JP6461939B2 - ケトン類を不斉還元するための新規なルテニウム触媒及びその使用 - Google Patents
ケトン類を不斉還元するための新規なルテニウム触媒及びその使用 Download PDFInfo
- Publication number
- JP6461939B2 JP6461939B2 JP2016523847A JP2016523847A JP6461939B2 JP 6461939 B2 JP6461939 B2 JP 6461939B2 JP 2016523847 A JP2016523847 A JP 2016523847A JP 2016523847 A JP2016523847 A JP 2016523847A JP 6461939 B2 JP6461939 B2 JP 6461939B2
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- Prior art keywords
- compound
- formula
- diamine ligand
- ketone
- ruthenium
- Prior art date
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- 150000002576 ketones Chemical class 0.000 title claims description 36
- 239000003054 catalyst Substances 0.000 title description 20
- 230000009467 reduction Effects 0.000 title description 11
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 title description 3
- 229910052707 ruthenium Inorganic materials 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 130
- 150000004985 diamines Chemical class 0.000 claims description 73
- 239000003446 ligand Substances 0.000 claims description 69
- 238000000034 method Methods 0.000 claims description 38
- 150000003304 ruthenium compounds Chemical class 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 238000011065 in-situ storage Methods 0.000 claims description 9
- 229940125898 compound 5 Drugs 0.000 claims description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 7
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- 229940125797 compound 12 Drugs 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 239000012041 precatalyst Substances 0.000 claims description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims 1
- 229940125851 compound 27 Drugs 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- -1 heteroaryl cyclic ketones Chemical class 0.000 description 8
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- 150000003997 cyclic ketones Chemical class 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical group NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 101100446506 Mus musculus Fgf3 gene Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- JAAJQSRLGAYGKZ-SNVBAGLBSA-N (1r)-1,2,3,4-tetrahydronaphthalen-1-ol Chemical compound C1=CC=C2[C@H](O)CCCC2=C1 JAAJQSRLGAYGKZ-SNVBAGLBSA-N 0.000 description 2
- JAAJQSRLGAYGKZ-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalen-1-ol Chemical compound C1=CC=C2C(O)CCCC2=C1 JAAJQSRLGAYGKZ-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical class C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 description 2
- WEGYGNROSJDEIW-UHFFFAOYSA-N 3-Acetylpyridine Chemical compound CC(=O)C1=CC=CN=C1 WEGYGNROSJDEIW-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 2
- 108010061846 Cholesterol Ester Transfer Proteins Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 101100348848 Mus musculus Notch4 gene Proteins 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- MXGXXBYVDMVJAO-UHFFFAOYSA-N [1-[2-bis(3,5-dimethylphenyl)phosphanylnaphthalen-1-yl]naphthalen-2-yl]-bis(3,5-dimethylphenyl)phosphane Chemical compound CC1=CC(C)=CC(P(C=2C=C(C)C=C(C)C=2)C=2C(=C3C=CC=CC3=CC=2)C=2C3=CC=CC=C3C=CC=2P(C=2C=C(C)C=C(C)C=2)C=2C=C(C)C=C(C)C=2)=C1 MXGXXBYVDMVJAO-UHFFFAOYSA-N 0.000 description 2
- IOPQYDKQISFMJI-UHFFFAOYSA-N [1-[2-bis(4-methylphenyl)phosphanylnaphthalen-1-yl]naphthalen-2-yl]-bis(4-methylphenyl)phosphane Chemical compound C1=CC(C)=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC(C)=CC=1)C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 IOPQYDKQISFMJI-UHFFFAOYSA-N 0.000 description 2
- JZOSBBLJKXSBBN-UHFFFAOYSA-N [3-(4-diphenylphosphanyl-2,6-dimethoxypyridin-3-yl)-2,6-dimethoxypyridin-4-yl]-diphenylphosphane Chemical compound COC=1N=C(OC)C=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1C=1C(OC)=NC(OC)=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 JZOSBBLJKXSBBN-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 2
- LOPKSXMQWBYUOI-DTWKUNHWSA-N (1r,2s)-1-amino-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2[C@@H](N)[C@@H](O)CC2=C1 LOPKSXMQWBYUOI-DTWKUNHWSA-N 0.000 description 1
- JAAJQSRLGAYGKZ-JTQLQIEISA-N (1s)-1,2,3,4-tetrahydronaphthalen-1-ol Chemical compound C1=CC=C2[C@@H](O)CCCC2=C1 JAAJQSRLGAYGKZ-JTQLQIEISA-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
- 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 1
- 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 1
- LYHOBZAADXPPNW-UHFFFAOYSA-N (r)-xylyl-phanephos Chemical compound CC1=CC(C)=CC(P(C=2C=C(C)C=C(C)C=2)C=2C=3CCC4=CC=C(C(=C4)P(C=4C=C(C)C=C(C)C=4)C=4C=C(C)C=C(C)C=4)CCC(=CC=3)C=2)=C1 LYHOBZAADXPPNW-UHFFFAOYSA-N 0.000 description 1
- WDYGPMAMBXJESZ-UHFFFAOYSA-N 1,1-bis(4-methoxyphenyl)-3-methylbutane-1,2-diamine Chemical compound C1=CC(OC)=CC=C1C(N)(C(N)C(C)C)C1=CC=C(OC)C=C1 WDYGPMAMBXJESZ-UHFFFAOYSA-N 0.000 description 1
- PONXTPCRRASWKW-UHFFFAOYSA-N 1,2-diphenylethane-1,2-diamine Chemical compound C=1C=CC=CC=1C(N)C(N)C1=CC=CC=C1 PONXTPCRRASWKW-UHFFFAOYSA-N 0.000 description 1
- WYECURVXVYPVAT-UHFFFAOYSA-N 1-(4-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Br)C=C1 WYECURVXVYPVAT-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- JVAWMZUJNSYUKK-UHFFFAOYSA-N 3,6-dihydro-2h-pyran-4-carbaldehyde Chemical compound O=CC1=CCOCC1 JVAWMZUJNSYUKK-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- ACZGCWSMSTYWDQ-UHFFFAOYSA-N 3h-1-benzofuran-2-one Chemical compound C1=CC=C2OC(=O)CC2=C1 ACZGCWSMSTYWDQ-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
- ZXLSKTZECNUVIS-UHFFFAOYSA-M 4-methyl-3-oxopentanoate Chemical compound CC(C)C(=O)CC([O-])=O ZXLSKTZECNUVIS-UHFFFAOYSA-M 0.000 description 1
- YHHBKPWMEXGLKE-UHFFFAOYSA-N 7,8-dihydro-6h-quinolin-5-one Chemical compound C1=CC=C2C(=O)CCCC2=N1 YHHBKPWMEXGLKE-UHFFFAOYSA-N 0.000 description 1
- WREVVZMUNPAPOV-UHFFFAOYSA-N 8-aminoquinoline Chemical compound C1=CN=C2C(N)=CC=CC2=C1 WREVVZMUNPAPOV-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 101000767160 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Intracellular protein transport protein USO1 Proteins 0.000 description 1
- JRTHAKOHBMETRC-UHFFFAOYSA-N [3-[4-bis(3,5-dimethylphenyl)phosphanyl-2,6-dimethoxypyridin-3-yl]-2,6-dimethoxypyridin-4-yl]-bis(3,5-dimethylphenyl)phosphane Chemical compound COC=1N=C(OC)C=C(P(C=2C=C(C)C=C(C)C=2)C=2C=C(C)C=C(C)C=2)C=1C=1C(OC)=NC(OC)=CC=1P(C=1C=C(C)C=C(C)C=1)C1=CC(C)=CC(C)=C1 JRTHAKOHBMETRC-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 125000005002 aryl methyl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KHYAFFAGZNCWPT-UHFFFAOYSA-N boron;n,n-diethylaniline Chemical compound [B].CCN(CC)C1=CC=CC=C1 KHYAFFAGZNCWPT-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-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
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009905 homogeneous catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- QBZUNIPJVKAQQC-XQRVVYSFSA-N methyl (z)-3-amino-4-methylpent-2-enoate Chemical compound COC(=O)\C=C(/N)C(C)C QBZUNIPJVKAQQC-XQRVVYSFSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- LCCNCVORNKJIRZ-UHFFFAOYSA-N parathion Chemical compound CCOP(=S)(OCC)OC1=CC=C([N+]([O-])=O)C=C1 LCCNCVORNKJIRZ-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- ROSKZJGILXBSFM-UHFFFAOYSA-N pyrimidin-2-ylmethanamine Chemical compound NCC1=NC=CC=N1 ROSKZJGILXBSFM-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux 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
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- 230000009466 transformation Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000013022 venting Methods 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
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Description
本発明は、キラルなビスジヒドロベンゾオキサホスホール配位子(BIBOP配位子)に基づく、アミンを調節可能な(amine-tunable)ルテニウム触媒の新たなファミリーに関する。この触媒は、ヘテロアリール環状ケトン類を含む、種々の高度に困難なケトン類の不斉な水素化及び移動水素化(transfer hydrogenation)に有用である。
ケトン類の不斉還元は、鏡像異性的に純粋なアルコール類、特にヘテロ環を有するそれらの調製のための、製薬工業において鍵となる変換である(例えば、The handbook of Homogeneous Hydrogenation (Eds.: J. G. De Vries, C. J. Elsevier), Willey-VCH, Weinheim, 2007;及びC. Hedberg, in Modern Reduction Methods (Eds.: P. G. Andersson, I. J. Munslow), WILEY-VCH, Weinheim, 2008, pp. 109-134を参照)。野依及びその共同研究者らが開発したキラルなRuCl2(ジホスフィン)(ジアミン)錯体は、広範なケトン類の高効率不斉水素化を触媒し、対応するアルコール類を与える(例えば、T. Ohkuma et al., J. Am. Chem. Soc. 1995, 117, 2675-2676;H. Doucet et al., Angew. Chem. Int. Ed. 1998, 37, 1703-1707;及びT. Ohkuma et al., J. Am. Chem. Soc. 1998, 120, 13529-13530を参照)。文献に記載されている多彩な触媒(例えば、K. Mikami et al., Angew. Chem. Int. Ed. 1999, 38, 495-497;M. J. Burk et al., Org. Lett. 2000, 2, 4173-4176;及びJ. Wu et al., Chem. Eur. J. 2003, 9, 2963-2968を参照)にもかかわらず、わずかなルテニウム触媒しか、1−テトラロン類のような環状ケトン類を水素化することができなかった(例えば、T. Ohkuma et al., Org. Lett. 2004, 6, 2681-2683;及びT. Touge et al., J. Am. Chem. Soc. 2011, 133, 14960-14963を参照)。更に、ヘテロアリール環状ケトン類の水素化の例は極めて稀である。本発明者らの知る限り、報告されている唯一のヘテロアリール環状ケトンの不斉水素化は、4,5,6,7−テトラヒドロフラン−4−オンの還元のための、天然マンニトールから誘導された1,4−ジアミンを用いたRu−BINAP錯体を利用していた(T. Ohkuma et al, Org. Lett. 2004, 6, 2681-2683を参照)。
したがって、不斉水素化、例えばスキーム1に示すようなものを行うためのより効率的な方法に対する需要が存在する。
本発明は、ルテニウム化合物を用いてケトン類の不斉還元を行う方法(「本発明の方法」)に関する。本発明はまた、本発明の方法を実施するのに有用な、新規なルテニウム化合物(「本発明の化合物」)に関する。
一つの実施態様(実施態様1)において、本発明は、式(Ia)及び(Ib):
[式中;
R1は、共に同一であり、−H、−CH3及び−OCH3より選択され;
下記式:
で示される部分は、下記化合物4、5、6、7、8、9、及び12:
よりなる群より選択されるジアミン配位子を示す]
で示されるルテニウム化合物に関する。
先に述べたように、本発明者らは、本発明の新規なルテニウム化合物が、キラルなアルコール類をもたらす、ケトン類の不斉水素化(本発明の方法)を行うための触媒として有用であることを見出した。典型的には、少なくとも約90%のケトンをアルコールに変換し、より好ましくは、少なくとも約95%のケトンをアルコールに変換し、最も好ましくは、少なくとも約99%のケトンをアルコールに変換する。
前記式Y1で示されるケトン及び対応する式X1で示されるキラルなアルコールは、下記:
に定義される通りであり、
該ルテニウム化合物は、
(a)R1が−OCH3であり、前記ジアミン配位子が化合物12である、実施態様1と同義の式(Ia)で示される化合物;又は
(b)R1が−OCH3であり、前記ジアミン配位子が化合物4、5、6及び7である、実施態様1と同義の式(Ib)で示される化合物
である、方法に関する。
前記式Y2で示されるケトン及び対応する式X2で示されるキラルなアルコールは、下記:
に定義される通りであり、
該ルテニウム化合物は、
(a)R1が−CH3であり、前記ジアミン配位子が化合物5である、実施態様1と同義の式(Ia)で示される化合物;
(b)R1が−OCH3であり、前記ジアミン配位子が化合物8、9若しくは12である、実施態様1と同義の式(Ia)で示される化合物;又は
(c)R1が−H若しくは−CH3であり、前記ジアミン配位子が化合物8である、実施態様1と同義の式(Ib)で示される化合物
である、方法に関する。
前記式Y3で示されるケトン及び対応する式X3で示されるキラルなアルコールは、下記:
に定義される通りであり、
該ルテニウム化合物は、
(a)R1が−OCH3であり、前記ジアミン配位子が化合物12である、実施態様1と同義の式(Ib)で示される化合物;又は
(b)R1が−OCH3であり、前記ジアミン配位子が化合物4、5、6及び7である、実施態様1と同義の式(Ia)で示される化合物
である、方法に関する。
前記式Y4で示されるケトン及び対応する式X4で示されるキラルなアルコールは、下記:
に定義される通りであり、そして、
該ルテニウム化合物は、
(a)R1が−CH3であり、前記ジアミン配位子が化合物5である、実施態様1と同義の式(Ib)で示される化合物;
(b)R1が−OCH3であり、前記ジアミン配位子が化合物8、9若しくは12である、実施態様1と同義の式(Ib)で示される化合物;又は
(c)R1が−H若しくは−CH3であり、前記ジアミン配位子が化合物8である、実施態様1と同義の式(Ia)で示される化合物
である、方法に関する。
[式中、R1は実施態様1で定義される通りである]で示される対応するプレ触媒(precatalysts)を、実施態様1と同義の式4、5、6、7、8、9又は12で示される適切な配位子と反応させることにより、インサイチューで調製することもできることが理解されよう。本明細書で使用する用語「単離された」は、本発明の方法におけるRu化合物及びその使用に関するものである場合、該Ru化合物が、使用前において、未反応の式(Va)又は(Vb)の化合物及びジアミン配位子から、実質的に分離されていることを意味する。
式(Va)で示される化合物を、前記式4で示されるジアミン配位子と反応させて、本発明の化合物を提供する工程;
式(Vb)で示される化合物を、前記式4で示されるジアミン配位子と反応させて、本発明の化合物を提供する工程;
式(Va)で示される化合物を、前記式5で示されるジアミン配位子と反応させて、本発明の化合物を提供する工程;
式(Vb)で示される化合物を、前記式5で示されるジアミン配位子と反応させて、本発明の化合物を提供する工程;
式(Va)で示される化合物を、前記式6で示されるジアミン配位子と反応させて、本発明の化合物を提供する工程;
式(Vb)で示される化合物を、前記式6で示されるジアミン配位子と反応させて、本発明の化合物を提供する工程;
式(Va)で示される化合物を、前記式7で示されるジアミン配位子と反応させて、本発明の化合物を提供する工程;
式(Vb)で示される化合物を、前記式7で示されるジアミン配位子と反応させて、本発明の化合物を提供する工程;
式(Va)で示される化合物を、前記式8で示されるジアミン配位子と反応させて、本発明の化合物を提供する工程;
式(Vb)で示される化合物を、前記式8で示されるジアミン配位子と反応させて、本発明の化合物を提供する工程;
式(Va)で示される化合物を、前記式9で示されるジアミン配位子と反応させて、本発明の化合物を提供する工程;
式(Vb)で示される化合物を、前記式9で示されるジアミン配位子と反応させて、本発明の化合物を提供する工程;
式(Va)で示される化合物を、前記式12で示されるジアミン配位子と反応させて、本発明の化合物を提供する工程;又は
式(Vb)で示される化合物を、前記式12で示されるジアミン配位子と反応させて、本発明の化合物を提供する工程を含む、方法に関する。
略語:
AcOH=酢酸
ampy=2−アミノメチルピリジン
amqui=8−アミノキノリン
BINAP=(R)−(+)−(1,1’−ビナフタレン−2,2’−ジイル)ビス(ジフェニルホスフィン)
i−Pr−BIMAH=2−(α−(i−プロピル)メタナミン)−1H−ベンゾイミダゾール
Xyl−BINAP=2,2’−ビス(ビス(3,5−ジメチルフェニル)ホスフィノ)−1,1’−ビナフタレン
DCM=ジクロロメタン
daipen=1,1−ビス(4−メトキシフェニル)−3−メチル−1,2−ブタンジアミン
dpen=1,2−ジフェニルエタン−1,2−ジアミン
IPA=イソプロピルアルコール
RUCYTM−XylBINAP=クロロ{(R)−(+)−2,2’−ビス[ジ(3,5−キシリル)ホスフィノ]−1,1’−ビナフチル}[1−(4−メトキシフェニル)−1−(4−メトキシフェニル−kC)−3−メチル−1,2−ブタンジアミン]ルテニウム(II)
paraphos=13−[(トリフェニルメトキシ)メチル]トリシクロ[8.2.2.24,7]ヘキサデカ−4,6,10,12,13,15−ヘキサエン−5,11−ジイル]ビス[ジフェニルホスフィン]
Xyl−Phanephos=4,12−ビス(ジ(3,5−キシリル)ホスフィノ)−[2.2]−パラシクロファン
P−phos=2,2’,6,6’−テトラメトキシ−4,4’−ビス(ジフェニルホスフィノ)−3,3’−ビピリジン
Xyl−Skewphos=2,4−ビス(ジ−3,5−キシリルホスフィノ)ペンタン
tBu=t−ブチル基
Tol=トリル基
Xyl=キシリル基
Me=メチル基
水素化の一般的手順:28の水素化は、典型的な反応手順を示すものである:1−テトラロン 28(10.0g、66.4mmol)及びRuCl2[(2R,2’R,3S,3’S)−MeO−BIBOP](amqui)27(1.0mg、0.001mmol、0.002mol%)の混合物に、イソプロパノール(40mL)及びtert−ブタノール中のt−BuOKの1M 溶液(1.33mL、1.33mmol、0.02当量)を添加した。オートクレーブ反応器を始めに窒素、次いで水素でパージし、次に反応混合物を、400psiの水素下に60℃で20時間撹拌した。水素ガスをベントした後、減圧下で溶媒を除去した。酢酸エチル/ヘキサン(0〜50%)を溶離液として用いるシリカゲルカラムクロマトグラフィーで残留物を精製すると、(R)−1,2,3,4−テトラヒドロ−1−ナフトール29(無色の油状物、9.6g、収率98%、96:4 er)を与えた。1,2,3,4−テトラヒドロ−1−ナフトールのerは、HPLC分析により測定した:カラム:Chiralcel OJ-3、4.6×150mm;溶離液:ヘプタン/イソプロパノール(95:5);流速:1mL/min;カラム温度:25℃;(R)−1,2,3,4−テトラヒドロ−1−ナフトールの保持時間(tR):7.45分(95.8%);(S)−1,2,3,4−テトラヒドロ−1−ナフトールのtR:5.75分(4.2%)
[α]D=−31.2(c=2.0、MeOH)
Claims (29)
- R1が−Hである、請求項1記載の式(Ia)又は(Ib)で示される化合物。
- R1が−CH3である、請求項1記載の式(Ia)又は(Ib)で示される化合物。
- R1が−OCH3である、請求項1記載の式(Ia)又は(Ib)で示される化合物。
- ジアミン配位子が化合物4である、請求項1記載の式(Ia)又は(Ib)で示される化合物。
- ジアミン配位子が化合物5である、請求項1記載の式(Ia)又は(Ib)で示される化合物。
- ジアミン配位子が化合物6である、請求項1記載の式(Ia)又は(Ib)で示される化合物。
- ジアミン配位子が化合物7である、請求項1記載の式(Ia)又は(Ib)で示される化合物。
- ジアミン配位子が化合物9である、請求項1記載の式(Ia)又は(Ib)で示される化合物。
- ジアミン配位子が化合物12である、請求項1記載の式(Ia)又は(Ib)で示される化合物。
- R1が−OCH3である、請求項5〜10のいずれか一項記載の式(Ia)又は(Ib)で示される化合物。
- ジアミン配位子が化合物8である、請求項1記載の式(Ia)又は(Ib)で示される化合物。
- R1が−Hである、請求項12記載の式(Ia)又は(Ib)で示される化合物。
- R1が−CH3である、請求項12記載の式(Ia)又は(Ib)で示される化合物。
- R1が−OCH3である、請求項12記載の式(Ia)又は(Ib)で示される化合物。
- 請求項1〜15のいずれか一項記載の式(Ia)で示される化合物。
- 請求項1〜15のいずれか一項記載の式(Ib)で示される化合物。
- 式X2で示されるキラルなアルコールを製造する方法であって、ルテニウム化合物の存在下に、式Y2で示されるケトンを水素と反応させる工程を含み、
式Y2で示されるケトン及び対応する式X2で示されるキラルなアルコールは、下記:
に定義される通りであり、
該ルテニウム化合物は、
(a)R1が−CH3であり、前記ジアミン配位子が化合物5である、請求項1と同義の式(Ia)で示される化合物;
(b)R1が−OCH3であり、前記ジアミン配位子が化合物8、9若しくは12である、請求項1と同義の式(Ia)で示される化合物;又は
(c)R1が−H若しくは−CH3であり、前記ジアミン配位子が化合物8である、請求項1と同義の式(Ib)で示される化合物
である、方法。 - 式X4で示されるキラルなアルコールを製造する方法であって、ルテニウム化合物の存在下に、式Y4で示されるケトンを水素と反応させる工程を含み、
式Y4で示されるケトン及び対応する式X4で示されるキラルなアルコールは、下記:
に定義される通りであり、
そして、
該ルテニウム化合物は、
(a)R1が−CH3であり、前記ジアミン配位子が化合物5である、請求項1と同義の式(Ib)で示される化合物;
(b)R1が−OCH3であり、前記ジアミン配位子が化合物8、9若しくは12である、請求項1と同義の式(Ib)で示される化合物;又は
(c)R1が−H若しくは−CH3であり、前記ジアミン配位子が化合物8である、請求項1と同義の式(Ia)で示される化合物
である、方法。 - 前記ケトンを、前記ルテニウム化合物と、水素との反応前に接触させる、請求項21〜24のいずれか一項記載の方法。
- 前記ケトンを、前記ルテニウム化合物及びtert−ブタノール中カリウムtert−ブトキシドの溶液と、水素との反応前に接触させる、請求項25記載の方法。
- 前記ケトンを、前記ルテニウム化合物、カリウムtert−ブトキシドの溶液及びイソプロパノールと、水素との反応前に接触させる、請求項26記載の方法。
- 前記ルテニウム化合物を、使用前に単離する、請求項21〜27のいずれか一項記載の方法。
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