CN114560753A - 羟基环氧素同类物的制备方法 - Google Patents
羟基环氧素同类物的制备方法 Download PDFInfo
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- CN114560753A CN114560753A CN202011353259.6A CN202011353259A CN114560753A CN 114560753 A CN114560753 A CN 114560753A CN 202011353259 A CN202011353259 A CN 202011353259A CN 114560753 A CN114560753 A CN 114560753A
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- compound
- alkynyl
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- catalyst
- alkenyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000004593 Epoxy Substances 0.000 title claims abstract description 14
- 239000000039 congener Substances 0.000 title claims abstract description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 title claims abstract description 13
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 19
- -1 silyl enol ether Chemical class 0.000 claims abstract description 15
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract description 14
- 238000006482 condensation reaction Methods 0.000 claims abstract description 11
- 230000001590 oxidative effect Effects 0.000 claims abstract description 9
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 claims abstract description 8
- YOXHCYXIAVIFCZ-UHFFFAOYSA-N cyclopropanol Chemical compound OC1CC1 YOXHCYXIAVIFCZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 6
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 3
- VQPFDLRNOCQMSN-UHFFFAOYSA-N bromosilane Chemical compound Br[SiH3] VQPFDLRNOCQMSN-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000004714 phosphonium salts Chemical class 0.000 claims abstract description 3
- 150000003017 phosphorus Chemical class 0.000 claims abstract description 3
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 40
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 38
- 239000003054 catalyst Substances 0.000 claims description 26
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 24
- HKFZDVPCCOOGEV-UHFFFAOYSA-N nickel(3+);borate Chemical compound [Ni+3].[O-]B([O-])[O-] HKFZDVPCCOOGEV-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 16
- 150000003254 radicals Chemical class 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 229940046892 lead acetate Drugs 0.000 claims description 12
- 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 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000376 reactant Substances 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 7
- SMBQBQBNOXIFSF-UHFFFAOYSA-N dilithium Chemical class [Li][Li] SMBQBQBNOXIFSF-UHFFFAOYSA-N 0.000 claims description 7
- 239000011981 lindlar catalyst Substances 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- BLHLJVCOVBYQQS-UHFFFAOYSA-N ethyllithium Chemical compound [Li]CC BLHLJVCOVBYQQS-UHFFFAOYSA-N 0.000 claims description 5
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 4
- 229940125773 compound 10 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 claims description 4
- 125000003147 glycosyl group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 229910052727 yttrium Inorganic materials 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 3
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- BKDLGMUIXWPYGD-UHFFFAOYSA-N tert-butyllithium Chemical class [Li]C(C)(C)C BKDLGMUIXWPYGD-UHFFFAOYSA-N 0.000 claims description 3
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- WFXSQUHWUJBZKY-UHFFFAOYSA-N ethanol;triphenylphosphane Chemical compound CCO.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 WFXSQUHWUJBZKY-UHFFFAOYSA-N 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000006197 hydroboration reaction Methods 0.000 abstract 1
- 229910003002 lithium salt Inorganic materials 0.000 abstract 1
- 159000000002 lithium salts Chemical class 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 239000000047 product Substances 0.000 description 19
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 230000003834 intracellular effect Effects 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 210000000440 neutrophil Anatomy 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- YYFLDZZDOUDZQM-UHFFFAOYSA-N 3-[1-[[4-(3-phenylquinolin-2-yl)phenyl]methyl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound O=C1NC2=CC=CC=C2N1C(CC1)CCN1CC(C=C1)=CC=C1C1=NC2=CC=CC=C2C=C1C1=CC=CC=C1 YYFLDZZDOUDZQM-UHFFFAOYSA-N 0.000 description 2
- NDCQPJCNZBQYAO-UHFFFAOYSA-N 4-[[3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenoxy]methyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1COC1=CC=CC(C=2C3=CC=CC(=C3N=CC=2C(=O)C=2C=CC=CC=2)C(F)(F)F)=C1 NDCQPJCNZBQYAO-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229940114079 arachidonic acid Drugs 0.000 description 2
- 235000021342 arachidonic acid Nutrition 0.000 description 2
- 230000035605 chemotaxis Effects 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 230000037353 metabolic pathway Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000019254 respiratory burst Effects 0.000 description 2
- 230000016160 smooth muscle contraction Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- 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 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SODQFLRLAOALCF-UHFFFAOYSA-N 1lambda3-bromacyclohexa-1,3,5-triene Chemical compound Br1=CC=CC=C1 SODQFLRLAOALCF-UHFFFAOYSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- 241000208199 Buxus sempervirens Species 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910015346 Ni2B Inorganic materials 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 229910020175 SiOH Inorganic materials 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910007565 Zn—Cu Inorganic materials 0.000 description 1
- WRLJWIVBUPYRTE-UHFFFAOYSA-N [B].[Ni].[Ni] Chemical group [B].[Ni].[Ni] WRLJWIVBUPYRTE-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229940088623 biologically active substance Drugs 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000005350 fused silica glass Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- DOAMZWOPDPPKJS-UHFFFAOYSA-N oxiran-2-ol Chemical class OC1CO1 DOAMZWOPDPPKJS-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 230000029537 positive regulation of insulin secretion Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/32—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions without formation of -OH groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/17—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrogenation of carbon-to-carbon double or triple bonds
-
- 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
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
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Abstract
本发明属于药物化学合成技术领域，涉及羟基环氧素同类物的制备方法。所述的羟基环氧素同类物的结构如式(A)或(B)所示：其中，R2、R3、R5、X如权利要求书和说明书所述。本发明的制备方法如下：含一个或两个三键的C8‑C12炔醇在与二乙基锌作用生成环丙基醇；环丙基醇将炔基氢化为烯基；随后将烯基氧化为醛；进一步与C6‑C10的炔基酸反应，经双锂盐催化的炔烃的硼氢化反应，生成C14‑C22的含有一个炔基及环丙烷的酸；进一步将炔基氢化，生成式(A)；含C6‑C10的1‑溴3‑醇酯化物在叔丁基二甲基硅烷催化下生成甲硅烷基烯醇醚；进一步生成与硅烷基溴化物结合的磷盐；上述磷盐与含有环丙烷的醛进行叶立德维蒂格缩合反应生成式(B)。本发明成本低、路线短、产率高。
Description
技术领域
本发明属于药物化学合成技术领域，涉及羟基环氧素同类物的制备方法。
背景技术
科学研究结果越来越清楚的表明，第二信使在维持人体各种代谢过程中的体内平衡方面起着重要作用。钙是第二信使的重要成员，而钙的调节已成为研究和控制可能由这些途径的异常调节而引起的代谢途径改变和病理状况的焦点。钙调节是通过打开或关闭门控离子通道来实现的，由此导致细胞内离子浓度的变化有两种方式：1)改变细胞膜上的电压，2)允许大量离子流入，两者均产生细胞内响应。以钙离子调节细胞信号通路而调节细胞功能包括炎症和平滑肌收缩。
炎症是人体对伤害的反应。炎症反应包括三个阶段：第一，增加受伤部位的血流量；第二，由于血管壁的内皮细胞收缩而引起的毛细血管通透性增加。第三，白细胞迁移至损伤部位。第三阶段称为趋化性。趋化性是一个复杂的过程，导致某些类型的白细胞(如嗜中性粒细胞)吞噬入侵物。中性粒细胞在机体炎症反应(如感染)的反应中起关键作用。中性粒细胞一旦到达炎症部位，就会被“激活”并释放出大量的氧化酶，称为呼吸爆发，有助于破坏侵入性物质。细胞内钙的增加被认为可以诱发与导致呼吸爆发。
自然界发现的羟基环氧素是花生四烯酸代谢途径的产物，它通过增加嗜中性粒细胞的细胞内钙流入量，调节第二信使钙离子通道而参与调节炎症和平滑肌收缩。羟基环氧素是花生四烯酸通过12-磷脂氧化酶途径代谢生成的具有的生物活性物质，现已分离出两种类型的羟基环氧素。大量研究显示羟基环氧素同类物具有多种药理作用，包括抑制细胞内钙升高，减轻炎症，抑制血小板凝固，刺激胰岛素分泌，治疗糖尿病，以及抑制实体肿瘤生长等。但是自然界存在的羟基环氧素不稳定，不能稳定合成。
传统的或已知的羟基环氧素同类物合成路线，在存在潜在不稳定的环丙烷环的情况下，同时对三个三键进行选择性加氢需要精心选择条件。为了去除主要由过氢化产物组成的杂质，必须使用制备型HPLC。因此，工艺放大会存在问题。
发明内容
为了克服现有技术的缺陷，本发明提供一种羟基环氧素同类物的制备方法，所述的制备方法成本低、路线短、产品的产率高、纯度高。
本发明提供一种新型快捷的有机化学法合成羟基环氧素同类物的方法。
本发明所述的羟基环氧素同类物的制备方法中：
所述的羟基环氧素同类物的结构如式(A)或(B)所示：
X为O,C,CH2,NH,S-C1-C6烷基，N-C1-C6烷基；Cn,(CH2)n,n＝2，3，4；或(CH2)m-Y,Y为S,NH,O；m为1，2，3；
R2为OH,H,卤素，C1-C6烷基,CH2OH,N3,NH2,SH2,CH2N3,OPO3H；
R3为C4-C10烷基，C4-C10烯基，C4-C10炔基；
R5为C1-C6烷基，C2-C6烯基或C2-C6炔基；饱和或不饱和的C1-C4醇；6-10元芳基；所述的芳基可以为-(CH 2)n-苯基，其中n为1至9；或Y-R1，其中Y是C1-C10烷基，C2-C10烯基，C2-C10炔基，所述的Y可选被-OH和/或卤素取代；
R1为OH，卤素，N3，NH2，COOR4或CONHR4，其中R4为H，C1-C6烷基，5-6元环烷基，5-6元芳基，糖基；
且优选R4为CH3，H，或可被COOH或5-6元杂环取代的C1-C10烷基；
所述的羟基环氧素同类物具有如下结构：
X为CH2；
R2为OH,H,卤素，C1-C6烷基,CH2OH,N3,NH2,SH2,CH2N3,OPO3H；
R3为C4-C10烷基，C4-C10烯基，C4-C10炔基；
R5为C1-C6烷基，C2-C6烯基或C2-C6炔基，或Y-R1，其中Y是C1-C10烷基，C2-C10烯基，C2-C10炔基，所述的Y可选被-OH和/或卤素取代；
R1为COOR4或CONHR4，其中R4为H，CH3，5-6元芳基，糖基；
进一步地，所述的羟基环氧素同类物具有如下结构：
本发明通过如下技术方案实现：
含一个或两个三键的C8-C12炔醇在铜锌混合物中与二乙基锌作用生成环丙基醇；环丙基醇在催化剂作用下将炔基氢化为烯基；随后将烯基氧化为醛；进一步与C6-C10的炔基酸共同反应，经双锂盐催化的炔烃的硼氢化反应，生成C14-C22的含有一个炔基及环丙烷的酸；进一步在催化剂作用下将炔基氢化，得式(A)化合物。
其中，
所述的氢化反应使用的催化剂为硼酸镍、Lindlar硼酸镍；
所述的氧化反应使用的氧化剂为氯化钴、草酰氯、德斯马丁高碘(Dess MartinPeriodinane)或2-碘氧基苯甲酸；
所述的双锂盐为甲基锂盐、乙基锂盐、叔丁基锂盐。
含C6-C10的1-溴3-醇酯化物在叔丁基二甲基硅烷催化下生成有区域选择性的甲硅烷基烯醇醚；进一步在三苯基磷催化下生成与硅烷基溴化物结合的磷盐；上述磷盐与式(A)化合物合成过程中生成的含有环丙烷的醛，进行叶立德维蒂格缩合反应生成式(B)化合物。
进一步地，本发明提供了式I或式II的制备方法：
式I的制备方法如下：
(1)醇1在无水乙醚中处理，得到2，3-环丙基醇2；
(2)2，3-环丙基醇2在催化剂作用下氢化生成化合物3；
(3)化合物3在氧化剂作用下氧化为醛4；
(4)醛4与末端乙炔的双锂盐5缩合得到6；
(5)6经过二次催化氢化生成式I化合物。
其中，
步骤(1)中，在二乙基锌和锌铜对存在下反应，铜锌对摩尔比为1:1，二乙基锌用量为反应物总体积的1-2％。
步骤(2)中，所述催化剂为硼酸镍催化剂或选择性Lindlar催化剂，选自硼酸镍、氯化钯、碳酸钙、乙酸铅和喹啉中的一种或几种。所述的催化剂优选硼酸镍、氯化钯、氯化钯和喹啉的组合物、氯化钯和乙酸铅的组合物、硼酸镍和喹啉的组合物。
当催化剂为氯化钯和喹啉的组合物、氯化钯和乙酸铅的组合物、硼酸镍和喹啉的组合物时，氯化钯：喹啉＝氯化钯：乙酸铅＝硼酸镍：喹啉＝5:1-10:1。
所述催化剂的质量比为反应物总质量的3-5％。
催化反应的溶剂为无水苯。
步骤(3)中，所述氧化剂为草酰氯(Oxalyl Chloride)、氯化钴、德斯马丁高碘DMP(Dess-Martin Periodinane)或2-碘氧基苯甲酸(IBX)。
步骤(4)中，所述缩合反应的缩合剂是甲基锂、乙基锂、叔丁基锂或乙基溴化镁；所述的双锂盐为甲基锂盐、乙基锂盐、叔丁基锂盐。
步骤(5)中，所述催化剂为Ni2B或选择性Lindlar催化剂，选自硼酸镍、氯化钯、碳酸钙、乙酸铅和喹啉中的一种或几种。所述的催化剂优选硼酸镍、氯化钯、氯化钯和喹啉的组合物、氯化钯和乙酸铅的组合物、硼酸镍和喹啉的组合物。
当催化剂为氯化钯和喹啉的组合物、氯化钯和乙酸铅的组合物、硼酸镍和喹啉的组合物时，氯化钯：喹啉＝氯化钯：乙酸铅＝硼酸镍：喹啉＝5:1-10:1。
所述催化剂的质量比为反应物总质量的2-5％。
式II的制备方法如下：
(1)化合物8与叔丁基二甲基烷硅(BDMSCL)tert-butyldimethylsilyl chloride反应，生成化合物9；
(2)化合物9与三苯基磷乙醇液进行叶立德维蒂格缩合反应,即刻与氢氧化钠水溶液激烈搅拌震荡，叶立德反应物用氯仿层萃取，得到化合物10；
(3)化合物10与化合物4反应，硅胶分离，乙醚萃取，得到式II化合物。
其中，
步骤(1)中，化合物8与BDMSCL的摩尔比为1：0.05-0.1，反应溶剂为乙醚，反应温度为室温；
步骤(2)中，反应溶剂为乙醇、甲苯或四氢呋喃，反应温度为室温；化合物9与三苯基磷的摩尔比：1：0.01-0.05。
步骤(3)中，反应溶剂为苯，反应温度为室温；反应物间4与反应物10的摩尔比：1-2：1。
传统的化合物(I)的制备方法是先形成环丙烷醇，在氯化钴催化下将醇氧化为醛，进一步缩合成含有三个炔基及一个环烷基的C14-C22的酯，再进一步在Lindlar催化下氢化反应生成化合物(I)。因为最后一步在有不稳定的环丙烷存在下需要经过两次彻底氢化反应将三个炔键氢化，此法不好控制氢化条件及产率，而且影响环丙烷的稳定性，易于解离，为此，本发明提供了可以通过常规方法从化合物(1)和(5)开始获得化合物(6)，由于一次只需要氢化一个三键，所以其氢化条件稳定，产率稳定且产率较高。本发明可以选择多种催化剂进行催化氢化，稳定性均较好。
本发明所述的制备方法成本低、路线短、产品的产率高，式I化合物的收率可达65％以上，式II化合物的收率可达75％以上。
具体实施方式
使用Kugelrohr设备(Aldrich，Milwaukee，WI)在规定的烘箱温度下对化合物(1)-(4)进行真空蒸馏。使用7.8x300 mmμPorasil SiO2色谱柱(马萨诸塞州沃特斯市，Waters)进行制备型HPLC，使用0.8％i-PrOH的己烷溶液用于化合物式I，和化合物式II.GC分析是在Hewlett-Packard 5700A气相色谱(Hewlett-Pack-ard,Palo Alto,Calif.)中进行的，使用60mX0.3mm玻璃毛细管住(SPB-1,Supelco,Bellefonte,Pa.)电子轰击质谱是在Hewlett-Packard GC MS上使用熔融硅胶甲基硅酮毛细管柱(fused silica methylsiliconecapilary column)(HP-1，12mX0.2mm)获得的。1H-NMR光谱是在Bruker-AM500(500MHz)光谱仪(Bruker，5Karlsruhe，德国)上以Me4Si作为内标(δ＝0)在CDCl3中获得的。
实验及制备中使用的药品及试剂，如Lindlar催化剂(Aldrich)和正丁基锂(n-BuLi的己烷溶液(Fluka，Buchs，瑞士)，如没特殊说明，均来自Sigma Aldrich。
式I化合物的制备：
实施例1:
中间产物(2)制备：
在先加入二乙基锌DEZ(Diethylzinc)0.1g的情况下，将Zn-Cu配对(摩尔数1：1，2.95g)加入无水乙醚(10mL)中制成悬浮液，将其回流5分钟。并将所得混合物在35℃搅拌1h。化合物(1)(0.33g)加入5mL乙醚，加入前述混合物中，并在搅拌下将混合物回流反应30分钟。混合物用乙醚萃取，干燥。蒸发溶剂后，将残余物真空蒸馏，得到279mg环丙醇产物(2)，产率为91％。
实施例2:
中间产物(3)制备：
将产物(2)(120mg)的无水苯(2mL)溶液，添加到含有Lindlar催化剂硼酸镍：喹啉10：1(100mg)的10ml苯中，搅拌直到完成氢消耗为止(30-60分钟，吸收了10mL的H2)。滤出催化剂，将滤液倒入氧化铝柱(pH 6.9-7.1)上。在室温下用8-15％EtOAc洗脱该柱，得到产物(3)，产率为92％。
实施例3:
中间产物(4)制备：
在3毫升(COCl)2(85mg)和分子筛3A(Aldrich)(120mg)的悬浮物中加入事先配制的产物(3)在0.5ml二氯甲烷溶液中，并加入10ul醋酸反应。30分钟后，加入20微升异丙醇将反应停止，混合物通过硅胶过滤并用己烷洗脱。蒸发溶剂得到18.2mg(92％)的醛产物(4)，产率为89％。
实施例4:
中间产物(6)制备：
将5-烯-8炔-壬酸(1.6g)在无水乙醚(100mL)中的溶液冷却至零度以下，添加正丁基锂(n-BuLi)(1.38g,的1.5M的己烷溶液)。将混合物搅拌30分钟，并加入在20ml乙醚中的醛产物(4)(0.77g)，然后加入20ml H2O以淬灭反应。将混合物调温至20℃。分离出醚层，残余物用乙醚萃取，并将溶剂蒸发至干，得到油状物，其可以被硅胶柱吸收。用10％EtOAc己烷液洗脱，除去溶剂，得到无色油状的含有一个炔基的终产物的前体产物(6)。
前体产物(6)的无水苯溶液添加到Lindlar催化剂硼酸镍：喹啉10：1中进行氢化反应，60分钟直到氢消耗尽为止，滤除催化剂，洗脱干燥得到式I化合物，产率95％。
使用HPLC(μPorasil 7.8x300mm，Waters)，洗脱液用0.5％异丙醇的己烷溶液分离出终产物7，即结构式(I)产物，并用210nm的UV检测。产物(I)极性大，无色油状物，融出时间为29.4分)。
化合物7：为无色油状物，1H-NMR-色谱(500MHz,δ,ppm):0.33(dt,1H,J5.1和8.4Hz,cyclopropyl-H),0.43(dt,1H,J5.1和8.4Hz,cyclopropyl-H),0.81(m,2H,H11+H12),0.89(t,3H,J6.7 Hz,H20)，1.25-1.36(m,6H,H17+H18+H19),1.58(d,1H,J3.2Hz,OH),1.70(quintet,2H,J7.4 Hz,H3)，1.96-2.10(m,6H,H4+H13+H16)，2.31(t,2H,J7.4 Hz,H2),2.74,2.84(m,2H,H7),3.67(s,3H,COOMe),3.97(ddd,1H,J3.0,7.3,和7.3Hz,H10),5.36-5.48(m,6H,olcfinic H).).tBDMSi衍生物质谱(m/z,相对强度％):462(0.04),431(0.35),405(20),334(4.7),324(2.8),215(4.2),211(3.0),169(6.0)，105(26)，75(100)。
实施例5：
式II化合物的制备：
化合物(8)250mg与5ml叔丁基二甲基氯硅烷(BDMSCL)tert-butyldimethylsilylchloride的无水乙醚中，在20-50度反应3-10个小时，进而与1摩尔当量的三苯基磷的乙醇水溶液进行叶立德维蒂格缩合反应，同时与1当量氢氧化钠水溶液激烈搅拌震荡，ylide叶立德反应物用氯仿层萃取，而后直接与化合物(4)的乙醚溶液室温反应10个小时。将反应混合物的有机层分离，灌入硅胶柱，用3：2的己烷：乙醚溶剂萃取，干燥，得到式II化合物，产率86％。
使用HPLC(μPorasil 7.8x300 mm，Waters)，洗脱液用0.8％异丙醇的己烷溶液分离出终产物11或结构式(II)，并用232nm的UV检测，结构式(II)产物为无色油状物.
化合物11：为无色油状物，极性低于式I化合物.Rf 0.46(C6H6-Et2O，85：15)，tBDMSi衍生物质谱(m/z,相对强度％):431([M-OMe]+,0.18),405([M-t-Bu]+,4.7),351([C1-C12]+,0.18),321([C8-C20]+,100)，197(62),189([C8-C20]-t-BuMe2SiOH,17),171(27),75(79),73(83).
实施例6：不同反应条件对本发明产物的产率的影响：
(1)反应条件对式I的产率的影响
本发明的氢化反应条件是影响本发明中式I产率的重要因素，在使用Lindlar催化剂进行氢化反应时，不同的催化剂、催化剂的浓度，反应时间，对产率都有影响。
结果表明，当催化剂浓度为3-5％时，反应时间为0.5-12小时，反应温度为25-40度时，步骤(2)和(5)产物的产率均在65％以上。当催化剂为氯化钯与喹啉的组合物、氯化钯与乙酸铅的组合物、硼酸镍和喹啉的组合物时，催化剂中氯化钯：喹啉、氯化钯：乙酸铅、硼酸镍：喹啉的重量比为10：1时，步骤(2)和(5)产物的产率均在85％以上。
(2)反应条件对式II的产率的影响
在进行三苯基磷的维蒂格缩合反应中，不同摩尔当量的氢氧化钠溶液、反应时间对产率都有影响。
| 1：氢氧化钠(当量数) | 反应时间(小时) | 产率(％) |
| 0.1 | 2.8 | 86.4 |
| 0.2 | 2.5 | 88.1 |
| 0.4 | 2.0 | 88.3 |
| 0.01 | 7.8 | 40.5 |
| 0.05 | 5.2 | 61.7 |
结果表明，当氢氧化钠为0.1-0.4当量，反应时间为2.0-2.8小时时，式II的产率为80％以上。
在进行三苯基磷的维蒂格缩合反应中，在相同的室温条件下，不同有机溶剂和反应时间对产率都有影响。
| 有机溶剂 | 反应时间(小时) | 产率(％) |
| 无水乙醚 | 3.0 | 86 |
| 无水乙醇 | 8.0 | 56.7 |
| 乙醇水溶液(95％) | 1.0 | 86.4 |
| 四氢呋喃 | 10.0 | 70.5 |
| 甲苯 | -- | -- |
结果表明，缩合反应中的溶剂优选为无水乙醚、95％乙醇溶液，反应时间为1-3小时，式II的产率为80％以上。
实施例7：现有技术与本发明技术方案对比：
Claims (10)
1.羟基环氧素同类物的制备方法，其特征在于，
含一个或两个三键的C8-C12炔醇在铜锌混合物中与二乙基锌作用生成环丙基醇；环丙基醇在催化剂作用下将炔基氢化为烯基；随后将烯基氧化为醛；进一步与C6-C10的炔基酸共同反应，经双锂盐催化的炔烃的硼氢化反应，生成C14-C22的含有一个炔基及环丙烷的酸；进一步在催化剂作用下将炔基氢化，得式(A)化合物；
含C6-C10的1-溴3-醇酯化物在叔丁基二甲基硅烷催化下生成有区域选择性的甲硅烷基烯醇醚；进一步在三苯基磷催化下生成与硅烷基溴化物结合的磷盐；上述磷盐与式(A)化合物合成过程中生成的含有环丙烷的醛，进行叶立德维蒂格缩合反应生成式(B)化合物；
其中，
X为O,C,CH2,NH,S-C1-C6烷基，N-C1-C6烷基；Cn,(CH2)n,n＝2，3，4；或(CH2)m-Y,Y为S,NH,O；m为1，2，3；
R2为OH,H,卤素，C1-C6烷基,CH2OH,N3,NH2,SH2,CH2N3,OPO3H；
R3为C4-C10烷基，C4-C10烯基，C4-C10炔基；
R5为C1-C6烷基，C2-C6烯基或C2-C6炔基；饱和或不饱和的C1-C4醇；6-10元芳基；所述的芳基可以为-(CH 2)n-苯基，其中n为1至9；或Y-R1，其中Y是C1-C10烷基，C2-C10烯基，C2-C10炔基，所述的Y可选被-OH和/或卤素取代；
R1为OH，卤素，N3，NH2，COOR4或CONHR4，其中R4为H，C1-C6烷基，5-6元环烷基，5-6元芳基，糖基；
且优选R4为CH3，H，或可被COOH或5-6元杂环取代的C1-C10烷基；
-·-·-·表示单键，双键或三键。
2.权利要求1所述的制备方法，其特征在于，
X为CH2；
R2为OH,H,卤素，C1-C6烷基,CH2OH,N3,NH2,SH2,CH2N3,OPO3H；
R3为C4-C10烷基，C4-C10烯基，C4-C10炔基；
R5为C1-C6烷基，C2-C6烯基或C2-C6炔基，或Y-R1，其中Y是C1-C10烷基，C2-C10烯基，C2-C10炔基，所述的Y可选被-OH和/或卤素取代；
R1为COOR4或CONHR4，其中R4为H，CH3，5-6元芳基，糖基；
-·-·-·表示单键，双键或三键。
3.权利要求1或2所述的制备方法，其特征在于，所述的羟基环氧素同类物结构如式(I)或(II)所示：
4.如权利要求3所述的制备方法，其特征在于，式(I)的制备方法如下：
(1)醇1在无水乙醚中处理，得到2，3-环丙基醇2；
(2)2，3-环丙基醇2在催化剂作用下氢化生成化合物3；
(3)化合物3在氧化剂作用下氧化为醛4；
(4)醛4与末端乙炔的双锂盐5缩合得到6；
(5)6经过两次催化氢化生成式I化合物；
5.如权利要求4所述的制备方法，其特征在于，步骤(2)或(5)中所述的催化剂为硼酸镍催化剂或选择性Lindlar催化剂，选自硼酸镍、氯化钯、碳酸钙、乙酸铅和喹啉中的一种或几种；所述的催化剂优选硼酸镍、氯化钯、氯化钯和喹啉的组合物、氯化钯和乙酸铅的组合物、硼酸镍和喹啉的组合物。
6.如权利要求4所述的制备方法，其特征在于，步骤(3)中所述氧化剂为草酰氯、氯化钴、德斯马丁高碘DMP或2-碘氧基苯甲酸。
7.如权利要求4所述的制备方法，其特征在于，步骤(4)中，所述缩合反应的缩合剂是甲基锂、乙基锂、叔丁基锂或乙基溴化镁；所述的双锂盐为甲基锂盐、乙基锂盐、叔丁基锂盐。
8.如权利要求3所述的制备方法，其特征在于，式(II)的制备方法如下：
(1)化合物8与叔丁基二甲基烷硅反应，生成化合物9；
(2)化合物9与三苯基磷乙醇液进行叶立德维蒂格缩合反应,即刻与氢氧化钠水溶液激烈搅拌震荡，叶立德反应物用氯仿层萃取，得到化合物10；
(3)化合物10与化合物4反应，硅胶分离，乙醚萃取，得到式II化合物；
9.如权利要求8所述的制备方法，其特征在于，
步骤(1)中，化合物8与叔丁基二甲基烷硅的摩尔比为1：0.05-0.1，反应溶剂为乙醚，反应温度为室温。
10.如权利要求8所述的制备方法，其特征在于，
步骤(2)中，反应溶剂为乙醇、甲苯或四氢呋喃，反应温度为室温；化合物9与三苯基磷的摩尔比：1：0.01-0.05；步骤(3)中，反应溶剂为苯，反应温度为室温；反应物间4与反应物10的摩尔比：1-2：1。
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| US20040132705A1 (en) * | 2000-11-09 | 2004-07-08 | Pace-Asciak Cecil R | Inhibitors of thromboxane formation and action |
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| US20040132705A1 (en) * | 2000-11-09 | 2004-07-08 | Pace-Asciak Cecil R | Inhibitors of thromboxane formation and action |
| KR20050054857A (ko) * | 2003-12-05 | 2005-06-10 | 라보라토리오스 비냐스, 에스.에이. | 모노할로게노비닐 화합물로부터 비타민 ｄ 유도체를획득하는 방법 |
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