JPH0374231B2 - - Google Patents
Info
- Publication number
- JPH0374231B2 JPH0374231B2 JP59028278A JP2827884A JPH0374231B2 JP H0374231 B2 JPH0374231 B2 JP H0374231B2 JP 59028278 A JP59028278 A JP 59028278A JP 2827884 A JP2827884 A JP 2827884A JP H0374231 B2 JPH0374231 B2 JP H0374231B2
- Authority
- JP
- Japan
- Prior art keywords
- add
- carboxylic acid
- solvent
- dichloro
- acid
- 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
- 150000002148 esters Chemical class 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 2
- OXNZWNNMJBOZQO-UHFFFAOYSA-N 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid Chemical compound C12=NC(Cl)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 OXNZWNNMJBOZQO-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 26
- -1 2,6-dihydro-3-fluoropyridine-5-carboxylic acid amide Chemical compound 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
- AKRHQLMLNZKYRK-UHFFFAOYSA-N 5-fluoro-6-hydroxy-2-oxo-1h-pyridine-3-carboxamide Chemical compound NC(=O)C1=CC(F)=C(O)N=C1O AKRHQLMLNZKYRK-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- DEDKKOOGYIMMBC-UHFFFAOYSA-N 2,6-dichloro-5-fluoropyridine-3-carbonitrile Chemical compound FC1=CC(C#N)=C(Cl)N=C1Cl DEDKKOOGYIMMBC-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- RWCZOVMOKFTUAD-UHFFFAOYSA-N ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylate Chemical compound C12=NC(Cl)=C(F)C=C2C(=O)C(C(=O)OCC)=CN1C1CC1 RWCZOVMOKFTUAD-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- HPOSEDFTMSDHFQ-UHFFFAOYSA-N ethyl 3-(2,6-dichloro-5-fluoropyridin-3-yl)propanoate Chemical compound CCOC(=O)CCC1=CC(F)=C(Cl)N=C1Cl HPOSEDFTMSDHFQ-UHFFFAOYSA-N 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- AATVXELAYCLVTJ-UHFFFAOYSA-N 2,6-dichloro-5-fluoropyridine-3-carbonyl chloride Chemical compound FC1=CC(C(Cl)=O)=C(Cl)N=C1Cl AATVXELAYCLVTJ-UHFFFAOYSA-N 0.000 description 2
- OCOBFMZGRJOSOU-UHFFFAOYSA-N 3-o-tert-butyl 1-o-ethyl propanedioate Chemical compound CCOC(=O)CC(=O)OC(C)(C)C OCOBFMZGRJOSOU-UHFFFAOYSA-N 0.000 description 2
- UYTWCEYZEQBILY-UHFFFAOYSA-N 4,6-dichloro-5-fluoropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=C(Cl)C(F)=C1Cl UYTWCEYZEQBILY-UHFFFAOYSA-N 0.000 description 2
- RVDLHGSZWAELAU-UHFFFAOYSA-N 5-tert-butylthiophene-2-carbonyl chloride Chemical compound CC(C)(C)C1=CC=C(C(Cl)=O)S1 RVDLHGSZWAELAU-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 150000002085 enols Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000010446 mirabilite Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 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
- 239000006228 supernatant Substances 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
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-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 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 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
- SCANHWGNLLBPRH-UHFFFAOYSA-N 7-chloro-1-cyclopropyl-6-fluoro-1,8-naphthyridin-4-one Chemical compound N1=C(Cl)C(F)=CC(C(C=C2)=O)=C1N2C1CC1 SCANHWGNLLBPRH-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 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
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- WJGAPUXHSQQWQF-UHFFFAOYSA-N acetic acid;hydrochloride Chemical compound Cl.CC(O)=O WJGAPUXHSQQWQF-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000004533 oil dispersion Substances 0.000 description 1
- PQUHFRSGVHFXNT-UHFFFAOYSA-N pcl5 pocl3 Chemical compound ClP(Cl)(Cl)=O.ClP(Cl)(Cl)(Cl)Cl PQUHFRSGVHFXNT-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension 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
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本発明は、優れた抗菌性化合物の中間体として
有用な化合物に関し、更に詳しくは、式で表さ
れる７−クロル−１−シクロプロピル−６−フル
オロ−１，４−ジヒドロ−４−オキソ−１，８−
ナフチリジン−３−カルボン酸またはそのエステ
ル及びその塩に関する。
本発明化合物の製造例を反応式を示して説明す
る。
公知化合物である２，６−ジヒドロ−３−フル
オロピリジン−５−カルボン酸アミド(1)を硫酸−
酢酸で加水分解し、得られるカルボン酸(4)を単
離、精製することなく、オキシ塩化リン−五塩化
リンで処理すると、２，６−ジクロル−３−フル
オロピリジン−５−カルボン酸クロリド(5)が得ら
れる。又、酸クロリド(5)は、公知の２，６−ジク
ロル−３−フルオロピリジン−５−カルボニトリ
ル(2)を加水分解して対応するカルボン酸(3)とし、
次いでチオニルクロライドとベンゼン中で還流す
ることによつても得ることができる。酸クロリド
(5)を、マグネシウムエトキシドとマロン酸エチル
−tert−ブチルから合成したエトキシマグネシウ
ムマロン酸エチル−tert−ブチルに加え、２，６
−ジクロル−５−フルオロニコチニルマロン酸エ
チル−tert−ブチル(6)を製し、これを、触媒量の
ｐ−トルエンスルホン酸と３〜５時間ベンゼン中
で還流すると２，６−ジクロル−５−フルオロニ
コチニル酢酸エチルエステル(7)（ケト、エノール
の混合物）が生成する。これをオルトギ酸エチル
と無水酢酸中で反応させて、３−エトキシ−２−
（２，６−ジクロル−５−フルオロニコチニル）
アクリル酸エチルエステル(8)とした後単離精製す
ることなく、ジクロルメタンに転溶し、室温下シ
クロプロプルアミンを加えると対応する３−シク
ロプロピルアミノ体(9)となる。これを無水ジオキ
サンに溶解し、水酸化ナトリウムを加えて５〜30
分還流し、シリカゲルカラムクロマトグラフイで
精製し、７−クロル−１−シクロプロピル−６−
フルオロ−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（Ia）を得ることができる。これを酸性または
アルカリ性で加水分解するとそのカルボン酸
（Ib）が得られる。
本発明化合物は、２−置換ピペラジンとジメチ
ルスルホキシド、ジメチルホルムアミド、ピリジ
ンの如き溶媒中で反応させると優れた抗菌活性を
有する７−置換−１，８−ナフチリジン−３−カ
ルボン酸類を導くことができる。
実施例
[1] ２，６−ジクロロ−３−フルオロピリジン
−５−カルボニトリル(2)12ｇを酢酸60ml、水
5.8ml、濃硫酸5.8mlの混液に加え、16時間還流
する。反応後、水200mlを加え、酢酸エチル150
mlで３回抽出し、抽出液を飽和食塩水100mlで
洗浄後、芒硝乾燥し、溶媒を留去し、２，６−
ジクロル−３−フルオロピリジン−５−カルボ
ン酸(3)6.8ｇを結晶性粉末として得る。
NMR（CDCl3）δppm：
8.10（1H，ｄ，Ｊ＝8.0Hz，aromatic Ｈ）
9.92（1H，ｄ・ｓ，−COOＨ）
[2] このカルボン酸(3)3.9ｇに塩化チオニル５ml
およびベンゼン60mlを加え、１時間還流する。
冷後溶媒を留去して、得られた残渣にベンゼン
を加え撹拌した後上澄のベンゼンを除く操作を
２回繰返し、酸クロライド(5)を油状物として得
る。これをエーテル20mlに溶解し、別にマロン
酸エチル−tert−ブチル3.67ｇおよびマグネシ
ウムエトキシド2.2ｇをエーテル40ml中で１時
間還流した後室温に戻して製した溶液中に徐々
に滴下する。滴下後15分間還流し、再び室温に
戻し、水を加え、硫酸でPH＜４とした後、エー
テルと分配し、さらに水層をエーテル100mlで
３回抽出する。エーテル抽出液を合わせ飽和食
塩水で洗つた後芒硝で脱水し、エーテルを留去
し、２，６−ジクロル−５−フルオロニコチオ
ニルマロン酸エチル−tert−ブチル(6)3.4ｇを油
状物として得る。
NMR（CDCl3）δppm：
1.48，1.58（tert−Buが２種類）
7.49（1H，ｄ，ピリジン核 Ｈ）
[3] ２，６−ジヒドロキシ−３−フルオロピリ
ジン−５−カルボン酸アミド(1)3.1ｇ（または
２，６−ジヒドロキシ−５−フルオロニコチン
酸アミド）を酢酸10ml、水１ml、硫酸４mlの混
液に加え、一昼夜還流する。冷後溶媒を減圧留
去し、残渣に氷水10mlを加え、炭酸水素ナトリ
ウムを加えて中和し、大量のクロロホルムで抽
出する。芒硝乾燥後、溶媒を留去して得られる
残渣を単離精製することなく、オキシ塩化リン
５ml−五塩化リン１ｇの混合物に加え、３時間
還流し、冷後溶媒を減圧留去する。得られた残
渣にベンゼン20mlを加えて撹拌し、上澄のベン
ゼンを除く操作を３回繰返し、２，６−ジクロ
ル−３−フルオロピリジン−５−カルボン酸ク
ロライド(5)2.2ｇを得る。
[4] ２，６−ジクロル−５−フルオロニコチオ
ニルマロン酸エチル−tert−ブチル(6)3.4ｇにｐ
−トルエンスルホン酸150mg、脱水ベンゼン100
mlを加えて３時間還流後、溶媒を減圧留去し、
残渣をジリカゲルカラムクロマトグラフイー
（50ｇ）を用いて精製し、ベンゼン溶出物とし
て２，６−ジクロル−５−フルオロ−ニコチニ
ル酢酸エチルエステル(7)2.3ｇを得る。
NMR（CDCl3）δppm：
1.35（3H，ｔ，Ｊ＝７Hz，−CH2CＨ 3）
4.28（2H，ｑ，Ｊ＝７Hz，−CH2CＨ 3）
4.08＆5.80（enol体）2H（−CO−ＣＨ 2−
COOEt）
7.78（1H，ｄ，Ｊ＝８Hz，ピリジンＨ）
[5] このβ−ケトエステル体(7)2.2ｇにオルトギ
酸エチル1.3ｇ、無水酢酸40mlを加え15分加熱
還流した後、溶媒を減圧留去し、得られた粗エ
トキシメチレン体(8)を単離精製することなく、
ジクロルメタン30mlを加え、氷冷下撹拌しつつ
シクロプロピルアミン500mgのジクロルメタン
溶液５mlを滴下する。室温に戻して20分撹拌
し、溶媒を留去し、得られた残渣をシリカゲル
20ｇのクロマトを用いて精製し、３％酢酸エチ
ル／ベンゼン溶出物として３−シクロプロピル
アミノ−２−（２，６−ジクロル−５−フルオ
ロニコチニル）アクリル酸エチルエステル(9)
1.3ｇを得る。
NMR（CDCl3）δppm：
0.8〜1.0（4H，ｍ，
The present invention relates to a compound useful as an intermediate for an excellent antibacterial compound, and more specifically to a compound represented by the formula 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo- 1,8-
This invention relates to naphthyridine-3-carboxylic acid or its ester and its salt. Examples of manufacturing the compounds of the present invention will be explained by showing reaction formulas. The known compound 2,6-dihydro-3-fluoropyridine-5-carboxylic acid amide (1) was dissolved in sulfuric acid.
Hydrolysis with acetic acid and treatment of the resulting carboxylic acid (4) with phosphorus oxychloride-phosphorus pentachloride without isolation or purification yields 2,6-dichloro-3-fluoropyridine-5-carboxylic acid chloride ( 5) is obtained. In addition, the acid chloride (5) is obtained by hydrolyzing the known 2,6-dichloro-3-fluoropyridine-5-carbonitrile (2) to produce the corresponding carboxylic acid (3),
It can also be obtained by subsequent refluxing in benzene with thionyl chloride. acid chloride
(5) was added to ethoxymagnesium ethyl tert-butyl malonate synthesized from magnesium ethoxide and ethyl tert-butyl malonate, and 2,6
Ethyl-tert-butyl-dichloro-5-fluoronicotinylmalonate (6) is prepared by refluxing it with a catalytic amount of p-toluenesulfonic acid in benzene for 3-5 hours. -Fluoronicotinyl acetate ethyl ester (7) (a mixture of keto and enol) is produced. This was reacted with ethyl orthoformate in acetic anhydride to produce 3-ethoxy-2-
(2,6-dichloro-5-fluoronicotinyl)
After preparing the acrylic acid ethyl ester (8), it is dissolved in dichloromethane without isolation and purification, and cyclopropylamine is added at room temperature to obtain the corresponding 3-cyclopropylamino compound (9). Dissolve this in anhydrous dioxane and add sodium hydroxide for 5 to 30 minutes.
The 7-chloro-1-cyclopropyl-6-
Fluoro-1,4-dihydro-4-oxo-1,
8-naphthyridine-3-carboxylic acid ethyl ester (Ia) can be obtained. When this is hydrolyzed in acidic or alkaline conditions, the carboxylic acid (Ib) is obtained. When the compound of the present invention is reacted with 2-substituted piperazine in a solvent such as dimethylsulfoxide, dimethylformamide, or pyridine, it can lead to 7-substituted-1,8-naphthyridine-3-carboxylic acids having excellent antibacterial activity. . Example [1] 12 g of 2,6-dichloro-3-fluoropyridine-5-carbonitrile (2) was mixed with 60 ml of acetic acid and water.
Add to a mixture of 5.8 ml and concentrated sulfuric acid and reflux for 16 hours. After the reaction, add 200ml of water and add 150ml of ethyl acetate.
ml three times, the extract was washed with 100 ml of saturated saline, dried with Glauber's salt, the solvent was distilled off, and 2,6-
6.8 g of dichloro-3-fluoropyridine-5-carboxylic acid (3) are obtained as a crystalline powder. NMR (CDCl 3 ) δppm: 8.10 (1H, d, J=8.0Hz, aromatic H ) 9.92 (1H, d・s, -COO H ) [2] Add 5 ml of thionyl chloride to 3.9 g of this carboxylic acid (3).
Add 60 ml of benzene and reflux for 1 hour.
After cooling, the solvent is distilled off, benzene is added to the resulting residue, stirred, and the supernatant benzene is removed. This operation is repeated twice to obtain acid chloride (5) as an oil. This was dissolved in 20 ml of ether, and separately, 3.67 g of ethyl tert-butyl malonate and 2.2 g of magnesium ethoxide were refluxed in 40 ml of ether for 1 hour, then returned to room temperature, and then gradually added dropwise to the solution prepared. After the dropwise addition, the mixture was refluxed for 15 minutes, returned to room temperature, water was added, the pH was adjusted to <4 with sulfuric acid, the mixture was partitioned with ether, and the aqueous layer was extracted three times with 100 ml of ether. The ether extracts were combined and washed with saturated brine, then dehydrated with Glauber's salt, the ether was distilled off, and 3.4 g of ethyl-tert-butyl 2,6-dichloro-5-fluoronicothionylmalonate (6) was obtained as an oil. obtain. NMR (CDCl 3 ) δppm: 1.48, 1.58 (2 types of tert-Bu) 7.49 (1H, d, pyridine nucleus H ) [3] 2,6-dihydroxy-3-fluoropyridine-5-carboxylic acid amide (1) Add 3.1 g (or 2,6-dihydroxy-5-fluoronicotinamide) to a mixture of 10 ml of acetic acid, 1 ml of water, and 4 ml of sulfuric acid, and reflux the mixture overnight. After cooling, the solvent is distilled off under reduced pressure, 10 ml of ice water is added to the residue, neutralized by adding sodium bicarbonate, and extracted with a large amount of chloroform. After drying the sodium sulfate, the solvent was distilled off, and the resulting residue was added to a mixture of 5 ml of phosphorus oxychloride and 1 g of phosphorus pentachloride without isolation and purification, and the mixture was refluxed for 3 hours, and after cooling, the solvent was distilled off under reduced pressure. Add 20 ml of benzene to the obtained residue, stir, and remove the supernatant benzene. The operation is repeated three times to obtain 2.2 g of 2,6-dichloro-3-fluoropyridine-5-carboxylic acid chloride (5). [4] 3.4 g of ethyl-tert-butyl 2,6-dichloro-5-fluoronicothionylmalonate (6)
-Toluenesulfonic acid 150mg, dehydrated benzene 100g
ml and after refluxing for 3 hours, the solvent was distilled off under reduced pressure.
The residue was purified using silica gel column chromatography (50 g) to obtain 2.3 g of 2,6-dichloro-5-fluoro-nicotinyl acetic acid ethyl ester (7) as a benzene eluate. NMR ( CDCl3 ) δppm : 1.35 (3H, t, J = 7Hz, -CH2CH3 ) 4.28 (2H, q , J = 7Hz, -CH2CH3 ) 4.08 & 5.80 (enol body) 2H ( -CO- CH2-
COOEt) 7.78 (1H, d, J = 8 Hz, pyridine H ) [5] To 2.2 g of this β-ketoester (7) were added 1.3 g of ethyl orthoformate and 40 ml of acetic anhydride, and after heating under reflux for 15 minutes, the solvent was removed under reduced pressure. Without isolating and purifying the crude ethoxymethylene compound (8) obtained by distillation,
Add 30 ml of dichloromethane, and dropwise add 5 ml of a dichloromethane solution containing 500 mg of cyclopropylamine while stirring under ice cooling. Return to room temperature, stir for 20 minutes, evaporate the solvent, and transfer the resulting residue to silica gel.
Purified using 20 g chromatography to give 3-cyclopropylamino-2-(2,6-dichloro-5-fluoronicotinyl)acrylic acid ethyl ester (9) as 3% ethyl acetate/benzene eluent.
Obtain 1.3g. NMR (CDCl 3 ) δppm: 0.8 to 1.0 (4H, m,
【式】） 1.06（3H，ｔ，Ｊ＝７Hz，−CH2CＨ 3） 3.00（1H，ｍ，[Formula]) 1.06 (3H, t, J=7Hz, -CH 2 C H 3 ) 3.00 (1H, m,
【式】）
4.02（2H，ｑ，Ｊ＝７Hz，−ＣＨ 2CH3）
8.21（1H，ｄ，Ｊ＝13Hz，ピリジンＨ）
[6] この化合物(9)690mgを水素化ナトリウム105
mg（50％oil dispersion）のジオキサン懸濁液
20mlに加え、10分間還流すると、反応液は赤色
に着色する。室温に戻し、氷水50ml中に注ぎ、
希塩酸酸性（PH＜３）とし、クロロホルム50ml
×３で抽出、芒硝乾燥後溶媒を留去し、残渣を
シリカゲル10ｇのカラムで精製し、クロロホル
ム溶出物として７−クロル−１−シクロプロピ
ル−６−フルオロ−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（Ia）を得、エタノールから再
結晶し無色針状晶270mgを得る。
融点175〜176.5℃
NMR（CDCl3）δppm：
0.9〜1.4（4H，ｍ，[Formula]) 4.02 (2H, q, J = 7Hz, -CH 2 CH 3 ) 8.21 (1H, d, J = 13Hz, pyridine H ) [6] 690 mg of this compound (9) was dissolved in sodium hydride 105
mg (50% oil dispersion) dioxane suspension
After adding to 20 ml and refluxing for 10 minutes, the reaction solution turns red. Bring to room temperature, pour into 50ml of ice water,
Dilute hydrochloric acid (PH<3) and add 50 ml of chloroform.
After extraction with 3×3 ml of sodium chloride and drying, the solvent was distilled off, and the residue was purified using a 10 g column of silica gel. -1,8-naphthyridine-3-carboxylic acid ethyl ester (Ia) was obtained and recrystallized from ethanol to obtain 270 mg of colorless needles. Melting point 175-176.5℃ NMR ( CDCl3 ) δppm: 0.9-1.4 (4H, m,
【式】） 1.40（3H，ｔ，Ｊ＝７Hz，−CH2CＨ 3） 3.64（1H，ｍ，[Formula]) 1.40 (3H, t, J=7Hz, -CH 2 C H 3 ) 3.64 (1H, m,
【式】）
4.40（2H，ｑ，Ｊ＝７Hz，−ＣＨ 2CH3）
8.42（1H，ｄ，Ｊ＝８Hz，Aroma C5−Ｈ）
8.64（1H，ｓ，C2−Ｈ）
元素分析値 C14H12ClFN2O3（310.71）として
計算値 Ｃ 54.12，Ｈ 3.89，Ｎ 9.01
分析値 Ｃ 54.31，Ｈ 3.87，Ｎ 9.00
[7] このエステル（Ia）350mgを酢酸−塩酸
（１：１）20mlの混液に加えて1.5時間還流す
る。反応後溶媒を減圧濃縮（５〜10ml）し、水
20mlを加えて析出晶を濾取し、水、エタノー
ル、エーテルで順次洗浄し、エタノールから再
結晶し、融点223〜224℃を示す７−クロル−１
−シクロプロピル−６−フルオロ−１，４−ジ
ヒドロ−４−オキソ−１，８−ナフチリジン−
３−カルボン酸（Ib）240ｇを得る。
NMR（CDCl3）δppm：
1.0〜1.4（4H，ｍ，[Formula]) 4.40 (2H, q, J = 7Hz, -CH 2 CH 3 ) 8.42 (1H, d, J = 8Hz, Aroma C 5 - H ) 8.64 (1H, s, C 2 - H ) Elemental analysis Value C 14 H 12 ClFN 2 O 3 (310.71) Calculated value C 54.12, H 3.89, N 9.01 Analytical value C 54.31, H 3.87, N 9.00 [7] 350 mg of this ester (Ia) was mixed with acetic acid-hydrochloric acid (1:1). ) Add to 20 ml of the mixture and reflux for 1.5 hours. After the reaction, concentrate the solvent under reduced pressure (5 to 10 ml) and add water.
20 ml of 7-chloro-1 was added, the precipitated crystals were collected by filtration, washed successively with water, ethanol, and ether, and recrystallized from ethanol.
-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-
240 g of 3-carboxylic acid (Ib) are obtained. NMR (CDCl 3 ) δppm: 1.0 to 1.4 (4H, m,
【式】） 3.8〜3.95（1H，ｍ，【formula】) 3.8~3.95 (1H, m,
【式】）
8.48（1H，ｄ，Ｊ＝８Hz、C5−Ｈ）
8.96（1H，ｓ，C2−Ｈ）
元素分析 C12H8FC1N2O3・1/4H2O（287.16）と
して
計算値 Ｃ 50.19，Ｈ 2.98，Ｎ 9.75
分析値 Ｃ 50.13，Ｈ 3.18，Ｎ 9.50
参考例
７−クロル−１−シクロプロピル−６−フルオ
ロ−１，４−ジヒドロ−４−オキソ−１，８−ナ
フチリジン−３−カルボン酸100mgに２−メチル
ピペラジン130mgおよびピリジン５mlを加え、外
温60〜70℃で30分撹拌する。溶媒を減圧留去し、
残渣にエタノール２mlを加えて結晶化させる。結
晶を濾取し、エタノール、エーテルで順次洗浄
し、乾燥して得た粗晶をエタノール10mlに懸濁さ
せ、濃アンモニア水を過剰に加えて溶解し、活性
炭処理した後濃縮し、アンモニアを除去し、透明
結晶として析出する１−シクロプロピル−６−フ
ルオロ−７−（３−メチル−１−ピペラジニル）−
１，４−ジヒドロ−４−オキソ−１，８−ナフチ
リジン−３−カルボン酸を40mgを得る。
融点 236〜239℃[Formula]) 8.48 (1H, d, J = 8Hz, C 5 - H ) 8.96 (1H, s, C 2 - H ) Elemental analysis C 12 H 8 FC1N 2 O 3 1 /4H 2 O (287.16) Calculated value C 50.19, H 2.98, N 9.75 Analytical value C 50.13, H 3.18, N 9.50 Reference example 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine Add 130 mg of 2-methylpiperazine and 5 ml of pyridine to 100 mg of -3-carboxylic acid, and stir at an external temperature of 60 to 70°C for 30 minutes. Remove the solvent under reduced pressure,
Add 2 ml of ethanol to the residue to crystallize it. The crystals were collected by filtration, washed sequentially with ethanol and ether, and dried. The resulting crude crystals were suspended in 10 ml of ethanol, dissolved by adding an excess of concentrated aqueous ammonia, treated with activated carbon, and then concentrated to remove ammonia. 1-Cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)- precipitated as transparent crystals.
40 mg of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is obtained. Melting point 236-239℃
Claims (1)
る７−クロル−１−シクロプロピル−６−フルオ
ロ−１，４−ジヒドロ−４−オキソ−１，８−ナ
フチリジン−３−カルボン酸またはそのエステル
及びその塩。[Claims] 1 formula (wherein R means a lower alkyl group) 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid or Its esters and its salts.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59028278A JPS60172981A (en) | 1984-02-17 | 1984-02-17 | 1,8-naphthyridine derivative |
| EP85400270A EP0160578B1 (en) | 1984-02-17 | 1985-02-15 | 1,8-naphthyridine derivatives |
| DE8585400270T DE3574380D1 (en) | 1984-02-17 | 1985-02-15 | 1,8-naphthyridine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59028278A JPS60172981A (en) | 1984-02-17 | 1984-02-17 | 1,8-naphthyridine derivative |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62233566A Division JPS6399070A (en) | 1987-09-17 | 1987-09-17 | 1,8-naphthyridine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60172981A JPS60172981A (en) | 1985-09-06 |
| JPH0374231B2 true JPH0374231B2 (en) | 1991-11-26 |
Family
ID=12244121
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59028278A Granted JPS60172981A (en) | 1984-02-17 | 1984-02-17 | 1,8-naphthyridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60172981A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9555803B2 (en) | 2002-05-03 | 2017-01-31 | Magna Electronics Inc. | Driver assistance system for vehicle |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6172753A (en) * | 1984-09-18 | 1986-04-14 | Dainippon Pharmaceut Co Ltd | Pyridyl ketone derivative |
| DE3508816A1 (en) * | 1985-01-10 | 1986-07-10 | Bayer Ag, 5090 Leverkusen | 6,7-DISUBSTITUTED 1-CYCLOPROPYL-1,4-DIHYDRO-4-OXO-1,8-NAPHTYRIDINE-3-CARBONIC ACIDS |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6089480A (en) * | 1983-10-21 | 1985-05-20 | Dainippon Pharmaceut Co Ltd | Pyridonecarboxylic acid derivative |
-
1984
- 1984-02-17 JP JP59028278A patent/JPS60172981A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6089480A (en) * | 1983-10-21 | 1985-05-20 | Dainippon Pharmaceut Co Ltd | Pyridonecarboxylic acid derivative |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9555803B2 (en) | 2002-05-03 | 2017-01-31 | Magna Electronics Inc. | Driver assistance system for vehicle |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60172981A (en) | 1985-09-06 |
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