CN107216302B - Synthesis method of flucloratadine - Google Patents
Synthesis method of flucloratadine Download PDFInfo
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- CN107216302B CN107216302B CN201710565804.XA CN201710565804A CN107216302B CN 107216302 B CN107216302 B CN 107216302B CN 201710565804 A CN201710565804 A CN 201710565804A CN 107216302 B CN107216302 B CN 107216302B
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- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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Abstract
The invention provides a synthesis method of fluoxalidine, which comprises the step of preparing the fluoxalidine by taking 3,5, 7-trihydroxy-2- (4-trifluoromethylphenyl) -4H-benzopyran-4-ketone as a raw material, and has the advantages that cheap and easily available silicon is adopted as a catalyst in a rearrangement reaction process, the obtained fluoxalidine has few impurities, the purity can reach 98 percent, and the yield can reach 50 percent by the existing chemical synthesis method.
Description
Technical Field
The invention relates to a synthesis method of fluccoladine, belonging to the field of chemical synthesis.
Background
The flucloratadine is a brand new effective monomer obtained by structural optimization on the basis of the alcloratadine, and the structural formula of the flucloratadine is shown as the following formula (A):
journal of Bioorganic and pharmaceutical chemistry (Bioorganic) in 2010&A paper named 7-O-arylmethyl galangin as a novel anti-hepatitis C inhibitor support (7-O-arylmethyl galangin as a novel scaffold for anti-HCVagens) is disclosed in Medicinal chemistry letters 20(2010), 5709, 5712. This article shows a reaction scheme for the preparation of a precursor compound of flucoradine, which gives the compound 2- (4-trifluoromethylphenyl) -3,5, 7-trihydroxy-4H-chromen-4-one. In the following structural formula R1Is trifluoromethyl (-CF)3) The reaction route is as follows:
the reaction condition of the step 1 is pyridine solvent and room temperature; step by stepThe reaction of step 2 is divided into two parts, the first part is cyclization reaction, the second part is hydrogenation reaction, wherein the reagent of cyclization reaction is K2CO3And tetrabutylammonium bromide (Bu)4NBr), wherein a reagent for hydrogenation reaction is a carbon palladium catalyst (Pd/C), and a reaction solvent is prepared by mixing the following components in a volume ratio of 1: 1 dichloromethane and methanol (CH)2C12/MeOH)。
The preparation method of flucoradine is disclosed in step 4 of example 1 of the patent application document with the application number WO2013104263 entitled "synthesis of polyhydroxy benzopyrone compounds and antitumor effect thereof". The method comprises the steps of taking 2- (4-trifluoromethylphenyl) -3,5, 7-trihydroxy-4H-benzopyran-4-ketone as a raw material, dissolving the compound and cesium carbonate in water, and dropwise adding isopentenyl bromide under the condition of ice-water bath. After the addition was completed, the reaction system was reacted at room temperature overnight, the pH was adjusted with hydrochloric acid, and then extracted with ethyl acetate 2 times. The organic phases were combined, washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product is purified by silica gel column chromatography, and the target compound of the flucoradine is obtained by taking ethyl acetate/petroleum ether (1:25) as eluent.
However, the present inventors found in practice that fluorine obtained by the prior art has a low yield and separation of by-products is difficult. Furthermore, the operation of silica gel column chromatography leads to low efficiency and excessive cost in large-scale industrial production.
Therefore, further research and study are needed to obtain a synthetic process suitable for large-scale industrialization to produce fluctuated fluoride based on the prior patent documents.
Disclosure of Invention
The invention aims to provide a synthesis method of fluccoladine. The method takes 3,5, 7-trihydroxy-2- (4-trifluoromethylphenyl) -4H-benzopyran-4-ketone as a starting material to prepare the flucloratadine through four-step reaction.
The invention provides a method for preparing fluclatable, 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 IICompounds 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
Compound (I)
D. General formula V
Deprotection of the compound to give formula A
Compound (C), wherein the catalyst of the rearrangement reaction of 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.
Most 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.
Most 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.
Preferably, the siliceous catalyst is selected from the group consisting of 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 product II is further included between the step A and the step B.
More preferably, water and ethyl acetate are added to the reaction solution of step a, separated, and the organic phase is purified.
Preferably, the organic phase is crystallized and purified by adding a crystallization solvent, 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, and purifying to obtain the compound shown in the formula A.
Preferably, the method further comprises a step I after the step D, adding an organic solvent containing ethyl acetate and an aqueous solution into the reaction solution of the step D for separating, concentrating, and cooling the concentrated solution to obtain the compound of the formula A.
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.
Most preferably, in the step I, the organic solvent containing ethyl acetate includes ethyl acetate and any one selected from tetrahydrofuran, ethanol, acetonitrile, 1, 4-dioxahexaalkane, dimethylamide and acetone.
The invention has the beneficial effects that the invention provides a novel synthesis method of the flucoradine, the synthesis method 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 operation is simpler, and the yield of the rearrangement reaction in the invention can reach about 50%. Experimental results show that the fluoxadine obtained by the chemical synthesis process has the advantages of low cost, simple and reliable operation and easy purification of the product, and compared with the raw material of 3,5, 7-trihydroxy-2- (4-trifluoromethylphenyl) -4H-benzopyran-4-one, the finally obtained fluoxadine product has the yield of more than 30 percent and the purity of more than 98 percent.
Detailed Description
Unless otherwise indicated, 3,5, 7-trihydroxy-2- (4-trifluoromethylphenyl) -4H-benzopyran-4-one, a compound of formula I herein, refers to a compound 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 the structure of an amide compound, which contains an amide bond and has the chemical structure ofWherein R is1，R2And R3May be hydrogen, hydrocarbyl, aryl or cyclic alkyl.
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 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 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.
The term "Mitsunobu reaction" herein is also referred to as Mitsunobu reaction, unless otherwise specified. In the present invention, the alcoholic hydroxyl group of the prenol acts as a mitsunobu reaction auxiliary: for example, one of triphenylphosphine and tributylphosphine and one of diisopropyl azodicarboxylate and diethyl azodicarboxylate, and nucleophilic substitution occurs with the phenolic hydroxyl at the 5-position of the compound of formula (II) under the action of a mixed reagent, thereby completing the reaction of step B, wherein the temperature of the mitsunobu reaction in the invention is-20-30 ℃.
Unless otherwise indicated, "PG" herein denotes a protecting group.
Unless otherwise indicated, the "acid scavenger" herein means a reagent that reacts with an acid in a reaction system in a chemical reaction, and reacts with the acid by the acid scavenger, thereby promoting the entire chemical reaction. In the whole reaction process, an acid-binding agent is consumed, and the acid-binding agent is an alkaline reagent.
Unless otherwise indicated, "Florisil" herein is available from Arcos Organics, Inc., Eikes organic company.
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.
Example 1
The starting material, 3,5, 7-trihydroxy-2- (4-trifluoromethylphenyl) -4H-benzopyran-4-one, was prepared according to the methods provided in the background.
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-2- (4-trifluoromethylphenyl) -4H-benzopyran-4-one (compound of formula I, 500g) and tetrahydrofuran (3.5L) were first charged to a reactor under nitrogen blanket, and the acid-binding agent N, N-diisopropylethylamine (480g) was added with stirring at 0 ℃. Bromomethyl methyl ether (MOMBr, 380g) 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
The reaction solution was used as it was in the next reaction without further treatment.
2) Preparation of compound of formula IVa (PG ═ MOM)
Reaction of
To the solution from the previous reaction was added potassium hydroxide (116g) under nitrogen, followed by the addition of isopentenyl bromide (DMABr, 308g) dropwise and temperature controlled at 30 ℃. After the dropwise addition, the mixture is heated to 40-50 ℃ and stirred for 10 hours until the reaction is finished.
Post-treatment
The reaction mixture was concentrated, and then ethyl acetate (3.5L) and an ammonium chloride solution (3.0L) were added thereto for liquid separation. The organic phase was washed successively with aqueous ammonium chloride (3.0L) and aqueous sodium chloride (2.5L). The organic phase is concentrated, n-heptane (5.0L) is added at 60-70 deg.C, then cooled to 0-10 deg.C, crystallized and filtered. Vacuum drying gave 572g of the compound of formula IVa, with a yield of 78% relative to the molar amount of the compound of formula IIa.
In addition, the present inventors investigated the reaction of IIa (PG ═ MOM) with isopentenyl bromide using different bases instead of sodium hydroxide and different solvents instead of tetrahydrofuran. Various bases include, but are not limited to, potassium carbonate, lithium diisopropylamide, sodium hexamethyldisilazide, potassium tert-butoxide, 1, 8-diazabicycloundece-7-ene (DBU), potassium hydroxide, diisopropylethylamine, and solvents include, but are not limited to, tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidinone.
3) Preparation of Compounds of formula Va
Catalytic rearrangement process
Reaction of
A reaction flask was charged with a compound of formula IVa (2g, 0.11mol), toluene (20mL), and Florisil (100-200 mesh, 50% by mass) under nitrogen. Heating the reaction solution to 85-95 ℃ and reacting for 5-7 hours.
Post-treatment
The reaction was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane (10 mL). The filtrates were combined, concentrated and purified by column chromatography to give 1g of the compound of formula Va in 50% yield relative to the molar amount of the compound of formula IVa.
Furthermore, the inventors investigated the reaction of IVa (PG ═ MOM methoxymethyl) undergoing claisen rearrangement under different catalyst conditions, as listed in the following table:
4) preparation of fluccoladine
Reaction of
Under nitrogen, the compound of formula Va (50g), tetrahydrofuran (250mL) and a solution of sulfuric acid in isopropanol (0.4M, 250mL) were added to the reactor in that order. The reaction solution was heated to 50 ℃ and reacted for 12 hours.
Post-treatment
The reaction mixture was cooled to 30 ℃ and then concentrated to about 250mL by slowly adding 8% aqueous potassium bicarbonate (250mL), followed by sequentially adding ethyl acetate (500mL) and tetrahydrofuran (100mL) and separating. The organic phase was washed with 15% aqueous sodium chloride (250 mL).
The organic phase was concentrated to about 150mL, ethyl acetate (300mL) and tetrahydrofuran (60mL) were added, the mixture was concentrated to about 150mL, and ethyl acetate (300mL) and tetrahydrofuran (60mL) were added and the mixture was concentrated to about 150 mL. Acetonitrile (550mL) was added at 65-75 ℃ and then cooled to-5 to 5 ℃. Filtration gave 25.5g of the compound of formula A in 62% yield based on the molar amount of the compound of formula Va.
Example 2
Methoxyethoxymethyl protection of the 3, 7-phenolic hydroxyl group
1) Preparation of compound of formula IIa (PG ═ methoxyethoxymethyl)
Reaction of
3,5, 7-Trihydroxyl-2- (4-trifluoromethylphenyl) -4H-benzopyran-4-one (compound of formula I, 2g), N, N-Dimethylformamide (DMF) (12mL) and 2-methoxyethoxy chloromethane (1.7g) (MEMCl) were charged to a reactor under nitrogen blanket, and Triethylamine (TEA) (1.8g) as an acid-binding agent was added at 0 ℃. The reaction was carried out at room temperature for 2 hours.
Post-treatment
Water (20mL) was added to the reaction mixture, which was then extracted twice with ethyl acetate (25mL), the organic phases were combined and concentrated, and purification was performed by silica gel column chromatography to give 1.37g of a yellow powder product in 45% yield.
Example 3
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 (20g), tetrahydrofuran (80mL), triphenylphosphine (25g) and isobutenol (5.4g) under nitrogen. The reaction mixture was cooled to-4 ℃ and a solution of diethyl azodicarboxylate (16.3g) in tetrahydrofuran (5mL,1mL/g) was slowly added dropwise thereto, after which the reaction was carried out at 0 ℃ for 2 hours.
Post-treatment
The reaction was concentrated and purified by silica gel column chromatography (eluent ratio petroleum ether: ethyl acetate: 3:1) to give the compound of formula IVa in 65% yield, molar ratio to the compound of formula IIa.
The procedure is as in example 1.
Claims (42)
1. A method for synthesizing fluccoladine, comprising 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 IVSubjecting 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
The compound is characterized in that the catalyst for rearrangement reaction in the step C is Florisil, the reaction temperature is 60-120 ℃, and the protecting groups PG of the phenolic hydroxyl groups at the 3-position and the 7-position of the compound in the formula II, the compound in the formula IV and the compound in the formula V are selected from one of methoxymethyl, 2-methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, benzyloxymethyl, benzyl, p-methoxybenzyl and trityl.
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
The substituent X in (A) is selected from one or more of bromine, chlorine, hydroxyl, p-toluenesulfonate and methanesulfonate.
4. The method as claimed in claim 3, wherein the compound of formula III is one or more selected from the group consisting of isopentenyl bromide, isopentenyl chloride, isopentenyl alcohol, prenyl p-toluenesulfonate and prenyl methanesulfonate.
5. 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.
6. The method according to claim 5, 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 comprises dichloromethane or chloroform; the amide solvent comprises one or more of N-methyl pyrrolidone, N-dimethyl acetamide and N, N-dimethyl formamide.
7. The process of claim 5, wherein an acid scavenger is also added to the reaction solvent.
8. The method of claim 7, 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 ℃.
9. The method according to claim 1, wherein in the step B, the reaction solvent contains one of a base and a mitsunobu reaction auxiliary and an aprotic polar solvent, and the reaction temperature is-20 to 70 ℃.
10. The method according to claim 9, wherein the aprotic polar solvent is selected from one or more of ethers, aromatic hydrocarbons, ketones, amide solvents, and halogenated alkane solvents.
11. The method according to claim 10, 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 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.
12. The method according to claim 9, 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.
13. The process according to claim 12, 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.
14. The method of claim 9 wherein the mitsunobu reaction co-agent comprises a reagent mixture of one of triphenylphosphine and tributylphosphine and one of diisopropyl azodicarboxylate and diethyl azodicarboxylate.
15. The method of claim 9, further comprising adding a catalyst in step B.
16. The process of claim 15 wherein the catalyst is sodium iodide or tetrabutylammonium bromide.
17. 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.
18. The method of claim 17, wherein the aprotic polar solvent is toluene.
19. 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.
20. The method according to claim 19, wherein the reaction solvent is one or two selected from the group consisting of alcohols and ethers.
21. The method according to claim 20, wherein the reaction solvent is a mixed solvent of isopropanol and one of tetrahydrofuran and 2-methyltetrahydrofuran.
22. The method of claim 21, wherein a deprotection reagent is also added in step D.
23. The method of claim 22, wherein the deprotecting agent comprises a dealkylether protecting agent.
24. The method of claim 23, wherein the dealkylether protecting agent is a protic acid or a lewis acid.
25. The method of claim 24, wherein the protic acid is sulfuric acid or hydrochloric acid.
26. The method of claim 1, 7 or 9, further comprising a step E of purifying the reaction product II between the step A and the step B.
27. The method of claim 26, wherein the organic phase is purified by adding water and ethyl acetate to the reaction solution of step a, separating the solution.
28. The process of claim 27, adding a crystallization solvent to the organic phase for purification by crystallization; the crystallization solvent is isopropanol.
29. The method of claim 7, further comprising adding a weak acid solution to the reaction solution of step a to neutralize unreacted acid scavenger.
30. The method according to claim 29, wherein said weak acid solution is an ammonium chloride solution.
31. The method of claim 9 or 17, further comprising a step F of purifying the reaction product IV between the step B and the step C.
32. The method according to claim 31, wherein the reaction mixture is separated by adding ethyl acetate and water.
33. The method of claim 31, by adding C to the organic phase6-C9Crystallizing the linear organic alkane, filtering and collecting filter cakes.
34. The method of claim 32, further neutralizing the base in the reaction solution with an ammonium chloride solution.
35. The method of claim 33, said C6-C9The linear organic alkane is n-hexane or n-heptane.
36. The method according to claim 17 or 19, further comprising, between step C and step D, step G: 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.
37. The process of claim 26, wherein the crystallization is carried out by adding a crystallization solvent to the organic phase.
38. The process of claim 37, further comprising adding acetonitrile or ethanol to the organic phase, concentrating to remove methane chloride, adding acetonitrile or ethanol as a crystallization solvent, cooling to-5 ℃ to 5 ℃, crystallizing, and filtering to obtain the compound of formula V.
39. The method according to claim 1 or 19, 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, and purifying to obtain the compound shown in the formula A.
40. The method according to claim 1 or 19, further comprising a step I of adding an organic solvent containing ethyl acetate and an aqueous solution to the reaction solution of step D, separating the mixture, concentrating the mixture, and cooling the concentrated solution to obtain the compound of formula A.
41. The method according to claim 1 or 19, 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.
42. The method according to claim 41, wherein in the step I, the organic solvent containing ethyl acetate comprises ethyl acetate and any one selected from tetrahydrofuran, ethanol, acetonitrile, 1, 4-dioxahexaalkane, dimethylamide and acetone.
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| CN101205223A (en) * | 2006-12-18 | 2008-06-25 | 李毅林 | Total synthesis method of natural product barrenwort glycosides compounds |
| CN103204838A (en) * | 2012-01-13 | 2013-07-17 | 北京盛诺基医药科技有限公司 | Synthesis of polyhydroxybenzo pyrone compound and antineoplastic effect of the compound |
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| CN103204838A (en) * | 2012-01-13 | 2013-07-17 | 北京盛诺基医药科技有限公司 | Synthesis of polyhydroxybenzo pyrone compound and antineoplastic effect of the compound |
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| First total synthesis of natural products cajanolactone A and cajanonic acid A;Wen-Zhang Chen，等;《Chinese Chemical Letters》;20140328;第25卷(第5期);第750页图1 * |
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