Polycyclic spiropyrrolidine compound and preparation method thereof

Abstract

The invention relates to the technical field of chemical synthesis, in particular to a polycyclic spiropyrrolidine compound and a preparation method thereof. The polycyclic spiropyrrolidine compound is prepared by carrying out two-component 1, 3-dipolar cycloaddition reaction on alpha, beta-unsaturated ketone substituted by different substituent groups and (E)-1-methyl-3-(3, 3, 3-trifluoropropylidene) indoline-2-ketone in an organic solvent under the catalytic action of a basic catalyst, the synthesis method is simple, the applicability is wide, and the preparation method is suitable for industrial production. The method can be carried out in a plurality of organic solvents, has good compatibility with a plurality of substituent groups, and has good air stability. The polycyclic spiropyrrolidine compound provided by the invention contains a spiropyrrolidine skeleton with potential biological activity, can provide a compound source for biological activity screening, and has important application value in the field of pharmacy.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a polycyclic spiropyrrolidine compound and its preparation method. Background Technology

[0002] The pyrrolidine ring is a five-membered nitrogen-containing heterocycle, a special structure in medicinal chemistry, and its derivatives are useful skeletons for discovering novel therapeutic agents. The pyrrolidine ring structure is ubiquitous in natural products, drugs, and bioactive compounds, such as spiroxindoles horsfiline, elacomine, and spirulina toxins, and has attracted considerable attention due to its pharmacological activities, including antibacterial, antiviral, and local anesthetic effects.

[0003] The importance of spiropyrrolidine scaffolds has sparked extensive research into efficient synthetic methods for them. Currently, numerous challenges remain in the enantioselective synthesis of spirocyclic pyrrolidines, failing to meet practical needs. However, the catalytic asymmetric 1,3-dipolar cycloaddition of azomethylamine ylides with electron-deficient alkene dipolarophiles provides an efficient route for the synthesis of spirocyclic pyrrolidine derivatives. Electron-deficient alkenes are typically limited to nitroalkenes, ketenes, α,β-unsaturated aldehydes, α,β-unsaturated ketones, and carboxylic acid derivatives.

[0004] Based on this, the present invention uses α,β-unsaturated ketones with different substituents as electron-deficient alkenes to undergo a two-component 1,3-dipolar cycloaddition reaction with (E)-1-methyl-3-(3,3,3-trifluoropropylene)indoline-2-one under the action of an alkaline catalyst, generating a series of novel polycyclic spiropyrrolidine derivatives. The aim is to provide compound sources for bioactivity screening and to provide technical references for their application in the pharmaceutical field. Summary of the Invention

[0005] The purpose of this invention is to provide a polycyclic spiropyrrolidine compound and its preparation method.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] The polycyclic spiropyrrolidine compounds of this invention have the structure shown in the following formula:

[0008]

[0009] R is selected from fluorine, chlorine, bromine, methyl, methoxy, nitro, and N,N-dimethyl.

[0010] Preferably, the polycyclic spiropyrrolidine compounds of the present invention have the following specific structures:

[0011]

[0012] The preparation method of the polycyclic spiropyrrolidine compound of the present invention comprises the following specific steps:

[0013] S1. α,β-unsaturated ketones with different substituents, (E)-1-methyl-3-(3,3,3-trifluoropropylidene)indoline-2-one, and a basic catalyst are stirred in an organic solvent at room temperature for 4-48 h. The general reaction formula is as follows:

[0014]

[0015] Wherein, R is selected from fluorine, chlorine, bromine, methyl, methoxy, nitro, N,N-dimethyl;

[0016] S2. After the reaction is complete, the reaction mixture is purified by silica gel column chromatography to obtain the final product.

[0017] Preferably, in the preparation method of the polycyclic spiropyrrolidine compound of the present invention, the reaction temperature in step S1 is 25°C.

[0018] Preferably, in the preparation method of the polycyclic spiropyrrolidine compound of the present invention, the organic solvent in step S1 is any one of acetonitrile, ethyl acetate, ethanol, tetrahydrofuran, toluene, 1,2-dichloroethane, dichloromethane, and water.

[0019] In a further preferred embodiment, in the method for preparing polycyclic spiropyrrolidine compounds of the present invention, the organic solvent in step S1 is dichloromethane.

[0020] Preferably, in the preparation method of the polycyclic spiropyrrolidine compound of the present invention, the alkaline catalyst in step S1 is any one of DMAP, Et3N, DIPEA, TBD, DABCO, and DBU.

[0021] In a further preferred embodiment, in the method for preparing polycyclic spiropyrrolidine compounds of the present invention, the alkaline catalyst in step S1 is DABCO.

[0022] Preferably, in the preparation method of the polycyclic spiropyrrolidine compound of the present invention, in step S1: the amount of the α,β-unsaturated ketone substituted with different substituents is 0.1 mmol; the amount of (E)-1-methyl-3-(3,3,3-trifluoropropylidene)indoline-2-one is 0.15 mmol; the amount of the alkaline catalyst is 10 mol%; and the amount of the organic solvent is 1 mL.

[0023] Preferably, in the preparation method of the polycyclic spiropyrrolidine compound of the present invention, the eluent for silica gel column chromatography in step S2 is petroleum ether and ethyl acetate in a volume ratio of 9:1.

[0024] The beneficial effects of this invention are:

[0025] 1. This invention provides a series of polycyclic spiropyrrolidine compounds by reacting (E)-1-methyl-3-(3,3,3-trifluoropropylidene)indoline-2-one with α,β-unsaturated ketones substituted with different substituents in an organic solvent under the catalysis of a basic catalyst, resulting in a two-component 1,3-dipolar cycloaddition reaction. The synthetic method is simple and widely applicable, can be carried out in various organic solvents, exhibits good compatibility with various substituents, and demonstrates good air stability. Furthermore, the polycyclic spiropyrrolidine compounds provided by this invention contain a spiropyrrolidine skeleton with potential biological activity, providing a source of compounds for bioactivity screening and possessing significant application value in the pharmaceutical field.

[0026] 2. The inventors screened the types of solvents and basic catalysts that affect the cycloaddition reaction in this study, and found that the optimal basic catalyst for the cycloaddition reaction is 10 mol% DABCO, and the optimal organic solvent is DCM. Attached Figure Description

[0027] Figure 1 This is a single crystal diagram of compound 3a. Detailed Implementation

[0028] The technical solution of the present invention will be described in detail below with reference to specific embodiments. The following embodiments are for explanation and illustration only, and do not constitute a limitation on the technical solution of the present invention.

[0029] Example 1

[0030] The specific steps for preparing compound 3a are as follows:

[0031] (1) (E)-3-benzylbenzylbenzofuran-2(3H)-one (0.1 mmol), (E)-1-methyl-3-(3,3,3-trifluoropropylidene)indoline-2-one (0.15 mmol), and DABCO (0.01 mmol) were stirred in 1.0 mL of dichloromethane at 25 °C for 4 h. The reaction formula is as follows:

[0032]

[0033] (2) After the reaction was completed, the reaction mixture was purified by silica gel column chromatography (the eluent was petroleum ether and ethyl acetate in a volume ratio of 9:1) to obtain compound 3a.

[0034] Example 2

[0035] The specific steps for preparing compound 3a are as follows:

[0036] (1) (E)-3-benzylbenzylbenzofuran-2(3H)-one (0.1 mmol), (E)-1-methyl-3-(3,3,3-trifluoropropylidene)indoline-2-one (0.15 mmol), and DABCO (0.01 mmol) were stirred in 1.0 mL of tetrahydrofuran at 25 °C for 8 h. The reaction formula is as follows:

[0037]

[0038] (2) After the reaction was completed, the reaction mixture was purified by silica gel column chromatography (the eluent was petroleum ether and ethyl acetate in a volume ratio of 9:1) to obtain compound 3a.

[0039] Example 3

[0040] The specific steps for preparing compound 3a are as follows:

[0041] (1) (E)-3-benzylbenzylbenzofuran-2(3H)-one (0.1 mmol), (E)-1-methyl-3-(3,3,3-trifluoropropylidene)indoline-2-one (0.15 mmol), and DBU (0.01 mmol) were stirred in 1.0 mL of dichloromethane at 25 °C for 2 h. The reaction formula is as follows:

[0042]

[0043] (2) After the reaction was completed, the reaction mixture was purified by silica gel column chromatography (the eluent was petroleum ether and ethyl acetate in a volume ratio of 9:1) to obtain compound 3a.

[0044] Example 4

[0045] The specific steps for preparing compound 3a are as follows:

[0046] (1) (E)-3-benzylbenzylbenzofuran-2(3H)-one (0.1 mmol), (E)-1-methyl-3-(3,3,3-trifluoropropylidene)indoline-2-one (0.15 mmol), and TBD (0.01 mmol) were stirred in 1.0 mL of dichloromethane at 25 °C for 1 h. The reaction formula is as follows:

[0047]

[0048] (2) After the reaction was completed, the reaction mixture was purified by silica gel column chromatography (the eluent was petroleum ether and ethyl acetate in a volume ratio of 9:1) to obtain compound 3a.

[0049] Example 5

[0050] Compounds 3b to 3x were prepared using α,β-unsaturated ketones containing different substituents and (E)-1-methyl-3-(3,3,3-trifluoropropylidene)indoline-2-one as reaction substrates, employing the same method and feed ratio as in Example 1. The general reaction formula is:

[0051]

[0052] The reaction times and product structures for preparing different products are as follows:

[0053]

[0054] To further verify the reliability of the present invention and select the optimal solution, the inventors conducted a series of experiments, as follows:

[0055] 1. Optimization of reaction conditions

[0056] To screen for the optimal basic catalyst and organic solvent, the research team first evaluated the reaction between (E)-3-benzylbenzylbenzofuran-2(3H)-one (1a) and (E)-1-methyl-3-(3,3,3-trifluoropropylidene)indoline-2-one (2), with the following general reaction formula:

[0057]

[0058] The results showed that, under the conditions of using DBU as a catalyst and dichloromethane (DCM) as a solvent, the reaction mixture was stirred at room temperature for 2 h, and then purified by silica gel column chromatography to obtain the product pyrrolidine compound 3a in 88% yield, with enantiomeric (dr) > 20:1.

[0059] Subsequently, the research team investigated the effects of various basic catalysts on the above reaction in DCM. The results showed that catalysts TBD, DMAP, triethylamine, DIPEA, and DABCO all effectively promoted the cycloaddition reaction, with yields of product 3a ranging from 85% to 98%. Among these, DABCO yielded the highest product yield. Therefore, DABCO was determined to be the optimal catalyst.

[0060] Furthermore, the research team investigated various reaction solvents and found that solvent polarity and solubility significantly affected the cycloaddition reaction. A 90% yield was obtained after 30 hours of reaction in the highly polar solvent water, but the reaction time was long. In contrast, a 46-hour reaction in the nonpolar solvent toluene yielded only 40% of the reaction. This is likely because the nonpolarity of toluene inhibits the effective dissolution of the substrate and catalyst, resulting in a slow reaction rate. Other solvents, such as ethanol, THF, ethyl acetate, DCE, and acetonitrile, showed acceptable yields, but the reaction times all exceeded 4 hours.

[0061] The effects of different catalysts and solvents on the cycloaddition reaction are shown in Table 1. The single crystal diagram of compound 3a is shown in the figure. Figure 1 As shown in the figure, the combined results of catalyst and solvent screening indicate that adding 10 mol% DABCO to the solvent DCM as a catalyst yields the best results for the above cycloaddition reaction, achieving higher yields and diastereoselectivity.

[0062] Table 1. Effects of different catalysts and solvents on the cycloaddition reaction.

[0063]

[0064]

[0065] 2. Structural characterization of polycyclic spiropyrrolidine compounds

[0066] The specific structures of the polycyclic spiropyrrolidine compounds studied in this research are as follows:

[0067]

[0068] (1) Compound 3a

[0069] (2'R,3S,4'R,5'R)-1”-methyl-4'-phenyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 202.9–204.4 °C; yield 98%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ7.57 (dd, J=7.7, 1.2Hz, 1H), 7.35 (d, J=7.0Hz, 2H), 7.2 8–7.26(m,2H),7.24–7.19(m,2H),7.17–7.13(m,1H),7.08(td,J=7.7,1.0Hz, 1H),7.04–7.00(m,1H),6.74(dt,J=8.2,0.8Hz,1H),6.70–6.68(m,2H),6.55( dt,J=7.8,0.8Hz,1H),5.71–5.64(m,1H),4.46(d,J=9.0Hz,1H),2.88(s,3H); 13C NMR (100MHz, CDCl3) δ177.95,176.04,153.38,143.71,135.03,130.81,129.67,129.50,128.54,127.92,127.50,125.73,1 25.49(q,J=280.7Hz),123.76,123.68,123.48,122.03,110.17,108.28,74.76,63.77,62.52(q,J=30.0Hz),54.40,25.84; 19 F NMR(377MHz, CDCl3)δ-74.08; IR(ATR):3411,3330,1802,1715,1614,1462,1378,1351,1 281,1234,1166,1132,1072,1031,882,800,751,721,701,676,615,594,571,534,491cm - ;HRMS(ESI):Exact mass calcd for C 26 H 19 F3N2NaO3[M+Na] + :487.1240,Found:487.1237.

[0070] (2) Compound 3b

[0071] (2'R,3S,4'R,5'R)-4'-(2-methoxyphenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione): White solid; melting point 229.1–230.3 °C; yield 97%. Results of NMR and high-resolution mass spectrometry are as follows: 11H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.6 Hz, 1H), 7.58 (dd, J = 7.7, 1.2 Hz, 1H), 7.26–7.22 (m, 1H), 7.15 (td, J = 7.8, 1.6 Hz, 1H), 7.09–7.03 (m, 2H), 6.99 (td, J = 7.8, 1.4 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.57–6.51 (m, 2H), 6.39 (dd, J = 8.2, 1.1 Hz, 1H), 6.28 (dd, J = 7.8, 1.3 Hz, 1H), 5.90–5.85 (m, 1H), 4.59 (d, J = 9.3 Hz, 1H), 3.15 (s, 3H), 3.06 (d, J = 8.1 Hz, 1H), 2.82 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ 178.25, 176.03, 156.72, 153.76, 143.87, 130.70, 129.02, 128.52, 127.13, 126.41, 125.68, 125.58 (q, J = 280.2 Hz), 124.61, 123.63, 123.39, 123.24, 122.76, 120.41, 109.40, 109.36, 108.17, 74.06, 62.60, 59.60 (q, J = 29.8 Hz), 54.34, 47.54, 25.62; 19 19F NMR (377 MHz, CDCl3) δ -73.94; IR (ATR): 3553, 3477, 3414, 3312, 3234, 3006, 2九百三十八年, 2836, 1795, 1714, 1614, 1495, 1462, 1377, 1281, 1248, 1188, 1139, 1120, 1078, 1028, 936, 875, 825, 753, 677, 677, 677, 677, 677, 623, 602, 570, 510, 492, 470 cm -1 ; HRMS (ESI): Exact mass calcd for C 27 H 21 F3N2NaO4 [M+Na] + : 517.1346, Found: 517.1345.

[0072] (3) Compound 3c

[0073] (2'R,3S,4'R,5'R)-4'-(3-methoxyphenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 202.5–204.5 °C; yield 97%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ7.56 (dd, J=7.6, 1.2Hz, 1H), 7.28–7.24 (m, 1H), 7.15– 7.08(m,2H),7.06–7.02(m,1H),6.97(d,J=7.7Hz,1H),6.90(s,1H),6.77–6 .72(m,3H),6.71–6.81(m,1H),6.54(dt,J=7.7,0.7Hz,1H),5.68–5.59(m,1 H),4.42(d,J=8.9Hz,1H),3.70(s,3H),3.08(d,J=8.2Hz,1H),2.88(s,3H); 13 C NMR (100MHz, CDCl3) δ177.95,175.97,159.61,153.34,143.70,136.50,130.80,129.70,129.50,127.40,125.71,125.46(q,J=280.6Hz ),123.74,123.63,123.56,121.99,121.82,115.21,113.48,110.16,108.27,74.66,63.69,62.66(q,J=29.9Hz),55.34,54.39,25.84; 19 FNMR(376MHz, CDCl3)δ-74.09; IR(ATR):3309,3050,2841,1807,1715,1610,1493,1466,1375,1 349,1278,1227,1163,1131,1083,1042,1029,995,879,754,696,627,605,574,521,487,466cm -1 ;HRMS(ESI):Exact mass calcd forC 27 H 21 F3N2NaO4[M+Na] + :517.1346,Found:517.1359.

[0074] (4) Compound 3d

[0075] (2'R,3S,4'R,5'R)-4'-(4-methoxyphenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 188.4–189.9 °C; yield 99%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ7.56 (dd, J=7.6, 1.2Hz, 1H), 7.29–7.24 (m, 3H), 7.10–7.02 (m, 2H), 6.76–6.73 (m, 5H), 6. 55(d,J=7.7Hz,1H),5.63–5.54(m,1H),4.41(d,J=9.0Hz,1H),3.73(s,3H),3.09(d,J=8.3Hz,1H),2.88(s,3H); 13 C NMR (100MHz, CDCl3) δ177.93,176.08,159.06,153.35,143.66,130.76,130.63,129.62,127.60,127.05,125.71,125.53(q,J= 280.7Hz),123.92,123.65,123.58,122.12,113.86,110.16,108.27,74.70,63.81,62.93(q,J=29.6Hz),55.27,53.89,25.85; 19 F NMR(377MHz, CDCl3)δ-74.08; IR(ATR):3414,3304,2931,2839,1803,1708,1614,1516,146 2,1377,1285,1159,1136,1081,1029,999,944,911,879,754,741,677,647,595,539,483cm -1 ;HRMS(ESI):Exact mass calcd for C 27 H 21 F3N2NaO4[M+Na] + :517.1346,Found:517.1352.

[0076] (5) Compound 3e

[0077] (2'R,3S,4'R,5'R)-1”-methyl-4'-(o-tolyl)-5'-(trifluoromethyl)-2H-dispiro[benzofura n-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 220.5–222.2 °C; yield 86%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ8.12(dd,J=8.0,1.2Hz,1H),7.55(dd,J=7.6,1.2Hz,1H),7.35–7.30( m,1H),7.28–7.23(m,1H),7.10–7.06(m,2H),7.02(td,J=7.8,1.4Hz,1H),6.88(d,J=7.5Hz ,1H),6.73(dd,J=8.0,1.0Hz,1H),6.64(td,J=7.7,1.1Hz,1H),6.52(dd,J=7.9,1.1Hz,2H) ,5.84–5.78(m,1H),4.59(d,J=8.8Hz,1H),3.08(d,J=8.2Hz,1H),2.85(s,3H),1.79(s,3H); 13 C NMR (100MHz, CDCl3) δ178.27,175.91,153.37,143.78,137.40,133.73,130.88,130.40,129.68,128.24,127.61,127.26,126.19,12 5.55,125.52(q,J=280.5),123.69,123.45,123.13,121.93,110.02,108.22,75.12,62.66,62.40(q,J=29.8),49.69,25.71,20.16; 19 F NMR(376MHz, CDCl3)δ-74.25; IR(ATR):3054,2941,1803,1716,1611,1493,1462,1401,1376,134 6,1285,1230,1169,1141,1123,1078,1028,991,880,865,741,677,626,599,574,536,489,469cm -1 ;HRMS(ESI):Exact mass calcd for C 27 H 21F3N2NaO3[M+Na] + :501.1396,Found:501.1404.

[0078] (6) Compound 3f

[0079] (2'R,3S,4'R,5'R)-1”-methyl-4'-(m-tolyl)-5'-(trifluoromethyl)-2H-dispiro[benzofur an-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point: 201.5–203.3°C; yield 89%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ7.57(dd,J=7.6,1.1Hz,1H),7.28–7.26(m,2H),7.24–7.22(m,1H),7.13–7.08(m,2H),7.07–7.01(m,2H),6.95( d,J=7.6Hz,1H),6.75–6.69(m,3H),6.55(dd,J=7.9,0.8Hz,1H),5.68–5.61(m,1H),4.42(d,J=9.1Hz,1H),2.88(s,3H),2.22(s,3H); 13 C NMR (100MHz, CDCl3) δ177.89,176.05,153.35,143.70,138.08,134.79,130.76,130.38,129.62,128.65,128.37,127.61,126.32,12 5.78,125.37(q,J=280.8Hz),123.97,123.63,123.43,122.15,110.13,108.26,74.68,63.86,62.52(q,J=2Hz),54.44,25.87,21.50; 19 F NMR(377MHz, CDCl3)δ-74.04; IR(ATR):3552,3476,3415,3295,3235,2929,1802,1705,1638,1617,14 94,1463,1400,1354,1290,1234,1167,1134,1109,1083,1029,991,881,754,738,696,627,479,406cm -1 ;HRMS(ESI):Exact mass calcd for C27 H 22 F3N2O3[M+H] + :479.1577,Found:479.1574.

[0080] (7) Compound 3g

[0081] (2'R,3S,4'R,5'R)-1”-methyl-4'-(p-tolyl)-5'-(trifluoromethyl)-2H-dispiro[benzofura n-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 213.3–214.5 °C; yield 95%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR(400MHz, CDCl3):7.57–7.55(m,1H),7.26–7.22(m,3H),7.08–7.00(m,4H),6.74–6.72(m,3H),6.55– 6.53(m,1H),5.67–5.58(m,1H),4.43(d,J=9.0Hz,1H),3.09(d,J=8.1Hz,1H),2.87(s,3H),2.24(s,3H); 13 C NMR (100MHz, CDCl3) δ177.89,176.03,153.30,143.64,137.54,131.84,130.74,129.60,129.33,129.21,127.58,125.68,125. 51(q,J=280.7Hz),123.88,123.60,123.49,122.08,110.10,108.25,74.70,63.76,62.62(q,J=29.9Hz),54.05,25.81,21.15; 19 F NMR(376MHz, CDCl3)δ-74.06; IR(ATR):3307,3476,3414,3551,2924,3235,1803,1709,1615,1615,1638,1463,1400,1378,1 287,1351,1235,1136,1136,1159,1081,880,755,1026,993,944,909,676,623,593,476,538,538,568,738,738,738,824cm -1 ;HRMS(ESI):Exact mass calcd for C27 H 21 F3N2NaO3[M+Na] + :501.1396,Found:501.1405.

[0082] (8) Compound 3h

[0083] (2'R,3S,4'S,5'R)-4'-(2-fluorophenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 195.5–197.3 °C; yield 91%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ7.95(t,J=7.5Hz,1H),7.57–7.55(m,1H),7.28–7.23(m,2H),7.20–7.14(m,1H),7.10–7.03(m,2H),6.78(d,J=8.0Hz,1H) ,6.69–6.60(m,2H),6.54(d,J=7.8Hz,1H),6.37(d,J=7.8Hz,1H),5.86– 5.77(m,1H),4.64(d,J=8.8Hz,1H),3.13(d,J=8.3Hz,1H),2.86(s,3H); 13 C NMR (100MHz, CDCl3) δ177.87, 175.79, 161.11 (d, J = 245.5Hz), 153.88, 143.83, 130.92 ,129.77,129.37(d,J=8.7Hz),128.57(d,J=3.2Hz),126.62,125.59,125.34(q,J=280. 6Hz),124.21(d,J=3.4Hz),123.80,123.38(d,J=13.9Hz),123.23,122.98,121.88,11 4.84(d,J=21.9Hz),110.22,108.32,74.66,62.57,60.47(q,J=30.3Hz),46.28,25.70; 19F NMR(377MHz, CDCl3)δ-74.10,-113.61; IR(ATR):3678,3313,2938,1792,1715,1638,1493,1474,1461,1388,1345,13 30,1262,1233,1188,1138,1109,1080,1042,947,888,875,784,764,753,709,677,648,624,602,572,514,489,428cm -1 ;HRMS(ESI):Exact mass calcd for C 26 H 18 F4N2NaO3[M+Na] + :505.1146,Found:505.1165.

[0084] (9) Compound 3i

[0085] (2'R,3S,4'R,5'R)-4'-(3-fluorophenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 187.1–188.5 °C; yield 99%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ7.55 (dd, J=7.7, 1.2Hz, 1H), 7.29–7.26 (m, 1H), 7.25 –7.19(m,1H),7.18–7.14(m,1H),7.10–7.03(m,3H),6.89–6.84(m,1H),6.7 6(dt,J=8.2,0.9Hz,1H),6.74–6.69(m,2H),6.55(dt,J=7.8,0.7Hz,1H),5. 66–5.58(m,1H),4.42(d,J=8.9Hz,1H),3.09(d,J=8.2Hz,1H),2.89(s,3H); 13C NMR (100MHz, CDCl3) δ177.88, 175.93, 162.85 (d, J = 246.3Hz), 153.44, 143.75, 137.73 (d,J=7.4Hz),130.92,130.04(d,J=8.4Hz),129.91,127.28,125.69,125.46(d,J=2.9H z),125.35(q,J=280.9Hz),123.75,123.69,123.42,121.68,116.56(d,J=22.4Hz),11 4.96(d,J=21.0Hz),110.36,108.36,74.74,63.50,62.81(q,J=29.9Hz),54.06,25.85; 19 F NMR(377MHz, CDCl3)δ-74.15,-112.37; IR(ATR):3514,3438,3292,3073,2920,1803,1708,1694,1614,1592,1 463,1378,1290,1242,1153,1138,1113,1084,1030,966,927,882,754,741,695,677,630,559,537,521,495cm -1 ;HRMS(ESI):Exactmass calcd for C 26 H 18 F4N2NaO3[M+Na] + :505.1146,Found:505.1139.

[0086] (10) Compound 3j

[0087] (2'R,3S,4'R,5'R)-4'-(4-fluorophenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 197.1–198.8 °C; yield 83%. Results of NMR and high-resolution mass spectrometry are as follows: 11H NMR (400 MHz, CDCl3) δ 7.56–7.54 (m, 1H), 7.38–7.34 (m, 2H), 7.28–7.24 (m, 1H), 7.10–7.03 (m, 2H), 6.94–6.89 (m, 2H), 6.77–6.72 (m, 2H), 6.69–6.66 (m, 1H), 6.56 (d, J = 7.8 Hz, 1H), 5.63–5.58 (m, 1H), 4.42 (d, J = 8.9 Hz, 1H), 3.10 (d, J = 8.0 Hz, 1H), 2.89 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ 177.90, 176.02, 162.25 (d, J = 247.1 Hz), 153.42, 143.69, 131.23 (d, J = 8.2 Hz), 130.99 (d, J = 3.5 Hz), 130.89, 129.83, 127.38, 125.69, 125.41 (q, J = 280.7 Hz), 123.75, 123.68, 123.56, 121.82, 115.50 (d, J = 21.6 Hz), 110.33, 108.36, 74.75, 63.56, 62.99 (q, J = 29.7 Hz), 53.78, 25.85; 19 19F NMR (377 MHz, CDCl3) δ -74.12, -114.15; IR (ATR): 3414, 3237, 1809, 1712, 1638, 1615, 1516, 1476, 1462, 1417, 1379, 1355, 1284, 1231, 1166, 1132, 1095, 1068, 1031, 995, 886, 840, 751, 675, 588, 588, 569, 535, 491, 456, 409 cm -1 ; HRMS (ESI): Exact mass calcd for C 26 H 19 F4N2O3 [M+H] + : 483.1326, Found: 483.1334.

[0088] (11) Compound 3k

[0089] (2'R,3S,4'S,5'R)-4'-(2-chlorophenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 236.2–237.4 °C; yield 63%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ8.14–8.12(m,1H),7.56(dd,J=7.7,1.2Hz,1H),7.41(td,J=7. 7,1.4Hz,1H),7.28–7.24(m,2H),7.14(td,J=7.7,1.5Hz,1H),7.10–7.02(m,3H),6. 75(dt,J=8.0,0.8Hz,1H),6.60(td,J=7.7,1.1Hz,1H),6.53(dt,J=7.8,0.7Hz,1H), 6.32(dd,J=7.8,1.4Hz,1H),5.86–5.79(m,1H),4.77(d,J=8.8Hz,1H),2.85(s,3H); 13 CNMR(100MHz, CDCl3)δ177.87,175.73,154.03,143.82,136.10,133.60,130.93,129.75,129.51,129.26,128.89,126.94,126.40, 125.57,125.36(q,J=280.6Hz),123.82,123.19,122.78,121.85,110.18,108.30,74.90,62.48,61.29(q,J=30.2Hz),50.15,25.69; 19 F NMR(377MHz, CDCl3)δ-74.14; IR(ATR):3469,3343,2924,1808,1711,1613,1462,1373,13 45,1281,1232,1172,1146,1134,1070,1035,991,945,880,754,676,623,572,493,471cm -1 ;HRMS(ESI):Exactmass calcd for C 26 H 17 Cl2F3N2NaO3[M+Na] + :555.0460,Found:555.0461.

[0090] (12) Compound 3l

[0091] (2'R,3S,4'R,5'R)-4'-(3-chlorophenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 205.9–206.7 °C; yield 95%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR(400MHz, CDCl3)δ7.55(dd,J=7.7,1.2Hz,1H),7.40(s,1H),7.29–7.24(m,2H),7.16–7.14(m,2H),7.10–7.07(m,1H),7.06–7 .04(m,1H),6.77–6.70(m,3H),6.56–6.54(m,1H),5.66–5.57(m,1H),4.39(d,J=8.9Hz,1H),3.09(d,J=8.1Hz,1H),2.89(s,3H); 13 C NMR (100MHz, CDCl3) δ177.82,175.89,153.40,143.72,137.24,134.44,130.92,129.94,129.78,129.73,128.17,127.81,127. 31,125.66,125.14(q,J=280.8Hz),123.72,123.38,121.58,110.39,108.36,74.71,63.44,62.71(q,J=30.3Hz),54.01,25.85; 19 F NMR(376MHz, CDCl3)δ-74.11; IR(ATR):3413,3295,3069,2925,1803,1706,1615,1574,1475,1376,1290, 1234,1167,1135,1021,991,945,898,881,813,794,755,717,693,676,628,597,579,510,479,462,418cm -1 ;HRMS(ESI):Exact mass calcd for C 26 H 18 ClF3N2NaO3[M+Na] +:521.0850,Found:521.0858.

[0092] (13) Compound 3m

[0093] (2'R,3S,4'R,5'R)-4'-(4-chlorophenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 206.9–208.4 °C; yield 99%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ7.55(dd,J=7.7,1.1Hz,1H),7.32(d,J=8.1Hz,2H),7.29–7.24(m,1H),7.21–7.19(m,2H),7.11–7.04(m,2H),6.75(td,J =8.1,7.5,1.0Hz,2H),6.68–6.66(m,1H),6.56(d,J=7.8Hz,1H),5.65–5.56(m,1H),4.40(d,J=8.9Hz,1H),3.10(d,J=8.2Hz,1H),2.89(s,3H); 13 C NMR (100MHz, CDCl3) δ177.86,175.95,153.40,143.68,133.78,133.74,130.94,130.92,129.92,128.76,127.34,125.66,1 25.35(q,J=279.9Hz),123.96,123.78,123.43,121.66,110.36,108.38,74.77,63.46,62.81(q,J=30.2Hz),53.78,25.84; 19 F NMR(376MHz, CDCl3)δ-74.12; IR(ATR):3560,3411,3305,1800,1709,1638,1616, 1495,1463,1378,1285,1232,1160,1138,1085,944,880,676,624,576,537,481cm -1 ;HRMS(ESI):Exactmass calcd for C 26 H 18 ClF3N2NaO3[M+Na] +:521.0850,Found:521.0855.

[0094] (14) Compound 3n

[0095] (2'R,3S,4'S,5'R)-4'-(2-bromophenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 260.1–262.2 °C; yield 53%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ8.18 (dd, J=7.9, 1.5Hz, 1H), 7.56 (dd, J=7.6, 1.1Hz, 1H ),7.46(td,J=7.6,1.3Hz,1H),7.29–7.24(m,3H),7.11–7.02(m,3H),6.75(d t,J=8.0,0.8Hz,1H),6.61(td,J=7.7,1.1Hz,1H),6.52(dt,J=7.8,0.7Hz,1H ),6.34–6.32(m,1H),5.82–5.76(m,1H),4.78(d,J=8.7Hz,1H),2.85(s,3H); 13 C NMR (100MHz, CDCl3) δ177.77,175.73,154.07,143.81,135.22,132.65,130.94,130.13,129.78,129.18,127.59,127.51,126.39,1 25.59,125.37(q,J=280.5Hz),123.81,123.23,122.74,121.83,110.24,108.28,75.00,62.49,61.88(q,J=29.9Hz),52.56,25.70; 19 F NMR(377MHz, CDCl3)δ-74.16; IR(ATR):3413,3332,3064,2971,1794,1705,1617,1495,1463,1395,1377,1354,1 286,1233,1162,1140,1081,1070,1023,950,912,882,868,802,767,743,697,675,622,597,571,538,493,468cm -1;HRMS(ESI):Exact mass calcd for C 26 H 19 BrF3N2O3[M+H] + :543.0526,Found:543.0522.

[0096] (15) Compound 3o

[0097] (2'R,3S,4'R,5'R)-4'-(3-bromophenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 211.8–213.4 °C; yield 98%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ7.56–7.53(m,2H),7.36–7.28(m,2H),7.27–7.25(m,1H),7.13–7.04(m,3H),6.78–6.74(m,2H),6.71( dd,J=7.9,1.5Hz,1H),6.56(d,J=7.8Hz,1H),5.66–5.57(m,1H),4.38(d,J=8.9Hz,1H),3.09(d,J=7.9Hz,1H),2.90(s,3H); 13 C NMR (100MHz, CDCl3) δ177.81,175.88,153.42,143.74,137.52,132.67,131.12,130.93,130.07,129.96,128.22,127.35,125. 68,125.30(q,J=280.7Hz),123.74,123.39,122.62,121.59,110.42,108.37,74.72,63.48,62.74(q,J=29.9Hz),54.03,25.88; 19 FNMR(376MHz, CDCl3)δ-74.09; IR(ATR):3552,3477,3414,3294,3065,2922,1803,1705,1615,1463,1397, 1376,1354,1289,1233,1166,1135,1083,1029,991,945,881,813,755,693,628,596,492,478,461,406cm -1;HRMS(ESI):Exact mass calcd for C 26 H 18 BrF3N2NaO3[M+Na] + :565.0345,Found:565.0346.

[0098] (16) Compound 3p

[0099] (2'R,3S,4'R,5'R)-4'-(4-bromophenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 204.5–206.7 °C; yield 98%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR(400MHz, CDCl3)δ7.54(dd,J=7.6,1.2Hz,1H),7.36–7.34(m,2H),7.28–7.24(m,3H),7.09–7.08(m,1H),7.06–7.04(m,1H),6.77– 6.74(m,2H),6.68–6.66(m,1H),6.55(d,J=7.8Hz,1H),5.65–5.56(m,1H),4.38(d,J=8.9Hz,1H),3.10(d,J=8.2Hz,1H),2.88(s,3H); 13 C NMR (100MHz, CDCl3) δ177.82,175.94,153.40,143.69,134.28,131.71,131.28,130.92,129.93,127.35,125.65,125.35(q ,J=280.8Hz),123.79,123.76,123.42,121.98,121.65,110.36,108.37,74.79,63.41,62.76(q,J=29.9Hz),53.84,25.83; 19 F NMR(376MHz, CDCl3)δ-74.12; IR(ATR):3414,3303,2928,1801,1706,1614,1492,1463,1378,1352, 1287,1234,1159,1136,1082,1012,943,910,879,754,738,696,675,644,594,573,537,492,477cm-1 ;HRMS(ESI):Exact mass calcd for C 26 H 19 BrF3N2O3[M+H] + :543.0526,Found:543.0525.

[0100] (17) Compound 3q

[0101] (2'R,3S,4'R,5'R)-1”-methyl-4'-(4-nitrophenyl)-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 201.8–202.4 °C; yield 99%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ8.11–8.09(m,2H),7.59(d,J=8.2Hz,2H),7.55(dd,J=7.6,1.2Hz,1H),7.30–7.26(m,2H),7.12–7.05(m,2H), 6.79(dd,J=8.1,1.1Hz,1H),6.71(td,J=7.7,1.1Hz,1H),6.60–6.56(m,2H),5.74–5.68(m,1H),4.50(d,J=8.7Hz,1H),2.91(s,3H); 13 CNMR (100MHz, CDCl3) δ177.67,175.80,153.50,147.44,143.73,142.84,131.14,130.69,130.29,126.97,125.64,125. 18(q,J=281.1Hz),123.94,123.73,122.91,121.16,110.67,108.52,74.89,63.25,62.77(q,J=30.6Hz),53.92,25.86; 19FNMR(377MHz, CDCl3)δ-74.02; IR(ATR):3414,3291,3236,1799,1717,1615,1515,1461,1385,1348,1266,1232,118 7,1135,1116,1078,1078,1044,1023,988,936,914,877,842,758,691,622,597,536,536,536,536,536,536,485cm -1 ;HRMS(ESI):Exact mass calcd for C 26 H 18 F3N3NaO5[M+Na] + :5532.1091,Found:5532.1086.

[0102] (18) Compound 3r

[0103] (2'R,3S,4'R,5'R)-4'-(4-(dimethylamino)phenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 173.2–174.2 °C; yield 86%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ7.57(dd,J=7.6,1.2Hz,1H),7.27–7.25(m,2H),7.23–7.19(m,2H),7.09(dd,J=7.7,1.0Hz,1H),7.06–7.01(m,1H),6.81(d d,J=7.9,1.6Hz,1H),6.77–6.73(m,2H),6.59–6.54(m,2H),5.55–5.53( m,1H),4.39(d,J=9.1Hz,1H),3.08–3.03(m,1H),2.88(d,J=1.9Hz,9H); 13C NMR (100MHz, CDCl3) δ177.67,175.80,153.50,147.44,143.73,142.84,131.14,130.69,130.29,126.97,125.64,125. 18(q,J=281.1Hz),123.94,123.73,122.91,121.16,110.67,108.52,74.89,63.25,62.77(q,J=30.6Hz),53.92,25.86; 19 F NMR(377MHz, CDCl3)δ-74.02; IR(ATR):3558,3412,3304,1803,1707,1615,1525,1478,1462,137 7,1350,1285,1235,1159,1125,1081,1027,947,880,814,757,694,677,646,589,567,539,483cm - ;HRMS(ESI):Exact mass calcd for C 28 H 24 F3N3NaO3[M+Na] + :530.1662,Found:530.1657.

[0104] (19) Compound 3s

[0105] (2'R,3S,4'R,5'R)-4'-(3,4-dimethylphenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 191.2–192.5 °C; yield 99%. Results of NMR and high-resolution mass spectrometry are as follows: 11H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 7.6, 1.2 Hz, 1H), 7.28–7.24 (m, 1H), 7.17–7.15 (m, 1H), 7.09 (dd, J = 7.7, 1.1 Hz, 1H), 7.07–7.03 (m, 1H), 7.01–6.97 (m, 2H), 6.80–6.77 (m, 1H), 6.75–6.71 (m, 2H), 6.55 (d, J = 7.7 Hz, 1H), 5.64–5.55 (m, 1H), 4.40 (d, J = 9.1 Hz, 1H), 3.07 (d, J = 8.2 Hz, 1H), 2.88 (s, 3H), 2.13 (d, J = 7.6 Hz, 6H); 13 13C NMR (100 MHz, CDCl3) δ 177.82, 176.05, 153.32, 143.66, 136.58, 136.17, 132.08, 130.90, 130.70, 129.72, 129.55, 127.73, 126.58, 125.76, 125.58 (q, J = 285.3 Hz), 124.15, 123.58, 123.42, 122.25, 110.09, 108.23, 74.67, 63.93, 62.68 (q, J = 29.9 Hz), 54.18, 25.88, 19.85, 19.50; 19 19F NMR (377 MHz, CDCl3) δ -74.00; IR (ATR): 3469, 3308, 2920, 1801, 1712, 1638, 1615, 1462, 1377, 1354, 1285, 1232, 1133, 1083, 1028, 927, 880, 819, 754, 678, 646, 581, 492 cm -1 ; HRMS (ESI): Exact mass calcd for C 28 H 23 F3N2NaO3 [M+Na] + : 515.1553, Found: 515.1552.

[0106] (Compound 3t)

[0107] (2'R,3S,4'R,5'R)-4'-(3,5-dimethylphenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 221.3–222.2 °C; yield 84%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR(400MHz, CDCl3)δ7.58(dd,J=7.7,1.1Hz,1H),7.29–7.24(m,1H),7.11–7.07(m,1H),7.06–7.01(m,1H),6.92(s,2H),6.80– 6.72(m,4H),6.55(d,J=7.8Hz,1H),5.66–5.56(m,1H),4.40(d,J=9.2Hz,1H),3.07(d,J=7.9Hz,1H),2.88(s,3H),2.20(s,6H); 13 CNMR(100MHz, CDCl3)δ177.82,176.06,153.29,143.67,137.85,134.50,130.71,129.57,129.53,127.69,127.21,125.81,125 .48(q,J=288.2Hz),124.16,123.57,123.37,122.23,110.09,108.23,74.57,63.92,62.45(q,J=29.7Hz),54.41,25.91,21.42; 19 F NMR(376MHz, CDCl3)δ-73.99; IR(ATR):3303,3005,2916,1800,1708,1614,1462,1375,1353,1286,1 231,1113,1085,1028,991,926,880,819,767,755,719,695,678,640,602,580,562,494,477,446cm -1 ;HRMS(ESI):Exact mass calcd for C 28 H 23 F3N2NaO3[M+Na] + :515.1553,Found:515.1552.

[0108] (21) Compound 3u

[0109] (2'R,3S,4'R,5'R)-1”-methyl-5'-(trifluoromethyl)-4'-(2,3,4-trimethoxyphenyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 155.5–156.7 °C; yield 83%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ7.57 (dd, J=7.6, 1.2Hz, 1H), 7.48 (d, J=8.7Hz, 1H), 7.26–7.2 2(m,2H),7.08(td,J=7.7,1.0Hz,1H),7.01–6.96(m,1H),6.75–6.70(m,2H),6.61(t d,J=7.7,1.0Hz,1H),6.52(d,J=7.8Hz,1H),6.36(dd,J=7.8,1.3Hz,1H),5.79–5.72 (m,1H),4.54(d,J=9.3Hz,1H),3.84(s,3H),3.50(s,3H),3.27(s,3H),2.82(s,3H); 13 C NMR (100MHz, CDCl3) δ 178.39, 176.13, 154.08, 153.25, 151.52, 143.82, 141.30, 130.72, 129.10, 126.78, 125.63, 125.59 (q, J = 280.3Hz), 123. 69,123.42,123.16,122.98,121.90,121.72,109.83,108.17,106.18, 74.32,62.84,60.50,60.12(q,J=30.0Hz),59.69,56.06,47.59,25.64; 19 F NMR (377MHz, CDCl3) δ-74.04; IR (ATR): 3477, 3414, 3300, 3235, 2940, 1803, 1717, 1616, 1498, 1464, 1422 ,1384,1352,1286,1252,1252,1233,1134,1096,1028,1001,948,911,881,807,764,681,623,487,455cm -1 ;HRMS(ESI):Exact mass calcd forC 29 H26 F3N2O6[M+H] + :555.1737,Found:555.1740.

[0110] (22) Compound 3v

[0111] (2'R,3S,4'R,5'R)-4'-(3,4-dichlorophenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 208.4–209.7 °C; yield 92%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ7.54–7.52(m,2H),7.32–7.25(m,3H),7.11–7.06(m,2H),6.82–6.78(m,2H),6.72–6.70 (m,1H),6.56(d,J=7.8Hz,1H),5.60–5.52(m,1H),4.35(d,J=8.8Hz,1H),3.09(d,J=8.2Hz,1H),2.90(s,3H); 13 C NMR (100MHz, CDCl3) δ177.73,175.84,153.48,143.74,135.64,132.72,132.12,131.68,131.02,130.50,130.15,129.04,127.23,1 25.64,125.20(q,J=286.4Hz),123.96,123.83,123.19,121.37,110.56,108.44,74.79,63.28,63.24(q,J=30.2Hz),53.61,25.88; 19 F NMR(377MHz, CDCl3)δ-74.11; IR(ATR):3559,3411,3304,2923,2852,1799,1706,1614,1491,1463,1414,1378,135 2,1288,1233,1162,1128,1084,1028,945,879,845,806,754,737,694,678,678,647,602,587,538,523,497,459cm -1 ;HRMS(ESI):Exact mass calcd for C26 H 18 ClF3N2NaO3[M+Na] + :521.0850,Found:521.0853.

[0112] (23) Compound 3w

[0113] (2'R,3S,4'R,5'R)-4'-(3,5-dichlorophenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 240.2–241.8 °C; yield 90%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ7.53(dd,J=7.6,1.2Hz,1H),7.33(s,2H),7.29–7.26(m,2H),7.18(t,J=1.9Hz,1H),7.12–7.09(m,1H),7.08–7. 06(m,1H),6.83–6.78(m,2H),6.75–6.73(m,1H),6.56(dt,J=7.8,0.7Hz,1H),5.59–5.52(m,1H),4.32(d,J=8.8Hz,1H),2.91(s,3H); 13 C NMR (100MHz, CDCl3) δ177.69,175.76,153.51,143.79,138.78,135.15,131.04,130.22,128.28,128.26,127.19,125.66 125.17(q,J=280.8Hz),123.95,123.82,123.12,121.27,110.64,108.44,74.74,63.26,63.13,62.98(q,J=30.0Hz),25.91; 19 F NMR(377MHz, CDCl3)δ-74.11; IR(ATR):3477,3414,3235,3077,1798,1706,1617,1567,1475,1399,1379,13 79,1354,1287,1232,1158,1139,1084,1031,923,895,880,800,760,754,693,675,633,600,539,513,492cm -1;HRMS(ESI):Exact mass calcd for C 26 H 18 Cl2F3N2O3[M+H] + :533.0641,Found:533.0640.

[0114] (24) Compound 3x

[0115] (2'R,3S,4'R,5'R)-4'-(3,5-dibromophenyl)-1”-methyl-5'-(trifluoromethyl)-2H-dispiro[benzofuran-3,3'-pyrrolidine-2',3”-indoline]-2,2”-dione: white solid; melting point 229.8–231.4 °C; yield 98%. Results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR (400MHz, CDCl3) δ7.54–7.48(m,4H),7.29–7.25(m,1H),7.13–7.02(m,2H),6.85–6.79(m,2H),6.74(dd,J=7.9 ,1.3Hz,1H),6.57(d,J=7.8Hz,1H),5.59–5.50(m,1H),4.31(d,J=8.8Hz,1H),3.08(d,J=8.1Hz,1H),2.92(s,3H); 13 C NMR (100MHz, CDCl3) δ177.67,175.73,153.48,143.78,139.28,133.75,131.55,131.04,130.24,127.22,125.66,125.43(q ,J=274.2Hz),123.98,123.81,123.11,123.05,121.23,110.65,108.44,74.70,63.28,62.96(q,J=30.5Hz),53.80,25.93; 19 F NMR(376MHz, CDCl3)δ-74.08; IR(ATR):3475,3413,3235,2923,1804,1707,1638,1616,1553,1476,1464,1400,1380,135 5,1284,1235,1165,1134,1096,1081,1029,991,944,922,880,832,805,764,752,738,692,675,630,598,538,512,490cm-1 ;HRMS(ESI):Exact mass calcd for C 26 H 17 Br2F3N2NaO3[M+Na] + :642.9450,Found:642.9442.

[0116] Although the present invention has been described in detail above with general descriptions, specific embodiments, and experiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A polycyclic spiropyrrolidine compound, characterized in that, The compound has the structure shown in the following formula: R is selected from fluorine, chlorine, bromine, methyl, methoxy, nitro, and N,N-dimethyl.

2. The polycyclic spiropyrrolidine compound according to claim 1, characterized in that, The polycyclic spiropyrrolidine compounds specifically have the following structures:

3. The method for preparing polycyclic spiropyrrolidine compounds as described in claim 1, characterized in that, The specific steps are as follows: S1. α,β-unsaturated ketones with different substituents, (E)-1-methyl-3-(3,3,3-trifluoropropylidene)indoline-2-one, and a basic catalyst are stirred in an organic solvent at room temperature for 4-48 h. The general reaction formula is as follows: Wherein, R is selected from fluorine, chlorine, bromine, methyl, methoxy, nitro, N,N-dimethyl; S2. After the reaction is complete, the reaction mixture is purified by silica gel column chromatography to obtain the final product.

4. The method for preparing polycyclic spiropyrrolidine compounds according to claim 3, characterized in that, The reaction temperature in step S1 is 25°C.

5. The method for preparing polycyclic spiropyrrolidine compounds according to claim 3, characterized in that, The organic solvent mentioned in step S1 is any one of acetonitrile, ethyl acetate, ethanol, tetrahydrofuran, toluene, 1,2-dichloroethane, dichloromethane, or water.

6. The method for preparing polycyclic spiropyrrolidine compounds according to claim 5, characterized in that, The organic solvent mentioned in step S1 is dichloromethane.

7. The method for preparing polycyclic spiropyrrolidine compounds according to claim 3, characterized in that, The alkaline catalyst mentioned in step S1 is any one of DMAP, Et3N, DIPEA, TBD, DABCO, and DBU.

8. The method for preparing polycyclic spiropyrrolidine compounds according to claim 7, characterized in that, The alkaline catalyst mentioned in step S1 is DABCO.

9. The method for preparing polycyclic spiropyrrolidine compounds according to claim 3, characterized in that, In step S1: the amount of the α,β-unsaturated ketones substituted with different substituents is 0.1 mmol; the amount of (E)-1-methyl-3-(3,3,3-trifluoropropylidene)indoline-2-one is 0.15 mmol; the amount of the alkaline catalyst is 10 mol%; and the amount of the organic solvent is 1 mL.

10. The method for preparing the polycyclic spiropyrrolidine compound according to claim 3, characterized in that, The eluent for silica gel column chromatography in step S2 is petroleum ether and ethyl acetate in a volume ratio of 9:1.

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