Method for enzymatic synthesis of xanthone compounds and derivatives thereof

Abstract

The application discloses a method for preparing xanthone compounds by taking aromatic aldehyde and 1,3-cyclohexanedione or dammarone as substrates and taking enzymes as catalysts. The xanthone compounds are sensitive to nucleophilic reagents and light energy, and thus have wide application in pharmaceutical chemistry and material science. The method provided by the application has high product yield, mild reaction condition, simple operation, low production cost, high yield, wide substrate spectrum, recyclable catalyst and small environmental pollution.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of biological catalysis, and relates to a method for synthesizing xanthone compounds and derivatives thereof by enzyme catalysis. BACKGROUND

[0002] Xanthone compounds are sensitive to nucleophiles and light energy, and are widely used in many aspects. In the field of medicinal chemistry, it has the effects of anticancer, antibacterial, antiviral, anti-AIDS, anti-malaria, and blood sugar reduction; in the field of material science, it is used to construct chiral bidentate ligands with catalytic action, is used to make fluorescent materials for biomolecular visualization, is applied to laser technology, organic light-emitting diodes, and PH probe making. Generally, the compounds are obtained by condensation and addition reaction of aromatic aldehyde and 1,3-cyclohexanedione or damino in the presence of acid-base catalysts such as taurine, sodium bisulfate, and Schiff base. However, these catalytic processes often require a large amount of toxic organic solvent which is difficult to handle, causing environmental pollution, and the reaction time is relatively long, and the product yield is also low. In recent years, new methods such as ultrasonic method, microwave method, and solvent-free grinding method have appeared, and various catalysts have appeared, including phase transfer catalyst TEBA, ionic liquid, magnetic nanoparticles, and supercritical diethyl ether. However, a large part of the above catalytic reaction systems have the defects of harsh reaction conditions, high cost, and difficult to obtain catalysts.

[0003] In recent years, enzymes have played an increasingly important role in organic synthesis, and multifunctional enzymes have been successfully applied to various C-C bond formation reactions. In 2012, papain was used to catalyze the condensation reaction of various aldehydes with acetylacetone and ethyl acetate in a 25% water-containing DMSO solution. In 2017, Novozym435 was used to catalyze the condensation reaction of acetaldehyde with acidic methylene compounds in anhydrous organic solvent. Protease from Streptomyces griseus (SGP) was used to catalyze the cyclization reaction of dimethyl ketone and aryl or alkyl substituted alpha, beta-unsaturated ketone or ester. PPL was used to catalyze the addition reaction of 4-hydroxycoumarin and alpha, beta-unsaturated ketone in a water-containing organic solvent to synthesize warfarin and its derivatives. SUMMARY

[0004] In view of the problems in the prior art, the application provides a method for synthesizing xanthone compounds by enzyme catalysis. The method uses enzymes as catalysts, and aromatic aldehyde and 1,3-cyclohexanedione or damino as substrates to synthesize xanthone compounds or derivatives thereof, and provides a new use of enzyme catalytic reaction.

[0005] To achieve the above-mentioned purpose, the technical scheme adopted by the application is as follows:

[0006] The application relates to a method for synthesizing xanthone compounds and derivatives thereof by using an enzyme as a catalyst, which comprises the following steps: taking aromatic aldehyde and 1,3-cyclohexanedione or dammarone as substrates, and taking an enzyme as a catalyst to carry out one-step reaction in a solvent to obtain xanthone compounds or derivatives of the xanthone compounds, wherein the derivatives of the xanthone compounds are of a structure as shown in formula I or formula II, the xanthone compounds are of a structure as shown in formula III or formula IV, and the reaction equation is as shown in the following formula:

[0007]

[0008] X1 is one of 4-Cl, 4-Br, 3-NO2, 4-NO2, 3-Cl, 4-F, 2,4-Cl2, 4-CN, H, 4-OCH3, 4-CH3, 4-OH, 4-C4H9, 4-CF3, 4-OH-3-OCH3, 2-F, 2-NO2 or 2-thiophenyl; X2 is one of 4-NO2, 4-Cl, 2-F, 2-NO2, H or 4-CH3; X3 is 2,6-Cl2 or 2-pyridyl; X4 is 2-OH or 2-OH-3-OCH3,

[0009] The enzyme is lipase, porcine pancreas trypsin or papain.

[0010] The enzyme is derived from animals, plants or microorganisms.

[0011] The lipase is one of Amano Lipase PS from Burkholderia cepacia, XHlip-F lipase, Novozym 435 lipase (lipase B from Candida antarctica, immobilized on a macroporous acrylic resin), lipase from Thermomyces lanuginosus, Candida rugosa lipase, lipase lipoprotein from Aspergillus niger and porcine pancreas lipase.

[0012] The preferred lipase is lipase from Thermomyces lanuginosus, which is abbreviated as lipase TLIM.

[0013] The solvent is an organic solvent with a water volume fraction of 0-70%, preferably the solvent is an organic solvent with a water content of 0.

[0014] The organic solvent is one or more of isopropyl alcohol, toluene, dichloromethane, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, diethyl ether, and n-hexane, preferably the organic solvent is n-hexane.

[0015] The molar ratio of the aromatic aldehyde to 1,3-cyclohexanedione or damitone is 1:2.

[0016] The amount of the enzyme used is 0

[0017] The reaction time is 2-32 h.

[0018] The reaction further comprises recovering the solvent after the reaction is completed.

[0019] The reaction further comprises recovering the enzyme after the reaction is completed.

[0020] The reaction further comprises washing the crude product with hot water after the reaction is completed.

[0021] The reaction further comprises recrystallizing the crude product with ethanol after the reaction is completed.

[0022] The present application has the following beneficial effects:

[0023] 1. A novel synthesis method of xanthone compounds and derivatives thereof is provided. The method uses an enzyme as a catalyst, and has the advantages of mild reaction conditions, simple operation, low production cost, high yield, less by-products, wide substrate application range, and less environmental pollution.

[0024] 2. The method discovers a new use of the enzyme, especially the C-C bond formation reaction using 1,3-cyclohexanedione or damitone as a substrate.

[0025] 3. The enzyme used in the present application has a low concentration and is easy to recover, has a high recovery efficiency, and the catalytic activity of the enzyme after recovery is basically unchanged.

[0026] 4. The method of the present application has a high product yield, and has a strong competitive advantage compared with other synthesis methods.

[0027] 5. The method of the present application uses a solvent that is easy to recover after treatment, and has a small post-treatment difficulty, is economical and environmentally friendly. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1is the nuclear magnetic resonance hydrogen spectrum of 2,2'-((4-chlorophenyl) methylene) bis(3-hydroxycyclohex-2-en-1-one) prepared in Example 1.

[0029] Figure 2 is the nuclear magnetic resonance hydrogen spectrum of 9-(2,6-dichlorophenyl)-3,4,5,6,7,9- hexahydro-1H-xanthene-1,8(2H)-dione prepared in Example 11.

[0030] Figure 3 is the nuclear magnetic resonance hydrogen spectrum of 9-(2-hydroxy-6-oxocyclohex-1-en-1- yl)-2,3,4,9-tetrahydro-1H-xanthene-1-one prepared in Example 12. DETAILED DESCRIPTION

[0031] The application is further described in conjunction with the following examples. The examples listed are intended to be illustrative only and are not meant to limit the scope of the application or the spirit or scope thereof in any way. EXAMPLES

[0032] The biological enzymes and other reagents involved in the application were purchased from the market, and the reagents were not further purified; the nuclear magnetic resonance hydrogen spectrum (1H NMR) was determined by a Bruker Advance 2B 400 nuclear magnetic resonance spectrometer, the frequency was 400 MHz, the solvent was deuterated chloroform, and the internal standard was tetramethylsilane (TMS).

[0033] Example 1

[0034] 1 mmol of p-chlorobenzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction bottle, then 50 mg of lipase TLIM, 5 mL of n-hexane were added, and the reaction was stirred at 35°C, and the reaction progress was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 18 h, the n-hexane was recovered by filtration, the filter residue was dissolved in dichloromethane and the enzyme was recovered by filtration, the dichloromethane in the filtrate was recovered by rotary evaporation under reduced pressure, and the crude product was obtained by washing the filter residue with hot water. The crude product was recrystallized with 95% ethanol to obtain the purified target product, which was a white solid with a yield of 97%, mp: 203-205°C; 1H NMR (400 MHz, CDCl3) δ 12.33 (s, 1H), 12.03 (s, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 5.40 (s, 1H), 2.68-2.52 (m, 4H), 2.50-2.33 (m, 4H), 2.02 (dt, J = 13.6, 7.6 Hz, 4H).

[0035] Example 2

[0036] Example 1 1 mmol of benzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction flask, then 50 mg of lipase TLIM, 5 mL of n-hexane were added, and the reaction was stirred at 35°C, and the progress of the reaction was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 18 h, the n-hexane was recovered by filtration, the residue was dissolved in dichloromethane and the enzyme was recovered by filtration, the filtrate was concentrated under reduced pressure to recover the dichloromethane, and the residue was washed with hot water to obtain the crude product, which was recrystallized from 95% ethanol to obtain the purified target product, which was a white solid with a yield of 93% and a m.p. of 208-209°C;1H NMR (400 MHz, CDCI3) δ 12.30 (s, 1 H), 11.96 (s, 1 H), 7.21 (t, J = 7.5 Hz, 2H), 7.14-7.09 (m, 1 H), 7.07-7.03 (m, 1 H), 5.42 (s, 1 H), 2.65-2.48 (m, 4H), 2.37 (ddt, J = 26.7, 17.7, 8.6 Hz, 4H), 1.99 (dq, J = 9.7, 4.7 Hz, 4H).

[0037] Example 3

[0038] 1 mmol of p-methoxybenzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction flask, then 50 mg of lipase TLIM, 5 mL of n-hexane were added, and the reaction was stirred at 35°C, and the progress of the reaction was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 16 h, the n-hexane was recovered by filtration, the residue was dissolved in dichloromethane and the enzyme was recovered by filtration, the filtrate was concentrated under reduced pressure to recover the dichloromethane, and the residue was washed with hot water to obtain the crude product, which was recrystallized from 95% ethanol to obtain the purified target product, which was a white solid with a yield of 88% and a m.p. of 186-187°C;1H NMR (400 MHz, CDCI3) δ 12.37 (s, 1 H), 12.08 (s, 1 H), 7.03-6.98 (m, 2H), 6.83-6.77 (m, 2H), 5.41 (s, 1 H), 3.78 (s, 3H), 2.60 (tt, J = 21.6, 3.6 Hz, 4H), 2.41 (ddt, J = 24.8, 17.6, 8.2 Hz, 4H), 2.02 (tt, J = 10.6, 5.1 Hz, 4H).

[0039] Example 4

[0040] Example 1 1 mmol of 3,4-dimethoxybenzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction flask, then 50 mg of lipase TLIM, 5 mL of n-hexane were added, and the reaction was stirred at 35°C. The progress of the reaction was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 24 h, the n-hexane was recovered by filtration, the residue was dissolved in dichloromethane and the enzyme was recovered by filtration, the filtrate was concentrated under reduced pressure to recover the dichloromethane, and the residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified target product, which was a white solid with a yield of 82% and a m.p. of 202-203°C.1H NMR (400 MHz, CDCI3) δ 12.34 (s, 1 H), 12.03 (s, 1 H), 7.27 (d, J = 8.2 Hz, 2 H), 7.05-6.99 (m, 2 H), 5.43 (s, 1 H), 2.67-2.53 (m, 4 H), 2.51-2.33 (m, 4 H), 2.08-1.97 (m, 4 H), 1.29 (s, 9 H).

[0041] Example 5

[0042] Example 6 1 mmol of 3,4-dimethoxybenzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction flask, then 50 mg of lipase TLIM, 5 mL of n-hexane were added, and the reaction was stirred at 35°C. The progress of the reaction was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 24 h, the n-hexane was recovered by filtration, the residue was dissolved in dichloromethane and the enzyme was recovered by filtration, the filtrate was concentrated under reduced pressure to recover the dichloromethane, and the residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified target product, which was a white solid with a yield of 82% and a m.p. of 202-203°C.1H NMR (400 MHz, CDCI3) δ 12.34 (s, 1 H), 12.03 (s, 1 H), 7.27 (d, J = 8.2 Hz, 2 H), 7.05-6.99 (m, 2 H), 5.43 (s, 1 H), 2.67-2.53 (m, 4 H), 2.51-2.33 (m, 4 H), 2.08-1.97 (m, 4 H), 1.29 (s, 9 H).

[0043] Example 6

[0044] 1 mmol of 2-thiophene benzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction flask, followed by 50 mg of lipase TLIM and 5 mL of n-hexane. The mixture was stirred at 35 °C, and the reaction progress was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 13 hours, hexane was recovered by filtration. The filter residue was dissolved in dichloromethane and filtered to recover the enzyme. The filtrate was evaporated under reduced pressure to recover dichloromethane. The filter residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified target product. The target product was a white solid with a yield of 85%, mp: 160-162℃; 1H NMR (400MHz, CDCl3) δ 12.74 (s, 1H), 12.11 (s, 1H), 7.10 (dt, J = 5.1, 1.1 Hz, 1H), 6.86 (dd, J = 5.1, 3.5 Hz, 1H), 6.64 (dt, J = 3.2, 1.5 Hz, 1H), 5.57 (s, 1H), 2.60 (tt, J = 13.6, 3.8 Hz, 4H), 2.47–2.31 (m, 4H), 2.04–1.93 (m, 4H).

[0045] Example 7

[0046] 1 mmol of p-chlorobenzaldehyde and 2 mmol of damione were added to a 10 mL reaction flask, followed by 50 mg of lipase TLIM and 5 mL of n-hexane. The mixture was stirred at 35 °C, and the reaction progress was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 18 hours, hexane was recovered by filtration. The filter residue was dissolved in dichloromethane and filtered to recover the enzyme. The filtrate was evaporated under reduced pressure to recover dichloromethane. The filter residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified target product. The target product was a white solid with a yield of 93%, mp: 153-154℃; 1H NMR (400MHz, CDCl3) δ 11.88 (s, 1H), 11.20 (s, 1H), 7.23 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 7.7 Hz, 2H), 5.47 (s, 1H), 2.39 (dq, J = 26.3, 17.7 Hz, 8H), 1.22 (s, 6H), 1.10 (s, 6H).

[0047] Example 8

[0048] 1 mmol benzaldehyde and 2 mmol damione were added to a 10 mL reaction flask, followed by 50 mg TLIM lipase and 5 mL n-hexane. The mixture was stirred at 35 °C, and the reaction progress was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 24 hours, hexane was recovered by filtration. The filter residue was dissolved in dichloromethane and filtered to recover the enzyme. The filtrate was evaporated under reduced pressure to recover dichloromethane. The filter residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified target product. The target product was a white solid with a yield of 90%, mp: 194-196℃; 1H NMR (400MHz, CDCl3) δ 11.92 (s, 1H), 11.09 (s, 1H), 7.30–7.22 (m, 2H), 7.17 (t, J = 6.8 Hz, 1H), 7.10 (d, J = 8.2 Hz, 2H), 5.54 (s, 1H), 2.37 (dt, J = 26.5, 16.6 Hz, 8H), 1.24 (s, 6H), 1.10 (s, 6H).

[0049] Example 9

[0050] 1 mmol of p-methylbenzaldehyde and 2 mmol of damione were added to a 10 mL reaction flask, followed by 50 mg of lipase TLIM and 5 mL of n-hexane. The mixture was stirred at 35 °C, and the reaction progress was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 30 hours, hexane was recovered by filtration. The filter residue was dissolved in dichloromethane and filtered to recover the enzyme. The filtrate was rotary evaporated under reduced pressure to recover dichloromethane. The filter residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified target product. The target product was a white solid with a yield of 82%, mp: 191-192℃; 1H NMR (400MHz, CDCl3) δ 11.92 (s, 1H), 11.04 (s, 1H), 7.08 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 7.6 Hz, 2H), 5.50 (s, 1H), 2.52–2.31 (m, 8H), 2.29 (s, 3H), 1.23 (s, 6H), 1.10 (s, 6H).

[0051] Example 10

[0052] To a 10 mL reaction flask was added 1 mmol of 2,6-dichlorobenzaldehyde and 2 mmol of 1,3-cyclohexanedione, followed by 50 mg of lipase TLIM, 5 mL of n-hexane, and the reaction was stirred at 35 °C. The progress of the reaction was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 32 h, the n-hexane was recovered by filtration, the residue was dissolved in dichloromethane and the enzyme was recovered by filtration, the filtrate was concentrated under reduced pressure to recover the dichloromethane, and the residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified target product, which was a white solid with a yield of 80% and a melting point of 260-262 °C.1H NMR (400 MHz, CDC13) δ 7.35 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 5.52 (s, 1H), 2.65 - 2.46 (m, 4H), 2.36 - 2.28 (m, 4H), 2.06 - 1.90 (m, 4H). HRMS (ESI-TOF) m / z [M+Na]+: 385.0369, found: 385.0383.

[0053] Example 11

[0054] To a 10 mL reaction flask was added 1 mmol of 2,6-dichlorobenzaldehyde and 2 mmol of 1,3-cyclohexanedione, followed by 50 mg of lipase TLIM, 5 mL of n-hexane, and the reaction was stirred at 35 °C. The progress of the reaction was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 32 h, the n-hexane was recovered by filtration, the residue was dissolved in dichloromethane and the enzyme was recovered by filtration, the filtrate was concentrated under reduced pressure to recover the dichloromethane, and the residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified target product, which was a white solid with a yield of 80% and a melting point of 260-262 °C.1H NMR (400 MHz, CDC13) δ 7.35 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 5.52 (s, 1H), 2.65 - 2.46 (m, 4H), 2.36 - 2.28 (m, 4H), 2.06 - 1.90 (m, 4H). HRMS (ESI-TOF) m / z [M+Na]+: 385.0369, found: 385.0383.

[0055] Example 12

[0056] 1 mmol of o-hydroxybenzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction flask, followed by 50 mg of lipase TLIM and 5 mL of n-hexane. The mixture was stirred at 35 °C, and the reaction progress was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 14 h, the n-hexane was recovered by filtration. The residue was dissolved in dichloromethane and the enzyme was recovered by filtration. The filtrate was evaporated under reduced pressure to recover dichloromethane. The residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified target product, which was a white solid with a yield of 85%, mp: 230-232 °C; 1H. NMR(400MHz, CDCl3)δ10.86(s,1H),7.15(dq,J=7.9,3.9Hz,1H),7.04–6.99(m,3H),4.64(s,1H),2.76(dt,J=17 .8, 4.7Hz, 1H), 2.65–2.48 (m, 3H), 2.42 (ddd, J=17.0, 11.4, 5.5Hz, 2H), 2.35–2.15 (m, 2H), δ2.11–1.87 (m, 4H).

[0057] Example 13 (Comparative Example)

[0058] 1 mmol of p-chlorobenzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction flask, followed by 50 mg of lipase DF and 5 mL of N,N-dimethylformamide. The mixture was stirred at 35 °C for 18 h. After 18 h, 10 mL of distilled water was added to the reaction solution, and the mixture was extracted with dichloromethane (2 × 15 mL). The organic phases were combined and concentrated. The concentrate was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain the target product, which was a white solid with a yield of 46%.

[0059] Example 14

[0060] Example 1 1

[0061] Example 15

[0062] Example 1 1

[0063] Example 16

[0064] Example 1 1

[0065] Example 17

[0066] Example 1 1

[0067] Example 18

[0068] 1 mmol of p-chlorobenzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction flask, followed by 50 mg of lipase TLIM and 5 mL of n-hexane. The mixture was stirred at 25 °C, and the reaction progress was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 18 hours, hexane was recovered by filtration. The filter residue was dissolved in dichloromethane and the enzyme was recovered by filtration. The filtrate was evaporated under reduced pressure to recover dichloromethane. The filter residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified target product. The target product was a white solid with a yield of 78%, mp: 203-205℃; 1H NMR (400MHz, CDCl3) δ 12.33 (s, 1H), 12.03 (s, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 5.40 (s, 1H), 2.68–2.52 (m, 4H), 2.50–2.33 (m, 4H), 2.02 (dt, J = 13.6, 7.6 Hz, 4H).

[0069] Example 19

[0070] 1 mmol of p-chlorobenzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction flask, followed by 50 mg of lipase TLIM and 5 mL of n-hexane. The mixture was stirred at 35 °C, and the reaction progress was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 18 hours, hexane was recovered by filtration. The filter residue was dissolved in dichloromethane and filtered to recover the enzyme. The filtrate was evaporated under reduced pressure to recover dichloromethane. The filter residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified target product. The target product was a white solid with a yield of 84%, mp: 203-205℃; 1H NMR (400MHz, CDCl3) δ 12.33 (s, 1H), 12.03 (s, 1H), 7.21 (d, J = 8.5Hz, 2H), 7.02 (d, J = 8.0Hz, 2H), 5.40 (s, 1H), 2.68–2.52 (m, 4H), 2.50–2.33 (m, 4H), 2.02 (dt, J = 13.6, 7.6Hz, 4H).

[0071] Example 20

[0072] To a 10 mL reaction flask was added 1 mmol of 2,4-dichlorobenzaldehyde and 2 mmol of 1,3-cyclohexanedione, followed by 5 mg of porcine pancreatic trypsin, 5 mL of water-n-hexane (water content 70% v / v), and the reaction was stirred at 45 °C. The progress of the reaction was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 10 h, the solvent was recovered by filtration, the residue was dissolved in dichloromethane and the enzyme was recovered by filtration, the filtrate was concentrated under reduced pressure to recover the dichloromethane, and the residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified product, which was a white solid, in a yield of 82%.

[0073] Example 21

[0074] To a 10 mL reaction flask was added 1 mmol of 2,4-dichlorobenzaldehyde and 2 mmol of 1,3-cyclohexanedione, followed by 5 mg of porcine pancreatic trypsin, 5 mL of water-n-hexane (water content 70% v / v), and the reaction was stirred at 45 °C. The progress of the reaction was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 10 h, the solvent was recovered by filtration, the residue was dissolved in dichloromethane and the enzyme was recovered by filtration, the filtrate was concentrated under reduced pressure to recover the dichloromethane, and the residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified product, which was a white solid, in a yield of 82%.

[0075] Example 22

[0076] To a 10 mL reaction flask was added 1 mmol of 2,4-dichlorobenzaldehyde and 2 mmol of 1,3-cyclohexanedione, followed by 5 mg of porcine pancreatic trypsin, 5 mL of water-n-hexane (water content 70% v / v), and the reaction was stirred at 45 °C. The progress of the reaction was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 10 h, the solvent was recovered by filtration, the residue was dissolved in dichloromethane and the enzyme was recovered by filtration, the filtrate was concentrated under reduced pressure to recover the dichloromethane, and the residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified product, which was a white solid, in a yield of 82%.

[0077] Example 23

[0078] Example 1 1

[0079] Example 12

[0080] Example 13

[0081] Example 14

[0082] Example 15

[0083] Example 16

[0084] Example 17

[0085] Example 18

[0086] 1 mmol of 2-hydroxy-3-methoxybenzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction flask, followed by 50 mg of papain and 5 mL of water-n-hexane (10% v / v). The mixture was stirred at 35 °C, and the reaction progress was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 15 h, the solvent was recovered by filtration. The residue was dissolved in dichloromethane and the enzyme was recovered by filtration. The filtrate was evaporated under reduced pressure to recover dichloromethane. The residue was washed with hot water to obtain the crude product, which was then recrystallized from 95% ethanol to obtain the purified product with a yield of 83%.

[0087] Example 28

[0088] 1 mmol of o-fluorobenzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction flask, followed by 50 mg of lipase TLIM and 5 mL of isopropanol. The mixture was stirred at 35 °C, and the reaction progress was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 12 h, the solvent was recovered by filtration. The residue was dissolved in dichloromethane and the enzyme was recovered by filtration. The filtrate was evaporated under reduced pressure to recover dichloromethane. The residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified product, with a yield of 84%.

[0089] Example 29

[0090] 1 mmol of p-chlorobenzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction flask, followed by 50 mg of the lipase TLIM recovered in Example 1 and 5 mL of n-hexane. The mixture was stirred at 35 °C, and the reaction progress was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 18 hours, hexane was recovered by filtration. The filter residue was dissolved in dichloromethane and the enzyme was recovered by filtration. The filtrate was evaporated under reduced pressure to recover dichloromethane. The filter residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified target product. The target product was a white solid with a yield of 92%, mp: 203-205℃; 1H NMR (400MHz, CDCl3) δ 12.33 (s, 1H), 12.03 (s, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 5.40 (s, 1H), 2.68–2.52 (m, 4H), 2.50–2.33 (m, 4H), 2.02 (dt, J = 13.6, 7.6 Hz, 4H).

[0091] Example 30

[0092] 1 mmol of p-chlorobenzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction flask, followed by 50 mg of the lipase TLIM recovered in Example 28 and 5 mL of n-hexane. The mixture was stirred at 35 °C, and the reaction progress was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 18 hours, hexane was recovered by filtration. The filter residue was dissolved in dichloromethane and filtered to recover the enzyme. The filtrate was evaporated under reduced pressure to recover dichloromethane. The filter residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified target product. The target product was a white solid with a yield of 90%, mp: 203-205℃; 1H NMR (400MHz, CDCl3) δ 12.33 (s, 1H), 12.03 (s, 1H), 7.21 (d, J = 8.5Hz, 2H), 7.02 (d, J = 8.0Hz, 2H), 5.40 (s, 1H), 2.68–2.52 (m, 4H), 2.50–2.33 (m, 4H), 2.02 (dt, J = 13.6, 7.6Hz, 4H).

[0093] Example 31

[0094] 1 mmol of p-chlorobenzaldehyde and 2 mmol of 1,3-cyclohexanedione were added to a 10 mL reaction flask, followed by 50 mg of the lipase TLIM recovered in Example 29 and 5 mL of n-hexane. The mixture was stirred at 35 °C, and the reaction progress was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 18 hours, hexane was recovered by filtration. The filter residue was dissolved in dichloromethane and filtered to recover the enzyme. The filtrate was evaporated under reduced pressure to recover dichloromethane. The filter residue was washed with hot water to obtain the crude product. The crude product was recrystallized from 95% ethanol to obtain the purified target product. The target product was a white solid with a yield of 87%, mp: 203-205℃; 1H NMR (400MHz, CDCl3) δ 12.33 (s, 1H), 12.03 (s, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 5.40 (s, 1H), 2.68–2.52 (m, 4H), 2.50–2.33 (m, 4H), 2.02 (dt, J = 13.6, 7.6 Hz, 4H).

[0095] Example 32

[0096] To a 10 mL reaction flask was added 1 mmol of 4-chlorobenzaldehyde and 2 mmol of 1,3-cyclohexanedione, followed by 50 mg of the lipase TLIM recovered in Example 30, 5 mL of n-hexane, and the reaction was stirred at 35 °C, and the progress of the reaction was monitored by TLC (dichloromethane / ethyl acetate, 2 / 1, v / v). After 18 h, the n-hexane was recovered by filtration, the filter residue was dissolved in dichloromethane and the enzyme was recovered by filtration, the dichloromethane was recovered by rotary evaporation under reduced pressure from the filtrate, the filter residue was washed with hot water to obtain the crude product, and the crude product was recrystallized from 95% ethanol to obtain the purified target product as a white solid in a yield of 85%, mp: 203-205 °C;1H NMR (400 MHz, CDCl3) δ 12.33 (s, 1H), 12.03 (s, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 5.40 (s, 1H), 2.68-2.52 (m, 4H), 2.50-2.33 (m, 4H), 2.02 (dt, J = 13.6, 7.6 Hz, 4H).

Claims

1. A method for enzyme-catalyzed synthesis of xanthone compounds and their derivatives, characterized in that, Using aromatic aldehydes and 1,3 - cyclohexanedione as substrates, and an enzyme as a catalyst, an xanthone compound or a derivative of an xanthone compound is obtained in one - step reaction in a solvent. The structure of the derivative of the xanthone compound is of formula I, and the structure of the xanthone compound is of formula III or formula IV; When obtaining the derivative of the xanthone compound, when the enzyme is porcine pancreas lipase and the solvent is dichloromethane, or when the enzyme is lipase from Thermomyces lanuginosus and the solvent is n - hexane or isopropanol; When obtaining the xanthone compound, the enzyme is lipase from Thermomyces lanuginosus and the solvent is n - hexane; The reaction equation is: ， ， ； where X1 is one of 4 - Cl, 4 - Br, 3 - NO2, 4 - NO2, 3 - Cl, 4 - F, 2,4 - Cl2, 4 - CN, H, 4 - OCH3, 4 - CH3, 4 - OH, 4 - C4H9, 4 - CF3, 4 - OH - 3 - OCH3, 2 - F, 2 - NO2 or 2 - thienyl; X3 is 2,6 - Cl2, The solvent is an organic solvent with a water content volume fraction of 0 - 70%; The dosage of the enzyme is 0 < c ≤ 10 mg / mL, where c is the concentration of the enzyme in the reaction system.

2. The method according to claim 1, characterized in that, The solvent is an organic solvent with a water content of 0.

3. The method according to claim 1, characterized in that, The organic solvent is n - hexane.

4. The method according to claim 1, characterized in that, The molar ratio of the aromatic aldehyde to 1,3 - cyclohexanedione is 1:

2.

5. The method according to claim 1, characterized in that, The concentration of the enzyme in the reaction system is 10 mg / mL.

6. The method according to claim 1, characterized in that, The temperature of the reaction is 25 - 65 °C.

7. The method according to claim 6, characterized in that, The temperature of the reaction is 35 °C.

8. The method according to claim 1, characterized in that, The reaction time is 2 - 32 h.

9. The method according to any one of claims 1-8, characterized in that, The method further includes the step of recovering the enzyme or the solvent after the reaction is completed.

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