CN111484471A - A kind of preparation method of high psyllium - Google Patents

Abstract

The invention relates to the field of chemical synthesis, and relates to a new preparation method of psyllium, in particular to a method for preparing synthetic psyllium by using scutellarin as a raw material. The method of the invention uses scutellarin as a raw material, and can efficiently semi-synthesize homophysate through the three-step reaction of carboxyl esterification, selective methylation and glycosyl hydrolysis. The invention has few reaction steps, only 3 steps, high reaction yield, cheap and easily available reaction reagents, low production cost; mild reaction conditions, no harsh reaction conditions, easy operation, and suitability for industrial production.

Description

A kind of preparation method of high psyllium

technical field

The invention relates to the field of chemical synthesis, and relates to a new preparation method of psyllium, in particular to a method for preparing synthetic psyllium by using scutellarin as a raw material.

Background technique

The data discloses that psyllium, also known as hispidulin, is an active ingredient of flavonoids extracted from Xinjiang snow lotus. In recent years, studies at home and abroad have shown that high psyllium has antibacterial, anti-inflammatory, antioxidant, antithrombotic, antiepileptic, antiosteoporotic, antimutagenic and neuroprotective effects. It has obvious inhibitory effect on the proliferation of human pancreatic cancer, gastric cancer, ovarian cancer, glioma and other cell lines.

Studies have shown that psyllium has a wide range of biological activities, and pharmacologists and medicinal chemists in the field have shown more and more interest in this compound; the current preparation and synthesis methods of psyllium mainly include semi-synthetic methods. Synthetic, total synthesis and enzymatic synthesis.

Semi-synthetic literature reports on psyllium are from the same research group: from 2013 to 2015, researchers reported the semi-synthetic preparation of psyllium using scutellarin as the starting material in four literatures; , using scutellarin as raw material, the total yield of 7-step reaction was 10.7% (Shen M.Z. et al. Lett. Org. Chem. 2013, 10, 733-737), and the total yield of 7-step reaction was 7.1% (Lin H .et al.Int.J.Mol.Sci.2015, 16, 7587-7594.), 6.3% overall yield in 4-step reaction (Zhang W. et al. Molecules 2015, 20, 10184-10191.) and 4 The total yield of 8.2% in the first step reaction (Zhang W. et al. J. Chem. Res. 2015, 39, 674-676.) completed the semi-synthesis of homophysate, but unfortunately, the reported semi-synthetic preparation was obtained The NMR spectral data of psyllium are quite different from those of psyllium obtained by extraction and separation and the NMR data of psyllium obtained by total synthesis, which proves that the structure of psyllium prepared by the semi-synthesis is wrong. That is: in the study, scutellarin was not prepared with scutellarin as the starting material.

The total synthesis method of high psyllium is reported in the following literature: in 2004, Kavvadias and his collaborators used 2,4,6-trihydroxyacetophenone as the starting material to complete the high-grade phytoplankton with a total yield of 1.1% through 9 steps of reaction. Total chemical synthesis of psyllium; (Kavvadias D. et al. Br. J. Pharmacol. 2004, 142, 811–820.) In 2015, Chao et al. took 2,4,6-trihydroxybenzaldehyde as the starting material through 11 steps The reaction completes the chemical total synthesis of high phytoplankton, but the total yield is only 1.6%; (ChaoS.W.et al.J.Nat.Prod.2015,78,1969-1976.) In order to improve the reaction yield to prepare A sufficient amount was obtained to meet the needs of biological activity research, and then Chen et al. optimized and improved the synthetic route, also using 2,4,6-trihydroxybenzaldehyde as the starting material, and finally obtained 26.9% of the total through 8-step reaction. The total synthesis of the compound was completed in yield, (ChenL.C.et al.Molecules2017,22,1897-1910.), the nuclear magnetic spectrum data of the above three kinds of total synthesis of psyllium were extracted from the original literature The NMR data of the isolated psyllium were consistent.

The enzymatic synthesis of psyllium is reported by the School of Pharmacy of Shandong University: the 6-O-methyltransferase of dichnium can efficiently selectively methylate the 6-phenolic hydroxyl group of scutellarin to obtain psyllium (Zhang Y.Y. et al. FEBSLetters, 2016, 590, 2619-2628), the NMR data of psyllium obtained by enzymatic synthesis are consistent with the NMR data of psyllium extracted and isolated from the original literature , but practice shows that the 6-O-methyltransferase used in the above preparation method is obtained by gene recombination, which has the defects of long cycle, small purification amount of enzyme, and unsuitable for large-scale industrialization.

Based on the current state of the prior art, the inventors of the present application intend to provide a new preparation method of phytoplankton.

SUMMARY OF THE INVENTION

The purpose of the present invention is to solve the deficiencies of the prior art, and provide a new preparation method of psyllium, in particular to a method for preparing synthetic psyllium by using scutellarin as a raw material.

The invention takes scutellarin as a starting material for semi-synthetic preparation of high psyllium, has short synthesis steps, low cost, high yield and high product purity, and is suitable for industrial production.

In order to achieve the above object, the present invention adopts the following technical solutions:

Preparation method of the present invention is, according to following reaction formula:

A kind of synthetic method of phytoplankton provided by the invention specifically comprises the following steps:

A: take scutellarin as starting material, under acidic catalyst conditions, carboxyl is methylated to obtain scutellarin methyl ester (compound 2);

b: scutellarin methyl ester (compound 2) generated above is nucleophilic substitution reaction with methyl iodide in the presence of acid binding agent to generate 6-OMe scutellarin methyl ester (compound 3);

c: subjecting the above-generated compound 3 to a hydrolysis reaction of the glycosidic bond under the action of an acidic catalyst to obtain the target compound 4.

The reaction solvent adopted in the above-mentioned reaction a step is methanol.

The acid catalyst adopted in the above-mentioned reaction a step is one of thionyl chloride, perchloric acid, concentrated sulfuric acid, concentrated nitric acid, trifluoroacetic acid, concentrated hydrochloric acid or a mixture thereof, preferably thionyl chloride or concentrated sulfuric acid.

The concentration of scutellarin in the methanol solution in the step a of the above reaction is preferably 10-100 mg mL ^-1 , more preferably 20-30 mg mL ^-1 .

The acid binding agent that above-mentioned reaction b step adopts is inorganic base such as: a kind of or their mixture in potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, potassium bicarbonate, sodium bicarbonate; Organic base such as: N,N- One of diisopropylethylamine, triethylamine, ethylenediamine, DBU or their mixture, preferably inorganic alkali potassium carbonate.

The organic solvent that the above-mentioned reaction b step adopts is a kind of or their mixture in N,N-dimethylformamide, N,N-dimethylacetamide, acetone, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, preferably N,N-dimethylformamide or N,N-dimethylacetamide.

In the above-mentioned reaction b step, the molar ratio of scutellarin methyl ester and methyl iodide is preferably 1:1 to 1:2, more preferably 1:1.2.

The acid catalyst adopted in the above-mentioned reaction c step is one of concentrated sulfuric acid, concentrated hydrochloric acid, concentrated nitric acid, and trifluoroacetic acid or a mixture thereof, preferably concentrated sulfuric acid.

The reaction solvent used in the above-mentioned reaction c step is one of ethanol, methanol, isopropanol, acetonitrile, water or a mixture thereof, preferably 90% ethanol.

The reaction temperature in the step c of the above reaction is preferably 60 to 150°C, more preferably 100 to 120°C.

The nuclear magnetic spectrum data of psyllium obtained by the present invention is consistent with the nuclear magnetic spectrum data of psyllium extracted and separated from the original document.

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

There are few reaction steps, only 3 steps, which is the shortest synthetic route for preparing high psyllium so far; the reaction yield is high, and the reaction yield is obviously higher than that reported in the existing literature; the reaction reagents are cheap and easy to obtain, and the production cost is low; the reaction conditions Mild, no harsh reaction conditions, suitable for industrial production.

The present invention can be better understood from the following examples. However, those skilled in the art can easily understand that the specific material ratios, process conditions and results described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention.

Detailed ways

Embodiment 1: Synthesis of scutellarin methyl ester 2

Add 200 mL of anhydrous methanol to a 500 mL round-bottomed flask, slowly add SOCl ₂ (7.25 mL, 100 mmol) dropwise under an ice bath, remove the ice bath after the dropwise addition, and continue stirring at room temperature for 1 h. Then add scutellarin 1 (4.62g, 10mmol), after stirring at room temperature for 9h, TLC (V _{ethyl acetate} :V _isopropanol :V _water =4:2:1) reaction is complete; direct filtration to obtain scutellarin Methyl ester 2 (4.67 g, 98%); ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.85 (s, 1H, 5-OH), 10.39 (s, 1H, 4'-OH), 7.93 ( d,J=9.0Hz,2H,H-2',H-6'),7.00(s,1H,H-8),6.94(d,J=9.0Hz,2H,H-3',H-5 '), 6.81(s, 1H, H-3), 5.28(d, J=7.0Hz, 1H, H-1"), 4.20(d, J=6.0Hz, 1H, H-2"), 3.70- 3.90(3H,m,other sugarprotons), 3.68(3H,s,-OCH3); ¹³ C-NMR (125MHz, DMSO-d ₆ ): δ182.8, 169.7, 164.5, 161.6, 151.3, 149.4, 147.3, 130.8, 128.9 , 121.7, 116.4, 106.3, 102.9, 100.2, 93.9, 75.7, 75.4, 73.1, 71.8, 52.4 (-OCH ₃ ).

Embodiment 2: Synthesis of scutellarin methyl ester 2

In a 500 mL round-bottomed flask, scutellarin 1 (4.62 g, 10 mmol) was suspended in 300 mL of anhydrous methanol, and concentrated sulfuric _acid (0.03 mL) was slowly added dropwise at room temperature. _Ester :V _isopropanol :V _water =4:2:1) The reaction is complete. Naturally cooled to room temperature and concentrated under reduced pressure to obtain scutellarin methyl ester 2 (4.72 g, 98%). ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.85(s,1H,5-OH),10.39(s,1H,4'-OH),7.93(d,J=9.0Hz,2H,H- 2',H-6'),7.00(s,1H,H-8),6.94(d,J=9.0Hz,2H,H-3',H-5'),6.81(s,1H,H- 3), 5.28(d, J＝7.0Hz, 1H, H-1”), 4.20(d, J＝6.0Hz, 1H, H-2”), 3.70-3.90(3H, m, other sugar protons), 3.68 (3H, s, -OCH3); ¹³ C-NMR (125MHz, DMSO-d ₆ ): δ182.8, 169.7, 164.5, 161.6, 151.3, 149.4, 147.3, 130.8, 128.9, 121.7, 116.4, 106.3, 102.9, 100.2 , 93.9, 75.7, 75.4, 73.1, 71.8, 52.4 (-OCH ₃ ).

Embodiment 3: Synthesis of scutellarin methyl ester 2

In a 500 mL round-bottomed flask, scutellarin 1 (4.62 g, 10 mmol) was suspended in 200 mL of anhydrous methanol, and 70% perchloric acid (0.03 mL) was slowly added dropwise at room temperature. The dropwise addition was completed, and after heating to reflux for 3h, TLC (V _{ethyl acetate} :V _isopropanol :V _water =4:2:1) reacted completely, naturally cooled to room temperature and then concentrated under reduced pressure to obtain scutellarin methyl ester 2( 4.72g, 98%). ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.85(s,1H,5-OH),10.39(s,1H,4'-OH),7.93(d,J=9.0Hz,2H,H- 2',H-6'),7.00(s,1H,H-8),6.94(d,J=9.0Hz,2H,H-3',H-5'),6.81(s,1H,H- 3), 5.28(d, J＝7.0Hz, 1H, H-1”), 4.20(d, J＝6.0Hz, 1H, H-2”), 3.70-3.90(3H, m, other sugar protons), 3.68 (3H, s, -OCH3); ¹³ C-NMR (125MHz, DMSO-d ₆ ): δ182.8, 169.7, 164.5, 161.6, 151.3, 149.4, 147.3, 130.8, 128.9, 121.7, 116.4, 106.3, 102.9, 100.2 , 93.9, 75.7, 75.4, 73.1, 71.8, 52.4 (-OCH ₃ ).

Example 4: Synthesis of 6-OMe scutellarin methyl ester 3

In a 250mL round-bottomed flask, compound 2 (3.81g, 8.0mmol) was dissolved in 50mL of N,N-dimethylformamide, and anhydrous K ₂ CO ₃ (1.66g, 12.0 mmol) was added under stirring at room temperature, and dropped under nitrogen protection. MeI (0.60 mL, 9.6 mmol) was added, and after stirring at 40°C overnight, TLC (V _{dichloromethane} :V _methanol =20:1) raw materials disappeared, the reaction system was poured into 50 mL of ice water, ethyl acetate (25 mL×3 ) extraction, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain compound 3 (1.53g, 39%); ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.98(s, 1H, 5 -OH), 10.42(s, 1H, 4'-OH), 7.95(d, J=7.8Hz, 2H, H-2', H-6'), 7.07(s, 1H, H-8), 6.95 (d,J＝8.1Hz,2H,H-3',H-5'),6.86(s,1H,H-3),5.62(d,J＝3.9Hz,1H),5.52(d,J＝ 5.3Hz,1H,H-1”),5.36(d,J=4.9Hz,2H),4.20(d,J=9.1Hz,1H),3.76(s,3H,-OCH3),3.66(s,3H ,-OCH3); ¹³ C-NMR (125MHz, DMSO-d ₆ ): δ182.33, 169.22, 164.38, 161.38, 155.94, 152.68, 152.13, 132.53, 128.59, 121.11, 116.02, 105.92, 102.77, 5, 9.39 75.30, 72.81, 71.34, 60.33, 52.03.

Example 5: Synthesis of 6-OMe scutellarin methyl ester 3

Compound 2 (3.81 g, 8.0 mmol) was dissolved in 50 mL of N,N-dimethylacetamide in a 250 mL round-bottomed flask, and anhydrous K ₂ CO ₃ (1.66 g, 12.0 mmol) was added under stirring at room temperature, and dropped under nitrogen protection. MeI (0.75 mL, 12.0 mmol) was added, and after stirring overnight at 40°C, TLC (V _{dichloromethane} :V _methanol = 20:1) raw materials disappeared, the reaction system was poured into 50 mL of ice water, ethyl acetate (25 mL × 3 ) extraction, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain compound 3 (1.26g, 32%); ¹ H-NMR (400MHz, DMSO-d ₆ )δ12.98(s, 1H, 5 -OH), 10.42(s, 1H, 4'-OH), 7.95(d, J=7.8Hz, 2H, H-2', H-6'), 7.07(s, 1H, H-8), 6.95 (d,J=8.1Hz,2H,H-3',H-5'),6.86(s,1H,H-3),5.62(d,J=3.9Hz,1H),5.52(d,J= 5.3Hz, 1H, H-1”), 5.36(d, J=4.9Hz, 2H), 4.20(d, J=9.1Hz, 1H), 3.76(s, 3H, -OCH3), 3.66(s, 3H ,-OCH3); ¹³ C-NMR (125MHz, DMSO-d ₆ ): δ182.33, 169.22, 164.38, 161.38, 155.94, 152.68, 152.13, 132.53, 128.59, 121.11, 116.02, 105.92, 102.77, 5, 9.39 75.30, 72.81, 71.34, 60.33, 52.03.

Example 6: Synthesis of 6-OMe scutellarin methyl ester 3

Compound 2 (3.81 g, 8.0 mmol) was dissolved in 50 mL of N,N-dimethylformamide in a 250 mL round-bottomed flask, anhydrous DIPEA (1.98 mL, 12.0 mmol) was added under stirring at room temperature, and MeI ( 0.60mL, 9.6mmol), after stirring overnight at 40°C, TLC (V _{dichloromethane} :V _methanol =20:1) raw materials disappeared, the reaction system was poured into 50mL ice water, extracted with ethyl acetate (25mL×3), Washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain compound 3 (1.14 g, 29%); ¹ H-NMR (400 MHz, DMSO-d ₆ )δ12.98 (s, 1H, 5-OH) ,10.42(s,1H,4'-OH),7.95(d,J＝7.8Hz,2H,H-2',H-6'),7.07(s,1H,H-8),6.95(d, J=8.1Hz, 2H, H-3', H-5'), 6.86(s, 1H, H-3), 5.62(d, J=3.9Hz, 1H), 5.52(d, J=5.3Hz, 1H,H-1”), 5.36(d,J=4.9Hz,2H), 4.20(d,J=9.1Hz,1H), 3.76(s,3H,-OCH3), 3.66(s,3H,-OCH3 ); ¹³ C-NMR (125MHz, DMSO-d ₆ ): δ182.33, 169.22, 164.38, 161.38, 155.94, 152.68, 152.13, 132.53, 128.59, 121.11, 116.02, 105.92, 102.77, 97.3, 9, 9,30,9 , 71.34, 60.33, 52.03.

Example 7: Synthesis of Holocene 4

Compound 3 (4.19 _g , 8.55 mmol) was suspended in a mixed solvent of 135 mL of ethanol and 18.8 mL of water in a 250 mL round-bottomed flask, and 18.8 mL of concentrated sulfuric acid was added dropwise with stirring at room temperature. _Methane :V _methanol =20:1) The raw material disappeared. Naturally cooled to room temperature, washed with water, extracted with ethyl acetate (100 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain psyllium (2.33 g, 91%); ¹ H-NMR ( 400MHz, DMSO-d ₆ )δ13.05(s, 1H), 10.72(s, 1H), 10.37(s, 1H), 7.92(d, J=8.5Hz, 2H), 6.92(d, J=8.5Hz) , 2H), 6.77(s, 1H), 6.59(s, 1H), 3.74(s, 3H); ¹³ C-NMR (125MHz, DMSO-d ₆ ): δ182.18, 163.86, 161.20, 157.28, 152.81, 152.43, 131.38, 128.51, 121.25, 116.00, 104.12, 102.41, 94.28, 60.00.

Example 8: Synthesis of Holocene 4

In a 250mL round-bottomed flask, compound 3 (4.19g, 8.55mmol) was suspended in a mixed solvent of 135mL isopropanol and 18.8mL water, and 18.8mL of concentrated sulfuric acid was added dropwise with stirring at room temperature. _{Dichloromethane} :V _methanol =20:1) the raw materials disappeared, naturally cooled to room temperature, washed with water, extracted with ethyl acetate (100 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and obtained by column chromatography element (2.30g, 90%); ¹ H-NMR (400MHz, DMSO-d ₆ )δ13.05(s, 1H), 10.72(s, 1H), 10.37(s, 1H), 7.92(d, J= 8.5Hz, 2H), 6.92(d, J=8.5Hz, 2H), 6.77(s, 1H), 6.59(s, 1H), 3.74(s, 3H); ¹³ C-NMR (125MHz, DMSO-d ₆ ): δ182.18, 163.86, 161.20, 157.28, 152.81, 152.43, 131.38, 128.51, 121.25, 116.00, 104.12, 102.41, 94.28, 60.00.

Example 9: Synthesis of Holocene 4

Compound 3 (4.19g, 8.55mmol) was suspended in a mixed solvent of 135mL ethanol and 18.8mL water in a 250mL round-bottomed flask, 18.8mL of concentrated hydrochloric acid was added dropwise with stirring at room temperature, and the addition was completed at 100 ° C and refluxed overnight, TLC (V _dichloride ) _Methane :V _methanol =20:1) the raw material disappeared, naturally cooled to room temperature, washed with water, extracted with ethyl acetate (100 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and column chromatography to obtain psyllium ( 1.82g, 71%); ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 13.05(s, 1H), 10.72(s, 1H), 10.37(s, 1H), 7.92(d, J=8.5Hz , 2H), 6.92(d, J=8.5Hz, 2H), 6.77(s, 1H), 6.59(s, 1H), 3.74(s, 3H); ¹³ C-NMR (125MHz, DMSO-d ₆ ): δ182.18, 163.86, 161.20, 157.28, 152.81, 152.43, 131.38, 128.51, 121.25, 116.00, 104.12, 102.41, 94.28, 60.00.

Claims (8)

1. a preparation method of psyllium, is characterized in that, it comprises the steps: a: take scutellarin as starting material, under the action of an acidic catalyst, carboxyl methyl esters are obtained to obtain scutellarin methyl ester; b: nucleophilic substitution reaction with methyl iodide occurs with the generated scutellarin methyl ester in the presence of acid binding agent to generate 6-OMe scutellarin methyl ester; c: hydrolyzing the generated 6-OMe scutellarin methyl ester under the action of an acidic catalyst to undergo a glycosidic bond hydrolysis reaction to prepare psyllium. 2. preparation method as claimed in claim 1, is characterized in that, the reaction solvent adopted in described step a is methanol; The concentration of scutellarin in methanol solution is 10～100mg mL ^-1 , preferably 20～30mg mL ^-1 . 3. preparation method as claimed in claim 1, is characterized in that, the acid catalyst described in described step a is in thionyl chloride, perchloric acid, vitriol oil, concentrated nitric acid, concentrated hydrochloric acid, trifluoroacetic acid. One or a mixture thereof, preferably thionyl chloride or concentrated sulfuric acid. 4. preparation method as claimed in claim 1, is characterized in that, the acid binding agent that described middle step b adopts is inorganic base, is selected from: potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, potassium bicarbonate, carbonic acid One of sodium hydrogen hydride or their mixture; organic base, selected from: one in N,N-diisopropylethylamine, triethylamine, ethylenediamine, DBU or their mixture, preferably inorganic base carbonic acid Potassium. 5. preparation method as claimed in claim 1 is characterized in that, the organic solvent adopted in described step b is N,N-dimethylformamide, N,N-dimethylacetamide, acetone, acetonitrile, One of tetrahydrofuran, chloroform, ethyl acetate or their mixture, preferably N,N-dimethylformamide or N,N-dimethylacetamide. 6 . The preparation method according to claim 1 , wherein the molar ratio of scutellarin methyl ester and methyl iodide in the step b is 1:1 to 1:2, preferably 1:1.2. 7 . 7. preparation method as claimed in claim 1, is characterized in that, the acid catalyst that adopts in described step c is a kind of or their mixture in vitriol oil, vitriol oil, vitriol oil, trifluoroacetic acid, preferred vitriol oil . 8. preparation method as claimed in claim 1, is characterized in that, the reaction solvent that described step c adopts is one or their mixture of ethanol, methanol, isopropanol, acetonitrile, water, preferably 90% ethanol; Reaction The temperature is 60 to 150°C, preferably 100 to 120°C.