CN102653533A

CN102653533A - Total synthesis method of mangostin

Info

Publication number: CN102653533A
Application number: CN2011103020408A
Authority: CN
Inventors: 王进欣; 叶红春; 王帆; 尤启冬; 顾勤兰
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2011-10-09
Filing date: 2011-10-09
Publication date: 2012-09-05
Anticipated expiration: 2031-10-09
Also published as: CN102653533B

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

The total synthesis method of a kind of mangostin (mangostin)

Technical field

The invention belongs to the field of chemical synthesis, be specifically related to the compound method of the natural product mangostin shown in a kind of formula (I) with good resistance tumor promotion, anti-inflammatory, anti-microbial activity.

Background technology

Mangosteen (Garcinia mangostana L) is a kind of plant that is distributed widely in the torrid areas, South East Asia; Its pericarp and bark are used to treat diseases such as heating, dysentery, wound infection by the local resident as traditional Chinese medicine have history for many years; And its fruit has abundant nutritive value; Title (Phytochemistry.1997,44:191-214 that the king of fruit is arranged; J Agric Food Chem.2007,55:7689-94; J Agric Food Chem.2002,50:7449-7454).Natural Medicine Chemistry is discovered a series of secondary metabolites that contain in this kind of plant of mangosteen, like the xanthone compound of ether ring type of closing and isopentene base class, confirms to have anticancer, anti-inflammatory, multiple biological activity such as antibiotic after deliberation.Particularly from peel of Carcinia mangostana L., separate and obtain a series of Mangostin compounds (Chinese names: mangostin): α-mangostin with isopentene group structure; β-mangostin, γ-mangostin and β-mangostin-OMe have extensive and good biological activity.In recent years; The research group at Japan scholar Yukihiro Akao and his place separation and Extraction from the pericarp of mangosteen and tree root obtains α-mangostin; β-mangostin; Four compounds of γ-mangostin and β-mangostin-OMe, and confirm that first three compound has the activity of resisting human colon cancer cell (DLD-1) very by force, IC ₅₀Value between 7.1～8.1uM (Int J Mol Sci.2008,9:355-370).Discovery γ-mangostin such as American scholar G.C.L.Ee have the good restraining effect to cancerous cell line CEM-SS cell, IC ₅₀The value for 4.7uM (Nat Pro Sci.2006,12:138-143).A plurality of xanthone compounds with isopentene group constitutional features that handles such as Ah-Reum Han obtain from natural product have carried out the external activity screening; Find that α-mangostin and β-mangostin have the activity of good inhibition CCL188 HT-29, IC ₅₀Value be respectively 1.7uM and 2.3uM (J Nat Prod.2009,72:2028-2031).

In view of mangostin unique chemical structure and biological activity, has the significance of carrying out composition optimizes and pharmacodynamic study in a deep going way.At present; Mangostin mainly obtains through two kinds of approach: one of which, and extraction separation obtains from natural product, and still 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; J Nat Prod, 2002,65:761-763; Phytochemistry, 1993,32:1245-1251); Its two, obtain through complete synthesis and semi-synthetic means.

Complete synthesis:

1981, Hiok-Huang Lee etc. proposed the method for the synthetic Mangostin of a kind of segmented first, has successfully obtained 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, and (J C S.Perkin I.1981; 3205-3213), its synthetic route is following:

2002, Japanese scholar Kazuhiko Iikubo is complete synthesis α-mangostin in the laboratory first.This route of Kazuhiko Iikubo has been selected the segmented synthesis method equally, and earlier synthetic fragment 1 and fragment 2 are constructed isopentene group functional group respectively on two fragments 1 and 2; Amalgamation is together more at last; Totally 21 steps reaction, yield is less than 3% (Tetrahedron Lett, 2002; 43:291-293), its synthetic route is following:

Reagent and condition: (a) BnBr, K ₂CO ₃, DMF, rt, 96%; (b) mCPBA, CH ₂Cl ₂, rt; 6M HCl, MeOH, rt, 95% in two steps; (c) Br ₂, CHCl ₃, rt, 84%; (d) allyl bromide, K ₂CO ₃, DMF, rt, 80%; (e) 160 ℃, 73%; (f) Mel, K ₂CO ₃, DMF, rt, 87%; (g) OsO ₄, NalO ₄, Et ₂O/H ₂O (1/1), rt, 95%; (h) iPrPh ₃P ⁺I ^-, nBuLi, THF, 0 ℃, 72%.

Reagent and condition: (a) NaH, MOMCl, DMF, rt, 96%; (b) nBuLi; Prenyl bromi de, THF, 0 ℃, 89%; (c) nBuLi; (EtO) ₂CO, THF, 0 ℃, 95%; (d) CSA, MeOH, 60 ℃, 100%; (e) TBSCl, DMAP, Et ₃N, DMF, rt, 100%; (f) DI BAL-H, toluene ,-78 ℃, 78%; (g) I BX, toluene/DMSO (1/1), rt, 76%; (h) NaH, MOMCl, CH ₂Cl ₂, rt, 65%; (i) TBAF, THF, 0 ℃, 100%; (j) BnBr, K ₂CO ₃, DMF, rt, 98%.

Reagent and condition: (a) nBuLi, THF ,-78 ℃, 49%; (b) I BX, toluene/DMSO (1/1), rt, 76%; (c) 10Pd/C, HCO ₂NH ₄, acetone, rt, 63%; (d) PPh ₃, CCl ₄, THF, rt, then silica gel, 43%

Semi-synthetic

γ-mangostin content in the mangosteen plant is rare, at present also not to its complete synthesis bibliographical information.Except extraction separation, it is semi-synthetic to utilize isolating natural product to carry out, and is the main means that obtain γ-mangostin.α-mangostin that domestic scholars Wei Yong cutting edge of a knife or a sword etc. utilizes extraction separation to obtain, through the demethylation of hydroiodic acid HI, high yield obtained γ-mangostin, (assay office, 2008,7:65-67), synthetic route is following:

Mainly have disadvantage in the above-mentioned compound method: 1. method one all is that reactions step is long through segmented synthetic method with method two, and yield is extremely low, severe reaction conditions, and most of reaction cost is too high, is difficult to adapt to scale operation; 2. method three is that to utilize isolating natural product to carry out semi-synthetic, but existing separation method complex steps, and the cycle is very long, and yield is extremely low, thereby the source is very limited.

The present invention is with 2,4,5-tri-alkoxy phenylformic acid and 1,3, and 5-tri-alkoxy benzene is starting raw material; Through chloride, friedel-crafts acylation, annulation prepares key intermediate: 1,3; 6,7-four alkoxyl group xanthone, again through dealkylation, allylate; Claisen rearrangement, methyl-etherified, oxidizing reaction, WITTING reaction and dealkylation reaction make mangostin.Compare with aforesaid method, involved in the present invention to reaction all be typical reaction, the raw material of employing is cheap and easy to get, reactions step is short, yield is higher.

Summary of the invention

The object of the present invention is to provide the compound method of the mangostin shown in a kind of formula (I), comprise the steps:

1. 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, the independent separately C that represents ₁～C ₅Direct-connected alkane.

(1) with 2,4 shown in (IV), 5-tri-alkoxy phenylformic acid is a raw material, makes 2,4 shown in the formula V, 5-tri-alkoxy Benzoyl chloride 99min. with the halogenating agent reaction:

This reaction is characterised in that halogenating agent is selected from one or more in thionyl chloride, oxalyl chloride, phosphorus trichloride or the phosphorus pentachloride, and 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, the formula V compound makes formula (VI) compound with equal tri-alkoxy benzene reaction:

This reaction is characterised in that; Lewis acid is selected from one or more in boron trifluoride, aluminum chloride, alchlor or the zinc chloride; Reaction solvent is a kind of in dithiocarbonic anhydride, oil of mirbane, anhydrous diethyl ether, the 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 makes the compound shown in the formula (VII) at alkaline condition refluxed Cheng Huan:

This reaction is characterised in that; Alkaline reagents is selected from one or more in salt of wormwood, yellow soda ash, sodium hydroxide, Pottasium Hydroxide, sodium hydrogencarbonate or the saleratus; 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 makes the compound shown in the formula (VIII) through the dealkylation reaction:

This reaction is characterised in that the dealkylation reaction reagent is selected from one or more in sulfuric acid, hydroiodic acid HI, Hydrogen bromide/acetic acid, the boron tribromide, and temperature of reaction is the boiling temperature of solvent for use, and the reaction times is 3.5～20 hours;

(5) under alkaline condition, formula (VIII) compound makes the compound shown in the formula (IX) through the allylate reaction:

This reaction is characterised in that; The allylate reaction reagent is selected from one or more in allyl acetate, chlorallylene, allyl bromide 98, the allyl alcohol; Alkaline reagents is selected from one or more in yellow soda ash, salt of wormwood, sodium hydroxide, Pottasium Hydroxide, sodium hydrogencarbonate or the saleratus; Reaction solvent is an acetone, and temperature of reaction is 40～56 ℃, and the reaction times is 18～24 hours;

(6) formula (IX) compound makes compound shown in the formula (X) in high temperature, polar solvent condition refluxed:

This reaction is characterised in that, polar solvent is selected from a kind of in toluene, phenyl ether, N, accelerine or N, the 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) under alkaline condition, formula (X) compound and methyl-etherified reagent react make the compound shown in the formula (XI):

This reaction is characterised in that; Methyl-etherified reagent is selected from a kind of in methyl-sulfate, methyl iodide, the chloromethyl ether; Alkaline reagents is selected from one or more in yellow soda ash, salt of wormwood, sodium hydroxide or the Pottasium Hydroxide; Reaction solvent is a kind of in methyl alcohol, ethanol, acetone or the ether, and temperature of reaction is the suitable temp between the boiling temperature of room temperature and solvent for use, and the reaction times is 0.8～4 hour;

(8) formula (XI) compound and oxidant reaction make the compound shown in the formula (XII):

This reaction is characterised in that; Oxygenant is selected from a kind of in a kind of and lead tetraacetate in the wet silver acetate of potassium permanganate, osmium tetroxide, potassium osmate or iodo-, sodium periodate, the periodic acid; The mixed solvent of the solvent of the preferred middle polarity of solvent, the trimethyl carbinol and water; Its volume ratio is preferably 3: 1: 1, and temperature of reaction is 25 ℃, and the reaction times is 8 hours;

(9) under coldcondition, formula (XII) compound and WITTING reagent (II) reaction make formula (III) compound, work as R ₁=R ₂=-CH ₃The time, make β-mangostin-OMe:

This reaction is characterised in that answering solvent is THF or ethers, and temperature of reaction is-78 ℃～0 ℃, and the reaction times is 6 hours;

(10) under hot conditions, formula (III) compound makes α-mangostin with the inorganic salt reaction that contains cyanide ion:

This reaction is characterised in that, the inorganic salt that contain cyanide ion are selected from one or more in sodium cyanide, Potssium Cyanide, the cuprous cyanide, the preferred DMSO of reaction solvent, and temperature of reaction is 140～200 ℃, the reaction times is 6～8 hours;

(11) under Lewis acid condition, α-mangostin makes γ-mangostin through demethylation reaction:

This reaction is characterised in that; Demethylation reaction carries out under Lewis acid condition, and wherein Lewis acid is selected from a kind of in aluminum chloride or the alchlor, and catalyzer is selected from the inorganic salt that contain iodide ion; Reaction solvent is selected from chloroform, methylene dichloride, 1; 2-ethylene dichloride, temperature of reaction are the boiling temperature of solvent for use, and the reaction times is 2 hours.

2. key intermediate (II) synthetic comprises following synthesis step:

(1) at high temperature, different propane of halo and triphenyl phosphorus sealed reaction get the bullion of halo sec.-propyl triphenylphosphine:

This reaction is characterised in that temperature of reaction is 120 ℃～150 ℃, and the reaction times is 12～24 hours;

(2) step (1) gained bullion recrystallization is obtained the halo sec.-propyl triphenylphosphine of purifying, this step is characterised in that preferred ether of the solvent of recrystallization and ethanol mixed solvent, its volume ratio are 100: 3～20: 3;

(3) with step (2) gained halo sec.-propyl triphenylphosphine and highly basic react triphenyl sec.-propyl phosphine alkane:

This reaction is characterised in that; Highly basic is selected from one or more in sodium ethylate, potassium tert.-butoxide, sodium hydride, sodium amide, diisopropylamino lithium, n-Butyl Lithium, the phenyl lithium; Halo sec.-propyl triphenylphosphine and alkaline mol ratio are 1: 1～1: 1.4; Reaction solvent is a kind of in ether or the THF, and temperature of reaction is-78 ℃～0 ℃, and the reaction times is 1 hour;

(4) step (1) is to step (3), and the different propane of halo is selected from a kind of in bromo propane or the chloroisopropane, and halo sec.-propyl triphenylphosphine is selected from a kind of in bromo sec.-propyl triphenylphosphine or the chloro sec.-propyl triphenylphosphine.

Embodiment

In order further to illustrate the present invention, provide some embodiment below, these embodiment are illustrative fully, they only are used for the present invention is specifically described, and are not to be understood that to be limitation of the present invention.

Embodiment 1

2,4, the preparation of 5-trimethoxy-benzoyl chloride (V):

With 2,4,5-trimethoxybenzoic acid 4.24g (0.02mol) is dissolved in the 50mL methylene dichloride, adds oxalyl chloride 6mL, stirring at room, and the evaporated under reduced pressure solvent directly drops into next step reaction.

Embodiment 2

2-hydroxyl-2 ', 4,4 ', 5 ', 6-pentamethoxyl UVNUL MS-40 (VIb) and 2-hydroxyl-2 ', 4,4 ', 5 ', the preparation of 6-pentamethoxyl UVNUL MS-40 (VIa):

At the solid 2,4 that embodiment 1 makes, add the 60mL ether in the 5-trimethoxy-benzoyl chloride (V); Slowly add 1,3,5-trimethoxy-benzene 3.30g (0.018mol); Add aluminum chloride 9.35g (0.07mol) in batches, reaction solution becomes blood red, has block sticky solid to occur.Remove ice bath, refluxed 36 hours.Use ethyl acetate extraction, purification by silica gel column chromatography (petrol ether/ethyl acetate=4: 1) gets yellow particle shape solid 2-hydroxyl-2 ', 4; 4 ', 5,6 '-pentamethoxyl UVNUL MS-40 (VIa) 1.3g, productive rate 20%; Compound 2-hydroxyl-2 ', 4,4 '; 5 ', 6-pentamethoxyl UVNUL MS-40 (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 _5’-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

1,3,6, the preparation of 7-tetramethoxy xanthone (VII):

With 2-hydroxyl-2 ', 4,4 ', 5,6 '-pentamethoxyl UVNUL MS-40 (VIa) or 2-hydroxyl-2 '; 4,4 ', 5 ', 6-pentamethoxyl UVNUL MS-40 (VIb) 3.48g (0.01mol) altogether is dissolved in the 60mL methyl alcohol, adds 90mL water and 6.0g (0.15mol) sodium hydroxide; 80 ℃ were refluxed 24 hours, were cooled to room temperature, a large amount of faint yellow cotton-shaped solids occurred, and recrystallizing methanol after the suction filtration drying obtains 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

1,7-dihydroxyl-3, the preparation of 6-dimethoxy-9H-xanthone (VIII):

With 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 min. 99.5; Nitrogen protection refluxed 1 hour is cooled to room temperature, in reaction solution impouring 150mL frozen water, leaves standstill the back suction filtration; Water successively, the saturated common salt water washing, purification by silica gel column chromatography behind the filtration cakes torrefaction (sherwood oil: ETHYLE ACETATE=10: 3), pale yellow powder shape solid 1; 7-dihydroxyl-3,6-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

3,6-dimethoxy-1, the preparation of 7-two allyloxys-9H-xanthone (IX):

With 1,7-dihydroxyl-3,6-dimethoxy-9H-xanthone (VIII) 1.44g (0.005mol) is dissolved in the 40mL acetone; Add salt of wormwood 4.14g (0.03mol) successively, Soiodin 10mg, allyl bromide 98 1.73mL (0.02mol); Back flow reaction 12 hours, (the sherwood oil: ETHYLE ACETATE=2: 1), get yellow-white pulverulent solids 3 of column chromatography behind the suction filtration; 6-dimethoxy-1,7-two allyloxys-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

3,6-dimethoxy-1,7-dihydroxyl-2, the preparation of 8-diallyl-9H-xanthone (X):

With 3,6-dimethoxy-1,7-two allyloxys-9H-xanthone (IX) 370mg (1mmol); N, N-Dimethylaniline15mL add in the 50mL two-neck bottle, and nitrogen protection heats up down; Refluxed 2 hours, and be cooled to room temperature, add 15% hydrochloric acid soln 30mL; Ethyl acetate extraction, saturated ammonium chloride solution washing, organic layer anhydrous sodium sulfate drying.Column chromatography purification (sherwood oil: ETHYLE ACETATE=4: 1), get the yellow needle-like solid 3 of product, 6-dimethoxy-1,7-dihydroxyl-2,8-diallyl-9H-xanthone (X) 320mg, yield 87%.

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

3,6,7-trimethoxy-1-hydroxyl-2, the preparation of 8-diallyl-9H-xanthone (XI):

With 3,6-dimethoxy-1,7-dihydroxyl-2,8-diallyl-9H-xanthone (X) 368mg (1mmol) is dissolved in the 30mL acetone; Add salt of wormwood 276mg (2mmol), methyl-sulfate 0.142mL (1.5mmol), back flow reaction 2 hours; Dried organic solvent is revolved in decompression behind the suction filtration, and the sodium hydroxide solution 25mL of adding 10% refluxed 1 hour, was cooled to room temperature; Add about Hydrogen chloride adjust pH to 3, dichloromethane extraction three times, wash three times after anhydrous sodium sulfate drying.Column chromatographic isolation and purification (sherwood oil: ETHYLE ACETATE=8: 1), obtain yellow blocks of solid (XI) 350mg, yield 91.6%.

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):

With 3,6,7-trimethoxy-1-hydroxyl-2,8-diallyl-9H-xanthone (XI) 764mg (2mmol; 1eq) be dissolved in the 1.8mL THF, add 6mL water successively, the 6mL trimethyl carbinol, 36.8mg (0.1mmol; 0.05eq) two hydration potassium osmates, stir and add 2.14g after 0.5 hour (room temperature reaction is suction filtration after 8 hours for 10mmol, 5eq) sodium periodate; Remove solvent under reduced pressure, add the methylene dichloride dissolving, use saturated sodium sulfite solution, water washing successively; Organic layer is used anhydrous sodium sulfate drying, obtains compound (XII), stores for future use.

Embodiment 9

The preparation of bromo sec.-propyl triphenylphosphine:

3.1g isopropyl bromide (0.025mol) and 6.6g triphenylphosphine (0.025mol) add in the tube sealing of a band piston, are heated to 110 ℃, sealed reaction 12 hours; Be cooled to room temperature; Use ether: the solvent recrystallization of methyl alcohol=10: 3, white powder solid 6.8g, yield 70%.

Mp:235～237 ℃ (literature value: 238～239 ℃).

Embodiment 10

The preparation of triphenyl sec.-propyl phosphine alkane and the preparation of β-mangostin-OMe:

In the 100mL three-necked bottle, add 2.30g (6mmol) bromo sec.-propyl triphenylphosphine, THF 30mL, cryosel is bathed cooling under the nitrogen protection, drips the hexane solution of 3.0mL (2.4M) n-Butyl Lithium, is warming up to stirring at room 1 hour, gets dark red liquid.Place cryosel to bathe in the flask that fills the scarlet reaction solution, add the tetrahydrofuran solution of compound (XII), room temperature reaction 6 hours, ethyl acetate extraction behind the evaporated under reduced pressure solvent merges organic layer, washing, anhydrous sodium sulfate drying.Column chromatographic isolation and purification (sherwood oil: ETHYLE ACETATE=4: 1), obtain yellow needle-like solid 372mg, yield 42.4%.

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, compound β-mangostin-Ome 50mg is dissolved among the 1.5mLDMSO, adds the 100mg sodium cyanide; Nitrogen protection, mixed solution stirred 6 hours down at 150 ℃, poured in the frozen water after being cooled to room temperature; Use ethyl acetate extraction, use saturated copperas solution successively, water; The saturated common salt water washing, anhydrous sodium sulfate drying.Column chromatographic isolation and purification (sherwood oil: ETHYLE ACETATE=6: 1), obtain yellow solid α-mangostin 30mg, yield 64%.

mp：180-182℃；

¹H-NMR(300MHz，CDCl ₃)：δ1.70，1.78，1.84，1.85(3H?each，s，CH ₃?x?4)，δ3.46，4.10(2Heach，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-mangostin100mg is dissolved in the 2mL ethylene dichloride, adds the 1.0mL pyridine, stir down slowly adding aluminum chloride, add the Soiodin of catalytic amount, mixed-liquor return is stopped reaction after 3 hours.After being cooled to room temperature, reaction solution is poured in the mixture of Hydrogen chloride and frozen water, used ethyl acetate extraction, merge organic layer, transfer PH with triethylamine.Organic layer is water and saturated common salt washing successively, anhydrous sodium sulfate drying.Column chromatographic isolation and purification (sherwood oil: ETHYLE ACETATE=2: 1), obtain yellow solid γ-mangostin 57mg, yield 60%.

mp：207-210℃；

¹H-NMR(600MHz，acetone-D ₆)：δ1.62，1.63(3H?each，s，H-5′H-5″)，δ1.78(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

1. a synthetic method of mangostin, its route is as follows:

This route includes the following steps:

Step (1): Using 2,4,5-trialkoxybenzoic acid shown in (IV) as a raw material, react with a halogenating agent to prepare 2,4,5-trialkoxybenzoic acid shown in formula (V) Benzoyl chloride;

Step (2): Under Lewis acid conditions, the compound of formula (V) is reacted with s-trialkoxybenzene to prepare the compound of formula (VI);

Step (3): the compound of formula (VI) is refluxed under basic conditions to form a ring to obtain the compound shown in formula (VII);

Step (4): the compound of formula (VII) is prepared by dealkylation reaction to the compound shown in formula (VIII);

Step (5): Under basic conditions, the compound of formula (VIII) is subjected to an allylation reaction to obtain the compound shown in formula (IX);

Step (6): The compound of formula (IX) is refluxed under high temperature and polar solvent conditions to obtain the compound shown in formula (X);

Step (7): Under alkaline conditions, the compound of formula (X) is reacted with a methylation reagent to obtain a compound shown in formula (XI);

Step (8): reacting the compound of formula (XI) with an oxidizing agent to prepare the compound shown in formula (XII);

Step (9): Under low temperature conditions, the compound of formula (XII) is reacted with WITTING reagent (II) to obtain the compound of formula (III). When R ₁ =R ₂ =-CH ₃ , β-mangostin-OMe is obtained;

Step (10): Under high temperature conditions, the compound of formula (III) reacts with an inorganic salt containing cyanide ions to prepare α-mangostin;

Step (11): Under Lewis acid conditions, α-mangostin is demethylated to prepare γ-mangostin;

In the 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 ₂ are the same or different, and each independently represents a straight chain alkane of C ₁ to C ₅ .

2. synthetic method according to claim 1, is characterized in that:

In step (1), the halogenating agent is selected from one or more of thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride, the reaction solvent is dichloromethane or DMF, and the reaction temperature is 100% of the solvent used. Boiling temperature, the reaction time is 18 to 24 hours;

In step (2), the Lewis acid is selected from one or more of boron trifluoride, aluminum trichloride, aluminum tribromide or zinc chloride, and the reaction solvent is carbon disulfide, nitrobenzene, anhydrous ether, bis One of ethyl chloride, the reaction temperature is the boiling temperature of the solvent used, and the reaction time is 24 to 48 hours;

In step (3), alkaline reagent is selected from one or more in potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate, solvent is the mixture of methanol and water, reaction temperature is the boiling temperature of the mixed solvent, and the reaction time is 20 to 24 hours;

In step (4), the dealkylation reagent is selected from one or more of sulfuric acid, hydroiodic acid, hydrobromic acid/acetic acid, boron tribromide, and the reaction temperature is the boiling temperature of the solvent used, and the reaction time is 3.5 to 20 hours;

In step (5), the allylation reagent is selected from one or more of allyl acetate, allyl chloride, allyl bromide, allyl alcohol, and the alkaline reagent is selected from sodium carbonate, carbonic acid One or more of potassium, sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate, the reaction solvent is acetone, the reaction temperature is 40-56°C, and the reaction time is 18-24 hours;

In step (6), the polar solvent is selected from one of toluene, diphenyl ether, N, N-dimethylaniline or N, N-diethylaniline, and the reaction temperature is the boiling temperature of the solvent used, and the reaction time is 3.5 to 6 hours;

In step (7), the etherification reagent is selected from one of dimethyl sulfate, methyl iodide, and chloromethyl ether, and the alkaline reagent is selected from one of sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide or more, the reaction solvent is one of methanol, ethanol, acetone or ether, the reaction temperature is a suitable temperature between room temperature and the boiling temperature of the solvent used, and the reaction time is 0.8 to 4 hours;

In step (8), oxidant is selected from a kind of in potassium permanganate, tetraoxide, potassium osmate or iodine-wet silver acetate and a kind of in lead tetraacetate, sodium periodate, periodic acid, solvent Preferred medium polarity solvent, the mixed solvent of tert-butanol and water, its volume ratio is preferably 3:1:1, and reaction temperature is 25 ℃, and reaction time is 8 hours;

In step (9), the reaction solvent is tetrahydrofuran or ethers, the reaction temperature is -78-0°C, and the reaction time is 6 hours;

In step (10), the inorganic salt containing cyanide ion is selected from one or more of sodium cyanide, potassium cyanide, and cuprous cyanide, the reaction solvent is preferably DMSO, the reaction temperature is 140-200 ° C, and the reaction time is 6 to 8 hours;

In step (11), the demethylation reaction is carried out under Lewis acid conditions, wherein the Lewis acid is selected from one of aluminum trichloride or aluminum tribromide, the catalyst is selected from inorganic salts containing iodide ions, and the reaction solvent is selected from From chloroform, dichloromethane, 1,2-dichloroethane, the reaction temperature is the boiling temperature of the solvent used, and the reaction time is 2 hours.

3. The preparation of key intermediate (II) comprises the following steps:

Step (1): Under high temperature, halogenated isopropane and triphenylphosphine seal reaction to obtain the crude product of halogenated isopropyltriphenylphosphine;

Step (2): recrystallizing the crude product obtained in step (1) to obtain purified haloisopropyltriphenylphosphine;

Step (3): reacting the halogenated isopropyltriphenylphosphine obtained in step (2) with a strong base to obtain triphenylisopropylphosphine.

4. The preparation method according to claim 3, characterized in that:

In step (1), the reaction temperature is 110-150°C, and the reaction time is 12-24 hours;

In step (2), the solvent for recrystallization is preferably a mixed solvent of ether and ethanol, and its volume ratio is 100:3 to 20:3;

In step (3), the strong base is selected from one or more of sodium ethoxide, potassium tert-butoxide, sodium hydride, sodium amide, lithium diisopropylamide, n-butyllithium, phenyllithium, halogenated isopropyl The molar ratio of triphenylphosphine to strong base is 1:1～1:1.4, the reaction solvent is a kind of in ether or tetrahydrofuran, the reaction temperature is -78～0°C, and the reaction time is 1 hour;

In step (1) to step (3), halogenated isopropane is selected from one of bromoisopropane or chloroisopropane, and halogenated isopropyltriphenylphosphine is selected from bromoisopropyltriphenyl One of phosphine or chloroisopropyltriphenylphosphine.