Chiral bis(trifluoromethylated) spirobenzothiophenone-fused pyrrolidine derivatives, their preparation methods and their applications

Abstract

The present invention discloses a class of chiral bis(trifluoromethylated) spirobenzothiophenone-fused pyrrolidine derivatives, belonging to the technical field of organic chemical synthesis. The preparation method is to dissolve the trifluoroethylimine (I) derived from benzothiophenedione and β-trifluoromethyl ketene (II) in an organic solvent, then add a chiral catalyst, and stir and react at room temperature. After the reaction is completed, the product (III) is obtained by separation and purification; the bis(trifluoromethylated) spirobenzothiophenone-fused pyrrolidine derivatives provided by the present invention have four consecutive chiral centers and easily functionalizable groups, which are convenient for the derivation and synthesis of other chiral polycyclic compounds, can provide more candidate molecules for the research and development of new drugs and the screening of drugs, and these compounds show good application prospects in anti-tumor aspects; the preparation method of the present invention has the advantages of novelty, simplicity, easy operation, mild reaction conditions, high yield, and high stereoselectivity.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to chiral bis(trifluoromethylated) spirobenzothiophenone-fused pyrrolidine derivatives, their preparation methods and their applications. Background Art

[0002] The trifluoromethyl functional group is widely present in natural or non-natural bioactive molecules, and most of these molecules are found to have good bioactivity and are an important source for the development of new drugs. In particular, introducing the trifluoromethyl functional group into drugs can change the physicochemical properties of the drugs and improve the metabolic stability, which has become a hot field in new drug research. However, according to the literature research, we found that the current research methods mainly focus on the asymmetric construction of compounds containing one trifluoromethyl group, while there is very little research on the asymmetric synthesis of compounds containing two trifluoromethyl functional groups, especially compounds containing two adjacent trifluoromethyl functional groups. Therefore, exploring simple and convenient synthesis methods to efficiently construct chiral compounds containing two adjacent trifluoromethyl functional groups has very important challenges and application values.

[0003] On the other hand, sulfur-containing heterocyclic compounds, especially compounds containing a benzothiophene structural unit, also usually have good bioactivity and are widely used in drug design. From the perspective of drug design, organically combining two or more pharmacodynamic functional groups into one molecule may produce unexpected bioactivity, which has very important significance. Summary of the Invention

[0004] One of the purposes of the present invention is to provide a new class of chiral bis(trifluoromethylated) spirobenzothiophenone-fused pyrrolidine derivatives to solve the above problems.

[0005] To achieve the above purpose, the technical solution of the present invention is as follows: A new class of chiral bis(trifluoromethylated) spirobenzothiophenone-fused pyrrolidine derivatives has the structure shown in the following structural formula (Ⅲ):

[0006]

[0007] In the above structural formula, the R group is a single substituent or a multi-substituent, and the substituents are selected from hydrogen, alkyl, alkoxy, halogen, nitro or cyano, etc.; the Ar group is various substituted aryl groups, heteroaryl groups, naphthyl groups, etc.

[0008] The present invention discloses for the first time a new class of chiral bis(trifluoromethylated) spirobenzothiophenone-fused pyrrolidine derivatives. This class of compounds simultaneously assembles multiple pharmacodynamic functional groups, such as two trifluoromethyl groups, benzothiophenone and pyrrolidine substructures, which can provide more candidate molecules for the research and development of new drugs and the screening of drugs.

[0009] Another object of the present invention is to provide a method for preparing the above-mentioned chiral bis(trifluoromethylated) spirobenzothiophenone pyrrolidine derivatives, and the technical solution adopted is as follows: Dissolve the trifluoroethylimine (I) derived from benzothiophenedione and β-trifluoromethyl ketene (II) in an organic solvent, then add a chiral catalyst, and stir the reaction at room temperature. After the reaction is completed, separate and purify to obtain the product (III), where,

[0010] The trifluoroethylimine (I) derived from benzothiophenedione has the following structure:

[0011]

[0012] β-trifluoromethyl ketene (II) has the following structure:

[0013]

[0014] The synthesis route is as follows:

[0015]

[0016] The present invention adopts the above-mentioned synthesis method to synthesize a series of novel chiral bis(trifluoromethylated) spirobenzothiophenone pyrrolidine derivatives.

[0017] As a preferred technical solution: The reaction solvent is selected from one or a mixture of toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, ether, acetonitrile, ethanol, methanol, 1,4-dioxane, chlorobenzene.

[0018] As a further preferred technical solution, the reaction solvent is dichloromethane, with a higher yield and higher stereoselectivity.

[0019] As a preferred technical solution, the chiral organic small molecule catalyst used has the structure of formula A or B or C or D as follows, that is, the catalyst used is preferably selected from one of them:

[0020]

[0021] Catalyst D is further preferably used, with higher enantioselectivity.

[0022] This application uses benzothiophenedione-derived trifluoroethylimine and β-trifluoromethyl ketene as raw materials, and undergoes an asymmetric [3+2] cycloaddition reaction under the catalysis of an organic small molecule catalyst to construct bis(trifluoromethylated) spirobenzothiophenone pyrrolidine derivatives with high stereoselectivity. It is worth noting that this type of compound simultaneously assembles multiple pharmacodynamic functional groups, such as two trifluoromethyl groups, benzothiophenone, and pyrrolidine substructures, which can not only provide new ideas and methods for the synthesis of this type of compound, but also greatly enrich the variety of such compounds and provide more candidate molecules for new drug screening.

[0023] The third object of the present invention is to provide the application of the above-mentioned chiral bis(trifluoromethylated) spirobenzothiophenone pyrrolidine derivatives in the preparation of anti-cancer drugs.

[0024] In addition, the application value of the compounds of the present invention also lies in that many existing trifluoromethyl-containing compounds, benzothiophene and pyrrolidine compounds have good biological activities. Therefore, it can be reasonably predicted that a large new class of compounds provided by the trifluoromethyl structural modification based on benzothiophene and pyrrolidine compounds of the present invention also have certain biological activities, thus providing a sufficient compound source for the screening of drug activities; in addition, it can provide more candidate molecules for the research and development of new drugs and the screening of drugs, especially high-throughput screening, and enrich the compound library of this type. In addition, the present invention provides a synthesis method with mild conditions and simple operation to obtain a series of chiral ortho-bis(trifluoromethylated) spirobenzothiophenone pyrrolidine derivatives.

[0025] The advantages of the present invention are as follows: The present invention uses benzothiophenedione-derived trifluoroethylimine and β-trifluoromethyl ketene as raw materials, and undergoes an asymmetric [3+2] cycloaddition reaction under the catalysis of an organic small molecule catalyst to prepare a series of structurally diverse chiral bis(trifluoromethylated) spirobenzothiophenone pyrrolidine derivatives. This compound has four consecutive chiral centers and easily functionalizable groups, which are convenient for the derivation and synthesis of other chiral polycyclic compounds, and can provide more candidate molecules for the research and development of new drugs and the screening of drugs, especially high-throughput screening, and enrich the compound library of this type; at the same time, through cell experiments, it is shown that the synthesized chiral bis(trifluoromethylated) spirobenzothiophenone pyrrolidine derivatives have good anti-cancer activities. This method has the advantages of mild reaction conditions, easy availability of raw materials and catalysts, simple operation, and very good stereoselectivity (>20:1 dr, 99% ee). Description of the Drawings

[0026] Figure 1 1H NMR spectrum of Ⅲ-a prepared in Example 1;

[0027] Figure 2 13C NMR spectrum of Ⅲ-a prepared in Example 1;

[0028] Figure 3 Single crystal diagram of Ⅲ-a prepared in Example 1 Detailed implementation manners

[0029] The present invention will be further described below in conjunction with embodiments

[0030] Example 1: Synthesis of compound (Ⅲ-a)

[0031]

[0032] Add benzothiophenedione-derived trifluoroethylimine (I-a) (0.13 mmol), β-trifluoromethyl ketene (II-a) (0.10 mmol), and chiral catalyst A-D (0.02 mmol) into a dry reaction test tube, and then add X mL of solvent, and stir the reaction at room temperature. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-a, specifically as follows:

[0033]

[0034] Table 1 Different reaction conditions

[0035]

[0036]

[0037] It can be seen from Table 1 that by investigating different catalysts and common solvents, finally using catalyst D, 0.5 mL of dichloromethane as the solvent, and the reaction temperature being room temperature is a more preferred scheme. Under the optimal scheme, the yield, melting point, stereoselectivity, optical rotation, hydrogen spectrum, carbon spectrum, and mass spectrum data of Ⅲ-a obtained are as follows: 77% yield, melting point of 164.3 - 165.1 °C; >20:1 dr, 97% ee; [α] D 20 =-28.6 (c 0.2, CH2Cl2); The ee was determined by HPLC (Chiralpak AD-H, EtOH / hexane = 5 / 95, flow rate 1.0 mL / min, λ = 254 nm, t minor = 6.6 min, t major = 11.8 min); 11H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.19–7.11 (m, 3H), 6.90 (d, J = 7.9 Hz, 1H), 4.51 (m, J = 7.1 Hz, 2H), 4.41 (d, J = 9.7 Hz, 1H), 2.66 (d, J = 5.1 Hz, 1H), 2.48 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 202.9, 192.1, 138.0, 136.9, 135.6, 133.9, 131.7, 131.7, 128.7, 128.6, 128.3, 125.9, 125.7 (q, J = 279.8 Hz, 1C), 124.5 (q, J = 281.8 Hz, 1C), 124.7, 123.5, 123.1, 120.3, 78.6, 77.5, 77.2, 76.8, 60.0 (q, J = 34.3 Hz, 1C), 59.5, 45.1 (q, J = 29.0 Hz, 1C), 21.5; HRMS (ESI-TOF) Calcd. for C 21 H 15 F6NO2SNa [M+Na] + : 482.0620; found: 482.0625.

[0038] The single crystal data of compound Ⅲ-a are shown in Table 2.

[0039] Table 2 Crystal data of compound Ⅲ-a (CCDC - 2297542)

[0040]

[0041]

[0042] The above-mentioned 1H NMR spectrum is as Figure 1 shown, the 13C NMR spectrum is as Figure 2 shown, and the single crystal is as Figure 3 shown.

[0043] Example 2: Synthesis of compound (Ⅲ-b)

[0044]

[0045] In a dry reaction tube, add benzothiophenedione-derived trifluoroethylimine (I-b) (0.13 mmol), β-trifluoromethyl ketene (II-a) (0.10 mmol), chiral catalyst D (0.02 mmol), and then add 0.5 mL of solvent. Stir the reaction at room temperature for 48 h. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-b.

[0046] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 13C NMR, and mass spectrometry data of the obtained Ⅲ-b are as follows: 51% yield, melting point 131.5 - 132.3 °C; >20:1 dr, 99% ee; [α] D 20 = +27.7 (c 0.7, CH2Cl2); The ee was determined by HPLC (Chiralpak IA, i PrOH / hexane = 10 / 90, flow rate 1.0 mL / min, λ = 254 nm, t minor = 8.0 min, t major = 11.6 min); 1 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.37 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 7.9 Hz, 1H), 7.16 (t, J = 7.6 Hz, 2H), 6.84 (s, 1H), 4.50 (m, 2H), 4.40 (d, J = 9.8 Hz, 1H), 2.64 (d, J = 5.5 Hz, 1H), 2.35 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 202.7, 192.0, 141.3, 135.5, 134.9, 133.8, 133.8, 129.7, 128.5, 128.4, 128.2, 125.6 (q, J = 279.8 Hz, 1C), 124.3 (q, J = 281.8 Hz, 1C), 124.1, 123.8, 78.3, 77.4, 77.3, 77.0, 76.7, 60.0 (q, J = 31.3 Hz, 1C) 53.5, 45.0 (q, J = 27.3 Hz, 1C), 21.5; HRMS (ESI-TOF) Calcd. for C 21 H 15 F6NO2SNa [M+Na] + : 482.0620; found: 482.0624.

[0047] Example 3: Synthesis of compound (Ⅲ-c)

[0048]

[0049] In a dry reaction tube, add benzo[b]thiophene-2,3-dione-derived trifluoroethylimine (I-c) (0.13 mmol), β-trifluoromethyl ketene (II-a) (0.10 mmol), and chiral catalyst D (0.02 mmol). Then add 0.5 mL of solvent and stir the reaction at room temperature for 48 h. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-c.

[0050] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 13C NMR, and mass spectrometry data of the obtained Ⅲ-c are as follows: yield of 62%, melting point of 179.3 - 180.0 °C; >20:1 dr, 98% ee; [α] D 20 = +27.7 (c 1.1, CH2Cl2); The ee was determined by HPLC (Chiralpak AD-H, EtOH / hexane = 5 / 95, flow rate 1.0 mL / min, λ = 254 nm, t minor = 7.0 min, t major = 22.9 min); 1 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 6.5 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.21–7.09 (m, 3H), 6.91 (d, J = 8.0 Hz, 1H), 4.52 (m, 2H), 4.41 (d, J = 9.7 Hz, 1H), 2.76 (q, J = 7.6 Hz, 2H), 2.66 (d, J = 5.0 Hz, 1H), 1.34 (t, J = 7.6 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 203.0, 192.1, 144.6, 136.8, 135.7, 133.9, 131.9, 130.6, 128.6, 128.3, 125.7 (q, J = 279.7 Hz, 1C), 124.5 (q, J = 281.8 Hz, 1C), 123.7, 123.6, 78.7, 60.1 (q, J = 33.2 Hz, 1C), 59.5, 45.1 (q, J = 29.3 Hz, 1C), 29.0, 16.2; HRMS (ESI-TOF) Calcd. for C 22 H 17 F6NO2SNa [M+Na] + : 496.0776; found: 496.0781.

[0051] Example 4: Synthesis of Compound (Ⅲ-d)

[0052]

[0053] Add benzo[b]thiophene-2,3-dione-derived trifluoroethylimine (I-d) (0.13 mmol), β-trifluoromethyl ketene (II-a) (0.10 mmol), and chiral catalyst D (0.02 mmol) into a dry reaction tube, and then add 0.5 mL of solvent. Stir the reaction at room temperature for 48 h. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain Compound Ⅲ-d.

[0054] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 13C NMR, and mass spectrometry data of the obtained Ⅲ-d are as follows: 51% yield; melting point is 143.1 - 143.9 °C; >20:1 dr, 98% ee; [α] D 20 = +49.5 (c 1.6, CH2Cl2); The ee was determined by HPLC (Chiralpak IA, i PrOH / hexane = 10 / 90, flow rate 1.0 mL / min, λ = 254 nm, t minor = 3.8 min, t major = 5.0 min); 1 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.37–7.28 (m, 3H), 7.12 (t, J = 7.7 Hz, 2H), 6.91 (d, J = 8.2 Hz, 1H), 4.52 (m, 2H), 4.40 (d, J = 9.7 Hz, 1H), 2.68 (s, 1H), 1.43 (s, 9H); 13 13C NMR (101 MHz, CDCl3) δ 203.1, 192.1, 151.7, 136.1, 135.6, 133.9, 131.7, 128.5, 128.3, 128.1, 125.7 (d, J = 279.8 Hz, 1C) 124.5 (q, J = 281.8 Hz, 1C), 123.4, 121.0, 78.8, 77.4, 60.0 (q, J = 32.3 Hz, 1C), 59.5, 44.9 (q, J = 30.3 Hz, 1C) 35.1, 31.5, 31.4; HRMS (ESI-TOF) Calcd. for C 24 H 21 F6NO2SNa [M+Na] +:524.1089; found:524.1093.

[0055] Example 5: Synthesis of Compound (Ⅲ-e)

[0056]

[0057] Add benzothiophenedione-derived trifluoroethylimine (I-e) (0.13 mmol), β-trifluoromethyl ketene (II-a) (0.10 mmol), and chiral catalyst D (0.02 mmol) to a dry reaction tube, and then add 0.5 mL of solvent. Stir the reaction at room temperature for 48 h. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-e.

[0058] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 13C NMR, and mass spectrometry data of the obtained Ⅲ-e are as follows: 63% yield, melting point 130.6 - 131.4 °C; >20:1 dr, 97% ee; [α] D 20 = +40.1 (c 0.6, CH2Cl2); The ee was determined by HPLC (Chiralpak IA, i PrOH / hexane = 10 / 90, flow rate 1.0 mL / min, λ = 254 nm, t minor = 9.1 min, t major = 9.7 min); 1 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.2 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.39 (t, J = 7.4 Hz, 3H), 7.21 (t, J = 7.7 Hz, 2H), 7.00 (s, 1H), 4.58–4.44 (m, 2H), 4.39 (d, J = 9.5 Hz, 1H), 2.67 (s, 1H); 13 13C NMR (101 MHz, CDCl3) δ 201.4, 191.7, 136.7, 136.5, 135.4, 134.9, 134.1, 128.4, 128.4, 127.8, 125.41 (q, J = 279.8 Hz, 1C), 125.36, 124.2 (q, J = 281.8 Hz, 1C), 123.5, 120.0, 78.1, 77.3, 60.0 (q, J = 30.3 Hz, 1C), 59.1, 44.7 (q, J = 29.3 Hz, 1C); HRMS (ESI-TOF) Calcd. for C 20 H 12ClF6NO2SNa[M+Na] + : 502.0074; found: 502.0073.

[0059] Example 6: Synthesis of compound (Ⅲ-f)

[0060]

[0061] Add benzothiophenedione-derived trifluoroethylimine (I-f) (0.13 mmol), β-trifluoromethyl ketene (II-a) (0.10 mmol), and chiral catalyst D (0.02 mmol) to a dry reaction tube, then add 0.5 mL of solvent, and stir the reaction at room temperature for 48 h. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-f.

[0062] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 13C NMR, and mass spectrometry data of the obtained Ⅲ-f are as follows: 56% yield, melting point 124.6 - 125.5 °C; >20:1 dr, 97% ee; [α] D 20 = -116.3 (c 0.7, CH2Cl2); The ee was determined by HPLC (Chiralpak AD-H, i PrOH / hexane = 5 / 95, flow rate 1.0 mL / min, λ = 254 nm, t minor = 13.0 min, t major = 21.9 min); 1 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.7 Hz, 1H), 7.43 (q, J = 7.6 Hz, 2H), 7.39–7.29 (m, 3H), 7.15 (t, J = 7.6 Hz, 2H), 7.01 (d, J = 7.8 Hz, 1H), 4.51 (m, 2H), 4.43 (d, J = 9.8 Hz, 1H), 2.69 (d, J = 4.9 Hz, 1H); 13 13C NMR (101 MHz, CDCl3) δ 202.5, 192.0, 136.9, 135.6, 135.2, 134.0, 130.9, 128.6, 128.4, 127.7, 125.7 (q, J = 279.8 Hz, 1C), 124.4 (q, J = 281.8 Hz, 1C), 124.3, 123.8, 78.5, 60.0 (q, J = 32.3 Hz, 1C), 59.4, 45.0 (q, J = 29.3 Hz, 1C); HRMS (ESI-TOF) Calcd. for C 20 H13 F6NO2SNa[M+Na] + : 468.0463; found: 468.0466.

[0063] Example 7: Synthesis of Compound (Ⅲ-g)

[0064]

[0065] In a dry reaction tube, add benzo[b]thiophene-2,3-dione-derived trifluoroethylimine (I-a) (0.13 mmol), β-trifluoromethyl ketene (II-b) (0.10 mmol), chiral catalyst D (0.02 mmol), and then add 0.5 mL of solvent. Stir the reaction at room temperature for 48 h. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain Compound Ⅲ-g.

[0066] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 13C NMR, and mass spectrometry data of the obtained Ⅲ-g are as follows: 57% yield, melting point 112.9 - 113.6 °C; >20:1 dr, 92% ee; [α] D 20 = +56.0 (c 1.0, CH2Cl2); The ee was determined by HPLC (Chiralpak IA, i PrOH / hexane = 20 / 80, flow rate 1.0 mL / min, λ = 254 nm, t minor = 4.7 min, t major = 6.7 min); 1 1H NMR (400 MHz, CDCl3) δ 7.47 (t, J = 7.6 Hz, 1H), 7.30 (s, 2H), 7.04 (t, J = 7.6 Hz, 2H), 6.79 (d, J = 7.9 Hz, 1H), 6.66 (dd, J = 11.1, 8.5 Hz, 1H), 4.60 (dd, J = 10.3, 2.3 Hz, 1H), 4.46 (m, 2H), 2.61 (d, J = 5.7 Hz, 1H), 2.41 (s, 3H); 1313C NMR (101 MHz, CDCl3) δ 203.3, 191.3, 160.5 (d, J = 253.5 Hz, 1C), 137.5, 135.5, 135.0 (d, J = 9.1 Hz, 1C), 131.5, 131.3 (d, J = 2.0 Hz, 1C), 125.7 (q, J = 279.8 Hz, 1C), 124.5 (q, J = 281.8 Hz, 1C), 125.4 (d, J = 1.0 Hz, 1C), 125.3, 125.2, 124.6 (d, J = 4.0 Hz, 1C), 122.9, 115.5 (d, J = 23.2 Hz, 1H), 77.4, 62.5, 59.8 (q, J = 32.3 Hz, 1C), 44.3 (q, J = 29.3 Hz, 1C), 21.3; HRMS (ESI-TOF) Calcd. for C 21 H 14 F7NO2SNa [M+Na] + : 500.0526; found: 500.0527.

[0067] Example 8: Synthesis of compound (Ⅲ-h)

[0068]

[0069] In a dry reaction tube, add benzothiophenedione-derived trifluoroethylimine (I-a) (0.13 mmol), β-trifluoromethyl ketene (II-c) (0.10 mmol), chiral catalyst D (0.02 mmol), and then add 0.5 mL of solvent. Stir the reaction at room temperature for 48 h. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-h.

[0070] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 13C NMR, and mass spectrometry data of the obtained Ⅲ-h are as follows: 60% yield, melting point 119.9 - 120.5 °C; >20:1 dr, 97% ee; [α] D 20 = -121.3 (c 0.2, CH2Cl2); The ee was determined by HPLC (Chiralpak AD-H, EtOH / hexane = 10 / 90, flow rate 1.0 mL / min, λ = 254 nm, t minor = 4.3 min, t major = 6.2 min); 11H NMR (400 MHz, 101 MHz, CDCl3) δ 7.47 (t, J = 7.6 Hz, 1H), 7.30 (s, 2H), 7.04 (t, J = 7.6 Hz, 2H), 6.79 (d, J = 7.9 Hz, 1H), 6.66 (dd, J = 11.1, 8.5 Hz, 1H), 4.60 (dd, J = 10.3, 2.3 Hz, 1H), 4.46 (m, 2H), 2.61 (d, J = 5.7 Hz, 1H), 2.41 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 203.1, 191.2, 160.4 (d, J = 253.5 Hz, 1C), 137.3, 135.3, 134.9 (d, J = 9.1 Hz, 1C), 131.4, 131.2 (d, J = 2.0 Hz, 1C), 130.9, 125.6 (q, J = 279.8 Hz, 1C), 125.3, 124.5 (d, J = 4.0 Hz, 1C), 124.4 (q, J = 281.8 Hz, 1C), 122.8, 115.4 (d, J = 23.2 Hz, 1C), 78.1, 77.2, 62.3, 59.7 (q, J = 34.3 Hz, 1C), 44.2 (q, J = 29.3 Hz, 1C), 21.2; HRMS (ESI-TOF) Calcd. for C 21 H 14 F7NO2SNa [M+Na] + : 500.0526; found: 500.0529.

[0071] Example 9: Synthesis of compound (Ⅲ-i)

[0072]

[0073] Add benzothiophenedione-derived trifluoroethylimine (I-a) (0.13 mmol), β-trifluoromethyl ketene (II-d) (0.10 mmol), and chiral catalyst D (0.02 mmol) to a dry reaction tube, then add 0.5 mL of solvent and stir the reaction at room temperature for 48 h. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-i.

[0074] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 13C NMR, and mass spectrometry data of the obtained Ⅲ-i are as follows: 66% yield, melting point 136.7 - 137.6 °C; >20:1 dr, 99% ee; [α] D 20= +23.4 (c 0.3, CH2Cl2); The ee was determined by HPLC (Chiralpak AD-H, EtOH / hexane = 10 / 90, flow rate 1.0 mL / min, λ = 254 nm, t minor = 4.5 min, t major = 5.7 min); 1 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 8.0 Hz, 1H), 4.50 (t, J = 6.3 Hz, 2H), 4.33 (d, J = 9.2 Hz, 1H), 2.68 (d, J = 4.6 Hz, 1H), 2.49 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 202.7, 190.8, 140.5, 138.1, 136.6, 133.7, 131.8, 131.5, 129.8, 128.6, 125.5 (q, J = 279.8 Hz, 1C), 124.5, 124.3 (q, J = 282.8 Hz, 1C), 123.6, 78.5, 77.3, 59.9 (q, J = 33.3 Hz, 1C), 59.4, 44.9 (q, J = 28.3 Hz, 1C), 21.4; HRMS (ESI-TOF) Calcd. for C 21 H 14 ClF6NO2SNa [M+Na] + : 516.0230; found: 516.0233.

[0075] Example 10: Synthesis of compound (Ⅲ-j)

[0076]

[0077] In a dry reaction tube, add benzothiophenedione-derived trifluoroethylimine (I-a) (0.13 mmol), β-trifluoromethyl ketene (II-e) (0.10 mmol), chiral catalyst D (0.02 mmol), and then add 0.5 mL of solvent. Stir the reaction at room temperature for 48 h. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-j.

[0078] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 13C NMR, and mass spectrometry data of the obtained Ⅲ-j are as follows: 60% yield, m.p. 125.3 - 126.1 °C; >20:1 dr, 97% ee; [α]D 20 = -16.1 (c 1.0, CH2Cl2); The ee was determined by HPLC (Chiralpak IA, i PrOH / hexane = 20 / 80, flow rate 1.0 mL / min, λ = 254 nm, t minor = 4.7 min, t major = 6.3 min); 1 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.28 (s, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 4.54–4.42 (m, 2H), 4.30 (d, J = 9.1 Hz, 1H), 2.68 (d, J = 4.5 Hz, 1H), 2.51 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 202.6, 190.6, 138.3, 137.0, 136.6, 136.2, 132.2, 131.5, 131.3, 129.9, 127.2, 125.5 (q, J = 279.8 Hz, 1C), 124.5, 124.3 (q, J = 282.8 Hz, 1C), 123.6, 122.3, 78.5, 77.2, 59.9 (q, J = 33.3 Hz, 1C), 59.4, 44.8 (q, J = 28.3 Hz, 1C), 21.5; HRMS (ESI-TOF) Calcd. for C 21 H 14 BrF6NO2SNa [M+Na] + : 561.9706; found: 561.9706.

[0079] Example 11: Synthesis of compound (Ⅲ-k)

[0080]

[0081] In a dry reaction tube, add benzo[b]thiophene-2,3-dione-derived trifluoroethyl imine (I-a) (0.13 mmol), β-trifluoromethyl ketene (II-f) (0.10 mmol), chiral catalyst D (0.02 mmol), and then add 0.5 mL of solvent. Stir the reaction at room temperature for 48 h. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-k.

[0082] The yields, melting points, stereoselectivities, optical rotations, 1H NMR spectra, 13C NMR spectra, and mass spectra of the obtained III-k were as follows: 48% yield, m.p. 217.1 - 217.9 °C; >20:1 dr, 94% ee; [α] D 20 = +85.9 (c 0.6, CH2Cl2); The ee was determined by HPLC (Chiralpak AD-H, i PrOH / hexane = 5 / 95, flow rate 1.0 mL / min, λ = 254 nm, t minor = 15.4 min, t major = 27.9 min); 1 1H NMR (400 MHz, CDCl3) δ 7.51–7.35 (m, 5H), 7.21 (d, J = 8.1 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 4.59–4.43 (m, 2H), 4.34 (d, J = 9.0 Hz, 1H), 2.69 (d, J = 4.5 Hz, 1H), 2.50 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 202.4, 191.1, 138.4, 138.3, 136.3, 132.0, 131.9, 131.3, 128.8, 125.4 (q, J = 279.4 Hz, 1C), 124.2, (q, J = 281.8 Hz, 1C), 117.5, 116.9, 78.5, 60.2 (q, J = 33.5 Hz, 1C), 59.8, 44.9 (q, J = 29.1 Hz, 1C), 21.4; HRMS (ESI-TOF) Calcd. for C 22 H 14 F6NO2SNa [M+Na] + : 507.0572; found: 507.0576.

[0083] Example 12: Synthesis of compound (III-l)

[0084]

[0085] In a dry reaction tube, benzo[b]thiophene-2,3-dione-derived trifluoroethyl imine (I-a) (0.13 mmol), β-trifluoromethyl ketene (II-g) (0.10 mmol), and chiral catalyst D (0.02 mmol) were added, and then 0.5 mL of solvent was added. The reaction was stirred at room temperature for 48 h. After the reaction was complete, the crude product was separated and purified by column chromatography to obtain compound III-l.

[0086] The yields, melting points, stereoselectivities, optical rotations, 1H NMR spectra, 13C NMR spectra and mass spectra of the obtained III-l are as follows: yield of 67%, melting point of 219.1 - 219.8 °C; >20:1 dr, 95% ee; [α] D 20 = -5.3 (c 0.8, CH2Cl2); The ee was determined by HPLC (Chiralpak AD-H, i PrOH / hexane = 5 / 95, flow rate 1.0 mL / min, λ = 254 nm, t minor = 14.9 min, t major = 27.1 min); 1 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 7.8 Hz, 1H), 4.84–4.68 (m, 1H), 4.54 (d, J = 7.9 Hz, 1H), 4.42–4.28 (m, 1H), 2.68 (d, J = 4.6 Hz, 1H), 2.28 (s, 3H); 1 13C NMR (400 MHz, CDCl3) δ 208.2, 192.5, 150.3, 140.0, 137.5, 132.5, 131.4, 129.6, 128.8, 128.7, 124.9 (q, J = 279.7 Hz, 1C), 124.0 (q, J = 280.4 Hz), 123.4, 122.9, 76.6, 58.9 (q, J = 32.5 Hz, 1C), 54.7, 43.9 (q, J = 29.3 Hz, 1C), 21.1; HRMS (ESI-TOF) Calcd. for C 22 H 14 F6N2O2SNa [M+Na] + : 527.0471; found: 527.0485.

[0087] Example 13: Synthesis of compound (III-m)

[0088]

[0089] In a dry reaction tube, add benzothiophenedione-derived trifluoroethylimine (I-a) (0.13 mmol), β-trifluoromethyl ketene (II-h) (0.10 mmol), and chiral catalyst D (0.02 mmol). Then add 0.5 mL of solvent and stir the reaction at room temperature for 48 h. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-m.

[0090] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 13C NMR, and mass spectrometry data of the obtained Ⅲ-m are as follows: 53% yield, melting point 180.5 - 181.3 °C; >20:1 dr, 98% ee; [α] D 20 = +82.0 (c 1.2, CH2Cl2); The ee was determined by HPLC (Chiralpak AD-H, EtOH / hexane = 10 / 90, flow rate 1.0 mL / min, λ = 254 nm, t minor = 4.8 min, t major = 6.6 min); 1 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.26 (d, J = 7.4 Hz, 2H), 7.17 (d, J = 8.0 Hz, 1H), 6.94 (t, J = 8.8 Hz, 3H), 4.51 (m, 2H), 4.38 (d, J = 9.5 Hz, 1H), 2.66 (d, J = 5.2 Hz, 1H), 2.49 (s, 3H), 2.30 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 202.9, 191.4, 145.0, 137.9, 137.1, 133.1, 131.7, 131.6, 129.1, 125.7 (q, J = 279.8 Hz, 1C), 124.7, 124.5 (q, J = 282.8 Hz, 1C), 123.6, 78.6, 77.4, 60.1 (q, J = 33.3 Hz, 1C), 59.4, 45.1 (q, J = 29.3 Hz, 1C), 21.8, 21.5; HRMS (ESI-TOF) Calcd. for C 22 H 17 F6NO2SNa [M+Na] + : 496.0776; found: 496.0796.

[0091] Example 14: Synthesis of compound (Ⅲ-n)

[0092]

[0093] In a dry reaction tube, add benzothiophenedione-derived trifluoroethylimine (I-a) (0.13 mmol), β-trifluoromethyl ketene (II-i) (0.10 mmol), chiral catalyst D (0.02 mmol), and then add 0.5 mL of solvent. Stir the reaction at room temperature for 48 h. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-n.

[0094] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 13C NMR, and mass spectrometry data of the obtained Ⅲ-n are as follows: 44% yield, melting point 185.8 - 186.5 °C; >20:1 dr, 99% ee; [α] D 20 = -341.4 (c 0.3, CH2Cl2); The ee was determined by HPLC (Chiralpak AD-H, i PrOH / hexane = 5 / 95, flow rate 1.0 mL / min, λ = 254 nm, t minor = 12.1 min, t major = 25.0 min); 1 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.34 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.61 (d, J = 8.4 Hz, 2H), 4.51 (m, 2H), 4.35 (d, J = 9.6 Hz, 1H), 3.78 (s, 3H), 2.65 (d, J = 5.0 Hz, 1H), 2.49 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 202.7, 189.9, 164.1, 137.8, 137.0, 131.6, 131.5, 130.9, 128.5, 125.6 (q, J = 279.8 Hz, 1C), 124.6, 124.4 (q, J = 282.8 Hz, 1C), 123.5, 113.4, 78.5, 77.2, 60.0 (q, J = 31.3 Hz, 1C), 59.2, 55.5, 45.0 (q, J = 29.3 Hz, 1C), 21.4; HRMS (ESI-TOF) Calcd. for C 22 H 17 F6NO3SNa [M + Na] + : 512.0726; found: 512.0731.

[0095] Example 15: Synthesis of compound (Ⅲ-o)

[0096]

[0097] In a dry reaction tube, add benzo[b]thiophene-2,3-dione-derived trifluoroethylimine (I-a) (0.13 mmol), β-trifluoromethyl ketene (II-j) (0.10 mmol), and chiral catalyst D (0.02 mmol), and then add 0.5 mL of solvent. Stir the reaction at room temperature for 48 h. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain compound Ⅲ-o.

[0098] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 13C NMR, and mass spectrometry data of the obtained Ⅲ-o are as follows: 52% yield, melting point 182.4 - 183.3 °C; >20:1 dr, 99% ee; [α] D 20 = +25.8 (c 0.8, CH2Cl2); The ee was determined by HPLC (Chiralpak AD-H, EtOH / hexane = 10 / 90, flow rate 1.0 mL / min, λ = 254 nm, t minor = 5.5 min, t major = 6.6 min); 1 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.7 Hz, 1H), 7.61–7.50 (m, 2H), 7.50–7.40 (m, 2H), 7.32 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 4.71–4.47 (m, 3H), 2.71 (d, J = 5.3 Hz, 1H), 2.57 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 202.8, 191.4, 137.9, 137.2, 135.7, 132.8, 131.8, 131.7, 131.7, 130.6, 129.3, 129.1, 128.5, 127.7, 126.8, 125.6 (q, J = 279.8 Hz, 1C), 124.7, 124.4 (q, J = 282.8 Hz, 1C), 124.1, 123.6, 78.7, 77.3, 60.0 (q, J = 32.3 Hz, 1C), 59.6, 45.0 (q, J = 29.3 Hz, 1C), 21.5; HRMS (ESI-TOF) Calcd. for C 25 H 17 F6NO2SNa [M+Na] +: 532.0776; found: 532.0775.

[0099] Example 16: Synthesis of Compound (Ⅲ-p)

[0100]

[0101] In a dry reaction tube, add benzothiophenedione-derived trifluoroethylimine (I-a) (0.13 mmol), β-trifluoromethyl ketene (II-k) (0.10 mmol), chiral catalyst D (0.02 mmol), and then add 0.5 mL of solvent. Stir the reaction at room temperature for 48 h. After the reaction is complete, the crude product is separated and purified by column chromatography to obtain Compound Ⅲ-p.

[0102] The yield, melting point, stereoselectivity, optical rotation, 1H NMR, 13C NMR, and mass spectrometry data of the obtained Ⅲ-p are as follows: 62% yield, melting point 168.4 - 169.3 °C; >20:1 dr, 97% ee; [α] D 20 = -19.7 (c 0.4, CH2Cl2); The ee was determined by HPLC (Chiralpak AD-H, EtOH / hexane = 10 / 90, flow rate 1.0 mL / min, λ = 254 nm, t minor = 5.5 min, t major = 8.8 min); 1 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.26 (d, J = 4.5 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 3.8 Hz, 1H), 7.10 (dd, J = 2.7, 1.3 Hz, 1H), 7.00 (d, J = 7.9 Hz, 1H), 4.48 (p, J = 7.4 Hz, 2H), 4.17 (d, J = 9.4 Hz, 1H), 2.68 (d, J = 4.4 Hz, 1H), 2.49 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 202.7, 185.3, 140.8, 138.1, 137.2, 133.2, 131.9, 131.9, 127.3, 126.4, 125.6 (q, J = 279.8 Hz, 1C), 124.6, 124.4 (q, J = 282.8 Hz, 1C), 123.7, 121.4, 78.7, 77.4, 61.3, 60.4 (q, J = 30.3 Hz, 1C), 44.8 (q, J = 28.2 Hz, 1C), 21.5; HRMS (ESI-TOF) Calcd. for C19 H 13 F6NO2SNa[M+Na] + : 488.0184; found: 488.0187.

[0103] Example 17

[0104] Activity experiment of the compounds prepared in Examples 1 - 16

[0105] Specific experimental operation: Using two cancer cell lines, namely leukemia cell K562 and human lung cancer cell A549, the anticancer activity of chiral bis(trifluoromethylated) spirobenzothiophenone pyrrolidine derivatives was evaluated by the MTT method. 5000 human leukemia cells K562 and human lung cancer cells A549 were respectively inoculated into 96 - well cell culture plates and allowed to grow for 24 hours. Then, a certain concentration of the above - synthesized compounds was added respectively, with the antitumor drug cisplatin as a control, and the cells were treated for 48 h. Then, the average 50% inhibitory concentration (IC 50 ) was measured. Each concentration was repeated at least 3 times, and all experiments were repeated 3 times. The average results are shown in Table 1.

[0106] Table 1: Results of cell activity assay

[0107]

[0108]

[0109] As can be seen from Table 1, the compounds of the present invention have both anti - K562 and anti - A549 activities.

[0110] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. Chiral bis(trifluoromethylated) spirobenzothiophenone-fused pyrrolidine derivatives, characterized in that, It has the structure shown in the following structural formula: 。 2. The preparation method of the chiral bis(trifluoromethylated) spirobenzothiophenone pyrrolidine derivatives according to claim 1, characterized in that: Dissolve the trifluoroethylimine (Ⅰ-a) derived from benzothiophenedione and β-trifluoromethyl ketene (Ⅱ-j) in an organic solvent, then add a chiral catalyst and stir the reaction at room temperature for 48 h. After the reaction is completed, separate and purify to obtain the product (Ⅲ-o). Among them, the trifluoroethylimine (Ⅰ-a) derived from benzothiophenedione has the following structure: , wherein, R is methyl; β-trifluoromethyl ketene (Ⅱ-j) has the following structure: , wherein, Ar is a naphthyl group; The chiral catalyst has the structure as shown in Formula D: 。 3. The method according to claim 2, characterized in that: The reaction solvent is selected from one or more of toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, ether, acetonitrile, ethanol, methanol, 1,4-dioxane, chlorobenzene.

4. The method according to claim 3, characterized in that: The reaction solvent is dichloromethane.

5. Use of the chiral bis(trifluoromethylated) spirobenzothiophenone pyrrolidine derivatives according to claim 1 in the preparation of anti-cancer drugs, characterized in that, The cancers are human leukemia cell K562 and human lung cancer cell A549.

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