CN109776558B - Tandem cyclization synthesis method of large steric hindrance xanthone and derivatives thereof - Google Patents
Tandem cyclization synthesis method of large steric hindrance xanthone and derivatives thereof Download PDFInfo
- Publication number
- CN109776558B CN109776558B CN201910071602.9A CN201910071602A CN109776558B CN 109776558 B CN109776558 B CN 109776558B CN 201910071602 A CN201910071602 A CN 201910071602A CN 109776558 B CN109776558 B CN 109776558B
- Authority
- CN
- China
- Prior art keywords
- compound
- equivalents
- equivalent
- hours
- xanthone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a serial cyclization synthesis method of large steric hindrance xanthone and derivatives thereof, which is characterized by comprising the following steps: at 135-145 ℃, the compound of the general formula I according to the equivalent ratio: the compound of the general formula II is 1-2: 1-3, enabling a compound in a general formula I and a compound in a general formula II to generate a compound in a general formula III under the action of a copper catalyst and a triphenylphosphine additive; the compound of the general formula I is
The compound of the general formula II is
The compound of the general formula III is
Description
Technical Field
The invention belongs to the field of natural product synthesis, and particularly relates to a serial cyclization synthesis method of large steric hindrance xanthone and derivatives thereof.
Background
Calophyllum (Calophyllum) is a gambogic (Guttiferae) plant, more than 80 kinds are distributed in the whole world, and are mainly distributed in tropical regions of Asia, south America and oceania, and 4 kinds of China are mainly distributed in Calophyllum inophyllum Lin, Calophyllum gracile Gardner et Champ, C.thorelii Pierre and Calophyllum inophyllum which are distributed in provinces such as Hainan, Guangdong, Guangxi and Taiwan, wherein the Calophyllum inophyllum is a special plant in Hainan and is also called as calanolia peltata, and grows in Hainan except in the northwest. Calophyllum plant has high medicinal value, and can be used for treating traumatic hemorrhage, traumatic injury, rheumatalgia, etc. in folk. Foreign scholars have conducted a great deal of research on chemical components of leaves, stems, roots, skins, seeds and other parts of calophyllum plants, and have obtained various compounds such as Xanthones (xanthenes), Coumarins (Coumarins), flavonoids (flavanones), terpenes (Terpennids) and the like. Pharmacological activity research shows that the xanthone compound has the functions of resisting leukemia, resisting tumor, resisting inflammation, resisting bacteria, resisting cell element, etc.; the flavonoids have the activities of dispelling wind-damp, treating skin inflammation and the like. The ethanol extract of root and stem of Calophyllum Membranaceum Gardn. et Champ. is separated and purified by modern chromatographic separation technique, and identified by physicochemical properties and spectrum method, wherein part of the extract is xanthone compound with isopentenyl group derivative. According to recent studies, such a xanthone compound having an isopentenyl group derivative has been reported to have a very good antitumor activity.
The xanthone compound is an important natural product, mainly comes from plants and microorganisms in the nature, and in the xanthone compound synthesized by a biological way, the types and the substitution positions of substituent groups are limited, and the compound which does not exist in the nature can be synthesized by a chemical synthesis method, so that the types of the xanthone compound can be enriched, the research on the structure-activity relationship of the xanthone compound is facilitated, the xanthone compound with a specific structure can be purposefully designed and synthesized, and the xanthone compound with the best activity can be found. For these reasons, research on the chemical synthesis of xanthone compounds has been carried out several decades ago. According to literature reports, the current methods for synthesizing xanthone compounds mainly comprise: the method can be used for replacing hydroxyl on 2-position by 2-hydroxyl on 2 ' -position when 2 ' -position on aromatic ring has easy-leaving functional group by dehydrating and closing ring by Friedel-Crafts reaction in the presence of 2-aryl ether benzoyl chloride, 2-aryl ether benzoic acid and strong acid (PPA, MsOH-P2O5) or dehydrofluorinating and closing ring by 2-hydroxyl-2 ' -fluorobenzene ketone. However, the current synthesis of xanthones requires the prior synthesis of aryl ether type substrates and is only applicable to simple products with fewer substituents.
Disclosure of Invention
The present invention aims to provide a serial cyclization synthesis method of a large steric hindrance xanthone and a derivative thereof, so as to solve at least one of the technical problems.
According to one aspect of the present invention, there is provided a serial cyclization synthesis method of a sterically hindered xanthone and its derivatives, characterized in that: at 135-145 ℃, the equivalent ratio is as follows: a compound of the general formula I: the general formula II compound is 1-2: 1-3, and the general formula I compound and the general formula II compound are reacted under the action of a copper catalyst and a triphenylphosphine additive to generate a general formula III compound; the compound of the general formula I is
The compound of the formula II
The compound of the formula III is
At least one of R1, R2, R3 and R4 in the general formula is isopentenyl.
Preferably, the copper catalyst is copper chloride.
Preferably, potassium phosphate is provided as a catalyst for the reaction of the compound of formula I and the compound of formula II, and toluene as a solvent to produce the compound of formula III.
Preferably, phloroglucinol and the compound of formula IV are used as reaction raw materials, and the compound of formula IV: the compound of the general formula III is prepared by feeding phloroglucinol in an equivalent ratio of 0.8-1.2: 0.8-2 according to the following specific synthetic route:
wherein the compound of formula IV is
The specific structure of the compound of the general formula I is
The specific structure of the compound of the general formula II is
The specific structure of the compound of the general formula III is
Preferably, phloroglucinol and the compound of formula V are used as reaction raw materials, and the compound of formula V: the phloroglucinol is fed in an equivalent ratio of 0.8-1.2: 0.8-2, and the compound of the general formula III is prepared according to the following specific synthetic route:
wherein the compound of formula V is
The specific structure of the compound of the general formula I is
The specific structure of the compound of the general formula II is
The specific structure of the compound of the general formula III is
Preferably, before the reactant is replaced by the isopentenyl group, the phenolic hydroxyl group which does not undergo cyclization reaction is protected by chloromethyl methyl ether, and after the isopentenyl group is introduced at a specific position on the benzene ring of the reactant, the protective group for protecting the phenolic hydroxyl group is removed.
Preferably, before the reactant is replaced by the isopentenyl group, the pH value of the system is controlled to be 4-12, the aldehyde carbonyl group is protected by ethylene glycol under the catalysis of p-toluenesulfonic acid, and after the isopentenyl group is introduced to a specific position on a benzene ring of the reactant, the protecting group for protecting the aldehyde carbonyl group is removed.
Preferably, the phenolic hydroxyl group is converted to a benzopyran compound by the following steps: providing protecting groups for all phenolic hydroxyl groups by using chloromethyl methyl ether; adding n-butyl lithium and bromobenzene to replace the hydrogen atom at the ortho position of the phenolic hydroxyl group to be converted by isopentenyl; step three, removing the protecting group; and step four, benzene is used as a solvent, and is refluxed under the catalysis of p-toluenesulfonic acid to obtain the benzopyran compound.
Preferably, the phenolic hydroxyl group is converted into the benzopyran compound by the following steps: under the catalysis of 1, 8-diazabicycloundecene-7-ene and trifluoroacetic anhydride, slowly dropwise adding an acetonitrile solution containing 2-5 equivalents of 2-methyl-3-butyn-2-ol, and carrying out substitution reaction on the phenolic hydroxyl to be converted and 2-methyl-3-butyn-2-ol to obtain 2-methyl-3-butyn-2-aryl ether; and step two, using dimethylformamide as a solvent, and carrying out cyclization reaction on the 2-methyl-3-butyne-2-aryl ether prepared in the step one at 140-150 ℃ to obtain the benzopyran compound.
Preferably, N is utilized during the synthesis2As a shielding gas.
The invention has the following advantages:
1. the method adopts easily available raw materials, sets a proper protection and deprotection mode for phenolic hydroxyl and aldehyde group of a raw material compound, and ensures that the compound still can keep a specific functional group structure after the synthesis process is finished.
2. During the synthesis, N is provided2The atmosphere protection can prevent the raw material phloroglucinol from being oxidized, the catalytic activity of the copper chloride is also kept, the total reaction time is greatly reduced when the reaction end point is reached, and the synthesis efficiency is improved.
3. The equivalent ratio is controlled within a certain range, and 2-methyl-3-butyn-2-ol is added into the reactant in a slow dropwise adding mode, so that the phenomenon that a plurality of phenolic hydroxyl groups in a reaction substrate simultaneously participate in the reaction to generate a high-proportion byproduct due to the excessive and over-concentrated 2-methyl-3-butyn-2-ol is avoided, and the yield of the target product is ensured.
4-by adopting the proper combination of the copper catalyst and other catalysts, additives and solvents, the one-step splicing cyclization of two substituted aromatic ring segments with large steric hindrance and large change of electrical property is efficiently realized to generate the xanthone compound with large steric hindrance, and the aryl ether type substrate does not need to be synthesized in advance in the synthesis process.
5. The invention can be used for synthesizing large steric hindrance xanthone compounds simultaneously containing isopentenyl and phenolic hydroxyl, and the compounds have good antitumor activity and can be applied to the preparation of antitumor drugs.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments.
The types of reagents are as follows: phloroglucinol, 2-methyl-3-buten-2-ol, acetonitrile, n-butyllithium (nBuLi), 1, 8-diazabicycloundecen-7-ene (DBU), trifluoroacetic anhydride (TFAA), chloromethyl methyl ether (MOMC1), bromobenzene, camphorsulfonic acid (CSA), p-toluenesulfonic acid (TsOH), 1, 8-diazabicycloundecen-7-ene (DBU), trifluoroacetic anhydride (TFAA), Dimethylformamide (DMF), triphenylphosphine (PPh)3)、CuCl2、K3PO4And toluene.
An experimental instrument: Bruker-AV300MHz type nuclear magnetic resonance apparatus (Bruker, Switzerland), DHG-9140A type constant temperature drying cabinet (Shanghai Pudongfeng scientific instruments Co., Ltd.), CLJBQ-3 type constant temperature magnetic stirrer (Zhengzhou Changcheng Kogyo Co., Ltd.), EYELA type rotary evaporator (Tokyo physical and chemical instruments exclusive factory), LGJ-12 freeze dryer (Consolid City Yingyu Hua instruments Co., Ltd.), FA2104 type electronic balance (Shanghai Hengping scientific instruments Co., Ltd.), LC-UV100 liquid chromatograph (Shanghai Wufeng scientific instruments Co., Ltd.), DZF-150 type small vacuum drying cabinet (Zhengzhou Changcheng Kogyo instruments Co., Ltd.), and KQ3200E type ultrasonic cleaner (Kunshan City ultrasonic instruments Co., Ltd.).
Example 1
This example uses compound 1 and phloroglucinol as starting materials in the presence of N2Under the protection of atmosphere, the following reactions are carried out:
adding 1 equivalent of compound 1, 3 equivalents of DBU and 0.01 equivalent of TFAA into a reaction bottle, slowly dropwise adding 3 equivalents of acetonitrile solution of 2-methyl-3-butyn-2-ol, and reacting the mixture with the compound 1 at 0 ℃ for 12 hours to generate a compound 2;
adding DMF as a solvent, heating the system to 145 ℃ by using microwave heating, preserving the temperature for 48 hours, and carrying out cyclization reaction on the compound 2 to synthesize a benzopyran type compound 3;
when the temperature is reduced to room temperature, 1.5 equivalents of phloroglucinol are added into a reaction bottle, 10 equivalents of NaH are added into the reactant dropwise, 12 equivalents of MOMC1 are added dropwise, the mixture is stirred for 11 hours, and the phenolic hydroxyl group of the reactant is protected by methoxy methyl (MOM);
dropwise adding 2.6 equivalents of nBuLi, stirring for 15 minutes, dropwise adding 3 equivalents of bromobenzene, reacting for 2 hours, replacing hydrogen atoms on benzene rings by isopentenyl groups, dropwise adding 5 equivalents of methanol solution of CSA, and reacting for 8 hours to generate a compound 5 and a compound 8;
refluxing in a benzene solution of TsOH to obtain a benzopyran type fragmented compound 9;
heating to 140 deg.C with microwave, adding 0.01 equivalent of CuCl20.03 equivalent of PPh3And 1.2 equivalents of K3PO4In toluene, compound 5 and compound 9 are coupledCyclization reaction gave compound 12, and the end of the reaction was monitored by Thin Layer Chromatography (TLC).
The synthetic route of this example is as follows:
comparative example 1
This example was set up as a comparative example to example 1, starting with compound 6 and phloroglucinol, and FeCl3As an alternative to the metal catalyst, the CuCl used in example 1 was used2The synthesis of compound 12 was carried out, the other operating steps of the synthesis process remaining the same as in example 1.
Comparative example 2
This example was set up as a comparative example to example 1, and the synthesis of compound 12 was carried out in an air atmosphere using compound 6 and phloroglucinol as starting materials, with the other steps of the synthesis procedure being identical to those of example 1.
Comparative example 3
The present example was designed as a comparative example to example 1, the present example was designed to synthesize compound 12 by using compound 6 and phloroglucinol as raw materials and adjusting the charge amount of phloroglucinol to 1 equivalent, and the other operation steps of the synthesis process were the same as those of example 1.
Comparative example 4
This example was set up as a control for example 1, starting with compound 6 and phloroglucinol, and the synthesis of compound 12 was carried out by adding 3 equivalents of 2-methyl-3-butyn-2-ol in acetonitrile to the reaction mass by rapid pouring, the other operating steps of the synthesis procedure remaining the same as in example 1.
Comparative example 5
This example was set up as a comparative example to example 1, and was carried out using compound 6 and phloroglucinol as starting materials for the synthesis of compound 12 without the addition of K3PO4The other operating steps were in accordance with example 1.
Comparative example 6
This example was set up as a comparative example to example 1, and was conducted in such a manner that compound 12 was synthesized from compound 6 and phloroglucinol, and 0.01 equivalent of CuCl was added to the compound 5 and compound 9 in the step of coupling cyclization reaction2Equivalent weight PPh3And equivalent of K3PO4The other steps of the procedure were the same as in example 1.
Example 2
This example uses compound 6 and phloroglucinol as starting materials in the presence of N2Under the protection of atmosphere, the following reactions are carried out:
adding 1.5 equivalents of phloroglucinol, 3 equivalents of DBU and 0.01 equivalent of TFAA into a reaction bottle, slowly dropwise adding 3 equivalents of acetonitrile solution of 2-methyl-3-butyn-2-ol, reacting the mixture with the compound 1 at 0 ℃ for 12 hours, adding DMF as a solvent, heating the system to 145 ℃ by using microwave heating, and preserving the temperature for 48 hours to generate a benzopyran compound 10;
cooling to room temperature, adding 1 equivalent of compound 6, equivalent of TsOH and equivalent of glycol into a reaction bottle, controlling the pH value of a reaction system to be 4-12, and providing a protecting group for aldehyde carbonyl of the compound 6 by using the glycol under the catalysis of the TsOH;
dropwise adding 10 equivalents of NaH into the reactant, then dropwise adding 12 equivalents of MOMC1, and stirring for 11 hours, wherein the phenolic hydroxyl group of the reactant is protected by methoxy methyl (MOM);
dropwise adding 2.6 equivalents of nBuLi, stirring for 15 minutes, dropwise adding 3 equivalents of bromobenzene, reacting for 2 hours, replacing hydrogen atoms on benzene rings by isopentenyl groups, and dropwise adding 5 equivalents of methanol solution of CSA to generate a compound 7 and a compound 11;
heating to 140 deg.C with microwave, adding 0.01 equivalent of CuCl20.03 equivalent of PPh3And 1.2 equivalents of K3PO4Compound 7 and compound 11 to produce compound 13, and monitoring the end of the reaction by Thin Layer Chromatography (TLC).
The synthetic route of this example is as follows:
comparative example 7
This example was set up as a comparative example to example 1, starting with compound 6 and phloroglucinol, and FeCl3As an alternative to the metal catalyst, the CuCl used in example 22The synthesis of compound 12 was carried out, the other operating steps of the synthesis process remaining the same as in example 2.
Comparative example 8
This example was set up as a comparative example to example 2, and the synthesis of compound 12 was carried out in an air atmosphere using compound 6 and phloroglucinol as starting materials, with the other steps of the synthesis procedure being identical to those of example 2.
Comparative example 9
The present example was designed as a comparative example to example 2, the present example was designed to synthesize compound 12 by using compound 6 and phloroglucinol as raw materials and adjusting the charge amount of phloroglucinol to 1 equivalent, and the other operation steps of the synthesis process were the same as those of example 2.
Comparative example 10
This example was set up as a control example for example 2, starting with compound 6 and phloroglucinol, and the synthesis of compound 12 was carried out by adding 3 equivalents of 2-methyl-3-butyn-2-ol in acetonitrile to the reaction mass by rapid pouring, the other operating steps of the synthesis procedure remaining the same as in example 2.
Comparative example 11
This example was set up as a comparative example to example 2, which was a synthesis of compound 12 starting from compound 6 and phloroglucinol without the addition of K3PO4The other operation steps were the same as in example 2.
Comparative example 12
This example was set up as a comparative example to example 2, which was carried out by starting with compound 6 and phloroglucinol to synthesize compound 12, and adding 0.01 equivalent of CuCl to compound 5 and compound 9 in the coupling cyclization reaction step2Equivalent weight PPh3And equivalent of K3PO4The other steps of the procedure were the same as in example 2.
EXAMPLE 3 isolation and characterization of the product
And cooling the mixture obtained by completely reacting the mixtures obtained in the examples 1 and 2 and the comparative examples 1-10 to room temperature, pouring the mixture into ice water, stirring vigorously for 2 hours, filtering after the solid is completely separated out, washing the solid with distilled water for 2-3 times, collecting a filter cake, separating and purifying by using an LC-UV100 liquid chromatograph (eluent is 65% of methanol and 0.1% of formic acid), removing the methanol by rotary evaporation, and freeze-drying to obtain a powder product. The product structure was determined using a nuclear magnetic resonance apparatus.
The structural characterization results are as follows:
compound 12: uv (meoh) λ max (log ∈)288(4.62), 299(4.56), 355 (4.37); IR (neat) vmax3448，1648cm-1；1H-NMR(500MHz)13.69(1H，s，1-OH)，7.99(1H，d，J＝10.0Hz，H-21)，6.73(1H，dd，J＝10.0，0.5Hz，H-11)，6.31(1H，d，J＝0.5Hz，H-4)，5.77(1H，d，J＝10.0Hz，H-22)，5.57(1H，d，J＝10.0Hz，H-12)，5.27(1H，tbr，J＝7.5Hz，H-17)，3.57(2H，d，J＝7.5Hz，H-16)，1.88(3H，s，H-20)，1.69(3H，s，H-19)，1.49(6H，s，H-24，H-25)，1.48(6H，s，H-14，H-15)；13C-NMR(125MHz)182.8(C，C-9)，159.8(C，C-3)，157.8(C，C-1)，156.5(C，C-4a)，150.9(C，C-10a)，148.6(C，C-6)，136.6(C，C-7)，132.7(C，C-18)，131.4(CH，C-22)，127.1(CH，C-12)，121.0(CH，C-21)，120.9(CH，C-17)，117.1(C，C-8)，115.7(CH，C-11)，115.3(C，C-5)，108.4(C，C-8a)，104.3，(C，C-9a)，103.8(C，C-2)，94.2(CH，C-4)，77.9(C，C-13)，76.9(C，C-23)，28.4(CH3，C-14，C-15)，27.4(CH3，C-24，C-25)，25.8(CH3，C-19)，22.6(CH2，C-16)，18.0(CH3，C-20)；EIMS m/z 460[M]+(15)，445(34)，401(23)，178(23)，149(62)，83(42)，71(52)，69(74)，57(100)；HREIMS m/z 460.1878(calcd.for C28H28O6，460.1886)。
Compound 13: uv (meoh): λ nax (log ε)299 (4.6); IR4KBr) vmax：3355，2974，2360，1651，1616，1574，1542，1458，1434，1280，1195，1153，1122，1056，995，837，721cm-1；1H-NMR(400MHz)13.92(1H，s，1-OH)，6.91(1H，s，H-5)，6.70(1H，d，J＝10.0Hz，H-11)，5.68(1H，d，J＝10.0Hz，H-12)，1.48(6H，s，H-14，H-15)，3.43(2H，d，J＝7.3Hz，H-16)，5.23(1H，t，J＝7.3Hz，H-17)，1.65(3H，s，H-20)，1.87(3H，s，H-19)，4.19(2H，d，J＝6.7Hz，H-21)，5.31(1H，t，J＝6.7Hz，H-22)，1.64(3H，s，H-25)，1.84(3H，s，H-24)；13C-NMR(100MHz)156.9(C，C-1)，104.7(C，C-2)，157.7(C，C-3)，106.9(C，C-4)，154.4(C，C-4a)，101.3(CH，C-5)，152.6(C，C-6)，141.8(C，C-7)，129.2(C，C-8)，111.9(C，C-8a)，183.5(C，C-9)，104.2(C，C-9a)，153.7(C，C-10a)，116.5(CH，C-11)，127.9(CH，C-12)，78.5(C，C-13)，28.4(CH3，C-14)，21.9(CH3，C-15)，26.3(CH2，C-16)，123.4(CH，C-17)，131.3(C，C-18)，25.9(CH3，C-20)，18.0(CH3，C-19)，263(CH2，C-2H，124.4(CH，C-22)，131.4(C，C-23)，25.9(CH3，C-24)，18.2(CH3，C-25)；negative EIMS m/z 461[M-H]-(100)；positive ESIMS m/z 485[M+Na]+(100)；HREIMS m/z 485.1939(calcd.for C28H30O6Na，485.1940)。
The length of time from the addition of the toluene solution containing the metal catalyst to the reaction end point, and the yield of the corresponding target product were counted in each experimental protocol, and the results are shown in table 1. The test results show that FeCl is used in comparative examples 1 and 73As a metal catalyst, the reaction substrate can not complete the cyclization reaction of the last step basically, and the yield of the target product is close to 0. Instead, CuCl is used2Examples 1 and 2 and comparative examples 2 to 6 and 8 to 12 as metal catalysts can produce a certain amount of target products, but the yield of the target products and the reaction time are different due to different synthetic routes: using N2The protection can effectively shorten the coupling cyclization reaction time, and the yield of the target product can be improved by adding the excessive phloroglucinol in a slow dropwise adding mode and adding 2-methyl-3-buten-2-ol and proper catalyst and solvent combination.
TABLE 1 time and product yield for the coupling cyclization reaction
Finally, it should be noted that the above-mentioned embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the same, and although the present invention is described in detail with reference to the above-mentioned embodiments, it should be understood by those skilled in the art that the modifications and equivalents of the specific embodiments of the present invention can be made by those skilled in the art after reading the present specification, but these modifications and variations do not depart from the scope of the claims of the present application.
Claims (4)
1. A serial cyclization synthesis method of large steric hindrance xanthone and derivatives thereof is characterized in that the synthesis route is as follows:
2. as in claimThe tandem cyclization synthesis method of the sterically hindered xanthone derivative as claimed in claim 1, characterized in that: using compound 1 and phloroglucinol as raw materials in N2Under the protection of atmosphere, the following reactions are carried out:
adding 1 equivalent of compound 1, 3 equivalents of DBU and 0.01 equivalent of TFAA into a reaction bottle, slowly dropwise adding 3 equivalents of acetonitrile solution of 2-methyl-3-butyn-2-ol, and reacting the mixture with the compound 1 at 0 ℃ for 12 hours to generate a compound 2;
adding DMF as a solvent, heating the system to 145 ℃ by using microwave heating, preserving the temperature for 48 hours, and carrying out cyclization reaction on the compound 2 to synthesize a benzopyran type compound 3;
when the temperature is reduced to room temperature, 1.5 equivalents of phloroglucinol are added into a reaction bottle, 10 equivalents of NaH are added into the reactant dropwise, 12 equivalents of MOMCl are added dropwise, the mixture is stirred for 11 hours, and the phenolic hydroxyl group of the reactant is protected by methoxy methyl;
dropwise adding 2.6 equivalents of nBuLi, stirring for 15 minutes, dropwise adding 3 equivalents of bromobenzene, reacting for 2 hours, replacing hydrogen atoms on benzene rings by isopentenyl groups, dropwise adding 5 equivalents of methanol solution of CSA, and reacting for 8 hours to generate a compound 5;
refluxing the compound 8 in a benzene solution of TsOH to obtain a benzopyran type fragmented compound 9;
heating to 140 deg.C with microwave, adding 0.01 equivalent of CuCl20.03 equivalent of PPh3And 1.2 equivalents of K3PO4Compound 5 and compound 9 to produce compound 12, and monitoring the end point of the reaction by thin layer chromatography analysis.
3. A tandem cyclization synthesis method of a large steric hindrance xanthone derivative is characterized in that the synthesis route is as follows:
4. a process for the tandem cyclization synthesis of sterically hindered xanthone derivatives as claimed in claim 3 which isIs characterized in that: using compound 6 and phloroglucinol as raw materials in N2Under the protection of atmosphere, the following reactions are carried out: adding 1.5 equivalents of phloroglucinol, 3 equivalents of DBU and 0.01 equivalent of TFAA into a reaction bottle, slowly dropwise adding 3 equivalents of acetonitrile solution of 2-methyl-3-butyn-2-ol, reacting the mixture with the compound 1 at 0 ℃ for 12 hours, adding DMF as a solvent, heating the system to 145 ℃ by using microwave heating, and preserving the temperature for 48 hours to generate a benzopyran compound 10;
cooling to room temperature, adding 1 equivalent of compound 6, equivalent of TsOH and equivalent of glycol into a reaction bottle, controlling the pH value of a reaction system to be 4-12, and under the catalysis of TsOH, providing a protecting group for aldehyde carbonyl of the compound 6 by using the glycol;
dropwise adding 10 equivalents of NaH into the reactant, then dropwise adding 12 equivalents of MOMCl, stirring for 11 hours, and protecting phenolic hydroxyl of the reactant by methoxy methyl;
dropwise adding 2.6 equivalents of nBuLi, stirring for 15 minutes, dropwise adding 3 equivalents of bromobenzene, reacting for 2 hours, replacing hydrogen atoms on benzene rings by isopentenyl groups, and dropwise adding 5 equivalents of methanol solution of CSA to generate a compound 7;
heating to 140 deg.C with microwave, adding 0.01 equivalent of CuCl20.03 equivalent of PPh3And 1.2 equivalents of K3PO4Compound 7 and compound 11 to produce compound 13, and monitoring the end point of the reaction by thin layer chromatography analysis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910071602.9A CN109776558B (en) | 2019-01-25 | 2019-01-25 | Tandem cyclization synthesis method of large steric hindrance xanthone and derivatives thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910071602.9A CN109776558B (en) | 2019-01-25 | 2019-01-25 | Tandem cyclization synthesis method of large steric hindrance xanthone and derivatives thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109776558A CN109776558A (en) | 2019-05-21 |
| CN109776558B true CN109776558B (en) | 2021-10-19 |
Family
ID=66502568
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910071602.9A Expired - Fee Related CN109776558B (en) | 2019-01-25 | 2019-01-25 | Tandem cyclization synthesis method of large steric hindrance xanthone and derivatives thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109776558B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004137210A (en) * | 2002-10-18 | 2004-05-13 | Eag Kk | Platelet-activating factor inhibitor, and cosmetic and pharmaceutical preparation |
| US20140107354A1 (en) * | 2012-10-12 | 2014-04-17 | Qian Wang | New Methodology for the Synthesis of Xanthones |
| CN108864058A (en) * | 2017-05-16 | 2018-11-23 | 成都必凯科技有限公司 | A kind of xanthone fluorochrome and application |
-
2019
- 2019-01-25 CN CN201910071602.9A patent/CN109776558B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004137210A (en) * | 2002-10-18 | 2004-05-13 | Eag Kk | Platelet-activating factor inhibitor, and cosmetic and pharmaceutical preparation |
| US20140107354A1 (en) * | 2012-10-12 | 2014-04-17 | Qian Wang | New Methodology for the Synthesis of Xanthones |
| CN108864058A (en) * | 2017-05-16 | 2018-11-23 | 成都必凯科技有限公司 | A kind of xanthone fluorochrome and application |
Non-Patent Citations (3)
| Title |
|---|
| "Copper-catalyzed ortho-acylation of phenols with aryl aldehydes and its application in one-step preparation of xanthones";Jun Hu et al.;《Chem. Commun.》;20121003;第48卷;第11256-11258页 * |
| "One-Step Synthesis of Xanthones Catalyzed by a Highly Efficient Copper-Based Magnetically Recoverable Nanocatalyst";Cintia A. Menendez et al.;《Organic Letters》;20140528;第16卷;第2846-2849页 * |
| "Total synthesis of tovophyllin B";Valer Jeso et al.;《Tetrahedron Letters》;20081225;第50卷;第1161-1163页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109776558A (en) | 2019-05-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2362819C (en) | Production of isoflavone derivatives | |
| Gerber et al. | Novel benzo [a] naphthacene quinones from an actinomycete, Frankia G-2 (ORS 020604) | |
| Chi et al. | Design, synthesis and structure–activity relationships of mangostin analogs as cytotoxic agents | |
| CN114524795B (en) | Improved rhodozyrtone preparation method | |
| CN109776558B (en) | Tandem cyclization synthesis method of large steric hindrance xanthone and derivatives thereof | |
| CN104592331B (en) | A kind of quercetin derivative and its preparation technology and application | |
| Stout et al. | Calophyllum products. IV. Papuanic and isopapuanic acids | |
| CN112047916A (en) | Method for synthesizing isolicoflavonol | |
| Nawghare et al. | Efficient Synthesis of 3‐Methyl‐Flavanones and Evaluation of Their Anti‐Bacterial Activity | |
| Briggs et al. | Chemistry of fungi. XI. Corticins A, B, and C, benzobisbenzofurans from Corticium caeruleum | |
| Aoyagi et al. | Semisynthesis of isetexane diterpenoid analogues and their cytotoxic activity | |
| Song et al. | New C19-and C18-Diterpenoid Alkaloids from Delphinium anthriscifolium var. savatieri | |
| Lee et al. | Phytochemical constituents from the leaves of soybean [Glycine max (L.) Merr.] | |
| CN108117542B (en) | Propionyl amino methoxyphenyl benzo [ d ] nitrogen hetero-pinyl quinazoline compound, preparation and application | |
| CN112679319A (en) | Synthesis method of 1,1' -deoxygossypol | |
| Pariollaud et al. | Total synthesis of (−)-bis-8, 8′-catechinylmethane isolated from cocoa liquor | |
| Fujita et al. | Synthesis of oroxylin A starting from naturally abundant baicalin | |
| Kjær et al. | A Synthesis of bikaverin (7, 12-dihydro-6, 11-dihydroxy-3, 8-dimethoxy-1-methyl-10 H-benzo [b] xanthene-7, 10, 12-trione) and some related benzoxanthones and quinones | |
| CN113929726B (en) | Mogrol derivative compound and preparation method and application thereof | |
| CN113264972B (en) | Method for preparing obeticholic acid | |
| CN116715675A (en) | Synthetic method of isopsoralen | |
| CN107021944B (en) | A kind of heterogeneous synthetic method of Dihydrobenzofuranes class compound | |
| Zhang et al. | Synthesis and Antiproliferative In‐Vitro Activity of Natural Flavans and Related Compounds | |
| CN116554189A (en) | Efficient preparation method of isopsoralen | |
| CN116574108A (en) | Synthesis method of psoralen |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20211019 Termination date: 20220125 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |