JP4173599B2 - Process for producing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline - Google Patents
Process for producing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline Download PDFInfo
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- JP4173599B2 JP4173599B2 JP10801699A JP10801699A JP4173599B2 JP 4173599 B2 JP4173599 B2 JP 4173599B2 JP 10801699 A JP10801699 A JP 10801699A JP 10801699 A JP10801699 A JP 10801699A JP 4173599 B2 JP4173599 B2 JP 4173599B2
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- 0 *OC(C=Cc1cccc(O)c1)=O Chemical compound *OC(C=Cc1cccc(O)c1)=O 0.000 description 2
- HOSGXJWQVBHGLT-UHFFFAOYSA-N Oc(cc1CC2)ccc1NC2=O Chemical compound Oc(cc1CC2)ccc1NC2=O HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 2
- QVWAEZJXDYOKEH-UHFFFAOYSA-N OC(CCc1cc(O)ccc1)=O Chemical compound OC(CCc1cc(O)ccc1)=O QVWAEZJXDYOKEH-UHFFFAOYSA-N 0.000 description 1
- WTODAECJBDKRCR-UHFFFAOYSA-N Oc1cccc(CCC(Cl)=O)c1 Chemical compound Oc1cccc(CCC(Cl)=O)c1 WTODAECJBDKRCR-UHFFFAOYSA-N 0.000 description 1
- DRDKPLZIVCGCRJ-UHFFFAOYSA-N Oc1cccc(CCC(NO)=O)c1 Chemical compound Oc1cccc(CCC(NO)=O)c1 DRDKPLZIVCGCRJ-UHFFFAOYSA-N 0.000 description 1
- XLYPHUGUKGMURE-UHFFFAOYSA-N [O-][N+](c(cc1)c(C=O)cc1O)=O Chemical compound [O-][N+](c(cc1)c(C=O)cc1O)=O XLYPHUGUKGMURE-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/06—Halogens; Compounds thereof
- B01J27/08—Halides
- B01J27/10—Chlorides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/27—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Quinoline Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明はシロスタゾル（Cilostazol)の合成中間体として有用な６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリンを製造する方法に関する。
【０００２】
【従来の技術】
シロスタゾルは血栓治療剤として使われており、その化学名は６−［４−（１−シクロヘキシル−５−テトラゾリル)ブトキシ]−１，２，３，４−テトラヒドロ−２−オキソキノリンであり、構造式は下記一般式（V）で表される。
【化５】
上記の一般式（V）のシロスタゾルは、合成中間体である一般式（I）で表される６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリンと５−ハロブチル−１−シクロヘキシルテトラゾルを反応させることにより製造できる（Chem. Pharm. Bull. 31, 1151-1157（1983)）。
【０００４】
一般式（I）の化合物と構造が類似している一般式（VII）の化合物を製造する方法が報告されている（Ber. 60, 858-864（1927)）。この方法によれば、下記反応式に示すように、一般式（VII）で表される化合物は一般式（VI）のＮ−（４−置換−ベンゾ）−３−クロロプロピオニルアミドを酸触媒である塩化アルミニウムの存在下、溶融状態で環化させることにより製造される。
【化６】
【０００５】
この方法は、溶媒を使わず、塩化アルミニウムと一般式（VI）の化合物をかなりの高温(200〜240℃)で反応させるために、特殊な装置を必要とする。また、均等に反応させることが難しいため、収率が低く不経済であり、危険性を伴うという欠点を有する。
【０００６】
一般式（I）の化合物は、ニトロケイ皮酸誘導体を経由して製造することもできる（Journal of the American Chemical Society, 66，1442-1443 (1944)）。具体的には、下記反応式に示すように、一般式（X）で表される５−ヒドロキシ−２−ニトロケイ皮酸アルキルを還元及び環化することによって一般式（I）の化合物が得られる。
【化７】
【０００７】
この方法において、出発物質である一般式（VIII）の５−ヒドロキシ−２−ニトロベンズアルデヒド及び一般式（IX）の３−ヒドロキシケイ皮酸アルキルが非常に高価であり、また、加圧条件で反応させるので爆発の危険性がある。さらに、加水素反応では圧縮された気体を扱うため、特殊な装置が必要であり、発火の危険性が非常に大きい水素を用いるため、工業化が難しいという欠点がある。。
【０００８】
また、ケイ皮酸誘導体を用いて一般式（I）の化合物を製造する方法が知られている（Journal of the American Chemical Society, 89，7131-7132 (1962)）。この方法においては、下記反応式に示すように、一般式（I）の化合物は一般式（XIII）の３−ヒドロキシシンナモヒドロキサム酸を環化することによって製造される。
【化８】
この方法は、出発物質である一般式（XI）の３−（３−ヒドロキシフェニル)プロピオン酸が非常に高価であること及び出発物質から三段階の反応工程が必要であるため非効率的であり、最終生産物の収率が52％と低いことが欠点である。
【００１０】
また、一般式（I）の化合物と構造が類似している一般式（XVI）で表される化合物を下記反応式に従って製造する方法が知られている（Journal of the Organic Chemistry, 36, 3975-3979 (1971)）。この方法においては、一般式（XIV）の４−置換−アクリルアニリドを環化して一般式（XV）の化合物を合成し、これを脱アルキル化することによって一般式（XVI）で表される６−ヒドロキシ−３−置換−４−ヒドロカルボスチリルが製造される。
【化９】
【００１１】
この方法は、一般式（XV）の化合物を製造する際、工業的に不適切な光反応を行うこと及びその収率が13％と非常に低い点で問題がある。
【００１２】
【発明が解決しようとする課題】
本発明は、工業的に安全かつ簡便で、安価に、収率よく６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリンを製造する方法を提供することを目的とする。
【００１３】
【課題を解決するための手段】
本発明者らは上記の従来の製造方法における問題点を解決するために研究を重ねた結果、安全で簡単に収率よく６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリンを製造する方法を見い出し、本発明を完成した。
すなわち、本発明は、下記一般式（II）で表されるＮ−（４−置換-ベンゾ）−３−クロロプロピオニルアミドを均一化剤の存在下でルイス酸と反応させる工程を含む一般式（I）で表される６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリンの製造方法を提供する。
【化１０】
【発明の実施の形態】
【００１４】
本発明の製造方法における反応工程は下記反応式で表される。
【化１２】
【００１５】
本発明における「均一化剤」とは、２種類以上の反応物質を均一に混濁させ、溶融状態での反応時の問題点である不均一な反応進行を改善し、熱伝達の減少を緩和させる物質である。換言すれば、未反応物をなくし、より低い温度で均一に反応を進行させる溶剤である。本発明の製造方法において用いられる均一化剤としては、デカヒドロナフタレン；ジフェニルエーテル，イソアミルエーテル、ベンジルエチルエーテル，ジグリム，トリグリムなどの高沸点のエーテル化合物；またはβ-ピネン、リモネン，テトラリンなどの炭化水素化合物が挙げられる。これらのうち、デカヒドロナフタレンが最も好ましい。
【００１６】
本発明の製造方法において用いられるルイス酸触媒としては、塩化アルミニウム、塩化亜鉛または四塩化チタニウムが挙げられ、特に塩化アルミニウムが好ましく用いられる。
反応は、一般式（II）の化合物に対して、ルイス酸を2〜10モル、好ましくは3〜5モル、均一化剤を1〜20ml/g、好ましくは1〜5ml/g使用し、0〜200℃、好ましくは120〜150℃で、2〜18時間、好ましくは6〜10時間行なわれる。
【００１７】
反応生成物である一般式（I）の化合物は、公知の方法、例えば、メタノールからの再結晶等により精製することができる。
【００１８】
出発物質である一般式（II）で表される化合物は、一般式（III）の４−置換−アニリンを一般式（IV）で表される３−クロロプロピオニルクロリドと反応させることにより、高収率(97％)で得ることができる。
【化１３】
【００１９】
この反応は、酢酸エチル、ジメチルホルムアミド及びジメチルスルホキシドのような極性有機溶媒、またはヘキサン、ベンゼンのような非極性有機溶媒中、10〜30℃で1〜3時間行われる。この時、４−置換−アニリンに対して、３−クロロプロピオニルクロリドを1〜5モル、好ましくは1.2〜2モル、上記溶媒を5〜20ml/g使用する。
【００２０】
得られた一般式（II）の化合物はイソプロパノールと水の混合液からの再結晶等公知の方法により精製することができる。
【００２１】
本発明の工程に従って製造された一般式（I）の６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリンは血栓治療剤であるシロスタゾルの合成中間体として有用である。
【００２２】
【実施例】
以下、本発明を実施例によりさらに詳しく説明するが、本発明はこれらに限定されるものではない。
【００２３】
［実施例１］ Ｎ−（４−ヒドロキシベンゾ)−３−クロロプロピオニルアミド（II）の製造
窒素気流下でマグネティックスタ−ラーを入れたフラスコ内に酢酸エチル1000ml及び４−ヒドロキシアニリン109.1g(1mol)を加えた。室温で酢酸エチル500mlで希釈した3-クロロプロピオニルクロリド190.5g(1.5mol)をフラスコ内にゆっくり滴下した後、反応液を1時間激しく撹拌した。この反応液に飽和炭酸ナトリウム1000mlを加え塩を完全に溶解させ、有機層を分離し、水500mlで洗浄した。分離した有機層を硫酸マグネシウムを用いて乾燥し、減圧蒸留により溶媒を除去した。残査をイソプロパノールと水の混合液で結晶化させ、薄紫色のＮ−（４−ヒドロキシベンゾ）−３−クロロプロピオニルアミド189.7g(95％)を得た。
融点：127℃〜129℃(実測：128℃〜129℃)。
IR:νmax(cm-1) 3300 (N-H strech), 3200 (O-H strech), 1655 (C=O strech),	1561, 1508, 1412, 1264, 1200, 980, 839。
1H NMR: δ 2.75 (2H, t, ClCH2CH 2 CO-), 3.86 (2H, t, ClCH 2 CH2CO-), 6.67〜7.38 (4H, q, Aromatic CH-), 9.17 (1H, s, HOPh-), 9.79 (1H, s, ClCH2CH2CONH-)。
【００２４】
［実施例２］ Ｎ−（４−メトキシベンゾ）−３−クロロプロピオニルアミド（II）の製造
窒素気流下でマグネティックスタ−ラーを入れたフラスコ内に酢酸エチル1000ml及び４−メトキシアニリン123.2g(1mol)を加えた。酢酸エチル500mlで希釈した3-クロロプロピオニルクロリド190.5g(1.5mol)を室温でフラスコ内にゆっくり滴下した後、反応液を1時間激しく撹拌した。この反応液に飽和炭酸ナトリウム1000mlを加え塩を完全に溶解させ、有機層を分離し、水500mlで洗浄した。分離した有機層を硫酸マグネシウムを用いて乾燥させ、減圧蒸留により溶媒を除去した。残査をイソプロパノールと水の混合液で結晶化させ、薄紫色のＮ−（４−メトキシベンズ）−３−クロロプロピオニルアミド207．3g(97％)を得た。
融点：120℃〜122℃(実測：121℃〜122℃)。
IR:νmax(cm-1) 3275 (N-H strech), 1653 (C=O strech), 1605, 1549, 1512, 1301, 1244, 1030, 929, 829。
1H NMR: δ 2.79 (2H, t, ClCH2CH 2 CO-), 3.79 (3H, s, CH 3 OPh-), 3.88 (2H, t, ClCH 2 CH2CO-), 6.85〜7.43 (4H, q, Aromatic CH-), 7.43 (1H, s, ClCH2CH2CONH-)。
【００２５】
［実施例３］ Ｎ−（４−エトキシベンゾ）−３−クロロプロピオニルアミド（II）の製造
窒素気流下でマグネティックスタ−ラーを入れたフラスコ内に酢酸エチル1000ml及び４−エトキシアニリン137.2g(1mol)を加えた。酢酸エチル500mlで希釈した３−クロロプロピオニルクロリド190.5g(1.5mol)を室温でフラスコ内にゆっくり滴下した後、反応液を1時間激しく撹拌した。この反応液に飽和炭酸ナトリウム1000mlを加え塩を完全に溶解させた後、有機層を分離し、水500mlで洗浄した。分離した有機層を硫酸マグネシウムを用いて乾燥させ、減圧蒸留により溶媒を除去した。残査をイソプロパノールと水の混合液中で結晶化させ、薄紫色のＮ−（４−エトキシベンゾ）−３−クロロプロピオニルアミド214.0g(94％)を得た。
融点：117℃〜119℃(実測：118℃〜119℃)。
IR: νmax (cm-1) 3280 (N-H strech), 1653 (C=O strech), 1605, 1548, 1511, 1308, 1241, 1047, 931, 830。
1H NMR: δ1.40 (3H, t, CH 3 CH2OPh-), 2.77 (2H, t, ClCH2CH 2 CO-), 3.86 (2H, t, ClCH 2 CH2CO-), 4.01 (2H, q, CH3CH 2 OPh-), 6.82〜7.40 (4H, q, Aromatic CH-), 7.56 (1H, s, ClCH2CH2CONH-)。
【００２６】
［実施例４］ ６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリン（I）の製造
窒素気流下でマグネティックスタ−ラーを入れたフラスコ内にデカヒドロナフタレン500ml、Ｎ−（４−ヒドロキシベンゾ）−３−クロロプロピオニルアミド199.1g(1mol)及び塩化アルミニウム667g(5mol)を加え、室温よりゆっくり温度を上昇させ150℃で8時間撹拌し反応させた。生成した固体を5℃に冷却し、水(1000ml)とクロロホルム(1000ml)を加え激しく撹拌し、粉砕した。生成物を濾取し、水及びクロロホルムで洗浄した。濾取した生成物を真空乾燥させ、６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリン146.9g(90％)を得た。
融点：235℃〜237℃(実測：236℃〜237℃)。
IR: νmax(cm-1) 3315 (N-H strech), 3200 (O-H strech), 1649 (C=O strech), 1502, 1392, 1287, 1252, 1151, 1116, 963, 813, 777。
1H NMR: δ2.35 (2H, t, -CH2CH 2 CO-), 2.76 (2H, t, -CH 2 CH2CO-), 6.51〜6.66 (3H, m, Aromatic CH-), 9.00 (1H, s, HOPh-), 9.79 (1H, s, -CH2CH2CONH-)。
【００２７】
［実施例５］ ６−ヒドロキシベンゾ−２−オキソ−１，２，３，４−テトラヒドロキノリン（I）の製造
窒素気流下でマグネティックスタ−ラーを入れたフラスコ内にデカヒドロナフタレン500ml、Ｎ−（４−メトキシベンゾ）−３−クロロプロピオニルアミド213.7g(1mol)及び塩化アルミニウム667g(5mol)を加えた。室温よりゆっくり温度を上昇させ反応液を150℃で8時間撹拌し反応させた。生成した固体を5℃に冷却し、水(1000ml)とクロロホルム(1000ml)を加えて激しく撹拌し粉砕した。生成物を濾取し、水及びクロロホルムで洗浄した。濾取した生成物を真空乾燥させ、６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリン155.0g(95％)を得た。
融点、IR及び1H NMRのデータは実施例４と同様である。
【００２８】
［実施例６］ ６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリン（I）の製造
窒素気流下でマグネティックスタ−ラーを入れたフラスコ内にデカヒドロナフタレン500ml、Ｎ−（４−メトキシベンゾ）−３−クロロプロピオニルアミド227.7g(1mol)及び塩化アルミニウム667g(5mol)を加えた後、室温よりゆっくり温度を上昇させ150℃で8時間撹拌し反応させた。生成した固体を5℃に冷却し、水(1000ml)とクロロホルム(1000ml)を加え、激しく撹拌し、粉砕した。生成物を濾取し、水及びクロロホルムで洗浄した。濾取した生成物を真空乾燥させ、６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリン145.2g(89％)を得た。
融点、IR及び1H NMRのデータは実施例４と同様である。
【００２９】
［実施例７］ ６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリン（I）の製造
窒素気流下でマグネティックスタ−ラーを入れたフラスコ内にデカヒドロナフタレン500ml、Ｎ−（４−メトキシベンゾ）−３−クロロプロピオニルアミド213.7g(1mol)及び塩化亜鉛681.5g(5mol)を加えた。室温よりゆっくり温度を上昇させ、150℃で12時間反応液を撹拌し反応させた。生成した固体を5℃に冷却し、水(1000ml)とクロロホルム(1000ml)を加えて激しく撹拌し粉砕した。生成物を濾取し、水及びクロロホルムで洗浄した。濾取した生成物を真空乾燥させ、６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリン143.6g(88％)を得た。
融点、IR及び1H NMRのデータは実施例４と同様である。
【００３０】
［実施例８］ ６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリン（I）の製造
窒素気流下でマグネティックスタ−ラーを入れたフラスコ内にデカヒドロナフタレン500ml、N-(4-メトキシベンゾ)-3-クロロプロピオニルアミド213.7g(1mol)及び四塩化チタニウム948.5g(5mol)を加えた。室温よりゆっくり温度を上昇させ、反応液を150℃で16時間撹拌し反応させた。生成した固体を5℃に冷却し、水(1000ml)とクロロホルム(1000ml)を加えて激しく撹拌し粉砕した。生成物を濾取し、水及びクロロホルムで洗浄した。濾取した生成物を真空乾燥させ、６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリン133.8g(82％)を得た。
融点、IR及び1H NMRのデータは実施例４と同様である。
【００３１】
【発明の効果】
本発明によれば、６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリンを簡単に、収率よく製造することができる。また、危険な副産物を生じることがないので、工業的な生産に容易に応用することができる。本発明によって得られる６−ヒドロキシ−２−オキソ−１，２，３，４−テトラヒドロキノリンは血栓治療剤であるシロスタゾルの合成中間体として有用である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a process for producing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline useful as a synthetic intermediate for cilostazol.
[0002]
[Prior art]
Cilostazol is used as a therapeutic agent for thrombosis, and its chemical name is 6- [4- (1-cyclohexyl-5-tetrazolyl) butoxy] -1,2,3,4-tetrahydro-2-oxoquinoline, The formula is represented by the following general formula (V).
[Chemical formula 5]
The cilostazol of the above general formula (V) is a synthetic intermediate of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline and 5-halobutyl-1- It can be produced by reacting cyclohexyltetrazole (Chem. Pharm. Bull. 31, 1151-1157 (1983)).
[0004]
A method for producing a compound of the general formula (VII) having a structure similar to that of the compound of the general formula (I) has been reported (Ber. 60, 858-864 (1927)). According to this method, as shown in the following reaction formula, the compound represented by the general formula (VII) is obtained by converting N- (4-substituted-benzo) -3-chloropropionylamide of the general formula (VI) with an acid catalyst. It is produced by cyclization in the molten state in the presence of certain aluminum chloride.
[Chemical 6]
[0005]
This method requires special equipment to react aluminum chloride with the compound of the general formula (VI) at a considerably high temperature (200 to 240 ° C.) without using a solvent. Moreover, since it is difficult to make it react uniformly, there exists a fault that a yield is low and it is uneconomical and accompanied by danger.
[0006]
The compound of general formula (I) can also be produced via a nitrocinnamic acid derivative (Journal of the American Chemical Society, 66, 1442-1443 (1944)). Specifically, as shown in the following reaction formula, the compound of the general formula (I) is obtained by reducing and cyclizing the alkyl 5-hydroxy-2-nitrocinnamate represented by the general formula (X). .
[Chemical 7]
[0007]
In this method, the starting materials 5-hydroxy-2-nitrobenzaldehyde of the general formula (VIII) and alkyl 3-hydroxycinnamate of the general formula (IX) are very expensive and are reacted under pressure conditions. There is a risk of explosion. Furthermore, in the hydrogenation reaction, since a compressed gas is handled, a special device is required, and hydrogen, which has a very high risk of ignition, is disadvantageous in that it is difficult to industrialize. .
[0008]
In addition, a method for producing a compound of general formula (I) using a cinnamic acid derivative is known (Journal of the American Chemical Society, 89, 7131-7132 (1962)). In this method, as shown in the following reaction formula, the compound of the general formula (I) is produced by cyclization of the 3-hydroxycinnamohydroxamic acid of the general formula (XIII).
[Chemical 8]
This method is inefficient because the starting material 3- (3-hydroxyphenyl) propionic acid of the general formula (XI) is very expensive and requires a three-step reaction process from the starting material. The disadvantage is that the final product yield is as low as 52%.
[0010]
Further, a method for producing a compound represented by the general formula (XVI) having a structure similar to that of the compound of the general formula (I) according to the following reaction formula is known (Journal of the Organic Chemistry, 36, 3975- 3979 (1971)). In this method, a 4-substituted-acrylanilide of the general formula (XIV) is cyclized to synthesize a compound of the general formula (XV), which is dealkylated to give 6 represented by the general formula (XVI). -Hydroxy-3-substituted-4-hydrocarbostyril is prepared.
[Chemical 9]
[0011]
This method has a problem in that an industrially inappropriate photoreaction is carried out when the compound of the general formula (XV) is produced, and the yield is as low as 13%.
[0012]
[Problems to be solved by the invention]
An object of the present invention is to provide a process for producing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline in an industrially safe and simple manner at a low cost and in a high yield.
[0013]
[Means for Solving the Problems]
As a result of repeated studies to solve the problems in the above conventional production methods, the present inventors have found that 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline is safe and easy in a high yield. The present invention has been completed by finding a method for producing the above.
That is, the present invention includes a step of reacting N- (4-substituted-benzo) -3-chloropropionylamide represented by the following general formula (II) with a Lewis acid in the presence of a homogenizing agent ( A method for producing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline represented by I) is provided.
Embedded image
DETAILED DESCRIPTION OF THE INVENTION
[0014]
The reaction step in the production method of the present invention is represented by the following reaction formula.
Embedded image
[0015]
The “homogenizing agent” in the present invention uniformly turbidizes two or more kinds of reactants, improves the heterogeneous reaction progress, which is a problem at the time of reaction in a molten state, and alleviates the decrease in heat transfer. It is a substance. In other words, it is a solvent that eliminates unreacted substances and allows the reaction to proceed uniformly at a lower temperature. Examples of the homogenizing agent used in the production method of the present invention include decahydronaphthalene; high-boiling ether compounds such as diphenyl ether, isoamyl ether, benzyl ethyl ether, diglyme, and triglyme; or hydrocarbons such as β-pinene, limonene, and tetralin. Compounds. Of these, decahydronaphthalene is most preferred.
[0016]
Examples of the Lewis acid catalyst used in the production method of the present invention include aluminum chloride, zinc chloride and titanium tetrachloride, and aluminum chloride is particularly preferably used.
In the reaction, Lewis acid is used in an amount of 2 to 10 mol, preferably 3 to 5 mol, and a homogenizing agent 1 to 20 ml / g, preferably 1 to 5 ml / g, based on the compound of general formula (II) It is carried out at ˜200 ° C., preferably 120 ° C. to 150 ° C., for 2 to 18 hours, preferably 6 to 10 hours.
[0017]
The compound of the general formula (I) which is a reaction product can be purified by a known method such as recrystallization from methanol.
[0018]
The compound represented by general formula (II), which is a starting material, is obtained by reacting 4-substituted-aniline of general formula (III) with 3-chloropropionyl chloride represented by general formula (IV). Rate (97%).
Embedded image
[0019]
This reaction is carried out in a polar organic solvent such as ethyl acetate, dimethylformamide and dimethyl sulfoxide, or a nonpolar organic solvent such as hexane and benzene at 10 to 30 ° C. for 1 to 3 hours. At this time, 1 to 5 mol, preferably 1.2 to 2 mol of 3-chloropropionyl chloride and 5 to 20 ml / g of the above solvent are used with respect to 4-substituted-aniline.
[0020]
The obtained compound of the general formula (II) can be purified by a known method such as recrystallization from a mixed solution of isopropanol and water.
[0021]
The 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline of general formula (I) produced according to the process of the present invention is useful as an intermediate for the synthesis of cilostazol, which is a thrombus therapeutic agent.
[0022]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these.
[0023]
Example 1 Production of N- (4-hydroxybenzo) -3-chloropropionylamide (II) 1000 ml of ethyl acetate and 109.1 g (1 mol of 4-hydroxyaniline) were placed in a flask containing a magnetic stirrer under a nitrogen stream. ) Was added. After 190.5 g (1.5 mol) of 3-chloropropionyl chloride diluted with 500 ml of ethyl acetate at room temperature was slowly dropped into the flask, the reaction solution was vigorously stirred for 1 hour. To this reaction solution, 1000 ml of saturated sodium carbonate was added to completely dissolve the salt, and the organic layer was separated and washed with 500 ml of water. The separated organic layer was dried using magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was crystallized with a mixed solution of isopropanol and water to obtain 189.7 g (95%) of light purple N- (4-hydroxybenzo) -3-chloropropionylamide.
Melting point: 127 ° C. to 129 ° C. (actual measurement: 128 ° C. to 129 ° C.).
IR: ν max (cm −1 ) 3300 (NH strech), 3200 (OH strech), 1655 (C = O strech), 	 1561, 1508, 1412, 1264, 1200, 980, 839.
1 H NMR: δ 2.75 (2H, t, ClCH 2 C H 2 CO-), 3.86 (2H, t, ClC H 2 CH 2 CO-), 6.67-7.38 (4H, q, Aromatic C H- ), 9.17 (1H, s, H OPh-) , 9.79 (1H, s, ClCH 2 CH 2 CON H -).
[0024]
Example 2 Production of N- (4-methoxybenzo) -3-chloropropionylamide (II) 1000 ml of ethyl acetate and 123.2 g (1 mol of 4-methoxyaniline) were placed in a flask containing a magnetic stirrer under a nitrogen stream. ) Was added. After 190.5 g (1.5 mol) of 3-chloropropionyl chloride diluted with 500 ml of ethyl acetate was slowly dropped into the flask at room temperature, the reaction solution was vigorously stirred for 1 hour. To this reaction solution, 1000 ml of saturated sodium carbonate was added to completely dissolve the salt, and the organic layer was separated and washed with 500 ml of water. The separated organic layer was dried using magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was crystallized with a mixture of isopropanol and water to obtain 207.3 g (97%) of pale purple N- (4-methoxybenz) -3-chloropropionylamide.
Melting point: 120 ° C. to 122 ° C. (actual measurement: 121 ° C. to 122 ° C.).
IR: ν max (cm −1 ) 3275 (NH strech), 1653 (C = O strech), 1605, 1549, 1512, 1301, 1244, 1030, 929, 829.
1 H NMR: δ 2.79 (2H, t, ClCH 2 C H 2 CO-), 3.79 (3H, s, C H 3 OPh-), 3.88 (2H, t, Cl CH 2 CH 2 CO-), 6.85 ~ 7.43 (4H, q, Aromatic C H- ), 7.43 (1H, s, ClCH 2 CH 2 CON H- ).
[0025]
Example 3 Production of N- (4-ethoxybenzo) -3-chloropropionylamide (II) 1000 ml of ethyl acetate and 137.2 g (1 mol of 4-ethoxyaniline) were placed in a flask containing a magnetic stirrer under a nitrogen stream. ) Was added. After 190.5 g (1.5 mol) of 3-chloropropionyl chloride diluted with 500 ml of ethyl acetate was slowly dropped into the flask at room temperature, the reaction mixture was vigorously stirred for 1 hour. To this reaction solution, 1000 ml of saturated sodium carbonate was added to completely dissolve the salt, and then the organic layer was separated and washed with 500 ml of water. The separated organic layer was dried using magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was crystallized in a mixture of isopropanol and water to obtain 214.0 g (94%) of pale purple N- (4-ethoxybenzo) -3-chloropropionylamide.
Melting point: 117 ° C to 119 ° C (actual measurement: 118 ° C to 119 ° C).
IR: νmax (cm −1 ) 3280 (NH strech), 1653 (C = O strech), 1605, 1548, 1511, 1308, 1241, 1047, 931, 830.
1 H NMR: δ1.40 (3H, t, C H 3 CH 2 OPh-), 2.77 (2H, t, ClCH 2 C H 2 CO-), 3.86 (2H, t, ClC H 2 CH 2 CO-) , 4.01 (2H, q, CH 3 C H 2 OPh-), 6.82~7.40 (4H, q, Aromatic C H -), 7.56 (1H, s, ClCH 2 CH 2 CON H -).
[0026]
[Example 4] Production of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline (I) 500 ml of decahydronaphthalene and N- (into a flask containing a magnetic stirrer under nitrogen flow. 199.1 g (1 mol) of 4-hydroxybenzo) -3-chloropropionylamide and 667 g (5 mol) of aluminum chloride were added, the temperature was slowly raised from room temperature, and the mixture was stirred and reacted at 150 ° C. for 8 hours. The produced solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, and the mixture was vigorously stirred and ground. The product was collected by filtration and washed with water and chloroform. The product collected by filtration was vacuum-dried to obtain 146.9 g (90%) of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline.
Melting point: 235 ° C. to 237 ° C. (actual measurement: 236 ° C. to 237 ° C.).
IR: ν max (cm −1 ) 3315 (NH strech), 3200 (OH strech), 1649 (C = O strech), 1502, 1392, 1287, 1252, 1151, 1116, 963, 813, 777.
1 H NMR: δ 2.35 (2H, t, -CH 2 C H 2 CO-), 2.76 (2H, t, -C H 2 CH 2 CO-), 6.51 ~ 6.66 (3H, m, Aromatic C H- ), 9.00 (1H, s, H OPh-), 9.79 (1H, s, -CH 2 CH 2 CON H- ).
[0027]
[Example 5] Production of 6-hydroxybenzo-2-oxo-1,2,3,4-tetrahydroquinoline (I) 500 ml of decahydronaphthalene and N- in a flask containing a magnetic stirrer under nitrogen flow 213.7 g (1 mol) of (4-methoxybenzo) -3-chloropropionylamide and 667 g (5 mol) of aluminum chloride were added. The temperature was slowly raised from room temperature, and the reaction solution was stirred at 150 ° C. for 8 hours to be reacted. The produced solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, and the mixture was vigorously stirred and ground. The product was collected by filtration and washed with water and chloroform. The product collected by filtration was vacuum-dried to obtain 155.0 g (95%) of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline.
Melting point, IR and 1 H NMR data are the same as in Example 4.
[0028]
Example 6 Production of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline (I) 500 ml of decahydronaphthalene and N- (into a flask containing a magnetic stirrer under a nitrogen stream. After adding 227.7 g (1 mol) of 4-methoxybenzo) -3-chloropropionylamide and 667 g (5 mol) of aluminum chloride, the temperature was slowly raised from room temperature and stirred at 150 ° C. for 8 hours for reaction. The produced solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, and the mixture was vigorously stirred and ground. The product was collected by filtration and washed with water and chloroform. The product collected by filtration was vacuum-dried to obtain 145.2 g (89%) of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline.
Melting point, IR and 1 H NMR data are the same as in Example 4.
[0029]
[Example 7] Production of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline (I) 500 ml of decahydronaphthalene and N- (into a flask containing a magnetic stirrer under nitrogen flow. 213.7 g (1 mol) of 4-methoxybenzo) -3-chloropropionylamide and 681.5 g (5 mol) of zinc chloride were added. The temperature was slowly raised from room temperature, and the reaction solution was stirred at 150 ° C. for 12 hours to be reacted. The produced solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, and the mixture was vigorously stirred and ground. The product was collected by filtration and washed with water and chloroform. The product collected by filtration was vacuum-dried to obtain 143.6 g (88%) of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline.
Melting point, IR and 1 H NMR data are the same as in Example 4.
[0030]
[Example 8] Production of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline (I) 500 ml of decahydronaphthalene, N- () in a flask containing a magnetic stirrer under a nitrogen stream 213.7 g (1 mol) of 4-methoxybenzo) -3-chloropropionylamide and 948.5 g (5 mol) of titanium tetrachloride were added. The temperature was raised slowly from room temperature, and the reaction solution was stirred at 150 ° C. for 16 hours to be reacted. The produced solid was cooled to 5 ° C., water (1000 ml) and chloroform (1000 ml) were added, and the mixture was vigorously stirred and ground. The product was collected by filtration and washed with water and chloroform. The product collected by filtration was vacuum-dried to obtain 133.8 g (82%) of 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline.
Melting point, IR and 1 H NMR data are the same as in Example 4.
[0031]
【The invention's effect】
According to the present invention, 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline can be easily produced with high yield. Further, since no dangerous by-product is generated, it can be easily applied to industrial production. The 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline obtained by the present invention is useful as a synthetic intermediate for cilostazol, which is a thrombus therapeutic agent.
Claims (6)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1999-4469 | 1999-02-09 | ||
| KR1019990004469A KR100302346B1 (en) | 1999-02-09 | 1999-02-09 | A method of preparing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline |
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| Publication Number | Publication Date |
|---|---|
| JP2000229944A JP2000229944A (en) | 2000-08-22 |
| JP4173599B2 true JP4173599B2 (en) | 2008-10-29 |
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| US6825214B2 (en) | 2000-08-14 | 2004-11-30 | Teva Pharmaceutical Industries, Ltd. | Substantially pure cilostazol and processes for making same |
| US20050101631A1 (en) | 2002-08-01 | 2005-05-12 | Otsuka Pharmaceuticals Company | Process for producing carbostyril derivatives |
| EP2527336A1 (en) | 2007-04-25 | 2012-11-28 | Concert Pharmaceuticals Inc. | Deuterated analogues of cilostazol |
| CN105111190B (en) * | 2015-09-17 | 2017-11-07 | 浙江金立源药业有限公司 | A kind of synthetic method of Cilostazol |
| CN107325078B (en) * | 2017-07-17 | 2020-01-07 | 烟台万润药业有限公司 | Preparation method of cilostazol |
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