CN107298667B - Method for synthesizing icaritin - Google Patents
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Abstract
The invention provides a synthesis method of icaritin, which comprises the step of preparing the icaritin by taking kaempferol-4-oxymethyl ether as a raw material.
Description
Technical Field
The invention relates to a synthesis method of icaritin, belonging to the field of chemical synthesis.
Background
The alcladine, also called icaritin and icaritin, is a new effective monomer obtained by the enzyme conversion of main active ingredient icariin extracted and separated from traditional Chinese medicine epimedium, and the structural formula of the monomer is shown as the following formula (A):
the preparation method of the compound is disclosed in CN 101302548B. The method takes icariin as a raw material, beta-glucosidase is used for hydrolysis, precipitate obtained by centrifuging hydrolysate is dissolved by acetone, and supernatant is obtained by centrifuging and filtering. And recrystallizing the supernatant obtained by centrifugation with water to obtain the pure icaritin.
In the chinese patent application No. 201010517793.6, a method for obtaining icaritin from icariin by using naringinase is disclosed, in which icaritin standard substance is dissolved in ethanol solvent, and naringinase is added at 40-70 deg.C for enzymolysis, thereby obtaining icaritin.
In the chinese patent with application number 200910184282.4, a preparation method of icaritin is disclosed, which takes epimedium as raw material, and obtains crude icaritin through steps of methanol extraction, helicase hydrolysis and the like. However, the preparation methods of icaritin are all enzymolysis extraction methods, have high production cost and are not suitable for large-scale use in production.
The Chinese patent with application number 200610165354.7 discloses a synthesis method of icaritin, which takes a compound with the following formula (I) as a starting material to prepare the icaritin. Compounds of formula (I), also known as kaempferol-4-oxomethyl ether, are commercially available and may be synthesized according to the procedures described in the patent, which describe the synthetic procedures as follows:
in the above synthesis steps, firstly, the starting material benzyl alcohol: namely, the compound (2) reacts with paraformaldehyde after hydrochloric acid gas is introduced, so that chloromethyl anisole is obtained: namely the compound (3), the chloromethyl anisole and cuprous cyanide are refluxed in ether to obtain the cyanomethyl anisole, namely the compound (4). And reacting the cyanomethyl anisole (4) with phloroglucinol and Lewis acid under the action of continuously introducing hydrochloric acid gas to generate a compound (5). Two phenolic hydroxyl groups of the compound (5) are subjected to tert-butyl dimethyl silicon-based selective protection and then react with p-methoxybenzoic acid to generate a compound (7), then the compound (9) is obtained through ring closing and silicon-based removal protection, and the compound (9) is subjected to debenzylation protection under the action of hydrogen to generate a compound shown in the formula (I), namely kaempferol-4-oxymethyl ether.
And (3) obtaining kaempferol-4-oxymethyl ether, namely after the compound (I), carrying out etherification reaction on the compound (I) and chloromethyl methyl ether, introducing an isopentenyl group, carrying out claisen rearrangement reaction by microwave, and finally removing ether by hydrochloric acid to obtain a target product icaritin, namely the compound of the formula (A). The reaction scheme is as follows:
however, in the above method, eight steps of reaction are performed in the synthesis of kaempferol-4-oxymethyl ether, and the operation is complicated; the claisen rearrangement reaction needs microwave-assisted heating, has high production cost and is not beneficial to large-scale industrial production.
An article entitled "synthesis of icaritin" was disclosed in organic chemistry, 3 months 2013, and the synthetic route in the article is the same as that of 200610165354.7. However, in the rearrangement process from the compound (12) to the compound (13), when tris (6,6,7,7,8,8, 8-heptafluoro-2, 2-dimethyl-3, 5-octanedione) europium is used as a catalyst, the reaction temperature in the catalytic process reaches 80 ℃ and the reaction time is 36 hours, and the yield is only 42%. In order to obtain compound 12 with higher purity for the next reaction, the article isolated compound (12) by column chromatography on silica gel. Although the separation is feasible in a laboratory, the cost is too high to be used properly in large-scale industrial production.
Therefore, it is necessary to research a method suitable for large-scale industrial synthesis of icaritin.
Disclosure of Invention
The invention aims to provide a method for synthesizing icaritin. The method takes kaempferol-4-oxymethyl ether as a starting material to prepare the icaritin through four steps of reaction.
The invention provides a synthesis method of icaritin on one hand, which comprises the following steps:
A. is represented by the formula I
The compound is used as a raw material to carry out the protection of 3-and 7-phenolic hydroxyl groups to obtain a compound shown in a formula II
A compound;
B. will be shown in the formula II
Compounds and formula III
Reacting the compound to obtain the formula IV
A compound;
C. general formula IV
Subjecting the compound to rearrangement reaction to obtain the compound of formula V
A compound;
D. general formula V
Deprotection of the compound to give formula A
Compound (C), the catalyst for the rearrangement reaction in step C is a silicon-containing catalyst.
Preferably, the protecting group PG of the phenolic hydroxyl at the 3-position and the 7-position of the compound of the formula II, the compound of the formula IV and the compound of the formula V is selected from one or more of methoxymethyl, 2-methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, benzyloxymethyl, benzyl, p-methoxybenzyl and trityl.
Preferably, the compound of formula I is reacted with one selected from bromomethyl ether, chloromethyl methyl ether, 2-methoxyethoxy chloromethane, 2-bromoethyl ether, 2-chloroethyl ethyl ether, dihydropyran, benzyl bromomethyl ether, benzyl chloromethyl ether, benzyl bromide, p-methoxybenzyl chloride and trityl chloride to obtain the compound of formula II.
Preferably, the compounds of formula III
The substituent X in (A) is selected from one or more of bromine, chlorine, hydroxyl, p-toluenesulfonate and methanesulfonate.
More preferably, the compound of formula III is selected from one or more of isopentenyl bromide, isopentenyl chloride, isopentenyl alcohol, isopentenyl p-toluenesulfonate ester and isopentenyl methanesulfonate ester.
Preferably, in the step a, the reaction solvent is one or more selected from ether solvents, halogenated alkanes and amide solvents.
More preferably, the ether solvent is selected from one or more of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane and 1, 2-diethoxyethane; the halogenated alkane solvent comprises dichloromethane or chloroform; the amide solvent comprises one or more of N-methyl pyrrolidone, N-dimethyl acetamide and N, N-dimethyl formamide.
Preferably, an acid scavenger is also added to the reaction solvent.
More preferably, the acid-binding agent is selected from organic amine, basic nitrogen-containing aromatic compound, hydride or carbonate, and the organic amine is selected from N, N-diisopropylethylamine or triethylamine; the basic nitrogen-containing aromatic compound is selected from pyridine or derivatives thereof; the hydride is sodium hydride; the carbonate is potassium carbonate, and the reaction temperature is 0-40 ℃.
Preferably, in the step B, the reaction solvent contains one of alkali and mitsunobu reaction auxiliary agent and aprotic polar solvent, and the reaction temperature is-20-70 ℃.
More preferably, the aprotic polar solvent is selected from one or more of ethers, aromatic hydrocarbons, ketones, amide solvents, and halogenated alkane solvents.
More preferably, the ether solvent is selected from one or more of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane and 1, 2-diethoxyethane solvent; the aromatic hydrocarbon solvent is selected from toluene or xylene solvent; the ketone solvent is selected from one or more of acetone, methyl butanone and methyl isobutyl ketone solvents; the amide solvent is one or more selected from N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone solvents; the halogenated alkane solvent is selected from dichloromethane or chloroform solvent.
Preferably, the base is selected from one or more of alkali metal carbonate, alkoxide, ammonia salt, organic amine salt, hydroxide, hydride, alkyl lithium compound and nitrogen-containing organic base.
More preferably, the carbonate of an alkali metal is selected from potassium carbonate or cesium carbonate; the alkoxide of alkali metal is selected from sodium methoxide or potassium tert-butoxide; the alkali metal ammonia salt is selected from sodium amide or potassium amide; the organic amine salt of an alkali metal is selected from lithium diisopropylamide, sodium hexamethyldisilazide or potassium hexamethyldisilazide; the hydroxide of alkali metal is potassium hydroxide or sodium hydroxide; the hydride of an alkali metal is sodium hydride; the alkyl lithium compound is selected from n-butyl lithium or phenyl lithium; the nitrogen-containing organic base is 1, 8-diazabicyclo-bicyclo (5,4,0) -7-undecene.
Preferably, the mitsunobu reaction auxiliary agent comprises a mixed reagent consisting of one of triphenylphosphine and tributylphosphine and one of diisopropyl azodicarboxylate and diethyl azodicarboxylate.
Preferably, a catalyst is also added in step B.
More preferably, the catalyst is sodium iodide or tetrabutylammonium bromide.
Preferably, the reaction solvent of step C is an aprotic polar solvent selected from one or more of toluene and xylene.
More preferably, the aprotic polar solvent is toluene.
More preferably, the silicon-containing catalyst is selected from catalysts comprising one or more of silica, Florisil and montmorillonite.
Most preferably, the siliceous catalyst is florisil.
Preferably, in step D, the reaction solvent is selected from one or more of water, carboxylic acid, amide, ester, alcohol and ether solvents.
More preferably, the reaction solvent is selected from one or both of alcohols and ethers.
Most preferably, the reaction solvent is a mixed solvent of isopropanol and one of tetrahydrofuran and 2-methyltetrahydrofuran.
Preferably, a deprotection reagent is also added in step D.
More preferably, the deprotecting reagent comprises a dealkylether protecting agent.
More preferably, the dealkylation ether protecting agent is a protonic acid or a Lewis acid.
Most preferably, the protic acid is sulfuric acid or hydrochloric acid.
Preferably, a step E of purifying the reaction product II is further included between the step A and the step B.
More preferably, water and ethyl acetate are added into the reaction liquid of the step A for liquid separation, and a crystallization solvent is added into the organic phase for crystallization and purification, wherein the crystallization solvent is isopropanol.
More preferably, a weak acid solution is further added to the reaction solution in step a to neutralize the unreacted acid-binding agent.
Most preferably, the weak acid solution is an ammonium chloride solution.
Preferably, a step F of purifying the reaction product IV is further included between the step B and the step C.
More preferably, ethyl acetate and water are added to the reaction solution, followed by liquid separation.
More preferably, by adding C to the organic phase6-C9Crystallizing the linear organic alkane, filtering and collecting filter cakes.
Still preferably, the alkali in the reaction solution is also neutralized with an ammonium chloride solution.
Most preferably, said C6-C9The linear organic alkane is n-hexane or n-heptane.
Preferably, a step G is further included between the step C and the step D: and C, filtering the reaction liquid in the step C, removing the silicon-containing catalyst in the reaction liquid, washing a filter cake by using methane chloride, combining the filtrates, and purifying.
More preferably, the crystallization is carried out by adding a crystallization solvent to the organic phase.
Most preferably, acetonitrile or ethanol is also added into the organic phase, the mixture is concentrated to remove methane chloride, acetonitrile or ethanol is added into the mixture to be used as a crystallization solvent, the temperature is reduced to-5 ℃ to 5 ℃, crystallization is carried out, and the compound of the formula V is obtained by filtration.
Preferably, step H is further included after step D: and D, adding water into the reaction liquid obtained in the step D, filtering, collecting a filter cake, dissolving the filter cake with ethanol, recrystallizing, filtering, and washing the filter cake again to obtain the compound shown in the formula A.
Preferably, the method further comprises a step I of adding an organic solvent containing ethyl acetate and an aqueous solution into the reaction solution of the step D for separating, concentrating, adding a crystallization solvent into the concentrated solution, and performing crystallization.
More preferably, a step J of adding carbonate or bicarbonate water solution to the reaction solution to neutralize the unreacted deprotection reagent is also included between the step D and the step I.
More preferably, in the step I, the organic solvent containing ethyl acetate includes ethyl acetate and any one selected from the group consisting of 2-methyltetrahydrofuran, acetonitrile and acetone.
Most preferably, the crystallization solvent is selected from one or both of 2-methyltetrahydrofuran and n-heptane.
The invention has the beneficial effects that the invention provides a novel method for synthesizing icaritin, which does not use the step of triggering Claisen (Claisen) rearrangement by microwave or catalyst tris (6,6,7,7,8,8, 8-heptafluoro-2, 2-dimethyl-3, 5-octanedione) europium in the prior art, but uses cheap and easily available silicon-containing catalyst, such as one or more selected from silicon dioxide, Florisil and montmorillonite, the reaction temperature is 60-120 ℃, compared with the prior art, the reaction is easier to operate, the post-treatment step is simpler, and the yield of the rearrangement reaction in the invention can reach about 50%. And the icaritin obtained by the existing chemical synthesis method has less impurities, and the finally obtained icaritin product has the total yield of more than 30 percent and the purity of more than 98 percent relative to the raw material of kaempferol-4-oxymethyl ether.
Detailed Description
Unless otherwise indicated, "kaempferol-4-oxomethyl ether" is also referred to herein as "3, 5, 7-trihydroxy-4' -methoxyflavone", kaempferide, having the following structural formula:
Unless otherwise indicated, "MOM" herein means methoxymethyl.
Unless otherwise indicated, "ethereal solvents" herein refer to solvents of the structure ethers formed by an oxygen atom connecting two alkyl or aryl groups, the ethers having the general formula: R-O-R ', wherein R and R' represent alkyl or aryl groups which may be the same or different from each other.
Unless otherwise indicated, "amide solvent" herein means a solvent having a structure of amide, which contains an amide bond and has a chemical structure of amide
Wherein R is1,R2And R3May be hydrogen or a hydrocarbon group.
Unless otherwise stated, the "silicon-containing catalyst" herein includes a catalyst containing one or more components of silica, friedrite and montmorillonite, for example, a silica gel or a magnesia-silica gel, which is a catalyst whose main component is silica, is also within the scope of the catalyst of the present invention.
Unless otherwise indicated, an "aprotic polar solvent" herein means a solvent that is aprotic in the molecule, but has a weaker tendency to accept protons and a different degree of ability to form hydrogen bonds.
Unless otherwise specified, "alcohol solvent" herein means a solvent having a structure of an alcohol, and is a compound in which a hydrogen atom in a side chain of an aliphatic hydrocarbon, alicyclic hydrocarbon or aromatic hydrocarbon is substituted with a hydroxyl group.
Unless otherwise indicated, "PG" herein denotes a protecting group.
Unless otherwise indicated, an "acid scavenger" herein refers to a reagent that reacts with an acid in a reactant in a chemical reaction by reacting with the acid, thereby promoting the entire chemical reaction. In the whole reaction process, the acid-binding agent is consumed.
Unless otherwise indicated, the reagent "tetrabutylammonium bromide" herein is available from Shanghai book, sub-medicine science and technology, Inc., under the trade designation B40912.
Unless otherwise indicated, the reagent "1-bromo-3-methyl-2-butene" herein is purchased from shanghai jiachen chemical company, inc.
Unless otherwise indicated, "Florisil" herein is available from Arcos Organics, Inc., Eikes organic company.
Example 1
1) Preparation of compound of formula IIa (PG ═ MOM)
Methoxymethyl protection of 3, 7-phenolic hydroxyl groups with bromomethyl methyl ether
Reaction of
3,5, 7-Trihydroxyl-4' -methoxyflavone (compound of formula I) (100g, 0.33mol) and tetrahydrofuran (1.0L, 10mL/g) were first charged to a reactor under nitrogen blanket, and the acid-binding agent N, N-diisopropylethylamine (93.8g, 0.73mol) was added with stirring at 0 ℃. Bromomethyl methyl ether (86.3g,0.69mol) was added dropwise while controlling the temperature below 10 ℃. After the dropwise addition, the temperature is raised to room temperature and 20 ℃ and the reaction is stirred for 3 hours until the reaction is complete.
Post-treatment
Water (300mL, 3mL/g) and ethyl acetate (400mL,4mL/g) were added to the reaction mixture, and the mixture was stirred for 30 minutes and separated. The organic phase was washed successively with a saturated aqueous ammonium chloride solution (300mL, 3g/L) and a 15% aqueous sodium chloride solution (300mL, 3mL/g) in terms of mass concentration. The organic phase was concentrated to approximately 200mL, isopropanol (500mL, 5mL/g) was added to the organic phase, stirred at 65 ℃ for 1 hour, then cooled to 0 ℃ over 2 hours, and stirred for 1 hour until a solid precipitated. Filtering, leaching the filter cake with isopropanol (100mL, 1.0mL/g), and vacuum drying to obtain 102g of a light yellow powder product, namely the compound of the formula IIa, with a molar ratio to the compound of the formula I, wherein the yield is 78.9%.
2) Preparation of compound of formula IVa (PG ═ MOM)
Reaction of
A reaction flask was charged with compound IIa (100g,0.26mol), N-methylpyrrolidinone (1.5L,15mL/g), potassium carbonate (53.4g,0.39mol) and sodium iodide (1.9g, 0.013mol) sequentially under nitrogen. Under vigorous stirring, isopentenyl bromide (13.6g,0.09mol) was added dropwise to the reaction mixture over 15 minutes, the temperature was controlled at 30 ℃ during the dropwise addition, and after the dropwise addition was completed, the mixture was stirred at 30 ℃ for 3 hours, and the same operation was repeated 3 times until the final amount of isopentenyl bromide added dropwise was 54.4 g. After the addition, the mixture was stirred for 10 hours until the reaction was completed.
Post-treatment
The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (200mL,2.0mL/g), and the filtrates were combined. Ethyl acetate (800mL,8.0mL/g), water (1L, 10mL/g) was added to the filtrate for liquid separation, the aqueous phase was extracted twice with ethyl acetate (500mL, 5mL/g), and the organic phases were combined. The organic phase was first neutralized with a saturated aqueous ammonium chloride solution (400mL,4mL/g) to neutralize potassium carbonate, followed by washing with water (400mL,4mL/g) and a 15% aqueous sodium chloride solution (400mL,4mL/g) in this order. The organic phase was concentrated to 200mL, heated to 55 deg.C, n-heptane (800mL,8.0mL/g) was added, and after stirring at 55 deg.C for 30 minutes, cooled to 10 deg.C over 2 hours, filtered, and the filter cake was washed with n-heptane (100mL,10 mL/g). Vacuum drying gave 89.0g of the compound of formula IVa, with a yield of 75.7% relative to the molar amount of the compound of formula IIa.
In addition, the present inventors studied the reaction between IIa (PG ═ MOM) and isopentenyl bromide under different conditions of base and solvent, and listed in table 1 below:
TABLE 1
3) Preparation of Compounds of formula Va
Reaction of
A reaction flask was charged with a compound of formula IVa (50g, 0.11mol), toluene (500mL,10mL/g) (solvent), Florisil (60-100 mesh, 25g,0.5g/g) under nitrogen. Heating the reaction solution to 80-90 ℃, and stirring for 18 hours.
Post-treatment
The reaction was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane (200mL,4 mL/g). The filtrates were combined and concentrated to 100 mL. Acetonitrile (250mL,5mL/g) was added to the concentrate, and the mixture was concentrated to 100 mL. Acetonitrile (250mL,5mL/g) was added and concentrated to 250 mL. Stirring at 50-60 deg.C for 1 hr, cooling to 0 deg.C within 2 hr, and stirring for 1 hr. Filtration and the filter cake washed with acetonitrile (50mL,1 mL/g). The filter cake was dried to give 24.0g of the compound of formula Va in 48.0% yield relative to the molar amount of the compound of formula IVa.
In addition, the present inventors studied the reaction conditions in which IVa (PG ═ MOM) undergoes claisen rearrangement under different catalyst conditions, and are listed in the following table 2:
TABLE 2
4) Preparation of icaritin
Reaction of
A compound of formula Va (10g,0.022mol), tetrahydrofuran (50mL,5mL/g), and a solution of sulfuric acid in isopropanol (0.54mol/L,50mL) were added to the reactor sequentially under nitrogen. The reaction mixture was heated to 50 ℃ and stirred for 12 hours to terminate the reaction.
Post-treatment
The reaction mixture was cooled to 30 ℃ and an 8% aqueous solution of potassium hydrogencarbonate (50mL,5mL/g) was slowly added to neutralize the unreacted sulfuric acid, and ethyl acetate (60mL,6mL/g) and tetrahydrofuran (30mL,3mL/g) (a mixed solution of ethyl acetate and tetrahydrofuran may also be added) were added to the reaction mixture in this order, stirred for 15 minutes, and separated. The organic phase was washed with a 15% by mass aqueous solution of sodium chloride (50mL,5 mL/g).
After concentrating the organic phase to 50mL, acetone (60mL,6mL/g) was added to the organic phase and concentrated to 50 mL; acetone (60mL,6mL/g) was added and concentrated to 40 mL. After isopropanol (40mL,4mL/g) was added slowly at 30-40 deg.C, n-heptane (50mL,5mL/g) was added. After stirring for 30 minutes, it was cooled to 0 ℃ over 2 hours. Filtration, washing of the filter cake with a crystallization solution (isopropanol: n-heptane, 1:3,10mL,10 mL/g) and drying gave the product. The weight of the product is as follows: 5.5g, 68.2% yield based on moles of compound of formula Va.
Example 2
Methoxyethoxymethyl protection of the 3, 7-phenolic hydroxyl group
1) Preparation of compound of formula IIb (PG ═ methoxyethoxymethyl)
Reaction of
3,5, 7-Trihydroxyflavone (compound of formula I) (500mg,1.67mmol), N, N-dimethylformamide (5mL,10mL/g) and 2-methoxyethoxy methyl chloride were added to a reactor under nitrogen, and sodium hydride (133mg, 60% dispersed in mineral oil, 5.54mmol), an acid-binding agent, was added with stirring at 0 ℃. The reaction was stirred at room temperature for 2 hours until the reaction was complete.
Post-treatment
Water (20mL, 4mL/g) was added to the reaction solution to quench. Extracted three times with ethyl acetate (25mL,5mL/g), the organic phases are combined and dried over anhydrous sodium sulfate. After filtration and concentration, purification by silica gel column chromatography (eluent ratio: petroleum ether: ethyl acetate: 3:1) gave 320mg of the compound of formula lib as a yellow powder in a molar ratio to the compound of formula I with a yield of 40.3%.
2) Preparation of compound of formula IVb (PG ═ methoxyethoxymethyl)
Reaction of
Under nitrogen, the compound of formula IIb (800mg,1.68mmol), tetrahydrofuran (solvent) (10mL,12mL/g), isopentenyl bromide (325mg, 2.18mmol), and potassium hydroxide (132mg,2.35mmol) were added to the reactor. The reaction was carried out at 50 ℃ for 14 hours until the reaction was complete.
Post-treatment
The reaction mixture was quenched by adding a saturated aqueous ammonium chloride solution (20mL, 25 mL/g). The mixture was extracted three times with ethyl acetate (50mL,60mL/g), the organic phases were combined, concentrated and purified by column chromatography on silica gel (eluent ratio petroleum ether: ethyl acetate: 3:1) to give 558mg of a pale yellow powder of the compound of formula IVb in a molar ratio to the compound of formula IIb with a yield of 61.0%. LCMS (ES, M/z):545[ M + H]+；1HNMR(300MHz,CDCl3):8.10-8.01(m,2H),7.05-6.99(m,2H),6.75(s,1H),6.44(s,1H),5.63-5.52(m,1H),5.36(s,2H),5.26(s,2H),4.70(d,J＝6.6Hz,2H),3.95-3.81(m,5H),3.66-3.53(m,4H),3.40(s,3H),3.30-3.21(m,5H),1.80(s,3H),1.77(s,3H)。
The next procedure was the same as in inventive example 1.
Example 3
Tetrahydropyranyl protection of 3, 7-phenolic hydroxy
1) Preparation of compound of formula IIc (PG ═ tetrahydropyranyl)
Reaction of
3,5, 7-Trihydroxyl-4' -methoxyflavone (compound of formula I) (1.0g,3.33mmol) and dihydropyran (15mL,15mL/g) were initially charged to a reactor under nitrogen blanket, and pyridinium p-toluenesulfonate (4g,15.9mmol) was added with stirring at 0 ℃. Stirred at room temperature for 14 hours.
Post-treatment
The reaction was concentrated and purified by silica gel column chromatography (eluent ratio petroleum ether: ethyl acetate: 3:1) to give 320mg of a pale yellow powder product, i.e. the compound of formula IIc, in a molar ratio to the compound of formula I, with a yield of 20.5%.1H NMR(300MHz,DMSO-d6):12.57(s,1H),8.06(d,J＝8.7Hz,2H),7.15(d,J＝9.0Hz,2H),6.79(s,1H),6.46(s,1H),5.70-5.67(m,2H),3.86(s,3H),3.73-3.32(m,4H),1.86-1.45(m,12H).
2) Preparation of compound of formula IVc (PG ═ tetrahydropyranyl)
Reaction of
Under nitrogen, the compound of formula IIc (300mg,0.64mmol), tetrahydrofuran (solvent) (5mL,17mL/g), isopentenyl bromide (190mg, 1.28mmol), tetrabutylammonium bromide (103mg,0.32mmol) and cesium carbonate (416mg,1.28mmol) were added to the reactor. The reaction was carried out at room temperature for 14 hours until completion.
Post-treatment
Ethyl acetate (15mL,50mL/g) was added to the reaction mixture to dilute the mixture, and the organic phase was washed with a saturated aqueous ammonium chloride solution (6mL,20mL/g), water (6mL,20mL/g), and a 15% aqueous sodium chloride solution (6mL,20mL/g), respectively. And drying the organic phase by using anhydrous sodium sulfate, filtering and concentrating to obtain a crude product IVc which is directly used for the next reaction.
The next procedure was the same as in inventive example 1.
Example 4
Benzyloxymethyl protection of 3, 7-phenolic hydroxyl group
1) Preparation of compound of formula IId (PG ═ benzyloxymethyl)
Reaction of
To a reactor was added 3,5, 7-trihydroxy-4' -methoxyflavone (compound of formula I) (1.0g,3.33mmol), N, N-dimethylformamide (solvent) (15mL,15mL/g) and benzyl chloromethyl ether (1.14g, 7.28mmol) under nitrogen, and sodium hydride (333mg, 60% dispersed in mineral oil, 8.33mmol) was added with stirring at 0 ℃. The reaction was stirred at room temperature for 3 hours until the reaction was complete.
Post-treatment
Water (30mL, 30mL/g) was added to the reaction solution to quench. Extracted three times with ethyl acetate (20mL,20mL/g), the organic phases are combined and dried over anhydrous sodium sulfate. After filtration and concentration, the product is purified by silica gel column chromatography (eluent ratio is petroleum ether: ethyl acetate: 5:1) to obtain 480mg of a yellow oily product, namely, a compound of formula IId, wherein the molar ratio of the compound of formula IId to the compound of formula I is 26.6%.
2) Preparation of compound of formula IVd (PG ═ benzyloxymethyl)
Reaction of
Under nitrogen, the compound of formula IId (500mg,0.92mmol), tetrahydrofuran (solvent) (5mL,10mL/g), isopentenyl bromide (274mg, 1.84mmol), tert-butyl ammonium bromide (149mg,0.46mmol) and cesium carbonate (602mg,1.85mmol) were added to the reactor. The reaction was carried out at 50 ℃ for 14 hours until the reaction was complete.
Post-treatment
The reaction was concentrated and purified by silica gel column chromatography (eluent ratio petroleum ether: ethyl acetate: 3:1) to yield 202mg of a white solid product, i.e., the compound of formula IVd, in a molar ratio to the compound of formula I, at 35.8%. LCMS (ES, M/z) 609[ M + H]+；1H NMR(300MHz,CDCl3):8.10-8.00(m,2H),7.42-7.31(m,5H),7.30-7.20(m,3H),7.10-6.95(m,4H),6.77(d,J＝2.1Hz,1H),6.51(d,J＝2.1Hz,1H),5.65-5.52(m,1H),5.40-5.31(m,4H),4.80-4.65(m,4H),4.44(s,2H),3.89(s,3H),1.85-1.70(m,6H)。
The next procedure was the same as in inventive example 1.
Example 5
3, 7-phenolic hydroxybenzyl protection
1) Preparation of compound of formula IIe (PG ═ benzyl)
Reaction of
3,5, 7-Trihydroxyl-4' -methoxyflavone (compound of formula I) (10g,0.033mol) and tetrahydrofuran (100mL,10mL/g) were initially charged to a reactor under nitrogen, and potassium carbonate (11g,0.083mol) was added with stirring at 0 ℃. Benzyl bromide (13.0g, 0.076mol) was added dropwise at 0 ℃ with temperature control. After the completion of the dropwise addition, the reaction mixture was stirred at 0 ℃ for 2 hours and then stirred at room temperature for 10 hours.
Post-treatment
The reaction solution was filtered at room temperature, and the filter cake was washed 2 times with ethyl acetate (50mL,5mL/g), and the filtrates were combined. The filtrate is washed by water (80mL,8mL/g), separated, the organic phase is concentrated, the mixed solvent (ethyl acetate/n-heptane 1:6, 100mL) is used for pulping, filtering and drying, 8.7g of light yellow powder product, namely the compound of the formula IIe, is obtained, the molar ratio of the compound of the formula I to the compound of the formula IIe is 54.3 percent.
2) Preparation of compound of formula IVe (PG ═ benzyl)
Reaction of
Under nitrogen, the compound of formula IIe (400mg,0.83mmol), tetrahydrofuran (solvent) (10mL,25mL/g), isopentenyl bromide (160mg, 1.07mmol), and potassium hydroxide (69mg,1.23mmol) were added to the reactor. The reaction was carried out at 50 ℃ for 14 hours until the reaction was complete.
Post-treatment
The reaction mixture was quenched by adding a saturated aqueous ammonium chloride solution (10mL,25 mL/g). Extracting with ethyl acetate (30mL,70mL/g) for three times, combining organic phases, concentrating, and purifying by silica gel column chromatography (eluent ratio is petroleum ether: ethyl acetate: 10:1) to obtain 253mg of a light yellow powder product, namely, a compound of formula IVe, wherein the molar ratio of the compound of formula IVe to the compound of formula IIe is 55.4%. LCMS (ES, M/z):549[ M + H]+；1HNMR(300MHz,CDCl3):8.02-7.97(m,2H),7.50-7.29(m,10H),6.98-6.90(m,2H),6.59(d,J＝2.1Hz,1H),6.45(d,J＝2.1Hz,1H),5.68-5.59(m,1H),5.15(s,2H),5.09(s,2H),4.72(d,J＝6.3Hz,2H),3.89(s,3H),1.77(s,3H),1.71(s,3H)。
The next procedure was the same as in inventive example 1.
Example 6
4' -methoxybenzyl protection of 3, 7-phenolic hydroxyl groups
1) Preparation of compound of formula IIf (PG ═ 4-methoxybenzyl)
Reaction of
3,5, 7-Trihydroxyl-4' -methoxyflavone (compound of formula I) (500mg,1.67mmol), N, N-dimethylformamide (5mL,10mL/g) and 4-methoxybenzyl chloride (667mg,3.32 mmol) were initially charged to a reactor under nitrogen blanket, potassium carbonate (460mg,3.33mmol) was added with stirring at 0 deg.C, and the reaction was stirred at room temperature for 14 hours.
Post-treatment
Water (20mL, 4mL/g) was added to the reaction solution to quench. Extracted three times with ethyl acetate (25mL,5mL/g), the organic phases are combined and dried over anhydrous sodium sulfate. After filtration and concentration, silica gel column chromatography purification (eluent ratio is petroleum ether: ethyl acetate: 3:1) is carried out to obtain 380mg of brown powder product, namely the compound of formula IIf, and the molar ratio of the compound of formula I to the compound of formula IIf is 42.2%.
2) Preparation of compound of formula IVf (PG ═ 4-methoxybenzyl)
Reaction of
Under nitrogen, the compound of formula IIf (450mg,0.83mmol), tetrahydrofuran (solvent) (10mL,22mL/g), isopentenyl bromide (161mg, 1.08mmol) and potassium hydroxide (65mg,1.17mmol) were added to the reactor. The reaction was carried out at 50 ℃ for 14 hours until the reaction was complete.
Post-treatment
The reaction mixture was quenched by adding a saturated aqueous ammonium chloride solution (10mL,25 mL/g). Extracting with ethyl acetate (30mL,70mL/g) for three times, combining organic phases, concentrating, and purifying by silica gel column chromatography (eluent ratio is petroleum ether: ethyl acetate: 3:1) to obtain 204mg of white powder product, i.e. the compound of formula IVf, and the molar ratio of the compound of formula IIf is 40.2%.
LCMS(ES,m/z):609[M+H]+；1HNMR(300MHz,CDCl3):8.10-7.90(m,2H),7.46-7.38(m,2H),7.37-7.30(m,2H),7.00-6.91(m,4H),6.83-6.76(m,2H),6.59(d,J＝2.1Hz,1H),6.44(d,J＝2.1Hz,1H),5.70-5.58(m,1H),5.07(s,2H),5.03(s,2H),4.72(d,J＝6.3Hz,2H),3.90(s,3H),3.86(s,3H),3.81(s,3H),1.81(s,3H),1.77(s,3H).
The next procedure was the same as in inventive example 1.
Example 7
Compound IVa (PG ═ MOM) was prepared from 3,5, 7-trihydroxy-4' -methoxyflavone (compound I) by one-pot synthesis
Reaction of
Under nitrogen protection, 3,5, 7-trihydroxy-4' -methoxyflavone (compound of formula I) (1570g, 5.2mol) and tetrahydrofuran (13L,8mL/g) were added to a reactor, followed by N, N-diisopropylethylamine (1680g,13mol) at 0 deg.C and stirring for 30 min. Bromomethyl methyl ether (1333g,10.66mol) was added dropwise at controlled temperature at 0 ℃. After the addition was complete, the reaction was stirred at room temperature of 20 ℃ for 3 hours until the reaction was complete. Filtration was carried out, the filter cake was washed with tetrahydrofuran (3L, 2mL/g), and the filtrates were combined.
The above filtrate was added to a reaction flask under nitrogen protection. Cooled to 15 ℃ and potassium hydroxide (410g,7.3mol) was added and stirred for 30 minutes. 1-bromo-3-methyl-2-butene (1013g,6.8mol) was added dropwise to the reaction mixture under vigorous stirring, the temperature was controlled at 15 ℃ during the dropwise addition, and after the dropwise addition was completed, the mixture was stirred at 40 ℃ for 15 hours.
Post-treatment
The reaction solution was cooled to 30 ℃ and concentrated to 13L. Ethyl acetate (24L, 15mL/g) and an aqueous 18% ammonium chloride solution (9L, 6mL/g) were added to the filtrate, and the mixture was stirred for 15 minutes. The organic phase was washed twice with a 15% by mass aqueous solution of sodium chloride (9L, 6 mL/g). The organic phase was concentrated to 5L, heated to 60 deg.C, n-heptane (16L, 10mL/g) was added, and after stirring at 60 deg.C for 30 minutes, it was cooled to 0-10 deg.C over 3 hours, and stirred for an additional 1 hour. Filtration and washing of the filter cake twice with n-heptane (1.5L,1 mL/g). Drying in vacuo afforded 1360g of the compound of formula IVa, in 57.0% yield relative to the molar amount of compound of formula I.
The next procedure was the same as in inventive example 1.
Example 8
1) The compound of formula IIa was prepared as in example 1.
2) Preparation of compound of formula IVa (PG ═ MOM)
Synthesis of IVa by mitsunobu reactionCompound (I)
Reaction of
A reaction flask was charged with a compound of formula IIa (4.8g, 12.4mmol), tetrahydrofuran (15mL,3mL/g) (solvent), triphenylphosphine (6.5g,24.7mmol), isopropenyl alcohol (1.6g,18.5mmol) under nitrogen. After cooling to-4 ℃ and slow dropwise addition of a solution of diethyl azodicarboxylate (4.3g,24.7mmol) in tetrahydrofuran (5mL,1mL/g), the mixture was stirred at 0 ℃ for 1 hour.
Post-treatment
The reaction mixture was concentrated and purified by silica gel column chromatography (eluent ratio: petroleum ether: ethyl acetate: 3:1) to give 3.8g of the compound of formula IVa with a molar ratio to the compound of formula IIa in a yield of 67.2%.
The preparation of icaritin is then the same as in example 1.
Claims (38)
1. A method for synthesizing icaritin comprises the following steps:
A. is represented by the formula I
The compound is used as a raw material to carry out the protection of 3-and 7-phenolic hydroxyl groups to obtain a compound shown in a formula II
A compound;
B. will be shown in the formula II
Compounds and formula III
Reacting the compound to obtain the formula IV
A compound;
C. general formula IV
Subjecting the compound to rearrangement reaction to obtain the compound of formula V
A compound;
D. general formula V
Deprotection of the compound to give formula A
A compound characterized in that the catalyst for rearrangement reaction in the step C is Florisil, and a step G is further included between the step C and the step D, wherein the reaction liquid in the step C is filtered to remove the Florisil catalyst in the reaction liquid, and chlorination is carried out by using methaneWashing the filter cake, combining the filtrates, purifying, adding acetonitrile or ethanol into the organic phase, concentrating to remove methane chloride, adding acetonitrile or ethanol as a crystallization solvent, cooling to-5 deg.C to 5 deg.C, crystallizing, and filtering to obtain a compound of formula V;
and the protecting group PG of 3-position and 7-position phenolic hydroxyl of the compound of formula II, the compound of formula IV and the compound of formula V is selected from one of methoxymethyl, 2-methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, benzyloxymethyl, benzyl, p-methoxybenzyl and triphenylmethyl; and said compound of formula III
The substituent X in (1) is selected from one of bromine, chlorine, hydroxyl, p-toluenesulfonate and methanesulfonate.
2. The process of claim 1, wherein the compound of formula I is reacted with one selected from the group consisting of bromomethyl ether, chloromethyl methyl ether, 2-methoxyethoxy methyl chloride, 2-bromoethyl ether, 2-chloroethyl ethyl ether, dihydropyran, benzyl bromomethyl ether, benzyl chloromethyl ether, benzyl bromide, p-methoxybenzyl chloride and trityl chloride to obtain the compound of formula II.
3. The method of claim 1, wherein the compound of formula III is selected from the group consisting of isopentenyl bromide, isopentenyl chloride, isopentenyl alcohol, prenyl p-toluenesulfonate, and prenyl methanesulfonate.
4. The method according to claim 1, wherein in the step a, the reaction solvent is one or more selected from the group consisting of ether solvents, halogenated alkanes and amide solvents.
5. The method according to claim 4, wherein the ether solvent is selected from one or more of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane and 1, 2-diethoxyethane; the halogenated alkane solvent is selected from dichloromethane or chloroform; the amide solvent is selected from one or more of N-methyl pyrrolidone, N-dimethyl acetamide and N, N-dimethyl formamide.
6. The method of claim 4, further comprising adding an acid scavenger to the reaction solvent.
7. The method of claim 6, wherein the acid scavenger is selected from the group consisting of an organic amine selected from the group consisting of N, N-diisopropylethylamine or triethylamine, a basic nitrogen-containing aromatic compound, a hydride, and a carbonate; the basic nitrogen-containing aromatic compound is selected from pyridine or derivatives thereof; the hydride is sodium hydride; the carbonate is potassium carbonate, and the reaction temperature is 0-40 ℃.
8. The method according to claim 1, wherein in the step B, the reaction solvent contains a base and an aprotic polar solvent, or the reaction solvent contains a mitsunobu reaction auxiliary and an aprotic polar solvent, and the reaction temperature is-20-70 ℃.
9. The method according to claim 8, wherein the aprotic polar solvent is selected from one or more of ethers, aromatic hydrocarbons, ketones, amide solvents, and halogenated alkane solvents.
10. The method according to claim 9, wherein the ether solvent is selected from one or more of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane and 1, 2-diethoxyethane solvent; the aromatic hydrocarbon solvent is selected from toluene or xylene solvent; the ketone solvent is selected from one or more of acetone, methyl butanone and methyl isobutyl ketone solvents; the amide solvent is one or more selected from N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone solvents; the halogenated alkane solvent is selected from dichloromethane or chloroform solvent.
11. The method according to claim 8, wherein the base is selected from one or more of carbonates, alkoxides, ammonia salts, organic amine salts, hydroxides, hydrides, alkyl lithiates and nitrogen-containing organic bases of alkali metals.
12. The process according to claim 11, the carbonate of an alkali metal is selected from potassium carbonate or cesium carbonate; the alkoxide of alkali metal is selected from sodium methoxide or potassium tert-butoxide; the alkali metal ammonia salt is selected from sodium amide or potassium amide; the organic amine salt of an alkali metal is selected from lithium diisopropylamide, sodium hexamethyldisilazide or potassium hexamethyldisilazide; the hydroxide of alkali metal is potassium hydroxide or sodium hydroxide; the hydride of an alkali metal is sodium hydride; the alkyl lithium compound is selected from n-butyl lithium or phenyl lithium; the nitrogen-containing organic base is 1, 8-diazabicyclo-bicyclo (5,4,0) -7-undecene.
13. The method of claim 8 wherein the mitsunobu reaction promoter is a reagent mixture of triphenylphosphine and tributylphosphine with diisopropyl azodicarboxylate and diethyl azodicarboxylate.
14. The method of claim 8, further comprising adding a catalyst in step B.
15. The process of claim 14 wherein the catalyst is sodium iodide or tetrabutylammonium bromide.
16. The method according to claim 1, wherein the reaction solvent of step C is an aprotic polar solvent selected from one or more of toluene and xylene.
17. The method of claim 16, wherein the aprotic polar solvent is toluene.
18. The method according to claim 1, wherein in the step D, the reaction solvent is one or more selected from the group consisting of water, carboxylic acids, amides, esters, alcohols, and ether solvents.
19. The method according to claim 18, wherein the reaction solvent is one or two selected from the group consisting of alcohols and ethers.
20. The method according to claim 19, wherein the reaction solvent is a mixed solvent of isopropanol and one of tetrahydrofuran and 2-methyltetrahydrofuran.
21. The method of claim 18, wherein a deprotection reagent is also added in step D.
22. The method of claim 21, wherein the deprotecting agent is selected from the group consisting of dealkylether protecting agents.
23. The method of claim 22, wherein the dealkylation ether protecting agent is a protic acid or a lewis acid.
24. The method of claim 23, wherein the protic acid is sulfuric acid or hydrochloric acid.
25. The method of claim 1, 6 or 8, further comprising a step E of purifying the reaction product II between the step A and the step B.
26. The method of claim 25, wherein the reaction solution of step a is added with water and ethyl acetate for liquid separation, and the organic phase is added with a crystallization solvent for crystallization and purification; the crystallization solvent is isopropanol.
27. The method of claim 26, further comprising adding a weak acid solution to the reaction solution of step a to neutralize unreacted acid scavenger.
28. The method according to claim 27, wherein said weak acid solution is an ammonium chloride solution.
29. The method of claim 8 or 16, further comprising a step F of purifying the reaction product IV between the step B and the step C.
30. The method according to claim 29, wherein the reaction mixture is separated by adding ethyl acetate and water.
31. The method of claim 30, by adding C to the organic phase6-C9Crystallizing the linear organic alkane, filtering and collecting filter cakes.
32. The method of claim 31, further neutralizing the base in the reaction solution with an ammonium chloride solution.
33. The method of claim 31, said C6-C9The linear organic alkane is n-hexane or n-heptane.
34. The method according to claim 1 or 18, further comprising, after said step D, a step H of: and D, adding water into the reaction liquid obtained in the step D, filtering, collecting a filter cake, dissolving the filter cake with ethanol, recrystallizing, filtering, and washing the filter cake again to obtain the compound shown in the formula A.
35. The method according to claim 1 or 18, further comprising a step I of adding an organic solvent containing ethyl acetate and an aqueous solution to the reaction solution of the step D, separating the mixture, concentrating the mixture, and adding a crystallization solvent to the concentrated solution to carry out crystallization.
36. The method according to claim 35, further comprising a step J of adding an aqueous solution of carbonate or bicarbonate to the reaction solution to neutralize the unreacted deprotecting reagent between the step D and the step I.
37. The method according to claim 36, wherein in the step I, the organic solvent containing ethyl acetate is ethyl acetate and any one selected from the group consisting of 2-methyltetrahydrofuran, acetonitrile and acetone.
38. The process according to claim 37, wherein the crystallization solvent is selected from one or both of 2-methyltetrahydrofuran and n-heptane.
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