KR101086177B1 - Process for Preparing --9-Fluoro-2,3-Dihydro-3S-Methyl-10-4-Methyl-1- Piperazinyl-7-Oxo-7H-Pyrido[1,2,3-de]-1,4-Benzoxazine-6-Carboxylic Acid as an Antibacterial Agent - Google Patents
Process for Preparing --9-Fluoro-2,3-Dihydro-3S-Methyl-10-4-Methyl-1- Piperazinyl-7-Oxo-7H-Pyrido[1,2,3-de]-1,4-Benzoxazine-6-Carboxylic Acid as an Antibacterial Agent Download PDFInfo
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- KR101086177B1 KR101086177B1 KR1020040045914A KR20040045914A KR101086177B1 KR 101086177 B1 KR101086177 B1 KR 101086177B1 KR 1020040045914 A KR1020040045914 A KR 1020040045914A KR 20040045914 A KR20040045914 A KR 20040045914A KR 101086177 B1 KR101086177 B1 KR 101086177B1
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- 0 *c(c(F)c1O)cc(F)c1F Chemical compound *c(c(F)c1O)cc(F)c1F 0.000 description 5
- PVOAHINGSUIXLS-UHFFFAOYSA-N CN1CCNCC1 Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- YYAFUGSJSHXYNK-UHFFFAOYSA-N OC(c(c(F)c1O)cc(F)c1F)=O Chemical compound OC(c(c(F)c1O)cc(F)c1F)=O YYAFUGSJSHXYNK-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
본 발명은 항균제로 유용한 하기 화학식1인 광학활성 카르복실산(레보플록사신)의 새로운 제조방법에 관한 것으로,The present invention relates to a novel method for preparing an optically active carboxylic acid (levofloxacin) of Formula 1 useful as an antibacterial agent,
더욱 상세하게는, 본 발명은 하기 화학식2 (3-히드록시-2,4,5-트리플루오르 벤조산)를 시발물질로 사용하여 하기 화학식1인 (-)-9-플루오르-2,3-디히드로-3(S)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7H-피리도[1,2,3-데]-1,4-벤즈옥사진-6-카르복실산 (레보플록사신, Levofloxacin)을 간단한 정제과정과 선택적인 반응을 통하여 높은 수율과 생산단가를 낮출수 있는 특징이 있는 레보플록사신의 제조방법에 관한 것이다.More specifically, the present invention uses the following formula 2 (3-hydroxy-2,4,5-trifluoro benzoic acid) as a starting material (-)-9-fluor-2,3-di Hydro-3 (S) -methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-dec] -1,4-benzoxazine-6 The present invention relates to a method for preparing levofloxacin, which is characterized by a high yield and a low production cost through simple purification and selective reaction of carboxylic acid (levofloxacin).
[화학식1][Formula 1]
[화학식2](2)
퀴놀론 카르복실산, 레보플록사신, L-알라니놀Quinolone Carboxylic Acid, Levofloxacin, L-Alaninol
Description
본 발명은 항균제로 유용한 하기 화학식1인 광학활성 카르복실산(레보플록사신)의 새로운 제조방법에 관한 것이다. 더욱 상세하게는 항균제인 광학활성 카르복실산(레보플록사신)의 제조에 있어서, 하기 화학식2의 화합물을 시발물질로 하여 1-메틸피페라진을 4번위치의 플루오르와 선택적인 반응을 하여 하기화학식3의 화합물을 합성하는 단계; L-알라닌을 금속환원제를 이용하여 L-알라니놀을 제조한후 하기 화학식5의 화합물을 합성하는 단계; 및 포타슘플루오라이드와 1,3-디사이클로헥실카르보디이미드 및 디에틸아조디카르복실에이트를 사용하여 고리화 반응을 하여 화학식7의 화합물을 합성하는 단계;를 포함하여 하기 화학식1(레보플록사신)의 화합물을 제조하는 것을 특징으로 하는 항균제인 레보플록사신의 제조방법을 제공함으로써 간단한 정제 과정과 선택적인 반응을 통하여 하기 화학식1(레보플록사신)을 높은 수율과 낮은 생산단가로 대량합성 할수 있는 레보플록사신의 제조방법에 관한 것이다.The present invention relates to a novel process for preparing an optically active carboxylic acid (levofloxacin) of formula 1 useful as an antimicrobial agent. More specifically, in the preparation of optically active carboxylic acid (levofloxacin) as an antimicrobial agent, 1-methylpiperazine is selectively reacted with fluorine at position 4 by using the compound represented by the following Chemical Formula 2 as a starting material. Synthesizing the compound; Preparing L-alanineol using a metal reducing agent for L-alanine, and then synthesizing the compound of Formula 5; And a cyclization reaction using potassium fluoride, 1,3-dicyclohexylcarbodiimide, and diethylazodicarboxylate to synthesize a compound of Chemical Formula 7, including the following Formula 1 (levofloxacin) By providing a method for the preparation of levofloxacin, an antimicrobial agent characterized in that the preparation of a compound, a method for preparing levofloxacin that can synthesize the following general formula (levofloxacin) in high yield and low production cost through a simple purification process and selective reaction will be.
[화학식1][Formula 1]
[화학식2](2)
[화학식3][Formula 3]
[화학식5][Formula 5]
[화학식7][Formula 7]
특히, 본 발명은 화학식2의 화합물을 시발물질로 사용하여 광학활성 카르복실산의 중간체, 유도체 및 레보플록사신의 제조에 관한 모든공정을 포함한다. In particular, the present invention encompasses all processes relating to the preparation of intermediates, derivatives and levofloxacin of optically active carboxylic acids using the compound of formula 2 as a starting material.
광학활성 퀴놀론카르복실산(레보플록사신)은 항균제로 유용한 약물이다. 특히, 화학식1의 화합물 8번위치에 1-메틸 피페라진을 도입하는 방법에는 여러 가지의 공개된 방법이 있으며 아래에 열거한 4가지의 방법이 대표적이라 하겠다. Optically active quinolonecarboxylic acid (levofloxacin) is a useful drug as an antibacterial agent. In particular, there are a number of published methods for introducing 1-methyl piperazine at compound 8 in Formula 1, and the four methods listed below are representative.
먼저, 하기 반응식1과 같이 2,3,4,5- 테트라플루오르 벤조산에 1-메틸피페라진을 도입하는 방법이 있으며, 이 방법의 일예가 대한민국 특허공개번호 제 2001-18721호에 기술되어 있다. First, there is a method of introducing 1-methylpiperazine into 2,3,4,5-tetrafluorobenzoic acid as in Scheme 1 below, an example of which is described in Korean Patent Publication No. 2001-18721.
또한, 하기 반응식2와 같이 2,3,4,5-테트라플루오르벤조일 아세테이트에 1-메틸피페라진을 반응시켜 제조하는 방법이 일본 특허 공개 소62-215, 591호에 기재되어 있다. In addition, a method of preparing by reacting 2,3,4,5-tetrafluorobenzoyl acetate with 1-methylpiperazine as in Scheme 2 is described in Japanese Patent Laid-Open No. 62-215, 591.
그러나, 위의 2가지 방법 모두 2번과 4번 위치의 플루오르와 1-메틸 피페라진이 경쟁적으로 반응하여 2번위치와 반응한 부가 반응 생성물이 많이 생성 (2번 위치 및 4번 위치의 생성율이 2:8)되며, 별도의 분리과정(실리카겔을 이용한 컬럼크로마토그래피)이 필요하므로 장시간의 정제 및 낮은 수율등의 문제점이 있다. However, in both of the above methods, fluorine and 1-methyl piperazine in positions 2 and 4 reacted competitively to generate a lot of additional reaction products reacted with position 2 (the production rate of positions 2 and 4 2: 8), and a separate separation process (column chromatography using silica gel) is required, which causes problems such as long-term purification and low yield.
[반응식1][Scheme 1]
[반응식2][Scheme 2]
또 다른 방법으로는 대한민국 특허공고번호 제1994-3757호에 기재된 하기 반응식3과 같이 광학분리된 벤즈옥사진에 고리화 반응을 한후 1-메틸 피페라진을 도입하는 방법이 있다. 그러나, 이 방법은 보론트리플루오라이드 디에틸에스테르와 같은 위험하고 강한독성의 물질을 사용해야 하며, 사용 용매로 끓는점과 점도가 높은 디메틸술폭사이드를 사용함으로써 잔류용매 제거가 곤란한 단점이 있다. Another method is to introduce a 1-methyl piperazine after the cyclization reaction to the benzoxazine optically separated as shown in Scheme 3 in the Republic of Korea Patent Publication No. 1994-757. However, this method has to use dangerous and strong toxic substances such as boron trifluoride diethyl ester, and it is difficult to remove residual solvent by using dimethyl sulfoxide having a high boiling point and high viscosity as a solvent used.
[반응식3]Scheme 3
또, 대한민국 특허공개번호 제2000-0056672호에 기재된 방법은 하기 반응식4와 같이 2,3,4,5-테트라플루오르벤조니트릴을 출발물질로 하여 1-메틸 피페라진을 도입하는 방법이다. 그러나, 이 방법은 위에서 설명한 반응식 1 및 2에 비해, 2번과 4번위치의 경쟁반응이 적어서 4번위치와 반응한 목적생성물의 수율을 향상시키는 장점은 있으나, 출발물질인 2,3,4,5-테트라플루오르벤조니트릴이 매우 고가의 시약(Aldrich 사 33,719-6)이므로 전체적인 생산단가의 상승을 유발시키는 단점이 있다. In addition, the method described in Korean Patent Publication No. 2000-0056672 is a method of introducing 1-methyl piperazine using 2,3,4,5-tetrafluorobenzonitrile as a starting material as in Scheme 4 below. However, this method has the advantage of improving the yield of the target product reacted with the position 4 and the position 2 and 4 compared to the reaction scheme 1 and 2 described above, but the starting material 2,3,4 Since, 5-tetrafluorobenzonitrile is a very expensive reagent (33,719-6, manufactured by Aldrich), there is a disadvantage that causes an increase in the overall production cost.
[반응식4][Scheme 4]
또한, 레보플록사신의 가장 핵심적인 중간체인 S-(-)광학활성벤즈옥사진 유도체을 만드는 과정에서 이미 공개된 대부분의 제조 방법에서는 고가의 L-알라니놀을 사용하여 제조단가의 상승을 유발시키는 단점을 갖고 있다.In addition, most of the manufacturing methods already disclosed in the process of making S-(-) optically active benzoxazine derivatives, which are the most important intermediates of levofloxacin, have the disadvantage of causing an increase in manufacturing cost using expensive L-alaninol. Have
따라서 상기에서 알수 있듯이, 기존의 방법으로서 레보플록사신을 제조하는 방법에는 고가의 시약, 낮은 수율, 실리카겔을 이용한 컬럼크로마토그래피의 장시간의 정제공정 및 높은 생산단가 등의 문제점이 있어왔다.Therefore, as can be seen from the above, the conventional method for preparing levofloxacin has problems such as expensive reagent, low yield, long time purification process of column chromatography using silica gel and high production cost.
이에 본 발명은 앞서 설명한 바와 같은 종래기술의 문제점을 더욱 효율적으로 해결하기 위하여 제공된 것으로써, 분 발명의 목적은 하기 화학식2(3-히드록시-2,4,5-트리플루오르 벤조산)를 시발물질로 사용하여 하기 화학식1인 (-)-9-플루오르-2,3-디히드로-3(S)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7H-피리도[1,2,3-데]-1,4-벤즈옥사진-6-카르복실산 (레보플록사신, Levofloxacin)을 간단한 정제과정과 선택적인 반응을 통하여 높은 수율과 생산단가를 낮출수 있는 특징이 있는 레보플록사신의 제조방법을 제공하는 것이다. Accordingly, the present invention is provided to solve the problems of the prior art as described above more efficiently, and the purpose of the invention is to formulate the following formula 2 (3-hydroxy-2,4,5-trifluoro benzoic acid) (-)-9-Fluoro-2,3-dihydro-3 (S) -methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyridine Figure 1,2,3-de] -1,4-benzoxazine-6-carboxylic acid (levofloxacin, Levofloxacin) is characterized by high yield and low production cost through simple purification and selective reaction. It is to provide a method for producing levofloxacin.
[화학식1][Formula 1]
[화학식2](2)
상기한 목적을 달성하기 위하여, 본 발명에 따른 항균제인 레보플록사신의 제조 방법은 하기 화학식2의 화합물을 시발물질로 하여 1-메틸피페라진을 4번위치의 플루오르와 선택적인 반응을 하여 하기화학식3의 화합물을 합성하는 단계; L-알라닌을 금속환원제를 이용하여 L-알라니놀을 제조한후 하기 화학식5의 화합물을 합성하는 단계; 및 포타슘플루오라이드와 1,3-디사이클로헥실카르보디이미드 및 디에틸아조디카르복실에이트를 사용하여 고리화 반응을 하여 화학식7의 화합물을 합성하는 단계;를 포함하여 하기 화학식1(레보플록사신)의 화합물을 제조할 수 있다.In order to achieve the above object, a method for preparing levofloxacin, an antimicrobial agent according to the present invention, by using the compound of the formula (2) as a starting material to selectively react 1-methylpiperazine with fluorine at position 4 Synthesizing the compound; Preparing L-alanineol using a metal reducing agent for L-alanine, and then synthesizing the compound of Formula 5; And a cyclization reaction using potassium fluoride, 1,3-dicyclohexylcarbodiimide, and diethylazodicarboxylate to synthesize a compound of Chemical Formula 7, including the following Formula 1 (levofloxacin) Compounds can be prepared.
[화학식1][Formula 1]
[화학식2](2)
[화학식3][Formula 3]
[화학식5][Formula 5]
[화학식7][Formula 7]
상기 화학식3의 화합물을 합성하는 단계가 트리에틸아민 및 피리딘으로 이루어지는 군으로부터 선택되는 강염기 1.1 내지 1.5당량의 존재하에 상기 화학식2의 화합물인 3-히드록시-2,4,5-트리플루오르 벤조산과 화학식2의 화합물 1.0당량에 대하여 1.1 내지 1.5당량의 1-메틸피페라진을 12시간 환류교반시키는 단계; 상기 강염기를 감압증류하여 제거하는 단계; 및 비수성 용매인 클로로포름, 디클로로메탄 및 에틸아세데이트로 이루어지는 군으로부터 선택되는 용매로 추출하는 단계;를 포 함하여 상기화학식 3의 화합물을 생성하는 단계일 수 있다.Synthesizing the compound of Formula 3 is 3-hydroxy-2,4,5-trifluoro benzoic acid as the compound of Formula 2 in the presence of 1.1 to 1.5 equivalents of a strong base selected from the group consisting of triethylamine and pyridine; 12 hours of reflux stirring of 1.1-1.5 equivalents of 1-methylpiperazine based on 1.0 equivalent of the compound of Formula 2; Removing the strong base by distillation under reduced pressure; And extracting with a solvent selected from the group consisting of chloroform, dichloromethane, and ethyl acetate, which are non-aqueous solvents.
상기 화학식5의 화합물을 합성하는 단계가 벤젠 및 톨루엔으로 이루어지는 군으로부터 선택되는 유기용매중에서 상기 화학식4의 화합물과 화학식4의 화합물의 1.0당량에 대하여 1.5 내지 3당량의 트리메틸오르소포메이트을 18시간동안 환류교반하는 단계; 벤젠 또는 톨루엔의 유기용매를 감압증류하여 제거하는 단계; 에탄올, 메탄올, 이소프로판올로 이루어지는 군으로부터 선택되어진 유기용매에 생성된 중간체와 L-알라닌을 환원시켜 만든 L-알라니놀 1.1 내지 2당량을 상온에서 3시간 교반 시키는 단계; 및 용매를 감압증류하여 제거하는 단계;를 포함하여 상기 화학식5의 화합물을 수득하는 단계일 수 있다.Synthesizing the compound of Formula 5 is refluxed for 1.5 hours to 3 equivalents of trimethyl orthoformate for 18 hours with respect to 1.0 equivalent of the compound of Formula 4 and the compound of Formula 4 in an organic solvent selected from the group consisting of benzene and toluene. Stirring; Removing the organic solvent of benzene or toluene by distillation under reduced pressure; Stirring 1.1 to 2 equivalents of L-alaninol produced by reducing the intermediate and L-alanine produced in the organic solvent selected from the group consisting of ethanol, methanol and isopropanol at room temperature for 3 hours; And distilling off the solvent under reduced pressure. It may be a step of obtaining the compound of Chemical Formula 5, including.
상기 화학식 7의 화합물을 합성하는 단계가 N,N`-디메틸포름아미드 및 디메틸설폭사이드로 이루어지는 군으로부터 선택되는 비극성 용매중에서 상기 화학식5의 화합물과 화학식5의 화합물 1.0당량에 대하여 1.5 내지 3당량의 포타슘플루라이드와 1.0 내지 1.5당량의 DCC(1,3-디사이클로헥실카르보디이미드) 및 1.0 내지 1.5당량의 DEAD(디에틸아조디카르복실레이트)를 적가하고 5시간 환류교반시키는 단계; 및 물을 넣고 결정화 하는 단계;를 포함하여 상기 화학식7의 화합물을 수득하는 단계일 수 있다.
Synthesizing the compound of Formula 7 is 1.5 to 3 equivalents based on 1.0 equivalent of the compound of Formula 5 and the compound of Formula 5 in a nonpolar solvent selected from the group consisting of N, N`-dimethylformamide and dimethyl sulfoxide. Adding potassium fluoride and 1.0-1.5 equivalents of DCC (1,3-dicyclohexylcarbodiimide) and 1.0-1.5 equivalents of DEAD (diethylazodicarboxylate) dropwise and refluxing for 5 hours; And it may be a step of obtaining a compound of Chemical Formula 7, including the step of adding water and crystallization.
이하, 본 발명에 대하여 상세히 설명하면 다음과 같다. Hereinafter, the present invention will be described in detail.
본 발명에 따른 레보플록사신의 제조는 하기 화학식2의 화합물을 시발물질로 하여 몇가지의 간단한 공정을 거쳐서 하기 반응공정과 같이 하기 화학식1의 화합물 을 제조할 수 있다.
In the preparation of levofloxacin according to the present invention, the compound of formula 1 may be prepared in the same manner as in the following reaction process through several simple steps using the compound of formula 2 as a starting material.
하기 반응식5와 같이 화학식2의 화합물인 3번위치에 히드록시가 도입된 3-히드록시-2,4,5-트리플루오르 벤조산을 시발물질로 사용함으로써 1-메틸 피페라진이 2번위치의 플루오르와 반응하여 생성되는 부가생성물을 줄여주고, 4번위치의 플루오르와 반응한 목적화합물의 생성을 높여주어 높은 수율을 얻을수 있으며 특히, 실 리카겔을 이용한 컬럼크로마토그래피와 같은 장시간을 필요로하는 별도의 분리과정이 필요하지 않아서 전체적인 생산공정의 감소와 생산단가를 낮출수 있는 장점이 있다. By using 3-hydroxy-2,4,5-trifluorobenzoic acid having hydroxy introduced at position 3 as the compound of Formula 2 as a starting material, as shown in Scheme 5, 1-methyl piperazine was substituted with fluorine at position 2 It can reduce the adducts produced by the reaction with and increase the production of the target compound reacted with the fluorine at position 4 to obtain a high yield. In particular, it requires a separate, which requires a long time such as column chromatography using silica gel Since no separation process is required, there is an advantage of reducing the overall production process and lowering the production cost.
[반응식5][Scheme 5]
이때, 사용되는 1-메틸피페라진의 당량은 화학식2에 대하여 1.1 내지 1.5이며 바람직하게는 1.2 내지 1.3이다. At this time, the equivalent of 1-methylpiperazine used is 1.1 to 1.5 with respect to Formula 2, preferably 1.2 to 1.3.
또한, 피리딘 또는 트리에틸아민과 같은 염기를 사용함으로써 반응이 어렵지 않고 반응시간도 약10~12시간으로 기존의 반응보다 짧은 장점이 있다. In addition, by using a base such as pyridine or triethylamine, the reaction is not difficult and the reaction time is about 10 to 12 hours, which is shorter than the conventional reaction.
이때, 사용되는 염기의 당량은 화학식2에 대하여 1.1 내지 1.5이며 바람직하게는 1.2 내지 1.3이다. At this time, the equivalent of the base used is 1.1 to 1.5 with respect to Formula 2 and preferably 1.2 to 1.3.
[반응식6]Scheme 6
레보플록사신에 사용되는 핵심적인 시약인 L-알라니놀은 매우 고가의 시약이지만, 상기 반응식 6을 통하여 간단하고 저렴하게 고수율로 합성이 가능하다. L-alaninol, which is a key reagent used for levofloxacin, is a very expensive reagent, but can be synthesized at high yield simply and inexpensively through Scheme 6.
레보플록사신의 핵심 중간체인 광학활성을 갖는 화학식5의 화합물을 만드는 과정에서 사용되는 L-알라니놀은 L-알라닌을 금속환원제를 이용하여 간단하고 빠르 게 합성할수 있으며 이때 사용되는 금속환원제는 리튬알루미늄하이드라이드 및 소디움보로하이드라이드로 이루어진 군으로 부터 선택되며, 반응 당량비는 L-알라닌에 대하여 1.1 내지 3이 바람직하고 더욱 바람직하게는 1.5내지 2이다. L-alaninol, which is used in the preparation of the compound of formula 5 having optical activity, which is a key intermediate of levofloxacin, can be synthesized quickly and easily by using a metal reducing agent. It is selected from the group consisting of a lide and sodium borohydride, the reaction equivalent ratio is preferably 1.1 to 3 with respect to L-alanine, more preferably 1.5 to 2.
이때 생성되는 L-알라니놀의 수율은 85 내지 90%이고 반응용매로는 비극성용매가 사용되며 바람직하게는 데트라하이드로퓨란이다. At this time, the yield of L- alaninol produced is 85 to 90% and a non-polar solvent is used as the reaction solvent, preferably detrahydrofuran.
또한, 이때 생성된 L-알라니놀은 하기 반응식7과 같이 화학식4와 반응하며 고수율로 화학식5를 합성할 수 있으며, 또한 저가의 L-알라닌을 환원하여 만든 L-알라니놀을 반응에 사용함으로써 전체적이 생산단가를 낮출수 있는 장점이 있다. In addition, the produced L- alaninol reacts with the formula (4) as shown in Scheme 7 and can be synthesized in a high yield in the formula (5), L- alaninol made by reducing the low-cost L- alanine to the reaction By using it, there is an advantage of lowering the overall production cost.
이때, 사용되는 트리메틸오르소포메이트의 당량비는 화학식4의 화합물에 대하여 1,5 내지 3이며 바람직하게는 1.5 내지 2이다. 또한 사용되는 용매는 벤젠 및 톨루엔으로 이루어진 군으로 부터 선택된다.At this time, the equivalence ratio of trimethyl orthoformate used is 1,5 to 3, preferably 1.5 to 2 with respect to the compound of the formula (4). The solvent used is also selected from the group consisting of benzene and toluene.
L-알라니놀의 당량비는 화학식4의 화합물에 대하여 1.1 내지 2이며 바람직하게는 1.1 내지 1.5이다. 이때 사용되는 용매는 에탄올, 메탄올 및 이소프로판올로 이루어지는 군으로부터 선택된다.The equivalent ratio of L-alaninol is 1.1 to 2 with respect to the compound of formula 4, preferably 1.1 to 1.5. The solvent used at this time is selected from the group consisting of ethanol, methanol and isopropanol.
[반응식7]Scheme 7
[반응식8]Scheme 8
상기 반응식8과 같이 중간체인 화학식5의 화합물을 포타슘 플루라이드를 N.N`-디메틸포름아미드 또는 디메틸 설폭사이드 용매하에 2 내지 3시간 환류반응시킨후 DCC(1,3-디사이클로헥실카르보디이미드)와 DEAD(디에틸아조디카르복실레이트)를 서서히 적가한후 3 내지 5시간 환류반응하여 레보플록사신의 가장 중요한 중간체인 고리화반응(화학식7)을 합성할 수 있다. The compound of formula 5, which is an intermediate as in Scheme 8, was refluxed with potassium fluoride in a solvent of NN`-dimethylformamide or dimethyl sulfoxide for 2 to 3 hours, followed by DCC (1,3-dicyclohexylcarbodiimide). DEAD (diethyl azodicarboxylate) is slowly added dropwise and refluxed for 3 to 5 hours to synthesize a cyclization reaction (Formula 7), which is the most important intermediate of levofloxacin.
이때 사용되는 포타슘플루라이드의 당량비는 화합물5에 대하여 1,5 내지 3이며 바람직하게는 2 내지 2.5이다. 또, DCC의 당량비는 화학식5에 대하여 1 내지 1.5이며 바람직하게는 1 내지 1.2이며, DEAD의 당량비는 화학식5에 대하여 1 내지 1.5이며 바람직하게는 1 내지 1.2이다.The equivalent ratio of potassium fluoride used at this time is 1,5 to 3 with respect to compound 5, preferably 2 to 2.5. In addition, the equivalent ratio of DCC is 1 to 1.5 with respect to the formula (5), preferably 1 to 1.2, the equivalent ratio of DEAD is 1 to 1.5 with respect to the formula (5), preferably 1 to 1.2.
이하 본 발명은 하기 실시예에 의해 상세히 설명한다. 단 하기 실시예는 본발명을 예시하는 것일뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.
Hereinafter, the present invention will be described in detail by the following examples. However, the following examples are merely to illustrate the present invention, the content of the present invention is not limited to the following examples.
[실시예1]Example 1
2,5-디플루오르-3-히드록시-4-(4-메틸-1-피페라지닐)벤조산의 제조Preparation of 2,5-difluoro-3-hydroxy-4- (4-methyl-1-piperazinyl) benzoic acid
3-히드록시-2,4,5-트리플루오르 벤조산 100g(0.52㏖)을 피리딘 50.5ml(0.63 ㏖)에 녹인후, 1-메틸피페라진 62.6g(0.63㏖)을 적가하고 12시간동안 환류하였다. 반응이 종결된후 피리딘을 감압증류하여 제거하고 디클로로메탄 2ℓ로 추출하고 물1.5ℓ로 세척하였다. 무수황산마그네슘으로 건조후 여과하고 용매를 감압농축하여 목적생성물 116 g(82%)을 수득하였다. 100 g (0.52 mol) of 3-hydroxy-2,4,5-trifluorobenzoic acid was dissolved in 50.5 ml (0.63 mol) of pyridine, and then 62.6 g (0.63 mol) of 1-methylpiperazine was added dropwise and refluxed for 12 hours. . After the reaction was terminated, pyridine was removed by distillation under reduced pressure, extracted with 2 L of dichloromethane and washed with 1.5 L of water. After drying over anhydrous magnesium sulfate and filtering, the solvent was concentrated under reduced pressure to give 116 g (82%) of the desired product.
1HNMR(CDCl3, ppm):2.33(3H,s), 2.43~2.55(4H,t), 3.31~3.41(4H,t), 6.93~7.01 (1H,m)
1 HNMR (CDCl 3 , ppm): 2.33 (3H, s), 2.43 ~ 2.55 (4H, t), 3.31 ~ 3.41 (4H, t), 6.93 ~ 7.01 (1H, m)
[실시예2]Example 2
에틸2-[2,5-디플루오르-3-히드록시-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트의 제조Ethyl 2- [2,5-difluoro-3-hydroxy-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy-2-ylamino) acrylic Manufacture of Rate
2,5-디플루오르-3-히드록시-4-(4-메틸-1-피페라지닐)벤조일 아세테이트 100g(0.29㏖)과 트리에틸오르소 포메이트 97.2ml(0.58㏖)을 600ml의 톨루엔에 녹인 용액을 18시간동안 환류반응한후 톨루엔을 감압증류하여 제거시키고 600ml의 에탄올에 다시녹였다. 100 g (0.29 mol) of 2,5-difluoro-3-hydroxy-4- (4-methyl-1-piperazinyl) benzoyl acetate and 97.2 ml (0.58 mol) of triethylortho formate were added to 600 ml of toluene. The dissolved solution was refluxed for 18 hours, and then toluene was removed by distillation under reduced pressure, and re-dissolved in 600 ml of ethanol.
여기에 (S)-(+)-2-아미노-1-프로판올 32.7g(0.44㏖)을 서서히 적가한후 상온에서 3시간 교반하였다. 완결이 종결된 후, 감압증류하여 에탄올을 제거시켜 목적생성물 116.1g(93%)을 수득하였다. 32.7 g (0.44 mol) of (S)-(+)-2-amino-1-propanol was slowly added dropwise thereto, followed by stirring at room temperature for 3 hours. After completion of the distillation under reduced pressure, ethanol was removed to give 116.1 g (93%) of the desired product.
1HNMR(CDCl3, ppm): 1.13(3H,t), 1.37(3H,d), 2.37(3H,s), 2.43~2.51(4H,m), 3.23 ~3.47(4H,m), 3.50~3.69(3H,m) 4.01~4.09(2H,q), 6.80~ 6.91(1H,m), 8.18(1H,d)
1 HNMR (CDCl 3 , ppm): 1.13 (3H, t), 1.37 (3H, d), 2.37 (3H, s), 2.43-2.51 (4H, m), 3.23-3.47 (4H, m), 3.50- 3.69 (3H, m) 4.01 ~ 4.09 (2H, q), 6.80 ~ 6.91 (1H, m), 8.18 (1H, d)
[실시예3]Example 3
에틸 9-플루오르-2,3-디히드로-3(S)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7H-피리도[1,2,3-데]-1,4-벤즈옥사진-6-카르복실레이트의 제조Ethyl 9-Fluoro-2,3-dihydro-3 (S) -methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-dec] Preparation of -1,4-benzoxazine-6-carboxylate
에틸 2-[2,5-디프루오르-3-히드록시-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트 100g(0.23㏖)을 N,N`-디메틸포름아미드 500ml에 녹인후 포타슘플루라이드 34g(0.59㏖)를 넣고 3시간 환류반응하였다.Ethyl 2- [2,5-difluoro-3-hydroxy-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy-2-ylamino) 100 g (0.23 mol) of acrylate was dissolved in 500 ml of N, N'-dimethylformamide, and 34 g (0.59 mol) of potassium fluoride was added thereto, followed by reflux reaction for 3 hours.
상기 반응물에 DCC 57g(0.28㏖)과 DEAD 48.8g(0.28㏖)을 천천히 적가한후 5시간 환류반응 시킨후 물 1.5ℓ를 가하여 결정화하고 여과 , 건조하여 목적 생성물 70.2g(77%)을 수득하였다. DCC 57g (0.28mol) and DEAD 48.8g (0.28mol) were slowly added dropwise to the reaction product, and the mixture was refluxed for 5 hours, and then 1.5L of water was added for crystallization, filtration and drying to obtain 70.2g (77%) of the desired product. .
1HNMR(CDCl3, ppm):1.41(3H,t), 1.57(3H,d), 2.35(3H,s), 2.51~2.60(4H,m), 1 HNMR (CDCl 3 , ppm): 1.41 (3H, t), 1.57 (3H, d), 2.35 (3H, s), 2.51-2.60 (4H, m),
3.37~3.43(4H,m), 4.31~4.47(3H,m), 7.69(1H,d), 8.51(1H,s)
3.37 ~ 3.43 (4H, m), 4.31 ~ 4.47 (3H, m), 7.69 (1H, d), 8.51 (1H, s)
[실시예4]Example 4
(-)-9-플루오르-2,3-디히드로-3(S)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7H-피리도[1,2,3-데]-1,4-벤즈옥사진-6-카르복실산의 제조(-)-9-Fluoro-2,3-dihydro-3 (S) -methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3 -De] -1,4-benzoxazine-6-carboxylic acid
에틸 9-플루오르-2,3-디히드로-3(S)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7H-피리도[1,2,3-데]-1,4-벤즈옥사진-6-카르복실레이트 100g(0.26㏖)을 초산과 물 과 황산(8:6:1)의 혼합용액 1ℓ 넣고 2~3시간 환류교반시켰다. 반응 종결후 상온으로 냉각시키면 결정을 생성시킨후. 생성된 결정을 여과하고 물로 세척한후 건조하여 목적생성물 88.2g(95%)을 수득하였다.Ethyl 9-Fluoro-2,3-dihydro-3 (S) -methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-dec] 100 g (0.26 mol) of -1,4-benzoxazine-6-carboxylate was added to 1 L of a mixed solution of acetic acid, water, and sulfuric acid (8: 6: 1), followed by stirring under reflux for 2 to 3 hours. After termination of the reaction, the reaction mixture was cooled to room temperature to form crystals. The resulting crystals were filtered, washed with water and dried to give 88.2 g (95%) of the desired product.
1HNMR(CDCl3, ppm): 1.65(3H,d), 2.40(3H,s), 2.52~2.60(4H,m), 3.43~3.49(4H,m), 4.37~4.53(3H,m), 7.77(1H,d), 8.65(1H,s)
1 HNMR (CDCl 3 , ppm): 1.65 (3H, d), 2.40 (3H, s), 2.52-2.60 (4H, m), 3.43-3.49 (4H, m), 4.37-4.53 (3H, m), 7.77 (1H, d), 8.65 (1H, s)
본 발명에 따른 항균제인 레보플록사신의 제조방법은 기존의 제조방법에 비하여, 선택적인 반응을 통한 높은 수율과 간편하고 빠른 정제 방법을 이용하여 전체적인 생산공정 시간이 단축되면서도 생산비용이 저렴하고 고순도의 제품을 생산할수 있는 장점이 있다. The preparation method of levofloxacin, an antimicrobial agent according to the present invention, compared to the conventional manufacturing method, using a high yield and a simple and rapid purification method through a selective reaction, while reducing the overall production process time, the production cost is low and high purity products There is an advantage to produce.
상기에서 본 발명은 기재된 구체예를 중심으로 상세히 설명되었지만, 본 발명의 범주 및 기술사상 범위내에서 다양한 변형 및 수정이 가능함은 당 업자에게 있어서 명백한 것이며, 이러한 변형 및 수정이 첨부된 특허 청구범위에 속하는 것도 당연한 것이다.While the invention has been described in detail above with reference to the described embodiments, it will be apparent to those skilled in the art that various modifications and variations are possible within the scope and spirit of the invention, and such variations and modifications are within the scope of the appended claims. It is natural to belong.
Claims (4)
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| KR1020040045914A KR101086177B1 (en) | 2004-06-21 | 2004-06-21 | Process for Preparing --9-Fluoro-2,3-Dihydro-3S-Methyl-10-4-Methyl-1- Piperazinyl-7-Oxo-7H-Pyrido[1,2,3-de]-1,4-Benzoxazine-6-Carboxylic Acid as an Antibacterial Agent |
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| KR1020040045914A KR101086177B1 (en) | 2004-06-21 | 2004-06-21 | Process for Preparing --9-Fluoro-2,3-Dihydro-3S-Methyl-10-4-Methyl-1- Piperazinyl-7-Oxo-7H-Pyrido[1,2,3-de]-1,4-Benzoxazine-6-Carboxylic Acid as an Antibacterial Agent |
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