JP6586863B2 - Method for producing compound having 3-oxabicyclo [3.3.0] octane skeleton, said compound, intermediate of said compound, sex stimulant of king beetle, and control agent for singing beetle - Google Patents
Method for producing compound having 3-oxabicyclo [3.3.0] octane skeleton, said compound, intermediate of said compound, sex stimulant of king beetle, and control agent for singing beetle Download PDFInfo
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- JP6586863B2 JP6586863B2 JP2015227736A JP2015227736A JP6586863B2 JP 6586863 B2 JP6586863 B2 JP 6586863B2 JP 2015227736 A JP2015227736 A JP 2015227736A JP 2015227736 A JP2015227736 A JP 2015227736A JP 6586863 B2 JP6586863 B2 JP 6586863B2
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- 150000001875 compounds Chemical class 0.000 title claims description 220
- 241000254173 Coleoptera Species 0.000 title claims description 39
- SPZXGRZMQWESTC-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]furan Chemical group C1OCC2CCCC21 SPZXGRZMQWESTC-UHFFFAOYSA-N 0.000 title claims description 19
- 238000004519 manufacturing process Methods 0.000 title claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 56
- -1 4-methoxyphenylmethyl group Chemical group 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 44
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 33
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 241000244615 Ergates faber Species 0.000 claims description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 16
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 230000000749 insecticidal effect Effects 0.000 claims description 15
- 125000003172 aldehyde group Chemical group 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 125000004043 oxo group Chemical group O=* 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- COKUIQKSCLYMNN-UHFFFAOYSA-N 4-methyloctacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCC(C)CCC COKUIQKSCLYMNN-UHFFFAOYSA-N 0.000 claims description 8
- BJQWYEJQWHSSCJ-UHFFFAOYSA-N heptacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCC BJQWYEJQWHSSCJ-UHFFFAOYSA-N 0.000 claims description 8
- 150000002430 hydrocarbons Chemical class 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- OLTHARGIAFTREU-UHFFFAOYSA-N 9-methylnonacosane Chemical compound CCCCCCCCCCCCCCCCCCCCC(C)CCCCCCCC OLTHARGIAFTREU-UHFFFAOYSA-N 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 7
- IGGUPRCHHJZPBS-UHFFFAOYSA-N nonacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCC IGGUPRCHHJZPBS-UHFFFAOYSA-N 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 claims description 6
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 229910001868 water Inorganic materials 0.000 claims description 5
- UPXMLPKPQMWALZ-UHFFFAOYSA-N 15-methylhentriacontane Chemical compound CCCCCCCCCCCCCCCCC(C)CCCCCCCCCCCCCC UPXMLPKPQMWALZ-UHFFFAOYSA-N 0.000 claims description 4
- RWVONPYEUYBBJH-UHFFFAOYSA-N 4-methylhexacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCC(C)CCC RWVONPYEUYBBJH-UHFFFAOYSA-N 0.000 claims description 4
- RLCPPUWUVWSWRU-UHFFFAOYSA-N 9-methylheptacosane Chemical compound CCCCCCCCCCCCCCCCCCC(C)CCCCCCCC RLCPPUWUVWSWRU-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- WRYNUJYAXVDTCB-UHFFFAOYSA-M acetyloxymercury Chemical compound CC(=O)O[Hg] WRYNUJYAXVDTCB-UHFFFAOYSA-M 0.000 claims description 4
- BDRZUARQSWNWBO-UHFFFAOYSA-N heptacosan-10-one Chemical compound CCCCCCCCCCCCCCCCCC(=O)CCCCCCCCC BDRZUARQSWNWBO-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- VAPFAAVJYYWRHJ-UHFFFAOYSA-M [Br-].CC(C)[Mg+].C1CCOC1 Chemical compound [Br-].CC(C)[Mg+].C1CCOC1 VAPFAAVJYYWRHJ-UHFFFAOYSA-M 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 156
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 77
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 48
- 238000005160 1H NMR spectroscopy Methods 0.000 description 47
- 238000003786 synthesis reaction Methods 0.000 description 43
- 229920006395 saturated elastomer Polymers 0.000 description 41
- 230000015572 biosynthetic process Effects 0.000 description 39
- 239000012043 crude product Substances 0.000 description 36
- 239000000243 solution Substances 0.000 description 32
- 235000019270 ammonium chloride Nutrition 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 24
- 238000010898 silica gel chromatography Methods 0.000 description 24
- 238000004458 analytical method Methods 0.000 description 23
- 239000012044 organic layer Substances 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- 239000002274 desiccant Substances 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 17
- 239000003921 oil Substances 0.000 description 16
- 230000001568 sexual effect Effects 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 229940126214 compound 3 Drugs 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 230000004936 stimulating effect Effects 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 229940125904 compound 1 Drugs 0.000 description 7
- 239000011521 glass Substances 0.000 description 7
- 238000010791 quenching Methods 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 239000000021 stimulant Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- SLTBMTIRYMGWLX-XMMPIXPASA-N (2r)-2-[(4-chloroanilino)carbamoylamino]-3-(1h-indol-3-yl)-n-(2-phenylethyl)propanamide Chemical compound C1=CC(Cl)=CC=C1NNC(=O)N[C@@H](C(=O)NCCC=1C=CC=CC=1)CC1=CNC2=CC=CC=C12 SLTBMTIRYMGWLX-XMMPIXPASA-N 0.000 description 4
- 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 4
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 4
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 4
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 4
- 229940126639 Compound 33 Drugs 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 229940125846 compound 25 Drugs 0.000 description 4
- 229940125877 compound 31 Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 150000002611 lead compounds Chemical class 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 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 4
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
- 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 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 3
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Landscapes
- Furan Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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Description
本発明は、3−オキサビシクロ[3.3.0]オクタン骨格を有する化合物の製造方法、前記化合物、前記化合物の中間体、ゴマダラカミキリの性刺激剤、及びゴマダラカミキリの防除剤に関する。 The present invention relates to a method for producing a compound having a 3-oxabicyclo [3.3.0] octane skeleton, the above compound, an intermediate of the above compound, a sex stimulant for the longhorn beetle, and a control agent for the longhorn beetle.
ゴマダラカミキリは、柑橘類など多種の本木植物に対する大害虫である。成虫の移動性が高く、産卵が樹皮下になされ、幼虫は幹内部を食害するため、殺虫剤による効率的な駆除が困難である。そこで性フェロモンを利用した防除剤の実用化が求められている。 The long-horned beetle is a great pest for a variety of main plants such as citrus fruits. Since adults have high mobility, egg laying is done under the tree, and larvae damage the inside of the trunk, so it is difficult to effectively control with insecticides. Therefore, practical application of a control agent using sex pheromone is required.
ゴマダラカミキリの雌性フェロモンの成分を検索した結果、炭化水素群(例えば、特許文献1参照)、ケトン群(例えば、特許文献2参照)、及び3−オキサビシクロ[3.3.0]オクタン骨格を有する化合物群(例えば、特許文献3、非特許文献1及び2参照)が同定され、これらの3つの化合物群を混合した場合に、最も強い性刺激活性があることが判明している(例えば、特許文献2参照)。 As a result of searching for a female pheromone component of the longhorn beetle, it has a hydrocarbon group (for example, see Patent Document 1), a ketone group (for example, see Patent Document 2), and a 3-oxabicyclo [3.3.0] octane skeleton. Compound groups (see, for example, Patent Document 3 and Non-Patent Documents 1 and 2) have been identified, and when these three compound groups are mixed, it has been found that they have the strongest sexual stimulating activity (for example, patents). Reference 2).
上記3つの化合物群のうち、炭化水素群の主要な8つの成分、及びケトン群の4つの成分は、化学合成により容易かつ大量に提供することができ、化学合成した化合物を用いた場合でも雌由来の成分と同等の性刺激活性が得られることが示されている。
しかし、炭化水素群とケトン群の成分に比べ、3−オキサビシクロ[3.3.0]オクタン骨格を有する化合物群の化学合成は、多数の不斉炭素をもつ骨格の合成例だけでなく、天然からの単離も他に全く知られていないため、容易ではない。したがって、3−オキサビシクロ[3.3.0]オクタン骨格を有するリード化合物から同等以上の活性を有し、より簡便に化学合成できる新規化合物の発明、及びその合成法の確立が望まれていた。
Of the above three compound groups, the eight main components of the hydrocarbon group and the four components of the ketone group can be provided easily and in large quantities by chemical synthesis, and even when chemically synthesized compounds are used, It has been shown that sexual stimulation activity equivalent to the component derived from can be obtained.
However, the chemical synthesis of compounds having a 3-oxabicyclo [3.3.0] octane skeleton is not only a synthesis example of a skeleton having a large number of asymmetric carbons, compared to the components of the hydrocarbon group and the ketone group, Isolation from nature is not easy because no other is known. Accordingly, there has been a demand for the invention of a novel compound having a comparable or higher activity from a lead compound having a 3-oxabicyclo [3.3.0] octane skeleton and capable of chemical synthesis more easily, and establishment of the synthesis method thereof. .
本発明は、前記従来における諸問題を解決し、以下の目的を達成することを課題とする。即ち、本発明は、3−オキサビシクロ[3.3.0]オクタン骨格を有するリード化合物からより簡便に化学合成可能な3−オキサビシクロ[3.3.0]オクタン骨格を有する化合物の製造方法、前記化合物、前記化合物の中間体、ゴマダラカミキリの性刺激剤、及びゴマダラカミキリの防除剤を提供することを目的とする。 An object of the present invention is to solve the conventional problems and achieve the following objects. That is, the present invention provides a method for producing a compound having a 3-oxabicyclo [3.3.0] octane skeleton that can be more easily chemically synthesized from a lead compound having a 3-oxabicyclo [3.3.0] octane skeleton. It is an object of the present invention to provide a compound, an intermediate of the compound, a sex stimulant for the long-horned beetle, and a control agent for the long-horned beetle.
本発明者らは、前記目的を解決すべく、鋭意検討した結果、3−オキサビシクロ[3.3.0]オクタン骨格を有する新規化合物を化学合成することに成功し、それらがゴマダラカミキリに対する優れた性刺激活性を有することを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above-mentioned object, the present inventors have succeeded in chemically synthesizing novel compounds having a 3-oxabicyclo [3.3.0] octane skeleton, which are superior to the longhorn beetle. It has been found that it has sex stimulating activity, and the present invention has been completed.
本発明は、本発明者らによる前記知見に基づくものであり、前記課題を解決するための手段としては、以下の通りである。即ち、
<1> 下記構造式21bで表される化合物を、触媒存在下で水素置換し、4−メトキシフェニルメチル基をトリクロロアセチル基に置換し、5位の水酸基をトリメチルシリル基で保護することにより、下記構造式24で表される化合物を生成させる工程と、
前記構造式24で表される化合物の2位にオキソ基を付与し、下記構造式25で表される化合物を生成させる工程と、
前記構造式25で表される化合物のトリクロロアセチル基をアルデヒド基に置換し、下記構造式27で表される化合物を生成させる工程と、
前記構造式27で表される化合物のアルデヒド基を順次反応させて2−メチル−5−ヒドロキシ−1−ペンテニル基に置換し、下記構造式31で表される化合物を生成させる工程と、
前記構造式31で表される化合物の2−メチル−5−ヒドロキシ−1−ペンテニル基を環化し、トリメチルシリル基を水酸基に置換し、下記構造式1で表される化合物を生成させる工程と、を含むことを特徴とする下記構造式1で表される化合物の製造方法である。
<2> 下記構造式21bで表される化合物を、触媒存在下で水素置換し、4−メトキシフェニルメチル基をトリクロロアセチル基に置換し、5位の水酸基をトリメチルシリル基で保護することにより、下記構造式24で表される化合物を生成させる工程と、
前記構造式24で表される化合物の2位にオキソ基を付与し、下記構造式25で表される化合物を生成させる工程と、
前記構造式25で表される化合物のトリクロロアセチル基を順次反応させてアセチル基に置換し、下記構造式2で表される化合物を生成させる工程と、を含むことを特徴とする下記構造式2で表される化合物の製造方法である。
<3> 下記構造式21bで表される化合物を、触媒存在下で水素置換し、4−メトキシフェニルメチル基をトリクロロアセチル基に置換し、5位の水酸基をトリメチルシリル基で保護することにより、下記構造式24で表される化合物を生成させる工程と、
前記構造式24で表される化合物の2位にオキソ基を付与し、下記構造式25で表される化合物を生成させる工程と、
前記構造式25で表される化合物のトリクロロアセチル基をアルデヒド基に置換し、下記構造式27で表される化合物を生成させる工程と、
前記構造式27で表される化合物のアルデヒド基を順次反応させて2−メチル−5−ヒドロキシ−1−ペンテニル基に置換し、下記構造式31で表される化合物を生成させる工程と、
前記構造式31で表される化合物のトリメチルシリル基を水酸基に置換し、下記構造式3で表される化合物を生成させる工程と、を含むことを特徴とする下記構造式3で表される化合物の製造方法である。
<4> 下記構造式1で表されることを特徴とする化合物である。
〔構造式1〕
〔構造式2〕
〔構造式3〕
<9> ヘプタコサン、ノナコサン、4−メチルヘキサコサン、4−メチルオクタコサン、9−メチルヘプタコサン、9−メチルノナコサン、15−メチルヘントリアコンタン、及び15−メチルヘントリトリアコンタンからなる群から選ばれる少なくとも1種の炭化水素を更に含む前記<8>に記載のゴマダラカミキリの性刺激剤である。
<10> ヘプタコサン−10−オン、(18Z)−ヘプタコセン−10−オン、及び(18Z,21Z)−ヘプタコサジエン−10−オンからなる群から選ばれる少なくとも1種のケトンを更に含む前記<8>から<9>のいずれかに記載のゴマダラカミキリの性刺激剤である。
<11> 基材に塗布又は含浸されてなる前記<8>から<10>のいずれかに記載のゴマダラカミキリの性刺激剤である。
<12> 前記<8>から<11>のいずれかに記載のゴマダラカミキリの性刺激剤を含むことを特徴とするゴマダラカミキリの防除剤である。
<13> 殺虫成分を更に含む前記<12>に記載のゴマダラカミキリの防除剤である。
The present invention is based on the above findings by the present inventors, and means for solving the above problems are as follows. That is,
<1> By substituting the compound represented by the following structural formula 21b with hydrogen in the presence of a catalyst, substituting the 4-methoxyphenylmethyl group with a trichloroacetyl group, and protecting the hydroxyl group at the 5-position with a trimethylsilyl group, Generating a compound represented by Structural Formula 24;
Adding an oxo group to the 2-position of the compound represented by Structural Formula 24 to form a compound represented by Structural Formula 25;
Replacing the trichloroacetyl group of the compound represented by the structural formula 25 with an aldehyde group to form a compound represented by the following structural formula 27;
A step of sequentially reacting an aldehyde group of the compound represented by the structural formula 27 and substituting it with a 2-methyl-5-hydroxy-1-pentenyl group to form a compound represented by the following structural formula 31;
Cyclizing the 2-methyl-5-hydroxy-1-pentenyl group of the compound represented by Structural Formula 31 and substituting the trimethylsilyl group with a hydroxyl group to form a compound represented by Structural Formula 1 below. It is a manufacturing method of the compound represented by following Structural formula 1 characterized by including.
<2> By substituting the compound represented by the following structural formula 21b with hydrogen in the presence of a catalyst, substituting the 4-methoxyphenylmethyl group with a trichloroacetyl group, and protecting the hydroxyl group at the 5-position with a trimethylsilyl group, Generating a compound represented by Structural Formula 24;
Adding an oxo group to the 2-position of the compound represented by Structural Formula 24 to form a compound represented by Structural Formula 25;
A step of sequentially reacting the trichloroacetyl group of the compound represented by the structural formula 25 to substitute an acetyl group to form a compound represented by the following structural formula 2; It is a manufacturing method of the compound represented by these.
<3> By substituting the compound represented by the following structural formula 21b with hydrogen in the presence of a catalyst, substituting the 4-methoxyphenylmethyl group with a trichloroacetyl group, and protecting the hydroxyl group at the 5-position with a trimethylsilyl group, Generating a compound represented by Structural Formula 24;
Adding an oxo group to the 2-position of the compound represented by Structural Formula 24 to form a compound represented by Structural Formula 25;
Replacing the trichloroacetyl group of the compound represented by the structural formula 25 with an aldehyde group to form a compound represented by the following structural formula 27;
A step of sequentially reacting an aldehyde group of the compound represented by the structural formula 27 and substituting it with a 2-methyl-5-hydroxy-1-pentenyl group to form a compound represented by the following structural formula 31;
Substituting the trimethylsilyl group of the compound represented by Structural Formula 31 with a hydroxyl group to form a compound represented by Structural Formula 3 below, It is a manufacturing method.
<4> A compound represented by the following structural formula 1.
[Structural formula 1]
[Structural formula 2]
[Structural formula 3]
<9> From the group consisting of heptacosan, nonacosane, 4-methylhexacosane, 4-methyloctacosane, 9-methylheptacosane, 9-methylnonacosane, 15-methylhentriacontane, and 15-methylhentriatritan The sex stimulant for longhorn beetle according to <8>, further including at least one selected hydrocarbon.
<10> From the above <8> further comprising at least one kind of ketone selected from the group consisting of heptacosane-10-one, (18Z) -heptacosen-10-one, and (18Z, 21Z) -heptacosadien-10-one <9> The sexual stimulant for longhorn beetle according to any one of <9>.
<11> The sex stimulant for longhorn beetle according to any one of <8> to <10>, which is applied or impregnated on a base material.
<12> A control agent for a long-horned beetle characterized by including the sex stimulant for long-horned beetle according to any one of <8> to <11>.
<13> The agent for controlling longhorn beetle according to <12>, further including an insecticidal component.
本発明によれば、従来における前記諸問題を解決し、前記目的を達成することができ、3−オキサビシクロ[3.3.0]オクタン骨格を有するリード化合物からより簡便に化学合成可能な3−オキサビシクロ[3.3.0]オクタン骨格を有する化合物の製造方法、前記化合物、前記化合物の中間体、ゴマダラカミキリの性刺激剤、及びゴマダラカミキリの防除剤を提供することができる。 According to the present invention, the above-mentioned problems can be solved and the object can be achieved, and chemical synthesis can be more easily performed from a lead compound having a 3-oxabicyclo [3.3.0] octane skeleton. -The manufacturing method of the compound which has oxabicyclo [3.3.0] octane frame | skeleton, the said compound, the intermediate body of the said compound, the sex stimulant of a Japanese pearl beetle, and the control agent of a Japanese common pearl beetle can be provided.
(化合物の製造方法)
本発明の化合物の製造方法は、下記構造式1で表される化合物(以下、「化合物1」と称することがある)の製造方法であって、
下記構造式21bで表される化合物を、触媒存在下で水素置換し、4−メトキシフェニルメチル基をトリクロロアセチル基に置換し、5位の水酸基をトリメチルシリル基で保護することにより、下記構造式24で表される化合物を生成させる工程と、
前記構造式24で表される化合物の2位にオキソ基を付与し、下記構造式25で表される化合物を生成させる工程と、
前記構造式25で表される化合物のトリクロロアセチル基をアルデヒド基に置換し、下記構造式27で表される化合物を生成させる工程と、
前記構造式27で表される化合物のアルデヒド基を順次反応させて2−メチル−5−ヒドロキシ−1−ペンテニル基に置換し、下記構造式31で表される化合物を生成させる工程と、
前記構造式31で表される化合物の2−メチル−5−ヒドロキシ−1−ペンテニル基を環化し、トリメチルシリル基を水酸基に置換し、前記構造式1で表される化合物を生成させる工程と、を含み、更に必要に応じて精製工程などのその他の工程を含む。
The method for producing a compound of the present invention is a method for producing a compound represented by the following structural formula 1 (hereinafter sometimes referred to as “compound 1”),
The compound represented by the following structural formula 21b was replaced with hydrogen in the presence of a catalyst, the 4-methoxyphenylmethyl group was replaced with a trichloroacetyl group, and the hydroxyl group at the 5-position was protected with a trimethylsilyl group, whereby the following structural formula 24 A step of producing a compound represented by:
Adding an oxo group to the 2-position of the compound represented by Structural Formula 24 to form a compound represented by Structural Formula 25;
Replacing the trichloroacetyl group of the compound represented by the structural formula 25 with an aldehyde group to form a compound represented by the following structural formula 27;
A step of sequentially reacting an aldehyde group of the compound represented by the structural formula 27 and substituting it with a 2-methyl-5-hydroxy-1-pentenyl group to form a compound represented by the following structural formula 31;
Cyclizing the 2-methyl-5-hydroxy-1-pentenyl group of the compound represented by Structural Formula 31 and substituting the trimethylsilyl group with a hydroxyl group to produce the compound represented by Structural Formula 1. And other steps such as a purification step as necessary.
また、本発明の化合物の製造方法は、下記構造式2で表される化合物(以下、「化合物2」と称することがある)の製造方法であって、
下記構造式21bで表される化合物を、触媒存在下で水素置換し、4−メトキシフェニルメチル基をトリクロロアセチル基に置換し、5位の水酸基をトリメチルシリル基で保護することにより、下記構造式24で表される化合物を生成させる工程と、
前記構造式24で表される化合物の2位にオキソ基を付与し、下記構造式25で表される化合物を生成させる工程と、
前記構造式25で表される化合物のトリクロロアセチル基を順次反応させてアセチル基に置換し、前記構造式2で表される化合物を生成させる工程と、を含み、更に必要に応じて精製工程などのその他の工程を含む。
The compound represented by the following structural formula 21b was replaced with hydrogen in the presence of a catalyst, the 4-methoxyphenylmethyl group was replaced with a trichloroacetyl group, and the hydroxyl group at the 5-position was protected with a trimethylsilyl group, whereby the following structural formula 24 A step of producing a compound represented by:
Adding an oxo group to the 2-position of the compound represented by Structural Formula 24 to form a compound represented by Structural Formula 25;
A step of sequentially reacting the trichloroacetyl group of the compound represented by the structural formula 25 and substituting the acetyl group to form a compound represented by the structural formula 2, and further purifying as necessary. Including other processes.
また、本発明の化合物の製造方法は、下記構造式3で表される化合物(以下、「化合物3」と称することがある)の製造方法であって、
下記構造式21bで表される化合物を、触媒存在下で水素置換し、4−メトキシフェニルメチル基をトリクロロアセチル基に置換し、5位の水酸基をトリメチルシリル基で保護することにより、下記構造式24で表される化合物を生成させる工程と、
前記構造式24で表される化合物の2位にオキソ基を付与し、下記構造式25で表される化合物を生成させる工程と、
前記構造式25で表される化合物のトリクロロアセチル基をアルデヒド基に置換し、下記構造式27で表される化合物を生成させる工程と、
前記構造式27で表される化合物のアルデヒド基を順次反応させて2−メチル−5−ヒドロキシ−1−ペンテニル基に置換し、下記構造式31で表される化合物を生成させる工程と、
前記構造式31で表される化合物のトリメチルシリル基を水酸基に置換し、前記構造式3で表される化合物を生成させる工程と、を含み、更に必要に応じて精製工程などのその他の工程を含む。
The compound represented by the following structural formula 21b was replaced with hydrogen in the presence of a catalyst, the 4-methoxyphenylmethyl group was replaced with a trichloroacetyl group, and the hydroxyl group at the 5-position was protected with a trimethylsilyl group, whereby the following structural formula 24 A step of producing a compound represented by:
Adding an oxo group to the 2-position of the compound represented by Structural Formula 24 to form a compound represented by Structural Formula 25;
Replacing the trichloroacetyl group of the compound represented by the structural formula 25 with an aldehyde group to form a compound represented by the following structural formula 27;
A step of sequentially reacting an aldehyde group of the compound represented by the structural formula 27 and substituting it with a 2-methyl-5-hydroxy-1-pentenyl group to form a compound represented by the following structural formula 31;
Substituting the trimethylsilyl group of the compound represented by the structural formula 31 with a hydroxyl group to form the compound represented by the structural formula 3, and further including other steps such as a purification step if necessary. .
(化合物)
本発明の化合物は、下記構造式1〜3のいずれかで表される3−オキサビシクロ[3.3.0]オクタン骨格を有する化合物(化合物1〜3)である。
前記化合物1は、本発明の化合物1の製造方法により、好適に製造することができる。
前記化合物2は、本発明の化合物2の製造方法により、好適に製造することができる。
前記化合物3は、本発明の化合物3の製造方法により、好適に製造することができる。
〔構造式1〕
The compound of the present invention is a compound (compounds 1 to 3) having a 3-oxabicyclo [3.3.0] octane skeleton represented by any of the following structural formulas 1 to 3.
The said compound 1 can be suitably manufactured with the manufacturing method of the compound 1 of this invention.
The said compound 2 can be suitably manufactured with the manufacturing method of the compound 2 of this invention.
The said compound 3 can be suitably manufactured with the manufacturing method of the compound 3 of this invention.
[Structural formula 1]
これまでに、3−オキサビシクロ[3.3.0]オクタン骨格を有する化合物群として、下記構造式4、5及び6のいずれかで表される化合物(以下、「化合物4、5及び6」と称することがある。)が、ゴマダラカミキリから単離され、化学構造について絶対配置が決定されている(Tetrahedron Letters,48(32),5609−5611(2007)参照)。
化合物6は、本発明の化合物3のジアステレオマーであり、したがって、化合物3及び化合物6の物理化学的性質及び生物学的作用は、互いに異なる。
Until now, as a compound group having a 3-oxabicyclo [3.3.0] octane skeleton, compounds represented by any one of the following structural formulas 4, 5 and 6 (hereinafter referred to as “compounds 4, 5 and 6”) Have been isolated from the long-horned beetle, and the absolute configuration of the chemical structure has been determined (see Tetrahedron Letters, 48 (32), 5609-5611 (2007)).
Compound 6 is a diastereomer of Compound 3 of the present invention, and thus the physicochemical properties and biological actions of Compound 3 and Compound 6 are different from each other.
なお、文献「Tetrahedron Letters,48(32),5609−5611(2007)」において絶対配置が決定された化合物4、5及び6については、まず、特許第4621904号公報にて単離同定が報告され、次いで、文献「Tetrahedron Letters,48(13),2395−2400(2007)」にて構造決定がなされ、それぞれゴマダラクトンA、B、及びCと命名された。そのため、特許第4621904号公報には、化合物4〜6とは3−オキサビシクロ[3.3.0]オクタン骨格上の一部炭素が異なる(即ち、化合物4〜6とジアステレオマー又は鏡像体の関係にある)絶対配置を有する化合物が記載されているものの、特許第4621904号公報に記載の化合物は、化合物4〜6と同じスペクトルを有するため、前記構造式4〜6のいずれかで表される化合物(化合物4〜6)の立体配置を有するものと解釈される。 Regarding compounds 4, 5 and 6 whose absolute configuration was determined in the document “Tetrahedron Letters, 48 (32), 5609-5611 (2007)”, first, isolation and identification were reported in Japanese Patent No. 4621904. Subsequently, the structure was determined in the document “Tetrahedron Letters, 48 (13), 2395-2400 (2007)” and named sesame lactones A, B, and C, respectively. Therefore, in Japanese Patent No. 4621904, compounds 4 to 6 are different in carbon on the 3-oxabicyclo [3.3.0] octane skeleton (that is, compounds 4 to 6 and diastereomers or enantiomers). However, since the compound described in Japanese Patent No. 4621904 has the same spectrum as the compounds 4 to 6, the compound represented by any one of the structural formulas 4 to 6 is described. It is interpreted that it has the configuration of the compound (compounds 4 to 6).
(中間体)
本発明の中間体は、下記構造式22〜33のいずれかで表される本発明の化合物4〜6の中間体である。
前記中間体は、本発明の化合物1〜3の製造方法における中間体である。
また、前記中間体は、本発明の化合物1〜3以外の、新たな3−オキサビシクロ[3.3.0]オクタン骨格を有する化合物を合成する際のリード化合物として有用である。
The intermediate of the present invention is an intermediate of compounds 4 to 6 of the present invention represented by any of the following structural formulas 22 to 33.
The said intermediate body is an intermediate body in the manufacturing method of the compounds 1-3 of this invention.
The intermediate is useful as a lead compound in the synthesis of a compound having a new 3-oxabicyclo [3.3.0] octane skeleton other than the compounds 1 to 3 of the present invention.
(ゴマダラカミキリの性刺激剤)
本発明のゴマダラカミキリの性刺激剤は、本発明の化合物を有効成分として含み、その他の性刺激剤を含むことが好ましく、更に必要に応じてその他の成分を含む。
(Sexually stimulating agent for longhorn beetle)
The sex stimulant of the long-horned beetle of the present invention contains the compound of the present invention as an active ingredient, preferably contains other sex stimulants, and further contains other ingredients as necessary.
<その他の性刺激剤>
前記その他の性刺激剤としては、ゴマダラカミキリに対する性刺激作用を有する化合物であれば特に制限はなく、目的に応じて適宜選択することができ、例えば、炭化水素、ケトンなどが挙げられる。これらは1種単独で使用してもよいし、2種以上を併用してもよい。
前記炭化水素としては、例えば、ヘプタコサン、ノナコサン、4−メチルヘキサコサン、4−メチルオクタコサン、9−メチルヘプタコサン、9−メチルノナコサン、15−メチルヘントリアコンタン、15−メチルヘントリトリアコンタンなどが挙げられる。これらは1種単独で使用してもよいし、2種以上を併用してもよい。
前記ケトンとしては、例えば、ヘプタコサン−10−オン、(18Z)−ヘプタコセン−10−オン、(18Z,21Z)−ヘプタコサジエン−10−オンなどが挙げられる。これらは1種単独で使用してもよいし、2種以上を併用してもよい。
<Other sex stimulants>
The other sexual stimulant is not particularly limited as long as it is a compound having a sexual stimulating action against a long-horned beetle, and can be appropriately selected according to the purpose. Examples thereof include hydrocarbons and ketones. These may be used individually by 1 type and may use 2 or more types together.
Examples of the hydrocarbon include heptacosane, nonacosane, 4-methylhexacosane, 4-methyloctacosane, 9-methylheptacosane, 9-methylnonacosane, 15-methylhentriacontane, 15-methylhentriatritan. Etc. These may be used individually by 1 type and may use 2 or more types together.
Examples of the ketone include heptacosane-10-one, (18Z) -heptacosen-10-one, and (18Z, 21Z) -heptacosadien-10-one. These may be used individually by 1 type and may use 2 or more types together.
<その他の成分>
前記その他の成分としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、溶媒、担体、徐放剤などが挙げられる。
前記溶媒としては、例えば、n−ヘキサン、酢酸エチル、メタノール、エタノールなどが挙げられる。
前記担体としては、例えば、プラスチック、不織布、ゴムセプタムなどが挙げられる。
前記徐放剤としては、例えば、ゲル状物質、多孔質物質、樹脂などが挙げられる。
<Other ingredients>
There is no restriction | limiting in particular as said other component, According to the objective, it can select suitably, For example, a solvent, a carrier, a sustained release agent, etc. are mentioned.
Examples of the solvent include n-hexane, ethyl acetate, methanol, ethanol and the like.
Examples of the carrier include plastic, non-woven fabric, and rubber septum.
Examples of the sustained release agent include a gel material, a porous material, and a resin.
前記ゴマダラカミキリの性刺激剤は、基材に塗布又は含浸されてなることが好ましい。
前記ゴマダラカミキリの性刺激剤が、前記基材に塗布されてなる場合、前記基材としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、ゼラチンカプセル、ガラス片、金属片、プラスチック片などが挙げられる。
前記基材の大きさとしては、ゴマダラカミキリの雌個体程度の大きさであれば特に制限はなく、目的に応じて適宜選択することができるが、長さ20mm〜40mm(例えば、35mm)、幅5mm〜15mm(例えば、12mm)、高さ5mm〜15mm(例えば、12mm)が好ましい。
前記基材の形状としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、円筒状、角柱状、球状、楕円球状などが挙げられる。
前記塗布は、ゴマダラカミキリの成虫雄が接触可能な状態に塗布されることが好ましい。
It is preferable that the sex stimulant for the longhorn beetle is applied or impregnated on a base material.
In the case where the sex stimulant for the longhorn beetle is applied to the substrate, the substrate is not particularly limited and may be appropriately selected depending on the intended purpose. For example, gelatin capsules, glass pieces, metal pieces And plastic pieces.
The size of the base material is not particularly limited as long as it is about the size of a female beetle, and can be appropriately selected according to the purpose. However, the length is 20 mm to 40 mm (for example, 35 mm), and the width is 5 mm. -15 mm (for example, 12 mm) and a height of 5 mm to 15 mm (for example, 12 mm) are preferable.
There is no restriction | limiting in particular as a shape of the said base material, According to the objective, it can select suitably, For example, cylindrical shape, prismatic shape, spherical shape, elliptical spherical shape etc. are mentioned.
It is preferable that the coating is performed in such a manner that an adult male of a long-horned beetle can be contacted.
前記ゴマダラカミキリの性刺激剤の塗布量としては、特に制限はなく、目的に応じて適宜選択できるが、1雌相当量の塗布量であっても前記性刺激活性を示すため、前記基材当たりの前記構造式1〜3のいずれかで表される化合物の量で、0.5μg〜25μgが好ましく、1μg〜10μgがより好ましい。 The application amount of the sex stimulant for the longhorn beetle is not particularly limited and can be appropriately selected according to the purpose. The amount of the compound represented by any one of the structural formulas 1 to 3 is preferably 0.5 μg to 25 μg, and more preferably 1 μg to 10 μg.
前記ゴマダラカミキリの性刺激剤が、前記基材に含浸されてなる場合、前記基材としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、不撚布、スポンジ状物体などが挙げられる。
この場合、前記溶媒に溶解した前記ゴマダラカミキリの性刺激剤が含浸されることが好ましい。
前記ゴマダラカミキリの性刺激剤の含有量としては、特に制限はなく、目的に応じて適宜選択できるが、前記基材の表面積あたりの前記溶媒に対する前記構造式1〜3のいずれかで表される化合物の含有量で、0.5μg/cm2〜20μg/cm2が好ましく、1μg/cm2〜10μg/cm2がより好ましく、前記基材の体積あたりの前記溶媒に対する前記構造式1〜3のいずれかで表される化合物の含有量で、50μg/cm3〜1000μg/cm3が好ましく、100μg/cm3〜200μg/cm3がより好ましい。
When the base material is impregnated with the sex stimulant of the longhorn beetle, the base material is not particularly limited and can be appropriately selected according to the purpose. For example, untwisted cloth, sponge-like object, etc. Is mentioned.
In this case, it is preferable to impregnate the sex stimulant of the longhorn beetle dissolved in the solvent.
There is no restriction | limiting in particular as content of the sex stimulant of the long-horned beetle, Although it can select suitably according to the objective, The compound represented by either of the said Structural formula 1-3 with respect to the said solvent per surface area of the said base material in content, preferably 0.5μg / cm 2 ~20μg / cm 2 , more preferably 1μg / cm 2 ~10μg / cm 2 , any of the structural formula 1-3 with respect to the solvent per volume of the substrate in content of the compound represented by either preferably 50μg / cm 3 ~1000μg / cm 3 , 100μg / cm 3 ~200μg / cm 3 is more preferable.
本発明のゴマダラカミキリの性刺激剤に、ゴマダラカミキリの雄がふ節や触角などで接触した場合、前記ゴマダラカミキリの性刺激剤を塗布した前記基材の表面や、近辺に存在する他のゴマダラカミキリの雄に対し、刺激活性を示すと共に、それを抱き込みさらに腹部末端の先端を前記物体や他の雄の下部に押しつけるという一連の行動を引き起こす活性(以下、「性刺激活性」と称する。)を示す。この一連の行動は、生きている雌に対する行動と全く同一で区別できない。 When the male sex beetle sex stimulant of the present invention comes into contact with a male sex beetle or tentacle, etc., the surface of the base material coated with the sex stimulant of the Japanese beetle beetle or other male beetle beetle males in the vicinity. On the other hand, it exhibits a stimulating activity and an activity that causes a series of actions (hereinafter referred to as “sexual stimulating activity”) that embraces it and presses the tip of the abdominal end against the lower part of the object or other male. This series of actions is exactly the same as the action on a living female and is indistinguishable.
(ゴマダラカミキリの防除剤)
本発明のゴマダラカミキリの防除剤は、本発明のゴマダラカミキリの性刺激剤を有効成分として含み、殺虫成分を含むことが好ましく、更に必要に応じてその他の成分を含む。
(Pesticide for longhorn beetle)
The control agent for the spotted longhorn beetle of the present invention contains the sex stimulant of the spotted longhorn beetle of the present invention as an active ingredient, preferably contains an insecticidal ingredient, and further contains other ingredients as necessary.
本発明のゴマダラカミキリの防除剤によれば、前記防除剤をゴマダラカミキリ発生域に設置又は散布することによって、雄成虫が前記性刺激剤を含む前記防除剤に長時間逗留し、雌成虫との交尾の機会が減少するため、次世代の生息密度を減じることができる。 According to the control agent of the spotted longhorn beetle of the present invention, by installing or spraying the control agent in the spot where the spotted longhorn beetle is generated, the male adult is allowed to stay in the control agent containing the sex stimulant for a long time, and mating with a female adult Because opportunities are reduced, the next generation density can be reduced.
<殺虫成分>
前記殺虫成分としては、特に制限はなく、目的に応じて適宜公知の殺虫成分を選択でき、例えば、合成殺虫活性成分、生物由来の殺虫活性成分などが挙げられる。
前記合成殺虫活性成分としては、例えば、有機リン、カーバメート、合成ピレスロイドなどが挙げられる。前記生物由来の殺虫活性成分としては、例えば、Beauveria bassiana(白きょう病菌)等の昆虫病原糸状菌などが挙げられる。
これらの中でも、標的外生物に対する安全性が高い点で生物由来の殺虫活性成分が好ましい。
<Insecticide ingredient>
There is no restriction | limiting in particular as said insecticidal component, According to the objective, a well-known insecticidal component can be selected suitably, For example, a synthetic insecticidal active component, a biologically derived insecticidal active component, etc. are mentioned.
Examples of the synthetic insecticidal active ingredient include organic phosphorus, carbamate, and synthetic pyrethroid. Examples of the insecticidal active ingredient derived from the organism include entomopathogenic filamentous fungi such as Beauveria bassiana.
Among these, an insecticidal active ingredient derived from an organism is preferable in terms of high safety against non-target organisms.
本発明のゴマダラカミキリの防除剤によれば、前記白きょう病菌のように、前記合成殺虫活性成分に比べてやや速効性に劣る成分を用いる場合においても、ゴマダラカミキリ雄成虫が本発明のゴマダラカミキリの性刺激剤の作用によって、前記防除剤に長時間逗留し、前記殺虫成分に曝露される時間が長くなるため、前記殺虫成分の効力を十分に発揮させることができる。
前記殺虫成分を併用する場合には、本発明のゴマダラカミキリの防除剤は、不撚布及びスポンジ状物体の少なくともいずれかに含浸されてなる前記ゴマダラカミキリの性刺激剤及び前記殺虫成分を含むことが、ゴマダラカミキリの生息密度をより速効的かつ簡便に減じることができる点で好ましい。前記不撚布又はスポンジ状物体を、樹幹の周囲に巻くことによって、ゴマダラカミキリを防除することができる。
According to the control agent of the spotted longhorn beetle of the present invention, even when using a component that is slightly inferior to the synthetic insecticidal active component, such as the white scab, the male spotted longhorn beetle is sexually stimulating the spotted longhorn beetle of the present invention. Because of the action of the agent, the insecticide stays in the control agent for a long time and is exposed to the insecticidal component for a long time, so that the efficacy of the insecticidal component can be sufficiently exerted.
In the case of using the insecticidal component in combination, the control agent of the spotted beetle of the present invention comprises the sex stimulant of the spotted beetle impregnated in at least one of a non-twisted cloth and a sponge-like object, and the insecticidal component. This is preferable in that the population density of the long-horned beetle can be reduced more quickly and easily. By winding the untwisted cloth or sponge-like object around the trunk, it is possible to control the longhorn beetle.
以下、実施例に基づいて本発明をより具体的に説明するが、本発明は以下の実施例に制限されるものではない。 EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example, this invention is not restrict | limited to a following example.
(合成例1:化合物1の合成)
下記反応式(1)−1及び反応式(1)−2に示す通り、化合物1の合成を行った。
(Synthesis Example 1: Synthesis of Compound 1)
Compound 1 was synthesized as shown in the following reaction formula (1) -1 and reaction formula (1) -2.
<化合物8の合成>
L−酒石酸ジメチル(下記構造式7で表される化合物7、1.0019g、5.57mmol)とp−トルエンスルホン酸(PTSA、21.4mg、0.11mmol)を2,2−ジメトキシプロパン(3.3mL、26.17mmol)に溶解させた混合液を60℃で19時間撹拌した。0℃で飽和炭酸水素ナトリウム水溶液を加えクエンチした。さらに酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液で1回、飽和食塩水で1回洗浄した。有機層を無水硫酸ナトリウムで乾燥させ、ろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物(下記構造式8で表される化合物8)を精製せず、次の反応に用いた。
<Synthesis of Compound 8>
Dimethyl L-tartrate (compound 7 represented by the following structural formula 7, 1.0019 g, 5.57 mmol) and p-toluenesulfonic acid (PTSA, 21.4 mg, 0.11 mmol) were mixed with 2,2-dimethoxypropane (3 .3 mL, 26.17 mmol) was stirred at 60 ° C. for 19 hours. The reaction was quenched by adding saturated aqueous sodium hydrogen carbonate solution at 0 ° C. Further, ethyl acetate was added, and the mixture was washed once with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure. The crude product (Compound 8 represented by the following structural formula 8) was used for the next reaction without purification.
<化合物9の合成>
得られた前記粗生成物をジエチルエーテル(18.2mL)に溶解させ、0℃で水素化アルミニウムリチウム(413.7mg、10.90mmol)を加え、室温で1時間16分間撹拌した。ジエチルエーテルを加え、硫酸ナトリウム10水和物(17.56g、54.51mmol)を加えクエンチし、終夜撹拌した。混合液をセライトろ過し、ろ液を減圧濃縮した。その粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し、淡黄色透明油状物として目的化合物(下記構造式9で表される化合物9、650.2mg、2段階収率72.0%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 9>
The obtained crude product was dissolved in diethyl ether (18.2 mL), lithium aluminum hydride (413.7 mg, 10.90 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hr 16 min. Diethyl ether was added and quenched with sodium sulfate decahydrate (17.56 g, 54.51 mmol) and stirred overnight. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate), and the target compound (compound 9, represented by structural formula 9 below, 650.2 mg, 2 step yield 72.0%) as a pale yellow transparent oily substance. Got. The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:4.03(2H,ddd,J=3.8Hz,2.3Hz,1.4Hz),3.82(2H,ddd,J=11.8Hz,2.3Hz,1.4Hz),3.70(2H,ddd,J=11.8Hz,2.3Hz,1.4Hz),1.44(6H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 4.03 (2H, ddd, J = 3.8 Hz, 2.3 Hz, 1.4 Hz), 3.82 (2H, ddd, J = 11.8 Hz, 2 .3 Hz, 1.4 Hz), 3.70 (2 H, ddd, J = 11.8 Hz, 2.3 Hz, 1.4 Hz), 1.44 (6 H, s)
<化合物10の合成>
化合物9(650.2mg、4.01mmol)をテトラヒドロフラン(20.1mL)に溶解させ、0℃で水素化ナトリウム(192.4mg、4.41mmol)を加え、0℃で30分間撹拌した。0℃でtert−ブチルジメチルシリルクロリド(638.7mg、4.41mmol)を加え、室温で1時間40分間撹拌した。0℃で、飽和塩化アンモニウム水溶液を加えクエンチした。酢酸エチルを加え、飽和塩化アンモニウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:1、体積比)で精製し、淡黄色透明油状物として目的化合物(下記構造式10で表される化合物10、982.8mg、収率88.5%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 10>
Compound 9 (650.2 mg, 4.01 mmol) was dissolved in tetrahydrofuran (20.1 mL), sodium hydride (192.4 mg, 4.41 mmol) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 30 min. Tert-butyldimethylsilyl chloride (638.7 mg, 4.41 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour and 40 minutes. At 0 ° C., a saturated aqueous ammonium chloride solution was added to quench the reaction. Ethyl acetate was added, and the mixture was washed once with a saturated aqueous solution of ammonium chloride and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1, volume ratio) to obtain the target compound (compound 10 represented by the following structural formula 10, 982.8 mg, as a pale yellow transparent oily product). Rate 88.5%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:3.99(1H,ddd,j=7.6Hz,4.6Hz,4.6Hz),3.90−3.85(2H,m),3.80−3.64(3H,m),1.42(3H,s),1.40(3H,s),0.90(9H,s),0.09(6H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 3.99 (1H, ddd, j = 7.6 Hz, 4.6 Hz, 4.6 Hz), 3.90-3.85 (2H, m), 3. 80-3.64 (3H, m), 1.42 (3H, s), 1.40 (3H, s), 0.90 (9H, s), 0.09 (6H, s)
<化合物11の合成>
化合物10(534.1mg、1.93mmol)をジクロロメタン(9.7mL)に溶解させ、−40℃でジイソプロピルエチルアミン(1mL、5.80mmol)を加え、さらに、−40℃でトリフルオロメタンスルホン酸無水物(485μL、2.90mmol)を加え37分間撹拌した。−40℃で飽和炭酸水素ナトリウム水溶液を加えクエンチした。室温にし、さらに酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液で1回、0.5規定塩酸で1回、さらに飽和炭酸水素ナトリウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させた。ろ過により乾燥剤を除去した後、減圧濃縮し、粗生成物をショートシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:1、体積比)により原点成分を分離し、その粗生成物(下記構造式11で表される化合物11)を次の反応に用いた。
<Synthesis of Compound 11>
Compound 10 (534.1 mg, 1.93 mmol) was dissolved in dichloromethane (9.7 mL), diisopropylethylamine (1 mL, 5.80 mmol) was added at −40 ° C., and trifluoromethanesulfonic anhydride was further added at −40 ° C. (485 μL, 2.90 mmol) was added and stirred for 37 minutes. It quenched by adding saturated sodium hydrogencarbonate aqueous solution at -40 degreeC. Bring to room temperature, add ethyl acetate, wash once with saturated aqueous sodium bicarbonate, once with 0.5N hydrochloric acid, once with saturated aqueous sodium bicarbonate, and once with saturated brine, and dry the organic layer. Dry with sodium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated from the origin component by short silica gel column chromatography (hexane: ethyl acetate = 3: 1, volume ratio), and the crude product (the following structural formula) Compound 11) represented by 11 was used in the next reaction.
<化合物12の合成>
シアン化銅(183.1mg、1.84mmol)をテトラヒドロフラン(10mL)に溶解させ、0℃で20分間撹拌した。0℃で臭化イソプロピルマグネシウム・テトラヒドロフラン溶液(49.0mL、24.54mmol)を加え30分間撹拌した。さらに、0℃でベンゼンと共沸させ脱水した化合物11(5.01g、12.27mmol)をテトラヒドロフラン(30mL)に溶解させた溶液を加え、3時間20分間撹拌した。0℃で飽和塩化アンモニウム水溶液を加え、クエンチした。さらに酢酸エチルを加え、飽和塩化アンモニウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=15:1、体積比)で精製し、極淡黄色透明油状物として目的化合物(下記構造式12で表される化合物12、3.43g、収率95.8%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 12>
Copper cyanide (183.1 mg, 1.84 mmol) was dissolved in tetrahydrofuran (10 mL) and stirred at 0 ° C. for 20 minutes. At 0 ° C., an isopropylmagnesium bromide-tetrahydrofuran solution (49.0 mL, 24.54 mmol) was added and stirred for 30 minutes. Further, a solution in which Compound 11 (5.01 g, 12.27 mmol) azeotropically distilled with benzene at 0 ° C. was dissolved in tetrahydrofuran (30 mL) was added, and the mixture was stirred for 3 hours and 20 minutes. Saturated aqueous ammonium chloride solution was added at 0 ° C. to quench. Further, ethyl acetate was added, and the mixture was washed once with a saturated aqueous ammonium chloride solution and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1, volume ratio), and the target compound (compound 12, represented by structural formula 12 below, 3.43 g, as an extremely pale yellow transparent oil) Yield 95.8%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)4.83−4.81(2H,m),4.13−4.10(1H,m),3.76−3.62(3H,m),2.35−2.33(2H,m),1.79(3H,s),1.41(3H,s),1.39(3H,s),0.90(9H,s),0.07(6H,s) 1 H-NMR (400 MHz, CDCl 3 ) 4.83-4.81 (2H, m), 4.13-4.10 (1H, m), 3.76-3.62 (3H, m), 2 .35-2.33 (2H, m), 1.79 (3H, s), 1.41 (3H, s), 1.39 (3H, s), 0.90 (9H, s),. 07 (6H, s)
<化合物13の合成>
化合物12(3.91g、13.00mmol)をテトラヒドロフラン(45.5mL)に溶解させ、室温でフッ化テトラブチルアンモニウム・テトラヒドロフラン溶液(19.5mL、19.50mmol)を加え、室温で1時間撹拌した。0℃で、飽和塩化アンモニウム水溶液を加えクエンチした。酢酸エチルを加え、飽和塩化アンモニウム水溶液で1回、飽和食塩水で1回洗浄した。水層に溶解した生成物を酢酸エチルで4回逆抽出した。有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:1、体積比)で精製し、淡黄色透明油状物として目的化合物(下記構造式13で表される化合物13、2.38g、収率98.0%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 13>
Compound 12 (3.91 g, 13.00 mmol) was dissolved in tetrahydrofuran (45.5 mL), tetrabutylammonium fluoride / tetrahydrofuran solution (19.5 mL, 19.50 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. . At 0 ° C., a saturated aqueous ammonium chloride solution was added to quench the reaction. Ethyl acetate was added, and the mixture was washed once with a saturated aqueous ammonium chloride solution and once with a saturated saline solution. The product dissolved in the aqueous layer was back extracted four times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the desiccant was removed by filtration, followed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1, volume ratio) to obtain the target compound (compound 13, represented by the following structural formula 13, 2.38 g, as a pale yellow transparent oily substance). The rate was 98.0%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:4.85−4.82(2H,m),4.09(1H,ddd,J=7.8Hz,7.4Hz,5.5Hz),3.83−3.74(2H,m),3.58(1H,dd,J=11.8Hz,4.1Hz),2.39(2H,dd,J=14.2Hz,7.3Hz)2.26(2H,dd,J=14.2Hz,5.5Hz),1.78(3H,s),1.43(3H,s),1.42(3H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 4.85-4.82 (2H, m), 4.09 (1H, ddd, J = 7.8 Hz, 7.4 Hz, 5.5 Hz), 3. 83-3.74 (2H, m), 3.58 (1H, dd, J = 11.8 Hz, 4.1 Hz), 2.39 (2H, dd, J = 14.2 Hz, 7.3 Hz) 26 (2H, dd, J = 14.2 Hz, 5.5 Hz), 1.78 (3H, s), 1.43 (3H, s), 1.42 (3H, s)
<化合物14の合成>
塩化オキサリル・ジクロロメタン溶液(20mL、38.34mmol)を室温でジクロロメタン(10mL)に加え、−70℃に冷却した。そこに、ジクロロメタン(10mL)に溶解させたジメチルスルホキシド(5.5mL、76.68mmol)を−70℃で加え、30分間撹拌した。ベンゼンと共沸させ脱水した化合物13(2.38g、12.78mmol)をジクロロメタン(20mL)に溶解させ、−70℃で加え、30分間撹拌した。さらに、−70℃でトリエチルアミン(13.4mL、95.85mmol)を加え30分間撹拌した。フラスコ内の固形物が溶解しなかったため、ジクロロメタン(20mL)を追加した。−40℃までゆるやかに昇温させ、十分な水に溶解させたリン酸二水素ナトリウム(12.0mg、76.68mmol)を加え、さらにゆるやかに室温まで昇温させた。室温でtert−ブタノール(64.0mL)を加え、さらに、室温で、2−methyl−2−buteneを加えた。さらに0℃で亜塩素酸ナトリウム(8.8g、76.68mmol)を加え、室温で1時間撹拌した。室温でリン酸二水素ナトリウム(4.0mg、25.56mmol)を加え、さらに、0℃で亜塩素酸ナトリウム(2.90g、25.56mmol)を加え、室温で1時間撹拌した。0℃で飽和食塩水を加え、クエンチした。酢酸エチルを加え、飽和食塩水で1回洗浄し、水層を3回酢酸エチルで逆抽出した。有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物(下記構造式14で表される化合物14)をそのまま次の反応へ用いた。
<Synthesis of Compound 14>
Oxalyl chloride / dichloromethane solution (20 mL, 38.34 mmol) was added to dichloromethane (10 mL) at room temperature and cooled to -70 ° C. Dimethyl sulfoxide (5.5 mL, 76.68 mmol) dissolved in dichloromethane (10 mL) was added thereto at −70 ° C., and the mixture was stirred for 30 minutes. Compound 13 (2.38 g, 12.78 mmol) azeotroped with benzene and dehydrated was dissolved in dichloromethane (20 mL), added at −70 ° C., and stirred for 30 minutes. Further, triethylamine (13.4 mL, 95.85 mmol) was added at −70 ° C., and the mixture was stirred for 30 minutes. Dichloromethane (20 mL) was added because the solid in the flask did not dissolve. The temperature was raised gently to −40 ° C., sodium dihydrogen phosphate (12.0 mg, 76.68 mmol) dissolved in sufficient water was added, and the temperature was further raised to room temperature. Tert-butanol (64.0 mL) was added at room temperature, and 2-methyl-2-butene was further added at room temperature. Further, sodium chlorite (8.8 g, 76.68 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Sodium dihydrogen phosphate (4.0 mg, 25.56 mmol) was added at room temperature, sodium chlorite (2.90 g, 25.56 mmol) was further added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Saturated brine was added at 0 ° C. to quench. Ethyl acetate was added, washed once with saturated brine, and the aqueous layer was back extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the desiccant was removed by filtration, followed by concentration under reduced pressure. The crude product (compound 14 represented by the following structural formula 14) was directly used in the next reaction.
<化合物15の合成>
化合物14を含む粗生成物をジクロロメタンに溶解させ、0℃でジイソプロピルエチルアミン(3.7mL、21.73mmol)、N,O−ジメチルヒドロキシルアミン塩酸塩(2.12g、21.73mmol)、ジシクロヘキシルカルボジイミド(4.00g、19.17mmol)、及びN,N−ジメチル−4−アミノピリジン(1.58g、12.78mmol)を加え、15時間撹拌した。0℃で飽和塩化アンモニウム水溶液を加えクエンチした。酢酸エチルを加え、セライトろ過により固形物を除去した。ろ液を飽和塩化アンモニウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させた。ろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:1、体積比)で精製し、淡黄色透明油状物として目的化合物(下記構造式15で表される化合物15、2.25g、3段階収率72.3%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 15>
The crude product containing compound 14 was dissolved in dichloromethane and diisopropylethylamine (3.7 mL, 21.73 mmol), N, O-dimethylhydroxylamine hydrochloride (2.12 g, 21.73 mmol), dicyclohexylcarbodiimide ( 4.00 g, 19.17 mmol) and N, N-dimethyl-4-aminopyridine (1.58 g, 12.78 mmol) were added and stirred for 15 hours. Quenched by adding saturated aqueous ammonium chloride at 0 ° C. Ethyl acetate was added and the solid was removed by celite filtration. The filtrate was washed once with saturated aqueous ammonium chloride solution and once with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The desiccant was removed by filtration and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1, volume ratio) to give the target compound (compound 15, represented by the following structural formula 15, 2.25 g, 3) as a pale yellow transparent oily substance. A step yield of 72.3%) was obtained. The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:4.82−4.80(2H,m),4.62(1H,m),4.48(1H,m),3.73(3H,s),3.22(3H,s),2.42(1H,dd,j=14.6Hz,7.7Hz),2.37(1H,dd,j=14.6Hz,7.7Hz),1.78(3H,s),1.48(3H,s),1.47(3H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 4.82-4.80 (2H, m), 4.62 (1H, m), 4.48 (1H, m), 3.73 (3H, s ), 3.22 (3H, s), 2.42 (1H, dd, j = 14.6 Hz, 7.7 Hz), 2.37 (1H, dd, j = 14.6 Hz, 7.7 Hz), 1 .78 (3H, s), 1.48 (3H, s), 1.47 (3H, s)
<化合物16の合成>
ベンゼンと共沸させ脱水した化合物15(1.22g、5.01mmol)をトルエンに溶解させ、−10℃で臭化メチルマグネシウム・ジエチルエーテル溶液(2.5mL、7.52mmol)を加え、−10℃で1時間撹拌した。−10℃で飽和塩化アンモニウム水溶液でクエンチし、室温でn−ペンタンを加え、飽和塩化アンモニウム水溶液で1回、飽和食塩水で1回洗浄した。有機層をシリカゲルろ過した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(n−ペンタン:ジエチルエーテル=8:1、体積比)で精製し、無色透明油状物として目的化合物(下記構造式16で表される化合物16、901.8mg、収率90.7%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 16>
Compound 15 (1.22 g, 5.01 mmol) dehydrated by azeotroping with benzene was dissolved in toluene, and a methylmagnesium bromide-diethyl ether solution (2.5 mL, 7.52 mmol) was added at −10 ° C., and −10 Stir for 1 hour at ° C. Quenched with a saturated aqueous ammonium chloride solution at −10 ° C., added n-pentane at room temperature, and washed once with a saturated aqueous ammonium chloride solution and once with a saturated saline solution. The organic layer was filtered through silica gel and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (n-pentane: diethyl ether = 8: 1, volume ratio), and the target compound (compound 16, represented by the following structural formula 16, 901.8 mg, as a colorless transparent oil) Yield 90.7%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:4.86−4.82(2H,m),4.16(1H,td,J=7.7Hz,3.7Hz),2.45(1H,dd,J=14.7Hz,3.7Hz),2.34(1H,dd,J=14.7Hz,7.7Hz),2.28(3H,s)1.78(3H,s),1.46(3H,s),1.42(3H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 4.86-4.82 (2H, m), 4.16 (1H, td, J = 7.7 Hz, 3.7 Hz), 2.45 (1H, dd, J = 14.7 Hz, 3.7 Hz), 2.34 (1H, dd, J = 14.7 Hz, 7.7 Hz), 2.28 (3H, s) 1.78 (3H, s), 1 .46 (3H, s), 1.42 (3H, s)
<化合物17の合成>
切削片状マグネシウム(47.5mg、1.95mmol)を真空中でヒートガンにより5分間加熱した。ジエチルエーテル(2.0mL)を加え、さらに、1,2−ジブロモエタン(2滴)を加えた。5分間超音波に当て、ジエチルエーテル(3.0mL)に溶解させたMPMO(CH2)3Br(253.3mg、0.98mmol)を加え30分間撹拌した。ジエチルエーテル(4.0ml)に溶解させた化合物16(64.6mg、0.33mmol)を加え、室温で1時間撹拌した。0℃で飽和塩化アンモニウム水溶液を加えクエンチした。酢酸エチルを加え、飽和塩化アンモニウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:1、体積比)で精製し、淡黄色透明油状物として目的化合物(下記構造式17で表される化合物17、117.2mg、収率95.1%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 17>
Chip-like magnesium (47.5 mg, 1.95 mmol) was heated in a vacuum with a heat gun for 5 minutes. Diethyl ether (2.0 mL) was added, followed by 1,2-dibromoethane (2 drops). Sonicated for 5 minutes, MPMO (CH 2 ) 3 Br (253.3 mg, 0.98 mmol) dissolved in diethyl ether (3.0 mL) was added and stirred for 30 minutes. Compound 16 (64.6 mg, 0.33 mmol) dissolved in diethyl ether (4.0 ml) was added, and the mixture was stirred at room temperature for 1 hour. Quenched by adding saturated aqueous ammonium chloride at 0 ° C. Ethyl acetate was added, and the mixture was washed once with a saturated aqueous solution of ammonium chloride and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1, volume ratio) to obtain the target compound (compound 17, 117.2 mg represented by the following structural formula 17 as a pale yellow transparent oil). Rate 95.1%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:7.27−7.23(2H,m),6.89−6.86(2H,m),4.84−4.80(2H,m),4.44(2H,s),4.19(1H,ddd,J=9.1Hz,7.7Hz,2.9Hz),3.80(3H,s),3.59(1H,d,J=7.7Hz),3.46(2H,t,J=6.3Hz),2.33(2H,m),2.26(1Hdd,J=14.7Hz,9.1Hz),1.80(3H,s),1.75−1.58(4H,m),1.41(3H,s),1.40(3h,s),1.11(3H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 7.27-7.23 (2H, m), 6.89-6.86 (2H, m), 4.84-4.80 (2H, m) , 4.44 (2H, s), 4.19 (1H, ddd, J = 9.1 Hz, 7.7 Hz, 2.9 Hz), 3.80 (3H, s), 3.59 (1H, d, J = 7.7 Hz), 3.46 (2 H, t, J = 6.3 Hz), 2.33 (2 H, m), 2.26 (1 Hdd, J = 14.7 Hz, 9.1 Hz), 1. 80 (3H, s), 1.75-1.58 (4H, m), 1.41 (3H, s), 1.40 (3h, s), 1.11 (3H, s)
<化合物18の合成>
化合物17(778.9mg、2.06mmol)をN,N−ジメチルホルムアミド(15mL)に溶解させ、0℃で水素化ナトリウム(449.0mg、10.29mmol)を加え、30分間撹拌した。0℃のまま、臭化アリル(1.35mL、15.43mmol)、ヨウ化テトラブチルアンモニウム(775.6mg、2.06mmol)を加え、室温で2時間30分間撹拌した。0℃で飽和塩化アンモニウム水溶液を加えクエンチした。酢酸エチルを加え、飽和塩化アンモニウム水溶液で1回、飽和食塩水で1回洗浄し、水層を酢酸エチルで2回逆抽出した。有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=9:1、体積比)で精製し、淡黄色透明油状物として目的化合物(下記構造式18で表される化合物18、824.4mg、収率95.7%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 18>
Compound 17 (778.9 mg, 2.06 mmol) was dissolved in N, N-dimethylformamide (15 mL), sodium hydride (449.0 mg, 10.29 mmol) was added at 0 ° C., and the mixture was stirred for 30 min. While maintaining at 0 ° C., allyl bromide (1.35 mL, 15.43 mmol) and tetrabutylammonium iodide (775.6 mg, 2.06 mmol) were added, and the mixture was stirred at room temperature for 2 hours and 30 minutes. Quenched by adding saturated aqueous ammonium chloride at 0 ° C. Ethyl acetate was added, washed once with a saturated aqueous ammonium chloride solution and once with a saturated saline solution, and the aqueous layer was back extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the desiccant was removed by filtration, followed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1, volume ratio) to obtain the target compound (compound 18, 824.4 mg represented by the following structural formula 18 as a pale yellow transparent oil). Rate 95.7%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:7.29−7.24(2H,m),6.92−6.87(2H,m),5.89(1H,ddt,J=17.2Hz,10.4Hz,5.2Hz),5.24(1H,ddd,J=17.2Hz,3.5Hz,1.7Hz),5.08(1H,ddd,J=10.4Hz,3.5Hz,1.7Hz),4.85−4.78(2H,m),4.43(2H,s),4.17(1H,ddd,J=9.9Hz,7.5Hz,2.6Hz),4.08(1H,ddt,J=12.5Hz,5.2Hz,1.5Hz),3.98(1H,ddt,J=12.5Hz,5.2Hz,1.5Hz),3.80(3H,s),3.76(1H,d,J=7.4Hz),3.47−3.40(2H,m),2.37(1H,d,J=14.9Hz),2.24(1H,dd,J=14.9Hz,9.7Hz),1.79(3H,s),1.75−1.58(4H,m),1.42(3H,s),1.38(3H,s),1.20(3H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 7.29-7.24 (2H, m), 6.92-6.87 (2H, m), 5.89 (1H, ddt, J = 17. 2 Hz, 10.4 Hz, 5.2 Hz), 5.24 (1 H, ddd, J = 17.2 Hz, 3.5 Hz, 1.7 Hz), 5.08 (1 H, ddd, J = 10.4 Hz, 3. 5 Hz, 1.7 Hz), 4.85-4.78 (2 H, m), 4.43 (2 H, s), 4.17 (1 H, ddd, J = 9.9 Hz, 7.5 Hz, 2.6 Hz) ), 4.08 (1H, ddt, J = 12.5 Hz, 5.2 Hz, 1.5 Hz), 3.98 (1H, ddt, J = 12.5 Hz, 5.2 Hz, 1.5 Hz), 3. 80 (3H, s), 3.76 (1H, d, J = 7.4 Hz), 3.47-3.40 (2H, m), 2 37 (1H, d, J = 14.9 Hz), 2.24 (1 H, dd, J = 14.9 Hz, 9.7 Hz), 1.79 (3H, s), 1.75-1.58 (4H , M), 1.42 (3H, s), 1.38 (3H, s), 1.20 (3H, s)
<化合物19の合成>
化合物18(409.2mg、0.98mmol)をジクロロメタン(230mL)に溶解させた。ジクロロメタン(15mL)に溶解させた第二世代グラブズ触媒(41.5mg、0.05mmol)を加えて50℃に昇温させ2時間撹拌した。さらに室温で第二世代グラブズ触媒(20mg、0.02mmol)を追加し、50℃で1時間撹拌した。別に化合物18(396.2mg、0.95mmol)をジクロロメタン(200mL)に溶解させた。ジクロロメタン(37mL)に溶解させた第二世代グラブズ触媒(80.4mg、0.10mmol)を加えて50℃に昇温させ1時間30分間撹拌した。そのまま減圧濃縮を行い、粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:1、体積比)で精製し、黄褐色透明油状物として目的化合物(下記構造式19で表される化合物19、699.9mg、収率93.1%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 19>
Compound 18 (409.2 mg, 0.98 mmol) was dissolved in dichloromethane (230 mL). Second generation Grubbs catalyst (41.5 mg, 0.05 mmol) dissolved in dichloromethane (15 mL) was added, the temperature was raised to 50 ° C., and the mixture was stirred for 2 hours. Furthermore, the 2nd generation Grubbs catalyst (20 mg, 0.02 mmol) was added at room temperature, and it stirred at 50 degreeC for 1 hour. Separately, compound 18 (396.2 mg, 0.95 mmol) was dissolved in dichloromethane (200 mL). Second generation Grubbs catalyst (80.4 mg, 0.10 mmol) dissolved in dichloromethane (37 mL) was added, the temperature was raised to 50 ° C., and the mixture was stirred for 1 hour 30 minutes. Concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1, volume ratio) to give the target compound (compound 19 represented by the following structural formula 19 as a tan transparent oil). 699.9 mg, 93.1% yield). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:7.29−7.24(2H,m),6.90−6.85(2H,m),5.55−5.48(1H,m),4.44(2H,s),4.33(1H,ddd,J=8.3Hz,7.5Hz,4.3Hz),3.93−3.91(3H,m),3.50−3.40(2H,m),2.76(1H,dd,J=16.3Hz,4.3Hz),2.33(1H,dd,J=16.3Hz,7.5Hz),1.77(3H,s),1.74−1.63(4H,m),1.36(3H,s),1.27(3H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 7.29-7.24 (2H, m), 6.90-6.85 (2H, m), 5.55-5.48 (1H, m) 4.44 (2H, s), 4.33 (1H, ddd, J = 8.3 Hz, 7.5 Hz, 4.3 Hz), 3.93-3.91 (3H, m), 3.50−. 3.40 (2H, m), 2.76 (1H, dd, J = 16.3 Hz, 4.3 Hz), 2.33 (1H, dd, J = 16.3 Hz, 7.5 Hz), 1.77 (3H, s), 1.74-1.63 (4H, m), 1.36 (3H, s), 1.27 (3H, s)
<化合物20の合成>
化合物19(49.9mg、0.13mmol)をメタノールに溶解させ、0℃で、1規定塩酸(0.5mL、0.50mmol)を加え、0℃で1時間、室温で1時間撹拌し、飽和炭酸水素ナトリウム水溶液を加えクエンチした。酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=2:1、体積比)で精製し、無色透明油状物として目的化合物(下記構造式20で表される化合物20、43.2mg、収率96.4%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 20>
Compound 19 (49.9 mg, 0.13 mmol) was dissolved in methanol, 1N hydrochloric acid (0.5 mL, 0.50 mmol) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1 hour, saturated. Aqueous sodium bicarbonate was added to quench. Ethyl acetate was added, and the mixture was washed once with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, volume ratio), and the target compound (compound 20, represented by Structural Formula 20 below, 43.2 mg, yield) was obtained as a colorless transparent oil. 96.4%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:7.30−7.20(2H,m),6.90−6.85(2H,m),4.43(2H,s),4.20−4.16(2H,m),3.92−3.85(2H,m),3.81(3H,s),3.71(1H,dd,J=8.9Hz,4.1Hz),3.53−3.38(3H,m),2.15−2.10(1H,m),2.03−1.92(2H,m),1.81(3H,dd,J=3.6Hz,2.0Hz),1.79−1.64(4H,m),1.27(3H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 7.30-7.20 (2H, m), 6.90-6.85 (2H, m), 4.43 (2H, s), 4.20 -4.16 (2H, m), 3.92-3.85 (2H, m), 3.81 (3H, s), 3.71 (1H, dd, J = 8.9 Hz, 4.1 Hz) , 3.53-3.38 (3H, m), 2.15-2.10 (1H, m), 2.03-1.92 (2H, m), 1.81 (3H, dd, J = 3.6 Hz, 2.0 Hz), 1.79-1.64 (4H, m), 1.27 (3H, s)
<化合物21a及び化合物21bの合成>
化合物20(589.9mg、1.68mmol)をジメチルスルホキシド(8.4mL)に溶解させ、室温で2−ヨードキシ安息香酸(1.40g、5.05mmol)を加え、室温で2時間撹拌した。飽和炭酸水素ナトリウム水溶液を加えクエンチした。さらに酢酸エチルを加え、2時間撹拌した。その後飽和炭酸水素ナトリウム水溶液で1回、飽和食塩水で1回洗浄し、水層を酢酸エチルで1回逆抽出した。有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=2:1、体積比)で精製し、無色透明油状物として目的化合物(下記構造式21bで表される化合物21b及び下記構造式21aで表される化合物21aの混合物、559.7mg、収率96.0%)を得た。さらに高速液体クロマトグラフィー(ヘキサン:酢酸エチル=2:1、体積比)でジアステレオマーの分離を行った。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 21a and Compound 21b>
Compound 20 (589.9 mg, 1.68 mmol) was dissolved in dimethyl sulfoxide (8.4 mL), 2-iodoxybenzoic acid (1.40 g, 5.05 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to quench. Further ethyl acetate was added and stirred for 2 hours. Thereafter, the mixture was washed once with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution, and the aqueous layer was back extracted once with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the desiccant was removed by filtration, followed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, volume ratio) to give the target compound (compound 21b represented by the following structural formula 21b and the following structural formula 21a as a colorless transparent oil). Of the compound 21a, 559.7 mg, yield 96.0%). Further, diastereomers were separated by high performance liquid chromatography (hexane: ethyl acetate = 2: 1, volume ratio). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
−化合物21b−
1H−NMR(400MHz,CDCl3)δ:7.28−7.25(2H,m),6.90−6.87(2H,m),6.02−5.98(1H,m),4.45(2H,s),3.98(1H,dd,J=9.7Hz,6.8Hz),3.81(3H,s),3.76(1H,dd,9.7Hz,2.3Hz),3.50−3.45(2H,m),3.16−3.10(1H,m),2.74−2.69(1H,bs),2.14(3H,t,J=2.3Hz),1.68(2H,m),1.60−1.50(2H,m),1.10(3H,s)
−化合物21a−
1H−NMR(400MHz,CDCl3)δ:7.25−7.22(2H,m),6.87−6.84(2H,m),6.02−5.98(1H,m),4.40(2H,s),4.03(1H,dd,J=9.7Hz,6.6Hz),3.80(3H,s),3.77(1H,dd,9.7Hz,2.2Hz),3.38(2H,t,J=6.6Hz),3.155−3.10(1H,m),2.66−2.61(1H,m),2.14(3H,t,J=2.2Hz),1.80−1.50(3H,m),1.40−1.33(1H,m),1.26(3H,s)
-Compound 21b-
1 H-NMR (400 MHz, CDCl 3 ) δ: 7.28-7.25 (2H, m), 6.90-6.87 (2H, m), 6.02-5.98 (1H, m) , 4.45 (2H, s), 3.98 (1H, dd, J = 9.7 Hz, 6.8 Hz), 3.81 (3H, s), 3.76 (1H, dd, 9.7 Hz, 2.3 Hz), 3.50-3.45 (2H, m), 3.16-3.10 (1H, m), 2.74-2.69 (1H, bs), 2.14 (3H, t, J = 2.3 Hz), 1.68 (2H, m), 1.60-1.50 (2H, m), 1.10 (3H, s)
-Compound 21a-
1 H-NMR (400 MHz, CDCl 3 ) δ: 7.25-7.22 (2H, m), 6.87-6.84 (2H, m), 6.02-5.98 (1H, m) , 4.40 (2H, s), 4.03 (1H, dd, J = 9.7 Hz, 6.6 Hz), 3.80 (3H, s), 3.77 (1H, dd, 9.7 Hz, 2.2 Hz), 3.38 (2 H, t, J = 6.6 Hz), 3.155-3.10 (1 H, m), 2.66-2.61 (1 H, m), 2.14 ( 3H, t, J = 2.2 Hz), 1.80-1.50 (3H, m), 1.40-1.33 (1H, m), 1.26 (3H, s)
<化合物22の合成>
化合物21b(58.5mg、0.17mmol)をメタノール(1.7mL)に溶解させ、室温で水酸化パラジウム/炭素(15.0mg、5.0質量%)を加え、水素置換により、水素雰囲気下で1時間撹拌した。窒素置換をして、セライトろ過により水酸化パラジウム/炭素を除去して減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチルのみ)で精製し、白色結晶として目的化合物(下記構造式22で表される化合物22、37.4mg、収率97.1%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 22>
Compound 21b (58.5 mg, 0.17 mmol) was dissolved in methanol (1.7 mL), palladium hydroxide / carbon (15.0 mg, 5.0 mass%) was added at room temperature, and hydrogen substitution was performed under a hydrogen atmosphere. For 1 hour. After replacing with nitrogen, palladium hydroxide / carbon was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate only) to obtain the target compound (compound 22, represented by the following structural formula 22, 37.4 mg, yield 97.1%) as white crystals. The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:4.02(1H,dd,J=10.3Hz,3.9Hz),3.97(1H,dd,J=10.3Hz,7.3Hz),3.74−3.62(2H,m),2.73−2.66(1H,m),2.40−2.33(2H,m),1.88−1.76(1H,m),1.73−1.52(3H,m),1.17(3H,d,J=6.2Hz),1.04(3H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 4.02 (1H, dd, J = 10.3 Hz, 3.9 Hz), 3.97 (1H, dd, J = 10.3 Hz, 7.3 Hz), 3.74-3.62 (2H, m), 2.73-2.66 (1H, m), 2.40-2.33 (2H, m), 1.88-1.76 (1H, m ), 1.73-1.52 (3H, m), 1.17 (3H, d, J = 6.2 Hz), 1.04 (3H, s)
<化合物23の合成>
化合物22(48.0mg、0.21mmol)をジクロロメタンに溶解させ、室温でピリジン(50.8μL、0.63mmol)、塩化トリクロロアセチル(36.1μL、0.32mmol)を加え、30分間撹拌した。0℃で飽和塩化アンモニウム水溶液を加えクエンチした。酢酸エチルを加え、飽和塩化アンモニウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=2:1、体積比)で精製し、淡黄色透明油状物として目的化合物(下記構造式23で表される化合物23、66.8mg、収率85.0%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 23>
Compound 22 (48.0 mg, 0.21 mmol) was dissolved in dichloromethane, pyridine (50.8 μL, 0.63 mmol) and trichloroacetyl chloride (36.1 μL, 0.32 mmol) were added at room temperature, and the mixture was stirred for 30 minutes. Quenched by adding saturated aqueous ammonium chloride at 0 ° C. Ethyl acetate was added, and the mixture was washed once with a saturated aqueous solution of ammonium chloride and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, volume ratio) to obtain the target compound (compound 23, 66.8 mg represented by the following structural formula 23, 66.8 mg) as a pale yellow transparent oily substance. 85.0%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:4.39(2H,t,J=6.3Hz),3.99(1H,dd,J=10.3Hz,3.2Hz),3.93(1H,dd,J=10.3Hz,7.9Hz),2.80−2.72(1H,m),2.70−2.63(1H,m),2/40−2/32(3H,m),1.92−1.72(3H,m),1.62−1.52(1H,m),1.17(3H,d,J=6.1Hz),1.03(3H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 4.39 (2H, t, J = 6.3 Hz), 3.99 (1H, dd, J = 10.3 Hz, 3.2 Hz), 3.93 ( 1H, dd, J = 10.3 Hz, 7.9 Hz), 2.80-2.72 (1H, m), 2.70-2.63 (1H, m), 2 / 40-2 / 32 (3H , M), 1.92-1.72 (3H, m), 1.62-1.52 (1H, m), 1.17 (3H, d, J = 6.1 Hz), 1.03 (3H , S)
<化合物24の合成>
化合物23(66.8mg、0.18mmol)をジクロロメタンに溶解させ、0℃で、2,6−ルチジン(187.4μL、1.61mmol)とトリフルオロメタンスルホン酸トリメチルシリル(155.5μL、0.81mmol)を加え、室温で30分間撹拌した。0℃で飽和炭酸水素ナトリウム水溶液を加えクエンチした。酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=5:1、体積比)で精製し、無色透明油状物として目的化合物(下記構造式24で表される化合物24、75.5mg、収率94.7%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 24>
Compound 23 (66.8 mg, 0.18 mmol) was dissolved in dichloromethane and at 0 ° C., 2,6-lutidine (187.4 μL, 1.61 mmol) and trimethylsilyl trifluoromethanesulfonate (155.5 μL, 0.81 mmol) And stirred at room temperature for 30 minutes. The reaction was quenched by adding saturated aqueous sodium hydrogen carbonate solution at 0 ° C. Ethyl acetate was added, and the mixture was washed once with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1, volume ratio), and the target compound (compound 24 represented by the following structural formula 24, 75.5 mg, yield) was obtained as a colorless transparent oil. 94.7%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:4.44−4.38(2H,m),3.97(1H,dd,J=10.2Hz,3.7Hz),3.92(1H,dd,J=10.7Hz,7.9Hz),2.65−2.58(1H,m),2.47−2.34(1H,m),2,33(1H,ddd,J=16.2Hz,6.3Hz,1.9Hz),2.18(1H,dd,J=16.2Hz,14.3Hz),1,87−1.73(3H,m),1.63−1.51(1H,m),1.14(3H,d,J=6.6Hz),1.06(3H,s),0.10(9H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 4.44-4.38 (2H, m), 3.97 (1H, dd, J = 10.2 Hz, 3.7 Hz), 3.92 (1H, dd, J = 10.7 Hz, 7.9 Hz), 2.65-2.58 (1H, m), 2.47-2.34 (1H, m), 2, 33 (1H, ddd, J = 16 .2 Hz, 6.3 Hz, 1.9 Hz), 2.18 (1 H, dd, J = 16.2 Hz, 14.3 Hz), 1,87-1.73 (3 H, m), 1.63-1. 51 (1H, m), 1.14 (3H, d, J = 6.6 Hz), 1.06 (3H, s), 0.10 (9H, s)
<化合物25の合成>
化合物24(71.4mg、0.19mmol)に四塩化炭素(400μL)とアセトニトリル(400μL)、水(600μL)を加え、さらに、室温で過ヨウ素酸ナトリウム(173.5mg、0.81mmol)を加え、溶解させた。さらに、室温で塩化ルテニウム(3.5mg、0.02mmol)を加え、室温で13時間撹拌した。さらに、室温で過ヨウ素酸ナトリウム(85.0mg、0.40mmol)、塩化ルテニウム(極少量)を追加し、2時間撹拌した。0℃でイソプロパノール(500.0μL、6.5mmol)を加え、クエンチした。さらに、飽和炭酸水素ナトリウム水溶液と酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=5:1、体積比)で精製し、白色結晶として目的化合物(下記構造式25で表される化合物25、71.2mg、収率95.4%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 25>
Compound 24 (71.4 mg, 0.19 mmol) was added with carbon tetrachloride (400 μL), acetonitrile (400 μL) and water (600 μL), and sodium periodate (173.5 mg, 0.81 mmol) was added at room temperature. , Dissolved. Furthermore, ruthenium chloride (3.5 mg, 0.02 mmol) was added at room temperature, and the mixture was stirred at room temperature for 13 hours. Furthermore, sodium periodate (85.0 mg, 0.40 mmol) and ruthenium chloride (very small amount) were added at room temperature, and the mixture was stirred for 2 hours. Quenched by adding isopropanol (500.0 μL, 6.5 mmol) at 0 ° C. Further, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, washed once with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution, the organic layer was dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. Concentrated. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1, volume ratio), and the target compound (compound 25 represented by the following structural formula 25, 71.2 mg, yield 95.) as white crystals. 4%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:4.45−4.30(2H,m),3.08−3.02(1H,m),2.65−2.48(1H,m),2.65−2.48(2H,m),2.10−1.76(5H,m),1.38(3H,d,J=6.6Hz),1.26(3H,s),0.12(9H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 4.45-4.30 (2H, m), 3.08-3.02 (1H, m), 2.65-2.48 (1H, m) , 2.65-2.48 (2H, m), 2.10-1.76 (5H, m), 1.38 (3H, d, J = 6.6 Hz), 1.26 (3H, s) , 0.12 (9H, s)
<化合物26の合成>
化合物25(50.3mg、0.11mmol)をテトラヒドロフランに溶解させ、室温でセスキ炭酸ナトリウム二水和物(123.6mg、0.55mmol)を加えた。さらに室温でメタノール(800μL)を加え、1時間撹拌した。0℃で飽和塩化アンモニウム水溶液を加えクエンチした。酢酸エチルを加え、飽和塩化アンモニウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=2:1、体積比)で精製し、無色透明油状物として目的化合物(下記構造式26で表される化合物26、34.1mg、収率94.2%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 26>
Compound 25 (50.3 mg, 0.11 mmol) was dissolved in tetrahydrofuran, and sodium sesquicarbonate dihydrate (123.6 mg, 0.55 mmol) was added at room temperature. Further, methanol (800 μL) was added at room temperature and stirred for 1 hour. Quenched by adding saturated aqueous ammonium chloride at 0 ° C. Ethyl acetate was added, and the mixture was washed once with a saturated aqueous solution of ammonium chloride and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, volume ratio), and the target compound (compound 26 represented by the following structural formula 26, 34.1 mg, yield) was obtained as a colorless transparent oil. 94.2%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:3.68−3.64(2H,m),3.09−3.06(1H,m),2.62−2.48(2H,m),2.10−2,00(1H,m),1.83−1.62(4H,m),1.38(3H,d,J=6.6Hz),1.27(3H,s),0.13(9H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 3.68-3.64 (2H, m), 3.09-3.06 (1H, m), 2.62-2.48 (2H, m) , 2.10-2, 00 (1H, m), 1.83-1.62 (4H, m), 1.38 (3H, d, J = 6.6 Hz), 1.27 (3H, s) , 0.13 (9H, s)
<化合物27の合成>
塩化オキサリル・ジクロロメタン溶液(370μL、0.74mmol)を室温でジクロロメタン(500μL)に加え、−70℃に冷却した。そこに、ジクロロメタン(500μL)に溶解させたジメチルスルホキシド(105μL、1.48mmol)を−70℃で加え、30分間撹拌した。トルエンと共沸させ脱水した化合物26(77.8mg、0.25mmol)をジクロロメタン(1.2mL)に溶解させ、−70℃で加え、30分間撹拌した。さらに、−70℃でトリエチルアミン(260μL、1.86mmol)を加え30分間撹拌した。−40℃で水を加え、クエンチした。室温まで昇温させ酢酸エチルを加え、0.5規定塩酸で1回、飽和炭酸水素ナトリウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:1、体積比)で精製し、無色透明油状物として目的化合物(下記構造式27で表される化合物27、74.3mg、収率96.1%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 27>
Oxalyl chloride / dichloromethane solution (370 μL, 0.74 mmol) was added to dichloromethane (500 μL) at room temperature and cooled to −70 ° C. Dimethyl sulfoxide (105 μL, 1.48 mmol) dissolved in dichloromethane (500 μL) was added thereto at −70 ° C. and stirred for 30 minutes. Compound 26 (77.8 mg, 0.25 mmol) azeotroped with toluene and dehydrated was dissolved in dichloromethane (1.2 mL), added at −70 ° C., and stirred for 30 minutes. Further, triethylamine (260 μL, 1.86 mmol) was added at −70 ° C. and stirred for 30 minutes. Water was added at -40 ° C to quench. Warm up to room temperature, add ethyl acetate, wash once with 0.5 N hydrochloric acid, once with saturated aqueous sodium bicarbonate, and once with saturated brine, dry the organic layer over anhydrous sodium sulfate, and filter to remove desiccant. Was removed, followed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1, volume ratio), and the target compound (compound 27 represented by the following structural formula 27, 74.3 mg, yield) was obtained as a colorless transparent oil. 96.1%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:9.80(1H,t,J=1.0Hz),3.10−3.07(1H,m),2.72−2.48(4H,m),2.13−1.93(3H,m),1.38(,d,J=6.6Hz),1.25(3H,s),0.13(9H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 9.80 (1H, t, J = 1.0 Hz), 3.10-3.07 (1H, m), 2.72-2.48 (4H, m), 2.13-1.93 (3H, m), 1.38 (, d, J = 6.6 Hz), 1.25 (3H, s), 0.13 (9H, s)
<化合物28の合成>
トルエンと共沸させ脱水した化合物27(13mg、0.04mmol)をテトラヒドロフラン(900μL)に溶解させ、−78℃で臭化イソプロピルマグネシウム・テトラヒドロフラン溶液(125μL、0.06mmol)を加え、−78℃で30分間撹拌した。0℃で飽和塩化アンモニウム水溶液を加えクエンチした。酢酸エチルを加え、飽和塩化アンモニウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=4:1、体積比)で精製し、無色透明油状物として目的化合物(下記構造式28で表される化合物28、11.2mg、収率75.7%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 28>
Compound 27 (13 mg, 0.04 mmol) azeotropically dehydrated with toluene was dissolved in tetrahydrofuran (900 μL), isopropylmagnesium bromide / tetrahydrofuran solution (125 μL, 0.06 mmol) was added at −78 ° C., and −78 ° C. Stir for 30 minutes. Quenched by adding saturated aqueous ammonium chloride at 0 ° C. Ethyl acetate was added, and the mixture was washed once with a saturated aqueous solution of ammonium chloride and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1, volume ratio), and the target compound (compound 28 represented by the following structural formula 28, 11.2 mg, yield) was obtained as a colorless transparent oil. 75.7%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:4.95−4.93(1H,m),4.87−4.84(1H,m),4.07−4.02(1H,m),3.10−3.05(1H,m),2.72−2.47(2H,m),2.10−1.95(1H,m),1.90−1.55(4H,m),1.72(3H,s),1.38(3H,d,J=6.6Hz),1.26(3H,s),0.13(9H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 4.95-4.93 (1H, m), 4.87-4.84 (1H, m), 4.07-4.02 (1H, m) 3.10-3.05 (1H, m), 2.72-2.47 (2H, m), 2.10-1.95 (1H, m), 1.90-1.55 (4H, m), 1.72 (3H, s), 1.38 (3H, d, J = 6.6 Hz), 1.26 (3H, s), 0.13 (9H, s)
<化合物29の合成>
化合物28(40.8mg、0.12mmol)をエチルビニルエーテル(2.5mL)に溶解させ、室温で酢酸水銀(18.4mg、0.06mmol)を加え、30℃に加熱し、23時間撹拌した。さらに室温で酢酸水銀(18.5mg、0.06mmol)を追加し、30℃で24時間撹拌した。0℃で飽和炭酸水素ナトリウム水溶液を加えクエンチした。酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物を、ショートカラムクロマトグラフィーにより残留試薬を除去後、粗生成物(下記構造式29で表される化合物29)を次の反応に用いた。
<Synthesis of Compound 29>
Compound 28 (40.8 mg, 0.12 mmol) was dissolved in ethyl vinyl ether (2.5 mL), mercury acetate (18.4 mg, 0.06 mmol) was added at room temperature, heated to 30 ° C., and stirred for 23 hours. Further, mercury acetate (18.5 mg, 0.06 mmol) was added at room temperature, and the mixture was stirred at 30 ° C. for 24 hours. The reaction was quenched by adding saturated aqueous sodium hydrogen carbonate solution at 0 ° C. Ethyl acetate was added, and the mixture was washed once with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure. After removing the residual reagent from the crude product by short column chromatography, the crude product (Compound 29 represented by Structural Formula 29 below) was used in the next reaction.
<化合物30の合成>
化合物29の合成における粗生成物をキシレン(2mL)に溶解させ130℃に加熱し2時間撹拌した。減圧濃縮によりキシレンを留去した後、粗生成物(下記構造式30で表される化合物30)を次の反応に用いた。
<Synthesis of Compound 30>
The crude product in the synthesis of Compound 29 was dissolved in xylene (2 mL), heated to 130 ° C. and stirred for 2 hours. After distilling off xylene by concentration under reduced pressure, the crude product (compound 30 represented by the following structural formula 30) was used in the next reaction.
<化合物31の合成>
水素化ホウ素ナトリウム(16.0mg、0.39mmol)とテトラヒドロフラン(1.0mL)の混合液に、酢酸(220μL、3.88mmol)を加えて15分間撹拌し、試薬を調製した。化合物30の合成における粗生成物をテトラヒドロフラン(1.5mL)に溶解させ、調製した試薬(610μL、0.19mmol)を加え、1時間撹拌した。さらに、調製した試薬(300μL、0.10mmol)を加え30分間撹拌した。さらに、調製した試薬(300μL、0.10mmol)を加え30分間撹拌した。調製した試薬(450μL、0.15mmol)を加え30分間撹拌した。0℃で飽和塩化アンモニウム水溶液を加えクエンチした。酢酸エチルを加え、飽和塩化アンモニウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:1、体積比)で精製し、無色透明油状物として目的化合物(下記構造式31で表される化合物31、30.3mg、収率81.7%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 31>
Acetic acid (220 μL, 3.88 mmol) was added to a mixed solution of sodium borohydride (16.0 mg, 0.39 mmol) and tetrahydrofuran (1.0 mL), and the mixture was stirred for 15 minutes to prepare a reagent. The crude product in the synthesis of Compound 30 was dissolved in tetrahydrofuran (1.5 mL), the prepared reagent (610 μL, 0.19 mmol) was added, and the mixture was stirred for 1 hour. Further, the prepared reagent (300 μL, 0.10 mmol) was added and stirred for 30 minutes. Further, the prepared reagent (300 μL, 0.10 mmol) was added and stirred for 30 minutes. The prepared reagent (450 μL, 0.15 mmol) was added and stirred for 30 minutes. Quenched by adding saturated aqueous ammonium chloride at 0 ° C. Ethyl acetate was added, and the mixture was washed once with a saturated aqueous solution of ammonium chloride and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1, volume ratio) to give the target compound (compound 31, represented by the following structural formula 31, 30.3 mg, yield) as a colorless transparent oil. 81.7%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:5.12(1H,td,7.0Hz,1.2Hz),3.63(2H,t,J=3.1Hz),3.10−3.05(1H,m),2.60−2.47(2H,m),2.22−2.00(5H,m),1.75−1.60(7H,m),1.39(3H,d,J=6.6Hz),1.27(3H,s),0.13(9H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 5.12 (1H, td, 7.0 Hz, 1.2 Hz), 3.63 (2H, t, J = 3.1 Hz), 3.10-3. 05 (1H, m), 2.60-2.47 (2H, m), 2.22-2.00 (5H, m), 1.75-1.60 (7H, m), 1.39 ( 3H, d, J = 6.6 Hz), 1.27 (3H, s), 0.13 (9H, s)
<化合物32の合成>
化合物31(3.0mg、0.0078mmol)をジクロロメタン(800μL)に溶解させ、室温でトリフルオロ酢酸(400μL)を加え30分間撹拌した。そのまま減圧濃縮し、粗生成物(下記構造式32で表される化合物32)を次の反応へ用いた。
<Synthesis of Compound 32>
Compound 31 (3.0 mg, 0.0078 mmol) was dissolved in dichloromethane (800 μL), trifluoroacetic acid (400 μL) was added at room temperature, and the mixture was stirred for 30 minutes. As it was concentrated under reduced pressure, the crude product (compound 32 represented by the following structural formula 32) was used for the next reaction.
<化合物1の合成>
フッ化テトラブチルアンモニウム・テトラヒドロフラン溶液(100μL、0.10mmol)と酢酸(6.0μL、0.10mmol)の混合液を調製した。化合物32の合成における粗生成物をテトラヒドロフラン(500μL)に溶解させ、調製した試薬(25μL、0.023mmol)を室温で加え、30分間撹拌した。そのまま減圧濃縮し、粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:2、体積比)で精製し、無色透明油状物として目的化合物(下記構造式1で表される化合物1、2.1mg、収率83.3%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 1>
A mixed solution of tetrabutylammonium fluoride / tetrahydrofuran solution (100 μL, 0.10 mmol) and acetic acid (6.0 μL, 0.10 mmol) was prepared. The crude product in the synthesis of Compound 32 was dissolved in tetrahydrofuran (500 μL), the prepared reagent (25 μL, 0.023 mmol) was added at room temperature, and the mixture was stirred for 30 minutes. Concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2, volume ratio) to give the target compound (compounds 1, 2 represented by the following structural formula 1 as a colorless transparent oil). 0.1 mg, yield 83.3%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:3.86−3.75(2H.m),3.17−3.12(1H,m),2.89(1H,bs),2.59−2.47(2H,m),2.23−2.14(1H,m),1.98−1.83(2H,m),1.80−1.45(8H,m),1.40(3H,d,J=6.6Hz),1.24(3H,s),1.17(3H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 3.86-3.75 (2H.m), 3.17-3.12 (1H, m), 2.89 (1H, bs), 2.59 -2.47 (2H, m), 2.23-2.14 (1H, m), 1.98-1.83 (2H, m), 1.80-1.45 (8H, m), 1 .40 (3H, d, J = 6.6 Hz), 1.24 (3H, s), 1.17 (3H, s)
〔反応式(1)−1〕
〔反応式(1)−2〕
ここで、前記反応式(1)−1及び反応式(1)−2中、Acはアセチルを表し、Buはブチルを表し、DCCはジシクロヘキシルカルボジイミドを表し、DMAPはN,N−ジメチル−4−アミノピリジンを表し、DMFはN,N−ジメチルホルムアミドを表し、DMSOはジメチルスルホキシドを表し、Etはエチルを表し、IBXは2−ヨードキシ安息香酸を表し、Meはメチルを表し、MPMは4−メトキシフェニルメチルを表し、PTSAはp−トルエンスルホン酸を表し、TBAFはフッ化テトラブチルアンモニウムを表し、TBSはTert−ブチルジメチルシリルを表し、THFはテトラヒドロフランを表し、TMSはトリメチルシリルを表し、Tf2Oはトリフルオロメタンスルホン酸無水物を表す。 In the reaction formulas (1) -1 and (1) -2, Ac represents acetyl, Bu represents butyl, DCC represents dicyclohexylcarbodiimide, and DMAP represents N, N-dimethyl-4- Represents aminopyridine, DMF represents N, N-dimethylformamide, DMSO represents dimethyl sulfoxide, Et represents ethyl, IBX represents 2-iodoxybenzoic acid, Me represents methyl, MPM represents 4-methoxy Represents phenylmethyl, PTSA represents p-toluenesulfonic acid, TBAF represents tetrabutylammonium fluoride, TBS represents Tert-butyldimethylsilyl, THF represents tetrahydrofuran, TMS represents trimethylsilyl, Tf 2 O Represents trifluoromethanesulfonic anhydride.
なお、前記反応式(1)−1及び反応式(1)−2中、化合物11までの合成は、文献「J.Org.Chem.,1987,52,3337.」にて報告されている。また、化合物11から12の誘導は、文献「Tetrahedron,2008,64,11313.」に報告されている。
また、化合物21a及び化合物21bまでの合成は、「第57回香料・テルペンおよび精油化学に関する討論会」(平成25年10月5日〜7日,埼玉大学)の講演要旨集p.280−282にて公表されている。
In addition, in the reaction formulas (1) -1 and (1) -2, the synthesis up to the compound 11 is reported in the document “J. Org. Chem., 1987, 52, 3337.”. The induction of compounds 11 to 12 is reported in the document “Tetrahedron, 2008, 64, 11313.”.
In addition, the synthesis to compound 21a and compound 21b is described in “Summary of the 57th Discussion on Fragrance, Terpene and Essential Oil Chemistry” (October 5-7, 2013, Saitama University) p. 280-282.
(合成例2:化合物2の合成)
下記反応式(2)に示す通り、化合物2の合成を行った。
(Synthesis Example 2: Synthesis of Compound 2)
As shown in the following reaction formula (2), compound 2 was synthesized.
<化合物33の合成>
化合物25(13.3mg、0.029mmol)をテトラヒドロフラン(1.2mL)に溶解させ、乳鉢で擂り潰した炭酸水素ナトリウム(49.1mg、0.579mmol)、乳鉢で擂り潰した炭酸カリウム(20.0mg、0.145mmol)を室温で加え、さらに水(116μL)を加えた。さらにメタノール(580μ)を加え、1時間撹拌した。0℃で飽和塩化アンモニウム水溶液を加えクエンチした。酢酸エチルを加え、飽和塩化アンモニウム水溶液で1回、飽和食塩水で1回洗浄し、、水層を酢酸エチルで1回逆抽出した。有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:1、体積比)、(ヘキサン:酢酸エチル=1:2、体積比)で精製した後、目的化合物として無色透明油状物(下記構造式26で表される化合物26、8.0mg、収率84.0%)、副生成物として無色透明油状物(下記構造式33で表される化合物33、1.9mg、27.1%)をそれぞれ得た。以下に、得られた化合物33の1H−NMRの機器分析値を示す。
<Synthesis of Compound 33>
Compound 25 (13.3 mg, 0.029 mmol) was dissolved in tetrahydrofuran (1.2 mL), sodium hydrogen carbonate (49.1 mg, 0.579 mmol) ground in a mortar, and potassium carbonate (20. 0 mg, 0.145 mmol) was added at room temperature and more water (116 μL) was added. Further, methanol (580 μ) was added and stirred for 1 hour. Quenched by adding saturated aqueous ammonium chloride at 0 ° C. Ethyl acetate was added, washed once with a saturated aqueous ammonium chloride solution and once with a saturated saline solution, and the aqueous layer was back extracted once with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the desiccant was removed by filtration, followed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, volume ratio), (hexane: ethyl acetate = 1: 2, volume ratio), and then colorless and transparent oily substance (the following structure) Compound 26 represented by formula 26, 8.0 mg, yield 84.0%), colorless transparent oil as a by-product (compound 33 represented by the following structural formula 33, 1.9 mg, 27.1%) Respectively. The instrumental analysis value of 1 H-NMR of the obtained compound 33 is shown below.
1H−NMR(400MHz,CDCl3)δ:3.70−3.62(2H,m),3.17−3.12(1H,m),2.60−2.50(2H,m),2.23−2.15(1H,m),1.90−1.63(4H,m),1.40(3H,d,J=6.6Hz),1.25(3H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 3.70-3.62 (2H, m), 3.17-3.12 (1H, m), 2.60-2.50 (2H, m) , 2.23-2.15 (1H, m), 1.90-1.63 (4H, m), 1.40 (3H, d, J = 6.6 Hz), 1.25 (3H, s)
<化合物2の合成>
化合物33(3.3mg、0.0136mmol)をN,N−ジメチルホルムアミド(500μL)に溶解させ、室温でピリジン(11μL、0.136mmol)を加え、さらに室温で無水酢酸(13μL、0.136mmol)を加え、N,N−ジメチル−4−アミノピリジン(極少量)を加え、30分間撹拌した。0℃で飽和炭酸水素ナトリウム水溶液を加えクエンチした。酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液で1回、飽和食塩水で1回洗浄し、有機層を無水硫酸ナトリウムで乾燥させろ過により乾燥剤を除去した後、減圧濃縮した。粗生成物を、シリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:1、体積比)で精製し、無色透明油状物として目的化合物(下記構造式2で表される化合物2、2.5mg、収率65.8%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 2>
Compound 33 (3.3 mg, 0.0136 mmol) was dissolved in N, N-dimethylformamide (500 μL), pyridine (11 μL, 0.136 mmol) was added at room temperature, and acetic anhydride (13 μL, 0.136 mmol) was further added at room temperature. N, N-dimethyl-4-aminopyridine (very small amount) was added and stirred for 30 minutes. The reaction was quenched by adding saturated aqueous sodium hydrogen carbonate solution at 0 ° C. Ethyl acetate was added, and the mixture was washed once with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, volume ratio) to obtain the target compound (compound 2, represented by the following structural formula 2, 2.5 mg as a colorless transparent oil). 65.8%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CDCl3)δ:4.08(2H,t,J=6.2Hz),3.16−3.13(1H,m),2.80(1H,bs),2.60−2.50(2H,m),2.25−2.10(1H,m),2.05(3H,s),1.90−1.70(4H,m),1.40(3H,d,J=6.6Hz),1.25(3H,s) 1 H-NMR (400 MHz, CDCl 3 ) δ: 4.08 (2H, t, J = 6.2 Hz), 3.16-3.13 (1H, m), 2.80 (1H, bs), 2 .60-2.50 (2H, m), 2.25-2.10 (1H, m), 2.05 (3H, s), 1.90-1.70 (4H, m), 1.40 (3H, d, J = 6.6 Hz), 1.25 (3H, s)
〔反応式(2)〕
ここで、前記反応式(2)中、Acはアセチルを表し、DMAPはN,N−ジメチル−4−アミノピリジンを表し、DMFはN,N−ジメチルホルムアミドを表し、Meはメチルを表し、THFはテトラヒドロフランを表し、TMSはトリメチルシリルを表す。 Here, in the reaction formula (2), Ac represents acetyl, DMAP represents N, N-dimethyl-4-aminopyridine, DMF represents N, N-dimethylformamide, Me represents methyl, THF Represents tetrahydrofuran, and TMS represents trimethylsilyl.
(合成例3:化合物3の合成)
下記反応式(3)に示す通り、化合物3の合成を行った。
(Synthesis Example 3: Synthesis of Compound 3)
Compound 3 was synthesized as shown in the following reaction formula (3).
<化合物3の合成>
フッ化テトラブチルアンモニウム・テトラヒドロフラン溶液(105μL、0.10mmol)と酢酸(6.0μL、0.10mmol)の混合液を調製した。化合物31(5.3mg、0.01mmol)をテトラヒドロフラン(950μL)に溶解させ、調製した試薬(45μL、0.04mmol)を室温で加え、30分間撹拌した。そのまま減圧濃縮し、粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=3:2)で精製し、無色透明油状物として目的化合物(下記構造式3で表される化合物3、4.4mg、収率100%)を得た。以下に、得られた化合物の1H−NMRの機器分析値を示す。
<Synthesis of Compound 3>
A mixed solution of tetrabutylammonium fluoride / tetrahydrofuran solution (105 μL, 0.10 mmol) and acetic acid (6.0 μL, 0.10 mmol) was prepared. Compound 31 (5.3 mg, 0.01 mmol) was dissolved in tetrahydrofuran (950 μL), the prepared reagent (45 μL, 0.04 mmol) was added at room temperature, and the mixture was stirred for 30 minutes. Concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give the target compound (compound 3, 4.4 mg represented by the following structural formula 3 as a colorless transparent oil) Yield 100%). The instrumental analysis value of 1 H-NMR of the obtained compound is shown below.
1H−NMR(400MHz,CD3OD)δ:5.17(1H,tq,7.2Hz,1.2Hz),4.60(1H,bs),3.51(2H,t,J=6.6Hz),3.14(1H,dd,J=7.7Hz,1,5Hz),
2.60−2.55(1H,m),2.50−2.45(1H,m),2.30−2.00(5H,m),1.76−1.72(1H,m),1.65−1.57(6H,m)1.34(3H,d,J=6.9Hz),1.27(3H,s)
1 H-NMR (400 MHz, CD 3 OD) δ: 5.17 (1H, tq, 7.2 Hz, 1.2 Hz), 4.60 (1H, bs), 3.51 (2H, t, J = 6) .6 Hz), 3.14 (1 H, dd, J = 7.7 Hz, 1, 5 Hz),
2.60-2.55 (1H, m), 2.50-2.45 (1H, m), 2.30-2.00 (5H, m), 1.76-1.72 (1H, m ), 1.65-1.57 (6H, m) 1.34 (3H, d, J = 6.9 Hz), 1.27 (3H, s)
〔反応式(3)〕
ここで、前記反応式(3)中、Acはアセチルを表し、TBAFはフッ化テトラブチルアンモニウムを表し、THFはテトラヒドロフランを表し、TMSはトリメチルシリルを表す。 In the reaction formula (3), Ac represents acetyl, TBAF represents tetrabutylammonium fluoride, THF represents tetrahydrofuran, and TMS represents trimethylsilyl.
(調製例1)
<性刺激剤aの調製>
雌鞘翅に含まれる合成炭化水素8成分として、ヘプタコサン7mg、ノナコサン2.7mg、4−メチルヘキサコサン8mg、4−メチルオクタコサン12.8mg、9−メチルヘプタコサン6.6mg、9−メチルノナコサン6.7mg、15−メチルヘントリアコンタン6.8mg、及び15−メチルヘントリトリアコンタン4.6mgと、合成ケトン3成分として、ヘプタコサン−10−オン25mg、及び(18Z)−ヘプタコセン−10−オン40μg、(18Z,21Z)−ヘプタコサジエン−10−オン100μgとを、ヘキサン5mL中に含まれるように混合して性刺激剤aを調製した。
直径12mm、長さ35mmで両端を丸めた黒ガラス棒の表面に、50μLの性刺激剤a(雌1頭分に相当)を塗布し、後述する比較例1の性刺激活性試験に用いる試料とした。
(Preparation Example 1)
<Preparation of Sexual Stimulant a>
As 8 components of synthetic hydrocarbons contained in female sheath pods, heptacosan 7 mg, nonacosan 2.7 mg, 4-methylhexacosane 8 mg, 4-methyloctacosane 12.8 mg, 9-methylheptacosane 6.6 mg, 9-methylnonacosan 6.7 mg, 15-methylhentriacontan 6.8 mg, and 15-methylhentriatritan 4.6 mg, heptacosane-10-one 25 mg, and (18Z) -heptacosen-10-one as three synthetic ketone components Sex stimulant a was prepared by mixing 40 μg, (18Z, 21Z) -heptacosadien-10-one 100 μg so as to be contained in 5 mL of hexane.
50 μL of sex stimulant a (corresponding to one female) was applied to the surface of a black glass rod having a diameter of 12 mm and a length of 35 mm rounded at both ends, and a sample used for the sex stimulating activity test of Comparative Example 1 described later. did.
(調製例2)
<性刺激剤bの調製>
直径12mm、長さ35mmで両端を丸めた黒ガラス棒の表面に、50μLの性刺激剤aと、以下の通り調製したメス粗抽出物(雌1頭分)とを混合塗布して、ポジティブコントロールとしての性刺激剤b、及び性刺激剤bを塗布した試料を調製した。
(Preparation Example 2)
<Preparation of sex stimulant b>
On the surface of a black glass rod with a diameter of 12 mm and a length of 35 mm rounded at both ends, 50 μL of sex stimulant a and a female crude extract (one female) prepared as follows were mixed and applied to make a positive control. As a sex stimulant b, and a sample coated with the sex stimulant b.
−雌粗抽出物の調製−
野外から採集したゴマダラカミキリの雌成虫528頭分の鞘翅をエーテル800mLで3回それぞれ5分間抽出し、抽出物を合わせた。抽出物をヘキサンに転溶し、雌粗抽出物を調製した。
-Preparation of female crude extract-
The pods of 528 adult females of the longhorn beetle collected from the field were extracted 3 times with 800 mL of ether for 5 minutes each, and the extracts were combined. The extract was dissolved in hexane to prepare a crude female extract.
(調製例3)
<性刺激剤Aの調製>
直径12mm、長さ35mmで両端を丸めた黒ガラス棒の表面に、50μLの性刺激剤aと、合成例1で得られた化合物1 1μg(雌1頭分に相当)とを混合塗布して、性刺激剤A、及び性刺激剤Aを塗布した試料を調製した。
(Preparation Example 3)
<Preparation of sex stimulant A>
50 μL of sex stimulant a and 1 μg of compound 1 obtained in Synthesis Example 1 (corresponding to one female) were mixed and applied to the surface of a black glass rod having a diameter of 12 mm and a length of 35 mm rounded at both ends. , Sex stimulant A, and a sample coated with sex stimulant A were prepared.
(調製例4)
<性刺激剤Bの調製>
直径12mm、長さ35mmで両端を丸めた黒ガラス棒の表面に塗布した1μgの性刺激剤aに、合成例2で得られた化合物2 1μg(雌1頭分に相当)とを混合塗布して、性刺激剤B、及び性刺激剤Bを塗布した試料を調製した。
(Preparation Example 4)
<Preparation of Sexual Stimulant B>
1 μg of the sex stimulant a applied to the surface of a black glass rod having a diameter of 12 mm and a length of 35 mm rounded at both ends was mixed and applied with 1 μg of the compound 2 obtained in Synthesis Example 2 (corresponding to one female). Then, sex stimulant B and a sample coated with sex stimulant B were prepared.
(調製例5)
<性刺激剤Cの調製>
直径12mm、長さ35mmで両端を丸めた黒ガラス棒の表面に塗布した1μgの性刺激剤aに、合成例3で得られた化合物3 1μg(雌1頭分に相当)とを混合塗布して、性刺激剤C、及び性刺激剤Cを塗布した試料を調製した。
(Preparation Example 5)
<Preparation of Sexual Stimulant C>
1 μg of the sex stimulant a applied to the surface of a black glass rod having a diameter of 12 mm and a length of 35 mm rounded at both ends was mixed and applied with 1 μg of the compound 3 obtained in Synthesis Example 3 (corresponding to one female). Then, sex stimulant C and a sample coated with sex stimulant C were prepared.
(調製例6〜8)
<性刺激剤D〜Fの調製>
調製例3〜5において、化合物1〜3の混合量を1μg(雌1頭分に相当)から5μg(雌5頭分に相当)に変更した以外は、調製例3〜5と同様にして、調製例6〜8の性刺激剤D〜F、及び性刺激剤D〜Fを塗布した試料をそれぞれ調製した。
(Preparation Examples 6 to 8)
<Preparation of sex stimulants D to F>
In Preparation Examples 3 to 5, in the same manner as in Preparation Examples 3 to 5, except that the mixing amount of Compounds 1 to 3 was changed from 1 μg (corresponding to one female) to 5 μg (corresponding to five females), Samples to which sex stimulants D to F and sex stimulants D to F of Preparation Examples 6 to 8 were applied were prepared.
(実施例1)
直径12mm、長さ35mmで両端を丸めた黒ガラス棒の表面に、1μgの性刺激剤Aを塗布した試料(調製例3)を用い、前記試料に触れたゴマダラカミキリの雄の腹曲げ行動を観察する検定法により、性刺激活性試験を行った。
具体的には、直径15センチのろ紙(No.2、アドバンテック株式会社製)に前記試料1つを貼りつけ、別のろ紙に乗せたゴマダラカミキリの成体雄(1個体)の触角が試料に触れるように入れて、透明プラスチックカップ(直径12cm×高さ10cm)でカバーして5分間の行動を観察した。供試個体数に対して、腹曲げ行動が観察された個体数(反応個体数)の割合(%)、及び「反応個体数/供試個体数」を下記表1に示した。
Example 1
Using a sample (Preparation Example 3) in which 1 μg of sex stimulant A was applied to the surface of a black glass rod with a diameter of 12 mm and a length of 35 mm rounded at both ends, the abdominal bending behavior of a long-horned beetle male touching the sample was observed. The sexually stimulating activity test was conducted by the assay method.
Specifically, one sample is attached to a filter paper (No. 2, manufactured by Advantech Co., Ltd.) having a diameter of 15 centimeters, and the antennae of an adult male (one individual) of the spotted beetle placed on another filter paper touches the sample. And covered with a transparent plastic cup (diameter 12 cm × height 10 cm), and the behavior for 5 minutes was observed. Table 1 below shows the ratio (%) of the number of individuals in which abdominal bending behavior was observed (the number of responding individuals) and the “number of responding individuals / number of test individuals” with respect to the number of test individuals.
(実施例2〜6)
実施例1において、下記表1に示す通り、性刺激剤Aを塗布した試料に代えて性刺激剤B〜Fを塗布した試料を用いた以外は、実施例1と同様にして、実施例2〜6を行った。結果を下記表1に示す。
(Examples 2 to 6)
In Example 1, as shown in Table 1 below, Example 2 was carried out in the same manner as in Example 1 except that samples applied with sexual stimulants B to F were used instead of the samples applied with sexual stimulant A. ~ 6 was performed. The results are shown in Table 1 below.
(比較例1〜2)
実施例1において、下記表1に示す通り、性刺激剤Aを塗布した試料に代えて性刺激剤a〜bを塗布した試料を用いた以外は、実施例1と同様にして、ネガティブコントロールとなる比較例1、及びポジティブコントロールとなる比較例2を行った。結果を下記表1に示す。
(Comparative Examples 1-2)
In Example 1, as shown in Table 1 below, in the same manner as in Example 1 except that the sample coated with sexual stimulant ab was used instead of the sample coated with sexual stimulant A, Comparative Example 1 and Comparative Example 2 serving as a positive control were performed. The results are shown in Table 1 below.
Claims (13)
前記構造式24で表される化合物の3−オキサビシクロ[3.3.0]オクタン骨格の2位にオキソ基を付与し、下記構造式25で表される化合物を生成させる工程と、
前記構造式25で表される化合物のトリクロロアセチル基をアルデヒド基に置換し、下記構造式27で表される化合物を生成させる工程と、
前記構造式27で表される化合物のアルデヒド基を順次反応させて2−メチル−5−ヒドロキシ−1−ペンテニル基に置換し、下記構造式31で表される化合物を生成させる工程と、
前記構造式31で表される化合物の2−メチル−5−ヒドロキシ−1−ペンテニル基を環化し、トリメチルシリル基を水酸基に置換し、下記構造式1で表される化合物を生成させる工程と、を含み、
前記構造式31で表される化合物を生成させる工程が、
脱水した前記構造式27で表される化合物をテトラヒドロフランに溶解させ、臭化イソプロピルマグネシウム・テトラヒドロフラン溶液を加えて反応させ、下記構造式28で表される化合物を生成させる処理と、
前記構造式28で表される化合物をエチルビニルエーテルに溶解させ、酢酸水銀を加えて反応させ、下記構造式29で表される化合物を生成させる処理と、
前記構造式29で表される化合物をキシレンに溶解させ、加熱して反応させ、下記構造式30で表される化合物を生成する処理と、
前記構造式30で表される化合物をテトラヒドロフランに溶解させ、酢酸を加えた水素化ホウ素ナトリウムとテトラヒドロフランの混合液を加えて反応させ、前記構造式31で表される化合物を生成させる処理と、を含むことを特徴とする下記構造式1で表される化合物の製造方法。
Adding a oxo group to the 2-position of the 3-oxabicyclo [3.3.0] octane skeleton of the compound represented by Structural Formula 24 to form a compound represented by Structural Formula 25 below;
Replacing the trichloroacetyl group of the compound represented by the structural formula 25 with an aldehyde group to form a compound represented by the following structural formula 27;
A step of sequentially reacting an aldehyde group of the compound represented by the structural formula 27 and substituting it with a 2-methyl-5-hydroxy-1-pentenyl group to form a compound represented by the following structural formula 31;
Cyclizing the 2-methyl-5-hydroxy-1-pentenyl group of the compound represented by Structural Formula 31 and substituting the trimethylsilyl group with a hydroxyl group to form a compound represented by Structural Formula 1 below. seen including,
Generating the compound represented by the structural formula 31;
A process of dissolving the dehydrated compound represented by the structural formula 27 in tetrahydrofuran, adding an isopropylmagnesium bromide-tetrahydrofuran solution to react to form a compound represented by the following structural formula 28;
A treatment of dissolving the compound represented by the structural formula 28 in ethyl vinyl ether, adding mercury acetate and reacting to form a compound represented by the following structural formula 29;
A process of dissolving the compound represented by the structural formula 29 in xylene and reacting by heating to produce a compound represented by the following structural formula 30;
Treating the compound represented by the structural formula 30 in tetrahydrofuran, adding a mixture of sodium borohydride to which acetic acid has been added and tetrahydrofuran, and reacting the mixture to form the compound represented by the structural formula 31; process for producing a compound represented by the following structural formula 1, wherein including Mukoto.
前記構造式24で表される化合物の3−オキサビシクロ[3.3.0]オクタン骨格の2位にオキソ基を付与し、下記構造式25で表される化合物を生成させる工程と、
前記構造式25で表される化合物のトリクロロアセチル基を順次反応させてアセチル基に置換し、下記構造式2で表される化合物を生成させる工程と、を含み、
前記構造式2で表される化合物を生成させる工程が、
前記構造式25で表される化合物をテトラヒドロフランに溶解させ、炭酸水素ナトリウム、炭酸カリウム、水、及びメタノールを加えて反応させ、下記構造式33で表される化合物を生成させる処理と、
前記構造式33で表される化合物をN,N−ジメチルホルムアミドに溶解させ、ピリジン、無水酢酸、及びN,N−ジメチル−4−アミノピリジンを加えて反応させ、前記構造式2で表される化合物を生成させる処理と、を含むことを特徴とする下記構造式2で表される化合物の製造方法。
Adding a oxo group to the 2-position of the 3-oxabicyclo [3.3.0] octane skeleton of the compound represented by Structural Formula 24 to form a compound represented by Structural Formula 25 below;
The structural formula and sequentially reacting trichloroacetyl group of compounds represented by 25 is replaced with an acetyl group, seen containing a step of producing a compound represented by the following structural formula 2, a,
The step of generating the compound represented by Structural Formula 2 comprises:
Treatment for dissolving the compound represented by the structural formula 25 in tetrahydrofuran, adding sodium hydrogen carbonate, potassium carbonate, water and methanol and reacting them to produce a compound represented by the following structural formula 33;
The compound represented by Structural Formula 33 is dissolved in N, N-dimethylformamide, and reacted by adding pyridine, acetic anhydride, and N, N-dimethyl-4-aminopyridine, and represented by Structural Formula 2. method for producing a compound of the processing to produce a compound, the represented by the following structural formula 2, wherein including Mukoto.
前記構造式24で表される化合物の3−オキサビシクロ[3.3.0]オクタン骨格の2位にオキソ基を付与し、下記構造式25で表される化合物を生成させる工程と、
前記構造式25で表される化合物のトリクロロアセチル基をアルデヒド基に置換し、下記構造式27で表される化合物を生成させる工程と、
前記構造式27で表される化合物のアルデヒド基を順次反応させて2−メチル−5−ヒドロキシ−1−ペンテニル基に置換し、下記構造式31で表される化合物を生成させる工程と、
前記構造式31で表される化合物のトリメチルシリル基を水酸基に置換し、下記構造式3で表される化合物を生成させる工程と、を含み、
前記構造式31で表される化合物を生成させる工程が、
脱水した前記構造式27で表される化合物をテトラヒドロフランに溶解させ、臭化イソプロピルマグネシウム・テトラヒドロフラン溶液を加えて反応させ、下記構造式28で表される化合物を生成させる処理と、
前記構造式28で表される化合物をエチルビニルエーテルに溶解させ、酢酸水銀を加えて反応させ、下記構造式29で表される化合物を生成させる処理と、
前記構造式29で表される化合物をキシレンに溶解させ、加熱して反応させ、下記構造式30で表される化合物を生成する処理と、
前記構造式30で表される化合物をテトラヒドロフランに溶解させ、酢酸を加えた水素化ホウ素ナトリウムとテトラヒドロフランの混合液を加えて反応させ、前記構造式31で表される化合物を生成させる処理と、を含むことを特徴とする下記構造式3で表される化合物の製造方法。
Adding a oxo group to the 2-position of the 3-oxabicyclo [3.3.0] octane skeleton of the compound represented by Structural Formula 24 to form a compound represented by Structural Formula 25 below;
Replacing the trichloroacetyl group of the compound represented by the structural formula 25 with an aldehyde group to form a compound represented by the following structural formula 27;
A step of sequentially reacting an aldehyde group of the compound represented by the structural formula 27 and substituting it with a 2-methyl-5-hydroxy-1-pentenyl group to form a compound represented by the following structural formula 31;
The trimethylsilyl group of the compound represented by the structural formula 31 substituted with a hydroxyl group, seen including a step of producing a compound represented by the following structural formula 3, a,
Generating the compound represented by the structural formula 31;
A process of dissolving the dehydrated compound represented by the structural formula 27 in tetrahydrofuran, adding an isopropylmagnesium bromide-tetrahydrofuran solution to react to form a compound represented by the following structural formula 28;
A treatment of dissolving the compound represented by the structural formula 28 in ethyl vinyl ether, adding mercury acetate and reacting to form a compound represented by the following structural formula 29;
A process of dissolving the compound represented by the structural formula 29 in xylene and reacting by heating to produce a compound represented by the following structural formula 30;
Treating the compound represented by the structural formula 30 in tetrahydrofuran, adding a mixture of sodium borohydride to which acetic acid has been added and tetrahydrofuran, and reacting the mixture to form the compound represented by the structural formula 31; process for producing a compound represented by the following structural formula 3 wherein free Mukoto.
〔構造式1〕
[Structural formula 1]
〔構造式2〕
[Structural formula 2]
〔構造式3〕
[Structural formula 3]
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