KR100494882B1 - A process for preparing (-)-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 - Google Patents
A process for preparing (-)-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 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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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
Abstract
본 발명은 하기 화학식 1의 (-)-9-플루오로-2,3-디히드로-3(S)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7H-피리도[1,2,3-데]-1,4-벤즈옥사진-6-카르복실산의 새로운 제조방법에 관한 것이다.The invention of the formula (1) to (-) - 9-fluoro-2,3-dihydro -3 (S) - methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7-H A novel process for preparing pyrido [1,2,3- de ] -1,4-benzoxazine-6-carboxylic acid.
Description
본 발명은 하기 화학식 1의 (-)-9-플루오로-2,3-디히드로-3(S)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7H-피리도[1,2,3-데]-1,4-벤즈옥사진-6-카르복실산의 새로운 제조방법에 관한 것이다.The invention of the formula (1) to (-) - 9-fluoro-2,3-dihydro -3 (S) - methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7-H A novel process for preparing pyrido [1,2,3- de ] -1,4-benzoxazine-6-carboxylic acid.
상기 (-)-9-플루오로-2,3-디히드로-3(S)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7H-피리도[1,2,3-데]-1,4-벤즈옥사진-6-카르복실산(별칭: 레보플록사신, Levofloxacin)은 기존의 항균제인 (±)-9-플루오로-2,3-디히드로-3-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7H-피리도[1,2,3-데]-1,4-벤즈옥사진-6-카르복실산(별칭: 오플록사신, Ofloxacin)보다 약한 독성을 가지며 강력한 항균 활성제로 작용한다(참조: 미국특허 제876,633호(1986년 6월20일) 및 Antimicrobial Agent & Chemotherapy, Vol. 29, 163∼164 (1986)).The (-) - 9-fluoro-2,3-dihydro -3 (S) - methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7-H-pyrido [1, 2,3- de ] -1,4-benzoxazine-6-carboxylic acid (alias levofloxacin, Levofloxacin) is a conventional antimicrobial agent (±) -9-fluoro-2,3-dihydro-3- methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7 H - pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylic acid (aka : Has weaker toxicity than Ofloxacin) and acts as a powerful antimicrobial agent (see US Patent 876,633 (June 20, 1986) and Antimicrobial Agent & Chemotherapy, Vol. 29, 163-164 (1986)). ).
상기 화학식 1의 레보플록사신을 제조하는 종래기술은, 예를 들어 한국특허 제060571호, 제075803호 및 제125115호에 개시되어 있다.The prior art for preparing levofloxacin of the formula (1) is disclosed in, for example, Korean Patent No. 0561,1,075803 and 125115.
이들 중, 한국특허 제060571호 및 075803호에 따르면 하기 반응식 1에 나타낸 바와 같이 하기 화학식 5의 3(S)-3-알킬-7,8-디할로게노-2,3-디히드로-4H-[1,4]-벤즈옥사진과 하기 화학식 6의 디에틸에톡시메틸렌말로레이트로부터 하기 화학식 7의 치환된 벤즈옥사진 유도체를 생성시키고, 이 화학식 7의 화합물로부터 산 촉매로 하여 하기 화학식 8의 S(-)-피리도벤즈옥사진 유도체를 생성시킨 후, 하기 화학식 9의 4-알킬-피페라진으로부터 염기성조건으로 하여 하기 화학식 10의 (-)-9-할로-2,3-디히드로-3(S)-알킬-10-(4-알킬-1-피페라지닐-7-옥소-7H-[1,2,3-데]-1,4-벤즈옥사진-6-카르복실산을 수득 할 수 있다.Among them, according to Korean Patent No. 060351 and 075803, 3 (S) -3-alkyl-7,8-dihalogeno-2,3-dihydro- 4H of Formula 5 as shown in Scheme 1 below Substituted benzoxazine derivatives of the following formula (7) were produced from-[1,4] -benzoxazine and diethylethoxymethylenemalorate of the following formula (6), After the S (-)-pyridobenzoxazine derivative was prepared, 4- (4-)-piperazine of the following formula (9) under the basic conditions (-)-9-halo-2,3-dihydro of the formula (10) -3 (S) - alkyl-10- (4-alkyl-1-piperazinyl-7-oxo--7 H - [1,2,3- de] -1,4-benzoxazine-6-carboxylic Acid can be obtained.
(식중, X1, X2는 각각 할로겐 원자이고, R1은 탄소수 1~4개의 알킬기이며, R2는 탄소수 1~3의 알킬기이다.)(Wherein X 1 and X 2 are each a halogen atom, R 1 is an alkyl group having 1 to 4 carbon atoms, and R 2 is an alkyl group having 1 to 3 carbon atoms.)
그러나 상기 방법은 상기 화학식 7의 화합물로부터 고리화 및 가수분해반응에 의한 상기 화학식 8의 화합물로의 합성시 그 수율이 56%로서 저조하며, 하기 반응식 2에 나타낸 바와 같이 출발물질인 상기 화학식 5의 화합물은 광학적 분리 방법으로 얻기 때문에 반응경로가 길고 비효율적이어서 공업적으로 적용하기 어렵다는 문제점이 있다.However, the method has a low yield of 56% when synthesized from the compound of Formula 7 to the compound of Formula 8 by cyclization and hydrolysis, and is a starting material of Formula 5 as shown in Scheme 2 below. Since the compound is obtained by the optical separation method, there is a problem that the reaction path is long and inefficient, and thus it is difficult to apply industrially.
(식중, X1, X2, R1 및 R2는 상기한 바와 같고, X3는 카르복실기 또는 이의 반응성 유도체이며, R3는 치환 술포닐기, 알콕시 카르보닐기 또는 아르알킬 옥시카르보닐기이고, n은 1~3의 정수이다.)Wherein X 1 , X 2 , R 1 and R 2 are as defined above, X 3 is a carboxyl group or a reactive derivative thereof, R 3 is a substituted sulfonyl group, alkoxycarbonyl group or aralkyl oxycarbonyl group, n is 1- Is an integer of 3.)
또한 한국특허 제125115호에 따르면 하기 화학식 15의 (+)-2-아미노메틸렌-3-옥소-3-페닐프로피오네이트 유도체를 염기성 용액에서 반응시켜 하기 화학식 16의 (-)-벤즈옥사진 유도체를 생성시키고, 이 화학식 16의 화합물과 하기 화학식 17의 피페라진 유도체로부터 염기성 조건하에서 하기 화학식 18의 (-)-피페라진벤즈옥사진 유도체를 77%의 수율로 얻는 방법이 개시되어 있다.In addition, according to Korean Patent No. 125115, a (+)-2-aminomethylene-3-oxo-3-phenylpropionate derivative of Formula 15 is reacted in a basic solution to give a (-)-benzoxazine derivative of Formula 16 And a compound of formula (16) and a piperazine derivative of formula (17) to obtain a (-)-piperazinebenzoxazine derivative of formula (18) under basic conditions in a yield of 77%.
(식중, R1, X1은 상기한 바와 같고, R4, R5, R6은 각각 수소원자 또는 탄소수 1~4개의 알킬기이며, X4 및 X5는 각각 할로겐원자 또는 니트로기이며, Z은 수소원자 또는 트리알킬실릴기를 나타낸다.)(Wherein R 1 , X 1 are as described above, R 4 , R 5 , R 6 are each a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, X 4 and X 5 are each a halogen atom or a nitro group, and Z is Represents a hydrogen atom or a trialkylsilyl group.)
그러나 하기 반응식 4에 나타낸 바와 같이 상기 화학식 15의 화합물을 얻기 위해서는 고가인 하기 화학식 19의 알킬 프로피올레이트를 사용하여야 하며, 하기 화학식 22의 화합물과 같은 보호기를 사용해야 하므로 반응경로가 길고 비효율적이어서 산업적으로 적용하기 어렵다는 문제가 있다.However, in order to obtain the compound of Chemical Formula 15, as shown in Scheme 4, an expensive alkyl propiolate of Chemical Formula 19 should be used, and since the protecting group such as the compound of Chemical Formula 22 should be used, the reaction pathway is long and inefficient, and thus industrially There is a problem that it is difficult to apply.
(식중, R1, X1, X4, X5는 상기한 바와 같고, R7 및 R8은 각각 탄소수 1~8개의 알킬기를 표시한다.)(Wherein R 1 , X 1 , X 4 , X 5 are as described above, and R 7 and R 8 each represent an alkyl group having 1 to 8 carbon atoms.)
본 발명자들은 상기 문제점들을 해결하기 위하여 많은 연구와 노력을 한 결과, 보다 간편하고 수득율이 높은 새로운 제조방법을 발견하게 되어 본 발명을 완성하였다.The present inventors have made a lot of research and efforts to solve the above problems, and as a result, have found a new manufacturing method which is simpler and higher in yield.
본 발명의 목적은 상기 레보플록사신의 제조방법을 제공하는 것이다.It is an object of the present invention to provide a process for the preparation of levofloxacin.
본 발명은 하기 화학식 1의 (-)-9-플루오로-2,3-디히드로-3(S)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7H-피리도[1,2,3-데]-1,4-벤즈옥사진-6-카르복실산(이하 레보플록사신이라 칭함)을 제조하는 방법에 관한 것이다.The invention of the formula (1) to (-) - 9-fluoro-2,3-dihydro -3 (S) - methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7-H -Pyrido [1,2,3- de ] -1,4-benzoxazine-6-carboxylic acid (hereinafter referred to as levofloxacin).
상기 제조방법을 하기 반응식 5를 들어 보다 상세히 설명하면 다음과 같다.The preparation method will be described in more detail with reference to Scheme 5 below.
상기 반응식 5에서, 광학활성을 갖는 상기 화학식 2의 에틸 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트로부터 염기성 용액하에 반응온도 20~200℃, 바람직하게는 100~120℃에서, 2~50시간 동안, 바람직하게는 22~28시간 동안 반응시켜 중간체인 상기 화학식 4의 화합물을 제조하고, 이를 알카리수용액하에 반응온도 20~200℃, 바람직하게는 80~100℃에서 0.1~5시간 동안, 바람직하게는 0.5~1시간 동안 반응시켜 상기 화학식 1의 레보플록사신을 제조할 수 있다.In Scheme 5, ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1 of Chemical Formula 2 having optical activity From hydroxypropy-2-ylamino) acrylate under a basic solution at a reaction temperature of 20 to 200 ° C., preferably at 100 to 120 ° C., for 2 to 50 hours, preferably 22 to 28 hours. To prepare a compound of the formula (4), it was reacted for 20 minutes to 200 ℃, preferably from 80 to 100 ℃ 0.1 to 5 hours, preferably 0.5 to 1 hour under alkaline aqueous solution to the levofloxacin of the formula (1) It can manufacture.
한편 상기 화학식 2의 화합물을 염기성 용액하에 반응시켜 상기 화학식 4의 화합물을 얻은 후, 이를 분리하지 않고 바로 알카리수용액하에 반응시켜 목적화합물을 얻는 것도 가능하다.Meanwhile, the compound of Formula 2 may be reacted under a basic solution to obtain a compound of Formula 4, and then reacted with an alkaline aqueous solution without separation to obtain the target compound.
상기 반응에서 사용하는 염기성 용액은 탄산칼륨, 중탄산칼륨, 탄산나트륨, 중탄산나트륨, 수산화나트륨, 수산화칼륨 또는 수소화나트륨 등으로 이루어진 용액을 예로 들 수 있다.The basic solution used in the reaction may be a solution consisting of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide or sodium hydride and the like.
상기 반응에서 사용하는 용매는 무수 다이옥산, 아세토니트릴, 디메틸포름아미드, 디메틸술폭시드 및 물 등으로 이루어진 군으루보터 선택되는 용매 또는 이들을 2종 이상 혼합하여 얻어지는 혼합용매를 예로 들 수 있다.Examples of the solvent used in the reaction include a solvent selected from the group consisting of anhydrous dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide, water, and the like, or a mixed solvent obtained by mixing two or more kinds thereof.
상기 반응식 5에서, 중간체로 생성되는 상기 화학식 3의 에틸 6,8-디플루오로-1,4-디히드로-1(S)-(1-히드록시프로피-2-닐)-7-(4-메틸-1-피페라지닐)-4-옥소퀴놀린-3-카르복실레이트와 상기 화학식 4의 에틸 9-플루오로-2,3-디히드로-3(S)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7H-피리도[1,2,3-데]-1,4-벤즈옥사진-6-카르복실레이트는 유기용매하에서 염기성 시약의 당량조절 및 세기변화로부터 각각 얻어지므로 그 존재를 확인할 수 있다.In Scheme 5, ethyl 6,8-difluoro-1,4-dihydro-1 (S)-(1-hydroxypropyn-2-yl) -7- (4 of formula 3 produced as an intermediate -Methyl-1-piperazinyl) -4-oxoquinoline-3-carboxylate and ethyl 9-fluoro-2,3-dihydro-3 (S) -methyl-10- (4- methyl-1-piperazinyl) -7-oxo-7 H - pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylate equivalent adjustment of the basic reagents under organic solvent And are obtained from the change in intensity, respectively, so that their presence can be confirmed.
또한 상기 화학식 2의 화합물은 신규화합물로서 본 발명자들에 의해 특허 출원중에 있으며, 그의 제조방법은 하기 반응식 6에 나타낸 바와 같이 하기 화학식 26의 에틸 2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)벤조일 아세테이트와 시판중인 하기 화학식 27의 트리에틸 올소포르메이트를 비극성용매하에, 20~200℃에서 2~50시간 반응시켜 중간체인 하기 화학식 28의 화합물을 제조하고, 다시 이 화학식 28의 화합물과 광학활성을 갖는 하기 화학식 29의 (S)-(+)-2-아미노-1-프로판올을 양성자성 극성용매하에, 0~100℃에서 1~10시간 반응시켜 높은 수율로 제조할 수 있다.In addition, the compound of Formula 2 is a novel compound is pending patent application by the present inventors, and its preparation method is ethyl 2,3,5-trifluoro-4- (4) of Formula 26 as shown in Scheme 6 below. -Methyl-1-piperazinyl) benzoyl acetate and commercially available triethyl oxoformate of formula (27) were reacted at 20 to 200 DEG C for 2 to 50 hours in a nonpolar solvent to prepare a compound of formula (28) as an intermediate. In addition, the compound of Formula 28 and (S)-(+)-2-amino-1-propanol of Formula 29 having optical activity were reacted at 0 to 100 ° C. for 1 to 10 hours under a protic polar solvent for high yield. It can be prepared as.
하기 실시예는 본 발명을 보다 구체적으로 설명하는 것이며, 본 발명의 범위를 제한하는 것은 아니다.The following examples illustrate the invention in more detail and do not limit the scope of the invention.
실시예 1: 에틸 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트의 제조Example 1: ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy-2-ylamino Production of acrylate
344.3g(1 mole)의 에틸 2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)벤조일 아세테이트와 296.4g(2 mole)의 트리에틸올소포르메이트를 2,000ml의 톨루엔에 녹인 용액을 110℃까지 가열하여 24시간 동안 교반하고 톨루엔을 감압증류하여 제거시킨 후 2,000ml의 에탄올에 다시 녹였다. 여기에 112.7g(1.5 mole)의 (S)-(+)-2-아미노-1-프로판올을 서서히 적가한 다음 상온에서 3시간 격렬하게 교반시켰다. 반응이 완결되면 감압증류하여 에탄올을 제거시켜 395.1g(92%)의 에틸 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트를 얻었다.2,000 ml of 344.3 g (1 mole) of ethyl 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) benzoyl acetate and 296.4 g (2 mole) of triethylolsoformate The solution dissolved in toluene was heated to 110 ° C., stirred for 24 hours, toluene was distilled off under reduced pressure, and then dissolved in 2,000 ml of ethanol. 112.7 g (1.5 mole) of (S)-(+)-2-amino-1-propanol was slowly added dropwise thereto, followed by vigorous stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove ethanol to thereby dissolve 395.1 g (92%) of ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 ( S)-(1-hydroxypropy-2-ylamino) acrylate was obtained.
IR: υmax(cm-1) 1,681, 1,668, 1,625IR: υ max (cm -1 ) 1,681, 1,668, 1,625
H1 NMR (CDCl3, 300MHz)(ppm):H 1 NMR (CDCl 3 , 300 MHz) (ppm):
0.98 and 1.09 (3H, 각각 t, -OCH2 CH 3), 1.35 (3H, d, -NHCHCH 3),0.98 and 1.09 (3H, t, -OCH 2 CH 3 ), 1.35 (3H, d, -NHCH CH 3 ),
1.80∼2.20 (1H, br, -OH), 2.35 (3H, s, =NCH3),1.80-2.20 (1H, br, -OH), 2.35 (3H, s, = NCH 3 ),
2.30∼2.65 (4H, m, 피페라진 H), 3.20∼3.50 (4H, m, 피페라진 H), 2.30 to 2.65 (4H, m, piperazine H), 3.20 to 3.50 (4H, m, piperazine H),
3.40∼3.60 (3H, m, =NCHCH 2O-), 4.03 and 4.07 (2H, 각각 q, -OCH 2CH 3),3.40 to 3.60 (3H, m, = N CHCH 2 O-), 4.03 and 4.07 (2H, q and -O CH 2 CH 3 ),
6.80∼6.90 (1H, m, 방향성 H), 8.15 and 8.20 (1H, 각각 d, =CHN=), 6.80 to 6.70 (1H, m, aromatic H), 8.15 and 8.20 (1H, d, = CHN =),
9.20∼9.70 및 10.50∼11.00 (1H, 및 br, =NH) 9.20-9.70 and 10.50-11.00 (1H, and br, = NH)
[α]D = -68.3° (c=0.12, CHCl3)[α] D = -68.3 ° (c = 0.12, CHCl 3 )
실시예 2: 에틸 9-플루오로-2,3-디히드로-3(S)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-Example 2: ethyl 9-fluoro-2,3-dihydro-3 (S) -methyl-10- (4-methyl-1-piperazinyl) -7-oxo- 7H7H -피리도[1,2,3--Pyrido [1,2,3- 데place ]-1,4-벤즈옥사진-6-카르복실레이트의 제조] -1,4-benzoxazine-6-carboxylate
429.4g(1mole)의 에틸 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트와 60g(2.5mole)의 수소화나트륨을 2,000ml의 무수 다이옥신에 녹인 용액을 90℃까지 가열하고 2시간 동안 교반하였다. 반응이 완결되면 500ml의 물을 가하고 희석 초산으로 중화 후 1,500ml의 클로로포름으로 추출한 다음, 황산 마그네슘으로 건조하고 감압증류하여 용매를 제거한 후 잔사를 아세트산 에틸로 결정화하여 미황색의 에틸 9-플루오로-2,3-디히드로-3(S)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7H-피리도[1,2,3-데]-1,4-벤즈옥사진-6-카르복실레이트 319.3g(82%)을 얻었다.429.4 g (1 mole) ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy-2- A solution of dimethylamino) acrylate and 60 g (2.5 mole) of sodium hydride in 2,000 ml of anhydrous dioxin was heated to 90 ° C. and stirred for 2 hours. After completion of the reaction, 500 ml of water was added, neutralized with diluted acetic acid, extracted with 1,500 ml of chloroform, dried over magnesium sulfate, distilled under reduced pressure to remove the solvent, and the residue was crystallized with ethyl acetate to give a slightly yellow ethyl 9-fluoro-2. , 3-dihydro-3 (S) -methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-dec] -1,4-benz 319.3 g (82%) of oxazine-6-carboxylate was obtained.
융점: 232~234℃(dec.)Melting Point: 232 ~ 234 ℃ (dec.)
IR: υmax(cm-1): 1710, 1615, 1593IR: υ max (cm -1 ): 1710, 1615, 1593
H1 NMR (CDCl3, 300MHz)(ppm):H 1 NMR (CDCl 3 , 300 MHz) (ppm):
1.40(3H, t, -OCH2 CH 3), 1.56(3H, d, -OCH2CHCH 3),1.40 (3H, t, -OCH 2 CH 3 ), 1.56 (3H, d, -OCH 2 CH CH 3 ),
2.37(3H, s, =NCH 3), 2.50~2.58(4H, m, 2×CH 2 N),2.37 (3H, s, = N CH 3 ), 2.50-2.58 (4H, m, 2 x CH 2 N),
3.36~3.41(4H, m, 2×CH 2 N), 4.27~4.43(3H, m, -OCH 2 CHCH3),3.36-3.41 (4H, m, 2 x CH 2 N), 4.27-4.43 (3H, m, -O CH 2 CH CH 3 ),
7.67(1H, d, 방향성 H), 8.49(1H, s, =NCH=)7.67 (1H, d, Directional H), 8.49 (1H, s, = NCH =)
[α]D = -90.2°(c-0.137, CHCl3)[a] D = -90.2 ° (c-0.137, CHCl3)
실시예 3: (-)-9-플루오로-2,3-디히드로-3(S)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7Example 3: (-)-9-fluoro-2,3-dihydro-3 (S) -methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7 HH -피리도[1,2,3--Pyrido [1,2,3- 데place ]-1,4-벤즈옥사진-6-카르복실산의 제조] -1,4-benzoxazine-6-carboxylic acid
429.4g(1 mole)의 에틸 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트와 60g(2.5 mole)의 수소화나트륨을 2,000ml의 무수 다이옥산에 녹인 용액을 90℃까지 가열하여 2시간 동안 교반한 후 500ml의 0.1N-수산화나트륨 수용액을 주입하고 계속적으로 30분간 교반하였다. 반응이 완결되면 감압증류하여 유기용매를 제거한 후, 500ml의 물을 추가 주입하고 희석 초산으로 중화한 후 1,500ml의 클로로포름으로 추출한 다음, 황산 마그네슘으로 건조하고 감압증류하여 용매를 제거한 후 잔사를 에탄올로 결정화하여 미황색의 (-)-9-플루오로-2,3-디히드로-3(S)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7H-피리도[1,2,3-데]-1,4-벤즈옥사진-6-카르복실산 282.9g(78%)을 얻었다.429.4 g (1 mole) ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy-2 -Nilamino) acrylate and 60 g (2.5 mole) of sodium hydride in 2,000 ml of anhydrous dioxane were heated to 90 ° C. and stirred for 2 hours, followed by injecting 500 ml of 0.1 N aqueous sodium hydroxide solution and continuously Stirred for a minute. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove the organic solvent. 500 ml of water was added thereto, neutralized with diluted acetic acid, extracted with 1,500 ml of chloroform, dried over magnesium sulfate, distilled under reduced pressure, and the solvent was removed. crystallized as a pale yellow (-) - 9-fluoro-2,3-dihydro -3 (S) - methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7-H-pyrido 282.9 g (78%) of [1,2,3- de ] -1,4-benzoxazine-6-carboxylic acid were obtained.
융점 : 213∼215℃ (dec.)Melting Point: 213∼215 ℃ (dec.)
IR: υmax(cm-1) 3,465, 1,718, 1,619IR: υ max (cm -1 ) 3,465, 1,718, 1,619
H1 NMR (CDCl3, 300MHz)(ppm)H 1 NMR (CDCl 3 , 300 MHz) (ppm)
1.62 (3H, d, -OCH2CHCH 3), 2.36 (3H, s, =NCH 3),1.62 (3H, d, -OCH 2 CH CH 3 ), 2.36 (3H, s, = N CH 3 ),
2.55∼2.61 (4H, m, 2×CH 2N), 3.42∼3.46 (4H, m, 2×CH 2N),2.55 to 2.61 (4H, m, 2 × CH 2 N), 3.42 to 3.46 (4H, m, 2 × CH 2 N),
4.35∼4.51 (3H, m, -OCH 2 CHCH3), 7.76 (1H, d, 방향성 H)4.35 to 4.51 (3H, m, -O CH 2 CH CH 3 ), 7.76 (1H, d, aromatic H)
8.63 (1H, s, =NCH=)8.63 (1H, s, = N CH =)
[α]D = -91.4° (c=0.137, CHCl3)[α] D = -91.4 ° (c = 0.137, CHCl 3 )
본 발명은 항균제로 유용한 레보플록사신을 보다 편리하고, 효율적인 방법으로 제조하는 새로운 방법을 제공할 수 있다.The present invention may provide a new method for preparing levofloxacin useful as an antimicrobial agent in a more convenient and efficient manner.
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| KR940004812A (en) * | 1992-08-25 | 1994-03-16 | 문정환 | Method for manufacturing memory cell of semiconductor device |
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| KR100248370B1 (en) * | 1997-12-04 | 2000-03-15 | 이종배 | Preparation of intermediate of (-)-3(s)-methylpyrido benzoxizine derivative |
| KR20000056615A (en) * | 1999-02-24 | 2000-09-15 | 윤종용 | Process for Preparing (-)Pyridobenzoxazine Carboxylic Acid Derivatives |
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| JPH0543464A (en) * | 1988-04-23 | 1993-02-23 | Toyama Chem Co Ltd | Antibacterial agent containing pyridonecarboxylic acid derivative or its salt |
| KR920012087A (en) * | 1990-12-27 | 1992-07-25 | 하기주 | Method for preparing benzoxazine derivatives |
| KR940004812A (en) * | 1992-08-25 | 1994-03-16 | 문정환 | Method for manufacturing memory cell of semiconductor device |
| KR0125115B1 (en) * | 1994-03-22 | 1997-12-05 | 김은영 | Process for preparing piperazinyl quinolone derivatives |
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| KR100840125B1 (en) * | 2001-06-28 | 2008-06-19 | 씨제이제일제당 (주) | High concentration water-solution composition including antibiotic compound |
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