Synthesis method of 6-cyclohexyl phenanthridine compound

Abstract

The invention discloses a synthesis method of a 6-cyclohexyl phenanthridine compound, and belongs to the technical field of organic synthesis.The synthesis method comprises the steps that a biaryl isonitrile compound and cyclohexane serve as raw materials, a specific copper-based photosensitizer and an oxidizing agent are added, illumination reaction is conducted for 15-48 hours at the temperature of 15-35 DEG C in an inert gas atmosphere, and the 6-cyclohexyl phenanthridine compound is obtained. After the reaction is finished, reaction liquid is subjected to post-treatment, separation and purification, and the 6-cyclohexyl phenanthridine compound is prepared. According to the method, cyclohexane serves as a reaction raw material and a reaction solvent at the same time, no extra organic solvent needs to be added, environment friendliness is achieved, meanwhile, the copper-based photosensitizer is used for replacing a precious metal photosensitizer and is low in price and easy to obtain, the reaction condition is mild, reaction can be conducted at the room temperature, and atom economy is high; the prepared 6-cyclohexyl phenanthridine compound can be used as a drug candidate or an organic synthesis intermediate.

Description

Technical Field

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

[0002] Nitrogen-containing heterocyclic structures are commonly found in natural products and bioactive molecules, and are also one of the most common structures of drug molecules. Phenanthridine is an important N-heterocyclic compound, which is often used as a drug or candidate drug in medicinal chemistry and has been shown to have a variety of biological activities, such as antibacterial, antitumor, cytotoxic and anti-leukemia activities. In the past decade, the free radical addition cascade reaction of 2-arylbenzene isonitrile has become a practical method for the synthesis of 6-substituted phenanthridine derivatives, but the reaction requires high temperature conditions to initiate, and the controllability of the reaction needs to be improved.

[0003] Alkanes are the main components of petroleum and natural gas and are widely distributed in nature. However, due to their inherent inertness and uncontrollable chemical selectivity, only a small amount of alkanes are used as economical chemical raw materials, which has led to the direct activation of C(sp 3 Therefore, if the chemical properties of N-heterocyclic compounds and alkanes are combined to achieve the transformation of natural alkanes, it can provide new opportunities for drug discovery and chemical industry.

[0004] The synthesis method of 6-substituted phenanthridine compounds has been reported one after another. For example, the Chinese patent document with publication number CN112062719A discloses a method for preparing 6-substituted alkyl phenanthridine compounds, in which biphenyl isonitrile compounds and fatty aldehyde compounds are dissolved in chlorobenzene solvent, and then ferrous sulfate and di-tert-butyl peroxide are added, and decarbonylation and free radical addition cyclization reactions are carried out at 130°C for 11 hours to obtain 6-substituted alkyl phenanthridine compounds. The Chinese patent document with publication number CN109422689A discloses a method for synthesizing 6-substituted phenanthridine compounds, which uses substituted azide terminal olefin compounds as starting materials and dimethyl azobisisobutyrate as a free radical source, in a copper catalyst and solvent, under the protection of inert gas, and reacts completely at a temperature of 50°C to 100°C, and the reaction solution is post-treated to prepare the corresponding 6-substituted phenanthridine and its derivatives. The temperature required in the above chemical reactions is relatively high, and the role of additional solvents is required.

[0005] In recent years, photocatalysis has become an ideal clean energy production technology and environmental pollution control technology. In view of the growing demand for sustainable and green methods in the field of synthetic chemistry, photochemical synthesis is undoubtedly regarded as an ideal reaction process. Photocatalytic reaction has now become a hot topic for scientists to study and is widely used in the preparation of N-heterocyclic compounds. In view of the problems existing in the above-mentioned prior art, it is very necessary to develop a photocatalytic synthesis scheme for 6-cyclohexylphenanthridine compounds with simple and easy-to-obtain raw materials, environmentally friendly, relatively cheap and easy-to-obtain catalysts, high atomic economy in the reaction process, and mild reaction. Summary of the invention

[0006] In view of the shortcomings of the prior art, the present invention provides a method for synthesizing 6-cyclohexylphenanthridine compounds. In the method, cyclohexane is used as both a reaction raw material and a reaction solvent, and no additional organic solvent is required. At the same time, a copper-based photosensitizer is used to replace a precious metal photosensitizer, which is cheap and easy to obtain, and the reaction conditions are mild, and the reaction can be carried out at room temperature.

[0007] The specific technical solutions adopted are as follows:

[0008] A method for synthesizing 6-cyclohexylphenanthridine compounds comprises the following steps:

[0009] The biaryl isonitrile compound represented by formula (I) and cyclohexane are used as raw materials, a copper-based photosensitizer represented by formula (III) and an oxidant are added, and the reaction is carried out under light at 15° C.-35° C. in an inert gas atmosphere for 15-48 hours. After the reaction is completed, the reaction solution is subjected to post-treatment, separation and purification to obtain a 6-cyclohexylphenanthridine compound represented by formula (IV);

[0010]

[0011] In formula (I) and formula (IV), R 1 is a substituent on the benzene ring, R 1 is hydrogen, methyl, ethyl, isopropyl, n-butyl, phenyl, chlorine, bromine, iodine or trifluoromethyl, R 2 is hydrogen, methyl, isopropyl, chloro, methoxy or naphthyl;

[0012] In formula (III), R 3 is H or phenyl, R 4 is H, methyl or isopropyl.

[0013] More preferably, R 1 is hydrogen, methyl, ethyl, isopropyl, n-butyl, phenyl, chlorine, bromine or iodine, R 2 is H, methyl, chloro, isopropyl or naphthyl.

[0014] More preferably, R 3 is phenyl, R4 It is isopropyl.

[0015] The reaction formula of the method of the present invention is expressed as:

[0016]

[0017] The biaryl isonitrile compound represented by the raw material formula (I) used in the present invention can be prepared by those skilled in the art according to the methods disclosed in existing literature; cyclohexane is a common chemical reagent and can be directly purchased.

[0018] Specifically, based on the molar number of the biaryl isonitrile compound represented by formula (I), the volume amount of cyclohexane is 1 to 10 mL / mmol, preferably 1 to 5 mL / mmol. In the reaction process of the present invention, cyclohexane is used as both a reaction raw material and a reaction solvent, and no additional organic solvent is added, which is green and environmentally friendly.

[0019] The copper-based photosensitizer represented by formula (III) can be prepared by itself according to the records in the literature.

[0020] The amount of the copper-based photosensitizer represented by formula (III) is 1% to 10% of the amount of the biaryl isonitrile compound represented by formula (I), preferably 2%.

[0021] The oxidant is at least one of tert-butyl peroxide (TBHP), hydrogen peroxide, and di-tert-butyl peroxide (DTBP), preferably DTBP.

[0022] Furthermore, the amount of the oxidant is 100% to 300% of the amount of the biaryl isonitrile compound represented by formula (I), preferably 300%.

[0023] Preferably, the inert gas atmosphere is a nitrogen atmosphere.

[0024] Specifically, the light irradiation reaction is carried out under the condition of 390-400nm visible light, preferably 398nm.

[0025] The post-treatment separation and purification method comprises: adding the reaction solution obtained after the reaction is completed to column chromatography silica gel, removing the solvent by reduced pressure distillation, loading the remaining mixture into a column, separating by column chromatography, using a mixed solvent of petroleum ether and ethyl acetate as an eluent, collecting the eluate containing the product, and evaporating the solvent from the eluate to obtain a 6-cyclohexylphenanthridine compound shown in formula (IV).

[0026] Furthermore, the method of the present invention is preferably carried out according to the following steps: using the biaryl isonitrile compound shown in formula (I) and cyclohexane as raw materials, adding the copper-based photosensitizer shown in formula (III) and the oxidant, stirring and reacting for 24 hours under nitrogen protection and room temperature illumination conditions, after the reaction is completed, adding column chromatography silica gel to the reaction solution, removing the solvent by reduced pressure distillation, loading the remaining mixture into a column, separating by column chromatography, using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1 as an eluent, collecting the eluate containing the product, and distilling off the solvent from the eluate to obtain a 6-cyclohexylphenanthridine compound shown in formula (IV).

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The photocatalytic synthesis method of 6-cyclohexylphenanthridine compounds provided by the present invention does not require the addition of additional organic solvents. Cyclohexane is used as both a reaction raw material and a reaction solvent, which is green and environmentally friendly. The catalyst used is a copper-based photosensitizer, which is cheaper and easier to obtain than precious metal catalysts. At the same time, the reaction of the present invention can be reacted at room temperature under light conditions, the reaction conditions are mild, and the energy consumption is low. In addition, the method of the present invention also has the characteristics of high atomic economy, simple operation, low equipment requirements, etc. DETAILED DESCRIPTION

[0029] The present invention will be further illustrated below in conjunction with the examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The operating methods in the following examples that do not specify specific conditions are usually performed under normal conditions or according to the conditions recommended by the manufacturer. The content that is not described in detail in this specification sheet belongs to the prior art known to professionals in the field. The experimental materials used in the following examples, if not otherwise specified, can be purchased by conventional biochemical reagent companies.

[0030] Specifically, the copper-based photosensitizer used in the embodiment is prepared according to the records in the existing literature (such as Hanyang Bao, Bingwei Zhou, Shu-Ping Luo, et al. P / N Heteroleptic Cu (I)-Photosensitizer-Catalyzed Deoxygenative Radical Alkylation of Aromatic Alkynes with Alkyl Aldehydes Using Dipropylamine as a Traceless Linker Agent [J]. ACS Catalysis, 2020,. DOI: 10.1021 / acscatal.0c02454.); the molecular structure of the prepared copper-based photosensitizer is as follows:

[0031]

[0032] Among them, R 3 is phenyl, R 4 It is isopropyl.

[0033] The prepared copper-based photosensitizer was subjected to single crystal cultivation and crystal testing to determine its chemical structure. The unit cell parameters are: α=90°,β=101.149(2)°,γ=90°,the unit cell volume is It belongs to the monoclinic crystal system, and the space group is P21 / n; its crystallographic parameters are shown in Table 1;

[0034] Table 1 Crystallographic parameters of copper-based photosensitizers

[0035]

[0036] Example 1

[0037] In this embodiment, the synthesized 6-cyclohexylphenanthridine compound is shown in the following formula:

[0038]

[0039] The synthesis method is as follows: 0.5mmol 2-phenylbenzene isonitrile (89.5mg), 5mL cyclohexane, about 2% (mol / mol) of the above-synthesized copper-based photosensitizer (11.5mg), 1.5mmol di-tert-butyl peroxide (DTBP) (219mg) are added to a 10mL pressure tube. Then, the air is replaced by nitrogen gas, the stopper is tightened, and the reaction is carried out for 24 hours at room temperature (about 25°C) under 398nm illumination and magnetic stirring. Then, after the reaction is completed, column chromatography silica gel is added to the reaction solution, the solvent is removed by vacuum distillation, the remaining mixture is loaded into a column, and separated by column chromatography, a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1 is used as an eluent, and the eluent containing the product is collected, and the eluent is evaporated to remove the solvent to obtain a pure product 6-cyclohexylphenanthridine. The substance is an off-white solid with a yield of 82%.

[0040] The characterization data of 6-cyclohexylphenanthridine are: 1 H NMR (400MHz, CDCl3) δ8.64(d,J=8.4Hz,1H),8.54(d,J=8.0Hz,1H),8.32(d,J=8.0Hz,1H),8.16(d,J=8.0Hz,1H),7.87-7.76 (m,1H),7.76-7.65(m,2H),7.64-7.55(m,1H),3.74-3.53(m,1H),2.19-1.80(m,7H),1.68-1.52(m,2H),1.52-1.39(m,1H).

[0041] 13 C NMR (100MHz, CDCl3) δ165.2,143.8,132.9,129.9,129.8,128.3,127.0,126.1,125.5,124.7,123.3,122.5,121.8,41.9,32.2,26.8,26.3.

[0042] Example 2

[0043] In this embodiment, the synthesized 6-cyclohexylphenanthridine compound is shown in the following formula:

[0044]

[0045] 0.5mmol 2-(4-chlorophenyl)benzene isonitrile (147.5mg), 5mL cyclohexane, about 2% (mol / mol) of the above-synthesized copper-based photosensitizer (11.5mg), 1.5mmol di-tert-butyl peroxide (DTBP) (219mg) were added to a 10mL pressure tube. Then, the air was replaced by nitrogen gas, the stopper was tightened, and the reaction was carried out for 24 hours at room temperature (about 25°C) under 398nm illumination and magnetic stirring. Then, after the reaction was completed, column chromatography silica gel was added to the reaction solution, the solvent was removed by vacuum distillation, the remaining mixture was loaded into a column, and separated by column chromatography, a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1 was used as an eluent, and the eluent containing the product was collected, and the eluent was evaporated to remove the solvent to obtain a pure product. The substance is an off-white solid with a yield of 76%.

[0046] The characterization data of the 6-cyclohexylphenanthridine compound are: 1 H NMR (400MHz, CDCl3) δ8.57(d,J=8.8Hz,1H),8.47(d,J=8.4Hz,1H),8.25(d,J=2.0Hz,1H),8.13(d,J=8.0Hz,1H),7 .85-7.67(m,2H),7.66-7.56(m,1H),3.60-3.41(m,1H),2.15-1.78(m,7H),1.64-1.52(m,2H),1.49-1.36(m,1H).

[0047] 13 C NMR (125MHz, CDCl3) δ163.2,142.8,132.1,130.4,129.4,129.1,127.7,125.5,124.7,124.0,123.4,121.7,120.7,40.9,31.2,25.7,25.2.

[0048] Example 3

[0049] In this embodiment, the synthesized 6-cyclohexylphenanthridine compound is shown in the following formula:

[0050]

[0051] 0.5mmol 2-(4-methoxyphenyl)-4-methylbenzene isocyanide (152.5mg), 5mL cyclohexane, about 2% (mol / mol) of the above-synthesized copper-based photosensitizer (11.5mg), 1.5mmol di-tert-butyl peroxide (DTBP) (219mg) were added to a 10mL pressure tube. Then, the air was replaced by nitrogen gas, the stopper was tightened, and the reaction was carried out for 24 hours at room temperature (about 25°C) under 398nm illumination and magnetic stirring. Then, after the reaction was completed, column chromatography silica gel was added to the reaction solution, the solvent was removed by vacuum distillation, the remaining mixture was loaded into a column, and separated by column chromatography, a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1 was used as an eluent, and the eluent containing the product was collected, and the eluent was evaporated to remove the solvent to obtain a pure product. The substance is an off-white solid with a yield of 70%.

[0052] The characterization data of the 6-cyclohexylphenanthridine compound are: 1 H NMR (400MHz, CDCl3), δ (ppm): 8.52 (d, J = 8.8Hz, 1H), 8.20 (s, 1H), 7.98 (d, J = 8.0Hz, 1H), 7.60 (d, J = 2.8Hz, 1H), 7.44 (dd, J = 8.4Hz, J = 1.6Hz, 1H),7.40(dd,J=9.2Hz,J=2.4Hz,1H),3.98(s,3H),3.51-3.45(m,1H),2.57(s,3H),2.09-1.82(m,7H),1.61-1.51(m,2H),1.47-1.41(m,1H);

[0053] 13 C NMR (100MHz, CDCl3), δ (ppm): 163.3, 158.4, 141.4, 135.9, 129.7, 129.1, 127.1 ,126.1,124.2,123.2,120.9,119.5,106.6,55.1,42.1,32.2,26.9,26.4,21.9.

[0054] Example 4

[0055] In this embodiment, the synthesized 6-cyclohexylphenanthridine compound is shown in the following formula:

[0056]

[0057] The synthesis method is as follows: 0.5mmol 2-phenylbenzene isonitrile (89.5mg), 5mL cyclohexane, about 2% (mol / mol) of the above-synthesized copper-based photosensitizer (11.5mg), and 1.0mmol di-tert-butyl peroxide (DTBP) (146mg) are added to a 10mL pressure tube. Then, the air is replaced by nitrogen gas, the stopper is tightened, and the reaction is carried out for 24 hours at room temperature (about 25°C) under 398nm illumination and magnetic stirring. Then, after the reaction is completed, column chromatography silica gel is added to the reaction solution, the solvent is removed by vacuum distillation, the remaining mixture is loaded into a column, and separated by column chromatography, a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1 is used as an eluent, and the eluent containing the product is collected, and the eluent is evaporated to remove the solvent to obtain a pure product 6-cyclohexylphenanthridine. The substance is an off-white solid with a yield of 68%. Reducing the amount of the oxidant di-tert-butyl peroxide (DTBP) reduces the reaction yield.

[0058] Comparative Example 1

[0059] In this comparative example, the synthesized 6-cyclohexylphenanthridine compound is shown in the following formula:

[0060]

[0061] 0.5mmol 2-(4-chlorophenyl)benzene isocyanide (147.5mg), 2.5mL cyclohexane and 2.5ml acetonitrile, about 2% (mol / mol) of the above-synthesized copper-based photosensitizer (11.5mg), 1.5mmol di-tert-butyl peroxide (DTBP) (219mg) were added to a 10mL pressure tube. Then, nitrogen was purged to replace the air, the stopper was tightened, and the reaction was stirred with magnetic force at 398nm illumination for 24 hours at room temperature (about 25°C). After the reaction was completed, a thin layer chromatography (TLC) plate was spotted, and it was found that there was a large amount of residual raw materials, and by-products were produced. It was shown that the additional addition of acetonitrile solvent was not conducive to the forward reaction, and would induce side reactions and reduce the reaction yield.

[0062] The embodiments described above provide a detailed description of the technical solutions of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, supplements or similar substitutions made within the scope of the principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 6-cyclohexylphenanthridine compounds, characterized in that: The following steps are involved: The biaryl isonitrile compound represented by formula (I) and cyclohexane are used as raw materials, a copper-based photosensitizer represented by formula (III) and an oxidant are added, and the reaction is carried out under light at 15° C.-35° C. in an inert gas atmosphere for 15-48 hours. After the reaction is completed, the reaction solution is subjected to post-treatment, separation and purification to obtain a 6-cyclohexylphenanthridine compound represented by formula (IV); In formula (I) and formula (IV), R 1 is a substituent on the benzene ring, R 1 is hydrogen, methyl, ethyl, isopropyl, n-butyl, phenyl, chlorine, bromine, iodine or trifluoromethyl, R 2 is hydrogen, methyl, isopropyl, chloro, methoxy or naphthyl; In formula (III), R 3 is H or phenyl, R 4 is H, methyl or isopropyl.

2. The method for synthesizing 6-cyclohexylphenanthridine compounds according to claim 1, wherein R 1 is hydrogen, methyl, ethyl, isopropyl, n-butyl, phenyl, chlorine, bromine or iodine, R 2 is H, methyl, chloro, isopropyl or naphthyl; and / or, R 3 is phenyl, R 4 It is isopropyl.

3. The synthetic method of 6-cyclohexylphenanthridine compounds according to claim 1, characterized in that, The volume amount of cyclohexane used is 1-10 mL / mmol based on the molar number of the biaryl isonitrile compound represented by formula (I).

4. The method for synthesizing 6-cyclohexylphenanthridine compounds according to claim 1, characterized in that: The amount of the copper-based photosensitizer represented by formula (III) is 1% to 10% of the amount of the biaryl isonitrile compound represented by formula (I).

5. The method for synthesizing 6-cyclohexylphenanthridine compounds according to claim 1, characterized in that: The oxidant is at least one of tert-butyl peroxide, hydrogen peroxide and di-tert-butyl peroxide.

6. The method for synthesizing 6-cyclohexylphenanthridine compounds according to claim 1, characterized in that: The amount of the oxidant is 100% to 300% of the amount of the biaryl isonitrile compound represented by formula (I).

7. The method for synthesizing 6-cyclohexylphenanthridine compounds according to claim 1, characterized in that: The inert gas atmosphere is a nitrogen atmosphere.

8. The method for synthesizing 6-cyclohexylphenanthridine compounds according to claim 1, characterized in that: The photoreaction was carried out under the condition of 390-400nm visible light.

9. The method for synthesizing 6-cyclohexylphenanthridine compounds according to claim 1, characterized in that: The post-treatment separation and purification method comprises: adding the reaction solution obtained after the reaction is completed to column chromatography silica gel, removing the solvent by reduced pressure distillation, loading the remaining mixture into a column, separating by column chromatography, using a mixed solvent of petroleum ether and ethyl acetate as an eluent, collecting the eluate containing the product, and evaporating the solvent from the eluate to obtain a 6-cyclohexylphenanthridine compound shown in formula (IV).

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