Preparation method of indole substituted dihydroisoquinoline compound

Abstract

The invention discloses a preparation method of an indole substituted dihydroisoquinoline compound. The structure of the compound is shown as a formula I, and the compound is prepared by taking o-alkynyl aromatic aldehyde as a raw material, carrying out condensation reaction with amine and then continuously reacting with indole. The method for synthesizing the indole substituted dihydroisoquinoline compound has the advantages of simple route, mild conditions, high yield, greenness and no catalyst. The indole-substituted dihydroisoquinoline compound disclosed by the invention has practical application value in the fields of tumor resistance and the like. (I)

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic chemical synthesis, and particularly relates to a preparation method of an indole-substituted dihydroisoquinoline compound. BACKGROUND

[0002] Isoquinoline and its derivatives are an important class of nitrogen-containing heterocyclic compounds, widely exist in natural alkaloids, have a variety of biological activities, such as anti-tumor, anti-virus, anti-bacterial, anti-inflammatory, and have important research value and application prospect in the field of pharmaceutical chemistry and functional materials. Therefore, developing efficient and green synthesis methods of isoquinoline compounds has been a research hotspot in organic synthesis and pharmaceutical chemistry.

[0003] Traditional isoquinoline synthesis methods mainly include Gabriel-Colman method, Pictet-Spengler method and Pomeranz-Fritsch method, etc. These methods usually need to use strong acid or strong base as catalyst, the reaction conditions are relatively severe, isomers are easy to produce, by-products are many, post-processing is complex, and the environment is not friendly. In recent years, transition metal-catalyzed cyclization reaction has become an important means to construct isoquinoline skeleton, such as ruthenium, rhodium, nickel, cobalt, silver, gold, copper, manganese and other metal-catalyzed reaction systems. Although these methods have improved the reaction efficiency and selectivity to some extent, there are still problems such as metal residues, high cost of catalysts, limited functional group tolerance, etc. In addition, some methods also need to use pre-functionalized substrates or directing groups, which increases the synthesis steps and atom economy.

[0004] Under the promotion of green chemistry and sustainable development concept, metal-free, catalyst-free and mild condition synthesis strategies are increasingly valued. Although some catalyst-free or non-metal catalytic systems have been reported for the synthesis of isoquinoline derivatives, such as iodine-catalyzed, selenium-catalyzed, and alkoxide-catalyzed methods, these methods often still have problems such as long reaction time, narrow substrate scope, low yield or the need for special reagents. Therefore, developing a simple operation, mild condition, metal-free catalyst, high atom economy and good functional group tolerance synthesis method of isoquinoline derivatives still has important theoretical and practical significance.

[0005] In particular, both indole and isoquinoline are superior skeletons with significant biological activity, and integrating both of them in the same molecule is expected to produce synergistic or enhanced biological activity, providing a new idea for the discovery of new drug lead compounds. At present, the synthesis of indole-substituted dihydroisoquinoline compounds is still relatively limited, especially the method of realizing efficient construction of such structure through catalyst-free one-pot tandem reaction is rare.

[0006] Based on this, this invention addresses the problems of catalyst use, harsh reaction conditions, and lengthy steps in existing isoquinoline synthesis methods, proposing a method for preparing indole-substituted dihydroisoquinoline compounds that requires no external catalyst, operates under mild conditions, and is simple to operate. This method uses readily available o-alkynyl aromatic aldehydes, amines, and indole as raw materials, and constructs a series of novel indole-substituted dihydroisoquinoline derivatives efficiently and in high yields through a condensation / cyclization tandem reaction. It avoids the use of strong acids, strong bases, or metal catalysts, aligning with the trend of green synthesis, and provides a material basis and methodological support for further research on the application of this type of compound in antibacterial and other biological activities. Summary of the Invention

[0007] To address the aforementioned problems associated with using strong acids or metal catalysts, this invention provides a method for the green synthesis of indole-substituted dihydroisoquinoline compounds under catalyst-free conditions, along with its application research.

[0008] The technical solution of this invention is as follows: A method for preparing a class of indole-substituted dihydroisoquinoline compounds includes the following steps:

[0009] (1) Take compound 1 and an appropriate amount of amine 2 and dissolve them in an organic solvent. The molar ratio of compound 1 to compound 2 is 1:1-1:2. Stir at room temperature for 1 hour to obtain intermediate 3. (2) Continue to add indole 4 to the reaction system of (1), wherein the molar ratio of indole 4 to compound 1 is 1:1-1:2. Heat the reaction, add water after the reaction is completed, extract with ethyl acetate and wash repeatedly, and separate and purify the crude product by chromatography.

[0010] The compounds listed above are distinguished by the numbers listed below them in the reaction formula.

[0011] Furthermore, in the synthesis step (1), the molar ratio of compound 1 to amine is preferably 1:1.

[0012] Furthermore, in the synthesis step (1), the organic solvent is preferably dimethyl sulfoxide.

[0013] Furthermore, in synthesis step (2), the molar ratio of compound 4 to compound 1 is preferably 1:1.2.

[0014] The beneficial effects of this invention are as follows: (1) This invention provides a class of indole-substituted dihydroisoquinoline compounds, which provide candidate substances for the study of antibacterial bioactive molecules.

[0015] (2) This invention provides a simple and efficient synthetic method for synthesizing indole-substituted dihydroisoquinoline compounds under catalyst-free conditions, which reduces environmental pollution. Detailed Implementation

[0016] The present invention will be further described in detail below through specific embodiments, but it should not be construed as limiting the scope of the above-described subject matter of the present invention to the following embodiments. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0017] Instruments and reagents used in this invention: Nuclear magnetic resonance spectrometer: Bruker AV-II 500 MHz NMR, TMS as internal standard, CDCl3 as solvent.

[0018] All reagents used were commercially available chemically pure or analytically pure. Example

[0019] The preparation method of the indole-substituted dihydroisoquinoline compound of the present invention is as follows:

[0020] (1) Dissolve 1 mmol of compound 1 and 1 mmol of amine in toluene and stir at room temperature for 1 hour.

[0021] (2) Add 1.2 mmol of indole 4 to the reaction system of (1), react at 80 degrees for 24 hours, add water after the reaction, extract with ethyl acetate and wash, and purify the target product by column chromatography. The yield of compound I is between 32% and 60%. Example

[0022] (1) Dissolve 1 mmol of compound 1 and 1 mmol of amine in dimethyl sulfoxide and stir at room temperature for 1 hour.

[0023] (2) Add 1.5 mmol of indole 4 to the reaction system of (1), react at 100 degrees for 24 hours, add water after the reaction, extract with ethyl acetate and wash, and purify the target product by column chromatography. The yield of compound I is between 39-78%. Example

[0024] (1) Take 1 mmol of compound 1 and 1 mmol of amine and dissolve them in N , N In dimethylformamide, stir at room temperature for 1 hour, then set aside for use.

[0025] (2) Add 1.5 mmol of indole 4 to the reaction system of (1), react at 100 degrees for 24 hours, add water after the reaction, extract with ethyl acetate and wash, and purify the target product by column chromatography. The yield of compound I is between 31% and 65%. Example

[0026] (1) Dissolve 1 mmol of compound 1 and 1 mmol of amine in 1,2-dichloroethane and stir at room temperature for 1 hour.

[0027] (2) Add 1.5 mmol of indole 4 to the reaction system of (1), react at 100 degrees for 24 hours, add water after the reaction, extract with ethyl acetate and wash, and purify the target product by column chromatography. The yield of compound I is between 20-53%. Example

[0028] The inhibitory activities of target compound I on breast cancer cells (231), gastric cancer cells (MKN45), colon cancer cells (RKO), liver cancer cells (Hep G2), and lung cancer cells (A549) are shown in Table 1. The experimental results show that In and Io have excellent inhibitory activities against breast cancer.

[0029]

[0030] The characterization data for each compound are as follows: Ia.1-(1H-indol-3-yl)-3-(4-methoxyphenyl)-2-phenyl-1,2-dihydroisoquinoline. 1 H NMR (400 MHz, Chloroform- d ) δ 8.13 – 8.11 (m, 1H),7.84 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.32 – 7.30 (m, 1H), 7.27 – 7.19 (m,5H), 7.16 – 7.09 (m, 5H), 6.85 – 6.82 (m, 1H), 6.71 (d, J = 8.9 Hz, 3H), 6.57(s, 1H), 6.42 (s, 1H), 3.70 (s, 3H). Ib.3-(4-chlorophenyl)-1-(1H-indol-3-yl)-2-(4-methoxyphenyl)-1,2-dihydroisoquinoline. 1 H NMR (400 MHz, Chloroform- d ) δ 8.11 – 8.09 (m, 1H),7.87 (s, 1H), 7.43 (d, J= 8.6 Hz, 2H), 7.32 – 7.24 (m, 3H), 7.21 – 7.15 (m,4H), 7.13 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 8.9 Hz, 2H), 6.69 – 6.67 (m, 3H),6.58 (s, 1H), 6.28 (s, 1H), 3.68 (s, 3H). I-c.1-(1H-indol-3-yl)-2,3-bis(4-methoxyphenyl)-1,2-dihydroisoquinoline. 1 H NMR (400 MHz, Chloroform- d ) δ 8.12 – 8.09(m, 1H), 7.84(s, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.31 – 7.28 (m, 1H), 7.24 – 7.18 (m, 5H),7.14 – 7.10 (m, 1H), 7.03 (d, J = 9.0 Hz, 2H), 6.74 (d, J = 1.5 Hz, 1H), 6.71(d, J = 8.8 Hz, 2H), 6.67 (d, J = 9.0 Hz, 2H), 6.51 (s, 1H), 6.27 (s, 1H),3.70 (s, 3H), 3.67 (s, 3H). I-d.2-(4-chlorophenyl)-1-(1H-indol-3-yl)-3-(4-methoxyphenyl)-1,2-dihydroisoquinoline. 1 H NMR (400 MHz, Chloroform- d ) δ 8.08 – 8.06 (m, 1H),7.85 (s, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.32 – 7.26 (m, 3H), 7.22 – 7.13 (m,4H), 7.08 (d, J = 9.0 Hz, 2H), 7.02 (d, J= 9.0 Hz, 2H), 6.72 (d, J = 8.8 Hz,3H), 6.57 (s, 1H), 6.34 (s, 1H), 3.71 (s, 3H). I-e.1-(1H-indol-3-yl)-3-(4-methoxyphenyl)-2-(p-tolyl)-1,2-dihydroisoquinoline. 1 H NMR (400 MHz, Chloroform- d ) δ 8.13 – 8.11 (m, 1H),7.83 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.29 – 7.10 (m, 7H), 7.01 (d, J = 8.5Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 8.8 Hz, 3H), 6.53 (s, 1H),6.36 (s, 1H), 3.69 (s, 3H), 2.18 (s, 3H). I-f.2,3-bis(4-methoxyphenyl)-1-(6-methyl-1H-indol-3-yl)-1,2-dihydroisoquinoline. 1 H NMR (400 MHz, Chloroform- d ) δ 7.97 (d, J = 8.1 Hz,1H), 7.71 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.23 – 7.08 (m, 4H), 7.04 – 6.99(m, 3H), 6.72 – 6.64 (m, 4H), 6.49 (s, 1H), 6.24 (s, 1H), 3.71 (s, 3H), 3.67(s, 3H), 2.45 (s, 3H). I-g.1-(6-chloro-1H-indol-3-yl)-2,3-bis(4-methoxyphenyl)-1,2-dihydroisoquinoline. 1 H NMR (400 MHz, Chloroform-d ) δ 7.99 (d, J = 8.5 Hz,1H), 7.85 (s, 1H), 7.42 – 7.40 (d, J = 8.8 Hz, 1H), 7.28 – 7.23 (m, 3H), 7.17– 7.14 (m, 3H), 7.01 (d, J = 9.0 Hz, 2H), 6.72 – 6.66 (m, 5H), 6.51 (s, 1H),6.22 (s, 1H), 3.71 (s, 3H), 3.68 (s, 3H). I-h.1-(6-bromo-1H-indol-3-yl)-2,3-bis(4-methoxyphenyl)-1,2-dihydroisoquinoline. 1 H NMR (400 MHz, Chloroform- d ) δ 7.95 (d, J = 8.5 Hz,1H), 7.88 (s, 1H), 7.45 (d, J = 1.7 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.30 –7.24 (m, 4H), 7.15 (s, 2H), 7.01 (d, J = 9.0 Hz, 2H), 6.73 – 6.66 (m, 4H),6.51 (s, 1H), 6.22 (s, 1H), 3.72 (s, 3H), 3.68 (s, 3H). I-i.1-(6-fluoro-1H-indol-3-yl)-2,3-bis(4-methoxyphenyl)-1,2-dihydroisoquinoline. 1 H NMR (400 MHz, Chloroform- d ) δ 8.01 – 7.97 (m, 1H),7.81 (s, 1H), 7.42 (d, J= 8.8 Hz, 2H), 7.24 – 7.23 (m, 2H), 7.16 – 7.13 (m,2H), 7.02 – 6.93 (m, 4H), 6.72 – 6.66 (m, 5H), 6.50 (s, 1H), 6.23 (s, 1H),3.71 (s, 3H), 3.67 (s, 3H). I-j.2-(4-fluorophenyl)-1-(1H-indol-3-yl)-3-(4-methoxyphenyl)-1,2-dihydroisoquinoline. 1 H NMR (400 MHz, Chloroform- d ) δ 8.07 (d, J = 6.4 Hz,1H), 7.79 (s, 1H), 7.40 (d, J = 8.9 Hz, 2H), 7.27 – 7.11 (m, 7H), 7.03 – (m,2H), 6.81 – 6.77 (m, 2H), 6.71 (d, J = 8.8 Hz, 3H), 6.53 (s, 1H), 6.28 (s,1H), 3.69 (s, 3H). I-k.2-(4-bromophenyl)-1-(1H-indol-3-yl)-3-(4-methoxyphenyl)-1,2-dihydroisoquinoline. 1 H NMR (400 MHz, Chloroform- d ) δ 8.07 – 8.04 (m, 1H),7.81 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.26 – 7.16 (m, 9H), 6.96 (d, J = 8.9Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 1.6 Hz, 1H), 6.57 (s, 1H),6.34 (s, 1H), 3.69 (s, 3H).

Claims

1. A method for preparing an indole-substituted dihydroisoquinoline compound, characterized in that, Includes the following steps: (1) Take compound 1 and an appropriate amount of amine 2 and dissolve them in an organic solvent. The molar ratio of compound 1 to compound 2 is 1:1-1:

2. Stir at room temperature for 1 hour to obtain intermediate 3. (2) Continue to add indole 4 to the reaction system of (1), wherein the molar ratio of indole 4 to compound 1 is 1:1-1:

2. Heat the reaction for 24 hours. After the reaction is completed, add water, extract with ethyl acetate and wash repeatedly. The crude product is separated and purified by chromatography.

2. The method for preparing the indole-substituted dihydroisoquinoline compound according to claim 1, characterized in that, In synthesis step (1), the organic solvent is 1,2-dichloroethane, toluene, N , N - Dimethylformamide, dimethyl sulfoxide.

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