A method for electrochemical synthesis of 9a-hydroxyhexahydroxanthone compounds

Abstract

The present invention discloses an electrochemical synthesis method of 9a-hydroxy hexahydroxanthone compounds, which is prepared by a one-step method. The preparation route is as follows: #imgabs0# wherein R 1 and R 2 are any of carboxylate, amide or cyano groups, R 3 is any one of an alkyl group, a phenyl group or a heterocyclic group, R 4 is a monosubstituted or polysubstituted group, which may be any of an alkyl, alkoxy, halogen, or aryl group; R is any of an alkyl, aryl, or heterocyclic substituent; and M is any of a metal such as Na, K, or Zn. The present invention provides an electrochemical synthesis method for α-hydroxyhexahydroxanthone compounds. Starting from an alkyl-substituted chromone, 9α-hydroxyhexahydroxanthone compounds are synthesized in one step using electrochemical conditions with a sulfinate. The reaction conditions are mild, the operation is simple, and the yield is excellent, conforming to the concept of green synthesis.

Description

Technical Field

[0001] The invention relates to an electrochemical synthesis method of 9a-hydroxyhexahydroxanthone compounds, belonging to the technical field of preparation of 9a-hydroxyhexahydroxanthone compounds. Background Art

[0002] Xanthone compounds are unique natural products found in nature, primarily as secondary metabolites of microorganisms and higher plants. They possess extensive biological activity and play important roles in organisms, attracting widespread attention from scientists. Xanthone natural products and their derivatives have complex molecular structures and are difficult to synthesize, making them a research hotspot in organic chemistry.

[0003]

[0004] Among them, derivatives based on the 9a-hydroxyhexahydroxanthone skeleton have potential pharmaceutical activity, but due to their unique structure, chemical synthesis presents a significant challenge, and related research reports are rare. According to literature research, only two synthetic methods for this type of compound have been reported by the Brase group in Germany. The synthetic routes are: (1)

[0006] (2)

[0008] That is, further transformation is required based on the pre-prepared fused tricyclic molecular skeleton, which greatly limits the structure of the target 9a-hydroxyhexahydroxanthone compound that can be obtained. Summary of the Invention

[0009] To overcome the shortcomings of the existing technology, the present invention provides an electrochemical synthesis method for 9a-hydroxyhexahydroxanthone compounds. Starting from an alkene-substituted chromone, 9a-hydroxyhexahydroxanthone compounds are synthesized in one step with sulfinate under electrochemical conditions. The reaction conditions are mild, the operation is simple, the yield is excellent, and it conforms to the concept of green synthesis.

[0010] In order to solve the above technical problems, the technical solutions adopted by the present invention are as follows:

[0011] A method for electrochemically synthesizing 9a-hydroxyhexahydroxanthone compounds is prepared by a one-step process. The preparation route is as follows:

[0012] Among them, R 1 and R 2 are any of carboxylate, amide or cyano groups, R 3is any one of an alkyl group, a phenyl group or a heterocyclic group, R 4 is a monosubstituted or polysubstituted group, which can be any one of alkyl, alkoxy, halogen or aryl; R is any one of alkyl, aryl or heterocyclic substituents, and M is any one of metals such as Na, K or Zn.

[0013] The above method has mild reaction conditions, simple operation, and is green and efficient.

[0014] As one specific implementation scheme, the electrochemical synthesis method of 9a-hydroxyhexahydroxanthone compounds is to dissolve an alkyl-substituted chromone, a sulfinate, an acid and an electrolyte in a solvent, insert an electrode into the system and energize it, stir the reaction, extract with a solvent after the reaction is completed, and then remove the solvent to obtain a crude product. Finally, the target 9a-hydroxyhexahydroxanthone product is obtained by column chromatography separation and purification.

[0015] In order to ensure the yield, after power on, stir at room temperature for 4 to 6 hours while maintaining the current at 8 to 10 mA. After power on, the present invention can be operated at room temperature without other heating, cooling and other operations.

[0016] In order to further improve the yield, the molar ratio of the alkyl-substituted chromone to the sulfinate is 1:(2-4), more preferably 1:4.

[0017] The above R 1 and R 2 and COOMe, COOEt, COOiPr, COOPh, CONH2 or CN. Of course, other groups other than these groups are also possible. Me is methyl, Et is ethyl, Pr is propyl, i represents iso, iPr is isopropyl, and Ph is phenyl.

[0018] In order to allow the reaction materials to fully contact and thus improve the yield, the solvent used for dissolution is a miscible solvent of an organic solvent and water. The organic solvent can be any one of tetrahydrofuran, acetonitrile, chlorobenzene, N,N-dimethylformamide (DMF), 1,4-dioxane or dimethyl sulfoxide (DMSO).

[0019] More preferably, the solvent used for dissolution is a miscible solvent of equal volumes of acetonitrile and water.

[0020] In order to improve the yield, the acid is acetic acid or benzoic acid.

[0021] The electrolyte may be any one of NH4I, NH4Br, LiClO4, TBAI, TBAB, TBAC or TBAF.

[0022] The positive and negative electrodes can be any one of a carbon electrode, a platinum electrode, a copper electrode, a zinc electrode, an iron electrode or a stainless steel electrode.

[0023] The synthesis of alkyl-substituted chromones comprises the following steps:

[0024] 1) Dissolve chromone-3-carboxaldehyde, malonate, and potassium carbonate in acetic anhydride and stir at 80±5°C for 3-4 hours. Then, cool the reaction to room temperature, add ice water to form a precipitate, and filter to obtain a light yellow solid. The molar ratio of chromone-3-carboxaldehyde, malonate, and potassium carbonate is 1:(1-2):(0.1-0.3).

[0025] 2) dissolving the light yellow solid obtained in step 1) in L-acetic acid, adding zinc powder, stirring at room temperature for 5-6 hours, filtering, adding ice water to the filtrate to form a precipitate, and filtering again to obtain a yellow solid; the molar ratio of chromone-3-carboxaldehyde to zinc powder is 1:(1-3);

[0026] 3) The yellow solid obtained in step 2) and NaH are dissolved in tetrahydrofuran solution, stirred at 0°C for half an hour, and then allyl bromide is added dropwise to the mixture, and stirred at room temperature for 1.5 to 2.5 hours. After the reaction is completed, the mixture is quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. Finally, the mixture is separated and purified by column chromatography to obtain an alkyl-substituted chromone; the molar ratio of chromone-3-carboxaldehyde, NaH and allyl bromide is 1:(0.2 to 0.3):(0.2 to 0.3).

[0027] The technologies not mentioned in this invention are all referred to the prior art.

[0028] The electrochemical synthesis method of α-hydroxyhexahydroxanthone compounds of the present invention starts from an alkyl-substituted chromone and a sulfinate under electrochemical conditions to synthesize 9α-hydroxyhexahydroxanthone compounds in one step. The reaction conditions are mild, the operation is simple, the yield is excellent, and it conforms to the concept of green synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is R in Example 1 1 =R 2 =COOEt,R 3 =Me,R 4 =H, R = 4-MePh compound H NMR spectrum ( 1 H NMR (400 MHz, CDCl 3 ).

[0030] Figure 2 is R in Example 1 1 =R 2 =COOEt,R 3 =Me,R4 =H, R = 4-MePh, the carbon NMR spectrum of the compound ( 13 C NMR (100 MHz, CDCl3).

[0031] Figure 3 is R in Example 6 1 =R 2 =COOEt,R 3 =Me,R 4 =H, R = 4-BrPh compound H NMR spectrum ( 1 H NMR (400 MHz, CDCl 3 ).

[0032] Figure 4 is R in Example 6 1 =R 2 =COOEt,R 3 =Me,R 4 =H, R = 4-BrPh the compound of carbon nuclear magnetic resonance spectrum ( 13 C NMR (100 MHz, CDCl3).

[0033] Figure 5 is R in Example 7 1 =R 2 =COOEt,R 3 =Me,R 4 =2-iPr, R=4-MePh H NMR spectrum of the compound ( 1 H NMR (400 MHz, CDCl 3 ).

[0034] Figure 6 is R in Example 7 1 =R 2 =COOEt,R 3 =Me,R 4 =2-iPr, R=4-MePh, the carbon NMR spectrum of the compound ( 13 C NMR (100 MHz, CDCl3).

[0035] Figure 7 is R in Example 8 1 =R 2 =COOMe,R 3 =Me,R 4 =H, R = 4-MePh compound H NMR spectrum ( 1 H NMR (400 MHz, CDCl 3 ).

[0036] Figure 8 is R in Example 8 1 =R 2=COOMe,R 3 =Me,R 4 =H, R = 4-MePh, the carbon NMR spectrum of the compound ( 13 C NMR (100 MHz, CDCl3). DETAILED DESCRIPTION

[0037] In order to better understand the present invention, the content of the present invention is further illustrated below in conjunction with the examples, but the content of the present invention is not limited to the following examples.

[0038] The room temperature in each case was 15 to 25°C.

[0039] Example 1

[0040] Weigh 0.3 mmol of alkyl-substituted chromone (R 1 =R 2 =COOEt,R 3 =Me,R 4 =H), 1.2mmol sodium p-toluenesulfinate, 1.2mmol acetic acid, and 0.3mmol NH4I were dissolved in a mixed solvent of 5mL acetonitrile and 5mL water. Metal platinum electrodes (10mm×10mm×0.2mm) were inserted into the solution as positive and negative electrodes, respectively. After the power was turned on, the current was controlled to be constant at 10mA, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added. After separation, the organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product. The target product was then separated and purified by column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio of 5:1) to obtain the target product. The hydrogen and carbon spectra are shown in Figure 2. Figure 1-2 As shown, the yield was 91% and the purity was >99.9%.

[0041] Example 2

[0042] Weigh 0.3 mmol of alkyl-substituted chromone (R 1 =R 2 =COOEt,R 3 =Me,R 4=H), 0.9mmol sodium p-toluenesulfinate, 1.2mmol acetic acid, and 0.3mmol NH4I were dissolved in a mixed solvent of 5mL acetonitrile and 5mL water. Metal platinum sheets (10mm×10mm×0.2mm) were inserted into the solution as positive and negative electrodes, respectively. After the power supply was turned on, the current was controlled to be constant at 10mA, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added. After separation, the organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product. The crude product was then separated and purified by column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio of 5:1) to obtain the target product with a yield of 83% and a purity of >99.9%. The hydrogen and carbon spectra were no different from those in Example 1 and are not repeated here.

[0043] Example 3

[0044] Weigh 0.3 mmol of alkyl-substituted chromone (R 1 =R 2 =COOEt,R 3 =Me,R 4 =H), 0.9mmol sodium p-toluenesulfinate, 1.2mmol acetic acid, and 0.3mmol NH4I were dissolved in a mixed solvent of 5mL tetrahydrofuran and 5mL water. Metal platinum sheets (10mm×10mm×0.2mm) were inserted into the solution as positive and negative electrodes, respectively. After the power supply was turned on, the current was controlled to be constant at 10mA, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added. After separation, the organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product. The crude product was then separated and purified by column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio of 5:1) to obtain the target product with a yield of 56% and a purity of>99.9%. The H and C spectra were no substantially different from those in Example 1 and are not repeated here.

[0045] Example 4

[0046] Weigh 0.3 mmol of alkyl-substituted chromone (R 1 =R 2 =COOEt,R 3 =Me,R 4=H), 0.9mmol sodium p-toluenesulfinate, 1.2mmol acetic acid, and 0.3mmol NH4I were dissolved in a mixed solvent of 5mL acetonitrile and 5mL water. Metal platinum sheets (10mm×10mm×0.2mm) were inserted into the solution as positive and negative electrodes, respectively. After the power supply was turned on, the current was controlled to be constant at 10mA, and the heating system was stirred at 40°C for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added. After separation, the organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product. The crude product was then separated and purified by column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio of 5:1) to obtain the target product with a yield of 61% and a purity of >99.9%. The hydrogen and carbon spectra were no different from those in Example 1 and are not repeated here.

[0047] Example 5

[0048] Weigh 0.3 mmol of alkyl-substituted chromone (R 1 =R 2 =COOEt,R 3 =Me,R 4 =H), 0.9mmol sodium p-toluenesulfinate, 1.2mmol acetic acid, and 0.3mmol NH4I were dissolved in a mixed solvent of 5mL acetonitrile and 5mL water. Metal platinum sheets (10mm×10mm×0.2mm) were inserted into the solution as positive and negative electrodes, respectively. After the power was turned on, the current was controlled to be constant at 6mA, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added. After separation, the organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product. The crude product was then separated and purified by column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio of 5:1) to obtain the target product with a yield of 64% and a purity of >99.9%. The H and C spectra were no different from those in Example 1 and are not repeated here.

[0049] Example 6

[0050] Weigh 0.3 mmol of alkyl-substituted chromone (R 1 =R 2 =COOEt,R 3 =Me,R 4=H), 1.2mmol sodium p-bromobenzenesulfinate, 1.2mmol acetic acid, and 0.3mmol NH4I were dissolved in a mixed solvent of 5mL acetonitrile and 5mL water. Metal platinum electrodes (10mm×10mm×0.2mm) were inserted into the solution as positive and negative electrodes, respectively. After the power was turned on, the current was controlled to be constant at 10mA, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added. After separation, the organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product. The target product was then separated and purified by column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio of 5:1) to obtain the target product with a yield of 90% and a purity of >99.9%. The hydrogen and carbon spectra were as shown in FIG. Figure 3-4 shown.

[0051] Example 7

[0052] Weigh 0.3 mmol of alkyl-substituted chromone (R 1 =R 2 =COOEt,R 3 =Me,R 4 =2-iPr), 1.2mmol sodium p-toluenesulfinate, 1.2mmol acetic acid, and 0.3mmol NH4I were dissolved in a mixed solvent of 5mL acetonitrile and 5mL water. Metal platinum electrodes (10mm×10mm×0.2mm) were inserted into the solution as positive and negative electrodes, respectively. After the power was turned on, the current was controlled to be constant at 10mA, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added. After separation, the organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product. The target product was then separated and purified by column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio of 5:1) to obtain the target product with a yield of 88% and a purity of >99.9%. The hydrogen and carbon spectra were as shown in FIG. Figure 5-6 shown.

[0053] Example 8

[0054] Weigh 0.3 mmol of alkyl-substituted chromone (R 1 =R 2 =COOMe,R 3 =Me,R 4=H), 1.2mmol sodium p-toluenesulfinate, 1.2mmol acetic acid, and 0.3mmol NH4I were dissolved in a mixed solvent of 5mL acetonitrile and 5mL water. Metal platinum electrodes (10mm×10mm×0.2mm) were inserted into the solution as positive and negative electrodes, respectively. After the power was turned on, the current was controlled to be constant at 10mA, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added. After separation, the organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain a crude product. The target product was then separated and purified by column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio of 5:1) to obtain the target product with a yield of 85% and a purity of >99.9%. The hydrogen and carbon spectra were as shown in FIG. Figure 7-8 shown.

[0055] Synthesis of alkyl-substituted chromones:

[0056] Example 1-6, R 1 =R 2 =COOEt, R 3 =Me, R 4 =H, the synthetic route is:

[0057]

[0058] Example 7, R 1 =R 2 =COOEt, R 3 =Me, R 4 =2-iPr, the synthetic route is:

[0059]

[0060] Example 8, R 1 =R 2 =COOMe, R 3 =Me, R 4 =H, the synthetic route is:

[0061]

[0062] 20 mmol of chromone-3-carboxaldehyde, 30 mmol of malonate, and 2 mmol of potassium carbonate were weighed and dissolved in 30 mL of acetic anhydride, stirred at 80°C for 4 hours, then the reactant was cooled to room temperature, ice water was added to form a precipitate, and filtered to obtain a light yellow solid. The solid was dissolved in 30 mL of acetic acid, 40 mmol of zinc powder was added, and the mixture was stirred at room temperature for 6 hours. After filtration, ice water was added to the filtrate to form a precipitate, and then filtered to obtain a yellow solid. The solid and 5.5 mmol of NaH were dissolved in 30 mL of tetrahydrofuran solution and stirred at 0°C for half an hour. Then, 5.5 mmol of allyl bromide was added dropwise to the mixture. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was quenched with 20 mL of saturated ammonium chloride solution and extracted with 30 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Finally, the alkyl-substituted chromone was separated and purified by column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio of 10:1), wherein, The yield is 82%; The yield is 71%; The yield was 76%.

Claims

1. A method for electrochemical synthesis of 9a-hydroxyhexahydroxanthone compounds, characterized in that: Prepared by one-step method, the preparation route is as follows: Among them, R 1 and R 2 are any of carboxylate, amide or cyano groups, R 3 is any one of an alkyl group, a phenyl group or a heterocyclic group, R 4 is any one of alkyl, alkoxy, halogen or aryl; R is any one of alkyl, aryl or heterocyclic substituents, and M is any one of Na, K or Zn; the preparation current is 8 to 10 mA.

2. The electrochemical synthesis method according to claim 1, wherein: The alkyl-substituted chromone, sulfinate, acid and electrolyte are dissolved in a solvent, electrodes are inserted into the system and energized, and the reaction is stirred. After the reaction is completed, the product is extracted with a solvent and then the solvent is removed to obtain a crude product. Finally, the crude product is separated and purified by column chromatography to obtain the target 9a-hydroxyhexahydroxanthone product.

3. The electrochemical synthesis method according to claim 2, wherein: After power is applied, the reaction is completed by stirring at room temperature for 4 to 6 hours.

4. The electrochemical synthesis method according to claim 2 or 3, wherein: The molar ratio of the alkyl-substituted chromone to the sulfinate is 1:(2-4).

5. The electrochemical synthesis method according to claim 2 or 3, wherein: The solvent used for dissolution is a mixed solvent of an organic solvent and water, and the organic solvent is any one of tetrahydrofuran, acetonitrile, chlorobenzene, N,N-dimethylformamide, 1,4-dioxane or dimethyl sulfoxide.

6. The electrochemical synthesis method according to claim 2 or 3, wherein: The solvent used for dissolution was a mixed solvent of equal volumes of acetonitrile and water.

7. The electrochemical synthesis method according to claim 2 or 3, wherein: The acid is acetic acid or benzoic acid.

8. The electrochemical synthesis method according to claim 2 or 3, wherein: The electrolyte is any one of NH4I, NH4Br, LiClO4, TBAI, TBAB, TBAC or TBAF; and the electrode is any one of a carbon electrode, a platinum electrode, a copper electrode or a stainless steel electrode.

9. The electrochemical synthesis method according to claim 2 or 3, wherein: The solvent used for extraction was a mixed solvent of equal volumes of ethyl acetate and water; the eluent used for column chromatography was a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:

1.

10. The electrochemical synthesis method according to claim 2 or 3, characterized in that: R 1 and R 2 They are COOMe, COOEt, COOiPr, COOPh, CONH2 or CN respectively.

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