3,3-Diaryl-phenyl acrylate derivatives and their synthesis methods

Abstract

The present invention discloses a 3,3-diaryl-phenyl acrylate derivative and a synthesis method thereof. Using o-bromostilbene as a raw material, under the catalysis of a palladium salt, a coupling reaction is carried out with phenyl formate to stereospecifically synthesize a series of 3,3-diaryl-phenyl acrylate derivatives with different structures, and the product can be further converted into the (Z)-Tamoxifen drug molecule. This method has easily available raw materials, simple operation, mild reaction conditions, and the functional groups have diversity.

Description

Technical Field

[0001] The present invention belongs to the field of synthesis of multi-substituted α,β-unsaturated acyl compounds, and particularly relates to a method for palladium-catalyzed stereospecific preparation of α,β-unsaturated ester compounds, namely 3,3-diaryl-acrylic acid phenyl ester derivatives. Background Art

[0002] Multi-substituted α,β-unsaturated acyl compounds, as a common organic compound in nature, have an important position in the fields of bioactive molecules and the like. For example, Rofecoxib with anti-inflammatory effects, Isodispar B as an HIV transcription inhibitor, Glycitein with anti-cancer effects, Himanimide that inhibits LPS-induced macrophage factor IL-6, Isotretinoin for treating severe acne, and the fungicide Flumorph all contain an α,β-unsaturated acyl skeleton. In addition, multi-substituted α,β-unsaturated acyl compounds have received extensive attention as synthetic intermediates. For example, they are used to construct the analgesic drug Tapentadol, the anti-breast cancer drug (Z)-Tamoxifen, and the stimulant LY500307 that stimulates ERβ through multiple steps such as reduction, and to construct cytotoxic lactone compounds through cyclization. Therefore, developing efficient and convenient methods for stereoselectively constructing multi-substituted α,β-unsaturated acyl compounds has important research significance.

[0003] Currently, the methods for constructing multi-substituted α,β-unsaturated acyl compounds mainly include elimination reactions of alcohols or halogenated hydrocarbons, oxidative dehydrogenation reactions, Wittig reactions, and alkynyl difunctionalization. However, these synthetic methods still have problems such as poor regioselectivity and stereoselectivity, which limit the generality of substrates. Therefore, the efficient, highly regioselective, and stereoselective synthesis of multi-substituted α,β-unsaturated acyl compounds remains a challenging task in organic synthesis. With the continuous development of C-H activation, the transition-metal-catalyzed C-H functionalization reaction of alkenyl groups to construct multi-substituted α,β-unsaturated acyl compounds is undoubtedly one of the simplest and most efficient approaches. Currently, the transition-metal-catalyzed C-H functionalization reaction of alkenyl groups to construct multi-substituted α,β-unsaturated acyl compounds can be mainly divided into two categories: 1) Using α,β-unsaturated acyl as the backbone to achieve C-H functionalization of alkenyl groups (Asian J. Org. Chem. 2020, 9, 480-491), but due to the influence of the steric hindrance and electronic properties of the substrates, its reactivity is low, and it is usually difficult to directly transform; 2) Through the transition-metal-catalyzed direct C-H acylation reaction of alkenes (ACS Catal. 2019, 9, 8128-8135; Org. Lett. 2016, 18, 5960-5963; Chem. Commun. 2014, 50, 12867-12869), but when the substrate does not contain a directing group, the stereoselectivity of the alkene cannot be controlled. In recent years, the stereoselective synthesis of multi-substituted alkenes has been achieved through the 1,4-palladium migration from aryl to alkenyl (J. Am. Chem. Soc. 2016, 138, 2897; Angew. Chem. Ed. Int. 2018, 57, 5871), but only reactions such as C-H borylation and alkenylation of alkenes have been realized, and the C-H carbonylation of alkenes using this strategy has not been reported yet. Summary of the Invention

[0004] The object of the present invention is to use o-bromostilbene 2 as a raw material to carry out a coupling reaction with phenyl formate 3 to achieve the construction of a C–C bond and stereospecifically and selectively synthesize multi-substituted α,β-unsaturated acyl compound 1. The present invention uses o-bromostilbene as a raw material and, under the catalysis of a palladium salt, undergoes a coupling reaction with phenyl formate to stereospecifically synthesize a series of 3,3-diaryl-phenyl acrylate derivatives with different structures, and the products can be further transformed into the (Z)-Tamoxifen drug molecule.

[0005] In order to achieve the above object, the technical solution of the present invention is as follows:

[0006] On the one hand, the present invention provides a 3,3-diaryl-phenyl acrylate derivative, and its molecular structural formula 1 is as follows:

[0007]

[0008] R 1 is methyl, methoxy, fluoro, chloro, trifluoromethyl, ethoxycarbonyl, nitro, cyano;

[0009] R 2 is methyl, methoxy, fluoro, trifluoromethyl, ethoxycarbonyl, nitro, cyano.

[0010] On the other hand, the present invention provides a method for synthesizing the above-mentioned 3,3-diaryl acrylate derivatives. Using a palladium salt as a catalyst, adding a solvent and an additive, and carrying out a coupling reaction of o-bromostilbene 2 and phenyl formate 3 under heating conditions to form 3,3-diaryl acrylate derivatives 1 (Reaction Scheme (1)). After the reaction is completed, the product is separated and characterized by conventional separation and purification methods to obtain the target product.

[0011]

[0012] The substituents R 1 and R 2 of o-bromostilbene 2 are the same as those described above: R 1 is methyl, methoxy, fluoro, chloro, trifluoromethyl, ethoxycarbonyl, nitro, cyano; R 2 is methyl, methoxy, fluoro, trifluoromethyl, ethoxycarbonyl, nitro, cyano;

[0013] Based on the above technical solutions, preferably, the catalyst is one of PdCl2, Pd(OAc)2, Pd(CF3CO2)2 or Pd(PPh3)2Cl2; among them, the reaction has the best effect when Pd(CF3CO2)2 is used as the catalyst, and the molar ratio of o-bromostilbene 2 to the catalyst is 1:0.01 - 1:0.1, preferably 1:0.1.

[0014] Based on the above technical solutions, preferably, the additive is one or more of cesium carbonate, sodium tert-butoxide, phenol, p-cresol, o-fluorophenol, sodium phenoxide; the reaction has the best effect when the reaction additive is sodium tert-butoxide.

[0015] Based on the above technical solutions, preferably, the solvent is one or more of 1,4-dioxane, dimethyl sulfoxide, acetonitrile, toluene, methanol, N,N-dimethylformamide or tetrahydrofuran; the reaction has the best effect when the reaction solvent is toluene.

[0016] Based on the above technical solutions, preferably, the reaction temperature is 25 - 130 °C; the reaction time is 6 - 48 hours, and the best reaction time is 12 - 24 hours; the optimal reaction temperature is 110 °C.

[0017] Based on the above technical solutions, preferably, the molar ratio of o-bromostilbene 2 to phenyl formate 3 is 1:1 - 1:3, and more preferably 1:2.

[0018] In the present invention, o-bromostilbene is used as a raw material, and undergoes a coupling reaction with phenyl formate under the catalysis of a palladium salt to stereospecifically synthesize a series of 3,3-diaryl-phenyl acrylate derivatives with different structures. The products can be further transformed into the (Z)-Tamoxifen drug molecule. Compared with the existing synthesis methods of polysubstituted alkene derivatives, the raw materials of the present invention are easily available, the operation is simple, and the reaction can stereospecifically construct polysubstituted α,β-unsaturated acyl compounds.

[0019] Beneficial effects

[0020] 1) The synthon o-bromostilbene 2 is easy to prepare in large quantities and can be used to synthesize different types and structures of 1,1-diaryl-2-oxoethylene derivatives 1.

[0021] 2) The olefin C-H bond acylation reaction has mild conditions, simple operation, high yield of the target product, wide substrate scope, high atom economy, and can stereoselectively synthesize polysubstituted α,β-unsaturated acyl compounds.

[0022] 3) No external oxidant or reductant needs to be added in the olefin C-H bond acylation reaction.

[0023] 4) The present invention can quickly, efficiently and conveniently synthesize the (Z)-Tamoxifen drug molecule. Specific embodiments

[0024] All the chemical reagents used are commercially available and are used directly without further treatment; o-bromostilbene 2 is synthesized according to the method reported in the literature (J. Am. Chem. Soc. 2016, 138, 2897)

[0025] The present invention uses simple o-bromostilbene 2 and phenyl formate 3 as raw materials and undergoes a cross-coupling reaction under the action of a palladium salt (Reaction Scheme 1).

[0026]

[0027] The specific process is as follows: Weigh 2-(2-bromovinyl)biphenyl (0.3 mmol), palladium salt (0.03 mmol), phenyl formate 3 (0.6 mmol), and sodium tert-butoxide (0.36 mmol) in a glove box and add them to a 25 mL flask with a side arm. Then add toluene (3 mL) under a nitrogen atmosphere and react at 110 °C for 24 h. After the reaction is complete, cool to room temperature and directly perform silica gel column chromatography (the eluent is petroleum ether (60 - 90 °C) / ethyl acetate: 10:1, v / v) to obtain the target product 1. The target product is confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0028] The following examples are helpful for further understanding of the present invention, but the content of the present invention is not limited thereto.

[0029] Example 1

[0030]

[0031] The specific process is as follows: Weigh 2-(2-bromovinyl)biphenyl 2b (82 mg, 0.3 mmol), Pd(CF3CO2)2 (10 mg, 0.03 mmol), 1,2-bis(diphenylphosphino)benzene (14 mg, 0.03 mmol), phenyl formate 3a (74 mg, 0.6 mmol), and sodium tert-butoxide (34.6 mg, 0.36 mmol) in a glove box and add them to a 25 mL flask with a side arm. Then add toluene (3 mL) under a nitrogen atmosphere and react at 110 °C for 12 h. After the reaction is complete, directly perform column chromatography (petroleum ether (60 - 90 °C) / ethyl acetate: 10:1, v / v) to obtain the white solid product 1b (86 mg, yield 91%). The target product is confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0032] Example 2

[0033]

[0034] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that the 2-(2-bromovinyl)biphenyl added to the reaction system is 3b (88 mg, 0.3 mmol). Stop the reaction and obtain the white solid target product 1b (93 mg, yield 91%) after post-treatment. The target product is confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0035] Example 3

[0036]

[0037] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that the o-bromostilbene added to the reaction system is 2d (87 mg, 0.3 mmol). The reaction was stopped, and after post-treatment, the target product 1d (88 mg, yield 89%) was obtained as a pale yellow solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0038] Example 4

[0039]

[0040] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that the o-bromostilbene added to the reaction system is 2e (83 mg, 0.3 mmol). The reaction was stopped, and after post-treatment, the target product 1e (83 mg, yield 87%) was obtained as a white solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0041] Example 5

[0042]

[0043] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that the o-bromostilbene added to the reaction system is 2f (82 mg, 0.3 mmol). The reaction was stopped, and after post-treatment, the target product 1f (92 mg, yield 95%) was obtained as a white solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0044] Example 6

[0045]

[0046] The reaction steps and operations are the same as those in Example 1. The difference from Example 1 is that the o-bromostilbene added to the reaction system is 2g (88 mg, 0.3 mmol). The reaction was stopped, and after post-treatment, the target product 1g (95 mg, yield 92%) was obtained as a white solid. The target product was confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0047] Application Example 7

[0048] The present invention can rapidly, efficiently, and conveniently synthesize the (Z)-Tamoxifen drug molecule, which is currently a drug used clinically for the prevention and treatment of breast cancer.

[0049]

[0050] The specific process is as follows: 1d (3.3 g, 10 mmol) was added to a reaction flask and dissolved in 100 mL of ultradry DCM. The reaction flask was placed at -78 °C and 27 mL of DIBAL-H (40 mmol) was added dropwise. The reaction was carried out under N2 protection for 1 h. After the reaction was complete, column chromatography (petroleum ether (60 - 90 °C) / ethyl acetate: 10:1, v / v) was directly carried out to obtain a pale yellow solid product 4 (2.1 g, yield 87%). 4 (2.1 g, 8.7 mmol) was placed in a reaction flask, arylboronic acid (4.0 equiv), potassium fluoride (4.0 equiv), Pd(OAc)2 (0.05 equiv) were added, and it was dissolved in propionic acid. The mixture was stirred in an oxygen-sealed tube at 40 °C for 24 h. After the reaction was complete, column chromatography (petroleum ether (60 - 90 °C) / ethyl acetate: 10:1, v / v) was directly carried out to obtain a pale yellow solid product 5 (2.2 g, yield 80%). 5 (2.2 g, 7 mmol) was placed in a reaction flask, then manganese dioxide and anhydrous dichloromethane were added and stirred at room temperature for 0.5 h. After the reaction was completed, it was filtered, and the solvent was removed by rotary evaporation under reduced pressure. The mixture and NaH (1.3 equiv) were added to the reaction flask, then methylphosphonium bromide (1.00 equiv) and THF were added under nitrogen. The solution was refluxed for 2 h, and the suspension was stirred at room temperature for 2 h. After the reaction was completed, it was filtered, and the solvent was removed by rotary evaporation under reduced pressure. A solution of palladium on activated carbon in ethyl acetate was added and stirred at room temperature under a hydrogen atmosphere for 2 h. The catalyst was filtered out and the volatiles were removed under reduced pressure to obtain product 8 (1.9 g, yield 86%). 8 (1.9 g, 6.0 mmol) was added dropwise with boron tribromide at -60 °C to obtain the demethylated product. Na2CO3 (2.0 equiv) was added to the DMF system and reacted for 12 h. The product (Z)-Tamoxifen as a white solid was obtained by column chromatography purification (1.9 g, yield 85%).

[0051] Characterization data of typical compounds

[0052] 3,3-Diaryl-acrylic acid phenyl ester derivative (1b), white solid. 1 H NMR (400 MHz, CDCl3) δ 7.35–7.38 (m, 3H), 7.30–7.23 (m, 6H), 7.16 (dd, J = 8.0, 2.3 Hz, 3H), 6.98 (d, J = 8.0 Hz, 2H), 6.55 (s, 1H), 2.37 (s, 3H); 1313C NMR (101 MHz, CDCl3) δ 164.5, 158.9, 150.8, 140.3, 138.9, 137.9, 129.34 (2C), 129.31 (3C), 128.6 (2C), 128.4, 128.1 (2C), 125.6, 121.7 (2C), 115.5, 21.4. C 22 H 18 HRMS theoretical value of O2 ([M + H] + ): 315.1385; Measured value: 315.1376.

[0053] 3,3 - Diarylacrylic acid phenyl ester derivative (1c), white solid. 1 1H NMR (600 MHz, CDCl3) δ 7.39 (dd, J = 5.2, 1.9 Hz, 3H), 7.35–7.29 (m, 6H), 7.28–7.25 (m, 2H), 7.16 (m, 1H), 7.00–6.94 (m, 2H), 6.55 (s, 1H). 13 13C NMR (101 MHz, CDCl3) δ 164.1, 157.3, 150.5, 139.1, 138.1, 136.0, 129.7 (2C), 129.25 (2C), 129.17 (2C), 128.75 (2C), 128.66, 128.1 (2C), 125.6, 121.5 (2C), 116.7. C 21 H 15 HRMS theoretical value of ClO2 ([M + H] + ): 335.0839; Measured value: 335.0832.

[0054] 3,3 - Diarylacrylic acid phenyl ester derivative (1d), light yellow solid. 1 1H NMR (400 MHz, CDCl3) δ 7.41–7.35 (m, 3H), 7.34–7.26 (m, 5H), 7.25 (d, J = 2.0 Hz, 1H), 7.17–7.11 (m, 1H), 7.01–6.96 (m, 2H), 6.91–6.84 (m, 2H), 6.52 (s, 1H), 3.83 (s, 3H). 13 13C NMR (151 MHz, CDCl3) δ 164.5, 161.1, 158.6, 150.7, 138.9, 132.9, 130.0 (2C), 129.19 (2C), 129.16 (2C), 128.3, 128.0 (2C), 125.4, 121.6 (2C), 114.1, 113.9 (2C). C 22 ​18 Theoretical HRMS value of O3 ([M+H] + ): 331.1334; Measured value: 331.1327.

[0055] 3,3-Diaryl acrylate phenyl ester derivative (1e), white solid. 1 H NMR (400 MHz, CDCl3) δ 7.42–7.38 (m, 1H), 7.37–7.29 (m, 6H), 7.28–7.24 (m, 2H), 7.20–7.14 (m, 1H), 7.11–7.04 (m, 2H), 7.03–7.00 (m, 2H), 6.57 (s, 1H). 13 C NMR (101 MHz, CDCl3) δ 164.3, 163.0 (d, CF, 1 J C-F = 248.0 Hz), 158.1, 150.6, 140.7, 134.4 (d, CF, 4 J C-F = 3.5 Hz), 131.3 (d, CF, 3 J C-F = 8.1 Hz), 130.1, 129.4 (2C), 128.7 (2C), 128.6 (2C), 125.8, 121.6 (2C), 116.6, 115.2 (d, CF, 2 J C-F = 21.7 Hz). C 21 H 15 Theoretical HRMS value of O2 ([M+H] + ): 319.1134; Measured value: 319.1128.

[0056] 3,3-Diaryl acrylate phenyl ester derivative (1f), white solid. 1 H NMR (400 MHz, CDCl3) δ 7.36–7.21 (m, 11H), 7.18 (m, 2H), 7.04 (d, J = 7.9 Hz, 2H), 6.22 (s, 1H), 2.10 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 164.6, 159.4, 150.7, 141.9, 138.6, 136.2, 130.9, 129.7, 129.5 (2C), 129.4 (2C), 128.9, 128.8, 128.0 (2C), 125.9, 125.8, 121.7 (2C), 119.1, 20.5. C 22 H 18 Theoretical HRMS value of O2 ([M+H]+ ): 315.1385; Measured value: 315.1376.

[0057] 3,3 - diaryl - phenyl acrylate derivative (1 g), white solid. 1 H NMR (400 MHz, CDCl3) δ 7.39–7.33 (m, 2H), 7.33–7.26 (m, 4H), 7.24–7.18 (m, 3H), 7.14–7.08 (m, 2H), 7.08–7.03 (m, 2H), 6.60 (s, 1H), 2.43 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 164.4, 162.9 (d, CF, 1 J C-F =247.8 Hz), 158.2, 150.7, 140.5, 137.8, 134.6 (d, CF, 4 J C-F =3.5 Hz), 131.3 (d, CF, 3 J C-F =8.2 Hz), 129.4 (2C) (d, J=1.2 Hz), 128.6 (2C), 125.7, 121.6 (2C), 115.6, 115.1 (d, 2 J C-F =21.6 Hz), 21.4. C 22 H 18 HRMS theoretical value of H + O2 ([M + H]

[0058] (Z) - Tamoxifen, white solid. 1 H NMR (300 MHz, CDCl3,) δ 7.42–7.37 (m, 2H), 7.33–7.28 (m, 3H), 7.22–7.16 (m, 5H), 6.82 (d, J=8.5 Hz, 2H,), 6.61 (d, J=8.5 Hz, 2H), 3.98 (t, J=5.8 Hz, 2H), 2.69 (t, J=5.8 Hz, 2H), 2.51 (q, J=7.4 Hz, 2H), 2.34 (s, 6H), 0.98 (t, J=7.4 Hz, 3H). 1313C NMR (75 MHz, CDCl3) δ 156.8, 143.9, 142.5, 141.3, 138.3, 135.6, 131.9, 129.7, 129.5, 128.1, 127.9, 126.5, 126.0, 113.5, 65.8, 58.3, 45.8, 29.0, 13.6. C 26 H 29 HRMS calculated for NO ([M + H] + ): 372.2372; found: 372.2384.

Claims

1. A synthesis method of 1b, characterized in that: Weigh 2b 82 mg, 0.3 mmol, Pd(CF3CO2)2 10 mg, 0.03 mmol, 1,2-bis(diphenylphosphino)benzene 14 mg, 0.03 mmol, 3a 74 mg, 0.6 mmol, and sodium tert-butoxide 34.6 mg, 0.36 mmol in a glove box and add them to a 25 mL round-bottom flask equipped with a side arm. Then add 3 mL of toluene under a nitrogen atmosphere and react at 110 °C for 12 h. After the reaction is complete, perform column chromatography directly with petroleum ether (60 - 90 °C) / ethyl acetate: 10:1, v / v to obtain the white solid product 1b; The synthetic route is as follows: .

2. A synthesis method of 1c, characterized in that: Weigh 2c 88 mg, 0.3 mmol, Pd(CF3CO2)2 10 mg, 0.03 mmol, 1,2-bis(diphenylphosphino)benzene 14 mg, 0.03 mmol, 3a 74 mg, 0.6 mmol, and sodium tert-butoxide 34.6 mg, 0.36 mmol in a glove box and add them to a 25 mL round-bottom flask equipped with a side arm. Then add 3 mL of toluene under a nitrogen atmosphere and react at 110 °C for 12 h. After the reaction is complete, perform column chromatography directly with petroleum ether (60 - 90 °C) / ethyl acetate: 10:1, v / v to obtain the white solid product 1c; The synthetic route is as follows: .

3. A synthesis method for 1D, characterized in that: Weigh 2d 87 mg, 0.3 mmol, Pd(CF3CO2)2 10 mg, 0.03 mmol, 1,2-bis(diphenylphosphino)benzene 14 mg, 0.03 mmol, 3a 74 mg, 0.6 mmol, and sodium tert-butoxide 34.6 mg, 0.36 mmol in a glove box and add them to a 25 mL round-bottom flask equipped with a side arm. Then add 3 mL of toluene under a nitrogen atmosphere and react at 110 °C for 12 h. After the reaction is complete, perform column chromatography directly with petroleum ether (60 - 90 °C) / ethyl acetate: 10:1, v / v to obtain the pale yellow solid product 1d; The synthetic route is as follows: .

4. A synthesis method of 1e, characterized in that: Weigh 2e 83 mg, 0.3 mmol, Pd(CF3CO2)2 10 mg, 0.03 mmol, 1,2-bis(diphenylphosphino)benzene 14 mg, 0.03 mmol, 3a 74 mg, 0.6 mmol, and sodium tert-butoxide 34.6 mg, 0.36 mmol in a glove box and add them to a 25 mL round-bottom flask equipped with a side arm. Then add 3 mL of toluene under a nitrogen atmosphere and react at 110 °C for 12 h. After the reaction is complete, perform column chromatography directly with petroleum ether (60 - 90 °C) / ethyl acetate: 10:1, v / v to obtain the white solid product 1e; The synthetic route is as follows: .

5. A synthesis method of 1f, characterized in that: Weigh 2f 82 mg, 0.3 mmol, Pd(CF3CO2)2 10 mg, 0.03 mmol, 1,2-bis(diphenylphosphino)benzene 14 mg, 0.03 mmol, 3a 74 mg, 0.6 mmol, and sodium tert-butoxide 34.6 mg, 0.36 mmol in a glove box and add them to a 25 mL round-bottom flask equipped with a side arm. Then add 3 mL of toluene under a nitrogen atmosphere and react at 110 °C for 12 h. After the reaction is complete, perform column chromatography directly with petroleum ether (60 - 90 °C) / ethyl acetate: 10:1, v / v to obtain the white solid product 1f; The synthetic route is as follows: .

6. A synthesis method of 1g, characterized in that: Weigh 2 g 88 mg, 0.3 mmol, 10 mg, 0.03 mmol of Pd(CF3CO2)2, 14 mg, 0.03 mmol of 1,2-bis(diphenylphosphino)benzene, 74 mg, 0.6 mmol of 3a, and 34.6 mg, 0.36 mmol of sodium tert-butoxide in a glove box and add them to a 25 mL flask with a side arm. Under a nitrogen atmosphere, add 3 mL of toluene and react at 110 °C for 12 h. After the reaction is complete, perform column chromatography directly with petroleum ether (60 - 90 °C) / ethyl acetate: 10:1, v / v to obtain 1 g of a white solid product. The synthetic route is as follows: .

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