CN101638426A - 雷公藤甲素的新合成方法 - Google Patents
雷公藤甲素的新合成方法 Download PDFInfo
- Publication number
- CN101638426A CN101638426A CN200910057348A CN200910057348A CN101638426A CN 101638426 A CN101638426 A CN 101638426A CN 200910057348 A CN200910057348 A CN 200910057348A CN 200910057348 A CN200910057348 A CN 200910057348A CN 101638426 A CN101638426 A CN 101638426A
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- Prior art keywords
- compound
- synthetic method
- triptolide
- key intermediate
- solution
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 30
- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical compound O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 title claims abstract description 17
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 239000002131 composite material Substances 0.000 title abstract 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 5
- 239000011630 iodine Substances 0.000 claims abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- 150000001299 aldehydes Chemical class 0.000 claims description 12
- 238000010189 synthetic method Methods 0.000 claims description 10
- -1 enol lactone Chemical class 0.000 claims description 9
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 229940126543 compound 14 Drugs 0.000 claims description 7
- 150000002085 enols Chemical class 0.000 claims description 7
- 230000003647 oxidation Effects 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 5
- 229940126214 compound 3 Drugs 0.000 claims description 5
- 239000003444 phase transfer catalyst Substances 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 4
- 238000007171 acid catalysis Methods 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000005882 aldol condensation reaction Methods 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 230000017858 demethylation Effects 0.000 claims 1
- 238000010520 demethylation reaction Methods 0.000 claims 1
- 238000013508 migration Methods 0.000 claims 1
- 230000005012 migration Effects 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 150000003335 secondary amines Chemical class 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 150000003512 tertiary amines Chemical class 0.000 claims 1
- 229910052723 transition metal Inorganic materials 0.000 claims 1
- 150000003624 transition metals Chemical class 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 2
- MDAIAXRTLTVEOU-UHFFFAOYSA-N 5-methoxy-3,4-dihydro-1h-naphthalen-2-one Chemical compound C1C(=O)CCC2=C1C=CC=C2OC MDAIAXRTLTVEOU-UHFFFAOYSA-N 0.000 abstract 1
- 230000006698 induction Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- 238000003756 stirring Methods 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 11
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 239000012279 sodium borohydride Substances 0.000 description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 150000002576 ketones Chemical class 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000012266 salt solution Substances 0.000 description 6
- 238000010025 steaming Methods 0.000 description 6
- 150000002596 lactones Chemical class 0.000 description 5
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 229910015845 BBr3 Inorganic materials 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 150000001993 dienes Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000010813 municipal solid waste Substances 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 229910004373 HOAc Inorganic materials 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 2
- 125000005103 alkyl silyl group Chemical group 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- HHVIBTZHLRERCL-UHFFFAOYSA-N methylsulphonylmethane Natural products CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
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- 230000007935 neutral effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N triethylsilyl chloride Natural products CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 1
- XLANSEUODTUTTO-UHFFFAOYSA-N 3-(2-iodoethyl)oxolan-2-one Chemical compound ICCC1CCOC1=O XLANSEUODTUTTO-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 241000349731 Afzelia bipindensis Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical class [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 229910020667 PBr3 Inorganic materials 0.000 description 1
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Natural products C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 1
- 229910018162 SeO2 Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
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- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WQAQPCDUOCURKW-UHFFFAOYSA-N butanethiol Chemical compound CCCCS WQAQPCDUOCURKW-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 229910001496 lithium tetrafluoroborate Inorganic materials 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 239000002583 male contraceptive agent Substances 0.000 description 1
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 230000002194 synthesizing effect Effects 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
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 125000006493 trifluoromethyl benzyl group Chemical group 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种新的有效的不对称合成雷公藤甲素的方法，属于化学合成领域。该方法以5－甲氧基－2－萘满酮和2－(2－碘乙基)－1，4－丁内酯为起始原料通过手性诱导合成雷公藤甲素，该路线简短，操作方便，收率高。由于反应条件温和，该合成方法很容易进行工艺化，进而用于目标化合物的大量合成。
Description
技术领域
本发明涉及一种有机化合物的合成方法，确切地讲是关于雷公藤甲素的合成方法。雷公藤甲素的结构见式1中化合物1。
技术背景
雷公藤甲素，也叫雷公藤内酯醇，是从中药雷公藤中分离出来的活性成分。文献披露该化合物有很好的抗肿瘤活性，而且该化合物还被发现在免疫抑制、做男性避孕药等方面有很好的活性。
关于雷公藤甲素的合成自1977年就有报道，到目前为止共有以下几种合成方法报道。
文献(G.A.Berchtold et al，J.Am.Chem.Soc.，1980，102，1200；J.Org.Chem.，1982，47，2364)披露了以6-甲氧基-1-萘满酮为起始原料合成雷公藤甲素的方法(见式2)。该方法经过八步反应完成了异丙基化，并得到6-异丙基-5-甲氧基-2-萘满酮，然后通过与2-(2-碘乙基)-1，4-丁内酯的烷基化、开内酯环、分子内羟醛缩合、还原、内酯环化、苄位氧化等步骤得到关键中间体18。进而经过还原、高碘酸钠氧化、间氯过氧苯甲酸氧化、碱性双氧化水氧化和硼氢化钠还原等得到目标化合物雷公藤甲素。该方法最大的缺陷是它合成的是外消旋的目标化合物。其次，该方法路线长，非对映选择性和区域选择性差。
式2
试剂与条件：a)NaH，HCO2Et，100％；b)n-BuSH，p-TsOH，72％；c)Me2CuLi，；d)Ac2O，92％ for 2steps；e)S/heat，68％；f)i.H3O+，98％；ii.Me2SO4，100％；g)Na/EtOH，100％；h)(CO2H)2，92％；i)Pyrrolidine，azeotropic reflux；j)i.MeI；ii.AcOH，98％；k)NaH，3-(2-iodoethyl)-dihydro furan-2(3H)-one，；l)Me2NH；m)CrO3，Pyridine；n)i.alumina；ii.P-TsOH；o)NaBH4；p)HCl；q)i.mCpBA；r)i.Et3N；ii.Me2SO4；s)H2/Pd；t)CrO3，HOAc；u)BBr3；v)NaBH4；w)NaIO4；x)mCpBA；y)NaBH4.
同时，文献(E.E.Van Tamelen et al，J.Am.Chem.Soc.，1980，102，5424)也报道了一种合成雷公藤甲素的方法(式3)。该方法也只能合成消旋的雷公藤甲素，而且路线很长。
式3
Reagents and Conditions：a)NaH；b)NaOMe；c)HOCH2CH2OH，H3O+；d)Li，NH3；e)(EtO)2P(O)Cl；f)Li，NH3，90％ for 3steps；g)H3O+，90％；h)CS2，Base；i)MeI，quantitive yield；j)CH2＝SMe2；k)HCl，84％；l)LDA，TBDMSCl；m)CH2＝CHCO2Me，86％；n)NaH，MeI；o)MeLi；p)MsCl；q)Li，NH3，65％；r)i.mCpBA；ii.LDA，86％；iii.SOCl2，83％；s)i.NaOAc；ii.NaOMe，70％；t)(MeO)CNMe2，80％；u)mCpBA，100％；v)LiHMDS；w)HCl，80％.
该作者后来还提供了另外一种方法(E.E.Van Tamelen et al，J.Am.Chem.Soc.，1982，104，1785；J.Am.Chem.Soc.，1982，104，867)(见式4)。但是，遗憾的是该方法依然是消旋的全合成。
式4
试剂与条件：a)LDA，CH2O，60％；b)PBr3，90％；c)NaH，99％；d)Ba(OH)2，92％；e)LiAlH4；f)i.LiBr，PBr3；ii.ZnBr2，70％；g)LiH，90％；h)SnCl4；i)MsCl，Et3N；j)mCpBA；k)LDA，51％.
雷公藤甲素的首次不对称全合成是1997年香港大学杨丹教授报道的方法(见式5)。该方法虽然提供了目标化合物的首次不对称全合成，但是该方法中依然有多步反应收率很低，操作很难，而且该方法的关键的不对称反应选择性不好。尤其是该方法收率很低，所以该反应不能用于合成大量的目标化合物。
式5
试剂与条件：a)MOMCl，NaH，THF，65oC，2.5h，99％；b)n-BuLi，THF，-40 to20oC，2h，then-78oC，CH3I，1h，98％；c)s-BuLi，THF，-78 to-30oC，2h，then-78oC，1h，98％；d)TMSCl，LiBF4，CH3CN，-10 to 25oC，4h，97％；e)Me2SO4，K2CO3，acetone，reflux，2.5h，100％；(f)SeO2，t-BuO2H(4.0equiv)，CH2Cl2，0oC，8h，then NaBH4，MeOH，73％；g)MsCl，Et3N，CH2Cl2，-40 to-20oC，1h，thenLiBr，THF，-20 to 25oC，2h，96％；h)CH3COCH2CO2CH3，NaH，n-BuLi，THF，0oC，1h，85％；i)Mn(OAc)3，68％；j)KHMDS，Tf2NPh；k)DiBAl-H；l)Pd(PPh3)4，CO；m)CrO3，HOAc，45％；n)BBr3；o)NaBH4；p)NaIO4；q)CF3COMe，NaHCO3，OXONE，CH3CN，Na2EDTA，70％；r)H2O2，NaOH；t)NaBH4
发明内容
本发明提供一种可以克服现有技术不足的方法。
本发明的方法以5-甲氧基-2-萘满酮和2-(2-碘乙基)-1，4-丁内酯为起始原料。合成路线如下：
式6
其中，R1为烷基，R2为三烃基硅基。4和5的反应所需的碱为无机碱，如氢氧化钠，氢氧化钾，等，所需的催化剂为手性相转移催化剂。化合物9转化为11的过程，是通过醛的烯醇醚化，然后催化氢化。这里烯醇醚化可以用强碱，包括醇钾和醇钠，氢化钠，烷基金属试剂，等；醚化可以用烷基硅基。化合物14项化合物3的转化是在Lewis酸或者质子酸催化下进行的。
本发明以手性季铵盐为相转移催化剂，催化化合物4和5的烷基化反应，得到化合物6，这是整个不对称合成的关键，它引入了分子的第一个手性中心。接下来，化合物6与二甲胺反应得到化合物7，进而将化合物7氧化为醛8，然后通过分子内羟醛缩合得到化合物9，化合物9烯醇醚化得到化合物10后，在Pd-C催化下氢化即可高选择性的得到化合物11，然后用碱处理即可环化得到内酯环化合物12。化合物12在三氧化铬作用下进行苄位氧化得到13，脱去甲基保护基后得到化合物14，14在质子酸催化下异丙基化得到期望的关键中间体3。化合物3只需要按照杨丹教授报道的方法即可经化合物2为前体转化为目标化合1。
本发明提供了一种新的有效的不对称合成雷公藤甲素的方法，该方法路线简短，操作方便，收率高。由于反应条件温和，该合成方法很容易进行工艺化，进而用于目标化合物的大量合成。
具体实施方式
本发明的实施按照式6进行，其中，R1为烷基，R2为三烃基硅基。4和5的反应所需的碱为无机碱，如氢氧化钠，氢氧化钾，等，所需的催化剂为手性相转移催化剂。化合物9转化为11的过程，是通过醛的烯醇醚化，然后催化氢化。这里烯醇醚化可以用强碱，包括醇钾和醇钠，氢化钠，烷基金属试剂，等；醚化可以用烷基硅基。化合物14项化合物3的转化是在Lewis酸或者质子酸催化下进行的。本实施例只是本发明过程的一种展示，不表示发明的适用范围。
实施例一
下面提供本发明的一个实施例，其中R1为甲基，R2为三甲基硅基。4和5的反应在对三氟甲基苄基辛克宁溴盐(式7)和氢氧化钠中进行，化合物9用氢化钠和三甲基氯硅烷烯醇醚化后在Pd-C催化下还原得到化合物10。化合物14用硫酸/异丙醇处理得到化合物3。
将酮4(7.98g，42mmol)碘代物5(30g，126mmol)和催化剂A(2.2g，4.2mmol)混合溶于甲苯中。0℃搅拌下，向上述溶液滴加50％NaOH水溶液(6mL)。滴加完毕，反应缓慢升至室温，搅拌48h。有机层分离，水相用乙醚萃取。合并有机相，蒸除溶剂，剩余物经硅胶柱层析(hexane/BtOAc 9∶1)，得到酮(R)-6。
将酮(R)-6(3.2g，10mmol)溶于二甲胺(60ml)，室温搅拌过夜。挥去过量二甲胺得到酰胺7。
将吡啶(18.6g，0.235mol)溶于二氯甲烷(100ml)中并冷至0℃。CrO3(11.7g，0.12mol)约20min内逐批加入上述溶液，加毕升至室温并搅拌15min。搅拌下将酰胺7(17.35g，50mmol)的二氯甲烷溶液(40ml)加入上述溶液中，15min后，反应液用乙醚稀释，倾倒出醚层，剩余物再次用乙醚洗涤。合并有机相，依次用1N NaOH，2N HCl，以及NaHCO3，水及饱和食盐水洗涤。挥去溶剂后剩余物硅胶柱层析得到醛8.
醛8(5.17g，15mmol)溶于乙酸乙酯(80mL)，向上述溶液中加入中性氧化铝(55g)，室温搅拌2天。原料消失后滤除氧化铝，向溶液中加入对甲苯磺酸(6mg)，迴馏分水2h。蒸除溶剂，剩余物经硅胶柱层析纯化，得到酰胺9.
将酰胺9(554mg，2mmol)溶于DMF(5mL)，依次加入DIPEA 0.8ml和TMSCl(0.3mL)。混合物加热至80℃反应8h。冷却后反应液搅拌下加到100g碎冰里，EA萃取，蒸除溶剂后得到二烯10。
二烯10(0.8g，2mmol)溶于干燥干燥乙酸乙酯(30ml)。加入Pd/C(10％，0.4g)，于40pis压力下加氢2h。滤除Pd/C，滤液中加入1N盐酸(2ml)，搅拌2h。减压浓缩得到醛11。
醛11(1g，3mmol)溶于甲醇(30ml)。室温下加入甲醇钠(165mg，3mmol)，搅拌36h。反应液用CH2Cl2(200ml)稀释，依次用H2O，2N HCl，以及NaHCO3，水及饱和食盐水洗涤。挥去溶剂后剩余物硅胶柱层析得到内酯12。
内酯12(3g，10.6mmol)溶于醋酸-H2O(9∶1)混合液，然后加入CrO3(2g，20mmol).室温搅拌8小时后，反应液用二氯甲烷稀释，依次用水，饱和碳酸氢钠溶液和盐水。蒸发干燥后的溶液得到残留物，纯化柱层析得到化合物13。
化合物13(596mg，2mmol)溶于CH2Cl2(30mL)。将BBr3(2ml，1M inCH2Cl2)于-78℃下加进上述溶液中，缓慢升值室温。反应液用二氯甲烷稀释，依次用水，饱和碳酸氢钠溶液和盐水。蒸发干燥后的溶液得到残留物，纯化柱层析得到化合物14。
化合物14(568mg，2mmol)溶于H2SO4(10mL)。搅拌下加入5mL异丙醇，混合物于80℃反应3h。冷却后反应液搅拌下加到100g碎冰里，二氯甲烷萃取，合并有机相用水，饱和碳酸氢钠溶液和盐水。蒸发干燥后的溶液得到残留物，纯化柱层析得到化合物15。
实施例二：
下面提供本发明的具体实施方式，其中R1为乙基，R2为三乙基硅基。4和5的反应在对三氟甲基苄基奎宁溴盐(催化剂B)和氢氧化钠中进行，化合物9用氢化钠和三乙基氯硅烷烯醇醚化后在Raney-Ni催化下还原得到化合物10。化合物14用甲磺酸/异丙醇处理得到化合物3。
将酮4(7.98g，42mmol)碘代物5(30g，126mmol)和催化剂B(2.2g，4.2mmol)混合溶于甲苯中。0℃搅拌下，向上述溶液滴加50％NaOH水溶液(6mL)。滴加完毕，反应缓慢升至室温，搅拌48h。有机层分离，水相用乙醚萃取。合并有机相，蒸除溶剂，剩余物经硅胶柱层析(hexane/BtOAc 9∶1)，得到酮(R)-6。
将酮(R)-6(3.2g，10mmol)溶于二乙胺水溶液(60ml)，室温搅拌过夜。挥去过量二甲胺得到酰胺7。
将吡啶(18.6g，0.235mol)溶于二氯甲烷(100ml)中并冷至0℃。CrO3(11.7g，0.12mol)约20min内逐批加入上述溶液，加毕升至室温并搅拌15min。搅拌下将酰胺7(17.35g，50mmol)的二氯甲烷溶液(40ml)加入上述溶液中，15min后，反应液用乙醚稀释，倾倒出醚层，剩余物再次用乙醚洗涤。合并有机相，依次用1N NaOH，2N HCl，以及NaHCO3，水及饱和食盐水洗涤。挥去溶剂后剩余物硅胶柱层析得到醛8.
醛8(5.17g，15mmol)溶于乙酸乙酯(80mL)，向上述溶液中加入中性氧化铝(55g)，室温搅拌2天。原料消失后滤除氧化铝，向溶液中加入对甲苯磺酸(6mg)，回流分水2h。蒸除溶剂，剩余物经硅胶柱层析纯化，得到酰胺9.
将酰胺9(554mg，2mmol)溶于DMF(5mL)，依次加入三乙胺0.8ml和TESCl(0.3mL)。混合物加热至80℃反应8h。冷却后反应液搅拌下加到100g碎冰里，乙酸乙酯萃取，蒸除溶剂后得到二烯10。
二烯10(0.8g，2mmol)溶于干燥干燥乙酸乙酯(30ml)。加入Raney Ni(10％，0.4g)，于40大气压下加氢2h。滤除Pd/C，滤液中加入1M盐酸(2ml)，搅拌2h。减压浓缩得到醛11。
醛11(1g，3mmol)溶于甲醇(30ml)。室温下加入丁基锂(3mmol)，搅拌36h。反应液用CH2Cl2(200ml)稀释，依次用H2O，2N HCl，以及NaHCO3，水及饱和食盐水洗涤。挥去溶剂后剩余物硅胶柱层析得到内酯12。
内酯12(3g，10.6mmol)溶于醋酸-H2O(9∶1)混合液，然后加入CrO3(2g，20mmol).室温搅拌8小时后，反应液用二氯甲烷稀释，依次用水，饱和碳酸氢钠溶液和盐水。蒸发干燥后的溶液得到残留物，纯化柱层析得到化合物13。
化合物13(596mg，2mmol)溶于CH2Cl2(30mL)。将BBr3(2ml，1M inCH2Cl2)于-78℃下加进上述溶液中，缓慢升值室温。反应液用二氯甲烷稀释，依次用水，饱和碳酸氢钠溶液和盐水。蒸发干燥后的溶液得到残留物，纯化柱层析得到化合物14。
化合物14(568mg，2mmol)溶于甲磺酸(10mL)。搅拌下加入5mL异丙醇，混合物于80℃反应3h。冷却后反应液搅拌下加到100g碎冰里，二氯甲烷萃取，合并有机相用水，饱和碳酸氢钠溶液和盐水。蒸发干燥后的溶液得到残留物，纯化柱层析得到化合物15。
Claims (6)
1.雷公藤甲素的制备方法，其特征以化合物3为关键中间体。
2.根据权利要求1所述的雷公藤甲素的合成方法中，关键中间体3的合成方法为：以5-甲氧基-2-萘满酮和2-(2-碘乙基)-1，4-丁内酯为起始原料，经过手性相转移催化剂催化的烷基化反应后得到化合物6，然后用二级胺打开内酯环，氧化醇成醛后，在发生分子内的羟醛缩合得到化合物9。化合物经过烯醇醚化、催化氢化得到化合物11。11在碱的作用下烯醇内酯环化并迁移双键得到化合物12。12进行苄位氧化、脱甲基保护基后，在酸催化下异丙基化即可得到关键的中间体化合物3。
3.根据权利要求2中所述的关键中间体3的合成方法中，5-甲氧基-2-萘满酮和2-(2-碘乙基)-1，4-丁内酯烷基化反应得到化合物6的过程中所使用的手性相转移催化剂为手性季铵盐。
4.根据权利要求2中所述的关键中间体3的合成方法中，化合物9转化为化合物11的过程中烯醇醚化所用的试剂为烷基硅醚和三级胺。
5.根据权利要求2中所述的关键中间体3的合成方法中，化合物9转化为化合物11的过程中催化氢化所用的催化剂为过渡金属催化剂。
6.根据权利要求2中所述的关键中间体3的合成方法中，化合物14转化为化合物3所用的酸为强质子酸。
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Cited By (6)
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| CN102258525A (zh) * | 2010-05-28 | 2011-11-30 | 上海汇伦生命科技有限公司 | Hq-091212的药物应用 |
| CN102766190A (zh) * | 2012-08-05 | 2012-11-07 | 兰州大学 | 雷公藤内酯醇中间体不对称合成方法 |
| CN102924411A (zh) * | 2012-11-14 | 2013-02-13 | 兰州大学 | 雷公藤内酯醇中间体的合成方法 |
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| CN116178479A (zh) * | 2022-09-09 | 2023-05-30 | 上海博璞诺科技发展有限公司 | 山海棠素甲醚的制备方法 |
| WO2023179351A1 (zh) * | 2022-03-21 | 2023-09-28 | 欣凯医药化工中间体（上海）有限公司 | 一种7-氧代雷酚内酯的不对称合成方法及其用途 |
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| CN102258525A (zh) * | 2010-05-28 | 2011-11-30 | 上海汇伦生命科技有限公司 | Hq-091212的药物应用 |
| CN102766190A (zh) * | 2012-08-05 | 2012-11-07 | 兰州大学 | 雷公藤内酯醇中间体不对称合成方法 |
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| CN102924411A (zh) * | 2012-11-14 | 2013-02-13 | 兰州大学 | 雷公藤内酯醇中间体的合成方法 |
| CN102924411B (zh) * | 2012-11-14 | 2016-08-17 | 兰州大学 | 雷公藤内酯醇中间体的合成方法 |
| CN113292630A (zh) * | 2021-04-29 | 2021-08-24 | 北京大学 | 不对称合成Triptonide和Triptolide的方法 |
| CN113292630B (zh) * | 2021-04-29 | 2022-08-05 | 北京大学 | 不对称合成Triptonide和Triptolide的方法 |
| WO2023179351A1 (zh) * | 2022-03-21 | 2023-09-28 | 欣凯医药化工中间体（上海）有限公司 | 一种7-氧代雷酚内酯的不对称合成方法及其用途 |
| CN116178479A (zh) * | 2022-09-09 | 2023-05-30 | 上海博璞诺科技发展有限公司 | 山海棠素甲醚的制备方法 |
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