KR19980047902A - Method for preparing beta-keto ester derivative which is a quinolone antibiotic intermediate - Google Patents
Method for preparing beta-keto ester derivative which is a quinolone antibiotic intermediate Download PDFInfo
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- KR19980047902A KR19980047902A KR1019960066428A KR19960066428A KR19980047902A KR 19980047902 A KR19980047902 A KR 19980047902A KR 1019960066428 A KR1019960066428 A KR 1019960066428A KR 19960066428 A KR19960066428 A KR 19960066428A KR 19980047902 A KR19980047902 A KR 19980047902A
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
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Abstract
본 발명은 퀴놀론계 항생제 중간체인 화학식 1의 베타-케토 에스테르의 제조방법에 관한 것으로서 화학식 2의 화합물을 아실화 반응시켜 제조한다.The present invention relates to a method for preparing a beta-keto ester of formula (1), which is a quinolone antibiotic intermediate, and is prepared by acylating a compound of formula (2).
보다 상세하게는 본 발명은 화학식 2의 화합물을 말론산모노에스테르 칼륨염으로 아실화 반응시켜 화학식 1의 화합물을 제조하는 방법에 관한 것으로서, 말론산모노에스테르 칼륨염을 용매 존재하에 트리알킬염화실란, 할로겐화리튬, 유기아민염기류로 처리한 후 화학식 2의 화합물과 반응시켜 화학식 1의 화합물을 제조한다.More specifically, the present invention relates to a method for preparing a compound of formula 1 by acylating a compound of formula (2) with a monoester potassium salt of malonic acid, wherein the trialkyl chloride silane is prepared in the presence of a solvent. After treating with a lithium halide or an organic amine base, the compound of Formula 1 is prepared by reacting with a compound of Formula 2.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
Description
[발명의명칭][Name of invention]
퀴놀론계 항생제 중간체인 베타-케토 에스테르 유도체의 제조방법Method for preparing beta-keto ester derivative which is a quinolone antibiotic intermediate
[발명의상세한설명]Detailed description of the invention
[발명의 목적][Purpose of invention]
본 발명은 퀴놀론계 항생제 중간체인 화학식 1의 베타-케토 에스테르의 제조방법에 관한 것으로서 화학식 2의 화합물을 아실화 반응시켜 제조한다.The present invention relates to a method for preparing a beta-keto ester of formula (1), which is a quinolone antibiotic intermediate, and is prepared by acylating a compound of formula (2).
좀 더 상세하게는, 본 발명은 화학식 2의 화합물을 말론산모노에스테르 칼륨염으로 아실화 반응시켜 화학식 1의 화합물을 제조하는 방법에 관한 것으로서 말론산 또는 에스테르 칼륨염을 트리알킬염화실란, 할로겐화리튬, 유기아민염기류로 처리한 후 화학식 2의 화합물과 반응시켜 화학식 1의 화합물을 제조한다.More specifically, the present invention relates to a method for preparing a compound of formula 1 by acylating a compound of formula (2) with a monoester potassium salt of malonic acid, wherein trialkyl chloride, lithium halide of malonic acid or ester potassium salt is prepared. After treating with an organic amine base, the compound of Formula 1 is prepared by reacting with a compound of Formula 2.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[발명이속하는기술분야및그분야의종래기술][Technical Field to which the Invention belongs and Conventional Technology in the Field]
본 발명의 베타-케토 에스테르 유도체는 1-치환된-6-플루오르-7-할로-1,4-디히드로-4-옥소-퀴놀린 카르복실산이나 1-치환된-6-플루오르-7-할로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산을 제조하기 위한 중간체로 사용된다 [Hagen et al., J. Med. Chem., 1991, 34, 1155-1161; McGuirk et al., J. Med. Chem., 1992, 35, 611-620; Miyamoto et al., Chem. Pharm. Bull., 1990, 38, 2472-2475].The beta-keto ester derivatives of the invention are 1-substituted-6-fluoro-7-halo-1,4-dihydro-4-oxo-quinoline carboxylic acid or 1-substituted-6-fluoro-7-halo It is used as an intermediate for preparing -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid [Hagen et al., J. Med. Chem., 1991, 34, 1155-1161; McGuirk et al., J. Med. Chem., 1992, 35, 611-620; Miyamoto et al., Chem. Pharm. Bull., 1990, 38, 2472-2475].
상기한 1-치환된-6-플루오르-7-할로-1,4-디히드로-4-옥소-퀴놀린 카르복실산 또는 1-치환된-6-플루오르-7-할로-1,4-디히드로-4-옥소-1,8-나프티리딘-3-카르복실산은 실제 세균감염증 치료에 널리 쓰이는 퀴놀린계 항생제의 제조에 이용되고 있다.1-substituted-6-fluoro-7-halo-1,4-dihydro-4-oxo-quinoline carboxylic acid or 1-substituted-6-fluoro-7-halo-1,4-dihydro 4-oxo-1,8-naphthyridine-3-carboxylic acid has been used to prepare quinoline antibiotics, which are widely used in the treatment of bacterial infections.
이와 같은 퀴놀린계 항생제의 중간체로 매우 중요한 베타-케토 에스테르 유도체를 제조하기 위하여 많은 연구가 진행되어 왔다.Many studies have been conducted to prepare beta-keto ester derivatives which are very important as intermediates of such quinoline antibiotics.
EP 0 342 849 A2 에 기재된 내용에 의하면 말론산모노에스테르를 부틸리튬, 수소화나트륨, 리튬 디이소프로필아미드 등과 같은 강염기를 이용하여 이중음이온을 만들어 화학식 2의 화합물과 반응시켜 화학식 1의 베타-케토 에스테르를 제조한다. 그 과정을 하기 반응식 1로 나타내었다.According to the contents described in EP 0 342 849 A2, the malonic acid monoester is prepared using a strong base such as butyllithium, sodium hydride, lithium diisopropylamide, and the like to react with a compound of formula 2 to react with a compound of formula 2 To prepare. The process is shown in Scheme 1 below.
[반응식 1]Scheme 1
그러나 이 방법은 사용되는 강염기들이 발화성을 가지고 있어서 화재가 일어날 위험이 있고, 상대적으로 고가이기 때문에 대량의 생산공정으로는 적합하지 않다. 또한 통상 이러한 강염기를 이용할 경우 반응 내부온도를 영하 수십 도로 낮추는 것이 일반적인데 그 조작이 수월하지 않으며, 말론산모노에스테르도 상업적으로 구매되는 칼륨염을 미리 산처리하여 용매로 추출한 후 건조하고 감압농축하여야 하는 등 공정이 복잡하다.However, this method is not suitable for large production processes because the strong bases used are ignitable and there is a risk of fire, which is relatively expensive. In addition, when using such a strong base, it is common to lower the reaction internal temperature to several tens of degrees. The operation is not easy, and the malonic acid monoester is also extracted with a solvent by pre-acidifying the potassium salt, which is commercially available, and dried and concentrated under reduced pressure. The process is complicated.
또 다른 합성법으로는 아세토페논계 화합물을 카아보네이트 수은염과 반응시키는 예가 있는데 [Ra'DI, S. 등, Collect. Czech. Chem. Commun, 1990, 55, 1311], 이 반응을 하기 반응식 2로 나타내었다.Another synthesis method is an example in which an acetophenone compound is reacted with a carbonate mercury salt [Ra'DI, S. et al., Collect. Czech. Chem. Commun, 1990, 55, 1311], this reaction is shown in Scheme 2 below.
[반응식 2]Scheme 2
이 방법에서는 수은과 같은 중금속이 이용되므로 의약품의 제조공정으로는 적당하지 않다.In this method, heavy metals such as mercury are used, which is not suitable for the manufacture of pharmaceuticals.
또 다른 방법으로는 말론산모노에스테르와 화학식 2의 화합물을 반응시켜 화학식 1의 베타-케토 에스테르 유도체를 제조하는 방법이 있다 [Clay, R. J., Synthesis, 1993, 3, 290-292]. 이를 하기 반응식 3으로 나타내었다.Another method is to prepare a beta-keto ester derivative of formula 1 by reacting the malonic acid monoester with a compound of formula [Clay, R. J., Synthesis, 1993, 3, 290-292]. This is represented by Scheme 3 below.
상기 반응은 가혹하지 않은 조건에서 고수율로 얻을 수 있는 장점이 있으나 루이스 산으로 이용되는 염화마그네슘이 반응 후처리에서 에멀젼을 형성하여 추출을 어렵게 하여 착물 (complex)을 분리하기 위해 진한 염산으로 처리해야 하는 공정상의 난점을 가지고 있다.The reaction can be obtained in high yield under harsh conditions, but magnesium chloride, which is used as a Lewis acid, forms an emulsion in the post-treatment of the reaction, making it difficult to extract so that it must be treated with concentrated hydrochloric acid to separate the complex. It has a difficult process.
또 다른 방법으로서 화이져 (Pfeitzer)의 합성방법은 모노말로네이트 칼륨염을 이용하여 반응 중간체로 마그네슘 킬레이트를 형성하고 이를 산 염화물 (acid chloride) 또는 산 이미다졸라이드 (acid imidazolide)와 반응시켜 베타-케토 에스테르를 제조한다 [대한민국 특허공고 93-5059호]. 이 방법은 염화마그네슘 대신 그리냐드 (Grignard) 시약을 이용하여 마그네슘 킬레이트를 형성하는데, 실시예에 사용된 염화메틸마그네슘은 고가이고, 인화성이 크며 수분에 민감하여 산업적으로 이용하기에 곤란하다는 단점이 있다.Another method for the synthesis of Pfeitzer is to form magnesium chelate as a reaction intermediate using a monomalonate potassium salt and react with acid chloride or acid imidazolide to form beta. Prepare a keto ester [Korean Patent Publication No. 93-5059]. This method forms magnesium chelate by using Grignard reagent instead of magnesium chloride. The methyl magnesium chloride used in the examples is expensive, highly flammable, sensitive to moisture, and difficult to industrially use. .
이에 본 발명자들은 상기한 공정들의 단점을 개선하고자 노력한 결과 말론산모노에스테르 칼륨염을 트리알킬염화실란과 할로겐화리튬 존재하에서 반응시키고, 유기 아민 염기를 처리한 후 한 반응기 안에서 화학식 2의 화합물을 반응시키면, 화학식 1의 화합물이 간단한 공정으로 고수율로 얻어지는 것을 발견하고 본 발명을 완성하였다.Accordingly, the present inventors have tried to improve the disadvantages of the above-described processes, and as a result, reacting the monomonoester potassium salt in the presence of trialkylsilane and lithium halide, treating the organic amine base, and reacting the compound of formula 2 in one reactor The present invention was completed by finding that the compound of Formula 1 is obtained in high yield by a simple process.
[발명이이루고자하는기술적과제][Technical Challenges to Invent]
본 발명은 퀴놀론계 항생제의 중간체로 사용되는 화학식 1의 베타-케토 에스테르의 제조방법에 관한 것으로서 화학식 2의 화합물을 아실화 반응시켜 제조한다.The present invention relates to a method for preparing a beta-keto ester of formula (1) used as an intermediate of a quinolone antibiotic, and is prepared by acylation of a compound of formula (2).
본 발명은 화학식 2의 화합물을 말론산모노에스테르 칼륨염으로 아실화 반응시켜 화학식 1의 화합물을 제조하는 방법에 관한 것으로서, 말론산모노에스테르 칼륨염을 용매 존재하에 트리알킬염화실란, 할로겐화리튬, 유기아민염기류로 처리한 후 화학식 2의 화합물과 반응시켜 화학식 1의 화합물을 제조한다.The present invention relates to a method for preparing a compound of formula (1) by acylating a compound of formula (2) with potassium salt of monomonic acid salt, wherein trialkyl chloride, lithium halide, organic, and the like of the The compound of formula 1 is prepared by treating with an amine base and reacting with the compound of formula 2.
본 발명의 용매는 비활성 극성용매로서, 테트라히드로퓨란, 아세토니트릴, 디메틸포름아미드 등이 포함될 수 있다.The solvent of the present invention is an inert polar solvent, and may include tetrahydrofuran, acetonitrile, dimethylformamide, and the like.
본 발명의 반응온도는 0℃ 내지 100℃ 이며, 바람직하기로는 상온 내지 40℃ 이다.The reaction temperature of the present invention is 0 ℃ to 100 ℃, preferably from room temperature to 40 ℃.
본 발명에서 사용되는 할로겐화리튬에는 불화리튬, 염화리튬, 브로모리튬 및 요오드리튬이 포함되며, 이 중 염화리튬 및 브로모리튬이 바람직하다.Lithium halides used in the present invention include lithium fluoride, lithium chloride, bromolithium and iodide, of which lithium chloride and bromolithium are preferred.
본 발명의 반응에 이용되는 유기염기아민에는 트리에틸아민, 디이소프로필에틸아민 등이 포함된다.The organic base amine used for the reaction of the present invention includes triethylamine, diisopropylethylamine and the like.
[발명의구성및작용]Composition and Action of the Invention
본 발명은 퀴놀론계 항생제 중간체인 화학식 1의 베타-케토 에스테르의 제조방법에 관한 것으로서 화학식 2의 화합물을 아실화 반응시켜 제조한다. 그 반응식을 하기 반응식 4로 나타내었다.The present invention relates to a method for preparing a beta-keto ester of formula (1), which is a quinolone antibiotic intermediate, and is prepared by acylating a compound of formula (2). The reaction scheme is shown in Scheme 4 below.
보다 상세하게는 본 발명은 화학식 2의 화합물을 말론산모노에스테르로 아실화시켜 화학식 1의 화합물을 제조하는 방법에 관한 것으로서, 말론산모노에스테르 칼륨염을 트리알킬염화실란과 할로겐화리튬 존재하에서 반응시킨 뒤 유기아민염기를 처리한 후 화학식 2의 화합물을 한 반응기 안에서 반응시킴으로써 화학식 1의 화합물을 얻는다.More particularly, the present invention relates to a method for preparing a compound of formula 1 by acylating a compound of formula (2) with malonic acid monoester, wherein the potassium salt of monosonic acid salt is reacted with trialkylsilane and lithium halide. After treating the organic amine base and then reacting the compound of formula 2 in one reactor to obtain a compound of formula (1).
[화학식 1][Formula 1]
상기 화학식 1에서 R은 C1∼C4의 알킬기이며,In Formula 1, R is a C1-C4 alkyl group,
X, Y 및 Z는 플루오르, 클로로, 브로모 등의 할로겐이거나 유기화합물의 제조에 통상 쓰이는 이탈기 또는 수소를 나타내며 기타 알킬, 아릴, 아미노, 니트로, 시아노 등이다. 바람직하기로는 X 및 Z는 서로 같거나 다른 할로겐이며, Y는 수소, 아미노, 니트로 또는 알킬이다. 더욱 바람직하기로는 X 및 Z는 동일하게 클로로이거나 플루오르이며, Y는 수소 또는 아미노이다.X, Y and Z represent halogens such as fluorine, chloro, bromo or the like or a leaving group or hydrogen commonly used in the preparation of organic compounds, and other alkyl, aryl, amino, nitro, cyano and the like. Preferably X and Z are the same or different halogen from each other and Y is hydrogen, amino, nitro or alkyl. More preferably X and Z are equally chloro or fluorine and Y is hydrogen or amino.
Q는 치환되지 않거나 치환된 탄소이거나 질소이며, 바람직하기로는 수소, 할로겐, 알킬 또는 알콕시로 치환된 탄소이거나 질소이다. 더욱 바람직하기로는 수소 또는 플루오르로 치환된 탄소 또는 질소이다.Q is unsubstituted or substituted carbon or nitrogen, preferably carbon or nitrogen substituted with hydrogen, halogen, alkyl or alkoxy. More preferably carbon or nitrogen substituted with hydrogen or fluorine.
[화학식 2][Formula 2]
상기 화학식 2에서 X, Y, Z 및 Q는 화학식 1에서와 같으며, L은 통상의 이탈기로서 할로겐, 알킬술포닐옥시 또는 아릴술포닐옥시이거나 이미다졸, 또는 포스페이트 계통의 활성 에스테르이거나, 무수물이다. 바람직하기로는 할로겐 또는 이미다졸이고, 더욱 바람직하기로는 염소이다.In Formula 2, X, Y, Z and Q are the same as in Formula 1, and L is halogen, alkylsulfonyloxy or arylsulfonyloxy or imidazole, or an anhydride as an ordinary leaving group, or an anhydride. to be. Preferably halogen or imidazole, more preferably chlorine.
상기 화학식 1의 화합물은 하기 화학식 3으로 표시되는 엔올 형태로도 존재할 수 있고 화학식 1과 화학식 3은 서로 토토머 관계이므로, 화학식 1에 화학식 3이 포함되는 것으로 본다.The compound of Chemical Formula 1 may also exist in the form of an enol represented by Chemical Formula 3, and Chemical Formula 1 and Chemical Formula 3 are tautomeric, and thus, Chemical Formula 1 is considered to include Chemical Formula 3.
[화학식 3][Formula 3]
[반응식 4]Scheme 4
상기 반응은 극성 용매에서 0℃ 내지 100℃ 온도 범위에서 반응하며, 바람직하기로는 상온 내지 40℃에서 반응한다.The reaction is carried out in a polar solvent in the temperature range of 0 ℃ to 100 ℃, preferably at room temperature to 40 ℃.
본 발명의 반응에 이용되는 용매는 비활성 극성 용매류가 적당하며 테트라히드로퓨란, 아세토니트릴, 디메틸포름아미드, 에틸아세테이트 등이 포함된다.Solvents used in the reaction of the present invention are suitable inert polar solvents and include tetrahydrofuran, acetonitrile, dimethylformamide, ethyl acetate and the like.
본 발명에서 이용되는 할로겐화리튬에는 불화리튬, 염화리튬, 브로모리튬 및 요오드리튬이 포함되며, 이 중 염화리튬 및 브로모리튬이 바람직하다.Lithium halides used in the present invention include lithium fluoride, lithium chloride, bromolithium and iodide, of which lithium chloride and bromolithium are preferred.
본 발명의 반응에 이용되는 유기염기아민에는 트리에틸아민, 디이소프로필에틸 아민 등이 포함된다.Organic base amines used in the reaction of the present invention include triethylamine, diisopropylethyl amine and the like.
말론산모노에스테르 칼륨염은 통상의 용매에 매우 낮은 용해도를 가져, 말론산모노에스테르 칼륨염을 반응에 이용하기 위해서는 많은 용매를 이용하거나 가온하여 반응시켜야 하는데 실제 이러한 경우 반응물에 균질하게 되기 어려운 난점이 있다. 이러한 문제점 때문에 종래에는 말론산모노에스테르를 산성화하여 카르복실산 형태로 얻은 후 사용하였다. 본 발명에서는 이러한 문제점을 해결하여, 할로겐화리튬을 말론산모노에스테르 칼륨염과 용매하에서 혼합함으로써 쉽게 균질하게 녹여 반응이 쉽게 일어나게 하였다.The malonic acid monoester potassium salt has very low solubility in a common solvent, and in order to use the malonic acid monoester potassium salt in a reaction, it is necessary to react with a large number of solvents or to warm it. have. For this reason, conventionally, the malonic acid monoester was acidified and used in the form of a carboxylic acid. In the present invention, this problem is solved, and the lithium halide is easily homogeneously dissolved by mixing the monoester potassium salt with malonic acid in a solvent so that the reaction occurs easily.
본 발명에서 사용되는 말론산모노에스테르 칼륨염은 시판되는 제품을 사용하거나, 디에틸 말로네이트를 에탄올에서 사포니피케이션하여 손쉽게 얻을 수 있다 [Strube, R.E., Organic Synthesis, 1963, Vol. Ⅳ, 417].The malonic acid monoester potassium salt used in the present invention can be easily obtained by using a commercially available product or by saponification of diethyl malonate in ethanol [Strube, R.E., Organic Synthesis, 1963, Vol. IV, 417].
말론산모노에스테르 칼륨염을 할로겐화리튬과 혼합하면 할로겐화칼륨이 침전되면서 말론산모노에스테르가 형성되고, 이 말론산모노에스테르는 용매에 녹아 균질용액을 형성한다. 이 용액에 트리알킬염화실란과 유기아민염기를 가한 후 화학식 2의 화합물을 넣어 한 반응기 안에서 반응을 종결시킨다. 반응은 짧은 시간 내에 종결되며 화학식 1의 화합물이 고수율로 얻어진다. 이 때 트리알킬염화실란은 화학식 2의 화합물에 대해 1:4 내지 1:6의 몰비로 첨가하며, 유기아민염기류는 화학식 2의 화합물에 대해 1:4 내지 1:6의 몰비로 첨가한다.When the malonic acid monoester potassium salt is mixed with lithium halide, potassium halide is precipitated to form malonic acid monoester, which is dissolved in a solvent to form a homogeneous solution. Trialkyl chloride and organic amine base are added to this solution, and the compound of Formula 2 is added to terminate the reaction in one reactor. The reaction ends in a short time and the compound of formula 1 is obtained in high yield. At this time, trialkyl chloride is added in a molar ratio of 1: 4 to 1: 6 to the compound of formula (2), and organic amine bases are added in a molar ratio of 1: 4 to 1: 6 to the compound of formula (2).
상기의 반응에 의하여 얻은 화학식 1의 화합물은 하기와 같이 분리 정제한다. 반응기에 묽은 산을 넣어 반응액을 산성으로 하면 층 분리가 일어난다. 수층을 에틸아세테이트로 추출하고 유기층을 모두 합쳐 탄산수소나트륨 수용액으로 세척한 후 포화 소금물로 세척하여 순도 높은 화학식 1의 화합물을 고수율로 얻는다.The compound of formula 1 obtained by the above reaction is separated and purified as follows. When dilute acid is added to the reactor to make the reaction acid, layer separation occurs. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with an aqueous solution of sodium bicarbonate and washed with saturated brine to obtain a high purity compound of formula 1 in high yield.
이하 본 발명을 실시예에 의거하여 설명하기로 한다. 실시예는 본 발명을 예시하는 것일 뿐 본 발명이 실시예로 한정되는 것은 아니다.Hereinafter, the present invention will be described based on examples. The examples are illustrative only of the present invention and the present invention is not limited to the examples.
실시예 1 에틸 2,6-디클로로-5-플루오르니코티노일 아세테이트의 합성Example 1 Synthesis of Ethyl 2,6-dichloro-5-fluoronicotinoyl acetate
말론산 모노 에틸 에스테르 칼륨염 (33.6 kg, 197.4 mol)과 무수 염화리튬 (8.3 kg, 195.8 mol)을 건조된 테트라히드로퓨란 590 L 에 넣고 잘 교반하였다 (∼120 rpm). 상기 현탁액을 약 40℃로 가열하여 균질하게 만든 후 염화칼륨이 침전한 것을 확인하였다. 반응물에 트리메틸염화실란 (22.3 kg, 205.3 mol)을 넣고 잠시 저어주고 트리에틸아민 (41.4 kg, 409 mol)을 넣었다. 2,6-디클로로-5-플루오르니코티노일 클로라이드 (21.3 kg, 97.1 mol)를 첨가하면 짧은 시간에 반응이 종결되었다. 묽은 염산 수용액 (∼2.5 N, HCl, 180 L)으로 반응액을 산성 (pH∼3)으로 만들고 층 분리한 후 수층을 에틸 아세테이트 (250L)를 넣어 추출하였다. 그런 다음 유기층을 모두 합쳐 포화 탄산 수소나트륨 수용액 270 L 로 세척하고 이를 다시 포화 소금물 230 L 로 세척하여 층 분리한 후 농축하여 노란 고체를 23.1 kg (∼90% 수율) 깨끗하게 얻었다.Malonic acid monoethyl ester potassium salt (33.6 kg, 197.4 mol) and anhydrous lithium chloride (8.3 kg, 195.8 mol) were placed in 590 L of dried tetrahydrofuran and stirred well (˜120 rpm). The suspension was heated to about 40 ° C. to make it homogeneous and then confirmed that potassium chloride precipitated. Trimethyl silane (22.3 kg, 205.3 mol) was added to the reaction, and the mixture was stirred for a while and triethylamine (41.4 kg, 409 mol) was added thereto. The reaction was terminated in a short time by the addition of 2,6-dichloro-5-fluoronicotinoyl chloride (21.3 kg, 97.1 mol). The reaction solution was made acidic (pH ~ 3) with dilute aqueous hydrochloric acid solution (˜2.5 N, HCl, 180 L), and the layers were separated. The aqueous layer was extracted with ethyl acetate (250 L). Then, the organic layers were combined and washed with 270 L of saturated aqueous sodium hydrogen carbonate solution, which was then washed with 230 L of saturated brine, and the layers were separated and concentrated to give 23.1 kg (˜90% yield) of a yellow solid.
* 순도 : 95% (1-H NMR, 표준 시료 : 아세트산)* Purity: 95% (1-H NMR, standard sample: acetic acid)
* X-선 결정 (X-ray crystallography) : 석유 에테르 (petroleum ether)로부 터 재결정* X-ray crystallography: recrystallization from petroleum ether
* 1-H NMR (CDCl3, δ, ppm): 1.264 (t, 7Hz, -OCH2CH3), 1.350 (t, 7Hz, -OCH2CH3), 4.096 (s, -COCH2COO-, 케토 폼), 4.205 (q, 7Hz, -OCH2CH3), 4.297 (q, 7Hz, -OCH2CH3), 5.836 (s, -C(OH)=CHCOO-, 엔올 폼), 7.841/7.837 (d×2, 7.5Hz, H-F coupling, Ar-H); 케토/엔올 비율 ∼ 1:1.5* 1-H NMR (CDCl3, δ, ppm): 1.264 (t, 7Hz, -OCH2CH3), 1.350 (t, 7Hz, -OCH2CH3), 4.096 (s, -COCH2COO-, ketoform), 4.205 (q, 7Hz , -OCH2CH3), 4.297 (q, 7Hz, -OCH2CH3), 5.836 (s, -C (OH) = CHCOO-, enol form), 7.841 / 7.837 (d × 2, 7.5Hz, HF coupling, Ar-H) ; Keto / enol ratio-1: 1.5
* FAB MS (positive) M + H = 281* FAB MS (positive) M + H = 281
실시예 2 에틸 2,6-디클로로-5-플루오르니코티노일 아세테이트의 합성Example 2 Synthesis of Ethyl 2,6-dichloro-5-fluoronicotinoyl acetate
칼륨 에틸말로네이트 255 g (1.5 mol)과 염화리튬 64 g (1.5 mol)을 에틸아세테이트 5 L 에 현탁한 후 약 40℃ 에서 잘 저어주면서 트리메틸염화실란 174 g (1.6 mol)을 적가하였다. 균질한 현탁액이 얻어진 뒤 상온으로 냉각하고 2,6-디클로로-5-플루오르니코티노일 클로라이드 228 g (1 mol)을 적가하였다. 약 30분 후 1 N 염산 수용액 약 1 L 를 가하고 유기층을 분리하여 포화 탄산수소나트륨 용액으로 세척한 뒤 감압 농축하여 표제화합물을 깨끗하게 215 g (77% 수율) 얻었다.255 g (1.5 mol) of potassium ethylmalonate and 64 g (1.5 mol) of lithium chloride were suspended in 5 L of ethyl acetate, and then 174 g (1.6 mol) of trimethyl chloride was added dropwise while stirring well at about 40 ° C. After a homogeneous suspension was obtained, it was cooled to room temperature and 228 g (1 mol) of 2,6-dichloro-5-fluoronicotinoyl chloride was added dropwise. After about 30 minutes, about 1 L of 1 N aqueous hydrochloric acid solution was added, the organic layer was separated, washed with saturated sodium bicarbonate solution, and concentrated under reduced pressure to obtain 215 g (77% yield) of the title compound.
* 1-H NMR (CDCl3, δ, ppm): 1.264 (t, 7Hz, -OCH2CH3), 1.350 (t, 7Hz, -OCH2CH3), 4.096 (s, -COCH2COO-, 케토 폼), 4.205 (q, 7Hz, -OCH2CH3), 4.297 (q, 7Hz, -OCH2CH3), 5.836 (s, -C(OH)=CHCOO-, 엔올 폼), 7.841/7.837 (d×2, 7.5Hz, H-F coupling, Ar-H); 케토/엔올 비율 ∼ 1:1.5* 1-H NMR (CDCl3, δ, ppm): 1.264 (t, 7Hz, -OCH2CH3), 1.350 (t, 7Hz, -OCH2CH3), 4.096 (s, -COCH2COO-, ketoform), 4.205 (q, 7Hz , -OCH2CH3), 4.297 (q, 7Hz, -OCH2CH3), 5.836 (s, -C (OH) = CHCOO-, enol form), 7.841 / 7.837 (d × 2, 7.5Hz, HF coupling, Ar-H) ; Keto / enol ratio-1: 1.5
실시예 3 에틸 2,6-디클로로-5-플루오르니코티노일 아세테이트의 합성Example 3 Synthesis of Ethyl 2,6-dichloro-5-fluoronicotinoyl acetate
에틸아세테이트 100 mL에 2,6-디클로로-5-플루오르니코틴산 21 g (0.1 mol)을 녹인 후 카보닐디이미다졸 17.8 g (0.11 mol)을 넣고 상온에서 2시간 동안 교반하였다. 이렇게 얻어진 용액을, 염화리튬, 트리메틸염화실란, 칼륨 에틸말로네이트 각 0.05 mol이 에틸아세테이트 200 mL에 현탁되어 약 2시간 교반된 반응액에 49 mL의 트리에틸아민을 처리한 후 적가하고, 1시간 후 1 N 염산 수용액 약 50 mL 를 넣고 교반하였다. 유기층을 분리한 뒤 포화 탄산수소나트륨 용액으로 세척하고 용매를 감압 농축하여 표제화합물을 23 g 얻었다.After dissolving 21 g (0.1 mol) of 2,6-dichloro-5-fluoronicotinic acid in 100 mL of ethyl acetate, 17.8 g (0.11 mol) of carbonyldiimidazole were added thereto, followed by stirring at room temperature for 2 hours. To this solution, 0.05 mol of lithium chloride, trimethyl chloride and potassium ethyl malonate were each suspended in 200 mL of ethyl acetate, treated with 49 mL of triethylamine in a stirred solution for about 2 hours, and then added dropwise thereto. After 50 mL of 1 N aqueous hydrochloric acid solution was added and stirred. The organic layer was separated, washed with saturated sodium hydrogen carbonate solution, and the solvent was concentrated under reduced pressure to obtain 23 g of the title compound.
* 1-H NMR (CDCl3, δ, ppm): 1.264 (t, 7Hz, -OCH2CH3), 1.350 (t, 7Hz, -OCH2CH3), 4.096 (s, -COCH2COO-, 케토 폼), 4.205 (q, 7Hz, -OCH2CH3), 4.297 (q, 7Hz, -OCH2CH3), 5.836 (s, -C(OH)=CHCOO-, 엔올 폼), 7.841/7.837 (d×2, 7.5Hz, H-F coupling, Ar-H); 케토/엔올 비율 ∼ 1:1.5* 1-H NMR (CDCl3, δ, ppm): 1.264 (t, 7Hz, -OCH2CH3), 1.350 (t, 7Hz, -OCH2CH3), 4.096 (s, -COCH2COO-, ketoform), 4.205 (q, 7Hz , -OCH2CH3), 4.297 (q, 7Hz, -OCH2CH3), 5.836 (s, -C (OH) = CHCOO-, enol form), 7.841 / 7.837 (d × 2, 7.5Hz, HF coupling, Ar-H) ; Keto / enol ratio-1: 1.5
실시예 4 에틸 2-(2,3,4,5,6-펜타플루오르벤조일)-아세테이트의 합성Example 4 Synthesis of Ethyl 2- (2,3,4,5,6-pentafluorobenzoyl) -acetate
실시예 1과 동일한 방법으로 말론산 모노 에틸 에스테르 칼륨염 (340 g, 2 mol), 무수 염화리튬 (85 g, 2 mol), 트리메틸클로로실란 (225 g, 2.07 mol)을 테트라히드로퓨란 3.5 L 에 섞고 트리에틸아민 (425 g, 4.2 mol)을 처리한 후 2,3,4,5,6-펜타플루오르벤조일 클로라이드 (220 g, 1 mol)를 첨가하고 5분 후 3 N HCl 수용액으로 pH∼3을 맞추었다. 이를 에틸 아세테이트 4L를 넣고 추출하여 층 분리한 다음 유기층을 포화 탄산수소 나트륨 수용액으로 세척하고 감압 농축하여 표제 화합물을 연노란색 오일로 256 g 얻었다 (수율 91%).In the same manner as in Example 1, malonic acid mono ethyl ester potassium salt (340 g, 2 mol), anhydrous lithium chloride (85 g, 2 mol), trimethylchlorosilane (225 g, 2.07 mol) were added to 3.5 L of tetrahydrofuran. After mixing and treating triethylamine (425 g, 4.2 mol), 2,3,4,5,6-pentafluorobenzoyl chloride (220 g, 1 mol) was added and after 5 minutes pH-3 with an aqueous 3 N HCl solution Matched. It was extracted with 4 L of ethyl acetate, and the layers were separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and concentrated under reduced pressure to give 256 g of the title compound as a pale yellow oil (yield 91%).
* 1-H NMR (CDCl3, δ, ppm): 1.0-1.2 (3H, 2t, -OCH2CH3), 3.7 (2H, s, -COCH2COO-), 4.0-4.2 (2H, 2q, -OCH2CH3), 5.25 (1H, s, -C(OH)=CHCOO-), 12.2 (-C(OH)=CH-); 케토/엔올 비율 ∼ 1:1* 1-H NMR (CDCl 3, δ, ppm): 1.0-1.2 (3H, 2t, -OCH 2 CH 3), 3.7 (2H, s, -COCH 2 COO-), 4.0-4.2 (2H, 2q, -OCH 2 CH 3), 5.25 ( 1H, s, -C (OH) = CHCOO-), 12.2 (-C (OH) = CH-); Keto / enol ratio to 1: 1
* FAB MS (positive) M + H = 283* FAB MS (positive) M + H = 283
실시예 5∼9Examples 5-9
기타 본 발명을 이용하여 합성된 화합물은 다음 표 1과 같다.Other compounds synthesized using the present invention are shown in Table 1 below.
[표 1]TABLE 1
[발명의효과][Effects of the Invention]
본 발명의 화학식 1의 화합물의 제조방법은, 할로겐화리튬을 사용하여 말론산모노에스테르 칼륨염을 용매에 균일하게 용해시킴으로써 다음 반응이 쉽고 빠르게 일어날 수 있게 하여 제조공정을 간단히 하였으며, 전 과정이 한 반응기에서 일어남으로써 조작이 용이하고, 목적 화합물이 고순도, 고수율로 얻어진다.In the method of preparing the compound of Formula 1 of the present invention, by using lithium halide uniformly dissolving the monoester potassium salt in a solvent, the following reaction can be easily and quickly occur, simplifying the manufacturing process, the whole process is one reactor It is easy to operate by rising at the, and a target compound is obtained with high purity and high yield.
더욱이 위험한 시약 및 원료를 이용하지 않으며 반응조건이 가혹하지 않고, 전 과정이 매우 빠르게 진행되므로 반응기의 회전율 또한 높다.In addition, the reactor is not rotated because of the use of dangerous reagents and raw materials, the reaction conditions are not severe, and the whole process proceeds very fast.
Claims (8)
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| KR1019960066428A KR100372563B1 (en) | 1996-12-16 | 1996-12-16 | Method for manufacturing beta-ketoester derivative as intermediate of quinolone based antibiotics |
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| KR1019960066428A KR100372563B1 (en) | 1996-12-16 | 1996-12-16 | Method for manufacturing beta-ketoester derivative as intermediate of quinolone based antibiotics |
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| US6987199B2 (en) | 2001-10-15 | 2006-01-17 | Lg Life Sciences Ltd. | Process for preparing beta-ketoester compound |
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| JPS62246541A (en) * | 1986-01-20 | 1987-10-27 | Kyorin Pharmaceut Co Ltd | Benzoylacetic acid ester derivative and production thereof |
| EP0449445A3 (en) * | 1990-03-27 | 1993-08-25 | Pfizer Inc. | Preparation of beta-ketoesters useful in preparing quinolone antibiotics |
| JP3542165B2 (en) * | 1994-05-19 | 2004-07-14 | 富山化学工業株式会社 | Novel quinolone carboxylic acid derivative or salt thereof |
| US5493025A (en) * | 1994-07-27 | 1996-02-20 | Rohm And Haas Company | Process for preparation of fluorinated beta-keto ester |
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| US6987199B2 (en) | 2001-10-15 | 2006-01-17 | Lg Life Sciences Ltd. | Process for preparing beta-ketoester compound |
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