KR100209298B1 - Novel amino-cyclic compound - Google Patents
Novel amino-cyclic compound Download PDFInfo
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- KR100209298B1 KR100209298B1 KR1019950056836A KR19950056836A KR100209298B1 KR 100209298 B1 KR100209298 B1 KR 100209298B1 KR 1019950056836 A KR1019950056836 A KR 1019950056836A KR 19950056836 A KR19950056836 A KR 19950056836A KR 100209298 B1 KR100209298 B1 KR 100209298B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D207/12—Oxygen or sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
Abstract
본 발명은 다음 일반식 (Ⅰ)로 표시되며 3번위치의 비대칭탄소로 생성되는 광학 이성질체를 포함하는 새로운 아민고리 화합물 및 그 산 부가염에 관한 것이다.The present invention relates to a novel amine ring compound and an acid addition salt thereof, which are represented by the following general formula (I) and contain an optical isomer produced by the asymmetric carbon at position 3.
상기식에서, R1, R2는 서로 같거나 다르며 각각 수소원자 또는 탄소수 1-3개의 저급알킬기를 나타내고 n은 1 또는 2의 정수이다.Wherein R 1 and R 2 are the same as or different from each other, and each represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and n is an integer of 1 or 2.
본 발명에 따른 상기 일반식 (Ⅰ)의 아민고리 화합물은 항균 활성을 갖는 각종 퀴놀론 유도체 화합물 제조시 도입기로 이용되는 원료 중간체로서 매우 유용하며 이 새로운 중간체를 도입한 퀴놀론 항균 화합물은 매우 뛰어난 항균 활성을 갖는다.The amine ring compound of the general formula (I) according to the present invention is very useful as a raw material intermediate used as an introduction material in the preparation of various quinolone derivative compounds having antibacterial activity, and the quinolone antibacterial compound introduced with this new intermediate has excellent antibacterial activity. Have
Description
본 발명은 다음 일반시 (Ⅰ)로 표시되는 새로운 아민고리 화합물 및 그 산 부가염에 과한 것이다.The present invention is in excess of the novel amine ring compound and acid addition salt thereof represented by the following general time (I).
상기식중에서 R1, R2는 서로 같거나 다르며 각각 수소원자 또는 탄소수 1-3개의 저급 알킬기를 나타내며 n은 1 또는 2 정수이다.Wherein R 1 and R 2 are the same as or different from each other, and each represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and n is an integer of 1 or 2;
일반식 (Ⅰ)으로 표시된 화합물은 3번 위치의 비대칭탄소로 인한 광학적 이성질체를 포함한다. 따라서 모든 광학 이성질체 및 그들의 혼합물은 편리상 단일 구조식으로 표기한다.Compounds represented by formula (I) include optical isomers due to the asymmetric carbon at position 3. Therefore, all optical isomers and mixtures thereof are conveniently expressed as single structural formula.
일반적으로 퀴놀론 카르복실산 항균제는 뛰어난 항균력과 광범위한 항균활성 화합물로서 이미 널리 사용되고 있으며 그 대표적인 예로서 노플록사신, 에녹사신, 시플록사신, 오플록사신 등이 현재 시판중에 있다.In general, the quinolone carboxylic acid antimicrobial agent is already widely used as an excellent antimicrobial activity and a wide range of antimicrobial active compounds, and representative examples thereof are nofloxacin, enoxacin, cifloxacin, and oploxacin.
그러나 이들 항균제의 경우 그람음성균에 대해서는 탁월한 항균력을 보여주지만 그람양성균에 대해서는 그 항균력이 현저히 떨어지고 또한 내성균 발현으로 인하여 새로운 향균제 개발이 요구되어지고 있다.However, these antimicrobial agents show excellent antimicrobial activity against gram-negative bacteria, but the antimicrobial activity is significantly reduced against gram-positive bacteria and development of new antimicrobial agents is required due to the expression of resistant bacteria.
이에 본 발명자들은 상술한 바와 같은 퀴놀론계 항균제의 단점을 보완하기 위해 기존의 퀴놀론 모핵의 C-7 위치에 새로운 도입기를 찾아내려는 연구 결과 본 발명을 완성하게 되었다.Accordingly, the present inventors have completed the present invention as a result of finding a new introducer at the C-7 position of the existing quinolone mother nucleus in order to compensate for the disadvantage of the quinolone antibacterial agent as described above.
따라서 본 발명은 퀴놀론계 항균화합물에 도입되는 매우 유용한 중간체인 상기 일반식 (Ⅰ)의 아민고리 화합물을 제공하는 데 그 목적이 있다.Accordingly, an object of the present invention is to provide an amine ring compound of the general formula (I), which is a very useful intermediate to be introduced into a quinolone antibacterial compound.
이러한 본 발명의 상기 일반식 (Ⅰ)의 화합물 제조 방법을 살펴보면 공지의 화합물인 일반식(Ⅱ) 화합물을 출발물질로 하여 다음의 반응과정을 거쳐 제조할 수 있다.Looking at the method for preparing the compound of the general formula (I) of the present invention can be prepared through the following reaction process using a compound of the general formula (II) as a known compound as a starting material.
상기식에서 R1, R2와 n은 전술한 바와 같고 R3는 벤질 또는 벤질옥시카르보닐과 같은 아민보호기이다.Wherein R 1 , R 2 and n are as described above and R 3 is an amine protecting group such as benzyl or benzyloxycarbonyl.
상기 반응과정에서 화합물(Ⅲ)는 화합물(Ⅲ)로부터 트리에틸아민, 디이소프로필에틸아민 등과 같은 적당한 염기 존재하에 벤질할라이드, 벤질클로로포메이트와 같은 아민보호기를 사용항 제조할 수 있고 이것은 디에틸 아조디카르복실레이트와 트리페닐포스핀 존재하에 N-히드록시프탈리미드와 반응시켜 화합물(Ⅳ)를 얻는다.Compound (III) can be prepared from compound (III) using an amine protecting group such as benzyl halide, benzyl chloroformate in the presence of a suitable base such as triethylamine, diisopropylethylamine, etc. Compound (IV) is obtained by reacting with N-hydroxyphthalimide in the presence of azodicarboxylate and triphenylphosphine.
화합물(Ⅳ)를 에탄올 용액하 히드라진 하이드레이트와 반응시켜 화합물(Ⅴ)를 만들고 이것을 팔라듐 존재하에 수소 반응시켜 상기 구조식 (Ⅰ)의 화합물을 얻을 수 있다.Compound (IV) may be reacted with hydrazine hydrate in ethanol solution to make compound (V), which may then be hydrogen reacted in the presence of palladium to afford the compound of formula (I).
이와 같은 본 발명에 따라 제조된 상기 일반식 (Ⅰ)의 새로운 아민고리 화합물은 항균활성을 갖는 각종 퀴놀론 유도체 화합물 제조시 도입기로 이용되는 원료화합물인 중간체로서 매우 유용하며 이러한 본 발명의 신규 화합물을 모핵에 도입한 퀴놀론 항균제는 뛰어난 항균활성을 나타낸다.The new amine ring compound of the general formula (I) prepared according to the present invention is very useful as an intermediate, which is a raw material used as an introducer in the preparation of various quinolone derivative compounds having antimicrobial activity, and the novel compound of the present invention The quinolone antibacterial agent introduced into the exhibits excellent antibacterial activity.
이하 본 발명을 실시예로 상세히 설명하는 바 본 발명이 다음의 실시예의 의해 한정되어지는 것은 아니다.Hereinafter, the present invention will be described in detail by way of examples, which should not be construed as limiting the present invention.
[실시예 1]Example 1
[1-벤질옥시카르보닐-3-히드록시피롤리딘][1-benzyloxycarbonyl-3-hydroxypyrrolidine]
3-히드록시피롤리딘 5g(57mmol)을 무수 디클로로메탄 100에 묽히고 디이소프로필에틸아민 12.02(69mmol)을 가한 후 0에서 벤질클로로포메이트 9.83(69mmol)를 천천히 첨가한 후 온도를 서서히 높혀 상온에서 4시간동안 교반시켰다.5 g (57 mmol) of 3-hydroxypyrrolidine was added to anhydrous dichloromethane 100 Dilute to diisopropylethylamine 12.02 0 after adding (69 mmol) Benzylchloroformate 9.83 (69 mmol) was slowly added and the temperature was gradually raised and stirred at room temperature for 4 hours.
반응액을 물과 소금물로서 차례로 씻어준 후 무수 MgSO4로 건조한 후 농축하여 목적화합물 11.96g(수율 95%)을 얻었다.The reaction solution was washed sequentially with water and brine, dried over anhydrous MgSO 4 , and concentrated to give 11.96 g (yield 95%) of the title compound.
1H-NMR(CDCl3, ppm) : 1.92(m, 2H) 2.83(s, 1H) 3.47(m, 4H) 4.41(m, 1H) 5.14(s, 2H) 7.34(m, 5H) 1 H-NMR (CDCl 3 , ppm): 1.92 (m, 2H) 2.83 (s, 1H) 3.47 (m, 4H) 4.41 (m, 1H) 5.14 (s, 2H) 7.34 (m, 5H)
[실시예 2]Example 2
[3-(1-벤질옥시카르보닐피롤리디녹시)프탈리미드][3- (1-benzyloxycarbonylpyrrolidinoxy) phthalimide]
무수 테트라히드로퓨란 200에 1-벤질옥시카르보닐-3-히드록시피롤리딘 8.03g(36mmol), 트리페닐포스핀 9.44g(36mmol)과 N-히드록시프탈리미드 5.92g (36mmol)을 차례로 가하여 녹인 후 0에서 디에틸 아조디카르복실레이트 6.23(39.6mmol)을 천천히 첨가한 후 상온에서 24시간동안 교반시켰다. 반응물을 농축시킨 후 디에틸에테르를 가하여 생성되는 트리페닐포스핀옥사이드를 거른 다음 칼럼크로마토그래피를 사용하여 목적화합물 7.22g를 분리하였다.(수율 55%)Anhydrous Tetrahydrofuran 200 8.03 g (36 mmol) of 1-benzyloxycarbonyl-3-hydroxypyrrolidine, 9.44 g (36 mmol) of triphenylphosphine and 5.92 g (36 mmol) of N-hydroxyphthalimide were added to each other, and dissolved. Diethyl azodicarboxylate 6.23 in (39.6 mmol) was added slowly and stirred at room temperature for 24 hours. The reaction was concentrated, diethyl ether was added, and the resulting triphenylphosphine oxide was filtered and 7.22 g of the target compound was separated by column chromatography. (Yield 55%)
1H-NMR(CDCl3, ppm) : 2.20(m, 2H) 3.72(s, 4H) 5.00(m, 1H) 5.20(m, 2H) 7.45(s, 5H) 7.80(m, 4H) 1 H-NMR (CDCl 3 , ppm): 2.20 (m, 2H) 3.72 (s, 4H) 5.00 (m, 1H) 5.20 (m, 2H) 7.45 (s, 5H) 7.80 (m, 4H)
[실시예 3]Example 3
[0-[3-(1-벤질옥시카르보닐피롤리디닐)]히드록시아민][0- [3- (1-benzyloxycarbonylpyrrolidinyl)] hydroxyamine]
3-(1-벤질옥시카르보닐피롤리디녹시)프탈리미드 6.56g(18mmol)을 50에탄올에 묽히고 히드라진 하이드레이트 1.1(18mmol)를 가해 2시간동안 상온에서 교반시킨 후 포화 탄산수소나트륨 30를 반응용기에 붓고 10분간 저어준 후 디에틸에테르로 3번 추출하였다. 유기층을 무수 MgSO4로 건조한 후 농축하여 칼럼크로마토그래피로 분리하여 목적화합물 2.53g을 얻었다.(수율 59.8%)6.56 g (18 mmol) of 3- (1-benzyloxycarbonylpyrrolidinoxy) phthalimide was added to 50 Dilute in ethanol and hydrazine hydrate 1.1 (18 mmol) was added and the mixture was stirred at room temperature for 2 hours, followed by saturated sodium hydrogen carbonate 30 Pour into the reaction vessel and stirred for 10 minutes and extracted three times with diethyl ether. The organic layer was dried over anhydrous MgSO 4 , concentrated and separated by column chromatography to obtain 2.53 g of the target compound. (Yield 59.8%)
1H-NMR(CDCl3, ppm) : 2.2(m, 2H) 3.73(s, 4H) 5.0(m, 1H) 5.17(m, 2H) 7.35(s, 5H) 7.8(s, 4H) 1 H-NMR (CDCl 3 , ppm): 2.2 (m, 2H) 3.73 (s, 4H) 5.0 (m, 1H) 5.17 (m, 2H) 7.35 (s, 5H) 7.8 (s, 4H)
[실시예 4]Example 4
[0-(3-피롤리디닐)히드록시아민의 제조][Preparation of 0- (3-pyrrolidinyl) hydroxyamine]
0-[3-(1-벤질옥시카르보닐피롤리디닐)]히드록시아민 2.3g(9.7mmol)을 100에탄올에 묽히고 10% 팔라듐 0.2g를 현탁시킨 다음 상온에서 3시간동안 30psi의 수소압력을 가하여 교반시킨 후 여과하여 여과액을 농축시켜 목적화합물 700을 얻었다.(수율 70%)2.3 g (9.7 mmol) of 0- [3- (1-benzyloxycarbonylpyrrolidinyl)] hydroxyamine Dilute in ethanol, suspend 0.2 g of 10% palladium, and then stir at 30 psi for 30 hours under hydrogen pressure at room temperature, filter, and concentrate the filtrate. Was obtained. (Yield 70%)
1H-NMR(CDCl3, ppm) : 1.73(m, 2H) 2.15-2.21(m, 4H) 4.37(m, 1H) 6.0(bs, 2H) 1 H-NMR (CDCl 3 , ppm): 1.73 (m, 2H) 2.15-2.21 (m, 4H) 4.37 (m, 1H) 6.0 (bs, 2H)
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| KR1019950056836A KR100209298B1 (en) | 1995-12-26 | 1995-12-26 | Novel amino-cyclic compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR19980015377A (en) * | 1996-08-21 | 1998-05-25 | 이웅열 | New quinolone carboxylic acid compounds and methods for their preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR19980015377A (en) * | 1996-08-21 | 1998-05-25 | 이웅열 | New quinolone carboxylic acid compounds and methods for their preparation |
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