KR100484386B1 - Process for the preparation of alkyl 2 - [2,3,5 -trifluoro - 4 - (4 - methyl-1-piperazinyl)] benzoyl - 3(S)-(1 - hydroxyprop - 2 - ylamino) acrylate - Google Patents
Process for the preparation of alkyl 2 - [2,3,5 -trifluoro - 4 - (4 - methyl-1-piperazinyl)] benzoyl - 3(S)-(1 - hydroxyprop - 2 - ylamino) acrylate Download PDFInfo
- Publication number
- KR100484386B1 KR100484386B1 KR10-2000-0058050A KR20000058050A KR100484386B1 KR 100484386 B1 KR100484386 B1 KR 100484386B1 KR 20000058050 A KR20000058050 A KR 20000058050A KR 100484386 B1 KR100484386 B1 KR 100484386B1
- Authority
- KR
- South Korea
- Prior art keywords
- methyl
- piperazinyl
- trifluoro
- benzoyl
- acrylate
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
본 발명은 알킬 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트로 명명되며, 활성 항균제로서 유용한 약제인 레보플록사신(Levofloxacin)의 제조 시에 중간체로 사용되는 광학활성을 갖는 하기 화학식 1의 화합물을 제조하는 방법에 관한 것이다.The present invention relates to alkyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy-2-ylamino) The present invention relates to a method for preparing a compound of formula 1 having an optical activity, which is named as an acrylate and is used as an intermediate in the preparation of levofloxacin, a drug useful as an active antibacterial agent.
(여기서 R은 C1 ~ C4의 알킬기이다).(Wherein R is an alkyl group of C 1 to C 4 ).
Description
본 발명은 알킬 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트로 명명되며 활성 항균제로서 유용한 약제인 레보플록사신(Levofloxacin)의 제조 시에 중간체로 사용되는 광학활성을 갖는 하기 화학식 1의 화합물을 제조하는 방법에 관한 것이다.The present invention relates to alkyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy-2-ylamino) The present invention relates to a method for preparing a compound of formula 1 having optical activity, which is used as an intermediate in the preparation of levofloxacin, which is a acrylate and is useful as an active antimicrobial agent.
(여기서 R은 C1 ~ C4의 알킬기이다).(Wherein R is an alkyl group of C 1 to C 4 ).
상기 화학식 1의 화합물은 광학활성을 갖는 화합물로서, R이 Ethyl(-CH2CH3)The compound of Formula 1 is a compound having optical activity, R is Ethyl (-CH 2 CH 3 )
인 화합물의 라세미체를 제조하는 방법은 한국특허 공개공보 제92-12087호에 개시되어 있다.A method for producing a racemate of a phosphorus compound is disclosed in Korean Patent Laid-Open Publication No. 92-12087.
상기 기술에 따르면, 하기 반응식 1에 나타낸 바와 같이 화학식 11의 에틸 2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)벤조일 아세테이트를 화학식 12의 디메틸포름아미드 디메틸아세탈 및 라세미체인 화학식 4의 2-아미노-1-프로판올과 반응시켜 화학식 14의 에틸 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3-(1-히드록시프로피-2-닐아미노)아크릴레이트를 얻을 수 있다.According to the above technique, ethyl 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) benzoyl acetate of formula 11 is substituted with dimethylformamide dimethylacetal of formula 12 as shown in Scheme 1 below. And ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl- of formula 14 by reacting with 2-amino-1-propanol of formula 4 which is a racemate 3- (1-hydroxypropy-2-ylamino) acrylate can be obtained.
그러나 상기 반응식 1의 제조방법은 출발물질인 화학식 12의 화합물이 고가이며 수분에 매우 민감하고 톨루엔등 인화성이 강한 용매를 사용하여 반응시키므로 산업적으로 적용하기에 부적절하다는 문제점이 있다. However, the preparation method of Scheme 1 has a problem that the compound of Formula 12, which is a starting material, is expensive and very sensitive to moisture, and reacts with a highly flammable solvent such as toluene, which is inappropriate for industrial application.
본 발명의 목적은 상기의 문제점을 해결하여 보다 간편하고 수득률이 높은, 알킬 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트의 제조방법을 제공하는 것으로 본 발명가들의 많은 연구와 노력 끝에 완성되었다. It is an object of the present invention to solve the above problems and to make alkyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 ( Providing a method for preparing S)-(1-hydroxypropy-2-ylamino) acrylate, the inventors have completed many studies and efforts.
본 발명은 알킬 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트로 명명되며 활성 항균제로서 유용한 약제인 레보플록사신(Levofloxacin)의 제조 시에 중간체로 사용되는 광학활성을 갖는 하기 화학식 1의 화합물을 제조하는 방법에 관한 것이다.The present invention relates to alkyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy-2-ylamino) The present invention relates to a method for preparing a compound of formula 1 having optical activity, which is used as an intermediate in the preparation of levofloxacin, which is a acrylate and is useful as an active antimicrobial agent.
(여기서 R은 C1 ~ C4의 알킬기이다).(Wherein R is an alkyl group of C 1 to C 4 ).
상기 화학식 1의 제조방법은 하기 반응식 2에 나타낸 바와 같다.The preparation method of Chemical Formula 1 is as shown in Scheme 2 below.
(여기서 R은 C1 ~ C4의 알킬기이다).(Wherein R is an alkyl group of C 1 to C 4 ).
상기의 반응식 2에 나타낸 바와 같이 화학식 2의 2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)벤조일클로라이드와 화학식 3의 알킬 3-(디메틸아미노)아크릴레이트를 극성용매 중에서 -5℃ 내지 100℃ 좋기로는 0℃ 내지 20℃에서 2시간 내지 50시간 좋기로는 12시간 내지 15시간 반응시켜 중간체인 화학식 5의 화합물을 제조하고, 이를 광학활성을 갖는 화학식 4의 (S)-(+)-2-아미노-1-프로판올을 양성자성 극성용매중에서 0℃ 내지 100℃ 좋기로는 10℃ 내지 30℃에서 1시간 내지 10시간 좋기로는 2시간 내지 3시간 반응시켜 정량적인 높은 수율로 간단히 제조할 수 있다. As shown in Scheme 2, 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) benzoyl chloride of formula 2 and alkyl 3- (dimethylamino) acrylate of formula 3 In the polar solvent, the reaction was carried out at -5 ° C. to 100 ° C., preferably at 0 ° C. to 20 ° C., for 2 hours to 50 hours, preferably for 12 hours to 15 hours, to prepare a compound of Formula 5, which is an intermediate. Reaction of (S)-(+)-2-amino-1-propanol at 0 ° C. to 100 ° C., preferably at 10 ° C. to 30 ° C., for 1 to 10 hours, preferably 2 to 3 hours in a protic polar solvent. It can be prepared simply by quantitative high yield.
한편 상기 화학식 2의 화합물을 극성용매 중에서 화학식 3의 알킬 3-(디메틸아미노)아크릴레이트와 반응시켜 상기 화학식 5의 화합물을 얻은 후, 이를 분리하지 않고 계속해서 상기 화학식 4의 화합물과 양성자성 극성용매하에 반응시켜 목적화합물을 얻는 것도 가능하다.Meanwhile, the compound of Chemical Formula 2 is reacted with alkyl 3- (dimethylamino) acrylate of Chemical Formula 3 in a polar solvent to obtain the compound of Chemical Formula 5, and then the compound of Chemical Formula 4 and the protic polar solvent are not separated. It is also possible to obtain the target compound by reaction under the following conditions.
상기 방법에서 사용되는 극성용매로는 디메틸술폭시드, 디메틸포름아미드, 디메틸아세트아미드, 아세토니트릴, 아세트산 에틸 중에서 선택된 용매 또는 이들 용매의 혼합물을 예로 들 수 있으며, 양성자성 극성용매로는 물이나 에탄올성 용매 중에서 선택된 용매 또는 이들 용매의 혼합물을 예로 들 수 있다.Examples of the polar solvent used in the above method include a solvent selected from dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetonitrile and ethyl acetate or a mixture of these solvents. The protic polar solvent is water or ethanol. Examples thereof include a solvent selected from the solvent or a mixture of these solvents.
출발물질로 사용되는 화학식 2의 화합물은 본 발명자들이 개발하여 특허출원 한 대한민국 특허출원 제 99-34792호로부터 얻을 수 있으며 간단히 설명하면 다음과 같다.The compound of Formula 2 used as a starting material can be obtained from Korean Patent Application No. 99-34792, which was developed and patented by the present inventors.
상기 반응식 3에서 나타낸 바와 같이 화학식 6의 2,3,4,5-테트라플루오로벤조산과 화학식 7의 4-메틸-1-피페라진을 극성용매중 반응시켜 화학식 8의 2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)벤조산을 얻고, 다시 화학식 8의 화합물에 염화티오닐과 같은 염화제를 사용하여 85%의 수율로 화학식 2의 화합물을 간단히 제조할 수 있다.As shown in Scheme 3, 2,3,4,5-tetrafluorobenzoic acid of Chemical Formula 6 and 4-methyl-1-piperazine of Chemical Formula 7 are reacted in a polar solvent to give 2,3,5-tri of Chemical Formula 8 Fluoro-4- (4-methyl-1-piperazinyl) benzoic acid can be obtained and the compound of formula (2) can be simply prepared in 85% yield using a chloride such as thionyl chloride in the compound of formula (8). have.
또한 광학활성을 갖는 하기 화학식 4의 화합물은 하기 반응식 4와 같이, 천연으로부터 구할 수 있으며 가격도 저렴한 화학식 9의 L-알라닌을 일반적인 환원제를 사용하여 환원시킴으로써 쉽게 얻을 수 있다. In addition, the compound of Formula 4 having optical activity can be easily obtained by reducing L-alanine of Formula 9, which can be obtained from nature and is inexpensive, using a general reducing agent, as in Scheme 4 below.
본 발명의 공정에 따라 제조된 알킬 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트는 항균제로 유용한 약제인 하기 화학식 10의 일명 레보플록사신(Levofloxacin)으로 명명되는 (-)-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{(-)-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-carboxy-Alkyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy- prepared according to the process of the invention 2-Nylamino) acrylate is (-)-9-fluoro-2,3-dihydro-3 (S) -methyl-10- named as Levofloxacin of the formula (4-methyl-1-piperazinyl) -7-oxo-7-H-pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylic acid {(-) - 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-carboxy-
lic acid}의 제조시 중간체로 사용할 수 있으며, 그 방법을 간단히 나타내면 하기 반응식 5와 같다.It can be used as an intermediate in the preparation of lic acid}, the method is shown in Scheme 5 below.
상기 반응식 5에서 나타낸 바와 같이, 광학활성을 갖는 상기 화학식 1의 알킬 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트로부터 염기성 용액하에 반응시켜 상기 화학식 10의 레보플록사신(Levofloxacin)을 제조할 수 있다. 이에 대한 상세한 내용은 본 발명자들이 개발하여 특허출원 한 대한민국 특허출원 제 99-34794호에 기재되어 있다.As shown in Scheme 5, alkyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S) of Chemical Formula 1 having optical activity Levofloxacin of Formula 10 may be prepared by reaction under basic solution from-(1-hydroxypropy-2-ylamino) acrylate. Details of this are described in Korean Patent Application No. 99-34794, which the inventors have developed and applied for.
이하에서 실시예를 들어 본 발명을 상세히 설명하나 하기 실시예에 의하여 본 발명의 범주가 제한되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Examples, but the scope of the present invention is not limited by the following Examples.
실시예 1 : (S)-(+)-2-아미노-1-프로판올의 제조Example 1: Preparation of (S)-(+)-2-amino-1-propanol
1L 반응부에 테트라히드로푸란 3.5L를 넣고 질소를 기류시키면서 반응부의 온도를 0℃까지 냉각했다. 이 반응부에 수소화알루미늄리튬 75.9g (2 몰)을 나누어서 가하고 30분간 교반하여 혼탁시킨 후 L-알라닌 89.1g (1 몰)을 반응부의 온도를 10℃ 이하로 유지하며 나누어서 가하고 24시간 동안 반응혼합액을 환류 교반했다. 반응이 완결되면 반응부의 온도를 0℃까지 냉각 후 정제수 360mL 및 15% 수산화나트륨수용액 90mL를 순차적으로 서서히 가하여 18∼22℃에서 3시간 동안 교반하고 침전물을 여과하여 제거했다. 이 여액을 황산마그네슘으로 건조 여과한 후 감압농축하여 61.6g (82 %)의 (S)-(+)-2-아미노-1-프로판올을 얻었다.3.5 L of tetrahydrofuran was put into a 1 L reaction part, and the temperature of the reaction part was cooled to 0 degreeC, flowing nitrogen. Lithium aluminum hydride 75.9 g (2 mol) was added to the reaction portion and stirred for 30 minutes, followed by turbidity. Then, 89.1 g (1 mol) of L-alanine was added thereto while maintaining the temperature of the reaction portion at 10 DEG C or lower, and the reaction mixture was stirred for 24 hours. It was stirred at reflux. After the reaction was completed, the reaction unit was cooled to 0 ° C., and then 360 mL of purified water and 90 mL of 15% aqueous sodium hydroxide solution were gradually added thereto, stirred at 18 to 22 ° C. for 3 hours, and the precipitate was filtered off. The filtrate was dried and filtered through magnesium sulfate and concentrated under reduced pressure to give 61.6 g (82%) of (S)-(+)-2-amino-1-propanol.
IR : max(cm-1) : 3,345, 3,307, 3,160, 1,621, 1,593IR: max (cm-1): 3,345, 3,307, 3,160, 1,621, 1,593
1H NMR (CDCl3, 300MHz)(ppm) : 1 H NMR (CDCl 3 , 300 MHz) (ppm):
1.03 (3H, d, =CHCH 3), 2.79 (1H, m, -OH),1.03 (3H, d, = CH CH 3 ), 2.79 (1H, m, -OH),
2.98 (1H, m, =CHCH3), 3.23 (2H, t, -NH2),2.98 (1H, m, = CH CH 3 ), 3.23 (2H, t, -NH 2 ),
3.51 (2H, d, -CH 2OH)3.51 (2H, d, -CH 2 OH)
[α]D = +18。 (c=1.8, H2O)[α] D = +18。 (c = 1.8, H 2 O)
실시예 2 : 2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)벤조산의Example 2 of 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) benzoic acid
제조Produce
194.1g (1 몰)의 2,3,4,5-트리플루오로벤조산, 150.3g (1.5 몰)의 4-메틸-1-피페라진 및 118.7g (1.5 몰)의 피리딘을 500ml의 디메틸술폭시드에 녹인 용액을 100℃까지 가열하여 24시간 동안 격렬하게 교반시켰다. 반응이 완결되면 200ml의 50%초산수용액을 가하여 결정화하고 여과 후 물로 세척 및 건조하여 미황색의 2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)벤조산 233.1g (85 %)을 얻었다.194.1 g (1 mol) of 2,3,4,5-trifluorobenzoic acid, 150.3 g (1.5 mol) of 4-methyl-1-piperazine and 118.7 g (1.5 mol) of pyridine in 500 ml of dimethylsulfoxide The solution dissolved in was heated to 100 ° C. and stirred vigorously for 24 hours. After completion of the reaction, 200 ml of 50% acetic acid solution was added for crystallization, filtration, washing with water and drying to give 233.1 g of pale yellow 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) benzoic acid ( 85%).
융점 : 244∼246℃ (dec.)Melting Point: 244∼246 ℃ (dec.)
IR : max(cm-1) : 3,435, 1,626, 1,561, 1,450IR: max (cm-1): 3,435, 1,626, 1,561, 1,450
1H NMR (D2O, 300MHz)(ppm) : 1 H NMR (D 2 O, 300 MHz) (ppm):
2.95 (3H, s, =NCH3), 3.08∼3.39 (2H, m, piperazine H),2.95 (3H, s, = NCH 3 ), 3.08 to 3.39 (2H, m, piperazine H),
3.42∼3.62 (2H, m, Piperazine H) 3.42-3.62 (2H, m, Piperazine H)
실시예 3 : 2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)벤조일클로라이드의Example 3 of 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) benzoylchloride
제조 Produce
274.2g (1 몰)의 2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)벤조산을 297.5g (2.5 몰)의 염화티오닐에 혼탁시킨 용액을 70℃까지 가열하여 5시간 동안 격렬하게 교반시켰다. 반응이 완결되면 감압증류로 염화티오닐을 제거하여 미황색의 결정인 2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일클로라이드 286.8 g (98 %)을 얻었다. 274.2 g (1 mol) of a solution of 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) benzoic acid suspended in 297.5 g (2.5 mol) of thionyl chloride was dissolved up to 70 ° C. Heated and stirred vigorously for 5 hours. Upon completion of the reaction, thionyl chloride was removed by distillation under reduced pressure to give 286.8 g (98%) of pale yellow crystals, 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl chloride. Got it.
융점 : 86∼88℃ (dec.)Melting Point: 86 ~ 88 ℃ (dec.)
IR : max(cm-1) : 3,427, 1,614, 1,531, 1,470IR: max (cm-1): 3,427, 1,614, 1,531, 1,470
1H NMR (CDCl3, 300MHz)(ppm) : 1 H NMR (CDCl 3 , 300 MHz) (ppm):
2.74 (3H, s, =NCH3), 3.28∼3.49 (2H, m, piperazine H),2.74 (3H, s, = NCH 3 ), 3.28 to 3.49 (2H, m, piperazine H),
3.72∼3.92 (2H, m, Piperazine H) 3.72-3.92 (2H, m, Piperazine H)
실시예 4 : 에틸 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3-Example 4: ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3-
(디메틸아미노)아크릴레이트의 제조Preparation of (dimethylamino) acrylate
3L 반응부에 아세트산 에틸 1.5L를 넣고 에틸 3-(디메틸아미노)아크릴레이트 143.2g (1 몰)을 가하여 완전히 녹인 후 트리에틸아민 206.5g (2 몰)을 가하고 반응부의 온도를 0℃까지 냉각하여 30분간 교반했다. 이 반응 혼합액에 2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일클로라이드 292.69g (1 몰)을 반응부의 온도를 10℃ 이하로 유지하며 나누어서 가하고 교반했다. 반응부의 온도를 10℃로 조정하여 14시간 동안 교반했다. 반응이 완결되면 반응부의 온도를 0℃까지 냉각한 후 침전물을 여과하여 제거 후 1N 염산수용액 1L로 세척하여 유기층을 분리하고 다시 1N 수산화나트륨수용액 및 포화 염화나트륨수용액 1L로 세척 후 유기층을 황산마그네슘으로 건조, 여과 및 감압농축하여 391.42g (98%)의 에틸 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3-(디메틸아미노)아크릴레이트를 얻었다.1.5L of ethyl acetate was added to the 3L reaction part, and 143.2g (1 mol) of ethyl 3- (dimethylamino) acrylate was completely dissolved. 206.5g (2 mol) of triethylamine was added thereto, and the temperature of the reaction part was cooled to 0 ° C. Stirred for 30 minutes. To this reaction mixture, 292.69 g (1 mol) of 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl chloride was added in portions while maintaining the temperature of the reaction portion at 10 占 폚 or lower, followed by stirring. did. The temperature of the reaction portion was adjusted to 10 ° C. and stirred for 14 hours. After the reaction was completed, the temperature of the reaction part was cooled to 0 ° C., the precipitate was filtered off, washed with 1 L of 1N aqueous hydrochloric acid solution, and the organic layer was separated. , Filtered and concentrated under reduced pressure to afford 391.42 g (98%) of ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3- (dimethylamino) acrylic The rate was obtained.
IR : max(cm-1) : 1,684, 1,667, 1,619, 1,553, 1248IR: max (cm-1): 1,684, 1,667, 1,619, 1,553, 1248
1H NMR (CDCl3, 300MHz)(ppm) : 1 H NMR (CDCl 3 , 300 MHz) (ppm):
0.96 (3H, t, -CO2CH2 CH 3), 2.83 (3H, s, =NCH3),0.96 (3H, t, -CO 2 CH 2 CH 3 ), 2.83 (3H, s, = NCH 3 ),
3.07 and 3.51 [8H, m, -N(CH3)2, and piperazine H],3.07 and 3.51 [8H, m, -N (CH 3 ) 2 , and piperazine H],
3.64∼3.85 (2H, m, Piperazine H) 3.64-3.85 (2H, m, Piperazine H)
3.97 (2H, q, -CO2 CH 2CH3)3.97 (2H, q, -CO 2 CH 2 CH 3 )
6.76∼7.02 (1H, m, Aromatic H), 6.76∼7.02 (1H, m, Aromatic H),
8.11 [1H, s, =CHN(CH3)2]8.11 [1H, s, = CH N (CH 3 ) 2 ]
실시예 5 : 에틸 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일Example 5 Ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl
-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트의 제조Preparation of -3 (S)-(1-hydroxypropy-2-ylamino) acrylate
3L 반응부에 에탄올 1.5L를 넣고 에틸 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3-(디메틸아미노)아크릴레이트 399.4g (1 몰)을 가하여 완전히 녹인 후 반응부의 온도를 0℃까지 냉각하여 30분간 교반했다. 이 반응부에 (S)-(+)-2-아미노-1-프로판올 112.7g (1.5 몰)을 에탄올 500mL에 희석시킨 용액을 반응부의 온도를 10℃ 이하로 유지하며 나누어서 가한 후 18∼22℃에서 3시간 교반시켰다. 반응 완결 후 감압농축하여 용매를 제거했다. 이 반응 농축액에 톨루엔 1L를 가하여 완전히 녹이고 정제수 1L를 가하여 2회 세척한 후 유기층을 분리했다. 이 유기층을 다시 10% 중탄산나트륨수용액 1L로 세척하여 유기층을 분리하고 황산마그네슘으로 건조, 여과 한 후 감압농축하여 416.56 (97%)의 에틸 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트를 얻었다.Add 1.5 L of ethanol to the 3 L reaction section and 399.4 g of ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3- (dimethylamino) acrylate 1 mole) was added and completely dissolved, and then the temperature of the reaction part was cooled to 0 ° C. and stirred for 30 minutes. A solution obtained by diluting 112.7 g (1.5 mole) of (S)-(+)-2-amino-1-propanol in 500 mL of ethanol was added to this reaction part while maintaining the temperature of the reaction part at 10 ° C. or lower, and then 18 to 22 ° C. Stirred for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent. 1 L of toluene was added to the reaction concentrate to completely dissolve, 1 L of purified water was added thereto, washed twice, and the organic layer was separated. The organic layer was washed again with 1 L of 10% aqueous sodium bicarbonate solution, and the organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 416.56 (97%) of ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy-2-ylamino) acrylate was obtained.
IR : max(cm-1) : 1,681, 1,668, 1,625IR: max (cm-1): 1,681, 1,668, 1,625
1H NMR (CDCl3, 300MHz)(ppm) : 1 H NMR (CDCl 3 , 300 MHz) (ppm):
0.98 and 1.09 (3H, each t, -OCH2 CH 3), 1.35 (3H, d, -NHCHCH 3),0.98 and 1.09 (3H, each 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, piperazine H), 3.20∼3.50 (4H, m, Piperazine 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, each q, -OCH 2 CH3),3.40 to 3.60 (3H, m, = N CHCH 2 O-), 4.03 and 4.07 (2H, each q, -O CH 2 CH 3 ),
6.80∼6.90 (1H, m, Aromatic H), 8.15 and 8.20 (1H, each d, =CHN=), 6.80∼6.90 (1H, m, Aromatic H), 8.15 and 8.20 (1H, each d, = CHN =),
9.20∼9.70 and 10.50∼11.00 (1H, each br, =NH) 9.20-9.70 and 10.50-11.00 (1H, each br, = NH)
[α]D = -68.3。 (c=0.12, CHCl3)[α] D = -68.3。 (c = 0.12, CHCl 3 )
실시예 6 : 에틸2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일Example 6: ethyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl
-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트의 제조Preparation of -3 (S)-(1-hydroxypropy-2-ylamino) acrylate
3L 반응부에 아세토니트릴 1.5L를 넣고 에틸 3-(디메틸아미노)아크릴레이트 143.2g (1 몰)을 가하여 완전히 녹인 후 트리에틸아민 206.5g (2 몰)을 가하고 반응부의 온도를 0℃까지 냉각하여 30분간 교반했다. 이 반응 혼합액에 2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일클로라이드 292.69g (1 몰)을 반응부의 온도를 10℃ 이하로 유지하며 나누어서 가하고 교반했다. 반응부의 온도를 10℃로 조정하여 14시간 동안 교반했다. 반응이 완결되면 반응부의 온도를 0℃까지 냉각한 후 침전물을 여과하여 제거 및 여액을 감압농축하여 용매를 제거했다. 이 반응 농축액에 에탄올 1.5L를 넣고 완전히 녹인 후 반응부의 온도를 0℃까지 냉각하여 30분간 교반했다. 이 반응부에 (S)-(+)-2-아미노-1-프로판올 112.7g (1.5 몰)을 에탄올 500mL에 희석시킨 용액을 반응부의 온도를 10℃ 이하로 유지하며 나누어서 가한 후 18∼22℃에서 3시간 교반시켰다. 반응 완결 후 감압농축하여 용매를 제거했다. 이 반응 농축액에 톨루엔 1L를 가하여 완전히 녹이고 정제수 1L를 가하여 2회 세척한 후 유기층을 분리했다. 이 유기층을 다시 10% 중탄산나트륨수용액 1L로 세척하여 유기층을 분리하고 황산마그네슘으로 건조, 여과 한 후 감압농축하여 407.97 (95%)의 에틸 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트를 얻었다.1.5L of acetonitrile was added to the 3L reaction section, and 143.2g (1 mol) of ethyl 3- (dimethylamino) acrylate was completely dissolved. 206.5g (2 mol) of triethylamine was added thereto, and the temperature of the reaction section was cooled to 0 ° C. Stirred for 30 minutes. To this reaction mixture, 292.69 g (1 mol) of 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl chloride was added in portions while maintaining the temperature of the reaction portion at 10 占 폚 or lower, followed by stirring. did. The temperature of the reaction portion was adjusted to 10 ° C. and stirred for 14 hours. After the reaction was completed, the temperature of the reaction part was cooled to 0 ° C., the precipitate was filtered off, and the filtrate was concentrated under reduced pressure to remove the solvent. 1.5 L of ethanol was added to this reaction concentrate, and after fully dissolving, the temperature of the reaction part was cooled to 0 ° C and stirred for 30 minutes. A solution obtained by diluting 112.7 g (1.5 mole) of (S)-(+)-2-amino-1-propanol in 500 mL of ethanol was added to this reaction part while maintaining the temperature of the reaction part at 10 ° C. or lower, and then 18 to 22 ° C. Stirred for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent. 1 L of toluene was added to the reaction concentrate to completely dissolve, 1 L of purified water was added thereto, washed twice, and the organic layer was separated. The organic layer was washed again with 1 L of 10% aqueous sodium bicarbonate solution, and the organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 407.97 (95%) of ethyl 2- [2,3,5-trifluoro-4-. (4-methyl-1-piperazinyl)] benzoyl-3 (S)-(1-hydroxypropy-2-ylamino) acrylate was obtained.
여기서 Spectrum data는 실시예 5와 동일하다.Here, the spectrum data is the same as in Example 5.
본 발명이 제공하는 방법으로 상기의 알킬 2-[2,3,5-트리플루오로-4-(4-메틸-1-피페라지닐)]벤조일-3-(S)-(1-히드록시프로피-2-닐아미노)아크릴레이트를 제조하면 높은 수율로 목적물질을 제조할 수 있고, 이 화합물은 항균제로서 유용한 약제인 레보플록사신(Levofloxacin)의 제조시 중간체로 유용하게 사용할 수 있다.According to the present invention, the above alkyl 2- [2,3,5-trifluoro-4- (4-methyl-1-piperazinyl)] benzoyl-3- (S)-(1-hydroxy Propi-2-ylamino) acrylate can be prepared in high yield, and the compound can be useful as an intermediate in the preparation of levofloxacin, a drug useful as an antibacterial agent.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2000-0058050A KR100484386B1 (en) | 2000-10-04 | 2000-10-04 | Process for the preparation of alkyl 2 - [2,3,5 -trifluoro - 4 - (4 - methyl-1-piperazinyl)] benzoyl - 3(S)-(1 - hydroxyprop - 2 - ylamino) acrylate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2000-0058050A KR100484386B1 (en) | 2000-10-04 | 2000-10-04 | Process for the preparation of alkyl 2 - [2,3,5 -trifluoro - 4 - (4 - methyl-1-piperazinyl)] benzoyl - 3(S)-(1 - hydroxyprop - 2 - ylamino) acrylate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20020026961A KR20020026961A (en) | 2002-04-13 |
| KR100484386B1 true KR100484386B1 (en) | 2005-04-22 |
Family
ID=19691613
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR10-2000-0058050A KR100484386B1 (en) | 2000-10-04 | 2000-10-04 | Process for the preparation of alkyl 2 - [2,3,5 -trifluoro - 4 - (4 - methyl-1-piperazinyl)] benzoyl - 3(S)-(1 - hydroxyprop - 2 - ylamino) acrylate |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR100484386B1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4255575A (en) * | 1979-05-04 | 1981-03-10 | Richardson-Merrell Inc. | 2-Hydroxy-5-(1-hydroxy-2-piperazinylethyl)-benzoic acid derivatives |
| US5380860A (en) * | 1990-03-27 | 1995-01-10 | Pfizer Inc. | Preparation of beta-ketoesters useful in preparing quinolone antibiotics |
| US5663411A (en) * | 1994-03-22 | 1997-09-02 | Korea Institute Of Science And Technology | (+)2-benzoyl-3-[(prop-2(S)-yl)amino]acrylate derivatives and a method for the preparation of the same |
| KR19990047362A (en) * | 1997-12-04 | 1999-07-05 | 이종배, 이성균 | Method for preparing (-)-3 (S) -methylpyridobenzoxazine intermediate derivative |
-
2000
- 2000-10-04 KR KR10-2000-0058050A patent/KR100484386B1/en active IP Right Grant
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4255575A (en) * | 1979-05-04 | 1981-03-10 | Richardson-Merrell Inc. | 2-Hydroxy-5-(1-hydroxy-2-piperazinylethyl)-benzoic acid derivatives |
| US5380860A (en) * | 1990-03-27 | 1995-01-10 | Pfizer Inc. | Preparation of beta-ketoesters useful in preparing quinolone antibiotics |
| US5663411A (en) * | 1994-03-22 | 1997-09-02 | Korea Institute Of Science And Technology | (+)2-benzoyl-3-[(prop-2(S)-yl)amino]acrylate derivatives and a method for the preparation of the same |
| KR19990047362A (en) * | 1997-12-04 | 1999-07-05 | 이종배, 이성균 | Method for preparing (-)-3 (S) -methylpyridobenzoxazine intermediate derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20020026961A (en) | 2002-04-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5247436B2 (en) | Method for producing methylene disulfonate compound | |
| KR101771997B1 (en) | Method for producing a methylene disulfonate compound | |
| KR100852962B1 (en) | Manufacturing method of 2-hydroxy-5-phenylalkylaminobenzoic acid derivatives and their salts | |
| KR100309871B1 (en) | Process for Preparing (-)Pyridobenzoxazine Carboxylic Acid Derivatives | |
| WO2008041734A1 (en) | Tertiary alkyl ester of oxodibenzoxepin acetic acid | |
| KR100484386B1 (en) | Process for the preparation of alkyl 2 - [2,3,5 -trifluoro - 4 - (4 - methyl-1-piperazinyl)] benzoyl - 3(S)-(1 - hydroxyprop - 2 - ylamino) acrylate | |
| JP5280115B2 (en) | Method for producing p-phenylenebis (trimellitic acid monoester anhydride) | |
| KR100253047B1 (en) | Verfahren zur herstellung von 8-chlorochinolomderivaten | |
| EP0543095B1 (en) | Method for producing 2-amino-6-halogenopurine and synthesis of an intermediate therefore | |
| JP2518014B2 (en) | Method for purifying α-substituted acetic acid | |
| US5446148A (en) | Method for the production of azaphenothiazines | |
| JP2009286717A (en) | Method for producing benzoxazinone compound | |
| JPH0477477A (en) | Production of thiadiazoleacetic acid derivative | |
| US7078543B2 (en) | Methods for producing oxirane carboxylic acids and derivatives thereof | |
| JPH06166683A (en) | Production of o,o'-diacyltartaric acid anhydride | |
| KR100494881B1 (en) | Ethyl 2-[2,3,5-trifluoro-4-(4-methyl-1-piperazinyl)]benzoyl-3(S)-(1-hydroxyprop-2-ylamino)acrylate and a process for preparing thereof | |
| KR100334462B1 (en) | A process for producing ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3(S)-(1-hydroxyprop-2-ylamino)acrylate | |
| JPH04270272A (en) | Production of aminoalkylmorpholine derivative | |
| KR101086177B1 (en) | 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 | |
| JPS6097951A (en) | Novel process for producing thiosulfonic acid derivative | |
| KR100230132B1 (en) | A process for pyrido benzoxazin derivatives & intermediates with optical activities | |
| JPH05320107A (en) | 3-dialkylamino-2-substituted benzoylacrylic acid derivative | |
| CN114560862A (en) | Synthesis method of pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivative thereof | |
| JP2008056815A (en) | Method for producing poly-indigo | |
| JPS59163370A (en) | Preparation of 0-(aminomethyl)phenylacetic lactam |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| FPAY | Annual fee payment |
Payment date: 20101224 Year of fee payment: 7 |
|
| FPAY | Annual fee payment |
Payment date: 20111228 Year of fee payment: 10 |
|
| FPAY | Annual fee payment |
Payment date: 20150106 Year of fee payment: 13 |
|
| FPAY | Annual fee payment |
Payment date: 20180529 Year of fee payment: 16 |