Electrochemical synthesis method of 9a-hydroxyhexahydroxanthone compound

Abstract

The invention discloses an electrochemical synthesis method of a 9a-hydroxyhexahydroxanthone compound, which is prepared by a one-step method, and the preparation route is as follows: # imgabs0, in which R1 and R2 are respectively any one of carboxylic ester group, amide group or cyano group, R3 is any one of alkyl group, phenyl group or heterocyclic group, R4 is monosubstituted or polysubstituted group, and n is 1-3. The alkyl group can be any one of alkyl group, alkoxy group, halogen or aryl group; r is any one of alkyl, aryl or heterocyclic substituent, and M is any one of metals such as Na, K or Zn. According to the electrochemical synthesis method of the alpha-hydroxyl hexahydroxanthone compound, the 9a-hydroxyl hexahydroxanthone compound is synthesized from the alkene alkyl substituted chromone and the sulfinate under the electrochemical condition in one step, the reaction condition is mild, the operation is simple, the yield is excellent, and the idea of green synthesis is met.

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 natural products with unique structures in nature. They are mostly found in the secondary metabolites of microorganisms or higher plants. They have rich biological activities and play an important role in organisms. They have attracted extensive attention from scientists. Xanthone natural products and their derivatives have complex molecular structures and are difficult to synthesize artificially. They have always been a hot topic in the field of organic chemistry.

[0003]

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

[0006] (2)

[0008] That is, it is necessary to further transform the prepared condensed tricyclic molecular skeleton, which greatly limits the structure of the target 9a-hydroxyhexahydroxanthone compound that can be obtained. Summary of the invention

[0009] In order to overcome the shortcomings of the prior art, the present invention provides an electrochemical synthesis method for 9a-hydroxyhexahydroxanthone compounds, starting from olefin-substituted chromone and sulfinate under electrochemical conditions, to synthesize 9a-hydroxyhexahydroxanthone compounds in one step, with mild reaction conditions, simple operation, excellent yield, and in line with 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 method, and the preparation route is as follows:

[0012] Among them, R 1 and R 2 are any of a carboxylate group, an amide group or a cyano group, 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 of the specific implementation schemes, the electrochemical synthesis method of 9a-hydroxyhexahydroxanthone compounds is to dissolve the olefin-substituted chromone, sulfinate, acid and electrolyte in a solvent, insert electrodes into the system and energize, stir the reaction, extract with a solvent after the reaction is completed, remove the solvent to obtain a crude product, and finally separate and purify by column chromatography to obtain the target 9a-hydroxyhexahydroxanthone product.

[0015] In order to ensure the yield, after power is turned on, the current is kept at 8-10 mA and stirred at room temperature for 4-6 hours. After the power is turned 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 olefin-substituted chromone to the sulfinate is 1:(2-4), more preferably 1:4.

[0017] The above R 1 and R 2 They are COOMe, COOEt, COOiPr, COOPh, CONH2 or CN respectively. Of course, they can also be other groups other than these groups. The aforementioned 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 dissolving 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 alkene substituted chromones comprises the following steps:

[0024] 1) dissolving chromone-3-carboxaldehyde, malonate and potassium carbonate in acetic anhydride, stirring at 80±5°C for 3-4 hours, then cooling the reactant to room temperature, adding ice water to form a precipitate, and filtering 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 to 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 to 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, quenching is performed with saturated ammonium chloride solution, and then extraction is performed with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. Finally, separation and purification are performed 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 the present invention are all referred to the prior art.

[0028] The electrochemical synthesis method of α-hydroxyhexahydroxanthone compounds of the present invention starts from alkene-substituted chromone and sulfinate under electrochemical conditions to synthesize 9α-hydroxyhexahydroxanthone compounds in one step, has mild reaction conditions, simple operation, excellent yield, and 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, CDCl3).

[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, CDCl3).

[0032] Figure 4 is R in Example 6 1 =R 2 =COOEt,R 3 =Me,R 4 =H, R = 4-BrPh, the carbon NMR spectrum of the compound ( 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 compound H NMR spectrum ( 1 H NMR (400 MHz, CDCl3).

[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, CDCl3).

[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 explained below in conjunction with the embodiments, but the content of the present invention is not limited to the following embodiments.

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

[0039] Example 1

[0040] Weigh 0.3 mmol of alkene-substituted chromone (R 1 =R 2 =COOEt,R 3 =Me,R 4 =H), 1.2mmol sodium p-toluenesulfinate, 1.2mmol acetic acid, 0.3mmol NH4I were dissolved in a mixed solvent of 5mL acetonitrile and 5mL water, and 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 10mA, and stirred at room temperature for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added, and after stratification, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, with a volume ratio of 5:1) to obtain the target product. The hydrogen spectrum and carbon spectrum are shown in the following figure. Figure 1-2 As shown, the yield was 91% and the purity was >99.9%.

[0041] Example 2

[0042] Weigh 0.3 mmol of alkene-substituted chromone (R 1 =R 2 =COOEt,R 3 =Me,R 4=H), 0.9mmol sodium p-toluenesulfinate, 1.2mmol acetic acid, 0.3mmol NH4I were dissolved in a mixed solvent of 5mL acetonitrile and 5mL water, and 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 10mA, and stirred at room temperature for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added, and the organic phase was dried over anhydrous sodium sulfate after stratification. The solvent was removed under reduced pressure to obtain a crude product, and then column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio of 5:1) was used to separate and purify the target product, with a yield of 83% and a purity of >99.9%. The hydrogen spectrum and carbon spectrum were no substantial difference from Example 1, and no further repetition was provided.

[0043] Example 3

[0044] Weigh 0.3 mmol of alkene-substituted chromone (R 1 =R 2 =COOEt,R 3 =Me,R 4 =H), 0.9mmol sodium p-toluenesulfinate, 1.2mmol acetic acid, 0.3mmol NH4I were dissolved in a mixed solvent of 5mL tetrahydrofuran and 5mL water, and 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 10mA, and stirred at room temperature for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added, and the organic phase was dried over anhydrous sodium sulfate after stratification. The solvent was removed under reduced pressure to obtain a crude product, and then column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio of 5:1) was used to separate and purify the target product, with a yield of 56% and a purity of >99.9%. The hydrogen spectrum and carbon spectrum were no substantial difference from Example 1, and no further repetition was provided.

[0045] Example 4

[0046] Weigh 0.3 mmol of alkene-substituted chromone (R 1 =R 2 =COOEt,R 3 =Me,R 4=H), 0.9mmol sodium p-toluenesulfinate, 1.2mmol acetic acid, 0.3mmol NH4I were dissolved in a mixed solvent of 5mL acetonitrile and 5mL water, and 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, and the organic phase was dried over anhydrous sodium sulfate after stratification, and the solvent was removed under reduced pressure to obtain a crude product, which 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 spectrum and carbon spectrum were no substantial difference from Example 1, and no further repetition was provided.

[0047] Example 5

[0048] Weigh 0.3 mmol of alkene-substituted chromone (R 1 =R 2 =COOEt,R 3 =Me,R 4 =H), 0.9mmol sodium p-toluenesulfinate, 1.2mmol acetic acid, 0.3mmol NH4I were dissolved in a mixed solvent of 5mL acetonitrile and 5mL water, and 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 stirred at room temperature for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added, and the organic phase was dried over anhydrous sodium sulfate after stratification. The solvent was removed under reduced pressure to obtain a crude product, and then column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio of 5:1) was used to separate and purify the target product, with a yield of 64% and a purity of >99.9%. The hydrogen spectrum and carbon spectrum were no substantial difference from Example 1, and no further repetition was provided.

[0049] Example 6

[0050] Weigh 0.3 mmol of alkene-substituted chromone (R 1 =R 2 =COOEt,R 3 =Me,R 4=H), 1.2mmol sodium p-bromobenzenesulfinate, 1.2mmol acetic acid, 0.3mmol NH4I were dissolved in a mixed solvent of 5mL acetonitrile and 5mL water, and 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 10mA, and stirred at room temperature for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added, and after stratification, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product, which 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 spectrum and carbon spectrum were as shown in Figure 3-4 shown.

[0051] Example 7

[0052] Weigh 0.3 mmol of alkene-substituted chromone (R 1 =R 2 =COOEt,R 3 =Me,R 4 =2-iPr), 1.2mmol sodium p-toluenesulfinate, 1.2mmol acetic acid, 0.3mmol NH4I were dissolved in a mixed solvent of 5mL acetonitrile and 5mL water, and 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 stirred at room temperature for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added, and after stratification, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product, which 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 spectrum and carbon spectrum are as shown in Figure 5-6 shown.

[0053] Example 8

[0054] Weigh 0.3 mmol of alkene-substituted chromone (R 1 =R 2 =COOMe,R 3 =Me,R 4=H), 1.2mmol sodium p-toluenesulfinate, 1.2mmol acetic acid, 0.3mmol NH4I were dissolved in a mixed solvent of 5mL acetonitrile and 5mL water, and 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 10mA, and stirred at room temperature for 6 hours. After the reaction was completed, 20mL ethyl acetate and 20mL water were added, and after stratification, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product, which 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 spectrum and carbon spectrum were as shown in Figure 7-8 shown.

[0055] Synthesis of olefin-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 malonic acid ester, 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 a light yellow solid was obtained by filtration. 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 a yellow solid was obtained by filtration. The solid and 5.5 mmol of NaH were dissolved in 30 mL of tetrahydrofuran solution, stirred at 0°C for half an hour, and 5.5 mmol of propylene bromide was added dropwise to the mixture. After the addition was completed, 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 then extracted with 30 mL of ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure. Finally, column chromatography (silica gel column, petroleum ether and ethyl acetate as eluents, volume ratio of 10:1) was used to separate and purify the alkene-substituted chromone, wherein, The yield is 82%; The yield is 71%; The yield was 76%.

Claims

1. An electrochemical synthesis method 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 a carboxylate group, an amide group or a cyano group, 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.

2. The electrochemical synthesis method according to claim 1, characterized in that: The olefin-substituted chromone, sulfinate, acid and electrolyte are dissolved in a solvent, electrodes are inserted into the system and energized, the reaction is stirred, and after the reaction is completed, the solvent is used for extraction, and the solvent is removed to obtain a crude product, and finally the target 9a-hydroxyhexahydroxanthone product is obtained by separation and purification by column chromatography.

3. The electrochemical synthesis method according to claim 2, characterized in that: After power is turned on, the reaction is completed by stirring at room temperature for 4 to 6 hours while maintaining a current of 8 to 10 mA.

4. The electrochemical synthesis method according to claim 2 or 3, characterized in that: 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, characterized in that: The solvent used for dissolving is a miscible 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, characterized in that: The solvent used for dissolution is a miscible solvent of equal volumes of acetonitrile and water.

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

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

9. The electrochemical synthesis method according to claim 2 or 3, characterized in that: 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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