JPH0430396B2 - - Google Patents
Info
- Publication number
- JPH0430396B2 JPH0430396B2 JP58220336A JP22033683A JPH0430396B2 JP H0430396 B2 JPH0430396 B2 JP H0430396B2 JP 58220336 A JP58220336 A JP 58220336A JP 22033683 A JP22033683 A JP 22033683A JP H0430396 B2 JPH0430396 B2 JP H0430396B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- melting point
- heating
- present
- 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 - Lifetime
Links
- 150000003839 salts Chemical class 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 description 38
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
- -1 benzene and toluene Chemical class 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000005452 food preservative Substances 0.000 description 2
- 235000019249 food preservative Nutrition 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XUNJSZSMARVWBT-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-4-oxo-7-pyridin-4-yl-1,8-naphthyridine-3-carboxylic acid Chemical compound C12=NC(C=3C=CN=CC=3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 XUNJSZSMARVWBT-UHFFFAOYSA-N 0.000 description 1
- VVAJMVGMVWGQAR-UHFFFAOYSA-N 5-nitro-2-oxo-6-pyridin-4-yl-1h-pyridine-3-carboxylic acid Chemical compound N1C(=O)C(C(=O)O)=CC([N+]([O-])=O)=C1C1=CC=NC=C1 VVAJMVGMVWGQAR-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 238000006350 Schiemann fluorination reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- ZRPBEAVKOMELBB-UHFFFAOYSA-N ethyl 3-(cyclopropylamino)propanoate Chemical compound CCOC(=O)CCNC1CC1 ZRPBEAVKOMELBB-UHFFFAOYSA-N 0.000 description 1
- SHQOVONJQDWWRC-UHFFFAOYSA-N ethyl 4-oxo-1h-1,8-naphthyridine-3-carboxylate Chemical compound N1=CC=CC2=C(O)C(C(=O)OCC)=CN=C21 SHQOVONJQDWWRC-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 208000010824 fish disease Diseases 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- XBLVHTDFJBKJLG-UHFFFAOYSA-N nicotinic acid ethyl ester Natural products CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- NLDYACGHTUPAQU-UHFFFAOYSA-N tetracyanoethylene Chemical group N#CC(C#N)=C(C#N)C#N NLDYACGHTUPAQU-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Food Preservation Except Freezing, Refrigeration, And Drying (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は下記式
で表わされる新規ピリジルナフチリジン誘導体お
よびその塩に関する。
式〔〕で表わされる化合物の塩としては、例
えば塩酸、硫酸、メタンスルホン酸の如き無機酸
もしくは有機酸との塩、あるいは式〔〕の化合
物のナトリウム塩やカリウム塩が具体的に挙げら
れる。
本発明化合物〔〕およびその塩は黄色ブドウ
球菌の如きグラム陽性菌、大腸菌の如きグラム陰
性菌、および緑膿菌を含むブドウ糖非醗酵菌に対
する抗菌活性が極めて強く、医薬のみならず動物
薬、魚病薬、食品防腐剤として種々の形態で使用
される。
本発明化合物〔〕およびその塩は、例えば以
下の方法によつて製造される。
本発明化合物〔〕は次の一般式
（式中、Ｙは同一または異つて低級アルキル基を
意味する。）
で表わされるピリジン誘導体をデイークマン
（Dieckmann）反応に通常用いられる塩基触媒の
存在下加熱し、下記一般式
（式中、Ｙは前掲と同じ。）
で表わされる化合物を生成せしめ、ついでこの化
合物〔〕を脱水素し、さらに加水分解すること
により製造することができる。
化合物〔〕を生成せしめる場合、原料化合物
〔〕を溶媒中、金属ナトリウム、水素化ナトリ
ウム、ナトリウムエチラート、カリウム ｔ−ブ
チラートの如き塩基触媒の存在下加熱反応せし
め、分子内閉環せしめることにより、化合物
〔〕が得られる。この際、触媒量のメタノール、
エタノール、ｔ−ブタノール等の低級アルコール
類を加えると反応が一層効果的に達成される。ベ
ンゼン、トルエンの如き芳香族炭化水素、ジオキ
サン、テトラヒドロフラン、１，２−ジメトキシ
エタン、ジエチレングリコールジメチルエーテル
の如きエーテル類が反応溶媒として好適である。
加熱温度は特に限定されないが通常60〜180℃の
温度が好ましい。
尚、化合物〔〕は下記一般式でも表示される
化合物である。
（式中、Ｙは前掲と同じ。）
化合物〔〕を脱水素するには、化合物に
〔〕に、不活性溶媒（例えばベンゼン、トルエ
ン、キシレン、酢酸エチル、ジオキサン、ｔ−ブ
チルアルコール、ジメチルホルムアミド、エタノ
ール等）中で、２，３−ジクロロ−５，６−ジシ
アノ−１，４−ベンゾキノン（DDQ）、テトラク
ロロ−１，４−ベンゾキノン（クロラニル）、テ
トラシアノエチレン、パラジウム−炭素、Ｎ−ブ
ロモコハク酸イミド（NBS）、二酸化マンガン、
あるいは二酸化ゼノンの如き通常の脱水素剤を、
室温または使用する溶媒の沸点付近で短時間加熱
反応させればよく、あるいは化合物〔〕をその
融点以上に直接加熱するか、またはベンゼン、ト
ルエン、ジオキサン、エタノール、ｎ−ヘキサ
ン、四塩化炭素、ジメチルホルムアミド、ジフエ
ニルエーテル等の不活性溶媒中で加熱するだけで
もよい。
かくして得られたエステル体は、常法によつて
これを加水分解し、本発明の化合物〔〕に変換
することができる。
本発明化合物〔〕はまた、次の方法によつて
も製造することが可能である。すなわち、下記式
で表わされる化合物の低級アルキルエステルの６
位のアミノ基を常法によりジアゾニウム塩に変換
すると共にシーマン（Schiemann）反応に付す
ことによつて、本発明の化合物〔〕のエステル
を生成せしめ、ついで常法によつてこれを加水分
解し、本発明の化合物〔〕を製造することがで
きる。
更に、上述の合成法以外にも、上述の単位反応
を目的に応じ適当に組み合わせることによつても
本発明の化合物を製造することができる。
原料化合物〔〕は参考例に記載の方法、ある
いはこれに準じた方法で製造され、原料化合物
〔〕のエステルは、ヨーロツパ特許公開公報No.
9425の開示、あるいは本発明の化合物〔〕の製
法に準じた方法で製造することができる。
このようにして製造される本発明の化合物は、
常法に従い単離、精製される。単離、精製条件に
よつて塩の形や遊離の形で得られるが、これらは
目的に応じて相互に変換され、目的とする形の本
発明の化合物が製造される。
かくして得られる化合物〔〕およびその塩は
いずれも新規化合物であり、極めて優れた抗菌活
性を示すので、抗菌剤として価値あるものであ
る。化合物〔〕はこれを人体および動物用医薬
は勿論のこと、魚病薬、農薬、食品の保存剤等と
しても使用することが可能である。
次に本発明の化合物の抗菌活性について、以下
にデータを挙げる。
The present invention is based on the following formula The present invention relates to a novel pyridylnaphthyridine derivative represented by and a salt thereof. Specific examples of the salt of the compound represented by formula [] include salts with inorganic or organic acids such as hydrochloric acid, sulfuric acid, and methanesulfonic acid, and sodium salts and potassium salts of the compound represented by formula []. The compound of the present invention [ ] and its salts have extremely strong antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus, Gram-negative bacteria such as Escherichia coli, and non-glucose-fermenting bacteria including Pseudomonas aeruginosa, and are useful not only for pharmaceuticals but also for veterinary medicine and fish. It is used in various forms as a medicine and food preservative. The compound of the present invention [] and its salt can be produced, for example, by the following method. The compound of the present invention [] has the following general formula (In the formula, Y means the same or different lower alkyl group.) The pyridine derivative represented by (In the formula, Y is the same as above.) It can be produced by producing a compound represented by the following formula, then dehydrogenating this compound [], and further hydrolyzing it. When producing the compound [], the starting compound [] is subjected to a heating reaction in a solvent in the presence of a base catalyst such as sodium metal, sodium hydride, sodium ethylate, or potassium t-butyrate to cause intramolecular ring closure. [] is obtained. At this time, a catalytic amount of methanol,
The reaction can be achieved more effectively by adding lower alcohols such as ethanol and t-butanol. Aromatic hydrocarbons such as benzene and toluene, and ethers such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane and diethylene glycol dimethyl ether are suitable as reaction solvents.
The heating temperature is not particularly limited, but a temperature of 60 to 180°C is usually preferred. Note that the compound [ ] is also represented by the following general formula. (In the formula, Y is the same as above.) To dehydrogenate the compound [], add an inert solvent (for example, benzene, toluene, xylene, ethyl acetate, dioxane, t-butyl alcohol, dimethylformamide) to the compound []. , 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), tetrachloro-1,4-benzoquinone (chloranil), tetracyanoethylene, palladium-carbon, N- Bromosuccinimide (NBS), manganese dioxide,
Or use a regular dehydrogenating agent such as xenone dioxide.
The reaction can be carried out by heating for a short time at room temperature or around the boiling point of the solvent used, or by directly heating the compound above its melting point, or by heating the compound [] directly to a temperature above its melting point, or by heating the compound [] directly to a temperature above its melting point, or by heating the compound [] directly to a temperature above its melting point, or by heating the compound [ ] directly to a temperature above its melting point, or by heating the compound [ ] directly to a temperature above its melting point, or by heating the compound [ ] directly to a temperature above its melting point, or by heating the compound [] directly to a temperature above its melting point, or by heating the compound [] directly to a temperature above its melting point, or by directly heating the compound [ ] to a temperature above its melting point, or by directly heating the compound [] to a temperature above its melting point. Simply heating in an inert solvent such as formamide or diphenyl ether may be sufficient. The ester thus obtained can be converted into the compound of the present invention by hydrolyzing it by a conventional method. The compound of the present invention [] can also be produced by the following method. In other words, the following formula 6 of the lower alkyl ester of the compound represented by
By converting the amino group at position into a diazonium salt by a conventional method and subjecting it to Schiemann reaction, an ester of the compound [ ] of the present invention is produced, which is then hydrolyzed by a conventional method, The compound [ ] of the present invention can be produced. Furthermore, in addition to the above-mentioned synthesis methods, the compounds of the present invention can also be produced by appropriately combining the above-mentioned unit reactions depending on the purpose. The raw material compound [] is produced by the method described in Reference Examples or a method similar thereto, and the ester of the raw material compound [] is produced by the method described in the European Patent Publication No.
It can be produced by a method according to the disclosure of No. 9425 or the method for producing the compound [] of the present invention. The compound of the present invention produced in this way is
Isolated and purified according to conventional methods. Depending on the isolation and purification conditions, the compound of the present invention can be obtained in the form of a salt or a free form, but these can be mutually converted depending on the purpose to produce the compound of the present invention in the desired form. The thus obtained compound [ ] and its salts are both new compounds and exhibit extremely excellent antibacterial activity, making them valuable as antibacterial agents. The compound [] can be used not only as a medicine for humans and animals, but also as a medicine for fish diseases, an agricultural chemical, a food preservative, and the like. Next, data regarding the antibacterial activity of the compounds of the present invention are listed below.
【表】
次に参考例および実施例を挙げ、本発明を更に
詳細に説明する。
参考例 １
５−ニトロ−６−（４−ピリジル）−１，２−ジ
ヒドロ−２−オキソニコチン酸2.0ｇにオキシ塩
化リン20mlを加えて、撹拌下に２時間加熱還流す
る。オキシ塩化リンを減圧で留去したのち、クロ
ロホルムとエタノールを加え、さらに１時間加熱
還流する。溶媒を減圧で留去し、残渣に氷水を加
え、10％水酸化ナトリウム水溶液でPH8.0とした
のち、クロロホルムで抽出する。クロロホルムを
留去し、残渣に３−（Ｎ−シクロプロピル）アミ
ノプロピオン酸エチルエステル2.4ｇとエタノー
ルを加え、撹拌下に1.5時間加熱還流する。溶媒
を減圧で留去したのち、シリカゲルカラムで処理
（溶出液：クロロホルム）して、２−〔Ｎ−シクロ
プロピル−Ｎ−（２−エトキシカルボニルエチル）
アミノ〕−５−ニトロ−６−（４−ピリジル）ニコ
チン酸エチルエステル2.0ｇを得る。融点106−
107℃：再結晶溶媒、イソプロピルエーテル。
参考例 ２
２−〔Ｎ−シクロプロピル−Ｎ−（２−エトキシ
カルボニルエチル）アミノ〕−５−ニトロ−６−
（４−ピリジル）ニコチン酸エチルエステル2.25
ｇと無水ｔ−ブチルアルコール230mlの混合物を
室温で撹拌し、これにカリウムｔ−ブチラート
920mgを徐徐に加える。10分後、酢酸を加えてPH
6.5〜7.0に調製し、析出した結晶を取する。水
およびアルコールで洗つて、１−シクロプロピル
−６−ニトロ−７−（４−ピリジル）−１，２，
３，４−テトラヒドロ−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1.6
ｇを得る。融点195−198℃：再結晶溶媒、エタノ
ール。
参考例 ３
１−シクロプロピル−６−ニトロ−７−（４−
ピリジル）−１，２，３，４−テトラヒドロ−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3.5ｇ、ジオキサン180ml、クロ
ラニル3.4ｇの混合物を撹拌下に15分間加熱還流
する。溶媒を減圧で留去し、残渣に1N水酸化ナ
トリウム水溶液を加えて、クロロホルムで抽出す
る。クロロホルムを減圧で留去して、１−シクロ
プロピル−６−ニトロ−７−（４−ピリジル）−
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3.0ｇを
得る。融点200−201℃：再結晶溶媒、エチルエス
テル。
実施例 １
(1) １−シクロプロピル−６−ニトロ−７−（４
−ピリジル）−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1.85ｇ、酢酸40ml、パラジウム−炭
素100mgの混合物を水素気流下で接触還元する。
理論量の水素を吸収したところで析出結晶を
取し、これに42％ホウフツ化水素酸25mlを加え
て不溶物を除く。この溶液を氷冷し、これに亜
硝酸ナトリウム500mgの水（３ml）溶液を０〜
３℃で加え、10分間撹拌する。冷エタノール25
ml、冷エーテル90mlを加え析出結晶を取す
る。十分に乾燥したのち、トルエン70mlに懸濁
し、100〜110℃で１時間加熱する。トルエンを
減圧で留去し、残渣に1N水酸化ナトリウム水
溶液を加え、クロロホルムで抽出する。クロロ
ホルムを留去し、残渣に酢酸エチルを加え、結
晶を取して、１−シクロプロピル−６−フル
オロ−７−（４−ピリジル）−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700mgを得る。融点209
−211℃：再結晶溶媒、酢酸エチルエステル。
(2) １−シクロプロピル−６−フルオロ−７−
（４−ピリジル）−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700mgと1N水酸化ナトリウム水溶
液20mlの混合物を90〜100℃で10分間加熱撹拌
する。冷却後、酢酸を加えてPH６〜７としたの
ち、クロロホルムで抽出する。クロロホルムを
減圧で留去し、１−シクロプロピル−６−フル
オロ−７−（４−ピリジル）−１，４−ジヒドロ
−４−オキソ−１，８−ナフチリジン−３−カ
ルボン酸350mgを得る。融点300℃以上：再結晶
溶媒、クロロホルム−エタノール。[Table] Next, the present invention will be explained in more detail with reference to Reference Examples and Examples. Reference Example 1 20 ml of phosphorus oxychloride was added to 2.0 g of 5-nitro-6-(4-pyridyl)-1,2-dihydro-2-oxonicotinic acid, and the mixture was heated under reflux for 2 hours while stirring. After phosphorus oxychloride was distilled off under reduced pressure, chloroform and ethanol were added, and the mixture was further heated under reflux for 1 hour. The solvent is distilled off under reduced pressure, ice water is added to the residue, the pH is adjusted to 8.0 with a 10% aqueous sodium hydroxide solution, and the mixture is extracted with chloroform. Chloroform was distilled off, 2.4 g of 3-(N-cyclopropyl)aminopropionic acid ethyl ester and ethanol were added to the residue, and the mixture was heated under reflux for 1.5 hours with stirring. After distilling off the solvent under reduced pressure, it was treated with a silica gel column (eluent: chloroform) to give 2-[N-cyclopropyl-N-(2-ethoxycarbonylethyl).
2.0 g of amino]-5-nitro-6-(4-pyridyl)nicotinic acid ethyl ester are obtained. Melting point 106−
107°C: Recrystallization solvent, isopropyl ether. Reference example 2 2-[N-cyclopropyl-N-(2-ethoxycarbonylethyl)amino]-5-nitro-6-
(4-pyridyl)nicotinic acid ethyl ester 2.25
A mixture of g and 230 ml of anhydrous t-butyl alcohol was stirred at room temperature, and potassium t-butyrate was added to the mixture.
Add 920 mg slowly. After 10 minutes, add acetic acid to adjust the pH.
Adjust the temperature to 6.5 to 7.0 and collect the precipitated crystals. After washing with water and alcohol, 1-cyclopropyl-6-nitro-7-(4-pyridyl)-1,2,
3,4-tetrahydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester 1.6
get g. Melting point 195-198°C: recrystallization solvent, ethanol. Reference example 3 1-cyclopropyl-6-nitro-7-(4-
pyridyl)-1,2,3,4-tetrahydro-4
A mixture of 3.5 g of -oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 180 ml of dioxane, and 3.4 g of chloranil is heated under reflux for 15 minutes with stirring. The solvent is distilled off under reduced pressure, 1N aqueous sodium hydroxide solution is added to the residue, and the mixture is extracted with chloroform. Chloroform was distilled off under reduced pressure to obtain 1-cyclopropyl-6-nitro-7-(4-pyridyl)-
3.0 g of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester are obtained. Melting point 200-201°C: recrystallization solvent, ethyl ester. Example 1 (1) 1-cyclopropyl-6-nitro-7-(4
A mixture of 1.85 g of -pyridyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 40 ml of acetic acid, and 100 mg of palladium-carbon is catalytically reduced under a hydrogen stream.
After absorbing the theoretical amount of hydrogen, collect the precipitated crystals and add 25 ml of 42% hydroborofluoric acid to remove insoluble matter. Cool this solution on ice, and add a solution of 500 mg of sodium nitrite in water (3 ml) to it.
Add at 3°C and stir for 10 minutes. cold ethanol 25
ml, add 90 ml of cold ether and collect the precipitated crystals. After sufficiently drying, suspend in 70 ml of toluene and heat at 100 to 110°C for 1 hour. Toluene was distilled off under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with chloroform. Chloroform was distilled off, ethyl acetate was added to the residue, and the crystals were collected to give 1-cyclopropyl-6-fluoro-7-(4-pyridyl)-1,4-dihydro-4-oxo-1,8- 700 mg of naphthyridine-3-carboxylic acid ethyl ester are obtained. melting point 209
−211°C: Recrystallization solvent, acetic acid ethyl ester. (2) 1-cyclopropyl-6-fluoro-7-
A mixture of 700 mg of (4-pyridyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester and 20 ml of 1N aqueous sodium hydroxide solution is heated and stirred at 90 to 100°C for 10 minutes. After cooling, acetic acid is added to adjust the pH to 6 to 7, followed by extraction with chloroform. Chloroform was distilled off under reduced pressure to obtain 350 mg of 1-cyclopropyl-6-fluoro-7-(4-pyridyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. Melting point 300°C or higher: recrystallization solvent, chloroform-ethanol.
Claims (1)
その塩。[Claims] 1. The following formula Pyridylnaphthyridine derivatives and salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58220336A JPS60112790A (en) | 1983-11-21 | 1983-11-21 | Pyridylnaphthyridine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58220336A JPS60112790A (en) | 1983-11-21 | 1983-11-21 | Pyridylnaphthyridine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60112790A JPS60112790A (en) | 1985-06-19 |
| JPH0430396B2 true JPH0430396B2 (en) | 1992-05-21 |
Family
ID=16749547
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58220336A Granted JPS60112790A (en) | 1983-11-21 | 1983-11-21 | Pyridylnaphthyridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60112790A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5531042A (en) * | 1978-08-25 | 1980-03-05 | Dainippon Pharmaceut Co Ltd | 1,8-naphthylidine derivative and its salt |
| JPS5649382A (en) * | 1979-09-28 | 1981-05-02 | Dainippon Pharmaceut Co Ltd | 6-fluoro-7-cyclic amino-1,8-naphthylidine derivative and its salt |
| JPS57106681A (en) * | 1980-12-24 | 1982-07-02 | Dainippon Pharmaceut Co Ltd | 1,8-naphthyridine derivative and its salt |
| JPS57146775A (en) * | 1981-03-06 | 1982-09-10 | Dainippon Pharmaceut Co Ltd | 1,8-naphthyridine derivative and its salt |
-
1983
- 1983-11-21 JP JP58220336A patent/JPS60112790A/en active Granted
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5531042A (en) * | 1978-08-25 | 1980-03-05 | Dainippon Pharmaceut Co Ltd | 1,8-naphthylidine derivative and its salt |
| JPS5649382A (en) * | 1979-09-28 | 1981-05-02 | Dainippon Pharmaceut Co Ltd | 6-fluoro-7-cyclic amino-1,8-naphthylidine derivative and its salt |
| JPS57106681A (en) * | 1980-12-24 | 1982-07-02 | Dainippon Pharmaceut Co Ltd | 1,8-naphthyridine derivative and its salt |
| JPS57146775A (en) * | 1981-03-06 | 1982-09-10 | Dainippon Pharmaceut Co Ltd | 1,8-naphthyridine derivative and its salt |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60112790A (en) | 1985-06-19 |
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