KR101973751B1 - Synthetic method of tetrahydroquinolines derivatives - Google Patents

Synthetic method of tetrahydroquinolines derivatives Download PDF

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KR101973751B1
KR101973751B1 KR1020170108554A KR20170108554A KR101973751B1 KR 101973751 B1 KR101973751 B1 KR 101973751B1 KR 1020170108554 A KR1020170108554 A KR 1020170108554A KR 20170108554 A KR20170108554 A KR 20170108554A KR 101973751 B1 KR101973751 B1 KR 101973751B1
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tetrahydroquinoline
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김대영
김연주
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순천향대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines

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Abstract

본 발명은 테트라하이드로퀴놀린 유도체의 제조방법에 관한 것으로, 구체적으로 루이스 산을 이용하여 오쏘-다이알킬아미노 나이트로스틸렌 유도체의 분자내 고리화 반응, 구체적으로 분자내 1,5-수소전이/고리화 반응을 통해 테트라하이드로퀴놀린 유도체를 제조하는 것에 관한 것이다. 본 발명의 제조방법은 마일드한 온도 조건에서 높은 수율로 생물학적으로 중요한 테트라하이드로퀴놀린의 다양한 유도체를 제조할 수 있다.The present invention relates to a process for preparing a tetrahydroquinoline derivative, and more particularly, to a process for producing an ortho-dialkylaminostrostene derivative by using a Lewis acid in an intramolecular cyclization reaction, specifically an intramolecular 1,5-hydrogen transfer / To a tetrahydroquinoline derivative through a reaction. The process of the present invention makes it possible to prepare various derivatives of tetrahydroquinoline which are biologically important in high yields under mild temperature conditions.

Description

테트라하이드로퀴놀린 유도체의 제조방법{Synthetic method of tetrahydroquinolines derivatives}TECHNICAL FIELD The present invention relates to a method for producing tetrahydroquinoline derivatives,

본 발명은 생리활성을 갖는 테트라하이드로퀴놀린 유도체를 효율적으로 제조하는 방법에 관한 것으로, 오쏘-다이알킬아미노 나이트로스틸렌 유도체(o-dialkyl amino nitrostyrene derivatives)를 분자내 1,5-수소전이/고리화 반응시켜 테트라하이드로퀴놀린 유도체를 제조하는 제조방법에 관한 것이다.The present invention relates to a method for efficiently producing a tetrahydroquinoline derivative having a physiological activity, which comprises reacting an o- dialkyl amino nitrostyrene derivative with an intramolecular 1,5-hydrogen transfer / cyclization And then reacting the resulting mixture to prepare a tetrahydroquinoline derivative.

테트라하이드로퀴놀린 유도체는 천연물의 핵심 골격으로 독특한 생리활성을 가지고 있어 의약화학 및 유기합성 분야에서 널리 연구되고 있으며 생리활성 물질 합성에 중요한 중간체로 사용되고 있다. 도 1은 다양한 테트라하이드로퀴놀린 유도체의 구조를 나타낸다.Tetrahydroquinoline derivatives have a unique physiological activity as a key skeleton of natural materials and are widely studied in the field of pharmaceutical chemistry and organic synthesis and are used as intermediates in the synthesis of physiologically active substances. Figure 1 shows the structure of various tetrahydroquinoline derivatives.

이러한 테트라하이드로퀴놀린 유도체 중 옥삼니퀸(oxamniquine)은 혈관기생충 치료제로 사용되고 있고, 비란트마이신(virantmycin)은 항생제로 사용되고 있다. 또한, L-689, 560은 NMDA 길항제 후보 물질로 개발 중에 있다.Of these tetrahydroquinoline derivatives, oxamniquine is used as a therapeutic agent for vascular parasites, and virantmycin is used as an antibiotic. In addition, L-689 and 560 are being developed as candidates for NMDA antagonists.

1,5-수소전이/고리화 반응은 테트라하이드로퀴놀린 유도체를 합성할 수 있는 유용한 방법 중에 하나이다. 이 반응은 분자 내에서 일어나는 반응으로 매우 효율적이고 반응 부산물이 생성되지 않으므로 매우 경제적인 반응이다. 테트라하이드로퀴놀린을 제조하는 방법에는 다양한 루이스(Lewis) 산 촉매 및 브론스테드(Bronsted) 산 촉매를 이용한 방법이 개발되었다. 그 중에서 2008년 Jordis의 논문에는 루이스 산 촉매를 사용해서 테트라하이드로퀴놀린의 합성한 것이 기재되어 있지만, 기재된 방법은 높은 온도(118℃)에서 80 시간 이상의 반응시간과 39% 이하의 낮은 수율로 한정된 유도체의 테트라하이드로퀴놀린을 합성하는 단점이 있다(Heterocycles, 2008, 75, 799-838 참조).The 1,5-hydrogen transfer / cyclization reaction is one of the useful methods for synthesizing tetrahydroquinoline derivatives. This reaction is a reaction that takes place in a molecule and is very economical because it is highly efficient and does not produce reaction by-products. Methods for preparing tetrahydroquinolines have been developed using a variety of Lewis acid catalysts and Bronsted acid catalysts. Among them, the 2008 Jordis article describes the synthesis of tetrahydroquinolines using Lewis acid catalysts, but the disclosed process is limited to reactions with a reaction time of at least 80 hours and a yield of less than 39% at high temperature (118 ° C) (See Heterocycles , 2008, 75 , 799-838). ≪ RTI ID = 0.0 >

본 발명은 루이스 산 촉매를 사용하면서 마일드한 온도 조건에서 오쏘-다이알킬아미노 나이트로스틸렌 유도체(o-dialkyl amino nitrostyrene derivatives)로부터 생물학적으로 중요한 테트라하이드로퀴놀린의 다양한 유도체를 합성하는 방법을 제공하는 것을 목적으로 한다.The present invention is a Lewis acid at a mild temperature conditions and using a catalyst ortho-object of the present invention to provide a method for synthesizing a variety of derivatives of styrene derivatives dialkylamino night (o -dialkyl amino nitrostyrene derivatives) biologically important from tetrahydroquinoline .

본 발명은 하기 화학식 1의 구조를 갖는 오쏘-다이알킬아미노 나이트로스틸렌 유도체를 루이스 산 촉매를 이용하여 분자내 1,5-수소전이/고리화 반응을 통해 하기 화학식 2의 구조를 갖는 테트라하이드로퀴놀린 유도체를 제조하는 것을 포함하는 테트라하이드로퀴놀린 유도체의 제조방법에 관한 것으로서, 화학식 1 및 2에서 상기 R1은 수소, 트리플루오로알킬, C1-C3 알콕시 또는 할로겐 원소이고, 상기 n은 1 내지 5의 정수이다.The present invention relates to an ortho-dialkylamino nitrostyrene derivative having a structure represented by the following general formula (1) by means of a 1,5-hydrogen transfer / cyclization reaction in the molecule using a Lewis acid catalyst and a tetrahydroquinoline Wherein R 1 is hydrogen, trifluoroalkyl, C 1 -C 3 alkoxy or halogen, and n is an integer of 1 to 3, Lt; / RTI >

[화학식 1][Chemical Formula 1]

Figure 112017082962199-pat00001
Figure 112017082962199-pat00001

[화학식 2](2)

Figure 112017082962199-pat00002
Figure 112017082962199-pat00002

바람직하게는, 상기 루이스 산 촉매는 Sc(OTf)3, La(OTf)3 또는 Yb(OTf)3이다.Preferably, the Lewis acid catalyst is Sc (OTf) 3 , La (OTf) 3 or Yb (OTf) 3 .

바람직하게는, 상기 루이스 산 촉매는 Sc(OTf)3이다.Preferably, the Lewis acid catalyst is Sc (OTf) 3 .

바람직하게는, 상기 반응은 아세토나이트릴 용매 하에서 일어난다.Preferably, the reaction takes place in an acetonitrile solvent.

바람직하게는, 상기 Sc(OTf)3 촉매의 양은 오쏘-다이알킬아미노 나이트로스틸렌 유도체의 몰 수에 대하여 5 내지 30 몰%이다.Preferably, the amount of the Sc (OTf) 3 catalyst is from 5 to 30 mol% relative to the molar number of ortho-dialkylamino styrene derivatives.

바람직하게는, 상기 방법은 80℃의 온도에서 12시간 내지 36시간 동안 진행된다.Preferably, the process is carried out at a temperature of 80 DEG C for 12 to 36 hours.

바람직하게는, 상기 테트라하이드로퀴놀린 유도체는 62% 이상의 수율로 얻어진다.Preferably, the tetrahydroquinoline derivative is obtained in a yield of 62% or more.

본 발명의 오쏘-다이알킬아미노 나이트로스틸렌 유도체를 분자내 1,5-수소전이/고리화 반응시켜 테트라하이드로퀴놀린 유도체를 제조하는 방법은 마일드한 온도 조건에서 높은 수율로 생물학적으로 중요한 테트라하이드로퀴놀린의 다양한 유도체를 제조할 수 있다.The method for preparing tetrahydroquinoline derivatives by the 1,5-hydrogen transfer / cyclization reaction of the ortho-dialkylaminostrostylene derivatives of the present invention is a method for the production of tetrahydroquinoline derivatives which are biologically important at mild temperature conditions Various derivatives can be prepared.

도 1은 다양한 테트라하이드로퀴놀린 유도체의 구조를 나타낸다.
도 2는 본 발명에 따른 실시예들의 화합물의 구조를 나타낸다.Figure 1 shows the structure of various tetrahydroquinoline derivatives.
Figure 2 shows the structure of the compounds of the examples according to the invention.

본 발명에서 사용되는 모든 기술용어는, 달리 정의되지 않는 이상, 하기의 정의를 가지며 본 발명의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미에 부합된다. 또한, 본 명세서에는 바람직한 방법이나 시료가 기재되나, 이와 유사하거나 동등한 것들도 본 발명의 범주에 포함된다.Unless defined otherwise, all technical terms used in the present invention have the following definitions and are consistent with the meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention.

본 명세서를 통해, 문맥에서 달리 필요하지 않으면, "포함하다" 및 "포함하는"이란 말은 제시된 단계 또는 구성요소, 또는 단계 또는 구성요소들의 군을 포함하나, 임의의 다른 단계 또는 구성요소, 또는 단계 또는 구성요소들의 군이 배제되지는 않음을 내포하는 것으로 이해하여야 한다. Throughout this specification, the words " comprises " and " comprising ", unless the context requires otherwise, include the steps or components, or groups of steps or elements, Steps, or groups of elements are not excluded.

본 발명은 오쏘-다이알킬아미노 나이트로스틸렌 유도체(o-dialkyl amino nitrostyrene derivatives)로부터 테트라하이드로퀴놀린 유도체를 효율적으로 제조하는 방법에 관한 것이다. 구체적으로 하기 화학식 1의 구조를 갖는 오쏘-다이알킬아미노 나이트로스틸렌 유도체(o-dialkyl amino nitrostyrene derivatives)를 아세토나이트릴 용매 하에서 루이스 산 촉매를 이용하여 분자내 1,5-수소전이/고리화 반응을 통해 하기 화학식 2의 구조를 갖는 테트라하이드로퀴놀린 유도체를 제조하는 방법에 관한 것으로, 하기 반응식 1과 같이 반응이 일어난다.The present invention is ortho-directed to a method for efficient production of a tetrahydroquinoline derivative dialkylamino night from a styrene derivative (o -dialkyl amino nitrostyrene derivatives). Specifically, o- dialkyl amino nitrostyrene derivatives having the structure of the following formula (1) are subjected to an intramolecular 1,5-hydrogen transfer / cyclization reaction using an Lewis acid catalyst in an acetonitrile solvent To a process for producing a tetrahydroquinoline derivative having a structure represented by the following formula (2), wherein the reaction is carried out as shown in the following reaction formula (1).

[반응식 1][Reaction Scheme 1]

Figure 112017082962199-pat00003
Figure 112017082962199-pat00003

[화학식 1][Chemical Formula 1]

Figure 112017082962199-pat00004
Figure 112017082962199-pat00004

상기 화학식 1로 나타낸 오쏘-다이알킬아미노 나이트로스틸렌 유도체는 상기 반응식 1의 반응물이다. 종래에는 1,5-수소전이/고리화 반응에 사용된 출발물질은 불포화된 알데하이드, 불포화된 에스터 구조에 국한되어 있었으나, 본 발명에서는 루이스 산 촉매를 사용하여 마일드한 조건에서 효율적으로 반응할 수 있는 반응물로서 오쏘-다이알킬아미노 나이트로스틸렌 유도체를 선택할 수 있었다.The ortho-dialkylaminostrostylene derivative represented by Formula 1 is a reaction product of Reaction Scheme 1 above. In the prior art, the starting material used in the 1,5-hydrogen transfer / cyclization reaction was limited to the unsaturated aldehyde and unsaturated ester structure. However, in the present invention, the Lewis acid catalyst can be used to efficiently react in a mild condition Ortho-dialkylamino nitrostyrene derivatives could be selected as reactants.

[화학식 2](2)

Figure 112017082962199-pat00005
.
Figure 112017082962199-pat00005
.

상기 화학식 2로 나타낸 테트라하이드로퀴놀린 유도체는 상기 반응식 1의 생성물이다.The tetrahydroquinoline derivative represented by Formula 2 is the product of Reaction Scheme 1.

상기 화학식 1 및 2에서 상기 R1은 수소, 트리플루오로알킬, C1-C3 알콕시 또는 할로겐 원소이고, 할로겐 원소는 플루오르(F), 염소(Cl), 브롬(Br) 및 아이오드(I)를 의미한다. 화학식 1 및 2에서 상기 n은 1 내지 5의 정수이며, n에 따라서 5각 내지 9각 고리일 수 있다.In the above formulas 1 and 2, R 1 is hydrogen, trifluoroalkyl, C 1 -C 3 alkoxy or a halogen element, and the halogen element is fluorine (F), chlorine (Cl), bromine (Br) ). In the general formulas (1) and (2), n is an integer of 1 to 5, and may be a 5- to 9-membered ring depending on n.

촉매는 루이스 산 촉매를 사용할 수 있다. 촉매는 Sc(OTf)3, La(OTf)3, Yb(OTf)3, Cu(OTf)3, AlCl3, InCl3 등의 모든 루이스 산 촉매을 사용할 수 있고, 바람직하게는 Sc(OTf)3, La(OTf)3 및 Yb(OTf)3를 사용할 수 있고, 가장 바람직하게는 Sc(OTf)3 촉매를 사용하는 경우에 가장 우수한 효율을 얻을 수 있다. 하기 화학식 3은 본 발명에서 루이스 산 촉매로 사용한 Sc(OTf)3 촉매이다.The catalyst may be a Lewis acid catalyst. The catalyst Sc (OTf) 3, La ( OTf) 3, Yb (OTf) 3, Cu (OTf) 3, AlCl 3, may be used InCl 3 all Lewis acids, such as chokmaeeul, preferably Sc (OTf) 3, La (OTf) 3 and Yb (OTf) 3 can be used, and the most excellent efficiency can be obtained when Sc (OTf) 3 catalyst is used most preferably. (3) is a Sc (OTf) 3 catalyst used as a Lewis acid catalyst in the present invention.

[화학식 3](3)

Figure 112017082962199-pat00006
Figure 112017082962199-pat00006

루이스 산 촉매를 이용하면 오쏘-다이알킬아미노 나이트로스틸렌 유도체(o-dialkyl amino nitrostyrene derivatives)에 나이트로기를 당겨서 알켄을 활성화시켜서 1,5-수소전이가 일어난 후 고리화 반응이 일어나 테트라하이드로퀴놀린 유도체를 합성할 수 있다. 또한, 촉매의 양은 오쏘-다이알킬아미노 나이트로스틸렌 유도체의 몰 수에 대하여 5 내지 30 몰%일 수 있다. 촉매의 양은 반응 시간 등을 고려하여 조절될 수 있다.When Lewis acid catalyst is used, the nitro group is pulled to o- dialkyl amino nitrostyrene derivatives to activate the alkene, resulting in the 1,5-hydrogen transfer, and then the cyclization reaction occurs to form the tetrahydroquinoline derivative Can be synthesized. In addition, the amount of catalyst may be from 5 to 30 mol% based on the number of moles of ortho-dialkylamino styrene derivatives. The amount of the catalyst can be controlled in consideration of the reaction time and the like.

본 발명에서 용매는 유기 용매를 사용할 수 있으며, 바람직하게는 아세토나이트릴을 사용할 수 있다.In the present invention, an organic solvent may be used as the solvent, and acetonitrile may be preferably used.

또한, 본 발명에 따른 테트라하이드로퀴놀린 유도체의 제조방법은 30℃ 내지 80℃의 온도에서 12시간 내지 36시간 동안 진행될 수 있고, 바람직하게는 80℃의 온도에서 12시간 내지 36시간 동안 진행될 수 있다.In addition, the process for preparing the tetrahydroquinoline derivative according to the present invention may be carried out at a temperature of 30 ° C to 80 ° C for 12 hours to 36 hours, preferably at a temperature of 80 ° C for 12 hours to 36 hours.

본 발명에 따른 일 예로서 화학식 1의 구조를 갖는 오쏘-다이알킬아미노 나이트로스틸렌 유도체(o-dialkyl amino nitrostyrene derivatives)를 아세토나이트릴 용매 하에서 Sc(OTf)3 촉매를 이용하여 분자내 1,5-수소전이/고리화 반응을 통해 하기 화학식 2의 구조를 갖는 테트라하이드로퀴놀린 유도체를 제조할 수 있으며, 이 때 반응은 하기 반응식 2와 같다.As an example according to the present invention, o- dialkyl amino nitrostyrene derivatives having the structure of the formula (1) can be prepared by reacting an o- dialkyl amino nitrostyrene derivative with a Sc (OTf) 3 catalyst in an acetonitrile solvent -Hydrogen transfer / cyclization, a tetrahydroquinoline derivative having a structure of the following formula (2) can be prepared.

[반응식 2][Reaction Scheme 2]

Figure 112017082962199-pat00007
Figure 112017082962199-pat00007

본 발명에 따른 제조방법으로 제조된 테트라하이드로퀴놀린 유도체는 43% 이상의 수율로 얻어질 수 있으며, 특히 Sc(OTf)3 촉매를 사용한 경우에 62% 이상의 수율로 얻어질 수 있다.The tetrahydroquinoline derivative prepared by the production process according to the present invention can be obtained in a yield of 43% or more, and particularly in a yield of 62% or more when using a Sc (OTf) 3 catalyst.

이하, 하기 실시예 등에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 다만, 하기 실시예 등은 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

실험예Experimental Example 1 One

루이스 산 촉매 및 용매에 따른 효과를 비교하기 위하여 실험을 진행하였다. 용매(2 mL)에 (E)-1-(2-(2-나이트로비닐)페닐)피롤리돈((E)-1-(2-(2-nitrovinyl)phenyl)pyrrolidine; 0.3 mmmol)과 촉매 10 mol%(반응물의 몰 수 대비)를 넣어 80℃의 온도에서 반응을 진행하였으며, 그 결과는 아래의 표 1과 같다.Experiments were conducted to compare the effects of Lewis acid catalysts and solvents. 0.3 mmol) of (E) -1- (2- (2-nitrovinyl) phenyl) pyrrolidone (E) The reaction was carried out at a temperature of 80 ° C by adding 10 mol% of the catalyst (in terms of the molar amount of the reactant). The results are shown in Table 1 below.

촉매catalyst 용매menstruum 시간(h)Time (h) 수율(%)yield(%) 실시예 1Example 1 La(OTf)3 La (OTf) 3 CH3CNCH 3 CN 3535 4343 실시예 2Example 2 Yb(OTf)3 Yb (OTf) 3 CH3CNCH 3 CN 3636 6363 실시예 3Example 3 Sc(OTf)3 Sc (OTf) 3 CH3CNCH 3 CN 2424 8080 비교예 1Comparative Example 1 Cu(OTf)3 Cu (OTf) 3 CH3CNCH 3 CN 3636 1212 비교예 2Comparative Example 2 AlCl3 AlCl 3 CH3CNCH 3 CN 3636 1010 비교예 3Comparative Example 3 InCl3 InCl 3 CH3CNCH 3 CN 3636 1515 비교예 4Comparative Example 4 Sc(OTf)3 Sc (OTf) 3 DMFDMF 4848 2121 비교예 5Comparative Example 5 Sc(OTf)3 Sc (OTf) 3 DMSODMSO 4848 2525 비교예 6Comparative Example 6 Sc(OTf)3 Sc (OTf) 3 EtOHEtOH 4848 1010

상기에서 알 수 있는 바와 같이, 루이스 산 촉매로 Sc(OTf)3, La(OTf)3 및 Yb(OTf)3를 사용하고, 용매로 CH3CN을 사용한 경우에 테트라하이드로퀴놀린 유도체의 수율이 우수한 것을 알 수 있다. 특히, 루이스 산 촉매로 Sc(OTf)3를 사용하고, 용매로 CH3CN을 사용한 경우에 가장 우수한 것을 알 수 있다.As can be seen from the above, when Sc (OTf) 3 , La (OTf) 3 and Yb (OTf) 3 are used as Lewis acid catalysts and CH 3 CN is used as a solvent, the yield of the tetrahydroquinoline derivative is excellent . Especially, Sc (OTf) 3 is used as a Lewis acid catalyst and CH 3 CN is used as a solvent.

실험예Experimental Example 2 2

루이스 산 촉매로 Sc(OTf)3를 사용하고, 용매로 CH3CN을 사용한 경우에 화학식 1의 구조를 갖는 다양한 오쏘-다이알킬아미노 나이트로스틸렌 유도체(o-dialkyl amino nitrostyrene derivatives)를 반응물로 하여 분자 내 1,5-수소전이/고리화 반응을 진행하여 테트라하이드로퀴놀린 유도체(화학식 2)를 합성하였으며 그 결과를 도 2 및 표 2에 나타내었다. 수율은 부분이성질체를 포함하여 나타내었으며, 부분이성질체의 비율은 1H NMR로 결정하였다.Various o- dialkyl amino nitrostyrene derivatives having the structure of the formula (1) are used as a reactant when Sc (OTf) 3 is used as a Lewis acid catalyst and CH 3 CN is used as a solvent The tetrahydroquinoline derivative (Formula 2) was synthesized by proceeding a 1,5-hydrogen transfer / cyclization reaction in the molecule. The results are shown in FIG. 2 and Table 2. Yields were shown including partial isomers, and the ratio of partial isomers was determined by 1 H NMR.

실시예Example 반응시간 (h)Reaction time (h) 수율 (%)Yield (%) 부분이성질체Partial isomer 33 2424 8080 >20:1> 20: 1 44 3636 6565 >20:1> 20: 1 55 2424 8585 >20:1> 20: 1 66 1212 9898 4:14: 1 77 1616 9696 3.3:13.3: 1 88 2424 6262 2.4:12.4: 1 99 2020 7979 1.5:11.5: 1 1010 2323 9595 5.9:15.9: 1 1111 2424 8282 4.2:14.2: 1 1212 1717 9999 1.5:11.5: 1 1313 2828 8080 1.6:11.6: 1 1414 1313 9898 2.5:12.5: 1 1515 2121 9999 2.2:12.2: 1 1616 1818 9191 1.6:11.6: 1

구체적인 실시예 3 내지 15의 반응물 및 생성물과 관련된 사항은 아래에 상세하게 기재하였다.The matters related to the reactants and products of concrete examples 3 to 15 are described in detail below.

실시예Example 3 : 43: 4 -나이트로-1,2,3,- Nitro-1, 2, 3, 3a,43a, 4 ,5-, 5- 헥사하이드로피롤로[1,2-a]퀴놀린Hexahydropyrrolo [1,2-a] quinoline (4-nitro-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline) (4-nitro-1,2,3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoline)

Figure 112017082962199-pat00008
Figure 112017082962199-pat00008

둥근 플라스크에 (E)-1-(2-(2-나이트로비닐)페닐)피롤리돈(0.3 mmol, R1이 H이고, n이 1인 화학식 1), Sc(OTf)3 촉매(0.003 mmol, 10 mol %), 아세토나이트릴(2 mL)을 넣고 80℃에서 환류시킨다. 반응 진행이 완료되면 반응혼합물을 농축하여 컬럼크로마토그래피(EtOAc/hexane = 1:30)로 분리정제하여 상기 구조를 갖는 실시예 3을 수득하였다. 1H NMR (400 MHz, CDCl3) d 7.15 (t, J=7.6Hz, 1H), 7.06 (d, J=7.2Hz, 1H),6.67 (t, J=7.2Hz, 1H), 6.50 (d, J=8.0Hz, 1H), 4.49-4.43 (m, 1H), 3.81-3.75 (m, 1H), 3.50-3.43 (m, 2H),3.31-3.25 (m, 2H), 2.07-1.94 (m, 4H); 13C NMR (100MHz, CDCl3) d 142.9, 128.9, 128.3, 117.3, 116.5, 111.2, 84.4, 60.3, 47.6, 33.7, 30.7, 23.4.In a round flask, Sc (OTf) 3 (0.3 mmol, R 1 is H and n is 1) (E) -1- (2- (2-nitrovinyl) phenyl) pyrrolidone The catalyst (0.003 mmol, 10 mol%) and acetonitrile (2 mL) were added and refluxed at 80 ° C. After completion of the reaction, the reaction mixture was concentrated and separated and purified by column chromatography (EtOAc / hexane = 1: 30) to obtain Example 3 having the above structure. 1 H NMR (400 MHz, CDCl 3) d 7.15 (t, J = 7.6Hz, 1H), 7.06 (d, J = 7.2Hz, 1H), 6.67 (t, J = 7.2Hz, 1H), 6.50 (d 2H), 3.31-3.25 (m, 2H), 2.07-1.94 (m, < RTI ID = 0.0 & , 4H); 13 C NMR (100 MHz, CDCl 3 ) d 142.9, 128.9, 128.3, 117.3, 116.5, 111.2, 84.4, 60.3, 47.6, 33.7, 30.7, 23.4.

실시예Example 4 : 74: 7 -- 플루오로Fluoro -4-나이트로-1,2,3,-4-nitro-1, 2, 3, 3a,43a, 4 ,5-, 5- 헥사하이드로피롤로[1,2-a]퀴놀린Hexahydropyrrolo [1,2-a] quinoline (7- (7- fluorofluoro -4-nitro-1,2,3,-4-nitro-1,2,3, 3a,43a, 4 ,5-, 5- hexahydropyrrolo[1,2-a]quinolinehexahydropyrrolo [1,2-a] quinoline ))

Figure 112017082962199-pat00009
Figure 112017082962199-pat00009

R1이 F이고, n이 1인 화학식 1의 반응물을 실시예 1과 동일한 조건으로 진행하여 상기 구조를 갖는 실시예 4를 수득하였다. 1H NMR (400 MHz, CDCl3) d 6.88-6.79 (m, 2H), 6.41 (q, J = 4.4 Hz, 1H), 4.48-4.42 (m, 1H), 3.76-3.70 (m, 1H), 3.50-3.40 (m, 2H), 3.29-3.22 (m, 2H), 2.07-1.97 (m, 4H); 13C NMR (100 MHz, CDCl3) d 139.6, 115.6, 115.4, 114.7, 114.5, 111.8, 84.1, 60.3, 48.1, 33.4, 30.6, 23.3; 19F NMR (376.17 Hz, CDCl3) d -130.2.The reaction product of formula (1) wherein R 1 is F and n is 1 is proceeded under the same conditions as in Example 1 to obtain Example 4 having the above structure. 1 H NMR (400 MHz, CDCl 3 )? 6.88-6.79 (m, 2H), 6.41 (q, J = 4.4 Hz, 1H), 4.48-4.42 3.50-3.40 (m, 2H), 3.29-3.22 (m, 2H), 2.07-1.97 (m, 4H); 13 C NMR (100 MHz, CDCl 3 ) d 139.6, 115.6, 115.4, 114.7, 114.5, 111.8, 84.1, 60.3, 48.1, 33.4, 30.6, 23.3; 19 F NMR (376.17 Hz, CDCl 3) d -130.2.

실시예Example 5 : 75: 7 -- 브로모Bromo -4-나이트로-1,2,3,-4-nitro-1, 2, 3, 3a,43a, 4 ,5-, 5- 헥사하이드로피롤로[1,2-a]퀴Hexahydropyrrolo [1,2-a] quinoline 놀린 (7-bromo-4-nitro-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoline)(7-bromo-4-nitro-1,2,3,3a, 4,5-hexahydropyrrolo [1,2-a] quinoline)

Figure 112017082962199-pat00010
Figure 112017082962199-pat00010

R1이 Br이고, n이 1인 화학식 1의 반응물을 실시예 1과 동일한 조건으로 진행하여 상기 구조를 갖는 실시예 5를 수득하였다. 1H NMR (400 MHz, CDCl3) d 7.21 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 6.35 (d, J = 8.4 Hz, 1H), 4.45-4.38 (m, 1H), 3.78-3.72 (m, 1H), 3.46-3.40 (m, 2H), 3.27-3.21 (m, 2H), 2.26-1.99 (m, 4H) ; 13C NMR (100 MHz, CDCl3) d 142.0, 131.3, 130.9, 119.3, 112.6, 108.1, 83.8, 60.2, 47.7, 33.3, 30.7, 23.4The reaction product of formula (1) wherein R 1 is Br and n is 1 is proceeded under the same conditions as in Example 1 to obtain Example 5 having the above structure. 1 H NMR (400 MHz, CDCl 3) d 7.21 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 6.35 (d, J = 8.4 Hz, 1H), 4.45-4.38 (m, 1H) , 3.78-3.72 (m, 1H), 3.46-3.40 (m, 2H), 3.27-3.21 (m, 2H), 2.26-1.99 (m, 4H); 13 C NMR (100 MHz, CDCl 3 ) d 142.0, 131.3, 130.9, 119.3, 112.6, 108.1, 83.8, 60.2, 47.7, 33.3, 30.7, 23.4

실시예Example 6 : 66: 6 -나이트로-5,6,- Nitro-5,6, 6a,76a, 7 ,8,9,10,11-, 8,9,10,11- 옥타하이드로아제피노[1,2-a]퀴Octahydroazepino [1,2-a] quinoline 놀린 (6-nitro-5,6,6a,7,8,9,10,11-octahydroazepino[1,2-a]quinoline)Nolin (6-nitro-5,6,6a, 7,8,9,10,11-octahydroazepino [1,2-a] quinoline)

Figure 112017082962199-pat00011
Figure 112017082962199-pat00011

R1이 H이고, n이 3인 화학식 1의 반응물을 실시예 1과 동일한 조건으로 진행하여 상기 구조를 갖는 실시예 6을 수득하였다. 1H NMR (400 MHz, CDCl3) d 7.09-7.04 (m, 2H), 6.67-6.58 (m, 2H), 4.92-4.67 (m, 1H), 4.17-4.10 (m, 1H), 3.87-3.81 (m, 1H), 3.54 (d, J = 17.2 Hz, 1H), 3.23-3.06 (m, 2H), 2.10-2.01 (m, 1H), 1.86-1.81 (m, 1H), 1.69-1.60 (m, 4H) , 1.55-1.38 (m, 2H); 13C NMR (100 MHz, CDCl3) d 142.4, 128.6, 127.4, 116.0, 115.4, 110.4, 81.4, 60.1, 48.9, 32.9, 26.8, 26.8, 26.6, 25.3.The reaction product of formula (1) wherein R 1 is H and n is 3 is proceeded under the same conditions as in Example 1 to obtain Example 6 having the above structure. 1 H NMR (400 MHz, CDCl 3 ) d 7.09-7.04 (m, 2H), 6.67-6.58 (m, 2H), 4.92-4.67 (m, 1H), 3.54 (d, J = 17.2 Hz, 1H), 3.23-3.06 (m, 2H), 2.10-2.01 (m, 1H), 1.86-1.81 , ≪ / RTI > 4H), 1.55-1.38 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) d 142.4, 128.6, 127.4, 116.0, 115.4, 110.4, 81.4, 60.1, 48.9, 32.9, 26.8, 26.8, 26.6, 25.3.

실시예Example 7 : 67: 6 -나이트로-6,- nitro-6, 6a,76a, 7 ,8,9,10,11,12-, 8,9,10,11,12- 옥타하이드로Octahydro -5H--5H- 아조시노[1,2-Azoxino [1,2- a]퀴놀린 (6-nitro-6,6a,7,8,9,10,11,12-octahydro-5H-azocino[1,2-a]quinoline)a] quinoline (6-nitro-6,6a, 7,8,9,10,11,12-octahydro-5H-azocino [

Figure 112017082962199-pat00012
Figure 112017082962199-pat00012

R1이 H이고, n이 4인 화학식 1의 반응물을 실시예 1과 동일한 조건으로 진행하여 상기 구조를 갖는 실시예 7을 수득하였다. 1H NMR (400 MHz, CDCl3) d 7.11 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.65 (q, J = 7.6 Hz, 2H), 4.64-4.63 (m, 1H), 4.20 (d, J = 9.6 Hz, 1H), 3.81-3.76 (m, 1H), 3.53 (d, J = 17.6 Hz, 1H), 3.20-3.11 (m, 2H), 2.05-1.43 (m, 10H); 13C NMR (100 MHz, CDCl3) d 142.8, 129.1, 127.8, 116.5, 116.2, 112.0, 81.6, 60.1, 53.6, 32.4, 27.4, 27.3, 27.1, 26.8, 25.9The reaction product of formula (1) wherein R 1 is H and n is 4 was proceeded under the same conditions as in Example 1 to obtain Example 7 having the above structure. 1 H NMR (400 MHz, CDCl 3) d 7.11 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.65 (q, J = 7.6 Hz, 2H), 4.64-4.63 (m, 1H), 4.20 (d, J = 9.6 Hz, 1H), 3.81-3.76 1.43 (m, 10 H); 13 C NMR (100 MHz, CDCl 3) d 142.8, 129.1, 127.8, 116.5, 116.2, 112.0, 81.6, 60.1, 53.6, 32.4, 27.4, 27.3, 27.1, 26.8, 25.9

실시예Example 8 : 38: 3 -- 플루오로Fluoro -6-나이트로-6,-6-nitro-6, 6a,76a, 7 ,8,9,10,11,12-, 8,9,10,11,12- 옥타하이드로Octahydro -5H--5H- 아Ah 조시노[1,2-a]퀴놀린 (3-2-a] quinoline (3- fluorofluoro -6-nitro-6,-6-nitro-6, 6a,76a, 7 ,8,9,10,11,12-, 8,9,10,11,12- octahydrooctahydro -5H-azocino[1,2-a]quinoline)-5H-azocino [1,2-a] quinoline < / RTI >

Figure 112017082962199-pat00013
Figure 112017082962199-pat00013

R1이 F이고, n이 4인 화학식 1의 반응물을 실시예 1과 동일한 조건으로 진행하여 상기 구조를 갖는 실시예 8을 수득하였다. 1H NMR (400 MHz, CDCl3) d 6.85-6.78 (m, 2H), 6.54 (q, J = 4.4 Hz, 1H), 4.65-4.62 (m, 1H), 4.20 (d, J = 9.2 Hz, 1H), 3.75-3.69 (m, 1H), 3.50 (d, J = 18 Hz, 1H), 2.04-1.67 (m, 7H), 1.52-1.38 (m, 3H); 13C NMR (100 MHz, CDCl3) d 139.1, 115.5, 115.3, 114.4, 114.2, 112.6, 81.42, 59.9, 53.9, 32.2, 27.4, 27.3, 27.2, 26.6, 25.9 ; 19F NMR (376.17 Hz, CDCl3) d -130.6.The reaction product of formula (1) wherein R 1 is F and n is 4 is proceeded under the same conditions as in Example 1 to obtain Example 8 having the above structure. 1 H NMR (400 MHz, CDCl 3) d 6.85-6.78 (m, 2H), 6.54 (q, J = 4.4 Hz, 1H), 4.65-4.62 (m, 1H), 4.20 (d, J = 9.2 Hz, 1H), 3.75-3.69 (m, 1H), 3.50 (d, J = 18Hz, 1H), 2.04-1.67 (m, 7H), 1.52-1.38 (m, 3H); 13 C NMR (100 MHz, CDCl 3) d 139.1, 115.5, 115.3, 114.4, 114.2, 112.6, 81.42, 59.9, 53.9, 32.2, 27.4, 27.3, 27.2, 26.6, 25.9; 19F NMR (376.17 Hz, CDCl 3 ) d -130.6.

실시예 9 : 3 - 브로모 -6-나이트로-6, 6a,7 ,8,9,10,11,12- 옥타하이드로 -5H- 아조 시노[1,2-a]퀴놀린 (3- bromo -6-nitro-6, 6a,7 ,8,9,10,11,12- octahydro -5H-azocino[1,2-a]quinoline) Example 9: 3-Bromo-6-nitro -6, 6a, 7, 8,9,10,11,12- octahydro -5H- Sino azo [1,2-a] quinoline (3- bromo-6- nitro-6, 6a, 7, 8,9,10,11,12- octahydro -5H-azocino [1,2-a] quinoline)

Figure 112017082962199-pat00014
Figure 112017082962199-pat00014

R1이 Br이고, n이 4인 화학식 1의 반응물을 실시예 1과 동일한 조건으로 진행하여 상기 구조를 갖는 실시예 9를 수득하였다. 1H NMR (400 MHz, CDCl3) d 7.19-7.16 (m, 2H), 6.50 (d, J = 8 Hz, 1H), 4.64-4.61 (m, 1H), 4.21-4.19 (m, 2H), 3.77-3.71 (m, 1H), 3.49 (d, J = 18 Hz, 1H), 3.16-3.08 (m, 2H), 2.04-1.68 ( m, 7H), 1.53-1.39 (m, 3H); 13C NMR (100 MHz, CDCl3) d 141.7, 131.5, 130.5, 118.3, 113.5, 108.2, 81.1, 60.1, 53.7, 32.4, 27.3, 27.0, 26.9, 26.2, 25.8The reaction product of the formula (1) wherein R 1 is Br and n is 4 was proceeded under the same conditions as in Example 1 to obtain Example 9 having the above structure. 1 H NMR (400 MHz, CDCl 3) d 7.19-7.16 (m, 2H), 6.50 (d, J = 8 Hz, 1H), 4.64-4.61 (m, 1H), 4.21-4.19 (m, 2H), 2H), 2.04-1.68 (m, 7H), 1.53-1. 39 (m, 3H); 3.77-3.71 (m, 1H), 3.49 (d, J = 18Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) d 141.7, 131.5, 130.5, 118.3, 113.5, 108.2, 81.1, 60.1, 53.7, 32.4, 27.3, 27.0, 26.9, 26.2, 25.8

실시예Example 10 : 310: 3 -- 클로로Chloro -6-나이트로-6,-6-nitro-6, 6a,76a, 7 ,8,9,10,11,12-, 8,9,10,11,12- 옥타하이드로Octahydro -5H--5H- 아Ah 조시노[1,2-a]퀴놀린 (3-2-a] quinoline (3- chlorochloro -6-nitro-6,-6-nitro-6, 6a,76a, 7 ,8,9,10,11,12-, 8,9,10,11,12- octahydrooctahydro -5H-azocino[1,2-a]quinoline)-5H-azocino [1,2-a] quinoline < / RTI >

Figure 112017082962199-pat00015
Figure 112017082962199-pat00015

R1이 Cl이고, n이 4인 화학식 1의 반응물을 실시예 1과 동일한 조건으로 진행하여 상기 구조를 갖는 실시예 10을 수득하였다. 1H NMR (400 MHz, CDCl3) d 7.06-7.03 (m, 2H), 6.55 (d, J = 8.8 Hz, 1H), 4.64-4.61 (m, 1H), 4.21 (d, J = 10.4 Hz, 1H), 3.77-3.71 (m, 1H), 3.50 (d, J = 18 Hz, 1H), 3.16-3.09 (m, 2H), 2.04-1.68 (m, 7H), 1.51-1.37 (m, 3H); 13C NMR (100 MHz, CDCl3) d 141.3, 128.7, 127.7, 121.1, 117.8, 113.1, 81.2, 60.1, 53.8, 32.4, 27.3, 27.1, 27.0, 26.3, 25.9The reaction product of formula (1) wherein R 1 is Cl and n is 4 is proceeded under the same conditions as in Example 1 to obtain Example 10 having the above structure. 1 H NMR (400 MHz, CDCl 3) d 7.06-7.03 (m, 2H), 6.55 (d, J = 8.8 Hz, 1H), 4.64-4.61 (m, 1H), 4.21 (d, J = 10.4 Hz, 2H), 2.04-1.68 (m, 7H), 1.51-1.37 (m, 3H), <; 13 C NMR (100 MHz, CDCl 3) d 141.3, 128.7, 127.7, 121.1, 117.8, 113.1, 81.2, 60.1, 53.8, 32.4, 27.3, 27.1, 27.0, 26.3, 25.9

실시예Example 11 : 611: 6 -나이트로-3-(-Nitro-3- ( tri플루오로methyltrifluoromethyl )-6,) -6, 6a,76a, 7 ,8,9,10,11,12-, 8,9,10,11,12- 옥타하Octaha 이드로-5H-아조시노[1,2-a]퀴놀린 (6-nitro-3-(Azido-5H-azo [1,2-a] quinoline (6-nitro-3- trifluoromethyltrifluoromethyl )-6,6a,7,8,9,10,11,12-octahydro-5H-azocino[1,2-a]quinoline)) -6,6a, 7,8,9,10,11,12-octahydro-5H-azocino [1,2-a] quinoline)

Figure 112017082962199-pat00016
Figure 112017082962199-pat00016

R1이 F3C이고, n이 4인 화학식 1의 반응물을 실시예 1과 동일한 조건으로 진행하여 상기 구조를 갖는 실시예 11을 수득하였다. 1H NMR (400 MHz, CDCl3) d 7.34-7.29 (m, 2H), 6.65 (d, J = 8.4 Hz, 1H), 4.68-4.65 (m, 1H), 4.68-4.65 (m, 1H), 4.27-4.24 (m, 1H), 3.86-3.80 (m, 1H), 3.57 (d, J = 18 Hz, 1H), 3.22-3.13 (m, 2H), 2.04-1.40 (m, 10H); 13C NMR (100 MHz, CDCl3) d 145.2, 126.3, 126.2 125.1, 125.0, 116.0, 111.4, 80.9, 60.3, 53.8, 32.7, 27.3, 26.8, 26.7, 26.4, 25.9, 14.1 ; 19F NMR (376.17 Hz, CDCl3) d -62.52The reaction product of formula (1) wherein R 1 is F 3 C and n is 4 is proceeded under the same conditions as in Example 1 to obtain Example 11 having the above structure. 1 H NMR (400 MHz, CDCl 3) d 7.34-7.29 (m, 2H), 6.65 (d, J = 8.4 Hz, 1H), 4.68-4.65 (m, 1H), 4.68-4.65 (m, 1H), 1H), 4.27-4.24 (m, 1H), 3.86-3.80 (m, 1H), 3.57 (d, J = 18Hz, 1H), 3.22-3.13 (m, 2H), 2.04-1.40 (m, 10H); 13 C NMR (100 MHz, CDCl 3 ) d 145.2, 126.3, 126.2, 125.1, 125.0, 116.0, 111.4, 80.9, 60.3, 53.8, 32.7, 27.3, 26.8, 26.7, 26.4, 25.9, 14.1; 19 F NMR (376.17 Hz, CDCl 3) d -62.52

실시예Example 12 : 212: 2 -- 클로로Chloro -6-나이트로-6,-6-nitro-6, 6a,76a, 7 ,8,9,10,11,12-, 8,9,10,11,12- 옥타하이드로Octahydro -5H--5H- 아Ah 조시노[1,2-a]퀴놀린 (2-≪ / RTI > 2-a] quinoline (2- chlorochloro -6-nitro-6,-6-nitro-6, 6a,76a, 7 ,8,9,10,11,12-, 8,9,10,11,12- octahydrooctahydro -5H-azocino[1,2-a]quinoline)-5H-azocino [1,2-a] quinoline < / RTI >

Figure 112017082962199-pat00017
Figure 112017082962199-pat00017

R1이 Cl이고, n이 4인 화학식 1의 반응물을 실시예 1과 동일한 조건으로 진행하여 상기 구조를 갖는 실시예 12를 수득하였다. 1H NMR (400 MHz, CDCl3) d 6.95 (d, J = 7.6 Hz, 1H), 6.64-6.59 (m, 2H), 4.63-4.62 (m, 1H), 4.21 (d, J = 10.4 Hz, 1H), 3.77-3.71 (m, 1H), 3.49 (d, J = 18 Hz, 1H), 3.17-3.09 (m, 2H), 2.05-1.45 (m, 10H); 13C NMR (100 MHz, CDCl3) d 146.7, 130.1, 128.3, 116.4, 114.6, 111.7, 81.2, 59.7, 53.7, 32.6, 27.3, 27.0, 26.8, 26.1, 25.8The reaction product of formula (1) wherein R 1 is Cl and n is 4 is proceeded under the same conditions as in Example 1 to obtain Example 12 having the above structure. 1 H NMR (400 MHz, CDCl 3) d 6.95 (d, J = 7.6 Hz, 1H), 6.64-6.59 (m, 2H), 4.63-4.62 (m, 1H), 4.21 (d, J = 10.4 Hz, 1H), 3.77-3.71 (m, 1H), 3.49 (d, J = 18 Hz, 1H), 3.17-3.09 (m, 2H), 2.05-1.45 (m, 10H); 13 C NMR (100 MHz, CDCl 3 ) d 146.7, 130.1, 128.3, 116.4, 114.6, 111.7, 81.2, 59.7, 53.7, 32.6, 27.3, 27.0, 26.8, 26.1, 25.8

실시예Example 13 : 213: 2 -- 메톡시Methoxy -6-나이트로-6,-6-nitro-6, 6a,76a, 7 ,8,9,10,11,12-, 8,9,10,11,12- 옥타하이드로Octahydro -5H--5H- 아Ah 조시노[1,2-a]퀴놀린 (2-≪ / RTI > 2-a] quinoline (2- methoxy메틸oxy -6-nitro-6,-6-nitro-6, 6a,76a, 7 ,8,9,10,11,12-, 8,9,10,11,12- octahydrooctahydro -5H-azocino[1,2-a]quinoline)-5H-azocino [1,2-a] quinoline < / RTI >

Figure 112017082962199-pat00018
Figure 112017082962199-pat00018

R1이 OMe이고, n이 4인 화학식 1의 반응물을 실시예 1과 동일한 조건으로 진행하여 상기 구조를 갖는 실시예 13을 수득하였다. 1H NMR (400 MHz, CDCl3) d 6.95 (d, J = 8 Hz, 1H), 4.62-4.61 (m, 1H), 4.18 (d, J = 9.6 Hz, 1H), 3.84-3.74 (m, 4H), 3.48 (d, J = 17.6 Hz, 1H), 3.17-3.01 (m, 2H), 2.04-1.43 (m, 10H); 13C NMR (100 MHz, CDCl3) d 159.5, 143.8, 129.7, 109.0, 101.2, 98.5, 81.7, 59.9, 55.1, 53.6, 32.5, 27.3, 27.1, 27.0 26.1, 25.9The reaction product of formula (1) wherein R 1 is OMe and n is 4 is proceeded under the same conditions as in Example 1 to obtain Example 13 having the above structure. 1 H NMR (400 MHz, CDCl 3) d 6.95 (d, J = 8 Hz, 1H), 4.62-4.61 (m, 1H), 4.18 (d, J = 9.6 Hz, 1H), 3.84-3.74 (m, 4H), 3.48 (d, J = 17.6 Hz, 1H), 3.17-3.01 (m, 2H), 2.04-1.43 (m, 10H); 13 C NMR (100 MHz, CDCl 3) d 159.5, 143.8, 129.7, 109.0, 101.2, 98.5, 81.7, 59.9, 55.1, 53.6, 32.5, 27.3, 27.1, 27.0 26.1, 25.9

실시예Example 14 : 614: 6 -나이트로-5,6,- Nitro-5,6, 6a,76a, 7 ,8,9,10,11,12,13-, 8,9,10,11,12,13- 데카하이드로아조니Decahydroazoni 노[1,2-a]퀴놀린 (6-nitro-5,6,1,2-a] quinoline (6-nitro-5, 6, 6a,76a, 7 ,8,9,10,11,12,13-, 8,9,10,11,12,13- decahydroazonino[1,2-a]decahydroazonino [1,2-a] quinoline)quinoline)

Figure 112017082962199-pat00019
Figure 112017082962199-pat00019

R1이 H이고, n이 5인 화학식 1의 반응물을 실시예 1과 동일한 조건으로 진행하여 상기 구조를 갖는 실시예 14를 수득하였다. 1H NMR (400 MHz, CDCl3) d 7.12 (t, J = 7.8 Hz, 1H), 7.06 (d, 7.6 Hz, 1H), 6.74-6.70 (m, 2H), 4.66-4.64 (m, 1H), 4.20 (d, J = 8.8 Hz, 1H), 3.68-3.63 (m, 1H), 3.50 (d, J = 18.4 Hz, 1H), 3.17-3.09 (m, 2H), 2.05-1.72 (m, 5H), 1.65-1.59(m, 2H), 1.53-1.37 (m, 5H); 13C NMR (100 MHz, CDCl3) d 143.6, 129.0, 127.7, 117.4, 117.2, 114.3, 81.4, 62.6, 56.9, 31.5, 28.3, 26.8, 26.3, 25.9, 25.6, 24.9The reaction product of formula (1) wherein R 1 is H and n is 5 is proceeded under the same conditions as in Example 1 to obtain Example 14 having the above structure. 1 H NMR (400 MHz, CDCl 3) d 7.12 (t, J = 7.8 Hz, 1H), 7.06 (d, 7.6 Hz, 1H), 6.74-6.70 (m, 2H), 4.66-4.64 (m, 1H) , 4.20 (d, J = 8.8 Hz, 1H), 3.68-3.63 (m, 1H), 3.50 (d, J = 18.4 Hz, 1H), 3.17-3.09 (m, 2H), 2.05-1.72 ), 1.65-1.59 (m, 2H), 1.53-1.37 (m, 5H); 13 C NMR (100 MHz, CDCl 3 ) d 143.6, 129.0, 127.7, 117.4, 117.2, 114.3, 81.4, 62.6, 56.9, 31.5, 28.3, 26.8, 26.3, 25.9, 25.6, 24.9

실시예Example 15 : 315: 3 -- 클로로Chloro -6-나이트로-5,6,-6-nitro-5,6, 6a,76a, 7 ,8,9,10,11,12,13-, 8,9,10,11,12,13- 데카하이드로아조니노[1,2-a]퀴놀린Decahydroazonino [l, 2-a] quinoline (3- (3- chlorochloro -6-nitro-5,6,-6-nitro-5,6, 6a,76a, 7 ,8,9,10,11,12,13-decahydroazonino[1,2-a]quinoline), 8,9,10,11,12,13-decahydroazonino [1,2-a] quinoline)

Figure 112017082962199-pat00020
Figure 112017082962199-pat00020

R1이 Cl이고, n이 5인 화학식 1의 반응물을 실시예 1과 동일한 조건으로 진행하여 상기 구조를 갖는 실시예 15를 수득하였다. 1H NMR (400 MHz, CDCl3) d 7.08-7.04 (m, 2H), 6.65 (d, J = 8.8 Hz, 1H), 4.66-4.63 (m, 1H), 4.19 (d, J = 10.8 Hz, 1H), 3.63-3.57 (m, 1H), 3.46 (d, J = 18.4 Hz, 1H), 3.15-3.05 (m, 2H), 2.04-1.59 (m, 7H), 1.54-1.33 (m, 5H); 13C NMR (100 MHz, CDCl3) d 142.1, 128.6, 127.6, 122.0, 118.8, 115.3, 81.0, 62.7, 57.1, 31.4, 28.1, 26.7, 26.0, 25.8, 25.5, 24.8The reaction product of formula (1) wherein R 1 is Cl and n is 5 is proceeded under the same conditions as in Example 1 to obtain Example 15 having the above structure. 1 H NMR (400 MHz, CDCl 3) d 7.08-7.04 (m, 2H), 6.65 (d, J = 8.8 Hz, 1H), 4.66-4.63 (m, 1H), 4.19 (d, J = 10.8 Hz, 2H), 2.04-1.59 (m, 7H), 1.54-1.33 (m, 5H), 3.63-3.57 (m, ; 13 C NMR (100 MHz, CDCl 3 ) d 142.1, 128.6, 127.6, 122.0, 118.8, 115.3, 81.0, 62.7, 57.1, 31.4, 28.1, 26.7, 26.0, 25.8, 25.5, 24.8

실시예Example 16 : 216: 2 -- 클로로Chloro -6-나이트로-5,6,-6-nitro-5,6, 6a,76a, 7 ,8,9,10,11,12,13-, 8,9,10,11,12,13- 데카하이드로아Decahydro 조니노[1,2-a]퀴놀린 (2-Lt; / RTI > [1,2-a] quinoline (2- chlorochloro -6-nitro-5,6,-6-nitro-5,6, 6a,76a, 7 ,8,9,10,11,12,13-decahydroazonino[1,2-a]quinoline), 8,9,10,11,12,13-decahydroazonino [1,2-a] quinoline)

Figure 112017082962199-pat00021
Figure 112017082962199-pat00021

R1이 Cl이고, n이 5인 화학식 1의 반응물을 실시예 1과 동일한 조건으로 진행하여 상기 구조를 갖는 실시예 16를 수득하였다. 1H NMR (400 MHz, CDCl3) d 6.98-6.96 (m, 1H), 6.69-6.67 (m, 2H), 4.65-4.63 (m, 1H), 4.20-4.15 (m, 1H), 3.66-3.60 (m, 1H), 3.46 (d, J = 18.4 Hz, 1H), 3.16-3.04 (m, 2H), 2.04-1.34 (m, 12H); 13C NMR (100 MHz, CDCl3) d 144.6, 133.1, 130.0, 117.4, 115.6, 113.8, 81.1, 62.5, 57.0, 31.7, 27.9, 26.7, 25.9, 25.8, 25.6, 24.8The reaction product of the formula (1) wherein R 1 is Cl and n is 5 was proceeded under the same conditions as in Example 1 to obtain Example 16 having the above structure. 1 H NMR (400 MHz, CDCl 3 ) d 6.98-6.96 (m, 1 H), 6.69-6.67 (m, 2H), 4.65-4.63 (m, 1H), 3.46 (d, J = 18.4 Hz, 1H), 3.16-3.04 (m, 2H), 2.04-1.34 (m, 12H); 13 C NMR (100 MHz, CDCl 3 ) d 144.6, 133.1, 130.0, 117.4, 115.6, 113.8, 81.1, 62.5, 57.0, 31.7, 27.9, 26.7, 25.9, 25.8, 25.6, 24.8

Claims (7)

하기 화학식 1의 구조를 갖는 오쏘-다이알킬아미노 나이트로스틸렌 유도체를 루이스 산 촉매를 이용하여 분자내 1,5-수소전이/고리화 반응을 통해 하기 화학식 2의 구조를 갖는 테트라하이드로퀴놀린 유도체를 제조하는 것을 포함하는, 테트라하이드로퀴놀린 유도체의 제조방법으로서,
상기 루이스 산 촉매는 Sc(OTf)3, La(OTf)3 또는 Yb(OTf)3이며
화학식 1 및 2에서 상기 R1은 수소, 트리플루오로알킬, C1-C3 알콕시 또는 할로겐 원소이고, 상기 n은 1 내지 5의 정수인, 테트라하이드로퀴놀린 유도체의 제조방법:
[화학식 1]
Figure 112018119746911-pat00022

[화학식 2]
Figure 112018119746911-pat00023
.An ortho-dialkylaminostrostyrene derivative having the structure represented by the following formula (1) was prepared by the intra-molecular 1,5-hydrogen transfer / cyclization reaction using a Lewis acid catalyst to produce a tetrahydroquinoline derivative A method for producing a tetrahydroquinoline derivative,
The Lewis acid catalyst is Sc (OTf) 3 , La (OTf) 3 or Yb (OTf) 3
Wherein R 1 is hydrogen, trifluoroalkyl, C 1 -C 3 alkoxy or halogen, and n is an integer of 1 to 5 in the general formulas (1) and (2). Process for producing tetrahydroquinoline derivative
[Chemical Formula 1]
Figure 112018119746911-pat00022

(2)
Figure 112018119746911-pat00023
. 제1항에 있어서,
상기 반응은 아세토나이트릴 용매 하에서 일어나는 것인, 테트라하이드로퀴놀린 유도체의 제조방법.The method according to claim 1,
Wherein the reaction takes place in an acetonitrile solvent. 제1항에 있어서,
상기 Sc(OTf)3 촉매의 양은 오쏘-다이알킬아미노 나이트로스틸렌 유도체의 몰 수에 대하여 5 내지 30 몰%인, 테트라하이드로퀴놀린 유도체의 제조방법.The method according to claim 1,
Wherein the amount of the Sc (OTf) 3 catalyst is 5 to 30 mol% based on the molar amount of the ortho-dialkylamino nitro styrene derivative. 제1항에 있어서,
상기 방법은 80℃의 온도에서 12시간 내지 36시간 동안 진행되는 것인, 테트라하이드로퀴놀린 유도체의 제조방법.The method according to claim 1,
Wherein the process is carried out at a temperature of < RTI ID = 0.0 > 80 C < / RTI > for from 12 hours to 36 hours. 제1항에 있어서,
상기 테트라하이드로퀴놀린 유도체는 62% 이상의 수율로 얻어지는 것인, 테트라하이드로퀴놀린 유도체의 제조방법.The method according to claim 1,
Wherein the tetrahydroquinoline derivative is obtained in a yield of 62% or more. 삭제delete 삭제delete
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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Chem. Rev., 111(11), 7157-7259, 2011.
Tetrahedron Letters, 37(40), 7163-7166, 1996.
박사학위논문, Elena Merisor, Hohenhein Univ., 2007,

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