Synthesis method of 6-trifluoromethylthio phenanthridine compound

Abstract

The invention discloses a synthesis method of a 6-trifluoromethylthio phenanthridine compound, and belongs to the technical field of organic synthesis. The phenanthridine compound containing the trifluoromethylthio group is prepared in one step by taking phenanthridine thione as a raw material and taking bromotrifluoromethane which is low in price and easy to obtain as a fluorinating reagent through a C = S free radical addition reaction under the action of visible light induction and a photocatalyst and alkali. The method has the characteristics of being green and safe, cheap and easily available in raw materials, high in atom economy, good in reaction regioselectivity, mild in reaction condition, wide in substrate application range, high in yield, easy in product purification and the like, and belongs to green synthesis.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing 6-trifluoromethylthiophenanthridine compounds. Background Art

[0002] Phenanthridines are an important class of nitrogen-containing heterocyclic compounds that are widely found in natural alkaloids and drug molecules. For example, a relatively representative natural benzophenanthridine alkaloid was isolated from the Amaryllidaceae plant Narcissus asturiensis. Proven to have anti-HIV type I protease activity; Humidinium bromide salt It is a commonly used multifunctional DNA / RNA intercalator; nitidine chloride with a benzophenanthridine structure It has many activities including anti-inflammatory, anti-tumor and anti-malarial.

[0003] Among various fluorine-containing groups, trifluoromethylthio (SCF3) has high lipid solubility and strong electron-withdrawing ability. It can be seen from the Hansch hydrophobicity parameter that trifluoromethylthio has the highest π coefficient among common fluorine-containing groups. Introducing it into drug molecules can greatly improve the lipid solubility of the molecule, increase the drug's permeability to cell membranes, and improve the bioavailability of the drug. In addition, due to the strong electron-withdrawing ability of trifluoromethylthio, the drug molecules modified by trifluoromethylthio have high metabolic stability. At present, the synthesis method of phenanthridine compounds containing trifluoromethylthio has not been studied much. The reported literature mainly uses phenanthridine N-oxide as a raw material for synthesis. The 2,4-dinitrobenzenesulfonyl chloride used in the synthesis process may have an explosive reaction in organic solvents, which poses a great safety hazard. At the same time, only one trifluoromethylthiophenanthridine compound was synthesized, and the substrate application range is narrow. Therefore, it is very necessary to explore a new, efficient and simple synthesis method to prepare more phenanthridine compounds containing trifluoromethylthio. Summary of the invention

[0004] The purpose of the present invention is to provide a method for synthesizing 6-trifluoromethylthiophenanthridine compounds to solve the problems existing in the above-mentioned prior art. The present invention uses phenanthridinethione as a raw material, trifluorobromomethane which is cheap and readily available as a fluorination agent, and under the induction of visible light and the action of a photocatalyst and a base, a phenanthridine compound containing trifluoromethylthio is prepared in one step through a free radical addition reaction of C=S. The method has the characteristics of being green and safe, cheap and readily available raw materials, high atom economy, good regional selectivity of the reaction, mild reaction conditions, wide application range of substrates, high yield, and easy purification of products, and belongs to green synthesis.

[0005] To achieve the above object, the present invention provides the following solutions:

[0006] One of the technical solutions of the present invention is a 6-trifluoromethylthiophenanthridine compound, the structural formula of which is shown in formula (1):

[0007]

[0008] Wherein, R is -H, -CH3, -OCH3, -F or -Cl.

[0009] Technical solution 2 of the present invention: A method for synthesizing the above-mentioned 6-trifluoromethylthiophenanthridine compounds, comprising the following steps:

[0010] The phenanthridinethione, a photocatalyst and a base are added to an organic solvent, and then CF3Br is introduced to carry out a visible light-induced reaction, and the 6-trifluoromethylthiophenanthridine compound is obtained after purification by column chromatography;

[0011] The structural formula of the phenanthione is as follows:

[0012]

[0013] Wherein, R is -H, -CH3, -OCH3, -F or -Cl.

[0014] The chemical reaction formula is as follows:

[0015]

[0016] Furthermore, the photocatalyst (PC) comprises fac-Ir III (ppy)3 (tris(2-phenylpyridine)iridium), Ru(bpy)3Cl2 (terpyridylruthenium chloride hexahydrate) or 4CzIPN (2,4,5,6-tetrakis(9-carbazolyl)isophthalonitrile);

[0017] The base includes K2CO3, KHCO 3、 Na2CO3, K3PO4, K2HPO4, Li2CO3, NaOAc, Et3N or 2,6-lutidine;

[0018] The organic solvent includes CH3CN, DMF, DMSO (dimethyl sulfoxide), THF, acetone or 1,4-dioxane.

[0019] Furthermore, the photocatalyst is fac-Ir III (ppy)3; the base is 2,6-dimethylpyridine; and the organic solvent is DMSO.

[0020] Furthermore, the molar ratio of the phenanthridinethione to the base is (1-3):(2-6).

[0021] Furthermore, the molar ratio of the phenanthridinethione to the base is 1:2.

[0022] Furthermore, the amount of the photocatalyst used is 0.5 to 1.5 mol% of the molar amount of phenanthridinethione.

[0023] The pressure of the CF3Br in the reaction system is 1.0-1.5 atm.

[0024] Furthermore, the amount of the photocatalyst used is 1.0 mol% of the molar amount of phenanthridinethione; and the pressure of the CF3Br in the reaction system is 1.0 atm.

[0025] Furthermore, the wavelength of the visible light is 390-460 nm;

[0026] The induction reaction time is 12 to 48 hours.

[0027] Furthermore, the induction reaction temperature is 25°C and the time is 24 hours.

[0028] Furthermore, the visible light is 5W, 10W, 15W or 20W blue light.

[0029] Furthermore, the visible light is 15W blue light.

[0030] Furthermore, the dosage ratio of the phenanthridinethione to the organic solvent is 0.2mmol:1-5mL.

[0031] Furthermore, the dosage ratio of the phenanthridinethione to the organic solvent is 0.2mmol:3mL.

[0032] Furthermore, the eluent used in the column chromatography purification is petroleum ether (PE) and ethyl acetate (EA) in a volume ratio of (100-60):1.

[0033] The third technical solution of the present invention: an application of the above-mentioned 6-trifluoromethylthiophenanthridine compound in the preparation of anti-inflammatory, anti-tumor or anti-malarial drugs.

[0034] The 6-trifluoromethylthiophenanthridine compound prepared by the present invention is a kind of nitrogen-containing heterocyclic compound, and nitrogen-containing heterocyclic compound generally has biological activity, such as anti-inflammatory, antibacterial and anti-tumor, therefore, the 6-trifluoromethylthiophenanthridine compound prepared by the present invention also has the above-mentioned biological activity. Meanwhile, because trifluoromethylthio (SCF3) has higher fat solubility and stronger electron-withdrawing ability, the drug molecule modified by trifluoromethylthio has higher metabolic stability, and can improve the bioavailability of the drug. Therefore, the phenanthridine compound containing trifluoromethylthio also has the above-mentioned biological activity.

[0035] The present invention discloses the following technical effects:

[0036] (1) The 6-trifluoromethylthiophenanthridine compounds of the present invention have anti-inflammatory, antibacterial or anti-tumor activities and can be used to prepare anti-inflammatory, anti-tumor or anti-malarial drugs.

[0037] (2) The present invention uses phenanthridinethione as a raw material and trifluorobromomethane as a fluorination agent. Under the induction of visible light and the action of a photocatalyst and a base, the trifluoromethyl free radical generated by trifluorobromomethane undergoes a free radical addition reaction with C=S to prepare a phenanthridine compound containing a trifluoromethylthio group in one step.

[0038] (3) The present invention is the first to use the free radical addition reaction involving phenanthridinethione for the synthesis of 6-trifluoromethylthiophenanthridine compounds, and the first to use trifluorobromomethane (CF3Br is a non-toxic, odorless, cheap and easily available industrial raw material. Compared with other fluorination agents, its greatest advantages are low price, easy availability and high atom economy) for the free radical addition reaction of C=S to construct a trifluoromethylthio group, providing a new raw material selection for the synthesis of 6-trifluoromethylthiophenanthridine compounds.

[0039] (4) The synthesis method provided by the present invention has a high degree of regioselectivity (i.e., all obtained are 6-trifluoromethylthiophenanthridine compounds), has the characteristics of short reaction steps, cheap and readily available raw materials, simple operation, mild reaction conditions, high reaction yield, and high purity of the obtained products, which conforms to the concept of green synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0041] Figure 1 6-trifluoromethylthiophenanthridine (3a) synthesized in Example 1 of the present invention 1 H NMR spectra;

[0042] Figure 2 6-trifluoromethylthiophenanthridine (3a) synthesized in Example 1 of the present invention 13 C NMR spectra;

[0043] Figure 3 6-trifluoromethylthiophenanthridine (3a) synthesized in Example 1 of the present invention 19 F NMR spectra;

[0044] Figure 4This is a high-resolution mass spectrometry monitoring diagram of 6-trifluoromethylthiophenanthridine (3a) synthesized in Example 1 of the present invention;

[0045] Figure 5 8-methyl-6-trifluoromethylthiophenanthridine (3b) synthesized in Example 2 of the present invention 1 H NMR spectra;

[0046] Figure 6 8-methyl-6-trifluoromethylthiophenanthridine (3b) synthesized in Example 2 of the present invention 13 C NMR spectra;

[0047] Figure 7 8-methyl-6-trifluoromethylthiophenanthridine (3b) synthesized in Example 2 of the present invention 19 F NMR spectra;

[0048] Figure 8 This is a high-resolution mass spectrum monitoring diagram of 8-methyl-6-trifluoromethylthiophenanthridine (3b) synthesized in Example 2 of the present invention;

[0049] Fig. 9 8-methoxy-6-trifluoromethylthiophenanthridine (3c) synthesized in Example 3 of the present invention 1 H NMR spectra;

[0050] Fig.10 8-methoxy-6-trifluoromethylthiophenanthridine (3c) synthesized in Example 3 of the present invention 13 C NMR spectra;

[0051] Fig.11 8-methoxy-6-trifluoromethylthiophenanthridine (3c) synthesized in Example 3 of the present invention 19 F NMR spectra;

[0052] Fig.12 This is a high-resolution mass spectrometry monitoring diagram of 8-methoxy-6-trifluoromethylthiophenanthridine (3c) synthesized in Example 3 of the present invention;

[0053] Fig.13 8-fluoro-6-trifluoromethylthiophenanthridine (3d) synthesized in Example 4 of the present invention 1 H NMR spectra;

[0054] Fig.14 8-fluoro-6-trifluoromethylthiophenanthridine (3d) synthesized in Example 4 of the present invention 13 C NMR spectra;

[0055] Fig.15 8-fluoro-6-trifluoromethylthiophenanthridine (3d) synthesized in Example 4 of the present invention 19 F NMR spectra;

[0056] Fig.16 This is a high-resolution mass spectrum monitoring diagram of 8-fluoro-6-trifluoromethylthiophenanthridine (3d) synthesized in Example 4 of the present invention;

[0057] Fig.17 8-chloro-6-trifluoromethylthiophenanthridine (3e) synthesized in Example 5 of the present invention 1 H NMR spectra;

[0058] Fig.18 8-chloro-6-trifluoromethylthiophenanthridine (3e) synthesized in Example 5 of the present invention 13 C NMR spectra;

[0059] Fig.19 8-chloro-6-trifluoromethylthiophenanthridine (3e) synthesized in Example 5 of the present invention 19 F NMR spectra;

[0060] Fig. 20 This is a high-resolution mass spectrum monitoring chart of 8-chloro-6-trifluoromethylthiophenanthridine (3e) synthesized in Example 5 of the present invention. DETAILED DESCRIPTION

[0061] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0062] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0063] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0064] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to the skilled artisan. The present invention description and examples are exemplary only.

[0065] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0066] The phenanthridine-6(5H)-thione (1a) used in the embodiment of the present invention is a known compound. Its synthesis method and structural characterization data can be found in the literature: Zhao CL, Han QY, Zhang CP. TfOH-promoted transition-metal-free cascade trifluoroethylation / cyclization of organic isothiocyanates byphenyl(2,2,2-trifluoroethyl)iodonium triflate[J]. Organic letters, 2018, 20(20): 6480-6484.

[0067] The 8-methylphenanthridine-6(5H)-thione (1b), 8-methoxyphenanthridine-6(5H)-thione (1c), 8-fluorophenanthridine-6(5H)-thione (1d) and 8-chlorophenanthridine-6(5H)-thione (1e) used in the examples of the present invention are new compounds, and their synthesis methods are the same as those mentioned above.

[0068] The chemical reaction formula of the specific synthesis method is as follows:

[0069]

[0070] The specific synthesis steps of phenanthridinethione 1b, 1c, 1d and 1e are as follows:

[0071] (1) Preparation of biphenyl-2-amine

[0072] A. Preparation of 4'-methyl-[1,1'-biphenyl]-2-amine: In a nitrogen atmosphere, 2-bromoaniline (0.86 g, 5.0 mmol), 4-methylphenylboronic acid (0.816 g, 6.0 mmol), Na2CO3 (1.33 g, 12.5 mmol), Pd(PPh3)4 (0.29 g, 0.25 mmol) and a solvent of toluene / ethanol / H2O (24 mL, 1:1:1 (v / v / v)) were added into a 100 mL Schlenk flask. The mixture was stirred at 80°C for 6 h. TLC detected that the raw material was completely converted. The mixture was cooled to room temperature, quenched with saturated NH4Cl aqueous solution, extracted with ethyl acetate (3×25 mL), and the organic layers were combined, dried over anhydrous Na2SO4, filtered, and spin-dried to obtain a crude product, which was then purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=10:1, volume ratio) to obtain 4'-methyl-[1,1'-biphenyl]-2-amine as a yellow oily liquid, 0.732 g, with a yield of 80%.

[0073] B. The preparation method of 4'-methoxy-[1,1'-biphenyl]-2-amine is the same as that of 4'-methyl-[1,1'-biphenyl]-2-amine, except that 4-methylphenylboric acid is replaced with an equal molar amount of 4-methoxyphenylboric acid; the product is a yellow oily liquid, 0.816 g, and the yield is 82%.

[0074] C. The preparation method of 4'-fluoro-[1,1'-biphenyl]-2-amine is the same as that of 4'-methyl-[1,1'-biphenyl]-2-amine, except that 4-methylphenylboric acid is replaced with an equal molar amount of 4-fluorophenylboric acid; the product is a yellow oily liquid, 0.73 g, and the yield is 78%.

[0075] D. The preparation method of 4'-chloro-[1,1'-biphenyl]-2-amine is the same as that of 4'-methyl-[1,1'-biphenyl]-2-amine, except that 4-methylphenylboric acid is replaced with an equal molar amount of 4-chlorophenylboric acid; the product is a yellow oily liquid, 0.812 g, and the yield is 80%.

[0076] (2) Preparation of biphenyl-2-isothiocyanate

[0077] A. Preparation of 4'-methyl-1,1'-biphenyl-2-isothiocyanate: 4'-methyl-[1,1'-biphenyl]-2-amine (0.632 g, 4.0 mmol), thiocarbonyldiimidazole (0.854 g, 4.8 mmol) and CH2Cl2 (15 mL) were added to a 100 mL round-bottom flask in an air atmosphere. The mixture was stirred at room temperature for 2 h. TLC detected that the raw material was completely converted. The solvent was removed under reduced pressure, and the residue was purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=15:1, volume ratio) to obtain 4'-methyl-1,1'-biphenyl-2-isothiocyanate, a colorless oily liquid, 0.855 g, with a yield of 95%.

[0078] B. Preparation of 4'-methoxy-1,1'-biphenyl-2-isothiocyanate The same as 4'-methyl-1,1'-biphenyl-2-isothiocyanate, the only difference is that 4'-methyl-[1,1'-biphenyl]-2-amine is replaced by an equal mole of 4'-methoxy-[1,1'-biphenyl]-2-amine; the product is a colorless oily liquid, 0.879g, and the yield is 89%;

[0079] C. Preparation of 4'-fluoro-1,1'-biphenyl-2-isothiocyanate The same as 4'-methyl-1,1'-biphenyl-2-isothiocyanate, the only difference is that 4'-methyl-[1,1'-biphenyl]-2-amine is replaced by an equal molar amount of 4'-fluoro-[1,1'-biphenyl]-2-amine; the product is a colorless oily liquid, 0.742g, and the yield is 83%;

[0080] D. Preparation of 4'-chloro-1,1'-biphenyl-2-isothiocyanate The same as 4'-methyl-1,1'-biphenyl-2-isothiocyanate, the only difference is that 4'-methyl-[1,1'-biphenyl]-2-amine is replaced by an equal molar amount of 4'-chloro-[1,1'-biphenyl]-2-amine; the product is a colorless oily liquid, 0.784g, and the yield is 80%;

[0081] (3) Preparation of phenanthridinethione

[0082] A. Preparation of 8-methylphenanthridine-6(5H)-thione (1b): 4'-methyl-1,1'-biphenyl-2-isothiocyanate (0.855 g, 3.8 mmol), trifluoromethanesulfonic acid (TfOH) (1.58 g, 11.4 mmol) and CH2Cl2 (12 mL) were added to a 50 mL round-bottom flask in an air atmosphere. The mixture was refluxed at 40°C for 6 h. After TLC detection, the conversion of the raw material was complete. The reaction mixture was cooled to room temperature and the system was neutralized with saturated Na2CO3 aqueous solution. When a yellow solid precipitated, the precipitate was collected, washed with ice H2O (3×10 mL) and dried to obtain 8-methylphenanthridine-6(5H)-thione (1b), a yellow solid, 0.795 g, with a yield of 93%.

[0083] The structural characterization data are as follows:

[0084] 1 H NMR(400MHz, DMSO-d6)δ8.84(s,1H),8.33(t,J=6.4Hz,2H),7.64(d,J=8.0Hz,1H), 7.57(d,J=8.0Hz,1H),7.45(t,J=7.6Hz,1H),7.27(t,J=7.6Hz,1H),2.46(s,3H).; 13 CNMR(150MHz,DMSO-d6)182.9,140.1,137.1,133.1,131.8,131.1,128.8,128.3,123.5,122.8,122.5,121.3,121.1,21.6.; HRMS(ESI):m / z calcd for chemical formula:C 14 H 12 NS[M+H] + 226.0685; found 226.0688.

[0085] B. The preparation method of 8-methoxyphenanthridine-6(5H)-thione (1c) is the same as that of 8-methylphenanthridine-6(5H)-thione (1b), except that 4'-methyl-1,1'-biphenyl-2-isothiocyanate is replaced with an equal molar amount of 4'-methoxy-1,1'-biphenyl-2-isothiocyanate; the product is a yellow solid, 0.809 g, and the yield is 92%;

[0086] The structural characterization data are as follows:

[0087] 1 H NMR (400MHz, DMSO-d6) δ8.57-8.29(m,3H),7.82-7.23(m,4H),3.91(s,3H).; 13CNMR(150MHz,DMSO-d6)182.8,159.4,135.7,132.1,129.0,125.0,124.8,124.1,123.0,122.7,120.7,117.7,112.9,55.9.; HRMS(ESI):m / z calcd for chemical formula:C 14 H 12 NOS[M+H] + 242.0634; found 242.0642.

[0088] C. The preparation method of 8-fluorophenanthridine-6(5H)-thione (1d) is the same as that of 8-methylphenanthridine-6(5H)-thione (1b), except that 4'-methyl-1,1'-biphenyl-2-isothiocyanate is replaced with an equal molar amount of 4'-fluoro-1,1'-biphenyl-2-isothiocyanate; the product is a yellow solid, 0.586 g, and the yield is 79%;

[0089] The structural characterization data are as follows:

[0090] 1 H NMR (400MHz, DMSO-d6) δ8.78(d,J=11.2Hz,1H),8.58(dd,J=9.2,5.6Hz,1H),8.38(d ,J=8.4Hz,1H),7.61(t,J=8.4Hz,2H),7.49(t,J=7.2Hz,1H),7.30(t,J=7.2Hz,1H).; 13 C NMR(150MHz,DMSO-d6)δ181.1,160.7(d,J C-F =240Hz),133.1(d,J C-F =5.9Hz),128.1,127.4,124.8,122.4,122.2,120.5,119.8,118.2,118.0,115.9(d,J C-F =22.8Hz). 19 F NMR(376MHz, DMSO-d6)δ-110.97(m).; HRMS(ESI):m / z calcd for chemical formula:C 13 H9NFS[M+H] + 230.04342; found 230.04355.

[0091] D. The preparation method of 8-chlorophenanthridine-6(5H)-thione (1e) is the same as that of 8-methylphenanthridine-6(5H)-thione (1b), except that 4'-methyl-1,1'-biphenyl-2-isothiocyanate is replaced with an equal molar amount of 4'-chloro-1,1'-biphenyl-2-isothiocyanate; the product is a yellow solid, 0.659 g, and the yield is 84%;

[0092] The structural characterization data are as follows:

[0093] 1 H NMR (400MHz, DMSO-d6) δ9.14(s,1H),8.47(d,J=8.8Hz,1H),8.32(d,J=8.0Hz,1H),7.69(d d,J=8.8,2.4Hz,1H),7.61(d,J=7.6Hz,1H),7.47(t,J=7.6Hz,1H),7.25(t,J=8.0Hz,1H).; 13 C NMR (150MHz, DMSO-d6) δ181.5,142.6,132.6,131.9,131.0,130.7,129.5,129.3,124.9,123.3,122.9,120.4,110.0; HRMS (ESI): m / z calcd for chemical formula:C 13 H9NClS[M+H] + 246.01387; found 246.01389.

[0094] Example 1

[0095] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0096] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1.0 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL DMSO were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature (25 ° C) for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=100:1, volume ratio) to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, mp88~89 ° C, 48.0 mg, and a yield of 86%.

[0097] The chemical reaction formula is as follows:

[0098]

[0099] through 1 H NMR, 13 C NMR, 19 F NMR, high-resolution mass spectrometry ( Figures 1 to 4 ), confirm that the product is a pure target compound. The characterization data of the corresponding product are:

[0100] NMR (400MHz, CDCl3) δ8.62(d,J=8.0Hz,1H),8.53(d,J=8.0Hz,1H),8.32(d,J=8.4

[0101] Hz,1H),8.19(d,J=6.4Hz,1H),7.89(t,J=8.4Hz,1H),7.78-7.68(m,3H);

[0102] 13 C NMR(150MHz,CDCl3)δ151.0(q,J C-F =2.4Hz),143.9,133.3,131.5,130.3,129.2,129.1(q,J C-F =307.5Hz),128.0,127.9,126.4,126.3(q,J C-F =1.5Hz),123.8,122.5,122.1;

[0103] 19 F NMR(376MHz, CDCl3)δ-38.62(s);

[0104] HRMS(ESI):m / z calcd for chemical formula:C 14 H9F3NS[M+H] + 280.04023; found 280.04071.

[0105] Example 2

[0106] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3b):

[0107] 8-Methylphenanthridine-6(5H)-thione (45.0 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL DMSO were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature (25°C) for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=100:1) to obtain 8-methyl-6-trifluoromethylthiophenanthridine (3b) as a white solid, mp85-86°C, 49.9 mg, and a yield of 85%.

[0108] The chemical reaction formula is as follows:

[0109]

[0110] through 1 H NMR, 13 C NMR, 19 F NMR, high-resolution mass spectrometry ( Figures 5 to 8 ), confirm that the product is a pure target compound.

[0111] 1 H NMR (400MHz, CDCl3) δ8.49 (d, J = 8.4Hz, 2H), 8.16 (d, J = 8.0Hz, 1H), 8.07 (s, 1H), 7.75-7.66 (m, 3H), 2.61 (s, 3H);

[0112] 13 C NMR(150MHz,CDCl3)δ150.6(q,J C-F=2.0Hz),143.6,138.2,133.2,131.1,130.2,129.1(q,J C-F =307.2Hz),128.8,127.9,126.4,125.7,123.9,122.4,121.9,21.7;

[0113] 19 F NMR(376MHz, CDCl3)δ-38.65(s);

[0114] HRMS(ESI):m / z calcd for chemical formula:C 15 H 10 F3NNaS[M+Na] + 316.0378; found 316.0381.

[0115] Example 3

[0116] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3c):

[0117] 8-methoxyphenanthridine-6(5H)-thione (48.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL DMSO were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature (25 ° C) for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE: EA = 80: 1) to obtain 8-methoxy-6-trifluoromethylthiophenanthridine (3c), a white solid, mp 109 ~ 110 ° C, 53 mg, and a yield of 86%.

[0118] The chemical reaction formula is as follows:

[0119]

[0120] through 1 H NMR, 13 C NMR, 19 F NMR, high-resolution mass spectrometry ( Figures 9 to 12 ), confirm that the product is a pure target compound.

[0121] 1H NMR (400MHz, CDCl3) δ8.52(d,J=9.2Hz,1H),8.45(d,J=8.0Hz,1H),8.16(d,J=7.6Hz,1H),7.72-7.66(m,3H),7.50(d,J=8.8Hz,1H),4.00(s,3H);

[0122] 13 C NMR(150MHz,CDCl3)δ159.1,149.6(q,J C-F =2.1Hz),143.1,130.3,129.2(q,J C-F =307.4Hz),128.2,128.1,128.0(q,J C-F =1.4Hz),127.7,124.2,124.0,122.4,121.6,106.3,55.6;

[0123] 19 F NMR(376MHz, CDCl3)δ-38.57(s);

[0124] HRMS(ESI):m / z calcd for chemical formula:C 15 H 10 F3NNaOS[M+Na] + 332.0327; found 332.0340.

[0125] Example 4

[0126] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3d):

[0127] 8-Fluorophanthridine-6(5H)-thione (45.8 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL DMSO were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature (25 ° C) for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE: EA = 50: 1) to obtain 8-fluoro-6-trifluoromethylthiophenanthridine (3d) as a white solid, mp 90-91 ° C, 38 mg, and a yield of 64%.

[0128] The chemical reaction formula is as follows:

[0129]

[0130] through 1 H NMR, 13 C NMR, 19 F NMR, high-resolution mass spectrometry ( Figures 13-16 ), confirm that the product is a pure target compound.

[0131] 1 H NMR(400MHz, CDCl3)δ8.62(dd,J=9.2,5.2Hz,1H),8.48(d,J=8.0Hz,1H),,8.19( d,J=8.0Hz,1H),8.00(d,J=9.2Hz,1H),7.78-7.72(m,2H),7.64(t,J=9.2Hz,1H);

[0132] 13 C NMR(150MHz,CDCl3)δ161.5,(d,J C-F =248.9Hz),149.7(q,J C-F =2.1Hz),143.6,130.5,130.0,129.2,129.0(q,J C-F =307.2Hz),128.6,125.2(d,J C-F =8.3Hz),127.8(d,J C-F =9.6Hz),123.4,121.8,120.8(d,J C-F =23.7Hz),111.4(d,J C-F =23.0Hz);

[0133] 19 F NMR (376MHz, CDCl3) δ-38.64(s), δ-110.05(m);

[0134] HRMS(ESI):m / z calcd for chemical formula:C 14 H8NF4S[M+H] + 298.0308; found 298.0316.

[0135] Example 5

[0136] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3e):

[0137] 8-Chlorophenanthridine-6(5H)-thione (49 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL DMSO were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature (25 ° C) for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE: EA = 50: 1) to obtain 8-chloro-6-trifluoromethylthiophenanthridine (3e) as a white solid, mp 97-98 ° C, 45 mg, and a yield of 72%.

[0138] The chemical reaction formula is as follows:

[0139]

[0140] through 1 H NMR, 13 C NMR, 19 F NMR, high-resolution mass spectrometry ( Figure 17-20 ), confirm that the product is a pure target compound.

[0141] 1 H NMR (400MHz, CDCl3) δ8.53(d,J=8.8Hz,1H),8.46(d,J=7.6Hz,1H),8.29(d,J=2.0Hz,1H),8.17(d,J=8.0Hz,1H),7.83-7.69(m,3H);

[0142] 13 C NMR(150MHz,CDCl3)δ149.6(q,J C-F =2.6Hz),143.8,134.0,132.1,131.6,130.4,129.6,128.9(q,J C-F =307.5Hz),128.5,127.2(q,J C-F =1.7Hz),125.7,124.2,123.2,121.9;

[0143] 19 F NMR(376MHz, CDCl3)δ-38.60(s);

[0144] HRMS(ESI):m / z calcd for chemical formula:C 14 H8ClF3NS[M+H] + 314.0013; found 314.0021.

[0145] Example 6

[0146] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0147] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1.0 mol%), K2CO3 (55.4 mg, 0.4 mmol, 2.0 equiv), and 3 mL CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=100:1) to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 23.4 mg, with a yield of 42%.

[0148] Example 7

[0149] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0150] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), KHCO3 (40 mg, 0.4 mmol, 2.0 equiv), and 3 mL CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=100:1) to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 37.4 mg, with a yield of 67%.

[0151] Example 8

[0152] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0153] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), Na2CO3 (42.4 mg, 0.4 mmol, 2.0 equiv), and 3 mL CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=100:1) to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 20.1 mg, with a yield of 36%.

[0154] Example 9

[0155] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0156] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), K3PO4 (84.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=100:1) to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 26.2 mg, with a yield of 47%.

[0157] Example 10

[0158] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0159] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), K2HPO4 (69.6 mg, 0.4 mmol, 2.0 equiv), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=100:1) to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 34.6 mg, with a yield of 62%.

[0160] Embodiment 11

[0161] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0162] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), Li2CO3 (30 mg, 0.4 mmol, 2.0 equiv), and 3 mL CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=100:1) to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 38.5 mg, with a yield of 69%.

[0163] Example 12

[0164] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0165] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL of CH3CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The reaction mixture was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=100:1) to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 41.9 mg, with a yield of 75%.

[0166] Example 13

[0167] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0168] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv) and 3 mL of DMF were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=100:1) to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 36.8 mg, with a yield of 66%.

[0169] Embodiment 14

[0170] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0171] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL of 1,4-dioxane were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=100:1) to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 8.4 mg, with a yield of 15%.

[0172] Embodiment 15

[0173] A method for synthesizing 6-trifluoromethylthiophenanthridine compounds (3a):

[0174] Phenanthridine-6(5H)-thione (42.2 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy)3 (1.31 mg, 1 mol%), 2,6-lutidine (42.8 mg, 0.4 mmol, 2.0 equiv), and 3 mL of acetone were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then flushed with CF3Br gas, which was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The Schlenk flask was placed under 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA=100:1) to obtain 6-trifluoromethylthiophenanthridine (3a) as a white solid, 35.7 mg, with a yield of 64%.

[0175] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A 6-trifluoromethylthiophenanthridine compound, characterized in that The structural formula is shown in formula (1): Wherein, R is -H, -CH3, -OCH3, -F or -Cl.

2. A method for synthesizing 6-trifluoromethylthiophenanthridine compounds according to claim 1, characterized in that: The following steps are involved: Adding phenanthridinethione, a photocatalyst and a base into an organic solvent, and then introducing CF3Br to carry out a visible light-induced reaction to obtain the 6-trifluoromethylthiophenanthridine compound; The structural formula of the phenanthione is as follows: Wherein, R is -H, -CH3, -OCH3, -F or -Cl.

3. The synthesis method according to claim 2, characterized in that The photocatalyst includes fac-Ir III (ppy)3, Ru(bpy)3Cl2 or 4CzIPN; The base includes K2CO3, KHCO 3、 Na2CO3, K3PO4, K2HPO4, Li2CO3, NaOAc, Et3N or 2,6-lutidine; The organic solvent includes CH3CN, DMF, DMSO, THF, acetone or 1,4-dioxane.

4. The synthesis method according to claim 2, characterized in that The molar ratio of the phenanthridinethione to the base is (1-3):(2-6).

5. The synthesis method according to claim 2, characterized in that The amount of the photocatalyst is 0.5 to 1.5 mol% of the molar amount of phenanthridinethione; The pressure of the CF3Br in the reaction system is 1.0-1.5 atm.

6. The synthesis method according to claim 2, characterized in that The wavelength of the visible light is 390-460nm; The induction reaction time is 12 to 48 hours.

7. Use of the 6-trifluoromethylthiophenanthridine compound according to claim 1 in the preparation of anti-inflammatory, anti-tumor or anti-malarial drugs.

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