JP6498614B2 - 光学活性カルボン酸エステルの製造方法 - Google Patents
光学活性カルボン酸エステルの製造方法 Download PDFInfo
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- JP6498614B2 JP6498614B2 JP2015560069A JP2015560069A JP6498614B2 JP 6498614 B2 JP6498614 B2 JP 6498614B2 JP 2015560069 A JP2015560069 A JP 2015560069A JP 2015560069 A JP2015560069 A JP 2015560069A JP 6498614 B2 JP6498614 B2 JP 6498614B2
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- JP
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- Prior art keywords
- group
- carboxylic acid
- optically active
- pyrrole
- acid ester
- 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.)
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- 238000000034 method Methods 0.000 title claims description 17
- 125000003262 carboxylic acid ester group Chemical class [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 title 1
- -1 1H-benzo [d] imidazol-1-yl group Chemical group 0.000 claims description 91
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 44
- 238000004519 manufacturing process Methods 0.000 claims description 30
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 230000003287 optical effect Effects 0.000 claims description 20
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 239000011982 enantioselective catalyst Substances 0.000 claims description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 239000002798 polar solvent Substances 0.000 claims description 12
- 150000008065 acid anhydrides Chemical class 0.000 claims description 10
- 125000001624 naphthyl group Chemical group 0.000 claims description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 claims description 7
- 150000002989 phenols Chemical class 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 6
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 claims description 6
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 claims description 6
- 125000005561 phenanthryl group Chemical group 0.000 claims description 6
- 150000001735 carboxylic acids Chemical class 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- GNVRJGIVDSQCOP-UHFFFAOYSA-N n-ethyl-n-methylethanamine Chemical compound CCN(C)CC GNVRJGIVDSQCOP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000962 organic group Chemical group 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 3
- VMOWKUTXPNPTEN-UHFFFAOYSA-N n,n-dimethylpropan-2-amine Chemical compound CC(C)N(C)C VMOWKUTXPNPTEN-UHFFFAOYSA-N 0.000 claims description 3
- ISRXMEYARGEVIU-UHFFFAOYSA-N n-methyl-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C)C(C)C ISRXMEYARGEVIU-UHFFFAOYSA-N 0.000 claims description 3
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical class OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 260
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 171
- 239000011734 sodium Substances 0.000 description 71
- 229910052739 hydrogen Inorganic materials 0.000 description 68
- 229910052786 argon Inorganic materials 0.000 description 63
- 238000006243 chemical reaction Methods 0.000 description 52
- 238000004896 high resolution mass spectrometry Methods 0.000 description 46
- 238000004128 high performance liquid chromatography Methods 0.000 description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 35
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 35
- 239000000243 solution Substances 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 239000012043 crude product Substances 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 16
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 12
- 229910010082 LiAlH Inorganic materials 0.000 description 12
- NHIXQVYVFRYTOB-UHFFFAOYSA-N dinaphthalen-1-ylmethanol Chemical compound C1=CC=C2C(C(C=3C4=CC=CC=C4C=CC=3)O)=CC=CC2=C1 NHIXQVYVFRYTOB-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 9
- 230000032050 esterification Effects 0.000 description 9
- 238000005886 esterification reaction Methods 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 230000010933 acylation Effects 0.000 description 7
- 238000005917 acylation reaction Methods 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
- SDSWSVBXRBXPRL-LBPRGKRZSA-N methyl (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 SDSWSVBXRBXPRL-LBPRGKRZSA-N 0.000 description 7
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 6
- BTWSOHYUYXKYPL-LSDHHAIUSA-N C(C1=CC=CC=C1)[C@@H]1N2CCC[C@@H]2CCC1 Chemical compound C(C1=CC=CC=C1)[C@@H]1N2CCC[C@@H]2CCC1 BTWSOHYUYXKYPL-LSDHHAIUSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 6
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 6
- JGYGUTJPICTFBW-UHFFFAOYSA-N 1-[methoxy(naphthalen-1-yl)methyl]naphthalene Chemical compound COC(C1=CC=CC2=CC=CC=C12)C1=CC=CC2=CC=CC=C12 JGYGUTJPICTFBW-UHFFFAOYSA-N 0.000 description 5
- JHDCRSBRRZPACW-UHFFFAOYSA-N 6,7-dihydro-5h-indolizin-8-one Chemical class O=C1CCCN2C=CC=C12 JHDCRSBRRZPACW-UHFFFAOYSA-N 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical class OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- HAJKHJOABGFIGP-UHFFFAOYSA-N indolizidine Chemical class C1CCCN2CCCC21 HAJKHJOABGFIGP-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ASSLUUIQXWYZPR-ZDUSSCGKSA-N (2s)-3-phenyl-2-pyrrol-1-ylpropan-1-ol Chemical compound C([C@@H](CO)N1C=CC=C1)C1=CC=CC=C1 ASSLUUIQXWYZPR-ZDUSSCGKSA-N 0.000 description 4
- YOUJHISGPTZGLN-CYBMUJFWSA-N (5R)-5-benzyl-6,7-dihydro-5H-indolizin-8-one Chemical compound C(C1=CC=CC=C1)[C@@H]1N2C=CC=C2C(CC1)=O YOUJHISGPTZGLN-CYBMUJFWSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 235000010233 benzoic acid Nutrition 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- CLPHAYNBNTVRDI-UHFFFAOYSA-N ditert-butyl propanedioate Chemical compound CC(C)(C)OC(=O)CC(=O)OC(C)(C)C CLPHAYNBNTVRDI-UHFFFAOYSA-N 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 0 *[C@@](C(OC(c1c(cccc2)c2ccc1)c1cccc2c1cccc2)=O)[n]1c2ccccc2nc1 Chemical compound *[C@@](C(OC(c1c(cccc2)c2ccc1)c1cccc2c1cccc2)=O)[n]1c2ccccc2nc1 0.000 description 3
- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- 150000001371 alpha-amino acids Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- YGCWPCVAVSIFLO-LBPRGKRZSA-N (2r)-2-phenyl-1,2-dihydroimidazo[2,1-b][1,3]benzothiazole Chemical compound C1([C@@H]2CN3C4=CC=CC=C4SC3=N2)=CC=CC=C1 YGCWPCVAVSIFLO-LBPRGKRZSA-N 0.000 description 2
- VPMIAOSOTOODMY-KJAPKAAFSA-N (4r)-6-[(e)-2-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1/C=C/C=1C(C(C)C)=NC(C(C)(C)C)=CC=1C1=CC=C(F)C=C1 VPMIAOSOTOODMY-KJAPKAAFSA-N 0.000 description 2
- UTOIEVWJKDLJGE-AQRBRUGDSA-N (4r,6s)-6-[(e)-2-[4-(4-fluorophenyl)-2,6-di(propan-2-yl)pyrimidin-5-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C=1C=C(F)C=CC=1C1=NC(C(C)C)=NC(C(C)C)=C1\C=C\[C@@H]1C[C@@H](O)CC(=O)O1 UTOIEVWJKDLJGE-AQRBRUGDSA-N 0.000 description 2
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical compound C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960001614 levamisole Drugs 0.000 description 2
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 2
- COCAUCFPFHUGAA-MGNBDDOMSA-N n-[3-[(1s,7s)-5-amino-4-thia-6-azabicyclo[5.1.0]oct-5-en-7-yl]-4-fluorophenyl]-5-chloropyridine-2-carboxamide Chemical compound C=1C=C(F)C([C@@]23N=C(SCC[C@@H]2C3)N)=CC=1NC(=O)C1=CC=C(Cl)C=N1 COCAUCFPFHUGAA-MGNBDDOMSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000005949 ozonolysis reaction Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- DQIPCIMKILIHLA-NSHDSACASA-N (2S)-2-(3-phenylpyrrol-1-yl)propan-1-ol Chemical compound C1(=CC=CC=C1)C1=CN(C=C1)[C@H](CO)C DQIPCIMKILIHLA-NSHDSACASA-N 0.000 description 1
- NLQQGJKMUASTIB-NSHDSACASA-N (2S)-2-carbazol-9-ylpropan-1-ol Chemical compound C1=CC=CC=2C3=CC=CC=C3N(C1=2)[C@H](CO)C NLQQGJKMUASTIB-NSHDSACASA-N 0.000 description 1
- SLHOMFAOUBLZRN-VIFPVBQESA-N (2S)-2-indol-1-ylpropan-1-ol Chemical compound N1(C=CC2=CC=CC=C12)[C@H](CO)C SLHOMFAOUBLZRN-VIFPVBQESA-N 0.000 description 1
- XUSGBSQBGZWTIT-ZDUSSCGKSA-N (2S)-3-(1H-indol-3-yl)-2-pyrrol-1-ylpropan-1-ol Chemical compound N1C=C(C2=CC=CC=C12)C[C@@H](CO)N1C=CC=C1 XUSGBSQBGZWTIT-ZDUSSCGKSA-N 0.000 description 1
- PHRABVHYUHIYGY-UHFFFAOYSA-N 1-methylnaphthalene Chemical group C1=CC=C2C([CH2])=CC=CC2=C1 PHRABVHYUHIYGY-UHFFFAOYSA-N 0.000 description 1
- YYEROYLAYAVZNW-UHFFFAOYSA-N 2-methyl-2-phenylpropanoic acid Chemical compound OC(=O)C(C)(C)C1=CC=CC=C1 YYEROYLAYAVZNW-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- OPGUZRRLMQSMAQ-UHFFFAOYSA-N 5-(4-methoxyphenyl)-1-phenylbenzimidazole Chemical compound C1=CC(OC)=CC=C1C1=CC=C(N(C=N2)C=3C=CC=CC=3)C2=C1 OPGUZRRLMQSMAQ-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- GOVXKUCVZUROAN-UHFFFAOYSA-N CCc1c[nH]c2c1cccc2 Chemical compound CCc1c[nH]c2c1cccc2 GOVXKUCVZUROAN-UHFFFAOYSA-N 0.000 description 1
- ADMBXFJYQPDWPN-FQEVSTJZSA-N C[C@@H](C(OC(c1cccc2c1cccc2)c1cccc2ccccc12)=O)N(C(c1ccccc11)=O)C1=O Chemical compound C[C@@H](C(OC(c1cccc2c1cccc2)c1cccc2ccccc12)=O)N(C(c1ccccc11)=O)C1=O ADMBXFJYQPDWPN-FQEVSTJZSA-N 0.000 description 1
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N Cc1cnc[nH]1 Chemical compound Cc1cnc[nH]1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000006898 Intramolecular Friedel-Crafts reaction Methods 0.000 description 1
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 1
- 229910010090 LiAlO 4 Inorganic materials 0.000 description 1
- FDAAVANEOUCASO-BHVANESWSA-N O=C([C@H](Cc1c(cccc2)c2ccc1)[n]1cccc1)OC(c1cccc2c1cccc2)c1c(cccc2)c2ccc1 Chemical compound O=C([C@H](Cc1c(cccc2)c2ccc1)[n]1cccc1)OC(c1cccc2c1cccc2)c1c(cccc2)c2ccc1 FDAAVANEOUCASO-BHVANESWSA-N 0.000 description 1
- WIMRLUOKAKYGII-YTTGMZPUSA-N O=C([C@H](Cc1ccccc1)[n]1cccc1)OC(c1cccc2c1cccc2)c1cccc2c1cccc2 Chemical compound O=C([C@H](Cc1ccccc1)[n]1cccc1)OC(c1cccc2c1cccc2)c1cccc2c1cccc2 WIMRLUOKAKYGII-YTTGMZPUSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004171 alkoxy aryl group Chemical group 0.000 description 1
- 125000005082 alkoxyalkenyl group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000005213 alkyl heteroaryl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229940093740 amino acid and derivative Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000005018 aryl alkenyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005015 aryl alkynyl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- CHIHQLCVLOXUJW-UHFFFAOYSA-N benzoic anhydride Chemical compound C=1C=CC=CC=1C(=O)OC(=O)C1=CC=CC=C1 CHIHQLCVLOXUJW-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- PBHZBAQPVHETGK-UHFFFAOYSA-L dipotassium 2,2-ditert-butylpropanedioate Chemical compound C(C)(C)(C)C(C(=O)[O-])(C(=O)[O-])C(C)(C)C.[K+].[K+] PBHZBAQPVHETGK-UHFFFAOYSA-L 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000004447 heteroarylalkenyl group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000005312 heteroarylalkynyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000005462 imide group Chemical group 0.000 description 1
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Classifications
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- C07B53/00—Asymmetric syntheses
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pyrrole Compounds (AREA)
Description
下記式(a):
で表されるラセミのカルボン酸と、下記式(b):
で表されるアルコール又は下記式(c):
で表されるフェノール誘導体とを、酸無水物及び不斉触媒の存在下、双極子モーメント3.5以上の極性溶媒中で反応させ、上記ラセミのカルボン酸のうち一方のエナンチオマーを選択的にエステル化するとともに、他方のエナンチオマーをラセミ化する工程を含む、光学活性カルボン酸エステルの製造方法。
のいずれかで表される、上記(1)に記載の光学活性カルボン酸エステルの製造方法。
で表されるラセミのα−アミノ酸のアミノ基を1H−ピロール−1−イル基に変換し、上記式(a)で表されるラセミのカルボン酸を得る工程をさらに含む、上記(3)に記載の光学活性カルボン酸エステルの製造方法。
本発明に係る製造方法で用いられる酸無水物は、脱水縮合剤として作用する。酸無水物としては、安息香酸、フェニル基にアルキル基、アルコキシ基、アミノ基、アルコキシアルキル基等の電子供与性基が結合した安息香酸、又はα位が4級炭素である多置換カルボン酸から得られるものが好ましく、安息香酸、炭素数1〜3のアルキル基又はアルコキシ基が結合した1〜3置換の安息香酸、ピバル酸、2−メチルー2−フェニルプロピオン酸、又は2,2−ジフェニルプロピオン酸から得られるものがより好ましい。
本発明に係る製造方法で用いられる極性溶媒は、双極子モーメントが3.5以上である。このような極性溶媒としては、N,N−ジメチルアセトアミド、N,N−ジメチルホルムアミド、1,3−ジメチル−2−イミダゾリジノン、N−メチルピロリドン、ジメチルスルホキシド、ニトロベンゼン、ピリダジン、ベンゾニトリル、プロピオニトリル等が挙げられる。双極子モーメントが3.5以上の極性溶媒を用いることによって、エステル化対象ではない光学活性カルボン酸のラセミ化が起こりやすくなる。
光学活性カルボン酸エステルの製造は、極性溶媒中に、ラセミのカルボン酸、アルコール又はフェノール誘導体、酸無水物、及び不斉触媒を添加することによって行われるが、反応系内に塩基を添加することが好ましい。この塩基としては、求核性を有さない有機塩基が好ましく、下記式(i):
で表されるアミンがより好ましい。R1、R2及びR3としては、炭素数1〜8のアルキル基であれば特に制限されないが、R1、R2及びR3のうち少なくとも1つがメチル基であることが好ましい。
酸無水物は、ラセミのカルボン酸と混合酸無水物をつくり、エナンチオ選択的にエステル化を進行させる中間体となるために必要であり、ラセミのカルボン酸に対して当量以上用いることが好ましく、1.0〜5.0当量用いることがより好ましい。
塩基は、反応進行に伴って生成する酸無水物由来の酸を中和する働きと、不斉触媒によって活性化される混合酸無水物のラセミ化を促進する働きとがある。塩基を添加しなくても反応は進行するが、ラセミ化を促進し、目的とする光学活性カルボン酸エステルの収率及び鏡像体過剰率を高くするためには、ラセミのカルボン酸に対し、1.2〜4.8当量添加することが好ましい。
不斉触媒は、エナンチオ選択的にエステル化を進行させるために必要であり、ラセミのカルボン酸に対し、0.1〜10モル%用いることが好ましい。
反応温度は−23〜30℃が好ましく、反応時間は10分間〜72時間が好ましい。
なお、実施例において、以下の略号を用いることがある。
Np:ナフチル
Piv2O:ピバル酸無水物
Me:メチル
Et:エチル
n−Pr:ノルマルプロピル
i−Pr:イソプロピル
n−Bu:ノルマルブチル
i−Bu:イソブチル
n−Hex:ノルマルヘキシル
Ac:アセチル
Ph:フェニル
Bn:ベンジル
Tr:トリチル
Ms:メタンスルホニル
Boc:ターシャリーブトキシカルボニル
DMF:ジメチルホルムアミド
DMA:ジメチルアセトアミド
tR:保持時間
得られた光学活性カルボン酸エステルの物性は以下のとおりである。
HPLC(CHIRALPAK IA−3,i−PrOH/ヘキサン=1/4,flow rate=0.75mL/min):tR=17.9min(54.9%),tR=24.4min(45.1%);
1H NMR(CDCl3):δ
8.42(s,1H,1’−H),
8.03−7.75(m,6H,Ar),
7.57−7.27(m,8H,Ar),
5.09(d,J=7.2Hz,1H,NH),
4.46(td,J=7.2,7.2Hz,1H,2−H),
1.40(s,9H,t−Bu),
1.38(d,J=7.2Hz,3H,3−CH3);
13C NMR(CDCl3):δ172.6(1),155.0(Boc),134.4,134.2,133.81,133.79,131.0,130.9,129.18,129.16,128.9,128.8,126.74,126.68,125.9,125.9,125.8,125.23,125.20,123.4,123.2,123.2,79.8(t−Bu),71.9(1’),49.5(2),28.3(t−Bu),18.7(3);
HR MS:calcd for C29H29NO4Na(M+Na+) 478.1989,found 478.1970.
HPLC(CHIRALPAK ID,i−PrOH/hexane=1/9,flow rate=0.75mL/min):tR=43.0min(25.6%),tR=51.9min(74.4%).
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/19,flow rate=0.75mL/min):tR=19.3min(66.1%),tR=21.8min(33.9%);
1H NMR(CDCl3):δ
8.40(s,1H,1’−H),
7.96−7.67(m,6H,Ar),
7.49−7.37(m,5H,Ar),
7.27−7.23(m,1H,Ar),
7.16−7.04(m,3H,Ar),
6.99−6.93(m,2H,Ar),
6.72−6.66(m,1H,Ar),
5.37(q,J=7.6Hz,1H,2−H),
1.66(d,J=7.6Hz,3H,3−CH3),
1.25(s,3H,CH3),
1.10(s,3H,CH3);
13C NMR(CDCl3):δ180.7,169.6(1),140.0,135.6,134.4,134.0,133.8,133.6,130.84,130.79,129.1,129.0,128.9,128.7,127.3,126.64,126.60,126.1,125.8,125.6,125.5,125.2,124.9,123.3,123.1,122.4,122.3,109.7,72.3(1’),48.7,43.7,24.4(Me),24.0(Me),14.1(3);
HR MS:calcd for C34H29NO3Na(M+Na+) 522.2040,found 522.2029.
HPLC(CHIRALCEL OD−H,i−PrOH/hexane=1/9,flow rate=0.75mL/min):tR=23.2min(91.9%),tR=30.7min(8.1%);
1H NMR(CDCl3):δ
8.45(s,1H,1’−H),
8.01−7.70(m,6H,Ar),
7.53−7.34(m,7H,Ar),
7.26−7.20(m,2H,Ar),
7.09(t,J=8.0Hz,1H,Ar),
6.92(t,J=7.6Hz,1H,Ar),
6.51(d,J=8.0Hz,1H,Ar),
5.35(q,J=7.2Hz,1H,2−H),
1.68(d,J=7.2Hz,3H,3−CH3);
13 NMR(CDCl3):δ182.3,168.9(1),157.7,148.9,137.8,133.9,133.8,133.7,130.84,130.81,129.40,129.40,129.37,129.0,128.9,126.7,126.7,126.5,125.9,125.8,125.8,125.3,125.2,125.0,123.6,123.3,123.2,117.6,111.5,73.4(1’),49.2(2),14.2(3);
HR MS:calcd for C32H23NO4Na(M+Na+) 508.1519,found 508.1526.
HPLC(CHIRALPAK IC−3,i−PrOH/hexane=1/19,flow rate=0.75mL/min):tR=46.3min(7.1%),tR=50.7min(92.9%);
1H NMR(CDCl3):δ
8.46(s,1H,1’−H),
8.01−7.71(m,6H,Ar),
7.54−7.33(m,6H,Ar),
7.27−7.09(m,3H,Ar),
7.01(ddd,J=8.0,7.6,1.2Hz,1H,Ar),
6.87(ddd,J=8.0,7.6,0.8Hz,1H,Ar),
6.73(dd,J=7.6,1.2Hz,1H,Ar),
5.24(q,J=7.6Hz,1H,2−H),
1.75(d,J=7.6Hz,3H,3−CH3);
13C NMR(CDCl3):δ168.7(1),154.0,142.5,133.95,133.89,133.8,133.7,130.9,130.8,129.4,129.3,129.2,129.0,128.9,126.8,126.7,126.1,126.0,125.88,125.86,125.2,125.1,123.6,123.2,123.1,122.5,110.1,109.9,73.0(1’),51.7(2),14.9(3);
HR MS:calcd for C31H23NO4Na(M+Na+) 496.1519,found 496.1496.
HPLC(CHIRALPAK AS−H,i−PrOH/hexane=1/9,flow rate=0.75mL/min):tR=31.2min(11.9%),tR=43.2min(88.1%);
1H NMR(CDCl3):δ
8.39(s,1H,1’−H),
8.09−7.78(m,6H,Ar),
7.56−7.29(m,8H,Ar),
5.04(q,J=7.2Hz,1H,2−H),
3.36−3.16(m,2H,3’−CH2),
2.38−2.20(m,2H,5’−CH2),
1.93−1.67(m,2H,4’−CH2),
1.42(d,J=7.2Hz,3H,3−CH3);
13C NMR(CDCl3):δ175.2,170.8(1),134.4,134.3,133.8,133.8,131.0,130.9,129.2,129.1,128.9,128.9,126.8,126.6,126.2,125.9,125.8,125.7,125.3,125.2,123.27,123.25,72.0(1’),49.5,43.4,30.7,18.0,14.7(3);
HR MS:calcd for C28H25NO3Na(M+Na+) 446.1727, found 446.1706.
1H NMR(CDCl3):δ
8.39(s,1H,1’−H),
8.05−7.72(m,6H,Ar),
7.54−7.28(m,6H,Ar),
7.15(d,J=7.2Hz,1H,Ar),
7.03(d,J=7.2Hz,1H,Ar),
6.73(t,J=2.0Hz,2H,pyrrole),
6.21(t,J=2.0Hz,2H,pyrrole),
4.86(q,J=7.2Hz,1H,2−H),
1.73(d,J=7.2Hz,3H,3−CH3);
13C NMR(CDCl3):δ170.2(1),134.2,134.0,133.8,133.7,131.0,130.8,129.2,129.1,128.9,128.8,126.8,126.7,126.1,125.9,125.8,125.5,125.3,125.3,123.2,123.1,119.8(pyrrole),108.8(pyrrole),71.9(1’),57.1(2),17.8(3);
HR MS:calcd for C28H23NO2Na(M+Na+) 428.1621, found 428.1603.
なお、化合物2gの鏡像体過剰率は、LiAlH4を用いて化合物2gを還元し、p−ニトロ安息香酸クロライドを用いてアシル化して、対応するp−ニトロ安息香酸エステル2g’に変換した後に求めた。
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/19,flow rate=0.75mL/min):tR=19.6min(92.8%),tR=22.0min(7.2%);
1H NMR(CDCl3):δ
8.32−8.22(m,2H,Ar),
8.18−8.06(m,2H,Ar),
6.77(t,J=2.0Hz,2H,pyrrole),
6.18(t,J=2.0Hz,2H,pyrrole),
4.59−4.40(m,3H,2−H,1−CH2),
1.61(d,J=6.4Hz,3H,3−CH3);
13C NMR(CDCl3):δ164.2,150.6,135.0,130.7,123.6,118.8(pyrrole),108.4(pyrrole),69.1(1),53.5(2),17.7(3);
HR MS:calcd for C14H14N2O4Na(M+Na+) 297.0846, found 297.0844.
1H NMR(CDCl3):δ
8.37(s,1H,1’−H),
7.93−7.72(m,6H,Ar),
7.67−7.60(m,1H,Ar),
7.50−7.33(m,4H,Ar),
7.26−7.00(m,7H,Ar),
6.98−6.88(m,1H,Ar),
6.52(d,J=3.2Hz,1H,Ar),
5.22(q,J=7.2Hz,1H,2−H),
1.81(d,J=7.2Hz,3H,3−CH3);
13C NMR(CDCl3):δ170.5(1),136.2,134.0,133.9,133.73,133.72,130.90,130.87,129.1,129.1,128.9,128.84,128.76,126.69,126.66,125.9,125.84,125.84,125.81,125.2,125.1,125.0,123.2,123.1,121.8,121.0,120.0,109.4,102.5,72.1(1’),53.9(2),17.0(3);
HR MS:calcd for C32H25NO2Na(M+Na+) 478.1778,found 478.1774.
なお、化合物2hの鏡像体過剰率は、LiAlH4を用いて化合物2hを還元し、対応するアルコール2h’に変換した後に求めた。
HPLC(CHIRALCEL OJ−H,i−PrOH/hexane=1/9,flow rate=0.75mL/min):tR=28.4min(4.7%),tR=33.5min(95.3%);
1H NMR(CDCl3):δ
7.64(d,J=8.4Hz,1H,Ar),
7.41(d,J=8.4Hz,1H,Ar),
7.30−7.17(m,2H,Ar),
7.11(ddd,J=8.0,7.6,0.8Hz,1H,Ar),
6.57(d,J=0.8Hz,1H,Ar),
4.67(tdd,J=6.8,6.4,5.2Hz,1H,2−H),
3.90(dd,J=11.6,6.4Hz,1H,1−CH2),
3.87(dd,J=11.6,5.2Hz,1H,1−CH2),
1.56(d,J=6.8Hz,3H,3−CH3),
1.48(br m,1H,OH);
13C NMR(CDCl3):δ136.2,128.6,124.2,121.5,121.0,119.6,109.5,102.0,66.4(1),53.1(2),16.9(3);
HR MS:calcd for C11H14NO(M+H+) 175.1070,found 175.1062.
HPLC(CHIRALPAK ID,i−PrOH/hexane=2/3,flow rate=0.5mL/min):tR=29.6min(11.3%),tR=35.9min(88.7%);
1H NMR(CDCl3):δ
8.41(s,1H,1’−H),
7.97(s,1H,benzimidazole−2’),
7.92−7.72(m,7H,Ar),
7.51−7.32(m,4H,Ar),
7.30−7.07(m,6H,Ar),
6.98(d,J=7.2Hz,1H,Ar),
5.18(q,J=7.2Hz,1H,2−H),
1.87(d,J=7.2Hz,3H,3−CH3);
13C NMR(CDCl3):δ169.3(1),143.7,141.2,141.2,133.78,133.76,133.7,133.5,133.4,130.82,130.80,129.34,129.31,128.9,128.9,126.7,125.93,125.93,125.91,125.8,125.10,125.07,123.1,123.0,122.9,122.5,120.5,109.9,72.8(1’),53.8(2),17.0(3);
HR MS:calcd for C31H25N2O2(M+H+) 457.1911,found 457.1911.
1H NMR(CDCl3):δ
8.48(s,1H,1’−H),
8.21−8.02(m,3H,Ar),
7.92−7.70(m,4H,Ar),
7.64(d,J=8.0Hz,1H,Ar),
7.56−7.45(m,2H,Ar),
7.41−7.06(m,10H,Ar),
6.91(t,J=7.8Hz,1H,Ar),
6.75(d,J=6.8Hz,1H,Ar),
5.47(q,J=7.2Hz,1H,2−H),
1.84(d,J=7.2Hz,3H,3−CH3);
13C NMR(CDCl3):δ170.2(1),139.6,134.4,133.9,133.8,133.6,131.1,130.6,129.3,129.0,128.73,128.67,126.9,126.6,126.4,125.9,125.7,125.6,125.5,125.2,124.9,123.5,123.3,123.2,120.2,119.4,109.6,72.3(1’),52.4(2),15.4(3);
HR MS:calcd for C36H27NO2Na(M+Na+) 528.1934,found 528.1942.
なお、化合物2jの鏡像体過剰率は、LiAlH4を用いて化合物2jを還元し、対応するアルコール2j’に変換した後に求めた。
HPLC(CHIRALCEL OD−H,i−PrOH/hexane=1/9,flow rate=1.0mL/min):tR=24.2min(18.0%),tR=35.0min(82.0%);
1H NMR(CDCl3):δ
8.09(d,J=7.6Hz,2H,Ar),
7.55−7.37(m,4H,Ar),
7.27−7.17(m,2H,Ar),
4.89(dtd,J=9.2,7.6,4.8Hz,1H,2−H),
4.26(dd,J=11.2,9.2Hz,1H,1−CH2),
3.91(dd,J=11.2,4.8Hz,1H,1−CH2),
1.64(d,J=7.6Hz,3H,3−CH3),
1.79−1.38(br m,1H,OH);
13C NMR(CDCl3):δ139.9,125.6,123.5,120.3,119.1,110.0,64.5(1),53.4(2),15.1(3);
HR MS:calcd for C15H15NONa(M+Na+) 248.1046,found 248.1052.
表中、E値は光学分割の効率を示す指標であり、E(%)=収率(%)×ee(%)×2÷100で定義される。動的速度論的光学分割におけるE値の理論的な上限値は200であり、E値が200であることは、ラセミ体の基質から光学的に純粋な目的物が100%の収率で得られたことを意味する。
得られた光学活性カルボン酸エステルの物性は以下のとおりである。
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=1.0mL/min):tR=13.4min(96.9%),tR=22.5min(3.1%);
1H NMR(CDCl3):δ
8.37(s,1H,1’−H),
8.02(d,J=5.6Hz,1H,Ar),
7.98−7.73(m,5H,Ar),
7.58−7.18(m,8H,Ar),
7.09−7.00(m,1H,Ar),
6.98−6.89(m,1H,Ar),
6.26−6.09(br m,2H,pyrrole,2−H),
2.28(s,3H,Ac−CH3),
1.66(d,J=7.2Hz,3H,3−CH3);
13C NMR(CDCl3):δ188.5(Ac),170.8(1),134.6,134.2,133.9,133.8,131.1,130.9,130.6,129.2,129.0,128.8,128.7,127.0,126.7,126.6,126.2,125.9,125.84,125.75,125.2,125.2,123.7,123.4,120.5,108.7,72.3(1’),55.7(2),27.1(Ac),17.7(3);
HR MS:calcd for C30H25NO3Na(M+Na+) 470.1727,found 470.1726.
HPLC(CHIRALPAK IC−3,i−PrOH/hexane=1/19,flow rate=0.75mL/min):tR=18.6min(5.9%),tR=21.5min(94.1%);
1H NMR(CDCl3):δ
8.41(s,1H,1’−H),
8.05−7.78(m,6H,Ar),
7.56−7.30(m,8H,Ar),
6.94(dd,J=2.8,1.6Hz,1H,pyrrole),
6.79(dd,J=4.0,1.6Hz,1H,pyrrole),
6.18(dd,J=4.0,2.8Hz,1H,pyrrole),
5.18(q,J=7.2Hz,1H,2−H),
1.77(d,J=7.2Hz,3H,3−CH3);
13C NMR(CDCl3):δ169.2(1),133.9,133.84,133.76,133.6,131.0,130.8,129.5,129.3,129.0,128.9,126.9,126.9,126.2,126.0,125.9,125.7,125.24,125.20,124.5,123.1,123.0,120.4,113.3,110.2,104.4,73.0(1’),56.0(2),18.0(3);
HR MS:calcd for C29H22N2O2Na(M+Na+) 453.1573,found 453.1571.
1H NMR(CDCl3):δ
8.33(s,1H,1’−H),
7.94−7.87(m,1H,Ar),
7.83−7.66(m,5H,Ar),
7.44−7.05(m,12H,Ar),
6.97(d,J=7.2Hz,1H,Ar),
6.91(dd,J=2.4,2.0Hz,1H,pyrrole),
6.65(dd,J=2.8,2.4Hz,1H,pyrrole),
6.42(dd,J=2.8,2.0Hz,1H,pyrrole),
4.75(q,J=7.2Hz,1H,2−H),
1.66(d,J=7.2Hz,3H,3−CH3);
13C NMR(CDCl3):δ170.0(1),135.7,134.1,134.0,133.8,133.7,131.0,130.8,129.3,129.1,128.9,128.8,128.5,128.5,126.8,126.7,126.2,125.9,125.8,125.6,125.50,125.47,125.3,125.1,123.13,123.10,120.9,116.5,107.0,72.1(1’),57.3(2),17.7(3);
HR MS:calcd for C34H27NO2Na(M+Na+) 504.1934,found 504.1948.
なお、化合物2mの鏡像体過剰率は、LiAlH4を用いて化合物2mを還元し、対応するアルコール2m’に変換した後に求めた。
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.75mL/min):tR=10.0min(91.0%),tR=11.5min(9.0%);
1H NMR(C6D6):δ
7.64−7.53(m,2H,Ar),
7.34−7.21(m,2H,Ar),
7.14−7.06(m,1H,Ar),
6.80(dd,J=2.2,1.8Hz,1H,pyrrole),
6.57(dd,J=2.6,1.8Hz,1H,pyrrole),
6.42(dd,J=2.6,2.2Hz,1H,pyrrole),
3.56−3.41(m,1H,2−H),
3.23−3.08(m,2H,1−CH2),
1.16−1.00(br m,1H,OH),
0.93(d,J=6.9Hz,3H,3−CH3);
13C NMR(C6D6):δ136.8,129.0,128.7,125.6,125.4,120.1,115.9,106.7,67.2(1),57.2(2),17.1(3);
HR MS:calcd for C13H15NONa(M+Na+) 224.1046,found 224.1040.
HPLC(CHIRALPAK IC−3,i−PrOH/hexane=3/7,flow rate=0.4mL/min):tR=36.9min(12.6%),tR=46.4min(87.4%);
1H NMR(CDCl3):δ
8.41(s,1H,1’−H),
7.99−7.76(m,6H,Ar),
7.55−7.26(m,6H,Ar),
7.26−7.17(m,2H,Ar),
7.09(d,J=7.2Hz,1H,Ar),
6.66(dd,J=2.8,2.4Hz,1H,pyrrole),
6.61(dd,J=2.8,1.6Hz,1H,pyrrole),
4.81(q,J=7.2Hz,1H,2−H),
2.31(s,3H,Ac−CH3),
1.73(d,J=7.2Hz,3H,3−CH3);
13C NMR(CDCl3):δ193.3(Ac),169.3(1),133.77,133.76,133.73,133.67,130.9,130.8,129.4,129.3,129.0,128.9,126.84,126.76,126.4,126.0,126.0,125.9,125.5,125.2,125.1,124.8,122.94,122.93,121.6,109.4,72.5(1’),57.6(2),27.0(Ac),17.8(3);
HR MS:calcd for C30H25NO3Na(M+Na+) 470.1727,found 470.1707.
HPLC(CHIRALCEL OD−H,i−PrOH/hexane=1/4,flow rate=0.75mL/min):tR=9.6min(7.5%),tR=16.2min(92.5%);
1H NMR(CDCl3):δ
8.35(s,1H,1’−H),
7.93−7.72(m,6H,Ar),
7.57(d,J=1.6Hz,1H,Ar),
7.49−7.31(m,4H,Ar),
7.28−7.14(m,3H,Ar),
7.07−6.91(m,4H,Ar),
6.44(d,J=3.2Hz,1H,indole−3’−H),
5.14(q,J=7.2Hz,1H,2−H),
1.80(d,J=7.2Hz,3H,3−CH3);
13C NMR(CDCl3):δ170.1(1),134.6,133.9,133.84,133.78,130.91,130.87,129.8,129.24,129.22,128.90,128.89,126.71,126.69,126.4,125.93,125.89,125.89,125.8,125.8,125.7,125.11,125.07,123.13,123.06,122.1,120.4,110.4,102.2,72.4(1’),54.2(2),16.9(3);
HR MS:calcd for C32H24ClNO2Na(M+Na+) 512.1388,found 512.1371.
HPLC(CHIRALCEL OD−H,i−PrOH/hexane=1/4,flow rate=0.75mL/min):tR=12.4min(9.8%),tR=30.8min(90.2%);
1H NMR(CDCl3):δ
8.36(s,1H,1’−H),
7.94−7.69(m,6H,Ar),
7.50−7.30(m,4H,Ar),
7.27−6.93(m,7H,Ar),
6.74(dd,J=9.2,2.8Hz,1H,indole−6’−H),
6.44(d,J=3.2Hz,1H,indole−3’−H),
5.14(q,J=7.2Hz,1H,2−H),
3.84(s,3H,indole−5’−OCH3),
1.79(d,J=7.2Hz,3H,3−CH3);
13C NMR(CDCl3):δ170.5(1),154.4,134.1,134.0,133.8,133.7,131.6,130.93,130.91,129.2,129.1,129.1,128.9,128.8,126.68,126.66,125.9,125.8,125.8,125.8,125.6,125.15,125.11,123.18,123.16,112.0,110.1,102.9,102.1,72.2(1’),55.9(5’−OCH3),54.1(2),16.9(3);
HR MS:calcd for C33H27NO3Na(M+Na+) 508.1883,found 508.1872.
HPLC(CHIRALCEL OD−H,i−PrOH/hexane=3/7,flow rate=0.75mL/min):tR=12.0min(92.1%),tR=18.8min(7.9%);
1H NMR(CDCl3):δ
8.41(d,J=8.0Hz,1H,indole−2’’−H),
8.39(s,1H,1’−H),
7.92−7.74(m,7H,Ar),
7.52−7.33(m,4H,Ar),
7.33−7.13(m,5H,Ar),
7.09(d,J=7.2Hz,1H,Ar),
7.02(d,J=7.2Hz,1H,Ar),
5.25(q,J=7.2Hz,1H,2−H),
2.38(s,3H,Ac−CH3),
1.87(d,J=7.2Hz,3H,3−CH3);
13C NMR(CDCl3):δ193.1(Ac),169.5(1),136.8,133.8,133.8,133.6,133.5,132.1,130.83,130.78,129.4,129.3,128.9,128.9,126.79,126.76,126.2,125.98,125.96,125.96,125.8,125.11,125.09,123.6,123.0,123.0,123.0,122.8,118.0,109.5,72.9(1’),54.2(2),27.5(Ac),17.1(3);
HR MS:calcd for C34H27NO3Na(M+Na+) 520.1883,found 520.1864.
得られた光学活性カルボン酸エステルの物性は以下のとおりである。
HPLC(CHIRALPAK OD−H×2,i−PrOH/hexane=1/9,flow rate=0.5mL/min):tR=26.4min(1.9%),tR=28.1min(98.1%)
その他の機器データは、試験例1のものと一致した。
HPLC(CHIRALPAK OD−H×2,i−PrOH/hexane=1/9,flow rate=0.5mL/min):tR=22.4min(87.6%),tR=24.21min(12.4%);
1H NMR(CDCl3):δ
8.40(s,1H,1’−H),
8.04−7.71(m,6H,Ar),
7.53−7.00(m,8H,Ar),
6.76−6.63(m,2H,pyrrole),
6.26−6.14(m,2H,pyrrole),
4.46(dd,J=9.2,6.6Hz,1H,2−H),
2.26−1.92(m,2H,3−CH2),
0.84(t,J=7.2Hz,3H,4−CH3);
13C NMR(CDCl3):δ169.7(1),134.3,134.1,133.8,133.7,131.0,130.9,129.2,129.0,128.9,128.8,126.7,126.6,126.0,125.9,125.8,125.6,125.2,125.2,123.2,123.1,120.0(pyrrole),108.7(pyrrole),71.9(1’),63.6(2),25.5(3),10.3(4);
HR MS:calcd for C29H25NO2Na(M+Na+) 442.1778,found 442.1757.
1H NMR(CDCl3):δ
8.33(s,1H,1’−H),
7.98−7.64(m,6H,Ar),
7.56−7.11(m,9H,Ar),
7.10−6.90(m,4H,Ar),
6.71(t,J=2.0Hz,2H,pyrrole),
6.18(t,J=2.0Hz,2H,pyrrole),
4.89(dd,J=8.0,7.6Hz,1H,2−H),
3.49(dd,J=14.0,8.0Hz,1H,3−CH2),
3.26(dd,J=14.0,7.6Hz,1H,3−CH2);
13C NMR(CDCl3):δ169.1(1),136.1,134.0,133.9,133.79,133.76,131.0,130.9,129.2,129.03,128.99,128.9,128.8,128.6,127.0,126.8,126.7,126.1,125.9,125.8,125.5,125.29,125.26,123.2,123.1,120.1(pyrrole),109.0(pyrrole),72.3(1’),63.5(2),38.6(3);
HR MS:calcd for C34H27NO2Na(M+Na+) 504.1934,found 504.1911.
なお、化合物2sの鏡像体過剰率は、LiAlH4を用いて化合物2sを還元し、対応するアルコール2s’に変換した後に求めた。
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/50,flow rate=0.75mL/min):tR=26.1min(93.5%),tR=48.2min(6.5%);
1H NMR(CDCl3):δ
7.34−7.13(m,3H,Ar),
7.08−6.94(m,2H,Ar),
6.70(t,J=2.0Hz,2H,pyrrole),
6.17(t,J=2.0Hz,2H,pyrrole),
4.20(tt,J=7.6,6.0Hz,1H,2−H),
3.83(dd,J=6.4,6.0Hz,2H,1−CH2),
3.06(d,J=7.6Hz,2H,3−CH2),
1.47(t,J=6.4Hz,1H,OH);
13C NMR(CDCl3):δ137.5,128.8,128.5,126.6,119.2(pyrrole),108.4(pyrrole),65.3,63.5,38.5(3);
HR MS:calcd for C13H15NONa(M+Na+) 224.1046,found 224.1044.
1H NMR(CDCl3):δ
8.39(s,1H,1’−H),
8.03−7.74(m,6H,Ar),
7.57−7.24(m,6H,Ar),
7.14(d,J=7.2Hz,1H,Ar),
7.04(d,J=7.2Hz,1H,Ar),
6.71(t,J=2.0Hz,2H,pyrrole),
6.19(t,J=2.0Hz,2H,pyrrole),
4.66(dd,J=9.2,6.4Hz,1H,2−H),
2.21−1.93(m,2H,3−CH2),
1.32−1.18(m,2H,4−CH2),
0.85(t,J=7.2Hz,3H,5−CH3);
13C NMR(CDCl3):δ169.9(1),134.3,134.1,133.83,133.78,131.0,130.9,129.2,129.0,128.9,128.8,126.7,126.6,126.1,125.9,125.8,125.6,125.3,125.3,123.2,123.2,120.0(pyrrole),108.7(pyrrole),71.9(1’),61.8(2),34.0(3),19.0(4),13.4(5);
HR MS:calcd for C30H27NO2Na(M+Na+) 456.1934,found 456.1932.
なお、化合物2tの鏡像体過剰率は、LiAlH4を用いて化合物2tを還元し、p−ニトロ安息香酸クロライドを用いてアシル化して、対応するp−ニトロ安息香酸エステル2t’に変換した後に求めた。
HPLC(CHIRALCEL OD−H,i−PrOH/hexane=1/50,flow rate=1.0mL/min):tR=15.7min(13.2%),tR=18.8min(86.8%);
1H NMR(CDCl3):δ
8.27(d,J=8.8Hz,2H,Ar),
8.09(d,J=8.8Hz,2H,Ar),
6.73(t,J=2.0Hz,2H,pyrrole),
6.18(t,J=2.0Hz,2H,pyrrole),
4.57(dd,J=11.2,4.4Hz,1H,1−CH2),
4.48(dd,J=11.2,8.0Hz,1H,1−CH2),
4.35−4.22(m,1H,2−H),
1.96−1.75(m,2H,3−CH2),
1.39−1.25(m,2H,4−CH2),
0.94(t,J=7.2Hz,3H,5−CH3);
13C NMR(CDCl3):δ164.4,150.4,130.7,123.6,119.1(pyrrole),108.4(pyrrole),68.3(1),58.3(2),34.0(3),19.1(4),13.7(5);
HR MS:calcd for C16H18N2O4Na(M+Na+) 325.1159,found 325.1164.
1H NMR(CDCl3):δ
8.35(s,1H,1’−H),
7.96−7.64(m,7H,Ar),
7.57−7.12(m,9H,Ar),
7.11−7.03(m,1H,Ar),
6.99−6.88(m,2H,Ar),
6.80−6.70(m,2H,pyrrole),
6.49(d,J=2.0Hz,1H,indole−2’’),
6.24−6.12(m,2H,pyrrole),
4.99(t,J=7.6Hz,1H,2−H),
3.68(dd,J=14.8,7.6Hz,1H,3−CH2),
3.39(dd,J=14.8,7.6Hz,1H,3−CH2);
13C NMR(CDCl3):δ169.6(1),135.9,134.0,133.9,133.7,133.7,130.9,130.8,129.1,129.0,128.81,128.77,126.9,126.7,126.7,126.0,125.84,125.79,125.6,125.2,125.2,123.21,123.18,123.0,122.1,120.1(pyrrole),119.6,118.2,111.1,109.9,108.8,72.1(1’),62.4(2),28.3(3);
HR MS:calcd for C36H28N2O2Na(M+Na+) 543.2043,found 543.2018.
なお、化合物2uの鏡像体過剰率は、LiAlH4を用いて化合物2uを還元し、対応するアルコール2u’に変換した後に求めた。
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.75mL/min):tR=26.1min(91.8%),tR=36.0min(8.2%);
1H NMR(DMSO−d6):δ
10.73(s,1H,indole−1’),
7.48(d,J=7.5Hz,1H,indole),
7.30(d,J=7.5Hz,1H,indole),
7.04(dd,J=7.5,7.5Hz,1H,indole),
6.96(dd,J=7.5,7.5Hz,1H,indole),
6.83−6.71(m,3H,indole,pyrrole),
6.01−5.85(m,2H,pyrrole),
4.90(t,J=5.5Hz,1H,OH),
4.21(ddt,J=8.5,6.5,5.5Hz,1H,2−H),
3.66(dd,J=5.5,5.5Hz,2H,1−CH2),
3.25(dd,J=14.5,6.5Hz,1H,3−H),
3.03(dd,J=14.5,8.5Hz,1H,3−H);
13C NMR(DMSO−d6):δ135.9,127.3,123.1,120.8,119.4,118.2,118.1,111.3,110.7,106.9,64.3(1),62.0(2),27.8(3);
HR MS:calcd for C15H16N2ONa(M+Na+) 263.1155,found 263.1156.
HPLC(CHIRALPAK IA−3,i−PrOH/hexane=1/9,flow rate=0.5mL/min):tR=12.2min(5.6%),tR=14.5min(94.4%);
1H NMR(CDCl3):δ
8.35(s,1H,1’−H),
7.90−7.68(m,6H,Ar),
7.86(d,J=7.2Hz,1H,indole−7’),
7.50−7.14(m,9H,Ar),
7.01(s,1H,indole−2’),
6.95(d,J=6.8Hz,1H,Ar),
6.91(d,J=7.2Hz,1H,Ar),
6.77(t,J=2.0Hz,2H,pyrrole),
6.21(t,J=2.0Hz,2H,pyrrole),
5.02(t,J=7.6Hz,1H,2−H),
3.63(dd,J=14.8,7.6Hz,1H,3−CH2),
3.33(dd,J=14.8,7.6Hz,1H,3−CH2),
1.61(s,9H,t−Bu);
13C NMR(CDCl3):δ169.2(1),149.4(Boc),135.3,133.9,133.8,133.69,133.67,130.9,130.8,129.8,129.2,129.0,128.84,128.75,126.7,126.6,125.94,125.85,125.8,125.5,125.2,125.1,124.5,124.2,123.1,123.0,122.6,120.0(pyrrole),118.5,115.3,114.7,109.1(pyrrole),83.5(t−Bu),72.3(1’),61.7(2),28.12(t−Bu),28.07(3);
HR MS:calcd for C41H36N2O4Na(M+Na+) 643.2567,found 643.2551.
HPLC(CHIRALPAK IA−3,i−PrOH/hexane=2/8,flow rate=0.75mL/min):tR=30.3min(5.8%),tR=32.9min(94.2%);
1H NMR(CDCl3):δ
8.35(s,1H,1’−H),
7.93−7.74(m,5H,Ar),
7.70(d,J=8.4Hz,1H,Ar),
7.54−7.18(m,6H,Ar),
7.12−6.98(m,5H,Ar),
6.95(d,J=7.2Hz,1H,Ar),
6.69(t,J=2.0Hz,2H,pyrrole),
6.18(t,J=2.0Hz,2H,pyrrole),
4.84(dd,J=8.0,7.6Hz,1H,2−H),
3.48(dd,J=14.0,7.6Hz,1H,3−CH2),
3.24(dd,J=14.0,8.0Hz,1H,3−CH2),
3.04(s,3H,Ms);
13C NMR(CDCl3):δ168.8(1),148.1,135.5,133.8,133.73,133.67,130.9,130.7,130.6,130.6,129.3,129.0,128.9,128.8,126.8,126.7,126.1,125.9,125.8,125.3,125.2,123.1,122.9,122.0,122.0,120.0(pyrrole),109.2(pyrrole),72.3(1’),63.1(2),37.8(Ms),37.2(Ms);
HR MS:calcd for C35H29NO5SNa(M+Na+) 598.1659,found 598.1663.
HPLC(CHIRALPAK ID,i−PrOH/hexane=2/8,flow rate=0.75mL/min):tR=29.9min(8.5%),tR=32.6min(91.5%);
1H NMR(CDCl3):δ
8.39(s,1H,1’−H),
8.02−7.66(m,6H,Ar),
7.55−7.39(m,3H,Ar),
7.37−7.20(m,4H,Ar),
7.09(d,J=6.8Hz,1H,Ar),
7.03−6.85(m,3H,Ar),
6.65(t,J=2.0Hz,2H,pyrrole),
6.16(t,J=2.0Hz,2H,pyrrole),
4.83(dd,J=9.2,6.4Hz,1H,2−H),
3.44(dd,J=14.0,6.4Hz,1H,3−CH2),
3.27(dd,J=14.0,9.2Hz,1H,3−CH2),
3.15(s,3H,Ms),3.05(s,3H,Ms);
13C NMR(CDCl3):δ168.5(1),140.8,139.9,137.1,133.78,133.76,133.7,133.6,130.9,130.6,129.4,129.1,129.0,128.81,128.77,128.77,127.0,126.7,126.3,126.0,125.8,125.2,125.2,124.3,124.2,123.0,122.8,120.1(pyrrole),109.4(pyrrole),72.4(1’),62.7(2),38.4(Ms),38.3(Ms),37.8(3);
HR MS:calcd for C36H31NO8S2Na(M+Na+) 692.1383,found 692.1412.
1H NMR(CDCl3):δ
8.41(s,1H,1’−H),
7.97−7.80(m,6H,Ar),
7.50−7.11(m,13H,Ar),
6.75(t,J=2.1Hz,2H,pyrrole),
6.18(t,J=2.1Hz,2H,pyrrole),
4.94(t,J=6.0Hz,1H,2−H),
4.42(d,J=12.0Hz,2H,Bn),
4.06(dd,J=9.8,6.0Hz,1H,3−CH2),
3.96(dd,J=9.8,6.0Hz,1H,3−CH2).
なお、化合物2yの鏡像体過剰率は、LiAlH4を用いて化合物2yを還元し、p−ニトロ安息香酸クロライドを用いてアシル化して、対応するp−ニトロ安息香酸エステル2y’に変換した後に求めた。
(S)−3−(benzyloxy)−2−(1H−pyrrol−1−yl)propyl 4−nitrobenzoate(2y’)
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.7mL/min):tR=22.7min(82.1%),tR=24.3min(17.9%);
1H NMR(CDCl3):δ
8.25(d,J=8.8Hz,2H,Ar),
8.06(d,J=8.8Hz,2H,Ar),
8.04−7.26(m,5H,Ar),
6.78(t,J=2.0Hz,2H,pyrrole),
6.18(t,J=2.0Hz,2H,pyrrole),
4,74(dd,J=11.2,4.8Hz,1H,1−CH2),
4.69(dd,J=11.2,7.6Hz,1H,1−CH2),
4.54(d,J=12.0Hz,2H,Bn)
4.57−4.50(m,1H,2−H),
3.88(dd,J=9.8,6.0Hz,1H,3−CH2),
3.85(dd,J=9.8,5.2Hz,1H,3−CH2),
13C NMR(CDCl3):δ164.2(1’),150.6,137.4,135.0,130.7,128.5,127.9,127.7,123.6,119.8(pyrrole),108.7(pyrrole),73.5(Bn),69.8(3),65.6(2),57.9(1);
IR(KBr):3109,3062,3031,2916,2862,1959,1728,1527,1350,1273,1103,725cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/99,flow rate=0.5mL/min):tR=28.8min(7.4%),tR=30.2min(92.6%);
1H NMR(CDCl3):δ
8.43(s,1H,1’−H),
8.02−7.23(m,6H,Ar),
7.55−7.07(m,8H,Ar),
6.76(t,J=2.2Hz,2H,pyrrole),
6.24(t,J=2.2Hz,2H,pyrrole),
5.66(ddt,J=17.0,10.0,6.8Hz,1H,4−H),
5.09(ddd,J=17.0,2.6,1.6Hz,1H,5−CH2),
5.05(ddd,J=10.0,2.6,1.2,1H,5−CH2),
2.98−2.76(m,2H,3−CH2);
13C NMR(CDCl3):δ169.2(1),134.1,133.9,133.8,133.7,132.1,131.0,130.8,129.3,129.0,128.9,128.8,126.8,126.6,126.2,125.9,125.8,125.5,125.26,125.25,123.22,123.17,120.0(pyrrole),118.9,108.9(pyrrole),72.1(1’),61.7(2),36.2(3);
HR MS:calcd for C30H25NO2Na(M+Na+) 454.1778,found 454.1789.
IR(KBr):3062,3016,2931,1743,1550,1389,1164,941,756cm−1.
HPLC(CHIRALPAK OD−H×2,i−PrOH/hexane=1/9,flow rate=0.5mL/min):tR=19.5min(95.5%),tR=23.5min(4.5%);
1H NMR(CDCl3):δ
8.38(s,1H,1’−H),
8.03−7.70(m,6H,Ar),
7.53−7.20(m,6H,Ar),
7.11(d,J=7.2Hz,1H,Ar),
7.01(d,J=7.2Hz,1H,Ar),
6.71(t,J=2.0Hz,2H,pyrrole),
6.18(t,J=2.0Hz,2H,pyrrole),
4.22(d,J=10.4Hz,1H,2−H),
2.95−2.36(m,1H,3−H),
0.97(d,J=6.4Hz,3H,4−CH3)
0.75(d,J=6.4Hz,3H,4−CH3);
13C NMR(CDCl3):δ169.4(1),134.2,134.0,133.81,133.76,131.0,130.9,129.2,129.0,128.9,128.8,126.7,126.6,126.1,125.9,125.8,125.5,125.2,125.2,123.22,123.18,120.3(pyrrole),108.6(pyrrole),71.9(1’),69.1(2),30.9(3),19.5(4),18.5(4);
HR MS:calcd for C30H27NO2Na(M+Na+) 456.1934,found 456.1932;
IR(KBr):3061,2967,2873,1740,1599,1509,1486,1180,783,735cm−1.
Mp:149−152℃(CHCl3/hexane)
Di(1−naphthyl)methyl (S)−2−(1H−pyrrole−1−yl)hexanoate(2bb)[表6中、エントリー5;収率定量的、79%ee]
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=2/98,flow rate=0.5mL/min):tR=20.1min(10.3%),tR=21.7min(89.7%);
1H NMR(CDCl3):δ
8.38(s,1H,1’−H),
7.97−7.79(m,6H,Ar),
7.50−7.03(m,8H,Ar),
6.71(t,J=2.1Hz,2H,pyrrole),
6.19(t,J=2.1Hz,2H,pyrrole),
4.64(dd,J=9.2,6.6Hz,1H,2−H),
2.14(ddt,J=20.4,9.2,3.2Hz,1H,3−CH2),
2.00(ddt,J=20.4,6.6,3.2Hz,1H,3−CH2),
1.31−1.15(m,4H,3−CH2,4−CH2),
0.80(t,J=7.0Hz,3H,6−CH3);
13C NMR(CDCl3):δ169.9(1),134.3,134.1,133.82,133.76,131.0,130.9,129.2,129.1,128.9,128.8,126.7,126.6,126.1,125.9,125.8,125.6,125.3,123.2,120.0(pyrrole),108.7(pyrrole),71.9(1’),62.1(2),31.8(3),27.9(4),22.1(5),13.7(6);
HR MS:calcd for C31H29NO2Na(M+Na+) 470.2091,found 470.2103;
IR(KBr):3052,2958,2929,2862,1745,1599,1510,1488,1162,796,721cm−1.
Mp:108−109℃(CH2Cl2/hexane)
1H NMR(CDCl3):δ
8.37(s,1H,1’−H),
7.97−7.80(m,6H,Ar),
7.51−7.01(m,8H,Ar),
6.71(t,J=2.2Hz,2H,pyrrole),
6.19(t,J=2.2Hz,2H,pyrrole),
4.75(dd,J=8.8,6.8Hz,1H,2−H),
1.97(ddd,J=12.0,8.8,3.8Hz,1H,3−CH2),
1.95(ddd,J=12.0,6.8,3.8Hz,1H,3−CH2),
1.47(qqt,J=6.4,6.4,3.8Hz,1H,4−H),
0.86(d,J=6.4Hz,6H,5−CH3);
13C NMR(CDCl3):δ170.0(1),134.2,134.1,133.81,133.76,131.0,130.9,129.2,129.0,128.9,128.8,126.7,126.6,126.1,125.9,125.8,125.6,125.3,123.1,120.1(pyrrole),108.7(pyrrole),71.9(1’),60.3(2),40.9(3),24.6(4),22.6(5),21.8(5);
HR MS:calcd for C31H30NO2(M+H+) 448.2271,found 448.2270;
IR(KBr):3057,2957,2931,1749,1597,1509,1173,961,774,723cm−1;
Mp:133−135℃(CH2Cl2/hexane)
なお、化合物2ccの鏡像体過剰率は、LiAlH4を用いて化合物2ccを還元し、p−ニトロ安息香酸クロライドを用いてアシル化して、対応するp−ニトロ安息香酸エステル2cc’に変換した後に求めた。
HPLC(CHIRALPAK OD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):tR=16.5min(13.2%),tR=18.2min(86.8%);
1H NMR(CDCl3):δ
8.26(d,J=8.8Hz,2H,Ar),
8.08(d,J=8.8Hz,2H,Ar),
8.01−7.20(m,7H,Ar),
6.73(t,J=2.2Hz,2H,pyrrole),
6.17(t,J=2.2Hz,2H,pyrrole),
4.55(dd,J=11.2,4.4Hz,1H,1−CH2),
4.45(dd,J=11.2,8.4Hz,1H,1−CH2),
4.41−4.34(m,1H,2−H),
1.91(dd,J=10.2,4.8Hz,1H,3−CH2),
1.88(dd,J=10.2,4.8Hz,1H,3−CH2),
1.64−1.46(m,2H,3−CH2,4−H),
0.95(d,J=6.4Hz,3H,5−CH3),
0.92(d,J=6.4Hz,3H,5−CH3);
13C NMR(CDCl3):δ164.3(1’),150.7,135.2,130.7,123.6,119.1(pyrrole),108.4(pyrrole),68.6(1),56.6(2),40.7(3),24.5(4),23.0(5),21.8(5);
HR MS:calcd for C17H21N2O4(M+H+) 317.1496,found 317.1502;
IR(KBr):3108,3074,2955,2933,2869,1729,1520,1270,1119,719cm−1.
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.7mL/min):tR=7.8min(10.5%),tR=8.2min(89.5%);
1H NMR(CDCl3):δ
8.38(s,1H,1’−H),
7.97−7.80(m,6H,Ar),
7.52−7.04(m,8H,Ar),
6.71(t,J=2.0Hz,2H,pyrrole),
6.19(t,J=2.0Hz,2H,pyrrole),
4.64(dd,J=8.8,6.8Hz,1H,2−H),
2.13(ddt,J=14.0,8.8,5.2Hz,1H,3−CH2),
2.00(ddt,J=14.0,6.8,5.2Hz,1H,3−CH2),
1.23−1.15(m,8H,4−CH2,5−CH2,6−CH2,7−CH2),
0.83(t,J=7.0Hz,3H,8−CH3);
13C NMR(CDCl3):δ169.9(1),134.3,134.1,133.81,133.76,131.0,130.9,129.2,129.1,128.9,128.8,126.7,126.6,126.1,125.9,125.8,125.6,125.3,123.2,120.0(pyrrole),108.7(pyrrole),71.9(1’),62.1(2),32.1(3),31.5(4),28.7(5),25.7(6),22.4(7),13.98(8);
HR MS:calcd for C33H33NO2Na(M+Na+) 498.2404,found 498.2421;
IR(KBr):3052,2954,2926,2856,1737,1598,1509,1159,1092,796,719cm−1;
Mp:96−97℃(CH2Cl2/hexane)
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=2/98,flow rate=0.5mL/min):tR=31.5min(2.9%),tR=43.3min(97.1%);
1H NMR(CDCl3):δ
8.40(s,1H,1’−H),
8.03−7.73(m,6H,Ar),
7.52−7.01(m,8H,Ar),
6.72(t,J=2.1Hz,2H,pyrrole),
6.20(t,J=2.1Hz,2H,pyrrole),
4.87(t,J=7.6Hz,1H,2−H),
3.04(ddd,J=16.8,7.6,2.6Hz,1H,3−CH2),
2.90(ddd,J=16.8,7.6,2.6Hz,1H,3−CH2),
1.96((t,J=2.6Hz,1H,5−H);
13C NMR(CDCl3):δ168.1(1),133.91,133.86,133.7,131.8,131.4,130.9,130.8,129.1,129.0,128.9,128.8,127.9,127.5,126.74,126.69,126.4,125.99,125.9,125.8,125.64,125.56,125.4,125.3,125.2,123.2,123.1,122.8,120.1(pyrrole),109.0(pyrrole),72.3(1’),62.4(2),35.8(3);
HR MS:calcd for C30H24NO2Na(M+Na+) 430.1802,found 430.1817;
IR(KBr):3054,3010,2958,1738,1598,1510,1273,1157,944,777,731cm−1.
1H NMR(CDCl3):δ
8.40(s,1H,1’−H),
8.00−7.87(m,6H,Ar),
7.85−7.00(m,13H,Ar),
6.71(t,J=2.1Hz,2H,pyrrole),
6.22(t,J=2.1Hz,2H,pyrrole),
4.61(dd,J=9.2,6.0Hz,1H,2−H),
2.60−2.29(m,4H,3−CH2,4−CH2);
13C NMR(CDCl3):δ169.6(1),140.0,134.2,134.0,133.84,133.76,131.0,130.8,129.3,129.04,128.96,128.8,128.5,126.8,126.7,126.3,126.2,125.9,125.8,125.5,125.3,123.18,123.16,120.1(pyrrole),108.9(pyrrole),71.98(1’),60.98(2),33.4(3),31.6(4);
HR MS:calcd for C35H29NO2Na(M+Na+) 518.2091,found 518.2077;
IR(KBr):3052,3025,2956,2925,2858,1737,1626,1490,1285,1174,794,728cm−1;
Mp:114−115℃(CH2Cl2/hexane)
なお、化合物2ffの鏡像体過剰率は、LiAlH4を用いて化合物2ffを還元し、p−ニトロ安息香酸クロライドを用いてアシル化して、対応するp−ニトロ安息香酸エステル2ff’に変換した後に求めた。
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):tR=21.9min(82.5%),tR=27.9min(17.5%);
1H NMR(CDCl3):δ
8.26(d,J=8.8Hz,2H,Ar),
8.07(d,J=8.8Hz,2H,Ar),
7.32−7.13(m,5H,Ar),
6.75(t,J=2.2Hz,2H,pyrrole),
6.22(t,J=2.2Hz,2H,pyrrole),
4.54(dd,J=11.6,5.2Hz,1H,1−CH2),
4.49(dd,J=11.6,7.4Hz,1H,1−CH2),
4.24(dddd,J=10.4,7.4,5.0,4.8Hz,1H,2−H),
2.68−2.48(m,2H,4−CH2)
2.28−2.16(m,2H,3−CH2);
13C NMR(CDCl3):δ164.2(1’),150.6,140.4,135.0,130.7,128.6,128.5,126.3,123.6,119.1(pyrrole),108.7(pyrrole),68.2(1),57.5(2),33.4(3),31.7(4);
IR(KBr):3109,3062,3024,2931,2862,1952,1728,1527,1273,1103,717cm−1
1H NMR(CDCl3):δ
8.34(s,1H,1’−H),
7.92−7.70(m,9H,Ar),
7.47−6.92(m,12H,Ar),
6.74(t,J=2.0Hz,2H,pyrrole),
6.19(t,J=2.0Hz,2H,pyrrole),
5.09(dd,J=7.8,6.8Hz,1H,2−H),
4.02(dd,J=14.4,7.8Hz,1H,3−CH2),
3.66(dd,J=14.4,6.8Hz,1H,3−CH2);
13C NMR(CDCl3):δ169.2(1),133.91,133.86,133.7,131.8,131.4,130.9,130.8,129.1,129.0,128.9,128.8,127.9,127.5,126.74,126.69,126.4,125.99,125.9,125.8,125.64,125.56,125.4,125.3,125.2,123.2,123.1,122.8,120.1(pyrrole),109.0(pyrrole),72.3(1’),62.4(2),35.8(3);
IR(KBr):3054,3010,2958,1738,1598,1510,1273,1157,944,777,731cm−1.
なお、化合物2ggの鏡像体過剰率は、LiAlH4を用いて化合物2ggを還元し、p−ニトロ安息香酸クロライドを用いてアシル化して、対応するp−ニトロ安息香酸エステル2gg’に変換した後に求めた。
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):tR=33.6min(92.9%),tR=36.8min(7.1%);
1H NMR(CDCl3):δ
8.24(d,J=8.8Hz,2H,Ar),
8.03(d,J=8.8Hz,2H,Ar),
8.01−7.20(m,7H,Ar),
6.77(t,J=2.0Hz,2H,pyrrole),
6.18(t,J=2.0Hz,2H,pyrrole),
4.77−4.70(m,1H,2−H),
4.64(dd,J=11.2,6.4Hz,1H,1−CH2),
4.60(dd,J=11.2,5.2Hz,1H,1−CH2),
3.70(dd,J=14.0,7.6Hz,1H,3−CH2),
3.66(dd,J=14.0,6.8Hz,1H,3−CH2);
13C NMR(CDCl3):δ164.1(1’),150.6,134.9,134.0,132.7,131.5,130.7,129.2,127.99,127.5,126.5,125.8,125.5,123.6,122.9,119.2(pyrrole),108.7(pyrrole),67.4(1),58.8(2),36.6(3);
IR(KBr):3109,3055,3008,2954,1952,1728,1527,1273,1095,725cm−1
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/9,flow rate=0.5mL/min):tR=15.1min(2.2%),tR=22.3min(97.8%);
1H NMR(CDCl3):δ
8.36(s,1H,1’−H),
7.94−7.27(m,12H,Ar),
7.12(dd,J=5.4,1.2Hz,1H,thiophen),
7.03(d,J=7.2Hz,1H,Ar),
6.93(d,J=7.2Hz,1H,Ar),
6.84(dd,J=5.4,3.2Hz,1H,thiophen),
6.72(t,J=2.0Hz,2H,pyrrole),
6.64(d,J=3.2Hz,1H,thiophen),
6.21(t,J=2.0Hz,2H,pyrrole),
4.89(t,J=7.6Hz,1H,2−H),
3.74(dd,J=14.8,7.6Hz,1H,3−CH2),
3.46(dd,J=14.8,7.6Hz,1H,3−CH2);
13C NMR(CDCl3):δ168.8(1),137.7,133.9,133.80,133.79,133.72,131.0,130.8,129.3,129.0,128.9,128.8,126.92,126.86,126.6,126.5,126.3,125.9,125.8,125.3,124.6,123.2,123.1,120.1(pyrrole),109.2(pyrrole),72.4(1’),63.3(2),32.7(3);
HR MS:calcd for C32H25NO2SNa(M+Na+) 510.1498,found 510.1505;
IR(KBr):3056.1741,1598,1509,1263,1167,955,778,727cm−1;
Mp:120−121℃(CH2Cl2/hexane).
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=3/7,flow rate=0.75mL/min):tR=22.6min(17.3%),tR=23.7min(82.7%);
1H NMR(CDCl3):δ
8.41(s,1H,1’−H),
7.99(d,J=8.4Hz,1H,Ar),
7.88−7.74(m,5H,Ar),
7.49−7.17(m,17H,Ar),
7.05(d,J=7.2Hz,1H,Ar),
7.00−6.92(m,6H,Ar),
6.63(t,J=2.0Hz,2H,pyrrole),
6.22(s,1H,imidazole),
6.11(t,J=2.0Hz,2H,pyrrole),
5.13(dd,J=10.0,5.6Hz,1H,2−H),
3.41(dd,J=14.8,5.6Hz,1H,3−CH2),
3.19(d,J=14.8,10.0Hz,1H,3−CH2);
13C NMR(CDCl3):δ169.3(1),149.4,142.2,138.1,135.5,134.1,134.0,133.7,133.6,130.9,130.8,129.6,129.1,128.9,128.7,127.8,126.7,126.5,126.1,125.8,125.6,125.5,125.2,125.1,123.1,123.0,120.0(pyrrole),119.9,108.4(pyrrole),106.4,75.0(Tr),71.8(1’),61.7(2),31.8(3);
HR MS:calcd for C50H39N3O2(M+H+) 714.3115,found 714.3104;
IR(KBr):3053,2923,1741,1598,1510,1486,1158,797,782,773,750,718cm−1;
Mp:191−194℃(AcOEt/hexane)
カルボン酸ジ(1−ナフチル)メチルエステル2sは難溶性であるため、まずエステル交換反応を行い、可溶性のカルボン酸メチルエステル3sを収率89%で得た。ジ(1−ナフチル)メチルエステル残基は、ジ(1−ナフチル)メチルメチルエーテルとして収率91%で単離された(式1)。次いで、カルボン酸メチルエステル3sをオゾン分解してからBoc保護し、高い鏡像体過剰率を維持したままでN−Boc−フェニルアラニンメチルエステル4sを収率70%で得た(式2、87%ee)。さらに、ジ(1−ナフチル)メチルメチルエーテルを加水分解して、ジ(1−ナフチル)メタノールを収率92%で回収した(式3)。
なお、ジ(1−ナフチル)メタノールの回収に関して、Birmanの報告ではカルボン酸ジ(1−ナフチル)メチルエステルをLiAlH4で還元して対応するアルコールを得ているが(X.Yang, V.B.Birman, Angew. Chem. Int. Ed., 2011,50, 5553−5555)、上記の方法では基質のカルボニル基が保持されるという利点がある。
各反応の詳細は以下のとおりである。
カルボン酸ジ(1−ナフチル)メチルエステル2s(211mg,0.439mmol)をメタノール(13.2mL)及びジクロロメタン(13.2mL)に溶解した溶液中に、1,4−ジオキサン(4.0M,4.39mL,17.6mmol)を0℃で加えた。反応液を室温で24時間撹拌した後、クロロホルムで抽出し、有機層を分取した。有機層を硫酸ナトリウムで乾燥した後、濾過、減圧濃縮して粗生成物を得た。粗生成物をシリカゲル薄層クロマトグラフィ(展開溶媒:トルエン)により分離し、淡黄色油状のカルボン酸メチルエステル3s(89.6mg,収率89%,87%ee)と、無色固体状のジ(1−ナフチル)メチルメチルエーテル(120mg,収率91%)を得た。
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/49,flow rate=0.75mL/min):tR=25.4min(93.6%),tR=37.6min(6.4%);
[α]D 26 −50.6(c 1.09,CHCl3);
IR(neat):3030,2952,2852,1745,1488,1169,726cm−1;
1H NMR(CDCl3):δ
7.29−7.19(m,3H,Ar),
7.07−6.98(m,2H,Ar),
6.71(t,2H,J=2.8Hz,pyrrole),
6.14(t,2H,J=2.8Hz,pyrrole),
4.75(dd,J=11.6,8.8Hz,1H,2−H),
3.70(s,3H,OCH3),
3.42(dd,J=18.4,8.8Hz,1H,3−CH2),
3.25(dd,J=18.4,11.6Hz,1H,3−CH2);
13C NMR(CDCl3):δ170.6(1),136.3,128.8,128.5,127.0,120.1(pyrrole),108.7(pyrrole),63.5(2),52.5(OCH3),39.5(3);
HR MS:calcd for C14H15NO2Na(M+Na+) 252.0995,found 252.1000.
Mp:139−141℃(AcOEt/hexane);
IR(KBr):2981,2880,1595,1508,1155,1092,815,790,777cm−1;
1H NMR(CDCl3):δ
8.10−7.98(m,2H,Ar),
7.93−7.87(m,2H,Ar),
7.85−7.78(m,2H,Ar),
7.53−7.35(m,8H,Ar),
6.72(s,1H,1−H),
3.62(s,3H,OCH3);
13C NMR(CDCl3):δ136.0,134.0,131.8,128.8,128.6,126.3,125.8,125.6,125.4,123.7,79.4(1),57.9(OCH3);
HR MS:calcd for C22H18ONa(M+Na+) 321.1250,found 321.1249.
カルボン酸メチルエステル3s(85.6mg,0.373mmol)をメタノール(15mL)に溶解した溶液を−78℃で2時間、オゾン処理した。反応液中にアルゴンガスを1分間バブリングした後、チオ尿素(34.1mg,0.448mmol)をメタノール(4mL)中に溶解した溶液を−78℃で添加した。次いで、反応液を−78℃で30分間、0℃で1時間撹拌し、セライト濾過した。濾液を減圧乾燥し、残渣をメタノール(7.46mL)に溶解した。
次いで、その混合液中に、塩酸を含有する1,4−ジオキサン(4.0M,7.46mL,29.8mmol)を0℃で加え、室温で6時間撹拌した。その液を減圧乾燥し、残渣をTHF(5mL)に懸濁させた。
次いで、その混合液中に飽和炭酸水素ナトリウム水溶液(5mL)及びジ(tert−ブチル)ジカーボネート(325mg,1.49mmol)を0℃で添加した。反応液を室温で60時間撹拌した後、水で希釈した。次いで、混合液を酢酸エチルで抽出し、有機層を分取した。有機層を硫酸ナトリウムで乾燥した後、濾過、減圧濃縮して粗生成物を得た。粗生成物をシリカゲル薄層クロマトグラフィ(展開溶媒:酢酸エチル/ヘキサン=6/14)により分離し、無色油状のN−Boc−フェニルアラニンメチルエステル4s(72.9mg,収率70%,87%ee)を得た。
HPLC(CHIRALPAK IB−3,i−PrOH/hexane=1/49,flow rate=0.75mL/min):tR=12.3min(6.6%),tR=14.4min(93.4%);
[α]D 25 +39.5(c 1.13,CHCl3).
なお、特定旋光度を含め、分光分析データは文献値と一致していた。
ジ(1−ナフチル)メチルメチルエーテル(119mg,0.399mmol)を1,4−ジオキサン(6.4mL)に溶解した溶液中に、スルホン酸水溶液(2M,3.2mL,6.4mmol)を室温で加えた。反応液を80℃で4時間加熱した後、室温で水を添加した。次いで、混合液を酢酸エチルで抽出し、有機層を分取した。有機層を硫酸ナトリウムで乾燥した後、濾過、減圧濃縮して粗生成物を得た。粗生成物をシリカゲル薄層クロマトグラフィ(展開溶媒:酢酸エチル/ヘキサン=1/3)により分離し、無色固体状のジ(1−ナフチル)メタノール(105mg,収率92%)を得た。なお、ジ(1−ナフチル)メタノールの分光分析データは文献値と一致していた。
カルボン酸ジ(1−ナフチル)メチルエステル2sを還元することにより、光学活性アルコール5sが収率89%で得られ、同時にジ(1−ナフチル)メタノールが収率96%で回収された(式4)。次いで、ジ(tert−ブチル)マロネートのカリウム塩を用いて対応するトリフルオロメタンスルホナート6sをアルキル化して、光学活性アルコール5sの2炭素伸長変換を行い、ジカルボン酸tert−ブチルジエステル7sを光学活性アルコール5sから収率91%で得た(式5)。次いで、ジカルボン酸tert−ブチルジエステル7sを脱炭酸及び分子内フリーデル−クラフツアシル化して6,7−ジヒドロインドリジン−8(5H)−オン誘導体8sを得、これをパラジウム炭素を用いて水素化し、単一のジアステレオマーとしてインドリジジン誘導体9sを得た。なお、中間体及び生成物9sの鏡像体過剰率は一連の変換中も維持された。
各反応の詳細は以下のとおりである。
カルボン酸ジ(1−ナフチル)メチルエステル2s(87%ee,196mg,0.407mmol)をテトラヒドロフラン(THF)(8.1mL)に溶解した溶液中に、LiAlO4(46.3mg,1.22mmol)を0℃で加えた。反応液を室温で3時間撹拌した後、水(60μL)及び水酸化ナトリウム水溶液(4.2M,60μL)を0℃で加えた。混合液を酢酸エチルとともに短セライトパッドで濾過し、濾液を減圧濃縮して粗生成物を得た。粗生成物をシリカゲル薄層クロマトグラフィ(展開溶媒:酢酸エチル/ヘキサン=9/11)により分離し、無色油状の光学活性アルコール5s(73.0mg,収率89%,88%ee)を得るとともに、ジ(1−ナフチル)メタノール(111mg,収率96%)を回収した。
HPLC(CHIRALPAK AD−H,i−PrOH/hexane=1/49,flow rate=0.75mL/min):tR=25.4min(93.9%),tR=37.4min(6.1%);
[α]D 27 −85.3(c 1.05,CHCl3);
IR(neat):3467,3028,2943,2877,1604,1493,725,702,636cm−1;
1H NMR(CDCl3):δ
7.34−7.13(m,3H,Ar),
7.08−6.94(m,2H,Ar),
6.70(t,J=2.0Hz,2H,pyrrole),
6.17(t,J=2.0Hz,2H,pyrrole),
4.20(tt,J=7.6,6.0Hz,1H,2−H),
3.83(dd,J=6.4,6.0Hz,2H,1−CH2),
3.06(d,J=7.6Hz,2H,3−CH2),
1.47(t,J=6.4Hz,1H,OH);
13C NMR(CDCl3):δ137.5,128.8,128.5,126.6,119.2(pyrrole),108.4(pyrrole),65.3,63.5,38.5(3);
HR MS:calcd for C13H15NONa(M+Na+) 224.1046,found 224.1044.
ジ(tert−ブチル)マロネート(2.76mL,12.4mL)をテトラヒドロフラン(THF)(22.4mL)に溶解した溶液中に、水素化カリウム(499mg,12.4mL)をTHF(6.2mL)に懸濁した液を0℃で滴下した。反応液を室温で18時間撹拌した後、ヘキサン(40mL)を加えた。その後、沈殿を濾別し、乾燥することにより、目的の化合物を無色固体として得た(2.57g,収率82%)。この化合物は、精製することなく以降の実験に使用した。
Mp:139−141℃(THF/hexane);
1H NMR(DMSO−d6):δ
1.41(s,1H,2−H),
1.27(s,18H,t−Bu).
光学活性アルコール5s(70.8mg,0.352mmol)及び2,6−ルチジン(81.1μL,0.704mmol)をジクロロメタン(4mL)に溶解した溶液中に、トリフルオロメタンスルホン酸無水物(70.9μL,0.422mmol)をジクロロメタン(4mL)に溶解した液を−30℃でゆっくりと加えた。反応液を−30℃で25分間撹拌した後、0.5Mの塩酸(6mL)を加えた。混合液をクロロホルムで抽出し、有機層を分取した。有機層を硫酸ナトリウムで乾燥した後、濾過、減圧濃縮して、トリフルオロメタンスルホナート6sの粗生成物を得た。この粗生成物は、精製することなく以降の実験に使用した。
HPLC(CHIRALPAK IA−3,i−PrOH/hexane=1/200,flow rate=0.75mL/min):tR=9.5min(93.6%),tR=11.9min(6.4%);
[α]D 27 −23.5(c 1.05,CHCl3);
IR(neat):2978,2935,1728,1489,1142,849,725cm−1;
1H NMR(C6D6):δ
7.06−6.94(m,3H,Ar),
6.79−6.74(m,2H,Ar),
6.48(t,J=2.0Hz,2H,pyrrole),
6.23(t,J=2.0Hz,2H,pyrrole),
4.16(dddd,J=11.6,8.6,6.0,4.0Hz,1H,2’−H),
3.07(dd,J=10.8,4.0Hz,1H,2−H),
2.74(dd,J=14.0,8.6Hz,1H,3’−CH2),
2.66(dd,J=14.0,6.0Hz,1H,3’−CH2),
2.50(ddd,J=14.4,10.8,4.0Hz,1H,1’−CH2),
2.32(ddd,J=14.4,11.6,4.0Hz,1H,1’−CH2),
1.29(s,9H,t−Bu),
1.28(s,9H,t−Bu);
13C NMR(C6D6):δ168.6(CO2t−Bu),168.5(CO2t−Bu),138.4,129.1,128.5,126.6,119.0(pyrrole),108.8(pyrrole),81.1(t−Bu),81.0(t−Bu),60.0(2’),50.8(2),43.6(3’),35.4(1’),27.8(t−Bu),27.7(t−Bu);
HR MS:calcd for C24H33NO4Na(M+Na+) 422.2302,found 422.2303.
ジカルボン酸tert−ブチルジエステル7s(121mg,0.303mmol)を1,4−ジオキサン(1.82mL)に溶解した溶液中に、12Mの塩酸(1.21mL)を加えた。反応液を0℃で3時間、室温で65時間撹拌した後、水を加えた。混合液を酢酸エチルで抽出し、有機層を分取した。有機層を硫酸ナトリウムで乾燥した後、濾過、減圧濃縮して粗生成物を得た。粗生成物をシリカゲル薄層クロマトグラフィ(展開溶媒:酢酸エチル/ヘキサン=1/1)により分離し、淡黄色油状の6,7−ジヒドロインドリジン−8(5H)−オン誘導体8s(58.8mg,収率86%,87%ee)を得た。
HPLC(CHIRALPAK IB−3,i−PrOH/hexane=1/9,flow rate=0.75mL/min):tR=24.5min(6.4%),tR=27.2min(93.6%);
[α]D 27 −86.2(c 1.02,CHCl3);
IR(neat):3024,2947,1658,1527,1496,748,702cm−1;
1H NMR(C6D6):δ
7.37−7.22(m,3H,Ar),
7.15−7.07(m,2H,Ar),
7.05(dd,J=4.0,2.0Hz,1H,pyrrole),
6.63(dd,J=2.4,2.0Hz,1H,pyrrole),
6.19(dd,J=4.0,2.4Hz,1H,pyrrole),
4.50−4.33(dddd,J=10.4,9.6,7.6,7.2Hz,1H,5−H),
3.22(dd,J=13.6,7.2Hz,1H,CH2Ph),
3.00(dd,J=13.6,7.6Hz,1H,CH2Ph),
2.73(ddd,J=18.0,11.2,5.2Hz,1H,7−CH2),
2.52(ddd,J=18.0,5.2,4.8Hz,1H,7−CH2),
2.32(dddd,J=11.2,10.8,9.6,4.8Hz,1H,6−CH2),
2.13(dddd,J=10.8,10.4,5.2,5.2Hz,1H,6−CH2);
13C NMR(C6D6):δ186.8,136.9,130.0,129.1,128.8,127.1,125.4,114.5,110.1,56.1(5),41.2(7),32.8(CH2Ph),27.4(6);
HR MS:calcd for C15H15NONa(M+Na+) 248.1078,found 248.1086.
6,7−ジヒドロインドリジン−8(5H)−オン誘導体8s(59.6mg,0.246mmol)及び硫酸(10μL)をメタノール(5.3mL)に溶解した溶液中に、パラジウム炭素(10%担持,50質量%,450mg,0.211mmol)を加えた。3atmの水素雰囲気下、混合液を室温で4日間撹拌した後、アルゴン置換した。混合液を短セライトパッドで濾過し、濾液を減圧濃縮した。残渣を1Mの塩酸(3mL)で希釈し、酢酸エチルで洗浄した。水酸化ナトリウム水溶液(4.2M,2mL)を用いて水層を塩基化した後、クロロホルムで抽出し、有機層を分取した。有機層を硫酸ナトリウムで乾燥した後、濾過、減圧濃縮して粗生成物を得た。粗生成物をシリカゲル薄層クロマトグラフィ(展開溶媒:28%アンモニア水/メタノール/クロロホルム=2/3/95)により分離し、無色油状のインドリジジン誘導体9s(31.1mg,収率53%,88%ee)を得た。
HPLC(CHIRALCEL OJ−H ×2,diethylamine/i−PrOH/hexane=0.2/1/100,flow rate=0.5mL/min):tR=16.7min(93.9%),tR=27.2min(6.1%);
[α]D 24 +66.4(c 1.01,CHCl3);
IR(neat):3024,2931,2862,1604,1496,1126,748cm−1;
1H NMR(C6D6):δ
7.25−7.04(m,5H,Ar),
3.26(ddd,J=8.8,8.8,2.2Hz,1H,3−CH2),
3.07(dd,J=13.0,4.0Hz,1H,CH2Ph),
2.48(dd,J=13.0,9.6Hz,1H,CH2Ph),
2.15(dddd,J=13.2,9.6,4.0,2.4Hz,1H,5−CH2),
1.94(ddd,J=8.8,8.8,8.8Hz,1H,3−CH2),
1.80−1.33(m,8H,1−CH2,2−CH2,6−CH2,8−CH2,8a−H),
1.27−0.96(m,3H,6−CH2,7−CH2);
13C NMR(C6D6):δ140.2,129.9,128.4,126.1,65.2,65.0,52.0,42.1,31.4,31.3,31.2,25.0,21.0;
HR MS:calcd for C15H22N(M+H+) 216.1747,found 216.1744.
Claims (10)
- 動的速度論的光学分割による光学活性カルボン酸エステルの製造方法であって、
下記式(a):
で表されるラセミのカルボン酸と、下記式(b):
で表されるアルコール又は下記式(c):
で表されるフェノール誘導体とを、酸無水物及び不斉触媒の存在下、双極子モーメント3.5以上の極性溶媒中で反応させ、前記ラセミのカルボン酸のうち一方のエナンチオマーを選択的にエステル化するとともに、他方のエナンチオマーをラセミ化する工程を含む、光学活性カルボン酸エステルの製造方法。 - 前記式(a)中のRa1が1H−ピロール−1−イル基である、請求項1又は2に記載の光学活性カルボン酸エステルの製造方法。
- 双極子モーメント3.5以上の極性溶媒が、ジメチルアセトアミド、ジメチルホルムアミド、1,3−ジメチル−2−イミダゾリジノン、N−メチルピロリドン又はジメチルスルホキシドである、請求項1〜3のいずれか1項に記載の光学活性カルボン酸エステルの製造方法。
- 前記工程を塩基の存在下に行う、請求項1〜4のいずれか1項に記載の光学活性カルボン酸エステルの製造方法。
- 前記R1、R2及びR3の少なくとも1つがメチル基である、請求項6に記載の光学活性カルボン酸エステルの製造方法。
- 前記塩基が、ジイソプロピルエチルアミン、トリエチルアミン、ジメチルエチルアミン、ジメチルイソプロピルアミン、ジエチルメチルアミン又はジイソプロピルメチルアミンである、請求項6に記載の光学活性カルボン酸エステルの製造方法。
- 動的速度論的光学分割により得られた光学活性カルボン酸エステルの1H−ピロール−1−イル基をアミノ基に変換する工程をさらに含む、請求項3又は9に記載の光学活性カルボン酸エステルの製造方法。
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