JPS6247187B2 - - Google Patents
Info
- Publication number
- JPS6247187B2 JPS6247187B2 JP10180580A JP10180580A JPS6247187B2 JP S6247187 B2 JPS6247187 B2 JP S6247187B2 JP 10180580 A JP10180580 A JP 10180580A JP 10180580 A JP10180580 A JP 10180580A JP S6247187 B2 JPS6247187 B2 JP S6247187B2
- Authority
- JP
- Japan
- Prior art keywords
- naphthyridine
- carboxylic acid
- analysis value
- dihydro
- chloroform
- 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
Links
- 150000001875 compounds Chemical class 0.000 claims description 23
- SNLMOXFUCILIPL-UHFFFAOYSA-N 1,8-naphthyridine-2-carboxylic acid Chemical compound C1=CC=NC2=NC(C(=O)O)=CC=C21 SNLMOXFUCILIPL-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- NTBRFQBGGBTBPM-UHFFFAOYSA-N 8-oxo-3,5-dihydro-2h-furo[3,2-b][1,8]naphthyridine-7-carboxylic acid Chemical compound C1=C2C(=O)C(C(=O)O)=CNC2=NC2=C1OCC2 NTBRFQBGGBTBPM-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 239000002904 solvent Substances 0.000 description 20
- 238000000921 elemental analysis Methods 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 15
- 238000001914 filtration Methods 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- 239000013078 crystal Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- -1 5,8-dihydro-5-hydroxyethyl-8-oxofuro[3,2-b]1,8-naphthyridine-7-carboxylic Chemical compound 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000010531 catalytic reduction reaction Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 150000005058 1,8-naphthyridines Chemical class 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 239000010446 mirabilite Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- BWKAYBPLDRWMCJ-UHFFFAOYSA-N 1,1-diethoxy-n,n-dimethylmethanamine Chemical compound CCOC(N(C)C)OCC BWKAYBPLDRWMCJ-UHFFFAOYSA-N 0.000 description 2
- CGXLVFZJJOXEDF-UHFFFAOYSA-N 1,8-naphthyridine-3-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CN=C21 CGXLVFZJJOXEDF-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- JFWURCREFDQUTD-UHFFFAOYSA-N ethyl 1,8-naphthyridine-3-carboxylate Chemical compound N1=CC=CC2=CC(C(=O)OCC)=CN=C21 JFWURCREFDQUTD-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- OCKHUPCREYAULF-UHFFFAOYSA-N n,n-dimethylformamide;n-methylmethanamine Chemical compound CNC.CN(C)C=O OCKHUPCREYAULF-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical compound CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- KBPHGYUXEIDPPV-UHFFFAOYSA-N 4-oxo-1h-1,8-naphthyridine-3-carboxylic acid Chemical compound C1=CC=C2C(=O)C(C(=O)O)=CNC2=N1 KBPHGYUXEIDPPV-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000012931 Urologic disease Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- OWAQXCQNWNJICI-UHFFFAOYSA-N benzene;chloroform Chemical compound ClC(Cl)Cl.C1=CC=CC=C1 OWAQXCQNWNJICI-UHFFFAOYSA-N 0.000 description 1
- WIRUZQNBHNAMAB-UHFFFAOYSA-N benzene;cyclohexane Chemical compound C1CCCCC1.C1=CC=CC=C1 WIRUZQNBHNAMAB-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- PIHWQJBFCRABCQ-UHFFFAOYSA-N ethyl 2-oxo-1h-1,8-naphthyridine-3-carboxylate Chemical compound C1=CN=C2NC(=O)C(C(=O)OCC)=CC2=C1 PIHWQJBFCRABCQ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 235000019645 odor Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は一般式
（式中、Ｒは水素または低級アルキル基を表わ
す）で示される新規な５・８−ジヒドロフロまた
は２・３・５・８−テトラヒドロフロ〔３・２−
ｂ〕１・８−ナフチリジン−７−カルボン酸およ
びその塩に関するものであり、５位に２−ヒドロ
キシエチル基が置換している点に特徴がある。こ
れらの化合物は優れた抗菌力を示し、しかも経口
で服用した場合に高濃度で尿中に排泄されること
から尿路疾患を主とした細菌感染症の治療剤とし
て用いることができる。
本発明の化合物の製造方法の例を反応式で示し
て説明する。
（式中、Ｒは上記に同じ。R1は
The present invention is based on the general formula A novel 5,8-dihydrofuro or 2,3,5,8-tetrahydrofuro [3,2-
b] This relates to 1,8-naphthyridine-7-carboxylic acid and its salts, and is characterized in that it is substituted with a 2-hydroxyethyl group at the 5-position. These compounds exhibit excellent antibacterial activity and are excreted in urine at high concentrations when taken orally, so they can be used as therapeutic agents for bacterial infections, mainly urinary tract diseases. An example of the method for producing the compound of the present invention will be explained using a reaction formula. (In the formula, R is the same as above. R 1 is
【式】を、R2は水素またはアシル
基を、R3およびR4は低級アルキル基を表わす。
ここでR5は水素あるいは２、３または４位アル
コキシ基、アルキル基を表わす）
すなわち、原料として使用される化合物〔２〕
をジアルキルホルムアミドジアルキルアセタール
および二級アミン、例えばジアルキルアミンと加
熱してエナミノ体〔３〕とし、ついでアルコール
中、無機酸、例えば臭化水素酸の存在下に加熱す
るとアセタール誘導体〔４〕を得る。ついで化合
物〔４〕を濃硫酸、三臭化燐等のルイス酸と処理
するとフラン環を形成してフロ〔３・２−ｂ〕
１・８−ナフチリジン誘導体〔５〕を得る。R2
がアシル基の場合はこれを加水分解とすると目的
とする５・８−ジヒドロ−５−ヒドロキシエチル
−８−オキソフロ〔３・２−ｂ〕１・８−ナフチ
リジン−７−カルボン酸〔６〕を得る。５−（２
−ヒドロキシエチル）−８−オキソ−２・３・
５・８−テトラヒドロフロ〔３・２−ｂ〕１・８
−ナフチリジン−７−カルボン酸〔７〕は化合物
〔６〕を常圧または中圧においてパラジウム炭等
の触媒の存在下に接触還元を行うことによつて製
造することができる。
なお、中間原料として用いた化合物〔２〕は、
例えば次の反応式で示した合成経路で得ることが
できる。
（式中、Ｒ、R1およびR2は上記に同じ。Ｘはハロ
ゲン原子を表わす）
本発明で得られた化合物〔６〕および〔７〕は
いずれも強い抗菌活性を示す。その代表例として
５・８−ジヒドロ−５−（２−ヒドロキシエチ
ル）−８−オキソフロ〔３・２−ｂ〕１・８−ナ
フチリジン−７−カルボン酸（〔６〕Ｒ＝Ｈ）
を、対応するＮ−エチル体である５−エチル−
５・８−ジヒドロ−８−オキソフロ〔３・２−
ｂ〕１・８−ナフチリジン−７−カルボン酸
〔Ａ〕およびピペミド酸〔PPA〕と抗菌活性を比
較すると第一表に示した結果が得られた。[Formula], R 2 represents hydrogen or an acyl group, and R 3 and R 4 represent a lower alkyl group.
(Here, R 5 represents hydrogen or an alkoxy group or alkyl group at the 2, 3 or 4 position) That is, the compound used as a raw material [2]
is heated with a dialkylformamide dialkyl acetal and a secondary amine such as a dialkylamine to form the enamino form [3], and then heated in an alcohol in the presence of an inorganic acid such as hydrobromic acid to obtain the acetal derivative [4]. Then, when compound [4] is treated with a Lewis acid such as concentrated sulfuric acid or phosphorus tribromide, a furan ring is formed to form furo [3.2-b].
A 1,8-naphthyridine derivative [5] is obtained. R2
When is an acyl group, if this is hydrolyzed, the desired 5,8-dihydro-5-hydroxyethyl-8-oxofuro[3,2-b]1,8-naphthyridine-7-carboxylic acid[6] is obtained. obtain. 5-(2
-hydroxyethyl)-8-oxo-2.3.
5,8-tetrahydrofuro[3,2-b]1,8
-Naphthyridine-7-carboxylic acid [7] can be produced by catalytic reduction of compound [6] in the presence of a catalyst such as palladium charcoal at normal or medium pressure. In addition, the compound [2] used as an intermediate raw material is
For example, it can be obtained by the synthetic route shown in the following reaction formula. (In the formula, R, R 1 and R 2 are the same as above. X represents a halogen atom) Compounds [6] and [7] obtained in the present invention both exhibit strong antibacterial activity. A typical example is 5,8-dihydro-5-(2-hydroxyethyl)-8-oxofuro[3,2-b]1,8-naphthyridine-7-carboxylic acid ([6]R=H)
and the corresponding N-ethyl form, 5-ethyl-
5,8-dihydro-8-oxofuro[3,2-
b] Comparing the antibacterial activity with 1,8-naphthyridine-7-carboxylic acid [A] and pipemic acid [PPA], the results shown in Table 1 were obtained.
【表】
また、上記化合物（〔７〕、Ｒ＝Ｈ）を化合物
〔Ａ〕と、ラツトに経口投与した場合の尿中濃度
について比較すると第二表に示すような結果が得
られた。[Table] Furthermore, when the above compound ([7], R=H) and compound [A] were orally administered to rats, the urinary concentration was compared, and the results shown in Table 2 were obtained.
【表】
参考例 １
６−ベンジルオキシ−４−ヒドロキシ−７−メ
チル−１・８−ナフチリジン−３−カルボン酸エ
チルエステル34ｇ、粉末炭酸カリウム15ｇ、エチ
レンブロムヒドリン22ｇをジメチルホルムアミド
（DMF）300ml中浴温100〜125℃で3.5時間反応さ
せる。溶媒を減圧留去し、残渣を水−クロロホル
ムで分配し、クロロホルム層を充分水洗後芒硝乾
燥し、クロロホルムを留去後エーテルを加え、沈
殿を濾取乾燥すると６−ベンジルオキシ−１−
（２−ヒドロキシエチル）−７−メチル−１・４−
ジヒドロ−４−オキソ−１・８−ナフチリジン−
３−カルボン酸エチルエステル34.5ｇの粉末を得
る。融点170.5℃。
元素分析値 C21H22N2O5として
計算値 Ｃ 65.95、Ｈ 5.80、Ｎ 7.33
分析値 Ｃ 66.04、Ｈ 5.81、Ｎ 7.44
参考例 ２
特願昭54−57652に記載した方法で得た３−（６
−エトキシ−３−エトキシカルボニル−４−ヒド
ロキシ−１・８−ナフチリジン−７−イル）アク
リル酸5.8ｇをトリフルオロ酢酸30mlに加え、こ
れに臭素6.0ｇをクロロホルム30mlにとかした溶
液を滴下して、２時間おだやかに還流する。反応
後、溶媒を留去し、残渣をクロロホルムと水で分
配する。クロロホルム層は水洗し、芒硝で乾燥し
たのち溶媒を留去する。残渣をエーテルで処理
し、析出晶を濾取すると融点＞300℃の２・３−
ジブロモ−３−（６−エトキシ−３−エトキシカ
ルボニル−４−ヒドロキシ−１・８−ナフチリジ
ン−７−イル）プロピオン酸8.0ｇを得る。
元素分析値 C16H16Br2N2O6として
計算値 Ｃ 39.05、Ｈ 3.28、Ｎ 5.69
分析値 Ｃ 39.18、Ｈ 3.36、Ｎ 5.48
上記化合物4.0ｇおよび炭酸水素ナトリウム4.0
ｇをジメチルホルムアミド24mlに加えて60〜70℃
で１時間撹拌する。溶媒を減圧留去し、残渣をク
ロロホルムと水で分配する。クロロホルム層は水
洗し、乾燥したのち溶媒を留去する。残渣をエー
テルで処理して不溶の結晶を濾取すると融点235
〜238℃の７−（２−ブロモビニル）−６−エトキ
シ−４−ヒドロキシ−１・８−ナフチリジン−３
−カルボン酸エチル2.23ｇを得る。
元素分析値 C15H15BrN2O4として
計算値 Ｃ 49.06、Ｈ 4.12、Ｎ 7.63
分析値 Ｃ 49.21、Ｈ 4.22、Ｎ 7.28
上記化合物10.6ｇ、炭酸カリウム8.8ｇおよび
酢酸２−ブロモエチル11.8ｇをジメチルホルムア
ミド150mlに加えて撹拌しつつ50〜60℃まで徐々
に加温し、同温度で1.5時間反応を続ける。不溶
物を濾去し、溶媒を留去したのち、残渣をクロロ
ホルムにとかしてシリカゲルカラムに注ぐ。クロ
ロホルムで溶出する部分から融点122〜124℃の１
−（２−アセトキシエチル）−７−（２−ブロモビ
ニル）−６−エトキシ−１・４−ジヒドロ−４−
オキソ−１・８−ナフチリジン−３−カルボン酸
エチル7.4ｇを得る。
元素分析値 C19H21BrN2O6として
計算値 Ｃ 50.34、Ｈ 4.67、Ｎ 6.18
理論値 Ｃ 50.04、Ｈ 4.84、Ｎ 6.31
上記化合物2.2ｇをエタノール65mlにとかし、
これに５％パラジウム炭400mgを加えて常圧で接
触還元を行う。触媒を濾去し、溶媒を留去したの
ち、残渣をベンゼン−シクロヘキサンから再結晶
すると融点109〜111℃の１−（２−アセトキシエ
チル−６−エトキシ−７−エチル−１・４−ジヒ
ドロ−４−オキソ−１・８−ナフチリジン−３−
カルボン酸エチル1.55ｇを得る。
元素分析値 C19H24N2O6として
計算値 Ｃ 60.62、Ｈ 6.43、Ｎ 7.44
分析値 Ｃ 60.49、Ｈ 6.20、Ｎ 7.45
無水塩化アルミニウム65ｇをジクロルメタンに
加えて室温で１時間撹拌したのち、上記化合物
7.0ｇのジクロルメタン溶液100mlをゆつくり滴下
する。室温で18時間撹拌したのち氷水にあけ、ク
ロロホルムで抽出する。抽出液は水洗し、乾燥し
たのち溶媒を留去する。残渣をエーテルで処理
し、析出晶を濾取する。クロロホルム−ベンゼン
から再結晶すると融点233〜235℃（分解）の１−
（２−アセトキシエチル）−７−メチル−６−ヒド
ロキシ−１・４−ジヒドロ−４−オキソ−１・８
−ナフチリジン−３−カルボン酸エチル5.0ｇを
得る。
元素分析値 C17H20N2O6として
計算値 Ｃ 58.61、Ｈ 5.79、Ｎ 8.04
分析値 Ｃ 58.76、Ｈ 5.63、Ｎ 8.00
上記化合物4.9ｇ、臭化ベンジル10ｇおよび炭
酸カリウム9.5ｇをジメチルホルムアミド100mlに
加えて60℃で１時間撹拌する。不溶物を濾去し、
溶媒を留去したのち残渣をベンゼンにとかして水
洗し、乾燥する。溶媒を留去し、残渣をヘキサン
で処理して析出物を濾取すると融点127〜128℃の
１−（２−アセトキシエチル）−６−ベンジルオキ
シ−７−エチル−１・４−ジヒドロ−４−オキソ
−１・８−ナフチリジン−３−カルボン酸エチル
5.2ｇを得る。
元素分析値 C24H26N2O6として
計算値 Ｃ 65.73、Ｈ 5.98、Ｎ 6.39
実験値 Ｃ 65.69、Ｈ 6.15、Ｎ 6.37
実施例 １
６−ベンジルオキシ−１−（２−ヒドロキシエ
チル）−７−メチル−１・４−ジヒドロ−４−オ
キソ−１・８−ナフチリジン−３−カルボン酸エ
チルエステル15ｇ、ジメチルホルムアミドジエチ
ルアセタール20ｇを３％ジメチルアミン−ジメチ
ルホルムアミド250ml中で浴温120℃、４時間撹拌
する。冷後、エーテル200mlを加え析出沈殿を濾
取し、エーテルで充分洗滌後乾燥すると黄色粉末
11.7ｇを得る。得られた粉末を濃塩酸10mlを含む
エタノール150ml中で12時間還流し、冷後析出晶
を濾取しエタノールで洗う。クロロホルム−イソ
プロピルエーテルから再結晶すると融点201〜203
℃の６−ベンジルオキシ−７−（２・２−ジエト
キシエチル）−１−（２−ヒドロキシエチル）−
１・４−ジヒドロ−４−オキソ−１・８−ナフチ
リジン−３−カルボン酸8.0ｇを得る。
元素分析値 C24H28N2O7として
計算値 Ｃ 63.14、Ｈ 6.18、Ｎ 6.14
分析値 Ｃ 62.86、Ｈ 6.02、Ｎ 6.09
上記化合物3.1ｇを無水酢酸５ml、ピリジン10
ml中に加え、溶液となるまで水浴で加熱した後６
時間室温放置する。溶媒を減圧留去後残渣を10倍
量のシリカゲルカラムクロマトで精製し、融点
111〜112℃の１−（２−アセトキシエチル）−６−
ベンジルオキシ−７−（２・２−ジエトキシエチ
ル）−１・４−ジヒドロ−４−オキソ−１・８−
ナフチリジン−３−カルボン酸2.1ｇを得る。
元素分析値 C26H30N2O8として
計算値 Ｃ 62.64、Ｈ 6.07 Ｎ 5.62
分析値 Ｃ 62.37、Ｈ 6.15、Ｎ 5.92
上記化合物3.0ｇの無水酢酸溶液10mlを濃硫酸
30mlに内温５〜10℃を保つ早さで滴下する。同温
度で40分反応させ、氷水300ml中に注ぎ、析出物
をクロロホルム200mlで抽出する。クロロホルム
層を水洗、芒硝乾燥しクロロホルムを留去し、残
渣をシリカゲル30ｇを用いて精製する。クロロホ
ルム−エタノールより再結晶し、５−（２−アセ
トキシエチル）−５・８−ジヒドロ−８−オキソ
フロ〔３・２−ｂ〕１・８−ナフチリジン−７−
カルボン酸〔５〕の結晶800mgを得る。融点258〜
259℃（分解）。
元素分析値 C15H12N2O6として
計算値 Ｃ 56.96、Ｈ 3.83、Ｎ 8.86
分析値 Ｃ 57.08、Ｈ 3.62、Ｎ 8.99
上記化合物200mgを濃塩酸５ml、エタノール50
ml中で３時間還流し、反応後溶媒を濃縮し、析出
晶を濾取すると融点295℃を示す５−（２−ヒドロ
キシエチル）−５・８−ジヒドロ−８−オキソフ
ロ〔３・２−ｂ〕１・８−ナフチリジン−７−カ
ルボン酸90mgを得る。
元素分析値 C13H10N2O5として
計算値 Ｃ 56.93、Ｈ 3.68、Ｎ 10.22
分析値 Ｃ 57.15、Ｈ 3.49、Ｎ 10.21
NMR（CF3COOH）：δ（ppm）
4.5〜4.75、5.35〜5.65（各2H、ｍ、Ｎ−ＣＨ
2CＨ 2OH）
7.45（1H、ｑ、３位Ｈ）
8.68（1H、ｄ、２位Ｈ）
9.22（1H、ｂ、ｓ、９位Ｈ）
9.80（1H、ｓ、６位Ｈ）
実施例 ２
上記化合物900mgをトリフルオル酢酸10ml、酢
酸50mlの混液に溶解し、５％パラジウム炭200mg
を加え室温で環元する。反応後溶媒を減圧留去
し、残渣を５倍量のシリカゲルカラムクロマトグ
ラフイーで精製して得られた白色粉末を５％
KOH水溶液20mlに溶解し、室温２時間撹拌す
る。反応後塩酸酸性として析出する沈殿を濾取
し、水洗、乾燥し、エタノールより再結して融点
265℃を示す５−（２−ヒドロキシエチル）−２・
３・５・８−テトラヒドロ−８−オキソフロ
〔３・２−ｂ〕１・８−ナフチリジン−７−カル
ボン酸210mgを得る。
元素分析値 C13H12N2O5として
計算値 Ｃ 56.52、Ｈ 4.38、Ｎ 10.14
分析値 Ｃ 56.67、Ｈ 4.24、Ｎ 9.86
NMR（CF3COOH）：δ（ppm）
3.6〜3.95、4.9〜5.3（各2H、ｍ、２位および
３位のCH2）
4.4〜4.7、5.3〜5.6（各2H、ｍ、Ｎ−ＣＨ 2CＨ
2OH）
8.14、9.55（各1H、ｓ、６位および９位Ｈ）
実施例 ３
１−（２−アセトキシエチル）−６−ベンジルオ
キシ−７−エチル−１・４−ジヒドロ−４−オキ
ソ−１・８−ナフチリジン−３−カルボン酸エチ
ル5.2ｇをジメチルホルムアミドジエチルアセタ
ール10ｇと３％ジメチルアミン−ジメチルホルム
アミド溶液80mlの混液に加えて、110℃で４時間
撹拌する。溶媒を減圧留去し残渣に47％臭化水素
酸３mlおよびエタノール150mlを加えて12時間還
流する。溶媒を減圧留去し、残渣に10％水酸化ナ
トリウム水溶液50mlおよびエタノール50mlを加え
て１時間加熱還流する。エタノールを留去し、塩
酸で中和する。析出物をクロロホルムで抽出し、
水洗したのち乾燥して溶媒を留去すると融点187
〜189℃の６−ベンジルオキシ−７−（２・２−ジ
エトキシ−１−メチルエチル）−１−（２−ヒドロ
キシエチル）−１・４−ジヒドロ−４−オキソ−
１・８−ナフチリジン−３−カルボン酸4.6ｇを
得る。
元素分析値 C25H30N2O7として
計算値 Ｃ 63.81、Ｈ 6.43、Ｎ 5.95
分析値 Ｃ 63.97、Ｈ 5.97、Ｎ 5.88
上記化合物2.8ｇをナフチリジン50mlにとかし
氷冷下に無水酢酸15mlを滴下する。10時間室温で
撹拌したのち溶媒を留去し、残渣をクロロホルム
にとかす。クロロホルム液は水洗し、乾燥したの
ち溶媒を留去する。残渣はベンゼン−石油エーテ
ルから再結晶すると融点118〜120℃の１−（２−
アセトキシエチル）−６−ベンジルオキシ−７−
（２・２−ジエトキシ−１−メチルエチル）−１・
４−ジヒドロ−４−オキソ−１・８−ナフチリジ
ン−３−カルボン酸3.0ｇを得る。
元素分析値 C27H32N2O8として
計算値 Ｃ 63.27、Ｈ 6.29、Ｎ 5.47
分析値 Ｃ 63.24、Ｈ 6.56、Ｎ 5.56
上記化合物530mgをエタノール10mlおよびメチ
ルエチルケトン10mlの混液にとかし、５％パラジ
ウム炭180mlを加えて常圧で接触還元する。触媒
を濾去し、溶媒を留去したのち残渣をシリカゲル
クロマトに付して１％メタノール含有クロロホル
ムで溶出する部分から融点130〜132℃の１−（２
−アセトキシエチル）−７−（２・２−ジエトキシ
−１−メチルエチル）−６−ヒドロキシ−１・４
−ジヒドロ−４−オキソ−１・８−ナフチリジン
−３−カルボン酸300mgを得る。
元素分析値 C20H26N2O8として
計算値 Ｃ 56.86、Ｈ 6.20、Ｎ 6.63
分析値 Ｃ 56.68、Ｈ 6.16、Ｎ 6.50
上記化合物160mgを酢酸1.2mlに懸濁し、室温に
おいて撹拌しつつ三臭化燐0.2mlを加え２時間反
応させる。氷冷下にメタノール４mlを加えて析出
晶を濾取し、乾燥すると融点265〜267℃（分解）
の５−（２−アセトキシエチル）−３−メチル−
５・８−ジヒドロ−８−オキソフロ〔３・２−
ｂ〕１・８−ナフチリジン−７−カルボン酸90mg
を得る。これを濃塩酸0.2ml、水１mlおよびエタ
ノール２mlの混液に加えて１時間還流する。冷後
水２mlを加えて析出晶を濾取し、クロロホルム−
メタノールの混液から再結晶すると融点270〜272
℃（分解）の５−（２−ヒドロキシエチル）−３−
メチル−５・８−ジヒドロ−８−オキソフロ
〔３・２−ｂ〕１・８−ナフチリジン−７−カル
ボン酸60mgを得る。
元素分析値 C14H12N2O5として
計算値 Ｃ 58.33、Ｈ 4.20、Ｎ 9.72
分析値 Ｃ 57.85、Ｈ 4.22、Ｎ 9.66
NMR（DMSO−d6）：δ（ppm）
2.28（3H、ｓ、３位CH3基）
3.87（2H、ｂ、ｄ、Ｎ−CH2CＨ 2OH）
4.78（2H、ｂ、ｔ、Ｎ−ＣＨ 2CH2OH）
4.99（1H、ｔ、OH基）
8.58、8.80、9.06（各1H、ｓ、２位、６位、９
位Ｈ）
実施例 ４
５−（２−アセトキシエチル）−３−メチル−
５・８−ジヒドロ−８−オキソフロ〔３・２−
ｂ〕１・８−ナフチリジン−７−カルボン酸70mg
をエタノール12mlおよびテトラヒドロフラン30ml
の混液にとかし、５％パラジウム炭40mgを加えて
常圧接触還元する。触媒を濾去し、溶媒を留去し
たのち残渣にベンゼンとヘキサンを加えて処理
し、析出晶を濾取する。この結晶を濃塩酸0.2
ml、水２mlおよびエタノール２mlの混液に加えて
１時間還流する。冷後水３mlを加えて析出晶を濾
取し、クロロホルム−メタノール−ベンゼンの混
液から再結晶すると融点258〜261℃（分解）の５
−（２−ヒドロキシエチル）−３−メチル−８−オ
キソ−２・３・５・８−テトラヒドロフロ〔３・
２−ｂ〕１・８−ナフチリジン−７−カルボン酸
40mgを得る。
元素分析値 C14H14N2O5として
計算値 Ｃ 57.93、Ｈ 4.86、Ｎ 9.65
分析値 Ｃ 57.69、Ｈ 4.62、Ｎ 9.63
NMR（DMSO−d6）：δ（ppm）
1.40（3H、ｄ、３位CH3基）
3.7〜3.9（3H、ｍ、Ｎ−CH2CＨ 2OHおよび３
位Ｈ）
4.39（1H、ｔ、ＯＨ基）
4.72（2H、ｔ、Ｎ−ＣＨ 2CH2OH）
5.00（2H、ｔ、２位H2）
7.87および8.95（各1H、ｓ、６位および９位
Ｈ） [Table] Reference Example 1 34 g of 6-benzyloxy-4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid ethyl ester, 15 g of powdered potassium carbonate, and 22 g of ethylene bromohydrin were added to 300 ml of dimethylformamide (DMF). React for 3.5 hours at a medium bath temperature of 100-125°C. The solvent was distilled off under reduced pressure, the residue was partitioned between water and chloroform, the chloroform layer was thoroughly washed with water and dried with mirabilite, the chloroform was distilled off, ether was added, and the precipitate was filtered and dried to give 6-benzyloxy-1-
(2-hydroxyethyl)-7-methyl-1,4-
Dihydro-4-oxo-1,8-naphthyridine-
34.5 g of 3-carboxylic acid ethyl ester powder is obtained. Melting point: 170.5℃. Elemental analysis value C 21 H 22 N 2 O 5 Calculated value C 65.95, H 5.80, N 7.33 Analysis value C 66.04, H 5.81, N 7.44 Reference example 2 3- obtained by the method described in Japanese patent application No. 54-57652 (6
-Ethoxy-3-ethoxycarbonyl-4-hydroxy-1,8-naphthyridin-7-yl) 5.8 g of acrylic acid was added to 30 ml of trifluoroacetic acid, and a solution of 6.0 g of bromine dissolved in 30 ml of chloroform was added dropwise thereto. , gently reflux for 2 hours. After the reaction, the solvent was distilled off and the residue was partitioned between chloroform and water. The chloroform layer was washed with water, dried with Glauber's salt, and then the solvent was distilled off. The residue was treated with ether and the precipitated crystals were collected by filtration to give a 2.3-
8.0 g of dibromo-3-(6-ethoxy-3-ethoxycarbonyl-4-hydroxy-1,8-naphthyridin-7-yl)propionic acid are obtained. Elemental analysis value C 16 H 16 Br 2 N 2 O 6 Calculated value C 39.05, H 3.28, N 5.69 Analysis value C 39.18, H 3.36, N 5.48 4.0 g of the above compound and 4.0 sodium bicarbonate
Add g to 24 ml of dimethylformamide and heat to 60-70℃.
Stir for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between chloroform and water. The chloroform layer is washed with water, dried, and then the solvent is distilled off. When the residue is treated with ether and the insoluble crystals are filtered off, the melting point is 235.
7-(2-bromovinyl)-6-ethoxy-4-hydroxy-1,8-naphthyridine-3 at ~238°C
-2.23 g of ethyl carboxylate are obtained. Elemental analysis value C 15 H 15 BrN 2 O 4 Calculated value C 49.06, H 4.12, N 7.63 Analysis value C 49.21, H 4.22, N 7.28 10.6 g of the above compound, 8.8 g of potassium carbonate and 11.8 g of 2-bromoethyl acetate were dissolved in dimethyl Add to 150 ml of formamide, gradually warm to 50-60°C while stirring, and continue the reaction at the same temperature for 1.5 hours. After filtering off insoluble matter and distilling off the solvent, the residue is dissolved in chloroform and poured into a silica gel column. 1 with a melting point of 122-124℃ from the part eluted with chloroform
-(2-acetoxyethyl)-7-(2-bromovinyl)-6-ethoxy-1,4-dihydro-4-
7.4 g of ethyl oxo-1,8-naphthyridine-3-carboxylate are obtained. Elemental analysis value C 19 H 21 BrN 2 O 6 Calculated value C 50.34, H 4.67, N 6.18 Theoretical value C 50.04, H 4.84, N 6.31 Dissolve 2.2 g of the above compound in 65 ml of ethanol,
Add 400 mg of 5% palladium on charcoal to this and perform catalytic reduction at normal pressure. After filtering off the catalyst and distilling off the solvent, the residue was recrystallized from benzene-cyclohexane to give 1-(2-acetoxyethyl-6-ethoxy-7-ethyl-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-
1.55 g of ethyl carboxylate is obtained. Elemental analysis value C 19 H 24 N 2 O 6 Calculated value C 60.62, H 6.43, N 7.44 Analysis value C 60.49, H 6.20, N 7.45 After adding 65 g of anhydrous aluminum chloride to dichloromethane and stirring at room temperature for 1 hour, the above Compound
Slowly drop 100 ml of a 7.0 g dichloromethane solution. After stirring at room temperature for 18 hours, pour into ice water and extract with chloroform. The extract is washed with water, dried, and then the solvent is distilled off. The residue was treated with ether and the precipitated crystals were collected by filtration. Recrystallization from chloroform-benzene gives 1-
(2-acetoxyethyl)-7-methyl-6-hydroxy-1,4-dihydro-4-oxo-1,8
-5.0 g of ethyl naphthyridine-3-carboxylate are obtained. Elemental analysis value C 17 H 20 N 2 O 6 Calculated value C 58.61, H 5.79, N 8.04 Analysis value C 58.76, H 5.63, N 8.00 4.9 g of the above compound, 10 g of benzyl bromide and 9.5 g of potassium carbonate were added to 100 ml of dimethylformamide. and stir at 60°C for 1 hour. Filter off insoluble matter,
After distilling off the solvent, the residue is dissolved in benzene, washed with water, and dried. The solvent was distilled off, the residue was treated with hexane, and the precipitate was collected by filtration to give 1-(2-acetoxyethyl)-6-benzyloxy-7-ethyl-1,4-dihydro-4 with a melting point of 127-128°C. -Ethyl oxo-1,8-naphthyridine-3-carboxylate
Obtain 5.2g. Elemental analysis value C 24 H 26 N 2 O 6 Calculated value C 65.73, H 5.98, N 6.39 Experimental value C 65.69, H 6.15, N 6.37 Example 1 6-benzyloxy-1-(2-hydroxyethyl)-7 -Methyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (15 g) and dimethylformamide diethyl acetal (20 g) in 3% dimethylamine-dimethylformamide (250 ml) at a bath temperature of 120°C for 4 hours. Stir. After cooling, add 200ml of ether and collect the precipitate by filtration, wash thoroughly with ether and dry to form a yellow powder.
Obtain 11.7g. The obtained powder is refluxed for 12 hours in 150 ml of ethanol containing 10 ml of concentrated hydrochloric acid, and after cooling, the precipitated crystals are collected by filtration and washed with ethanol. Melting point 201-203 when recrystallized from chloroform-isopropyl ether
6-benzyloxy-7-(2,2-diethoxyethyl)-1-(2-hydroxyethyl)- at °C
8.0 g of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. Elemental analysis value C 24 H 28 N 2 O 7 Calculated value C 63.14, H 6.18, N 6.14 Analysis value C 62.86, H 6.02, N 6.09 3.1 g of the above compound was mixed with 5 ml of acetic anhydride and 10 ml of pyridine.
ml and heated in a water bath until it becomes a solution.
Leave at room temperature for an hour. After evaporating the solvent under reduced pressure, the residue was purified with 10 times the amount of silica gel column chromatography, and the melting point
1-(2-acetoxyethyl)-6- at 111-112℃
Benzyloxy-7-(2,2-diethoxyethyl)-1,4-dihydro-4-oxo-1,8-
2.1 g of naphthyridine-3-carboxylic acid are obtained. Elemental analysis value C 26 H 30 N 2 O Calculated value as 8 C 62.64, H 6.07 N 5.62 Analysis value C 62.37, H 6.15, N 5.92 Add 10 ml of acetic anhydride solution of 3.0 g of the above compound to concentrated sulfuric acid.
Drop into 30ml at a rate that maintains the internal temperature of 5-10℃. The mixture was reacted at the same temperature for 40 minutes, poured into 300 ml of ice water, and the precipitate was extracted with 200 ml of chloroform. The chloroform layer is washed with water, dried over Glauber's salt, the chloroform is distilled off, and the residue is purified using 30 g of silica gel. Recrystallized from chloroform-ethanol to give 5-(2-acetoxyethyl)-5,8-dihydro-8-oxofuro[3,2-b]1,8-naphthyridine-7-
Obtain 800 mg of crystals of carboxylic acid [5]. Melting point 258~
259℃ (decomposition). Elemental analysis value C 15 H 12 N 2 O 6 Calculated value C 56.96, H 3.83, N 8.86 Analysis value C 57.08, H 3.62, N 8.99 200 mg of the above compound was mixed with 5 ml of concentrated hydrochloric acid and 50 ml of ethanol.
After the reaction, the solvent was concentrated and the precipitated crystals were collected by filtration to give 5-(2-hydroxyethyl)-5,8-dihydro-8-oxofuro[3,2-b], which had a melting point of 295°C. ] 90 mg of 1,8-naphthyridine-7-carboxylic acid was obtained. Elemental analysis value C 13 H 10 N 2 O 5 Calculated value C 56.93, H 3.68, N 10.22 Analysis value C 57.15, H 3.49, N 10.21 NMR (CF 3 COOH): δ (ppm) 4.5-4.75, 5.35-5.65 (each 2H, m, N-C H
2 C H 2 OH) 7.45 (1H, q, H at 3rd position) 8.68 (1H, d, H at 2nd position) 9.22 (1H, b, s, H at 9th position) 9.80 (1H, s, H at 6th position) 2 Dissolve 900 mg of the above compound in a mixture of 10 ml of trifluoroacetic acid and 50 ml of acetic acid, and add 200 mg of 5% palladium on charcoal.
Add and recycle at room temperature. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified using 5 times the amount of silica gel column chromatography to obtain a white powder with a concentration of 5%.
Dissolve in 20 ml of KOH aqueous solution and stir at room temperature for 2 hours. After the reaction, the precipitate that precipitates as acidic hydrochloric acid is collected by filtration, washed with water, dried, and reconsolidated with ethanol to determine the melting point.
5-(2-hydroxyethyl)-2・ exhibiting 265℃
210 mg of 3,5,8-tetrahydro-8-oxofuro[3,2-b]1,8-naphthyridine-7-carboxylic acid are obtained. Elemental analysis value C 13 H 12 N 2 O Calculated value as 5 C 56.52, H 4.38, N 10.14 Analysis value C 56.67, H 4.24, N 9.86 NMR (CF 3 COOH): δ (ppm) 3.6-3.95, 4.9-5.3 (each 2H, m, CH 2 at 2nd and 3rd positions) 4.4-4.7, 5.3-5.6 (each 2H, m, N-C H 2 C H
2OH ) 8.14, 9.55 (1H, s, 6th and 9th position H) Example 3 1-(2-acetoxyethyl)-6-benzyloxy-7-ethyl-1,4-dihydro-4-oxo- Add 5.2 g of ethyl 1,8-naphthyridine-3-carboxylate to a mixture of 10 g of dimethylformamide diethyl acetal and 80 ml of 3% dimethylamine-dimethylformamide solution, and stir at 110°C for 4 hours. The solvent was distilled off under reduced pressure, and 3 ml of 47% hydrobromic acid and 150 ml of ethanol were added to the residue, followed by refluxing for 12 hours. The solvent is distilled off under reduced pressure, and to the residue are added 50 ml of 10% aqueous sodium hydroxide solution and 50 ml of ethanol, and the mixture is heated under reflux for 1 hour. Ethanol is distilled off and neutralized with hydrochloric acid. Extract the precipitate with chloroform,
After washing with water and drying to remove the solvent, the melting point is 187.
6-benzyloxy-7-(2,2-diethoxy-1-methylethyl)-1-(2-hydroxyethyl)-1,4-dihydro-4-oxo- at ~189°C
4.6 g of 1,8-naphthyridine-3-carboxylic acid are obtained. Elemental analysis value C 25 H 30 N 2 O 7 Calculated value C 63.81, H 6.43, N 5.95 Analysis value C 63.97, H 5.97, N 5.88 Dissolve 2.8 g of the above compound in 50 ml of naphthyridine and dropwise add 15 ml of acetic anhydride under ice cooling. do. After stirring at room temperature for 10 hours, the solvent was distilled off and the residue was dissolved in chloroform. The chloroform solution is washed with water, dried, and then the solvent is distilled off. The residue is recrystallized from benzene-petroleum ether to give 1-(2-
acetoxyethyl)-6-benzyloxy-7-
(2,2-diethoxy-1-methylethyl)-1.
3.0 g of 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. Elemental analysis value C 27 H 32 N 2 O Calculated value as 8 C 63.27, H 6.29, N 5.47 Analysis value C 63.24, H 6.56, N 5.56 Dissolve 530 mg of the above compound in a mixture of 10 ml of ethanol and 10 ml of methyl ethyl ketone, and add 5% palladium on charcoal. Add 180ml and perform catalytic reduction at normal pressure. After filtering off the catalyst and distilling off the solvent, the residue was subjected to silica gel chromatography and eluted with chloroform containing 1% methanol.
-acetoxyethyl)-7-(2,2-diethoxy-1-methylethyl)-6-hydroxy-1,4
300 mg of -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid are obtained. Elemental analysis value C 20 H 26 N 2 O 8 Calculated value C 56.86, H 6.20, N 6.63 Analysis value C 56.68, H 6.16, N 6.50 160 mg of the above compound was suspended in 1.2 ml of acetic acid, and the three odors were dissolved with stirring at room temperature. Add 0.2 ml of phosphorus and react for 2 hours. Add 4 ml of methanol under ice cooling, collect the precipitated crystals by filtration, and dry to obtain a melting point of 265-267°C (decomposition).
5-(2-acetoxyethyl)-3-methyl-
5,8-dihydro-8-oxofuro[3,2-
b] 1,8-naphthyridine-7-carboxylic acid 90 mg
get. This was added to a mixture of 0.2 ml of concentrated hydrochloric acid, 1 ml of water and 2 ml of ethanol, and the mixture was refluxed for 1 hour. After cooling, add 2 ml of water, collect the precipitated crystals by filtration, and add chloroform-
When recrystallized from a mixture of methanol, the melting point is 270-272.
5-(2-hydroxyethyl)-3- at °C (decomposition)
60 mg of methyl-5,8-dihydro-8-oxofuro[3,2-b]1,8-naphthyridine-7-carboxylic acid are obtained. Elemental analysis value C 14 H 12 N 2 O 5 Calculated value C 58.33, H 4.20, N 9.72 Analysis value C 57.85, H 4.22, N 9.66 NMR (DMSO-d 6 ): δ (ppm) 2.28 (3H, s, 3-position CH 3 group) 3.87 (2H, b, d, N-CH 2 C H 2 OH) 4.78 (2H, b, t, N-C H 2 CH 2 OH) 4.99 (1H, t, OH group) 8.58 , 8.80, 9.06 (each 1H, s, 2nd place, 6th place, 9th place)
Position H) Example 4 5-(2-acetoxyethyl)-3-methyl-
5,8-dihydro-8-oxofuro[3,2-
b] 1,8-naphthyridine-7-carboxylic acid 70mg
12ml of ethanol and 30ml of tetrahydrofuran
Dissolve in a mixed solution, add 40 mg of 5% palladium on charcoal, and perform atmospheric catalytic reduction. After the catalyst is filtered off and the solvent is distilled off, the residue is treated with benzene and hexane, and the precipitated crystals are collected by filtration. Add these crystals to concentrated hydrochloric acid with 0.2
ml, added to a mixture of 2 ml of water and 2 ml of ethanol, and refluxed for 1 hour. After cooling, add 3 ml of water, collect the precipitated crystals by filtration, and recrystallize from a mixture of chloroform, methanol, and benzene to obtain 5.
-(2-hydroxyethyl)-3-methyl-8-oxo-2,3,5,8-tetrahydrofuro[3.
2-b] 1,8-naphthyridine-7-carboxylic acid
Get 40mg. Elemental analysis value C 14 H 14 N 2 O 5 Calculated value C 57.93, H 4.86, N 9.65 Analysis value C 57.69, H 4.62, N 9.63 NMR (DMSO-d 6 ): δ (ppm) 1.40 (3H, d, 3-position CH 3 group) 3.7 to 3.9 (3H, m, N-CH 2 C H 2 OH and 3
position H) 4.39 (1H, t, O H group) 4.72 (2H, t, N-C H 2 CH 2 OH) 5.00 (2H, t, 2-position H 2 ) 7.87 and 8.95 (1H, s, 6-position each) and 9th position H)
Claims (1)
で示される５・８−ジヒドロフロまたは２・３・
５・８−テトラヒドロフロ〔３・２−ｂ〕１・８
−ナフチリジン−７−カルボン酸誘導体またはそ
の塩。 ２ ５・８−ジヒドロ−５−（２−ヒドロキシエ
チル）−８−オキソフロ〔３・２−ｂ〕１・８−
ナフチリジン−７−カルボン酸またはその塩であ
る特許請求の範囲第１項記載の化合物。 ３ ５−（２−ヒドロキシエチル）−８−オキソ−
２・３・５・８−テトラヒドロフロ〔３・２−
ｂ〕１・８−ナフチリジン−７−カルボン酸また
はその塩である特許請求の範囲第１項記載の化合
物。 ４ ５・８−ジヒドロ−５−（２−ヒドロキシエ
チル）−３−メチル−８−オキソフロ〔３・２−
ｂ〕１・８−ナフチリジン−７−カルボン酸また
はその塩である特許請求の範囲第１項記載の化合
物。 ５ ５−（２−ヒドロキシエチル）−３−メチル−
８−オキソ−２・３・５・８−テトラヒドロフロ
〔３・２−ｂ〕１・８−ナフチリジン−７−カル
ボン酸またはその塩である特許請求の範囲第１項
記載の化合物。[Claims] 1. General formula (In the formula, R represents hydrogen or a lower alkyl group)
5,8-dihydrofuro or 2,3-
5,8-tetrahydrofuro[3,2-b]1,8
-Naphthyridine-7-carboxylic acid derivative or salt thereof. 2 5,8-dihydro-5-(2-hydroxyethyl)-8-oxofuro[3,2-b]1,8-
The compound according to claim 1, which is naphthyridine-7-carboxylic acid or a salt thereof. 3 5-(2-hydroxyethyl)-8-oxo-
2,3,5,8-tetrahydrofuro [3,2-
b] The compound according to claim 1, which is 1,8-naphthyridine-7-carboxylic acid or a salt thereof. 4 5,8-dihydro-5-(2-hydroxyethyl)-3-methyl-8-oxofuro[3,2-
b] The compound according to claim 1, which is 1,8-naphthyridine-7-carboxylic acid or a salt thereof. 5 5-(2-hydroxyethyl)-3-methyl-
The compound according to claim 1, which is 8-oxo-2,3,5,8-tetrahydrofuro[3,2-b]1,8-naphthyridine-7-carboxylic acid or a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10180580A JPS5726688A (en) | 1980-07-24 | 1980-07-24 | Furo 3,2-b 1,8-naphthyridine-7-carboxylic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10180580A JPS5726688A (en) | 1980-07-24 | 1980-07-24 | Furo 3,2-b 1,8-naphthyridine-7-carboxylic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5726688A JPS5726688A (en) | 1982-02-12 |
| JPS6247187B2 true JPS6247187B2 (en) | 1987-10-06 |
Family
ID=14310345
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10180580A Granted JPS5726688A (en) | 1980-07-24 | 1980-07-24 | Furo 3,2-b 1,8-naphthyridine-7-carboxylic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5726688A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5446109A (en) * | 1993-02-23 | 1995-08-29 | Teijin Limited | Polyamide/aliphatic polyester block copolymer, process for the production thereof, and blend containing the same |
| US5854376A (en) * | 1995-03-09 | 1998-12-29 | Sekisui Kaseihin Kogyo Kabushiki Kaisha | Aliphatic ester-amide copolymer resins |
| US10954231B2 (en) | 2006-10-16 | 2021-03-23 | Bionomics Limited | Anxiolytic compounds |
| PT2074123E (en) * | 2006-10-16 | 2013-01-22 | Bionomics Ltd | Novel anxiolytic compounds |
| EP2681198A4 (en) | 2011-03-02 | 2014-09-03 | Bionomics Ltd | Novel small-molecules as therapeutics |
| US9133188B2 (en) | 2011-05-12 | 2015-09-15 | Bionomics Limited | Methods for preparing naphthyridines |
-
1980
- 1980-07-24 JP JP10180580A patent/JPS5726688A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5726688A (en) | 1982-02-12 |
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