CN115215830A - C-8 hydroxyl substituted brazilein analogue and preparation method and application thereof - Google Patents

C-8 hydroxyl substituted brazilein analogue and preparation method and application thereof Download PDF

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CN115215830A
CN115215830A CN202210987236.3A CN202210987236A CN115215830A CN 115215830 A CN115215830 A CN 115215830A CN 202210987236 A CN202210987236 A CN 202210987236A CN 115215830 A CN115215830 A CN 115215830A
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杨喜花
黄双平
刘江涛
韩雪
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Shanxi Tumour Hospital
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Abstract

The invention relates to a C-8 hydroxyl substituted brazilein analogue, a preparation method and application thereof. Using compound 3, 4-dimethoxy benzyl alcohol as initial material, using Ts protection reaction, SN 2 The method comprises the following steps of reaction, hydroxyl iodination reaction, lithium aluminum hydride reduction reaction, acetylation reaction, ts protection reaction, epoxidation into ether hydrolysis one-pot reaction, parikh-Doering oxidation reaction, prins/Friedel-Crafts one-pot reaction and low-temperature demethylation reaction, and the target brazilin analogue is synthesized. The C-8 hydroxyl substituted Brazil threoThe lignin analog can be used for preparing medicines for treating bladder cancer.

Description

C-8 hydroxyl substituted brazilein analogue and preparation method and application thereof
Technical Field
The invention relates to an anti-tumor drug and a synthesis method thereof, in particular to a C-8 hydroxyl substituted brazilein analogue, a preparation method thereof and application thereof in the aspect of anti-tumor.
Background
The brazilin natural products are a special compound in the traditional Chinese medicine sappan wood, are mainly separated from sappan wood, are discovered successively from the beginning of the 50 s of the 20 th century, and are mainly separated and identified as the following 6 compounds: brazilin, brazilein, brazilide A, haematoxylin, haematoxylane, and Brazilane. The compounds have similar chemical structures, have chroman rings and belong to homoisoflavone derivatives.
The chemical methods for synthesizing brazilein and analogues thereof reported in the literature at present mainly comprise: (1) A research paper entitled The synthesis of Brazilin and Haematoxylin published by Morsingh et al in 1970 on Tetrahedron; (2) A research paper entitled First Synthesis of (+) -Brazilane from (+) -Brazilin published by Jinzhu Xu et al in 1996 on Tetrahedron Letters; (3) Lee et al, 2008, on J. Am. Chem. Soc. A research paper entitled Gold-Catalyzed deoxygenitive Nazarov cycling of 2,4-Dien-1-als for Stereoselective Synthesis of high by Substriented cyclents; (4) A research paper entitled Formal synthesis of (+) -brozilin and total synthesis of (+) -brozilane published by Jiillu Singh Yadav et al in 2014 on Tetrahedron; (5) A research paper entitled Design and synthesis of a hybrid frame of orange and chrome, and total synthesis of a homoisolavonoid, brozilane, published by Jinwoo Kim et al in 2018 on org. Biomol. Chem. The above synthetic route generally has the defects of strict control of reaction conditions, more reaction byproducts and the like.
Disclosure of Invention
The invention aims to provide a novel brazilin analogue and a preparation method and application thereof.
According to one aspect of the invention, the brazilin analogue with the hydroxyl substituted at the C-8 position has the following structure:
Figure 731716DEST_PATH_IMAGE001
the Brazilin analogue with the hydroxyl substituted at the C-8 position provided by the invention is a novel compound, is obtained by introducing an-OH group at the C-8 position in a D ring of Brazilin, and is not reported in the prior art.
According to another aspect of the present invention, there is provided the above-described method for preparing a brazilin analog substituted with a hydroxyl group at the C-8 position, comprising the steps of:
step one, taking 3, 4-dimethoxy benzyl alcohol which is a compound in a formula 1 as an initial raw material, taking dichloromethane as a solvent, adding triethylamine, 4-dimethoxy pyridine and p-toluenesulfonyl chloride into the initial raw material, and performing a mesylation reaction to protect a hydroxyl group, thereby obtaining a compound in a formula 2;
dissolving sodium hydride in a tetrahydrofuran and N, N-dimethylformamide solution, dropwise adding diethyl malonate into the tetrahydrofuran and N, N-dimethylformamide solution, and then dropwise adding a compound shown in the formula 2 into the reaction solution to react to obtain a compound shown in the formula 3;
dissolving the compound shown in the formula 3 in a tetrahydrofuran solution, and sequentially adding elemental iodine and sodium acetate into the tetrahydrofuran solution to obtain a compound shown in a formula 4;
step four, dripping the compound of the formula 4 dissolved in the tetrahydrofuran solution into the tetrahydrofuran solution of lithium aluminum hydride to perform a reduction reaction to obtain a compound of the formula 5;
reacting the compound shown in the formula 5 with acetic anhydride under the condition of taking anhydrous acetonitrile as a solvent, and performing acetyl protection to obtain a compound shown in a formula 6;
sixthly, reacting the compound shown in the formula 6 with p-toluenesulfonyl chloride, triethylamine and 4-dimethylaminopyridine by using anhydrous dichloromethane as a solvent to obtain a compound shown in a formula 7;
step seven, dissolving cesium carbonate and 2, 3-dimethoxyphenol in an N, N dimethylformamide solution at a high temperature, and then dropwise adding a compound of formula 7 dissolved in the N, N dimethylformamide solution to obtain a compound of formula 8;
step eight, adding the compound shown in the formula 8 into a dichloromethane solution containing dimethoxy sulfoxide, sulfur trioxide pyridine and N, N-diisopropylethylamine at the temperature of minus 20 +/-2 ℃ to perform Parikh-Doering oxidation reaction to obtain a compound shown in the formula 9;
step nine, dissolving the compound shown in the formula 9 in dichloromethane, adding trifluoroacetic acid into the dichloromethane, and carrying out Prins/Friedel-Crafts series reaction to obtain a compound shown in the formula 10;
dissolving the compound shown in the formula 10 in dichloromethane at-78 +/-2 ℃, adding a dichloromethane solution of boron tribromide, and performing demethyl ether protection to obtain a target product shown in the formula 11;
the reaction formula is as follows:
Figure 258644DEST_PATH_IMAGE003
further, in the first step, under the protection of nitrogen and at 0 ℃, the compound 3, 4-dimethoxybenzyl alcohol is dissolved in a dichloromethane solution, and DMAP (4-dimethylaminopyridine), tsCl (p-toluenesulfonyl chloride) and Et are sequentially added into the dichloromethane solution 3 N (triethylamine), and then stirring and reacting at room temperature; after the reaction is finished, adding water to quench the reaction, extracting with water, collecting the organic phase, drying with anhydrous sodium sulfate, filtering and concentrating to obtain the compound of formula 2.
Further, in the second step, sodium hydride is dissolved in THF (tetrahydrofuran), DMF (at 0 ℃ under the protection of nitrogen gasN,N-dimethylformamide); then adding diethyl malonate into the flask drop by drop, stirring at 0 ℃, and then adding the compound shown in the formula 2 drop by drop to react; after the reaction is finished, the reaction product is moved to room temperature, 2M hydrochloric acid solution is used for dropwise adding and quenching, ethyl acetate is used for extraction, anhydrous sodium sulfate is used for drying, and the compound of the formula 3 is obtained through filtration, concentration, separation and purification.
Further, in the third step, dissolving the compound of the formula 3 in a tetrahydrofuran solution, sequentially adding elemental iodine and sodium acetate into the tetrahydrofuran solution, then heating to 35 ℃, continuously blowing air into a reaction bottle and stirring for reaction for 48 hours, after the reaction is completed, adding a saturated sodium thiosulfate aqueous solution to quench the reaction, extracting the residual liquid with dichloromethane, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering and concentrating to obtain the compound of the formula 4.
Further, in the fourth step, under the protection of ice-water bath at 0 ℃ and nitrogen, dissolving lithium aluminum hydride in a tetrahydrofuran solution, dropwise adding a compound of formula 4 dissolved in tetrahydrofuran, stirring at 0 ℃, and then moving to room temperature for reaction; after the reaction is finished, cooling the reaction system to 0 ℃, dropwise adding 15% sodium hydroxide solution for quenching, adding dilute hydrochloric acid to adjust the pH of the solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering to remove solid impurities, and separating and purifying the product after reduced pressure concentration to obtain the compound of the formula 5.
Further, in the fifth step, under the protection of nitrogen, dissolving the compound of formula 5 in acetonitrile solution, sequentially adding tetrabutylammonium acetate and acetic anhydride, and heating and stirring for reaction; after the reaction is finished, directly removing the reaction liquid under reduced pressure, and separating and purifying the product to obtain the compound shown in the formula 6.
Further, in the sixth step, the compound of formula 6 is dissolved in dichloromethane under the protection of nitrogen, and DMAP (4-dimethylaminopyridine), p-toluenesulfonyl chloride and triethylamine are sequentially added in an ice water bath, and then the reaction is stirred at room temperature. After the reaction is finished, adding water to quench the reaction, extracting with dichloromethane, and extracting with anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate under reduced pressure, separating and purifying to obtain the compound shown in the formula 7.
Further, in step seven, 2, 3-dimethoxyphenol and cesium carbonate are added and dissolved inN,NHeating to 60 ℃ in dimethylformamide, stirring for reaction, adding the compound of formula 7 into the reaction bottle, continuously heating to 85 ℃ for stirring for reaction, adding water for quenching reaction after the reaction is finished, extracting the reaction solution with ethyl acetate, merging organic phases, washing with saturated NaCl aqueous solution, drying, filtering, concentrating filtrate, separating and purifying to obtain the compound of formula 8.
Further, in the eighth step, the compound of the formula 8 is dissolved in anhydrous dichloromethane at-20 ℃ under the protection of nitrogen, DIPEA (diisopropylethylamine), DMSO (dimethyl sulfoxide), and sulfur trioxide pyridine are sequentially added into the anhydrous dichloromethane, then the temperature is raised to room temperature for reaction, after the reaction is completed, water is added for quenching reaction, ethyl acetate is used for extraction, organic phases are combined and washed by saturated NaCl aqueous solution, the organic phase is dried, filtrate is filtered and concentrated, and the compound of the formula 9 is obtained through separation and purification.
Further, in the ninth step, the compound of formula 9 is dissolved in anhydrous dichloromethane in ice water bath and under nitrogen protection, TFA (trifluoroacetic acid) is slowly added, after the reaction is completed, saturated sodium bicarbonate solution is added to quench the reaction, the reaction solution is extracted with dichloromethane, the organic phase is dried with anhydrous sodium sulfate, filtered, concentrated and separated to obtain the compound of formula 10.
Further, in the tenth step, under the protection of nitrogen, dissolving the compound of formula 10 in anhydrous dichloromethane, then cooling to-78 ℃, dropwise adding boron tribromide, and stirring at-78 ℃ for reaction; after the reaction is finished, adding water to quench the reaction, concentrating under reduced pressure, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, separating and purifying to obtain the compound shown in the formula 11.
According to the above reaction scheme, using known compound 1 as starting material, using Ts protection reaction, SN 2 Reacting, hydroxyl group reaction is carried out by iodine, lithium aluminum hydride reduction reaction, acetylation reaction, ts protection reaction, epoxidation into ether hydrolysis one-pot reaction, parikh-Doering oxidation reaction, prins/Friedel-Crafts one-pot reaction and low-temperature demethylation reaction, thus synthesizing the target brazilin analog.
The synthetic method uses conventional chemical reagents, has mild reaction conditions, simple operation, relatively high speed, less reaction byproducts and greatly shortened synthetic steps, thereby reducing the synthetic cost. Compared with the prior art, the method belongs to a safe, environment-friendly, simple and efficient synthesis route.
The C-8 hydroxyl substituted brazilein analogue belongs to a compound with anticancer activity, and according to another aspect of the invention, the invention provides the application of the C-8 hydroxyl substituted brazilein analogue in preparing a medicament for treating bladder cancer.
Drawings
Fig. 1 to 14 are NMR charts of the following compounds, respectively. Wherein, FIG. 1 shows a compound of formula 3 -1 H NMR; FIG. 2 shows a compound of formula 4 -1 H NMR; FIG. 3 shows a compound of formula 4 -13 C NMR; FIG. 4 is a compound of formula 5 -1 H NMR; FIG. 5 shows compounds of formula 5 -13 C NMR; FIG. 6 is a compound of formula 6 -1 H NMR; FIG. 7 is a compound of formula 6 -13 C NMR; FIG. 8 is a compound of formula 7 -1 H NMR; FIG. 9 is a compound of formula 7 -13 C NMR; FIG. 10 shows compounds of formula 8 -1 H NMR; FIG. 11 is a compound of formula 8 -13 C NMR; FIG. 12 shows compounds of formula 10 - 1 H NMR; FIG. 13 is a compound of formula 10 -13 C NMR; FIG. 14 is a compound of formula 11 -1 H NMR。
Detailed Description
The following examples are intended to further illustrate embodiments of the invention without departing from the scope of the subject matter of the invention, and the scope of the invention is not limited by the examples. Unless otherwise specifically indicated, the materials and reagents used in the present invention are available from commercial products in the art.
Synthesis of compounds of formula 2:
compound 3, 4-Dimethoxybenzyl alcohol of formula 1 (6 mL,41.3 mmol) was dissolved in 100 mL of dry dichloromethane solution (100 mL), and DMAP (4-dimethylaminopyridine) (2.62 g,21.45 mmol), tsCl (p-toluenesulfonyl chloride) 8.16 g (8.16 g,42.8 mmol), et (p-toluenesulfonyl chloride) were sequentially added thereto 3 N (triethylamine) 5mL (5mL, 35.82 mmol). The reaction was then stirred at room temperature for 1 h. To be monitored by TLCV(Petroleum ether):V(ethyl acetate) = 5: 1,R f = 0.5]after completion of the reaction, water was added to quench the reaction, the residue was extracted with water (50 mL. Times.3), the organic phase was collected and anhydrous Na was added 2 SO 4 Drying (sodium sulfate), filtration and concentration gave compound 2 (6.98 g) in 91% yield.
Synthesis of compounds of formula 3:
THF (tetrahydrofuran) (24 mL), DMF (N, N) was added in an ice-water bath at 0 ℃ under nitrogen protectionN,NDimethylformamide) (24 mL) was dissolved with sodium hydride (1.38g, 20.12 mmol). Diethyl malonate (6.6 mL,43.47 mmol) is added dropwise into the flask, and after stirring at 0 ℃ for 30 min, compound 2 (5.4 g,16.77 mmol) is added dropwise and reacted for 12 h. After the reaction is finished, the reaction system is moved to room temperature and dissolved by 2M hydrochloric acidThe solution was quenched dropwise, extracted with ethyl acetate (50 mL. Times.3), anhydrous Na 2 SO 4 Drying, filtering to remove solid impurities, concentrating under reduced pressure, and performing column chromatographyV(Petroleum ether):V(ethyl acetate) = 2: 1,R f = 0.6]the product was isolated and purified, and finally the eluent was concentrated to give colorless transparent liquid 3 (4.81 g) in 92% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 6.75 (d, J = 8.50 Hz, 1H), 6.73 (d, J = 1.70 Hz, 1H), 6.71 (s, 1H), 4.13 (qd, J = 7.12, 3.95 Hz, 4H), 3.83 (s,3H), 3.82 (s, 3H), 3.59 (t, J = 7.74 Hz, 1H), 3.14 (d, J = 7.79 Hz, 2H), 1.19 (t, J = 7.08 Hz, 6H). HRMS (ESI-TOF) calcd for C 16 H 22 O 6 H [M+H] + 311.1494, found 311.1493.
Synthesis of compounds of formula 4:
compound 3 (0.2 g,0.64 mmol) was dissolved in a tetrahydrofuran solution (6 mL), and elemental iodine (0.164g, 0.64 mmol) and sodium acetate (0.088g, 0.64 mmol) were added thereto in this order. Then the temperature is increased to 35 ℃, and air is continuously blown into the reaction bottle and is stirred for reaction for 48 hours. To be monitored by TLCV(Petroleum ether):V(ethyl acetate) = 2: 1]After completion of the reaction, the reaction was quenched by addition of a saturated aqueous solution of sodium thiosulfate, most of the tetrahydrofuran was removed under reduced pressure, the residue was extracted with methylene chloride (10 mL. Times.3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatographyV(Petroleum ether):V(ethyl acetate) = 2: 1,R f = 0.3]pale yellow oily liquid 4 (0.18 g) was obtained in 90% yield. 1 H NMR (600 MHz, CHCl 3 ) δ: 6.80 (s, 1H), 6.77-6.73 (m, 2H), 4.26-4.20 (m, 4H), 3.83 (s, 6H), 3.27 (s, 2H), 1.27 (t, J = 7.1 Hz, 6H); 13 C NMR (151 MHz, CHCl 3 ) δ: 170.04, 148.57, 148.29, 127.17, 122.50, 113.86, 110.92, 79.44, 62.60, 55.88, 55.87, 40.20, 14.12; HRMS (ESI-TOF) calcd for C 16 H 22 O 7 H [M+H] + 327.1444, found 327.1446.
Synthesis of compounds of formula 5:
lithium aluminum hydride (0.072 g,1.85 mmol) was added to a solution of anhydrous tetrahydrofuran (5 mL) in an ice-water bath at 0 ℃ under nitrogen. A solution of compound 4 (0.3 g,0.92 mmol) in tetrahydrofuran (5 mL) was then added dropwise to the flask and stirred at 0 ℃ for 30 min before moving to room temperature for reaction for 3h. After the reaction is finished, cooling the reaction system to 0 ℃, dropwise adding 15% sodium hydroxide solution for quenching, adding dilute hydrochloric acid to adjust the pH of the solution to about 5, extracting with ethyl acetate (10 mL multiplied by 3), and adding anhydrous Na 2 SO 4 Drying, filtering to remove solid impurities, concentrating under reduced pressure, and purifying with column chromatography [ 2 ]V(Petroleum ether):V(ethyl acetate) = 1: 4,R f = 0.3]the purified product was isolated and the final eluent was concentrated to give 5 (0.168 g) as a colorless oil in 75% yield. 1 H NMR (600 MHz, CHCl 3 ) δ: 6.79 (d, J = 2.0Hz, 1H), 6.77 (s,1H), 6.74 (dd, J = 8.1, 1.7 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.53 (dd, J = 26.7, 11.2 Hz, 4H), 3.02(brs, 3H), 2.71 (s, 2H); 13 C NMR (151 MHz, CHCl 3 ) δ: 148.90, 148.07, 128.66, 122.50, 113.88, 111.29, 74.43, 66.28, 62.60, 56.30, 40.18, 29.87; HRMS (ESI-TOF) calcd for C 12 H 18 O 5 H [M+H] + 243.1232, found 243.1231.
Synthesis of compounds of formula 6:
under the protection of nitrogen, compound 5 (1.182 g,4.9 mmol) is dissolved in acetonitrile solution (15 mL), tetrabutylammonium acetate (2.94 g,9.8 mmol) and acetic anhydride (0.28mL, 3.0 mmol) are added in sequence, the temperature is raised to 40 ℃, and the reaction is stirred for 3h. After the reaction is completed, the reaction solution is directly removed under reduced pressure and subjected to column chromatographyV(Petroleum ether):V(ethyl acetate) = 1: 1,R f =0.3]the purified product was isolated to give 6 (1.15 g) as a dark yellow oily liquid in 72% yield. 1 H NMR (600 MHz, CHCl 3 ) δ: 6.77 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 6.70 (dd, J = 8.1, 1.9 Hz, 1H), 3.99 (s, 4H), 3.82 (s, 6H), 2.78 (s, 2H), 2.07 (s, 6H); 13 C NMR (151 MHz, CHCl 3 ) δ: 170.85, 148.76, 148.08, 127.28, 122.48, 113.50, 111.13, 72.46, 66.27, 55.85, 55.81, 40.22, 20.87; HRMS (ESI-TOF) calcd for C 14 H 20 O 6 H [M+H] + 285.1338, found 285.1336.
Synthesis of compounds of formula 7:
compound 6 (0.14 g,0.49 mmol) is dissolved in dichloromethane (3 mL) under the protection of ice-water bath and nitrogen, DMAP (4-dimethylaminopyridine) (0.019 g,0.15 mmol), p-toluenesulfonyl chloride (0.113 g,0.59 mmol) and triethylamine (0.14mL, 0.98 mmol) are sequentially added to the solution, and then the reaction flask is moved to room temperature and stirred for 1 h. To be monitored by TLCV(Petroleum ether):V(ethyl acetate) = 2: 3]After completion of the reaction, the reaction was quenched with water and extracted with dichloromethane (5 mL. Times.3), and the organic phases were combined and extracted with anhydrous Na 2 SO 4 Drying, filtering to remove sodium sulfate, concentrating the filtrate under reduced pressure, separating the residual liquid by column chromatography, collecting the eluent containing the target product, and concentrating under reduced pressure to obtain pale yellow oily liquid 7 (0.179 g), yield 83%. 1 H NMR (600 MHz, CHCl 3 ) δ: 7.78 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 6.77(s, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.67 (dd, J = 8.1, 1.9 Hz, 1H), 3.99 (q, J = 11.6 Hz, 2H), 3.88 (q, J = 7.8 Hz, 2H), 3.85 (d, J = 2.5 Hz, 6H), 2.78 (dd, J = 33.1, 14.0 Hz, 2H), 2.45 (s, 3H), 1.99 (s, 3H); 13 C NMR (151 MHz, CHCl 3 ) δ: 170.77, 149.10, 148.42, 145.31, 132.54, 130.07, 128.17, 126.65, 122.60, 113.71, 111.34, 72.28, 70.32, 66.32, 56.00, 39.72, 21.78, 20.78; HRMS (ESI-TOF) calcd for C 21 H 26 O 8 SH [M+H] + 439.1427, found 439.1422.
Synthesis of compounds of formula 8:
adding 2, 3-dimethoxyphenol (0.094 mL,0.69 mmol) and cesium carbonate (0.74 g,2.27 mmol) into a 25 mL round-bottomed flask containing N, N-dimethylformamide (3 mL) under a nitrogen atmosphere, heating to 60 ℃, stirring for reaction for 30 min, adding compound 7 (0.2 g,0.46 mmol) into the reaction flask, and reacting 7After h, the temperature is continuously raised to 90 ℃, the reaction is stirred for 1h, and the TLC monitoring is carried outV(Petroleum ether):V(ethyl acetate) = 1: 1,R f = 0.3]after completion of the reaction, the reaction was quenched by adding water, the reaction solution was extracted with ethyl acetate (5 mL. Times.3), the organic phases were combined and washed 5 times with saturated aqueous NaCl solution, and the organic phase was washed with anhydrous Na 2 SO 4 Drying, filtering to remove solid, concentrating the filtrate, and subjecting the residual solution to column chromatographyV(Petroleum ether):V(ethyl acetate) = 1: 1]This was isolated as 8 (0.12 g) as a brown oil in 71% yield. 1 H NMR (600 MHz, CDCl 3 ) δ 6.95 (t, J = 8.35 Hz, 1H), 6.80 (s, 1H), 6.78 (d, J = 1.69 Hz, 2H), 6.60 (d, J = 8.43 Hz, 1H), 6.51 (d, J = 7.09 Hz, 1H), 3.89 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.81 (d, J = 9.13 Hz, 1H), 3.75 (d, J = 11.29 Hz, 1H), 3.72 (s, 3H), 3.65 (d, J = 11.28 Hz, 1H), 2.94 (d, J = 13.81 Hz, 1H), 2.90 (d, J = 13.80 Hz, 1H). 13 C NMR (151 MHz, CDCl 3 ) δ 153.75, 152.58, 148.86, 147.98, 138.73, 128.54, 124.08, 122.42, 113.65, 111.14, 107.60, 106.21, 74.00, 72.60, 66.55, 61.17, 56.18, 55.96, 55.77, 40.24. HRMS (ESI-TOF) calcd for C 20 H 26 O 7 H [M+H] + 379.1757, found 379.1755.
Synthesis of a compound of formula 9:
compound 8 (0.58 g,1.53 mmol) was dissolved in a 25 mL round bottom flask with anhydrous dichloromethane (8 mL) under nitrogen protection, the reaction flask was placed in an ice-water bath, DIEPA (diisopropylethylamine) (1.33 mL,7.64 mmol), DMSO (dimethyl sulfoxide) (1.09 mL,15.23 mmol), pyridine trioxide (1.22 g,7.66 mmol) were added sequentially thereto, the reaction was stirred at 0 ℃ for 1h, after completion of TLC monitoring [ V (petroleum ether) = V (ethyl acetate) = 1: 1, rf = 0.4] reaction, the reaction was quenched by addition of an appropriate amount of dilute hydrochloric acid, the reaction solution was extracted with dichloromethane (3 mL × 3), the organic phase was dried with anhydrous Na2SO4, solids were removed by filtration, the filtrate was concentrated to remove the organic solvent, and the residue was isolated by column chromatography [ V (petroleum ether): V (ethyl acetate): 1] to give 9 (0.36 g) as a yellow oil with a yield of 62%.
Synthesis of compounds of formula 10:
after compound 9 (0.21 g,0.56 mmol) was dissolved in anhydrous dichloromethane in an ice water bath under nitrogen protection, 6 equivalents of TFA (trifluoroacetic acid) (0.25 mL,3.36 mmol) was slowly added, the color of the reaction solution was observed to change to amber, and upon TLC monitoring [ V (petroleum ether) = V (ethyl acetate) = 1: 1, rf = 0.4-0.6] completion of the reaction, the reaction was quenched by addition of an appropriate amount of saturated sodium bicarbonate solution, the reaction solution was extracted with dichloromethane (5 mL × 3), the organic phase was dried with anhydrous Na2SO4, the solid was removed by filtration, the filtrate was concentrated to remove the organic solvent, and the residue was separated by column chromatography [ V (petroleum ether) = V (ethyl acetate) = 2: 1] to give 10 (0.18 g) of white solid in 92% yield. 1H NMR (600 MHz, CDCl 3) δ 7.10 (d, J = 8.58 Hz, 1H), 6.79 (s, 1H), 6.74 (s, 1H), 6.68 (d, J = 8.56 Hz, 1H), 4.14 (dd, J = 12.85, 1.70 Hz, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.85 (s, 1H), 3.84 (s, 3H), 3.25 (d, J = 15.78 Hz, 1H), 2.91 (d, J = 15.83 Hz, 1H), 13C NMR (151 MHz, 107 cl 3) δ 152.21, 148.94, 148.56, 147.57, 137.78, 135.97, 130.78, 124.90, 116.50, 108.57, 107.106, 107.08, CDCl 3.21, 148.94, 148.56, 14919.77, 19.77, 19.42, 19.26.26, 19H + 20 TOF, 19.26.26.26.26H, 12H, + 12H.
Synthesis of the target product formula 11:
compound 10 (0.1 g,0.28 mmol) was added to a 25 mL round bottom flask charged with anhydrous dichloromethane (3 mL) under nitrogen, then cooled to-78 deg.C, boron tribromide (0.7 mL,1.4 mmol, 2M) was added dropwise to the reaction and the reaction stirred at-78 deg.C for 1 h. For TLC monitoring [ V (petroleum ether) = 1: 2, rf = 0.3]After the reaction, water was added to quench the reaction, the reaction mixture was concentrated under reduced pressure to remove methylene chloride, the reaction mixture was extracted with ethyl acetate (3 mL. Times.3), the organic phase was dried over anhydrous Na2SO4, the solid was removed by filtration, and the residue obtained after the organic phase was concentrated was subjected to column chromatography [ V (petroleum ether): V (ethyl acetate) = 1: 2)]Red solid 11 (0.056 g) was isolated in 67% yield. 1 H NMR (400 MHz, DMSO) δ 6.64 (s, 1H), 6.62 (d, J = 8.5 Hz, 1H), 6.53 (s, 1H), 6.41 (d, J = 8.3 Hz, 1H), 3.90 (d, J = 11.0 Hz, 1H), 3.85 (s, 1H), 3.59 (d, J = 11.0 Hz, 1H), 2.88 (d, J = 15.7 Hz, 1H), 2.72 (d, J = 15.8 Hz, 1H). HRMS (ESI-TOF) calcd for C 16 H 14 O 6 H [M+H] + 303.0868 found 303.0869.
Inhibition of C-8 hydroxyl substituted brazilin analogue on bladder cancer cell T24
Experimental materials:
1. cell lines: t24 cells.
2, reagents and consumables: mcCoy's 5A basal medium was purchased from Wuhan Punuo Sai Life technologies, inc.; fetal bovine serum was purchased from Gibco, usa; trypsin and Tetramethylazoloyl blue (MTT) were purchased from Solarbio, beijing; dimethyl sulfoxide (DMSO) was purchased from Tianjin, nature Chemicals, inc.; 96 well cell culture plates were purchased from Corning, usa.
3. Medicine preparation: c-8 hydroxyl substituted brazilin analog.
4. The biological safety cabinet of instrument: qingdaohai medical low temperature science and technology, inc.; CO 2 2 An incubator: germany Thermo310; an inverted microscope: leica 090-135.001 in Germany; an optical microscope: olympus CX21FS1, japan; an electronic balance: ATY224 of shimadzu corporation; sunRise microplate reader: tecan Inc. Austria.
Experimental method
1. Experiment grouping
Cell-free medium zero-adjusted group, blank control group, brazilin analogs 200, 125, 78.125, 48.83, 30.52, 19.07 μ g/ml.
2. Cell culture
Culturing T24 cells in McCoy's 5A medium containing 10% fetal bovine serum, setting at 37 deg.C, 5% 2 And culturing in a constant-temperature incubator with saturated humidity. The experiment was performed by taking cells in the logarithmic growth phase and digesting the cells with 0.25% trypsin to prepare a cell suspension.
3 MTT method for detecting influence of brazilin analogue on T24 cell inhibition rate in 24 hours
3.1 T24 cells were cultured at 8X 10 3 One well per well was inoculated into a 96-well plate, and 100. Mu.l of the medium was added to each well, which was incubated at 37 ℃ and 5% CO 2 The culture was carried out overnight in an incubator.
3.2 After the cells adhere to the wall, the original culture medium is removed, 200 mul of culture medium containing drugs with different concentrations is added according to the grouping method, a cell-free culture medium is set as a zero setting group (5 duplicate wells are set), each drug group is provided with 5 duplicate wells, and a blank control group is provided with 10 duplicate wells.
3.3 adding medicine for 24h, removing the original culture medium, adding 100 μ l of culture medium containing 0.5mg/ml MTT into each well, and continuing to culture for 4h. After 4h, the medium containing MTT in the wells was removed, 150. Mu.l DMSO was added to each well, the mixture was placed in a microplate reader and shaken at a low speed for 10min to dissolve the crystals sufficiently, and the absorbance (OD value) at a wavelength of 492nm was measured. The inhibition rate of each concentration of the drug on the T24 cells was calculated.
Inhibition (%) = (control mean OD value-experimental mean OD value)/control mean OD value × 100%.
Statistical method
Statistical analysis is carried out by SPSS 21.0 statistical software, data are normally distributed, ANOVO single-factor variance analysis is adopted, and variance is adoptedLSD-t Checking, and using varianceDunnett’s T3And (6) checking. If the data are distributed in a non-normal way, a non-parametric test is adopted,P<a difference of 0.05 is statistically significant.
Results of the experiment
The inhibition of the brazilin analogue on T24 is 88.01 percent at the maximum concentration of 200 mug/ml, and then the inhibition rate is gradually reduced along with the reduction of the drug concentration, and is dose-dependent. The IC50 of the Brazilian hematoxylin analogue on bladder cancer cells for 24h was calculated to be 75.33. Mu.g/ml.
OD (optical density) values and inhibition rates of various experimental groups after different concentrations of brazilein analogs act on bladder cancer cell T24 for 24 hours
Grouping OD value Inhibition rate
Control group 0.734±0.034 —
200μg/ml 0.088±0.022 * 88.01%
125μg/ml 0.176±0.053 * 76.02%
78.125μg/ml 0.353±0.064* 51.91%
48.83μg/ml 0.506±0.074 * 31.06%
30.52μg/ml 0.632±0.066 * 13.90%
19.07 μg/ml 0.705±0.085 * 3.95%
Note: * P <0.05 compared to control.

Claims (13)

1. The C-8 hydroxyl substituted brazilein analogue is characterized by having the following structure:
Figure 39495DEST_PATH_IMAGE001
。
2. the method for preparing a brazilin analog substituted with hydroxyl at C-8 position according to claim 1, comprising the steps of:
step one, taking 3, 4-dimethoxybenzyl alcohol of a compound in a formula 1 as an initial raw material, taking dichloromethane as a solvent, adding triethylamine, 4-dimethoxypyridine and p-toluenesulfonyl chloride into the initial raw material, and carrying out a mesylation reaction on a protecting group on a hydroxyl group to obtain a compound in a formula 2;
dissolving sodium hydride in a tetrahydrofuran and N, N-dimethylformamide solution, dropwise adding diethyl malonate into the tetrahydrofuran and N, N-dimethylformamide solution, and then dropwise adding a compound shown in the formula 2 into the reaction solution to react to obtain a compound shown in the formula 3;
dissolving the compound shown in the formula 3 in a tetrahydrofuran solution, dropwise adding iodine and sodium acetate trihydrate into the tetrahydrofuran solution, and reacting to obtain a compound shown in a formula 4;
step four, dripping the compound of the formula 4 dissolved in the tetrahydrofuran solution into the tetrahydrofuran solution of lithium aluminum hydride for reduction reaction to obtain a compound of a formula 5;
reacting the compound shown in the formula 5 with acetic anhydride under the condition of taking anhydrous acetonitrile as a solvent, and performing acetyl protection to obtain a compound shown in a formula 6;
sixthly, reacting the compound shown in the formula 6 with p-toluenesulfonyl chloride, triethylamine and 4-dimethylaminopyridine by using anhydrous dichloromethane as a solvent to obtain a compound shown in a formula 7;
step seven, dissolving cesium carbonate and 2, 3-dimethoxyphenol in an N, N dimethylformamide solution at high temperature, and then dropwise adding a compound of formula 7 dissolved in the N, N dimethylformamide solution to obtain a compound of formula 8;
step eight, dissolving the compound shown in the formula 8 in a dichloromethane solution at the temperature of minus 20 +/-2 ℃, adding N, N-diisopropylethylamine, dimethoxy sulfoxide and sulfur trioxide pyridine, and carrying out Parikh-Doering oxidation reaction to obtain a compound shown in the formula 9;
step nine, dissolving the compound shown in the formula 9 in dichloromethane, adding trifluoroacetic acid into the dichloromethane, and performing Prins/Friedel-Crafts series reaction to obtain a compound shown in a formula 10;
step ten, dissolving the compound of formula 10 in dichloromethane at-78 ± 2 ℃, adding boron tribromide, and removing ether for protection to obtain the target compound of formula 11.
3. The reaction formula is as follows:
Figure DEST_PATH_IMAGE003
the method of claim 2, wherein: in the first step, under the protection of nitrogen and 0 ℃, the compound 3, 4-dimethoxy benzyl alcohol is dissolved in a dichloromethane solution, and DMAP (4-dimethylamino pyridine), tsCl (p-toluenesulfonyl chloride) and Et are sequentially added into the dichloromethane solution 3 N (triethylamine), and then stirring at room temperature for reaction; after the reaction is finished, adding water to quench the reaction, extracting with water, collecting the organic phase, drying with anhydrous sodium sulfate, filtering and concentrating to obtain the compound of formula 2.
4. The production method according to claim 2 or 3, characterized in that: in the second step, sodium hydride is dissolved in THF (tetrahydrofuran), DMF (tetrahydrofuran) under the protection of nitrogen and in an ice-water bath at 0 DEG CN,N-dimethylformamide); then adding diethyl malonate into the flask drop by drop, stirring at 0 ℃, and then adding the compound shown in the formula 2 drop by drop to react; after the reaction is finished, moving to room temperature, dropwise adding and quenching by using a 2M hydrochloric acid solution, extracting by using ethyl acetate, drying by using anhydrous sodium sulfate, filtering, concentrating, separating and purifying to finally obtain the compound shown in the formula 3.
5. The method of claim 4, wherein: in the third step, the compound shown in the formula 3 is dissolved in a tetrahydrofuran solution, elemental iodine and sodium acetate are sequentially added into the tetrahydrofuran solution, then the temperature is raised to 35 ℃, air is continuously blown into a reaction bottle, and the mixture is stirred and reacts for 48 hours; after the reaction was completed, a saturated aqueous solution of sodium thiosulfate was added to quench the reaction, the residual solution was extracted with dichloromethane, the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the compound of formula 4.
6. The production method according to claim 2 or 5, characterized in that: in the fourth step, under the protection of ice-water bath at 0 ℃ and nitrogen, dissolving lithium aluminum hydride in a tetrahydrofuran solution, dropwise adding a compound of formula 4 dissolved in tetrahydrofuran, stirring at 0 ℃, and then moving to room temperature for reaction; after the reaction is finished, cooling the reaction system to 0 ℃, dropwise adding and quenching the reaction system by using 15% sodium hydroxide solution, adding dilute hydrochloric acid to adjust the pH of the solution, extracting the solution by using ethyl acetate, drying the solution by using anhydrous sodium sulfate, filtering the solution to remove solid impurities, and separating and purifying the product after reduced pressure concentration to obtain the compound shown in the formula 5.
7. The method of manufacturing according to claim 6, characterized in that: dissolving the compound shown in the formula 5 in an acetonitrile solution under the protection of nitrogen, sequentially adding tetrabutylammonium acetate and acetic anhydride, and heating and stirring for reaction; after the reaction is finished, directly removing the reaction liquid under reduced pressure, and separating and purifying the product to obtain the compound shown in the formula 6.
8. The production method according to claim 2 or 7, characterized in that: in the sixth step, under the protection of nitrogen, dissolving the compound shown in the formula 6 in dichloromethane, sequentially adding DMAP (4-dimethylaminopyridine), p-toluenesulfonyl chloride and triethylamine in an ice water bath, and then stirring at room temperature for reaction;
after the reaction is finished, adding water to quench the reaction, extracting with dichloromethane, and extracting with anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate under reduced pressure, separating and purifying to obtain the compound shown in the formula 7.
9. The method of claim 8, wherein: in the seventh step, 2, 3-dimethoxyphenol and cesium carbonate are added and dissolved inN,NHeating to 60 ℃ in dimethylformamide, stirring for reaction, adding the compound of formula 7 into the reaction bottle, continuously heating to 85 ℃ for stirring for reaction, adding water for quenching reaction after the reaction is finished, extracting the reaction solution with ethyl acetate, merging organic phases, washing with saturated NaCl aqueous solution, drying, filtering, concentrating filtrate, separating and purifying to obtain the compound of formula 8.
10. The production method according to claim 2 or 9, characterized in that: and step eight, dissolving the compound shown in the formula 8 into anhydrous dichloromethane at-20 ℃ under the protection of nitrogen, sequentially adding DIPEA (diisopropylethylamine), DMSO (dimethyl sulfoxide) and pyridine trioxide, heating to room temperature for reaction, adding water after the reaction is finished, quenching the reaction, extracting with ethyl acetate, combining organic phases, washing with a saturated NaCl aqueous solution, drying the organic phases, filtering and concentrating filtrate, and separating and purifying to obtain the compound shown in the formula 9.
11. The method for producing as claimed in claim 10, characterized in that: in the ninth step, the compound shown in the formula 9 is dissolved in anhydrous dichloromethane in ice water bath and under the protection of nitrogen, TFA (trifluoroacetic acid) is slowly added, after the reaction is finished, saturated sodium bicarbonate solution is added to quench the reaction, dichloromethane is used for extracting the reaction solution, the organic phase is dried by anhydrous sodium sulfate, and the compound shown in the formula 10 is obtained by filtration, concentration and separation.
12. The method of claim 11, wherein: in the tenth step, under the protection of nitrogen, dissolving the compound shown in the formula 10 in anhydrous dichloromethane, then cooling to-78 ℃, dropwise adding boron tribromide, and stirring at-78 ℃ for reaction; after the reaction is finished, adding water to quench the reaction, decompressing and concentrating, extracting by ethyl acetate, drying the organic phase by anhydrous sodium sulfate, filtering and concentrating, separating and purifying to obtain the compound shown in the formula 11.
13. Use of the brazilin analog of claim 1 in the manufacture of a medicament for the treatment of bladder cancer.
CN202210987236.3A 2022-08-17 2022-08-17 C-8 hydroxyl substituted brazilein analogue and preparation method and application thereof Pending CN115215830A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101045046A (en) * 2006-03-31 2007-10-03 上海安普生物科技有限公司 Use of Brazil hemoatoxy type compound for preparing antineoplastic
CN101904892A (en) * 2010-05-22 2010-12-08 山西省肿瘤医院 Preparation process for Sappan Wood extract perfusate and application thereof in treating bladder cancer
CN112574163A (en) * 2021-01-29 2021-03-30 山西省肿瘤研究所 Method for synthesizing Brazilin natural product (+) -Brazilin
CN112608296A (en) * 2021-01-12 2021-04-06 山西省肿瘤研究所 Method for synthesizing brazilanin natural product Brazilane

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101045046A (en) * 2006-03-31 2007-10-03 上海安普生物科技有限公司 Use of Brazil hemoatoxy type compound for preparing antineoplastic
CN101904892A (en) * 2010-05-22 2010-12-08 山西省肿瘤医院 Preparation process for Sappan Wood extract perfusate and application thereof in treating bladder cancer
CN112608296A (en) * 2021-01-12 2021-04-06 山西省肿瘤研究所 Method for synthesizing brazilanin natural product Brazilane
CN112574163A (en) * 2021-01-29 2021-03-30 山西省肿瘤研究所 Method for synthesizing Brazilin natural product (+) -Brazilin

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