JP5382667B2 - Production of cyclic compounds - Google Patents
Production of cyclic compounds Download PDFInfo
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- JP5382667B2 JP5382667B2 JP2011190250A JP2011190250A JP5382667B2 JP 5382667 B2 JP5382667 B2 JP 5382667B2 JP 2011190250 A JP2011190250 A JP 2011190250A JP 2011190250 A JP2011190250 A JP 2011190250A JP 5382667 B2 JP5382667 B2 JP 5382667B2
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- Japan
- Prior art keywords
- represented
- reaction
- following formula
- halogen atom
- produced
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000004519 manufacturing process Methods 0.000 title claims description 23
- 150000001923 cyclic compounds Chemical class 0.000 title 1
- OSOIQJGOYGSIMF-UHFFFAOYSA-N cyclopentadecanone Chemical compound O=C1CCCCCCCCCCCCCC1 OSOIQJGOYGSIMF-UHFFFAOYSA-N 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 26
- 239000003054 catalyst Substances 0.000 claims description 16
- 150000001336 alkenes Chemical group 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000003180 beta-lactone group Chemical group 0.000 claims description 11
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 150000002430 hydrocarbons Chemical group 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 150000004820 halides Chemical class 0.000 claims description 7
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 6
- 101150065749 Churc1 gene Proteins 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 102100038239 Protein Churchill Human genes 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 150000002009 diols Chemical class 0.000 claims description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 4
- QPXJVYUZWDGUBO-PHDIDXHHSA-N (2r,3r)-1,4-dimethoxybutane-2,3-diol Chemical compound COC[C@@H](O)[C@H](O)COC QPXJVYUZWDGUBO-PHDIDXHHSA-N 0.000 claims description 2
- OGZAWLNZWFBVSV-UHFFFAOYSA-N 2-bromocyclopentadecan-1-one Chemical compound BrC1CCCCCCCCCCCCCC1=O OGZAWLNZWFBVSV-UHFFFAOYSA-N 0.000 claims description 2
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000006932 Simmons-Smith cyclopropanation reaction Methods 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 238000005907 ketalization reaction Methods 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 238000007269 dehydrobromination reaction Methods 0.000 claims 1
- 230000000447 dimerizing effect Effects 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 239000013078 crystal Substances 0.000 description 20
- 239000003446 ligand Substances 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000011259 mixed solution Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 235000002597 Solanum melongena Nutrition 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 10
- -1 nitrogen-containing cyclic compounds Chemical class 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 241000402754 Erythranthe moschata Species 0.000 description 7
- 238000006471 dimerization reaction Methods 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- KWKAKUADMBZCLK-UHFFFAOYSA-N 1-octene Chemical compound CCCCCCC=C KWKAKUADMBZCLK-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000007810 chemical reaction solvent Substances 0.000 description 6
- 239000000539 dimer Substances 0.000 description 6
- GJBXIPOYHVMPQJ-UHFFFAOYSA-N hexadecane-1,16-diol Chemical compound OCCCCCCCCCCCCCCCCO GJBXIPOYHVMPQJ-UHFFFAOYSA-N 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- ALHUZKCOMYUFRB-OAHLLOKOSA-N Muscone Chemical compound C[C@@H]1CCCCCCCCCCCCC(=O)C1 ALHUZKCOMYUFRB-OAHLLOKOSA-N 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000012973 diazabicyclooctane Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- CPOFMOWDMVWCLF-UHFFFAOYSA-N methyl(oxo)alumane Chemical compound C[Al]=O CPOFMOWDMVWCLF-UHFFFAOYSA-N 0.000 description 5
- ALHUZKCOMYUFRB-UHFFFAOYSA-N muskone Natural products CC1CCCCCCCCCCCCC(=O)C1 ALHUZKCOMYUFRB-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 235000005811 Viola adunca Nutrition 0.000 description 4
- 235000013487 Viola odorata Nutrition 0.000 description 4
- 240000009038 Viola odorata Species 0.000 description 4
- 235000002254 Viola papilionacea Nutrition 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229910017053 inorganic salt Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 229910052723 transition metal Inorganic materials 0.000 description 4
- 150000003624 transition metals Chemical class 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229960001701 chloroform Drugs 0.000 description 3
- 229910017052 cobalt Inorganic materials 0.000 description 3
- 239000010941 cobalt Substances 0.000 description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 3
- 238000006114 decarboxylation reaction Methods 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- QQHJDPROMQRDLA-UHFFFAOYSA-N hexadecanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCC(O)=O QQHJDPROMQRDLA-UHFFFAOYSA-N 0.000 description 3
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 3
- WXPWPYISTQCNDP-UHFFFAOYSA-N oct-7-en-1-ol Chemical compound OCCCCCCC=C WXPWPYISTQCNDP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- BEZVGIHGZPLGBL-UHFFFAOYSA-N 2,6-diacetylpyridine Chemical compound CC(=O)C1=CC=CC(C(C)=O)=N1 BEZVGIHGZPLGBL-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 239000003810 Jones reagent Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229910052804 chromium Inorganic materials 0.000 description 2
- 239000011651 chromium Substances 0.000 description 2
- 239000003426 co-catalyst Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- KWIIZDCFNQCZDC-UHFFFAOYSA-N oct-1-enoxymethylbenzene Chemical compound CCCCCCC=COCC1=CC=CC=C1 KWIIZDCFNQCZDC-UHFFFAOYSA-N 0.000 description 2
- LIINGNMKNRSOGW-UHFFFAOYSA-N oct-7-enal Chemical compound C=CCCCCCC=O LIINGNMKNRSOGW-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 238000010485 C−C bond formation reaction Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- 238000006809 Jones oxidation reaction Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001416180 Moschidae Species 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 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 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 229910004349 Ti-Al Inorganic materials 0.000 description 1
- 229910004692 Ti—Al Inorganic materials 0.000 description 1
- 239000011954 Ziegler–Natta catalyst Substances 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 238000005865 alkene metathesis reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 description 1
- WHVXVDDUYCELKP-UHFFFAOYSA-N butatriene Chemical compound C=C=C=C WHVXVDDUYCELKP-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 150000001868 cobalt Chemical class 0.000 description 1
- GFHNAMRJFCEERV-UHFFFAOYSA-L cobalt chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Co+2] GFHNAMRJFCEERV-UHFFFAOYSA-L 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229960002089 ferrous chloride Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000011984 grubbs catalyst Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- 125000001449 isopropyl group Chemical class [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- NLPPUQVEOVLFRU-UHFFFAOYSA-N oct-1-enyl benzoate Chemical class CCCCCCC=COC(=O)C1=CC=CC=C1 NLPPUQVEOVLFRU-UHFFFAOYSA-N 0.000 description 1
- UFKYSJJDMSXCBR-UHFFFAOYSA-N oct-7-enoxymethylbenzene Chemical compound C=CCCCCCCOCC1=CC=CC=C1 UFKYSJJDMSXCBR-UHFFFAOYSA-N 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000003808 silyl group Chemical class [H][Si]([H])([H])[*] 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical class [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
この発明は、末端オレフィンの二量化反応により線状化合物を優先的に製造し、これを利用してエキザルトンやムスコンを製造することができる方法に関する。 This invention relates to a method for the linear compounds preferentially prepared by dimerization of terminal olefins, Ru can be produced Ekizaruton and muscone by using this.
ムスクは、香料として香水や化粧品等に広く用いられている。しかし、天然ムスクはジャコウジカなどから取るため、「絶滅のおそれある野生動植物の種の国際取引に関する条約」（ワシントン条約）によって、その商業的利用はほぼ不可能である。そのため、ニトロムスクをはじめとする人工ムスクが代替品として汎用されるようになっている。
天然ムスクの香気成分であるムスコン（化２、Ｒ＝Ｍｅ）及びエキザルトン（化２、Ｒ＝Ｈ）は、１５員環という特異な構造を持っているため、その合成は困難である。近年では、いくつかの合成法が報告されているが、いずれも合成に多段階を有する方法や入手困難な長鎖化合物を原料とするため高価となり、工業的な合成に向かない。そこで、効率の良い合成法が求められている。
Musk is widely used as a fragrance in perfumes and cosmetics. However, because natural musk is taken from musk deer, etc., its commercial use is almost impossible under the “Convention on the International Trade of Endangered Wild Animal and Plant Species” (Washington Convention). Therefore, artificial musks such as nitro musk are widely used as an alternative.
Muscon (Chemical Formula 2, R = Me) and Exalton (Chemical Formula 2, R = H), which are fragrance components of natural musk, have a unique structure of 15-membered rings, and are therefore difficult to synthesize. In recent years, several synthesis methods have been reported, but all of them are expensive due to the use of multi-step synthesis methods and long-chain compounds that are difficult to obtain, and are not suitable for industrial synthesis. Therefore, an efficient synthesis method is required.
ムスコンの最初の全合成に成功したのは、ドイツのZieglerであった（非特許文献１）。ニトリル基を両末端に有する鎖状化合物を高度希釈条件下、リチウムアミドを触媒として作用させ、分子内Thrope反応により環化した。
エキザルトンなどのムスクの合成には、環化原料である１６炭素化合物を効率良く入手することが鍵である。そこで１６炭素化合物のような長鎖化合物の合成法として、入手容易な８炭素化合物同士をカップリングさせ、２倍の炭素鎖にすることが考えられてきた。
このような炭素間結合形成反応として、Heck反応(非特許文献２)、Suzukiカップリング反応(非特許文献３)、Grubbs触媒を用いたオレフィンメタセシス反応(非特許文献４)などが検討されているが、特に、本発明に近い技術として、Ziegler-Natta触媒のようなTi-Al系金属など様々な遷移金属を中心金属とした遷移金属錯体であるビスイミノピリジル錯体を用いた1−ブテンの二量化反応が報告されている（非特許文献５，６）。
It was Ziegler in Germany that succeeded in the first total synthesis of Muscon (Non-patent Document 1). A chain compound having a nitrile group at both ends was cyclized by intramolecular Thrope reaction using lithium amide as a catalyst under highly diluted conditions.
The key to the synthesis of musks such as exalton is to efficiently obtain 16-carbon compounds as cyclization raw materials. Thus, as a method for synthesizing a long-chain compound such as a 16-carbon compound, it has been considered to couple easily available 8-carbon compounds to a double carbon chain.
As such a carbon-carbon bond forming reaction, a Heck reaction (Non-patent document 2), a Suzuki coupling reaction (Non-patent document 3), an olefin metathesis reaction using a Grubbs catalyst (Non-patent document 4), and the like have been studied. However, in particular, as a technique close to the present invention, 2-butene diene using a biiminopyridyl complex which is a transition metal complex having various transition metals such as a Ti-Al-based metal such as a Ziegler-Natta catalyst as a central metal. Quantification reactions have been reported (Non-Patent Documents 5 and 6).
ビスイミノピリジル錯体を触媒として用いた1−ブテンの二量化反応（非特許文献５，６）においては、下式に示すように反応に位置選択性がある（式中、波線はシス若しくはトランス又はこれらの混在を示す。以下同じ。）。
本発明は、このようなビスイミノピリジル錯体触媒を用いた末端オレフィンの二量化反応において線状化合物（linear体）を効率よく合成し、エキザルトンやムスコンを効率よく合成する方法を提供することを目的とする。
In the dimerization reaction of 1-butene using a biiminopyridyl complex as a catalyst (Non-patent Documents 5 and 6), the reaction has regioselectivity as shown in the following formula (wherein the wavy line is cis or trans or (The same shall apply hereinafter.)
The present invention is to provide a method of such bis imino linear compounds in the dimerization reaction of terminal olefins with pyridyl complex catalyst (linear body) efficiently synthesized, to synthesize efficiently et Kizaruton and muscone Objective.
本発明者らは、ビスイミノピリジル錯体触媒に注目し、触媒配位子及び中心金属の検討を行った結果、中心金属を適切に選択し、ビスイミノピリジル錯体の触媒中心金属の周辺に立体的制御能力を持った配位子を選択することにより、末端オレフィンの二量化反応において線状化合物を効率よく合成することができることを見出し、本発明を完成させるに至った。 The inventors of the present invention focused on the bisiminopyridyl complex catalyst and, as a result of examining the catalytic ligand and the central metal, appropriately selected the central metal and formed a three-dimensional structure around the catalytic central metal of the bisiminopyridyl complex. It has been found that by selecting a ligand having a control ability, a linear compound can be efficiently synthesized in a dimerization reaction of a terminal olefin, and the present invention has been completed.
即ち、本発明は、一般式
Ｒ４ＣＨ２ＣＨ＝ＣＨＣＨ２ＣＨ２ＣＨ２Ｒ４
(式中、Ｒ４は−（ＣＨ ２ ） ５ ＯＹ (式中、Ｙは水素原子又は水酸基の保護基を表す。)を表す。)で表される線状化合物を水素化して、下式
ＨＯ−ＣＨ ２ −（ＣＨ ２ ＣＨ ２ ） ７ −ＣＨ ２ ＯＨ
で表されるジオールを生成させ、これを酸化してジカルボン酸として、これにハロゲン化剤を作用させて、下式
ＺＣＯ−（ＣＨ ２ ＣＨ ２ ） ７ −ＣＯＺ
(式中、Ｚはハロゲン原子を表す。)で表される酸ハロゲン化物へ誘導して、下式
That is, the present invention relates to the general formula R 4 CH 2 CH═CHCH 2 CH 2 CH 2 R 4.
(Wherein R 4 represents — (CH 2 ) 5 OY (wherein Y represents a hydrogen atom or a hydroxyl-protecting group)), and a linear compound represented by the following formula is hydrogenated.
HO—CH 2 — (CH 2 CH 2 ) 7 —CH 2 OH
A diol represented by the following formula is generated, and this is oxidized to form a dicarboxylic acid.
ZCO— (CH 2 CH 2 ) 7 —COZ
(Wherein, Z is represented. The halogen atom) to induce the acid halide represented by the following formula
また本発明は、このエキザルトンを使用してムスコンを製造する方法である。
Moreover, this invention is a method of manufacturing a muscone using this exalton .
本発明の触媒は下式で表される。
Ｘは、それぞれ同じであっても異なってもよく、ハロゲン原子又はアルキル基、好ましくはハロゲン原子、より好ましくは塩素原子又は臭素原子を表す。アルキル基としてはメチル基が好ましい。
その他上記化合物（化１）のベンゼン環はアルキル基やアリール基などの置換基を有していてもよい。
The catalyst of the present invention is represented by the following formula.
X may be the same or different and each represents a halogen atom or an alkyl group, preferably a halogen atom, more preferably a chlorine atom or a bromine atom. The alkyl group is preferably a methyl group.
In addition, the benzene ring of the above compound (Chemical Formula 1) may have a substituent such as an alkyl group or an aryl group.
本発明はコバルトと上記配位子との錯体である。錯体形成は、通常室温の有機溶媒中で配位子とコバルト塩を溶解させることにより行うことができる。
本発明においては、遷移金属としてコバルトを用いることにより、他の遷移金属を用いた場合に比べて、末端オレフィンを二量化する際に線状化合物の選択性を格段に改善することができた。
The present invention is a complex of cobalt and the above ligand. Complex formation can be performed by dissolving a ligand and a cobalt salt in an organic solvent usually at room temperature.
In the present invention, by using cobalt as the transition metal, the selectivity of the linear compound can be remarkably improved when the terminal olefin is dimerized as compared with the case where other transition metals are used.
本発明においては、上記触媒を用いて末端オレフィンを二量化する。
基質である末端オレフィンは下式で表される。
ＣＨ２＝ＣＨＣＨ２Ｒ４
Ｒ４は炭素数２以上の炭化水素基、好ましくは炭素数が２〜１５のアルキル基、より好ましくは炭素数が３〜５のアルキル基を表す。
溶媒は、有機溶媒であれば特に限定は無いがトルエンやＭＡＯが好ましく用いられる。
触媒の濃度は、好ましくは０．０１〜０．２Ｍである。
反応温度は、通常―２５℃〜室温で行われ、反応時間は３０分以上である。
In the present invention, the terminal olefin is dimerized using the catalyst.
The terminal olefin as a substrate is represented by the following formula.
CH 2 = CHCH 2 R 4
R 4 represents a hydrocarbon group having 2 or more carbon atoms, preferably an alkyl group having 2 to 15 carbon atoms, more preferably an alkyl group having 3 to 5 carbon atoms.
The solvent is not particularly limited as long as it is an organic solvent, but toluene and MAO are preferably used.
The concentration of the catalyst is preferably 0.01 to 0.2M.
The reaction temperature is usually from −25 ° C. to room temperature, and the reaction time is 30 minutes or longer.
この反応の結果下式で表される線状化合物が優先的に生成する。
Ｒ４ＣＨ２ＣＨ＝ＣＨＣＨ２ＣＨ２ＣＨ２Ｒ４
この反応に際して下式で表される側鎖化合物も生成するがその収率は低い。
Ｒ４ＣＨ２ＣＨ＝ＣＨＣＨ（ＣＨ３）ＣＨ２Ｒ４
この段階で適宜公知の手段により線状化合物のみを精製して利用してもよい。
このようにして得られる線状化合物は様々な化合物の原料として有用である。その例として、エキザルトン及びムスコンの製造方法を以下に示す。
As a result of this reaction, a linear compound represented by the following formula is preferentially produced.
R 4 CH 2 CH═CHCH 2 CH 2 CH 2 R 4
In this reaction, a side chain compound represented by the following formula is also produced, but the yield is low.
R 4 CH 2 CH═CHCH (CH 3 ) CH 2 R 4
At this stage, only the linear compound may be purified and used by known means.
The linear compound thus obtained is useful as a raw material for various compounds. As an example, a method for producing Exalton and Muscon is shown below.
（１）エキザルトン(exaltone)は以下の工程により製造することができる。
(i)上記一般式中のＲ４が
−（ＣＨ２）５ＯＹ
(式中、Ｙは水素原子又は水酸基の保護基を表す。)で表される末端オレフィンを二量化する。この保護基として、ベンジル基、t-ブチル基、i-プロピル基、シリル基、アセチル基、RCO-基（Ｒは炭化水素基を表す。）などを用いることができる。
例えば、7−オクテン−1−オールを水素化ナトリウム等を用いてベンジルブロミドと反応させて、水酸基を保護する。得られたベンジルエーテルを本発明の触媒とMAO（Methylaluminoxane）存在下でトルエンなどの有機溶媒中で反応させて、二量化する。本発明の方法により線状化合物(linear体)が優先的に得られる。必要に応じて線状化合物を精製してもよい。
(1) Exaltone can be produced by the following steps.
(i) R 4 in the above general formula is — (CH 2 ) 5 OY
(Wherein Y represents a hydrogen atom or a protecting group for a hydroxyl group) is dimerized. As this protecting group, benzyl group, t-butyl group, i-propyl group, silyl group, acetyl group, RCO- group (R represents a hydrocarbon group) and the like can be used.
For example, 7-octen-1-ol is reacted with benzyl bromide using sodium hydride or the like to protect the hydroxyl group. The obtained benzyl ether is reacted with the catalyst of the present invention in the presence of MAO (Methylaluminoxane) in an organic solvent such as toluene to dimerize. A linear compound (linear body) is preferentially obtained by the method of the present invention. You may refine | purify a linear compound as needed.
(ii)得られた線状化合物を水素化する。例えば、二量体をPd-C等により水素添加する。同時に保護基の脱保護を行ってもよい。この結果1,16-ヘキサデカンジオールが得られる。
(iii)これにハロゲン化剤を作用させて酸ハロゲン化物へ誘導してβ−ラクトンを生成させる。
例えば、上記のジオールをJones酸化法等によりに酸化してジカルボン酸として、このジカルボン酸を塩化チオニル、オキサリルクロリド等により酸ハロゲン化物へ誘導する。この反応は、通常生成する酸ハロゲン化物が空気中で不安定であるため禁水及びアルゴン雰囲気下で行うことがよい。また、この反応はほとんど副反応を起こさないため、粗生成物のまま次の反応に用ることができる。
得られた酸ハロゲン化物にDABCO(1,4-ジアザビシクロ[2,2,2]オクタン)等を作用させてβ−ラクトンを生成する。このDABCOの高度希釈溶液に、酸ハロゲン化物の溶液を長時間かけて滴下することが好ましい。DABCOの代わりに、N-メチルピロリドン、4-(ジメチルアミノ)ピリジン、キヌクリジン等の含窒素環状化合物やテトラメチルエチルジアミン等の脂肪族アミン等を用いてもよい。
(ii) The resulting linear compound is hydrogenated. For example, the dimer is hydrogenated with Pd—C or the like. At the same time, the protecting group may be deprotected. As a result, 1,16-hexadecanediol is obtained.
(iii) A halogenating agent is allowed to act on this to produce an acid halide to produce β-lactone.
For example, the above diol is oxidized by the Jones oxidation method or the like to form a dicarboxylic acid, and the dicarboxylic acid is derived into an acid halide by thionyl chloride, oxalyl chloride or the like. This reaction is preferably carried out in a water-free and argon atmosphere because the acid halide that is usually produced is unstable in the air. Moreover, since this reaction hardly causes a side reaction, it can be used in the next reaction as a crude product.
The resulting acid halide is reacted with DABCO (1,4-diazabicyclo [2,2,2] octane) to produce β-lactone. The acid halide solution is preferably added dropwise to the highly diluted solution of DABCO over a long period of time. Instead of DABCO, nitrogen-containing cyclic compounds such as N-methylpyrrolidone, 4- (dimethylamino) pyridine and quinuclidine, aliphatic amines such as tetramethylethyldiamine, and the like may be used.
(iv)得られたβ−ラクトンを酸性条件で脱炭酸する。その結果エキザルトンが生成する。この脱炭酸を効率よく行うために、シリカゲルによる酸性条件で行うことが好ましい。すなわち、トリクロルメタン等の酸化剤の存在下、β−ラクトンをシリカゲルに接触させることにより、緩やかな酸化条件が得られ脱炭酸が容易に進行する。例えば、上記β−ラクトンを含む溶液をトリクロルエタンを含むシリカゲルカラムクロマトグラフィーに数回通すこと等により加水分解及び脱炭酸を行う。 (iv) The obtained β-lactone is decarboxylated under acidic conditions. As a result, exalton is generated. In order to efficiently perform this decarboxylation, it is preferable to carry out under acidic conditions using silica gel. That is, by bringing β-lactone into contact with silica gel in the presence of an oxidizing agent such as trichloromethane, mild oxidation conditions are obtained and decarboxylation proceeds easily. For example, hydrolysis and decarboxylation are performed by passing the solution containing β-lactone through silica gel column chromatography containing trichloroethane several times.
（２）エキザルトンからムスコン(muscone)は以下の工程により製造することができる。 シクロペンタデカノン（エキザルトン）を臭素化して、２−ブロモシクロペンタデカノンを合成する。これにトリエチルアミン等の塩基により脱臭化水素（ＨＢｒ）を行ってα、β不飽和ケトンへ導き、ジオール成分として１，４−ジ−O−メチル−Ｄ−スレイトールを用いたケタール化により（Ｅ）−α，β−不飽和ケタールを得る。（Ｅ）−α，β−不飽和ケタールを、ジエチルエーテル還流下で過剰のシモンズ−スミス試薬で処理し、シクロプロパンケタールジアステレオマーを得る。このジアステレオマーを加水分解して、芳香を有するビシクロケトンを得る。このビシクロケトンのシクロプロパン環を還元開環し、生成したアルコールを酸化してムスコンを得る。 (2) Muscone from exalton can be produced by the following process. Cyclopentadecanone (exalton) is brominated to synthesize 2-bromocyclopentadecanone. This is dehydrobromated (HBr) with a base such as triethylamine to lead to an α, β unsaturated ketone, and by ketalization using 1,4-di-O-methyl-D-threitol as the diol component (E) -Α, β-unsaturated ketals are obtained. The (E) -α, β-unsaturated ketal is treated with an excess of Simmons-Smith reagent under diethyl ether reflux to give the cyclopropane ketal diastereomer. This diastereomer is hydrolyzed to obtain an aromatic bicycloketone. The cyclopropane ring of this bicycloketone is reduced and opened, and the resulting alcohol is oxidized to obtain muscone.
以下、実施例にて本発明を例証するが本発明を限定することを意図するものではない。
触媒配位子は、2,6−ジアセチルピリジンを出発原料として様々なアミンとイミノ化することにより合成した。
製造例１
本製造例では2，6-ビス(イミノ)ピリジル配位子(化合物1)を合成した。
反応容器（50mlナスフラスコ）は予め真空下加熱し禁水条件にて行い、また反応溶媒も乾燥したものを用いた。アルゴンガス雰囲気下、2，6−ジアセチルピリジン0.49g（3.0mmol）と塩化メチレン20mlの混合溶液にアニリン1.26g，1.24ml（13.5mmol）を加えた。この反応溶液にギ酸（97%）を5drops加え、室温で40時間撹拌した。反応溶液をエバポレーターにて濃縮し、真空乾燥した。その後、反応フラスコを冷凍庫にて−40℃に冷却した。反応フラスコに氷浴で冷却したメタノールを徐々に加えることで黄色結晶が析出した。その結晶を吸引濾過し、氷浴で冷却したメタノールで洗った。その結晶を真空乾燥し黄色結晶を0.65g（Y．68%）得た。
1H-NMR(CDCL3) δ ppm 2.41(s, 6H), 6.85(d, J = 7.9Hz, 4H), 7.12(t, Ｊ = 7.3Hz, 2H), 7.38(t, J = 7.3Hz, 4H), 7.88(t, J = 7.9Hz, 1H), 8.34(d, J = 7.9Hz, 2H)
The following examples illustrate the invention but are not intended to limit the invention.
The catalyst ligand was synthesized by iminating with various amines using 2,6-diacetylpyridine as a starting material.
Production Example 1
In this production example, a 2,6-bis (imino) pyridyl ligand (Compound 1) was synthesized.
The reaction vessel (50 ml eggplant flask) was heated under vacuum in advance under water-free conditions, and the reaction solvent was also dried. Under an argon gas atmosphere, 1.26 g and 1.24 ml (13.5 mmol) of aniline were added to a mixed solution of 0.49 g (3.0 mmol) of 2,6-diacetylpyridine and 20 ml of methylene chloride. To this reaction solution, 5 drops of formic acid (97%) was added and stirred at room temperature for 40 hours. The reaction solution was concentrated with an evaporator and dried in vacuum. Thereafter, the reaction flask was cooled to −40 ° C. in a freezer. Yellow crystals were precipitated by gradually adding methanol cooled in an ice bath to the reaction flask. The crystals were filtered off with suction and washed with methanol cooled in an ice bath. The crystals were vacuum-dried to obtain 0.65 g (Y. 68%) of yellow crystals.
1 H-NMR (CDCL 3 ) δ ppm 2.41 (s, 6H), 6.85 (d, J = 7.9Hz, 4H), 7.12 (t, J = 7.3Hz, 2H), 7.38 (t, J = 7.3Hz, 4H), 7.88 (t, J = 7.9Hz, 1H), 8.34 (d, J = 7.9Hz, 2H)
ピリジンの置換基を適宜変更して同様の反応で下記配位子（化合物2-8）を製造した。
製造された2，6-ビス(イミノ)ピリジル配位子(化合物2)の分析データを下記に示す。
1H-NMR(CDCL3) δ ppm 2.13(s, 6H), 2.34(s, 6H), 6.69(d, J = 6.6Hz, 2H), 7.03(t, J = 7.3Hz, 2H), 7.21(m, 4H), 7.89(t, J = 7.9Hz, 1H), 8.41(d, J = 7.9Hz, 2H)
製造された2，6-ビス(イミノ)ピリジル配位子(化合物3)の分析データを下記に示す。
1H-NMR(CDCL3) δ ppm 2.01(s, 6H), 2.34(s, 12H), 6.59(d, J = 7.9Hz, 2H), 7.02(t, J = 7.9Hz, 4H), 7.87(t, J = 7.9Hz, 1H), 8.38(d, J = 7.9Hz, 2H)
製造された2，6-ビス(イミノ)ピリジル配位子(化合物4)の分析データを下記に示す。
1H-NMR(CDCL3) δ ppm 2.11(s, 6H), 2.34(s, 6H), 6.63(d, J = 8.6Hz, 2H), 7.20(t, J = 8.6Hz, 4H), 7.90(t, J = 7.9Hz, 1H), 8.38(d, J = 7.9Hz, 2H)
13C-NMR(CDCL3) δ ppm 167.4, 155.0, 136.8, 130.1, 128.4, 126.3, 122.3, 119.3, 17.8, 16.5
製造された2，6-ビス(イミノ)ピリジル配位子(化合物5)の分析データを下記に示す。
1H-NMR(CDCL3) δ ppm 1.16(t, J = 7.9Hz, 6H), 2.37(s, 6H), 2.52(q, J = 7.9Hz, 4H), 6.67(d, J = 7.9Hz, 2H), 7.02(dt, J = 19.8, 7.9Hz, 6H), 7.89(t, J = 7.9Hz, 1H), 8.40(d, J = 7.9Hz, 2H)
製造された2，6-ビス(イミノ)ピリジル配位子(化合物6)の分析データを下記に示す。
1H-NMR(CDCL3) δ ppm 1.15(t, J = 7.25, 6H), 2.36(s, 6H),2.48(q, J = 7.25, 4H), 6.55(d, J = 8.6Hz, 2H), 7.32(dd, J = 8.6, 2.0Hz, 2H), 7.39(d, J = 2.0Hz, 2H), 7.90(t, J = 7.9Hz, 1H), 8.38(d, J = 7.9Hz, 2H)
13C-NMR(CDCL3) δ ppm 167.1, 155.0, 148.1, 136.8, 135.7, 131.4, 129.1, 122.3, 119.8, 116.6, 24.7, 16.5, 13.9
製造された2，6-ビス(イミノ)ピリジル配位子(化合物7)の分析データを下記に示す。
1H-NMR(CDCL3) δ ppm 1.20(d, J = 7.3Hz, 12H), 2.39(s, 6H), 2.52(dq, J = 6.9, 7.3Hz, 2H), 6.65(d, J = 7.9Hz, 2H), 7.02(m, 6H), 7.90(t, J = 7.9Hz, 1H), 8.41(d, J = 7.9Hz, 2H)
製造された2，6-ビス(イミノ)ピリジル配位子(化合物8)の分析データを下記に示す。
1H-NMR(CDCL3) δ ppm 2.41(s, 6H), 6.85(d, J = 7.3Hz, 2H), 7.47(m, 6H), 7.65(d, J = 8.6Hz, 2H), 7.82(d, J = 8.6Hz, 2H), 7.88(d, J = 7.9Hz, 2H), 8.00(t, J = 7.9Hz, 1H), 8.60(d, J = 7.9Hz, 2H)
Analytical data of the produced 2,6-bis (imino) pyridyl ligand (compound 2) is shown below.
1 H-NMR (CDCL 3 ) δ ppm 2.13 (s, 6H), 2.34 (s, 6H), 6.69 (d, J = 6.6Hz, 2H), 7.03 (t, J = 7.3Hz, 2H), 7.21 ( m, 4H), 7.89 (t, J = 7.9Hz, 1H), 8.41 (d, J = 7.9Hz, 2H)
Analytical data of the produced 2,6-bis (imino) pyridyl ligand (Compound 3) is shown below.
1 H-NMR (CDCL 3 ) δ ppm 2.01 (s, 6H), 2.34 (s, 12H), 6.59 (d, J = 7.9Hz, 2H), 7.02 (t, J = 7.9Hz, 4H), 7.87 ( t, J = 7.9Hz, 1H), 8.38 (d, J = 7.9Hz, 2H)
Analytical data of the produced 2,6-bis (imino) pyridyl ligand (Compound 4) is shown below.
1 H-NMR (CDCL 3 ) δ ppm 2.11 (s, 6H), 2.34 (s, 6H), 6.63 (d, J = 8.6Hz, 2H), 7.20 (t, J = 8.6Hz, 4H), 7.90 ( t, J = 7.9Hz, 1H), 8.38 (d, J = 7.9Hz, 2H)
13 C-NMR (CDCL 3 ) δ ppm 167.4, 155.0, 136.8, 130.1, 128.4, 126.3, 122.3, 119.3, 17.8, 16.5
Analytical data of the produced 2,6-bis (imino) pyridyl ligand (Compound 5) are shown below.
1 H-NMR (CDCL 3 ) δ ppm 1.16 (t, J = 7.9Hz, 6H), 2.37 (s, 6H), 2.52 (q, J = 7.9Hz, 4H), 6.67 (d, J = 7.9Hz, 2H), 7.02 (dt, J = 19.8, 7.9Hz, 6H), 7.89 (t, J = 7.9Hz, 1H), 8.40 (d, J = 7.9Hz, 2H)
Analytical data of the produced 2,6-bis (imino) pyridyl ligand (Compound 6) is shown below.
1 H-NMR (CDCL 3 ) δ ppm 1.15 (t, J = 7.25, 6H), 2.36 (s, 6H), 2.48 (q, J = 7.25, 4H), 6.55 (d, J = 8.6Hz, 2H) , 7.32 (dd, J = 8.6, 2.0Hz, 2H), 7.39 (d, J = 2.0Hz, 2H), 7.90 (t, J = 7.9Hz, 1H), 8.38 (d, J = 7.9Hz, 2H)
13 C-NMR (CDCL 3 ) δ ppm 167.1, 155.0, 148.1, 136.8, 135.7, 131.4, 129.1, 122.3, 119.8, 116.6, 24.7, 16.5, 13.9
Analytical data of the produced 2,6-bis (imino) pyridyl ligand (Compound 7) is shown below.
1 H-NMR (CDCL 3 ) δ ppm 1.20 (d, J = 7.3Hz, 12H), 2.39 (s, 6H), 2.52 (dq, J = 6.9, 7.3Hz, 2H), 6.65 (d, J = 7.9 Hz, 2H), 7.02 (m, 6H), 7.90 (t, J = 7.9Hz, 1H), 8.41 (d, J = 7.9Hz, 2H)
The analytical data of the produced 2,6-bis (imino) pyridyl ligand (Compound 8) are shown below.
1 H-NMR (CDCL 3 ) δ ppm 2.41 (s, 6H), 6.85 (d, J = 7.3Hz, 2H), 7.47 (m, 6H), 7.65 (d, J = 8.6Hz, 2H), 7.82 ( d, J = 8.6Hz, 2H), 7.88 (d, J = 7.9Hz, 2H), 8.00 (t, J = 7.9Hz, 1H), 8.60 (d, J = 7.9Hz, 2H)
製造例２
本製造例では製造例１で製造した各配位子とコバルトとの錯体を製造した。
反応容器（10mlナスフラスコ）は、予め真空化加熱し禁水条件にて行い、また反応溶媒も乾燥したものを用いた。アルゴンガス雰囲気下、ビスイミノピリジル配位子0.3mmolとTHF3mlの混合溶液に塩化コバルト(II)六水和物（CoCl2・6H2O）0.25mmolを加えた。室温で5分間撹拌すると、青紫色の結晶が析出してくる。反応容器にエーテルを加え、結晶を完全に析出させる。吸引濾過により、溶媒を除去しエーテル及びｎ−ペンタンで洗浄する。その結晶を真空乾燥し青紫色結晶を収率87〜96％で得た。
Production Example 2
In this production example, a complex of each ligand produced in Production Example 1 and cobalt was produced.
The reaction vessel (10 ml eggplant flask) was preliminarily heated under vacuum and in water-free conditions, and the reaction solvent was also dried. Under an argon gas atmosphere, 0.25 mmol of cobalt (II) chloride hexahydrate (CoCl 2 .6H 2 O) was added to a mixed solution of 0.3 mmol of the bisiminopyridyl ligand and 3 ml of THF. When the mixture is stirred at room temperature for 5 minutes, blue-violet crystals are precipitated. Ether is added to the reaction vessel to completely precipitate the crystals. The solvent is removed by suction filtration and washed with ether and n-pentane. The crystals were vacuum-dried to obtain blue-violet crystals with a yield of 87 to 96%.
製造例３
本製造例では製造例１で製造した各配位子と鉄との錯体を製造した。
反応容器（10mlナスフラスコ）は、予め真空化加熱し禁水条件にて行い、また反応溶媒も乾燥したものを用いた。アルゴンガス雰囲気下、ビスイミノピリジル配位子0.3mmolとTHF 3mlの混合溶液に塩化第一鉄四水和物（FeCl2・4H2O）0.25mmolを加えた。室温で5分間撹拌すると、青紫色の結晶が析出してくる。反応容器にエーテルを加え、結晶を完全に析出させる。吸引濾過により、溶媒を除去しエーテル及びｎ−ペンタンで洗浄する。その結晶を真空乾燥し青紫色結晶を収率90〜100％で得た。
Production Example 3
In this production example, a complex of each ligand produced in Production Example 1 and iron was produced.
The reaction vessel (10 ml eggplant flask) was preliminarily heated under vacuum and in water-free conditions, and the reaction solvent was also dried. Under an argon gas atmosphere, 0.25 mmol of ferrous chloride tetrahydrate (FeCl 2 .4H 2 O) was added to a mixed solution of 0.3 mmol of the bisiminopyridyl ligand and 3 ml of THF. When the mixture is stirred at room temperature for 5 minutes, blue-violet crystals are precipitated. Ether is added to the reaction vessel to completely precipitate the crystals. The solvent is removed by suction filtration and washed with ether and n-pentane. The crystals were vacuum-dried to obtain blue-violet crystals with a yield of 90-100%.
製造例４
本製造例では、上記製造例２で得た触媒（Co触媒）を用いて1−オクテンの二量化反応を行った。
反応容器（10mlナスフラスコ）は、予め真空化加熱し禁水条件にて行った。アルゴンガス雰囲気下、2.0×10−3molの各触媒と10mmolの1−オクテン混合溶液を室温で数分間撹拌した。その反応溶液に、10％MAOトルエン溶液0.4mlを加え、室温（あるいは0，−40，−78℃）で30分撹拌した。反応溶液を水の入ったビーカーに少しずつ加え反応を終了させる。このとき無機塩として水酸化アルミニウムが生成するので吸引濾過により除去し、濾液をヘキサンにより抽出した。エバポレーターにより濃縮しシリカゲルカラムクロマトグラフィー（ヘキサン、20倍）により精製し、真空乾燥することで二量体を収率24〜78%で得た。さらに位置選択性を決定するために、オレフィンの水素化を行った。二量体に対して10wt%の10%Pd-Cを加え、酢酸エチルを10ml加え水素ガス雰囲気下1日撹拌した。この反応は、定量的に進行するため、反応の位置選択性には影響しない。この反応物を1H-NMRによりオレフィンが完全に水素化されているかを確認した。GC14Aにより位置選択性を算出した。GC条件（INJ:250℃，DET:250℃，COL INIT.TEMP:200℃，COL INIT.TIME:3min，COL PROG.RATE:10℃，COL FINAL.TEMP:250℃，COL FINAL.TIME:20min）linear体検出時間：7〜8mim, branched体：6〜7min
Production Example 4
In this Production Example, 1-octene dimerization reaction was performed using the catalyst (Co catalyst) obtained in Production Example 2 above.
The reaction vessel (10 ml eggplant flask) was preliminarily heated under vacuum and in water-free conditions. Under an argon gas atmosphere, 2.0 × 10 −3 mol of each catalyst and 10 mmol of 1-octene mixed solution were stirred at room temperature for several minutes. To the reaction solution, 0.4 ml of 10% MAO toluene solution was added and stirred at room temperature (or 0, -40, -78 ° C) for 30 minutes. The reaction solution is gradually added to a beaker containing water to complete the reaction. At this time, aluminum hydroxide was produced as an inorganic salt, and thus it was removed by suction filtration, and the filtrate was extracted with hexane. The dimer was obtained in a yield of 24-78% by concentrating with an evaporator, purifying by silica gel column chromatography (hexane, 20 times), and vacuum drying. In addition, olefins were hydrogenated to determine regioselectivity. 10 wt% of 10% Pd—C was added to the dimer, 10 ml of ethyl acetate was added, and the mixture was stirred in a hydrogen gas atmosphere for 1 day. Since this reaction proceeds quantitatively, it does not affect the regioselectivity of the reaction. This reaction product was confirmed by 1 H-NMR to confirm that the olefin was completely hydrogenated. Regioselectivity was calculated by GC14A. GC conditions (INJ: 250 ° C, DET: 250 ° C, COL INIT.TEMP: 200 ° C, COL INIT.TIME: 3min, COL PROG.RATE: 10 ° C, COL FINAL.TEMP: 250 ° C, COL FINAL.TIME: 20min ) Linear detection time: 7-8mim, branched: 6-7min
結果を下表に示す。
後記の製造例５のFe触媒を用いた場合に比べ、本実施例のCo触媒を用いた場合には、収率は低いが、ほぼ位置選択的にLinear体を与えた。
Entry1,2,5,6では直接的に立体の大きさによる制御を検討したところ、R1がHでは、二量体がほとんど得られなかった。これは立体的に小さすぎるために制御されず、原料のオレフィンが異性化した生成物を与えてしまうためであると考えられる。
Entry2,5,7ではentry5の時最も収率良く二量体が得られた。これらの反応を通して位置選択性は高選択性を保持した。
R3については、電子吸引性のハロゲンの場合に、収率が高かった。
Compared with the case where the Fe catalyst of Production Example 5 described later was used, when the Co catalyst of this example was used, the yield was low, but the linear body was given almost regioselectively.
In Entry1,2,5,6, the control by the size of the solid was examined directly. When R 1 was H, almost no dimer was obtained. This is considered to be because it is not controlled because it is too small three-dimensionally and gives a product in which the raw material olefin is isomerized.
In Entry2,5,7, the dimer was obtained in the best yield for entry5. Through these reactions, the regioselectivity kept high selectivity.
For R 3 , the yield was high in the case of electron withdrawing halogen.
製造例５
本比較例では、上記製造例３で得た触媒（Fe触媒）を用いて製造例４と同様の条件で1−オクテンの二量化反応を行った。結果を下表に示す。
In this comparative example, 1-octene dimerization reaction was performed under the same conditions as in Production Example 4 using the catalyst (Fe catalyst) obtained in Production Example 3 above. The results are shown in the table below.
Feを中心金属とした場合、良好な収率で二量化が進行するが、側鎖化合物(branched)が高収率で生成し、目的である線状化合物(linear)の収率は製造例４のものより劣り、位置選択性は高いものではなかった。 When Fe is used as the central metal, dimerization proceeds with a good yield, but a side chain compound (branched) is produced in a high yield, and the yield of the target linear compound (linear) is as shown in Production Example 4. The position selectivity was not high.
実施例１
本実施例ではエキザルトンの合成を行った。
200mlナスフラスコを用いて、窒素ガス雰囲気下、7−オクテナール(化合物32）17.0g，20ml（0.135mol）とエタノール70mlの混合溶液を氷浴により冷却した。その混合溶液に水素化ホウ素ナトリウム2.55g（0.068mol）を少しずつ加え、その後45分間撹拌した。反応溶液に1Ｎ塩酸を加え中和し、生成した無機塩を吸引濾過し除去した。濾液を酢酸エチルにより抽出し、エバポレーターにより濃縮した。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＝5／1，50倍）により精製し、７−オクテン−１−オール(化合物33）を14.0g（Y．81%）得た。
1H-NMR(CDCL3) δ ppm 1.36(bs, 6H), 1.57(bs, 3H), 2.04(t, J = 6.6Hz, 2H)
3.63(t, J = 6.6Hz, 2H), 4.97(m, 2H), 5.81(tdq, J = 20.1, 17.1, 3.3Hz, 1H)
IR(neat) cm-1 638, 728, 911, 996, 1058, 1463, 1642, 2858, 2930, 3078, 3332
Example 1
In this example, exalton was synthesized.
Using a 200 ml eggplant flask, a mixed solution of 17.0 g, 20 ml (0.135 mol) of 7-octenal (compound 32) and 70 ml of ethanol was cooled with an ice bath in a nitrogen gas atmosphere. To the mixed solution, 2.55 g (0.068 mol) of sodium borohydride was added little by little, and then stirred for 45 minutes. The reaction solution was neutralized with 1N hydrochloric acid, and the produced inorganic salt was removed by suction filtration. The filtrate was extracted with ethyl acetate and concentrated by an evaporator. The product was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1, 50 times) to obtain 14.0 g (Y. 81%) of 7-octen-1-ol (compound 33).
1 H-NMR (CDCL 3 ) δ ppm 1.36 (bs, 6H), 1.57 (bs, 3H), 2.04 (t, J = 6.6Hz, 2H)
3.63 (t, J = 6.6Hz, 2H), 4.97 (m, 2H), 5.81 (tdq, J = 20.1, 17.1, 3.3Hz, 1H)
IR (neat) cm -1 638, 728, 911, 996, 1058, 1463, 1642, 2858, 2930, 3078, 3332
反応容器（200ml二口ナスフラスコ）は、予め真空化加熱し禁水条件にて行い、また反応溶媒も乾燥したものを用いた。水素化ナトリウムは、油との混合物であるためヘキサンにより洗浄して用いた。窒素ガス雰囲気下、水素化ナトリウム0.96g（40mmol）とTHF100mlの混合溶液を氷浴により冷却した。その混合溶液を0℃に保ちながら、7−オクテン‐1−オール5.13g（40mmol）を30分かけて滴下した。続いてベンジルブロミド3.42g，2.40ml（20mmol）を滴下し混合溶液に加えた。室温に上昇させ、一日撹拌した。反応混合物に氷浴で冷却しながら0.1N塩酸を弱酸性になるまで加えた。無機塩が生成するので吸引濾過により除去し濾液をエーテルにより抽出し、濃縮した。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＝9／1，50倍）により精製し、７−オクテニルベンジルエーテル(化合物34）を4.26g（Y．98%）で得た。
1H-NMR(CDCL3) δ ppm 1.34(bs, 6H), 1.62(m, 2H), 2.04(m, 2H), 3.46(t, J=6.6Hz, 2H), 4.50(s, 2H), 4.97(m, 2H), 5.81(tdq, J=20.8, 16.8, 3.3Hz, 1H), 7.31(m, 5H)
IR(neat) cm-1 698, 735, 910, 995, 1029, 1104, 1204, 1362, 1455, 1496, 1640, 2856, 2931, 2976, 3031, 3066, 3480
The reaction vessel (200 ml two-necked eggplant flask) was preliminarily heated under vacuum and in water-free conditions, and the reaction solvent was also dried. Since sodium hydride is a mixture with oil, it was used after washing with hexane. Under a nitrogen gas atmosphere, a mixed solution of 0.96 g (40 mmol) of sodium hydride and 100 ml of THF was cooled with an ice bath. While maintaining the mixed solution at 0 ° C., 5.13 g (40 mmol) of 7-octen-1-ol was added dropwise over 30 minutes. Subsequently, 3.42 g and 2.40 ml (20 mmol) of benzyl bromide were added dropwise to the mixed solution. Raised to room temperature and stirred for one day. While cooling with an ice bath, 0.1N hydrochloric acid was added to the reaction mixture until it became weakly acidic. Since an inorganic salt was formed, it was removed by suction filtration, and the filtrate was extracted with ether and concentrated. The product was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1, 50 times) to obtain 7.26 g (Y. 98%) of 7-octenylbenzyl ether (Compound 34).
1 H-NMR (CDCL 3 ) δ ppm 1.34 (bs, 6H), 1.62 (m, 2H), 2.04 (m, 2H), 3.46 (t, J = 6.6Hz, 2H), 4.50 (s, 2H), 4.97 (m, 2H), 5.81 (tdq, J = 20.8, 16.8, 3.3Hz, 1H), 7.31 (m, 5H)
IR (neat) cm -1 698, 735, 910, 995, 1029, 1104, 1204, 1362, 1455, 1496, 1640, 2856, 2931, 2976, 3031, 3066, 3480
以上の反応式を以下に示す。
反応容器（100mlナスフラスコ）は、予め真空化加熱し禁水条件にて行い、また反応溶媒も乾燥したものを用いた。アルゴンガス雰囲気下、触媒(19)70.68mg（0.15mmol）とベンジルオクテニルエーテル（34）16.37g，17.79ml（75mmol）の混合溶液を‐25℃で数分撹拌した。10%MAO 31.5mlをゆっくり加え30分撹拌した。反応溶液を水の入ったビーカーに少しずつ加え反応を終了させる。このとき無機塩として水酸化アルミニウムが生成するので吸引濾過により除去し、濾液をヘキサンにより抽出した。エバポレーターにより濃縮し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、50倍）により精製し、無色の液体ベンゾイルオクテニルエーテル２量体(化合物35）6.55g（Y．40%）を得た。
位置選択性については、次段階のオレフィンの水素化と脱保護後にGC14Aにより測定した。なお、次段階の反応は、定量的に進行するため、反応の位置選択性の変化は次反応後でも変化しない。
1H-NMR(CDCL3) δ ppm 1.36(m, 8H), 1.61(t, J = 5.9Hz, 8H), 2.01(m, 4H), 3.46(t, J = 6.6Hz, 4H), 4.50(s, 2H), 5.41(m, 2H), 7.32(m, 10H)
The reaction vessel (100 ml eggplant flask) was previously heated under vacuum and in a water-free condition, and the reaction solvent was also dried. Under an argon gas atmosphere, a mixed solution of 70.68 mg (0.15 mmol) of the catalyst (19), 16.37 g of benzyl octenyl ether (34) and 17.79 ml (75 mmol) was stirred at −25 ° C. for several minutes. Slowly added 31.5 ml of 10% MAO and stirred for 30 minutes. The reaction solution is gradually added to a beaker containing water to complete the reaction. At this time, aluminum hydroxide was produced as an inorganic salt, and thus it was removed by suction filtration, and the filtrate was extracted with hexane. Concentrated by an evaporator and purified by silica gel column chromatography (hexane / ethyl acetate = 9/1, 50 times) to obtain 6.55 g (Y. 40%) of colorless liquid benzoyloctenyl ether dimer (compound 35). .
Regioselectivity was measured by GC14A after the next stage olefin hydrogenation and deprotection. In addition, since the reaction at the next stage proceeds quantitatively, the change in the position selectivity of the reaction does not change even after the next reaction.
1 H-NMR (CDCL 3 ) δ ppm 1.36 (m, 8H), 1.61 (t, J = 5.9Hz, 8H), 2.01 (m, 4H), 3.46 (t, J = 6.6Hz, 4H), 4.50 ( s, 2H), 5.41 (m, 2H), 7.32 (m, 10H)
以上の反応式を以下に示す。
反応容器は、200mlナスフラスコを用いた。二量体6.55g（15mmol）と10%Pd-C 2gの混合溶液にEtOH 150mlを加える。この混合溶液を水素ガス雰囲気下1日撹拌する。このとき、TLCによりベンジル保護が完全に外れるまで反応時間は調整する。このとき反応が完結しなければ、Pd-C，水素ガスを追加する。このオレフィンの水素化と脱保護は、ほぼ定量的に進行する。反応生成物をセライト濾過し、濃縮する。結晶が析出するので、ヘキサンで洗浄し、吸引濾過により白色結晶（1，16−ヘキサデカンジオール(化合物36））を3.87ｇ（quant．）で得た。GC14Aによりlinear体100％であった。
1H-NMR(CDCL3) δ ppm 1.26(bs, 22H), 1.58(bs, 8H), 3.63(m, 4H)
IR(neat) cm-1 692, 720, 732, 1028, 1044, 1062, 1072, 1124, 1409, 1462, 1473, 1560, 1646, 2850, 2919, 3286
m.p. 91.7〜92.4℃（lit．92.0〜93.0℃）
GC条件（INJ:250℃，DET:250℃，COL INIT.TEMP:200℃，COL INIT.TIME:3min，COL PROG.RATE:10℃，COL FINAL.TEMP:250℃，COL FINAL.TIME:20min）linear体検出時間：29min
The reaction vessel used was a 200 ml eggplant flask. 150 ml of EtOH is added to a mixed solution of 6.55 g (15 mmol) of dimer and 2 g of 10% Pd—C. The mixed solution is stirred for 1 day under a hydrogen gas atmosphere. At this time, the reaction time is adjusted until the benzyl protection is completely removed by TLC. If the reaction is not completed at this time, Pd-C and hydrogen gas are added. This olefin hydrogenation and deprotection proceeds almost quantitatively. The reaction product is filtered through celite and concentrated. Since crystals were precipitated, the crystals were washed with hexane, and 3.87 g (quant.) Of white crystals (1,16-hexadecanediol (compound 36)) were obtained by suction filtration. It was 100% linear by GC14A.
1 H-NMR (CDCL3) δ ppm 1.26 (bs, 22H), 1.58 (bs, 8H), 3.63 (m, 4H)
IR (neat) cm -1 692, 720, 732, 1028, 1044, 1062, 1072, 1124, 1409, 1462, 1473, 1560, 1646, 2850, 2919, 3286
mp 91.7-92.4 ° C (lit. 92.0-93.0 ° C)
GC conditions (INJ: 250 ° C, DET: 250 ° C, COL INIT.TEMP: 200 ° C, COL INIT.TIME: 3min, COL PROG.RATE: 10 ° C, COL FINAL.TEMP: 250 ° C, COL FINAL.TIME: 20min ) Linear detection time: 29min
Jones試薬は以下のようにして調整した。反応容器（20mlナスフラスコ）に三酸化クロム1.8g（17.8mmol）と水5.6mlを加えた。氷浴により冷却し、95％硫酸1.61mlを滴下した。超音波により反応容器内の固体を完全に溶解させた。
200mlナスフラスコに1，16−ヘキサデカンジオール0.77g（2.96mmol）とアセトン110mlを加える。超音波により固体を完全に溶解させ、反応系を20℃に保ちながら、上記で調整したJones試薬を滴下した。滴下後、4時間撹拌する、反応後、濃縮しアセトンを除去する。残分には、青色のクロム固体と白色の結晶が残っている。ここに水を加えクロムを完全に溶解させた。吸引濾過することでクロム水溶液と白色結晶を分離し、その結晶をさらに水で洗浄する。得られた結晶をテトラヒドロフランに溶解させた（THFの飽和溶液になるようにする）。さらにヘキサンを加えると白色結晶が再度析出してくるので濾過し、真空乾燥することでヘキサデカンニ酸(化合物37）を0.77g（Y．91%）で得た。
1H-NMR(d6DMSO) δ ppm 1.24(bs, 20H), 1.52(bs, 4H), 2.17(t, J=7.3Hz, 4H)（Aldrich date baseと比較カルボン酸のHは検出できない）
IR(neat) cm-1 548, 685, 724, 939, 1184, 1216, 1258, 1298, 1431, 1468, 1701, 2689, 2851, 2919
m.p. 120.1〜122.9℃（lit．122.0〜124.0℃）
Jones reagent was prepared as follows. To a reaction vessel (20 ml eggplant flask), 1.8 g (17.8 mmol) of chromium trioxide and 5.6 ml of water were added. The mixture was cooled in an ice bath and 1.61 ml of 95% sulfuric acid was added dropwise. The solid in the reaction vessel was completely dissolved by ultrasonic waves.
To a 200 ml eggplant flask, add 0.77 g (2.96 mmol) of 1,16-hexadecanediol and 110 ml of acetone. The solids were completely dissolved by ultrasonic waves, and the Jones reagent prepared above was added dropwise while maintaining the reaction system at 20 ° C. After dropping, the mixture is stirred for 4 hours. After the reaction, it is concentrated to remove acetone. In the residue, a blue chrome solid and white crystals remain. Water was added thereto to completely dissolve chromium. The aqueous chromium solution and white crystals are separated by suction filtration, and the crystals are further washed with water. The obtained crystals were dissolved in tetrahydrofuran (so that a saturated solution of THF was obtained). Further, when hexane was added, white crystals were precipitated again, which was filtered and dried under vacuum to obtain 0.77 g (Y. 91%) of hexadecanoic acid (Compound 37).
1 H-NMR (d6DMSO) δ ppm 1.24 (bs, 20H), 1.52 (bs, 4H), 2.17 (t, J = 7.3Hz, 4H) (Aldrich date base and H of carboxylic acid cannot be detected)
IR (neat) cm -1 548, 685, 724, 939, 1184, 1216, 1258, 1298, 1431, 1468, 1701, 2689, 2851, 2919
mp 120.1-122.9 ° C (lit. 122.0-124.0 ° C)
反応容器（50mlナスフラスコ）は、予め真空化加熱し禁水条件にて行った。反応に用いる塩化チオニルは、常圧蒸留により精製したものを用いた。（b.ｐ. 77.5℃）窒素ガス雰囲気下、ヘキサデカン二酸（37）1.01g（3.5mmol）と塩化チオニル（14.0mmol）の混合溶液を30分かけてゆっくり昇温し、還流条件下2時間撹拌した。濃縮することにより、塩化チオニルを留去することで、酸クロリド粗生成物（酸クロリド(化合物38））1.13g（Y．99%）を得た。この反応は副反応がほとんど起こらないことより、組成生物を次段階に用いた。
1H-NMR(CDCL3) δ ppm 1.27(s, 20H), 1.70(t, J=7.3Hz, 4H), 2.88(t, J = 7.3Hz, 4H)
IR(neat) cm-1 571, 595, 692, 726, 955, 1136, 1404, 1466, 1803, 2855, 2928
The reaction vessel (50 ml eggplant flask) was heated in advance under vacuum and in water-free conditions. Thionyl chloride used for the reaction was purified by atmospheric distillation. (B.p. 77.5 ° C) Under a nitrogen gas atmosphere, the temperature of a mixed solution of hexadecanedioic acid (37) 1.01 g (3.5 mmol) and thionyl chloride (14.0 mmol) was slowly increased over 30 minutes, and refluxed for 2 hours. Stir. By concentration, thionyl chloride was distilled off to obtain 1.13 g (Y. 99%) of a crude acid chloride product (acid chloride (compound 38)). Since this reaction hardly caused side reactions, the composition organism was used in the next step.
1 H-NMR (CDCL 3 ) δ ppm 1.27 (s, 20H), 1.70 (t, J = 7.3Hz, 4H), 2.88 (t, J = 7.3Hz, 4H)
IR (neat) cm -1 571, 595, 692, 726, 955, 1136, 1404, 1466, 1803, 2855, 2928
以上の反応式を以下に示す。
反応容器（200mlナスフラスコ）は、予め真空化加熱し禁水条件にて行い、また反応溶媒も乾燥したものを用いた。DABCOは、エーテルで再結晶することにより精製したものを用いた。DABCO 0.10g（0.31mmol）のTHF（60ml）溶液0.07Mを40℃に昇温する。酸クロリド(38)0.100gのTHF溶液（酸クロリド0.31mmol／THF3.5ml）0.09Mをマイクロフィーダーにより四時間かけて滴下した。滴下後、30分撹拌し、塩酸により中和した。エーテル抽出を行い硫酸マグネシウム乾燥後、濾過し硫酸マグネシウムを除去し、濃縮した。シリカゲルカラムクロマトグラフィー（クロロホルム／ヘキサン1：1，100倍）を行い、β-ラクトン(化合物41）を0.054g（Y．70%）で得た。
1H-NMR(CDCL3) δ ppm 0.85-2.41(m, 24H), 4.05(bs, 1H), 4.68(dd, J=10.6,4.0Hz, 1H)
The reaction vessel (200 ml eggplant flask) was preliminarily heated under vacuum and under water-free conditions, and the reaction solvent was also dried. DABCO used was purified by recrystallization from ether. A 0.07M solution of DABCO (0.10 g, 0.31 mmol) in THF (60 ml) is heated to 40 ° C. Acid chloride (38) 0.100 g of a THF solution (acid chloride 0.31 mmol / THF 3.5 ml) 0.09M was added dropwise over 4 hours using a microfeeder. After dropping, the mixture was stirred for 30 minutes and neutralized with hydrochloric acid. The mixture was extracted with ether, dried over magnesium sulfate, filtered to remove magnesium sulfate, and concentrated. Silica gel column chromatography (chloroform / hexane 1: 1, 100 times) was performed to obtain β-lactone (Compound 41) at 0.054 g (Y. 70%).
1 H-NMR (CDCL 3 ) δ ppm 0.85-2.41 (m, 24H), 4.05 (bs, 1H), 4.68 (dd, J = 10.6, 4.0Hz, 1H)
β-lactone 0.054g（0.25mmol）をシリカゲルカラムクロマトグラフィー（クロロホルム，50倍）を数回行うことで、エキザルトン(化合物2）を0.054g（Y．96%）で得た。
1H-NMR(CDCL3) δ ppm 1.30(m, 20H), 1.65(t, J=7.3Hz, 4H), 2.42(t, J = 7.3Hz, 4H)
IR(neat) cm-1 711, 734, 1079, 1127, 1153, 1215, 1286, 1368, 1409, 1460, 1712, 2856, 2934
β-lactone 0.054 g (0.25 mmol) was subjected to silica gel column chromatography (chloroform, 50 times) several times to obtain exalton (compound 2) at 0.054 g (Y. 96%).
1 H-NMR (CDCL 3 ) δ ppm 1.30 (m, 20H), 1.65 (t, J = 7.3Hz, 4H), 2.42 (t, J = 7.3Hz, 4H)
IR (neat) cm -1 711, 734, 1079, 1127, 1153, 1215, 1286, 1368, 1409, 1460, 1712, 2856, 2934
以上の反応式を以下に示す。
Claims (4)
Ｒ４ＣＨ２ＣＨ＝ＣＨＣＨ２ＣＨ２ＣＨ２Ｒ４
(式中、Ｒ４は−（ＣＨ ２ ） ５ ＯＹ (式中、Ｙは水素原子又は水酸基の保護基を表す。)を表す。)で表される線状化合物を水素化して、下式
ＨＯ−ＣＨ ２ −（ＣＨ ２ ＣＨ ２ ） ７ −ＣＨ ２ ＯＨ
で表されるジオールを生成させ、これを酸化してジカルボン酸として、これにハロゲン化剤を作用させて、下式
ＺＣＯ−（ＣＨ ２ ＣＨ ２ ） ７ −ＣＯＺ
(式中、Ｚはハロゲン原子を表す。)で表される酸ハロゲン化物へ誘導して、下式
(Wherein R 4 represents — (CH 2 ) 5 OY (wherein Y represents a hydrogen atom or a hydroxyl-protecting group)), and a linear compound represented by the following formula is hydrogenated.
HO—CH 2 — (CH 2 CH 2 ) 7 —CH 2 OH
A diol represented by the following formula is generated, and this is oxidized to form a dicarboxylic acid.
ZCO— (CH 2 CH 2 ) 7 —COZ
(Wherein, Z is represented. The halogen atom) to induce the acid halide represented by the following formula
ＣＨ２＝ＣＨＣＨ２ Ｒ ４
(式中、Ｒ４は上記と同様である。)で表される末端オレフィンを二量化することにより製造される請求項１に記載のエキザルトンを製造する方法。 The linear compound has the general formula
The method for producing exalton according to claim 1, which is produced by dimerizing a terminal olefin represented by the formula (wherein R 4 is as defined above ).
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