KR101304952B1 - Method for preparation of tetrahydroquinoline derivatives - Google Patents

Method for preparation of tetrahydroquinoline derivatives Download PDF

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KR101304952B1
KR101304952B1 KR1020110138624A KR20110138624A KR101304952B1 KR 101304952 B1 KR101304952 B1 KR 101304952B1 KR 1020110138624 A KR1020110138624 A KR 1020110138624A KR 20110138624 A KR20110138624 A KR 20110138624A KR 101304952 B1 KR101304952 B1 KR 101304952B1
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formula
derivative
alkyl group
tetrahydroquinoline
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KR20130071232A (en
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김대영
강영구
김혜림
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순천향대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine

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Abstract

테트라하이드로퀴놀린 유도체의 제조방법은, 오쏘-다이아킬아미노 알킬리덴 말로네이트를, 싸이오유레아 유도체 촉매 존재 하에 반응시켜 테트라하이드로퀴놀린 유도체를 제조한다.
상기 제조방법은 싸이오유레아 유도체 촉매를 이용하여 테트라하이드로퀴놀린 유도체를 효율적으로 제조할 수 있다. In the method for producing a tetrahydroquinoline derivative, ortho-diakylamino alkylidene malonate is reacted in the presence of a thiourea derivative catalyst to produce a tetrahydroquinoline derivative.
The preparation method can efficiently prepare a tetrahydroquinoline derivative using a thiourea derivative catalyst.

Description

테트라하이드로퀴놀린 유도체의 제조방법{Method for preparation of tetrahydroquinoline derivatives}Method for preparation of tetrahydroquinoline derivatives

본 발명은 테트라하이드로퀴놀린(tetrahydroquinoline) 유도체의 제조방법에 관한 것으로, 특히 오쏘-다이아킬아미노 알킬리덴 말로네이트(o-dialkylamino-substituted alkylidene malonate)를, 싸이오유레아(thiourea) 유도체 촉매를 이용한 1,5-수소 전이 및 고리화 반응을 통해 테트라하이드로퀴놀린 유도체의 제조방법에 관한 것이다.
The present invention relates to a method for preparing a tetrahydroquinoline derivative, in particular, ortho-diaalkylamino-substituted alkylidene malonate, 1, using a thiourea derivative catalyst The present invention relates to a method for preparing a tetrahydroquinoline derivative through 5-hydrogen transfer and cyclization reaction.

테트라하이드로퀴놀린 화합물은 제약, 재료과학, 생명과학 분야에 사용되는 유용한 화합물이므로 많은 연구가 진행되고 있는 분야이다. 분자내 산화 환원 방법을 통한 테트라하이드로퀴놀린 화합물을 합성하는 방법은 일부 알려져 있다. 이러한 방법은 금속을 촉매로 사용하기 때문에 반응 조건이 까다로우며, 비싼 금속 촉매를 사용하는 단점을 갖고 있다 (Org. Lett. 2009, 11, 129).
Tetrahydroquinoline compound is a useful compound used in the pharmaceutical, material science, and life science fields, and therefore, a lot of research is being conducted. Some methods for synthesizing tetrahydroquinoline compounds via intramolecular redox methods are known. This method is difficult because of the use of metal as a catalyst and has the disadvantage of using an expensive metal catalyst (Org. Lett. 2009, 11, 129).

본 발명의 목적은 상술한 바와 같은 문제점을 해결하기 위해 이루어진 것으로서, 짧은 반응시간, 높은 수율로 테트라하이드로퀴놀린 유도체의 제조방법을 제공하는 것이다.
An object of the present invention is to solve the problems as described above, to provide a method for preparing a tetrahydroquinoline derivative in a short reaction time, high yield.

상기 목적을 달성하기 위해 본 발명에 따른 테트라하이드로퀴놀린 유도체의 제조방법은 싸이오유레아 유도체 촉매 존재 하에 오쏘-다이아킬아미노 알킬리덴 말로네이트를 반응시켜 테트라하이드로퀴놀린 유도체를 제조하는 것을 특징으로 한다.In order to achieve the above object, a method for preparing a tetrahydroquinoline derivative according to the present invention is characterized in that tetrahydroquinoline derivatives are prepared by reacting ortho-diacylamino alkylidene malonate in the presence of a thiourea derivative catalyst.

상술한 바와 같이, 본 발명에 따른 테트라하이드로퀴놀린 유도체의 제조방법에 의하면, 값이 저렴하고, 취급하기 매우 용이한 싸이오유레아 유도체 촉매를 이용하여 테트라하이드로퀴놀린 유도체를 합성할 수 있으며, 높은 수율로 테트라하이드로퀴놀린 유도체를 합성할 수 있다는 효과가 얻어진다.
As described above, according to the method for preparing a tetrahydroquinoline derivative according to the present invention, a tetrahydroquinoline derivative can be synthesized using a thiourea derivative catalyst which is inexpensive and very easy to handle, and has a high yield. The effect of being able to synthesize tetrahydroquinoline derivatives is obtained.

본 발명의 상기 및 그 밖의 목적과 새로운 특징은 본 명세서의 기술 및 첨부 도면에 의해 더욱 명확하게 될 것이다.These and other objects and novel features of the present invention will become more apparent from the description of the present specification and the accompanying drawings.

본 발명의 일 실시 예에 따른 테트라하이드로퀴놀린 유도체의 제조방법은, 오쏘-다이아킬아미노 알킬리덴 말로네이트를, 싸이오유레아 유도체 촉매 존재 하에 반응시켜 테트라하이드로퀴놀린 유도체를 제조한다. 상기 제조방법은 싸이오유레아 유도체 촉매를 이용하여 테트라하이드로퀴놀린 유도체를 효율적으로 제조하기 위한 것이다. In the method for preparing a tetrahydroquinoline derivative according to an embodiment of the present invention, ortho-diacylamino alkylidene malonate is reacted in the presence of a thiourea derivative catalyst to prepare a tetrahydroquinoline derivative. The preparation method is for efficiently preparing a tetrahydroquinoline derivative using a thiourea derivative catalyst.

일 실시 예에서, 상기 싸이오유레아 유도체 촉매의 함량은, 반응 물질들의 전체 몰수를 기준으로 5 내지 30 몰% 이다. In one embodiment, the content of the thiourea derivative catalyst is 5 to 30 mol% based on the total moles of the reactants.

일 실시 예에서, 상기 촉매는, 하기 화학식 1로 표현될 수 있다.In one embodiment, the catalyst may be represented by the following formula (1).

Figure 112013057283418-pat00015
Figure 112013057283418-pat00015

또 다른 일 실시 예에서, 상기 오쏘-다이아킬아미노 알킬리덴 말로네이트 화합물은 하기 화학식 2로 표현될 수 있다. In another embodiment, the ortho-diaalkylamino alkylidene malonate compound may be represented by the following Chemical Formula 2.

Figure 112011101537924-pat00002
Figure 112011101537924-pat00002

상기 R1 는 수소 또는 할로겐 원소로, 플루오로(F), 클로로(Cl), 브로모(Br), 또는 아이오도(I) 이다.R 1 is hydrogen or a halogen element, and is fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

상기 R2 및 R3는 모두 C3-C6 알킬기로 서로 연결되어 5-8각 고리를 형성할 수 있다. 또는, 상기 R2 및 R3는 방향족이 포함된 고리 화합물인 1,2,3,4-테트라하이드로아이소퀴놀린(1,2,3,4-tetrahydroisoquinoline), 또는 아이소인돌린(isoindoline)일 수 있다.R 2 and R 3 may both be connected to each other to form a C 5 -C 6 alkyl group. Alternatively, R 2 and R 3 may be 1,2,3,4-tetrahydroisoquinoline (1,2,3,4-tetrahydroisoquinoline), or isoindoline, which are aromatic ring compounds. .

상기 R4는 C1-C10 알킬기로 선형 또는 가지형 알킬기이다
R 4 is a C 1 -C 10 alkyl group or a linear or branched alkyl group

일 실시 예에서, 톨루엔 용매하에 오쏘-다이아킬아미노 알킬리덴 말로네이트는 싸이오유레아 유도체 촉매 존재하에서 환류시켜 테트라하이드로퀴놀린 유도체를 제조할 수 있다. 구체적인 반응식은 하기 반응식 1과 같다. In one embodiment, ortho-diakylamino alkylidene malonate can be refluxed in the presence of a thiourea derivative catalyst in a toluene solvent to prepare a tetrahydroquinoline derivative. Specific reaction schemes are the same as in Scheme 1 below.

[반응식 1][Reaction Scheme 1]

Figure 112013057283418-pat00016
Figure 112013057283418-pat00016

위 반응식 1에서 R1 내지 R2, R3 R4는 위에서 정의한 바와 같다.In Scheme 1, R 1 to R 2 , R 3 R 4 are as defined above.

일 실시 예에서, 상기 테트라하이드로퀴놀린 유도체는, 화학식 3의 구조를 갖는 화합물일 수 있다.In one embodiment, the tetrahydroquinoline derivative may be a compound having a structure of formula (3).

Figure 112011101537924-pat00004
Figure 112011101537924-pat00004

위 화학식 3에서 R1 내지 R2, R3 R4는 위에서 정의한 바와 같다.
In Formula 3, R 1 to R 2 , R 3 R 4 are as defined above.

이하, 하기 실시 예 등에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 다만, 하기 실시 예 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 and the like are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

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본 발명에서 사용한 촉매는 테트라하이드로퀴놀린 유도체를 제조하는데 효과적인 것을 알 수 있다.
It can be seen that the catalyst used in the present invention is effective for preparing a tetrahydroquinoline derivative.

[실시 예 1] Dimethyl 6a,7,8,9,10,11-hexahydroazepino[1,2-a]Example 1 Dimethyl 6a, 7,8,9,10,11-hexahydroazepino [1,2-a]

quinoline-6,6(5H)-dicarboxylatequinoline-6,6 (5 H) -dicarboxylate

Figure 112011101537924-pat00006
Figure 112011101537924-pat00006

플라스크에 오쏘-다이아킬아미노 알킬리덴 말로네이트(화학식 2) 0.1 mmol을 넣고 톨루엔 1 mL를 넣은 후 상온에서 교반하였다. 그런 다음, 싸이오유레아 유도체 촉매(화학식 1) 30 몰%을 넣고 4시간 환류한다. 반응이 완료되면 반응혼합물을 농축하여 컬럼크로마토그래피로 분리 정제하여 dimethyl 6a,7,8,9,10,11-hexahydroazepino[1,2-a]quinoline-6,6(5H)-dicarboxylate[화학식 3]을 99% 수율로 얻었다.0.1 mmol of ortho-diaalkylamino alkylidene malonate (Formula 2) was added to the flask, and 1 mL of toluene was added thereto, followed by stirring at room temperature. Then, 30 mol% of a thiourea derivative catalyst (Formula 1) was added thereto, and the mixture was refluxed for 4 hours. After completion of reaction to give the reaction mixture was concentrated and separated by column chromatography to give dimethyl 6a, 7,8,9,10,11-hexahydroazepino [1,2 -a] quinoline-6,6 (5 H) -dicarboxylate [ formula 3] was obtained in 99% yield.

1H NMR (200 MHz, CDCl3) δ7.08-7.01 (m, 2H), 6.61-6.51 (m, 2H), 4.10 (d, J=1.2, 1H), 3.90-3.86 (m, 1H), 3.86-3.71 (m, 3H), 3.17-3.62 (m, 3H), 3.33 (d, J=1.2, 1H), 3.30-3.18 (m, 1H), 2.12-1.99 (m, 1H), 1.71-1.41(m, 7H).; 13C NMR (50 MHz, CDCl3) δ169.65, 169.47, 142.36, 128.98, 127.28, 116.90, 115.30, 109.72, 60.26, 55.37, 52.53, 49.69, 30.59, 28.47, 27.22, 25.98, 25.61, 25.45.
 1 H NMR (200 MHz, CDCl 3 ) δ 7.08-7.01 (m, 2H), 6.61-6.51 (m, 2H), 4.10 (d, J = 1.2, 1H), 3.90-3.86 (m, 1H), 3.86-3.71 (m, 3H), 3.17-3.62 (m, 3H), 3.33 (d, J = 1.2, 1H), 3.30-3.18 (m, 1H), 2.12-1.99 (m, 1H), 1.71-1.41 (m, 7 H) .; 13 C NMR (50 MHz, CDCl 3 ) δ 169.65, 169.47, 142.36, 128.98, 127.28, 116.90, 115.30, 109.72, 60.26, 55.37, 52.53, 49.69, 30.59, 28.47, 27.22, 25.98, 25.61, 25.45.

[실시 예 2]Dimethyl 1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoline-4,4(5H)-dicarboxylateExample 2 Dimethyl 1,2,3,3a-tetrahydropyrrolo [1,2-a] quinoline-4,4 (5H) -dicarboxylate

Figure 112011101537924-pat00007
Figure 112011101537924-pat00007

상기 실시 예 1과 동일한 방법으로 168시간 환류하여 dimethyl 1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoline-4,4(5H)-dicarboxylate[화학식 3]를 83% 수율로 얻었다.168 hours of reflux in the same manner as in Example 1 to obtain dimethyl 1,2,3,3a-tetrahydropyrrolo [1,2-a] quinoline-4,4 (5H) -dicarboxylate [Formula 3] in 83% yield.

1H NMR δ7.10 (t, J =7.7 Hz, 1H), 7.03 (d, J = 7.4, 1H), 6.62 (t, J = 7.4 Hz, 1H), 6.48 (d, J = 8.1 Hz, 1H), 3.85-3.76 (m, 4H), 3.59 (d, J= 0.9 Hz, 3H), 3.44-3.23 (m, 4H), 2.52-2.40 (m, 1H), 2.23-2.04 (m, 2H), 2.03-1.90 (m, 1H).; 13C NMR (125 MHz, CDCl3) δ171.35, 168.94, 143.70, 128.37, 127.43, 118.56, 115.88, 110.84, 62.02, 53.13, 52.55, 52.01, 47.30, 36.79, 27.77, 23.40.
 1 H NMR δ 7.10 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 7.4, 1H), 6.62 (t, J = 7.4 Hz, 1H), 6.48 (d, J = 8.1 Hz, 1H ), 3.85-3.76 (m, 4H), 3.59 (d, J = 0.9 Hz, 3H), 3.44-3.23 (m, 4H), 2.52-2.40 (m, 1H), 2.23-2.04 (m, 2H), 2.03-1.90 (m, 1 H) .; 13 C NMR (125 MHz, CDCl 3 ) δ 171.35, 168.94, 143.70, 128.37, 127.43, 118.56, 115.88, 110.84, 62.02, 53.13, 52.55, 52.01, 47.30, 36.79, 27.77, 23.40.

[실시 예 3] Dimethyl 8-bromo-1,2,3,3a-tetrahydropyrrolo[1,2,-a]Example 3 Dimethyl 8-bromo-1,2,3,3a-tetrahydropyrrolo [1,2, -a]

quinoline-4,4(5H)-dicarboxylatequinoline-4,4 (5H) -dicarboxylate

Figure 112011101537924-pat00008
Figure 112011101537924-pat00008

상기 실시 예 1과 동일한 방법으로 168시간 환류하여 dimethyl 8-bromo-1,2,3,3a-tetrahydropyrrolo[1,2,-a]quinoline-4,4(5H)-dicarboxylate[화학식 3]를 80% 수율로 얻었다.In the same manner as in Example 1, the mixture was refluxed for 168 hours to give dimethyl 8-bromo-1,2,3,3a-tetrahydropyrrolo [1,2, -a] quinoline-4,4 (5H) -dicarboxylate [Chemical Formula 3] 80 Obtained in% yield.

1H NMR (200 MHz, CDCl3) δ7.17-7.11(m, 2H), 6.30 (d, J=10.0 Hz, 1H), 3.73-3.68 (m, 4H), 3.68-3.58 (m, 3H), 3.29-3.14(m, 4H), 2.40-2.34 (m, 1H), 2.16-1.88(m, 3H).; 13C NMR (50 MHz, CDCl3) δ171.08, 168.76, 142.71, 130.82, 130.17, 120.61, 112.36, 107.52, 62.01, 53.26 52.76, 52.25, 47.46, 36.46, 27.83, 23.42.
 1 H NMR (200 MHz, CDCl 3 ) δ 7.17-7.11 (m, 2H), 6.30 (d, J = 10.0 Hz, 1H), 3.73-3.68 (m, 4H), 3.68-3.58 (m, 3H) , 3.29-3.14 (m, 4H), 2.40-2.34 (m, 1H), 2.16-1.88 (m, 3H) .; 13 C NMR (50 MHz, CDCl 3 ) δ 171.08, 168.76, 142.71, 130.82, 130.17, 120.61, 112.36, 107.52, 62.01, 53.26 52.76, 52.25, 47.46, 36.46, 27.83, 23.42.

[실시 예 4] Dimethyl 2,3,4,4a-tetrahydro-1H-pyrido[1,2-a]Example 4 Dimethyl 2,3,4,4a-tetrahydro-1H-pyrido [1,2-a]

quinoline-5,5(6H)-dicarboxylatequinoline-5,5 (6H) -dicarboxylate

Figure 112011101537924-pat00009
Figure 112011101537924-pat00009

상기 실시 예 1과 동일한 방법으로 7시간 환류하여 dimethyl 2,3,4,4a-tetrahydro-1H-pyrido[1,2-a]quinoline-5,5(6H)-dicarboxylate[화학식 3]를 99% 수율로 얻었다.It was refluxed for 7 hours in the same manner as in Example 1 and 99% of dimethyl 2,3,4,4a-tetrahydro-1H-pyrido [1,2-a] quinoline-5,5 (6H) -dicarboxylate [Formula 3] Obtained in yield.

1H NMR (200 MHz, CDCl3) δ7.11-7.01 (m, 2H), 6.74-6.60 (m, 2H), 4.03-3.81(m, 2H), 3.71(s, 6H), 3.61-3.31(m, 4H), 3.16 (d, J=3.0 Hz, 1H), 3.06-3.02 (m, 1H), 1.17-1.74 (m, 1H), 1.74-1.62 (m, 2H), 1.62-1.45 (m, 3H).; 13C NMR (125 MHz, CDCl3) δ169.64, 169.34, 143.54, 128.83, 127.39, 120.47, 116.91, 112.09, 59.75, 56.79, 52.62, 52.45, 48.43, 29.79, 25.74, 25.23, 22.47.
 1 H NMR (200 MHz, CDCl 3 ) δ7.11-7.01 (m, 2H), 6.74-6.60 (m, 2H), 4.03-3.81 (m, 2H), 3.71 (s, 6H), 3.61-3.31 ( m, 4H), 3.16 (d, J = 3.0 Hz, 1H), 3.06-3.02 (m, 1H), 1.17-1.74 (m, 1H), 1.74-1.62 (m, 2H), 1.62-1.45 (m, 3H) .; 13 C NMR (125 MHz, CDCl 3 ) δ 169.64, 169.34, 143.54, 128.83, 127.39, 120.47, 116.91, 112.09, 59.75, 56.79, 52.62, 52.45, 48.43, 29.79, 25.74, 25.23, 22.47.

[실시 예 5] Dimethyl 2-bromo-6a,7,8,9,10,11-hexahydroazepinop[1,2-a]Example 5 Dimethyl 2-bromo-6a, 7,8,9,10,11-hexahydroazepinop [1,2-a]

quinoline-6,6(5H)-dicarboxylatequinoline-6,6 (5H) -dicarboxylate

Figure 112011101537924-pat00010
Figure 112011101537924-pat00010

상기 실시 예 1과 동일한 방법으로 168시간 환류하여 dimethyl 2-bromo-6a,7,8,9,10,11-hexahydroazepinop[1,2-a]quinoline-6,6(5H)-dicarboxylate[화학식 3]를 86% 수율로 얻었다.In the same manner as in Example 1, the mixture was refluxed for 168 hours to give dimethyl 2-bromo-6a, 7,8,9,10,11-hexahydroazepinop [1,2-a] quinoline-6,6 (5H) -dicarboxylate [Formula 3] ] Was obtained in 86% yield.

1H NMR (200 MHz, CDCl3) δ7.10 (d, J=8.0 Hz, 2H), 6.39 (d, J=10.3 Hz, 1H), 4.08 (d, J=14.3 Hz, 1H), 3.85-3.82 (m, 1H), 3.76-3.67 (m, 3H), 3.67-3.62 (m, 3H), 3.26-3.11 (m, 3H), 1.99-1.94 (m, 1H), 1.65-1.25(m, 7H).; 13C NMR (50 MHz, CDCl3) δ169.49, 141.62, 131.52, 130.13, 119.31, 111.54, 107.05, 60.50, 55.33, 52.55, 50.02, 30.72, 28.38, 27.04, 26.00, 25.69.
 1 H NMR (200 MHz, CDCl 3 ) δ 7.10 (d, J = 8.0 Hz, 2H), 6.39 (d, J = 10.3 Hz, 1H), 4.08 (d, J = 14.3 Hz, 1H), 3.85- 3.82 (m, 1H), 3.76-3.67 (m, 3H), 3.67-3.62 (m, 3H), 3.26-3.11 (m, 3H), 1.99-1.94 (m, 1H), 1.65-1.25 (m, 7H ) .; 13 C NMR (50 MHz, CDCl 3 ) δ 169.49, 141.62, 131.52, 130.13, 119.31, 111.54, 107.05, 60.50, 55.33, 52.55, 50.02, 30.72, 28.38, 27.04, 26.00, 25.69.

[실시 예 6] dimethyl 7,8,9,10,11,12-hexahydro-5H-azocino[1,2-a]Example 6 dimethyl 7,8,9,10,11,12-hexahydro-5H-azocino [1,2-a]

quinoline-6,6(6a H)-dicarboxylatequinoline-6,6 (6a H) -dicarboxylate

Figure 112011101537924-pat00011
Figure 112011101537924-pat00011

상기 실시 예 1과 동일한 방법으로 48시간 환류하여 dimethyl 7,8,9,10,11,12-hexahydro-5H-azocino[1,2-a]quinoline-6,6(6a H)-dicarboxylate [화학식 3]를 88% 수율로 얻었다.48 hours reflux in the same manner as in Example 1, dimethyl 7,8,9,10,11,12-hexahydro-5H-azocino [1,2-a] quinoline-6,6 (6a H) -dicarboxylate 3] was obtained in 88% yield.

1H NMR (200 MHz, CDCl3) δ7.10-7.02 (m, 2H), 6.63-6.56 (m, 2H), 4.19-4.13 (m, 1H), 3.80-3.68 (m, 4H), 3.68-3.50 (m,3H), 3.42-3.20 (m, 3H), 1.79-1.32 (m, 10H).; 13C NMR (125 MHz, CDCl3) δ170.15, 169.75, 142.81, 129.28, 127.34, 117.87, 115.77, 111.56, 60.38, 55.79, 54.44, 52.84, 52.65, 30.65, 28.57, 27.67, 27.63, 27.38, 25.96.
 1 H NMR (200 MHz, CDCl 3 ) δ7.10-7.02 (m, 2H), 6.63-6.56 (m, 2H), 4.19-4.13 (m, 1H), 3.80-3.68 (m, 4H), 3.68- 3.50 (m, 3 H), 3.42-3.20 (m, 3 H), 1.79-1.32 (m, 10 H) .; 13 C NMR (125 MHz, CDCl 3 ) δ 170.15, 169.75, 142.81, 129.28, 127.34, 117.87, 115.77, 111.56, 60.38, 55.79, 54.44, 52.84, 52.65, 30.65, 28.57, 27.67, 27.63, 27.38, 25.96.

[실시 예 7] Dimethyl 11b,13-dihydro-6H-isoquinolino[2,1-a]quinoline-12,12(7H)-dicarboxylateExample 7 Dimethyl 11b, 13-dihydro-6H-isoquinolino [2,1-a] quinoline-12,12 (7H) -dicarboxylate

Figure 112011101537924-pat00012
Figure 112011101537924-pat00012

상기 실시예 1과 동일한 방법으로 9시간 환류하여 dimethyl 11b,13-dihydro-6H-isoquinolino[2,1-a]quinoline-12,12(7H)-dicarboxylate[화학식 3]를 90% 수율로 얻었다.It was refluxed for 9 hours in the same manner as in Example 1 to obtain dimethyl 11b, 13-dihydro-6H-isoquinolino [2,1-a] quinoline-12,12 (7H) -dicarboxylate [Formula 3] in 90% yield.

1H NMR (200 MHz, CDCl3) δ7.16-7.01(m, 6H), 6.79-6.69(m, 2H), 5.04 (s, 1H), 3.93-3.72 (m, 1H), 3.72-3.64 (m, 4H), 3.64-3.54 (m, 3H), 3.42 (d= 14.5, 1H), 3.27-3.23 (m, 2H), 2.77-2.69 (m, 1H).; 13C NMR (125 MHz, CDCl3) δ170.74, 169.56, 145.27, 136.81, 134.83, 128.79, 128.52, 126.88, 126.79, 125.83, 125.60, 121.38, 118.08, 112.01, 61.23, 59.39, 52.79, 52.41, 43.75, 34.04, 28.08.
 1 H NMR (200 MHz, CDCl 3 ) δ7.16-7.01 (m, 6H), 6.79-6.69 (m, 2H), 5.04 (s, 1H), 3.93-3.72 (m, 1H), 3.72-3.64 ( m, 4H), 3.64-3.54 (m, 3H), 3.42 (d = 14.5, 1H), 3.27-3.23 (m, 2H), 2.77-2.69 (m, 1H) .; 13 C NMR (125 MHz, CDCl 3 ) δ 170.74, 169.56, 145.27, 136.81, 134.83, 128.79, 128.52, 126.88, 126.79, 125.83, 125.60, 121.38, 118.08, 112.01, 61.23, 59.39, 52.79, 52.41, 43.75, 43.75, 43.75 34.04, 28.08.

이상 본 발명자에 의해서 이루어진 발명을 상기 실시 예에 따라 구체적으로 설명하였지만, 본 발명은 상기 실시 예에 한정되는 것은 아니고 그 요지를 이탈하지 않는 범위에서 여러 가지로 변경 가능한 것은 물론이다.
Although the present invention has been described in detail with reference to the above embodiments, it is needless to say that the present invention is not limited to the above-described embodiments, and various modifications may be made without departing from the spirit of the present invention.

본 발명에 따른 테트라하이드로퀴놀린 유도체의 제조방법은 싸이오유레아 유도체 촉매를 이용하여 테트라하이드로퀴놀린 유도체를 효율적으로 제조하는데 유용하다.The method for producing a tetrahydroquinoline derivative according to the present invention is useful for efficiently preparing a tetrahydroquinoline derivative using a thiourea derivative catalyst.

Claims (6)

하기 [화학식 2]의 구조를 갖는 오쏘-다이아킬아미노 알킬리덴 말로네이트(o-dialkylamino-substituted alkylidene malonate)를, 하기 [화학식 1]의 구조를 갖는 싸이오유레아(thiourea) 유도체 촉매 존재 하에서, 하기 [반응식 1]과 같이 반응시키는 것을 특징으로 하는 테트라하이드로퀴놀린 유도체의 제조방법.
[화학식 2]
Figure 112013057283418-pat00017

[화학식 1]
Figure 112013057283418-pat00018

[반응식 1]
Figure 112013057283418-pat00019


상기 R1 은 수소 또는 할로겐 원소로, 할로겐은 플루오로(F), 클로로(Cl), 브로모(Br), 또는 아이오도(I)이고, 상기 R2 및 R3는 모두 C3-C6 알킬기로서 서로 연결되어 5-8각 고리를 형성하거나, 상기 R2 및 R3는 방향족이 포함된 고리 화합물인 1,2,3,4-테트라하이드로아이소퀴놀린(1,2,3,4-tetrahydroisoquinoline), 또는 아이소인돌린(isoindoline)이며, 상기 R4는 C1-C10 알킬기로서 선형 또는 가지형 알킬기임.Ortho-diaalkylamino-substituted alkylidene malonate having the structure of [Formula 2] in the presence of a thiourea derivative catalyst having the structure of [Formula 1] A method for producing a tetrahydroquinoline derivative, which is reacted as in [Scheme 1].
(2)
Figure 112013057283418-pat00017

[Formula 1]
Figure 112013057283418-pat00018

[Reaction Scheme 1]
Figure 112013057283418-pat00019


R 1 is hydrogen or a halogen element, halogen is fluoro (F), chloro (Cl), bromo (Br), or iodo (I), and R 2 and R 3 are both C 3 -C 6 An alkyl group is connected to each other to form a 5-8 cyclic ring, or R 2 and R 3 are 1,2,3,4-tetrahydroisoquinoline (1,2,3,4-tetrahydroisoquinoline), which are aromatic ring compounds ), Or isoindoline, wherein R 4 is a C 1 -C 10 alkyl group, which is a linear or branched alkyl group. 삭제delete 제 1항에 있어서,
톨루엔 용매하에 오쏘-다이아킬아미노 알킬리덴 말로네이트를 싸이오유레아 유도체 촉매 존재 하에서 환류시켜 하기 [화학식 3]의 구조를 갖는 것을 특징으로 하는 테트라하이드로퀴놀린 유도체를 제조방법.
[ 화학식 3 ]
Figure 112013057283418-pat00014

상기 R1 은 수소 또는 할로겐 원소로, 할로겐은 플루오로(F), 클로로(Cl), 브로모(Br), 또는 아이오도(I)이고, 상기 R2 및 R3는 모두 C3-C6 알킬기로서 서로 연결되어 5-8각 고리를 형성하거나, 상기 R2 및 R3는 방향족이 포함된 고리 화합물인 1,2,3,4-테트라하이드로아이소퀴놀린(1,2,3,4-tetrahydroisoquinoline), 또는 아이소인돌린(isoindoline)이며, 상기 R4는 C1-C10 알킬기로서 선형 또는 가지형 알킬기임.The method of claim 1,
A method for producing a tetrahydroquinoline derivative characterized by having an ortho-diaalkylamino alkylidene malonate refluxed in the presence of a thiourea derivative catalyst in a toluene solvent to have the structure of [Formula 3].
[Formula 3]
Figure 112013057283418-pat00014

R 1 is hydrogen or a halogen element, halogen is fluoro (F), chloro (Cl), bromo (Br), or iodo (I), and R 2 and R 3 are both C 3 -C 6 An alkyl group is connected to each other to form a 5-8 cyclic ring, or R 2 and R 3 are 1,2,3,4-tetrahydroisoquinoline (1,2,3,4-tetrahydroisoquinoline), which are aromatic ring compounds ), Or isoindoline, wherein R 4 is a C 1 -C 10 alkyl group, which is a linear or branched alkyl group. 삭제delete 제1항에 있어서,
상기 싸이오유레아 유도체 촉매는 반응 물질들의 전체 몰수를 기준으로, 5 내지 30 몰%인 것을 특징으로 하는 테트라하이트로퀴놀린 유도체의 제조방법
The method of claim 1,
The thiourea derivative catalyst is a method for producing a tetrahytroquinoline derivative, characterized in that 5 to 30 mol% based on the total number of moles of the reactants.
삭제delete
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