Compound Pterosinade A and preparation method thereof
Through a series of organic synthesis steps, Pterosinsade A and its isomers were successfully prepared, which solved the problem of lack of its chemical synthesis method in the prior art, and achieved simplification of the synthesis method and expansion of application prospects.
Patent Information
- Application Number
- CN202411922656.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-25
- Publication Date
- 2025-04-08
AI Technical Summary
The lack of chemical synthesis methods of Pterosinsade A in the prior art limits its application in drug development and research.
Through a series of organic synthesis steps, including the reaction of compound (I) with propylene oxide (II), alkylation of alcohol hydroxyl groups, acylation, oxidation-acylation and elimination reactions, Pterosinsade A and its isomers are finally obtained through chiral resolution.
It provides a simple and easy-to-operate Pterosinsade A synthesis method, which has important practical value and application prospects, filling the gap in the lack of chemical synthesis methods in the prior art.
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Figure CN119775119A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of chemical medicine, and specifically relates to a compound Pterosinsade A and a preparation method thereof. Background Art
[0002] Chinese patent CN202211665537.0 discloses a monomer compound Pterosinsade A, which is extracted from rough pteris, and has the effects of inhibiting oxidative stress damage of nerve cells, promoting the secretion of brain-derived neurotrophic factor by hippocampal neurons, reducing the expression of inflammatory factors, and regulating the differentiation of hippocampal neural stem cells into neurons. It has the effect of promoting hippocampal neurogenesis and exerts its effect by activating the Wnt signaling pathway. Studies have shown that Pterosinsade A can reduce the apoptosis of neural stem cells overexpressing the APP gene, promote their proliferation and neuronal differentiation. In addition, Pterosinsade A also promotes hippocampal neurogenesis together with Pteris laeta Wall. extracts, and has potential applications in drugs for the treatment of Alzheimer's disease. These findings indicate that Pterosinsade A and extracts derived from it have potential therapeutic effects in preventing cognitive impairment, but there is currently no chemical synthesis method for Pterosinsade A. Based on this, the present invention provides a method for synthesizing Pterosinsade A. Summary of the invention
[0003] The object of the present invention is to provide a method for preparing a compound Pterosinsade A, comprising the following steps:
[0004] Step 1, compound (I) reacts with propylene oxide (II) to obtain compound (III);
[0005]
[0006] wherein R1 is selected from F, Cl, Br, I, boric acid, boric ester or triflate;
[0007] Step 2, the alcoholic hydroxyl group of compound (III) undergoes an alkylation reaction to obtain compound (IV);
[0008]
[0009] Step 3, 2-methylmalonic acid (V) is used to prepare 2-methylmalonyl dichloride (VI);
[0010]
[0011] Step 4, compound (IV) undergoes Friedel-Crafts acylation reaction with (VI) to obtain compound (VII);
[0012]
[0013] Step 5, compound (VII) undergoes oxidation-acylation reaction to obtain compound (VIII);
[0014]
[0015] Step 6, compound (VIII) undergoes elimination reaction to obtain compound (IX);
[0016]
[0017] Step 7, performing chiral separation on compound (IX) to obtain compound Pterosinsade A (PA for short) and its isomer Pterosinsade B (PB for short);
[0018]
[0019] Furthermore, in step 1, in the presence of an organic solvent, compound (I) is mixed with n-BuLi and propylene oxide (II) at a molar ratio of 1:(1-3):(1-3) at -78-0°C, and then the temperature is naturally raised to room temperature for reaction for 0.5-6h to obtain compound (III).
[0020] Furthermore, the organic solvent in step 1 includes tetrahydrofuran, methyltetrahydrofuran, dioxane, diethyl ether or ethylene glycol dimethyl ether.
[0021] Furthermore, in step 2, in the presence of an organic solvent, compound (III) is reacted with a basic inorganic salt and a methylating agent in a molar ratio of 1:(1-3):(1-3) at 10-60° C. for 1-12 h to obtain compound (IV).
[0022] Furthermore, in step 2, the alkaline inorganic salt includes NaH, KH, CaH2, sodium tert-butoxide, sodium methoxide or sodium ethoxide, etc.; the methylating agent includes methyl iodide, methyl bromide, dimethyl sulfate or dimethyl carbonate, etc.; the organic solvent includes tetrahydrofuran, methyltetrahydrofuran, dioxane, ether or ethylene glycol dimethyl ether, etc.
[0023] Furthermore, in step 3, 2-methylmalonic acid (V) is stirred in the presence of thionyl chloride or phosphorus oxychloride at 50-100° C. for 12-48 h to obtain 2-methylmalonyl dichloride (VI).
[0024] Further, in step 4, compound (IV) is reacted with Lewis acid and 2-methylmalonyl chloride (VI) in an organic solvent at 40-60° C. for 1-6 hours to obtain compound (VII); wherein the molar ratio of compound (IV), Lewis acid and 2-methylmalonyl chloride (VI) is 1:(1-5):(1-3).
[0025] Furthermore, in step 4, the organic solvent includes CS2, CH2Cl2, CHCl3, CCl4, acetonitrile, ether or ethylene glycol dimethyl ether, etc.; the Lewis acid includes AlCl3, BF3, ZnCl2 or TiCl4, etc.
[0026] Further, in step 5, compound (VII) is reacted with Pb(OAc)4 in a molar ratio of 1:(1-5) at room temperature for 8-24 hours to obtain compound (VIII).
[0027] Furthermore, in step 6, compound (VIII) is subjected to elimination reaction with a demethylation and acetylating agent in a molar ratio of 1:(2-10), the reaction temperature is 60-100° C., and the reaction time is 8-24 h to obtain compound (IX).
[0028] Furthermore, the demethylation and acetylation reagent is HBr or EtSH.
[0029] Beneficial effects of the invention: The invention provides a method for preparing Pterosinsade A, which has simple synthesis steps and is easy to operate, and has important practical value and application prospects. BRIEF DESCRIPTION OF THE DRAWINGS
[0030] Figure 1 The following is a reaction scheme of the synthesis method of the present invention.
[0031] Figure 2 This is the H NMR spectrum of 2-(2,6-dimethylphenyl)ethanol synthesized in Example 1.
[0032] Figure 3 This is the H NMR spectrum of 2-(2-methoxyethyl)-1,3-dimethylbenzene synthesized in Example 1.
[0033] Figure 4 This is the H NMR spectrum of 5-(2-methoxyethyl)-2,4,6-trimethyl-1H-indene-1,3(2H)-dione synthesized in Example 1.
[0034] Figure 5 This is the H NMR spectrum of 5-(2-methoxyethyl)-2,4,6-trimethyl-1,3-diketo-2,3-dihydro-1H-inden-2-yl acetate synthesized in Example 1.
[0035] Figure 6 This is the H NMR spectrum (400 MHz, DMSO) of compound PA synthesized in Example 1.
[0036] Figure 7 This is the H NMR spectrum (400 MHz, DMSO) of compound PB synthesized in Example 1. DETAILED DESCRIPTION
[0037] The following is a detailed description of the embodiments of the present invention in conjunction with the accompanying drawings and technical solutions, but the present invention is not limited thereto.
[0038] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and biological materials are commercially available unless otherwise specified.
[0039] Example 1
[0040] Step 1: Dissolve 20.0 g of 2-bromo-1,3-dimethylbenzene (Compound I) in 200 mL of THF in a 500 mL three-necked flask, then cool to -78°C, and slowly add 52 mL of n-BuLi (2.5 M in hexane) while maintaining -78°C. After the addition is complete, warm the temperature to room temperature and stir for 0.5 h. Then cool the temperature to -78°C again, and slowly add 72 mL of propylene oxide (Compound II) (3 M in THF). After the addition is complete, warm the reaction solution to room temperature and stir for 3 h. After TLC detected that the reaction was complete, the reaction solution was slowly dispersed in ice water, and 200 mL of saturated aqueous ammonium chloride solution was slowly added to quench the reaction. The mixture was extracted with EA (200 mL×3), and the organic phases were combined, washed with 50 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure with a water pump to obtain a crude product, which was purified by a forward silica gel column (petroleum ether / ethyl acetate=2 / 1) to obtain 12 g of a white solid compound 2-(2,6-dimethylphenyl)ethanol (Compound III) in a yield of 75%.
[0041] I HNMR (400MHz, CDCl3) δ = 7.03 (3H, m), 3.76 (2H, t, J = 7.6Hz), 2.97 (2H, t, J = 7.6Hz), 2.36 (6H, s).
[0042] Step 2: In a 100mL three-necked flask, 1.9g NaH was dissolved in 30mL THF, 6.0g 2-(2,6-dimethylphenyl)ethanol (Compound III) was slowly added in an ice-water bath, and then the mixture was heated to room temperature and stirred for 0.5h, and then 8.5g CH3I was slowly added to the reaction solution in an ice-water bath, and the mixture was heated to room temperature and stirred for 8h. TLC detected that the reaction was complete, 30mL H2O was slowly added dropwise at 0°C to quench the reaction, and EA was extracted (30mL×3), the organic phases were combined, and the organic phases were washed with 15mL saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a normal silica gel column (petroleum ether / ethyl acetate=2 / 1) to obtain 6.7g of a colorless oily compound 2-(2-methoxyethyl)-1,3-dimethylbenzene (Compound IV), with a yield of 99%.
[0043] I HNMR (400MHz, CDCl3) δ = 7.00 (3H, m), 3.44 (2H, t, J = 7.6Hz), 3.37 (3H, s), 2.96 (2H, t, J = 7.6Hz), 2.34 (6H, s).
[0044] Step 3: Dissolve 2.0 g of 2-methylmalonic acid (Compound V) in 8.0 g of SOCl2 and stir at 60°C for 24 h. After the reaction, concentrate the reaction solution under reduced pressure at a water bath temperature of 30°C to obtain 2.3 g of a yellow oily product compound 2-methylmalonyl dichloride (Compound VI) with a yield of 87%.
[0045] Step 4: 3.3 g of AlCl3 and 1.0 g of 2-(2-methoxyethyl)-1,3-dimethylbenzene (Compound IV) were dissolved in 10 mL of CS2 in a three-necked flask, and 1.88 g of 2-methylmalonyl dichloride (Compound VI) was slowly added to the mixed solution at 50°C. After the addition was complete, the mixture was stirred at 50°C for 2 h. After TLC detection, the thick reaction solution was slowly poured into ice water, extracted with DCM (20 mL×3), the organic phases were combined, washed with 10 mL of saturated brine, and dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the mixture was purified by a normal silica gel column (petroleum ether / ethyl acetate=5 / 1) to obtain 0.28 g of a yellow solid 5-(2-methoxyethyl)-2,4,6-trimethyl-1H-indene-1,3(2H)-dione (Compound VII), with a yield of 18.8%.
[0046] IHNMR (400MHz, CDCl3) δ = 7.62 (1H, s), 3.51 (2H, t, J = 7.6Hz), 3.35 (3H, s), 3.10 (2 H,t,J=7.6Hz),2.97(1H,q,7.6Hz),2.77(3H,s),2.52(3H,s),1.36(3H,d,7.6Hz).
[0047] Step 5: 5.9 g of 5-(2-methoxyethyl)-2,4,6-trimethyl-1H-indene-1,3(2H)-dione (Compound VII) was dissolved in 90 mL of DCM, 21.2 g of Pb(OAc)4 was added at room temperature, and the mixture was stirred at room temperature for 16 h. The reaction was complete by TLC spot plate detection, and HCl solution (45 mL, 1 M) was added at room temperature to quench the reaction, and DCM was extracted (90 mL×3), and the organic phases were combined, washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a normal silica gel column (petroleum ether / ethyl acetate=4 / 1) to obtain 2.1 g of yellow oily compound 5-(2-methoxyethyl)-2,4,6-trimethyl-1,3-dione-2,3-dihydro-1H-indene-2-yl acetate (Compound VIII), with a yield of 30.9%.
[0048] IHNMR (400MHz, CDCl3) δ = 7.62 (1H, s), 3.51 (2H, t, J = 7.6Hz), 3.34 (3H, s), 3.0 7(2H,t,J=7.6Hz),2.74(3H,s),2.51(3H,s),2.11(3H,s),1.49(3H,d,7.6Hz).
[0049] Step 6: 2.4 g of 5-(2-methoxyethyl)-2,4,6-trimethyl-1,3-dione-2,3-dihydro-1H-inden-2-yl acetate (Compound VIII) was added to 24 mL of HBr (48%) aqueous solution, and the mixture was heated to 80° C. and stirred for 16 h. The reaction was complete as detected by TLC and LCMS. After concentration under reduced pressure, 40 mL of saturated NaHCO3 solution was added for alkalization, and the mixture was extracted with EA (40 mL×3). The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by forward silica gel column (DCM / EA=1 / 1) to obtain a yellow solid compound 2-hydroxy-5-(2-hydroxyethyl)-2,4,6-trimethyl-1H-indene-1,3(2H)-dione (Compound IX). Pterosinsade A (0.5 g) and isomer Pterosinsade B (0.6 g) were obtained by chiral separation with yields of 26% and 31%, respectively.
[0050] Proton spectrum of Pterosinsade A: I HNMR (400MHz, DMSO) δ=7.61(1H,s),6.08(1H,s),4.83(1H,m),3.51(2H,t,J=7.6Hz), 2.95(2H,t,J=7.6Hz), 2.60(3H,s), 2.52(3H,s),1.20(1H,s).
[0051] Proton spectrum of Pterosinsade B: I HNMR (400MHz, DMSO) δ=7.61(1H,s),6.08(1H,s),4.83(1H,m),3.51(2H,t,J=7.6Hz), 2.95(2H,t,J=7.6Hz), 2.60(3H,s), 2.52(3H,s),1.20(1H,s).
[0052] Example 2
[0053] Step 1: Dissolve 20.0 g of 2-bromo-1,3-dimethylbenzene (Compound I) in 200 mL of THF in a 500 mL three-necked flask, then cool to -78°C, and slowly add 52 mL of n-BuLi (2.5 M in hexane) while maintaining -78°C. After the addition is complete, warm the temperature to room temperature and stir for 0.5 h. Then cool the temperature to -78°C again, and slowly add 72 mL of propylene oxide (Compound II) (3 M in THF). After the addition is complete, warm the reaction solution to room temperature and stir for 3 h. After TLC detected that the reaction was complete, the reaction solution was slowly dispersed in ice water, and 200 mL of saturated aqueous ammonium chloride solution was slowly added to quench the reaction. The mixture was extracted with EA (200 mL×3), and the organic phases were combined, washed with 50 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure with a water pump to obtain a crude product, which was purified by a forward silica gel column (petroleum ether / ethyl acetate=2 / 1) to obtain 12 g of a white solid compound 2-(2,6-dimethylphenyl)ethanol (Compound III) in a yield of 75%.
[0054] I HNMR (400MHz, CDCl3) δ = 7.03 (3H, m), 3.76 (2H, t, J = 7.6Hz), 2.97 (2H, t, J = 7.6Hz), 2.36 (6H, s).
[0055] Step 2: In a 100 mL three-necked flask, 2.7 g NaOCH3 was dissolved in 30 mL methanol, 3.0 g 2-(2,6-dimethylphenyl)ethanol (Compound III) was slowly added in an ice-water bath, and then the mixture was heated to room temperature and stirred for 0.5 h, and then 4.25 g CH3I was slowly added to the reaction solution in an ice-water bath, and the mixture was heated to 60 ° C and stirred for 8 h. The reaction was complete by TLC detection, and 30 mL H2O was slowly added dropwise at 0 ° C to quench the reaction, and EA was extracted (30 mL × 3), and the organic phases were combined, and the organic phases were washed with 15 mL saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a normal silica gel column (petroleum ether / ethyl acetate = 2 / 1) to obtain 2.2 g of a colorless oily compound 2-(2-methoxyethyl)-1,3-dimethylbenzene (Compound IV), with a yield of 67.1%.
[0056] Step 3: Dissolve 2.0 g of 2-methylmalonic acid (Compound V) in 10.0 g of POCl3 and stir at 60°C for 24 h. After the reaction, concentrate the reaction solution under reduced pressure at 60°C in a water bath to obtain 1.6 g of a yellow oily product compound 2-methylmalonyl dichloride (Compound VI) with a yield of 60.5%.
[0057] Step 4: 3.3 g of AlCl3 and 1.0 g of 2-(2-methoxyethyl)-1,3-dimethylbenzene (Compound IV) were dissolved in 10 mL of CCl4 in a three-necked flask, and 1.88 g of 2-methylmalonyl dichloride (Compound VI) was slowly added to the mixed solution at 60°C. After the addition was complete, the mixture was stirred at 60°C for 3 h. After the reaction was complete by TLC, the thick reaction solution was slowly poured into ice water, extracted with DCM (20 mL×3), the organic phases were combined, washed with 10 mL of saturated brine, and dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the mixture was purified by a normal silica gel column (petroleum ether / ethyl acetate=5 / 1) to obtain 0.2 g of a yellow solid 5-(2-methoxyethyl)-2,4,6-trimethyl-1H-indene-1,3(2H)-dione (Compound VII), with a yield of 13.4%.
[0058] Step 5: 5.9 g of 5-(2-methoxyethyl)-2,4,6-trimethyl-1H-indene-1,3(2H)-dione (Compound VII) was dissolved in 90 mL of DCM, 21.2 g of Pb(OAc)4 was added at room temperature, and the mixture was stirred at room temperature for 16 h. The reaction was complete by TLC spot plate detection, and HCl solution (45 mL, 1 M) was added at room temperature to quench the reaction, and DCM was extracted (90 mL×3), and the organic phases were combined, washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a normal silica gel column (petroleum ether / ethyl acetate=4 / 1) to obtain 2.1 g of yellow oily compound 5-(2-methoxyethyl)-2,4,6-trimethyl-1,3-dione-2,3-dihydro-1H-indene-2-yl acetate (Compound VIII), with a yield of 30.9%.
[0059] IHNMR (400MHz, CDCl3) δ = 7.62 (1H, s), 3.51 (2H, t, J = 7.6Hz), 3.34 (3H, s), 3.0 7(2H,t,J=7.6Hz),2.74(3H,s),2.51(3H,s),2.11(3H,s),1.49(3H,d,7.6Hz).
[0060] Step 6: Add 2.4 g of 5-(2-methoxyethyl)-2,4,6-trimethyl-1,3-dione-2,3-dihydro-1H-inden-2-yl acetate (Compound VIII) to 20 mL of NaOH (40%) aqueous solution, add 2.5 g of EtSH, and heat the mixture to 100° C. and stir for 12 h. TLC and LCMS detected that the reaction was complete. After concentration under reduced pressure, 40 mL of saturated NaHCO3 solution was added for alkalization, extracted with EA (40 mL×3), the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by forward silica gel column (DCM / EA=1 / 1) to obtain 0.78 g of yellow solid compound 2-hydroxy-5-(2-hydroxyethyl)-2,4,6-trimethyl-1H-indene-1,3(2H)-dione (Compound IX) with a yield of 40%. Pterosinsade A (yield 20%) and isomer Pterosinsade B (yield 24%) were obtained by chiral resolution.
[0061] Proton spectrum of Pterosinsade A: IHNMR (400MHz, DMSO) δ=7.61(1H,s),6.08(1H,s),4.83(1H,m),3.51(2H,t,J=7.6Hz), 2.95(2H,t,J=7.6Hz), 2.60(3H,s), 2.52(3H,s),1.20(1H,s).
[0062] Proton spectrum of Pterosinsade B: I HNMR (400MHz, DMSO) δ=7.61(1H,s),6.08(1H,s),4.83(1H,m),3.51(2H,t,J=7.6Hz), 2.95(2H,t,J=7.6Hz), 2.60(3H,s), 2.52(3H,s),1.20(1H,s).
[0063] Example 3
[0064] Step 1: Dissolve 20.0 g of 2-bromo-1,3-dimethylbenzene (Compound I) in 200 mL of THF in a 500 mL three-necked flask, then cool to -78°C, and slowly add 52 mL of n-BuLi (2.5 M in hexane) while maintaining -78°C. After the addition is complete, warm the temperature to room temperature and stir for 0.5 h. Then cool the temperature to -78°C again, and slowly add 72 mL of propylene oxide (Compound II) (3 M in THF). After the addition is complete, warm the reaction solution to room temperature and stir for 3 h. After TLC detected that the reaction was complete, the reaction solution was slowly dispersed in ice water, and 200 mL of saturated aqueous ammonium chloride solution was slowly added to quench the reaction. The mixture was extracted with EA (200 mL×3), and the organic phases were combined, washed with 50 mL of saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure with a water pump to obtain a crude product, which was purified by a forward silica gel column (petroleum ether / ethyl acetate=2 / 1) to obtain 12 g of a white solid compound 2-(2,6-dimethylphenyl)ethanol (Compound III) in a yield of 75%.
[0065] I HNMR (400MHz, CDCl3) δ = 7.03 (3H, m), 3.76 (2H, t, J = 7.6Hz), 2.97 (2H, t, J = 7.6Hz), 2.36 (6H, s).
[0066] Step 2: In a 100mL three-necked flask, 1.9g NaH was dissolved in 30mL THF, 6.0g 2-(2,6-dimethylphenyl)ethanol (Compound III) was slowly added in an ice-water bath, and then the mixture was heated to room temperature and stirred for 0.5h, and then 8.5g CH3I was slowly added to the reaction solution in an ice-water bath, and the mixture was heated to room temperature and stirred for 8h. TLC detected that the reaction was complete, 30mL H2O was slowly added dropwise at 0°C to quench the reaction, and EA was extracted (30mL×3), the organic phases were combined, and the organic phases were washed with 15mL saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a normal silica gel column (petroleum ether / ethyl acetate=2 / 1) to obtain 6.7g of a colorless oily compound 2-(2-methoxyethyl)-1,3-dimethylbenzene (Compound IV), with a yield of 99%.
[0067] I HNMR (400MHz, CDCl3) δ = 7.00 (3H, m), 3.44 (2H, t, J = 7.6Hz), 3.37 (3H, s), 2.96 (2H, t, J = 7.6Hz), 2.34 (6H, s).
[0068] Step 3: Dissolve 2.0 g of 2-methylmalonic acid (Compound V) in 10.0 g of POCl3 and stir at 100°C for 24 h. After the reaction, concentrate the reaction solution under reduced pressure at a water bath temperature of 80°C to obtain 1.2 g of a yellow oily product compound 2-methylmalonyl dichloride (Compound VI) with a yield of 45.4%.
[0069] Step 4: 3.3 g of AlCl3 and 1.0 g of 2-(2-methoxyethyl)-1,3-dimethylbenzene (Compound IV) were dissolved in 10 mL of CCl4 in a three-necked flask, and 1.88 g of 2-methylmalonyl dichloride (Compound VI) was slowly added to the mixed solution at 60°C. After the addition was complete, the mixture was stirred at 60°C for 3 h. After the reaction was complete by TLC, the thick reaction solution was slowly poured into ice water, extracted with DCM (20 mL×3), the organic phases were combined, washed with 10 mL of saturated brine, and dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the mixture was purified by a normal silica gel column (petroleum ether / ethyl acetate=5 / 1) to obtain 0.2 g of a yellow solid 5-(2-methoxyethyl)-2,4,6-trimethyl-1H-indene-1,3(2H)-dione (Compound VII), with a yield of 13.4%.
[0070] Step 5: 5.9 g of 5-(2-methoxyethyl)-2,4,6-trimethyl-1H-indene-1,3(2H)-dione (Compound VII) was dissolved in 90 mL of DCM, 21.2 g of Pb(OAc)4 was added at room temperature, and the mixture was stirred at room temperature for 16 h. The reaction was complete by TLC spot plate detection, and HCl solution (45 mL, 1 M) was added at room temperature to quench the reaction, and DCM was extracted (90 mL×3), and the organic phases were combined, washed with 40 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a normal silica gel column (petroleum ether / ethyl acetate=4 / 1) to obtain 2.1 g of yellow oily compound 5-(2-methoxyethyl)-2,4,6-trimethyl-1,3-dione-2,3-dihydro-1H-indene-2-yl acetate (Compound VIII), with a yield of 30.9%.
[0071] IHNMR (400MHz, CDCl3) δ = 7.62 (1H, s), 3.51 (2H, t, J = 7.6Hz), 3.34 (3H, s), 3.0 7(2H,t,J=7.6Hz),2.74(3H,s),2.51(3H,s),2.11(3H,s),1.49(3H,d,7.6Hz).
[0072] Step 6: 2.4 g of 5-(2-methoxyethyl)-2,4,6-trimethyl-1,3-dione-2,3-dihydro-1H-inden-2-yl acetate (Compound VIII) was added to 24 mL of HBr (48%) aqueous solution, and the mixture was heated to 80° C. and stirred for 16 h. The reaction was complete as detected by TLC and LCMS. After concentration under reduced pressure, 40 mL of saturated NaHCO3 solution was added for alkalization, and the mixture was extracted with EA (40 mL×3). The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by forward silica gel column (DCM / EA=1 / 1) to obtain a yellow solid compound 2-hydroxy-5-(2-hydroxyethyl)-2,4,6-trimethyl-1H-indene-1,3(2H)-dione (Compound IX). Pterosinsade A (0.5 g) and isomer Pterosinsade B (0.6 g) were obtained by chiral separation with yields of 26% and 31%, respectively.
[0073] Proton spectrum of Pterosinsade A: I HNMR (400MHz, DMSO) δ=7.61(1H,s),6.08(1H,s),4.83(1H,m),3.51(2H,t,J=7.6Hz), 2.95(2H,t,J=7.6Hz), 2.60(3H,s), 2.52(3H,s),1.20(1H,s).
[0074] Proton spectrum of Pterosinsade B: I HNMR (400MHz, DMSO) δ=7.61(1H,s),6.08(1H,s),4.83(1H,m),3.51(2H,t,J=7.6Hz), 2.95(2H,t,J=7.6Hz), 2.60(3H,s), 2.52(3H,s),1.20(1H,s).
[0075] The above-described embodiments are all preferred implementations of the present invention, and do not limit the present invention in other forms. Any technician familiar with the profession may use the above content to make changes or follow suit. However, any changes made to the above embodiments based on the essence of the method of the present invention without departing from the content of the scheme in the present invention still fall within the scope of protection of the present invention.
Claims
1. A method for preparing the compound PterosinsadeA, characterized in that: include: Step 1, compound (I) reacts with propylene oxide (II) to obtain compound (III); wherein R1 is selected from F, Cl, Br, I, boric acid, boric ester or triflate; Step 2, the alcoholic hydroxyl group of compound (III) undergoes an alkylation reaction to obtain compound (IV); Step 3, 2-methylmalonic acid (V) is used to prepare 2-methylmalonyl dichloride (VI); Step 4, compound (IV) undergoes Friedel-Crafts acylation reaction with (VI) to obtain compound (VII); Step 5, compound (VII) undergoes oxidation-acylation reaction to obtain compound (VIII); Step 6, compound (VIII) undergoes elimination reaction to obtain compound (IX); Step 7, performing chiral separation on compound (IX) to obtain compound Pterosinsade A and its isomer Pterosinsade B; 2. The method for preparing the compound Pterosinsade A according to claim 1, characterized in that: In step 1, in the presence of an organic solvent, compound (I) is mixed with n-BuLi and propylene oxide (II) at a molar ratio of 1:(1-3):(1-3) at -78-0°C, and then the mixture is naturally heated to room temperature for reaction for 0.5-6h to obtain compound (III).
3. The method for preparing the compound Pterosinsade A according to claim 2, characterized in that: In step 2, in the presence of an organic solvent, compound (III) is reacted with a basic inorganic salt and a methylating agent in a molar ratio of 1:(1-3):(1-3) at 10-60° C. for 1-12 hours to obtain compound (IV).
4. The method for preparing the compound Pterosinsade A according to claim 3, characterized in that: In step 1 and step 2, the organic solvent includes tetrahydrofuran, methyltetrahydrofuran, dioxane, ether or ethylene glycol dimethyl ether; in step 2, the alkaline inorganic salt includes NaH, KH, CaH2, sodium tert-butoxide, sodium methoxide or sodium ethoxide, and the methylating agent includes methyl iodide, methyl bromide, dimethyl sulfate or dimethyl carbonate.
5. The method for preparing the compound Pterosinsade A according to any one of claims 1 to 4, characterized in that: In step 3, 2-methylmalonic acid (V) is stirred in the presence of thionyl chloride or phosphorus oxychloride at 50-100° C. for 12-48 h to obtain 2-methylmalonyl dichloride (VI).
6. The method for preparing the compound Pterosinsade A according to claim 5, characterized in that: In step 4, compound (IV) is reacted with Lewis acid and 2-methylmalonyl chloride (VI) in an organic solvent at 40-60° C. for 1-6 hours to obtain compound (VII); wherein the molar ratio of compound (IV), Lewis acid and 2-methylmalonyl chloride (VI) is 1:(1-5):(1-3).
7. The method for preparing the compound Pterosinsade A according to claim 6, characterized in that: In step 4, the organic solvent includes CS2, CH2Cl2, CHCl3, CCl4, acetonitrile, ether or ethylene glycol dimethyl ether; the Lewis acid includes AlCl3, BF3, ZnCl2 or TiCl4.
8. The method for preparing the compound Pterosinsade A according to claim 1, characterized in that: In step 5, compound (VII) is reacted with Pb(OAc)4 in a molar ratio of 1:(1-5) at room temperature for 8-24 hours to obtain compound (VIII).
9. The method for preparing the compound Pterosinsade A according to claim 1, characterized in that: In step 6, compound (VIII) is subjected to elimination reaction with a demethylation and acetylating agent in a molar ratio of 1:(2-10), the reaction temperature is 60-100° C., and the reaction time is 8-24 h to obtain compound (IX).
10. The method for preparing the compound Pterosinsade A according to claim 9, characterized in that: In step 6, the demethylation and acetylation reagent is HBr or EtSH.
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Monomer compound in effective part of pteris crassifolia, preparation method, application and medicine
CN116265428A