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CN-121991046-A - Synthesis method of indole-substituted dihydrothiophene compound

CN121991046ACN 121991046 ACN121991046 ACN 121991046ACN-121991046-A

Abstract

The invention belongs to the field of organic chemical synthesis, and in particular relates to a synthesis method of indole-substituted dihydrothiophene compounds. The method takes indole oxide-derived MBH ester and alpha-enol dithioester as raw materials, and realizes the reaction through DABCO catalysis and a two-step one-pot method under the mild room temperature condition without separating intermediates. The method has the advantages of simple and convenient process operation, mild conditions, controllable raw material cost and environmental friendliness. The obtained product has novel structure and good yield, and has remarkable application potential in the fields of drug research and development such as antibiosis, anti-inflammatory, anti-tumor and the like.

Inventors

  • LI FURONG
  • WANG JINTAO

Assignees

  • 欧锐斯(海南)生物科技有限公司

Dates

Publication Date
20260508
Application Date
20260225

Claims (5)

  1. 1. The synthesis method of the indole-substituted dihydrothiophene compound is characterized by comprising the following steps of: S1, dissolving a compound II, a compound III and 1, 4-diazabicyclo [2.2.2] octane serving as a base 1 in a solvent, and reacting at room temperature until the raw materials are completely consumed to obtain a reaction intermediate; S2, directly adding alkali 2 and di-tert-butyl dicarbonate into a system containing a reaction intermediate, and continuing to react at room temperature; s3, after the reaction is completed, washing, extracting, drying and removing the organic solvent from the reaction mixture to obtain a crude product; s4, purifying the crude product through silica gel column chromatography to obtain indole substituted dihydrothiophene compounds with a structure shown in a formula I; the compound II is MBH ester derived from oxindole, and the structure of the compound II is shown in a formula II; The compound III is alpha-enol dithioester, and the structure is shown as a formula III; the reaction formula is shown as formula II: II (II) Wherein: r 1 is alkyl including methyl, allyl and benzyl; R 2 is methyl, methoxy, halogen atom, nitro or ester group; R 3 is an ester group or a cyano electron withdrawing group; R 4 is alkyl including methyl, cyclopropyl, isopropyl, isobutyl, halogen, methyl, methoxy, ester, cyano-substituted phenyl, naphthyl and heteroaryl including furyl, thienyl, pyridyl; R 5 is alkyl including allyl, benzyl, methyl, ethyl and tertiary butyl.
  2. 2. The method for synthesizing indole-substituted dihydrothiophene according to claim 1, wherein the solvent is selected from toluene, acetonitrile, 1, 4-dioxane, 1, 2-dichloroethane, acetone, dichloromethane, ethyl acetate, ethanol, chloroform, or one of N, N-dimethylformamide or tetrahydrofuran.
  3. 3. The method for synthesizing indole-substituted dihydrothiophene compounds according to claim 1, wherein 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, and preferably, the base 2 is sodium hydride.
  4. 4. The method for synthesizing the indole-substituted dihydrothiophene compound according to claim 1, wherein the molar ratio of the compound II to the compound III is 1:1 to 1:2, the amount of the base 1 is more than 0.1 equivalent of the molar amount of the compound II, and the amount of the base 2 is more than 0.5 equivalent of the molar amount of the compound II.
  5. 5. The method for synthesizing indole-substituted dihydrothiophene compounds according to claim 1, wherein in step S4, the eluent used in the silica gel column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio is 40:1 to 5:1.

Description

Synthesis method of indole-substituted dihydrothiophene compound Technical Field The invention belongs to the field of organic chemical synthesis, and in particular relates to a synthesis method of indole-substituted dihydrothiophene compounds. Background Sulfur-containing compounds play an indispensable key role in various physiological activities of life bodies, and a plurality of organic sulfur molecules have been successfully applied in the development and industrialization processes of clinical medicines and pesticides. Among them, penicillin and cephalosporin beta-lactam antibiotics are typical, and sulfur-containing five-membered or six-membered heterocycle with parallel ring structure is embedded in the molecular structure of the medicine, which is itself and artificially synthesized homolog, so far, the medicine is still a core medicine for clinical treatment of bacterial infection. For decades, tetrahydrothiophene compounds (i.e. biotin, also known as vitamin H core structure) which take natural products as raw materials are successfully separated and purified, and the compounds show various remarkable biological activities (see in particular ：Synthetic access to thiolane-based therapeutics and biological activity studies, Eur. J. Med. Chem. 2021, 224, 113659）. The functional molecular fragment hybridization combination is used as one of core strategies in the field of drug design, and the core principle is to integrate different types of dominant framework structures in biological molecules, so as to construct hybrid molecules with multiple excellent characteristics. The strategy has obtained extensive research and practical application in the field of drug development by virtue of its unique design advantages, and provides a key thought and technical support for the creation of novel drugs (related research can be clearly confirmed by referring to ：Molecular hybridization tool in development of furoxan-based no-donor prodrugs, ChemMedChem, 2017, 12, 622; Molecular hybridization as a strategy for developing artemisinin-derived anticancer candidates, Pharmaceutics, 2023, 15, 2185; Molecular hybridization: a useful tool in the design of new drug prototypes, Curr. Med. Chem., 2007, 14, 1829）. a large number of past researches, and compared with a single parent compound, the hybrid molecule has a plurality of outstanding advantages: not only can present enhanced biological activity and even brand new biological activity, but also can obviously improve pharmacodynamics and pharmacokinetics characteristics of the medicine, effectively reduce toxic and side effects, and can realize multi-target synergistic effect, thereby providing brand new possibility for solving the treatment problem 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）. typical examples such as a molecule CUDC-907, which is constructed by embedding a Histone Deacetylase (HDAC) inhibiting functional group (hydroxamic acid) in the core structural backbone of a phosphatidylinositol 3-kinase (PI 3K) inhibitor, the proliferation inhibition activity and pro-apoptosis activity of the hybrid molecule on tumor cells are remarkably improved, and the hybrid molecule is currently advanced to a clinical test stage by Curis company as a PI3K/HDAC double-target inhibitor (related research is shown in ：Chemical hybridization of sulfasalazine and dihydroartemisinin promotes brain tumor cell 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）., and in general, the molecular hybrid generation technology not only builds a high-efficiency path for the research and development of multifunctional medicaments, but also is hopeful to break through the clinical treatment bottleneck of multi-medicament resistance. Indole substituted thiophene is used as an active group formed by a hybridization splicing technology, and the derivative of the indole substituted thiophene effectively integrates the structural advantages of two compounds of indole and thiophene, and has potential excellent biological activity. Researches prove that the indole hydrogenated thiophene skeleton can be used as a CRTH2 inhibitor (such as indole derivatives reported in Preparation of indole derivatives as CRTH2 inhibitors,CN107987066;Indole derivative used as CRTH2 inhibitor,WO2018014869 patent), has remarkable anti-tumor activity （Green preparation of benzothiophene-carbazole bridged ring compounds as anti-tumor agents,CN120247925, and anti-tumor activity characteristics similar to benzothiophene-carbazole fused ring compounds, and provides an important direction for drug development in the related fields. However, the whole synthesis technology of the existing thiophene compounds faces a plurality of dilemmas, a