KR101122397B1 - An economical synthesis of ailanthoidol - Google Patents

An economical synthesis of ailanthoidol Download PDF

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KR101122397B1
KR101122397B1 KR1020090117486A KR20090117486A KR101122397B1 KR 101122397 B1 KR101122397 B1 KR 101122397B1 KR 1020090117486 A KR1020090117486 A KR 1020090117486A KR 20090117486 A KR20090117486 A KR 20090117486A KR 101122397 B1 KR101122397 B1 KR 101122397B1
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전종갑
박상재
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한림대학교 산학협력단
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Abstract

본 발명은 민간요법으로 이용 되어오는 산초나무속 머귀나무의 활성성분으로 뛰어난 항염작용이 예측되는 ailanthoidol의 합성을 바닐린 화합물로부터 총 5단계의 짧은 반응 및 높은 수율 (총 72%)로 합성하는 방법의 개발에 관한 것으로, 기존 합성법에서 문제가 되는 긴 반응단계와 낮은 수율방법을 요오드를 도입한 커플링-고리화 동시반응을 이용하여 해결한 경제적 ailanthoidol 합성방법의 개발을 포함하는 것을 특징으로 한다. The present invention is a method for synthesizing the synthesis of ailanthoidol, which is expected to have an excellent anti-inflammatory activity, as an active ingredient of hawthorn locust tree, which is used as a folk remedy, from a vanillin compound in a short reaction and a high yield (72% in total). The present invention relates to the development of an economical ailanthoidol synthesis method in which a long reaction step and a low yield method, which are a problem in the conventional synthesis method, are solved by using a coupling-ring simultaneous reaction in which iodine is introduced.

Ailanthoidol, 항염작용, 산초나무, 머귀나무, 커플링-고리화 동시반응 Ailanthoidol, Anti-Inflammatory, Japanese Herb, Redwood, Coupling-ring Synchronization

Description

Ａｉｌａｎｔｈｏｉｄｏｌ의 경제적 합성 {An economical synthesis of ailanthoidol}{An economical synthesis of ailanthoidol} Ａｉｌａｎｔｈｏｉｄｏｌ

본 발명은 강력한 항염작용이 기대되는 머귀나무의 활성성분 ailanthoidol의 경제적 합성법으로 바닐린 화합물로부터 총 5단계의 짧은 반응 및 높은 수율로 전합성 하는 방법의 개발에 관한 것이다.The present invention relates to the development of a method of synthesizing a total of five steps from a vanillin compound with a short yield and a high yield as an economic synthesis method of the active ingredient ailanthoidol of the locust tree, which is expected to have strong anti-inflammatory action.

산초나무속 머귀나무 (Zanthoxylum ailanthoides) 의 수피와 잎은 오랫동안 다양한 민간요법으로 이용되어오고 있으며 주요성분으로 ailanthoidol이 분리되었다 [Phytochemistry, 1994, 36, 213]. 기존의 합성방법들은 바닐린 [J. Org. Chem., 2002, 67, 6772; Tetrahedron Lett., 1998, 39, 6581] 및 5-bromo-2-hydroxy-3-methoxybenzaldehyde [J. Org. Chem., 2003, 68, 2968] 을 출발물질로 하여 26-50%의 낮은 수율로 ailanthoidol을 합성하였다. 특히, 기존의 합성방법들은 커플링 반응 및 벤조푸란 고리화 반응이 치환그룹에 따라 매우 민감하며 반응성이 떨어져 합성의 효율성과 경제성을 매우 감소시킨다. Ailanthoidol은 아직 많이 연구되지 않은 화합물로서 약효에 관한 결과가 전혀 밝혀진 바 없다. 따라서 구하기 어려운 천연물의 활성성분에 대한 효율적, 경제적 합성방법의 개발에 대한 요구가 증대되고 있다. Bark and leaves of Zanthoxylum ailanthoides have long been used in various folk remedies, and ailanthoidol has been isolated as a major component [Phytochemistry, 1994, 36, 213]. Existing synthetic methods are described in vanillin [J. Org. Chem., 2002, 67, 6772; Tetrahedron Lett., 1998, 39, 6581] and 5-bromo-2-hydroxy-3-methoxybenzaldehyde [J. Org. Chem., 2003, 68, 2968] as a starting material to synthesize ailanthoidol in a low yield of 26-50%. In particular, the existing synthetic methods are very sensitive to the coupling group and benzofuran cyclization reaction depending on the substitution group, and the reactivity is very low, reducing the efficiency and economic efficiency of the synthesis. Ailanthoidol is a compound that has not been studied much yet. Therefore, there is an increasing demand for the development of efficient and economical synthetic methods for active ingredients that are difficult to obtain.

다음의 반응식 1은 상기 반응을 도식적으로 표시한 것이다.The following scheme 1 schematically illustrates the reaction.

반응식 1Scheme 1

Figure 112009074011321-pat00001
Figure 112009074011321-pat00001

Ailanthoidol의 합성은 상업적으로 싸게 구할 수 있는 바닐린 (화학식 1)을 황산은을 이용한 요오드화 반응으로 ortho-요오드페놀 유도체 (화학식 2)를 합성하고 여기에 copper acetylide를 이용한 Sonogashira coupling반응으로 아세틸렌 유도체의 합성과 동시에 분자내 히드록시 그룹에 의한 고리화 반응이 일어나게 함으로서 벤조푸란 화합물 (화학식 3)을 높은 수율로 합성한다. Wittig 반응으로 carbethoxyethenyl 유도체 (화학식 4)을 합성한다. TiCl4를 이용한 탈벤질화 반응으로 벤조푸란 알코올 화합물 (화학식 5)를 합성 후 DIBAL-H를 이용한 환원반응으로 에스테르가 환원된 ailanthoidol (화학식 6)을 합성한다. 바닐린을 출발물질로 하는 기존 합성법 [J. Org. Chem., 2002, 67, 6772]에서는 브롬을 이용한 커플링반응 및 고리화 반응을 포함하여 전체 11 단계를 거쳐 26%의 수율로 ailanthoidol을 합성하여 경제성과 실효성이 떨어진다.Synthesis of ailanthoidol was performed by synthesizing ortho-iodine phenol derivatives (Formula 2) by commercially inexpensive vanillin (Formula 1) using silver sulphate iodide, followed by synthesis of acetylene derivatives by Sonogashira coupling reaction using copper acetylide. At the same time, a cyclization reaction with an intramolecular hydroxy group occurs to synthesize the benzofuran compound (Formula 3) in high yield. Wittig reaction to synthesize a carbethoxyethenyl derivative (Formula 4). A benzofuran alcohol compound (Formula 5) is synthesized by a debenzylation reaction using TiCl 4 , followed by synthesis of ailanthoidol (Formula 6) reduced in ester by a reduction reaction using DIBAL-H. Conventional synthesis method using vanillin as starting material [J. Org. Chem., 2002, 67, 6772] synthesized ailanthoidol in 26% yield in 11 steps, including coupling and cyclization using bromine.

따라서, 본 발명은 이러한 문제점을 해결하고자 요오드를 벤젠고리에 도입하여 Sonogashira coupling 반응이 보호기의 도입 없이도 일어날 수 있게 하고 커플링과 고리화 반응이 동일반응 조건 내에서 순차적으로 동시에 일어날 수 있게 함으로서 ailanthoidol 합성의 경제성 및 효율성을 높이는 합성방법을 제공하는 데 있다.Therefore, in order to solve this problem, the present invention introduces iodine into the benzene ring so that the Sonogashira coupling reaction can occur without the introduction of a protecting group, and the coupling and cyclization reactions can occur simultaneously in the same reaction conditions sequentially. To provide a synthetic method to increase the economics and efficiency of the system.

상기 목적에 따라, 본 발명에서는 요오드를 바닐린의 ortho-페놀 위치에 선택적으로 도입하여 Sonogashira coupling 반응이 보호기 없이도 잘 일어나게 하고 커플링과 벤조푸란 고리화 반응이 순차적으로 동시에 높은 반응성을 보이는 방법을 제공한다. In accordance with the above object, the present invention provides a method of selectively introducing iodine at the ortho-phenol position of vanillin so that the Sonogashira coupling reaction occurs well without a protecting group, and the coupling and benzofuran cyclization reactions are sequentially and simultaneously highly reactive. .

화학식 1의 화합물로부터 화학식 6의 ailanthoidol을 제조하는데 있어 화학식 2, 화학식 3, 화학식 4, 화학식 5를 거치는 5단계로 반응단계를 간소화함으로 기존 발표된 ailanthoidol 합성법중 가장 효율적이며 수율이 가장 높은 합성방법이다 (전체수율 72%). 특히, 요오드그룹을 도입한 Sonogashira coupling 반응의 생성물이 같은 반응조건에서 동시에 벤조푸란 고리화 반응으로 연결되어 반응단계를 간소화함과 아울러 반응수율을 높이는 방법의 개발로 합성의 효율성 및 경제성을 크게 높였다.In preparing the ailanthoidol of the formula (6) from the compound of the formula (1) by simplifying the reaction step in five steps through the formulas (2), (3), (4) and (5), it is the most efficient and highest yield synthesis method among the published ailanthoidol synthesis methods. (72% overall yield). In particular, the product of the Sonogashira coupling reaction with iodine group was simultaneously linked to the benzofuran cyclization reaction under the same reaction conditions, thereby simplifying the reaction step and improving the reaction yield.

이하 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail.

본 발명에서 출발물질로 사용되는 바닐린 (vanillin)은 하기 화학식 1로 표시된다:Vanillin used as a starting material in the present invention is represented by the following formula (1):

Figure 112009074011321-pat00002
Figure 112009074011321-pat00002

상기 식에서, 바닐린은 알드리치등의 시약회사에서 쉽게 구입할 수 있으며 에탄올 용매에 녹여서 사용한다.In the above formula, vanillin can be easily purchased from a reagent company such as Aldrich and used by dissolving in ethanol solvent.

Figure 112009074011321-pat00003
Figure 112009074011321-pat00003

상기식에서 4-hydroxy-3-iodo-5-methoxybenzaldehyde은 출발물질 바닐린으로부터 황산은을 이용한 요오드화 반응으로 얻어진다.In the above formula, 4-hydroxy-3-iodo-5-methoxybenzaldehyde is obtained from the starting material vanillin by iodide using silver sulfate.

Figure 112009074011321-pat00004
Figure 112009074011321-pat00004

상기식에서 2-(4-benzyloxy-3-methoxyphenyl)-7-methoxybenzofuran-5-carbaldehyde은 화학식 2와 acethylene 유도체와의 Sonogashira coupling 반응의 생성물이 같은 조건에서 연속해서 동시에 일어나는 분자 내 고리화 반응으로 얻어진다.In the above formula, 2- (4-benzyloxy-3-methoxyphenyl) -7-methoxybenzofuran-5-carbaldehyde is obtained by intramolecular cyclization reaction in which the product of Sonogashira coupling reaction with Chemical Formula 2 and acethylene derivatives is carried out simultaneously under the same conditions. .

Figure 112009074011321-pat00005
Figure 112009074011321-pat00005

상기식에서 2-(4-benzyloxy-3-methoxyphenyl)-5-(carbethoxyethenyl)-7-methoxybenzofuran은 화학식 3과의 Wittig 반응으로 얻어진다.In the above formula, 2- (4-benzyloxy-3-methoxyphenyl) -5- (carbethoxyethenyl) -7-methoxybenzofuran is obtained by Wittig reaction with Chemical Formula 3.

Figure 112009074011321-pat00006
Figure 112009074011321-pat00006

상기식에서 2-(4-hydroxy-3-methoxyphenyl)-5-(carbethoxyethenyl)-7-methoxybenzofuran은 화학식 4와 TiCl4을 이용한 탈벤질화 반응으로 얻어진다.In the above formula, 2- (4-hydroxy-3-methoxyphenyl) -5- (carbethoxyethenyl) -7-methoxybenzofuran is obtained by debenzylation using Chemical Formula 4 and TiCl 4 .

Figure 112009074011321-pat00007
Figure 112009074011321-pat00007

상기식에서 ailanthoidol은 화학식 5와 DIBAL-H와의 환원반응으로 얻어진다.In the above formula, ailanthoidol is obtained by a reduction reaction between Formula 5 and DIBAL-H.

이하 본 발명을 하기 실시예에 의하여 더욱 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들만으로 한정되 는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

실시예Example

실시예 1Example 1

바닐린 (화학식 1)으로부터 화학식 2의 합성방법 Synthesis of Chemical Formula 2 from Vanillin (Formula 1)

Vanillin (1g, 6.57mmol), iodine (2.08g, 7.89mmol) 및 silver sulfate (2.46g, 7.89mmol)를 EtOH (50mL)에 녹인 후 실온에서 1시간동안 교반 한 뒤 물을 첨가하여 반응을 종결 시키고 CH2Cl2로 추출한다. 추출 후 유기층을 물과 brine으로 씻어주고 Na2SO4를 이용하여 건조 후 감압 증류하여 남은 물질을 컬럼크로마토그래피 (EtOAc:Hexane=1:2)로 분리하여 하얀 고체인 목적 화합물 2를 얻었다. Vanillin (1g, 6.57mmol), iodine (2.08g, 7.89mmol) and silver sulfate (2.46g, 7.89mmol) were dissolved in EtOH (50mL), stirred at room temperature for 1 hour and water was added to terminate the reaction. Extract with CH 2 Cl 2 . After extraction, the organic layer was washed with water and brine, dried using Na 2 SO 4, and distilled under reduced pressure. The remaining material was separated by column chromatography (EtOAc: Hexane = 1: 2) to obtain the title compound 2 as a white solid.

수율 : 1.55g, 85%Yield: 1.55 g, 85%

R f 0.34 (EtOAc:Hexane=1:3); m.p. 178-181oC; 1H NMR (300 MHz, CDCl3) d 3.97 (3H, s, OCH3), 6.69 (1H, s, OH), 7.36 (1H, d, J=1.5Hz, C6-H), 7.81 (1H, d, J=1.5Hz, C2-H), 9.75 (1H,s,CHO). 13C NMR (75 MHz, CDCl3) d 56.8 (OMe), 80.7 (C3-I), 108.8 (C6), 131.2 (C1), 136.4 (C2), 146.6 (C5), 151.5 (C4), 189.7 (C=O). R f 0.34 (EtOAc: Hexane = 1: 3); mp 178-181 o C; 1 H NMR (300 MHz, CDCl 3 ) d 3.97 (3H, s, OCH 3 ), 6.69 (1H, s, OH), 7.36 (1H, d, J = 1.5 Hz, C6-H), 7.81 (1H, d, J = 1.5 Hz, C2-H), 9.75 (1H, s, CHO). 13 C NMR (75 MHz, CDCl 3 ) d 56.8 (OMe), 80.7 (C3-I), 108.8 (C6), 131.2 (C1), 136.4 (C2), 146.6 (C5), 151.5 (C4), 189.7 ( C = O).

실시예 2Example 2

화학식 2로부터 화학식 3의 합성방법Synthesis of Chemical Formula 3 from Chemical Formula 2

화학식 2의 화합물 0.145g (0.523mmol)을 Pd(PPh3)4 (0.018g, 0.026mmol), 1-benzyloxy-4-ethynyl-2-methoxybenzene (0.187g, 0.784mmol), CuI (0.005g, 0.026mmol) 및 DMF (8mL)에 녹여 준다. 여기에 Et3N (0.146mL, 1.046mmol)을 넣어주고 실온에서 14시간 동안 질소기류 하에 교반시킨다. 반응 후 물을 넣어주고 CH2Cl2로 추출한다. 추출 후 유기층을 물로 씻어주고 Na2SO4로 건조 시키고 감압 증류하여 남은 물질을 컬럼크로마토그래피 (EtOAc:Hexane=1:4)로 분리하여 노란 고체인 목적 화합물 3을 얻었다. 0.145 g (0.523 mmol) of a compound of Formula 2 was added to Pd (PPh 3 ) 4 (0.018 g, 0.026 mmol), 1-benzyloxy-4-ethynyl-2-methoxybenzene (0.187 g, 0.784 mmol), CuI (0.005 g, 0.026 mmol) and DMF (8 mL). Et 3 N (0.146 mL, 1.046 mmol) was added thereto and stirred at room temperature under a nitrogen stream for 14 hours. After the reaction, add water and extract with CH 2 Cl 2 . After extraction, the organic layer was washed with water, dried over Na 2 SO 4 , and distilled under reduced pressure. The remaining material was separated by column chromatography (EtOAc: Hexane = 1: 4) to obtain the title compound 3 as a yellow solid.

R f 0.3 (EtOAc:Hexane=1:2); m.p. 160-162; 1H NMR (300 MHz, CDCl3) d 3.98 (3H, s, C3’-OCH3), 4.06 (3H, s, C7-OCH3), 5.19 (2H, s), 6.91 (1H, s, C3-H), 6.93 (1H, s, C2’-H), 7.29-7.45 (8H, m), 7.65 (1H, s, C4-H), 9.96 (1H, s, CHO). 13C NMR (75 MHz, CDCl3) d 56.5 (x2), 71.2, 100.9, 104.5, 108.9, 114.0, 118.5, 119.2, 123,1, 127.5, 128.2, 128.8, 131.2, 133.6, 136.8, 146.0, 147.6, 149.3, 149.9, 158.0, 191.9 (C=O). R f 0.3 (EtOAc: Hexane = 1: 2); mp 160-162; 1 H NMR (300 MHz, CDCl 3 ) d 3.98 (3H, s, C3′-OCH 3 ), 4.06 (3H, s, C7-OCH 3 ), 5.19 (2H, s), 6.91 (1H, s, C3 -H), 6.93 (1H, s, C2'-H), 7.29-7.45 (8H, m), 7.65 (1H, s, C4-H), 9.96 (1H, s, CHO). 13 C NMR (75 MHz, CDCl 3 ) d 56.5 (x2), 71.2, 100.9, 104.5, 108.9, 114.0, 118.5, 119.2, 123,1, 127.5, 128.2, 128.8, 131.2, 133.6, 136.8, 146.0, 147.6, 149.3, 149.9, 158.0, 191.9 (C = O).

실시예 3Example 3

화학식 3으로부터 화학식 4의 합성방법Synthesis of Chemical Formula 4 from Chemical Formula 3

화학식 3의 화합물 0.270g (0.75mmol) 와 (carbethoxymethylene) triphenylphosphorane (0.264g, 0.99mmol)을 CH2Cl2 (20mL)에 녹여준다. 이 혼합물을 6시간동안 질소기류 하에서 환류 시킨 후 실온으로 냉각한다. 여기에 물을 넣어주고 CH2Cl2로 추출한다. 추출 후 유기층을 brine으로 씻어 주고 Na2SO4로 건조 시킨 후 감압 증류하여 남은 물질을 컬럼크로마토그래피 (EtOAc:Hexane=1:6)로 분리하여 하얀 고체인 목적 화합물 4를 얻었다.0.270 g (0.75 mmol) of the compound of Formula 3 and (carbethoxymethylene) triphenylphosphorane (0.264 g, 0.99 mmol) were added to CH 2 Cl 2. Dissolve in (20mL). The mixture is refluxed under nitrogen stream for 6 hours and then cooled to room temperature. Add water and extract with CH 2 Cl 2 . After extraction, the organic layer was washed with brine, dried over Na 2 SO 4, and distilled under reduced pressure. The remaining material was separated by column chromatography (EtOAc: Hexane = 1: 6) to obtain the title compound 4 as a white solid.

수율 : 0.341g, 99%Yield: 0.341 g, 99%

R f 0.2 (EtOAc:Hexane=1:4); m.p. 142-144oC; 1H NMR (300 MHz, acetone-d 6) d 1.28 (3H, t, J=7.1Hz, CH3), 3.92 (3H, s), 4.07 (3H, s), 4.20 (2H, q, J=7.1Hz, OCH2), 5.15 (2H, s), 6.52 (1H, d, J=16.0Hz, trans ethenyl C1-H), 6.52 (1H, d, J=16Hz), 7.12 (1H, d, J=8.3Hz), 7.15 (1H, s), 7.26 (1H, d, J=1.4Hz), 7.31-7.52 (8H, m), 7.72 (1H, d, J=16.0Hz, trans ethenyl C2-H). 13C NMR (75 MHz, acetone-d 6) d 14.8 (CH3), 56.5 (OCH3), 56.7 (OCH3), 60.8 (OCH2), 71.5 (OCH2), 101.7, 106.5, 109.8, 115.1, 118.1 (trans ethenyl-C1), 118.8, 124.3, 128.7, 128.9, 129.4, 131.9, 132.5, 138.4, 146.1 (trans ethenyl-C2), 146.1, 146.6, 150.5, 151.3, 158.1, 167.4 (C=O). R f 0.2 (EtOAc: Hexane = 1: 4); mp 142-144 o C; 1 H NMR (300 MHz, acetone- d 6 ) d 1.28 (3H, t, J = 7.1 Hz, CH 3 ), 3.92 (3H, s), 4.07 (3H, s), 4.20 (2H, q, J = 7.1 Hz, OCH 2 ), 5.15 (2H, s), 6.52 (1H, d, J = 16.0 Hz, trans ethenyl C1-H), 6.52 (1H, d, J = 16 Hz), 7.12 (1H, d, J = 8.3 Hz), 7.15 (1H, s), 7.26 (1H, d, J = 1.4 Hz), 7.31- 7.52 (8H, m), 7.72 (1H, d, J = 16.0 Hz, trans ethenyl C2-H). 13 C NMR (75 MHz, acetone- d 6 ) d 14.8 (CH 3 ), 56.5 (OCH 3 ), 56.7 (OCH 3 ), 60.8 (OCH 2 ), 71.5 (OCH 2 ), 101.7, 106.5, 109.8, 115.1 , 118.1 ( trans ethenyl-C1), 118.8, 124.3, 128.7, 128.9, 129.4, 131.9, 132.5, 138.4, 146.1 ( trans ethenyl-C2), 146.1, 146.6, 150.5, 151.3, 158.1, 167.4 (C = O).

실시예 4Example 4

화학식 4로부터 화학식 5의 합성방법Synthesis of Chemical Formula 5 from Chemical Formula 4

화학식 4의 화합물 0.29g (0.63mmol)을 질소 기류 하에서 CH2Cl2 (20mL)에 녹인 후 실온에서 TiCl4 (0.7mL, 0.7mmol, 1.0M in CH2Cl2)를 천천히 넣어주고 실온에서 1시간동안 질소 기류 하에 교반시킨다. 반응 종결 후 실온에서 MeOH을 넣어 반응을 종결시키고 용매를 감압 증류하여 제거하고 남은 물질을 컬럼크로마토그래피 (EtOAc:Hexane=1:4)로 분리하여 하얀 고체인 목적 화합물 5를 얻었다. A compound 0.29g (0.63mmol) of the formula (4) in a nitrogen atmosphere CH 2 Cl 2 (20mL) and then at room temperature TiCl 4 (0.7 mL, 0.7 mmol, 1.0 M in CH 2 Cl 2 ) was slowly added and stirred under nitrogen stream for 1 hour at room temperature. After completion of the reaction, MeOH was added at room temperature to terminate the reaction. The solvent was distilled off under reduced pressure, and the remaining material was separated by column chromatography (EtOAc: Hexane = 1: 4) to obtain the title compound 5 as a white solid.

수율 : 0.228g, 98%Yield: 0.228 g, 98%

R f 0.5 (EtOAc:Hexane=1:2); m.p. 149-151oC; 1H NMR (300 MHz, acetone-d 6) δ 1.27 (3H, t, J=7.1Hz, CH3), 3.91 (3H, s), 4.07 (3H, s), 4.20 (2H, q, J=7.1Hz, OCH2), 6.52 (1H, d, J=16.0Hz ,trans ethenyl C1-H), 6.94 (1H, d, J=8.2Hz), 7.07 (1H, s), 7.24 (1H, d, J=1.4Hz), 7.41 (1H, dd, J=8.2, 2.0Hz), 7.70 (1H, d, J=16.0Hz, trans ethenyl C2-H), 8.07 (1H,s). 13C NMR (75 MHz, acetone-d 6) δ 14.8 (CH3), 56.6 (OCH3), 56.6 (OCH3), 60.9 (OCH2), 100.1, 106.5, 109.4, 115.5, 116.6 (trans ethenyl-C1), 118.0, 119.5, 123.0, 129.5, 131.9, 132.6, 146.1 (trans ethenyl-C2), 146.6, 148.9 (x2), 158.4, 167.5 (C=O). R f 0.5 (EtOAc: Hexane = 1: 2); mp 149-151 o C; 1 H NMR (300 MHz, acetone- d 6 ) δ 1.27 (3H, t, J = 7.1 Hz, CH 3 ), 3.91 (3H, s), 4.07 (3H, s), 4.20 (2H, q, J = 7.1 Hz, OCH 2 ), 6.52 (1H, d, J = 16.0 Hz, trans ethenyl C1-H), 6.94 (1H, d, J = 8.2 Hz), 7.07 (1H, s), 7.24 (1H, d, J = 1.4 Hz), 7.41 (1H, dd, J = 8.2, 2.0 Hz) , 7.70 (1H, d, J = 16.0 Hz, t rans ethenyl C2-H), 8.07 (1 H, s). 13 C NMR (75 MHz, acetone- d 6 ) δ 14.8 (CH 3 ), 56.6 (OCH 3 ), 56.6 (OCH 3 ), 60.9 (OCH 2 ), 100.1, 106.5, 109.4, 115.5, 116.6 ( trans ethenyl-C1), 118.0, 119.5, 123.0, 129.5, 131.9, 132.6, 146.1 ( trans ethenyl-C2), 146.6, 148.9 (x2), 158.4, 167.5 (C = O).

실시예 5Example 5

화학식 5로부터 ailanthoidol (화학식 6)의 합성방법Synthesis method of ailanthoidol (Formula 6) from Chemical Formula 5

화학식 5의 화합물 0.17g (0.46mmol)을 THF (10mL)에 녹인 후 DIBAL-H (0.25ml, 1.9mmol, 1.0M in CH2Cl2)를 넣어주고 -78에서 질소기류 하에 천천히 적가 하였다. 실온까지 서서히 온도를 올리며 12시간 교반후 포화 Na2CO3 ?10H2O수용액을 넣어주고 생성된 알루미늄 겔상의 물질을 CH2Cl2 (50mL)을 넣어서 희석시킨 뒤 알루미늄 겔 물질을 EtOAc로 세척하면서 여과하였다. 감압 증류하여 남은 물질을 ethyl alcohol로 재결정하여 하얀 고체인 목적 화합물 6을 얻었다. 0.17 g (0.46 mmol) of the compound of Formula 5 was dissolved in THF (10 mL), and DIBAL-H (0.25 mL, 1.9 mmol, 1.0 M in CH 2 Cl 2 ) was added thereto, and slowly added dropwise under nitrogen stream at -78. After slowly raising the temperature to room temperature and stirring for 12 hours, saturated Na 2 CO 3 ? Aqueous 10H 2 O solution was added and the resulting aluminum gel-like material was diluted with CH 2 Cl 2 (50 mL), and the aluminum gel material was filtered while washing with EtOAc. After distillation under reduced pressure, the remaining material was recrystallized with ethyl alcohol to obtain the title compound (6) as a white solid.

수율 : 0.143g, 95%Yield: 0.143 g, 95%

R f 0.6 (EtOAc:Hexane=3:1); m.p. 199-201oC; 1H NMR (300 MHz, DMSO-d 6) δ 3.87 (3H, s, C7-OCH3), 3.93 (3H, s, C3'-OCH3), 4.13 (2H, d, J=4.7Hz, CH2OH), 5.59 (1H, s), 6.31 (1H, dt, J=5.0, 15.8Hz, trans ethenyl C2-H), 6.57 (1H, d, J=15.8Hz, trans ethenyl C1-H), 6.86 (1H, d, J=8.2Hz, C5'-H), 6.90 (1H, s, C2'-H), 7.03 (1H, d, J=1.4Hz, C3-H), 7.10 (1H, s), 7.29 (1H, dd, J=1.4, 8.2Hz, C6'-H), 7.33 (1H, s, C4-H). 13C NMR (75 MHz, DMSO-d 6) δ 55.7 (C3'-OCH3, C7-OCH3), 61.6 (CH2OH), 100.1 (C3), 104.3 (C4), 108.6 (C6), 110.8 (C2'), 115.8 (C6'), 117.8 (C5'), 121.0 (trans ethenyl C2),128.9 (C1'), 129.5 (C3a), 130.7 (trans ethenyl C1), 133.1 (C5), 142.3 (C7), 144.5 (C4'), 147.5 (C3'), 147.8 (C7a), 156.1 (C2). R f 0.6 (EtOAc: Hexane = 3: 1); mp 199-201 o C; 1 H NMR (300 MHz, DMSO- d 6 ) δ 3.87 (3H, s, C7-OCH 3 ), 3.93 (3H, s, C3'-OCH 3 ), 4.13 (2H, d, J = 4.7 Hz, CH 2 OH), 5.59 (1H, s), 6.31 (1H, dt, J = 5.0, 15.8 Hz, trans ethenyl C2-H), 6.57 (1H, d, J = 15.8 Hz, trans ethenyl C1-H), 6.86 (1H, d, J = 8.2 Hz, C5'-H), 6.90 (1H, s, C2'-H), 7.03 (1H, d, J = 1.4 Hz, C3-H) , 7.10 (1H, s), 7.29 (1H, doublet of doublets, J = 1.4, 8.2 Hz, C6′-H), 7.33 (1H, s, C4-H). 13 C NMR (75 MHz, DMSO- d 6 ) δ 55.7 (C3'-OCH 3 , C7-OCH 3 ), 61.6 (CH 2 OH), 100.1 (C3), 104.3 (C4), 108.6 (C6), 110.8 (C2 '), 115.8 (C6'), 117.8 (C5 '), 121.0 ( trans ethenyl C2), 128.9 (C1 '), 129.5 (C3a), 130.7 ( trans ethenyl C1), 133.1 (C5), 142.3 (C7), 144.5 (C4'), 147.5 (C3 '), 147.8 (C7a), 156.1 (C2).

Claims (4)

화학식 1로 표시되는 바닐린으로부터 화학식 6으로 표시되는 ailanthoidol을 합성하는 방법에 있어서 화학식 2로 표시되는 iodobenzaldehyde가 같은 반응조건에서 Sonogashira coupling 반응과 고리화반응이 동시에 일어남으로 화학식 3을 중간화합물로 거쳐 생성되는 것을 특징으로 하는 방법In the method for synthesizing ailanthoidol represented by Chemical Formula 6 from vanillin represented by Chemical Formula 1, iodobenzaldehyde represented by Chemical Formula 2 is formed via Intermediate Compound 3 through Sonogashira coupling reaction and cyclization reaction under the same reaction conditions. Method characterized by 화학식 1Formula 1
Figure 112009074011321-pat00008
Figure 112009074011321-pat00008
 화학식 2Formula 2
Figure 112009074011321-pat00009
Figure 112009074011321-pat00009
 화학식 3Formula 3
Figure 112009074011321-pat00010
Figure 112009074011321-pat00010
 화학식 66
Figure 112009074011321-pat00011
Figure 112009074011321-pat00011
 제 1항에 있어서, 상기 화학식 6 화합물을 합성하는 방법에 있어서 화학식 3과 (carbethoxymethylene)triphenylphosphorane을 이용한 Wittig 반응으로 화학식 4를 중간화합물로 거쳐 생성되는 것을 특징으로 하는 방법The method of claim 1, wherein in the method for synthesizing the compound of Formula 6, the Wittig reaction using Formula 3 and (carbethoxymethylene) triphenylphosphorane is produced via Formula 4 as an intermediate compound. 화학식 4Formula 4
Figure 112009074011321-pat00012
Figure 112009074011321-pat00012
 제 1항에 있어서, 상기 화학식 6 화합물을 합성하는 방법에 있어서 화학식 4에서 TiCl4를 이용한 탈벤질화 반응으로 화학식 5를 중간화합물로 거쳐 생성되는 것을 특징으로 하는 방법The method of claim 1, wherein in the method for synthesizing the compound of Chemical Formula 6, a debenzylation reaction using TiCl 4 in Chemical Formula 4 is produced via Chemical Formula 5 as an intermediate compound. 화학식 5Formula 5
Figure 112009074011321-pat00013
Figure 112009074011321-pat00013
 제 1항에 있어서, 상기 화학식 6 화합물을 합성하는 방법에 있어서 화학식 5에서 DIBAL-H (Diisobuthylaluminum hydride)를 이용한 환원반응으로 화학식 6으로 표시되는 최종화합물을 생성하는 것을 특징으로 하는 방법The method of claim 1, wherein in the method for synthesizing the compound of Chemical Formula 6, the final compound represented by Chemical Formula 6 is produced by a reduction reaction using DIBAL-H (Diisobuthylaluminum hydride) in Chemical Formula 5.
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