CN117265556A - Electrochemical preparation method and application of 1, 3-diaryl mercapto indolizine derivative - Google Patents

Electrochemical preparation method and application of 1, 3-diaryl mercapto indolizine derivative Download PDF

Info

Publication number
CN117265556A
CN117265556A CN202311304944.3A CN202311304944A CN117265556A CN 117265556 A CN117265556 A CN 117265556A CN 202311304944 A CN202311304944 A CN 202311304944A CN 117265556 A CN117265556 A CN 117265556A
Authority
CN
China
Prior art keywords
indolizine
diaryl
mercapto
alkyl
derivative
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202311304944.3A
Other languages
Chinese (zh)
Inventor
段震
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Taoshu Biotechnology Co ltd
Original Assignee
Shanghai Taoshu Biotechnology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Taoshu Biotechnology Co ltd filed Critical Shanghai Taoshu Biotechnology Co ltd
Priority to CN202311304944.3A priority Critical patent/CN117265556A/en
Publication of CN117265556A publication Critical patent/CN117265556A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B3/00—Electrolytic production of organic compounds
    • C25B3/01—Products
    • C25B3/09—Nitrogen containing compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B3/00—Electrolytic production of organic compounds
    • C25B3/01—Products
    • C25B3/05—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B3/00—Electrolytic production of organic compounds
    • C25B3/01—Products
    • C25B3/11—Halogen containing compounds
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B3/00—Electrolytic production of organic compounds
    • C25B3/20—Processes

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Electrochemistry (AREA)
  • Materials Engineering (AREA)
  • Metallurgy (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Indole Compounds (AREA)

Abstract

The invention provides an electrochemical preparation method and application of 1, 3-diaryl mercapto indolizine derivatives, and belongs to the technical field of organic synthesis, namely a strategy for directly synthesizing 1, 3-diaryl mercapto indolizine derivatives through electrocatalysis. The 1, 3-diaryl mercapto indolizine derivative is synthesized from commercially available basic raw materials such as thiophenol, indolizine and the like. Compared with the traditional construction method of the indolizine derivative, the method has the advantages of safe and nontoxic raw material source, electricity as energy source, environment-friendly reaction condition, environment-friendly property and high efficiency, and provides a novel way of 1, 3-diaryl mercapto indolizine derivative for organic chemistry researchers. The 1, 3-diaryl mercapto indolizine derivative prepared by the invention has a certain anticancer cell proliferation activity, has good yield in gram-scale reaction, and has potential application prospect in industrial production.

Description

Electrochemical preparation method and application of 1, 3-diaryl mercapto indolizine derivative
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to an electrochemical preparation method and application of a 1, 3-diaryl mercapto indolizine derivative.
Background
Indolizine, also known as indolizine, is a common practice for various small molecule drug discovery programsPrivilege architecture. Functionalized indolizines find wide application in natural products and synthetic drugs that are associated with a wide range of biological activities such as antifungal, anticancer, antioxidant, phosphatase inhibition and antagonists. In particular, 3-sulfinyl indolizine is a ligand for the CRTH2 receptor, which is valuable in the treatment of various respiratory diseases [1] . Furthermore, indolizine derivatives are the core framework of many fluorescent materials. Because of their potential nature and application, considerable attention has been paid to developing new methods for synthesizing these compounds. In general, pyridine derivatives are used as substrates in the main synthetic method for constructing indolizines. Many different methods have also been developed to synthesize these key compounds [2-3] 。
In the prior art, two main routes exist for synthesizing indolizine derivatives. In the first route, pyridinium salt is prepared by pyridine derivative and halogenated compound, and then the pyridinium salt reacts with alkyne to prepare polysubstituted indolizine, the main problem of the route is that the price of alkyne, the limitation of alkyne structure and the availability of alkyne are more problematic, so that the structural diversity and adjustability of target products in preparing polysubstituted indolizine by using the route are poor, and the cost is very high. In the second route, the multi-substituted pyridine is prepared by preparing a pyridinium salt from a pyridine derivative and a halogenated compound and then reacting the pyridinium salt with an electron-deficient olefin in the presence of an oxidant. Compared with the first route, the second route has great advantages, such as rich alkene structure, low price and easy acquisition. However, there are different problems with the various oxidants used in this route. In view of the popularity of indolizines in various biological activities and substance chemistry, there remains a need to develop powerful methods of indolizine synthesis.
The electrocatalytic electrosynthesis is an organic synthesis method with high efficiency, environmental protection and strong controllability, and has wide application prospect. With the continuous development and improvement of electrocatalysts, electrocatalytic electrosynthesis plays an increasingly important role in various fields. In the last decade, electrocatalytic and electrosynthesis have shown a lot of novel and leading-edge hot research directions in basic theory and application research, continuously attract the attention and investment of scientific researchers, continuously merge the discipline knowledge of materials, energy sources, environment, information, AI intelligence and the like, and come into the development period of gold. The use of electrocatalytic synthesis chemistry has attracted the interest of most organic synthesis researchers in recent years. Electrocatalytic conversion is considered to be a promising alternative to organic synthesis under mild conditions. They provide a unique direct route that can make the molecular structure generally difficult to synthesize using other reaction types. The development of electrocatalytic reactions is an attractive synthetic strategy in synthetic chemistry. Compared with the transition metal catalyst, the electrolyte has the advantages of low cost, strong synthesis universality, no toxicity, environmental protection and the like.
Currently, there is no disclosure of the relevant prior art for the electrocatalytic synthesis of indolizine derivatives.
[1]Yang DT,Radtke J,Mellerup SK,et al.One-Pot Synthesis of Brightly Fluorescent Mes2B-Functionalized Indolizine Derivatives via Cycloaddition Reactions[J].Org Lett.2015May 15；17(10):2486-9.
[2]Prasad ChD,Kumar S,Sattar M,Adhikary A,et al.Metal free sulfenylation and bis-sulfenylation of indoles:persulfate mediated synthesis[J].Org Biomol Chem.2013Dec 14；11(46):8036-40.
[3]Nalbandian CJ,Miller EM,Toenjes ST,et al.A conjugate Lewis base-
acid catalyst for the sulfenylation of nitrogen containing heterocycles under mild conditions[J].Chem Commun(Camb).2017Jan 26；53(9):1494-1497.
Disclosure of Invention
Based on the problems and the defects existing in the prior art, the invention aims to provide an electrochemical preparation method and application of 1, 3-diaryl mercapto indolizine derivatives, and provides a novel way for preparing 1, 3-diaryl mercapto indolizine derivatives, which is safe and nontoxic in raw material source, takes electricity as energy, is environment-friendly, and has green reaction condition and high efficiency. The 1, 3-diaryl mercapto indolizine derivative prepared by the invention has a certain anticancer cell proliferation activity, has good yield in gram-scale reaction, and has potential application prospect in industrial production.
Terminology:
1. indolizine: also known as indolizine, is a privileged structure commonly used in various small molecule drug discovery programs, and functionalized indolizines find wide application in natural products and synthetic drugs, which are associated with a wide range of biological activities.
2. An electrolyte: the electrolyte is a compound that is dissolved in an aqueous solution or is capable of conducting itself in a molten state. The ionization degree can be classified into strong electrolyte and weak electrolyte, and almost all of them are ionized, and only a small part of them are ionized.
3. Solvent: a liquid that solubilizes solid, liquid, or gaseous solutes, which then become a solution, the solvent typically has a relatively low boiling point and is readily volatile, or can be removed by distillation, leaving behind a dissolved species, and therefore the solvent is not chemically reactive with the solute.
4. Tetrabutylammonium iodide: white crystalline powder. Slightly soluble in water (10 g/100 mL) and methanol.
5. Sodium bromide: colorless cubic crystal or white granular powder, sodium bromide is slightly dissolved in alcohol and can react with dilute sulfuric acid to produce hydrogen bromide. Under acidic conditions, sodium bromide can be oxidized to free bromine.
6. Potassium iodide: is an inorganic compound, has a chemical formula of KI, is colorless or white crystal, and is odorless and easily soluble in water and ethanol. The aqueous solution was darkened with light and iodine was liberated.
7. IC50: also called half-inhibitory concentration, can be used as an indicator of the antitumor activity of a drug, and can indicate the half-amount of a drug or inhibitor in inhibiting a substance such as an enzyme, a cellular receptor or a microorganism, and the value can be used to measure the ability of the drug to induce apoptosis, i.e., the stronger the induction ability, the lower the value. The inhibition of tumor cells by drugs can be studied by calculating IC50 values in apoptosis experiments.
In one aspect, the invention provides a method for preparing a 1, 3-diaryl indolizine derivative, which comprises the following steps: indolizine is used as a raw material, alkyl or aryl mercaptan is used as a sulfur source, and under the action of an electrocatalytic system, the 1, 3-diaryl mercapto indolizine derivative is prepared;
the indolizine derivative has a structure shown in a formula 1:
wherein the R is 1 、R 2 Each independently selected from aryl or alkyl.
In particular, the electrocatalytic system includes a power source, an electrolyte, and a solvent.
Further specifically, the power supply is a direct current power supply.
Preferably, the conditions of the power supply direct current power supply are as follows: the current is 5-15mA and the voltage is 10-20V.
Further preferably, the conditions of the power supply direct current power supply are as follows: the current was 10mA and the voltage was 15V.
Specifically, the electrolyte is one or more of tetrabutylammonium iodide, sodium bromide, potassium iodide and sodium iodide.
Further specifically, the electrolyte is one or more of tetrabutylammonium iodide and sodium bromide.
Preferably, the electrolyte is tetrabutylammonium iodide.
Specifically, the solvent is selected from one or more of 1, 2-dichloroethane, dimethyl sulfoxide, acetonitrile, N-dimethylformamide, dichloromethane and water.
Further specifically, the solvent is selected from one or more of 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, dichloromethane and water.
Preferably, the solvent is selected from one or more of acetonitrile, N-dimethylformamide, dichloromethane and water.
Preferably, the solvent is selected from one or more of acetonitrile, dichloromethane and water.
Further preferably, the solvent is selected from acetonitrile and water, and the solvent is a mixed solvent.
Specifically, the mixed solvent water: the ratio of acetonitrile is selected from 1:1-6.
Further specifically, the mixed solvent water: the acetonitrile ratio is selected from 1:1-5
Preferably, the mixed solvent water: the acetonitrile ratio is selected from 1:2-5
Preferably, the mixed solvent water: the acetonitrile ratio is selected from 1:3-5
Further preferably, the mixed solvent water: acetonitrile ratio of 1:5
Specifically, the structure of the product 1, 3-diaryl indolizine derivative is shown as a formula 2:
wherein the R is 1 、R 2 、R 3 Each independently selected from aryl, alkyl, or electron withdrawing groups.
Further specifically, R in the structural formula of the 1, 3-diaryl mercapto indolizine derivative 1 Selected from H, alkyl or substituted aryl;
the R is 2 Selected from H, alkyl or halogen;
the R is 3 Selected from H, alkyl, halogen or trifluoromethyl.
Preferably, the structural formula of the 1, 3-diaryl indolizine derivative comprises, but is not limited to, the following structure:
specifically, the molar ratio of indolizine to thiol is selected from 1:1.2-6.
More specifically, the molar ratio of indolizine to thiol is chosen from 1:1.4-5.8.
Preferably, the molar ratio of indolizine to thiol is chosen from 1:1.6-5.6; further preferably 1:
1.8-5.4; still more preferably 1:2-5.2; still more preferably 1:2.2-5; still more preferably 1:2.4-4.8; still more preferably 1:2.6 to 4.6; still more preferably 1:2.8-4.4; still more preferably 1:3-4.2; still more preferably 1:3.2-4.0; still more preferably 1:3.4-3.8; still more preferably 1:3.4-3.6.
Specifically, the molar ratio of the electrolyte to indolizine is selected from 0.001-7:1.
further specifically, the molar ratio of electrolyte to indolizine is selected from 1-5:1.
preferably, the molar ratio of electrolyte to indolizine is chosen from 2-7:1, a step of; further preferably 3 to 7:1, a step of; still more preferably 4-7:1.
specifically, the synthetic route of the preparation method is as follows:
wherein the R is 1 、R 2 、R 3 Each independently selected from aryl, alkyl, or electron withdrawing groups; the method comprises the steps of carrying out a first treatment on the surface of the Preferably said R 1 、R 2 、R 3 Each independently selected from aryl, C1-C5 alkyl, or halogen.
More specifically, the molar ratio of reactant 1 to reactant 2 is selected from 1:1.2-6.
Preferably, the molar ratio of reactant 1 to reactant 2 is selected from 1:1.4-5.8; further preferably 1:1.6-5.6; still more preferably 1:1.8-5.4; still more preferably 1:2-5.2; still more preferably 1:2.2-5; still more preferably 1:2.4-4.8; still more preferably 1:2.6 to 4.6; still more preferably 1:2.8-4.4; still more preferably 1:3-4.2; still more preferably 1:3.2-4.0; still more preferably 1:3.4-3.8; still more preferably 1:3.4-3.6.
In yet another aspect, the present application provides a compound prepared by the above preparation method, the compound selected from the following structures:
in a further aspect, the present application provides a method of preparation as described above and/or use of the above compounds, including use in the agrochemical, fluorescent, pharmaceutical, medical and/or chemical fields.
In particular, the use includes use in the preparation of anti-cancer drugs.
Further specifically, the use includes use in the manufacture of a medicament for the prevention and treatment of cancer.
Preferably, the cancer includes pancreatic cancer, cervical cancer, colorectal cancer, lung cancer, hepatocellular cancer, renal cancer, gastric cancer, bile duct cancer, and the like.
Further preferably, the cancer comprises hepatocellular carcinoma, cervical cancer.
The beneficial effects of the invention are as follows:
(1) The raw materials of the invention are safe and nontoxic, electricity is used as energy, the environment-friendly reaction condition is green and efficient, and a novel way of 1, 3-diaryl mercapto indolizine derivatives is provided for organic chemistry researchers.
(2) The invention synthesizes the 1, 3-diaryl indolizine derivative directly by electrocatalytic reaction, and the prepared 1, 3-diaryl indolizine derivative has certain anticancer cell proliferation activity and good yield in gram-scale reaction.
(3) The method for preparing the 1, 3-diaryl mercapto indolizine derivative has the advantages of simple operation, no metal participation, wide application range of reaction substrates, good regioselectivity, high yield, capability of synthesizing a series of 1, 3-diaryl mercapto indolizine derivatives in a green and efficient manner, and wide application prospect in the aspects of agricultural chemicals, medicine preparation and fluorescent materials.
Drawings
FIG. 1 is a hydrogen spectrum of a compound prepared in example 1 of the present invention.
FIG. 2 is a carbon spectrum of the compound prepared in example 1 of the present invention.
FIG. 3 is a hydrogen spectrum of the compound prepared in example 2 of the present invention.
FIG. 4 is a carbon spectrum of the compound prepared in example 2 of the present invention.
FIG. 5 is a hydrogen spectrum of the compound prepared in example 3 of the present invention.
FIG. 6 is a carbon spectrum of the compound prepared in example 3 of the present invention.
FIG. 7 is a hydrogen spectrum of the compound prepared in example 4 of the present invention.
FIG. 8 is a carbon spectrum of the compound prepared in example 4 of the present invention.
FIG. 9 is a hydrogen spectrum of the compound prepared in example 5 of the present invention.
FIG. 10 is a carbon spectrum of the compound prepared in example 5 of the present invention.
FIG. 11 is a hydrogen spectrum of the compound prepared in example 6 of the present invention.
FIG. 12 is a carbon spectrum of the compound prepared in example 6 of the present invention.
FIG. 13 is a hydrogen spectrum of the compound prepared in example 7 of the present invention.
FIG. 14 is a carbon spectrum of the compound prepared in example 7 of the present invention.
FIG. 15 is a hydrogen spectrum of the compound prepared in example 8 of the present invention.
FIG. 16 is a carbon spectrum of a compound prepared in example 8 of the present invention.
FIG. 17 is a hydrogen spectrum of the compound prepared in example 9 of the present invention.
FIG. 18 is a carbon spectrum of the compound prepared in example 9 of the present invention.
FIG. 19 is a hydrogen spectrum of the compound prepared in example 10 of the present invention.
FIG. 20 is a carbon spectrum of the compound prepared in example 10 of the present invention.
FIG. 21 is a hydrogen spectrum of the compound prepared in example 11 of the present invention.
FIG. 22 is a carbon spectrum of the compound prepared in example 11 of the present invention.
Detailed Description
The present invention will be described with reference to specific examples, which are not intended to limit the invention, but are merely illustrative of the invention so that the technical scheme of the invention can be more easily understood and grasped. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.
Example 1
19.4mg (0.1 mmol) of indolizine, 96.5mg-167.3mg (0.4 mmol-0.7 mmol) of tetrabutylammonium iodide and 13.22mg-66.06mg (0.12 mmol-0.6 mmol) of phenylthiol are placed in a 25mL test tube with a stirrer, a mixed solution of 5mL of acetonitrile and water is added at room temperature, stirring is carried out for 6 hours under the condition of power supply, and the target product is obtained by flash column chromatography after spin drying, wherein the yield is 90%.
1H NMR(400MHz,Chloroform-d)δ8.32(d,J＝7.2Hz,1H),7.68(d,J＝8.8Hz,1H),7.42(dd,J＝7.6,2.0Hz,2H),7.30(d,J＝6.0Hz,2H),7.22-7.07(m,6H),7.05-7.03(m,1H),7.00(dd,J＝8.4,1.2Hz,3H),6.90(d,J＝7.2Hz,2H),6.74-6.70(m,1H).
13C NMR(101MHz,CDCl3)δ141.6,140.1,139.4,136.6,133.1,130.4,129.3,128.7,127.8,127.6,125.6,125.2,125.2,124.6,124.5,122.2,117.8,112.8,107.6,97.4.
HR-ESI-MS m/z calcd.for C26H19NS2[M+H]+:409.0959,found:409.0955.
Example 2
19.4mg (0.1 mmol) of indolizine, 96.5mg-167.3mg (0.4 mmol-0.7 mmol) of tetrabutylammonium iodide and 15.22mg-75.11mg (0.12 mmol-0.6 mmol) of o-methylbenzene mercaptan are placed in a 25mL test tube with a stirrer, a mixed solution of 5mL of acetonitrile and water is added at room temperature, stirring is carried out for 6 hours under the condition of power supply, and the target product is obtained by flash column chromatography after spin drying, wherein the yield is 80%.
1H NMR(400MHz,CDCl3)δ8.40(t,J＝6.1Hz,1H),7.83-7.78(m,1H),7.58(s,2H),7.47-7.42(m,3H),7.33-7.25(m,2H),7.15(dd,J＝15.0,6.0Hz,5H),6.88-6.81(m,2H),2.59(s,6H).
13C NMR(101MHz,CDCl3)δ141.98,139.64,139.28,135.76,134.83,134.39,133.29,130.66,130.49,130.18,130.01,129.69,127.85,127.62,126.92,126.44,125.39,124.66,124.39,124.10,122.13,118.01,112.82,107.00,97.05,19.78,19.66.
HR-ESI-MS m/z calcd.for C28H23NS2[M+H]+:438.1345,found:438.1340.
Example 3
19.4mg (0.1 mmol) of indolizine, 96.5mg-167.3mg (0.4 mmol-0.7 mmol) of tetrabutylammonium iodide and 15.4mg-61.4mg (0.12 mmol-0.6 mmol) of 3-fluorobenzene thiol are placed in a 25mL test tube with a stirrer, after 5mL of a mixed solution of acetonitrile and water is added at room temperature, stirring is carried out for 6 hours under the condition of power supply, and the target product is obtained by flash column chromatography after spin drying, and the yield is 84%.
1H NMR(400MHz,CDCl3)δ8.37(d,J＝7.0Hz,1H),7.73(d,J＝8.9Hz,1H),7.45-7.41(m,2H),7.39-7.34(m,3H),7.11-7.06(m,1H),6.98(dd,J＝8.3,5.0Hz,2H),6.95-6.93(m,1H),6.92-6.85(m,5H),6.80(td,J＝6.8,1.3Hz,1H).
13C NMR(101MHz,Chloroform-d)δ162.26(d,J＝50.9Hz),159.83(d,J＝49.5Hz),141.52,139.22,134.85(d,J＝3.0Hz),133.00,131.41(d,J＝3.2Hz),130.47,127.83,127.73,127.37(d,J＝8.0Hz),127.29(d,J＝8.1Hz),124.38,122.38,117.80,116.43(d,J＝22.1Hz),115.80(d,J＝22.0Hz),112.89,108.20,98.28.
HR-ESI-MS m/z calcd.for C26H17F2NS2[M+H]+:446.0843,found:446.0840.
Example 4
19.4mg (0.1 mmol) of indolizine, 96.5mg-167.3mg (0.4 mmol-0.7 mmol) of tetrabutylammonium iodide and 21.36mg-106.8mg (0.06 mmol-0.3 mmol) of 3-trifluoromethylbenzenethiol are placed in a 25mL test tube with a stirrer, 5mL of a mixed solution of acetonitrile and water is added at room temperature, the mixture is stirred for 6 hours under the power-on condition, and the target product is obtained by flash column chromatography after spin drying, and the yield is 82%.
1H NMR(400MHz,CDCl3)δ8.36(d,J＝7.0Hz,1H),7.70(d,J＝8.9Hz,1H),7.40-7.36(m,3H),7.35-7.32(m,3H),7.31-7.26(m,3H),7.23(s,2H),7.14-
7.08(m,2H),6.93(d,J＝7.8Hz,1H),6.83(t,J＝6.8Hz,1H).
13C NMR(101MHz,CDCl3)δ154.99,142.37,141.53,139.55,138.25,132.61,131.88,131.56,130.97,130.24,129.76,129.11,128.22,128.03,127.97,124.43,124.22,122.97,122.53,122.06,121.84,121.49,117.76,113.31,108.69,106.93,96.71.
HR-ESI-MS m/z calcd.for C28H17F6NS2[M+H]+:546.0779,found:546.0775.
Example 5
19.4mg (0.1 mmol) of indolizine, 96.5mg-167.3mg (0.4 mmol-0.7 mmol) of tetrabutylammonium iodide and 25.6mg-128.1mg (0.12 mmol-0.6 mmol) of 3-trifluoromethyl-4-chlorobenzenethiol are placed in a 25mL test tube with a stirrer, 5mL of a mixed solution of acetonitrile and water is added at room temperature, stirring is carried out for 6 hours under the condition of electrification, and the target product is obtained by flash column chromatography after spin drying, wherein the yield is 81%.
1H NMR(400MHz,CDCl3)δ8.26(d,J＝7.0Hz,1H),7.60(d,J＝8.4Hz,1H),7.28(s,5H),7.21(d,J＝8.3Hz,3H),7.17-7.14(m,1H),7.08-7.02(m,1H),6.90(d,J＝8.4Hz,1H),6.79-6.72(m,2H).
13C NMR(101MHz,CDCl3)δ142.45,139.62,139.54,136.28,132.26,131.63,130.13,129.06,128.97,128.16,128.10,124.33,124.05(q,J＝5.6Hz).,123.77，123.70(q,J＝5.6Hz),123.62,123.38,120.96,117.65,113.59,106.62,96.41.
Example 6
21.02mg (0.1 mmol) of 8-methyl-2-phenylindolizine, 96.5mg-167.3mg (0.4 mmol-0.7 mmol) of tetrabutylammonium iodide and 13.22mg-66.06mg (0.12 mmol-0.6 mmol) of phenylthiol are placed in a 25mL test tube with a stirrer, 5mL of a mixed solution of acetonitrile and water is added at room temperature, stirring is carried out for 6 hours under the condition of electrification, and flash column chromatography is carried out after spin drying to obtain the target product with 80% yield.
1H NMR(400MHz,Chloroform-d)δ8.32(d,J＝6.8Hz,1H),7.36(d,J＝19.6Hz,5H),7.23(t,J＝6.9Hz,4H),7.15(t,J＝7.2Hz,1H),7.08(t,J＝7.6Hz,1H),7.03(d,J＝8.0Hz,2H),6.94(d,J＝8.0Hz,2H),6.79(d,J＝6.8Hz,1H),6.66(t,J＝6.8Hz,1H),2.78(s,3H).
13C NMR(101MHz,CDCl3)δ143.0,142.7,138.3,136.7,133.4,130.6,130.0,129.2,128.8,127.6,127.5,125.5,125.2,124.7,124.2,123.3,123.0,112.23,108.1,97.7,19.6.
Example 7
21.02mg (0.1 mmol) of 7-methyl-2-phenylindolizine, 96.5mg-167.3mg (0.4 mmol-0.7 mmol) of tetrabutylammonium iodide and 13.22mg-66.06mg (0.12 mmol-0.6 mmol) of phenylthiol are placed in a 25mL test tube with a stirrer, 5mL of a mixed solution of acetonitrile and water is added at room temperature, stirring is carried out for 6 hours under the condition of electrification, and flash column chromatography is carried out after spin drying to obtain the target product with 74 percent of yield.
1H NMR(400MHz,CDCl3)δ8.22(d,J＝6.8Hz,1H),7.43(d,J＝23.2Hz,3H),7.30(s,3H),7.23-7.16(m,4H),7.13(d,J＝7.2Hz,1H),7.07(d,J＝7.6Hz,1H),7.01(d,J＝7.6Hz,2H),6.91(d,J＝7.2Hz,2H),6.59(d,J＝6.8Hz,1H),2.34(s,3H).
13C NMR(101MHz,CDCl3)δ140.5,139.9,139.8,139.8,137.1,137.0,133.3,133.2,130.4,129.3,128.8,127.7,127.5,125.5,125.1,125.1,124.5,124.0,116.2,115.5,29.7.
Example 8
22.1mg (0.1 mmol) of 6, 8-dimethyl-2-phenylindolizine, 96.5mg-167.3mg (0.4 mmol-0.7 mmol) of tetrabutylammonium iodide and 13.22mg-66.06mg (0.12 mmol-0.6 mmol) of phenylthiol are placed in a 25mL test tube with a stirrer, a mixed solution of 5mL of acetonitrile and water is added at room temperature, stirring is carried out for 6 hours under the condition of electrification, and the target product is obtained by flash column chromatography after spin drying, wherein the yield is 82%.
1H NMR(400MHz,Chloroform-d)δ8.09(s,1H),7.33-7.28(m,2H),7.28-7.22(m,3H),7.21-7.13(m,4H),7.09(t,J＝7.2Hz,1H),7.02(d,J＝7.6Hz,3H),6.97(d,J＝7.2Hz,2H),6.89(d,J＝7.2Hz,2H),6.61(s,1H),2.68(s,3H),2.18(s,3H).
13C NMR(101MHz,CDCl3)δ142.9,142.7,137.1,133.6,130.5,129.3,129.2,128.8,127.5,127.4,126.6,125.4,125.1,124.7,124.2,121.8,120.7,107.6,97.3,19.4,18.2.
ESI-MS m/z(％)437(100)[M+H]+；Anal.Calcd for C28H23NS2 C,76.85；H,5.30；N,3.20；Found:C,76.86；H,5.31；N,3.22.
Example 9
25.3mg (0.1 mmol) of 2- (3, 4-dimethoxyphenyl) indolizine, 96.5mg-167.3mg (0.4 mmol-0.7 mmol) of tetrabutylammonium iodide and 13.22mg-66.06mg (0.12 mmol-0.6 mmol) of phenylthiol are placed in a 25mL test tube with a stirrer, a mixed solution of 5mL of acetonitrile and water is added at room temperature, stirred for 6 hours under the energizing condition, and the target product is obtained by flash column chromatography after spin drying, 71% yield.
1H NMR(400MHz,CDCl3)δ8.40(d,J＝7.2Hz,1H),7.74(d,J＝8.8Hz,1H),7.25-7.18(m,4H),7.14(t,J＝7.2Hz,1H),7.07(t,J＝7.2Hz,4H),7.02(d,J＝6.4Hz,1H),6.95(d,J＝7.6Hz,2H),6.91(s,1H),6.84(d,J＝8.4Hz,1H),6.78(t,J＝6.4Hz,1H),3.85(s,3H),3.38(s,3H).
13C NMR(101MHz,CDCl3)δ148.4,148.0,141.4,140.6,139.9,137.2,129.3,128.8,125.6,125.5,125.0,125.0,124.5,124.4,122.5,122.3,117.7,113.7,112.8,110.5,107.4,96.8,55.6,55.0.
Example 10
23.8mg (0.1 mmol) of 2-phenyl-1, 3-oxyethyl indolizine, 96.5mg-167.3mg (0.4 mmol-0.7 mmol) of tetrabutylammonium iodide, 13.22mg-66.06mg (0.12 mmol-0.6 mmol) of phenylthiol are placed in a 25mL test tube with a stirrer, a mixed solution of 5mL of acetonitrile and water is added at room temperature, stirring is carried out for 6 hours under the condition of electrification, and the target product is obtained by flash column chromatography after spin drying in 85% yield.
1H NMR(400MHz,CDCl3)δ8.33(d,J＝7.2Hz,1H),7.69(d,J＝8.8Hz,1H),7.21(dt,J＝15.2,7.6Hz,4H),7.13(t,J＝7.2Hz,1H),7.09-7.03(m,2H),7.01(d,J＝7.6Hz,2H),6.92(d,J＝2.8Hz,3H),6.90(s,0H),6.77(dd,J＝14.4,7.6Hz,2H),5.93(s,2H).
13C NMR(101MHz,CDCl3)δ147.2,147.0,141.4,140.1,139.4,136.6,129.32,128.79,126.79,125.62,125.22,125.17,124.65,124.49,124.30,122.23,117.8,112.8,110.9,107.9,107.6,100.9,97.4.
Example 11
21.02mg (0.1 mmol) of 2- (3-methylphenyl) indolizine, 96.5mg-167.3mg (0.4 mmol-0.7 mmol) of tetrabutylammonium iodide and 13.22mg-66.06mg (0.12 mmol-0.6 mmol) of phenylthiol are placed in a 25mL test tube with a stirrer, 5mL of a mixed solution of acetonitrile and water is added at room temperature, stirring is carried out for 6 hours under the condition of electrification, and flash column chromatography is carried out after spin drying to obtain the target product with 80% yield.
1H NMR(400MHz,CDCl3)δ8.38(d,J＝9.6Hz,1H),7.74(d,J＝7.6Hz,1H),7.27-7.19(m,7H),7.16(d,J＝6.8Hz,2H),7.12-7.03(m,4H),6.96(d,J＝1.2Hz,2H),6.77(t,J＝6.8Hz,1H),2.29(s,3H).
13C NMR(101MHz,CDCl3)δ141.8,140.3,139.4,137.1,136.8,133.0,131.3,129.2,128.7,128.4,127.6,127.4,125.5,125.4,125.3,124.6,124.5,122.1,117.8,112.7,107.7,97.6,21.4.
The data show that the yield of the indolizine derivative in the 1, 3-diaryl mercapto prepared by the preparation method provided by the application is between 71% and 90%, and the yield is higher. When the raw material is indolizine and the sulfur source is benzene mercaptan, the yield of the prepared target product is highest and is up to 90%.
Experimental example 1MTT test
MTT test was performed on the 1, 3-diarylmercaptan derivatives prepared in example 4, example 9 and example 11, and HepG2 (human hepatoma cell) and HeLa (cervical carcinoma cell) were selected as cells using Ornitinib (AZD-9291) as a positive control drug.
The specific operation method is as follows:
(1) Cell resuscitation, culture and passaging
The frozen cells were taken out of the refrigerator, quickly placed in a thermostatic water bath at 37.5℃for thawing, then the thawed cells were added into an ep tube containing 1mL of DMEM in an ultra clean bench, placed in a centrifuge, centrifuged at 1000rpm for 3 minutes, the supernatant was discarded after completion, and the complete medium (DMEM medium+10% bovine serum albumin FBS) was added, after being blown uniformly, taken into a flask. When the color of the culture medium changes, the culture medium is replaced. When the cells grew to 90% of the flask, passaging was performed by first pouring out the old medium, slowly adding 2mL of PBS to wash the flask, then adding 0.5mL of pancreatin for digestion, when the cells were observed to start to fall off, adding the medium and gently beating until the cells completely fall off, then collecting the cell suspension, centrifuging at 1000rpm for 3 minutes, discarding the supernatant, adding the complete medium, beating uniformly, and then sub-packaging into two flasks.
(2) MTT method
Taking logarithmic growth cells, digesting and blowing to uniformly distribute the cells, then performing cell counting, and thenIt was then diluted to 6X 10 with complete medium 3 (cell/mL), 100. Mu.L of the cell suspension was uniformly added to a 96-well plate (36 wells at the edge were not added), and the mixture was placed in an incubator, and after 12 hours of cell attachment, the mixture was administered. The drug was set at 5 concentrations (90, 30, 10, 3.3, 1.1 μm) and 3 multiplex wells were set. Incubation in the incubator was continued for 48 hours after dosing. After the completion of incubation, the stock solution was discarded, 10. Mu.L of MTT solution (5 mg/mL) and 90. Mu.L of a blank medium (DMEM medium) were added, and the incubation was continued for 4 hours, followed by discarding the stock solution, adding 100. Mu.L of DMSO solution for dissolution, shaking for 15 minutes using a shaker, and measuring the absorbance value of each well at 490nm using an ELISA reader. Finally, cell viability was calculated using the following formula: survival= (OD Test sample -OD Blank space )/(OD Negative control -OD Blank space )×100％。
IC for analyzing compounds 50 The values show that the series of compounds have certain inhibitory activity on the above cell lines, and the results are shown in table 1:
table 1 in vitro antiproliferative activity of certain compounds
The above data show that the 1, 3-diarylmercaptan derivatives prepared according to examples 4, 9 and 11 have a certain inhibitory effect on both HepG2 and HeLa cells.
The above detailed description is directed to a specific description of one possible embodiment of the invention, which is not intended to limit the scope of the invention. It should be noted that all equivalent implementations or modifications that do not depart from the spirit and scope of the present invention are intended to be included within the scope of the present invention. The scope of the invention should therefore be determined by the appended claims.

Claims (10)

1. A process for the preparation of 1, 3-diarylmercaptan derivatives, comprising the steps of: the indolizine derivative is used as a raw material, alkyl or aryl mercaptan is used as a sulfur source, and the 1, 3-diaryl mercapto indolizine derivative is prepared under the action of an electrocatalytic system;
the indolizine derivative has a structure shown in a formula 1:
wherein the R is 1 、R 2 Each independently selected from aryl or alkyl.
2. The method of claim 1, wherein the electrocatalytic system comprises a power source, an electrolyte, and a solvent;
the power supply is a direct current power supply, and the conditions of the direct current power supply are as follows: the current is 5-15mA, and the voltage is 10-20V;
the electrolyte is one or more of tetrabutylammonium iodide, sodium bromide, potassium iodide and sodium iodide; preferably tetrabutylammonium iodide;
the solvent is one or more selected from 1, 2-dichloroethane, dimethyl sulfoxide, acetonitrile, N-dimethylformamide, dichloromethane and water.
3. The method according to claim 2, wherein the solvent is a mixed solvent of acetonitrile and water, and the solvent water: the volume ratio of acetonitrile is 1:5.
4. the preparation method of claim 1, wherein the 1, 3-diaryl indolizine derivative has a structure as shown in formula 2:
wherein the R is 1 、R 2 、R 3 Each independently selected from aryl, alkyl, or electron withdrawing groups.
5. The process according to claim 4, wherein R in the structural formula of the 1, 3-diarylmercaptan derivative is 1 Selected from H, alkyl or substituted aryl;
the R is 2 Selected from H, alkyl or halogen;
the R is 3 Selected from H, alkyl, halogen or trifluoromethyl.
6. The process according to claim 5, wherein the structural formula of the 1, 3-diarylmercaptan derivative is selected from the group consisting of:
7. the preparation method according to any one of claims 1 to 6, wherein the synthetic route of the preparation method is:
wherein the R is 1 、R 2 、R 3 Each independently selected from aryl, alkyl, or electron withdrawing groups; preferably said R 1 、R 2 、R 3 Each independently selected from aryl, C1-C5 alkyl, or halogen.
8. A compound prepared by the preparation process according to any one of claims 1 to 7, selected from the following structures:
9. the method of preparation according to any one of claims 1 to 8 and/or the use of a compound according to claim 10, characterized in that the use comprises use in the agrochemicals, fluorescent materials, pharmaceutical, medical and/or chemical fields.
10. The use according to claim 9, characterized in that the use comprises the use in the preparation of anticancer drugs.
CN202311304944.3A 2023-10-09 2023-10-09 Electrochemical preparation method and application of 1, 3-diaryl mercapto indolizine derivative Pending CN117265556A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202311304944.3A CN117265556A (en) 2023-10-09 2023-10-09 Electrochemical preparation method and application of 1, 3-diaryl mercapto indolizine derivative

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202311304944.3A CN117265556A (en) 2023-10-09 2023-10-09 Electrochemical preparation method and application of 1, 3-diaryl mercapto indolizine derivative

Publications (1)

Publication Number Publication Date
CN117265556A true CN117265556A (en) 2023-12-22

Family

ID=89221285

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202311304944.3A Pending CN117265556A (en) 2023-10-09 2023-10-09 Electrochemical preparation method and application of 1, 3-diaryl mercapto indolizine derivative

Country Status (1)

Country Link
CN (1) CN117265556A (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008140150A1 (en) * 2007-05-15 2008-11-20 Food Science Co., Ltd. Novel octahydro-indeno derivatives and pharmaceutical composition comprising the same
CN107620088A (en) * 2017-09-14 2018-01-23 浙江工业大学 A kind of method that electrochemical catalytic oxidation synthesizes 3 sulfydryl indole class compounds
CN108640916A (en) * 2018-06-07 2018-10-12 广东药科大学 One kind has the thio indolizine class compound and its derivative of active anticancer
CN111072653A (en) * 2019-12-26 2020-04-28 浙江工业大学 Method for directly synthesizing 1, 3-disulfo-indolizine compound from substituted 2-aryl indolizine
CN114790553A (en) * 2022-03-02 2022-07-26 南京先进生物材料与过程装备研究院有限公司 Method for performing difluoromethylation modification on indole C-2 position in electrochemical system
CN115652346A (en) * 2022-12-14 2023-01-31 浙江工业大学 Method for synthesizing 3-mercaptoindolizine compound by electrocatalytic oxidation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008140150A1 (en) * 2007-05-15 2008-11-20 Food Science Co., Ltd. Novel octahydro-indeno derivatives and pharmaceutical composition comprising the same
CN107620088A (en) * 2017-09-14 2018-01-23 浙江工业大学 A kind of method that electrochemical catalytic oxidation synthesizes 3 sulfydryl indole class compounds
CN108640916A (en) * 2018-06-07 2018-10-12 广东药科大学 One kind has the thio indolizine class compound and its derivative of active anticancer
CN111072653A (en) * 2019-12-26 2020-04-28 浙江工业大学 Method for directly synthesizing 1, 3-disulfo-indolizine compound from substituted 2-aryl indolizine
CN114790553A (en) * 2022-03-02 2022-07-26 南京先进生物材料与过程装备研究院有限公司 Method for performing difluoromethylation modification on indole C-2 position in electrochemical system
CN115652346A (en) * 2022-12-14 2023-01-31 浙江工业大学 Method for synthesizing 3-mercaptoindolizine compound by electrocatalytic oxidation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AMREEN CHOUHAN等: "Electrochemical direct C–H mono and bischalcogenation of indolizine frameworks under oxidant-free conditions", 《ORGANIC&BIOMOLECULAR CHEMISTRY》》, 1 September 2023 (2023-09-01), pages 7643 - 7653 *
GUANTING LI等: "Dithiolation indolizine exerts viability suppression effects on A549 cells via triggering intrinsic apoptotic pathways and inducing G2/M phase arrest", 《BIOMEDICINE & PHARMACOTHERAPY》, 31 December 2021 (2021-12-31), pages 1 - 10 *
YU ZHU等: "NH4I-catalyzed C–S bond formation via an oxidation relay strategy: Efficient access to dithioether decorated indolizines", 《TETRAHEDRON LETTERS》, 31 December 2020 (2020-12-31), pages 1 - 5 *
乐贵洲;黄乾明;邹平;: "中氮茚的合成研究进展", 有机化学, no. 09, 15 September 2007 (2007-09-15), pages 31 - 39 *

Similar Documents

Publication Publication Date Title
Ratković et al. Synthesis, characterization, electrochemical studies and antitumor activity of some new chalcone analogues containing ferrocenyl pyrazole moiety
Dunkley et al. Synthesis and biological evaluation of a novel phenyl substituted sydnone series as potential antitumor agents
Verbitskiy et al. Combination of the Suzuki–Miyaura cross-coupling and nucleophilic aromatic substitution of hydrogen (SNH) reactions as a versatile route to pyrimidines bearing thiophene fragments
Satyendra et al. Synthesis, in vitro antioxidant, anthelmintic and molecular docking studies of novel dichloro substituted benzoxazole-triazolo-thione derivatives
Broch et al. Synthesis and in vitro antiproliferative activities of quinoline derivatives
Schumacher et al. The potential antioxidant activity of 2, 3-dihydroselenophene, a prototype drug of 4-aryl-2, 3-dihydroselenophenes
Arthuis et al. Domino approach to 2-aroyltrimethoxyindoles as novel heterocyclic combretastatin A4 analogues
CN104109115B (en) Phenylpropionic acid compound, its pharmaceutical composition, preparation method and the purposes of a kind of nitrogen heterocyclic ring link
Granchi et al. Design, synthesis and biological evaluation of second-generation benzoylpiperidine derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors
Obermoser et al. New telmisartan-derived PPARγ agonists: impact of the 3D-binding mode on the pharmacological profile
Gozzi et al. Phenolic indeno [1, 2-b] indoles as ABCG2-selective potent and non-toxic inhibitors stimulating basal ATPase activity
Bao et al. Novel NO-releasing plumbagin derivatives: design, synthesis and evaluation of antiproliferative activity
Cui et al. Oxidative umpolung selenocyanation of ketones and arenes: An efficient protocol to the synthesis of selenocyanates
Macías-Pérez et al. Ethers and esters derived from apocynin avoid the interaction between p47 phox and p22 phox subunits of NADPH oxidase: evaluation in vitro and in silico
Iqbal et al. Substituted phenyl [(5-benzyl-1, 3, 4-oxadiazol-2-yl) sulfanyl] acetates/acetamides as alkaline phosphatase inhibitors: Synthesis, computational studies, enzyme inhibitory kinetics and DNA binding studies
Qin et al. A Mild and Direct C (sp3)–S Cross-Coupling of Oxindoles with Thiols: Synthesis of Unsymmetrical 3-Thiooxindoles
CN104926785B (en) A kind of selenium heteroaromatic ring derivative and preparation method thereof
CN108586311B (en) Preparation method of 3-thioether indole or 3-seleno-ether indole
Bhoi et al. An efficient synthesis of rearranged new biologically active benzimidazoles derived from 2-formyl carvacrol
CN105111244B (en) Bicyclic [2.2.1] vinyl compound in heptan of ferrocene oxygen bridge
Majumdar et al. Synthesis of tricyclic and tetracyclic sultones by Pd-catalyzed intramolecular cyclization
Chaudhury et al. Structure‐based design, synthesis, and biological evaluation of hsp90β‐selective inhibitors
Chen et al. Synthesis and structure–activity relationships of guaiane-type sesquiterpene lactone derivatives with respect to inhibiting NO production in lipopolysaccharide-induced RAW 264.7 macrophages
CN103880623A (en) 4,2',4'-triethoxy-5' substituted chalcone derivatives and preparation method and application thereof
CN117265556A (en) Electrochemical preparation method and application of 1, 3-diaryl mercapto indolizine derivative

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination