JP4826863B2 - Method for producing 4-substituted cyclohexanone derivative - Google Patents
Method for producing 4-substituted cyclohexanone derivative Download PDFInfo
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- JP4826863B2 JP4826863B2 JP2001098175A JP2001098175A JP4826863B2 JP 4826863 B2 JP4826863 B2 JP 4826863B2 JP 2001098175 A JP2001098175 A JP 2001098175A JP 2001098175 A JP2001098175 A JP 2001098175A JP 4826863 B2 JP4826863 B2 JP 4826863B2
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- 238000004519 manufacturing process Methods 0.000 title claims description 28
- -1 4-substituted cyclohexanone Chemical class 0.000 title claims description 26
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 10
- HPXRVTGHNJAIIH-PTQBSOBMSA-N cyclohexanol Chemical class O[13CH]1CCCCC1 HPXRVTGHNJAIIH-PTQBSOBMSA-N 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000004956 cyclohexylene group Chemical group 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 229910052720 vanadium Inorganic materials 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000000596 cyclohexenyl group Chemical class C1(=CCCCC1)* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 238000010531 catalytic reduction reaction Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000004973 liquid crystal related substance Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000012769 display material Substances 0.000 description 4
- 239000012776 electronic material Substances 0.000 description 4
- 239000003205 fragrance Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- ZNWLFTSPNBLXGL-UHFFFAOYSA-N 4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexan-1-one Chemical compound C1CC(=O)CCC1C1CCC2(OCCO2)CC1 ZNWLFTSPNBLXGL-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000005708 Sodium hypochlorite Substances 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000006317 isomerization reaction Methods 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ZBTMRBYMKUEVEU-UHFFFAOYSA-N 1-bromo-4-methylbenzene Chemical compound CC1=CC=C(Br)C=C1 ZBTMRBYMKUEVEU-UHFFFAOYSA-N 0.000 description 2
- RHBYPVNVDQMSFG-UHFFFAOYSA-N 4-(4-hydroxycyclohexyl)cyclohexan-1-one Chemical compound C1CC(O)CCC1C1CCC(=O)CC1 RHBYPVNVDQMSFG-UHFFFAOYSA-N 0.000 description 2
- GOSPUCRVGGFLQA-UHFFFAOYSA-N 4-(4-methoxycyclohexyl)cyclohexan-1-one Chemical compound C1CC(OC)CCC1C1CCC(=O)CC1 GOSPUCRVGGFLQA-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000005594 diketone group Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000011968 lewis acid catalyst Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000008204 material by function Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- AALUTIYNYXEFNT-UHFFFAOYSA-N trimethylsilane hydroiodide Chemical compound C[SiH](C)C.I AALUTIYNYXEFNT-UHFFFAOYSA-N 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- RNOKTKOGJCSZOY-UHFFFAOYSA-N 1-[4-(4-methoxycyclohexyl)cyclohexyl]-4-methylbenzene Chemical compound C1CC(OC)CCC1C1CCC(C=2C=CC(C)=CC=2)CC1 RNOKTKOGJCSZOY-UHFFFAOYSA-N 0.000 description 1
- RKWWASUTWAFKHA-UHFFFAOYSA-N 1-bromo-2,3-difluorobenzene Chemical compound FC1=CC=CC(Br)=C1F RKWWASUTWAFKHA-UHFFFAOYSA-N 0.000 description 1
- ISAOUZVKYLHALD-UHFFFAOYSA-N 1-chloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)NC(=O)NC1=O ISAOUZVKYLHALD-UHFFFAOYSA-N 0.000 description 1
- VPWNQTHUCYMVMZ-UHFFFAOYSA-N 4,4'-sulfonyldiphenol Chemical class C1=CC(O)=CC=C1S(=O)(=O)C1=CC=C(O)C=C1 VPWNQTHUCYMVMZ-UHFFFAOYSA-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
- BSEAXOKTPOWGRM-UHFFFAOYSA-N 8-[4-(4-methylphenyl)cyclohex-3-en-1-yl]-1,4-dioxaspiro[4.5]decane Chemical compound Cc1ccc(cc1)C1=CCC(CC1)C1CCC2(CC1)OCCO2 BSEAXOKTPOWGRM-UHFFFAOYSA-N 0.000 description 1
- ZETHHMPKDUSZQQ-UHFFFAOYSA-N Betulafolienepentol Natural products C1C=C(C)CCC(C(C)CCC=C(C)C)C2C(OC)OC(OC)C2=C1 ZETHHMPKDUSZQQ-UHFFFAOYSA-N 0.000 description 1
- 229930185605 Bisphenol Natural products 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- JQBHUBNDHJOFNP-UHFFFAOYSA-N CC1=CC=C(C=C1)C2=CCC(CC2)C3CCC(CC3)OC Chemical compound CC1=CC=C(C=C1)C2=CCC(CC2)C3CCC(CC3)OC JQBHUBNDHJOFNP-UHFFFAOYSA-N 0.000 description 1
- ZKQDCIXGCQPQNV-UHFFFAOYSA-N Calcium hypochlorite Chemical compound [Ca+2].Cl[O-].Cl[O-] ZKQDCIXGCQPQNV-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- PCSMJKASWLYICJ-UHFFFAOYSA-N Succinic aldehyde Chemical compound O=CCCC=O PCSMJKASWLYICJ-UHFFFAOYSA-N 0.000 description 1
- GPWHDDKQSYOYBF-UHFFFAOYSA-N ac1l2u0q Chemical compound Br[Br-]Br GPWHDDKQSYOYBF-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000004419 alkynylene group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical group BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical group 0.000 description 1
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical compound OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 description 1
- 229940077239 chlorous acid Drugs 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- HEOKFDGOFROELJ-UHFFFAOYSA-N diacetal Natural products COc1ccc(C=C/c2cc(O)cc(OC3OC(COC(=O)c4cc(O)c(O)c(O)c4)C(O)C(O)C3O)c2)cc1O HEOKFDGOFROELJ-UHFFFAOYSA-N 0.000 description 1
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Chemical compound CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- CUILPNURFADTPE-UHFFFAOYSA-N hypobromous acid Chemical compound BrO CUILPNURFADTPE-UHFFFAOYSA-N 0.000 description 1
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical class Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は液晶表示材料等の電子材料や機能性材料または医農薬や香料、各種添加剤およびそれらの合成中間体として有用な、4-置換シクロヘキサノン誘導体の製造に関する。
【０００２】
【従来の技術】
4-置換シクロヘキサノン誘導体は液晶表示材料等の電子材料や機能性材料または医農薬や香料、各種添加剤およびそれらの合成中間体として有用であり、製造中間体として重要である。特にアリールシクロヘキシル基を有する4-置換シクロヘキサノン誘導体はSTN液晶表示用等として用いられるアルケニル系液晶化合物の中間体として、非常に重要である。このアリールシクロヘキシル基を有する4-置換シクロヘキサノン誘導体はこれまで、例えばビシクロヘキサン-4,4'-ジオンモノエチレンアセタールのごとき、ジケトン化合物のモノアセタールを原料として製造されていた。このようなモノアセタールは通常ジケトンのモノアセタール化により製造される。しかしながら、ジケトン化合物を選択的にモノアセタール化することは容易ではなく、通常、原料のジケトンとジアセタール体及びモノアセタールの混合物から必要なモノアセタールのみを分離する必要があり、コストの上昇が避けられなかった。そのため、アリールシクロヘキシル基を有する4-置換シクロヘキサノン誘導体を得るために、ジケトンのモノアセタール以外の安価な化合物を原料とした製造方法が望まれていた。
【０００３】
【発明が解決しようとする課題】
本発明が解決しようとする課題は、アリールシクロヘキシル基を有する4-置換シクロヘキサノン誘導体を得るための、より安価で入手容易な化合物を原料とする製造方法を提供することにある。
【０００４】
【課題を解決するための手段】
本発明は、上記課題を解決するために鋭意検討した結果、ビスフェノール類の接触還元等により容易に得られるヒドロキシケトンを原料として、アリールシクロヘキシル基を有する4-置換シクロヘキサノン誘導体が容易に製造できることを見出し、本発明を完成するに至った。
【０００５】
すなわち、本発明は一般式(I)
【化７】
【０００６】
【化８】
【０００７】
【化９】
【０００８】
【発明の実施の形態】
上述のごとく、本発明の製造方法により得られるアリール基を有する4-置換シクロヘキサノン誘導体は一般式(I)
【化１０】
【０００９】
一般式(I)において、Vは単結合または炭素原子数1〜4のアルキレン基を表すが、単結合または-CH2CH2-が好ましく、単結合が最も好ましい。
【００１０】
Arは置換基を有していてもよいアリール基を表すが、アリール基としてはフェニル基、テトラヒドロナフチル基、ナフチル基、ピリミジル基、ピリジル基、ピラジル基、ビフェニリル基、フリル基、ピロリル基、オキサゾリル基、イソオキサゾリル基、チアゾリル基、イソチアゾリル基、イミダゾリル基、ベンゾフリル基、イソベンゾフリル基、インドリル基、イソインドリル基、キノリル基、イソキノリル基、ナフチリジル基、ベンゾイミダゾリル基、キノキサリル基、キナゾリル基等をあげることができるが、フェニル基、ナフチル基及びビフェニリル基が好ましく、フェニル基が最も好ましい。
【００１１】
これらの基が有していてもよい置換基としては、製造上の反応工程で不活性な基であれば特に制限はないが、フッ素原子、塩素原子、アルキル基、アラルキル基、アルコキシル基、あるいは1個以上のフッ素原子により置換されたアルキル基、アラルキル基、アルコキシル基が好ましい。
【００１２】
特にArとしては一般式(IV)
【化１１】
【００１３】
一般式(IV)においてX1、X2及びX3はそれぞれ独立的に水素原子またはフッ素原子を表すが、(X1、X2、X3)として(H、H、H)、(F、H、H)、(F、F、H)または(F、H、F)の組み合わせが好ましい。
【００１４】
Yは水素原子、フッ素原子、塩素原子、RまたはORを表す。ここでRは直鎖状でも分岐状でもあるいは環状部を含んでいてもよい炭素原子数1〜10のアルキル基を表すが、炭素原子数1〜7のアルコキシル基または1〜5個のフッ素原子により置換されていてもよい。Yとしては水素原子、フッ素原子、トリフルオロメトキシ基、ジフルオロメトキシ基、トリフルオロメチル基、メトキシ基、エトキシ基、メチル基またはエチル基が好ましい。
【００１５】
本発明の製造方法において、一般式(I)の化合物は一般式(III)
【化１２】
【００１６】
この酸化工程において、酸化剤としては2級アルコールをケトンに酸化しうるものであれば特に制限はないが、ハロゲン系酸化剤またはクロム酸系酸化剤が好ましく、特に塩素、臭素等のハロゲン、次亜塩素酸、次亜臭素酸等の次亜ハロゲン酸、次亜塩素酸ナトリウム、次亜臭素酸ナトリウム、さらし粉等の次亜ハロゲン酸塩、N-クロロこはく酸イミド、N-ブロモこはく酸イミド、N-ブロモアセトアミド、N-クロロイソシアヌル酸等のN-ハロカルボン酸アミドが好ましく、次亜塩素酸ナトリウム、さらし粉等の次亜塩素酸塩が最も好ましい。
【００１７】
(III)の酸化により得られた一般式(I)の化合物はさらなる精製工程を経ることなく、所望の目的に供することが可能な場合もあり、あるいは再結晶、蒸留、カラムクロマトグラフィー等の通常の精製手段により精製して用いる場合もある。
【００１８】
一般式(I)において、シクロヘキシレン基の1,4-位はトランス配置であることが好ましいが、(I)までの製造工程において、トランス体への異性化工程を含まない場合には得られた(I)は通常シス体とトランス体の混合物である。その場合には得られた(I)をいったんアセタール化し、強塩基またはルイス酸触媒等の存在下にトランス体に異性化し、その後に脱アセタール化することが好ましい。強塩基としてはN,N-ジメチルホルムアミド(DMF)等の非プロトン性極性溶媒下でのt-ブトキシカリウムが好ましく、ルイス酸としては塩化アルミニウムが好ましいが、通常はt-ブトキシカリウムが最も好ましい。
【００１９】
本発明においては原料として一般式(II)
【化１３】
【００２０】
【化１４】
一般式(III)のシクロヘキサノール誘導体を一般式(II)のヒドロキシケトンを原料として製造するルートはいくつか存在するが、以下に示すルートが好ましい。
【００２１】
即ち(II)のヒドロキシケトンの水酸基を保護することにより一般式(V)
【化１５】
【００２２】
この水酸基が保護されたヒドロキシケトン類に一般式 Ar-M (VI)で表される有機金属反応剤を反応させることによりシクロヘキサノール誘導体が得られる。ここでMは金属原子または金属原子を含む基を表し、カルボニル基に求核付加する限り特に制限はないが、MgBr、MgI、MgClまたはLiが特に好ましい。前述のArの定義に従って、(VI)としてより好ましい形態は、一般式(VI')
【化１６】
【００２３】
得られたシクロヘキサノール誘導体から脱水することにより一般式(VIII)
【化１７】
【００２４】
(VIII)のシクロヘキセン誘導体を接触還元することにより一般式(IX)
【化１８】
【００２５】
還元は水素雰囲気下、遷移金属触媒存在下に行われる。
【００２６】
水素圧は常圧付近以上であれば特に制限はないが、0.1MPa〜4MPaが好ましく、0.1MPa〜1MPaがより好ましく、0.1MPa〜0.4MPaがさらに好ましい。
【００２７】
遷移金属触媒としては、通常の接触還元に用いられるものであれば特に制限はないが、パラジウム/炭素、白金/炭素、ルテニウム/炭素等の炭素に担持された金属、あるいはラネーニッケル等のラネー金属等が好ましい。
【００２８】
保護基Zとしてベンジル基を用いた場合、この工程で脱保護されることがあるので、その場合には必要に応じて再度水酸基を保護することが好ましい。
【００２９】
得られた(IX)のシクロヘキシレン基の1,4-位は通常シス及びトランス体の混合物である。目的の一般式(I)においてシクロヘキシレン基の1,4-位はトランス体であることが好ましいが、そのためにはこの工程の後でシス体をトランス体に異性化しておくことが好ましい。
【００３０】
異性化は強塩基あるいはルイス酸触媒の存在下に行われる。強塩基としてはN,N-ジメチルホルムアミド(DMF)等の非プロトン性極性溶媒下でのt-ブトキシカリウムが好ましく、ルイス酸としては塩化アルミニウムが好ましいが、保護基としてテトラヒドロピラニル基、テトラヒドロフリル基、メトキシメチル基またはエトキシメチル基を用いる場合には塩基触媒、通常はt-ブトキシカリウムが最も好ましい。
【００３１】
一般式(IX)の化合物を脱保護することにより一般式(III)のシクロヘキサノール誘導体を得ることができる。
【００３２】
脱保護は保護基がテトラヒドロピラニル基、テトラヒドロフリル基、メトキシメチル基またはエトキシメチル基の場合にはプロトン性溶媒存在下に酸で処理することにより、メチル基の場合には三臭化ホウ素、塩化アルミニウムとのルイス酸、ヨウ化トリメチルシリル、ジメチルスルフィド等のスルフィド類、あるいはこれらを組み合わせてもちいることにより脱メチル化することができる。ベンジル基の場合には接触還元により脱保護が可能である。
【００３３】
以上のようにして、一般式(II)で表されるヒドロキシケトンから、一般式(I)で表される4-置換シクロヘキサノン誘導体を製造することができる。
【００３４】
得られた(I)の化合物は液晶表示材料等の電子材料や機能性材料または医農薬や香料、各種添加剤およびそれらの合成中間体として有用であるが、本発明は一般式(I)の化合物のなかで、以下の(Ia-1)〜(Ib-21)で示される化合物の製造方法として好ましい。
【００３５】
【化１９】
【化２０】
以下、実施例を挙げて本発明を更に詳述するが、本発明はこれらの実施例に限定されるものではない。
【００３７】
(実施例1) トランス-4'-(4-メチルフェニル)ビシクロヘキサン-4-オン(Ia-16)の製造
1-a) 4'-ヒドロキシビシクロヘキサン-4-オン(この化合物はビフェノールから特開平12-159718号公報に準じた方法で製造でき、シス及びトランス体の混合物である。)19.6gの50mLテトラヒドロフラン(THF)溶液をTHF200mL中に懸濁させた水素化ナトリウム(50％)5.0gに滴下した。室温で1時間攪拌した後、ヨウ化メチル15gのTHF30mL溶液を30分かけて滴下した。3時間攪拌した後、水を加えて過剰の水素化ナトリウムを分解し、塩酸酸性としてトルエンで抽出した。水洗後、溶媒を溜去して4'-メトキシビシクロヘキサン-4-オン18gを得た。
1-b) 17.1gのp-ブロモトルエンと2.4gのマグネシウムから調製したグリニャール反応剤溶液中に、室温で上記4'-メトキシビシクロヘキサン-4-オンの全量のTHT溶液を滴下した。室温で3時間攪拌した後、水次いで塩酸を加えて反応を停止させ、トルエンで抽出した。水、及び飽和食塩水で洗浄後、無水硫酸ナトリウムで脱水乾燥させた。
1-c) 濾過後、トルエンが約50mLになるまで減圧濃縮し、これに0.5gのp-トルエンスルホン酸1水和物を加え、溜出する水を除去しながら、4時間加熱還流させた。室温まで冷却し、重曹水次いで水で洗浄し、無水硫酸ナトリウムで脱水乾燥させた。濾過後減圧下に溶媒を溜去して、1-(4-メチルフェニル)-4-(4-メトキシシクロヘキシル)シクロヘキサ-1-エン19.8gを得た。
1-d) この全量をエタノール100mLに溶解し、1.0gの5％パラジウム/炭素とともにオートクレーブ中で、室温で4時間接触還元(水素圧0.4MPa)した。触媒を濾別後、減圧下に溶媒を溜去して4-(4-メチルフェニル)-4'-メトキシビシクロヘキサン19.0gを得た。
1-e) この全量を200mLのDMFに溶解し、5.6gのt-ブトキシカリウムを加え、80℃で2時間加熱攪拌した。放冷後、水を加え、塩酸水で中和した後、ヘキサンで抽出した。ヘキサン相は水で洗浄した後、無水硫酸ナトリウムで脱水乾燥させた。濾過後減圧下に溶媒を溜去して得られた粗生成物をエタノールから再結晶させて、トランス-4-(4-メチルフェニル)-4'-メトキシビシクロヘキサンの白色結晶14.5gを得た。
1-f)この全量をジクロロメタン100mLに溶解し、水冷下、ヨウ化トリメチルシラン15gを加え、室温に戻して8時間攪拌させた。水を加え、トルエンで抽出し、減圧下に溶媒を溜去して、トランス-4-(4-メチルフェニル)-4'-ヒドロキシビシクロヘキサン12.0gを得た。
1-g) この全量をジクロロメタン50mLに溶解し、酢酸50mLを加え、激しく攪拌しながら、これに8％次亜塩素酸ナトリウム水溶液(アンチホルミン)100mLを滴下した。4時間攪拌後、亜硫酸水素ナトリウム水溶液を加えて過剰の酸化剤を分解し、水を加え、トルエンで抽出した。水、飽和食塩水で洗浄後、溶媒を濃縮して得られた粗生成物をエタノールから再結晶させて、表記のトランス-4'-(4-メチルフェニル)ビシクロヘキサン-4-オン(Ia-16)の白色結晶8.5gを得た。
【００３８】
(比較例1) ビシクロヘキサン-4,4'-ジオンモノエチレンアセタールを原料とする表記のトランス-4'-(4-メチルフェニル)ビシクロヘキサン-4-オン(Ia-16)の製造
p-ブロモトルエン16.3gから調製したグリニャール反応剤に、ビシクロヘキサン-4,4'-ジオンモノエチレンアセタール12.0gを滴下して反応させ、シクロヘキサノール誘導体16.7gを得た。これをトルエンに溶解し、0.5gの硫酸水素ナトリウムを加えて共沸する水を除去しながら加熱還流させ、4-(4-メチルフェニル)ビシクロヘキサ-3-エン-4'-オンエチレンアセタール12.0gを得た。この全量を酢酸エチルに溶解し、ラネーニッケル0.6gを加え、オートクレーブ中水素圧0.5MPaで接触還元して、4-(4-メチルフェニル)ビシクロヘキサン-4'-オンエチレンアセタール11.5gを得た。この全量をDMFに溶解し、t-ブトキシカリウム2.2gを加え、100℃で4時間加熱還流させた。水次いで塩酸水を加えて中和し、トルエンで抽出し、溶媒を濃縮して得られた残渣をエタノールから再結晶させてトランス-4-(4-メチルフェニル)ビシクロヘキサン-4'-オンエチレンアセタール8.5gを得た。この全量をトルエンに溶解し、酢酸及び希硫酸を加え、5時間加熱攪拌させた。水を加え中和後、トルエンで抽出し、得られた粗生成物をエタノールから再結晶させて表記のトランス-4'-(4-メチルフェニル)ビシクロヘキサン-4-オン(Ia-16)の白色結晶6.4gを得た。
【００３９】
従って原料としてを用いた場合でも実施例1と同様に目的のトランス-4'-(4-メチルフェニル)ビシクロヘキサン-4-オンを得ることができるが、ビシクロヘキサン-4,4'-ジオンモノエチレンアセタールは4'-ヒドロキシビシクロヘキサン-4-オンと比較してはるかに高価であり、実施例1がコスト的に優れていることは明らかである。
【００４０】
(実施例2) トランス-4'-(3,4-ジフルオロフェニル)ビシクロヘキサン-4-オン(Ia-16)の製造
実施例1-b)においてp-ブロモベンゼンに換えて、3,4-ジフルオロブロモベンゼンを用い、1-d)において還元触媒としてパラジウム/炭素に換えて、高活性ラネーニッケルを用い、1-e)における異性化を室温で行った以外は同様にして、同様の収率で表記のトランス-4'-(3,4-ジフルオロフェニル)ビシクロヘキサン-4-オン(Ia-16)の白色結晶を得た。
【００４１】
(実施例3) トランス-4'-(3,4-ジフルオロフェニル)ビシクロヘキサン-4-オン(Ia-16)の製造
実施例1-f)においてヨウ化トリメチルシランに換えて、塩化トリメチルシランとヨウ化ナトリウムを用いてトランス-4-(4-メチルフェニル)-4'-ヒドロキシビシクロヘキサンを製造した以外は実施例1と同様にしてトランス-4'-(4-メチルフェニル)ビシクロヘキサン-4-オン(Ia-16)を得た。
【００４２】
(実施例4) トランス-4'-(3,5-ジフルオロ-4-メトキシフェニル)ビシクロヘキサン-4-オン(Ia-12)の製造
実施例1-a)において、ヨウ化メチルに換えて塩化ベンジルを用い、1-d)における接触還元の水素圧を0.1MPaとし、1-f)の脱保護工程を水素圧0.5MPa、50℃の接触還元で実施した以外は実施例1と同様にして、トランス-4'-(3,5-ジフルオロ-4-メトキシフェニル)ビシクロヘキサン-4-オン(Ia-12)の白色結晶を得た。
【００４３】
【発明の効果】
本発明はアリールシクロヘキシル基を有する4-置換シクロヘキサノン誘導体の製造において、原料として高価なジケトン化合物のモノアセタールに換えて、安価で入手容易なヒドロキシケトンを原料とする方法を提供し、これにより所望のアリールシクロヘキシル基を有する4-置換シクロヘキサノン誘導体のより安価な製造を可能とした。得られたアリールシクロヘキシル基を有する4-置換シクロヘキサノン誘導体は、液晶表示材料等の電子材料や機能性材料または医農薬や香料、各種添加剤およびそれらの合成中間体として極めて有用である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to the production of 4-substituted cyclohexanone derivatives that are useful as electronic materials such as liquid crystal display materials, functional materials, medicines and agricultural chemicals, fragrances, various additives, and synthetic intermediates thereof.
[0002]
[Prior art]
4-Substituted cyclohexanone derivatives are useful as electronic materials such as liquid crystal display materials, functional materials, medical pesticides, fragrances, various additives, and synthetic intermediates thereof, and are important as production intermediates. In particular, a 4-substituted cyclohexanone derivative having an arylcyclohexyl group is very important as an intermediate of an alkenyl liquid crystal compound used for STN liquid crystal display or the like. This 4-substituted cyclohexanone derivative having an arylcyclohexyl group has heretofore been produced from a monoacetal of a diketone compound, such as bicyclohexane-4,4′-dione monoethylene acetal. Such monoacetals are usually produced by monoacetalization of diketones. However, it is not easy to selectively monoacetalize the diketone compound, and it is usually necessary to separate only the necessary monoacetal from the mixture of the raw diketone, diacetal and monoacetal, and an increase in cost can be avoided. There wasn't. Therefore, in order to obtain a 4-substituted cyclohexanone derivative having an arylcyclohexyl group, a production method using an inexpensive compound other than the diacetone monoacetal as a raw material has been desired.
[0003]
[Problems to be solved by the invention]
The problem to be solved by the present invention is to provide a method for producing a 4-substituted cyclohexanone derivative having an arylcyclohexyl group, starting from a less expensive and easily available compound.
[0004]
[Means for Solving the Problems]
As a result of diligent studies to solve the above problems, the present invention has found that 4-substituted cyclohexanone derivatives having an arylcyclohexyl group can be easily produced from a hydroxyketone easily obtained by catalytic reduction of bisphenols or the like as a raw material. The present invention has been completed.
[0005]
That is, the present invention relates to the general formula (I)
[Chemical 7]
[0006]
[Chemical 8]
[0007]
[Chemical 9]
[0008]
DETAILED DESCRIPTION OF THE INVENTION
As described above, the 4-substituted cyclohexanone derivative having an aryl group obtained by the production method of the present invention has the general formula (I)
[Chemical Formula 10]
[0009]
In the general formula (I), V represents a single bond or an alkylene group having 1 to 4 carbon atoms, preferably a single bond or —CH 2 CH 2 —, and most preferably a single bond.
[0010]
Ar represents an aryl group which may have a substituent, and as the aryl group, a phenyl group, a tetrahydronaphthyl group, a naphthyl group, a pyrimidyl group, a pyridyl group, a pyrazyl group, a biphenylyl group, a furyl group, a pyrrolyl group, an oxazolyl Group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, benzofuryl group, isobenzofuryl group, indolyl group, isoindolyl group, quinolyl group, isoquinolyl group, naphthyridyl group, benzimidazolyl group, quinoxalyl group, quinazolyl group, etc. However, a phenyl group, a naphthyl group and a biphenylyl group are preferable, and a phenyl group is most preferable.
[0011]
The substituent that these groups may have is not particularly limited as long as it is an inactive group in the reaction step of production, but a fluorine atom, a chlorine atom, an alkyl group, an aralkyl group, an alkoxyl group, or Alkyl groups, aralkyl groups and alkoxyl groups substituted with one or more fluorine atoms are preferred.
[0012]
Especially as Ar, the general formula (IV)
Embedded image
[0013]
In the general formula (IV), X 1 , X 2 and X 3 each independently represent a hydrogen atom or a fluorine atom, and (X 1 , X 2 , X 3 ) are (H, H, H), (F, H, H), (F, F, H) or combinations of (F, H, F) are preferred.
[0014]
Y represents a hydrogen atom, a fluorine atom, a chlorine atom, R or OR. Here, R represents an alkyl group having 1 to 10 carbon atoms which may be linear, branched or cyclic, but is an alkoxyl group having 1 to 7 carbon atoms or 1 to 5 fluorine atoms. May be substituted. Y is preferably a hydrogen atom, a fluorine atom, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, a methoxy group, an ethoxy group, a methyl group or an ethyl group.
[0015]
In the production method of the present invention, the compound of the general formula (I) is represented by the general formula (III)
Embedded image
[0016]
In this oxidation step, the oxidizing agent is not particularly limited as long as it can oxidize a secondary alcohol to a ketone, but a halogen-based oxidizing agent or a chromic acid-based oxidizing agent is preferable, and in particular, halogens such as chlorine and bromine, Hypohalous acid such as chlorous acid and hypobromous acid, sodium hypochlorite, sodium hypobromite, hypohalite such as bleaching powder, N-chlorosuccinimide, N-bromosuccinimide, N-halocarboxylic amides such as N-bromoacetamide and N-chloroisocyanuric acid are preferred, and hypochlorites such as sodium hypochlorite and bleached powder are most preferred.
[0017]
The compound of the general formula (I) obtained by oxidation of (III) may be able to be used for a desired purpose without going through further purification steps. Ordinarily, such as recrystallization, distillation, column chromatography, etc. In some cases, it is used after being purified by the purification means.
[0018]
In the general formula (I), the 1,4-position of the cyclohexylene group is preferably in the trans configuration, but it is obtained when the production steps up to (I) do not include the isomerization step into the trans isomer. (I) is usually a mixture of cis and trans isomers. In that case, it is preferable that the obtained (I) is once acetalized, isomerized to a trans isomer in the presence of a strong base or a Lewis acid catalyst, and then deacetalized. The strong base is preferably t-butoxy potassium in an aprotic polar solvent such as N, N-dimethylformamide (DMF), and the Lewis acid is preferably aluminum chloride, but usually t-butoxy potassium is most preferred.
[0019]
In the present invention, the general formula (II) is used as a raw material.
Embedded image
[0020]
Embedded image
There are several routes for producing the cyclohexanol derivative of the general formula (III) from the hydroxyketone of the general formula (II), but the route shown below is preferable.
[0021]
That is, by protecting the hydroxyl group of the hydroxyketone of (II), the general formula (V)
Embedded image
[0022]
A cyclohexanol derivative can be obtained by reacting the hydroxyketone protected with a hydroxyl group with an organometallic reagent represented by the general formula Ar-M (VI). Here, M represents a metal atom or a group containing a metal atom, and is not particularly limited as long as nucleophilic addition is performed on a carbonyl group, but MgBr, MgI, MgCl or Li is particularly preferable. According to the above definition of Ar, a more preferable form as (VI) is represented by the general formula (VI ′)
Embedded image
[0023]
By dehydrating the obtained cyclohexanol derivative, the general formula (VIII)
Embedded image
[0024]
By catalytic reduction of the cyclohexene derivative of (VIII), the general formula (IX)
Embedded image
[0025]
The reduction is performed in a hydrogen atmosphere and in the presence of a transition metal catalyst.
[0026]
The hydrogen pressure is not particularly limited as long as it is near normal pressure, but is preferably 0.1 MPa to 4 MPa, more preferably 0.1 MPa to 1 MPa, and further preferably 0.1 MPa to 0.4 MPa.
[0027]
The transition metal catalyst is not particularly limited as long as it is used for ordinary catalytic reduction, but metal supported on carbon such as palladium / carbon, platinum / carbon, ruthenium / carbon, or Raney metal such as Raney nickel, etc. Is preferred.
[0028]
When a benzyl group is used as the protecting group Z, it may be deprotected in this step. In this case, it is preferable to protect the hydroxyl group again if necessary.
[0029]
The 1,4-position of the obtained (IX) cyclohexylene group is usually a mixture of cis and trans isomers. In the target general formula (I), the 1,4-position of the cyclohexylene group is preferably a trans isomer. For this purpose, it is preferable to isomerize the cis isomer to the trans isomer after this step.
[0030]
Isomerization is carried out in the presence of a strong base or Lewis acid catalyst. The strong base is preferably t-butoxy potassium in an aprotic polar solvent such as N, N-dimethylformamide (DMF), and the Lewis acid is preferably aluminum chloride, but the protective group is a tetrahydropyranyl group, tetrahydrofuryl. When a group, methoxymethyl group or ethoxymethyl group is used, a base catalyst, usually t-butoxy potassium, is most preferred.
[0031]
A cyclohexanol derivative of the general formula (III) can be obtained by deprotecting the compound of the general formula (IX).
[0032]
Deprotection is carried out by treating with an acid in the presence of a protic solvent when the protecting group is a tetrahydropyranyl group, a tetrahydrofuryl group, a methoxymethyl group or an ethoxymethyl group, and in the case of a methyl group, boron tribromide, It can be demethylated by using Lewis acid with aluminum chloride, sulfides such as trimethylsilyl iodide, dimethyl sulfide, or a combination thereof. In the case of a benzyl group, deprotection is possible by catalytic reduction.
[0033]
As described above, the 4-substituted cyclohexanone derivative represented by the general formula (I) can be produced from the hydroxyketone represented by the general formula (II).
[0034]
The obtained compound (I) is useful as an electronic material such as a liquid crystal display material, a functional material, a medical pesticide, a fragrance, various additives, and synthetic intermediates thereof. Among the compounds, it is preferable as a method for producing the compounds represented by the following (Ia-1) to (Ib-21).
[0035]
Embedded image
Embedded image
EXAMPLES Hereinafter, although an Example is given and this invention is further explained in full detail, this invention is not limited to these Examples.
[0037]
Example 1 Production of trans-4 ′-(4-methylphenyl) bicyclohexane-4-one (Ia-16)
1-a) 4′-hydroxybicyclohexane-4-one (This compound can be produced from biphenol by a method according to JP-A-12-159718 and is a mixture of cis and trans isomers) 19.6 g of 50 mL tetrahydrofuran The (THF) solution was added dropwise to 5.0 g of sodium hydride (50%) suspended in 200 mL of THF. After stirring for 1 hour at room temperature, a solution of 15 g of methyl iodide in 30 mL of THF was added dropwise over 30 minutes. After stirring for 3 hours, excess sodium hydride was decomposed by adding water, acidified with hydrochloric acid and extracted with toluene. After washing with water, the solvent was distilled off to obtain 18 g of 4′-methoxybicyclohexane-4-one.
1-b) The above-mentioned 4′-methoxybicyclohexane-4-one THT solution was added dropwise at room temperature to a Grignard reactant solution prepared from 17.1 g of p-bromotoluene and 2.4 g of magnesium. After stirring at room temperature for 3 hours, water and then hydrochloric acid were added to stop the reaction, and the mixture was extracted with toluene. After washing with water and saturated saline, it was dehydrated and dried over anhydrous sodium sulfate.
1-c) After filtration, the solution was concentrated under reduced pressure until toluene was about 50 mL, and 0.5 g of p-toluenesulfonic acid monohydrate was added thereto, and the mixture was heated to reflux for 4 hours while removing the distilled water. . The mixture was cooled to room temperature, washed with aqueous sodium bicarbonate and then with water, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 19.8 g of 1- (4-methylphenyl) -4- (4-methoxycyclohexyl) cyclohex-1-ene.
1-d) This whole amount was dissolved in 100 mL of ethanol and subjected to catalytic reduction (hydrogen pressure 0.4 MPa) for 4 hours at room temperature in an autoclave with 1.0 g of 5% palladium / carbon. After the catalyst was filtered off, the solvent was distilled off under reduced pressure to obtain 19.0 g of 4- (4-methylphenyl) -4′-methoxybicyclohexane.
1-e) This whole amount was dissolved in 200 mL of DMF, 5.6 g of t-butoxypotassium was added, and the mixture was heated with stirring at 80 ° C. for 2 hours. After allowing to cool, water was added, neutralized with aqueous hydrochloric acid, and extracted with hexane. The hexane phase was washed with water and then dehydrated and dried over anhydrous sodium sulfate. After filtration, the crude product obtained by distilling off the solvent under reduced pressure was recrystallized from ethanol to obtain 14.5 g of trans-4- (4-methylphenyl) -4′-methoxybicyclohexane as white crystals. .
1-f) The whole amount was dissolved in 100 mL of dichloromethane, and 15 g of trimethylsilane iodide was added under water cooling, and the mixture was returned to room temperature and stirred for 8 hours. Water was added, extraction was performed with toluene, and the solvent was distilled off under reduced pressure to obtain 12.0 g of trans-4- (4-methylphenyl) -4′-hydroxybicyclohexane.
1-g) The whole amount was dissolved in 50 mL of dichloromethane, 50 mL of acetic acid was added, and 100 mL of an 8% aqueous sodium hypochlorite solution (antiformin) was added dropwise thereto while stirring vigorously. After stirring for 4 hours, an aqueous sodium hydrogen sulfite solution was added to decompose excess oxidant, water was added, and the mixture was extracted with toluene. After washing with water and saturated brine, the crude product obtained by concentrating the solvent was recrystallized from ethanol to give the title trans-4 ′-(4-methylphenyl) bicyclohexane-4-one (Ia- 8.5 g of white crystals of 16) were obtained.
[0038]
(Comparative Example 1) Production of the indicated trans-4 '-(4-methylphenyl) bicyclohexane-4-one (Ia-16) using bicyclohexane-4,4'-dione monoethylene acetal as a raw material
Bicyclohexane-4,4′-dione monoethylene acetal (12.0 g) was added dropwise to the Grignard reactant prepared from 16.3 g of p-bromotoluene to react to obtain 16.7 g of a cyclohexanol derivative. This was dissolved in toluene, 0.5 g of sodium hydrogensulfate was added and the mixture was heated to reflux while removing azeotropic water, and 4- (4-methylphenyl) bicyclohex-3-ene-4'-one ethylene acetal 12.0 g was obtained. This total amount was dissolved in ethyl acetate, 0.6 g of Raney nickel was added, and catalytic reduction was carried out at a hydrogen pressure of 0.5 MPa in an autoclave to obtain 11.5 g of 4- (4-methylphenyl) bicyclohexane-4′-one ethylene acetal. The whole amount was dissolved in DMF, 2.2 g of potassium t-butoxy was added, and the mixture was heated to reflux at 100 ° C. for 4 hours. Water and then hydrochloric acid were added to neutralize, extracted with toluene, the solvent was concentrated, and the resulting residue was recrystallized from ethanol to obtain trans-4- (4-methylphenyl) bicyclohexane-4'-one ethylene Acetal 8.5 g was obtained. The whole amount was dissolved in toluene, acetic acid and dilute sulfuric acid were added, and the mixture was heated and stirred for 5 hours. After neutralization with water, extraction with toluene, the resulting crude product was recrystallized from ethanol to give the trans-4 '-(4-methylphenyl) bicyclohexane-4-one (Ia-16) 6.4 g of white crystals were obtained.
[0039]
Therefore, even when used as a raw material, the desired trans-4 ′-(4-methylphenyl) bicyclohexane-4-one can be obtained in the same manner as in Example 1, but bicyclohexane-4,4′-dione mono It is clear that ethylene acetal is much more expensive than 4'-hydroxybicyclohexane-4-one and that Example 1 is cost effective.
[0040]
(Example 2) Production of trans-4 '-(3,4-difluorophenyl) bicyclohexane-4-one (Ia-16) In Example 1-b), p-bromobenzene was replaced with 3,4- In the same manner, except that difluorobromobenzene was used, 1-d) was replaced with palladium / carbon as a reduction catalyst, highly active Raney nickel was used, and isomerization in 1-e) was performed at room temperature. White crystals of the indicated trans-4 ′-(3,4-difluorophenyl) bicyclohexane-4-one (Ia-16) were obtained.
[0041]
(Example 3) Production of trans-4 '-(3,4-difluorophenyl) bicyclohexane-4-one (Ia-16) In Example 1-f), instead of trimethylsilane iodide, Trans-4 '-(4-methylphenyl) bicyclohexane-4 was prepared in the same manner as in Example 1 except that trans-4- (4-methylphenyl) -4'-hydroxybicyclohexane was prepared using sodium iodide. -Obtained ON (Ia-16).
[0042]
(Example 4) Production of trans-4 '-(3,5-difluoro-4-methoxyphenyl) bicyclohexane-4-one (Ia-12) In Example 1-a), chloride was replaced with methyl iodide. Example 1 except that benzyl was used, the hydrogen pressure of catalytic reduction in 1-d) was 0.1 MPa, and the deprotection step of 1-f) was carried out by catalytic reduction at a hydrogen pressure of 0.5 MPa and 50 ° C. A white crystal of trans-4 ′-(3,5-difluoro-4-methoxyphenyl) bicyclohexane-4-one (Ia-12) was obtained.
[0043]
【The invention's effect】
The present invention provides a method using a low-cost and easily available hydroxyketone as a raw material instead of a monoacetal of an expensive diketone compound as a raw material in the production of a 4-substituted cyclohexanone derivative having an arylcyclohexyl group. A cheaper production of a 4-substituted cyclohexanone derivative having an arylcyclohexyl group was made possible. The resulting 4-substituted cyclohexanone derivative having an arylcyclohexyl group is extremely useful as an electronic material such as a liquid crystal display material, a functional material, a medical pesticide, a fragrance, various additives, and synthetic intermediates thereof.
Claims (7)
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