KR100542324B1 - 2,2-Dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran libraries by parallel synthesis on the solid-phase - Google Patents
2,2-Dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran libraries by parallel synthesis on the solid-phase Download PDFInfo
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Abstract
본 발명은 신규 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 유도체와, 조합화학 합성기술중 하나인 고체상 평형합성법을 이용하여 상기한 신규 화합물을 고효율로 합성하는 방법, 그리고 상기한 신규 화합물이 우수한 지질 과산화 억제 효과를 나타내므로 지질 과산화의 촉진 또는 산화물질의 축적으로 유발되는 질환의 예방 및 치료제로 사용하는 용도에 관한 것이다.The present invention uses a novel 2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran derivative and a solid phase equilibrium synthesis method, one of the combinatorial chemical synthesis techniques, to synthesize the above novel compounds with high efficiency. The present invention relates to a method for use as an agent for the prevention and treatment of diseases caused by the promotion of lipid peroxidation or the accumulation of oxides because the novel compounds exhibit excellent lipid peroxidation inhibitory effects.
조합화학 합성, 고체상 평형 합성, 항산화제, 지질 과산화 억제, 뇌신경질환 치료제, 고혈압치료제, 당뇨병치료제, 약리적 효능, 벤조피란, 라이브러리Combination Chemical Synthesis, Solid Equilibrium Synthesis, Antioxidants, Inhibition of Lipid Peroxidation, Cerebral Nerve Disease, Hypertension, Diabetes, Pharmacological Effects, Benzopyran, Library
Description
본 발명은 신규 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 유도체와, 조합화학 합성기술중 하나인 고체상 평형합성법을 이용하여 상기한 신규 화합물을 고효율로 합성하는 방법, 그리고 상기한 신규 화합물이 우수한 지질 과산화 억제 효과를 나타내므로 지질 과산화의 촉진 또는 산화물질의 축적으로 유발되는 질환의 예방 및 치료제로 사용하는 용도에 관한 것이다.The present invention uses a novel 2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran derivative and a solid phase equilibrium synthesis method, one of the combinatorial chemical synthesis techniques, to synthesize the above novel compounds with high efficiency. The present invention relates to a method for use as an agent for the prevention and treatment of diseases caused by the promotion of lipid peroxidation or the accumulation of oxides because the novel compounds exhibit excellent lipid peroxidation inhibitory effects.
신경세포의 손상 또는 사멸은 뇌졸중, 뇌외상, 알츠하이머 병, 파킨슨 병에 이르는 여러 가지 신경계 질환의 주원인으로 알려져 있다[G.J. Zoppo et al., Drugs 54, 9 (1997); I. Sziraki et al., Neurosci. 85, 1101 (1998)]. 신경세포를 손상시키는 요인으로는 여러 가지가 알려져 있으며, 대표적으로는 신경세포 내 철 농도의 증가, 활성산소의 증가, 산화물질의 증가 등을 꼽을 수 있다[M.P. Mattson et al., Methods Cell Biol. 46, 187 (1995); Y. Goodman et al. , Brain Res. 706, 328 (1996)].Injury or death of neurons is known to be a major cause of various neurological diseases, including stroke, brain trauma, Alzheimer's disease and Parkinson's disease [GJ Zoppo et al. , Drugs 54 , 9 ( 1997 ); I. Sziraki et al. , Neurosci. 85 , 1101 ( 1998 )]. Many factors are known to damage neurons, and the representative ones include increasing iron concentrations, increasing free radicals, and increasing oxides in neurons [MP Mattson et al. , Methods Cell Biol. 46 , 187 ( 1995 ); Y. Goodman et al. , Brain Res. 706 , 328 ( 1996 ).
신경세포 내에 철 농도가 증가하면 NO 등의 산소 유리기(oxygen free radical)가 형성되고, 산소 유리기가 과도하게 많이 생성되면 그로 인해 지질 과산화가 촉진되고 산화 물질이 증가하여 세포 내에 축적된다. 세포 내에 축적된 산화 물질은 상기와 같은 신경계 질환 외에 관절염 등의 염증성 질환, 심근경색증, 치매 등을 일으킬 뿐만 아니라, 허혈성 질환에 있어서 재관류시 조직이 손상되거나 세균이 감염되어 장기가 내독소에 의해 손상되는 등 각종 급만성 조직 또는 장기의 손상을 일으키는 것으로 알려져 있다.When iron concentration increases in nerve cells, oxygen free radicals such as NO are formed. When excessively large amounts of oxygen free radicals are generated, lipid peroxidation is promoted and oxidizing substances are increased and accumulated in cells. Oxidized substances accumulated in the cells not only cause inflammatory diseases such as arthritis, myocardial infarction, and dementia in addition to the neurological diseases described above, but also damage organs by endotoxins due to tissue damage or bacterial infection during reperfusion in ischemic diseases. It is known to cause damage to various acute tissues or organs.
따라서 신경세포 내 철 농도의 증가에 의한 신경세포의 손상을 방지하고 지질 과산화를 방지하며 내독소 등에 의한 NO의 생성을 억제하는 물질을 개발함으로써, 신경세포의 손상 또는 사멸에 기인한 여러 가지 질병을 예방 또는 치료할 수 있다. 현재 항산화 물질들이 신경세포 내 철에 의한 신경세포의 손상과 사멸을 완화시킨다는 결과가 보고되었고, 산화적 스트레스에 의한 신경세포의 손상을 막아주는 약물을 개발하고자 하는 노력이 진행 중이다[Y. Zhang et al., J. Cereb. Blood Flow Metab. 13, 378 (1993)].Therefore, by developing a substance that prevents damage to nerve cells by increasing iron concentration in the nerve cells, prevents lipid peroxidation, and inhibits NO production by endotoxins, various diseases caused by nerve cell damage or death are developed. Can be prevented or treated. Currently, antioxidants have been reported to mitigate neuronal damage and death by iron in neurons, and efforts are underway to develop drugs to prevent neuronal damage caused by oxidative stress [Y. Zhang et al. , J. Cereb. Blood Flow Metab. 13 , 378 ( 1993 ).
벤조피란을 골격으로 하는 천연물 및 합성물은 항산화 활성을 보유하고 있어 신경질환 치료제, 고혈압 치료제 및 당뇨병 치료제 등의 약리적 효능을 보유한 화합물 개발하는데 있어 기본 골격구조로 널리 알려져 있고, 또한 폭넓게 활용되고 있다.Benzopyran skeleton and natural products and synthetic compounds have antioxidant activity and are widely known and widely used as a basic skeletal structure in the development of compounds possessing pharmacological effects such as neurological diseases, hypertensions and diabetes treatments.
한편, 조합화학 합성기술을 이용하여 다양한 치환체를 가진 벤조피란 라이브 러리를 구축하는 것은 신약개발의 초기단계에서의 생물학적 유효화합물(hit compound) 및 선도물질(lead compound)의 탐색에 유용하게 활용될 수 있다.On the other hand, building a benzopyran library with various substituents using combinatorial chemical synthesis can be useful in the search for bio-hit compounds and lead compounds in the early stages of drug development. have.
특히 분자내에 다양한 치환체의 도입이 가능하고 인접하는 탄소에 하이드록시가 있으면 에스테르, 에테르 등의 다양한 관능기의 도입으로 조합화학 합성기술에 의하여 대량 및 집중 라이브러리를 효율적으로 구축하는 것은 선도물질 탐색에 유용한 분자다양성 확보전략 차원에서 중요하다.In particular, if various substituents can be introduced into the molecule, and if there is hydroxy at adjacent carbons, the efficient construction of a large-scale and concentrated library by combinatorial chemical synthesis technology by introducing various functional groups such as esters and ethers can be useful for the search for leading substances. This is important in terms of strategies for securing diversity.
조합화학 합성(combinatorial chemical synthesis)은 신물질 개발의 새로운 합성기술로서, 기존의 고전적인 유기합성기술이 한번의 반응으로 한 개의 화합물을 합성하는데 반하여, 조합화학 합성기술은 보다 다양하고 많은 수의 화합물을 동시에 합성하거나, 다단계의 합성공정을 자동화 할 수 있는 고효율 화학물질 합성법이라 할 수 있다. 이러한 조합화학 합성의 도입으로 인하여 새로운 구조의 생물학적 유효화합물(hit compound) 및 선도물질(lead compound)의 탐색과 이의 구조 및 활성을 최적화 하는 것이 용이해졌다.Combinatorial chemical synthesis is a new synthesis of new material development, whereas conventional organic synthesis synthesizes a single compound in a single reaction, whereas combinatorial chemical synthesis involves a greater variety of compounds. It is a high-efficiency chemical synthesis method that can synthesize at the same time or automate the multi-step synthesis process. The introduction of combinatorial chemical synthesis facilitates the search for new structures of biological hit compounds and lead compounds, as well as optimization of their structure and activity.
또한, 조합화학 합성기술은 대부분이 고체 지지체 상에서 반응공정이 수행되므로 연속적인 다단계 반응 및 반응공정의 자동화가 가능하고, 생성물의 분리 정제공정이 매우 간단하므로 고효율 약효검정(High Throughput Screening; HTS)이 가능하다는 장점이 있다.In addition, in the combination chemical synthesis technology, most of the reaction process is performed on a solid support, it is possible to automate continuous multistage reactions and reaction processes, and the separation and purification process of the product is very simple, so that high throughput screening (HTS) is achieved. The advantage is that it is possible.
이처럼 조합화학 합성기술이 기존 합성기술의 비경제성 및 비효율성을 극복시킨 새로운 합성기술인데도 불구하고, 이를 유기합성분야에 쉽게 적용할 수 없었던 몇 가지 이유가 있다. 그 대표적인 원인중의 하나가 고체 지지체상 화학반 응의 대부분이 반응시약을 과량으로 사용하기 때문에 경우에 따라서는 원하지 않는 부반응을 일으키는 것과, 선택 사용되는 고체 지지체의 물리적 특성에 따라 사용되어 질 수 있는 용매의 제한성으로 인하여 반응조건의 선택 폭이 극히 좁다는 것이다. 고체상 조합화학 합성분야에는 고체 지지체로서 메리필드 레진(Merrifield resin)과 왕 레진(Wang resin)을 널리 사용하고 있으나, 이들 지지체는 알코올 및 물 등과 같이 극성이 큰 용매에서 팽윤효과(swelling effect)가 극히 낮아서 반응에 필요한 용매의 선택에 많은 제한을 받는다. 따라서 고체상 화학반응을 이용하여 다양한 유도체를 합성하기 위해서는 고체 지지체 및 반응시약의 선택과 반응조건의 탐색이 중요한 요소로 작용한다.Although combinatorial chemical synthesis is a new synthetic technology that overcomes the inefficiency and inefficiency of the existing synthetic technology, there are several reasons why it could not be easily applied to the field of organic synthesis. One of the typical causes is that most of the chemical reactions on the solid support use excessive amounts of reaction reagents, which in some cases cause unwanted side reactions and may be used depending on the physical properties of the solid support used. Due to the limitation of the solvent, the choice of reaction conditions is extremely narrow. In the field of solid-phase combinatorial chemical synthesis, Merrifield resin and Wang resin are widely used as solid supports, but these supports have very swelling effects in polar solvents such as alcohol and water. It is low and thus places a lot of restrictions on the choice of solvents required for the reaction. Therefore, in order to synthesize various derivatives using solid phase chemical reaction, selection of solid support and reaction reagents and search of reaction conditions are important factors.
본 발명자들은 항산화제, 신경질환 치료제, 고혈압 치료제 및 당뇨병 치료제 등의 약리적 효능을 보유한 화합물 합성에 벤조피란 유도체가 유용하다는 사실에 착안하여 고체상에서 조합화학 합성기술을 이용하여 효율적으로 벤조피란 라이브러리를 구축할 수 있는 방법을 개발하고자 연구 노력하였다. 그 결과, 일반적으로 용액상의 고전적인 화학반응에서는 매 단계마다 반응, 반응후 처리 정제, 및 구조확인 작업을 거치는 방법으로 목표화합물을 합성하는데 반하여, 본 발명자들은 고체상 평형 합성법을 이용한 조합화학 합성기술로 3 단계의 반응을 연속으로 반응을 수행한 다음, 용이한 반응 후 처리과정을 거쳐서 단기간에 효율적으로 대량의 목표 화합물인 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 라이브러리를 높은 수율로 얻게됨으로써 본 발명을 완성하게 되었다. The inventors have found that benzopyran derivatives are useful for synthesizing compounds possessing pharmacological effects such as antioxidants, neurological diseases, hypertension and diabetes treatment, and efficiently construct a benzopyran library using combinatorial chemical synthesis on solid phase. Research efforts have been made to develop ways to do this. As a result, in general, in the classical chemical reaction of the solution phase, the target compound is synthesized by the reaction, the post-reaction treatment purification, and the structure confirmation operation at every stage, and the present inventors use a combination chemical synthesis technique using a solid phase equilibrium synthesis method. After carrying out the reaction in three stages in succession, and then through easy reaction treatment process, a large amount of target compound 2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzo in a short time and efficiently The pyran library was obtained in high yield to complete the present invention.
따라서, 본 발명은 의약품 합성에 유효한 신규 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 유도체를 제공하는데 그 목적이 있다.It is therefore an object of the present invention to provide novel 2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran derivatives that are effective for drug synthesis.
또한, 본 발명은 고체상 평형합성법을 이용함으로써 연속적인 다단계 반응공정의 자동화와 최종화합물의 화학적 구조분석이 용이하며, 제조 수율이 우수한 등의 장점을 가지는 고체상 평형합성법에 의한 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬아미노 벤조피란 유도체의 합성방법을 제공하는데 다른 목적이 있다.In addition, the present invention is easy to automate the continuous multi-step reaction process and chemical structural analysis of the final compound by using the solid phase equilibrium synthesis method, 2,2-dimethyl-3 by solid phase equilibrium synthesis method having the advantages of excellent production yield Another object is to provide a method for synthesizing a -hydroxy-4-alkoxy-6-alkylamino benzopyran derivative.
또한, 본 발명은 지질 과산화 억제 활성이 우수하므로 지질 과산화의 촉진 또는 산화물질의 축적으로 유발되는 질환의 예방 및 치료제로서 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 유도체를 사용하는 용도를 제공하는데 다른 목적이 있다.
In addition, since the present invention has excellent lipid peroxidation inhibitory activity, 2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran as an agent for the prevention and treatment of diseases caused by the promotion of lipid peroxidation or the accumulation of oxides It is another object to provide the use of derivatives.
본 발명은 하기 화학식 (4a)로 표시되는 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 유도체를 그 특징으로 한다.The present invention is characterized by the 2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran derivative represented by the following general formula (4a).
상기 화학식 (4a)에서, R1a는 알릴기, 벤질기 또는 치환된 벤질기, 나프틸메틸기, 또는 펜에틸기를 나타내고; R2는 C1∼C10의 알킬기, 벤질기 또는 치환된 벤질기, 또는 -(CH2)n-페닐기(이때, n은 2 또는 3의 정수)를 나타내고; 이때 치환된 벤질기는 할로겐원자, 니트로기, C1∼C10의 알킬기, C1∼C10의 알콕시기 및 C1∼C10의 할로알킬기 중에서 선택된 치환체가 1 내지 4개 치환된 벤질기를 나타낸다.In the formula (4a), R 1a represents an allyl group, benzyl group or substituted benzyl group, naphthylmethyl group, or phenethyl group; R 2 represents a C 1 to C 10 alkyl group, benzyl group or substituted benzyl group, or — (CH 2 ) n -phenyl group, where n is an integer of 2 or 3; In this case, the substituted benzyl group represents a benzyl group in which 1 to 4 substituents selected from a halogen atom, a nitro group, a C 1 to C 10 alkyl group, a C 1 to C 10 alkoxy group, and a C 1 to C 10 haloalkyl group are substituted.
한편, 본 발명이 목적하는 하기 화학식 (4)로 표시되는 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 유도체는 광학이성체 화합물로서, 통상의 분리방법에 의하여 각각의 이성체 화합물로 분리할 수도 있다.On the other hand, 2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran derivatives represented by the following general formula (4), which is the object of the present invention, are optical isomer compounds, respectively, by conventional separation methods. It can also be separated by isomer compounds.
이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.
본 발명은 하기 화학식 (4)로 표시되는 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 유도체와, 상기한 신규 벤조피란 유도체를 용액상 화학 반응이 아닌 고체상 평형 합성법을 이용하여 효율적으로 구축할 수 있도록 하는 조합화학 합성기술법에 의한 제조방법, 그리고 상기한 신규 화합물을 지질 과산화의 촉진 또는 산화물질의 축적으로 유발되는 질환의 예방 및 치료제로 사용하는 용도를 그 특징으로 한다.The present invention is a solid phase equilibrium of a 2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran derivative represented by the following formula (4) with the novel benzopyran derivative described above rather than a solution phase chemical reaction. It is characterized by the manufacturing method by the combination chemical synthesis technique which can be efficiently constructed using the synthesis method, and the use of the new compound as a preventive and therapeutic agent for diseases caused by the promotion of lipid peroxidation or the accumulation of oxides. do.
본 발명에 따른 하기 화학식 (4)로 표시되는 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 유도체를 조합화학 합성기술법에 의해 제조하는 반응을 간략히 도시하면 하기 반응식 1과 같다.A reaction for preparing a 2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran derivative represented by the following general formula (4) according to the present invention by a combination chemical synthesis technique is shown briefly. Same as 1.
상기 반응식 1에서, R1은 C1∼C10의 알킬기, 알릴기, 벤질기 또는 치환된 벤질기, 나프틸메틸기, 또는 펜에틸기를 나타내고; R2는 C1∼C10의 알킬기, 벤질기 또는 치환된 벤질기, 또는 -(CH2)n-페닐기(이때, n은 2 또는 3의 정수)를 나타내고; 이때 치환된 벤질기는 할로겐원자, 니트로기, C1∼C10의 알킬기, C1∼C10의 알콕시기 및 C1∼C10의 할로알킬기 중에서 선택된 치환체가 1 내지 4개 치환된 벤질기를 나타내고; X는 할로겐원자를 나타내고; ⓟ는 폴리스티렌-디비닐벤젠, 메타아크릴산-디메틸아크릴아미드 및 하이드록시 메타아크릴산 중에서 선택된 고분자 중합체 형태의 고체 지지체를 나타낸다.In the above scheme 1, R 1 is C 1 ~C 10 alkyl group, an allyl group, a benzyl group or substituted benzyl group, a naphthylmethyl group, or the pen represents an ethyl group; R 2 represents a C 1 to C 10 alkyl group, benzyl group or substituted benzyl group, or — (CH 2 ) n -phenyl group, where n is an integer of 2 or 3; Wherein the substituted benzyl group represents a benzyl group in which 1 to 4 substituents are selected from a halogen atom, a nitro group, a C 1 to C 10 alkyl group, a C 1 to C 10 alkoxy group and a C 1 to C 10 haloalkyl group; X represents a halogen atom; Ⓟ represents a solid support in the form of a high molecular polymer selected from polystyrene-divinylbenzene, methacrylic acid-dimethylacrylamide and hydroxy methacrylic acid.
본 발명에 따른 제조방법중에 합성되는 반응 중간체로서 상기 화학식 (3)으로 표시되는 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 카바메이트 레진 역시 광학이성체인 바, 필요에 따라 각각의 이성체 화합물로 분리할 수도 있다.As the reaction intermediate synthesized in the preparation method according to the present invention, 2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino carbamate resin represented by the formula (3) is also an optical isomer. It can also be separated into individual isomeric compounds.
상기 반응식 1에 따른 본 발명의 제조방법은 다음과 같은 과정이 포함된다: 상기 화학식 (1)로 표시되는 카바메이트 링커로 연결된 벤조피란의 질소원자에 선택적으로 알킬 치환기의 도입반응을 수행하여 상기 화학식 (2)로 표시되는 N-알킬 치환된 카바메이트 레진을 합성하는 제 1 단계 반응; 상기 화학식 (2)로 표시되는 화합물에 메타-클로로과벤조산(m-CPBA)과 알코올을 넣어서 에폭시화 반응과 알콕시 부가반응을 동시에 수행하여 상기 화학식 (3)으로 표시되는 2,2-디메틸-3-하이드록시-6-알킬 아미노 벤조피란 형태의 레진을 합성하는 제 2 단계 반응; 그리고 상기 화학식 (3)으로 표시되는 화합물을 트리플루오로아세트산(TFA)을 포함하는 디클로로메탄 용액 또는 유기산을 포함하는 유기용매를 사용하여 탈리하여 상기 화학식 (4)로 표시되는 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 유도체를 합성하는 제 3 단계 반응.The preparation method of the present invention according to Scheme 1 includes the following processes: by selectively introducing an alkyl substituent to a nitrogen atom of benzopyran linked by a carbamate linker represented by Formula (1), A first step of synthesizing the N-alkyl substituted carbamate resin represented by (2); Meta-chloroperbenzoic acid ( m- CPBA) and an alcohol are added to the compound represented by the above formula (2) to simultaneously perform the epoxidation reaction and the alkoxy addition reaction to the 2,2-dimethyl-3- represented by the above formula (3). A second step reaction of synthesizing resin in the form of hydroxy-6-alkyl amino benzopyran; And the compound represented by the formula (3) is desorbed using a dichloromethane solution containing trifluoroacetic acid (TFA) or an organic solvent containing an organic acid and is represented by the formula (4). Third step reaction to synthesize 3-hydroxy-4-alkoxy-6-alkyl amino benzopyran derivatives.
본 발명자들의 실험결과에 따르면, 상기 화학식 (1)로 표시되는 고체 지지체상의 카바메이트 형태의 벤조피란 레진을 N-알킬화 반응과, 하이드록시 알콕시화 반응을 연속적으로 수행하게 되면, 고전적인 용액상 반응으로 수행하는 것에 비하여 정제과정을 대폭 줄임으로써 단기간에 다양한 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미로 벤조피란 유도체를 합성할 수 있었다.According to the experimental results of the present inventors, when the benzopyran resin of the carbamate form on the solid support represented by the formula (1) is continuously subjected to the N-alkylation reaction and the hydroxy alkoxylation reaction, the classical solution phase reaction By greatly reducing the purification process as compared to the above it was possible to synthesize a variety of 2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl ami benzopyran derivatives in a short time.
본 발명에 따른 반응공정, 용매계의 조성 및 반응조건의 선택범위를 구체적으로 설명하면 다음과 같다.Referring to the reaction process according to the invention, the composition of the solvent system and the selection range of the reaction conditions in detail.
본 발명에서 용매로서는 왕 레진(Wang resin)이나 메리필드 레진(Merrifield resin)의 팽윤효과(swelling effect)가 뛰어난 유기용매를 사용한다. 제 1 단계 반응에서는 디메틸술폭사이드(DMSO) 또는 테트라하이드로퓨란(THF)을 용매로 사용하며, 이때 염기로는 리튬 t-부톡시드(LiOtBu)를, 친전자체로 알킬브로마이드를 각각 3 당량 정도 사용하는 것이 좋으며, 바람직하기로는 2 당량 내외의 범위로 사용하는 것이 경제성이 뛰어나다.In the present invention, an organic solvent having excellent swelling effect of Wang resin or Merrifield resin is used as the solvent. In the first stage reaction, dimethyl sulfoxide (DMSO) or tetrahydrofuran (THF) is used as a solvent, wherein about 3 equivalents of lithium t -butoxide (LiO t Bu) is used as the base and alkyl bromide is used as the electrophile. It is good to use, Preferably it is excellent in economy to use in about 2 equivalents.
제 2 단계 반응에서는 메타-클로로과벤조산(m-CPBA) 산화반응시 생성되는 부산물인 3-클로로벤조산의 부가반응을 억제하기 위하여 m-CPBA를 3 당량 이내로 투입하고, 특히 m-CPBA를 투입하기 전에 알콕시기 전구체인 알코올류를 미리 과량 투입하고 15분 이상 충분히 흔들어 혼합한 후, 산화제를 투입하는 것이 바람직하다. 그 이유는 알콕시기가 산화반응 후, 생성되는 3-클로로벤조산의 양보다 절대우위에 있도록 하여 부산물의 생성을 억제하고자 하기 때문이다. 알콕시 전구체로서 알코올류는 지방족 알코올류를 일컫는 것으로 예를 들어, 메탄올, 에탄올, 이소-프로필 알콜, 벤질알콜, 치환된 벤질알콜, 또는 측쇄에 지방족 알콜이 존재하고 아민기와 카르복실산 부분이 보호기로 보호된 아미노산류를 말한다.The second step in the reaction of meta-chloroperbenzoic acid (m -CPBA) In the m -CPBA in order to suppress the addition reaction of 3-chlorobenzoic acid by-product produced during the oxidation reaction within 3 equivalents and, in particular before its use the m -CPBA It is preferable to add an oxidizing agent after the excess of alcohols which are alkoxy group precursors are mixed in advance for 15 minutes or more, and it mixes well enough. This is because the alkoxy group is intended to suppress the formation of by-products by allowing the alkoxy group to be absolutely superior to the amount of 3-chlorobenzoic acid produced after the oxidation reaction. Alcohols as alkoxy precursors refer to aliphatic alcohols, for example, methanol, ethanol, iso-propyl alcohol, benzyl alcohol, substituted benzyl alcohol, or aliphatic alcohol in the side chain and the amine group and carboxylic acid moiety as a protecting group. Refers to protected amino acids.
제 3 단계 반응에서는 트리플루오로아세트산(TFA)을 포함하는 디클로로메탄 용액 또는 유기산을 포함하는 유기용매를 사용하는 탈리반응을 수행하여 본 발명이 목적하는 상기 화학식 (4)로 표시되는 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 라이브러리를 얻는다.In the third step reaction, a dechlorination reaction using a dichloromethane solution containing trifluoroacetic acid (TFA) or an organic solvent containing an organic acid is carried out so that the present invention is represented by the general formula (4). Obtain a dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran library.
또한, 본 발명에 따른 상기 화학식 (4)로 표시되는 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 라이브러리의 생성여부를 확인하기 위하여, 반응 후 최종 단계에서 상기 화학식 (3)으로 표시되는 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 레진으로부터 탈리된 목적화합물을 다중 컬럼장비를 이용하여 플래쉬 컬럼 크로마토그래피로 정제 분리한 다 음, NMR 및 Mass 스펙트럼으로 구조를 분석 및 확인하였다. 반응중간체인 화학식 (1), (2) 및 (3)으로 표시되는 레진은 ATR-FTIR을 측정함으로써 반응 진행 정도를 확인하였다.In addition, to confirm the generation of the 2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran library represented by the formula (4) according to the present invention, in the final step after the reaction The target compound desorbed from 2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran resin represented by the formula (3) is purified and separated by flash column chromatography using a multi-column apparatus. Well, the structure was analyzed and confirmed by NMR and Mass spectra. The resins represented by the formulas (1), (2) and (3), which are reaction intermediates, confirmed the progress of the reaction by measuring ATR-FTIR.
한편, 본 발명의 화합물들은 철에 의한 지질 과산화를 억제하는 활성이 우수하여 지질 과산화 억제제로 사용될 수 있으며, 지질 과산화가 촉진되고 산화물질이 축적되어 유발되는 각종 질환의 예방 및 치료제로서 유용하게 사용될 수 있다. 즉, 본 발명의 화합물들은 세포막의 주요성분인 지질을 공격하여 세포독성을 갖는 과산화지질을 생성시키거나 세포막을 파괴함으로써 유발되는 암, 동맥경화, 당뇨, 뇌졸중, 치매, 파킨슨씨 병, 노화 등의 질환을 예방 또는 치료하는 약물로 사용될 수 있다.On the other hand, the compounds of the present invention can be used as a lipid peroxidation inhibitor due to the excellent activity of inhibiting lipid peroxidation by iron, it can be usefully used as a preventive and therapeutic agent for various diseases caused by lipid peroxidation and the accumulation of oxides have. That is, the compounds of the present invention attack lipids, which are the major components of cell membranes, to produce cytotoxic lipid peroxide or destroy cell membranes, such as cancer, arteriosclerosis, diabetes, stroke, dementia, Parkinson's disease, and aging. It can be used as a drug for preventing or treating a disease.
따라서, 본 발명은 2,2-디메틸-3-알킬에테르-4-알콕시-6-알킬아미노 벤조피란 유도체 또는 약제학적으로 허용 가능한 이들의 염이 유효성분으로 함유되어 있어 지질 과산화의 촉진 또는 산화물질의 축적으로 유발되는 각종 질환의 예방 및 치료제로 유효한 약제조성물을 포함한다.Accordingly, the present invention contains a 2,2-dimethyl-3-alkylether-4-alkoxy-6-alkylamino benzopyran derivative or a pharmaceutically acceptable salt thereof as an active ingredient, thereby promoting lipid peroxidation or oxidizing It includes a pharmaceutical composition effective for the prevention and treatment of various diseases caused by accumulation.
본 발명에서의 약제학적으로 허용 가능한 염은 당해 기술분야에서 통상적인 방법에 의해 제조될 수 있는 것으로, 예를 들면, 염산, 브롬화수소, 황산, 황산수소나트륨, 인산, 탄산 등의 무기산과의 염 또는 개미산, 초산, 옥살산, 벤조산, 시트르산, 타르타르산, 글루콘산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산(아스피린)과 같은 유기산과 함께 약제학적으로 허용 가능한 이들의 산의 염을 형성하거나, 또는 나트륨, 칼륨 등의 알칼리금속이온과 반응하여 이들의 금속염을 형성하거나, 또는 암모늄 이온과 반응하여 또 다른 형태의 약제학적으로 허용가능한 염을 형성할 수도 있다.Pharmaceutically acceptable salts in the present invention can be prepared by conventional methods in the art, for example, salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid, and the like. Or pharmaceutically acceptable organic compounds, such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestyic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin) It is also possible to form salts of acids, or to react with alkali metal ions such as sodium, potassium, to form their metal salts, or to react with ammonium ions to form another form of a pharmaceutically acceptable salt.
또한, 본 발명의 약제 조성물은 2,2-디메틸-3-알킬에테르-4-알콕시-6-알킬아미노 벤조피란 유도체 또는 약제학적으로 허용 가능한 이들의 염에 통상의 무독성 약제학적으로 허용 가능한 담체, 보강제 및 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제 예를 들면 정제, 캅셀제, 트로키제, 액제, 현탁제 등의 경구투여용 제제 또는 비경구투여용 제제로 제제화할 수 있다. 또한, 본 발명에 따른 화합물의 인체에 대한 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환정도에 따라 달라질 수 있으며, 몸무게가 70 ㎏인 성인환자를 기준으로 할 때 일반적으로 0.01 ∼ 1000 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.In addition, the pharmaceutical compositions of the present invention are conventional non-toxic pharmaceutically acceptable carriers in 2,2-dimethyl-3-alkylether-4-alkoxy-6-alkylamino benzopyran derivatives or pharmaceutically acceptable salts thereof, Adjuvants, excipients and the like can be added to formulate common oral or parenteral formulations such as tablets, capsules, troches, solutions, suspensions, and the like in the pharmaceutical art. In addition, the dosage of the compound according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 0.01-1000 mg / day, and can be dividedly administered once a day to several times at fixed time intervals according to the judgment of a doctor or a pharmacist.
이상에서 설명한 바와 같은 본 발명은 다음의 실시예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이에 한정되는 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 thereto.
실시예 I: 올레핀 레진 1의 N-알킬 치환 반응 및 탈리반응 Example I: N-alkyl Substitution and Desorption of Olefin Resin 1
I-1) 올레핀 레진 1의 N-메틸치환 반응 및 탈리반응I-1) N-methyl Substitution and Desorption Reaction of Olefin Resin 1
화학식 (1)로 표시되는 벤조피란 형태의 카바메이트 레진(200.00 ㎎, 0.11 mmol)을 디메틸슬폭사이드(DMSO)(3 ㎖)에 넣고 상온에서 10분간 흔들고, 테트라히드로퓨란(THF)에 녹아 있는 1 몰 농도의 리튬 t-부톡시드(LiOtBu) (0.33 ㎖, 0.33 mmol)를 가한 후, 같은 온도에서 20분간 흔들어 혼합한 다음, 요오드메탄(MeI) (0.020 ㎖, 0.33 mmol)를 가한 후 35 ℃에서 15시간동안 흔들어 혼합하였다. 반응종료 후, 반응혼합물을 여과하고 DMF, MC, MC/MeOH, MeOH로 반복 세척하여 화학식 (2a)로 표시되는 담갈색 고체인 N-메틸 카바메이트 레진(205.7 ㎎)을 얻었다. (ATR-FTIR 분석결과; N-methylation carbamate: 1700 ㎝-1)Carbamate resin (200.00 mg, 0.11 mmol) in the form of benzopyran represented by the formula (1) was added to dimethylsulfoxide (DMSO) (3 ml), shaken at room temperature for 10 minutes, and dissolved in tetrahydrofuran (THF). Lithium t -butoxide (LiO t Bu) (0.33 mL, 0.33 mmol) was added at a molar concentration, followed by mixing for 20 minutes at the same temperature, followed by addition of iodine methane (MeI) (0.020 mL, 0.33 mmol), followed by 35 Shake and mix for 15 h. After completion of the reaction, the reaction mixture was filtered and washed repeatedly with DMF, MC, MC / MeOH, MeOH to obtain N-methyl carbamate resin (205.7 mg) as a pale brown solid represented by the formula (2a). (ATR-FTIR Analysis; N-methylation carbamate: 1700 cm -1 )
수득된 N-메틸 카바메이트 레진 (2a)을 디클로로메탄(5 ㎖) 용액에 넣고 흔들고 트리플루오로아세트산(TFA) (1 ㎖)을 가한 후, 실온에서 4시간동안 흔들었다. 반응 종료 후, 반응혼합물을 여과하고 여과물을 CH2Cl2와 MeOH로 반복 세척하고 여과액을 합하여 농축하였다. 농축된 혼합물에 에틸아세테이트(3 ㎖)를 가한 후 음이온 교환 수지 레진(SAX resin; strong anion exchange resin)에 여과시키고 에틸아세테이트로 반복 세척하여 잔여 트리플루오로아세트산을 제거하였다. 여과액을 감압농축한 후, 헥산/에틸아세테이트 (4/1, v/v)의 혼합용매하에서 실리카겔상의 컬럼 크로마토그래피로 분리 정제하여 화학식 (5a)로 표시되는 담황색 오일(17.7 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 81%)를 얻었다.The obtained N-methyl carbamate resin (2a) was added to a dichloromethane (5 mL) solution, shaken and trifluoroacetic acid (TFA) (1 mL) was added, followed by shaking at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered, the filtrate was washed repeatedly with CH 2 Cl 2 and MeOH, and the filtrates were combined and concentrated. Ethyl acetate (3 ml) was added to the concentrated mixture, which was then filtered through SAX resin (strong anion exchange resin) and washed repeatedly with ethyl acetate to remove residual trifluoroacetic acid. The filtrate was concentrated under reduced pressure, and then purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (4/1, v / v ) to give a pale yellow oil (17.7 mg, resin 1) represented by the formula (5a); yield = 81%) from a loading capacity of 0.55 mmol / g.
1H NMR(300 MHz, CDCl3) δ(PPM) 6.67 (d, 1H, J=8.5Hz), 6.45(dd, 1H, J =8.5 Hz, J= 2.7), 6.33(d, 1H, J=2.7 Hz), 6.27(d, 1H, J=9.7 Hz), 5.62 (d, 1H, J=9.7 Hz), 2.80(s, 3H), 1.40(s, 6H); HRMS 189.1157 1 H NMR (300 MHz, CDCl 3) δ (PPM) 6.67 (d, 1H, J = 8.5Hz), 6.45 (dd, 1H, J = 8.5 Hz, J = 2.7), 6.33 (d, 1H, J = 2.7 Hz), 6.27 (d, 1H, J = 9.7 Hz), 5.62 (d, 1H, J = 9.7 Hz), 2.80 (s, 3H), 1.40 (s, 6H); HRMS 189.1157
I-2) 올레핀 레진 1의 N-에틸 치환 반응 및 탈리반응I-2) N-ethyl Substitution and Desorption of Olefin Resin 1
화학식 (1)로 표시되는 벤조피란 형태의 카바메이트 레진(200.00 ㎎, 0.11 mmol)을 디메틸슬폭사이드(DMSO) (3 ㎖)에 넣고 상온에서 10분간 흔들고, 테트라히드로퓨란(THF)에 녹아 있는 1 몰 농도의 리튬 t-부톡시드(LiOtBu) (0.33 ㎖, 0.33 mmol)를 가한 후, 같은 온도에서 20분간 흔들어 혼합한 다음, 요오드에탄(EtI) (0.026 ㎖, 0.33 mmol)를 가한 후 35 ℃에서 15시간동안 흔들어 혼합하였다. 반응종료 후, 반응혼합물을 여과하고 DMF, MC, MC/MeOH, MeOH로 반복 세척하여 화학식 (2b)로 표시되는 담갈색 고체인 N-메틸 카바메이트 레진(205.3 ㎎)을 얻었다. (ATR-FTIR 분석결과; N-methylation carbamate: 1700 ㎝-1)Carbamate resin (200.00 mg, 0.11 mmol) in the form of benzopyran represented by the formula (1) was added to dimethylsulfoxide (DMSO) (3 ml), shaken at room temperature for 10 minutes, and dissolved in tetrahydrofuran (THF). Lithium t -butoxide (LiO t Bu) (0.33 mL, 0.33 mmol) was added at a molar concentration, followed by mixing for 20 minutes at the same temperature, followed by addition of iodine ethane (EtI) (0.026 mL, 0.33 mmol), followed by 35 Shake and mix for 15 h. After completion of the reaction, the reaction mixture was filtered and washed repeatedly with DMF, MC, MC / MeOH, MeOH to obtain N-methyl carbamate resin (205.3 mg) as a pale brown solid represented by the formula (2b). (ATR-FTIR Analysis; N-methylation carbamate: 1700 cm -1 )
수득된 N-메틸 카바메이트 레진 (2b)을 디클로로메탄(5 ㎖) 용액에 넣고 흔들고 트리플루오로아세트산(TFA) (1 ㎖)을 가한 후, 실온에서 4시간동안 흔들었다. 반응 종료 후, 반응혼합물을 여과하고 여과물을 CH2Cl2와 MeOH로 반복 세척하고 여과액을 합하여 농축하였다. 농축된 혼합물에 에틸아세테이트(3 ㎖)를 가한 후 음이온 교환 수지 레진(SAX resin; strong anion exchange resin)에 여과시키고 에틸아세테이트로 반복 세척하여 잔여 트리플루오로아세트산을 제거하였다. 여과액을 감압농축한 후, 헥산/에틸아세테이트(4/1, v/v)의 혼합용매하에서 실리카겔상의 컬럼 크로마토그래피로 분리 정제하여 화학식 (5b)로 표시되는 담황색 오일 (19.5 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 84%)를 얻었다.The obtained N-methyl carbamate resin (2b) was added to a dichloromethane (5 mL) solution, shaken, trifluoroacetic acid (TFA) (1 mL) was added, and then shaken at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered, the filtrate was washed repeatedly with CH 2 Cl 2 and MeOH, and the filtrates were combined and concentrated. Ethyl acetate (3 ml) was added to the concentrated mixture, which was then filtered through SAX resin (strong anion exchange resin) and washed repeatedly with ethyl acetate to remove residual trifluoroacetic acid. The filtrate was concentrated under reduced pressure, and then purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (4/1, v / v ) to give a pale yellow oil (19.5 mg, Resin 1; yield = 84%) from loading capacity of 0.55 mmol / g.
HRMS 203.2867HRMS 203.2867
I-3) 올레핀 레진 1의 N-2-프로필 치환 반응 및 탈리반응I-3) N-2-propyl Substitution and Desorption of Olefin Resin 1
화학식 (1)로 표시되는 벤조피란 형태의 카바메이트 레진(200.00 ㎎, 0.11 mmol)을 디메틸슬폭사이드(DMSO) (3 ㎖)에 넣고 상온에서 10분간 흔들고, 테트라히드로퓨란(THF)에 녹아 있는 1 몰 농도의 리튬 t-부톡시드(LiOtBu) (0.33 ㎖, 0.33 mmol)를 가한 후, 같은 온도에서 20분간 흔들어 혼합하였다. 2-요오드프로판(2-ProI) (0.033 ㎖, 0.33 mmol)를 가한 후 35 ℃에서 15시간동안 흔들어 혼합하였다. 반응종료 후, 반응혼합물을 여과하고 DMF, MC, MC/MeOH, MeOH로 반복 세척하여 화학식 (2c)로 표시되는 담갈색 고체인 N-이소프로필 카바메이트 레진 (204.5 ㎎)을 얻었다. (ATR-FTIR 분석결과; N-methylation carbamate: 1700 ㎝-1)Carbamate resin (200.00 mg, 0.11 mmol) in the form of benzopyran represented by the formula (1) was added to dimethylsulfoxide (DMSO) (3 ml), shaken at room temperature for 10 minutes, and dissolved in tetrahydrofuran (THF). Molar lithium t -butoxide (LiO t Bu) (0.33 mL, 0.33 mmol) was added, followed by mixing for 20 minutes at the same temperature. 2-Iopropane (2-ProI) (0.033 mL, 0.33 mmol) was added and stirred at 35 ° C. for 15 hours to mix. After completion of the reaction, the reaction mixture was filtered and washed repeatedly with DMF, MC, MC / MeOH, MeOH to obtain N-isopropyl carbamate resin (204.5 mg) as a pale brown solid represented by the formula (2c). (ATR-FTIR Analysis; N-methylation carbamate: 1700 cm -1 )
수득된 N-이소프로필 카바메이트 레진 (2c)을 디클로로메탄(5 ㎖) 용액에 넣고 흔들고 트리플루오로아세트산(TFA) (1 ㎖)을 가한 후, 실온에서 4시간동안 흔들었다. 반응 종료 후, 반응혼합물을 여과하고 여과물을 CH2Cl2와 MeOH로 반복 세척하고 여과액을 합하여 농축하였다. 농축된 혼합물에 에틸아세테이트(3 ㎖) 를 가한 후 음이온 교환 수지 레진(SAX resin; strong anion exchange resin)에 여과시키고 에틸아세테이트로 반복 세척하여 잔여 트리플루오로아세트산을 제거하였다. 여과액을 감압농축한 후, 헥산/에틸아세테이트(4/1, v/v)의 혼합용매하에서 실리카겔상의 컬럼 크로마토그래피로 분리 정제하여 화학식 (5c)로 표시되는 담황색 오일(19.4 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 79%)를 얻었다.The obtained N-isopropyl carbamate resin (2c) was added to a dichloromethane (5 mL) solution, shaken and trifluoroacetic acid (TFA) (1 mL) was added, followed by shaking at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered, the filtrate was washed repeatedly with CH 2 Cl 2 and MeOH, and the filtrates were combined and concentrated. Ethyl acetate (3 ml) was added to the concentrated mixture, which was then filtered through SAX resin (strong anion exchange resin) and washed repeatedly with ethyl acetate to remove residual trifluoroacetic acid. The filtrate was concentrated under reduced pressure, and then purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (4/1, v / v ) to give a pale yellow oil (19.4 mg, Resin 1; yield = 79%) from a loading capacity of 0.55 mmol / g.
HRMS 217.3134HRMS 217.3134
I-4) 벤조피란 레진 1의 N-부틸 치환 반응 및 탈리반응I-4) N-butyl Substitution and Desorption of Benzopyran Resin 1
화학식 (1)로 표시되는 벤조피란 형태의 카바메이트 레진(200.00 ㎎, 0.11 mmol)을 디메틸슬폭사이드(DMSO) (3 ㎖)에 넣고 상온에서 10분간 흔들고, 테트라히드로퓨란(THF)에 녹아 있는 1 몰 농도의 리튬 t-부톡시드(LiOtBu) (0.33 ㎖, 0.33 mmol)를 가한 후, 같은 온도에서 20분간 흔들어 혼합한 다음, 요오드부탄(BuI) (0.038 ㎖, 0.33 mmol)를 가한 후 35 ℃에서 15시간동안 흔들어 혼합하였다. 반응종료 후, 반응혼합물을 여과하고 DMF, MC, MC/MeOH, MeOH로 반복 세척하여 화학식 (2d)로 표시되는 담갈색 고체인 N-부틸 카바메이트 레진(203.9 ㎎)을 얻었다. (ATR-FTIR 분석결과; N-methylation carbamate: 1700 ㎝-1)Carbamate resin (200.00 mg, 0.11 mmol) in the form of benzopyran represented by the formula (1) was added to dimethylsulfoxide (DMSO) (3 ml), shaken at room temperature for 10 minutes, and dissolved in tetrahydrofuran (THF). Lithium t -butoxide (LiO t Bu) (0.33 mL, 0.33 mmol) was added at a molar concentration, followed by mixing for 20 minutes at the same temperature, followed by addition of iobutane (BuI) (0.038 mL, 0.33 mmol), followed by 35 Shake and mix for 15 h. After completion of the reaction, the reaction mixture was filtered and washed repeatedly with DMF, MC, MC / MeOH, MeOH to obtain N-butyl carbamate resin (203.9 mg) as a pale brown solid represented by the formula (2d). (ATR-FTIR Analysis; N-methylation carbamate: 1700 cm -1 )
수득된 N-부틸 카바메이트 레진 (2d)을 디클로로메탄(5 ㎖) 용액에 넣고 흔들고 트리플루오로아세트산(TFA) (1 ㎖)을 가한 후, 실온에서 4시간동안 흔들었다. 반응 종료 후, 반응혼합물을 여과하고 여과물을 CH2Cl2와 MeOH로 반복 세척하고 여과액을 합하여 농축하였다. 농축된 혼합물에 에틸아세테이트(3 ㎖)를 가한 후 음이온 교환 수지 레진(SAX resin; strong anion exchange resin)에 여과시키고 에틸아세테이트로 반복 세척하여 잔여 트리플루오로아세트산을 제거하였다. 여과액을 감압농축한 후, 헥산/에틸아세테이트 (4/1, v/v)의 혼합용매하에서 실리카겔상의 컬럼 크로마토그래피로 분리 정제하여 화학식 (5d)로 표시되는 담황색 오일 (20.7 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 80%)를 얻었다.The obtained N-butyl carbamate resin (2d) was added to a dichloromethane (5 mL) solution, shaken and trifluoroacetic acid (TFA) (1 mL) was added, followed by shaking at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered, the filtrate was washed repeatedly with CH 2 Cl 2 and MeOH, and the filtrates were combined and concentrated. Ethyl acetate (3 ml) was added to the concentrated mixture, which was then filtered through SAX resin (strong anion exchange resin) and washed repeatedly with ethyl acetate to remove residual trifluoroacetic acid. The filtrate was concentrated under reduced pressure, and then purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (4/1, v / v ) to give a pale yellow oil (20.7 mg, resin 1; yield = 80%) from loading capacity of 0.55 mmol / g).
HRMS 231.3409 HRMS 231.3409
I-5) 벤조피란 레진 1의 N-펜틸 치환 반응 및 탈리반응 I-5) N-pentyl Substitution and Desorption of Benzopyran Resin 1
화학식 (1)로 표시되는 벤조피란 형태의 카바메이트 레진(200.00 ㎎, 0.11 mmol)을 디메틸슬폭사이드(DMSO) (3 ㎖)에 넣고 상온에서 10분간 흔들고, 테트라히드로퓨란(THF)에 녹아 있는 1 몰 농도의 리튬 t-부톡시드 (LiOtBu) (0.33 ㎖, 0.33 mmol)를 가한 후, 같은 온도에서 20분간 흔들어 혼합한 다음, 요오드펜탄(PenI) (0.043 ㎖, 0.33 mmol)를 가한 후 35 ℃에서 15시간동안 흔들어 혼합하였다. 반응종료 후, 반응혼합물을 여과하고 DMF, MC, MC/MeOH, MeOH로 반복 세척하여 화학식 (2e)로 표시되는 담갈색 고체인 N-펜틸 카바메이트 레진 (203.9 ㎎)을 얻었다. (ATR-FTIR 분석결과; N-methylation carbamate: 1700 ㎝-1)Carbamate resin (200.00 mg, 0.11 mmol) in the form of benzopyran represented by the formula (1) was added to dimethylsulfoxide (DMSO) (3 ml), shaken at room temperature for 10 minutes, and dissolved in tetrahydrofuran (THF). Lithium t -butoxide (LiO t Bu) (0.33 mL, 0.33 mmol) was added at a molar concentration, followed by mixing for 20 minutes at the same temperature, followed by addition of pentane pentane (PenI) (0.043 mL, 0.33 mmol), followed by 35 Shake and mix for 15 h. After completion of the reaction, the reaction mixture was filtered and washed repeatedly with DMF, MC, MC / MeOH, MeOH to obtain N-pentyl carbamate resin (203.9 mg) as a pale brown solid represented by the formula (2e). (ATR-FTIR Analysis; N-methylation carbamate: 1700 cm -1 )
수득된 N-펜틸 카바메이트 레진 (2e)을 디클로로메탄(5 ㎖) 용액에 넣고 흔들고 트리플루오로아세트산(TFA) (1 ㎖)을 가한 후, 실온에서 4시간동안 흔들었다. 반응 종료 후, 반응혼합물을 여과하고 여과물을 CH2Cl2와 MeOH로 반복 세척하고 여과액을 합하여 농축하였다. 농축된 혼합물에 에틸아세테이트(3 ㎖)를 가한 후 음이온 교환 수지 레진(SAX resin; strong anion exchange resin)에 여과시키고 에틸아세테이트로 반복 세척하여 잔여 트리플루오로아세트산을 제거하였다. 여과액을 감압농축한 후, 헥산/에틸아세테이트(4/1, v/v)의 혼합용매하에서 실리카겔상의 컬럼 크로마토그래피로 분리 정제하여 화학식 (5e)로 표시되는 담황색 오일(22.1 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 80%)를 얻었다.The obtained N-pentyl carbamate resin (2e) was added to a dichloromethane (5 mL) solution, shaken, trifluoroacetic acid (TFA) (1 mL) was added, and then shaken at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered, the filtrate was washed repeatedly with CH 2 Cl 2 and MeOH, and the filtrates were combined and concentrated. Ethyl acetate (3 ml) was added to the concentrated mixture, which was then filtered through SAX resin (strong anion exchange resin) and washed repeatedly with ethyl acetate to remove residual trifluoroacetic acid. The filtrate was concentrated under reduced pressure, and then purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (4/1, v / v ) to give a pale yellow oil (22.1 mg, resin 1; yield = 80%) from loading capacity of 0.55 mmol / g).
1H NMR(300 MHz, CDCl3) δ(PPM) 6.64 (d, 1H, J=8.5 Hz), 6.43(dd, 1H, J =8.5 Hz, J=2.8 Hz), 6.31(d, 1H, J=2.8 Hz), 6.26(d, 1H, J=9.7 Hz), 5.61 (d, 1H, J=9.7 Hz), 3.04(t, 2H, 7.1Hz), 1.60 (m, 2H), 1.39∼1.34(m, 10H), 0.91(t, 3H, J=6.7 Hz); 13C (75 MHz) δ145.23, 142.08, 131.56, 122.61, 121.91, 116.80, 114.23, 111.29, 75.47, 45.40, 29.32, 29.17, 27.55, 22.49, 14.02; HRMS 245.1780 1 H NMR (300 MHz, CDCl 3 ) δ (PPM) 6.64 (d, 1H, J = 8.5 Hz), 6.43 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.31 (d, 1H, J = 2.8 Hz), 6.26 (d, 1H, J = 9.7 Hz), 5.61 (d, 1H, J = 9.7 Hz), 3.04 (t, 2H, 7.1 Hz), 1.60 (m, 2H), 1.39-1.34 ( m, 10H), 0.91 (t, 3H, J = 6.7 Hz); 13 C (75 MHz) δ 145.23, 142.08, 131.56, 122.61, 121.91, 116.80, 114.23, 111.29, 75.47, 45.40, 29.32, 29.17, 27.55, 22.49, 14.02; HRMS 245.1780
I-6) 벤조피란 레진 1의 N-벤질 치환 반응 및 탈리반응 I-6) N-benzyl Substitution and Desorption of Benzopyran Resin 1
화학식 (1)로 표시되는 벤조피란 형태의 카바메이트 레진(200.00 ㎎, 0.11 mmol)을 디메틸슬폭사이드(DMSO) (3 ㎖)에 넣고 상온에서 10분간 흔들고, 테트라히드로퓨란(THF)에 녹아 있는 1 몰 농도의 리튬 t-부톡시드 (LiOtBu) (0.33 ㎖, 0.33 mmol)를 가한 후, 같은 온도에서 20분간 흔들어 혼합한 다음, 벤질 브로마이드(BnBr) (0.039 ㎖, 0.33 mmol)를 가한 후 35 ℃에서 15시간동안 흔들어 혼합하였다. 반응종료 후, 반응혼합물을 여과하고 DMF, MC, MC/MeOH, MeOH로 반복 세척하여 화학식 (2f)로 표시되는 담갈색 고체인 N-벤질 카바메이트 레진(203.9 ㎎)을 얻었다. (ATR-FTIR 분석결과; N-methylation carbamate: 1700 ㎝-1)Carbamate resin (200.00 mg, 0.11 mmol) in the form of benzopyran represented by the formula (1) was added to dimethylsulfoxide (DMSO) (3 ml), shaken at room temperature for 10 minutes, and dissolved in tetrahydrofuran (THF). Molar lithium t -butoxide (LiO t Bu) (0.33 mL, 0.33 mmol) was added, followed by mixing for 20 minutes at the same temperature, followed by addition of benzyl bromide (BnBr) (0.039 mL, 0.33 mmol), followed by 35 Shake and mix for 15 h. After completion of the reaction, the reaction mixture was filtered and washed repeatedly with DMF, MC, MC / MeOH, MeOH to obtain N-benzyl carbamate resin (203.9 mg) as a pale brown solid represented by the formula (2f). (ATR-FTIR Analysis; N-methylation carbamate: 1700 cm -1 )
수득된 N-벤질 카바메이트 레진 (2f)을 디클로로메탄(5 ㎖) 용액에 넣고 흔들고 트리플루오로아세트산(TFA) (1 ㎖)을 가한 후, 실온에서 4시간동안 흔들었다. 반응 종료 후, 반응혼합물을 여과하고 여과물을 CH2Cl2와 MeOH로 반복 세척하고 여과액을 합하여 농축하였다. 농축된 혼합물에 에틸아세테이트 (3 ㎖)를 가한 후 음이온 교환 수지 레진(SAX resin; strong anion exchange resin)에 여과시키고 에 틸아세테이트로 반복 세척하여 잔여 트리플루오로아세트산을 제거하였다. 여과액을 감압농축한 후, 헥산/에틸아세테이트 (4/1, v/v)의 혼합용매하에서 실리카겔상의 컬럼 크로마토그래피로 분리 정제하여 화학식 (5f)로 표시되는 담황색 오일(25.0 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 85%)를 얻었다.The obtained N-benzyl carbamate resin (2f) was added to a dichloromethane (5 mL) solution, shaken, trifluoroacetic acid (TFA) (1 mL) was added, and then shaken at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered, the filtrate was washed repeatedly with CH 2 Cl 2 and MeOH, and the filtrates were combined and concentrated. Ethyl acetate (3 ml) was added to the concentrated mixture, which was then filtered through SAX resin (strong anion exchange resin) and washed repeatedly with ethyl acetate to remove residual trifluoroacetic acid. The filtrate was concentrated under reduced pressure, and then purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (4/1, v / v ) to give a pale yellow oil (25.0 mg, resin 1; yield = 85% from a loading capacity of 0.55 mmol / g).
1H NMR(300 MHz, CDCl3) δ(PPM) 7.39∼7.26(m, 5H), 6.64(d, 1H, J=8.5 Hz), 6.45(dd, 1H, J=8.5 Hz, J=2.8Hz), 6.33(d, 1H, J=2.8 Hz), 6.24(d, 1H, J=9.7 Hz), 5.60(d, 1H, J=9.7Hz), 4.27(s, 2H), 1.39(s, 6H); 13C(75 MHz) δ145.17, 142.19, 139.52, 131.59, 128.55, 127.62, 127.17, 122.58, 121.90, 116.80, 113.88, 111.00, 75.46, 49.34, 27.55; HRMS 265.1467 1 H NMR (300 MHz, CDCl 3 ) δ (PPM) 7.39-7.26 (m, 5H), 6.64 (d, 1H, J = 8.5 Hz), 6.45 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz ), 6.33 (d, 1H, J = 2.8 Hz), 6.24 (d, 1H, J = 9.7 Hz), 5.60 (d, 1H, J = 9.7 Hz), 4.27 (s, 2H), 1.39 (s, 6H) ); 13 C (75 MHz) δ 145.17, 142.19, 139.52, 131.59, 128.55, 127.62, 127.17, 122.58, 121.90, 116.80, 113.88, 111.00, 75.46, 49.34, 27.55; HRMS 265.1467
I-7) 벤조피란 레진 1의 N-(2-메틸)벤질치환 반응(5g) 및 탈리반응 I-7) N- (2-methyl) benzyl Substitution Reaction (5g) and Desorption of Benzopyran Resin 1
상기의 동일한 조건으로 화학식 (5g)로 표시되는 담황색 오일(24.2 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 78%)를 얻었다.Under the same conditions, a pale yellow oil (24.2 mg, resin 1; yield = 78% from loading capacity of 0.55 mmol / g) represented by the formula (5 g) was obtained.
1H NMR(300 MHz, CDCl3) δ(PPM) 7.33(s, 1H), 7.21∼7.17(m, 3H), 6.66(d, 1H, J=8.5 Hz), 6.46(dd, 1H, J=8.5 Hz, J=2.8 Hz), 6.34(d, 1H, J=2.8 Hz), 6.25(d, 1H, J=9.7Hz), 5.61(d, 1H, J=9.7Hz), 4.21(s, 2H), 2.37(s, 3H), 1.40(s, 6H); HRMS 279.1623 1 H NMR (300 MHz, CDCl 3 ) δ (PPM) 7.33 (s, 1H), 7.21 to 7.17 (m, 3H), 6.66 (d, 1H, J = 8.5 Hz), 6.46 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz, 6.34 (d, 1H, J = 2.8 Hz), 6.25 (d, 1H, J = 9.7 Hz), 5.61 (d, 1H, J = 9.7 Hz), 4.21 (s, 2H ), 2.37 (s, 3 H), 1.40 (s, 6 H); HRMS 279.1623
I-8) 벤조피란 레진 1의 N-(4-메틸)벤질치환 반응(5h) 및 탈리반응 I-8) N- (4-methyl) benzyl substitution reaction of benzopyran resin 1 (5h) and desorption reaction
상기의 동일한 조건으로 화학식 (5h)로 표시되는 담황색 오일(27.3 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 87%)를 얻었다.Under the same conditions, a pale yellow oil (27.3 mg, resin 1; yield = 87% from loading capacity of 0.55 mmol / g) represented by the formula (5h) was obtained.
1H NMR(300 MHz, CDCl3) δ(PPM) 7.25(dAB, 2H, J=8.0Hz), 7.14(d AB, 1H, J =8.0Hz), 6.64(d, 1H, J=8.4 Hz), 6.47(dd, 1H, J=8.6 Hz, J=2.7Hz), 6.36(d, 1H, J=2.7 Hz), 6.24(d, 1H, J=9.5Hz), 5.60(d, 1H, J=9.7Hz), 4.21(s, 2H), 2.34(s, 3H), 1.40(s, 6H); 13C(75 MHz) δ145.69, 141.30, 136.99, 135.79, 131.61, 129.24, 127.83, 122.52, 121.92, 116.83, 114.57, 111.69; HRMS 279.1623 1 H NMR (300 MHz, CDCl 3 ) δ (PPM) 7.25 (d AB , 2H, J = 8.0 Hz), 7.14 (d AB , 1H, J = 8.0 Hz), 6.64 (d, 1H, J = 8.4 Hz ), 6.47 (dd, 1H, J = 8.6 Hz, J = 2.7 Hz), 6.36 (d, 1H, J = 2.7 Hz), 6.24 (d, 1H, J = 9.5 Hz), 5.60 (d, 1H, J = 9.7 Hz), 4.21 (s, 2H), 2.34 (s, 3H), 1.40 (s, 6H); 13 C (75 MHz) δ 145.69, 141.30, 136.99, 135.79, 131.61, 129.24, 127.83, 122.52, 121.92, 116.83, 114.57, 111.69; HRMS 279.1623
I-9) 벤조피란 레진 1의 N-(4-I-9) N- (4- of Benzopyran Resin 1 tt -부틸)벤질치환 반응(5i) 및 탈리반응 -Butyl) benzyl substitution reaction (5i) and desorption reaction
상기의 동일한 조건으로 화학식 (5i)로 표시되는 담황색 오일(28.7 ㎎, 레 진 1; loading capacity 0.55 mmol/g로부터 yield = 80%)를 얻었다.Under the same conditions, a pale yellow oil (28.7 mg, resin 1; yield = 80% from loading capacity of 0.55 mmol / g) represented by Chemical Formula (5i) was obtained.
1H NMR(300 MHz, CDCl3) δ(PPM) 7.38∼7.29 (m, 4H), 6.65(d, 1H, J=8.5Hz), 6.47(dd, 1H, 8.5 Hz, J=2.8Hz), 6.47(dd, 1H, J=8.5 Hz, J=2.8Hz), 6.36(d, 1H, J=2.8 Hz), 6.25(d, 1H, 9.7Hz), 5.61 (d, 1H, J=9.7Hz), 4.22(s, 2H), 1.40(s, 6H), 1.32(s, 9H); 13C(75 MHz) δ150.39, 145.84, 141.12, 135.63, 131.64, 127.75, 125.50, 122.51, 121.94, 116.85, 114.74, 111.84, 75.59, 49.66, 34.49, 31.33, 27.59; HRMS 321.2093 1 H NMR (300 MHz, CDCl 3 ) δ (PPM) 7.38-7.29 (m, 4H), 6.65 (d, 1H, J = 8.5 Hz), 6.47 (dd, 1H, 8.5 Hz, J = 2.8 Hz), 6.47 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.36 (d, 1H, J = 2.8 Hz), 6.25 (d, 1H, 9.7 Hz), 5.61 (d, 1H, J = 9.7 Hz) 4.22 (s, 2H), 1.40 (s, 6H), 1.32 (s, 9H); 13 C (75 MHz) δ 150.39, 145.84, 141.12, 135.63, 131.64, 127.75, 125.50, 122.51, 121.94, 116.85, 114.74, 111.84, 75.59, 49.66, 34.49, 31.33, 27.59; HRMS 321.2093
I-10) 벤조피란 레진 1의 N-(4-플루오로)벤질치환 반응(5I-10) N- (4-fluoro) benzyl substitution of benzopyran resin 1 (5 JJ ) 및 탈리반응 ) And desorption reaction
상기의 동일한 조건으로 화학식 (5j)로 표시되는 담황색 오일(26.4 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 83%)를 얻었다.Under the same conditions, a pale yellow oil (26.4 mg, resin 1; yield = 83% from loading capacity of 0.55 mmol / g) represented by the formula (5j) was obtained.
1H NMR(300 MHz, CDCl3) δ(PPM) 7.33∼7.30 (m, 2H), 7.02∼6.99 (m, 2H), 6.64(d, 1H, J=5.1 Hz), 6.45(dd, 1H, J=5.1 Hz, J=1.7 Hz), 6.34(d, 1H, J=1.7 Hz), 6.23(d, 1H, J=5.8Hz), 5.61 (d, 1H, J=5.8 Hz), 4.22(s, 2H), 1.39(s, 6H); 13C (75 MHz) δ163.03, 161.08, 145.61, 141.43, 134.87, 131.70, 129.22, 122.46, 121.95, 116.85, 115.45, 115.28, 114.29, 111.44, 75.56, 48.92, 27.57; HRMS 283.1375 1 H NMR (300 MHz, CDCl 3 ) δ (PPM) 7.33 to 7.30 (m, 2H), 7.02 to 6.99 (m, 2H), 6.64 (d, 1H, J = 5.1 Hz), 6.45 (dd, 1H, J = 5.1 Hz, J = 1.7 Hz), 6.34 (d, 1H, J = 1.7 Hz), 6.23 (d, 1H, J = 5.8Hz), 5.61 (d, 1H, J = 5.8 Hz), 4.22 (s , 2H), 1.39 (s, 6H); 13 C (75 MHz) δ 163.03, 161.08, 145.61, 141.43, 134.87, 131.70, 129.22, 122.46, 121.95, 116.85, 115.45, 115.28, 114.29, 111.44, 75.56, 48.92, 27.57; HRMS 283.1375
I-11) 벤조피란 레진 1의 N-(3-플로오로)벤질치환 반응(5k) 및 탈리반응 I-11) N- (3-fluoro) benzyl substitution reaction (5k) and desorption reaction of benzopyran resin 1
상기의 동일한 조건으로 화학식 (5k)로 표시되는 담황색 오일 (24.8 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 78%)를 얻었다.Under the same conditions, a pale yellow oil (24.8 mg, resin 1; yield = 78% from loading capacity of 0.55 mmol / g) represented by the formula (5k) was obtained.
1H NMR(300 MHz, CDCl3) δ(PPM) 6.64(d, 1H, J=8.5Hz), 6.43(dd, 1H, J =8.5 Hz, J=2.8), 6.31(d, 1H, J=2.8 Hz), 6.26(d, 1H, J=9.7 Hz), 5.61(d, 1H, J=9.7 Hz), 3.04(t, 2H, 7.1Hz), 1.60(m, 2H), 1.39∼1.34(m, 10H), 0.91(t, 3H, J =6.7 Hz); HRMS 283.1372 1 H NMR (300 MHz, CDCl 3) δ (PPM) 6.64 (d, 1H, J = 8.5Hz), 6.43 (dd, 1H, J = 8.5 Hz, J = 2.8), 6.31 (d, 1H, J = 2.8 Hz), 6.26 (d, 1H, J = 9.7 Hz), 5.61 (d, 1H, J = 9.7 Hz), 3.04 (t, 2H, 7.1 Hz), 1.60 (m, 2H), 1.39-1.34 (m , 10H), 0.91 (t, 3H, J = 6.7 Hz); HRMS 283.1372
I-12) 벤조피란 레진 1의 N-(2,5-디메틸)벤질치환 반응(5l) 및 탈리반응 I-12) N- (2,5-dimethyl) benzyl substitution reaction (5l) and desorption reaction of benzopyran resin 1
상기의 동일한 조건으로 화학식 (5l)로 표시되는 담황색 오일(25.1 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 77%)를 얻었다.Under the same conditions, a pale yellow oil (25.1 mg, resin 1; yield = 77% from loading capacity of 0.55 mmol / g) represented by Chemical Formula (5l) was obtained.
1H NMR(300 MHz, CDCl3) δ(PPM) 7.10 (s, 1H), 6.97 (s, 2H), 6.86(dd, 1H, J =5.1 Hz, J=1.5Hz), 6.79(d, 1H, J=1.5 Hz), 6.67 (d, 1H, J=5.1 Hz), 6.22(d, 1H, J=5.9Hz), 5.64 (d, 1H, J=5.9 Hz), 4.21(s, 2H), 2.22(s, 3H), 2.11(s, 3H), 1.40(s, 6H); HRMS 293.1789 1 H NMR (300 MHz, CDCl 3 ) δ (PPM) 7.10 (s, 1H), 6.97 (s, 2H), 6.86 (dd, 1H, J = 5.1 Hz, J = 1.5 Hz), 6.79 (d, 1H , J = 1.5 Hz), 6.67 (d, 1H, J = 5.1 Hz), 6.22 (d, 1H, J = 5.9 Hz), 5.64 (d, 1H, J = 5.9 Hz), 4.21 (s, 2H), 2.22 (s, 3H), 2.11 (s, 3H), 1.40 (s, 6H); HRMS 293.1789
I-13) 벤조피란 레진 1의 N-(2-플로오로-4-브로모)벤질치환 반응(5m) 및 탈리반응 I-13) N- (2-fluoro-4-bromo) benzyl substitution reaction (5m) and desorption reaction of benzopyran resin 1
상기의 동일한 조건으로 화학식 (5m)로 표시되는 담황색 오일(31.4 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 79%)를 얻었다.Under the same conditions, a pale yellow oil (31.4 mg, resin 1; yield = 79% from loading capacity of 0.55 mmol / g) represented by the formula (5m) was obtained.
1H NMR(300 MHz, CDCl3) δ(PPM) 7.28∼7.21(m, 3H), 6.63(d, 1H, J=5.4 Hz), 6.45(dd, 1H, J=5.4Hz, J=1.7 Hz), 6.34(d, 1H, J=1.7 Hz), 6.22(d, 1H, J=5.8 Hz), 5.61(d, 1H, J=5.8Hz), 4.29(s, 2H), 1.39(s, 6H); HRMS 361.0478 1 H NMR (300 MHz, CDCl 3 ) δ (PPM) 7.28 to 7.21 (m, 3H), 6.63 (d, 1H, J = 5.4 Hz), 6.45 (dd, 1H, J = 5.4 Hz, J = 1.7 Hz ), 6.34 (d, 1H, J = 1.7 Hz), 6.22 (d, 1H, J = 5.8 Hz), 5.61 (d, 1H, J = 5.8 Hz), 4.29 (s, 2H), 1.39 (s, 6H) ); HRMS 361.0478
I-14) 벤조피란 레진 1의 N-알킬치환 반응(5n) 및 탈리반응 I-14) N-alkyl Substitution Reaction (5n) and Desorption Reaction of Benzopyran Resin 1
상기의 동일한 조건으로 화학식 (5n)으로 표시되는 담황색 오일(28.2 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 82%)를 얻었다.Under the same conditions, a pale yellow oil (28.2 mg, resin 1; yield = 82% from loading capacity of 0.55 mmol / g) represented by the formula (5n) was obtained.
1H NMR(300 MHz, CDCl3) δ(PPM) 7.82∼7.79 (m, 4H), 7.48∼7.45(m, 3H), 6.66(d, 1H, J=5.1 Hz), 6.54(dd, 1H, J=5.1 Hz, J=1.7Hz), 6.46(d, 1H, J=1.7 Hz), 6.23(d, 1H, J=5.9Hz), 5.61(d, 1H, J=5.9Hz), 4.41(s, 2H), 1.41(s, 6H); HRMS 315.1619 1 H NMR (300 MHz, CDCl 3 ) δ (PPM) 7.82-7.79 (m, 4H), 7.48-7.45 (m, 3H), 6.66 (d, 1H, J = 5.1 Hz), 6.54 (dd, 1H, J = 5.1 Hz, J = 1.7 Hz), 6.46 (d, 1H, J = 1.7 Hz), 6.23 (d, 1H, J = 5.9 Hz), 5.61 (d, 1H, J = 5.9 Hz), 4.41 (s , 2H), 1.41 (s, 6H); HRMS 315.1619
I-15) 벤조피란 레진 1의 N-페에틸치환 반응(5o) 및 탈리반응 I-15) N-Phenyl Substitution Reaction (5o) and Desorption Reaction of Benzopyran Resin 1
상기의 동일한 조건으로 화학식 (5o)로 표시되는 담황색 오일 (26.2 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 85%)를 얻었다.Under the same conditions, a pale yellow oil (26.2 mg, resin 1; yield = 85% from loading capacity of 0.55 mmol / g) represented by the formula (5o) was obtained.
1H NMR(300 MHz, CDCl3) δ(PPM) 7.37∼7.22 (m, 5H), 6.66(d, 1H, J=5.1 Hz), 6.61(d, 1H, J=9.5 Hz), 6.50(dd, 1H, J=5.1 Hz, J=1.7Hz), 6.38(d, 1H, J=1.7 Hz), 6.33(dd, 1H, J=9.5Hz, J=3.5Hz), 6.26(d, 1H, J=5.9Hz), 5.61(d, 1H, J=5.9Hz), 3.87(dd, 1H, J=3.5Hz, J=0.9Hz), 1.40(s, 6H); 13C (75 MHz) δ145.40, 141.83, 136.86, 131.60, 131.57, 128.53, 127.48, 127.13, 126.30, 122.58, 121.93, 116.82, 114.36, 111.46, 75.51, 47.41, 27.57; HRMS 279.1623 1 H NMR (300 MHz, CDCl 3 ) δ (PPM) 7.37 to 7.22 (m, 5H), 6.66 (d, 1H, J = 5.1 Hz), 6.61 (d, 1H, J = 9.5 Hz), 6.50 (dd , 1H, J = 5.1 Hz, J = 1.7 Hz, 6.38 (d, 1H, J = 1.7 Hz), 6.33 (dd, 1H, J = 9.5 Hz, J = 3.5 Hz), 6.26 (d, 1H, J = 5.9 Hz), 5.61 (d, 1H, J = 5.9 Hz), 3.87 (dd, 1H, J = 3.5 Hz, J = 0.9 Hz), 1.40 (s, 6H); 13 C (75 MHz) δ 145.40, 141.83, 136.86, 131.60, 131.57, 128.53, 127.48, 127.13, 126.30, 122.58, 121.93, 116.82, 114.36, 111.46, 75.51, 47.41, 27.57; HRMS 279.1623
I-16) 벤조피란 레진 1의 N-(4-메톡시)벤질치환 반응(5p) 및 탈리반응 I-16) N- (4-methoxy) benzyl substitution reaction of benzopyran resin 1 (5p) and desorption reaction
상기의 동일한 조건으로 화학식 (5p)로 표시되는 담황색 오일 (25.0 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 77%)를 얻었다.Under the same conditions, a pale yellow oil (25.0 mg, resin 1; yield = 77% from loading capacity of 0.55 mmol / g) represented by the formula (5p) was obtained.
HRMS 295.3845HRMS 295.3845
I-17) 벤조피란 레진 1의 N-(4-트리플루오로메틸)벤질치환 반응(5q) 및 탈리반응 I-17) N- (4-trifluoromethyl) benzyl substitution reaction (5q) and desorption reaction of benzopyran resin 1
상기의 동일한 조건으로 화학식 (5q)로 표시되는 담황색 오일 (30.5 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 81%)를 얻었다.Under the same conditions, a pale yellow oil (30.5 mg, resin 1; yield = 81% from loading capacity of 0.55 mmol / g) represented by the formula (5q) was obtained.
HRMS 333.3568HRMS 333.3568
I-18) 벤조피란 레진 1의 N-(2,4,6-트리메틸)벤질치환 반응(5r) 및 탈리반응I-18) N- (2,4,6-trimethyl) benzyl substitution (5r) and desorption reaction of benzopyran resin 1
상기의 동일한 조건으로 화학식 (5r)로 표시되는 담황색 오일 (26.3 ㎎, 레 진 1; loading capacity 0.55 mmol/g로부터 yield = 78%)를 얻었다.Under the same conditions, a pale yellow oil (26.3 mg, resin 1; yield = 78% from loading capacity of 0.55 mmol / g) represented by the formula (5r) was obtained.
HRMS 307.4397HRMS 307.4397
I-19) 벤조피란 레진 1의 N-알릴치환 반응(5s) 및 탈리반응I-19) N-allyl Substitution Reaction (5s) and Desorption Reaction of Benzopyran Resin 1
상기의 동일한 조건으로 화학식 (5s)로 표시되는 담황색 오일 (18.8 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 77%)를 얻었다.Under the same conditions, a pale yellow oil (18.8 mg, resin 1; yield = 77% from loading capacity of 0.55 mmol / g) represented by the formula (5s) was obtained.
1H NMR(300 MHz, CDCl3) δ(PPM) 6.65(d, 1H, J=5.1 Hz), 6.51(dd, 1H, J =5.1 Hz, J=1.7 Hz), 6.40(d, 1H, J=1.7Hz), 6.25(d, 1H, J=5.9 Hz), 5.95(m, 1H), 5.61(d, 1H, J=5.9Hz), 5.28(dd, 1H, J=10.2 Hz, J=0.9 Hz), 5.16(dd, 1H, J=6.0 Hz, J=0.9 Hz), 3.72(d, 2H, J=2.4 Hz), 1.40(s, 6H); 13C (75 MHz) δ145.96, 140.75, 134.91, 131.64, 122.47, 121.92, 116.96, 116.83, 115.00, 112.13, 75.61, 48.36, 27.61; HRMS 215.1319 1 H NMR (300 MHz, CDCl 3 ) δ (PPM) 6.65 (d, 1H, J = 5.1 Hz), 6.51 (dd, 1H, J = 5.1 Hz, J = 1.7 Hz), 6.40 (d, 1H, J = 1.7 Hz), 6.25 (d, 1H, J = 5.9 Hz), 5.95 (m, 1H), 5.61 (d, 1H, J = 5.9 Hz), 5.28 (dd, 1H, J = 10.2 Hz, J = 0.9 Hz), 5.16 (dd, 1H, J = 6.0 Hz, J = 0.9 Hz), 3.72 (d, 2H, J = 2.4 Hz), 1.40 (s, 6H); 13 C (75 MHz) δ 145.96, 140.75, 134.91, 131.64, 122.47, 121.92, 116.96, 116.83, 115.00, 112.13, 75.61, 48.36, 27.61; HRMS 215.1319
I-20) 벤조피란 레진 1의 N-프로파길치환 반응(5t) 및 탈리반응I-20) N-propargyl Substitution Reaction (5t) and Desorption Reaction of Benzopyran Resin 1
상기의 동일한 조건으로 화학식 (5t)로 표시되는 담황색 오일 (17.3 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 71%)를 얻었다.Under the same conditions, a pale yellow oil (17.3 mg, resin 1; yield = 71% from loading capacity of 0.55 mmol / g) represented by the formula (5t) was obtained.
1H NMR(300 MHz, CDCl3) δ(PPM) 6.68(d, 1H, J=5.1Hz), 6.50(dd, 1H, J =5.1Hz, J=1.7Hz), 6.38(d, 1H, J=1.7 Hz), 6.27(d, 1H, J=5.9 Hz), 5.62(d, 1H, J=5.9 Hz), 3.88(d, 2H, 1.5Hz), 2.21(t, 1H, 1.5), 1.40(s, 6H); HRMS 213.2815 1 H NMR (300 MHz, CDCl 3 ) δ (PPM) 6.68 (d, 1H, J = 5.1 Hz), 6.50 (dd, 1H, J = 5.1 Hz, J = 1.7 Hz), 6.38 (d, 1H, J = 1.7 Hz), 6.27 (d, 1H, J = 5.9 Hz), 5.62 (d, 1H, J = 5.9 Hz), 3.88 (d, 2H, 1.5 Hz), 2.21 (t, 1H, 1.5), 1.40 ( s, 6H); HRMS 213.2815
I-21) 벤조피란 레진 1의 N-신나밀치환 반응(5u) 및 탈리반응I-21) N-cinnamil substitution reaction (5u) and desorption reaction of benzopyran resin 1
상기의 동일한 조건으로 화학식 (5u)로 표시되는 담황색 오일 (23.6 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 73%)를 얻었다.Under the same conditions, a pale yellow oil (23.6 mg, resin 1; yield = 73% from loading capacity of 0.55 mmol / g) represented by the formula (5u) was obtained.
1H NMR(300 MHz, CDCl3) δ(PPM) 7.37∼7.22(m, 5H), 6.66(d, 1H, J=5.1 Hz), 6.61(d, 1H, J=9.5 Hz), 6.50(dd, 1H, J=5.1 Hz, J=1.7Hz), 6.38(d, 1H, J=1.7 Hz), 6.33(dd, 1H, J=9.5Hz, J=3.5Hz), 6.26(d, 1H, J=5.9Hz), 5.61(d, 1H, J=5.9Hz), 3.87(dd, 1H, J=3.5Hz, J=0.9Hz), 1.40(s, 6H); 13C (75 MHz) δ145.40, 141.83, 136.86, 131.60, 131.57, 128.53, 127.48, 127.13, 126.30, 122.58, 121.93, 116.82, 114.36, 111.46, 75.51, 47.41, 27.57; HRMS 291.3965 1 H NMR (300 MHz, CDCl 3 ) δ (PPM) 7.37 to 7.22 (m, 5H), 6.66 (d, 1H, J = 5.1 Hz), 6.61 (d, 1H, J = 9.5 Hz), 6.50 (dd , 1H, J = 5.1 Hz, J = 1.7 Hz, 6.38 (d, 1H, J = 1.7 Hz), 6.33 (dd, 1H, J = 9.5 Hz, J = 3.5 Hz), 6.26 (d, 1H, J = 5.9 Hz), 5.61 (d, 1H, J = 5.9 Hz), 3.87 (dd, 1H, J = 3.5 Hz, J = 0.9 Hz), 1.40 (s, 6H); 13 C (75 MHz) δ 145.40, 141.83, 136.86, 131.60, 131.57, 128.53, 127.48, 127.13, 126.30, 122.58, 121.93, 116.82, 114.36, 111.46, 75.51, 47.41, 27.57; HRMS 291.3965
실시예 Ⅱ: N-메틸치환된 올레핀 레진(2a)의 하이드록시 알콕시 부가반응 및 탈리반응 Example II Hydroxy Alkoxy Addition and Desorption of N-Methyl-Substituted Olefin Resins (2a)
Ⅱ-1) N-메틸치환된 올레핀 레진(2a)의 하이드록시 메톡시 부가반응 및 탈리반응II-1) Hydroxymethoxy Addition and Desorption Reaction of N-Methyl Substituted Olefin Resin (2a)
화학식 (2a)로 표시되는 N-메틸치환된 올레핀 레진(200.00 ㎎, 0.11 mmol)을 디클로로메탄(3 ㎖)과 메탄올(3 ㎖) 혼합용액에 넣고 30분간 흔들고, 메타-클로로과벤조산(m-CPBA) (81 ㎎, 0.55 mmol)을 상온에서 가한 다음, 35 ℃에서 15시간 흔들어 반응하였다. 반응종료 후, 반응혼합물을 여과하고 DMF, MC, MC/MeOH, MeOH로 반복 세척하여 화학식 (3-1)로 표시되는 옅은 노란색 고체인 레진(208.6 ㎎)을 얻었다. 수득된 레진 (3-1)을 디클로로메탄(5 ㎖) 용액에 넣고 흔들고 트리플루오로아세트산(TFA) (1 ㎖)을 가한 후, 실온에서 4시간동안 흔들었다. 반응 종료 후, 반응혼합물을 여과하고 여과물을 CH2Cl2와 MeOH로 반복 세척하고 여과액을 합하여 농축하였다. 농축된 혼합물에 에틸아세테이트(3 ㎖)를 가한 후 음이온 교환 수지 레진(SAX resin; strong anion exchange resin)에 여과시키고 에틸아세테이트로 반복 세척하여 잔여 트리플루오로아세트산을 제거하였다. 여과 액을 감압농축한 후, 헥산/에틸아세테이트(4/1, v/v)의 혼합용매하에서 실리카겔상의 컬럼 크로마토그래피로 분리 정제하여 화합물번호 (4-1)로 표시되는 담황색 오일 (16.3 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 63%)를 얻었다.N-methyl-substituted olefin resin (200.00 mg, 0.11 mmol) represented by the formula (2a) was added to a mixed solution of dichloromethane (3 ml) and methanol (3 ml) and shaken for 30 minutes, followed by meta-chloroperbenzoic acid ( m- CPBA). ) (81 mg, 0.55 mmol) was added at room temperature, followed by reaction at 35 ° C. for 15 hours. After completion of the reaction, the reaction mixture was filtered and washed repeatedly with DMF, MC, MC / MeOH, MeOH to give a resin (208.6 mg) as a pale yellow solid represented by the formula (3-1). The obtained resin (3-1) was added to a dichloromethane (5 mL) solution, shaken, trifluoroacetic acid (TFA) (1 mL) was added, and then shaken at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered, the filtrate was washed repeatedly with CH 2 Cl 2 and MeOH, and the filtrates were combined and concentrated. Ethyl acetate (3 ml) was added to the concentrated mixture, which was then filtered through SAX resin (strong anion exchange resin) and washed repeatedly with ethyl acetate to remove residual trifluoroacetic acid. The filtrate was concentrated under reduced pressure, and then purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (4/1, v / v ) to obtain a pale yellow oil (16.3 mg, Resin 1; yield = 63% from loading capacity 0.55 mmol / g) was obtained.
1H NMR(300 MHz, CDCl3) δ(PPM) 6.69(d, 1H, J=5.2Hz), 6.65(d, 1H, J =1.7Hz), 6.58(dd, 1H, J=5.2Hz, J=1.7Hz), 4.34(d, 1H, J=4.4 Hz), 3.84(d, 1H, J=4.4 Hz), 3.49(s, 3H), 2.82(s, 3H), 1.43(s, 3H), 1.26(s, 3H); 13C (75 MHz) δ145.49, 143.00,121.33, 117.84, 115.50, 111.70, 78.16, 71.99, 55.70, 31.90, 25.68, 20.04; M/S 237.30 1 H NMR (300 MHz, CDCl 3 ) δ (PPM) 6.69 (d, 1H, J = 5.2 Hz), 6.65 (d, 1H, J = 1.7 Hz), 6.58 (dd, 1H, J = 5.2 Hz, J = 1.7 Hz), 4.34 (d, 1H, J = 4.4 Hz), 3.84 (d, 1H, J = 4.4 Hz), 3.49 (s, 3H), 2.82 (s, 3H), 1.43 (s, 3H), 1.26 (s, 3 H); 13 C (75 MHz) δ 145.49, 143.00, 121.33, 117.84, 115.50, 111.70, 78.16, 71.99, 55.70, 31.90, 25.68, 20.04; M / S 237.30
Ⅱ-2) N-메틸치환된 올레핀 레진(2a)의 하이드록시 에톡시 부가반응 및 탈리반응II-2) Hydroxyethoxy Addition and Desorption of N-Methyl Substituted Olefin Resin (2a)
화학식 (2a)로 표시되는 N-메틸치환된 올레핀 레진(200.00 ㎎, 0.11 mmol)을 디클로로메탄(3 ㎖)과 에탄올(3 ㎖) 혼합용액에 넣고 30분간 흔들고, 메타-클로로과벤조산(m-CPBA) (81 ㎎, 0.55 mmol)을 상온에서 가한 다음, 35 ℃에서 15시간 흔들어 반응하였다. 반응종료 후, 반응혼합물을 여과하고 DMF, MC, MC/MeOH, MeOH로 반복 세척하여 화학식 (3-2)로 표시되는 옅은 노란색 고체인 레진(207.4 ㎎)을 얻었다. 수득된 레진 (3-2)를 디클로로메탄(5 ㎖) 용액에 넣고 흔들고 트리플루오로아세트산(TFA) (1 ㎖)을 가한 후, 실온에서 4시간동안 흔들었다. 반응 종료 후, 반응혼합물을 여과하고 여과물을 CH2Cl2와 MeOH로 반복 세척하고 여과액을 합하여 농축하였다. 농축된 혼합물에 에틸아세테이트(3 ㎖)를 가한 후 음이온 교환 수지 레진(SAX resin; strong anion exchange resin)에 여과시키고 에틸아세테이트로 반복 세척하여 잔여 트리플루오로아세트산을 제거하였다. 여과액을 감압농축한 후, 헥산/에틸아세테이트(4/1, v/v)의 혼합용매하에서 실리카겔상의 컬럼 크로마토그래피로 분리 정제하여 화합물번호 (4-2)로 표시되는 담황색 오일 (16.7 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 60 %)를 얻었다. The formula (2a) N- methyl substituted olefin resin (200.00 ㎎, 0.11 mmol) represented by dichloromethane (3 ㎖) and ethanol (3 ㎖) into a mixed solution stirs for 30 minutes, meta-chloroperbenzoic acid (m -CPBA ) (81 mg, 0.55 mmol) was added at room temperature, followed by reaction at 35 ° C. for 15 hours. After completion of the reaction, the reaction mixture was filtered and washed repeatedly with DMF, MC, MC / MeOH, MeOH to obtain a resin (207.4 mg) as a pale yellow solid represented by the formula (3-2). The obtained resin (3-2) was added to a dichloromethane (5 mL) solution, shaken and trifluoroacetic acid (TFA) (1 mL) was added, followed by shaking at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered, the filtrate was washed repeatedly with CH 2 Cl 2 and MeOH, and the filtrates were combined and concentrated. Ethyl acetate (3 ml) was added to the concentrated mixture, which was then filtered through SAX resin (strong anion exchange resin) and washed repeatedly with ethyl acetate to remove residual trifluoroacetic acid. The filtrate was concentrated under reduced pressure, and then purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (4/1, v / v ) to give a pale yellow oil (16.7 mg, Resin 1; yield = 60% from loading capacity 0.55 mmol / g) was obtained.
1H NMR(200 MHz, CDCl3) δ(PPM) 6.70∼6.50(m, 3H), 4.36(d, 1H, J=7.4 Hz), 3.82∼3.67(m, 3H), 2.81(s, 3H), 1.43(s, 3H), 1.32∼1.25(m, 6H); M/S 251.33 1 H NMR (200 MHz, CDCl 3 ) δ (PPM) 6.70 to 6.50 (m, 3H), 4.36 (d, 1H, J = 7.4 Hz), 3.82 to 3.67 (m, 3H), 2.81 (s, 3H) , 1.43 (s, 3H), 1.32-1.25 (m, 6H); M / S 251.33
Ⅱ-3) N-메틸치환된 올레핀 레진(2a)의 하이드록시 2-프로폭시 부가반응 및 탈리반응II-3) Hydroxy 2-propoxy addition and desorption reaction of N-methyl substituted olefin resin (2a)
화학식 (2a)로 표시되는 N-메틸치환된 올레핀 레진 (200.00 ㎎, 0.11 mmol) 을 디클로로메탄(3 ㎖)과 2-프로판올(3 ㎖) 혼합용액에 넣고 30분간 흔들고, 메타-클로로과벤조산(m-CPBA) (81 ㎎, 0.55 mmol)을 상온에서 가한 다음, 35에서 15시간 흔들어 반응하였다. 반응종료 후, 반응혼합물을 여과하고 DMF, MC, MC/MeOH, MeOH로 반복 세척하여 화학식 (3-3)으로 표시되는 옅은 노란색 고체인 레진 (206.8 ㎎)을 얻었다. 수득된 레진 (3-3)을 디클로로메탄(5 ㎖) 용액에 넣고 흔들고 트리플루오로아세트산(TFA, 1 ㎖)을 가한 후, 실온에서 4시간동안 흔들었다. 반응 종료 후, 반응혼합물을 여과하고 여과물을 CH2Cl2와 MeOH로 반복 세척하고 여과액을 합하여 농축하였다. 농축된 혼합물에 에틸아세테이트 (3 ㎖)를 가한 후 음이온 교환 수지 레진(SAX resin; strong anion exchange resin)에 여과시키고 에틸아세테이트로 반복 세척하여 잔여 트리플루오로아세트산을 제거하였다. 여과액을 감압농축한 후, 헥산/에틸아세테이트(4/1, v/v)의 혼합용매하에서 실리카겔상의 컬럼 크로마토그래피로 분리 정제하여 화합물번호 (4-3)로 표시되는 담황색 오일 (14.8 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 56 %)를 얻었다. N-methyl-substituted olefin resin (200.00 mg, 0.11 mmol) represented by the formula (2a) was added to a mixed solution of dichloromethane (3 mL) and 2-propanol (3 mL), and shaken for 30 minutes, followed by meta-chloroperbenzoic acid ( m -CPBA) (81 mg, 0.55 mmol) was added at room temperature and then reacted by shaking at 35 to 15 hours. After completion of the reaction, the reaction mixture was filtered and washed repeatedly with DMF, MC, MC / MeOH, MeOH to give a resin (206.8 mg) as a pale yellow solid represented by the formula (3-3). The obtained resin (3-3) was added to a dichloromethane (5 mL) solution, shaken and trifluoroacetic acid (TFA, 1 mL) was added, followed by shaking at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered, the filtrate was washed repeatedly with CH 2 Cl 2 and MeOH, and the filtrates were combined and concentrated. Ethyl acetate (3 ml) was added to the concentrated mixture, which was then filtered through SAX resin (strong anion exchange resin) and washed repeatedly with ethyl acetate to remove residual trifluoroacetic acid. The filtrate was concentrated under reduced pressure, and then purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (4/1, v / v ) to give a pale yellow oil (14.8 mg, Resin 1; yield = 56% from loading capacity of 0.55 mmol / g) was obtained.
M/S 265.36M / S 265.36
Ⅱ-4) N-메틸치환된 올레핀 레진(2a)의 하이드록시 부톡시 부가반응 및 탈리반응II-4) Hydroxy Butoxy Addition and Desorption of N-Methyl Substituted Olefin Resin (2a)
화학식 (2a)로 표시되는 N-메틸치환된 올레핀 레진 (200.00 ㎎, 0.11 mmol)을 디클로로메탄(3 ㎖)과 부탄올(3 ㎖) 혼합용액에 넣고 30분간 흔들고, 메타-클로로과벤조산(m-CPBA) (81 ㎎, 0.55 mmol)을 상온에서 가한 다음, 35에서 15시간 흔들어 반응하였다. 반응종료 후, 반응혼합물을 여과하고 DMF, MC, MC/MeOH, MeOH로 반복 세척하여 화학식 (3-4)로 표시되는 옅은 노란색 고체인 레진(208.3 ㎎)을 얻었다. 수득된 레진 (3-4)을 디클로로메탄(5 ㎖) 용액에 넣고 흔들고 트리플루오로아세트산(TFA) (1 ㎖)을 가한 후, 실온에서 4시간동안 흔들었다. 반응 종료 후, 반응혼합물을 여과하고 여과물을 CH2Cl2와 MeOH로 반복 세척하고 여과액을 합하여 농축하였다. 농축된 혼합물에 에틸아세테이트(3 ㎖)를 가한 후 음이온 교환 수지 레진(SAX resin; strong anion exchange resin)에 여과시키고 에틸아세테이트로 반복 세척하여 잔여 트리플루오로아세트산을 제거하였다. 여과액을 감압농축한 후, 헥산/에틸아세테이트(4/1, v/v)의 혼합용매하에서 실리카겔상의 컬럼 크로마토그래피로 분리 정제하여 화합물번호 (4-4)로 표시되는 담황색 오일(19.1 ㎎, 레진 1; loading capacity 0.55 mmol/g로부터 yield = 62 %)를 얻었다. N-methyl-substituted olefin resin (200.00 mg, 0.11 mmol) represented by the formula (2a) was added to a mixed solution of dichloromethane (3 mL) and butanol (3 mL), and shaken for 30 minutes, followed by meta-chloroperbenzoic acid ( m- CPBA). ) (81 mg, 0.55 mmol) was added at room temperature, followed by shaking at 35 for 15 hours. After completion of the reaction, the reaction mixture was filtered and washed repeatedly with DMF, MC, MC / MeOH, MeOH to give a resin (208.3 mg) as a pale yellow solid represented by the formula (3-4). The obtained resin (3-4) was added to a dichloromethane (5 mL) solution, shaken and trifluoroacetic acid (TFA) (1 mL) was added, followed by shaking at room temperature for 4 hours. After the reaction was completed, the reaction mixture was filtered, the filtrate was washed repeatedly with CH 2 Cl 2 and MeOH, and the filtrates were combined and concentrated. Ethyl acetate (3 ml) was added to the concentrated mixture, which was then filtered through SAX resin (strong anion exchange resin) and washed repeatedly with ethyl acetate to remove residual trifluoroacetic acid. The filtrate was concentrated under reduced pressure, and then purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (4/1, v / v ) to give a pale yellow oil (19.1 mg, represented by the compound number (4-4), Resin 1; yield = 62% from loading capacity of 0.55 mmol / g) was obtained.
1H NMR(200 MHz, CDCl3) δ(PPM) 6.70∼6.50(m, 3H), 4.35(d, 1H, J=7.2 Hz), 3.80(d, 1H, J=7.2 Hz) 3.67(t, 2H, J=6.2 Hz ), 2.81(s, 3H), 1.67∼1.53(m, 2H), 1.49∼1.30(m, 2H), 1.42(s, 3H), 1.25(s, 3H), 0.94(t, 3H, J=7.2 Hz); M/S 279.38 1 H NMR (200 MHz, CDCl 3 ) δ (PPM) 6.70 to 6.50 (m, 3H), 4.35 (d, 1H, J = 7.2 Hz), 3.80 (d, 1H, J = 7.2 Hz) 3.67 (t, 2H, J = 6.2 Hz), 2.81 (s, 3H), 1.67-1.53 (m, 2H), 1.49-1.30 (m, 2H), 1.42 (s, 3H), 1.25 (s, 3H), 0.94 (t , 3H, J = 7.2 Hz); M / S 279.38
상기 실시예와 동일하게 고체상 평형합성법으로 합성된 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 유도체를 다음 표 1에 정리하여 나타내었다.2,2-dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran derivatives synthesized by the solid-phase equilibrium synthesis method in the same manner as in the above embodiment are shown in Table 1 below.
다음 표 1의 라이브러리를 완성하기 위하여 각 치환기의 조합을 수행하기 위하여 사용된 전구체는 다음과 같다. 예컨대 R1 전구체로는 CH3I, C2H 5I, tBuI, 4-BuI, 4-F-C4H9I, 4-Me-C4H9I, 2-CH3-C4 H9I, 3-Cl-C4H9I, 4-tBu-C4H9I, 3-F-C 4H9I 를 사용하였고, R2 전구체로는 CH3OH, C2H5OH, iPrOH, tBuOH, C4H9OH, 2-Ph-EtOH, 2-싸이클로헥실-EtOH 를 사용하였다.The precursors used to perform the combination of each substituent to complete the library of Table 1 are as follows. For example, R 1 precursors include CH 3 I, C 2 H 5 I, t BuI, 4-BuI, 4-FC 4 H 9 I, 4-Me-C 4 H 9 I, 2-CH 3 -C 4 H 9 I, 3-Cl-C 4 H 9 I, 4- t Bu-C 4 H 9 I, 3-FC 4 H 9 I was used, and R 2 precursors are CH 3 OH, C 2 H 5 OH, i PrOH, t BuOH, C 4 H 9 OH, 2-Ph-EtOH, 2-cyclohexyl-EtOH were used.
..
다음은 본 발명에 따른 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.The following are some examples of formulation methods containing the compound according to the present invention as an active ingredient, but the present invention is not limited thereto.
제제 1 : 정제(직접 가압) Formulation 1 : tablet (direct pressure)
활성성분 5.0 ㎎을 체로 친 후, 락토스 14.1 ㎎, 크로스포비돈 USNF 0.8 ㎎ 및 마그네슘 스테아레이트 0.1 ㎎을 혼합하고 가압하여 정제로 만들었다.After sifting 5.0 mg of active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to form a tablet.
제제 2 : 정제(습식 조립) Formulation 2 : Tablet (Wet Granulation)
활성성분 5.0 ㎎을 체로 친 후, 락토스 16.0 ㎎과 녹말 4.0 ㎎을 섞었다. 폴리솔베이트 80 0.3 ㎎을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 디옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 만들었다. After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.
제제 3 : 분말과 캡슐제 Formulation 3 : Powders and Capsules
활성성분 5.0 ㎎을 체로 친 후에, 락토스 14.8 ㎎, 폴리비닐 피롤리돈 10.0 ㎎, 마그네슘 스테아레이트 0.2 ㎎와 함께 섞었다. 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다. 5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. No. solid the mixture using a suitable device. Filled in 5 gelatin capsules.
제제 4 : 주사제 Formulation 4 : Injection
활성성분으로서 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na2HPO4·12H2O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다. Injectables were prepared by containing 100 mg as the active ingredient, followed by the addition of 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O and 2974 mg of distilled water.
또한, 본 발명에 따른 화합물들의 철에 의해 유발되는 지질 과산화를 억제하는 효과를 알아보기 위하여, 다음과 같은 실험을 수행하였다.In addition, to investigate the effect of inhibiting lipid peroxidation induced by iron of the compounds according to the present invention, the following experiment was performed.
실험예: 지질 과산화 억제 효과Experimental Example: Lipid Peroxidation Inhibitory Effect
쥐(rat)의 뇌를 크렙스(Krebs) 완충액(15 mM HEPES, 10 mM glucose, 140 mM NaCl, 3.6 mM KCl, 1.5 mM CaCl2, 1.4 mM KH2PO4, 0.7 mM MgCl2, PH 7.4)에 넣어 균질화한 후 12,000 rpm으로 10분간 원심분리하여 상등액인 뇌 균질물을 지질의 원료로 사용하였다. Rat brains were treated with Krebs buffer (15 mM HEPES, 10 mM glucose, 140 mM NaCl, 3.6 mM KCl, 1.5 mM CaCl 2 , 1.4 mM KH 2 PO 4 , 0.7 mM MgCl 2 , P H 7.4) After homogenization, the mixture was centrifuged at 12,000 rpm for 10 minutes, and the supernatant of the brain homogenate was used as a raw material of lipid.
뇌균질물에 최종 농도 400 μM가 되도록 FeCl2를 가하고 37 ℃에서 30분간 방치하여 산화를 촉진시켰다. 이때, 시험 물질은 12.5 μM 씩 첨가하였고, 대조군으로는 용매로서 디메틸설폭사이드(DMSO)만을 첨가한 것을 사용하였다.FeCl 2 was added to the brain homogenate to a final concentration of 400 μM and left at 37 ° C. for 30 minutes to promote oxidation. At this time, 12.5 μM was added to the test material, and only dimethyl sulfoxide (DMSO) was added as a solvent.
뇌 균질물에 철이 첨가되면 산화가 촉진되어 지질 과산화 산물인 말론디알데하이드(Malondialdehyde, MDA)의 양이 증가하므로, MDA 정량법으로 지질 과산화 정도를 판단하였다. MDA 정량법은 시료를 TBA(2-thiobarbituric acid)와 반응시켜 530 nm에서의 흡광도를 측정하는 것이 일반적이지만, 끓이는 단계가 포함되기 때문에 대용량의 시료를 처리하기에는 부적합하다. 따라서 본 발명에서는 TBA 대신에 발색시약인 N-메틸-2-페닐인돌(N-methyl-2-phenylindole)을 사용하였다. 이 경우 MDA 한 분자와 N-메틸-2-페닐인돌 두 분자가 반응하여 발색체를 형성하고 이 발색체는 586 nm에서 최대 흡광도를 나타내며, 끓이는 과정을 필요로 하지 않는다 (Bioxytech™ LPO-586 Kit로 흡광도 측정). 시험 물질의 지질 과산화 억제 효과는 대조군의 MDA 양을 기준으로 했을 때 MDA의 양이 감소된 정도를 %로 계산하였다. 저해 효과가 80% 이상인 시험물질은 여러 농도에서 대조군의 MDA 양을 기준으로 했을 때, MDA 양의 감소율을 계산하여 농도-지질과산화저해효과 반응곡선을 구하고, 최소선형회귀(least linear regression) 분석을 통해 약물 투여에 의한 50% 저해농도인 IC50를 산출하여 결과를 다음 표 2에 나타내었다. The addition of iron to brain homogenates promotes oxidation, increasing the amount of malondialdehyde (MDA), a lipid peroxidation product, and thus the degree of lipid peroxidation was determined by MDA assay. MDA quantitation is typically used to measure absorbance at 530 nm by reacting a sample with 2-thiobarbituric acid (TBA), but is not suitable for processing large samples because of the boiling step. Therefore, in the present invention, N-methyl-2-phenylindole, which is a coloring reagent, was used instead of TBA. In this case, one molecule of MDA and two molecules of N-methyl-2-phenylindole react to form a chromosome, which exhibits a maximum absorbance at 586 nm and does not require boiling (Bioxytech ™ LPO-586 Kit). Absorbance measurements). The lipid peroxidation inhibitory effect of the test substance was calculated as a percentage of the amount of MDA decrease based on the amount of MDA of the control group. For test substances with an inhibitory effect of more than 80%, the concentration-lipid peroxidation effect response curve was calculated by calculating the rate of decrease of MDA amount based on the MDA amount of the control group at various concentrations, and the least linear regression analysis was performed. Through the calculation of IC 50 , a 50% inhibitory concentration by drug administration, the results are shown in Table 2 below.
또한, 다음 표 2에는 현재 시중에서 시판되고 있는 대표적인 항산화제 예를 들면 프로메타진(Promethazine), 트로록스(Trolox), 프로부콜(Probucol) 및 N-프로필 갈레이트(N-propyl gallate)를 대조약제로 사용하여 상기와 동일한 방법으로 50% 저해농도(IC50)를 산출하여 나타내었다.Table 2 also shows representative antioxidants currently on the market such as Promethazine, Trolox, Probucol and N-propyl gallate. In the same manner as above, the 50% inhibitory concentration (IC 50 ) was calculated and used as a medicament.
상기 표 2에서 볼 수 있는 바와 같이, 본 발명의 화합물들은 철에 의한 지질 과산화를 억제하는 활성을 가지고 있다. 특히 화합물 4-111 및 4-115은 각각 1.0 μM 이하의 억제율을 나타내어 철에 의한 지질 과산화를 억제하는 효과가 매우 강력함을 알 수 있다.As can be seen in Table 2, the compounds of the present invention have the activity of inhibiting lipid peroxidation by iron. In particular, compounds 4-111 and 4-115 show an inhibitory rate of 1.0 μM or less, respectively, and thus, the effect of inhibiting lipid peroxidation by iron is very strong.
이상에서 밝힌 바와 같이, 일반적으로 다단계 공정의 반응을 용액상에서 수행하며 여러 번의 반응후 처리과정 및 정제과정을 거쳐야만 되는데 비하여, 본 발명에 따른 고체상 평형합성법을 이용한 2,2-디메틸-3-하이드록시-6-알킬 아미노 벤조피란 유도체 제조방법은 반응후 처리과정 및 정제과정을 대폭 줄임으로써 단기간에 대량의 라이브러리를 구축할 수 있다. 특히, 본 발명에 따른 반응을 수행함에 있어 제 1 단계에서 화학식 (2)로 표시되는 N-알킬치환된 카바메이트 레진 생성반응, 제 2 단계에서는 화학식 (3)으로 표시되는 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 레진의 생성반응, 제 3 단계 반응에서는 25% TFA/CH2Cl2 용액을 사용하여 화학식 (4)로 표시되는 목적화합물인 2,2-디메틸-3-하이드록시-4-알콕시-6-알킬 아미노 벤조피란 유도체 제조과정을 고체상 평형합성법을 이용하여 반응후의 처리과정 및 정제과정을 자동화하였다.As described above, in general, the reaction of the multi-step process is performed in a solution phase, and after several reactions, a treatment process and a purification process must be performed, whereas 2,2-dimethyl-3-hydroxy using the solid phase equilibrium synthesis method according to the present invention. The method for preparing a -6-alkyl amino benzopyran derivative can construct a large amount of libraries in a short time by greatly reducing post-reaction treatment and purification. In particular, in carrying out the reaction according to the present invention, N-alkyl-substituted carbamate resin production reaction represented by formula (2) in the first step, and 2,2-dimethyl- represented by formula (3) in the second step Formation reaction of 3-hydroxy-4-alkoxy-6-alkyl amino benzopyran resin, in the third stage reaction, using the 25% TFA / CH 2 Cl 2 solution, the target compound represented by the formula (4) 2,2 The preparation of -dimethyl-3-hydroxy-4-alkoxy-6-alkyl amino benzopyran derivatives was automated using a solid-phase equilibrium method to post-reaction treatment and purification.
따라서, 본 발명은 고체상 평형합성법을 이용한 3-하이드록시 벤조피란 라이브러리의 구축기술을 확립함으로써, 조합화학 합성기술의 응용성을 높였으며, 이는 지질 과산화가 촉진되고 신경세포 내에 산화물질이 축적되어 유발되는 질환 예컨대 뇌졸중, 치매 등과 같은 뇌신경계 질환 뿐만 아니라 관절염 등의 염증성 질환, 심근 경색증, 급만성 조직 손상의 예방제 또는 치료제의 개발에 유용한 새로운 구조의 선도물질(lead Compound)의 탐색 및 구조와 기능의 최적화를 하는 것이 보다 용이해졌다.Therefore, the present invention has established a technique for constructing a 3-hydroxy benzopyran library using a solid-phase equilibrium synthesis method, thereby increasing the applicability of combinatorial chemical synthesis technology, which promotes lipid peroxidation and accumulates oxides in neurons. Exploration and structure and function of lead compounds with new structures useful for the development of preventive or therapeutic agents for inflammatory diseases such as arthritis, myocardial infarction, acute tissue damage, as well as cerebral nervous system diseases such as stroke and dementia. It's easier to optimize.
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