KR101453413B1 - Method for preparation of alpha-carboline derivatives - Google Patents
Method for preparation of alpha-carboline derivatives Download PDFInfo
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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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Abstract
알파-카르볼린 유도체의 제조방법이 개시되어 있다. 본 발명은, (E)-3-(2-사이클릭아미노-인돌릴)아크릴알데하이드 화합물을 1,1,2-트리클로로에탄 용매, 유기 촉매와 산 첨가제 존재하에서, 1,5-수소 전이 반응을 통해 알파-카르볼린 유도체를 합성하는 것을 특징으로 한다.A process for preparing alpha-carboline derivatives is disclosed. The present invention relates to a process for the production of 1,5-hydrogen transfer reaction of (E) -3- (2-cyclic amino-indolyl) acrylaldehyde compound in a 1,1,2- trichloroethane solvent, To synthesize an alpha-carboline derivative.
Description
본 발명은 생리활성을 갖고 있는 알파-카르볼린 유도체 (alpha-carboline derivatives)의 제조방법에 관한 것으로, 특히 유기 촉매를 이용하여 높은 수율로 알파-카르볼린 유도체의 제조방법에 관한 것이다.The present invention relates to a process for preparing alpha-carboline derivatives having physiological activity, and more particularly, to a process for preparing alpha-carbolin derivatives in high yield using an organic catalyst.
화합물을 얻는 방법으로 가장 효율적이고 경제적이 방법은 촉매를 이용한 방법으로 다양한 중간체를 제조하는 촉매 반응의 개발은 의학화학분야에서 매우 중요하다. 따라서 공기나 수분에 안정하고 저렴한 촉매를 이용한 반응의 개발은 매우 필요하고 중요하다.The most efficient and economical method for obtaining compounds is the development of catalytic reactions for the preparation of various intermediates by means of catalysts is of great importance in the field of medical chemistry. Therefore, the development of reactions using stable and inexpensive catalysts for air or moisture is very necessary and important.
알파-카르볼린 유도체들은 생리활성과 관련하여 매우 중요하게 인식되어 이들의 합성은 매우 중요하다. 유기 촉매를 이용한 알파-카르볼린 유도체의 제조 방법은 아직 개발되지 않았다. 본 발명에서는 유기촉매를 이용하여 알파-카르볼린 유도체를 합성하였다.Alpha-carboline derivatives are very important in relation to their physiological activity and their synthesis is very important. Methods for preparing alpha-carboline derivatives using organic catalysts have not yet been developed. In the present invention, an alpha-carboline derivative was synthesized using an organic catalyst.
본 발명의 목적은 유기 촉매를 이용하여 높은 수율로 알파-카르볼린 유도체의 제조방법을 제공하는 데 있다.It is an object of the present invention to provide a process for preparing alpha-carbolin derivatives in high yield using an organic catalyst.
상기 목적을 달성하기 위해 본 발명에 따른 알파-카르볼린 유도체의 제조방법은, 하기 [반응식1]과 같이, [화학식 2] 구조를 갖는 (E)-3-(2-사이클릭아미노-인돌릴)아크릴알데하이드 화합물을 1,1,2-트리클로로에탄 용매, 유기 촉매와 산 첨가제 존재하에서, 1,5-수소 전이 반응을 통해 [화학식 3] 구조를 갖는 알파-카르볼린 유도체를 합성하는 것을 특징으로 한다.In order to accomplish the above object, the present invention provides a process for preparing an alpha-carboline derivative, which comprises reacting (E) -3- (2-cyclic amino-indolyl ) Acrylic aldehyde compound is synthesized through a 1,5-hydrogen transfer reaction in the presence of a 1,1,2-trichloroethane solvent, an organic catalyst and an acid additive, .
[반응식 1] [Reaction Scheme 1]
상기 R1과 R2는 서로 연결되어 5각, 6각, 7각, 8각, 9각 고리 또는 테트라하이드로아이소퀴놀린일 수 있음Wherein R 1 and R 2 may be connected to each other to form a pentagon, a hexagon, a hexagon, an octagon, a 9-ring, or a tetrahydroisoquinoline
[화학식 2](2)
상기 R1과 R2는 서로 연결되어 5각, 6각, 7각, 8각, 9각 고리 또는 테트라하이드로아이소퀴놀린일 수 있음Wherein R 1 and R 2 may be connected to each other to form a pentagon, a hexagon, a hexagon, an octagon, a 9-ring, or a tetrahydroisoquinoline
[화학식 3] (3)
상기 R1과 R2는 서로 연결되어 5각, 6각, 7각, 8각, 9각 고리 또는 테트라하이드로아이소퀴놀린일 수 있음.R 1 and R 2 may be connected to each other to form a pentagon, a hexagon, a hexagon, an octagon, a 9-ring, or a tetrahydroisoquinoline.
상술한 바와 같이, 본 발명에서 공기나 수분에 안정하고 취급이 용이한 유기 촉매를 이용하여 높은 수율 알파-카르볼린 유도체를 효율적으로 제조할 수 있다는 효과가 얻어진다.As described above, in the present invention, it is possible to efficiently produce a high-yield alpha-carboline derivative by using an organic catalyst which is stable to air or moisture and easy to handle.
본 발명의 상기 및 그 밖의 목적과 새로운 특징은 본 명세서에 의해서 더욱 명확하게 될 것이다. 먼저 본 발명에 따른 알파-카르볼린 유도체의 제조방법의 특징에 대해 설명한다.These and other objects and novel features of the present invention will become more apparent from the following description. First, the characteristics of the method for producing an alpha-carboline derivative according to the present invention will be described.
본 발명의 일 실시 예에 따른 알파-카르볼린 유도체의 제조방법은, 하기 [반응식1]과 같이, [화학식 2] 구조를 갖는 (E)-3-(2-사이클릭아미노-인돌릴)아크릴알데하이드 화합물을 1,1,2-트리클로로에탄 용매, 유기 촉매와 산 첨가제 존재하에서, 1,5-수소 전이 반응을 통해 [화학식 3] 구조를 갖는 알파-카르볼린 유도체를 합성하는 것이다. 상기 제조방법은 유기 촉매를 이용하여 높은 수율로 알파-카르볼린 유도체를 효율적으로 제조하기 위한 것이다.
The process for preparing an alpha-carboline derivative according to an embodiment of the present invention comprises reacting (E) -3- (2-cyclic amino-indolyl) acryl Carbene derivatives having a structure of formula (3) through a 1,5-hydrogen transfer reaction in the presence of a 1,1,2-trichloroethane solvent, an organic catalyst and an acid additive. The preparation method is for efficiently producing an alpha-carbolin derivative with high yield using an organic catalyst.
[반응식 1] [Reaction Scheme 1]
상기 R1과 R2는 서로 연결되어 5각, 6각, 7각, 8각, 9각 고리 또는 테트라하이드로아이소퀴놀린일 수 있음
Wherein R 1 and R 2 may be connected to each other to form a pentagon, a hexagon, a hexagon, an octagon, a 9-ring, or a tetrahydroisoquinoline
위 제조방법에서 사용되는 유기 촉매는 하기 [화학식 1]의 피롤리딘(pyrrolidine)이다.The organic catalyst used in the above production process is pyrrolidine of the following formula (1).
[화학식 1][Chemical Formula 1]
유기 촉매인 상기 화학식 1의 함량은 반응 물질들의 전체 몰수를 기준으로, 30몰%이다. 30몰%를 사용하면 수율이 높은 알파-카르볼린 유도체를 효율적으로 제조할 수 있다.
The content of the organic catalyst represented by the formula (1) is 30 mol% based on the total moles of the reactants. When 30 mol% is used, an alpha-carboline derivative having a high yield can be efficiently produced.
(E)-3-(2-사이클릭아미노-인돌릴)아크릴알데하이드는 하기의 화학식 2의 구조를 갖는 화합물일 수 있다.(E) -3- (2-cyclic amino-indolyl) acrylaldehyde may be a compound having the structure of the following formula (2).
[화학식 2](2)
상기 R1과 R2는 서로 연결되어 5각, 6각, 7각, 8각, 9각 고리 또는 테트라하이드로아이소퀴놀린일 수 있다.
The R 1 and R 2 may be connected to each other to form a pentagon, a hexagon, a hexagon, an octagon, a 9-ring, or a tetrahydroisoquinoline.
알파-카르볼린 화합물은 화학식 3의 구조를 갖는 화합물일 수 있다.The alpha-carboline compound may be a compound having the structure of Formula (3).
[화학식 3](3)
상기 R1과 R2는 서로 연결되어 5각, 6각, 7각, 8각, 9각 고리 또는 테트라하이드로아이소퀴놀린일 수 있다.
The R 1 and R 2 may be connected to each other to form a pentagon, a hexagon, a hexagon, an octagon, a 9-ring, or a tetrahydroisoquinoline.
상기 첨가제는 CF3CO2H, HClO4, HBr, (+,-)-camphorsulfonic acid, 2,4-dinitrobeznenesulfonic acid, CF3SO3H 중 어느 하나의 화합물일 수 있다. 상기 첨가제는 CF3SO3H 일 때 가장 바람직하며, CF3SO3H는 화학식 4의 구조를 갖는 화합물이다.The additive may be any one of CF 3 CO 2 H, HClO 4 , HBr, (+, -) - camphorsulfonic acid, 2,4-dinitrobenzenesulfonic acid and CF 3 SO 3 H. The additive is most preferably CF 3 SO 3 H, and CF 3 SO 3 H is a compound having the structure of formula (4).
[화학식 4][Chemical Formula 4]
상기 화학식 4에서 첨가제 함량은 반응 물질들의 전체 몰수를 기준으로, 30 몰%인 것을 특징으로 한다.
In the formula (4), the content of the additive is 30 mol% based on the total molar amount of the reactants.
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 are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.
알파-카르볼린 유도체의 합성을 위해 하기 반응식 2와 같이 피롤리딘과 첨가제 존재 하에서 반응을 수행한 결과 높은 수율로 알파-카르볼린 유도체를 합성하였다.For the synthesis of alpha-carboline derivatives, alpha-carboline derivatives were synthesized in high yield by reaction with pyrrolidine in the presence of an additive as shown in Scheme 2 below.
[반응식 2][Reaction Scheme 2]
a 수율은 부분입체이성질체를 합친 수율, b 부분입체이성질체 비율은 1H NMR로 결정.
a The yield was the combined yield of diastereomers, b The diastereomeric ratio was determined by 1 H NMR.
[실시예 1][Example 1]
12-tosyl-2,3,4,5,5a,6,7,12-octahydro-1H-azepino[1',2':1,6]pyrido[2,3-b]indole-6-carbaldehyde (3a)12-tosyl-2,3,4,5,5a, 6,7,12-octahydro-1H-azepino [1 ', 2': 1,6] pyrido [2,3- b] indole-6-carbaldehyde ( 3a )
플라스크에 (E)-3-(2-(azepan-1-yl)-1-tosyl-1H-indol-3-yl)acrylaldehyde (42.2 mg, 0.1 mmol), 상기 촉매 (2.1 mg, 0.03 mmol), 1,1,2-trichloroethane 1 mL로 녹인 후 첨가제 (4.5 mg, 0.03 mmol)을 넣고 12시간 동안 환류한다. 반응 진행이 완료되면 반응 혼합물을 농축 후, 컬럼크로마토크래피로 분리 정제하여 화학식 3을 89% 수율, 부분입체이성질체 비율 66:34로 얻었다. Major diastereomer. 1H NMR (400 MHz, CDCl3) δ = 9.84 (s, 1H), 8.15-8.09 (m, 1H) 7.76-7.71 (m, 3H), 7.44-7.39 (m, 3H), 6.86-6.85 (m, 1H), 3.85 (dd, J = 6.0 Hz, 3.0 Hz, 1H), 3.82-3.79 (m, 1H), 3.22-3.09 (m, 2H), 3.02 (dd, J = 8.0 Hz, 6.5 Hz, 1 H), 2.54-2.52 (m, 1H), 2.23 (s, 3H), 2.09-2.05 (m, 1H), 1.74-1.71 (m, 1H), 1.67-1.57 (m, 5H), 1.37-1.34 (m, 1H).
To the flask was added the above catalyst (2.1 mg, 0.03 mmol), (E) -3- (2- (azepan-1-yl) -1-tosyl-1H-indol- After dissolving in 1 mL of 1,1,2-trichloroethane, add the additive (4.5 mg, 0.03 mmol) and reflux for 12 hours. After completion of the reaction, the reaction mixture was concentrated and then separated and purified by column chromatography to obtain the compound of formula (3) in a yield of 89%, diastereomer ratio of 66:34. Major diastereomer. 1 H NMR (400 MHz, CDCl 3) δ = 9.84 (s, 1H), 8.15-8.09 (m, 1H) 7.76-7.71 (m, 3H), 7.44-7.39 (m, 3H), 6.86-6.85 (m (M, 2H), 3.02 (dd, J = 8.0 Hz, 6.5 Hz, 1H), 3.85 (dd, J = 6.0 Hz, 3.0 Hz, 1H), 3.82-3.79 1H), 1.67-1.57 (m, 5H), 1.37-1.34 (m, 2H), 2.54-2.52 m, 1H).
[실시예 2][Example 2]
11-tosyl-1,2,3,4,4a,5,6,11-octahydroindolo[3,2-c]quinolizine-5-carbaldehyde (3b)11-tosyl-1,2,3,4,4a, 5,6,11-octahydroindolo [3,2-c] quinolizine-5-carbaldehyde ( 3b )
실시예 1과 동일한 방법으로 진행하여 화학식 3을 65% 수율, 부분입체이성질체 비율 90:10로 얻었다.
Proceeding in the same manner as in Example 1, the compound of Formula 3 was obtained in a yield of 65% and a diastereomer ratio of 90:10.
[실시예 3][Example 3]
10-tosyl-2,3,3a,4,5,10-hexahydro-1H-indolizino[5,6-b]indole-4-carbaldehyde (3c)10-tosyl-2,3,3a, 4,5,10-hexahydro-1H-indolizino [5,6-b] indole-4-carbaldehyde ( 3c )
실시예 1과 동일한 방법으로 진행하여 화학식 3을 65% 수율, 부분입체이성질체 비율 90:10로 얻었다.
Proceeding in the same manner as in Example 1, the compound of Formula 3 was obtained in a yield of 65% and a diastereomer ratio of 90:10.
[실시예 4][Example 4]
(6aR)-13-tosyl-1,2,3,4,5,6,6a,7,8,13-decahydroazocino[1',2':1,6]pyrido[2,3-b]indole-7-carbaldehyde (3d)(6aR) -13-tosyl-1,2,3,4,5,6,6a, 7,8,13-decahydroazocino [1 ', 2': 1,6] pyrido [2,3- b] indole- 7-carbaldehyde ( 3d )
실시예 1과 동일한 방법으로 진행하여 화학식 3을 90% 수율, 부분입체이성질체 비율 67:23로 얻었다.
Proceeding in the same manner as in Example 1, the compound of Formula 3 was obtained in a yield of 90% and a diastereomer ratio of 67:23.
[실시예 5][Example 5]
14-tosyl-2,3,4,5,6,7,7a,8,9,14-decahydro-1H-azonino[1',2':1,6]pyrido[2,3-b]indole-8-carbaldehyde (3e)14-tosyl-2,3,4,5,6,7,7a, 8,9,14-decahydro-1H-azonino [1 ', 2': 1,6] pyrido [2,3- b] indole- 8-carbaldehyde ( 3e )
실시예 1과 동일한 방법으로 진행하여 화학식 3을 95% 수율, 부분입체이성질체 비율 55:45로 얻었다.
Proceeding in the same manner as in Example 1, the compound of Formula 3 was obtained in a yield of 95% and a diastereomer ratio of 55:45.
[실시예 6][Example 6]
13-tosyl-1,2,6b,7,8,13-hexahydroindolo[3',2':5,6]pyrido[2,1-a]isoquinoline-7-carbaldehyde (3f)13-tosyl-1,2,6b, 7,8,13-hexahydroindolo [3 ', 2': 5,6] pyrido [2,1-a] isoquinoline-7-carbaldehyde ( 3f )
실시예 1과 동일한 방법으로 진행하여 화학식 3을 95% 수율, 부분입체이성질체 비율 52:48로 얻었다.
Proceeding in the same manner as in Example 1, the compound of Formula 3 was obtained in a 95% yield and a diastereomer ratio of 52:48.
Claims (5)
[반응식 1]
상기 R1과 R2는 서로 연결되어 5각, 6각, 7각, 8각, 9각 고리 또는 테트라하이드로아이소퀴놀린일 수 있음
[화학식 1]
[화학식 2]
상기 R1과 R2는 서로 연결되어 5각, 6각, 7각, 8각, 9각 고리 또는 테트라하이드로아이소퀴놀린일 수 있음
[화학식 3]
상기 R1과 R2는 서로 연결되어 5각, 6각, 7각, 8각, 9각 고리 또는 테트라하이드로아이소퀴놀린일 수 있음.
[화학식 4]
(E) -3- (2-cyclic amino-indolyl) acrylaldehyde compound having a structure of the formula (2) is reacted with a 1,1,2-trichloroethane solvent and a [ Characterized in synthesizing an alpha-carboline derivative having a structure of formula (3) through 1,5-hydrogen transfer reaction in the presence of pyrrolidine of formula (1) and CF 3 SO 3 H of formula (4) A method for producing a carbolin derivative.
[Reaction Scheme 1]
Wherein R 1 and R 2 may be connected to each other to form a pentagon, a hexagon, a hexagon, an octagon, a 9-ring, or a tetrahydroisoquinoline
[Chemical Formula 1]
(2)
Wherein R 1 and R 2 may be connected to each other to form a pentagon, a hexagon, a hexagon, an octagon, a 9-ring, or a tetrahydroisoquinoline
(3)
R 1 and R 2 may be connected to each other to form a pentagon, a hexagon, a hexagon, an octagon, a 9-ring, or a tetrahydroisoquinoline.
[Chemical Formula 4]
상기 피롤리딘의 함량은, 반응 물질들의 전체 몰수를 기준으로, 30 몰%인 것을 특징으로 하는 알파-카르볼린 유도체의 제조방법.
The method according to claim 1,
Wherein the content of pyrrolidine is 30 mol% based on the total moles of reactants.
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| J. AM. CHEM. SOC. 2009, 131, 13226-13227 * |
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