CN106674155B - The enantioselective synthesis method of 18 carbon diene of chirality (3Z, 9Z) -6,7- epoxy - Google Patents
The enantioselective synthesis method of 18 carbon diene of chirality (3Z, 9Z) -6,7- epoxy Download PDFInfo
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- CN106674155B CN106674155B CN201611137397.4A CN201611137397A CN106674155B CN 106674155 B CN106674155 B CN 106674155B CN 201611137397 A CN201611137397 A CN 201611137397A CN 106674155 B CN106674155 B CN 106674155B
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- methylene chloride
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- -1 carbon diene Chemical class 0.000 title claims abstract description 98
- 229910052799 carbon Inorganic materials 0.000 title claims abstract description 60
- 239000004593 Epoxy Substances 0.000 title claims abstract description 48
- 238000001308 synthesis method Methods 0.000 title abstract description 4
- 241001046947 Ectropis obliqua Species 0.000 claims abstract description 35
- 239000000877 Sex Attractant Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 271
- 238000006243 chemical reaction Methods 0.000 claims description 93
- 239000000243 solution Substances 0.000 claims description 76
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 73
- 239000007788 liquid Substances 0.000 claims description 67
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 63
- 150000001875 compounds Chemical class 0.000 claims description 60
- 239000012071 phase Substances 0.000 claims description 49
- 238000000926 separation method Methods 0.000 claims description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
- 239000012043 crude product Substances 0.000 claims description 46
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 45
- 239000012074 organic phase Substances 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 238000001914 filtration Methods 0.000 claims description 36
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 31
- 238000010791 quenching Methods 0.000 claims description 31
- 230000000171 quenching effect Effects 0.000 claims description 31
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 26
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 23
- 238000000746 purification Methods 0.000 claims description 21
- 229920006395 saturated elastomer Polymers 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 239000012266 salt solution Substances 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 16
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tert-butyl alcohol Substances CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 16
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 15
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 14
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 14
- 238000000605 extraction Methods 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- 239000011981 lindlar catalyst Substances 0.000 claims description 12
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 11
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 11
- 229940126543 compound 14 Drugs 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 10
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 229940125898 compound 5 Drugs 0.000 claims description 9
- 229910015900 BF3 Inorganic materials 0.000 claims description 8
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- 239000012065 filter cake Substances 0.000 claims description 8
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 7
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 7
- 229940125797 compound 12 Drugs 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000010936 titanium Substances 0.000 claims description 7
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- 229910052719 titanium Inorganic materials 0.000 claims description 6
- 230000008859 change Effects 0.000 claims description 5
- 229940125773 compound 10 Drugs 0.000 claims description 5
- 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 5
- YNLAOSYQHBDIKW-UHFFFAOYSA-M diethylaluminium chloride Chemical compound CC[Al](Cl)CC YNLAOSYQHBDIKW-UHFFFAOYSA-M 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 150000002978 peroxides Chemical class 0.000 claims description 4
- 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 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims 1
- KISFFWNZZFRNSC-UHFFFAOYSA-M diethylalumanylium;hexane;chloride Chemical compound [Cl-].CC[Al+]CC.CCCCCC KISFFWNZZFRNSC-UHFFFAOYSA-M 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 24
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
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- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 10
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- RLJWTAURUFQFJP-UHFFFAOYSA-N propan-2-ol;titanium Chemical group [Ti].CC(C)O.CC(C)O.CC(C)O.CC(C)O RLJWTAURUFQFJP-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
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- 239000003513 alkali Substances 0.000 description 8
- VXUYXOFXAQZZMF-UHFFFAOYSA-N tetraisopropyl titanate Substances CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 8
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 7
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
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- 150000004696 coordination complex Chemical class 0.000 description 2
- ILLHQJIJCRNRCJ-UHFFFAOYSA-N dec-1-yne Chemical compound CCCCCCCCC#C ILLHQJIJCRNRCJ-UHFFFAOYSA-N 0.000 description 2
- XEBCWEDRGPSHQH-HTQZYQBOSA-N dipropan-2-yl (2r,3r)-2,3-dihydroxybutanedioate Chemical group CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C XEBCWEDRGPSHQH-HTQZYQBOSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000004575 stone Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- QIJZNDSLUNIYAD-UHFFFAOYSA-N 1,2-dibromobut-1-ene Chemical compound CCC(Br)=CBr QIJZNDSLUNIYAD-UHFFFAOYSA-N 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010008428 Chemical poisoning Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241001634830 Geometridae Species 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 244000020551 Helianthus annuus Species 0.000 description 1
- 235000003222 Helianthus annuus Nutrition 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010027439 Metal poisoning Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 235000010726 Vigna sinensis Nutrition 0.000 description 1
- 244000042314 Vigna unguiculata Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- YSAVZVORKRDODB-PHDIDXHHSA-N diethyl (2r,3r)-2,3-dihydroxybutanedioate Chemical compound CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC YSAVZVORKRDODB-PHDIDXHHSA-N 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- XEBCWEDRGPSHQH-YUMQZZPRSA-N dipropan-2-yl (2s,3s)-2,3-dihydroxybutanedioate Chemical class CC(C)OC(=O)[C@@H](O)[C@H](O)C(=O)OC(C)C XEBCWEDRGPSHQH-YUMQZZPRSA-N 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 230000009746 freeze damage Effects 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 208000008127 lead poisoning Diseases 0.000 description 1
- 229960003019 loprazolam Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000447 pesticide residue Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000009329 sexual behaviour Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the enantioselective synthesis methods of 18 carbon diene of chirality (3Z, 9Z) -6,7- epoxy, belong to tea geometrid Prevention Technique field.(2Z, 5Z)-octadiene -1- alcohol (3) to be easy to get of the invention provides efficient, the tea geometrid sex pheromone levo form of highly-solid selectively and the synthetic method of d-isomer for starting material.Each step operation of the present invention is simple, and purifying is simple, and many steps, which are not required to purifying, can directly carry out the next step, and agents useful for same is the common cheap reagent that is easy to get, and route is shorter, is suitble to large-scale production.The present invention also passes through EAG (tentaculum electric potential) and wind tunnel experiment has tentatively judged the ability that levo form 1 has preferably trapping tea geometrid, and d-isomer 2 does not have tea geometrid trapping activity substantially.This makes asymmetric syntheses optical activity sex pheromone be expected to be used widely in agriculture green prevention and treatment.
Description
Technical field
The present invention relates to the enantioselective synthesis methods of 18 carbon diene of chirality (3Z, 9Z) -6,7- epoxy, belong to tea ruler
Earwig Prevention Technique field.
Background technique
Tea geometrid category Lepidoptera (Lepidoptera), Geometridae (Geometriidae), Ennominae
(Ennominae), also known as arch encircles worm, measures cun a worm, hang spring worm, is the primary pest in China, Su-Wan area tea place, Zhejiang.Generation occurs in it
In number different, 1 year 5~7 generation of generations with current year weather conditions, harm extremely weighs when outburst, entirely whole tea leaf and tender shoots are eaten
Light, only remaining limb and vein, shape lead to 60% or more the tealeaves underproduction as burnt, and can lead to that tea tree early ageing, cold-hartliness be poor, the winter
Season is vulnerable to consequences such as freeze injuries.Tea geometrid is affected to tea yield, quality and tea tree tree vigo(u)r, causes harm to summer, autumn tea most heavy；It removes
It endangers outside tea tree, can also endanger soybean, cowpea, sesame, sunflower etc..Although cultural control and physical control are prevented and treated in tea geometrid
In still have a use, but high-efficient, speed is fast, territory restriction is small, using easy, prevention and treatment is wide since chemical insecticide prevention and treatment has
The advantages that, therefore tea geometrid prevention and treatment is mainly controlled by chemical pesticides at present.For many years, largely same using pesticide poisoning pest
When cause natural enemy to come to harm, the drug resistance of pest enhancing, cause the pesticide residue in environmental pollution and tealeaves, these are also straight
Connect the export trade and human health for affecting tealeaves.Therefore environmental-friendly biological pesticide is increasingly becoming control of insect from now on
Developing direction, wherein insect sex pheromone Prevention Technique is with a wide range of applications.
Nankai University's Liu's Tianlin etc. successfully synthesizes seven kinds of candidate compounds, indoor biometrics the experimental results showed that (3Z, 6Z,
9Z)-ten eight carbon triolefins and-ten eight carbon diene of (3Z, 9Z) -6,7- epoxy are lured with stronger tea geometrid draws active (Liu Tianlin, Lee
The synthesis Nankai University journal of several active constituents of tea geometrid sex pheromone such as rectification of name: natural science edition .1994,1:82-
86).2010, as if Xiao Chun seminar, Agricultural University Of Anhui is successfully divided in the female moth sexual gland extract of tea geometrid with solvent extraction method
From identify above two compound and determined tea geometrid sex pheromone group become-ten eight carbon two of (3Z, 9Z) -6,7- epoxy
Alkene (main component) and (3Z, 6Z, 9Z)-ten eight carbon triolefin (accessory constituent) (Yang Yunqiu, as if the tea geometrid sexual behaviour such as spring dawn
Habit preliminary study China's agronomy is notified to .2008,24:339-342.).However tea ruler only is completed there are two seminar over 30 years
Earwig sex pheromone is left-handed and the enantioselective synthesis of d-isomer, still has certain limitation in synthetic method；Natural tea geometrid
The configuration of sex pheromone does not determine that the bioactivity difference of two kinds of enantiomers is not also studied yet.Therefore synthesizing optical is active
Tea geometrid sex pheromone is of great significance for realizing green prevention and treatment, improving Chinese tea industry competitiveness.
As shown in Figure 1, the optical isomer compound 1 (levo form) of 18 carbon diene of (3Z, 9Z) -6,7- epoxy and the 2 (right sides
Revolve body).
Reported method of asymmetric synthesis is as follows: 1986, Millar group (Millar, J.G.et
al.Synthesis of Chiral Bis-Homoallylic Epoxides.A New Class of Lepidopteran
Sex Attractants.J.Org.Chem.1986,51:4726-4728) in synthesis moon moth sex pheromone enantiomer series derivatives
When object, sets out from intermediate (2Z, 5Z)-octadiene -1- alcohol, synthesized optically active compound 1 and 2, gross production rate reaches respectively
To 21% and 26%.Its synthetic route is as shown in Figure 2.The major defect of this method is that cis- alkenyl Grignard Reagent is difficult to prepare,
Usually have cis-trans isomerism；Final step coupling reaction yield is low, poor selectivity, purification difficult, is unfavorable for closing on a large scale
At (compound is write a Chinese character in simplified form: Br2It is bromine simple substance, MeONa is sodium methoxide, CH2Cl2It is methylene chloride, Mg is magnesium metal, and THF is tetrahydro
Furans, Ti (i-PrO)4It is tetraisopropoxy titanium, L- (+)-DIPT is L-TARTARIC ACID diisopropyl ester, t-BuO2H is the tertiary fourth of peroxide
Alcohol, PPh3It is triphenylphosphine, imidazole is imidazoles, I2It is elemental iodine, Et2O is ether, CH3CN is acetonitrile, and HMPA is pregnancy
Base phosphamide, D- (-)-DIPT are D- tartaric acid diisopropyl esters.).
Nearest Zheng Jian cutting edge of a knife or a sword and Huang Peiqiang et al. a kind of (the three-dimensional choosing of tea geometrid sex pheromone of Zheng Jianfeng, Liang Pan, Huang Peiqiang
Selecting property synthesizes Chinese invention patent .CN102911136B.) using cis-2-butene-Isosorbide-5-Nitrae-glycol as starting material, it is anti-with six steps
It answers, 17% total recovery obtains enantiomter 1 and 2.Its synthetic route is as shown in Figure 3.The disadvantages of the method are as follows centre used
Body 1,2- dibromo butene be difficult to prepare and it is extremely unstable be not easy to store, synthetic intermediate 2,-ten four carbon alcohols trifluoro of 3- epoxy -5- alkynes
Methane sulfonate property is active, and the reaction such as elimination easily occurs, and is unfavorable for the progress of subsequent reactions, and reaction often needs at low temperature
(compound is write a Chinese character in simplified form: SOCl for (subzero 60 DEG C or less) progress2It is thionyl chloride, THF is tetrahydrofuran, and CuI is cuprous iodide, NaI
It is sodium iodide, K2CO3It is potassium carbonate, DMF is n,N-Dimethylformamide, and 1-Decyne is 1- decine, and silica gel is silicon
Glue, CaH2It is calcium hydride, CH2Cl2It is methylene chloride, Tf2O is Trifluoromethanesulfonic anhydride, NEt3It is triethylamine, n-BuLi is positive fourth
Base lithium, n-hexane are n-hexanes).
Summary of the invention
To solve the above-mentioned problems, the present invention provides a kind of efficient, highly selective and easy to operate about tea geometrid
Sex pheromone levo form 1 [18 carbon diene of (-)-(3Z, 9Z, 6S, 7R) -6,7- epoxy] or d-isomer 2 [(+)-(3Z, 9Z,
6R, 7S) 18 carbon diene of -6,7- epoxy] synthetic method.
The synthetic method of the levo form or d-isomer is with any one in formula (A), formula (B), formula (C), formula (D)
Kind or multiple compounds are starting material or intermediate to synthesize [(-)-(3Z, 9Z, 6S, the 7R) -6,7- epoxy of levo form 1
18 carbon diene] or d-isomer 2 [18 carbon diene of (+)-(3Z, 9Z, 6R, 7S) -6,7- epoxy].
In formula (A), 2 and 3 have chirality, and formula (A) compound is (2R, 3S) configuration or (2S, 3R) configuration or it is mixed
Close object；R1For p-toluenesulfonyl, mesyl, benzenesulfonyl, p-nitrophenyl sulfonyl etc. is easy to as hydroxyl leaving group
Protecting group, preferred R1For p-toluenesulfonyl.
In formula (B), 2 and 3 have chirality, and formula (B) compound is (2R, 3R) configuration or (2S, 3S) configuration or it is mixed
Close object；R1For p-toluenesulfonyl, mesyl, benzenesulfonyl, p-nitrophenyl sulfonyl etc. is easy to as hydroxyl leaving group
Protecting group, preferred R1For p-toluenesulfonyl.X is Cl, the halogens such as Br, I；Preferably, X Cl.
In formula (C), 2 and 3 have chirality, and formula (C) compound is (2R, 3R) configuration or (2S, 3S) configuration or it is mixed
Close object；X is Cl, the halogens such as Br, I；Preferably, X Cl.
In formula (D), 2 and 3 have chirality, and formula (D) compound is (2R, 3R) configuration or (2S, 3S) configuration or it is mixed
Close object；X is Cl, the halogens such as Br, I；Preferably, X Cl.
In one embodiment, the synthetic route of the levo form or d-isomer includes the following steps (a) to step
(e) any one in or multiple steps:
Step (a):
Step (b):
Step (c):
Step (d):
Step (e): formula (D) compound through ring closure reaction, catalytic hydrogenation reaction obtain levo form 1 [(-)-(3Z, 9Z, 6S,
7R) 18 carbon diene of -6,7- epoxy] or d-isomer 2 [18 carbon diene of (+)-(3Z, 9Z, 6R, 7S) -6,7- epoxy].
In one embodiment, the step (a) is that epoxidation reaction first occurs to react with sulphonic acid anhydride or sulfonic acid chloride again
Obtain formula (A) compound.
In one embodiment, the step (a) is in -40~20 DEG C, halogenated hydrocarbon solvent, in catalyst, oxidation
Epoxidation reaction occurs under the effects of agent and additive；Then in -20~20 DEG C, halogenated hydrocarbons or ether solvent, in organic base
Under effect, reacted with sulphonic acid anhydride or sulfonic acid chloride.
In one embodiment, the step (b) be at -40~0 DEG C, in halogenated hydrocarbons or ether solvent, on road
Lewis acid and the lower generation epoxy ring opening reaction of nucleopilic reagent effect.
In one embodiment, the step (c) is at 0~30 DEG C, in alcohols polar aprotic solvent, inorganic
Alkali effect is lower to occur ring closure reaction.
In one embodiment, the step (d) is at -40~0 DEG C, in ether solvent, in alkali, lewis acid
Lower and 1- decine is acted on complexing agent, and epoxy ring opening reaction occurs.
In one embodiment, the step (e) is at 0~30 DEG C, in alcohols polar aprotic solvent, inorganic
Alkali effect is lower to occur ring closure reaction；Then at 0~30 DEG C, in low boiling point alkane solvent, the ethers or halogenated being saturated by hydrogen
In hydrocarbon solvent, catalytic hydrogenation reaction occurs under lindlar catalyst effect.
In one embodiment, the levo form 1 [18 carbon diene of (-)-(3Z, 9Z, 6S, 7R) -6,7- epoxy]
Synthetic route is as follows:
The synthetic route of the d-isomer 2 [18 carbon diene of (+)-(3Z, 9Z, 6R, 7S) -6,7- epoxy] is as follows:
In statement below, specific synthetic product intermediate is to use Arabic numerals according to the number in structural formula
It indicates, the absolute configuration of R or S expression compound.
In one embodiment, starting material of the invention (2Z, 5Z)-octadiene -1- alcohol (3) can refer to literature method
(J.Org.Chem.1986,51:4726-4728) it is quickly obtained.
In one embodiment, 1)~7 the synthetic method of levo form 1 of the invention includes the following steps):
1) at -40~20 DEG C, compound 3 in halogenated hydrocarbon solvent, catalyst, oxidant and the additive the effects of under
Occur epoxidation reaction, using be quenched, extract, dry, be concentrated after obtain compound 4.
2) at -20~20 DEG C, compound 4 in halogenated hydrocarbons or ether solvent, organic base effect under, with sulphonic acid anhydride or
Sulfonic acid chloride reaction, using extraction, drying, concentration, obtains compound 5 after purification.
3) at -40~0 DEG C, compound 5 is in halogenated hydrocarbons or ether solvent, under lewis acid and nucleopilic reagent effect
Occur epoxy ring opening reaction, using be quenched, extract, dry, be concentrated after obtain compound 6.
4) at 0~30 DEG C, under inorganic base effect ring closure reaction occurs for compound 6 in alcohols polar aprotic solvent,
Using obtaining compound 7 after extraction, drying, concentration.
5) at -40~0 DEG C, compound 7 in ether solvent, alkali, lewis acid and complexing agent effect under with the 1- last of the ten Heavenly stems
Epoxy ring opening reaction occurs for alkynes, using being quenched, extract, dry, be concentrated, obtain compound 8 after purification.
6) at 0~30 DEG C, under inorganic base effect ring closure reaction occurs for compound 8 in alcohols polar aprotic solvent,
Using obtaining compound 9 after extraction, drying, concentration.
7) at 0~30 DEG C, compound 9 in low boiling point alkane solvent, ethers or the halogenated hydrocarbon solvent being saturated by hydrogen,
Catalytic hydrogenation reaction occurs under lindlar catalyst effect, using filtering, concentration, obtains compound 1 after purification.
In one embodiment, 8)~14 the synthetic method of d-isomer 2 of the invention includes the following steps):
8) at -40~20 DEG C, compound 3 in halogenated hydrocarbon solvent, catalyst, oxidant and the additive the effects of under
Occur epoxidation reaction, using be quenched, extract, dry, be concentrated after obtain compound 10.
9) at -20~20 DEG C, compound 10 is in halogenated hydrocarbons or ether solvent, under organic base effect, with sulphonic acid anhydride
Or sulfonic acid chloride reaction, using extraction, drying, concentration, compound 11 is obtained after purification.
10) at -40~0 DEG C, compound 11 is acted in halogenated hydrocarbons or ether solvent in lewis acid and nucleopilic reagent
Lower generation epoxy ring opening reaction, using be quenched, extract, dry, be concentrated after obtain compound 12.
11) at 0~30 DEG C, compound 12 is in alcohols polar aprotic solvent, and generation cyclization is anti-under inorganic base effect
It answers, using obtaining compound 13 after extraction, drying, concentration.
12) at -40~0 DEG C, compound 13 in ether solvent, alkali, lewis acid and complexing agent effect under with 1-
Epoxy ring opening reaction occurs for decine, using being quenched, extract, dry, be concentrated, obtain compound 14 after purification.
13) at 0~30 DEG C, compound 14 is in alcohols polar aprotic solvent, and generation cyclization is anti-under inorganic base effect
It answers, using obtaining compound 15 after extraction, drying, concentration.
14) at 0~30 DEG C, compound 15 is in low boiling point alkane solvent, ethers or the halogenated hydrocarbon solvent being saturated by hydrogen
In, catalytic hydrogenation reaction occurs under lindlar catalyst effect, using filtering, concentration, obtains compound 2 after purification.
In one embodiment, the halogenated hydrocarbon solvent (step 1), step 2), step 3), step 7), step 8), step
It is rapid 9), in step 10) or step 14)), can be selected from C1~C4Halogenated hydrocarbons, especially dichloromethane or chloroform etc..
In one embodiment, in step 1) (or step (a)), the catalyst is titanium catalyst, especially
The metal complex catalysts that tetraisopropyl titanate and D- tartrate are formed.
In one embodiment, in step 1) (or step (a)), the D- tartrate is that D- tartaric acid two is different
Propyl ester and/or D- ethyl tartrate.
In one embodiment, in step 1) (or step (a)), the compound 3: tetraisopropyl titanate: D-
Tartrate: the molar ratio of tert-Butanol peroxide can be 1:1:1.1:2.
In one embodiment, in step 1), (in (or step (a), step 8)), the oxidant can be anhydrous mistake
The nonane solution of the oxygen tert-butyl alcohol.
In one embodiment, in step 1) (or step (a), step 8)), the main function of the additive
It is water suction.
In one embodiment, in step 1) (or step (a), step 8)), the additive isMolecular sieve,Molecular sieve,Molecular sieve, the silica gel of 100~200 mesh or 300~400 mesh and calcium hydride etc..
In one embodiment, ether solvent (step (a), step 2), step 3), step 5), step 7), the step
It is rapid 9), in step 10), step 12) or step 14)) be selected from C2~C4Aliphatic ether or alicyclic ether etc., especially ether or four
Hydrogen furans etc..
In one embodiment, in step 2) (or step (a), step 9)), tertiary amine is can be selected in the organic base
Deng especially imidazoles, pyridine, triethylamine, diisopropyl ethyl amine, diazabicylo (DBU) or triethylene diamine (DABCO)
Deng.
In one embodiment, in step 2) (or step (a), step 9)), trifluoro is can be selected in the sulphonic acid anhydride
Methane sulfonyl chloride, paratoluensulfonyl chloride, benzene sulfonyl chloride, 4-Nitrobenzenesulfonyl chloride can be selected in Loprazolam acid anhydride etc., the sulfonic acid chloride
Deng.
In one embodiment, (or the chemical combination of the compound 4 in step 2) (perhaps step (a), step 9))
Object 10): organic base: the molar ratio of sulphonic acid anhydride or sulfonic acid chloride can be 1:2.0:1.5.
In one embodiment, in step 3) (or step (b), step 10)), alkane is can be selected in the lewis acid
Base aluminium chloride, alkylmagnesium chloride etc., especially dimethylaluminum chloride, diethyl aluminum chloride, di-n-butyl aluminium chloride, diisobutyl
Aluminium chloride etc..
In one embodiment, (or the formula of the compound 5 in step 3) (perhaps step (b), step 10))
(A) compound, compound 11): lewis acidic molar ratio can be 1:2.0.
In one embodiment, the alcohols polar aprotic solvent (step 4), step (c), step 6), step 11) or
In person's step 13)) it can be selected from C1~C4Fatty alcohol, especially methanol or ethyl alcohol etc.；
In one embodiment, inorganic in the step 4), step (c), step 6), step 11) or step 13)
Alkali can be sodium carbonate, potassium carbonate or cesium carbonate etc..
In one embodiment, (or the formula (B) of the compound 6 in step 4) (perhaps step c), step 11))
Compound, compound 12): the molar ratio of inorganic base can be 1:2.0.
In one embodiment, in step 5) (or step (d), step 12)), the lewis acid can be trifluoro
Change borate ether.
In one embodiment, in step 5) (or step (d), step 12)), the complexing agent can be hexamethyl
Phosphoric triamide.
In one embodiment, in step 5) (or step (d), step 12)), alkali can be n-BuLi, Zhong Ding
Base lithium or tert-butyl lithium.
In one embodiment, (or the formula of the compound 7 in step 5) (perhaps step (d), step 12))
(C) compound, compound 13): alkali: lewis acid: complexing agent: the molar ratio of 1- decine can be 1:3.0:3.0:3.0:2.0.
In one embodiment, (or the formula of the compound 8 in step 6) (perhaps step (e), step 13))
(D) compound, compound 14): the molar ratio of inorganic base can be 1:3.0.
In one embodiment, in step 7) (or step (e), step 14)), the low boiling point alkane solvent can
Selected from C5~C6Aliphatic saturated alkane etc., especially pentane, hexamethylene or n-hexane etc..
In one embodiment, in step 7) (or step (e), step 14)), the lindlar catalyst is optional
The Metal Palladium etc. being poisoned from metal lead poisoning or quinoline, catalyst carrier is calcium carbonate or barium sulfate etc..
In one embodiment, (or the chemical combination of the compound 9 in step 7) (perhaps step (e), step 14))
Object 15): the mass fraction ratio of catalyst can be 10:1.
In one embodiment, in step 8) (or step (a)), the catalyst is titanium catalyst, especially
The metal complex catalysts that tetraisopropyl titanate and L-TARTARIC ACID ester are formed.
In one embodiment, in step 8) (or step (a)), the compound 3: tetraisopropyl titanate: L- wine
Stone acid esters: the molar ratio of tert-Butanol peroxide can be 1:1:1.1:2.
In one embodiment, the L-TARTARIC ACID ester is L-TARTARIC ACID diisopropyl ester and/or L-TARTARIC ACID diethylester.
The present invention also provides application of the method in terms of tea geometrid prevention and treatment.
The present invention determines two kinds of mappings by carrying out biological activity test to optically active levo form 1 and d-isomer 2
Activity difference between isomers.
The present invention also provides a kind of tea geometrid tentaculum electric potential reagent, the reagent with levo form [(-)-(3Z, 9Z, 6S,
7R) 18 carbon diene of -6,7- epoxy] it is effective component or principle active component.
In one embodiment, levo form [(-)-(3Z, 9Z, 6S, 7R) -6,7- ring in the effective component of the reagent
18 carbon diene of oxygen] mass fraction be reagent 95% or more, 92% or more, 93%~98%, 72%~85% etc..
In one embodiment, (3Z, 6Z, 9Z) 18 carbon triolefin is also contained in the reagent.
Advantages of the present invention and effect:
(1) present invention with (2Z, 5Z)-octadiene -1- alcohol (3) for being easy to get for starting material, efficiently, highly-solid selectively
Tea geometrid sex pheromone levo form 1 [18 carbon diene of (-)-(3Z, 9Z, 6S, 7R) -6,7- epoxy] and d-isomer 2 are synthesized
[18 carbon diene of (+)-(3Z, 9Z, 6R, 7S) -6,7- epoxy].
(2) each step operation of the present invention is simple, and purifying is simple, and many steps are not required to purifying, and can directly to carry out lower step anti-
It answers, agents useful for same is the common cheap reagent that is easy to get, and route is shorter, is suitble to large-scale production.
(3) present invention is through the synthesis of 7 step total recoverys 27% (-)-(3Z, 9Z, 6S, 7R) -1, and enantioselectivity (ee) is up to
99%；98% is up to through the synthesis of 7 step total recoverys 24% (+)-(3Z, 9Z, 6R, 7S) -2, enantioselectivity (ee).
(4) invention is tested by EAG (tentaculum electric potential), and discovery tea geometrid obviously wants the Electroantennogram response of levo form 1
Higher than d-isomer 2, tea geometrid trapping bait can be prepared into.
Detailed description of the invention:
The optical isomer compound of 18 carbon diene of Fig. 1: (3Z, 9Z) -6,7- epoxy；
A kind of synthetic route of the optical isomer of 18 carbon diene of Fig. 2: (3Z, 9Z) -6,7- epoxy；
Another synthetic route of the optical isomer of 18 carbon diene of Fig. 3: (3Z, 9Z) -6,7- epoxy；
Fig. 4:: Electroantennogram response figure of the single compound to tea geometrid；Wherein epoxide and (3Z, 6Z, 9Z) ten
The proportion of eight carbon triolefins is 6:4；
Fig. 5: Electroantennogram response figure of the binary mixture to tea geometrid；Wherein epoxide and (3Z, 6Z, 9Z) 18
The proportion of carbon triolefin is 6:4.
Specific embodiment
The present invention is further elaborated combined with specific embodiments below.
Embodiment 1
Step 1)It synthesizes (2R, 3S, 5Z) -2,3- epoxy -5- octen-1-ol (4)
Under nitrogen atmosphere protection, with 500mg silica gel mixing 200mg calcium hydride, methylene chloride (25mL) solvent and titanium is added
Sour tetra-isopropyl (3.0mL, 10mmol), is placed at -30 DEG C and stirs, sequentially add D- (-)-ethyl tartrate (2.27g,
The methylene chloride of methylene chloride (10mL) solution, (2Z, 5Z)-octadiene -1- alcohol (3) (1.26g, 10mmol) 11mmol)
(5mL) solution, tert-Butanol peroxide (3.7mL, 20mmol, 5.5M in n-Nonane) then react 2 days in -30 DEG C.With
After the aqueous citric acid solution quenching reaction of 30mL10%, heating stands liquid separation, and water phase is extracted with methylene chloride (2 × 20mL), closes
And organic phase washed again with saturated salt solution (3 × 30mL), be dried over anhydrous sodium sulfate, after filtering and concentrating crude product chemical combination
Object 4 directly carries out next step reaction without purifying.
Step 2)It synthesizes (2R, 3S, 5Z) -2,3- epoxy -5- octen-1-ol p-methyl benzenesulfonic acid ester (5)
Crude product 4 is dissolved in methylene chloride (30mL), triethylamine (2.8mL, 20mmol) is added at 0 DEG C and to toluene
Sulfonic acid chloride (2.86g, 15mmol) continues to stir and slowly returns back to room temperature, after 30mL saturated ammonium chloride solution quenching reaction,
Liquid separation is stood, water phase is extracted with methylene chloride (2 × 20mL), and combined organic phase is washed with saturated salt solution (3 × 30mL) again,
It is dried over anhydrous sodium sulfate, filtering and concentrating obtains compound 5 (1.81g, two step yields 61%) after purification, colourless liquid, [α]D 20=
+ 15.34 (c=1.74in CH2Cl2)；1H NMR(400MHz,CDCl3) δ 7.74 (d, J=8.0Hz, 2H), 7.29 (d, J=
8.0Hz, 2H), 5.51-5.38 (m, 1H), 5.29-5.15 (m, 1H), 4.14 (dd, J=11.2,4.8Hz, 1H), 4.03 (dd, J
=11.2,6.5Hz, 1H), 3.14-3.03 (m, 1H), 2.99-2.87 (m, 1H), 2.38 (s, 3H), 2.26-2.16 (m, 1H),
2.09-1.99 (m, 1H), 1.97-1.86 (m, 2H), 0.88 (t, J=7.5Hz, 3H)；13C NMR(101MHz,CDCl3)δ
145.18,134.98,132.58,129.94,127.96,122.13,68.08,55.92,53.02,26.01,21.64,
20.65,14.07；IR(KBr):γ3060,2960,2932,1625,1448,1250,1098,795,691cm-1；HRMS(ESI)
calculated for C18H20NO[M+H]+:297.11605,found 297.11529.
Step 3)Synthesize the chloro- 5- octen-1-ol p-methyl benzenesulfonic acid ester (6) of (2R, 3R, 5Z) -2- hydroxyl -3-
Under nitrogen atmosphere protection, compound 5 (1.48g, 5mmol) is dissolved in anhydrous tetrahydro furan (50mL), at -40 DEG C
Lower dropwise addition diethyl aluminum chloride (10mL, 10mmol, 1.0M in n-hexane).Half an hour is reacted in continuation at the same temperature
Afterwards, with 10mL saturated ammonium chloride solution quenching reaction, liquid separation, water phase ethyl acetate (3 × 20mL) extraction.Combined organic phase
Concentration is dried, filtered with anhydrous sodium sulfate and obtains compound 6, directly carries out next step reaction without purifying.
Step 4)Synthesize the chloro- 5- octene (7) of (2R, 3R, 5Z) -1,2- epoxy -3-
Crude product 6 is dissolved in methanol (30mL), natrium carbonicum calcinatum (1.06g, 10mmol) is added at 0 DEG C, reaction one
After hour, solvent is added 30mL water and 20mL methylene chloride after being concentrated under reduced pressure, liquid separation, and water phase is with methylene chloride (2 × 20mL)
Extraction, combined organic phase are washed with saturated salt solution (3 × 30mL) again, are dried over anhydrous sodium sulfate, and filtering and concentrating, which obtains, slightly to be produced
Product compound 7 directly carries out next step reaction without purifying.
Step 5)Synthesize the chloro- 18 carbon -3- alkene -9- alkynes -7- alcohol (8) of (6R, 7R, 3Z) -6-
Under nitrogen atmosphere protection, 1- decine (1.38g, 10mmol) is dissolved in anhydrous tetrahydro furan (30mL), at -40 DEG C
Lower dropwise addition n-BuLi (6.3mL, 15mmol, 2.4M in n-hexane).It reacts at the same temperature and three is added ten minutes later
Boron fluoride diethyl ether solution (1.9mL, 15mmol) and hexamethylphosphoramide (2.6mL, 15mmol), then react and be added dropwise ten minutes later
The tetrahydrofuran solution (10mL) of crude product 7.Continue after reacting half an hour at the same temperature, with 10mL saturated ammonium chloride solution
Quenching reaction, liquid separation, water phase are extracted with ethyl acetate (3 × 20mL).Combined organic phase is dried, filtered dense with anhydrous sodium sulfate
Contracting obtains compound 8 (942mg, three step yields 63%) after purification, colourless liquid, [α]D 20=+9.44 (c=1.48in CH2Cl2)
；1H NMR(400MHz,CDCl3) δ 5.49 (dd, J=17.0,7.3Hz, 1H), 5.32 (dd, J=17.0,8.0Hz, 1H), 4.12
(dd, J=9.4,4.5Hz, 1H), 3.75 (d, J=5.6Hz, 1H), 2.67-2.34 (m, 4H), 2.13-1.98 (m, 4H),
1.48-1.35 (m, 2H), 1.30-1.15 (m, 10H), 0.91 (t, J=7.5Hz, 3H), 0.81 (t, J=6.4Hz, 3H)；13C
NMR(101MHz,CDCl3)δ135.30,123.84,83.48,75.08,71.78,66.01,32.85,31.92,29.29,
29.18,28.96,25.36,22.74,20.84,18.79,14.17,14.14；IR(KBr):γ3055,2960,2932,
2205,1621,1430,1098,693cm-1；HRMS(ESI)calculated for C18H20NO[M+H]+:299.21417,
found 299.21459.
Step 6)Synthesize (6S, 7R, 3Z)-ten eight carbon -3- alkene -9- alkynes (9)
Compound 8 (600mg, 2.0mmol) is dissolved in methanol (15mL), at 0 DEG C be added natrium carbonicum calcinatum (636mg,
6mmol).After the reaction was continued one hour, 30mL water and 50mL methylene chloride, liquid separation is added in solvent after being concentrated under reduced pressure, and water phase is used
Methylene chloride (2 × 20mL) extraction, combined organic phase are washed with saturated salt solution (3 × 30mL) again, dry through anhydrous sodium sulfate
Dry, filtering and concentrating obtains crude product compound 9, directly carries out next step reaction without purifying.
Step 7)Synthesize left-handed -18 carbon diene (1) of (3Z, 9Z, 6S, 7R) -6,7- epoxy
Under room temperature and nitrogen atmosphere, to lindlar catalyst (Pd/BaSO4/ quinoline, 50mg, 10wt%) in be added chemical combination
Methylene chloride (20mL) solution of object 9, reaction filtered away catalyst after two hours, and filter cake is washed with methylene chloride, filtrate warp
Colourless liquid 1 (375mg, two step yields 71%) are obtained after concentrating and purifying.[α]D 20=-1.29 (c=1.5in CH2Cl2)；1H NMR
(400MHz,CDCl3)δ5.60-5.50(m,2H),5.47-5.37(m,2H),2.97-2.91(m,2H),2.45-2.36(m,
2H), 2.26-2.16 (m, 2H), 2.09-1.99 (m, 4H), 1.37-1.26 (m, 12H), 0.99 (t, J=7.5Hz, 3H), 0.87
(t, J=7.0Hz, 3H)；13C-NMR(CDCl3,101MHz)δ(ppm):134.49,133.01,123.21,122.58,57.62,
31.81,29.65,29.49,29.18,27.33,22.65,14.15,14.01；IR(KBr):γ2956,2921,1734,
1657,1459,1260,1015cm-1；HRMS(ESI)calculated for C18H20NO[M+H]+:265.25314,found
265.25247.
Step 8)It synthesizes (2S, 3R, 5Z) -2,3- epoxy -5- octen-1-ol (10)
Under nitrogen atmosphere protection, with 600mg silica gel mixing 300mg calcium hydride, methylene chloride (35mL) solvent and titanium is added
Sour tetra-isopropyl (4.5mL, 15mmol), is placed at -30 DEG C and stirs, sequentially add L- (+)-ethyl tartrate (3.4g,
The methylene chloride of methylene chloride (15mL) solution, (2Z, 5Z)-octadiene -1- alcohol (3) (1.89g, 15mmol) 16.5mmol)
(10mL) solution, tert-Butanol peroxide (5.5mL, 30mmol, 5.5M in n-Nonane) then react 2 days in -30 DEG C.With
After the aqueous citric acid solution quenching reaction of 30mL10%, heating stands liquid separation, and water phase is extracted with methylene chloride (2 × 30mL), closes
And organic phase washed again with saturated salt solution (3 × 30mL), be dried over anhydrous sodium sulfate, after filtering and concentrating crude product chemical combination
Object 10 directly carries out next step reaction without purifying.
Step 9)It synthesizes (2S, 3R, 5Z) -2,3- epoxy -5- octen-1-ol p-methyl benzenesulfonic acid ester (11)
Crude product 10 is dissolved in methylene chloride (40mL), triethylamine (4.2mL, 30mmol) is added at 0 DEG C and to first
Benzene sulfonyl chloride (4.29g, 22.5mmol) continues to stir and slowly returns back to room temperature, is quenched instead with 30mL saturated ammonium chloride solution
Ying Hou stands liquid separation, and water phase is extracted with methylene chloride (2 × 30mL), and combined organic phase uses saturated salt solution (3 × 30mL) again
Washing, is dried over anhydrous sodium sulfate, and filtering and concentrating obtains compound 11 (2.62g, two step yields 59%) after purification, colourless liquid,
[α]D 20=-14.88 (c=1.69in CH2Cl2)；1H NMR(400MHz,CDCl3) δ 7.74 (d, J=8.0Hz, 2H), 7.29
(d, J=8.0Hz, 2H), 5.51-5.38 (m, 1H), 5.29-5.15 (m, 1H), 4.14 (dd, J=11.2,4.8Hz, 1H),
4.03 (dd, J=11.2,6.5Hz, 1H), 3.14-3.03 (m, 1H), 2.99-2.87 (m, 1H), 2.38 (s, 3H), 2.26-
2.16 (m, 1H), 2.09-1.99 (m, 1H), 1.97-1.86 (m, 2H), 0.88 (t, J=7.5Hz, 3H)；13C NMR(101MHz,
CDCl3)δ145.18,134.98,132.58,129.94,127.96,122.13,68.08,55.92,53.02,26.01,
21.64,20.65,14.07；IR(KBr):γ3060,2960,2932,1625,1448,1250,1098,795,691cm-1；
HRMS(ESI)calculated for C18H20NO[M+H]+:297.11605,found 297.11544.
Step 10)Synthesize the chloro- 5- octen-1-ol p-methyl benzenesulfonic acid ester (12) of (2S, 3S, 5Z) -2- hydroxyl -3-
Under nitrogen atmosphere protection, compound 11 (1.48g, 5mmol) is dissolved in anhydrous tetrahydro furan (50mL), -40
Diethyl aluminum chloride (10mL, 10mmol, 1.0M in n-hexane) is added dropwise at DEG C.Half an hour is reacted in continuation at the same temperature
Afterwards, with 10mL saturated ammonium chloride solution quenching reaction, liquid separation, water phase ethyl acetate (3 × 20mL) extraction.Combined organic phase
Concentration is dried, filtered with anhydrous sodium sulfate and obtains compound 12, directly carries out next step reaction without purifying.
Step 11)Synthesize the chloro- 5- octene (13) of (2S, 3S, 5Z) -1,2- epoxy -3-
Crude product 12 is dissolved in methanol (30mL), natrium carbonicum calcinatum (1.06g, 10mmol) is added at 0 DEG C, reaction one
After hour, solvent is added 30mL water and 20mL methylene chloride after being concentrated under reduced pressure, liquid separation, and water phase is with methylene chloride (2 × 20mL)
Extraction, combined organic phase are washed with saturated salt solution (3 × 30mL) again, are dried over anhydrous sodium sulfate, and filtering and concentrating, which obtains, slightly to be produced
Product compound 13 directly carries out next step reaction without purifying.
Step 12)Synthesize the chloro- 18 carbon -3- alkene -9- alkynes -7- alcohol (14) of (6S, 7S, 3Z) -6-
Under nitrogen atmosphere protection, 1- decine (1.38g, 10mmol) is dissolved in anhydrous tetrahydro furan (30mL), at -40 DEG C
Lower dropwise addition n-BuLi (6.3mL, 15mmol, 2.4M in n-hexane).It reacts at the same temperature and three is added ten minutes later
Boron fluoride diethyl ether solution (1.9mL, 15mmol) and hexamethylphosphoramide (2.6mL, 15mmol), then react and be added dropwise ten minutes later
The tetrahydrofuran solution (10mL) of crude product 13.Continue after reacting half an hour at the same temperature, it is molten with 10mL saturated ammonium chloride
Liquid quenching reaction, liquid separation, water phase are extracted with ethyl acetate (3 × 20mL).Combined organic phase is dried, filtered with anhydrous sodium sulfate
Compound 14 (897mg, three step yields 60%) are obtained after concentrating and purifying, colourless liquid, [α]D 20=-9.12 (c=1.40in
CH2Cl2)；1H NMR(400MHz,CDCl3) δ 5.49 (dd, J=17.0,7.3Hz, 1H), 5.32 (dd, J=17.0,8.0Hz,
1H), 4.12 (dd, J=9.4,4.5Hz, 1H), 3.75 (d, J=5.6Hz, 1H), 2.67-2.34 (m, 4H), 2.13-1.98 (m,
4H), 1.48-1.35 (m, 2H), 1.30-1.15 (m, 10H), 0.91 (t, J=7.5Hz, 3H), 0.81 (t, J=6.4Hz, 3H)
；13C NMR(101MHz,CDCl3)δ135.30,123.84,83.48,75.08,71.78,66.01,32.85,31.92,
29.29,29.18,28.96,25.36,22.74,20.84,18.79,14.17,14.14；IR(KBr):γ3055,2960,
2932,2205,1621,1430,1098,693cm-1；HRMS(ESI)calculated for C18H20NO[M+H]+:
299.21417,found 299.21463.
Step 13)Synthesize (6R, 7S, 3Z)-ten eight carbon -3- alkene -9- alkynes (15)
Compound 14 (600mg, 2.0mmol) is dissolved in methanol (15mL), natrium carbonicum calcinatum is added at 0 DEG C
(636mg, 6mmol).After the reaction was continued one hour, solvent is added 30mL water and 50mL methylene chloride after being concentrated under reduced pressure, liquid separation,
Water phase is extracted with methylene chloride (2 × 20mL), and combined organic phase is washed with saturated salt solution (3 × 30mL) again, through anhydrous sulphur
Sour sodium, which dries, filters, is concentrated to give crude product compound 15, directly carries out next step reaction without purifying.
Step 14)Synthesize 18 carbon diene (2) of dextrorotation-(3Z, 9Z, 6R, 7S) -6,7- epoxy
Under room temperature and nitrogen atmosphere, to lindlar catalyst (Pd/BaSO4/ quinoline, 50mg, 10wt%) in be added chemical combination
Methylene chloride (20mL) solution of object 15, reaction filtered away catalyst after two hours, and filter cake is washed with methylene chloride, filtrate warp
Colourless liquid 2 (364mg, two step yields 69%) are obtained after concentrating and purifying.[α]D 20=+1.62 (c=1.1in CH2Cl2)；1H NMR
(400MHz,CDCl3)δ5.60-5.50(m,2H),5.47-5.37(m,2H),2.97-2.91(m,2H),2.45-2.36(m,
2H), 2.26-2.16 (m, 2H), 2.09-1.99 (m, 4H), 1.37-1.26 (m, 12H), 0.99 (t, J=7.5Hz, 3H), 0.87
(t, J=7.0Hz, 3H)；13C-NMR(CDCl3,101MHz)δ(ppm):134.49,133.01,123.21,122.58,57.62,
31.81,29.65,29.49,29.18,27.33,22.65,14.15,14.01；IR(KBr):γ2956,2921,1734,
1657,1459,1260,1015cm-1；HRMS(ESI)calculated for C18H20NO[M+H]+:265.25314,found
265.25247.
Embodiment 2
Step 1)It synthesizes (2R, 3S, 5Z) -2,3- epoxy -5- octen-1-ol (4)
Under nitrogen atmosphere protection, to 500mgMethylene chloride (25mL) solvent and tetraisopropyl titanate is added in molecular sieve
(3.0mL, 10mmol) is placed at -30 DEG C and stirs, and sequentially adds the two of D- (-)-ethyl tartrate (2.27g, 11mmol)
Methylene chloride (5mL) solution, peroxide of chloromethanes (10mL) solution, (2Z, 5Z)-octadiene -1- alcohol (3) (1.26g, 10mmol)
The tert-butyl alcohol (3.7mL, 20mmol, 5.5M in n-Nonane) then reacts 2 days in -30 DEG C.With 10% aqueous citric acid solution
After quenching reaction, heating stands liquid separation, and water phase is extracted with dichloromethane, and combined organic phase uses saturated common salt water washing again, warp
Anhydrous sodium sulfate obtains crude product compound 4 after drying, filtering concentration, directly carries out next step reaction without purifying.
Step 2)It synthesizes (2R, 3S, 5Z) -2,3- epoxy -5- octen-1-ol p-methyl benzenesulfonic acid ester (5)
Crude product 4 is dissolved in pyridine (30mL), paratoluensulfonyl chloride is added at 0 DEG C, continues to stir and slowly reply
Liquid separation is stood after saturated ammonium chloride solution quenching reaction to room temperature, water phase is extracted with methylene chloride (2 × 20mL), merging
Organic phase successively uses 1M hydrochloric acid, saturated common salt water washing, is dried over anhydrous sodium sulfate, and filtering and concentrating obtains colourless liquid after purification
It closes object 5 (two step yields 56%).
Step 3)Synthesize the chloro- 5- octen-1-ol p-methyl benzenesulfonic acid ester (6) of (2R, 3R, 5Z) -2- hydroxyl -3-
Under nitrogen atmosphere protection, compound 5 is dissolved in anhydrous ether, dimethylaluminum chloride (0.9M is added dropwise at -40 DEG C
in heptane).Continue after reacting half an hour at the same temperature, with saturated ammonium chloride solution quenching reaction, liquid separation, water phase is used
Ethyl acetate extraction.Combined organic phase with anhydrous sodium sulfate dry, filter concentration obtain compound 6, without purifying directly into
Row reacts in next step.
Step 4)Synthesize the chloro- 5- octene (7) of (2R, 3R, 5Z) -1,2- epoxy -3-
Crude product 6 is dissolved in methanol, Anhydrous potassium carbonate is added at 0 DEG C, after reaction one hour, solvent is through being concentrated under reduced pressure
Water is added afterwards and methylene chloride, liquid separation, water phase are extracted with dichloromethane, combined organic phase uses saturated common salt water washing again, warp
Anhydrous sodium sulfate, which dries, filters, is concentrated to give crude product compound 7, directly carries out next step reaction without purifying.
Step 5)Synthesize the chloro- 18 carbon -3- alkene -9- alkynes -7- alcohol (8) of (6R, 7R, 3Z) -6-
Under nitrogen atmosphere protection, 1- decine is dissolved in anhydrous tetrahydro furan, tert-butyl lithium (1.6M is added dropwise at -40 DEG C
in pentane).It reacts at the same temperature and boron trifluoride ether solution and hexamethylphosphoramide is added ten minutes later, then instead
The tetrahydrofuran solution of crude product 7 should be added dropwise ten minutes later.Continue after reacting half an hour at the same temperature, uses saturated ammonium chloride
Solution quenching reaction, liquid separation, water phase are extracted with ethyl acetate.Combined organic phase with anhydrous sodium sulfate dry, filter concentration it is pure
Colourless liquid compound 8 (three step yields 55%) is obtained after change.
Step 6)Synthesize (6S, 7R, 3Z)-ten eight carbon -3- alkene -9- alkynes (9)
Compound 8 is dissolved in methanol, Anhydrous potassium carbonate is added at 0 DEG C.After the reaction was continued one hour, solvent is through depressurizing
Water is added after concentration and methylene chloride, liquid separation, water phase are extracted with dichloromethane, combined organic phase is washed with saturated common salt again
It washs, is dried over anhydrous sodium sulfate, filtering and concentrating obtains crude product compound 9, directly carries out next step reaction without purifying.
Step 7)Synthesize left-handed -18 carbon diene (1) of (3Z, 9Z, 6S, 7R) -6,7- epoxy
Under 0 DEG C and nitrogen atmosphere, to lindlar catalyst (Pd/CaCO3/Pd2+, 10wt%) in be added compound 9 second
Ethereal solution, reaction filtered away catalyst after two hours, and filter cake is washed with ether, and concentrating filter liquor obtains colourless liquid 1 after purification
(two step yields 73%).
Step 8)It synthesizes (2S, 3R, 5Z) -2,3- epoxy -5- octen-1-ol (10)
Under nitrogen atmosphere protection, to 700mgMethylene chloride (35mL) solvent and tetraisopropyl titanate is added in molecular sieve
(4.5mL, 15mmol) is placed at -30 DEG C and stirs, and sequentially adds L- (+)-ethyl tartrate (3.4g, 16.5mmol)
Methylene chloride (15mL) solution, (2Z, 5Z)-octadiene -1- alcohol (3) (1.89g, 15mmol) methylene chloride (10mL) solution,
Tert-Butanol peroxide (5.5mL, 30mmol, 5.5M in n-Nonane) then reacts 2 days in -30 DEG C.With 10% citric acid water
After solution quenching reaction, heating stands liquid separation, and water phase is extracted with dichloromethane, and combined organic phase is washed with saturated common salt again
It washs, is dried over anhydrous sodium sulfate, crude product compound 10 is obtained after filtering and concentrating, directly carry out next step reaction without purifying.
Step 9)It synthesizes (2S, 3R, 5Z) -2,3- epoxy -5- octen-1-ol p-methyl benzenesulfonic acid ester (11)
Crude product 10 is dissolved in pyridine (30mL), paratoluensulfonyl chloride is added at 0 DEG C, continues to stir and slowly reply
To room temperature, after saturated ammonium chloride solution quenching reaction, stand liquid separation, water phase is extracted with dichloromethane, combined organic phase according to
It is secondary to use 1M hydrochloric acid, saturated common salt water washing, it is dried over anhydrous sodium sulfate, filtering and concentrating obtains (the two step yields of compound 11 after purification
57%).
Step 10)Synthesize the chloro- 5- octen-1-ol p-methyl benzenesulfonic acid ester (12) of (2S, 3S, 5Z) -2- hydroxyl -3-
Under nitrogen atmosphere protection, compound 11 is dissolved in anhydrous ether, dimethylaluminum chloride is added dropwise at -40 DEG C
(0.9M in heptane).Continue after reacting half an hour at the same temperature, with saturated ammonium chloride solution quenching reaction, liquid separation,
Water phase is extracted with ethyl acetate.Combined organic phase dries, filters concentration with anhydrous sodium sulfate and obtains compound 12, without purifying
Directly carry out next step reaction.
Step 11)Synthesize the chloro- 5- octene (13) of (2S, 3S, 5Z) -1,2- epoxy -3-
Crude product 12 is dissolved in methanol, Anhydrous potassium carbonate is added at 0 DEG C, after reaction one hour, solvent is dense through depressurizing
It being added after contracting and methylene chloride, liquid separation, water phase is extracted with dichloromethane, combined organic phase uses saturated common salt water washing again,
It is dried over anhydrous sodium sulfate, filtering and concentrating obtains crude product compound 13, directly carries out next step reaction without purifying.
Step 12)Synthesize the chloro- 18 carbon -3- alkene -9- alkynes -7- alcohol (14) of (6S, 7S, 3Z) -6-
Under nitrogen atmosphere protection, 1- decine is dissolved in anhydrous tetrahydro furan, tert-butyl lithium (1.6M is added dropwise at -40 DEG C
in pentane).It reacts at the same temperature and boron trifluoride ether solution and hexamethylphosphoramide is added ten minutes later, then instead
The tetrahydrofuran solution of crude product 13 should be added dropwise ten minutes later.Continue after reacting half an hour at the same temperature, with saturation chlorination
Ammonium salt solution quenching reaction, liquid separation, water phase are extracted with ethyl acetate.Combined organic phase dries, filters concentration with anhydrous sodium sulfate
Obtain compound 14 (three step yields 62%) after purification.
Step 13)Synthesize (6R, 7S, 3Z)-ten eight carbon -3- alkene -9- alkynes (15)
Compound 14 is dissolved in methanol, Anhydrous potassium carbonate is added at 0 DEG C.After the reaction was continued one hour, solvent is through subtracting
Water is added after pressure concentration and methylene chloride, liquid separation, water phase are extracted with dichloromethane, combined organic phase is washed with saturated common salt again
It washs, is dried over anhydrous sodium sulfate, filtering and concentrating obtains crude product compound 15, directly carries out next step reaction without purifying.
Step 14)Synthesize 18 carbon diene (2) of dextrorotation-(3Z, 9Z, 6R, 7S) -6,7- epoxy
Under 0 DEG C and nitrogen atmosphere, to lindlar catalyst (Pd/CaCO3/Pd2+, 10wt%) in be added compound 15 second
Ethereal solution, reaction filtered away catalyst after two hours, and filter cake is washed with ether, and concentrating filter liquor obtains colourless liquid 2 after purification
(two step yields 70%).
Embodiment 3
Step 1)It synthesizes (2R, 3S, 5Z) -2,3- epoxy -5- octen-1-ol (4)
Under nitrogen atmosphere protection, to 500mgMethylene chloride (25mL) solvent and tetraisopropyl titanate is added in molecular sieve
(3.0mL, 10mmol) is placed at -30 DEG C and stirs, and sequentially adds the two of D- (-)-ethyl tartrate (2.27g, 11mmol)
Methylene chloride (5mL) solution, peroxide of chloromethanes (10mL) solution, (2Z, 5Z)-octadiene -1- alcohol (3) (1.26g, 10mmol)
The tert-butyl alcohol (3.7mL, 20mmol, 5.5M in n-Nonane) then reacts 2 days in -30 DEG C.With 10% aqueous citric acid solution
After quenching reaction, heating stands liquid separation, and water phase is extracted with dichloromethane, and combined organic phase uses saturated common salt water washing again, warp
Anhydrous sodium sulfate obtains crude product compound 4 after drying, filtering concentration, directly carries out next step reaction without purifying.
Step 2)It synthesizes (2R, 3S, 5Z) -2,3- epoxy -5- octen-1-ol p-methyl benzenesulfonic acid ester (5)
Crude product 4 is dissolved in anhydrous tetrahydro furan, imidazoles and paratoluensulfonyl chloride are added at 0 DEG C, continues stirring simultaneously
Room temperature slowly is returned back to, after saturated ammonium chloride solution quenching reaction, stands liquid separation, water phase is extracted with dichloromethane, merging
Organic phase successively uses 1M hydrochloric acid, saturated common salt water washing, is dried over anhydrous sodium sulfate, and filtering and concentrating obtains colourless liquid after purification
It closes object 5 (two step yields 64%).
Step 3)Synthesize the chloro- 5- octen-1-ol p-methyl benzenesulfonic acid ester (6) of (2R, 3R, 5Z) -2- hydroxyl -3-
Under nitrogen atmosphere protection, compound 5 is dissolved in methylene chloride, diisobutyl aluminum chloride is added dropwise at -40 DEG C
(0.8M in heptane).Continue after reacting half an hour at the same temperature, with saturated ammonium chloride solution quenching reaction, liquid separation,
Water phase is extracted with dichloromethane.Combined organic phase dries, filters concentration with anhydrous sodium sulfate and obtains compound 6, without purifying
Directly carry out next step reaction.
Step 4)Synthesize the chloro- 5- octene (7) of (2R, 3R, 5Z) -1,2- epoxy -3-
Crude product 6 is dissolved in dehydrated alcohol, Anhydrous potassium carbonate is added at 0 DEG C, after reaction one hour, solvent is through depressurizing
Water is added after concentration and methylene chloride, liquid separation, water phase are extracted with dichloromethane, combined organic phase is washed with saturated common salt again
It washs, is dried over anhydrous sodium sulfate, filtering and concentrating obtains crude product compound 7, directly carries out next step reaction without purifying.
Step 5)Synthesize the chloro- 18 carbon -3- alkene -9- alkynes -7- alcohol (8) of (6R, 7R, 3Z) -6-
Under nitrogen atmosphere protection, 1- decine is dissolved in anhydrous ether, n-BuLi (2.4M in is added dropwise at -40 DEG C
n-hexane).It reacts at the same temperature and boron trifluoride ether solution and hexamethylphosphoramide is added ten minutes later, then react
The tetrahydrofuran solution of crude product 7 is added dropwise ten minutes later.Continue after reacting half an hour at the same temperature, it is molten with saturated ammonium chloride
Liquid quenching reaction, liquid separation, water phase are extracted with ethyl acetate.Combined organic phase dries, filters concentrating and purifying with anhydrous sodium sulfate
Obtain colourless liquid compound 8 (three step yields 57%) afterwards.
Step 6)Synthesize (6S, 7R, 3Z)-ten eight carbon -3- alkene -9- alkynes (9)
Compound 8 is dissolved in dehydrated alcohol, Anhydrous potassium carbonate is added at 0 DEG C.After the reaction was continued one hour, solvent warp
Water is added after reduced pressure and methylene chloride, liquid separation, water phase are extracted with dichloromethane, combined organic phase uses saturated salt solution again
Washing, is dried over anhydrous sodium sulfate, and filtering and concentrating obtains crude product compound 9, directly carries out next step reaction without purifying.
Step 7)Synthesize left-handed -18 carbon diene (1) of (3Z, 9Z, 6S, 7R) -6,7- epoxy
Under 0 DEG C and nitrogen atmosphere, to lindlar catalyst (Pd/BaSO4/ quinoline, 10wt%) in be added compound 9 stone
Oily ethereal solution, reaction filtered away catalyst after two hours, and filter cake is washed with ether, and concentrating filter liquor obtains colourless liquid after purification
1 (two step yields 72%).
Step 8)It synthesizes (2S, 3R, 5Z) -2,3- epoxy -5- octen-1-ol (10)
Under nitrogen atmosphere protection, to 700mgMethylene chloride (35mL) solvent and tetraisopropyl titanate is added in molecular sieve
(4.5mL, 15mmol) is placed at -30 DEG C and stirs, and sequentially adds L- (+)-ethyl tartrate (3.4g, 16.5mmol)
Methylene chloride (15mL) solution, (2Z, 5Z)-octadiene -1- alcohol (3) (1.89g, 15mmol) methylene chloride (10mL) solution,
Tert-Butanol peroxide (5.5mL, 30mmol, 5.5M in n-Nonane) then reacts 2 days in -30 DEG C.With 10% citric acid water
After solution quenching reaction, heating stands liquid separation, and water phase is extracted with dichloromethane, and combined organic phase is washed with saturated common salt again
It washs, is dried over anhydrous sodium sulfate, crude product compound 10 is obtained after filtering and concentrating, directly carry out next step reaction without purifying.
Step 9)It synthesizes (2S, 3R, 5Z) -2,3- epoxy -5- octen-1-ol p-methyl benzenesulfonic acid ester (11)
Crude product 10 is dissolved in tetrahydrofuran, imidazoles and paratoluensulfonyl chloride are added at 0 DEG C, continues stirring and slow
Return back to room temperature, after saturated ammonium chloride solution quenching reaction, stand liquid separation, water phase is extracted with dichloromethane, merging it is organic
1M hydrochloric acid, saturated common salt water washing are mutually successively used, is dried over anhydrous sodium sulfate, filtering and concentrating obtains (two steps of compound 11 after purification
Yield 58%).
Step 10)Synthesize the chloro- 5- octen-1-ol p-methyl benzenesulfonic acid ester (12) of (2S, 3S, 5Z) -2- hydroxyl -3-
Under nitrogen atmosphere protection, compound 11 is dissolved in no methylene chloride, diisobutyl aluminum chloride is added dropwise at -40 DEG C
(0.8M in heptane).Continue after reacting half an hour at the same temperature, with saturated ammonium chloride solution quenching reaction, liquid separation,
Water phase is extracted with dichloromethane.Combined organic phase dries, filters concentration with anhydrous sodium sulfate and obtains compound 12, without purifying
Directly carry out next step reaction.
Step 11)Synthesize the chloro- 5- octene (13) of (2S, 3S, 5Z) -1,2- epoxy -3-
Crude product 12 is dissolved in dehydrated alcohol, Anhydrous potassium carbonate is added at 0 DEG C, after reaction one hour, solvent is through subtracting
Water is added after pressure concentration and methylene chloride, liquid separation, water phase are extracted with dichloromethane, combined organic phase is washed with saturated common salt again
It washs, is dried over anhydrous sodium sulfate, filtering and concentrating obtains crude product compound 13, directly carries out next step reaction without purifying.
Step 12)Synthesize the chloro- 18 carbon -3- alkene -9- alkynes -7- alcohol (14) of (6S, 7S, 3Z) -6-
Under nitrogen atmosphere protection, 1- decine is dissolved in anhydrous ether, n-BuLi (2.4M in is added dropwise at -40 DEG C
n-hexane).It reacts at the same temperature and boron trifluoride ether solution and hexamethylphosphoramide is added ten minutes later, then react
The tetrahydrofuran solution of crude product 13 is added dropwise ten minutes later.Continue after reacting half an hour at the same temperature, uses saturated ammonium chloride
Solution quenching reaction, liquid separation, water phase are extracted with ethyl acetate.Combined organic phase with anhydrous sodium sulfate dry, filter concentration it is pure
Compound 14 (three step yields 62%) is obtained after change.
Step 13)Synthesize (6R, 7S, 3Z)-ten eight carbon -3- alkene -9- alkynes (15)
Compound 14 is dissolved in dehydrated alcohol, Anhydrous potassium carbonate is added at 0 DEG C.After the reaction was continued one hour, solvent
Water is added after being concentrated under reduced pressure and methylene chloride, liquid separation, water phase are extracted with dichloromethane, combined organic phase uses saturated common salt again
Water washing is dried over anhydrous sodium sulfate, and filtering and concentrating obtains crude product compound 15, directly carries out next step reaction without purifying.
Step 14)Synthesize 18 carbon diene (2) of dextrorotation-(3Z, 9Z, 6R, 7S) -6,7- epoxy
Under 0 DEG C and nitrogen atmosphere, to lindlar catalyst (Pd/BaSO4/ quinoline, 10wt%) in compound 15 is added
Petroleum ether solution, reaction two hours after filter away catalyst, filter cake is washed with ether, concentrating filter liquor after purification colourless liquid
Body 2 (two step yields 67%).
Embodiment 4:
The present invention by EAG (tentaculum electric potential) test to the tea geometrid sex pheromone levo form 1 of synthesis [(-)-(3Z, 9Z,
6S, 7R) 18 carbon diene of -6,7- epoxy], d-isomer 2 [18 carbon diene of (+)-(3Z, 9Z, 6R, 7S) -6,7- epoxy] and
The compounds such as known tea geometrid sex pheromone racemic modification have carried out biological activity test, as a result as shown in Fig. 4-Fig. 5.As a result
Show either pure levo form, d-isomer and racemic modification, or these types of isomers and (3Z, 6Z, 9Z)-ten eight carbon three
The proportion mixture of alkene (triene), tea geometrid are substantially higher in d-isomer 2 Electroantennogram response of levo form 1.
The present invention also passes through wind tunnel experiment to the tea geometrid sex pheromone levo form 1 [(-)-(3Z, 9Z, 6S, 7R)-of synthesis
18 carbon diene of 6,7- epoxy], d-isomer 2 [18 carbon diene of (+)-(3Z, 9Z, 6R, 7S) -6,7- epoxy] and known tea
The compounds such as looper sex pheromone racemic modification have carried out biological activity test, the results are shown in Table 1.As a result levo form 1 is again showed that
The activity of trapping tea geometrid is apparently higher than d-isomer 2.
Wind tunnel experiment of the different trapping baits of table 1 to tea geometrid
Its absolute configuration is identified since natural tea geometrid sex pheromone is difficult to separate, it can be with by the above biological activity test
The levo form 1 that the preliminary judgement present invention synthesizes has the ability of preferably trapping tea geometrid, and d-isomer 2 is basic for tea geometrid
Do not trap activity.
The foregoing is merely preferred embodiments of the invention, are not intended to restrict the invention, although referring to previous examples
It describes the invention in detail, for those skilled in the art, foregoing embodiments can still be remembered
The technical solution of load is modified or equivalent replacement of some of the technical features.It is all in spirit and original of the invention
Any modification, equivalent replacement, improvement and so within then, should all be included in the protection scope of the present invention.
Claims (2)
1. a kind of synthesis side of tea geometrid sex pheromone levo form 1 [18 carbon diene of (-)-(3Z, 9Z, 6S, 7R) -6,7- epoxy]
Method, which is characterized in that the synthetic route of the levo form 1 [18 carbon diene of (-)-(3Z, 9Z, 6S, 7R) -6,7- epoxy] is such as
Under:
Include the following steps 1)~7):
1) under nitrogen atmosphere protection, with 500mg silica gel mixing 200mg calcium hydride, 25mL dichloromethane solvent and 3.0mL titanium is added
Sour tetra-isopropyl is placed at -30 DEG C and stirs, and sequentially adds D- (-)-ethyl tartrate dichloromethane of 10mL1.1mol/L
Alkane solution, the dichloromethane solution of (2Z, 5Z)-octadiene -1- alcohol (3) of 5mL2mol/L, 3.7mL 5.5M tert-Butanol peroxide
N -nonane solution, then in -30 DEG C react 2 days；It after the aqueous citric acid solution quenching reaction of 30mL10%, heats up, stands
Liquid separation, water phase are extracted with 2 × 20mL of methylene chloride, and combined organic phase is washed with 3 × 30mL of saturated salt solution again, through anhydrous sulphur
Sour sodium obtains crude product compound 4 after drying, filtering concentration, directly carries out next step reaction without purifying；
2) crude product 4 is dissolved in 30mL methylene chloride, 2.8mL triethylamine and 2.86g paratoluensulfonyl chloride is added at 0 DEG C,
Continue to stir and slowly return back to room temperature, after 30mL saturated ammonium chloride solution quenching reaction, stands liquid separation, water phase dichloromethane
2 × 20mL of alkane extraction, combined organic phase are washed with 3 × 30mL of saturated salt solution again, are dried over anhydrous sodium sulfate, filtering and concentrating
Compound 5 is obtained after purification；
3) under nitrogen atmosphere protection, 1.48g compound 5 is dissolved in 50mL anhydrous tetrahydro furan, 10mL is added dropwise at -40 DEG C
The hexane solution of the diethyl aluminum chloride of 1.0M continues after reacting half an hour at the same temperature, with 10mL saturated ammonium chloride
Solution quenching reaction, liquid separation, water phase are extracted with 3 × 20mL of ethyl acetate, and combined organic phase is dried, filtered with anhydrous sodium sulfate
Concentration obtains compound 6, directly carries out next step reaction without purifying；
4) crude product 6 is dissolved in 30mL methanol, 1.06g natrium carbonicum calcinatum is added at 0 DEG C, after reaction one hour, solvent warp
30mL water and 20mL methylene chloride, liquid separation are added after reduced pressure, water phase is extracted with 2 × 20mL of methylene chloride, merging it is organic
3 × 30mL of Xiang Zaiyong saturated salt solution washing, is dried over anhydrous sodium sulfate, and filtering and concentrating obtains crude product compound 7, without purifying
Directly carry out next step reaction；
5) under nitrogen atmosphere protection, 1.38g1- decine is dissolved in 30mL anhydrous tetrahydro furan, 6.3mL is added dropwise at -40 DEG C
The hexane solution of 2.4M n-BuLi, react at the same temperature ten minutes later be added 1.9mL boron trifluoride ether solution and
2.6mL hexamethylphosphoramide, then the tetrahydrofuran solution that 10mL crude product 7 is added dropwise ten minutes later is reacted, continue in Xiang Tongwen
After degree lower reaction half an hour, with 10mL saturated ammonium chloride solution quenching reaction, liquid separation, water phase is extracted with 3 × 20mL of ethyl acetate,
Combined organic phase obtains compound 8 after drying, filtering concentrating and purifying with anhydrous sodium sulfate；
6) 600mg compound 8 is dissolved in 15mL methanol, 636mg natrium carbonicum calcinatum is added at 0 DEG C, the reaction was continued one hour
Afterwards, 30mL water and 50mL methylene chloride, liquid separation is added in solvent after being concentrated under reduced pressure, and water phase is extracted with 2 × 20mL of methylene chloride, closes
And organic phase washed again with 3 × 30mL of saturated salt solution, be dried over anhydrous sodium sulfate, filtering and concentrating obtains crude product compound 9,
Next step reaction is directly carried out without purifying；
7) under room temperature and nitrogen atmosphere, to the Pd/BaSO of 50mg, 10wt%420mL chemical combination is added in/quinoline lindlar catalyst
The dichloromethane solution of object 9, Filtration of catalyst after reaction two hours, filter cake are washed with methylene chloride, and concentrating filter liquor is pure
Colourless liquid 1 is obtained after change.
2. a kind of preparation side of tea geometrid sex pheromone d-isomer 2 [18 carbon diene of (+)-(3Z, 9Z, 6R, 7S) -6,7- epoxy]
Method, which is characterized in that the synthetic route of the d-isomer 2 [18 carbon diene of (+)-(3Z, 9Z, 6R, 7S) -6,7- epoxy] is such as
Under:
Include the following steps 8)~14):
8) under nitrogen atmosphere protection, with 600mg silica gel mixing 300mg calcium hydride, 35mL dichloromethane solvent and 4.5mL titanium is added
Sour tetra-isopropyl is placed at -30 DEG C and stirs, and sequentially adds L- (+)-ethyl tartrate dichloromethane of 15mL1.1mol/L
Alkane solution, the dichloromethane solution of (2Z, 5Z)-octadiene -1- alcohol (3) of 10mL1.5mol/L, 5.5mL 5.5M peroxide uncle
The n -nonane solution of butanol then reacts 2 days in -30 DEG C, after the aqueous citric acid solution quenching reaction of 30mL10%, heating,
Liquid separation is stood, water phase is extracted with 2 × 30mL of methylene chloride, and combined organic phase is washed with 3 × 30mL of saturated salt solution again, through nothing
Aqueous sodium persulfate obtains crude product compound 10 after drying, filtering concentration, directly carries out next step reaction without purifying；
9) crude product 10 is dissolved in 40mL methylene chloride, 4.2mL triethylamine and 4.29g paratoluensulfonyl chloride is added at 0 DEG C,
Continue to stir and slowly return back to room temperature, after 30mL saturated ammonium chloride solution quenching reaction, stands liquid separation, water phase dichloromethane
2 × 30mL of alkane extraction, combined organic phase are washed with 3 × 30mL of saturated salt solution again, are dried over anhydrous sodium sulfate, filtering and concentrating
Compound 11 is obtained after purification；
10) under nitrogen atmosphere protection, 1.48g compound 11 is dissolved in 50mL anhydrous tetrahydro furan, 10mL is added dropwise at -40 DEG C
The diethyl aluminum chloride hexane solution of 1.0M continues after reacting half an hour at the same temperature, molten with 10mL saturated ammonium chloride
Liquid quenching reaction, liquid separation, water phase are extracted with 3 × 20mL of ethyl acetate, and combined organic phase is dried, filtered dense with anhydrous sodium sulfate
Contracting obtains compound 12, directly carries out next step reaction without purifying；
11) crude product 12 is dissolved in 30mL methanol, 1.06g natrium carbonicum calcinatum is added at 0 DEG C, after reaction one hour, solvent
30mL water and 20mL methylene chloride, liquid separation are added after being concentrated under reduced pressure, water phase is extracted with 2 × 20mL of methylene chloride, and merging has
Machine 3 × 30mL of Xiang Zaiyong saturated salt solution washing, is dried over anhydrous sodium sulfate, filtering and concentrating obtains crude product compound 13, is not necessarily to
Purifying directly carries out next step reaction；
12) under nitrogen atmosphere protection, 1.38g1- decine is dissolved in 30mL anhydrous tetrahydro furan, 6.3mL is added dropwise at -40 DEG C
The n-BuLi hexane solution of 2.4M, react at the same temperature ten minutes later be added 1.9mL boron trifluoride ether solution and
2.6mL hexamethylphosphoramide, then react and the tetrahydrofuran solution containing 10mL crude product 13 is added dropwise ten minutes later, continue in phase
After synthermal lower reaction half an hour, with 10mL saturated ammonium chloride solution quenching reaction, liquid separation, water phase 3 × 20mL of ethyl acetate
Extraction, combined organic phase obtain compound 14 after drying, filtering concentrating and purifying with anhydrous sodium sulfate；
13) 600mg compound 14 is dissolved in 15mL methanol, 636mg natrium carbonicum calcinatum is added at 0 DEG C, it is one small that the reaction was continued
30mL water and 50mL methylene chloride, liquid separation is added in Shi Hou, solvent after being concentrated under reduced pressure, and water phase is extracted with 2 × 20mL of methylene chloride,
Combined organic phase is washed with 3 × 30mL of saturated salt solution again, is dried over anhydrous sodium sulfate, and filtering and concentrating obtains crude product compound
15, next step reaction is directly carried out without purifying；
14) under room temperature and nitrogen atmosphere, to 50mg, the Pd/BaSO of 10wt%420mL chemical combination is added in/quinoline lindlar catalyst
The dichloromethane solution of object 15, Filtration of catalyst after reaction two hours, filter cake are washed with methylene chloride, and concentrating filter liquor is pure
Colourless liquid 2 is obtained after change.
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