A method for preparing indenoisoquinoline derivatives

Abstract

This patent application discloses a method for preparing an indenoisoquinoline derivative. The method uses an easily synthesized benzyl imide ethyl ester compound (Formula II) and a propargyl carbonate compound or a propargyl alcohol compound (Formula III) as substrates, and obtains an indenoisoquinoline derivative through a divalent ruthenium-catalyzed bilateral aromatic ring C-H activation / cyclization reaction. Specifically, through a simple one-pot method, the transformation uses propargyl carbonate or propargyl alcohol as a transient directing group to assist the regioselective carbon-hydrogen bond activation and cyclization of alkynes. Subsequently, propargyl carbonate also acts as an activating group to attack the intramolecular aromatic ring through in situ generated carbon cations to obtain an indenoisoquinoline compound. This method has the characteristics of high efficiency, wide substrate range, high regioselectivity, and chemical selectivity. At the same time, it uses simple and easily available imine esters and propargyl carbonates with intramolecular oxidizing properties as reaction substrates. In addition, the product obtained by the transformation is also easy to be further transformed later.

Description

Technical Field

[0001] The present patent application relates to the technical field of organic compound synthesis, and more specifically, to a method for preparing an indenoisoquinoline derivative. Background Art

[0002] As an important component of heterocyclic compounds, nitrogen-containing heterocycles are widely present in many natural products and drug molecules with physiological and pharmacological activities. The effective construction of nitrogen-containing heterocycles can not only achieve further modification of natural products and drug molecules, but also enrich their types to further promote the development of medicinal chemistry and medicine. Indenoisoquinoline is a class of compounds with anti-tumor activity. This class of compounds can overcome the defects of camptothecin-type topoisomerase I inhibitors and obtain anti-tumor compounds with more stable activity and less toxicity. With the deepening of research, it is found that indenoisoquinoline compounds also have Top1-Tdp1 dual inhibitory activity and potential tumor prevention effects. However, the number of indenoisoquinoline skeletons in nature cannot meet people's needs, so the efficient modular synthesis of this class of compounds has good value.

[0003] In the early days, people discovered some synthetic methods to prepare indenoisoquinoline derivatives, mainly relying on the condensation of aniline and aldehyde followed by the addition of high phthalic anhydride for condensation, and finally dehydrogenation and cyclization to obtain the indenoisoquinoline skeleton, such as the two-step synthesis reported by Cushman to prepare indenoisoquinoline derivatives (J.Org.Chem, 1978, 19, 3781.), but the reaction requires the addition of n-butyl lithium and methylsulfonyl chloride once after esterification to cause dehydrogenation, and there are too many synthetic impurities, which increases the difficulty of separation and greatly reduces the overall yield. Therefore, it is particularly important to develop new methods to construct indenoisoquinoline derivatives.

[0004] On the other hand, the functionalization cyclization reaction of aromatic CH bonds with various coupling reagents under transition metal catalysis provides an effective method for the rapid construction of nitrogen-containing heterocyclic skeletons. Many transition metal catalysts and coupling reagents have been developed for the construction of different skeletons, especially for the synthesis of bioactive molecules and drug molecules with nitrogen-containing heterocyclic skeletons. Alkynes can effectively construct new carbon-carbon bonds and carbon-hetero bonds through alkyne insertion and subsequent cyclization under transition metal catalysis.

[0005] There are three basic types of CH activation reactions involving propargyl carbonates: 1) the formation of allene products through migration insertion and β-O elimination of alkynes, such as the reaction of Frank Glorius with N-pyridindole as a directing group (Angew. Chem. Int. Ed. 2017, 56, 6660–6664) and the reaction of Akira Aso with N-methoxybenzamide as a directing group (Nat. Commun., 2015, 6, 7946); 2) as an internal oxidant and transient directing group, participating in the cycloaddition of alkynes to obtain a single-configuration cyclized product, such as Frank 3) After cycloaddition and β-O elimination, the products of co-diene are generated, such as the reaction of Zhu Jing's nitrogen nitroso group as a directing group (J.Am.Chem.Soc.2013,135,468-473.). There are many cycloaddition reactions involving propargyl carbonate, but there are few reports on the simultaneous activation of the CH bond of the diaromatic ring and the formation of a tetracyclic fused heterocycle by two cyclizations.

[0006] Patent application content

[0007] In order to overcome at least one problem existing in the prior art, the present patent application provides a method for preparing an indenoisoquinoline derivative. The preparation method in the present patent application is to use propargyl carbonate as a transient directing group to assist the regioselective carbon-hydrogen bond activation and cyclization of alkynes under one-pot conditions, and then propargyl carbonate also acts as an activating group to generate a carbon cation in situ to attack the aromatic ring in the molecule to obtain an indenoisoquinoline derivative.

[0008] In order to solve the above technical problems, the technical solution adopted by this patent application is:

[0009] A method for preparing an indenoisoquinoline derivative comprises reacting an ethyl benzimidate compound (Formula II) with a propargyl carbonate compound or a propargyl alcohol compound (Formula III) in an inert solvent and under the action of a metal catalyst to obtain an indenoisoquinoline derivative (Formula I). ​​The reaction equation is as follows:

[0010]

[0011] Among them, Ar 1 is a benzene ring or naphthalene ring substituted with a trifluoromethyl, halogen, ether, phenyl or alkyl functional group, Ar 2 It is a benzene ring or thiophene heterocyclic compound substituted with an alkyl or phenyl functional group, and R is hydrogen, methyl formate, ethyl formate, isobutyl formate, etc.

[0012] Compared with the prior art, the beneficial effects of this patent application are:

[0013] The preparation method of indenoisoquinoline derivatives provided by the patent application is based on the fact that propargyl carbonate itself has certain oxidizing properties and easy leaving properties, and can coordinate with metal catalysts, which solves the problem of regional selectivity after alkyne insertion. When the carbon-oxygen bond is broken, an intramolecular Friedel-Crafts reaction is easily generated to obtain the target compound. The molecular skeleton exhibits good anti-tumor activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 The hydrogen nuclear magnetic resonance spectrum of compound 1a prepared in Example 1 of the present patent application;

[0015] Figure 2 The carbon NMR spectrum of compound 1a prepared in Example 1 of the present patent application;

[0016] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of compound 1b prepared in Example 2 of this patent application;

[0017] Figure 4 The carbon NMR spectrum of compound 1b prepared in Example 2 of the present patent application;

[0018] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of compound 1c prepared in Example 3 of this patent application;

[0019] Figure 6 The carbon NMR spectrum of compound 1c prepared in Example 3 of the present patent application;

[0020] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of compound 1d prepared in Example 4 of this patent application;

[0021] Figure 8 The carbon NMR spectrum of compound 1d prepared in Example 4 of the present patent application;

[0022] Fig. 9 The NMR fluorine spectrum of compound 1d prepared in Example 4 of the present patent application;

[0023] Fig.10 This is the hydrogen nuclear magnetic resonance spectrum of compound 1e prepared in Example 5 of this patent application;

[0024] Fig.11 The carbon NMR spectrum of compound 1e prepared in Example 5 of the present patent application;

[0025] Fig.12 The NMR fluorine spectrum of compound 1e prepared in Example 5 of the present patent application;

[0026] Fig.13This is the hydrogen nuclear magnetic resonance spectrum of compound 1f prepared in Example 6 of this patent application;

[0027] Fig.14 The carbon NMR spectrum of compound 1f prepared in Example 6 of the present patent application;

[0028] Fig.15 This is the hydrogen nuclear magnetic resonance spectrum of compound 1g prepared in Example 7 of this patent application;

[0029] Fig.16 The carbon NMR spectrum of compound 1g prepared in Example 7 of the present patent application;

[0030] Fig.17 This is the hydrogen nuclear magnetic resonance spectrum of compound 1h prepared in Example 8 of this patent application;

[0031] Fig.18 This is the carbon NMR spectrum of compound 1h prepared in Example 8 of this patent application. DETAILED DESCRIPTION

[0032] The embodiments of the present patent application will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present patent application and should not be considered to limit the scope of the present patent application. If the specific conditions are not specified in the examples, they are carried out according to the normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0033] It should be noted that:

[0034] In this patent application, unless otherwise specified, all implementation methods and preferred implementation methods mentioned herein can be combined with each other to form a new technical solution.

[0035] In this patent application, unless otherwise specified, each reaction or operation step can be carried out sequentially or in a sequential manner. Preferably, the reaction method herein is carried out sequentially.

[0036] Unless otherwise specified, the professional and scientific terms used herein are the same as those familiar to those skilled in the art. In addition, any method or material similar or equivalent to the described content may also be applied to this patent application.

[0037] The applicant of the present patent has found that: Alkynes can effectively construct new carbon-carbon bonds and carbon-hetero bonds through alkyne insertion and subsequent cyclization under transition metal catalysis, and propargyl carbonate has an easy leaving group at the propargyl position, which is easy to obtain valuable intermediates in organic synthesis and is widely used in various reactions, especially tandem reactions, but rarely involves CH functionalization. In addition, propargyl carbonate itself can participate in coordination with metal catalysts, and it is easy to obtain a single-configuration product when the cycloaddition of alkynes occurs, which solves the problem of regioselectivity when alkynes participate in cycloaddition. Therefore, propargyl carbonate is an excellent coupling reagent.

[0038] Based on the research of our group on the activation of carbon-hydrogen bonds assisted by easily converted weakly coordinating functional groups (ACS Catal., 2019, 9, 8749-8756; ChemCatChem, 2020, 12, 2358-2384 (invited review); Org.Chem.Front., 2019, 6, 284-289. (title paper); Chem.Commun., 2020, 56, 11255-11258. Chin.J.Chem.2020, 38, 929-934. (title paper, selected as "Breaking Report") Chem. Commun., 2021, 57, 8075-8078; Org. Chem. Front., 2021, 8, 6484-6490 (title page paper); Org. Chem. Front., 2022, 9, 2746-2752.), the present invention uses easily convertible directing group imine esters and versatile propargyl carbonates as substrates. Under one-pot conditions, propargyl carbonate is used as a transient directing group to assist the regioselective carbon-hydrogen bond activation and cyclization of alkynes. Subsequently, propargyl carbonate is also used as an activating group to in situ generate a carbon cation to attack the aromatic ring in the molecule to obtain an indenoisoquinoline compound, which provides value for its application in the field of biomedicine.

[0039] A method for preparing an indenoisoquinoline derivative, characterized in that: in an inert solvent and under the action of a metal catalyst, a benzimidic acid ethyl ester compound (Formula II) is reacted with a propargyl carbonate compound or a propargyl alcohol compound (Formula III) to obtain an indenoisoquinoline derivative (Formula I), and the reaction equation is as follows:

[0040]

[0041] Among them, Ar 1 is a benzene ring or naphthalene ring substituted with a trifluoromethyl, halogen, ether, phenyl or alkyl functional group, Ar 2 It is a benzene ring or thiophene heterocyclic compound substituted with an alkyl or phenyl functional group, and R is hydrogen, methyl formate, ethyl formate, isobutyl formate, etc.

[0042] This patent application uses easily convertible directing group imine esters and versatile propargyl carbonate as substrates. Under one-pot conditions, propargyl carbonate is used as a transient directing group to assist in the regioselective carbon-hydrogen bond activation and cyclization of alkynes. Subsequently, propargyl carbonate is also used as an activating group to in situ generate carbon cations to attack the aromatic rings within the molecule to obtain indenoisoquinoline compounds, which provide value for their application in the biomedical field.

[0043] The reaction mechanism in this patent application is expressed in the chemical reaction equation as follows, wherein the ethyl imide group is used as the directing group DG 1 , as a directing group to assist the metal catalyst in directional activation of the ortho-CH bond to form the rhodium metal complex intermediate IV. Since -OR in the alkyne can serve as a transient directing group DG 2 Coordinated with the rhodium catalyst, DG 2 It will approach the side of the rhodium intermediate IV, and then migrate and insert into the alkyne to form the intermediate V, which has only one specific configuration and has high regioselectivity. Subsequently, the propargyl carbonate also acts as an activating group to attack the aromatic ring VI in the molecule by in situ generating a carbon cation to obtain an indenoisoquinoline compound derivative I.

[0044]

[0045] In some embodiments, the inert solvent is one or more of toluene, tetrahydrofuran, 1,4-dioxane, N,N'-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, 1,2-dichloroethane, ethanol, trifluoroethanol, and hexafluoroisopropanol.

[0046] In some preferred embodiments, the metal catalyst is: the metal catalyst is: any one or more of pentamethylcyclopentadienyl rhodium chloride dimer, dichlorobis(4-methylisopropylphenyl)ruthenium, pentamethylcyclopentadienyl iridium chloride dimer.

[0047] In some preferred embodiments, the halogen atom extractor is one of silver hexafluoroantimonate and silver bistrifluoromethanesulfonyl imide or a combination thereof.

[0048] In some preferred embodiments, the oxidant is one or more of silver acetate, silver carbonate, copper acetate, and silver oxide.

[0049] In some preferred embodiments, the additive is one or more of adamantanecarboxylic acid, trifluoroacetic acid, silver trifluoroacetate, and o-nitrobenzoic acid.

[0050] In some preferred embodiments, the amount of the metal catalyst is 5 mol% of the amount of the ethyl benzimidate compound (Formula II).

[0051] In some preferred embodiments, the reaction temperature is 60°C to 100°C.

[0052] In some preferred embodiments, the reaction is carried out for 12-24 hours.

[0053] In some preferred embodiments, the preparation method of the above-mentioned indenoisoquinoline derivative comprises the following specific operation steps: S1: in a reactor, in air, add 2.1 mg of dichlorobis(4-methylisopropylphenyl)ruthenium, 3.9 mg of silver trifluoromethanesulfonimide, 39.8 mg of copper acetate, 9.0 mg of adamantanecarboxylic acid, 1.0 mL of solvent hexafluoroisopropanol, 29.8 mg of ethyl benzyl imide, and 52.0 mg of propargyl carbonate in sequence;

[0054] S2: react at 100°C for 12 hours;

[0055] S3: After the reaction is completed, the mixture is separated by column chromatography to obtain the target compound.

[0056] Next, the preparation method of the indenoisoquinoline derivatives of the present patent application is described in detail with specific examples.

[0057] Example 1 Preparation of 5-ethoxy-7,7-dimethyl-7H-indeno[2,1-c]isoquinoline (1a)

[0058] Under an atmospheric pressure, ethyl benzyl imide compound 2a (29.8 mg, 0.20 mmol), (2-methyl-4-phenylbut-3-yn-2-yl) isobutyl carbonate 3a (52.0 mg, 0.20 mmol), divalent ruthenium catalyst [Ru(p-cymene)Cl2]2 (2.5 mg, 0.004 mmol), silver bistrifluoromethanesulfonimide (3.9 mg, 0.01 mmol), copper acetate (39.8 mg, 0.04 mmol), adamantanecarboxylic acid (9.0 mg, 0.05 mmol), hexafluoroisopropanol (HFIP, 1.0 mL) were added to a 20 mL reaction tube in sequence, and the mixture was reacted at 100°C for 12 hours. After the reaction, the mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated to obtain a crude product. The obtained crude product was separated by thin layer chromatography using a prepared silica gel plate, and the selected developing solvent or eluent was petroleum ether, to obtain 5-ethoxy-7,7-dimethyl-7H-indeno[2,1-c]isoquinoline (1a) with a yield of 58%.

[0059] The chemical reaction equation corresponding to this embodiment is as follows:

[0060]

[0061] Example 1 The H-NMR and C-NMR spectra of the prepared compounds are as follows: Figure 1 and Figure 2 As shown. Figure 1 It can be seen that: 1 H NMR (400MHz,CDCl3)δ8.50(d,J=8.4Hz,1H),8.40(d,J=7.6Hz,1H),8.11(d,J=7.6Hz,1H),7.80-7.76(m,1H),7.56-7.49(m,2H),7.56-7.5(m,1H),7.40-7.38(m,1H),7.32-7.28(m,1H),4.70(q,J=6.8Hz,2H),1.55(t,J=7.2Hz,3H),1.51(s,6H). The molecular hydrogen spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Figure 2 It can be seen that: 13 C NMR (100MHz, CDCl3) δ164.4, 160.8, 152.4, 139.1, 134.1, 131.0, 130.7, 128.1, 126.9, 125.5, 125.2, 125.2, 122.7, 122.4, 121.5, 118.8, 118.5, 62.1, 46.9, 25.0, 14.6. The molecular carbon spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Combined with the results of the above nuclear magnetic hydrogen spectrum and carbon spectrum, it can be seen that the product obtained in Example 1 is 5-ethoxy-7,7-dimethyl-7H-indeno[2,1-c]isoquinoline (1a).

[0062] In this embodiment, the preparation method of the indenoisoquinoline derivative 5-ethoxy-7,7-dimethyl-7H-indeno[2,1-c]isoquinoline (1a) adopts a one-pot method and a one-step synthesis, which is easy to operate and has few synthetic impurities. The crude product can be separated and purified by conventional thin-layer chromatography, which greatly reduces the difficulty of separation. The yield of the preparation reaction is good and can reach 58%. Therefore, the reaction has high step economy and atom economy.

[0063] The chemical transformation in this example provides a method for rapidly constructing indenoisoquinoline derivatives, which contain an ethoxy group that is easily converted and easily removed, thus facilitating subsequent modification.

[0064] Example 2 Preparation of 5-ethoxy-2,7,7-trimethyl-7H-indeno[2,1-c]isoquinoline (1b)

[0065] Under an atmospheric pressure, ethyl 4-methylbenzimidate compound 2b (32.6 mg, 0.20 mmol), (2-methyl-4-phenylbut-3-yn-2-yl) isobutyl carbonate 3a (52.0 mg, 0.20 mmol), divalent ruthenium catalyst [Ru(p-cymene)Cl2]2 (2.5 mg, 0.004 mmol), silver hexafluoroantimonate (3.5 mg, 0.01 mmol), copper acetate (39.8 mg, 0.04 mmol), adamantanecarboxylic acid (9.0 mg, 0.05 mmol), hexafluoroisopropanol (HFIP, 1.0 mL) were added to a 20 mL reaction tube in sequence, and the mixture was reacted at 100°C for 12 hours. After the reaction, the mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated to obtain a crude product. The crude product was separated by thin layer chromatography using a prepared silica gel plate, and petroleum ether was selected as the developing solvent or eluent to obtain 5-ethoxy-2,7,7-trimethyl-7H-indeno[2,1-c]isoquinoline (1b) with a yield of 58%.

[0066] The chemical reaction equation corresponding to this embodiment is as follows:

[0067]

[0068] Example 2 The H-NMR and C-NMR spectra of the prepared compounds are as follows: Figure 3 and Figure 4 As shown. Figure 3 It can be seen that: 1 H NMR (400MHz,CDCl3)δ8.27(d,J=8.4Hz,2H),8.12(d,J=7.6Hz,1H),7.50(d,J=7.6Hz,1H),7.40(t,J=7.6Hz,1H),7.35(d,J=8.8Hz,1H),7.30(d,J=7.2Hz,1H),4.68(q,J=7.1Hz,2H),2.62(s,3H),1.53(t,J=7.2Hz,3H),1.50(s,6H). The molecular hydrogen spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Figure 4 It can be seen that: 13C NMR (100MHz, CDCl3) δ164.5, 160.8, 152.4, 141.0, 139.3, 134.5, 127.2, 126.8, 125.3, 125.0, 122.3, 122.1, 121.5, 118.0, 117.0, 62.0, 46.8, 25.0, 22.4, 14.6. The molecular carbon spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Combined with the results of the above nuclear magnetic hydrogen spectrum and carbon spectrum, it can be seen that the product obtained in Example 2 is 5-ethoxy-2,7,7-trimethyl-7H-indeno[2,1-c]isoquinoline (1b).

[0069] The propargyl carbonate in the (2-methyl-4-phenylbut-3-yn-2-yl)isobutyl carbonate 3a in this embodiment has an easy leaving group at the propargyl position, which is easy to obtain valuable intermediates in organic synthesis and can be applied to CH functionalization. In addition, the propargyl carbonate itself can participate in coordination with metal catalysts, and when the cycloaddition of alkynes occurs, it is easy to obtain a single-configuration product, indenoisoquinoline derivative 1b, which solves the problem of regioselectivity when alkynes participate in the cycloaddition. Therefore, propargyl carbonate is an excellent coupling reagent, which simultaneously participates in activating the CH bond of the biaromatic ring and undergoes two cyclizations to obtain a tetracyclic condensed heterocycle.

[0070] Therefore, the preparation method of the indenoisoquinoline derivative in this embodiment has the characteristics of high efficiency, high regioselectivity, and chemical selectivity, and uses easily available imine esters and propargyl carbonates with intramolecular oxidizing properties as reaction substrates. In addition, the product obtained by the conversion is also easy to be further converted subsequently.

[0071] Example 3 Preparation of 3-chloro-5-ethoxy-7,7-dimethyl-7H-indeno[2,1-c]isoquinoline (1c)

[0072] Under an atmospheric pressure, ethyl 3-chlorobenzimidate compound 2c (36.6 mg, 0.20 mmol), (2-methyl-4-phenylbut-3-yn-2-yl) isobutyl carbonate 3a (52.0 mg, 0.20 mmol), divalent ruthenium catalyst [Ru(p-cymene)Cl2]2 (2.5 mg, 0.004 mmol), silver trifluoromethanesulfonyl imide (3.9 mg, 0.01 mmol), copper acetate (39.8 mg, 0.04 mmol), silver trifluoroacetate (AgTFA, 11.0 mg, 0.05 mmol), hexafluoroisopropanol (HFIP, 1.0 mL) were added to a 20 mL reaction tube in sequence, and the mixture was reacted at 100°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated to obtain a crude product. The crude product was separated by thin layer chromatography using a prepared silica gel plate, and petroleum ether was selected as the developing solvent or eluent to obtain 3-chloro-5-ethoxy-7,7-dimethyl-7H-indeno[2,1-c]isoquinoline (1c) with a yield of 55%.

[0073] The chemical reaction equation corresponding to this embodiment is as follows:

[0074]

[0075] Example 3 The H-NMR and C-NMR spectra of the prepared compounds are as follows: Figure 5 and Figure 6 As shown. Figure 5 It can be seen that: 1 H NMR (400MHz,CDCl3)δ8.68(s,1H),8.59(d,J=8.8Hz,1H),8.09(d,J=7.6Hz,1H),7.94(dd,J=8.8,2.0Hz,1H),7.52(d,J=7.2Hz,1H),7.44-7.41(m,1H),7.35-7.31(m,1H),4.73(q,J=7.2Hz,2H),1.57(t,J=7.2Hz,3H),1.52(s,6H). The molecular hydrogen spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Figure 6 It can be seen that: 13C NMR (100MHz, CDCl3) δ166.9, 161.1, 152.2, 138.3, 127.1, 126.4, 125.8, 123.7, 123.5, 122.59, 121.5, 118.5, 117.9, 62.7, 47.2, 24.9, 14.5. The molecular carbon spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Combined with the results of the above nuclear magnetic hydrogen spectrum and carbon spectrum, it can be seen that the product obtained in Example 3 is 3-chloro-5-ethoxy-7,7-dimethyl-7H-indeno[2,1-c]isoquinoline (1c).

[0076] The preparation method in this embodiment is based on the fact that the propargyl carbonate compound (2-methyl-4-phenylbut-3-yn-2-yl) isobutyl carbonate 3a itself has certain oxidizing properties and easy leaving properties, and can coordinate with the metal catalyst, thereby solving the problem of regioselectivity after alkyne insertion. When the carbon-oxygen bond is broken, an intramolecular Friedel-Crafts reaction is easily generated, thereby obtaining the target compound 3-chloro-5-ethoxy-7,7-dimethyl-7H-indeno[2,1-c]isoquinoline (1c).

[0077] Therefore, the preparation method of the indenoisoquinoline derivative in this embodiment is a green and efficient synthesis method. The method has the characteristics of easy availability of raw materials, high atom economy and step economy. Under relatively mild reaction conditions, the indenoisoquinoline derivative compound 3-chloro-5-ethoxy-7,7-dimethyl-7H-indeno[2,1-c]isoquinoline (1c) is efficiently synthesized.

[0078] Example 4 Preparation of 5-ethoxy-7,7-dimethyl-9-phenyl-2-(trifluoromethyl)-7H-indeno[2,1-c]isoquinoline (1d)

[0079] Under an atmospheric pressure, ethyl 4-trifluoromethylbenzanilide 2d (43.4 mg, 0.20 mmol), methyl 4-([1,1'-biphenyl]-4-yl)-2-methylbutan-3-2-yl carbonate 3b (58.8 mg, 0.20 mmol), divalent ruthenium catalyst [Ru(p-cymene)Cl2]2 (2.5 mg, 0.004 mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01 mmol), copper acetate (39.8 mg, 0.04 mmol), o-nitrobenzoic acid (o-NO2PhCOOH, 8.4 mg, 0.05 mmol), hexafluoroisopropanol (HFIP, 1.0 mL) were added to a 20 mL reaction tube in sequence, and the mixture was reacted at 100°C for 12 hours. After the reaction, the mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated to obtain a crude product. The crude product was separated by thin layer chromatography using a prepared silica gel plate, and the selected developing solvent or eluent was petroleum ether, to obtain 5-ethoxy-7,7-dimethyl-9-phenyl-2-(trifluoromethyl)-7H-indeno[2,1-c]isoquinoline (1d) with a yield of 61%.

[0080] The chemical reaction equation corresponding to this embodiment is as follows:

[0081]

[0082] Example 4 The H-NMR, C-NMR and F-NMR spectra of the prepared compound are as follows: Figure 7 , Figure 8 and Fig. 9 As shown. Figure 7 It can be seen that: 1H NMR (400MHz, CDCl3) δ8.78 (s, 1H), 8.52 (d, J = 8.8Hz, 1H), 8.14 (d, J = 8.0Hz, 1H), 7.75-7.68 (m, 5H), 7.49 (t, J = 7.6Hz, 2H), 7.38 (t, J = 7.2Hz, 1H), 4.73 (q, J = 7.2Hz, 2H), 1.57 (s, 6H), 1.26 (t, J = 7.2Hz, 3H). The molecular hydrogen spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Figure 8 It can be seen that: 13 C NMR (100 MHz, CDCl3) δ 171.2, 166.1, 160.6, 153.0, 141.4, 138.9, 137.4, 133.2, 132.4, 130.8 (q, J = 34.0 Hz), 128.9, 127.2, 126.8, 126.2, 125.5 (q, J = 3.0 Hz), 122.6 (q, J = 254.0 Hz), 122.8, 121.7, 121.0, 62.7, 47.3, 25.04, 14.56. Fig. 9 It can be seen that: 19 F NMR (100MHz, CDCl3) δ-62.7. Combining the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum, it can be seen that the product prepared in Example 4 is 5-ethoxy-7,7-dimethyl-9-phenyl-2-(trifluoromethyl)-7H-indeno[2,1-c]isoquinoline (1d).

[0083] The preparation method of the indenoisoquinoline derivative in this embodiment is a simple one-pot method. The transformation is assisted by propargyl carbonate as a transient directing group to activate and cyclize the regioselective carbon-hydrogen bond of the alkyne. Subsequently, the propargyl carbonate is also used as an activating group to attack the aromatic ring in the molecule by in situ generating a carbon cation to obtain an indenoisoquinoline compound. The reaction in this embodiment only needs to be stirred in an atmosphere of 1 atmosphere at a relatively mild temperature of 100° C. for 12 hours, then cooled, and then a series of subsequent treatments are performed to obtain the final target product compound 5-ethoxy-7,7-dimethyl-9-phenyl-2-(trifluoromethyl)-7H-indeno[2,1-c]isoquinoline (1d) with a good yield (61%).

[0084] Therefore, the preparation method of the indenoisoquinoline derivative in this embodiment has the characteristics of high efficiency, wide substrate range, high regioselectivity, and chemical selectivity, and uses simple and easily available imine esters and propargyl carbonates with intramolecular oxidizing properties as reaction substrates. In addition, the product obtained by the transformation is also easy to be further transformed subsequently.

[0085] Example 5 Preparation of 5-ethoxy-2,3-difluoro-7,7,9-trimethyl-7H-indeno[2,1-c]isoquinoline (1e)

[0086] Under an atmospheric pressure, ethyl 3,4-difluorobenzanilide 2e (37.0 mg, 0.20 mmol), ethyl (2-methyl-4-(p-tolyl)but-3-yn-2-yl) carbonate 3c (58.8 mg, 0.20 mmol), divalent ruthenium catalyst [Ru(p-cymene)Cl2]2 (2.5 mg, 0.004 mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01 mmol), copper acetate (39.8 mg, 0.04 mmol), trifluoroacetic acid (TFA, 5.7 mg, 0.05 mmol), hexafluoroisopropanol (HFIP, 1.0 mL) were added to a 20 mL reaction tube in sequence, and the mixture was reacted at 100°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated to obtain a crude product. The crude product was separated by thin layer chromatography using a prepared silica gel plate, and petroleum ether was selected as the developing solvent or eluent to obtain 5-ethoxy-2,3-difluoro-7,7,9-trimethyl-7H-indeno[2,1-c]isoquinoline (1e) with a yield of 55%.

[0087] The chemical reaction equation corresponding to this embodiment is as follows:

[0088]

[0089] Example 5 The H-NMR, C-NMR and F-NMR spectra of the prepared compound are as follows: Fig.10 , Fig.11 and Fig.12 As shown. Fig.10 It can be seen that: 1 H NMR (400MHz,CDCl3)δ8.20-8.16(m,2H),7.36-7.29(m,1H),7.21-7.20(m,1H),4.68(q,J=9.2Hz,2H),2.45(s,1H),1.54(t,J=6.8Hz,3H),1.49(s,3H). The molecular hydrogen spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Fig.11 It can be seen that: 13 C NMR (100 MHz, CDCl3) δ 166.3, 159.7, 152.1, 135.5, 134.8, 131.1, 130.9, 128.8, 128.0 (d, J = 4.0 Hz), 127.1, 123.7, 123.0, 122.5 (q, J = 4.0 Hz), 116.5, 115.3, 115.1, 62.5, 46.8, 25.3, 21.4, 14.54. Fig.12 It can be seen that: 19 F NMR (100MHz, CDCl3) δ -134.2, -135.9. Combining the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum, it can be seen that the product prepared in Example 5 is 5-ethoxy-2,3-difluoro-7,7,9-trimethyl-7H-indeno[2,1-c]isoquinoline (1e).

[0090] This example also uses the easily convertible directing group imine ester 3,4-difluorobenzanilide ethyl ester compound 2e and the versatile propargyl carbonate (2-methyl-4-(p-tolyl)but-3-yn-2-yl) ethyl carbonate 3c as substrates. Under one-pot conditions, propargyl carbonate is used as a transient directing group to assist the regioselective carbon-hydrogen bond activation and cyclization of the alkyne. Subsequently, propargyl carbonate is also used as an activating group to attack the aromatic ring in the molecule by in situ generating a carbon cation to obtain an indenoisoquinoline compound, which provides value for its application in the biomedical field.

[0091] The preparation method has the characteristics of high efficiency, wide substrate range, high regioselectivity, and chemical selectivity. It uses easily available imine esters and propargyl carbonates with intramolecular oxidizability as reaction substrates. In addition, the product obtained by the transformation is also easy to be further transformed subsequently.

[0092] Example 6 Preparation of 5-ethoxy-7,7,9-trimethyl-2-phenyl-7H-indeno[2,1-c]isoquinoline (1f)

[0093] In an atmosphere of air at atmospheric pressure, ethyl 4-phenylbenzimidate 2f (45.0 mg, 0.20 mmol), methyl ((2-methyl-4-(p-tolyl)but-3-yn-2-yl) carbonate 3e (46.2 mg, 0.20 mmol), divalent ruthenium catalyst [Ru(p-cymene)Cl2]2 (2.5 mg, 0.004 mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01 mmol), copper acetate (39.8 mg, 0.04mmol), adamantanecarboxylic acid (1-AdCOOH, 9.0mg, 0.05mmol), trifluoroethanol (TFE, 1.0mL), react at 60°C for 12 hours. After the reaction is completed, cool to room temperature, filter through diatomaceous earth and concentrate to obtain a crude product. The crude product is separated by thin layer chromatography using the prepared silica gel plate, and the selected developing solvent or eluent is petroleum ether, to obtain 5-ethoxy-7,7,9-trimethyl-2-phenyl-7H-indeno[2,1-c]isoquinoline (1f) with a yield of 58%.

[0094] The chemical reaction equation corresponding to this embodiment is as follows:

[0095]

[0096] Example 6 The H-NMR and C-NMR spectra of the prepared compound are as follows: Fig.13 and Fig.14 As shown. Fig.13 It can be seen that: 1 H NMR (400MHz,CDCl3)δ8.64(d,J=2.0Hz,1H),8.44(d,J=8.8Hz,1H),8.03(d,J=7.6Hz,1H),7.81-7.75(m,3H),7.58-7.54(m,2H),7.48-7.44(m,1H),7.34-7.33(m,1H),7.23-7.20(m,1H),4.72(q,J=7.2Hz,2H),2.48(s,3H),1.56(t,J=6.8Hz,3H),1.52(s,6H). The molecular hydrogen spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Fig.14 It can be seen that:13 C NMR (100MHz, CDCl3) δ164.8, 160.3, 152.3, 143.7, 141.1, 136.5, 135.0, 134.5, 131.1, 129.0, 127.9, 127.7, 127.6, 125.9, 124.7, 123.3, 121.3, 121.0, 117.7, 62.1, 46.8, 25.1, 21.6, 14.6. Combining the results of the above H NMR spectrum and C NMR spectrum, it can be seen that the product obtained in Example 6 is 5-ethoxy-7,7,9-trimethyl-2-phenyl-7H-indeno[2,1-c]isoquinoline (1f).

[0097] In this embodiment, the preparation method of the indenoisoquinoline derivative 5-ethoxy-7,7,9-trimethyl-2-phenyl-7H-indeno[2,1-c]isoquinoline (1f) adopts a one-pot method and a one-step synthesis, which is easy to operate and has few synthetic impurities. The crude product can be separated and purified by conventional thin layer chromatography, which greatly reduces the difficulty of separation. The yield of the preparation reaction is good and can reach 58%. Therefore, the reaction has high step economy and atom economy.

[0098] The chemical transformation in this example provides a method for rapidly constructing indenoisoquinoline derivatives, which contain an ethoxy group that is easily converted and easily removed, thus facilitating subsequent modification.

[0099] Example 7 Preparation of 5-ethoxy-2-methoxy-7,7-dimethyl-7H-thieno[3',2':3,4]cyclopentyl[1,2-c]isoquinoline (1 g)

[0100] Under an atmospheric pressure air atmosphere, 2 g (35.8 mg, 0.20 mmol) of ethyl 4-methoxybenzimidate, methyl ((2-methyl-4-(thiophen-3-yl)but-3-yn-2-yl)carbonate 3e (44.8 mg, 0.20 mmol), divalent ruthenium catalyst [Ru(p-cymene)Cl2]2 (2.5 mg, 0.004 mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01 mmol), copper acetate (39.8 mg, 0.04 mmol), adamantanecarboxylic acid (9.0 mg, 0.05 mmol), hexafluoroisopropanol (HFIP, 1.0 mL), react at a temperature of 100°C for 12 hours. After the reaction is completed, cool to room temperature, filter through diatomaceous earth and concentrate to obtain a crude product. The crude product is separated by thin layer chromatography using the prepared silica gel plate, and the selected developing solvent or eluent is petroleum ether: ethyl acetate in a ratio of 50:1, and 5-ethoxy-2-methoxy-7,7-dimethyl-7H-thieno[3',2':3,4]cyclopentyl[1,2-c]isoquinoline (1 g) is obtained with a yield of 65%.

[0101] The chemical reaction equation corresponding to this embodiment is as follows:

[0102]

[0103] Example 7 The H-NMR and C-NMR spectra of the prepared compound are as follows: Fig.15 and Fig.16 As shown. Fig.15 It can be seen that: 1 H NMR (400 MHz, CDCl3) δ8.25 (d, J = 9.2 Hz, 1H), 7.53 (d, J = 5.2 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H), 7.13 (dd, J = 9.2, 2.4 Hz, 1H), 4.64 (q, J = 6.8 Hz, 2H), 4.01 (s, 3H), 1.55 (s, 6H), 1.52 (t, J = 7.2 Hz, 3H). The molecular hydrogen spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Fig.16 It can be seen that: 13C NMR (100 MHz, CDCl3) δ166.1, 161.0, 158.9, 152.3, 140.44, 134.1, 127.0, 126.5, 119.7, 118.3, 116.8, 113.2, 102.1, 61.9, 55.31, 47.42, 25.6, 14.7. Combining the results of the above nuclear magnetic hydrogen spectrum and carbon spectrum, it can be seen that the product prepared in Example 7 is 5-ethoxy-2-methoxy-7,7-dimethyl-7H-thieno[3',2':3,4]cyclopentyl[1,2-c]isoquinoline (1g).

[0104] The propargyl carbonate in the ((2-methyl-4-(thien-3-yl)but-3-yn-2-yl)methyl carbonate 3e in this embodiment has an easy leaving group at the propargyl position, which is easy to obtain valuable intermediates in organic synthesis and can be applied to CH functionalization. In addition, the propargyl carbonate itself can participate in coordination with metal catalysts, and it is easy to obtain a single-configuration product when the cycloaddition of alkynes occurs. The indenoisoquinoline derivative 5-ethoxy-2-methoxy-7,7-dimethyl-7H-thieno[3',2':3,4]cyclopentyl[1,2-c]isoquinoline (1g) solves the problem of regioselectivity when alkynes participate in cycloaddition. Therefore, propargyl carbonate is an excellent coupling reagent, which simultaneously participates in activating the CH bond of the biaromatic ring and undergoes two cyclizations to obtain a tetracyclic condensed heterocycle.

[0105] Therefore, the preparation method of the indenoisoquinoline derivative in this embodiment has the characteristics of high efficiency, high regioselectivity, and chemical selectivity, and uses easily available imine esters and propargyl carbonates with intramolecular oxidizing properties as reaction substrates. In addition, the product obtained by the conversion is also easy to be further converted subsequently.

[0106] Example 8 Preparation of 7-ethoxy-5,5-dimethyl-5H-benzo[g]indeno[2,1-c]isoquinoline (1h)

[0107] In an atmosphere of air at atmospheric pressure, 2-naphthylcarboximidate ethyl ester 2g (39.8mg, 0.20mmol), (2-methyl-4-phenylbut-3-yn-2-ol 3f (32.0mg, 0.20mmol), divalent ruthenium catalyst [Ru(p-cymene)Cl2]2 (2.5mg, 0.004mmol), silver trifluoromethanesulfonimide (3.9mg, 0.01mmol), copper acetate (39.8mg, 0.01mmol) were added in sequence into a 20mL reaction tube. , 0.04mmol), adamantanecarboxylic acid (9.0mg, 0.05mmol), hexafluoroisopropanol (HFIP, 1.0mL), react at 100℃ for 12 hours. After the reaction, cool to room temperature, filter through diatomaceous earth and concentrate to obtain a crude product. The crude product is separated by thin layer chromatography using the prepared silica gel plate, and the selected developing solvent or eluent is petroleum ether, to obtain 7-ethoxy-5,5-dimethyl-5H-benzo[g]indeno[2,1-c]isoquinoline (1h) with a yield of 50%.

[0108] The chemical reaction equation corresponding to this embodiment is as follows:

[0109]

[0110] Example 8 The H-NMR and C-NMR spectra of the prepared compound are as follows: Fig.17 and Fig.18 As shown. Fig.17 It can be seen that: 1 H NMR (400MHz,CDCl3)δ9.02(s,1H),8.98(s,1H),8.30(d,J=7.6Hz,1H),8.11(t,J=7.6Hz,2H),7.63-7.59(m,1H),7.54-7.52(m,2H),7.49-7.45(m,1H),7.34-7.32(m,1H),4.78(q,J=7.2Hz,3H),1.62(t,J=7.2Hz,3H),1.54(s,6H). The molecular hydrogen spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Fig.18 It can be seen that: 13 C NMR (100MHz, CDCl3) δ163.0, 161.5, 152.4, 139.5, 134.5, 130.8, 129.3, 128.1, 127.5, 126.9, 125.8, 125.4, 125.0, 122.3, 121.4, 120.9, 118.6, 117.6, 62.4, 47.0, 24.8, 14.6. Combining the results of the above H NMR spectrum and C NMR spectrum, it can be seen that the product obtained in Example 8 is 7-ethoxy-5,5-dimethyl-5H-benzo[g]indeno[2,1-c]isoquinoline (1h).

[0111] The preparation method in this embodiment is based on the fact that the propargyl alcohol compound (2-methyl-4-phenylbut-3-yn-2-ol 3f itself has certain oxidizing properties and easy leaving properties, and can coordinate with the metal catalyst, thereby solving the problem of regioselectivity after alkyne insertion. When the carbon-oxygen bond is broken, an intramolecular Friedel-Crafts reaction is easily carried out to obtain the target compound 7-ethoxy-5,5-dimethyl-5H-benzo[g]indeno[2,1-c]isoquinoline (1h).

[0112] Therefore, the preparation method of the indenoisoquinoline derivative in this embodiment is a green and efficient synthesis method. The method has the characteristics of easy availability of raw materials, high atom economy and step economy. Under relatively mild reaction conditions, the indenoisoquinoline derivative compound 7-ethoxy-5,5-dimethyl-5H-benzo[g]indeno[2,1-c]isoquinoline (1h) is efficiently synthesized.

[0113] In summary, this patent application uses easily convertible directing group imine esters and versatile propargyl carbonate as substrates. Under one-pot conditions, propargyl carbonate is used as a transient directing group to assist in the regioselective carbon-hydrogen bond activation and cyclization of alkynes. Subsequently, propargyl carbonate is also used as an activating group to in situ generate carbon cations to attack the aromatic rings within the molecule to obtain indenoisoquinoline compounds, which provide value for their application in the biomedical field.

[0114] Based on the fact that propargyl carbonate itself has certain oxidizing properties and easy leaving properties, and can coordinate with metal catalysts, the problem of regional selectivity after alkyne insertion is solved. When the carbon-oxygen bond breaks, an intramolecular Friedel-Crafts reaction is easily carried out to obtain the target compound. This molecular skeleton exhibits good anti-tumor activity.

[0115] At the same time, the preparation method of the indenoisoquinoline derivatives of the present patent application has the characteristics of high efficiency, wide substrate range, high regional and chemical selectivity, and uses simple and easily available imine esters and propargyl carbonates with intramolecular oxidizing properties as reaction substrates. In addition, the products obtained by the transformation are also easy to be further transformed subsequently.

[0116] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "illustrative embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiments or examples are included in at least one embodiment or example of this patent application. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner.

[0117] Although several embodiments of the present patent application have been shown and described, those skilled in the art will appreciate that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present patent application, and the scope of the present patent application is defined by the claims and their equivalents.

Claims

1. A method for preparing an indenoisoquinoline derivative, characterized in that: In an inert solvent and under the action of a metal catalyst, a benzyl imide ethyl ester compound (Formula II) is reacted with a propargyl carbonate compound or a propargyl alcohol compound (Formula III) to obtain an indenoisoquinoline derivative (Formula I), and the reaction equation is as follows: Among them, Ar 1 is 4-methylphenyl, 4-trifluoromethylphenyl, 3-chlorophenyl, 3,4-difluorophenyl, phenyl, 4-phenylphenyl, 4-methoxyphenyl or 2-naphthyl, Ar 2 is phenyl, [1,1'-biphenyl]-4-yl, p-methylphenyl, thiophene-3-yl, R is hydrogen, methyl formate or ethyl formate, isobutyl formate, The metal catalyst is dichlorobis(4-methylisopropylphenyl)ruthenium, The halogen atom extractor is one of silver hexafluoroantimonate and silver bis(trifluoromethanesulfonyl)imide or a combination thereof, The oxidant is copper acetate, The additive is one or more of adamantanecarboxylic acid, trifluoroacetic acid, silver trifluoroacetate, o-nitrobenzoic acid, hexafluoroisopropanol or trifluoroethanol, The inert solvent is one or more of trifluoroethanol and hexafluoroisopropanol. The amount of the metal catalyst used is 2 mol% of the amount of the ethyl benzimidate compound of formula II. The amount of the halogen atom extractor is 5 mol% of the amount of the benzimidic acid ethyl ester compound of formula II. The amount of the oxidant is 20 mol% of the amount of the ethyl benzimidate compound of formula II. The amount of the additive is 25 mol% of the amount of the benzimidic acid ethyl ester compound of formula II. The reaction is carried out at 100°C or 60°C for 12 hours.

2. The method for preparing an indenoisoquinoline derivative according to claim 1, characterized in that: The specific steps include the following: S1: In a reactor, 2.1 mg of dichlorobis(4-methylisopropylphenyl)ruthenium, 3.9 mg of silver trifluoromethanesulfonimide, 39.8 mg of copper acetate, 9.0 mg of adamantanecarboxylic acid, 1.0 mL of solvent hexafluoroisopropanol, 29.8 mg of ethyl benzyl imide, and 52.0 mg of propargyl carbonate were added in sequence in air; S2: react at 100°C for 12 hours; S3: After the reaction is completed, the mixture is separated by column chromatography to obtain the target compound.

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