JP5597973B2 - Process for producing compound having trans-1,4-cyclohexylene structure - Google Patents
Process for producing compound having trans-1,4-cyclohexylene structure Download PDFInfo
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- JP5597973B2 JP5597973B2 JP2009259822A JP2009259822A JP5597973B2 JP 5597973 B2 JP5597973 B2 JP 5597973B2 JP 2009259822 A JP2009259822 A JP 2009259822A JP 2009259822 A JP2009259822 A JP 2009259822A JP 5597973 B2 JP5597973 B2 JP 5597973B2
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- 150000001875 compounds Chemical class 0.000 title claims description 40
- 238000000034 method Methods 0.000 title description 15
- 125000005407 trans-1,4-cyclohexylene group Chemical group [H]C1([H])C([H])([H])[C@]([H])([*:2])C([H])([H])C([H])([H])[C@@]1([H])[*:1] 0.000 title description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 238000004519 manufacturing process Methods 0.000 claims description 22
- -1 pyridine-2,5-diyl group Chemical group 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 11
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000002798 polar solvent Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 229910052723 transition metal Inorganic materials 0.000 claims description 7
- 150000003624 transition metals Chemical class 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 125000004955 1,4-cyclohexylene group Chemical group [H]C1([H])C([H])([H])C([H])([*:1])C([H])([H])C([H])([H])C1([H])[*:2] 0.000 claims description 3
- VBQCHPIMZGQLAZ-UHFFFAOYSA-N phosphorane Chemical class [PH5] VBQCHPIMZGQLAZ-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 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 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 238000006317 isomerization reaction Methods 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- 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 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000003849 aromatic solvent Substances 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 150000001935 cyclohexenes Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000011916 stereoselective reduction Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KORMYSCDCHFFMN-UHFFFAOYSA-N 1-ethyl-4-(4-propylcyclohexyl)cyclohexane Chemical group C1CC(CCC)CCC1C1CCC(CC)CC1 KORMYSCDCHFFMN-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 125000005714 2,5- (1,3-dioxanylene) group Chemical group [H]C1([H])OC([H])([*:1])OC([H])([H])C1([H])[*:2] 0.000 description 2
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- TWXWPPKDQOWNSX-UHFFFAOYSA-N dicyclohexylmethanone Chemical class C1CCCCC1C(=O)C1CCCCC1 TWXWPPKDQOWNSX-UHFFFAOYSA-N 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- WCMSFBRREKZZFL-UHFFFAOYSA-N 3-cyclohexen-1-yl-Benzene Chemical class C1CCCC(C=2C=CC=CC=2)=C1 WCMSFBRREKZZFL-UHFFFAOYSA-N 0.000 description 1
- XVKFDCVTYBMNRZ-UHFFFAOYSA-N 3-methylidenecyclohexene Chemical class C=C1CCCC=C1 XVKFDCVTYBMNRZ-UHFFFAOYSA-N 0.000 description 1
- MMCDZLFBJGBEFO-UHFFFAOYSA-N 4-(2-ethoxy-2-oxoethylidene)cyclohexane-1-carboxylic acid Chemical compound CCOC(=O)C=C1CCC(C(O)=O)CC1 MMCDZLFBJGBEFO-UHFFFAOYSA-N 0.000 description 1
- AKCZQKBKWXBJOF-UHFFFAOYSA-N 4-(4-propylcyclohexyl)cyclohexan-1-one Chemical compound C1CC(CCC)CCC1C1CCC(=O)CC1 AKCZQKBKWXBJOF-UHFFFAOYSA-N 0.000 description 1
- 229910001148 Al-Li alloy Inorganic materials 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000004429 atom Chemical group 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
- 150000001721 carbon Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000001934 cyclohexanes Chemical class 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- JHYNXXDQQHTCHJ-UHFFFAOYSA-M ethyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC)C1=CC=CC=C1 JHYNXXDQQHTCHJ-UHFFFAOYSA-M 0.000 description 1
- BPBOWYWUOUJKLO-UHFFFAOYSA-N ethylidenecyclohexane Chemical group CC=C1CCCCC1 BPBOWYWUOUJKLO-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- KWLMIXQRALPRBC-UHFFFAOYSA-L hectorite Chemical compound [Li+].[OH-].[OH-].[Na+].[Mg+2].O1[Si]2([O-])O[Si]1([O-])O[Si]([O-])(O1)O[Si]1([O-])O2 KWLMIXQRALPRBC-UHFFFAOYSA-L 0.000 description 1
- 229910000271 hectorite Inorganic materials 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- YULMNMJFAZWLLN-UHFFFAOYSA-N methylenecyclohexane Chemical group C=C1CCCCC1 YULMNMJFAZWLLN-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
本発明はトランス‐1,4-シクロヘキシレン構造を有する化合物の製造に関する。 The present invention relates to the production of compounds having a trans-1,4-cyclohexylene structure.
トランス‐シクロヘキシレン構造を有する化合物は、医薬品、農薬、液晶材料等の原料としてしばしば用いられる。シクロヘキサンはシス体、トランス体の異性体が存在するが、その中でもトランス体が物性的に有用な場合が多い。 Compounds having a trans-cyclohexylene structure are often used as raw materials for pharmaceuticals, agricultural chemicals, liquid crystal materials and the like. Cyclohexane has cis and trans isomers, and among them, the trans isomer is often useful in terms of physical properties.
これまでトランス体のみを選択的に製造する方法について検討がなされてきたが、短工程で収率よくトランス‐シクロヘキシレン構造を有する化合物を得る方法はなかった。その製造方法は大きく分けて、シス体とトランス体の混合物を得た後に異性化反応によりトランス体過剰の混合物とし、精製によりトランス体を得る方法、及びその前駆体であるシクロヘキセン誘導体又はシクロヘキセン誘導体及びメチレンシクロヘキセン誘導体の混合物を用いて、トランス体を優先的に生成するように還元する方法の二つがある。 So far, a method for selectively producing only the trans form has been studied, but there has been no method for obtaining a compound having a trans-cyclohexylene structure in a short process with a high yield. The production method is roughly divided into a method for obtaining a trans isomer by purification after obtaining a mixture of cis isomer and trans isomer after obtaining a mixture of cis isomer and trans isomer, and a cyclohexene derivative or cyclohexene derivative as a precursor thereof, and There are two methods for reducing the trans isomer so that it is preferentially produced using a mixture of methylenecyclohexene derivatives.
具体的に、トランス‐1,4-シクロヘキシレン構造を有する化合物を異性化により製造する方法としては、シス体及びトランス体の混合物として得られたシクロヘキシルケトン誘導体を異性化反応によりトランス体の比率を過剰とした後に、ヒドラジンによりカルボニル基を還元してトランス‐アルキルシクロヘキサン誘導体とする方法（特許文献１）や、同様に異性化反応により得たトランス-p-トリルスルホニルオキシメチルシクロヘキサン誘導体を、水素化アルミニウムリチウムにより還元し、トランス‐メチルシクロヘキサン誘導体とする方法（特許文献１）が知られている。また、シクロヘキセニルベンゼン誘導体や、アルキル-シクロヘキセン誘導体の接触水素化を行い、シス体とトランス体との異性体混合物として得た後、チオ尿素により異性化反応を行い、1,4-トランス‐アルキルシクロヘキサン誘導体を得る方法が知られている（特許文献１）。しかしながら、これらの方法では、目的化合物を製造する過程のいずれかの段階において、シス体とトランス体との異性体混合物の異性化反応を行う必要がある。また、通常異性化反応を行う際には反応点となる活性部位がなくてはならず、基質選択性がある。例えば1,4-アルキルシクロヘキサン誘導体のようにカルボニル基等の活性部位が無い化合物の異性化を行う場合は、1,4-アルキルシクロヘキサン誘導体を直接異性化するのではなく、例えばシクロヘキシルケトン誘導体の状態で異性化を行い、その後還元して1,4-トランス‐アルキルシクロヘキサン誘導体を得るという複雑な工程が必要であった。 Specifically, as a method for producing a compound having a trans-1,4-cyclohexylene structure by isomerization, a cyclohexyl ketone derivative obtained as a mixture of a cis isomer and a trans isomer is subjected to an isomerization reaction to increase the ratio of the trans isomer. After the excess, the carbonyl group is reduced with hydrazine to form a trans-alkylcyclohexane derivative (Patent Document 1), or the trans-p-tolylsulfonyloxymethylcyclohexane derivative obtained by isomerization is also hydrogenated. A method (Patent Document 1) in which reduction with aluminum lithium to form a trans-methylcyclohexane derivative is known. In addition, after catalytic hydrogenation of cyclohexenylbenzene derivatives and alkyl-cyclohexene derivatives, it was obtained as a mixture of cis and trans isomers, followed by isomerization with thiourea, and 1,4-trans-alkyl A method for obtaining a cyclohexane derivative is known (Patent Document 1). However, in these methods, it is necessary to carry out an isomerization reaction of an isomer mixture of a cis isomer and a trans isomer at any stage in the process of producing the target compound. Moreover, when performing an isomerization reaction normally, there must be an active site as a reaction site, and there is substrate selectivity. For example, when isomerizing a compound having no active site such as a carbonyl group, such as a 1,4-alkylcyclohexane derivative, the 1,4-alkylcyclohexane derivative is not directly isomerized, for example, in the state of a cyclohexyl ketone derivative. The process involved isomerization at 1 and subsequent reduction to give 1,4-trans-alkylcyclohexane derivatives.
また、トランス‐1,4-シクロヘキシレン構造を有する化合物を立体選択的な還元により製造する方法として、メチレンシクロへキサン構造を有する化合物の接触水素化が、数例知られている。例えば、4-（カルボエトキシメチレン）シクロヘキサンカルボン酸を接触水素化するもの（特許文献２）や、４位にtert-ブチル基の置換したエチリデンシクロヘキサンの接触水素化がある（非特許文献１）。これらの方法は、いずれも反応溶媒としてエタノールのようなアルコール系溶媒が用いられているが、これらの反応では基質選択性があり置換基に酸素原子を有している化合物を原料として用いた場合に、得られる化合物のトランス体の割合が多くなっている。このため、すべての化合物に適用できる方法ではなく、アルキルシクロヘキサンのようなシクロヘキサン骨格に直接結合している原子が炭素原子と水素原子のみのような化合物はこの方法では立体選択的な還元により製造することは出来なかった。また従来の立体選択的な還元はシス体とトランス体との選択率が低く、トランス体の生成比としてそれぞれ72％、68%と、十分でなかった。このようにシクロヘキサン構造内に不飽和結合を持つシクロヘキセン誘導体の接触還元ではトランス体を選択的に得ることは困難であった。 As a method for producing a compound having a trans-1,4-cyclohexylene structure by stereoselective reduction, several examples of catalytic hydrogenation of a compound having a methylenecyclohexane structure are known. For example, there are catalytic hydrogenation of 4- (carboethoxymethylene) cyclohexanecarboxylic acid (Patent Document 2) and catalytic hydrogenation of ethylidenecyclohexane substituted with a tert-butyl group at the 4-position (Non-Patent Document 1). In any of these methods, an alcohol solvent such as ethanol is used as a reaction solvent. However, in these reactions, a compound having a substrate selectivity and having an oxygen atom as a substituent is used as a raw material. In addition, the ratio of the trans isomer of the obtained compound is increased. For this reason, this method is not applicable to all compounds. In this method, a compound in which atoms directly bonded to the cyclohexane skeleton such as alkylcyclohexane are only carbon atoms and hydrogen atoms is produced by stereoselective reduction. I couldn't. Further, conventional stereoselective reduction has a low selectivity between the cis form and the trans form, and the production ratio of the trans form is 72% and 68%, respectively. Thus, it was difficult to selectively obtain a trans isomer by catalytic reduction of a cyclohexene derivative having an unsaturated bond in the cyclohexane structure.
本発明の解決しようとする課題は、トランス‐1,4-シクロヘキシレン構造を有する化合物を、より簡便にかつ効率的に製造することができる製造方法を提供することにある。 An object of the present invention is to provide a production method capable of producing a compound having a trans-1,4-cyclohexylene structure more simply and efficiently.
上記課題を解決するために鋭意検討した結果、アルキルメチレンシクロへキサン誘導体を、非プロトン性極性溶媒である酢酸エチル、アセトン、テトラヒドロフランを反応溶媒として用いて接触水素化を行うことにより、トランス‐1,4-アルキルシクロヘキシレン構造を有する化合物を１工程でかつ高い選択性で得ることが出来る。これにより従来法では不可欠であった煩雑な異性化処理やカルボニル基の還元工程等を省略可能な方法を見出し、本発明を完成するに至った。 As a result of diligent investigations to solve the above problems, trans-1 was obtained by catalytic hydrogenation of alkylmethylenecyclohexane derivatives using aprotic polar solvents such as ethyl acetate, acetone, and tetrahydrofuran as reaction solvents. , A compound having a 4-alkylcyclohexylene structure can be obtained in one step with high selectivity. As a result, the inventors have found a method capable of omitting the complicated isomerization treatment and the carbonyl group reduction step which are indispensable in the conventional method, and have completed the present invention.
すなわち本発明は一般式（ＩＩＩ） That is, the present invention relates to the general formula (III)
（式中、Ｒ１、Ａ１、Ｌ１及びｎは請求項１記載の一般式（Ｉ）におけるＲ１、Ａ１、Ｌ１及びｎと同じ意味を表す。）で表される化合物に、一般式（ＩＶ） (Wherein R 1 , A 1 , L 1 and n represent the same meaning as R 1 , A 1 , L 1 and n in the general formula (I) according to claim 1), Formula (IV)
（式中、Ｒ2は請求項１記載の一般式（Ｉ）におけるＲ2と同じ意味を表し、Ｘ−はＣｌ−、Ｂｒ−、Ｉ−を表す。）で表される化合物に塩基を作用させ調製したイリド及び／又はホスホラン、
又は、一般式（Ｖ）
(Wherein R 2 represents the same meaning as R 2 in the general formula (I) according to claim 1, and X − represents Cl − , Br − or I − ). Prepared ylides and / or phosphoranes,
Or general formula (V)
（式中、Ｒ2は請求項１記載の一般式（Ｉ）におけるＲ2と同じ意味を表し、Ｒ5は炭素数１〜１２のアルキル基又は炭素数２〜１２のアルケニル基を表す。）で表される化合物に塩基を作用させ調製したカルボアニオンを作用させることにより得られる請求項１記載の一般式（Ｉ） (In the formula, R 2 represents the same meaning as R 2 in the general formula (I) according to claim 1, and R 5 represents an alkyl group having 1 to 12 carbon atoms or an alkenyl group having 2 to 12 carbon atoms.) The general formula (I) according to claim 1, which is obtained by allowing a carbanion prepared by acting a base to act on the compound represented by formula (I).
（式中、Ｒ１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、炭素数１〜１２のアルキル基、炭素数２〜１２のアルケニル基、炭素数１〜１２のアルコキシ基又は炭素数２〜１２のアルケニルオキシ基を表し、これら基中の１個以上の水素原子は独立的にフッ素原子に置換されていてもよく、また非隣接の−ＣＨ２−基は独立的に−Ｏ−、−ＣＯ−、−ＣＯＯ−又は−ＯＣＯ−に置換されていてもよく、Ｒ２は、水素原子、炭素数１〜１２のアルキル基、炭素数２〜１２のアルケニル基、炭素数１〜１２のアルコキシ基又は炭素数２〜１２のアルケニルオキシ基を表し、Ａ１はフッ素原子によって置換されていても良い１，４−フェニレン基、１，４−シクロヘキシレン基、ピリジン−２，５−ジイル基、ピリミジン−２，５−ジイル基、ナフタレン−２，６−ジイル基、テトラヒドロナフタレン−２，６−ジイル基又は１，３−ジオキサン−２，５−ジイル基を表し、Ｌ１は単結合、−ＣＨ２ＣＨ２−、−ＣＨ２Ｏ−、−ＯＣＨ２−、−ＣＦ２Ｏ−、−ＯＣＦ２−、−ＣＨ＝ＣＨ−又は−Ｃ≡Ｃ−を表し、ｎは０、１、２又は３を表すが、Ａ１が複数存在する場合には同一であっても異なっていても良く、Ｌ１が複数存在する場合には同一であっても異なっていても良い。）で表される化合物を水素雰囲気下、非プロトン性極性溶媒中で、遷移金属触媒により接触水素化反応を行うことによる一般式（ＩＩ） (In the formula, R 1 is a hydrogen atom, a fluorine atom, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, or 1 to 1 carbon atoms. Represents an alkoxy group having 12 carbon atoms or an alkenyloxy group having 2 to 12 carbon atoms, and one or more hydrogen atoms in these groups may be independently substituted with fluorine atoms, or a non-adjacent —CH 2 — group. May be independently substituted with —O—, —CO—, —COO— or —OCO—, and R 2 represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or an alkenyl group having 2 to 12 carbon atoms. Group, an alkoxy group having 1 to 12 carbon atoms or an alkenyloxy group having 2 to 12 carbon atoms, A 1 is a 1,4-phenylene group, 1,4-cyclohexylene group optionally substituted by a fluorine atom, Pilisi -2,5-diyl group, pyrimidine-2,5-diyl group, naphthalene-2,6-diyl group, tetrahydronaphthalene-2,6-diyl group or 1,3-dioxane-2,5-diyl group , L 1 represents a single bond, —CH 2 CH 2 —, —CH 2 O—, —OCH 2 —, —CF 2 O—, —OCF 2 —, —CH═CH— or —C≡C—, n represents 0, 1, 2 or 3, and when a plurality of A 1 are present, they may be the same or different, and when a plurality of L 1 are present, they may be the same or different. The compound represented by formula (II) is obtained by conducting a catalytic hydrogenation reaction with a transition metal catalyst in an aprotic polar solvent in a hydrogen atmosphere.
（式中、Ｒ３は、一般式（Ｉ）におけるＲ１と同じ意味を表すが、Ｒ１に−ＣＨ＝ＣＨ−が存在する場合には−ＣＨ２ＣＨ２−に置き換え、Ｒ４は、一般式（Ｉ）におけるＲ２と同じ意味を表すが、Ｒ２に−ＣＨ＝ＣＨ−が存在する場合には−ＣＨ２ＣＨ２−に置き換え、Ａ１は一般式（Ｉ）におけるＡ１と同じ意味を表し、Ｌ２は一般式（Ｉ）におけるＬ１と同じ意味を表すが、Ｌ１が−ＣＨ＝ＣＨ−及び−Ｃ≡Ｃ−を表す場合にはＬ２は−ＣＨ２ＣＨ２−を表し、ｎは一般式（Ｉ）におけるｎと同じ意味を表し、Ａ２が複数存在する場合には同一であっても異なっていても良く、Ｌ２が複数存在する場合には同一であっても異なっていても良い。）で表される化合物の製造方法を提供する。 (In the formula, R 3 represents the same meaning as R 1 in formula (I), but when —CH═CH— is present in R 1 , R 3 is replaced with —CH 2 CH 2 —, and R 4 is represents the same meaning as R 2 in formula (I), when the -CH = CH- is present in R 2 is -CH 2 CH 2 - replaced, a 1 and a 1 in the general formula (I) L 2 represents the same meaning as L 1 in the general formula (I), but when L 1 represents —CH═CH— and —C≡C—, L 2 represents —CH 2 CH 2. N represents the same meaning as n in formula (I), and may be the same or different when a plurality of A 2 are present, and the same when a plurality of L 2 are present. Or may be different.) Is provided.
一般式（Ｉ）の接触水素化により一般式（ＩＩ）を得る反応は、遷移金属触媒を使用するが、遷移金属としては白金族金属、鉄族金属が好ましく、具体的にはパラジウム、ルテニウム、白金、ロジウム及びニッケル等が好ましく、パラジウムがより好ましい。これら金属はそのまま反応系に加えることも出来るが、担体に担持して使用することが好ましい。担体としては多孔性の物質であれば特に制限されないが、アルミナ、シリカゲル、ゼオライト、珪藻土、チタニア、ジルコニア、テニオライト、ヘクトライト及び活性炭を挙げることができるが、アルミナ、シリカゲル及び活性炭が好ましく、活性炭が更に好ましい。 The reaction for obtaining the general formula (II) by catalytic hydrogenation of the general formula (I) uses a transition metal catalyst, and the transition metal is preferably a platinum group metal or an iron group metal, specifically, palladium, ruthenium, Platinum, rhodium, nickel and the like are preferable, and palladium is more preferable. These metals can be added to the reaction system as they are, but it is preferable to use them supported on a carrier. The carrier is not particularly limited as long as it is a porous substance, and examples thereof include alumina, silica gel, zeolite, diatomaceous earth, titania, zirconia, teniolite, hectorite, and activated carbon. Alumina, silica gel, and activated carbon are preferable, and activated carbon is used. Further preferred.
遷移金属触媒は使用前に水素雰囲気下に置き、水素を吸着させておくとより好ましい。 More preferably, the transition metal catalyst is placed in a hydrogen atmosphere before use to adsorb hydrogen.
反応時に使用する溶媒としては、非プロトン性極性溶媒を必要とするが、酢酸エチル、酢酸メチル等のエステル系溶媒、テトラヒドロフラン（ＴＨＦ）、ジエチルエーテル、ジイソプロピルエーテル、メチルtert-ブチルエーテル等のエーテル系溶媒や、アセトン、メチルエチルケトン等のケトン溶媒、を単独又は混合して用いることができるが、酢酸エチル、アセトン、テトラヒドロフラン（ＴＨＦ）を用いることが好ましい。更にこれら非プロトン性極性溶媒のみでは基質（一般式（Ｉ）で表される化合物）が溶解できない場合にベンゼン、トルエン、キシレン、メシチレン、クロロベンゼン等の芳香族系溶媒等を添加しても良い。しかし、芳香族系溶媒の添加量を多くすると、接触水素化後のトランス体の選択率が低下してしまう。このため、非プロトン性極性溶媒８０％、芳香族系溶媒２０％の混合溶媒を用いることが好ましく、非プロトン性極性溶媒９０％、芳香族系溶媒１０％の混合溶媒を用いることが好ましい。例えば、溶媒として酢酸エチルとトルエンの混合溶媒を用いる場合、酢酸エチル８０％、トルエン２０％の混合比の混合溶媒又は酢酸エチル９０％、トルエン１０％の混合比の混合溶媒を用いることが好ましい。 As a solvent used in the reaction, an aprotic polar solvent is required, but ester solvents such as ethyl acetate and methyl acetate, ether solvents such as tetrahydrofuran (THF), diethyl ether, diisopropyl ether, and methyl tert-butyl ether. Alternatively, ketone solvents such as acetone and methyl ethyl ketone can be used alone or as a mixture, but it is preferable to use ethyl acetate, acetone, or tetrahydrofuran (THF). Furthermore, when the substrate (compound represented by the general formula (I)) cannot be dissolved only with these aprotic polar solvents, aromatic solvents such as benzene, toluene, xylene, mesitylene, and chlorobenzene may be added. However, when the addition amount of the aromatic solvent is increased, the selectivity of the trans form after catalytic hydrogenation is lowered. Therefore, a mixed solvent of 80% aprotic polar solvent and 20% aromatic solvent is preferably used, and a mixed solvent of 90% aprotic polar solvent and 10% aromatic solvent is preferably used. For example, when a mixed solvent of ethyl acetate and toluene is used as the solvent, it is preferable to use a mixed solvent having a mixing ratio of 80% ethyl acetate and 20% toluene or a mixed solvent having a mixing ratio of 90% ethyl acetate and 10% toluene.
反応温度は溶媒の凝固点から還流温度範囲で行うことができるが、20℃から還流温度が好ましく、下限温度としては40℃が好ましく、50℃が更に好ましい。上限温度としては75℃が好ましく、70℃が好ましく、60℃が更に好ましい。 The reaction temperature can be in the range from the freezing point of the solvent to the reflux temperature, preferably from 20 ° C to the reflux temperature, and the lower limit temperature is preferably 40 ° C, more preferably 50 ° C. The upper limit temperature is preferably 75 ° C, preferably 70 ° C, and more preferably 60 ° C.
一般式（Ｉ）においてＲ１は、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、炭素数１〜１２のアルキル基、炭素数２〜１２のアルケニル基、炭素数１〜１２のアルコキシ基又は炭素数２〜１２のアルケニルオキシ基を表し、１個以上の水素原子は独立的にフッ素原子に置換されていてもよく、また−ＣＨ２−基は独立的に−Ｏ−、−ＣＯ−、−ＣＯＯ−又は−ＯＣＯ−に置換されていてもよいが、フッ素原子、炭素数1〜8のアルキル基、炭素数2〜8のアルケニル基、炭素数1〜7のアルコキシ基又は炭素数2〜7のアルケニルオキシ基が好ましく、フッ素原子、炭素原子数2〜5の直鎖状アルキル基、ビニル基、3-ブテニル基、3-ブテニルオキシ基、トランス-1-プロペン-1-イル基、4-ペンテニルオキシ基又はトランス-3-ペンテン-1-イル基がより好ましく、Ｒ２は、水素原子、炭素数１〜１２のアルキル基、炭素数２〜１２のアルケニル基、炭素数１〜１２のアルコキシ基又は炭素数２〜１２のアルケニルオキシ基を表すが、炭素数1〜8のアルキル基、炭素数2〜8のアルケニル基、炭素数1〜7のアルコキシ基又は炭素数2〜7のアルケニルオキシ基が好ましく、炭素原子数2〜5の直鎖状アルキル基、ビニル基、3-ブテニル基、3-ブテニルオキシ基、トランス-1-プロペン-1-イル基、4-ペンテニルオキシ基又はトランス-3-ペンテン-1-イル基がより好ましく、Ａ１はフッ素原子によって置換されていても良い１，４−フェニレン基、１，４−シクロヘキシレン基、ピリジン−２，５−ジイル基、ピリミジン−２，５−ジイル基、ナフタレン−２，６−ジイル基、テトラヒドロナフタレン−２，６−ジイル基又は１，３−ジオキサン−２，５−ジイル基を表すが、トランス-1,4-シクロヘキシレン基又は1個以上のフッ素原子に置換されていてもよい1,4-フェニレン基が好ましく、トランス-1,4-シクロヘキシレン基又は無置換の1,4-フェニレン基がより好ましく、Ｌ１は単結合、−ＣＨ２ＣＨ２−、−ＣＨ２Ｏ−、−ＯＣＨ２−、−ＣＦ２Ｏ−、−ＯＣＦ２−、−ＣＨ＝ＣＨ−及び−Ｃ≡Ｃ−を表すが、単結合又は−ＣＨ２ＣＨ２−が好ましく、ｎは０、１又は２を表すが、ｎが２を表す場合に複数存在するAは同一であっても異なっていても良く、１又は２が好ましい。 In the general formula (I), R 1 is a fluorine atom, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, or 1 to 12 carbon atoms. Or an alkenyloxy group having 2 to 12 carbon atoms, wherein one or more hydrogen atoms may be independently substituted with fluorine atoms, and a —CH 2 — group is independently —O—, -CO-, -COO- or -OCO- may be substituted, but a fluorine atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 7 carbon atoms or An alkenyloxy group having 2 to 7 carbon atoms is preferable, a fluorine atom, a linear alkyl group having 2 to 5 carbon atoms, a vinyl group, a 3-butenyl group, a 3-butenyloxy group, trans-1-propen-1-yl Group, 4-pentenyloxy group or A trans-3-penten-1-yl group is more preferable, and R 2 represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, or a carbon number. Represents an alkenyloxy group having 2 to 12 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 7 carbon atoms or an alkenyloxy group having 2 to 7 carbon atoms, C2-C5 linear alkyl group, vinyl group, 3-butenyl group, 3-butenyloxy group, trans-1-propen-1-yl group, 4-pentenyloxy group or trans-3-pentene-1 -Yl group is more preferred, and A 1 is 1,4-phenylene group, 1,4-cyclohexylene group, pyridine-2,5-diyl group, pyrimidine-2,5-diyl optionally substituted by a fluorine atom. Group, naphthalene-2,6-diyl group, te Represents a lahydronaphthalene-2,6-diyl group or a 1,3-dioxane-2,5-diyl group, but may be substituted with a trans-1,4-cyclohexylene group or one or more fluorine atoms 1,4-phenylene group is preferable, trans-1,4-cyclohexylene group or unsubstituted 1,4-phenylene group is more preferable, and L 1 is a single bond, —CH 2 CH 2 —, —CH 2 O— , —OCH 2 —, —CF 2 O—, —OCF 2 —, —CH═CH— and —C≡C—, preferably a single bond or —CH 2 CH 2 —, and n is 0, 1 or 2 represents, when n represents 2, a plurality of A may be the same or different, and 1 or 2 is preferable.
一般式（ＩＩ）において、Ｒ３、Ｒ４、Ａ２、Ｌ２及びｎは、原料として用いた一般式（Ｉ）で表される化合物における対応するものと同一のものを表すが、接触水素化により還元される−ＣＨ＝ＣＨ−及び−Ｃ≡Ｃ−は−ＣＨ２ＣＨ２−と置き換える。 In the general formula (II), R 3 , R 4 , A 2 , L 2 and n are the same as the corresponding compounds in the compound represented by the general formula (I) used as a raw material, but catalytic hydrogen —CH═CH— and —C≡C—, which are reduced by conversion, are replaced with —CH 2 CH 2 —.
一般式（ＩＩＩ）、（ＩＶ）及び（Ｖ）で表される化合物は一般式（Ｉ）で表される化合物の原料でありＲ１、Ｒ２、Ａ１、Ｌ１及びｎは、原料として用いた一般式（Ｉ）で表される化合物における対応するものと同一のものを表す。なお、一般式（Ｖ）におけるＲ５は炭素数１〜１２のアルキル基、炭素数２〜１２のアルケニル基を表すが、炭素数1〜8のアルキル基、又は炭素数1〜7のアルケニル基が好ましく、炭素原子数2〜5の直鎖状アルキル基又は炭素原子数2〜5の直鎖状アルケニル基がより好ましい。 The compounds represented by the general formulas (III), (IV) and (V) are raw materials of the compound represented by the general formula (I), and R 1 , R 2 , A 1 , L 1 and n are used as raw materials. The same thing as the corresponding thing in the compound represented with general formula (I) used is represented. In general formula (V), R 5 represents an alkyl group having 1 to 12 carbon atoms or an alkenyl group having 2 to 12 carbon atoms, but an alkyl group having 1 to 8 carbon atoms or an alkenyl group having 1 to 7 carbon atoms. Are preferable, and a linear alkyl group having 2 to 5 carbon atoms or a linear alkenyl group having 2 to 5 carbon atoms is more preferable.
一般式（Ｉ）で表される化合物は、一般式（ＩＩＩ）で表される化合物と一般式（ＩＶ）又は一般式（Ｖ）で表される化合物を塩基存在下に反応させることにより製造するが、一般式（ＩＩＩ）で表される化合物と一般式（ＩＶ）又は一般式（Ｖ）で表される化合物を共存させた状態で塩基を加えても良いし、一般式（ＩＶ）又は一般式（Ｖ）で表される化合物と塩基を作用させその後に一般式（ＩＩＩ）で表される化合物と反応させても良い。 The compound represented by general formula (I) is produced by reacting the compound represented by general formula (III) with the compound represented by general formula (IV) or general formula (V) in the presence of a base. However, a base may be added in the state where the compound represented by the general formula (III) and the compound represented by the general formula (IV) or the general formula (V) coexist, or the general formula (IV) or the general formula A compound represented by the formula (V) and a base may be allowed to act, and then reacted with a compound represented by the general formula (III).
塩基としては、一般式（ＩＶ）で表される化合物を用いる場合は、金属アルコキシド、アルキル金属又は金属アミドを用いることが好ましく、具体的にはナトリウムメトキシド、ナトリウムエトキシド、ナトリウムtert-ブトキシド、カリウムtert-ブトキシドが好ましく、ナトリウムtert-ブトキシド又はカリウムtert-ブトキシドがより好ましく、一般式（V）で表される化合物を用いる場合は、アルキル金属又は金属アミドを用いることが好ましく、具体的にはn-ブチルリチウム、sec-ブチルリチウム、tert-ブチルリチウム、リチウムジイソプロピルアミド（ＬＤＡ）等が好ましく、n-ブチルリチウム又はリチウムジイソプロピルアミド（ＬＤＡ）がより好ましい。 When the compound represented by the general formula (IV) is used as the base, it is preferable to use a metal alkoxide, an alkyl metal or a metal amide, specifically sodium methoxide, sodium ethoxide, sodium tert-butoxide, Potassium tert-butoxide is preferable, sodium tert-butoxide or potassium tert-butoxide is more preferable, and when using the compound represented by the general formula (V), it is preferable to use an alkyl metal or a metal amide, specifically n-Butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide (LDA) and the like are preferable, and n-butyllithium or lithium diisopropylamide (LDA) is more preferable.
上記反応の際に使用する溶媒としては、反応を好適に進行させるものであればいずれでも構わないが、テトラヒドロフラン（ＴＨＦ）、ジエチルエーテル、ジイソプロピルエーテル、メチルt-ブチルエーテル等のエーテル系溶媒や、N,N-ジメチルホルムアミド（ＤＭＦ）、N,N-ジメチルアセトアミド（ＤＭＡ）、N-メチルピロリドン等のアミド系溶媒を単独又は混合して用いることができるが、テトラヒドロフラン（ＴＨＦ）を用いることが好ましい。 Any solvent can be used as the solvent used in the above reaction as long as it allows the reaction to proceed suitably. However, ether solvents such as tetrahydrofuran (THF), diethyl ether, diisopropyl ether, methyl t-butyl ether, N Amide solvents such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA) and N-methylpyrrolidone can be used alone or in combination, but tetrahydrofuran (THF) is preferably used.
反応温度は溶媒の凝固点から還流温度範囲で行うことができるが、-10℃から20℃が好ましい。 The reaction temperature can be in the range from the freezing point of the solvent to the reflux temperature, but it is preferably from -10 ° C to 20 ° C.
本願発明は、一般式（ＩＩ）で表される化合物を効率的に製造することができるが、次に示す化合物の製造がより好適である。
（式中、Ｒ３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、炭素数１〜８のアルキル基、炭素数２〜８のアルケニル基、炭素数１〜８のアルコキシ基又は炭素数２〜８のアルケニルオキシ基を表し、Ｒ４は水素原子、炭素数１〜８のアルキル基、炭素数２〜８のアルケニル基、炭素数１〜８のアルコキシ基又は炭素数２〜８のアルケニルオキシ基を表す。） (In the formula, R 3 is a hydrogen atom, a fluorine atom, a trifluoromethoxy group, a difluoromethoxy group, a trifluoromethyl group, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms. R 4 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or a carbon atom. Represents an alkenyloxy group of formula 2 to 8.)
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。
以下、下記の略語を使用する。
Ｐｒ：プロピル基
Ｂｕ：ブチル基
ＴＨＦ：テトラヒドロフラン
（実施例１）トランス、トランス-4-エチル-4’-プロピルビシクロへキシルの製造
EXAMPLES Hereinafter, although an Example is given and this invention is further explained in full detail, this invention is not limited to these Examples.
The following abbreviations are used below.
Pr: Propyl group Bu: Butyl group THF: Tetrahydrofuran (Example 1) Production of trans, trans-4-ethyl-4'-propylbicyclohexyl
2Lの4つ口フラスコ（メカニカルスターラー、温度計付）にエチルトリフェニルホスホニウムブロミド400g、4-（トランス-4’-プロピルシクロヘキシル）シクロへキサノン 200gおよびテトラヒドロフラン（THF）500mLを入れ、氷冷した。そこへカリウムt-ブトキシド122gのTHF溶液（360 mL）を30分間かけて滴下し、10℃で2時間撹拌した。水を加え、しばらく撹拌した後有機層を分取し、水層をヘキサンで抽出した。有機層を合わせ、水、50%メタノール水溶液、飽和食塩水で洗浄し、溶媒を減圧留去した後、精製を行い、トランス-4-エチリデン-4’-プロピルビシクロへキシル186 gを得た。
1H-NMR (400 MHz, CDCl3)：0.85-1.15 (m, 17H), 1.27-1.31 (m, 3H), 1.54-1.76 (m, 6H), 1.94-2.01 (m, 1H), 2.15-2.21 (m, 1H), 2.59-2.65 (m, 1H) , 5.10-5.15 (m, 1H).
Ethyltriphenylphosphonium bromide (400 g), 4- (trans-4′-propylcyclohexyl) cyclohexanone (200 g) and tetrahydrofuran (THF) (500 mL) were placed in a 2 L four-necked flask (mechanical stirrer, equipped with thermometer), and ice-cooled. Thereto was added dropwise a THF solution (360 mL) of 122 g of potassium t-butoxide over 30 minutes, and the mixture was stirred at 10 ° C. for 2 hours. After adding water and stirring for a while, the organic layer was separated, and the aqueous layer was extracted with hexane. The organic layers were combined, washed with water, 50% aqueous methanol and saturated brine, and the solvent was distilled off under reduced pressure, followed by purification to obtain 186 g of trans-4-ethylidene-4'-propylbicyclohexyl.
1 H-NMR (400 MHz, CDCl 3 ): 0.85-1.15 (m, 17H), 1.27-1.31 (m, 3H), 1.54-1.76 (m, 6H), 1.94-2.01 (m, 1H), 2.15- 2.21 (m, 1H), 2.59-2.65 (m, 1H), 5.10-5.15 (m, 1H).
トランス-4-エチリデン-4’-プロピルビシクロへキシル80 g 、5%パラジウムカーボン 4g (50wt.%含水品)の酢酸エチル溶液(400 mL)を、水素圧0.5MPaとした後、55℃にて5時間撹拌する。触媒を濾別し、溶媒を留去することで、トランス、トランス体とトランス、シス体の混合物として得られた。異性体比をGCで測定すると、トランス、シス体；15％、トランス、トランス体；85％であった。本願発明の製造方法により85％の高い純度でトランス、トランス体を得ることができた。再結晶とシリカゲルカラムクロマトグラフィーで精製し、トランス、トランス-4-エチル-4’-プロピルビシクロへキシル45 gを得た。
1H-NMR (400 MHz, CDCl3)：0.82-1.04 (m, 17H), 1.11-1.20 (m, 5H), 1.27-1.33 (m, 2H), 1.68-1.78 (m, 8H).
（実施例2）
実施例1において、水素添加反応の反応溶媒をテトラヒドロフラン（THF）に変更した以外は同様にしてトランス、トランス-4-エチル-4’-プロピルビシクロへキシルの製造を行った。実施例と同様、異性体比をGCで測定すると、トランス、シス体；15％、トランス、トランス体；85％であった。本願発明の製造方法により85％の高い純度でトランス、トランス体を得ることができた。
（実施例3）
実施例1において、水素添加反応の反応溶媒をアセトンに変更した以外は同様にしてトランス、トランス-4-エチル-4’-プロピルビシクロへキシルの製造を行った。実施例と同様、異性体比をGCで測定すると、トランス、シス体；15％、トランス、トランス体；85％であった。本願発明の製造方法により85％の高い純度でトランス、トランス体を得ることができた。
（比較例1）
実施例1において、水素添加反応の反応溶媒をエタノールに変更した以外は同様にしてトランス、トランス-4-エチル-4’-プロピルビシクロへキシルの製造を行った。実施例と同様、異性体比をGCで測定すると、トランス、シス体；21％、トランス、トランス体；79％であった。比較例1の製造方法ではトランス-トランス体の割合が本願発明の製造方法より6％も低いものであった。
Ethyl acetate solution (400 mL) of trans-4-ethylidene-4'-propylbicyclohexyl 80 g, 5% palladium carbon 4 g (50 wt.% Water-containing product) was adjusted to a hydrogen pressure of 0.5 MPa, and then at 55 ° C. Stir for 5 hours. The catalyst was removed by filtration, and the solvent was distilled off to obtain a mixture of trans, trans isomer and trans, cis isomer. The isomer ratio was measured by GC and found to be trans, cis isomer; 15%, trans, trans isomer; 85%. By the production method of the present invention, a trans and trans isomer could be obtained with a high purity of 85%. Purification by recrystallization and silica gel column chromatography gave 45 g of trans, trans-4-ethyl-4'-propylbicyclohexyl.
1 H-NMR (400 MHz, CDCl 3 ): 0.82-1.04 (m, 17H), 1.11-1.20 (m, 5H), 1.27-1.33 (m, 2H), 1.68-1.78 (m, 8H).
(Example 2)
In Example 1, trans and trans-4-ethyl-4′-propylbicyclohexyl were produced in the same manner except that the reaction solvent for the hydrogenation reaction was changed to tetrahydrofuran (THF). As in the Examples, the isomer ratio was measured by GC to be trans, cis form: 15%, trans, trans form: 85%. By the production method of the present invention, a trans and trans isomer could be obtained with a high purity of 85%.
(Example 3)
In Example 1, trans and trans-4-ethyl-4′-propylbicyclohexyl were produced in the same manner except that the reaction solvent for the hydrogenation reaction was changed to acetone. As in the Examples, the isomer ratio was measured by GC to be trans, cis form: 15%, trans, trans form: 85%. By the production method of the present invention, a trans and trans isomer could be obtained with a high purity of 85%.
(Comparative Example 1)
In Example 1, trans and trans-4-ethyl-4′-propylbicyclohexyl were produced in the same manner except that the reaction solvent for the hydrogenation reaction was changed to ethanol. As in the Examples, the isomer ratio was measured by GC to be trans, cis form: 21%, trans, trans form: 79%. In the production method of Comparative Example 1, the ratio of the trans-trans isomer was 6% lower than that of the production method of the present invention.
Claims (8)
又は、一般式（Ｖ）
Or general formula (V)
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| CN (1) | CN102060641B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5476569A (en) * | 1977-11-30 | 1979-06-19 | Kao Corp | Endo-2-methylperhydrotriquinacene and its preparation |
| JP3275265B2 (en) * | 1992-02-17 | 2002-04-15 | チッソ株式会社 | Trifluoromethoxy compound and liquid crystal composition containing the compound |
| JP3780547B2 (en) * | 1995-09-13 | 2006-05-31 | 大日本インキ化学工業株式会社 | Bicyclohexane derivative |
| DE59704519D1 (en) * | 1996-10-02 | 2001-10-11 | Merck Patent Gmbh | Bisalkenylbicyclohexane and liquid crystalline medium |
| US6380205B1 (en) * | 1999-10-29 | 2002-04-30 | Merck & Co., Inc. | 2-cyclohexyl quinazoline NMDA/NR2B antagonists |
| JP2004256490A (en) * | 2003-02-27 | 2004-09-16 | Nagase Chemtex Corp | Method for producing trans-cyclohexane derivative |
| JP5318367B2 (en) * | 2006-05-10 | 2013-10-16 | 三星ディスプレイ株式會社 | Dimethylenecyclohexane compound, method for producing the same, and organic light-emitting device including the same |
| CN1962580A (en) * | 2006-11-20 | 2007-05-16 | 烟台万润精细化工有限责任公司 | Method for preparing dicyclohexyl monomer liquid crystal by utilizing Grignard reaction |
| JP5146719B2 (en) * | 2007-06-29 | 2013-02-20 | Ｄｉｃ株式会社 | Cyclohexylmethylphosphonate derivatives |
| JP5401085B2 (en) * | 2007-11-29 | 2014-01-29 | Ａｇｃセイミケミカル株式会社 | Fluorine-containing liquid crystal compound, liquid crystal composition containing the same, and liquid crystal electro-optical element |
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| Publication number | Publication date |
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| JP2011105612A (en) | 2011-06-02 |
| CN102060641B (en) | 2014-11-05 |
| CN102060641A (en) | 2011-05-18 |
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