JP3892503B2 - Racemization of optically active amines using catalytic reduction catalysts - Google Patents
Racemization of optically active amines using catalytic reduction catalysts Download PDFInfo
- Publication number
- JP3892503B2 JP3892503B2 JP23174196A JP23174196A JP3892503B2 JP 3892503 B2 JP3892503 B2 JP 3892503B2 JP 23174196 A JP23174196 A JP 23174196A JP 23174196 A JP23174196 A JP 23174196A JP 3892503 B2 JP3892503 B2 JP 3892503B2
- Authority
- JP
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- Prior art keywords
- group
- optically active
- racemization
- catalyst
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 230000006340 racemization Effects 0.000 title claims description 31
- 239000003054 catalyst Substances 0.000 title claims description 30
- 150000001412 amines Chemical class 0.000 title claims description 23
- 238000010531 catalytic reduction reaction Methods 0.000 title claims description 16
- 238000000034 method Methods 0.000 claims description 48
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 32
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 25
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical group [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 229910021529 ammonia Inorganic materials 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 239000010941 cobalt Substances 0.000 claims description 11
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 11
- 229910017052 cobalt Inorganic materials 0.000 claims description 10
- 239000007868 Raney catalyst Substances 0.000 claims description 9
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical group [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- -1 amine compound Chemical class 0.000 description 44
- 238000006243 chemical reaction Methods 0.000 description 27
- 125000003118 aryl group Chemical group 0.000 description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 230000003287 optical effect Effects 0.000 description 14
- 125000003277 amino group Chemical group 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910052759 nickel Inorganic materials 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 125000004806 1-methylethylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000004807 2-methylethylene group Chemical group [H]C([H])([H])C([H])([*:2])C([H])([H])[*:1] 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000004816 2,2-dimethylethylene group Chemical group [H]C([H])([H])C([*:2])(C([H])([H])[H])C([H])([H])[*:1] 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 125000000579 2,2-diphenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(C1=C([H])C([H])=C([H])C([H])=C1[H])C([H])([H])* 0.000 description 1
- MFSJSVNVUDQHLV-UHFFFAOYSA-N 2-(3-benzoylphenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1.OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFSJSVNVUDQHLV-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- VDMAQVANUGNDOM-UHFFFAOYSA-N 3-methyl-2-phenylbutan-1-amine Chemical compound CC(C)C(CN)C1=CC=CC=C1 VDMAQVANUGNDOM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229910000838 Al alloy Inorganic materials 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910000531 Co alloy Inorganic materials 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- FQMNVNKBWNEVMK-UHFFFAOYSA-J barium(2+);platinum(2+);disulfate Chemical compound [Ba+2].[Pt+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O FQMNVNKBWNEVMK-UHFFFAOYSA-J 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 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
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- JGDFBJMWFLXCLJ-UHFFFAOYSA-N copper chromite Chemical compound [Cu]=O.[Cu]=O.O=[Cr]O[Cr]=O JGDFBJMWFLXCLJ-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000006608 n-octyloxy group Chemical group 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HZPNKQREYVVATQ-UHFFFAOYSA-L nickel(2+);diformate Chemical compound [Ni+2].[O-]C=O.[O-]C=O HZPNKQREYVVATQ-UHFFFAOYSA-L 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl 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
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、下記式(１)で表される光学活性アミンに接触還元触媒を作用させることからなる、該光学活性アミンのラセミ化法に関する。さらに詳しくは、本発明は、アンモニアの存在下および／または水素の非存在下に、接触還元触媒を作用させることからなる該光学活性アミンのラセミ化法に関する。
【０００２】
【従来の技術】
以下の式(１)：
【化３】
Ｒ2はＣ1〜Ｃ8アルキル基；１〜３個のアリール基で置換されたＣ1〜Ｃ8アルキル基；Ｃ1〜Ｃ8アルコキシ基；１〜３個のアリール基で置換されたＣ1〜Ｃ8アルコキシ基；またはＲ1と同一ではない未置換アリール基；１〜５個のＣ1〜Ｃ4アルキル基、Ｃ1〜Ｃ4アルコキシ基および／またはハロゲン原子で置換されたアリール基；または未置換もしくは置換された複素環基を示し、
Ｒ3およびＲ4は、同一または異なっていてよく、水素原子、Ｃ1〜Ｃ4アルキル基、１〜３個のアリール基で置換されたＣ1〜Ｃ4アルキル基またはＣ1〜Ｃ4アルキル−ＣＯ−基を示し、
ＡはＣ1〜Ｃ10アルキレン基を示し、そして
＊は不斉炭素原子の位置を示す]
で表される光学活性アミンは、光学分割剤や不斉補助基として、不斉反応における金属配位子、あるいは医薬品中間体として有用である。
【０００３】
特に、Ｒ1がフェニルであり、Ｒ2がイソプロピルであり、Ｒ3およびＲ4が共に水素原子であり、Ａがメチレンである式(１)で表される光学活性なアミン、即ち、光学活性な３−メチル−２−フェニルブチルアミン(ＰＢＡ)は光学分割剤として有用な化合物である。この化合物は、ラセミ体のイブブロフェン[２−(４−イソブチルフェニル)−プロピオン酸]やケトプロフェン[２−(３−ベンゾイルフェニル)−プロピオン酸]等から、消炎鎮痛剤、解熱剤、あるいは抗リウマチ剤として有用な光学活性な一方の異性体のみを得るための光学分割剤として用いられている(特開平５−２２９９８６および特開平８−１５１３４４)。
【０００４】
現在のところ、光学活性なＰＢＡは、ラセミ体のＰＢＡをマンデル酸等の光学活性な酸により分割すること(特開昭６１−１７２８５３)、あるいはＰＢＡのアミドを酵素により選択的に加水分解すること(出願番号平７−２１５７２２)によって得ることができる。また、酵素によりニトリルを光学選択的に水和する反応を利用する方法も開発されている(特開平７−３０３４９６)。
【０００５】
一般に、一方の立体配置を有する光学活性化合物が所望であり、かつ該光学活性化合物をラセミ体の光学分割によって得る場合には、所望の光学活性化合物は最大でも５０％の収率でしか得られず、所望ではない光学活性化合物が５０％残ることになる。従って、光学分割法によって光学活性化合物を得る場合には、この所望ではない光学活性化合物の立体配置を反転および／またはラセミ化する方法の開発が、所望の光学活性化合物の収率を高めるために重要である。
【０００６】
アミノ基のα位の炭素が不斉炭素であるアミン化合物をラセミ化する方法としては、ラネーニッケルやラネーコバルト等の接触還元触媒と水素加圧下に加熱することによる方法(特開昭６３−１８５９４３)、カルボニル化合物との反応により生成したイミンを利用する方法(特開昭６３−２３８２４、特開平７−１８８１２０)、水素化ナトリウムまたはナトリウムアミドを用いる方法[ＤＥ-ＯＳ(独公開明細書) ２,３４８,８０１]、アルミナ等の担体または多環芳香族により活性化したナトリウムを用いる方法(特開昭５０−５０３２８、特開昭５０−５０３４４、特開昭５０−４９２３５)などが開発されている。
しかし、現在までのところ、アミノ基のβ位およびそれ以遠の炭素が不斉炭素であるアミン化合物(例えば、ＰＢＡ)を効率的にラセミ化する方法は知られていない。
【０００７】
【発明が解決しようとする課題】
本発明者らはこれらの事実に鑑み、工業的に実用可能な、アミノ基のβ位およびそれ以遠の炭素が不斉炭素であるアミン化合物(例えば、ＰＢＡ)を効率的にラセミ化する方法を開発しようとした。
【０００８】
【課題を解決するための手段】
ここに、驚くべきことに、アミノ基のβ位およびそれ以遠の炭素が不斉炭素であるアミン化合物に接触還元触媒を作用させることにより、該アミン化合物を効率的にラセミ化しうることを見い出した。さらに、アンモニアの存在下および／または水素の非存在下に接触還元触媒を作用させると、一層効率よくラセミ化が進行することを見い出した。
【０００９】
即ち、本発明は、以下の式(１)：
【化４】
Ｒ2はＣ1〜Ｃ8アルキル基；１〜３個のアリール基で置換されたＣ1〜Ｃ8アルキル基；Ｃ1〜Ｃ8アルコキシ基；１〜３個のアリール基で置換されたＣ1〜Ｃ8アルコキシ基；またはＲ1と同一ではない未置換アリール基；１〜５個のＣ1〜Ｃ4アルキル基、Ｃ1〜Ｃ4アルコキシ基および／またはハロゲン原子で置換されたアリール基；または未置換もしくは置換された複素環基を示し、
Ｒ3およびＲ4は、同一または異なっていてよく、水素原子、Ｃ1〜Ｃ4アルキル基、１〜３個のアリール基で置換されたＣ1〜Ｃ4アルキル基またはＣ1〜Ｃ4アルキル−ＣＯ−基を示し、
ＡはＣ1〜Ｃ10アルキレン基を示し、そして
＊は不斉炭素原子の位置を示す]
で表される光学活性アミンのラセミ化法であって、該アミンに接触還元触媒を作用させることを特徴とするラセミ化法を提供するものである。本方法は、アンモニアの存在下および／または水素の非存在下に行うのが好ましい。
【００１０】
光学活性な化合物のラセミ化を塩基により行う場合には、不斉炭素上の水素の引き抜き反応が必須である。従って、より酸性度の高い水素が結合している不斉炭素ほど、その位置でのラセミ化が起こりやすくなる。アミノ基のβ位およびそれ以遠の炭素に結合している水素の酸性度は、誘起効果が減少するためにアミノ基のα位の炭素に結合している水素の酸性度に比べて低くなる。従って、アミノ基のα位に不斉炭素を有するアミン化合物を効率良くラセミ化することができた方法が、β位またはそれ以遠に不斉炭素を有するアミン化合物にも同様に適用できると予測することはできない。
【００１１】
上記のように、アミノ基のα位に不斉炭素を有するアミン化合物をラセミ化する方法はいくつか知られている。これら方法の中には、ラネーニッケルやラネーコバルトなどの接触還元触媒と水素加圧下に加熱する方法(特開昭６３−１８５９４３)が含まれる。しかし、この方法がβ位またはそれ以遠に不斉炭素を有するアミン化合物に適用された例はなく、この方法をこのようなアミン化合物に適用した場合には、他の水素化ナトリウムやナトリウムアミドを用いる方法と同様に効率の低下が予想された。
本発明者らは、このような状況下で、接触還元触媒を用いる方法が他の方法よりも優れ、アミノ基のβ位またはそれ以遠に不斉炭素を有するアミン化合物を効率良くラセミ化しうることを見い出した。さらに、アンモニアの存在下および／または水素の非存在下に接触還元触媒を用いると、ラセミ化反応に伴うアミン化合物の分解が抑制されたり、効率が向上したりすることを見い出し、本発明を完成するに至った。
【００１２】
【発明の実施の形態】
本発明の方法を適用することができる光学活性なアミン化合物は、アミノ基のβ位またはそれ以遠に不斉炭素を有する上記式(１)で表されるアミン化合物である。
本明細書において、アリール基とは、１価の芳香族炭化水素基を意味し、例えば、フェニル、ビフェニリルまたはナフチル基などが含まれる。
【００１３】
Ｃ1〜Ｃ4アルキル基およびＣ1〜Ｃ8アルキル基とは、それぞれ１〜４個および１〜８個の炭素原子を有する直鎖または分岐鎖のアルキル基を意味する。従って、Ｃ1〜Ｃ4アルキル基には、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチルまたはt-ブチル基などが含まれ、Ｃ1〜Ｃ8アルキル基には、Ｃ1〜Ｃ4アルキル基に加えて、例えば、n-ペンチル、ネオペンチル、n-ヘキシルまたはn-オクチル基などが含まれる。
【００１４】
Ｃ1〜Ｃ4アルコキシ基およびＣ1〜Ｃ8アルコキシ基とは、アルキル部分がそれぞれ１〜４個および１〜８個の炭素原子を有する直鎖または分岐鎖のアルキル基からなるアルコキシ基を意味する。従って、Ｃ1〜Ｃ4アルコキシ基には、例えば、メトキシ、エトキシ、n-プロポキシ、イソプロポキシ、n-ブトキシまたはt-ブトキシ基などが含まれ、Ｃ1〜Ｃ8アルコキシ基には、Ｃ1〜Ｃ4アルコキシ基に加えて、例えば、n-ペンチルオキシ、ネオペンチルオキシ、n-ヘキシルオキシまたはn-オクチルオキシ基などが含まれる。
【００１５】
ハロゲン原子とは、フッ素、塩素、臭素またはヨウ素を意味する。
【００１６】
１〜５個のＣ1〜Ｃ4アルキル基、Ｃ1〜Ｃ4アルコキシ基および／またはハロゲン原子で置換されたアリール基とは、１〜５個の上記定義のＣ1〜Ｃ4アルキル基、Ｃ1〜Ｃ4アルコキシ基および／またはハロゲン原子で置換された上記定義のアリール基を意味する。置換基が複数存在する場合、それらは同一または異なる基またはハロゲン原子から選択されてよい。このような置換されたアリール基の例には、例えば、p-、m-またはo-フルオロ、クロロ、ブロモ、メトキシ、エトキシ、ブトキシ、メチル、エチル、プロピル、ブチル、イソブチルフェニル基、あるいは、メシチル基、ペンタフルオロフェニル基などが含まれる。
【００１７】
１〜３個のアリール基で置換されたＣ1〜Ｃ4アルキル基およびＣ1〜Ｃ8アルキル基とは、１〜３個の上記定義のアリール基で置換された上記定義のＣ1〜Ｃ4アルキル基およびＣ1〜Ｃ8アルキル基を意味する。このようなアリール置換されたアルキル基には、例えば、１-または２-フェニルエチル、２,２-ジフェニルエチル、１,１,１-トリフェニルエチル基などが含まれる。
【００１８】
１〜３個のアリール基で置換されたＣ1〜Ｃ4アルコキシ基およびＣ1〜Ｃ8アルコキシ基とは、１〜３個の上記定義のアリール基で置換された上記定義のＣ1〜Ｃ4アルコキシ基およびＣ1〜Ｃ8アルコキシ基を意味する。このようなアリール置換されたアルコキシ基には、例えば、ベンジルオキシ、ジフェニルメトキシ、トリフェニルメトキシ基などが含まれる。
【００１９】
Ｃ1〜Ｃ4アルキル−ＣＯ−基とは、カルボニル基に上記定義のＣ1〜Ｃ4アルキル基が結合しているアシル基を意味し、例えば、アセチル、プロピオニル、ブチリル、イソブチリル、バレリルまたはピバロイル基などが含まれる。
Ｃ1〜Ｃ4アルキレン基およびＣ1〜Ｃ10アルキレン基とは、それぞれ１〜４個および１〜１０個の炭素原子を有する直鎖または分岐鎖のアルキレン基を意味し、例えば、メチレン、エチレン、プロピレン、ブチレン、１-または２-メチルエチレン、１,１-、１,２-または２,２-ジメチルエチレン基などが含まれる。
【００２０】
未置換または置換された複素環基には、例えば、フリル、チエニル、オキサゾリル、チアゾリル、ピリジル、ピリミジニル、あるいは、Ｎ−アルキルピロリル、イミダゾリル、ピラゾリル基などが含まれる。
【００２１】
上記式(１)で表されるアミン化合物の中に、本方法を適用するに好ましい群が存在する。
即ち、本方法は、Ｒ1が未置換のフェニルもしくはナフチル基；１〜５個のＣ1〜Ｃ4アルキル基、Ｃ1〜Ｃ4アルコキシ基および／またはハロゲン原子で置換されたフェニルもしくはナフチル基；または未置換の複素環基であり、Ｒ2がＣ1〜Ｃ4アルキル基；１〜３個のフェニル基で置換されたＣ1〜Ｃ4アルキル基；Ｃ1〜Ｃ4アルコキシ基；１〜３個のフェニル基で置換されたＣ1〜Ｃ4アルコキシ基；または未置換の複素環基であり、Ｒ3およびＲ4が同一または異なって水素原子、Ｃ1〜Ｃ4アルキル基または１〜３個のフェニル基で置換されたＣ1〜Ｃ4アルキル基であり、ＡがＣ1〜Ｃ6アルキレン基である式(１)で表される光学活性アミンをラセミ化するために用いるのが好ましい。
【００２２】
より好ましくは、本方法は、Ｒ1が未置換のフェニル基または１〜５個のＣ1〜Ｃ4アルキル基、Ｃ1〜Ｃ4アルコキシ基および／またはハロゲン原子で置換されたフェニル基であり、Ｒ2がＣ1〜Ｃ4アルキル基または１〜３個のフェニル基で置換されたＣ1〜Ｃ4アルキル基であり、Ｒ3およびＲ4が同一または異なって水素原子またはＣ1〜Ｃ4アルキル基であり、Ａがメチレンまたはエチレン基である式(１)で表される光学活性アミンをラセミ化するために用いる。
【００２３】
さらに好ましくは、本方法は、以下の式(２)：
【化５】
で表される光学活性アミンをラセミ化するために用いる。
【００２４】
より好ましくは、本方法は、Ｒ5が水素原子、メチル基、メトキシ基または塩素原子であり、Ｒ6がイソプロピル基であり、Ｒ7が水素原子またはエチル基である上記式(２)で表される光学活性アミンをラセミ化するために用いる。
最も好ましくは、本方法は、Ｒ5が水素原子であり、Ｒ6がイソプロピル基であり、Ｒ7が水素原子である上記式(２)で表される光学活性アミン(ＰＢＡ)をラセミ化するために用いる。
【００２５】
上記の式(１)または式(２)で表されるアミン化合物のラセミ体は、既知の有機合成によって、または市販品から入手することができる。本方法に従ってラセミ化する光学活性なアミン化合物は、このようなラセミ体を光学分割して、一方の所望の光学活性体を分離した残りであることが多い。従って、本方法において用いる光学活性なアミン化合物は、光学純度がほぼ１００％ee(エナンチオマー過剰率)であることもあるし、また、それより低く、２０〜９９％ee程度であることもある。
【００２６】
また、本方法において、光学活性アミンをラセミ化するとは、比較的高い光学純度のアミンを、より低い光学純度のアミンに変換することを意味する。即ち、本方法により、下記式で表されるラセミ化率を５０％以上、好ましくは８０％以上、さらに好ましくは９５％以上に向上させることができる。
【数１】
本方法において、接触還元触媒とは、接触還元に用いられる金属触媒を意味する。金属としては、白金、パラジウムなどの貴金属、ニッケル、コバルト、鉄、銅などが用いられる。形態としては、例えば、白金は白金黒、コロイド白金、酸化白金などであってよく、ニッケルは還元ニッケル、漆原ニッケル、蟻酸ニッケルなどであってよい。また、ニッケル、コバルト、鉄などはラネーニッケル、ラネーコバルト、ラネー鉄などのラネー触媒の形態であってよい。担体を併用する形態、例えば、パラジウム−炭素、パラジウム−炭酸カルシウム、白金−硫酸バリウム、ニッケル−珪藻土、亜クロム酸銅などであってもよい。
これら触媒の中で、本方法に好ましいのはラネー触媒であり、特にラネーニッケルまたはラネーコバルトが好ましく、さらに好ましくはニッケル、コバルトのアルミニウム合金からの調製触媒である。
上記の触媒は、いずれも市販品から入手することができる。
触媒の使用量に特に限定はないが、アミン化合物１重量部に対して、触媒を０.０１〜１.０重量部、好ましくは０.０５〜０.５重量部の量で用いる。
【００２８】
本ラセミ化反応は、通常はオートクレーブのような密閉容器中、光学活性アミンを接触還元触媒とともに加熱および撹拌することによって行うことができる。また、通常は反応容器の空隙を窒素などの不活性気体で置換する。反応溶媒は、特に必要ではないが、所望により水またはトルエンなどの不活性有機溶媒を用いてもよい。
【００２９】
本ラセミ化反応は、アンモニアの存在下に行うのが有利であることがわかった。反応系中にアンモニアが存在すると、アミン化合物の分解および高沸点第二アミンの副生成が抑制されるので、高い回収率でアミン化合物のラセミ化を達成することができる。
本方法において、使用するアンモニアの形態には特に制限はなく、その水溶液でもよいし、またガス状のものを使用してもよい。しかし、操作性の観点から、アンモニアは水溶液として用いるのが普通であり、その濃度は５〜２８％であるのが好ましい。アンモニアの添加量に特に限定はないが、原料の光学活性アミン１当量に対して、通常はアンモニアを０.１〜３.０当量、好ましくは０.２〜１.５当量となるように反応系に加える。
【００３０】
さらに、本ラセミ化反応は、水素の非存在下に行うのが有利であることがわかった。本方法においては、上記の特開昭６３−１８５９４３に開示された方法のような水素加圧下の条件は必須ではなく、水素の存在により反応後に得られるアミン化合物の化学純度を低下させることもあるので、水素の非存在下にラセミ化を行う方が好ましい場合もある。
【００３１】
本ラセミ化反応の反応温度は、通常は１００〜２５０℃、好ましくは１５０〜２００℃、さらに好ましくは１６０〜１８０℃である。
反応時間は、使用する触媒の種類および量、アンモニアの濃度および量、反応温度ならびに撹拌状態などの反応条件により変化するが、通常は５０時間以内、より普通には１０〜２５時間である。
【００３２】
反応終了後、反応混合物を酸性条件下に有機溶媒を用いて抽出することにより副生成物を有機層に、アミン化合物を水層に移行させる。有機溶媒としては、水と混和しないトルエン、ヘキサン、エーテル、エステルなどを用いることができる。次いで、水層を水酸化ナトリウムなどの塩基でアルカリ性とし、上記のような有機溶媒により抽出することにより、目的のアミン化合物を得る。この操作により十分純度の高いアミン化合物が得られるが、必要に応じて蒸留などを行って、より高純度の目的アミン化合物を得ることができる。
【００３３】
【実施例】
本発明を実施例に基づいてさらに具体的に説明するが、本発明はこれら実施例に限定されるものではない。
実施例において、ＰＢＡの光学純度は、以下の条件下で高速液体クロマトグラフィー分析することにより測定し、エナンチオマー過剰率(％ee)で表した。
カラム：クラウンパック(CRAWNPAK)ＣＲ(＋)
[ダイセル(Daicel)] ０.４×１５cm
溶離液：０.１Ｎ ＨＣlＯ4水溶液／メタノール＝８５／１５
流 速：０.８ml／分
温 度：４０℃
検 出：ＵＶ ２１０nm
ＰＢＡの化学純度は、以下の条件下でガスクロマトグラフィー分析することにより測定し、単純面積百分率(％)で表した。
カ ラ ム：ＣＢＰＩ-Ｍ２５-０.２５[島津製作所]
カラム槽：４０℃、昇温速度１０℃／分、２５０℃、１９分保持
気 化 室：２７０℃
検 出：ＦＩＤ、２９０℃
【００３４】
実施例１ ラネーニッケル触媒による(Ｒ)−ＰＢＡのラセミ化
２３０ml容量のＳＵＳ３１６製オートクレーブに、(Ｒ)−ＰＢＡ[光学純度４７.２％ee、化学純度９８.９％](４０.００g)、ラネーニッケル触媒(８.０g)および２８％アンモニア水(１８.６g)を仕込み、密閉し、窒素置換を行った。次いで、撹拌を開始し、温度１６５℃、内圧１７kg／cm2Ｇで２２.５時間反応させた。反応終了後に冷却し、反応液を分析した結果、ＰＢＡの光学純度は７.１％ee、化学純度は９３.８％であることがわかった。
この反応混合物を濾過し、濾塊をトルエン(４０g)、さらに水(４０g)で洗浄した。この濾液および洗浄液を合わせ、これに３５％塩酸(２２.９４g)を加えて抽出を行った。この水層に２９％水酸化ナトリウム水溶液(３１.２６g)を加えてアルカリ性とし、新たなトルエン(６０g)で抽出を行った。この水層をもう一度新たなトルエン(６０g)で抽出した。これらのトルエン抽出液を合わせ、減圧濃縮し、３６.６８gの残留物(化学純度９５.７％)を得た。
さらに、この残留物を減圧蒸留により精製した結果、光学純度７.１％ee、化学純度９９.６％のＰＢＡが３３.５２g得られた。回収率は８３.８％、ラセミ化率は８５.０％であった。
【００３５】
実施例２および３
反応温度および反応時間を変えて、またはアンモニア水を添加せずに、実施例１と同様にして反応を行った。これらの結果を、実施例１の結果とともに以下の表１に示す。これらの結果から、アンモニアの非存在下でもラセミ化は効率良く進行するものの、ＰＢＡの化学純度はやや低下し、アンモニア水の添加が望ましいことがわかる。
【００３６】
実施例４〜６
アンモニア水を添加せず、水素の存在下に実施例１の反応を行った。水素は窒素置換した後に圧入した。これらの結果も以下の表１に示す。これらの結果から、水素の存在下でもラセミ化は効率良く進行するものの、ＰＢＡの化学純度は低下することがわかる。
【表１】
実施例７〜１１
触媒量およびアンモニア水濃度を変化させて、実施例１と同様にして反応を行った。アンモニア水濃度は、２８％アンモニア水をそのまま、またはこれに水を加えて希釈することによって調整した。これらの結果を、実施例１および２の結果とともに、以下の表２に示す。これらの結果から、アンモニア濃度を低下させることにより若干化学純度が低下するものの、ラセミ化の速度が速くなることがわかる。
【表２】
実施例 12 〜 14 ラネーコバルト触媒による(Ｒ)−ＰＢＡのラセミ化
ラセミ化触媒にラネーコバルト触媒を用い、触媒量を変化させて、実施例１と同様にして反応を行った。これらの結果を、以下の表３に示す。これらの結果から、ラネーコバルト触媒を用いても、ラネーニッケル触媒と同様に効率良くラセミ化反応が進行することがわかる。
【表３】
【発明の効果】
以上に説明したように、本方法を用いることによりアミノ基のβ位およびそれ以遠に不斉炭素を有する光学活性アミン、例えば光学活性ＰＢＡを効率よくラセミ化することができる。即ち、本方法と光学分割法とを組合せることにより、所望とする一方の立体配置を有する光学活性アミンを効率良く生産することが可能である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for racemization of an optically active amine, which comprises reacting an optically active amine represented by the following formula (1) with a catalytic reduction catalyst. More particularly, the present invention relates to a method for racemization of the optically active amine, which comprises reacting a catalytic reduction catalyst in the presence of ammonia and / or in the absence of hydrogen.
[0002]
[Prior art]
The following formula (1):
[Chemical 3]
R 2 is a C 1 -C 8 alkyl group; a C 1 -C 8 alkyl group substituted with 1 to 3 aryl groups; a C 1 -C 8 alkoxy group; a C substituted with 1 to 3 aryl groups 1 -C 8 alkoxy group; or R 1 and unsubstituted aryl groups are not identical; 1-5 C 1 -C 4 alkyl group, C 1 -C 4 alkoxy and / or aryl group substituted with a halogen atom Or represents an unsubstituted or substituted heterocyclic group,
R 3 and R 4 may be the same or different, a hydrogen atom, C 1 -C 4 alkyl group, C 1 substituted with 1-3 aryl group -C 4 alkyl or C 1 -C 4 alkyl A —CO— group,
A represents a C 1 -C 10 alkylene group, and * indicates the position of an asymmetric carbon atom
The optically active amine represented by is useful as an optical resolution agent or an asymmetric auxiliary group, as a metal ligand in an asymmetric reaction, or as a pharmaceutical intermediate.
[0003]
In particular, R 1 is phenyl, R 2 is isopropyl, R 3 and R 4 are both hydrogen atoms, and A is methylene, an optically active amine represented by formula (1), ie, optical activity 3-methyl-2-phenylbutylamine (PBA) is a useful compound as an optical resolution agent. This compound is a racemic ibubrofen [2- (4-isobutylphenyl) -propionic acid], ketoprofen [2- (3-benzoylphenyl) -propionic acid], etc., as an anti-inflammatory analgesic, antipyretic or antirheumatic agent. It is used as an optical resolving agent for obtaining only one useful optically active isomer (JP-A-5-229986 and JP-A-8-151344).
[0004]
At present, optically active PBA is obtained by resolving racemic PBA with an optically active acid such as mandelic acid (Japanese Patent Laid-Open No. 61-172853), or by selectively hydrolyzing the amide of PBA with an enzyme. (Application No. 7-215722). Also, a method utilizing a reaction for optically hydrating nitrile with an enzyme has been developed (Japanese Patent Laid-Open No. 7-303496).
[0005]
In general, when an optically active compound having one configuration is desired and the optically active compound is obtained by optical resolution of a racemate, the desired optically active compound can be obtained only in a yield of 50% at the maximum. This leaves 50% of the optically active compound which is not desired. Therefore, in the case of obtaining an optically active compound by an optical resolution method, the development of a method for inverting and / or racemizing the configuration of this undesirable optically active compound is intended to increase the yield of the desired optically active compound. is important.
[0006]
As a method for racemizing an amine compound in which the α-position carbon of the amino group is an asymmetric carbon, a method by heating under a hydrogen pressure with a catalytic reduction catalyst such as Raney nickel or Raney cobalt (JP-A-63-185943) , A method using an imine formed by reaction with a carbonyl compound (Japanese Patent Laid-Open No. 63-23824, Japanese Patent Laid-Open No. 7-188120), a method using sodium hydride or sodium amide [DE-OS (German Published Specification) 2, 348,801], a method using a carrier such as alumina or sodium activated by polycyclic aromatics (JP 50-50328, JP 50-50344, JP 50-49235), and the like have been developed. .
However, until now, there is no known method for efficiently racemizing an amine compound (for example, PBA) in which the β-position of the amino group and further carbon are asymmetric carbons.
[0007]
[Problems to be solved by the invention]
In view of these facts, the present inventors have developed an industrially practical method for efficiently racemizing an amine compound (for example, PBA) in which the β-position of the amino group and further carbon are asymmetric carbons. Tried to develop.
[0008]
[Means for Solving the Problems]
Here, surprisingly, it has been found that the amine compound can be efficiently racemized by causing a catalytic reduction catalyst to act on an amine compound in which the β-position of the amino group and beyond are asymmetric carbons. . Furthermore, it has been found that racemization proceeds more efficiently when the catalytic reduction catalyst is allowed to act in the presence of ammonia and / or in the absence of hydrogen.
[0009]
That is, the present invention provides the following formula (1):
[Formula 4]
R 2 is a C 1 -C 8 alkyl group; a C 1 -C 8 alkyl group substituted with 1 to 3 aryl groups; a C 1 -C 8 alkoxy group; a C substituted with 1 to 3 aryl groups 1 -C 8 alkoxy group; or R 1 and unsubstituted aryl groups are not identical; 1-5 C 1 -C 4 alkyl group, C 1 -C 4 alkoxy and / or aryl group substituted with a halogen atom Or represents an unsubstituted or substituted heterocyclic group,
R 3 and R 4 may be the same or different, a hydrogen atom, C 1 -C 4 alkyl group, C 1 substituted with 1-3 aryl group -C 4 alkyl or C 1 -C 4 alkyl A —CO— group,
A represents a C 1 -C 10 alkylene group, and * indicates the position of an asymmetric carbon atom
A racemization method of an optically active amine represented by the formula: wherein a catalytic reduction catalyst is allowed to act on the amine. The process is preferably carried out in the presence of ammonia and / or in the absence of hydrogen.
[0010]
When the racemization of an optically active compound is performed with a base, a hydrogen abstraction reaction on the asymmetric carbon is essential. Therefore, the asymmetric carbon to which hydrogen having higher acidity is bonded is more likely to racemize at that position. The acidity of hydrogen bonded to the β-position of the amino group and further carbon is lower than the acidity of hydrogen bonded to the α-position carbon of the amino group due to the reduced induction effect. Therefore, it is predicted that the method capable of efficiently racemizing an amine compound having an asymmetric carbon at the α-position of the amino group can be similarly applied to an amine compound having an asymmetric carbon at the β-position or beyond. It is not possible.
[0011]
As described above, several methods for racemizing an amine compound having an asymmetric carbon at the α-position of an amino group are known. These methods include a catalytic reduction catalyst such as Raney nickel or Raney cobalt and a method of heating under hydrogen pressure (Japanese Patent Laid-Open No. 63-185943). However, there is no example in which this method is applied to an amine compound having an asymmetric carbon at the β-position or beyond, and when this method is applied to such an amine compound, other sodium hydride or sodium amide is added. Similar to the method used, a decrease in efficiency was expected.
Under these circumstances, the present inventors are able to efficiently racemize an amine compound having an asymmetric carbon at the β-position of the amino group or beyond since the method using a catalytic reduction catalyst is superior to other methods. I found out. Furthermore, when a catalytic reduction catalyst is used in the presence of ammonia and / or in the absence of hydrogen, it is found that the decomposition of the amine compound accompanying the racemization reaction is suppressed and the efficiency is improved, and the present invention is completed. It came to do.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
The optically active amine compound to which the method of the present invention can be applied is an amine compound represented by the above formula (1) having an asymmetric carbon at the β-position of the amino group or beyond.
In the present specification, the aryl group means a monovalent aromatic hydrocarbon group, and includes, for example, a phenyl, biphenylyl or naphthyl group.
[0013]
The C 1 -C 4 alkyl groups and C 1 -C 8 alkyl group means a straight or branched chain alkyl group having 1-4 and 1-8 carbon atoms respectively. Thus, the C 1 -C 4 alkyl group, e.g., methyl, ethyl, n- propyl, isopropyl, include such n- butyl or t- butyl group, a C 1 -C 8 alkyl group, C 1 ~ In addition to the C 4 alkyl group, for example, an n-pentyl, neopentyl, n-hexyl or n-octyl group is included.
[0014]
C 1 -C 4 alkoxy group and C 1 -C 8 alkoxy group mean an alkoxy group whose alkyl part consists of a linear or branched alkyl group having 1 to 4 and 1 to 8 carbon atoms, respectively. To do. Accordingly, C 1 -C 4 alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or t-butoxy groups, and C 1 -C 8 alkoxy groups include C 1 in addition to -C 4 alkoxy group, for example, n- pentyloxy, neo-pentyloxy, and the like n- hexyloxy or n- octyloxy group.
[0015]
A halogen atom means fluorine, chlorine, bromine or iodine.
[0016]
1-5 C 1 -C 4 alkyl groups, C 1 -C 4 alkoxy groups and / or aryl groups substituted with halogen atoms are 1-5 C 1 -C 4 alkyl groups as defined above, means C 1 -C 4 alkoxy groups and / or have been defined above aryl groups substituted by a halogen atom. When there are a plurality of substituents, they may be selected from the same or different groups or halogen atoms. Examples of such substituted aryl groups include, for example, p-, m- or o-fluoro, chloro, bromo, methoxy, ethoxy, butoxy, methyl, ethyl, propyl, butyl, isobutylphenyl groups, or mesityl Groups, pentafluorophenyl groups and the like.
[0017]
The 1-3 C 1 substituted with an aryl group -C 4 alkyl groups and C 1 -C 8 alkyl group, C 1 -C one to three of the above definition of has been defined above substituted with an aryl group 4 means an alkyl group and a C 1 -C 8 alkyl group. Such aryl-substituted alkyl groups include, for example, 1- or 2-phenylethyl, 2,2-diphenylethyl, 1,1,1-triphenylethyl groups, and the like.
[0018]
The 1 to 3 C 1 -C 4 alkoxy group and C 1 -C 8 alkoxy group substituted with an aryl group, C 1 -C one to three of the above definition of has been defined above substituted with an aryl group 4 means an alkoxy group and a C 1 -C 8 alkoxy group. Such aryl-substituted alkoxy groups include, for example, benzyloxy, diphenylmethoxy, triphenylmethoxy groups and the like.
[0019]
C 1 -C 4 alkyl-CO— group means an acyl group in which a C 1 -C 4 alkyl group as defined above is bonded to a carbonyl group, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl or pivaloyl Group etc. are included.
C 1 -C 4 alkylene group and C 1 -C 10 alkylene group mean straight or branched alkylene groups having 1 to 4 and 1 to 10 carbon atoms, respectively, such as methylene, ethylene , Propylene, butylene, 1- or 2-methylethylene, 1,1-, 1,2- or 2,2-dimethylethylene groups and the like.
[0020]
Unsubstituted or substituted heterocyclic groups include, for example, furyl, thienyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, or N-alkylpyrrolyl, imidazolyl, pyrazolyl groups and the like.
[0021]
Among the amine compounds represented by the above formula (1), there is a preferred group for applying this method.
That is, in this method, R 1 is an unsubstituted phenyl or naphthyl group; a phenyl or naphthyl group substituted with 1 to 5 C 1 to C 4 alkyl groups, C 1 to C 4 alkoxy groups and / or halogen atoms. Or an unsubstituted heterocyclic group, wherein R 2 is a C 1 -C 4 alkyl group; a C 1 -C 4 alkyl group substituted with 1 to 3 phenyl groups; a C 1 -C 4 alkoxy group; A C 1 -C 4 alkoxy group substituted with ˜3 phenyl groups; or an unsubstituted heterocyclic group, wherein R 3 and R 4 are the same or different and represent a hydrogen atom, a C 1 -C 4 alkyl group or 1 Used to racemize an optically active amine represented by the formula (1), which is a C 1 -C 4 alkyl group substituted with 3 phenyl groups, and A is a C 1 -C 6 alkylene group Is preferred.
[0022]
More preferably, in the method, R 1 is an unsubstituted phenyl group or a phenyl group substituted with 1 to 5 C 1 -C 4 alkyl groups, C 1 -C 4 alkoxy groups and / or halogen atoms. R 2 is a C 1 -C 4 alkyl group or a C 1 -C 4 alkyl group substituted with 1 to 3 phenyl groups, and R 3 and R 4 are the same or different and are a hydrogen atom or C 1 -C It is used to racemize an optically active amine represented by the formula (1), which is a 4 alkyl group and A is a methylene or ethylene group.
[0023]
More preferably, the method comprises the following formula (2):
[Chemical formula 5]
Is used for racemization.
[0024]
More preferably, this method is represented by the above formula (2) wherein R 5 is a hydrogen atom, a methyl group, a methoxy group or a chlorine atom, R 6 is an isopropyl group, and R 7 is a hydrogen atom or an ethyl group. Used to racemize the optically active amine.
Most preferably, this method racemizes the optically active amine (PBA) represented by the above formula (2), wherein R 5 is a hydrogen atom, R 6 is an isopropyl group, and R 7 is a hydrogen atom. Use for.
[0025]
The racemate of the amine compound represented by the above formula (1) or formula (2) can be obtained by known organic synthesis or from a commercial product. The optically active amine compound that is racemized according to the present method is often the residue obtained by optically resolving such a racemate and separating one desired optically active substance. Therefore, the optically active amine compound used in the present method may have an optical purity of almost 100% ee (enantiomeric excess), or lower and about 20 to 99% ee.
[0026]
In this method, racemization of an optically active amine means conversion of a relatively high optical purity amine to a lower optical purity amine. That is, by this method, the racemization rate represented by the following formula can be improved to 50% or more, preferably 80% or more, and more preferably 95% or more.
[Expression 1]
In the present method, the catalytic reduction catalyst means a metal catalyst used for catalytic reduction. As the metal, noble metals such as platinum and palladium, nickel, cobalt, iron, copper and the like are used. As a form, for example, platinum may be platinum black, colloidal platinum, platinum oxide or the like, and nickel may be reduced nickel, lacquer raw nickel, nickel formate, or the like. Moreover, nickel, cobalt, iron, etc. may be in the form of a Raney catalyst such as Raney nickel, Raney cobalt, Raney iron or the like. The form which uses a support | carrier together, for example, palladium-carbon, palladium-calcium carbonate, platinum-barium sulfate, nickel-diatomaceous earth, copper chromite, etc. may be sufficient.
Among these catalysts, Raney catalysts are preferred for the present process, Raney nickel or Raney cobalt is particularly preferred, and catalysts prepared from aluminum alloys of nickel and cobalt are more preferred.
Any of the above catalysts can be obtained from commercial products.
The amount of the catalyst used is not particularly limited, but the catalyst is used in an amount of 0.01 to 1.0 part by weight, preferably 0.05 to 0.5 part by weight, based on 1 part by weight of the amine compound.
[0028]
This racemization reaction can be usually carried out by heating and stirring the optically active amine together with the catalytic reduction catalyst in a closed container such as an autoclave. Further, the space in the reaction vessel is usually replaced with an inert gas such as nitrogen. A reaction solvent is not particularly required, but an inert organic solvent such as water or toluene may be used if desired.
[0029]
It has been found that this racemization reaction is advantageously carried out in the presence of ammonia. When ammonia is present in the reaction system, decomposition of the amine compound and by-product formation of a high-boiling secondary amine are suppressed, so that the racemization of the amine compound can be achieved with a high recovery rate.
In the present method, the form of ammonia to be used is not particularly limited, and an aqueous solution thereof or a gaseous one may be used. However, from the viewpoint of operability, ammonia is usually used as an aqueous solution, and its concentration is preferably 5 to 28%. Although the amount of ammonia added is not particularly limited, the reaction is usually performed so that the amount of ammonia is 0.1 to 3.0 equivalents, preferably 0.2 to 1.5 equivalents, with respect to 1 equivalent of the optically active amine of the raw material. Add to the system.
[0030]
Furthermore, it has been found that this racemization reaction is advantageously performed in the absence of hydrogen. In this method, the conditions under hydrogen pressure as in the method disclosed in JP-A-63-185943 are not essential, and the presence of hydrogen may lower the chemical purity of the amine compound obtained after the reaction. Therefore, it may be preferable to perform racemization in the absence of hydrogen.
[0031]
The reaction temperature of the racemization reaction is usually 100 to 250 ° C, preferably 150 to 200 ° C, more preferably 160 to 180 ° C.
The reaction time varies depending on the reaction conditions such as the type and amount of the catalyst used, the concentration and amount of ammonia, the reaction temperature, and the stirring state, but is usually within 50 hours, more usually from 10 to 25 hours.
[0032]
After completion of the reaction, the by-product is transferred to the organic layer and the amine compound is transferred to the aqueous layer by extracting the reaction mixture with an organic solvent under acidic conditions. As the organic solvent, toluene, hexane, ether, ester and the like which are immiscible with water can be used. Next, the target amine compound is obtained by making the aqueous layer alkaline with a base such as sodium hydroxide and extracting with an organic solvent as described above. By this operation, an amine compound with sufficiently high purity can be obtained, but if necessary, distillation or the like can be performed to obtain a target amine compound with higher purity.
[0033]
【Example】
The present invention will be described more specifically based on examples, but the present invention is not limited to these examples.
In the examples, the optical purity of PBA was measured by high performance liquid chromatography analysis under the following conditions, and expressed as an enantiomeric excess (% ee).
Column: Crown Pack (CRAWNPAK) CR (+)
[Daicel] 0.4 × 15cm
Eluent: 0.1 N HClO 4 aqueous solution / methanol = 85/15
Flow rate: 0.8ml / min Temperature: 40 ° C
Detection: UV 210nm
The chemical purity of PBA was measured by gas chromatography analysis under the following conditions, and expressed as a simple area percentage (%).
Column: CBPI-M25-0.25 [Shimadzu Corporation]
Column tank: 40 ° C, heating rate 10 ° C / min, 250 ° C, 19 minutes Retention vaporization Chamber: 270 ° C
Detection: FID, 290 ° C
[0034]
Example 1 Racemization of (R) -PBA with Raney Nickel Catalyst A 230 ml capacity SUS316 autoclave was charged with (R) -PBA [optical purity 47.2% ee, chemical purity 98.9%] (40.00 g), Raney nickel. A catalyst (8.0 g) and 28% aqueous ammonia (18.6 g) were charged, sealed, and purged with nitrogen. Next, stirring was started, and the reaction was carried out at a temperature of 165 ° C. and an internal pressure of 17 kg / cm 2 G for 22.5 hours. As a result of cooling after completion of the reaction and analysis of the reaction solution, it was found that the optical purity of PBA was 7.1% ee and the chemical purity was 93.8%.
The reaction mixture was filtered and the filter cake was washed with toluene (40 g) and water (40 g). The filtrate and the washing solution were combined, and 35% hydrochloric acid (22.94 g) was added thereto for extraction. The aqueous layer was made alkaline by adding a 29% aqueous sodium hydroxide solution (31.26 g) and extracted with fresh toluene (60 g). This aqueous layer was extracted once more with fresh toluene (60 g). These toluene extracts were combined and concentrated under reduced pressure to obtain 36.68 g of residue (chemical purity 95.7%).
Further, the residue was purified by distillation under reduced pressure. As a result, 33.52 g of PBA having an optical purity of 7.1% ee and a chemical purity of 99.6% was obtained. The recovery rate was 83.8%, and the racemization rate was 85.0%.
[0035]
Examples 2 and 3
The reaction was carried out in the same manner as in Example 1 while changing the reaction temperature and reaction time or without adding aqueous ammonia. These results are shown in Table 1 below together with the results of Example 1. From these results, it can be seen that although the racemization proceeds efficiently even in the absence of ammonia, the chemical purity of PBA is somewhat lowered and the addition of aqueous ammonia is desirable.
[0036]
Examples 4-6
The reaction of Example 1 was carried out in the presence of hydrogen without adding aqueous ammonia. Hydrogen was injected after purging with nitrogen. These results are also shown in Table 1 below. These results show that although the racemization proceeds efficiently even in the presence of hydrogen, the chemical purity of PBA decreases.
[Table 1]
Examples 7-11
The reaction was carried out in the same manner as in Example 1 while changing the catalyst amount and the ammonia water concentration. The ammonia water concentration was adjusted by diluting 28% ammonia water as it was or adding water thereto. These results are shown in Table 2 below together with the results of Examples 1 and 2. From these results, it can be seen that by decreasing the ammonia concentration, the chemical purity is slightly reduced, but the rate of racemization is increased.
[Table 2]
Examples 12 to 14 (R) -PBA racemization with Raney cobalt catalyst The Raney cobalt catalyst was used as the racemization catalyst and the amount of the catalyst was changed to carry out the reaction in the same manner as in Example 1. These results are shown in Table 3 below. From these results, it can be seen that even when the Raney cobalt catalyst is used, the racemization reaction proceeds as efficiently as the Raney nickel catalyst.
[Table 3]
【The invention's effect】
As described above, by using this method, an optically active amine having an asymmetric carbon at the β-position of the amino group and beyond, for example, optically active PBA can be racemized efficiently. That is, by combining this method and the optical resolution method, it is possible to efficiently produce an optically active amine having one desired configuration.
Claims (6)
Ｒ ２ はＣ １ 〜Ｃ ４ アルキル基または１〜３個のフェニル基で置換されたＣ １ 〜Ｃ ４ アルキル基を示し、
Ｒ ３ およびＲ ４ は同一または異なって水素原子またはＣ １ 〜Ｃ ４ アルキル基を示し、
Ａはメチレンまたはエチレン基を示し、そして
＊は不斉炭素原子の位置を示す]
で表される光学活性アミンのラセミ化法であって、該アミンに、水素の非存在下に接触還元触媒を作用させることを特徴とするラセミ化法。The following formula (1):
R 2 represents a C 1 -C 4 alkyl group or a C 1 -C 4 alkyl group substituted with 1 to 3 phenyl groups ,
R 3 and R 4 are the same or different and each represents a hydrogen atom or a C 1 -C 4 alkyl group,
A represents a methylene or ethylene group , and * represents the position of an asymmetric carbon atom]
A racemization method of an optically active amine represented by the formula , wherein a catalytic reduction catalyst is allowed to act on the amine in the absence of hydrogen .
で表される光学活性アミンをラセミ化する請求項１に記載のラセミ化法。The following formula (2):
In racemization method of claim 1, racemization of an optically active amine represented.
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| JP23174196A JP3892503B2 (en) | 1996-09-02 | 1996-09-02 | Racemization of optically active amines using catalytic reduction catalysts |
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| JP23174196A JP3892503B2 (en) | 1996-09-02 | 1996-09-02 | Racemization of optically active amines using catalytic reduction catalysts |
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| JP3892503B2 true JP3892503B2 (en) | 2007-03-14 |
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| US9765032B2 (en) * | 2014-02-07 | 2017-09-19 | Sumitomo Chemical Company, Limited | Method for producing (R)-1,1,3-trimethyl-4-aminoindane |
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