KR20090118417A - Novel cyclic compounds and process for preparing them - Google Patents

Novel cyclic compounds and process for preparing them Download PDF

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KR20090118417A
KR20090118417A KR1020080044182A KR20080044182A KR20090118417A KR 20090118417 A KR20090118417 A KR 20090118417A KR 1020080044182 A KR1020080044182 A KR 1020080044182A KR 20080044182 A KR20080044182 A KR 20080044182A KR 20090118417 A KR20090118417 A KR 20090118417A
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ethyl
phenyl
methylene
alkyl
methyl
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KR101014890B1 (en
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이필호
강영진
김현석
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강원대학교산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms

Abstract

PURPOSE: A novel cyclic compound and a manufacturing method are provided to use as a good precursor in natural material synthesis or medicinal or pharmaceutical filed. CONSTITUTION: A cyclic compound is denoted by the chemical formula 1a. In the chemical formula 1a, D1-X1 is CX1 or CX1X2; D2-X2 is oxygen(O), CX1X2, or CX2; A is H or straight or branched C1-C10 alkyl; and R1 and R2 are same or different H, straight or branched C1-C10 alkyl or phenyl.

Description

신규 고리화합물과 이의 제조방법{Novel cyclic compounds and process for preparing them}Novel cyclic compounds and process for preparing them

본 발명은 신규 고리화합물과 이의 제조방법에 관한 것으로, 보다 상세하게는 하기 화학식 2로 표시되는 비닐 알렌(vinyl allene) 유도체와 하기 화학식 3으로 표시되는 친디엔체와의 딜스-엘더(Diels-Alder) 반응을 수행하여 제조된 하기 화학식 1로 표시되는 신규 고리화합물과 이의 제조방법에 관한 것이다.The present invention relates to a novel cyclic compound and a method for preparing the same, and more specifically, Diels-Alder of a vinyl allene derivative represented by the following Chemical Formula 2 and a diene die represented by the following Chemical Formula 3 The present invention relates to a novel cyclic compound represented by the following Chemical Formula 1 and a method for preparing the same.

Figure 112008033895875-PAT00004
Figure 112008033895875-PAT00004

상기 반응식에서,

Figure 112008033895875-PAT00005
는 단일결합 또는 이중결합을 나타내고;
Figure 112008033895875-PAT00006
는 이중결합 또는 삼중결합을 나타내고; D1-X1은 CX1, 또는 CX1X2이고; D2-X2는 산소원자(O), CX1X2, 또는 CX2이며; A는 H, 또는 직쇄 또는 분쇄의 C1-10알킬이고; R1 및 R2는 서로 같거나 다른 것으로 H, 직쇄 또는 분쇄의 C1-10알킬, 또는 페닐이거나, 또는 R1 및 R2가 서로 결합하여 형성된 탄소원자 5 내지 10개의 지방족 또는 방향족 고리기 또는 접합 고 리기이고; X1 및 X2는 서로 같거나 다른 것으로 H, C1-10알킬, C(O)C1-10알킬, 및 C(O)OC1-10알킬 중에서 선택되거나, 또는 X1 및 X2가 서로 결합하여
Figure 112008033895875-PAT00007
를 형성하고, 이때 Q는 O, S, N(R3), C1 - 10알킬렌, 및 페닐렌 중에서 선택된 2가기이고, R3은 H, 직쇄 또는 분쇄의 C1-10알킬, 또는 페닐이다.In the above scheme,
Figure 112008033895875-PAT00005
Represents a single bond or a double bond;
Figure 112008033895875-PAT00006
Represents a double bond or a triple bond; D 1 -X 1 is CX 1 , Or CX 1 X 2 ; D 2 -X 2 is the oxygen atom (O), CX 1 X 2 , Or CX 2 ; A is H or straight or branched C 1-10 alkyl; R 1 and R 2 are the same or different from each other and are H, straight or branched C 1-10 alkyl, or phenyl, or R 1 and R 2 are an aliphatic or aromatic ring group having 5 to 10 carbon atoms formed by bonding to each other or A junction ring; X 1 and X 2 are the same or different and are selected from H, C 1-10 alkyl, C (O) C 1-10 alkyl, and C (O) OC 1-10 alkyl, or X 1 and X 2 are In combination with each other
Figure 112008033895875-PAT00007
To form, wherein Q is O, S, N (R 3 ), C 1 - 10 alkylene group, and a divalent group selected from phenylene, R 3 is H, C 1-10 straight or branched chain alkyl, or phenyl to be.

딜스-엘더(Diels-Alder) 반응은 디엔 화합물과 친디엔체가 분자간 [4+2]고리화 첨가반응으로 6각형 고리화합물을 합성하는 데에 있어서 가장 대표적인 반응이고 수많은 문헌들이 보고되었으며, 현재에도 많은 연구가 수행되고 있다. 하지만 디엔 화합물로서 비닐 알렌화합물을 사용하는 딜스-엘더(Diels-Alder) 반응은 많이 알려져 있지 않다. 그 이유는, 비닐 알렌화합물의 제조방법에 제한성을 가지고 있기 때문에 쉽게 합성할 수 없다는 단점이 있기 때문이다.Diels-Alder reaction is the most representative reaction of diene compounds and dienophiles in the synthesis of hexagonal cyclic compounds by intermolecular [4 + 2] cycloaddition reaction. Research is being done. However, Diels-Alder reaction using vinyl allene compound as diene compound is not known much. The reason is that there is a disadvantage in that it cannot be easily synthesized because it has limitations in the production method of the vinyl allene compound.

최근에 보고된 비닐 알렌화합물의 제조방법으로는, 인듐 금속과 프로파질 할라이드 유도체를 반응시켜 얻어지는 유기인듐 시약을 비닐 할라이드와 혹은 비닐 트리플레이트의 교차-짝지움 반응을 통해 선택적으로 합성한 예가 있다. 이러한 비닐 알렌화합물은 분자내에 알렌 치환기를 포함하고 있어서 유기 합성에서 중요한 전구체로 사용될 수 있으며, 전이금속을 이용한 유기반응에도 사용될 수 있고 디엔 골격을 가지고 있기 때문에 친디엔체와의 딜스-엘더(Diels-Alder)에도 유용하 게 사용될 수 있다. [Chem. Commun. 1985, 467; J. Am. Chem. Soc. 1988, 110, 6432; Chem. Commun. 1993, 270; J. Org. Chem. 1998, 63, 5238; Angew. Chem. Int. Ed . 2002, 41, 3901; J. Org . Chem. 2003, 68, 7845; J. Org . Chem. 2006, 71, 9153].A recently reported method for producing a vinyl allene compound is an example of selectively synthesizing an organic indium reagent obtained by reacting an indium metal with a propazyl halide derivative through a cross-coupling reaction of vinyl halide or vinyl triflate. These vinyl allene compounds contain allen substituents in the molecule, which can be used as an important precursor in organic synthesis, can be used in organic reactions using transition metals, and have a diene skeleton. Alder can also be useful. Chem. Commun . 1985 , 467; J. Am. Chem. Soc. 1988 , 110 , 6432; Chem. Commun . 1993 , 270; J. Org. Chem . 1998 , 63 , 5238; Angew. Chem. Int. Ed . 2002 , 41 , 3901; J. Org . Chem . 2003 , 68 , 7845; J. Org . Chem . 2006 , 71 , 9153].

본 발명의 목적은 신규 구조의 고리화합물을 제공하는 것이다.It is an object of the present invention to provide a cyclic compound of novel structure.

본 발명의 다른 목적은 유기인듐 시약과 비닐 할라이드 혹은 비닐 트리플레이트의 교차 짝지움 반응으로부터 얻어지는 비닐 알렌화합물을, 친디엔체와 딜스-엘더(Diels-Alder) 반응을 수행하여 신규 구조의 고리화합물을 제조하는 방법을 제공하는 것이다.Another object of the present invention is to obtain a cyclic compound having a novel structure by carrying out a Diels-Alder reaction with a diene compound and a vinyl allene compound obtained from a cross-coupling reaction between an organoindium reagent and a vinyl halide or vinyl triflate. It is to provide a method of manufacturing.

본 발명은 하기 화학식 1로 표시되는 신규의 고리 화합물을 그 특징으로 한다.The present invention is characterized by a novel ring compound represented by the following formula (1).

Figure 112008033895875-PAT00008
Figure 112008033895875-PAT00008

상기 화학식 1에서,

Figure 112008033895875-PAT00009
는 단일결합, 또는 이중결합을 나타내고; D1-X1은 CX1, 또는 CX1X2이고; D2-X2는 산소원자(O), CX1X2, 또는 CX2이며; A는 H, 또는 직쇄 또는 분쇄의 C1 - 10알킬이고; R1 및 R2는 서로 같거나 다른 것으로 H, 직쇄 또는 분쇄의 C1 - 10알킬, 또는 페닐이거나, 또는 R1 및 R2가 서로 결합하여 형성된 탄소원자 5 내지 10개의 지방족 또는 방향족 고리기 또는 접합 고리기이고; X1 및 X2는 서로 같거나 다른 것으로 H, C1-10알킬, C(O)C1-10알킬, 및 C(O)OC1-10알킬 중에서 선택되거나, 또는 X1 및 X2가 서로 결합하여
Figure 112008033895875-PAT00010
를 형성하고, 이때 Q는 O, S, N(R3), C1 - 10알킬렌, 및 페닐렌 중에서 선택된 2가기이고, R3은 H, 직쇄 또는 분쇄의 C1 - 10알킬, 또는 페닐이다.In Chemical Formula 1,
Figure 112008033895875-PAT00009
Represents a single bond or a double bond; D 1 -X 1 is CX 1 , Or CX 1 X 2 ; D 2 -X 2 is the oxygen atom (O), CX 1 X 2 , Or CX 2 ; A is H, or straight or C 1 of the crushing-10 alkyl; R 1 and R 2 are each the same or different to H, linear or grinding C 1 - or 10-alkyl, or phenyl, or R 1 and R 2 are combined to provided the carbon atoms of 5 to 10 aliphatic or aromatic group or one another Conjugated ring group; X 1 and X 2 are the same or different and are selected from H, C 1-10 alkyl, C (O) C 1-10 alkyl, and C (O) OC 1-10 alkyl, or X 1 and X 2 are In combination with each other
Figure 112008033895875-PAT00010
To form, wherein Q is O, S, N (R 3 ), C 1 - 10 alkylene, and a selected second top from phenylene, R 3 is H, a straight or branched chain C 1 - 10 alkyl, or phenyl to be.

또한, 본 발명은 하기 화학식 2로 표시되는 비닐 알렌 유도체와 하기 화학식 3으로 표시되는 친디엔체와 딜스-엘더(Diels-Alder) 반응을 수행하여 제조하는, 상기 화학식 1로 표시되는 고리화합물의 제조방법을 그 특징으로 한다.In addition, the present invention is prepared by carrying out a Diels-Alder reaction with the vinylene derivative represented by the following formula (2) and the dienophile represented by the following formula (3), to prepare a cyclic compound represented by the formula (1) The method is characterized by that.

Figure 112008033895875-PAT00011
Figure 112008033895875-PAT00011

Figure 112008033895875-PAT00012
Figure 112008033895875-PAT00012

상기 화학식 2, 또는 3에서, A, D1, D2, R1, R2, X1, 및 X2는 각각 상기에서 정의한 바와 같다.In Formula 2 or 3, A, D 1 , D 2 , R 1 , R 2 , X 1 , and X 2 are each as defined above.

본 발명에 따른 상기 화학식 1로 표시되는 고리화합물이 있어, 바람직하기로는 D1-X1은 CX1, 또는 CX1X2이고; D2-X2는 산소원자(O), CX1X2, 또는 CX2이며; A는 H, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸이고; R1 및 R2는 서로 같거나 다른 것으로 H, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 또는 페닐이거나, 또는 R1 및 R2가 서로 결합하여 -(CH2)n- (이때, n=3-8), -C(=O)(CH2)n- (이때, n=3-8), 또는

Figure 112008033895875-PAT00013
(이때, m1 또는 m2는 0-3이고, Z는 H, C1-6알킬 또는 C1-6알콕시)를 형성하고; X1 및 X2는 서로 같거나 다른 것으로 H, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 메톡시카보닐, 에톡시카보닐, 프로필카보닐, 또는 부틸카보닐이거나, 또는 X1 및 X2가 서로 결합하여 형성된 -C(O)OC(O)-, -C(O)SC(O)-, -C(O)N(H)C(O)-, -C(O)N(CH3)C(O)-, -C(O)N(C2H5)C(O)-, -C(O)N(Ph)C(O)-, -C(O)CH2C(O)-, 또는 -C(O)CH2CH2C(O)-이다.There is a cyclic compound represented by Formula 1 according to the present invention, preferably D 1 -X 1 is CX 1 , Or CX 1 X 2 ; D 2 -X 2 is the oxygen atom (O), CX 1 X 2 , Or CX 2 ; A is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl; R 1 and R 2 are the same or different from each other and are H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or phenyl, or R 1 and R 2 are bonded to each other-(CH 2 ) n- ( where n = 3-8), -C (= O) (CH 2 ) n- (where n = 3-8), or
Figure 112008033895875-PAT00013
Wherein m 1 or m 2 is 0-3 and Z is H, C 1-6 alkyl or C 1-6 alkoxy; X 1 and X 2 are the same or different from each other and are H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxycarbonyl, ethoxycarbonyl, propylcarbonyl, or butylcarbonyl Or -C (O) OC (O)-, -C (O) SC (O)-, -C (O) N (H) C (O)-,-formed by combining X 1 and X 2 with each other C (O) N (CH 3 ) C (O)-, -C (O) N (C 2 H 5 ) C (O)-, -C (O) N (Ph) C (O)-, -C (O) CH 2 C (O)-or -C (O) CH 2 CH 2 C (O)-.

본 발명에 따른 상기 화학식 1로 표시되는 고리화합물이 있어, 보다 바람직하기로는 하기에 나타낸 화합물이다. There is a cyclic compound represented by the formula (1) according to the present invention, more preferably the compound shown below.

Figure 112008033895875-PAT00014
,
Figure 112008033895875-PAT00015
,
Figure 112008033895875-PAT00016
,
Figure 112008033895875-PAT00017
,
Figure 112008033895875-PAT00018
,
Figure 112008033895875-PAT00014
,
Figure 112008033895875-PAT00015
,
Figure 112008033895875-PAT00016
,
Figure 112008033895875-PAT00017
,
Figure 112008033895875-PAT00018
,

Figure 112008033895875-PAT00019
,
Figure 112008033895875-PAT00020
,
Figure 112008033895875-PAT00021
,
Figure 112008033895875-PAT00022
Figure 112008033895875-PAT00019
,
Figure 112008033895875-PAT00020
,
Figure 112008033895875-PAT00021
,
Figure 112008033895875-PAT00022

상기 화합물에 있어서, A는 H, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸이고; R1은 H, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 또는 페닐이고; X1 및 X2는 서로 같거나 다른 것으로 H, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 메톡시카보닐, 에톡시카보닐, 프로필카보닐, 또는 부틸카보닐이거나, 또는 X1 및 X2가 서로 결합하여 형성된 -C(O)OC(O)-, -C(O)SC(O)-, -C(O)N(H)C(O)-, -C(O)N(CH3)C(O)-, -C(O)N(C2H5)C(O)-, -C(O)N(Ph)C(O)-, -C(O)CH2C(O)-, 또는 -C(O)CH2CH2C(O)-이다.In the compound, A is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl; R 1 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or phenyl; X 1 and X 2 are the same or different from each other and are H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxycarbonyl, ethoxycarbonyl, propylcarbonyl, or butylcarbonyl Or -C (O) OC (O)-, -C (O) SC (O)-, -C (O) N (H) C (O)-,-formed by combining X 1 and X 2 with each other C (O) N (CH 3 ) C (O)-, -C (O) N (C 2 H 5 ) C (O)-, -C (O) N (Ph) C (O)-, -C (O) CH 2 C (O)-or -C (O) CH 2 CH 2 C (O)-.

본 발명에 따른 상기 화학식 1로 표시되는 고리화합물을 구체적으로 예시하면 다음과 같다 :Specific examples of the cyclic compound represented by Formula 1 according to the present invention are as follows:

5-에틸-4-메틸렌-3a,7,8,9,9a,9b-헥사하이드로-4H-나프토[1,2-c]퓨란-1,3,6-트라이온,5-ethyl-4-methylene-3a, 7,8,9,9a, 9b-hexahydro- 4H -naphtho [1,2- c ] furan-1,3,6-trione,

5-에틸-4-메틸렌-2-페닐-3a,7,8,9,9a,9b-헥사하이드로-4H-벤조[e]아이소인돌-1,3,6-트라이온,5-ethyl-4-methylene-2-phenyl-3a, 7,8,9,9a, 9b-hexahydro- 4H -benzo [ e ] isoindole-1,3,6-trione,

4-에틸-3-메틸-5-옥소-5,6,7,8-테트라하이드로-나프탈렌-1,2-다이카복실릭산 다이메틸 에스터,4-ethyl-3-methyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-1,2-dicarboxylic acid dimethyl ester,

4-에틸-3-메틸렌-5-옥소-3,5,6,7,8,8a-헥사하이드로-2H-크로멘-2-카복시릭산 에틸 에스터,4-ethyl-3-methylene-5-oxo-3,5,6,7,8,8a-hexahydro- 2H -chromen-2-carboxylic acid ethyl ester,

5-메틸-4-메틸렌-6-페닐-3a,4,7,7a-테트라하이드로아이소벤조퓨란-1,3-다이온,5-methyl-4-methylene-6-phenyl-3a, 4,7,7a-tetrahydroisobenzofuran-1,3-dione,

다이메틸 3,4-다이메틸-5-페닐프탈레이트,Dimethyl 3,4-dimethyl-5-phenylphthalate,

5-에틸-4-메틸렌-6-페닐-3a,4,7,7a-테트라하이드로아이소벤조퓨란-1,3-다이온,5-ethyl-4-methylene-6-phenyl-3a, 4,7,7a-tetrahydroisobenzofuran-1,3-dione,

5-에틸-4-메틸렌-2,6-다이페닐-3a,4,7,7a-테트라하이드로아이소인돌-1,3-다이온,5-ethyl-4-methylene-2,6-diphenyl-3a, 4,7,7a-tetrahydroisoindole-1,3-dione,

2-에틸-1-메틸렌-3-페닐-1,4,4a,9a-테트라하이드로안트라퀴논,2-ethyl-1-methylene-3-phenyl-1,4,4a, 9a-tetrahydroanthraquinone,

4-에틸-3-메틸렌-5-페닐-사이클로헥스-4-엔-1,2-다이카복실산 다이메틸 에스터,4-ethyl-3-methylene-5-phenyl-cyclohex-4-ene-1,2-dicarboxylic acid dimethyl ester,

4-에틸-5-메틸렌-3-페닐-사이클로헥스-3-엔 카복실산 에틸 에스터,4-ethyl-5-methylene-3-phenyl-cyclohex-3-ene carboxylic acid ethyl ester,

3-에틸-2-메틸렌-4-페닐-사이클로헥스-3-엔 카복실산 에틸 에스터,3-ethyl-2-methylene-4-phenyl-cyclohex-3-ene carboxylic acid ethyl ester,

4-에틸-3-메틸렌-5-페닐-3,6-다이하이드로-2H-피란-2-카복실산 에틸 에스터,4-ethyl-3-methylene-5-phenyl-3,6-dihydro- 2H -pyran-2-carboxylic acid ethyl ester,

에틸 4-에틸-5-메틸-3-페닐 벤조에이트,Ethyl 4-ethyl-5-methyl-3-phenyl benzoate,

8-터셔리-부틸-4-메틸렌-2-페닐-3a,4,6,7,8,9a,9b-옥타하이드로벤조[e]아이소인돌-1,3-다이온,8-tertiary-butyl-4-methylene-2-phenyl-3a, 4,6,7,8,9a, 9b-octahydrobenzo [e] isoindole-1,3-dione,

4-메톡시-12-메틸렌-16-페닐-6,7,8,12,13,14-헥사하이드로-16-아자-사이클로펜타[a]펜안쓰렌-15,17-다이온.4-methoxy-12-methylene-16-phenyl-6,7,8,12,13,14-hexahydro-16-aza-cyclopenta [a] phenanthrene-15,17-dione.

한편, 본 발명은 상기 화학식 1로 표시되는 고리화합물의 제조방법을 권리범위로 포함한다. 본 발명에 따른 상기 화학식 1로 표시되는 고리화합물의 제조방법은, 하기 반응식 1에 나타낸 바와 같이 하기 화학식 2로 표시되는 비닐 알렌 유도체와 하기 화학식 3으로 표시되는 친디엔체와 딜스-엘더(Diels-Alder) 반응을 수행하여 이루어진다.On the other hand, the present invention includes a method for producing a cyclic compound represented by the formula (1) as a scope. The method for preparing a cyclic compound represented by Chemical Formula 1 according to the present invention includes a vinyl allene derivative represented by Chemical Formula 2, a dienophile represented by Chemical Formula 3, and Diels-Elder as shown in the following Chemical Formula 1. Alder) reaction is carried out.

Figure 112008033895875-PAT00023
Figure 112008033895875-PAT00023

상기 반응식 1에서, A, D1, D2, R1, R2, X1, 및 X2는 각각 상기에서 정의한 바와 같다.In Scheme 1, A, D 1 , D 2 , R 1 , R 2 , X 1 , and X 2 are as defined above, respectively.

상기 반응식 1에 따른 딜스-엘더(Diels-Alder) 반응에 사용되는 반응 용매는 통상의 유기용매로서, 예를 들면 다이클로로메탄(CH2Cl2), 톨루엔(toluene), 벤젠(benzene), 테트라히드로퓨란-(THF), 다이메틸포름아미드(DMF) 등을 사용할 수 있으며, 바람직하게는 다이클로로메탄(CH2Cl2), 톨루엔(toluene)을 사용하여 수행하는 것이다. The reaction solvent used for the Diels-Alder reaction according to Scheme 1 is a conventional organic solvent, for example, dichloromethane (CH 2 Cl 2 ), toluene, benzene, tetra Hydrofuran- (THF), dimethylformamide (DMF) and the like can be used, preferably, dichloromethane (CH 2 Cl 2 ), toluene (toluene).

반응 온도는 친디엔체의 종류에 따라 다르며, 톨루엔(toluene)을 용매로 사용할 경우는 25℃ 내지 100℃에서 딜스-엘더(Diels-Alder) 반응을 수행하며, 다이클로로메탄(CH2Cl2)을 용매로 사용할 경우는 25℃ 내지 65℃에서 딜스-엘더(Diels-Alder) 반응을 수행할 수 있다.The reaction temperature varies depending on the type of dienophile. When toluene is used as a solvent, the Diels-Alder reaction is performed at 25 ° C. to 100 ° C., and dichloromethane (CH 2 Cl 2 ) is used. In the case of using as a solvent, the Diels-Alder reaction may be performed at 25 ° C to 65 ° C.

반응 시간은 반응물질, 용매의 종류 및 용매의 양에 따라 달라질 수 있으며, TLC 등을 통하여 출발물질인 비닐 알렌화합물이 모두 소모되었음을 확인한 후 반응을 완결시키도록 한다. 반응이 완결되면, 추출과정을 통해 감압하에서 용매를 증류시킨 후 관 크로마토그래피 또는 재결정 등의 통상의 방법을 통하여 목적물을 분리 정제할 수도 있다.The reaction time may vary depending on the reactants, the type of solvent, and the amount of the solvent. After confirming that all of the starting material vinyl allene compounds are consumed through TLC, the reaction is completed. After the reaction is completed, the solvent may be distilled off under reduced pressure through an extraction process, and then the target product may be separated and purified through conventional methods such as column chromatography or recrystallization.

본 발명에 따른 제조방법에서 출발물질로 사용하는 상기 화학식 2로 표시되는 비닐 알렌 유도체는, 하기 반응식 2에 나타낸 바와 같이 할라이드 금속염과 팔라듐(Pd) 촉매 존재 하에서 프로파질 할라이드 유도체와 인듐 금속을 반응시켜 유기인듐 시약을 제조하며, 제조된 유기인듐 시약을 별도의 분리 정제과정 없이 비닐 할라이드 혹은 비닐 트리플레이트 유도체를 직접 첨가하여 교차-짝지움 반응을 수행하는 일용기 반응(one-pot reaction)에 의해 제조하여 사용할 수 있다. 이때 사용되는 할라이드 금속염으로는 대표적으로 리튬 요오다이드(LiI)가 사용될 수 있다. The vinyl allene derivative represented by Chemical Formula 2, which is used as a starting material in the preparation method according to the present invention, is reacted with a propazyl halide derivative and an indium metal in the presence of a halide metal salt and a palladium (Pd) catalyst as shown in Scheme 2 below. The organic indium reagent is prepared, and the prepared organic indium reagent is prepared by a one-pot reaction in which a cross-pairing reaction is performed by directly adding a vinyl halide or vinyl triflate derivative without separate separation and purification. Can be used. At this time, as the halide metal salt used, lithium iodide (LiI) may be typically used.

Figure 112008033895875-PAT00024
Figure 112008033895875-PAT00024

상기 반응식 2에서, A, R1, 및 R2는 각각 상기에서 정의한 바와 같다.In Scheme 2, A, R 1 , and R 2 are each as defined above.

본 발명에 따른 제조방법에서 사용되는 상기 화학식 3으로 표시되는 친디엔체를 구체적으로 예시하면 다이메틸아세틸렌다이카복실에이트(3a), 말레익 언하이드라이드(3b), N-페닐말레이미드(3c), 다이메틸 말리에이트(3d), 에틸 아크릴에이트(3e), 에틸프로피올레이트(3f), 에틸 글리옥살에이트(3g), 나프토퀴논(3h)이 포함될 수 있다.Specific examples of the dienophile represented by Chemical Formula 3 used in the preparation method according to the present invention include dimethylacetylene dicarboxylate (3a), maleic hydride (3b), and N-phenylmaleimide (3c). , Dimethyl maleate (3d), ethyl acrylate (3e), ethylpropiolate (3f), ethyl glyoxalate (3g), naphthoquinone (3h).

Figure 112008033895875-PAT00025
Figure 112008033895875-PAT00025

상기 화학식 3으로 표시되는 친디엔체의 사용량은 그 종류에 따라 다를 수 있는 데, 일반적으로 상기 화학식 2로 표시되는 비닐 알렌화합물에 대하여 1 당량 내지 30 당량 범위로 사용하도록 한다. 보다 구체적으로는 다이메틸 말리에이트(3e)를 친디엔체로 사용하는 경우 상기 화학식 2로 표시되는 비닐 알렌화합물에 대하여 3 당량 정도 사용하고, 에틸 아크릴에이트(3f)를 친디엔체로 사용하는 경우 상기 화학식 2로 표시되는 비닐 알렌화합물에 대하여 5 당량 정도 사용하며, 에틸 글리옥살에이트(3g)를 친디엔체로 사용하는 경우 상기 화학식 2로 표시되는 비닐 알렌화합물에 대하여 30 당량 정도 사용한다.The amount of the dienophile represented by Chemical Formula 3 may vary depending on the type thereof, and is generally used in the range of 1 equivalent to 30 equivalents with respect to the vinyl allene compound represented by Chemical Formula 2. More specifically, when dimethyl maleate (3e) is used as the dienophile, about 3 equivalents of the vinyl allene compound represented by Formula 2 is used, and when ethyl acrylate (3f) is used as the dienophile, About 5 equivalents of the vinyl allene compound represented by 2 is used. When ethyl glyoxalate (3 g) is used as the dienophile, about 30 equivalents of the vinyl allene compound represented by the formula (2) is used.

이상에서 설명한 바와 같은 본 발명은 다음의 실시예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이들 실시예에 의해 국한되는 것은 아니다.The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited to these examples.

[[ 실시예Example ]]

실시예 1. 5-에틸-4-메틸렌-3a,7,8,9,9a,9b-헥사하이드로-4H-나프토[1,2-c]퓨란-1,3,6-트라이온의 제조Example 1. 5-ethyl-4-methylene-3a, 7,8,9,9a, 9b-hexahydro- 4H -naphtho [1,2- c ] furan-1,3,6-trione Produce

Figure 112008033895875-PAT00026
Figure 112008033895875-PAT00026

2-(1-에틸-프로파-1,2-다이에닐)-사이클로헤세-2-엔온 (48.7 mg, 0.3 mmol)과 말레익 언하이드라이드 (29.4 mg, 0.3 mmol)을 CH2Cl2 용매 1.0 mL에 녹인 후 실온에서 13시간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)를 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 CH2Cl2와 헥산으로 재결정하여 표제화합물인 5-에틸-4-메틸렌- 3a,7,8,9,9a,9b-헥사하이드로-4H-나프토[1,2-c]퓨란-1,3,6-트라이온 (60 mg, 77%)을 얻었다.2- (1-ethyl-propa-1,2-dienyl) -cyclohes-2-enone (48.7 mg, 0.3 mmol) and maleic anhydride (29.4 mg, 0.3 mmol) were CH 2 Cl 2 After dissolving in 1.0 mL of solvent, the mixture was stirred for 13 hours at room temperature, and saturated NaHCO 3 aqueous solution (10 mL) was added to terminate the reaction. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. After removal of the solvent, the residue was recrystallized from CH 2 Cl 2 and hexane to give the title compound, 5-ethyl-4-methylene-3a, 7,8,9,9a, 9b-hexahydro- 4H -naphtho [1,2- c ] Furan-1,3,6-trione (60 mg, 77%) was obtained.

1H NMR (400 MHz, CDCl3, 25℃, TMS) δ5.65 (d, J = 17.8 Hz, 2H), 4.02 (d, J = 9.52 Hz, 1H), 3.46 (dd, J = 5.14, 5.16 Hz, 1H), 3.19-3.10 (m, 1H), 2.68-2.63 (m, 1H), 2.56-2.55 (m, 1H), 2.52-2.49 (m, 1H), 2.45-2.36 (m, 1H), 2.31-2.22 (m, 2H), 2.07-1.97 (m, 2H), 1.75-1.63 (m, 1H), 1.00 (t, J = 7.39 Hz, 3H) 1 H NMR (400 MHz, CDCl 3, 25 ° C., TMS) δ5.65 (d, J = 17.8 Hz, 2H), 4.02 (d, J = 9.52 Hz, 1H), 3.46 (dd, J = 5.14, 5.16 Hz, 1H), 3.19-3.10 (m, 1H), 2.68-2.63 (m, 1H), 2.56-2.55 (m, 1H), 2.52-2.49 (m, 1H), 2.45-2.36 (m, 1H), 2.31-2.22 (m, 2H), 2.07-1.97 (m, 2H), 1.75-1.63 (m, 1H), 1.00 (t, J = 7.39 Hz, 3H)

실시예 2. 5-에틸-4-메틸렌-2-페닐-3a,7,8,9,9a,9b-헥사하이드로-4H-벤조[e]아이소인돌-1,3,6-트라이온의 제조Example 2. 5-ethyl-4-methylene-2-phenyl-3a, 7,8,9,9a, 9b-hexahydro- 4H -benzo [ e ] isoindole-1,3,6-trione Produce

Figure 112008033895875-PAT00027
Figure 112008033895875-PAT00027

2-(1-에틸-프로파-1,2-다이에닐)-사이클로헤세-2-엔온 (49 mg, 0.3 mmol)과 N-페닐말레이미드 (52 mg, 0.3 mmol)을 CH2Cl2 용매 1.0 mL에 녹인 후 실온에서 13시간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)을 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 CH2Cl2와 헥산으로 재결정하여 표제 화합물인 5-에틸-4-메틸렌-2-페닐- 3a,7,8,9,9a,9b-헥사하이드로-4H-벤조[e]아이소인돌-1,3,6-트라이온 (83 mg, 83%)을 얻었다.2- (1-ethyl-propa-1,2-dienyl) -cyclohes-2-enone (49 mg, 0.3 mmol) and N -phenylmaleimide (52 mg, 0.3 mmol) were CH 2 Cl 2 After dissolving in 1.0 mL of solvent, the mixture was stirred for 13 hours at room temperature, and saturated NaHCO 3 aqueous solution (10 mL) was added to terminate the reaction. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. The solvent was removed and then recrystallized with CH 2 Cl 2 and hexane to give the title compound, 5-ethyl-4-methylene-2-phenyl-3a, 7,8,9,9a, 9b-hexahydro- 4H -benzo [ e ]. Isoindole-1,3,6-trione (83 mg, 83%) was obtained.

1H NMR (400 MHz, CDCl3, 25℃, TMS) δ7.45-7.38 (m, 3H), 7.14 (d, J = 7.45 Hz, 2H), 5.63 (d, J = 4.80 Hz, 2H), 3.89 (d, J = 8.70 Hz, 1H), 3.34 (dd, J = 4.95, 4.82 Hz, 1H), 3.19 (dd, J = 7.33, 7.35Hz, 1H), 2.73-2.67 (m, 1H), 2.55-2.33 (m, 3H), 2.27-2.19 (m, 1H), 2.07-1.99 (m, 2H), 1.75-1.63 (m, 1H), 1.00 (t, J = 7.36 Hz, 3H) 1 H NMR (400 MHz, CDCl 3, 25 ° C., TMS) δ 7.45-7.38 (m, 3H), 7.14 (d, J = 7.45 Hz, 2H), 5.63 (d, J = 4.80 Hz, 2H), 3.89 (d, J = 8.70 Hz, 1H), 3.34 (dd, J = 4.95, 4.82 Hz, 1H), 3.19 (dd, J = 7.33, 7.35 Hz, 1H), 2.73-2.67 (m, 1H), 2.55 -2.33 (m, 3H), 2.27-2.19 (m, 1H), 2.07-1.99 (m, 2H), 1.75-1.63 (m, 1H), 1.00 (t, J = 7.36 Hz, 3H)

실시예 3. 4-에틸-3-메틸-5-옥소-5,6,7,8-테트라하이드로-나프탈렌-1,2-다이카복실릭산 다이메틸 에스터의 제조Example 3. Preparation of 4-ethyl-3-methyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-1,2-dicarboxylic acid dimethyl ester

Figure 112008033895875-PAT00028
Figure 112008033895875-PAT00028

2-(1-에틸-프로파-1,2-다이에닐)-사이클로헤세-2-엔온 (49 mg, 0.3 mmol)과 다이메틸아세틸렌다이카복실에이트 (213 mg, 1.5 mmol)를 CH2Cl2 용매 1.0 mL에 녹인 후 60 ℃에서 15시간 교반시킨 후 실리카겔 2 g과 CH2Cl2 용매 5.0 mL을 추가로 넣어서 실온에서 30분간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)를 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 CH2Cl2와 헥산으로 재결정하여 표제 화합물인 4-에틸-3-메틸-5-옥소-5,6,7,8-테트라하이드로-나프탈렌-1,2-다이카복실릭산 다이메틸 에스터 (87 mg, 95%)를 얻었다.2- (1-ethyl-propa-1,2-dienyl) -cyclohes-2-enone (49 mg, 0.3 mmol) and dimethylacetylenedicarboxylate (213 mg, 1.5 mmol) were CH 2 Cl 2 After dissolving in 1.0 mL of solvent, stirred at 60 ° C. for 15 hours, additionally 2 g of silica gel and 5.0 mL of CH 2 Cl 2 solvent were stirred at room temperature for 30 minutes, and then saturated aqueous NaHCO 3 solution (10 mL) was added to terminate the reaction. I was. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. The solvent was removed and then recrystallized from CH 2 Cl 2 and hexane to give the title compound, 4-ethyl-3-methyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-1,2-dicarboxylate dimethyl. Ester (87 mg, 95%) was obtained.

1H NMR (400 MHz, CDCl3, 25℃, TMS) δ3.90 (s, 3H), 3.87 (s, J = 3H), 3.02-2.94 (m, 4H), 2.67 (t, J = 6.75 Hz, 2H), 2.33 (s, 3H), 2.07-2.01 (m, 2H), 1.20 (t, J = 7.33 Hz, 3H) 1 H NMR (400 MHz, CDCl 3, 25 ° C., TMS) δ 3.90 (s, 3H), 3.87 (s, J = 3H), 3.02-2.94 (m, 4H), 2.67 (t, J = 6.75 Hz , 2H), 2.33 (s, 3H), 2.07-2.01 (m, 2H), 1.20 (t, J = 7.33 Hz, 3H)

실시예 4. 4-에틸-3-메틸렌-5-옥소-3,5,6,7,8,8a-헥사하이드로-2H-크로멘-2-카복시릭산 에틸 에스터의 제조Example 4. Preparation of 4-ethyl-3-methylene-5-oxo-3,5,6,7,8,8a-hexahydro- 2H -chromen-2-carboxylic acid ethyl ester

Figure 112008033895875-PAT00029
Figure 112008033895875-PAT00029

2-(1-에틸-프로파-1,2-다이에닐)-사이클로헤세-2-엔온 (49 mg, 0.3 mmol)과 에틸 글리옥살에이트 (61 mg, 0.6 mmol)를 CH2Cl2 용매 1.0 mL에 녹인 후 60 ℃에서 16시간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)을 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 관 크로마토그래피로 분리하여 표제 화합물인 4-에틸-3-메틸렌-5-옥소-3,5,6,7,8,8a-헥사하이드로-2H-크로멘-2-카복시릭산 에틸 에스터 (66 mg, 87%)를 얻었다.2- (1-ethyl-propa-1,2-dienyl) -cyclohes-2-enone (49 mg, 0.3 mmol) and ethyl glyoxalate (61 mg, 0.6 mmol) in CH 2 Cl 2 solvent After dissolving in 1.0 mL and stirring for 16 hours at 60 ℃ saturated aqueous NaHCO 3 (10 mL) was added to terminate the reaction. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. The solvent was removed and the residue was separated by column chromatography to obtain the title compound, 4-ethyl-3-methylene-5-oxo-3,5,6,7,8,8a-hexahydro- 2H -chromen-2-carboxylic acid. Ethyl ester (66 mg, 87%) was obtained.

1H NMR (400 MHz, CDCl3, 25℃, TMS) δ5.56 (s, 1H), 5.27 (s, 1H), 4.74 (t, J = 1.53, 1H), 4.42-4.30 (m, 3H), 2.59-2.28 (m, 5H), 2.07-2.00 (m, 1H), 1.92-1.82 (m, 1H), 1.75-1.63 (m, 1H), 1.35 (t, J = 7.11, 3H), 1.13 (t, J = 7.45 Hz, 3H) 1 H NMR (400 MHz, CDCl 3, 25 ° C., TMS) δ5.56 (s, 1H), 5.27 (s, 1H), 4.74 (t, J = 1.53, 1H), 4.42-4.30 (m, 3H) , 2.59-2.28 (m, 5H), 2.07-2.00 (m, 1H), 1.92-1.82 (m, 1H), 1.75-1.63 (m, 1H), 1.35 (t, J = 7.11, 3H), 1.13 ( t, J = 7.45 Hz, 3H)

실시예 5. 5-메틸-4-메틸렌-6-페닐-3a,4,7,7a-테트라하이드로아이소벤조퓨란-1,3-다이온의 제조Example 5. Preparation of 5-methyl-4-methylene-6-phenyl-3a, 4,7,7a-tetrahydroisobenzofuran-1,3-dione

Figure 112008033895875-PAT00030
Figure 112008033895875-PAT00030

(2-메틸-1-메틸렌-부타-2,3-다이에닐)-벤젠 (47 mg, 0.3 mmol)과 말레익 언하이드라이드 (29 mg, 0.3 mmol)를 톨루엔 용매 1.0 mL에 녹인 후 100 ℃에서 4시간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)를 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 CH2Cl2와 헥산으로 재결정하여 표제 화합물인 5-메틸-4-메틸렌-6-페닐- 3a,4,7,7a-테트라하이드로아이소벤조퓨란-1,3-다이온 (73 mg, 96%)을 얻었다.(2-methyl-1-methylene-buta-2,3-dienyl) -benzene (47 mg, 0.3 mmol) and maleic anhydride (29 mg, 0.3 mmol) were dissolved in 1.0 mL of toluene solvent and then 100 After stirring for 4 h at saturated aqueous NaHCO 3 (10 mL) was added to terminate the reaction. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. The solvent was removed and then recrystallized from CH 2 Cl 2 and hexane to give the title compound, 5-methyl-4-methylene-6-phenyl-3a, 4,7,7a-tetrahydroisobenzofuran-1,3-dione (73 mg, 96%).

1H NMR (300 MHz, CDCl3, 25℃, TMS) δ7.40-7.29 (m, 3H), 7.18-7.15 (m, 2H), 5.50 (d, J = 14.50, 2H), 4.06 (d, J = 9.34, 1H), 3.59-3.53 (m, 1H), 2.98-2.68 (m, 2H), 1.82 (d, J = 1.53, 3H) 1 H NMR (300 MHz, CDCl 3, 25 ° C., TMS) δ 7.40-7.29 (m, 3H), 7.18-7.15 (m, 2H), 5.50 (d, J = 14.50, 2H), 4.06 (d, J = 9.34, 1H), 3.59-3.53 (m, 1H), 2.98-2.68 (m, 2H), 1.82 (d, J = 1.53, 3H)

실시예 6. 다이메틸 3,4-다이메틸-5-페닐프탈레이트의 제조Example 6 Preparation of Dimethyl 3,4-dimethyl-5-phenylphthalate

Figure 112008033895875-PAT00031
Figure 112008033895875-PAT00031

(2-메틸-1-메틸렌-부타-2,3-다이에닐)-벤젠 (47 mg, 0.3 mmol)과 다이메틸아세틸렌다이카복실에이트 (43 mg, 0.3 mmol)를 톨루엔 용매 1.0 mL에 녹인 후 100 ℃에서 6시간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)를 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 관 크로마토그래피로 분리하여 표제 화합물인 다이메틸 3,4-다이메틸-5-페닐프탈레이트 (73 mg, 82%)를 얻었다.(2-methyl-1-methylene-buta-2,3-dienyl) -benzene (47 mg, 0.3 mmol) and dimethylacetylenedicarboxylate (43 mg, 0.3 mmol) were dissolved in 1.0 mL of toluene solvent. After stirring for 6 hours at 100 ℃ saturated aqueous NaHCO 3 (10 mL) was added to terminate the reaction. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. The solvent was removed and then separated by column chromatography to obtain the title compound dimethyl 3,4-dimethyl-5-phenylphthalate (73 mg, 82%).

1H NMR (300 MHz, CDCl3, 25℃, TMS) δ7.78 (s, 1H), 7.43-7.40 (m, 3H), 7.28-7.25 (m, 2H), 3.99 (s, 3H), 3.86 (s, 3H), 2.30 (s, 3H), 2.21 (s, 3H) 1 H NMR (300 MHz, CDCl 3, 25 ° C., TMS) δ7.78 (s, 1H), 7.43-7.40 (m, 3H), 7.28-7.25 (m, 2H), 3.99 (s, 3H), 3.86 (s, 3H), 2.30 (s, 3H), 2.21 (s, 3H)

실시예 7. 5-에틸-4-메틸렌-6-페닐-3a,4,7,7a-테트라하이드로아이소벤조퓨란-1,3-다이온의 제조Example 7. Preparation of 5-ethyl-4-methylene-6-phenyl-3a, 4,7,7a-tetrahydroisobenzofuran-1,3-dione

Figure 112008033895875-PAT00032
Figure 112008033895875-PAT00032

(2-에틸-1-메틸렌-부타-2,3-다이에닐)-벤젠 (50 mg, 0.3 mmol)과 말레익 언하이드라이드 (29 mg, 0.3 mmol)을 톨루엔 용매 1.0 mL에 녹인 후 100 ℃에서 3시간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)을 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 CH2Cl2와 헥산으로 재결정하여 표제 화합물인 5-에틸-4-메틸렌-6-페닐-3a,4,7,7a-테트라하이드로아이소벤조퓨란-1,3-다이온 (63 mg, 80%)을 얻었다.(2-ethyl-1-methylene-buta-2,3-dienyl) -benzene (50 mg, 0.3 mmol) and maleic anhydride (29 mg, 0.3 mmol) were dissolved in 1.0 mL of toluene solvent and then 100 After stirring for 3 hours at 0 ° C., saturated NaHCO 3 aqueous solution (10 mL) was added to terminate the reaction. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. The solvent was removed and then recrystallized with CH 2 Cl 2 and hexane to give the title compound, 5-ethyl-4-methylene-6-phenyl-3a, 4,7,7a-tetrahydroisobenzofuran-1,3-dione (63 mg, 80%).

1H NMR (400 MHz, CDCl3, 25℃, TMS) δ7.38-7.12 (m, 5H), 5.49 (d, J = 0.68 Hz 1H), 5.46 (d, J = 0.68, 1H), 4.05 (d, J = 9.49, 1H), 3.56 (ddd, J = 9.49, 6.61, 2.64, 1H), 2.87 (dd, J = 16.23, 2.64, 1H), 2.67 (ddd, J = 16.23, 6.61, 2.20, 1H), 2.35 (dq, J = 14.28, 7.42, 1H), 2.19 (dqd, J = 14.28, 7,42, 2.20, 1H) ,0.87 (t, 7.42, 3H) 1 H NMR (400 MHz, CDCl 3, 25 ° C., TMS) δ7.38-7.12 (m, 5H), 5.49 (d, J = 0.68 Hz 1H), 5.46 (d, J = 0.68, 1H), 4.05 ( d, J = 9.49, 1H), 3.56 (ddd, J = 9.49, 6.61, 2.64, 1H), 2.87 (dd, J = 16.23, 2.64, 1H), 2.67 (ddd, J = 16.23, 6.61, 2.20, 1H ), 2.35 (dq, J = 14.28, 7.42, 1H), 2.19 (dqd, J = 14.28, 7,42, 2.20, 1H), 0.87 (t, 7.42, 3H)

실시예 8. 5-에틸-4-메틸렌-2,6-다이페닐-3a,4,7,7a-테트라하이드로아이소인돌-1,3-다이온의 제조Example 8. Preparation of 5-ethyl-4-methylene-2,6-diphenyl-3a, 4,7,7a-tetrahydroisoindole-1,3-dione

Figure 112008033895875-PAT00033
Figure 112008033895875-PAT00033

(2-에틸-1-메틸렌-부타-2,3-다이에닐)-벤젠 (50 mg, 0.3 mmol)과 N-페닐말레이미드 (52 mg, 0.3 mmol)를 톨루엔 용매 1.0 mL에 녹인 후 100 ℃에서 4시간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)을 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 CH2Cl2와 헥산으로 재결정하여 표제 화합물인 5-에틸-4-메틸렌-2,6-다이페닐-3a,4,7,7a-테트라하이드로아이소인돌-1,3-다이온 (88 mg, 85%)을 얻었다.(2-ethyl-1-methylene-buta-2,3-dienyl) -benzene (50 mg, 0.3 mmol) and N -phenylmaleimide (52 mg, 0.3 mmol) were dissolved in 1.0 mL of toluene solvent and then 100 After stirring for 4 h at saturated aqueous NaHCO 3 (10 mL) was added to terminate the reaction. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. After removing the solvent, recrystallized with CH 2 Cl 2 and hexane to give the title compound, 5-ethyl-4-methylene-2,6-diphenyl-3a, 4,7,7a-tetrahydroisoindole-1,3-dione (88 mg, 85%) was obtained.

1H NMR (400 MHz, CDCl3, 25℃, TMS) δ7.63-7.11 (m, 10H), 5.21 (d, J = 5.25 Hz 1H), 5.12 (d, J = 5.25, 1H), 3.41 (d, J = 2.73, 1H), 2.79 (d, J = 2.73, 1H), 2.49-2.41 (m, 1H), 2.25-2.13 (m, 1H), 1.97 (q, J = 1.37, 2H), 1.06 (t, J = 0.86, 3H) 1 H NMR (400 MHz, CDCl 3, 25 ° C., TMS) δ7.63-7.11 (m, 10H), 5.21 (d, J = 5.25 Hz 1H), 5.12 (d, J = 5.25, 1H), 3.41 ( d, J = 2.73, 1H), 2.79 (d, J = 2.73, 1H), 2.49-2.41 (m, 1H), 2.25-2.13 (m, 1H), 1.97 (q, J = 1.37, 2H), 1.06 (t, J = 0.86, 3H)

실시예 9. 2-에틸-1-메틸렌-3-페닐-1,4,4a,9a-테트라하이드로안트라퀴논의 제조Example 9. Preparation of 2-ethyl-1-methylene-3-phenyl-1,4,4a, 9a-tetrahydroanthraquinone

Figure 112008033895875-PAT00034
Figure 112008033895875-PAT00034

(2-에틸-1-메틸렌-부타-2,3-다이에닐)-벤젠 (50 mg, 0.3 mmol)과 나프토퀴논 (95 mg, 0.6 mmol)을 톨루엔 용매 1.0 mL에 녹인 후 100 ℃에서 3시간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)를 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 CH2Cl2와 헥산으로 재결정하여 표제 화합물인 2-에틸-1-메틸렌-3-페닐-1,4,4a,9a-테트라하이드로안트라퀴논 (86 mg, 87%)을 얻었다.(2-ethyl-1-methylene-buta-2,3-dienyl) -benzene (50 mg, 0.3 mmol) and naphthoquinone (95 mg, 0.6 mmol) were dissolved in 1.0 mL of toluene solvent and then at 100 ° C. After stirring for 3 hours, saturated NaHCO 3 aqueous solution (10 mL) was added to terminate the reaction. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. The solvent was removed and then recrystallized with CH 2 Cl 2 and hexane to obtain the title compound 2-ethyl-1-methylene-3-phenyl-1,4,4a, 9a-tetrahydroanthraquinone (86 mg, 87%).

1H NMR (400 MHz, CDCl3, 25℃, TMS) δ8.11-7.34 (m, 5H), 7.30-7.21 (m, 4H), 5.33 (d, J = 4.09, 1H), 4.88 (t, J = 0.71, 1H), 4.12-4.10 (m, 1H), 3.58 (q, J = 5.56 1H), 2.95 (qq, J = 6.07, 6.03, 1H), 2.61 (dd, J = 5.40, 5.40, 1H), 2.14 (q, J = 7.45, 2H), 0.92 (t, J = 7.45, 3H) 1 H NMR (400 MHz, CDCl 3, 25 ° C., TMS) δ8.11-7.34 (m, 5H), 7.30-7.21 (m, 4H), 5.33 (d, J = 4.09, 1H), 4.88 (t, J = 0.71, 1H), 4.12-4.10 (m, 1H), 3.58 (q, J = 5.56 1H), 2.95 (qq, J = 6.07, 6.03, 1H), 2.61 (dd, J = 5.40, 5.40, 1H ), 2.14 (q, J = 7.45, 2H), 0.92 (t, J = 7.45, 3H)

실시예 10. 4-에틸-3-메틸렌-5-페닐-사이클로헥스-4-엔-1,2-다이카복실산 다이메틸 에스터의 제조Example 10 Preparation of 4-ethyl-3-methylene-5-phenyl-cyclohex-4-ene-1,2-dicarboxylic acid dimethyl ester

Figure 112008033895875-PAT00035
Figure 112008033895875-PAT00035

(2-에틸-1-메틸렌-부타-2,3-다이에닐)-벤젠 (50 mg, 0.3 mmol)과 다이메틸 말레이트 (112 mg, 0.9 mmol)를 톨루엔 용매 1.0 mL에 녹인 후 100 ℃에서 24시간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)을 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 CH2Cl2와 헥산으로 재결정하여 표제 화합물인 4-에틸-3-메틸렌-5-페닐-사이클로헥스-4-엔-1,2-다이카복실산 다이메틸 (72 mg, 70%)을 얻었다.(2-ethyl-1-methylene-buta-2,3-dienyl) -benzene (50 mg, 0.3 mmol) and dimethyl malate (112 mg, 0.9 mmol) were dissolved in 1.0 mL of toluene solvent and then 100 ° C. After stirring for 24 hours, saturated NaHCO 3 aqueous solution (10 mL) was added to terminate the reaction. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. The solvent was removed and recrystallized with CH 2 Cl 2 and hexane to give the title compound 4-ethyl-3-methylene-5-phenyl-cyclohex-4-ene-1,2-dicarboxylic acid dimethyl (72 mg, 70%) Got.

1H NMR (400 MHz, CDCl3, 25℃, TMS) δ7.34-7.09 (m, 5H), 5.29 (s, 1H), 5.22 (s, 1H), 3.93 (d, J = 3.56, 1H), 3.70 (d, J = 8.57 6H), 3.05-2.94 (m, 2H), 2.69-2.58 (m, 1H) 2.25-2.58 (m, 1H), 2.25-2.05 (m, 2H), 0.91 (t, J = 7.43, 3H) 1 H NMR (400 MHz, CDCl 3, 25 ° C., TMS) δ7.34-7.09 (m, 5H), 5.29 (s, 1H), 5.22 (s, 1H), 3.93 (d, J = 3.56, 1H) , 3.70 (d, J = 8.57 6H), 3.05-2.94 (m, 2H), 2.69-2.58 (m, 1H) 2.25-2.58 (m, 1H), 2.25-2.05 (m, 2H), 0.91 (t, J = 7.43, 3H)

실시예 11. 4-에틸-5-메틸렌-3-페닐-사이클로헥스-3-엔 카복실산 에틸 에스터 및 3-에틸-2-메틸렌-4-페닐-사이클로헥스-3-엔 카복실산 에틸 에스터의 제조Example 11. Preparation of 4-ethyl-5-methylene-3-phenyl-cyclohex-3-ene carboxylic acid ethyl ester and 3-ethyl-2-methylene-4-phenyl-cyclohex-3-ene carboxylic acid ethyl ester

Figure 112008033895875-PAT00036
Figure 112008033895875-PAT00036

(2-에틸-1-메틸렌-부타-2,3-다이에닐)-벤젠 (50 mg, 0.3 mmol)과 에틸 아크릴에이트 (150 mg, 1.5 mmol)을 톨루엔 용매 1.0 mL에 녹인 후 100 ℃에서 20시간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)를 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 CH2Cl2와 헥산으로 재결정하여 주생성물로서 4-에틸-5-메틸렌-3-페닐-사이클로헥스-3-엔 카복실산 에틸 에스터 (42 mg, 51%) 및 부생성물로서 3-에틸-2-메틸렌-4-페닐-사이클로헥스-3-엔 카복실산 에틸 에스터 (20 mg, 25%)를 각각 얻었다.(2-ethyl-1-methylene-buta-2,3-dienyl) -benzene (50 mg, 0.3 mmol) and ethyl acrylate (150 mg, 1.5 mmol) were dissolved in 1.0 mL of toluene solvent and then at 100 ° C. After stirring for 20 hours, saturated NaHCO 3 aqueous solution (10 mL) was added to terminate the reaction. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. The solvent was removed and then recrystallized from CH 2 Cl 2 and hexane to give 4-ethyl-5-methylene-3-phenyl-cyclohex-3-ene carboxylic acid ethyl ester (42 mg, 51%) as a main product and 3- as a by-product. Ethyl-2-methylene-4-phenyl-cyclohex-3-ene carboxylic acid ethyl ester (20 mg, 25%) was obtained respectively.

4-에틸-5-메틸렌-3-페닐-사이클로헥스-3-엔 카복실산 에틸 에스터 : 4-Ethyl-5-methylene-3-phenyl-cyclohex-3-ene carboxylic acid ethyl ester :

1H NMR (400 MHz, CDCl3, 25℃, TMS) 7.35 (m, 2H), 7.27 (m, 1H), 7.16 (d, J = 6.83 Hz, 2H), 5.09 (s, 1H), 4.97 (s, 1H), 4.14 (q, J = 7.11 Hz, 2H), 2.83-2.77 (m, 1H), 2.71 (dd, J = 14.1, 3.46 Hz, 1H), 2.65-2.54 (m, 3H), 2.18-2.07 (m, 2H), 1.25 (t, J = 7.16 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H) 1 H NMR (400 MHz, CDCl 3, 25 ° C., TMS) 7.35 (m, 2H), 7.27 (m, 1H), 7.16 (d, J = 6.83 Hz, 2H), 5.09 (s, 1H), 4.97 ( s, 1H), 4.14 (q, J = 7.11 Hz, 2H), 2.83-2.77 (m, 1H), 2.71 (dd, J = 14.1, 3.46 Hz, 1H), 2.65-2.54 (m, 3H), 2.18 -2.07 (m, 2H), 1.25 (t, J = 7.16 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H)

3-에틸-2-메틸렌-4-페닐-사이클로헥스-3-엔 카복실산 에틸 에스터 : 3-Ethyl-2-methylene-4-phenyl-cyclohex-3-ene carboxylic acid ethyl ester :

1H NMR (400 MHz, CDCl3, 25℃, TMS) 7.33 (t, J = 7.38 Hz, 2H), 7.24 (m, 1H), 7.12 (m, 2H), 5.22 (s, 1H), 4.98 (s, 1H), 4.19 (m, 2H), 3.40 (t, J = 5.18 Hz, 1H), 2.49 (m, 1H), 2.33 (dt, J = 18.4, 5.20 Hz, 1H), 2.25-2.12 (m, 3H), 1.98 (m, 1H), 1.28 (t, J = 7.10 Hz, 3H), 0.95 (t, J = 7.44 Hz, 3H) 1 H NMR (400 MHz, CDCl 3, 25 ° C., TMS) 7.33 (t, J = 7.38 Hz, 2H), 7.24 (m, 1H), 7.12 (m, 2H), 5.22 (s, 1H), 4.98 ( s, 1H), 4.19 (m, 2H), 3.40 (t, J = 5.18 Hz, 1H), 2.49 (m, 1H), 2.33 (dt, J = 18.4, 5.20 Hz, 1H), 2.25-2.12 (m , 3H), 1.98 (m, 1H), 1.28 (t, J = 7.10 Hz, 3H), 0.95 (t, J = 7.44 Hz, 3H)

실시예 12. 4-에틸-3-메틸렌-5-페닐-3,6-다이하이드로-2H-피란-2-카복실산 에틸 에스터의 제조Example 12 Preparation of 4-ethyl-3-methylene-5-phenyl-3,6-dihydro- 2H -pyran-2-carboxylic acid ethyl ester

Figure 112008033895875-PAT00037
Figure 112008033895875-PAT00037

(2-에틸-1-메틸렌-부타-2,3-다이에닐)-벤젠 (50 mg, 0.3 mmol)과 에틸 글리옥살에이트 (92 mg, 0.9 mmol)를 톨루엔 용매 1.0 mL에 녹인 후 100 ℃에서 20시간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)을 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 CH2Cl2와 헥산으로 재결정하여 표제 화합물인 4-에틸-3-메틸렌-5-페닐-3,6-다이하이드로-2H-피란-2-카복실산 에틸 에스터 (65 mg, 수율 80%)을 얻었다.(2-ethyl-1-methylene-buta-2,3-dienyl) -benzene (50 mg, 0.3 mmol) and ethyl glyoxalate (92 mg, 0.9 mmol) were dissolved in 1.0 mL of toluene solvent and then 100 ° C. After stirring for 20 hours, saturated NaHCO 3 aqueous solution (10 mL) was added to terminate the reaction. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. The solvent was removed and recrystallized with CH 2 Cl 2 and hexane to give the title compound, 4-ethyl-3-methylene-5-phenyl-3,6-dihydro- 2H -pyran-2-carboxylic acid ethyl ester (65 mg, yield). 80%).

1H NMR (400 MHz, CDCl3, 25℃, TMS) δ7.37-7.15 (m, 5H), 5.32 (s, 1H), 5.15 (s, 1H), 4.88 (s, 1H), 4.72 (d, J = 17.11, 1H), 4.37 (d, J = 17.11, 1H), 4.28 (q, J = 7.12, 2H), 2.19 (q, J = 7.29, 2H), 1.32 (t, J = 7.14, 3H), 0.97 (t, J = 7.47, 3H) 1 H NMR (400 MHz, CDCl 3, 25 ° C., TMS) δ7.37-7.15 (m, 5H), 5.32 (s, 1H), 5.15 (s, 1H), 4.88 (s, 1H), 4.72 (d , J = 17.11, 1H), 4.37 (d, J = 17.11, 1H), 4.28 (q, J = 7.12, 2H), 2.19 (q, J = 7.29, 2H), 1.32 (t, J = 7.14, 3H ), 0.97 (t, J = 7.47, 3H)

실시예 13. 에틸 4-에틸-5-메틸-3-페닐 벤조에이트의 제조Example 13. Preparation of Ethyl 4-ethyl-5-methyl-3-phenyl benzoate

Figure 112008033895875-PAT00038
Figure 112008033895875-PAT00038

(2-에틸-1-메틸렌-부타-2,3-다이에닐)-벤젠 (50 mg, 0.3 mmol)과 에틸 프로피올에이트 (88 mg, 0.9 mmol)를 톨루엔 용매 1.0 mL에 녹인 후 100 ℃에서 20시간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)을 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 CH2Cl2와 헥산으로 재결정하여 표제 화합물인 에틸 4-에틸-5-메틸-3-페닐 (52 mg, 65%)을 얻었다.(2-ethyl-1-methylene-buta-2,3-dienyl) -benzene (50 mg, 0.3 mmol) and ethyl propiolate (88 mg, 0.9 mmol) were dissolved in 1.0 mL of toluene solvent and then 100 ° C. After stirring for 20 hours, saturated NaHCO 3 aqueous solution (10 mL) was added to terminate the reaction. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. The solvent was removed and then recrystallized with CH 2 Cl 2 and hexane to obtain the title compound ethyl 4-ethyl-5-methyl-3-phenyl (52 mg, 65%).

1H NMR (400 MHz, CDCl3, 25℃, TMS) δ7.88 (d, J = 1.23 1H), 7.74 (d, J = 1.65 1H), 7.47-7.24 (m, 5H), 4.42-4.34 (m, 2H), 2.67-2.59 (m, 2H), 2.47 (s, 3H), 1.39 (t, J = 7.13, 3H), 1.01 (t, J = 7.52, 3H) 1 H NMR (400 MHz, CDCl 3, 25 ° C., TMS) δ 7.88 (d, J = 1.23 1H), 7.74 (d, J = 1.65 1H), 7.47-7.24 (m, 5H), 4.42-4.34 ( m, 2H), 2.67-2.59 (m, 2H), 2.47 (s, 3H), 1.39 (t, J = 7.13, 3H), 1.01 (t, J = 7.52, 3H)

실시예 14. 8-터셔리-부틸-4-메틸렌-2-페닐-3a,4,6,7,8,9a,9b-옥타하이드로벤조[e]아이소인돌-1,3-다이온의 제조Example 14. Preparation of 8-tertiary-butyl-4-methylene-2-phenyl-3a, 4,6,7,8,9a, 9b-octahydrobenzo [e] isoindole-1,3-dione

Figure 112008033895875-PAT00039
Figure 112008033895875-PAT00039

4-터셔리-부틸-1-프로파-1,2-다이엔일-사이클로헥센 (53 mg, 0.3 mmol)과 N-페닐말레이미드 (52 mg, 0.3 mmol)를 톨루엔 용매 1.0 mL에 녹인 후 100 ℃에서 12시간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)을 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 관 크로마토그래피로 분리하여 표제 화합물인 8-터셔리-부틸-4-메틸렌-2-페닐-3a,4,6,7,8,9a,9b-옥타하이드로벤조[e]아이소인돌-1,3-다이온 (94 mg, 92%)을 얻었다.4-tert-butyl-1-propa-1,2-dienyl-cyclohexene (53 mg, 0.3 mmol) and N -phenylmaleimide (52 mg, 0.3 mmol) were dissolved in 1.0 mL of toluene solvent. After stirring for 12 hours at 100 ℃ saturated aqueous NaHCO 3 (10 mL) was added to terminate the reaction. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. The solvent was removed and the residue was separated by column chromatography to obtain the title compound, 8-tert-butyl-4-methylene-2-phenyl-3a, 4,6,7,8,9a, 9b-octahydrobenzo [e] isoindole. -1,3-dione (94 mg, 92%) was obtained.

1H NMR (400 MHz, CDCl3, 25℃, TMS) δ7.44 (t, J = 7.70 Hz, 2H), 7.36 (t, J = 7.47 Hz, 1H), 7.23 (d, J = 7.56 Hz, 2H), 6.04 (s, 1H), 5.30 (s, 1H), 5.17 (s, 1H), 3.80 (d, J = 8.30 Hz, 1H), 3.36 (dd, J = 8.01, 6.86 Hz, 1H), 2.77 (m, 1H), 2.37 (m, 1H), 2.25 (m, 1H), 2.02 (td, J = 12.65, 8.87 Hz, 1H), 1.73 (m, 2H), 1.52 (m, 1H), 1.32 (qd, J = 12.48, 5.41 Hz, 1H) 1 H NMR (400 MHz, CDCl 3, 25 ° C., TMS) δ 7.44 (t, J = 7.70 Hz, 2H), 7.36 (t, J = 7.47 Hz, 1H), 7.23 (d, J = 7.56 Hz, 2H), 6.04 (s, 1H), 5.30 (s, 1H), 5.17 (s, 1H), 3.80 (d, J = 8.30 Hz, 1H), 3.36 (dd, J = 8.01, 6.86 Hz, 1H), 2.77 (m, 1H), 2.37 (m, 1H), 2.25 (m, 1H), 2.02 (td, J = 12.65, 8.87 Hz, 1H), 1.73 (m, 2H), 1.52 (m, 1H), 1.32 (qd, J = 12.48, 5.41 Hz, 1H)

실시예 15. 4-메톡시-12-메틸렌-16-페닐-6,7,8,12,13,14-헥사하이드로-16-아 자-사이클로펜타[a]펜안쓰렌-15,17-다이온의 제조Example 15. 4-methoxy-12-methylene-16-phenyl-6,7,8,12,13,14-hexahydro-16-aza-cyclopenta [a] phenanthrene-15,17- Preparation of Dion

Figure 112008033895875-PAT00040
Figure 112008033895875-PAT00040

8-메톡시-4-프로파-1,2-다이엔일-1,2-다이하이드로-나프탈렌 (59 mg, 0.3 mmol)과 N-페닐말레이미드 (52 mg, 0.3 mmol)를 톨루엔 용매 1.0 mL에 녹인 후 100 ℃에서 12시간 교반시킨 후 포화 NaHCO3 수용액 (10 mL)을 가해 반응을 종결시켰다. 이 혼합물은 CH2Cl2 용매 (20 mL× 3)로 추출하고 포화 염화나트륨 수용액 (20 mL)으로 씻어주었다. 추출한 유기층은 무수 MgSO4로 건조하고 여과하였다. 용매를 제거 후 관 크로마토그래피로 분리하여 표제화합물인 4-메톡시-12-메틸렌-16-페닐-6,7,8,12,13,14-헥사하이드로-16-아자-사이클로펜타[a]펜안쓰렌-15,17-다이온 (82 mg, 74%)을 얻었다.8-methoxy-4-propa-1,2-dienyl-1,2-dihydro-naphthalene (59 mg, 0.3 mmol) and N -phenylmaleimide (52 mg, 0.3 mmol) in toluene solvent 1.0 After dissolving in mL and stirring for 12 hours at 100 ℃ saturated aqueous NaHCO 3 (10 mL) was added to terminate the reaction. This mixture was extracted with CH 2 Cl 2 solvent (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 mL). The extracted organic layer was dried over anhydrous MgSO 4 and filtered. The solvent was removed and the residue was separated by column chromatography to obtain the title compound 4-methoxy-12-methylene-16-phenyl-6,7,8,12,13,14-hexahydro-16-aza-cyclopenta [a]. Phenanthren-15,17-dione (82 mg, 74%) was obtained.

1H NMR (400 MHz, CDCl3, 25℃, TMS) δ7.41 (m, 2H), 7.33 (m, 1H), 7.23 (m, 3H), 7.14 (t, J = 8.05 Hz, 1H), 6.85 (d, J = 2.25 Hz, 1H), 6.75 (d, J = 8.02 Hz, 1H), 5.52 (s, 1H), 5.35 (s, 1H), 3.92 (d, J = 8.09 Hz, 1H), 3.83 (s, 3H), 3.50 (dd, J = 8.07, 5.44 Hz, 1H), 3.27 (td, J = 16.33, 3.32 Hz, 1H), 2.88 (m, 1H), 2.55 (qd, J = 13.06, 3.81 Hz, 1H), 2.33 (m, 1H), 2.13 (m, 1H) 1 H NMR (400 MHz, CDCl 3, 25 ° C., TMS) δ 7.41 (m, 2H), 7.33 (m, 1H), 7.23 (m, 3H), 7.14 (t, J = 8.05 Hz, 1H), 6.85 (d, J = 2.25 Hz, 1H), 6.75 (d, J = 8.02 Hz, 1H), 5.52 (s, 1H), 5.35 (s, 1H), 3.92 (d, J = 8.09 Hz, 1H), 3.83 (s, 3H), 3.50 (dd, J = 8.07, 5.44 Hz, 1H), 3.27 (td, J = 16.33, 3.32 Hz, 1H), 2.88 (m, 1H), 2.55 (qd, J = 13.06, 3.81 Hz, 1H), 2.33 (m, 1H), 2.13 (m, 1H)

본 발명에 따른 상기 화학식 1로 표시되는 6각형의 고리화합물 유도체는 비닐 알렌화합물과 친디엔체와의 딜스-엘더(Diels-Alder) 반응으로부터 유도되는 화합물로서, 분자내에 메틸렌 작용기를 가지고 있어 천연물의 합성에 매우 유용하다. Hexagonal cyclic compound derivative represented by Chemical Formula 1 according to the present invention is a compound derived from the Diels-Alder reaction between vinyl allene compound and dienophile, and has a methylene functional group in the molecule, Very useful for synthesis

본 발명에 따른 하기 화학식 1로 표시되는 6각형의 고리 화합물 유도체는 하기 화학식 2로 표시되는 비닐 알렌 유도체와 하기 화학식 3으로 표시되는 친디엔체와의 딜스-엘더(Diels-Alder) 반응을 통해 좋은 수득률로 합성할 수 있다. 합성된 6각형의 고리 화합물은 분자내에 메틸렌 치환기를 가지고 있어서 천연물의 합성이나 의약화학에 있어서 좋은 전구체로 사용될 수 있다.The hexagonal cyclic compound derivative represented by the following Chemical Formula 1 according to the present invention may be prepared by a Diels-Alder reaction between the vinylene derivative represented by the following Chemical Formula 2 and the dienophile represented by the following Chemical Formula 3 It can be synthesized in yield. Since the synthesized hexagonal ring compound has a methylene substituent in the molecule, it can be used as a good precursor in natural product synthesis or medicinal chemistry.

Claims (8)

하기 화학식 1a로 표시되는 고리 화합물 :A cyclic compound represented by the formula (1a): [화학식 1a][Formula 1a]
Figure 112008033895875-PAT00041
Figure 112008033895875-PAT00041
 상기 화학식 1에서, In Chemical Formula 1,
Figure 112008033895875-PAT00042
는 단일결합, 또는 이중결합을 나타내고; D1-X1은 CX1, 또는 CX1X2이고; D2-X2는 산소원자(O), CX1X2, 또는 CX2이며; A는 H, 또는 직쇄 또는 분쇄의 C1-10알킬이고; R1 및 R2는 서로 같거나 다른 것으로 H, 직쇄 또는 분쇄의 C1-10알킬, 또는 페닐이거나, 또는 R1 및 R2가 서로 결합하여 형성된 탄소원자 5 내지 10개의 지방족 또는 방향족 고리기 또는 접합 고리기이고; X1 및 X2는 서로 같거나 다른 것으로 H, C1-10알킬, C(O)C1- 10알킬, 및 C(O)OC1- 10알킬 중에서 선택되거나, 또는 X1 및 X2가 서로 결합하여
Figure 112008033895875-PAT00043
를 형성하고, 이때 Q는 O, S, N(R3), C1 - 10알킬렌, 및 페닐렌 중에서 선택된 2가기이고, R3은 H, 직쇄 또는 분쇄의 C1 - 10알킬, 또는 페닐이다.
Figure 112008033895875-PAT00042
Represents a single bond or a double bond; D 1 -X 1 is CX 1 , Or CX 1 X 2 ; D 2 -X 2 is the oxygen atom (O), CX 1 X 2 , Or CX 2 ; A is H or straight or branched C 1-10 alkyl; R 1 and R 2 are the same or different from each other and are H, straight or branched C 1-10 alkyl, or phenyl, or R 1 and R 2 are an aliphatic or aromatic ring group having 5 to 10 carbon atoms formed by bonding to each other or Conjugated ring group; X 1 and X 2 is alkyl, H, C 1-10 to be equal to or different from each other, C (O) C 1- 10 alkyl, and C (O) or OC selected from 1- 10 alkyl, or X 1 and X 2 is In combination with each other
Figure 112008033895875-PAT00043
To form, wherein Q is O, S, N (R 3 ), C 1 - 10 alkylene, and a selected second top from phenylene, R 3 is H, a straight or branched chain C 1 - 10 alkyl, or phenyl to be. 제1항에 있어서,The method of claim 1, D1-X1은 CX1 또는 CX1X2이고; D 1 -X 1 is CX 1 or CX 1 X 2 ; D2-X2는 산소원자(O), CX1X2, 또는 CX2이고;D 2 -X 2 is the oxygen atom (O), CX 1 X 2 , Or CX 2 ; A는 H, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸이고;A is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl; R1 및 R2는 서로 같거나 다른 것으로 H, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 또는 페닐이거나, 또는 R1 및 R2가 서로 결합하여 -(CH2)n- (이때, n=3-8), -C(=O)(CH2)n- (이때, n=3-8), 또는
Figure 112008033895875-PAT00044
(이때, m1 또는 m2는 0-3이고, Z는 H, C1-6알킬 또는 C1-6알콕시)를 형성하고;R 1 and R 2 are the same or different from each other and are H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or phenyl, or R 1 and R 2 are bonded to each other-(CH 2 ) n- ( where n = 3-8), -C (= O) (CH 2 ) n- (where n = 3-8), or
Figure 112008033895875-PAT00044
Wherein m 1 or m 2 is 0-3 and Z is H, C 1-6 alkyl or C 1-6 alkoxy; X1 및 X2는 서로 같거나 다른 것으로 H, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 메톡시카보닐, 에톡시카보닐, 프로필카보닐, 또는 부틸카보닐이거나, 또는 X1 및 X2가 서로 결합하여 형성된 -C(O)OC(O)-, -C(O)SC(O)-, -C(O)N(H)C(O)-, -C(O)N(CH3)C(O)-, -C(O)N(C2H5)C(O)-, -C(O)N(Ph)C(O)-, -C(O)CH2C(O)-, 또는 -C(O)CH2CH2C(O)-이다.X 1 and X 2 are the same or different from each other and are H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxycarbonyl, ethoxycarbonyl, propylcarbonyl, or butylcarbonyl Or -C (O) OC (O)-, -C (O) SC (O)-, -C (O) N (H) C (O)-,-formed by combining X 1 and X 2 with each other C (O) N (CH 3 ) C (O)-, -C (O) N (C 2 H 5 ) C (O)-, -C (O) N (Ph) C (O)-, -C (O) CH 2 C (O)-or -C (O) CH 2 CH 2 C (O)-. 제1항에 있어서, 하기에서 선택된 화합물 :A compound according to claim 1 selected from:
Figure 112008033895875-PAT00045
,
Figure 112008033895875-PAT00046
,
Figure 112008033895875-PAT00047
,
Figure 112008033895875-PAT00048
,
Figure 112008033895875-PAT00049
,
Figure 112008033895875-PAT00045
,
Figure 112008033895875-PAT00046
,
Figure 112008033895875-PAT00047
,
Figure 112008033895875-PAT00048
,
Figure 112008033895875-PAT00049
,
Figure 112008033895875-PAT00050
,
Figure 112008033895875-PAT00051
,
Figure 112008033895875-PAT00052
, 또는
Figure 112008033895875-PAT00053
Figure 112008033895875-PAT00050
,
Figure 112008033895875-PAT00051
,
Figure 112008033895875-PAT00052
, or
Figure 112008033895875-PAT00053
 상기 화합물에 있어서, In the compound, A는 H, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸이고; R1은 H, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 또는 페닐이고; X1 및 X2는 서로 같거나 다른 것으로 H, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 메톡시카보닐, 에톡시카보닐, 프로필카보닐, 또는 부틸카보닐이거나, 또는 X1 및 X2가 서로 결합하여 형성된 -C(O)OC(O)-, -C(O)SC(O)-, -C(O)N(H)C(O)-, -C(O)N(CH3)C(O)-, -C(O)N(C2H5)C(O)-, -C(O)N(Ph)C(O)-, -C(O)CH2C(O)-, 또는 -C(O)CH2CH2C(O)-이다.A is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl; R 1 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or phenyl; X 1 and X 2 are the same or different from each other and are H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxycarbonyl, ethoxycarbonyl, propylcarbonyl, or butylcarbonyl Or -C (O) OC (O)-, -C (O) SC (O)-, -C (O) N (H) C (O)-,-formed by combining X 1 and X 2 with each other C (O) N (CH 3 ) C (O)-, -C (O) N (C 2 H 5 ) C (O)-, -C (O) N (Ph) C (O)-, -C (O) CH 2 C (O)-or -C (O) CH 2 CH 2 C (O)-. 제1항에 있어서, 하기에서 선택된 화합물 :A compound according to claim 1 selected from: 5-에틸-4-메틸렌-3a,7,8,9,9a,9b-헥사하이드로-4H-나프토[1,2-c]퓨란-1,3,6-트라이온,5-ethyl-4-methylene-3a, 7,8,9,9a, 9b-hexahydro- 4H -naphtho [1,2- c ] furan-1,3,6-trione, 5-에틸-4-메틸렌-2-페닐-3a,7,8,9,9a,9b-헥사하이드로-4H-벤조[e]아이소인돌-1,3,6-트라이온,5-ethyl-4-methylene-2-phenyl-3a, 7,8,9,9a, 9b-hexahydro- 4H -benzo [ e ] isoindole-1,3,6-trione, 4-에틸-3-메틸-5-옥소-5,6,7,8-테트라하이드로-나프탈렌-1,2-다이카복실릭산 다이메틸 에스터,4-ethyl-3-methyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-1,2-dicarboxylic acid dimethyl ester, 4-에틸-3-메틸렌-5-옥소-3,5,6,7,8,8a-헥사하이드로-2H-크로멘-2-카복시릭산 에틸 에스터,4-ethyl-3-methylene-5-oxo-3,5,6,7,8,8a-hexahydro- 2H -chromen-2-carboxylic acid ethyl ester, 5-메틸-4-메틸렌-6-페닐-3a,4,7,7a-테트라하이드로아이소벤조퓨란-1,3-다이온,5-methyl-4-methylene-6-phenyl-3a, 4,7,7a-tetrahydroisobenzofuran-1,3-dione, 다이메틸 3,4-다이메틸-5-페닐프탈레이트,Dimethyl 3,4-dimethyl-5-phenylphthalate, 5-에틸-4-메틸렌-6-페닐-3a,4,7,7a-테트라하이드로아이소벤조퓨란-1,3-다이온,5-ethyl-4-methylene-6-phenyl-3a, 4,7,7a-tetrahydroisobenzofuran-1,3-dione, 5-에틸-4-메틸렌-2,6-다이페닐-3a,4,7,7a-테트라하이드로아이소인돌-1,3-다이온,5-ethyl-4-methylene-2,6-diphenyl-3a, 4,7,7a-tetrahydroisoindole-1,3-dione, 2-에틸-1-메틸렌-3-페닐-1,4,4a,9a-테트라하이드로안트라퀴논,2-ethyl-1-methylene-3-phenyl-1,4,4a, 9a-tetrahydroanthraquinone, 4-에틸-3-메틸렌-5-페닐-사이클로헥스-4-엔-1,2-다이카복실산 다이메틸 에스터,4-ethyl-3-methylene-5-phenyl-cyclohex-4-ene-1,2-dicarboxylic acid dimethyl ester, 4-에틸-5-메틸렌-3-페닐-사이클로헥스-3-엔 카복실산 에틸 에스터,4-ethyl-5-methylene-3-phenyl-cyclohex-3-ene carboxylic acid ethyl ester, 3-에틸-2-메틸렌-4-페닐-사이클로헥스-3-엔 카복실산 에틸 에스터,3-ethyl-2-methylene-4-phenyl-cyclohex-3-ene carboxylic acid ethyl ester, 4-에틸-3-메틸렌-5-페닐-3,6-다이하이드로-2H-피란-2-카복실산 에틸 에스터,4-ethyl-3-methylene-5-phenyl-3,6-dihydro- 2H -pyran-2-carboxylic acid ethyl ester, 에틸 4-에틸-5-메틸-3-페닐 벤조에이트,Ethyl 4-ethyl-5-methyl-3-phenyl benzoate, 8-터셔리-부틸-4-메틸렌-2-페닐-3a,4,6,7,8,9a,9b-옥타하이드로벤조[e]아이소인돌-1,3-다이온, 또는8-tertiary-butyl-4-methylene-2-phenyl-3a, 4,6,7,8,9a, 9b-octahydrobenzo [e] isoindole-1,3-dione, or 4-메톡시-12-메틸렌-16-페닐-6,7,8,12,13,14-헥사하이드로-16-아자-사이클로펜타[a]펜안쓰렌-15,17-다이온.4-methoxy-12-methylene-16-phenyl-6,7,8,12,13,14-hexahydro-16-aza-cyclopenta [a] phenanthrene-15,17-dione. 하기 화학식 2로 표시되는 비닐 알렌 유도체와 하기 화학식 3으로 표시되는 친디엔체와 딜스-엘더(Diels-Alder) 반응을 수행하여 제조하는 것을 특징으로 하는 하기 화학식 1로 표시되는 고리화합물의 제조방법 :Method for producing a cyclic compound represented by the formula (1) characterized in that the vinyl allene derivative represented by the formula (2) and the diene-Alder (Diels-Alder) reaction represented by the formula (3) [화학식 2][Formula 2]
Figure 112008033895875-PAT00054
Figure 112008033895875-PAT00054
 [화학식 3][Formula 3]
Figure 112008033895875-PAT00055
Figure 112008033895875-PAT00055
 [화학식 1][Formula 1]
Figure 112008033895875-PAT00056
Figure 112008033895875-PAT00056
 상기 화학식 1, 2, 또는 3에서, In Chemical Formula 1, 2, or 3,
Figure 112008033895875-PAT00057
는 단일결합 또는 이중결합을 나타내고;
Figure 112008033895875-PAT00058
는 이중결합 또는 삼중결합을 나타내고; D1-X1은 CX1, 또는 CX1X2이고; D2-X2는 산소원자(O), CX1X2, 또는 CX2이며; A는 H, 또는 직쇄 또는 분쇄의 C1-10알킬이고; R1 및 R2는 서로 같거나 다른 것으로 H, 직쇄 또는 분쇄의 C1-10알킬, 또는 페닐이거나, 또는 R1 및 R2가 서로 결합하여 형성된 탄소원자 5 내지 10개의 지방족 또는 방향족 고리기 또는 접합 고리기이고; X1 및 X2는 서로 같거나 다른 것으로 H, C1-10알킬, C(O)C1-10알킬, 및 C(O)OC1-10알킬 중에서 선택되거나, 또는 X1 및 X2가 서로 결합하여
Figure 112008033895875-PAT00059
를 형성하고, 이때 Q는 O, S, N(R3), C1 - 10알킬렌, 및 페닐렌 중에서 선택된 2가기이고, R3은 H, 직쇄 또는 분쇄의 C1-10알킬, 또는 페닐이다.
Figure 112008033895875-PAT00057
Represents a single bond or a double bond;
Figure 112008033895875-PAT00058
Represents a double bond or a triple bond; D 1 -X 1 is CX 1 , Or CX 1 X 2 ; D 2 -X 2 is the oxygen atom (O), CX 1 X 2 , Or CX 2 ; A is H or straight or branched C 1-10 alkyl; R 1 and R 2 are the same or different from each other and are H, straight or branched C 1-10 alkyl, or phenyl, or R 1 and R 2 are an aliphatic or aromatic ring group having 5 to 10 carbon atoms formed by bonding to each other or Conjugated ring group; X 1 and X 2 are the same or different and are selected from H, C 1-10 alkyl, C (O) C 1-10 alkyl, and C (O) OC 1-10 alkyl, or X 1 and X 2 are In combination with each other
Figure 112008033895875-PAT00059
To form, wherein Q is O, S, N (R 3 ), C 1 - 10 alkylene group, and a divalent group selected from phenylene, R 3 is H, C 1-10 straight or branched chain alkyl, or phenyl to be. 제5항에 있어서, 상기 화학식 3으로 표시되는 친디엔체는 하기 화학식 (3a) 내지 (3h)로부터 선택되는 것을 특징으로 하는 제조방법 :The method according to claim 5, wherein the dienophile represented by Chemical Formula 3 is selected from the following Chemical Formulas (3a) to (3h):
Figure 112008033895875-PAT00060
Figure 112008033895875-PAT00060
 제5항 또는 제6항에 있어서,The method according to claim 5 or 6, 상기 화학식 3으로 표시되는 친디엔체는 상기 화학식 2로 표시되는 비닐 알렌 유도체를 기준으로 1.0 당량에서 30 당량 범위로 사용하는 것을 특징으로 하는 제조방법.The dienophile represented by Chemical Formula 3 may be used in an amount of 1.0 equivalent to 30 equivalents based on the vinyl allene derivative represented by Chemical Formula 2. 제5항에 있어서, 상기 화학식 2로 표시되는 비닐 알렌 유도체는 하기로부터 선택되는 것을 특징으로 하는 제조방법 :The method of claim 5, wherein the vinyl allene derivative represented by Formula 2 is selected from:
Figure 112008033895875-PAT00061
Figure 112008033895875-PAT00061
 상기 화학식에서, A는 H, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸이고; R1은 H, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 또는 페닐이다.In the above formula, A is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl; R 1 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or phenyl.
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