NO148322B - CATALYST FOR ASYMMETRIC HYDROGENERATION - Google Patents
CATALYST FOR ASYMMETRIC HYDROGENERATIONInfo
- Publication number
- NO148322B NO148322B NO77770472A NO770472A NO148322B NO 148322 B NO148322 B NO 148322B NO 77770472 A NO77770472 A NO 77770472A NO 770472 A NO770472 A NO 770472A NO 148322 B NO148322 B NO 148322B
- Authority
- NO
- Norway
- Prior art keywords
- optically active
- parts
- catalyst
- mixture
- hydrogenation
- Prior art date
Links
- 239000003054 catalyst Substances 0.000 title claims description 41
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 33
- -1 rhodium coordination complex Chemical class 0.000 claims description 30
- 238000005984 hydrogenation reaction Methods 0.000 claims description 23
- 239000003446 ligand Substances 0.000 claims description 23
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000010948 rhodium Substances 0.000 claims description 12
- ZMKOZQRDFHXOIH-UHFFFAOYSA-N cyclohexyl-[(2-methoxyphenyl)methyl]-methylphosphane Chemical compound COC1=CC=CC=C1CP(C)C1CCCCC1 ZMKOZQRDFHXOIH-UHFFFAOYSA-N 0.000 claims description 9
- 229910052703 rhodium Inorganic materials 0.000 claims description 9
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 7
- WGHMKSPHCLPBTN-UHFFFAOYSA-N (2-methoxyphenyl)methyl-methyl-phenylphosphane Chemical compound COC1=CC=CC=C1CP(C)C1=CC=CC=C1 WGHMKSPHCLPBTN-UHFFFAOYSA-N 0.000 claims description 6
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 39
- 239000000203 mixture Substances 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 230000003287 optical effect Effects 0.000 description 15
- 239000001257 hydrogen Substances 0.000 description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 239000000463 material Substances 0.000 description 9
- 229910052751 metal Inorganic materials 0.000 description 9
- 239000002184 metal Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 150000001371 alpha-amino acids Chemical class 0.000 description 5
- 235000008206 alpha-amino acids Nutrition 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 150000004696 coordination complex Chemical class 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000002091 cationic group Chemical group 0.000 description 4
- 239000000460 chlorine Chemical group 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 4
- 125000004437 phosphorous atom Chemical group 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- ODTCNJWUFHCFJB-ZDUSSCGKSA-N (2s)-2-benzamido-3-(4-hydroxy-3-methoxyphenyl)propanoic acid Chemical compound C1=C(O)C(OC)=CC(C[C@H](NC(=O)C=2C=CC=CC=2)C(O)=O)=C1 ODTCNJWUFHCFJB-ZDUSSCGKSA-N 0.000 description 3
- PRBHEGAFLDMLAL-UHFFFAOYSA-N 1,5-Hexadiene Natural products CC=CCC=C PRBHEGAFLDMLAL-UHFFFAOYSA-N 0.000 description 3
- VFLJJPXIIVSKKP-UHFFFAOYSA-N 1-methoxy-2-[[methyl(phenyl)phosphoryl]methyl]benzene Chemical compound COC1=CC=CC=C1CP(C)(=O)C1=CC=CC=C1 VFLJJPXIIVSKKP-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- LMZLQYYLELWCCW-UHFFFAOYSA-N dimethoxy(phenyl)phosphane Chemical compound COP(OC)C1=CC=CC=C1 LMZLQYYLELWCCW-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- PYGSKMBEVAICCR-UHFFFAOYSA-N hexa-1,5-diene Chemical compound C=CCCC=C PYGSKMBEVAICCR-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 2
- HTDQSWDEWGSAMN-UHFFFAOYSA-N 1-bromo-2-methoxybenzene Chemical compound COC1=CC=CC=C1Br HTDQSWDEWGSAMN-UHFFFAOYSA-N 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- SSYWXIPQHQHKGX-UHFFFAOYSA-N 2-benzamido-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoic acid Chemical compound C1=C(O)C(OC)=CC(C=C(NC(=O)C=2C=CC=CC=2)C(O)=O)=C1 SSYWXIPQHQHKGX-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229960003767 alanine Drugs 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000011630 iodine Chemical group 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- JXGFKVWTMPAMLL-UHFFFAOYSA-N methyl(phenyl)phosphane;hydrochloride Chemical compound Cl.CPC1=CC=CC=C1 JXGFKVWTMPAMLL-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 2
- 235000008729 phenylalanine Nutrition 0.000 description 2
- 150000003003 phosphines Chemical class 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 150000003283 rhodium Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- VDQDYKCTFBKCBO-UHFFFAOYSA-N (2-methoxycyclohexyl)methyl-phenylphosphane Chemical compound COC1CCCCC1CPC1=CC=CC=C1 VDQDYKCTFBKCBO-UHFFFAOYSA-N 0.000 description 1
- SGVUASDJMDTSKZ-UHFFFAOYSA-N 1-[[cyclohexyl(methyl)phosphoryl]methyl]-2-methoxybenzene Chemical compound COC1=CC=CC=C1CP(C)(=O)C1CCCCC1 SGVUASDJMDTSKZ-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- RMSGQZDGSZOJMU-UHFFFAOYSA-N 1-butyl-2-phenylbenzene Chemical group CCCCC1=CC=CC=C1C1=CC=CC=C1 RMSGQZDGSZOJMU-UHFFFAOYSA-N 0.000 description 1
- SOMMFGSFLILBJJ-UHFFFAOYSA-N 2-acetamido-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoic acid;acetic acid Chemical compound CC(O)=O.COC1=CC(C=C(NC(C)=O)C(O)=O)=CC=C1O SOMMFGSFLILBJJ-UHFFFAOYSA-N 0.000 description 1
- IEMBHEXZQPUYLB-UHFFFAOYSA-N 2-cyclopentylethyl(phenyl)phosphane Chemical compound C=1C=CC=CC=1PCCC1CCCC1 IEMBHEXZQPUYLB-UHFFFAOYSA-N 0.000 description 1
- KWCCJONWEMODEY-UHFFFAOYSA-N 2-methylpropyl(propan-2-yl)phosphane Chemical compound CC(C)CPC(C)C KWCCJONWEMODEY-UHFFFAOYSA-N 0.000 description 1
- VCDUANKYHKNFSH-UHFFFAOYSA-N 4-[benzyl(phenyl)phosphanyl]-n,n-dimethylaniline Chemical compound C1=CC(N(C)C)=CC=C1P(C=1C=CC=CC=1)CC1=CC=CC=C1 VCDUANKYHKNFSH-UHFFFAOYSA-N 0.000 description 1
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 description 1
- 229940000681 5-hydroxytryptophan Drugs 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- PZZOZEXYXWZSKD-UHFFFAOYSA-N CC(C)C1C(CC2(C=CC=CC2)P(O)=O)CC(C)CC1 Chemical compound CC(C)C1C(CC2(C=CC=CC2)P(O)=O)CC(C)CC1 PZZOZEXYXWZSKD-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- NIGWMJHCCYYCSF-UHFFFAOYSA-N Fenclonine Chemical compound OC(=O)C(N)CC1=CC=C(Cl)C=C1 NIGWMJHCCYYCSF-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229910004721 HSiCl3 Inorganic materials 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- HARAJSLHEXQGPQ-UHFFFAOYSA-K [Cl-].C=CCCC=C.[Rh+3].[Cl-].[Cl-] Chemical compound [Cl-].C=CCCC=C.[Rh+3].[Cl-].[Cl-] HARAJSLHEXQGPQ-UHFFFAOYSA-K 0.000 description 1
- RTAAKNLNWIHGGX-UHFFFAOYSA-N [methoxy(methyl)phosphoryl]benzene Chemical compound COP(C)(=O)C1=CC=CC=C1 RTAAKNLNWIHGGX-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 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
- INANVXNIFVFBAR-UHFFFAOYSA-N benzyl(methyl)phosphinic acid Chemical compound CP(O)(=O)CC1=CC=CC=C1 INANVXNIFVFBAR-UHFFFAOYSA-N 0.000 description 1
- MRZIDGQXLPIADL-UHFFFAOYSA-N benzyl(phenyl)phosphane Chemical compound C=1C=CC=CC=1CPC1=CC=CC=C1 MRZIDGQXLPIADL-UHFFFAOYSA-N 0.000 description 1
- HIEDUWPOQBEHCE-UHFFFAOYSA-N benzyl-(2-methoxyphenyl)phosphane Chemical compound COC1=CC=CC=C1PCC1=CC=CC=C1 HIEDUWPOQBEHCE-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 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
- CPRXHCAKYVTPFP-UHFFFAOYSA-N butyl(ethyl)phosphane Chemical compound CCCCPCC CPRXHCAKYVTPFP-UHFFFAOYSA-N 0.000 description 1
- PVWYTIFUYYJMQO-UHFFFAOYSA-N butyl(phenyl)phosphane Chemical compound CCCCPC1=CC=CC=C1 PVWYTIFUYYJMQO-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000012018 catalyst precursor Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 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 1
- PUDIEEJVYDKCIW-UHFFFAOYSA-N cyclohexylmethyl(propan-2-yl)phosphane Chemical compound CC(C)PCC1CCCCC1 PUDIEEJVYDKCIW-UHFFFAOYSA-N 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- IMDXZWRLUZPMDH-UHFFFAOYSA-N dichlorophenylphosphine Chemical compound ClP(Cl)C1=CC=CC=C1 IMDXZWRLUZPMDH-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- BXDCELKJGGVUHD-UHFFFAOYSA-N ethyl(methyl)phosphane Chemical compound CCPC BXDCELKJGGVUHD-UHFFFAOYSA-N 0.000 description 1
- ZNOXPPRACNEBIA-UHFFFAOYSA-N ethyl(phenyl)phosphane Chemical compound CCPC1=CC=CC=C1 ZNOXPPRACNEBIA-UHFFFAOYSA-N 0.000 description 1
- HRJJVCGLLPYZNH-UHFFFAOYSA-N ethyl-(2-methylpropyl)-propan-2-ylphosphane Chemical compound CCP(C(C)C)CC(C)C HRJJVCGLLPYZNH-UHFFFAOYSA-N 0.000 description 1
- ZAZSASKTAHXEJH-UHFFFAOYSA-N ethyl-phenyl-(2,4,5-trimethylphenyl)phosphane Chemical compound C=1C(C)=C(C)C=C(C)C=1P(CC)C1=CC=CC=C1 ZAZSASKTAHXEJH-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Chemical group 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- MHERPFVRWOTBSF-UHFFFAOYSA-N methyl(phenyl)phosphane Chemical compound CPC1=CC=CC=C1 MHERPFVRWOTBSF-UHFFFAOYSA-N 0.000 description 1
- ZCCDHRRDZKZPPO-UHFFFAOYSA-N methyl(propan-2-yl)phosphane Chemical compound CPC(C)C ZCCDHRRDZKZPPO-UHFFFAOYSA-N 0.000 description 1
- CEBQGWNXQABKAI-UHFFFAOYSA-N methyl-(4-methylphenyl)-phenylphosphane Chemical compound C=1C=C(C)C=CC=1P(C)C1=CC=CC=C1 CEBQGWNXQABKAI-UHFFFAOYSA-N 0.000 description 1
- WWVAMIGSRSNKPQ-UHFFFAOYSA-N methyl-phenyl-propan-2-ylphosphane Chemical compound CC(C)P(C)C1=CC=CC=C1 WWVAMIGSRSNKPQ-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- LDCYZAJDBXYCGN-UHFFFAOYSA-N oxitriptan Natural products C1=C(O)C=C2C(CC(N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- VGARCGGLEUCMSB-UHFFFAOYSA-N phenyl(propyl)phosphane Chemical compound CCCPC1=CC=CC=C1 VGARCGGLEUCMSB-UHFFFAOYSA-N 0.000 description 1
- DHOSYPAFKOKZNK-UHFFFAOYSA-N phenyl(pyridin-2-ylmethyl)phosphane Chemical compound C=1C=CC=NC=1CPC1=CC=CC=C1 DHOSYPAFKOKZNK-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 150000002994 phenylalanines Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- MDDUHVRJJAFRAU-YZNNVMRBSA-N tert-butyl-[(1r,3s,5z)-3-[tert-butyl(dimethyl)silyl]oxy-5-(2-diphenylphosphorylethylidene)-4-methylidenecyclohexyl]oxy-dimethylsilane Chemical compound C1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C(=C)\C1=C/CP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 MDDUHVRJJAFRAU-YZNNVMRBSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 239000005052 trichlorosilane Substances 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
Landscapes
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Foreliggende oppfinnelse vedrører en katalysator av den art The present invention relates to a catalyst of that kind
som er angitt i krav l's ingress. which is stated in claim l's preamble.
'j 'j
Når et olefin, som i sin mettede form er optisk aktivt, blir hydrogenert, er det vanlige sluttproduktet optiskt inaktivt hovedsakelig fordi en ekvivalent mengde av begge enantiomor- When an olefin, which in its saturated form is optically active, is hydrogenated, the usual end product is optically inactive mainly because an equivalent amount of both enantiomers
fer (racemisk blanding) dannes. For å erholde den ønskede enantiomorf må blandingen separeres i sine optiske komponen- fer (racemic mixture) is formed. To obtain the desired enantiomorph, the mixture must be separated into its optical components
ter. Denne fremgangsmåte er arbeidskrevende og dyr, og resul- ter. This method is labor-intensive and expensive, and resul-
terer ofte i destruksjon av den uønskede enantiomorf. På often results in the destruction of the undesired enantiomorph. On
grunn av disse vanskeligheter har en økt oppmerksomhet blitt viet de asymmetriske synteser, hvorved i hovedsak en av enantiomorfene erholdes. because of these difficulties, increased attention has been devoted to asymmetric syntheses, whereby essentially one of the enantiomorphs is obtained.
Det har nå blitt funnet at utmerkede utbytter av en ønsket enantiomorf av a-aminosyrer kan erholdes av de olefiniske forbindelser som er 3-substituerte-a-aeylamido-akrylsyrer og/eller deres salter ved hydrogenering av olefinbindingen i nærvær av et nytt optisk aktivt koordinert metallkompleks som hydrogeneringskatalysator. En slik reaksjon illustreres ved hjelp av følgende ligning: It has now been found that excellent yields of a desired enantiomorph of α-amino acids can be obtained from the olefinic compounds which are 3-substituted-α-aeylamido-acrylic acids and/or their salts by hydrogenation of the olefinic bond in the presence of a new optically active coordinated metal complex as hydrogenation catalyst. Such a reaction is illustrated using the following equation:
3-substitu.enten kan eksemplifiseres ved slike grupper som hydrogen, alkyl, substituert alkyl, aryl, substituert aryl, The 3-substituent can be exemplified by such groups as hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,
aralkyl, amino, benzylamino, dibenzylamino, nitro, karbok- aralkyl, amino, benzylamino, dibenzylamino, nitro, carboxy-
syl og karboksylester, o.l.. syl and carboxyl ester, etc.
Eksempler på a-aminosyrer, hvis enantiomorfer kan hurtig fremstilles med katalysatoren ifølge nærværende oppfinnel- Examples of α-amino acids, whose enantiomorphs can be rapidly prepared with the catalyst according to the present invention
se, er alanin, p-klorfenylalanin, tryptofan, fenylalanin, 3-(3,4-dihydroksyfenyl)-alanin, 5-hydroksytryptofan, lysin, see, is alanine, p-chlorophenylalanine, tryptophan, phenylalanine, 3-(3,4-dihydroxyphenyl)-alanine, 5-hydroxytryptophan, lysine,
histidin, tyrosin, leucin, glutaminsyre og valin. histidine, tyrosine, leucine, glutamic acid and valine.
Ytterligere eksempler på forbindelser som kan hydrogeneres med foreliggende katalysator er vist i NO' pat. nr. 142. 075. Further examples of compounds which can be hydrogenated with the present catalyst are shown in NO' pat. No. 142.075.
De optisk aktive hydrogenerings-katalysatorer ifølge oppfinnelsen er løselige, koordinerte otmplekser, som inneholder et metall i kombinasjon med minst en optisk aktiv fosfin-ligand. Disse katalysatorer er løselige i reaksjonsmassen, og det refereres derfor til disse som "homogene" katalysatorer . The optically active hydrogenation catalysts according to the invention are soluble, coordinated otmplexes, which contain a metal in combination with at least one optically active phosphine ligand. These catalysts are soluble in the reaction mass, and are therefore referred to as "homogeneous" catalysts.
Fosfin-liganden kan f.eks. være av formelen AR^R^R^, hvor A The phosphine ligand can e.g. be of the formula AR^R^R^, where A
5 6 V 5 6 V
betyr fosfor og R , R og R velges uavhengig av hverandre fra gruppen bestående av hydrogen; alkyl eller alkoksy, med minst et karbonatom og maksimalt 12 karbonatomer; substituert alkyl hvorved man ved nevnte substitusjon utvelger grupper bestående av amino, karbonyl, aryl, nitro og alkoksy, hvorved nevnte alkoksy har maksimalt 4 karbonatomer; aryl; aryloksy; fenyl; substituert fenyl, hvorved man ved nevnte substitusjon utvelger grupper bestående av alkoksy og alkyl, hydroksy, aryloksy, amino og nitro, og at det ved nevnte substitusjon forekommer mindre enn 3 substituenter; cykloalkyl med minst 3 karbonatomer; substituert cykloalkyl; pyrryl; tienyl; furyl; pyridyl; piperidyl; og 3-kolesteryl. Minst en av ligandene er optisk aktiv og inneholder en o-anisylgruppe. means phosphorus and R , R and R are independently selected from the group consisting of hydrogen; alkyl or alkoxy, having at least one carbon atom and a maximum of 12 carbon atoms; substituted alkyl whereby, by said substitution, groups consisting of amino, carbonyl, aryl, nitro and alkoxy are selected, whereby said alkoxy has a maximum of 4 carbon atoms; aryl; aryloxy; phenyl; substituted phenyl, whereby in said substitution one selects groups consisting of alkoxy and alkyl, hydroxy, aryloxy, amino and nitro, and that in said substitution less than 3 substituents occur; cycloalkyl of at least 3 carbon atoms; substituted cycloalkyl; pyrryl; thienyl; furyl; pyridyl; piperidyl; and 3-cholesteryl. At least one of the ligands is optically active and contains an o-anisyl group.
Den optiske aktiviteten til katalysatoren ifølge nærværende oppfinnelse skyldes fosfin-liganden. Denne optiske aktivitet skyldes at en optisk aktiv gruppe er bundet til fosfor-atornet. The optical activity of the catalyst according to the present invention is due to the phosphine ligand. This optical activity is due to an optically active group being bound to the phosphorus atom.
Katalysatoren er særpreget ved det som er angitt i krav l's karakteriserende del. The catalyst is characterized by what is stated in the characterizing part of claim 1.
I de ovennevnte koordinerte metallkompleksformlene, behøver bare en ligand (L) å være optisk aktiv. In the above coordinated metal complex formulas, only one ligand (L) need be optically active.
Den optiske aktiviteten av liganden skyldes en optisk aktiv gruppe som er bundet til fosforatomet,og det behøver bare være én slik gruppe, og de andre to gruppene kan være like eller inaktive. I dette tilfelle behøver bare en av gruppene R 5 , R 6 eller R 7 å være optisk aktive, hvorved de resterende to grupper kan være like eller inaktive. The optical activity of the ligand is due to an optically active group that is bound to the phosphorus atom, and there only needs to be one such group, and the other two groups can be the same or inactive. In this case, only one of the groups R 5 , R 6 or R 7 needs to be optically active, whereby the remaining two groups can be the same or inactive.
Katalysatorer omfatter koordinerte metallkomplekser med ne-denstående formler. I formlene indikerer en stjerne asymmetri og således optisk aktivitet. Stjernen angir et asymmetrisk atom eller en dissymmetrisk gruppe. Som eksempel viser R at fosfor er asymmetrisk. Når ingen stjerne finnes, så indikerer dette at ingen optisk aktivitet foreligger. Catalysts comprise coordinated metal complexes with the formulas below. In the formulas, a star indicates asymmetry and thus optical activity. The asterisk indicates an asymmetric atom or a dissymmetric group. As an example, R shows that phosphorus is asymmetric. When no star is found, this indicates that there is no optical activity.
4 4
5 6 7 5 6 7
hvor A, R , R og R har tidligere angitte betydninger, og X er valgt fra gruppen bestående av hydrogen, fluor, brom, klor og jod. where A, R , R and R have previously indicated meanings, and X is selected from the group consisting of hydrogen, fluorine, bromine, chlorine and iodine.
Det fremgår av de ovenfor anførte katalysatorer at den dis-^ symmetriske gruppen kan være R<5>, R<6> eller R<7> og ikke begrenset til bare en gruppe. Dessuten kan det forekomme en kombinasjon av deler som er bundet til metallet. It appears from the catalysts listed above that the dissymmetrical group can be R<5>, R<6> or R<7> and is not limited to just one group. In addition, there may be a combination of parts that are bonded to the metal.
Det fremgår at de ovenfor angitte formler ikke' bare representerer de koordinerte metallkomplekser, som inneholder to eller tre ligander som i formlen;i RhXnL3, men at de også representerer koordinerte metallkomplekser hvori antallet ligande-metall-koordinerte bindinger er beskrevet ved antallet av L i formelen, og hvorved disse bindinger er be-stemt av ligandene av flertannet type. Selv om det f.eks. bare kan være to ligander i et spesielt koordinasjonsme-tallkompleks, vil formlen RhX^L^ fremdeles stå for komplek-set ;hvis en eller to ligander er totannet, dvs. at de gir to koordinasjonsbindinger. På samme måte representerer formlen RhXnL^ også de komplekser hvori det bare finnes en ligande nærværende, og hvis denne ligande er tretannet vil den gi tre koordinasjonsbindinger. It appears that the above-mentioned formulas not only represent the coordinated metal complexes, which contain two or three ligands as in the formula RhXnL3, but that they also represent coordinated metal complexes in which the number of ligand-metal coordinated bonds is described by the number of L in the formula, and whereby these bonds are determined by the multidentate type ligands. Although it e.g. can only be two ligands in a particular coordination metal complex, the formula RhX^L^ will still stand for the complex; if one or two ligands are bidentate, i.e. they give two coordination bonds. In the same way, the formula RhXnL^ also represents those complexes in which there is only one ligand present, and if this ligand is tridentate it will give three coordination bonds.
Substituentene på fosfor-atomene omfatter eksempelvis føl-gende: metyl, etyl, propyl, isopropyl, butyl og dets isomerer, pentyl og dets isomerer, heksyl og dets isomerer, hep-tyl og dets isomerer, oktyl og dets isomerer, nonyl og dets isomerer, desyl og dets isomerer, undesyl og dets isomerer, dodesyl og dets isomerer, cyklopropyl, cyklobutyl, cyklopen-tyl, cykloheksyl, fenyl, acetoksylfenyl, metylfenyl, etyl-fenyl, propylfenyl, butylfenyl, dimetylfenyl, trimetylfenyl, dietylfenyl, hydroksyfenyl, fenoksyfenyl, o-anisyl, 3-kolesteryl, benzyl, pyrryl, furyl, pyridyl, tienyl, piperidyl, mentyl, bornyl og pinyl. The substituents on the phosphorus atoms include, for example, the following: methyl, ethyl, propyl, isopropyl, butyl and its isomers, pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers , decyl and its isomers, undecyl and its isomers, dodecyl and its isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, acetoxyphenyl, methylphenyl, ethylphenyl, propylphenyl, butylphenyl, dimethylphenyl, trimethylphenyl, diethylphenyl, hydroxyphenyl, phenoxyphenyl, o-anisyl, 3-cholesteryl, benzyl, pyrryl, furyl, pyridyl, thienyl, piperidyl, menthyl, bornyl and pinyl.
En fortegnelse over optisk aktivt fosfin, som kan anvendes, omfatter følgende uten å være begrenset bare til disse: metyletylfosfin, metylisopropylfosfin, etylbutylfosfin, isopropyl-isobutylfosfin, metylfenylfosfin, etylfenylfosfin, propylfenylfosfin, butylfenylfosfin, fenylbenzylfosfin, fe-nylpyrrolfosfin, etylisopropylisobutylfosfin, metylfenyl-4-metylfenylfosfin, etylfenyl-4^metylfenylfosfin, metyliso-propylfenylfosfin, etylfenyl-2,4,5-trimetylfenylfosfin, fe-nylbenzyl-4-dimetylaminofenylfosfin, fenylpyridylmetylfos-fin, fenylcyklopentyletylfosfin, cykloheksylmetylisopropyl-fosfin, o-metoksyfenylmetylfenylfosfin, o-metoksyfenylcyklo-heksylmetylfosfin. A list of optically active phosphine that may be used includes, but is not limited to, methylethylphosphine, methylisopropylphosphine, ethylbutylphosphine, isopropylisobutylphosphine, methylphenylphosphine, ethylphenylphosphine, propylphenylphosphine, butylphenylphosphine, phenylbenzylphosphine, phenylpyrrolephosphine, ethylisopropylisobutylphosphine, methylphenyl-4 -methylphenylphosphine, ethylphenyl-4^methylphenylphosphine, methyliso-propylphenylphosphine, ethylphenyl-2,4,5-trimethylphenylphosphine, phenylbenzyl-4-dimethylaminophenylphosphine, phenylpyridylmethylphosphine, phenylcyclopentylethylphosphine, cyclohexylmethylisopropylphosphine, o-methoxyphenylmethylphenylphosphine, o-methoxyphenylcyclohexylmethylphosphine .
De optisk aktive fosfiner inneholder minst en fenylgruppe som har en substituent i orto.stilling, nemlig en metoksy-gruppe. Utmerkede resultater har blitt oppnådd med metyl-fenyl-o-anisylfosfin og metylcykloheksyl-o-anisylfosfin. Den sistnevnte forbindelse, fremstilt sammen med det optisk aktive koordinerte metallkomplekset som hydrogeneringskata-lysatorer er nye blandinger. Det har vist seg at de ønskede enantiomorfer av substituerte og usubstituerte fenylalaniner lett kan fremstilles med utmerket utbytte ved å anvende slike optisk aktive ligander ved fremgangsmåten ifølge oppfinnelsen . The optically active phosphines contain at least one phenyl group which has a substituent in the ortho position, namely a methoxy group. Excellent results have been obtained with methyl-phenyl-o-anisylphosphine and methylcyclohexyl-o-anisylphosphine. The latter compound, prepared together with the optically active coordinated metal complex as hydrogenation catalysts are new compounds. It has been shown that the desired enantiomorphs of substituted and unsubstituted phenylalanines can be easily prepared with excellent yield by using such optically active ligands in the method according to the invention.
Selv om bare én optisk aktiv gruppe eller ligand er nød-vendig i koordinas jonsmetall^-komplekskatalysatoren , foretrekkes det av hensyn til enkel fremstilling at alle tre ligander er de samme i ovenfor beskrevne formel RhXnL^. Det foretrekkes også at asymmetrien henføres til fosforatomet. Although only one optically active group or ligand is necessary in the coordination ion metal^ complex catalyst, it is preferred for reasons of ease of preparation that all three ligands are the same in the above-described formula RhXnL^. It is also preferred that the asymmetry be attributed to the phosphorus atom.
Kationiske koordinasjonsmetallkomplekser, som inneholder 2 ekvivalenter fosfin pr. mol rhodium og en chelat-dannende bis-olefin, kan også anvendes som katalysatorer ifølge nærværende oppfinnelse. F.eks. ved å anvende de organiske rho-diumkomplekser, som beskrevet ovenfor, kan man fremstille slike kationiske koordinasjon-rhodium-komplekser ved å til-berede en oppslemning av organisk rhodiumkompleks i en al-kohol, som f.eks. etanol, og tilsetning av 2 ekvivalenter av det optisk aktive fosfin slik at en ioneløsning dannes, hvoretter man tilsetter et egnet anion, som f.eks. tetrafluorborat, tetrafenylborat eller et eller annet anion som kan bevirke utfelling eller krystallisasjon av et fast, kat-ionisk koordinasjonsmetallkompleks, enten direkte fra løs-ningen eller etter behandling i et passende løsningsmiddel. Cationic coordination metal complexes, containing 2 equivalents of phosphine per mol rhodium and a chelating bis-olefin, can also be used as catalysts according to the present invention. E.g. by using the organic rhodium complexes, as described above, such cationic coordination rhodium complexes can be prepared by preparing a slurry of organic rhodium complex in an alcohol, such as e.g. ethanol, and adding 2 equivalents of the optically active phosphine so that an ionic solution is formed, after which a suitable anion is added, such as e.g. tetrafluoroborate, tetraphenylborate or some other anion which can cause precipitation or crystallization of a solid, cationic coordination metal complex, either directly from the solution or after treatment in a suitable solvent.
Eksempler på kationiske koordinasjonsmetallkomplekser er cyklooktadien-1,5-bis(metylcykloheksyl-o-anisylfosfin) rho-diumtetrafluorborat, cyklooktadien-1,5-bis(metyl-cykloheksyl-l-anisylfosfin) rhodium-tetrafenylborat og bicyklo-2.2.l-hepta-2,5-dien-bis(metylcykloheksyl-o-anisylfosfin)-rhodium-tetrafluorborat. Examples of cationic coordination metal complexes are cyclooctadiene-1,5-bis(methylcyclohexyl-o-anisylphosphine)rhodium tetrafluoroborate, cyclooctadiene-1,5-bis(methyl-cyclohexyl-l-anisylphosphine)rhodium tetraphenylborate and bicyclo-2.2.l-hepta -2,5-diene-bis(methylcyclohexyl-o-anisylphosphine)-rhodium tetrafluoroborate.
Det er antatt at katalysatoren i virkeligheten er nærværende som en katalysator-prekursor, og at katalysatoren ved kontakt med hydrogen omdannes til en aktiv form. Denne om-dannelse kan naturligvis utføres under den egentlige hydrogeneringen av olefinbindingen, eller den kan utføres ved å utsette katalysatoren (eller prekursoren) for hydrogen før tilsetningen til olefinmaterialet for hydrogenering. It is assumed that the catalyst is actually present as a catalyst precursor, and that the catalyst is converted into an active form on contact with hydrogen. This conversion can of course be carried out during the actual hydrogenation of the olefin bond, or it can be carried out by exposing the catalyst (or precursor) to hydrogen prior to addition to the olefin material for hydrogenation.
Hydrogeneringsreaksjoner utføres vanligvis i et løsnings-middel, som f.eks. benzen, etanol, toluen, cykloheksan, og blandinger av disse løsningsmidler. Et nesten hvilket som helst løsningsmiddel av aromatisk eller mettet alkan eller cykloalkan, og som er inaktivt overfor hydrogeneringsbe-tingelsene under reaksjonen , kan anvendes. Hydrogenation reactions are usually carried out in a solvent, such as e.g. benzene, ethanol, toluene, cyclohexane, and mixtures of these solvents. Almost any solvent of aromatic or saturated alkane or cycloalkane, and which is inactive to the hydrogenation conditions during the reaction, can be used.
Som ovenfor nevnt blir katalysatoren tilsatt løsningsmidlet enten som en forbindelse pr. se eller i form av dens komponenter som deretter danner katalysatoren in situ. Når katalysatoren tilsettes i form av dens komponenter, kan den tilsettes før eller samtidig med den 3-substituerte a-acylamido-akrylsyren. Komponenter for fremstilling av katalysatoren in situ er løselige metallforbindelser og optisk aktiv fosfin-ligand. As mentioned above, the catalyst is added to the solvent either as a compound per see or in the form of its components which then form the catalyst in situ. When the catalyst is added in the form of its components, it can be added before or simultaneously with the 3-substituted α-acylamido-acrylic acid. Components for producing the catalyst in situ are soluble metal compounds and optically active phosphine ligand.
Katalysatoren kan anvendes i en katalytisk virksom mengde, hvilken vanligvis ligger i området fra ca. 0,0001% til ca. 5 vekt-% metallinnhold basert på 3_substituert-a-acylamido-akrylsyre og/eller innholdet av dennes salter. The catalyst can be used in a catalytically effective amount, which is usually in the range from approx. 0.0001% to approx. 5% by weight metal content based on 3_substituted-α-acylamido-acrylic acid and/or the content of its salts.
Som tidligere nevnt har det blitt funnet at den asymmetriske hydrogeneringen forsterkes i nærvær av en base ireak--sjonsmassen. Selv om den asymmetriske hydrogeneringen kan utføres i en reaksjonsmasse som er fri for base, og selv om den kan utføres under sure betingelser, så forsterkes hydrogeneringen ved tilsetning av små mengder, og som kan oppgå til en ekvivalent, basisk materiale pr. mol akrylsyre. Det er overraskende at en liten mengde tilsatt basisk materiale til selv en sur reaksjonsmasse, vil resultere i en forsterket asymmetrisk hydrogenering, og i virkeligheten er det funnet at dannelsen av en liten mengde salt av akrylsyre er tilstrekkelig for å oppnå disse forbedrede resultater . As previously mentioned, it has been found that the asymmetric hydrogenation is enhanced in the presence of a base in the reaction mass. Although the asymmetric hydrogenation can be carried out in a reaction mass that is free of base, and even if it can be carried out under acidic conditions, the hydrogenation is enhanced by the addition of small amounts, which can amount to one equivalent basic material per moles of acrylic acid. It is surprising that a small amount of basic material added to even an acidic reaction mass will result in an enhanced asymmetric hydrogenation, and in fact it has been found that the formation of a small amount of salt of acrylic acid is sufficient to achieve these improved results.
En del baser som kan anvendes er tertiære baser, som f.eks. trietylamin, NaOH, og nesten et hvilket som helst basisk materiale som kan danne et salt med karboksylsyrene. Some bases that can be used are tertiary bases, such as e.g. triethylamine, NaOH, and almost any basic material that can form a salt with the carboxylic acids.
Etter tilsetning av komponentene til løsningsmidlet, tilsettes hydrogen til blandingen, inntil ca. 1 til ca. 5 ganger molmengden av 3-substituert-a-acylamido-akrylsyre, eller i et mengdeforhold som er nødvendig for å fullføre hydrogeneringen til det ønskete punkt. Reaksjonssystemets trykk vil nødvendigvis variere beroende på typen 3-substituert-—a-acylamido-akrylsyre, katalysatortype, hydrogene-ringsapparaturens størrelse, komponentenes mengdeforhold og mengde løsningsmiddel og/eller base. Lavere trykk, som omfatter atmosfærisk eller subatmosfærisk trykk, kan anvendes såvel som høyere trykk. After adding the components to the solvent, hydrogen is added to the mixture, until approx. 1 to approx. 5 times the molar amount of 3-substituted-α-acylamido-acrylic acid, or in an amount ratio necessary to complete the hydrogenation to the desired point. The pressure of the reaction system will necessarily vary depending on the type of 3-substituted-α-acylamido-acrylic acid, catalyst type, the size of the hydrogenation apparatus, the ratio of the components and the amount of solvent and/or base. Lower pressures, including atmospheric or subatmospheric pressure, can be used as well as higher pressures.
Reaksjonstemperaturene kan ligge i området rundt ca. -20°C til ca. 110°C. Høyere temperaturer kan anvendes, men er normalt ikke nødvendig og kan lede til en økning av bireak-sjoner. The reaction temperatures can be in the range of approx. -20°C to approx. 110°C. Higher temperatures can be used, but are not normally necessary and can lead to an increase in side reactions.
Etter å ha fullført reaksjonen, hvilket bestemmes ved hjelp av konvensjonelle metoder, fjernes løsningsmidlet, og pro-duktene og katalysatoren separeres ved hjelp av konvensjonelle metoder. After completion of the reaction, as determined by conventional methods, the solvent is removed and the products and catalyst are separated by conventional methods.
Ønskede enantiomorfer av a-aminosyrene kan fremstilles ved hydrogenering av den passende [3-substituerte-a-acylamido-akrylsyren ifølge nærværende oppfinnelse, hvoretter man fjerner acylgruppen fra ct-amino- og andre blokkeringsgrup-per ved konvensjonelle metoder, for derved å erholde den ønskede enantiomorfe forbindelse. Desired enantiomorphs of the α-amino acids can be prepared by hydrogenation of the appropriate [3-substituted-α-acylamido-acrylic acid according to the present invention, after which the acyl group is removed from α-amino and other blocking groups by conventional methods, thereby obtaining the desired enantiomorphic compound.
Det har blitt funnet at a-aminosyrer fremstilt av p-substituert-a-acylamido-akrylsyrer og/eller deres salter lett kan fremstilles med en stor overvekt av den ønskede enantiomorfe forbindelse. Derved blir nærværende katalysator spesielt verdifull. It has been found that α-amino acids prepared from β-substituted-α-acylamido-acrylic acids and/or their salts can be readily prepared with a large predominance of the desired enantiomorphic compound. Thereby, the present catalyst becomes particularly valuable.
Følgende eksempler skal illustrere oppfinnelsen. I det føl-gende betyr "deler" vektsdeler hvis ikke annet sies. I eksemplene bestemmes % optisk renhet ved hjelp av følgende ligning, (de optiske aktiviteter som uttrykkes som spesifikke rotasjoner måles i samme løsningsmiddel): The following examples shall illustrate the invention. In the following, "parts" means parts by weight unless otherwise stated. In the examples, % optical purity is determined using the following equation, (the optical activities expressed as specific rotations are measured in the same solvent):
EKSEMPEL 1 EXAMPLE 1
De optiske aktive fosfiner kan fremstilles ifølge fremgangs- , måten til Mislow og Korpiun, J. Am. Chem. Soc. 89, 4784 The optically active phosphines can be prepared according to the procedure of Mislow and Korpiun, J. Am. Chem. Soc. 89, 4784
(1967). (1967).
Til en egnet beholder utstyrt med en røreanordning, et tem-peraturmålingsinstrument og en materialbeskiktningsanord-ning, ble det tilsatt 250 deler fenyldiklorfosfin, 240 deler pyridin og 49 5 deler heksan. Løsningen ble avkjølt To a suitable container equipped with a stirring device, a temperature measuring instrument and a material coating device, 250 parts of phenyldichlorophosphine, 240 parts of pyridine and 495 parts of hexane were added. The solution was cooled
til ca. 5 - 10°C og en blanding som besto av 96 deler metanol og 27 deler heksan ble tilsatt under omrøring og under en periode på ca. 1 - 1/2 time. Den erhddte blandingen ble ytterligere omrørt 2 - 1/2 time under oppvarmning til ca. 25°C. Deretter fant reaksjonen sted i en inert nitrogenatmosfære. to approx. 5 - 10°C and a mixture consisting of 96 parts methanol and 27 parts hexane was added with stirring and over a period of approx. 1 - 1/2 hour. The hardened mixture was further stirred for 2 - 1/2 hours while heating to approx. 25°C. The reaction then took place in an inert nitrogen atmosphere.
Pyridinhydroklorid, som ble dannet under reaksjonen, ble fjernet ved filtrering, og filtratet ble oppkonsentrert. Den gule resten ble destillert under oppsamling av en ved 95,5-97°C/17 mm kokende fargeløs fraksjon (82% utbytte dimetylfenylfosfonitt). [Harwood and Grisley, J. Am. Chem. Soc, 82, 423 (1960)]. Pyridine hydrochloride, which was formed during the reaction, was removed by filtration, and the filtrate was concentrated. The yellow residue was distilled collecting a colorless fraction boiling at 95.5-97°C/17 mm (82% yield dimethylphenylphosphonite). [Harwood and Grisley, J. Am. Chem. Soc, 82, 423 (1960)].
Til en egnet beholder som var utstyrt med en røreanordning, et temperaturmåleinstrument og materialbeskikningsanordnin-ger ble tilført 11 deler dimetylfenylfosfonitt, 2,5 deler metyljodid og 9 deler toluen. Den erholdte løsningen ble oppvarmet langsomt. Reaksjonen er eksoterm og temperaturen øker fra ca. 110°C, reaksjonsblandingen holdes ved en temperatur på ca. 100-120°C og ytterligere 185 deler dimetylfenylfosfonitt tilsettes langsomt. Ytterligere mengder metyl jodid, dvs. mengdeøkninger på ca. 1 del, tilsettes.lei-lighetsvis under f osf onitt-tilsetningen. Reaks jonsblandin-gen ble holdt ved ca. 110°C ytterligere 1 time fulgt av tilsetning av komponentene. Reaksjonsblandingen ble deretter destillert, og fraksjonen som kokte ved 148-149°C/17 mm ble oppsamlet. (96% utbytte metylfenylmetylfosfinat.) 11 parts of dimethylphenylphosphonite, 2.5 parts of methyl iodide and 9 parts of toluene were added to a suitable container which was equipped with a stirring device, a temperature measuring instrument and material deposition devices. The resulting solution was heated slowly. The reaction is exothermic and the temperature increases from approx. 110°C, the reaction mixture is kept at a temperature of approx. 100-120°C and a further 185 parts of dimethylphenylphosphonite are added slowly. Additional quantities of methyl iodide, i.e. quantity increases of approx. 1 part, is added, if necessary, during the phosphate addition. Reak's ion mixture was kept at approx. 110°C for a further 1 hour followed by addition of the components. The reaction mixture was then distilled, and the fraction boiling at 148-149°C/17 mm was collected. (96% yield methylphenylmethylphosphinate.)
[Harwood and Grisley J. Am. Chem. Soc, 82, 423 (1960)]. [Harwood and Grisley J. Am. Chem. Soc, 82, 423 (1960)].
Til en egnet beholder utstyrt med en røreanordning, en kon-densasjonsanordning, temperaturmåleinstrument og en matet1 rialbeskikningsanordning, ble tilsatt 187 deler metylfenyl-metylf osf inat og 1600 deler karbontetraklorid. Til denne blandingen ble det tilsatt 229 deler fosforpentaklorid for-delt på tre porsjoner på hver 50 deler og en porsjon på 79 deler. En temperaturøkning ble iakttatt under tilsetningen av de første tre porsjoner. Blandingen ble omrørt ved ca. 60°C to timer, og deretter ble karbontetraklorid og fos-foroksyklorid fjernet ved destillasjon. Resten ble destillert og fraksjonen som kokte ved 138-141°C/17 mm ble oppsamlet (95% utbytte metylfenylfosfinklorid). [Metode ifølge organisk kjemi (Houben-Weyl) vol. XII/I, s. 243], To a suitable container equipped with a stirring device, a condensing device, a temperature measuring instrument and a material-dispensing device, 187 parts of methylphenyl-methylphosphinate and 1600 parts of carbon tetrachloride were added. To this mixture was added 229 parts of phosphorus pentachloride divided into three portions of 50 parts each and one portion of 79 parts. A temperature rise was observed during the addition of the first three portions. The mixture was stirred at approx. 60°C for two hours, and then carbon tetrachloride and phosphorus oxychloride were removed by distillation. The residue was distilled and the fraction boiling at 138-141°C/17 mm was collected (95% yield methylphenylphosphine chloride). [Method according to organic chemistry (Houben-Weyl) vol. XII/I, p. 243],
Til en egnet beholder utstyrt med en røreanordning, en kon-densasjonsanordning, et temperaturmåleinstrument og en materialbeskikningsanordning, ble det tilsatt 78 deler 1-mentol Ua]^<5> = -50° i etanol) og 72 deler dietyleter. Til den erholdte løsning ble det tilsatt 119 deler trietylamin, og den erholdte blandingen ble avkjølt ved ca. 0°C. Til denne blandingen ble det under omrøring tilsatt 87 deler metylfenylfosfinklorid over en tidpseriode på ca. 1 - 1/2 time og ved en temperatur på ca. 0°C. Blandingen fikk opp-varmes til ca. 25°C og ble deretter oppvarmet under tilba-keløp ca. 10 - 1/2 time. To a suitable vessel equipped with a stirring device, a condensing device, a temperature measuring instrument and a material deposition device, 78 parts of 1-menthol (Ua]^<5> = -50° in ethanol) and 72 parts of diethyl ether were added. 119 parts of triethylamine were added to the resulting solution, and the resulting mixture was cooled at approx. 0°C. To this mixture, 87 parts of methylphenylphosphine chloride were added with stirring over a time period of approx. 1 - 1/2 hour and at a temperature of approx. 0°C. The mixture was allowed to heat up to approx. 25°C and was then heated under reflux for approx. 10 - 1/2 hour.
For å fjerne trietylaminhydrokloridet ble blandingen filtrert og filtratet oppkonsentrert. Det konsentrerte filtratet ga et fast stoff-utbytte som smeltet ved 50-65°C, og som utgjør en blanding diastereoisomerer av 1-mentyl-me-tylfenylfosfinat (60% S og 40% R). To remove the triethylamine hydrochloride, the mixture was filtered and the filtrate concentrated. The concentrated filtrate gave a solid yield melting at 50-65°C, which is a mixture of diastereoisomers of 1-menthyl-methylphenylphosphinate (60% S and 40% R).
Den ovenfor fremstilte blandingen diastereoisomerer av 1-mentylmetylfenylfosfinat ble renset ved krystallisasjon mange ganger i heksan fulgt av krystallisasjon i dietyleter og ga et fast stoff som smelter ved 78 - 82°C, og som foreligger i S form av 1-JTientyl-metylf enylfosf inat, The above-prepared mixture of diastereoisomers of 1-menthylmethylphenylphosphinate was purified by crystallization several times in hexane followed by crystallization in diethyl ether and gave a solid melting at 78-82°C, which is in the S form of 1-Jthientylmethylphenylphosphinate ,
Til en egnet beholder utstyrt med en rør,eanordni-ng, tempe-raturmåleinstrument, materialbeskikningsanordning pg kon-densator, ble det under en inert nitrogenatmosfære tilsatt 18,3 deler magnesiumspon, 13 deler dietyleter og en for igangsettelsen av reaksjonen nødvendig mengde jod. En mindre mengde o-anisylbromid ble tilsatt for å starte reaksjonen, og deretter ble en blanding bestående av 138 deler o-bromanisol og 400 deler dietyleter tilsatt så langsomt at et passende tilbakeløp av reaksjonsblandingen kunne holdes. Etter at blandingen var tilsatt alt ble den holdt under til-bakeløp ytterligere 2 timer. Under an inert nitrogen atmosphere, 18.3 parts of magnesium shavings, 13 parts of diethyl ether and an amount of iodine necessary for the initiation of the reaction were added to a suitable container equipped with a tube, device, temperature measuring instrument, material deposition device and condenser. A small amount of o-anisyl bromide was added to start the reaction, and then a mixture consisting of 138 parts of o-bromoanisole and 400 parts of diethyl ether was added so slowly that a suitable reflux of the reaction mixture could be maintained. After the mixture was all added, it was kept under reflux for a further 2 hours.
Til denne blandingen ble det tilsatt en blanding bestående av 74 deler av enten R- eller S-formen av 1-mentyl-metyl-fenylfosfinat (valget av S- eller R-formen avhenger av den enantiomorf som ønskes etter den asymmetriske hydrogeneringen) og 450 deler benzen. Dietyleteren ble deretter fjernet og den erholdte blandingen oppvarmet 64 timer ved 78°C. To this mixture was added a mixture consisting of 74 parts of either the R or S form of 1-menthyl-methyl-phenylphosphinate (the choice of the S or R form depends on the enantiomorph desired after the asymmetric hydrogenation) and 450 splits benzene. The diethyl ether was then removed and the resulting mixture heated for 64 hours at 78°C.
Reaksjonsproduktet av magnesiumkomplekset ble dekomponert The reaction product of the magnesium complex was decomposed
i en løsning av ammoniumklorid, og produktet ekstrahert fra den vandige fase med benzen. Etter fjerning av benzen ble restoljen destillert, hvorved man etter en forfraksjon bestående av mentol erholdt et produkt med kokepunkt fra 180 in a solution of ammonium chloride, and the product extracted from the aqueous phase with benzene. After removal of benzene, the residual oil was distilled, whereby, after a pre-fraction consisting of menthol, a product with a boiling point of 180
- 190°C ved 0,5 mm trykk. Det rå metylfenyl-o-anisylfosfin-oksydet ble erholdt med 60%'ig utbytte. Ved å anvende R-formen erholdt man et produkt med en spesifikk rotasjon [a]^5= +27° (metanol). Ved å anvende S-formen erholdt man et produkt med den motsatt rotasjon. - 190°C at 0.5 mm pressure. The crude methylphenyl-o-anisylphosphine oxide was obtained in 60% yield. By using the R form, a product was obtained with a specific rotation [a]^5= +27° (methanol). By using the S shape, a product with the opposite rotation was obtained.
Til en egnet beholder utstyrt med røreanordning, temperaturmåleinstrument og en materialbeskikningsanordning, ble det under inert nitrogenatmosfære tilsatt 16 deler triklor-silan og 100 deler benzen ved ca. 5°C. Til denne blandingen ble det ved 4 - 6°C tilsatt en blanding av 12 deler trietylamin og 50 deler benzen. Den erholdte blandingen ble oppvarmet til 70°C og en blanding bestående av 7,5 deler optisk aktiv metylfenyl-o-anisylfosfinoksyd i 30 deler benzen ble tilsatt. Blandingen ble oppvarmet til 70°C 1 time og deretter avkjølt til 25°C. Under an inert nitrogen atmosphere, 16 parts of trichlorosilane and 100 parts of benzene were added to a suitable container equipped with a stirring device, a temperature measuring instrument and a material coating device at approx. 5°C. A mixture of 12 parts triethylamine and 50 parts benzene was added to this mixture at 4 - 6°C. The resulting mixture was heated to 70°C and a mixture consisting of 7.5 parts of optically active methylphenyl-o-anisylphosphine oxide in 30 parts of benzene was added. The mixture was heated to 70°C for 1 hour and then cooled to 25°C.
Reaksjonsproduktet bestående av silikonkomplekset ble dekomponert ved tilsetning under nitrogenatmosfære av 75 deler 20%'ig natriumhydroksyd ved 25°C under kjøling. Fra det organiske sjiktet erholdt man det ønskede metylfenyl-o-anisylfosfin, som hadde en spesifikk rotasjon [a]^ = +41° (metanol) når det ovennevnte fremstilte fosfinoksyd med en spesxfikk rotasjon [a]D 25 +27 o (metanol) ble anvendt. Med det motsatt enantiomorfe fosfinoksyd ble et fosfin med motsatt rotasjon erholdt. The reaction product consisting of the silicone complex was decomposed by addition under a nitrogen atmosphere of 75 parts of 20% sodium hydroxide at 25°C under cooling. From the organic layer, the desired methylphenyl-o-anisylphosphine was obtained, which had a specific rotation [a]^ = +41° (methanol) when the above-mentioned produced phosphine oxide with a specific rotation [a]D 25 +27 o (methanol) was applied. With the opposite enantiomorphic phosphine oxide, a phosphine with opposite rotation was obtained.
EKSEMPEL 2 EXAMPLE 2
Fremstilling av metylcykloheksyl- o- anisylfosfin Preparation of methylcyclohexyl-o-anisylphosphine
Til en 1 liter autoklav ble det tilsatt 143 deler (+)-metylf enyl-o-anisylfosfinoksyd (fremstilt ifølge ovennevnte), 28 deler 5%'ig rhodium på karbon og 250 deler metanol. Satsen ble oppvarmet til 75°C og omrørt under 56 kg/cm<2> hydrogen. Etter avsluttet hydrogenopptagelse viste nmr-analyser at reaksjonen, som illustreres ved ovennevnte ligning, var 75% fullstendig. Ytterligere 7,0 deler katalysator ble tilsatt, hvoretter et trykk tilsvarende 56 kg/cm 2 ble pålagt og satsen fikk gå til 96% reaksjon. To a 1 liter autoclave were added 143 parts of (+)-methylphenyl-o-anisylphosphine oxide (prepared according to the above), 28 parts of 5% rhodium on carbon and 250 parts of methanol. The batch was heated to 75°C and stirred under 56 kg/cm<2> of hydrogen. After completion of hydrogen absorption, nmr analyzes showed that the reaction, which is illustrated by the above-mentioned equation, was 75% complete. A further 7.0 parts of catalyst were added, after which a pressure corresponding to 56 kg/cm 2 was applied and the batch allowed to go to 96% reaction.
Katalysatoren ble filtrert og metanol fjernet i vakuum. Rå-oljen ble opptatt i 200 deler dibutyleter og avkjølt til 0°C. Krystallene, som ble separert, ble filtrert og vasket med heksan. Det ble erholdt 6 3 deler metylcykloheksyl-o-anisylf osf inoksyd , som smelter ved 108-110°Cog som har en The catalyst was filtered and methanol removed in vacuo. The crude oil was taken up in 200 parts of dibutyl ether and cooled to 0°C. The crystals, which were separated, were filtered and washed with hexane. 6 3 parts of methylcyclohexyl-o-anisyl phosphine oxide were obtained, which melts at 108-110°C and has a
20 20
spesifikk rotasjon [a]D = +63 (metanol). specific rotation [a]D = +63 (methanol).
Det ovenstående fosfinoksydet kan reduseres til metylcykloheksyl-o-anisylf osf in med 95%'ig utbytte ved å anvende HSiCl3 og trietylamin, og som er beskrevet tidligere for metylfenyl-o-anisylfosfin. Det resulterende metylcykloheksyl-o-anisylf osf inet er en løsning med den spesifikke ro-20 The above phosphine oxide can be reduced to methylcyclohexyl-o-anisylphosphine with a 95% yield by using HSiCl3 and triethylamine, and which was described earlier for methylphenyl-o-anisylphosphine. The resulting methylcyclohexyl-o-anisylphosphine is a solution with the specific ro-20
tasjon [ct]<Dw> = +98,5° (metanol). tation [ct]<Dw> = +98.5° (methanol).
EKSEMPEL 3 EXAMPLE 3
Asymmetrisk hydrogenering av a- benzamido- 4- hydroksy- 3-cinnaminsyre Asymmetric hydrogenation of a-benzamido-4-hydroxy-3-cinnamic acid
Til en hydrogeneringsapparatur utstyrt med en trykkmåler, temperaturmåleinstrument og oppvarmningsanordning, ble det tilsatt 25 deler <x-benzamido-4-hydroksy-3-metoksy-cinna-minsyre og 186 deler metanol og 64 deler 5%'ig natriumhydroksyd. Satsen ble omhyggelig spylt for å fjerne ethvert spor av luft, og til slutt ble trykket regulert til 3,5 kg/cm med hydrogen ved 25°C. To a hydrogenation apparatus equipped with a pressure gauge, temperature measuring instrument and heating device, 25 parts of <x-benzamido-4-hydroxy-3-methoxy-cinnamic acid and 186 parts of methanol and 64 parts of 5% sodium hydroxide were added. The batch was carefully purged to remove any trace of air and finally the pressure was regulated to 3.5 kg/cm with hydrogen at 25°C.
En katalysatorløsning ble tilberedt ved å oppløse 0,0059 g rhodium-1,5-heksadienklorid ([Rh(1,5-heksadien)Cl]2) J.Am. Chem.Soc. 86, 217 (1964) i 2 ml benzen under nitrogenatmosfære. Deretter ble 0,0139 g (+)-metylfenyl-o-anisylfosfin i 1,3 ml benzen tilsatt. Deretter fikk hydrogen strøm-me gjennom blandingen 5 minutter. Den erholdte katalysator-løsningen ble deretter trykket inn i en autoklav ved hjelp av hydrogentrykk. Hydrogeneringen starter med en gang og er fullført etter 3-4 timer ved 25°C og 3,5 kg/cm<2>. A catalyst solution was prepared by dissolving 0.0059 g of rhodium-1,5-hexadiene chloride ([Rh(1,5-hexadiene)Cl] 2 ) J. Am. Chem.Soc. 86, 217 (1964) in 2 ml of benzene under a nitrogen atmosphere. Then 0.0139 g of (+)-methylphenyl-o-anisylphosphine in 1.3 ml of benzene was added. Hydrogen was then allowed to flow through the mixture for 5 minutes. The resulting catalyst solution was then pressed into an autoclave using hydrogen pressure. The hydrogenation starts immediately and is completed after 3-4 hours at 25°C and 3.5 kg/cm<2>.
En prøve av den erholdte løsningen viser en optisk renhet på 56,4 %, og dette tilsvarer 78/22 L/D-blanding av natri-umsaltet til N-benzoyl-3-(4-hydroksy-3-metoksyfenyl)-alanin . A sample of the solution obtained shows an optical purity of 56.4%, and this corresponds to a 78/22 L/D mixture of the sodium salt of N-benzoyl-3-(4-hydroxy-3-methoxyphenyl)-alanine.
Den N-benzoylsubstituerte aminosyren kan erholdes ved 95%'ig utbytte ved å fordampe bort metanolen og nøytralisere na-triumsaltet med saltsyre. The N-benzoyl-substituted amino acid can be obtained in 95% yield by evaporating off the methanol and neutralizing the sodium salt with hydrochloric acid.
Den erholdte L-enantiomorf kan omdannes til L-D0PA ved hjelp av enkel hydrolyse, som derved fjerner de blokkerende grupper, benzoyl og metyl i 3-substitusjonsstilling i fenyl. The obtained L-enantiomorph can be converted to L-DOPA by means of simple hydrolysis, which thereby removes the blocking groups, benzoyl and methyl in the 3-substitution position in phenyl.
EKSEMPEL 4 EXAMPLE 4
En 1 liter autoklav ble tilsatt 25,0 g a-benzamido-4-hydroksy-3-metoksy-cinnaminsyre, 300 ml metanol og 0,6 ml 5%'ig vandig NaOH. Satsen ble omrørt ved 25°C under 2,8 kg/cm<2 >ren hydrogen inntil man hadde forsikret seg om at det ikke var noen lekkasje. Deretter ble ca. 1 ml (0,01% Rh, 0,05% fosfin) av den følgende katalysatorløsning tilsatt ved hjelp av et membran slik at trykket ikke blir påvirket, 25.0 g of α-benzamido-4-hydroxy-3-methoxy-cinnamic acid, 300 ml of methanol and 0.6 ml of 5% aqueous NaOH were added to a 1 liter autoclave. The batch was stirred at 25°C under 2.8 kg/cm<2 >pure hydrogen until it was ensured that there was no leakage. Subsequently, approx. 1 ml (0.01% Rh, 0.05% phosphine) of the following catalyst solution added by means of a membrane so that the pressure is not affected,
[katalysatorløsningen ble tilberedt ved å løse under nitro- [the catalyst solution was prepared by dissolving under nitro-
genatmosfære 0,0050 g [Rh (1,5-heksadien)Cl]2 i 0,33 ml løsning av metylfenyl-o-anisylfosfin med en spesifikk rotasjon [a]D 25 = +42 o (metanol) i benzen, som inneholdt 0,041 g/ml og utspedning til 1 ml med metanol]. gene atmosphere 0.0050 g [Rh (1,5-hexadiene)Cl]2 in 0.33 ml solution of methylphenyl-o-anisylphosphine with a specific rotation [a]D 25 = +42 o (methanol) in benzene, which contained 0.041 g/ml and diluting to 1 ml with methanol].
En omrøringshastighet på 1400 opm. holdes i reaksjonsmassen, og hydrogen begynner å absorbere etter 2-5 minutters induksjonsperiode og hydrogeneringen er avsluttet på 2 timer. A stirring speed of 1400 rpm. is kept in the reaction mass, and hydrogen begins to absorb after a 2-5 minute induction period and the hydrogenation is finished in 2 hours.
Metanolfordampes og syren løses i en mol vandig NaOH. Den nøytrale katalysatoren blir ekstrahert med benzen og satt bort for gjenvinning. Den frie aminosyren blir deretter bunnfelt ved hjelp av konsentrert HC1 under krystallisering. Man erholder 24 g N-benzoyl-3-(4-hydroksy-3-metoksyfenyl)-alanin, som inneholder 73% L-enantiomorf og 27% D-enantiomorf. L-enantiomorfen kan omdannes til L-DOPA ved hydroly-sering som vist i eksempel 4. Methanol is evaporated and the acid is dissolved in one mole of aqueous NaOH. The neutral catalyst is extracted with benzene and set aside for recovery. The free amino acid is then precipitated using concentrated HCl during crystallization. 24 g of N-benzoyl-3-(4-hydroxy-3-methoxyphenyl)-alanine is obtained, which contains 73% L-enantiomorph and 27% D-enantiomorph. The L-enantiomorph can be converted to L-DOPA by hydrolysis as shown in example 4.
EKSEMPLENE 5 - IQ THE EXAMPLES 5 - IQ
Andre optiske aktive a-aminosyrer ble fremstilt .som beskrevet i eksemplene 3 og 4, sammen med de hydro-generte' olefinforbindelser, fosfinliganden som anven- Other optically active α-amino acids were prepared as described in Examples 3 and 4, together with the hydrogenated olefin compounds, the phosphine ligand using
des i rhodiumkatalysatoren og den erholdte optiske renheten er som følger: des in the rhodium catalyst and the optical purity obtained are as follows:
EKSEMPEL 11 EXAMPLE 11
En autoklav ble tilsatt 25,0 g (0,085 mol) a-acetamido-4-hydroksy-3-metoksy-cinnaminsyreacetat, 300 ml metanol og 0,36 ml 50%'ig NaOH. Autoklaven ble satt under 2,5 kg/ cm2 trykk med en 50/50 blanding av N2 og H2. An autoclave was charged with 25.0 g (0.085 mol) of α-acetamido-4-hydroxy-3-methoxycinnamic acid acetate, 300 ml of methanol and 0.36 ml of 50% NaOH. The autoclave was put under 2.5 kg/cm2 pressure with a 50/50 mixture of N2 and H2.
En katalysatorløsning ble tilberedt ved å oppløse 0,0050 g (0,023 mekv.) av [Rh(1,5-heksadien)Cl]2 i 0,5 ml benzen og under nitrogenatmosfære å tilsette 0,051 mekv. (+)-metylcykloheksyl-o-anisyl-fosfin (optisk renhet = ca. 90%) i 2,4 ml benzen. Hydrogen fikk boble gjennom løsningen 10 minutter . A catalyst solution was prepared by dissolving 0.0050 g (0.023 meq) of [Rh(1,5-hexadiene)Cl]2 in 0.5 ml of benzene and, under a nitrogen atmosphere, adding 0.051 meq. (+)-methylcyclohexyl-o-anisyl-phosphine (optical purity = about 90%) in 2.4 ml of benzene. Hydrogen was allowed to bubble through the solution for 10 minutes.
Katalysatorløsningen ble deretter tilsatt til autoklaven. Hydrogeneringen ble utført ved 60°C og avsluttet på 4 timer. The catalyst solution was then added to the autoclave. The hydrogenation was carried out at 60°C and finished in 4 hours.
Produktet som ble erholdt ved fordampning av løsningsmidlet var N^acetyl-3-(4-hydroksy-3-metoksyfenyl)"alanin-acetat, som hadde en spesifikk rotasjon [<x]D 25 = +38,2' (Na-salt i vann). Ren N-acetyl-3- (4-hydroksy--3-metoksyfenyl) -L-alanin-acetat, såvel som et natriumsalt i vann, hadde en spesifikk The product obtained by evaporation of the solvent was N^acetyl-3-(4-hydroxy-3-methoxyphenyl)"alanine acetate, which had a specific rotation [<x]D 25 = +38.2' (Na salt in water).Pure N-acetyl-3-(4-hydroxy--3-methoxyphenyl)-L-alanine acetate, as well as a sodium salt in water, had a specific
2 5 o 2 5 o
rotasjon [ct]D = + 54,0 . rotation [ct]D = + 54.0 .
Således var den optiske renheten til hydrogeneringsproduk-tet 70,7 % eller bedre enn 85 % av L-enantiomorf og 15% av D-enantiomorf. Thus, the optical purity of the hydrogenation product was 70.7% or better than 85% of L-enantiomorph and 15% of D-enantiomorph.
Ved å anvende en lignende fremgangsmåte og med (-)-metyl-cykloheksyl^o-anisylfosfin (optisk renhet = ca. 80%) erholdt man et hydrogeneringsprodukt som inneholdt hovedsakelig D-enantiomorf (optisk renhet for reaksjonsprodukt-blandingen var 65%). Således kunne ved passende valg av (+)-eller (-)-fosfin hovedsakelig en enantiomorf fremstilles. By using a similar procedure and with (-)-methyl-cyclohexyl^o-anisylphosphine (optical purity = approx. 80%), a hydrogenation product containing mainly D-enantiomorph was obtained (optical purity of the reaction product mixture was 65%). Thus, by suitable choice of (+)- or (-)-phosphine, mainly one enantiomorph could be prepared.
EKSEMPEL 12 EXAMPLE 12
En lignende fremgangsmåte som beskrevet i eksempel 21 ble anvendt på (-)-metylcykloheksyl-o-anisylfosfin, som optisk aktiv ligande og a-benzamido-4-hydroksy-3-metoksy-cinna-minsyre som (3-substituert-a-acylamido-akrylsyre. A similar procedure as described in example 21 was applied to (-)-methylcyclohexyl-o-anisylphosphine, as optically active ligand and α-benzamido-4-hydroxy-3-methoxy-cinnamic acid as (3-substituted-α-acylamido -acrylic acid.
Det erholdte hydrogeneringsprodukt var N-benzoyl-3-(4-hydroksy-3-metoksyfenyl)-alanin som inneholdt hovedsakelig D-enantlomorf (reaksjonsproduktblandingens optiske renhet = ca. 65 %). The hydrogenation product obtained was N-benzoyl-3-(4-hydroxy-3-methoxyphenyl)-alanine which contained mainly D-enantlomorph (optical purity of the reaction product mixture = approx. 65%).
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO770472A NO148322C (en) | 1970-05-11 | 1977-02-11 | CATALYST FOR ASYMMETRIC HYDROGENERATION |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US3647170A | 1970-05-11 | 1970-05-11 | |
US12211671A | 1971-03-08 | 1971-03-08 | |
NO1757/71A NO142075C (en) | 1970-05-11 | 1971-05-10 | PROCEDURE FOR ASYMMETRIC HYDROGENERATION |
NO770472A NO148322C (en) | 1970-05-11 | 1977-02-11 | CATALYST FOR ASYMMETRIC HYDROGENERATION |
Publications (3)
Publication Number | Publication Date |
---|---|
NO770472L NO770472L (en) | 1971-11-12 |
NO148322B true NO148322B (en) | 1983-06-13 |
NO148322C NO148322C (en) | 1983-09-21 |
Family
ID=27483984
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO770472A NO148322C (en) | 1970-05-11 | 1977-02-11 | CATALYST FOR ASYMMETRIC HYDROGENERATION |
Country Status (1)
Country | Link |
---|---|
NO (1) | NO148322C (en) |
-
1977
- 1977-02-11 NO NO770472A patent/NO148322C/en unknown
Also Published As
Publication number | Publication date |
---|---|
NO770472L (en) | 1971-11-12 |
NO148322C (en) | 1983-09-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
SU663273A3 (en) | Optically active catalyst for asymmetrical hydrogenation of substituted acrylic acids | |
US3849480A (en) | Catalytic asymmetric hydrogenation | |
ES2708693T3 (en) | Method for producing compound with carbonyl group using ruthenium-carbonyl complex having tridentate ligand as oxidation dehydrogenation catalyst | |
JPH0641171A (en) | Ferrocenyldiphosphine as ligand of homogeneous catalyst | |
JPS6152139B2 (en) | ||
US4124533A (en) | Metal coordination complexes containing optically active phosphine or arsine ligands | |
US3968147A (en) | Asymmetric reduction of ketones to form optically active alcohols | |
EP0380463A2 (en) | Method for preparing (R)-succinic acid derivatives | |
JPS6097054A (en) | Selective catalytic hydrogenation | |
US4142992A (en) | Asymmetric catalysis | |
US7473793B2 (en) | Transition metal complex and process for producing optically active alcohol | |
US4261919A (en) | Catalytic asymmetric hydrogenation | |
US4265827A (en) | Catalytic asymmetric hydrogenation | |
WO1992019630A1 (en) | Chiral tridentate bis(phospholane) ligands | |
US20050107638A1 (en) | Transfer hydrogenation processes and catalysts | |
CA1142947A (en) | Optically active 1,2-bis-(diphenyl-phosphino) compounds and metal complexes containing them as chiral ligands as well as their use | |
US4166824A (en) | Chiral rhodium-diphosphine catalyst capable of catalytic reduction of a tetramisole precursor to give a significant excess of the desired S-(-)isomer, levamisole | |
US5324850A (en) | Preparation of chiral catalysts based on ruthenium and phosphorus complexes | |
NO148322B (en) | CATALYST FOR ASYMMETRIC HYDROGENERATION | |
US4294989A (en) | Methylcyclohexyl-O-anisylphosphine | |
NO142075B (en) | PROCEDURE FOR ASYMMETRIC HYDROGENERATION | |
JP5599664B2 (en) | Process for producing optically active 1,2-bis (dialkylphosphino) benzene derivative | |
JPH1180179A (en) | Phosphine compound and rhodium complex containing the same as ligand | |
CA1094095A (en) | Asymmetric catalysis | |
US4515731A (en) | Asymmetric catalysis |