US20070060656A1 - Optically active nitro alcohol derivatives, optically active amino alcohol derivatives, and process for producing thereof - Google Patents
Optically active nitro alcohol derivatives, optically active amino alcohol derivatives, and process for producing thereof Download PDFInfo
- Publication number
- US20070060656A1 US20070060656A1 US11/595,987 US59598706A US2007060656A1 US 20070060656 A1 US20070060656 A1 US 20070060656A1 US 59598706 A US59598706 A US 59598706A US 2007060656 A1 US2007060656 A1 US 2007060656A1
- Authority
- US
- United States
- Prior art keywords
- optically active
- group
- nitro
- hydrogen atom
- rare earth
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 64
- 150000001414 amino alcohols Chemical class 0.000 title abstract description 14
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 title description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 62
- 230000003287 optical effect Effects 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 21
- 239000002994 raw material Substances 0.000 claims description 5
- -1 nitro alcohols Chemical class 0.000 abstract description 39
- 239000003814 drug Substances 0.000 abstract description 11
- 229940124630 bronchodilator Drugs 0.000 abstract description 4
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 86
- 229910052761 rare earth metal Inorganic materials 0.000 description 77
- 150000002910 rare earth metals Chemical class 0.000 description 76
- 150000001875 compounds Chemical class 0.000 description 39
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 32
- 238000002360 preparation method Methods 0.000 description 30
- 238000003786 synthesis reaction Methods 0.000 description 29
- 230000015572 biosynthetic process Effects 0.000 description 28
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 28
- 0 CC.CC.[4*]C(C(O)C1=CC=CC=C1)[N+](=O)[O-] Chemical compound CC.CC.[4*]C(C(O)C1=CC=CC=C1)[N+](=O)[O-] 0.000 description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 25
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 239000003054 catalyst Substances 0.000 description 24
- 239000000203 mixture Substances 0.000 description 24
- 230000035484 reaction time Effects 0.000 description 22
- 125000003277 amino group Chemical group 0.000 description 20
- 239000012298 atmosphere Substances 0.000 description 18
- 229910052786 argon Inorganic materials 0.000 description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 16
- 150000001728 carbonyl compounds Chemical class 0.000 description 15
- 239000003446 ligand Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 150000001299 aldehydes Chemical class 0.000 description 14
- SFWYFTZCWXVZOP-INIZCTEOSA-N (1r)-1-[3,4-bis[[tert-butyl(dimethyl)silyl]oxy]phenyl]-2-nitroethanol Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=C([C@@H](O)C[N+]([O-])=O)C=C1O[Si](C)(C)C(C)(C)C SFWYFTZCWXVZOP-INIZCTEOSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000006722 reduction reaction Methods 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 230000004048 modification Effects 0.000 description 10
- 238000012986 modification Methods 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- OTENVZJLWMQSAT-UHFFFAOYSA-N 3,4-bis[[tert-butyl(dimethyl)silyl]oxy]benzaldehyde Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=C(C=O)C=C1O[Si](C)(C)C(C)(C)C OTENVZJLWMQSAT-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000013543 active substance Substances 0.000 description 7
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 7
- 125000004971 nitroalkyl group Chemical group 0.000 description 7
- ULSIYEODSMZIPX-UHFFFAOYSA-N phenylethanolamine Chemical compound NCC(O)C1=CC=CC=C1 ULSIYEODSMZIPX-UHFFFAOYSA-N 0.000 description 7
- GLMSATMVHBUPKH-UHFFFAOYSA-N 1-[3,5-bis(phenylmethoxy)phenyl]-2-nitroethanol Chemical compound C=1C(OCC=2C=CC=CC=2)=CC(C(C[N+]([O-])=O)O)=CC=1OCC1=CC=CC=C1 GLMSATMVHBUPKH-UHFFFAOYSA-N 0.000 description 6
- CIJACALGDAFWIN-UHFFFAOYSA-N 4-[4-(methoxymethoxy)phenyl]butanoic acid Chemical compound COCOC1=CC=C(CCCC(O)=O)C=C1 CIJACALGDAFWIN-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000006842 Henry reaction Methods 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- NEOSFTXNNNEDMY-UHFFFAOYSA-N 1-(2,2-dimethyl-4h-1,3-benzodioxin-6-yl)-2-nitroethanol Chemical compound [O-][N+](=O)CC(O)C1=CC=C2OC(C)(C)OCC2=C1 NEOSFTXNNNEDMY-UHFFFAOYSA-N 0.000 description 5
- XMKJTXBNEGPUAH-UHFFFAOYSA-N 1-[4-[tert-butyl(dimethyl)silyl]oxy-3-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]-2-nitroethanol Chemical compound CC(C)(C)[Si](C)(C)OCC1=CC(C(O)C[N+]([O-])=O)=CC=C1O[Si](C)(C)C(C)(C)C XMKJTXBNEGPUAH-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 229910052772 Samarium Inorganic materials 0.000 description 4
- ISUISGJUXVBWBZ-UHFFFAOYSA-N [4-(1-hydroxy-2-nitroethyl)phenyl] benzoate Chemical compound C1=CC(C(C[N+]([O-])=O)O)=CC=C1OC(=O)C1=CC=CC=C1 ISUISGJUXVBWBZ-UHFFFAOYSA-N 0.000 description 4
- 150000003935 benzaldehydes Chemical class 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- SFWYFTZCWXVZOP-MRXNPFEDSA-N (1s)-1-[3,4-bis[[tert-butyl(dimethyl)silyl]oxy]phenyl]-2-nitroethanol Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=C([C@H](O)C[N+]([O-])=O)C=C1O[Si](C)(C)C(C)(C)C SFWYFTZCWXVZOP-MRXNPFEDSA-N 0.000 description 3
- WYHMNJKAVNPOOR-UHFFFAOYSA-N (2-acetyloxy-4-formylphenyl) acetate Chemical compound CC(=O)OC1=CC=C(C=O)C=C1OC(C)=O WYHMNJKAVNPOOR-UHFFFAOYSA-N 0.000 description 3
- KYZWJGYDXCOKRS-UHFFFAOYSA-N (4-formylphenyl) benzoate Chemical compound C1=CC(C=O)=CC=C1OC(=O)C1=CC=CC=C1 KYZWJGYDXCOKRS-UHFFFAOYSA-N 0.000 description 3
- SFWYFTZCWXVZOP-UHFFFAOYSA-N 1-[3,4-bis[[tert-butyl(dimethyl)silyl]oxy]phenyl]-2-nitroethanol Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=C(C(O)C[N+]([O-])=O)C=C1O[Si](C)(C)C(C)(C)C SFWYFTZCWXVZOP-UHFFFAOYSA-N 0.000 description 3
- OWNWYCOLFIFTLK-YDALLXLXSA-N 4-[(1r)-2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;hydron;chloride Chemical compound Cl.CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 OWNWYCOLFIFTLK-YDALLXLXSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 229910052688 Gadolinium Inorganic materials 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000004703 alkoxides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 229910052746 lanthanum Inorganic materials 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 239000003071 vasodilator agent Substances 0.000 description 3
- WJUFSDZVCOTFON-UHFFFAOYSA-N veratraldehyde Chemical compound COC1=CC=C(C=O)C=C1OC WJUFSDZVCOTFON-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 2
- AOMQIZUQJSVRST-QMMMGPOBSA-N (1r)-1-(3,4-dimethoxyphenyl)-2-nitroethanol Chemical compound COC1=CC=C([C@@H](O)C[N+]([O-])=O)C=C1OC AOMQIZUQJSVRST-QMMMGPOBSA-N 0.000 description 2
- ZDTPGOFRVWSBGZ-FQEVSTJZSA-N (1r)-1-[3,4-bis(phenylmethoxy)phenyl]-2-nitroethanol Chemical compound C=1C=CC=CC=1COC1=CC([C@H](C[N+]([O-])=O)O)=CC=C1OCC1=CC=CC=C1 ZDTPGOFRVWSBGZ-FQEVSTJZSA-N 0.000 description 2
- XUEWIQNQPBSCOR-MRVPVSSYSA-N (1s)-2-nitro-1-phenylethanol Chemical compound [O-][N+](=O)C[C@@H](O)C1=CC=CC=C1 XUEWIQNQPBSCOR-MRVPVSSYSA-N 0.000 description 2
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical class C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 description 2
- AOMQIZUQJSVRST-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-2-nitroethanol Chemical compound COC1=CC=C(C(O)C[N+]([O-])=O)C=C1OC AOMQIZUQJSVRST-UHFFFAOYSA-N 0.000 description 2
- ZDTPGOFRVWSBGZ-UHFFFAOYSA-N 1-[3,4-bis(phenylmethoxy)phenyl]-2-nitroethanol Chemical compound C=1C=CC=CC=1COC1=CC(C(C[N+]([O-])=O)O)=CC=C1OCC1=CC=CC=C1 ZDTPGOFRVWSBGZ-UHFFFAOYSA-N 0.000 description 2
- AOSFYDFNDYTSCJ-UHFFFAOYSA-N 1-[3,5-bis[[tert-butyl(dimethyl)silyl]oxy]phenyl]-2-nitroethanol Chemical compound CC(C)(C)[Si](C)(C)OC1=CC(O[Si](C)(C)C(C)(C)C)=CC(C(O)C[N+]([O-])=O)=C1 AOSFYDFNDYTSCJ-UHFFFAOYSA-N 0.000 description 2
- PYVBGEUEQLAGGN-UHFFFAOYSA-N 2,3,6-trihydroxybenzaldehyde Chemical compound OC1=CC=C(O)C(C=O)=C1O PYVBGEUEQLAGGN-UHFFFAOYSA-N 0.000 description 2
- IXWOUPGDGMCKGT-UHFFFAOYSA-N 2,3-dihydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1O IXWOUPGDGMCKGT-UHFFFAOYSA-N 0.000 description 2
- WNCNWLVQSHZVKV-UHFFFAOYSA-N 2,4,5-trihydroxybenzaldehyde Chemical compound OC1=CC(O)=C(C=O)C=C1O WNCNWLVQSHZVKV-UHFFFAOYSA-N 0.000 description 2
- BTQAJGSMXCDDAJ-UHFFFAOYSA-N 2,4,6-trihydroxybenzaldehyde Chemical compound OC1=CC(O)=C(C=O)C(O)=C1 BTQAJGSMXCDDAJ-UHFFFAOYSA-N 0.000 description 2
- IUNJCFABHJZSKB-UHFFFAOYSA-N 2,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C(O)=C1 IUNJCFABHJZSKB-UHFFFAOYSA-N 0.000 description 2
- CLFRCXCBWIQVRN-UHFFFAOYSA-N 2,5-dihydroxybenzaldehyde Chemical compound OC1=CC=C(O)C(C=O)=C1 CLFRCXCBWIQVRN-UHFFFAOYSA-N 0.000 description 2
- XTAAANMPVNIYBF-UHFFFAOYSA-N 2-amino-1-(2,2-dimethyl-4h-1,3-benzodioxin-6-yl)ethanol Chemical compound NCC(O)C1=CC=C2OC(C)(C)OCC2=C1 XTAAANMPVNIYBF-UHFFFAOYSA-N 0.000 description 2
- 229940083239 2-amino-1-phenylethanol derivative Drugs 0.000 description 2
- XDDLXZHBWVFPRG-UHFFFAOYSA-N 3,4-bis(phenylmethoxy)benzaldehyde Chemical compound C=1C=CC=CC=1COC1=CC(C=O)=CC=C1OCC1=CC=CC=C1 XDDLXZHBWVFPRG-UHFFFAOYSA-N 0.000 description 2
- IBGBGRVKPALMCQ-UHFFFAOYSA-N 3,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1O IBGBGRVKPALMCQ-UHFFFAOYSA-N 0.000 description 2
- SXHKYXQQKFOFCY-UHFFFAOYSA-N 3,5-dibenzyl-2-(2-formylphenoxy)benzaldehyde Chemical compound O=CC1=CC=CC=C1OC(C(=CC(CC=1C=CC=CC=1)=C1)C=O)=C1CC1=CC=CC=C1 SXHKYXQQKFOFCY-UHFFFAOYSA-N 0.000 description 2
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 2
- HLWOFCDYWNASDT-UHFFFAOYSA-N 4-[tert-butyl(dimethyl)silyl]oxy-3-[[tert-butyl(dimethyl)silyl]oxymethyl]benzaldehyde Chemical compound CC(C)(C)[Si](C)(C)OCC1=CC(C=O)=CC=C1O[Si](C)(C)C(C)(C)C HLWOFCDYWNASDT-UHFFFAOYSA-N 0.000 description 2
- VYTYSPHDRKSRDB-UHFFFAOYSA-N 4-hydroxy-2-(hydroxymethyl)benzaldehyde Chemical compound OCC1=CC(O)=CC=C1C=O VYTYSPHDRKSRDB-UHFFFAOYSA-N 0.000 description 2
- SCXZNYRQOPBUTM-UHFFFAOYSA-N 4-hydroxy-3-(hydroxymethyl)benzaldehyde Chemical compound OCC1=CC(C=O)=CC=C1O SCXZNYRQOPBUTM-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XYYJTUTUQAPVFS-UHFFFAOYSA-N CC.CC.[H]C(=O)C1=CC=CC=C1 Chemical compound CC.CC.[H]C(=O)C1=CC=CC=C1 XYYJTUTUQAPVFS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 229910052693 Europium Inorganic materials 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 229910052779 Neodymium Inorganic materials 0.000 description 2
- IIRWWTKISYTTBL-SFHVURJKSA-N OC1=CC=C(CCCCNC[C@H](O)C2=CC(O)=C(O)C=C2)C=C1 Chemical compound OC1=CC=C(CCCCNC[C@H](O)C2=CC(O)=C(O)C=C2)C=C1 IIRWWTKISYTTBL-SFHVURJKSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 229910019020 PtO2 Inorganic materials 0.000 description 2
- 229910052771 Terbium Inorganic materials 0.000 description 2
- 229910052769 Ytterbium Inorganic materials 0.000 description 2
- BPNKVSKNJKREON-UHFFFAOYSA-N [2-acetyloxy-4-(1-hydroxy-2-nitroethyl)phenyl] acetate Chemical compound CC(=O)OC1=CC=C(C(O)C[N+]([O-])=O)C=C1OC(C)=O BPNKVSKNJKREON-UHFFFAOYSA-N 0.000 description 2
- BPNKVSKNJKREON-JTQLQIEISA-N [2-acetyloxy-4-[(1r)-1-hydroxy-2-nitroethyl]phenyl] acetate Chemical compound CC(=O)OC1=CC=C([C@@H](O)C[N+]([O-])=O)C=C1OC(C)=O BPNKVSKNJKREON-JTQLQIEISA-N 0.000 description 2
- PHITXMZDHRNAGA-UHFFFAOYSA-N [2-benzoyloxy-5-(1-hydroxy-2-nitroethyl)phenyl]methyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC(C(C[N+]([O-])=O)O)=CC=C1OC(=O)C1=CC=CC=C1 PHITXMZDHRNAGA-UHFFFAOYSA-N 0.000 description 2
- LYAZWVMKSACRFO-UHFFFAOYSA-N [3-acetyloxy-5-(1-hydroxy-2-nitroethyl)phenyl] acetate Chemical compound CC(=O)OC1=CC(OC(C)=O)=CC(C(O)C[N+]([O-])=O)=C1 LYAZWVMKSACRFO-UHFFFAOYSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 229960004162 bamethan Drugs 0.000 description 2
- RDUHXGIIUDVSHR-UHFFFAOYSA-N bamethan Chemical compound CCCCNCC(O)C1=CC=C(O)C=C1 RDUHXGIIUDVSHR-UHFFFAOYSA-N 0.000 description 2
- 229960004731 bamethan sulfate Drugs 0.000 description 2
- PARMADWNFXEEFC-UHFFFAOYSA-N bamethan sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[NH2+]CC(O)C1=CC=C(O)C=C1.CCCC[NH2+]CC(O)C1=CC=C(O)C=C1 PARMADWNFXEEFC-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 150000002736 metal compounds Chemical class 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
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- GIZSHQYTTBQKOQ-UHFFFAOYSA-N threo-Syringoylglycerol Chemical group COC1=CC(C(O)C(O)CO)=CC(OC)=C1O GIZSHQYTTBQKOQ-UHFFFAOYSA-N 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
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- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
- B01J31/223—At least two oxygen atoms present in one at least bidentate or bridging ligand
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- C07C205/14—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to acyclic carbon atoms
- C07C205/16—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to acyclic carbon atoms of a carbon skeleton containing six-membered aromatic rings
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- C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
- C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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- C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
- C07C215/60—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
- C07C217/10—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical containing six-membered aromatic rings
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- C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
- C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
- C07C217/70—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C07C219/28—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C219/30—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
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- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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- B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
- B01J2231/341—1,2-additions, e.g. aldol or Knoevenagel condensations
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Definitions
- the present invention relates to optically active 1-substituted phenyl-2-nitro alcohol derivatives and the process for producing thereof, to optically active 1-substituted phenyl-2-amino alcohol derivatives and the process for producing thereof, and to the process for producing (R)-albutamin and (R)-sarmeterol using these compounds.
- optically active nitro alcohols of the present invention are useful in the medical field, particularly as a synthetic intermediate of nitrogenous compounds useful for thrombotic diseases, for example, cerebral infarction, myocardial infarction, angina pectoris, and peripheral arterial occlusion; of optically active albuterol, optically active sarmeterol, (R)-albutamin, and optically active terbutaline hydrochloride which are useful as a bronchodilator; and of optically active bamethan sulfate useful as a vasodilator. And these compounds can be produced in high yields and industrially advantageously with the process for producing thereof of the present invention.
- optically active amino alcohols of the present invention can be obtained from the above optically active nitro alcohols, and they are also useful intermediates of pharmaceuticals such as a thrombolytic agent, a central nervous system agent, an antiadipogenous agent and an antiasthmatic agent.
- optically active nitro alcohols of the present invention are novel substances obtained by the nitro-aldol reaction between nitromethane and benzaldehyde derivatives.
- the nitro-group containing compounds (intermediates) of the present invention have not been known yet, and the only example is (S)-1-phenyl-2-nitroethanol, which has no substituent, reported by the present inventors. Accordingly, the process for producing a group of pharmaceuticals which are to be produced from optically active 1-substituted phenyl-2-nitro alcohol derivatives has not been known, either.
- optically active 1-substituted phenyl-2-amino alcohol derivatives of the present invention are a group of the compounds obtained from the novel optically active 1-substituted phenyl-2-nitro alcohol derivatives of the present invention.
- Japanese Patent Application Laid-Open No. 64-9979 Japanese Patent Publication No. 4-48791
- Japanese Patent Publication No. 4-48791 Japanese Patent Publication No. 4-48791
- Japanese Patent Application Laid-Open No. 2-85247 there is disclosed the method of subjecting the racemic modification of 2-amino-1-(4-chlorophenyl) ethanol to optical resolution using D-tartaric acid.
- a racemic modification of 1-phenyl-2-aminoethanol is a known compound, for example, in Japanese Patent Application Laid-Open No. 58-203950, there is disclosed the synthetic method in which 1-(3,4-dihidroxyphenyl)-2-nitroethanol is subjected to a catalytic hydrogen addition reaction using Raney nickel to proceed the reduction reaction quantitatively, so as to obtain a racemic modification of 1-(3,4-dihidroxyphenyl)-2-aminoethanol; however, the disclosure makes no concrete reference to the optically active substances of 1-substituted phenyl-2-aminoethanol.
- optically active 1-substituted phenyl-2-nitroethanol derivatives have not existed to date, and the products obtained by the reduction of the nitro group thereof, optically active 1-substituted phenyl-2-aminoethanol derivatives, have not been produced.
- European Patent No. 0,006,735 specification describes that the intended pharmaceuticals can be synthesized by reacting a racemic and optically active amino alcohol compound with a carbonyl compound or a halide; however, actually disclosed in its embodiments is only the process for producing racemic sarmeterol by reacting a racemic amino alcohol compound with a carbonyl compound or a halide.
- optically active 1-substituted phenyl-2-nitroethanol compounds have not existed to date, therefore, the process for producing optically active albutamin and optically active sarmeterol using optically active catechol amines obtained by the reduction of the nitro group thereof has not been known.
- the present invention has been made in light of the foregoing problems of the prior arts. Accordingly, it is an object of the present invention to provide optically active 1-substituted phenyl-2-nitro alcohol derivatives and optically active 1-substituted phenyl-2-amino alcohol derivatives obtained by reducing the optically active 1-substituted phenyl-2-nitro alcohol derivatives of the present invention both of which are useful as an intermediate of pharmaceuticals such as (R)-albutamin, (R)-sarmeterol, (R)-albuterol and (R)-terbutaline hydrochloride which are useful as a bronchodilator, and bamethan sulfate which is useful as a vasohypotonic.
- Another object of the present invention is to provide a process for producing these compounds.
- another object of the present invention is to provide (R)-albutamin and (R)-sarmeterol produced using these compounds.
- the present inventors came to know that, for the optically active nitro alcohol derivatives, a group of the intended compounds can be obtained using the group of rare earth metal complexes described by themselves in U.S. Pat. No. 5,336,653 specification and Tetrahedron Letters (1993) vol. 34, p. 2657 etc.
- the present inventors came to know that, for the optically active amino alcohol derivatives, a group of the intended compounds can be easily obtained by subjecting the optically active nitro alcohol derivatives obtained as above to catalytic hydrogen addition in an organic solvent. And the present inventors found that they can achieve the above objects with these knowledge and have finally completed the present invention.
- the optically active 1-substituted phenyl-2-nitro alcohol derivatives of the present invention are characterized by the following formula (1), in which n and m represent the positive integers satisfying 0 ⁇ n+m ⁇ 5; R 1 and R 2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and when n+m is 2 or more, R 1 and R 2 can either be independent of each other or form a ring among R 1 s, R 2 s, or R 1 s plus R 2 s; R 3 represents —(CH 2 ) l —, in which 1 is 1, 2 or 3; R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group.
- formula (1) in which n and m represent the positive integers satisfying 0 ⁇ n+m ⁇ 5; R 1 and R 2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and when n+m is 2 or more, R 1 and R 2 can either be independent of each other or form a
- Suitable examples of the optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohols of the present invention are characterized by the following formula (1-1), in which R 5 and R 6 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring; R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group.
- (R)-albutamin etc. useful as a pharmaceutical, can be produced from the compounds of the above group of which R 4 is a hydrogen atom and isomer type is R-type, by converting the nitro group into an amino group, reacting the amino group with a carbonyl compound or an alkyl halide compound, and then eliminating the hydroxyl-protective group.
- Suitable examples of the optically active 1-(3-hydroxymethyl-4-hydroxyphenyl)-2-nitro alcohols of the present invention are characterized by the following formula (1-2), in which R 1 and R 2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring; R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group.
- (R)-sarmeterol, (R)-albuterol etc. useful as a pharmaceutical, can be produced from the compounds of the above group of which R 4 is a hydrogen atom and isomer type is R-type, by converting the nitro group into an amino group, reacting the amino group with a carbonyl compound or an alkyl halide compound, and then eliminating the hydroxyl-protective group.
- Suitable examples of the optically active 1-(3,5-dihydroxyphenyl)-2-nitro alcohols of the present invention are characterized by the following formula (1-3), in which R 1 and R 2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring; R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group.
- Optically active terbutaline etc. useful as a bronchodilator, can be produced from the compounds of the above group of R 4 is a hydrogen atom, by converting the nitro group into an amino group, reacting the amino group with a carbonyl compound or an alkyl halide compound, and then eliminating the hydroxyl-protective group.
- Suitable examples of the optically active 1-(4-hydroxyphenyl)-2-nitro alcohols of the present invention are characterized by the following formula (1-4), in which R 1 represents a hydrogen atom or a hydroxyl-protective group, respectively, and it can either be independent of each other or form a ring; R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group.
- Optically active bamethan etc. useful as a vasohypotonic, can be produced from the compounds of the above group of which R 4 is a hydrogen atom, by converting the nitro group into an amino group, reacting the amino group of the amino alcohol with a carbonyl compound or an alkyl halide compound, and then eliminating the hydroxyl-protective group.
- optically active nitro alcohols of the present invention are as follows.
- optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives (optically active 1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol) of formula (1-1), in which R 4 is a hydrogen atom, and each of R 5 and R 6 is a t-butyldimethylsiloxy group.
- Optically active albutamin etc. useful as a pharmaceutical can be produced from this compound by converting the nitro group into an amino group, reacting the optically active amino alcohol with a carbonyl compound (for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.), and then eliminating the hydroxyl-protective group.
- a carbonyl compound for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.
- optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives (optically active 1-(3,4-dimethoxyphenyl)-2-nitroethanol) of formula (1-1), in which R 4 is a hydrogen atom, and each of R 5 and R 6 is a methyl group.
- Optically active albutamin etc. useful as a pharmaceutical can be produced from this compound by converting the nitro group into an amino group, reacting the amino alcohol with a carbonyl compound (for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.), and then eliminating the hydroxyl-protective group.
- a carbonyl compound for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.
- optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives (optically active 1-(3,4-dibenzyloxyphenyl)-2-nitroethanol) of formula (1-1), in which R 4 is a hydrogen atom, and each of R 5 and R 6 is a benzyl group.
- Optically active albutamin etc. useful as a pharmaceutical can be produced from this compound by converting the nitro group into an amino group, reacting the optically active amino alcohol with a carbonyl compound (for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.), and then eliminating the hydroxyl-protective group.
- a carbonyl compound for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.
- optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives (optically active 1-(3,4-diacetoxyphenyl)-2-nitroethanol) of formula (1-1), in which R 4 is a hydrogen atom, and each of R 5 and R 6 is an acetyl group.
- Optically active albutamin etc. useful as a pharmaceutical can be produced from this compound by converting the nitro group into an amino group, reacting the optically active amino alcohol with a carbonyl compound (for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.), and then eliminating the hydroxyl-protective group.
- a carbonyl compound for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.
- optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives (optically active ⁇ -nitromethyl-piperonyl alcohol) of formula (1-1), in which R 4 is a hydrogen atom, and R 5 and R 6 are cyclized with a methylene group.
- Optically active albutamin etc. useful as a pharmaceutical can be produced from this compound by converting into an amino group, reacting the optically active amino alcohol with a carbonyl compound (for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.), and then eliminating the hydroxyl-protective group.
- a carbonyl compound for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.
- Optically active sarmeterol etc. useful as a pharmaceutical can be produced from this compound by converting into an amino group, reacting the amino group with a carbonyl compound, and then eliminating the hydroxyl-protective group.
- Optically active terbutaline etc. useful as a pharmaceutical can be produced from this compound by converting into an amino group, reacting the amino group with a carbonyl compound, and then eliminating the hydroxyl-protective group.
- optically active 1-(4-benzoyloxyphenyl)-2-nitroethanol of formula (1-4) set forth in claim 1 characterized in that R 4 is a hydrogen atom and R 1 is a benzoyl group.
- Optically active bamethan etc. useful as a pharmaceutical can be produced from this compound by converting into an amino group, reacting the amino group with a carbonyl compound, and then eliminating the hydroxyl-protective group.
- the process for stereoselectively producing optically active nitro alcohols of the present invention is characterized in that, when producing optically active 1-substituted phenyl-2-nitro alcohol derivatives, an aldehyde of the following formula (2), in which R 5 and R 6 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring together; R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, is reacted with a nitro alkane derivative of the following formula (3), R 4 —CH 2 —NO 2 (3) in which R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, in the presence of a rare earth metal complex having an optically active ligand.
- an aldehyde of the following formula (2) in which R 5 and R 6 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring
- the process for stereoselectively producing optically active nitro alcohols of the present invention is characterized in that, when producing optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives, an aldehyde of the following formula (2-1), in which R 5 and R 6 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring together; R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, is reacted with a nitro alkane derivative of the following formula (3), R 4 —CH 2 —NO 2 (3) in which R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, in the presence of a rare earth metal complex having an optically active ligand.
- an aldehyde of the following formula (2-1) in which R 5 and R 6 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or
- the process for stereoselectively producing optically active nitro alcohols of the present invention is characterized in that, when producing optically active 1-(3-hydroxymethyl-4-hydroxyphenyl)-2-nitro alcohol derivatives, an aldehyde of the following formula (2-2), in which R 1 and R 2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring together; R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, is reacted with a nitro alkane derivative of the following formula (3), R 4 —CH 2 —NO 2 (3) in which R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, in the presence of a rare earth metal complex having an optically active ligand.
- an aldehyde of the following formula (2-2) in which R 1 and R 2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other
- the process for stereoselectively producing optically active nitro alcohols of the present invention is characterized in that, when producing optically active 1-(3,5-dihydroxyphenyl)-2-nitro alcohol derivatives, an aldehyde of the following formula (2-3), in which R 1 and R 2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring together; R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, is reacted with a nitro alkane derivative of the following formula (3), R 4 —CH 2 —NO 2 (3) in which R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, in the presence of a rare earth metal complex having an optically active ligand.
- an aldehyde of the following formula (2-3) in which R 1 and R 2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or
- the process for stereoselectively producing optically active nitro alcohols of the present invention is characterized in that, when producing optically active 1-(4-hydroxyphenyl)-2-nitro alcohol derivatives, an aldehyde of the following formula (2-4), in which R 1 represents a hydrogen atom or a hydroxyl-protective group; R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, is reacted with a nitro alkane derivative of the following formula (3), R 4 —CH 2 —NO 2 (3) in which R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group, in the presence of a rare earth metal complex having an optically active ligand.
- an aldehyde of the following formula (2-4) in which R 1 represents a hydrogen atom or a hydroxyl-protective group
- R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group
- R 4 represents a hydrogen atom, an alkyl group,
- Suitable examples of the process for stereoselectively producing optically active nitro alcohols of the present invention include the following embodiments.
- optically active nitro alcohol derivatives characterized in that, when producing an optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula (1-1) in which R 4 is a hydrogen atom and each of R 5 and R 6 is a t-butyldimethylsiloxy group (optically active 1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol), an aldehyde of the following formula (4) is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand.
- the process for stereoselectively producing optically active nitro alcohol derivatives characterized in that, when producing an optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula (1-1) in which R 4 is a hydrogen atom and each of R 5 and R 6 is a methyl group (optically active 1-(3,4-dimethoxyphenyl)-2-nitroethanol), an aldehyde of the following formula (5) is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand.
- the process for stereoselectively producing optically active nitro alcohol derivatives characterized in that, when producing an optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula (1-1) in which R 4 is a hydrogen atom and each of R 5 and R 6 is a benzyl group (optically active 1-(3,4-dibenzyloxyphenyl)-2-nitroethanol), an aldehyde of the following formula (6) is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand.
- the process for stereoselectively producing optically active nitro alcohol derivatives characterized in that, when producing an optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula (1-1) in which R 4 is a hydrogen atom and each of R 5 and R 6 is a acetyl group (optically active 1-(3,4-diacetoxyphenyl)-2-nitroethanol), an aldehyde of the following formula (7) is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand.
- the process for stereoselectively producing optically active nitro alcohol derivatives characterized in that, when producing an optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula (1-1) in which R 4 is a hydrogen atom and R 5 and R 6 are cyclized with a methylene group (optically active ⁇ -nitromethyl-piperonyl alcohol), an aldehyde of the following formula (8) is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand.
- the rare earth metal complexes as above are preferably prepared from an alkoxide of Y, La, Nd, Sm, Eu, Gd, Tb, Dy, Pr or Yb, or a trichloride of these rare earth metals; an optically active 1,1′-bi-2-naphthol derivative of the following formula (12) or the following formula (13) in which each of R 7 and R 8 independently represent a hydrogen atom, an alkyl group of C 1 -C 4 , an ethynyl group, a trialkylsilylethynyl group, or a phenyl group, and R 7 can be at any position of 4, 5, 6 and 7, and R 8 at any position of 4′, 5′, 6′ and 7′; and an alkaline metal compound of lithium, sodium, or potassium.
- the rare earth metal complexes to be used are prepared in such a way that the composition ratio of the alkoxide or trichloride of the above rare earth metals, the optically active 1,1′-bi-2-naphthol compound, and the alkaline metal is within the range of 1:1-3:0-10.
- the optically active 1-substituted phenyl-2-amino alcohol derivatives of the present invention are characterized by the following formula (14), in which n and m represent the positive integers satisfying 0 ⁇ n+m ⁇ 5; R 1 and R 2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and when n+m is 2 or more, R 1 and R 2 can either be independent of each other or form a ring among R 1 s, among R 2 s, and among R 1 (s) and R 2 (s); R 3 represents —(CH 2 ) l — in which l represents 0, 1, or 3; R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group.
- formula (14) in which n and m represent the positive integers satisfying 0 ⁇ n+m ⁇ 5; R 1 and R 2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and when n+m is 2 or more, R 1 and R 2 can either be
- optically active 1-substituted phenyl-2-amino alcohol derivatives of the present invention are the optically active 1-(3,4-dihydroxyphenyl)-2-amino alcohol derivatives of the following formula (14-1) in which R 5 and R 6 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring; R 4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group.
- the process for producing the optically active amino alcohol derivatives of the present invention is characterized in that, when producing optically active 1-substituted phenyl-2-amino alcohol derivatives, the optically active 1-substituted phenyl-2-nitro alcohol derivatives described above are stereoselectively reduced.
- optically active albutamin and sarmeterol can be produced by reacting these optically active amino alcohol derivatives with a carbonyl compound or an alkyl halide so as to introduce an alkyl group etc. into the amino group, and then eliminating hydroxyl-protective group; therefore, the optically active nitro alcohol derivatives and optically active amino alcohols of the present invention are useful pharmaceutical intermediates.
- nitro-aldol reaction between a benzaldehyde derivative and a nitro alkane proceeds in the presence of a basic catalyst.
- the asymmetric nitro-aldol reaction according to the present invention can be carried out by the reaction of a benzaldehyde derivative and a nitro alkane in the presence of a rare earth metal complex having an optically active ligand.
- optically active 1,1′-bi-2-naphthol derivatives of the following formula (12) or the following formula (13) in which R 7 and R 8 independently represent a hydrogen atom, an alkyl group of C 1 -C 4 , an ethynyl group, a trialkylsilylethynyl group, or a phenyl group, and R 7 can be at any position of 4, 5, 6 and 7, and R 8 at any position of 4′, 5′, 6′ and 7′.
- reaction equation 1 The process for preparing a rare earth metal complex solution can be briefly illustrated by the following (reaction equation 1), although the process is described in detail in the foregoing literature. This is exemplary of the process of this invention, and it is to be understood that the invention is not intended to be limited to the specific process.
- the present invention uses only one type of isomer, R-type or S-type, of the above optically active binaphthols.
- R 7 can be at any position of 3, 4, 5, 6 and 7, and R 8 at any position of 3′, 4′, 5′, 6′ and 7′, and it is found at present that, in terms of yield and optical purity, good results are obtained particularly from the optically active binaphthol having substituents at 6 and 6′ positions.
- R 7 and R 8 include a hydrogen atom; an alkyl group of methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, or t-butyl; a phenyl group; an alkenyl group; a trialkylsilylethynyl group (in this case, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, or t-butyl, tow alkyls can be different from each other or can be the same); a cyano group; and a halogen; and any combination can be adopted.
- rare earth metals of the rare earth metal compounds include Y, La, Nd, Sm, Eu, Gd, Tb, Dy, Pr, and Yb, any of the metals can be used suitably.
- rare earth metal compounds examples include an alkoxide (including methoxide, ethoxide, propoxide, isopropoxide, n-butoxide, s-butoxide, and t-butoxide), a chloride (including both an anhydride and a hydride), and a nitrate, and any of them can be used preferably.
- alkaline metal compounds used for the preparation of rare earth metal complexes include alkylalkaline metals (for example, methyllithium and n-butyllithium), alkaline metal hydroxides (for example, lithium hydroxide, sodium hydroxide and potassium hydroxide).
- alkylalkaline metals for example, methyllithium and n-butyllithium
- alkaline metal hydroxides for example, lithium hydroxide, sodium hydroxide and potassium hydroxide.
- solvents used in the preparation of a rare earth metal complex solution include THF; however, the present invention is not limited to the specific solvent, and any solvents can be used as long as they do not change the structure of the rare earth metal complexes.
- THF include ether-based solvents (for example, diethyl ether and 1,4-dioxane), halogen-based solvents (for example, methylene chloride, chloroform, 1,1,1-trichloroethane and monochlorobenzene), hydrocarbon-based solvents (for example, benzene, toluene, n-hexane and n-heptane), and fatty acid esters (for example, ethyl acetate and methyl acetate), in addition, polar solvents such as dimethyl sulfoxide, N,N′-dimethylformamide, etc. can also be used. These solvents can be used in a single form or as a mixture of 2 or more types.
- aldehydes used as a raw material for the process of the present invention include 2-hydroxybenzaldehyde, 3-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 2,3-dihydroxybenzaldehyde, 2,4-dihydroxybenzaldehyde, 2,5-dihydroxybenzaldehyde, 2,6-dihydroxybenzaldehyde, 3,4-dihydroxybenzaldehyde, 3,5-dihydroxybenzaldehyde, 2,3,4-trihydroxybenzaldehyde, 2,3,5-trihydroxybenzaldehyde, 2,3,6-trihydroxybenzaldehyde, 2,4,5-trihydroxybenzaldehyde, 2,4,6-trihydroxybenzaldehyde, 2-hydroxy-3-hydroxymethylbenzaldehyde, 2-hydroxy-4-hydroxymethylbenzaldehyde, 2-hydroxy-5-hydroxymethylbenzaldehyde, 2-hydroxy-6-hydroxymethylbenzaldehyde, 3-hydroxy-2-hydroxymethylbenzaldehyde, 3-hydroxy
- hydroxyl-protective groups used in the present invention include a methyl group, a tetrahydropyranyl group, an allyl group, an isopropyl group, a t-butyl group, a benzyl group, an acetyl group, and a trimethylsilyl group which are described in Protective Groups in Organic Synthesis.
- optically active 1-substituted phenyl-2-amino alcohol derivatives of the present invention are synthesized by dissolving the corresponding optically active 1-substituted phenyl-2-nitroethanol compounds in an organic solvent, dispersing a catalytic hydrogen addition catalyst, and subjecting the optically active 1-substituted phenyl-2-nitroethanol compounds to hydrogen addition under hydrogen pressure.
- organic solvents examples include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl butyrate, and ethyl butyrate; however, the present invention is not intended to be limited to the specific solvent, and these alcohols and esters can be used in a single form or as a mixture in desired proportions.
- alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol
- esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl butyrate, and ethyl butyrate; however, the present invention is not intended to be limited to the specific solvent, and these alcohols and esters can
- catalytic hydrogen addition catalysts usual hydrogen addition catalysts are satisfactory, and the examples include Pt—C, Pd—C and PtO 2 .
- the present invention is not intended to be limited to the specific amount of catalyst, considering the reaction time, 0.01 wt % ormore of catalyst is preferably added based on the substrate (nitro alcohol).
- the present invention is not intended to be limited to the specific reaction temperature, considering the intramolecular dehydration of nitro alcohols and the racemization of the products, the temperature is preferably 50° C. and below.
- the present invention is not intended to be limited to the specific hydrogen pressure and preferably the pressure is in the range from 0.1 to 30 MPa, considering the production equipment, more preferably in the range from 0.1 to 1 MPa.
- optical purity was determined by liquid chromatography (HPLC) (CHIRALPAK AD or CHIRALCEL OD by Daicel Chemical Industries, Ltd.). And 1 H-NMR was measured with JNM-EX-270 (270 MHz) by JEOL.
- a rare earth metal complex solution B0 was prepared following the same procedure as in the preparation of the rare earth metal complex solution A0, except that lanthanum triisopropoxy La (Oi-Pr) 3 was used instead of samarium triisopropoxy Sm (Oi-Pr) 3 .
- a rare earth metal complex solution C0 was prepared following the same procedure as in the preparation of the rare earth metal complex solution A0, except that dysprosium triisopropoxy Dy (Oi-Pr) 3 was used instead of Sm (Oi-Pr) 3 .
- a rare earth metal complex solution D0 was prepared following the same procedure as in the preparation of the rare earth metal complex solution A0, except that gadolinium triisopropoxy Gd (Oi-Pr) 3 was used instead of Sm (Oi-Pr) 3 .
- a rare earth metal complex solution E0 was prepared following the same procedure as in the preparation of the rare earth metal complex solution A0, except that praseodymium triisopropoxy Pr (Oi-Pr) 3 was used instead of Sm (Oi-Pr) 3 .
- a metal complex solution was prepared following the same procedure as in the preparation of the rare earth metal complex solution A0, except that (R)-1,1′-dihydroxy-2,2′-binaphthalene was used instead of (S)-6,6′-bis(triethylsilylethynyl)-1,1′-dihydroxy-2,2′-binaphthalene, after which 54 ⁇ l of hexane solution of 1.72 mol/dm 3 n-BuLi (0.093 mmol) was added dropwise, so as to prepare a rare earth metal complex solution F1.
- the rare earth metal complex solution F1 (10 ml) and 0.80 g (13.0 mmol) of nitromethane were mixed and stirred together for 30 minutes under the atmosphere of nitrogen.
- a solution of 1.00 g (2.6 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde dissolved in 20 ml of THF was added dropwise to the mixture.
- (S)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with an optical purity of 93% e.e. was obtained in a yield of 85%.
- Optically active 1-(4-benzoyloxyphenyl)-2-nitroethanol with an optical purity of 50% e.e. was obtained from 4-benzoyloxybenzaldehyde using the rare earth metal complex solution F1 under the atmosphere of nitrogen at ⁇ 30° C. after 24-hour reaction time.
- the intended compound with an optical purity of 12% e.e. was obtained in a yield of 12% from the optically active 1-(3,5-dibenzoyloxyphenyl)-2-nitroethanol obtained in example 14 using 10% Pd/C.
- the intended compound was obtained from the optically active 1-(4-t-butyldimethylsiloxy-3-t-butyldimethylsiloxymethylphenyl)-2-nitroethanol obtained in example 18 using 10% Pd/C.
- the intended compound was obtained from the optically active 2,2-dimethyl- ⁇ -nitromethyl-1,3-benzodioxane-6-methanol obtained in example 17 using 10% Pd/C.
- Amine was obtained from the optically active 2,2-dimethyl- ⁇ -aminomethyl-1,3-benzodioxane-6-methanol synthesized in example 26 and 6-(1-phenyl-butoxy)hexaaldehyde through subjecting them to reduction and amination, then the hydroxyl-protective group of the amine compound was deprotected using hydrochloric acid, so as to obtain the intended compound, (R)-sarmeterol. The angle of rotation was measured using the compound's salt of hydroxy naphthoic acid.
- optically active 1-substituted phenyl-2-nitro alcohol derivatives and optically active 1-substituted phenyl-2-amino alcohol derivatives which are useful as pharmaceutical intermediates, and, in addition, the process for producing these compounds can be provided using a specific group of rare earth metal complexes.
- optically active 1-substituted phenyl-2-nitro alcohol derivatives which are used as a material for pharmaceuticals, such as (R) -albutamin, have been synthesized, and the process for producing thereof has been established.
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Abstract
Optically active 1-substituted phenyl-2-nitro alcohol derivatives having the formula (1)
and the process for producing thereof, and 1-substituted phenyl-2-amino alcohol derivatives having the formula (2)
and the process for producing thereof from the optically active 1-substituted phenyl-2-nitro alcohol derivatives. From these nitro alcohols, pharmaceuticals such as (R)-albutamin and (R)-sarmeterol useful as a bronchodilator is obtained via optically active amino alcohols which are useful pharmaceutical intermediates.
and the process for producing thereof, and 1-substituted phenyl-2-amino alcohol derivatives having the formula (2)
Description
- The present invention relates to optically active 1-substituted phenyl-2-nitro alcohol derivatives and the process for producing thereof, to optically active 1-substituted phenyl-2-amino alcohol derivatives and the process for producing thereof, and to the process for producing (R)-albutamin and (R)-sarmeterol using these compounds.
- The optically active nitro alcohols of the present invention are useful in the medical field, particularly as a synthetic intermediate of nitrogenous compounds useful for thrombotic diseases, for example, cerebral infarction, myocardial infarction, angina pectoris, and peripheral arterial occlusion; of optically active albuterol, optically active sarmeterol, (R)-albutamin, and optically active terbutaline hydrochloride which are useful as a bronchodilator; and of optically active bamethan sulfate useful as a vasodilator. And these compounds can be produced in high yields and industrially advantageously with the process for producing thereof of the present invention.
- The optically active amino alcohols of the present invention can be obtained from the above optically active nitro alcohols, and they are also useful intermediates of pharmaceuticals such as a thrombolytic agent, a central nervous system agent, an antiadipogenous agent and an antiasthmatic agent.
- The optically active nitro alcohols of the present invention are novel substances obtained by the nitro-aldol reaction between nitromethane and benzaldehyde derivatives.
- It is widely known that such a nitro-aldol reaction proceeds in the presence of a base. For example, in Japanese Patent Application Laid-Open No. 58-203950, there is disclosed the nitro-aldol reaction performed in the presence of triethylamine which gives a racemic modification of benznitro alcohol. And in Tetrahedron Letters (1975) p. 4057, there is disclosed the reaction between 2-chlorobenzaldehyde and nitroethane under a catalyst of an optically active compound which gives an asymmetric nitro alcohol in which a substituent is a chloride.
- Further, the present inventors has reported in Tetrahedron Letters (1993) Vol. 34, p. 2657 that the reaction between benzaldehyde and nitromethane under a catalyst of lanthanum-lithium-(R)-binaphthol complex at −50° C. gives (S)-1-phenyl-2-nitro ethanol in a yield of 84% (40% e.e.), and when carried out under a catalyst of samarium-lithium-(R)-binaphthol complex at −40° C., the reaction gives the same compound in a yield of 90% (62% e.e.) ((R) or (S) in the name of each compound represents R or S isomer, respectively, showing the compound's configuration).
- The yields and optical purities described above, however, are not satisfactory ones. In addition, an asymmetric nitro-aldol reaction of benzaldehyde compounds having a hydroxyl group or those having a hydroxyl group with a protecting group has not been found yet and the reaction products, optically active 1-substituted phenyl-2-nitro alcohol derivatives, have not been known yet, either.
- But at the same time, it is hoped now that pharmaceuticals produced from benznitro alcohol derivatives will be supplied in the form of a single optical isomer rather than in the form of a racemic modification. The reason is that, when only one type of structure is therapeutically effective, the other type of optically active substance is no better than impurities and likely to cause adverse effects. In order to meet such a demand, various types of asymmetric synthesis and optical resolution of a racemic modification have been carried out as a method of obtaining pharmaceuticals of optically active substances.
- However, as described above, the nitro-group containing compounds (intermediates) of the present invention have not been known yet, and the only example is (S)-1-phenyl-2-nitroethanol, which has no substituent, reported by the present inventors. Accordingly, the process for producing a group of pharmaceuticals which are to be produced from optically active 1-substituted phenyl-2-nitro alcohol derivatives has not been known, either.
- The optically active 1-substituted phenyl-2-amino alcohol derivatives of the present invention are a group of the compounds obtained from the novel optically active 1-substituted phenyl-2-nitro alcohol derivatives of the present invention.
- On the other hand, as a method of producing optically active 1-substituted phenyl-2-amino alcohol derivatives, various types of asymmetric synthesis and optical resolution of a racemic modification have been carried out, and various processes for producing compounds similar to these ones have been also reported.
- For example, as a method using optical resolution, in Japanese Patent Application Laid-Open No. 64-9979 (Japanese Patent Publication No. 4-48791), there is disclosed a method of producing (R) isomer of 2-amino-1-(3-chlorophenyl)ethanol from the racemic modification using N-(t-butoxycarbonyl)-D-alanine. And in Japanese Patent Application Laid-Open No. 2-85247, there is disclosed the method of subjecting the racemic modification of 2-amino-1-(4-chlorophenyl) ethanol to optical resolution using D-tartaric acid.
- As a method using an asymmetric reduction reaction, for example, in Chemical and Pharmaceutical Bulletin (1995) vol. 43-5, p.738, there is disclosed the process for producing (S)-1-phenyl-2-[N-(2-chloroethyl)]aminoethanol hydrochloride from 2-[N-(2-chloroethyl)]aminophenone hydrochloride.
- And as a method using microorganisms, for example, in Chemistry Express (1989) vol. 4-9, p.621, there is disclosed the process for producing optically active 2-amino-1-phenylethanol from 2-amino-1-phenylethanol and α-aminoacetophenone as raw materials by microorganisms of Staphyrococcus, Micrococcus, Rhodococcus, and Niseria.
- Further, in Japanese Patent Application Laid-Open No. 8-98697, there is disclosed the process for producing optically active 2-amino-1-phenylethanol derivatives from 2-amino-1-phenylethanol derivatives using various microorganisms.
- With the method using optical resolution, however, even if optical resolution is carried out perfectly, the maximum yield expected is only 50% per reaction, and moreover, it is difficult to collect the optically active substances desired in a good yield. Accordingly, in order to improve the yield of optically active substances, it becomes necessary to further racemize unnecessary chiral compounds and to carry out optical resolution of the obtained racemic modifications repeatedly. Thus, using optical resolution can not produce the optically active substances desired effectively and industrially, therefore it can not be a satisfactory method.
- Further, with the method using a usual hydrogen-reduction reaction of which typical example is the above asymmetric reduction reaction, unless the hydrogen pressure is high, the reaction often does not proceed. Thus the method is not appropriate, and moreover, since it has to use a special catalyst, the treatment of the catalyst has been a problem.
- For the reduction reaction of optically active nitro alcohols, U.S. Pat. No. 5,099,067 reports that the reduction reaction of erythro/threo forms of β-nitro alcohol proceeds at room temperature by adding ammonium formate.
- For example, in Japanese Patent Application Laid-Open No. 6-256270, the present inventors report that (S)-(−)-propranolol is obtained in a yield of 90% from (S)-3-(α-naphthoxy)nitropropane-2-ol in the presence of PtO2 at 50° C. under atmospheric pressure. Further, the present inventors report in Journal of the Organic Chemistry (1995) vol. 60, p. 7388 that 2-amino-1,3-alkyldiol is obtained in a yield of 71% in the presence of Pd—C.
- These reduction reactions, however, are limited to the cases where the reduction reaction occurs on racemic modifications, and where, when the reaction occurs on optically active substances, a phenyl group has no substituent or only chlors as a substituent. There is no prior art known which is related directly to the reduction reaction intended by the present invention during which a steric structure of phenyl group having a hydroxyl group is maintained.
- A racemic modification of 1-phenyl-2-aminoethanol is a known compound, for example, in Japanese Patent Application Laid-Open No. 58-203950, there is disclosed the synthetic method in which 1-(3,4-dihidroxyphenyl)-2-nitroethanol is subjected to a catalytic hydrogen addition reaction using Raney nickel to proceed the reduction reaction quantitatively, so as to obtain a racemic modification of 1-(3,4-dihidroxyphenyl)-2-aminoethanol; however, the disclosure makes no concrete reference to the optically active substances of 1-substituted phenyl-2-aminoethanol.
- Thus, optically active 1-substituted phenyl-2-nitroethanol derivatives have not existed to date, and the products obtained by the reduction of the nitro group thereof, optically active 1-substituted phenyl-2-aminoethanol derivatives, have not been produced.
- On the other hand, 1-substituted phenyl-2-aminoethanol derivatives are widely known compounds as a useful pharmaceutical intermediate.
- For example, European Patent No. 0,006,735 specification describes that the intended pharmaceuticals can be synthesized by reacting a racemic and optically active amino alcohol compound with a carbonyl compound or a halide; however, actually disclosed in its embodiments is only the process for producing racemic sarmeterol by reacting a racemic amino alcohol compound with a carbonyl compound or a halide.
- In U.S. Pat. No. 5,442,118 specification there is disclosed the process for producing (R)-albuterol and in European Patent Publication No. 0,422,889 specification there is disclosed the process for producing (R)-sarmeterol; however, their production process is long, and the intended compound is obtained from the optically active styrene oxane derivatives which have been obtained from acetophenone derivatives as a raw material. In these patents, there is no embodiment in which the optically active 1-substituted phenyl-2-nitroethanol derivatives of the present invention are used.
- Thus, optically active 1-substituted phenyl-2-nitroethanol compounds have not existed to date, therefore, the process for producing optically active albutamin and optically active sarmeterol using optically active catechol amines obtained by the reduction of the nitro group thereof has not been known.
- The present invention has been made in light of the foregoing problems of the prior arts. Accordingly, it is an object of the present invention to provide optically active 1-substituted phenyl-2-nitro alcohol derivatives and optically active 1-substituted phenyl-2-amino alcohol derivatives obtained by reducing the optically active 1-substituted phenyl-2-nitro alcohol derivatives of the present invention both of which are useful as an intermediate of pharmaceuticals such as (R)-albutamin, (R)-sarmeterol, (R)-albuterol and (R)-terbutaline hydrochloride which are useful as a bronchodilator, and bamethan sulfate which is useful as a vasohypotonic. Another object of the present invention is to provide a process for producing these compounds. And another object of the present invention is to provide (R)-albutamin and (R)-sarmeterol produced using these compounds.
- After concentrating their energy on the study to achieve the above objects, the present inventors came to know that, for the optically active nitro alcohol derivatives, a group of the intended compounds can be obtained using the group of rare earth metal complexes described by themselves in U.S. Pat. No. 5,336,653 specification and Tetrahedron Letters (1993) vol. 34, p. 2657 etc. At the same time, the present inventors came to know that, for the optically active amino alcohol derivatives, a group of the intended compounds can be easily obtained by subjecting the optically active nitro alcohol derivatives obtained as above to catalytic hydrogen addition in an organic solvent. And the present inventors found that they can achieve the above objects with these knowledge and have finally completed the present invention.
- Specifically, the optically active 1-substituted phenyl-2-nitro alcohol derivatives of the present invention are characterized by the following formula (1),
in which n and m represent the positive integers satisfying 0<n+m≦5; R1 and R2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and when n+m is 2 or more, R1 and R2 can either be independent of each other or form a ring among R1s, R2s, or R1s plus R2s; R3 represents —(CH2)l—, in which 1 is 1, 2 or 3; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group. - Suitable examples of the optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohols of the present invention are characterized by the following formula (1-1),
in which R5 and R6 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group. (R)-albutamin etc., useful as a pharmaceutical, can be produced from the compounds of the above group of which R4 is a hydrogen atom and isomer type is R-type, by converting the nitro group into an amino group, reacting the amino group with a carbonyl compound or an alkyl halide compound, and then eliminating the hydroxyl-protective group. - Suitable examples of the optically active 1-(3-hydroxymethyl-4-hydroxyphenyl)-2-nitro alcohols of the present invention are characterized by the following formula (1-2),
in which R1 and R2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group. (R)-sarmeterol, (R)-albuterol etc., useful as a pharmaceutical, can be produced from the compounds of the above group of which R4 is a hydrogen atom and isomer type is R-type, by converting the nitro group into an amino group, reacting the amino group with a carbonyl compound or an alkyl halide compound, and then eliminating the hydroxyl-protective group. - Suitable examples of the optically active 1-(3,5-dihydroxyphenyl)-2-nitro alcohols of the present invention are characterized by the following formula (1-3),
in which R1 and R2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group. - Optically active terbutaline etc., useful as a bronchodilator, can be produced from the compounds of the above group of R4 is a hydrogen atom, by converting the nitro group into an amino group, reacting the amino group with a carbonyl compound or an alkyl halide compound, and then eliminating the hydroxyl-protective group.
- Suitable examples of the optically active 1-(4-hydroxyphenyl)-2-nitro alcohols of the present invention are characterized by the following formula (1-4),
in which R1 represents a hydrogen atom or a hydroxyl-protective group, respectively, and it can either be independent of each other or form a ring; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group. - Optically active bamethan etc., useful as a vasohypotonic, can be produced from the compounds of the above group of which R4 is a hydrogen atom, by converting the nitro group into an amino group, reacting the amino group of the amino alcohol with a carbonyl compound or an alkyl halide compound, and then eliminating the hydroxyl-protective group.
- Other suitable examples of the optically active nitro alcohols of the present invention are as follows.
- The optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives (optically active 1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol) of formula (1-1), in which R4 is a hydrogen atom, and each of R5 and R6 is a t-butyldimethylsiloxy group.
- Optically active albutamin etc. useful as a pharmaceutical can be produced from this compound by converting the nitro group into an amino group, reacting the optically active amino alcohol with a carbonyl compound (for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.), and then eliminating the hydroxyl-protective group.
- The optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives (optically active 1-(3,4-dimethoxyphenyl)-2-nitroethanol) of formula (1-1), in which R4 is a hydrogen atom, and each of R5 and R6 is a methyl group.
- Optically active albutamin etc. useful as a pharmaceutical can be produced from this compound by converting the nitro group into an amino group, reacting the amino alcohol with a carbonyl compound (for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.), and then eliminating the hydroxyl-protective group.
- The optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives (optically active 1-(3,4-dibenzyloxyphenyl)-2-nitroethanol) of formula (1-1), in which R4 is a hydrogen atom, and each of R5 and R6 is a benzyl group.
- Optically active albutamin etc. useful as a pharmaceutical can be produced from this compound by converting the nitro group into an amino group, reacting the optically active amino alcohol with a carbonyl compound (for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.), and then eliminating the hydroxyl-protective group.
- The optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives (optically active 1-(3,4-diacetoxyphenyl)-2-nitroethanol) of formula (1-1), in which R4 is a hydrogen atom, and each of R5 and R6 is an acetyl group.
- Optically active albutamin etc. useful as a pharmaceutical can be produced from this compound by converting the nitro group into an amino group, reacting the optically active amino alcohol with a carbonyl compound (for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.), and then eliminating the hydroxyl-protective group.
- The optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives (optically active α-nitromethyl-piperonyl alcohol) of formula (1-1), in which R4 is a hydrogen atom, and R5 and R6 are cyclized with a methylene group.
- Optically active albutamin etc. useful as a pharmaceutical can be produced from this compound by converting into an amino group, reacting the optically active amino alcohol with a carbonyl compound (for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.), and then eliminating the hydroxyl-protective group.
- The optically active 2,2-dimethyl-α-nitromethyl-1,3-benzodioxan-6-methanol of formula (1-2), in which R4 is a hydrogen atom, and R1 and R2 are cyclized.
- Optically active sarmeterol etc. useful as a pharmaceutical can be produced from this compound by converting into an amino group, reacting the amino group with a carbonyl compound, and then eliminating the hydroxyl-protective group.
- The optically active 1-(3,5-dibenzyloxyphenyl)-2-nitroethanol of formula (1-3), in which R4 is a hydrogen atom, and each of R1 and R2 is a benzyl group.
- Optically active terbutaline etc. useful as a pharmaceutical can be produced from this compound by converting into an amino group, reacting the amino group with a carbonyl compound, and then eliminating the hydroxyl-protective group.
- The optically active 1-(4-benzoyloxyphenyl)-2-nitroethanol of formula (1-4) set forth in claim 1, characterized in that R4 is a hydrogen atom and R1 is a benzoyl group. Optically active bamethan etc. useful as a pharmaceutical can be produced from this compound by converting into an amino group, reacting the amino group with a carbonyl compound, and then eliminating the hydroxyl-protective group.
- The process for stereoselectively producing optically active nitro alcohols of the present invention is characterized in that, when producing optically active 1-substituted phenyl-2-nitro alcohol derivatives, an aldehyde of the following formula (2),
in which R5 and R6 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring together; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group,
is reacted with a nitro alkane derivative of the following formula (3),
R4—CH2—NO2 (3)
in which R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group,
in the presence of a rare earth metal complex having an optically active ligand. - Likewise, the process for stereoselectively producing optically active nitro alcohols of the present invention is characterized in that, when producing optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives, an aldehyde of the following formula (2-1),
in which R5 and R6 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring together; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group,
is reacted with a nitro alkane derivative of the following formula (3),
R4—CH2—NO2 (3)
in which R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group,
in the presence of a rare earth metal complex having an optically active ligand. - Likewise, the process for stereoselectively producing optically active nitro alcohols of the present invention is characterized in that, when producing optically active 1-(3-hydroxymethyl-4-hydroxyphenyl)-2-nitro alcohol derivatives, an aldehyde of the following formula (2-2),
in which R1 and R2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring together; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group,
is reacted with a nitro alkane derivative of the following formula (3),
R4—CH2—NO2 (3)
in which R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group,
in the presence of a rare earth metal complex having an optically active ligand. - Likewise, the process for stereoselectively producing optically active nitro alcohols of the present invention is characterized in that, when producing optically active 1-(3,5-dihydroxyphenyl)-2-nitro alcohol derivatives, an aldehyde of the following formula (2-3),
in which R1 and R2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring together; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group,
is reacted with a nitro alkane derivative of the following formula (3),
R4—CH2—NO2 (3)
in which R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group,
in the presence of a rare earth metal complex having an optically active ligand. - Likewise, the process for stereoselectively producing optically active nitro alcohols of the present invention is characterized in that, when producing optically active 1-(4-hydroxyphenyl)-2-nitro alcohol derivatives, an aldehyde of the following formula (2-4),
in which R1 represents a hydrogen atom or a hydroxyl-protective group; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group,
is reacted with a nitro alkane derivative of the following formula (3),
R4—CH2—NO2 (3)
in which R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group,
in the presence of a rare earth metal complex having an optically active ligand. - Suitable examples of the process for stereoselectively producing optically active nitro alcohols of the present invention include the following embodiments.
- The process for stereoselectively producing optically active nitro alcohol derivatives characterized in that, when producing an optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula (1-1) in which R4 is a hydrogen atom and each of R5 and R6 is a t-butyldimethylsiloxy group (optically active 1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol), an aldehyde of the following formula (4)
is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand. - The process for stereoselectively producing optically active nitro alcohol derivatives characterized in that, when producing an optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula (1-1) in which R4 is a hydrogen atom and each of R5 and R6 is a methyl group (optically active 1-(3,4-dimethoxyphenyl)-2-nitroethanol), an aldehyde of the following formula (5)
is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand. - The process for stereoselectively producing optically active nitro alcohol derivatives characterized in that, when producing an optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula (1-1) in which R4 is a hydrogen atom and each of R5 and R6 is a benzyl group (optically active 1-(3,4-dibenzyloxyphenyl)-2-nitroethanol), an aldehyde of the following formula (6)
is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand. - The process for stereoselectively producing optically active nitro alcohol derivatives characterized in that, when producing an optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula (1-1) in which R4 is a hydrogen atom and each of R5 and R6 is a acetyl group (optically active 1-(3,4-diacetoxyphenyl)-2-nitroethanol), an aldehyde of the following formula (7)
is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand. - The process for stereoselectively producing optically active nitro alcohol derivatives characterized in that, when producing an optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula (1-1) in which R4 is a hydrogen atom and R5 and R6 are cyclized with a methylene group (optically active α-nitromethyl-piperonyl alcohol), an aldehyde of the following formula (8)
is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand. - The process for stereoselectively producing optically active, nitro alcohol derivatives characterized in that, when producing an optically active 2,2-dimethyl-α-nitromethyl-1,3-benzodioxane-6-methanol of the formula (1-2) in which R4 is a hydrogen atom and R1 and R2 are cyclized, an aldehyde of the following formula (9)
is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand. - The process for stereoselectively producing optically active nitro alcohol derivatives characterized in that, when producing an optically active 1-(3,5-dibenzyloxyphenyl)-2-nitroethanol of the formula (1-3) in which R4 is a hydrogen atom and each of R1 and R2 is a benzyl group, an aldehyde of the following formula (10)
is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand. - The process for stereoselectively producing optically active nitro alcohol derivatives characterized in that, when producing optically active 1-(4-benzoyloxyphenyl)-2-nitroethanol of the formula (1-4) as described in claim 1 in which R4 is a hydrogen atom and R1 is a benzoyl group, an aldehyde of the following formula (11)
is reacted with nitromethane in the presence of a rare earth metal complex having an optically active ligand. - In the process for stereoselectively producing optically active nitro alcohol derivatives as described above, the rare earth metal complexes as above are preferably prepared from an alkoxide of Y, La, Nd, Sm, Eu, Gd, Tb, Dy, Pr or Yb, or a trichloride of these rare earth metals; an optically active 1,1′-bi-2-naphthol derivative of the following formula (12)
or the following formula (13)
in which each of R7 and R8 independently represent a hydrogen atom, an alkyl group of C1-C4, an ethynyl group, a trialkylsilylethynyl group, or a phenyl group, and R7 can be at any position of 4, 5, 6 and 7, and R8 at any position of 4′, 5′, 6′ and 7′;
and an alkaline metal compound of lithium, sodium, or potassium. - Further, in the process for stereoselectively producing optically active nitro alcohol derivatives as described above, it is more preferable that the rare earth metal complexes to be used are prepared in such a way that the composition ratio of the alkoxide or trichloride of the above rare earth metals, the optically active 1,1′-bi-2-naphthol compound, and the alkaline metal is within the range of 1:1-3:0-10.
- The optically active 1-substituted phenyl-2-amino alcohol derivatives of the present invention are characterized by the following formula (14),
in which n and m represent the positive integers satisfying 0<n+m≦5; R1 and R2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and when n+m is 2 or more, R1 and R2 can either be independent of each other or form a ring among R1s, among R2s, and among R1 (s) and R2 (s); R3 represents —(CH2)l— in which l represents 0, 1, or 3; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group. - Suitable examples of the optically active 1-substituted phenyl-2-amino alcohol derivatives of the present invention are the optically active 1-(3,4-dihydroxyphenyl)-2-amino alcohol derivatives of the following formula (14-1)
in which R5 and R6 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they can either be independent of each other or form a ring; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group. - And the process for producing the optically active amino alcohol derivatives of the present invention is characterized in that, when producing optically active 1-substituted phenyl-2-amino alcohol derivatives, the optically active 1-substituted phenyl-2-nitro alcohol derivatives described above are stereoselectively reduced.
- Pharmaceuticals such as optically active albutamin and sarmeterol can be produced by reacting these optically active amino alcohol derivatives with a carbonyl compound or an alkyl halide so as to introduce an alkyl group etc. into the amino group, and then eliminating hydroxyl-protective group; therefore, the optically active nitro alcohol derivatives and optically active amino alcohols of the present invention are useful pharmaceutical intermediates.
- Now the process for producing the optically active nitro alcohol derivatives of the present invention will be described below.
- In general, nitro-aldol reaction between a benzaldehyde derivative and a nitro alkane proceeds in the presence of a basic catalyst. The asymmetric nitro-aldol reaction according to the present invention can be carried out by the reaction of a benzaldehyde derivative and a nitro alkane in the presence of a rare earth metal complex having an optically active ligand.
- In this case, as a supplying source of an optically active ligand, preferable are optically active 1,1′-bi-2-naphthol derivatives of the following formula (12)
or the following formula (13)
in which R7 and R8 independently represent a hydrogen atom, an alkyl group of C1-C4, an ethynyl group, a trialkylsilylethynyl group, or a phenyl group, and R7 can be at any position of 4, 5, 6 and 7, and R8 at any position of 4′, 5′, 6′ and 7′. - The process for preparing a rare earth metal complex solution can be briefly illustrated by the following (reaction equation 1),
although the process is described in detail in the foregoing literature. This is exemplary of the process of this invention, and it is to be understood that the invention is not intended to be limited to the specific process. - The present invention uses only one type of isomer, R-type or S-type, of the above optically active binaphthols. For the optically active binaphthols, R7 can be at any position of 3, 4, 5, 6 and 7, and R8 at any position of 3′, 4′, 5′, 6′ and 7′, and it is found at present that, in terms of yield and optical purity, good results are obtained particularly from the optically active binaphthol having substituents at 6 and 6′ positions.
- Examples of R7 and R8 include a hydrogen atom; an alkyl group of methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, or t-butyl; a phenyl group; an alkenyl group; a trialkylsilylethynyl group (in this case, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, or t-butyl, tow alkyls can be different from each other or can be the same); a cyano group; and a halogen; and any combination can be adopted.
- Examples of the rare earth metals of the rare earth metal compounds include Y, La, Nd, Sm, Eu, Gd, Tb, Dy, Pr, and Yb, any of the metals can be used suitably.
- Examples of the rare earth metal compounds include an alkoxide (including methoxide, ethoxide, propoxide, isopropoxide, n-butoxide, s-butoxide, and t-butoxide), a chloride (including both an anhydride and a hydride), and a nitrate, and any of them can be used preferably.
- Examples of the alkaline metal compounds used for the preparation of rare earth metal complexes include alkylalkaline metals (for example, methyllithium and n-butyllithium), alkaline metal hydroxides (for example, lithium hydroxide, sodium hydroxide and potassium hydroxide).
- Examples of solvents used in the preparation of a rare earth metal complex solution include THF; however, the present invention is not limited to the specific solvent, and any solvents can be used as long as they do not change the structure of the rare earth metal complexes. Examples other than THF include ether-based solvents (for example, diethyl ether and 1,4-dioxane), halogen-based solvents (for example, methylene chloride, chloroform, 1,1,1-trichloroethane and monochlorobenzene), hydrocarbon-based solvents (for example, benzene, toluene, n-hexane and n-heptane), and fatty acid esters (for example, ethyl acetate and methyl acetate), in addition, polar solvents such as dimethyl sulfoxide, N,N′-dimethylformamide, etc. can also be used. These solvents can be used in a single form or as a mixture of 2 or more types.
- Examples of aldehydes used as a raw material for the process of the present invention include 2-hydroxybenzaldehyde, 3-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 2,3-dihydroxybenzaldehyde, 2,4-dihydroxybenzaldehyde, 2,5-dihydroxybenzaldehyde, 2,6-dihydroxybenzaldehyde, 3,4-dihydroxybenzaldehyde, 3,5-dihydroxybenzaldehyde, 2,3,4-trihydroxybenzaldehyde, 2,3,5-trihydroxybenzaldehyde, 2,3,6-trihydroxybenzaldehyde, 2,4,5-trihydroxybenzaldehyde, 2,4,6-trihydroxybenzaldehyde, 2-hydroxy-3-hydroxymethylbenzaldehyde, 2-hydroxy-4-hydroxymethylbenzaldehyde, 2-hydroxy-5-hydroxymethylbenzaldehyde, 2-hydroxy-6-hydroxymethylbenzaldehyde, 3-hydroxy-2-hydroxymethylbenzaldehyde, 3-hydroxy-4-hydroxymethylbenzaldehyde, 3-hydroxy-5-hydroxymethylbenzaldehyde, 3-hydroxy-6-hydroxymethylbenzaldehyde, 4-hydroxy-2-hydroxymethylbenzaldehyde, 4-hydroxy-3-hydroxymethylbenzaldehyde, 4-hydroxy-5-hydroxymethylbenzaldehyde, 4-hydroxy-6-hydroxymethylbenzaldehyde, and the compounds as above of which aromatic hydroxyl group is protected with a hydroxyl-protective group (for example, t-butyldimethylsilyl group).
- Examples of hydroxyl-protective groups used in the present invention include a methyl group, a tetrahydropyranyl group, an allyl group, an isopropyl group, a t-butyl group, a benzyl group, an acetyl group, and a trimethylsilyl group which are described in Protective Groups in Organic Synthesis.
- Now the process for producing the optically active amino alcohol derivatives of the present invention will be described.
- The optically active 1-substituted phenyl-2-amino alcohol derivatives of the present invention are synthesized by dissolving the corresponding optically active 1-substituted phenyl-2-nitroethanol compounds in an organic solvent, dispersing a catalytic hydrogen addition catalyst, and subjecting the optically active 1-substituted phenyl-2-nitroethanol compounds to hydrogen addition under hydrogen pressure.
- Examples of the organic solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl butyrate, and ethyl butyrate; however, the present invention is not intended to be limited to the specific solvent, and these alcohols and esters can be used in a single form or as a mixture in desired proportions.
- For the catalytic hydrogen addition catalysts, usual hydrogen addition catalysts are satisfactory, and the examples include Pt—C, Pd—C and PtO2.
- Although the present invention is not intended to be limited to the specific amount of catalyst, considering the reaction time, 0.01 wt % ormore of catalyst is preferably added based on the substrate (nitro alcohol).
- Further, although the present invention is not intended to be limited to the specific reaction temperature, considering the intramolecular dehydration of nitro alcohols and the racemization of the products, the temperature is preferably 50° C. and below.
- Further, although the present invention is not intended to be limited to the specific hydrogen pressure and preferably the pressure is in the range from 0.1 to 30 MPa, considering the production equipment, more preferably in the range from 0.1 to 1 MPa.
- The present invention is illustrated by the following embodiments and catalyst preparation examples, however, it is to be understood that the invention is not intended to be limited to the specific embodiments.
- In each example, optical purity was determined by liquid chromatography (HPLC) (CHIRALPAK AD or CHIRALCEL OD by Daicel Chemical Industries, Ltd.). And 1H-NMR was measured with JNM-EX-270 (270 MHz) by JEOL.
- [Preparation of Rare Earth Metal Complex Solution A0]
- 58.0 mg (0.103 mmol) of (S)-6,6′-bis(triethylsilylethynyl)-1,1′-dihydroxy-2,2′-binaphthalene was dried in a vacuum at 50° C. for 2 hours. (S)-6,6′-bis(trimethylsilylethynyl)-1,1′-dihydroxy-2,2′-binaphthalene was dissolved in 880 μl of THF under an argon stream, and 172 μl of a solution of 11.3 mg (0.0344 mmol) of triisopropoxy samarium Sm (Oi-Pr)3 in 0.2mol/dm3 THF was added dropwise at 0° C. After stirring at room temperature for 30 minutes, 60 μl of a hexane solution of 1.72 mol/dm3 n-BuLi (0.103 mmol) was added dropwise at 0° C. Then, the solution was stirred at room temperature overnight and 35 μl of THF solution containing water (0.035 mmol) was added, so as to prepare 0.03 mol/dm3 THF solution of a complex catalyst (A0), as above.
- [Preparation of Rare Earth Metal Complex Solution A1]
- 54 μl of hexane solution of 1.72 mol/dm3 n-BuLi (0.103 mmol) was added dropwise to the rare earth metal complex solution A0, so as to prepare a rare earth metal complex solution A1.
- [Preparation of Rare Earth Metal Complex Solution B0]
- A rare earth metal complex solution B0 was prepared following the same procedure as in the preparation of the rare earth metal complex solution A0, except that lanthanum triisopropoxy La (Oi-Pr)3 was used instead of samarium triisopropoxy Sm (Oi-Pr)3.
- [Preparation of Rare Earth Metal Complex Solution B1]
- 54 μl of hexane solution of 1.72 mol/dm3 n-BuLi (0.093 mmol) was added dropwise to the rare earth metal complex solution B0, so as to prepare a rare earth metal complex solution B1.
- [Preparation of Rare Earth Metal Complex Solution C0]
- A rare earth metal complex solution C0 was prepared following the same procedure as in the preparation of the rare earth metal complex solution A0, except that dysprosium triisopropoxy Dy (Oi-Pr)3 was used instead of Sm (Oi-Pr)3.
- [Preparation of Rare Earth Metal Complex Solution C1]
- 54 μl of hexane solution of 1.72 mol/dm3 n-BuLi (0.093 mmol) was added dropwise to the rare earth metal-complex solution C0, so as to prepare a rare earth metal complex solution C1.
- [Preparation of Rare Earth Metal Complex Solution D0]
- A rare earth metal complex solution D0 was prepared following the same procedure as in the preparation of the rare earth metal complex solution A0, except that gadolinium triisopropoxy Gd (Oi-Pr)3 was used instead of Sm (Oi-Pr)3.
- [Preparation of Rare Earth Metal Complex Solution D1]
- 54 μl of hexane solution of 1.72 mol/dm3 n-BuLi (0.093 mmol) was added dropwise to the rare earth metal complex solution D0, so as to prepare a rare earth metal complex solution D1.
- [Preparation of Rare Earth Metal Complex Solution E0]
- A rare earth metal complex solution E0 was prepared following the same procedure as in the preparation of the rare earth metal complex solution A0, except that praseodymium triisopropoxy Pr (Oi-Pr)3 was used instead of Sm (Oi-Pr)3.
- [Preparation of Rare Earth Metal Complex Solution E1]
- 54 μl of hexane solution of 1.72 mol/dm3 n-BuLi (0.093 mmol) was added dropwise to the rare earth metal complex solution E0, so as to prepare a rare earth metal complex solution E1.
- [Preparation of Rare Earth Metal Complex Solution F1]
- A metal complex solution was prepared following the same procedure as in the preparation of the rare earth metal complex solution A0, except that (R)-1,1′-dihydroxy-2,2′-binaphthalene was used instead of (S)-6,6′-bis(triethylsilylethynyl)-1,1′-dihydroxy-2,2′-binaphthalene, after which 54 μl of hexane solution of 1.72 mol/dm3 n-BuLi (0.093 mmol) was added dropwise, so as to prepare a rare earth metal complex solution F1.
- 100 mg (0.26 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.30 ml of rare earth metal complex solution A1 was mixed into the solution. After stirring for 30 minutes, 79.3 mg (1.3 mmol) of nitromethane was added dropwise to the mixture. After 67-hour reaction time, 2 ml of 1 N aqueous solution of hydrochloric acid was added to stop the reaction. Then, after 50 ml of ethyl accetate was added, the mixture was subjected to oil-water separation twice with 20 ml of saturated salt solution and once with 20 ml of water, and the ethyl accetate layer was dehydrated with sodium sulfate anhydride and concentrated with an evaporator, followed by the purification of the concentrate by silica gel chromatography (n-hexane/acetone=10/1), after which (R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with an optical purity of 92% e.e. was obtained in a yield of 93%.
- 1H-NMR (CDCl3): δ 6.87 - 6.81 (m, 3H), 5.37-5.29 (m, 1H), 4.62-4.42 (m, 2H), 2.62 (br, 1H), 0.99 (s, 9H), 0.98 (s, 9H), 0.20 (s, 6H)
- 110 mg (0.29 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.32 ml of rare earth metal complex solution A0 was mixed into the solution. After stirring for 30 minutes, 88.5 mg (1.45 mmol) of nitromethane was added dropwise to the mixture. After 67-hour reaction time, (R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with an optical purity of 92% e.e. was obtained in a yield of 74%.
- 100 mg (0.55 mmol) of 3,4-dimethoxybenzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.60 ml of rare earth metal complex solution A1 was mixed into the solution. After stirring for 30 minutes, 168 mg (2.75 mmol) of nitromethane was added dropwise to the mixture. After 97-hour reaction time, (R)-1-(3,4-dimethoxyphenyl)-2-nitroethanol with an optical purity of 32% e.e. was obtained in a yield of 61%.
- 1H-NMR (CDCl3): δ 6.94-6.85 (m, 3H), 5.47-5.38 (m, 1H), 4.66-4.46 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 2.73 (br, 1H)
- 100 mg (0.30 mmol) of 3,4-dibenzyloxybenzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.33 ml of rare earth metal complex solution A1 was mixed into the solution. After stirring for 30 minutes, 91.6,mg (1.50 mmol) of nitromethane was added dropwise to the mixture. After 75-hour reaction time, (R)-1-(3,4-dibenzyloxyphenyl)-2-nitroethanol with an optical purity 59% e.e. was obtained in a yield of 90%.
- 1H-NMR (CDCl3): δ 7.45-7.20 (m, 10H), 7.00-6.86 (m, 3H), 5.38-5.26 (m, 1H), 5.17 (s, 2H), 5.16 (s, 2H), 4.57-4.38 (m, 2H), 2.67 (br, 1H)
- 102 mg (0.43 mmol) of 3,4-diacetoxybenzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.48 ml of rare earth metal complex solution A1 was mixed into the solution. After stirring for 30 minutes, 131 mg (2.15 mmol) of nitromethane was added dropwise to the mixture. After 68-hour reaction time, (R)-1-(3,4-diacetoxyphenyl)-2-nitroethanol with an optical purity of 59% e.e. was obtained in a yield of 87%.
- 1H-NMR (CDCl3): δ 7.32-7.19 (m, 3H), 5.55-5.40 (m, 1H), 4.63-4.42 (m, 2H), 2.62 (br, 1H), 2.30 (s, 3H), 2.29 (s, 3H)
- 105 mg (0.28 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.31 ml of rare earth metal complex solution D1 was mixed into the solution. After stirring for 30 minutes, 85.5 mg (1.40 mmol) of nitromethane was added dropwise to the mixture. After 61-hour reaction time, (R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with an optical purity of 87% e.e. was obtained in a yield of 86%.
- 100 mg (0.26 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.31 ml of rare earth metal complex solution B1 was mixed into the solution. After stirring for 30 minutes, 79.3 mg (1.30 mmol) of nitromethane was added dropwise to the mixture. After 66-hour reaction time, (R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with an optical purity of 79% e.e. was obtained in a yield of 89%.
- 100 mg (0.26 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.31 ml of rare earth metal complex solution E1 was mixed into the solution. After stirring for 30 minutes, 79.3 mg (1.30 mmol) of nitromethane was added dropwise to the mixture. After 66-hour reaction time, (R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with an optical purity of 84% e.e. was obtained in a yield of 86%.
- 102 mg (0.27 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.30 ml of rare earth metal complex solution C1 was mixed into the solution. After stirring for 30 minutes, 82.4 mg (1.35 mmol) of nitromethane was added dropwise to the mixture. After 66-hour reaction time, (R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with an optical purity of 68% e.e. was obtained in a yield of 72%.
- The rare earth metal complex solution F1 (10 ml) and 0.80 g (13.0 mmol) of nitromethane were mixed and stirred together for 30 minutes under the atmosphere of nitrogen. A solution of 1.00 g (2.6 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde dissolved in 20 ml of THF was added dropwise to the mixture. After 24-hour reaction time, (S)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with an optical purity of 93% e.e. was obtained in a yield of 85%.
- (R)-α-nitromethyl-piperonyl alcohol with an optical purity of 73% e.e. was obtained from piperonal using the rare earth metal complex solution A1 under the atmosphere of argon at −40° C. after 50-hour reaction time.
- 1H-NMR (CDCl3): δ 6.90-6.82 (m, 3H), 5.99 (s, 2H), 5.41-5.35 (m, 1H), 4.62-4.43 (m, 2H), 2.70 (br, 1H)
- 100 mg (0.26 mmol) of 3,5-di(t-butyldimethylsiloxy)benzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.30 ml of rare earth metal complex solution A1 was mixed into the solution. After stirring for 30 minutes, 159 mg (2.6 mmol) of nitromethane was added dropwise to the mixture. After 140-hour reaction time, optically active 1-(3,5-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with an optical purity of 62% e.e. was obtained in a yield of 93%.
- 1H-NMR (CDCl3): δ 6.86-6.83 (m, 3H), 5.34 (m, 1H), 4.57 (dd, J=13.3, 9.4 Hz, 1H), 4.46 (dd, J=13.3, 3.1 Hz, 1H), 2.64 (d, J=3.5 Hz, 1H), 0.99 (s, 9H), 0.98 (s, 9H), 0.20 (s, 12H)
- 100 mg (0.30 mmol) of 3, 5-dibenzyloxydibenzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.35 ml of rare earth metal complex solution A1 was mixed into the solution. After stirring for 30 minutes, 183 mg (3.0 mmol) of nitromethane was added dropwise to the mixture. After 71-hour reaction time, optically active 1-(3,5-dibenzyloxyphenyl)-2-nitroethanol with an optical purity of 68% e.e. was obtained in a yield of 84%.
- 1H-NMR (CDCl3): δ 7.45-7.30 (m, 10H), 6.65-6.58 (m, 3H), 5.42-5.36 (m, 1H), 5.04 (s, 4H), 4.62-4.45 (m, 2H), 2.74 (d, 1H)
- 100 mg (0.3 mmol) of 3,5-dibenzyloxydibenzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.32 ml of rare earth metal complex solution A1 was mixed into the solution. After stirring for 30 minutes, 183 mg (29.9 mmol) of nitromethane was added dropwise to the mixture. After 88-hour reaction time, optically active 1-(3,5-dibenzyloxyphenyl)-2-nitroethanol with an optical purity of 88% e.e. was obtained in a yield of 100%.
- 1H-NMR (CDCl3) δ 7.45-7.30 (m, 10H), 6.65-6.58 (m, 3H), 5.42-5.36 (m, 1H), 5.04 (s, 4H), 4.62-4.45 (m, 2H), 2.74 (d, 1H)
- 102 mg (0.43 mmol) of 3,5-diacetoxybenzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.45 ml of rare earth metal complex solution A1 was mixed into the solution. After stirring for 30 minutes, 262 mg (4.3 mmol) of nitromethane was added dropwise to the mixture. After 44-hour reaction time, optically active 1-(3,5-diacetoxyphenyl)-2-nitroethanol with an optical purity of 86% e.e. was obtained in a yield of 89%.
- 1H-NMR (CDCl3): δ 7.07 (d, 2H), 6.91 (t, 1H), 5.48-5.41 (m, 1H), 4.61-4.48 (m, 2H), 3.03 (d, 1H), 2.29 (s, 6H)
- The rare earth metal complex solution A1 (0.10 ml) and 66 mg (1.07 mmol) of nitromethane were stirred at −40° C. for 30 minutes, then 0.39 ml of solution of 41 mg (0.11 mmol) of 4-t-butyldimethylsiloxy-3-t-butyldimethylsiloxymethylbenzaldehyde in THF was added dropwise to the mixture. After 69-hour reaction time, optically active 1-(4-t-butyldimethylsiloxy-3-t-butyldimethylsiloxymethylphenyl)-2-nitroethanol with an optical purity of 37% e.e. was obtained in a yield of 35%.
- 1H-NMR (CDCl3): δ 7.47 (d, j=2.0 Hz, 1H), 7.16 (dd, j=8.5, 2.0 Hz, 1H), 6.76 (d, j=8.5 Hz, 1H), 5.41 (ddd, j=9.5, 3.5, 3.0 Hz, 1H), 4.74 (s, 2H), 4.61 (dd, j=13.5, 9.0 Hz, 1H), 4.48 (dd, j=13.5, 3.0 Hz, 1H), 2.65 (d, j=3.5 Hz, 1H), 1.00 (s, 9H), 0.96 (s, 9H), 0.22 (s, 6H), 0.11 (s, 6H)
- 100 mg (0.52 mmol) of 2,2-dimethyl-1,3-benzodioxane-6-acetoaldehyde was dissolved in 1.9 ml of THF under the atmosphere of argon at −40° C., and the rare earth metal complex solution A1 was mixed into the solution. After stirring for 30 minutes, 318 mg (5.2 mmol) of nitromethane was added dropwise to the mixture. After 61-hour reaction time, optically active 2,2-dimethyl-α-nitromethyl-1,3-benzodioxane-6-methanol with an optical purity of 87% e.e. was obtained in a yield of 86%.
- The rare earth metal complex solution B1 and 65 mg (1.07 mmol) of nitromethane were stirred at −40° C. for 30 minutes, then 0.40 ml of solution of 42 g (0.11 mmol) of 4-t-butyldimethylsiloxy-3-t-butyldimethylsiloxymethylbenzaldehyde in THF was added dropwise to the mixture. After 67-hour reaction time, optically active 1-(4-t-butyldimethylsiloxy-3-t-butyldimethylsiloxymethylphenyl)-2-nitroethanol with an optical purity of 30% e.e. was obtained in a yield of 30%..
- The rare earth metal complex solution A1 and 149 mg (2.44 mmol) of nitromethane were stirred at −40° C. for 30 minutes, then 0.89 ml of solution of 88 mg (0.24 mmol) of 4-benzoyloxy-3-benzoyloxymethylbenzaldehyde in THF was added dropwise to the mixture. After 69-hour reaction time, optically active 1-(4-benzoyloxy-3-benzoyloxymethylphenyl)-2-nitroethanol with an optical purity of 64% e.e. was obtained in a yield of 86%.
- Optically active 1-(4-benzoyloxyphenyl)-2-nitroethanol with an optical purity of 50% e.e. was obtained from 4-benzoyloxybenzaldehyde using the rare earth metal complex solution F1 under the atmosphere of nitrogen at −30° C. after 24-hour reaction time.
- (S,S)-1-(4-benzoyloxyphenyl)-2-nitropropanol (30% e.e.), the threo form/erythro form ratio is 1.8/1.0, was obtained from 4-benzoyloxybenzaldehyde and nitroethane using the rare earth metal complex solution F1 under the atmosphere of nitrogen at −30° C. after 24-hour reaction time.
- 100 mg of optically active 1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol obtained in example 1 was dissolved in 10 ml of methanol, and 10 mg of 10% Pd/C was added to the solution, after which the mixture was reacted at 20° C. under the hydrogen pressure of 0.1 MPa for 20 hours, so as to obtain 89.3 mg of the intended compound (in a yield of 96%, with an optical purity of 94% e.e.).
- IR (neat) cm−1: 3859, 2928
- 1H-NMR (CDCl3): δ 6.85-6.76 (m, 3H), 4.54 (dd, j=8.0, 4.0 Hz, 1H), 2.97 (dd, j=12.0, 4.0 Hz, 1H), 2.81 (dd, j=12.0, 8.0 Hz, 1H), 0.98 (s, 18H), 0.19 (s, 12H)
- 13C-NMR (CDCl3, 97.9 MHz): 146.7, 146.3, 135.5, 120.8, 118.8, 73.7, 49.1, 25.9, 18.4, −4.1
- [α]25 D=−21.9 (c1.15, CHCl3)
- 98 mg of (S)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol obtained in example 10 was dissolved in 10 ml of methanol, and 10 mg of 10% Pd/C was added to the solution, after which the mixture was reacted at 20° C. under the hydrogen pressure of 0.3 MPa for 5 hours, so as to obtain 85 mg of the intended compound.
- [α]25 D=+21.5 (c1.10, CHCl3)
- The intended compound with an optical purity of 12% e.e. was obtained in a yield of 12% from the optically active 1-(3,5-dibenzoyloxyphenyl)-2-nitroethanol obtained in example 14 using 10% Pd/C.
- [α]25 D=−2.3 (c0.32, EtOH)
- The intended compound was obtained from the optically active 1-(4-t-butyldimethylsiloxy-3-t-butyldimethylsiloxymethylphenyl)-2-nitroethanol obtained in example 18 using 10% Pd/C.
- [α]25 D=−2.9 (c0.35, EtOH)
- The intended compound was obtained from the optically active 2,2-dimethyl-α-nitromethyl-1,3-benzodioxane-6-methanol obtained in example 17 using 10% Pd/C.
- [α]25 D=−2.2 (c0.25, EtOH)
- 89.3 mg of (−)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-aminoethanol, 50.0 mg of 4-(4-methoxymethoxyphenyl)butanoic acid, diethylphosphorylcyanide, and triethylamine were dissolved in N,N-dimethylformamide at 0° C., reacted at room temperature, so as to obtain 108.6 mg (in a yield of 82%) of amide compound. The amide compound obtained was reduced with lithium aluminium halide in an ether solvent at reflux temperature, so as to quantitatively obtain amine. And 55.6 mg of (R)-albutamin which is the intended compound was obtained by deprotecting the hydroxyl-protective group of the amine in a methanol—THF solvent at room temperature using hydrochloric acid.
- [α]25 D=−17 (c1.15, EtOH)
- Amine was obtained from the optically active 2,2-dimethyl-α-aminomethyl-1,3-benzodioxane-6-methanol synthesized in example 26 and 6-(1-phenyl-butoxy)hexaaldehyde through subjecting them to reduction and amination, then the hydroxyl-protective group of the amine compound was deprotected using hydrochloric acid, so as to obtain the intended compound, (R)-sarmeterol. The angle of rotation was measured using the compound's salt of hydroxy naphthoic acid.
- [α]25 D=−3.1 (c0.30, MeOH)
- As described above, according to the present invention, optically active 1-substituted phenyl-2-nitro alcohol derivatives and optically active 1-substituted phenyl-2-amino alcohol derivatives, which are useful as pharmaceutical intermediates, and, in addition, the process for producing these compounds can be provided using a specific group of rare earth metal complexes.
- Specifically, according to the present invention, optically active 1-substituted phenyl-2-nitro alcohol derivatives which are used as a material for pharmaceuticals, such as (R) -albutamin, have been synthesized, and the process for producing thereof has been established.
- At the same time, the process for producing optically active 1-substituted phenyl-2-amino alcohol derivatives which are to become useful intermediates of pharmaceuticals from optically active 1-substituted phenyl-2-nitro alcohol derivatives has been established, and the process for producing pharmaceuticals, (R) -albutamin and (R) -sarmeterol, from optically active 1-substituted phenyl-2-amino ethanol derivatives has been established.
Claims (5)
1-30. (canceled)
31. A process for producing an optically active 1-substituted phenyl-2-amino alcohol derivative of the following formula (14)
in which n and m represent positive integers satisfying 0<n+m≦5; R1 and R2 represent a hydrogen atom or a hydroxyl-protective group, respectively and when n+m is 2 or more, R1 and R2 are independent of each other or form a ring among R1s, among R2s, and among R1(s) and R2(s); R3 represents —(CH2)l— in which l is 0, 1, 2 or 3; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group,
which comprises stereoselectively reducing an optically active 1-substituted phenyl-2-nitro alcohol derivative of the following formula (1)
in which n and m represent positive integers satisfying 0<n+m≦5; R1 and R2 represent a hydrogen atom or a hydroxyl-protective group, respectively, and when n+m is 2 or more, R1 and R2 are independent of each other or form a ring among R1s, among R2s, and among R1(s) and R2(s); R3 represents —(CH2)l— in which l is 0, 1, 2 or 3; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group; and * represents an optically active site, and when R4 is a hydrogen atom, optical activity at the site to which R4 is added is lost and * is omitted.
32. A process for producing an optically active 1-(3,4-dihydroxyphenyl)-2-amino alcohol derivative of the following formula (14-1)
in which R5 and R6 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they are independent of each other or form a ring: R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group,
which comprises stereoselectively reducing an optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the following formula (1-1)
in which R5 and R6 represent a hydrogen atom or a hydroxyl-protective group, respectively, and they are independent of each other or form a ring; R4 represents a hydrogen atom, an alkyl group, or a hydroxymethyl group; and * represents an optically active site, and when R4 is a hydrogen atom, optical activity at the site to which R4 is added is lost and * is omitted.
33. A process for producing (R)-albutamin having the following formula (15),
characterized in that the (R)-1-(3,4-dihydroxyphenyl)-2-amino alcohol derivative of the following formula (14-2)
is used as a raw material which is obtained by reducing the (R)-1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the following formula (1-5).
34. A process for producing (R)-sarmeterol having the following formula (16),
characterized in that the (R)-1-(3-hydroxymethyl-4-hydroxyphenyl)-2-amino alcohol derivative of the following formula (14-3)
is used as a raw material which is obtained by reducing the (R)-1-(3-hydroxymethyl-4-hydroxyphenyl)-2-nitro alcohol derivative of the following formula (1-6).
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- 1997-11-20 EP EP97912527A patent/EP0947498B1/en not_active Expired - Lifetime
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Also Published As
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EP0947498A1 (en) | 1999-10-06 |
WO1998024753A1 (en) | 1998-06-11 |
EP0947498A4 (en) | 2000-03-15 |
US20050148801A1 (en) | 2005-07-07 |
US6632955B1 (en) | 2003-10-14 |
DE69730737D1 (en) | 2004-10-21 |
EP0947498B1 (en) | 2004-09-15 |
US20020193447A1 (en) | 2002-12-19 |
US7205425B2 (en) | 2007-04-17 |
AU4967997A (en) | 1998-06-29 |
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