Method for preparing N, N-difluorobenzenesulfonamide compound under fluorine-free gas condition

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing an N, N-difluorobenzenesulfonamide compound under a fluorine-free gas condition. The method comprises the following steps: by taking a benzenesulfonamide compound as an initiator, preparing N-chlorobenzenesulfonamide sodium salt from the benzenesulfonamide compound by using tert-butyl hypochlorite, generating N-fluoro-N-chlorobenzenesulfonamide by using Selectfluor oxidation, and selectively reducing the N-fluoro-N-chlorobenzenesulfonamide into N-fluorobenzenesulfonamide by using sodium borohydride, thereby obtaining the N-fluorobenzenesulfonamide. And finally, carrying out fluorination by using a Selectfluor reagent, so as to generate the target product N, N-difluorobenzenesulfonamide. The method does not need to use highly toxic fluorine gas, the synthesis condition is mild, the separation condition is simple, and the yield is high.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing N,N-difluorobenzenesulfonamide compounds under fluorine-free conditions. Background Technology

[0002] N,N-difluorobenzenesulfonamides, as novel multifunctional reagents, can serve as both electrophilic fluorine sources and nitrogen radicals for use as radical amination agents, showing great promise in organic synthesis. However, the current lack of effective synthetic methods severely limits their properties and applications in organic synthesis.

[0003] The first synthetic method mainly uses N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (Selectfluor®) reagent to oxidize N-fluorobenzenesulfonamides in acetone-sodium hydroxide solution to prepare N,N-difluorobenzenesulfonamide compounds (such as...). Figure 1 (See also Zhang, Wenqing; Yang, Xianjin) Journal of Fluorine Chemistry 2021, 248 (, 109823); however, N-fluorosulfonamides are relatively rare, and their synthesis requires the use of fluorine gas. The second synthetic method utilizes fluorine gas to directly oxidize benzenesulfonamides (e.g., 109823); but N-fluorosulfonamides are less readily available, and their synthesis requires the use of fluorine gas. Figure 2 (See patent: CN107129449A). Fluorine gas has strong oxidizing and toxic properties, requiring harsh experimental conditions. In addition, the strong oxidizing properties of fluorine gas can lead to poor compatibility of reaction functional groups. For example, if the aromatic ring of benzenesulfonamide has functional groups that are easily oxidized by fluorine gas, it will result in no product or a very low yield. Summary of the Invention

[0004] To address the technical problems of existing synthetic routes requiring the use of fluorine gas and having low yields, this invention provides a method for preparing N,N-difluorobenzenesulfonamide compounds without using fluorine gas.

[0005] The present invention adopts the following technical solution: A method for preparing N,N-difluorobenzenesulfonamide compounds, the synthetic route of which is shown in reaction formula I, wherein R is selected from H, C1-C4 alkyl, halogen, C1-C4 alkoxy, CF3, OCF3, CN, or carbonyl, etc. .

[0006] The method uses benzenesulfonamide compounds as starting materials. The benzenesulfonamide compounds are prepared into N-chlorobenzenesulfonamide sodium salts using tert-butyl hypochlorite. Then, N-fluoro-N-chlorobenzenesulfonamide is generated by oxidation using Selectfluor®. Next, N-fluoro-N-chlorobenzenesulfonamide is selectively reduced to N-fluorobenzenesulfonamide using sodium borohydride. Finally, fluorination is performed using Selectfluor® reagent to generate the target product N,N-difluorobenzenesulfonamide.

[0007] Furthermore, the preparation method includes the following steps: (1) A benzenesulfonamide compound (compound 1) and tert-butyl hypochlorite (chlorination reagent) are reacted in sodium hydroxide solution at room temperature for 0.5-2 h to prepare the crude product of N-chlorobenzenesulfonamide compound (compound 2), wherein the molar ratio of benzenesulfonamide compound, tert-butyl hypochlorite and sodium hydroxide is 1:1-2:1-2; (2) The crude product of N-chlorobenzenesulfonamide compound was reacted with N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (Selectfluor®) reagent in aqueous solution at room temperature for 6-24 h to generate crude product of N-fluoro-N-chlorobenzenesulfonamide compound (compound 3). The molar ratio of crude product of N-chlorobenzenesulfonamide compound to N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) was 1:1.1-3. (3) The crude product of N-fluoro-N-chlorobenzenesulfonamide compound reacts with sodium borohydride in methanol solution at -30°C until the crude product of N-fluoro-N-chlorobenzenesulfonamide compound is completely reacted and reduced to generate crude product of N-fluorobenzenesulfonamide compound (compound 4). The molar ratio of N-fluoro-N-chlorobenzenesulfonamide compound to sodium borohydride is 1:0.3~1. (4) The crude product of N-fluorobenzenesulfonamide (compound 4) and N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) were reacted in acetone-sodium hydroxide aqueous solution at 0°C for 2-10 h. After separation and purification, the target product N,N-difluorobenzenesulfonamide (compound 5) was obtained. The molar ratio of the crude product of N-fluorobenzenesulfonamide, sodium hydroxide and N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) was 1:1~2:1.1~3.

[0008] Further, in step (4), the N,N-difluorobenzenesulfonamide compound is selected from N,N-difluorobenzenesulfonamides ( N, N -difluorobenzenesulfonamide), N,N-difluoro-4-methylbenzenesulfonamide ( N, N-difluoro-4-methylbenzenesulfonamide), N,N-difluoro-4-methylbenzenesulfonamide- 15 N( N , N -difluoro-4-methylbenzenesulfonamide- 15 N), N,N-difluoro-4-fluorobenzenesulfonamide ( N , N 4-fluorobenzenesulfonamide), N,N-difluoro-4-chlorobenzenesulfonamide (4-chloro- N , N -difluorobenzenesulfonamide), N,N-difluoro-4-bromo-benzenesulfonamide (4-bromo- N , N -difluoro-benzenesulfonamide), or N,N-difluoro-4-(trifluoromethyl)benzenesulfonamide ( N , N -difluoro-4-(trifluoromethyl)benzenesulfonamide). N,N-Difluoro-4-methylbenzenesulfonamide- 15 In N, nitrogen is 15 Nitrogen isotopes.

[0009] Further, in step (1), after the reaction, the mixture is concentrated under reduced pressure, filtered, and washed with diethyl ether to obtain the crude product of N-chlorobenzenesulfonamide.

[0010] Further, in step (2), the reaction is carried out under stirring conditions; after the reaction is completed, the mixture is extracted with dichloromethane and water in sequence, the organic phases are combined, and the crude product of N-fluoro-N-chlorobenzenesulfonamide is obtained by drying with anhydrous sodium sulfate and concentrating under reduced pressure.

[0011] Further, in step (3), the crude product of N-fluoro-N-chlorobenzenesulfonamide is first mixed and dissolved with methanol, and then sodium borohydride is added in portions to react. After the reaction is completed, the mixture is extracted with dichloromethane and water, the organic phases are combined, and the crude product of N-fluoro-N-chlorobenzenesulfonamide is obtained by drying with anhydrous sodium sulfate and concentrating under reduced pressure.

[0012] Further, in step (4), N-fluoro-N-chlorobenzenesulfonamide compounds are mixed with acetone and cooled to below 0°C. Sodium hydroxide is then added, and after thorough stirring, N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) is added in two portions for reaction. After the reaction is completed, the mixture is extracted with dichloromethane and water in sequence. The organic phases are combined, dried with anhydrous sodium sulfate and concentrated under reduced pressure, and then separated and purified by silica gel column chromatography.

[0013] Further, in step (4), the eluent for the silica gel column chromatography is: petroleum ether and ethyl acetate in a ratio of 200:1.

[0014] Compared with the prior art, the beneficial effects of the present invention include at least the following: 1. This invention uses sodium borohydride as a reducing agent to achieve highly selective reduction of the nitrogen-chlorine bond in N-fluoro-N-chlorobenzenesulfonamide to N-fluorobenzenesulfonamide. The preparation method does not require the use of highly toxic fluorine gas, the synthesis conditions are mild, and the separation conditions are simple.

[0015] 2. The preparation method of the present invention can efficiently synthesize various N,N-difluorobenzenesulfonamide compounds with different substituents, and has strong versatility. Attached Figure Description

[0016] Figure 1 This describes the existing synthetic route for N,N-difluorobenzenesulfonamide compounds. Figure 1 .

[0017] Figure 2 This describes the existing synthetic route for N,N-difluorobenzenesulfonamide compounds. Figure 2 .

[0018] Figure 3 This is a synthetic route diagram for N,N-difluorobenzenesulfonamide compounds in Example 1. Detailed Implementation

[0019] To make the objectives, technical solutions, and beneficial effects of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. Examples of the embodiments are shown in the accompanying drawings. It should be understood that the specific embodiments described in the following embodiments of the invention are merely illustrative examples of specific implementations of the invention and are intended to explain the invention, but do not constitute a limitation thereof.

[0020] The endpoints of the ranges and any values ​​disclosed herein are not limited to the exact ranges or values, which should be understood to include those close to them.

[0021] The embodiments of the present invention employ Figure 3The synthetic route shown is used to prepare N,N-difluorobenzenesulfonamides, where R is H,4-Me,4-F,4-Cl,4-Br,4-CF3.

[0022] Example 1: Preparation of N,N-difluorobenzenesulfonamide The synthesis steps are as follows: Step 1: Add benzenesulfonamide (1.0 equivalent) to a round-bottom flask equipped with a magnetic stirrer, add sodium hydroxide (1.0 equivalent) and deionized water, stir until completely dissolved, then add tert-butyl hypochlorite (1.1 equivalent), and react at room temperature for 1 hour. Monitor the reaction progress using thin-layer chromatography. After the reaction is complete, concentrate the reaction solution under reduced pressure, filter, and wash the residue with diethyl ether to obtain crude product 1.

[0023] Step 2: Place crude product 1 (1.0 equivalent) in a reaction flask equipped with a stir bar, add deionized water and stir until dissolved. Add Selectfluor (1.5 equivalent), and stir the reaction at room temperature for 12 hours. After the reaction is complete, extract the mixture with dichloromethane (3 × 30 mL) and water. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove the solvent to obtain crude product 2.

[0024] Step 3: Transfer crude product 2 (1.0 equivalent) to a round-bottom flask equipped with a stir bar, add methanol, stir until completely dissolved, and cool to -30°C. Add sodium borohydride (0.4 equivalent) in portions, monitoring the reaction progress in real time by thin-layer chromatography until crude product 2 has completely reacted. After the reaction is complete, extract with dichloromethane (3 × 30 mL) and water, combine the organic phases, dry them over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 3.

[0025] Step 4: Place crude product 3 (1.0 equivalent) in a reaction flask equipped with a stir bar, add acetone and cool to 0°C, then add sodium hydroxide (1.2 equivalent). After stirring at 0°C for 1 hour, add Selectfluor (1.5 equivalent) in two portions and react at 0°C for 4 hours. Monitor the reaction progress by thin-layer chromatography. After the reaction is complete, extract the reaction solution with dichloromethane (3 × 30 mL) and water. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure. Separate and purify the residue by silica gel column chromatography (eluent: petroleum ether / ethyl acetate) to obtain final product 4, N,N-difluorobenzenesulfonamide, a colorless oil with a yield of 32%.

[0026] The nuclear magnetic resonance, infrared spectroscopy, and high-resolution time-of-flight mass spectrometry data of N,N-difluorobenzenesulfonamide (R = H) are as follows: 1 H NMR (400 MHz, CDCl3): δ = 8.07 (d, J= 6.2 Hz, 2H), 7.90 (t, J = 7.6Hz, 1H), 7.71 (t, J = 8.0 Hz, 2H). 13 C NMR (151 MHz, CDCl3): δ = 137.4, 132.0, 129.9, 127.7. 19 F NMR (376 MHz, CDCl3): δ = 40.38. IR (Neat) cm -1 :3073, 2920, 2849, 1581, 1449, 1394, 2846, 2915, 3076,1193, 1085, 971, 879, 742, 676, 575, 517, 409. HRMS (m / z): [M + H] + calcd. for C6H6F2NO2S + ,194.0082; found, 194.0083. Example 2: Preparation of N,N-difluoro-4-methylbenzenesulfonamide Using the same method as in Example 1, N,N-difluoro-4-methylbenzenesulfonamide was prepared from the raw material 4-methylbenzenesulfonamide. The solid was yellow and the yield was 37%.

[0027] The nuclear magnetic resonance, infrared, and high-resolution time-of-flight mass spectrometry data for N,N-difluoro-4-methylbenzenesulfonamide (R = 4-Me) are as follows: 1 H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.3Hz, 2H), 2.54 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 149.3, 132.0, 130.6, 124.5, 22.1. 19 F NMR (376 MHz, CDCl3): δ = 40.35. IR (Neat) cm -1:3097, 3071, 2927, 2851, 1592, 1388, 1305, 1192, 1173,1082, 977, 871, 808, 708, 665, 615, 569, 508, 450. HRMS (m / z): [M + H] + calcd. for C7H8F2NO2S + , 208.0239; found, 208.0245. Example 3: N,N-Difluoro-4-methylbenzenesulfonamide- 15 Preparation of N Using the same method as in Example 1, the raw material 4-methylbenzenesulfonamide- 15 N,N-difluoro-4-methylbenzenesulfonamide- 15 N is a yellow solid with a yield of 40%.

[0028] The nuclear magnetic resonance, infrared, and high-resolution time-of-flight mass spectrometry data for N,N-difluoro-4-methylbenzenesulfonamide (R = 4-Me) are as follows: 1 H NMR (600 MHz, CDCl3): δ = 7.94 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4Hz, 2H), 2.53 (s, 3H). 13 C NMR (151 MHz, CDCl3): δ = 149.3, 132.0, 130.6, 124.6, 22.0. 19 F NMR (565 MHz, CDCl3): δ = 40.21 (d, J C-F = 20.8 Hz), 39.94 (d, J C-F =20.8 Hz). 15 N NMR (61 MHz, CDCl3): δ = 345.30 (t, J N-F = 153.8 Hz). IR (Neat) cm -1:3097, 3068, 2960, 2927, 1934, 1594, 1388, 1303, 1195,1177, 1084, 947, 852, 804, 702, 665, 611, 567, 530, 504, 472, 448. HRMS (m / z): [M + H] + calcd. for C7H8F2 15 NO2S + , 209.0209; found, 209.0219. Example 4: Preparation of N,N-difluoro-4-fluorobenzenesulfonamide Using the same method as in Example 1, N,N-difluoro-4-fluorobenzenesulfonamide was prepared from the raw material 4-F-benzenesulfonamide. The resulting product was a yellow oil with a yield of 36%.

[0029] The nuclear magnetic resonance, infrared, and high-resolution time-of-flight mass spectrometry data for N,N-difluoro-4-fluorobenzenesulfonamide (R = 4-F) are as follows: 1 H NMR (400 MHz, CDCl3): δ = 8.11 (dd, J = 9.0, 4.9 Hz, 2H), 7.40 (t, J =8.5 Hz, 2H). 13 C NMR (101 MHz, CDCl3): δ = 168.2 (d, J C-F = 263.0 Hz), 135.2 (d, J C-F =10.6 Hz), 123.6, 117.6 (d, J C-F = 23.1 Hz). 19 F NMR (376 MHz, CDCl3): δ =41.02, -96.03. IR (Neat) cm -1 :3111, 1914, 1587, 1492, 1396, 1297, 1247, 1188, 1159,1085, 1013, 978, 877, 836, 720, 677, 615, 572, 510, 473. HRMS (m / z): [M + H]+ calcd. for C6H5F3NO2S + , 211.9988; found, 211.9992. Example 5: Preparation of N,N-difluoro-4-chlorobenzenesulfonamide Using the same method as in Example 1, N,N-difluoro-4-chlorobenzenesulfonamide was prepared from the raw material 4-chloro-benzenesulfonamide. The solid was yellow and the yield was 40%.

[0030] The nuclear magnetic resonance, infrared, and high-resolution time-of-flight mass spectrometry data for N,N-difluoro-4-chlorobenzenesulfonamide (R = 4-Cl) are as follows: mp: 30-31 ℃ 1 H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 6.8 Hz, 2H), 7.69 (d, J = 8.8Hz, 2H). 13 C NMR (101 MHz, CDCl3): δ = 144.8, 133.3, 130.4, 126.0. 19 F NMR (376 MHz, CDCl3): δ = 41.07. IR (Neat) cm -1 :3102, 2956, 1574, 1466, 1395, 1285, 1185, 1084, 970,871, 824, 761, 687, 626, 581, 518, 478, 440. HRMS (m / z): [M + Na] + calcd. for C6H4ClF2NNaO2S + , 249.9511; found,249.9514. Example 6: Preparation of N,N-difluoro-4-bromobenzenesulfonamide Using the same method as in Example 1, N,N-difluoro-4-bromobenzenesulfonamide was prepared from the raw material 4-bromo-benzenesulfonamide. It was a white solid with a yield of 30%.

[0031] The nuclear magnetic resonance, infrared, and high-resolution time-of-flight mass spectrometry data for N,N-difluoro-4-bromobenzenesulfonamide (R = 4-Br) are as follows: 1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.9 Hz, 2H), 7.86 (d, J = 8.9Hz, 2H). 13 C NMR (101 MHz, CDCl3): δ = 133.7, 133.4, 133.1, 126.6. 19 F NMR (376 MHz, CDCl3): δ = 41.05. IR (Neat) cm -1 :3101, 2953, 1565, 1390, 1292, 1177, 1064, 1007, 964,875, 821, 749, 675, 608, 571, 517, 410. HRMS (m / z): [M + H] + calcd. for C6H5BrF2NO2S + , 271.9187; found,271.9195. Example 7: N , N Preparation of 4-difluorotrifluoromethylbenzenesulfonamide Using the same method as in Example 1, 4-trifluoromethylbenzenesulfonamide was prepared. N , N -Difluoro-4-trifluoromethylbenzenesulfonamide, a yellow oily substance, with a yield of 30%.

[0032] N , N The nuclear magnetic resonance, infrared, and high-resolution time-of-flight mass spectrometry data for difluoro-4-trifluoromethylbenzenesulfonamide (R = 4-CF3) are as follows: 1 H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4Hz, 2H). 13 C NMR (101 MHz, CDCl3): 138.7, 132.6, 131.5, 127.0 (q, J C-F = 3.7 Hz), 124.0. 19 F NMR (376 MHz, CDCl3): δ = 41.29, -63.57. IR (Neat) cm -1 :3108, 3061, 1403, 1316, 1177, 1141, 1059, 1014, 978,883, 843, 786, 721, 672, 600, 518, 471, 423. HRMS (m / z): [M + H] + calcd. for C7H5F5NO2S + , 261.9956; found, 261.9958. Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and do not constitute a limitation on the content of the present invention. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, including combining various technical features in any other suitable manner. These simple modifications and combinations should also be regarded as the content disclosed in the present invention and all fall within the protection scope of the present invention.

Claims

1. A method for preparing an N,N-difluorobenzenesulfonamide compound, characterized in that, The synthetic route is shown in reaction formula I, where R is selected from H, C1-C4 alkyl, halogen, C1-C4 alkoxy, CF3, OCF3, CN, or carbonyl. 。 2. The preparation method according to claim 1, characterized in that, The preparation method includes the following steps: (1) A benzenesulfonamide compound is reacted with tert-butyl hypochlorite in a sodium hydroxide solution at room temperature for 0.5-2 h to prepare a crude product of N-chlorobenzenesulfonamide compound, wherein the molar ratio of the benzenesulfonamide compound, tert-butyl hypochlorite and sodium hydroxide is 1:1-2:1-2; (2) The crude product of N-chlorobenzenesulfonamide compound is reacted with N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) reagent in aqueous solution at room temperature for 6-24 h to oxidize and generate the crude product of N-fluoro-N-chlorobenzenesulfonamide compound. The molar ratio of the crude product of N-chlorobenzenesulfonamide compound to N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) is 1:1.1-3. (3) The crude product of N-fluoro-N-chlorobenzenesulfonamide compound is reacted with sodium borohydride in methanol solution at -30°C or below until the crude product of N-fluoro-N-chlorobenzenesulfonamide compound is completely reacted and reduced to generate crude product of N-fluorobenzenesulfonamide compound. The molar ratio of N-fluoro-N-chlorobenzenesulfonamide compound to sodium borohydride is 1:0.3~1. (4) The crude product of N-fluorobenzenesulfonamide compound and N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) were reacted in acetone-sodium hydroxide aqueous solution at 0°C for 2-10 h. After separation and purification, the target product N,N-difluorobenzenesulfonamide compound was obtained. The molar ratio of the crude product of N-fluorobenzenesulfonamide compound, sodium hydroxide and N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) was 1:1-2:1.1-3.

3. The preparation method according to claim 2, characterized in that, In step (4), the N,N-difluorobenzenesulfonamide compound is selected from N,N-difluorobenzenesulfonamide, N,N-difluoro-4-methylbenzenesulfonamide, and N,N-difluoro-4-methylbenzenesulfonamide. 15 N, N, N-difluoro-4-fluorobenzenesulfonamide, N, N-difluoro-4-chlorobenzenesulfonamide, N, N-difluoro-4-bromo-benzenesulfonamide, or N, N-difluoro-4-(trifluoromethyl)benzenesulfonamide.

4. The preparation method according to claim 2, characterized in that, In step (1), after the reaction, the mixture is concentrated under reduced pressure, filtered, and washed with diethyl ether to obtain the crude product of N-chlorobenzenesulfonamide.

5. The preparation method according to claim 2, characterized in that, In step (2), the reaction is carried out under stirring conditions; after the reaction is completed, the mixture is extracted with dichloromethane and water, the organic phases are combined, dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude N-fluoro-N-chlorobenzenesulfonamide compounds.

6. The preparation method according to claim 2, characterized in that, In step (3), the crude product of N-fluoro-N-chlorobenzenesulfonamide is first mixed and dissolved with methanol, and then sodium borohydride is added in portions to carry out the reaction.

7. The preparation method according to claim 6, characterized in that, In step (3), after the reaction is complete, the mixture is extracted with dichloromethane and water in sequence, the organic phases are combined, dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product of N-fluoro-N-chlorobenzenesulfonamide compounds.

8. The preparation method according to claim 2, characterized in that, In step (4), N-fluoro-N-chlorobenzenesulfonamide compounds are mixed with acetone and cooled to below 0°C. Sodium hydroxide is then added, and after thorough stirring, N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) is added in two batches to carry out the reaction.

9. The preparation method according to claim 8, characterized in that, In step (4), after the reaction is complete, the mixture is extracted with dichloromethane and water in sequence, the organic phases are combined, dried with anhydrous sodium sulfate and concentrated under reduced pressure, and then separated and purified by silica gel column chromatography.

10. The preparation method according to claim 9, characterized in that, In step (4), the eluent for the silica gel column chromatography is: petroleum ether and ethyl acetate in a ratio of 200:1.

Images