JPS6361941B2 - - Google Patents
Info
- Publication number
- JPS6361941B2 JPS6361941B2 JP54131629A JP13162979A JPS6361941B2 JP S6361941 B2 JPS6361941 B2 JP S6361941B2 JP 54131629 A JP54131629 A JP 54131629A JP 13162979 A JP13162979 A JP 13162979A JP S6361941 B2 JPS6361941 B2 JP S6361941B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- compound
- reaction
- acid
- group
- 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
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- 125000005843 halogen group Chemical group 0.000 claims description 15
- 125000003277 amino group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 3
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- -1 acetylamino, propionylamino, butyrylamino Chemical group 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 239000012442 inert solvent Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 4
- 150000007514 bases Chemical class 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000001119 stannous chloride Substances 0.000 description 4
- 235000011150 stannous chloride Nutrition 0.000 description 4
- DNKVZRWMEGSLOU-UHFFFAOYSA-N 6-chloro-2-methyl-5-nitroquinoline Chemical compound [O-][N+](=O)C1=C(Cl)C=CC2=NC(C)=CC=C21 DNKVZRWMEGSLOU-UHFFFAOYSA-N 0.000 description 3
- PQRVSWVLDAPYBG-UHFFFAOYSA-N 6-fluoro-2-methyl-5-nitroquinoline Chemical compound [O-][N+](=O)C1=C(F)C=CC2=NC(C)=CC=C21 PQRVSWVLDAPYBG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000010531 catalytic reduction reaction Methods 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000006396 nitration reaction Methods 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- UJLNMPLONUMQOO-UHFFFAOYSA-N 5-chloro-2-methylquinolin-6-ol Chemical compound ClC1=C(O)C=CC2=NC(C)=CC=C21 UJLNMPLONUMQOO-UHFFFAOYSA-N 0.000 description 2
- LAXPLKHRIWVALF-UHFFFAOYSA-N 6-chloro-2-methylquinolin-5-amine Chemical compound NC1=C(Cl)C=CC2=NC(C)=CC=C21 LAXPLKHRIWVALF-UHFFFAOYSA-N 0.000 description 2
- YOQADHGBMFCUMX-UHFFFAOYSA-N 6-fluoro-2-methylquinolin-5-amine Chemical compound NC1=C(F)C=CC2=NC(C)=CC=C21 YOQADHGBMFCUMX-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- ARHFGYSYDLLEQZ-UHFFFAOYSA-N n-(6-fluoro-2-methylquinolin-5-yl)acetamide Chemical compound CC1=CC=C2C(NC(=O)C)=C(F)C=CC2=N1 ARHFGYSYDLLEQZ-UHFFFAOYSA-N 0.000 description 2
- 230000000802 nitrating effect Effects 0.000 description 2
- 239000004323 potassium nitrate Substances 0.000 description 2
- 235000010333 potassium nitrate Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003248 quinolines Chemical class 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 229910052718 tin Inorganic materials 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
- WHSHMXLCBVHPPP-UHFFFAOYSA-N (6-chloroquinolin-2-yl)methanamine Chemical compound C1=C(Cl)C=CC2=NC(CN)=CC=C21 WHSHMXLCBVHPPP-UHFFFAOYSA-N 0.000 description 1
- DBGSRZSKGVSXRK-UHFFFAOYSA-N 1-[2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]acetyl]-3,6-dihydro-2H-pyridine-4-carboxylic acid Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CCC(=CC1)C(=O)O DBGSRZSKGVSXRK-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OCCIBGIEIBQGAJ-UHFFFAOYSA-N 6-chloro-2-methylquinoline Chemical compound C1=C(Cl)C=CC2=NC(C)=CC=C21 OCCIBGIEIBQGAJ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 229910001963 alkali metal nitrate Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000004304 potassium nitrite Substances 0.000 description 1
- 235000010289 potassium nitrite Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- 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
Landscapes
- Quinoline Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 本発明はキノリン誘導体に関する。[Detailed description of the invention] The present invention relates to quinoline derivatives.
本発明のキノリン誘導体は下記一般式(1)で表わ
される。 The quinoline derivative of the present invention is represented by the following general formula (1).
〔式中R1は低級アルキル基を、R2はハロゲン
原子、ニトロ基、アミノ基又は低級アルカノイル
アミノ基を、R3はハロゲン原子又は水酸基をそ
れぞれ示す。但しR2及びR3は同時にハロゲン原
子であつてはならない。〕
上記一般式(1)で表わされる本発明の化合物は優
れた抗菌作用及び抗マラリア作用を有しており、
抗菌剤及び抗マラリア剤として有用である。 [In the formula, R 1 represents a lower alkyl group, R 2 represents a halogen atom, a nitro group, an amino group, or a lower alkanoylamino group, and R 3 represents a halogen atom or a hydroxyl group, respectively. However, R 2 and R 3 must not be halogen atoms at the same time. ] The compound of the present invention represented by the above general formula (1) has excellent antibacterial and antimalarial effects,
Useful as an antibacterial and antimalarial agent.
一般式(1)に於て、R1で示される低級アルキル
基としてはメチル、エチル、プロピル、イソプロ
ピル、ブチル、tert−ブチル基等を例示できる
が、好ましくはメチル基を挙げることができる。
またR2及びR3で示されるハロゲン原子としては
塩素原子、臭素原子、沃素原子及び弗素原子を挙
げることができる。R2で示されるハロゲン原子
としては塩素原子及び臭素原子が好ましく、R3
で示されるハロゲン原子としては弗素原子及び塩
素原子が好ましい。またR2で示される低級アル
カノイルアミノ基としては例えばホルミムアミ
ノ、アセチルアミノ、プロピオニルアミノ、ブチ
リルアミノ、イソブチリルアミノ基等を、好まし
くはアセチルアミノ基を挙げることができる。 In general formula (1), examples of the lower alkyl group represented by R 1 include methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl groups, with methyl being preferred.
Further, examples of the halogen atom represented by R 2 and R 3 include a chlorine atom, a bromine atom, an iodine atom, and a fluorine atom. The halogen atom represented by R 2 is preferably a chlorine atom or a bromine atom, and R 3
The halogen atom represented by is preferably a fluorine atom or a chlorine atom. Examples of the lower alkanoylamino group represented by R 2 include formiamino, acetylamino, propionylamino, butyrylamino, and isobutyrylamino groups, preferably acetylamino.
本発明の代表的な化合物を以下に挙げる。 Representative compounds of the present invention are listed below.
Γ ５−ニトロ−６−クロルキナルジン
Γ ５−ニトロ−６−フルオロキナルジン
Γ ５−アミノ−６−クロルキナルジン
Γ ５−アミノ−６−フルオロキナルジン
Γ ５−アセチルアミノ−６−クロルキナルジン
Γ ５−アセチルアミノ−６−フルオロキナルジ
ン
Γ ６−ヒドロキシ−５−クロルキナルジン
Γ ６−ヒドロキシ−５−ニトロキナルジン
Γ ５−クロル−６−イソブチリルアミノキナル
ジン
Γ ６−ヒドロキシ−５−アミノキナルジン
本発明の化合物は種々の方法により製造される
が、その好ましい一例として例えば下記反応行程
式−１に示す方法により製造される。Γ 5-nitro-6-chloroquinaldine Γ 5-nitro-6-fluoroquinaldine Γ 5-amino-6-chloroquinaldine Γ 5-amino-6-fluoroquinaldine Γ 5-acetylamino-6-chlorquinaldine Zine Γ 5-acetylamino-6-fluoroquinaldine Γ 6-hydroxy-5-chloroquinaldine Γ 6-hydroxy-5-nitroquinaldine Γ 5-chloro-6-isobutyrylaminoquinaldine Γ 6-hydroxy- 5-Aminoquinaldine The compound of the present invention can be produced by various methods, and a preferred example thereof is produced by the method shown in Reaction Scheme-1 below.
〔式中X1及びX2はハロゲン原子、R4は水素原
子又は低級アルキル基を示す。R1及びR3は前記
に同じ。〕
即ち一般式(1)の化合物のうち、R2がニトロ基
を示し且つR3がハロゲン原子を示す化合物（一
般式（1a）の化合物）は公知の一般式(2)で表わ
される化合物をニトロ化することにより製造さ
れ、またR2がニトロ基を示し且つR3が水酸基を
示す化合物（一般式（1b）の化合物）は一般式
（1a）の化合物のハロゲン原子を水酸基で置換す
ることにより製造される。また一般式(1)の化合物
のうち、R2がアミノ基を示す化合物（一般式
（1c）の化合物）は上記で得られる一般式（1a）
の化合物又はアミノ一般式（1b）の化合物のニ
トロ基を還元することにより、R2が低級アルカ
ノイル基を示す化合物（一般式（1d）の化合物）
は一般式（1c）の化合物のアミノ基を低級アルカ
ノイル化することにより、R2がハロゲン原子を
示す化合物（一般式（1e）の化合物）は一般式
（1c）の化合物のアミノ基をハロゲン置換するこ
とによりそれぞれ製造される。 [In the formula, X 1 and X 2 represent a halogen atom, and R 4 represents a hydrogen atom or a lower alkyl group. R 1 and R 3 are the same as above. ] That is, among the compounds of general formula (1), a compound in which R 2 represents a nitro group and R 3 represents a halogen atom (compounds of general formula (1a)) is a compound represented by the known general formula (2). A compound produced by nitration and in which R 2 represents a nitro group and R 3 represents a hydroxyl group (compounds of general formula (1b)) is produced by replacing the halogen atom of the compound of general formula (1a) with a hydroxyl group. Manufactured by. Furthermore, among the compounds of general formula (1), compounds in which R 2 represents an amino group (compounds of general formula (1c)) have the general formula (1a) obtained above.
Compounds in which R 2 represents a lower alkanoyl group (compounds of general formula (1d)) by reducing the nitro group of the compound or amino compound of general formula (1b)
By converting the amino group of the compound of general formula (1c) into lower alkanoylation, a compound in which R 2 represents a halogen atom (compound of general formula (1e)) is obtained by substituting the amino group of the compound of general formula (1c) with halogen. Each is manufactured by
上記反応行程式−１に於て、一般式(2)で表わさ
れる化合物のニトロ化反応は、通常の芳香族化合
物のニトロ化反応条件下に、例えば無溶媒もしく
は適当な不活性溶媒中ニトロ化剤を用いて行なわ
れる。不活性溶媒としては例えば酢酸、無水酢
酸、濃硫酸等を、またニトロ化剤としては例えば
発煙硝酸、濃硝酸、混酸（硫酸、発煙硫酸、リン
酸又は無水酢酸と硝酸）、硝酸カリウム、硝酸ナ
トリウム等のアルカリ金属硝酸塩と硝酸等を夫々
挙げることができる。上記ニトロ化剤の使用量は
原料化合物に対し等モル以上、通常過剰量とすれ
ばよく、反応は有利には０〜15℃下に１〜４時間
で実施される。 In the above reaction scheme-1, the nitration reaction of the compound represented by the general formula (2) is carried out under the usual nitration reaction conditions for aromatic compounds, for example, without a solvent or in a suitable inert solvent. This is done using a drug. Examples of inert solvents include acetic acid, acetic anhydride, concentrated sulfuric acid, etc., and examples of nitrating agents include fuming nitric acid, concentrated nitric acid, mixed acids (sulfuric acid, oleum, phosphoric acid, or acetic anhydride and nitric acid), potassium nitrate, sodium nitrate, etc. Examples include alkali metal nitrates and nitric acid, respectively. The amount of the nitrating agent used may be at least equimolar to the starting compound, usually in excess, and the reaction is preferably carried out at 0 to 15°C for 1 to 4 hours.
一般式（1a）の化合物のハロゲン原子を水酸
基で置換する反応は、例えば水酸化ナトリウム、
水酸化カリウム等のアルカリ金属水酸化物の存在
下に水等の適当な不活性溶媒中にて行なわれる。
該反応は有利には80〜120℃下１〜３時間程度で
行なわれる。 The reaction of replacing the halogen atom of the compound of general formula (1a) with a hydroxyl group can be carried out using, for example, sodium hydroxide,
It is carried out in a suitable inert solvent such as water in the presence of an alkali metal hydroxide such as potassium hydroxide.
The reaction is advantageously carried out at 80-120°C for about 1-3 hours.
上記により得られる一般式（1a）及び一般式
（1b）で表わされる化合物のニトロ基の還元反応
は、例えば適当な不活性溶媒中、鉄、亜鉛、錫も
しくは塩化第一錫と酸（例えば塩酸、硫酸等）、
又は鉄、硫酸第一鉄、亜酸もしくは錫とアルカリ
金属水酸化物、硫化物、亜硫酸塩等との混合物等
を還元剤として用いるか或いはパラジウム炭素等
の接触還元触媒を用いて接触還元することにより
行なわれる。ここで不活性溶媒としては例えば
水、酢酸、メタノール、エタノール、ジオキサン
等を挙げることができる。上記還元反応の条件と
しては用いられる還元剤によつて適宜選択すれば
よく、例えば塩化第一錫と塩酸とを還元剤として
用いる場合有利には70〜100℃下に0.5〜１時間程
度反応を行なうのがよく、また接触還元反応によ
る場合有利には室温下に0.5〜数時間程度反応を
行なうのがよい。還元剤の使用量としては原料化
合物に対して少なくとも等モル量、通常は等モル
〜２倍モル量用いられる。 The reduction reaction of the nitro group of the compounds represented by the general formulas (1a) and (1b) obtained above can be carried out, for example, by combining iron, zinc, tin, or stannous chloride with an acid (for example, hydrochloric acid) in a suitable inert solvent. , sulfuric acid, etc.),
Or catalytic reduction using a mixture of iron, ferrous sulfate, suboxide or tin with alkali metal hydroxide, sulfide, sulfite, etc. as a reducing agent, or using a catalytic reduction catalyst such as palladium on carbon. This is done by Examples of the inert solvent include water, acetic acid, methanol, ethanol, and dioxane. The conditions for the above reduction reaction may be appropriately selected depending on the reducing agent used. For example, when stannous chloride and hydrochloric acid are used as reducing agents, it is advantageous to carry out the reaction at 70 to 100°C for about 0.5 to 1 hour. In the case of a catalytic reduction reaction, it is preferable to carry out the reaction at room temperature for about 0.5 to several hours. The amount of the reducing agent to be used is at least equimolar, usually equimolar to twice the molar amount of the raw material compound.
上記で得られる一般式（1c）の化合物のアミノ
基のハロゲン置換反応はジアゾ化反応を経由する
サンドマイヤー反応を適用することにより行ない
得る。一般式（1c）の化合物のジアゾ化は例えば
水、塩酸、硫酸等の溶媒中ジアゾ化剤として例え
ば亜硝酸ソーダ又は亜硝酸カリウムと塩酸又は硫
酸とを用い、−30℃〜室温下0.5〜２時間程度で有
利に行なわれる。斯くして生成する一般式（1c）
のジアゾニウム塩は通常単離もしくは単離するこ
となく、これに塩化第一錫、臭化第一銅、沃化カ
リ、テトラフルオロボロンヒドリド等のハロゲン
化剤を０〜50℃下0.5〜２時間程度反応させるこ
とにより一般式（1e）で表わされる化合物が収得
される。上記ジアゾ化剤及びハロゲン化剤の使用
量としては原料化合物に対しそれぞれ等モル量以
上、通常は等モル〜２倍モル量である。 The halogen substitution reaction of the amino group of the compound of general formula (1c) obtained above can be carried out by applying Sandmeyer reaction via diazotization reaction. Diazotization of the compound of general formula (1c) is carried out using, for example, sodium nitrite or potassium nitrite and hydrochloric acid or sulfuric acid as a diazotizing agent in a solvent such as water, hydrochloric acid, or sulfuric acid at -30°C to room temperature for 0.5 to 2 hours. It is carried out to an advantageous extent. The general formula (1c) thus generated
The diazonium salt is usually isolated or not isolated, and is treated with a halogenating agent such as stannous chloride, cuprous bromide, potassium iodide, or tetrafluoroboron hydride at 0 to 50°C for 0.5 to 2 hours. A compound represented by the general formula (1e) is obtained by carrying out the reaction to a certain extent. The amounts of the diazotizing agent and halogenating agent to be used are at least equimolar, usually equimolar to twice the molar amount, relative to the raw material compound.
一般式（1c）の化合物のアミノ基の低級アルカ
ノイル化は例えば塩基性化合物の存在下無溶媒又
は適当な不活性溶媒中で低級アルカン酸無水物も
しくは低級アルカン酸ハロゲン化物を反応させる
ことにより行なわれる。用いられる塩基性化合物
としてはピリジン、トリエチルアミン、炭酸ナト
リウム等を例示でき、また不活性溶媒としては酢
酸、ピリジン、ジオキサン、ベンゼン等を例示で
きる。低級アルカン酸無水物もしくは低級アルカ
ン酸ハロゲン化物の使用量としては原料化合物に
対し等モル量以上、通常は等モル〜２倍モル量で
ある。該反応は有利には室温〜100℃下0.5〜数時
間程度で行なわれる。 Lower alkanoylation of the amino group of the compound of general formula (1c) is carried out, for example, by reacting a lower alkanoic anhydride or a lower alkanoic acid halide in the presence of a basic compound without a solvent or in a suitable inert solvent. . Examples of the basic compound used include pyridine, triethylamine, sodium carbonate, etc., and examples of the inert solvent include acetic acid, pyridine, dioxane, benzene, etc. The amount of the lower alkanoic acid anhydride or lower alkanoic acid halide to be used is at least an equimolar amount, usually an equimolar to twice the molar amount, relative to the raw material compound. The reaction is advantageously carried out at room temperature to 100°C for about 0.5 to several hours.
斯くして得られる一般式(1)で表わされる化合物
は、薬理的に許容される酸付加塩とすることがで
き、本発明はこの酸付加塩をも包含する。酸付加
塩の形成に用いられる酸として例えば塩酸、硫
酸、臭化水素酸、ｐ−トルエンスルホン酸、酢
酸、蓚酸等を例示できる。 The compound represented by the general formula (1) thus obtained can be made into a pharmacologically acceptable acid addition salt, and the present invention also includes this acid addition salt. Examples of acids used to form acid addition salts include hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, acetic acid, and oxalic acid.
また一般式(1)で表わされる化合物は、之を医薬
的に許容される塩基性化合物で処理して容易に塩
とすることができ、本発明はこの塩をも包含す
る。用いられる塩基性化合物としては例えば水酸
化ナトリウム、水酸化カリウム、水酸化カルシウ
ム、水酸化アルミニウムを例示できる。 Further, the compound represented by the general formula (1) can be easily converted into a salt by treating it with a pharmaceutically acceptable basic compound, and the present invention also includes this salt. Examples of the basic compound that can be used include sodium hydroxide, potassium hydroxide, calcium hydroxide, and aluminum hydroxide.
斯くして得られる一般式(1)の化合物及びその塩
は、上記した反応行程の終了後に慣用の分離手段
により容易に単離精製できる。分離手段としては
例えば溶媒抽出法、希釈法、沈殿法、再結晶法、
中和法、カラムクロマトグラフイー等を例示でき
る。 The compound of general formula (1) and its salt thus obtained can be easily isolated and purified by conventional separation means after the above-described reaction steps are completed. Examples of separation methods include solvent extraction, dilution, precipitation, recrystallization,
Examples include neutralization method and column chromatography.
更に本発明の化合物は下記反応行程式−２及び
３に示す如く抗菌剤として有用な一般式(6)の化合
物及び一般式(7)の化合物を合成するための中間体
としても有用である。 Furthermore, the compounds of the present invention are useful as intermediates for synthesizing compounds of general formula (6) and compounds of general formula (7), which are useful as antibacterial agents, as shown in reaction schemes 2 and 3 below.
〔上記各式中R5は水素原子、低級アルキル基
又は低級アルカノイル基を示す。R1、R2、R3及
びX2は前記に同じ。〕
以下に実施例を挙げる。 [In each of the above formulas, R 5 represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group. R 1 , R 2 , R 3 and X 2 are the same as above. ] Examples are given below.
実施例 １
６−クロルキナルジン11gを濃硫酸15mlに溶解
し氷冷する。次に硝酸カリウム7.1gを濃硫酸20ml
に溶解した溶液を滴下する。このとき反応温度を
10℃以下に保つ。滴下後１時間同温度にてかくは
ん後、氷200g中に投入する。続いて10％苛性ソ
ーダにて内温20℃を越えない様注意しながらアル
カリ性とすると淡黄色の沈殿が析出する。沈殿物
を取し水洗後、エタノールにて再結晶すること
によつて５−ニトロ−６−クロルキナルジン
12.3gを得る。淡黄色稜状晶、mp.123〜124℃
実施例 ２
実施例１と同様にして淡黄色稜状晶の５−ニト
ロ−６−フルオロキナルジンを得る。mp.113〜
114℃
実施例 ３
塩化第一スズ25gを濃塩酸50mlに溶解し５−ニ
トロ−６−クロルキナルジン6.7gを加え水浴上80
〜90℃にて30分間反応する。反応液を氷冷し30％
苛性ソーダにてアルカリ性（PH10）とし、クロロ
ホルム500ml及びセライトを用いて過、抽出す
る。クロロホルム層を無水硫酸ナトリウムで乾燥
後、濃縮しベンゼン−ヘキサンにて再結晶し５−
アミノ−６−クロルキナルジン4.5gを得る。無色
板状晶、mp.196〜197℃
実施例 ４
実施例３と同様にして白色板状晶の５−アミノ
−６−フルオロキナルジンを得る。mp.133〜134
℃
実施例 ５
５−ニトロ−６−フルオルキナルジン5gを10
％苛性ソーダ50mlに懸濁させ、１時間還流する。
還流後過し、シリカゲルカラムクロマトグラフ
イー（クロロホルム溶媒）にて精製することによ
つて５−ニトロ−６−ヒドロキシキナルジン2.7g
を得る。淡黄色稜状晶、mp.131〜132℃
実施例 ６
６−クロル−５−アミノキナルジン5gに15ml
の無水酢酸を加え80℃、30分間加熱すると系内は
固化する。固型物を過し、少量の水（10〜20
ml）で洗浄したのち、メタノール100mlに溶解し
活性炭処理後濃縮することによつて６−クロル−
５−アセチルアミノキナルジン酢酸塩4.3gを得
る。mp.236〜237℃、白色針状晶
実施例 ７
実施例６と同様にして６−フルオロ−５−アセ
チルアミノキナルジン（無色針状晶）を得る。Example 1 11 g of 6-chloroquinaldine was dissolved in 15 ml of concentrated sulfuric acid and cooled on ice. Next, add 7.1g of potassium nitrate to 20ml of concentrated sulfuric acid.
Add the solution dissolved in the solution dropwise. At this time, the reaction temperature is
Keep below 10℃. After dropping, stir at the same temperature for 1 hour, then pour into 200g of ice. Next, the mixture is made alkaline with 10% caustic soda, taking care not to exceed the internal temperature of 20°C, and a pale yellow precipitate precipitates out. The precipitate was collected, washed with water, and recrystallized with ethanol to obtain 5-nitro-6-chloroquinaldine.
Get 12.3g. Pale yellow ridge-like crystals, mp. 123-124°C Example 2 In the same manner as in Example 1, 5-nitro-6-fluoroquinaldine in the form of pale yellow ridge-like crystals is obtained. mp.113～
114℃ Example 3 Dissolve 25g of stannous chloride in 50ml of concentrated hydrochloric acid, add 6.7g of 5-nitro-6-chloroquinaldine, and place on a water bath for 80 minutes.
React for 30 minutes at ~90°C. Cool the reaction solution on ice to 30%
Make alkaline (PH10) with caustic soda, filter and extract using 500ml of chloroform and Celite. The chloroform layer was dried over anhydrous sodium sulfate, concentrated, and recrystallized from benzene-hexane to give 5-
4.5 g of amino-6-chloroquinaldine are obtained. Colorless plate-like crystals, mp. 196-197°C Example 4 In the same manner as in Example 3, 5-amino-6-fluoroquinaldine in the form of white plate-like crystals was obtained. mp.133~134
℃ Example 5 5-nitro-6-fluoroquinaldine 5g
% caustic soda and reflux for 1 hour.
After refluxing, filtration and purification by silica gel column chromatography (chloroform solvent) yielded 2.7 g of 5-nitro-6-hydroxyquinaldine.
get. Pale yellow edge-like crystals, mp.131-132℃ Example 6 15 ml to 5 g of 6-chloro-5-aminoquinaldine
Add acetic anhydride and heat at 80℃ for 30 minutes to solidify the system. Strain the solids and add a small amount of water (10-20
ml), then dissolved in 100 ml of methanol, treated with activated carbon, and concentrated.
4.3 g of 5-acetylaminoquinaldine acetate is obtained. mp.236-237°C, white needle crystals Example 7 6-Fluoro-5-acetylaminoquinaldine (colorless needle crystals) was obtained in the same manner as in Example 6.
実施例 ８
５−ニトロ−６−ヒドロキシキナルジンを用
い、実施例３と同様にして、５−アミノ−６−ヒ
ドロキシキナルジンを得る。NMRによりその生
成を確認した。Example 8 5-Amino-6-hydroxyquinaldine is obtained in the same manner as in Example 3 using 5-nitro-6-hydroxyquinaldine. Its formation was confirmed by NMR.
上記で得られる５−アミノ−６−ヒドロキシキ
ナルジン6gを濃塩酸12mlと水６mlの混液に溶解
し氷冷下、亜硝酸ソーダ2.6gを水10mlに溶解した
溶液を０〜５℃にて滴下する。同温度にて１時間
反応後、塩化第一銅5gを濃塩酸６mlに溶解した
溶液に加え、水浴上80℃にて２時間反応させる。
続いて氷冷し、28％アンモニア水にてアルカリ性
とし、クロロホルム300ml及びセライトを用いて
過、抽出する。クロロホルム層を無水硫酸ナト
リウムにて乾燥後濃縮し、シリカゲルカラムクロ
マトグラフイー（クロロホルム：メタノール＝
20：１）にて単離、精製することにより3.7gの５
−クロル−６−ヒドロキシキナルジンを得る。 Dissolve 6 g of 5-amino-6-hydroxyquinaldine obtained above in a mixture of 12 ml of concentrated hydrochloric acid and 6 ml of water, and dropwise add a solution of 2.6 g of sodium nitrite dissolved in 10 ml of water at 0 to 5°C under ice cooling. do. After reacting at the same temperature for 1 hour, add 5 g of cuprous chloride to 6 ml of concentrated hydrochloric acid and react for 2 hours at 80°C on a water bath.
Subsequently, the mixture is cooled on ice, made alkaline with 28% aqueous ammonia, filtered and extracted using 300 ml of chloroform and Celite. The chloroform layer was dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (chloroform:methanol=
20:1), 3.7g of 5
-chloro-6-hydroxyquinaldine is obtained.
淡紫色稜状晶 mp.181−182℃。 Light purple ridge-like crystals mp.181−182℃.
Claims (1)
原子、ニトロ基、アミノ基又は低級アルカノイル
アミノ基を、R3はハロゲン原子又は水酸基をそ
れぞれ示す。但しR2及びR3は同時にハロゲン原
子であつてはならない。〕 で表わされるキノリン誘導体及びその塩。[Claims] 1. General formula [In the formula, R 1 represents a lower alkyl group, R 2 represents a halogen atom, a nitro group, an amino group, or a lower alkanoylamino group, and R 3 represents a halogen atom or a hydroxyl group, respectively. However, R 2 and R 3 must not be halogen atoms at the same time. ] A quinoline derivative represented by these and its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13162979A JPS5655371A (en) | 1979-10-11 | 1979-10-11 | Quinoline derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13162979A JPS5655371A (en) | 1979-10-11 | 1979-10-11 | Quinoline derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5655371A JPS5655371A (en) | 1981-05-15 |
| JPS6361941B2 true JPS6361941B2 (en) | 1988-11-30 |
Family
ID=15062509
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13162979A Granted JPS5655371A (en) | 1979-10-11 | 1979-10-11 | Quinoline derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5655371A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57193459A (en) * | 1981-05-22 | 1982-11-27 | Otsuka Pharmaceut Co Ltd | Quinoline derivative |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5445338A (en) * | 1977-09-19 | 1979-04-10 | Nippon Chem Ind Co Ltd:The | Production of quinophthalone pigment |
-
1979
- 1979-10-11 JP JP13162979A patent/JPS5655371A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5445338A (en) * | 1977-09-19 | 1979-04-10 | Nippon Chem Ind Co Ltd:The | Production of quinophthalone pigment |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5655371A (en) | 1981-05-15 |
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