CN102653533A - Total synthesis method of mangostin - Google Patents
Total synthesis method of mangostin Download PDFInfo
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- CN102653533A CN102653533A CN2011103020408A CN201110302040A CN102653533A CN 102653533 A CN102653533 A CN 102653533A CN 2011103020408 A CN2011103020408 A CN 2011103020408A CN 201110302040 A CN201110302040 A CN 201110302040A CN 102653533 A CN102653533 A CN 102653533A
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- GNRIZKKCNOBBMO-UHFFFAOYSA-N alpha-mangostin Chemical compound OC1=C(CC=C(C)C)C(O)=C2C(=O)C3=C(CC=C(C)C)C(OC)=C(O)C=C3OC2=C1 GNRIZKKCNOBBMO-UHFFFAOYSA-N 0.000 title claims abstract description 25
- QTDMGAWIBXJNRR-UHFFFAOYSA-N Mangostin Natural products CC(=CCc1c(O)cc2Oc3cc(C)c(O)c(CC=C(C)C)c3C(=O)c2c1O)C QTDMGAWIBXJNRR-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 14
- 238000006257 total synthesis reaction Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 76
- 238000006900 dealkylation reaction Methods 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 230000035484 reaction time Effects 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- VEZXFTKZUMARDU-UHFFFAOYSA-N gamma-mangostin Chemical compound OC1=C(O)C(CC=C(C)C)=C2C(=O)C3=C(O)C(CC=C(C)C)=C(O)C=C3OC2=C1 VEZXFTKZUMARDU-UHFFFAOYSA-N 0.000 claims description 20
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000007810 chemical reaction solvent Substances 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 238000009835 boiling Methods 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 12
- 239000002841 Lewis acid Substances 0.000 claims description 11
- ZVFQDLCERPGZMO-UHFFFAOYSA-N alpha-mangostin Natural products OC1=C(CC=C(C)C)C(O)=C2C(=O)C3=C(CC=C(C)C)C(OC)=C(O)C=C3CC2=C1 ZVFQDLCERPGZMO-UHFFFAOYSA-N 0.000 claims description 11
- 150000007517 lewis acids Chemical class 0.000 claims description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- ACRGTLGOYYTGNX-UHFFFAOYSA-N gamma-mangostin Natural products OC1=C(O)C=C2C(=O)C3=C(O)C(CC=C(C)C)=C(O)C=C3OC2=C1 ACRGTLGOYYTGNX-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 235000015320 potassium carbonate Nutrition 0.000 claims description 8
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 8
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 6
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 6
- 238000010520 demethylation reaction Methods 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims description 4
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 239000001294 propane Substances 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- -1 iodo- Chemical class 0.000 claims description 3
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 claims description 2
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical group ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 2
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- HRQGCQVOJVTVLU-UHFFFAOYSA-N bis(chloromethyl) ether Chemical compound ClCOCCl HRQGCQVOJVTVLU-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 2
- JMVOCSLPMGHXPG-UHFFFAOYSA-N dipotassium;dioxido(dioxo)osmium Chemical compound [K+].[K+].[O-][Os]([O-])(=O)=O JMVOCSLPMGHXPG-UHFFFAOYSA-N 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 claims description 2
- 229940006461 iodide ion Drugs 0.000 claims description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 2
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 claims description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012285 osmium tetroxide Substances 0.000 claims description 2
- 229910000489 osmium tetroxide Inorganic materials 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- HVAMZGADVCBITI-UHFFFAOYSA-M pent-4-enoate Chemical compound [O-]C(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-M 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940071536 silver acetate Drugs 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- JNELGWHKGNBSMD-UHFFFAOYSA-N xanthone Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3OC2=C1 JNELGWHKGNBSMD-UHFFFAOYSA-N 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 229930014626 natural product Natural products 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 4
- 238000005821 Claisen rearrangement reaction Methods 0.000 abstract description 2
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 abstract description 2
- 230000020335 dealkylation Effects 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 abstract 2
- 239000005711 Benzoic acid Substances 0.000 abstract 1
- 238000010917 Friedel-Crafts cyclization Methods 0.000 abstract 1
- 206010061218 Inflammation Diseases 0.000 abstract 1
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 238000005937 allylation reaction Methods 0.000 abstract 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract 1
- 230000000259 anti-tumor effect Effects 0.000 abstract 1
- 235000010233 benzoic acid Nutrition 0.000 abstract 1
- 238000005660 chlorination reaction Methods 0.000 abstract 1
- 230000011987 methylation Effects 0.000 abstract 1
- 238000007069 methylation reaction Methods 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- SGQWQUYTTYVSBS-UHFFFAOYSA-N 1,3,6,7-tetramethoxyxanthen-9-one Chemical compound COC1=C(OC)C=C2C(=O)C3=C(OC)C=C(OC)C=C3OC2=C1 SGQWQUYTTYVSBS-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- YRKKJHJIWCRNCW-UHFFFAOYSA-N beta-Mangostin Chemical compound O1C2=CC(O)=C(OC)C(CC=C(C)C)=C2C(=O)C2=C1C=C(OC)C(CC=C(C)C)=C2O YRKKJHJIWCRNCW-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 240000006053 Garcinia mangostana Species 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical compound CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 description 4
- 238000007445 Chromatographic isolation Methods 0.000 description 4
- 235000017048 Garcinia mangostana Nutrition 0.000 description 4
- 238000011097 chromatography purification Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- LKUDPHPHKOZXCD-UHFFFAOYSA-N 1,3,5-trimethoxybenzene Chemical compound COC1=CC(OC)=CC(OC)=C1 LKUDPHPHKOZXCD-UHFFFAOYSA-N 0.000 description 2
- KVZUCOGWKYOPID-UHFFFAOYSA-N 2,4,5-Trimethoxybenzoic acid Chemical compound COC1=CC(OC)=C(C(O)=O)C=C1OC KVZUCOGWKYOPID-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 2
- QLUQJJQNWLPDOM-UHFFFAOYSA-N 1,7-dihydroxy-3,6-dimethoxyxanthen-9-one Chemical compound COC1=C(O)C=C2C(=O)C3=C(O)C=C(OC)C=C3OC2=C1 QLUQJJQNWLPDOM-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 0 CC(C)=CCc(c(O)c12)c(*)cc1Oc1cc(*)c(*)c(CC=C(C)C)c1C2=O Chemical compound CC(C)=CCc(c(O)c12)c(*)cc1Oc1cc(*)c(*)c(CC=C(C)C)c1C2=O 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 101100381997 Danio rerio tbc1d32 gene Proteins 0.000 description 1
- 101100381999 Mus musculus Tbc1d32 gene Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 238000005267 amalgamation Methods 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical class O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 150000007964 xanthones Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 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 (4)
1. the compound method of a mangostin, its route is following:
This route comprises the steps:
Step (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;
Step (2): under Lewis acid condition, the formula V compound makes formula (VI) compound with equal tri-alkoxy benzene reaction;
Step (3): formula (VI) compound makes the compound shown in the formula (VII) at alkaline condition refluxed Cheng Huan;
Step (4): formula (VII) compound makes the compound shown in the formula (VIII) through the dealkylation reaction;
Step (5):. under alkaline condition, formula (VIII) compound makes the compound shown in the formula (IX) through the allylate reaction;
Step (6): formula (IX) compound makes compound shown in the formula (X) in high temperature, polar solvent condition refluxed;
Step (7): under alkaline condition, formula (X) compound and methyl-etherified reagent react make the compound shown in the formula (XI);
Step (8): formula (XI) compound and oxidant reaction make the compound shown in the formula (XII);
Step (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;
Step (10): under hot conditions, formula (III) compound makes α-mangostin with the inorganic salt reaction that contains cyanide ion;
Step (11): under the Lewis acid condition, α-mangostin makes γ-mangostin through demethylation reaction;
In with 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.
2. compound method according to claim 1 is characterized in that:
In the step (1), 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;
In the step (2); 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, and temperature of reaction is the boiling temperature of solvent for use, and the reaction times is 24～48 hours;
In the step (3); 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;
In the step (4), 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;
In the step (5); 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;
In the step (6), 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;
In the step (7); 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;
In the step (8); 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;
In the step (9), reaction solvent is THF or ethers, and temperature of reaction is-78～0 ℃, and the reaction times is 6 hours;
In the step (10), 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;
In the step (11); 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.
3. the preparation of key intermediate (II) may further comprise the steps:
Step (1): at high temperature, different propane of halo and triphenyl phosphorus sealed reaction get the bullion of halo sec.-propyl triphenylphosphine;
Step (2): the halo sec.-propyl triphenylphosphine that step (1) gained bullion recrystallization is obtained purifying;
Step (3): with step (2) gained halo sec.-propyl triphenylphosphine and highly basic react triphenyl sec.-propyl phosphine alkane.
4. preparation method according to claim 3 is characterized in that:
In the step (1), temperature of reaction is 110～150 ℃, and the reaction times is 12～24 hours;
In the step (2), preferred ether of the solvent of recrystallization and ethanol mixed solvent, its volume ratio are 100: 3～20: 3;
In the step (3); 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;
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.
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