CN117800978A - Evodiamine analogue, and preparation method and application thereof - Google Patents

Evodiamine analogue, and preparation method and application thereof Download PDF

Info

Publication number
CN117800978A
CN117800978A CN202311796875.2A CN202311796875A CN117800978A CN 117800978 A CN117800978 A CN 117800978A CN 202311796875 A CN202311796875 A CN 202311796875A CN 117800978 A CN117800978 A CN 117800978A
Authority
CN
China
Prior art keywords
mmol
reaction
dichloromethane
compound
methyl
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
CN202311796875.2A
Other languages
Chinese (zh)
Inventor
孔翔飞
王良风
周超
张林峰
苟田田
王桂霞
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.)
Guilin University of Technology
Original Assignee
Guilin University of Technology
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 Guilin University of Technology filed Critical Guilin University of Technology
Priority to CN202311796875.2A priority Critical patent/CN117800978A/en
Publication of CN117800978A publication Critical patent/CN117800978A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)

Abstract

The invention relates to an rutaecarpine analogue, a preparation method and application thereof, belonging to the field of pharmaceutical chemical synthesis. The rutaecarpine analogue is synthesized by taking the 4 (3H) -quinazolinone derivative as a substrate and iron phthalocyanine as a catalyst through intramolecular hydrogen reaction, and has high yield and low production cost. When the concentration is 25 mu m and the LPS concentration is 1 mu g/mL, the release inhibition capacity of the compounds 1c,1t,1u and 1v on NO is better than that of the anti-inflammatory drug indomethacin, and 1a,1b and 1i are equivalent to that of the indomethacin; the compounds 1c,1t,1u and 1v with stronger NO release inhibiting ability have weaker cytotoxic effect on RAW264.7 cells; has obvious anti-inflammatory effect, low toxicity, high medical value and wide market prospect.

Description

Evodiamine analogue, and preparation method and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to an rutaecarpine analogue, a preparation method and application thereof.
Background
Quinazolinone structures are one of the important nitrogen heterocycles in organic synthesis. It is ubiquitous in natural products and bioactive compounds and plays an important role as a pharmacophore in drug development. Evodiamine and derivatives thereof are an important alkaloid containing quinazolinone and indolyl groups, and a great deal of researches show that the evodia amine analogues and other compounds containing quinazolinone have remarkable anti-obesity, anti-platelet aggregation, anti-inflammatory, antibacterial, anti-diabetes and anticancer activities. Therefore, by carrying out structural modification on the rutaecarpine analogue, novel compounds with wide biological activity can be obtained. At present, the synthesis method of rutaecarpine and derivatives thereof is mainly based on routes of tryptamine and derivatives thereof, which results in insufficient structural diversity of rutaecarpine analogues. Therefore, the development of a new corneobase skeleton construction method has urgent and application prospects. The hydrogen-borrowing reaction is a type of reaction that is of great interest in the field of organic synthesis. The reaction is usually carried out by taking alcohol as an alkylating reagent, and only water is used as a byproduct, so that the method is a green sustainable synthesis method. In recent years, with the intensive research of hydrogen-borrowing reaction, transition metal catalyzed alkylation of indole at C3 or N1 position has been developed. The invention utilizes intramolecular hydrogen reaction to synthesize a series of rutaecarpine analogues and derivatives thereof.
The new rutaecarpine analogue is synthesized recently, and the compound is not reported in any literature at present.
Disclosure of Invention
The main content of the invention is to provide a method for synthesizing rutaecarpine analogues, which takes isatoic anhydride and derivatives thereof, 1H-indole-2-formaldehyde and derivatives thereof, ethanolamine and the like as raw materials, takes iron phthalocyanine as a catalyst and utilizes intramolecular hydrogen reaction to synthesize the rutaecarpine analogues. The synthetic route is shown in figure 1: the method comprises the steps of taking isatoic anhydride and derivatives thereof as raw materials, synthesizing derivatives (I) of anthranilamide, carrying out condensation reaction and oxidation reaction on the derivatives (I) and 1H-indole-2-formaldehyde and derivatives thereof under an acidic condition to generate 4 (3H) -quinazolinone derivatives (II), and finally, carrying out ring closure reaction when iron phthalocyanine is catalyzed to generate a target compound (III). Wherein R is 1 And R is 2 Is F, cl, br, methyl, methoxy and other substituents; r is R 3 Is H, hydroxymethyl and other substituents.
The invention also provides application of the rutaecarpine analogue in preparing anti-inflammatory drugs. When the concentration is 25 mu m and the LPS concentration is 1 mu g/mL, the release inhibition capacity of the compounds 1c,1t,1u and 1v on NO is better than that of the anti-inflammatory drug indomethacin, and 1a,1b and 1i are equivalent to that of the indomethacin; the compounds 1c,1t,1u and 1v with stronger NO release inhibiting ability have weaker cytotoxic effect on RAW 264.7 cells; has obvious anti-inflammatory effect, low toxicity, high medical value and wide market prospect.
The invention has the advantages that:
1. under mild conditions, the compound I and 1H-indole-2-carbaldehyde, derivatives thereof and the like undergo condensation reaction and oxidation reaction to produce the 4 (3H) -quinazolinone derivative (II) with high yield.
2. The target compound (III) is produced in a high yield by using cheap iron phthalocyanine as a catalyst.
3. The byproduct of the reaction is only water, and the synthesis method is environment-friendly.
4. The rutaecarpine analogue synthesized by the scheme has obvious anti-inflammatory effect and low toxicity, and can be used for preparing anti-inflammatory medicaments in various dosage forms.
Drawings
FIG. 1 is a synthetic route for preparing rutaecarpine analogues in accordance with the present invention.
Detailed Description
The invention will be described below in connection with specific embodiments. It should be noted that the following examples are only for illustrating the present invention, and are not intended to limit the present invention. Other various combinations and modifications within the inventive concept may be made without departing from the spirit or scope of the invention.
In the embodiments to be described below, 1 the internal standard at the time of H NMR testing was Tetramethylsilane (TMS).
Example 1:
the reaction steps are as follows:
1. synthesis of Compound 1a
Acetonitrile (30 mL) and ethanolamine (1.5 mmol,91.6 mg) were added sequentially to a 100 mL round bottom flask under electromagnetic stirring, isatoic anhydride (1 mmol,163.1 mg) was then added under ice water bath, reaction was continued at room temperature for 30 min at 0℃for 4 h, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) gives 162 mg as a white solid compound 3a (90% yield).
Under electromagnetic stirring, compound 3a (0.5 mmol,90 mg), tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted under nitrogen atmosphere at room temperature for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (DDQ, 0.6 mmol,136 mg) was added under an ice-water bath, the reaction was continued at room temperature for 30 min for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to give 131.2 mg as yellow solid compound 4a (86% yield).
In a dry reaction tube with magnetic stirring bar, compound 4a (0.1 mmol,30.6 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) to give 26.4. 26.4 mg as yellow solid compound 1a (yield 90%). 1 H NMR (500 MHz，CDCl 3 ) δ 8.30 (d, J = 8.0 Hz, 1H), 7.78–7.70 (m, 3H), 7.59 (s, 1H), 7.46–7.43 (m, 1H), 7.39–7.34 (m, 2H), 7.20 (t, J = 7.3 Hz, 1H), 4.67 (t, J = 5.8 Hz, 2H), 4.44 (t, J = 5.8 Hz, 2H)。
2. Synthesis of Compound 1b
Acetonitrile (30 mL) and ethanolamine (1.5 mmol,91.6 mg) were added sequentially to a 100 mL round bottom flask under electromagnetic stirring, then 5-methoxyisatoic anhydride (1 mmol,193 mg) was added under ice water bath, reaction was continued at 0℃for 30 min and then at room temperature for 4 h, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) to give 168 mg as a white solid compound 3b (yield 80%).
Under electromagnetic stirring, 3b (0.5 mmol,105 mg), tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, the reaction was continued at room temperature for 30 min for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to give 129 mg as yellow solid compound 4b (77% yield).
In a dry reaction tube with magnetic stirring bar, compound 4b (0.1 mmol,33.5 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) to give 20.6. 20.6 mg as a yellow solid compound 1b (yield 65%). 1 H NMR (500 MHz，DMSO) δ 7.83 (s, 1H), 7.71–7.66 (m, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.37 (s, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 4.56 (s, 2H), 3.90 (s, 3H), 3.33 (s, 2H)。
3. Synthesis of Compound 1c
Acetonitrile (30 mL) and ethanolamine (1.5 mmol,91.6 mg) were sequentially added to a 100 mL round bottom flask under electromagnetic stirring, then 5-bromoisatoic anhydride (1 mmol,240.9 mg) was added under ice water bath, reaction was continued at room temperature for 4 h after 30 min at 0℃and the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) to afford compound 3c as a white solid 196 mg (76% yield).
Under electromagnetic stirring, 3c (0.5 mmol,129 mg), tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, the reaction was continued at room temperature for 30 min, 4H was continued, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to give 152 mg as a white solid compound 4c (79% yield).
In a dry reaction tube with magnetic stirring bar, compound 4c (0.1 mmol,38.3 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) to give 28.4. 28.4 mg as a white solid compound 1c (yield 78%). 1H NMR (500 MHz, CDCl) 3 ) δ 8.38 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.53 (s, 1H), 7.35 (s, 2H), 7.20 (s, 1H), 4.64 (s, 2H), 4.42 (s, 2H)。
4. Synthesis of Compound 1d
Acetonitrile (30 mL) and ethanolamine (1.5 mmol,91.6 mg) were sequentially added to a 100 mL round bottom flask under electromagnetic stirring, then 5-fluoroisatoic anhydride (1 mmol,181 mg) was added under ice-water bath, the reaction was continued at room temperature for 4 h after 30 min at 0℃and the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) to give 156.5. 156.5 mg as a white solid compound 3d (yield 79%).
Under electromagnetic stirring, 3d (0.5 mmol,99 mg), tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg) and p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice water bath, the reaction was continued at room temperature for 30 min for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to give 117.9. 117.9 mg as a yellow solid compound 4d (73% yield).
In a dry reaction tube with magnetic stirring bar, compound 4d (0.1 mmol,32.3 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) to give 25.9. 25.9 mg as a yellow solid compound 1d (yield 85%). 1H NMR (500 MHz, DMSO) δ8.26-8.18 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.50-7.44 (m, 1H), 7.44 (s, 1H), 7.37-7.32 (m, 2H), 7.16 (t, J=7.5 Hz, 1H), 4.55 (s, 4H).
5. Synthesis of Compound 1e
Acetonitrile (30 mL) and ethanolamine (1.5 mmol,91.6 mg) were added sequentially to a 100 mL round bottom flask under electromagnetic stirring, then 5-chloroisatoic anhydride (1 mmol,197 mg) was added under ice water bath, the reaction was continued at room temperature for 4h after 30 min at 0℃and the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) to give 188 mg as a white solid compound 3e (88% yield).
Under electromagnetic stirring, 3e (0.5 mmol,107 mg), tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, the reaction was continued at room temperature for 30 min for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to give 149 mg as yellow solid compound 4e (88% yield).
In a dry reaction tube with magnetic stirring bar, compound 4e (0.1 mmol,33.9 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) to give 26.3 mg as yellow solid compound 1e (yield 82%). 1 H NMR (500 MHz，DMSO) δ 8.04 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 4.54 (s, 4H)。
6. Synthesis of Compound 1f
Acetonitrile (30 mL) and ethanolamine (1.5 mmol,91.6 mg) were sequentially added to a 100 mL round bottom flask under electromagnetic stirring, then 5-methylisatoic anhydride (1 mmol,177 mg) was added under ice-water bath, reaction was continued at room temperature for 4 h after 30 min at 0℃and the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) gives 145.6 mg as a white solid compound 3f (75% yield).
Under electromagnetic stirring, 3f (0.5 mmol,97 mg), tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, the reaction was continued at room temperature for 30 min for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to give 138.8. 138.8 mg as a white solid compound 4f (yield 87%).
In a dry reaction tube with magnetic stirring bar, compound 4f (0.1 mmol,31.9 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) to give 22.3 mg as a white solid compound 1f (yield 74%). 1 H NMR (500 MHz，DMSO) δ 7.95 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.64 – 7.58 (m, 3H), 7.38 (s, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 4.54 (s, 4H), 2.45 (s, 3H)。
7. Synthesis of Compound 1g
Acetonitrile (30 mL) and ethanolamine (1.5 mmol,91.6 mg) were sequentially added to a 100 mL round bottom flask under electromagnetic stirring, then 4, 5-dimethoxy isatoic anhydride (1 mmol,223 mg) was added under ice water bath, reaction was continued at room temperature for 4 h after 30 min at 0℃and the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) to give 187.3 mg as a white solid compound 3g (yield 78%).
3g (0.5 mmol,120 mg) of the compound, tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg) and paratoluenesulfonic acid hydrate (0.25 mmol,47.5 mg) are sequentially added to a 100 mL round-bottomed flask under electromagnetic stirring, the mixture is reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) is added under ice-water bath, the reaction is continued for 30 min for 4H at room temperature, the solvent is removed under reduced pressure after the reaction is completed, and the obtained crude product is purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to give 158.8. 158.8 mg as yellow solid compound 4g (yield 87%).
In a dry reaction tube with magnetic stirring bar, 4g (0.1 mmol,36.5 mg) of the compound, iron phthalocyanine (0.01 mmol,5.7 mg) and tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was carried out at 150℃for 12 hours, after the completion of the TLC monitoring, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) to give 19.1 g of compound (mg) as a yellow solid (yield 55%). 1 H NMR (500 MHz，CDCl 3 ) δ 7.74 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7.40–7.33 (m, 2H), 7.22–7.19 (m, 1H), 7.18 (d, J = 5.0 Hz, 1H), 4.67 (t, J = 6.0 Hz, 2H), 4.49–4.42 (m, 2H), 4.03 (s, 3H), 4.02 (s, 3H)。
8. Synthesis of Compound 1h
Acetonitrile (30 mL) and ethanolamine (1.5 mmol,91.6 mg) were sequentially added to a 100 mL round bottom flask under electromagnetic stirring, then 4-bromoisatoic anhydride (1 mmol,240.9 mg) was added under ice water bath, reaction was continued at room temperature for 4 h after 30 min at 0℃and the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) to give 190.9 mg as a white solid compound 3h (yield 74%).
Under electromagnetic stirring, the compound 3H (0.5 mmol,129 mg), tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were successively added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere with 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, after 30 min the reaction was continued at room temperature with 4H, after the reaction was completed the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) gave 153.2. 153.2 mg as a yellow solid compound for 4h (80% yield).
In a dry reaction tube with magnetic stirring bar, the compound (0.1 mmol,38.3 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were added successively, the reaction was carried out at 150℃for 12 hours, after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) to give 21.9. 21.9 mg as a yellow solid compound 1h (yield 60%). 1 H NMR (500 MHz，CDCl 3 ) δ 8.11 (d, J = 5.0 Hz, 1H), 7.91 (s, 1H), 7.74 (d, J = 6.5 Hz, 1H), 7.57–7.49 (m, 2H), 7.36 (s, 2H), 7.20 (s, 1H), 4.64 (s, 2H), 4.43 (s, 2H)。
9. Synthesis of Compound 1i
Acetonitrile (30 mL) and ethanolamine (1.5 mmol,91.6 mg) were sequentially added to a 100 mL round bottom flask under electromagnetic stirring, then 4-fluoroisatoic anhydride (1 mmol,181 mg) was added under ice-water bath, the reaction was continued at room temperature for 4h after 30 min at 0℃and the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) to give 164.4 mg as a white solid compound 3i (yield 83%).
Under electromagnetic stirring, 3i (0.5 mmol,99 mg), tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, the reaction was continued at room temperature for 30 min for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to afford 150 mg as a white solid compound 4i (93% yield).
In a dry reaction tube with magnetic stirring bar, compound 4i (0.1 mmol,32.3 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) to give 22 mg as a white solid compound 1i (yield 72%). 1 H NMR (500 MHz，DMSO) δ 8.21 (t, J = 7.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 10.5 Hz, 1H), 7.43 (s, 1H), 7.34 (d, J = 6.5 Hz, 2H), 7.15 (t, J = 7.5 Hz, 1H), 4.55 (s, 4H)。
10. Synthesis of Compound 1j
Acetonitrile (30 mL) and ethanolamine (1.5 mmol,91.6 mg) were added sequentially to a 100 mL round bottom flask under electromagnetic stirring, then 4-chloroisatoic anhydride (1 mmol,197 mg) was added under ice water bath, the reaction was continued at room temperature for 4 h after 30 min at 0℃and the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) gives 177.6 mg as a white solid compound 3j (83% yield).
Under electromagnetic stirring, 3j (0.5 mmol,107 mg), tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, the reaction was continued at room temperature for 30 min for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to give 135.6. 135.6 mg as a white solid compound 4j (yield 80%).
In a dry reaction tube with magnetic stirring bar, compound 4j (0.1 mmol,33.9 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) gave 22.5. 22.5 mg as a white solid compound 1j (70% yield). 1 H NMR (500 MHz，DMSO) δ 8.13 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 10.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.43 (s, 1H), 7.33 (s, 1H), 7.16 (d, J = 7.0Hz, 1H), 4.54 (s, 4H)。
11. Synthesis of Compound 1k
Acetonitrile (30 mL) and ethanolamine (1.5 mmol,91.6 mg) were sequentially added to a 100 mL round bottom flask under electromagnetic stirring, then 3-methylisatoic anhydride (1 mmol,177 mg) was added under ice-water bath, reaction was continued at room temperature for 4 h after 30 min at 0℃and the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) gives 149.5 mg as a white solid compound 3k (77% yield).
Under electromagnetic stirring, 3k (0.5 mmol,97 mg) of the compound, tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg) and p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, after 30 min of reaction, the reaction was continued at room temperature for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) gives 118 mg as a yellow solid compound 4k (yield 74%).
In a dry reaction tube with magnetic stirring bar, compound 4k (0.1 mmol,31.9 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) to give 18.7. 18.7 mg as yellow solid compound 1k (yield 62%). 1 H NMR (500 MHz，DMSO) δ 8.00 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.0 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 4.54 (s, 4H), 2.62 (s, 3H)。
12. Synthesis of Compound 1l
Acetonitrile (30 mL) and ethanolamine (1.5 mmol,91.6 mg) were added sequentially to a 100 mL round bottom flask under electromagnetic stirring, then 3-methoxyisatoic anhydride (1 mmol,193 mg) was added under ice water bath, reaction was continued at 0℃for 30 min and then at room temperature for 4 h, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) to give 159.6. 159.6 mg as a white solid compound 3l (yield 76%).
3l (0.5 mmol,105 mg) of the compound, tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg) and paratoluenesulfonic acid hydrate (0.25 mmol,47.5 mg) are sequentially added to a 100 mL round-bottomed flask under electromagnetic stirring, the mixture is reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) is added under ice-water bath, the reaction is continued for 30 min for 4H at room temperature, the solvent is removed under reduced pressure after the reaction is completed, and the obtained crude product is purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to give 134 mg as a yellow solid compound 4l (yield 80%).
In a dry reaction tube with magnetic stirring bar, 4l (0.1 mmol,33.5 mg) of the compound, iron phthalocyanine (0.01 mmol,5.7 mg) and tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was carried out at 150℃for 12 hours, after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) to give 21.6. 21.6 mg as yellow solid compound 1l (yield 68%). 1 H NMR (500 MHz，DMSO) δ 7.73 (t, J = 7.0 Hz, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.44 – 7.36 (m, 3H), 7.32 (t, J = 7.8 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 4.55 (s, 4H), 3.97 (s, 3H)。
13. Synthesis of Compound 1m
Under electromagnetic stirring, compound 3a (0.5 mmol,90 mg), tetrahydrofuran (30 mL), 6-chloro-1H-indole-2-carbaldehyde (0.75 mmol,134.2 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), paratoluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, after 30 min of reaction, the reaction was continued at room temperature for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to give 142.4 mg as a yellow solid compound 4m (84% yield).
In a dry reaction tube with magnetic stirring bar, compound 4m (0.1 mmol,33.9 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) gives 27 mg as a yellow solid compound 1m (84% yield). 1 H NMR (500 MHz，DMSO) δ 8.15 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.77 (s, 1H), 7.70 (t, J = 9.0 Hz, 2H), 7.49 (t, J = 7.5Hz, 1H), 7.43 (s, 1H), 7.15 (d, J = 8.5 Hz, 1H), 4.55 (s, 4H)。
14. Synthesis of Compound 1n
Compound 3a (0.5 mmol,90 mg), tetrahydrofuran (30 mL), 5-chloro-1H-indole-2-carbaldehyde (0.75 mmol,134.2 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), p-toluenesulfonic acid hydrate (0.25 mm) were stirred electromagneticallyol,47.5, mg), was successively introduced into a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4 h, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice water bath, the reaction was continued at room temperature for 30 min, the reaction was continued for 4 h at room temperature, the solvent was removed under reduced pressure after completion of the reaction, and the obtained crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to give 135.6. 135.6 mg as yellow solid compound 4n (yield 80%).
In a dry reaction tube with magnetic stirring bar, compound 4N (0.1 mmol,33.9 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) gave 22.8 mg as yellow solid compound 1n (yield 74%). 1 H NMR (500 MHz，DMSO) δ 8.16 (t, J = 8.5 Hz, 1H), 7.85–7.77 (m, 2H), 7.74–7.69 (m, 1H), 7.68–7.61 (m, 1H), 7.5–7.47 (m, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.31 (t, J = 8.8 Hz, 1H), 4.55 (d, J = 8.5 Hz, 4H)。
15. Synthesis of Compound 1o
Under electromagnetic stirring, compound 3a (0.5 mmol,90 mg), tetrahydrofuran (30 mL), 6-bromo-1H-indole-2-carbaldehyde (0.75 mmol,167.2 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), paratoluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, after 30 min the reaction was continued for 4H at room temperature, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to give 141.7 mg as a yellow solid compound 4o (yield 74%).
In a dry reaction tube with magnetic stirring bar, compound 4o (0.1 mmol,38.3 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were added successively, the reaction was carried out at 150℃for 12 hours, after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) to give 25.2. 25.2 mg as a white solid compound 1o (yield 69%). 1 H NMR (500 MHz，DMSO) δ 8.15 (d, J = 8.0Hz, 1H), 7.92 (s, 1H), 7.82 (t, J = 7.7 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.42 (s, 1H), 7.27–7.25 (m, 1H), 4.55 (s, 4H)。
16. Synthesis of Compound 1p
Under electromagnetic stirring, compound 3a (0.5 mmol,90 mg), tetrahydrofuran (30 mL), 5-chloro-1H-indole-2-carbaldehyde (0.75 mmol,119.3 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), paratoluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, after 30 min of reaction, the reaction was continued at room temperature for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to give 132.4 mg as a yellow solid compound 4p (yield 83%).
In a dry reaction tube with magnetic stirring bar, compound 4p (0.1 mmol,31.9 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloro-sMethane : V Petroleum ether =3:1) to give 21.1. 21.1 mg as a white solid compound 1p (yield 70%). 1 H NMR (500 MHz，DMSO) δ 8.17 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.50 (s, 3H), 7.34 (s, 1H), 7.16 (d, J = 8.5 Hz, 1H), 4.53 (d, J = 14.5 Hz, 4H), 2.41 (s, 3H)。
17. Synthesis of Compound 1q
Under electromagnetic stirring, compound 3a (0.5 mmol,90 mg), tetrahydrofuran (30 mL), 4-methoxy-1H-indole-2-carbaldehyde (0.75 mmol,131.3 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), paratoluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere with 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, after 30 min of reaction, the reaction was continued at room temperature with 4H, after completion of the reaction the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) to give 137.4 mg as a yellow solid compound 4q (yield 82%).
In a dry reaction tube with magnetic stirring bar, compound 4q (0.1 mmol,.5 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) to give 19.6 mg as yellow solid compound 1q (yield 62%). 1 H NMR (500 MHz，DMSO) 8.16 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.36 (s, 1H), 7.25 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 6.63 (d, J = 7.5 Hz, 1H), 4.57– 4.48 (m, 4H), 3.93 (s, 3H)。
18. Synthesis of Compound 1r
Under electromagnetic stirring, compound 3a (0.5 mmol,90 mg), tetrahydrofuran (30 mL), 5-methoxy-1H-indole-2-carbaldehyde (0.75 mmol,131.3 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), paratoluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, after 30 min of reaction, the reaction was continued at room temperature for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) gives 117 mg as a yellow solid compound 4r (70% yield).
In a dry reaction tube with magnetic stirring bar, compound 4r (0.1 mmol,33.5 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) to give 21.6 mg as yellow solid compound 1r (yield 68%). 1 H NMR (500 MHz，DMSO) δ 8.16 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.53–7.46 (m, 2H), 7.33 (s, 1H), 7.18 (d, J = 2.5 Hz, 1H), 6.98–6.96 (m, 1H), 4.57–4.52 (m, 2H), 4.51–4.48 (m, 2H), 3.80 (s, 3H)。
19. Synthesis of Compound 1s
Compound 3d (0.5 mmol,99 mg), tetrahydrofuran (30 mL), 5-methoxy-1H-indole-2-carbaldehyde (0.75 mmol,131.3 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), p-toluene were stirred electromagneticallySulfonic acid hydrate (0.25 mmol,47.5 mg) was added sequentially to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4 h, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice water bath, the reaction was continued for 30 min at room temperature for 4 h, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =100:3) gave 130.7. 130.7 mg as yellow solid compound 4s (yield 74%).
In a dry reaction tube with magnetic stirring bar, compound 4s (0.1 mmol,35.3 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was completed at 150℃and after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Petroleum ether =3:1) gave 24.1 mg as a yellow solid compound 1s (yield 72%). 1 H NMR (500 MHz，CDCl 3 ) δ 7.92 (dd, J = 8.5, 3.0 Hz, 1H), 7.74 (q, J = 4.5 Hz, 1H), 7.49 –7.45 (m, 1H), 7.44 (s, 1H), 7.28 (s, 1H), 7.12 (d, J = 2.5 Hz, 1H), 7.03 – 7.01 (m, 1H), 4.65 (t, J = 5.8 Hz, 2H), 4.40 (t, J = 5.8 Hz, 2H), 3.88 (s, 3H)。
20. Synthesis of Compound 1t
Acetonitrile (30 mL) and 2-amino-1, 3-propanediol (1.5 mmol,136.6 mg) were added sequentially to a 100 mL round bottom flask under electromagnetic stirring, isatoic anhydride (1 mmol,163 mg) was then added under ice water bath, reaction was continued at 0℃for 30 min and then at room temperature for 4 h, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =40:1) gives 172.2. 172.2 mg as a white solid compound 3t (82% yield).
Compound 3t (0.5 mmol,105 mg), tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde are stirred electromagnetically (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), paratoluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were successively added to a 100 mL round bottom flask, the mixture was reacted under nitrogen atmosphere at room temperature for 4 h, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under an ice water bath, the reaction was continued for 30 min, the reaction was continued at room temperature for 4 h, the solvent was removed under reduced pressure after the reaction was completed, and the obtained crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) to give 142.4 mg as a yellow solid compound 4t (yield 85%).
In a dry reaction tube with magnetic stirring bar, compound 4t (0.1 mmol,33.5 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was carried out at 150℃for 24 hours, after the completion of the TLC monitoring, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Methanol =200:1) gave 26 mg as yellow solid compound 1t (82% yield). 1 H NMR (500 MHz，DMSO) δ 8.19 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.76–7.70 (m, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 5.44–5.34 (m, 2H), 4.99–4.96 (m, 2H), 4.38–4.35 (m, 2H), 3.48 (d, J = 9.5 Hz, 1H), 3.25 (d, J = 8.5 Hz, 1H)。
21. Synthesis of Compound 1u
Acetonitrile (30 mL) and 2-amino-1, 3-propanediol (1.5 mmol,136.6 mg) were added sequentially to a 100 mL round bottom flask under electromagnetic stirring, then 5-fluoroisatoic anhydride (1 mmol,181 mg) was added under ice water bath, reaction was continued at room temperature for 4 h after 30 min at 0deg.C, the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =40:1) to give 150.5. 150.5 mg as a white solid compound 3u (yieldRate 66%).
Under electromagnetic stirring, 3t (0.5 mmol,114 mg), tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, the reaction was continued at room temperature for 30 min for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) to give 130.6 mg as yellow solid compound 4u (yield 74%).
In a dry reaction tube with magnetic stirring bar, compound 4u (0.1 mmol,35.3 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was carried out at 150℃for 24 hours, after the completion of the TLC monitoring, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Methanol =200:1) to give 23.9 mg as yellow solid compound 1u (yield 68%). 1 H NMR (500 MHz，DMSO) δ 7.88–7.86 (m, 1H), 7.81–7.79 (m, 1H), 7.77–7.72 (m, 2H), 7.63 (d, J = 8.5 Hz, 1H), 7.41 (s, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 5.37 (t, J = 6.0 Hz, 2H), 4.97 (d, J = 6.5 Hz, 1H), 4.37–4.34 (m, 1H), 3.50–3.46 (m, 1H), 3.28–3.22 (m, 1H)。
22. Synthesis of Compound 1v
Acetonitrile (30 mL) and 2-amino-1, 3-propanediol (1.5 mmol,136.6 mg) are sequentially added into a 100 mL round bottom flask under electromagnetic stirring, then 5-bromoisatoic anhydride (1 mmol,241 mg) is added under ice water bath, reaction is continued at room temperature for 4 h after 30 min at 0 ℃, the solvent is removed under reduced pressure, and the obtained crude product is purified by silica gel column chromatographyEluent V Dichloromethane (dichloromethane) : V Methanol =40:1) gives 178.6 mg as a white solid compound 3v (62% yield).
Under electromagnetic stirring, 3V (0.5 mmol,144 mg), tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, the reaction was continued at room temperature for 30 min for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) gives 185.9 mg as a green solid compound 4v (yield 90%).
In a dry reaction tube with magnetic stirring bar, compound 4V (0.1 mmol,41.3 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were added successively, the reaction was carried out at 150℃for 24 hours, after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Methanol =200:1) gives 32.8 mg as a green solid compound 1v (83% yield). 1 H NMR (500 MHz，DMSO) δ 8.25 (s, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.67–7.62 (m, 2H), 7.43 (s, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 5.36 (d, J = 6.0 Hz, 2H), 4.96 (d, J = 6.5 Hz, 1H), 4.37–4.33 (m, 1H), 3.50–3.46 (m, 1H), 3.28–3.18 (m, 1H)。
23. Synthesis of Compound 1w
Acetonitrile (30 mL) and 2-amino-1, 3-propanediol (1.5 mmol,136.6 mg) were added sequentially to a 100 mL round bottom flask with electromagnetic stirring, then 5-methoxyisatoic anhydride (1 mmol,193 mg) was added under an ice water bath, inReacting at 0deg.C for 30 min, reacting at room temperature for 4 h, removing solvent under reduced pressure, purifying the crude product by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =40:1) to afford compound 3w as a white solid of 136.86 mg (57% yield).
Under electromagnetic stirring, 3w (0.5 mmol,120 mg) of the compound, tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg) and p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, after 30 min of reaction, the reaction was continued at room temperature for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) to give 142.4 mg as a yellow solid compound 4w (78% yield).
In a dry reaction tube with magnetic stirring bar, compound 4w (0.1 mmol,36.5 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was carried out at 150℃for 24 hours, after the completion of the TLC monitoring, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Methanol =200:1) gave 24.3 mg as yellow solid compound 1w (70% yield). 1 H NMR (500 MHz，DMSO) δ 7.73–7.66 (m, 2H), 7.62 (d, J = 8.5 Hz, 1H), 7.59–7.55 (m, 1H), 7.45 –7.48 (m, 1H), 7.37–7.28 (m, 2H), 7.15 (t, J = 7.5 Hz, 1H), 5.35–5.40 (m, 2H), 4.96 (d, J = 13.0 Hz, 1H), 4.33–4.36 (m, 1H), 3.90 (s, 3H), 3.45–3.49 (m, 1H), 3.20–3.26 (m, 1H)。
24. Synthesis of Compound 1x
Acetonitrile (30 mL) and 2-amino-1, 3-propanediol (1.5 mmol,136.6 mg) were stirred electromagneticallyAdded into a 100 mL round bottom flask, then added with 3-methyl isatoic anhydride (1 mmol,177 mg) under ice water bath, reacted for 30 min at 0 ℃ and then reacted for 4 h at room temperature, the solvent is removed under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =40:1) gives 121 mg as a white solid compound 3x (54% yield).
Under electromagnetic stirring, 3X (0.5 mmol,112 mg), tetrahydrofuran (30 mL), 1H-indole-2-carbaldehyde (0.75 mmol,109 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), and p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, the reaction was continued at room temperature for 30 min for 4H, the solvent was removed under reduced pressure after the reaction was completed, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) gave 153.6 mg as yellow solid compound 4x (88% yield).
In a dry reaction tube with magnetic stirring bar, compound 4x (0.1 mmol,34.9 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were added successively, the reaction was carried out at 150℃for 24 hours, after the TLC monitoring the reaction was completed, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Methanol =200:1) gives 16.6 mg as a yellow solid compound 1x (yield 50%). 1 H NMR (500 MHz，DMSO) δ 8.03 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 5.37 (t, J = 5.5 Hz, 2H), 4.97 (d, J = 6.5 Hz, 1H), 4.37–4.34 (m, 1H), 3.50–3.46 (m, 1H), 3.26–3.13 (m, 1H), 2.64 (s, 3H)。
25. Synthesis of Compound 1y
Under electromagnetic stirring, 3t (0.5 mmol,105 mg) of the compound, tetrahydrofuran (30 mL), 6-bromo-1H-indole-2-carbaldehyde (0.75 mmol,167.2 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg) and p-toluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were sequentially added to a 100 mL round bottom flask, the mixture was reacted at room temperature under nitrogen atmosphere for 4H, then 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) was added under ice-water bath, after 30 min of reaction, the reaction was continued at room temperature for 4H, after completion of the reaction the solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) gave 165.2 mg as yellow solid compound 4y (80% yield).
In a dry reaction tube with magnetic stirring bar, compound 4y (0.1 mmol,41.3 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was carried out at 150℃for 24 hours, after the completion of the TLC monitoring, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Methanol =200:1) to give 28.4. 28.4 mg as a yellow solid compound 1y (yield 72%). 1 H NMR (500 MHz，DMSO) δ 8.18 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.72–7.66 (m, 2H), 7.53 (t, J = 7.5 Hz, 1H), 7.42 (s, 1H), 7.28 (d, J = 8.5 Hz, 1H), 5.35 (s, 2H), 5.00 (t, J = 14.8 Hz, 1H), 4.39–4.28 (m, 1H), 3.49–4.45 (m, 1H), 3.33– 3.22 (m, 1H)。
26. Synthesis of Compound 1z
Under electromagnetic stirring, compound 3t (0.5 mmol,105 mg), tetrahydrofuran (30 mL), 6-chloro-1H-indole-2-carbaldehyde (0.75 mmol,134.5 mg), anhydrous magnesium sulfate (1.65 mmol,198.6 mg), paratoluenesulfonic acid hydrate (0.25 mmol,47.5 mg) were added sequentially to a 100 mL round bottom flask, the mixture was stirred in a flaskReacting at room temperature under nitrogen atmosphere for 4 h, adding 2, 3-dichloro-5, 6-dicyanobenzoquinone (0.6 mmol,136 mg) under ice-water bath, reacting for 30 min, continuing to react at room temperature for 4 h, removing solvent under reduced pressure after the reaction is complete, purifying the obtained crude product by silica gel column chromatography (eluent: V) Dichloromethane (dichloromethane) : V Methanol =50:1) gave 156.8 mg as yellow solid compound 4z (85% yield).
In a dry reaction tube with magnetic stirring bar, compound 4z (0.1 mmol,36.9 mg), iron phthalocyanine (0.01 mmol,5.7 mg), tripotassium phosphate (0.15 mmol,31.8 mg), N, N-dimethylformamide (1 mL) were successively added, the reaction was carried out at 150℃for 24 hours, after the completion of the TLC monitoring, the reaction solution was extracted with water and methylene chloride, the solvent was removed under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: V Dichloromethane (dichloromethane) : V Methanol =200:1) gave 26.3 mg as yellow solid compound 1z (75% yield). 1 H NMR (500 MHz，DMSO) δ 8.19 (d, J = 8.0 Hz, 1H), 7.87–7.81 (m, 2H), 7.73 (t, J = 8.5 Hz, 2H), 7.53 (t, J = 7.5 Hz, 1H), 7.43 (s, 1H), 7.18–7.16 (m, 1H), 5.35 (t, J = 6.0 Hz, 2H), 5.00 (d, J = 6.5 Hz, 1H), 4.37–4.33 (m, 1H), 3.50–3.46 (m, 1H), 3.29–3.14 (m, 1H)。
And (3) performing primary screening on the anti-inflammatory activity of the target product. The anti-inflammatory activity evaluation method is determined by determining the inhibition of Lipopolysaccharide (LPS) -induced release of mouse macrophage RAW 264.7 NO by using Griess method. The results of the experiment for inhibiting lipopolysaccharide-induced release of NO by mouse macrophage RAW 264.7 with a part of the target compounds are shown in Table 1. The effect of the target compound on RAW 264.7 cell viability at a concentration of 25 μm is shown in table 2.
TABLE 1
Compounds of formula (I) Concentration of released NO (μmol/L)
LPS 20.68±0.34
1a 14.32±0.47
1b 15.01±0.27
1c 11.36±0.16
1i 14.77±0.31
1t 8.41±0.52
1u 6.13±0.28
1v 8.07±0.19
Indometacin 13.18±0.23
TABLE 2
Compounds of formula (I) Cell viability (%)
1a 88.37±2.58
1b 98.26±1.34
1c 103.48±1.76
1i 118.60±0.63
1t 122.09±4.29
1u 111.62±1.12
1v 97.67±2.46
Indometacin 111.04±3.31
From the above test results, the compound 1c,1t,1u,1v has better ability to inhibit the release of NO than the anti-inflammatory agent indomethacin, while 1a,1b,1i is equivalent to indomethacin when the concentration is 25 μm and the LPS concentration is 1 μg/mL; the compounds 1c,1t,1u and 1v with stronger NO release inhibiting ability have weaker cytotoxic effect on RAW 264.7 cells; has obvious anti-inflammatory effect and low toxicity.
While the invention has been described in detail in the foregoing general description and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.

Claims (5)

1. The rutaecarpine analogue is characterized in that the compound is simultaneously substituted at C2 and N3 positions of quinazolinone, and the structural general formula is as follows:wherein R is 1 And R is 2 Can be H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, amino, fluoro, chloro, bromo, trifluoromethyl; r is R 3 Can be H, methyl, hydroxymethyl, methoxymethyl.
2. The rutaecarpine analogue according to claim 1, characterized in that R 1 And R is 2 Can be H, methoxy, ethoxy, methyl, nitro, fluoro, chloro, bromo, trifluoromethyl; r is R 3 Can be H, methyl, hydroxymethyl, methoxymethyl.
3. The rutaecarpine analogue according to claim 1, characterized in that R 1 Can be H, methoxy, methyl, fluorine, chlorine and bromine; r is R 2 Can be H, methoxy, methyl, chlorine and bromine; r is R 3 Can be H or hydroxymethyl.
4. A method for preparing an analogue of rutaecarpine according to any one of claims 1-3, characterized by the specific steps of:
(1) The isatoic anhydride and the derivatives thereof are used as raw materials, and undergo an acylation reaction with ethanolamine and the derivatives thereof to generate benzamide derivatives, and the molecular structural formula is as follows:wherein R is 1 Is H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluoro, chloro, bromo, trifluoromethyl; r is R 3 Is H, methyl, hydroxymethyl, methoxymethyl;
(2) The 2-aminobenzamide derivative prepared in the step (1) and 1H-indole-2-formaldehyde and derivatives thereof undergo condensation reaction and oxidation reaction under acidic conditions to generate a 4 (3H) -quinazolinone derivative, and the molecular structural formula of the 4 (3H) -quinazolinone derivative is as follows:wherein R is 1 And R is 2 Can be H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluoro, chloro, bromo, trifluoromethyl; r is R 3 Is H, methyl, hydroxymethyl, methoxymethyl;
(3) Taking iron phthalocyanine as a catalyst, and carrying out intramolecular hydrogen borrowing reaction on the 4 (3H) -quinazolinone derivative prepared in the step (2) to generate evodiamine analogues and derivatives thereof, wherein the molecular structural formula is as follows:wherein R is 1 And R is 2 Can be H, methoxy, ethoxy, methyl, ethyl, phenyl, benzyl, nitro, fluoro, chloro, bromo, trifluoromethyl; r is R 3 Is H, methyl, hydroxymethyl, methoxymethyl.
5. Use of an rutaecarpine analogue according to any one of claims 1-3 for the preparation of an anti-inflammatory medicament.
CN202311796875.2A 2023-12-25 2023-12-25 Evodiamine analogue, and preparation method and application thereof Pending CN117800978A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202311796875.2A CN117800978A (en) 2023-12-25 2023-12-25 Evodiamine analogue, and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202311796875.2A CN117800978A (en) 2023-12-25 2023-12-25 Evodiamine analogue, and preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN117800978A true CN117800978A (en) 2024-04-02

Family

ID=90429310

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202311796875.2A Pending CN117800978A (en) 2023-12-25 2023-12-25 Evodiamine analogue, and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN117800978A (en)

Similar Documents

Publication Publication Date Title
Gupta et al. Substrate-controlled product-selectivity in the reaction of the Bestmann–Ohira reagent with N-unprotected isatin-derived olefins
US4426382A (en) 4-Amino-6,7-dimethoxy-2-piperazinylquinazoline derivatives, their preparation and use
FI59799B (en) NYTT FOERFARANDE FOER FRAMSTAELLNING AV 6,7-DIMETOXY-4-AMINO-2- (4- (2-FUROYL) -PIPERAZIN-1-YL) -QUINAZOLINE FOER ANVAENDNING SOM ETT ANTIHYPERTENSIVT MEDEL
JP6944682B2 (en) Method for producing benzimidazole compound
CN111848526B (en) Polysubstituted 1, 4-dihydropyridazine and pyridazine derivatives and synthetic method thereof
JP2020518661A5 (en)
CN117800978A (en) Evodiamine analogue, and preparation method and application thereof
CN112028808A (en) Preparation method of N-substituted-3-methylmercapto-4-morpholinyl maleimide compound
CN116283831A (en) P-nitrobenzene derivative and preparation method and application thereof
Aiello et al. Polycondensed nitrogen heterocycles. VII. 5, 6‐Dihydro‐7‐h‐pyrrolo [1, 2‐D]‐[1, 4] benzodiazepin‐6‐ones. A novel series of annelatcd 1, 4‐benzodiazepines
AU642182B2 (en) 5-(2-methyl-4,4,4-trifluorobutyl-carbamoyl)indole derivatives
CN113336703B (en) Synthesis of 1,3,4, 5-tetrasubstituted 1H-pyrazole derivatives
Shaikh et al. Boric acid catalyzed one-pot synthesis of [1, 2, 4] triazolo quinazolinone Derivatives
EP4215521A1 (en) Fused ring diimide derivative, preparation method therefor and use thereof
CN111808121A (en) Novel high-B-ring berberine analogue containing heteroatom and C-H activation synthesis method thereof
CN117800977A (en) Preparation method and application of 2, 3-condensed quinazolinone compound
CN101580492A (en) Method for preparing antiseptic triaryl-2-pyrazoline derivative by microwave
Shen et al. Catalyst-free synthesis of isoindolin-1-imine derivatives via multi-component reaction in water medium
CN110804007B (en) Polysubstituted pyrrole derivative and preparation method thereof
CN114920684B (en) Selenium-containing benzamide compound and synthetic method and application thereof
Maji et al. An Efficient Approach Towards the Synthesis of Nintedanib
CN116063230B (en) Sinomenine 1-position substituted derivative, and preparation method and application thereof
Kumar et al. Synthesis of some novel 1, 2, 4-triazolo [4, 3-a] 2h-pyrano [3, 2-e] pyridine derivatives
CN112724063B (en) Preparation method of 3-iodine-4-amido maleimide compound
CN115611901B (en) Azepine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof

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