Synthetic method of indole-substituted dihydrothiophene compound

Abstract

The invention belongs to the field of organic chemical synthesis, and particularly relates to a synthesis method of an indole-substituted dihydrothiophene compound. According to the method, MBH ester derived from oxoindole and alpha-enol dithioester are taken as raw materials, reaction is realized through DABCO catalysis and a'two-step one-pot method 'under a mild room temperature condition, and an intermediate does not need to be separated. The method is simple and convenient in process operation, mild in condition, controllable in raw material cost and environment-friendly. The obtained product is novel in structure and good in yield, and has remarkable application potential in the fields of research and development of antibacterial, anti-inflammatory and anti-tumor drugs and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis, specifically relating to a method for synthesizing indole-substituted dihydrothiophene compounds. Background Technology

[0002] Sulfur-containing compounds play an indispensable and crucial role in various physiological activities of living organisms, and numerous organosulfur molecules have been successfully applied in the research and development and industrialization of clinical drugs and pesticides. Penicillin and cephalosporin β-lactam antibiotics are typical examples; these drugs all incorporate sulfur-containing five- or six-membered heterocycles with fused ring structures in their molecular structures. They, along with their synthetically produced homologues, remain core drug categories for the clinical treatment of bacterial infections. In recent decades, tetrahydrothiophene compounds (i.e., biotin, also known as the core structure of vitamin H) derived from natural products have been successfully isolated and purified. These compounds exhibit a variety of significant biological activities (see: Synthetic access to thiolane-based therapeutics and biological activity studies, Eur. J. Med. Chem. 2021, 224, 113659).

[0003] Hybridization of functional molecular fragments is one of the core strategies in drug design. Its core principle lies in integrating different types of advantageous skeletal structures in biomolecules to construct hybrid molecules with multiple superior properties. This strategy, with its unique design advantages, has been widely researched and applied in drug development, providing key ideas and technical support for the creation of novel drugs (related research can be found in: Molecular hybridization tool in development of furoxan-based no-donor prodrugs, ChemMedChem, 2017, 12, 622; Molecular hybridization as a strategy for developing artemisinin-derivedanticancer candidates, Pharmaceutics, 2023, 15, 2185; Molecular hybridization: a useful tool in the design of new drug prototypes, Curr. Med.Chem., 2007, 14, 1829). Numerous previous studies have clearly demonstrated that hybrid molecules possess many significant advantages over single parent compounds: they can not only exhibit enhanced or even novel biological activities, but also significantly improve the pharmacodynamics and pharmacokinetic properties of drugs, effectively reduce toxic side effects, and achieve synergistic effects on multiple targets, providing new possibilities for solving the treatment challenges of complex diseases (see: A molecular hybridization approach for the design of potent, highly selective, and brain-penetrant N-myristoyltransferase inhibitors, J. Med. Chem. 2018, 61, 8374). A typical example is the molecule CUDC-907, which is constructed by embedding the histone deacetylase (HDAC) inhibitory functional group (hydroxamic acid) into the core structural framework of a phosphatidylinositol 3-kinase (PI3K) inhibitor.Compared to single-target PI3K inhibitors or HDAC inhibitors, this hybrid molecule significantly enhances both the inhibitory activity against tumor cell proliferation and the pro-apoptotic activity. It has already been advanced to clinical trials by Curis as a dual-target PI3K / HDAC inhibitor (see: Chemical hybridization of sulfasalazine and dihydroartemisinin promotes brain tumorcell death, cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling, Clin. Cancer Res. 2012, 18, 4104–4113). Overall, molecular hybridization technology not only provides an efficient pathway for the development of multifunctional drugs but also holds promise for overcoming the clinical bottleneck of multidrug resistance. Therefore, the design, synthesis, and pharmacological activity evaluation of functionalized hybrid molecules possess extremely high academic value and application prospects. Related research may further promote the clinical development of more efficient and less toxic novel drugs, bringing breakthroughs to the field of disease treatment.

[0004] Indole-substituted thiophene, as an active group formed through hybrid splicing technology, effectively integrates the structural advantages of both indole and thiophene compounds, possessing potentially excellent biological activities. Existing studies have confirmed that the indole-hydrogenated thiophene skeleton can serve as a CRTH2 inhibitor (e.g., Preparation of indole derivatives as CRTH2 inhibitors, CN107987066; Indole derivative used as CRTH2 inhibitor, indole derivatives reported in patent WO2018014869), and also possesses significant antitumor activity (Green preparation of benzothiophene-carbazole bridged ring compounds as anti-tumor agents, CN120247925, exhibiting antitumor activity characteristics similar to benzothiophene-carbazole fused-ring compounds), providing an important direction for drug development in related fields. However, existing synthetic techniques for thiophene compounds generally face many challenges, specifically including a narrow substrate applicability range, stringent reaction conditions, low product yields, a wide variety of byproducts, and high preparation costs. For example, the selective synthesis of indole derivatives often requires multi-step reaction processes and frequently faces the challenge of separating regioisomers; the synthesis of thiophene compounds mostly relies on highly functionalized reaction precursors, a limitation that particularly restricts the large-scale preparation and practical application of polysubstituted thiophene compounds. Against this backdrop, developing a synthetic method with mild reaction conditions, simple and efficient operation, and capable of constructing novel polysubstituted thiophene compounds has become an urgent need to further expand the application of these compounds in pharmaceuticals, pesticides, and other fields. Summary of the Invention

[0005] To overcome the shortcomings of existing technologies, this invention provides a method for synthesizing indole-substituted dihydrothiophene compounds. This invention designs a one-pot reaction between an indole-derived MBH ester and an α-enol dithioester to construct a novel polysubstituted thiophene compound. This method is mild, requiring no stringent temperature or pressure conditions; it is simple and efficient, completing the reaction in one step, reducing reaction steps and intermediate product losses. Furthermore, this synthetic method has not been previously reported in the literature, demonstrating its innovation and uniqueness.

[0006] The specific technical solution of the present invention is as follows:

[0007] One of the technical solutions of this invention is to provide a method for synthesizing indole-substituted dihydrothiophene compounds, characterized by comprising the following steps:

[0008] S1. Compound II, Compound III and 1,4-diazabicyclo[2.2.2]octane (as base 1) are dissolved in a solvent and reacted at room temperature until the starting material is completely consumed to obtain a reaction intermediate.

[0009] S2. Add base 2 and di-tert-butyl dicarbonate directly to the system containing the reaction intermediate, and continue the reaction at room temperature;

[0010] S3. After the reaction is complete, the reaction mixture is washed with water, extracted, dried and the organic solvent is removed to obtain the crude product.

[0011] S4. The crude product was purified by silica gel column chromatography to obtain indole-substituted dihydrothiophene compounds with the structure shown in Formula I.

[0012] Compound II is an MBH ester derived from oxidized indole, with the structure shown in Formula II;

[0013] Compound III is an α-enol dithioester, with the structure shown in Formula III;

[0014] The reaction formula is shown in Formula II:

[0015]

[0016] Formula II

[0017] in:

[0018] R 1 It includes alkyl groups including methyl, allyl, and benzyl;

[0019] R 2 The groups are methyl, methoxy, halogen, nitro, and ester groups.

[0020] R 3 It is an electron-withdrawing group, either an ester group or a cyano group;

[0021] R 4 It includes alkyl groups including methyl, cyclopropyl, isopropyl, and isobutyl; halogenated, methyl, methoxy, ester, and cyano-substituted phenyl and naphthyl groups; and heteroaryl groups including furanyl, thiophene, and pyridyl groups.

[0022] R 5 It can be an alkyl group including allyl, benzyl, methyl, ethyl, and tert-butyl.

[0023] As a further option for the synthesis method of the present invention, the solvent is selected from one of toluene, acetonitrile, 1,4-dioxane, 1,2-dichloroethane, acetone, dichloromethane, ethyl acetate, ethanol, chloroform, or N,N-dimethylformamide or tetrahydrofuran.

[0024] As a further option of the synthesis method of the present invention, the base 2 is selected from potassium tert-butoxide, potassium carbonate, sodium carbonate, triethylamine, sodium methoxide, sodium hydroxide, sodium hydride, 1,4-diazabicyclo[2.2.2]octane or cesium carbonate; preferably, the base 2 is sodium hydride.

[0025] As a further option of the synthesis method of the present invention, the molar ratio of compound II to compound III is 1:1 to 1:2; the amount of base 1 is 0.1 equivalent or more of the molar amount of compound II; and the amount of base 2 is 0.5 equivalent or more of the molar amount of compound II.

[0026] As a further option of the synthesis method of the present invention, in step S4, the eluent used for silica gel column chromatography is a mixed solvent of petroleum ether and ethyl acetate, with a volume ratio of 40:1 to 5:1.

[0027] The beneficial effects of the technical solutions provided in this application include at least the following:

[0028] This invention overcomes the limitations of traditional synthetic techniques by innovatively designing a two-step, one-pot reaction pathway for the reaction of indole-derived MBH esters and α-enol dithioesters. This eliminates the need for intermediate separation, allowing for multi-step transformations to be completed directly within the same reaction system. Compared to the cumbersome stepwise reaction processes in existing technologies, this method significantly reduces the number of steps and avoids losses during intermediate product separation, thereby significantly improving synthetic efficiency and raw material conversion rate. This provides an efficient and feasible technical solution for large-scale preparation.

[0029] The entire reaction is carried out at room temperature, eliminating the need for harsh reaction environments such as high temperatures. The starting materials used in the synthesis are indole-derived MBH esters and α-enol dithioesters, both readily available and conventional reagents in organic synthesis, requiring no special preparation or expensive procurement. Common organic solvents such as toluene and dichloroethane are used as solvents, eliminating reliance on rare or expensive reaction media. Furthermore, the reaction does not require high-valent transition metal catalysts, only low-cost base reagents such as DABCO and sodium hydride, significantly reducing the cost of raw materials and reagents. This invention emphasizes environmental friendliness in its synthetic design, avoiding the use of toxic and odorous sulfur sources and exhibiting high operability. In addition, this invention has extremely high tolerance for the functional groups of the reaction substrates; substituents in the substrates can remain stable, and the substitution positions are flexible and diverse. By adjusting the type and position of the R1-R5 substituents in the substrates, a series of structurally diverse polysubstituted thiophene compounds can be rapidly synthesized, overcoming the limitations of the narrow substrate range of traditional synthetic methods and meeting the customized needs of different fields such as pharmaceuticals and pesticides for compounds with specific structures.

[0030] Experimental verification shows that the yield of the target product synthesized in this invention can reach over 74%, and the purity is high after purification by silica gel column chromatography. The structure has been fully verified by methods such as 1H NMR spectroscopy, 1C NMR spectroscopy, and high-resolution mass spectrometry, and the product exhibits strong stability and reliability. Since indole-substituted thiophene compounds possess both the biological activities and functional properties of two parent structures, they have broad application prospects in the development of antibacterial, anti-inflammatory, and antitumor drugs. The technical solution of this invention provides key support for material innovation and product development in related fields. Attached Figure Description

[0031] Figure 1 The nuclear magnetic resonance spectrum (H NMR spectrum) of product I-1 obtained in the embodiments of the present invention is shown.

[0032] Figure 2 The image shows the nuclear magnetic resonance (carbon) spectrum of product I-1 obtained in the embodiments of the present invention. Detailed Implementation

[0033] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0034] The following are preferred embodiments for the preparation of compounds according to the present invention. In all the following embodiments, NMR spectroscopy detection was obtained primarily by nuclear magnetic resonance in CDCl3. δ values ​​are relative to internal standards (CHCl3 calibration δ 7.26). 1 H NMR and 77.15 13 C10 NMR. High-resolution mass spectrometry (HRMS) was obtained using a 4G quadrupole time-of-flight (QTof) mass spectrometer.

[0035] Preparation procedure of target product I

[0036] 1. Preparation of experimental instruments and reagents: 25 mL glass reaction flask, 1 compatible magnetic stir bar, magnetic stirrer; indigo-derived MBH carbonate (0.2 mmol, denoted as Reagent II), α-enol dithioester (0.24 mmol, denoted as Reagent III), 1,4-diazabicyclo[2.2.2]octane (6.7 mg), 1,2-dichloroethane (2.0 mL, as reaction solvent), sodium hydride (16 mg), di-tert-butyl carbonate (92 μL); dichloromethane: appropriate amount (for extraction of aqueous phase), anhydrous sodium sulfate: appropriate amount (for drying organic phase); eluent: a mixture of petroleum ether (PE) and ethyl acetate (EtOAc), prepared in a volume ratio gradient from 15:1 to 5:1.

[0037] 2. First step reaction: Preparation of intermediates

[0038] Reagents II, III, and solvent DCE were added sequentially to a 25 mL reaction flask equipped with a magnetic stirrer. Finally, the base DABCO was added as a catalyst. The flask was gently agitated to allow for initial mixing. The reaction flask was placed at room temperature, and the magnetic stirrer was turned on. The stirring rate was controlled to ensure uniform mixing of the reaction system, and the reaction was continued for 4 to 6 hours. During stirring, the reaction progress was monitored in real time using thin-layer chromatography (TLC), with the consumption of reagents as the determining factor. When TLC showed that the reagents were completely consumed, the first step of the reaction was stopped, at which point an intermediate was formed in the reaction system.

[0039] 3. Second step reaction: Preparation of the target product precursor

[0040] In the reaction system containing the intermediate, sodium hydride and di-tert-butyl carbonate were added sequentially. During the addition process, the reaction system was kept below room temperature to avoid drastic local temperature changes caused by reagent addition. Magnetic stirring was maintained at room temperature for 30 minutes. Simultaneously, the consumption of the intermediate was monitored by TLC. The second step of the reaction was stopped when TLC showed complete consumption of the intermediate.

[0041] 4. Reaction quenching and post-treatment

[0042] Slowly add an appropriate amount of water to the above reaction system while stirring to neutralize the NaH component and quench the reaction. At this point, the system will separate into an organic phase and an aqueous phase. Use a separatory funnel to separate the organic phase and collect it separately. Then, add an appropriate amount of dichloromethane to the remaining aqueous phase, shake the separatory funnel thoroughly, and extract. Repeat the extraction 1 to 2 times, and combine all the extracted organic phases. Add an appropriate amount of anhydrous sodium sulfate to the combined organic phase, shake gently, and let it stand for 30 minutes to absorb the residual water in the organic phase. Then, remove the anhydrous sodium sulfate by vacuum filtration and collect the filtrate. Place the filtrate in a rotary evaporator and concentrate it under vacuum to remove the organic solvent, obtaining a crude product residue.

[0043] 5. Purification of target product I

[0044] The crude product residue was purified by silica gel column chromatography. The residue was uniformly loaded onto the top of a silica gel column, and a prepared mixture of petroleum ether (PE) and ethyl acetate (EtOAc) (volume ratio 15:1 to 5:1) was used as the eluent. Elution was performed slowly in a gradient manner, initially at 15:1 and gradually adjusted to 5:1. The composition of the eluent was monitored by TLC, and the eluent fraction containing target product I was collected. The collected fraction was concentrated under vacuum to remove the eluent, ultimately yielding purified target product I.

[0045]

[0046] Compound I-1 (80 mg, Yield = 74%, R f = 0.50 (PE / EA = 3:1)) wasisolated as a yellow solid; mp 144−145 o C. 1 H NMR (500 MHz, (CD3)2CO) δ 7.75(d, J = 7.8 Hz, 1H), 7.69–7.65 (m, 2H), 7.54–7.49 (m, 1H), 7.48–7.44 (m, 2H),7.43 (d, J = 8.2 Hz, 1H), 7.27–7.22 (m, 1H), 7.16–7.12 (m, 1H), 4.28 (d, J =15.4 Hz, 1H), 3.79 (d, J = 15.5 Hz,1H), 3.78 (s, 3H), 3.59 (s, 3H), 2.52 (s,3H), 1.52 (s, 9H); 13C NMR (125 MHz, (CD3)2CO) δ 189.1, 172.7, 159.7, 150.7,141.7, 140.0, 133.5, 131.8, 129.1, 128.4, 125.5, 124.8, 123.0, 121.1, 120.9,110.7, 98.9, 86.2, 63.5, 53.9, 48.9, 28.5, 27.6, 17.6; ESI-HRMS m / z calcd for C 28 H 30 NO6S2 [M + H] + 540.1509, found 540.1511.

[0047] The basic principles of this application have been described above with reference to specific embodiments. However, it should be noted that the advantages, benefits, and effects mentioned in this application are merely examples and not limitations, and should not be considered as essential features of each embodiment of this application. Furthermore, the specific details disclosed above are for illustrative and facilitative purposes only, and are not limitations. These details do not limit the application to the necessity of employing the aforementioned specific details for implementation.

[0048] The above description of the disclosed aspects is provided to enable any person skilled in the art to make or use this application. Various modifications to these aspects will be readily apparent to those skilled in the art, and the general principles defined herein can be applied to other aspects without departing from the scope of this application. Therefore, this application is not intended to be limited to the aspects shown herein, but rather to be carried out within the widest scope consistent with the principles and novel features of the invention herein.

[0049] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Any modifications or equivalent substitutions made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A method for synthesizing indole-substituted dihydrothiophene compounds, characterized in that, Includes the following steps: S1. Compound II, Compound III and 1,4-diazabicyclo[2.2.2]octane (as base 1) are dissolved in a solvent and reacted at room temperature until the starting material is completely consumed to obtain a reaction intermediate. S2. Add base 2 and di-tert-butyl dicarbonate directly to the system containing the reaction intermediate, and continue the reaction at room temperature; S3. After the reaction is complete, the reaction mixture is washed with water, extracted, dried and the organic solvent is removed to obtain the crude product. S4. The crude product was purified by silica gel column chromatography to obtain indole-substituted dihydrothiophene compounds with the structure shown in Formula I. Compound II is an MBH ester derived from oxidized indole, with the structure shown in Formula II; Compound III is an α-enol dithioester, with the structure shown in Formula III; The reaction formula is shown in Formula II: Formula II in: R 1 It includes alkyl groups including methyl, allyl, and benzyl; R 2 The groups are methyl, methoxy, halogen, nitro, and ester groups. R 3 It is an electron-withdrawing group, either an ester group or a cyano group; R 4 It includes alkyl groups including methyl, cyclopropyl, isopropyl, and isobutyl; halogenated, methyl, methoxy, ester, and cyano-substituted phenyl and naphthyl groups; and heteroaryl groups including furanyl, thiophene, and pyridyl groups. R 5 It can be an alkyl group including allyl, benzyl, methyl, ethyl, and tert-butyl.

2. The method for synthesizing indole-substituted dihydrothiophene compounds according to claim 1, characterized in that, The solvent is selected from one of toluene, acetonitrile, 1,4-dioxane, 1,2-dichloroethane, acetone, dichloromethane, ethyl acetate, ethanol, chloroform, or N,N-dimethylformamide or tetrahydrofuran.

3. The method for synthesizing indole-substituted dihydrothiophene compounds according to claim 1, characterized in that, The base 2 is selected from potassium tert-butoxide, potassium carbonate, sodium carbonate, triethylamine, sodium methoxide, sodium hydroxide, sodium hydride, 1,4-diazabicyclo[2.2.2]octane or cesium carbonate; preferably, the base 2 is sodium hydride.

4. The method for synthesizing indole-substituted dihydrothiophene compounds according to claim 1, characterized in that, The molar ratio of compound II to compound III is 1:1 to 1:2; the amount of base 1 used is more than 0.1 molar equivalent of compound II; the amount of base 2 used is more than 0.5 molar equivalent of compound II.

5. The method for synthesizing indole-substituted dihydrothiophene compounds according to claim 1, characterized in that, In step S4, the eluent used in the silica gel column chromatography is a mixed solvent of petroleum ether and ethyl acetate, with a volume ratio of 40:1 to 5:1.

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