JPS6410514B2 - - Google Patents
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- Publication number
- JPS6410514B2 JPS6410514B2 JP9209680A JP9209680A JPS6410514B2 JP S6410514 B2 JPS6410514 B2 JP S6410514B2 JP 9209680 A JP9209680 A JP 9209680A JP 9209680 A JP9209680 A JP 9209680A JP S6410514 B2 JPS6410514 B2 JP S6410514B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- general formula
- chr
- lower alkyl
- 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.)
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- 150000001875 compounds Chemical class 0.000 claims description 31
- -1 phenylsulfonyloxy group Chemical group 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- LOTBYPQQWICYBB-UHFFFAOYSA-N methyl n-hexyl-n-[2-(hexylamino)ethyl]carbamate Chemical compound CCCCCCNCCN(C(=O)OC)CCCCCC LOTBYPQQWICYBB-UHFFFAOYSA-N 0.000 claims description 2
- KPPVNWGJXFMGAM-UUILKARUSA-N (e)-2-methyl-1-(6-methyl-3,4-dihydro-2h-quinolin-1-yl)but-2-en-1-one Chemical compound CC1=CC=C2N(C(=O)C(/C)=C/C)CCCC2=C1 KPPVNWGJXFMGAM-UUILKARUSA-N 0.000 claims 1
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical group NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 238000000921 elemental analysis Methods 0.000 description 8
- 239000013078 crystal Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- HYKFPJAARRNNRX-UHFFFAOYSA-N 2,3,4,4a,9,9a-hexahydro-1h-carbazole Chemical compound C1=CC=C2C3CCCCC3NC2=C1 HYKFPJAARRNNRX-UHFFFAOYSA-N 0.000 description 1
- DRKSMCFPUOMHMK-UHFFFAOYSA-N 2,3,4,5,6,9-hexahydro-1h-carbazole Chemical compound C1=CCCC2=C1NC1=C2CCCC1 DRKSMCFPUOMHMK-UHFFFAOYSA-N 0.000 description 1
- JZICUKPOZUKZLL-UHFFFAOYSA-N 2-methyl-1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2NC(C)CCC2=C1 JZICUKPOZUKZLL-UHFFFAOYSA-N 0.000 description 1
- QOMCOKJKSCUOBB-UHFFFAOYSA-N 9h-carbazole-4-carboxylic acid Chemical compound N1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O QOMCOKJKSCUOBB-UHFFFAOYSA-N 0.000 description 1
- 101100439662 Arabidopsis thaliana CHR5 gene Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004429 atom Chemical group 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
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- AEDIXYWIVPYNBI-UHFFFAOYSA-N heptanamide Chemical group CCCCCCC(N)=O AEDIXYWIVPYNBI-UHFFFAOYSA-N 0.000 description 1
- ALBYIUDWACNRRB-UHFFFAOYSA-N hexanamide Chemical compound CCCCCC(N)=O ALBYIUDWACNRRB-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Description
本発明はベンゾヘテロ環誘導体、更に詳しくは
一般式
〔式中、R1及びR2は、水素原子、低級アルキル
基、低級アルコキシ基、低級アルカンスルホニル
オキシ基、ハロゲン原子、ヒドロキシ基、ニトロ
基、シアノ基、トリフルオロメチル基、アミノ
基、低級アルカノイルアミド基、トリフルオロア
セトアミド基、Ｎ，Ｎ−ジ低級アルキルアミノ基
又はフエニル環上に低級アルキル基、低級アルコ
キシ基もしくはニトロ基を有することのあるフエ
ニルスルホニルオキシ基を示す。またR1及びR2
は両者で隣接環位置に結合する低級アルキレンジ
オキシ基を示してもよい。基−Ａ−は−CHR3−
（CHR4）n−CHR5−（R3、R4及びR5は水素原子、
低級アルキル基又はトリフルオロメチル基及びｍ
は０又は１を示す）を示すか又は
The present invention relates to benzoheterocyclic derivatives, more specifically, the general formula [In the formula, R 1 and R 2 are hydrogen atom, lower alkyl group, lower alkoxy group, lower alkanesulfonyloxy group, halogen atom, hydroxy group, nitro group, cyano group, trifluoromethyl group, amino group, lower alkanoyl It represents an amide group, a trifluoroacetamido group, an N,N-dilower alkylamino group, or a phenylsulfonyloxy group which may have a lower alkyl group, a lower alkoxy group, or a nitro group on the phenyl ring. Also R 1 and R 2
may both represent lower alkylenedioxy groups bonded to adjacent ring positions. The group -A- is -CHR 3 -
(CHR 4 ) n −CHR 5 − (R 3 , R 4 and R 5 are hydrogen atoms,
lower alkyl group or trifluoromethyl group and m
indicates 0 or 1) or
【式】を
示す。但し基−Ａ−がCH2−（CH2）n−CHR5′−
（R5′は水素原子又は低級アルキル基を示す、ｍは
上記に同じ）及びR1がハロゲン原子を示す場合、
R2は水素原子及びハロゲン原子であつてはなら
ない。〕で表わされるベンゾヘテロ環誘導体の新
規な製造法に関する。
上記一般式（）で表わされるベンゾヘテロ環
誘導体は優れた抗菌作用を有し医薬品として重要
な化合物である。
本発明の目的は、上記一般式（）で表わされ
るベンゾヘテロ環誘導体を、短かい工程で、多大
の労力及び時間を必要とすることなく、しかも好
収率で製造し得る新規な方法を提供することにあ
る。
即ち本発明は、一般式
〔式中R1、R2及び基−Ａ−は前記に同じ〕
で表わされるＮ−シクロイソプロピリデニルマロ
ネート置換ベンゾヘテロ環化合物をポリリン酸と
共に加熱して一般式
〔式中、R1、R2及び基−Ａ−は前記に同じ。〕
で表わされるベンゾヘテロ環誘導体を得ることを
特徴とするベンゾヘテロ環誘導体の製造法に係
る。
本明細書においてR1、R2及び基−Ａ−で示さ
れる各基としては具体的には以下の基を例示でき
る。
Γ低級アルキル基…メチル、エチル、プロピル、
ブチル、tert−ブチル、ペンチル、ヘキシル基
等。
Γ低級アルコキシ基…メトキシ、エトキシ、プロ
ポキシ、イソプロポキシ、ブトキシ、tert−ブ
トキシ、ペンチルオキシ、ヘキシルオキシ基
等。
Γ低級アルカンスルホニルオキシ基…メタンスル
ホニルオキシ、エタンスルホニルオキシ、プロ
パンスルホニルオキシ、ブタンスルホニルオキ
シ、tert−ブタンスルホニルオキシ、ペンタン
スルホニルオキシ、ヘキサンスルホニルオキシ
基等。
Γハロゲン原子…沃素、塩素、臭素、弗素原子
等。
Γ低級アルカノイルアミド基…ホルムアミド、ア
セトアミド、プロピオニルアミド、ブタノイル
アミド、ペンタノイルアミド、ヘキサノイルア
ミド、ヘプタノイルアミド基等。
ΓＮ，Ｎ−ジ低級アルキルアミノ基…Ｎ，Ｎ−ジ
メチルアミノ、Ｎ，Ｎ−ジエチルアミノ、Ｎ，
Ｎ−ジプロピルアミノ、Ｎ，Ｎ−ジブチルアミ
ノ、Ｎ，Ｎ−ジペンチルアミノ、Ｎ，Ｎ−ジヘ
キシルアミノ基等。
Γフエニル環上に低級アルキル基、低級アルコキ
シ基もしくはニトロ基を有することのあるフエ
ニルスルホニルオキシ基…４−メチルフエニル
スルホニルオキシ、２−ヘキシルフエニルスル
ホニルオキシ、４−プロピルフエニルスルホニ
ルオキシ、４−ニトロフエニルスルホニルオキ
シ、２−メトキシフエニルスルホニルオキシ、
４−エトキシフエニルスルホニルオキシ、３−
プロポキシフエニルスルホニルオキシ、２−ヘ
キシルオキシフエニルスルホニルオキシ基等。
Γ低級アルキレンジオキシ基…メチレンジオキ
シ、エチレンジオキシ、トリメチレンジオキシ
基等。
本発明において出発原料として用いられる一般
式（）で表わされるＮ−シクロイソプロピリデ
ニルマロネート置換ベンゾヘテロ環化合物は、本
発明者らが始めて見い出した文献未載の新規化合
物である。本発明は該化合物を単にポリリン酸と
共に加熱するという簡便な操作のみで目的とする
一般式（）で表わされるベンゾヘテロ環誘導体
が一挙にしかも好収率で収得されるという事実の
発明に基づいて完成されている。
上記一般式（）で表わされる化合物は、例え
ば一般式
〔式中R1、R2及び基−Ａ−は前記に同じ〕
で表わされる公知のベンゾヘテロ環化合物と一般
式
〔式中R6は低級アルキル基を示す。〕
で表わされる公知のシクロイソプロピリデニル低
級アルコキシマロネートとを反応させることによ
り好収率で製造される。それ故本発明では入手容
易な公知化合物から僅か二工程で目的とする一般
式（）で表わされるベンゾヘテロ環誘導体を極
めて容易に且つ好収率で製造し得る。
上記一般式（）の化合物及び一般式（）の
化合物の反応は、無溶媒下または適当な溶媒中に
て行なわれる。用いられる溶媒としては例えばメ
タノール、エタノール、イソプロパノール等のア
ルコール類、ベンゼン、トルエン等の芳香族炭化
水素類、アセトニトリル、ジメチルホルムアミ
ド、ジメチルスルホキシド、ヘキサメチルリン酸
アミド等を例示できる。上記反応は無溶媒下に行
なわれるのが好ましい。一般式（）の化合物及
び一般式（）の化合物の使用割合としては特に
限定がなく広い範囲内で適宜選択することができ
るが、通常前者に対して後者を等モル量程度以
上、好ましくは等モル〜1.5倍モル量用いるのが
よい。上記反応は通常室温〜150℃程度、好まし
くは60〜120℃にて行なわれ、一般に0.5〜３時間
程度で反応は終了する。斯くして一般式（）で
表わされるＮ−シクロイソプロピリデニルマロネ
ート置換ベンゾヘテロ環化合物を収得できる。
本発明方法は、上記の如くして製造される一般
式（）の化合物をポリリンと共に加熱反応させ
ることにより容易に実施され、該加熱により一般
式（）の化合物が環化されて目的とする一般式
（）の化合物が容易に好収率で生成する。殊に
一般式（）で表わされる化合物を上述した方法
に従い製造後単離精製することなく反応混合物の
まま本発明反応に供給する時には、目的化合物で
ある一般式（）で表わされるベンゾヘテロ環誘
導体を公知化合物より一層の好収率で得ることが
できる。
本発明の一般式（）の化合物とポリリン酸と
の加熱反応において、ポリリン酸の使用量として
は、特に限定がなく広い範囲内で適宜選択するこ
とができるが、通常一般式（）の化合物に対し
て等モル量〜大過剰量、好ましくは10〜20倍モル
量用いるのがよい。該反応は通常50〜200℃程度、
好ましくは100〜150℃にて行なわれ、一般式に
0.5〜６時間程度で反応は終了する。
斯くして生成する一般式（）で表わされるベ
ンゾヘテロ環誘導体は慣用の単離手段、例えば
過、再結晶、カラムクロマトグラフイー、プレパ
ラテイブ薄層クロマトグラフイー等により反応混
合物から容易に単離精製される。
以下に実施例を挙げる。
実施例 １
(a) イソプロピリデニルメトキシメチレンマロネ
ート８ｇに6.6ｇの６−メチル−１，２，３，
４−テトラヒドロキナルジンを加えると室温に
て発泡が見られ、次に油浴上120℃にて５分間
撹拌することにより固化させて還式イソプロピ
リデニル Ｎ−（６−メチル−１，２，３，４
−テトラヒドロ−１−キナルジニル）−アミノ
メチレンマロネート12.0ｇを得る（収率93％）。
mp195〜198℃。
該化合物は、IRスペクトル、NMRスペクト
ル及び元素分析により同定される。
元素分析値
計算値（％） C68.57 H6.67 N4.44
実測値（％） C68.30 H6.81 N4.30
(b) 五酸化リン25ｇとリン酸25ｇから調製される
ポリリン酸を120℃に加温しておき、上記(a)で
得られた環式イソプロピリデニル Ｎ−（６−
メチル−１，２，３，４−テトラヒドロ−１−
キナルジニル）−アミノメチレンマロネート4.7
ｇを少量ずつ添加する。添加後120〜130℃にて
30分間加熱反応後冷却し、水200ml加えると白
濁する。次に10％水酸化ナトリウム水溶液を加
えPH10としたのち不溶物を過する。液を濃
塩酸にPH３とし析出する結晶を取し乾燥後、
ジメチルホルムアミドより再結晶し６，７−ジ
ヒドロ−９−メチル−５−メチル−１−オキソ
−1H，5H−ベンゾ〔ij〕キノリジン−２−カ
ルボン酸3.3ｇを得る（収率86％）。
mp 255〜257℃。
元素分析値
計算値（％） C70.04 H5.84 N5.45
実測値（％） C69.90 H5.95 N5.21
実施例 ２
イソプロピリデニルメトキシメチレンマロネー
ト８ｇに6.6ｇの６−メチル−１，２，３，４−
テトラヒドロキナルジンを室温にて加える。続い
て油浴上110℃にて５分間撹拌すると固化する。
次にリン酸80ｇと五酸化リン80ｇより得られるポ
リリン酸中に先の固体を加える。油浴上130〜140
℃にて40分間加熱後、室温迄冷却し500mlの水に
投入する。20％苛性ソーダ水溶液を加えPH11とし
不溶物を過し、液に濃塩酸を加えPH３とする
と結晶が析出する。過、水洗し乾燥することに
よつて11.7ｇの９−メチル−５−メチル−１−オ
キソ−６，７−ジヒドロ−1H，5H−ベンゾ〔ij〕
キノリジン−２−カルボン酸を得る（収率92％）。
この化合物をさらにジメチルホルムアミドにて
再結晶して上記化合物9.2ｇを得る（収率87％）。
mp 255〜257℃
元素分析値
計算値（％） C70.04 H5.84 N5.45
実測値（％） C70.25 H5.60 N5.28
適当な原料を用い、上記実施例１及び２と同様
にして下記第１表記載の各化合物を得る。第１表
には得られた各化合物を、下記（ａ）における
Ra〜Rfにて示し、また該化合物の融点（mp、
℃）を併記する。
[Formula] is shown. However, the group -A- is CH2- ( CH2 ) n - CHR5'-
(R 5 ' represents a hydrogen atom or a lower alkyl group, m is the same as above) and when R 1 represents a halogen atom,
R 2 must not be a hydrogen atom or a halogen atom. This invention relates to a novel method for producing a benzoheterocyclic derivative represented by the following. The benzoheterocyclic derivative represented by the above general formula () has excellent antibacterial activity and is an important compound as a pharmaceutical. An object of the present invention is to provide a novel method for producing a benzoheterocyclic derivative represented by the above general formula () in a short process, without requiring much labor and time, and with a good yield. There is a particular thing. That is, the present invention is based on the general formula [In the formula, R 1 , R 2 and the group -A- are the same as above] The N-cycloisopropylidenyl malonate-substituted benzoheterocyclic compound represented by the formula is heated with polyphosphoric acid to form the general formula [In the formula, R 1 , R 2 and the group -A- are the same as above. ] This relates to a method for producing a benzoheterocyclic derivative, which is characterized by obtaining a benzoheterocyclic derivative represented by the following. In this specification, the following groups can be specifically exemplified as each group represented by R 1 , R 2 and group -A-. ΓLower alkyl group...methyl, ethyl, propyl,
Butyl, tert-butyl, pentyl, hexyl groups, etc. ΓLower alkoxy group: methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy group, etc. ΓLower alkanesulfonyloxy group: methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy, hexanesulfonyloxy group, etc. ΓHalogen atoms...Iodine, chlorine, bromine, fluorine atoms, etc. ΓLower alkanoylamide group: formamide, acetamide, propionylamide, butanoylamide, pentanoylamide, hexanoylamide, heptanoylamide group, etc. ΓN,N-di-lower alkylamino group...N,N-dimethylamino, N,N-diethylamino, N,
N-dipropylamino, N,N-dibutylamino, N,N-dipentylamino, N,N-dihexylamino groups, etc. Phenylsulfonyloxy group which may have a lower alkyl group, lower alkoxy group or nitro group on the Γ phenyl ring...4-methylphenylsulfonyloxy, 2-hexylphenylsulfonyloxy, 4-propylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 2-methoxyphenylsulfonyloxy,
4-ethoxyphenylsulfonyloxy, 3-
Propoxyphenylsulfonyloxy, 2-hexyloxyphenylsulfonyloxy groups, etc. ΓLower alkylenedioxy group...methylenedioxy, ethylenedioxy, trimethylenedioxy group, etc. The N-cycloisopropylidenyl malonate-substituted benzoheterocyclic compound represented by the general formula () used as a starting material in the present invention is a novel compound discovered for the first time by the present inventors and which has not been described in any literature. The present invention was completed based on the fact that the desired benzoheterocyclic derivative represented by the general formula () can be obtained all at once and in a good yield by simply heating the compound with polyphosphoric acid. has been done. The compound represented by the above general formula () is, for example, a compound represented by the general formula [In the formula, R 1 , R 2 and the group -A- are the same as above] A known benzoheterocyclic compound represented by the general formula [In the formula, R 6 represents a lower alkyl group. ] It is produced in a good yield by reacting it with a known cycloisopropylidenyl lower alkoxymalonate represented by: Therefore, in the present invention, the desired benzoheterocyclic derivative represented by the general formula () can be produced extremely easily and in a good yield from readily available known compounds in just two steps. The reaction of the compound of general formula () and the compound of general formula () above is carried out without a solvent or in an appropriate solvent. Examples of solvents that can be used include alcohols such as methanol, ethanol, and isopropanol, aromatic hydrocarbons such as benzene and toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric acid amide. The above reaction is preferably carried out without a solvent. The ratio of the compound of general formula () and the compound of general formula () to be used is not particularly limited and can be appropriately selected within a wide range, but usually the latter is used in an equimolar amount or more, preferably an equal molar amount to the former. It is preferable to use a molar to 1.5 times molar amount. The above reaction is usually carried out at room temperature to about 150°C, preferably 60 to 120°C, and is generally completed in about 0.5 to 3 hours. In this way, an N-cycloisopropylidenylmalonate-substituted benzoheterocyclic compound represented by the general formula () can be obtained. The method of the present invention can be easily carried out by heating and reacting the compound of general formula () produced as described above with polyphosphorus, and by the heating, the compound of general formula () is cyclized to obtain the desired general compound. Compounds of formula () are readily produced in good yields. In particular, when the compound represented by the general formula () is supplied to the reaction of the present invention as a reaction mixture without being isolated and purified according to the above-mentioned method, the benzoheterocyclic derivative represented by the general formula (), which is the target compound, is It can be obtained in a higher yield than known compounds. In the thermal reaction between the compound of general formula () and polyphosphoric acid of the present invention, the amount of polyphosphoric acid to be used is not particularly limited and can be appropriately selected within a wide range. It is preferable to use an equimolar amount to a large excess amount, preferably 10 to 20 times the molar amount. The reaction is usually carried out at a temperature of about 50 to 200°C.
It is preferably carried out at 100 to 150°C, and the general formula is
The reaction is completed in about 0.5 to 6 hours. The benzoheterocyclic derivative represented by the general formula () thus produced can be easily isolated and purified from the reaction mixture by conventional isolation means such as filtration, recrystallization, column chromatography, preparative thin layer chromatography, etc. Ru. Examples are given below. Example 1 (a) 6.6 g of 6-methyl-1,2,3,
When 4-tetrahydroquinaldine was added, foaming was observed at room temperature, and then it was solidified by stirring on an oil bath at 120°C for 5 minutes to form reduced isopropylidenyl N-(6-methyl-1,2, 3,4
12.0 g of -tetrahydro-1-quinaldinyl)-aminomethylene malonate are obtained (yield 93%).
mp195~198℃. The compound is identified by IR spectrum, NMR spectrum and elemental analysis. Elemental analysis value Calculated value (%) C68.57 H6.67 N4.44 Actual value (%) C68.30 H6.81 N4.30 (b) Polyphosphoric acid prepared from 25 g of phosphorus pentoxide and 25 g of phosphoric acid at 120 The cyclic isopropylidenyl N-(6-
Methyl-1,2,3,4-tetrahydro-1-
quinaldinyl)-aminomethylene malonate 4.7
Add g in small portions. At 120-130℃ after addition
After heating reaction for 30 minutes, cool and add 200ml of water to make it cloudy. Next, add a 10% aqueous sodium hydroxide solution to adjust the pH to 10, and filter out insoluble matter. The solution was adjusted to pH 3 with concentrated hydrochloric acid, the precipitated crystals were removed, and after drying,
Recrystallization from dimethylformamide gave 3.3 g of 6,7-dihydro-9-methyl-5-methyl-1-oxo-1H,5H-benzo[ij]quinolidine-2-carboxylic acid (yield 86%). mp 255-257℃. Elemental analysis value Calculated value (%) C70.04 H5.84 N5.45 Actual value (%) C69.90 H5.95 N5.21 Example 2 6.6 g of 6-methyl- to 8 g of isopropylidenyl methoxy methylene malonate 1, 2, 3, 4-
Add tetrahydroquinaldine at room temperature. Subsequently, the mixture is stirred on an oil bath at 110°C for 5 minutes to solidify.
Next, add the above solid to polyphosphoric acid obtained from 80 g of phosphoric acid and 80 g of phosphorus pentoxide. Oil bath top 130-140
After heating at ℃ for 40 minutes, cool to room temperature and pour into 500ml of water. Add a 20% aqueous solution of caustic soda to bring the pH to 11, filter out insoluble matter, and add concentrated hydrochloric acid to the solution to bring the pH to 3, causing crystals to precipitate. By filtering, washing with water and drying, 11.7 g of 9-methyl-5-methyl-1-oxo-6,7-dihydro-1H,5H-benzo [ij]
Quinolidine-2-carboxylic acid is obtained (yield 92%). This compound is further recrystallized from dimethylformamide to obtain 9.2 g of the above compound (yield: 87%). mp 255-257℃ Elemental analysis value Calculated value (%) C70.04 H5.84 N5.45 Actual value (%) C70.25 H5.60 N5.28 Same as in Examples 1 and 2 above using appropriate raw materials to obtain each compound listed in Table 1 below. Table 1 shows each compound obtained in (a) below.
R a to R f , and the melting point (mp,
℃) is also written.
【表】【table】
【表】【table】
【表】
実施例 ３
(a) イソプロピリデニルメトキシメチレンマロネ
ート８ｇに7.1ｇの１，２，３，４，4a，9a−
ヘキサヒドロカルバゾールを加えると室温にて
発泡が見られる。次に油浴上120℃にて５分間
撹拌することにより固化させて環式イソプロピ
リデニル−Ｎ−（１，２，３，４−4a，9a−ヘ
キサヒドロカルバゾール−９−イル）−アミノ
メチレンマロネート12.2ｇを得る（収率91％）。
該化合物はIR分析、NMR分析及び元素分析よ
り同定される。
mp 175〜178℃。
元素分析値
計算値（％） C69.72 H6.42 N4.28
実測値（％） C69.58 H6.25 N4.45
(b) 五酸化リン25ｇとリン酸25ｇとから調製され
るポリリン酸を120℃に加温しておき、これに
上記(a)で得た環式イソプロピリデニル−Ｎ−
（１，２，３，４，4a，9a−ヘキサヒドロカル
バゾール−９−イル）−アミノメチレンマロネ
ート4.9ｇを少量づつ添加する。添加後120〜
130℃にて30分間加熱反応させ、冷却し、水200
mlを加えると白濁する。次に10％水酸化ナトリ
ウム水溶液を加えPH10とした後不溶物を過す
る。液を濃塩酸にてPH３として、析出する結
晶を取し乾燥後、クロロホルム−ヘキサンよ
り再結晶して、7a，８，９，10，11，11a−ヘ
キサハイドロ−４−オキソ−4H−ピリド〔３，
２，１−jk〕カルバゾール−５−カルボン酸
3.3ｇを得る（収率85％）。
mp 238〜241℃。
淡黄色無定形結晶。
元素分析値
計算値（％） C71.38 H5.58 N5.20
実測値（％） C71.15 H5.32 N5.42
実施例 ４
イソプロピリデニルメトキシメチレンマロネー
ト８ｇに7.1ｇの１，２，３，４，4a，9a−ヘキ
サヒドロカルバゾールを室温下に添加する。続い
て油浴上110℃にて５分間撹拌すると固化する。
次にリン酸80ｇと五酸化リン80ｇとから得られる
ポリリン酸中に先の固体を加え、油浴上130〜140
℃にて40分間加熱後、室温まで冷却し、500mlの
水中に投入する。20％苛性ソーダ水溶液を加え、
PH10とした後不溶物を過する。液を濃塩酸に
てPH３とすると結晶が析出する。これを過水洗
乾燥し、クロロホルム−ヘキサンより再結晶し
て、7a，８，９，10，11，11a−ヘキサハイドロ
−４−オキソ−4H−ピリド〔３，２，１−jk〕
カルバゾール−５−カルボン酸9.3ｇを得る（収
率84％）。mp238〜241℃。
淡黄色無定形結晶
元素分析値
計算値（％） C71.38 H5.58 N5.20
実測値（％） C71.50 H5.30 N5.02
適当な原料を用い、上記実施例３及び４と同様
にして下記第２表の各化合物を得る。第２表には
得られた化合物を、下記一般式（ｂ）における
Ra〜Rcにて示し、また該化合物の融点（mp、
℃）を併記する。
[Table] Example 3 (a) 7.1 g of 1,2,3,4,4a,9a- in 8 g of isopropylidenyl methoxymethylene malonate
When hexahydrocarbazole is added, foaming is observed at room temperature. Next, it was solidified by stirring on an oil bath at 120°C for 5 minutes to form a cyclic isopropylidenyl-N-(1,2,3,4-4a,9a-hexahydrocarbazol-9-yl)-aminomethylene. 12.2 g of malonate are obtained (91% yield).
The compound is identified by IR analysis, NMR analysis and elemental analysis. mp 175-178℃. Elemental analysis value Calculated value (%) C69.72 H6.42 N4.28 Actual value (%) C69.58 H6.25 N4.45 (b) Polyphosphoric acid prepared from 25 g of phosphorus pentoxide and 25 g of phosphoric acid The mixture was heated to 120°C, and the cyclic isopropylidenyl-N- obtained in (a) above was added to the mixture.
4.9 g of (1,2,3,4,4a,9a-hexahydrocarbazol-9-yl)-aminomethylene malonate are added in portions. 120~ after addition
Heat reaction at 130℃ for 30 minutes, cool, and add 200℃ of water.
When ml is added, it becomes cloudy. Next, add a 10% aqueous sodium hydroxide solution to adjust the pH to 10, and filter out insoluble matter. The solution was adjusted to pH 3 with concentrated hydrochloric acid, the precipitated crystals were collected, dried, and recrystallized from chloroform-hexane to give 7a, 8, 9, 10, 11, 11a-hexahydro-4-oxo-4H-pyrid [ 3,
2,1-jk]carbazole-5-carboxylic acid
Obtain 3.3 g (85% yield). mp 238-241℃. Pale yellow amorphous crystal. Elemental analysis value Calculated value (%) C71.38 H5.58 N5.20 Actual value (%) C71.15 H5.32 N5.42 Example 4 7.1 g of 1, 2, 3,4,4a,9a-hexahydrocarbazole is added at room temperature. Subsequently, the mixture is stirred on an oil bath at 110°C for 5 minutes to solidify.
Next, the above solid was added to polyphosphoric acid obtained from 80 g of phosphoric acid and 80 g of phosphorus pentoxide, and the mixture was heated to 130-140 g on an oil bath.
After heating at ℃ for 40 minutes, cool to room temperature and pour into 500 ml of water. Add 20% caustic soda aqueous solution,
After adjusting the pH to 10, filter out insoluble matter. When the solution is adjusted to pH 3 with concentrated hydrochloric acid, crystals will precipitate. This was washed with water, dried, and recrystallized from chloroform-hexane to yield 7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrid [3,2,1-jk]
9.3 g of carbazole-5-carboxylic acid are obtained (yield 84%). mp238~241℃. Pale yellow amorphous crystal elemental analysis value Calculated value (%) C71.38 H5.58 N5.20 Actual value (%) C71.50 H5.30 N5.02 Same as in Examples 3 and 4 above using appropriate raw materials to obtain each compound in Table 2 below. Table 2 shows the obtained compounds in the following general formula (b).
The melting point ( mp ,
℃) is also written.
Claims (1)
低級アルコキシ基、低級アルカンスルホニルオキ
シ基、ハロゲン原子、ヒドロキシ基、ニトロ基、
シアノ基、トリフルオロメチル基、アミノ基、低
級アルカノイルアミド基、トリフルオロアセトア
ミド基、Ｎ，Ｎ−ジ低級アルキルアミノ基又はフ
エニル環上に低級アルキル基、低級アルコキシ基
もしくはニトロ基を有することのあるフエニルス
ルホニルオキシ基を示す。またR1及びR2は両者
で隣接環位置に結合する低級アルキレンジオキシ
基を示してもよい。基−Ａ−は−CHR3−
（CHR4）n−CHR5−（R3、R4及びR5は水素原子、
低級アルキル基又はトリフルオロメチル基及びｍ
は０又は１を示す）を示すか又は【式】を 示す。但し基−Ａ−が−CH2−（CH2）n−
CHR5′−（R5′は水素原子又は低級アルキル基を示
す、ｍは上記に同じ）及びR1がハロゲン原子を
示す場合、R2は水素原子及びハロゲン原子であ
つてはならない。〕で表わされるＮ−シクロイソ
プロピリデニルマロネート置換ベンゾヘテロ環化
合物をポリリン酸と共に加熱して一般式 〔式中R1、R2及びＡは前記に同じ〕 で表わされるベンゾヘテロ環誘導体を得ることを
特徴とするベンゾヘテロ環誘導体の製造法。[Claims] 1. General formula [In the formula, R 1 and R 2 are a hydrogen atom, a lower alkyl group,
Lower alkoxy group, lower alkanesulfonyloxy group, halogen atom, hydroxy group, nitro group,
Cyano group, trifluoromethyl group, amino group, lower alkanoylamide group, trifluoroacetamide group, N,N-dilower alkylamino group, or may have a lower alkyl group, lower alkoxy group, or nitro group on the phenyl ring. Indicates a phenylsulfonyloxy group. Further, R 1 and R 2 may both represent a lower alkylenedioxy group bonded to adjacent ring positions. The group -A- is -CHR 3 -
(CHR 4 ) n −CHR 5 − (R 3 , R 4 and R 5 are hydrogen atoms,
lower alkyl group or trifluoromethyl group and m
represents 0 or 1) or represents [Formula]. However, the group -A- is -CH2- ( CH2 ) n-
When CHR 5 '- (R 5 ' represents a hydrogen atom or a lower alkyl group, m is the same as above) and R 1 represents a halogen atom, R 2 must not be a hydrogen atom or a halogen atom. ] The N-cycloisopropylidenyl malonate-substituted benzoheterocyclic compound represented by the formula is heated with polyphosphoric acid to form the general formula [In the formula, R 1 , R 2 and A are the same as above] A method for producing a benzoheterocyclic derivative, which is characterized in that a benzoheterocyclic derivative is obtained.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9209680A JPS5716882A (en) | 1980-07-04 | 1980-07-04 | Production of benzo-heteroring derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9209680A JPS5716882A (en) | 1980-07-04 | 1980-07-04 | Production of benzo-heteroring derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5716882A JPS5716882A (en) | 1982-01-28 |
| JPS6410514B2 true JPS6410514B2 (en) | 1989-02-22 |
Family
ID=14044908
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP9209680A Granted JPS5716882A (en) | 1980-07-04 | 1980-07-04 | Production of benzo-heteroring derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5716882A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59137482A (en) * | 1983-01-26 | 1984-08-07 | Otsuka Pharmaceut Co Ltd | Pyrrolo(3,2,1,-ij)quinoline-5-carboxylic acid derivative |
| JPS60161987A (en) * | 1984-01-31 | 1985-08-23 | Otsuka Pharmaceut Co Ltd | Benzoheterocyclic ring derivative |
| DE102017218114A1 (en) | 2017-10-11 | 2019-04-11 | Leuphana Universität Lüneburg Stiftung Öffentlichen Rechts | Biodegradable quinolone antibiotics |
-
1980
- 1980-07-04 JP JP9209680A patent/JPS5716882A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5716882A (en) | 1982-01-28 |
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