JP6779322B2 - トランス−1,4−二置換シクロヘキサン誘導体の製造方法 - Google Patents
トランス−1,4−二置換シクロヘキサン誘導体の製造方法 Download PDFInfo
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- JP6779322B2 JP6779322B2 JP2018568588A JP2018568588A JP6779322B2 JP 6779322 B2 JP6779322 B2 JP 6779322B2 JP 2018568588 A JP2018568588 A JP 2018568588A JP 2018568588 A JP2018568588 A JP 2018568588A JP 6779322 B2 JP6779322 B2 JP 6779322B2
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- cyclohexane
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- -1 Trans-1,4-Disubstituted Cyclohexane Chemical class 0.000 title claims description 64
- 238000004519 manufacturing process Methods 0.000 title claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 50
- 125000004432 carbon atom Chemical group C* 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 30
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 238000006317 isomerization reaction Methods 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 3
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 46
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 45
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- 238000004458 analytical method Methods 0.000 description 25
- 238000000034 method Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000000758 substrate Substances 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 10
- 239000000523 sample Substances 0.000 description 9
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 7
- 239000012300 argon atmosphere Substances 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 6
- 238000004817 gas chromatography Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- QYGWJCMCLQAINT-BIZGZAPZSA-N CCCCC(CC1)CCC1[C@H]1CC[C@H](CCC)CC1 Chemical compound CCCCC(CC1)CCC1[C@H]1CC[C@H](CCC)CC1 QYGWJCMCLQAINT-BIZGZAPZSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 150000001934 cyclohexanes Chemical class 0.000 description 5
- 238000001542 size-exclusion chromatography Methods 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 239000004973 liquid crystal related substance Substances 0.000 description 4
- CFJYNSNXFXLKNS-UHFFFAOYSA-N p-menthane Chemical compound CC(C)C1CCC(C)CC1 CFJYNSNXFXLKNS-UHFFFAOYSA-N 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- BWJHJLINOYAPEG-HOTGVXAUSA-N 8-chloro-6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclopentyl]-7-methyl-2H-1,3-benzoxazin-4-one Chemical compound ClC1=C(C(=CC=2C(N(COC=21)[C@@H]1[C@H](CCC1)O)=O)CC=1C=NC(=CC=1)Cl)C BWJHJLINOYAPEG-HOTGVXAUSA-N 0.000 description 3
- QYGWJCMCLQAINT-VVPTUSLJSA-N CCCC[C@H]1CC[C@@H](CC1)[C@H]1CC[C@H](CCC)CC1 Chemical compound CCCC[C@H]1CC[C@@H](CC1)[C@H]1CC[C@H](CCC)CC1 QYGWJCMCLQAINT-VVPTUSLJSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- VLLNJDMHDJRNFK-UHFFFAOYSA-N adamantan-1-ol Chemical compound C1C(C2)CC3CC2CC1(O)C3 VLLNJDMHDJRNFK-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 230000010354 integration Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 150000003509 tertiary alcohols Chemical class 0.000 description 3
- PWGUTKLGUISGAE-UHFFFAOYSA-N (4-propylcyclohexyl)benzene Chemical compound C1CC(CCC)CCC1C1=CC=CC=C1 PWGUTKLGUISGAE-UHFFFAOYSA-N 0.000 description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 2
- IBFAIOMGVHPWRQ-UHFFFAOYSA-N 1-ethoxy-2,3-difluoro-4-[4-(4-propylcyclohexyl)phenyl]benzene Chemical compound C1CC(CCC)CCC1C1=CC=C(C=2C(=C(F)C(OCC)=CC=2)F)C=C1 IBFAIOMGVHPWRQ-UHFFFAOYSA-N 0.000 description 2
- OXBRRUNAAVNTOZ-UHFFFAOYSA-N 1-ethoxy-4-(4-propylcyclohexyl)benzene Chemical compound C1CC(CCC)CCC1C1=CC=C(OCC)C=C1 OXBRRUNAAVNTOZ-UHFFFAOYSA-N 0.000 description 2
- GXMLXDAPXSEBBT-UHFFFAOYSA-N 1-fluoro-4-(4-propylcyclohexyl)benzene Chemical compound C1CC(CCC)CCC1C1=CC=C(F)C=C1 GXMLXDAPXSEBBT-UHFFFAOYSA-N 0.000 description 2
- HUVDPJLMBKTWES-UHFFFAOYSA-N 2-butyl-1,3-difluoro-5-(4-propylcyclohexyl)benzene Chemical compound C1=C(F)C(CCCC)=C(F)C=C1C1CCC(CCC)CC1 HUVDPJLMBKTWES-UHFFFAOYSA-N 0.000 description 2
- GBBJCQYRJMHONR-UHFFFAOYSA-N 2-fluoro-1-methyl-4-(4-propylcyclohexyl)benzene Chemical compound C1CC(CCC)CCC1C1=CC=C(C)C(F)=C1 GBBJCQYRJMHONR-UHFFFAOYSA-N 0.000 description 2
- SFBJLQVBBPBWHI-UHFFFAOYSA-N 2-fluoro-4-methyl-1-(4-propylcyclohexyl)benzene Chemical compound CCCC1CCC(CC1)C1=CC=C(C)C=C1F SFBJLQVBBPBWHI-UHFFFAOYSA-N 0.000 description 2
- KORMYSCDCHFFMN-WXFZTKORSA-N CCCC(CC1)CCC1[C@H]1CC[C@H](CC)CC1 Chemical compound CCCC(CC1)CCC1[C@H]1CC[C@H](CC)CC1 KORMYSCDCHFFMN-WXFZTKORSA-N 0.000 description 2
- KDVKBFMGDZIYON-OFVLBHHSSA-N CCCCCC1CCC(CC1)[C@H]1CC[C@H](CCC)CC1 Chemical compound CCCCCC1CCC(CC1)[C@H]1CC[C@H](CCC)CC1 KDVKBFMGDZIYON-OFVLBHHSSA-N 0.000 description 2
- GZMMUVKMQPSLLS-SNXBXODESA-N CCC[C@H]1CC[C@@H](CC1)C1CCC(CC1)c1ccccc1 Chemical compound CCC[C@H]1CC[C@@H](CC1)C1CCC(CC1)c1ccccc1 GZMMUVKMQPSLLS-SNXBXODESA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000000538 analytical sample Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
- 125000001207 fluorophenyl group Chemical group 0.000 description 2
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 2
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
- 150000002605 large molecules Chemical class 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- DEDZSLCZHWTGOR-UHFFFAOYSA-N n-propylcyclohexane Natural products CCCC1CCCCC1 DEDZSLCZHWTGOR-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229930004008 p-menthane Natural products 0.000 description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 2
- 125000005003 perfluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 2
- 125000005804 perfluoroheptyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 2
- 125000005007 perfluorooctyl group Chemical group FC(C(C(C(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)F)(F)* 0.000 description 2
- 125000005008 perfluoropentyl group Chemical group FC(C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)(F)* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- 238000009834 vaporization Methods 0.000 description 2
- 230000008016 vaporization Effects 0.000 description 2
- JNUZADQZHYFJGW-JOCHJYFZSA-N (2R)-N-[3-[5-fluoro-2-(2-fluoro-3-methylsulfonylanilino)pyrimidin-4-yl]-1H-indol-7-yl]-3-methoxy-2-(4-methylpiperazin-1-yl)propanamide Chemical compound FC=1C(=NC(=NC=1)NC1=C(C(=CC=C1)S(=O)(=O)C)F)C1=CNC2=C(C=CC=C12)NC([C@@H](COC)N1CCN(CC1)C)=O JNUZADQZHYFJGW-JOCHJYFZSA-N 0.000 description 1
- KEEKMOIRJUWKNK-CABZTGNLSA-N (2S)-2-[[2-[(4R)-4-(difluoromethyl)-2-oxo-1,3-thiazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide Chemical compound FC([C@H]1N(C(SC1)=O)C=1N=C2N(CCOC3=C2C=CC(=C3)N[C@H](C(=O)N)C)C=1)F KEEKMOIRJUWKNK-CABZTGNLSA-N 0.000 description 1
- WMWOAQARUZYORF-UHFFFAOYSA-N (4-butylcyclohexyl)benzene Chemical compound C1CC(CCCC)CCC1C1=CC=CC=C1 WMWOAQARUZYORF-UHFFFAOYSA-N 0.000 description 1
- QYGIOYGZDDSCAJ-UHFFFAOYSA-N (4-hexylcyclohexyl)benzene Chemical compound C1CC(CCCCCC)CCC1C1=CC=CC=C1 QYGIOYGZDDSCAJ-UHFFFAOYSA-N 0.000 description 1
- FCAWXWGFZYRQJZ-UHFFFAOYSA-N (4-pentylcyclohexyl)benzene Chemical compound C1CC(CCCCC)CCC1C1=CC=CC=C1 FCAWXWGFZYRQJZ-UHFFFAOYSA-N 0.000 description 1
- LCFFREMLXLZNHE-GBOLQPHISA-N (e)-2-[(3r)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile Chemical compound C12=C(N)N=CN=C2N([C@@H]2CCCN(C2)C(=O)C(/C#N)=C/C(C)(C)N2CCN(CC2)C2COC2)N=C1C(C(=C1)F)=CC=C1OC1=CC=CC=C1 LCFFREMLXLZNHE-GBOLQPHISA-N 0.000 description 1
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 1
- FMLRFBWDFNGYCV-UHFFFAOYSA-N 1,2,3-trifluoro-5-(4-hexylcyclohexyl)benzene Chemical compound C1CC(CCCCCC)CCC1C1=CC(F)=C(F)C(F)=C1 FMLRFBWDFNGYCV-UHFFFAOYSA-N 0.000 description 1
- MKTOMUXBVNLBGF-UHFFFAOYSA-N 1,2,3-trifluoro-5-(4-propylcyclohexyl)benzene Chemical compound C1CC(CCC)CCC1C1=CC(F)=C(F)C(F)=C1 MKTOMUXBVNLBGF-UHFFFAOYSA-N 0.000 description 1
- AYFPNRLYKGMWJN-UHFFFAOYSA-N 1,2,3-trifluoro-5-[2-fluoro-4-(4-propylcyclohexyl)phenyl]benzene Chemical compound C1CC(CCC)CCC1C1=CC=C(C=2C=C(F)C(F)=C(F)C=2)C(F)=C1 AYFPNRLYKGMWJN-UHFFFAOYSA-N 0.000 description 1
- KNKRKFALVUDBJE-UHFFFAOYSA-N 1,2-dichloropropane Chemical compound CC(Cl)CCl KNKRKFALVUDBJE-UHFFFAOYSA-N 0.000 description 1
- WHQZSIVEXAFGOD-UHFFFAOYSA-N 1,2-difluoro-4-(4-propylcyclohexyl)benzene Chemical compound C1CC(CCC)CCC1C1=CC=C(F)C(F)=C1 WHQZSIVEXAFGOD-UHFFFAOYSA-N 0.000 description 1
- MNLYHAXJCXKSEZ-UHFFFAOYSA-N 1,2-difluoro-4-[2-fluoro-4-(4-propylcyclohexyl)phenyl]benzene Chemical compound C1CC(CCC)CCC1C1=CC=C(C=2C=C(F)C(F)=CC=2)C(F)=C1 MNLYHAXJCXKSEZ-UHFFFAOYSA-N 0.000 description 1
- VULXHDGYVHCLLN-UHFFFAOYSA-N 1,2-difluoro-4-[4-(4-propylcyclohexyl)phenyl]benzene Chemical compound C1CC(CCC)CCC1C1=CC=C(C=2C=C(F)C(F)=CC=2)C=C1 VULXHDGYVHCLLN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VNKUVFOAQZJVHQ-UHFFFAOYSA-N 1-(4-butylcyclohexyl)-4-(4-ethylphenyl)benzene Chemical compound C1CC(CCCC)CCC1C1=CC=C(C=2C=CC(CC)=CC=2)C=C1 VNKUVFOAQZJVHQ-UHFFFAOYSA-N 0.000 description 1
- OJMKNDIJVXBHFQ-UHFFFAOYSA-N 1-(4-butylcyclohexyl)-4-[4-(trifluoromethyl)phenyl]benzene Chemical compound C1CC(CCCC)CCC1C1=CC=C(C=2C=CC(=CC=2)C(F)(F)F)C=C1 OJMKNDIJVXBHFQ-UHFFFAOYSA-N 0.000 description 1
- SPUIKFOOAHSYCG-UHFFFAOYSA-N 1-(4-butylcyclohexyl)-4-ethoxy-2,3-difluorobenzene Chemical compound C1CC(CCCC)CCC1C1=CC=C(OCC)C(F)=C1F SPUIKFOOAHSYCG-UHFFFAOYSA-N 0.000 description 1
- GNOASZZLPQGQQA-UHFFFAOYSA-N 1-(4-butylcyclohexyl)-4-phenylbenzene Chemical compound C1CC(CCCC)CCC1C1=CC=C(C=2C=CC=CC=2)C=C1 GNOASZZLPQGQQA-UHFFFAOYSA-N 0.000 description 1
- ACMCKOGGHYLPOX-UHFFFAOYSA-N 1-(4-hexylcyclohexyl)-4-(trifluoromethyl)benzene Chemical compound C1CC(CCCCCC)CCC1C1=CC=C(C(F)(F)F)C=C1 ACMCKOGGHYLPOX-UHFFFAOYSA-N 0.000 description 1
- ISFYMITVSXCODU-UHFFFAOYSA-N 1-(4-hexylcyclohexyl)-4-phenylbenzene Chemical compound C1(=CC=C(C=C1)C1CCC(CC1)CCCCCC)C1=CC=CC=C1 ISFYMITVSXCODU-UHFFFAOYSA-N 0.000 description 1
- QKYROPHAJBWGMB-UHFFFAOYSA-N 1-(4-pentylcyclohexyl)-4-(trifluoromethoxy)benzene Chemical compound C1CC(CCCCC)CCC1C1=CC=C(OC(F)(F)F)C=C1 QKYROPHAJBWGMB-UHFFFAOYSA-N 0.000 description 1
- SSSJMLTXWSVLTL-UHFFFAOYSA-N 1-(4-pentylcyclohexyl)-4-phenylbenzene Chemical compound C1CC(CCCCC)CCC1C1=CC=C(C=2C=CC=CC=2)C=C1 SSSJMLTXWSVLTL-UHFFFAOYSA-N 0.000 description 1
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- RFIOVDXKZOZKKR-UHFFFAOYSA-N 1-but-3-enyl-4-pentylcyclohexane Chemical compound C(CC=C)C1CCC(CC1)CCCCC RFIOVDXKZOZKKR-UHFFFAOYSA-N 0.000 description 1
- DDPXSULTSPAXKW-UHFFFAOYSA-N 1-but-3-enyl-4-propylcyclohexane Chemical compound CCCC1CCC(CCC=C)CC1 DDPXSULTSPAXKW-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- OMEHFZJSPMFZBS-UHFFFAOYSA-N 1-butyl-4-[4-(4-propylcyclohexyl)phenyl]benzene Chemical compound C1=CC(CCCC)=CC=C1C1=CC=C(C2CCC(CCC)CC2)C=C1 OMEHFZJSPMFZBS-UHFFFAOYSA-N 0.000 description 1
- OUKPZMHGBOPJRD-UHFFFAOYSA-N 1-butyl-4-pentylcyclohexane Chemical compound CCCCCC1CCC(CCCC)CC1 OUKPZMHGBOPJRD-UHFFFAOYSA-N 0.000 description 1
- KRONIACUXPAUDO-UHFFFAOYSA-N 1-butyl-4-propylcyclohexane Chemical compound CCCCC1CCC(CCC)CC1 KRONIACUXPAUDO-UHFFFAOYSA-N 0.000 description 1
- PHKHUNJBFLBFDC-UHFFFAOYSA-N 1-cyclohexyl-4-(trifluoromethoxy)benzene Chemical compound C1=CC(OC(F)(F)F)=CC=C1C1CCCCC1 PHKHUNJBFLBFDC-UHFFFAOYSA-N 0.000 description 1
- WQLMITAVFBXRKU-UHFFFAOYSA-N 1-ethenyl-4-propylcyclohexane Chemical compound CCCC1CCC(C=C)CC1 WQLMITAVFBXRKU-UHFFFAOYSA-N 0.000 description 1
- VHOVOABTBUSQRB-UHFFFAOYSA-N 1-ethoxy-2,3-difluoro-4-(4-hexylcyclohexyl)benzene Chemical compound C1CC(CCCCCC)CCC1C1=CC=C(OCC)C(F)=C1F VHOVOABTBUSQRB-UHFFFAOYSA-N 0.000 description 1
- BOAHGIPRRKDVQY-UHFFFAOYSA-N 1-ethoxy-2,3-difluoro-4-(4-propylcyclohexyl)benzene Chemical compound C1CC(CCC)CCC1C1=CC=C(OCC)C(F)=C1F BOAHGIPRRKDVQY-UHFFFAOYSA-N 0.000 description 1
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- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- IGARGHRYKHJQSM-UHFFFAOYSA-N cyclohexylbenzene Chemical class C1CCCCC1C1=CC=CC=C1 IGARGHRYKHJQSM-UHFFFAOYSA-N 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006612 decyloxy group Chemical group 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005446 heptyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000011964 heteropoly acid Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- VZUGBLTVBZJZOE-KRWDZBQOSA-N n-[3-[(4s)-2-amino-1,4-dimethyl-6-oxo-5h-pyrimidin-4-yl]phenyl]-5-chloropyrimidine-2-carboxamide Chemical compound N1=C(N)N(C)C(=O)C[C@@]1(C)C1=CC=CC(NC(=O)C=2N=CC(Cl)=CN=2)=C1 VZUGBLTVBZJZOE-KRWDZBQOSA-N 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006611 nonyloxy group Chemical group 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- JGTNAGYHADQMCM-UHFFFAOYSA-N perfluorobutanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F JGTNAGYHADQMCM-UHFFFAOYSA-N 0.000 description 1
- 125000005005 perfluorohexyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000004262 preparative liquid chromatography Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003333 secondary alcohols Chemical group 0.000 description 1
- 150000005376 secondary alkyl halides Chemical class 0.000 description 1
- OEBIHOVSAMBXIB-SJKOYZFVSA-N selitrectinib Chemical compound C[C@@H]1CCC2=NC=C(F)C=C2[C@H]2CCCN2C2=NC3=C(C=NN3C=C2)C(=O)N1 OEBIHOVSAMBXIB-SJKOYZFVSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 150000005377 tertiary alkyl halides Chemical class 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
- C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/32—Preparation of ethers by isomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C5/00—Preparation of hydrocarbons from hydrocarbons containing the same number of carbon atoms
- C07C5/22—Preparation of hydrocarbons from hydrocarbons containing the same number of carbon atoms by isomerisation
- C07C5/27—Rearrangement of carbon atoms in the hydrocarbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B61/00—Other general methods
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
本発明の課題は、液晶化合物として有用なトランス−1,4−二置換シクロヘキサン誘導体を高分子量体の副生を少なくして効率的に製造する方法を提供することにある。
すなわち本発明は、一般式(1)で表されるシス及びトランス混合物である1,4−二置換シクロヘキサン誘導体を、一般式(1)で表されるシス及びトランス混合物である1,4−二置換シクロヘキサン誘導体に対して80モル%以下の一般式(4)で表されるスルホン酸のみの存在下、異性化させることを特徴とする、一般式(1a)で表されるトランス−1,4−二置換シクロヘキサン誘導体の製造方法に関するものである。
R1、R2、R3及びR6で表される炭素数1から10のアルキル基としては、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、sec−ブチル基、tert−ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基等を例示することができる。取り扱いが容易な点で、炭素数1から5の直鎖のアルキル基を用いることが好ましい。
なお、上記の「スルホン酸(4)のみの存在下」とは、スルホン酸(4)以外には、異性化の反応速度に影響する働きをする物質が存在しないという意味であり、溶媒やごく微量の不純物等の存在を排除するものではない。
本発明の製造方法の原料であるシス及びトランス混合物である1,4−二置換シクロヘキサン誘導体(1)は、文献記載(特許文献1及び2)の方法で調製することができる。
また、本発明の製造法において、異性化を行う際に、スルホン酸(4)以外の物質、例えば特許文献6に記載の第二級もしくは第三級のアルキルハライド、スルホン酸の第二級もしくは第三級のアルキルエステル、および第二級もしくは第三級のアルコールを触媒として用いない。
得られた化合物は、1H NMR、19F{1H} NMRおよび13C NMR分析で得られる核磁気共鳴スペクトルにより同定した。1,4−二置換シクロヘキサン誘導体のトランス体、シス体の比率は、ガスクロマトグラフィー(GC)分析で得られるガスクロマトグラムの面積値、1H NMR分析又は19F{1H} NMR分析で得られる核磁気共鳴スペクトルの積分値から算出した。高分子量不純物は、サイズ排除クロマトグラフィー分析により測定した。まず分析方法について説明する。
測定装置は、Ascend−400(ブルカーバイオスピン(株)社製)を用いた。測定は、実施例等で製造したサンプルを、CDCl3に溶解し、室温で、400MHz、積算回数16回の条件で行った。化学シフトδ値のゼロ点の基準物質としてはテトラメチルシラン(TMS)を用いた。
測定装置は、Ascend−400(ブルカーバイオスピン(株)社製)を用いた。測定は、実施例等で製造したサンプルを、CDCl3に溶解し、室温で、376MHz、積算回数16回、1Hデカップリングの条件で行った。
測定装置は、ULTRASHIELD PLUS−400(ブルカーバイオスピン(株)社製)を用いた。測定は、実施例等で製造したサンプルを、CDCl3に溶解し、室温で、100MHz、積算回数128回の条件で行った。化学シフトδ値のゼロ点の基準物質としてはテトラメチルシラン(TMS)を用いた。
測定装置は、島津製作所製のGC−17A型ガスクロマトグラフを用いた。カラムは、アジレント・テクノロジー(株)社製のキャピラリーカラムDB−5MS(長さ30m、内径0.25mm、膜厚0.25μm;固定液相はフェニルアリーレンポリマー;無極性)を用いた。キャリアーガスとしてはヘリウムを用い、流量は90mL/分に調整した。
試料気化室の温度を280℃、検出器(FID)部分の温度を280℃に設定した。
記録計としては島津製作所製のC−R6A型Chromatopacを用いた。得られたガスクロマトグラムには、成分化合物に対応するピークの保持時間およびピークの面積値が示されている。
測定装置は、ジーエルサイエンス(株)社製のGL−7400型高速液体クロマトグラフを用いた。カラムは、東ソー(株)社製のカラムTSKgel superH5000(長さ15cm、内径6mm、粒径3μm、孔径6.5nm)、TSKgel superH3000(長さ15cm、内径6mm、粒径3μm、孔径7.5nm)、TSKgel superH2000(長さ15cm、内径6mm、粒径3μm、孔径2.0nm)およびTSKgel superH1000(長さ15cm、内径6mm、粒径3μm、孔径1.5nm)各1本をこの順で直列に連結して用い、カラム温度を40℃に設定した。移動相としてはテトラヒドロフランを用い、流量は0.4mL/分に調整した。検出器はジーエルサイエンス(株)社製のRI検出器GL−7454を用いた。
試料はテトラヒドロフランに溶解して、10mg/mLの溶液となるように調製し、得られた溶液20μLをカラムに注入した。
下表の条件(表中、TfOHはトリフルオロメタンスルホン酸を、NfOHはノナフルオロブタン−1−スルホン酸を、ClSO3Hはクロロスルホン酸を、DCMはジクロロメタンを、CHCl3はクロロホルムを、DCEは1,2−ジクロロエタンを表す)を用いたこと以外は実施例−1と同様の手順で反応および分析を行った。
トリフルオロメタンスルホン酸をクロロスルホン酸(69.9mg,0.6mmol)へと変更した以外は実施例−21と同様に反応および分析を行ったところ、トランス体:シス体=95.89:4.11であった。
トリフルオロメタンスルホン酸をノナフルオロブタン−1−スルホン酸(180mg,0.6mmol)へと変更した以外は実施例−21と同様に反応および分析を行ったところ、トランス体:シス体=95.89:4.11であった。
反応温度を−50℃へと変更した以外は実施例−24と同様に反応および分析を行ったところ、トランス体:シス体=98.83:1.17であった。
反応時間を18時間へと変更した以外は実施例−24と同様に反応および分析を行ったところ、トランス体:シス体=98.62:1.38であった。
トリフルオロメタンスルホン酸を(360mg,2.4mmol)用いたこと以外は実施例−1と同様に反応を行ったところ、1−ブチル−4−(トランス−4−プロピルシクロヘキシル)シクロヘキサン(トランス体:シス体=95.59:4.41)以外に多数の副生成物の生成を確認した。
アルゴン雰囲気下、トリフルオロメタンスルホン酸(90.0mg,0.6mmol)とジクロロメタン(1.6mL)との混合液を−20℃に冷却した。この混合液に1−アダマンタノールのジクロロメタン溶液(0.4mL,0.12mmol)を滴下し、次いで1−ブチル−4−(トランス−4−プロピルシクロヘキシル)シクロヘキサン(529mg,2mmol,トランス体:シス体=21.53:78.47)を滴下し、同温で3時間撹拌し、反応させた。この反応液に飽和重曹水(2mL)およびヘキサン(4mL)を加えて室温下で5分間撹拌し、得られたヘキサン層を無水硫酸マグネシウムで乾燥し、濃縮したところトランス−1−ブチル−4−(トランス−4−プロピルシクロヘキシル)シクロヘキサン(トランス体:シス体=98.16:1.84)を得た。また、アダマンタンの生成を確認した。サイズ排除クロマトグラフィーにて分析したところ、高分子量不純物を6.00%含んでいた。
アルゴン雰囲気下、トリフルオロメタンスルホン酸(90.0mg,0.6mmol)とジクロロメタン(1.0mL)との混合液を−20℃に冷却した。この混合液に1−アダマンタノールのジクロロメタン溶液(1.0mL,0.30mmol)を滴下し、次いで1−ブチル−4−(トランス−4−プロピルシクロヘキシル)シクロヘキサン(529mg,2mmol,トランス体:シス体=21.53:78.47)を滴下し、同温で3時間撹拌し、反応させた。この反応液に飽和重曹水(2mL)およびヘキサン(4mL)を加えて室温下で5分間撹拌し、得られたヘキサン層を無水硫酸マグネシウムで乾燥し、濃縮したところトランス−1−ブチル−4−(トランス−4−プロピルシクロヘキシル)シクロヘキサン(トランス体:シス体=53.46:46.54)を得た。また、アダマンタンの生成を確認した。サイズ排除クロマトグラフィーにて分析したところ、高分子量不純物を12.03%含んでいた。
Claims (5)
- 一般式(1)で表されるシス及びトランス混合物である1,4−二置換シクロヘキサン誘導体を、一般式(1)で表されるシス及びトランス混合物である1,4−二置換シクロヘキサン誘導体に対して80モル%以下の一般式(4)で表されるスルホン酸のみの存在下、−78℃から−10℃の範囲から選ばれた温度で異性化させることを特徴とする、一般式(1a)で表されるトランス−1,4−二置換シクロヘキサン誘導体の製造方法。
- R1が一般式(2)で表されるシクロへキシル基であり、R2は炭素数1から10のアルキル基又は炭素数2から10のアルケニル基である請求項1に記載の製造方法。
- R8がトリフルオロメチル基又は塩素原子である請求項1又は2に記載の製造方法。
- ジクロロメタン、クロロホルム及び1,2−ジクロロエタンからなる群から選択される1種以上の溶媒中で異性化を行うことを特徴とする請求項1から3のいずれか一項に記載の製造方法。
- 一般式(4)で表されるスルホン酸の使用量が、一般式(1)で表されるシス及びトランス混合物である1,4−二置換シクロヘキサン誘導体に対して、1モル%から40モル%の範囲から選ばれた使用量である請求項1から4のいずれか一項に記載の製造方法。
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