JP4867071B2 - Method for producing quinoline derivative - Google Patents
Method for producing quinoline derivative Download PDFInfo
- Publication number
- JP4867071B2 JP4867071B2 JP2001037106A JP2001037106A JP4867071B2 JP 4867071 B2 JP4867071 B2 JP 4867071B2 JP 2001037106 A JP2001037106 A JP 2001037106A JP 2001037106 A JP2001037106 A JP 2001037106A JP 4867071 B2 JP4867071 B2 JP 4867071B2
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- JP
- Japan
- Prior art keywords
- group
- carbon atoms
- substituent
- alkyl group
- independently
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title claims 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 73
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 35
- -1 phosphonium salt compound Chemical class 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000002947 alkylene group Chemical group 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000000732 arylene group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 19
- WRXZCLBKDXISQA-UHFFFAOYSA-N 2-chloro-7-methoxyquinoline-3-carbaldehyde Chemical compound C1=C(C=O)C(Cl)=NC2=CC(OC)=CC=C21 WRXZCLBKDXISQA-UHFFFAOYSA-N 0.000 description 18
- 150000004714 phosphonium salts Chemical class 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 150000003248 quinolines Chemical class 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- JAHBIRPTCXOGLB-UHFFFAOYSA-N 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde Chemical compound C1=CC(F)=CC=C1C1=C(C=O)C(C2CC2)=NC2=CC=CC=C12 JAHBIRPTCXOGLB-UHFFFAOYSA-N 0.000 description 8
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 8
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 230000003301 hydrolyzing effect Effects 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- FRHRVQQUICVJDG-UHFFFAOYSA-M 1,3-dioxolan-2-ylmethyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)CC1OCCO1 FRHRVQQUICVJDG-UHFFFAOYSA-M 0.000 description 4
- LUQYELQXRPNKRY-UHFFFAOYSA-N 2-diethoxyphosphoryl-1,1-diethoxyethane Chemical compound CCOC(OCC)CP(=O)(OCC)OCC LUQYELQXRPNKRY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000004036 acetal group Chemical group 0.000 description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 125000001841 imino group Chemical group [H]N=* 0.000 description 3
- 229910052987 metal hydride Inorganic materials 0.000 description 3
- 150000004681 metal hydrides Chemical class 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 2
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 2
- 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 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- GCOCYGLSBKOTBU-ZHACJKMWSA-N n-[(e)-2-diethoxyphosphorylethenyl]cyclohexanamine Chemical compound CCOP(=O)(OCC)\C=C\NC1CCCCC1 GCOCYGLSBKOTBU-ZHACJKMWSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- FFFXIQFESQNINT-UHFFFAOYSA-N (2-aminophenyl)-(4-fluorophenyl)methanone Chemical compound NC1=CC=CC=C1C(=O)C1=CC=C(F)C=C1 FFFXIQFESQNINT-UHFFFAOYSA-N 0.000 description 1
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 description 1
- UJXBDMBSVXZOBW-UHFFFAOYSA-M 1,3-dioxolan-2-ylmethyl(triphenyl)phosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)CC1OCCO1 UJXBDMBSVXZOBW-UHFFFAOYSA-M 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CKIIJIDEWWXQEA-UHFFFAOYSA-N 2-(bromomethyl)-1,3-dioxolane Chemical compound BrCC1OCCO1 CKIIJIDEWWXQEA-UHFFFAOYSA-N 0.000 description 1
- LILXDMFJXYAKMK-UHFFFAOYSA-N 2-bromo-1,1-diethoxyethane Chemical compound CCOC(CBr)OCC LILXDMFJXYAKMK-UHFFFAOYSA-N 0.000 description 1
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 1
- BVCNMNAUQZYOFT-UHFFFAOYSA-N 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylic acid Chemical compound OC(=O)C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 BVCNMNAUQZYOFT-UHFFFAOYSA-N 0.000 description 1
- ZBPYWQLAIDVQDF-UHFFFAOYSA-N 2-dimethoxyphosphoryl-1,1-dimethoxyethane Chemical compound COC(OC)CP(=O)(OC)OC ZBPYWQLAIDVQDF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 0 C*C(C[N+](*)([O-])O)*C Chemical compound C*C(C[N+](*)([O-])O)*C 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- JYVXNLLUYHCIIH-ZCFIWIBFSA-N R-mevalonolactone, (-)- Chemical class C[C@@]1(O)CCOC(=O)C1 JYVXNLLUYHCIIH-ZCFIWIBFSA-N 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical group C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 1
- GOPYZMJAIPBUGX-UHFFFAOYSA-N [O-2].[O-2].[Mn+4] Chemical class [O-2].[O-2].[Mn+4] GOPYZMJAIPBUGX-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 150000004791 alkyl magnesium halides Chemical class 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 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
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ZTWTYVWXUKTLCP-UHFFFAOYSA-L ethenyl-dioxido-oxo-$l^{5}-phosphane Chemical compound [O-]P([O-])(=O)C=C ZTWTYVWXUKTLCP-UHFFFAOYSA-L 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- BLHLJVCOVBYQQS-UHFFFAOYSA-N ethyllithium Chemical compound [Li]CC BLHLJVCOVBYQQS-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- AHNJTQYTRPXLLG-UHFFFAOYSA-N lithium;diethylazanide Chemical compound [Li+].CC[N-]CC AHNJTQYTRPXLLG-UHFFFAOYSA-N 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- UODMSBYDFUPQHC-UHFFFAOYSA-M magnesium;di(propan-2-yl)azanide;bromide Chemical compound CC(C)N([Mg]Br)C(C)C UODMSBYDFUPQHC-UHFFFAOYSA-M 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000003208 petroleum Substances 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
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- WARKYKQCOXTIAO-UHFFFAOYSA-N tributyl(2-ethoxyethenyl)stannane Chemical group CCCC[Sn](CCCC)(CCCC)\C=C/OCC WARKYKQCOXTIAO-UHFFFAOYSA-N 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000007934 α,β-unsaturated carboxylic acids Chemical class 0.000 description 1
Landscapes
- Quinoline Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、キノリン誘導体の製造方法に関する。本発明で得られるキノリン誘導体は医薬・農薬などの合成中間体として有用であり、例えば（Ｅ）−３−（４’−（４”−フルオロフェニル）−２’−シクロプロピルキノリン−３’−イル）プロペンアルデヒドはコレステロール生合成の律速酵素であるＨＭＧ−ＣｏＡ還元酵素の阻害剤として知られるキノリン系メバロノラクトン誘導体の重要な合成中間体である。
【０００２】
【従来の技術】
キノリン誘導体、例えば（Ｅ）−３−（４’−（４”−フルオロフェニル）−２’−シクロプロピルキノリン−３’−イル）プロペンアルデヒドの合成方法としては、▲１▼テトラヒドロフラン中でシス−１−エトキシ−２−（トリ−ｎ−ブチルスタニル）エチレンにブチルリチウムを作用させ、次いで−６０〜−７８℃で４−（４’−フルオロフェニル）−２−シクロプロピルキノリン−３−カルバルデヒドと反応させ、得られたビニルエーテル体を酸触媒の存在下で加水分解する方法、または▲２▼４−（４’−フルオロフェニル）−２−シクロプロピルキノリン−３−カルバルデヒドにアルコキシカルボニルメチルホスホネートを反応させて相当するα，β−不飽和カルボン酸エステルを得、次いでこの化合物のエステル部分を例えばジイソブチルアルミニウムヒドリドなどの金属水素化物で還元してアルコールに変換した後、活性二酸化マンガンなどの酸化剤を用いて酸化する方法が知られている（特開平１−２７９８６６号公報参照）。
【０００３】
【発明が解決しようとする課題】
上記▲１▼の方法は、用いる有機スズ化合物が工業的に入手困難である上、−６０〜−７８℃という極低温で反応させなければならず、特殊な反応設備を必要とする問題点を有する。上記▲２▼の方法では、エステル部分を還元する際に用いる金属水素化物の取り扱いが困難である。また、いずれの方法も目的物を得るまでに複数の工程を経る必要があり、（Ｅ）−３−（４’−（４”−フルオロフェニル）−２’−シクロプロピルキノリン−３’−イル）プロペンアルデヒドのようなキノリン誘導体の工業的な製造方法として必ずしも有利とは言えない。
【０００４】
しかして、本発明の目的は、工業的に入手容易で、かつ取り扱いの容易な薬品を用い、キノリン誘導体をより短い工程で、効率よく工業的に有利に製造し得る方法を提供することにある。
【０００５】
【課題を解決するための手段】
本発明によれば、上記の目的は、一般式（Ｉ）
【０００６】
【化６】
（式中、Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5およびＲ6はそれぞれ独立に水素原子、ハロゲン原子、トリフルオロメチル基、トリフルオロメトキシ基、保護されていてもよい水酸基、置換基を有していてもよいアルキル基、置換基を有していてもよいシクロアルキル基、置換基を有していてもよいアリール基、置換基を有していてもよいアラルキル基、置換基を有していてもよいアルコキシル基または置換基を有していてもよいアリールオキシ基を表す。）
で示されるキノリンカルバルデヒド（以下、キノリンカルバルデヒド（Ｉ）と略称する）を、塩基の存在下、以下の化合物（ａ）〜（ｃ）：
（ａ）一般式（ＩＩ）
【０００８】
【化７】
（式中、Ｒ7およびＲ8はそれぞれ独立に水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアシル基もしくは置換基を有していてもよいアラルキル基を表すか、または一緒になってアルキレン基、アリーレン基もしくはアラルキレン基を表し、Ｒ9は置換基を有していてもよいアルキル基または置換基を有していてもよいアリール基を表し、Ｘはハロゲン原子を表す。）
で示されるホスホニウム塩化合物（以下、ホスホニウム塩（ＩＩ）と略称する）、
（ｂ）一般式（ＩＩＩ）
【００１０】
【化８】
（式中、Ｒ7、Ｒ8およびＲ9は前記定義のとおりである。）
で示されるホスホネート化合物（以下、ホスホネート（ＩＩＩ）と略称する）または
（ｃ）一般式（ＩＶ）
【００１２】
【化９】
（式中、Ｒ9は前記定義のとおりであり、Ｒ10およびＲ11はそれぞれ独立に水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいシクロアルキル基、置換基を有していてもよいアリール基もしくは置換基を有していてもよいアラルキル基を表すか、または一緒になってアルキレン基、アリーレン基もしくはアラルキレン基を表す。）
で示されるホスホネート化合物（以下、ホスホネート（ＩＶ）と略称する）；のいずれか１種の化合物と反応させ、次いで加水分解させることを特徴とする一般式（Ｖ）
【００１４】
【化１０】
（式中、Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5およびＲ6は前記定義のとおりである。）
で示されるキノリン誘導体（以下、キノリン誘導体（Ｖ）と略称する）の製造方法を提供することによって達成される。
【００１６】
好ましい実施態様において、Ｒ1、Ｒ2、Ｒ3およびＲ6は水素原子であり、Ｒ4はハロゲン原子であり、Ｒ5は炭素数１〜６のアルキル基または炭素数３〜６のシクロアルキル基であり、Ｒ7およびＲ8はそれぞれ独立に炭素数１〜６のアルキル基、炭素数３〜６のシクロアルキル基、フェニル基、ナフチル基もしくはベンジル基であるか、または一緒になって炭素数２〜６のアルキレン基もしくは炭素数６〜１０のアリーレン基であり、Ｒ9は炭素数１〜６のアルキル基またはフェニル基であり、Ｒ10およびＲ11はそれぞれ独立に炭素数１〜６のアルキル基、炭素数３〜６のシクロアルキル基、フェニル基、ナフチル基もしくはベンジル基であるか、または一緒になって炭素数２〜６のアルキレン基もしくは炭素数６〜１０のアリーレン基である。
【００１７】
さらに好ましい実施態様において、Ｒ4はフッ素原子であり、Ｒ7およびＲ8はそれぞれ独立に炭素数１〜６のアルキル基であるか、または一緒になって炭素数２〜６のアルキレン基であり、Ｒ10およびＲ11はそれぞれ独立に炭素数１〜６のアルキル基であるか、または一緒になって炭素数２〜６のアルキレン基である。
【００１８】
【発明の実施の形態】
上記一般式中、Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7、Ｒ8、Ｒ9、Ｒ10およびＲ11が表すアルキル基としては、好ましくは炭素数１〜６の直鎖状または分岐鎖状のアルキル基が挙げられ、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔｅｒｔ−ブチル基などが挙げられる。これらのアルキル基は置換基を有していてもよく、かかる置換基としては、例えば水酸基；メトキシ基、エトキシ基、プロポキシ基、ブトキシ基などの好ましくは炭素数１〜４のアルコキシル基などが挙げられる。
【００１９】
Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ10およびＲ11が表すシクロアルキル基としては、好ましくは炭素数３〜６のシクロアルキル基が挙げられ、例えばシクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基などが挙げられる。これらのシクロアルキル基は置換基を有していてもよく、かかる置換基としては、例えば水酸基；メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔｅｒｔ−ブチル基などの好ましくは炭素数１〜６のアルキル基；メトキシ基、エトキシ基、プロポキシ基、ブトキシ基などの好ましくは炭素数１〜４のアルコキシル基；フェニル基、ｐ−メトキシフェニル基、ｐ−クロロフェニル基などの好ましくは炭素数６〜１０のアリール基などが挙げられる。
【００２０】
Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ9、Ｒ10およびＲ11が表すアリール基としては、好ましくは炭素数６〜１０のアリール基が挙げられ、例えばフェニル基、ナフチル基などが挙げられる。これらのアリール基は置換基を有していてもよく、かかる置換基としては、例えば水酸基；メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔｅｒｔ−ブチル基などの好ましくは炭素数１〜６のアルキル基；メトキシ基、エトキシ基、プロポキシ基、ブトキシ基などの好ましくは炭素数１〜４のアルコキシル基；フェニル基、ｐ−メトキシフェニル基、ｐ−クロロフェニル基などの好ましくは炭素数６〜１０のアリール基が挙げられる。
【００２１】
Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7、Ｒ8、Ｒ10およびＲ11が表すアラルキル基としては、アルキル部分として好ましくは炭素数１〜６のアルキル基を有し、アリール部分として好ましくは炭素数６〜１０のアリール基を有するアラルキル基が挙げられ、例えばベンジル基、ナフチルメチル基などが挙げられる。これらのアラルキル基は置換基を有していてもよく、かかる置換基としては、例えば水酸基；メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔｅｒｔ−ブチル基などの好ましくは炭素数１〜６のアルキル基；メトキシ基、エトキシ基、プロポキシ基、ブトキシ基などの好ましくは炭素数１〜４のアルコキシル基；フェニル基、ｐ−メトキシフェニル基、ｐ−クロロフェニル基などの好ましくは炭素数６〜１０のアリール基が挙げられる。
【００２２】
Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6およびＸが表す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、ヨウ素原子などが挙げられ、好ましくはフッ素原子が挙げられる。
【００２３】
Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5およびＲ6が表すアルコキシル基としては、好ましくは炭素数１〜４の直鎖状または分岐鎖状のアルコキシル基が挙げられ、例えばメトキシ基、エトキシ基、プロポキシ基、ブトキシ基などが挙げられる。これらのアルコキシル基は置換基を有していてもよく、かかる置換基としては、例えば水酸基；メトキシ基、エトキシ基、プロポキシ基、ブトキシ基などの好ましくは炭素数１〜４のアルコキシル基；フェニル基、ｐ−メトキシフェニル基、ｐ−クロロフェニル基などの好ましくは炭素数６〜１０のアリール基などが挙げられる。
【００２４】
Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5およびＲ6が表すアリールオキシ基としては、アリール部分として好ましくは炭素数６〜１０のアリール基を有するアリールオキシ基が挙げられ、例えばフェノキシ基、トリルオキシ基、ナフチルオキシ基などが挙げられる。これらのアリールオキシ基は置換基を有していてもよく、かかる置換基としては、例えば水酸基；メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔｅｒｔ−ブチル基などの好ましくは炭素数１〜６のアルキル基；メトキシ基、エトキシ基、プロポキシ基、ブトキシ基などの好ましくは炭素数１〜４のアルコキシル基；フェニル基、ｐ−メトキシフェニル基、ｐ−クロロフェニル基などの好ましくは炭素数６〜１０のアリール基が挙げられる。
【００２５】
Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5およびＲ6が表す水酸基は保護されていてもよく、水酸基の保護基としては、水酸基を保護する目的のために通常用いられる保護基であれば特に制限はなく、例えばベンジル基などのアラルキル基；トリメチルシリル基、ｔｅｒｔ−ブチルジメチルシリル基、ｔｅｒｔ−ブチルジフェニルシリル基などの三置換シリル基；メトキシメチル基、１−エトキシエチル基、テトラヒドロフラニル基、テトラヒドロピラニル基などのアセタール型保護基などが挙げられる。
【００２６】
Ｒ7およびＲ8が表すアシル基としては、例えばアセチル基などの好ましくはアルキル部分として炭素数１〜６の直鎖状または分岐鎖状のアルキル基を有するアルキルカルボニル基；ベンゾイル基などの好ましくはアリール部分として炭素数６〜１０のアリール基を有するアリールカルボニル基などが挙げられる。これらのアシル基は置換基を有していてもよく、かかる置換基としては、例えば水酸基；メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔｅｒｔ−ブチル基などの好ましくは炭素数１〜６のアルキル基；メトキシ基、エトキシ基、プロポキシ基、ブトキシ基などの好ましくは炭素数１〜４のアルコキシル基；フェニル基、ｐ−メトキシフェニル基、ｐ−クロロフェニル基などの好ましくは炭素数６〜１０のアリール基が挙げられる。
【００２７】
Ｒ7およびＲ8、ならびにＲ10およびＲ11が一緒になって表すアルキレン基としては、好ましくは炭素数２〜６の直鎖状または分岐鎖状のアルキレン基が挙げられ、例えばエチレン基、プロピレン基、ブチレン基、ペンチレン基などが挙げられる。Ｒ7およびＲ8、ならびにＲ10およびＲ11が一緒になって表すアリーレン基としては、好ましくは炭素数６〜１０のアリーレン基が挙げられ、例えばｏ−フェニレン基、２，３−ナフタレンジイル基などが挙げられる。Ｒ7およびＲ8、ならびにＲ10およびＲ11が一緒になって表すアラルキレン基としては、アルキレン部分として好ましくは炭素数２〜６のアルキレン基を有し、アリーレン部分として好ましくは炭素数６〜１０のアリーレン基を有するアラルキレン基が挙げられ、例えば１，２−ベンゾ−２−ブテン基、２，３−ナフト−２−ブテン基などが挙げられる。
【００２８】
キノリンカルバルデヒド（Ｉ）およびキノリン誘導体（Ｖ）として、好ましくは、Ｒ1、Ｒ2、Ｒ3およびＲ6が水素原子であり、Ｒ4がハロゲン原子であり、Ｒ5が炭素数１〜６のアルキル基または炭素数３〜６のシクロアルキル基である化合物が挙げられる。
【００２９】
より好ましいキノリンカルバルデヒド（Ｉ）およびキノリン誘導体（Ｖ）として、Ｒ1、Ｒ2、Ｒ3およびＲ6が水素原子であり、Ｒ4がフッ素原子であり、Ｒ5が炭素数１〜６のアルキル基または炭素数３〜６のシクロアルキル基である化合物が挙げられる。
【００３０】
さらに好ましいキノリンカルバルデヒド（Ｉ）およびキノリン誘導体（Ｖ）として、Ｒ1、Ｒ2、Ｒ3およびＲ6が水素原子であり、Ｒ4がフッ素原子であり、Ｒ5がイソプロピル基またはシクロプロピル基である化合物が挙げられる。
【００３１】
ホスホニウム塩（ＩＩ）およびホスホネート（ＩＩＩ）として、好ましくはＲ7およびＲ8がそれぞれ独立に炭素数１〜６のアルキル基、炭素数３〜６のシクロアルキル基、フェニル基、ナフチル基もしくはベンジル基であるか、または一緒になって炭素数２〜６のアルキレン基もしくは炭素数６〜１０のアリーレン基であり、Ｒ9が炭素数１〜６のアルキル基またはフェニル基である化合物が挙げられる。
【００３２】
より好ましいホスホニウム塩（ＩＩ）およびホスホネート（ＩＩＩ）として、Ｒ7およびＲ8がそれぞれ独立に炭素数１〜６のアルキル基であるか、または一緒になって炭素数２〜６のアルキレン基であり、Ｒ9が炭素数１〜６のアルキル基またはフェニル基である化合物が挙げられる。
【００３３】
ホスホネート（ＩＶ）として、好ましくはＲ9が炭素数１〜６のアルキル基またはフェニル基であり、Ｒ10およびＲ11がそれぞれ独立に炭素数１〜６のアルキル基、炭素数３〜６のシクロアルキル基、フェニル基、ナフチル基もしくはベンジル基であるか、または一緒になって炭素数２〜６のアルキレン基もしくは炭素数６〜１０のアリーレン基である化合物が挙げられる。
【００３４】
より好ましいホスホネート（ＩＶ）として、Ｒ9が炭素数１〜６のアルキル基またはフェニル基であり、Ｒ10およびＲ11がそれぞれ独立に炭素数１〜６のアルキル基であるか、または一緒になって炭素数２〜６のアルキレン基である化合物が挙げられる。
【００３５】
本発明のキノリン誘導体（Ｖ）の製造方法は、キノリンカルバルデヒド（Ｉ）を、塩基の存在下でホスホニウム塩（ＩＩ）、ホスホネート（ＩＩＩ）またはホスホネート（ＩＶ）のいずれか１種の化合物と反応させ、次いで加水分解させることを特徴とする。すなわち、以下のスキーム１に示されるように、ホスホニウム塩（ＩＩ）、ホスホネート（ＩＩＩ）またはホスホネート（ＩＶ）に塩基が作用することにより生成する活性中間体（ホスホラン化合物）とキノリンカルバルデヒド（Ｉ）を反応させる工程（工程１）、およびかかる反応で得られた生成物（ｉａ）または（ｉｂ）のアセタール基部分またはイミノ基部分を加水分解する工程（工程２）からなる。本製造方法においてホスホニウム塩（ＩＩ）、ホスホネート（ＩＩＩ）またはホスホネート（ＩＶ）に塩基が作用することにより生成する活性中間体（ホスホラン化合物）を単離して、キノリンカルバルデヒド（Ｉ）との反応に付すことも可能であり、かかる方法も本発明に含まれる。
【００３６】
【化１１】
（式中、各記号は前記定義のとおりである。）
【００３８】
本発明の方法では、キノリンカルバルデヒド（Ｉ）を、塩基の存在下でホスホニウム塩（ＩＩ）、ホスホネート（ＩＩＩ）またはホスホネート（ＩＶ）と反応させることで、反応系内で生成する活性中間体（ホスホラン化合物）を直ちにキノリンカルバルデヒド（Ｉ）と反応させ、かかる反応により得られる生成物を精製または精製せずに加水分解することで、キノリン誘導体（Ｖ）を有利に製造することができる。
【００３９】
以下、本発明の方法を各工程ごとに説明する。
【００４０】
［工程１］キノリンカルバルデヒド（Ｉ）を、塩基の存在下でホスホニウム塩（ＩＩ）、ホスホネート（ＩＩＩ）またはホスホネート（ＩＶ）と反応させる工程
【００４１】
ホスホニウム塩（ＩＩ）としては、例えば（１，３−ジオキソラン−２−イルメチル）トリフェニルホスホニウムブロミド、（１，３−ジオキソラン−２−イルメチル）トリフェニルホスホニウムヨージドなどが挙げられる。ホスホネート（ＩＩＩ）としては、例えばジエチルホスホノアセトアルデヒドジエチルアセタール、ジメチルホスホノアセトアルデヒドジメチルアセタールなどが挙げられる。ホスホネート（ＩＶ）としては、例えばジエチル−２−（シクロヘキシルアミノ）ビニルホスホネート、ジメチル−２−（シクロヘキシルアミノ）ビニルホスホネートなどが挙げられる。
【００４２】
ホスホニウム塩（ＩＩ）、ホスホネート（ＩＩＩ）またはホスホネート（ＩＶ）の使用量は、キノリンカルバルデヒド（Ｉ）１モルに対して１〜１０モル倍の範囲が好ましく、１〜２モル倍の範囲がより好ましい。
【００４３】
塩基としては、例えば、炭酸ナトリウム、炭酸カリウムなどのアルカリ金属炭酸塩；水酸化ナトリウム、水酸化カリウムなどのアルカリ金属水酸化物；メチルリチウム、エチルリチウム、ｎ−ブチルリチウム、ｓｅｃ−ブチルリチウム、ｔｅｒｔ−ブチルリチウム、フェニルリチウムなどの有機リチウム化合物；メチルマグネシウムクロリド、エチルマグネシウムブロミドなどのアルキルマグネシウムハライド；リチウムアミド、ナトリウムアミド、カリウムアミド、リチウムジエチルアミド、リチウムジイソプロピルアミド、リチウムビストリメチルシリルアミド、ナトリウムビストリメチルシリルアミド、カリウムビストリメチルシリルアミド、ブロモマグネシウムジイソプロピルアミドなどの金属アミド；リチウムメトキシド、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウムｔｅｒｔ−ブトキシド、カリウムｔｅｒｔ−ブトキシドなどの金属アルコキシド；水素化リチウム、水素化ナトリウム、水素化カリウムなどのアルカリ金属水素化物などが挙げられる。これらの中でも、生成する活性中間体（ホスホラン化合物）の安定性が高いなどの観点から、水素化ナトリウム、ｎ−ブチルリチウム、ｔｅｒｔ−ブチルリチウム、カリウムｔｅｒｔ−ブトキシドを用いるのが好ましい。塩基の使用量に特に制限はないが、反応を円滑に進行させる観点からは、通常ホスホニウム塩（ＩＩ）、ホスホネート（ＩＩＩ）またはホスホネート（ＩＶ）１モルに対して０．１モル以上を用いるのが好ましく、０．５〜２モル倍の範囲で用いるのがより好ましい。
【００４４】
当該工程は、溶媒の存在下に行うのが好ましい。使用できる溶媒としては、反応に悪影響を及ぼさない限り特に制限はなく、例えばペンタン、ヘキサン、ヘプタン、シクロヘキサン、メチルシクロヘキサンなどの脂肪族炭化水素；ベンゼン、トルエン、キシレンなどの芳香族炭化水素；メタノール、エタノール、イソプロパノール、ｎ−ブタノール、ｔｅｒｔ−ブタノールなどのアルコール；ジエチルエーテル、ジイソプロピルエーテル、ｔｅｒｔ−ブチルメチルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル；塩化メチレン、クロロホルム、１，２−ジクロロエタンなどのハロゲン化炭化水素；アセトニトリル、ベンゾニトリルなどのニトリル；ピリジンなどの含窒素芳香環化合物；ジメチルホルムアミド、Ｎ−メチルピロリドン、Ｎ，Ｎ’−ジメチルイミダゾリジノン、ヘキサメチルホスホリックトリアミドなどのアミド；ジメチルスルホキシド、Ｎ，Ｎ，Ｎ’，Ｎ’-テトラメチルエチレンジアミン、アンモニア；またはこれらの混合物が挙げられる。これらの中でも、反応系内で生成する活性中間体（ホスホラン化合物）の安定性の観点から、ベンゼン、トルエン、キシレンなどの芳香族炭化水素；ジエチルエーテル、ジイソプロピルエーテル、ｔｅｒｔ−ブチルメチルエーテル、テトラヒドロフラン、ジオキサンなどのエーテル；ジメチルホルムアミド、ジメチルスルホキシドが好ましい。溶媒の使用量に特に制限はないが、通常キノリンカルバルデヒド（Ｉ）に対し１〜２００重量倍の範囲が好ましく、５〜２０重量倍の範囲がより好ましい。
【００４５】
反応温度は、使用するホスホニウム塩（ＩＩ）、ホスホネート（ＩＩＩ）またはホスホネート（ＩＶ）の種類、塩基の種類、溶媒の種類により異なるが、通常−１００〜１００℃の範囲が好ましく、−５０〜３０℃の範囲がより好ましい。また、反応時間は、反応温度によっても異なるが、通常０．１〜２４時間の範囲が好ましい。
【００４６】
反応は、アルゴンなどの不活性ガス雰囲気下、ホスホニウム塩（ＩＩ）、ホスホネート（ＩＩＩ）またはホスホネート（ＩＶ）を溶媒に溶解させて、この溶液に塩基を添加した後、キノリンカルバルデヒド（Ｉ）を添加し、所定温度で攪拌することにより行うのが好ましい。反応終了後、反応混合物を水にあけ、酢酸エチル、ヘキサンなどの有機溶媒で抽出し、必要に応じて抽出液を水、飽和塩化ナトリウム水溶液、炭酸水素ナトリウム水溶液などで洗浄し、無水硫酸ナトリウム、無水硫酸マグネシウムなどの乾燥剤で乾燥後、濃縮することにより粗生成物を得る。得られた粗生成物は、必要に応じてさらに再結晶、蒸留、カラムクロマトグラフィーなどの通常の精製手段を用いて精製した後に、アセタール基部分またはイミノ基部分を加水分解する工程に付してもよいが、該精製を行わず、そのまま加水分解工程に付すことができる。
【００４７】
［工程２］工程１の生成物のアセタール基部分またはイミノ基部分を加水分解する工程
【００４８】
当該工程は、水を含む溶媒中で酸を作用させる一般的な加水分解反応条件を用いることができる。水の使用量に特に制限はないが、通常、先の工程で原料として用いるキノリンカルバルデヒド（Ｉ）１モルに対して１モル以上を用いるのが好ましく、１〜１０モル倍の範囲で用いるのがより好ましい。
【００４９】
酸としては、例えば、塩酸、硫酸、リン酸、過塩素酸などの鉱酸；酢酸、プロピオン酸、ｐ−トルエンスルホン酸、メタンスルホン酸、シュウ酸などの有機酸またはその水和物もしくはその塩が挙げられる。酸の使用量に特に制限はないが、通常、先の工程で原料として用いるキノリンカルバルデヒド（Ｉ）の使用量に対して０．０１〜５モル倍の範囲であるのが好ましい。
【００５０】
加水分解工程は溶媒の存在下に行うのが好ましい。使用する溶媒としては、反応に悪影響を与えない限り特に制限はなく、例えばメタノール、エタノール、プロパノール、イソプロパノール、ブタノール、ｓｅｃ−ブタノール、ｔｅｒｔ−ブタノールなどのアルコール；ジエチルエーテル、テトラヒドロフラン、ジメトキシエタンなどのエーテル；ペンタン、ヘキサン、ヘプタン、オクタン、石油エーテル、ベンゼン、トルエン、キシレンなどの炭化水素；ジメチルホルムアミド、Ｎ−メチルピロリドン、Ｎ，Ｎ’−ジメチルイミダゾリジノン、ヘキサメチルホスホリックトリアミドなどのアミド；アセトニトリルなどのニトリル；ジメチルスルホキシド；またはこれらの混合溶媒が挙げられる。溶媒の使用量に特に制限はないが、通常、先の工程で原料として用いるキノリンカルバルデヒド（Ｉ）の使用量に対して１〜２００重量倍の範囲が好ましい。
【００５１】
反応温度は、使用する酸の種類、溶媒の種類により異なるが、通常０〜１００℃の範囲が好ましい。また、反応時間は、反応温度によっても異なるが、通常１〜２４時間の範囲が好ましい。
【００５２】
このようにして得られたキノリン誘導体（Ｖ）は、通常の有機化合物の単離・精製に用いられる方法により単離・精製することができる。例えば、反応終了後の反応液に、必要に応じて炭酸水素ナトリウム水溶液、ナトリウムメトキシドなどの塩基を加えて酸を中和した後、ジエチルエーテル、酢酸エチル、塩化メチレンなどの有機溶媒で抽出する。抽出液を必要に応じて水、飽和塩化ナトリウム水溶液、炭酸水素ナトリウム水溶液などで洗浄することにより酸性物質および水溶性物質を除去し、無水硫酸ナトリウム、無水硫酸マグネシウムなどの乾燥剤で乾燥した後、濃縮し、得られる粗生成物を蒸留、クロマトグラフィー、再結晶などにより精製する。
【００５３】
なお、本発明で原料として用いるキノリンカルバルデヒド（Ｉ）、例えば４−（４’−フルオロフェニル）−２−シクロプロピルキノリン−３−カルバルデヒドは、２−アミノ−４’−フルオロベンゾフェノンと３−シクロプロピル−３−オキソプロパン酸エステルを酸触媒存在下で縮合させて４−（４’−フルオロフェニル）−２−シクロプロピルキノリン−３−カルボン酸エステルを得（ジャーナル オブ オーガニック ケミストリー（Ｊ．Ｏｒｇ．Ｃｈｅｍ．）、３１巻、２８９９頁（１９６６年）；ヘテロサイクルズ（Ｈｅｔｅｒｏｃｙｃｌｅｓ）、５０巻、４７９頁（１９９９年）参照）、この化合物のエステル部分をジイソブチルアルミニウムヒドリドなどの各種金属水素化物で還元して４−（４’−フルオロフェニル）−２−シクロプロピル−３−ヒドロキシメチルキノリンを得、次いでこの化合物をピリジニウムクロロクロメート、オキザリルクロリド／ジメチルスルホキシド／第３級アミン（Ｓｗｅｒｎ酸化）、三酸化硫黄ピリジン錯体などで酸化することにより製造することができる（特開平１−２７９８６６号公報参照）。
【００５４】
また、ホスホニウム塩（ＩＩ）、例えば（１，３−ジオキソラン−２−イルメチル）トリフェニルホスホニウムブロミドは、例えばブロモアセトアルデヒドエチレンアセタールとトリフェニルホスフィンを反応させることで容易に合成することができる。ホスホネート（ＩＩＩ）、例えばジエチルホスホノアセトアルデヒドジエチルアセタールは、ブロモアセトアルデヒドジエチルアセタールと亜リン酸トリエチルを反応させることで合成することができる。ホスホネート（ＩＶ）、例えばジエチル−２−（シクロヘキシルアミノ）ビニルホスホネートは、ジエチルホスホノアセトアルデヒドジエチルアセタールのアセタール部分を加水分解し、得られたアルデヒドとシクロヘキシルアミンを反応させることで合成することができる（オーガニック シンセシス（Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｅｓ）、５３巻、４４頁（１９７３年）参照）。
【００５５】
【実施例】
以下、実施例により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より何ら制限されるものではない。
【００５６】
実施例１
アルゴン雰囲気下、（１，３−ジオキソラン−２−イルメチル）トリフェニルホスホニウムブロミド１．５５ｇ（３．６１ｍｍｏｌ）に無水ジメチルスルホキシド１０．０ｍｌを加えて溶解させ、この溶液にｔｅｒｔ−ブチルリチウム（１．５１Ｍ、ｎ−ペンタン溶液）２．４０ｍｌ（３．６２ｍｍｏｌ）を２０〜３０℃で２分間かけて滴下した。混合物を室温で１５分間攪拌した後、この溶液に、４−（４’−フルオロフェニル）−２−シクロプロピルキノリン−３−カルバルデヒド１．００ｇ（３．４４ｍｍｏｌ）を無水ジメチルスルホキシド５ｍｌに溶解させて得られた溶液を、２０〜３０℃で５分間かけて滴下し、滴下終了後、同温度で９０分間攪拌した。反応混合液に水１０ｍｌを加え、有機層を分離した。水層をヘキサン２０ｍｌで２回抽出し、先に分離した有機層と抽出液を合わせて水１０ｍｌで２回洗浄し、無水硫酸ナトリウムで乾燥後、減圧下で濃縮した。得られた粗生成物にテトラヒドロフラン２０ｍｌを加えて溶解させた後、２モル／Ｌの塩酸１０ｍｌを加えて室温で３０分間静置した。この混合物からテトラヒドロフランを減圧下で留去し、得られた赤色の残留物をクロロホルム１０ｍｌで溶解した後、さらにヘキサン３０ｍｌおよび飽和炭酸水素ナトリウム水溶液５０ｍｌを加えて分液し、有機層を分離した。水層をヘキサン５０ｍｌで２回抽出し、先に分離した有機層と抽出液を合わせて濃縮後、得られた粗生成物をカラムクロマトグラフィーにより精製することにより、淡黄色結晶として、下記の物性を有する（Ｅ）−３−（４’−（４”−フルオロフェニル）−２’−シクロプロピルキノリン−３’−イル）プロペンアルデヒドを０．９９ｇ（収率９０．９％）得た。
【００５７】
融点：１２４−１３２℃
1Ｈ−ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ3，ＴＭＳ，ｐｐｍ） δ：１．０８−１．１３（２Ｈ，ｍ，ＣＨ2），１．４１−１．４５（２Ｈ，ｍ，ＣＨ2），２．３２−２．３８（１Ｈ，ｍ，ＣＨ），６．４５（１Ｈ，ｄｄ，Ｊ＝８，１６Ｈｚ），７．２２−７．２５（４Ｈ，ｍ，Ａｒ−Ｈ），７．３５−７．３９（２Ｈ，ｍ，Ａｒ−Ｈ），７．５６（１Ｈ，ｄ，Ｊ＝１６Ｈｚ），７．６７（１Ｈ，ｄｄｄ，Ｊ＝３，６，８Ｈｚ，Ａｒ−Ｈ），７．９８（１Ｈ，ｄ，Ｊ＝８Ｈｚ，Ａｒ−Ｈ），９．５１（１Ｈ，ｄ，Ｊ＝８Ｈｚ）．
【００５８】
実施例２
アルゴン雰囲気下、６０％油性水素化ナトリウム１６５ｍｇ（４．１２ｍｍｏｌ）をテトラヒドロフラン８２５ｍｇ中で攪拌しつつ６０℃に昇温した。この溶液に無水ジメチルスルホキシド３８６ｍｇ（４．９４ｍｍｏｌ）をテトラヒドロフラン８２５ｍｇに溶解させて得られた溶液を滴下した。２時間攪拌後、２０℃まで冷却した。次に、アルゴン雰囲気下、（１，３−ジオキソラン−２−イルメチル）トリフェニルホスホニウムブロミド２．２１ｇ（５．１５ｍｍｏｌ）をテトラヒドロフラン８．８４ｇ中で攪拌している中に、先に調製した水素化ナトリウム、無水ジメチルスルホキシドおよびテトラヒドロフランの混合液を添加し、１時間攪拌後、０℃まで冷却した。この溶液に、４−（４’−フルオロフェニル）−２−シクロプロピルキノリン−３−カルバルデヒド１．００ｇ（３．４４ｍｍｏｌ）をテトラヒドロフラン４ｇに溶解させて得られた溶液を、０〜５℃で５分間かけて滴下し、滴下終了後、同温度で６０分間攪拌した。反応混合液に水５ｇを加えたのち、減圧下で溶媒を留去し、析出した固体をトルエン１０ｇで溶解し、水１０ｇで２回洗浄した。０．５モル／Ｌの塩酸１０ｍｌを加え、５時間攪拌後、静置し、下層を分離し、有機層を飽和炭酸水素ナトリウム水溶液１０ｇ、水１０ｇで順次洗浄した。溶媒を留去し、得られた粗生成物をカラムクロマトグラフィーにより精製し、（Ｅ）−３−（４’−（４”−フルオロフェニル）−２’−シクロプロピルキノリン−３’−イル）プロペンアルデヒド０．９３ｇ（収率８５．４％）を得た。
【００５９】
実施例３
アルゴン雰囲気下、ジエチルホスホノアセトアルデヒドジエチルアセタール１．０５ｇ（４．１２ｍｍｏｌ）にテトラヒドロフラン１０ｍｌを加えて溶解させて−３０〜−２０℃に冷却し、この溶液にｎ−ブチルリチウム（１．６Ｍ、ｎ−ヘキサン溶液）２．６０ｍｌ（４．１６ｍｍｏｌ）を−３０〜−２０℃で５分間かけて滴下した。混合物を同温度で１時間攪拌した後、この溶液に、４−（４’−フルオロフェニル）−２−シクロプロピルキノリン−３−カルバルデヒド１．００ｇ（３．４４ｍｍｏｌ）をテトラヒドロフラン１０ｍｌに溶解させて得られた溶液を、−３０〜−２０℃で５分間かけて滴下し、滴下終了後、室温に昇温して２時間攪拌した。反応混合液を氷水１００ｍｌに加え、酢酸エチル５０ｍｌで３回抽出し、抽出液を合わせて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、濃縮した。得られた残留物にトルエン２０ｍｌおよび１０％過塩素酸水溶液１０ｍｌを加え、４０〜５０℃で１時間加熱した。混合物を室温まで冷却し、炭酸水素ナトリウム水溶液で中和した後、トルエン５０ｍｌで３回抽出した。抽出液を合わせて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、濃縮して得られた粗生成物１．６ｇをカラムクロマトグラフィーにより精製し、（Ｅ）−３−（４’−（４”−フルオロフェニル）−２’−シクロプロピルキノリン−３’−イル）プロペンアルデヒド０．９２ｇ（収率８４．５％）を得た。
【００６０】
実施例４
アルゴン雰囲気下、水素化ナトリウム９８．３ｍｇ（４．１０ｍｍｏｌ）をテトラヒドロフラン１０ｍｌに懸濁させて得られた溶液を−１０〜−５℃に冷却し、この溶液に、ジエチル−２−（シクロヘキシルアミノ）ビニルホスホネート１．３４ｇ（５．１３ｍｍｏｌ）をテトラヒドロフラン１０ｍｌに溶解させて得られた溶液を５分間かけて滴下し、滴下終了後、−１０〜−５℃で１時間攪拌した。この溶液に、４−（４'−フルオロフェニル）−２−シクロプロピルキノリン−３−カルバルデヒド１．００ｇ（３．４４ｍｍｏｌ）をテトラヒドロフラン２０ｍｌに溶解させて得られた溶液を、−１０〜−５℃で５分間かけて滴下し、滴下終了後、還流温度に加熱して１時間攪拌した。反応混合液を室温まで冷却した後、氷水３００ｍｌに加えて酢酸エチル１００ｍｌで３回抽出し、抽出液を合わせて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、濃縮した。得られた残留物にトルエン２０ｍｌおよびシュウ酸二水和物１．５ｇ（１１．９ｍｍｏｌ）を水２０ｍｌに溶解させて得られた溶液を加え、６０〜７０℃で１時間加熱した。混合物を室温まで冷却し、有機層と水層を分離した。水層をトルエン２０ｍｌで２回抽出した。抽出液を先に分離した有機層と合わせて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、濃縮して得られた粗生成物１．６ｇをカラムクロマトグラフィーにより精製し、（Ｅ）−３−（４’−（４”−フルオロフェニル）−２’−シクロプロピルキノリン−３’−イル）プロペンアルデヒド０．９５ｇ（収率８６．５％）を得た。
【００６１】
【発明の効果】
本発明によれば、医薬・農薬などの合成中間体として有用なキノリン誘導体、例えばコレステロール生合成の律速酵素であるＨＭＧ−ＣｏＡ還元酵素の阻害剤として知られるキノリン系メバロノラクトン誘導体の重要な合成中間体である（Ｅ）−３−（４’−（４”−フルオロフェニル）−２’−シクロプロピルキノリン−３’−イル）プロペンアルデヒドのようなキノリン誘導体を、短工程で、効率よく工業的に有利に製造することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a quinoline derivative. The quinoline derivative obtained in the present invention is useful as a synthetic intermediate for pharmaceuticals and agricultural chemicals. For example, (E) -3- (4 ′-(4 ″ -fluorophenyl) -2′-cyclopropylquinoline-3′- Yl) propenaldehyde is an important synthetic intermediate of a quinoline mevalonolactone derivative known as an inhibitor of HMG-CoA reductase, which is the rate-limiting enzyme of cholesterol biosynthesis.
[0002]
[Prior art]
As a synthesis method of a quinoline derivative such as (E) -3- (4 ′-(4 ″ -fluorophenyl) -2′-cyclopropylquinolin-3′-yl) propenaldehyde, (1) cis- 1-Ethoxy-2- (tri-n-butylstannyl) ethylene is allowed to act on butyllithium and then at −60 to −78 ° C. with 4- (4′-fluorophenyl) -2-cyclopropylquinoline-3-carbaldehyde. (2) 4- (4′-fluorophenyl) -2-cyclopropylquinoline-3-carbaldehyde is reacted with alkoxycarbonylmethylphosphonate by hydrolysis by reacting the resulting vinyl ether form in the presence of an acid catalyst. Reaction to give the corresponding α, β-unsaturated carboxylic acid ester, After conversion to the alcohol by reduction with a metal hydride such as Le aluminum hydride, a method of oxidation with an oxidizing agent such as activated manganese dioxide is known (see Japanese Patent Laid-Open No. 1-279866).
[0003]
[Problems to be solved by the invention]
In the method (1), the organotin compound to be used is industrially difficult to obtain and must be reacted at an extremely low temperature of −60 to −78 ° C., which requires special reaction equipment. Have. In the method (2), it is difficult to handle a metal hydride used for reducing the ester moiety. In addition, any method needs to go through a plurality of steps to obtain the target product, and (E) -3- (4 ′-(4 ″ -fluorophenyl) -2′-cyclopropylquinolin-3′-yl ) It is not necessarily advantageous as an industrial production method for quinoline derivatives such as propene aldehyde.
[0004]
Therefore, an object of the present invention is to provide a method capable of producing a quinoline derivative efficiently and industrially advantageously in a shorter process using a chemical that is industrially easily available and easy to handle. .
[0005]
[Means for Solving the Problems]
According to the invention, the above object is achieved by the general formula (I)
[0006]
[Chemical 6]
(Wherein R 1 , R 2 , R Three , R Four , R Five And R 6 Each independently represents a hydrogen atom, a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a hydroxyl group that may be protected, an alkyl group that may have a substituent, or a cyclo that may have a substituent. An alkyl group, an aryl group which may have a substituent, an aralkyl group which may have a substituent, an alkoxyl group which may have a substituent, or an aryloxy which may have a substituent Represents a group. )
In the presence of a base, the following compounds (a) to (c) are prepared from quinoline carbaldehyde represented by the following formula (hereinafter abbreviated as quinoline carbaldehyde (I)):
(A) General formula (II)
[0008]
[Chemical 7]
(Wherein R 7 And R 8 Each independently represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted acyl group or an optionally substituted aralkyl group, or together. Represents an alkylene group, an arylene group or an aralkylene group, and R 9 Represents an alkyl group which may have a substituent or an aryl group which may have a substituent, and X represents a halogen atom. )
A phosphonium salt compound (hereinafter abbreviated as phosphonium salt (II)),
(B) General formula (III)
[0010]
[Chemical 8]
(Wherein R 7 , R 8 And R 9 Is as defined above. )
Or a phosphonate compound (hereinafter abbreviated as phosphonate (III)) or
(C) General formula (IV)
[0012]
[Chemical 9]
(Wherein R 9 Is as defined above, R Ten And R 11 Each independently has a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or substituent. Or an aralkyl group which may be an alkylene group, an arylene group or an aralkylene group. )
A phosphonate compound represented by formula (hereinafter abbreviated as phosphonate (IV)); and a reaction with a compound of the general formula (V)
[0014]
[Chemical Formula 10]
(Wherein R 1 , R 2 , R Three , R Four , R Five And R 6 Is as defined above. )
This is achieved by providing a method for producing a quinoline derivative represented by formula (hereinafter abbreviated as quinoline derivative (V)).
[0016]
In a preferred embodiment, R 1 , R 2 , R Three And R 6 Is a hydrogen atom and R Four Is a halogen atom and R Five Is an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, and R 7 And R 8 Are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group, a naphthyl group or a benzyl group, or together, an alkylene group or carbon having 2 to 6 carbon atoms An arylene group of several 6 to 10 and R 9 Is an alkyl group having 1 to 6 carbon atoms or a phenyl group, and R Ten And R 11 Are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group, a naphthyl group or a benzyl group, or together, an alkylene group or carbon having 2 to 6 carbon atoms It is an arylene group of several 6 to 10.
[0017]
In a further preferred embodiment, R Four Is a fluorine atom and R 7 And R 8 Are each independently an alkyl group having 1 to 6 carbon atoms, or together, an alkylene group having 2 to 6 carbon atoms, and R Ten And R 11 Each independently represents an alkyl group having 1 to 6 carbon atoms, or together, an alkylene group having 2 to 6 carbon atoms.
[0018]
DETAILED DESCRIPTION OF THE INVENTION
In the above general formula, R 1 , R 2 , R Three , R Four , R Five , R 6 , R 7 , R 8 , R 9 , R Ten And R 11 The alkyl group represented by is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert- A butyl group etc. are mentioned. These alkyl groups may have a substituent, and examples of the substituent include a hydroxyl group; preferably an alkoxyl group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, and a butoxy group. It is done.
[0019]
R 1 , R 2 , R Three , R Four , R Five , R 6 , R Ten And R 11 The cycloalkyl group represented by is preferably a cycloalkyl group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. These cycloalkyl groups may have a substituent. Examples of the substituent include a hydroxyl group; a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and the like. Is an alkyl group having 1 to 6 carbon atoms; preferably a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like, preferably an alkoxyl group having 1 to 4 carbon atoms; a phenyl group, a p-methoxyphenyl group, a p-chlorophenyl group or the like Includes an aryl group having 6 to 10 carbon atoms.
[0020]
R 1 , R 2 , R Three , R Four , R Five , R 6 , R 9 , R Ten And R 11 The aryl group represented by preferably includes an aryl group having 6 to 10 carbon atoms, and examples thereof include a phenyl group and a naphthyl group. These aryl groups may have a substituent. Examples of the substituent include a hydroxyl group; a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a tert-butyl group. An alkyl group having 1 to 6 carbon atoms; preferably an alkoxyl group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group; preferably a phenyl group, a p-methoxyphenyl group and a p-chlorophenyl group Examples thereof include aryl groups having 6 to 10 carbon atoms.
[0021]
R 1 , R 2 , R Three , R Four , R Five , R 6 , R 7 , R 8 , R Ten And R 11 As the aralkyl group represented by the formula, an alkyl group preferably has an alkyl group having 1 to 6 carbon atoms, and the aryl part preferably has an aryl group having 6 to 10 carbon atoms, such as benzyl group and naphthyl group. A methyl group etc. are mentioned. These aralkyl groups may have a substituent. Examples of the substituent include a hydroxyl group; a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a tert-butyl group. An alkyl group having 1 to 6 carbon atoms; preferably an alkoxyl group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group; preferably a phenyl group, a p-methoxyphenyl group and a p-chlorophenyl group Examples thereof include aryl groups having 6 to 10 carbon atoms.
[0022]
R 1 , R 2 , R Three , R Four , R Five , R 6 Examples of the halogen atom represented by X and X include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom is preferable.
[0023]
R 1 , R 2 , R Three , R Four , R Five And R 6 The alkoxyl group represented by is preferably a linear or branched alkoxyl group having 1 to 4 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group. These alkoxyl groups may have a substituent, such as a hydroxyl group; preferably an alkoxyl group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, or a butoxy group; a phenyl group And preferably an aryl group having 6 to 10 carbon atoms such as p-methoxyphenyl group and p-chlorophenyl group.
[0024]
R 1 , R 2 , R Three , R Four , R Five And R 6 The aryloxy group represented by represents an aryloxy group having preferably an aryl group having 6 to 10 carbon atoms as the aryl moiety, and examples thereof include a phenoxy group, a tolyloxy group, and a naphthyloxy group. These aryloxy groups may have a substituent. Examples of the substituent include a hydroxyl group; a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and the like. Is an alkyl group having 1 to 6 carbon atoms; preferably a methoxy group, an ethoxy group, a propoxy group, a butoxy group or the like, preferably an alkoxyl group having 1 to 4 carbon atoms; a phenyl group, a p-methoxyphenyl group, a p-chlorophenyl group or the like Is an aryl group having 6 to 10 carbon atoms.
[0025]
R 1 , R 2 , R Three , R Four , R Five And R 6 The hydroxyl group represented by may be protected, and the protecting group for the hydroxyl group is not particularly limited as long as it is a protecting group usually used for the purpose of protecting the hydroxyl group. For example, an aralkyl group such as a benzyl group; a trimethylsilyl group; Examples thereof include trisubstituted silyl groups such as tert-butyldimethylsilyl group and tert-butyldiphenylsilyl group; and acetal type protecting groups such as methoxymethyl group, 1-ethoxyethyl group, tetrahydrofuranyl group and tetrahydropyranyl group.
[0026]
R 7 And R 8 As the acyl group represented by, for example, an acetyl group or the like, preferably an alkylcarbonyl group having a linear or branched alkyl group having 1 to 6 carbon atoms as an alkyl moiety; a benzoyl group or the like, preferably an aryl moiety having carbon atoms Examples include arylcarbonyl groups having 6 to 10 aryl groups. These acyl groups may have a substituent. Examples of the substituent include a hydroxyl group; a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a tert-butyl group. An alkyl group having 1 to 6 carbon atoms; preferably an alkoxyl group having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group; preferably a phenyl group, a p-methoxyphenyl group and a p-chlorophenyl group Examples thereof include aryl groups having 6 to 10 carbon atoms.
[0027]
R 7 And R 8 And R Ten And R 11 As the alkylene group represented by the above, a linear or branched alkylene group having 2 to 6 carbon atoms is preferable, and examples thereof include an ethylene group, a propylene group, a butylene group, and a pentylene group. R 7 And R 8 And R Ten And R 11 As the arylene group represented by the above, an arylene group having 6 to 10 carbon atoms is preferable, and examples thereof include an o-phenylene group and a 2,3-naphthalenediyl group. R 7 And R 8 And R Ten And R 11 As the aralkylene group represented by the above, an alkylene moiety preferably has an alkylene group having 2 to 6 carbon atoms, and the arylene moiety preferably has an arylene group having 6 to 10 carbon atoms. Examples include 1,2-benzo-2-butene group and 2,3-naphth-2-butene group.
[0028]
The quinoline carbaldehyde (I) and the quinoline derivative (V) are preferably R 1 , R 2 , R Three And R 6 Is a hydrogen atom and R Four Is a halogen atom and R Five In which C 1 is an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms.
[0029]
More preferred quinoline carbaldehyde (I) and quinoline derivative (V) include R 1 , R 2 , R Three And R 6 Is a hydrogen atom and R Four Is a fluorine atom and R Five In which C 1 is an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms.
[0030]
More preferred quinoline carbaldehyde (I) and quinoline derivative (V) include R 1 , R 2 , R Three And R 6 Is a hydrogen atom and R Four Is a fluorine atom and R Five In which is an isopropyl group or a cyclopropyl group.
[0031]
As phosphonium salt (II) and phosphonate (III), preferably R 7 And R 8 Are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group, a naphthyl group or a benzyl group, or together, an alkylene group or carbon having 2 to 6 carbon atoms An arylene group of several 6 to 10 and R 9 In which C 1 is an alkyl group having 1 to 6 carbon atoms or a phenyl group.
[0032]
More preferred phosphonium salts (II) and phosphonates (III) include R 7 And R 8 Are each independently an alkyl group having 1 to 6 carbon atoms, or together are an alkylene group having 2 to 6 carbon atoms, and R 9 In which C 1 is an alkyl group having 1 to 6 carbon atoms or a phenyl group.
[0033]
As phosphonate (IV), preferably R 9 Is an alkyl group having 1 to 6 carbon atoms or a phenyl group, and R Ten And R 11 Are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group, a naphthyl group or a benzyl group, or together, an alkylene group or carbon having 2 to 6 carbon atoms Examples thereof include compounds having an arylene group of several 6 to 10.
[0034]
More preferred phosphonate (IV) is R 9 Is an alkyl group having 1 to 6 carbon atoms or a phenyl group, and R Ten And R 11 Are each independently an alkyl group having 1 to 6 carbon atoms, or a compound having an alkylene group having 2 to 6 carbon atoms together.
[0035]
In the process for producing a quinoline derivative (V) of the present invention, quinoline carbaldehyde (I) is reacted with any one compound of phosphonium salt (II), phosphonate (III) or phosphonate (IV) in the presence of a base. And then hydrolyzed. That is, as shown in Scheme 1 below, an active intermediate (phosphorane compound) produced by the action of a base on a phosphonium salt (II), phosphonate (III) or phosphonate (IV) and a quinoline carbaldehyde (I) (Step 1), and the step (step 2) of hydrolyzing the acetal group part or imino group part of the product (ia) or (ib) obtained by such reaction. In this production method, an active intermediate (phosphorane compound) produced by the action of a base on phosphonium salt (II), phosphonate (III) or phosphonate (IV) is isolated and reacted with quinoline carbaldehyde (I). Such a method is also included in the present invention.
[0036]
Embedded image
(In the formula, each symbol is as defined above.)
[0038]
According to the method of the present invention, an active intermediate produced in a reaction system by reacting quinoline carbaldehyde (I) with phosphonium salt (II), phosphonate (III) or phosphonate (IV) in the presence of a base ( The quinoline derivative (V) can be advantageously produced by immediately reacting the phosphorane compound) with the quinoline carbaldehyde (I) and hydrolyzing the product obtained by such reaction without purification or purification.
[0039]
Hereinafter, the method of the present invention will be described for each step.
[0040]
[Step 1] A step of reacting quinoline carbaldehyde (I) with phosphonium salt (II), phosphonate (III) or phosphonate (IV) in the presence of a base.
[0041]
Examples of the phosphonium salt (II) include (1,3-dioxolan-2-ylmethyl) triphenylphosphonium bromide, (1,3-dioxolan-2-ylmethyl) triphenylphosphonium iodide, and the like. Examples of the phosphonate (III) include diethyl phosphonoacetaldehyde diethyl acetal, dimethylphosphonoacetaldehyde dimethyl acetal, and the like. Examples of the phosphonate (IV) include diethyl-2- (cyclohexylamino) vinylphosphonate and dimethyl-2- (cyclohexylamino) vinylphosphonate.
[0042]
The amount of the phosphonium salt (II), phosphonate (III) or phosphonate (IV) used is preferably in the range of 1 to 10 mol times, more preferably in the range of 1 to 2 mol times relative to 1 mol of the quinoline carbaldehyde (I). preferable.
[0043]
Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; methyl lithium, ethyl lithium, n-butyl lithium, sec-butyl lithium, tert -Organic lithium compounds such as butyl lithium and phenyl lithium; alkyl magnesium halides such as methyl magnesium chloride and ethyl magnesium bromide; lithium amide, sodium amide, potassium amide, lithium diethyl amide, lithium diisopropyl amide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide , Metal amides such as potassium bistrimethylsilylamide, bromomagnesium diisopropylamide; lithium methoxide, sodium Mumetokishido, sodium ethoxide, sodium tert- butoxide, metal alkoxides such as potassium tert- butoxide; lithium hydride, sodium hydride, and alkali metal hydrides such as potassium hydride. Among these, sodium hydride, n-butyllithium, tert-butyllithium, and potassium tert-butoxide are preferably used from the viewpoint of high stability of the generated active intermediate (phosphorane compound). Although there is no restriction | limiting in particular in the usage-amount of a base, From a viewpoint of making reaction progress smoothly, 0.1 mol or more is normally used with respect to 1 mol of phosphonium salt (II), phosphonate (III), or phosphonate (IV). It is more preferable to use in the range of 0.5 to 2 mole times.
[0044]
This step is preferably performed in the presence of a solvent. The solvent that can be used is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aliphatic hydrocarbons such as pentane, hexane, heptane, cyclohexane, and methylcyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; methanol, Alcohols such as ethanol, isopropanol, n-butanol, tert-butanol; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane Nitriles such as acetonitrile and benzonitrile; nitrogen-containing aromatic ring compounds such as pyridine; dimethylformamide, N-methylpyrrolidone, N, N′-dimethylimidazolidinone, hexide Amides such as samethylphosphoric triamide; dimethyl sulfoxide, N, N, N ′, N′-tetramethylethylenediamine, ammonia; or mixtures thereof. Among these, from the viewpoint of the stability of the active intermediate (phosphorane compound) generated in the reaction system, aromatic hydrocarbons such as benzene, toluene, xylene; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane; dimethylformamide and dimethyl sulfoxide are preferred. Although there is no restriction | limiting in particular in the usage-amount of a solvent, Usually, the range of 1 to 200 weight times is preferable with respect to quinoline carbaldehyde (I), and the range of 5 to 20 weight times is more preferable.
[0045]
The reaction temperature varies depending on the type of phosphonium salt (II), phosphonate (III) or phosphonate (IV) used, the type of base, and the type of solvent, but is usually in the range of −100 to 100 ° C., and −50 to 30 A range of ° C is more preferred. Moreover, although reaction time changes also with reaction temperature, the range of 0.1 to 24 hours is preferable normally.
[0046]
The reaction is carried out by dissolving phosphonium salt (II), phosphonate (III) or phosphonate (IV) in a solvent under an inert gas atmosphere such as argon, adding a base to this solution, and then adding quinoline carbaldehyde (I). It is preferable to carry out by adding and stirring at a predetermined temperature. After completion of the reaction, the reaction mixture is poured into water and extracted with an organic solvent such as ethyl acetate or hexane. If necessary, the extract is washed with water, a saturated aqueous sodium chloride solution, an aqueous sodium hydrogen carbonate solution, etc. A crude product is obtained by drying with a drying agent such as anhydrous magnesium sulfate and then concentrating. The obtained crude product is further subjected to a step of hydrolyzing the acetal group part or imino group part after further purification using ordinary purification means such as recrystallization, distillation, column chromatography, etc., if necessary. However, it can be directly subjected to the hydrolysis step without performing the purification.
[0047]
[Step 2] Step of hydrolyzing the acetal group part or imino group part of the product of Step 1
[0048]
The said process can use the general hydrolysis reaction conditions which make an acid act in the solvent containing water. Although there is no restriction | limiting in particular in the usage-amount of water, Usually, it is preferable to use 1 mol or more with respect to 1 mol of quinoline carbaldehyde (I) used as a raw material at a previous process, and it uses it in the range of 1-10 mol times. Is more preferable.
[0049]
Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and perchloric acid; organic acids such as acetic acid, propionic acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, and hydrates or salts thereof. Is mentioned. Although there is no restriction | limiting in particular in the usage-amount of an acid, Usually, it is preferable that it is the range of 0.01-5 mol times with respect to the usage-amount of the quinoline carbaldehyde (I) used as a raw material at a previous process.
[0050]
The hydrolysis step is preferably performed in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not adversely influence the reaction. For example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol and tert-butanol; ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane Hydrocarbons such as pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene; amides such as dimethylformamide, N-methylpyrrolidone, N, N′-dimethylimidazolidinone, hexamethylphosphoric triamide; Nitriles such as acetonitrile; dimethyl sulfoxide; or a mixed solvent thereof. Although there is no restriction | limiting in particular in the usage-amount of a solvent, Usually, the range of 1 to 200 weight times is preferable with respect to the usage-amount of the quinoline carbaldehyde (I) used as a raw material at a previous process.
[0051]
Although reaction temperature changes with the kind of acid to be used and the kind of solvent, the range of 0-100 degreeC is preferable normally. Moreover, although reaction time changes also with reaction temperature, the range of 1 to 24 hours is preferable normally.
[0052]
The quinoline derivative (V) thus obtained can be isolated and purified by a method used for usual isolation and purification of organic compounds. For example, after completion of the reaction, a base such as aqueous sodium hydrogen carbonate solution or sodium methoxide is added to the reaction solution as necessary to neutralize the acid, followed by extraction with an organic solvent such as diethyl ether, ethyl acetate, or methylene chloride. . The extract is washed with water, a saturated aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate as necessary to remove acidic and water-soluble substances, and dried with a drying agent such as anhydrous sodium sulfate or anhydrous magnesium sulfate. Concentrate and purify the resulting crude product by distillation, chromatography, recrystallization, and the like.
[0053]
Note that quinoline carbaldehyde (I) used as a raw material in the present invention, such as 4- (4′-fluorophenyl) -2-cyclopropylquinoline-3-carbaldehyde, is 2-amino-4′-fluorobenzophenone and 3- Cyclopropyl-3-oxopropanoic acid ester is condensed in the presence of an acid catalyst to give 4- (4′-fluorophenyl) -2-cyclopropylquinoline-3-carboxylic acid ester (Journal of Organic Chemistry (J. Org Chem.), 31, p. 2899 (1966); Heterocycles, p. 50, p. 479 (1999)), the ester moiety of this compound is replaced with various metal hydrides such as diisobutylaluminum hydride. Reduction to 4- (4′-fluorophenyl) -2-cyclop Lopyl-3-hydroxymethylquinoline can be obtained and then this compound can be prepared by oxidation with pyridinium chlorochromate, oxalyl chloride / dimethyl sulfoxide / tertiary amine (Swern oxidation), sulfur trioxide pyridine complex, etc. (See JP-A-1-279866).
[0054]
Moreover, phosphonium salt (II), for example, (1,3-dioxolan-2-ylmethyl) triphenylphosphonium bromide can be easily synthesized by reacting, for example, bromoacetaldehyde ethylene acetal and triphenylphosphine. Phosphonate (III), for example diethylphosphonoacetaldehyde diethyl acetal, can be synthesized by reacting bromoacetaldehyde diethyl acetal with triethyl phosphite. Phosphonate (IV), for example, diethyl-2- (cyclohexylamino) vinylphosphonate, can be synthesized by hydrolyzing the acetal part of diethylphosphonoacetaldehyde diethyl acetal and reacting the resulting aldehyde with cyclohexylamine ( Organic Synthesis, 53, 44 (1973)).
[0055]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not restrict | limited at all by these Examples.
[0056]
Example 1
Under an argon atmosphere, 10.0 ml of anhydrous dimethyl sulfoxide was dissolved in 1.55 g (3.61 mmol) of (1,3-dioxolan-2-ylmethyl) triphenylphosphonium bromide, and tert-butyllithium (1. 51M, n-pentane solution) 2.40 ml (3.62 mmol) was added dropwise at 20-30 ° C. over 2 minutes. After the mixture was stirred at room temperature for 15 minutes, 1.00 g (3.44 mmol) of 4- (4′-fluorophenyl) -2-cyclopropylquinoline-3-carbaldehyde was dissolved in 5 ml of anhydrous dimethyl sulfoxide in this solution. The obtained solution was added dropwise at 20 to 30 ° C. over 5 minutes, and after completion of the addition, the solution was stirred at the same temperature for 90 minutes. 10 ml of water was added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted twice with 20 ml of hexane, the organic layer separated earlier and the extract were combined, washed twice with 10 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the obtained crude product, 20 ml of tetrahydrofuran was added and dissolved, 10 ml of 2 mol / L hydrochloric acid was added, and the mixture was allowed to stand at room temperature for 30 minutes. Tetrahydrofuran was distilled off from this mixture under reduced pressure, and the resulting red residue was dissolved in 10 ml of chloroform. Then, 30 ml of hexane and 50 ml of saturated aqueous sodium hydrogen carbonate solution were added to separate the layers, and the organic layer was separated. The aqueous layer was extracted twice with 50 ml of hexane, the organic layer separated earlier and the extract were combined and concentrated, and the resulting crude product was purified by column chromatography to give the following physical properties as pale yellow crystals. (E) -3- (4 ′-(4 ″ -fluorophenyl) -2′-cyclopropylquinolin-3′-yl) propenaldehyde having a benzene yield of 90.9% (yield 90.9%).
[0057]
Melting point: 124-132 ° C
1 H-NMR (600 MHz, CDCl Three , TMS, ppm) δ: 1.08-1.13 (2H, m, CH 2 ), 1.41-1.45 (2H, m, CH 2 ), 2.32-2.38 (1H, m, CH), 6.45 (1H, dd, J = 8, 16 Hz), 7.22-7.25 (4H, m, Ar-H), 7 .35-7.39 (2H, m, Ar-H), 7.56 (1H, d, J = 16 Hz), 7.67 (1H, ddd, J = 3, 6, 8 Hz, Ar-H), 7.98 (1H, d, J = 8 Hz, Ar-H), 9.51 (1H, d, J = 8 Hz).
[0058]
Example 2
Under an argon atmosphere, 165 mg (4.12 mmol) of 60% oily sodium hydride was heated to 60 ° C. while stirring in 825 mg of tetrahydrofuran. To this solution, a solution obtained by dissolving 386 mg (4.94 mmol) of anhydrous dimethyl sulfoxide in 825 mg of tetrahydrofuran was added dropwise. After stirring for 2 hours, the mixture was cooled to 20 ° C. Next, the hydrogenation prepared above was carried out while stirring 2.21 g (5.15 mmol) of (1,3-dioxolan-2-ylmethyl) triphenylphosphonium bromide in 8.84 g of tetrahydrofuran under an argon atmosphere. A mixed solution of sodium, anhydrous dimethyl sulfoxide and tetrahydrofuran was added, stirred for 1 hour, and then cooled to 0 ° C. To this solution, 1.00 g (3.44 mmol) of 4- (4′-fluorophenyl) -2-cyclopropylquinoline-3-carbaldehyde was dissolved in 4 g of tetrahydrofuran. The solution was added dropwise over 5 minutes, and stirred for 60 minutes at the same temperature after completion of the addition. After adding 5 g of water to the reaction mixture, the solvent was distilled off under reduced pressure, and the precipitated solid was dissolved in 10 g of toluene and washed twice with 10 g of water. After adding 10 ml of 0.5 mol / L hydrochloric acid and stirring for 5 hours, the mixture was allowed to stand, the lower layer was separated, and the organic layer was washed successively with 10 g of saturated aqueous sodium bicarbonate and 10 g of water. The solvent was distilled off, and the resulting crude product was purified by column chromatography to obtain (E) -3- (4 ′-(4 ″ -fluorophenyl) -2′-cyclopropylquinolin-3′-yl). 0.93 g (yield 85.4%) of propene aldehyde was obtained.
[0059]
Example 3
Under an argon atmosphere, 10 ml of tetrahydrofuran was dissolved in 1.05 g (4.12 mmol) of diethylphosphonoacetaldehyde diethyl acetal and cooled to −30 to −20 ° C., and n-butyllithium (1.6 M, n -Hexane solution) 2.60 ml (4.16 mmol) was added dropwise at -30 to -20 ° C over 5 minutes. The mixture was stirred at the same temperature for 1 hour, and then 1.00 g (3.44 mmol) of 4- (4′-fluorophenyl) -2-cyclopropylquinoline-3-carbaldehyde was dissolved in 10 ml of tetrahydrofuran. The obtained solution was added dropwise at −30 to −20 ° C. over 5 minutes, and after completion of the addition, the temperature was raised to room temperature and stirred for 2 hours. The reaction mixture was added to 100 ml of ice water and extracted three times with 50 ml of ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. To the obtained residue, 20 ml of toluene and 10 ml of 10% aqueous perchloric acid solution were added and heated at 40-50 ° C. for 1 hour. The mixture was cooled to room temperature, neutralized with an aqueous sodium bicarbonate solution, and extracted three times with 50 ml of toluene. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 1.6 g of a crude product, which was purified by column chromatography to give (E) -3- (4 ′-( 4 "-fluorophenyl) -2'-cyclopropylquinolin-3'-yl) propenaldehyde (0.92 g, yield 84.5%) was obtained.
[0060]
Example 4
Under an argon atmosphere, a solution obtained by suspending 98.3 mg (4.10 mmol) of sodium hydride in 10 ml of tetrahydrofuran was cooled to −10 to −5 ° C., and diethyl-2- (cyclohexylamino) was added to this solution. A solution obtained by dissolving 1.34 g (5.13 mmol) of vinylphosphonate in 10 ml of tetrahydrofuran was added dropwise over 5 minutes. After completion of the addition, the solution was stirred at −10 to −5 ° C. for 1 hour. To this solution, 1.00 g (3.44 mmol) of 4- (4′-fluorophenyl) -2-cyclopropylquinoline-3-carbaldehyde was dissolved in 20 ml of tetrahydrofuran, and a solution obtained from −10 to −5 The mixture was added dropwise at 5 ° C. over 5 minutes. After completion of the addition, the mixture was heated to reflux temperature and stirred for 1 hour. The reaction mixture was cooled to room temperature, then added to 300 ml of ice water and extracted three times with 100 ml of ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. A solution obtained by dissolving 20 ml of toluene and 1.5 g (11.9 mmol) of oxalic acid dihydrate in 20 ml of water was added to the obtained residue, and the mixture was heated at 60 to 70 ° C. for 1 hour. The mixture was cooled to room temperature and the organic and aqueous layers were separated. The aqueous layer was extracted twice with 20 ml of toluene. The extract was combined with the previously separated organic layer, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 1.6 g of a crude product, which was purified by column chromatography. 0.95 g (yield: 86.5%) of 3- (4 ′-(4 ″ -fluorophenyl) -2′-cyclopropylquinolin-3′-yl) propenaldehyde was obtained.
[0061]
【Effect of the invention】
INDUSTRIAL APPLICABILITY According to the present invention, an important synthetic intermediate of a quinoline-based mevalonolactone derivative known as an inhibitor of HMG-CoA reductase, which is a rate-limiting enzyme of cholesterol biosynthesis, is useful as a synthetic intermediate for pharmaceuticals and agricultural chemicals. A quinoline derivative such as (E) -3- (4 ′-(4 ″ -fluorophenyl) -2′-cyclopropylquinolin-3′-yl) propenaldehyde is efficiently and industrially produced in a short process. It can be produced advantageously.
Claims (3)
で示されるキノリンカルバルデヒドを、塩基の存在下、以下の化合物（ａ）〜（ｃ）：
（ａ）一般式（ＩＩ）
で示されるホスホニウム塩化合物、
（ｂ）一般式（ＩＩＩ）
で示されるホスホネート化合物または
（ｃ）一般式（ＩＶ）
で示されるホスホネート化合物；のいずれか１種の化合物と−５０℃〜３０℃の範囲で反応させ、次いで加水分解させることを特徴とする一般式（Ｖ）
で示されるキノリン誘導体の製造方法。Formula (I)
In the presence of a base, the following compounds (a) to (c):
(A) General formula (II)
A phosphonium salt compound represented by:
(B) General formula (III)
Or a phosphonate compound represented by formula (IV):
A phosphonate compound represented by the general formula (V), wherein the compound is reacted in the range of −50 ° C. to 30 ° C. and then hydrolyzed.
The manufacturing method of the quinoline derivative shown by these.
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| AU2004228485A1 (en) * | 2003-04-04 | 2004-10-21 | Nissan Chemical Industries, Ltd. | Process for producing quinoline compound |
| KR102736128B1 (en) * | 2019-09-11 | 2024-12-02 | 주식회사 엘지에너지솔루션 | Non-aqueous electrolyte for lithium secondary battery and lithium secondary battery comprising the same |
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|---|---|---|---|---|
| JP2569746B2 (en) * | 1987-08-20 | 1997-01-08 | 日産化学工業株式会社 | Quinoline mevalonolactones |
| JP3130342B2 (en) * | 1991-10-04 | 2001-01-31 | 日産化学工業株式会社 | Atherosclerotic intimal thickening inhibitor |
| JP4281248B2 (en) * | 1998-07-23 | 2009-06-17 | 日産化学工業株式会社 | Process for producing quinoline derivative and intermediate |
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