Preparation method of naphthodiazepine indole derivative

Abstract

The invention discloses a method for preparing a naphthodiazepine indole derivative, which comprises the following steps: adding tri (dibenzylideneacetone) dipalladium (0)-chloroform adduct, bis (2-diphenylphosphinophenyl) ether and alkali into a reactor, adding a certain amount of solvent under the protection of argon, and stirring for a period of time; the preparation method comprises the following steps: dissolving N-(4-methylbenzenesulfonyl)-1-(2-indolyl)-2-naphthylamine and methyl (1-arylpropyl-2-alkyne-1-yl) carbonate in a certain amount of solvent, adding into a reactor, reacting at room temperature, and detecting that the reaction is complete by TLC (Thin Layer Chromatography). And after the reaction is finished, filtering, concentrating filtrate under reduced pressure, and performing column chromatography to obtain a pure product of the naphthodiazepine indole derivative. According to the technical scheme, the method has the characteristics of diversified substrate raw material sources, simple synthesis steps, mild reaction conditions, simplicity and convenience in operation, good reaction selectivity, complex and diversified target compound structures, and the like, and the product further contains olefin and amino functional groups for further structural modification.

Description

Technical Field

[0001] The invention relates to the technical field of organic compound synthesis, and in particular to a method for preparing naphthodiazepine indole derivatives. Background Art

[0002] Naphthodiazepine and indole compounds are an important class of nitrogen-containing heterocyclic compounds with important physiological and pharmacological activities (Bioorganic & Medicinal Chemistry Letters, 2003, 13, 2369). The development of simple and efficient methods to synthesize this class of compounds is of great significance for the development and research of new drugs.

[0003] The preparation methods of fused diazepine indole derivatives reported in the literature mainly include: using indole-substituted aromatic amine and chloroacetyl chloride as raw materials, generating substituted amide derivatives under the action of sodium acetate, and then undergoing intramolecular cyclization reaction under the action of sodium hydride to generate fused diazepine indole derivatives.

[0004]

[0005] This method has limited sources of substrate raw materials and requires the use of reagents such as chloroacetyl chloride and sodium hydride, which is inconvenient to operate and poses safety hazards; the product has a simple structure and a single functional group form, making it difficult to further modify its structure. Summary of the invention

[0006] The purpose of the present invention is to provide a method for preparing naphthodiazepine indole derivatives, which has the characteristics of diversified substrate raw material sources, simple synthesis steps, mild reaction conditions, simple operation, good reaction selectivity, complex and diverse target compound structures, and the product also contains olefins and amino functional groups for further structural modification.

[0007] The technical solution of the present invention is as follows: step 1: under the protection of argon, a certain amount of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, bis(2-diphenylphosphophenyl)ether, base, N-(4-methylbenzenesulfonyl)-1-(2-indolyl)-2-naphthylamine, methyl(1-arylprop-2-yn-1-yl)carbonate and solvent tetrahydrofuran are reacted at room temperature; step 2: after the reaction is completed, filtering, concentrating the filtrate under reduced pressure, and performing column chromatography to obtain a pure naphthodiazepine indole derivative.

[0008] Preferably, in step one, tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, bis(2-diphenylphosphophenyl)ether and a base are first added to a reactor, a certain amount of solvent is added under argon protection, and the mixture is stirred for a period of time. Then, N-(4-methylbenzenesulfonyl)-1-(2-indolyl)-2-naphthylamine and methyl(1-arylprop-2-yn-1-yl)carbonate and a certain amount of solvent are mixed evenly and then added to the reactor to react at room temperature.

[0009] Preferably, the reaction temperature in step 1 is 20-40°C.

[0010] Preferably, the reaction time in step 1 is 6-24 hours.

[0011] Preferably, the base in step 1 is cesium carbonate.

[0012] Preferably, the solvent in step 1 is acetonitrile, 1,4-dioxane, or tetrahydrofuran.

[0013] Preferably, in step 1, the molar ratio of N-(4-methylbenzenesulfonyl)-1-(2-indolyl)-2-naphthylamine, methyl(1-arylprop-2-yn-1-yl)carbonate, tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, bis(2-diphenylphosphophenyl)ether and base is 1.0:1.0-2.0:0.01-0.10:0.01-0.10:0.05-0.20.

[0015] Preferably, the methyl (1-arylprop-2-yn-1-yl) carbonate is one of methyl (1-phenylprop-2-yn-1-yl) carbonate, methyl (1-(3-methylphenyl)prop-2-yn-1-yl) carbonate, methyl (1-(4-methylphenyl)prop-2-yn-1-yl) carbonate, and methyl (1-(3-chlorophenyl)prop-2-yn-1-yl) carbonate.

[0016] The above technical scheme has the following beneficial effects: 1. The sources of substrate raw materials are diverse; 2. The synthesis steps are concise, the reaction conditions are mild, and the operation is simple; 2. The reaction selectivity is good, and the target compound structures are complex and diverse; 3. The product contains olefin and amino functional groups for further structural modification, which provide chemically modified reaction sites for further improving the molecular stability and improving the selectivity of the molecule for the target site. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Attached Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 1.

[0018] Attached Figure 2 The hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 2 is shown in FIG.

[0019] Attached Figure 3 The hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 3 is shown in FIG.

[0020] Attached Figure 4 The hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 4 is shown in FIG. DETAILED DESCRIPTION

[0021] The following is a description of the implementation of the present invention by means of specific embodiments. Those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

[0022] Example embodiments will now be described more fully with reference to the accompanying drawings. However, example embodiments can be implemented in a variety of forms and should not be construed as being limited to the examples set forth herein; on the contrary, these embodiments are provided so that the present invention will be more comprehensive and complete, and the concept of the example embodiments will be fully conveyed to those skilled in the art. The described features, structures, or characteristics may be combined in one or more embodiments in any suitable manner. In the following description, many specific details are provided to provide a full understanding of the embodiments of the present invention. However, those skilled in the art will appreciate that the technical solutions of the present invention may be practiced while omitting one or more of the specific details, or other methods, components, devices, steps, etc. may be adopted. In other cases, known technical solutions are not shown or described in detail to avoid obscuring various aspects of the present invention.

[0023] Embodiment 1:

[0024] Step 1: Add tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (0.0075mmol), bis(2-diphenylphosphinophenyl)ether (0.015mmol), cesium carbonate (0.030mmol) to a 25mL reaction tube, add 2.0mL tetrahydrofuran under argon protection, and stir for a while. Dissolve N-(4-methylbenzenesulfonyl)-1-(2-indolyl)-2-naphthylamine (0.3mmol) and methyl (1-phenylprop-2-yn-1-yl) carbonate (0.45mmol) in 4.0mL tetrahydrofuran, add to the reactor, and react at room temperature for 12 hours;

[0025] Step 2: After the reaction is completed, the mixture is filtered and the filtrate is concentrated under reduced pressure. Column chromatography is performed to obtain pure 9-benzylidene-7-toluenesulfonyl-8,9-dihydro-7H-naphtho[2',1':5,6][1,4]diazepine[1,7-a]indole, the molecular formula of which is:

[0026]

[0027] Yield: 82%; the product is a white solid; the H NMR spectrum of the product is as follows Figure 1As shown: (CDCl3, 400MHz) (δ, ppm): 8.53 (d, J = 7.6Hz, 1H), 7.99-7.90 (m, 2H), 7.82 (d, J = 7.2Hz, 1H), 7.58-7.52 (m, 2H), 7.43 (d, J = 8.0Hz, 1H), 7.00 (d, J = 8.4Hz, 3H), 6.96 (d, J = 7.6Hz, 1 H),6.94-6.88(m,2H),6.77(d,J=8.0Hz,1H),6.58(s,1H),6.52(d,J=8.0Hz,2H),6.45(d ,J=7.2Hz,2H),6.40(s,1H),5.55(d,J=15.6Hz,1H),4.72(d,J=15.6Hz,1H),2.14(s,3H).

[0028] Carbon NMR: (CDCl3, 100 MHz) (δ, ppm): 142.7, 136.3, 134.0, 133.9, 133.5, 132.9, 132.7, 131.9, 130.0, 129.5, 129.2, 128.9, 128.5, 128.2, 128.2, 128.1, 128.0, 127.1, 126.9, 126.4, 126.3, 122.7, 120.4, 120.3, 60.0, 21.5.

[0029] High resolution mass spectrometry (ESI) m / z calcd for C 34 H 27 N2O2S[M+H] + 527.1793, found 527.1795.

[0030] Embodiment 2:

[0031] Step 1: Add tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (0.0075mmol), bis(2-diphenylphosphinophenyl)ether (0.015mmol), cesium carbonate (0.030mmol) to a 25mL reaction tube, add 2.0mL tetrahydrofuran under argon protection, and stir for a while. Dissolve N-(4-methylbenzenesulfonyl)-1-(2-indolyl)-2-naphthylamine (0.3mmol) and methyl (1-(3-methylphenyl)prop-2-yn-1-yl) carbonate (0.45mmol) in 4.0mL tetrahydrofuran, add to the reactor, and react at room temperature for 12 hours;

[0032] Step 2: After the reaction is completed, filter and concentrate the filtrate under reduced pressure. Column chromatography is used to obtain pure 9-(3-methylphenyl)methylene-7-toluenesulfonyl-8,9-dihydro-7H-naphtho[2',1':5,6][1,4]diazepine[1,7-a]indole, the molecular formula of which is:

[0033]

[0034] Yield: 75%; the product is a white solid; the H NMR spectrum of the product is as follows Figure 2 Shown as: (CDCl3, 400MHz) (δ, ppm): 8.58-8.51 (m, 1H), 7.99-7.90 (m, 2H), 7.85 (d, J = 8.4 Hz,1H),7.58-7.52(m,2H),7.47(d,J=7.6Hz,1H),7.09-6.98(m,4H),6.84(d,J=8. 0Hz,1H),6.73(d,J=8.0Hz,2H),6.54(d,J=7.6Hz,3H),6.42(s,1H),6.36(d,J=7.6 Hz, 2H), 5.55 (d, J = 15.2Hz, 1H), 4.72 (d, J = 15.2Hz, 1H), 2.16 (s, 3H), 2.08 (s, 3H).

[0035] Carbon NMR: (CDCl3, 100 MHz) (δ, ppm): 142.7, 138.1, 136.4, 134.0, 133.5, 132.7, 131.9, 130.1, 129.6, 129.4, 129.0, 128.9, 128.5, 128.4, 128.1, 128.0, 127.1, 126.9, 126.4, 126.3, 122.7, 120.5, 120.2, 110.6, 106.7, 60.1, 21.5, 21.1.

[0036] High resolution mass spectrometry (ESI) m / z calcd for C 35 H 29 N2O2S[M+H] + 541.1950,found 541.1949.

[0037] Embodiment 3:

[0038] Step 1: Add tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (0.0075mmol), bis(2-diphenylphosphinophenyl)ether (0.015mmol), cesium carbonate (0.030mmol) to a 25mL reaction tube, add 2.0mL tetrahydrofuran under argon protection, and stir for a while. Dissolve N-(4-methylbenzenesulfonyl)-1-(2-indolyl)-2-naphthylamine (0.3mmol) and methyl (1-(4-methylphenyl)prop-2-yn-1-yl) carbonate (0.45mmol) in 4.0mL tetrahydrofuran and add to the reactor.

[0039] The reaction was carried out at room temperature for 12 hours;

[0040] Step 2: After the reaction is completed, filter and concentrate the filtrate under reduced pressure. Column chromatography is used to obtain pure 9-(4-methylphenyl)methylene-7-toluenesulfonyl-8,9-dihydro-7H-naphtho[2',1':5,6][1,4]diazepine[1,7-a]indole, the molecular formula of which is:

[0041]

[0042] Yield: 69%; the product is a white solid; the H NMR spectrum of the product is as follows Figure 3 Shown as: (CDCl3, 400MHz) (δ, ppm): 8.60-8.52 (m, 1H), 7.99-7.91 (m, 2H), 7.84 (d, J =8.4Hz,1H),7.59-7.52(m,2H),7.45(d,J=7.6Hz,1H),7.06-6.95(m,4H),6.83 -6.73(m,3H),6.58-6.50(m,3H),6.42(s,1H),6.28(s,1H),6.23(d,J=7.2Hz, 1H), 5.56 (d, J = 15.6Hz, 1H), 4.72 (d, J = 15.2Hz, 1H), 2.15 (s, 3H), 1.99 (s, 3H).

[0043] Carbon NMR: (CDCl3, 100 MHz) (δ, ppm): 142.7, 137.6, 136.4, 134.1, 134.0, 133.5, 132.8, 131.9, 130.1, 129.6, 129.4, 129.1, 129.0, 128.9, 128.8, 128.5, 128.0, 127.1, 126.9, 126.4, 126.3, 124.9, 122.6, 120.4, 120.2, 110.5, 106.7, 60.1, 21.5, 21.2.

[0044] High resolution mass spectrometry (ESI) m / z calcd for C 35 H 29 N2O2S[M+H] + 541.1950, found 541.1956.

[0045] Embodiment 4:

[0046] Step 1: Add tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (0.0075mmol), bis(2-diphenylphosphinophenyl)ether (0.015mmol), cesium carbonate (0.030mmol) to a 25mL reaction tube, add 2.0mL tetrahydrofuran under argon protection, and stir for a while. Dissolve N-(4-methylbenzenesulfonyl)-1-(2-indolyl)-2-naphthylamine (0.3mmol) and methyl (1-(3-chlorophenyl)prop-2-yn-1-yl) carbonate (0.45mmol) in 4.0mL tetrahydrofuran and add to the reactor.

[0047] The reaction was carried out at room temperature for 12 hours;

[0048] Step 2: After the reaction is completed, the mixture is filtered and the filtrate is concentrated under reduced pressure. Column chromatography is performed to obtain pure 9-(3-chlorophenyl)methylene-7-toluenesulfonyl-8,9-dihydro-7H-naphtho[2',1':5,6][1,4]diazepine[1,7-a]indole, the molecular formula of which is:

[0049]

[0050] Yield: 78%; the product is a white solid; the H NMR spectrum of the product is as follows Figure 4 As shown: (CDCl3, 400MHz) (δ, ppm): 8.65-8.52 (m, 1H), 7.95 (s, 1H), 7.84 (d, J = 8.8Hz, 1H), 7.60-7.55 (m, 2H), 7.49-7.43 (m, 2H), 7.34-7.28 (m, 1H), 7.15 (d, J = 7.6Hz, 1H), 7.02 (s, 1H), 7.00 (s, 1 H),6.89(d,J=8.0Hz,1H),6.80(d,J=8.0Hz,1H),6.76(d,J=8.4Hz,1H),6.55-6.47(m,3H),6. 45(s,2H),6.27(d,J=8.0Hz,1H),5.56(d,J=14.8Hz,1H),4.70(d,J=15.6Hz,1H),2.14(s,3H).

[0051] Carbon NMR: (CDCl3, 100 MHz) (δ, ppm): 142.9, 136.3, 134.9, 134.2, 134.0, 133.8, 133.6, 132.6, 132.0, 131.1, 130.1, 129.8, 129.7, 129.5, 129.0, 128.6, 128.3, 128.0, 127.4, 127.3, 127.1, 126.8, 126.4, 126.3, 125.8, 123.0, 120.6, 120.6, 110.4, 107.3, 59.8, 21.5.

[0052] High resolution mass spectrometry (ESI) m / z calcd for C 34 H 26 ClN2O2S[M+H] + 561.1404, found 561.1405.

[0053] The method for preparing naphthodiazepine and indole derivative substrates has multiple sources of raw materials; the synthesis steps are concise, the reaction conditions are mild, and the operation is simple; the reaction selectivity is good, and the target compound structures are complex and diverse; 3. The product contains olefin and amino functional groups that can be further modified in structure, which is of great significance in the development and research of new drugs, and provides chemically modified reaction sites for further improving molecular stability and improving the selectivity of molecules for target sites.

[0054] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. A method for preparing naphthodiazepine indole derivatives, characterized in that: It includes the following steps: Step 1: Under argon protection, a certain amount of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, bis(2-diphenylphosphinophenyl)ether, a base, N-(4-methylbenzenesulfonyl)-1-(2-indolyl)-2-naphthylamine, methyl(1-arylprop-2-yn-1-yl)carbonate and solvent tetrahydrofuran are reacted at room temperature; Step 2: After the reaction is completed, filter, concentrate the filtrate under reduced pressure, and perform column chromatography to obtain a pure naphthodiazepine indole derivative.

2. A method for preparing naphthodiazepine indole derivatives according to claim 1, characterized in that: In step one, tri(dibenzylideneacetone)dipalladium(0)-chloroform adduct, bis(2-diphenylphosphinophenyl)ether and a base are first added to a reactor, and a certain amount of solvent is added under argon protection, and stirred for a period of time. Then, N-(4-methylbenzenesulfonyl)-1-(2-indolyl)-2-naphthylamine and methyl(1-arylprop-2-yn-1-yl)carbonate and a certain amount of solvent are mixed evenly, added to the reactor, and reacted at room temperature.

3. The method for preparing naphthodiazepine indole derivatives according to claim 1, characterized in that: The reaction temperature in step 1 is 20-40°C.

4. The method for preparing naphthodiazepine indole derivatives according to claim 1, characterized in that: The reaction time in step 1 is 6-24 hours.

5. The method for preparing naphthodiazepine indole derivatives according to claim 1, characterized in that: In step 1, the base is cesium carbonate.

6. The method for preparing naphthodiazepine indole derivatives according to claim 1, characterized in that: In step 1, the solvent is acetonitrile, 1,4-dioxane or tetrahydrofuran.

7. The method for preparing naphthodiazepine indole derivatives according to claim 1, characterized in that: In step 1, the molar ratio of N-(4-methylbenzenesulfonyl)-1-(2-indolyl)-2-naphthylamine, methyl(1-arylprop-2-yn-1-yl)carbonate, tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, bis(2-diphenylphosphophenyl)ether and base is 1.0:1.0-2.0:0.01-0.10:0.01-0.10:0.05-0.

20.

8. The method for preparing naphthodiazepine indole derivatives according to claim 1, characterized in that: The methyl (1-aryl prop-2-yn-1-yl) carbonate is one of methyl (1-phenyl prop-2-yn-1-yl) carbonate, methyl (1-(3-methylphenyl) prop-2-yn-1-yl) carbonate, methyl (1-(4-methylphenyl) prop-2-yn-1-yl) carbonate, and methyl (1-(3-chlorophenyl) prop-2-yn-1-yl) carbonate.

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