CN108047291B - Synthetic method of houttuynine sodium bisulfite heterozygosis flavonoid compound - Google Patents
Synthetic method of houttuynine sodium bisulfite heterozygosis flavonoid compound Download PDFInfo
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Abstract
The invention discloses a synthesis method of a houttuynine sodium bisulfite heterozygous flavonoid compound. The invention reacts compound 1-I with acetylation reagent; stirring the obtained 1-II and 1-undecayne under the protection of inert gas to carry out a light-shielding reaction; stirring the obtained 1-III and alkali for reaction at-10-30 ℃; reacting the obtained 1-IV with 2-acetyl-3, 5-bis (benzyloxy) phenol; stirring the obtained 1-V, iodine and DMSO for reaction at 50-150 ℃; reacting the obtained 1-VI with oxone and p-toluenesulfonic acid under the condition that the pH value is 9-12; carrying out reflux stirring reaction on the obtained 1-VII, acid and water at the temperature of 80-130 ℃; stirring the obtained 1-VIII and bromosugar for reaction; removing the protecting group of the obtained 1-IX to obtain 1-X; and reacting the 1-X with an oxidant to obtain the 1-XI. The method is simple and has high yield.
Description
Technical Field
The invention belongs to the field of compound synthesis, and particularly relates to a synthesis method of a houttuynine sodium bisulfite heterozygosis flavonoid compound.
Background
The natural products Houttuynoid B, Houttuynoid G, Houttuynoid H, Houttuynoid I, Houttuynoid J and Houttuynoid L are houttuynin heterozygotic flavone compounds, and are flavone compounds extracted and separated from the traditional Chinese medicine houttuynia cordata. The structural formula is as follows:
the houttuynin heterozygosis flavonoid compound is a flavonoid compound with a novel framework structure formed by natural heterozygosis of houttuynin and quercetin in the houttuynia cordata. Pharmacological experimental research proves that the compound has better anti-herpes virus (HSV) activity. Preliminary mechanism research shows that the compound acts on the virus infection stage, possibly related to gB, gD, gH, gL and other main envelope proteins, and shows that the compound has different action mechanisms from the existing nucleoside drugs. Has the potential of being developed into medicaments. Further research on the anti-herpes virus pharmacological activity of the compounds requires a large amount of raw material supply, and the extraction and separation are complicated and the cost is high. Therefore, we carried out a total synthesis study on the protein, and provide a raw material basis for the subsequent study.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a synthesis method of a houttuynine sodium bisulfite heterozygotic flavonoid compound.
The purpose of the invention is realized by the following technical scheme: a synthetic method of houttuynine sodium bisulfite heterozygote flavonoid compound, the synthetic route is shown in figure 1, the concrete steps are as follows:
(1) stirring the compound 1-I shown as the formula 1-I, an acetylation reagent, pyridine and 4-dimethylamino pyridine at room temperature, and reacting in a dark place to obtain a compound 1-II shown as the formula 1-II;
(2) adding the compound 1-II, triethylamine, bis (triphenylphosphine) palladium dichloride, cuprous iodide and 1-undecayne into a solvent, and stirring at room temperature under the protection of inert gas and keeping out of the sun to react to obtain a compound 1-III shown as a formula 1-III;
(3) stirring the compound 1-III, alkali and a solvent at-10-30 ℃ for reaction to obtain a compound 1-IV shown as a formula 1-IV;
(4) reacting the compound 1-IV and 2-acetyl-3, 5-bis (benzyloxy) phenol in the presence of alkali in a solvent at room temperature under stirring to obtain a compound 1-V shown in a formula 1-V;
(5) reacting the compound 1-V with iodine and DMSO under stirring at 50-150 deg.C to obtain compound 1-VI shown in formula 1-VI;
(6) reacting the compound 1-VI with oxone complex salt and p-toluenesulfonic acid in a solvent under the condition that the pH value is 9-12 to obtain a compound 1-VII shown in a formula 1-VII;
(7) carrying out reflux stirring reaction on the compounds 1-VII, acid and water at the temperature of 80-130 ℃ to obtain compounds 1-VIII shown in the formulas 1-VIII;
(8) stirring the compound 1-VIII and bromosugar in a solvent in the presence of alkali to react to obtain flavonoid glycoside compounds 1-IX shown in the formula 1-IX;
(9) the compound 1-IX is carried out in the presence of alkali and Pd/H2Removing a protecting group under the condition, and stirring in a solvent for reaction to obtain a compound 1-X shown as a formula 1-X;
(10) adding the compound 1-X and an oxidant into a solvent, and reacting by taking N-methyl-N-morpholine oxide as a catalyst to obtain a compound 1-XI shown in a formula 1-XI;
wherein the structural formula of each compound is as follows:
wherein the content of the first and second substances,
R1the group comprises methyl, benzyl and acetyl; preferably a benzyl group;
R2groups include hydrogen and 2-undecanone;
R3the group is a halogen group and comprises a chlorine group and an iodine group; preferably an iodine group;
R4the group comprises methyl, benzyl and acetyl; preferably a benzyl group;
R5the groups are shown in the following table:
R6the groups are shown in the following table:
the room temperature herein is 10 to 30 ℃ and preferably 18 to 27 ℃.
The acetylating reagent described in step (1) is preferably acetic anhydride.
The acetylation reagent in the step (1) is used for acetylating hydroxyl in the compound I, and the dosage of the acetylation reagent is as follows: hydroxyl group ≧ molar ratio 1:1, calculating.
The pyridine in the step (1) is preferably anhydrous pyridine. Pyridine is used as a base, and the using amount of the pyridine is preferably 1-3 times of the molar amount of the compound I.
The amount of 4-dimethylaminopyridine used in step (1) is a catalytic equivalent, preferably 5% of the molar amount of compound I.
The time for the reaction in the step (1) in the dark is preferably 17 h.
After the light-shielding reaction in the step (1), the method further comprises a purification step, which is specifically as follows: py was removed, the pH was then adjusted to neutral, extraction was carried out with ethyl acetate, and the resulting organic phase was washed with a saturated sodium chloride solution and dried to give a white solid as compound II.
The solvent in the step (2) is preferably one or at least two of tetrahydrofuran, N-dimethylformamide, dichloromethane, dimethyl sulfoxide, toluene and N, N-dimethylacetamide; more preferably tetrahydrofuran.
The triethylamine in the step (2) is anhydrous triethylamine. Triethylamine is used as the base, and the dosage of the triethylamine is preferably 1-2 times of the molar quantity of the compound II.
The amount of the bis (triphenylphosphine) palladium dichloride used in the step (2) is 5% of the catalytic equivalent, preferably the molar amount of the compound II.
The amount of cuprous iodide used in step (2) is a catalytic equivalent, preferably 10% of the molar amount of compound II.
The inert gas in step (2) is preferably nitrogen.
The time for the reaction in step (2) is preferably 20 h.
After the reaction is carried out in a dark place in the step (2), the method further comprises a purification step, which is specifically as follows: adding saturated ammonium chloride solution to quench the reaction; then, the mixture is extracted by ethyl acetate, the obtained organic phase is washed by saturated saline, water is removed, the organic phase is put on a silica gel column, a solvent obtained by mixing petroleum ether and ethyl acetate according to the volume ratio of 30:1 is used as an eluent, and the substance obtained by separation and purification is the compound III.
The solvent in the step (3) is preferably one or at least two of methanol, tetrahydrofuran, water, dichloromethane, dimethyl sulfoxide, toluene and N, N-dimethylformamide; more preferably a solvent obtained by mixing methanol, tetrahydrofuran and water in a volume ratio of 5:8: 5.
The base used in step (3) includes, but is not limited to: sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide; lithium hydroxide is preferred.
The amount of the base used in the step (3) is preferably 2 to 5 times the molar amount of the compound III.
The stirring reaction temperature in the step (3) is preferably 0-10 ℃.
The stirring reaction time in the step (3) is preferably 2 hours.
After the stirring reaction in the step (3), further comprising a purification step, which is specifically as follows: diluting with dichloromethane, adjusting pH to neutral, extracting with dichloromethane, removing water from the obtained organic phase, separating with silica gel column, eluting with solvent composed of Petroleum Ether (PE) and Dichloromethane (DCM) at volume ratio of 25:1, and drying to obtain white solid as compound IV.
The solvent in the step (4) is preferably one or more of methanol, ethanol, propanol, butanol, pentanol and 1, 3-propylene glycol; ethanol is more preferred.
The base in step (4) includes, but is not limited to: sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide; sodium hydroxide is preferred.
The amount of the base used in the step (4) is preferably 10 to 25 times the molar amount of the compound IV.
The stirring reaction time in the step (4) is preferably 48 h.
After the stirring reaction in the step (4), further comprising a purification step, which is specifically as follows: adjusting pH to 5 in ice bath, precipitating yellow solid after acidification, filtering, and recrystallizing with anhydrous ethanol to obtain yellow solid as compound V.
The iodine used in step (5) is present in catalytic equivalents, preferably 10% of the molar amount of compounds 1-V.
The DMSO described in step (5) is preferably an anhydrous reagent. DMSO is used as a solvent and a catalyst, and the using amount of the DMSO is preferably 20-50 times of the molar amount of the compound VI.
The temperature of the stirring reaction in the step (5) is preferably 80-120 ℃; more preferably 110 deg.c.
The stirring reaction time in the step (5) is preferably 14 h.
After the stirring reaction in the step (5), further comprising a purification step, specifically as follows: cooling to room temperature, adjusting the pH value to 5-7, extracting with ethyl acetate, washing the obtained organic phase with saturated salt water, removing water, concentrating, and purifying by silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 2: 1 drying the solvent to obtain a white solid
Preferably, in the step (6), the compound 1-VI reacts with oxone complex salt in a solvent under the condition that the pH value is 9-12, standing and layering are carried out, an organic phase is separated, a water phase is extracted by dichloromethane, the combined organic phase is washed by saturated sodium thiosulfate and saturated common salt water respectively, the water content of the organic phase is removed, filtering is carried out, p-toluenesulfonic acid in the obtained filtrate is stirred and reacts at room temperature, and the solvent is removed after filtering.
The solvent in the step (6) is preferably a composite solvent obtained by mixing one or at least two of dichloromethane, chloroform, ethyl acetate, methanol and tetrahydrofuran with acetone; preferably dichloromethane/acetone; more preferably a solvent obtained by mixing dichloromethane and acetone in a volume ratio of 4: 3.
The pH value described in step (6) is achieved by using an alkaline buffer.
The alkaline buffer is preferably a sodium carbonate/bicarbonate system.
The amount of the oxone complex salt used in the step (6) is preferably 12 times the molar amount of the compounds 1 to VI.
The potassium hydrogen persulfate composite salt in the step (6) is preferably added in two times, the first addition is added after reaction for a period of time, and the reaction is carried out for a period of time.
The period of time is preferably 15 hours.
The amount of p-toluenesulfonic acid used in step (6) is catalytic equivalent, preferably 2% of the molar amount of compounds 1 to VI.
The reaction time in the step (6) is preferably 30-32 h.
After the reaction in step (6), further comprising a purification step, specifically as follows: filtering, spin-drying, purifying by silica gel column chromatography, eluting with solvent prepared from petroleum ether and ethyl acetate at a ratio of 6:1, and drying to obtain yellow solid as compound VII.
The acid in the step (7) is preferably one or at least two of formic acid, acetic acid, propionic acid, butyric acid and citric acid; more preferably acetic acid. The amount of acid used is preferably 200-1000 times the molar amount of reactant VII.
The temperature of the reflux stirring reaction in the step (7) is preferably 90-120 ℃; more preferably 110 deg.c.
The reflux stirring reaction time in the step (7) is preferably 16 h.
After the reflux stirring reaction in the step (7), further comprising a purification step: extracting with dichloromethane, washing the organic phase with saturated saline solution, removing water, filtering, concentrating, purifying by silica gel column chromatography, and eluting with petroleum ether and ethyl acetate according to a volume ratio of 6:1 to yield a yellow solid as compound VIII.
The base described in step (8) includes, but is not limited to: one or at least two of sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate and potassium hydroxide; preferably potassium carbonate.
The amount of the base used in the step (8) is preferably 2 to 5 times the molar amount of the compound VIII.
The solvent in the step (8) comprises: dichloromethane, tetrahydrofuran, DMF, DMSO; preferably DMF.
The brominated sugar in the step (8) is represented by structural formulas A-D:
the reaction time in step (8) is preferably 12 hours.
After the reaction in the step (8), further comprising a purification step: water was added, extraction was then carried out with ethyl acetate, and the resulting organic phase was washed with saturated brine, followed by removal of water, filtration and concentration to give a pale yellow solid as compound IX.
Step (9) is preferably: reacting the compounds 1-IX in a solvent in the presence of a base, neutralizing with a cation exchange resin, filtering, and spin-drying; the resulting oil was dissolved in a solvent, Pd (OH) was added2Replacing gas in the system with hydrogen, stirring for reaction at room temperature, filtering, and drying the obtained filtrate to obtain the compound X.
The stirring reaction time is preferably 12 hours.
The base described in step (9) includes, but is not limited to: one or at least two of sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate and potassium hydroxide; preferably potassium carbonate.
The amount of the base used in the step (9) is preferably 3 to 7 times the molar amount of the compound IX.
Pd (OH) described in step (9)2The amount of (A) is a catalytic equivalent, preferably 10% of the molar amount of compounds 1 to IX.
The solvent in the step (9) is preferably one or two of tetrahydrofuran and methanol; more preferably a mixed solvent of tetrahydrofuran and methanol at a volume ratio of 1: 1.
The oxidant described in step (10) includes but is not limited to: one or at least two of oxygen, ozone, manganese dioxide, PCC, osmium tetroxide, hydrogen peroxide, sulfuric acid and phosphorus pentoxide; osmium tetroxide is preferred.
The amount of the oxidizing agent used in the step (10) is preferably 0.5 to 2 times the molar amount of the compound X.
The solvent in the step (10) is preferably a solvent obtained by mixing acetone and water; more preferably a solvent obtained by mixing acetone and water in a volume ratio of 5: 1.
The N-methyl-N-morpholine oxide described in step (10) is preferably used in an amount of 1 to 2 times the molar amount of compound X.
The stirring reaction time in the step (10) is preferably 12 hours.
After the stirring reaction in the step (10), the method further comprises a purification step as follows: adding ethyl acetate into the reaction system, adding a saturated sodium thiosulfate solution, and stirring; extraction with ethyl acetate and washing of the organic phase with saturated brine, removal of water, filtration and concentration gave compound XI as a yellow solid.
In the context of the present invention,
R1,R2,R3,R4,R5,R6the structure of the group is shown in table 1 below:
TABLE 1
R2、R6The structures of (a) and the names of compounds 1-XI are shown in Table 2:
TABLE 2
Compared with the prior art, the invention has the following advantages and effects: the synthesis method provided by the invention is simple, has high yield, and can provide the yield requirement for related research.
Drawings
FIG. 1 is a synthetic scheme of the present invention.
FIG. 2 is a schematic diagram of a specific synthesis scheme for Houttuynoid G, a hybrid flavone of Houttuynoid G, provided in example 1.
FIG. 3 is a schematic diagram of a specific synthesis scheme for Houttuynoid H, a hybrid flavone of Houttuynoid H, provided in example 2.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Example 1: total synthesis of houttuynin heterozygotic flavone Houttuynoid G
The route is shown in fig. 2, and the specific steps are as follows:
① preparation of Compound II
Reference is made to the preparation of compound I (Shen, S.D.; Zhang, G.P.; Lei, M.; Hu, L.H. first synthetic of salvianolic acid C, ournefolic acid A, andtousnefolal. ARKIVOC.2012,6,204-. The obtained 4-benzyl-3-hydroxy-2-iodo-p-hydroxybenzaldehyde is used as a compound I.
4-benzyl-3-hydroxy-2-iodo-p-hydroxybenzaldehyde (17g, 48.02mmol), pyridine (Py, 6.8ml), 4-dimethylaminopyridine (DMAP, 293mg,2.39mmol) were added to a 250ml single-neck flask and stirred. Acetic anhydride (6.8ml) was slowly added dropwise, stirred at room temperature and reacted for 17h with exclusion of light. Py was removed by a rotary evaporator, followed by adjusting pH to neutral with 10% by mass of dilute hydrochloric acid, extraction with Ethyl Acetate (EA), washing of the organic phase with a saturated sodium chloride solution 2 times, and removal of water from the solvent by addition of anhydrous magnesium sulfate. The solvent was removed by rotary evaporator to give compound II as a white solid (18.83 g, 99% yield).
Nuclear magnetic resonance hydrogen spectrum data of compound II:1H NMR(300MHz,CDCl3):δ9.98(s,1H),7.79(d,J＝9.0Hz,1H),7.43–7.30(m,5H),7.04(d,J＝6.0Hz,1H),5.18(s,2H),2.38(s,3H)。
② preparation of Compound III
A250 ml two-necked flask was charged with Compound II (18.81g,47.47mmol), tetrahydrofuran (THF, 120ml), and triethylamine (NEt)338 ml); bis (triphenylphosphine) palladium (II) chloride (Pd (PPh) was added3)2Cl21.665g,2.37mmol), cuprous iodide (0.9g,4.72mmol), nitrogen blanket. 1-undecayne (13.9ml) was taken out by a syringe, slowly added to the reaction flask, and stirred at room temperature for 20 hours in the dark. 30ml of a saturated ammonium chloride solution was added thereto, and the reaction was quenched by stirring for 30 minutes. The solution was transferred to a separatory funnel and extracted with EA, the aqueous phase required 2 extractions and the organic phases were combined. The organic phase was then washed 1 time with saturated brine, and water was removed from the solvent by addition of anhydrous magnesium sulfate. Separating and purifying with silica gel column (eluent, petroleum ether: ethyl acetate, volume ratio 30:1) to obtain brown black oily product, standing the oily product to obtain solid, i.e. compound III (14.4 g, yield 85%).
Nuclear magnetic resonance hydrogen spectrum data of compound III:1H NMR(300MHz,CDCl3):δ10.34(s,1H),7.77(d,J＝6.0Hz,1H),7.43–7.29(m,5H),6.99(d,J＝9.0Hz,1H),5.16(s,2H),2.50(t,J＝15.0Hz,2H),2.34(s,3H),1.70–1.57(m,2H),1.51–1.39(m,2H),1.29(d,J＝3.0Hz,10H),0.88(t,J＝12.0Hz,3H)。
③ preparation of Compound IV
A250 ml single-neck flask was charged with Compound III (13.2g, 31.42mmol), THF (40ml), MeOH (25ml), H2O (25ml) was stirred at 0 ℃ in a cryometer. Slowly add lioh2O (3.96g, 94.28mmol), the reaction was stirred at zero degrees for 2 h. Diluting with 50ml of Dichloromethane (DCM), adjusting the pH to about 7 with 10% by mass of dilute HC, extracting the aqueous phase 1 time with dichloromethane, combining the organic phases of DCM, and removing the water from the solvent by adding anhydrous sodium sulfate. The reaction product was separated and purified by silica gel column (eluent, PE: DCM ═ 25:1), and dried to give a white solid, i.e. compound IV (6 g obtained, 50% yield).
Nuclear magnetic resonance hydrogen spectral data of compound IV:1H NMR(300MHz,CDCl3):δ10.00(s,1H),7.57(d,J＝12.0Hz,1H),7.53–7.33(m,5H),7.17(s,1H),6.86(d,J＝12.0Hz,1H),5.39(s,2H),2.83(t,J＝15.0Hz,2H),1.86–1.71(m,2H),1.47–1.21(m,12H),0.88(t,J＝12.0Hz,3H)。
④ preparation of Compound V
Compound IV (2.13g,5.632mmol,1equiv) and 2-acetyl-3, 5-bis (benzyloxy) phenol (1.7g,4.9mmol,1equiv) were added to a single-neck flask, 10ml of ethanol was added, and after compound IV and 2-acetyl-3, 5-bis (benzyloxy) phenol were dissolved by heating to 60 ℃, 5ml of 50% (w/w) aqueous sodium hydroxide solution was added dropwise, and after completion of the addition, room temperature was returned to room temperature, and stirring was continued for 48 hours. After the reaction on the plate was completed, the pH was adjusted to 5 in an ice bath with dilute hydrochloric acid of 10% (V/V), a yellow solid precipitated after acidification, and the yellow solid was filtered and recrystallized from absolute ethanol to obtain Compound V (3.324 g, 98% yield).
Nuclear magnetic resonance hydrogen spectrum data of compound V:1H NMR(300MHz,CDCl3):δ11.58,8.03,7.78,7.57,7.45,7.37,7.29,7.17,6.69,6.27,6.26,5.14,5.12,2.82,1.58,1.28,1.25,0.89。
⑤ preparation of Compound VI
To Compound V (2.3g,3.818mmol,1equiv) in a dry two-necked flask was added 10ml of anhydrous DMSO, catalytic amount of I2(80mg,0.31mmol,0.1 equiv). Heated to 110 ℃ and reacted for 14 hours. After cooling to room temperature, 15m 10% (v/v) of dilute hydrochloric acid was added, extraction was performed with ethyl acetate (15mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography (petroleum ether: ethyl acetate 2: 1, volume ratio), and dried to obtain a white solid, that is, compound VI (2.04 g, yield 89%).
Nuclear magnetic resonance hydrogen spectrum data of compound VI: :1H NMR(300MHz,CDCl3):δ7.81,7.48,7.40,7.32,7.20,6.86,6.72,6.40,6.30,5.16,5.14,2.91,1.59,1.29,1.26,0.89。
⑥ preparation of Compound VII
Compound VI (1.6g,2.665mmol) was dissolved in CH2Cl2In a mixed solvent of acetone (volume ratio 4:3,70 mL). 90mL of sodium carbonate/sodium bicarbonate buffer (Na) was added2CO38g of NaHCO33.8g dissolved in 200mL of water), stirred vigorously at room temperature, and then slowly added dropwise with 5.60mL of an aqueous solution of 5g of oxone complex salt was added dropwise over about 40 minutes, and the reaction was carried out at room temperature for 15 hours overnight. 60mL of an aqueous solution containing 5.5g of oxone complex salt was slowly added dropwise the next day, and the reaction was continued at room temperature for 15 hours after completion of the dropwise addition for about 40 minutes. The pH of the reaction system was maintained at about 9 throughout the addition and the reaction. Standing for layering, separating an organic phase, extracting an aqueous phase with dichloromethane, washing the combined organic phase with saturated sodium thiosulfate and saturated common salt water for 3 times, drying the organic phase with anhydrous sodium sulfate, filtering, adding 5mg of p-toluenesulfonic acid into a filtrate, stirring at room temperature for reacting for about 1.5h, filtering, spin-drying, purifying by silica gel column chromatography (petroleum ether: ethyl acetate ═ 6:1, volume ratio), and drying to obtain a yellow solid, namely the compound VII (1.23 g is obtained, and the yield is 75%).
Nuclear magnetic resonance hydrogen spectrum data of compound VII:1H NMR(300MHz,CDCl3):δ7.80,7.47,7.39,7.31,7.19,6.85,6.71,6.29,5.15,5.13,4.08,2.88,1.59,1.29,1.26,0.89.
⑦ preparation of Compound VIII
Into a single-neck flask were added compound VII (200mg,0.324mmol), acetic acid (13mL), H2O (3mL), heated to 110 ℃ under reflux for 16h, extracted with dichloromethane (10mL × 3), and the combined organic phases washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography (petroleum ether: ethyl acetate 6:1 by volume), and dried to give compound VIII as a yellow solid (145 mg, 85% yield).
Nuclear magnetic resonance hydrogen spectrum data of compound VIII:1H NMR(300MHz,CDCl3):δ11.63,7.81,7.48,7.40,7.32,7.20,6.74,6.72,6.17,5.47,5.16,5.14,2.98,1.59,1.29,1.26,0.89。
⑧ preparation of Compound IX
In a dry two-necked flask was added compound VIII (80mg,0.126mmol,1equiv), bromo-sugar [ 2-bromoacetylated galactose (77mg,0.189mmol,1.5equiv)]Anhydrous K2CO3(74mg,0.5mmol) and 5ml of anhydrous DMF was added. The reaction was stirred at room temperature (25 ℃) for 12 hours under argon. After the reaction is completed, water is addedExtracted three times with ethyl acetate, the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a pale yellow solid, compound IX (129 mg, 99% yield) without further purification. Preparation of 2-bromoacetylated galactose (Liu, S.; Ben, R.N.C-Linked Galactosyl series AFGP antibodies as Poten specific catalysis inhibition. org.Lett.2005,7, 2385-.
Nuclear magnetic resonance hydrogen spectrum data of compound IX:1H NMR(300MHz,CDCl3):δ11.63,7.81,7.48,7.40,7.32,7.20,7.10,6.74,6.72,6.17,6.15,5.59,5.35,5.16,5.14,4.62,4.09,4.06,2.93,2.04,2.02,1.59,1.29,1.26,0.89.
⑨ preparation of Compound X
In a single-neck flask, compound IX (50mg,0.052mmol,1equiv), K were charged2CO3(34mg,0.25mmol,5equiv) and a mixed solvent (THF: MeOH: 1 by volume, total 6 ml). Stirring at room temperature for 1.5h, neutralizing with cation exchange resin, filtering, and spin drying. The dried oil was dissolved in a mixed solvent (THF: MeOH: volume ratio 1:1, total 5ml), and a catalytic amount of Pd (OH) was added2The gas in the system was replaced with hydrogen, stirred at room temperature for 12 hours, filtered through celite, and the filtrate was spin-dried to give a yellow solid, compound X (31 mg, 98% yield).
Nuclear magnetic resonance hydrogen spectrum data of compound X:1H NMR(300MHz,CDCl3):δ11.63,7.64,7.05,6.77,6.72,6.02,5.94,5.43,5.02,4.89,4.29,4.07,3.98,3.69,3.66,3.44,2.83,2.25,1.60,1.59,1.29,1.27,1.26,0.89。
⑩ preparation of Compound XI
Compound X (20mg,0.032mmol,1equiv), N-methyl-N-morpholine oxide (7mg,0.064mmol,2equiv) were added to a single vial followed by acetone (5ml), water (1ml) and osmium tetroxide (OsO)48mg,0.032mmol,1 equiv). The reaction was stirred at room temperature for 12 h. 10ml of ethyl acetate was added to the reaction system, followed by addition of 10ml of a saturated sodium thiosulfate solution and stirring for 30 minutes. Extracting with ethyl acetate, washing the organic phase with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and passing throughFiltration, concentration, separation and purification gave a yellow solid, compound XI (10 mg, 50% yield).
Nuclear magnetic resonance hydrogen spectroscopy data for compound XI:1H NMR(300MHz,CDCl3):δ11.63,7.38,7.14,6.11,6.02,5.94,5.24,5.00,4.51,4.37,4.02,3.99,3.88,3.73,3.69,3.44,2.92,2.87,2.09,1.61,1.26,1.25,0.89。
example 2: total synthesis of houttuynin heterozygotic flavone Houttuynoid H
The route is shown in fig. 3, and the specific steps are as follows:
① preparation of Compound II
Reference is made to the preparation of compound I (Shen, S.D.; Zhang, G.P.; Lei, M.; Hu, L.H. first synthetic of salvianolic acid C, ournefolic acid A, andtousnefolal. ARKIVOC.2012,6,204-. The obtained 4-benzyl-3-hydroxy-2-iodo-p-hydroxybenzaldehyde is used as a compound I.
4-benzyl-3-hydroxy-2-iodo-p-hydroxybenzaldehyde I (17g, 48.02mmol), pyridine (6.8ml), 4-dimethylaminopyridine (DMAP, 293mg,2.39mmol) were added to a 250ml single-neck flask and stirred. Acetic anhydride (6.8ml) was slowly added dropwise, stirred at room temperature and reacted for 17h with exclusion of light. Py was removed by a rotary evaporator, followed by adjusting pH to neutral with 10% by mass of dilute hydrochloric acid, extraction with Ethyl Acetate (EA), washing of the organic phase with a saturated sodium chloride solution 2 times, and removal of water from the solvent by addition of anhydrous magnesium sulfate. The solvent was removed by rotary evaporator to give compound II as a white solid (18.83 g, 99% yield).
Nuclear magnetic resonance hydrogen spectrum data of compound II:1H NMR(300MHz,CDCl3):δ9.98(s,1H),7.79(d,J＝9.0Hz,1H),7.43–7.30(m,5H),7.04(d,J＝6.0Hz,1H),5.18(s,2H),2.38(s,3H)。
② preparation of Compound III
A250 ml two-necked flask was charged with Compound II (18.81g,47.47mmol), tetrahydrofuran (THF, 120ml), and triethylamine (NEt)338 ml); bis (triphenylphosphine) palladium (II) chloride (Pd (PPh) was added3)2Cl21.665g,2.37mmol), cuprous iodide (0.9g,4.72mmol), nitrogen blanket. 1-undecayne (13.9ml) was taken out by a syringe and slowly added into the reaction flaskThe mixture was stirred at room temperature for 20 hours with the exclusion of light. 30ml of a saturated ammonium chloride solution was added thereto, and the reaction was quenched by stirring for 30 minutes. The solution was transferred to a separatory funnel and extracted with EA, the aqueous phase required 2 extractions and the organic phases were combined. The organic phase was then washed 1 time with saturated brine, and water was removed from the solvent by addition of anhydrous magnesium sulfate. Separating and purifying with silica gel column (eluent, petroleum ether: ethyl acetate, volume ratio 30:1) to obtain brown black oily product, standing the oily product to obtain solid, i.e. compound III (14.4 g, yield 85%).
Nuclear magnetic resonance hydrogen spectrum data of compound III:1H NMR(300MHz,CDCl3):δ10.34(s,1H),7.77(d,J＝6.0Hz,1H),7.43–7.29(m,5H),6.99(d,J＝9.0Hz,1H),5.16(s,2H),2.50(t,J＝15.0Hz,2H),2.34(s,3H),1.70–1.57(m,2H),1.51–1.39(m,2H),1.29(d,J＝3.0Hz,10H),0.88(t,J＝12.0Hz,3H)。
③ preparation of Compound IV
A250 ml single-neck flask was charged with Compound III (13.2g, 31.42mmol), THF (40ml), MeOH (25ml), H2O (25ml) was stirred at 0 ℃ in a cryometer. Slowly add lioh2O (3.96g, 94.28mmol), the reaction was stirred at zero degrees for 2 h. Diluting with 50ml of Dichloromethane (DCM), adjusting the pH to about 7 with 10% by mass of dilute HC, extracting the aqueous phase 1 time with dichloromethane, combining the organic phases of DCM, and removing the water from the solvent by adding anhydrous sodium sulfate. The reaction product was separated and purified by silica gel column (eluent, PE: DCM ═ 25:1) to give compound IV as a white solid (6 g obtained, 50% yield).
Nuclear magnetic resonance hydrogen spectral data of compound IV:1H NMR(300MHz,CDCl3):δ10.00(s,1H),7.57(d,J＝12.0Hz,1H),7.53–7.33(m,5H),7.17(s,1H),6.86(d,J＝12.0Hz,1H),5.39(s,2H),2.83(t,J＝15.0Hz,2H),1.86–1.71(m,2H),1.47–1.21(m,12H),0.88(t,J＝12.0Hz,3H)。
④ preparation of Compound V
Compound IV (2.13g,5.632mmol,1equiv) and 2-acetyl-3, 5-bis (benzyloxy) phenol (1.7g,4.9mmol,1equiv) were added to a single-neck flask, 10ml of ethanol was added, and after compound IV and 2-acetyl-3, 5-bis (benzyloxy) phenol were dissolved by heating to 60 ℃, 5ml of 50% (w/w) aqueous sodium hydroxide solution was added dropwise, and after completion of the addition, room temperature was returned to room temperature, and stirring was continued for 48 hours. After the reaction on the plate was completed, the pH was adjusted to 5 in an ice bath with dilute hydrochloric acid of 10% (V/V), a yellow solid precipitated after acidification, and the yellow solid was filtered and recrystallized from absolute ethanol to obtain Compound V (3.324 g, 98% yield).
Nuclear magnetic resonance hydrogen spectrum data of compound V:1H NMR(300MHz,CDCl3):δ11.58,8.03,7.78,7.57,7.45,7.37,7.29,7.17,6.69,6.27,6.26,5.14,5.12,2.82,1.58,1.28,1.25,0.89。
⑤ preparation of Compound VI
To Compound V (2.3g,3.818mmol,1equiv) in a dry two-necked flask was added 10ml of anhydrous DMSO, catalytic amount of I2(80mg,0.31mmol,0.1 equiv). Heated to 110 ℃ and reacted for 14 hours. After cooling to room temperature, 15m 10% (v/v) of dilute hydrochloric acid was added, extraction was performed with ethyl acetate (15mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2: 1, volume ratio) to obtain compound VI as a white solid (2.04 g obtained, yield 89%).
Nuclear magnetic resonance hydrogen spectrum data of compound VI: :1H NMR(300MHz,CDCl3):δ7.81,7.48,7.40,7.32,7.20,6.86,6.72,6.40,6.30,5.16,5.14,2.91,1.59,1.29,1.26,0.89。
⑥ preparation of Compound VII
Compound VI (1.6g,2.665mmol) was dissolved in CH2Cl2In a mixed solvent of acetone (volume ratio 4:3,70 mL). 90mL of sodium carbonate/sodium bicarbonate buffer (Na) was added2CO38g of NaHCO33.8g of the aqueous solution was dissolved in 200mL of water), stirred vigorously at room temperature, and then 60mL of an aqueous solution containing 5.5g of oxone complex salt was slowly added dropwise thereto, after completion of the addition for about 40 minutes, the reaction was carried out at room temperature for 15 hours overnight. 60mL of an aqueous solution containing 5.5g of oxone complex salt was slowly added dropwise the next day, and the reaction was continued at room temperature for 15 hours after completion of the dropwise addition for about 40 minutes. The pH of the reaction system was maintained at about 9 throughout the addition and the reaction. Standing for layering, separating organic phase, extracting water phase with dichloromethane, and mixing organic phasesThe organic phase was washed 3 times with saturated sodium thiosulfate and saturated brine, respectively, and dried over anhydrous sodium sulfate, filtered, and then 5mg of p-toluenesulfonic acid was added to the filtrate, and the mixture was stirred at room temperature for about 1.5h, filtered, spun-dried, and purified by silica gel column chromatography (petroleum ether: ethyl acetate 6:1, volume ratio) to obtain a yellow solid, which was compound VII (1.23 g obtained, yield 75%).
Nuclear magnetic resonance hydrogen spectrum data of compound VII:1H NMR(300MHz,CDCl3):δ7.80,7.47,7.39,7.31,7.19,6.85,6.71,6.29,5.15,5.13,4.08,2.88,1.59,1.29,1.26,0.89.
⑦ preparation of Compound VIII
Into a single-neck flask were added compound VII (200mg,0.324mmol), acetic acid (13mL), H2O (3mL), heated to 110 ℃ under reflux for 16h, extracted with dichloromethane (10mL × 3), and the combined organic phases washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate 6:1 by volume) to give compound VIII as a yellow solid (145 mg, 85% yield).
Nuclear magnetic resonance hydrogen spectrum data of compound VIII:1H NMR(300MHz,CDCl3):δ11.63,7.81,7.48,7.40,7.32,7.20,6.74,6.72,6.17,5.47,5.16,5.14,2.98,1.59,1.29,1.26,0.89。
⑧ preparation of Compound IX
In a dry two-necked flask, compound VIII (80mg,0.126mmol,1equiv), bromosugar (75mg,0.189mmol,1.5equiv), anhydrous K2CO3(74mg,0.5mmol) and 5ml of anhydrous DMF was added. The reaction was stirred at room temperature (25 ℃) for 12 hours under argon. After the reaction was complete, water was added, extraction was carried out three times with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid, i.e., compound IX (129 mg, yield 99%) without further purification.
Nuclear magnetic resonance hydrogen spectrum data of compound IX:1H NMR(300MHz,CDCl3):δ11.63,7.81,7.48,7.40,7.32,7.20,7.10,6.74,6.72,6.17,6.15,5.59,5.35,5.16,5.14,4.62,4.09,4.06,2.93,2.04,2.02,1.59,1.29,1.26,0.89.
wherein the preparation process of the bromosugar is as follows:
galactose a (98mg,0.544mmol,1equiv), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI, 104.28mg,0.544mmol,1equiv), dicyclohexylcarbodiimide (DCC, 112mg,0.544mmol,1equiv), n-decanoic acid (94mg,0.544mmol,1equiv) were added to 10ml of anhydrous dichloromethane, the reaction was stirred at room temperature for 12 hours, the reaction solution was filtered, concentrated to obtain a white oily liquid, and then subjected to HPLC (75%: 25%: MeOH: H: 1equiv)2O) isolated to b (90mg, 50%).
Nuclear magnetic resonance hydrogen spectrum data of compound b:1H NMR(300MHz,CDCl3):δ5.53,4.42,4.17,4.11,4.11,3.98,3.94,2.60,2.30,2.09,1.95,1.64,1.32,1.25,1.17,0.88.
compound b (84mg,0.251mmol) was dissolved in 5mL of dichloromethane, and 33% HBr in acetic acid (33% w/w,0.45mL,2mmol,8equiv) was added dropwise to the reaction system over 10 minutes from the dropping funnel. After stirring at room temperature for 4 hours, the mixture was diluted with 13ml of dichloromethane, washed twice with 30ml of saturated sodium bicarbonate solution and twice with 20ml of water. The combined organic phases were dried over anhydrous sodium sulfate, filtered and dried by spinning to obtain a white oily compound, i.e., compound c, which was the target product, bromo-sugar (100 mg).
Nuclear magnetic resonance hydrogen spectrum data of compound c:1H NMR(300MHz,CDCl3):δ5.31,4.47,4.47,4.32,4.10,4.06,3.90,3.20,2.32,1.72,1.66,1.52,1.33,1.26,0.89.
⑨ preparation of Compound X
In a single-neck flask, compound IX (49mg,0.052mmol,1equiv) was added, dissolved in a mixed solution of MeOH and THF (THF: MeOH: 1 by volume, 5ml total), and 5mg of pd (oh) was added2The gas in the system was replaced with hydrogen, stirred at room temperature for 12 hours, filtered through celite, and the filtrate was spin-dried to give a yellow solid, compound X (31 mg, 98% yield).
Nuclear magnetic resonance hydrogen spectrum data of compound X:1H NMR(300MHz,CDCl3):δ11.63,7.64,7.05,6.77,6.72,6.02,5.94,5.43,5.02,4.89,4.29,4.07,3.98,3.69,3.66,3.44,2.83,2.25,1.60,1.59,1.29,1.27,1.26,0.89。
⑩ preparation of Compound XI
Compound X (25mg,0.032mmol,1equiv), N-methyl-N-morpholine oxide (7mg,0.064mmol,2equiv) were added to a single vial followed by acetone (5ml), water (1ml) and osmium tetroxide (OsO)48mg,0.032mmol,1 equiv). The reaction was stirred at room temperature for 12 h. 10ml of ethyl acetate was added to the reaction system, followed by addition of 10ml of a saturated sodium thiosulfate solution and stirring for 30 minutes. Extraction was performed with ethyl acetate, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, separated, purified, and dried to obtain a yellow solid, which was compound XI (10 mg obtained, yield 50%).
Nuclear magnetic resonance hydrogen spectroscopy data for compound XI:1H NMR(300MHz,CDCl3):δ11.63,7.38,7.14,6.11,6.02,5.94,5.24,5.00,4.51,4.37,4.02,3.99,3.88,3.73,3.69,3.44,2.92,2.87,2.09,1.61,1.26,1.25,0.89。
the above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A synthetic method of houttuynine sodium bisulfite heterozygous flavonoid compound is characterized in that the method comprises the following steps:
(1) stirring the compound 1-I shown as the formula 1-I, an acetylation reagent, pyridine and 4-dimethylamino pyridine at room temperature, and reacting in a dark place to obtain a compound 1-II shown as the formula 1-II;
(2) adding the compound 1-II, triethylamine, bis (triphenylphosphine) palladium dichloride, cuprous iodide and 1-undecayne into a solvent, and stirring at room temperature under the protection of inert gas and keeping out of the sun to react to obtain a compound 1-III shown as a formula 1-III;
(3) stirring the compound 1-III, alkali and a solvent at-10-30 ℃ for reaction to obtain a compound 1-IV shown as a formula 1-IV;
(4) reacting the compound 1-IV and 2-acetyl-3, 5-bis (benzyloxy) phenol in the presence of alkali in a solvent at room temperature under stirring to obtain a compound 1-V shown in a formula 1-V;
(5) reacting the compound 1-V with iodine and DMSO under stirring at 50-150 deg.C to obtain compound 1-VI shown in formula 1-VI;
(6) reacting the compound 1-VI with oxone complex salt and p-toluenesulfonic acid in a solvent under the condition that the pH value is 9-12 to obtain a compound 1-VII shown in a formula 1-VII;
(7) carrying out reflux stirring reaction on the compounds 1-VII, acid and water at the temperature of 80-130 ℃ to obtain compounds 1-VIII shown in the formulas 1-VIII;
(8) stirring the compound 1-VIII and bromosugar in a solvent in the presence of alkali to react to obtain flavonoid glycoside compounds 1-IX shown in the formula 1-IX;
(9) the compound 1-IX is carried out in the presence of alkali and Pd/H2Removing a protecting group under the condition, and stirring in a solvent for reaction to obtain a compound 1-X shown as a formula 1-X;
(10) adding the compound 1-X and an oxidant into a solvent, and reacting by taking N-methyl-N-morpholine oxide as a catalyst to obtain a compound 1-XI shown in a formula 1-XI;
wherein the structural formula of each compound is as follows:
wherein the content of the first and second substances,
R1the group comprises methyl, benzyl and acetyl;
R2groups include hydrogen and 2-undecanone;
R3the group is a halogen group;
R4the group comprises methyl, benzyl and acetyl;
R5the groups are shown below:
R6the groups are shown below:
2. the method of synthesizing houttuynine sodium bisulfite heteroflavonoid compound of claim 1, characterized in that:
said R1The group is benzyl;
said R3The group is chlorine group or iodine group;
R4the group comprises benzyl.
3. The method of synthesizing houttuynine sodium bisulfite heteroflavonoid compound of claim 1, characterized in that:
the acetylation reagent in the step (1) is acetic anhydride;
the solvent in the step (2) is one or at least two of tetrahydrofuran, N-dimethylformamide, dichloromethane, dimethyl sulfoxide, toluene and N, N-dimethylacetamide;
the inert gas in the step (2) is nitrogen;
the solvent in the step (3) is one or at least two of methanol, tetrahydrofuran, water, dichloromethane, dimethyl sulfoxide, toluene and N, N-dimethylformamide;
the base used in step (3) includes, but is not limited to: sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide;
the solvent in the step (4) is one or more of methanol, ethanol, propanol, butanol, pentanol and 1, 3-propylene glycol;
the base in step (4) includes, but is not limited to: sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide;
the solvent in the step (6) is a composite solvent obtained by mixing one or at least two of dichloromethane, chloroform, ethyl acetate, methanol and tetrahydrofuran with acetone;
the pH value in the step (6) is realized by using an alkaline buffer solution;
the acid in the step (7) is one or at least two of formic acid, acetic acid, propionic acid, butyric acid and citric acid;
the base described in step (8) includes, but is not limited to: one or at least two of sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate and potassium hydroxide;
the solvent in the step (8) comprises: dichloromethane, tetrahydrofuran, DMF, DMSO;
the base described in step (9) includes, but is not limited to: one or at least two of sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate and potassium hydroxide;
the solvent in the step (9) is one or two of tetrahydrofuran and methanol;
the oxidant described in step (10) includes but is not limited to: one or at least two of oxygen, ozone, manganese dioxide, PCC, osmium tetroxide, hydrogen peroxide and phosphorus pentoxide;
the solvent in the step (10) is a solvent obtained by mixing acetone and water.
4. The method of synthesizing houttuynine sodium bisulfite heteroflavonoid compound of claim 1, characterized in that:
the dosage of the acetylation reagent in the step (1) is as follows according to acetyl groups of the acetylation reagent: hydroxyl group ratio ≧ 1 of compound 1-I: 1, calculating;
the using amount of the pyridine in the step (1) is 1-3 times of the molar amount of the compound 1-I;
the dosage of the 4-dimethylaminopyridine in the step (1) is 5 percent of the molar weight of the compound 1-I;
the dosage of the triethylamine in the step (2) is 1-2 times of the molar weight of the compound 1-II;
the usage amount of the bis (triphenylphosphine) palladium dichloride in the step (2) is 5 percent of the molar amount of the compound 1-II;
the dosage of the cuprous iodide in the step (2) is 10 percent of the molar weight of the compound 1-II;
the dosage of the alkali in the step (3) is 2 to 5 times of the molar weight of the compound 1 to III;
the dosage of the alkali in the step (4) is 10 to 25 times of the molar weight of the compound 1 to IV;
the dosage of the iodine in the step (5) is 10 percent of the molar weight of the compound 1-V;
the dosage of DMSO in the step (5) is 20-50 times of the molar quantity of the compounds 1-VI;
the dosage of the potassium hydrogen persulfate composite salt in the step (6) is 12 times of the molar quantity of the compounds 1-VI;
the dosage of the p-toluenesulfonic acid in the step (6) is 2 percent of the molar weight of the compound 1-VI;
the amount of the acid used in the step (7) is 1000 times of the molar amount of the compounds 1-VII;
the dosage of the alkali in the step (8) is 2 to 5 times of the molar weight of the compound 1 to VIII;
the dosage of the alkali in the step (9) is 3 to 7 times of the molar weight of the compound 1 to IX;
the dosage of the oxidant in the step (10) is 0.5 to 2 times of the molar weight of the compound 1 to X;
the dosage of the N-methyl-N-morpholine oxide in the step (10) is 1-2 times of the molar quantity of the compound 1-X.
5. The method of synthesizing houttuynine sodium bisulfite heteroflavonoid compound of claim 1, characterized in that:
the reaction time in the step (1) is 17h in a dark state;
the reaction time in the step (2) is 20 h;
the stirring reaction time in the step (3) is 2 hours;
the stirring reaction time in the step (4) is 48 h;
the temperature of the stirring reaction in the step (5) is 80-120 ℃;
the stirring reaction time in the step (5) is 14 h;
the reaction time in the step (6) is 30-32 h;
the temperature of the reflux stirring reaction in the step (7) is 90-120 ℃;
the reflux stirring reaction time in the step (7) is 16 h;
the reaction time in the step (8) is 12 h;
the reaction time in the step (10) is 12 h.
6. The method of synthesizing houttuynine sodium bisulfite heteroflavonoid compound of claim 1, characterized in that:
after the light-shielding reaction in the step (1), the method further comprises a purification step, which is specifically as follows: removing Py, adjusting pH to neutral, extracting with ethyl acetate to obtain an organic phase, washing with saturated sodium chloride solution, and drying to obtain a white solid, namely a compound 1-II;
after the reaction is carried out in a dark place in the step (2), the method further comprises a purification step, which is specifically as follows: adding saturated ammonium chloride solution to quench the reaction; extracting with ethyl acetate, washing the obtained organic phase with saturated saline, removing water, loading on silica gel column, eluting with solvent containing petroleum ether and ethyl acetate at volume ratio of 30:1, and separating and purifying to obtain compound 1-III;
after the stirring reaction in the step (3), further comprising a purification step, which is specifically as follows: diluting with dichloromethane, adjusting pH to neutral, extracting with dichloromethane to obtain organic phase, removing water, separating with silica gel column, eluting with solvent composed of petroleum ether and dichloromethane at volume ratio of 25:1, and drying to obtain white solid compound 1-IV;
after the stirring reaction in the step (4), further comprising a purification step, which is specifically as follows: adjusting pH to 5 in ice bath, precipitating yellow solid after acidification, filtering, and recrystallizing with anhydrous ethanol to obtain yellow solid compound 1-V;
after the stirring reaction in the step (5), further comprising a purification step, specifically as follows: cooling to room temperature, adjusting the pH value to 5-7, extracting with ethyl acetate, washing the obtained organic phase with saturated salt water, removing water, concentrating, and purifying by silica gel column chromatography, wherein an eluent is petroleum ether and ethyl acetate in a volume ratio of 2: 1, drying to obtain a white solid which is a compound 1-VI;
after the reaction in step (6), further comprising a purification step, specifically as follows: filtering, spin-drying, purifying by silica gel column chromatography, eluting with solvent prepared from petroleum ether and ethyl acetate at a ratio of 6:1, and drying to obtain yellow solid as compound 1-VII;
after the reflux stirring reaction in the step (7), further comprising a purification step: extracting with dichloromethane, washing the organic phase with saturated saline solution, removing water, filtering, concentrating, purifying by silica gel column chromatography, and eluting with petroleum ether and ethyl acetate according to a volume ratio of 6:1, drying to obtain a yellow solid which is a compound 1-VIII;
after the reaction in the step (8), further comprising a purification step: adding water, extracting with ethyl acetate, washing the obtained organic phase with saturated salt water, removing water, filtering, and concentrating to obtain light yellow solid as compound 1-IX;
the step (10) further comprises a purification step after the reaction, and comprises the following steps: adding ethyl acetate into the reaction system, adding a saturated sodium thiosulfate solution, and stirring; extraction with ethyl acetate and washing of the organic phase with saturated brine, removal of water, filtration and concentration gave a yellow solid as compound 1-XI.
7. The method of synthesizing houttuynine sodium bisulfite heteroflavonoid compound of claim 1, characterized in that:
the step (6) is as follows: reacting the compound 1-VI with potassium hydrogen persulfate composite salt in a solvent under the condition that the pH value is 9-12, standing for layering, separating an organic phase, extracting an aqueous phase with dichloromethane, washing the combined organic phase with saturated sodium thiosulfate and saturated common salt water respectively, removing water in the organic phase, filtering, adding p-toluenesulfonic acid into the obtained filtrate, stirring for reaction at room temperature, filtering, and removing the solvent.
8. The method of synthesizing houttuynine sodium bisulfite heteroflavonoid compound of claim 7, characterized in that:
and (3) adding the potassium hydrogen persulfate composite salt in the step (6) by two times, adding the potassium hydrogen persulfate composite salt after reacting for a period of time for the first time, and reacting for a period of time again.
9. The method of synthesizing houttuynine sodium bisulfite heteroflavonoid compound of claim 1, characterized in that:
the brominated sugar in the step (8) is represented by structural formulas A-D:
10. the method of synthesizing houttuynine sodium bisulfite heteroflavonoid compound of claim 1, characterized in that:
the step (9) is as follows: reacting the compounds 1-IX in a solvent in the presence of a base, neutralizing with a cation exchange resin, filtering, and spin-drying; the resulting oil was dissolved in a solvent, Pd (OH) was added2Replacing gas in the system with hydrogen, stirring for reaction at room temperature, filtering, and drying the obtained filtrate to obtain the compound 1-X.
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| CN103304609A (en) * | 2012-03-10 | 2013-09-18 | 中国科学院广州生物医药与健康研究院 | Houttuynoid and preparation method and application thereof |
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| A Method for Highly Synthetic Benzofuran Ring;Jilin Fan, et al.;《J Pharm Biomed Sci》;20170513;第7卷(第5期);第144-146页 * |
| Anti HSV-1 Flavonoid Derivatives Tethered with Houttuynin from Houttuynia cordata;Shao-Dan Chen, et al.;《Planta Med》;20131128;第79卷;第1742-1748页 * |
| Total Synthesis of the Antiviral Natural Product Houttuynoid B;Thomas Kerl, et al.;《Chem. Eur. J.》;20160127;第22卷;第2935-2938页 * |
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