Method for catalyzing indole compound to be converted into quinoline compound and application

Abstract

The invention belongs to the technical field of organic chemical medicines, and particularly relates to a method for catalyzing an indole compound to be converted into a quinoline compound and application of the quinoline compound. According to the method, the indole compound is used as a substrate, flavin small molecules are used as a catalyst, and catalytic conversion is carried out to obtain the corresponding quinoline compound. The method disclosed by the invention is mild in reaction condition, high in conversion rate, simple and convenient to operate, green and environment-friendly.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry and pharmaceutical technology, specifically relating to a method for catalyzing the conversion of indole compounds into quinoline compounds and its application. Background Technology

[0002] Compounds containing indole and / or quinoline skeletons are widely found in organisms such as plants, microorganisms, and animals. These compounds possess complex and diverse chemical structures and exhibit a variety of biological activities, such as antitumor, antihypertensive, anti-inflammatory, and antibacterial activity. Therefore, both the indole and quinoline rings are dominant core skeletons, playing important roles in drugs and pharmaceutical intermediates.

[0003] Catalytic conversion of indole-containing compounds to quinoline-containing compounds not only provides a new modification and derivatization scheme for indole-containing compounds but also offers an efficient preparation method for quinoline compounds, which is of great significance. Reported methods for converting indole-containing compounds to quinoline-containing compounds generally require strongly alkaline conditions such as t-BuOK, NaH, or the use of oxidants such as hydrogen peroxide or sodium periodate as catalysts. These reaction conditions are relatively harsh, with numerous side reactions and poor selectivity. There are also some reports of using enzymes to catalyze the conversion of indole rings to quinoline rings. However, few enzymes are known to catalyze the expansion of indole rings to quinoline rings, such as flavoprotein TsrE and cytochrome P450 monooxygenase PbaB. Furthermore, existing enzymes catalyzing the conversion of indole-containing compounds to quinoline-containing compounds have very limited substrates and suffer from low enzyme activity and poor substrate adaptability, making them unsuitable for the large-scale catalytic conversion of indole-containing compounds.

[0004] Therefore, developing a mild and environmentally friendly non-enzymatic catalytic method is of great significance for the structural modification and diversification of indole compounds, especially for the synthesis of drugs and their intermediates. Summary of the Invention

[0005] The purpose of this invention is to provide a method and application for catalytically converting indole compounds into quinoline compounds.

[0006] To achieve the above-mentioned objectives, the technical solution adopted in this invention is: a method for preparing quinoline compounds, using indole compounds as substrates and flavin small molecules as catalysts, to catalytically convert the quinoline compounds. The indole compounds may be indole-type monoterpenoid indole alkaloids; representative indole compounds may be strictosamide, vincosamide, yohimbine, geissoschizine methyl ether, or tadalafil, etc. The flavin small molecules are preferably any one or a combination of riboflavin, riboflavin mononucleotide, and riboflavin adenine dinucleotide; the flavin small molecules are further preferably riboflavin mononucleotide.

[0007] Preferably, the method includes the following steps: adding indole compounds and flavin molecules to a buffer solution, stirring and mixing, and reacting at 30–90°C for 2–24 hours. Preferably, the molar ratio of indole compounds to flavin molecules is 1:1; the pH of the reaction buffer solution is 6.8–10.6.

[0008] This invention offers the following advantages: It uses indole compounds (such as strictosamide, vincosamide, yohimbine, geissoschizine methyl ether, tadalafil, etc.) as substrates and small flavin molecules (mainly riboflavin, riboflavin mononucleotide, and riboflavin adenine dinucleotide) as catalysts to catalytically convert them into quinoline compounds. Compared to traditional methods, this invention does not rely on enzymes, oxidation catalysts, or alkaline conditions. The reaction system is green and environmentally friendly, easy to operate, has mild catalytic conditions, strong substrate adaptability, is applicable to a variety of indole compounds, has high conversion rates, clear pathways, and is easy to scale up and industrialize. Furthermore, this invention is not limited to indole-type monoterpenoid indole alkaloids; it can catalytically convert any indole-structured skeletal compound into its corresponding quinoline compound, demonstrating broad application prospects. Attached Figure Description

[0009] Figure 1 HPLC-DAD analysis of FMN-catalyzed conversion of strictosamide to pumiloside;

[0010] Figure 2 This is the standard curve for hydrogen peroxide.

[0011] Figure 3 This represents the change in hydrogen peroxide concentration over time during the reaction.

[0012] Figure 4 To analyze the effects of different gases on the reaction using HPLC-DAD;

[0013] Figure 5 The effects of different types of flavin molecules and reducing coenzymes on the reaction;

[0014] Figure 6 The effect of FMN concentration on the reaction;

[0015] Figure 7 The effect of reaction temperature on the reaction;

[0016] Figure 8 The effect of buffer type and pH on the reaction;

[0017] Figure 9 HPLC-DAD analysis of FMN-catalyzed conversion of vincosamide to (3R)-pumiloside;

[0018] Figure 10 The UV absorption spectrum of (3R)-pumiloside;

[0019] Figure 11 High-resolution mass spectrometry data of (3R)-pumiloside;

[0020] Figure 12 HPLC-DAD analysis of the product obtained by FMN-catalyzed yohimbine production;

[0021] Figure 13 The UV absorption spectrum of the product obtained by FMN-catalyzed yohimbine;

[0022] Figure 14 High-resolution mass spectrometry data of the product obtained by FMN-catalyzed yohimbine;

[0023] Figure 15 HPLC-DAD analysis of the product obtained by FMN-catalyzed geissoschizine;

[0024] Figure 16 UV absorption spectrum for obtaining the product of FMN-catalyzed geissoschizine;

[0025] Figure 17 High-resolution mass spectrometry data of the product obtained by FMN catalysis of geissoschizine;

[0026] Figure 18 HPLC-DAD analysis of the product obtained by FMN-catalyzed tadalafil;

[0027] Figure 19 The UV absorption spectrum of the product obtained by FMN-catalyzed tadalafil;

[0028] Figure 20High-resolution mass spectrometry data of the product obtained by FMN-catalyzed tadalafil. Detailed Implementation

[0029] This invention provides a method for catalytically converting indole compounds into quinoline compounds. The method uses indole-type monoterpenoid indole alkaloids as substrates and flavin small molecules as catalysts to carry out the catalytic conversion to obtain quinoline compounds.

[0030] The indole compounds include strictosamide (isovinylin lactam, C... 26 H 30 N2O8), vincosamide (C) 26 H 30 N2O8), yohimbine (C 21 H 26 N2O3), geissoschizine methyl ether (C 22 H 26 N2O3), tadalafil (C 22 H 19 Representative indole compounds include N3O4. The flavin small molecule is a class of organic compounds based on a pteridine structure, derived from an isorhozine ring. The flavin group often combines with adenosine diphosphate (ADP) to form riboflavin adenine dinucleotide (FAD), or with riboside or phosphate to form riboflavin mononucleotide (FMN). Both forms serve as cofactors for flavoproteins. The flavin small molecule can be any one or a combination of several of riboflavin, riboflavin mononucleotide, and riboflavin adenine dinucleotide. Quinoline compounds prepared using the method of this invention include: quinoline-type monoterpenoid indole alkaloid pumiloside (C... 26 H 28 N2O9), (3R)-pumiloside, etc.

[0031] The method specifically includes the following steps: stirring and mixing indole compounds, flavin molecules, and Tris-HCl buffer or Glycine-NaOH buffer (pH = 6.8–10.6) (preferably using Tris-HCl buffer with pH = 8), reacting at 4–90°C for 2–72 h until the substrate reaction is complete (TLC detection results can be used as the standard), and then the reaction is terminated.

[0032] The molar ratio of indole compounds to flavin molecules is 0.25:1 to 20:1; the preferred molar ratio is 1:1.

[0033] This invention also extends the above-mentioned flavin small molecule catalytic method to compounds containing indole structural skeletons, including yohimbine, geissoschizine methylether, and tadalafil.

[0034] The following will clearly and completely describe the conversion method, reaction optimization, and substrate applicability of flavin small molecules catalyzing the conversion of indole compounds to quinoline compounds, based on experimental data and spectra from the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the implementation content. Unless otherwise specified, the technical means used in the embodiments are all conventional means well known to those skilled in the art; unless otherwise specified, all data in this document are the average values ​​after at least three independent repeated experiments, and the data obtained from the repeated experiments have good reproducibility and consistency.

[0035] Example 1: FMN-catalyzed conversion of strictosamide to pumiloside

[0036] 1. The reaction equation is as follows:

[0037]

[0038] The 50 μL reaction system contained strictosamide (final concentration 200 μM), FMN (final concentration 200 μM), and 50 mM Tris-HCl buffer (pH 8.0). Each reaction solution was loaded into an EP tube and incubated at 37°C until the substrate reaction was complete for TLC detection (approximately 24 hours). After the reaction, the reaction solution was directly used for HPLC-DAD and HRMS analysis.

[0039] HPLC-DAD detection results are as follows Figure 1 As shown, the results indicate that the reaction produced a new product peak with an HPLC retention time consistent with that of the pumiloid standard. The UV spectrum of this product exhibits characteristic absorptions at 244, 314, and 327 nm, consistent with the UV characteristic absorptions of pumiloid. High-resolution mass spectrometry analysis shows that the molecular ion peak of this product is at m / z 535.1692 ([M+Na)). + This data is consistent with that of the pumiloside standard. These results indicate that the flavin molecule catalyzes an oxidative rearrangement of strictosamide, generating pumiloside with a quinoline backbone.

[0040] 2. A commercially available hydrogen peroxide detection kit was used to quantitatively detect the amount of hydrogen peroxide generated during the reaction process. Following the kit instructions, a standard curve was plotted at 595 nm using 0–40 μM hydrogen peroxide standard solutions. Every 1 hour, 20 μL of sample was taken from the reaction solution, and 200 μL of dye working solution was added. The mixture was incubated at room temperature for 20 min. The absorbance at 595 nm was read using a microplate reader. A standard curve was plotted at 595 nm. Figure 2 As shown.

[0041] Using the standard curve, calculate the hydrogen peroxide concentration in the flavin-catalyzed reaction of strictosamide to pumiloside, such as... Figure 3 As shown, the results indicate that oxygen is converted into hydrogen peroxide during the reaction, and the concentration of hydrogen peroxide continues to increase during the reaction.

[0042] Example 2: Effects of reaction conditions and other factors on the catalytic conversion of strictosamide to pumiloside by flavin small molecules

[0043] 1. Effect of the reaction on oxygen dependence

[0044] The reactions in Example 1 were carried out under argon, air, and oxygen conditions, respectively. Following the reaction system conditions and reactant amounts in Example 1, 5 mL of a reaction system using strictosamide as the substrate and FMN as the catalyst was prepared in a 25 mL flask. The flask was then evacuated, and three treatments were set up, each purged with argon, air, or oxygen, respectively, repeated three times to ensure complete gas replacement. Each reaction system was then stirred on a magnetic stirrer and reacted at 37°C for 2 h. The products were analyzed by HPLC-DAD and HRMS, and the results are as follows. Figure 4 As shown.

[0045] The results showed that pumiloside was almost undetectable in an argon atmosphere; the reaction efficiency was highest in air, while the yield decreased under pure oxygen conditions, indicating that excessive oxygen may inhibit the reaction.

[0046] 2. The effect of flavin small molecule type on the reaction

[0047] Following the method in Example 1, with all other conditions exactly the same, the small flavin molecule FMN was replaced in equal amounts with FAD or riboflavin. The results are as follows: Figure 5 As shown.

[0048] The results showed that all three flavin molecules could catalyze the conversion of strictosamide to pumiloside, but the conversion rates differed significantly: FMN exhibited the highest catalytic activity with a product yield of 45%, FAD-catalyzed product yield was 2.5%, and riboflavin-catalyzed product yield was 10%. Therefore, FMN was determined to be the optimal catalytic molecule.

[0049] 3. The effect of reduced coenzyme on the reaction

[0050] Following the method of Example 1, with all other conditions exactly the same, an additional 5 mM NADPH or NADH was added to the reaction system. The results are as follows: Figure 5 As shown.

[0051] The results showed that even with the addition of NADPH or NADH, pumiloside could still be obtained, but the product pumiloside was significantly reduced. This indicates that the strictosamide oxidation reaction mediated by flavin molecules does not depend on reducing coenzymes such as NAD(P)H and belongs to the direct dehydrogenation type of oxidation reaction.

[0052] 4. Effect of flavin small molecule concentration on the reaction

[0053] Following the method in Example 1, with all other conditions identical, the FMN concentrations were set to 0.05, 0.1, 0.2, 0.5, 1, 2, and 4 mM, and the reaction was carried out at 37°C for 2 hours before HPLC detection. The results are as follows... Figure 6 As shown.

[0054] The results showed that pumiloside could be obtained using different concentrations of FMN; the reaction was optimal and the yield was highest at a concentration of 200 μM (molar ratio of FMN to strictosamide was 1:1).

[0055] 5. The effect of reaction temperature on the reaction

[0056] Following the method of Example 1, with all other conditions identical, the reaction temperature was set in a 10°C gradient, ranging from 10 to 90°C. Product yield was measured after 2 hours. Results are as follows... Figure 7 As shown.

[0057] The results showed that all reactions could proceed and pumiloside could be obtained at the tested reaction temperatures. The yield increased sharply when the temperature was above 40℃, and the optimal reaction temperature was 50-70℃. Excessively high temperatures may lead to a decrease in FMN stability, which in turn leads to a decrease in yield.

[0058] 6. The effect of buffer type and reaction pH on the reaction

[0059] Following the method of Example 1, with all other conditions identical, the pH of Tris-HCl was set to 6.8, 7.5, and 8.0, respectively. Following the method of Example 1, with all other conditions identical, Tris-HCl was replaced with an equal amount of Glycine-NaOH, and the pH of the Glycine-NaOH was set to 8.8, 9.5, 10.0, and 10.6, respectively. The product yield was measured after each group reacted for 2 hours. The results are as follows... Figure 8 As shown.

[0060] The results showed that the reaction could be completed using different buffers; the highest yield was achieved using Tris-HCl buffer at pH 8.0, which may be because the specific buffer at this pH is more suitable for the stable existence of FMN and the maintenance of substrate ion state.

[0061] Example 3: Flavin small molecules catalyze the conversion of other indole compounds to obtain quinoline compounds.

[0062] 1. Flavin molecule catalyzes the conversion of indole-type monoterpenoid indole alkaloid vincosamide to quinoline-type monoterpenoid indole alkaloid (3R)-pumiloside. The reaction equation is as follows:

[0063]

[0064] The reaction system was the same as in Example 1: a 50 μL reaction system containing vincosamide (final concentration 200 μM), flavin small molecule FMN (final concentration 200 μM), and 50 mM Tris-HCl buffer (pH = 8.0), and reacted at 37°C for 24 h. After the reaction, the product was analyzed by HPLC-DAD. Figure 9 and Figure 10 ) and HPLC-DAD-HRMS ( Figure 11 Analysis showed that the new product had an m / z of 513.1886, an increase of 14 Da compared to the substrate. Figure 11 HPLC-DAD analysis showed that the characteristic UV absorption of the reaction product red-shifted from 280 nm to 311 nm and 324 nm. Figure 10 The product exhibits UV absorption characteristics consistent with quinoline compounds and was identified as (3R)-pumiloside.

[0065] 2. Flavin molecule catalyzes the conversion of indole-type monoterpenoid indole alkaloid yohimbine to neoquinoline-type monoterpenoid indole alkaloid. The reaction equation is as follows:

[0066]

[0067] The reaction system was the same as in Example 1: a 50 μL reaction system containing yohimbine (final concentration 200 μM), flavin small molecule FMN (final concentration 200 μM), and 50 mM Tris-HCl buffer (pH = 8.0). The mixture was incubated at 37°C for 24 h. After the reaction, the product was analyzed by HPLC-DAD. Figure 12 and Figure 13 ) and HPLC-DAD-HRMS ( Figure 14 Analysis. HPLC-DAD-HRMS results showed that the new product had an m / z of 369.1811, an increase of 14 Da in molecular weight compared to the substrate. Figure 11 HPLC-DAD analysis showed that the UV absorption of the reaction product red-shifted from 266 nm to 306 nm and 322 nm. Figure 13 The product exhibits UV absorption characteristics consistent with quinoline compounds and was identified as methyl(5bS,6aS,7R,8S,10aR)-8-hydroxy-14-oxo-5,5b,6,6a,7,8,9,10,10a,11,13,14-dodecahydrobenzo[6,7]indolizino[1,2-b]quinoline-7-carboxylate. The NMR data for this product are shown in Table 1.

[0068] Table 1 Comparison of Product NMR Data

[0069]

[0070]

[0071] 3. Flavin molecule catalyzes the conversion of indole-type monoterpenoid indole alkaloid geissoschizine methyl ether into neoquinoline-type monoterpenoid indole alkaloids. The reaction equation is as follows:

[0072]

[0073] The reaction system was the same as in Example 1: a 50 μL reaction system containing geissoschizine methyl ether (final concentration 200 μM), flavin small molecule FMN (final concentration 200 μM), and 50 mM Tris-HCl buffer (pH = 8.0), and reacted at 37°C for 24 h. After the reaction, the product was analyzed by HPLC-DAD. Figure 15 and Figure 16 ) and HPLC-DAD-HRMS ( Figure 17 Analysis showed that the new product had an m / z of 381.1819, an increase of 14 Da compared to the substrate. Figure 17 HPLC-DAD analysis showed that the UV absorption of the reaction product red-shifted from 280 nm to 311 nm and 324 nm. Figure 16 The product exhibits UV absorption characteristics consistent with quinoline compounds and has been identified as methyl(E)-2-((5bS,7S,Z)-8-ethylidene-12-oxo-5,5b,6,7,8,9,11,12-octa hydroindolizino[1,2-b]quinolin-7-yl)-3-methoxyacrylate.

[0074] 4. Flavin molecule catalyzes the conversion of indole-type compound tadalafil to quinoline-type compound. The reaction equation is as follows:

[0075]

[0076] The reaction system design was consistent with Example 1: a 50 μL reaction system containing tadalafil (final concentration 200 μM), flavin small molecule FMN (final concentration 200 μM), and 50 mM Tris-HCl buffer (pH = 8.0), mixed thoroughly, and reacted at 37°C for 24 h. After the reaction, the product was analyzed by HPLC-DAD. Figure 18 and Figure 19 ) and HPLC-DAD-HRMS ( Figure 20 Analysis. HPLC-DAD-HRMS results showed that the new product had an m / z of 404.1239, an increase of 14 Da in molecular weight compared to the substrate. Figure 20 HPLC-DAD analysis showed that the characteristic UV absorption of the reaction product red-shifted from 280 nm to 311 nm and 324 nm. Figure 19 The product exhibits UV absorption characteristics consistent with quinoline compounds and has been identified as (6R,12bR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,7,12b-tetrahydropyrazino[1',2':1,5]pyrrolo[3,4-b]quinoline-1,4,12(6H)-trione.

[0077] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Any modifications, alterations, substitutions, or variations made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention shall fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for preparing quinoline compounds, characterized in that: Using indole compounds as substrates and flavin molecules as catalysts, the quinoline compounds were obtained through catalytic conversion.

2. The method according to claim 1, characterized in that: The indole compounds are indole-type monoterpenoid indole alkaloids.

3. The method according to claim 2, characterized in that: The indole-type monoterpenoid indole alkaloids are strictosamide, vincosamide, yohimbine, or geissoschizine methyl ether.

4. The method according to claim 1, characterized in that: The indole compound is tadalafil.

5. The method according to any one of claims 1 to 4, characterized in that: The flavin molecule is any one or a combination of several of riboflavin, riboflavin mononucleotide, and riboflavin adenine dinucleotide.

6. The method according to any one of claims 1 to 4, characterized in that: The method includes the following steps: adding indole compounds and flavin molecules to a buffer solution, stirring and mixing, and reacting at 4–90°C until the substrate has completely reacted.

7. The method according to any one of claims 1 to 4, characterized in that: The molar ratio of indole compounds to flavin molecules is (0.25:1) to (20:1).

8. The method according to claim 6, characterized in that: The pH of the buffer solution is 6.8–10.6.

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