WO2017010558A1 - Method for producing compound - Google Patents
Method for producing compound Download PDFInfo
- Publication number
- WO2017010558A1 WO2017010558A1 PCT/JP2016/070920 JP2016070920W WO2017010558A1 WO 2017010558 A1 WO2017010558 A1 WO 2017010558A1 JP 2016070920 W JP2016070920 W JP 2016070920W WO 2017010558 A1 WO2017010558 A1 WO 2017010558A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- general formula
- group
- copper
- compound
- compound represented
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 91
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 125000003118 aryl group Chemical group 0.000 claims abstract description 34
- 239000003446 ligand Substances 0.000 claims abstract description 26
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 13
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 10
- 125000001424 substituent group Chemical group 0.000 claims description 41
- 239000005749 Copper compound Substances 0.000 claims description 21
- 150000001880 copper compounds Chemical class 0.000 claims description 21
- 150000004699 copper complex 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 10
- 238000002156 mixing Methods 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 abstract description 4
- 125000003277 amino group Chemical group 0.000 abstract 3
- -1 halide ion Chemical class 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- 239000010949 copper Substances 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 29
- 238000003786 synthesis reaction Methods 0.000 description 29
- 229910052802 copper Inorganic materials 0.000 description 28
- 239000012044 organic layer Substances 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 239000000460 chlorine Substances 0.000 description 17
- CKLPLPZSUQEDRT-WPCRTTGESA-N nitd609 Chemical compound O=C1NC2=CC=C(Cl)C=C2[C@@]11C(NC=2C3=CC(F)=C(Cl)C=2)=C3C[C@H](C)N1 CKLPLPZSUQEDRT-WPCRTTGESA-N 0.000 description 16
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- 125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- 239000012043 crude product Substances 0.000 description 13
- 239000011734 sodium Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 150000002430 hydrocarbons Chemical group 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 150000001879 copper Chemical class 0.000 description 7
- 229910052698 phosphorus Inorganic materials 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 238000005905 alkynylation reaction Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 3
- 239000005751 Copper oxide Substances 0.000 description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229910000431 copper oxide Inorganic materials 0.000 description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 3
- OMZSGWSJDCOLKM-UHFFFAOYSA-N copper(II) sulfide Chemical compound [S-2].[Cu+2] OMZSGWSJDCOLKM-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- QSKGNZIBBYDNNK-XMMPIXPASA-N COC1=CC=C(C=C1)C(=O)N2C3=C(C=C(C=C3)Cl)[C@](C2=O)(C4=CC5=CC(=C(C=C5N4)Cl)F)N Chemical compound COC1=CC=C(C=C1)C(=O)N2C3=C(C=C(C=C3)Cl)[C@](C2=O)(C4=CC5=CC(=C(C=C5N4)Cl)F)N QSKGNZIBBYDNNK-XMMPIXPASA-N 0.000 description 2
- JJLJMEJHUUYSSY-UHFFFAOYSA-L Copper hydroxide Chemical compound [OH-].[OH-].[Cu+2] JJLJMEJHUUYSSY-UHFFFAOYSA-L 0.000 description 2
- 239000005750 Copper hydroxide Substances 0.000 description 2
- 229910021594 Copper(II) fluoride Inorganic materials 0.000 description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000224016 Plasmodium Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 150000004696 coordination complex Chemical class 0.000 description 2
- YEOCHZFPBYUXMC-UHFFFAOYSA-L copper benzoate Chemical compound [Cu+2].[O-]C(=O)C1=CC=CC=C1.[O-]C(=O)C1=CC=CC=C1 YEOCHZFPBYUXMC-UHFFFAOYSA-L 0.000 description 2
- LTYZGLKKXZXSEC-UHFFFAOYSA-N copper dihydride Chemical compound [CuH2] LTYZGLKKXZXSEC-UHFFFAOYSA-N 0.000 description 2
- 229910000050 copper hydride Inorganic materials 0.000 description 2
- 229910001956 copper hydroxide Inorganic materials 0.000 description 2
- TYIFJJCPKPPNPM-UHFFFAOYSA-N copper(1+);1,3,5-trimethylbenzene-6-ide Chemical compound [Cu+].CC1=CC(C)=[C-]C(C)=C1 TYIFJJCPKPPNPM-UHFFFAOYSA-N 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- GWFAVIIMQDUCRA-UHFFFAOYSA-L copper(ii) fluoride Chemical compound [F-].[F-].[Cu+2] GWFAVIIMQDUCRA-UHFFFAOYSA-L 0.000 description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 2
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- XNEQAVYOCNWYNZ-UHFFFAOYSA-L copper;dinitrite Chemical compound [Cu+2].[O-]N=O.[O-]N=O XNEQAVYOCNWYNZ-UHFFFAOYSA-L 0.000 description 2
- KZITYRHGEGKWLV-UHFFFAOYSA-L copper;diphenoxide Chemical compound [Cu+2].[O-]C1=CC=CC=C1.[O-]C1=CC=CC=C1 KZITYRHGEGKWLV-UHFFFAOYSA-L 0.000 description 2
- 239000011982 enantioselective catalyst Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- CVBUKMMMRLOKQR-UHFFFAOYSA-N 1-phenylbutane-1,3-dione Chemical compound CC(=O)CC(=O)C1=CC=CC=C1 CVBUKMMMRLOKQR-UHFFFAOYSA-N 0.000 description 1
- XFEKIQFBJSDMQB-UHFFFAOYSA-N 2,2,2-trichloroethylbenzene Chemical compound ClC(Cl)(Cl)CC1=CC=CC=C1 XFEKIQFBJSDMQB-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- HNNQYHFROJDYHQ-UHFFFAOYSA-N 3-(4-ethylcyclohexyl)propanoic acid 3-(3-ethylcyclopentyl)propanoic acid Chemical compound CCC1CCC(CCC(O)=O)C1.CCC1CCC(CCC(O)=O)CC1 HNNQYHFROJDYHQ-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- KEHNRUNQZGRQHU-UHFFFAOYSA-N 4-oxopentanal Chemical compound CC(=O)CCC=O KEHNRUNQZGRQHU-UHFFFAOYSA-N 0.000 description 1
- AGJFGOXERJLOIX-UHFFFAOYSA-N 5,5,5-trifluoro-4-oxopentanal Chemical compound FC(F)(F)C(=O)CCC=O AGJFGOXERJLOIX-UHFFFAOYSA-N 0.000 description 1
- XHDJYQWGFIBCEP-UHFFFAOYSA-N 5-Chloro-1H-indole-2,3-dione Chemical compound ClC1=CC=C2NC(=O)C(=O)C2=C1 XHDJYQWGFIBCEP-UHFFFAOYSA-N 0.000 description 1
- WQBUKFBIUICFGZ-UHFFFAOYSA-N 5-chloro-1-[(4-methoxyphenyl)methyl]indole-2,3-dione Chemical compound C1=CC(OC)=CC=C1CN1C2=CC=C(Cl)C=C2C(=O)C1=O WQBUKFBIUICFGZ-UHFFFAOYSA-N 0.000 description 1
- FLAUECBHLKJEAX-UHFFFAOYSA-N 5-chloro-2-ethyl-4-fluoroaniline Chemical compound CCc1cc(F)c(Cl)cc1N FLAUECBHLKJEAX-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FSHDEWGNPHTSTJ-UHFFFAOYSA-N CCC1=C(C(=C(C=C1OC(=O)N)Cl)F)C(C)(C)C Chemical compound CCC1=C(C(=C(C=C1OC(=O)N)Cl)F)C(C)(C)C FSHDEWGNPHTSTJ-UHFFFAOYSA-N 0.000 description 1
- RHUXDIRGUNCNMF-UHFFFAOYSA-N COC1=CC=C(C=C1)C(=O)N2C3=C(C=C(C=C3)Cl)C(=O)C2=O Chemical compound COC1=CC=C(C=C1)C(=O)N2C3=C(C=C(C=C3)Cl)C(=O)C2=O RHUXDIRGUNCNMF-UHFFFAOYSA-N 0.000 description 1
- DNXSGHQBAIKZLI-UHFFFAOYSA-N C[Si](C)(C)C#C[Cu] Chemical compound C[Si](C)(C)C#C[Cu] DNXSGHQBAIKZLI-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical compound [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- OCUCCJIRFHNWBP-IYEMJOQQSA-L Copper gluconate Chemical compound [Cu+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O OCUCCJIRFHNWBP-IYEMJOQQSA-L 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L Oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- DOVLHZIEMGDZIW-UHFFFAOYSA-N [Cu+3].[O-]B([O-])[O-] Chemical compound [Cu+3].[O-]B([O-])[O-] DOVLHZIEMGDZIW-UHFFFAOYSA-N 0.000 description 1
- DUAHLEGVGGUOBC-UHFFFAOYSA-N [amino(phenyl)phosphinothioyl]benzene Chemical compound C=1C=CC=CC=1P(=S)(N)C1=CC=CC=C1 DUAHLEGVGGUOBC-UHFFFAOYSA-N 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 229940063013 borate ion Drugs 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 229940005989 chlorate ion Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940116318 copper carbonate Drugs 0.000 description 1
- LQKXNGIPVZDTEX-UHFFFAOYSA-N copper monohydride triphenylphosphane Chemical compound [CuH].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 LQKXNGIPVZDTEX-UHFFFAOYSA-N 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- LLTVNDUCLWASHR-UHFFFAOYSA-M copper(1+);4-methylbenzenesulfonate Chemical compound [Cu+].CC1=CC=C(S([O-])(=O)=O)C=C1 LLTVNDUCLWASHR-UHFFFAOYSA-M 0.000 description 1
- RFKZUAOAYVHBOY-UHFFFAOYSA-M copper(1+);acetate Chemical compound [Cu+].CC([O-])=O RFKZUAOAYVHBOY-UHFFFAOYSA-M 0.000 description 1
- JZIFHBROONLVNA-UHFFFAOYSA-M copper(1+);chlorate Chemical compound [Cu+].[O-]Cl(=O)=O JZIFHBROONLVNA-UHFFFAOYSA-M 0.000 description 1
- VUDZLFZYTMZBPP-UHFFFAOYSA-N copper(1+);ethyne Chemical compound [Cu+].[C-]#C VUDZLFZYTMZBPP-UHFFFAOYSA-N 0.000 description 1
- SDJPQMNENZXXKT-UHFFFAOYSA-M copper(1+);methanesulfonate Chemical compound [Cu+].CS([O-])(=O)=O SDJPQMNENZXXKT-UHFFFAOYSA-M 0.000 description 1
- MLZZMQAJXLZTDM-UHFFFAOYSA-M copper(1+);nitrite Chemical compound [Cu+].[O-]N=O MLZZMQAJXLZTDM-UHFFFAOYSA-M 0.000 description 1
- PDZKZMQQDCHTNF-UHFFFAOYSA-M copper(1+);thiocyanate Chemical compound [Cu+].[S-]C#N PDZKZMQQDCHTNF-UHFFFAOYSA-M 0.000 description 1
- 229910000009 copper(II) carbonate Inorganic materials 0.000 description 1
- 229910000153 copper(II) phosphate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- YRNNKGFMTBWUGL-UHFFFAOYSA-L copper(ii) perchlorate Chemical compound [Cu+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O YRNNKGFMTBWUGL-UHFFFAOYSA-L 0.000 description 1
- GQDHEYWVLBJKBA-UHFFFAOYSA-H copper(ii) phosphate Chemical compound [Cu+2].[Cu+2].[Cu+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GQDHEYWVLBJKBA-UHFFFAOYSA-H 0.000 description 1
- MAUZTCHAIPUZJB-OLXYHTOASA-L copper;(2r,3r)-2,3-dihydroxybutanedioate;hydrate Chemical compound O.[Cu+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O MAUZTCHAIPUZJB-OLXYHTOASA-L 0.000 description 1
- SVOAENZIOKPANY-CVBJKYQLSA-L copper;(z)-octadec-9-enoate Chemical compound [Cu+2].CCCCCCCC\C=C/CCCCCCCC([O-])=O.CCCCCCCC\C=C/CCCCCCCC([O-])=O SVOAENZIOKPANY-CVBJKYQLSA-L 0.000 description 1
- CMRVDFLZXRTMTH-UHFFFAOYSA-L copper;2-carboxyphenolate Chemical compound [Cu+2].OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O CMRVDFLZXRTMTH-UHFFFAOYSA-L 0.000 description 1
- DYROSKSLMAPFBZ-UHFFFAOYSA-L copper;2-hydroxypropanoate Chemical compound [Cu+2].CC(O)C([O-])=O.CC(O)C([O-])=O DYROSKSLMAPFBZ-UHFFFAOYSA-L 0.000 description 1
- DUNDEGLXXDOWLN-UHFFFAOYSA-N copper;2-methylpropan-2-olate Chemical compound [Cu+2].CC(C)(C)[O-].CC(C)(C)[O-] DUNDEGLXXDOWLN-UHFFFAOYSA-N 0.000 description 1
- MRYMYQPDGZIGDM-UHFFFAOYSA-L copper;4-methylbenzenesulfonate Chemical compound [Cu+2].CC1=CC=C(S([O-])(=O)=O)C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 MRYMYQPDGZIGDM-UHFFFAOYSA-L 0.000 description 1
- VUWZDHZJZQTKAY-UHFFFAOYSA-L copper;benzenethiolate Chemical compound [Cu+2].[S-]C1=CC=CC=C1.[S-]C1=CC=CC=C1 VUWZDHZJZQTKAY-UHFFFAOYSA-L 0.000 description 1
- LEKPFOXEZRZPGW-UHFFFAOYSA-N copper;dicyanide Chemical compound [Cu+2].N#[C-].N#[C-] LEKPFOXEZRZPGW-UHFFFAOYSA-N 0.000 description 1
- SGSWHTFHCGHXTF-UHFFFAOYSA-N copper;dicyclohexylazanide Chemical compound [Cu+2].C1CCCCC1[N-]C1CCCCC1.C1CCCCC1[N-]C1CCCCC1 SGSWHTFHCGHXTF-UHFFFAOYSA-N 0.000 description 1
- HFDWIMBEIXDNQS-UHFFFAOYSA-L copper;diformate Chemical compound [Cu+2].[O-]C=O.[O-]C=O HFDWIMBEIXDNQS-UHFFFAOYSA-L 0.000 description 1
- LLVVIWYEOKVOFV-UHFFFAOYSA-L copper;diiodate Chemical compound [Cu+2].[O-]I(=O)=O.[O-]I(=O)=O LLVVIWYEOKVOFV-UHFFFAOYSA-L 0.000 description 1
- ZZBBCSFCMKWYQR-UHFFFAOYSA-N copper;dioxido(oxo)silane Chemical compound [Cu+2].[O-][Si]([O-])=O ZZBBCSFCMKWYQR-UHFFFAOYSA-N 0.000 description 1
- BQVVSSAWECGTRN-UHFFFAOYSA-L copper;dithiocyanate Chemical compound [Cu+2].[S-]C#N.[S-]C#N BQVVSSAWECGTRN-UHFFFAOYSA-L 0.000 description 1
- BWLYQXJZLBBGCK-UHFFFAOYSA-N copper;dodecanoic acid Chemical compound [Cu].CCCCCCCCCCCC(O)=O BWLYQXJZLBBGCK-UHFFFAOYSA-N 0.000 description 1
- CRCKGIUJMFFISH-UHFFFAOYSA-N copper;ethanolate Chemical compound [Cu+2].CC[O-].CC[O-] CRCKGIUJMFFISH-UHFFFAOYSA-N 0.000 description 1
- WFIPUECTLSDQKU-UHFFFAOYSA-N copper;ethyl 3-oxobutanoate Chemical compound [Cu].CCOC(=O)CC(C)=O WFIPUECTLSDQKU-UHFFFAOYSA-N 0.000 description 1
- SDFNZYMSEOUVIF-UHFFFAOYSA-N copper;methanesulfonic acid Chemical compound [Cu].CS(O)(=O)=O SDFNZYMSEOUVIF-UHFFFAOYSA-N 0.000 description 1
- AYNQPTYHFBBKFC-UHFFFAOYSA-N copper;methanolate Chemical compound [Cu+2].[O-]C.[O-]C AYNQPTYHFBBKFC-UHFFFAOYSA-N 0.000 description 1
- PEVZEFCZINKUCG-UHFFFAOYSA-L copper;octadecanoate Chemical compound [Cu+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O PEVZEFCZINKUCG-UHFFFAOYSA-L 0.000 description 1
- VNZQQAVATKSIBR-UHFFFAOYSA-L copper;octanoate Chemical compound [Cu+2].CCCCCCCC([O-])=O.CCCCCCCC([O-])=O VNZQQAVATKSIBR-UHFFFAOYSA-L 0.000 description 1
- QYCVHILLJSYYBD-UHFFFAOYSA-L copper;oxalate Chemical compound [Cu+2].[O-]C(=O)C([O-])=O QYCVHILLJSYYBD-UHFFFAOYSA-L 0.000 description 1
- GSCLWPQCXDSGBU-UHFFFAOYSA-L copper;phthalate Chemical compound [Cu+2].[O-]C(=O)C1=CC=CC=C1C([O-])=O GSCLWPQCXDSGBU-UHFFFAOYSA-L 0.000 description 1
- VNGORJHUDAPOQZ-UHFFFAOYSA-N copper;propan-2-olate Chemical compound [Cu+2].CC(C)[O-].CC(C)[O-] VNGORJHUDAPOQZ-UHFFFAOYSA-N 0.000 description 1
- LZJJVTQGPPWQFS-UHFFFAOYSA-L copper;propanoate Chemical compound [Cu+2].CCC([O-])=O.CCC([O-])=O LZJJVTQGPPWQFS-UHFFFAOYSA-L 0.000 description 1
- ZHOLKSYCHRKNCU-UHFFFAOYSA-H copper;silicon(4+);hexafluoride Chemical compound [F-].[F-].[F-].[F-].[F-].[F-].[Si+4].[Cu+2] ZHOLKSYCHRKNCU-UHFFFAOYSA-H 0.000 description 1
- FMWMEQINULDRBI-UHFFFAOYSA-L copper;sulfite Chemical compound [Cu+2].[O-]S([O-])=O FMWMEQINULDRBI-UHFFFAOYSA-L 0.000 description 1
- KVBHFBAACGHMKE-UHFFFAOYSA-N copper;triphenylphosphane Chemical compound [Cu].[Cu].[Cu].[Cu].[Cu].[Cu].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 KVBHFBAACGHMKE-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000011646 cupric carbonate Substances 0.000 description 1
- 235000019854 cupric carbonate Nutrition 0.000 description 1
- 239000011642 cupric gluconate Substances 0.000 description 1
- 235000019856 cupric gluconate Nutrition 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- PEVJCYPAFCUXEZ-UHFFFAOYSA-J dicopper;phosphonato phosphate Chemical compound [Cu+2].[Cu+2].[O-]P([O-])(=O)OP([O-])([O-])=O PEVJCYPAFCUXEZ-UHFFFAOYSA-J 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 229940005633 iodate ion Drugs 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([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
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229940005654 nitrite ion Drugs 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- AHKZTVQIVOEVFO-UHFFFAOYSA-N oxide(2-) Chemical compound [O-2] AHKZTVQIVOEVFO-UHFFFAOYSA-N 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940085991 phosphate ion Drugs 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 238000000711 polarimetry Methods 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- STDMRMREKPZQFJ-UHFFFAOYSA-H tricopper;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Cu+2].[Cu+2].[Cu+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O STDMRMREKPZQFJ-UHFFFAOYSA-H 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 208000037972 tropical disease Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—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
- C07D471/12—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 three hetero rings
- C07D471/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a method for producing an optically active compound that is very useful for the synthesis of NITD609, and a method for producing NITD609.
- Non-Patent Documents 1 and 2 In 2010, Novartis Institute for Tropical Diseases reported a compound represented by the following structural formula (NITD609) having antimalarial activity (see Non-Patent Documents 1 and 2).
- This compound is a malaria parasite Plasmodium. Which has acquired resistance to other antimalarial agents. Falciparum and Plasmodium. It has been reported that it also exhibits activity against Vivax, and the clinical trial is currently proceeding to a phase II trial.
- the product is obtained as a racemate, and then the target product is obtained by optical resolution using a chiral column, leaving problems in terms of synthesis efficiency.
- the method relies on enzymatic methods.
- an object of the present invention is to provide a method for producing an optically active compound that is very useful for the synthesis of NITD609 and a method for producing NITD609.
- the method for producing a compound of the present invention is a method for producing a compound represented by the following general formula (1), A compound represented by the following general formula (2) and a compound represented by the following general formula (3) in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A) It includes a reaction step of reacting to obtain a compound represented by the general formula (1).
- R 1 represents either a hydrogen atom or an amino-protecting group.
- R 2 represents either a hydrogen atom or an amino-protecting group.
- R 11 represents an aromatic group which may have a substituent.
- R 12 represents an aromatic group which may have a substituent.
- R 13 represents either a hydrogen atom or an amino-protecting group.
- R represents any of an alkyl group having 1 to 6 carbon atoms, an aryl group, a substituted aryl group, an aralkyl group, and a ring-substituted aralkyl group.
- the manufacturing method of the compound of this invention is a manufacturing method of the compound represented by following Structural formula (1), A compound represented by the following general formula (2) and a compound represented by the following general formula (3) in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A) It includes a reaction step of reacting to obtain a compound represented by the general formula (1).
- R 1 represents either a hydrogen atom or an amino-protecting group.
- R 2 represents either a hydrogen atom or an amino-protecting group.
- R 11 represents an aromatic group which may have a substituent.
- R 12 represents an aromatic group which may have a substituent.
- R 13 represents either a hydrogen atom or an amino-protecting group.
- R represents any of an alkyl group having 1 to 6 carbon atoms, an aryl group, a substituted aryl group, an aralkyl group, and a ring-substituted aralkyl group.
- a method for producing an optically active compound that can solve the above-mentioned problems and achieve the above-mentioned object and is very useful for the synthesis of NITD 609, and a method for producing NITD 609. it can.
- the present inventors planned a synthesis strategy of NITD609 applying the catalytic asymmetric alkynylation reaction shown in the above-mentioned Scheme 1 as shown in Scheme 2 below.
- This synthetic strategy was developed by the present inventors as the title of “Asymmetric Synthesis of NITD609 Utilizing Catalytic Asymmetric Alkynylation Reaction”. (2014) and 134th Annual Meeting (2015) and their abstracts [Japan Pharmaceutical Association 133rd Annual Meeting 28S-am03 (133th Annual Meeting), Japan Pharmaceutical Association 134th Annual Meeting 28D-pm15 (134th Annual Meeting)].
- the present inventors conducted a study.
- the present inventors examined in detail the stereochemistry of the epimer obtained in the previous report by the synthesis strategy of the above Scheme 2. As a result, it was found that in the obtained product, the product that can be separated from the diastereomer is mainly composed of the enantiomer of NITD609.
- the present inventors have completed the present invention by reviewing the production method of Compound C in the synthesis strategy shown in the above-mentioned Scheme 2.
- the present invention is an invention that can be achieved only by the present inventions that have obtained this knowledge.
- the method for producing a compound of the present invention (part 1) is a method for producing a compound represented by the following general formula (1), which includes at least a reaction step, and further includes other steps as necessary.
- the reaction step is a step of obtaining a compound represented by the general formula (1) by reacting a compound represented by the following general formula (2) with a compound represented by the following general formula (3). .
- This reaction is performed in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A).
- R 1 represents either a hydrogen atom or an amino-protecting group.
- R 2 represents either a hydrogen atom or an amino-protecting group.
- R 11 represents an aromatic group which may have a substituent.
- R 12 represents an aromatic group which may have a substituent.
- R 13 represents either a hydrogen atom or an amino-protecting group.
- the amino protecting group in R 1 , R 2 , and R 13 is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a methoxycarbonyl group, a tert-butoxycarbonyl group, Examples include benzyloxycarbonyl group, allyloxycarbonyl group, formyl group, acetyl group, benzoyl group, methyl group, ethyl group, allyl group, and benzenesulfonyl group.
- the aromatic group in the aromatic group which may have the substituent of R 11 and R 12 may be either a monocyclic structure or a polycyclic structure. Of these, a phenyl group, a 1-naphthyl group, and a 2-naphthyl group are preferable.
- the number of carbon atoms of the aromatic group that may have a substituent is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 6 to 15.
- an aromatic hydrocarbon group is preferable.
- carbon number of the aromatic group which may have the said substituent means the total carbon number also including carbon number of this substituent here, when these have a substituent.
- the substituent of the aromatic group that may have the substituent is not particularly limited and may be appropriately selected depending on the intended purpose. For example, it has a halogen atom, an alkoxy group, or a substituent. Or an alkyl group that may be used.
- the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.
- the alkoxy group include an alkoxy group having 1 to 6 carbon atoms.
- Examples of the alkyl group include an alkyl group having 1 to 6 carbon atoms.
- Examples of the substituent in the alkyl group which may have a substituent include a halogen atom.
- Examples of the alkyl group which may have a substituent include a trifluoromethyl group.
- the catalyst contains an asymmetric ligand represented by the following general formula (A).
- the catalyst is, for example, a metal complex.
- a metal complex As the metal complex, a copper complex is preferable.
- the copper complex is obtained, for example, by mixing a copper compound and an asymmetric ligand represented by the general formula (A).
- asymmetric ligand represented by formula (A)- The asymmetric ligand represented by the following general formula (A) is a ligand described in WO 91/17998 pamphlet and Japanese Patent No. 2975683, and the like, and is an enantioselective catalyst. It is known as a ligand that forms The asymmetric ligand represented by the general formula (A) is also referred to as (R, R) -2,5-substituted-BPE because of its stereochemistry.
- R represents any of an alkyl group having 1 to 6 carbon atoms, an aryl group, a substituted aryl group, an aralkyl group, and a ring-substituted aralkyl group.
- alkyl group having 1 to 6 carbon atoms examples include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, t-butyl group, n-pentyl group, and n-hexyl group. Is mentioned.
- Examples of the aryl group include a phenyl group and a naphthyl group.
- Examples of the substituent in the substituted aryl group include an alkyl group.
- Examples of the alkyl group include an alkyl group having 1 to 6 carbon atoms.
- Examples of the substituted aryl group include a p-tolyl group.
- aralkyl group examples include a benzyl group and a phenethyl group.
- R is preferably a phenyl group. That is, the asymmetric ligand represented by the general formula (A) is preferably an asymmetric ligand represented by the following structural formula (A-1) [(R, R) -Ph-BPE]. However, in the structural formula (A-1), Ph represents a phenyl group.
- the copper compound is not particularly limited and may be appropriately selected depending on the intended purpose as long as an asymmetric copper complex can be obtained by reacting with the asymmetric ligand represented by the general formula (A). it can.
- Examples of the copper compound include a compound containing monovalent or divalent copper, and examples thereof include a copper salt and other copper compounds.
- Copper salt-- Examples of the copper salt include a copper salt represented by the following general formula (B-1). [Cu n11 X 1 n12 ] n13 general formula (B-1) (In the formula, n12 X 1 s are the same or different and each represents an anion, and n11 to n13 each independently represent a natural number.)
- anion represented by X 1, not particularly limited and may be appropriately selected depending on the intended purpose, for example, nitrate ion, nitrite ion, halide ion, sulfate ion, sulfite ion, sulfonate ion, sulfamic acid Ion, carbonate ion, hydroxide ion, carboxylate ion, sulfide ion, thiocyanate ion, phosphate ion, pyrophosphate ion, oxide ion, phosphide ion, chlorate ion, perchlorate ion, iodate ion Hexafluorosilicate ion, cyanide ion, borate ion, metaborate ion, borofluoride ion, and the like.
- Examples of the halide ions include fluoride ions, chloride ions, bromide ions, and iodide ions.
- Examples of the sulfonate ion include groups represented by R 105 SO 3 — (R 105 represents a hydrocarbon group which may have a substituent). Specific examples of the sulfonate ion include methanesulfonate ion, benzenesulfonate ion, trifluoromethanesulfonate ion, p-toluenesulfonate ion, and the like.
- Examples of the carboxylate ion include R 106 COO ⁇ (R 106 represents a hydrocarbon group which may have a substituent).
- carboxylate ion examples include, for example, acetate ion, formate ion, propionate ion, gluconate ion, oleate ion, oxalate ion, benzoate ion, phthalate ion, trifluoroacetate ion, and the like. It is done.
- N11 and n12 each independently represent a natural number, preferably a natural number of 1 to 10.
- the copper salt include the following copper salts.
- -Copper nitrate eg, copper nitrate (I), copper nitrate (II), etc.
- Copper nitrite for example, copper (I) nitrite, copper (II) nitrite, etc.]
- Copper halide for example, copper (I) chloride, copper (II) chloride, copper (I) bromide, copper (II) bromide, copper fluoride (I), copper (II) fluoride, copper iodide (I), copper (II) iodide, etc.
- -Copper sulfate eg, copper (II) sulfate]
- Copper sulfite eg, copper (II) sulfite]
- -Copper sulfonate for example, copper (I) methanesulfonate, copper (II) methanesulfonate, copper (I) p-to
- copper compounds examples include copper compounds represented by the following general formula (B-2). [Cu n14 X 2 n15] n16 general formula (B-2) [Wherein, n15 X 2 s are the same or different and may be a hydrocarbon group which may have a substituent, OR 101 (R 101 represents a hydrocarbon group which may have a substituent)] , NR 102 2 (two R 102 are the same or different and each represents a hydrogen atom or a hydrocarbon group optionally having a substituent), PR 103 2 (two R 103 are the same or different Represents a hydrocarbon group which may have a substituent), SR 104 (R 104 represents a hydrocarbon group which may have a substituent), 1,3-dicarbonyl compound or its Enolate or hydride, and n14 to n16 each independently represents a natural number. ]
- n14 and n15 each independently represent a natural number, preferably a natural number of 1 to 10.
- OR 101 represented by X 2 include, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, s-butoxy group, tert-butoxy group, phenoxy group and the like. Can be mentioned.
- Examples of the NR 102 for example, dimethylamino group, diethylamino group, dicyclohexyl amino group, and a diphenylamino group.
- Specific examples of the PR 103 for example, dimethyl phosphino group, diethylphosphino group, di (tert- butyl) phosphino group, dicyclohexylphosphino group, and diphenylphosphino groups.
- Specific examples of the SR 104 include SMe, SEt, SBu, SPh, S (CH 3 C 6 H 5 ), and the like.
- Me represents a methyl group
- Et represents an ethyl group.
- Specific examples of the 1,3-dicarbonyl compound or enolate thereof include, for example, 2,5-pentanedione (acac), 1,1,1-trifluoro-2,5-pentanedione, 1,1,1 , 3,3,3-hexafluoropentanedione (hfac), benzoylacetone, methyl acetoacetate, ethyl acetoacetate and the like.
- Specific examples of the copper compound represented by the general formula (B-2) include the following copper compounds. ⁇ Copper alkoxides (eg, copper dimethoxide, copper diethoxide, copper diisopropoxide, copper tert-butoxide, etc.) ⁇ Copper phenoxide (for example, copper phenoxide) ⁇ Copper phosphides (eg, copper di (tert-butyl phosphide), copper dicyclohexyl phosphide, copper diphenyl phosphide, etc.) ⁇ Copper amide (for example, copper dicyclohexylamide) ⁇ Copper thiolate (eg, copper butane thiolate, copper thiophenolate, etc.) ⁇ Copper 1,3-dicarbonyl compounds or enolate thereof [eg, copper 2,4-pentanedionate, copper benzoylacetonate, copper 1,3-diphenyl-1,3-propanedionate, copper ethy
- copper compounds include, for example, copper compounds represented by the following general formula (B-3). [HCuP (R 107 ) 3 ] n17 general formula (B-3) (In the formula, three R 107 s are the same or different and each represents an optionally substituted hydrocarbon group, and n17 represents a natural number.)
- copper compound represented by the general formula (B-3) include, for example, copper (I) hydride (triphenylphosphine) hexamer (Strike reagent).
- copper compound represented by the general formula (B-3) examples include hydrido (triphenylphosphine) copper (I) hexamer.
- Copper compounds such as the copper salt and other copper compounds are salts of alkali metals (for example, lithium, sodium, potassium, rubidium, cesium, etc.) and alkaline earth metals (for example, magnesium, calcium, strontium, barium, etc.) And may form a double salt.
- alkali metals for example, lithium, sodium, potassium, rubidium, cesium, etc.
- alkaline earth metals for example, magnesium, calcium, strontium, barium, etc.
- the double salt to be formed include KCuF 3 , K 3 [CuF 6 ], CuCN ⁇ LiCl, Li 2 CuCl 4 , Li 2 CuCl 3 , LiCuBr 2 and the like.
- These copper salts and the other copper compounds may be anhydrous or hydrated.
- copper compounds may be used alone or in appropriate combination of two or more.
- the said copper compound may use a commercial item, or what was suitably manufactured by the method as described in the conventional method or the literature described in this specification, etc. may be used.
- mesityl copper (I) is preferable from the viewpoint of catalytic activity.
- the ratio of the compound represented by the general formula (2) and the compound represented by the general formula (3) in the reaction step is not particularly limited and may be appropriately selected depending on the purpose.
- the compound represented by the general formula (2) is preferably 1.0 equivalent to 3.0 equivalents relative to the compound represented by the general formula (3).
- the solvent used in the reaction step is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include THF (tetrahydrofuran) and DMF (N, N-dimethylformamide). These may be used individually by 1 type and may use 2 or more types together.
- the amount of the catalyst used in the reaction step is not particularly limited and may be appropriately selected depending on the intended purpose. It is 0.1 mol% to 10 mol based on the compound represented by the general formula (3). %, More preferably 1 mol% to 8 mol%, particularly preferably 3 mol% to 6 mol%.
- the reaction temperature in the reaction step is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably ⁇ 50 ° C. to ⁇ 20 ° C. Since the reaction proceeds under mild conditions, the reaction can be performed without controlling the reaction temperature. Therefore, for example, it can be performed at room temperature. Examples of the room temperature include 20 ° C. to 30 ° C.
- the reaction time in the reaction step is not particularly limited and may be appropriately selected depending on the intended purpose. It is preferably 24 hours to 100 hours, and preferably 48 hours to 96 hours.
- Part 2 The method for producing a compound of the present invention (Part 2) is a method for producing a compound (NITD609) represented by the following structural formula (1), which includes at least a reaction step, and further includes other steps as necessary. Including.
- reaction process is the same as the said reaction process in the manufacturing method of the compound represented by the said General formula (1), A preferable aspect is also the same.
- the other step is not particularly limited as long as it is a step of obtaining the compound represented by the structural formula (1) using the compound represented by the general formula (1), and is appropriately selected depending on the purpose.
- a method of synthesizing according to the scheme 2 can be mentioned.
- the following series of reactions can be mentioned.
- Such a series of reactions is also described in detail in the following examples. Individual reactions in such a series of reactions can be carried out without trial and error by those skilled in the art who have contacted the following scheme and the examples described below.
- the 1 H NMR measurement result of the obtained compound is shown below.
- the 1 H NMR measurement result of the obtained compound is shown below.
- Example 3 (Example 3 and Reference Example)
- the reaction was carried out by changing the reaction temperature and reaction time as shown in Table 1 below. The results are shown in Table 1. Note that Entry 6 in Table 1 corresponds to Example 1.
- a reference example (Entry 01, 02) using (S, S) -Ph-BPE is shown. In the reference example, it was confirmed that a product having a stereochemistry opposite to the product of the reaction of Scheme 7 was obtained.
- R 1 represents either a hydrogen atom or an amino-protecting group.
- R 2 represents either a hydrogen atom or an amino-protecting group.
- R 11 represents an aromatic group which may have a substituent.
- R 12 represents an aromatic group which may have a substituent.
- R 13 represents either a hydrogen atom or an amino-protecting group.
- R represents any of an alkyl group having 1 to 6 carbon atoms, an aryl group, a substituted aryl group, an aralkyl group, and a ring-substituted aralkyl group.
- R of the asymmetric ligand represented by the general formula (A) is a phenyl group.
- the catalyst is a copper complex.
- ⁇ 4> The method for producing a compound according to ⁇ 3>, wherein the copper complex is obtained by mixing a copper compound and an asymmetric ligand represented by the general formula (A).
- R 1 represents either a hydrogen atom or an amino-protecting group.
- R 2 represents either a hydrogen atom or an amino-protecting group.
- R 11 represents an aromatic group which may have a substituent.
- R 12 represents an aromatic group which may have a substituent.
- R 13 represents either a hydrogen atom or an amino-protecting group.
- R represents any of an alkyl group having 1 to 6 carbon atoms, an aryl group, a substituted aryl group, an aralkyl group, and a ring-substituted aralkyl group.
- ⁇ 7> The method for producing a compound according to ⁇ 5>, wherein the catalyst is a copper complex.
- ⁇ 8> The method for producing a compound according to ⁇ 7>, wherein the copper complex is obtained by mixing a copper compound and an asymmetric ligand represented by the general formula (A).
- the method for producing a compound of the present invention can be suitably used for producing so-called NITD609.
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Abstract
This method for producing a compound represented by general formula (1) comprises a reaction step for reacting a compound represented by general formula (2) with a compound represented by general formula (3) in the presence of a catalyst containing an asymmetric ligand represented by general formula (A), to obtain the compound represented by general formula (1). However, in general formula (1) and general formula (2), R1 represents either a hydrogen atom or a protecting group for an amino group and R2 represents either a hydrogen atom or a protecting group for an amino group. In general formula (1) and general formula (3), R11 represents an optionally substituted aromatic group, R12 represents an optionally substituted aromatic group, and R13 represents either a hydrogen atom or a protecting group for an amino group. However, in general formula (A), R represents any one of an alkyl group having 1-6 carbon atoms, an aryl group, a substituted aryl group, an aralkyl group, and a ring-substituted aralkyl group.
Description
本発明は、ＮＩＴＤ６０９の合成に非常に有用な光学活性化合物を製造する方法、並びにＮＩＴＤ６０９の製造方法に関する。
The present invention relates to a method for producing an optically active compound that is very useful for the synthesis of NITD609, and a method for producing NITD609.
２０１０年、Ｎｏｖａｒｔｉｓ Ｉｎｓｔｉｔｕｔｅ ｆｏｒ Ｔｒｏｐｉｃａｌ Ｄｉｓｅａｓｅｓによって抗マラリア活性を有する下記構造式で表される化合物（ＮＩＴＤ６０９）が報告された（非特許文献１及び２参照）。
In 2010, Novartis Institute for Tropical Diseases reported a compound represented by the following structural formula (NITD609) having antimalarial activity (see Non-Patent Documents 1 and 2).
この化合物は、他の抗マラリア剤に対し耐性を獲得したマラリア原虫Ｐｌａｓｍｏｄｉｕｍ． Ｆａｌｃｉｐａｒｕｍ、及びＰｌａｓｍｏｄｉｕｍ． Ｖｉｖａｘに対しても活性を示すことが報告されており、現在、治験が第二相試験に進んでいる。
This compound is a malaria parasite Plasmodium. Which has acquired resistance to other antimalarial agents. Falciparum and Plasmodium. It has been reported that it also exhibits activity against Vivax, and the clinical trial is currently proceeding to a phase II trial.
しかしながら、最初に報告されている本化合物の合成法では、生成物をラセミ体として合成後、キラルカラムによる光学分割によって目的物を得ており、合成効率の点で問題が残されており、改良合成法は酵素法に頼っている。
However, in the first method for synthesizing this compound, the product is obtained as a racemate, and then the target product is obtained by optical resolution using a chiral column, leaving problems in terms of synthesis efficiency. The method relies on enzymatic methods.
したがって、ＮＩＴＤ６０９の合成に有用な純化学的な光学活性化合物の製造方法が求められているのが現状である。
Therefore, at present, there is a demand for a method for producing a pure chemical optically active compound useful for the synthesis of NITD609.
本発明は、従来における前記諸問題を解決し、以下の目的を達成することを課題とする。即ち、本発明は、ＮＩＴＤ６０９の合成に非常に有用な光学活性化合物を製造する方法、並びにＮＩＴＤ６０９の製造方法を提供することを目的とする。
This invention makes it a subject to solve the said various problems in the past and to achieve the following objectives. That is, an object of the present invention is to provide a method for producing an optically active compound that is very useful for the synthesis of NITD609 and a method for producing NITD609.
前記課題を解決するための手段としては、以下の通りである。即ち、
本発明の化合物の製造方法は、下記一般式（１）で表される化合物の製造方法であって、
下記一般式（２）で表される化合物と、下記一般式（３）で表される化合物とを、下記一般式（Ａ）で表される不斉配位子を含有する触媒の存在下で反応させ、前記一般式（１）で表される化合物を得る反応工程を含むことを特徴とする。
ただし、前記一般式（１）、及び前記一般式（２）中、Ｒ１は、水素原子、及びアミノ基の保護基のいずれかを表す。Ｒ２は、水素原子、及びアミノ基の保護基のいずれかを表す。前記一般式（１）、及び前記一般式（３）中、Ｒ１１は、置換基を有していてもよい芳香族基を表す。Ｒ１２は、置換基を有していてもよい芳香族基を表す。Ｒ１３は、水素原子、及びアミノ基の保護基のいずれかを表す。
ただし、前記一般式（Ａ）中、Ｒは、炭素数１～６のアルキル基、アリール基、置換アリール基、アラルキル基、及び環置換アラルキル基のいずれかを表す。
Means for solving the problems are as follows. That is,
The method for producing a compound of the present invention is a method for producing a compound represented by the following general formula (1),
A compound represented by the following general formula (2) and a compound represented by the following general formula (3) in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A) It includes a reaction step of reacting to obtain a compound represented by the general formula (1).
However, in the general formula (1) and the general formula (2), R 1 represents either a hydrogen atom or an amino-protecting group. R 2 represents either a hydrogen atom or an amino-protecting group. In the general formula (1) and the general formula (3), R 11 represents an aromatic group which may have a substituent. R 12 represents an aromatic group which may have a substituent. R 13 represents either a hydrogen atom or an amino-protecting group.
In the general formula (A), R represents any of an alkyl group having 1 to 6 carbon atoms, an aryl group, a substituted aryl group, an aralkyl group, and a ring-substituted aralkyl group.
本発明の化合物の製造方法は、下記一般式（１）で表される化合物の製造方法であって、
下記一般式（２）で表される化合物と、下記一般式（３）で表される化合物とを、下記一般式（Ａ）で表される不斉配位子を含有する触媒の存在下で反応させ、前記一般式（１）で表される化合物を得る反応工程を含むことを特徴とする。
The method for producing a compound of the present invention is a method for producing a compound represented by the following general formula (1),
A compound represented by the following general formula (2) and a compound represented by the following general formula (3) in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A) It includes a reaction step of reacting to obtain a compound represented by the general formula (1).
また、本発明の化合物の製造方法は、下記構造式（１）で表される化合物の製造方法であって、
下記一般式（２）で表される化合物と、下記一般式（３）で表される化合物とを、下記一般式（Ａ）で表される不斉配位子を含有する触媒の存在下で反応させ、前記一般式（１）で表される化合物を得る反応工程を含むことを特徴とする。
ただし、前記一般式（１）、及び前記一般式（２）中、Ｒ１は、水素原子、及びアミノ基の保護基のいずれかを表す。Ｒ２は、水素原子、及びアミノ基の保護基のいずれかを表す。前記一般式（１）、及び前記一般式（３）中、Ｒ１１は、置換基を有していてもよい芳香族基を表す。Ｒ１２は、置換基を有していてもよい芳香族基を表す。Ｒ１３は、水素原子、及びアミノ基の保護基のいずれかを表す。
ただし、前記一般式（Ａ）中、Ｒは、炭素数１～６のアルキル基、アリール基、置換アリール基、アラルキル基、及び環置換アラルキル基のいずれかを表す。
Moreover, the manufacturing method of the compound of this invention is a manufacturing method of the compound represented by following Structural formula (1),
A compound represented by the following general formula (2) and a compound represented by the following general formula (3) in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A) It includes a reaction step of reacting to obtain a compound represented by the general formula (1).
However, in the general formula (1) and the general formula (2), R 1 represents either a hydrogen atom or an amino-protecting group. R 2 represents either a hydrogen atom or an amino-protecting group. In the general formula (1) and the general formula (3), R 11 represents an aromatic group which may have a substituent. R 12 represents an aromatic group which may have a substituent. R 13 represents either a hydrogen atom or an amino-protecting group.
In the general formula (A), R represents any of an alkyl group having 1 to 6 carbon atoms, an aryl group, a substituted aryl group, an aralkyl group, and a ring-substituted aralkyl group.
下記一般式（２）で表される化合物と、下記一般式（３）で表される化合物とを、下記一般式（Ａ）で表される不斉配位子を含有する触媒の存在下で反応させ、前記一般式（１）で表される化合物を得る反応工程を含むことを特徴とする。
A compound represented by the following general formula (2) and a compound represented by the following general formula (3) in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A) It includes a reaction step of reacting to obtain a compound represented by the general formula (1).
本発明によれば、従来における前記諸問題を解決し、前記目的を達成することができ、ＮＩＴＤ６０９の合成に非常に有用な光学活性化合物を製造する方法、並びにＮＩＴＤ６０９の製造方法を提供することができる。
According to the present invention, there are provided a method for producing an optically active compound that can solve the above-mentioned problems and achieve the above-mentioned object and is very useful for the synthesis of NITD 609, and a method for producing NITD 609. it can.
本明細書、及び特許請求の範囲に記載された化学式及び一般式における立体配置は、特に言及しない場合には、絶対配置を表す。
The steric configurations in the chemical formulas and general formulas described in this specification and in the claims represent absolute configurations unless otherwise specified.
本発明者らは、ＮＩＴＤ６０９の効率的な合成方法について鋭意検討を行った。
本発明者らは、以下のＳｃｈｅｍｅ １に示す触媒的不斉アルキニル化反応に着目した。
ここで、「Ｐｈ」は、フェニル基を表す。Ｒ１、Ｒ２、及びＲ３は、置換基を表す。
このＳｃｈｅｍｅ １に示す反応は、非特許文献（Ｙｉｎ， Ｌ．； Ｏｔｓｕｋａ， Ｙ．； Ｔａｋａｄａ， Ｈ．； Ｍｏｕｒｉ， Ｓ．； Ｙａｚａｋｉ， Ｒ．； Ｋｕｍａｇａｉ， Ｎ．； Ｓｈｉｂａｓａｋｉ， Ｍ． Ｏｒｇ． Ｌｅｔｔ． ２０１３， １５， ６９８）で報告されている。 The present inventors diligently studied on an efficient synthesis method of NITD609.
The present inventors paid attention to the catalytic asymmetric alkynylation reaction shown in Scheme 1 below.
Here, “Ph” represents a phenyl group. R 1 , R 2 , and R 3 represent a substituent.
This reaction shown in Scheme 1 is described in non-patent literature (Yin, L .; Otsuka, Y .; Takada, H .; Mouri, S .; Yazaki, R .; Kumagai, N .; Shibasaki, M. Ort. 2013, 15, 698).
本発明者らは、以下のＳｃｈｅｍｅ １に示す触媒的不斉アルキニル化反応に着目した。
このＳｃｈｅｍｅ １に示す反応は、非特許文献（Ｙｉｎ， Ｌ．； Ｏｔｓｕｋａ， Ｙ．； Ｔａｋａｄａ， Ｈ．； Ｍｏｕｒｉ， Ｓ．； Ｙａｚａｋｉ， Ｒ．； Ｋｕｍａｇａｉ， Ｎ．； Ｓｈｉｂａｓａｋｉ， Ｍ． Ｏｒｇ． Ｌｅｔｔ． ２０１３， １５， ６９８）で報告されている。 The present inventors diligently studied on an efficient synthesis method of NITD609.
The present inventors paid attention to the catalytic asymmetric alkynylation reaction shown in Scheme 1 below.
This reaction shown in Scheme 1 is described in non-patent literature (Yin, L .; Otsuka, Y .; Takada, H .; Mouri, S .; Yazaki, R .; Kumagai, N .; Shibasaki, M. Ort. 2013, 15, 698).
本発明者らは、前記Ｓｃｈｅｍｅ １に示す触媒的不斉アルキニル化反応を応用したＮＩＴＤ６０９の合成戦略を以下のＳｃｈｅｍｅ ２のように計画した。
この合成戦略は、本発明者らによって、「触媒的不斉アルキニル化反応を利用したＮＩＴＤ６０９の不斉合成研究」という発表題目として、公益財団法人 日本薬学会が開催した日本薬学会第１３３年会（２０１４年）及び第１３４年会（２０１５年）、及びそれらの要旨集〔日本薬学会第１３３年会要旨集２８Ｓ－ａｍ０３（１３３年会），日本薬学会第１３４年会要旨集２８Ｄ－ｐｍ１５（１３４年会）〕において報告されている。
The present inventors planned a synthesis strategy of NITD609 applying the catalytic asymmetric alkynylation reaction shown in the above-mentioned Scheme 1 as shown in Scheme 2 below.
This synthetic strategy was developed by the present inventors as the title of “Asymmetric Synthesis of NITD609 Utilizing Catalytic Asymmetric Alkynylation Reaction”. (2014) and 134th Annual Meeting (2015) and their abstracts [Japan Pharmaceutical Association 133rd Annual Meeting 28S-am03 (133th Annual Meeting), Japan Pharmaceutical Association 134th Annual Meeting 28D-pm15 (134th Annual Meeting)].
この合成戦略に基づく実際の合成においては、前記Ｓｃｈｅｍｅ ２に記載の化合物Ｃを合成するために、前記Ｓｃｈｅｍｅ １を参考にして、下記Ｓｃｈｅｍｅ ３に示す合成を試みている。
In the actual synthesis based on this synthesis strategy, in order to synthesize the compound C described in the above Scheme 2, the synthesis shown in the following Scheme 3 is attempted with reference to the above Scheme 1.
ところが、結論としては、得られた結果物は、ＮＩＴＤ６０９のエピマーであった。ここまでは既報により報告されている。
However, as a conclusion, the resulting product was an epimer of NITD609. So far, it has been reported in previous reports.
更に本発明者らは、検討を行った。
本発明者らは、前記Ｓｃｈｅｍｅ ２の合成戦略によって既報において得られたエピマーの立体化学を詳細に検討した。そのところ、得られた結果物において、ジアステレオマーと分離可能な生成物は、ＮＩＴＤ６０９のエナンチオマーが主成分であることを知見した。 Furthermore, the present inventors conducted a study.
The present inventors examined in detail the stereochemistry of the epimer obtained in the previous report by the synthesis strategy of the above Scheme 2. As a result, it was found that in the obtained product, the product that can be separated from the diastereomer is mainly composed of the enantiomer of NITD609.
本発明者らは、前記Ｓｃｈｅｍｅ ２の合成戦略によって既報において得られたエピマーの立体化学を詳細に検討した。そのところ、得られた結果物において、ジアステレオマーと分離可能な生成物は、ＮＩＴＤ６０９のエナンチオマーが主成分であることを知見した。 Furthermore, the present inventors conducted a study.
The present inventors examined in detail the stereochemistry of the epimer obtained in the previous report by the synthesis strategy of the above Scheme 2. As a result, it was found that in the obtained product, the product that can be separated from the diastereomer is mainly composed of the enantiomer of NITD609.
そこで、本発明者らは、更に検討を行った。
前記Ｓｃｈｅｍｅ １に示す触媒的不斉アルキニル化反応を応用して、前記Ｓｃｈｅｍｅ ３に示す化合物Ｃ１を得ようとすると、前記Ｓｃｈｅｍｅ ３に示す不斉触媒を用いるのが、当業者の当然の思考である。
しかし、本発明者らは、前記知見（ＮＩＴＤ６０９のエナンチオマーが主成分であること）を踏まえ、前記Ｓｃｈｅｍｅ ２の合成戦略、及び、前記Ｓｃｈｅｍｅ ３の合成を再度詳細に検討した。
その結果、前記Ｓｃｈｅｍｅ ３の反応では、驚くべきことに、Ｃ１の光学異性体である、下記構造式（Ｃ１－Ａ）で表される化合物が生成していることを知見した。
Therefore, the present inventors further studied.
By applying the catalytic asymmetric alkynylation reaction shown in Scheme 1 to obtain the compound C1 shown in Scheme 3, it is a natural idea of those skilled in the art to use the asymmetric catalyst shown in Scheme 3. is there.
However, the present inventors examined the synthesis strategy of the Scheme 2 and the synthesis of the Scheme 3 again in detail based on the above findings (the enantiomer of NITD609 is the main component).
As a result, it was found that in the reaction of Scheme 3, a compound represented by the following structural formula (C1-A), which is an optical isomer of C1, was generated.
前記Ｓｃｈｅｍｅ １に示す触媒的不斉アルキニル化反応を応用して、前記Ｓｃｈｅｍｅ ３に示す化合物Ｃ１を得ようとすると、前記Ｓｃｈｅｍｅ ３に示す不斉触媒を用いるのが、当業者の当然の思考である。
しかし、本発明者らは、前記知見（ＮＩＴＤ６０９のエナンチオマーが主成分であること）を踏まえ、前記Ｓｃｈｅｍｅ ２の合成戦略、及び、前記Ｓｃｈｅｍｅ ３の合成を再度詳細に検討した。
その結果、前記Ｓｃｈｅｍｅ ３の反応では、驚くべきことに、Ｃ１の光学異性体である、下記構造式（Ｃ１－Ａ）で表される化合物が生成していることを知見した。
By applying the catalytic asymmetric alkynylation reaction shown in Scheme 1 to obtain the compound C1 shown in Scheme 3, it is a natural idea of those skilled in the art to use the asymmetric catalyst shown in Scheme 3. is there.
However, the present inventors examined the synthesis strategy of the Scheme 2 and the synthesis of the Scheme 3 again in detail based on the above findings (the enantiomer of NITD609 is the main component).
As a result, it was found that in the reaction of Scheme 3, a compound represented by the following structural formula (C1-A), which is an optical isomer of C1, was generated.
そこで、本発明らは、この知見を踏まえ、前記Ｓｃｈｅｍｅ ２で示される合成戦略において、化合物Ｃの製造方法を見直すことで、本発明の完成に至った。即ち、本発明は、この知見を手に入れた本発明らであったからこそ成し得た発明である。
Therefore, based on this finding, the present inventors have completed the present invention by reviewing the production method of Compound C in the synthesis strategy shown in the above-mentioned Scheme 2. In other words, the present invention is an invention that can be achieved only by the present inventions that have obtained this knowledge.
（一般式（１）で表される化合物の製造方法）
本発明の化合物の製造方法（その１）は、下記一般式（１）で表される化合物の製造方法であって、反応工程を少なくとも含み、更に必要に応じて、その他の工程を含む。 (Method for producing the compound represented by the general formula (1))
The method for producing a compound of the present invention (part 1) is a method for producing a compound represented by the following general formula (1), which includes at least a reaction step, and further includes other steps as necessary.
本発明の化合物の製造方法（その１）は、下記一般式（１）で表される化合物の製造方法であって、反応工程を少なくとも含み、更に必要に応じて、その他の工程を含む。 (Method for producing the compound represented by the general formula (1))
The method for producing a compound of the present invention (part 1) is a method for producing a compound represented by the following general formula (1), which includes at least a reaction step, and further includes other steps as necessary.
＜反応工程＞
前記反応工程は、下記一般式（２）で表される化合物と、下記一般式（３）で表される化合物とを反応させ、前記一般式（１）で表される化合物を得る工程である。
この反応は、下記一般式（Ａ）で表される不斉配位子を含有する触媒の存在下で行われる。 <Reaction process>
The reaction step is a step of obtaining a compound represented by the general formula (1) by reacting a compound represented by the following general formula (2) with a compound represented by the following general formula (3). .
This reaction is performed in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A).
前記反応工程は、下記一般式（２）で表される化合物と、下記一般式（３）で表される化合物とを反応させ、前記一般式（１）で表される化合物を得る工程である。
この反応は、下記一般式（Ａ）で表される不斉配位子を含有する触媒の存在下で行われる。 <Reaction process>
The reaction step is a step of obtaining a compound represented by the general formula (1) by reacting a compound represented by the following general formula (2) with a compound represented by the following general formula (3). .
This reaction is performed in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A).
＜＜一般式（１）で表される化合物、一般式（２）で表される化合物、一般式（３）で表される化合物＞＞
ただし、前記一般式（１）、及び前記一般式（２）中、Ｒ１は、水素原子、及びアミノ基の保護基のいずれかを表す。Ｒ２は、水素原子、及びアミノ基の保護基のいずれかを表す。前記一般式（１）、及び前記一般式（３）中、Ｒ１１は、置換基を有していてもよい芳香族基を表す。Ｒ１２は、置換基を有していてもよい芳香族基を表す。Ｒ１３は、水素原子、及びアミノ基の保護基のいずれかを表す。
<< Compound Represented by General Formula (1), Compound Represented by General Formula (2), Compound Represented by General Formula (3) >>
However, in the general formula (1) and the general formula (2), R 1 represents either a hydrogen atom or an amino-protecting group. R 2 represents either a hydrogen atom or an amino-protecting group. In the general formula (1) and the general formula (3), R 11 represents an aromatic group which may have a substituent. R 12 represents an aromatic group which may have a substituent. R 13 represents either a hydrogen atom or an amino-protecting group.
－アミノ基の保護基－
前記Ｒ１、前記Ｒ２、及び前記Ｒ１３における前記アミノ基の保護基としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、メトキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基、ベンジルオキシカルボニル基、アリルオキシカルボニル基、ホルミル基、アセチル基、ベンゾイル基、メチル基、エチル基、アリル基、ベンゼンスルホニル基などが挙げられる。 -Amino protecting group-
The amino protecting group in R 1 , R 2 , and R 13 is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a methoxycarbonyl group, a tert-butoxycarbonyl group, Examples include benzyloxycarbonyl group, allyloxycarbonyl group, formyl group, acetyl group, benzoyl group, methyl group, ethyl group, allyl group, and benzenesulfonyl group.
前記Ｒ１、前記Ｒ２、及び前記Ｒ１３における前記アミノ基の保護基としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、メトキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基、ベンジルオキシカルボニル基、アリルオキシカルボニル基、ホルミル基、アセチル基、ベンゾイル基、メチル基、エチル基、アリル基、ベンゼンスルホニル基などが挙げられる。 -Amino protecting group-
The amino protecting group in R 1 , R 2 , and R 13 is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a methoxycarbonyl group, a tert-butoxycarbonyl group, Examples include benzyloxycarbonyl group, allyloxycarbonyl group, formyl group, acetyl group, benzoyl group, methyl group, ethyl group, allyl group, and benzenesulfonyl group.
－置換基を有していてもよい芳香族基－
前記Ｒ１１、及び前記Ｒ１２の前記置換基を有していてもよい芳香族基における芳香族基は、単環構造及び多環構造のいずれでもよい。なかでも、フェニル基、１－ナフチル基、２－ナフチル基が好ましい。 -Aromatic group which may have a substituent-
The aromatic group in the aromatic group which may have the substituent of R 11 and R 12 may be either a monocyclic structure or a polycyclic structure. Of these, a phenyl group, a 1-naphthyl group, and a 2-naphthyl group are preferable.
前記Ｒ１１、及び前記Ｒ１２の前記置換基を有していてもよい芳香族基における芳香族基は、単環構造及び多環構造のいずれでもよい。なかでも、フェニル基、１－ナフチル基、２－ナフチル基が好ましい。 -Aromatic group which may have a substituent-
The aromatic group in the aromatic group which may have the substituent of R 11 and R 12 may be either a monocyclic structure or a polycyclic structure. Of these, a phenyl group, a 1-naphthyl group, and a 2-naphthyl group are preferable.
前記置換基を有していてもよい芳香族基の炭素数としては、特に制限はなく、目的に応じて適宜選択することができるが、６～１５が好ましい。
前記芳香族基としては、芳香族炭化水素基が好ましい。
なお、ここで、前記置換基を有していてもよい芳香族基の炭素数は、これらが置換基を有する場合、該置換基の炭素数も含む合計の炭素数を意味する。 The number of carbon atoms of the aromatic group that may have a substituent is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 6 to 15.
As the aromatic group, an aromatic hydrocarbon group is preferable.
In addition, carbon number of the aromatic group which may have the said substituent means the total carbon number also including carbon number of this substituent here, when these have a substituent.
前記芳香族基としては、芳香族炭化水素基が好ましい。
なお、ここで、前記置換基を有していてもよい芳香族基の炭素数は、これらが置換基を有する場合、該置換基の炭素数も含む合計の炭素数を意味する。 The number of carbon atoms of the aromatic group that may have a substituent is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 6 to 15.
As the aromatic group, an aromatic hydrocarbon group is preferable.
In addition, carbon number of the aromatic group which may have the said substituent means the total carbon number also including carbon number of this substituent here, when these have a substituent.
前記置換基を有していてもよい芳香族基の置換基としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、ハロゲン原子、アルコキシ基、置換基を有していてもよいアルキル基などが挙げられる。前記ハロゲン原子としては、例えば、フッ素原子、塩素原子、臭素原子などが挙げられる。前記アルコキシ基としては、例えば、炭素数１～６のアルコキシ基などが挙げられる。前記アルキル基としては、例えば、炭素数１～６のアルキル基などが挙げられる。前記置換基を有していてもよいアルキル基における置換基としては、例えば、ハロゲン原子などが挙げられる。前記置換基を有していてもよいアルキル基としては、例えば、トリフルオロメチル基などが挙げられる。
The substituent of the aromatic group that may have the substituent is not particularly limited and may be appropriately selected depending on the intended purpose. For example, it has a halogen atom, an alkoxy group, or a substituent. Or an alkyl group that may be used. Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. Examples of the alkoxy group include an alkoxy group having 1 to 6 carbon atoms. Examples of the alkyl group include an alkyl group having 1 to 6 carbon atoms. Examples of the substituent in the alkyl group which may have a substituent include a halogen atom. Examples of the alkyl group which may have a substituent include a trifluoromethyl group.
前記芳香族基における前記置換基の数としては、特に制限はなく、目的に応じて適宜選択することができる。前記置換基の数としては、例えば、１つ～４つなどが挙げられる。
前記芳香族基における前記置換基の位置としては、特に制限はなく、目的に応じて適宜選択することができ、オルト位、パラ位、及びメタ位のいずれでもよい。
複数の前記置換基が、前記芳香族基に結合する場合、それらの置換基は、同じ置換基であってもよいし、異なる置換基であってもよい。 There is no restriction | limiting in particular as the number of the said substituents in the said aromatic group, According to the objective, it can select suitably. Examples of the number of substituents include 1 to 4 and the like.
There is no restriction | limiting in particular as a position of the said substituent in the said aromatic group, According to the objective, it can select suitably, Any of ortho position, para position, and meta position may be sufficient.
When a plurality of the substituents are bonded to the aromatic group, the substituents may be the same substituent or different substituents.
前記芳香族基における前記置換基の位置としては、特に制限はなく、目的に応じて適宜選択することができ、オルト位、パラ位、及びメタ位のいずれでもよい。
複数の前記置換基が、前記芳香族基に結合する場合、それらの置換基は、同じ置換基であってもよいし、異なる置換基であってもよい。 There is no restriction | limiting in particular as the number of the said substituents in the said aromatic group, According to the objective, it can select suitably. Examples of the number of substituents include 1 to 4 and the like.
There is no restriction | limiting in particular as a position of the said substituent in the said aromatic group, According to the objective, it can select suitably, Any of ortho position, para position, and meta position may be sufficient.
When a plurality of the substituents are bonded to the aromatic group, the substituents may be the same substituent or different substituents.
＜＜触媒＞＞
前記触媒は、下記一般式（Ａ）で表される不斉配位子を含有する。 << Catalyst >>
The catalyst contains an asymmetric ligand represented by the following general formula (A).
前記触媒は、下記一般式（Ａ）で表される不斉配位子を含有する。 << Catalyst >>
The catalyst contains an asymmetric ligand represented by the following general formula (A).
前記触媒は、例えば、金属錯体である。前記金属錯体としては、銅錯体が好ましい。前記触媒として、前記銅錯体を用いることにより、安価な銅を触媒源に用い、高いエナンチオ選択性で前記一般式（１）で表される化合物を得ることができる。
前記銅錯体は、例えば、銅化合物と、前記一般式（Ａ）で表される不斉配位子とを混合して得られる。 The catalyst is, for example, a metal complex. As the metal complex, a copper complex is preferable. By using the copper complex as the catalyst, it is possible to obtain a compound represented by the general formula (1) with high enantioselectivity using inexpensive copper as a catalyst source.
The copper complex is obtained, for example, by mixing a copper compound and an asymmetric ligand represented by the general formula (A).
前記銅錯体は、例えば、銅化合物と、前記一般式（Ａ）で表される不斉配位子とを混合して得られる。 The catalyst is, for example, a metal complex. As the metal complex, a copper complex is preferable. By using the copper complex as the catalyst, it is possible to obtain a compound represented by the general formula (1) with high enantioselectivity using inexpensive copper as a catalyst source.
The copper complex is obtained, for example, by mixing a copper compound and an asymmetric ligand represented by the general formula (A).
－一般式（Ａ）で表される不斉配位子－
下記一般式（Ａ）で表される不斉配位子は、国際公開ＷＯ９１／１７９９８号パンフレット、及びその日本特許第２９７５６８３号公報などに掲載されている配位子であって、エナンチオ選択的触媒を形成する配位子として知られている。前記一般式（Ａ）で表される不斉配位子は、その立体化学から、（Ｒ，Ｒ）－２，５置換－ＢＰＥとも称される。
ただし、前記一般式（Ａ）中、Ｒは、炭素数１～６のアルキル基、アリール基、置換アリール基、アラルキル基、及び環置換アラルキル基のいずれかを表す。
-Asymmetric ligand represented by formula (A)-
The asymmetric ligand represented by the following general formula (A) is a ligand described in WO 91/17998 pamphlet and Japanese Patent No. 2975683, and the like, and is an enantioselective catalyst. It is known as a ligand that forms The asymmetric ligand represented by the general formula (A) is also referred to as (R, R) -2,5-substituted-BPE because of its stereochemistry.
In the general formula (A), R represents any of an alkyl group having 1 to 6 carbon atoms, an aryl group, a substituted aryl group, an aralkyl group, and a ring-substituted aralkyl group.
下記一般式（Ａ）で表される不斉配位子は、国際公開ＷＯ９１／１７９９８号パンフレット、及びその日本特許第２９７５６８３号公報などに掲載されている配位子であって、エナンチオ選択的触媒を形成する配位子として知られている。前記一般式（Ａ）で表される不斉配位子は、その立体化学から、（Ｒ，Ｒ）－２，５置換－ＢＰＥとも称される。
The asymmetric ligand represented by the following general formula (A) is a ligand described in WO 91/17998 pamphlet and Japanese Patent No. 2975683, and the like, and is an enantioselective catalyst. It is known as a ligand that forms The asymmetric ligand represented by the general formula (A) is also referred to as (R, R) -2,5-substituted-BPE because of its stereochemistry.
前記炭素数１～６のアルキル基としては、例えば、メチル基、エチル基、ｎ－プロピル基、ｉ－プロピル基、ｎ－ブチル基、ｔ－ブチル基、ｎ－ペンチル基、ｎ－ヘキシル基などが挙げられる。
Examples of the alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, t-butyl group, n-pentyl group, and n-hexyl group. Is mentioned.
前記アリール基としては、例えば、フェニル基、ナフチル基などが挙げられる。
前記置換アリール基における置換基としては、例えば、アルキル基などが挙げられる。前記アルキル基としては、例えば、炭素数１～６のアルキル基などが挙げられる。
前記置換アリール基としては、例えば、ｐ－トリル基などが挙げられる。 Examples of the aryl group include a phenyl group and a naphthyl group.
Examples of the substituent in the substituted aryl group include an alkyl group. Examples of the alkyl group include an alkyl group having 1 to 6 carbon atoms.
Examples of the substituted aryl group include a p-tolyl group.
前記置換アリール基における置換基としては、例えば、アルキル基などが挙げられる。前記アルキル基としては、例えば、炭素数１～６のアルキル基などが挙げられる。
前記置換アリール基としては、例えば、ｐ－トリル基などが挙げられる。 Examples of the aryl group include a phenyl group and a naphthyl group.
Examples of the substituent in the substituted aryl group include an alkyl group. Examples of the alkyl group include an alkyl group having 1 to 6 carbon atoms.
Examples of the substituted aryl group include a p-tolyl group.
前記アラルキル基としては、例えば、ベンジル基、フェネチル基などが挙げられる。
Examples of the aralkyl group include a benzyl group and a phenethyl group.
これらのなかでも、立体選択性の点で、Ｒとしては、フェニル基が好ましい。即ち、前記一般式（Ａ）で表される不斉配位子は、下記構造式（Ａ－１）で表される不斉配位子〔（Ｒ，Ｒ）－Ｐｈ－ＢＰＥ〕が好ましい。
ただし、前記構造式（Ａ－１）中、Ｐｈは、フェニル基を表す。
Among these, from the viewpoint of stereoselectivity, R is preferably a phenyl group. That is, the asymmetric ligand represented by the general formula (A) is preferably an asymmetric ligand represented by the following structural formula (A-1) [(R, R) -Ph-BPE].
However, in the structural formula (A-1), Ph represents a phenyl group.
－銅化合物－
前記銅化合物としては、前記一般式（Ａ）で表される不斉配位子と反応させることにより不斉銅錯体を得ることができれば、特に制限はなく、目的に応じて適宜選択することができる。 -Copper compound-
The copper compound is not particularly limited and may be appropriately selected depending on the intended purpose as long as an asymmetric copper complex can be obtained by reacting with the asymmetric ligand represented by the general formula (A). it can.
前記銅化合物としては、前記一般式（Ａ）で表される不斉配位子と反応させることにより不斉銅錯体を得ることができれば、特に制限はなく、目的に応じて適宜選択することができる。 -Copper compound-
The copper compound is not particularly limited and may be appropriately selected depending on the intended purpose as long as an asymmetric copper complex can be obtained by reacting with the asymmetric ligand represented by the general formula (A). it can.
前記銅化合物としては、例えば、一価又は二価の銅を含有する化合物が挙げられ、例えば、銅塩、その他の銅化合物などが挙げられる。
Examples of the copper compound include a compound containing monovalent or divalent copper, and examples thereof include a copper salt and other copper compounds.
－－銅塩－－
前記銅塩としては、例えば下記一般式（Ｂ－１）で表される銅塩などが挙げられる。
［Ｃｕｎ１１Ｘ１ ｎ１２］ｎ１３ 一般式（Ｂ－１）
（式中、ｎ１２個のＸ１は同一又は異なって、アニオンを示し、ｎ１１～ｎ１３は夫々独立して、自然数を示す。） --- Copper salt--
Examples of the copper salt include a copper salt represented by the following general formula (B-1).
[Cu n11 X 1 n12 ] n13 general formula (B-1)
(In the formula, n12 X 1 s are the same or different and each represents an anion, and n11 to n13 each independently represent a natural number.)
前記銅塩としては、例えば下記一般式（Ｂ－１）で表される銅塩などが挙げられる。
［Ｃｕｎ１１Ｘ１ ｎ１２］ｎ１３ 一般式（Ｂ－１）
（式中、ｎ１２個のＸ１は同一又は異なって、アニオンを示し、ｎ１１～ｎ１３は夫々独立して、自然数を示す。） --- Copper salt--
Examples of the copper salt include a copper salt represented by the following general formula (B-1).
[Cu n11 X 1 n12 ] n13 general formula (B-1)
(In the formula, n12 X 1 s are the same or different and each represents an anion, and n11 to n13 each independently represent a natural number.)
Ｘ１で示されるアニオンとしては、特に制限はなく、目的に応じて適宜選択することができ、例えば、硝酸イオン、亜硝酸イオン、ハロゲン化物イオン、硫酸イオン、亜硫酸イオン、スルホン酸イオン、スルファミン酸イオン、炭酸イオン、水酸化物イオン、カルボン酸イオン、硫化物イオン、チオシアン酸イオン、リン酸イオン、ピロリン酸イオン、酸化物イオン、リン化物イオン、塩素酸イオン、過塩素酸イオン、ヨウ素酸イオン、ヘキサフルオロケイ酸イオン、シアン化物イオン、ホウ酸イオン、メタホウ酸イオン、ほうフッ化物イオンなどが挙げられる。
Examples of the anion represented by X 1, not particularly limited and may be appropriately selected depending on the intended purpose, for example, nitrate ion, nitrite ion, halide ion, sulfate ion, sulfite ion, sulfonate ion, sulfamic acid Ion, carbonate ion, hydroxide ion, carboxylate ion, sulfide ion, thiocyanate ion, phosphate ion, pyrophosphate ion, oxide ion, phosphide ion, chlorate ion, perchlorate ion, iodate ion Hexafluorosilicate ion, cyanide ion, borate ion, metaborate ion, borofluoride ion, and the like.
前記ハロゲン化物イオンとしては、例えば、フッ化物イオン、塩化物イオン、臭化物イオン、ヨウ化物イオンなどが挙げられる。
前記スルホン酸イオンとしては、例えば、Ｒ１０５ＳＯ３ －（Ｒ１０５は置換基を有していてもよい炭化水素基を示す。）などで示される基が挙げられる。前記スルホン酸イオンの具体例としては、例えば、メタンスルホン酸イオン、ベンゼンスルホン酸イオン、トリフルオロメタンスルホン酸イオン、ｐ－トルエンスルホン酸イオンなどが挙げられる。
前記カルボン酸イオンとしては、例えば、Ｒ１０６ＣＯＯ－（Ｒ１０６は置換基を有していてもよい炭化水素基を示す。）などで示される。前記カルボン酸イオンの具体例としては、例えば、酢酸イオン、ぎ酸イオン、プロピオン酸イオン、グルコン酸イオン、オレイン酸イオン、しゅう酸イオン、安息香酸イオン、フタル酸イオン、トリフルオロ酢酸イオンなどが挙げられる。 Examples of the halide ions include fluoride ions, chloride ions, bromide ions, and iodide ions.
Examples of the sulfonate ion include groups represented by R 105 SO 3 — (R 105 represents a hydrocarbon group which may have a substituent). Specific examples of the sulfonate ion include methanesulfonate ion, benzenesulfonate ion, trifluoromethanesulfonate ion, p-toluenesulfonate ion, and the like.
Examples of the carboxylate ion include R 106 COO − (R 106 represents a hydrocarbon group which may have a substituent). Specific examples of the carboxylate ion include, for example, acetate ion, formate ion, propionate ion, gluconate ion, oleate ion, oxalate ion, benzoate ion, phthalate ion, trifluoroacetate ion, and the like. It is done.
前記スルホン酸イオンとしては、例えば、Ｒ１０５ＳＯ３ －（Ｒ１０５は置換基を有していてもよい炭化水素基を示す。）などで示される基が挙げられる。前記スルホン酸イオンの具体例としては、例えば、メタンスルホン酸イオン、ベンゼンスルホン酸イオン、トリフルオロメタンスルホン酸イオン、ｐ－トルエンスルホン酸イオンなどが挙げられる。
前記カルボン酸イオンとしては、例えば、Ｒ１０６ＣＯＯ－（Ｒ１０６は置換基を有していてもよい炭化水素基を示す。）などで示される。前記カルボン酸イオンの具体例としては、例えば、酢酸イオン、ぎ酸イオン、プロピオン酸イオン、グルコン酸イオン、オレイン酸イオン、しゅう酸イオン、安息香酸イオン、フタル酸イオン、トリフルオロ酢酸イオンなどが挙げられる。 Examples of the halide ions include fluoride ions, chloride ions, bromide ions, and iodide ions.
Examples of the sulfonate ion include groups represented by R 105 SO 3 — (R 105 represents a hydrocarbon group which may have a substituent). Specific examples of the sulfonate ion include methanesulfonate ion, benzenesulfonate ion, trifluoromethanesulfonate ion, p-toluenesulfonate ion, and the like.
Examples of the carboxylate ion include R 106 COO − (R 106 represents a hydrocarbon group which may have a substituent). Specific examples of the carboxylate ion include, for example, acetate ion, formate ion, propionate ion, gluconate ion, oleate ion, oxalate ion, benzoate ion, phthalate ion, trifluoroacetate ion, and the like. It is done.
ｎ１１及びｎ１２は夫々独立して自然数を示すが、好ましくは１～１０の自然数である。
N11 and n12 each independently represent a natural number, preferably a natural number of 1 to 10.
前記銅塩の具体例としては、例えば、以下の銅塩などが挙げられる。
・硝酸銅〔例えば、硝酸銅（Ｉ）、硝酸銅（ＩＩ）等〕
・亜硝酸銅〔例えば、亜硝酸銅（Ｉ）、亜硝酸銅（ＩＩ）等〕
・ハロゲン化銅〔例えば、塩化銅（Ｉ）、塩化銅（ＩＩ）、臭化銅（Ｉ）、臭化銅（ＩＩ）、フッ化銅（Ｉ）、フッ化銅（ＩＩ）、ヨウ化銅（Ｉ）、ヨウ化銅（ＩＩ）等〕
・硫酸銅〔例えば、硫酸銅（ＩＩ）等〕
・亜硫酸銅〔例えば、亜硫酸銅（ＩＩ）等〕
・スルホン酸銅〔例えば、メタンスルホン酸銅（Ｉ）、メタンスルホン酸銅（ＩＩ）、ｐ－トルエンスルホン酸銅（Ｉ）、ｐ－トルエンスルホン酸銅（ＩＩ）、トリフルオロメタンスルホン酸銅（Ｉ）、トリフルオロメタンスルホン酸銅（ＩＩ）等〕
・スルファミン酸銅〔例えば、スルファミン酸銅（ＩＩ）等〕
・炭酸銅〔例えば、炭酸銅（ＩＩ）等〕
・水酸化銅〔例えば、水酸化銅（ＩＩ）等〕
・カルボン酸銅〔例えば、酢酸銅（Ｉ）、酢酸銅（ＩＩ）、ギ酸銅（ＩＩ）、プロピオン酸銅（ＩＩ）、グルコン酸銅（ＩＩ）、オレイン酸銅（ＩＩ）、シュウ酸銅（ＩＩ）、安息香酸銅（ＩＩ）、フタル酸銅（ＩＩ）、カプリル酸銅（ＩＩ）、クエン酸銅（ＩＩ）、サリチル酸銅（ＩＩ）、酒石酸銅（ＩＩ）、ステアリン酸銅（ＩＩ）、ナフテン酸銅、乳酸銅（ＩＩ）、ラウリン酸銅（ＩＩ）等〕
・硫化銅〔例えば、硫化銅（Ｉ）、硫化銅（ＩＩ）等〕
・チオシアン酸銅〔例えば、チオシアン酸銅（Ｉ）、チオシアン酸銅（ＩＩ）等〕
・リン酸銅〔例えば、リン酸銅（ＩＩ）、ピロリン酸銅（ＩＩ）等〕
・酸化銅〔例えば、酸化銅（Ｉ）、酸化銅（ＩＩ）等〕
・過ハロゲン化酸銅〔例えば、塩素酸銅（Ｉ）、過塩素酸銅（ＩＩ）等〕
・ハロゲン化酸銅〔例えば、ヨウ素酸銅（ＩＩ）等〕
・ケイ酸銅〔例えば、ヘキサフルオロケイ酸銅等〕
・シアン化銅〔例えば、シアン化銅（Ｉ）、シアン化銅（ＩＩ）等〕
・ホウ酸銅〔例えば、ホウ酸銅、メタホウ酸銅、銅テトラフルオロボレート等〕 Specific examples of the copper salt include the following copper salts.
-Copper nitrate [eg, copper nitrate (I), copper nitrate (II), etc.]
・ Copper nitrite [for example, copper (I) nitrite, copper (II) nitrite, etc.]
· Copper halide [for example, copper (I) chloride, copper (II) chloride, copper (I) bromide, copper (II) bromide, copper fluoride (I), copper (II) fluoride, copper iodide (I), copper (II) iodide, etc.]
-Copper sulfate [eg, copper (II) sulfate]
・ Copper sulfite [eg, copper (II) sulfite]
-Copper sulfonate [for example, copper (I) methanesulfonate, copper (II) methanesulfonate, copper (I) p-toluenesulfonate, copper (II) p-toluenesulfonate, copper trifluoromethanesulfonate (I ), Copper (II) trifluoromethanesulfonate, etc.]
-Copper sulfamate [for example, copper (II) sulfamate]
・ Copper carbonate [for example, copper (II) carbonate, etc.]
・ Copper hydroxide [eg copper hydroxide (II), etc.]
-Copper carboxylate [eg, copper (I) acetate, copper (II) acetate, copper (II) formate, copper (II) propionate, copper (II) gluconate, copper (II) oleate, copper oxalate ( II), copper (II) benzoate, copper (II) phthalate, copper (II) caprylate, copper (II) citrate, copper (II) salicylate, copper (II) tartrate, copper (II) stearate, Naphthenic acid copper, copper lactate (II), lauric acid copper (II), etc.]
・ Copper sulfide [for example, copper sulfide (I), copper sulfide (II), etc.]
-Copper thiocyanate [for example, copper (I) thiocyanate, copper (II) thiocyanate, etc.]
-Copper phosphate [for example, copper (II) phosphate, copper (II) pyrophosphate, etc.]
・ Copper oxide [eg, copper oxide (I), copper oxide (II), etc.]
-Copper perhalogenate [eg, copper (I) chlorate, copper (II) perchlorate, etc.]
・ Copper halides [for example, copper (II) iodate, etc.]
・ Copper silicate (eg copper hexafluorosilicate)
-Copper cyanide [for example, copper (I) cyanide, copper (II) cyanide, etc.]
-Copper borate (for example, copper borate, copper metaborate, copper tetrafluoroborate, etc.)
・硝酸銅〔例えば、硝酸銅（Ｉ）、硝酸銅（ＩＩ）等〕
・亜硝酸銅〔例えば、亜硝酸銅（Ｉ）、亜硝酸銅（ＩＩ）等〕
・ハロゲン化銅〔例えば、塩化銅（Ｉ）、塩化銅（ＩＩ）、臭化銅（Ｉ）、臭化銅（ＩＩ）、フッ化銅（Ｉ）、フッ化銅（ＩＩ）、ヨウ化銅（Ｉ）、ヨウ化銅（ＩＩ）等〕
・硫酸銅〔例えば、硫酸銅（ＩＩ）等〕
・亜硫酸銅〔例えば、亜硫酸銅（ＩＩ）等〕
・スルホン酸銅〔例えば、メタンスルホン酸銅（Ｉ）、メタンスルホン酸銅（ＩＩ）、ｐ－トルエンスルホン酸銅（Ｉ）、ｐ－トルエンスルホン酸銅（ＩＩ）、トリフルオロメタンスルホン酸銅（Ｉ）、トリフルオロメタンスルホン酸銅（ＩＩ）等〕
・スルファミン酸銅〔例えば、スルファミン酸銅（ＩＩ）等〕
・炭酸銅〔例えば、炭酸銅（ＩＩ）等〕
・水酸化銅〔例えば、水酸化銅（ＩＩ）等〕
・カルボン酸銅〔例えば、酢酸銅（Ｉ）、酢酸銅（ＩＩ）、ギ酸銅（ＩＩ）、プロピオン酸銅（ＩＩ）、グルコン酸銅（ＩＩ）、オレイン酸銅（ＩＩ）、シュウ酸銅（ＩＩ）、安息香酸銅（ＩＩ）、フタル酸銅（ＩＩ）、カプリル酸銅（ＩＩ）、クエン酸銅（ＩＩ）、サリチル酸銅（ＩＩ）、酒石酸銅（ＩＩ）、ステアリン酸銅（ＩＩ）、ナフテン酸銅、乳酸銅（ＩＩ）、ラウリン酸銅（ＩＩ）等〕
・硫化銅〔例えば、硫化銅（Ｉ）、硫化銅（ＩＩ）等〕
・チオシアン酸銅〔例えば、チオシアン酸銅（Ｉ）、チオシアン酸銅（ＩＩ）等〕
・リン酸銅〔例えば、リン酸銅（ＩＩ）、ピロリン酸銅（ＩＩ）等〕
・酸化銅〔例えば、酸化銅（Ｉ）、酸化銅（ＩＩ）等〕
・過ハロゲン化酸銅〔例えば、塩素酸銅（Ｉ）、過塩素酸銅（ＩＩ）等〕
・ハロゲン化酸銅〔例えば、ヨウ素酸銅（ＩＩ）等〕
・ケイ酸銅〔例えば、ヘキサフルオロケイ酸銅等〕
・シアン化銅〔例えば、シアン化銅（Ｉ）、シアン化銅（ＩＩ）等〕
・ホウ酸銅〔例えば、ホウ酸銅、メタホウ酸銅、銅テトラフルオロボレート等〕 Specific examples of the copper salt include the following copper salts.
-Copper nitrate [eg, copper nitrate (I), copper nitrate (II), etc.]
・ Copper nitrite [for example, copper (I) nitrite, copper (II) nitrite, etc.]
· Copper halide [for example, copper (I) chloride, copper (II) chloride, copper (I) bromide, copper (II) bromide, copper fluoride (I), copper (II) fluoride, copper iodide (I), copper (II) iodide, etc.]
-Copper sulfate [eg, copper (II) sulfate]
・ Copper sulfite [eg, copper (II) sulfite]
-Copper sulfonate [for example, copper (I) methanesulfonate, copper (II) methanesulfonate, copper (I) p-toluenesulfonate, copper (II) p-toluenesulfonate, copper trifluoromethanesulfonate (I ), Copper (II) trifluoromethanesulfonate, etc.]
-Copper sulfamate [for example, copper (II) sulfamate]
・ Copper carbonate [for example, copper (II) carbonate, etc.]
・ Copper hydroxide [eg copper hydroxide (II), etc.]
-Copper carboxylate [eg, copper (I) acetate, copper (II) acetate, copper (II) formate, copper (II) propionate, copper (II) gluconate, copper (II) oleate, copper oxalate ( II), copper (II) benzoate, copper (II) phthalate, copper (II) caprylate, copper (II) citrate, copper (II) salicylate, copper (II) tartrate, copper (II) stearate, Naphthenic acid copper, copper lactate (II), lauric acid copper (II), etc.]
・ Copper sulfide [for example, copper sulfide (I), copper sulfide (II), etc.]
-Copper thiocyanate [for example, copper (I) thiocyanate, copper (II) thiocyanate, etc.]
-Copper phosphate [for example, copper (II) phosphate, copper (II) pyrophosphate, etc.]
・ Copper oxide [eg, copper oxide (I), copper oxide (II), etc.]
-Copper perhalogenate [eg, copper (I) chlorate, copper (II) perchlorate, etc.]
・ Copper halides [for example, copper (II) iodate, etc.]
・ Copper silicate (eg copper hexafluorosilicate)
-Copper cyanide [for example, copper (I) cyanide, copper (II) cyanide, etc.]
-Copper borate (for example, copper borate, copper metaborate, copper tetrafluoroborate, etc.)
－－その他の銅化合物－－
その他の銅化合物としては、例えば下記一般式（Ｂ－２）で表される銅化合物などが挙げられる。
［Ｃｕｎ１４Ｘ２ ｎ１５］ｎ１６ 一般式（Ｂ－２）
［式中、ｎ１５個のＸ２は同一又は異なって、置換基を有していてもよい炭化水素基、ＯＲ１０１（Ｒ１０１は置換基を有していてもよい炭化水素基を示す。）、ＮＲ１０２ ２（２個のＲ１０２は同一又は異なって、水素原子又は置換基を有していてもよい炭化水素基を示す。）、ＰＲ１０３ ２（２個のＲ１０３は同一又は異なって、置換基を有していてもよい炭化水素基を示す。）、ＳＲ１０４（Ｒ１０４は置換基を有していてもよい炭化水素基を示す。）、１，３－ジカルボニル化合物或いはそのエノラート又はヒドリドを示し、ｎ１４～ｎ１６は夫々独立して、自然数を示す。］ -Other copper compounds-
Examples of other copper compounds include copper compounds represented by the following general formula (B-2).
[Cu n14 X 2 n15] n16 general formula (B-2)
[Wherein, n15 X 2 s are the same or different and may be a hydrocarbon group which may have a substituent, OR 101 (R 101 represents a hydrocarbon group which may have a substituent)] , NR 102 2 (two R 102 are the same or different and each represents a hydrogen atom or a hydrocarbon group optionally having a substituent), PR 103 2 (two R 103 are the same or different Represents a hydrocarbon group which may have a substituent), SR 104 (R 104 represents a hydrocarbon group which may have a substituent), 1,3-dicarbonyl compound or its Enolate or hydride, and n14 to n16 each independently represents a natural number. ]
その他の銅化合物としては、例えば下記一般式（Ｂ－２）で表される銅化合物などが挙げられる。
［Ｃｕｎ１４Ｘ２ ｎ１５］ｎ１６ 一般式（Ｂ－２）
［式中、ｎ１５個のＸ２は同一又は異なって、置換基を有していてもよい炭化水素基、ＯＲ１０１（Ｒ１０１は置換基を有していてもよい炭化水素基を示す。）、ＮＲ１０２ ２（２個のＲ１０２は同一又は異なって、水素原子又は置換基を有していてもよい炭化水素基を示す。）、ＰＲ１０３ ２（２個のＲ１０３は同一又は異なって、置換基を有していてもよい炭化水素基を示す。）、ＳＲ１０４（Ｒ１０４は置換基を有していてもよい炭化水素基を示す。）、１，３－ジカルボニル化合物或いはそのエノラート又はヒドリドを示し、ｎ１４～ｎ１６は夫々独立して、自然数を示す。］ -Other copper compounds-
Examples of other copper compounds include copper compounds represented by the following general formula (B-2).
[Cu n14 X 2 n15] n16 general formula (B-2)
[Wherein, n15 X 2 s are the same or different and may be a hydrocarbon group which may have a substituent, OR 101 (R 101 represents a hydrocarbon group which may have a substituent)] , NR 102 2 (two R 102 are the same or different and each represents a hydrogen atom or a hydrocarbon group optionally having a substituent), PR 103 2 (two R 103 are the same or different Represents a hydrocarbon group which may have a substituent), SR 104 (R 104 represents a hydrocarbon group which may have a substituent), 1,3-dicarbonyl compound or its Enolate or hydride, and n14 to n16 each independently represents a natural number. ]
前記一般式（Ｂ－２）において、ｎ１４及びｎ１５は夫々独立して自然数を示すが、好ましくは１～１０の自然数である。
In the above general formula (B-2), n14 and n15 each independently represent a natural number, preferably a natural number of 1 to 10.
前記Ｘ２で示されるＯＲ１０１の具体例としては、例えば、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、ｓ－ブトキシ基、ｔｅｒｔ－ブトキシ基、フェノキシ基などが挙げられる。
前記ＮＲ１０２ ２の具体例としては、例えば、ジメチルアミノ基、ジエチルアミノ基、ジシクロヘキシルアミノ基、ジフェニルアミノ基などが挙げられる。
前記ＰＲ１０３ ２の具体例としては、例えば、ジメチルホスフィノ基、ジエチルホスフィノ基、ジ（ｔｅｒｔ－ブチル）ホスフィノ基、ジシクロヘキシルホスフィノ基、ジフェニルホスフィノ基などが挙げられる。
前記ＳＲ１０４の具体例としては、ＳＭｅ、ＳＥｔ、ＳＢｕ、ＳＰｈ、Ｓ（ＣＨ３Ｃ６Ｈ５）などが挙げられる。ここで、「Ｍｅ」はメチル基を表し、「Ｅｔ」はエチル基を表す。
前記１，３－ジカルボニル化合物或いはそのエノラートの具体例としては、例えば、２，５－ペンタンジオン（ａｃａｃ）、１，１，１－トリフルオロ－２，５－ペンタンジオン、１，１，１，３，３，３－ヘキサフルオロペンタンジオン（ｈｆａｃ）、ベンゾイルアセトン、アセト酢酸メチル、アセト酢酸エチルなどが挙げられる。 Specific examples of OR 101 represented by X 2 include, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, s-butoxy group, tert-butoxy group, phenoxy group and the like. Can be mentioned.
Examples of the NR 102 2, for example, dimethylamino group, diethylamino group, dicyclohexyl amino group, and a diphenylamino group.
Specific examples of the PR 103 2, for example, dimethyl phosphino group, diethylphosphino group, di (tert- butyl) phosphino group, dicyclohexylphosphino group, and diphenylphosphino groups.
Specific examples of the SR 104 include SMe, SEt, SBu, SPh, S (CH 3 C 6 H 5 ), and the like. Here, “Me” represents a methyl group, and “Et” represents an ethyl group.
Specific examples of the 1,3-dicarbonyl compound or enolate thereof include, for example, 2,5-pentanedione (acac), 1,1,1-trifluoro-2,5-pentanedione, 1,1,1 , 3,3,3-hexafluoropentanedione (hfac), benzoylacetone, methyl acetoacetate, ethyl acetoacetate and the like.
前記ＮＲ１０２ ２の具体例としては、例えば、ジメチルアミノ基、ジエチルアミノ基、ジシクロヘキシルアミノ基、ジフェニルアミノ基などが挙げられる。
前記ＰＲ１０３ ２の具体例としては、例えば、ジメチルホスフィノ基、ジエチルホスフィノ基、ジ（ｔｅｒｔ－ブチル）ホスフィノ基、ジシクロヘキシルホスフィノ基、ジフェニルホスフィノ基などが挙げられる。
前記ＳＲ１０４の具体例としては、ＳＭｅ、ＳＥｔ、ＳＢｕ、ＳＰｈ、Ｓ（ＣＨ３Ｃ６Ｈ５）などが挙げられる。ここで、「Ｍｅ」はメチル基を表し、「Ｅｔ」はエチル基を表す。
前記１，３－ジカルボニル化合物或いはそのエノラートの具体例としては、例えば、２，５－ペンタンジオン（ａｃａｃ）、１，１，１－トリフルオロ－２，５－ペンタンジオン、１，１，１，３，３，３－ヘキサフルオロペンタンジオン（ｈｆａｃ）、ベンゾイルアセトン、アセト酢酸メチル、アセト酢酸エチルなどが挙げられる。 Specific examples of OR 101 represented by X 2 include, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, s-butoxy group, tert-butoxy group, phenoxy group and the like. Can be mentioned.
Examples of the NR 102 2, for example, dimethylamino group, diethylamino group, dicyclohexyl amino group, and a diphenylamino group.
Specific examples of the PR 103 2, for example, dimethyl phosphino group, diethylphosphino group, di (tert- butyl) phosphino group, dicyclohexylphosphino group, and diphenylphosphino groups.
Specific examples of the SR 104 include SMe, SEt, SBu, SPh, S (CH 3 C 6 H 5 ), and the like. Here, “Me” represents a methyl group, and “Et” represents an ethyl group.
Specific examples of the 1,3-dicarbonyl compound or enolate thereof include, for example, 2,5-pentanedione (acac), 1,1,1-trifluoro-2,5-pentanedione, 1,1,1 , 3,3,3-hexafluoropentanedione (hfac), benzoylacetone, methyl acetoacetate, ethyl acetoacetate and the like.
前記一般式（Ｂ－２）で表される銅化合物の具体例としては、例えば、以下の銅化合物などが挙げられる。
・銅アルコキシド〔例えば、銅ジメトキシド、銅ジエトキシド、銅ジイソプロポキシド、銅ｔｅｒｔ－ブトキシド等〕
・銅フェノキシド〔例えば、銅フェノキシド等〕
・銅ホスフィド〔例えば、銅ジ（ｔｅｒｔ－ブチルホスフィド）、銅ジシクロヘキシルホスフィド、銅ジフェニルホスフィド等〕
・銅アミド〔例えば、銅ジシクロヘキシルアミド等〕
・銅チオレート〔例えば、銅ブタンチオレート、銅チオフェノレート等〕
・銅１，３－ジカルボニル化合物或いはそのエノラート〔例えば、銅２，４－ペンタンジオネート、銅ベンゾイルアセトネート、銅１，３－ジフェニル－１，３－プロパンジオネート、銅エチルアセトアセテート、銅トリフルオロペンタンジオネート、銅ヘキサフルオロペンタンジオネート等〕
・水素化銅
・炭化水素化銅〔例えば、メシチル銅、エチニル銅等〕
・シリル化銅〔例えば、トリメチルシリルエチニル銅等〕 Specific examples of the copper compound represented by the general formula (B-2) include the following copper compounds.
・ Copper alkoxides (eg, copper dimethoxide, copper diethoxide, copper diisopropoxide, copper tert-butoxide, etc.)
・ Copper phenoxide (for example, copper phenoxide)
・ Copper phosphides (eg, copper di (tert-butyl phosphide), copper dicyclohexyl phosphide, copper diphenyl phosphide, etc.)
・ Copper amide (for example, copper dicyclohexylamide)
・ Copper thiolate (eg, copper butane thiolate, copper thiophenolate, etc.)
・ Copper 1,3-dicarbonyl compounds or enolate thereof [eg, copper 2,4-pentanedionate, copper benzoylacetonate, copper 1,3-diphenyl-1,3-propanedionate, copper ethyl acetoacetate, copper (Trifluoropentanedionate, copper hexafluoropentanedionate, etc.)
・ Copper hydride ・ Copper hydride (eg mesityl copper, ethynyl copper, etc.)
・ Silylated copper (for example, trimethylsilylethynyl copper, etc.)
・銅アルコキシド〔例えば、銅ジメトキシド、銅ジエトキシド、銅ジイソプロポキシド、銅ｔｅｒｔ－ブトキシド等〕
・銅フェノキシド〔例えば、銅フェノキシド等〕
・銅ホスフィド〔例えば、銅ジ（ｔｅｒｔ－ブチルホスフィド）、銅ジシクロヘキシルホスフィド、銅ジフェニルホスフィド等〕
・銅アミド〔例えば、銅ジシクロヘキシルアミド等〕
・銅チオレート〔例えば、銅ブタンチオレート、銅チオフェノレート等〕
・銅１，３－ジカルボニル化合物或いはそのエノラート〔例えば、銅２，４－ペンタンジオネート、銅ベンゾイルアセトネート、銅１，３－ジフェニル－１，３－プロパンジオネート、銅エチルアセトアセテート、銅トリフルオロペンタンジオネート、銅ヘキサフルオロペンタンジオネート等〕
・水素化銅
・炭化水素化銅〔例えば、メシチル銅、エチニル銅等〕
・シリル化銅〔例えば、トリメチルシリルエチニル銅等〕 Specific examples of the copper compound represented by the general formula (B-2) include the following copper compounds.
・ Copper alkoxides (eg, copper dimethoxide, copper diethoxide, copper diisopropoxide, copper tert-butoxide, etc.)
・ Copper phenoxide (for example, copper phenoxide)
・ Copper phosphides (eg, copper di (tert-butyl phosphide), copper dicyclohexyl phosphide, copper diphenyl phosphide, etc.)
・ Copper amide (for example, copper dicyclohexylamide)
・ Copper thiolate (eg, copper butane thiolate, copper thiophenolate, etc.)
・ Copper 1,3-dicarbonyl compounds or enolate thereof [eg, copper 2,4-pentanedionate, copper benzoylacetonate, copper 1,3-diphenyl-1,3-propanedionate, copper ethyl acetoacetate, copper (Trifluoropentanedionate, copper hexafluoropentanedionate, etc.)
・ Copper hydride ・ Copper hydride (eg mesityl copper, ethynyl copper, etc.)
・ Silylated copper (for example, trimethylsilylethynyl copper, etc.)
その他の銅化合物は、また、例えば下記一般式（Ｂ－３）で表される銅化合物などが挙げられる。
［ＨＣｕＰ（Ｒ１０７）３］ｎ１７ 一般式（Ｂ－３）
（式中、３個のＲ１０７は同一又は異なって、置換基を有していてもよい炭化水素基を示し、ｎ１７は自然数を示す。） Other copper compounds include, for example, copper compounds represented by the following general formula (B-3).
[HCuP (R 107 ) 3 ] n17 general formula (B-3)
(In the formula, three R 107 s are the same or different and each represents an optionally substituted hydrocarbon group, and n17 represents a natural number.)
［ＨＣｕＰ（Ｒ１０７）３］ｎ１７ 一般式（Ｂ－３）
（式中、３個のＲ１０７は同一又は異なって、置換基を有していてもよい炭化水素基を示し、ｎ１７は自然数を示す。） Other copper compounds include, for example, copper compounds represented by the following general formula (B-3).
[HCuP (R 107 ) 3 ] n17 general formula (B-3)
(In the formula, three R 107 s are the same or different and each represents an optionally substituted hydrocarbon group, and n17 represents a natural number.)
前記一般式（Ｂ－３）で表される銅化合物の具体例としては、例えば、水素化銅（Ｉ）（トリフェニルホスフィン）ヘキサマー（Ｓｔｒｙｋｅｒ試薬）などが挙げられる。
Specific examples of the copper compound represented by the general formula (B-3) include, for example, copper (I) hydride (triphenylphosphine) hexamer (Strike reagent).
前記一般式（Ｂ－３）で表される銅化合物の具体例としては、例えば、ヒドリド（トリフェニルホスフィン）銅（Ｉ）ヘキサマーなどが挙げられる。
Specific examples of the copper compound represented by the general formula (B-3) include hydrido (triphenylphosphine) copper (I) hexamer.
前記銅塩及び前記その他の銅化合物等の銅化合物は、アルカリ金属（例えば、リチウム、ナトリウム、カリウム、ルビジウム、セシウム等）やアルカリ土類金属（例えば、マグネシウム、カルシウム、ストロンチウム、バリウム等）の塩と複塩を形成していてもよい。形成される複塩の具体例としては、例えば、ＫＣｕＦ３、Ｋ３［ＣｕＦ６］、ＣｕＣＮ・ＬｉＣｌ、Ｌｉ２ＣｕＣｌ４、Ｌｉ２ＣｕＣｌ３、ＬｉＣｕＢｒ２などが挙げられる。これら銅塩及び上記その他の銅化合物は、無水物でも水和物でもよい。
Copper compounds such as the copper salt and other copper compounds are salts of alkali metals (for example, lithium, sodium, potassium, rubidium, cesium, etc.) and alkaline earth metals (for example, magnesium, calcium, strontium, barium, etc.) And may form a double salt. Specific examples of the double salt to be formed include KCuF 3 , K 3 [CuF 6 ], CuCN · LiCl, Li 2 CuCl 4 , Li 2 CuCl 3 , LiCuBr 2 and the like. These copper salts and the other copper compounds may be anhydrous or hydrated.
これらの銅化合物は、夫々単独で用いても２種以上適宜組み合わせて用いてもよい。
また、前記銅化合物は、市販品を用いても、或いは常法や、本明細書に記載の文献等に記載の方法で適宜製造したものを用いてもよい。 These copper compounds may be used alone or in appropriate combination of two or more.
Moreover, the said copper compound may use a commercial item, or what was suitably manufactured by the method as described in the conventional method or the literature described in this specification, etc. may be used.
また、前記銅化合物は、市販品を用いても、或いは常法や、本明細書に記載の文献等に記載の方法で適宜製造したものを用いてもよい。 These copper compounds may be used alone or in appropriate combination of two or more.
Moreover, the said copper compound may use a commercial item, or what was suitably manufactured by the method as described in the conventional method or the literature described in this specification, etc. may be used.
これらの中でも、触媒活性の点から、メシチル銅（Ｉ）が好ましい。
Among these, mesityl copper (I) is preferable from the viewpoint of catalytic activity.
＜＜反応条件＞＞
前記反応工程における前記一般式（２）で表される化合物と前記一般式（３）で表される化合物との割合としては、特に制限はなく、目的に応じて適宜選択することができるが、前記一般式（３）で表される化合物に対して、前記一般式（２）で表される化合物が１．０当量～３．０当量であることが好ましい。 << Reaction conditions >>
The ratio of the compound represented by the general formula (2) and the compound represented by the general formula (3) in the reaction step is not particularly limited and may be appropriately selected depending on the purpose. The compound represented by the general formula (2) is preferably 1.0 equivalent to 3.0 equivalents relative to the compound represented by the general formula (3).
前記反応工程における前記一般式（２）で表される化合物と前記一般式（３）で表される化合物との割合としては、特に制限はなく、目的に応じて適宜選択することができるが、前記一般式（３）で表される化合物に対して、前記一般式（２）で表される化合物が１．０当量～３．０当量であることが好ましい。 << Reaction conditions >>
The ratio of the compound represented by the general formula (2) and the compound represented by the general formula (3) in the reaction step is not particularly limited and may be appropriately selected depending on the purpose. The compound represented by the general formula (2) is preferably 1.0 equivalent to 3.0 equivalents relative to the compound represented by the general formula (3).
前記反応工程において使用される溶媒としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、ＴＨＦ（テトラヒドロフラン）、ＤＭＦ（Ｎ，Ｎ－ジメチルホルムアミド）などが挙げられる。これらは、１種単独で使用してもよいし、２種以上を併用してもよい。
The solvent used in the reaction step is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include THF (tetrahydrofuran) and DMF (N, N-dimethylformamide). These may be used individually by 1 type and may use 2 or more types together.
前記反応工程における前記触媒の使用量としては、特に制限はなく、目的に応じて適宜選択することができるが、前記一般式（３）で表される化合物に対して、０．１ｍｏｌ％～１０ｍｏｌ％が好ましく、１ｍｏｌ％～８ｍｏｌ％がより好ましく、３ｍｏｌ％～６ｍｏｌ％が特に好ましい。
The amount of the catalyst used in the reaction step is not particularly limited and may be appropriately selected depending on the intended purpose. It is 0.1 mol% to 10 mol based on the compound represented by the general formula (3). %, More preferably 1 mol% to 8 mol%, particularly preferably 3 mol% to 6 mol%.
前記反応工程における反応温度としては、特に制限はなく、目的に応じて適宜選択することができるが、－５０℃～－２０℃が好ましい。穏和な条件で反応が進行するため、反応温度を制御せずに行うことができる。そのため、例えば、常温で行うことができる。前記常温としては、例えば、２０℃～３０℃などが挙げられる。
前記反応工程における反応時間としては、特に制限はなく、目的に応じて適宜選択することができるが、２４時間～１００時間が好ましく、４８時間～９６時間が好ましい。 The reaction temperature in the reaction step is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably −50 ° C. to −20 ° C. Since the reaction proceeds under mild conditions, the reaction can be performed without controlling the reaction temperature. Therefore, for example, it can be performed at room temperature. Examples of the room temperature include 20 ° C. to 30 ° C.
The reaction time in the reaction step is not particularly limited and may be appropriately selected depending on the intended purpose. It is preferably 24 hours to 100 hours, and preferably 48 hours to 96 hours.
前記反応工程における反応時間としては、特に制限はなく、目的に応じて適宜選択することができるが、２４時間～１００時間が好ましく、４８時間～９６時間が好ましい。 The reaction temperature in the reaction step is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably −50 ° C. to −20 ° C. Since the reaction proceeds under mild conditions, the reaction can be performed without controlling the reaction temperature. Therefore, for example, it can be performed at room temperature. Examples of the room temperature include 20 ° C. to 30 ° C.
The reaction time in the reaction step is not particularly limited and may be appropriately selected depending on the intended purpose. It is preferably 24 hours to 100 hours, and preferably 48 hours to 96 hours.
（構造式（１）で表される化合物の製造方法）
本発明の化合物の製造方法（その２）は、下記構造式（１）で表される化合物（ＮＩＴＤ６０９）の製造方法であって、反応工程を少なくとも含み、更に必要に応じて、その他の工程を含む。
(Method for producing compound represented by structural formula (1))
The method for producing a compound of the present invention (Part 2) is a method for producing a compound (NITD609) represented by the following structural formula (1), which includes at least a reaction step, and further includes other steps as necessary. Including.
本発明の化合物の製造方法（その２）は、下記構造式（１）で表される化合物（ＮＩＴＤ６０９）の製造方法であって、反応工程を少なくとも含み、更に必要に応じて、その他の工程を含む。
The method for producing a compound of the present invention (Part 2) is a method for producing a compound (NITD609) represented by the following structural formula (1), which includes at least a reaction step, and further includes other steps as necessary. Including.
＜反応工程＞
前記反応工程は、前記一般式（１）で表される化合物の製造方法における前記反応工程と同じであり、好ましい態様も同じである。 <Reaction process>
The said reaction process is the same as the said reaction process in the manufacturing method of the compound represented by the said General formula (1), A preferable aspect is also the same.
前記反応工程は、前記一般式（１）で表される化合物の製造方法における前記反応工程と同じであり、好ましい態様も同じである。 <Reaction process>
The said reaction process is the same as the said reaction process in the manufacturing method of the compound represented by the said General formula (1), A preferable aspect is also the same.
＜その他の工程＞
前記その他の工程としては、前記一般式（１）で表される化合物を用いて、前記構造式（１）で表される化合物を得る工程であれば、特に制限はなく、目的に応じて適宜選択することができ、例えば、前記Ｓｃｈｅｍｅ ２に従って、合成を行う方法が挙げられる。
具体的には、例えば、以下の一連の反応が挙げられる。係る一連の反応は、以下の実施例においても詳述されている。係る一連の反応における個々の反応は、下記スキーム及び後述する実施例に接した当業者であれば、試行錯誤を要せずに行うことができる。
<Other processes>
The other step is not particularly limited as long as it is a step of obtaining the compound represented by the structural formula (1) using the compound represented by the general formula (1), and is appropriately selected depending on the purpose. For example, a method of synthesizing according to the scheme 2 can be mentioned.
Specifically, for example, the following series of reactions can be mentioned. Such a series of reactions is also described in detail in the following examples. Individual reactions in such a series of reactions can be carried out without trial and error by those skilled in the art who have contacted the following scheme and the examples described below.
前記その他の工程としては、前記一般式（１）で表される化合物を用いて、前記構造式（１）で表される化合物を得る工程であれば、特に制限はなく、目的に応じて適宜選択することができ、例えば、前記Ｓｃｈｅｍｅ ２に従って、合成を行う方法が挙げられる。
具体的には、例えば、以下の一連の反応が挙げられる。係る一連の反応は、以下の実施例においても詳述されている。係る一連の反応における個々の反応は、下記スキーム及び後述する実施例に接した当業者であれば、試行錯誤を要せずに行うことができる。
The other step is not particularly limited as long as it is a step of obtaining the compound represented by the structural formula (1) using the compound represented by the general formula (1), and is appropriately selected depending on the purpose. For example, a method of synthesizing according to the scheme 2 can be mentioned.
Specifically, for example, the following series of reactions can be mentioned. Such a series of reactions is also described in detail in the following examples. Individual reactions in such a series of reactions can be carried out without trial and error by those skilled in the art who have contacted the following scheme and the examples described below.
以下に本発明の実施例を挙げて本発明を具体的に説明するが、本発明はこれらの実施例に何ら限定されるものではない。
なお、以下の実施例において、
「Ｂｏｃ」は、「ｔｅｒｔ－ブトキシカルボニル基」を表す。
「Ａｃ」は、「アセチル基」を表す。
「Ｅｔ」は、「エチル基」を表す。
「ＤＭＦ」は、「Ｎ，Ｎ－ジメチルホルムアミド」を表す。
「ＰＭＢ」は、「ｐ－メトキシベンジル基」を表す。
「Ｐｈ」は、「フェニル基」を表す。
「ＴＨＦ」は、「テトラヒドロフラン」を表す。
「ＴＦＡ」は、「トリフルオロ酢酸」を表す。
「Ｃｂｚ」は、「ベンジルオキシカルボニル基」を表す。
「Ｍｅ」は、「メチル基」を表す。
「Ｔｆ」は、「トリフルオロメチルスルホニル基」を表す。
「ＤＣＥ」は、「ジクロロエタン」を表す。 EXAMPLES The present invention will be specifically described below with reference to examples of the present invention, but the present invention is not limited to these examples.
In the following examples,
“Boc” represents a “tert-butoxycarbonyl group”.
“Ac” represents an “acetyl group”.
“Et” represents “ethyl group”.
“DMF” represents “N, N-dimethylformamide”.
“PMB” represents “p-methoxybenzyl group”.
“Ph” represents a “phenyl group”.
“THF” represents “tetrahydrofuran”.
“TFA” represents “trifluoroacetic acid”.
“Cbz” represents “benzyloxycarbonyl group”.
“Me” represents “methyl group”.
“Tf” represents a “trifluoromethylsulfonyl group”.
“DCE” represents “dichloroethane”.
なお、以下の実施例において、
「Ｂｏｃ」は、「ｔｅｒｔ－ブトキシカルボニル基」を表す。
「Ａｃ」は、「アセチル基」を表す。
「Ｅｔ」は、「エチル基」を表す。
「ＤＭＦ」は、「Ｎ，Ｎ－ジメチルホルムアミド」を表す。
「ＰＭＢ」は、「ｐ－メトキシベンジル基」を表す。
「Ｐｈ」は、「フェニル基」を表す。
「ＴＨＦ」は、「テトラヒドロフラン」を表す。
「ＴＦＡ」は、「トリフルオロ酢酸」を表す。
「Ｃｂｚ」は、「ベンジルオキシカルボニル基」を表す。
「Ｍｅ」は、「メチル基」を表す。
「Ｔｆ」は、「トリフルオロメチルスルホニル基」を表す。
「ＤＣＥ」は、「ジクロロエタン」を表す。 EXAMPLES The present invention will be specifically described below with reference to examples of the present invention, but the present invention is not limited to these examples.
In the following examples,
“Boc” represents a “tert-butoxycarbonyl group”.
“Ac” represents an “acetyl group”.
“Et” represents “ethyl group”.
“DMF” represents “N, N-dimethylformamide”.
“PMB” represents “p-methoxybenzyl group”.
“Ph” represents a “phenyl group”.
“THF” represents “tetrahydrofuran”.
“TFA” represents “trifluoroacetic acid”.
“Cbz” represents “benzyloxycarbonyl group”.
“Me” represents “methyl group”.
“Tf” represents a “trifluoromethylsulfonyl group”.
“DCE” represents “dichloroethane”.
（合成例１）
以下のＳｃｈｅｍｅ ４に従って、合成を行った。
(Synthesis Example 1)
Synthesis was performed according to Scheme 4 below.
以下のＳｃｈｅｍｅ ４に従って、合成を行った。
Synthesis was performed according to Scheme 4 below.
５－Ｃｈｌｏｒｏ－２－ｅｔｈｙｎｙｌ－４－ｆｌｕｏｒｏａｎｉｌｉｎｅ（３４．０ｍｇ， ０．２００５ｍｍｏｌ）に室温でＢｏｃ２Ｏ（５２．５ｍｇ， ０．２４０６ｍｍｏｌ）を加え８０℃で１８時間撹拌したのち、Ｂｏｃ２Ｏ（２６．３ｍｇ， ０．１２０５ｍｍｏｌ）を加えさらに８時間撹拌した。さらにＢｏｃ２Ｏ（２６．３ｍｇ， ０．１２０５ｍｍｏｌ）を加え１７時間撹拌したのちに室温まで冷却し、反応混合物をシリカゲルカラムクロマトグラフィ〔ＡｃＯＥｔ／Ｈｅｘａｎｅ＝１／３９（体積比）〕にて精製しｔｅｒｔ－Ｂｕｔｙｌ （５－ｃｈｌｏｒｏ－２－ｅｔｈｙｎｙｌ－４－ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃａｒｂａｍａｔｅ（４９．９ｍｇ，収率９２％）を得た。
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３）： δ ８．２９（ｄ， Ｊ＝６．８ Ｈｚ， １Ｈ）， ７．１６（ｄ， Ｊ＝８．８ Ｈｚ， １Ｈ）， ７．１８－７．０４（ｂｒ， １Ｈ）， ３．５２（ｓ， ３Ｈ）， １．５１ ｐｐｍ（ｓ， Ｈ）． Boc 2 O (52.5 mg, 0.2406 mmol) was added to 5-Chloro-2-ethyl-4-fluoroaniline (34.0 mg, 0.2005 mmol) at room temperature, and the mixture was stirred at 80 ° C. for 18 hours, and then Boc 2 O ( 26.3 mg, 0.1205 mmol) was added, and the mixture was further stirred for 8 hours. Further, Boc 2 O (26.3 mg, 0.1205 mmol) was added, and the mixture was stirred for 17 hours and then cooled to room temperature. The reaction mixture was purified by silica gel column chromatography [AcOEt / Hexane = 1/39 (volume ratio)] and tert. -Butyl (5-chloro-2-ethyl-4-fluorophenyl) carbamate (49.9 mg, 92% yield) was obtained.
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ): δ 8.29 (d, J = 6.8 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.18-7. 04 (br, 1H), 3.52 (s, 3H), 1.51 ppm (s, H).
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３）： δ ８．２９（ｄ， Ｊ＝６．８ Ｈｚ， １Ｈ）， ７．１６（ｄ， Ｊ＝８．８ Ｈｚ， １Ｈ）， ７．１８－７．０４（ｂｒ， １Ｈ）， ３．５２（ｓ， ３Ｈ）， １．５１ ｐｐｍ（ｓ， Ｈ）． Boc 2 O (52.5 mg, 0.2406 mmol) was added to 5-Chloro-2-ethyl-4-fluoroaniline (34.0 mg, 0.2005 mmol) at room temperature, and the mixture was stirred at 80 ° C. for 18 hours, and then Boc 2 O ( 26.3 mg, 0.1205 mmol) was added, and the mixture was further stirred for 8 hours. Further, Boc 2 O (26.3 mg, 0.1205 mmol) was added, and the mixture was stirred for 17 hours and then cooled to room temperature. The reaction mixture was purified by silica gel column chromatography [AcOEt / Hexane = 1/39 (volume ratio)] and tert. -Butyl (5-chloro-2-ethyl-4-fluorophenyl) carbamate (49.9 mg, 92% yield) was obtained.
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ): δ 8.29 (d, J = 6.8 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.18-7. 04 (br, 1H), 3.52 (s, 3H), 1.51 ppm (s, H).
（合成例２）
以下のＳｃｈｅｍｅ ５に従って、合成を行った。
(Synthesis Example 2)
Synthesis was performed according to Scheme 5 below.
以下のＳｃｈｅｍｅ ５に従って、合成を行った。
Synthesis was performed according to Scheme 5 below.
市販の５－Ｃｈｌｏｒｏｉｓａｔｉｎ（９．０８ｇ， ５０．００ｍｍｏｌ）をＤＭＦ（２５ｍｌ）に溶解し、室温でＫ２ＣＯ３（８．９８ｇ， ６５．００ｍｍｏｌ）、ＫＩ（８３．０ｍｇ， ０．５００ｍｍｏｌ）、及びＰＭＢＣｌ（８．１４ｍｌ， ６０．００ｍｍｏｌ）を加え４．５時間撹拌した。５０％ ＮａＣｌａｑ．（３００ｍｌ）、及び１．２Ｍ ＨＣｌａｑ．（１００ｍｌ）を加え反応を停止後、ＡｃＯＥｔ（１００ｍｌ）で３回抽出し、有機層をｓａｔ．ＮａＨＣＯ３ａｑ．で１回、及び飽和食塩水で１回洗浄した。有機層をＮａ２ＳＯ４で脱水後、溶媒を留去した。粗生成物をＣＨ２Ｃｌ２／Ｈｅｘａｎｅで再結晶し、５－Ｃｈｌｏｒｏ－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）ｉｎｄｏｌｉｎｅ－２，３－ｄｉｏｎｅ（１４．８０ｇ，収率９８％）を得た。
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ７．５４（ｄ， Ｊ＝２．４ Ｈｚ， １Ｈ）， ７．４２（ｄｄ， Ｊ＝８．４， ２．４ Ｈｚ， １Ｈ）， ７．２２（ｄ， Ｊ＝８．８ Ｈｚ， ２Ｈ）， ６．８５（ｄ， Ｊ＝８．４ Ｈｚ， ２Ｈ）， ６．７２（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ４．８４（ｓ， ２Ｈ）， ３．７７ ｐｐｍ（ｓ， ３Ｈ）． Commercially available 5-Chloroisatin (9.08 g, 50.00 mmol) was dissolved in DMF (25 ml), and K 2 CO 3 (8.98 g, 65.00 mmol), KI (83.0 mg, 0.500 mmol), And PMBCl (8.14 ml, 60.00 mmol) were added and stirred for 4.5 hours. 50% NaClaq. (300 ml), and 1.2 M HCl aq. (100 ml) was added to stop the reaction, followed by extraction with AcOEt (100 ml) three times, and the organic layer was washed with sat. NaHCO 3 aq. And once with saturated saline. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The crude product was recrystallized with CH 2 Cl 2 / Hexane to obtain 5-Chloro-1- (4-methoxybenzoyl) indolin-2,3-dione (14.80 g, yield 98%).
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (d, J = 2.4 Hz, 1H), 7.42 (dd, J = 8.4, 2.4 Hz, 1H), 7.22 (D, J = 8.8 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 1H), 4.84 (s , 2H), 3.77 ppm (s, 3H).
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ７．５４（ｄ， Ｊ＝２．４ Ｈｚ， １Ｈ）， ７．４２（ｄｄ， Ｊ＝８．４， ２．４ Ｈｚ， １Ｈ）， ７．２２（ｄ， Ｊ＝８．８ Ｈｚ， ２Ｈ）， ６．８５（ｄ， Ｊ＝８．４ Ｈｚ， ２Ｈ）， ６．７２（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ４．８４（ｓ， ２Ｈ）， ３．７７ ｐｐｍ（ｓ， ３Ｈ）． Commercially available 5-Chloroisatin (9.08 g, 50.00 mmol) was dissolved in DMF (25 ml), and K 2 CO 3 (8.98 g, 65.00 mmol), KI (83.0 mg, 0.500 mmol), And PMBCl (8.14 ml, 60.00 mmol) were added and stirred for 4.5 hours. 50% NaClaq. (300 ml), and 1.2 M HCl aq. (100 ml) was added to stop the reaction, followed by extraction with AcOEt (100 ml) three times, and the organic layer was washed with sat. NaHCO 3 aq. And once with saturated saline. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The crude product was recrystallized with CH 2 Cl 2 / Hexane to obtain 5-Chloro-1- (4-methoxybenzoyl) indolin-2,3-dione (14.80 g, yield 98%).
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (d, J = 2.4 Hz, 1H), 7.42 (dd, J = 8.4, 2.4 Hz, 1H), 7.22 (D, J = 8.8 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 1H), 4.84 (s , 2H), 3.77 ppm (s, 3H).
（合成例３）
以下のＳｃｈｅｍｅ ６に従って、合成を行った。
(Synthesis Example 3)
Synthesis was performed according to Scheme 6 below.
以下のＳｃｈｅｍｅ ６に従って、合成を行った。
Synthesis was performed according to Scheme 6 below.
５－Ｃｈｌｏｒｏ－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）ｉｎｄｏｌｉｎｅ－２，３－ｄｉｏｎｅ（６０３．４ｍｇ， ２．０００ｍｍｏｌ）をＣＨ２Ｃｌ２（２０ｍｌ）に溶解し、－７８℃にてＥｔ３Ｎ（１．３９ｍｌ， １０．００ｍｍｏｌ）、及びＴｉＣｌ４（１．０Ｍ ｓｏｌｕｔｉｏｎ ｉｎ ＣＨ２Ｃｌ２， ２．４０ｍｌ， ２．４００ｍｍｏｌ）を加え－４０℃で１５分撹拌したのち、Ｐｈ２Ｐ（＝Ｓ）ＮＨ２（４９０ｍｇ， ２．１００ｍｍｏｌ）を加え２６時間撹拌した。ｓａｔ．ＮＨ３ ｉｎ ＣＨ２Ｃｌ２（５．０ｍｌ）を加え反応を停止後、析出物をＣｅｌｉｔｅ ｐａｄにて分離した。ろ液を濃縮後、粗生成物をＴＨＦ／Ｈｅｘａｎｅで再結晶し、（Ｚ）－Ｎ－（５－Ｃｈｌｏｒｏ－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌｉｄｅｎｅ）－Ｐ，Ｐ－ｄｉｐｈｅｎｙｌｐｈｏｓｐｈｉｎｏｔｈｉｏｉｃ ａｍｉｄｅ（６９５．９ｍｇ， 収率６７％）を得た。
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ８．１２－８．０２（ｍ， ５Ｈ）， ７．４８－７．４０（ｍ， ６Ｈ）， ７．２６（ｄｄ， Ｊ＝８．４， ２．０ Ｈｚ， １Ｈ）， ７．１７（ｄ， Ｊ＝８．８ Ｈｚ， ２Ｈ）， ６．８２（ｄｔ， Ｊ＝６．４， ２．０ Ｈｚ， ２Ｈ）， ６．６０（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ４．７８（ｓ， ２Ｈ）， ３．７５ ｐｐｍ（ｓ， ３Ｈ）． 5-Chloro-1- (4-methoxybenzyl) indolin-2,3-dione (603.4 mg, 2.000 mmol) was dissolved in CH 2 Cl 2 (20 ml), and Et 3 N (1. 39 ml, 10.00 mmol) and TiCl 4 (1.0 M solution in CH 2 Cl 2 , 2.40 ml, 2.400 mmol) were added, and the mixture was stirred at −40 ° C. for 15 minutes, and then Ph 2 P (═S) NH 2 (490 mg, 2.100 mmol) was added and stirred for 26 hours. sat. NH 3 in CH 2 Cl 2 (5.0 ml) was added to stop the reaction, and the precipitate was separated by Celite pad. After concentrating the filtrate, the crude product was recrystallized with THF / Hexane, and (Z) -N- (5-Chloro-1- (4-methoxybenzoyl) -2-oxoindolin-3-ylidene) -P, P- A diphenylphosphinothioic amide (695.9 mg, 67% yield) was obtained.
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ) δ 8.12-8.02 (m, 5H), 7.48-7.40 (m, 6H), 7.26 (dd, J = 8.4, 2 0.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.82 (dt, J = 6.4, 2.0 Hz, 2H), 6.60 (d, J = 8.4 Hz, 1H), 4.78 (s, 2H), 3.75 ppm (s, 3H).
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ８．１２－８．０２（ｍ， ５Ｈ）， ７．４８－７．４０（ｍ， ６Ｈ）， ７．２６（ｄｄ， Ｊ＝８．４， ２．０ Ｈｚ， １Ｈ）， ７．１７（ｄ， Ｊ＝８．８ Ｈｚ， ２Ｈ）， ６．８２（ｄｔ， Ｊ＝６．４， ２．０ Ｈｚ， ２Ｈ）， ６．６０（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ４．７８（ｓ， ２Ｈ）， ３．７５ ｐｐｍ（ｓ， ３Ｈ）． 5-Chloro-1- (4-methoxybenzyl) indolin-2,3-dione (603.4 mg, 2.000 mmol) was dissolved in CH 2 Cl 2 (20 ml), and Et 3 N (1. 39 ml, 10.00 mmol) and TiCl 4 (1.0 M solution in CH 2 Cl 2 , 2.40 ml, 2.400 mmol) were added, and the mixture was stirred at −40 ° C. for 15 minutes, and then Ph 2 P (═S) NH 2 (490 mg, 2.100 mmol) was added and stirred for 26 hours. sat. NH 3 in CH 2 Cl 2 (5.0 ml) was added to stop the reaction, and the precipitate was separated by Celite pad. After concentrating the filtrate, the crude product was recrystallized with THF / Hexane, and (Z) -N- (5-Chloro-1- (4-methoxybenzoyl) -2-oxoindolin-3-ylidene) -P, P- A diphenylphosphinothioic amide (695.9 mg, 67% yield) was obtained.
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ) δ 8.12-8.02 (m, 5H), 7.48-7.40 (m, 6H), 7.26 (dd, J = 8.4, 2 0.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 6.82 (dt, J = 6.4, 2.0 Hz, 2H), 6.60 (d, J = 8.4 Hz, 1H), 4.78 (s, 2H), 3.75 ppm (s, 3H).
（実施例１）
以下のＳｃｈｅｍｅ ７に従って、合成を行った。
Example 1
Synthesis was performed according to Scheme 7 below.
以下のＳｃｈｅｍｅ ７に従って、合成を行った。
Synthesis was performed according to Scheme 7 below.
（Ｒ，Ｒ）－Ｐｈ－ＢＰＥ（１５２ｍｇ， ０．３００ｍｍｏｌ）、及びｍｅｓｉｔｙｌｃｏｐｐｅｒ（５７．７ｍｇ， ０．３００ｍｍｏｌ）をＡｒ雰囲気下、室温にてＤＭＦ（６０ｍｌ）に溶解し、１５分撹拌したのち、ｔｅｒｔ－Ｂｕｔｙｌ－（５－ｃｈｌｏｒｏ－２－ｅｔｈｙｎｙｌ－４－ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃａｒｂａｍａｔｅ（１．９４ｇ， ７．２００ｍｍｏｌ）を加え１０分撹拌した。－３０℃に冷却後、（Ｚ）－Ｎ－（５－Ｃｈｌｏｒｏ－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌｉｄｅｎｅ）－Ｐ，Ｐ－ｄｉｐｈｅｎｙｌｐｈｏｓｐｈｉｎｏｔｈｉｏｉｃ ａｍｉｄｅ（３．１０ｇ， ６．０００ｍｍｏｌ）を加え２４時間撹拌した。１．２Ｍ ＨＣｌａｑ．（１０ｍｌ）を加え反応を停止後、ＡｃＯＥｔ（５０ｍｌ）で３回抽出し、有機層をｓａｔ．ＮａＨＣＯ３ａｑ．で１回、５０％食塩水で１回、及び飽和食塩水で１回洗浄した。有機層をＮａ２ＳＯ４で脱水後、溶媒を留去した。粗生成物をシリカゲルカラムクロマトグラフィ〔ＴＨＦ／Ｈｅｘａｎｅ＝１／３（体積比）〕で精製し、ｔｅｒｔ－Ｂｕｔｙｌ （Ｓ）－（５－ｃｈｌｏｒｏ－２－（（５－ｃｈｌｏｒｏ－３－（（ｄｉｐｈｅｎｙｌｐｈｏｓｐｈｏｒｏｔｈｉｏｙｌ）ａｍｉｎｏ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）ｅｔｈｙｎｙｌ）－４－ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃａｒｂａｍａｔｅ（４．５６ｇ， 収率９７％， ９６％ｅｅ）を得た。
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ８．２３（ｄ， Ｊ＝６．８ Ｈｚ， １Ｈ）， ８．１０（ｄｄｄ， Ｊ＝１４．０， ８．０， １．６ Ｈｚ， ２Ｈ）， ７．８４（ｄ， Ｊ＝２．０ Ｈｚ， １Ｈ）， ７．８０（ｄｄｄ， Ｊ＝１３．６， ７．２， １．２ Ｈｚ， ２Ｈ）， ７．６７（ｓ， １Ｈ）， ７．４８－７．３８（ｍ， ３Ｈ）， ７．３５（ｔｄ， Ｊ＝８．０， ２．０ Ｈｚ， １Ｈ）， ７．２８－７．２２（ｍ， ３Ｈ）， ７．０１（ｄｄ， Ｊ＝８．４， ２．０ Ｈｚ， １Ｈ）， ６．９０（ｄ， Ｊ＝８．８ Ｈｚ， ２Ｈ）， ６．８６（ｄｔ， Ｊ＝８．８， ２．０ Ｈｚ， ２Ｈ）， ６．５６（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ４．９１ （ｄ， Ｊ＝１５．６ Ｈｚ， １Ｈ）， ４．８２（ｄ， Ｊ＝１５．６ Ｈｚ， １Ｈ）， ３．７６（ｓ， ３Ｈ）， ３．６１（ｄ， Ｊ＝４．４ Ｈｚ， １Ｈ）， １．５６ ｐｐｍ（ｓ， ９Ｈ）．
得られた化合物の旋光度測定結果を以下に示す。
［α］Ｄ ２３ ９１．１ （ｃ ０．９９， ＣＨＣｌ３）．
得られた化合物のキラルＨＰＬＣ測定結果を以下に示す。
ＨＰＬＣ ａｎａｌｙｓｉｓ （ＣＨＩＲＡＬＰＡＫ ＩＡ （φ ＝ ０．４６ ｃｍ ｘ ２５ ｃｍ）， ｎ－ｈｅｘａｎｅ／２－ｐｒｏｐａｎｏｌ ＝ ９０／１０， ｆｌｏｗ ｒａｔｅ ＝ １．０ ｍＬ／ｍｉｎ， ｄｅｔｅｃｔｉｏｎ ａｔ ２５４ ｎｍ， ｔＲ ＝ １４．３ ｍｉｎ （ｍｉｎｏｒ）， ２２．９ ｍｉｎ （ｍａｊｏｒ）． (R, R) -Ph-BPE (152 mg, 0.300 mmol) and messylcopper (57.7 mg, 0.300 mmol) were dissolved in DMF (60 ml) at room temperature under an Ar atmosphere and stirred for 15 minutes. tert-Butyl- (5-chloro-2-ethyl-4-fluorophenyl) carbamate (1.94 g, 7.200 mmol) was added and stirred for 10 minutes. After cooling to −30 ° C., (Z) -N- (5-Chloro-1- (4-methoxybenzoyl) -2-oxoindolin-3-ylidene) -P, P-diphenylphosphinothioamide (3.10 g, 6.000 mmol) And stirred for 24 hours. 1.2M HClaq. (10 ml) was added to stop the reaction, followed by extraction three times with AcOEt (50 ml), and the organic layer was washed with sat. NaHCO 3 aq. And once with 50% saline and once with saturated saline. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The crude product was purified by silica gel column chromatography [THF / Hexane = 1/3 (volume ratio)] and tert-Butyl (S)-(5-chloro-2-((5-chloro-3-thio ((diphenylphosphothiothiol)). amino) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) ethyl) -4-fluorophenyl) carbamate (4.56 g, yield 97%, 96% ee).
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (d, J = 6.8 Hz, 1H), 8.10 (ddd, J = 14.0, 8.0, 1.6 Hz, 2H) 7.84 (d, J = 2.0 Hz, 1H), 7.80 (ddd, J = 13.6, 7.2, 1.2 Hz, 2H), 7.67 (s, 1H), 7.48-7.38 (m, 3H), 7.35 (td, J = 8.0, 2.0 Hz, 1H), 7.28-7.22 (m, 3H), 7.01 ( dd, J = 8.4, 2.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.86 (dt, J = 8.8, 2.0 Hz, 2H) ), 6.56 (d, J = 8.4 Hz, 1H), 4.91 (d, J = 15.6 Hz, 1H), 4.82 (d, J = 15.6 Hz, 1H), .76 (s, 3H), 3.61 (d, J = 4.4 Hz, 1H), 1.56 ppm (s, 9H).
The optical rotation measurement result of the obtained compound is shown below.
[Α] D 23 91.1 (c 0.99, CHCl 3 ).
The results of chiral HPLC measurement of the obtained compound are shown below.
HPLC analysis (CHIRALPAK IA (φ = 0.46 cm × 25 cm), n-hexane / 2-propanol = 90/10, flow rate = 1.0 mL / min, detection at 254 nm, t R = 14.3. min (minor), 22.9 min (major).
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ８．２３（ｄ， Ｊ＝６．８ Ｈｚ， １Ｈ）， ８．１０（ｄｄｄ， Ｊ＝１４．０， ８．０， １．６ Ｈｚ， ２Ｈ）， ７．８４（ｄ， Ｊ＝２．０ Ｈｚ， １Ｈ）， ７．８０（ｄｄｄ， Ｊ＝１３．６， ７．２， １．２ Ｈｚ， ２Ｈ）， ７．６７（ｓ， １Ｈ）， ７．４８－７．３８（ｍ， ３Ｈ）， ７．３５（ｔｄ， Ｊ＝８．０， ２．０ Ｈｚ， １Ｈ）， ７．２８－７．２２（ｍ， ３Ｈ）， ７．０１（ｄｄ， Ｊ＝８．４， ２．０ Ｈｚ， １Ｈ）， ６．９０（ｄ， Ｊ＝８．８ Ｈｚ， ２Ｈ）， ６．８６（ｄｔ， Ｊ＝８．８， ２．０ Ｈｚ， ２Ｈ）， ６．５６（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ４．９１ （ｄ， Ｊ＝１５．６ Ｈｚ， １Ｈ）， ４．８２（ｄ， Ｊ＝１５．６ Ｈｚ， １Ｈ）， ３．７６（ｓ， ３Ｈ）， ３．６１（ｄ， Ｊ＝４．４ Ｈｚ， １Ｈ）， １．５６ ｐｐｍ（ｓ， ９Ｈ）．
得られた化合物の旋光度測定結果を以下に示す。
［α］Ｄ ２３ ９１．１ （ｃ ０．９９， ＣＨＣｌ３）．
得られた化合物のキラルＨＰＬＣ測定結果を以下に示す。
ＨＰＬＣ ａｎａｌｙｓｉｓ （ＣＨＩＲＡＬＰＡＫ ＩＡ （φ ＝ ０．４６ ｃｍ ｘ ２５ ｃｍ）， ｎ－ｈｅｘａｎｅ／２－ｐｒｏｐａｎｏｌ ＝ ９０／１０， ｆｌｏｗ ｒａｔｅ ＝ １．０ ｍＬ／ｍｉｎ， ｄｅｔｅｃｔｉｏｎ ａｔ ２５４ ｎｍ， ｔＲ ＝ １４．３ ｍｉｎ （ｍｉｎｏｒ）， ２２．９ ｍｉｎ （ｍａｊｏｒ）． (R, R) -Ph-BPE (152 mg, 0.300 mmol) and messylcopper (57.7 mg, 0.300 mmol) were dissolved in DMF (60 ml) at room temperature under an Ar atmosphere and stirred for 15 minutes. tert-Butyl- (5-chloro-2-ethyl-4-fluorophenyl) carbamate (1.94 g, 7.200 mmol) was added and stirred for 10 minutes. After cooling to −30 ° C., (Z) -N- (5-Chloro-1- (4-methoxybenzoyl) -2-oxoindolin-3-ylidene) -P, P-diphenylphosphinothioamide (3.10 g, 6.000 mmol) And stirred for 24 hours. 1.2M HClaq. (10 ml) was added to stop the reaction, followed by extraction three times with AcOEt (50 ml), and the organic layer was washed with sat. NaHCO 3 aq. And once with 50% saline and once with saturated saline. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The crude product was purified by silica gel column chromatography [THF / Hexane = 1/3 (volume ratio)] and tert-Butyl (S)-(5-chloro-2-((5-chloro-3-thio ((diphenylphosphothiothiol)). amino) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) ethyl) -4-fluorophenyl) carbamate (4.56 g, yield 97%, 96% ee).
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (d, J = 6.8 Hz, 1H), 8.10 (ddd, J = 14.0, 8.0, 1.6 Hz, 2H) 7.84 (d, J = 2.0 Hz, 1H), 7.80 (ddd, J = 13.6, 7.2, 1.2 Hz, 2H), 7.67 (s, 1H), 7.48-7.38 (m, 3H), 7.35 (td, J = 8.0, 2.0 Hz, 1H), 7.28-7.22 (m, 3H), 7.01 ( dd, J = 8.4, 2.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.86 (dt, J = 8.8, 2.0 Hz, 2H) ), 6.56 (d, J = 8.4 Hz, 1H), 4.91 (d, J = 15.6 Hz, 1H), 4.82 (d, J = 15.6 Hz, 1H), .76 (s, 3H), 3.61 (d, J = 4.4 Hz, 1H), 1.56 ppm (s, 9H).
The optical rotation measurement result of the obtained compound is shown below.
[Α] D 23 91.1 (c 0.99, CHCl 3 ).
The results of chiral HPLC measurement of the obtained compound are shown below.
HPLC analysis (CHIRALPAK IA (φ = 0.46 cm × 25 cm), n-hexane / 2-propanol = 90/10, flow rate = 1.0 mL / min, detection at 254 nm, t R = 14.3. min (minor), 22.9 min (major).
（実施例２）
＜Ｓｃｈｅｍｅ ８＞
以下のＳｃｈｅｍｅ ８に従って、合成を行った。
(Example 2)
<Scheme 8>
Synthesis was performed according to Scheme 8 below.
＜Ｓｃｈｅｍｅ ８＞
以下のＳｃｈｅｍｅ ８に従って、合成を行った。
<Scheme 8>
Synthesis was performed according to Scheme 8 below.
ｔｅｒｔ－Ｂｕｔｙｌ （Ｓ）－（５－ｃｈｌｏｒｏ－２－（（５－ｃｈｌｏｒｏ－３－（（ｄｉｐｈｅｎｙｌｐｈｏｓｐｈｏｒｏｔｈｉｏｙｌ）ａｍｉｎｏ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）ｅｔｈｙｎｙｌ）－４－ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃａｒｂａｍａｔｅ（４．５６ｇ， ５．７９９ｍｍｏｌ）をＣＨ２Ｃｌ２（４６ｍｌ）に溶解し、Ａｒ雰囲気下－１５℃にてＴＦＡ（１２ｍｌ）を加えたのち、－１０℃にて９時間撹拌した。－７８℃に冷却後、Ｅｔ３Ｎ（２５．３ｍｌ）、５０％食塩水（８０ｍｌ）、及びＣＨ２Ｃｌ２（５０ｍｌ）を順次加え反応を停止後、ＣＨ２Ｃｌ２（５０ｍｌ）で３回抽出し、有機層をｓａｔ．ＮａＨＣＯ３ａｑ．で１回、１．２Ｍ ＨＣｌａｑ．で１回、ｓａｔ．ＮａＨＣＯ３ａｑ．で１回、及び飽和食塩水で１回洗浄した。有機層をＮａ２ＳＯ４で脱水後、溶媒を留去した。粗生成物をシリカゲルカラムクロマトグラフィ〔ＴＨＦ／Ｈｅｘａｎｅ＝１／３～１／２．５（体積比）〕で精製し、（Ｓ）－Ｎ－（３－（（２－Ａｍｉｎｏ－４－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏｐｈｅｎｙｌ）ｅｔｈｙｎｙｌ）－５－ｃｈｌｏｒｏ－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）－Ｐ，Ｐ－ｄｉｐｈｅｎｙｌｐｈｏｓｐｈｉｎｏｔｈｉｏｉｃ ａｍｉｄｅ（２．６１ｇ， 収率６６％）を得た。
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ８．０６（ｄｄｄ， Ｊ＝１４．０， ８．４， １．６ Ｈｚ， ２Ｈ）， ７．７８（ｄｄｄ， Ｊ＝１３．６， ８．４， １．２ Ｈｚ， ２Ｈ）， ７．６５（ｄ， Ｊ＝２．０ Ｈｚ， １Ｈ）， ７．５１－７．４０（ｍ， ３Ｈ）， ７．３４（ｔｄ， Ｊ＝７．２， ２．０ Ｈｚ， １Ｈ）， ７．２８－７．２１（ｍ， ４Ｈ）， ６．９８（ｄｄ， Ｊ＝８．４， ２．０ Ｈｚ， １Ｈ）， ６．８６（ｔｄ， Ｊ＝８．８， ２．８ Ｈｚ， ２Ｈ）， ６．８３（ｄ， Ｊ＝８．８ Ｈｚ， １Ｈ）， ６．６２（ｄ， Ｊ＝６．４ Ｈｚ， １Ｈ）， ６．５４（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ４．９１（ｄ， Ｊ＝１５．６ Ｈｚ， １Ｈ）， ４．８０（ｄ， Ｊ＝１５．２ Ｈｚ， １Ｈ）， ４．４４－４．３４（ｂｒ， １Ｈ）， ３．７７（ｓ， ３Ｈ）， ３．６８ ｐｐｍ（ｄ， Ｊ＝４．４ Ｈｚ， １Ｈ）． tert-Butyl (S)-(5-chloro-2-((5-chloro-3-((diphenylphosphothioyl) amino) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) ethyl) -4- Fluorophenyl) carbamate (4.56 g, 5.799 mmol) was dissolved in CH 2 Cl 2 (46 ml), TFA (12 ml) was added at −15 ° C. under Ar atmosphere, and the mixture was stirred at −10 ° C. for 9 hours. . After cooling to −78 ° C., Et 3 N (25.3 ml), 50% brine (80 ml), and CH 2 Cl 2 (50 ml) were added sequentially to stop the reaction, and then 3 times with CH 2 Cl 2 (50 ml). Extract the organic layer with sat. NaHCO 3 aq. Once at 1.2 M HCl aq. Once, sat. NaHCO 3 aq. And once with saturated saline. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The crude product was purified by silica gel column chromatography [THF / Hexane = 1/3 to 1 / 2.5 (volume ratio)], and (S) -N- (3-((2-Amino-4-chloro-5 -Fluorophenyl) ethynyl) -5-chloro-1- (4-methoxybenzoyl) -2-oxoindolin-3-yl) -P, P-diphenylphosphinothioic amide (2.61 g, 66% yield) was obtained.
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (ddd, J = 14.0, 8.4, 1.6 Hz, 2H), 7.78 (ddd, J = 13.6, 8.4 , 1.2 Hz, 2H), 7.65 (d, J = 2.0 Hz, 1H), 7.51-7.40 (m, 3H), 7.34 (td, J = 7.2) 2.0 Hz, 1H), 7.28-7.21 (m, 4H), 6.98 (dd, J = 8.4, 2.0 Hz, 1H), 6.86 (td, J = 8 .8, 2.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 1H), 6.62 (d, J = 6.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 4.91 (d, J = 15.6 Hz, 1H), 4.80 (d, J = 15.2 Hz, 1H), 4.44-4.34 (br 1H), 3.77 (s, 3H), 3.68 ppm (d, J = 4.4 Hz, 1H).
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ８．０６（ｄｄｄ， Ｊ＝１４．０， ８．４， １．６ Ｈｚ， ２Ｈ）， ７．７８（ｄｄｄ， Ｊ＝１３．６， ８．４， １．２ Ｈｚ， ２Ｈ）， ７．６５（ｄ， Ｊ＝２．０ Ｈｚ， １Ｈ）， ７．５１－７．４０（ｍ， ３Ｈ）， ７．３４（ｔｄ， Ｊ＝７．２， ２．０ Ｈｚ， １Ｈ）， ７．２８－７．２１（ｍ， ４Ｈ）， ６．９８（ｄｄ， Ｊ＝８．４， ２．０ Ｈｚ， １Ｈ）， ６．８６（ｔｄ， Ｊ＝８．８， ２．８ Ｈｚ， ２Ｈ）， ６．８３（ｄ， Ｊ＝８．８ Ｈｚ， １Ｈ）， ６．６２（ｄ， Ｊ＝６．４ Ｈｚ， １Ｈ）， ６．５４（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ４．９１（ｄ， Ｊ＝１５．６ Ｈｚ， １Ｈ）， ４．８０（ｄ， Ｊ＝１５．２ Ｈｚ， １Ｈ）， ４．４４－４．３４（ｂｒ， １Ｈ）， ３．７７（ｓ， ３Ｈ）， ３．６８ ｐｐｍ（ｄ， Ｊ＝４．４ Ｈｚ， １Ｈ）． tert-Butyl (S)-(5-chloro-2-((5-chloro-3-((diphenylphosphothioyl) amino) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) ethyl) -4- Fluorophenyl) carbamate (4.56 g, 5.799 mmol) was dissolved in CH 2 Cl 2 (46 ml), TFA (12 ml) was added at −15 ° C. under Ar atmosphere, and the mixture was stirred at −10 ° C. for 9 hours. . After cooling to −78 ° C., Et 3 N (25.3 ml), 50% brine (80 ml), and CH 2 Cl 2 (50 ml) were added sequentially to stop the reaction, and then 3 times with CH 2 Cl 2 (50 ml). Extract the organic layer with sat. NaHCO 3 aq. Once at 1.2 M HCl aq. Once, sat. NaHCO 3 aq. And once with saturated saline. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The crude product was purified by silica gel column chromatography [THF / Hexane = 1/3 to 1 / 2.5 (volume ratio)], and (S) -N- (3-((2-Amino-4-chloro-5 -Fluorophenyl) ethynyl) -5-chloro-1- (4-methoxybenzoyl) -2-oxoindolin-3-yl) -P, P-diphenylphosphinothioic amide (2.61 g, 66% yield) was obtained.
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (ddd, J = 14.0, 8.4, 1.6 Hz, 2H), 7.78 (ddd, J = 13.6, 8.4 , 1.2 Hz, 2H), 7.65 (d, J = 2.0 Hz, 1H), 7.51-7.40 (m, 3H), 7.34 (td, J = 7.2) 2.0 Hz, 1H), 7.28-7.21 (m, 4H), 6.98 (dd, J = 8.4, 2.0 Hz, 1H), 6.86 (td, J = 8 .8, 2.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 1H), 6.62 (d, J = 6.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 4.91 (d, J = 15.6 Hz, 1H), 4.80 (d, J = 15.2 Hz, 1H), 4.44-4.34 (br 1H), 3.77 (s, 3H), 3.68 ppm (d, J = 4.4 Hz, 1H).
＜Ｓｃｈｅｍｅ ９＞
以下のＳｃｈｅｍｅ ９に従って、合成を行った。
<Scheme 9>
Synthesis was performed according to Scheme 9 below.
以下のＳｃｈｅｍｅ ９に従って、合成を行った。
Synthesis was performed according to Scheme 9 below.
（Ｓ）－Ｎ－（３－（（２－Ａｍｉｎｏ－４－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏｐｈｅｎｙｌ）ｅｔｈｙｎｙｌ）－５－ｃｈｌｏｒｏ－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）－Ｐ，Ｐ－ｄｉｐｈｅｎｙｌｐｈｏｓｐｈｉｎｏｔｈｉｏｉｃ ａｍｉｄｅ（２．５７ｇ， ３．７３６ｍｍｏｌ）、及びＣｕＩ（７１．２ｍｇ， ０．３７３６ｍｍｏｌ）をＡｒ雰囲気下ＤＭＦ（３７．４ｍｌ）に溶解し、９０℃にて１４時間撹拌した。室温に冷却後、５０％食塩水（１００ｍｌ）を加え反応を停止後、ＡｃＯＥｔ（５０ｍｌ）で３回抽出し、有機層を飽和食塩水で１回洗浄した。有機層をＮａ２ＳＯ４で脱水後、溶媒を留去した。粗生成物をシリカゲルカラムクロマトグラフィ〔ＴＨＦ／Ｈｅｘａｎｅ＝１／３（体積比）〕で精製し、（Ｒ）－Ｎ－（５－Ｃｈｌｏｒｏ－３－（６－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏ－１Ｈ－ｉｎｄｏｌ－２－ｙｌ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）－Ｐ，Ｐ－ｄｉｐｈｅｎｙｌｐｈｏｓｐｈｉｎｏｔｈｉｏｉｃ ａｍｉｄｅ（２．４０ｇ， 収率９３％）を得た。
得られた（Ｒ）－Ｎ－（５－Ｃｈｌｏｒｏ－３－（６－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏ－１Ｈ－ｉｎｄｏｌ－２－ｙｌ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）－Ｐ，Ｐ－ｄｉｐｈｅｎｙｌｐｈｏｓｐｈｉｎｏｔｈｉｏｉｃ ａｍｉｄｅ（３．０７ｇ， ９６％ｅｅ）にＡｃＯＥｔ／Ｈｅｘａｎｅにて再結晶を行うと、結晶（ｒａｃｅｍａｔｅ）とろ液（２．９５ｇ， 収率９６％， ９９．８％ｅｅ）が得られた。
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ９．８８－９．８０（ｂｒ， １Ｈ）， ７．８８（ｄｄｄ， Ｊ＝１４．０， ８．４， １．６ Ｈｚ， ２Ｈ）， ７．７８（ｄｄｄ， １４．０， ８．４， １．２ Ｈｚ， ２Ｈ）， ７．５０（ｔｄ， Ｊ＝７．６， ２．０ Ｈｚ， １Ｈ）， ７．４２（ｔｄ， Ｊ＝７．６， ３．６ Ｈｚ， ２Ｈ）， ７．３５（ｔｄ， Ｊ＝７．６， １．６ Ｈｚ， １Ｈ）， ７．３８－７．３２（ｍ， ２Ｈ）， ７．２１（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ７．１６（ｄ， Ｊ＝９．６ Ｈｚ， １Ｈ）， ６．９９（ｄｄ， Ｊ＝８．４， ２．４ Ｈｚ， １Ｈ）， ６．８３（ｄｔ， Ｊ＝８．８， ２．８ Ｈｚ， ２Ｈ）， ６．５５（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ６．１２（ｄ， Ｊ＝１．６ Ｈｚ， １Ｈ）， ６．９５（ｄ， Ｊ＝１５．２ Ｈｚ， １Ｈ）， ４．７０（ｄ， Ｊ＝１５．６ Ｈｚ， １Ｈ）， ４．０２（ｄ， Ｊ＝５．６ Ｈｚ， １Ｈ）， ３．７４ ｐｐｍ（ｓ， ３Ｈ）． (S) -N- (3-((2-Amino-4-chloro-5-fluorophenyl) ethyl) -5-chloro-1- (4-methoxybenzoyl) -2-oxindolin-3-yl) -P, P -Diphenylphosphinoicamide (2.57 g, 3.736 mmol) and CuI (71.2 mg, 0.3736 mmol) were dissolved in DMF (37.4 ml) under an Ar atmosphere and stirred at 90 ° C. for 14 hours. After cooling to room temperature, 50% brine (100 ml) was added to stop the reaction, followed by extraction three times with AcOEt (50 ml), and the organic layer was washed once with saturated brine. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The crude product was purified by silica gel column chromatography [THF / Hexane = 1/3 (volume ratio)], and (R) -N- (5-Chloro-3- (6-chloro-5-fluoro-1H-indol- 2-yl) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) -P, P-diphenylphosphinothioic amide (2.40 g, yield 93%) was obtained.
Obtained (R) -N- (5-Chloro-3- (6-chloro-5-fluoro-1H-indol-2-yl) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl Recrystallization of -P, P-diphenylphosphinothioamide (3.07 g, 96% ee) with AcOEt / Hexane gave crystals and a filtrate (2.95 g, yield 96%, 99.8% ee). was gotten.
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ) δ 9.88-9.80 (br, 1H), 7.88 (ddd, J = 14.0, 8.4, 1.6 Hz, 2H), 7. 78 (ddd, 14.0, 8.4, 1.2 Hz, 2H), 7.50 (td, J = 7.6, 2.0 Hz, 1H), 7.42 (td, J = 7. 6, 3.6 Hz, 2H), 7.35 (td, J = 7.6, 1.6 Hz, 1H), 7.38-7.32 (m, 2H), 7.21 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 9.6 Hz, 1H), 6.99 (dd, J = 8.4, 2.4 Hz, 1H), 6.83 (dt) , J = 8.8, 2.8 Hz, 2H), 6.55 (d, J = 8.4 Hz, 1H), 6.12 (d, J = 1.6 Hz, 1H), 6.95. d, J = 15.2 Hz, 1H), 4.70 (d, J = 15.6 Hz, 1H), 4.02 (d, J = 5.6 Hz, 1H), 3.74 ppm (s) , 3H).
得られた（Ｒ）－Ｎ－（５－Ｃｈｌｏｒｏ－３－（６－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏ－１Ｈ－ｉｎｄｏｌ－２－ｙｌ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）－Ｐ，Ｐ－ｄｉｐｈｅｎｙｌｐｈｏｓｐｈｉｎｏｔｈｉｏｉｃ ａｍｉｄｅ（３．０７ｇ， ９６％ｅｅ）にＡｃＯＥｔ／Ｈｅｘａｎｅにて再結晶を行うと、結晶（ｒａｃｅｍａｔｅ）とろ液（２．９５ｇ， 収率９６％， ９９．８％ｅｅ）が得られた。
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ９．８８－９．８０（ｂｒ， １Ｈ）， ７．８８（ｄｄｄ， Ｊ＝１４．０， ８．４， １．６ Ｈｚ， ２Ｈ）， ７．７８（ｄｄｄ， １４．０， ８．４， １．２ Ｈｚ， ２Ｈ）， ７．５０（ｔｄ， Ｊ＝７．６， ２．０ Ｈｚ， １Ｈ）， ７．４２（ｔｄ， Ｊ＝７．６， ３．６ Ｈｚ， ２Ｈ）， ７．３５（ｔｄ， Ｊ＝７．６， １．６ Ｈｚ， １Ｈ）， ７．３８－７．３２（ｍ， ２Ｈ）， ７．２１（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ７．１６（ｄ， Ｊ＝９．６ Ｈｚ， １Ｈ）， ６．９９（ｄｄ， Ｊ＝８．４， ２．４ Ｈｚ， １Ｈ）， ６．８３（ｄｔ， Ｊ＝８．８， ２．８ Ｈｚ， ２Ｈ）， ６．５５（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ６．１２（ｄ， Ｊ＝１．６ Ｈｚ， １Ｈ）， ６．９５（ｄ， Ｊ＝１５．２ Ｈｚ， １Ｈ）， ４．７０（ｄ， Ｊ＝１５．６ Ｈｚ， １Ｈ）， ４．０２（ｄ， Ｊ＝５．６ Ｈｚ， １Ｈ）， ３．７４ ｐｐｍ（ｓ， ３Ｈ）． (S) -N- (3-((2-Amino-4-chloro-5-fluorophenyl) ethyl) -5-chloro-1- (4-methoxybenzoyl) -2-oxindolin-3-yl) -P, P -Diphenylphosphinoicamide (2.57 g, 3.736 mmol) and CuI (71.2 mg, 0.3736 mmol) were dissolved in DMF (37.4 ml) under an Ar atmosphere and stirred at 90 ° C. for 14 hours. After cooling to room temperature, 50% brine (100 ml) was added to stop the reaction, followed by extraction three times with AcOEt (50 ml), and the organic layer was washed once with saturated brine. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The crude product was purified by silica gel column chromatography [THF / Hexane = 1/3 (volume ratio)], and (R) -N- (5-Chloro-3- (6-chloro-5-fluoro-1H-indol- 2-yl) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) -P, P-diphenylphosphinothioic amide (2.40 g, yield 93%) was obtained.
Obtained (R) -N- (5-Chloro-3- (6-chloro-5-fluoro-1H-indol-2-yl) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl Recrystallization of -P, P-diphenylphosphinothioamide (3.07 g, 96% ee) with AcOEt / Hexane gave crystals and a filtrate (2.95 g, yield 96%, 99.8% ee). was gotten.
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ) δ 9.88-9.80 (br, 1H), 7.88 (ddd, J = 14.0, 8.4, 1.6 Hz, 2H), 7. 78 (ddd, 14.0, 8.4, 1.2 Hz, 2H), 7.50 (td, J = 7.6, 2.0 Hz, 1H), 7.42 (td, J = 7. 6, 3.6 Hz, 2H), 7.35 (td, J = 7.6, 1.6 Hz, 1H), 7.38-7.32 (m, 2H), 7.21 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 9.6 Hz, 1H), 6.99 (dd, J = 8.4, 2.4 Hz, 1H), 6.83 (dt) , J = 8.8, 2.8 Hz, 2H), 6.55 (d, J = 8.4 Hz, 1H), 6.12 (d, J = 1.6 Hz, 1H), 6.95. d, J = 15.2 Hz, 1H), 4.70 (d, J = 15.6 Hz, 1H), 4.02 (d, J = 5.6 Hz, 1H), 3.74 ppm (s) , 3H).
＜Ｓｃｈｅｍｅ １０＞
以下のＳｃｈｅｍｅ １０に従って、合成を行った。
<Scheme 10>
Synthesis was performed according to Scheme 10 below.
以下のＳｃｈｅｍｅ １０に従って、合成を行った。
Synthesis was performed according to Scheme 10 below.
（Ｒ）－Ｎ－（５－Ｃｈｌｏｒｏ－３－（６－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏ－１Ｈ－ｉｎｄｏｌ－２－ｙｌ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）－Ｐ，Ｐ－ｄｉｐｈｅｎｙｌｐｈｏｓｐｈｉｎｏｔｈｉｏｉｃ ａｍｉｄｅ（２．９０ｇ， ４．２１７ｍｍｏｌ）をＡｒ雰囲気下ＣＨ３ＣＮ（２１０ｍｌ）に溶解し、室温でＲａｎｅｙ－Ｎｉ（ｃａ．２１．１ｇ）を加えたのちに６０℃にて４時間撹拌した。室温に冷却後、ＡｃＯＨ（２５．３ｍｌ）を加えさらに３時間撹拌した。ＴＨＦ（２００ｍｌ）を加えたのちにＣｅｌｉｔｅ ｐａｄにてろ過をし、ろ液を留去した。ＣＨ２Ｃｌ２（５０ｍｌ）、及び２Ｍ ＮａＯＨ ａｑ．（２５０ｍｌ）を加えたのちＣＨ２Ｃｌ２（２００ｍｌ）で３回抽出し、有機層を５０％食塩水（２０００ｍｌ）で１回、及び飽和食塩水で１回洗浄した。有機層をＮａ２ＳＯ４で脱水後、溶媒を留去した。得られた（Ｒ）－３－Ａｍｉｎｏ－５－ｃｈｌｏｒｏ－３－（６－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏ－１Ｈ－ｉｎｄｏｌ－２－ｙｌ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）ｉｎｄｏｌｉｎ－２－ｏｎｅを含む粗生成物を精製せずに次の反応に用いた。
(R) -N- (5-Chloro-3- (6-chloro-5-fluoro-1H-indol-2-yl) -1- (4-methoxybenzyl) -2-oxindolin-3-yl) -P, P-diphenylphosphinoicamide (2.90 g, 4.217 mmol) was dissolved in CH 3 CN (210 ml) under an Ar atmosphere, and after addition of Raney-Ni (ca.21.1 g) at room temperature, 4 hours at 60 ° C. Stir. After cooling to room temperature, AcOH (25.3 ml) was added and the mixture was further stirred for 3 hours. After adding THF (200 ml), the mixture was filtered through Celite pad, and the filtrate was distilled off. CH 2 Cl 2 (50 ml), and 2M NaOH aq. (250 ml) was added, followed by extraction three times with CH 2 Cl 2 (200 ml), and the organic layer was washed once with 50% brine (2000 ml) and once with saturated brine. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. Crude containing the obtained (R) -3-Amino-5-chloro-3- (6-chloro-5-fluoro-1H-indol-2-yl) -1- (4-methoxybenzoyl) indolin-2-one The product was used in the next reaction without purification.
＜Ｓｃｈｅｍｅ １１＞
以下のＳｃｈｅｍｅ １１に従って、合成を行った。
<Scheme 11>
Synthesis was performed according to Scheme 11 below.
以下のＳｃｈｅｍｅ １１に従って、合成を行った。
Synthesis was performed according to Scheme 11 below.
（Ｒ）－３－Ａｍｉｎｏ－５－ｃｈｌｏｒｏ－３－（６－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏ－１Ｈ－ｉｎｄｏｌ－２－ｙｌ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）ｉｎｄｏｌｉｎ－２－ｏｎｅを含む粗生成物をＣＨ２Ｃｌ２（１０．５ｍｌ）、及びｐｙｒｉｄｉｎｅ（１０．５ｍｌ）に溶解し、Ａｒ雰囲気下０℃にてＢｅｎｚｙｌ ｃｈｌｏｒｏｆｏｒｍａｔｅ（２．３８ｍｌ， １６．８７ｍｍｏｌ）を加えたのち、室温にて３０分撹拌した。０℃に冷却後、１．２Ｍ ＨＣｌａｑ．（４０ｍｌ）を加え反応を停止後、ＡｃＯＥｔ（５０ｍｌ）で３回抽出し、有機層をｓａｔ．ＮａＨＣＯ３ａｑ．で１回、及び飽和食塩水で１回洗浄した。有機層をＮａ２ＳＯ４で脱水後、溶媒を留去した。得られたＢｅｎｚｙｌ （Ｒ）－（５－ｃｈｌｏｒｏ－３－（６－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏ－１Ｈ－ｉｎｄｏｌ－２－ｙｌ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）ｃａｒｂａｍａｔｅを含む粗生成物を精製せずに次の反応に用いた。
A crude product containing (R) -3-Amino-5-chloro-3- (6-chloro-5-fluoro-1H-indol-2-yl) -1- (4-methoxybenzoyl) indolin-2-one Dissolve in CH 2 Cl 2 (10.5 ml) and pyridine (10.5 ml), add Benzyl chloroform (2.38 ml, 16.87 mmol) at 0 ° C. under Ar atmosphere, then stir at room temperature for 30 minutes did. After cooling to 0 ° C., 1.2 M HClaq. (40 ml) was added to stop the reaction, followed by extraction three times with AcOEt (50 ml), and the organic layer was washed with sat. NaHCO 3 aq. And once with saturated saline. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. Benzyl (R)-(5-chloro-3- (6-chloro-5-fluoro-1H-indol-2-yl) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) carbamate obtained The crude product containing was used in the next reaction without purification.
＜Ｓｃｈｅｍｅ １２＞
以下のＳｃｈｅｍｅ １２に従って、合成を行った。
<Scheme 12>
Synthesis was performed according to Scheme 12 below.
以下のＳｃｈｅｍｅ １２に従って、合成を行った。
Synthesis was performed according to Scheme 12 below.
Ｂｅｎｚｙｌ（Ｒ）－（５－ｃｈｌｏｒｏ－３－（６－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏ－１Ｈ－ｉｎｄｏｌ－２－ｙｌ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）ｃａｒｂａｍａｔｅを含む粗生成物をＰＯＣｌ３（３．３６ｍｌ）に溶解し、Ａｒ雰囲気下０℃にてＤＭＦ（０．８４ｍｌ）を加えたのち、室温にて５時間撹拌した。０℃に冷却後、ＣＨ２Ｃｌ２（５０ｍｌ）を加えたのち、反応混合物を２Ｍ ＮａＯＨａｑ．（１００ｍｌ）を含む氷浴へ１０回に分けて注いだ。これをＣＨ２Ｃｌ２（１００ｍｌ）で３回抽出し、有機層を５０％食塩水で１回、及び飽和食塩水で１回洗浄した。有機層をＮａ２ＳＯ４で脱水後、溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィ〔ＡｃＯＥｔ／Ｈｅｘａｎｅ＝１／４～１／２（体積比）〕で精製し、Ｂｅｎｚｙｌ （Ｒ）－（５－ｃｈｌｏｒｏ－３－（６－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏ－３－ｆｏｒｍｙｌ－１Ｈ－ｉｎｄｏｌ－２－ｙｌ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）ｃａｒｂａｍａｔｅ（１．０５ｇ， 収率４０％， ３ｓｔｅｐｓ）を得た。
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ９．７０－９．３４（ｂｒ， ２Ｈ）， ８．０４（ｄ， Ｊ＝９．６ Ｈｚ， １Ｈ）， ７．４８（ｄ， Ｊ＝２．０ Ｈｚ， １Ｈ）， ７．３０－７．２３（ｍ， ３Ｈ）， ７．２１（ｄ， Ｊ＝６．０ Ｈｚ， １Ｈ）， ７．１６－７．０２（ｂｒ， ４Ｈ）， ６．８６－６．８２（ｂｒ， １Ｈ）， ６．７８（ｄ， Ｊ＝８．４ Ｈｚ， ２Ｈ）， ６．７０（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ５．０２（ｄ， Ｊ＝１１．６ Ｈｚ， １Ｈ）， ４．９８－４．８８（ｂｒ， １Ｈ）， ４．８２－４．６６（ｂｒ， ２Ｈ）， ３．７２ ｐｐｍ（ｓ， ３Ｈ）． Benzyl (R)-(5-chloro-3- (6-chloro-5-fluoro-1H-indol-2-yl) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) carbamate The product was dissolved in POCl 3 (3.36 ml), DMF (0.84 ml) was added at 0 ° C. under an Ar atmosphere, and the mixture was stirred at room temperature for 5 hr. After cooling to 0 ° C., CH 2 Cl 2 (50 ml) was added, and then the reaction mixture was diluted with 2M NaOH aq. (100 ml) was poured into an ice bath in 10 portions. This was extracted 3 times with CH 2 Cl 2 (100 ml), and the organic layer was washed once with 50% brine and once with saturated brine. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography [AcOEt / Hexane = 1/4 to 1/2 (volume ratio)], and Benzyl (R)-(5-chloro-3- (6-chloro-5- Fluoro-3-formyl-1H-indol-2-yl) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) carbamate (1.05 g, 40% yield, 3 steps) was obtained.
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ) δ 9.70-9.34 (br, 2H), 8.04 (d, J = 9.6 Hz, 1H), 7.48 (d, J = 2. 0 Hz, 1H), 7.30-7.23 (m, 3H), 7.21 (d, J = 6.0 Hz, 1H), 7.16-7.02 (br, 4H), 6. 86-6.82 (br, 1H), 6.78 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 1H), 5.02 (d, J = 11.6 Hz, 1H), 4.98-4.88 (br, 1H), 4.82-4.66 (br, 2H), 3.72 ppm (s, 3H).
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ９．７０－９．３４（ｂｒ， ２Ｈ）， ８．０４（ｄ， Ｊ＝９．６ Ｈｚ， １Ｈ）， ７．４８（ｄ， Ｊ＝２．０ Ｈｚ， １Ｈ）， ７．３０－７．２３（ｍ， ３Ｈ）， ７．２１（ｄ， Ｊ＝６．０ Ｈｚ， １Ｈ）， ７．１６－７．０２（ｂｒ， ４Ｈ）， ６．８６－６．８２（ｂｒ， １Ｈ）， ６．７８（ｄ， Ｊ＝８．４ Ｈｚ， ２Ｈ）， ６．７０（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ５．０２（ｄ， Ｊ＝１１．６ Ｈｚ， １Ｈ）， ４．９８－４．８８（ｂｒ， １Ｈ）， ４．８２－４．６６（ｂｒ， ２Ｈ）， ３．７２ ｐｐｍ（ｓ， ３Ｈ）． Benzyl (R)-(5-chloro-3- (6-chloro-5-fluoro-1H-indol-2-yl) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) carbamate The product was dissolved in POCl 3 (3.36 ml), DMF (0.84 ml) was added at 0 ° C. under an Ar atmosphere, and the mixture was stirred at room temperature for 5 hr. After cooling to 0 ° C., CH 2 Cl 2 (50 ml) was added, and then the reaction mixture was diluted with 2M NaOH aq. (100 ml) was poured into an ice bath in 10 portions. This was extracted 3 times with CH 2 Cl 2 (100 ml), and the organic layer was washed once with 50% brine and once with saturated brine. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography [AcOEt / Hexane = 1/4 to 1/2 (volume ratio)], and Benzyl (R)-(5-chloro-3- (6-chloro-5- Fluoro-3-formyl-1H-indol-2-yl) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) carbamate (1.05 g, 40% yield, 3 steps) was obtained.
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ) δ 9.70-9.34 (br, 2H), 8.04 (d, J = 9.6 Hz, 1H), 7.48 (d, J = 2. 0 Hz, 1H), 7.30-7.23 (m, 3H), 7.21 (d, J = 6.0 Hz, 1H), 7.16-7.02 (br, 4H), 6. 86-6.82 (br, 1H), 6.78 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 1H), 5.02 (d, J = 11.6 Hz, 1H), 4.98-4.88 (br, 1H), 4.82-4.66 (br, 2H), 3.72 ppm (s, 3H).
＜Ｓｃｈｅｍｅ １３＞
以下のＳｃｈｅｍｅ １３に従って、合成を行った。
<Scheme 13>
Synthesis was performed according to Scheme 13 below.
以下のＳｃｈｅｍｅ １３に従って、合成を行った。
Synthesis was performed according to Scheme 13 below.
Ｂｅｎｚｙｌ （Ｒ）－（５－ｃｈｌｏｒｏ－３－（６－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏ－３－ｆｏｒｍｙｌ－１Ｈ－ｉｎｄｏｌ－２－ｙｌ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）ｃａｒｂａｍａｔｅ（１２７ｍｇ， ０．２０００ｍｍｏｌ）をＥｔＮＯ２（１６．０ｍｌ）に溶解し、室温でＮＨ４ＯＡｃ（２３１ｍｇ， ３．０００ｍｍｏｌ）を加え６０℃で４８時間撹拌した。室温に冷却後、５０％食塩水（１０ｍｌ）を加え反応を停止後、ＡｃＯＥｔ（２０ｍｌ）で３回抽出し、有機層を飽和食塩水で１回洗浄した。有機層をＮａ２ＳＯ４で脱水後、溶媒を留去した。得られたＢｅｎｚｙｌ （Ｒ，Ｅ）－（５－ｃｈｌｏｒｏ－３－（６－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏ－３－（２－ｎｉｔｒｏｐｒｏｐ－１－ｅｎ－１－ｙｌ）－１Ｈ－ｉｎｄｏｌ－２－ｙｌ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）ｃａｒｂａｍａｔｅを含む粗生成物を精製せずに次の反応に用いた。
Benzyl (R)-(5-chloro-3- (6-chloro-5-fluoro-3-formyl-1H-indol-2-yl) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl carbamate (127 mg, 0.2000 mmol) was dissolved in EtNO 2 (16.0 ml), NH 4 OAc (231 mg, 3.000 mmol) was added at room temperature, and the mixture was stirred at 60 ° C. for 48 hours. After cooling to room temperature, 50% brine (10 ml) was added to stop the reaction, followed by extraction three times with AcOEt (20 ml), and the organic layer was washed once with saturated brine. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. Benzyl (R, E)-(5-chloro-3- (6-chloro-5-fluoro-3- (2-nitroprop-1-en-1-yl) -1H-indol-2-yl) obtained The crude product containing -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) carbamate was used in the next reaction without purification.
＜Ｓｃｈｅｍｅ １４＞
以下のＳｃｈｅｍｅ １４に従って、合成を行った。
<Scheme 14>
Synthesis was performed according to Scheme 14 below.
以下のＳｃｈｅｍｅ １４に従って、合成を行った。
Synthesis was performed according to Scheme 14 below.
Ｂｅｎｚｙｌ （Ｒ，Ｅ）－（５－ｃｈｌｏｒｏ－３－（６－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏ－３－（２－ｎｉｔｒｏｐｒｏｐ－１－ｅｎ－１－ｙｌ）－１Ｈ－ｉｎｄｏｌ－２－ｙｌ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）ｃａｒｂａｍａｔｅを含む粗生成物をＥｔＯＨ（１．９０ｍｌ）、及びＡｃＯＨ（０．１０ｍｌ）に溶解し、室温で亜鉛粉末（１３１ｍｇ，２．０００ｍｍｏｌ）を加えたのちに６０℃で１時間半撹拌した。２Ｍ ＨＣｌ（ｉｎ ＭｅＯＨ）を４．０ｍｌ、Ｈ２Ｏを１．０ｍｌ加えたのち、さらに４時間撹拌した。室温に冷却後、ｓａｔ．ＮａＨＣＯ３ａｑ．（２０ｍｌ）を加えたのちＡｃＯＥｔ（２０ｍｌ）で３回抽出し、有機層を飽和食塩水で１回洗浄した。有機層をＮａ２ＳＯ４で脱水後、溶媒を留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィ〔ＡｃＯＥｔ／Ｈｅｘａｎｅ＝１／３（体積比）〕にて精製し、Ｂｅｎｚｙｌ （Ｒ）－（５－ｃｈｌｏｒｏ－３－（６－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏ－３－（２－ｏｘｏｐｒｏｐｙｌ）－１Ｈ－ｉｎｄｏｌ－２－ｙｌ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）ｃａｒｂａｍａｔｅ（６７．９ｍｇ， 収率５１％，２ｓｔｅｐｓ）を得た。
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ７．８１（ｓ， １Ｈ）， ７．４１（ｄ， Ｊ＝２．０ Ｈｚ， １Ｈ）， ７．３４－７．２５（ｍ， ６Ｈ）， ７．１７－７．０６（ｂｒ， ２Ｈ）， ７．１０（ｄ， Ｊ＝９．２ Ｈｚ， １Ｈ）， ６．７７（ｄ， Ｊ＝８．４ Ｈｚ， ２Ｈ）， ６．６５（ｄ， Ｊ＝８．０ Ｈｚ， １Ｈ）， ５．０７（ｄ， Ｊ＝１２．８ Ｈｚ， １Ｈ）， ５．０４－４．７５（ｂｒ， ２Ｈ）， ４．７２（ｄ， Ｊ＝１５．２ Ｈｚ， １Ｈ）， ４．５３（ｄ， Ｊ＝１７．６ Ｈｚ， １Ｈ）， ３．８７（ｄ， Ｊ＝１７．６ Ｈｚ， １Ｈ）， ３．７３（ｓ， ３Ｈ）， ２．３１ ｐｐｍ（ｓ， ３Ｈ）． Benzyl (R, E)-(5-chloro-3- (6-chloro-5-fluoro-3- (2-nitroprop-1-en-1-yl) -1H-indol-2-yl) -1- A crude product containing (4-methoxybenzoyl) -2-oxindolin-3-yl) carbamate was dissolved in EtOH (1.90 ml) and AcOH (0.10 ml), and zinc powder (131 mg, 2.000 mmol) at room temperature. After stirring, the mixture was stirred at 60 ° C. for 1.5 hours. After adding 4.0 ml of 2M HCl (in MeOH) and 1.0 ml of H 2 O, the mixture was further stirred for 4 hours. After cooling to room temperature, sat. NaHCO 3 aq. (20 ml) was added, followed by extraction three times with AcOEt (20 ml), and the organic layer was washed once with saturated brine. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography [AcOEt / Hexane = 1/3 (volume ratio)], and Benzyl (R)-(5-chloro-3- (6-chloro-5-fluoro-3). -(2-oxopropyl) -1H-indol-2-yl) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) carbamate (67.9 mg, 51% yield, 2 steps) was obtained.
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (s, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.34-7.25 (m, 6H), 7 .17-7.06 (br, 2H), 7.10 (d, J = 9.2 Hz, 1H), 6.77 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.0 Hz, 1H), 5.07 (d, J = 12.8 Hz, 1H), 5.04-4.75 (br, 2H), 4.72 (d, J = 15.2. Hz, 1H), 4.53 (d, J = 17.6 Hz, 1H), 3.87 (d, J = 17.6 Hz, 1H), 3.73 (s, 3H), 2.31 ppm (S, 3H).
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３） δ ７．８１（ｓ， １Ｈ）， ７．４１（ｄ， Ｊ＝２．０ Ｈｚ， １Ｈ）， ７．３４－７．２５（ｍ， ６Ｈ）， ７．１７－７．０６（ｂｒ， ２Ｈ）， ７．１０（ｄ， Ｊ＝９．２ Ｈｚ， １Ｈ）， ６．７７（ｄ， Ｊ＝８．４ Ｈｚ， ２Ｈ）， ６．６５（ｄ， Ｊ＝８．０ Ｈｚ， １Ｈ）， ５．０７（ｄ， Ｊ＝１２．８ Ｈｚ， １Ｈ）， ５．０４－４．７５（ｂｒ， ２Ｈ）， ４．７２（ｄ， Ｊ＝１５．２ Ｈｚ， １Ｈ）， ４．５３（ｄ， Ｊ＝１７．６ Ｈｚ， １Ｈ）， ３．８７（ｄ， Ｊ＝１７．６ Ｈｚ， １Ｈ）， ３．７３（ｓ， ３Ｈ）， ２．３１ ｐｐｍ（ｓ， ３Ｈ）． Benzyl (R, E)-(5-chloro-3- (6-chloro-5-fluoro-3- (2-nitroprop-1-en-1-yl) -1H-indol-2-yl) -1- A crude product containing (4-methoxybenzoyl) -2-oxindolin-3-yl) carbamate was dissolved in EtOH (1.90 ml) and AcOH (0.10 ml), and zinc powder (131 mg, 2.000 mmol) at room temperature. After stirring, the mixture was stirred at 60 ° C. for 1.5 hours. After adding 4.0 ml of 2M HCl (in MeOH) and 1.0 ml of H 2 O, the mixture was further stirred for 4 hours. After cooling to room temperature, sat. NaHCO 3 aq. (20 ml) was added, followed by extraction three times with AcOEt (20 ml), and the organic layer was washed once with saturated brine. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The obtained crude product was purified by silica gel column chromatography [AcOEt / Hexane = 1/3 (volume ratio)], and Benzyl (R)-(5-chloro-3- (6-chloro-5-fluoro-3). -(2-oxopropyl) -1H-indol-2-yl) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) carbamate (67.9 mg, 51% yield, 2 steps) was obtained.
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (s, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.34-7.25 (m, 6H), 7 .17-7.06 (br, 2H), 7.10 (d, J = 9.2 Hz, 1H), 6.77 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.0 Hz, 1H), 5.07 (d, J = 12.8 Hz, 1H), 5.04-4.75 (br, 2H), 4.72 (d, J = 15.2. Hz, 1H), 4.53 (d, J = 17.6 Hz, 1H), 3.87 (d, J = 17.6 Hz, 1H), 3.73 (s, 3H), 2.31 ppm (S, 3H).
＜Ｓｃｈｅｍｅ １５＞
以下のＳｃｈｅｍｅ １５に従って、合成を行った。
<Scheme 15>
Synthesis was performed according to the following Scheme 15.
以下のＳｃｈｅｍｅ １５に従って、合成を行った。
Synthesis was performed according to the following Scheme 15.
Ｐｄ（ＯＡｃ）２（４．１ｍｇ， ０．０１８２６ｍｍｏｌ）をＡｒ雰囲気下ＣＨ２Ｃｌ２（０．９ｍｌ）に溶解し室温でＥｔ３Ｎ（５．１μｌ， ０．０３６４９ｍｍｏｌ）、及びＴｒｉｅｔｈｙｌｓｉｌａｎｅ（ＴＥＳＨ、８７．０μｌ， ０．５４６１ｍｍｏｌ）を加え１０分間撹拌した。この溶液の４１８μｌをＢｅｎｚｙｌ （Ｒ）－（５－ｃｈｌｏｒｏ－３－（６－ｃｈｌｏｒｏ－５－ｆｌｕｏｒｏ－３－（２－ｏｘｏｐｒｏｐｙｌ）－１Ｈ－ｉｎｄｏｌ－２－ｙｌ）－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－２－ｏｘｏｉｎｄｏｌｉｎ－３－ｙｌ）ｃａｒｂａｍａｔｅ（５５．９ｍｇ， ０．０８４６３ｍｍｏｌ）をＣＨ２Ｃｌ２（４３２μｌ）に溶解した溶液に加えた。３時間撹拌したのち０℃へ冷却後Ｔｒｉｆｌｕｏｒｏａｃｅｔｉｃ ａｃｉｄ（２５９μｌ， ０．３３８５ｍｍｏｌ）を加え、室温で１．５時間撹拌した。反応終了後Ａｒ雰囲気下にて減圧留去し、反応を停止した。これをＣＨ２Ｃｌ２（８５０μｌ）に溶解し－３０℃にてＢＨ３・２－ｐｉｃｏｌｉｎｅ（２７．２ｍｇ， ０．２５３９ｍｍｏｌ）を加え２時間撹拌した。１．２Ｍ ＨＣｌａｑ．（５．０ｍｌ）を加え反応を停止後、ＡｃＯＥｔ（２０ｍｌ）で３回抽出し、有機層をｓａｔ．ＮａＨＣＯ３ａｑ．で１回、及び飽和食塩水で１回洗浄した。有機層をＮａ２ＳＯ４で脱水後、溶媒を留去した。粗生成物をシリカゲルカラムクロマトグラフィ〔ＡｃＯＥｔ／Ｈｅｘａｎｅ＝１／２．５（体積比）〕で精製し、（３Ｒ，３’Ｓ）－５，７’－Ｄｉｃｈｌｏｒｏ－６’－ｆｌｕｏｒｏ－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－３’－ｍｅｔｈｙｌ－２’，３’，４’，９’－ｔｅｔｒａｈｙｄｒｏｓｐｉｒｏ［ｉｎｄｏｌｉｎｅ－３，１’－ｐｙｒｉｄｏ［３，４－ｂ］ｉｎｄｏｌ］－２－ｏｎｅ（３７．９ｍｇ， 収率８８％）を得た。
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．７０（ｓ， １Ｈ）， ７．４５（ｄ， Ｊ＝１０．０ Ｈｚ， １Ｈ）， ７．３６（ｄｄ， Ｊ＝８．４， ２．４ Ｈｚ， １Ｈ）， ７．３２（ｄ， Ｊ＝８．４ Ｈｚ， ２Ｈ）， ７．２８（ｄ， Ｊ＝６．４ Ｈｚ， １Ｈ）， ７．１２（ｄ， Ｊ＝２．０ Ｈｚ， １Ｈ）， ６．９８（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ６．９０（ｄｔ， Ｊ＝８．８， ２．０ Ｈｚ， ２Ｈ）， ４．８３（ｄ， Ｊ＝１５．６ Ｈｚ， １Ｈ）， ４．７７（ｄ， Ｊ＝１５．６ Ｈｚ， １Ｈ）， ４．０２－３．８８（ｍ， １Ｈ）， ３．７３（ｓ， ３Ｈ）， ３．１９（ｄ， Ｊ＝６．４ Ｈｚ， １Ｈ）， ２．８１（ｄｄ， Ｊ＝１５．２， ４．０ Ｈｚ， １Ｈ）， ２．４１（ｄｄ， Ｊ＝１５．２， １０．４ Ｈｚ， １Ｈ）， １．１８ ｐｐｍ（ｄ， Ｊ＝６．４ Ｈｚ， ３Ｈ）． Pd (OAc) 2 (4.1 mg, 0.01826 mmol) was dissolved in CH 2 Cl 2 (0.9 ml) under an Ar atmosphere, and Et 3 N (5.1 μl, 0.03649 mmol) and Triethylsilane (TESH, (87.0 μl, 0.5461 mmol) was added and the mixture was stirred for 10 minutes. 418 μl of this solution was added to Benzyl (R)-(5-chloro-3- (6-chloro-5-fluoro-3- (2-oxopropyl) -1H-indol-2-yl) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) carbamate (55.9 mg, 0.08463 mmol) was added to a solution of CH 2 Cl 2 (432 μl). After stirring for 3 hours and cooling to 0 ° C., trifluoroacetic acid (259 μl, 0.3385 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction was stopped by distilling off under reduced pressure under Ar atmosphere. This was dissolved in CH 2 Cl 2 (850 μl), BH 3 · 2-picoline (27.2 mg, 0.2539 mmol) was added at −30 ° C., and the mixture was stirred for 2 hours. 1.2M HClaq. (5.0 ml) was added to stop the reaction, followed by extraction three times with AcOEt (20 ml), and the organic layer was washed with sat. NaHCO 3 aq. And once with saturated saline. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The crude product was purified by silica gel column chromatography [AcOEt / Hexane = 1 / 2.5 (volume ratio)], and (3R, 3 ′S) -5,7′-Dichroro-6′-fluor-1- (4 -Methoxybenzoyl) -3'-methyl-2 ', 3', 4 ', 9'-tetrahydrospiro [indolin-3,1'-pyrido [3,4-b] indol] -2-one (37.9 mg, yield) 88%).
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, DMSO-d 6 ) δ 10.70 (s, 1H), 7.45 (d, J = 10.0 Hz, 1H), 7.36 (dd, J = 8.4, 2.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 6.4 Hz, 1H), 7.12 (d, J = 2. 0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.90 (dt, J = 8.8, 2.0 Hz, 2H), 4.83 (d, J = 15.6 Hz, 1H), 4.77 (d, J = 15.6 Hz, 1H), 4.02-3.88 (m, 1H), 3.73 (s, 3H), 3.19 ( d, J = 6.4 Hz, 1H), 2.81 (dd, J = 15.2, 4.0 Hz, 1H), 2.41 (dd, J = 15.2, 10.4 Hz, H), 1.18 ppm (d, J = 6.4 Hz, 3H).
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．７０（ｓ， １Ｈ）， ７．４５（ｄ， Ｊ＝１０．０ Ｈｚ， １Ｈ）， ７．３６（ｄｄ， Ｊ＝８．４， ２．４ Ｈｚ， １Ｈ）， ７．３２（ｄ， Ｊ＝８．４ Ｈｚ， ２Ｈ）， ７．２８（ｄ， Ｊ＝６．４ Ｈｚ， １Ｈ）， ７．１２（ｄ， Ｊ＝２．０ Ｈｚ， １Ｈ）， ６．９８（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ６．９０（ｄｔ， Ｊ＝８．８， ２．０ Ｈｚ， ２Ｈ）， ４．８３（ｄ， Ｊ＝１５．６ Ｈｚ， １Ｈ）， ４．７７（ｄ， Ｊ＝１５．６ Ｈｚ， １Ｈ）， ４．０２－３．８８（ｍ， １Ｈ）， ３．７３（ｓ， ３Ｈ）， ３．１９（ｄ， Ｊ＝６．４ Ｈｚ， １Ｈ）， ２．８１（ｄｄ， Ｊ＝１５．２， ４．０ Ｈｚ， １Ｈ）， ２．４１（ｄｄ， Ｊ＝１５．２， １０．４ Ｈｚ， １Ｈ）， １．１８ ｐｐｍ（ｄ， Ｊ＝６．４ Ｈｚ， ３Ｈ）． Pd (OAc) 2 (4.1 mg, 0.01826 mmol) was dissolved in CH 2 Cl 2 (0.9 ml) under an Ar atmosphere, and Et 3 N (5.1 μl, 0.03649 mmol) and Triethylsilane (TESH, (87.0 μl, 0.5461 mmol) was added and the mixture was stirred for 10 minutes. 418 μl of this solution was added to Benzyl (R)-(5-chloro-3- (6-chloro-5-fluoro-3- (2-oxopropyl) -1H-indol-2-yl) -1- (4-methoxybenzoyl) -2-oxindolin-3-yl) carbamate (55.9 mg, 0.08463 mmol) was added to a solution of CH 2 Cl 2 (432 μl). After stirring for 3 hours and cooling to 0 ° C., trifluoroacetic acid (259 μl, 0.3385 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction was stopped by distilling off under reduced pressure under Ar atmosphere. This was dissolved in CH 2 Cl 2 (850 μl), BH 3 · 2-picoline (27.2 mg, 0.2539 mmol) was added at −30 ° C., and the mixture was stirred for 2 hours. 1.2M HClaq. (5.0 ml) was added to stop the reaction, followed by extraction three times with AcOEt (20 ml), and the organic layer was washed with sat. NaHCO 3 aq. And once with saturated saline. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The crude product was purified by silica gel column chromatography [AcOEt / Hexane = 1 / 2.5 (volume ratio)], and (3R, 3 ′S) -5,7′-Dichroro-6′-fluor-1- (4 -Methoxybenzoyl) -3'-methyl-2 ', 3', 4 ', 9'-tetrahydrospiro [indolin-3,1'-pyrido [3,4-b] indol] -2-one (37.9 mg, yield) 88%).
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, DMSO-d 6 ) δ 10.70 (s, 1H), 7.45 (d, J = 10.0 Hz, 1H), 7.36 (dd, J = 8.4, 2.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 6.4 Hz, 1H), 7.12 (d, J = 2. 0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.90 (dt, J = 8.8, 2.0 Hz, 2H), 4.83 (d, J = 15.6 Hz, 1H), 4.77 (d, J = 15.6 Hz, 1H), 4.02-3.88 (m, 1H), 3.73 (s, 3H), 3.19 ( d, J = 6.4 Hz, 1H), 2.81 (dd, J = 15.2, 4.0 Hz, 1H), 2.41 (dd, J = 15.2, 10.4 Hz, H), 1.18 ppm (d, J = 6.4 Hz, 3H).
＜Ｓｃｈｅｍｅ １６＞
以下のＳｃｈｅｍｅ １６に従って、合成を行った。
<Scheme 16>
Synthesis was performed according to Scheme 16 below.
以下のＳｃｈｅｍｅ １６に従って、合成を行った。
Synthesis was performed according to Scheme 16 below.
（３Ｒ，３’Ｓ）－５，７’－Ｄｉｃｈｌｏｒｏ－６’－ｆｌｕｏｒｏ－１－（４－ｍｅｔｈｏｘｙｂｅｎｚｙｌ）－３’－ｍｅｔｈｙｌ－２’，３’，４’，９’－ｔｅｔｒａｈｙｄｒｏｓｐｉｒｏ［ｉｎｄｏｌｉｎｅ－３，１’－ｐｙｒｉｄｏ［３，４－ｂ］ｉｎｄｏｌ］－２－ｏｎｅ（３７．９ｍｇ， ０．０７４２６ｍｍｏｌ）をＣＨ２Ｃｌ２（１．３５ｍｌ）に溶解し、－２０℃でＴｒｉｆｌｕｏｒｏｍｅｔｈａｎｅｓｕｌｆｏｎｉｃ ａｃｉｄ（０．１５ｍｌ）を加え１３．５時間撹拌した。ｓａｔ．ＮａＨＣＯ３ａｑ．（１０ｍｌ）を加え反応を停止後ＡｃＯＥｔ（２０ｍｌ）で３回抽出し、有機層を飽和食塩水で１回洗浄した。有機層をＮａ２ＳＯ４で脱水後、溶媒を留去した。粗生成物をシリカゲルカラムクロマトグラフィ〔ＭｅＯＨ／ＣＨ２Ｃｌ２＝１／３９（体積比）〕で精製し、（３Ｒ，３’Ｓ）－５，７’－Ｄｉｃｈｌｏｒｏ－６’－ｆｌｕｏｒｏ－３’－ｍｅｔｈｙｌ－２’，３’，４’，９’－ｔｅｔｒａｈｙｄｒｏｓｐｉｒｏ［ｉｎｄｏｌｉｎｅ－３，１’－ｐｙｒｉｄｏ［３，４－ｂ］ｉｎｄｏｌ］－２－ｏｎｅ（１７．５ｍｇ， 収率６０％）を得た。
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．６９（ｓ， １Ｈ）， １０．５４（ｓ， １Ｈ）， ７．４２（ｄ， Ｊ＝１０．０ Ｈｚ， １Ｈ）， ７．３２（ｄｄ， Ｊ＝８．４， ２．４ Ｈｚ， １Ｈ）， ７．２５（ｄ， Ｊ＝８．０ Ｈｚ， １Ｈ）， ７．０３（ｄ， Ｊ＝２．４ Ｈｚ， １Ｈ）， ６．９２（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ３．９６－３．８３（ｍ， １Ｈ）， ３．１１（ｄ， Ｊ＝４．８ Ｈｚ， １Ｈ）， ２．７６（ｄｄ， Ｊ＝１５．２， ３．６ Ｈｚ， １Ｈ）， ２．３６（ｄｄ， Ｊ＝１５．２， １０．８ Ｈｚ， １Ｈ）， １．１５ ｐｐｍ（ｄ， Ｊ＝６．４ Ｈｚ， ３Ｈ）． (3R, 3'S) -5,7'-Dichroro-6'-fluoro-1- (4-methoxybenzoyl) -3'-methyl-2 ', 3', 4 ', 9'-tetrahydrospiro [indoline-3 , 1′-pyrido [3,4-b] indol] -2-one (37.9 mg, 0.07426 mmol) was dissolved in CH 2 Cl 2 (1.35 ml) and trifluorethansulfuric acid (0. 15 ml) was added and stirred for 13.5 hours. sat. NaHCO 3 aq. (10 ml) was added to stop the reaction, followed by extraction three times with AcOEt (20 ml), and the organic layer was washed once with saturated brine. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The crude product was purified by silica gel column chromatography [MeOH / CH 2 Cl 2 = 1/39 (volume ratio)] and (3R, 3 ′S) -5,7′-Dichroro-6′-fluoro-3′- methyl-2 ′, 3 ′, 4 ′, 9′-tetrahydrospiro [indoline-3,1′-pyrido [3,4-b] indol] -2-one (17.5 mg, 60% yield) was obtained. .
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 10.54 (s, 1H), 7.42 (d, J = 10.0 Hz, 1H), 7.32 (Dd, J = 8.4, 2.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6 .92 (d, J = 8.4 Hz, 1H), 3.96-3.83 (m, 1H), 3.11 (d, J = 4.8 Hz, 1H), 2.76 (dd, J = 15.2, 3.6 Hz, 1H), 2.36 (dd, J = 15.2, 10.8 Hz, 1H), 1.15 ppm (d, J = 6.4 Hz, 3H) .
得られた化合物の１Ｈ ＮＭＲ測定結果を以下に示す。
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＤＭＳＯ－ｄ６） δ １０．６９（ｓ， １Ｈ）， １０．５４（ｓ， １Ｈ）， ７．４２（ｄ， Ｊ＝１０．０ Ｈｚ， １Ｈ）， ７．３２（ｄｄ， Ｊ＝８．４， ２．４ Ｈｚ， １Ｈ）， ７．２５（ｄ， Ｊ＝８．０ Ｈｚ， １Ｈ）， ７．０３（ｄ， Ｊ＝２．４ Ｈｚ， １Ｈ）， ６．９２（ｄ， Ｊ＝８．４ Ｈｚ， １Ｈ）， ３．９６－３．８３（ｍ， １Ｈ）， ３．１１（ｄ， Ｊ＝４．８ Ｈｚ， １Ｈ）， ２．７６（ｄｄ， Ｊ＝１５．２， ３．６ Ｈｚ， １Ｈ）， ２．３６（ｄｄ， Ｊ＝１５．２， １０．８ Ｈｚ， １Ｈ）， １．１５ ｐｐｍ（ｄ， Ｊ＝６．４ Ｈｚ， ３Ｈ）． (3R, 3'S) -5,7'-Dichroro-6'-fluoro-1- (4-methoxybenzoyl) -3'-methyl-2 ', 3', 4 ', 9'-tetrahydrospiro [indoline-3 , 1′-pyrido [3,4-b] indol] -2-one (37.9 mg, 0.07426 mmol) was dissolved in CH 2 Cl 2 (1.35 ml) and trifluorethansulfuric acid (0. 15 ml) was added and stirred for 13.5 hours. sat. NaHCO 3 aq. (10 ml) was added to stop the reaction, followed by extraction three times with AcOEt (20 ml), and the organic layer was washed once with saturated brine. The organic layer was dehydrated with Na 2 SO 4 and the solvent was distilled off. The crude product was purified by silica gel column chromatography [MeOH / CH 2 Cl 2 = 1/39 (volume ratio)] and (3R, 3 ′S) -5,7′-Dichroro-6′-fluoro-3′- methyl-2 ′, 3 ′, 4 ′, 9′-tetrahydrospiro [indoline-3,1′-pyrido [3,4-b] indol] -2-one (17.5 mg, 60% yield) was obtained. .
The 1 H NMR measurement result of the obtained compound is shown below.
1 H NMR (400 MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 10.54 (s, 1H), 7.42 (d, J = 10.0 Hz, 1H), 7.32 (Dd, J = 8.4, 2.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6 .92 (d, J = 8.4 Hz, 1H), 3.96-3.83 (m, 1H), 3.11 (d, J = 4.8 Hz, 1H), 2.76 (dd, J = 15.2, 3.6 Hz, 1H), 2.36 (dd, J = 15.2, 10.8 Hz, 1H), 1.15 ppm (d, J = 6.4 Hz, 3H) .
（実施例３及び参考例）
実施例１において、反応温度、反応時間を以下の表１に記載のように変更して、反応を行った。結果を表１に示した。なお、表１のＥｎｔｒｙ ６は、実施例１に対応する。
なお、参考までに、（Ｓ，Ｓ）－Ｐｈ－ＢＰＥを用いた参考例（Ｅｎｔｒｙ ０１，０２）を示した。参考例では、Ｓｃｈｅｍｅ ７の反応の生成物とは逆の立体化学を有する生成物が得られていることを確認した。 (Example 3 and Reference Example)
In Example 1, the reaction was carried out by changing the reaction temperature and reaction time as shown in Table 1 below. The results are shown in Table 1. Note that Entry 6 in Table 1 corresponds to Example 1.
For reference, a reference example (Entry 01, 02) using (S, S) -Ph-BPE is shown. In the reference example, it was confirmed that a product having a stereochemistry opposite to the product of the reaction of Scheme 7 was obtained.
実施例１において、反応温度、反応時間を以下の表１に記載のように変更して、反応を行った。結果を表１に示した。なお、表１のＥｎｔｒｙ ６は、実施例１に対応する。
なお、参考までに、（Ｓ，Ｓ）－Ｐｈ－ＢＰＥを用いた参考例（Ｅｎｔｒｙ ０１，０２）を示した。参考例では、Ｓｃｈｅｍｅ ７の反応の生成物とは逆の立体化学を有する生成物が得られていることを確認した。 (Example 3 and Reference Example)
In Example 1, the reaction was carried out by changing the reaction temperature and reaction time as shown in Table 1 below. The results are shown in Table 1. Note that Entry 6 in Table 1 corresponds to Example 1.
For reference, a reference example (Entry 01, 02) using (S, S) -Ph-BPE is shown. In the reference example, it was confirmed that a product having a stereochemistry opposite to the product of the reaction of Scheme 7 was obtained.
本発明の態様は、例えば、以下の通りである。
＜１＞ 下記一般式（１）で表される化合物の製造方法であって、
下記一般式（２）で表される化合物と、下記一般式（３）で表される化合物とを、下記一般式（Ａ）で表される不斉配位子を含有する触媒の存在下で反応させ、前記一般式（１）で表される化合物を得る反応工程を含むことを特徴とする化合物の製造方法である。
ただし、前記一般式（１）、及び前記一般式（２）中、Ｒ１は、水素原子、及びアミノ基の保護基のいずれかを表す。Ｒ２は、水素原子、及びアミノ基の保護基のいずれかを表す。前記一般式（１）、及び前記一般式（３）中、Ｒ１１は、置換基を有していてもよい芳香族基を表す。Ｒ１２は、置換基を有していてもよい芳香族基を表す。Ｒ１３は、水素原子、及びアミノ基の保護基のいずれかを表す。
ただし、前記一般式（Ａ）中、Ｒは、炭素数１～６のアルキル基、アリール基、置換アリール基、アラルキル基、及び環置換アラルキル基のいずれかを表す。
＜２＞ 前記一般式（Ａ）で表される不斉配位子のＲが、フェニル基である前記＜１＞に記載の化合物の製造方法である。
＜３＞ 前記触媒が、銅錯体である前記＜１＞に記載の化合物の製造方法である。
＜４＞ 前記銅錯体が、銅化合物と、前記一般式（Ａ）で表される不斉配位子とを混合して得られる前記＜３＞に記載の化合物の製造方法である。
＜５＞ 下記構造式（１）で表される化合物の製造方法であって、
下記一般式（２）で表される化合物と、下記一般式（３）で表される化合物とを、下記一般式（Ａ）で表される不斉配位子を含有する触媒の存在下で反応させ、前記一般式（１）で表される化合物を得る反応工程を含むことを特徴とする化合物の製造方法である。
ただし、前記一般式（１）、及び前記一般式（２）中、Ｒ１は、水素原子、及びアミノ基の保護基のいずれかを表す。Ｒ２は、水素原子、及びアミノ基の保護基のいずれかを表す。前記一般式（１）、及び前記一般式（３）中、Ｒ１１は、置換基を有していてもよい芳香族基を表す。Ｒ１２は、置換基を有していてもよい芳香族基を表す。Ｒ１３は、水素原子、及びアミノ基の保護基のいずれかを表す。
ただし、前記一般式（Ａ）中、Ｒは、炭素数１～６のアルキル基、アリール基、置換アリール基、アラルキル基、及び環置換アラルキル基のいずれかを表す。
＜６＞ 前記一般式（Ａ）で表される不斉配位子のＲが、フェニル基である前記＜５＞に記載の化合物の製造方法である。
＜７＞ 前記触媒が、銅錯体である前記＜５＞に記載の化合物の製造方法である。
＜８＞ 前記銅錯体が、銅化合物と、前記一般式（Ａ）で表される不斉配位子とを混合して得られる前記＜７＞に記載の化合物の製造方法である。 Aspects of the present invention are as follows, for example.
<1> A method for producing a compound represented by the following general formula (1),
A compound represented by the following general formula (2) and a compound represented by the following general formula (3) in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A) It is a manufacturing method of the compound characterized by including the reaction process of making it react and obtaining the compound represented by the said General formula (1).
However, in the general formula (1) and the general formula (2), R 1 represents either a hydrogen atom or an amino-protecting group. R 2 represents either a hydrogen atom or an amino-protecting group. In the general formula (1) and the general formula (3), R 11 represents an aromatic group which may have a substituent. R 12 represents an aromatic group which may have a substituent. R 13 represents either a hydrogen atom or an amino-protecting group.
In the general formula (A), R represents any of an alkyl group having 1 to 6 carbon atoms, an aryl group, a substituted aryl group, an aralkyl group, and a ring-substituted aralkyl group.
<2> The method for producing a compound according to <1>, wherein R of the asymmetric ligand represented by the general formula (A) is a phenyl group.
<3> The method for producing a compound according to <1>, wherein the catalyst is a copper complex.
<4> The method for producing a compound according to <3>, wherein the copper complex is obtained by mixing a copper compound and an asymmetric ligand represented by the general formula (A).
<5> A method for producing a compound represented by the following structural formula (1),
A compound represented by the following general formula (2) and a compound represented by the following general formula (3) in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A) It is a manufacturing method of the compound characterized by including the reaction process of making it react and obtaining the compound represented by the said General formula (1).
However, in the general formula (1) and the general formula (2), R 1 represents either a hydrogen atom or an amino-protecting group. R 2 represents either a hydrogen atom or an amino-protecting group. In the general formula (1) and the general formula (3), R 11 represents an aromatic group which may have a substituent. R 12 represents an aromatic group which may have a substituent. R 13 represents either a hydrogen atom or an amino-protecting group.
In the general formula (A), R represents any of an alkyl group having 1 to 6 carbon atoms, an aryl group, a substituted aryl group, an aralkyl group, and a ring-substituted aralkyl group.
<6> The method for producing a compound according to <5>, wherein R of the asymmetric ligand represented by the general formula (A) is a phenyl group.
<7> The method for producing a compound according to <5>, wherein the catalyst is a copper complex.
<8> The method for producing a compound according to <7>, wherein the copper complex is obtained by mixing a copper compound and an asymmetric ligand represented by the general formula (A).
＜１＞ 下記一般式（１）で表される化合物の製造方法であって、
下記一般式（２）で表される化合物と、下記一般式（３）で表される化合物とを、下記一般式（Ａ）で表される不斉配位子を含有する触媒の存在下で反応させ、前記一般式（１）で表される化合物を得る反応工程を含むことを特徴とする化合物の製造方法である。
＜２＞ 前記一般式（Ａ）で表される不斉配位子のＲが、フェニル基である前記＜１＞に記載の化合物の製造方法である。
＜３＞ 前記触媒が、銅錯体である前記＜１＞に記載の化合物の製造方法である。
＜４＞ 前記銅錯体が、銅化合物と、前記一般式（Ａ）で表される不斉配位子とを混合して得られる前記＜３＞に記載の化合物の製造方法である。
＜５＞ 下記構造式（１）で表される化合物の製造方法であって、
下記一般式（２）で表される化合物と、下記一般式（３）で表される化合物とを、下記一般式（Ａ）で表される不斉配位子を含有する触媒の存在下で反応させ、前記一般式（１）で表される化合物を得る反応工程を含むことを特徴とする化合物の製造方法である。
＜６＞ 前記一般式（Ａ）で表される不斉配位子のＲが、フェニル基である前記＜５＞に記載の化合物の製造方法である。
＜７＞ 前記触媒が、銅錯体である前記＜５＞に記載の化合物の製造方法である。
＜８＞ 前記銅錯体が、銅化合物と、前記一般式（Ａ）で表される不斉配位子とを混合して得られる前記＜７＞に記載の化合物の製造方法である。 Aspects of the present invention are as follows, for example.
<1> A method for producing a compound represented by the following general formula (1),
A compound represented by the following general formula (2) and a compound represented by the following general formula (3) in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A) It is a manufacturing method of the compound characterized by including the reaction process of making it react and obtaining the compound represented by the said General formula (1).
<2> The method for producing a compound according to <1>, wherein R of the asymmetric ligand represented by the general formula (A) is a phenyl group.
<3> The method for producing a compound according to <1>, wherein the catalyst is a copper complex.
<4> The method for producing a compound according to <3>, wherein the copper complex is obtained by mixing a copper compound and an asymmetric ligand represented by the general formula (A).
<5> A method for producing a compound represented by the following structural formula (1),
A compound represented by the following general formula (2) and a compound represented by the following general formula (3) in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A) It is a manufacturing method of the compound characterized by including the reaction process of making it react and obtaining the compound represented by the said General formula (1).
<6> The method for producing a compound according to <5>, wherein R of the asymmetric ligand represented by the general formula (A) is a phenyl group.
<7> The method for producing a compound according to <5>, wherein the catalyst is a copper complex.
<8> The method for producing a compound according to <7>, wherein the copper complex is obtained by mixing a copper compound and an asymmetric ligand represented by the general formula (A).
本発明の化合物の製造方法は、所謂ＮＩＴＤ６０９の製造に好適に用いることができる。
The method for producing a compound of the present invention can be suitably used for producing so-called NITD609.
The method for producing a compound of the present invention can be suitably used for producing so-called NITD609.
Claims (8)
- 下記一般式（１）で表される化合物の製造方法であって、
下記一般式（２）で表される化合物と、下記一般式（３）で表される化合物とを、下記一般式（Ａ）で表される不斉配位子を含有する触媒の存在下で反応させ、前記一般式（１）で表される化合物を得る反応工程を含むことを特徴とする化合物の製造方法。
A compound represented by the following general formula (2) and a compound represented by the following general formula (3) in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A) The manufacturing method of the compound characterized by including the reaction process of making it react and obtaining the compound represented by the said General formula (1).
- 前記一般式（Ａ）で表される不斉配位子のＲが、フェニル基である請求項１に記載の化合物の製造方法。 The method for producing a compound according to claim 1, wherein R of the asymmetric ligand represented by the general formula (A) is a phenyl group.
- 前記触媒が、銅錯体である請求項１に記載の化合物の製造方法。 The method for producing a compound according to claim 1, wherein the catalyst is a copper complex.
- 前記銅錯体が、銅化合物と、前記一般式（Ａ）で表される不斉配位子とを混合して得られる請求項３に記載の化合物の製造方法。 The method for producing a compound according to claim 3, wherein the copper complex is obtained by mixing a copper compound and the asymmetric ligand represented by the general formula (A).
- 下記構造式（１）で表される化合物の製造方法であって、
下記一般式（２）で表される化合物と、下記一般式（３）で表される化合物とを、下記一般式（Ａ）で表される不斉配位子を含有する触媒の存在下で反応させ、前記一般式（１）で表される化合物を得る反応工程を含むことを特徴とする化合物の製造方法。
A compound represented by the following general formula (2) and a compound represented by the following general formula (3) in the presence of a catalyst containing an asymmetric ligand represented by the following general formula (A) The manufacturing method of the compound characterized by including the reaction process of making it react and obtaining the compound represented by the said General formula (1).
- 前記一般式（Ａ）で表される不斉配位子のＲが、フェニル基である請求項５に記載の化合物の製造方法。 The method for producing a compound according to claim 5, wherein R of the asymmetric ligand represented by the general formula (A) is a phenyl group.
- 前記触媒が、銅錯体である請求項５に記載の化合物の製造方法。 The method for producing a compound according to claim 5, wherein the catalyst is a copper complex.
- 前記銅錯体が、銅化合物と、前記一般式（Ａ）で表される不斉配位子とを混合して得られる請求項７に記載の化合物の製造方法。 The method for producing a compound according to claim 7, wherein the copper complex is obtained by mixing a copper compound and an asymmetric ligand represented by the general formula (A).
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|---|---|---|---|---|
| CN110437230A (en) * | 2019-08-29 | 2019-11-12 | 中国科学院上海有机化学研究所 | A kind of three-level aminated compounds and biphosphine ligand, wherein mesosome and preparation method |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05507078A (en) * | 1990-05-17 | 1993-10-14 | イー・アイ・デユポン・ドウ・ヌムール・アンド・カンパニー | chiral phosphorane transition metal catalyst |
| JP2011518852A (en) * | 2008-04-29 | 2011-06-30 | ノバルティス アーゲー | Spiro-indole derivatives for the treatment of parasitic diseases |
| JP2015512381A (en) * | 2012-03-23 | 2015-04-27 | ノバルティス アーゲー | Chemical processes for the preparation of spiroindolones and their intermediates |
| CN104926813A (en) * | 2015-05-15 | 2015-09-23 | 四川大学 | Method for asymmetric catalytic synthesis of spirocyclic tetrahydrocarbazoline compound |
-
2015
- 2015-07-15 JP JP2015141582A patent/JP2017024992A/en active Pending
-
2016
- 2016-07-14 WO PCT/JP2016/070920 patent/WO2017010558A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05507078A (en) * | 1990-05-17 | 1993-10-14 | イー・アイ・デユポン・ドウ・ヌムール・アンド・カンパニー | chiral phosphorane transition metal catalyst |
| JP2011518852A (en) * | 2008-04-29 | 2011-06-30 | ノバルティス アーゲー | Spiro-indole derivatives for the treatment of parasitic diseases |
| JP2015512381A (en) * | 2012-03-23 | 2015-04-27 | ノバルティス アーゲー | Chemical processes for the preparation of spiroindolones and their intermediates |
| CN104926813A (en) * | 2015-05-15 | 2015-09-23 | 四川大学 | Method for asymmetric catalytic synthesis of spirocyclic tetrahydrocarbazoline compound |
Non-Patent Citations (7)
| Title |
|---|
| BIN ZOU ET AL.: "Mechanistic Study of the Spiroindolones: A New Class of Antimalarials", MOLECULES, vol. 17, 2012, pages 10131 - 10141, XP055345333 * |
| HAIFENG ZHENG ET AL.: "Regio- and Enantioselective Aza-Diels-Alder Reactions of 3-vinylindoles: A Concise Synthesis of the Antimalarial Spiroindolone NITD609", ANGEWANDTE CHEMIE , INTERNATIONAL EDITION, vol. 54, no. 37, 23 July 2015 (2015-07-23), pages 10958 - 10962, XP055345339 * |
| HISASHI TAKADA ET AL.: "Stereoselective Total Synthesis of KAE609 via Direct Catalytic Asymmetric Alkynylation to Ketimine", ORGANIC LETTERS, vol. 17, no. 19, 14 September 2015 (2015-09-14), pages 4762 - 4765 * |
| JACOB P. MACDONALD ET AL.: "Catalytic Stereoselective Synthesis of Diverse Oxindoles and Spirooxindoles from Isatins", ACS COMBINATORIAL SCIENCE, vol. 14, no. 4, 2012, pages 285 - 293, XP055345335 * |
| JOSEPH J. BADILLO ET AL.: "Enantioselective Pictet-Spengler reactions of isatins for the synthesis of spiroindolones", TETRAHEDRON LETTERS, vol. 52, no. 43, 2011, pages 5550 - 5553, XP028391249 * |
| SARA DUCE ET AL.: "An Easy Entry to Optically Active Spiroindolinones: Chiral Bronsted Acid- Catalysed Pictet-Spengler Reactions of Isatins", ADVANCED SYNTHESIS & CATALYSIS, vol. 353, no. 6, 2011, pages 860 - 864 * |
| SHAOQUAN LIN ET AL.: "Catalytic Asymmetric Mannich-Type Reaction of N-Alkylidene-a- Aminoacetonitrile with Ketimines", ANGEW. CHEM. INT. ED., vol. 54, 3 March 2015 (2015-03-03), pages 5183 - 5186, XP055345332 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110437230A (en) * | 2019-08-29 | 2019-11-12 | 中国科学院上海有机化学研究所 | A kind of three-level aminated compounds and biphosphine ligand, wherein mesosome and preparation method |
| CN110437230B (en) * | 2019-08-29 | 2022-06-21 | 中国科学院上海有机化学研究所 | Tertiary amine compound, diphosphine ligand, intermediate and preparation method thereof |
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