JP3569280B1 - Method for producing optically active alcohol - Google Patents
Method for producing optically active alcohol Download PDFInfo
- Publication number
- JP3569280B1 JP3569280B1 JP2004059915A JP2004059915A JP3569280B1 JP 3569280 B1 JP3569280 B1 JP 3569280B1 JP 2004059915 A JP2004059915 A JP 2004059915A JP 2004059915 A JP2004059915 A JP 2004059915A JP 3569280 B1 JP3569280 B1 JP 3569280B1
- Authority
- JP
- Japan
- Prior art keywords
- optically active
- group
- active alcohol
- carbonyl compound
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 58
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 7
- 150000001728 carbonyl compounds Chemical class 0.000 claims abstract description 30
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 12
- 239000010948 rhodium Substances 0.000 claims abstract description 12
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000004985 diamines Chemical class 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 7
- ZKMZPXWMMSBLNO-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-one Chemical compound C1CC2C(=O)CN1CC2 ZKMZPXWMMSBLNO-UHFFFAOYSA-N 0.000 claims description 15
- 150000002430 hydrocarbons Chemical group 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 10
- 238000010586 diagram Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 25
- 239000003054 catalyst Substances 0.000 description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 17
- 229910052739 hydrogen Inorganic materials 0.000 description 17
- 239000001257 hydrogen Substances 0.000 description 17
- -1 nitrogen-containing compound Chemical class 0.000 description 15
- SSJXIUAHEKJCMH-WDSKDSINSA-N (1s,2s)-cyclohexane-1,2-diamine Chemical compound N[C@H]1CCCC[C@@H]1N SSJXIUAHEKJCMH-WDSKDSINSA-N 0.000 description 9
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- 229910001220 stainless steel Inorganic materials 0.000 description 7
- 239000010935 stainless steel Substances 0.000 description 7
- IVLICPVPXWEGCA-ZETCQYMHSA-N (3r)-1-azabicyclo[2.2.2]octan-3-ol Chemical compound C1CC2[C@@H](O)CN1CC2 IVLICPVPXWEGCA-ZETCQYMHSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- UDSBNHFABKWTHB-UHFFFAOYSA-N [Rh+].ClC1=CC=CCCCC1 Chemical class [Rh+].ClC1=CC=CCCCC1 UDSBNHFABKWTHB-UHFFFAOYSA-N 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- 239000012327 Ruthenium complex Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- WDYGPMAMBXJESZ-SFHVURJKSA-N (2s)-1,1-bis(4-methoxyphenyl)-3-methylbutane-1,2-diamine Chemical compound C1=CC(OC)=CC=C1C(N)([C@@H](N)C(C)C)C1=CC=C(OC)C=C1 WDYGPMAMBXJESZ-SFHVURJKSA-N 0.000 description 3
- IVLICPVPXWEGCA-UHFFFAOYSA-N 3-quinuclidinol Chemical compound C1C[C@@H]2C(O)C[N@]1CC2 IVLICPVPXWEGCA-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IVLICPVPXWEGCA-SSDOTTSWSA-N (3s)-1-azabicyclo[2.2.2]octan-3-ol Chemical compound C1CC2[C@H](O)CN1CC2 IVLICPVPXWEGCA-SSDOTTSWSA-N 0.000 description 2
- LAXRNWSASWOFOT-UHFFFAOYSA-J (cymene)ruthenium dichloride dimer Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Ru+2].[Ru+2].CC(C)C1=CC=C(C)C=C1.CC(C)C1=CC=C(C)C=C1 LAXRNWSASWOFOT-UHFFFAOYSA-J 0.000 description 2
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- XSAYZAUNJMRRIR-UHFFFAOYSA-N 2-acetylnaphthalene Chemical compound C1=CC=CC2=CC(C(=O)C)=CC=C21 XSAYZAUNJMRRIR-UHFFFAOYSA-N 0.000 description 2
- KCKZIWSINLBROE-UHFFFAOYSA-N 3,4-dihydro-1h-naphthalen-2-one Chemical compound C1=CC=C2CC(=O)CCC2=C1 KCKZIWSINLBROE-UHFFFAOYSA-N 0.000 description 2
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 description 2
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 150000001805 chlorine compounds Chemical group 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
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052741 iridium Inorganic materials 0.000 description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- UOPFIWYXBIHPIP-SFTDATJTSA-N n-[(1s,2s)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 UOPFIWYXBIHPIP-SFTDATJTSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- QCCDLTOVEPVEJK-UHFFFAOYSA-N phenylacetone Chemical compound CC(=O)CC1=CC=CC=C1 QCCDLTOVEPVEJK-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
- PONXTPCRRASWKW-ZIAGYGMSSA-N (1r,2r)-1,2-diphenylethane-1,2-diamine Chemical compound C1([C@@H](N)[C@H](N)C=2C=CC=CC=2)=CC=CC=C1 PONXTPCRRASWKW-ZIAGYGMSSA-N 0.000 description 1
- SSJXIUAHEKJCMH-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-diamine Chemical compound N[C@@H]1CCCC[C@H]1N SSJXIUAHEKJCMH-PHDIDXHHSA-N 0.000 description 1
- WDYGPMAMBXJESZ-GOSISDBHSA-N (2r)-1,1-bis(4-methoxyphenyl)-3-methylbutane-1,2-diamine Chemical compound C1=CC(OC)=CC=C1C(N)([C@H](N)C(C)C)C1=CC=C(OC)C=C1 WDYGPMAMBXJESZ-GOSISDBHSA-N 0.000 description 1
- CJLVEEKBJGYLAZ-MRXNPFEDSA-N (2r)-1,1-dinaphthalen-1-ylpropane-1,2-diamine Chemical compound C1=CC=C2C(C(N)(C=3C4=CC=CC=C4C=CC=3)[C@H](N)C)=CC=CC2=C1 CJLVEEKBJGYLAZ-MRXNPFEDSA-N 0.000 description 1
- GHWVXCQZPNWFRO-QWWZWVQMSA-N (2r,3r)-butane-2,3-diamine Chemical compound C[C@@H](N)[C@@H](C)N GHWVXCQZPNWFRO-QWWZWVQMSA-N 0.000 description 1
- CJLVEEKBJGYLAZ-INIZCTEOSA-N (2s)-1,1-dinaphthalen-1-ylpropane-1,2-diamine Chemical compound C1=CC=C2C(C(N)(C=3C4=CC=CC=C4C=CC=3)[C@@H](N)C)=CC=CC2=C1 CJLVEEKBJGYLAZ-INIZCTEOSA-N 0.000 description 1
- GHWVXCQZPNWFRO-IMJSIDKUSA-N (2s,3s)-butane-2,3-diamine Chemical compound C[C@H](N)[C@H](C)N GHWVXCQZPNWFRO-IMJSIDKUSA-N 0.000 description 1
- WAPNOHKVXSQRPX-SSDOTTSWSA-N (R)-1-phenylethanol Chemical compound C[C@@H](O)C1=CC=CC=C1 WAPNOHKVXSQRPX-SSDOTTSWSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VFPKIWATTACVJR-UHFFFAOYSA-N 1-(dimethylamino)propan-2-one Chemical compound CN(C)CC(C)=O VFPKIWATTACVJR-UHFFFAOYSA-N 0.000 description 1
- HJYVFFLYCSUEOE-UHFFFAOYSA-N 1-(oxolan-3-yl)ethanone Chemical compound CC(=O)C1CCOC1 HJYVFFLYCSUEOE-UHFFFAOYSA-N 0.000 description 1
- FJXLZNSVOSVTPH-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-2-one Chemical class C1CN2C(=O)CC1CC2 FJXLZNSVOSVTPH-UHFFFAOYSA-N 0.000 description 1
- BJNCVECKNVBHBP-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-yl butanoate Chemical compound C1CC2C(OC(=O)CCC)CN1CC2 BJNCVECKNVBHBP-UHFFFAOYSA-N 0.000 description 1
- RIFKADJTWUGDOV-UHFFFAOYSA-N 1-cyclohexylethanone Chemical compound CC(=O)C1CCCCC1 RIFKADJTWUGDOV-UHFFFAOYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BUWPZNOVIHAWHW-UHFFFAOYSA-N 2,3-dihydro-1h-quinolin-4-one Chemical compound C1=CC=C2C(=O)CCNC2=C1 BUWPZNOVIHAWHW-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical group CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- IEMMBWWQXVXBEU-UHFFFAOYSA-N 2-acetylfuran Chemical compound CC(=O)C1=CC=CO1 IEMMBWWQXVXBEU-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- LFSAPCRASZRSKS-UHFFFAOYSA-N 2-methylcyclohexan-1-one Chemical compound CC1CCCCC1=O LFSAPCRASZRSKS-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- CKQHAYFOPRIUOM-UHFFFAOYSA-N 3'-Aminoacetophenone Chemical compound CC(=O)C1=CC=CC(N)=C1 CKQHAYFOPRIUOM-UHFFFAOYSA-N 0.000 description 1
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 1
- MSTDXOZUKAQDRL-UHFFFAOYSA-N 4-Chromanone Chemical compound C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-UHFFFAOYSA-N 0.000 description 1
- SUVYXKDAVYFUMG-UHFFFAOYSA-N 4-aminobutan-2-one Chemical compound CC(=O)CCN SUVYXKDAVYFUMG-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 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
- CFXLRVAGMWGFMU-UHFFFAOYSA-N [Rh+].BrC1=CC=CCCCC1 Chemical class [Rh+].BrC1=CC=CCCCC1 CFXLRVAGMWGFMU-UHFFFAOYSA-N 0.000 description 1
- JUEJDZCJJLZFSS-KLXURFKVSA-M [Rh+].C1=CC=CCCCC1.C([C@@H](O)C1=CC=CC=C1)(=O)[O-] Chemical class [Rh+].C1=CC=CCCCC1.C([C@@H](O)C1=CC=CC=C1)(=O)[O-] JUEJDZCJJLZFSS-KLXURFKVSA-M 0.000 description 1
- BGJDNRGMAKYYSX-UHFFFAOYSA-N [Rh+].C1CC2=CC(Cl)=C1C2 Chemical class [Rh+].C1CC2=CC(Cl)=C1C2 BGJDNRGMAKYYSX-UHFFFAOYSA-N 0.000 description 1
- LHVYUZOINAZCIX-UHFFFAOYSA-N [Rh+].C1CCC=CC=CC1 Chemical class [Rh+].C1CCC=CC=CC1 LHVYUZOINAZCIX-UHFFFAOYSA-N 0.000 description 1
- GDUTVUMWVNRSNU-UHFFFAOYSA-N [Rh+].IC1=CC=CCCCC1 Chemical class [Rh+].IC1=CC=CCCCC1 GDUTVUMWVNRSNU-UHFFFAOYSA-N 0.000 description 1
- DOOCJNDHRGOROA-UHFFFAOYSA-N [Rh].NC1=CC=C(C=C1)C.ClC1=CC=CCCCC1 Chemical compound [Rh].NC1=CC=C(C=C1)C.ClC1=CC=CCCCC1 DOOCJNDHRGOROA-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 150000003997 cyclic ketones Chemical class 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- PONXTPCRRASWKW-KBPBESRZSA-N diphenylethylenediamine Chemical compound C1([C@H](N)[C@@H](N)C=2C=CC=CC=2)=CC=CC=C1 PONXTPCRRASWKW-KBPBESRZSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical group [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- MDWCIKACMBMJFA-UHFFFAOYSA-N isoquinolin-1-yl(phenyl)methanone Chemical compound N=1C=CC2=CC=CC=C2C=1C(=O)C1=CC=CC=C1 MDWCIKACMBMJFA-UHFFFAOYSA-N 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid 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
- LPEKGGXMPWTOCB-GSVOUGTGSA-N methyl (R)-lactate Chemical compound COC(=O)[C@@H](C)O LPEKGGXMPWTOCB-GSVOUGTGSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- CWKLZLBVOJRSOM-UHFFFAOYSA-N methyl pyruvate Chemical compound COC(=O)C(C)=O CWKLZLBVOJRSOM-UHFFFAOYSA-N 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- UOPFIWYXBIHPIP-UHFFFAOYSA-N n-(2-amino-1,2-diphenylethyl)-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(C=1C=CC=CC=1)C(N)C1=CC=CC=C1 UOPFIWYXBIHPIP-UHFFFAOYSA-N 0.000 description 1
- UOPFIWYXBIHPIP-NHCUHLMSSA-N n-[(1r,2r)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H](C=1C=CC=CC=1)[C@H](N)C1=CC=CC=C1 UOPFIWYXBIHPIP-NHCUHLMSSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 238000000711 polarimetry Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Abstract
【課題】 プロキラルなカルボニル化合物を不斉水素化し、対応する光学活性アルコールを高い鏡像体過剰率で、かつ高収率に工業的に有利に製造する方法を提供する。
【解決手段】 プロキラルなカルボニル化合物を不斉水素化して光学活性アルコールを得る際に、ロジウム錯体あるいはその塩、特定の光学活性ジホスフィン、特定の光学活性ジアミンの存在下において、塩基を添加せずに水素添加することを特徴とする光学活性アルコールの製造方法。
【選択図】 なし
PROBLEM TO BE SOLVED: To provide a process for asymmetrically hydrogenating a prochiral carbonyl compound to industrially advantageously produce a corresponding optically active alcohol in a high enantiomeric excess and in a high yield.
SOLUTION: When obtaining an optically active alcohol by asymmetric hydrogenation of a prochiral carbonyl compound, in the presence of a rhodium complex or a salt thereof, a specific optically active diphosphine, and a specific optically active diamine, without adding a base. A method for producing an optically active alcohol, comprising hydrogenating.
[Selection diagram] None
Description
本発明は、プロキラルなカルボニル化合物を不斉水素化して光学活性アルコールを製造方法に関する。 The present invention relates to a method for producing an optically active alcohol by asymmetric hydrogenation of a prochiral carbonyl compound.
本発明方法の目的化合物である光学活性アルコールは種々の医薬や農薬の原料・中間体として有用である。 The optically active alcohol which is the target compound of the method of the present invention is useful as a raw material / intermediate of various medicines and agricultural chemicals.
光学活性アルコールを得る方法として、プロキラルなカルボニル化合物を不斉金属錯体触媒の存在下で不斉水素化する方法がある。特許文献１には、遷移金属触媒、アルカリ金属またはアルカリ土類金属の水酸化物などの塩基、及び光学活性含窒素化合物の存在下でカルボニル化合物を不斉水素化する方法が開示されている。特許文献２には、特定の光学活性ホスフィンと特定の光学活性ジアミンが配位したルテニウム錯体を触媒として使用し、カルボニル化合物を水素化する方法が開示されている。しかしながら、カルボニル化合物や触媒によっては、塩基を添加することにより、反応の進行を抑制することや、得られる光学活性アルコールの鏡像体過剰率の低下を引き起こすこともあった。また、カルボニル化合物によっては、特許文献２に記載されている特定の光学活性ホスフィンと特定の光学活性ジアミンが配位したルテニウム錯体を使用した場合でも、満足する鏡像体過剰率を有するアルコールが得られないことがあった。 As a method for obtaining an optically active alcohol, there is a method for asymmetric hydrogenation of a prochiral carbonyl compound in the presence of an asymmetric metal complex catalyst. Patent Document 1 discloses a method for asymmetric hydrogenation of a carbonyl compound in the presence of a transition metal catalyst, a base such as an alkali metal or alkaline earth metal hydroxide, and an optically active nitrogen-containing compound. Patent Document 2 discloses a method of hydrogenating a carbonyl compound using a ruthenium complex in which a specific optically active phosphine and a specific optically active diamine are coordinated as a catalyst. However, depending on the carbonyl compound or catalyst, addition of a base may suppress the progress of the reaction or cause a decrease in the enantiomeric excess of the obtained optically active alcohol. Further, depending on the carbonyl compound, even when a ruthenium complex in which a specific optically active phosphine and a specific optically active diamine are coordinated as described in Patent Document 2 is used, an alcohol having a satisfactory enantiomeric excess can be obtained. There was nothing.
非特許文献１には、プロキラルなカルボニル化合物を、特定の光学活性（ヒドロキシアルキルフェロセニル）ホスフィンを配位したロジウム錯体の存在下に水素化する方法が開示されている。しかしながら、カルボニル化合物によっては、満足する鏡像体過剰率を有するアルコールが得られないことがあった。 Non-Patent Document 1 discloses a method for hydrogenating a prochiral carbonyl compound in the presence of a rhodium complex to which a specific optically active (hydroxyalkylferrocenyl) phosphine is coordinated. However, depending on the carbonyl compound, an alcohol having a satisfactory enantiomeric excess may not be obtained.
医薬の原料・中間体として有用な光学活性アルコールの一つとして、光学活性３−キヌクリジノールがある。特許文献３には、３−キヌクリジノンおよびそのルイス酸との付加物、およびこれらに対応する特定の第三および第四塩からなる化合物から選んだキヌクリジノン誘導体を、キラルなジホスフィンを有するロジウム、イリジウムまたはルテニウム錯体の存在下に水素化する方法が開示されている。しかしながら、３−キヌクリジノンを不斉水素化した場合は、得られる光学活性３−キヌクリジノールの鏡像体過剰率が２０％以下と極めて低かった。３−キヌクリジノンの第三および第四塩では鏡像体過剰率は向上するが、三級塩化や四級塩化、さらに水素化後に３−キヌクリジノール遊離体にする煩雑な工程が必要であった。いずれも、工業的に満足のできる方法ではなかった。
本発明が解決しようとする課題は、プロキラルなカルボニル化合物を不斉水素化し、対応する光学活性アルコールを高い鏡像体過剰率で、かつ高収率に工業的に有利に製造する方法を提供することである。 The problem to be solved by the present invention is to provide a method for asymmetrically hydrogenating a prochiral carbonyl compound to industrially advantageously produce the corresponding optically active alcohol with a high enantiomeric excess and in a high yield. It is.
本発明者らは、プロキラルなカルボニル化合物を不斉水素化して光学活性アルコールを得る際に、ロジウム錯体あるいはその塩、光学活性ジホスフィン及び光学活性ジアミンの存在下において、塩基を添加せずに水素添加することにより、所望する鏡像体の含有率の高い光学活性アルコールを得ることを見出し、本発明を完成するに至った。 The present inventors have found that when an asymmetric hydrogenation of a prochiral carbonyl compound is performed to obtain an optically active alcohol, hydrogenation is performed without adding a base in the presence of a rhodium complex or a salt thereof, an optically active diphosphine, and an optically active diamine. As a result, they have found that an optically active alcohol having a high content of a desired enantiomer is obtained, and the present invention has been completed.
すなわち、上記課題を解決するための第１の発明は、プロキラルなカルボニル化合物を不斉水素化して光学活性アルコールを得る際に、ロジウム錯体あるいはその塩、一般式（１） That is, a first aspect of the present invention for solving the above-mentioned problems is that when a prochiral carbonyl compound is asymmetrically hydrogenated to obtain an optically active alcohol, a rhodium complex or a salt thereof, a compound represented by the general formula (1):
上記課題を解決するための第２の発明は、上記第1の発明であって、光学活性ジホスフィン配位子が、一般式（３） A second invention for solving the above-mentioned problem is the first invention, wherein the optically active diphosphine ligand has a general formula (3)
上記課題を解決するための第３の発明は、上記第1あるいは第２の発明であって、プロキラルなカルボニル化合物が３−キヌクリジノンであることを特徴とするものである。 A third invention for solving the above-mentioned problems is the first or second invention, wherein the prochiral carbonyl compound is 3-quinuclidinone.
本発明によれば、プロキラルなカルボニル化合物から、高収率かつ高い鏡像体過 剰率で対応する光学活性アルコールを製造することができる。 According to the present invention, a corresponding optically active alcohol can be produced from a prochiral carbonyl compound with a high yield and a high enantiomeric excess.
以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明における、プロキラルなカルボニル化合物としては、２−ブタノン、３−メチル−２−ブタノン、シクロヘキシルメチルケトン、４−アミノ−２−ブタノン、３−アセチルテトラヒドロフラン、Ｎ，Ｎ−ジメチルアミノアセトンなどカルボニル基に置換基を有していてもよい飽和炭化水素基が結合したプロキラルなケトン；メチルベンジルケトン、アセトフェノン、４’−メチルアセトフェノン、３’−アミノアセトフェノン、２−アセチルナフタレン、２−アセチルフラン、３−アセチルピリジンなどカルボニル基に置換基を有していてもよい飽和炭化水素基および、置換基を有していてもよい芳香族単環または多環式基あるいはヘテロ芳香族単環または多環式基など不飽和炭化水素基が結合したプロキラルなケトン；２−ベンゾイルナフタレン、１−イソキノリニルフェニルケトンなどカルボニル基に置換基を有していてもよい芳香族単環または多環式基あるいはヘテロ芳香族単環または多環式基など不飽和炭化水素基が結合したプロキラルなケトン；２−メチルシクロヘキサノン、β−テトラロン、２，３−ジヒドロ−１Ｈ−キノリン−４−オン、３，４−ジヒドロ−２Ｈ−１−ベンゾピラン−４−オン、３−キヌクリジノンなど置換基を有してもよいプロキラルな環状ケトンなどを挙げることができる。置換基としては、水酸基、アミノ基、アルコキシ基、カルボニル基、アミド基などが例示できる。 In the present invention, examples of the prochiral carbonyl compound include carbonyl groups such as 2-butanone, 3-methyl-2-butanone, cyclohexylmethyl ketone, 4-amino-2-butanone, 3-acetyltetrahydrofuran, and N, N-dimethylaminoacetone. A prochiral ketone having an optionally substituted saturated hydrocarbon group; methylbenzylketone, acetophenone, 4′-methylacetophenone, 3′-aminoacetophenone, 2-acetylnaphthalene, 2-acetylfuran, 3 A saturated hydrocarbon group which may have a substituent on a carbonyl group such as -acetylpyridine, and an aromatic monocyclic or polycyclic group or a heteroaromatic monocyclic or polycyclic group which may have a substituent A prochiral ketone to which an unsaturated hydrocarbon group such as a group is bonded; Unsaturated hydrocarbon groups such as an aromatic monocyclic or polycyclic group or a heteroaromatic monocyclic or polycyclic group which may have a substituent on a carbonyl group such as naphthalene and 1-isoquinolinylphenyl ketone Bound prochiral ketones; 2-methylcyclohexanone, β-tetralone, 2,3-dihydro-1H-quinolin-4-one, 3,4-dihydro-2H-1-benzopyran-4-one, 3-quinuclidinone, etc. And a prochiral cyclic ketone which may have a group. Examples of the substituent include a hydroxyl group, an amino group, an alkoxy group, a carbonyl group, and an amide group.
使用するロジウム錯体あるいは塩については、光学活性ジホスフィン及び光学活性ジアミンが容易に配位子置換できる構造の化合物であれば、特に制限はない。例えば、クロロ（シクロオクタジエン）ロジウム（Ｉ）ダイマー、ブロモ（シクロオクタジエン）ロジウム（I）ダイマー、ヨード（シクロオクタジエン）ロジウム（I）ダイマー、クロロ（シクロオクタジエン）（ピペリジン）ロジウム（I）、クロロ（シクロオクタジエン）（ｐ−トルイジン）ロジウム（I）、クロロ（ノルボルナジエン）ロジウム（Ｉ）ダイマー、アセタト（シクロオクタジエン）ロジウム（I）ダイマー、L-マンデレート（シクロオクタジエン）ロジウム（I）ダイマー、ジクロロテトラエチレンニロジウム（I）、ビス（ノルボルナジエン）ロジウム（I）テトラフルオロボレートなどが挙げられる。ロジウムの原子価は、配位子の種類及び溶媒等の外的条件により変化するために、原子状態から種々のイオンの価数までとり得る。具体的には０〜＋３であり、水素化反応における触媒調製段階において、ロジウムの原子価が＋１であることが望ましい。 The rhodium complex or salt to be used is not particularly limited as long as the compound has a structure in which the optically active diphosphine and the optically active diamine can be easily substituted with a ligand. For example, chloro (cyclooctadiene) rhodium (I) dimer, bromo (cyclooctadiene) rhodium (I) dimer, iodo (cyclooctadiene) rhodium (I) dimer, chloro (cyclooctadiene) (piperidine) rhodium (I) ), Chloro (cyclooctadiene) (p-toluidine) rhodium (I), chloro (norbornadiene) rhodium (I) dimer, acetato (cyclooctadiene) rhodium (I) dimer, L-mandelate (cyclooctadiene) rhodium ( I) dimer, dichlorotetraethylene iridium (I), bis (norbornadiene) rhodium (I) tetrafluoroborate and the like. The valence of rhodium varies from the atomic state to the valence of various ions because it changes depending on external conditions such as the type of ligand and solvent. Specifically, it is preferably 0 to +3, and the valence of rhodium is preferably +1 in the catalyst preparation stage in the hydrogenation reaction.
前記一般式（１）で示される光学活性ジホスフィン中のリン原子に結合するＲ1、Ｒ2、Ｒ3及びＲ4としては、互いに独立に、メチル基、エチル基、n−プロピル基、イソプロピル基などのアルキル基；シクロペンチル基、シクロヘキシル基などのシクロアルキル基；フェニル基、２−メチルフェニル基、４−メチルフェニル基、４−メトキシフェニル基、ナフチル基などのアリール基；ベンジル基などを挙げることができる。フェロセン骨格内のシクロペンタジエニル基に結合するＲ5及びＲ6としては、互いに独立に、水素原子、エチル基、n−プロピル基、イソプロピル基などのアルキル基；ビニル基などのアリル基、シクロペンチル基、シクロヘキシル基などのシクロアルキル基、フェニル基、２−メチルフェニル基などのアリール基；２−ヒドロキシエチル基、１−ヒドロキシエチル基、（１Ｒ）−１−ヒドロキシエチル基、（１Ｓ）−１−ヒドロキシエチル基、１−ヒドロキシプロピル基、（１Ｒ）−１−ヒドロキシプロピル基、（１Ｓ）−１−ヒドロキシプロピル基、２−（Ｎ，Ｎ−ジメチルアミノ）エチル基、１−（Ｎ，Ｎ−ジメチルアミノ）エチル基、（１Ｒ）−１−（Ｎ，Ｎ−ジメチルアミノ）エチル基、（１Ｓ）−１−（Ｎ，Ｎ−ジメチルアミノ）エチル基、２−メトキシエチル基、１−メトキシエチル基、（１Ｒ）−１−メトキシエチル基、２−アセチルエチル基、１−アセチルエチル基、（１Ｒ）−１−アセチルエチル基、（１Ｓ）−１−アセチルエチル基、１−フェニルヒドロキシメチル基、（１Ｒ）−１−フェニルヒドロキシメチル基、（１Ｓ）−１−フェニルヒドロキシメチル基、アセチル基、アセトアミド基などの置換基として水酸基、アミノ基、アルコキシ基、カルボニル基、アミド基を有する炭化水素基を挙げることができる。 R 1 , R 2 , R 3, and R 4 bonded to the phosphorus atom in the optically active diphosphine represented by the general formula (1) each independently represent a methyl group, an ethyl group, an n-propyl group, or an isopropyl group. Alkyl groups such as cyclopentyl group and cyclohexyl group; aryl groups such as phenyl group, 2-methylphenyl group, 4-methylphenyl group, 4-methoxyphenyl group and naphthyl group; benzyl group and the like. Can be. R 5 and R 6 bonded to the cyclopentadienyl group in the ferrocene skeleton each independently represent a hydrogen atom, an alkyl group such as an ethyl group, an n-propyl group, or an isopropyl group; an allyl group such as a vinyl group; Group, cycloalkyl group such as cyclohexyl group, aryl group such as phenyl group and 2-methylphenyl group; 2-hydroxyethyl group, 1-hydroxyethyl group, (1R) -1-hydroxyethyl group, (1S) -1 -Hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 2- (N, N-dimethylamino) ethyl group, 1- (N, N -Dimethylamino) ethyl group, (1R) -1- (N, N-dimethylamino) ethyl group, (1S) -1- (N, N-dimethylamino) Ethyl group, 2-methoxyethyl group, 1-methoxyethyl group, (1R) -1-methoxyethyl group, 2-acetylethyl group, 1-acetylethyl group, (1R) -1-acetylethyl group, (1S) -1-acetylethyl group, 1-phenylhydroxymethyl group, (1R) -1-phenylhydroxymethyl group, (1S) -1-phenylhydroxymethyl group, acetyl group, acetyl group, hydroxyl group and amino group as substituents , An alkoxy group, a carbonyl group, and a hydrocarbon group having an amide group.
前記一般式（１）で表される光学活性ジホスフィンとしては、（Ｒ）−１’，２−ビス（ジフェニルホスフィノ）フェロセニルエタン、（Ｓ）−１’，２−ビス（ジフェニルホスフィノ）フェロセニルエタン、（Ｓ）−１−［（Ｒ）−１’，２−ビス（ジフェニルホスフィノ）フェロセニル］エタノール（以下、「（Ｓ，Ｒ）−ＢＰＰＦＯＨ」と略称する）、（Ｒ）−１−［（Ｓ）−１’，２−ビス（ジフェニルホスフィノ）フェロセニル］エタノール（以下、「（Ｒ，Ｓ）−ＢＰＰＦＯＨ」と略称する）、（Ｓ）−Ｎ，Ｎ−ジメチル−１−［（Ｒ）−１’，２−ビス（ジフェニルホスフィノ）フェロセニル］エチルアミン（以下、「（Ｓ，Ｒ）−ＢＰＰＦＡ」と略称する）、（Ｒ）−Ｎ，Ｎ−ジメチル−１−［（Ｓ）−１’，２−ビス（ジフェニルホスフィノ）フェロセニル］エチルアミン（以下、「（Ｒ，Ｓ）−ＢＰＰＦＡ」と略称する）などを挙げることができる。好ましくは、（Ｓ，Ｒ）−ＢＰＰＦＯＨ、（Ｒ，Ｓ）−ＢＰＰＦＯＨ、（Ｓ，Ｒ）−ＢＰＰＦＡ、（Ｒ，Ｓ）−ＢＰＰＦＡなど、Ｒ5あるいはＲ6が不斉中心を有する基である一般式（１）で示される光学活性ジホスフィンである。さらに好ましくは、（Ｓ，Ｒ）−ＢＰＰＦＯＨ、（Ｒ，Ｓ）−ＢＰＰＦＯＨなど、一般式（３）もしくは（４）で示される光学活性ジホスフィンである。 Examples of the optically active diphosphine represented by the general formula (1) include (R) -1 ′, 2-bis (diphenylphosphino) ferrocenylethane and (S) -1 ′, 2-bis (diphenylphosphino). ) Ferrocenylethane, (S) -1-[(R) -1 ′, 2-bis (diphenylphosphino) ferrocenyl] ethanol (hereinafter abbreviated as “(S, R) -BPPFOH”), (R ) -1-[(S) -1 ′, 2-bis (diphenylphosphino) ferrocenyl] ethanol (hereinafter abbreviated as “(R, S) -BPPFOH”), (S) -N, N-dimethyl- 1-[(R) -1 ′, 2-bis (diphenylphosphino) ferrocenyl] ethylamine (hereinafter abbreviated as “(S, R) -BPPFA”), (R) -N, N-dimethyl-1- [(S) -1 ′, 2-bis (diphenyl Sufino) ferrocenyl] ethylamine (hereinafter referred to as "(R, S) -BPPFA" abbreviated as), and the like. Preferably, R 5 or R 6 is a group having an asymmetric center, such as (S, R) -BPPFOH, (R, S) -BPPFOH, (S, R) -BPPFA, (R, S) -BPPFA. An optically active diphosphine represented by the general formula (1). More preferred are optically active diphosphines represented by the general formula (3) or (4), such as (S, R) -BPPFOH and (R, S) -BPPFOH.
前記一般式（２）で示される光学活性ジアミンとしては、（１Ｓ，２Ｓ）−ＤＰＥＮ：（１Ｓ，２Ｓ）−１，２−ジフェニル−１，２−エタンジアミン、（１Ｒ，２Ｒ）−１，２−ジフェニル−１，２−エタンジアミン（以下、「（１Ｒ，２Ｒ）−ＤＰＥＮ」と略称する）、（１Ｓ，２Ｓ）−１，２−シクロヘキサンジアミン、（１Ｒ，２Ｒ）−１，２−シクロヘキサンジアミン、（２Ｓ，３Ｓ）−２，３−ブタンジアミン、（２Ｒ，３Ｒ）−２，３−ブタンジアミン、（２Ｓ）−１，１−ビス（ｐ−メトキシフェニル）−２−イソプロピル−１，２−エタンジアミン（以下、「（Ｓ）−ＤＡＩＰＥＮ」と略称する）、（２Ｒ）−１，１−ビス（ｐ−メトキシフェニル）−２−イソプロピル−１，２−エタンジアミン（以下、「（Ｒ）−ＤＡＩＰＥＮ」と略称する）、（２Ｓ）−１，１−ビスナフチル−２−メチル−１，２−エタンジアミン、（２Ｒ）−１，１−ビスナフチル−２−メチル−１，２−エタンジアミン、（１Ｓ，２Ｓ）−ＴｓＤＰＥＮ：Ｎ−（ｐ−トルエンスルホニル）−（１Ｓ，２Ｓ）−１，２−ジフェニル−１，２−エタンジアミン、Ｎ−（ｐ−トルエンスルホニル）−（１Ｒ，２Ｒ）−１，２−ジフェニル−１，２−エタンジアミン（以下、「（１Ｒ，２Ｒ）−ＴｓＤＰＥＮ」と略称する）などを挙げることができる。より好ましくは、光学活性ＤＰＥＮ、光学活性ＤＡＩＰＥＮ、もしくは光学活性ＴｓＤＰＥＮである。 As the optically active diamine represented by the general formula (2), (1S, 2S) -DPEN: (1S, 2S) -1,2-diphenyl-1,2-ethanediamine, (1R, 2R) -1, 2-diphenyl-1,2-ethanediamine (hereinafter abbreviated as "(1R, 2R) -DPEN"), (1S, 2S) -1,2-cyclohexanediamine, (1R, 2R) -1,2- Cyclohexanediamine, (2S, 3S) -2,3-butanediamine, (2R, 3R) -2,3-butanediamine, (2S) -1,1-bis (p-methoxyphenyl) -2-isopropyl-1 , 2-ethanediamine (hereinafter abbreviated as "(S) -DAIPEN"), (2R) -1,1-bis (p-methoxyphenyl) -2-isopropyl-1,2-ethanediamine (hereinafter, referred to as "(S) -DAIPEN"). (R) -DA PEN)), (2S) -1,1-bisnaphthyl-2-methyl-1,2-ethanediamine, (2R) -1,1-bisnaphthyl-2-methyl-1,2-ethanediamine, ( 1S, 2S) -TsDPEN: N- (p-toluenesulfonyl)-(1S, 2S) -1,2-diphenyl-1,2-ethanediamine, N- (p-toluenesulfonyl)-(1R, 2R)- 1,2-diphenyl-1,2-ethanediamine (hereinafter abbreviated as “(1R, 2R) -TsDPEN”) and the like can be mentioned. More preferably, it is optically active DPEN, optically active DAIPEN, or optically active TsDPEN.
ロジウム錯体あるいはその塩の使用量は、カルボニル化合物や触媒の種類によって異なるが、カルボニル化合物に対して、通常、１／５０〜１／１００００倍モル、好ましくは、１／５００〜１／２０００倍モルである。１／１００００倍モル未満では反応が極めて遅くなり未反応のカルボニル化合物が残存し易くなるので好ましくない。１／５０倍モルを越えて使用しても、特段の効果は見られず、経済的に不利なので好ましくない。 The amount of the rhodium complex or a salt thereof varies depending on the type of the carbonyl compound or the catalyst, but is usually 1/50 to 1/10000 times mol, preferably 1/500 to 1/2000 times mol with respect to the carbonyl compound. It is. If the molar ratio is less than 1 / 10,000 times, the reaction becomes extremely slow and unreacted carbonyl compound tends to remain. Even if it is used in an amount of more than 1/50 mol, no particular effect is seen and it is economically disadvantageous, so that it is not preferable.
前記一般式（１）で表される光学活性ジホスフィンの使用量は、ロジウムに対して、１.０〜１．５倍モルであることが望ましい。１.０倍モル未満では、得られる光学活性アルコールの鏡像体過剰率が著しく低下する。１.５倍モルを超えて使用すると、触媒の反応性を低下させるので好ましくない。 The amount of the optically active diphosphine represented by the general formula (1) is desirably 1.0 to 1.5 times mol of rhodium. If the molar ratio is less than 1.0, the enantiomeric excess of the obtained optically active alcohol is remarkably reduced. If it is used in excess of 1.5 moles, the reactivity of the catalyst is undesirably reduced.
前記一般式（２）で表される光学活性ジアミンの使用量は、ロジウムに対して０．５〜２．０倍モルであることが望ましい。０．５倍モル未満では、得られる光学活性アルコールの光学収率が著しく低下する。２.０倍モルを超えて使用すると、触媒の反応性を著しく低下させるので好ましくない。 The amount of the optically active diamine represented by the general formula (2) is desirably 0.5 to 2.0 times the mol of rhodium. When the molar ratio is less than 0.5 times, the optical yield of the obtained optically active alcohol is significantly reduced. Use of more than 2.0 moles is undesirable because it significantly reduces the reactivity of the catalyst.
不斉水素化反応に使用する溶媒は、カルボニル化合物及び触媒を可溶化するものであれば、特に制限はない。その具体例としては、メタノール、エタノール、１−プロパノール、２−プロパノール、１−ブタノール、ベンジルアルコールなどのアルコール類、ペンタン、ヘキサン、シクロヘキサン、メチルシクロヘキサン、ベンゼン、トルエン、キシレン、メシチレンのような脂肪族及び芳香族炭化水素類、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、エチレングリコールジメチルエーテル、１，４−ジオキサンなどのエーテル類、ジクロロメタン、クロロホルム、１，１，２，２−テトラクロロエタンなどのハロゲン化炭化水素類、酢酸エチル、γ−ブチロラクトンなどのエステル及びラクトン類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチルピロリドンのようなカルボキサミド及びラクタム類である。これらの溶媒は単独で、あるいは２種類以上を混合して使用することもできる。基質が液体でかつ、触媒を可溶化するものであれば、溶媒を使用しなくてもよい。 The solvent used in the asymmetric hydrogenation reaction is not particularly limited as long as it can solubilize the carbonyl compound and the catalyst. Specific examples thereof include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and benzyl alcohol, and aliphatics such as pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene, xylene and mesitylene. And aromatic hydrocarbons, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, ethylene glycol dimethyl ether and 1,4-dioxane, and halogenated hydrocarbons such as dichloromethane, chloroform, 1,1,2,2-tetrachloroethane and the like. , Ethyl acetate, esters and lactones such as γ-butyrolactone, carboxamides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; It is a class. These solvents can be used alone or in combination of two or more. As long as the substrate is liquid and solubilizes the catalyst, a solvent need not be used.
溶媒の使用量は、カルボニル化合物に対して１／１０〜１００００重量倍であるが、好ましくは１／１０〜１００倍重量である。溶媒の使用量がカルボニル化合物に対して１／１０未満の場合は、カルボニル化合物を溶解するのに不十分で反応性を著しく低下させるので好ましくない。カルボニル化合物に対して、溶媒を１００００重量倍を越えて使用しても特段の効果は見られず、経済的に不利なので好ましくない。 The amount of the solvent used is 1/10 to 10000 times by weight, preferably 1/10 to 100 times by weight of the carbonyl compound. When the amount of the solvent used is less than 1/10 of the carbonyl compound, it is not preferable because it is insufficient to dissolve the carbonyl compound and the reactivity is significantly reduced. If the solvent is used in an amount of more than 10,000 times by weight with respect to the carbonyl compound, no particular effect is observed, and this is not preferable because it is economically disadvantageous.
水素圧は、０．１〜２０ＭＰａまで使用可能であるが、好ましくは０．５〜１０ＭＰａが望ましい。水素圧が０．１ＭＰａ未満の場合は、反応が極めて遅くなり未反応のカルボニル化合物が残存し易くなるので好ましくない。水素圧が２０ＭＰａを超えて使用しても特段の効果は認められず、経済的に不利であるので好ましくない。 The hydrogen pressure can be used up to 0.1 to 20 MPa, but preferably 0.5 to 10 MPa. If the hydrogen pressure is less than 0.1 MPa, the reaction becomes extremely slow, and unreacted carbonyl compounds tend to remain, which is not preferable. Even if the hydrogen pressure exceeds 20 MPa, no particular effect is observed, which is not preferable because it is economically disadvantageous.
反応温度は、通常−５０℃〜１００℃まで使用可能であるが、好ましくは１０〜４０℃である。温度が−５０℃未満の場合は、反応が極めて遅くなり未反応のカルボニル化合物が残存し易くなるので好ましくない。温度が１００℃を越えると、錯体触媒の安定性が著しく低下し、得られる光学活性アルコールの鏡像体過剰率が低下するので好ましくない。 The reaction temperature can be usually used from -50C to 100C, but is preferably from 10C to 40C. If the temperature is lower than −50 ° C., the reaction becomes extremely slow, and unreacted carbonyl compound tends to remain, which is not preferable. If the temperature exceeds 100 ° C., the stability of the complex catalyst is remarkably reduced, and the enantiomeric excess of the obtained optically active alcohol is undesirably reduced.
反応終了後は、溶媒抽出、蒸留、再結晶、クロマトグラフィーなど通常の有機合成化学的手法により、単離・精製を行い、目的物を得ることができる。目的物の構造は、1H−NMR、旋光度測定、高速液体クロマトグラフ、ガスクロマトグラフなどの公知の分析手段によって決定することができる。 After completion of the reaction, the desired product can be obtained by performing isolation and purification by ordinary organic synthetic chemistry techniques such as solvent extraction, distillation, recrystallization, and chromatography. The structure of the target substance can be determined by known analytical means such as 1H-NMR, optical rotation measurement, high performance liquid chromatography, gas chromatography and the like.
次に、実施例を示し、更に詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 Next, examples will be shown and described in more detail, but the present invention is not limited to these examples.
窒素ガスで置換したグローブボックス内で触媒溶液を調製して、水素化反応に使用した。 A catalyst solution was prepared in a glove box purged with nitrogen gas and used for a hydrogenation reaction.
水素化反応でのカルボニル化合物の転化率は、ガスクロマトグラフで決定した。得られる光学活性アルコールの鏡像体過剰率（％ｅｅ）は、高速液体クロマトグラフで決定した。 The conversion of the carbonyl compound in the hydrogenation reaction was determined by gas chromatography. The enantiomeric excess (% ee) of the obtained optically active alcohol was determined by high performance liquid chromatography.
試験管にクロロ（シクロオクタジエン）ロジウム（Ｉ）ダイマー４．９ｍｇ、（Ｓ，Ｒ）−ＢＰＰＦＯＨ１３．２ｍｇ、（１Ｒ，２Ｒ）−ＤＰＥＮ４．５ｍｇをエタノール２ｍＬに溶解し、触媒溶液を調製した。つづいて、別の試験管に３−キヌクリジノン５００ｍｇをエタノール８ｍＬに溶解し、基質溶液を調製した。２つの溶液を混合し、内容積２００ｍＬのステンレス製耐圧反応容器内に入れ、水素を水素圧３．５ＭＰａとなるように導入し、３０℃で１６時間攪拌した。反応液を減圧下濃縮し、溶媒を留去した。残渣１０ｍｇをメタノール１ｍＬに溶解し、ガスクロマトグラフにより分析したところ、転化率は１００％であった。反応液の残渣を無水酪酸と反応させて、３−キヌクリジノール酪酸エステルに変換後、高速液体クロマトグラフにより分析したところ、Ｒ−３−キヌクリジノールが鏡像体過剰率６８．９％ｅｅで生成していた。 In a test tube, 4.9 mg of chloro (cyclooctadiene) rhodium (I) dimer, 13.2 mg of (S, R) -BPPFOH, and 4.5 mg of (1R, 2R) -DPEN were dissolved in 2 mL of ethanol to prepare a catalyst solution. Subsequently, 500 mg of 3-quinuclidinone was dissolved in 8 mL of ethanol in another test tube to prepare a substrate solution. The two solutions were mixed, placed in a 200-mL stainless steel pressure-resistant reaction vessel, and hydrogen was introduced so that the hydrogen pressure became 3.5 MPa, followed by stirring at 30 ° C. for 16 hours. The reaction solution was concentrated under reduced pressure, and the solvent was distilled off. When 10 mg of the residue was dissolved in 1 mL of methanol and analyzed by gas chromatography, the conversion was 100%. The residue of the reaction solution was reacted with butyric anhydride to convert it into 3-quinuclidinol butyrate, and then analyzed by high performance liquid chromatography. As a result, it was found that R-3-quinuclidinol was formed at an enantiomeric excess of 68.9% ee. .
（Ｓ，Ｒ）−ＢＰＰＦＯＨ及び（１Ｒ，２Ｒ）ＤＰＥＮに代えて（Ｒ，Ｓ）−ＢＰＰＦＯＨ及び（１Ｓ，２Ｓ）−ＤＰＥＮを使用した以外は、実施例１と同様に処理した。転化率１００％、鏡像体過剰率６８．０％ｅｅでＳ−３−キヌクリジノールが得られた。 Processing was performed in the same manner as in Example 1 except that (R, S) -BPPFOH and (1S, 2S) -DPEN were used instead of (S, R) -BPPFOH and (1R, 2R) DPEN. S-3-quinuclidinol was obtained at a conversion of 100% and an enantiomeric excess of 68.0% ee.
（Ｓ，Ｒ）−ＢＰＰＦＯＨに代えて（Ｒ，Ｓ）−ＢＰＰＦＯＨを、３−キヌクリジノン５００ｍｇに代えてアセトフェノン４８０ｍｇを使用した以外は、実施例１と同様に処理した。添加率１００％、鏡像体過剰率７２．１％ｅｅで（Ｒ）−１−フェニルエタノールが得られた。 The same treatment as in Example 1 was conducted, except that (R, S) -BPPFOH was used instead of (S, R) -BPPFOH and 480 mg of acetophenone was used instead of 500 mg of 3-quinuclidinone. (R) -1-phenylethanol was obtained at an addition rate of 100% and an enantiomeric excess of 72.1% ee.
（Ｓ，Ｒ）−ＢＰＰＦＯＨに代えて（Ｒ，Ｓ）−ＢＰＰＦＯＨを、３−キヌクリジノン５００ｍｇに代えてピルビン酸メチル４０８ｍｇを使用した、実施例１と同様に処理した。添加率１００％、鏡像体過剰率９３．５％ｅｅで（Ｒ）−乳酸メチルが得られた。 Treatment was performed in the same manner as in Example 1 using (R, S) -BPPFOH instead of (S, R) -BPPFOH and 408 mg of methyl pyruvate instead of 500 mg of 3-quinuclidinone. (R) -methyl lactate was obtained at an addition rate of 100% and an enantiomeric excess of 93.5% ee.
試験管にクロロ（シクロオクタジエン）ロジウム（I）ダイマー４．９ｍｇ、（Ｓ）−１，１’−ビスナフチル−２，２’−ビス（ジフェニルホスフィン）（以下、「（Ｓ）−ＢＩＮＡＰ」と略称する）１３．９ｍｇをＴＨＦ２ｍＬに溶解し、触媒溶液を調製した。つづいて、別の試験管に３−キヌクリジノン２５０ｍｇをエタノール８ｍＬに溶解し、基質溶液を調製した。２つの溶液を混合し、内容積２００ｍＬのステンレス製耐圧反応容器内に入れ、水素を水素圧３．５ＭＰａとなるように導入し、３０℃で２０時間攪拌した。以降、実施例１と同様に処理した。転化率７９％、鏡像体過剰率５．６％ｅｅで、Ｒ−３−キヌクリジノールが得られた。 In a test tube, 4.9 mg of chloro (cyclooctadiene) rhodium (I) dimer, (S) -1,1′-bisnaphthyl-2,2′-bis (diphenylphosphine) (hereinafter “(S) -BINAP” 13.9 mg) was dissolved in 2 mL of THF to prepare a catalyst solution. Subsequently, 250 mg of 3-quinuclidinone was dissolved in 8 mL of ethanol in another test tube to prepare a substrate solution. The two solutions were mixed, placed in a stainless steel pressure-resistant reaction vessel having an internal volume of 200 mL, hydrogen was introduced so as to have a hydrogen pressure of 3.5 MPa, and the mixture was stirred at 30 ° C. for 20 hours. Thereafter, the same processing as in Example 1 was performed. R-3-quinuclidinol was obtained at a conversion of 79% and an enantiomeric excess of 5.6% ee.
試験管にクロロ（シクロオクタジエン）ロジウム（I）ダイマー４．９ｍｇ、（Ｓ）−ＢＩＮＡＰ１３．９ｍｇ、（１Ｒ，２Ｒ）−ＤＰＥＮ４．７ｍｇをＴＨＦ２ｍＬに溶解し、触媒溶液を調製した。別の試験管に３−キヌクリジノン２５０ｍｇをエタノール８ｍＬに溶解し、基質溶液を調製した。２つの溶液を混合し、内容積２００ｍＬのステンレス製耐圧反応容器内に入れ、水素を水素圧３．５ＭＰａとなるように導入し、３０℃で２０時間攪拌した。以降、実施例１と同様に処理した。転化率２１％、鏡像体過剰率５．２％ｅｅで、Ｒ−３−キヌクリジノールが得られた。 In a test tube, 4.9 mg of chloro (cyclooctadiene) rhodium (I) dimer, 13.9 mg of (S) -BINAP, and 4.7 mg of (1R, 2R) -DPEN were dissolved in 2 mL of THF to prepare a catalyst solution. In another test tube, 250 mg of 3-quinuclidinone was dissolved in 8 mL of ethanol to prepare a substrate solution. The two solutions were mixed, placed in a stainless steel pressure-resistant reaction vessel having an internal volume of 200 mL, hydrogen was introduced so as to have a hydrogen pressure of 3.5 MPa, and the mixture was stirred at 30 ° C. for 20 hours. Thereafter, the same processing as in Example 1 was performed. R-3-quinuclidinol was obtained at a conversion of 21% and an enantiomeric excess of 5.2% ee.
試験管にクロロ（シクロオクタジエン）ロジウム（I）ダイマー２．５ｍｇ、（Ｓ，Ｒ）−ＢＰＰＦＯＨ６．６ｍｇをエタノール２ｍＬに溶解し、触媒溶液を調製した。別の試験管に３−キヌクリジノン３１３ｍｇをエタノール８ｍＬに溶解し、基質溶液を調製した。２つの溶液を混合し、内容積２００ｍＬのステンレス製耐圧反応容器内に入れ、水素を水素圧３．５ＭＰａとなるように導入し、３０℃で１６時間攪拌した。以降、実施例１と同様に処理した。転化率９５％、鏡像体過剰率３１．６％ｅｅで、Ｒ−３−キヌクリジノールが得られた。 In a test tube, 2.5 mg of chloro (cyclooctadiene) rhodium (I) dimer and 6.6 mg of (S, R) -BPPFOH were dissolved in 2 mL of ethanol to prepare a catalyst solution. In another test tube, 313 mg of 3-quinuclidinone was dissolved in 8 mL of ethanol to prepare a substrate solution. The two solutions were mixed, placed in a 200-mL stainless steel pressure-resistant reaction vessel, and hydrogen was introduced so that the hydrogen pressure became 3.5 MPa, followed by stirring at 30 ° C. for 16 hours. Thereafter, the same processing as in Example 1 was performed. R-3-quinuclidinol was obtained at a conversion of 95% and an enantiomeric excess of 31.6% ee.
試験管にクロロ（シクロオクタジエン）ロジウム（Ｉ）ダイマー４．９ｍｇ、（Ｓ，Ｒ）−ＢＰＰＦＯＨ１３．２ｍｇ、（１Ｒ、２Ｒ）−ＤＰＥＮ４．５ｍｇをエタノール２ｍＬに溶解し、触媒溶液を調製した。別の試験管に３−キヌクリジノン３１３ｍｇ及びｔ−ブトキシカリウム１１２ｍｇをエタノール８ｍＬに溶解し、基質溶液を調製した。２つの溶液を混合し、内容積２００ｍＬのステンレス製耐圧反応容器内に入れ、水素を水素圧３．５ＭＰａとなるように導入し、３０℃で１６時間攪拌した。以降、実施例１と同様に処理した。転化率１００％、鏡像体過剰率１２．１％で、Ｒ−３−キヌクリジノールが得られた。 In a test tube, 4.9 mg of chloro (cyclooctadiene) rhodium (I) dimer, 13.2 mg of (S, R) -BPPFOH, and 4.5 mg of (1R, 2R) -DPEN were dissolved in 2 mL of ethanol to prepare a catalyst solution. In another test tube, 313 mg of 3-quinuclidinone and 112 mg of potassium t-butoxy were dissolved in 8 mL of ethanol to prepare a substrate solution. The two solutions were mixed, placed in a 200-mL stainless steel pressure-resistant reaction vessel, and hydrogen was introduced so that the hydrogen pressure became 3.5 MPa, followed by stirring at 30 ° C. for 16 hours. Thereafter, the same processing as in Example 1 was performed. R-3-quinuclidinol was obtained at a conversion of 100% and an enantiomeric excess of 12.1%.
試験管にジクロロ（ｐ−シメン）ルテニウム（II）ダイマー６．１ｍｇ、（Ｓ，Ｒ）−ＢＰＰＦＯＨ１３．２ｍｇ、（１Ｒ、２Ｒ）−ＤＰＥＮ４．５ｍｇをエタノール２ｍＬに溶解し、触媒溶液を調製した。別の試験管に３−キヌクリジノン５００ｍｇをエタノール８ｍＬに溶解し、基質溶液を調製した。２つの溶液を混合し、内容積２００ｍＬのステンレス製耐圧反応容器内に入れ、水素を水素圧３．５ＭＰａとなるように導入し、３０℃で１４時間攪拌した。以降、実施例１と同様に処理した。転化率８％、鏡像体過剰率２２．２％ｅｅで、Ｒ−３−キヌクリジノールが得られた。 In a test tube, 6.1 mg of dichloro (p-cymene) ruthenium (II) dimer, 13.2 mg of (S, R) -BPPFOH, and 4.5 mg of (1R, 2R) -DPEN were dissolved in 2 mL of ethanol to prepare a catalyst solution. In a separate test tube, 500 mg of 3-quinuclidinone was dissolved in 8 mL of ethanol to prepare a substrate solution. The two solutions were mixed, placed in a stainless steel pressure-resistant reaction vessel having an internal volume of 200 mL, hydrogen was introduced so as to have a hydrogen pressure of 3.5 MPa, and the mixture was stirred at 30 ° C. for 14 hours. Thereafter, the same processing as in Example 1 was performed. R-3-quinuclidinol was obtained at a conversion of 8% and an enantiomeric excess of 22.2% ee.
試験管にジクロロ（ｐ−シメン）ルテニウム（II）ダイマー６．１ｍｇ、（Ｒ，Ｓ）−ＢＰＰＦＯＨ１３．２ｍｇ、（１Ｓ、２Ｓ）−ＤＰＥＮ４．５ｍｇをエタノール２ｍＬに溶解し、触媒溶液を調製した。別の試験管に３−キヌクリジノン２５０ｍｇとｔ−ブトキシカリウム１１２ｍｇをエタノール８ｍＬに溶解し、基質溶液を調製した。２つの溶液を混合し、内容積２００ｍＬのステンレス製耐圧反応容器内に入れ、水素を水素圧３．５ＭＰａとなるように導入し、３０℃で３日間攪拌した。以降、実施例１と同様に処理した。転化率９８％、鏡像体過剰率９．０％ｅｅで、Ｓ−３−キヌクリジノールが得られた。 In a test tube, 6.1 mg of dichloro (p-cymene) ruthenium (II) dimer, 13.2 mg of (R, S) -BPPFOH, and 4.5 mg of (1S, 2S) -DPEN were dissolved in 2 mL of ethanol to prepare a catalyst solution. In another test tube, 250 mg of 3-quinuclidinone and 112 mg of potassium t-butoxide were dissolved in 8 mL of ethanol to prepare a substrate solution. The two solutions were mixed, placed in a stainless steel pressure-resistant reaction vessel having an internal volume of 200 mL, hydrogen was introduced so as to have a hydrogen pressure of 3.5 MPa, and the mixture was stirred at 30 ° C. for 3 days. Thereafter, the same processing as in Example 1 was performed. With a conversion of 98% and an enantiomeric excess of 9.0% ee, S-3-quinuclidinol was obtained.
上記の結果を、表１にまとめた。比較例４から、塩基を添加するにより、得られる光学活性アルコールの鏡像体過剰率が低いことは明らかである。また、比較例５および６から、光学活性ホスフィン、光学活性ジアミン、ルテニウム錯体触媒の存在下で水素化した場合は、極めて反応が遅く、得られる光学活性アルコールの鏡像体過剰率も低いことは明らかである。 The above results are summarized in Table 1. From Comparative Example 4, it is clear that the enantiomeric excess of the optically active alcohol obtained by adding the base is low. From Comparative Examples 5 and 6, it is clear that when hydrogenation is carried out in the presence of an optically active phosphine, an optically active diamine and a ruthenium complex catalyst, the reaction is extremely slow and the enantiomeric excess of the obtained optically active alcohol is low. It is.
本発明によれば、プロキラルなカルボニル化合物から、高収率かつ高い鏡像体過剰率で対応する光学活性アルコールを有用に製造することができる。
According to the present invention, a corresponding optically active alcohol can be usefully produced from a prochiral carbonyl compound in a high yield and a high enantiomeric excess.
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