A method for preparing a natural product 6-HHS

Abstract

The application provides a preparation method of a natural product 6-HHS, which comprises the following steps: reacting a compound 1, sanguinare, with vinylmagnesium bromide to prepare a compound 2; and reacting the compound 2 with borane tetrahydrofuran complex to prepare 6-HHS. The application uses sanguinare as a raw material to prepare the natural product 6-HHS, has a short synthesis route, high synthesis efficiency, a yield of each step is more than 85%, the comprehensive yield of the natural product 6-HHS can reach 76%, and the operation is simple, the purity is high, and the application can provide a simple and efficient way for chemical synthesis of 6-HHS.

Description

Technical Field

[0001] This invention belongs to the field of natural compound synthesis technology, specifically relating to a method for preparing the natural product 6-HHS. Background Technology

[0002] Natural products serve as an important source of drugs and lead compounds, possessing advantages such as unique mechanisms, significant efficacy, low toxicity, and few side effects. Many widely used and well-known natural products, such as artemisinin, paclitaxel, and vincristine, originate from a rich variety of herbs found in China. Therefore, structural optimization of natural lead compounds can yield candidate drugs for cancer treatment.

[0003] The natural product 6-(2-hydroxyethyl)-5,6-dihydrosanguinarine (6-HHS) is extracted from the medicinal plant *Corydalis fancifolia* and possesses a benzophenanthridine core. Natural products with this core and their derivatives exhibit inhibitory activity against various cancers; in particular, studies have shown that these natural products can inhibit tumor stemness. However, the natural sources of 6-HHS are very limited, and to date, no efficient synthetic route for 6-HHS has been found. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for preparing the natural product 6-HHS, which addresses the shortcomings of the prior art. This method uses sanguisorbin as a raw material to prepare the natural product 6-HHS. The synthetic route is short, the synthetic efficiency is high, the yield of each step is above 85%, and the overall yield of the natural product 6-HHS can reach 76%. Moreover, the operation is simple and the purity is high, which can provide a simple and efficient route for the chemical synthesis of 6-HHS.

[0005] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is: a method for preparing the natural product 6-HHS, the method being as follows:

[0006] S1. Under argon protection, compound 1, sanguinarine, was dissolved in anhydrous tetrahydrofuran solution. The resulting solution was then cooled to 0°C, and a tetrahydrofuran solution of vinyl magnesium bromide was added dropwise. The reaction was stirred at room temperature for 10 hours, and the reaction was quenched with saturated ammonium chloride solution. The solvent tetrahydrofuran was then distilled off under reduced pressure. The remaining organic matter was washed with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The mixture was then separated by column chromatography to obtain compound 2.

[0007] The structural formula of compound 1 is as follows: The structural formula of compound 2 is as follows: ;

[0008] S2. Under argon protection, compound 2 obtained in S1 was dissolved in anhydrous tetrahydrofuran. The resulting solution was then cooled to 0°C, and a tetrahydrofuran solution of the borane tetrahydrofuran complex was added dropwise. The mixture was stirred at room temperature for 10 hours. Then, anhydrous methanol was added to the system at 0°C, and the mixture was brought back to room temperature and stirred for 1 hour. A mixture containing sodium hydroxide and hydrogen peroxide was then added, and the reaction was stirred at room temperature for 24 hours. The solvent tetrahydrofuran was then distilled off under reduced pressure. The remaining organic matter was washed with deionized water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The mixture was then separated by column chromatography to obtain compound 3, 6-(2-hydroxyethyl)-5,6-dihydrosanguinarine, named natural product 6-HHS. The structural formula of natural product 6-HHS is as follows: ;

[0009] The mixture containing sodium hydroxide and hydrogen peroxide is prepared by mixing a 10% sodium hydroxide aqueous solution and a 30% hydrogen peroxide aqueous solution.

[0010] Preferably, the molar ratio of vinyl magnesium bromide in the tetrahydrofuran solution of sanguisorbine and vinyl magnesium bromide in S1 is 1:5.

[0011] Preferably, the ethyl acetate in S1 is extracted three times.

[0012] Preferably, the column chromatography separation conditions in S1 are: silica gel as the stationary phase and the mobile phase polarity is ethyl acetate: petroleum ether = 1v: 90v.

[0013] Preferably, the mixture containing sodium hydroxide and hydrogen peroxide in S2 is prepared by mixing a 10% sodium hydroxide aqueous solution and a 30% hydrogen peroxide aqueous solution in a volume ratio of 4:0.83.

[0014] Preferably, the molar ratio of the boranetetrahydrofuran complex in the tetrahydrofuran solution of compound 2 and the boranetetrahydrofuran complex in S2 is 1:5.

[0015] Preferably, the ethyl acetate extraction in S2 is performed three times.

[0016] Preferably, the column chromatography separation conditions in S2 are: silica gel as the stationary phase and the mobile phase polarity is ethyl acetate:petroleum ether = 1v:6v.

[0017] The present invention also provides the application of the natural product 6-HHS prepared by the above preparation method, wherein the natural product 6-HHS is used to prepare anti-tumor drugs.

[0018] Compared with the prior art, the present invention has the following advantages:

[0019] This invention uses sanguinarine as a raw material to prepare the natural product 6-HHS. The synthetic route is short and the synthesis efficiency is high, with a yield of over 85% for each step. The overall yield of the natural product 6-HHS can reach 76%. Moreover, the operation is simple and the purity is high, which can provide a simple and efficient route for the chemical synthesis of 6-HHS.

[0020] The present invention will now be described in further detail with reference to the accompanying drawings and embodiments. Attached Figure Description

[0021] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of compound 2 prepared in Example 1 of this invention.

[0022] Figure 2 This is the carbon NMR spectrum of compound 2 prepared in Example 1 of this invention.

[0023] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of compound 3 prepared in Example 2 of this invention.

[0024] Figure 4 This is the carbon NMR spectrum of compound 3 prepared in Example 2 of this invention. Detailed Implementation

[0025] Example 1

[0026] This embodiment describes a method for preparing compound 2, which is as follows:

[0027] Under argon protection, compound 1, sanguinarine (1 g, 3 mmol), was dissolved in 150 mL of anhydrous tetrahydrofuran (THF) solution. The resulting solution was then cooled to 0 °C, and a 1 mol / L tetrahydrofuran solution of vinyl magnesium bromide (15 mL, 15 mmol) was added dropwise. The reaction was stirred at room temperature for 10 h, and the reaction was quenched with saturated ammonium chloride (6.95 M) solution. The solvent tetrahydrofuran was then distilled off under reduced pressure. The remaining organic matter was washed with saturated ammonium chloride solution and extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The mixture was then separated by column chromatography under the following conditions: silica gel as the stationary phase and ethyl acetate:petroleum ether polarity = 1:90 (volume ratio) as the mobile phase, yielding a white solid compound 2 (0.97 g, 90% yield).

[0028] The structural formula of compound 1 is as follows: The structural formula of compound 2 is as follows: .

[0029] Figure 1-2The NMR spectra of compound 2 are shown below, specifically the proton and carbon NMR spectra.

[0030] 1 H NMR (400 MHz, Chloroform-d) δ 7.77 (s, 1H), 7.67 (d, J = 8.5 Hz,1H), 7.46 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.10 (s, 1H), 6.88(d, J = 8.1 Hz, 1H), 6.05 (t, J = 7.7 Hz, 4H), 5.82 (td, J = 12.4, 9.1, 4.9Hz, 1H), 4.94 (d, J = 17.3 Hz, 1H), 4.87 (d, J = 9.8 Hz, 2H), 2.71 (s, 3H).

[0031] 13 C NMR (100 MHz, Chloroform-d) δ 148.2, 147.5, 147.0, 145.1, 130.9,123.9, 120.1, 116.5, 107.5, 104.4, 101.5, 101.0, 100.8, 59.4, 42.8, 29.7.

[0032] HRMS (ESI) calculated for: C 22 H 18 NO4 + [M+H] + :360.1230, found: 360.1232.

[0033] Example 2

[0034] This example illustrates a method for preparing the natural product 6-HHS:

[0035] Under argon protection, compound 2 (0.97 g, 2.70 mmol) from Example 1 was dissolved in 31 mL of anhydrous tetrahydrofuran. The resulting solution was then cooled to 0 °C, and a tetrahydrofuran solution of 1 mol / L borane tetrahydrofuran complex (13.50 mL, 13.50 mmol of borane tetrahydrofuran complex) was added dropwise. The mixture was stirred at room temperature for 10 h, and then at 0 °C, 2 mL of anhydrous methanol was added to the system, which was then restored to room temperature and stirred for 1 h. A mixture containing sodium hydroxide and hydrogen peroxide was then added, and the reaction was stirred at room temperature for 24 h. The solvent tetrahydrofuran was then distilled off under reduced pressure, and the remaining... The organic matter was washed with deionized water, then extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The mixture was then separated by column chromatography under the following conditions: silica gel as the stationary phase and a mobile phase polarity of ethyl acetate:petroleum ether = 1:6 (volume ratio). Compound 3 (0.86 g, yield: 85%), namely 6-(2-hydroxyethyl)-5,6-dihydrosanguinarine, was named natural product 6-HHS. The structural formula of natural product 6-HHS is as follows: ;

[0036] The mixture containing sodium hydroxide and hydrogen peroxide is composed of a 10% sodium hydroxide aqueous solution (4 mL) and a 30% hydrogen peroxide aqueous solution (0.83 mL).

[0037] Compound 3 was finally prepared from sanguinarine in Example 1, with an overall yield of 76%.

[0038] Figure 3-4 The NMR spectra of compound 3 are shown below, specifically the proton and carbon NMR spectra.

[0039] 1H NMR (400 MHz, Chloroform-d) δ 7.71 (d, J = 8.6 Hz, 1H), 7.59 (s,1H), 7.53 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.13 (s, 1H), 6.89(d, J = 8.1 Hz, 1H), 6.10 – 6.04 (m, 4H), 5.32 (s, 1H), 4.53 (s, 1H), 3.82(ddt, J = 30.6, 10.7, 6.3 Hz, 2H), 2.73 (s, 3H), 1.82 (d, J = 12.2 Hz, 1H),1.60 (dd, J = 15.2, 4.5 Hz, 1H).

[0040] 13 C NMR (100 MHz, Chloroform-d) δ 148.6, 147.7, 147.1, 144.4, 131.1,125.5, 123.9, 120.1, 116.8, 107.5, 104.6, 101.5, 101.2, 99.9, 56.9, 53.4,43.1, 35.2.

[0041] HRMS (ESI) calculated for: C 22 H 20 NO5 + [M+H] + :378.1336, found: 378.1339.

[0042] The application of the natural product 6-HHS prepared by the preparation method of the present invention, wherein the natural product 6-HHS is used to prepare anti-tumor drugs.

[0043] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention in any way. Any simple modifications, alterations, and equivalent changes made to the above embodiments based on the inventive essence shall still fall within the protection scope of the present invention.

Claims

1. A method for preparing the natural product 6-HHS, characterized in that, The method is as follows: S1. Under argon protection, compound 1, sanguinarine, is dissolved in anhydrous tetrahydrofuran solution. The resulting solution is then cooled to 0°C, and a tetrahydrofuran solution of vinyl magnesium bromide is added dropwise. The reaction is stirred at room temperature for 10 hours, and the reaction is quenched with saturated ammonium chloride solution. The solvent tetrahydrofuran is then distilled off under reduced pressure. The remaining organic matter is washed with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases are combined. The mixture is washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and the solvent is distilled off under reduced pressure. The mixture is then separated by column chromatography to obtain compound 2. The structural formula of compound 1 is as follows: The structural formula of compound 2 is as follows: The molar ratio of vinyl magnesium bromide in the tetrahydrofuran solution of sanguisorbin and vinyl magnesium bromide in S1 is 1:5; the column chromatography separation conditions in S1 are: silica gel as the stationary phase, and the mobile phase polarity is ethyl acetate:petroleum ether = 1v:90v; the ethyl acetate extraction in S1 is performed 3 times. S2. Under argon protection, compound 2 obtained in S1 was dissolved in anhydrous tetrahydrofuran. The resulting solution was then cooled to 0°C, and a tetrahydrofuran solution of the borane tetrahydrofuran complex was added dropwise. The mixture was stirred at room temperature for 10 hours. Then, anhydrous methanol was added to the system at 0°C, and the mixture was brought back to room temperature and stirred for 1 hour. A mixture containing sodium hydroxide and hydrogen peroxide was then added, and the reaction was stirred at room temperature for 24 hours. The solvent tetrahydrofuran was then distilled off under reduced pressure. The remaining organic matter was washed with deionized water, extracted with ethyl acetate, and the organic phases were combined. After washing with saturated brine, drying with anhydrous sodium sulfate, and filtering, the solvent was distilled off under reduced pressure. The mixture was then separated by column chromatography to obtain compound 3, named natural product 6-HHS. The structural formula of natural product 6-HHS is as follows: The mixture containing sodium hydroxide and hydrogen peroxide in S2 is prepared by mixing a 10% sodium hydroxide aqueous solution and a 30% hydrogen peroxide aqueous solution in a volume ratio of 4:0.83; the molar ratio of the boranetetrahydrofuran complex in the tetrahydrofuran solution of compound 2 and the boranetetrahydrofuran complex in S2 is 1:5; the column chromatography separation conditions in S2 are: silica gel as the stationary phase, and the mobile phase polarity is ethyl acetate:petroleum ether = 1v:6v; the ethyl acetate extraction in S2 is performed 3 times.

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