CN107216303B - Synthesis method of fluccoladine - Google Patents
Synthesis method of fluccoladine Download PDFInfo
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- CN107216303B CN107216303B CN201710565817.7A CN201710565817A CN107216303B CN 107216303 B CN107216303 B CN 107216303B CN 201710565817 A CN201710565817 A CN 201710565817A CN 107216303 B CN107216303 B CN 107216303B
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
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- C07D311/28—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
- 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 fluclatadine, which comprises the step of preparing icaritin by taking 2- (4-trifluoromethylphenyl) -3,5, 7-trihydroxy-4H-benzopyran-4-ketone as a raw material.
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; the reaction in the step 2 is divided into two parts, wherein the first part is cyclization reaction, the second part is hydrogenation reaction, and the reagent for 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 provides a synthesis method of fluccoladine. The method takes 2- (4-trifluoromethylphenyl) -3,5, 7-trihydroxy-4H-benzopyran-4-ketone as a starting material to prepare the flucloratadine through four-step reaction.
The method 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
The compound, the catalyst used in the rearrangement reaction of step C, is a Lewis acid catalyst for the lanthanide metal.
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.
Most preferably, the compound of formula I is obtained by reaction with one selected from 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.
Preference is given toA compound of the 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.
Most 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 system contains one of alkali and a mitsunobu reaction auxiliary agent and an 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.
Most 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, in said step C, said catalyst is a lewis acid catalyst formed from a lanthanide metal and an acid having a pKa of less than 6.0.
Most preferably, the lanthanide metal is europium or ytterbium and the catalyst is a europium salt or a ytterbium salt.
Preferably, the solvent of step C is dichloromethane.
Preferably, the europium salt catalyst is a europium salt of an acid having a pKa of less than 6.0.
More preferably, the europium salt is selected from one or more of europium acetate, europium nitrate, europium perchlorate, europium sulfate, europium triflate, europium trifluoroacetate, europium phosphate, europium fluoride, europium chloride, europium bromide, europium iodide and europium oxalate.
Most preferably, the catalyst is europium triflate.
Preferably, the ytterbium salt catalyst is a ytterbium salt of an acid having a pKa of less than 6.0.
More preferably, the ytterbium salt is selected from one or more of ytterbium acetate, ytterbium nitrate, ytterbium perchlorate, ytterbium sulfate, ytterbium trifluoromethanesulfonate, ytterbium trifluoroacetate, ytterbium phosphate, ytterbium fluoride, ytterbium chloride, ytterbium bromide, ytterbium iodide and ytterbium oxalate.
Most preferably, the catalyst is ytterbium triflate.
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 D, adding the methane chloride and the aqueous solution into the reaction solution in the step C, separating the solution, and adding a crystallization solvent into the organic phase to crystallize.
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, 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.
Still preferably, in step I, the organic solvent containing ethyl acetate includes ethyl acetate and any one or more solvents selected from tetrahydrofuran, ethanol, acetonitrile, 1, 4-dioxane, dimethylamide and acetone.
In step B of the present invention, the reaction solvent is an aprotic polar solvent. When the compound of the formula III is one or more of isopentenyl bromide, isopentenyl chloride, prenyl p-toluenesulfonate and prenyl methanesulfonate, adding alkali into the system, and optionally adding a catalyst into the system, wherein the reaction temperature is 0-70 ℃; when the compound of formula III is isopentenol, the reaction uses a mitsunobu reaction, one of mitsunobu reaction aids and an aprotic polar solvent are added into a system, and the reaction temperature is-20-30 ℃.
The invention has the beneficial effects that the invention provides a novel synthesis method of fluoxalidine, which uses Lewis acid of lanthanide metal as a catalyst of rearrangement reaction, preferably Lewis acid formed by europium salt or ytterbium salt and acid with pKa less than 6.0 as a catalyst, for example, europium salt is selected from one or more of europium acetate, europium nitrate, europium perchlorate, europium sulfate, europium trifluoromethanesulfonate, europium trifluoroacetate, europium phosphate, europium fluoride, europium chloride, europium bromide, europium iodide and europium oxalate; the ytterbium salt is selected from one or more of ytterbium acetate, ytterbium nitrate, ytterbium perchlorate, ytterbium sulfate, ytterbium trifluoromethanesulfonate, ytterbium trifluoroacetate, ytterbium phosphate, ytterbium fluoride, ytterbium chloride, ytterbium bromide, ytterbium iodide and ytterbium oxalate; the reaction temperature is-20-40 ℃; thus, the side products in the rearrangement reaction are reduced and the post-treatment step is simpler. The synthesis method provided in the patent document WO2013104263 does not use a catalyst, has long reaction time, more reaction byproducts and low yield of the target product, and the yield is lower than 10% relative to the raw material of 2- (4-trifluoromethylphenyl) -3,5, 7-trihydroxy-4H-benzopyran-4-one. The yield of the rearrangement reaction in the invention can reach more than 60%. Meanwhile, the test result shows that the obtained impurities are few and easy to purify, and compared with the raw material, the 2- (4-trifluoromethylphenyl) -3,5, 7-trihydroxy-4H-benzopyran-4-ketone of the finally obtained fluocortine product has the yield of more than 30 percent and the purity of more than 98 percent.
Detailed Description
Unless otherwise indicated, 2- (4-trifluoromethylphenyl) -3,5, 7-trihydroxy-4H-benzopyran-4-one, i.e., the compound of formula I, herein refers to a compound having the following structural formula:
The term "PG" herein denotes a protecting group (protecting group) unless otherwise specified.
The term "MOM" herein means methoxymethyl unless otherwise specified.
Unless otherwise indicated, the term "ethereal solvent" as used herein means a solvent of the structure of an ether formed by an oxygen atom connecting two alkyl or aryl groups, the ether 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 specified, the term "amide solvent" herein means a solvent having the structure of an amide compound, both of which contain an amide bond, having the chemical structure of
Wherein R is1、R2And R3Can be hydrogen, alkyl or aryl or cyclic alkanes.
The term "aprotic polar solvent" as used herein, unless otherwise indicated, refers to a solvent which 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 indicated, the term "acid scavenger" herein means a reagent that reacts with an acid in a reaction system in a chemical reaction, and reacts with the acid through 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.
The term "Mitsunobu reaction" herein is also referred to as Mitsunobu reaction, unless otherwise specified. In the present invention, the mitsunobu reaction assistant: for example, one of triphenylphosphine and tributylphosphine and one of diisopropyl azodicarboxylate and diethyl azodicarboxylate, the compound of formula III and the phenolic hydroxyl at the 5-position of the compound of formula II are subjected to nucleophilic substitution under the action of a mixed reagent, so as to complete the reaction of step B, wherein the mitsunobu reaction temperature in the invention is-20-30 ℃.
Unless otherwise specified, the term "lewis acid catalyst formed of a lanthanide metal and an acid having a pKa of less than 6.0" as used herein means a compound formed by combining the metal ion of the lanthanide with the acid ion of the acid having a pKa of less than 6.0.
The term "ytterbium salt" herein denotes a metal ytterbium ion (Yb), unless otherwise specified3+) A compound that binds to an acid ion.
The term "europium salt" herein denotes the metal europium ion (Eu), unless otherwise specified3+) A compound that binds to an acid ion.
The term "alcohol solvent" as used herein means a solvent having an alcohol structure, and is a compound in which a hydrogen atom in a side chain of an aliphatic hydrocarbon, an alicyclic hydrocarbon or an aromatic hydrocarbon is substituted with a hydroxyl group, unless otherwise specified.
Unless otherwise indicated, the europium triflate used herein is a Lewis acid having the formula
In this context "europium triflate" is used as catalyst for the Claisen (Claisen) rearrangement reaction.
Unless otherwise indicated, "ytterbium triflate" as used herein is a Lewis acid having the formula
Ytterbium triflate is used herein as a catalyst for the Claisen (Claisen) rearrangement reaction.
Unless otherwise indicated, the reagent europium triflate herein is available from Shanghai Sijin chemical technology Co., Ltd, under the trade designation SY 01009.
Unless otherwise indicated, the reagent "ytterbium triflate" herein is available from Shanghai Sijin chemical technology Co., Ltd, under the trade designation SY 01030.
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
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 was concentrated and n-heptane (5.0L) was added at 60-70 deg.C, then cooled to 0-10 deg.C 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 potassium 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
3Eu (OTf) catalytic rearrangement process
Reaction of
Under nitrogen protection, the compound of formula IVa (400g), dichloromethane (4.0L) were added to the reaction flask, the reaction was cooled to 0 to-5 deg.C, and then europium triflate, Eu (OTf)3(24.2g), and the mixture was stirred at 0 ℃ for 2 hours.
Post-treatment
Dichloromethane (3.2L) and aqueous sodium hydrogencarbonate (2.0L) were added to the reaction mixture to separate the layers. The organic phase was washed with a saturated sodium chloride solution (2.0L), concentrated to about 1.2L, and then acetonitrile (2.0L) was added and concentrated to about 1.2L. Then acetonitrile (2.0L) is added, the mixture is concentrated to about 1.2L, and the temperature is reduced to about 0 ℃. Filtration and drying gave 307g of the compound of formula Va, which was obtained in a yield of 77% based on the molar amount of the compound of formula IVa.
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 product in 62% yield based on moles of compound of formula Va.
Example 2
1) Preparation of compound of formula IIa (PG ═ MOM)
Methoxymethyl protection of 3, 7-phenolic hydroxyl groups with chloromethyl methyl ether
Reaction of
3,5, 7-Trihydroxyl-2- (4-trifluoromethylphenyl) -4H-benzopyran-4-one (compound of formula I, 5g) and dichloromethane (50mL) were added to a reactor under nitrogen blanket, and acid-binding agent N, N-diisopropylethylamine (5.1g) was added at 0 ℃. Chloromethyl methyl ether (2.7g) was added dropwise at 15 ℃ with the temperature being controlled. After the completion of the dropwise addition, the reaction was carried out at 15 ℃ for 4 hours.Post-treatment
To the reaction mixture were added water (15mL) and ethyl acetate (20mL), and the mixture was stirred for 30 minutes, separated, and the organic phase was washed with a saturated ammonium chloride solution (15 mL). The organic phase was concentrated to approximately 10mL, then isopropanol (25mL) was added at 60 deg.C, followed by cooling to-5 deg.C and stirring until a solid precipitated. Filtering, leaching the filter cake with isopropanol (5mL), and drying to obtain 4.4g of a light yellow powder product, namely a compound shown in the formula IIa, which has a molar ratio to the compound shown in the formula I, and the yield is 70%.
2) Preparation of compound of formula IVa (PG ═ MOM)
Introduction of isopentenyl groups with 1-chloro-3-methyl-2-butene
Reaction of
A reaction flask was charged with compound IIa (20g), N-dimethylformamide (120mL), cesium carbonate (14.5g), and tetrabutylammonium bromide (6.5g) sequentially under nitrogen. 1-chloro-3-methyl-2-butene (5.1g) was added dropwise at 0 to 10 ℃ and stirred at room temperature for 18 hours after the addition.
Post-treatment
The reaction was filtered at room temperature, the filter cake was washed 2 times with ethyl acetate (100mL), and the filtrates were combined. The filtrate was washed with water (160mL), separated, and the organic phase was concentrated to give a crude product, which was slurried with a mixed solvent (ethyl acetate/n-hexane 1:6, 200mL), filtered, and the filter cake was dried to give 16.2g of the compound of formula IVa, with a yield of 70% of the compound of formula IVa relative to the molar amount of the compound of formula IIa.
3) Preparation of compound of formula Va (PG ═ MOM)
3Yb (OTf) catalyzed rearrangement reaction
Reaction of
Under nitrogen, the reaction flask was charged with compound of formula IVa (10g), dichloromethane (100mL), then cooled to 0 deg.C and charged with ytterbium triflate, Yb (OTf)3(0.63g) was reacted at 0 ℃ for 2 hours.
Post-treatment
Methylene chloride (70mL) and a 5% aqueous solution of sodium hydrogencarbonate (50mL) were added to the reaction mixture, and the mixture was separated. The organic phase was washed with saturated sodium chloride solution (50mL) and concentrated to 30 mL. Ethanol (50mL) was added to the concentrate, and the mixture was concentrated to 30 mL. Ethanol (50mL) was added and the mixture was concentrated to 60 mL. The temperature was reduced from 65-75 ℃ to 0 ℃ and the filter cake was dried to obtain 5.3g of the compound of formula Va in a yield of 53% relative to the molar amount of the compound of formula IVa.
4) Preparation of fluccoladine
Reaction of
Under nitrogen, the compound of formula Va (10g, 0.022mol), 1, 4-dioxane (100mL) and isopropanol (200mL) were added to the reactor in that order. After stirring for 5 minutes, a solution of hydrochloric acid (43g) in 1, 4-dioxane (120mL) was added dropwise, and after completion of the addition, the mixture was heated under reflux for 6 hours.
Post-treatment
Water (600mL) was added to the reaction mixture, followed by precipitation of a solid, filtration, and washing of the cake with water (45 mL). The obtained filter cake was dissolved and purified in ethanol (50mL), and the filter cake was dried to obtain 6.2g of a pale yellow solid, i.e., the compound of formula a, in a yield of 75% relative to the molar amount of the compound of formula Va.
Example 3
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.
The next procedure was the same as in inventive example 1.
Example 4
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 (37)
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 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
The compound is characterized in that the catalyst used in the rearrangement reaction in the step C is europium trifluoromethanesulfonate or ytterbium trifluoromethanesulfonate, the protecting groups PG of the phenolic hydroxyl groups at the 3-position and the 7-position of the compound in the formula IV and the compound in the formula V are selected from one or more of methoxymethyl, 2-methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, benzyloxymethyl, benzyl, p-methoxybenzyl and trityl, and the compound in the formula III is
The substituent X in (A) is selected from one or more 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 according to claim 1, 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.
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 comprises dichloromethane or chloroform; the amide solvent comprises 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 system contains one of alkali and a mitsunobu reaction auxiliary agent 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 comprises a reagent mixture of one of triphenylphosphine and tributylphosphine and one of 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 process of claim 1, wherein the solvent of step C is dichloromethane.
17. 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.
18. The method according to claim 17, wherein the reaction solvent is one or two selected from the group consisting of alcohols and ethers.
19. The method according to claim 17, wherein the reaction solvent is a mixed solvent of isopropanol and one of tetrahydrofuran and 2-methyltetrahydrofuran.
20. The method of claim 17, wherein a deprotection reagent is also added in step D.
21. The method of claim 20, wherein the deprotecting agent comprises a dealkylether protecting agent.
22. The method of claim 21, wherein the dealkylation ether protecting agent is a protic acid or a lewis acid.
23. The method of claim 22, wherein the protic acid is sulfuric acid or hydrochloric acid.
24. The method of claim 6 or 8, further comprising a step E of purifying the reaction product II between the step A and the step B.
25. The method according to claim 24, wherein the reaction solution in 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.
26. The method of claim 25, further comprising adding a weak acid solution to the reaction solution of step a to neutralize unreacted acid scavenger.
27. The method according to claim 26, wherein said weak acid solution is an ammonium chloride solution.
28. The method of claim 8 or 9, further comprising a step F of purifying the reaction product IV between the step B and the step C.
29. The method according to claim 28, wherein the reaction mixture is separated by adding ethyl acetate and water.
30. The method of claim 29, further comprising adding C to the organic phase6-C9Crystallizing the linear organic alkane, filtering and collecting filter cakes.
31. The method of claim 29, further neutralizing the base in the reaction solution with an ammonium chloride solution.
32. The method of claim 31, said C6-C9The linear organic alkane is n-hexane or n-heptane.
33. The method according to claim 1 or 16, further comprising, between step C and step D, step G: and D, adding the methane chloride and the aqueous solution into the reaction solution in the step C, separating the solution, and adding a crystallization solvent into the organic phase to crystallize.
34. The process of claim 33, 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.
35. The method according to claim 1 or 17, 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.
36. The method according to claim 1, 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 for separation, concentrating, and cooling the concentrated solution to obtain the compound of the formula A, and a step J of adding an aqueous solution of carbonate or bicarbonate to the reaction solution to neutralize the unreacted deprotection reagent between the step D and the step I.
37. The method according to claim 36, wherein in step I, the organic solvent containing ethyl acetate comprises ethyl acetate and any one or more solvents 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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| 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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| Synthesis of icariin from kaempferol through regioselective methylation and para-Claisen–Cope rearrangement;Qinggang Mei，等;《Beilstein J.Org.Chem.》;20150720;第11卷;第1221页图1 * |
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