A polysubstituted persulfide furan derivative and its preparation method and application

Abstract

The present invention belongs to the technical field of organic synthesis, and specifically relates to a polysubstituted persulfide furan derivative, a preparation method, and applications thereof. The present invention prepares a polysubstituted persulfide furan derivative by mixing a conjugated alkyne-enone, an acetic acid disulfide derivative, an additive, and a solvent, and stirring the mixture. The method of preparing the polysubstituted persulfide furan derivative of the present invention is simple to operate, does not involve metals, has a wide range of reaction substrate applicability, exhibits good regioselectivity, and provides high yield. It can be used to efficiently and environmentally synthesize a series of polysubstituted persulfide furan derivatives, and has broad application prospects in agrochemicals, pharmaceutical preparation, and fluorescent materials.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a polysubstituted persulfide furan derivative and a preparation method and application thereof. Background Art

[0002] Polysulfides are present in a variety of therapeutic drugs and play unique roles. Sulfur, as a scaffold, is a ubiquitous structural unit in biomolecules. They act as bridges, adding additional stability to the three-dimensional structure of proteins, which is essential for protein folding and function. Furthermore, their pharmacology and pharmacokinetics are often modulated by varying the position or amount of sulfur within the structure.

[0003] Disulfide bonds also enable the efficient connection of biologically active macromolecules through reversible covalent bonding. Compounds containing disulfide bonds are widely present in nature. Disulfide bonds enhance the stability of higher-order structures and are commonly found in natural products, food chemistry, and pharmaceutical chemistry. Examples include disulfide bridges in insulin, allicin, the main component of garlic, and the anticancer drug romidepsin. These higher-order structures are essential for the high efficiency and specificity of biological effects. Therefore, disulfide bonds are of great research value and are a core component of modern drug development. The introduction of disulfide groups to construct asymmetric disulfides has attracted significant attention from organic synthesizers over the past decade. Traditional methods for constructing asymmetric disulfides involve gradually introducing sulfur atoms, i.e., forming SS bonds, to achieve the synthesis of asymmetric disulfides. However, these methods have limitations, such as the strong pungent odor of thiols and the need for the use of transition metals, some of which are precious metals.

[0004] Polysubstituted furans have important applications in organic chemistry, serving not only as key building blocks for a variety of important pharmaceuticals and natural products but also as versatile building blocks for constructing highly complex target structures in numerous total syntheses. Consequently, efforts have been devoted to developing efficient methods for preparing substituted furans.

[0005] In 1990, Marshall's group discovered that ketene can isomerize to furans in acetonitrile in the presence of catalytic amounts of AgNO₃, AgBF₄, or (Ph₃P)₃RhCl. Hashmi found that ketene could also be readily converted to furans using CuCl, [Rh₂(OAc)₄], or [Ru(Cl)₂(CO)₃]₂ as catalysts. Aso et al. discovered that ketene can undergo cyclization / coupling reactions with aryl halides, alkenyl halides, or iodoalkenyl esters catalyzed by Pd(PPh₃)₄ / Ag₂CO₃, thereby forming polysubstituted furans.

[0006]

[0007] Fukuda reported that the Pd-catalyzed cyclization of β,γ-alkynones first formed a palladium intermediate with a furan ring. This intermediate could not only be depalladiumed by protons to form a furan product, but also react with allyl chloride to produce a 3-allylfuran product, as shown below.

[0008]

[0009] Chinese invention patent application CN101805317A discloses a method for synthesizing polysubstituted furan compounds, wherein 3-iodo-2-propene-1-ol undergoes a Sonogashira coupling reaction with a terminal propargyl alcohol to generate 4-alkyne-2-hexene-1,6-diol, which then undergoes an isomeric cyclocoupling reaction with allyl bromide under the catalysis of palladium chloride to generate a series of polysubstituted furan compounds, as shown below.

[0010]

[0011] However, none of the above-mentioned polysubstituted furan compounds involve the introduction of disulfide groups to construct asymmetric disulfides. Therefore, the present invention develops a simple, green and efficient method for synthesizing polysubstituted furan disulfides. Summary of the Invention

[0012] To address the above issues, the present invention provides a polysubstituted persulfide furan derivative, a preparation method, and applications thereof. The polysubstituted persulfide furan derivative prepared by the present invention exhibits certain anti-cancer cell proliferation activity and a good yield in the reaction, showing potential application prospects in industrial production.

[0013] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0014] A polysubstituted persulfide furan derivative, the structural formula of which is as follows:

[0015]

[0016] wherein R is selected from any one of benzyl Bn, thienyl, cyclohexyl, n-hexyl, 4-MeC6H4CH2, 4-MeOC6H4CH2, 4-ClC6H4CH2, and 4-FC6H4CH2;

[0017] R 1 Any one selected from phenyl, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-FC6H4, 4-EtO2CC6H4, 3-FC6H4 and 3-MeC6H4;

[0018] R 2Any one selected from acetyl, propionyl, isobutyryl, benzoyl, CO2Me and CO2Et;

[0019] R 3 Any of methyl, ethyl, isopropyl, phenyl and cyclopropyl.

[0020] The present invention also relates to a method for preparing the polysubstituted persulfide furan derivative, comprising the following steps: mixing a conjugated acetylene ketone, an acetic acid dithioester derivative, an additive, and a solvent, and stirring to obtain a polysubstituted persulfide furan derivative; the structural formulas of the conjugated acetylene ketone and the acetic acid dithioester derivative are as follows:

[0021]

[0022] Preferably, the additive is selected from one or more of p-toluenesulfonic acid, pivalic acid, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0023] Preferably, the solvent is selected from one or more of diethyl ether, dichloromethane, acetone, 1,2-dichloroethane, chloroform, carbon tetrachloride, toluene, trifluorotoluene, chlorobenzene, methylcyclohexane, cyclohexane, cyclopentane, n-hexane, methyl tert-butyl ether, cyclopentane, diethyl ether, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide and water.

[0024] Further preferably, the solvent is selected from one or more of 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, dichloromethane and acetone.

[0025] Preferably, the molar ratio of the conjugated alkyne-enone, the acetic acid disulfide derivative and the catalyst is 1:0.8-2.8:0.5-7.

[0026] More preferably, the molar ratio of the conjugated alkyne-enone, acetic acid disulfide derivative and catalyst is 1:1-2:1-4

[0027] Preferably, the molar volume ratio of the conjugated alkyne-enone to the solvent is 1 mol:20-50 L.

[0028] Preferably, the stirring temperature is 40-80° C., and the stirring time is 2-7 h.

[0029] The present invention also relates to the use of the multi-substituted persulfide furan derivatives in the preparation of anticancer cell drugs.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] The preparation method of the invention can synthesize various persulfide furan derivatives from conjugated ketene and acetyl-masked disulfide nucleophilic reagent under the condition of not containing transition metal.

[0032] The preparation method of the present invention is simple to operate, does not involve metal, has a wide range of application of reaction substrates, good regional selectivity, and high yield. It can be used to synthesize a series of persulfide furan derivatives in a green and efficient manner, and has broad application prospects in agrochemicals, drug preparation, and fluorescent materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is the hydrogen spectrum of the compound prepared in Example 1 of the present invention;

[0034] Figure 2 This is the carbon spectrum of the compound prepared in Example 1 of the present invention;

[0035] Figure 3 This is the hydrogen spectrum of the compound prepared in Example 2 of the present invention;

[0036] Figure 4 This is the carbon spectrum of the compound prepared in Example 2 of the present invention;

[0037] Figure 5 This is the hydrogen spectrum of the compound prepared in Example 3 of the present invention;

[0038] Figure 6 This is the carbon spectrum of the compound prepared in Example 3 of the present invention;

[0039] Figure 7 This is the hydrogen spectrum of the compound prepared in Example 4 of the present invention;

[0040] Figure 8 This is the carbon spectrum of the compound prepared in Example 4 of the present invention;

[0041] Figure 9 This is the hydrogen spectrum of the compound prepared in Example 5 of the present invention;

[0042] Figure 10 This is the carbon spectrum of the compound prepared in Example 5 of the present invention;

[0043] Figure 11 This is the hydrogen spectrum of the compound prepared in Example 6 of the present invention;

[0044] Figure 12 This is the carbon spectrum of the compound prepared in Example 6 of the present invention;

[0045] Figure 13 This is the hydrogen spectrum of the compound prepared in Example 7 of the present invention;

[0046] Figure 14 This is the carbon spectrum of the compound prepared in Example 7 of the present invention;

[0047] Figure 15 This is the hydrogen spectrum of the compound prepared in Example 8 of the present invention;

[0048] Figure 16 This is the carbon spectrum of the compound prepared in Example 8 of the present invention;

[0049] Figure 17 This is the hydrogen spectrum of the compound prepared in Example 9 of the present invention;

[0050] Figure 18 This is the carbon spectrum of the compound prepared in Example 9 of the present invention;

[0051] Figure 19 This is the hydrogen spectrum of the compound prepared in Example 10 of the present invention;

[0052] Figure 20 This is the carbon spectrum of the compound prepared in Example 10 of the present invention;

[0053] Figure 21 This is the hydrogen spectrum of the compound prepared in Example 11 of the present invention;

[0054] Figure 22 This is the carbon spectrum of the compound prepared in Example 11 of the present invention. DETAILED DESCRIPTION

[0055] The technical solutions in the embodiments of the present invention are further clearly described. The described embodiments are only a part of the present invention and are used to explain the present invention, but not to limit the present invention. Therefore, other embodiments obtained by other technicians in this field without creative work all fall within the scope of protection of the present invention.

[0056] The basic raw materials such as the conjugated alkyne ketone and acetic acid disulfide involved in the present invention can be purchased through commercial channels.

[0057] Example 1

[0058] 21.0 mg (0.1 mmol) of conjugated enone (1a), 51.6 mg (0.3 mmol) of p-toluenesulfonic acid (TsOH), and 23.8 mg (0.12 mmol) of SS-benzylethane (peroxydisulfide) (2a) were placed in a 25 mL test tube with a stirring bar. After adding 2 mL of acetone solvent at 25 ° C, the mixture was stirred at 70 ° C for 2 hours. After spin drying, the target product was obtained by flash column chromatography with a yield of 84%.

[0059]

[0060] 1H NMR(400MHz,Chloroform-d)δ7.36-7.34(m,5H),7.33-7.30(m,3H),7.25-7.21(m,2H),6.42( s,1H),4.64(s,1H),3.60(d,J=12.5Hz,1H),3.55(d,J=12.5Hz,1H),2.58(s,3H),2.38(s,3H).

[0061] 13 C NMR (101MHz, CDCl3) δ194.0,158.7,150.4,137.6,137.2,129.5,128.9,128.8,128.7,128.3,127.7,122.2,109.8,53.1,43.4,29.3,14.7.

[0062] HRMS (GC / TOF) m / z: [M] + :Calcd for C 21 H 20 O2S2 368.0905; found:368.0901.

[0063] Example 2

[0064] 21.0 mg (0.1 mmol) of conjugated enone (1a), 51.6 mg (0.3 mmol) of p-toluenesulfonic acid (TsOH), and 25.6 mg (0.12 mmol) of SS-(2-bromobenzyl)ethane (peroxydisulfide) (2b) were placed in a 25 mL test tube with a stirring bar. After adding 2 mL of acetone solvent at 25 ° C, the mixture was stirred at 70 ° C for 2 hours. After spin drying, the target product was obtained by rapid column chromatography with an 80% yield.

[0065]

[0066] 1 H NMR(400MHz,Chloroform-d)δ7.60(d,J=7.9Hz,1H),7.42-7.31(m,5H),7.31-7.27(m,2H),7.23-7.14(m, 1H), 6.42 (s, 1H), 4.62 (s, 1H), 3.79 (d, J = 12.7Hz, 1H), 3.73 (d, J = 12.8Hz, 1H), 2.58 (s, 3H), 2.39 (s, 3H).

[0067] 13C NMR (101MHz, CDCl3) δ194.1,158.8,150.1,137.4,136.8,133.3,131.8,129. 4,128.8,128.8,128.4,127.5,124.8,122.2,110.2,53.3,43.8,29.3,14.7.

[0068] HRMS (GC / TOF) m / z: [M] + :Calcd for C 21 H 19 BrO2S2 446.0010; Found:446.0015.

[0069] Example 3

[0070] 21.0 mg (0.1 mmol) of conjugated enone (1a), 51.6 mg (0.3 mmol) of p-toluenesulfonic acid (TsOH), and 27.5 mg (0.12 mmol) of SS-(4-methoxyphenyl)ethane (peroxydisulfide) (2c) were placed in a 25 mL test tube with a stirring bar. After adding 2 mL of acetone solution at 25 ° C, the mixture was stirred at 70 ° C for 2 hours. After spin drying, the target product was obtained by flash column chromatography with a yield of 86%.

[0071]

[0072] 1 H NMR(400MHz,Chloroform-d)δ7.43-7.31(m,5H),7.14(d,J=8.3Hz,2H),6.87(d,J=8.3Hz,2H),6.46(s,1 H),4.72(s,1H),3.81(s,3H),3.54(d,J=12.4Hz,1H),3.50(d,J=12.4Hz,1H),2.59(s,3H),2.39(s,3H).

[0073] 13 C NMR (101MHz, CDCl3) δ194.0,159.2,158.7,150.5,137.7,130.7,129.0,128.9,128.8,128.3,122.3,114.1,109.8,55.4,53.2,42.8,29.3,14.7.

[0074] HRMS (GC / TOF) m / z: [M] + :Calcd for C 22 H 22O3S2 398.1010; found:398.1016.

[0075] Example 4

[0076] 21.0 mg (0.1 mmol) of conjugated enone (1a), 51.6 mg (0.3 mmol) of p-toluenesulfonic acid (TsOH), and 26.04 mg (0.12 mmol) of SS-(4-fluorophenyl)ethane (peroxydithio) (2d) were placed in a 25 mL test tube with a stirring bar. After adding 2 mL of acetone solution at 25 ° C, the mixture was stirred at 70 ° C for 5 hours. After spin drying, the target product was obtained by flash column chromatography with a yield of 72%.

[0077]

[0078] 1 H NMR(400MHz,Chloroform-d)δ7.39-7.32(m,5H),7.18-7.15(m,2H),7.01(t,J=8.6Hz,2H),6.45 (s,1H),4.75(s,1H),3.52(d,J=12.6Hz,1H),3.48(d,J=12.6Hz,1H),2.59(s,3H),2.38(s,3H).

[0079] 13 C NMR(101MHz, CDCl3)δ194.0,162.4(d,J=246.5Hz),158.8,150.4,137.7,133.0(d,J=3.2Hz),131 .1(d,J=8.1Hz),128.9,128.8,128.4,122.4,115.6(d,J=21.4Hz),109.8,53.5,42.5,29.3,14.7.

[0080] 19 F NMR (376MHz,CDCl3)δ-114.46.

[0081] HRMS (GC / TOF) m / z: [M] + :Calcd for C 21 H 19 FO2S2 386.0810; found:386.0814.

[0082] Example 5

[0083] 21.0 mg (0.1 mmol) of conjugated enone (1a), 51.6 mg (0.3 mmol) of p-toluenesulfonic acid (TsOH), and 22.8 mg (0.12 mmol) of SS-(thienyl)ethane (peroxydithio) (2e) were placed in a 25 mL test tube with a stirring bar. After adding 2 mL of acetone solution at 25 ° C, the mixture was stirred at 70 ° C for 2 hours. After spin drying, the target product was obtained by flash column chromatography with a yield of 83%.

[0084]

[0085] 1 H NMR(400MHz,Chloroform-d)δ7.39(d,J=7.7Hz,2H),7.36-7.29(m,4H),6.95(d,J= 3.0Hz,1H),6.92-6.86(m,1H),6.39(s,1H),5.22(s,1H),2.58(s,3H),2.35(s,3H).

[0086] 13 C NMR (101MHz, Chloroform-d) δ194.2,158.7,150.7,137.9,136.1,132.0,131.1,128.8,128.5,128.2,127.5,122.1,109.5,54.4,29.3,14.6.

[0087] HRMS (GC / TOF) m / z: [M] + :Calcd for C 18 H 16 O2S3 360.0312,found:360.0313.

[0088] Example 6

[0089] 21.0 mg (0.1 mmol) of conjugated enone (1a), 51.6 mg (0.3 mmol) of p-toluenesulfonic acid (TsOH), and 27.4 mg (0.12 mmol) of SS-(3,4-dimethylbenzyl)ethane (peroxydisulfide) (2f) were placed in a 25 mL test tube with a stirring bar. After adding 2 mL of acetone solution at 25 ° C, the mixture was stirred at 70 ° C for 2 hours, and then dried by spin drying and flash column chromatography to obtain the target product with a yield of 89%.

[0090]

[0091] 1H NMR(400MHz,Chloroform-d)δ7.38-7.32(d,J=4.1Hz,5H),7.10(d,J=7.5Hz,1H),7.03-6.93(m,2H),6.44( s,1H),4.67(s,1H),3.55(d,J=12.4Hz,1H),3.54(d,J=12.4Hz,1H),2.59(s,3H),2.39(s,3H),2.27(s,6H).

[0092] 13 C NMR (101MHz, CDCl3) δ194.1,158.7,150.6,137.7,136.9,136.2,134.4,130.8,129 .9,128.9,128.8,128.3,126.9,122.3,109.8,53.1,43.3,29.3,19.9,19.6,14.7.

[0093] HRMS (GC / TOF) m / z: [M] + :Calcd for C 23 H 24 O2S2 396.1218,found:396.1222.

[0094] Example 7

[0095] 21.0 mg (0.1 mmol) of conjugated enone (1a), 51.68 mg (0.4 mmol) of N,N-diisopropylethylamine, and 53.6 mg (0.2 mmol) of SS-(2,6-dichlorobenzyl)ethane (peroxydisulfide) (2 g) were placed in a 25 mL test tube with a stirring bar. After adding 4 mL of dichloromethane solution at 25 ° C, the mixture was stirred at 40 ° C for 10 hours. After spin drying, the target product was obtained by flash column chromatography with a yield of 75%.

[0096]

[0097] 1 H NMR(400MHz,Chloroform-d)δ7.43(d,J=7.4Hz,2H),7.38-7.34(m,2H),7.33-7.28(m,3H) ,7.15(t,J=8.0Hz,1H),6.48(s,1H),4.98(s,1H),4.08(s,2H),2.59(s,3H),2.38(s,3H).

[0098] 13C NMR (101MHz, CDCl3) δ194.1,158.9,150.3,137.4,136.0,133.7,129.2,128.9,128.8,128.5,128.4,122.3,110.1,53.7,39.2,29.3,14.7.

[0099] HRMS (GC / TOF) m / z: [M] + :Calcd for C 21 H 18 Cl2O2S2 436.0215,found:436.0217.

[0100] Example 8

[0101] 26.8 mg (0.1 mmol) of conjugated enone (1b), 51.6 mg (0.3 mmol) of p-toluenesulfonic acid, and 23.8 mg (0.12 mmol) of SS-benzylethane (peroxydisulfide) (2a) were placed in a 25 mL test tube with a stirring bar. After adding 2 mL of acetone solution at 25 ° C, the mixture was stirred at 70 ° C for 2 hours. After spin drying, the target product was obtained by flash column chromatography with a yield of 81%.

[0102]

[0103] 1 H NMR(400MHz,Chloroform-d)δ7.41-7.34(m,3H),7.33-7.29(m,5H),7.26-7.18(m,2H),6.46(s,1H),4.58 (s,1H),4.30(q,J=7.1Hz,2H),3.55(s,2H),2.81-2.74(m,1H),1.35(t,J=7.1Hz,3H),1.09-1.04(m,4H).

[0104] 13 C NMR (101MHz, CDCl3) δ164.3,163.5,149.0,137.7,137.3,129.6,128.8,128. 7,128.7,128.2,127.7,113.9,110.5,60.2,53.1,43.4,14.5,9.5,9.1,8.9.

[0105] HRMS (GC / QTOF) m / z: [M] + :Calcd for C 24 H 24 O3S2 424.1167, found:424.1170.

[0106] Example 9

[0107] 33.6 mg (0.1 mmol) of 1c, 10.2 mg (0.1 mmol) of pivalic acid, and 29.7 mg (0.15 mmol) of SS-benzylethane (peroxydisulfide) (2a) were placed in a 25 mL test tube with a stirring bar. 2 mL of acetonitrile solution was added at 25 ° C. The mixture was stirred at 70 ° C for 4 hours. After drying, the target product was obtained by flash column chromatography with a yield of 73%.

[0108]

[0109] 1 H NMR(400MHz,Chloroform-d)δ7.83(d,J=8.0Hz,2H),7.70-7.65(m,2H),7.51(t,J=7.2Hz,1H),7.44(d,J=7.6Hz,2H),7.38(t, J=7.6Hz,4H),7.35-7.28(m,7H),7.26-7.23(m,2H),6.49(s,1H),4.71(s,1H),3.66(d,J=12.4Hz,1H),3.62(d,J=12.5Hz,1H).

[0110] 13 C NMR (101MHz, CDCl3) δ191.7,156.0,151.4,138.0,137.4,137.3,133.1,129.9,129.7,129.3 ,129.0,128.9,128.7,128.5,128.5,128.4,128.4,127.8,127.6,121.6,113.3,53.1,43.6.

[0111] HRMS (GC / QTOF) (m / z): [M] + :calcd for C 31 H 24 OS2 492.1218, found:492.1216.

[0112] Example 10

[0113] 25.7 mg (0.1 mmol) of 1d, 51.6 mg (0.3 mmol) of p-toluenesulfonic acid, and 23.8 mg (0.12 mmol) of SS-benzylethane (peroxydisulfide) (2a) were placed in a 25 mL test tube with a stirring bar. After adding 2 mL of acetone solution at 25 ° C, the mixture was stirred at 70 ° C for 2 hours. After drying by spin-drying, the target product was obtained by flash column chromatography with a yield of 81%.

[0114]

[0115] 1 H NMR(400MHz,Chloroform-d)δ7.39-7.32(m,3H),7.32-7.26(m,4H),7.25-7.24(m,1H),7.22-7.19(m,1 H),6.41(s,1H),4.52(s,1H),3.64(d,J=12.4Hz,1H),3.61(d,J=12.8Hz,1H),2.57(s,3H),2.38(s,3H).

[0116] 13 C NMR (101MHz, CDCl3) δ193.9,158.9,149.7,139.6,137.2,134.5,130.0,129. 6,129.0,128.8,128.4,127.8,127.0,122.3,110.0,52.4,43.4,29.3,14.7.

[0117] 19 F NMR(376MHz,Chloroform-d)δ-113.44.

[0118] HR-ESI-MS m / z calcd.for[M] + :Calcd for C 21 H 19 O2S2 402.0515,found:402.0518.

[0119] Example 11

[0120] 23.1 mg (0.1 mmol) of conjugated enone (1e), 51.6 mg (0.3 mmol) of p-toluenesulfonic acid, and 19.8 mg (0.1 mmol) of SS-benzylethane (peroxydisulfide) (2a) were placed in a 25 mL test tube with a stirring bar. 2 mL of N,N-dimethylformamide solution was added at 25 ° C. The mixture was stirred at 80 ° C for 2 hours. After drying by spin-drying, the target product was obtained by flash column chromatography with a yield of 72%.

[0121]

[0122] 1 H NMR(400MHz,Chloroform-d)δ7.38-7.27(m,6H),7.24(d,J=1.4Hz,1H),7.03(t,J=8.6Hz,2H),6. 39(s,1H),4.55(s,1H),3.64(s,J=12.8Hz,1H),3.60(d,J=12.4Hz,1H),2.58(s,3H),2.38(s,3H).

[0123] 13 C NMR (101MHz, CDCl3) δ194.0,162.6(d,J=247.2Hz),158.9,150.2,137.3,133.4,130.6(d,J =8.1Hz),129.6,128.8,127.8,122.3,115.7(d,J=21.6Hz),109.9,52.2,43.5,29.3,14.7.

[0124] HRMS (GC / QTOF) m / z: [M] + :Calcd for C 21 H 19 FO2S2 386.0810,found:386.0815.

[0125] Comparative Example 1

[0126] 21.0 mg (0.1 mmol) of conjugated enone (1a), 51.6 mg (0.3 mmol) of p-toluenesulfonic acid (TsOH), and 23.8 mg (0.12 mmol) of SS-benzylethane (peroxydisulfide) (2a) were placed in a 25 mL test tube with a stirring bar. After adding 2 mL of toluene solvent at 25 ° C, the mixture was stirred at 70 ° C for 2 hours. After spin drying, the target product was obtained by flash column chromatography with a yield of 45%.

[0127] Comparative Example 2

[0128] 21.0 mg (0.1 mmol) of conjugated enone (1a), 51.6 mg (0.3 mmol) of p-toluenesulfonic acid (TsOH), and 23.8 mg (0.12 mmol) of SS-benzylethane (peroxydisulfide) (2a) were placed in a 25 mL test tube with a stirring bar. After adding 2 mL of acetone solvent at 25°C, stirring was continued at 25°C for 2 hours. After spin drying, the target product was obtained by rapid column chromatography with a yield of 41%.

[0129] Comparative Example 3

[0130] 21.0 mg (0.1 mmol) of conjugated enone (1a), 41.5 mg (0.3 mmol) of potassium carbonate (K2CO3), and 23.8 mg (0.12 mmol) of SS-benzylethane (peroxydisulfide) (2a) were placed in a 25 mL test tube with a stirring bar. After adding 2 mL of acetone solvent at 25 ° C, the mixture was stirred at 70 ° C for 2 hours. After spin drying, the target product was obtained by flash column chromatography with a yield of 28%.

[0131] Effect test

[0132] MTT test was performed on the products of Examples 1, 3-5, 11 and Comparative Examples 1-3, using osimertinib (AZD-9291, Apinno brand) as a positive control drug, and HepG2 (human liver cancer cells, from Guangzhou Medical University) and HeLa (cervical cancer cells, from Guangzhou Medical University) cells.

[0133] The specific operation method is as follows:

[0134] (1) Cell recovery, culture and passage

[0135] After the frozen cells were taken out of the refrigerator, they were quickly thawed in a 37.5°C constant temperature water bath. The thawed cells were then added to a centrifuge tube containing 1 mL of DMEM (Gibco brand) in a clean bench and placed in a centrifuge. The tube was centrifuged at 1000 rpm for 3 minutes. After the supernatant was discarded, complete culture medium (DMEM medium + 10% bovine serum albumin FBS) was added (bovine serum albumin FBS was purchased from ExCell Bio brand). After pipetting evenly, the cells were transferred to a culture flask. When the color of the culture medium changed, the culture medium was replaced. When the cells grew to 90% of the culture flask, they were passaged. First, the old culture medium was poured out, 2 mL of PBS was slowly added to wash the culture flask, and then 0.5 mL of trypsin (Tci, derived from porcine pancreas) was added for digestion. When the cells began to fall off, culture medium was added and gently pipetted until the cells were completely detached. The cell suspension was then collected and centrifuged at 1000 rpm for 3 minutes. The supernatant was discarded, complete culture medium was added, pipetted evenly, and then divided into two culture flasks.

[0136] (2) MTT method

[0137] Take the logarithmically growing cells, digest them and pipette to evenly distribute the cells, then count the cells and dilute them to 6×10 3 (cell / mL), evenly add 100μL cell suspension to the 96-well plate (do not add to the 36 wells on the edge), place it in the incubator, and after 12 hours of cell attachment, administer the drug. Set 5 drug concentrations (90μM, 30μM, 10μM, 3.3μM, 1.1μM, 0uM) and set 3 replicates. After administration, continue to incubate in the incubator for 48 hours. After the incubation is completed, discard the stock solution, add 10μL of MTT solution (5mg / mL) and 90μL of blank culture medium (DMEM culture medium), continue to culture for 4 hours, then discard the stock solution, add 100μL DMSO solution to dissolve, shake on a shaker for 15 minutes, and use an enzyme reader to measure the absorbance value of each well at a wavelength of 490nm. Finally, the cell survival rate is calculated using the following formula:

[0138] Survival rate=(OD "test sample" - OD "blank") / (OD "negative control" - OD "blank") x 100%.

[0139] Negative control: culture medium + cells (no drugs added); blank control: simple culture medium (no cells added).

[0140] IC of analyzed compounds 50 The values showed that this series of compounds had certain inhibitory activity against the above cell lines, and the results are shown in Table 1.

[0141] Table 1 In vitro anti-cancer cell proliferation activity of some compounds

[0142]

[0143] The above detailed description is a specific description of one feasible embodiment of the present invention. This embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not depart from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A polysubstituted persulfide furan derivative, characterized in that: The structural formula is as follows: ； wherein R is selected from any one of benzyl, thienyl, cyclohexyl, n-hexyl, 4-MeC6H4CH2, 4-MeOC6H4CH2, 4-ClC6H4CH2, and 4-FC6H4CH2; R 1 Any one selected from phenyl, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-FC6H4, 4-EtO2CC6H4, 3-FC6H4 and 3-MeC6H4; R 2 Any one selected from acetyl, propionyl, isobutyryl, benzoyl, CO2Me and CO2Et; R 3 Any one selected from methyl, ethyl, isopropyl, phenyl and cyclopropyl.

2. A method for preparing the polysubstituted persulfide furan derivative according to claim 1, characterized in that: The method comprises the following steps: mixing a conjugated acetylene ketone, an acetic acid disulfide derivative, an additive and a solvent, and stirring the mixture to obtain a polysubstituted persulfide furan derivative; the structural formulas of the conjugated acetylene ketone and the acetic acid disulfide derivative are as follows: ； ； The additive is selected from one or more of p-toluenesulfonic acid, pivalic acid, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

3. The preparation method according to claim 2, characterized in that The solvent is selected from any one of diethyl ether, dichloromethane, acetone, 1,2-dichloroethane, chloroform, carbon tetrachloride, toluene, trifluorotoluene, chlorobenzene, methylcyclohexane, cyclohexane, cyclopentane, n-hexane, methyl tert-butyl ether, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide and water.

4. The preparation method according to claim 3, characterized in that The solvent is selected from any one of 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, dichloromethane and acetone.

5. The preparation method according to claim 2, characterized in that The molar ratio of the conjugated alkyne-enone, the acetic acid dithioester derivative and the additive is 1:0.8-2.8:0.5-7.

6. The preparation method according to claim 2, characterized in that The molar ratio of the conjugated alkyne-enone, the acetic acid dithioester derivative and the additive is 1:1-2:1-4.

7. The preparation method according to claim 2, characterized in that The molar volume ratio of the conjugated alkyne-enone to the solvent is 1 mol:20-50L.

8. The preparation method according to claim 2, characterized in that The stirring temperature is 40-80° C., and the stirring time is 2-7 h.

9. Use of the polysubstituted persulfide furan derivative according to claim 1 in the preparation of anticancer drug.

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