CN102653533B - Total synthesis method of mangostin - Google Patents
Total synthesis method of mangostin Download PDFInfo
- Publication number
- CN102653533B CN102653533B CN201110302040.8A CN201110302040A CN102653533B CN 102653533 B CN102653533 B CN 102653533B CN 201110302040 A CN201110302040 A CN 201110302040A CN 102653533 B CN102653533 B CN 102653533B
- Authority
- CN
- China
- Prior art keywords
- reaction
- formula
- solvent
- temperature
- compound
- 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.)
- Active
Links
- 0 CC(C)=CCc(c(OCc1ccccc1)c1)c(*)c(C=O)c1OCc1ccccc1 Chemical compound CC(C)=CCc(c(OCc1ccccc1)c1)c(*)c(C=O)c1OCc1ccccc1 0.000 description 5
- GNRIZKKCNOBBMO-UHFFFAOYSA-N CC(C)=CCc(c(O)c(c(Oc(c1c2CC=C(C)C)cc(O)c2OC)c2)C1=O)c2O Chemical compound CC(C)=CCc(c(O)c(c(Oc(c1c2CC=C(C)C)cc(O)c2OC)c2)C1=O)c2O GNRIZKKCNOBBMO-UHFFFAOYSA-N 0.000 description 1
- JEWIIDGEULEWHG-UHFFFAOYSA-N CC(C)=CCc(c(OC)c(cc1OCc2ccccc2)OCc2ccccc2)c1Br Chemical compound CC(C)=CCc(c(OC)c(cc1OCc2ccccc2)OCc2ccccc2)c1Br JEWIIDGEULEWHG-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention belongs to the field of chemical synthesis, in particular relates to a synthesis method of a natural product mangostin which is shown in the formula (I) and has good anti-tumor activity, anti-inflammation activity and anti-bacterial activity. The method provided by the invention comprises the following steps of: taking 2,4,5-trialkoxy benzoic acid and 1,3,5-trialkoxy benzene as initial raw materials; carrying out acyl chlorination, Friedel-Crafts acylation and cyclization to prepare a key intermediate 1,3,6,7-tetraalkoxy xanthone; and then, carrying out dealkylation, allylation, Claisen rearrangement, methylation, oxidation reaction, WITTING reaction and dealkylation reaction so as to prepare the mangostin.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to the synthetic method of natural product mangostin with good anti-tumor activity, anti-inflammatory, anti-microbial activity shown in a kind of formula (I).
Background technology
Mangosteen (Garcinia mangostana L) is a kind of plant being distributed widely in torrid areas, South East Asia, its pericarp and bark to be used for the treatment of the diseases such as heating, dysentery, wound infection by local resident as traditional Chinese medicine have history for many years, and its fruit has abundant nutritive value, there are title (Phytochemistry.1997, the 44:191-214 of the king of fruit; J Agric Food Chem.2007,55:7689-94; J Agric Food Chem.2002,50:7449-7454).Natural Medicine Chemistry research finds the series of secondary metabolite contained in mangosteen this kind of plant, as ether ring closes the xanthone compound of class and isopentene base class, confirms to have anticancer, anti-inflammatory, the multiple biological activity such as antibacterial after deliberation.Particularly be separated from peel of Carcinia mangostana L. and obtain a series of mangostin compounds with isopentene group structure: α-mangostin, β-mangostin, γ-mangostin and β-mangostin-OMe have extensive and good biological activity.In recent years, the research group at Japanese scholars Yukihiro Akao and his place obtains α-mangostin from separation and Extraction the pericarp and tree root of mangosteen, β-mangostin, γ-mangostin and β-mangostin-OMe four compound, and confirm that first three compound has the activity resisting very by force human colon cancer cell (DLD-1), IC
50value is between 7.1 ~ 8.1uM (Int J Mol Sci.2008,9:355-370).American scholar G.C.L.Ee etc. find that γ-mangostin has good restraining effect, IC to cancerous cell line CEM-SS cell
50value is 4.7uM (Nat Pro Sci.2006,12:138-143).Ah-Rem Han etc. has carried out external activity screening the multiple xanthone compounds with isopentene group constitutional features obtained from natural product, find that α-mangostin and β-mangostin have the activity of good suppression CCL188 HT-29, IC
50value is respectively 1.7uM and 2.3uM (J Nat Prod.2009,72:2028-2031).
In view of chemical structure and the biological activity of mangostin uniqueness, there is the significance carrying out composition optimizes and pharmacodynamic study in a deep going way.At present, mangostin obtains mainly through two kinds of approach: one, and from natural product, extraction and isolation obtains, but existing extraction and separation method complex steps, process are very complicated, the cycle is very long, and yield extremely low (Phytomedicine.2005,12:203-208; JNat Prod, 2002,65:761-763; Phytochemistry, 1993,32:1245-1251); Its two, obtained by complete synthesis and semi-synthetic means.
Complete synthesis:
1981, Hiok-Huang Lee etc. proposes the method for a kind of point of segment condense mangostin first, successfully obtain 3,6,7-trimethoxy-γ-mangostin and 3,6-dimethoxy-γ-mangostin, this route has certain study on the synthesis to be worth, but step is numerous and diverse, and yield is extremely low (J C S.Perkin I.1981,3205-3213), its synthetic route is as follows:
2002, Japanese scholars Kazuhiko Iikubo is complete synthesis α-mangostin in laboratory first.This route of Kazuhiko Iikubo have selected a point fragment synthesis method equally, first synthesize fragment 1 and fragment 2, two fragments 1 and 2 construct isopentene group functional group respectively, last split more together, totally 21 step reactions, yield is less than 3% (Tetrahedron Lett, 2002,43:291-293), its synthetic route is as follows:
Semi-synthetic
γ-mangostin content in mangosteen plant is rare, bibliographical information also not complete synthesis to it at present.Except extraction and isolation, utilizing the natural product be separated to carry out semi-synthetic, is the Main Means obtaining γ-mangostin.α-mangostin that domestic scholars Wei Yong cutting edge of a knife or a sword etc. utilizes extraction and isolation to obtain, through the demethylation of hydroiodic acid HI, high yield obtain γ-mangostin, (assay office, 2008,7:65-67), synthetic route is as follows:
Mainly there is its own shortcomings in above-mentioned synthetic method: 1. method one and method two are all the methods by point segment condense, and reactions steps is long, and yield is extremely low, severe reaction conditions, and most of reaction cost is too high, be difficult to adapt to scale operation; 2. method three is that the natural product utilizing oneself to be separated carries out semi-synthetic, but existing separation method complex steps, and the cycle is very long, and yield is extremely low, thus originates very limited.
The present invention is with 2,4,5-tri-alkoxy phenylformic acid and 1; 3,5-tri-alkoxy benzene is starting raw material, passes through chloride; friedel-crafts acylation, annulation prepares key intermediate: 1, and 3; 6,7-tetra-alkoxyl group xanthone, then through dealkylation; allylate, Claisen rearrangement, methyl-etherified; oxidizing reaction, Wittig reaction and the obtained mangostin of dealkylation reaction.Compared with aforesaid method, involved in the present invention to reaction be all typical reaction, the raw material of employing is cheap and easy to get, and reactions steps is short, and yield is higher.
Summary of the invention
The object of the present invention is to provide the synthetic method of the mangostin shown in a kind of formula (I), comprise the steps:
1. with in following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII), R
1r
2identical or different, independently represent C separately
1~ C
5straight chained alkyl.
(1) with 2,4,5-tri-alkoxy phenylformic acid shown in (IV) for raw material, react 2,4,5-tri-alkoxy Benzoyl chlorides shown in obtained formula (V) with halogenating agent:
The feature of this reaction is, halogenating agent be selected from thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride one or more, reaction solvent is methylene dichloride or DMF, and temperature of reaction is the boiling temperature of solvent for use, and the reaction times is 18 ~ 24 hours;
(2) under Lewis acid condition, under Lewis acid condition, formula (V) compound and equal tri-alkoxy benzene react obtained formula (VI) compound:
The feature of this reaction is, Lewis acid be selected from boron trifluoride, aluminum chloride, alchlor or zinc chloride one or more, reaction solvent is the one in dithiocarbonic anhydride, oil of mirbane, anhydrous diethyl ether, ethylene dichloride, temperature of reaction is the boiling temperature of solvent for use, and the reaction times is 24 ~ 48 hours;
(3) formula (VI) compound refluxes into ring in the basic conditions and obtains the compound shown in formula (VII):
The feature of this reaction is, alkaline reagents be selected from salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or saleratus one or more, solvent is the mixture of methyl alcohol and water, and temperature of reaction is the boiling temperature of mixed solvent, and the reaction times is 20 ~ 24 hours;
(4) formula (VII) compound is through the compound shown in the obtained formula (VIII) of dealkylation reaction:
The feature of this reaction is, dealkylation reaction reagent be selected from sulfuric acid, hydroiodic acid HI, Hydrogen bromide/acetic acid, boron tribromide one or more, temperature of reaction is the boiling temperature of solvent for use, and the reaction times is 3.5 ~ 20 hours;
(5) in the basic conditions, formula (VIII) compound obtains the compound shown in formula (IX) through allylation reaction:
The feature of this reaction is, allylation reaction reagent be selected from allyl acetate, chlorallylene, allyl bromide 98, allyl alcohol one or more, alkaline reagents be selected from sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium bicarbonate or saleratus one or more, reaction solvent is acetone, temperature of reaction is 40 ~ 56 DEG C, and the reaction times is 18 ~ 24 hours;
(6) formula (IX) compound refluxes and obtains compound shown in formula (X) under high temperature, polar solvent conditions:
The feature of this reaction is, polar solvent is selected from the one in toluene, phenyl ether, N, accelerine or N, N-Diethyl Aniline, and temperature of reaction is the boiling temperature of solvent for use, and the reaction times is 3.5 ~ 6 hours;
(7) in the basic conditions, formula (X) compound and methyl-etherified reagent react obtain the compound shown in formula (XI):
The feature of this reaction is, methyl-etherified reagent is selected from the one in methyl-sulfate, methyl iodide, chloromethyl ether, alkaline reagents be selected from sodium carbonate, salt of wormwood, sodium hydroxide or potassium hydroxide one or more, reaction solvent is the one in methyl alcohol, ethanol, acetone or ether, temperature of reaction is the suitable temp between room temperature and the boiling temperature of solvent for use, and the reaction times is 0.8 ~ 4 hour;
(8) formula (XI) compound and oxidant reaction obtain the compound shown in formula (XII):
The feature of this reaction is, oxygenant is selected from the one in a kind of and lead tetraacetate in potassium permanganate, osmium tetroxide, potassium osmate or iodo-wet silver acetate, sodium periodate, periodic acid, the mixed solvent of the preferred tetrahydrofuran (THF) of solvent, the trimethyl carbinol and water, its volume ratio is preferably 3: 1: 1, temperature of reaction is 25 DEG C, and the reaction times is 8 hours;
(9) under cryogenic, formula (XII) compound and triphenyl sec.-propyl phosphine alkane react obtained formula (III) compound:
The feature of this reaction is, reaction solvent is ethers, and temperature of reaction is-78 DEG C ~ 0 DEG C, and the reaction times is 6 hours;
(10) under the high temperature conditions, formula (III) compound obtains α-mangostin with the inorganic salt reaction containing cyanide ion:
The feature of this reaction is, the inorganic salt containing cyanide ion be selected from sodium cyanide, potassium cyanide, cuprous cyanide one or more, the preferred DMSO of reaction solvent, temperature of reaction is 140 ~ 200 DEG C, and the reaction times is 6 ~ 8 hours;
(11) under Lewis acid condition, α-mangostin obtains γ-mangostin through demethylation reaction:
The feature of this reaction is, demethylation reaction carries out under Lewis acid condition, wherein Lewis acid is selected from the one in aluminum chloride or alchlor, catalyzer is selected from the inorganic salt containing iodide ion, reaction solvent is selected from chloroform, methylene dichloride, 1,2-ethylene dichloride, temperature of reaction is the boiling temperature of solvent for use, and the reaction times is 2 hours.
2. the synthesis of key intermediate (II) comprises following synthesis step:
(1) at high temperature, halo isopropyl alkane and triphenyl phosphorus sealed reaction obtain the crude product of haloisopropyl triphenylphosphine:
The feature of this reaction is, temperature of reaction is 120 DEG C ~ 150 DEG C, and the reaction times is 12 ~ 24 hours;
(2) step (1) gained crude product recrystallization is obtained the haloisopropyl triphenylphosphine of purifying, the feature of this step is, the preferred ether of solvent of recrystallization and the mixed solvent of ethanol, and its volume ratio is 100: 3 ~ 20: 3;
(3) step (2) gained haloisopropyl triphenylphosphine and highly basic are reacted to obtain triphenyl sec.-propyl phosphine alkane:
The feature of this reaction is, highly basic be selected from sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diisopropylamino lithium, n-Butyl Lithium, phenyl lithium one or more, the mol ratio of haloisopropyl triphenylphosphine and highly basic is 1: 1 ~ 1: 1.4, reaction solvent is the one in ether or tetrahydrofuran (THF), temperature of reaction is-78 DEG C ~ 0 DEG C, and the reaction times is 1 hour;
(4) step (1) is in step (3), halo isopropyl alkane is selected from the one in bromo propane or chloroisopropane, and haloisopropyl triphenylphosphine is selected from the one in bromo isopropyl triphenyl phosphine or chloro isopropyl triphenyl phosphine.
Embodiment
In order to illustrate the present invention further, provide some embodiments below, these embodiments are illustrative completely, and they are only used for specifically describing the present invention, not should be understood to limitation of the present invention.
Embodiment 1
The preparation of 2,4,5-trimethoxy-benzoyl chloride (V):
2,4,5-trimethoxybenzoic acid 4.24g (0.02mol) is dissolved in 50mL methylene dichloride, adds oxalyl chloride 6mL, stirring at room temperature, evaporated under reduced pressure solvent, directly drop into next step reaction.
Embodiment 2
2-hydroxyl-2 ', 4,4 ', 5 ', 6-pentamethoxyl benzophenone (VIb) and 2-hydroxyls-2 ', the preparation of 4,4 ', 5 ', 6-pentamethoxyl benzophenone (VIa):
At the solid 2 that embodiment 1 is obtained, 4,60mL ether is added in 5-trimethoxy-benzoyl chloride (V), slowly add 1,3,5-trimethoxy-benzene 3.30g (0.018mol), adds aluminum chloride 9.35g (0.07mol) in batches, reaction solution becomes blood red, has block sticky solid to occur.Remove ice bath, reflux 36 hours.Extract by ethyl acetate, purification by silica gel column chromatography (petrol ether/ethyl acetate=4: 1) obtain yellow particle shape solid 2-hydroxyl-2 ', 4,4 ', 5,6 '-pentamethoxyl benzophenone (VI a) 1.3g, productive rate 20%, compound 2-hydroxyl-2 ', 4,4 ', 5 ', 6-pentamethoxyl benzophenone (VIb) 1.5g, productive rate 22%.
Compound VI a
1H-NMR(300MHz，CDCl
3)：δ3.72(s，6H，C
4-OCH
3，C
5-OCH
3)，δ3.86(s，3H，C
4'-OCH
3)，δ3.88(s，6H，C
2'-OCH
3，C
6'-OCH
3)，δ6.55(s，1H，C
6-H)，δ6.78(d，2H，C
3'-H，C
s ’-H)，δ7.03(d，1H，C
6-H)，δ7.43(s，1H，C
6-H)，δ12.46(s，1H，C
2-OH)；
EI-MS(m/z)：348(M
+)，333，317，180，152.
Compound VI b
1H-NMR(300MHz，CDCl
3)：δ3.54(s，3H，C
4-OCH
3)，δ3.62(s，6H，C
2-OCH
3，C
6-OCH
3)，δ3.85(s，3H，C
5'-OCH
3)，δ3.89(s，3H，C
6-OCH
3)，δ3.99(s，3H，C
4'-OCH
3)，δ3.85(s，3H，C
2'-OCH
3)，δ6.06(s，6H，C
3-H，C
5-H)，δ6.37(s，3H，C
3 ’-H，δ7.34(s，3H，C
6'-H)；
EI-MS(m/z)：362(M
+)，345，331，317，195，151.
Embodiment 3
The preparation of 1,3,6,7-tetramethoxy xanthone (VII):
By 2-hydroxyl-2 ', 4,4 ', 5,6 '-pentamethoxyl benzophenone (VI a) or 2-hydroxyl-2 ', 4, (VI b) is total to 3.48g (0.01mol) is dissolved in 60mL methyl alcohol 4 ', 5 ', 6-pentamethoxyl benzophenone, add 90mL water and 6.0g (0.15mol) sodium hydroxide, 80 DEG C are refluxed 24 hours, are cooled to room temperature, occur a large amount of faint yellow fluffy solid, recrystallizing methanol after suction filtration drying, obtain off-white color amorphous solid 1,3,6,7-tetramethoxy xanthone (VII) 2.76g, yield 87.3%.
1H-NMR(300MHz，CDCl
3)：δ3.90(s，3H，C
3-OCH
3)，δ3.97(s，6H，C
6-OCH
3，C
7-OCH
3)，δ3.98(s，3H，C
1-OCH
3)，δ6.34(s，1H，C
4-H)，δ6.46(s，1H，C
5-H)，δ6.81(s，1H，C
2-H)，δ7.65(s，1H，C
8-H)；
EI-MS(m/z)：316(M
+)，299，287，270，185，83.
Embodiment 4
The preparation of 1,7-dihydroxyl-3,6-dimethoxy-9H-xanthone (VIII):
By 1; 3; 6; 7-tetramethoxy xanthone (VII) 4.74g (0.015mol) is dissolved in the solvent of 45mL Hydrogen bromide and 55mL Glacial acetic acid; reflux 1 hour under nitrogen protection; be cooled to room temperature; by in reaction solution impouring 150mL frozen water, suction filtration after leaving standstill, uses water successively; saturated common salt water washing; after filtration cakes torrefaction, (sherwood oil: ethyl acetate=10: 3), obtains pale yellow powder shape solid 1,7-dihydroxyl-3 to purification by silica gel column chromatography; 6-dimethoxy-9H-xanthone (VIII) 2.80g, yield 65%.
1H-NMR(300MHz，CDCl
3)：δ3.91(s，3H，C
3-OCH
3)，δ4.11(s，3H，C
6-OCH
3)，δ5.53(s，1H，C
7-OH)，δ6.41(s，1H，C
4-H)，δ6.44(s，1H，C
5-H)，δ6.86(s，1H，C
2-H)，δ7.66(s，1H，C
8-H)，δ13.05(s，1H，C
1-OH)；
EI-MS(m/z)：288(M
+)，273，259，169，141，85.
Embodiment 5
The preparation of 3,6-dimethoxy-1,7-bis-allyloxy-9H-xanthone (IX):
By 1,7-dihydroxyl-3,6-dimethoxy-9H-xanthone (VIII) 1.44g (0.005mol) is dissolved in 40mL acetone, add salt of wormwood 4.14g (0.03mol) successively, sodium iodide 10mg, allyl bromide 98 1.73mL (0.02mol), back flow reaction 12 hours, column chromatography (sherwood oil: ethyl acetate=2: 1) after suction filtration, obtain yellow-white pulverulent solids 3,6-dimethoxy-1,7-bis-allyloxy-9H-xanthone (IX) 1.68g, yield 91.3%.
mp：135～137℃；
1H-NMR(300MHz，CDCl
3)：δ3.67(d，J＝6.12Hz，2H，-CH
2-)，δ3.94(s，3H，C
3-OCH
3)，δ4.16(s，3H，C
6-OCH
3)，δ4.24(d，J＝6.42Hz，2H，-CH
2-)，δ5.12(d，J＝9.22Hz，2H，＝CH
2)，δ5.43(d，J＝7.43Hz，2H，＝CH
2)，δ6.23(m，1H，-CH＝)，δ6.33(m，1H，-CH＝)，δ6.44(s，1H，C
4-H)，δ6.49(s，1H，C
5-H)，δ7.10(s，1H，C
2-H)，δ7.88(s，1H，C
8-H)；
EI-MS(m/z)：368(M
+)，353，339，327，243，215.
Embodiment 6
The preparation of 3,6-dimethoxy-1,7-dihydroxyl-2,8-diallyl-9H-xanthone (X):
By 3; 6-dimethoxy-1,7-bis-allyloxy-9H-xanthone (IX) 370mg (1mmol), N; N-Dimethylaniline15mL adds in 50mL two-neck bottle; heat up under nitrogen protection, reflux 2 hours, be cooled to room temperature; add 15% hydrochloric acid soln 30mL; extraction into ethyl acetate, saturated ammonium chloride solution washs, organic layer anhydrous sodium sulfate drying.(sherwood oil: ethyl acetate=4: 1) obtains product yellow needles solid 3,6-dimethoxy-1,7-dihydroxyl-2,8-diallyl-9H-xanthone (X) 320mg, yield 87% to column chromatography purification.
mp：197～198℃；
1H-NMR(300MHz，CDCl
3)：δ3.40(d，J＝6.22Hz，2H，-CH
2-)，δ3.86(s，3H，C
3-OCH
3)，δ4.01(s，3H，C
6-OCH
3)，δ4.19(d，J＝4.12Hz，2H，-CH
2-)，δ4.94(m，4H，2-CH
2-)，δ5.64(s，1H，C
7-OH)，δ5.93 (m，1H，-CH＝)，δ6.01(m，1H，-CH＝)，δ6.32(s，1H，C
4-H)，δ6.75(s，1H，C
5-H)，δ13.50(s，1H，C
1-OH)；
Embodiment 7
The preparation of 3,6,7-trimethoxy-1-hydroxyl-2,8-diallyl-9H-xanthone (XI):
By 3,6-dimethoxy-1,7-dihydroxyl-2,8-diallyl-9H-xanthone (X) 368mg (1mmol) is dissolved in 30mL acetone, add salt of wormwood 276mg (2mmol), methyl-sulfate 0.142mL (1.5mmol), back flow reaction 2 hours, after suction filtration, decompression is spin-dried for organic solvent, the sodium hydroxide solution 25mL adding 10% refluxes 1 hour, is cooled to room temperature, about adding dilute hydrochloric acid adjust pH to 3, dichloromethane extraction three times, anhydrous sodium sulfate drying after washing three times.(sherwood oil: ethyl acetate=8: 1) obtains yellow blocks of solid (XI) 350mg, yield 91.6% to column chromatographic isolation and purification.
mp：167～168℃；
1H-NMR(300MHz，CDCl
3)：δ3.38(d，J＝6.12Hz，2H，-CH
2-)，δ3.85(s，3H，C
3-OCH
3)，δ4.04(s，3H，C
6-OCH
3)，δ4.12(s，3H，C
7-OCH
3)，δ4.26(d，J＝10.12Hz，2H，-CH
2-)，δ4.96(m，4H，2-CH
2-)，δ5.96(m，1H，-CH＝)，δ6.01(m，1H，-CH＝)，δ6.36(s，1H，C
4-H)，δ6.75(s，1H，C
5-H)，δ13.09(s，1H，C
1-OH)；
EI-MS(m/z)：382(M
+)，367，352，277，169，98，55.
Embodiment 8
The preparation of compound (XII):
By 3, 6, 7-trimethoxy-1-hydroxyl-2, 8-diallyl-9H-xanthone (XI) 764mg (2mmol, 1eq) be dissolved in 18mL tetrahydrofuran (THF), add 6mL water successively, the 6mL trimethyl carbinol, 36.8mg (0.1mmol, 0.05eq) two hydration potassium osmates, stir and add 2.14g (10mmol after 0.5 hour, 5eq) sodium periodate, room temperature reaction is suction filtration after 8 hours, remove solvent under reduced pressure, add methylene dichloride to dissolve, use saturated sodium sulfite solution successively, water washing, organic over anhydrous dried over sodium sulfate, obtain compound (XII), store for future use.
Embodiment 9
The preparation of bromo isopropyl triphenyl phosphine:
3.1g isopropyl bromide (0.025mol) and 6.6g triphenylphosphine (0.025mol) add in the tube sealing of a band piston, be heated to 110 DEG C, sealed reaction 12 hours, be cooled to room temperature, with ether: methyl alcohol=10: the solvent recrystallization of 3, obtain white powdery solids 6.8g, yield 70%.
Mp:235 ~ 237 DEG C (literature value: 238 ~ 239 DEG C).
Embodiment 10
The preparation of each and β-mangostin-OMe of the system of triphenyl sec.-propyl phosphine alkane:
2.30g (6mmol) bromo isopropyl triphenyl phosphine is added in 100mL three-necked bottle; tetrahydrofuran (THF) 30mL, under nitrogen protection, cryosel bath cooling, drips the hexane solution of 3.0mL (2.4M) n-Butyl Lithium; be warming up to stirring at room temperature 1 hour, obtain dark red liquid.The flask filling scarlet reaction solution is placed in cryosel bath, adds the tetrahydrofuran solution of compound (Ⅻ), room temperature reaction 6 hours, after evaporated under reduced pressure solvent, ethyl acetate is extracted, and merges organic layer, washing, anhydrous sodium sulfate drying.(sherwood oil: ethyl acetate=4: 1) obtains yellow needles solid 372mg, yield 42.4% to column chromatographic isolation and purification.
mp：116～118℃；
1H-NMR(300MHz，CDCl
3)：δ1.64(s，6H，2×-CH
3)，δ1.79(s，3H，-CH
3)，δ1.89(s，3H，-CH
3)，δ3.34(d，J＝9.12Hz，2H，-CH
2-)，3.79～4.14(t，9H，-OCH
3)，δ4.12(m，2H，-CH
2-)，δ5.18(m，2H，2×-CH＝)，δ6.57(s，1H，C
4-H)，δ6.73(s，1H，C
5-H)，δ13.48(s，1H，C
1--OH)；
EI-MS(m/z)：438(M
+)，423，409，367，277，199，77.
Embodiment 11
The preparation of α-mangostin:
At room temperature; by compound β-mangostin-Ome 50mg is dissolved in 1.5mLDMSO; add 100mg sodium cyanide, nitrogen protection, mixed solution stirs 6 hours at 150 DEG C; pour into after being cooled to room temperature in frozen water; be extracted with ethyl acetate, use saturated copperas solution successively, water; saturated common salt water washing, anhydrous sodium sulfate drying.(sherwood oil: ethyl acetate=6: 1) obtains yellow solid α-mangostin 30mg, yield 64% to column chromatographic isolation and purification.
mp：180-182℃；
1H-NMR(300MHz，CDCl
3)：δ1.70，1.78，1.84，1.85(3H each，s，CH
3x 4)，δ3.46，4.10(2H each，d，J＝7.0Hz，J＝5.9Hz，-CH
2-)，δ3.81(3H，s，C
7-O CH
3)，δ5.26-5.312H，m，(2×-CH＝)，δ6.30，6.83(1H each，s，C
4，C
5-H)，δ13.78(1H，s，C
1-OH)；
HR-EIMS(m/z)：410.1728.
Embodiment 12
The preparation of γ-mangostin:
Compound α-mangostin 100mg is dissolved in 2mL ethylene dichloride, adds 1.0mL pyridine, slowly add aluminum chloride under stirring, add the sodium iodide of catalytic amount, mixed-liquor return is stopped reaction after 3 hours.After being cooled to room temperature, reaction solution being poured in the mixture of dilute hydrochloric acid and frozen water, be extracted with ethyl acetate, merge organic layer, adjust PH with triethylamine.Organic layer is washed with water and saturated common salt successively, anhydrous sodium sulfate drying.(sherwood oil: ethyl acetate=2: 1) obtains yellow solid γ-mangostin 57mg, yield 60% to column chromatographic isolation and purification.
mp∶207-210℃；
1H-NMR(600MHz，acetone-D
6)：δ1.62，1.63(3H each，s，H-5′H-5")，δ 1.78(3H，s，H-4")， 1.79(3H，s，H-4′)，3.48(2H，d，J＝7.2Hz，H-1″)，3.92(3H，s，OCH
3)，4.25(2H，d，J＝6.0Hz，H-1)，5.40(2H，m，H-2′and H-2″)，6.53(1H，s，H-8)，6.95(1H，s，H-1)，13.92(1H，s，C
5-OH)；
ESI-MS(m/z)：409[M-H]
-.
Claims (2)
1. a synthetic method for mangostin, its route is as follows:
This route comprises the steps:
Step (1): with 2,4,5-tri-alkoxy phenylformic acid shown in (IV) for raw material, reacts 2,4,5-tri-alkoxy Benzoyl chlorides shown in obtained formula (V) with halogenating agent;
Step (2): under Lewis acid condition, formula (V) compound and equal tri-alkoxy benzene react obtained formula (VI) compound;
Step (3): formula (VI) compound refluxes into ring in the basic conditions and obtains the compound shown in formula (VII);
Step (4): formula (VII) compound is through the compound shown in the obtained formula (VIII) of dealkylation reaction;
Step (5): in the basic conditions, formula (VIII) compound obtains the compound shown in formula (IX) through allylation reaction:
Step (6): formula (IX) compound refluxes and obtains compound shown in formula (X) under high temperature, polar solvent conditions,
Step (7): in the basic conditions, formula (X) compound and methyl-etherified reagent react obtain the compound shown in formula (XI);
Step (8): formula (XI) compound and oxidant reaction obtain the compound shown in formula (XII);
Step (9): under cryogenic, formula (XII) compound and triphenyl sec.-propyl phosphine alkane react obtained formula (III) compound;
Step (10): under the high temperature conditions, formula (III) compound obtains α-mangostin with the inorganic salt reaction containing cyanide ion;
Step (11): under Lewis acid condition, α-mangostin obtains γ-mangostin through demethylation reaction;
With in above formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII), R
1, R
2identical or different, independently represent C separately
1~ C
5straight chained alkyl.
2. synthetic method according to claim 1, is characterized in that:
In step (1), halogenating agent be selected from thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride one or more, reaction solvent is methylene dichloride or DMF, and temperature of reaction is the boiling temperature of solvent for use, and the reaction times is 18 ~ 24 hours;
In step (2), Lewis acid be selected from boron trifluoride, aluminum chloride, alchlor or zinc chloride one or more, reaction solvent is the one in dithiocarbonic anhydride, oil of mirbane, anhydrous diethyl ether, ethylene dichloride, temperature of reaction is the boiling temperature of solvent for use, and the reaction times is 24 ~ 48 hours;
In step (3), alkaline reagents be selected from salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or saleratus one or more, solvent is the mixture of methyl alcohol and water, and temperature of reaction is the boiling temperature of mixed solvent, and the reaction times is 20 ~ 24 hours;
In step (4), dealkylation reaction reagent be selected from sulfuric acid, hydroiodic acid HI, Hydrogen bromide/acetic acid, boron tribromide one or more, temperature of reaction is the boiling temperature of solvent for use, and the reaction times is 3.5 ~ 20 hours;
In step (5), allylation reaction reagent be selected from allyl acetate, chlorallylene, allyl bromide 98, allyl alcohol one or more, alkaline reagents be selected from sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium bicarbonate or saleratus one or more, reaction solvent is acetone, temperature of reaction is 40 ~ 56 DEG C, and the reaction times is 18 ~ 24 hours;
In step (6), polar solvent is selected from the one in toluene, phenyl ether, N, accelerine or N, N-Diethyl Aniline, and temperature of reaction is the boiling temperature of solvent for use, and the reaction times is 3.5 ~ 6 hours;
In step (7), methyl-etherified reagent is selected from the one in methyl-sulfate, methyl iodide, chloromethyl ether, alkaline reagents be selected from sodium carbonate, salt of wormwood, sodium hydroxide or potassium hydroxide one or more, reaction solvent is the one in methyl alcohol, ethanol, acetone or ether, temperature of reaction is the suitable temp between room temperature and the boiling temperature of solvent for use, and the reaction times is 0.8 ~ 4 hour;
In step (8), oxygenant is selected from the one in a kind of and lead tetraacetate in potassium permanganate, osmium tetroxide, potassium osmate or iodo-wet silver acetate, sodium periodate, periodic acid, the mixed solvent of the preferred tetrahydrofuran (THF) of solvent, the trimethyl carbinol and water, its volume ratio is preferably 3: 1: 1, temperature of reaction is 25 DEG C, and the reaction times is 8 hours;
In step (9), reaction solvent is ethers, and temperature of reaction is-78 ~ 0 DEG C, and the reaction times is 6 hours;
In step (10), the inorganic salt containing cyanide ion be selected from sodium cyanide, potassium cyanide, cuprous cyanide one or more, the preferred DMSO of reaction solvent, temperature of reaction is 140 ~ 200 DEG C, and the reaction times is 6 ~ 8 hours;
In step (11), demethylation reaction carries out under Lewis acid condition, wherein Lewis acid is selected from the one in aluminum chloride or alchlor, catalyzer is selected from the inorganic salt containing iodide ion, reaction solvent is selected from chloroform, methylene dichloride, 1,2-ethylene dichloride, temperature of reaction is the boiling temperature of solvent for use, and the reaction times is 2 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110302040.8A CN102653533B (en) | 2011-10-09 | 2011-10-09 | Total synthesis method of mangostin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110302040.8A CN102653533B (en) | 2011-10-09 | 2011-10-09 | Total synthesis method of mangostin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102653533A CN102653533A (en) | 2012-09-05 |
| CN102653533B true CN102653533B (en) | 2015-04-29 |
Family
ID=46729278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110302040.8A Active CN102653533B (en) | 2011-10-09 | 2011-10-09 | Total synthesis method of mangostin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102653533B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319448B (en) * | 2013-04-02 | 2016-04-27 | 中国药科大学 | A kind of Xanthone derivative and Synthesis and applications thereof |
| CN103709135B (en) * | 2013-12-23 | 2016-08-17 | 广西师范大学 | Ton ketone derivatives and its preparation method and application |
| CN103880807B (en) * | 2014-03-18 | 2016-09-28 | 杭州博麦医药科技有限公司 | The synthesis technique of high-purity alpha-mangostin |
| CN103864747B (en) * | 2014-03-28 | 2016-06-22 | 中国药科大学 | The total synthesis method of mangostin |
| CN106554341B (en) * | 2015-09-30 | 2019-05-21 | 南京美竹医药科技有限公司 | The preparation method and purposes of a kind of mangostin and the like |
| CN105503809A (en) * | 2015-12-29 | 2016-04-20 | 陕西嘉禾生物科技股份有限公司 | Synthetic method of gamma-mangostin |
| CN106977489B (en) * | 2017-04-20 | 2019-05-31 | 清华大学 | A method of preparing polysubstituted xanthones derivative |
| CN107857751A (en) * | 2017-12-18 | 2018-03-30 | 上海中医药大学 | A kind of compound and preparation method thereof, pharmaceutical composition and purposes |
| CN113456824B (en) * | 2020-03-31 | 2023-03-31 | 四川大学华西医院 | Anti-tumor drug-loading nano composite material |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4603213A (en) * | 1984-09-27 | 1986-07-29 | Ortho Pharmaceutical Corporation | Total synthesis of 1RS,4SR,5RS-4-(4,8-dimethyl-5-hydroxy-7-nonen-1-yl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-acetic acid |
| CN101955475A (en) * | 2010-05-25 | 2011-01-26 | 苏州派腾生物医药科技有限公司 | Preparation method of alpha-mangostin |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004042428A (en) * | 2002-07-11 | 2004-02-12 | Konica Minolta Holdings Inc | Image forming method and ink jet recording equipment used therefor |
| JP2007153773A (en) * | 2005-12-02 | 2007-06-21 | Shiseido Co Ltd | Xanthone derivative, and skin care preparation and pharmaceutical composition each containing the same |
-
2011
- 2011-10-09 CN CN201110302040.8A patent/CN102653533B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4603213A (en) * | 1984-09-27 | 1986-07-29 | Ortho Pharmaceutical Corporation | Total synthesis of 1RS,4SR,5RS-4-(4,8-dimethyl-5-hydroxy-7-nonen-1-yl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-acetic acid |
| CN101955475A (en) * | 2010-05-25 | 2011-01-26 | 苏州派腾生物医药科技有限公司 | Preparation method of alpha-mangostin |
Non-Patent Citations (6)
| Title |
|---|
| A New [2 + 2] Functionalization of C60 with Alkyl-Substituted 1,3-Butadienes: A Mechanistic Approach. Stereochemistry and Isotope Effects;Georgios Vassilikogiannakis，等;《J. Am. Chem. Soc.》;19980915;第120卷(第38期);9911-9920 * |
| The first direct synthesis of α-mangostin, a potent inhibitor of the acidic sphingomyelinase;Kazuhiko Iikubo，等;《Tetrahedron Letters》;20020131;第43卷(第2期);291–293 * |
| Wittig反应研究进展;王平 等;《科技信息》;20100430(第10期);94-95 * |
| 呫吨酮类衍生物的合成与体外抗氧化活性研究;路浩;《大连理工大学硕士学位论文》;20090831;9-17 * |
| 赵佳.山竹黄酮的提取、合成、分析及性质研究.《西北大学硕士学位论文》.2008,17-19. * |
| 邱惊雷.天然产物Malabaricone C的全合成研究.《四川大学硕士学位论文》.2008,16-17. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102653533A (en) | 2012-09-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102653533B (en) | Total synthesis method of mangostin | |
| CN105218606B (en) | A kind of method for preparing scutellarin | |
| CN101712601B (en) | Method for synthesizing phyllocnistis citrella stainton pheromone compound | |
| CN102617302B (en) | Process for synthesizing trimethoxyphenyl stilbene | |
| CN113735847B (en) | Synthetic preparation method of berberine hydrochloride | |
| WO2001060774A1 (en) | Synthesis of resveratrol | |
| CN105218499B (en) | A kind of method for preparing Scutellarein | |
| CN101195575B (en) | process for producing (E)-3-dimethoxy-4'-acetoxy diphenyl ethylene | |
| CN106146457B (en) | 5-chloro-2-acyl chloride thiophene intermediate and preparation method thereof | |
| CN101684112A (en) | Preparation method of 5,6,7,4'-tetramethoxy flavones of scutellarin and aglucone key intermediate thereof | |
| CN101186563A (en) | 3,5-dimethoxyl or 3,5-dihydroxy diphenylethene compounds and preparation method thereof | |
| CN102766088A (en) | Novel process for synchronizing 4,4'-dibromo-2,2'-bipyridyl | |
| CN102060826A (en) | Method for synthesizing 7-methoxyl-4'-substituted flavonoids compound | |
| CN104945458B (en) | A kind of synthetic method of progesterone | |
| CN111943817B (en) | Resveratrol analogue containing long conjugated structure and preparation method and application thereof | |
| CN101792451A (en) | Full synthesis method of 4'',5''-dihydroxyl-5-methoxyl-[6'',6''-dimethyl pyran (2'',3'':7,8)] Hirtellanine A | |
| CN104356103A (en) | Synthetic method of 6, 7-dimethoxyl coumarin | |
| CN103864747A (en) | Novel synthesis method of mangostin | |
| CN103319497A (en) | Preparation method of natural product Hirtellanine B and derivatives thereof, and application of natural product Hirtellanine B and derivatives thereof in tumor treatment drug preparation | |
| CN108947953B (en) | Synthetic method of flavonoid derivative | |
| CN106083790B (en) | A kind of synthetic method of 2- (1- hydroxyl -4- ketone -2,5- cyclohexadiene)-pyrans -4- ketone | |
| CN1297552C (en) | Process for synthesizing luteolin | |
| CN107793302B (en) | Method for preparing 10, 10-disubstituted-2-bromoanthrone | |
| CN104387221A (en) | Synthesis method of peretinoin decarboxylative body impurities | |
| CN110642671A (en) | System and method for continuously preparing Grignard reagent to synthesize phenethyl alcohol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |