A method for synthesizing 1-methyl-5-(1-pyridyl-1-trimethylsilylmethyl)indole compound

Abstract

The present invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing 1-methyl-5-(2-trimethylsilylmethylpyridyl)indole compounds. 2-(trimethylsilyl)methylpyridine and 5-bromoindole are mixed with an organic solvent, tetrahydrofuran, in the presence of a transition metal catalyst (nickel chloride), a nitrogen ligand (bipyridine), and a Brønsted base (lithium bis(trimethylsilylamide)), and subjected to a cross-coupling reaction to synthesize 1-methyl-5-(2-trimethylsilylmethylpyridyl)indole compounds. The present invention uses cheap nickel metal as a catalyst, and nickel-catalyzed 2-(trimethylsilyl)methylpyridine and 1-methyl-5-bromoindole direct heteroarylation reaction has the advantages of mild reaction conditions and high yield.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing a 1-methyl-5-(2-trimethylsilylmethylpyridyl)indole compound. Background Art

[0002] In medicinal chemistry, the rapid functionalization of heterocyclic compounds has attracted considerable attention. Indole, as a multifunctional pharmacophore, has attracted considerable attention due to its unique skeletal structure and wide range of physiological activities. In recent years, extensive research has been conducted to explore the diverse therapeutic potential of the indole group. Over the past five years, various indole analogs have been widely used as active pharmacophores in anticancer, anticonvulsant, antibacterial, antituberculosis, antimalarial, antiviral, and antidiabetic applications.

[0003] For example, growth hormone secretion is regulated by two hypothalamic hormones: growth hormone-releasing hormone and somatostatin. Some small-molecule peptides containing indole groups can also affect growth hormone secretion. These substances are called growth hormone-releasing hormone (GHS). Macimorenlin Acetate, the only marketed oral growth hormone-releasing hormone receptor (GHSR) agonist, can be used to treat growth hormone deficiency in adults. In 2015, Panobinostat Lactate, developed by Novartis, received approval from the US FDA. As the first histone deacetylase (HDAC) inhibitor for the treatment of multiple myeloma, it inhibits HDAC activity at the nanomolar level. It is used in combination with bortezomib and dexamethasone for the treatment of multiple myeloma patients who have received at least two prior therapies, including bortezomib and an immunosuppressant (IMiD). In addition, drugs such as Rucaparib Camsylate, Anlotinib Dihydrochloride, and Golotimod, which have anti-tumor effects, and Dolastron Mesylate Hydrate, which can control vomiting reactions, all contain indole groups.

[0004]

[0005] Indole was first prepared by Adolf von Baeyer in 1866 through the reduction of oxindoles. The ten freely mobile π electrons in its molecular structure contribute to its weak basicity. This property stems from the nitrogen lone electron pair joining the π electron system and circulating freely within the indole ring. Consequently, the nitrogen lone electron pair is unavailable for protonation and is instead protonated at the C-3 position, preserving aromaticity. Indole plays an important role in various chemical reactions, including electrophilic substitution, organometallic indole complex formation, carboionization, oxidation, and cycloaddition reactions, particularly at the C-3 position. Indole is solid at room temperature and occurs naturally in human feces, giving it a distinctive odor. However, at lower concentrations, indole exhibits a floral aroma, making it a component of many floral fragrances, perfumes, and coal tar. Furthermore, indole participates in numerous biochemical reactions in vivo and regulates various aspects of bacterial physiology, including spore formation, plasmid stability, drug resistance, biofilm formation, and pathogenicity.

[0006] Furthermore, the early introduction of the trimethylsilyl group allows for simple oxidation reactions in subsequent studies, facilitating the introduction of other groups into the drug for functional modification. Furthermore, as an equivalent substitute for the tert-butyl group, the trimethylsilyl group itself can be used in drug modification. Its lipophilicity is stronger than that of the tert-butyl group, thus affecting drug metabolism in the body. Lipophilic, highly silicon-based alternatives can significantly increase drug distribution volume, provide good tissue penetration, increase the apparent oil-water partition coefficient, enhance the drug's blood-brain barrier permeability, and thus enhance central nervous system activity. Therefore, silicon-based alternatives can prolong the duration of drug action and thus improve drug efficacy.

[0007] In previous studies, we have found that 2-(trimethylsilyl)methylpyridine can be coupled with aryl bromides to generate related products under palladium catalysis, but palladium catalysis is relatively expensive.

[0008] Summary of the Invention

[0009] The present invention provides a nickel-catalyzed cross-coupling reaction of 1-methyl-5-bromoindole and 2-(trimethylsilyl)methylpyridine, which can obtain a 1-methyl-5-(1-pyridyl-1-trimethylsilylmethyl)indole compound with biological activity and medicinal value. The 1-methyl-5-(1-pyridyl-1-trimethylsilylmethyl)indole compound is synthesized in a direct and easy-to-operate method, and the synthesis method is simple and efficient.

[0010] The specific plan is as follows:

[0011]

[0012] A method for synthesizing a 1-methyl-5-(1-pyridyl-1-trimethylsilylmethyl)indole compound comprises the following steps: using 2-(trimethylsilyl)methylpyridine shown in Formula 1 and 1-methyl-5-bromoindole shown in Formula 2, in the presence of a transition metal catalyst nickel chloride, a nitrogen ligand bipyridine, and a Brønsted base lithium bistrimethylsilylamide, and mixing with an organic solvent to carry out a cross-coupling reaction to synthesize the 1-methyl-5-(1-pyridyl-1-trimethylsilylmethyl)indole compound shown in Formula 3.

[0013] The method of the invention can realize the nickel-catalyzed coupling reaction of 2-(trimethylsilyl)methylpyridine and 1-methyl-5-bromoindole to generate a 1-methyl-5-(1-pyridyl-1-trimethylsilylmethyl)indole compound with excellent yield; and the raw materials used in the synthesis method are simple and economical.

[0014] Preferably, the reaction is carried out under the protection of an inert gas, argon.

[0015] Preferably, the synthesis occurs in the presence of a transition metal catalyst, a nitrogen ligand and an organic solvent.

[0016] Preferably, the transition metal catalyst is a nickel catalyst; and the nitrogen ligand is bipyridine.

[0017] Preferably, the nickel catalyst is nickel chloride.

[0018] Preferably, the organic solvent is tetrahydrofuran.

[0019] Preferably, in the reaction, the molar ratio of 2-(trimethylsilyl)methylpyridine represented by Formula 1, 1-methyl-5-bromoindole represented by Formula 2, and the catalyst is: 1-2:1-2:0.05-0.2; and the reaction temperature is 60°C.

[0020] Preferably, the method of the present invention can be used to synthesize a 1-methyl-5-(1-pyridyl-1-trimethylsilylmethyl)indole compound having the following structure:

[0021]

[0022] In the presence of transition metal catalyst nickel chloride, Brønsted base lithium bis(trimethylsilyl)amide and nitrogen ligand bipyridine, 2-(trimethylsilyl)methylpyridine and 1-methyl-5-bromoindole undergo a cross-coupling reaction to ultimately prepare 1-methyl-5-(1-pyridyl-1-trimethylsilylmethyl)indole.

[0023] The technical solution of the present invention can achieve at least one of the following beneficial effects:

[0024] The raw materials used in the synthesis method of the present invention are cheap and easily available;

[0025] The present invention uses nickel-catalyzed 2-(trimethylsilyl)methylpyridine and 1-methyl-5-bromoindole to undergo a coupling reaction, which reduces the loss of raw materials and improves the yield of the product due to the reduced reaction steps.

[0026] The operation steps required by the present invention are relatively simple, and no extreme heating or cooling is required. The reaction can be performed under normal pressure, which is safe and convenient. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1A This is the H NMR spectrum of the product obtained in Example 1;

[0028] Figure 1B The carbon nuclear magnetic resonance spectrum of the product obtained in Example 1 is shown in FIG. DETAILED DESCRIPTION

[0029] For the convenience of those skilled in the art to understand, the concept of the present invention is further described below in conjunction with the embodiments. The specific description of the following examples is not a limitation of the present invention, but is only for the convenience of those skilled in the art to understand the technical solution. The various raw materials involved in the description are all purchased from the market, or through simple synthesis, and other medicines are purchased from Anaiji, Bi De, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta or J&K., and the nuclear magnetic resonance spectrometer model is Bruker 400M.

[0030] Example 1

[0031] In a glove box, under argon atmosphere at room temperature, nickel chloride (0.01 mmol, 0.05 equiv), bipyridine (0.015 mmol, 0.055 equiv), and tetrahydrofuran (0.5 mL) were added to a microwave tube equipped with a stirrer. After stirring for 1 hour, lithium bis(trimethylsilyl)amide (0.6 mmol, 3 equiv) was added, followed by 2-(trimethylsilyl)methylpyridine (0.2 mmol, 1.0 equiv, 33.0 mg) and 1-methyl-5-bromoindole (0.4 mmol, 2 equiv, 83.6 mg). The microwave tube was sealed and removed from the glove box. The reaction mixture was stirred at 60°C for 12 hours. After 12 hours, the resulting brown-black solution was quenched by adding two drops of water to the microwave tube with a syringe, and the microwave tube was opened. 5 mL of ethyl acetate was added to the resulting solution, and the crude product was filtered. The solvent was removed by rotary evaporation. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 1-methyl-5-(2-trimethylsilylmethylpyridyl)indole (50.0 mg, 85% yield). The H and C NMR spectra of the product were Figure 1A and Figure 1B , the spectrum data is: 1H NMR (400MHz, CDCl3) δ: 8.55-8.52 (m, 1H), 7.59 (s, 1H), 7.49-7.45 (m, 1H), 7.23-7.22 (m, 2H), 7.1 4-7.13 (m, 1H), 7.01-6.96 (m, 2h), 6.46-6.39 (m, 1H), 3.81 (s, 1H), 3.74 (s, 3H), 0.05 (s, 9H)ppm. 13 C{ 1 H} NMR (101MHz, CDCl3) δ: 164.2, 148.7, 135.8, 135.0, 132.5, 128.7, 128.6, 123.3, 123.1, 120.4, 119.8, 108.7, 100. 6, 48.3, 32.8, -1.7ppm. IR (neat): 3026, 1637, 1492, 1447, 1229, 1192, 1047, 1024, 953, 761, 732, 698, 589, 547, 455.

[0032] The first group of experiments is Example 1, and the corresponding NMR spectrum of the product is Figure 1A and Figure 1B .

[0033] The table lists the structural formula of the product in Example 1, and the last column lists the yield of the product in Example 1.

[0034]

Claims

1. A method for synthesizing a 1-methyl-5-(1-pyridyl-1-trimethylsilylmethyl)indole compound, characterized in that: 2-(trimethylsilyl)methylpyridine shown in Formula 1 and 1-methyl-5-bromoindole shown in Formula 2 are mixed with an organic solvent in the presence of a nickel catalyst, a nitrogen ligand, and a Brønsted base to perform a cross-coupling reaction to synthesize a 1-methyl-5-(1-pyridyl-1-trimethylsilylmethyl)indole compound shown in Formula 3; The nickel catalyst is nickel chloride; The nitrogen ligand is bipyridine.

2. The synthesis method according to claim 1, wherein The reaction was carried out under the protection of inert gas argon.

3. The synthesis method according to claim 1, wherein The organic solvent is tetrahydrofuran.

4. The synthesis method according to claim 1, wherein In the reaction, the molar ratio of 2-(trimethylsilyl)methylpyridine shown in formula 1, 1-methyl-5-bromoindole shown in formula 2 and the catalyst is: 1-2:1-2:0.05-0.2; and the reaction temperature is 60°C.

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