A full synthesis method of psoralin

Abstract

The application belongs to the technical field of medicine preparation, and discloses a full synthesis method of bakuchiol, which comprises the following steps: S1, adding N,N-dimethylformamide, daidzin and N,N-diisopropylethylamine into a container, and then adding 2-(trimethylsilyl)ethoxymethyl chloride dropwise to obtain a first intermediate; S2, adding acetone, potassium iodide, anhydrous potassium carbonate, the first intermediate obtained in the step S1 and 3-chloro-3-methyl-1-butyne into the container in sequence to obtain a second intermediate through reaction; S3, adding N,N-diethyl aniline and the second intermediate obtained in the step S2 into a reaction container to obtain a third intermediate; and S4, adding anhydrous ethanol and the third intermediate obtained in the step S3 into a reaction container, and then adding 6M hydrochloric acid ethanol solution to obtain bakuchiol through reaction; and the application solves the problems of the existing bakuchiol synthesis method, such as the use of unsafe chemical reagents, long synthesis route and low total yield.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a total synthesis method for psoralen. Background Technology

[0002] Atherosclerosis, obesity, diabetes, chronic non-healing wounds, neurodegenerative diseases, and cancer are all related to chronic inflammation. Inflammation is a defense mechanism of the body against harmful substances invading tissues and organs, aiming to repair and heal damaged tissues and organs. However, prolonged inflammation can damage the body, affecting the normal function of tissues and organs, gradually leading to chronic inflammation, and ultimately causing other malignant diseases that endanger human life. Anti-inflammatory drugs are widely used to treat inflammatory diseases. However, whether using glucocorticoids or nonsteroidal anti-inflammatory drugs (NSAIDs), long-term use in treating chronic inflammation can produce toxic side effects and complications, affecting the body's health and function. Furthermore, drug development currently faces the challenge of "more investment, fewer drugs." Therefore, utilizing the potential phytochemicals in medicinal plants offers a promising new approach for the treatment of chronic inflammation. The active ingredients in these natural products provide multiple anti-inflammatory mechanisms and have demonstrated good safety profiles.

[0003] Psoralea corylifolia, an isoflavone component of the traditional Chinese herbal medicine Psoralea corylifolia, can express pharmacological activities through multiple pathways, exhibiting anti-cancer, anti-inflammatory, anti-obesity, anti-aging, and anti-bone disease effects. It expresses anti-inflammatory effects and demonstrates therapeutic efficacy against chronic inflammatory diseases through pathways such as mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB); it also expresses therapeutic effects against cancer through P-STAT3 and STAT3 and inhibition of downstream pathways. Therefore, psoralea corylifolia possesses potential in anti-inflammatory activity.

[0004] However, the content of psoralen in the traditional Chinese medicine Psoralea corylifolia is only 0.024-0.042%, and only 12.5 mg of psoralen can be extracted from each kilogram of Psoralea corylifolia, making it difficult to extract in large quantities. Furthermore, some existing chemical synthesis methods for psoralen use unsafe chemical reagents, have long synthetic routes, and produce low overall yields of psoralen. Summary of the Invention

[0005] The present invention aims to provide a total synthesis method for psoralen, in order to solve the problems of unsafe chemical reagents, long synthetic routes, and low overall yield in existing psoralen synthesis methods.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] A method for the total synthesis of psoralen, comprising the following steps:

[0008] S1. Synthetic intermediate: 3-(4-hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methoxy)-4H-benzopyran-4-one

[0009] N,N-dimethylformamide and daidzein were added to a reaction vessel, stirred and cooled, then N,N-diisopropylethylamine was added, followed by the slow dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride. The reaction was first carried out in an ice bath, then at room temperature, and then detected by thin-layer chromatography. The reaction was quenched by adding ammonium chloride aqueous solution, and then extracted with ethyl acetate. The organic phase obtained by extraction was subjected to the first post-treatment to obtain the first intermediate.

[0010] S2. Synthetic intermediate: 3-(4-((2-methyl-but-3-yn-2-yl)oxy)phenyl)7-((2-(trimethylsilyl)ethoxy)methoxy)-4H-benzopyran-4-one

[0011] Acetone, potassium iodide, anhydrous potassium carbonate, and the first intermediate obtained in step S1 were added sequentially to the reaction vessel under nitrogen protection. The vessel was then placed in an oil bath and refluxed. 3-Chloro-3-methyl-1-butyne was slowly added to continue the reaction. The reaction system turned yellow and turbid. Thin-layer chromatography was then performed for detection. The mixture was then cooled to room temperature and filtered. The filter cake was washed with acetone and concentrated under reduced pressure to obtain a gel-like solid. The gel-like solid was then dissolved in methyl tert-butyl ether. The resulting organic phase was then subjected to a second post-treatment to obtain the second intermediate.

[0012] S3. Synthesis of the third intermediate: 2',2'-dimethyl-7-((2-(trimethylsilyl)ethoxy)methoxy)-2'H,4H-[3,6'-biphenylpyran]-4-one

[0013] N,N-diethylaniline and the second intermediate obtained in step S2 were added to the reaction vessel and stirred until dissolved. The mixture was placed in a heating module and refluxed. Then, thin-layer chromatography was performed for detection. The mixture was cooled to room temperature and diluted with methyl tert-butyl ether. The resulting organic phase was subjected to a third post-treatment to obtain the third intermediate.

[0014] S4. Synthetic psoralen: 7-hydroxy-2',2'-dimethyl-2'H,4H-[3,6'-biphenylpyran]-4-one

[0015] Anhydrous ethanol and the third intermediate obtained in step S3 were added to the reaction vessel and stirred until dissolved. Then, 6M hydrochloric acid ethanol solution was added and the mixture was reacted overnight at room temperature. Thin-layer chromatography was then performed for detection, followed by filtration. Saturated sodium bicarbonate solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic phase obtained from the extraction was subjected to a fourth post-treatment to obtain psoralen.

[0016] Furthermore, in S1, the molar ratio of daidzein, N,N-diisopropylethylamine, and 2-(trimethylsilyl)ethoxymethyl chloride is 1:3-5:1-1.5; the reaction time is first 1 hour in an ice bath, and then 6 hours at room temperature.

[0017] Further, in S1, the first post-processing includes: washing the extracted organic phase sequentially with water and saturated brine, drying it with anhydrous sodium sulfate, and then sequentially filtering, concentrating under reduced pressure, and performing silica gel column chromatography.

[0018] Further, in S2, the molar ratio of potassium iodide, anhydrous potassium carbonate, the first intermediate obtained in step S1, and 3-chloro-3-methyl-1-butyne is 7:8.5:4~6:10~12; the oil bath temperature is 80℃; the reflux time is 5min; 3-chloro-3-methyl-1-butyne is added slowly, and the reaction continues for 48h.

[0019] Further, in S2, the second post-treatment includes: washing the dissolved organic phase with saturated sodium bicarbonate aqueous solution and saturated brine respectively, drying it with anhydrous sodium sulfate, and then sequentially performing filtration, vacuum concentration and silica gel column chromatography.

[0020] Further, in S3, N,N-diethylaniline and the second intermediate obtained in step S2 are refluxed in a heating module at a temperature of 220°C for 3 hours.

[0021] Furthermore, in S3, the third post-processing includes: washing the diluted organic phase with hydrochloric acid, then with saturated brine, then drying with anhydrous sodium sulfate, followed by filtration, vacuum concentration, and silica gel column chromatography.

[0022] Further, in S4, the third intermediate obtained in step S3 is reacted with an ethanol solution of 6M hydrochloric acid at a molar ratio of 1:14 to 18 at room temperature.

[0023] Furthermore, in S4, the fourth post-processing includes: washing the extracted organic phase with saturated brine, drying it with anhydrous sodium sulfate, and then sequentially filtering, concentrating under reduced pressure, and performing silica gel column chromatography.

[0024] The beneficial effects of the technical solution are:

[0025] 1. This invention uses safe chemical reagents, is environmentally friendly, and is inexpensive;

[0026] 2. This invention uses only four reaction steps, resulting in a short reaction route and high efficiency;

[0027] 3. The present invention uses (trimethylsilyl)ethoxymethyl (SEM) selectively protecting the 7-position phenolic hydroxyl group of daidzein to synthesize the first intermediate, which is then subjected to substitution, cyclization and deprotection reactions to obtain psoralen. The new synthesis method of psoralen has mild reaction conditions and is environmentally friendly, with a total yield of up to 36.5%. Attached Figure Description

[0028] Figure 1 Here is a synthetic route diagram of psoralen according to the present invention: Detailed Implementation

[0029] The present invention will be further described in detail below with reference to the embodiments:

[0030] A method for the total synthesis of psoralen, comprising the following steps:

[0031] S1. Synthetic intermediate: 3-(4-hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methoxy)-4H-benzopyran-4-one

[0032] Add 30 mL of N,N-dimethylformamide and 5.08 g of daidzein to a 100 mL round-bottom flask, stir until dissolved, then cool to 0 °C, add 10.5 mL of N,N-diisopropylethylamine, and then slowly add 3.9 mL of 2-(trimethylsilyl)ethoxymethyl chloride. React in an ice bath for 1 h, then at room temperature for 6 h. Detect the reaction as complete by thin-layer chromatography (TLC), then add 50 mL of ammonium chloride aqueous solution to quench the reaction, and extract with ethyl acetate. Wash the extracted organic phase successively with water and saturated brine, then dry with anhydrous sodium sulfate, and then filter, concentrate under reduced pressure, and perform silica gel column chromatography to obtain 5.65 g of the first intermediate. The first intermediate is a white solid with a melting point of 103.6-104.3 °C and a yield of 73.0%.

[0033] The first intermediate was subjected to proton NMR, carbon NMR, and high-resolution mass spectrometry. The experimental data are as follows:

[0034] 1H NMR spectrum: 1H NMR (500MHz, CDCl3) δ8.23(d,J=8.5Hz,1H),7.94(s,1H),7.31(d,J=8.5Hz,2H),7.11–7.07(m ,2H),6.82(d,J=8.5Hz,2H),5.33(s,2H),3.81–3.77(m,2H),1.00–0.96(m,2H),0.01(s,9H).

[0035] Carbon NMR spectrum: 13 C NMR (126MHz, CDCl3) δ176.95,161.99,157.99,156.65,152.86,130.41,127.92 ,125.42,123.33,118.94,116.05,115.91,103.10,93.01,67.05,18.19,-1.29.

[0036] High-resolution mass spectrometry: HRMS(ESI) m / z, calcd. for C 21 H 25 O5Si[M+H] + 385.1466, found 385.1473.

[0037] The solvent and ratio for thin-layer chromatography (TLC) are petroleum ether:ethyl acetate = 1:1, v / v, with UV colorimetry; the mobile phase for silica gel chromatography uses a petroleum ether and ethyl acetate system, with petroleum ether:ethyl acetate = 1:1.

[0038] S2. Synthetic intermediate: 3-(4-((2-methyl-but-3-yn-2-yl)oxy)phenyl)7-((2-(trimethylsilyl)ethoxy)methoxy)-4H-benzopyran-4-one

[0039] 70 mL of acetone, 2.33 g of potassium iodide, 2.35 g of anhydrous potassium carbonate, and 3.84 g of the first intermediate obtained in step S1 were added sequentially to a 250 mL round-bottom flask. The flask was then protected with nitrogen and refluxed in an 80 °C oil bath for 5 min. 2.7 mL of 3-chloro-3-methyl-1-butyne was then slowly added, and the reaction continued for 48 h. The reaction system became yellow and turbid. Thin-layer chromatography (TLC) confirmed that the reaction was essentially complete. The mixture was then cooled to room temperature and filtered. The filter cake was washed with acetone and concentrated under reduced pressure to obtain a gelatinous solid. The gelatinous solid was dissolved in methyl tert-butyl ether. The dissolved organic phase was washed with saturated sodium bicarbonate aqueous solution and saturated brine, respectively, and dried with anhydrous sodium sulfate. The mixture was then filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain 3.06 g of the second intermediate. The second intermediate was a white solid with a melting point of 131.5-132.3 °C and a yield of 68.0%.

[0040] The second intermediate was subjected to proton NMR, carbon NMR, and high-resolution mass spectrometry. The experimental data are as follows:

[0041] 1H NMR spectrum 1 H NMR (400MHz, CDCl3) δ8.22(d,J=9.2Hz,1H),7.95(s,1H),7.48(d,J=8.4Hz,2H),7.27(d,J=8.8Hz,2H),7.1 0–7.06(m,2H),5.32(s,2H),3.81–3.76(m,2H),2.58(s,1H),1.67(s,6H),0.99–0.95(m,2H),0.01(s,9H).

[0042] Carbon NMR Spectroscopy 13 C NMR (101MHz, CDCl3) δ176.03,161.84,157.80,155.76,152.62,129.69,127.91,126.33,124. 95,121.22,119.16,115.69,103.14,93.02,86.13,74.16,72.51,67.01,29.74,18.20,-1.29.

[0043] High-resolution mass spectrometry (HRMS(ESI)) m / z, calcd. for C 26 H 31 O5Si[M+H] + 451.1936, found 451.1966.

[0044] The solvent and ratio for thin-layer chromatography (TLC) are petroleum ether:ethyl acetate = 6:1, v / v, with UV colorimetry; the mobile phase for silica gel chromatography uses a petroleum ether and ethyl acetate system, with petroleum ether:ethyl acetate = 6:1.

[0045] S3. Synthesis of the third intermediate: 2',2'-dimethyl-7-((2-(trimethylsilyl)ethoxy)methoxy)-2'H,4H-[3,6'-biphenylpyran]-4-one

[0046] Add 30 mL of N,N-diethylaniline and 4.50 g of the second intermediate obtained in step S2 to a 100 mL round-bottom flask, stir until dissolved, place in a 220 °C heating module, reflux for 3 h, then detect the reaction completion by thin-layer chromatography (TLC), cool to room temperature, dilute with methyl tert-butyl ether, wash the diluted organic phase with 6 mol / L hydrochloric acid, wash with saturated brine, dry with anhydrous sodium sulfate, then filter, concentrate under reduced pressure and precipitate by silica gel column chromatography to obtain 4.28 g of the third intermediate, which is a colorless oil with a yield of 95.0%.

[0047] The third intermediate was subjected to proton NMR, carbon NMR, and high-resolution mass spectrometry. The experimental data are as follows:

[0048] 1H NMR spectrum: 1 H NMR (500MHz, CDCl3) δ8.22–8.19(m,1H),7.92(s,1H),7.26(dd,J=8.0,2.0Hz,1H),7.24(d,J=2.0Hz,1H),7.08–7.05(m,2H),6.82(d,J= 8.0Hz,1H),6.35(d,J=9.5Hz,1H),5.62(d,J=9.5Hz,1H),5.31(s,2H),3.80–3.76(m,2H),1.45(s,6H),0.99–0.95(m,2H),0.01(s,9H).

[0049] Carbon NMR spectrum: 13 C NMR (126MHz, CDCl3) δ176.01,161.75,157.74,153.18,152.29,130.97,129.57,127.86,127.17,124.9 2,124.31,122.38,121.29,119.13,116.46,115.58,103.09,92.99,76.59,66.97,28.23,18.17,-1.31.

[0050] High-resolution mass spectrometry: HRMS(ESI) m / z, calcd. for C 26 H 31 O5Si[M+H] + 451.1936, found 451.1979.

[0051] The solvent and ratio for thin-layer chromatography (TLC) are petroleum ether:ethyl acetate = 8:1, v / v, with UV colorimetry; the mobile phase for silica gel chromatography uses a petroleum ether and ethyl acetate system, with petroleum ether:ethyl acetate = 6:1.

[0052] S4. Synthetic psoralen: 7-hydroxy-2',2'-dimethyl-2'H,4H-[3,6'-biphenylpyran]-4-one

[0053] Add 105 mL of anhydrous ethanol and 9.45 g of the third intermediate obtained in step S3 to a 500 mL reaction flask, stir until dissolved, then add 50 mL of ethanol solution with a concentration of 6 mol / L hydrochloric acid, react overnight at room temperature, and then detect the completion of the reaction by thin-layer chromatography (TLC). Filter the solution, and the filter cake is psoralen. Add saturated sodium bicarbonate solution to the filtrate, extract with ethyl acetate, wash the extracted organic phase with saturated brine, dry with anhydrous sodium sulfate, and then filter, concentrate under reduced pressure, and perform silica gel column chromatography to obtain 5.2 g of psoralen, with a yield of 77.4%. Psoralen is a white solid with a melting point of 232.6-234.3 °C.

[0054] The psoralen was subjected to proton NMR, carbon NMR, and high-resolution mass spectrometry. The experimental data are as follows:

[0055] 1H NMR spectrum: 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),8.32(s,1H),7.97(d,J=8.8Hz,1H),7.30(dd,J=8.2,2.2Hz,1H),7.27(d,J=2.0Hz,1H),6.9 4(dd,J=8.8,2.4Hz,1H),6.86(d,J=2.4Hz,1H),6.78(d,J=8.0Hz,1H),6.42(d,J=9.6Hz,1H),5.76(d,J=9.6Hz,1H),1.39(s,6H).

[0056] Carbon NMR spectrum: 13C NMR(101MHz,DMSO-d6)δ174.55,162.57,157.42,153.12,152.18,131.19,129.64,127.27 ,126.93,124.45,123.13,121.73,120.57,116.59,115.55,115.18,102.13,76.24,27.72.

[0057] High-resolution mass spectrometry: HRMS(ESI) m / z, calcd. for C 20 H 17 O4[M+H] + 321.1122, found 321.1146.

[0058] The solvent and ratio for thin-layer chromatography (TLC) are petroleum ether:ethyl acetate = 2:1, v / v, with UV colorimetry; the mobile phase for silica gel chromatography uses a petroleum ether and ethyl acetate system, with petroleum ether:ethyl acetate = 2:1.

[0059] The route map for synthesizing psoralen is attached. Figure 1 As shown, a: N,N-diisopropylethylamine, N,N-dimethylformamide, 0℃~room temperature, 6h; b: g potassium iodide, potassium carbonate, acetone, 80℃, 48h; c: N,N-diethylaniline, reflux, 3h; d: 6mol / L hydrochloric acid ethanol, room temperature, overnight.

[0060] In summary, this invention synthesizes a first intermediate by selectively protecting the 7-position phenolic hydroxyl group of daidzein with (trimethylsilyl)ethoxymethyl (SEM), followed by substitution, cyclization, and deprotection reactions to obtain psoralen. This novel synthetic method for psoralen utilizes mild reaction conditions and is environmentally friendly, achieving an overall yield of 36.5%.

[0061] The above descriptions are merely embodiments of the present invention, and common knowledge regarding specific technical solutions or characteristics is not elaborated upon here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A method for the total synthesis of psoralen, characterized in that, Includes the following steps: S1. Synthetic intermediate: 3-(4-hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methoxy)-4H-benzopyran-4-one N,N-dimethylformamide and daidzein were added to a reaction vessel, stirred and cooled, then N,N-diisopropylethylamine was added, followed by the slow dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride. The reaction was first carried out in an ice bath, then at room temperature, and then detected by thin-layer chromatography. The reaction was quenched by adding ammonium chloride aqueous solution, and then extracted with ethyl acetate. The organic phase obtained by extraction was subjected to the first post-treatment to obtain the first intermediate. S2. Synthetic intermediate: 3-(4-((2-methyl-but-3-yn-2-yl)oxy)phenyl)7-((2-(trimethylsilyl)ethoxy)methoxy)-4H-benzopyran-4-one Acetone, potassium iodide, anhydrous potassium carbonate, and the first intermediate obtained in step S1 were added sequentially to the reaction vessel under nitrogen protection. The vessel was then placed in an oil bath and refluxed. 3-Chloro-3-methyl-1-butyne was slowly added to continue the reaction. The reaction system turned yellow and turbid. Thin-layer chromatography was then performed for detection. The mixture was then cooled to room temperature and filtered. The filter cake was washed with acetone and concentrated under reduced pressure to obtain a gel-like solid. The gel-like solid was then dissolved in methyl tert-butyl ether. The resulting organic phase was then subjected to a second post-treatment to obtain the second intermediate. S3. Synthesis of the third intermediate: 2',2'-dimethyl-7-((2-(trimethylsilyl)ethoxy)methoxy)-2'H,4H-[3,6'-biphenylpyran]-4-one N,N-diethylaniline and the second intermediate obtained in step S2 were added to the reaction vessel and stirred until dissolved. The mixture was placed in a heating module and refluxed. Then, thin-layer chromatography was performed for detection. The mixture was cooled to room temperature and diluted with methyl tert-butyl ether. The resulting organic phase was subjected to a third post-treatment to obtain the third intermediate. S4. Synthetic psoralen: 7-hydroxy-2',2'-dimethyl-2'H,4H-[3,6'-biphenylpyran]-4-one Anhydrous ethanol and the third intermediate obtained in step S3 were added to the reaction vessel and stirred until dissolved. Then, 6M hydrochloric acid ethanol solution was added and the mixture was reacted overnight at room temperature. Thin-layer chromatography was then performed for detection, followed by filtration. Saturated sodium bicarbonate solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic phase obtained from the extraction was subjected to a fourth post-treatment to obtain psoralen.

2. The total synthesis method of psoralen according to claim 1, characterized in that: In S1, the molar ratio of daidzein, N,N-diisopropylethylamine, and 2-(trimethylsilyl)ethoxymethyl chloride is 1:3-5:1-1.5; the reaction is first carried out in an ice bath for 1 hour, and then at room temperature for 6 hours.

3. The total synthesis method of psoralen according to claim 1, characterized in that: In S1, the first post-processing includes: washing the extracted organic phase sequentially with water and saturated brine, drying it with anhydrous sodium sulfate, and then sequentially filtering, concentrating under reduced pressure, and performing silica gel column chromatography.

4. The total synthesis method of psoralen according to claim 1, characterized in that: In step S2, the molar ratio of potassium iodide, anhydrous potassium carbonate, the first intermediate obtained in step S1, and 3-chloro-3-methyl-1-butyne is 7:8.5:4~6:10~12; the oil bath temperature is 80℃; the reflux time is 5 min; 3-chloro-3-methyl-1-butyne is added slowly, and the reaction continues for 48 h.

5. The total synthesis method of psoralen according to claim 1, characterized in that: In S2, the second post-processing includes: washing the dissolved organic phase with saturated sodium bicarbonate aqueous solution and saturated brine, respectively, drying it with anhydrous sodium sulfate, and then sequentially performing filtration, vacuum concentration and silica gel column chromatography.

6. The total synthesis method of psoralen according to claim 1, characterized in that: In step S3, N,N-diethylaniline and the second intermediate obtained in step S2 are refluxed in a heating module at a temperature of 220°C for 3 hours.

7. The total synthesis method of psoralen according to claim 1, characterized in that: In S3, the third post-processing includes: washing the diluted organic phase with hydrochloric acid, then with saturated brine, then drying with anhydrous sodium sulfate, followed by filtration, vacuum concentration, and silica gel column chromatography.

8. The total synthesis method of psoralen according to claim 1, characterized in that: In S4, the third intermediate obtained in step S3 is reacted with an ethanol solution of 6M hydrochloric acid at a molar ratio of 1:14 to 18 at room temperature.

9. The total synthesis method of psoralen according to claim 1, characterized in that: In S4, the fourth post-processing includes: washing the extracted organic phase with saturated brine, drying it with anhydrous sodium sulfate, and then sequentially filtering, concentrating under reduced pressure, and performing silica gel column chromatography.

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