Novel synthesis method of 4-arylpyridine derivative

Abstract

The invention discloses a novel synthesis method of a 4-aryl pyridine derivative. According to the method, in an organic solvent system, a 4-pyridyl phosphine salt derivative and an aryl alkoxy silane compound are used as raw materials, palladium salt is used as a catalyst, under the action of an activating agent and a phosphine ligand, heating reflux is performed under the stirring condition, reaction liquid is subjected to aftertreatment, and the 4-arylated pyridine derivative is obtained. The raw materials involved in the invention can be directly purchased or simply prepared, the post-treatment process flow is simple to operate, the risk of environmental pollution is avoided, and the product is easy to separate and purify. Related products can be provided for biological, medical and photoelectric functional materials and the like, and wide application value is achieved.

Description

Technical Field

[0001] This invention belongs to the field of organic synthetic chemistry technology, and relates to a new method for synthesizing 4-arylpyridine derivatives. Background Technology

[0002] 4-Arylpyridine is an important structural unit cell, widely found in many pharmaceuticals, pesticides, natural products, and bioactive molecules. Therefore, developing simple, efficient, and highly selective methods for synthesizing 4-arylpyridine derivatives has always been a crucial research topic in synthetic chemistry. Currently reported catalytic reaction systems have many drawbacks, such as narrow substrate scope, harsh reaction conditions, relatively excessive additives, and low yields, lacking practical application value. Therefore, developing a novel, green, efficient, and practical method for synthesizing 4-arylpyridine derivatives is of significant value. 4-Pyridylphosphine salts and phenylalkoxysilanes are two common raw materials widely used in organic synthesis. Therefore, screening suitable metal catalytic systems to develop novel coupling reactions involving 4-pyridylphosphine salts and phenylalkoxysilanes has significant research value and broad application prospects.

[0003] Palladium-catalyzed organic synthesis reactions are a hot topic in organic chemistry research. Various palladium-catalyzed organic synthesis reactions have been reported, such as carbon-carbon coupling reactions, carbon-heteroatom coupling reactions, intramolecular reactions, and multicomponent reactions. The coupling reaction between 4-pyridylphosphine salts and phenylalkoxysilanes under palladium catalysis exhibits advantages such as high catalytic efficiency, mild reaction conditions, and high selectivity, making it particularly suitable for industrial production. This type of reaction also boasts advantages such as simple operation and readily available raw materials. Summary of the Invention

[0004] The purpose of this invention is to provide a novel method for the synthesis of 4-arylpyridine derivatives. A series of functionalized 4-arylpyridine derivatives were prepared by coupling reaction between 4-pyridylphosphine salt derivatives and arylalkoxysilanes under palladium salt catalysis. The objective of this invention is to construct various functionalized 4-arylpyridine derivatives by reacting simple and easily prepared 4-pyridylphosphine salt derivatives with arylalkoxysilanes, thus enriching the synthetic methods for this type of skeletal compound. Simultaneously, it provides a new method for the efficient and precise synthesis of 4-arylpyridine compounds.

[0005] To achieve the above and other related objectives, the technical solution provided by the present invention is as follows: 1. A novel method for synthesizing 4-arylpyridine derivatives, characterized in that, in an organic solvent system, 4-pyridylphosphine salt derivatives and arylalkoxysilane compounds are used as raw materials, palladium salt is used as a catalyst, and under the action of an activator and a phosphine ligand, the mixture is heated to reflux under stirring conditions. After post-treatment, the reaction solution yields 4-arylpyridine derivatives.

[0006] The organic solvent is at least one of ethanol, tert-butanol, tetrahydrofuran, N,N-dimethylformamide and 1,4-dioxane;

[0007] The palladium salt is at least one of tetra(triphenylphosphine)palladium, dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine (II), bis(di-tert-butylphenylphosphine)palladium (II) dichloride, and allyl palladium (II) dimer, and its amount is 5-15 mol% of the 4-pyridylphosphine salt derivative;

[0008] The activator is at least one of tetrabutylammonium fluoride and triethylamine hydrogen fluoride, and its amount is 1-3 times the mass of the 4-pyridylphosphine salt derivative;

[0009] The phosphine ligand is at least one selected from 2-di-tert-butylphosphine-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, 2-bicyclohexylphosphine-2′-methylbiphenyl, 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl, 1,2-bis(diphenylphosphine)ethane, and 1,6-bis(diphenylphosphine)hexane, and its amount is 5-15 mol% of the 4-pyridylphosphine salt derivative;

[0010] The molar ratio of 4-pyridylphosphine salt derivatives to arylalkoxysilane compounds is 1:2-5;

[0011]

[0012] R and R' independently represent hydrogen, aryl, alkyl, alkoxy, ester, cyano, trifluoromethyl, fluorine, and chlorine, and can be monosubstituted, disubstituted, or trisubstituted.

[0013] The preferred technical solution is that the palladium salt is an allyl palladium(II) chloride dimer.

[0014] A preferred technical solution is that the organic solvent is a mixed solvent composed of ethanol and tetrahydrofuran, with a ratio of V... 乙醇 :V 四氢呋喃 =1:1.

[0015] A preferred technical solution is that the amount of organic solvent used is 0.5 mmol / mL of the 4-pyridylphosphine salt derivative.

[0016] The preferred technical solution is to track the reaction by TLC, wherein the developing solvent used for the TLC reaction is petroleum ether: ethyl acetate = 20:1, V / V.

[0017] The preferred technical solution is that the post-treatment method of the reaction solution is as follows: after the reaction is completed, the reaction solution is poured into saturated brine, extracted with dichloromethane, the organic phase is backwashed with saturated brine, dried with anhydrous sodium sulfate, filtered, distilled under reduced pressure, and then separated by silica gel column chromatography. The resulting eluent is distilled under reduced pressure to obtain 4-arylpyridine derivatives.

[0018] The preferred technical solution is that the eluent for the silica gel column chromatography is petroleum ether: ethyl acetate = 20:1, V / V.

[0019] Due to the application of the above technical solution, the advantages of this invention compared with the prior art are:

[0020] This invention features simple operation, readily available raw materials and reagents, a green and environmentally friendly reaction system, and easy separation and purification of products. It is suitable for synthesizing various highly functionalized 4-arylpyridine derivatives, and is particularly suitable for large-scale industrial production. It can efficiently and in high yield produce high-purity 4-arylpyridine compounds. Attached Figure Description

[0021] Figure 1 It is 4-arylpyridine 3a 1 H-NMR spectrum.

[0022] Figure 2 It is 4-arylpyridine 3a 13 C-NMR spectrum.

[0023] Figure 3 4-arylpyridine 3b 1 H-NMR spectrum.

[0024] Figure 4 4-arylpyridine 3b 13 C-NMR spectrum.

[0025] Figure 5 4-arylpyridine 3c 1 H-NMR spectrum.

[0026] Figure 6 4-arylpyridine 3c 13 C-NMR spectrum.

[0027] Figure 7 4-arylpyridine 3d 1 H-NMR spectrum.

[0028] Figure 8 4-arylpyridine 3d13 C-NMR spectrum.

[0029] Figure 9 4-arylpyridine 3e 1 H-NMR spectrum.

[0030] Figure 10 4-arylpyridine 3e 13 C-NMR spectrum.

[0031] Figure 11 It is 4-arylpyridine 4b 1 H-NMR spectrum.

[0032] Figure 12 It is 4-arylpyridine 4b 13 C-NMR spectrum.

[0033] Figure 13 It is 4-arylpyridine 4b 19 F-NMR spectrum.

[0034] Figure 14 It is 4-arylpyridine 4c 1 H-NMR spectrum.

[0035] Figure 15 It is 4-arylpyridine 4c 13 C-NMR spectrum.

[0036] Figure 16 4-arylpyridine 4d 1 H-NMR spectrum.

[0037] Figure 17 4-arylpyridine 4d 13 C-NMR spectrum.

[0038] Figure 18 It is 4-arylpyridine 4e 1 H-NMR spectrum.

[0039] Figure 19 It is 4-arylpyridine 4e 13 C-NMR spectrum.

[0040] Figure 20 4-arylpyridine 4f 1 H-NMR spectrum.

[0041] Figure 21 4-arylpyridine 4f 13 C-NMR spectrum.

[0042] Figure 22 This is the reaction equation for the present invention. Detailed Implementation

[0043] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification.

[0044] Please see Figure 1-22 It should be understood that the structures, proportions, sizes, etc., illustrated in the accompanying drawings are merely for illustrative purposes to aid those skilled in the art and to facilitate understanding and reading. They are not intended to limit the scope of the invention and therefore have no substantial technical significance. Any modifications to the structure, changes in proportions, or adjustments to size, without affecting the effectiveness and purpose of the invention, should still fall within the scope of the technical content disclosed in this invention. Furthermore, the terms such as "upper," "lower," "left," "right," "middle," and "one" used in this specification are merely for clarity and not intended to limit the scope of the invention. Changes or adjustments to their relative relationships, without substantially altering the technical content, should also be considered within the scope of the invention's implementation.

[0045] Unless otherwise specified, all reagents or materials described in the following examples are commercially available.

[0046] Example 1: Preparation of 4-arylpyridine derivative 3a:

[0047]

[0048] Anhydrous tetrahydrofuran (1.0 mL), anhydrous ethanol (1.0 mL), 4-pyridylphosphine salt 1a (0.489 g, 1.0 mmol), and phenyltrimethoxysilane 2a (0.594 g, 3.0 mmol) were added to a 35 mL pressure-resistant tube equipped with a magnetic stirrer. Allyl palladium(II) chloride dimer (0.038 g, 0.10 mmol), 2-di-tert-butylphosphine-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (0.048 g, 0.10 mmol), and triethylamine trihydrofluoride (0.323 g, 2.0 mmol) were then added. After thorough mixing, the mixture was placed in an oil bath at 130 °C and stirred for 20 h. Thin-layer chromatography (developing solvent V) was then performed. 石油醚 :V 乙酸乙酯 =20:1) The reaction was complete when the starting material disappeared. The reaction solution was poured into saturated brine (15 mL), extracted with dichloromethane (3 × 10 mL), and the organic phases were combined. The organic phase was backwashed with water (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a viscous solid. Finally, the solid was subjected to silica gel column chromatography (eluent: V). 石油醚 :V 乙酸乙酯=20:1) to obtain a colorless solid, which was identified by NMR as 4-arylpyridine derivative 3a, with a yield of 80%.

[0049] Spectral analysis data 3a:

[0050] White solid 1 H NMR (500MHz, CDCl3) δ8.67 (d, J = 6.2 Hz, 2H), 7.65 (d, J = 7.0 Hz, 2H), 7.53-7.42 (m, 5H). 13 C NMR (126MHz, CDCl3) δ150.14,148.37,138.07,129.10,129.06,126.98,121.65.

[0051] Example 2: A novel method for synthesizing a 4-arylpyridine derivative

[0052] Using 2b instead of 2a in Example 1, with other operating conditions the same as in Example 1, the yield was 65%.

[0053]

[0054] Spectral analysis data 3b:

[0055] White solid 1 H NMR (500MHz, CDCl3) δ8.68(d,J=5.2Hz,2H),7.56-7.51(m,2H),7.44(d,J=8.2Hz,2H),7.38(t,J=7.5Hz,1H),7.29-7.25(m,1H),2.44(s,3H). 13 C NMR (126MHz, CDCl3) δ149.87,149.09,138.83,137.70,129.98,129.01,127.67,124.07,121.86,21.45.

[0056] Example 3: A novel method for synthesizing a 4-arylpyridine derivative

[0057] Using 2c instead of 2a in Example 1, with other operating conditions the same as in Example 1, the yield was 82%.

[0058]

[0059] Spectral analysis data 3c:

[0060] White solid 1H NMR (500MHz, CDCl3) δ8.69-8.63(m,2H),7.49(d,J=4.5Hz,2H),7.39(d,J=8.0Hz ,1H),7.24-7.19(m,1H),7.15(d,J=4.0Hz,1H),7.00-6.96(m,1H),3.87(s,3H). 13 C NMR (126MHz, CDCl3) δ160.03, 150.04, 148.27, 139.40, 130.10, 121.66, 119.30, 114.25, 112.68, 55.27.

[0061] Example 4: A novel method for synthesizing a 4-arylpyridine derivative

[0062] Using 2d instead of 2a in Example 1, with other operating conditions the same as in Example 1, the yield was 68%.

[0063]

[0064] 3D Spectral Analysis Data:

[0065] White solid 1 H NMR (500MHz, CDCl3) δ8.66-8.61(m,2H),7.49(d,J=6.3Hz,2H),7.23(dd,J=8.3, 2.1Hz, 1H), 7.14 (d, J = 2.1Hz, 1H), 6.97 (d, J = 8.3Hz, 1H), 3.95 (d, J = 14.5Hz, 6H). 13 C NMR (126MHz, CDCl3) δ149.89,149.23,148.09,131.92,130.37,128.37,121.11,119.51,111.33,109.63,55.84,55.82.

[0066] Example 5: A novel method for synthesizing a 4-arylpyridine derivative

[0067] Using 2e instead of 2a in Example 1, with other operating conditions the same as in Example 1, the yield was 64%.

[0068]

[0069] Spectral analysis data 3e:

[0070] White solid 1H NMR (500MHz, CDCl3) δ8.61-8.57(m,2H),7.46-7.40(m,2H),7.28(s,2H),3.76(s,3H),2.35(s,6H). 13 C NMR (126MHz, CDCl3) δ157.89,149.87,148.02,133.32,131.58,127.36,121.32,59.67,16.18.

[0071] Example 6: A novel method for synthesizing a 4-arylpyridine derivative

[0072] Preparation of 4-arylpyridine derivative 4b: 1b was used instead of 1a in Example 1, and other operating conditions were the same as in Example 1. The yield was 59%.

[0073]

[0074] Spectral analysis data 4b:

[0075] Pale yellow solid, 1 H NMR (500MHz, CDCl3) δ8.26 (d, J=5.2Hz, 1H), 7.65-7.60 (m, 2H), 7.53-7.45 (m, 3H), 7.40 (dd, J=5.2, 1.9Hz, 1H), 7.13 (s, 1H). 13 C NMR (126MHz, CDCl3) δ164.45 (d, J = 238.1Hz), 154.03 (d, J = 8.2Hz), 147.91 (d, J = 15.4Hz), 136.97(d,J=3.3Hz),129.65,129.19,126.99,119.49(d,J=3.8Hz),107.05(d,J=37.8Hz). 19 F NMR (471MHz, CDCl3) δ-68.21.

[0076] Example 7: A novel method for synthesizing a 4-arylpyridine derivative

[0077] Using 1c instead of 1a in Example 1, with other operating conditions the same as in Example 1, the yield was 70%.

[0078]

[0079] Spectral analysis data 4c:

[0080] White solid 1H NMR (500MHz, CDCl3) δ8.65-8.60(m,2H),7.34(d,J=5.0Hz,1H),7.28-7.23(m,6H),7.17-7.13(m,4H). 13 C NMR (126MHz, CDCl3) δ150.92,148.60,147.64,138.51,137.60,135.70,129.74,129.25,128.20,127.78,127.25,124.54.

[0081] Example 8: A novel method for synthesizing a 4-arylpyridine derivative

[0082] Using 1d instead of 1a in Example 1, with other operating conditions the same as in Example 1, the yield was 55%.

[0083]

[0084] Spectral analysis data 4d:

[0085] Pale yellow solid, 1 H NMR (500MHz, CDCl3) δ8.35 (s, 1H), 7.54 (d, J = 7.2Hz, 2H), 7.47-7.38 (m, 3H), 2.58 (d, J = 13.0Hz, 6H). 13 C NMR (126MHz, CDCl3) δ150.97, 150.76, 150.27, 141.12, 138.64, 128.88, 128.39, 128.29, 22.98, 21.17.

[0086] Example 9: A novel method for synthesizing a 4-arylpyridine derivative

[0087] Using 1e instead of 1a in Example 1, with other operating conditions the same as in Example 1, the yield was 52%.

[0088]

[0089] Spectral analysis data 4e:

[0090] White solid 1 H NMR (500MHz, CDCl3) δ8.77(d,J=5.1Hz,1H),8.36(d,J=1.8Hz,1H),7.70-7.65(m ,3H),7.48(dt,J=13.7,6.8Hz,3H),4.49(t,J=7.2Hz,2H),1.45(t,J=7.1Hz,3H). 13C NMR (126MHz, CDCl3) δ165.29,150.21,149.51,148.70,137.07,129.48,129.17,126.98,124.43,122.97,61.99,14.30.

[0091] Example 10: A novel method for synthesizing a 4-arylpyridine derivative

[0092] Using 1f instead of 1a in Example 1, with other operating conditions the same as in Example 1, the yield was 53%.

[0093]

[0094] Spectral analysis data from 4f:

[0095] White solid 1 H NMR (500MHz, CDCl3) δ8.75(d,J=5.0Hz,1H),8.08-8.05(m,2H),7.94(d,J=1.6Hz,1H),7.73-7.68(m,2H),7.55-7.41(m,7H). 13 C NMR (126MHz, CDCl3) δ158.02,150.04,149.22,139.43,138.45,129.07,129.00,128.98,128.73,127.03,126.99,120.21,118.73.

[0096] Example 11: A novel method for synthesizing a 4-arylpyridine derivative

[0097] A method for preparing multifunctionalized 4-arylpyridine compounds. In this invention, palladium catalysis was used to achieve a cross-coupling reaction between 4-pyridylphosphine salt and phenylalkoxysilane, resulting in the preparation of a series of functionalized 4-arylpyridine compounds.

[0098] The reaction equations for the synthesis of 4-arylpyridine compounds involved in this invention are as follows:

[0099]

[0100] The reaction involves heating a 4-pyridylphosphine salt compound (1) with an aryltrialkoxysilane (2) to 130°C and reacting them in a non-aqueous solvent to obtain a functionalized 4-arylpyridine derivative 3, wherein R and R' are hydrogen, aryl, alkyl, alkoxy, trifluoromethyl, halogen, etc., and can be monosubstituted, disubstituted, or even trisubstituted.

[0101] The method of this invention can efficiently prepare high-purity 4-arylpyridine derivatives. The specific preparation process is as follows:

[0102] At a certain temperature, in a selected solvent, and under the combined action of an activator, phosphine ligand, and a catalyst, functionalized 4-arylpyridine derivatives 3 are synthesized from 4-pyridylphosphine salts and arylalkoxysilanes. The phenylalkoxysilane can be phenyltrimethoxysilane, phenyltriethoxysilane, diphenyldimethoxysilane, or phenyldimethoxymethylsilane, with phenyltrimethoxysilane showing the best reaction performance. Among the 4-pyridylphosphine salts, 4-pyridyltriphenylphosphine trifluoromethanesulfonate shows the best effect.

[0103] The amount of aryltrialkoxysilane 2 is three times that of 4-pyridylphosphine salt 1; the reaction temperature is 120-140℃, with 130℃ being optimal. Solvents selected included ethanol (with or without water), tert-butanol, tetrahydrofuran, N,N-dimethylformamide, and 1,4-dioxane. Mixtures of these solvents were also tested as reaction media, with a 1:1 ethanol / tetrahydrofuran mixture proving optimal. Activators screened included cesium fluoride, potassium fluoride, copper fluoride, silver fluoride, tetrabutylammonium fluoride, and triethylamine hydrogen fluoride. Triethylamine hydrogen fluoride showed the best activation effect, with an amount 1-5 times that of 4-pyridylphosphine salt 1, and 2.0 equivalents yielding the best activation. Phosphine ligands screened included S-(+)-1,1'-binaphthyl-2,2'-diphenylphosphine, (S)-(-)-5,5-bis(diphenylphosphino)-4,4-bis-1,3-benzodioxane, and 2-di-tert-butylphosphine-3,4,5,6- Tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, 2-bicyclohexylphosphine-2′-methylbiphenyl, 2,2′-bis(diphenylphosphine)-1,1′-naphthyl, 1,2-bis(diphenylphosphine)ethane, and 1,6-bis(diphenylphosphine)hexane were selected. Among them, 2-di-tert-butylphosphine-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl showed the best performance, with an amount of 10 mol%. The catalysts screened were palladium acetate, palladium chloride, palladium trimethylacetate, dichloro[1,1′-di(diphenylphosphine)ferrocene]palladium, bistriphenylphosphine dichloride, dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II), palladium trifluoroacetate, palladium acetylacetonate, and allyl palladium(II) dimer. It was found that allyl palladium(II) chloride dimer can be used to efficiently prepare functionalized 4-arylpyridine derivative 3, with an amount of 10 mol%.

[0104] The above description is merely a preferred embodiment for explaining the present invention and is not intended to limit the present invention in any way. Therefore, any modifications or changes made to the present invention under the same inventive spirit should still be included within the scope of protection intended by the present invention.

Claims

1. A novel method for synthesizing 4-arylpyridine derivatives, characterized in that: In an organic solvent system, a 4-pyridylphosphine salt derivative and an aryl alkoxysilane compound are used as raw materials, a palladium salt is used as a catalyst, and under the action of an activator and a phosphine ligand, the mixture is heated under stirring and refluxed, and the reaction solution is post-treated to obtain a 4-arylated pyridine derivative; Wherein, the organic solvent is at least one of ethanol, tert-butyl alcohol, tetrahydrofuran, N,N-dimethylformamide and 1,4-dioxane; The palladium salt is at least one of tetrakis(triphenylphosphine)palladium, dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II), bis(di-tert-butylphenylphosphine)palladium(II) dichloride and allylpalladium(II) chloride dimer, and the amount thereof is 5-15 mol% of the 4-pyridylphosphine salt derivative; The activator is at least one of tetrabutylammonium fluoride and triethylamine hydrogen fluoride, and its amount is 1-3 times the mass of the 4-pyridylphosphonium salt derivative; The phosphine ligand is at least one of 2-di-tert-butylphosphine-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl, 2-dicyclohexylphosphine-2′-methylbiphenyl, 2,2′-bis(diphenylphosphine)-1,1′-binaphthyl, 1,2-bis(diphenylphosphine)ethane and 1,6-bis(diphenylphosphine)hexane, and the amount thereof is 5-15 mol% of the 4-pyridylphosphine salt derivative; The molar ratio of the 4-pyridylphosphonium salt derivative and the aryl alkoxysilane compound is 1:2-5; R and R' independently represent hydrogen, aryl, alkyl, alkoxy, ester, cyano, trifluoromethyl, fluorine, chlorine, and are monosubstituted, disubstituted or trisubstituted.

2. A novel method for synthesizing a 4-arylpyridine derivative according to claim 1, characterized in that: The palladium salt is allylpalladium (II) chloride dimer.

3. The novel method for synthesizing a 4-arylpyridine derivative according to claim 1, characterized in that: The organic solvent is a mixed solvent formed by mixing ethanol and tetrahydrofuran, the ratio of which is V 乙醇 :V 四氢呋喃 =1:

1.

4. The novel method for synthesizing a 4-arylpyridine derivative according to claim 1, characterized in that: The amount of the organic solvent used is 0.5 mmol / mL of the 4-pyridylphosphonium salt derivative.

5. The novel method for synthesizing a 4-arylpyridine derivative according to claim 1, characterized in that: The reaction was tracked by TLC. The developing solvent used for TLC tracking was petroleum ether:ethyl acetate = 20:1, V / V.

6. The novel method for synthesizing a 4-arylpyridine derivative according to claim 1, characterized in that: The post-treatment method of the reaction solution is: after the reaction is completed, the reaction solution is poured into saturated brine, extracted with dichloromethane, the organic phase is backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, and then separated by silica gel column chromatography, and the obtained eluent is distilled under reduced pressure to obtain a 4-arylated pyridine derivative.

7. A novel method for synthesizing 4-arylpyridine derivatives according to claim 6, characterized in that: The eluent of the silica gel column chromatography is petroleum ether:ethyl acetate=20:1, V / V.

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