WO2007006230A1 - Procédé de préparation d’érianine - Google Patents
Procédé de préparation d’érianine Download PDFInfo
- Publication number
- WO2007006230A1 WO2007006230A1 PCT/CN2006/001649 CN2006001649W WO2007006230A1 WO 2007006230 A1 WO2007006230 A1 WO 2007006230A1 CN 2006001649 W CN2006001649 W CN 2006001649W WO 2007006230 A1 WO2007006230 A1 WO 2007006230A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- group
- reaction
- organic solvent
- Prior art date
Links
- UXDFUVFNIAJEGM-UHFFFAOYSA-N 2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)ethyl]phenol Chemical compound C1=C(O)C(OC)=CC=C1CCC1=CC(OC)=C(OC)C(OC)=C1 UXDFUVFNIAJEGM-UHFFFAOYSA-N 0.000 title abstract description 6
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 claims abstract description 37
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- 239000004166 Lanolin Substances 0.000 claims description 35
- 229940039717 lanolin Drugs 0.000 claims description 35
- 235000019388 lanolin Nutrition 0.000 claims description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 28
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 239000003054 catalyst Substances 0.000 claims description 25
- 239000003960 organic solvent Substances 0.000 claims description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
- 125000006239 protecting group Chemical group 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 12
- 239000012442 inert solvent Substances 0.000 claims description 11
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 9
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 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 7
- 150000002148 esters Chemical class 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 5
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 229940073608 benzyl chloride Drugs 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 239000002635 aromatic organic solvent Substances 0.000 claims description 3
- SHWBBTGHDNDPTJ-UHFFFAOYSA-N FN(F)P(=O)(N(F)F)N(F)F Chemical compound FN(F)P(=O)(N(F)F)N(F)F SHWBBTGHDNDPTJ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- WABAEEDHTRIFPM-UHFFFAOYSA-N hydroxy-sulfanyl-sulfanylidene-$l^{4}-sulfane Chemical compound SS(S)=O WABAEEDHTRIFPM-UHFFFAOYSA-N 0.000 claims description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims 1
- OSNIIMCBVLBNGS-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-yl)-2-(dimethylamino)propan-1-one Chemical compound CN(C)C(C)C(=O)C1=CC=C2OCOC2=C1 OSNIIMCBVLBNGS-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- -1 phosphonate ester Chemical class 0.000 abstract description 17
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 abstract description 6
- 238000010511 deprotection reaction Methods 0.000 abstract description 6
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 abstract 1
- 229960005537 combretastatin A-4 Drugs 0.000 abstract 1
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 abstract 1
- 150000004714 phosphonium salts Chemical class 0.000 abstract 1
- 239000000047 product Substances 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000013078 crystal Substances 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 239000007787 solid Substances 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000005806 3,4,5-trimethoxybenzyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1C([H])([H])* 0.000 description 5
- QEGDRYOJTONTLO-UHFFFAOYSA-N 5-(bromomethyl)-1,2,3-trimethoxybenzene Chemical compound COC1=CC(CBr)=CC(OC)=C1OC QEGDRYOJTONTLO-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000004342 Benzoyl peroxide Substances 0.000 description 4
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 102000004243 Tubulin Human genes 0.000 description 4
- 108090000704 Tubulin Proteins 0.000 description 4
- 235000019400 benzoyl peroxide Nutrition 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 241001523681 Dendrobium Species 0.000 description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- QPHLRCUCFDXGLY-UHFFFAOYSA-N (3,4,5-trimethoxyphenyl)methanol Chemical compound COC1=CC(CO)=CC(OC)=C1OC QPHLRCUCFDXGLY-UHFFFAOYSA-N 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-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
- 240000004638 Dendrobium nobile Species 0.000 description 2
- 102000016942 Elastin Human genes 0.000 description 2
- 108010014258 Elastin Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- OQAGVSWESNCJJT-UHFFFAOYSA-N Methyl 3-methylbutanoate Chemical compound COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229920002549 elastin Polymers 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000012263 liquid product Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000029115 microtubule polymerization Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001792 phenanthrenyl group Chemical class C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- IYPQNHOFBMQJFX-UHFFFAOYSA-N 3,4,5-tris-decoxybenzaldehyde Chemical compound CCCCCCCCCCOC1=CC(C=O)=CC(OCCCCCCCCCC)=C1OCCCCCCCCCC IYPQNHOFBMQJFX-UHFFFAOYSA-N 0.000 description 1
- WUVFMWOVTWSINJ-UHFFFAOYSA-N 3-methylbutyl hydrogen sulfate Chemical compound CC(C)CCOS(O)(=O)=O WUVFMWOVTWSINJ-UHFFFAOYSA-N 0.000 description 1
- CYWHLOXWVAWMFO-UHFFFAOYSA-N 3-sulfanyl-1h-pyridine-2-thione Chemical compound SC1=CC=CN=C1S CYWHLOXWVAWMFO-UHFFFAOYSA-N 0.000 description 1
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- VLSMHEGGTFMBBZ-OOZYFLPDSA-M Kainate Chemical compound CC(=C)[C@H]1C[NH2+][C@H](C([O-])=O)[C@H]1CC([O-])=O VLSMHEGGTFMBBZ-OOZYFLPDSA-M 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000233855 Orchidaceae Species 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
- GUQSCTMNEWWGCC-UHFFFAOYSA-L [O-]OOOOOOOO[O-].[Na+].[Na+] Chemical compound [O-]OOOOOOOO[O-].[Na+].[Na+] GUQSCTMNEWWGCC-UHFFFAOYSA-L 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000000469 ethanolic extract Substances 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- JLHMVTORNNQCRM-UHFFFAOYSA-N ethylphosphine Chemical compound CCP JLHMVTORNNQCRM-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical class C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical class [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- XRBCRPZXSCBRTK-UHFFFAOYSA-N phosphonous acid Chemical class OPO XRBCRPZXSCBRTK-UHFFFAOYSA-N 0.000 description 1
- 150000008039 phosphoramides Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- VMXUWOKSQNHOCA-UKTHLTGXSA-N ranitidine Chemical compound [O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-UKTHLTGXSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- UNWUYTNKSRTDDC-UHFFFAOYSA-N tert-butylsilane Chemical compound CC(C)(C)[SiH3] UNWUYTNKSRTDDC-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-O triphenylphosphanium Chemical compound C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-O 0.000 description 1
- WLOQLWBIJZDHET-UHFFFAOYSA-N triphenylsulfonium Chemical compound C1=CC=CC=C1[S+](C=1C=CC=CC=1)C1=CC=CC=C1 WLOQLWBIJZDHET-UHFFFAOYSA-N 0.000 description 1
- 239000012953 triphenylsulfonium Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/20—Preparation of ethers by reactions not forming ether-oxygen bonds by hydrogenation of carbon-to-carbon double or triple bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)
Definitions
- the present invention relates to a process for the preparation of lanolin. Background technique
- Dihydrobenzidine and phenanthrene compounds in Dendrobium nobile have different degrees of inhibition on the growth of tumor cell line K 526 , especially the live 'I' of Erianin (DihydroCombretastatin A - 4 ). .
- Lanolin has antiprotonic effects on many tumor cells, and its target is the tubulin of cells. It inhibits the polymerization of tubulin, stimulates the hydrolysis of tubulin-dependent GTP, and competes with colchicine for binding proteins. Li Yunman et al.
- lanolin 2-decyloxy-5-[2-(3,4,5-trimethoxyphenyl)]ethylphenol
- the molecular formula is C 1S H 22 0 5
- the molecular weight is 318.35. Its chemical structure is shown in the following formula.
- the preparation method of lanolin is to extract lanolin from the traditional Chinese medicine Dendrobium using traditional Chinese medicine separation and extraction technology.
- Chinese Patent Application No. 03115752.1 discloses a method for extracting lanolin from sputum, including supercritical co 2 extraction and column chromatography using anhydrous ethanol, methanol, acetone, etc. as an entrainer, and co 2 as an extraction medium from orchidaceae.
- the anti-tumor component lanolin was extracted from the plant sarcophagus; the crude extract obtained was subjected to silica gel column chromatography separation and recrystallization by using petroleum ether: ethyl acetate solution as eluent to obtain a refined extract.
- sodium hydrogen hydride and sodium decoxide are used in the above reference, and potassium t-butoxide is used in the present invention.
- Sodium hydride is unstable, but sodium steroxide is more stable than potassium t-butoxide, mainly potassium t-butoxide is more alkaline, which is more conducive to witing reaction.
- the present invention crystallizes the cis-trans isomer.
- the next step is to facilitate accurate feeding, reduce the synthesis cost, and increase the yield (up to 80.48%, literature yield 72%).
- the invention is a by-product of direct recrystallization to remove liquid, which is simple and advanced, high in efficiency, and suitable for industrial production.
- the reaction of the present invention does not require high vacuum distillation distillation, high temperature and high pressure reaction with strict production conditions and low yield, the reaction reaction is mild, and there is no operation such as cumbersome and inefficient column chromatography; therefore, the yield per step Both are controlled above 80%, and the single step yield and overall yield are high.
- the kainate synthesis intermediate CA4 mentioned in the process of combretastatin synthesis (antitumor agent 291 cobstatin (A4, A5, A6) in 10,000 and synthetic JMed. Chem. 1995 George R. Pettit)
- a synthetic route in which tert-butylsilane (Si(CH3)2C(CH3)3) for phenolic hydroxyl protection is used.
- the benzyl protection of the present invention can be directly deprotected during the hydrogenation process.
- n-butyllithium is used, and potassium t-butoxide is used in the present invention. Potassium tert-butoxide is cheaper, safer and easier to handle. Summary of the invention
- the invention adopts the chemical synthesis method for the first time to prepare the lanolin, the chemical raw materials are simple and easy to obtain, the reagents used are also cheap, and it is suitable for industrial model production.
- the present invention provides a method of preparing lanolin comprising the steps of:
- step A2 hydrogenation reaction: the compound of the formula (III) obtained in the step A1 is subjected to a hydrogenation reaction with hydrogen to prepare a compound of the formula (IV), the reaction is carried out in an organic solvent, and the catalyst is a hydrogenation catalyst;
- X is a halogen selected from the group consisting of Cl, Br, I, wherein Br is preferred;
- R is a phenolic hydroxyl protecting group selected from the group consisting of a benzyl group, a tetrahydropyranyl group, an acetyl group, and a t-butyl group. Although only a few preferred protecting groups are listed above, in addition, many groups can be used as the phenolic hydroxyl protecting group, but among them, benzyl deprotection is most convenient, and therefore R is preferably a benzyl group in the present invention.
- the synthetic route is:
- the compound of the formula (I) is a 3,4,5-trimethoxybenzyl bromidetriphenylphosphine salt, and the compound of the formula ( ⁇ ) is a hydroxy-protected iso-vanillin, a formula (III)
- the compound is a cis-trans isomer.
- step A1
- the inert solvent used in the reaction is one or more selected from the group consisting of dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetonitrile, hexafluorophosphoramide, carbon tetrachloride, wherein Tetrahydrofuran is preferred.
- the base used in the reaction may generally include various salts, such as sodium carbonate, sodium carbonate, sodium hydride, potassium hydride, and the like, and similar bases; potassium t-butoxide, pyrimidine, various An organic base such as dimercaptopyridine, 4-dimethylaminopyridine, triethylamine or diisopropylethylamine and a similar base.
- organic bases such as potassium t-butoxide, diisopropylethylamine, triethylamine, diisopropylethylamine and the like are preferred.
- potassium t-butoxide is used as the base used in the reaction.
- the reaction system for the bonding reaction is stirred at room temperature for 5 minutes, cooled in a water bath, and a solution of the compound of the formula ( ⁇ ) is slowly added dropwise, and the mixture is stirred for 20 minutes, and then stirred at room temperature for 30 minutes.
- the organic solvents disclosed in the present invention are classified into aromatics, ketones, esters, and alcohols.
- the aromatic organic solvent includes benzene, toluene, xylene, styrene, etc.;
- the ketone organic solvent includes acetone, cyclohexanone, methyl ethyl ketone, etc.;
- the ester organic solvent includes ethyl acetate, butyl acetate, methyl isovalerate, etc.
- Alcohol organic solvents include decyl alcohol, ethanol, butanol, isopropanol and the like.
- the organic solvent is one or more selected from the group consisting of an ester organic solvent, an alcohol organic solvent, and the like, and a mixed solvent of ethyl acetate and ethanol is preferable.
- the hydrogenation catalyst is one or more selected from the group consisting of a palladium catalyst and a nickel catalyst, such as a palladium carbon catalyst and a nickel aluminum catalyst.
- a palladium catalyst and a nickel catalyst such as a palladium carbon catalyst and a nickel aluminum catalyst.
- palladium on carbon is selected as the hydrogenation catalyst.
- step A3
- R is a benzyl group
- the protecting group can be simultaneously removed in the hydrogenation reaction of the step A2. If other phenolic hydroxyl protecting groups, such as tetrahydrofuranyl, are used for protection, the protecting group can be removed by conventional deprotection methods in the art to give the final product, elastin.
- the compound (III) wherein R is a benzyl group is dissolved in ethyl acetate and absolute ethanol to obtain a pale yellow solution, and 5% palladium on carbon is added, and the mixture is stirred. 3 ⁇ 4, stirring at room temperature for 3 hr, filtered and concentrated to give a crude compound of compound I. White crystals.
- the compound of the above formula (I) can be produced from 3,4,5-trimethoxybenzaldehyde or 3,4,5-tridecyloxyindole according to a conventional synthesis method in the art.
- the synthesis method provided by the present invention may comprise the following steps:
- a compound of the formula (V) is prepared by a reducing agent to prepare a compound of the formula (VI); b, a compound of the formula (VI) is reacted with a halide to prepare a compound of the formula (VII); The compound of the formula (VII) is reacted with triphenylphosphine to prepare a compound of the formula (I).
- the synthetic route is:
- triphenylphosphine can also be replaced by ethyl phosphine to carry out a similar reaction to synthesize lanolin.
- step a the compound (V) is first dissolved in anhydrous ethanol at a temperature of 40 ( ⁇ 5) ° C, then sodium borohydride is added and heated to reflux; after the reaction is completed, deionized water, absolute ethanol, The mixture was washed with sodium hydroxide and dried over anhydrous magnesium sulfate, and evaporated to dryness
- step c triphenylphosphonium is added to the compound (VII), dissolved immediately, heated under reflux, suction filtered, and dried in vacuo to give 3,4,5-trimethoxybenzyl bromidetriphenylphosphonium salt (I). The acetone was washed to obtain a pure white solid.
- a compound of the formula (VII) is prepared by a method of brominating 3,4,5-trimethoxyantimonybenzene.
- the compound of the formula ((R) is obtained by protecting the hydroxyl group of the isovanillin ( ⁇ ) by an esterification method or a Si method, and is preferably protected with a benzyl group.
- the protecting group can be simultaneously removed in the hydrogenation reaction; if protected with a tetrahydropyranyl group or the like, the protecting group can be removed by other conventional methods in the art to obtain the final product, e.
- the compound of the formula (X) is a compound obtained by protecting a hydroxyl group of the isovanillin (VIII) with a benzyl group, which can be passed through
- the synthetic route is prepared:
- the isovanillin (VIII) should be heated to 40 ° C to be dissolved, potassium carbonate is added, benzyl chloride (IX) is added under stirring, and the mixture is heated to reflux. After the reaction is completed, it is cooled to 50. The solution was filtered while hot, and the filtrate was placed in a water tank to cool overnight. The crystals were precipitated, suction filtered, and dried in vacuo to give white crystals (X) as white crystals.
- the invention also provides another chemical synthesis method of lanolin, which comprises the following steps:
- X is a halogen selected from the group consisting of Cl, Br, I, preferably Br;
- R is a phenolic hydroxyl protecting group selected from the group consisting of a benzyl group, a tetrahydropyranyl group, an acetyl group, and a t-butyl group. Although only a few preferred protecting groups are listed above, in addition, many groups can be used as the phenolic hydroxyl protecting group, but among them, benzyl deprotection is most convenient, and therefore R is preferably a benzyl group in the present invention.
- the synthetic route is:
- the 3,4,5-trimethoxyantimonybenzene is brominated with N-bromosuccinimide (NBS) and benzoyl peroxide (BPO).
- NBS N-bromosuccinimide
- BPO benzoyl peroxide
- VII 3,4,5-trimethoxybenzyl bromide
- step B1
- Triethyl phosphite can also be replaced by other phosphorus reagents such as phosphonates, phosphonites, phosphine oxides, phosphoramides, etc., to carry out a similar reaction to synthesize lanolin.
- step B2
- the inert solvent used in the reaction is one or more selected from the group consisting of dioxane, tetrahydrofuran, dimethylformamide, dimercaptosulfoxide, acetonitrile, hexamethyl amide, carbon tetrachloride, wherein Tetrahydrofuran is preferred.
- the base used in the reaction may generally include various organic bases and inorganic bases, of which an organic base such as potassium t-butoxide, diisopropylethylamine, triethylamine, diisopropylethylamine or the like is preferable.
- an organic base such as potassium t-butoxide, diisopropylethylamine, triethylamine, diisopropylethylamine or the like is preferable.
- potassium t-butoxide is used as the base used in the reaction.
- compound (XI) and benzyl-protected iso-vanillin (II) are reacted in tetrahydrofuran containing potassium t-butoxide to form compound (III), washed, dried, concentrated, Recrystallize and set aside.
- step B3
- the organic solvent is one or more selected from the group consisting of an ester organic solvent, an alcohol organic solvent, and the like, and a mixed solvent of ethyl acetate and ethanol is preferred.
- the hydrogenation catalyst is one or more selected from the group consisting of a palladium catalyst and a nickel catalyst, such as a palladium carbon catalyst and a nickel aluminum catalyst.
- a palladium catalyst and a nickel catalyst such as a palladium carbon catalyst and a nickel aluminum catalyst.
- palladium on carbon is selected as the hydrogenation catalyst.
- step B4
- R is a benzyl group
- the protecting group can be simultaneously removed in the hydrogenation reaction of the step A2. If other phenolic hydroxyl protecting groups, such as tetrahydrofuranyl, are used for protection, the protecting group can be removed by conventional deprotection methods in the art to give the final product, elastin.
- Figure 1 is a nuclear magnetic resonance analysis spectrum (carbon spectrum) of the finished product of the preparation of the present invention
- Figure 2 is a nuclear magnetic resonance analysis spectrum (hydrogen spectrum) of the finished product of the lanolin prepared by the present invention
- Figure 3 is an infrared analysis spectrum of the finished product of the lanolin prepared by the present invention.
- Figure 4 - Figure 6 is a mass spectrometric analysis of the finished product of the lanolin prepared by the present invention.
- test materials used in the present invention are commercially available products unless otherwise specified.
- the obtained product was subjected to the next reaction without further purification. If you want to obtain a pure product, you can distill it under reduced pressure and collect BP216 - 218 °C / 12mmHg.
- the reaction product was diluted with 40 mmol of diethyl ether (if it was not completely dissolved, a small amount of dichloromethane was added), washed with water and washed with saturated sodium chloride. After the anhydrous stone was dried over sodium sulfate, the filtrate was concentrated to give a yellow product. It can be recrystallized from Zhengjikeng/ethyl acetate.
- the product after the bond formation reaction is 1.0 g, 5% palladium on carbon catalyst 0.25 g, ethanol 100 ml, at 70 to 75
- the invention adopts the chemical synthesis method for the first time to prepare the lanolin, the chemical raw materials are simple and easy to obtain, the reagents used are also cheap, the operation process is simple and safe, the product yield is high, and the product is suitable for industrial scale production.
- the above description of the preferred embodiments of the present invention is not intended to limit the scope of the invention, and those skilled in the art can make various changes or modifications in accordance with the present invention without departing from the spirit and scope of the invention.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cosmetics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
P T/CN2006/001649
毛兰素的制备方法
技术领域
本发明涉及毛兰素的制备方法。 背景技术
癌症已成为仅次于心血管疾病的人类第二类杀手。目前常用抗癌化疗与放 疗的方法可造成对人体不利的严重毒副反应。国内外的专家已发现中药石斛具 有抗肿瘤、抗衰老及扩张血管等作用,其乙醇提取物及其联苄类化合物具有不 同程度的体内抗肿瘤活性作用。 石斛的活性成分已引起国内外的关注。
王天山等的研究结果(鼓槌石斛中化学成分对 K562肿瘤细胞株生长抑制 作用体外试验, 天然产物研究与开发, 1997, 9 (2 ), 1 ~3 )表明, 联苄类和 菲类化合物对体外培养的鼠类 Lm。微管蛋白的聚集及有丝分裂、 P388细胞株、 多 种人体肿瘤细胞株如 A - 549、 MCF - 7、 HT - 29 : SKMEL - 5、 MLM、 SK - OV - 3、 HL - 60均有抑制作用。 鼓槌石斛中的二氢联苄类和菲类化合物对肿 瘤细胞林 K526的生长具有不同程度的抑制作用, 尤以毛兰素 (Erianin、 DihydroCombretastatin A - 4 ) 的活' I"生最强。
毛兰素对小鼠肝癌的作用最强, 抑瘤率为 50.82%。有关研究(中国药科大 学学报, 1994, 25 (3 ), 188-189 )还推测毛兰素的毒副作用远低于肿瘤化疗 药物 5FU。 毛兰素对许多肿瘤细胞有反质子作用, 其作用的靶点是细胞的微管 蛋白。 它能抑制微管蛋白的聚合, 刺激依赖微管蛋白的 GTP的水解, 且和秋水 仙碱竟争性结合蛋白。 李运曼等的研究表明 (毛兰素诱导人白血病 HL - 60细 胞的凋亡, 中国药理学报, 2001 , 22 (11 ) ) , 毛兰素显著抑制人类白血病 HL - 60细胞的生长, 其抑制作用可能是通过诱导细胞凋亡和改变 HL - 60细胞 的 bcl - 2和 bax基因表达而实现的。
毛兰素
目前,毛兰素的制备方法均为采用中药分离提取技术从中药石斛中提取毛 兰素。 中国专利申请 03115752.1公开了 斛中提取毛兰素的方法, 包括应 用超临界 co2萃取和柱层析法以无水乙醇、 甲醇、 丙酮等为夹带剂, 以 co2 等为提取介质从兰科植物石斛中提取抗肿瘤成分毛兰素;对所得的粗提物再以 石油醚:醋酸乙酯溶液为洗脱剂进行硅胶柱柱层析分离及重结晶等步骤获得精 提物。
由于上述提取方法对技术要求较高, 且其原料石斛的来源较紧缺, 不利于 大规模生产。
另外相关文献 2-二苯乙烯和双氢化 1 , 2-二苯乙烯衍生物的合成和作 为抑制微管聚合的潜在抗肿瘤剂的价值 J.Med.Chem.1991 Mark Cushman )中涉 及到 1 , 2-二苯乙晞类化合物的合成, 但没有具体涉及到毛兰素的合成。 而且 没有详细的中间体合成工艺、 收率等信息。 文中酚羟基保护采用叔丁基硅烷 ( silyloxylated ) , 本发明主要是苄基保护, 这样在脱保护基可以在后面的加 氢反应中一起完成。 加氢脱苄更简单易行,适合工业生产。 另外在 witing反应 中, 上述参考文献中用氢钠和曱醇钠, 本发明用的是叔丁醇钾。 氢钠不稳定, 但曱醇钠比叔丁醇钾稳定 ,主要是叔丁醇钾碱性更强,更利于 witing反应进行。
有失毛生素合 的 献(烷氧基取代二芳基化合物的合成和与微管聚合抑 制作用的环分离的相互作用:在最适度聚合反应条件下的抑制作用的不同的增 强作用。 J.Med.Chem.1992 Zelleka Getahun ) , 其反应原料和本发明不同,本发 明以 3.4.5-三曱氧基苯甲醛和异香兰素为原料,都是在原料市场上经常用到的 , 价格低廉, 既可以购买也可以自己生产,避免因原料价格的浮动对产品成本产 生大的影响。文献中合成中间体顺反异构体后没有将其结晶出来,直接做下去, 不利于下一步反应的进行和本步收率的计算,本发明是将顺反异构体结晶出来
T N2 06/001649 后进行下一步, 便于精确的投料, 降低合成成本, 提高收率(达 80.48 % , 文 献收率 72 % ) 。 文献中加氢还原后还需要过柱纯化, 效率低, 本发明是直接 做重结晶除去液体的副产物氯化苄,操作简单先进,效率高,适合工业化生产。 由于本发明反应中没有对生产条件要求苛刻、收率低的高真空蒸馏精馏、 高温 高压反应, 反应奈件温和, 也没有操作繁琐、 效率低下的柱层析等操作; 所以 每步收率都控制在 80 %以上, 单步收率和整体收率艮高。
在考布他汀合成的工艺 (抗肿瘤剂 291 考布他汀 (A4, A5, A6 ) 的分萬 和合成 JMed.Chem.1995 George R. Pettit )中提到的毛兰素合成的中间体 CA4 的合成路线, 其中酚羟基保护用的叔丁基硅烷(Si(CH3)2C(CH3)3 ) 。 本发明 的苄基保护, 可以在氢化过程中直接脱保护。 文献 witting反应中用正丁基锂, 本发明用叔丁醇钾。 叔丁醇钾更便宜更安全, 且操作简便。 发明内容
本发明的目的在于提供一种毛兰素的制备方法。本发明首次采用化学合成 方法制备毛兰素, 其化学原料简便易得, 所用试剂也较便宜, 适宜工业见模生 产。
根据本发明的目的, 本发明提供了一种毛兰素的制备方法,其包括下述步 驟:
Al、 成键反应: 使通式(I ) 的化合物与通式(Π ) 的化合物发生成键反 应, 制备得到式(III ) 的化合物, 反应在含碱的惰性溶剂中进行;
A2、 加氢反应: 使由步驟 A1得到的式(III )的化合物与氢气发生加氢反 应, 制备得到式(IV )的化合物, 反应在有机溶剂中进行, 催化剂为加氢催化 剂;
A3、 羟基脱保护反应: 使由步骤 A2得到的式(IV )的化合物的羟基保护 基 R脱去, 制备得到毛兰素。
其中, X为选自 Cl、 Br、 I的卤素, 其中优选 Br;
R为选自苄基、 四氢吡喃基、 乙酰基、 叔丁基的酚羟基保护基。 以上只是 列举了几种较佳的保护基, 此外还有很多基团可用作酚羟基保护基,但是其中 苄基脱保护最为方便, 因此在本发明中 R优选为苄基。
N2006/001649
合成路线为:
在步骤 A1中:
反应中所用的惰性溶剂为选自二氧杂环己烷、 四氢呋喃、 二甲基曱酰胺、 二甲基亚砜、 乙腈、 六曱基磷酰胺、 四氯化碳的一种或多种, 其中优选四氢呋 喃。
反应中所用的碱通常可包括各种有才/W成和无才 W咸, 例如碳酸钠、 碳酸甲、 氢化钠、 氢化钾等无机碱及类似的碱; 叔丁醇钾、 嘧啶、 各种二曱基吡啶、 4 -二甲基氨基吡啶、 三乙胺、二异丙基乙胺等有机碱及类似的碱。 其中优选有 机碱, 如叔丁醇钾、 二异丙基乙胺、 三乙胺、 二异丙基乙胺等。 在本发明的一 个优选实施方案中, 选用叔丁醇钾作为本反应所用的碱。
在本发明的一个优选实施方式中,成键反应的反应体系在室温搅拌 5min, 水浴冷却,緩慢滴加式(Π )的化合物的溶液, 20min滴完,再室温搅拌 30min, 反应完全后, 乙醚萃取, 干燥, 过滤, 浓缩至干, 得油状物, 用无水乙醇固化, 抽滤得淡黄色固体; 再用无水乙醇加热溶解后, 室温搅拌, 抽滤, 洗涤, 红外 灯干燥, 得淡黄色粉末固体, 即纯的式(III ) 的顺反异构体。
在步骤 A2中:
本发明所迷的有机溶剂分为芳香族类、 酮类、 酯类和醇类。 芳香族类有机 溶剂包括苯、 甲苯、 二甲苯、 苯乙烯等; 酮类有机溶剂包括丙酮、 环乙酮、 甲 乙酮等; 酯类有机溶剂包括醋酸乙酯、 醋酸丁酯、 异戊酸甲酯等; 醇类有机溶 剂包括曱醇、 乙醇、 丁醇、 异丙醇等。
步骤 A2中, 所述有机溶剂为选自酯类有机溶剂、 醇类有机溶剂等的一种 或多种, 其中优选乙酸乙酯和乙醇的混合溶剂。
所述加氢催化剂为选自钯系催化剂、镍系催化剂的一种或多种, 如钯炭催 化剂、镍铝催化剂。 在本发明的一个优选实施方式中, 选用钯炭作为加氢催化 剂。
在步骤 A3中:
优选的, R为苄基, 当 R为苄基时, 可在步骤 A2的加氢反应中同时去除 保护基。 若用其它酚羟基保护基, 如四氢呋喃基等保护, 可用本领域的常规脱 保护基的方法去除保护基, 得到最终产物毛兰素。
在本发明的一个优选实施方式中,加氢反应时,将 R为苄基的化合物( III ) 溶解在乙酸乙酯和无水乙醇中, 得淡黄色溶液, 加入 5%钯炭, 搅拌下通 ¾, 室温搅拌 3hr, 过滤, 浓缩, 得油状物式 I化合物粗品; 再用无水乙醚溶解、 过滤, 室温静止, 有晶体析出, 并放置过夜, 过滤, 滤饼用乙醚洗涤, 得到毛 兰素的白色晶体。
进一步的,上述式(I )的化合物,可按照本领域的常规合成方法, 由 3,4,5- 三甲氧基苯甲醛或者 3,4,5-三曱氧基曱苯制备得到。
当采用 3,4,5-三曱氧基苯曱醛为起始原料时, 本发明提供的合成方法可包 括下述步骤:
a、 使式(V )的化合物在还原剂的作用下, 制备得到式(VI )的化合物; b、 使式(VI ) 的化合物与卤化物反应, 制备得到通式(VII ) 的化合物; c、 使式(VII ) 的化合物与三苯基膦反应, 制备得到通式(I )的化合物。 合成路线为:
(V) (VI) (VII) (')
在步骤 c中, 三苯基膦还可以被乙基膦代替, 进行相似的反应, 从而合成 毛兰素。
在本发明的一个具体实施方式中:
步骤 a中, 化合物(V) 需先在无水乙醇中加热溶解, 温度在 40 ( ±5) °C, 再加入硼氢化钠并加热回流; 反应完全后, 用去离子水、 无水乙醇、 氢氧 化钠洗涤, 并用无水硫酸镁干燥过夜, 并用旋转蒸发仪浓缩至干, 得无色油状 物的化合物 (VI); 减压蒸馏可纯化。
步骤 b中,将等量的三溴化磷溶于二氯曱烷中,緩慢滴加到溶解有化合物 (VI) 的二氯甲烷中,.室温反应 50min后, 水浴冷却, 再洗涤、 浓缩、 干燥; 用乙酸乙酯正己烷 =1: 3重结晶, 可得到白色片状晶体(VII )。
步骤 c中, 向化合物 (VII) 中加入三苯基瞵, 立即溶解, 加热回流并抽 滤、 真空干燥得 3,4,5-三甲氧基苄溴三苯基膦盐(I), 可以用丙酮洗涤, 得白 色粉末固体的纯品。
在本发明的另一个具体实施方式中, 采用将 3,4,5-三曱氧基曱苯溴化的方 法, 制备得到式(VII) 的化合物。
式( Π )的化合物为用酯化法或 si化法等保护异香兰素( νιπ )的羟基所得, 其中优选用苄基保护。
若用苄基保护,可在加氢反应中同时去除保护基;若用四氢吡喃基等保护, 可用本领域的其它常规方法去除保护基, 得到最终产物毛兰素。
进一步的, 当通式(Π) 中的 R为苄基时, 为式(X) 的化合物, 即是将 异香兰素(VIII) 中的羟基用苄基保护所得到的化合物, 其可以通过下述合成 路线制备得到:
在本发明的一个优选实施方式中, 异香兰素(VIII)应加热到 40°C待溶解 后, 加入碳酸钾, 搅拌下加入氯化苄(IX), 加热回流, 反应完全后, 冷却到 50°C 趁热过滤, 滤液放入水箱中冷却过夜, 晶体析出, 抽滤, 真空干燥后, 得白色针状晶体化合物 (X); 可以用无水乙醇重结晶, 得到白色柱状晶体。
本发明还提供了另一种毛兰素的化学合成方法, 其包括下述步骤:
Bl、 使式(VII)的化合物与亚磷酸三乙酯 ((C2H50)3P)反应, 制备得到 式(XI) 的化合物, 反应在芳香族类有机溶剂中进行;
B2、 使式(XI)的化合物与式(II)的化合物反应, 制备得到式(III)的 化合物, 反应在含碱的惰性溶剂中进行;
B3、 使式(III) 的化合物与氢气发生加氢反应, 制备得到式 (IV) 的化 合物, 反应在有机溶剂中进行, 催化剂为加氢催化剂;
B4、 使由步骤 B3得到的式(IV)的化合物的羟基保护基 R脱去, 制备得 到毛兰素;
其中, X为选自 Cl、 Br、 I的卤素, 优选 Br;
R为选自苄基、 四氢吡喃基、 乙酰基、 叔丁基的酚羟基保护基。 以上只是 列举了几种较佳的保护基,此外还有很多基团可用作酚羟基保护基,但是其中 苄基脱保护最为方便, 因此在本发明中 R优选为苄基。
合成路线为:
在本发明的一个具体实施方式中, 使 3,4,5-三曱氧基曱苯与 N -溴代丁二 酰亚胺(NBS )和过氧化苯曱酰(BPO )发生溴代反应, 制备得到 3,4,5-三甲 氧基溴化苄 (VII ), 反应在诸如四氯化碳的惰性溶剂中进行。
在步骤 B1中:
亚磷酸三乙酯还可被其它磷试剂, 如膦酸酯、 亚膦酸酯、 氧化膦、 磷酰胺 等代替, 进行相似的反应, 从而合成毛兰素。
在本发明的一个具体实施方式中, 3,4,5-三曱氧基溴化苄(VII )和亚磷酸 三乙酯在甲苯中搅拌回流反应 10 ~ 14小时, 稍冷却后, 减压蒸餾, 蒸去曱苯 和亚磷酸三乙酯, 得液体产物 (XI )。
在步骤 B2中:
反应中所用的惰性溶剂为选自二氧杂环己烷、 四氢呋喃、 二甲基甲酰胺、 二曱基亚砜、 乙腈、 六曱基碑酰胺、 四氯化碳的一种或多种, 其中优选四氢呋 喃。
反应中所用的碱通常可包括各种有机碱和无机碱,其中优选有机碱,如叔 丁醇钾、 二异丙基乙胺、 三乙胺、 二异丙基乙胺等。 在本发明的一个优选实施 方案中, 选用叔丁醇钾作为本反应所用的碱。
在本发明的一个具体实施方式中, 使化合物(XI )和苄基保护的异香兰素 ( II )在含叔丁醇钾的四氢呋喃中反应, 生成化合物 (III ), 经洗涤、 干燥、 浓缩、 重结晶后备用。
在步骤 B3中:
所述有机溶剂为选自酯类有机溶剂、醇类有机溶剂等的一种或多种, 其中 优选乙酸乙酯和乙醇的混合溶剂。
所述加氢催化剂为选自钯系催化剂、镍系催化剂的一种或多种, 如钯炭催 化剂、镍铝催化剂。在本发明的一个优选实施方式中, 选用钯炭作为加氢催化 剂。
在步骤 B4中:
优选的, R为苄基, 当 R为苄基时, 可在步骤 A2的加氢反应中同时去除 保护基。 若用其它酚羟基保护基, 如四氢呋喃基等保护, 可用本领域的常规脱 保护基的方法去除保护基, 得到最终产物毛兰素。
以下, 结合附图, 通过对本发明具体实施方式的描述, 详细说明而不限制 本发明。 附图的简要说明
图 1为本发明制备的毛兰素成品的核磁共振分析图谱(碳谱);
图 2为本发明制备的毛兰素成品的核磁共振分析图谱(氢谱);
图 3为本发明制备的毛兰素成品的红外分析图谱。
图 4 -图 6为本发明制备的毛兰素成品的质谱分析图谱。 发明的具体实施方式
本发明所用的试验材料, 如无特别说明, 均为市售购买产品。
【实施例 1】毛兰素的化学合成
1、 3,4,5-三曱氧基苯甲醇的制备
250ml的三颈瓶中, 加入 3,4,5-三甲氧基苯甲醛 15g ( 76.45mmol ), 200ml 的无水乙醇, 加热 40。C溶解, 再加入硼氢化钠 1.48g ( 38.23mmol ), 加热回流 45min 后, TLC 检测, 反应完全后, 冷却至室温, 加入去离子水 10ml
( 555.8mmol ), 淬灭后, 抽滤, 滤渣用 20ml无水乙醇洗涤, 合并滤液后, 用 旋转蒸发仪浓缩至干, 加入 100ml二氯甲烷溶解, 用 2N氢氧化钠溶液 50ml χ 2洗涤, 再用去离子氷 50ml X 2洗涤, 加入适量的无水硫酸镁干燥过夜。 过 滤, 用 20ml二氯曱垸洗涤滤渣,合并滤液, 用旋转蒸发仪浓缩至干, 得 3,4,5- 三甲氧基苯甲醇, 无色油状物 14.05g, 收率 92.72%。
得到的产物不需要进一步純化, 即可进行下一步反应。 若想得到纯品可 以减压蒸馏, 收集 BP216 - 218°C/12mmHg的镏分。
2、 3,4,5-三曱氧基苄溴的制备
3,4,5-三甲氧基苯曱醇 14.05g ( 70.89mmol ), 用 100ml二氯甲烷溶解, 加 入到 250ml的三颈瓶中, 三溴化磷 6.73ml ( 70.89mmol )溶于 25ml二氯曱烷 中, 室温反应 50min后, 冰浴冷却, 緩慢滴加 18ml去离子水 18ml ( l.Omol ), 淬灭反应。 然后再用 100 mi x 2去离子水洗涤, 无水 u酸镁干燥, 过滤, 用 20ml二氯甲烷洗涤滤渣, 合并滤液, 用旋转蒸发仪浓缩至干, 真空干燥, 得 3,4,5-三甲氧基苄淡, 淡黄色固体 16.05g, 收率 84.44%。
得到的产物不需要进一步纯化, 即可进行下一步反应。 若想得到纯品可 以用乙酸乙酯: 正己烷 =1: 3重结晶, 得到白.色片状晶体。
3、 3,4,5-三甲氧基苄溴三苯基膦盐的制备
3,4,5-三曱氧基苄溴 16.05g( 61.47mmol )溶于 150ml甲苯中 ,加入到 250ml 的三颈瓶中, 加入三苯基瞵 16,12g ( 61.47mmol ), 立即溶解, 加热回流 lhr, 有白色固体析出, 冷却到室温, 抽滤, 滤饼用 30ml曱苯洗涤, 真空干燥后, 得 3,4,5-三甲氧基苄溴三苯基膦盐, 白色粉末固体 27.81g, 收率为 86.44% 得到的产物不需要进一步纯化, 即可进行下一步反应。若想得到纯品可以 用丙酮洗涤固体, 得白色粉末固体。
4、 苄基保护异香兰素的制备
250ml三颈瓶中, 加入异香兰素 15g ( 98.59mmol ), 200ml无水乙醇, 加 热到 40 °C溶解, 加入碳酸钾 9g ( 65.07mmol ), 搅拌下加入氯化苄 15ml ( 130.13mmol ), 加热回流 lhr, TLC检测反应完全后, 冷却到 5(TC , 趁热过 滤, 滤液放入水箱中冷却过夜, 晶体析出, 抽滤, 滤饼用 30ml无水乙醇洗涤, 真空干燥后, 得苄基保护异香兰素, 白色针状晶体 19.72g, 收率为 82.56%。
P T/CN2006/001649 得到的产物不需要进一步纯化, 即可进行下一步反应。 若想得到纯品可以 用无水乙醇重结晶, 得到白色柱状晶体。 -
5、 顺反异构体的制备
250ml 三颈瓶中, 加入 3,4,5-三曱氧基苄溴三苯基磷盐 20.00g ( 38.21mmol ), 150ml 四氢呋喃, 搅拌悬浮液, 苄基保护异香兰素 lO.OOg ( 41.27mmol )溶于 70ml四氢呋喃, 放入 100ml的滴液漏斗中。 反应瓶中加 入固体叔丁醇钾 7.46g ( 66.49mmol ), 反应体系变为血红色, 室温搅拌 5min, 緩慢滴加苄基保护异香兰素的溶液,再室温搅拌 20min, TLC检测反应完全后, 倒入 500ml的分液漏斗中,加入 140ml去离子水后,溶液分层,加入乙醚 300ml x 2萃取, 合并乙醚层, 用无水硫酸镁干燥, 过滤, 滤饼用 50m】 乙醚洗涤, 滤液旋转蒸发仪浓缩至干, 得油状物 25g, 加入 20ml无水乙醇固化, 抽滤得 淡黄色固体 12.50g, 收率为 80.48%。
6、 顺反异构体的重结晶
50ml 的圆底烧瓶中, 加入顺反异构本 12.50g ( 30J5mmol ), 加入 20ml 无水乙醇, 加热部分固体溶解后, 室温搅拌, 抽滤, 滤饼用 10ml的无水乙醚 洗涤后,红外灯干燥,得纯顺反异构体 9.27g,淡黄色粉末固体,收率为 74.16%。
7、 毛兰素的制备
250ml的三颈瓶中, 加入纯顺反异构体 5.14g ( 12.56mmol ), 溶于 100ml 乙酸乙酯和 60ml无水乙醇中, 淡黄色溶液, 加入 5%4巴炭 0.50g后, 搅拌下通 氢气,室温搅拌 lhr,过滤,得无色滤液,旋转蒸发仪浓缩至干,得油状物 4.05g, 毛兰素粗品, 收率为 100%。
8、 毛兰素的精制
500ml的圆^烧瓶中, 加入毛兰素粗品 4.05g ( 12.72mmol ), 用 20ml无 水乙醇溶解, 若有不溶物, 过滤除去, 室温静止, 有晶体析出, 放置过夜, 溶 剂挥发完全, 大量白色晶体析出。 过滤, 滤饼用乙醇洗涤, 白色晶体 3.56g, 收率为 100%。
毛兰素成品的物理性质测定结果:
( 1 ) 熔点: 76-77摄氏度
( 2 ) 核磁共振分析:
仪器: Avance DMX500 溶剂: 氘代曱醇, 结果见图 1和图 2。
( 3 ) 红外分析:
仪器: Nicolet E.S.P560型, 结果见图 3。
(4) 质谱分析:
仪器: HP6890/5973 GC/MS联用仪, 结果见图 4 ~图 6。
由以上分析结果可见, 按照本发明方法制备获得了毛兰素成品,
【实施例 2】毛兰素的化学合成
1、 3,4,5-三曱氧基曱苯的溴化
将 lOmmol 3,4,5-三曱氧基曱苯加入 50ml的三口烧瓶中, 加入 20ml四氯 化碳, 加热搅拌至油浴 82 84 °C , 使反应液回流, 然后分批加入 lOmmol的 N -溴代丁二酰亚胺( NBS )和 0.5mmol过氧化苯曱酰( BPO )的混合物, 加料 时间约为 10min, 加完后继续搅拌反应 20min, 然后过滤。 滤液经水洗、 饱和 氯化钠溶液洗,无水硫酸镁干燥后过滤,滤液蒸干后过柱,收集极性最大组分, 得到产物 3,4,5-三曱氧基溴化苄。
2、 与亚磷酸三乙酯反应
lOmmol 3,4,5-三甲氧基溴化苄, 50mmol亚磷酸三乙酯, 40ml的甲苯, 搅 拌回流反应 12hr。 稍冷却后, 减压蒸馏, 蒸去甲苯和亚磷酸三乙酯 (10 ~ 20mmHg/80°C ), 得液体产物 ( XI )。
3、 成键反应
3.1 异香兰素的苄基保护
将异香兰素 6.6mmol、苄氯 13.9 mmol、无水碳酸钟 4.7 mmol、 乙醇 15ml, 混合搅拌回流 5hr。 反应结束后浓缩, 然后重新溶解在 10ml的 CHzCL中, 5% 的氢氧化钠溶液洗( 3 10ml ), 然后有机层用饱和氯化钠溶液( 2 X 10ml )、 水(2 x 10ml ) 洗, 最后用无水硫酸钠干燥。 滤液浓缩得产物。 产物在甲醇 / 二氯甲烷中重结晶。
3.2苄基保护的异香兰素反应
将第二步反应产物 10mmol、 苄基保护的异香兰素 10mmol、 30ml四氢呋 喃( THF ),升温至回流并搅拌, 然后分批加入 12mmol叔丁醇钾( t - BuOK ),
防止剧烈沸腾。 加完后继续反应 lhr。 反应产物用 40mmol乙醚稀释(若没完 全溶解, 可加少量二氯甲烷), 水洗、 饱和氯化钠洗。 无水石充酸钠干燥后, 滤 液浓缩得黄色产物。 可用正己坑 /乙酸乙酯重结晶。
4、 力口氢反应
将成键反应后的产物 1.0g、 5%钯炭催化剂 0.25g、 乙醇 100ml、 在 70 ~ 75
°C的油浴下, 搅拌下并通氢气 lhr。 然后过滤, 滤液浓缩后得黄色粘稠液体。 将此黄色液体过柱, 得白色固体产物毛兰素。 工业应用性
本发明首次采用化学合成方法制备毛兰素,其化学原料简便易得, 所用试 剂也较便宜, 操作工艺简单安全, 产物收率高, 适宜工业规模生产。 以上对本发明较佳实施方式的描述并不限制本发明,本领域技术人员可以 根据本发明作出各种改变或变形, 只要不脱离本发明的精神, 均应属于本发明 所附权利要求的范围。
Claims
1、 一种毛兰素的制备方法, 其特征在于, 包括下述步骤:
Al、 使通式(I )的化合物与通式(II )的化合物发生成键反应, 制备得 到式(III ) 的化合物, 反应在含碱的惰性溶剂中进行;
A2、 使由步驟 A1得到的式(III ) 的化合物与氢气发生加氢反应, 制备 得到式(IV ) 的化合物, 反应在有机溶剂中进行, 催化剂为加氢催化剂;
A3、 使由步骤 A2得到的式(IV )的化合物的羟基保护基 R脱去, 制备 得到毛兰素;
其中, X为选自 Cl、 Br、 I的卤素;
R为选自苄基、 四氢吡喃基、 乙酰基、 叔丁基的酚羟基保护基; 合成路线为:
2、 权利要求 1所述的制备方法, 其特征在于, 在步骤 A1中, 所述惰性溶剂为选自二氧杂环己烷、 四氢呋喃、 二甲基甲酰胺、 二甲基 亚砜、 乙腈、 六曱基碑酰胺、 四氯化碳的一种或多种;
所述碱为有机碱。
3、权利要求 2所述的制备方法,其特征在于,所述惰性溶剂为四氢呋喃,
所述碱为叔丁醇钾。
4、 权利要求 1所述的制备方法, 其特征在于, 在步骤 A2中,
所述有机溶剂为选自酯类有机溶剂、 醇类有机溶剂的一种或多种; 所述加氢催化剂为选自钯系催化剂、 镍系催化剂的一种或多种。
5、权利要求 4所述的制备方法, 其特征在于, 所述有机溶剂为乙酸乙酯 和乙醇的混合溶剂; 所述加氢催化剂为钯炭。
6、 权利要求 1所述的制备方法, 其特征在于, R为苄基, 当 R为苄基 时, 在步骤 A2的加氢反应中同时去除保护基。
7、 权利要求 1所述的制备方法, 其特征在于, 从 3,4,5-三曱氧基苯曱醛 制备得到所述式(I) 的化合物; 或者从 3,4,5-三曱氧基曱苯制备得到所述式
(I) 的化合物。
8、 权利要求 7所述的制备方法, 其特征在于, 其包括下述步骤: a、使式(V)的化合物在还原剂的作用下, 制备得到式(VI)的化合物; b、 使式(VI) 的化合物与卤化物反应, 制备得到式(VII) 的化合物; c、 使式(VII) 的化合物与三苯基膦反应, 制备得到式(I) 的化合物; 合成路线为:
(V) (VI) (VII)
9、 权利要求 1所述的制备方法, 其特征在于, R为苄基时, 使式(VIII) 的异香兰素和式(IX) 的氯化苄反应, 制备得到式(X) 的化合物;
其合成反应式为:
10、 一种毛兰素的制备方法, 其特征在于, 包括下述步骤:
Bl、 使式(VII) 的化合物与亚磷酸三乙酯 ((C2H50)3P)反应, 制备得 到式(XI) 的化合物, 反应在芳香族类有机溶剂中进行;
B2、 使式(XI) 的化合物与式(II) 的化合物反应, 制备得到式(III) 的化合物, 反应在含碱的惰性溶剂中进行;
B3、 使式(III)的化合物与氢气发生加氢反应, 制备得到式(IV)的化 合物, 反应在有机溶剂中进行, 催化剂为加氢催化剂;
B4、 使由步骤 B3得到的式(IV)的化合物的羟基保护基 R脱去, 制备 得到毛兰素;
其中, X为选自 Cl、 Br、 I的卤素;
R为选自苄基、 四氢吡喃基、 乙酰基、 叔丁基的酚羟基保护基; 合成路线为:
11、 权利要求 10所述的制备方法, 其特征在于,
在步骤 B2中,
• 所述惰性溶剂为选自二氧杂环己烷、 四氢呋喃、 二甲基甲酰胺、 二曱基 亚砜、 乙腈、 六曱基磷酰胺、 四氯化碳的一种或多种,
所述碱为有机碱;
在步骤 B3中,
所述有机溶剂为选自酯类有机溶剂、 醇类有机溶剂的一种或多种 , 所述加氢催化剂为选自钯系催化剂、 镍系催化剂的一种或多种。
12、 权利要求 11所述的制备方法, 其特征在于,
在步骤 B2中, 所述惰性溶剂为四氢呋喃, 所述碱为叔丁醇钾; 在步骤 B3 中, 所述有机溶剂为乙酸乙酯和乙醇的混合溶剂, 所述加氢 催化剂为钯炭。
13、 权利要求 10所述的制备方法, 其特征在于, R为苄基, 当 R为苄 基时, 在步骤 B3的加氢反应中同时去除保护基。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/995,672 US7897820B2 (en) | 2005-07-13 | 2006-07-12 | Process for preparing erianin |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2005100830554A CN1896042B (zh) | 2005-07-13 | 2005-07-13 | 毛兰素的制备方法 |
CN200510083055.4 | 2005-07-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007006230A1 true WO2007006230A1 (fr) | 2007-01-18 |
Family
ID=37608720
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2006/001649 WO2007006230A1 (fr) | 2005-07-13 | 2006-07-12 | Procédé de préparation d’érianine |
Country Status (3)
Country | Link |
---|---|
US (1) | US7897820B2 (zh) |
CN (1) | CN1896042B (zh) |
WO (1) | WO2007006230A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101735888B (zh) * | 2009-12-09 | 2012-09-26 | 浙江森宇实业有限公司 | 一种铁皮石斛花挥发油的提取方法 |
CN113956122A (zh) * | 2021-11-24 | 2022-01-21 | 广西师范大学 | 一种基于绿色化学的有机合成方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5430062A (en) * | 1992-05-21 | 1995-07-04 | Research Corporation Technologies, Inc. | Stilbene derivatives as anticancer agents |
US6759555B2 (en) * | 2002-04-11 | 2004-07-06 | Aventis Pharma S.A. | Process for the preparation of combretastatins |
CN1660745A (zh) * | 2004-12-23 | 2005-08-31 | 中国科学院广州化学研究所 | 3-羟基-4,3',4',5'-四甲氧基联苄的制备方法 |
CN1704393A (zh) * | 2004-05-25 | 2005-12-07 | 浙江大德药业集团有限公司 | 聚合物固载合成康博泰定 |
-
2005
- 2005-07-13 CN CN2005100830554A patent/CN1896042B/zh not_active Expired - Fee Related
-
2006
- 2006-07-12 WO PCT/CN2006/001649 patent/WO2007006230A1/zh active Application Filing
- 2006-07-12 US US11/995,672 patent/US7897820B2/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5430062A (en) * | 1992-05-21 | 1995-07-04 | Research Corporation Technologies, Inc. | Stilbene derivatives as anticancer agents |
US6759555B2 (en) * | 2002-04-11 | 2004-07-06 | Aventis Pharma S.A. | Process for the preparation of combretastatins |
CN1704393A (zh) * | 2004-05-25 | 2005-12-07 | 浙江大德药业集团有限公司 | 聚合物固载合成康博泰定 |
CN1660745A (zh) * | 2004-12-23 | 2005-08-31 | 中国科学院广州化学研究所 | 3-羟基-4,3',4',5'-四甲氧基联苄的制备方法 |
Non-Patent Citations (1)
Title |
---|
GETAHUN Z. ET AL.: "Synthesis of Alkoxy-Substituted Diaryl Compounds and Correlation of Ring Separation with Inhibition of Tubulin Polymerization Differential Enhancement of Inhibitory Effects under Suboptimal Polymerization Reaction Conditions", J. MED. CHEM., vol. 35, no. 6, 1992, pages 1058 - 1067, XP002906721 * |
Also Published As
Publication number | Publication date |
---|---|
US7897820B2 (en) | 2011-03-01 |
US20090018369A1 (en) | 2009-01-15 |
CN1896042A (zh) | 2007-01-17 |
CN1896042B (zh) | 2010-12-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108689968B (zh) | 两种化合物及其制备方法和在合成布瓦西坦中的用途 | |
CN103476762B (zh) | 用于生产曲前列环素的中间体的合成 | |
JPS59219256A (ja) | フエノ−ル誘導体、その製法及びこの化合物を含む発情抑制剤 | |
JPH06100485A (ja) | 新規なアルケン誘導体の製造法 | |
US6552213B1 (en) | Stereoselective route to produce tris-O-substituted-(E)-1-(3,5-dihydroxyphenyl)-2-(4-hydroxyphenyl)ethene, an intermediate in the synthesis of trans-resveratrol | |
HU200742B (en) | Process for producing new alkane and alkene halides and pharmaceutical compositions comprising same | |
US20080306028A1 (en) | Erianin Salts, Their Preparation Methods and Pharmaceutical Compositions Containing the Same | |
CN106573904A (zh) | 用于产生贝前列素及其衍生物的方法 | |
CA1110261A (en) | 3-¬2-hydroxy-4-(substituted)phenyl|-cycloalkanone and cycloalkanol analgesic agents and intermediates therefor | |
WO2007006230A1 (fr) | Procédé de préparation d’érianine | |
DE60121809T2 (de) | Materialien und verfahren zur herstellung von stilbenen | |
CN1948274B (zh) | 白藜芦醇衍生物及其制备方法和用途 | |
CN110240539B (zh) | 一种氟取代二苯乙烷类化合物及制备方法和应用 | |
JPH01249783A (ja) | 新規安息香酸誘導体及びその製造方法 | |
CN106278857A (zh) | α,β‑不饱和羰基四氢萘酮衍生物及其应用 | |
Bauer et al. | Sugar-based monodentate phosphoramidite ligands for Cu-catalyzed enantioselective conjugate addition to enones | |
CN110526805B (zh) | 一种氟取代二苯乙烷衍生物及制备方法和应用 | |
JP2846418B2 (ja) | ナフタレン誘導体 | |
JPH07267941A (ja) | 3−アリール−グリシド酸エステル誘導体およびその製造方法 | |
JP2003327574A (ja) | ショウガオール類の製造方法および合成用中間体 | |
Yamato et al. | Electrophilic substitution of 7-tert-butyl-1-substituted pyrenes. A new route for the preparation of 1, 3-disubstituted pyrenes | |
EP1037876A1 (en) | Biphenyl derivatives as pharmaceuticals | |
EP0116787B1 (en) | 1,1-diphenylpropanol derivatives, process for their preparation and pharmaceutical compositions containing them | |
CN101830848B (zh) | 一种多胺衍生物及其制备方法和应用 | |
CA1119190A (en) | 1-amino-3-aryloxy-2-propanols |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
DPE2 | Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWW | Wipo information: withdrawn in national office |
Country of ref document: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 11995672 Country of ref document: US |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 06761404 Country of ref document: EP Kind code of ref document: A1 |