalyst and a large number of redox agents, the reaction is carried out under normal pressure, operation is easy and convenient, raw materials are cheap and easy to obtain, and the method is suitable for large-scale production.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis and relates to a method for synthesizing pyrrole compounds. Background Art

[0002] Pyrrole is a very important five-membered aromatic heterocycle and is a key structure in many natural products, synthetic drugs, and new materials. The traditional method for preparing pyrrole compounds is to obtain pyrrole molecules through the condensation reaction of carbonyl compounds and amines, such as Knorr pyrrole synthesis, Hantzsch pyrrole synthesis, Barton–Zard pyrrole synthesis reaction, and Paal-Knorr reaction. However, such reactions often need to be carried out under harsh reaction conditions such as high temperature, strong acid, and strong base, so the functional group tolerance is poor, and selectivity problems often occur in the synthesis of polysubstituted pyrrole rings, which limits their application. In recent years, transition metal-catalyzed cyclization and multicomponent coupling have been developed for the synthesis of polysubstituted pyrroles. Some specific existing methods for synthesizing pyrrole compounds are introduced below.

[0003] Literature 1 (Wang H Y, Mueller D S, Sachwani R M, et al. Regioselective synthesis of 2,3,4- or 2,3,5-trisubstituted pyrroles via [3,3] or [1,3] rearrangements of O-vinyl oximes [J]. The Journal of Organic Chemistry, 2011, 76(9): 3203-3221.) uses an iridium catalyst to isomerize O-allyl oxime to O-vinyl oxime, and further converts O-vinyl oxime into 2,3,4- or 2,3,5-trisubstituted pyrrole. The regioselectivity of pyrrole formation can be controlled by reaction conditions with different bases such as DBU. The disadvantages of this method are that it requires precious metal catalysts such as iridium and silver, and the reaction precursors need to be synthesized in multiple steps, and the substrate scope is limited. The reaction formula is as follows:

[0004]

[0005] Reference 2 (Li L, Zhao M N, Ren Z H, et al. Synthesis of tetrasubstituted NHpyrroles and polysubstituted furans via an addition and cyclization strategy[J]. Synthesis, 2012, 44(04): 532-540.) uses iron chloride to catalyze the cyclization of β-nitrostyrene and enaminocarbonates to construct polysubstituted pyrroles. The method is relatively simple but requires a metal catalyst and has a very limited substrate scope. The yields of some structures are very low (less than 40%), and its reaction formula is as follows:

[0006]

[0007] Reference 3 (Umeda R, Mashino T, Nishiyama Y. Synthesis of multisubstituted 1H-pyrrole: Selenium-catalyzed reaction of γ-nitro substituted carbonyl compoundsand carbon monoxide[J]. Tetrahedron, 2014, 70(29): 4395-4399.) uses selenium as a catalyst and carbon monoxide as a reducing agent to convert γ-nitro substituted carbonyl compounds into polysubstituted pyrrole compounds. However, this method uses gases as raw materials, the reaction is carried out at high temperature, and the reaction precursors need to be prepared in multiple steps, which limits its application. Its reaction formula is as follows:

[0008]

[0009] Reference 4 (Wu W, Wen S, Zhang X, et al. Silver-Catalyzed RegioselectiveSynthesis of Highly Substituted 2-Trifluoromethyl Pyrroles[J]. OrganicLetters, 2021, 23(16): 6352-6356.) uses vinyl azide and ethyl 4,4,4-trifluoro-3-oxobutyrate to regioselectively synthesize polysubstituted 2-trifluoromethyl pyrrole derivatives by silver catalysis. The reaction has a high yield and can be scaled up to the gram scale. However, this method also uses a silver catalyst and the substrate has certain limitations. Its reaction formula is as follows:

[0010]

[0011] The above synthetic routes for pyrrole have certain drawbacks. For example, the reaction often requires noble metal catalysts and other additives, which brings certain problems in post-treatment. The reaction substrates need to be pre-synthesized in multiple steps and have a limited scope, etc. Therefore, there is an urgent need to develop a pyrrole synthesis method that does not require expensive and complex metal catalysts, additives, and has simple reaction conditions. Summary of the Invention

[0012] The object of the present invention is to provide a method for synthesizing pyrrole compounds. This method uses β-nitrostyrene compounds and α-fluoro-β-ketoester compounds as raw materials. During the reaction process, no additional catalyst needs to be added, the reaction conditions are simple and mild, the raw materials are easily available, and the whole reaction is simple and feasible.

[0013] The technical solution for achieving the object of the present invention is as follows:

[0014] A method for synthesizing pyrrole compounds, and the principle of the synthetic route is as follows:

[0015]

[0016] Wherein R 1 is hydrogen, methyl, fluoro group, R 2 is hydrogen, methyl, R 3 is methyl, trifluoromethyl, R 4 is ethyl, benzyl,

[0017] The specific steps are as follows:

[0018] Mix β-nitrostyrene compound (B), α-fluoro-β-ketoester compound (C), cesium carbonate and ethanol, and carry out an addition reaction under an oil bath condition of 40 - 60 °C. After the reaction is completed, cool to room temperature, then successively add acetic acid and zinc granules, and carry out a ring-forming reaction under an oil bath condition of 60 - 100 °C. After the reaction is completed, cool to room temperature, extract the reaction solution, distill off the solvent under reduced pressure for the obtained organic phase, and then carry out column chromatography using an eluent to separate and obtain pyrrole compound (A).

[0019] Further, the β-nitrostyrene compounds are β-nitrostyrene, p-fluoro-β-nitrostyrene, p-methyl-β-nitrostyrene or (E)-(2-nitroprop-1-en-1-yl)benzene; the α-fluoro-β-ketoester compounds are ethyl 2-fluoroacetoacetate, ethyl 2,4,4,4-tetrafluoro-3-oxobutyrate or benzyl 2-fluoro-3-oxobutyrate; the pyrrole compounds are ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylate, ethyl 4-(4-fluorophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate, benzyl 4-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylate, ethyl 4-(p-tolyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate or ethyl 2,5-dimethyl-4-phenyl-1H-pyrrole-3-carboxylate.

[0020] Further, the molar ratio of the β-nitrostyrene compounds to the α-fluoro-β-ketoester compounds is 1:1.5 - 1:2, preferably 1:1.5.

[0021] Further, the molar ratio of the β-nitrostyrene compounds to cesium carbonate is 1:1.5 - 1:2, preferably 1:1.5.

[0022] Further, the addition reaction time is 2 - 4 h, preferably 3 h.

[0023] Further, the cyclization reaction time is 6 - 12 h, preferably 9 h.

[0024] Further, the extraction solvent is a mixed solution of ethyl acetate and water with a volume ratio of 1:1.

[0025] Further, the eluent is a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 3:7.

[0026] Compared with the prior art, the remarkable advantages of the present invention are as follows:

[0027] (1) The reaction conditions of the present invention are simple and mild, without the need for expensive and complex catalysts, and the reaction is carried out under atmospheric pressure, which is easy to operate.

[0028] (2) The reaction steps of the present invention are simple and the conversion rate is high, and high-purity products can be conveniently obtained, which is suitable for large-scale industrial production.

[0029] (3) The raw materials used in the present invention, β-nitrostyrene compounds and α-fluoro-β-ketoester compounds, are easily obtained, have a low commercial price, and are stable in properties and easy to use. Description of the Drawings

[0030] Figure 1 is the 1 1H NMR spectrum of ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylate;

[0031] Figure 2 is the 13 C NMR spectrum of ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylate;

[0032] Figure 3 is the 1 H NMR spectrum of ethyl 4-(4-fluorophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate;

[0033] Figure 4 is the 19 F NMR spectrum of ethyl 4-(4-fluorophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate;

[0034] Figure 5 is the 1 H NMR spectrum of benzyl 4-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylate;

[0035] Figure 6 is the 19 F NMR spectrum of benzyl 4-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylate;

[0036] Figure 7 is the 1 H NMR spectrum of ethyl 4-(p-tolyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate;

[0037] Figure 8 is the 19 F NMR spectrum of ethyl 4-(p-tolyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate;

[0038] Figure 9 is the 1 H NMR spectrum of ethyl 2,5-dimethyl-4-phenyl-1H-pyrrole-3-carboxylate;

[0039] Figure 10 is the 13 C NMR spectrum of ethyl 2,5-dimethyl-4-phenyl-1H-pyrrole-3-carboxylate. Detailed implementation manners

[0040] To better understand the present invention, the technical solutions of the present invention will be further described in detail below through specific examples and drawings.

[0041] Example 1

[0042] 74.5 mg (0.5 mmol) of β-nitrostyrene, 111 mg (0.75 mmol) of ethyl 2-fluoroacetoacetate, 244 mg (0.75 mmol) of cesium carbonate and 3 ml of ethanol were successively added to a reaction tube. Subsequently, the reaction was stirred and heated to 40 °C using an oil bath for 3 hours. After the reaction was completed, it was cooled to room temperature. Then, 3 ml of acetic acid and 162 mg (2.5 mmol) of zinc granules were successively added to the reaction tube, and the reaction was stirred and heated to 90 °C using an oil bath for 9 hours. After the reaction was completed, it was cooled to room temperature, and extracted three times with ethyl acetate and water. The combined organic phases were concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (eluent: a mixture of ethyl acetate and petroleum ether with a volume ratio of 3:7) to obtain 77.8 mg of ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylate, with a yield of 68%.

[0043] For ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylate 1 The 1H NMR spectrum is shown in Figure 1 , 13 The 13C NMR spectrum is shown in Figure 2 .

[0044] 1 1H NMR (500 MHz, Chloroform-d) δ 9.08 (s, 1H), 7.29 (d, J = 4.3 Hz, 4H), 7.24 (p, J = 4.2 Hz, 1H), 6.57 (s, 1H), 4.10 (q, J = 7.1 Hz, 2H), 2.34 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H).

[0045] 13 13C NMR (126 MHz, Chloroform-d) δ 165.93, 134.21, 132.34, 128.24, 126.56, 125.29, 121.27, 115.24, 103.99, 58.91, 12.96, 8.95.

[0046] Example 2

[0047] 83.5 mg (0.5 mmol) of 4-fluorobenzylidene nitroethane, 151 mg (0.75 mmol) of ethyl 2,4,4,4-tetrafluoro-3-oxobutyrate, 244 mg (0.75 mmol) of cesium carbonate and 3 ml of ethanol were added to a reaction tube. Subsequently, the reaction was stirred and heated to 40 °C using an oil bath for 3 hours. After the reaction was completed, it was cooled to room temperature. 3 ml of acetic acid and 162 mg (2.5 mmol) of zinc granules were successively added to the reaction tube, and the reaction was again stirred and heated to 90 °C using an oil bath for 9 hours. After the reaction was completed and cooled to room temperature, it was extracted three times with ethyl acetate and water, and the combined organic phase was concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (eluent: a mixture of ethyl acetate and petroleum ether with a volume ratio of 3:7) to obtain 91.5 mg of ethyl 4-(4-fluorophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate, with a yield of 61%.

[0048] For ethyl 4-(4-fluorophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate 1 The 1H NMR spectrum is shown in Figure 3 , 19 The 19F NMR spectrum is shown in Figure 4 .

[0049] 1 1H NMR (500 MHz, Chloroform-d) δ 9.22 (s, 1H), 7.32 (dd, J = 8.5, 5.5 Hz, 2H), 7.02 (t, J = 8.7 Hz, 2H), 6.75 (d, J = 2.5 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H).

[0050] 19 19F NMR (470 MHz, Chloroform-d) δ -57.84 (s, 3F), -114.37 (s, 1F).

[0051] Example 3

[0052] 83.5 mg (0.5 mmol) of 4-fluorobenzylidene nitroethane, 144 mg (0.75 mmol) of benzyl 2-fluoro-3-oxobutanoate, 244 mg (0.75 mmol) of cesium carbonate and 3 ml of ethanol were added to a reaction tube. Subsequently, the reaction was stirred and heated to 40 °C using an oil bath for 3 hours. After the reaction, it was cooled to room temperature. Then, 3 ml of acetic acid and 162 mg (2.5 mmol) of zinc granules were successively added to the reaction tube, and the reaction was again stirred and heated to 90 °C using an oil bath for 9 hours. After the reaction, it was cooled to room temperature, and extracted three times with ethyl acetate and water. The combined organic phases were concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (eluent: a mixture of ethyl acetate and petroleum ether with a volume ratio of 3:7) to obtain 88.1 mg of benzyl 4-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylate, with a yield of 57%.

[0053] of benzyl 4-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylate 1 The Figure 5 , 19 The Figure 6 .

[0054] 1 H NMR (500 MHz, Chloroform-d) δ 8.63 - 8.37 (m, 1H), 7.37 (d, J = 4.4 Hz, 2H), 7.29 (t, J = 2.9 Hz, 3H), 7.16 (dd, J = 7.0, 2.8 Hz, 2H), 6.96 - 6.92 (m, 2H), 6.54 - 6.47 (m, 1H), 5.17 (s, 2H), 2.52 (s, 3H).

[0055] 19 F NMR (470 MHz, Chloroform-d) δ -116.03.

[0056] Example 4

[0057] 81.5 mg (0.5 mmol) of p-methyl-β-nitrostyrene, 151 mg (0.75 mmol) of ethyl 2,4,4,4-tetrafluoro-3-oxobutyrate, 244 mg (0.75 mmol) of cesium carbonate and 3 ml of ethanol were added to a reaction tube. Subsequently, the reaction was stirred and heated to 40 °C using an oil bath for 3 hours. After the reaction was completed, it was cooled to room temperature. Then, 3 ml of acetic acid and 162 mg (2.5 mmol) of zinc granules were successively added to the reaction tube. Again, the reaction was stirred and heated to 90 °C using an oil bath for 9 hours. After the reaction was completed and cooled to room temperature, it was extracted three times with ethyl acetate and water. The combined organic phases were concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (eluent: a mixture of ethyl acetate and petroleum ether with a volume ratio of 3:7) to obtain 93.5 mg of ethyl 4-(p-tolyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate, with a yield of 63%.

[0058] For ethyl 4-(p-tolyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate 1 The 1H NMR spectrum is shown in Figure 7 , 19 The 19F NMR spectrum is shown in Figure 8 .

[0059] 1 1H NMR (500 MHz, Chloroform-d) δ 9.06 (s, 1H), 7.30 - 7.25 (m, 2H), 7.16 (d, J = 7.8 Hz, 2H), 6.78 (d, J = 2.7 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H).

[0060] 19 19F NMR (470 MHz, Chloroform-d) δ -57.73.

[0061] Example 5

[0062] 81.5 mg (0.5 mmol) of (E)-(2-nitroprop-1-en-1-yl)benzene, 111 mg (0.75 mmol) of ethyl 2-fluoroacetoacetate, 244 mg (0.75 mmol) of cesium carbonate and 3 ml of ethanol were added to a reaction tube. Subsequently, the reaction was stirred and heated to 40 °C using an oil bath and reacted for 3 hours. After the reaction was completed, it was cooled to room temperature. Then, 3 ml of acetic acid and 162 mg (2.5 mmol) of zinc granules were successively added to the reaction tube. Again, the reaction was stirred and heated to 90 °C using an oil bath and reacted for 9 hours. After the reaction was completed and cooled to room temperature, it was extracted three times with ethyl acetate and water, and the combined organic phases were concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether with a volume ratio of 3:7) to obtain 78.9 mg of ethyl 2,5-dimethyl-4-phenyl-1H-pyrrole-3-carboxylate, with a yield of 65%.

[0063] For ethyl 2,5-dimethyl-4-phenyl-1H-pyrrole-3-carboxylate 1 The 1H NMR spectrum is shown in Figure 9 , 13 The 13C NMR spectrum is shown in Figure 10 .

[0064] 1 1H NMR (500 MHz, Chloroform-d) δ 8.76 (s, 1H), 7.30 (t, J = 7.4 Hz, 2H), 7.25 - 7.19 (m, 1H), 7.17 (d, J = 7.5 Hz, 2H), 4.01 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 2.07 (s, 3H), 1.02 (t, J = 7.1 Hz, 3H).

[0065] 13 13C NMR (126 MHz, Chloroform-d) δ 166.24, 134.86, 131.00, 129.36, 126.39, 124.94, 122.60, 116.98, 103.52, 58.62, 12.82, 8.85, 7.78.

[0066] Comparative Example 1

[0067] In this comparative example, sodium carbonate was used as the catalyst. Specifically:

[0068] 74.5 mg (0.5 mmol) of β-nitrostyrene, 111 mg (0.75 mmol) of ethyl 2-fluoroacetoacetate, 79.5 mg (0.75 mmol) of sodium carbonate and 3 ml of ethanol were successively added into a reaction tube. Subsequently, the reaction was stirred and heated to 40 °C using an oil bath and reacted for 3 hours. After the reaction, it was cooled to room temperature. Then, 3 ml of acetic acid and 162 mg (2.5 mmol) of zinc granules were successively added to the reaction tube. Again, the reaction was stirred and heated to 90 °C using an oil bath and reacted for 9 hours. After the reaction, it was cooled to room temperature, and extracted three times with ethyl acetate and water. The combined organic phases were concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether with a volume ratio of 3:7) to obtain 26.3 mg of ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylate, with a yield of 23%.

[0069] Comparative Example 2

[0070] In this comparative example, cesium carbonate was used as the catalyst. Specifically:

[0071] 74.5 mg (0.5 mmol) of β-nitrostyrene, 111 mg (0.75 mmol) of ethyl 2-fluoroacetoacetate, 244 mg (0.75 mmol) of cesium carbonate and 3 ml of methanol were successively added into a reaction tube. Subsequently, the reaction was stirred and heated to 40 °C using an oil bath and reacted for 3 hours. After the reaction, it was cooled to room temperature. Then, 3 ml of acetic acid and 162 mg (2.5 mmol) of zinc granules were successively added to the reaction tube. Again, the reaction was stirred and heated to 90 °C using an oil bath and reacted for 9 hours. After the reaction, it was cooled to room temperature, and extracted three times with ethyl acetate and water. The combined organic phases were concentrated under reduced pressure to remove the solvent. The crude product was separated by column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether with a volume ratio of 3:7) to obtain 46.9 mg of ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylate, with a yield of 41%.

[0072] Comparative Example 3

[0073] In this comparative example, acetonitrile was used as the reaction solvent. Specifically:

[0074] 74.5 mg (0.5 mmol) of β-nitrostyrene, 111 mg (0.75 mmol) of ethyl 2-fluoroacetoacetate, 244 mg (0.75 mmol) of cesium carbonate and 3 ml of acetonitrile were successively added to a reaction tube. Subsequently, the reaction was stirred and heated to 40 °C using an oil bath and reacted for 3 hours. After the reaction was completed, it was cooled to room temperature. 3 ml of acetic acid and 162 mg (2.5 mmol) of zinc granules were successively added to the reaction tube, and the reaction was stirred and heated to 90 °C again using an oil bath and reacted for 9 hours. After the reaction was completed, it was cooled to room temperature, and extracted three times with ethyl acetate and water. The combined organic phases were concentrated under reduced pressure to remove the solvent. The crude product was not obtained the corresponding ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylate product via column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether with a volume ratio of 3:7).

Claims

1. A method for synthesizing pyrrole compounds, characterized in that, the specific steps are as follows: Mix a β-nitrostyrene compound, an α-fluoro-β-ketoester compound, cesium carbonate and ethanol, and carry out an addition reaction under an oil bath condition of 40-60 °C. After the reaction is completed, cool to room temperature, and then successively add acetic acid and zinc granules, and carry out a cyclization reaction under an oil bath condition of 60-100 °C. After the reaction is completed, cool to room temperature, extract the reaction solution, distill off the solvent under reduced pressure for the obtained organic phase, and then carry out column chromatography using an eluent to separate and obtain pyrrole compounds.

2. The method according to claim 1, characterized in that, the β-nitrostyrene compound is β-nitrostyrene, p-fluoro-β-nitrostyrene, p-methyl-β-nitrostyrene or (E)-(2-nitroprop-1-en-1-yl)benzene; the α-fluoro-β-ketoester compound is ethyl 2-fluoroacetoacetate, ethyl 2,4,4,4-tetrafluoro-3-oxobutyrate or benzyl 2-fluoro-3-oxobutyrate; the pyrrole compound is ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylate, ethyl 4-(4-fluorophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate, benzyl 4-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylate, ethyl 4-(p-tolyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate or ethyl 2,5-dimethyl-4-phenyl-1H-pyrrole-3-carboxylate.

3. The method according to claim 1, characterized in that, the molar ratio of the β-nitrostyrene compound to the α-fluoro-β-ketoester compound is 1:1.5 - 1:

2.

4. The method according to claim 1, characterized in that, the molar ratio of the β-nitrostyrene compound to cesium carbonate is 1:1.5 - 1:

2.

5. The method according to claim 1, characterized in that, the addition reaction time is 2 - 4 h.

6. The method according to claim 1, characterized in that, the cyclization reaction time is 6 - 12 h.

7. The method according to claim 1, characterized in that, the addition reaction time is 3 h and the cyclization reaction time is 9 h.

8. The method according to claim 1, characterized in that, the extraction solvent is a mixed solution of ethyl acetate and water with a volume ratio of 1:

1.

9. The method according to claim 1, characterized in that, the eluent is a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 3:7.

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