KR20210050300A - Indolizine core skeleton-Based Emissive Fluorescent Compounds and Use thereof - Google Patents

Indolizine core skeleton-Based Emissive Fluorescent Compounds and Use thereof Download PDF

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KR20210050300A
KR20210050300A KR1020190134753A KR20190134753A KR20210050300A KR 20210050300 A KR20210050300 A KR 20210050300A KR 1020190134753 A KR1020190134753 A KR 1020190134753A KR 20190134753 A KR20190134753 A KR 20190134753A KR 20210050300 A KR20210050300 A KR 20210050300A
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김은하
신익수
고정길
최상기
김현기
안정모
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아주대학교산학협력단
숭실대학교산학협력단
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Abstract

The present invention relates to indolizine skeleton-based radioactive fluorescent compounds and a use thereof, and more particularly, to indolizine skeleton-based radioactive fluorescent compounds, a manufacturing method thereof, a composition for detecting volatile organic compounds (VOC) containing the same, and a method for detecting a sensor and volatile organic compounds. In the present invention, as a result of detecting 35 different VOC substances using a fluorescent sensor array coated with a fluorescent compound and image analysis technology, the indolizine-based fluorescent sensor array shows different change patterns in response to 35 types of VOCs. As a result of learning the image pattern using statistical analysis and machine learning algorithms, the learned algorithm, which was able to detect volatile organic compounds with a high accuracy of 97%, has confirmed. The fluorescent compunds are represented by a chemical formula 1.

Description

인돌리진 골격체 기반 방사성 형광 화합물 및 이의 용도{Indolizine core skeleton-Based Emissive Fluorescent Compounds and Use thereof}Indolizine core skeleton-Based Emissive Fluorescent Compounds and Use thereof

본 발명은 인돌리진 골격체 기반 방사성 형광 화합물 및 이의 용도에 관한 것으로, 보다 상세하게는 인돌리진 골격체 기반 방사성 형광 화합물, 이의 제조방법 및 이를 포함하는 휘발성 유기화합물(Volatile Organic Compounds; VOC) 검출용 조성물, 센서 및 휘발성 유기화합물 검출 방법에 관한 것이다. The present invention relates to an indolizine skeleton-based radioactive fluorescent compound and its use, and more particularly, to an indolizine skeleton-based radioactive fluorescent compound, a method for preparing the same, and volatile organic compounds (VOC) detection including the same. It relates to a composition, a sensor, and a method for detecting volatile organic compounds.

21세기는 인구의 급증과 산업 성장에 의한 인위적인 영향으로 인해 환경오염이 일어나고 있으며, 인류는 환경이 오염되고 있는 점을 인지함과 동시에 환경적 요인으로 인한 건강에도 관심이 증가하고 21세기는 인구의 급증과 산업 성장에 의한 인위적인 영향으로 인해 환경오염이 일어나고 있으며, 인류는 환경이 오염되고 있는 점을 인지함과 동시에 환경적 요인으로 인한 건강에도 관심이 증가하고 있는 추세이다. 크게 수질, 토양, 대기 및 음식물 등의 환경오염으로 인해 질병이 유도되고 있으며, 이러한 오염원은 이온 크로마토그래피, 고속액체 크로마토그래피, 액체 크로마토그래피-질량분석법 등으로 검출하는 방법이 사용되고 있으나, 상기 방법들은 측정 대상 물질에 따라 전처리 과정이 상이하며, 정밀분석에 실험실용 고가의 대형 장비가 사용되고, 분석에 전문가가 필요하기 때문에 현장에서 직접 데이터를 확보하기에는 어려운 실정이다. In the 21st century, environmental pollution is occurring due to the artificial influence of the rapid increase in population and industrial growth. At the same time, humanity is aware that the environment is being polluted, and at the same time, interest in health due to environmental factors increases. Environmental pollution is occurring due to the artificial influence of the rapid increase and industrial growth. At the same time, humanity is aware that the environment is being polluted, and at the same time, interest in health due to environmental factors is increasing. Diseases are largely induced by environmental pollution such as water quality, soil, air, and food, and these pollutants are detected by ion chromatography, high performance liquid chromatography, liquid chromatography-mass spectrometry, etc. The pretreatment process is different depending on the material to be measured, expensive laboratory equipment is used for precise analysis, and because an expert is required for analysis, it is difficult to obtain data directly in the field.

특히, 환경 유독물질 요소 중 하나인 휘발성 유기 화합물(Volatile Organic Compounds; VOC)은 비점이 낮아서 대기중으로 쉽게 증발되는 액체 또는 기체상 유기화합물을 총칭으로써, 산업체에서 많이 사용하는 용매, 화학 및 제약공장, 플라스틱 건조공정, 새집 증후군 등 생활 주변에서 주로 배출되는 것으로 알려져 있다. 휘발성 유기 화합물이 인체에 미치는 영향으로는 호흡기자극, 발암성, 심장과 간장, 위장 신경계 등의 이상 유발과 중추 신경의 이상을 유발하며, 휘발성 유기 화합물에 노출되었을 때 피로, 두통, 졸음, 현기증, 심장의 부정맥을 일으킨다고 보고되었다.In particular, volatile organic compounds (VOC), one of the elements of environmental toxic substances, are a generic term for liquid or gaseous organic compounds that are easily evaporated into the atmosphere due to their low boiling point. It is known to be mainly discharged from the surroundings of life such as plastic drying process and sick house syndrome. The effects of volatile organic compounds on the human body include respiratory irritation, carcinogenicity, causing abnormalities in the heart and liver, gastrointestinal nervous system, and central nervous system. When exposed to volatile organic compounds, fatigue, headache, drowsiness, dizziness, It has been reported to cause cardiac arrhythmias.

한편 형광 현상은 사용이 간단하고, 여기 파장과 발광 파장의 특성상 신호 대 잡음비가 높으며, 단분자를 분석할 수 있을 정도로 민감도가 매우 높기 때문에, 형광 현상을 이용한 센서는 높은 감도와 응답 시간이 빠르다는 장점을 가지고 있다. 일반적으로 형광센서는 분석하고자 하는 이온 또는 물질이 센서의 인식부분과 결합하게 되면 신호를 나타내는 부분에서 형광 변화가 관찰되고 이를 이용하여 물질의 존재 여부 또는 농도를 검출하게 된다. 최근에는 이러한 형광화학센서를 이용하여 환경적으로 중요한 이온 및 중성 유기 분자를 검출하기 위한 연구가 이루어지고 있다. 형광화학센서는 세포 내 이미징, 환경 유독 물질 검출, 신경 독가스 검출, 효소 반응속도 측정 및 분자 연산 등에 응용되고 있으나, 기존 시스템은 일반적으로 단일 피분석물에 대해 높은 선택성과 감도를 지니는 형광화학센서 개발에 초점이 맞춰져 있어 여러가지 표적 물질을 하나의 검출법으로 분석하기에는 제한적이다. On the other hand, the fluorescence phenomenon is simple to use, the signal-to-noise ratio is high due to the characteristics of the excitation wavelength and the emission wavelength, and the sensitivity is very high enough to analyze a single molecule.Therefore, the sensor using the fluorescence phenomenon has high sensitivity and fast response time. It has an advantage. In general, in a fluorescence sensor, when an ion or a substance to be analyzed is combined with a recognition part of the sensor, a change in fluorescence is observed in a part representing a signal, and the presence or concentration of the substance is detected by using this change. Recently, research has been conducted to detect environmentally important ions and neutral organic molecules using such a fluorescent chemical sensor. Fluorescent chemical sensors are applied to intracellular imaging, environmental toxic substances detection, neurotoxic gas detection, enzyme reaction rate measurement, and molecular calculation, but conventional systems generally develop fluorescent chemical sensors with high selectivity and sensitivity for a single analyte. As the focus is on, it is limited to analyze various target substances with a single detection method.

이에 반해 형광 어레이 시스템은, 시스템을 이루고 있는 각각의 형광 물질들이 하나 이상의 피분석물과 상호 작용을 할 수 있으므로, 형광화학센서 어레이에서 관찰되는 제 각각의 형광물질들의 형광 물성 변화의 합이 특정 표적 물질에 대해 어레이 전체적이 관점에서 특이적 패턴을 이루게 된다. 따라서, 어레이 시스템은 각각의 형광물질이 분석물에 대해 선택적으로 반응하지 않아도 되므로 구축이 상대적으로 용이하며, 한번 구축되면 질병 진단에 있어서 특이적 마커 부재시에도 적용이 가능하여 폭넓은 질병에 대해 진단이 가능하다는 장점이 있다. 또한, 최근 급속도로 발전하고 있는 딥러닝, 머신러닝 등의 인공지능 기술은 어레이와 표적 물질의 상호작용에 의해 생긴 신호로부터 분석이 용이한 패턴을 찾아낼 수 있다. In contrast, in the fluorescence array system, since each of the fluorescent materials constituting the system can interact with one or more analytes, the sum of the changes in the fluorescence properties of each of the fluorescent materials observed in the fluorescent chemical sensor array is a specific target. For the material, the array as a whole forms a specific pattern in terms of it. Therefore, the array system is relatively easy to construct because each fluorescent substance does not have to react selectively to the analyte, and once constructed, it can be applied even in the absence of a specific marker in disease diagnosis, allowing diagnosis of a wide range of diseases. There is an advantage that it is possible. In addition, artificial intelligence technologies such as deep learning and machine learning, which are rapidly developing in recent years, can find patterns that are easy to analyze from signals generated by the interaction between arrays and target materials.

이에 본 발명자들은 이러한 형광 어레이 구축을 위한 인돌리진 중심골격체를 기반으로 하는 신규한 형광 코어 스켈레톤의 새로운 디자인을 발견하였으며, 이러한 어레이 기술의 가능성을 확인하기 위해 본 발명에서는 휘발성 유기 화합물 검출에 관련 기술을 적용하고자 하였다. 형광물질을 이용한 휘발성 유기 화합물을 검출하는 센서 어레이의 개발은 다양한 연구 분야에서 관심이 높으나, 새로운 형광 물질 골격체를 이용한 센서 어레이의 개발은 미흡한 수준으로, 본 발명에서는 휘발성 유기화합물을 실시간으로 모니터링하기 위한 신규한 형광물질을 개발하기 위해 예의 노력한 결과, 인돌리진 골격체를 기반으로 하는 방사성 형광 화합물을 개발하였으며, 총 75개의 형광물질이 도포된 센서 어레이를 제작하였다. 본 발명의 센서 어레이를 이용하여 휘발성 유기 화합물을 검출하고, 통계 분석 및 머신러닝 알고리즘을 이용하여 이미지 패턴을 학습시킨 결과, 학습된 알고리즘이 97%의 높은 정확도로 휘발성 유기 화합물을 검출할 수 있는 것을 확인하고, 본 발명을 완성하였다. Accordingly, the present inventors discovered a new design of a novel fluorescent core skeleton based on an indolizine central skeleton for constructing such a fluorescent array, and in order to confirm the possibility of such an array technology, the present invention relates to the detection of volatile organic compounds. I tried to apply. Development of a sensor array for detecting volatile organic compounds using fluorescent materials is of high interest in various research fields, but development of a sensor array using a new fluorescent material skeleton is insufficient. In the present invention, real-time monitoring of volatile organic compounds is performed. As a result of diligent efforts to develop a novel fluorescent material for this, a radioactive fluorescent compound based on an indolizine skeleton was developed, and a sensor array coated with a total of 75 fluorescent materials was fabricated. As a result of detecting volatile organic compounds using the sensor array of the present invention, and learning image patterns using statistical analysis and machine learning algorithms, the learned algorithm was able to detect volatile organic compounds with a high accuracy of 97%. Confirmed and completed the present invention.

본 발명의 목적은 인돌리진 골격체 기반 방사성 형광 화합물 및 이의 제조방법을 제공하는 데 있다.An object of the present invention is to provide a radioactive fluorescent compound based on an indolizine skeleton and a method for preparing the same.

본 발명의 다른 목적은 상기 형광 화합물을 포함하는 휘발성 유기화합물(Volatile Organic Compounds; VOC) 검출용 조성물을 제공하는 데 있다.Another object of the present invention is to provide a composition for detecting volatile organic compounds (VOC) including the fluorescent compound.

본 발명의 또 다른 목적은 상기 형광 화합물이 고정된 휘발성 유기화합물 검출용 센서 어레이 및 이를 이용한 휘발성 유기화합물 검출 방법을 제공하는 데 있다. Another object of the present invention is to provide a sensor array for detecting volatile organic compounds in which the fluorescent compounds are fixed, and a method for detecting volatile organic compounds using the same.

상기 목적을 달성하기 위해, To achieve the above object,

본 발명은 하기 화학식 1로 표시되는 형광 화합물을 제공한다.The present invention provides a fluorescent compound represented by the following formula (1).

[화학식 1][Formula 1]

Figure pat00001
Figure pat00001

상기 화학식 1에서, In Formula 1,

R1는 수소; 니트릴기; 할로겐; 니트로기; C1-C6의 알콕시기; C6-C20의 아릴기; C5-C20의 시클로헤테로고리기; 보론기; 아자이드기; NR4R5(여기에서, R4 및 R5는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임), 니트릴, C1-C6의 알콕시, 할로겐, 보론기, 하이드록시기 또는 CH2NR4R5 (여기에서, R4 및 R5는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임)로 치환된 C6-C20의 아릴기; C1-C8의 직쇄 또는 측쇄 알킬기; C2-C8의 알케닐기; C2-C8의 알키닐기; C3-C8의 시클로알킬기; 또는 C4-C20의 헤테로아릴기이고,R 1 is hydrogen; Nitrile group; halogen; Nitro group; C1-C6 alkoxy group; C6-C20 aryl group; C5-C20 cycloheterocyclic group; Boron group; Azide group; NR 4 R 5 (wherein R 4 and R 5 are each independently hydrogen, C1-C10 alkyl group, C6-C20 aryl group or C4-C20 heteroaryl group), nitrile, C1-C6 alkoxy, halogen , A boron group, a hydroxy group, or CH 2 NR 4 R 5 (wherein R 4 and R 5 are each independently hydrogen, a C1-C10 alkyl group, a C6-C20 aryl group, or a C4-C20 heteroaryl group) A C6-C20 aryl group substituted with; C1-C8 linear or branched alkyl group; C2-C8 alkenyl group; C2-C8 alkynyl group; C3-C8 cycloalkyl group; Or a C4-C20 heteroaryl group,

R2는 수소; C1-C8의 직쇄 또는 측쇄 알킬기; C2-C8의 알케닐기; C2-C8의 알키닐기; C3-C8의 시클로알킬기; 하이드록시기; C1-C6의 알콕시기; 폴리에틸렌글라이콜기; 니트릴기; 니트로기; 카르복실기; 설포닐기; 아자이드기; 메탄설포닐기; 말레이미드기; 터셔리-부틸디메틸실릴기(TBS)로 보호된 알콜; 또는 NR6R7(여기에서, R6 및 R7는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임)이고,R 2 is hydrogen; C1-C8 linear or branched alkyl group; C2-C8 alkenyl group; C2-C8 alkynyl group; C3-C8 cycloalkyl group; Hydroxy group; C1-C6 alkoxy group; Polyethylene glycol group; Nitrile group; Nitro group; Carboxyl group; Sulfonyl group; Azide group; Methanesulfonyl group; Maleimide group; Alcohols protected by tertiary-butyldimethylsilyl group (TBS); Or NR 6 R 7 (wherein R 6 and R 7 are each independently hydrogen, a C1-C10 alkyl group, a C6-C20 aryl group or a C4-C20 heteroaryl group),

R3는 수소; 할로겐; 니트릴기; 보론기; 하이드록시기; COY(여기에서 Y는 수소, C1-C8의 직쇄 또는 측쇄 알킬기, C2-C8의 알케닐기, C2-C8의 알키닐기, C3-C8의 시클로알킬기, 또는 NR8R9(여기에서, R8 및 R9는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임]); C1-C6의 알콕시기; C6-C20의 아릴기; 또는 NR10R11(여기에서, R10 및 R11는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임), 니트릴 또는 할로겐으로 치환된 C6-C20의 아릴기이다.R 3 is hydrogen; halogen; Nitrile group; Boron group; Hydroxy group; COY (wherein Y is hydrogen, a C1-C8 linear or branched alkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, a C3-C8 cycloalkyl group, or NR 8 R 9 (herein, R 8 and Each R 9 is independently hydrogen, a C1-C10 alkyl group, a C6-C20 aryl group, or a C4-C20 heteroaryl group]); C1-C6 alkoxy group; C6-C20 aryl group; Or NR 10 R 11 (Wherein, R 10 and R 11 are each independently hydrogen, a C1-C10 alkyl group, a C6-C20 aryl group, or a C4-C20 heteroaryl group), a C6-C20 aryl group substituted with nitrile or halogen. .

본 발명의 바람직한 일실시예에 있어서, 상기 R1은 수소; 트리플루오로메틸기(Trifluoromethyl); 아세틸기; 메톡시기; 또는 다이메틸아민기이고, 상기 R2는 메틸; 트리플루오로메틸페닐기; 페닐기; 메톡시페닐기; 또는 다이에틸아민페닐기이며, 상기 R3는 수소; 트리플루오로메틸기(Trifluoromethyl); 또는 아세틸기일 수 있다. In a preferred embodiment of the present invention, R 1 is hydrogen; Trifluoromethyl group; Acetyl group; Methoxy group; Or a dimethylamine group, and R 2 is methyl; Trifluoromethylphenyl group; Phenyl group; Methoxyphenyl group; Or a diethylaminephenyl group, and R 3 is hydrogen; Trifluoromethyl group; Or it may be an acetyl group.

본 발명의 바람직한 다른 일실시예에 있어서, 상기 화학식 1은 하기 화학식 1-1 내지 화학식 1-75로 구성된 군에서 선택된 1종 이상으로 표시될 수 있다. In another preferred embodiment of the present invention, Formula 1 may be represented by one or more selected from the group consisting of the following Formulas 1-1 to 1-75.

[화학식 1-1][Formula 1-1]

Figure pat00002
Figure pat00002

[화학식 1-2][Formula 1-2]

Figure pat00003
Figure pat00003

[화학식 1-3][Formula 1-3]

Figure pat00004
Figure pat00004

[화학식 1-4][Formula 1-4]

Figure pat00005
Figure pat00005

[화학식 1-5][Formula 1-5]

Figure pat00006
Figure pat00006

[화학식 1-6][Formula 1-6]

Figure pat00007
Figure pat00007

[화학식 1-7][Formula 1-7]

Figure pat00008
Figure pat00008

[화학식 1-8][Formula 1-8]

Figure pat00009
Figure pat00009

[화학식 1-9][Formula 1-9]

Figure pat00010
Figure pat00010

[화학식 1-10][Formula 1-10]

Figure pat00011
Figure pat00011

[화학식 1-11][Formula 1-11]

Figure pat00012
Figure pat00012

[화학식 1-12][Formula 1-12]

Figure pat00013
Figure pat00013

[화학식 1-13][Formula 1-13]

Figure pat00014
Figure pat00014

[화학식 1-14][Formula 1-14]

Figure pat00015
Figure pat00015

[화학식 1-15][Formula 1-15]

Figure pat00016
Figure pat00016

[화학식 1-16][Formula 1-16]

Figure pat00017
Figure pat00017

[화학식 1-17][Formula 1-17]

Figure pat00018
Figure pat00018

[화학식 1-18][Formula 1-18]

Figure pat00019
Figure pat00019

[화학식 1-19][Formula 1-19]

Figure pat00020
Figure pat00020

[화학식 1-20][Formula 1-20]

Figure pat00021
Figure pat00021

[화학식 1-21][Formula 1-21]

Figure pat00022
Figure pat00022

[화학식 1-22][Formula 1-22]

Figure pat00023
Figure pat00023

[화학식 1-23][Formula 1-23]

Figure pat00024
Figure pat00024

[화학식 1-24][Formula 1-24]

Figure pat00025
Figure pat00025

[화학식 1-25][Formula 1-25]

Figure pat00026
Figure pat00026

[화학식 1-26][Formula 1-26]

Figure pat00027
Figure pat00027

[화학식 1-27][Formula 1-27]

Figure pat00028
Figure pat00028

[화학식 1-28][Formula 1-28]

Figure pat00029
Figure pat00029

[화학식 1-29][Formula 1-29]

Figure pat00030
Figure pat00030

[화학식 1-30][Formula 1-30]

Figure pat00031
Figure pat00031

[화학식 1-31][Formula 1-31]

Figure pat00032
Figure pat00032

[화학식 1-32][Formula 1-32]

Figure pat00033
Figure pat00033

[화학식 1-33][Formula 1-33]

Figure pat00034
Figure pat00034

[화학식 1-34][Formula 1-34]

Figure pat00035
Figure pat00035

[화학식 1-35][Formula 1-35]

Figure pat00036
Figure pat00036

[화학식 1-36][Formula 1-36]

Figure pat00037
Figure pat00037

[화학식 1-37][Formula 1-37]

Figure pat00038
Figure pat00038

[화학식 1-38][Formula 1-38]

Figure pat00039
Figure pat00039

[화학식 1-39][Formula 1-39]

Figure pat00040
Figure pat00040

[화학식 1-40][Formula 1-40]

Figure pat00041
Figure pat00041

[화학식 1-41][Formula 1-41]

Figure pat00042
Figure pat00042

[화학식 1-42][Formula 1-42]

Figure pat00043
Figure pat00043

[화학식 1-43][Formula 1-43]

Figure pat00044
Figure pat00044

[화학식 1-44][Formula 1-44]

Figure pat00045
Figure pat00045

[화학식 1-45][Formula 1-45]

Figure pat00046
Figure pat00046

[화학식 1-46][Formula 1-46]

Figure pat00047
Figure pat00047

[화학식 1-47][Formula 1-47]

Figure pat00048
Figure pat00048

[화학식 1-48][Formula 1-48]

Figure pat00049
Figure pat00049

[화학식 1-49][Formula 1-49]

Figure pat00050
Figure pat00050

[화학식 1-50][Formula 1-50]

Figure pat00051
Figure pat00051

[화학식 1-51][Chemical Formula 1-51]

Figure pat00052
Figure pat00052

[화학식 1-52][Formula 1-52]

Figure pat00053
Figure pat00053

[화학식 1-53][Formula 1-53]

Figure pat00054
Figure pat00054

[화학식 1-54][Formula 1-54]

Figure pat00055
Figure pat00055

[화학식 1-55][Formula 1-55]

Figure pat00056
Figure pat00056

[화학식 1-56][Formula 1-56]

Figure pat00057
Figure pat00057

[화학식 1-57][Formula 1-57]

Figure pat00058
Figure pat00058

[화학식 1-58][Formula 1-58]

Figure pat00059
Figure pat00059

[화학식 1-59][Formula 1-59]

Figure pat00060
Figure pat00060

[화학식 1-60][Formula 1-60]

Figure pat00061
Figure pat00061

[화학식 1-61][Formula 1-61]

Figure pat00062
Figure pat00062

[화학식 1-62][Formula 1-62]

Figure pat00063
Figure pat00063

[화학식 1-63][Formula 1-63]

Figure pat00064
Figure pat00064

[화학식 1-64][Formula 1-64]

Figure pat00065
Figure pat00065

[화학식 1-65][Formula 1-65]

Figure pat00066
Figure pat00066

[화학식 1-66][Formula 1-66]

Figure pat00067
Figure pat00067

[화학식 1-67][Formula 1-67]

Figure pat00068
Figure pat00068

[화학식 1-68][Formula 1-68]

Figure pat00069
Figure pat00069

[화학식 1-69][Formula 1-69]

Figure pat00070
Figure pat00070

[화학식 1-70][Formula 1-70]

Figure pat00071
Figure pat00071

[화학식 1-71][Formula 1-71]

Figure pat00072
Figure pat00072

[화학식 1-72][Formula 1-72]

Figure pat00073
Figure pat00073

[화학식 1-73][Chemical Formula 1-73]

Figure pat00074
Figure pat00074

[화학식 1-74][Formula 1-74]

Figure pat00075
Figure pat00075

[화학식 1-75][Formula 1-75]

Figure pat00076
Figure pat00076

본 발명에 있어서, 상기 형광 화합물의 발광 파장은 400nm 내지 620nm이며, 액체상 또는 고체상 형광현상(solid state fluorescence)을 나타낼 수 있다.In the present invention, the emission wavelength of the fluorescent compound is 400 nm to 620 nm, and may exhibit liquid or solid state fluorescence.

또한, 본 발명은 (a) 화학식 A의 화합물 및 화학식 B의 화합물을 반응시켜, 화학식 C의 화합물을 제조하는 단계; In addition, the present invention comprises the steps of (a) reacting a compound of formula A and a compound of formula B to prepare a compound of formula C;

(b) 상기 화학식 C의 화합물과 에틸아크릴레이트(ethyl acrylate), 아세트산나트륨(sodium acetate) 및 구리아세트산 모노수화물(Copper(II) Acetate monohydrate)을 반응시켜 화학식 D의 화합물을 제조하는 단계;(b) reacting the compound of Formula C with ethyl acrylate, sodium acetate, and copper acetic acid monohydrate to prepare a compound of Formula D;

(c) 상기 화학식 D의 화합물 및 NBS(N-Bromosuccinimide)를 반응시켜 화학식 E의 화합물을 제조하는 단계; 및 (c) preparing a compound of Formula E by reacting the compound of Formula D and NBS (N-Bromosuccinimide); And

(d) 상기 화학식 E의 화합물 및 화학식 F의 화합물을 반응시켜 화학식 1의 화합물을 제조하는 단계를 포함하며, 하기 반응식 1로 표시되는 화학식 1의 형광 화합물의 제조방법을 제공한다:(d) reacting the compound of Formula E and the compound of Formula F to prepare a compound of Formula 1, and provides a method for preparing a fluorescent compound of Formula 1 represented by the following Scheme 1:

[반응식 1][Scheme 1]

Figure pat00077
Figure pat00077

상기 R1은 수소; 트리플루오로메틸기(Trifluoromethyl); 아세틸기; 메톡시기; 또는 다이메틸아민기이고, 상기 R2는 메틸; 트리플루오로메틸페닐기; 페닐기; 메톡시페닐기; 또는 다이에틸아민페닐기이며, 상기 R3는 수소; 트리플루오로메틸기(Trifluoromethyl); 또는 아세틸기이다.R 1 is hydrogen; Trifluoromethyl group; Acetyl group; Methoxy group; Or a dimethylamine group, and R 2 is methyl; Trifluoromethylphenyl group; Phenyl group; Methoxyphenyl group; Or a diethylaminephenyl group, and R 3 is hydrogen; Trifluoromethyl group; Or an acetyl group.

다른 목적을 달성하기 위해, 본 발명은 상기 형광 화합물을 포함하는 휘발성 유기화합물(Volatile Organic Compounds; VOC) 검출용 조성물을 제공한다. In order to achieve another object, the present invention provides a composition for detecting volatile organic compounds (VOC) including the fluorescent compound.

또 다른 목적을 달성하기 위해, 본 발명은 상기 형광 화합물을 포함하는 휘발성 유기화합물 검출용 센서 어레이를 제공한다. In order to achieve another object, the present invention provides a sensor array for detecting volatile organic compounds including the fluorescent compound.

본 발명의 바람직한 일실시예에 있어서, 상기 휘발성 유기화합물은 특별한 제한은 없지만, 바람직 하게는 에탄올(Ethanol), 1-부탄올(1-Butanol), 1-(펜탄올(1-Pentanol), 1-헥산올(1-Hexanol), 3-헥산올(3-Hexanol), 페놀(Phenol), 1-헵탄올(1-Heptanol), 1-데칸올(1-Decanol), 2-데칸올(2-Decanol), 3-데칸올(3-Decanol), 1-도데칸올(1-Dodecanol), 사이클로펜탄올(Cyclopentanol), 사이클로헥산올(Cyclohexanol), 사이클로헵탄올(Cycloheptanol), 벤젠(Benzene), 아세톤(Acetone), 2-옥탄온(2-Octanone), 2-피콜린(2-Picoline), 3-피콜린(3-Picoline), 3-아세틸피리딘(3-Acetylpyridine), 4-아세틸피리딘(4-Acetylpyridine), 2-헵틸아민(2-Heptylamine), 디-엔-프로필아민(Di-n-propylamine), 2-페닐에틸아민(2-Phenylethylamine), 사이클로옥틸아민(Cyclooctylaime), 프로피온산(Propionic acid), 3-브롬프로피온산(3-Bromopropionic acid), 2-메틸부티르산(2-Methylbutyric acid), 포름산(Formic acid), 발레르산(Valeric acid), 트리플루오로 아세트산(Trifluoroacetic acid), 브로모아세트산(Bromoacetic acid), 아세트산(Acetic acid), 트리클로로아세트산(Trichloroacetic acid) 및 2-클로로프로피온산(2-Chloropropionic acid)으로 구성된 군에서 선택된 1종 이상의 물질일 수 있다. In a preferred embodiment of the present invention, the volatile organic compound is not particularly limited, but preferably ethanol (Ethanol), 1-butanol (1-Butanol), 1- (pentanol (1-Pentanol), 1- Hexanol (1-Hexanol), 3-hexanol (3-Hexanol), phenol (Phenol), 1-heptanol (1-Heptanol), 1-decanol (1-Decanol), 2-decanol (2- Decanol), 3-Decanol, 1-Dodecanol, Cyclopentanol, Cyclohexanol, Cycloheptanol, Benzene, Acetone (Acetone), 2-Octanone, 2-Picoline, 3-Picoline, 3-Acetylpyridine, 4-acetylpyridine (4) -Acetylpyridine), 2-Heptylamine, Di-n-propylamine, 2-Phenylethylamine, Cyclooctylamine, Propionic acid ), 3-Bromopropionic acid, 2-Methylbutyric acid, Formic acid, Valeric acid, Trifluoroacetic acid, Bromoacetic acid ( Bromoacetic acid), acetic acid, trichloroacetic acid, and 2-chloropropionic acid may be one or more substances selected from the group consisting of.

또한, 본 발명은 상기 형광 화합물을 이용한 휘발성 유기 화합물 검출 방법을 제공한다. In addition, the present invention provides a method for detecting a volatile organic compound using the fluorescent compound.

본 발명의 바람직한 일실시예에 있어서, 상기 방법은 (a) 형광 화합물이 고정된 휘발성 유기 화합물 검출용 센서 어레이에 휘발성 물질을 노출시킨 후, 형광 패턴 변화를 측정하는 단계; 및 In a preferred embodiment of the present invention, the method comprises the steps of: (a) exposing a volatile material to a sensor array for detecting a volatile organic compound to which a fluorescent compound is fixed, and then measuring a change in a fluorescence pattern; And

(b) 상기 패턴 변화를 머신 러닝 알고리즘을 통해 학습시키는 단계;를 포함하는 방법으로 수행될 수 있다. (b) learning the pattern change through a machine learning algorithm.

본 발명의 바람직한 다른 일실시예에 있어서, 상기 (b) 단계는 패턴의 RGB 거리, 색정보값(Hue value) 또는 CIEDE2000 정보를 머신 러닝 알고리즘을 통해 학습시킬 수 있다.In another preferred embodiment of the present invention, in step (b), the RGB distance, hue value, or CIEDE2000 information of the pattern may be learned through a machine learning algorithm.

본 발명에서는 형광 화합물이 도포된 형광 센서 어레이 및 이미지 분석 기술을 이용하여 35가지 서로 다른 VOC 물질을 검출한 결과, 인돌리진 기반 형광 센서 어레이가 35가지의 VOC에 반응하여 제 각각의 변화 패턴을 보여준다는 것을 확인하였으며, 통계 분석 및 머신 러닝 알고리즘을 이용하여 이미지 패턴을 학습시킨 결과, 학습된 알고리즘이 97%의 높은 정확도로 휘발성 유기 화합물을 검출할 수 있는 것을 확인하였다.In the present invention, as a result of detecting 35 different VOC substances using a fluorescent sensor array coated with a fluorescent compound and an image analysis technology, the indolizine-based fluorescent sensor array reacts to 35 types of VOCs and shows each change pattern. As a result of learning the image pattern using statistical analysis and machine learning algorithm, it was confirmed that the learned algorithm can detect volatile organic compounds with a high accuracy of 97%.

도 1은 인돌리진 구조의 분자오비탈 계산 결과를 나타낸 도면이다.
도 2는 본 발명의 신규 형광 화합물의 화학적 구조와 호모(HOMO) 및 루모(LUMO)의 모양을 나타낸 모식도이다.
도 3은 본 발명의 신규 형광 화합물의 제조방법을 나타낸 모식도이다.
도 4는 신규 합성된 형광 화합물들의 구조(GxF 1 ~ 25)를 나타낸 도면이다.
도 5는 신규 합성된 형광 화합물들의 구조(GxF 26 ~ 50)를 나타낸 도면이다.
도 6은 신규 합성된 형광 화합물들의 구조(GxF 51 ~ 75)를 나타낸 도면이다.
도 7은 전 가시광선 영역에 걸친 발광 파장을 보이는 형광 화합물의 특징을 나타낸 도면이다.
도 8은 형광 화합물 중 GxF 63 물질의 분자 오비탈의 모양과 용매의 유전율에 따른 형광 물성 변화를 나타낸 도면이다.
도 9는 전 가시광선 영역에서 GxF 물질들의 고체형광을 관찰한 도면이다.
도 10은 서로 다른 VOC 노출에 따른 GxF 물질의 고체상에서 형광 변화를 관찰한 도면이다.
도 11은 본 발명의 신규 형광 화합물인 GxF 물질을 고체상으로 고정한 형광 센서 어레이 구현예 및 UV 조건에서 센서 어레이의 형광 정도를 나타낸 도면이다.
도 12는 GxF 물질이 고체상으로 고정된 형광 센서 어레이에 VOC를 노출시키기 위한 밀폐 용기를 나타낸 도면이다. (a) GxF 1 ~ 25, (b) GxF 26 ~ 50, (c) GxF 51 ~ 75를 각각 고정한 센서 어레이이다.
도 13은 3D 프린팅을 활용한 형광 센서 어레이 모니터링용 디바이스 구현예를 나타낸 도면이다.
도 14는 자체 색정보 알고리즘 개발을 통한 VOC 노출 전후의 색정보 분석 과정을 나타낸 도면이다.
도 15는 형광 센서 어레이에 다양한 VOC를 노출시킨 후, 형광 정도를 관찰한 도면으로 각 VOC 별로 5번 반복 실험을 수행하였다.
도 16은 각각의 VOC에 대해 서로 다른 변화양상을 보이는 형광 센서 어레이를 나타낸 도면이다.
도 17은 VOC 종류에 따른 형광 센서 어레이 페턴 변화를 주성분 분석법으로 분석한 결과를 나타낸 도면이다.
도 18은 머신러닝 알고리즘을 이용하여 분석한 VOC 예측결과를 나타낸 도면이다.
1 is a diagram showing the molecular orbital calculation result of an indolizine structure.
FIG. 2 is a schematic diagram showing the chemical structure and shapes of HOMO and LUMO of the novel fluorescent compound of the present invention.
3 is a schematic diagram showing a method for preparing a novel fluorescent compound of the present invention.
4 is a diagram showing the structures (GxF 1 to 25) of newly synthesized fluorescent compounds.
5 is a diagram showing the structures (GxF 26 to 50) of newly synthesized fluorescent compounds.
6 is a diagram showing the structures (GxF 51 to 75) of newly synthesized fluorescent compounds.
7 is a diagram showing the characteristics of a fluorescent compound showing an emission wavelength over the entire visible light region.
8 is a diagram showing a change in fluorescence properties according to the shape of a molecular orbital of a GxF 63 material among fluorescent compounds and the dielectric constant of a solvent.
9 is a diagram illustrating solid fluorescence of GxF materials in the entire visible light region.
10 is a diagram illustrating a change in fluorescence in a solid phase of a GxF material according to different VOC exposures.
11 is a diagram showing an embodiment of a fluorescence sensor array in which a GxF material, which is a novel fluorescent compound of the present invention, is fixed in a solid phase and the degree of fluorescence of the sensor array under UV conditions.
12 is a view showing a sealed container for exposing VOCs to a fluorescent sensor array in which a GxF material is fixed in a solid phase. It is a sensor array in which (a) GxF 1 ~ 25, (b) GxF 26 ~ 50, and (c) GxF 51 ~ 75 are fixed respectively.
13 is a diagram showing an embodiment of a device for monitoring a fluorescent sensor array using 3D printing.
14 is a diagram showing a process of analyzing color information before and after VOC exposure through development of its own color information algorithm.
FIG. 15 is a diagram illustrating the degree of fluorescence after exposure of various VOCs to the fluorescence sensor array, and an experiment was repeated 5 times for each VOC.
16 is a diagram showing a fluorescence sensor array showing different patterns of change for each VOC.
17 is a view showing the result of analyzing the change of the fluorescence sensor array pattern according to the type of VOC by the principal component analysis method.
18 is a diagram showing VOC prediction results analyzed using a machine learning algorithm.

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

본 발명은 일관점에서, 하기 화학식 1로 표시되는 형광 화합물에 관한 것이다. In a single point of view, the present invention relates to a fluorescent compound represented by the following formula (1).

[화학식 1][Formula 1]

Figure pat00078
Figure pat00078

상기 화학식 1에서In Formula 1 above

R1는 수소; 니트릴기; 할로겐; 니트로기; C1-C6의 알콕시기; C6-C20의 아릴기; C5-C20의 시클로헤테로고리기; 보론기; 아자이드기; NR4R5(여기에서, R4 및 R5는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임), 니트릴, C1-C6의 알콕시, 할로겐, 보론기, 하이드록시기 또는 CH2NR4R5 (여기에서, R4 및 R5는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임)로 치환된 C6-C20의 아릴기; C1-C8의 직쇄 또는 측쇄 알킬기; C2-C8의 알케닐기; C2-C8의 알키닐기; C3-C8의 시클로알킬기; 또는 C4-C20의 헤테로아릴기이고,R 1 is hydrogen; Nitrile group; halogen; Nitro group; C1-C6 alkoxy group; C6-C20 aryl group; C5-C20 cycloheterocyclic group; Boron group; Azide group; NR 4 R 5 (wherein R 4 and R 5 are each independently hydrogen, C1-C10 alkyl group, C6-C20 aryl group or C4-C20 heteroaryl group), nitrile, C1-C6 alkoxy, halogen , A boron group, a hydroxy group, or CH 2 NR 4 R 5 (wherein R 4 and R 5 are each independently hydrogen, a C1-C10 alkyl group, a C6-C20 aryl group, or a C4-C20 heteroaryl group) A C6-C20 aryl group substituted with; C1-C8 linear or branched alkyl group; C2-C8 alkenyl group; C2-C8 alkynyl group; C3-C8 cycloalkyl group; Or a C4-C20 heteroaryl group,

R2는 수소; C1-C8의 직쇄 또는 측쇄 알킬기; C2-C8의 알케닐기; C2-C8의 알키닐기; C3-C8의 시클로알킬기; 하이드록시기; C1-C6의 알콕시기; 폴리에틸렌글라이콜기; 니트릴기; 니트로기; 카르복실기; 설포닐기; 아자이드기; 메탄설포닐기; 말레이미드기; 터셔리-부틸디메틸실릴기(TBS)로 보호된 알콜; 또는 NR6R7(여기에서, R6 및 R7는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임)이고,R 2 is hydrogen; C1-C8 linear or branched alkyl group; C2-C8 alkenyl group; C2-C8 alkynyl group; C3-C8 cycloalkyl group; Hydroxy group; C1-C6 alkoxy group; Polyethylene glycol group; Nitrile group; Nitro group; Carboxyl group; Sulfonyl group; Azide group; Methanesulfonyl group; Maleimide group; Alcohols protected by tertiary-butyldimethylsilyl group (TBS); Or NR 6 R 7 (wherein R 6 and R 7 are each independently hydrogen, a C1-C10 alkyl group, a C6-C20 aryl group or a C4-C20 heteroaryl group),

R3는 수소; 할로겐; 니트릴기; 보론기; 하이드록시기; COY(여기에서 Y는 수소, C1-C8의 직쇄 또는 측쇄 알킬기, C2-C8의 알케닐기, C2-C8의 알키닐기, C3-C8의 시클로알킬기, 또는 NR8R9(여기에서, R8 및 R9는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임]); C1-C6의 알콕시기; C6-C20의 아릴기; 또는 NR10R11(여기에서, R10 및 R11는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임), 니트릴 또는 할로겐으로 치환된 C6-C20의 아릴기이다.R 3 is hydrogen; halogen; Nitrile group; Boron group; Hydroxy group; COY (wherein Y is hydrogen, a C1-C8 linear or branched alkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, a C3-C8 cycloalkyl group, or NR 8 R 9 (herein, R 8 and Each R 9 is independently hydrogen, a C1-C10 alkyl group, a C6-C20 aryl group, or a C4-C20 heteroaryl group]); C1-C6 alkoxy group; C6-C20 aryl group; Or NR 10 R 11 (Wherein, R 10 and R 11 are each independently hydrogen, a C1-C10 alkyl group, a C6-C20 aryl group, or a C4-C20 heteroaryl group), a C6-C20 aryl group substituted with nitrile or halogen. .

본 발명에 있어서, R1은 수소; 트리플루오로메틸기(Trifluoromethyl); 아세틸기; 메톡시기; 또는 다이메틸아민기이고, 상기 R2는 메틸; 트리플루오로메틸페닐기; 페닐기; 메톡시페닐기; 또는 다이에틸아민페닐기이며, 상기 R3는 수소; 트리플루오로메틸기(Trifluoromethyl); 또는 아세틸기일 수 있다. In the present invention, R 1 is hydrogen; Trifluoromethyl group; Acetyl group; Methoxy group; Or a dimethylamine group, and R 2 is methyl; Trifluoromethylphenyl group; Phenyl group; Methoxyphenyl group; Or a diethylaminephenyl group, and R 3 is hydrogen; Trifluoromethyl group; Or it may be an acetyl group.

바람직하게, 상기 화학식 1은 하기 화학식 1-1 내지 화학식 1-75으로 구성된 군에서 선택된 1종 이상으로 표시될 수 있다. Preferably, Formula 1 may be represented by one or more selected from the group consisting of the following Formulas 1-1 to 1-75.

[화학식 1-1][Formula 1-1]

Figure pat00079
Figure pat00079

[화학식 1-2][Formula 1-2]

Figure pat00080
Figure pat00080

[화학식 1-3][Formula 1-3]

Figure pat00081
Figure pat00081

[화학식 1-4][Formula 1-4]

Figure pat00082
Figure pat00082

[화학식 1-5][Formula 1-5]

Figure pat00083
Figure pat00083

[화학식 1-6][Formula 1-6]

Figure pat00084
Figure pat00084

[화학식 1-7][Formula 1-7]

Figure pat00085
Figure pat00085

[화학식 1-8][Formula 1-8]

Figure pat00086
Figure pat00086

[화학식 1-9][Formula 1-9]

Figure pat00087
Figure pat00087

[화학식 1-10][Formula 1-10]

Figure pat00088
Figure pat00088

[화학식 1-11][Formula 1-11]

Figure pat00089
Figure pat00089

[화학식 1-12][Formula 1-12]

Figure pat00090
Figure pat00090

[화학식 1-13][Formula 1-13]

Figure pat00091
Figure pat00091

[화학식 1-14][Formula 1-14]

Figure pat00092
Figure pat00092

[화학식 1-15][Formula 1-15]

Figure pat00093
Figure pat00093

[화학식 1-16][Formula 1-16]

Figure pat00094
Figure pat00094

[화학식 1-17][Formula 1-17]

Figure pat00095
Figure pat00095

[화학식 1-18][Formula 1-18]

Figure pat00096
Figure pat00096

[화학식 1-19][Formula 1-19]

Figure pat00097
Figure pat00097

[화학식 1-20][Formula 1-20]

Figure pat00098
Figure pat00098

[화학식 1-21][Formula 1-21]

Figure pat00099
Figure pat00099

[화학식 1-22][Formula 1-22]

Figure pat00100
Figure pat00100

[화학식 1-23][Formula 1-23]

Figure pat00101
Figure pat00101

[화학식 1-24][Formula 1-24]

Figure pat00102
Figure pat00102

[화학식 1-25][Formula 1-25]

Figure pat00103
Figure pat00103

[화학식 1-26][Formula 1-26]

Figure pat00104
Figure pat00104

[화학식 1-27][Formula 1-27]

Figure pat00105
Figure pat00105

[화학식 1-28][Formula 1-28]

Figure pat00106
Figure pat00106

[화학식 1-29][Formula 1-29]

Figure pat00107
Figure pat00107

[화학식 1-30][Formula 1-30]

Figure pat00108
Figure pat00108

[화학식 1-31][Formula 1-31]

Figure pat00109
Figure pat00109

[화학식 1-32][Formula 1-32]

Figure pat00110
Figure pat00110

[화학식 1-33][Formula 1-33]

Figure pat00111
Figure pat00111

[화학식 1-34][Formula 1-34]

Figure pat00112
Figure pat00112

[화학식 1-35][Formula 1-35]

Figure pat00113
Figure pat00113

[화학식 1-36][Formula 1-36]

Figure pat00114
Figure pat00114

[화학식 1-37][Formula 1-37]

Figure pat00115
Figure pat00115

[화학식 1-38][Formula 1-38]

Figure pat00116
Figure pat00116

[화학식 1-39][Formula 1-39]

Figure pat00117
Figure pat00117

[화학식 1-40][Formula 1-40]

Figure pat00118
Figure pat00118

[화학식 1-41][Formula 1-41]

Figure pat00119
Figure pat00119

[화학식 1-42][Formula 1-42]

Figure pat00120
Figure pat00120

[화학식 1-43][Formula 1-43]

Figure pat00121
Figure pat00121

[화학식 1-44][Formula 1-44]

Figure pat00122
Figure pat00122

[화학식 1-45][Formula 1-45]

Figure pat00123
Figure pat00123

[화학식 1-46][Formula 1-46]

Figure pat00124
Figure pat00124

[화학식 1-47][Formula 1-47]

Figure pat00125
Figure pat00125

[화학식 1-48][Formula 1-48]

Figure pat00126
Figure pat00126

[화학식 1-49][Formula 1-49]

Figure pat00127
Figure pat00127

[화학식 1-50][Formula 1-50]

Figure pat00128
Figure pat00128

[화학식 1-51][Chemical Formula 1-51]

Figure pat00129
Figure pat00129

[화학식 1-52][Formula 1-52]

Figure pat00130
Figure pat00130

[화학식 1-53][Formula 1-53]

Figure pat00131
Figure pat00131

[화학식 1-54][Formula 1-54]

Figure pat00132
Figure pat00132

[화학식 1-55][Formula 1-55]

Figure pat00133
Figure pat00133

[화학식 1-56][Formula 1-56]

Figure pat00134
Figure pat00134

[화학식 1-57][Formula 1-57]

Figure pat00135
Figure pat00135

[화학식 1-58][Formula 1-58]

Figure pat00136
Figure pat00136

[화학식 1-59][Formula 1-59]

Figure pat00137
Figure pat00137

[화학식 1-60][Formula 1-60]

Figure pat00138
Figure pat00138

[화학식 1-61][Formula 1-61]

Figure pat00139
Figure pat00139

[화학식 1-62][Formula 1-62]

Figure pat00140
Figure pat00140

[화학식 1-63][Formula 1-63]

Figure pat00141
Figure pat00141

[화학식 1-64][Formula 1-64]

Figure pat00142
Figure pat00142

[화학식 1-65][Formula 1-65]

Figure pat00143
Figure pat00143

[화학식 1-66][Formula 1-66]

Figure pat00144
Figure pat00144

[화학식 1-67][Formula 1-67]

Figure pat00145
Figure pat00145

[화학식 1-68][Formula 1-68]

Figure pat00146
Figure pat00146

[화학식 1-69][Formula 1-69]

Figure pat00147
Figure pat00147

[화학식 1-70][Formula 1-70]

Figure pat00148
Figure pat00148

[화학식 1-71][Formula 1-71]

Figure pat00149
Figure pat00149

[화학식 1-72][Formula 1-72]

Figure pat00150
Figure pat00150

[화학식 1-73][Chemical Formula 1-73]

Figure pat00151
Figure pat00151

[화학식 1-74][Formula 1-74]

Figure pat00152
Figure pat00152

[화학식 1-75][Formula 1-75]

Figure pat00153
Figure pat00153

본 발명에 있어서, 상기 형광 화합물의 발광 파장은 400nm 내지 620nm이며, 액체상 또는 고체상 형광현상(solid state fluorescence)을 나타내는 것을 특징으로 한다.In the present invention, the fluorescent compound has an emission wavelength of 400 nm to 620 nm, and exhibits liquid or solid state fluorescence.

본 발명에서는 휘발성 유기 화합물을 실시간 모니터링하기 위해 인돌리진 골격체 기반의 신규한 형광 물질을 합성하고자 하였다. 먼저, 인돌리진 기반의 라이브러리 구축을 위하여 TD-DFT 계산법을 활용하여 분자오비탈 계산을 수행하였으며, 그 결과, 도 1에 나타난 바와 같이, 인돌리진 구조의 C1, C3, C6 위치의 HOMO와 LUMO lobe의 차이가 큰 것으로 판명되었다.In the present invention, in order to monitor volatile organic compounds in real time, a novel fluorescent material based on an indolizine skeleton was synthesized. First, molecular orbital calculations were performed using the TD-DFT calculation method to construct an indolizine-based library.As a result, as shown in FIG. 1, the HOMO and LUMO lobes at positions C1, C3, and C6 of the indolizine structure The difference turned out to be large.

이를 바탕으로 아래 구조와 같은 구조를 최종적으로 형광 물질 라이브러리 구축을 위해 설정 하였고 이를 갤럭시 플로어(GalaxyFluor; GxF, 이하, "GxF" 또는 "GxF 물질"로 표기함)로 명명하였으며, 양자계산 결과 GxF 물질의 경우 HOMO와 LUMO lobe의 구획화가 명확히 일어나고 있음을 확인하여 분자내 전하이동(Intramolecular Charge Transfer: ICT) 형상을 유도할 수 있음을 검증하였다 (도 2).Based on this, a structure like the one below was finally set up for the construction of a fluorescent material library, and it was named as Galaxy Floor (GalaxyFluor; GxF, hereinafter referred to as "GxF" or "GxF material"), and as a result of quantum calculation, GxF material In the case of, it was verified that the compartmentalization of the HOMO and LUMO lobe is clearly occurring, and it was verified that intramolecular charge transfer (ICT) shape can be induced (FIG. 2).

본 발명은 다른 관점에서, (a) 화학식 A의 화합물 및 화학식 B의 화합물을 반응시켜, 화학식 C의 화합물을 제조하는 단계; In another aspect, the present invention comprises the steps of: (a) reacting a compound of formula A and a compound of formula B to prepare a compound of formula C;

(b) 상기 화학식 C의 화합물과 에틸아크릴레이트(ethyl acrylate), 아세트산나트륨(sodium acetate) 및 구리아세트산 모노수화물(Copper(II) Acetate monohydrate)을 반응시켜 화학식 D의 화합물을 제조하는 단계;(b) reacting the compound of Formula C with ethyl acrylate, sodium acetate, and copper acetic acid monohydrate to prepare a compound of Formula D;

(c) 상기 화학식 D의 화합물 및 NBS(N-Bromosuccinimide)를 반응시켜 화학식 E의 화합물을 제조하는 단계; 및 (c) preparing a compound of Formula E by reacting the compound of Formula D and NBS (N-Bromosuccinimide); And

(d) 상기 화학식 E의 화합물 및 화학식 F의 화합물을 반응시켜 화학식 1의 화합물을 제조하는 단계를 포함하며, 하기 반응식 1로 표시되는 화학식 1의 형광 화합물의 제조방법에 관한 것이다.(d) reacting the compound of Formula E and the compound of Formula F to prepare a compound of Formula 1, and relates to a method for preparing a fluorescent compound of Formula 1 represented by the following Scheme 1.

[반응식 1][Scheme 1]

Figure pat00154
Figure pat00154

상기 반응식 1에서 R1는 수소; 트리플루오로메틸기(Trifluoromethyl); 아세틸기; 메톡시기; 또는 다이메틸아민기이고, 상기 R2는 메틸; 트리플루오로메틸페닐기; 페닐기; 메톡시페닐기; 또는 다이에틸아민페닐기이며, 상기 R3는 수소; 트리플루오로메틸기(Trifluoromethyl); 또는 아세틸기일 수 있다. In Scheme 1, R 1 is hydrogen; Trifluoromethyl group; Acetyl group; Methoxy group; Or a dimethylamine group, and R 2 is methyl; Trifluoromethylphenyl group; Phenyl group; Methoxyphenyl group; Or a diethylaminephenyl group, and R 3 is hydrogen; Trifluoromethyl group; Or it may be an acetyl group.

구체적으로, 도 3에 나타난 방법으로 본 발명의 형광 화합물인 GxF 물질을 합성할 수 있으며, 보다 구체적으로 본 발명에 따른 형광 화합물의 제조방법을 단계별로 상세히 설명하면 다음과 같다. Specifically, the GxF material, which is the fluorescent compound of the present invention, can be synthesized by the method shown in FIG. 3, and more specifically, the method of preparing the fluorescent compound according to the present invention will be described step by step in detail.

a) 단계: 피리딘 물질의 아실화a) step: acylation of the pyridine material

본 단계에서는 화합물 B를 알킬 할라이드를 이용하여 아실화 한다. In this step, compound B is acylated using an alkyl halide.

상기의 아실화는 당업계에서 알려진 통상의 방법을 이용하여 제한 없이 수행될 수 있는데, 바람직하게는 상기 알킬 할라이드로서 화합물 B는 R2 치환기를 함유하는 2-브로모-1-[4-(트리플루오로메틸)페닐]에탄-1-온(2-bromo-1-[4-(trifluoromethyl)-phenyl]ethane-1-one), 클로로아세톤(chloroacetone), 2-브로모아세토페논(2-bromoacetophenone), 2-브로모4-메톡시아세토페논(2-bromo-4-methoxyacetophenone), 2-브로모-4'-(다이에틸아미노_아세토-페논(2-Bromo-4'-(diethylamino)aceto-phenone)등과 같은 친전자성 모이어티(electrophilic moiety)를 함유하는 것을 사용하고 R3 치환기를 갖는 피리딘을 사용한다. The acylation may be performed without limitation using a conventional method known in the art. Preferably, as the alkyl halide, compound B is 2 -bromo-1-[4-(tri Fluoromethyl)phenyl]ethane-1-one (2-bromo-1-[4-(trifluoromethyl)-phenyl]ethane-1-one), chloroacetone, 2-bromoacetophenone ), 2-bromo-4-methoxyacetophenone, 2-bromo-4'-(diethylamino_aceto-phenone (2-Bromo-4'-(diethylamino)aceto) -Phenone), etc. containing an electrophilic moiety is used, and a pyridine having an R 3 substituent is used.

구체적으로 알킬할라이드와 피리딘의 유기혼합물 용액을, 적정 온도(20℃ 내지 100℃)에서 1 ~ 24시간 동안 교반하여 피리딘 염 화합물을 산출한다. 이때, 상기 반응을 보내는데 있어 사용되는 유기용매는 통상의 유기용매를 사용할 수 있으며, 알킬할라이드 및 피리딘 화합물의 구체적인 종류에 따라 당업자가 적절히 결정할 수 있다. Specifically, a solution of an organic mixture of alkyl halide and pyridine is stirred at an appropriate temperature (20°C to 100°C) for 1 to 24 hours to obtain a pyridine salt compound. At this time, the organic solvent used to send the reaction may be a conventional organic solvent, and can be appropriately determined by a person skilled in the art according to specific types of alkyl halide and pyridine compounds.

b) 단계: 1,3-디폴라 고리화 반응b) Step: 1,3-dipolar cyclization reaction

a) 단계에서 얻어진 아실화된 화학식 c로 표현되는 화합물을 에틸아크릴레이트(ethyl acrylate), 아세트산나트륨(sodium acetate) 및 구리아세트산 모노수화물(Copper(II) Acetate monohydrate)을 반응시켜 화학식D 로 표현되는 화합물을 얻는 단계이다. The acylated compound represented by formula c obtained in step a) is reacted with ethyl acrylate, sodium acetate, and copper acetic acid monohydrate. This is the step of obtaining a compound.

구체적으로, 상기 a) 단계에서 얻어진 아실화된 화합물 유기혼합물 용액을, 적정 온도 (50℃ 내지 120℃)에서 1 ~ 24시간 동안 교반한뒤, 통상의 추출, 건조, 여과, 농축 및 정제 과정을 거쳐 화학식 D로 표현되는 화합물을 산출한다. 이때, 상기 반응을 보내는데 있어 사용되는 유기용매는 통상의 유기용매를 사용할 수 있으며, 화합물의 구체적인 종류에 따라 당업자가 적절히 결정할 수 있다. Specifically, the acylated compound organic mixture solution obtained in step a) is stirred at an appropriate temperature (50° C. to 120° C.) for 1 to 24 hours, and then the usual extraction, drying, filtration, concentration, and purification processes are performed. Through the process, a compound represented by Formula D is obtained. At this time, the organic solvent used to send the reaction may be a conventional organic solvent, and can be appropriately determined by a person skilled in the art according to the specific type of the compound.

c)단계: Br 치환기 도입 단계 c) step: Br substituent introduction step

화학식 D로 표현되는 화합물을 비누화 반응(Saponification)과 브롬화 (Bromination) 반응을 거쳐 화학식 E로 표현되는 화합물을 얻는 단계이다.This is a step of obtaining a compound represented by Formula E through saponification and bromination reactions of the compound represented by Formula D.

상기의 반응은 당업계에서 알려진 통상의 방법을 이용하여 제한 없이 수행될 수 있는데, 바람직하게는 먼저 상기 화학식 D로 표현되는 화합물을 유기용매에 용해 시키고 수산화리튬(Lithium hydroxide), 수산화칼륨(Potassium hydroxide), 수산화 나트륨(sodium hydroxide)과 같은 강염기를 첨가 하고 생성된 유기혼합물 용액을 적정 온도(50℃ 내지 120℃)에서 1 ~ 24시간 동안 교반한뒤, 통상의 추출, 건조, 여과, 농축 및 정제 과정을 거쳐 중간 물질을 얻어 낸다. 이후 중간 물질을 적절한 유기용매에 녹이고 이후 NBS(N-Bromosuccinimide)를 처리한후 생성된 유기혼합물 용액을 적정 온도 (50℃ 내지 120℃)에서 1 ~ 24시간 동안 교반한뒤, 통상의 추출, 건조, 여과, 농축 및 정제 과정을 거쳐 화학식 E로 표현되는 화합물을 산출한다. 이때, 상기 반응을 보내는데 있어 사용되는 유기용매는 통상의 유기용매를 사용할 수 있으며, 화합물의 구체적인 종류에 따라 당업자가 적절히 결정할 수 있다. The above reaction can be carried out without limitation using a conventional method known in the art. Preferably, the compound represented by Formula D is first dissolved in an organic solvent, and then lithium hydroxide and potassium hydroxide. ), a strong base such as sodium hydroxide is added, and the resulting organic mixture solution is stirred at an appropriate temperature (50°C to 120°C) for 1 to 24 hours, followed by normal extraction, drying, filtration, concentration and purification Through the process, an intermediate material is obtained. After dissolving the intermediate material in an appropriate organic solvent, after treatment with NBS (N-Bromosuccinimide), the resulting organic mixture solution was stirred at an appropriate temperature (50℃ to 120℃) for 1 to 24 hours, followed by normal extraction and drying. , Filtration, concentration and purification to yield the compound represented by the formula (E). At this time, the organic solvent used to send the reaction may be a conventional organic solvent, and can be appropriately determined by a person skilled in the art according to the specific type of the compound.

d) 단계: Suzuki coupling 단계d) Step: Suzuki coupling step

화학식 E로 표현되는 화합물을 화학식 F로 표현되는 화합물과 Pd 촉매를 사용하여 반응 시켜 본 발명의 형광 화합물을 얻는 단계이다. This is a step to obtain a fluorescent compound of the present invention by reacting a compound represented by Formula E with a compound represented by Formula F using a Pd catalyst.

상기의 반응은 당업계에서 알려진 통상의 방법을 이용하여 제한 없이 수행될 수 있는데, 먼저 상기 R1 치환기를 포함하는 화학식 F로 표현되는 화합물은 특별히 제한되지 않으며, 바람직하게는 경우 트리플루오로페닐 보론산(triflulorophenyl boronic acid), 4-아세틸페닐 보론산(4-acetylphenyl boronic acid), 페닐 보론산(phenyl boronic acid), 4-메톡시페닐 보론산(4-methoxyphenyl boronic acid), 4-(다이메틸아미노)페닐 보론산(4-(dimethylamino)phenyl boronic acid)을 사용할 수 있다. 상기의 반응은, 통상의 유기용매 내에서 R1 치환기를 갖는 화학식 F로 표현되는 화합물과 c) 단계에서 얻어진 화학식 E로 표현되는 화합물을 Pd(PPh3)4과 Sodium carbonate와 혼합하고, 생성된 유기혼합물 용액을 적정 온도 (50℃ 내지 120℃)에서 1 ~ 24시간 동안 교반한뒤, 통상의 추출, 건조, 여과, 농축 및 정제 과정을 거쳐 본 발명의 형광 화합물을 얻어 낸다. 이때, 상기 반응을 보내는데 있어 사용되는 유기용매는 통상의 유기용매를 사용할 수 있으며, 화합물의 구체적인 종류에 따라 당업자가 적절히 결정할 수 있다. The above reaction may be carried out without limitation using a conventional method known in the art. First, the compound represented by Formula F including the R1 substituent is not particularly limited, and preferably, trifluorophenyl boronic acid (triflulorophenyl boronic acid), 4-acetylphenyl boronic acid, phenyl boronic acid, 4-methoxyphenyl boronic acid, 4-(dimethylamino ) Phenyl boronic acid (4- (dimethylamino) phenyl boronic acid) can be used. The above reaction is performed by mixing a compound represented by Formula F having an R 1 substituent and a compound represented by Formula E obtained in step c) with Pd(PPh 3 ) 4 and Sodium carbonate in a common organic solvent, The organic mixture solution is stirred at an appropriate temperature (50° C. to 120° C.) for 1 to 24 hours, and then subjected to conventional extraction, drying, filtration, concentration, and purification processes to obtain the fluorescent compound of the present invention. At this time, the organic solvent used to send the reaction may be a conventional organic solvent, and can be appropriately determined by a person skilled in the art according to the specific type of the compound.

본 발명의 구체적인 일구현예에서는 조합화학적 합성법을 개발하여 화학식 2 내지 화학식 76으로 표시되는 총 75가지의 신규 형광 물질을 합성하였으며, 각각 GxF 1 내지 GxF 75로 명명하였다.In a specific embodiment of the present invention, a combinatorial chemical synthesis method was developed to synthesize a total of 75 novel fluorescent substances represented by Chemical Formulas 2 to 76, and were named GxF 1 to GxF 75, respectively.

본 발명의 방법으로 합성된 GxF 물질들의 광물리학적 특성을 관찰하여 표 1에 나타내었다. GxF 물질들은 발광파장이 416 nm에서 620 nm에 이르는 전 가시광선 영역을 아우르는 것을 확인하였고, 특히 도 7에 나타난 바와 같이 고체상 형광현상을 (solid state fluorescence) 나타낼 수 있다는 것을 확인하였다.The photophysical properties of the GxF materials synthesized by the method of the present invention were observed and shown in Table 1. It was confirmed that the GxF materials cover the entire visible light range from 416 nm to 620 nm, and in particular, as shown in FIG. 7, it was confirmed that they can exhibit solid state fluorescence.

초기에 예상한대로 이 물질들이 ICT 현상을 통해 주변 환경에 감응하여 형광물성 변화가 나타나는지를 확인하였으며, 도 8에 나타난 바와 같이, GxF 63 물질의 경우 용액상에서 용매의 유전율 (dielectric constant)변화에 따라 형광 밝기에 영향을 받는다는 것을 확인하였다.As initially expected, it was confirmed that these materials responded to the surrounding environment through the ICT phenomenon, and the fluorescent properties changed. As shown in FIG. 8, in the case of the GxF 63 material, fluorescence according to the change of the dielectric constant of the solvent in the solution phase. It was confirmed that it was affected by the brightness.

또한, GxF 물질이 고체상태 형광을 나타내는지를 확인한 결과, 4가지의 서로 다른 GxF 물질들(GxF 1, GxF 3, GxF 5, GxF 11)이 고체상태에서도 전 가시 광선영역을 아우르는 발광 파장을 지니고 있음을 확인하였다.In addition, as a result of confirming whether the GxF material exhibits solid state fluorescence, four different GxF materials (GxF 1, GxF 3, GxF 5, GxF 11) have an emission wavelength covering the entire visible light region even in a solid state. Was confirmed.

상기 결과를 바탕으로, 본 발명에서는 GxF 물질들이 VOC에 감응하여 고체상태에서 형광 변화가 일어나는지 확인하기 위해, GxF 15, GxF 40, GxF 65 물질을 필름으로 유리 위에 도포한 다음, 3가지 서로 다른 VOC 증기(Ethyl acetate, acetic acid, ethylamine)를 노출시켜 형광 변화를 관찰하였다. 그 결과, 도 10에 나타난 바와 같이, 세 가지 물질이 세 가지의 서로 다른 VOC에 노출되어 제 각각의 형광 현상의 변화가 유도 될 수 있음을 확인하였다.Based on the above results, in the present invention, in order to confirm whether the fluorescence change occurs in the solid state in response to VOCs of GxF materials, GxF 15, GxF 40, and GxF 65 materials are applied as a film on the glass, and then three different VOCs Changes in fluorescence were observed by exposure to vapor (Ethyl acetate, acetic acid, ethylamine). As a result, as shown in FIG. 10, it was confirmed that the three substances were exposed to three different VOCs to induce a change in each of the fluorescence phenomena.

본 발명은 또 다른 관점에서, 상기 형광 화합물을 포함하는 휘발성 유기화합물(Volatile Organic Compounds; VOC) 검출용 조성물에 관한 것이다. In another aspect, the present invention relates to a composition for detecting volatile organic compounds (VOC) including the fluorescent compound.

본 발명은 또 다른 관점에서, 상기 형광 화합물이 고정된 휘발성 유기화합물 검출용 센서 어레이에 관한 것이다. In another aspect, the present invention relates to a sensor array for detecting a volatile organic compound to which the fluorescent compound is fixed.

본 발명에 있어서, 상기 휘발성 유기화합물은 특별한 제한은 없지만, 바람직 하게는 에탄올(Ethanol), 1-부탄올(1-Butanol), 1-(펜탄올(1-Pentanol), 1-헥산올(1-Hexanol), 3-헥산올(3-Hexanol), 페놀(Phenol), 1-헵탄올(1-Heptanol), 1-데칸올(1-Decanol), 2-데칸올(2-Decanol), 3-데칸올(3-Decanol), 1-도데칸올(1-Dodecanol), 사이클로펜탄올(Cyclopentanol), 사이클로헥산올(Cyclohexanol), 사이클로헵탄올(Cycloheptanol), 벤젠(Benzene), 아세톤(Acetone), 2-옥탄온(2-Octanone), 2-피콜린(2-Picoline), 3-피콜린(3-Picoline), 3-아세틸피리딘(3-Acetylpyridine), 4-아세틸피리딘(4-Acetylpyridine), 2-헵틸아민(2-Heptylamine), 디-엔-프로필아민(Di-n-propylamine), 2-페닐에틸아민(2-Phenylethylamine), 사이클로옥틸아민(Cyclooctylaime), 프로피온산(Propionic acid), 3-브롬프로피온산(3-Bromopropionic acid), 2-메틸부티르산(2-Methylbutyric acid), 포름산(Formic acid), 발레르산(Valeric acid), 트리플루오로 아세트산(Trifluoroacetic acid), 브로모아세트산(Bromoacetic acid), 아세트산(Acetic acid), 트리클로로아세트산(Trichloroacetic acid) 및 2-클로로프로피온산(2-Chloropropionic acid)으로 구성된 군에서 선택된 1종 이상의 물질일 수 있다. In the present invention, the volatile organic compound is not particularly limited, but preferably ethanol (Ethanol), 1-butanol (1-Butanol), 1- (pentanol (1-Pentanol), 1-hexanol (1- Hexanol), 3-hexanol (3-Hexanol), phenol (Phenol), 1-heptanol (1-Heptanol), 1-decanol (1-Decanol), 2-decanol (2-Decanol), 3- Decanol, 1-Dodecanol, Cyclopentanol, Cyclohexanol, Cycloheptanol, Benzene, Acetone, 2 -Octanone, 2-Picoline, 3-Picoline, 3-acetylpyridine, 4-Acetylpyridine, 2 -Heptylamine (2-Heptylamine), di-en-propylamine (Di-n-propylamine), 2-phenylethylamine (2-Phenylethylamine), cyclooctylamine (Cyclooctylaime), propionic acid (Propionic acid), 3-bromine Propionic acid (3-Bromopropionic acid), 2-Methylbutyric acid, Formic acid (Formic acid), Valeric acid (Valeric acid), Trifluoroacetic acid (Trifluoroacetic acid), Bromoacetic acid (Bromoacetic acid), acetic acid It may be one or more substances selected from the group consisting of (Acetic acid), trichloroacetic acid, and 2-Chloropropionic acid.

본 발명에 있어서, 상기 센서 어레이는 기판에 화학식 2 내지 화학식 76으로 표시되는 화합물이 패턴화 되어 고정되어 있을 수 있다. 본 발명에서는 기판으로 바람직하게 필터 페이퍼를 사용하였으나, 이에 한정되지 않고 형광 물질을 고정할 수 있는 물질을 제한없이 사용할 수 있다. In the present invention, the sensor array may be fixed by patterning the compounds represented by Chemical Formulas 2 to 76 on a substrate. In the present invention, filter paper is preferably used as the substrate, but the present invention is not limited thereto, and a material capable of fixing the fluorescent material may be used without limitation.

본 발명의 구체적인 일구현예에서는, 형광 물질들의 균일한 도포를 위하여 필터 페이터 상에 왁스 프린팅을 활용하여 어레이 틀을 제조하였으며, 75개의 GxF 물질을 왁스로 코팅된 어레이에 스팟팅(spotting)을 하였다. 도 11과 같이, 2.5 cm X 2.5 cm 크기의 형광센서 어레이당 25 가지의 신규 형광체가 들어간 센서 어레이를 제조하였으며, 형광 물질의 발광정도를 UV 상에서 관찰하였다. In a specific embodiment of the present invention, an array frame was manufactured using wax printing on a filter paper for uniform application of fluorescent materials, and 75 GxF materials were spotted on an array coated with wax. . As shown in FIG. 11, a sensor array containing 25 new phosphors per fluorescent sensor array having a size of 2.5 cm X 2.5 cm was prepared, and the degree of luminescence of the fluorescent material was observed under UV.

본 발명은 또 다른 관점에서, 상기 형광 화합물을 이용한 휘발성 유기 화합물 검출 방법에 관한 것이다. In another aspect, the present invention relates to a method for detecting a volatile organic compound using the fluorescent compound.

본 발명에 있어서, 상기 방법은 (a) 형광 화합물이 고정된 휘발성 유기 화합물 검출용 센서 어레이에 휘발성 물질을 노출시킨 후, 형광 패턴 변화를 측정하는 단계; 및 In the present invention, the method comprises the steps of: (a) exposing a volatile material to a sensor array for detecting a volatile organic compound to which a fluorescent compound is immobilized, and then measuring a change in a fluorescence pattern; And

(b) 상기 패턴 변화를 머신 러닝 알고리즘을 통해 학습시키는 단계;를 포함하는 방법으로 수행될 수 있다. (b) learning the pattern change through a machine learning algorithm.

본 발명에 있어서, 상기 (b) 단계는 패턴의 RGB 거리, 색 정보값(Hue value) 및 CIEDE2000 정보를 머신 러닝 알고리즘을 통해 학습시키는 것을 특징으로 한다. In the present invention, step (b) is characterized in that the RGB distance, hue value, and CIEDE2000 information of the pattern are learned through a machine learning algorithm.

본 발명의 구체적일 일구현예에서, 형광 센서 어레이가 VOC와 반응하여 특정 형광 패턴을 형성 할 수 있는지 여부를 확인하기 위하여 75종의 GxF 물질이 각각 25종씩 도포된 3가지의 형광 센서 어레이를 도 12과 같은 밀폐된 용기 안에 도입하여 VOC에 노출 시키고자 하였다. In one specific embodiment of the present invention, in order to check whether the fluorescent sensor array can react with VOC to form a specific fluorescent pattern, three fluorescent sensor arrays each coated with 75 kinds of GxF materials are illustrated. It was intended to be exposed to VOC by introducing it into a closed container such as 12

또한, 형광 어레이의 패턴 형성에 관한 연구를 위해서 노출된 센서 어레이의 VOC 노출에 따른 색, 밝기 변화를 동일하게 볼 수 있는 시스템의 최적화가 필요하였으며, 본 발명에서는 이를 위해 3D 프린팅 기술을 활용하여 자외선 광원의 위치와 스마트폰 카메라의 위치를 조절하여 이상적인 빛 구도를 구현할 수 있는 시스템을 고안하였으며, 이를 도 13에 나타내었다. 이를 통해 얻어진 형광 센서 어레이의 색변화 정보를 자동으로 분석할 수 있는 머신 러닝 알고리즘을 개발하여 도 14에 나타난 방법과 같이, RGB, HSV, CIELAB의 색공간안에서의 변화 정보를 분석하였다. In addition, for a study on the pattern formation of a fluorescent array, it was necessary to optimize a system that can see changes in color and brightness according to VOC exposure of the exposed sensor array. A system capable of implementing an ideal light composition was devised by adjusting the location of the light source and the location of the smartphone camera, which is shown in FIG. 13. A machine learning algorithm capable of automatically analyzing the color change information of the fluorescence sensor array obtained through this was developed, and change information in the color space of RGB, HSV, and CIELAB was analyzed as shown in FIG. 14.

35가지 서로 다른 VOC 물질에 대해 5반복 노출시킨 다음, 형광 센서들의 각 변화를 모니터링 한 결과, 도 16에 나타난 바와 같이, 인돌리진 기반 형광 센서 어레이가 35가지의 VOC에 반응하여 제각각의 변화 패턴을 보여준다는 것을 확인하였다. As a result of monitoring each change of the fluorescent sensors after 5 repeated exposures to 35 different VOC materials, as shown in FIG. 16, the indolizine-based fluorescent sensor array reacts to 35 types of VOCs to determine each change pattern. I confirmed that it shows.

특히 이러한 변화 패턴들의 경우 주성분 분석법(Principle Component Analysis)을 통해 각각의 VOC들이 구분되어 질 수 있음을 확인하였으며, 노출 전/후의 Hue value(색정보값)을 이용하여 PCA(Principle Component Analysis)분석한 결과 카복실산(Carboxylic acid, 58.1%), 알콜(Alcohol, 57.6%), 지방족 아민(Aliphatic amine, 61.9%) 및 방향족 아민(Aromatic amine, 53.4%)으로 판별이 되는 것을 확인하였다 (도 17). In particular, in the case of these change patterns, it was confirmed that each VOC can be classified through principle component analysis, and PCA (Principle Component Analysis) analysis was performed using the Hue value (color information value) before/after exposure. As a result, it was confirmed that it was identified as carboxylic acid (Carboxylic acid, 58.1%), alcohol (Alcohol, 57.6%), aliphatic amine (Aliphatic amine, 61.9%) and aromatic amine (Aromatic amine, 53.4%) (FIG. 17).

상기 결과를 토대로 인공지능을 활용하여 VOC 종류를 더 구분 지어줄 수 있는지 확인하기 위해 형광 센서 어레이의 패턴 변화 정보 중에서 RGB, Hue value, CIEDE2000(색의 밝기와 색의 차이값)를 머신 러닝 알고리즘(machine learning algorithm)에 학습시켜 VOC 판별 정도를 확인하였다. 그 결과 도 18에 나타난 바와 같이, 학습된 알고리즘이 97%의 높은 정확도로 형광 센서 이미지 패턴 변화 분석을 통해 VOC를 정확히 예측해 낼 수 있음을 확인 하였다. Based on the above results, RGB, Hue value, and CIEDE2000 (difference between color brightness and color) among the pattern change information of the fluorescence sensor array are used in a machine learning algorithm ( machine learning algorithm) and confirmed the degree of VOC discrimination. As a result, as shown in FIG. 18, it was confirmed that the learned algorithm can accurately predict VOC through analysis of changes in the fluorescence sensor image pattern with a high accuracy of 97%.

즉, 본 발명에서는 인돌리진 기반 신규 형광 중심골격이 전 가시 광선 영역을 아우를수 있는 형광 물질들을 만들어 낼 수 있음을 확인하였으며, 특히, 신규 인돌리진 형광 물질이 고체상에서의 형광현상을 나타낼 수 있음을 확인하였고 주변 환경에 감응하여 형광 물성 변화가 일어 날 수 있음을 확인하였다.That is, in the present invention, it was confirmed that the new fluorescent central skeleton based on indolizine can produce fluorescent materials that can cover the entire visible light region, and in particular, the novel indolizine fluorescent material can exhibit a fluorescence phenomenon in the solid phase. And it was confirmed that changes in fluorescence properties may occur in response to the surrounding environment.

또한, 신규 형광 물질의 특징을 활용하여 VOC 검출용 형광센서 어레이를 구축하였으며, 구축된 센서 어레이가 특정 VOC에 감응하여 특이적 형광 패턴을 형성할 뿐만 아니라. 이미지 분석기술과 머신러닝 알고리즘을 활용하여 이렇게 형성된 패턴을 머신 러닝 알고리즘에 학습시킨 결과, 높은 정확도로 VOC를 검출할 수 있는 것을 확인하였다.In addition, a fluorescence sensor array for VOC detection was constructed by utilizing the characteristics of a novel fluorescent material, and the constructed sensor array not only forms a specific fluorescence pattern in response to a specific VOC. As a result of learning the pattern formed in this way into a machine learning algorithm using image analysis technology and machine learning algorithm, it was confirmed that VOC can be detected with high accuracy.

이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다.Hereinafter, the present invention will be described in more detail through examples.

이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.These examples are for illustrative purposes only, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not construed as being limited by these examples.

인돌리진 기반 신규 형광 물질 합성Synthesis of new fluorescent materials based on indolizine

본 발명에서는 휘발성 유기 화합물을 실시간 모니터링하기 위해 인돌리진 골격체 기반의 신규한 형광 물질을 합성하였다. In the present invention, a novel fluorescent material based on an indolizine skeleton was synthesized to monitor volatile organic compounds in real time.

구체적으로, 반응식 1 및 도 3에 나타난 방법으로 신규 형광 물질인 갤럭시 플로어(GalaxyFluor; GxF)를 합성하였으며, 화학식 1의 형광 화합물이 하기와 같은 치환기를 가지도록 각각 조합하여 최종 75종의 신규한 GxF 물질을 합성하였다:Specifically, a novel fluorescent material, Galaxy Fluor (GxF), was synthesized by the method shown in Scheme 1 and FIG. 3, and the fluorescent compounds of Formula 1 were each combined to have the following substituents, resulting in a final 75 kinds of new GxFs. The material was synthesized:

R1: 수소(-H), 트리플루오로메틸기(Trifluoromethyl; -CF3), 아세틸기(-COCH3), 메톡시기(-OCH3), 다이메틸아민이기(Dimethylamine; DMA; -N(CH3)2)R 1: hydrogen (-H), trifluoromethyl group (Trifluoromethyl; -CF 3), acetyl group (-COCH 3), a methoxy group (-OCH 3), dimethyl amine is (Dimethylamine; DMA; -N (CH 3 ) 2 )

R2: 메틸(-CH3), 트리플루오로메틸페닐기(Trifluoromethylphenyl; -CF3Ph), 페닐기(-Ph), 메톡시페닐기(OCH3Ph), 다이에틸아민페닐기(Diethylaminephenyl; -N(C2H5)2Ph)R 2 : methyl (-CH 3 ), trifluoromethylphenyl group (Trifluoromethylphenyl; -CF 3 Ph), phenyl group (-Ph), methoxyphenyl group (OCH 3 Ph), diethylaminephenyl group (Diethylaminephenyl; -N(C 2 H 5 ) 2 Ph)

R3: 수소(-H), 트리플루오로메틸기(Trifluoromethyl; -CF3), 아세틸기(-COCH3).R 3 : hydrogen (-H), trifluoromethyl (-CF 3 ), acetyl group (-COCH 3 ).

1H 및 13C NMR 스펙트럼은 JEOL ECZ-600R (JEOL Ltd, Japan)를 사용하여 기록되었으며, 화학적 이동(chemical shift)은 내부 테트라메틸실란 표준의 ppm의 낮은 장(downfield) 범위를 측정하였다. The 1 H and 13 C NMR spectra were recorded using JEOL ECZ-600R (JEOL Ltd, Japan), and the chemical shift measured the downfield range of ppm of the internal tetramethylsilane standard.

다중도(multiplicity)는 다음과 같이 표시하였다: s(singlet); d(doublet); t(triplet); q(quartet); m(multiplet); dd(doublet of doublet); ddd(doublet of doublet of doublet); dt(doublet of triplet); td(triplet of doublet); brs(broad singlet).The multiplicity was expressed as follows: s (singlet); d(doublet); t(triplet); q(quartet); m (multiplet); dd (doublet of doublet); ddd (doublet of doublet of doublet); dt (doublet of triplet); td (triplet of doublet); brs (broad singlet).

커플링 상수는 Hz로 기록하였다. 질량 분석(routine mass analyses)은 역상컬럼(C-18, 50Х 2.1mm, 5㎛)이 구비된 LC/MS 시스템과 전자 분무 이온화(ESI) 또 는 대기압 화학 이온화(APCI)를 이용한 광다이오드 분석 탐지기 상에서 수행되었다.Coupling constants were reported in Hz. Routine mass analyses are an LC/MS system equipped with a reversed-phase column (C-18, 50 Х 2.1 mm, 5 μm) and a photodiode analysis detector using electron spray ionization (ESI) or atmospheric pressure chemical ionization (APCI). Performed on.

화합물의 분자량 분석은 고분해능 질량분석기(LRMS; high-resolution mass spectrometry)에 의해 확인하였다. LRMS 분석은 LCMS-2020 (Shimadzu, Japan) 를 사용하여 수행하였다.The molecular weight analysis of the compound was confirmed by high-resolution mass spectrometry (LRMS). LRMS analysis was performed using LCMS-2020 (Shimadzu, Japan).

합성한 75종의 GxF 물질은 도 4 내지 도 6에 나타내었으며, 물질 각각의 합성 방법은 다음과 같다:The synthesized 75 kinds of GxF materials are shown in FIGS. 4 to 6, and the synthesis method of each of the materials is as follows:

<GxF 1 ~ 5><GxF 1 ~ 5>

IA-E : 하기 반응식 2와 같이 합성하였으며, 구체적으로, 4(트리플루오로메틸)피리딘(4-(trifluoromethyl)pyridine, 637 μL, 5.50 mmol) 및 2-브로모-1-[4-(4(트리플루오로메틸)-페닐]에탄-1-온(2-bromo-1-[4-(trifluoromethyl)-phenyl]ethane-1-one, 1.54 g, 5.70 mmol)이 포함된 디메틸포름아미드(dimethylformamide; DMF, 10.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(ethyl acrylate, 293 μL, 2.75 mmol), 구리(II) 아세테이트 모노하이드레이트(copper(II) acetate monohydrate, 1.64 g, 8.25 mmol) 및 소듐 아세테이트(sodium acetate, 1.35 g, 16.5 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트(copper acetate)를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(silica-gel flash column chromatography, EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IA-E(518 mg, 1.20 mmol, 43.8% 수율)를 수득 하였다. IA-E : Synthesized as in Scheme 2 below, specifically, 4 (trifluoromethyl) pyridine (4- (trifluoromethyl) pyridine, 637 μL, 5.50 mmol) and 2-bromo-1-[4- (4 (trifluoro Dimethylformamide (dimethylformamide; DMF, containing romethyl)-phenyl]ethane-1-one (2-bromo-1-[4-(trifluoromethyl)-phenyl]ethane-1-one, 1.54 g, 5.70 mmol) 10.0 mL) was stirred at 100° C. overnight, and then ethyl acrylate (293 μL, 2.75 mmol), copper (II) acetate monohydrate, 1.64 g, 8.25 mmol) and sodium Acetate (sodium acetate, 1.35 g, 16.5 mmol) was added and stirred for 16 hours at 100° C. After completion of the reaction, it was monitored by TLC, and then copper acetate was removed by filtration through a pad of Celite. , The resulting filtrate was concentrated in vacuo The resulting crude product was washed with water and the organic material was extracted 3 times with DCM The extracted organic material was combined, dried over anhydrous Na 2 SO 4 and then concentrated. The organic phase was purified by silica-gel flash column chromatography (1-15% hexane containing EtOAc) to obtain a yellow solid compound IA-E (518 mg, 1.20 mmol, 43.8% yield). I did.

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 10.0 (d, J = 7.2 Hz, 1H), 8.70 (s, 1H), 7.91 (d, J = 7.6 Hz 2H), 7.82 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H); 13C NMR(100 MHz, CDCl3), δ 184.0, 162.8, 141.9, 137.7, 133.3, 132.6, 129.3, 128.9, 125.3, 124.7, 124.0, 122.6, 122.0, 121.2, 117.1, 110.9, 108.9, 60.6, 14.4. 1 H NMR (400 MHz, CDCl 3 ) δ 10.0 (d, J = 7.2 Hz, 1H), 8.70 (s, 1H), 7.91 (d, J = 7.6 Hz 2H), 7.82 (s, 1H), 7.79 ( d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 184.0, 162.8, 141.9, 137.7, 133.3, 132.6, 129.3, 128.9, 125.3, 124.7, 124.0, 122.6, 122.0, 121.2, 117.1, 110.9, 108.9, 60.6, 14.4.

IA-B : IA-E(517.9 mg, 1.206 mmol)가 포함된 메탄올(10 mL)에 KOH (5386 mg, 96.00 mmol)를 첨가한 후, 실온에서 하룻밤 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 갈색고체의 화합물 IA-A를 수득하였다. IA-B : KOH (5386 mg, 96.00 mmol) was added to methanol (10 mL) containing IA-E (517.9 mg, 1.206 mmol), followed by stirring at room temperature overnight. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water and dried in a drying oven to obtain a brown solid compound IA-A.

수득한 화합물 IA-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IA-A이 포함된 DMF (10.0 mL)에 소듐 바이카보네이트(sodium bicarbonate, 302.4 mg, 3.600 mmol)를 첨가하고 및 NBS(320.3 mg, 1.800 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - ethyl acetate 12%)로 정제하여 황색 고체의 화합물 IA-B(434.1 mg, 0.99 mmol, 82.9% 수율)를 수득 하였다.The obtained compound IA-A was used in the next step without further purification, sodium bicarbonate (302.4 mg, 3.600 mmol) was added to DMF (10.0 mL) containing IA-A, and NBS (320.3 mg) , 1.800 mmol) was added in portions at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8-ethyl acetate 12%) to obtain a yellow solid compound IA-B (434.1 mg, 0.99 mmol, 82.9% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 95.5 (d, J = 7.2 Hz, 1H), 7.90 (s, 2H), 7.87 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H), 7.13 (d, J = 7.2 Hz, 1H); 13C NMR(100 MHz, NNN) δ 183.1, 142.4, 135.0, 133.1, 129.2, 127.6, 126.6, 125.6, 125.5, 124.4, 123.0, 121.7, 115.4, 110.4, 93.0; LRMS (ESI) m/z calcd for C17H8BrF6NO [M+Na]+ : 435.0, found : 436.3. 1 H NMR (400 MHz, CDCl 3 ) δ 95.5 (d, J = 7.2 Hz, 1H), 7.90 (s, 2H), 7.87 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H), 7.13 (d, J = 7.2 Hz, 1H); 13 C NMR (100 MHz, NNN) δ 183.1, 142.4, 135.0, 133.1, 129.2, 127.6, 126.6, 125.6, 125.5, 124.4, 123.0, 121.7, 115.4, 110.4, 93.0; LRMS (ESI) m/z calcd for C 17 H 8 BrF 6 NO [M+Na] + : 435.0, found: 436.3.

[반응식 2][Scheme 2]

Figure pat00155
Figure pat00155

화합물 GxF 1 : Compound GxF 1 :

IA-B(50.4 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(4-triflulorophenyl boronic acid, 88.0 mg, 0.46 mmol), 테트라키스(트리페닐 포스핀)팔라듐(Tetrakis(triphenyl phosphine)palladium, 231 mg, 20.0 mol%) 및 소듐 카보네이트(Sodium carbonate, 49.0 mg, 0.46 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-1로 표시되는 황색 고체의 화합물 GxF 1(50.0 mg, 0.09 mmol, 86.7% 수율)을 수득 하였다.4-triflulorophenyl boronic acid, 88.0 mg, 0.46 mmol), tetrakis in a solution containing IA-B (50.4 mg, 0.11 mmol) and a mixture of DMF and water 2: 1 After (triphenyl phosphine) palladium (Tetrakis (triphenyl phosphine) palladium, 231 mg, 20.0 mol%) and sodium carbonate (Sodium carbonate, 49.0 mg, 0.46 mmol) were added, the mixture was stirred at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 1 (50.0 mg, 0.09 mmol, 86.7) represented by the following formula 1-1. % Yield) was obtained.

[화학식 1-1][Formula 1-1]

Figure pat00156
Figure pat00156

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 10.6 (d, J = 7.6 Hz, 1H), 8.11 (s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.18 (d, J = 7.4 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 183.9, 142.9, 137.1, 134.4, 133.4, 133.1, 129.5, 129.2, 128.3, 127.3, 127.0, 126.2, 126.0, 125.6, 125.1, 124.5, 123.2, 122.8, 122.4, 121.8, 119.2, 115.3, 110.4; LRMS (ESI) m/z calcd for C24H12F9NO [M+Na]+ : 501.1, found : 502.1. 1 H NMR (400 MHz, CDCl 3 ) δ 10.6 (d, J = 7.6 Hz, 1H), 8.11 (s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz , 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.18 (d, J = 7.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.9, 142.9, 137.1, 134.4, 133.4, 133.1, 129.5, 129.2, 128.3, 127.3, 127.0, 126.2, 126.0, 125.6, 125.1, 124.5, 123.2, 122.8, 122.4, 121.8 , 119.2, 115.3, 110.4; LRMS (ESI) m/z calcd for C 24 H 12 F 9 NO [M+Na] + : 501.1, found: 502.1.

화합물 GxF 2 : Compound GxF 2 :

IA-B(50.2 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(4-acetylphenyl boronic acid , 75.0 mg, 0.46 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(49.0 mg, 0.46 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-2로 표시되는 황색 고체의 화합물 GxF 2(48.4 mg, 0.10 mmol, 88.5% 수율)을 수득 하였다.4-acetylphenyl boronic acid (4-acetylphenyl boronic acid, 75.0 mg, 0.46 mmol), tetrakis (tri Phenyl phosphine) palladium (231 mg, 20.0 mol%) and sodium carbonate (49.0 mg, 0.46 mmol) were added, followed by stirring at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 2 (48.4 mg, 0.10 mmol, 88.5) represented by the following Formula 1-2. % Yield) was obtained.

[화학식 1-2][Formula 1-2]

Figure pat00157
Figure pat00157

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 10.0 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 8.07 (d, J = 6.8 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 6.8 Hz, 2H), 7.54 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 197.2, 183.9, 142.9, 138.2, 135.8, 134.4, 133.0, 129.5, 129.3, 129.2, 128.0, 127.3, 126.9, 125.9, 125.6, 124.5, 123.3, 122.4, 121.8, 119.4, 115.5, 115.4, 110.4, 26.9; LRMS (ESI) m/z calcd for C25H15F6NO2 [M+Na]+ : 475.1, found : 476.2. 1 H NMR (400 MHz, CDCl 3 ) δ 10.0 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 8.07 (d, J = 6.8 Hz, 2H), 7.95 (d, J = 8.4 Hz , 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 6.8 Hz, 2H), 7.54 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.2, 183.9, 142.9, 138.2, 135.8, 134.4, 133.0, 129.5, 129.3, 129.2, 128.0, 127.3, 126.9, 125.9, 125.6, 124.5, 123.3, 122.4, 121.8, 119.4 , 115.5, 115.4, 110.4, 26.9; LRMS (ESI) m/z calcd for C 25 H 15 F 6 NO 2 [M+Na] + : 475.1, found: 476.2.

화합물 GxF 3 : Compound GxF 3 :

IA-B(51.2 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(phenyl boronic acid, 57.0 mg, 0.46 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(49.0 mg, 0.46 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-3으로 표시되는 황색 고체의 화합물 GxF 3(48.7 mg, 0.11 mmol, 96.0% 수율)을 수득 하였다.Phenyl boronic acid (57.0 mg, 0.46 mmol), tetrakis (triphenyl phosphine) palladium in a solution containing IA-B (51.2 mg, 0.11 mmol) and a mixture of DMF and water 2: 1 (231 mg, 20.0 mol%) and sodium carbonate (49.0 mg, 0.46 mmol) were added, followed by stirring at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 3 (48.7 mg, 0.11 mmol, 96.0) represented by the following Chemical Formula 1-3 (48.7 mg, 0.11 mmol, 96.0). % Yield) was obtained.

[화학식 1-3][Formula 1-3]

Figure pat00158
Figure pat00158

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 10.04 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.55 (s, 1H), 7.53 (d, J = 3.6 Hz, 2H), 7.49 (d, J = 3.2 Hz, 2H), 7.39 (d, J = 7.2 Hz, 1H) 7.13 (dd, J = 7.4 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 183.7, 143.1, 134.4, 133.3, 133.2, 132.9, 129.3, 129.2, 128.1, 127.5, 126.6, 125.8, 125.5, 125.4, 125.1, 124.7, 122.9, 122.0, 120.9, 115.7, 110.1. 1 H NMR (400 MHz, CDCl 3 ) δ 10.04 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz , 2H), 7.55 (s, 1H), 7.53 (d, J = 3.6 Hz, 2H), 7.49 (d, J = 3.2 Hz, 2H), 7.39 (d, J = 7.2 Hz, 1H) 7.13 (dd, J = 7.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.7, 143.1, 134.4, 133.3, 133.2, 132.9, 129.3, 129.2, 128.1, 127.5, 126.6, 125.8, 125.5, 125.4, 125.1, 124.7, 122.9, 122.0, 120.9, 115.7 , 110.1.

화합물 GxF 4 : Compound GxF 4 :

IA-B(51.0 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(4-methoxyphenyl boronic acid, 71.0 mg, 0.46 mmol), 테트라키스(트리페닐 포스핀)팔라듐(Tetrakis(triphenyl phosphine)palladium, 231 mg, 20.0 mol%) 및 소듐 카보네이트(Sodium carbonate, 49.0 mg, 0.46 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-4로 표시되는 황색 고체의 화합물 GxF 4(51.4 mg, 0.11 mmol, 94.8% 수율)을 수득 하였다.In a solution containing IA-B (51.0 mg, 0.11 mmol) and a mixture of DMF and water 2: 1, 4-methoxyphenyl boronic acid (71.0 mg, 0.46 mmol), tetrakis ( After adding triphenyl phosphine) palladium (Tetrakis (triphenyl phosphine) palladium, 231 mg, 20.0 mol%) and sodium carbonate (Sodium carbonate, 49.0 mg, 0.46 mmol), the mixture was stirred at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 4 (51.4 mg, 0.11 mmol, 94.8) represented by the following formula 1-4. % Yield) was obtained.

[화학식 1-4][Formula 1-4]

Figure pat00159
Figure pat00159

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 10.02 (d, J = 6.8 Hz, 1H), 8.08 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.46 (s, 1H), 7.42 (d, J = 5.0 Hz, 2H), 7.10 (d, J = 7.4 Hz, 1H), 7.02 (d, J = 4.6 Hz, 2H), 3.86 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 183.5, 159.0, 143.1, 134.4, 133.0, 132.7, 129.2, 127.6, 126.3, 125.9, 125.6, 125.5, 125.4, 125.4, 125.1, 125.6, 122.7, 122.4, 121.9, 120.7, 115.7, 114.6, 114.1, 109.9; LRMS (ESI) m/z calcd C24H15F6NO2 for [M+Na]+ : 463.1, found : 464.1. 1 H NMR (400 MHz, CDCl 3 ) δ 10.02 (d, J = 6.8 Hz, 1H), 8.08 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz , 2H), 7.46 (s, 1H), 7.42 (d, J = 5.0 Hz, 2H), 7.10 (d, J = 7.4 Hz, 1H), 7.02 (d, J = 4.6 Hz, 2H), 3.86 (s , 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.5, 159.0, 143.1, 134.4, 133.0, 132.7, 129.2, 127.6, 126.3, 125.9, 125.6, 125.5, 125.4, 125.4, 125.1, 125.6, 122.7, 122.4, 121.9, 120.7 , 115.7, 114.6, 114.1, 109.9; LRMS (ESI) m/z calcd C 24 H 15 F 6 NO 2 for [M+Na] + : 463.1, found: 464.1.

화합물 GxF 5 : Compound GxF 5 :

IA-B(51.4 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(4-(dimethylamino)phenyl boronic acid, 78.0 mg, 0.47 mmol), 테트라키스(트리페닐 포스핀)팔라듐(Tetrakis(triphenyl phosphine)palladium, 231 mg, 20.0 mol%) 및 소듐 카보네이트(Sodium carbonate, 50mg, 0.47 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-5로 표시되는 주황색 고체의 화합물 GxF 5(51.5 mg, 0.10 mmol, 91.6% 수율)을 수득 하였다.4-(dimethylamino)phenyl boronic acid, 78.0 mg, 0.47 in a solution containing IA-B (51.4 mg, 0.11 mmol) and a mixture of DMF and water 2: 1 mmol), tetrakis (triphenyl phosphine) palladium (Tetrakis (triphenyl phosphine) palladium, 231 mg, 20.0 mol%) and sodium carbonate (Sodium carbonate, 50 mg, 0.47 mmol) were added, and then at 100° C. for 12 hours Stirred. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%), and the orange solid compound GxF 5 (51.5 mg, 0.10 mmol, 91.6) represented by the following formula 1-5 % Yield) was obtained.

[화학식 1-5][Formula 1-5]

Figure pat00160
Figure pat00160

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 10.01 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 7.94 (d, J = 8 Hz, 2H), 7.78 (d, J = 8 Hz, 2H), 7.41 (d, J = 5.0 Hz, 2H), 7.40 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz, 2H), 3.02 (d, J = 6.4 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 183.4, 149.8, 143.3, 134.3, 132.9, 132.6, 129.2, 129.1, 128.8, 125.9, 125.7, 125.5, 125.1, 124.7, 122.6, 122.4, 122.0, 121.5, 121.4, 121.0, 116.0, 115.9, 112.9, 109.7, 40.6; LRMS (ESI) m/z calcd for C25H18F6N2O[M+Na]+ : 476.1, found : 476.2. 1 H NMR (400 MHz, CDCl 3 ) δ 10.01 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 7.94 (d, J = 8 Hz, 2H), 7.78 (d, J = 8 Hz , 2H), 7.41 (d, J = 5.0 Hz, 2H), 7.40 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz, 2H), 3.02 (d , J = 6.4 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.4, 149.8, 143.3, 134.3, 132.9, 132.6, 129.2, 129.1, 128.8, 125.9, 125.7, 125.5, 125.1, 124.7, 122.6, 122.4, 122.0, 121.5, 121.4, 121.0 , 116.0, 115.9, 112.9, 109.7, 40.6; LRMS (ESI) m/z calcd for C 25 H 18 F 6 N 2 O[M+Na] + : 476.1, found: 476.2.

<GxF 6 ~ 10><GxF 6 ~ 10>

IB-E : 하기 반응식 3과 같이 합성하였으며, 구체적으로, 4(트리플루오로메틸)피리딘(695 μL, 6.00 mmol) 및 클로로아세톤(chloroacetone,501 μL, 6.30 mmol)이 포함된 DMF(10.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(320 μL, 3 mmol), 구리(II) 아세테이트 모노하이드레이트(1.79 g, 9.00 mmol) 및 소듐 아세테이트(1476.5 mg, 18 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IB-E(659.5 mg, 2.2 mmol, 73.4% 수율)를 수득 하였다. IB-E : Synthesized as in Scheme 3 below, and specifically, DMF (10.0 mL) containing 4 (trifluoromethyl) pyridine (695 μL, 6.00 mmol) and chloroacetone (chloroacetone, 501 μL, 6.30 mmol) was prepared at 100° C. After stirring overnight at, ethyl acrylate (320 μL, 3 mmol), copper (II) acetate monohydrate (1.79 g, 9.00 mmol) and sodium acetate (1476.5 mg, 18 mmol) were added thereto at 100° C. for 16 hours. While stirring. After completion of the reaction, after monitoring by TLC, copper acetate was removed by filtration through a pad of Celite, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water and the organic material was extracted 3 times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (hexane 1-15% containing EtOAc) to obtain a yellow solid compound IB-E (659.5 mg, 2.2 mmol, 73.4% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.96 (d, J = 7.2 Hz, 1H), 8.66 (t, J = 1.2Hz, 1H), 8.06 (s, 1H), 7.15 (dd, J = 2 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 2.63(s, 3H), 1.45 (t, J = 7.0 Hz, 3H); 13C NMR(400 MHz, CDCl3) δ 188.0, 163.1, 136.7, 129.1, 128.3, 128.0, 127.6, 127.3, 126.9, 126.0, 124.2, 123.4, 121.5, 118.8, 116.9, 116.8, 110.5, 110.4, 108.1, 60.6, 27.5, 14.5; LRMS (ESI) m/z calcd for C14H12F3NO3 [M+Na]+ : 299.1, found : 300.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.96 (d, J = 7.2 Hz, 1H), 8.66 (t, J = 1.2Hz, 1H), 8.06 (s, 1H), 7.15 (dd, J = 2 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 2.63 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H); 13 C NMR (400 MHz, CDCl 3 ) δ 188.0, 163.1, 136.7, 129.1, 128.3, 128.0, 127.6, 127.3, 126.9, 126.0, 124.2, 123.4, 121.5, 118.8, 116.9, 116.8, 110.5, 110.4, 108.1, 60.6 , 27.5, 14.5; LRMS (ESI) m/z calcd for C 14 H 12 F 3 NO 3 [M+Na] + : 299.1, found: 300.1.

IB-B : IB-E(0.66 g, 2.20 mmol)가 포함된 메탄올(10 mL)에 KOH (5386 mg, 96.00 mmol)를 첨가한 후, 실온에서 4시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 갈색고체의 화합물 IB-A를 수득하였다. IB-B : KOH (5386 mg, 96.00 mmol) was added to methanol (10 mL) containing IB-E (0.66 g, 2.20 mmol), followed by stirring at room temperature for 4 hours. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water and dried in a drying oven to obtain a brown solid compound IB-A.

수득한 화합물 IB-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IB-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(554 mg, 6.60 mmol)를 첨가하고 및 NBS(587 mg, 3.30 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - ethyl acetate 12%)로 정제하여 황색 고체의 화합물 IB-B(588 mg, 1.92 mmol, 100% 수율)를 수득 하였다.The obtained compound IB-A was used in the next step without further purification, sodium bicarbonate (554 mg, 6.60 mmol) was added to DMF (10.0 mL) containing IB-A, and NBS (587 mg, 3.30 mmol) ) Was added partially at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8-ethyl acetate 12%) to obtain a yellow solid compound IB-B (588 mg, 1.92 mmol, 100% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.88 (d, J = 7.2 Hz, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 2.59 (s, 1H); 13C NMR(100 MHz, CDCl3) δ 204.4, 186.9, 133.6, 128.7, 124.9, 123.5, 121.7, 115.2, 109.7, 92.0, 27.5. 1 H NMR (400 MHz, CDCl 3 ) δ 9.88 (d, J = 7.2 Hz, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 2.59 (s, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 204.4, 186.9, 133.6, 128.7, 124.9, 123.5, 121.7, 115.2, 109.7, 92.0, 27.5.

[반응식 3][Scheme 3]

Figure pat00161
Figure pat00161

화합물 GxF 6 : Compound GxF 6 :

IB-B(74.6 mg, 0.24 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리풀로로페닐 보론산(103 mg, 0.97 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(49.0 mg, 0.46 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-6으로 표시되는 황색 고체의 화합물 GxF 6(75.9 mg, 0.2 mmol, 85% 수율)을 수득 하였다.4-trifluorophenyl boronic acid (103 mg, 0.97 mmol), tetrakis (triphenyl phosphine) in a solution containing IB-B (74.6 mg, 0.24 mmol) and a mixture of DMF and water 2: 1 ) Palladium (231 mg, 20.0 mol%) and sodium carbonate (49.0 mg, 0.46 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to obtain a yellow solid compound GxF 6 (75.9 mg, 0.2 mmol, 85) represented by the following formula 1-6. % Yield) was obtained.

[화학식 1-6][Formula 1-6]

Figure pat00162
Figure pat00162

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.95 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.71 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.03 (dd, J = 7.6 Hz, 1H), 2.65 (s, 1H); 13C NMR(100 MHz, CDCl3) δ 187.6, 137.4, 133.0, 129.2, 129.0, 128.1, 126.1, 125.7, 125.5, 124.6, 123.8, 123.1, 122.8, 121.9, 118.2, 115.1, 109.7, 27.8; LRMS (ESI) m/z calcd for C18H11F6NO [M+Na]+ : 371.1, found : 372.1. 1 H NMR (400 MHz, CDCl 3 ) δ 9.95 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.71 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.03 (dd, J = 7.6 Hz, 1H), 2.65 (s, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 187.6, 137.4, 133.0, 129.2, 129.0, 128.1, 126.1, 125.7, 125.5, 124.6, 123.8, 123.1, 122.8, 121.9, 118.2, 115.1, 109.7, 27.8; LRMS (ESI) m/z calcd for C 18 H 11 F 6 NO [M+Na] + : 371.1, found: 372.1.

화합물 GxF 7 : Compound GxF 7 :

IB-B(52.4 mg, 0.22 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(144 mg, 0.88 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(93.0 mg, 0.88 mmol)를 첨가한 후, 100℃에서 17시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-7로 표시되는 황색 고체의 화합물 GxF 7(56.4 mg, 0.16 mmol, 74.2% 수율)을 수득 하였다.In a solution containing IB-B (52.4 mg, 0.22 mmol) and a mixture of DMF and water 2: 1, 4-acetylphenyl boronic acid (144 mg, 0.88 mmol), tetrakis (triphenyl phosphine) palladium ( 231 mg, 20.0 mol%) and sodium carbonate (93.0 mg, 0.88 mmol) were added, followed by stirring at 100° C. for 17 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to obtain a yellow solid compound GxF 7 (56.4 mg, 0.16 mmol, 74.2) represented by the following formula 1-7. % Yield) was obtained.

[화학식 1-7][Formula 1-7]

Figure pat00163
Figure pat00163

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.91 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 2.63 (s, 3H), 2.61 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.4, 187.9, 144.4, 138.8, 136.7, 135.8, 133.3, 129.5, 128.0, 127.6, 124.9, 124.1, 123.4, 122.1, 118.7, 115.5, 109.9, 28.1, 27.1; LRMS (ESI) m/z calcd for C19H14F3NO2 [M+Na]+ : 345.1, found : 346.1. 1 H NMR (400 MHz, CDCl 3 ) δ 9.91 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.72 (s , 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 2.63 (s, 3H), 2.61 (s , 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.4, 187.9, 144.4, 138.8, 136.7, 135.8, 133.3, 129.5, 128.0, 127.6, 124.9, 124.1, 123.4, 122.1, 118.7, 115.5, 109.9, 28.1, 27.1; LRMS (ESI) m/z calcd for C 19 H 14 F 3 NO 2 [M+Na] + : 345.1, found: 346.1.

화합물 GxF 8 : Compound GxF 8 :

IB-B(73.8 mg, 0.24 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(117 mg, 0.96 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(102mg, 0.96 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-8로 표시되는 황색 고체의 화합물 GxF 8(79.8 mg, 0.26 mmol, 100% 수율)을 수득 하였다.Phenyl boronic acid (117 mg, 0.96 mmol), tetrakis (triphenyl phosphine) palladium (231 mg, in a solution containing IB-B (73.8 mg, 0.24 mmol) and a mixture of DMF and water 2: 1) 20.0 mol%) and sodium carbonate (102 mg, 0.96 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 8 (79.8 mg, 0.26 mmol, 100) represented by the following formula 1-8. % Yield) was obtained.

[화학식 1-8][Formula 1-8]

Figure pat00164
Figure pat00164

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.94 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.07 (dd, J = 7.2 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 3.90 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 184.2, 162.6, 137.5, 133.3, 132.1, 131.2, 129.2, 128.1, 126.1, 126.0, 125.8, 125.1, 123.7, 118.2, 113.7, 109.5, 55.6. 1 H NMR (400 MHz, CDCl 3 ) δ 9.94 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.4 Hz , 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.07 (dd, J = 7.2 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 3.90 (s , 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.2, 162.6, 137.5, 133.3, 132.1, 131.2, 129.2, 128.1, 126.1, 126.0, 125.8, 125.1, 123.7, 118.2, 113.7, 109.5, 55.6.

화합물 GxF 9 : Compound GxF 9 :

IB-B(52.1 mg, 0.22 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(133 mg, 0.87 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트((92.7 mg, 0.87 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-9로 표시되는 황색 고체의 화합물 GxF 9(547.2 mg, 0.14 mmol, 64% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (133 mg, 0.87 mmol), tetrakis (triphenyl phosphine) palladium in a solution containing IB-B (52.1 mg, 0.22 mmol) and a mixture of DMF and water 2:1 (231 mg, 20.0 mol%) and sodium carbonate ((92.7 mg, 0.87 mmol) were added, and then stirred for 8 hours at 100° C. After completion of the reaction, the reaction was monitored by TLC, washed with water, and the organic material was DCM. The extracted organic substances were combined, dried over anhydrous Na 2 SO 4 and concentrated, the concentrated organic phase was subjected to silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%). Purified with GxF 9 (547.2 mg, 0.14 mmol, 64% yield) as a yellow solid represented by the following Chemical Formula 1-9.

[화학식 1-9][Formula 1-9]

Figure pat00165
Figure pat00165

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.89 (d, J = 7.2 Hz, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 7.2 Hz, 1H), 3.87 (s, 3H), 2.62 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 187.4, 158.8, 132.8, 129.1, 128.8, 126.0, 125.0, 124.8, 124.6, 123.3, 122.7, 122.1, 119.8, 115.5, 114.5, 109.2, 55.5, 27.7; LRMS (ESI) m/z calcd for C18H14F3NO2 [M+Na]+ : 333.11, found : 334.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.89 (d, J = 7.2 Hz, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 7.2 Hz, 1H), 3.87 (s, 3H), 2.62 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 187.4, 158.8, 132.8, 129.1, 128.8, 126.0, 125.0, 124.8, 124.6, 123.3, 122.7, 122.1, 119.8, 115.5, 114.5, 109.2, 55.5, 27.7; LRMS (ESI) m/z calcd for C 18 H 14 F 3 NO 2 [M+Na] + : 333.11, found: 334.2.

화합물 GxF 10 : Compound GxF 10 :

IB-B(77.8 mg, 0.25 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(167 mg, 1.01 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(108 mg, 1.01 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-10로 표시되는 황색 고체의 화합물 GxF 10(85.3 mg, 0.25 mmol, 100% 수율)을 수득 하였다.In a solution containing IB-B (77.8 mg, 0.25 mmol) and a mixture of DMF and water 2: 1, 4-(dimethylamino) phenyl boronic acid (167 mg, 1.01 mmol), tetrakis (triphenyl phosphine) Fin) palladium (231 mg, 20.0 mol%) and sodium carbonate (108 mg, 1.01 mmol) were added, followed by stirring at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 10 (85.3 mg, 0.25 mmol, 100) represented by the following formula 1-10 (85.3 mg, 0.25 mmol, 100). % Yield) was obtained.

[화학식 1-10][Formula 1-10]

Figure pat00166
Figure pat00166

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.88 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.57 (s, 1H), 7.41 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 3.01 (s, 6H), 2.62 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 186.9, 149.3, 132.4, 128.3, 124.5, 124.1, 123.8, 122.9, 121.9, 121.8, 121.1, 121.0, 120.1, 115.4, 112.5, 108.6, 40.2, 27.3; LRMS (ESI) m/z calcd for C19H17F3N2O [M+Na]+ : 346.1, found : 347.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.88 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.57 (s, 1H), 7.41 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 3.01 (s, 6H), 2.62 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.9, 149.3, 132.4, 128.3, 124.5, 124.1, 123.8, 122.9, 121.9, 121.8, 121.1, 121.0, 120.1, 115.4, 112.5, 108.6, 40.2, 27.3; LRMS (ESI) m/z calcd for C 19 H 17 F 3 N 2 O [M+Na] + : 346.1, found: 347.2.

<GxF 11 ~ 15><GxF 11 ~ 15>

IC-E : 하기 반응식 4와 같이 합성하였으며, 구체적으로, 4(트리플루오로메틸)피리딘(348 μL, 3.00 mmol) 및 2-브로모아세토페논(2-bromoacetophenone; 627 mg, 3.15 mmol)이 포함된 DMF(7.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(160 μL, 0.50 mmol), 구리(II) 아세테이트 모노하이드레이트(898 mg, 1.50 mmol) 및 소듐 아세테이트(738 mg, 9.00 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IC-E(481.9 mg, 1.3 mmol, 88.9% 수율)를 수득 하였다. IC-E : It was synthesized as shown in Scheme 4 below, and specifically, DMF containing 4 (trifluoromethyl) pyridine (348 μL, 3.00 mmol) and 2-bromoacetophenone (627 mg, 3.15 mmol) ( 7.0 mL) was stirred at 100° C. overnight, and then ethyl acrylate (160 μL, 0.50 mmol), copper (II) acetate monohydrate (898 mg, 1.50 mmol) and sodium acetate (738 mg, 9.00 mmol) were added. Then, the mixture was stirred at 100° C. for 16 hours. After completion of the reaction, after monitoring by TLC, copper acetate was removed by filtration through a pad of Celite, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water and the organic material was extracted 3 times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (hexane 1-15% containing EtOAc) to obtain a yellow solid compound IC-E (481.9 mg, 1.3 mmol, 88.9% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.88 (d, J = 7.6 Hz, 1H), 8.59 (s, 1H), 7.78 (s, 1H), 7.74 (d, J = 6.8 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.10 (dd, J = 7.4 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H); 13C NMR(100 MHz, CDCl3) δ 185.3, 163.0, 138.8, 137.2, 131.7, 129.2, 128.8, 128.5, 128.3, 128.2, 128.0, 124.2, 123.2, 121.5, 117.0, 110.4, 108.5, 60.5, 14.5; LRMS (ESI) m/z calcd for C19H14F3NO [M+Na]+ : 361.1, found : 362.1. 1 H NMR (400 MHz, CDCl 3 ) δ 9.88 (d, J = 7.6 Hz, 1H), 8.59 (s, 1H), 7.78 (s, 1H), 7.74 (d, J = 6.8 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.10 (dd, J = 7.4 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.37 (t , J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 185.3, 163.0, 138.8, 137.2, 131.7, 129.2, 128.8, 128.5, 128.3, 128.2, 128.0, 124.2, 123.2, 121.5, 117.0, 110.4, 108.5, 60.5, 14.5; LRMS (ESI) m/z calcd for C 19 H 14 F 3 NO [M+Na] + : 361.1, found: 362.1.

IC-B : IC-E(481.9 mg, 1.3 mmol)가 포함된 메탄올(10 mL)에 KOH (519mg, 10.0 mmol)를 첨가한 후, 실온에서 4시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 IC-A를 수득하였다. IC-B : After adding KOH (519mg, 10.0 mmol) to methanol (10 mL) containing IC-E (481.9 mg, 1.3 mmol), the mixture was stirred at room temperature for 4 hours. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water and dried in a drying oven to obtain a white solid compound IC-A.

수득한 화합물 IC-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IC-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(162.4 mg, 1.9 mmol)를 첨가하고 및 NBS(172.0 mg, 0.9 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - ethyl acetate 12%)로 정제하여 황색 고체의 화합물 IC-B(219.2 mg, 0.595 mmol, 99.2% 수율)를 수득 하였다.The obtained compound IC-A was used in the next step without further purification, sodium bicarbonate (162.4 mg, 1.9 mmol) was added to DMF (10.0 mL) containing IC-A, and NBS (172.0 mg, 0.9 mmol) ) Was added partially at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8-ethyl acetate 12%) to obtain a yellow solid compound IC-B (219.2 mg, 0.595 mmol, 99.2% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.96 (d, J = 7.6 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.46 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 185.4, 139.1, 134.2, 131.7, 128.9, 128.8, 128.3, 127.4, 126.1, 125.7, 124.4, 123.2, 121.7, 115.1, 109.8, 92.3; LRMS (ESI) m/z calcd for C16H9BrF3NO [M+Na]+ : 367.0, found : 368.0. 1 H NMR (400 MHz, CDCl 3 ) δ 9.96 (d, J = 7.6 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.59 (t, J = 7.4 Hz , 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.46 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 185.4, 139.1, 134.2, 131.7, 128.9, 128.8, 128.3, 127.4, 126.1, 125.7, 124.4, 123.2, 121.7, 115.1, 109.8, 92.3; LRMS (ESI) m/z calcd for C 16 H 9 BrF 3 NO [M+Na] + : 367.0, found: 368.0.

[반응식 4][Scheme 4]

Figure pat00167
Figure pat00167

화합물 GxF 11 : Compound GxF 11 :

IC-B(51.2 mg, 0.14 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(106 mg, 0.55 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(59.0 mg, 0.55 mmol)를 첨가한 후, 100℃에서 5시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-11로 표시되는 황색 고체의 화합물 GxF 11(54.0 mg, 0.12 mmol, 89.0% 수율)을 수득 하였다.In a solution containing IC-B (51.2 mg, 0.14 mmol) and a mixture of DMF and water 2: 1, 4-trifluorophenyl boronic acid (106 mg, 0.55 mmol), tetrakis (triphenyl phosphine) After adding palladium (231 mg, 20.0 mol%) and sodium carbonate (59.0 mg, 0.55 mmol), the mixture was stirred at 100° C. for 5 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to obtain a yellow solid compound GxF 11 (54.0 mg, 0.12 mmol, 89.0) represented by the following formula 1-11. % Yield) was obtained.

[화학식 1-11][Formula 1-11]

Figure pat00168
Figure pat00168

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 10.05 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 7.85 (dd, J = 8.2 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.60 (t, J = 6.8 Hz, 1H), 7.57 (s, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 7.4 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 185.5, 139.8, 137.5, 133.9, 131.8, 129.5, 129.1, 128.6, 128.3, 126.4, 126.2, 126.2, 126.0, 125.8, 123.8, 118.7, 115.3, 110.0, 110.0, 47.1, 34.7; LRMS (ESI) m/z calcd for C23H13F6NO [M+Na]+ : 433.1, found : 434.3. 1 H NMR (400 MHz, CDCl 3 ) δ 10.05 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 7.85 (dd, J = 8.2 Hz, 2H), 7.74 (d, J = 8.0 Hz , 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.60 (t, J = 6.8 Hz, 1H), 7.57 (s, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.14 (d , J = 7.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 185.5, 139.8, 137.5, 133.9, 131.8, 129.5, 129.1, 128.6, 128.3, 126.4, 126.2, 126.2, 126.0, 125.8, 123.8, 118.7, 115.3, 110.0, 110.0, 47.1 , 34.7; LRMS (ESI) m/z calcd for C 23 H 13 F 6 NO [M+Na] + : 433.1, found: 434.3.

화합물 GxF 12 : Compound GxF 12 :

IC-B(36.9 mg, 0.1 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(65.6 mg, 0.4 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(42.4 mg, 0.4 mmol)를 첨가한 후, 100℃에서 6시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-12로 표시되는 황색 고체의 화합물 GxF 12(38.1 mg, 0.09 mmol, 93.5% 수율)을 수득 하였다.In a solution containing IC-B (36.9 mg, 0.1 mmol) and a mixture of DMF and water 2: 1, 4-acetylphenyl boronic acid (65.6 mg, 0.4 mmol), tetrakis (triphenyl phosphine) palladium ( 231 mg, 20.0 mol%) and sodium carbonate (42.4 mg, 0.4 mmol) were added, followed by stirring at 100° C. for 6 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 12 (38.1 mg, 0.09 mmol, 93.5) represented by the following formula 1-12. % Yield) was obtained.

[화학식 1-12][Formula 1-12]

Figure pat00169
Figure pat00169

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 10.03 (d, J = 7.2 Hz, 1H), 8.13 (s,1H), 8.06 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H), 7.52 (d, J = 7.4 Hz, 3H), 7.12 (dd, J = 7.2 Hz, 1H), 2.65 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.5, 185.6, 139.9, 138.8, 135.8, 134.1, 132.0, 129.7, 129.5, 129.3, 128.7, 128.1, 126.8, 126.5, 126.1, 124.9, 123.9, 122.2, 119.1, 115.6, 115.6, 110.1, 110.2, 27.1; LRMS (ESI) m/z calcd for C24H16F3NO2 [M+Na]+ : 407.1, found : 408.1. 1 H NMR (400 MHz, CDCl 3 ) δ 10.03 (d, J = 7.2 Hz, 1H), 8.13 (s,1H), 8.06 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz , 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H), 7.52 (d, J = 7.4 Hz, 3H), 7.12 (dd, J = 7.2 Hz, 1H), 2.65 (s , 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.5, 185.6, 139.9, 138.8, 135.8, 134.1, 132.0, 129.7, 129.5, 129.3, 128.7, 128.1, 126.8, 126.5, 126.1, 124.9, 123.9, 122.2, 119.1, 115.6 , 115.6, 110.1, 110.2, 27.1; LRMS (ESI) m/z calcd for C 24 H 16 F 3 NO 2 [M+Na] + : 407.1, found: 408.1.

화합물 GxF 13 : Compound GxF 13 :

IC-B(40.5 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(53.7 mg, 0.44 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(46.6mg, 0.44 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-13으로 표시되는 황색 고체의 화합물 GxF 13(79.8 mg, 0.10 mmol, 94.5% 수율)을 수득 하였다.In a solution containing IC-B (40.5 mg, 0.11 mmol) and a mixture of DMF and water 2: 1, phenyl boronic acid (53.7 mg, 0.44 mmol), tetrakis (triphenyl phosphine) palladium (231 mg, 20.0 mol%) and sodium carbonate (46.6 mg, 0.44 mmol) were added, followed by stirring at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 13 (79.8 mg, 0.10 mmol, 94.5) represented by the following formula 1-13. % Yield) was obtained.

[화학식 1-13][Formula 1-13]

Figure pat00170
Figure pat00170

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 10.04 (d, J = 7.2 Hz, 1H), 8.12 (s, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 6.0 Hz, 1H), 7.52 (m, 7H), 7.38 (d, J = 7.6 Hz, 1H), 7.10 (dd, J = 7.6 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 185.3, 140.0, 133.8, 133.7, 131.5, 129.2, 129.1, 129.1, 128.4, 128.1, 127.3, 126.0, 125.8, 125.7, 123.4, 122.1, 120.4, 115.7, 115.6, 109.6, 47.0, 34.6; LRMS (ESI) m/z calcd for C22H14F3NO [M+Na]+ : 365.1, found : 366.1. 1 H NMR (400 MHz, CDCl 3 ) δ 10.04 (d, J = 7.2 Hz, 1H), 8.12 (s, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 6.0 Hz , 1H), 7.52 (m, 7H), 7.38 (d, J = 7.6 Hz, 1H), 7.10 (dd, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 185.3, 140.0, 133.8, 133.7, 131.5, 129.2, 129.1, 129.1, 128.4, 128.1, 127.3, 126.0, 125.8, 125.7, 123.4, 122.1, 120.4, 115.7, 115.6, 109.6 , 47.0, 34.6; LRMS (ESI) m/z calcd for C 22 H 14 F 3 NO [M+Na] + : 365.1, found: 366.1.

화합물 GxF 14 : Compound GxF 14 :

IC-B(47.9 mg, 0.13 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(79.0 mg, 0.52 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(55.1 mg, 0.52 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-14로 표시되는 황색 고체의 화합물 GxF 14(57.6 mg, 0.14 mmol, 100% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (79.0 mg, 0.52 mmol), tetrakis (triphenyl phosphine) palladium in a solution containing IC-B (47.9 mg, 0.13 mmol) and a mixture of DMF and water 2:1 (231 mg, 20.0 mol%) and sodium carbonate (55.1 mg, 0.52 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 14 (57.6 mg, 0.14 mmol, 100) represented by the following formula 1-14. % Yield) was obtained.

[화학식 1-14][Formula 1-14]

Figure pat00171
Figure pat00171

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 10.02 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.85 (d, J = 6.8 Hz, 2H), 7.58 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.48 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.07 (dd, J = 7.2 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 185.1, 158.8, 139.9, 133,6, 131.4, 129.2, 129.0(2), 128.3, 125.9, 125.6, 125.5, 125.4, 125.2, 123.1, 120.1, 115.6, 115.5, 114.5, 109.4, 109.3, 55.5; LRMS (ESI) m/z calcd for C23H16F3NO2 [M+Na]+ : 395.1, found : 396.1. 1 H NMR (400 MHz, CDCl 3 ), δ 10.02 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.85 (d, J = 6.8 Hz, 2H), 7.58 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.48 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.07 (dd, J = 7.2 Hz, 1H), 7.02 ( d, J = 8.8 Hz, 2H), 3.86 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 185.1, 158.8, 139.9, 133,6, 131.4, 129.2, 129.0(2), 128.3, 125.9, 125.6, 125.5, 125.4, 125.2, 123.1, 120.1, 115.6, 115.5, 114.5, 109.4, 109.3, 55.5; LRMS (ESI) m/z calcd for C 23 H 16 F 3 NO 2 [M+Na] + : 395.1, found: 396.1.

화합물 GxF 15 : Compound GxF 15 :

IC-B(39.5 mg, 0.10 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(45.5 mg, 0.43 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(108 mg, 1.01 mmol)를 첨가한 후, 100℃에서 19시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-15로 표시되는 황색 고체의 화합물 GxF 15(43.5 mg, 0.10 mmol, 99.7% 수율)을 수득 하였다.In a solution containing IC-B (39.5 mg, 0.10 mmol) and a mixture of DMF and water 2: 1, 4- (dimethylamino) phenyl boronic acid (45.5 mg, 0.43 mmol), tetrakis (triphenyl phosphine) Fin) palladium (231 mg, 20.0 mol%) and sodium carbonate (108 mg, 1.01 mmol) were added, followed by stirring at 100° C. for 19 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 15 (43.5 mg, 0.10 mmol, 99.7) represented by the following formula 1-15. % Yield) was obtained.

[화학식 1-15][Formula 1-15]

Figure pat00172
Figure pat00172

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 10.02 (d, J = 7.2 Hz, 1H), 8.11 (s, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.57 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.05 (dd, J = 7.4 Hz, 1H), 6.87 (d, J = 8.0 Hz, 2H), 3.02 (s, 6H); 13C NMR(100 MHz, CDCl3) δ 185.2, 166.7, 149.8, 140.3, 133.8, 131.5, 129.2, 129.0, 128.4, 127.3, 125.8, 125.4, 125.1, 125.0, 123.2, 122.3, 121.0, 116.1, 116.0, 113.2, 109.4, 47.1, 41.0, 34.7; LRMS (ESI) m/z calcd for C24H19F3N2O [M+Na]+ : 408.1, found : 409.2. 1 H NMR (400 MHz, CDCl 3 ) δ 10.02 (d, J = 7.2 Hz, 1H), 8.11 (s, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.57 (d, J = 7.2 Hz , 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.05 (dd, J = 7.4 Hz, 1H), 6.87 (d , J = 8.0 Hz, 2H), 3.02 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 185.2, 166.7, 149.8, 140.3, 133.8, 131.5, 129.2, 129.0, 128.4, 127.3, 125.8, 125.4, 125.1, 125.0, 123.2, 122.3, 121.0, 116.1, 116.0, 113.2 , 109.4, 47.1, 41.0, 34.7; LRMS (ESI) m/z calcd for C 24 H 19 F 3 N 2 O [M+Na] + : 408.1, found: 409.2.

<GxF 16 ~ 20><GxF 16 ~ 20>

ID-E : 하기 반응식 5와 같이 합성하였으며, 구체적으로, 4(트리플루오로메틸)피리딘(695 μL, 6.00 mmol) 및 2-브로모-4-메톡시아세토페논(2-bromo-4-methoxyacetophenone, 1.44 g, 6.30 mmol)이 포함된 DMF(10.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(320 μL, 3.00 mmol), 구리(II) 아세테이트 모노하이드레이트(1.79 g, 9.00 mmol) 및 소듐 아세테이트(1.47 g, 18.0 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 ID-E(1.02 g, 2.63 mmol, 87.6% 수율)를 수득 하였다. ID-E : Synthesized as in Scheme 5 below, specifically, 4 (trifluoromethyl) pyridine (695 μL, 6.00 mmol) and 2-bromo-4-methoxyacetophenone (2-bromo-4-methoxyacetophenone, 1.44 g) , 6.30 mmol) containing DMF (10.0 mL) was stirred at 100° C. overnight, followed by ethyl acrylate (320 μL, 3.00 mmol), copper (II) acetate monohydrate (1.79 g, 9.00 mmol) and sodium acetate. (1.47 g, 18.0 mmol) was added and stirred at 100° C. for 16 hours. After completion of the reaction, after monitoring by TLC, copper acetate was removed by filtration through a pad of Celite, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water and the organic material was extracted 3 times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (hexane 1-15% containing EtOAc) to obtain a yellow solid compound ID-E (1.02 g, 2.63 mmol, 87.6% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.93 (d, J = 7.2 Hz, 1H), 8.69 (s, 1H), 7.89 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 7.4Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 4.41 (d, J = 7.2 Hz, 2H), 3.92 (s, 3H), 1.42 (d, J = 6.6 Hz, 3H); 13C NMR(100 MHz, CDCl3) δ 184.1, 163.2, 162.7, 137.0, 131.3, 131.1, 129.2, 127.9, 127.8, 127.6, 124.3, 123.3, 121.6, 121.3, 116.9, 113.6, 110.1, 108.2, 60.5, 55.4, 14.5; LRMS (ESI) m/z calcd for C20H16F3NO4 [M+Na]+ : 391.1, found : 392.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.93 (d, J = 7.2 Hz, 1H), 8.69 (s, 1H), 7.89 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 7.4 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 4.41 (d, J = 7.2 Hz, 2H), 3.92 (s, 3H), 1.42 (d, J = 6.6 Hz , 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.1, 163.2, 162.7, 137.0, 131.3, 131.1, 129.2, 127.9, 127.8, 127.6, 124.3, 123.3, 121.6, 121.3, 116.9, 113.6, 110.1, 108.2, 60.5, 55.4 , 14.5; LRMS (ESI) m/z calcd for C 20 H 16 F 3 NO 4 [M+Na] + : 391.1, found: 392.2.

ID-B : ID-E(1.02 g, 2.62 mmol)가 포함된 메탄올(18 mL)에 KOH(5.91 g, 105 mmol)를 첨가한 후, 실온에서 4시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 ID-A를 수득하였다. ID-B : After adding KOH (5.91 g, 105 mmol) to methanol (18 mL) containing ID-E (1.02 g, 2.62 mmol), the mixture was stirred at room temperature for 4 hours. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water, and dried in a drying oven to obtain a white solid compound ID-A.

수득한 화합물 ID-A는 추가 정제없이 바로 다음 단계에 사용하였으며, ID-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(660 mg, 7.86 mmol)를 첨가하고 및 NBS(699 mg, 3.93 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - ethyl acetate 12%)로 정제하여 황색 고체의 화합물 ID-B(0.93 g, 2.36 mmol, 90.0% 수율)를 수득 하였다.The obtained compound ID-A was used in the next step without further purification, sodium bicarbonate (660 mg, 7.86 mmol) was added to DMF (10.0 mL) containing ID-A, and NBS (699 mg, 3.93 mmol) ) Was added partially at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8-ethyl acetate 12%) to obtain a yellow solid compound ID-B (0.93 g, 2.36 mmol, 90.0% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.88 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.46 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 183.3, 162.5, 133.8, 131.5, 131.1, 128.8, 126.7, 125.6, 125.3. 124.4, 123.3, 121.7, 121.3, 115.1, 109.4, 62.0, 55.5. 1 H NMR (400 MHz, CDCl 3 ) δ 9.88 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.46 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.3, 162.5, 133.8, 131.5, 131.1, 128.8, 126.7, 125.6, 125.3. 124.4, 123.3, 121.7, 121.3, 115.1, 109.4, 62.0, 55.5.

[반응식 5][Scheme 5]

Figure pat00173
Figure pat00173

화합물 GxF 16 : Compound GxF 16 :

ID-B(1.05 g, 0.26 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(202 mg, 1.06 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(112 mg, 1.06 mmol)를 첨가한 후, 100℃에서 5시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-16으로 표시되는 황색 고체의 화합물 GxF 16(90.2 mg, 0.19 mmol, 73.4% 수율)을 수득 하였다.In a solution containing ID-B (1.05 g, 0.26 mmol) and a mixture of DMF and water 2: 1, 4-trifluorophenyl boronic acid (202 mg, 1.06 mmol), tetrakis (triphenyl phosphine) After adding palladium (231 mg, 20.0 mol%) and sodium carbonate (112 mg, 1.06 mmol), the mixture was stirred at 100° C. for 5 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 16 (90.2 mg, 0.19 mmol, 73.4) represented by the following formula 1-16. % Yield) was obtained.

[화학식 1-16][Formula 1-16]

Figure pat00174
Figure pat00174

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.91 (d, J = 7.2 Hz, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 7.51 (m, 6H), 7.37 (t, J = 7.2 Hz, 1H), 2.63 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 187.4, 133.6, 132.8, 129.0, 128.8, 127.9, 127.1, 125.2, 124.9, 124.7, 123.4, 122.9, 122.0, 119.9, 115.4, 115.4, 109.3, 109.2, 27.7. 1 H NMR (400 MHz, CDCl 3 ) δ 9.91 (d, J = 7.2 Hz, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 7.51 (m, 6H), 7.37 (t, J = 7.2 Hz, 1H), 2.63 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 187.4, 133.6, 132.8, 129.0, 128.8, 127.9, 127.1, 125.2, 124.9, 124.7, 123.4, 122.9, 122.0, 119.9, 115.4, 115.4, 109.3, 109.2, 27.7.

화합물 GxF 17 : Compound GxF 17 :

ID-B(94.3 mg, 0.23 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(155 mg, 0.94 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(100 mg, 0.94 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-17로 표시되는 황색 고체의 화합물 GxF 17(118 mg, 0.27 mmol, 100% 수율)을 수득 하였다.In a solution containing ID-B (94.3 mg, 0.23 mmol) and a mixture of DMF and water 2: 1, 4-acetylphenyl boronic acid (155 mg, 0.94 mmol), tetrakis (triphenyl phosphine) palladium ( 231 mg, 20.0 mol%) and sodium carbonate (100 mg, 0.94 mmol) were added, followed by stirring at 100° C. for 9 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 17 (118 mg, 0.27 mmol, 100) represented by the following formula 1-17. % Yield) was obtained.

[화학식 1-17][Formula 1-17]

Figure pat00175
Figure pat00175

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.96 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 8.07 (t, J = 8.2 Hz, 3H), 7.88 (d, J = 9.2 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.09 (dd, J = 7.4 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H), 2.66 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.0, 183.8, 162.4, 143.8, 138.4, 136.2, 135.2, 133.0, 131.8, 131.1, 129.0, 128.7, 127.5, 127.1, 125.4, 124.9, 124.5, 123.6, 121.8, 118.3, 115.1, 113.5, 109.2, 55.4, 26.6; LRMS (ESI) m/z calcd for C25H18F3NO3[M+Na]+ : 437.1, found : 438.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.96 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 8.07 (t, J = 8.2 Hz, 3H), 7.88 (d, J = 9.2 Hz , 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.09 (dd, J = 7.4 Hz, 1H), 7.03 (d , J = 8.8 Hz, 1H), 3.91 (s, 3H), 2.66 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.0, 183.8, 162.4, 143.8, 138.4, 136.2, 135.2, 133.0, 131.8, 131.1, 129.0, 128.7, 127.5, 127.1, 125.4, 124.9, 124.5, 123.6, 121.8, 118.3 , 115.1, 113.5, 109.2, 55.4, 26.6; LRMS (ESI) m/z calcd for C 25 H 18 F 3 NO 3 [M+Na] + : 437.1, found: 438.2.

화합물 GxF 18 : Compound GxF 18 :

ID-B(94.0 mg, 0.23 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(115 mg, 0.94 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(100 mg, 0.94 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-18로 표시되는 황색 고체의 화합물 GxF 18(97.6 mg, 0.24 mmol, 100% 수율)을 수득 하였다.In a solution containing ID-B (94.0 mg, 0.23 mmol) and a mixture of DMF and water 2: 1, phenyl boronic acid (115 mg, 0.94 mmol), tetrakis (triphenyl phosphine) palladium (231 mg, 20.0 mol%) and sodium carbonate (100 mg, 0.94 mmol) were added, followed by stirring at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 18 (97.6 mg, 0.24 mmol, 100) represented by the following formula 1-18. % Yield) was obtained.

[화학식 1-18][Formula 1-18]

Figure pat00176
Figure pat00176

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.95 (d, J = 7.6 Hz, 1H), 8.11 (s,1H), 7.88 (d, J = 8.8 Hz, 2H), 7.56(m, 3H), 7.49 (t, J = 7.8 Hz, 2H), 7.38 (q, J = 7.6 Hz, 1H), 7.06 (dd, J = 7.8 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 3.91 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 184.5, 162.7, 134.1, 133.6, 132.7, 131.6, 129.4, 129.3, 128.4, 127.5, 125.8, 125.5, 125.4, 125.1, 123.7, 122.4, 120.3, 115.9, 115.8, 114.0, 109.6, 109.5, 55.9; LRMS (ESI) m/z calcd for C23H16F3NO2 [M+Na]+ : 395.1, found : 396.1. 1 H NMR (400 MHz, CDCl 3 ) δ 9.95 (d, J = 7.6 Hz, 1H), 8.11 (s,1H), 7.88 (d, J = 8.8 Hz, 2H), 7.56 (m, 3H), 7.49 (t, J = 7.8 Hz, 2H), 7.38 (q, J = 7.6 Hz, 1H), 7.06 (dd, J = 7.8 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 3.91 (s , 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.5, 162.7, 134.1, 133.6, 132.7, 131.6, 129.4, 129.3, 128.4, 127.5, 125.8, 125.5, 125.4, 125.1, 123.7, 122.4, 120.3, 115.9, 115.8, 114.0 , 109.6, 109.5, 55.9; LRMS (ESI) m/z calcd for C 23 H 16 F 3 NO 2 [M+Na] + : 395.1, found: 396.1.

화합물 GxF 19 : Compound GxF 19 :

ID-B(120 mg, 0.30 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(182 mg, 1.20 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(127 mg, 1.20 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-19로 표시되는 황색 고체의 화합물 GxF 19(125.6 mg, 0.29 mmol, 98.4% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (182 mg, 1.20 mmol), tetrakis (triphenyl phosphine) palladium in a solution containing ID-B (120 mg, 0.30 mmol) and a mixture of DMF and water 2: 1 (231 mg, 20.0 mol%) and sodium carbonate (127 mg, 1.20 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 19 (125.6 mg, 0.29 mmol, 98.4) represented by the following Formula 1-19 (125.6 mg, 0.29 mmol, 98.4). % Yield) was obtained.

[화학식 1-19][Formula 1-19]

Figure pat00177
Figure pat00177

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.93 (d, J = 7.6 Hz, 1H), 8.05 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.49 (s, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 6.4 Hz, 3H), 7.01 (d, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.87 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 183.8, 162.2, 158.7, 133.0, 132.2, 131.1, 129.0, 128.8, 126.0, 124.9, 124.8, 124.7, 124.6, 123.1, 122.1, 119.7, 115.4, 115.4, 114.4, 113.5, 108.8, 108.9, 55.4, 55.3; LRMS (ESI) m/z calcd for C24H18F3NO3[M+Na]+ : 425.1, found : 426.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.93 (d, J = 7.6 Hz, 1H), 8.05 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.49 (s, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 6.4 Hz, 3H), 7.01 (d, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.87 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.8, 162.2, 158.7, 133.0, 132.2, 131.1, 129.0, 128.8, 126.0, 124.9, 124.8, 124.7, 124.6, 123.1, 122.1, 119.7, 115.4, 115.4, 114.4, 113.5 , 108.8, 108.9, 55.4, 55.3; LRMS (ESI) m/z calcd for C 24 H 18 F 3 NO 3 [M+Na] + : 425.1, found: 426.2.

화합물 GxF 20 : Compound GxF 20 :

ID-B(1.32 mg, 0.33 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(220 mg, 1.33 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(141 mg, 1.33 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-20으로 표시되는 황색 고체의 화합물 GxF 20(151 mg, 0.34 mmol, 100% 수율)을 수득 하였다.In a solution containing ID-B (1.32 mg, 0.33 mmol) and a mixture of DMF and water 2: 1, 4- (dimethylamino) phenyl boronic acid (220 mg, 1.33 mmol), tetrakis (triphenyl phosphine) Fin) palladium (231 mg, 20.0 mol%) and sodium carbonate (141 mg, 1.33 mmol) were added, followed by stirring at 100° C. for 9 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 20 (151 mg, 0.34 mmol, 100) represented by the following formula 1-20. % Yield) was obtained.

[화학식 1-20][Formula 1-20]

Figure pat00178
Figure pat00178

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.92 (d, J = 7.6 Hz, 1H), 8.08 (s,1H), 7.87 (d, J = 7.6 Hz, 2H), 7.48 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 3H), 6.85 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 3.01 (s, 6H); 13C NMR(100 MHz, CDCl3) δ 183.8, 162.1, 149.5, 133.0, 132.4, 131.1, 128.7, 128.6, 127.5, 124.8, 124.5, 124.4, 124.2, 123.8, 123.0, 122.1, 121.4, 120.5, 119.4, 115.7, 113.4, 112.7, 108.7, 55.4, 40.5; LRMS (ESI) m/z calcd for C25H21F3N2O2 [M+Na]+ : 438.2, found : 439.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.92 (d, J = 7.6 Hz, 1H), 8.08 (s,1H), 7.87 (d, J = 7.6 Hz, 2H), 7.48 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 3H), 6.85 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 3.01 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.8, 162.1, 149.5, 133.0, 132.4, 131.1, 128.7, 128.6, 127.5, 124.8, 124.5, 124.4, 124.2, 123.8, 123.0, 122.1, 121.4, 120.5, 119.4, 115.7 , 113.4, 112.7, 108.7, 55.4, 40.5; LRMS (ESI) m/z calcd for C 25 H 21 F 3 N 2 O 2 [M+Na] + : 438.2, found: 439.2.

<GxF 21 ~ 25><GxF 21 ~ 25>

IE-E : 하기 반응식 6과 같이 합성하였으며, 구체적으로, 4(트리플루오로메틸)피리딘(695 μL, 6.00 mmol) 및 2-브로모-4'-(다이에틸아미노)아세토페논(2-Bromo-4’-(diethylamino)aceto-phenone, 1.70 mL, 6.30 mmol)이 포함된 DMF(6.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(320 μL, 3.00 mmol), 구리(II) 아세테이트 모노하이드레이트(1.79 g, 9.00 mmol) 및 소듐 아세테이트(1.47 g, 18.0 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IE-E(1.12 g, 2.60 mmol, 86.9% 수율)를 수득 하였다. IE-E : Synthesized as in Scheme 6 below, specifically, 4 (trifluoromethyl) pyridine (695 μL, 6.00 mmol) and 2-bromo-4'- (diethylamino) acetophenone (2-Bromo-4' DMF (6.0 mL) containing -(diethylamino)aceto-phenone, 1.70 mL, 6.30 mmol) was stirred overnight at 100°C, and then ethylacrylate (320 μL, 3.00 mmol), copper (II) acetate monohydrate (1.79 g, 9.00 mmol) and sodium acetate (1.47 g, 18.0 mmol) were added, followed by stirring at 100°C for 16 hours. After completion of the reaction, after monitoring by TLC, copper acetate was removed by filtration through a pad of Celite, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water and the organic material was extracted 3 times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (hexane 1-15% containing EtOAc) to obtain a yellow solid compound IE-E (1.12 g, 2.60 mmol, 86.9% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.83 (d, J = 8.0 Hz, 1H), 8.66 (s, 1H), 7.91 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 5.4 Hz, 2H), 4.41 (q, J = 6.9, 2H), 3.46 (q, J = 6.6 Hz, 4H), 1.43 (t, J = 5.2, 3H), 1.25 (d, J = 5.5 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 182.8, 163.1, 150.4, 136.1, 131.4, 128.9, 126.7, 126.4, 126.1, 124.6, 124.3, 123.6, 121.6, 116.5(2), 109.8, 109.1, 109.2, 107.4, 60.0, 44.2, 14.3, 12.3; LRMS (ESI) m/z calcd for C23H23F3N2O3[M+Na]+ : 432.2, found : 433.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.83 (d, J = 8.0 Hz, 1H), 8.66 (s, 1H), 7.91 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 5.4 Hz, 2H), 4.41 (q, J = 6.9, 2H), 3.46 (q, J = 6.6 Hz, 4H), 1.43 (t, J = 5.2, 3H), 1.25 (d, J = 5.5 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 182.8, 163.1, 150.4, 136.1, 131.4, 128.9, 126.7, 126.4, 126.1, 124.6, 124.3, 123.6, 121.6, 116.5(2), 109.8, 109.1, 109.2, 107.4, 60.0, 44.2, 14.3, 12.3; LRMS (ESI) m/z calcd for C 23 H 23 F 3 N 2 O 3 [M+Na] + : 432.2, found: 433.2.

IE-B : IE-E(1.12 g, 2.60 mmol)가 포함된 메탄올(10 mL)에 KOH(5.85 g, 104 mmol)를 첨가한 후, 실온에서 4시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 IE-A를 수득하였다. IE-B : After adding KOH (5.85 g, 104 mmol) to methanol (10 mL) containing IE-E (1.12 g, 2.60 mmol), the mixture was stirred at room temperature for 4 hours. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water, and dried in a drying oven to obtain a white solid compound IE-A.

수득한 화합물 IE-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IE-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(655 mg, 7.80 mmol)를 첨가하고 및 NBS(694 mg, 3.90 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - ethyl acetate 12%)로 정제하여 황색 고체의 화합물 IE-B(829 mg, 1.88 mmol, 72.6% 수율)를 수득 하였다.The obtained compound IE-A was used in the next step without further purification, sodium bicarbonate (655 mg, 7.80 mmol) was added to DMF (10.0 mL) containing IE-A, and NBS (694 mg, 3.90 mmol) ) Was added partially at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8-ethyl acetate 12%) to obtain a yellow solid compound IE-B (829 mg, 1.88 mmol, 72.6% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.83 (d, J = 8.0 Hz, 1H), 8.66 (s, 1H), 7.91 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 5.4 Hz, 2H), 4.41 (q, J = 6.9, 2H), 3.46 (q, J = 6.6 Hz, 4H), 1.43 (t, J = 5.2, 3H), 1.25 (d, J = 5.5 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 182.0, 152.9, 135.2, 134.2, 133.9, 129.0, 128.8, 126.9, 126.0, 125.7, 124.6, 123.2, 122.3, 121.9, 120.1, 115.3, 92.5, 46.5, 12.8, 12.7. 1 H NMR (400 MHz, CDCl 3 ), δ 9.83 (d, J = 8.0 Hz, 1H), 8.66 (s, 1H), 7.91 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 5.4 Hz, 2H), 4.41 (q, J = 6.9, 2H), 3.46 (q, J = 6.6 Hz, 4H), 1.43 (t , J = 5.2, 3H), 1.25 (d, J = 5.5 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 182.0, 152.9, 135.2, 134.2, 133.9, 129.0, 128.8, 126.9, 126.0, 125.7, 124.6, 123.2, 122.3, 121.9, 120.1, 115.3, 92.5, 46.5, 12.8, 12.7 .

[반응식 6][Scheme 6]

Figure pat00179
Figure pat00179

화합물 GxF 21 : Compound GxF 21 :

IE-B(54.0 mg, 0.12 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(94.4 mg, 0.49 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(52.7 mg, 0.49 mmol)를 첨가한 후, 100℃에서 5시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-21로 표시되는 황색 고체의 화합물 GxF 21(43.1 mg, 0.08 mmol, 68.8% 수율)을 수득 하였다.4-trifluorophenyl boronic acid (94.4 mg, 0.49 mmol), tetrakis (triphenyl phosphine) in a solution containing IE-B (54.0 mg, 0.12 mmol) and a 2:1 mixture of DMF and water After adding palladium (231 mg, 20.0 mol%) and sodium carbonate (52.7 mg, 0.49 mmol), the mixture was stirred at 100° C. for 5 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%), and a yellow solid compound GxF 21 (43.1 mg, 0.08 mmol, 68.8) represented by the following formula 1-21 % Yield) was obtained.

[화학식 1-21][Formula 1-21]

Figure pat00180
Figure pat00180

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.95 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.83 (dd, J = 8.6 Hz, 1H), 7.76 (s, 1H), 7.74 (d, J = 5.6 Hz, 1H), 7.67 (m, 5H), 7.64 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 6.6 Hz, 1H), 3.00 (q, J = 6.9 Hz, 4H), 0.98 (t, J = 7.0 Hz, 6H); 13C NMR δ 184.3, 152.6, 145.1, 137.7, 133.6, 133.5, 133.2, 132.5, 130.1, 129.4, 129.3, 129.0(2), 128.3, 126.3, 126.2(2), 125.7, 125.6, 125.5, 125.1, 124.0, 120.0, 118.4, 46.0, 12.4; LRMS (ESI) m/z calcd for C27H22F6N2O[M+Na]+ : 504.2, found 505.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.95 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.83 (dd, J = 8.6 Hz, 1H), 7.76 (s, 1H), 7.74 (d, J = 5.6 Hz, 1H), 7.67 (m, 5H), 7.64 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 6.6 Hz, 1H), 3.00 (q, J = 6.9 Hz, 4H), 0.98 (t, J = 7.0 Hz, 6H); 13 C NMR δ 184.3, 152.6, 145.1, 137.7, 133.6, 133.5, 133.2, 132.5, 130.1, 129.4, 129.3, 129.0(2), 128.3, 126.3, 126.2(2), 125.7, 125.6, 125.5, 125.1, 124.0, 120.0, 118.4, 46.0, 12.4; LRMS (ESI) m/z calcd for C 27 H 22 F 6 N 2 O[M+Na] + : 504.2, found 505.2.

화합물 GxF 22 : Compound GxF 22 :

IE-B(49.7 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(74.2 mg, 0.45 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(48.0 mg, 0.45 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-22로 표시되는 황색 고체의 화합물 GxF 22(9.70 mg, 0.02 mmol, 18% 수율)을 수득 하였다.In a solution containing IE-B (49.7 mg, 0.11 mmol) and a mixture of DMF and water 2: 1, 4-acetylphenyl boronic acid (74.2 mg, 0.45 mmol), tetrakis (triphenyl phosphine) palladium ( 231 mg, 20.0 mol%) and sodium carbonate (48.0 mg, 0.45 mmol) were added, followed by stirring at 100° C. for 9 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%), and a yellow solid compound GxF 22 (9.70 mg, 0.02 mmol, 18) represented by the following formula 1-22 % Yield) was obtained.

[화학식 1-22][Formula 1-22]

Figure pat00181
Figure pat00181

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.95 (d, J = 7.6 Hz, 1H), 8.12(s, 1H), 8.08(d, J = 8.4 Hz, 2H), 7.91(d, J = 2.0 Hz, 1H), 7.30(m, 2H), 7.67(d, J = 8.8 Hz, 2H), 7.63(s, 1H), 7.00(m, 2H), 3.29(q, J = 7.0 Hz, 4H), 2.66(s, 3H), 1.14(t, J = 7.2 Hz, 6H); 13C NMR δ 197.2, 183.1, 151.4, 138.6, 135.6, 133.6, 133.3, 132.1, 129.2, 128.7, 128.2, 127.9, 125.2, 121.5, 118.8, 46.1, 29.9, 26.9, 12.7; LRMS (ESI) m/z calcd for C28H25F3N2O2[M+Na]+ : 478.2, found 479.3. 1 H NMR (400 MHz, CDCl 3 ), δ 9.95 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 2.0 Hz, 1H), 7.30 (m, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.63 (s, 1H), 7.00 (m, 2H), 3.29 (q, J = 7.0 Hz, 4H), 2.66 (s, 3H), 1.14 (t, J = 7.2 Hz, 6H); 13 C NMR δ 197.2, 183.1, 151.4, 138.6, 135.6, 133.6, 133.3, 132.1, 129.2, 128.7, 128.2, 127.9, 125.2, 121.5, 118.8, 46.1, 29.9, 26.9, 12.7; LRMS (ESI) m/z calcd for C 28 H 25 F 3 N 2 O 2 [M+Na] + : 478.2, found 479.3.

화합물 GxF 23 : Compound GxF 23 :

IE-B(50.0 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(55.0 mg, 0.45 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(49.0 mg, 0.45 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-23으로 표시되는 황색 고체의 화합물 GxF 23(39.9 mg, 0.09 mmol, 80.1% 수율)을 수득 하였다.In a solution containing IE-B (50.0 mg, 0.11 mmol) and a mixture of DMF and water 2: 1, phenyl boronic acid (55.0 mg, 0.45 mmol), tetrakis (triphenyl phosphine) palladium (231 mg, 20.0 mol%) and sodium carbonate (49.0 mg, 0.45 mmol) were added, followed by stirring at 100° C. for 9 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%), and a yellow solid compound GxF 23 (39.9 mg, 0.09 mmol, 80.1) represented by the following formula 1-23 % Yield) was obtained.

[화학식 1-23][Formula 1-23]

Figure pat00182
Figure pat00182

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.96 (d, J = 7.2 Hz, 1H), 8.11 (s,1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.59 (t, J = 7.6 Hz, 3H), 7.50 (t, J = 6.8 Hz, 1H), 7.40 (m, 2H), 7.32 (d, J = 6.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 3.03 (q, J = 6.5 Hz, 4H), 1.01 (t, J = 6.6 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 184.7, 152.6, 141.7, 135.1, 134.2, 133.6, 133.5, 132.5, 129.7, 129.4, 129.3, 128.8, 128.7, 128.4, 127.4, 127.1, 125.3, 125.2, 124.0, 120.2, 119.8, 115.9, 109.4, 46.1, 12.6; LRMS (ESI) m/z calcd for C26H23F3N2O[M+Na]+ : 436.2, found 437.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.96 (d, J = 7.2 Hz, 1H), 8.11 (s,1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.59 (t, J = 7.6 Hz, 3H), 7.50 (t, J = 6.8 Hz, 1H), 7.40 (m, 2H), 7.32 (d, J = 6.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 3.03 (q, J = 6.5 Hz, 4H), 1.01 (t, J = 6.6 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.7, 152.6, 141.7, 135.1, 134.2, 133.6, 133.5, 132.5, 129.7, 129.4, 129.3, 128.8, 128.7, 128.4, 127.4, 127.1, 125.3, 125.2, 124.0, 120.2 , 119.8, 115.9, 109.4, 46.1, 12.6; LRMS (ESI) m/z calcd for C 26 H 23 F 3 N 2 O[M+Na] + : 436.2, found 437.2.

화합물 GxF 24 : Compound GxF 24 :

IE-B(53.7 mg, 0.12 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(74.0 mg, 0.48 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(52.0 mg, 0.48 mmol)를 첨가한 후, 100℃에서 10시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-24로 표시되는 황색 고체의 화합물 GxF 24(44.8 mg, 0.09 mmol, 78.7% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (74.0 mg, 0.48 mmol), tetrakis (triphenyl phosphine) palladium in a solution containing IE-B (53.7 mg, 0.12 mmol) and a mixture of DMF and water 2:1 (231 mg, 20.0 mol%) and sodium carbonate (52.0 mg, 0.48 mmol) were added, followed by stirring at 100° C. for 10 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 24 (44.8 mg, 0.09 mmol, 78.7) represented by the following Formula 1-24. % Yield) was obtained.

[화학식 1-24][Formula 1-24]

Figure pat00183
Figure pat00183

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.84 (d, J = 7.6 Hz, 1H), 8.02 (s, 1H), 7.86 (d, J = 9.2 Hz, 2H), 7.54 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.96 (dd, J = 7.6 Hz, 1H), 6.71 (d, J = 9.2 Hz, 2H), 3.87 (s, 3H), 3.45 (q, J = 6.9 Hz, 4H), 1.23 (t, J = 7.2 Hz, 6H).; 13C NMR(100 MHz, CDCl3) δ 184.0, 152.0, 141.0, 134.4, 133.6, 133.0, 132.8, 131.9, 129.0, 128.7, 128.2, 128.1, 127.8, 126.8, 126.5, 124.9, 124.7, 124.5, 123.3, 121.8, 119.6, 119.1, 115.2, 108.8, 45.4, 29.6, 12.0. 1 H NMR (400 MHz, CDCl 3 ), δ 9.84 (d, J = 7.6 Hz, 1H), 8.02 (s, 1H), 7.86 (d, J = 9.2 Hz, 2H), 7.54 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.96 (dd, J = 7.6 Hz, 1H), 6.71 (d, J = 9.2 Hz, 2H), 3.87 ( s, 3H), 3.45 (q, J = 6.9 Hz, 4H), 1.23 (t, J = 7.2 Hz, 6H).; 13 C NMR (100 MHz, CDCl 3 ) δ 184.0, 152.0, 141.0, 134.4, 133.6, 133.0, 132.8, 131.9, 129.0, 128.7, 128.2, 128.1, 127.8, 126.8, 126.5, 124.9, 124.7, 124.5, 123.3, 121.8 , 119.6, 119.1, 115.2, 108.8, 45.4, 29.6, 12.0.

화합물 GxF 25 : Compound GxF 25 :

IE-B(57.5 mg, 0.13 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(88.0 mg, 0.52 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(55.5 mg, 0.52 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-25로 표시되는 황색 고체의 화합물 GxF 25(43.1 mg, 0.08 mmol, 72.4% 수율)을 수득 하였다.In a solution containing IE-B (57.5 mg, 0.13 mmol) and a mixture of DMF and water 2: 1, 4- (dimethylamino) phenyl boronic acid (88.0 mg, 0.52 mmol), tetrakis (triphenyl phosphine) Fin) palladium (231 mg, 20.0 mol%) and sodium carbonate (55.5 mg, 0.52 mmol) were added, followed by stirring at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 25 (43.1 mg, 0.08 mmol, 72.4) represented by the following formula 1-25. % Yield) was obtained.

[화학식 1-25][Formula 1-25]

Figure pat00184
Figure pat00184

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.95 (d, J = 7.2 Hz, 1H), 8.10 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.61 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.00 (dd, J = 7.4 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 3.07 (q, J = 7.1 Hz, 4H), 3.03 (s, 3H), 3.00 (s, 3H), 1.01 (d, J = 7.2 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 184.2, 151.8, 149.3, 149.0, 134.6, 132.7, 132.2, 129.0, 128.8, 128.6, 128.5, 128.1, 124.6, 124.2, 124.1, 123.8, 123.2, 121.9, 121.5, 120.1, 119.2, 115.5, 112.6, 112.1, 108.4, 45.1, 40.4, 11.9; LRMS (ESI) m/z calcd for C28H28F3N3O [M+Na]+ : 479.2, found 480.4. 1 H NMR (400 MHz, CDCl 3 ), δ 9.95 (d, J = 7.2 Hz, 1H), 8.10 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.61 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.00 ( dd, J = 7.4 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 3.07 (q, J = 7.1 Hz, 4H), 3.03 (s, 3H), 3.00 (s, 3H), 1.01 (d, J = 7.2 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.2, 151.8, 149.3, 149.0, 134.6, 132.7, 132.2, 129.0, 128.8, 128.6, 128.5, 128.1, 124.6, 124.2, 124.1, 123.8, 123.2, 121.9, 121.5, 120.1 , 119.2, 115.5, 112.6, 112.1, 108.4, 45.1, 40.4, 11.9; LRMS (ESI) m/z calcd for C 28 H 28 F 3 N 3 O [M+Na] + : 479.2, found 480.4.

<GxF 26 ~ 30><GxF 26 ~ 30>

IF-E : 하기 반응식 7과 같이 합성하였으며, 구체적으로, 4-아세틸피리딘(4-Acetylpyridine, 394.6 μL, 3.567 mmol) 및 2-브로모-4’-(트리플루오로메틸)아세토페논(2-Bromo-4’-(trifluoromethyl)acetophenone, 1.0 g, 3.8 mmol)이 포함된 DMF(12.0 mL)을 80℃에서 4시간 동안 교반한 다음, 에틸아크릴레이트(193.6 μl, 1.79 mmol), 구리(II) 아세테이트 모노하이드레이트(2.14 g, 10.7 mmol) 및 소듐 아세테이트(1.17 g, 14.3 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 황색 고체의 화합물 IF-E(556.5 mg, 77.3% 수율)를 수득 하였다. IF-E : Synthesized as in Scheme 7 below, specifically, 4-acetylpyridine (4-Acetylpyridine, 394.6 μL, 3.567 mmol) and 2-bromo-4'-(trifluoromethyl)acetophenone (2-Bromo-4 DMF (12.0 mL) containing'-(trifluoromethyl)acetophenone, 1.0 g, 3.8 mmol) was stirred at 80°C for 4 hours, and then ethyl acrylate (193.6 μl, 1.79 mmol), copper (II) acetate monohydrate (2.14 g, 10.7 mmol) and sodium acetate (1.17 g, 14.3 mmol) were added, followed by stirring at 100° C. for 16 hours. After completion of the reaction, after monitoring by TLC, copper acetate was removed by filtration through a pad of Celite, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water and the organic material was extracted 3 times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to obtain a yellow solid compound IF-E (556.5 mg, 77.3% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.87 (dd, J = 7.2, 1.2 Hz, 1H), 8.96 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.79 (m, 3H), 7.61 (dd, J = 7.4, 2.4 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H); 13C NMR(100 MHz, CDCl3) 195.6, 184.4, 163.5, 142.5, 138.8, 134.8,133.7, 133.3, 129.4, 129.1, 128.9, 125.8, 125.7 (2), 125.2, 123.4, 122.5, 121.6, 121.1, 113.1, 109.9 60.9, 26.6, 14.9; LRMS (ESI) m/z calcd for C21H16F3NO4 [M+Na]+ : 403.1, found : 404.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.87 (dd, J = 7.2, 1.2 Hz, 1H), 8.96 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.79 (m, 3H ), 7.61 (dd, J = 7.4, 2.4 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) 195.6, 184.4, 163.5, 142.5, 138.8, 134.8,133.7, 133.3, 129.4, 129.1, 128.9, 125.8, 125.7 (2), 125.2, 123.4, 122.5, 121.6, 121.1, 113.1 , 109.9 60.9, 26.6, 14.9; LRMS (ESI) m/z calcd for C 21 H 16 F 3 NO 4 [M+Na] + : 403.1, found: 404.2.

IF-B : IF-E(556.5 mg, 1.379 mmol)가 포함된 메탄올(5 mL)에 KOH(2.21 g, 55.2 mmol)를 첨가한 후, 실온에서 하룻밤 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 갈색고체의 화합물 IF-A를 수득하였다. IF-B : KOH (2.21 g, 55.2 mmol) was added to methanol (5 mL) containing IF-E (556.5 mg, 1.379 mmol), followed by stirring at room temperature overnight. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water and dried in a drying oven to obtain a brown solid compound IF-A.

수득한 화합물 IF-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IF-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(350.3 mg, 4.170 mmol)를 첨가하고 및 NBS(259.6 mg, 1.459 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 황색 고체의 화합물 IF-B(358.6 mg, 63.4%수율)를 수득 하였다.The obtained compound IF-A was used in the next step without further purification, sodium bicarbonate (350.3 mg, 4.170 mmol) was added to DMF (10.0 mL) containing IF-A, and NBS (259.6 mg, 1.459 mmol) ) Was added partially at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to obtain a yellow solid compound IF-B (358.6 mg, 63.4% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.87 (d, J = 7.4 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.53 (dd, J = 7.4, 2 Hz, 1H), 7.39 (s, 1H), 2.72 (s, 3H); 13C NMR(100 MHz, CDCl3) 195.2, 183.3, 142.7, 135.8, 133.5, 133.2, 132.8, 129.3, 128.5, 127.6, 125.7(2), 125.2, 123.5, 122.5, 119.2, 112.5, 94.5, 26.7; LRMS (ESI) m/z calcd for C18H11BrF3NO2 [M+Na]+ : 409.0, found : 410.0. 1 H NMR (400 MHz, CDCl 3 ), δ 9.87 (d, J = 7.4 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.53 (dd, J = 7.4, 2 Hz, 1H), 7.39 (s, 1H), 2.72 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) 195.2, 183.3, 142.7, 135.8, 133.5, 133.2, 132.8, 129.3, 128.5, 127.6, 125.7(2), 125.2, 123.5, 122.5, 119.2, 112.5, 94.5, 26.7; LRMS (ESI) m/z calcd for C 18 H 11 BrF 3 NO 2 [M+Na] + : 409.0, found: 410.0.

[반응식 7][Scheme 7]

Figure pat00185
Figure pat00185

화합물 GxF 26 : Compound GxF 26 :

IF-B(30.0 mg, 0.063 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(35.9 mg, 0.189 mmol), 테트라키스(트리페닐 포스핀)팔라듐(15.0 mg, 0.013 mmol) 및 소듐 카보네이트(33.6 mg, 0.315 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-26으로 표시되는 황색 고체의 화합물 GxF 26(28.6 mg, 95.4% 수율)을 수득 하였다.4-trifluorophenyl boronic acid (35.9 mg, 0.189 mmol), tetrakis (triphenyl phosphine) in a solution containing IF-B (30.0 mg, 0.063 mmol) and a 10:1 mixture of DMF and water After adding palladium (15.0 mg, 0.013 mmol) and sodium carbonate (33.6 mg, 0.315 mmol), the mixture was stirred at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 26 (28.6 mg, 95.4% yield) represented by the following formula 1-26 Was obtained.

[화학식 1-26][Formula 1-26]

Figure pat00186
Figure pat00186

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.97(d, J = 7.4 Hz, 1H), 8.42(s, 1H), 7.95(d, J = 8 Hz, 2H), 7.78(dd, J = 19 Hz, 4 H), 7.95(d, J= 8 Hz, 2H), 7.55(dd, J = 7.2 Hz, 1H), 7.49(s, 1H), 2.67(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.3, 184.0,143.1,137.4, 135.3, 133.5, 133.1, 129.7, 129.4, 129.3, 128.7, 128.5, 126.3, 126.3, 125.8, 125.7, 125.7, 125.2, 123.7, 122.9, 122.5, 120.5, 119.1, 112.6, 26.8; LRMS (ESI) m/z calcd for C25H15F6NO2 [M+Na]+ : 375.1, found : 376.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.97 (d, J = 7.4 Hz, 1H), 8.42 (s, 1H), 7.95 (d, J = 8 Hz, 2H), 7.78 (dd, J = 19 Hz, 4H), 7.95 (d, J = 8 Hz, 2H), 7.55 (dd, J = 7.2 Hz, 1H), 7.49 (s, 1H), 2.67 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.3, 184.0,143.1,137.4, 135.3, 133.5, 133.1, 129.7, 129.4, 129.3, 128.7, 128.5, 126.3, 126.3, 125.8, 125.7, 125.7, 125.2, 123.7, 122.9, 122.5, 120.5, 119.1, 112.6, 26.8; LRMS (ESI) m/z calcd for C 25 H 15 F 6 NO 2 [M+Na] + : 375.1, found: 376.1.

화합물 GxF 27 : Compound GxF 27 :

IF-B(30.0 mg, 0.063 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(31.0 mg, 0.189 mmol), 테트라키스(트리페닐 포스핀)팔라듐(15.0 mg, 0.013 mmol) 및 소듐 카보네이트(33.6 mg, 0.315 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-27로 표시되는 황색 고체의 화합물 GxF 27(27.3 mg, 96.3% 수율)을 수득 하였다.In a solution containing IF-B (30.0 mg, 0.063 mmol) and a mixture of DMF and water 10:1, 4-acetylphenyl boronic acid (31.0 mg, 0.189 mmol), tetrakis (triphenyl phosphine) palladium ( 15.0 mg, 0.013 mmol) and sodium carbonate (33.6 mg, 0.315 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 27 (27.3 mg, 96.3% yield) represented by the following formula 1-27 Was obtained.

[화학식 1-27][Formula 1-27]

Figure pat00187
Figure pat00187

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ9.97(d, J = 7.2 Hz, 1H), 8.46(s, 1H), 8.08(d, J = 8.4 Hz, 2H), 7.96(d, J = 8.4 Hz, 2H), 7.90(d, J = 8.4 Hz, 1H), 7.80(d, J = 8.4 Hz, 2H), 7.67(d, J = 6.6 Hz, 2H), 7.55(dd, J = 7.4 Hz, 2 Hz, 1H), 7.51 (s, 1H), 6.90(d, J = 8.4 Hz, 1H), 2.68(s, 3H), 2.66(s, 3H); 13C NMR(100 MHz, CDCl3), δ 197.4, 195.4, 185.5, 140.0, 138.9, 135.7, 134.8, 132.6, 131.8, 129.4,129.2, 128.6, 128.1, 125.8, 124.3, 120.4,119.3, 112.2, 27.0, 26.7.; LRMS (ESI) m/z calcd for C26H18F3NO3 [M+Na]+ : 449.1, found :450.0. 1 H NMR (400 MHz, CDCl 3 ), δ 9.97 (d, J = 7.2 Hz, 1H), 8.46 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 6.6 Hz, 2H), 7.55 (dd, J = 7.4 Hz, 2 Hz, 1H), 7.51 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 2.68 (s, 3H), 2.66 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 197.4, 195.4, 185.5, 140.0, 138.9, 135.7, 134.8, 132.6, 131.8, 129.4,129.2, 128.6, 128.1, 125.8, 124.3, 120.4,119.3, 112.2, 27.0, 26.7.; LRMS (ESI) m/z calcd for C 26 H 18 F 3 NO 3 [M+Na] + : 449.1, found: 450.0.

화합물 GxF 28 : Compound GxF 28 :

IF-B(30.0 mg, 0.063 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(23.0 mg, 0.189 mmol), 테트라키스(트리페닐 포스핀)팔라듐(15.0 mg, 0.013 mmol) 및 소듐 카보네이트(33.6 mg, 0.315 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-28으로 표시되는 황색 고체의 화합물 GxF 28(23.6 mg, 91.9% 수율)을 수득 하였다.In a solution containing IF-B (30.0 mg, 0.063 mmol) and a mixture of DMF and water 10:1, 4-acetylphenyl boronic acid (23.0 mg, 0.189 mmol), tetrakis (triphenyl phosphine) palladium ( 15.0 mg, 0.013 mmol) and sodium carbonate (33.6 mg, 0.315 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 28 (23.6 mg, 91.9% yield) represented by Formula 1-28 below. Was obtained.

[화학식 1-28][Formula 1-28]

Figure pat00188
Figure pat00188

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.94(d, J = 8 Hz, 1H), 8.41(s, 1H), 7.86(d, J = 6.8 Hz, 2H), 7.72(dd, J = 23 Hz, 8 Hz, 4H), 7.62(t, J = 5.2, 2 Hz, 1H), 7.54(m, 4H), 2.67(s, 3H); 13C NMR(100 MHz, CDCl3), 195.4, 185.5, 140.0, 137.8, 134.7, 132.6, 131.8, 129.5, 129.2, 128.6, 128.4, 126.3, 126.2, 125.8, 124.2, 120.1, 119.1, 112.2, 26.7; LRMS (ESI) LRMS (ESI) m/z calcd for C24H16F3NO2 [M+Na]+ : 407.1, found : 408.2. 1 H NMR (400 MHz, CDCl 3) , δ 9.94 (d, J = 8 Hz, 1H), 8.41 (s, 1H), 7.86 (d, J = 6.8 Hz, 2H), 7.72 (dd, J = 23 Hz, 8 Hz, 4H), 7.62 (t, J = 5.2, 2 Hz, 1H), 7.54 (m, 4H), 2.67 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), 195.4, 185.5, 140.0, 137.8, 134.7, 132.6, 131.8, 129.5, 129.2, 128.6, 128.4, 126.3, 126.2, 125.8, 124.2, 120.1, 119.1, 112.2, 26.7; LRMS (ESI) LRMS (ESI) m/z calcd for C 24 H 16 F 3 NO 2 [M+Na] + : 407.1, found: 408.2.

화합물 GxF 29 : Compound GxF 29 :

IF-B(30.0 mg, 0.063 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(28.7 mg, 0.189 mmol), 테트라키스(트리페닐 포스핀)팔라듐(15.0 mg, 0.013 mmol) 및 소듐 카보네이트(33.6 mg, 0.315 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-29로 표시되는 황색 고체의 화합물 GxF 29(25.4 mg, 92.2% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (28.7 mg, 0.189 mmol), tetrakis (triphenyl phosphine) palladium in a solution containing IF-B (30.0 mg, 0.063 mmol) and a 10:1 mixture of DMF and water (15.0 mg, 0.013 mmol) and sodium carbonate (33.6 mg, 0.315 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 29 (25.4 mg, 92.2% yield) represented by the following formula 1-29. Was obtained.

[화학식 1-29][Formula 1-29]

Figure pat00189
Figure pat00189

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.92(d, J = 7.4 Hz, 1H), 8.39(s, 1H), 7.94(d, J = 8 Hz, 2H), 7.78(d, J = 8.4 Hz, 2H), 7.49(m, 3H), 7.38(s, 1H), 7.04(d, J = 8.8Hz, 1H), 3.88(s, 3H), 2.66(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.5, 183.7, 159.2, 143.4, 135.2, 133.2, 132.9, 132.4, 129.5, 129.4, 128.5, 126.1, 125.6, 125.5, 125.4, 125.3, 123.3, 122.6, 122.3,119.8,116.2, 115.0, 114.8, 112.2, 56.1, 55.7, 30.1, 26.7; LRMS (ESI) m/z calcd for C25H18F3NO3 [M+Na]+ : 437.1, found : 438.2. 1 H NMR (400 MHz, CDCl 3) , δ 9.92 (d, J = 7.4 Hz, 1H), 8.39 (s, 1H), 7.94 (d, J = 8 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.49 (m, 3H), 7.38 (s, 1H), 7.04 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H), 2.66 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.5, 183.7, 159.2, 143.4, 135.2, 133.2, 132.9, 132.4, 129.5, 129.4, 128.5, 126.1, 125.6, 125.5, 125.4, 125.3, 123.3, 122.6, 122.3, 119.8, 116.2, 115.0, 114.8, 112.2, 56.1, 55.7, 30.1, 26.7; LRMS (ESI) m/z calcd for C 25 H 18 F 3 NO 3 [M+Na] + : 437.1, found: 438.2.

화합물 GxF 30 : Compound GxF 30 :

IF-B(30.0 mg, 0.063 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(31.2 mg, 0.189 mmol), 테트라키스(트리페닐 포스핀)팔라듐(15.0 mg, 0.013 mmol) 및 소듐 카보네이트(33.6 mg, 0.315 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-30으로 표시되는 주황색 고체의 화합물 GxF 30(26.5 mg, 93.5% 수율)을 수득 하였다.In a solution containing IF-B (30.0 mg, 0.063 mmol), DMF and water 10:1, 4-(dimethylamino)phenylboronic acid (31.2 mg, 0.189 mmol), tetrakis (triphenylphos) Fin) palladium (15.0 mg, 0.013 mmol) and sodium carbonate (33.6 mg, 0.315 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%), and the orange solid compound GxF 30 (26.5 mg, 93.5% yield) represented by the following formula 1-30 (26.5 mg, 93.5% yield) Was obtained.

[화학식 1-30][Formula 1-30]

Figure pat00190
Figure pat00190

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) , δ 9.91(d, J = 7.6 Hz, 1H), 8.43(s, 1H), 7.95(d, J = 8 Hz, 2H), 7.78(d, J = 8 Hz, 2H), 7.46(m, 3H), 7.36(s, 1H), 6.85(d, J = 8 Hz, 2H), 3.03(s, 6H), 2.65(s, 3H); 13C NMR(100 MHz, CDCl3) , δ 195.5, 183.6, 150.0, 143.6, 135.2, 133.1, 132.8, 132.1, 129.4, 129.1, 128.4, 125.5, 125.5, 125.3, 125.0, 123.3, 123.1, 122.6, 121.5, 120.2, 113.1, 112.0, 40.9, 30.1, 26.6; LRMS (ESI) m/z calcd for C26H21N2O2 [M+Na]+ : 450.2, found : 451.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.91 (d, J = 7.6 Hz, 1H), 8.43 (s, 1H), 7.95 (d, J = 8 Hz, 2H), 7.78 (d, J = 8 Hz, 2H), 7.46 (m, 3H), 7.36 (s, 1H), 6.85 (d, J = 8 Hz, 2H), 3.03 (s, 6H), 2.65 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.5, 183.6, 150.0, 143.6, 135.2, 133.1, 132.8, 132.1, 129.4, 129.1, 128.4, 125.5, 125.5, 125.3, 125.0, 123.3, 123.1, 122.6, 121.5, 120.2, 113.1, 112.0, 40.9, 30.1, 26.6; LRMS (ESI) m/z calcd for C 26 H 21 N 2 O 2 [M+Na]+: 450.2, found: 451.2.

<GxF 31 ~ 35><GxF 31 ~ 35>

IG-E : 하기 반응식 8과 같이 합성하였으며, 구체적으로, 4-아세틸피리딘(158.1 μL, 1.431 mmol) 및 2-클로로아세톤(2-chloroacetone, 120.7 μL, 1.5 mmol)이 포함된 DMF(12.0 mL)을 80℃에서 4시간 동안 교반한 다음, 에틸아크릴레이트(77.5 μl, 0.715 mmol), 구리(II) 아세테이트 모노하이드레이트(856.5 mg, 4.29 mmol) 및 소듐 아세테이트(469.2 mg, 5.72 mmol)를 첨가하여 100℃에서 5시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 황색 고체의 화합물 IG-E(166.7 mg, 85.3% 수율)를 수득 하였다. IG-E : Synthesized as in Scheme 8 below, specifically, DMF (12.0 mL) containing 4-acetylpyridine (158.1 μL, 1.431 mmol) and 2-chloroacetone (2-chloroacetone, 120.7 μL, 1.5 mmol) at 80° C. After stirring at for 4 hours, ethyl acrylate (77.5 μl, 0.715 mmol), copper (II) acetate monohydrate (856.5 mg, 4.29 mmol) and sodium acetate (469.2 mg, 5.72 mmol) were added thereto at 100° C. for 5 Stir for hours. After completion of the reaction, after monitoring by TLC, copper acetate was removed by filtration through a pad of Celite, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water and the organic material was extracted 3 times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to obtain a yellow solid compound IG-E (166.7 mg, 85.3% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.85(d, J = 6.8 Hz, 1H), 8.80(s, 1H), 7.44(d, J = 7.4 Hz, 1H), 4.39(q, J = 14.2 Hz, 2H), 2.62(s, 3H), 2.58(s, 3H), 1.43(t, J = 7.6Hz, 3H); 13C NMR(100 MHz, CDCl3), δ 185.4, 159.1, 140.2, 134.6, 131.8, 131.6, 129.5, 129.2, 128.5, 128.3, 126.4, 125.4, 123.8, 121.8, 121.6, 119.9, 114.8, 111.7, 55.7, 26.7; LRMS (ESI) m/z calcd for C15H15NO4 [M+Na]+ : 273.3, found : 274.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.85 (d, J = 6.8 Hz, 1H), 8.80(s, 1H), 7.44(d, J = 7.4 Hz, 1H), 4.39(q, J = 14.2 Hz, 2H), 2.62(s, 3H), 2.58(s, 3H) , 1.43 (t, J = 7.6 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 185.4, 159.1, 140.2, 134.6, 131.8, 131.6, 129.5, 129.2, 128.5, 128.3, 126.4, 125.4, 123.8, 121.8, 121.6, 119.9, 114.8, 111.7, 55.7, 26.7 ; LRMS (ESI) m/z calcd for C 15 H 15 NO 4 [M+Na] + : 273.3, found: 274.1.

IG-B : IG-E(166.7 mg, 0.610 mmol)가 포함된 메탄올(5 mL)에 KOH(1.37 g, 24.4 mmol)를 첨가한 후, 실온에서 하룻밤 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 갈색고체의 화합물 IG-A를 수득하였다. IG-B : KOH (1.37 g, 24.4 mmol) was added to methanol (5 mL) containing IG-E (166.7 mg, 0.610 mmol), followed by stirring at room temperature overnight. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water and dried in a drying oven to obtain a brown solid compound IG-A.

수득한 화합물 IG-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IG-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(51.2 mg, 1.83 mmol)를 첨가하고 및 NBS(108.5 mg, 0.64 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 황색 고체의 화합물 IG-B(135.5 mg, 79.3% 수율)를 수득 하였다.The obtained compound IG-A was used in the next step without further purification, sodium bicarbonate (51.2 mg, 1.83 mmol) was added to DMF (10.0 mL) containing IG-A, and NBS (108.5 mg, 0.64 mmol) ) Was added partially at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to obtain a yellow solid compound IG-B (135.5 mg, 79.3% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.65(d, J = 7.4 Hz, 1H), 8.00(s, 1H),7.49(s, 1H), 7.32(d, 7.4Hz), 2.63(s, 3H), 2.53(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.2, 187.1, 134.4, 131.7, 128.0, 124.8, 124.1, 119.1, 111.8, 93.6, 27.9, 26.6; LRMS (ESI) m/z calcd for C12H10BrNO2 [M+Na]+ : 280.1, found : 280.0. 1 H NMR (400 MHz, CDCl 3 ), δ 9.65 ( d, J = 7.4 Hz, 1H), 8.00 (s, 1H), 7.49 (s, 1H), 7.32 (d, 7.4 Hz), 2.63 (s, 3H), 2.53 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.2, 187.1, 134.4, 131.7, 128.0, 124.8, 124.1, 119.1, 111.8, 93.6, 27.9, 26.6; LRMS (ESI) m/z calcd for C 12 H 10 BrNO 2 [M+Na] + : 280.1, found: 280.0.

[반응식 8][Scheme 8]

Figure pat00191
Figure pat00191

화합물 GxF 31 : Compound GxF 31 :

IG-B(25.0 mg, 0.089 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(50.71 mg, 0.27 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.58 mg, 0.018 mmol) 및 소듐 카보네이트(47.13 mg, 0.45 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-31으로 표시되는 황색 고체의 화합물 GxF 31(29.9 mg, 97.2% 수율)을 수득 하였다.4-trifluorophenyl boronic acid (50.71 mg, 0.27 mmol), tetrakis (triphenyl phosphine) in a solution containing IG-B (25.0 mg, 0.089 mmol) and a 10:1 mixture of DMF and water After adding palladium (20.58 mg, 0.018 mmol) and sodium carbonate (47.13 mg, 0.45 mmol), the mixture was stirred at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 31 (29.9 mg, 97.2% yield) represented by the following Formula 1-31. Was obtained.

[화학식 1-31][Formula 1-31]

Figure pat00192
Figure pat00192

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.86(d, J = 7.6 Hz, 1H), 8.36(s, 1H), 7.74(dd, J = 8.4, 24.6 Hz, 5H), 7.43(d, J = 8 Hz, 1H), 2.66(s, 3H), 2.64(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.5, 187.9, 156.9, 137.8, 134.0, 132.1, 129.5, 129.1, 128.4, 126.3, 126.3, 125.7, 124.4, 123.1, 123.0, 119.8, 119.1, 112.1, 28.1, 26.7; LRMS (ESI) m/z calcd for C19H14F3NO2 [M+Na]+ : 345.3, found : 346.1. 1 H NMR (400 MHz, CDCl 3) , δ 9.86 (d, J = 7.6 Hz, 1H), 8.36 (s, 1H), 7.74 (dd, J = 8.4, 24.6 Hz, 5H), 7.43 (d, J = 8 Hz, 1H), 2.66 (s, 3H), 2.64 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.5, 187.9, 156.9, 137.8, 134.0, 132.1, 129.5, 129.1, 128.4, 126.3, 126.3, 125.7, 124.4, 123.1, 123.0, 119.8, 119.1, 112.1, 28.1, 26.7; LRMS (ESI) m/z calcd for C 19 H 14 F 3 NO 2 [M+Na] + : 345.3, found: 346.1.

화합물 GxF 32 : Compound GxF 32 :

IG-B(25.0 mg, 0.089 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(43.78 mg, 0.27 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.58 mg, 0.018 mmol) 및 소듐 카보네이트(47.13 mg, 0.45 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-32로 표시되는 황색 고체의 화합물 GxF 32(27.6 mg, 97.2% 수율)을 수득 하였다.4-acetylphenyl boronic acid (43.78 mg, 0.27 mmol), tetrakis (triphenyl phosphine) palladium ( 20.58 mg, 0.018 mmol) and sodium carbonate (47.13 mg, 0.45 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 32 (27.6 mg, 97.2% yield) represented by the following Chemical Formula 1-32. Was obtained.

[화학식 1-32][Formula 1-32]

Figure pat00193
Figure pat00193

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) , δ 9.86(d, J = 7.4 Hz, 1H), 8.39(s, 1H), 8.10(d, J = 6.6 Hz, 2H), 7.70(d, J = 5.2Hz, 2H), 7.69(s, 1H), 7.42(dd, J = 2 Hz, 7.2 Hz, 1H), 2.67(s, 3H), 2.66(s, 3H), 2.64(s, 3H); 13C NMR(100 MHz, CDCl3) , δ 197.5, 195.5, 187.9, 139.0, 135.7, 134.1, 132.1, 129.4, 128.5, 128.1, 124.4, 123.1, 120.1, 119.3,112.1, 28.1, 27.1, 26.7; LRMS (ESI) m/z calcd for C20H17NO3 [M+Na]+ : 319.4, found : 320.1. 1 H NMR (400 MHz, CDCl 3) , δ 9.86 (d, J = 7.4 Hz, 1H), 8.39 (s, 1H), 8.10 (d, J = 6.6 Hz, 2H), 7.70 (d, J = 5.2 Hz, 2H), 7.69 (s, 1H), 7.42 (dd, J = 2 Hz, 7.2 Hz, 1H), 2.67 (s, 3H), 2.66 (s, 3H), 2.64 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 197.5, 195.5, 187.9, 139.0, 135.7, 134.1, 132.1, 129.4, 128.5, 128.1, 124.4, 123.1, 120.1, 119.3,112.1, 28.1, 27.1, 26.7; LRMS (ESI) m/z calcd for C 20 H 17 NO 3 [M+Na]+: 319.4, found: 320.1.

화합물 GxF 33 : Compound GxF 33 :

IG-B(25.0 mg, 0.089 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 페닐 보론산(32.56 mg, 0.27 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.58 mg, 0.018 mmol) 및 소듐 카보네이트(47.13 mg, 0.45 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-33으로 표시되는 황색 고체의 화합물 GxF 33(23.5 mg, 95.4% 수율)을 수득 하였다.Phenyl boronic acid (32.56 mg, 0.27 mmol), tetrakis (triphenyl phosphine) palladium (20.58 mg,) in a solution containing IG-B (25.0 mg, 0.089 mmol) and a 10:1 mixture of DMF and water 0.018 mmol) and sodium carbonate (47.13 mg, 0.45 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 33 (23.5 mg, 95.4% yield) represented by the following Chemical Formula 1-33. Was obtained.

[화학식 1-33][Formula 1-33]

Figure pat00194
Figure pat00194

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.81(d, J = 7.4 Hz, 1H), 8.37(s, 1H), 7.64(s, 1H), 7.59(d, J = 7.4 Hz, 2H), 7.51(t, J = 7.2 Hz, 2H), 7.40(t, J = 7.2 Hz, 2H), 2.64(s, 3H), 2.61(s, 3H); 13C NMR(100 MHz, CDCl3) , δ 195.6, 187.8, 134.1, 133.9, 131.6, 129.3, 128.3, 128.2, 127.4, 124.1, 122.9, 121.7, 119.8, 111.7, 28.1, 26.7; LRMS (ESI) m/z calcd for C18H15NO2 [M+Na]+ : 277.3, found : 278.3. 1 H NMR (400 MHz, CDCl 3 ), δ 9.81 (d, J = 7.4 Hz, 1H), 8.37 (s, 1H), 7.64 (s, 1H), 7.59 (d, J = 7.4 Hz, 2H), 7.51 (t, J = 7.2 Hz, 2H), 7.40 (t, J = 7.2 Hz, 2H), 2.64 (s, 3H), 2.61 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.6, 187.8, 134.1, 133.9, 131.6, 129.3, 128.3, 128.2, 127.4, 124.1, 122.9, 121.7, 119.8, 111.7, 28.1, 26.7; LRMS (ESI) m/z calcd for C 18 H 15 NO 2 [M+Na] + : 277.3, found: 278.3.

화합물 GxF 34 : Compound GxF 34 :

IG-B(25.0 mg, 0.089 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(40.57 mg, 0.27 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.58 mg, 0.018 mmol) 및 소듐 카보네이트(47.13 mg, 0.45 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-34로 표시되는 황색 고체의 화합물 GxF 34(26.5 mg, 96.9% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (40.57 mg, 0.27 mmol), tetrakis (triphenyl phosphine) palladium in a solution containing IG-B (25.0 mg, 0.089 mmol) and a 10:1 mixture of DMF and water (20.58 mg, 0.018 mmol) and sodium carbonate (47.13 mg, 0.45 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 34 (26.5 mg, 96.9% yield) represented by the following Formula 1-34. Was obtained.

[화학식 1-34][Formula 1-34]

Figure pat00195
Figure pat00195

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.78(d, J = 7.4 Hz, 1H), 8.31(s, 1H), 7.57(s, 1H), 7.49(d, J = 6.6 Hz, 2H), 7.35(dd, J = 2 H, 7.4 Hz, 1H), 7.05(s, 1H), 7.03(s, 1H),3.88(s, 3H), 2.62(s, 3H), 2.60(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.6, 187.7, 159.1, 133.8, 131.3, 129.4, 128.1, 126.5, 124.0, 122.6, 121.6, 119.9, 114.8, 111.5, 55.7, 28.0, 26.6; LRMS (ESI) m/z calcd for C19H17NO3 [M+Na]+ : 307.4, found : 308.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.78 (d, J = 7.4 Hz, 1H), 8.31 (s, 1H), 7.57 (s, 1H), 7.49 (d, J = 6.6 Hz, 2H), 7.35 (dd, J = 2H, 7.4 Hz, 1H), 7.05 (s, 1H), 7.03 (s, 1H), 3.88 (s, 3H), 2.62 (s, 3H), 2.60 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.6, 187.7, 159.1, 133.8, 131.3, 129.4, 128.1, 126.5, 124.0, 122.6, 121.6, 119.9, 114.8, 111.5, 55.7, 28.0, 26.6; LRMS (ESI) m/z calcd for C 19 H 17 NO 3 [M+Na] + : 307.4, found: 308.1.

화합물 GxF 35 : Compound GxF 35 :

IG-B(25.0 mg, 0.089 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(44.06 mg, 0.27 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.58 mg, 0.018 mmol) 및 소듐 카보네이트(47.13 mg, 0.45 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-35로 표시되는 황색 고체의 화합물 GxF 35(26.9 mg, 94.8% 수율)을 수득 하였다.4-(dimethylamino)phenyl boronic acid (44.06 mg, 0.27 mmol), tetrakis (triphenyl phosphonic acid) in a solution containing IG-B (25.0 mg, 0.089 mmol) and a 10:1 mixture of DMF and water Fin) palladium (20.58 mg, 0.018 mmol) and sodium carbonate (47.13 mg, 0.45 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 35 (26.9 mg, 94.8% yield) represented by the following Formula 1-35. Was obtained.

[화학식 1-35][Formula 1-35]

Figure pat00196
Figure pat00196

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.78(d, J = 6.8 Hz), 8.36(s, 1H), 7.56(s, 1H), 7.47(dd, J = 2.4, 9.2 Hz, 2H), 7.36(dd, J = 2, 2Hz, 1H), 6.87(d, J = 8.8 Hz), 3.03(s, 6H), 2.63(s, 3H), 2.60(s, 3H); 13C NMR(100 MHz, CDCl3) , δ 195.7, 187.7, 149.9, 33.8, 131.0, 129.1, 128.0, 124.0, 122.4, 122.3, 122.0, 121.6(2), 120.3, 113.2, 111.4, 111.2, 40.9, 28.1, 26.6; LRMS (ESI) m/z calcd for C20H17NO3 [M+Na]+ : 320.2, found : 321.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.78 (d, J = 6.8 Hz), 8.36 (s, 1H), 7.56 (s, 1H), 7.47 (dd, J = 2.4, 9.2 Hz, 2H), 7.36 (dd, J = 2, 2 Hz, 1H), 6.87 (d, J = 8.8 Hz), 3.03 (s, 6H), 2.63 (s, 3H), 2.60 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.7, 187.7, 149.9, 33.8, 131.0, 129.1, 128.0, 124.0, 122.4, 122.3, 122.0, 121.6(2), 120.3, 113.2, 111.4, 111.2, 40.9, 28.1 , 26.6; LRMS (ESI) m/z calcd for C 20 H 17 NO 3 [M+Na] + : 320.2, found: 321.2.

<GxF 36 ~ 40><GxF 36 ~ 40>

IH-E : 하기 반응식 9와 같이 합성하였으며, 구체적으로, 4-아세틸피리딘(105.9 μL, 0.957 mmol) 및 2-브로모아세토페논(2-bromoacetophenone, 200.0 mg, 1.01 mmol)이 포함된 DMF(4.0 mL)을 80℃에서 5시간 동안 교반한 다음, 에틸아크릴레이트(51.8 μl, 0.479 mmol), 구리(II) 아세테이트 모노하이드레이트(573.2 mg, 2.87 mmol) 및 소듐 아세테이트(314.0 mg, 3.83 mmol)를 첨가하여 100℃에서 5시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 황색 고체의 화합물 IH-E(556.5 mg, 77.3% 수율)를 수득 하였다. IH-E : It was synthesized as in Scheme 9 below, and specifically, DMF (4.0 mL) containing 4-acetylpyridine (105.9 μL, 0.957 mmol) and 2-bromoacetophenone (2-bromoacetophenone, 200.0 mg, 1.01 mmol) After stirring at 80° C. for 5 hours, ethyl acrylate (51.8 μl, 0.479 mmol), copper(II) acetate monohydrate (573.2 mg, 2.87 mmol) and sodium acetate (314.0 mg, 3.83 mmol) were added to 100° C. Stir for 5 hours at. After completion of the reaction, after monitoring by TLC, copper acetate was removed by filtration through a pad of Celite, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water and the organic material was extracted 3 times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to obtain a yellow solid compound IH-E (556.5 mg, 77.3% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ9.83 (dd, J = 7.2, 0.8 Hz, 1H), 8.90(s, 1H), 7.80(m, 3H), 7.54(m, 4H) 4.38(q, 2H), 2.69(s, 3H); 13C NMR(100 MHz, CDCl3) 195.7, 163.7, 139.4, 138.3, 134.3, 132.1, 129.2, 128.9, 128.9, 128.9,121.1, 60.8, 26.6, 14.9; LRMS (ESI) m/z calcd for C20H17NO4 [M+Na]+ : 335.1 ,found : 336.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.83 (dd, J = 7.2, 0.8 Hz, 1H), 8.90 (s, 1H), 7.80 (m, 3H), 7.54 (m, 4H) 4.38 (q, 2H) ), 2.69 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) 195.7, 163.7, 139.4, 138.3, 134.3, 132.1, 129.2, 128.9, 128.9, 128.9,121.1, 60.8, 26.6, 14.9; LRMS (ESI) m/z calcd for C 20 H 17 NO 4 [M+Na] + : 335.1 ,found: 336.2.

IH-B : IH-E(200.0 mg, 0.60 mmol)가 포함된 메탄올(4 mL)에 KOH(336.8 mg, 6.0 mmol)를 첨가한 후, 실온에서 하룻밤 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 갈색고체의 화합물 IH-A를 수득하였다. IH-B : KOH (336.8 mg, 6.0 mmol) was added to methanol (4 mL) containing IH-E (200.0 mg, 0.60 mmol), followed by stirring at room temperature overnight. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water and dried in a drying oven to obtain a brown solid compound IH-A.

수득한 화합물 IH-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IH-A이 포함된 DMF(2.0 mL)에 소듐 바이카보네이트(131.1 mg, 1.56 mmol)를 첨가하고 및 NBS(97.9 mg, 0.55 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 황색 고체의 화합물 IH-B(135.2 mg, 76.3% 수율)를 수득 하였다.The obtained compound IH-A was used in the next step without further purification, sodium bicarbonate (131.1 mg, 1.56 mmol) was added to DMF (2.0 mL) containing IH-A, and NBS (97.9 mg, 0.55 mmol) ) Was added partially at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to obtain a yellow solid compound IH-B (135.2 mg, 76.3% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.85(d, J = 7.4 Hz, 1H), 8.17(s, 1H), 7.8(d, J = 7.6 Hz, 2H), 7.52(m,5H), 2.71(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.3, 184.8, 139.5, 135.2, 132.2, 131.9, 129.1, 128.6, 128.3, 127.5, 123.9, 119.2, 112.0, 94.1, 26.7; LRMS (ESI) m/z calcd for C17H12BrNO2 [M+Na]+ : 341.0, found : x. 1 H NMR (400 MHz, CDCl 3 ), δ 9.85 (d, J = 7.4 Hz, 1H), 8.17 (s, 1H), 7.8 (d, J = 7.6 Hz, 2H), 7.52 (m,5H), 2.71 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.3, 184.8, 139.5, 135.2, 132.2, 131.9, 129.1, 128.6, 128.3, 127.5, 123.9, 119.2, 112.0, 94.1, 26.7; LRMS (ESI) m/z calcd for C 17 H 12 BrNO 2 [M+Na] + : 341.0, found: x.

[반응식 9][Scheme 9]

Figure pat00197
Figure pat00197

화합물 GxF 36 : Compound GxF 36 :

IG-B(30.0 mg, 0.088 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(49.95 mg, 0.26 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.28 mg, 0.018 mmol) 및 소듐 카보네이트(46.4 mg, 0.44 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 40%)로 정제하여 하기 화학식 1-36으로 표시되는 황색 고체의 화합물 GxF 36(33.8 mg, 94.3% 수율)을 수득 하였다.4-trifluorophenyl boronic acid (49.95 mg, 0.26 mmol), tetrakis (triphenyl phosphine) in a solution containing IG-B (30.0 mg, 0.088 mmol) and a 10:1 mixture of DMF and water After adding palladium (20.28 mg, 0.018 mmol) and sodium carbonate (46.4 mg, 0.44 mmol), the mixture was stirred at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 40%) to form a yellow solid compound GxF 36 (33.8 mg, 94.3% yield) represented by the following formula 1-36. Was obtained.

[화학식 1-36][Formula 1-36]

Figure pat00198
Figure pat00198

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) δ 9.92(d, J = 7.6 Hz, 1H), 8.09(s, 1H), 7.85(dd, J = 8.2 Hz, 2H), 7.74(d, J = 8.0 Hz, 2H), 7.66(d, J = 8.0 Hz, 2H), 7.60(t, J = 6.8 Hz, 1H), 7.57(s, 1H), 7.54(d, J = 7.6 Hz, 2H), 7.14(d, J = 7.4 Hz, 1H); 13C NMR(100 MHz, CDCl3) 185.5, 139.9, 137.5, 133.1, 131.8, 129.5, 129.8, 128.2, 128.3, 126.4, 126.7, 126.2, 126.1, 125.4, 123.8, 118., 115.7, 110.0, 110.0, 47.1, 34.4; LRMS (ESI) m/z calcd for C24H16F3NO2 [M+Na]+ : 407.1, found : 408.1. 1 H NMR (400 MHz, CDCl 3 ) δ 9.92 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 7.85 (dd, J = 8.2 Hz, 2H), 7.74 (d, J = 8.0 Hz , 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.60 (t, J = 6.8 Hz, 1H), 7.57 (s, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.14 (d , J = 7.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) 185.5, 139.9, 137.5, 133.1, 131.8, 129.5, 129.8, 128.2, 128.3, 126.4, 126.7, 126.2, 126.1, 125.4, 123.8, 118., 115.7, 110.0, 110.0, 47.1 , 34.4; LRMS (ESI) m/z calcd for C 24 H 16 F 3 NO 2 [M+Na] + : 407.1, found: 408.1.

화합물 GxF 37 : Compound GxF 37 :

IG-B(30.0 mg, 0.088 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(343.12 mg, 0.26 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.28 mg, 0.018 mmol) 및 소듐 카보네이트(46.4 mg, 0.44 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-37로 표시되는 황색 고체의 화합물 GxF 37(32.1 mg, 95.6% 수율)을 수득 하였다.4-acetylphenyl boronic acid (343.12 mg, 0.26 mmol), tetrakis (triphenyl phosphine) palladium ( 20.28 mg, 0.018 mmol) and sodium carbonate (46.4 mg, 0.44 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 37 (32.1 mg, 95.6% yield) represented by Formula 1-37 below. Was obtained.

[화학식 1-37][Formula 1-37]

Figure pat00199
Figure pat00199

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.92(d, J = 8 Hz, 1H), 8.44(s, 1H), 8.07(d, J = 7.2 Hz, 2H), 7.85(d, J = 7.6 Hz, 2H), 7.54(m, 5 H), 2.66(s, 3H), 2.65(s, 3H); 13C NMR(100 MHz, CDCl3), δ 197.4, 195.4, 185.5, 140.0, 138.9, 135.7, 134.8, 132.6, 131.8, 129.4,129.2, 128.6, 128.1, 125.8, 124.3, 120.4,119.3, 112.2, 27.0, 26.7.; LRMS (ESI) m/z calcd for C25H19NO3 [M+Na]+ : 381.1, found : 382.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.92 (d, J = 8 Hz, 1H), 8.44 (s, 1H), 8.07 (d, J = 7.2 Hz, 2H), 7.85 (d, J = 7.6 Hz, 2H), 7.54 (m, 5H), 2.66 (s, 3H), 2.65 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 197.4, 195.4, 185.5, 140.0, 138.9, 135.7, 134.8, 132.6, 131.8, 129.4,129.2, 128.6, 128.1, 125.8, 124.3, 120.4,119.3, 112.2, 27.0, 26.7.; LRMS (ESI) m/z calcd for C 25 H 19 NO 3 [M+Na] + : 381.1, found: 382.2.

화합물 GxF 38 : Compound GxF 38 :

IG-B(30.0 mg, 0.088 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 메틸 보론산(32.07 mg, 0.26 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.28 mg, 0.018 mmol) 및 소듐 카보네이트(46.4 mg, 0.44 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-38으로 표시되는 황색 고체의 화합물 GxF 38(28.5 mg, 95.4% 수율)을 수득 하였다.Methyl boronic acid (32.07 mg, 0.26 mmol), tetrakis (triphenyl phosphine) palladium (20.28 mg,) in a solution containing IG-B (30.0 mg, 0.088 mmol) and a 10:1 mixture of DMF and water 0.018 mmol) and sodium carbonate (46.4 mg, 0.44 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 38 (28.5 mg, 95.4% yield) represented by the following formula 1-38. Was obtained.

[화학식 1-38][Formula 1-38]

Figure pat00200
Figure pat00200

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.92(d, J = 7.6 Hz, 1H), 8.43(s, 1H), 7.86(d, J = 6.4 Hz, 2H), 7.58(m, 3H), 7.50(m, J= 30.4 Hz, 7H),7.38(t, J = 7.2 Hz, 1H), 2.65(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.6, 185.5, 140.2, 134.7, 134.1, 132.1, 131.7, 129.3, 129.2, 128.5, 128.3, 125.7, 119.8, 111.8; LRMS (ESI) m/z calcd for C23H17NO2 [M+Na]+ : 339.1, found : 340.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.92 (d, J = 7.6 Hz, 1H), 8.43 (s, 1H), 7.86 (d, J = 6.4 Hz, 2H), 7.58 (m, 3H), 7.50 (m, J = 30.4 Hz, 7H), 7.38 (t, J = 7.2 Hz, 1H), 2.65 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.6, 185.5, 140.2, 134.7, 134.1, 132.1, 131.7, 129.3, 129.2, 128.5, 128.3, 125.7, 119.8, 111.8; LRMS (ESI) m/z calcd for C 23 H 17 NO 2 [M+Na]+: 339.1, found: 340.2.

화합물 GxF 39 : Compound GxF 39 :

IG-B(30.0 mg, 0.088 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(4-methoxyphenyl boronic acid, 39.97 mg, 0.26 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.28 mg, 0.018 mmol) 및 소듐 카보네이트(46.4 mg, 0.44 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-39로 표시되는 황색 고체의 화합물 GxF 39(30.1 mg, 92.7% 수율)을 수득 하였다.In a solution containing IG-B (30.0 mg, 0.088 mmol) and a mixture of DMF and water 10:1, 4-methoxyphenyl boronic acid (39.97 mg, 0.26 mmol), tetrakis ( Triphenyl phosphine) palladium (20.28 mg, 0.018 mmol) and sodium carbonate (46.4 mg, 0.44 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 39 (30.1 mg, 92.7% yield) represented by the following formula 1-39. Was obtained.

[화학식 1-39][Formula 1-39]

Figure pat00201
Figure pat00201

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) 9.89(d,e J = 8 Hz, 1H), 8.36(s, 1H), 7.84(d, 8.2 Hz, 2H), 7.51(m,7H), 7.03(d, 7Hz, 2H), 3.87(s, 3H), 2.65(s, 3H); 13C NMR(100 MHz, CDCl3) 195.6, 185.4, 159.1, 140.2, 134.6, 131.8, 131.6, 129.5, 129.2, 128.5, 128.3, 126.4, 125.4, 123.8, 121.8, 121.6, 119.9, 114.8, 111.7, 55.7, 26.7; LRMS (ESI) m/z calcd for C24H19NO3 [M+Na]+ :369.1, found : 370.2. 1 H NMR (400 MHz, CDCl 3 ) 9.89 (d,e J = 8 Hz, 1H), 8.36 (s, 1H), 7.84 (d, 8.2 Hz, 2H), 7.51 (m,7H), 7.03 (d , 7 Hz, 2H), 3.87 (s, 3H), 2.65 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) 195.6, 185.4, 159.1, 140.2, 134.6, 131.8, 131.6, 129.5, 129.2, 128.5, 128.3, 126.4, 125.4, 123.8, 121.8, 121.6, 119.9, 114.8, 111.7, 55.7, 26.7; LRMS (ESI) m/z calcd for C 24 H 19 NO 3 [M+Na]+ :369.1, found: 370.2.

화합물 GxF 40 : Compound GxF 40 :

IG-B(30.0 mg, 0.088 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액에 페닐(다이메틸아미노)페닐 보론산(phenyl (dimethylamino)phenylboronic acid, 43.40 mg, 0.26 mmol), 테트라키스(트리페닐 포스핀)팔라듐(20.28 mg, 0.018 mmol) 및 소듐 카보네이트(46.4 mg, 0.44 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-40으로 표시되는 주황색 고체의 화합물 GxF 40(32.9 mg, 94.9% 수율)을 수득 하였다.Phenyl (dimethylamino) phenylboronic acid, 43.40 mg, 0.26 mmol) in a solution containing IG-B (30.0 mg, 0.088 mmol) and a mixture of DMF and water 10:1, After tetrakis (triphenyl phosphine) palladium (20.28 mg, 0.018 mmol) and sodium carbonate (46.4 mg, 0.44 mmol) were added, the mixture was stirred at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form an orange solid compound GxF 40 (32.9 mg, 94.9% yield) represented by Formula 1-40 below. Was obtained.

[화학식 1-40][Formula 1-40]

Figure pat00202
Figure pat00202

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.89(d, J = 7.4 Hz, 1H), 8.41(s, 1H), 7.86(d, J = 8.2 Hz, 2H), 7.51(m, 8H), 6.85(d, J = 7.8 Hz, 2H), 3.02(s, 6H), 2.65(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.6, 185.3, 149.9, 140.4, 134.5, 131.5, 131.5, 129.3, 129.1, 128.5, 128.2, 125.0, 123.8, 122.6, 121.9, 120.3, 113.1, 111.5, 53.8, 40.9, 26.6; LRMS (ESI) m/z calcd for C25H22N2O2 [M+Na]+ : 382.2, found : 383.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.89 (d, J = 7.4 Hz, 1H), 8.41 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.51 (m, 8H), 6.85 (d, J = 7.8 Hz, 2H), 3.02 (s, 6H), 2.65 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.6, 185.3, 149.9, 140.4, 134.5, 131.5, 131.5, 129.3, 129.1, 128.5, 128.2, 125.0, 123.8, 122.6, 121.9, 120.3, 113.1, 111.5, 53.8, 40.9, 26.6; LRMS (ESI) m/z calcd for C 25 H 22 N 2 O 2 [M+Na]+: 382.2, found: 383.2.

<GxF 41 ~ 45><GxF 41 ~ 45>

II-E : 하기 반응식 10과 같이 합성하였으며, 구체적으로, 4-아세틸피리딘(585.2 μL, 5.29 mmol) 및 2-브로모아세토페논(1.5 g, 5.6 mmol)이 포함된 DMF(17.6 mL)을 80℃에서 5시간 동안 교반한 다음, 에틸아크릴레이트(286.6 μl, 2.65 mmol), 구리(II) 아세테이트 모노하이드레이트(3.17 g, 15.87 mmol) 및 소듐 아세테이트(1.74 g, 21.16 mmol)를 첨가하여 100℃에서 5시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 황색 고체의 화합물 II-E(709.8 mg, 73.3% 수율)를 수득 하였다. II-E : Synthesized as in Reaction Scheme 10 below, and specifically, DMF (17.6 mL) containing 4-acetylpyridine (585.2 μL, 5.29 mmol) and 2-bromoacetophenone (1.5 g, 5.6 mmol) was 5 at 80°C. After stirring for an hour, ethyl acrylate (286.6 μl, 2.65 mmol), copper (II) acetate monohydrate (3.17 g, 15.87 mmol) and sodium acetate (1.74 g, 21.16 mmol) were added thereto at 100° C. for 5 hours. Stirred. After completion of the reaction, after monitoring by TLC, copper acetate was removed by filtration through a pad of Celite, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water and the organic material was extracted 3 times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to obtain Compound II-E (709.8 mg, 73.3% yield) as a yellow solid.

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) 9.62 (dd J = 7.4, 0.4 Hz, 1H), 8.76 (s, 1H), 7.74(dd, J = 6.6, 2 Hz, 2 H), 7.69 (s, 1H), 7.39 (dd, J = 7.4, 2 Hz, 1H), 6.92(dd, J = 6.8, 2 Hz, 2H), 4.33(q, J = 7.2 Hz, 2H), 3.82(s,3H), 2.61(s, 3H), 1.362(t, J = 7.2 Hz, 3H); 13C NMR(100 MHz, CDCl3) 195.6, 184.3, 163.4, 162.8, 137.6, 133.7, 131.9, 131.4, 128.4, 127.5, 123.2, 120.9, 113. 8, 112.5, 109.1, 60.6, 55.6, 26.4, 14.8; LRMS (ESI) m/z calcd for C21H19NO4 [M+Na]+ : 365.1 ,found :366.2. 1 H NMR (400 MHz, CDCl 3 ) 9.62 (dd J = 7.4, 0.4 Hz, 1H), 8.76 (s, 1H), 7.74 (dd, J = 6.6, 2 Hz, 2 H), 7.69 (s, 1H ), 7.39 (dd, J = 7.4, 2 Hz, 1H), 6.92 (dd, J = 6.8, 2 Hz, 2H), 4.33 (q, J = 7.2 Hz, 2H), 3.82 (s,3H), 2.61 (s, 3H), 1.362 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) 195.6, 184.3, 163.4, 162.8, 137.6, 133.7, 131.9, 131.4, 128.4, 127.5, 123.2, 120.9, 113. 8, 112.5, 109.1, 60.6, 55.6, 26.4, 14.8; LRMS (ESI) m/z calcd for C 21 H 19 NO 4 [M+Na]+: 365.1 ,found :366.2.

II-B : II-E(709.8 mg, 1.94 mmol)가 포함된 메탄올(19 mL)에 KOH(3.1 g, 77.6 mmol)를 첨가한 후, 실온에서 하룻밤 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 갈색고체의 화합물 II-A를 수득하였다. II-B : KOH (3.1 g, 77.6 mmol) was added to methanol (19 mL) containing II-E (709.8 mg, 1.94 mmol), followed by stirring at room temperature overnight. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water and dried in a drying oven to obtain a brown solid compound II-A.

수득한 화합물 II-A는 추가 정제없이 바로 다음 단계에 사용하였으며, II-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(478.9 mg, 5.7 mmol)를 첨가하고 및 NBS(354.9 mg, 2.0 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 황색 고체의 화합물 II-B(462.0 mg, 72.1% 수율)를 수득 하였다.The obtained compound II-A was used in the next step without further purification, sodium bicarbonate (478.9 mg, 5.7 mmol) was added to DMF (10.0 mL) containing II-A, and NBS (354.9 mg, 2.0 mmol) ) Was added partially at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to obtain Compound II-B (462.0 mg, 72.1% yield) as a yellow solid.

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) 9.73(d, J = 7.2Hz,1 H), 8.12(s, 1H), 7.81(d, J = 8.8 Hz, 2H), 7.42 (m, 1H), 6.99(d, 2H), 3.88(s, 3H), 2.68(s, 3H); 13C NMR(100 MHz, CDCl3)195.3, 183.7, 162.8, 134.8, 132.0, 131.9, 131.4, 128.1, 126.9, 124.0, 119.3, 113.9, 111.7, 93.9, 55.8, 26.6; LRMS (ESI) m/z calcd for C18H14NO4 [M+Na]+ : 372. 2 ,found : 372.1. 1 H NMR (400 MHz, CDCl 3 ) 9.73 (d, J = 7.2 Hz, 1 H), 8.12 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.42 (m, 1H), 6.99 (d, 2H), 3.88 (s, 3H), 2.68 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) 195.3, 183.7, 162.8, 134.8, 132.0, 131.9, 131.4, 128.1, 126.9, 124.0, 119.3, 113.9, 111.7, 93.9, 55.8, 26.6; LRMS (ESI) m/z calcd for C 18 H 14 NO 4 [M+Na]+: 372. 2 ,found: 372.1.

[반응식 10][Scheme 10]

Figure pat00203
Figure pat00203

화합물 GxF 41 : Compound GxF 41 :

II-B(30.0 mg, 0.081 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-트리플로로페닐 보론산(46.2 mg, 0.243 mmol), 테트라키스(트리페닐 포스핀)팔라듐(18.7 mg, 0.016 mmol) 및 소듐 카보네이트(42.9 mg, 0.405 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 40%)로 정제하여 하기 화학식 1-41로 표시되는 황색 고체의 화합물 GxF 41(34.4 mg, 97.2% 수율)을 수득 하였다.In a solution (1.1 mL) containing II-B (30.0 mg, 0.081 mmol) and a 10:1 mixture of DMF and water, 4-trifluorophenyl boronic acid (46.2 mg, 0.243 mmol), tetrakis (tri Phenyl phosphine) palladium (18.7 mg, 0.016 mmol) and sodium carbonate (42.9 mg, 0.405 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 40%) to form a yellow solid compound GxF 41 (34.4 mg, 97.2% yield) represented by the following formula 1-41. Was obtained.

[화학식 1-41][Formula 1-41]

Figure pat00204
Figure pat00204

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3) 9.84 (d, J = 7.4 Hz, 1H), 8.39(s, 1H), 7.88(d, J = 6.8Hz, 2H), 7.72(q, J = 1.2 Hz, 4H), 7.54(s, 1H), 7.45(dd, J = 7.2, 2 Hz, 2H), 3.90(s, 3H), 2.66(s, 3H); 13C NMR(100 MHz, CDCl3) 195.6, 184.5, 162.8, 137.9, 134.3, 132.8, 132.4, 132.2, 131.5, 129.4, 129.0, 128.4, 126.3, 126.2, 125.7, 125.3, 124.3, 123.0, 122.5, 119.9, 119.3, 115.8, 114.0, 111.9; LRMS (ESI) m/z calcd for C25H18F3NO3 [M+Na]+ :437.1, found : 438.2. 1 H NMR (400 MHz, CDCl 3 ) 9.84 (d, J = 7.4 Hz, 1H), 8.39 (s, 1H), 7.88 (d, J = 6.8 Hz, 2H), 7.72 (q, J = 1.2 Hz, 4H), 7.54 (s, 1H), 7.45 (dd, J = 7.2, 2 Hz, 2H), 3.90 (s, 3H), 2.66 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) 195.6, 184.5, 162.8, 137.9, 134.3, 132.8, 132.4, 132.2, 131.5, 129.4, 129.0, 128.4, 126.3, 126.2, 125.7, 125.3, 124.3, 123.0, 122.5, 119.9, 119.3, 115.8, 114.0, 111.9; LRMS (ESI) m/z calcd for C 25 H 18 F 3 NO 3 [M+Na]+ :437.1, found: 438.2.

화합물 GxF 42 : Compound GxF 42 :

II-B(30.0 mg, 0.081 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-아세틸페닐 보론산(39.8 mg, 0.243 mmol), 테트라키스(트리페닐 포스핀)팔라듐(18.7 mg, 0.016 mmol) 및 소듐 카보네이트(42.9 mg, 0.405 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-42로 표시되는 황색 고체의 화합물 GxF 42(32.5 mg, 97.5% 수율)을 수득 하였다.4-acetylphenyl boronic acid (39.8 mg, 0.243 mmol), tetrakis (triphenyl phosphonic acid) in a solution (1.1 mL) containing II-B (30.0 mg, 0.081 mmol) and a mixture of DMF and water 10:1 Fin) palladium (18.7 mg, 0.016 mmol) and sodium carbonate (42.9 mg, 0.405 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 42 (32.5 mg, 97.5% yield) represented by the following formula 1-42. Was obtained.

[화학식 1-42][Formula 1-42]

Figure pat00205
Figure pat00205

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.84(d, J = 7.2 Hz, 1H), 8.4(s, 1H), 8.07(d, J = 8 Hz, 2H), 7.88(dd, J = 7, 2Hz, 2 H), 7.68(d, J = 8.4 Hz, 2H), 7.56(s, 1H) 7.45 (dd, J = 7.4, 2 Hz), 3.90(s, 3H), 2.65(s, 3H); 13C NMR(100 MHz, CDCl3), δ 197.4, 195.5, 184.5, 162.8, 139.1, 135.6, 134.3, 132.4, 132.3, 131.5, 129.4, 128.4, 128.1, 125.2, 124.4, 120.1, 119.4, 114.0, 111.9, 55.8, 30.1, 27.0, 26.7; LRMS (ESI) m/z calcd for C26H21NO4 [M+Na]+ :411.5, found : 412.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.84 (d, J = 7.2 Hz, 1H), 8.4 (s, 1H), 8.07 (d, J = 8 Hz, 2H), 7.88 (dd, J = 7 , 2Hz, 2H), 7.68(d, J = 8.4 Hz, 2H), 7.56(s, 1H) 7.45 (dd, J = 7.4, 2 Hz), 3.90(s, 3H), 2.65(s, 3H) ; 13 C NMR (100 MHz, CDCl 3 ), δ 197.4, 195.5, 184.5, 162.8, 139.1, 135.6, 134.3, 132.4, 132.3, 131.5, 129.4, 128.4, 128.1, 125.2, 124.4, 120.1, 119.4, 114.0, 111.9, 55.8, 30.1, 27.0, 26.7; LRMS (ESI) m/z calcd for C 26 H 21 NO 4 [M+Na]+ :411.5, found: 412.2.

화합물 GxF 43 : Compound GxF 43 :

II-B(30.0 mg, 0.081 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 벤젠 보론산(benzene boronic acid, 29.6 mg, 0.243 mmol), 테트라키스(트리페닐 포스핀)팔라듐(18.7 mg, 0.016 mmol) 및 소듐 카보네이트(42.9 mg, 0.405 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-43으로 표시되는 황색 고체의 화합물 GxF 43(28.9 mg, 96.6% 수율)을 수득 하였다.Benzene boronic acid (29.6 mg, 0.243 mmol), tetrakis (triphenyl) in a solution (1.1 mL) containing II-B (30.0 mg, 0.081 mmol) and a 10:1 mixture of DMF and water Phosphine) palladium (18.7 mg, 0.016 mmol) and sodium carbonate (42.9 mg, 0.405 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 43 (28.9 mg, 96.6% yield) represented by the following formula 1-43. Was obtained.

[화학식 1-43][Formula 1-43]

Figure pat00206
Figure pat00206

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.84(d, J = 7.2, 0.8 Hz, 1 H), 8.42(s, 1H), 7.89(dd, J = 7.6, 2Hz, 2H), 7.58(d, J = 1.2 Hz, 2H), 7.51(m, 3H), 7.43(dd, J = 7.6, 2 Hz, 1H), 7.35(t, J = 7.2 Hz, 1H), 7.13(s, 2H), 7.01(d, J = 6.8 Hz, 2H), 3.9 (s, 3H), 2.64(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.63, 184.4, 162.6, 134.2(2),132.7, 131.8, 131.5, 129.3, 129.3, 128.2, 127.4, 125.1, 124.1,121.7,121.6,113.9, 111.5, 55.8, 30.1, 26.7; LRMS (ESI) m/z calcd for C26H21NO4 [M+Na]+ :369.1, found : 370.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.84 (d, J = 7.2, 0.8 Hz, 1 H), 8.42 (s, 1H), 7.89 (dd, J = 7.6, 2 Hz, 2H), 7.58 (d , J = 1.2 Hz, 2H), 7.51 (m, 3H), 7.43 (dd, J = 7.6, 2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.13 (s, 2H), 7.01 (d, J = 6.8 Hz, 2H), 3.9 (s, 3H), 2.64 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.63, 184.4, 162.6, 134.2(2),132.7, 131.8, 131.5, 129.3, 129.3, 128.2, 127.4, 125.1, 124.1,121.7,121.6,113.9, 111.5, 55.8 , 30.1, 26.7; LRMS (ESI) m/z calcd for C 26 H 21 NO 4 [M+Na]+ :369.1, found: 370.2.

화합물 GxF 44 : Compound GxF 44 :

II-B(30.0 mg, 0.081 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-메톡시페닐 보론산(36.9 mg, 0.243 mmol), 테트라키스(트리페닐 포스핀)팔라듐(18.7 mg, 0.016 mmol) 및 소듐 카보네이트(42.9 mg, 0.405 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-44로 표시되는 황색 고체의 화합물 GxF 44(30.4 mg, 94.0% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (36.9 mg, 0.243 mmol), tetrakis (triphenyl) in a solution (1.1 mL) containing II-B (30.0 mg, 0.081 mmol) and a 10:1 mixture of DMF and water Phosphine) palladium (18.7 mg, 0.016 mmol) and sodium carbonate (42.9 mg, 0.405 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 44 (30.4 mg, 94.0% yield) represented by the following formula 1-44. Was obtained.

[화학식 1-44][Formula 1-44]

Figure pat00207
Figure pat00207

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.80(d, J = 7.2 Hz, 1H), 8.36(s, 1H), 7.87(d, J = 7 Hz, 2 H), 7.49(d, J = 6.6 Hz, 2H), 7.45(s, 1H), 7.40(dd, J = 7.2, 2 Hz, 1H), 7.02(m, 4H), 3.90(s, 3H), 3.87(s, 3H), 2.63(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.6, 184.4, 162.6, 159.0, 134.2, 132.7, 131.5, 129.5, 128.1, 126.6, 124.8, 124.0, 121.6, 119.9, 114.8, 113.8, 111.4, 55.8, 55.7, 26.6 LRMS (ESI) m/z calcd for C25H21NO4 [M+Na]+ :399.2, found : 400.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.80 (d, J = 7.2 Hz, 1H), 8.36 (s, 1H), 7.87 (d, J = 7 Hz, 2H), 7.49 (d, J = 6.6 Hz, 2H), 7.45(s, 1H), 7.40(dd, J = 7.2, 2 Hz, 1H), 7.02(m, 4H), 3.90(s, 3H), 3.87(s, 3H), 2.63( s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.6, 184.4, 162.6, 159.0, 134.2, 132.7, 131.5, 129.5, 128.1, 126.6, 124.8, 124.0, 121.6, 119.9, 114.8, 113.8, 111.4, 55.8, 55.7, 26.6 LRMS (ESI) m/z calcd for C 25 H 21 NO 4 [M+Na]+ :399.2, found: 400.2.

화합물 GxF 45 : Compound GxF 45 :

II-B(30.0 mg, 0.081 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-다이메틸아미노페닐 보론산(40.0 mg, 0.24 mmol), 테트라키스(트리페닐 포스핀)팔라듐(18.7 mg, 0.016 mmol) 및 소듐 카보네이트(42.9 mg, 0.405 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-45로 표시되는 황색 고체의 화합물 GxF 45(31.2 mg, 93.3% 수율)을 수득 하였다.In a solution (1.1 mL) containing II-B (30.0 mg, 0.081 mmol) and a 10:1 mixture of DMF and water, 4-dimethylaminophenyl boronic acid (40.0 mg, 0.24 mmol), tetrakis (tri Phenyl phosphine) palladium (18.7 mg, 0.016 mmol) and sodium carbonate (42.9 mg, 0.405 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 45 (31.2 mg, 93.3% yield) represented by the following formula 1-45. Was obtained.

[화학식 1-45][Formula 1-45]

Figure pat00208
Figure pat00208

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.80(d, J = 7.2 Hz, 1H), 8.40(s, 1H), 7.88(d, J = 2.8 Hz, 2H), 7.46(m, 3H), 7.40 (dd, J = 7.4, 2 Hz, 1H), 7.00(d, J = 6.6 Hz, 2H), 6.86(d, J = 6.8 Hz, 2H), 3.90(s, 3H), 3.02(s, 6H), 2.63(s, 3H); 13C NMR(100 MHz, CDCl3), δ 195.7, 184.4, 162.5, 149.9, 134.1, 132.9, 131.5, 131.2, 129.1, 128.0, 124.5, 124.0, 122.4, 122.1, 120.4, 113.8, 113.2, 111.2, 55.8, 40.9, 26; LRMS (ESI) m/z calcd for C26H24N2O3 [M+Na]+ :412.2, found : 413.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.80 (d, J = 7.2 Hz, 1H), 8.40 (s, 1H), 7.88 (d, J = 2.8 Hz, 2H), 7.46 (m, 3H), 7.40 (dd, J = 7.4, 2 Hz, 1H), 7.00 (d, J = 6.6 Hz, 2H), 6.86 (d, J = 6.8 Hz, 2H), 3.90 (s, 3H), 3.02 (s, 6H) ), 2.63 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.7, 184.4, 162.5, 149.9, 134.1, 132.9, 131.5, 131.2, 129.1, 128.0, 124.5, 124.0, 122.4, 122.1, 120.4, 113.8, 113.2, 111.2, 55.8, 40.9, 26; LRMS (ESI) m/z calcd for C 26 H 24 N 2 O 3 [M+Na]+ :412.2, found: 413.2.

<GxF 46 ~ 50><GxF 46 ~ 50>

IJ-E : 하기 반응식 11과 같이 합성하였으며, 구체적으로, 4-아세틸피리딘(194.9 μL, 1.76 mm) 및 2-브로모-4'-다이에틸아미노아세토페논(500 mg, 1.85 mmol)이 포함된 DMF(6.0 mL)을 80℃에서 5시간 동안 교반한 다음, 에틸아크릴레이트(88.1 μl, 0.88 mmol), 구리(II) 아세테이트 모노하이드레이트(1.05 g, 5.28 mmol) 및 소듐 아세테이트(577.5 mg, 7.04 mmol)를 첨가하여 100℃에서 5시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 황색 고체의 화합물 IJ-E(295.6 mg, 82.7% 수율)를 수득 하였다. IJ-E : Synthesized as in Scheme 11 below, specifically, 4-acetylpyridine (194.9 μL, 1.76 mm) and 2-bromo-4'-diethylaminoacetophenone (500 mg, 1.85 mmol) containing DMF (6.0 mL) was stirred at 80° C. for 5 hours, and then ethyl acrylate (88.1 μl, 0.88 mmol), copper (II) acetate monohydrate (1.05 g, 5.28 mmol) and sodium acetate (577.5 mg, 7.04 mmol) were added. And stirred at 100° C. for 5 hours. After completion of the reaction, after monitoring by TLC, copper acetate was removed by filtration through a pad of Celite, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water and the organic material was extracted 3 times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to obtain a yellow solid compound IJ-E (295.6 mg, 82.7% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.66(d, J = 7.6 Hz, 1H), 8.89(s, 1H), 7.8(m, 3H), 7.46(dd, J = 7.6Hz, 2Hz, 1H), 6.69(d, J = 7 Hz, 2H), 4.39(q, J = 7.2Hz, 2H), 3.43(q, J = 7.2 Hz, 4H), 2.68(s, 3H), 1.42(t, J = 7.2 Hz, 3H), 1.21(t, J = 7.2Hz, 6H); 13C NMR(100 MHz, CDCl3), δ 195.9, 183.9, 164.1, 151.0, 137.5, 133.3, 132.3, 132.2, 128.5, 127.1, 125.4, 124.7, 121.6, 121.3, 111.7, 110.5, 108.8, 60.6, 44.9, 26.5, 14.9, 13.0; LRMS (ESI) m/z calcd for C24H26N2O4 [M+Na]+ : 406.2, found : 407.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.66 (d, J = 7.6 Hz, 1H), 8.89 (s, 1H), 7.8 (m, 3H), 7.46 (dd, J = 7.6Hz, 2Hz, 1H ), 6.69 (d, J = 7 Hz, 2H), 4.39 (q, J = 7.2 Hz, 2H), 3.43 (q, J = 7.2 Hz, 4H), 2.68 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.9, 183.9, 164.1, 151.0, 137.5, 133.3, 132.3, 132.2, 128.5, 127.1, 125.4, 124.7, 121.6, 121.3, 111.7, 110.5, 108.8, 60.6, 44.9, 26.5, 14.9, 13.0; LRMS (ESI) m/z calcd for C 24 H 26 N 2 O 4 [M+Na]+: 406.2, found: 407.2.

IJ-B : IJ-E(295.6 mg, 0.73 mmol)가 포함된 메탄올(16 mL)에 KOH(1.63 g, 29.2 mmol)를 첨가한 후, 실온에서 하룻밤 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 갈색고체의 화합물 IJ-A를 수득하였다. IJ-B : KOH (1.63 g, 29.2 mmol) was added to methanol (16 mL) containing IJ-E (295.6 mg, 0.73 mmol), followed by stirring at room temperature overnight. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water and dried in a drying oven to obtain a brown solid compound IJ-A.

수득한 화합물 IJ-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IJ-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(306.6 mg, 3.65 mmol)를 첨가하고 및 NBS(136.4 mg, 0.77 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 황색 고체의 화합물 IJ-B(241.0 mg, 80.1% 수율)를 수득 하였다.The obtained compound IJ-A was used in the next step without further purification, sodium bicarbonate (306.6 mg, 3.65 mmol) was added to DMF (10.0 mL) containing IJ-A, and NBS (136.4 mg, 0.77 mmol) ) Was added partially at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to obtain a yellow solid compound IJ-B (241.0 mg, 80.1% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.61(d, J = 7.2 Hz, 1H), 8.06(s, 1H), 7.77(d, J = 8.8 Hz, 2H), 7.42(s, 1H), 7.32(dd, J = 2 Hz, 7.4 Hz), 6.66(d, J = 8.8 Hz, 2H), 3.42(q, 7.2 Hz, 4H), 2.64(s, 3H), 1.21(t, J = 7.2 Hz, 6H); 13C NMR(100 MHz, CDCl3), δ 195.4, 183.1, 150.9, 133.9, 132.1, 131.0, 127.8, 125.9, 125.6, 124.6, 119.4, 111.0, 110.5, 93.4, 77.7, 77.4, 77.1, 44.9, 26.6, 13.0; LRMS (ESI) m/z calcd for C21H21BrN2O2 [M+Na]+ : 412.08 ,found : x. 1 H NMR (400 MHz, CDCl 3 ), δ 9.61 (d, J = 7.2 Hz, 1H), 8.06 (s, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.42 (s, 1H), 7.32 (dd, J = 2 Hz, 7.4 Hz), 6.66 (d, J = 8.8 Hz, 2H), 3.42 (q, 7.2 Hz, 4H), 2.64 (s, 3H), 1.21 (t, J = 7.2 Hz , 6H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.4, 183.1, 150.9, 133.9, 132.1, 131.0, 127.8, 125.9, 125.6, 124.6, 119.4, 111.0, 110.5, 93.4, 77.7, 77.4, 77.1, 44.9, 26.6, 13.0; LRMS (ESI) m/z calcd for C21H21BrN2O2 [M+Na]+: 412.08 ,found: x.

[반응식 11][Scheme 11]

Figure pat00209
Figure pat00209

화합물 GxF 46 : Compound GxF 46 :

IJ-B(20.0 mg, 0.048 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-트리플로로페닐 보론산(27.3 mg, 0.14 mmol), 테트라키스(트리페닐 포스핀)팔라듐(11.1 mg, 0.01 mmol) 및 소듐 카보네이트(25.4 mg, 0.24 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 40%)로 정제하여 하기 화학식 1-46으로 표시되는 황색 고체의 화합물 GxF 46(22.2 mg, 96.6% 수율)을 수득 하였다.In a solution (1.1 mL) containing IJ-B (20.0 mg, 0.048 mmol) and a 10:1 mixture of DMF and water, 4-trifluorophenyl boronic acid (27.3 mg, 0.14 mmol), tetrakis (tri Phenyl phosphine) palladium (11.1 mg, 0.01 mmol) and sodium carbonate (25.4 mg, 0.24 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 40%) to form a yellow solid compound GxF 46 (22.2 mg, 96.6% yield) represented by the following formula 1-46. Was obtained.

[화학식 1-46][Formula 1-46]

Figure pat00210
Figure pat00210

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.75(d, J = 7.7 Hz, 1H), 8.39(s,1H), 7.88(d, 7.2 Hz, 2H), 7.73(q, J = 8.8 Hz, 5.2 Hz, 4H), 7.59(s, 1H), 7.40(dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.72(d, J = 9.2 Hz, 2H), 3.46(q, J = 7.2 Hz, 4H), 2.65(s, 3H), 1.24(t, J = 7.2 Hz, 6H); 13C NMR(100 MHz, CDCl3), δ 195.6, 183.9, 150.9, 138.3, 133.5, 132.2, 131.5, 128.3, 128.2, 126.2, 126.0, 125.0, 124.3, 119.5, 119.4, 111.3, 110.5, 44.9, 26.7, 13.0; LRMS (ESI) m/z calcd for C28H25F3N2O2 [M+Na]+ : 478.2, found : x. 1 H NMR (400 MHz, CDCl 3 ), δ 9.75 (d, J = 7.7 Hz, 1H), 8.39 (s, 1H), 7.88 (d, 7.2 Hz, 2H), 7.73 (q, J = 8.8 Hz, 5.2 Hz, 4H), 7.59 (s, 1H), 7.40 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.72 (d, J = 9.2 Hz, 2H), 3.46 (q, J = 7.2 Hz, 4H ), 2.65 (s, 3H), 1.24 (t, J = 7.2 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.6, 183.9, 150.9, 138.3, 133.5, 132.2, 131.5, 128.3, 128.2, 126.2, 126.0, 125.0, 124.3, 119.5, 119.4, 111.3, 110.5, 44.9, 26.7, 13.0; LRMS (ESI) m/z calcd for C 28 H 25 F 3 N 2 O 2 [M+Na]+: 478.2, found: x.

화합물 GxF 47 : Compound GxF 47 :

IJ-B(20.0 mg, 0.048 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-아세틸페닐 보론산(323.6 mg, 0.14 mmol), 테트라키스(트리페닐 포스핀)팔라듐(11.1 mg, 0.01 mmol) 및 소듐 카보네이트(25.4 mg, 0.24 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-47로 표시되는 황색 고체의 화합물 GxF 47(20.5 mg, 94.5% 수율)을 수득 하였다.4-acetylphenyl boronic acid (323.6 mg, 0.14 mmol), tetrakis (triphenyl phosphonic acid) in a solution (1.1 mL) containing IJ-B (20.0 mg, 0.048 mmol) and a 10:1 mixture of DMF and water Fin) palladium (11.1 mg, 0.01 mmol) and sodium carbonate (25.4 mg, 0.24 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 47 (20.5 mg, 94.5% yield) represented by the following formula 1-47. Was obtained.

[화학식 1-47][Formula 1-47]

Figure pat00211
Figure pat00211

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.74(d, J= 7.4Hz, 1H), 8.43(s, 1H), 8.08(d, J = 6.4 Hz, 2H), 7.87(d, J = 7.2Hz, 2H), 7.70(d, J = 6.8 Hz, 2H), 7.61(s, 1H), 7.39(dd, J = 7.8 Hz, 1H), 6.72(d, J = 7.2Hz, 2H), 3.46(q, J = 7.2Hz, 4H), 2.67(s, 3H), 2.65(s, 3H), 1.24(t, J = 7.2Hz, 6H); 13C NMR(100 MHz, CDCl3), δ 197.5, 195.6, 183.9, 150.9, 139.5, 135.4, 133.6, 132.2, 131.5, 129.4, 128.2, 128.0, 126.0, 125.1, 124.3, 119.7, 119.6, 111.3, 110.6,44.9, 27.0, 26.7, 13.0; LRMS (ESI) m/z calcd for C29H28N2O3 [M+Na]+ : 452.1, found : x. 1 H NMR (400 MHz, CDCl 3 ), δ 9.74 (d, J = 7.4 Hz, 1H), 8.43 (s, 1H), 8.08 (d, J = 6.4 Hz, 2H), 7.87 (d, J = 7.2 Hz, 2H), 7.70 (d, J = 6.8 Hz, 2H), 7.61 (s, 1H), 7.39 (dd, J = 7.8 Hz, 1H), 6.72 (d, J = 7.2 Hz, 2H), 3.46 ( q, J = 7.2 Hz, 4H), 2.67 (s, 3H), 2.65 (s, 3H), 1.24 (t, J = 7.2 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ), δ 197.5, 195.6, 183.9, 150.9, 139.5, 135.4, 133.6, 132.2, 131.5, 129.4, 128.2, 128.0, 126.0, 125.1, 124.3, 119.7, 119.6, 111.3, 110.6, 44.9, 27.0, 26.7, 13.0; LRMS (ESI) m/z calcd for C 29 H 28 N 2 O 3 [M+Na] + : 452.1, found: x.

화합물 GxF 48 : Compound GxF 48 :

IJ-B(20.0 mg, 0.048 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-벤젠 보론산(23.8 mg, 0.14 mmol),테트라키스(트리페닐 포스핀)팔라듐(11.1 mg, 0.01 mmol) 및 소듐 카보네이트(17.6 mg, 0.24 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-48로 표시되는 황색 고체의 화합물 GxF 48(18.2 mg, 92.2% 수율)을 수득 하였다.4-benzene boronic acid (23.8 mg, 0.14 mmol), tetrakis (triphenylphosphine) in a solution (1.1 mL) containing IJ-B (20.0 mg, 0.048 mmol) and a 10:1 mixture of DMF and water ) Palladium (11.1 mg, 0.01 mmol) and sodium carbonate (17.6 mg, 0.24 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 48 (18.2 mg, 92.2% yield) represented by Formula 1-48 below. Was obtained.

[화학식 1-48][Formula 1-48]

Figure pat00212
Figure pat00212

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.73(d, J = 7.4Hz, 1H), 8.41(s, 1H), 7.88(d, J = 8Hz, 2H), 7.60(d, J = 8.2 Hz, 2H), 7.57(s, 1H), 7.52(t, J = 7.2Hz, 2H), 7.37(m, 2H), 6.71(d, J = 9.2Hz, 2H), 3.45(q, J = 6.8Hz, 4H), 2.63(s, 3H), 1.24(t, J = 7.2Hz, 6H); 13C NMR(100 MHz, CDCl3), δ 195.7, 184.0, 150.8, 134.6, 133.4, 132.1, 131.0 129.2, 128.3, 128.0, 127.1, 126.3, 124.7, 1242.3, 121.3, 120.0, 110.9, 110.5, 44.9, 26.6, 13.0; LRMS (ESI) m/z calcd for C27H26N2O2 [M+Na]+ : 410.2, found : x. 1 H NMR (400 MHz, CDCl 3 ), δ 9.73 (d, J = 7.4 Hz, 1H), 8.41 (s, 1H), 7.88 (d, J = 8Hz, 2H), 7.60 (d, J = 8.2 Hz , 2H), 7.57(s, 1H), 7.52(t, J = 7.2Hz, 2H), 7.37(m, 2H), 6.71(d, J = 9.2Hz, 2H), 3.45(q, J = 6.8Hz , 4H), 2.63 (s, 3H), 1.24 (t, J = 7.2 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.7, 184.0, 150.8, 134.6, 133.4, 132.1, 131.0 129.2, 128.3, 128.0, 127.1, 126.3, 124.7, 1242.3, 121.3, 120.0, 110.9, 110.5, 44.9, 26.6 , 13.0; LRMS (ESI) m/z calcd for C 27 H 26 N 2 O 2 [M+Na]+: 410.2, found: x.

화합물 GxF 49 : Compound GxF 49 :

IJ-B(20.0 mg, 0.048 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-메톡시페닐 보론산(21.9 mg, 0.14 mmol), 테트라키스(트리페닐 포스핀)팔라듐(11.1 mg, 0.01 mmol) 및 소듐 카보네이트(25.4 mg, 0.24 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-49로 표시되는 황색 고체의 화합물 GxF 49(19.7 mg, 93.4% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (21.9 mg, 0.14 mmol), tetrakis (triphenyl) in a solution (1.1 mL) containing IJ-B (20.0 mg, 0.048 mmol) and a 10:1 mixture of DMF and water Phosphine) palladium (11.1 mg, 0.01 mmol) and sodium carbonate (25.4 mg, 0.24 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 49 (19.7 mg, 93.4% yield) represented by the following formula 1-49. Was obtained.

[화학식 1-49][Formula 1-49]

Figure pat00213
Figure pat00213

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.72(d, J = 7.8 Hz, 1H), 8.36(s, 1H), 7.87(d, J = 7.2 Hz, 2H), 7.52(d, J = 6.6Hz, 3H), 7.35(dd, J = 1.6 Hz, 7.6 Hz, 1H), 7.04(d, J = 6.6 Hz, 2H), 6.71(d, J = 8.8 Hz, 2H), 3.88(s, 3H), 3.45(q, J = 8 Hz, 4H), 2.63(s, 3H), 1.23(t, J = 7.2Hz, 6H); 13C NMR(100 MHz, CDCl3), δ 195.7, 183.9, 158.9, 150.7, 133.3, 132.1, 130.7, 129.5, 127.9, 127.0, 126.4, 124.6, 124.0, 121.2, 120.1, 114.7, 110.8, 110.5, 55.7, 44.9, 26.6, 13.0; LRMS (ESI) m/z calcd for C28H28N2O3 [M+Na]+ : 440.2, found : x. 1 H NMR (400 MHz, CDCl 3 ), δ 9.72 (d, J = 7.8 Hz, 1H), 8.36 (s, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.52 (d, J = 6.6 Hz, 3H), 7.35 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 7.04 (d, J = 6.6 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H) , 3.45 (q, J = 8 Hz, 4H), 2.63 (s, 3H), 1.23 (t, J = 7.2 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.7, 183.9, 158.9, 150.7, 133.3, 132.1, 130.7, 129.5, 127.9, 127.0, 126.4, 124.6, 124.0, 121.2, 120.1, 114.7, 110.8, 110.5, 55.7, 44.9, 26.6, 13.0; LRMS (ESI) m/z calcd for C 28 H 28 N 2 O 3 [M+Na]+: 440.2, found: x.

화합물 GxF 50 : Compound GxF 50 :

IJ-B(20.0 mg, 0.048 mmol)를 포함하고 DMF 및 물이 10 : 1로 혼합되어 있는 용액(1.1 mL)에 4-다이메틸아미노페닐 보론산(23.8 mg, 0.14 mmol), 테트라키스(트리페닐 포스핀)팔라듐(11.1 mg, 0.01 mmol) 및 소듐 카보네이트(25.4 mg, 0.24 mmol)를 첨가한 후, 100℃에서 8시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-50으로 표시되는 황색 고체의 화합물 GxF 50(20.2 mg, 93.0% 수율)을 수득 하였다.4-dimethylaminophenyl boronic acid (23.8 mg, 0.14 mmol), tetrakis (tri Phenyl phosphine) palladium (11.1 mg, 0.01 mmol) and sodium carbonate (25.4 mg, 0.24 mmol) were added, followed by stirring at 100° C. for 8 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to form a yellow solid compound GxF 50 (20.2 mg, 93.0% yield) represented by Formula 1-50 below. Was obtained.

[화학식 1-50][Formula 1-50]

Figure pat00214
Figure pat00214

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.70(d, J = 7.2 Hz, 1H), 8.39(s, 1H), 7.87(d, J = 9.2 Hz, 2H), 7.49(d, J = 8.6Hz, 3H), 7.34(dd, 2.0Hz, 7.6Hz, 1H), 6.87(d, J = 8.8Hz, 2H), 6.70(d, J = 8.8 Hz, 2H), 3.45(q, J = 7.6Hz, 4H), 3.03(s, 6H), 2.62(s, 3H), 1.24(t, J = 6.8Hz, 6H); 13C NMR(100 MHz, CDCl3), δ 195.8, 183.0, 150.7, 149.8, 133.3, 132.2, 130.4, 129.1, 127.8, 126.4, 124.6, 123.8, 122.5, 122.0, 120.6, 113.2, 110.6, 110.5, 44.9, 41.0, 26.5, 13.0; LRMS (ESI) m/z calcd for C29H31N3O2 [M+Na]+ : 453.2, found : x. 1 H NMR (400 MHz, CDCl 3 ), δ 9.70 (d, J = 7.2 Hz, 1H), 8.39 (s, 1H), 7.87 (d, J = 9.2 Hz, 2H), 7.49 (d, J = 8.6 Hz, 3H), 7.34(dd, 2.0Hz, 7.6Hz, 1H), 6.87(d, J = 8.8Hz, 2H), 6.70(d, J = 8.8 Hz, 2H), 3.45(q, J = 7.6Hz , 4H), 3.03 (s, 6H), 2.62 (s, 3H), 1.24 (t, J = 6.8 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ), δ 195.8, 183.0, 150.7, 149.8, 133.3, 132.2, 130.4, 129.1, 127.8, 126.4, 124.6, 123.8, 122.5, 122.0, 120.6, 113.2, 110.6, 110.5, 44.9, 41.0, 26.5, 13.0; LRMS (ESI) m/z calcd for C 29 H 31 N 3 O 2 [M+Na]+: 453.2, found: x.

<GxF 51 ~ 55><GxF 51 ~ 55>

IK-E : 하기 반응식 12와 같이 합성하였으며, 구체적으로, 피리딘(pyridine, 564 μL, 7 mmol) 및 2-브로모-1-[4-(4(트리플루오로메틸)-페닐]에탄-1-온(1.96 mL, 7.35 mmol)이 포함된 DMF(15.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(372 μL, 3.50 mmol), 구리(II) 아세테이트 모노하이드레이트(2.09 g, 10.5 mmol) 및 소듐 아세테이트(1.72 g, 21.0 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IK-E(906 mg, 2.50 mmol, 71.6% 수율)를 수득 하였다. IK-E : Synthesized as in Reaction Scheme 12, specifically, pyridine (pyridine, 564 μL, 7 mmol) and 2-bromo-1-[4-(4(trifluoromethyl)-phenyl]ethan-1-one ( DMF (15.0 mL) containing 1.96 mL, 7.35 mmol) was stirred at 100° C. overnight, and then ethyl acrylate (372 μL, 3.50 mmol), copper (II) acetate monohydrate (2.09 g, 10.5 mmol) and Sodium acetate (1.72 g, 21.0 mmol) was added and stirred for 16 hours at 100° C. After completion of the reaction, it was monitored by TLC, and then copper acetate was removed by filtration through a pad of Celite, and the resulting filtrate was removed. The resulting crude product was washed with water and the organics were extracted 3 times with DCM The extracted organics were combined, dried over anhydrous Na 2 SO 4 and concentrated, The concentrated organic phase was silica-gel flash Purified by column chromatography (hexane 1-15% containing EtOAc) to obtain a yellow solid compound IK-E (906 mg, 2.50 mmol, 71.6% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.98(d, J = 6.8 Hz, 1H), 8.42(d, J = 9.2 Hz, 1H), 7.91(d, J = 8.0 Hz, 2H), 7.78(d, J = 8.4 Hz, 2H), 7.76(s, 1H), 7.50(t, J = 8.0 Hz, 1H), 7.14(d, J = 6.2 Hz, 1H), 4.38(q, J = 7.1 Hz, 2H), 1.40(t, J = 7.1 Hz, 3H); 13C NMR(100 MHz, CDCl3) δ 183.6, 163.6, 142.9, 140.0, 132.9, 132.6, 129.1, 129.9, 128.9, 128.1, 125.3(3), 125.0, 122.3, 121.9, 121.4, 119.5, 115.6, 106.8, 60.3, 14.7; LRMS (ESI) m/z calcd for C19H14F3NO3 [M+Na]+ : 361.1, found : 362.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.98 (d, J = 6.8 Hz, 1H), 8.42 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.78 ( d, J = 8.4 Hz, 2H), 7.76 (s, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 6.2 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.6, 163.6, 142.9, 140.0, 132.9, 132.6, 129.1, 129.9, 128.9, 128.1, 125.3(3), 125.0, 122.3, 121.9, 121.4, 119.5, 115.6, 106.8, 60.3, 14.7; LRMS (ESI) m/z calcd for C 19 H 14 F 3 NO 3 [M+Na] + : 361.1, found: 362.1.

IK-B : IK-E(632 mg, 2.50 mmol)가 포함된 메탄올(20 mL)에 KOH(8.44 g, 150 mmol)를 첨가한 후, 실온에서 4시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 IK-A를 수득하였다. IK-B : KOH (8.44 g, 150 mmol) was added to methanol (20 mL) containing IK-E (632 mg, 2.50 mmol), followed by stirring at room temperature for 4 hours. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water, and dried in a drying oven to obtain a white solid compound IK-A.

수득한 화합물 IK-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IK-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(630 mg, 7.50 mmol)를 첨가하고 및 NBS(667 mg, 3.75 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - ethyl acetate 12%)로 정제하여 황색 고체의 화합물 IK-B(664 mg, 1.80 mmol, 72.1% 수율)를 수득 하였다.The obtained compound IK-A was used in the next step without further purification, sodium bicarbonate (630 mg, 7.50 mmol) was added to DMF (10.0 mL) containing IK-A, and NBS (667 mg, 3.75 mmol) ) Was added partially at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8-ethyl acetate 12%) to obtain a yellow solid compound IK-B (664 mg, 1.80 mmol, 72.1% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.96 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 9.2 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.32 (s, 1H), 7.05 (t, J = 7.0 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 181.4, 142.9, 136.6, 132.4, 128.8, 128.3, 126.5, 125.4, 125.0, 124.9, 122.2, 121.3, 116.7, 114.6, 89.9;LRMS (ESI) m/z calcd for C16H9BrF3NO[M+Na]+ : 367.0, found : 368.0. 1 H NMR (400 MHz, CDCl 3 ), δ 9.96 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.64 ( d, J = 9.2 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.32 (s, 1H), 7.05 (t, J = 7.0 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 181.4, 142.9, 136.6, 132.4, 128.8, 128.3, 126.5, 125.4, 125.0, 124.9, 122.2, 121.3, 116.7, 114.6, 89.9; LRMS (ESI) m/z calcd for C 16 H 9 BrF 3 NO[M+Na] + : 367.0, found: 368.0.

[반응식 12][Scheme 12]

Figure pat00215
Figure pat00215

화합물 GxF 51 : Compound GxF 51 :

IK-B(59.0 mg, 0.16 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(122 mg, 0.64 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(68.0 mg, 0.64 mmol)를 첨가한 후, 100℃에서 1시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-51으로 표시되는 황색 고체의 화합물 GxF 51(62.1 mg, 0.14 mmol, 89.5% 수율)을 수득 하였다.4-trifluorophenyl boronic acid (122 mg, 0.64 mmol), tetrakis (triphenyl phosphine) in a solution containing IK-B (59.0 mg, 0.16 mmol) and a mixture of DMF and water 2: 1 After adding palladium (231 mg, 20.0 mol%) and sodium carbonate (68.0 mg, 0.64 mmol), the mixture was stirred at 100° C. for 1 hour. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 51 (62.1 mg, 0.14 mmol, 89.5) represented by the following formula 1-51. % Yield) was obtained.

[화학식 1-51][Chemical Formula 1-51]

Figure pat00216
Figure pat00216

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 10.05 (d, J = 6.8 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.68 (q, J = 8.0 Hz, 5H), 7.43 (s, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 6.2 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 182.8, 143.6, 138.0, 136.7, 132.7, 132.4, 129.2, 129.0, 128.7, 128.4, 127.8, 126.2, 125.8, 125.8, 125.5, 125.4, 125.3(2), 122.1, 117.3, 116.4, 114.9. 1 H NMR (400 MHz, CDCl 3 ), δ 10.05 (d, J = 6.8 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.78 ( d, J = 8.4 Hz, 2H), 7.68 (q, J = 8.0 Hz, 5H), 7.43 (s, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 6.2 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 182.8, 143.6, 138.0, 136.7, 132.7, 132.4, 129.2, 129.0, 128.7, 128.4, 127.8, 126.2, 125.8, 125.8, 125.5, 125.4, 125.3(2), 122.1, 117.3, 116.4, 114.9.

화합물 GxF 52 : Compound GxF 52 :

IK-B(58.6 mg, 0.16 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(104 mg, 0.64 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(67.5 mg, 0.64 mmol)를 첨가한 후, 100℃에서 7시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-52로 표시되는 황색 고체의 화합물 GxF 52(58.4 mg, 0.14 mmol, 89.5% 수율)을 수득 하였다.In a solution containing IK-B (58.6 mg, 0.16 mmol) and a mixture of DMF and water 2: 1, 4-acetylphenyl boronic acid (104 mg, 0.64 mmol), tetrakis (triphenyl phosphine) palladium ( 231 mg, 20.0 mol%) and sodium carbonate (67.5 mg, 0.64 mmol) were added, followed by stirring at 100° C. for 7 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to obtain a yellow solid compound GxF 52 (58.4 mg, 0.14 mmol, 89.5) represented by the following formula 1-52. % Yield) was obtained.

[화학식 1-52][Formula 1-52]

Figure pat00217
Figure pat00217

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 10.03 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 9.2 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.34 (s, 1H), 7.27 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 3H), 3.86 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 182.3, 158.5, 144.0, 136.8, 132.4, 132.0, 129.0(2), 126.6, 125.3, 125.2(2), 125.1(2), 124.9, 122.5, 121.5, 118.0, 117.6, 114.5, 114.3, 55.4. 1 H NMR (400 MHz, CDCl 3 ), δ 10.03 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 9.2 Hz, 1H), 7.77 ( d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.34 (s, 1H), 7.27 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 3H), 3.86 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 182.3, 158.5, 144.0, 136.8, 132.4, 132.0, 129.0(2), 126.6, 125.3, 125.2(2), 125.1(2), 124.9, 122.5, 121.5, 118.0, 117.6, 114.5, 114.3, 55.4.

화합물 GxF 53 : Compound GxF 53 :

IK-B(53.0 mg, 0.14 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(71.2 mg, 0.57 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(61.0 mg, 0.57 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-53으로 표시되는 황색 고체의 화합물 GxF 53(53.1 mg, 0.14 mmol, 100% 수율)을 수득 하였다.Phenyl boronic acid (71.2 mg, 0.57 mmol), tetrakis (triphenyl phosphine) palladium (231 mg, in a solution containing IK-B (53.0 mg, 0.14 mmol) and a mixture of DMF and water 2: 1) 20.0 mol%) and sodium carbonate (61.0 mg, 0.57 mmol) were added, followed by stirring at 100° C. for 9 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 53 (53.1 mg, 0.14 mmol, 100) represented by the following formula 1-53 (53.1 mg, 0.14 mmol, 100). % Yield) was obtained.

[화학식 1-53][Formula 1-53]

Figure pat00218
Figure pat00218

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 10.04 (d, J = 6.8 Hz, 1H), 7.92 (t, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.8 Hz, 2H), 7.39 (s, 1H), 7.32 (m, 3H), 6.97 (t, J = 6.6 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 182.5, 143.9, 136.8, 134.2, 132.5, 132.1, 129.1, 129.0, 128.9, 127.8, 126.7, 125.6, 125.3, 125.2, 122.5, 121.7, 118.2, 117.6, 114.6; LRMS (ESI) m/z calcd for C22H14F3NO[M+Na]+ : 365.1, found : 366.1. 1 H NMR (400 MHz, CDCl 3 ), δ 10.04 (d, J = 6.8 Hz, 1H), 7.92 (t, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.55 ( d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.8 Hz, 2H), 7.39 (s, 1H), 7.32 (m, 3H), 6.97 (t, J = 6.6 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 182.5, 143.9, 136.8, 134.2, 132.5, 132.1, 129.1, 129.0, 128.9, 127.8, 126.7, 125.6, 125.3, 125.2, 122.5, 121.7, 118.2, 117.6, 114.6; LRMS (ESI) m/z calcd for C 22 H 14 F 3 NO[M+Na] + : 365.1, found: 366.1.

화합물 GxF 54 : Compound GxF 54 :

IK-B(56.2 mg, 0.15 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(92.8 mg, 0.61 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(64.7 mg, 0.61 mmol)를 첨가한 후, 100℃에서 10시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-54로 표시되는 황색 고체의 화합물 GxF 54(65.9 mg, 0.16 mmol, 100% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (92.8 mg, 0.61 mmol), tetrakis (triphenyl phosphine) palladium in a solution containing IK-B (56.2 mg, 0.15 mmol) and a mixture of DMF and water 2: 1 (231 mg, 20.0 mol%) and sodium carbonate (64.7 mg, 0.61 mmol) were added, followed by stirring at 100° C. for 10 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%), and a yellow solid compound GxF 54 (65.9 mg, 0.16 mmol, 100) represented by the following formula 1-54. % Yield) was obtained.

[화학식 1-54][Formula 1-54]

Figure pat00219
Figure pat00219

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.99 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.42 (s,1H), 7.32 (t, J = 8.0 Hz, 1H), 7.01 (t, J = 6.8 Hz, 1H), 2.60 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.1, 182.6, 144.0, 143.5, 139.1, 136.7, 136.3, 135.0, 132.6, 132.2, 129.1, 128.9, 128.8, 127.4, 127.2, 126.2, 125.2, 122.4, 122.1, 117.4, 116.6, 114.9, 26.7; LRMS (ESI) m/z calcd for [M+Na]+ : 395.1, found : 396.4. 1 H NMR (400 MHz, CDCl 3 ), δ 9.99 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.73 ( d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.42 (s,1H), 7.32 (t, J = 8.0 Hz, 1H), 7.01 (t, J = 6.8 Hz, 1H), 2.60 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.1, 182.6, 144.0, 143.5, 139.1, 136.7, 136.3, 135.0, 132.6, 132.2, 129.1, 128.9, 128.8, 127.4, 127.2, 126.2, 125.2, 122.4, 122.1, 117.4 , 116.6, 114.9, 26.7; LRMS (ESI) m/z calcd for [M+Na] + : 395.1, found: 396.4.

화합물 GxF 55 : Compound GxF 55 :

IK-B(60.6 mg, 0.16 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(108.6 mg, 0.66 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(69.7 mg, 0.66 mmol)를 첨가한 후, 100℃에서 11시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-55로 표시되는 황색 고체의 화합물 GxF 55(59.5 mg, 0.14 mmol, 91% 수율)을 수득 하였다.In a solution containing IK-B (60.6 mg, 0.16 mmol) and a mixture of DMF and water 2: 1, 4-(dimethylamino) phenyl boronic acid (108.6 mg, 0.66 mmol), tetrakis (triphenyl phosphine) Fin) palladium (231 mg, 20.0 mol%) and sodium carbonate (69.7 mg, 0.66 mmol) were added, followed by stirring at 100° C. for 11 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to obtain a yellow solid compound GxF 55 (59.5 mg, 0.14 mmol, 91) represented by the following formula 1-55. % Yield) was obtained.

[화학식 1-55][Formula 1-55]

Figure pat00220
Figure pat00220

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 10.03 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.31 (s, 1H), 7.27 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 6.9 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 2.98 (s, 6H); 13C NMR(100 MHz, CDCl3) δ 181.7, 149.1,143.8, 136.5, 131.9, 131.6, 128.8, 128.6, 128.3, 124.9, 124.8, 124.7, 124.3, 122.2, 121.8, 121.1, 118.4, 117.5, 114.1, 112.5, 40.3; LRMS (ESI) m/z calcd for C24H19F3N2O [M+Na]+ : 408.1, found : 409.2. 1 H NMR (400 MHz, CDCl 3 ), δ 10.03 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.75 ( d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.31 (s, 1H), 7.27 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 6.9 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 2.98 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 181.7, 149.1,143.8, 136.5, 131.9, 131.6, 128.8, 128.6, 128.3, 124.9, 124.8, 124.7, 124.3, 122.2, 121.8, 121.1, 118.4, 117.5, 114.1, 112.5 , 40.3; LRMS (ESI) m/z calcd for C 24 H 19 F 3 N 2 O [M+Na] + : 408.1, found: 409.2.

<GxF 56 ~ 60><GxF 56 ~ 60>

IL-E : 하기 반응식 13과 같이 합성하였으며, 구체적으로, 피리딘(564 μL, 7.00 mmol) 및 클로로아세톤(chloroacetone, 585 μL, 7.35 mmol)이 포함된 DMF(15.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(373 μL, 3.50 mmol), 구리(II) 아세테이트 모노하이드레이트(2.09 g, 10.5 mmol) 및 소듐 아세테이트(1.72 g, 21.0 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IL-E(633 mg, 2.73 mmol, 85.0% 수율)를 수득 하였다. IL-E : Synthesized as in Scheme 13 below, specifically, DMF (15.0 mL) containing pyridine (564 μL, 7.00 mmol) and chloroacetone (chloroacetone, 585 μL, 7.35 mmol) was stirred at 100° C. overnight, Ethyl acrylate (373 μL, 3.50 mmol), copper (II) acetate monohydrate (2.09 g, 10.5 mmol) and sodium acetate (1.72 g, 21.0 mmol) were added, followed by stirring at 100° C. for 16 hours. After completion of the reaction, after monitoring by TLC, copper acetate was removed by filtration through a pad of Celite, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water and the organic material was extracted 3 times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (hexane 1-15% containing EtOAc) to obtain a yellow solid compound IL-E (633 mg, 2.73 mmol, 85.0% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.88 (d, J = 6.4 Hz, 1H), 8.34(d, J = 5.0 Hz, 1H), 7.99(s, 1H), 7.38(q, J = 9.3 Hz, 1H), 6.95(t, J = 7.0 Hz, 1H), 4.39(q, J = 7.1 Hz, 2H), 2.60(s, 3H), 1.43(t, J = 7.2 Hz, 3H); 13C NMR(100 MHz, CDCl3) δ 187.6, 164.0, 139.2, 129.1, 127.2, 126.2, 122.7, 119.4, 115.2, 105.8, 60.3, 27.6, 14.9 ; LRMS (ESI) m/z calcd for C13H13NO3 [M+Na]+ : 231.1, found : 232.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.88 (d, J = 6.4 Hz, 1H), 8.34 (d, J = 5.0 Hz, 1H), 7.99 (s, 1H), 7.38 (q, J = 9.3 Hz, 1H), 6.95 (t, J = 7.0 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 2.60 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 187.6, 164.0, 139.2, 129.1, 127.2, 126.2, 122.7, 119.4, 115.2, 105.8, 60.3, 27.6, 14.9; LRMS (ESI) m/z calcd for C 13 H 13 NO 3 [M+Na] + : 231.1, found: 232.1.

IL-B : IL-E(633 mg, 2.73 mmol)가 포함된 메탄올(20 mL)에 KOH(6.14 g, 109 mmol)를 첨가한 후, 실온에서 4시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 IL-A를 수득하였다. IL-B : After adding KOH (6.14 g, 109 mmol) to methanol (20 mL) containing IL-E (633 mg, 2.73 mmol), the mixture was stirred at room temperature for 4 hours. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water and dried in a drying oven to obtain a white solid compound IL-A.

수득한 화합물 IL-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IL-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(688 mg, 8.19 mmol)를 첨가하고 및 NBS(2.18 g, 12.3 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - ethyl acetate 12%)로 정제하여 황색 고체의 화합물 IL-B(477 mg, 2.0 mmol, 73.4% 수율)를 수득 하였다.The obtained compound IL-A was used in the next step without further purification, sodium bicarbonate (688 mg, 8.19 mmol) was added to DMF (10.0 mL) containing IL-A, and NBS (2.18 g, 12.3 mmol) was added, and NBS (2.18 g, 12.3 mmol) was added. ) Was added partially at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8-ethyl acetate 12%) to obtain a yellow solid compound IL-B (477 mg, 2.0 mmol, 73.4% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.83 (d, J = 6.8 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.51 (s, 1H), 7.22 (q, J = 7.8 Hz, 1H), 6.91 (t, J = 6.4 Hz, 1H), 2.54 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 185.5, 135.4, 127.9, 124.0, 123.8, 121.9, 116.5, 113.9, 88.5, 27.1; LRMS (ESI) m/z calcd for C10H8BrNO[M+Na]+ : 237.0, found :238.0. 1 H NMR (400 MHz, CDCl 3 ), δ 9.83 (d, J = 6.8 Hz, 1H), 7.56 (d, J = 9.2 Hz, 1H), 7.51 (s, 1H), 7.22 (q, J = 7.8 Hz, 1H), 6.91 (t, J = 6.4 Hz, 1H), 2.54 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) [ delta] 185.5, 135.4, 127.9, 124.0, 123.8, 121.9, 116.5, 113.9, 88.5, 27.1; LRMS (ESI) m/z calcd for C 10 H 8 BrNO[M+Na] + : 237.0, found: 238.0.

[반응식 13][Scheme 13]

Figure pat00221
Figure pat00221

화합물 GxF 56 : Compound GxF 56 :

IL-B(21.7 mg, 0.09 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(69.0 mg, 0.36 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(39.0 mg, 0.36 mmol)를 첨가한 후, 100℃에서 10시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-56으로 표시되는 황색 고체의 화합물 GxF 56(24.4 mg, 0.08 mmol, 89.3% 수율)을 수득 하였다.In a solution containing IL-B (21.7 mg, 0.09 mmol) and a mixture of DMF and water 2: 1, 4-trifluorophenyl boronic acid (69.0 mg, 0.36 mmol), tetrakis (triphenyl phosphine) After adding palladium (231 mg, 20.0 mol%) and sodium carbonate (39.0 mg, 0.36 mmol), the mixture was stirred at 100° C. for 10 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to obtain a yellow solid compound GxF 56 (24.4 mg, 0.08 mmol, 89.3) represented by the following formula 1-56. % Yield) was obtained.

[화학식 1-56][Formula 1-56]

Figure pat00222
Figure pat00222

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.93 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 9.2 Hz, 2H), 7.69 (d, J = 4.4 Hz, 2H), 7.65 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.24 (dd, J = 10.0 Hz, 1H), 6.95 (t, J = 7.0 Hz, 1H), 2.62 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 186.8, 138.4, 135.7, 129.0, 128.1, 127.8, 125.8, 125.8, 125.6, 125.1, 122.8, 122.6, 117.1, 115.5(2), 114.4, 27.5; LRMS (ESI) m/z calcd for C17H12F3NO [M+Na]+ : 303.1, found : 304.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.93 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 9.2 Hz, 2H), 7.69 (d, J = 4.4 Hz, 2H), 7.65 ( s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.24 (dd, J = 10.0 Hz, 1H), 6.95 (t, J = 7.0 Hz, 1H), 2.62 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.8, 138.4, 135.7, 129.0, 128.1, 127.8, 125.8, 125.8, 125.6, 125.1, 122.8, 122.6, 117.1, 115.5(2), 114.4, 27.5; LRMS (ESI) m/z calcd for C 17 H 12 F 3 NO [M+Na] + : 303.1, found: 304.1.

화합물 GxF 57 : Compound GxF 57 :

IL-B(25.8 mg, 0.10 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(71.0 mg, 0.43mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(46.0 mg, 0.43 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-57로 표시되는 황색 고체의 화합물 GxF 57(19.0 mg, 0.06 mmol, 63.4% 수율)을 수득 하였다.In a solution containing IL-B (25.8 mg, 0.10 mmol) and a mixture of DMF and water 2: 1, 4-acetylphenyl boronic acid (71.0 mg, 0.43 mmol), tetrakis (triphenyl phosphine) palladium ( 231 mg, 20.0 mol%) and sodium carbonate (46.0 mg, 0.43 mmol) were added, followed by stirring at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to obtain a yellow solid compound GxF 57 (19.0 mg, 0.06 mmol, 63.4) represented by the following formula 1-57. % Yield) was obtained.

[화학식 1-57][Formula 1-57]

Figure pat00223
Figure pat00223

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.91 (d, J = 6.8 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.66 (d, J = 3.6 Hz, 2H), 7.23 (dd, J = 7.8 Hz, 1H), 6.93 (t, J = 6.9 Hz, 1H), 2.63 (s, 3H), 2.61 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.5, 186.9, 139.9, 135.7, 134.9, 129.1, 127.6, 127.5, 125.3, 122.9, 122.8, 117.5, 115.7, 114.5, 27.7, 27.0; LRMS (ESI) m/z calcd for C18H15NO2 [M+Na]+ : 277. 1, found : 278.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.91 (d, J = 6.8 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.8 Hz, 1H), 7.68 ( s, 1H), 7.66 (d, J = 3.6 Hz, 2H), 7.23 (dd, J = 7.8 Hz, 1H), 6.93 (t, J = 6.9 Hz, 1H), 2.63 (s, 3H), 2.61 ( s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.5, 186.9, 139.9, 135.7, 134.9, 129.1, 127.6, 127.5, 125.3, 122.9, 122.8, 117.5, 115.7, 114.5, 27.7, 27.0; LRMS (ESI) m/z calcd for C 18 H 15 NO 2 [M+Na] + : 277. 1, found: 278.1.

화합물 GxF 58 : Compound GxF 58 :

IL-B(54.4 mg, 0.23 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(111 mg, 0.91 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(97.0 mg, 0.91 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-58로 표시되는 황색 고체의 화합물 GxF 58(66.8 mg, 0.28 mmol, 100% 수율)을 수득 하였다.In a solution containing IL-B (54.4 mg, 0.23 mmol) and a mixture of DMF and water 2: 1, phenyl boronic acid (111 mg, 0.91 mmol), tetrakis (triphenyl phosphine) palladium (231 mg, 20.0 mol%) and sodium carbonate (97.0 mg, 0.91 mmol) were added, followed by stirring at 100° C. for 9 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 58 (66.8 mg, 0.28 mmol, 100) represented by the following formula 1-58. % Yield) was obtained.

[화학식 1-58][Formula 1-58]

Figure pat00224
Figure pat00224

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.91 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.58 (d, J = 7.2 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.90 (t, J = 6.8 Hz, 1H), 2.60 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 186.2, 135.2, 134.4, 128.5, 128.4, 127.6, 126.2, 124.0, 122.2, 122.0, 117.2, 116.7, 113.7, 27.2; LRMS (ESI) m/z calcd for C16H13NO [M+Na]+ : 235.1, found : 236.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.91 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.58 (d, J = 7.2 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6.90 (t, J = 6.8 Hz, 1H), 2.60 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.2, 135.2, 134.4, 128.5, 128.4, 127.6, 126.2, 124.0, 122.2, 122.0, 117.2, 116.7, 113.7, 27.2; LRMS (ESI) m/z calcd for C 16 H 13 NO [M+Na] + : 235.1, found: 236.1.

화합물 GxF 59 : Compound GxF 59 :

IL-B(20.3 mg, 0.08 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(52.0 mg, 0.34 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(36.0 mg, 0.34 mmol)를 첨가한 후, 100℃에서 13시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-59로 표시되는 황색 고체의 화합물 GxF 59(13.3 mg, 0.05 mmol, 62.6% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (52.0 mg, 0.34 mmol), tetrakis (triphenyl phosphine) palladium in a solution containing IL-B (20.3 mg, 0.08 mmol) and a mixture of DMF and water 2: 1 (231 mg, 20.0 mol%) and sodium carbonate (36.0 mg, 0.34 mmol) were added, followed by stirring at 100° C. for 13 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%), and a yellow solid compound GxF 59 (13.3 mg, 0.05 mmol, 62.6) represented by the following formula 1-59 % Yield) was obtained.

[화학식 1-59][Formula 1-59]

Figure pat00225
Figure pat00225

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.90 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 6.8 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.16 (t, J = 7.7 Hz, 1H), 7.01 (t, J = 6.8 Hz, 2H), 6.88 (t, J = 6.8 Hz, 1H), 3.87 (s, 3H), 2.60 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 186.4, 158.3, 135.5, 129.0, 128.7, 127.2, 124.0, 122.2, 117.5, 116.8, 114.3, 113.9, 55.5, 27.5; LRMS (ESI) m/z calcd for C17H15NO2[M+Na]+ : 265.1, found : 266.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.90 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 6.8 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.16 (t, J = 7.7 Hz, 1H), 7.01 (t, J = 6.8 Hz, 2H), 6.88 (t, J = 6.8 Hz, 1H), 3.87 (s, 3H), 2.60 ( s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.4, 158.3, 135.5, 129.0, 128.7, 127.2, 124.0, 122.2, 117.5, 116.8, 114.3, 113.9, 55.5, 27.5; LRMS (ESI) m/z calcd for C 17 H 15 NO 2 [M+Na] + : 265.1, found: 266.1.

화합물 GxF 60 : Compound GxF 60 :

IL-B(27.5 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(76.0 mg, 0.46 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(49.0 mg, 0.46 mmol)를 첨가한 후, 100℃에서 11시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-60으로 표시되는 황색 고체의 화합물 GxF 60(12.5 mg, 0.04 mmol, 40.8% 수율)을 수득 하였다.In a solution containing IL-B (27.5 mg, 0.11 mmol) and a mixture of DMF and water 2: 1, 4- (dimethylamino) phenyl boronic acid (76.0 mg, 0.46 mmol), tetrakis (triphenyl phosphine) Fin) palladium (231 mg, 20.0 mol%) and sodium carbonate (49.0 mg, 0.46 mmol) were added, followed by stirring at 100° C. for 11 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%), and a yellow solid compound GxF 60 (12.5 mg, 0.04 mmol, 40.8) represented by the following formula 1-60 (12.5 mg, 0.04 mmol, 40.8) % Yield) was obtained.

[화학식 1-60][Formula 1-60]

Figure pat00226
Figure pat00226

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.89 (d, J = 6.4 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.46 (d, J = 7.2 Hz, 2H), 7.13 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 6.8 Hz, 3H), 3.00 (s, 6H), 2.59 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 186.2, 149.3, 135.5, 128.7, 123.7, 122.8, 122.0, 121.9, 117.7, 117.5, 113.8, 113.0, 40.8, 27.5; LRMS (ESI) m/z calcd for C18H18N2O [M+Na]+ : 278.1, found : 279.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.89 (d, J = 6.4 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.46 (d, J = 7.2 Hz, 2H), 7.13 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 6.8 Hz, 3H), 3.00 (s, 6H), 2.59 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 186.2, 149.3, 135.5, 128.7, 123.7, 122.8, 122.0, 121.9, 117.7, 117.5, 113.8, 113.0, 40.8, 27.5; LRMS (ESI) m/z calcd for C 18 H 18 N 2 O [M+Na] + : 278.1, found: 279.2.

<GxF 61 ~ 65><GxF 61 ~ 65>

IM-E : 하기 반응식 14와 같이 합성하였으며, 구체적으로, 피리딘(564 μL, 7.00 mmol) 및 브로모아세토페논(1.46 g, 7.35 mmol)이 포함된 DMF(15.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(373 μL, 3.50 mmol), 구리(II) 아세테이트 모노하이드레이트(2.09 g, 10.5 mmol) 및 소듐 아세테이트(1.72 g, 21.0 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IM-E(616 mg, 2.10 mmol, 60% 수율)를 수득 하였다. IM-E : Synthesized as in Scheme 14 below, specifically, DMF (15.0 mL) containing pyridine (564 μL, 7.00 mmol) and bromoacetophenone (1.46 g, 7.35 mmol) was stirred at 100° C. overnight, Ethyl acrylate (373 μL, 3.50 mmol), copper (II) acetate monohydrate (2.09 g, 10.5 mmol) and sodium acetate (1.72 g, 21.0 mmol) were added, followed by stirring at 100° C. for 16 hours. After completion of the reaction, after monitoring by TLC, copper acetate was removed by filtration through a pad of Celite, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water and the organic material was extracted 3 times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (hexane 1-15% containing EtOAc) to obtain a yellow solid compound IM-E (616 mg, 2.10 mmol, 60% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.83(d, J = 7.2 Hz, 1H), 8.25(d, J = 9.0 Hz, 1H), 7.73(d, J = 7.2 Hz, 2H), 7.71(s, 1H), 7.46(d, J = 7.2 Hz, 1H), 7.40(t, J = 7.2 Hz, 2H), 7.29(t, J = 8.0 Hz, 1H), 6.93(t, J = 7.0 Hz, 1H), 4.29(q, J = 7.0 Hz, 2H), 1.31(t, J = 7.0 Hz, 3H); 13C NMR(100 MHz, CDCl3) δ 184.8, 163.4, 139.5, 139.3, 131.1, 128.7, 128.6, 128.4, 128.0, 127.2, 122.1, 121.2, 119.0, 114.9, 105.9, 59.9, 14.5; LRMS (ESI) m/z calcd for C18H15NO3 [M+Na]+ : 293.1, found : 294.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.83 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 7.2 Hz, 2H), 7.71 ( s, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.40 (t, J = 7.2 Hz, 2H), 7.29 (t, J = 8.0 Hz, 1H), 6.93 (t, J = 7.0 Hz, 1H), 4.29 (q, J = 7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.8, 163.4, 139.5, 139.3, 131.1, 128.7, 128.6, 128.4, 128.0, 127.2, 122.1, 121.2, 119.0, 114.9, 105.9, 59.9, 14.5; LRMS (ESI) m/z calcd for C 18 H 15 NO 3 [M+Na] + : 293.1, found: 294.2.

IM-B : IM-E(616 mg, 2.10 mmol)가 포함된 메탄올(20 mL)에 KOH(7.06 g, 126 mmol)를 첨가한 후, 실온에서 4시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 IM-A를 수득하였다. IM-B : After adding KOH (7.06 g, 126 mmol) to methanol (20 mL) containing IM-E (616 mg, 2.10 mmol), the mixture was stirred at room temperature for 4 hours. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water and dried in a drying oven to obtain a white solid compound IM-A.

수득한 화합물 IM-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IM-A이 포함된 DMF(10.0 mL)에 소듐 바이카보네이트(529 mg, 6.30 mmol)를 첨가하고 및 NBS(561 mg, 3.15 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - ethyl acetate 12%)로 정제하여 황색 고체의 화합물 IM-B(590 mg, 1.96 mmol, 93.6% 수율)를 수득 하였다.The obtained compound IM-A was used in the next step without further purification, sodium bicarbonate (529 mg, 6.30 mmol) was added to DMF (10.0 mL) containing IM-A, and NBS (561 mg, 3.15 mmol) ) Was added partially at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8-ethyl acetate 12%) to obtain a yellow solid compound IM-B (590 mg, 1.96 mmol, 93.6% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 10.04 (d, J = 6.8 Hz, 1H), 7.78 (d, J = 6.4 Hz, 2H), 7.61 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.50 (d, J =7.6 Hz, 2H), 7.37 (s, 1H), 7.30 (m, 1H), 6.98 (t, J = 7.0 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 184.0, 140.3, 136.9, 131.3, 129.0, 128.8, 128.5, 127.2, 125.4, 122.3, 117.3, 114.8, 89.9, 47.1, 34.8; LRMS (ESI) m/z calcd for C15H10BrNO [M+Na]+ : 299.0, found : 300.0. 1 H NMR (400 MHz, CDCl 3 ), δ 10.04 (d, J = 6.8 Hz, 1H), 7.78 (d, J = 6.4 Hz, 2H), 7.61 (d, J = 8.8 Hz, 1H), 7.54 ( d, J = 7.6 Hz, 1H), 7.50 (d, J =7.6 Hz, 2H), 7.37 (s, 1H), 7.30 (m, 1H), 6.98 (t, J = 7.0 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.0, 140.3, 136.9, 131.3, 129.0, 128.8, 128.5, 127.2, 125.4, 122.3, 117.3, 114.8, 89.9, 47.1, 34.8; LRMS (ESI) m/z calcd for C 15 H 10 BrNO [M+Na] + : 299.0, found: 300.0.

[반응식 14][Scheme 14]

Figure pat00227
Figure pat00227

화합물 GxF 61 : Compound GxF 61 :

IM-B(59.4 mg, 0.19 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(150 mg, 0.79 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(84.0 mg, 0.79 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-61로 표시되는 황색 고체의 화합물 GxF 61(33.9 mg, 0.09 mmol, 46.8% 수율)을 수득 하였다.4-trifluorophenyl boronic acid (150 mg, 0.79 mmol), tetrakis (triphenyl phosphine) in a solution containing IM-B (59.4 mg, 0.19 mmol) and a mixture of DMF and water 2: 1 After adding palladium (231 mg, 20.0 mol%) and sodium carbonate (84.0 mg, 0.79 mmol), the mixture was stirred at 100° C. for 9 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%), and a yellow solid compound GxF 61 (33.9 mg, 0.09 mmol, 46.8) represented by the following formula 1-61 % Yield) was obtained.

[화학식 1-61][Formula 1-61]

Figure pat00228
Figure pat00228

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 10.04 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.84 (m, J = 6.8 Hz, 2H), 7.67 (m, J = 2.4 Hz,4H), 7.56 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.49 (s, 1H), 7.31 (m, J = 7.9 Hz, 1H), 6.96 (m, J = 6.9 Hz, 1H); 13C NMR(400 MHz, CDCl3) δ 184.5, 140.4, 138.3, 136.1, 131.0, 129.0, 128.8, 128.7, 128.4, 128.2, 128.0, 127.7, 125.7, 125.7, 125.7, 125.6, 125.4, 122.9, 122.4, 117.1, 115.8, 114.4; LRMS (ESI) m/z calcd for C22H14F3NO [M+Na]+ : 365.1, found : 366.1. 1 H NMR (400 MHz, CDCl 3 ), δ 10.04 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.84 (m, J = 6.8 Hz, 2H), 7.67 ( m, J = 2.4 Hz,4H), 7.56 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.49 (s, 1H), 7.31 (m, J = 7.9 Hz, 1H), 6.96 (m, J = 6.9 Hz, 1H); 13 C NMR (400 MHz, CDCl 3 ) δ 184.5, 140.4, 138.3, 136.1, 131.0, 129.0, 128.8, 128.7, 128.4, 128.2, 128.0, 127.7, 125.7, 125.7, 125.7, 125.6, 125.4, 122.9, 122.4, 117.1 , 115.8, 114.4; LRMS (ESI) m/z calcd for C 22 H 14 F 3 NO [M+Na] + : 365.1, found: 366.1.

화합물 GxF 62 : Compound GxF 62 :

IM-B(55.5 mg, 0.18 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(121 mg, 0.74 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(78.7 mg, 0.74 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-62로 표시되는 황색 고체의 화합물 GxF 62(50.0 mg, 0.14 mmol, 79.2% 수율)을 수득 하였다.In a solution containing IM-B (55.5 mg, 0.18 mmol) and a mixture of DMF and water 2: 1, 4-acetylphenyl boronic acid (121 mg, 0.74 mmol), tetrakis (triphenyl phosphine) palladium ( 231 mg, 20.0 mol%) and sodium carbonate (78.7 mg, 0.74 mmol) were added, followed by stirring at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%), and a yellow solid compound GxF 62 (50.0 mg, 0.14 mmol, 79.2) represented by the following formula 1-62 % Yield) was obtained.

[화학식 1-62][Formula 1-62]

Figure pat00229
Figure pat00229

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 10.02 (d, J = 6.8 Hz, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.89 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 6.8 Hz, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.2 Hz, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.29 (t, J = 7.0 Hz, 1H), 7.00 (t, J = 6.6 Hz, 1H), 2.63 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.0, 184.3, 143.9, 140.3, 139.4, 136.2, 136.1, 134.6, 130.9, 128.9, 128.8, 128.7, 128.1, 127.2, 127.1, 125.6, 125.3, 122.4, 117.2, 115.9, 114.4, 26.7, 26.6; LRMS (ESI) m/z calcd for C23H17NO2 [M+Na]+ : 339.1, found :340.2. 1 H NMR (400 MHz, CDCl 3 ), δ 10.02 (d, J = 6.8 Hz, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.89 (d, J = 8.8 Hz, 1H), 7.84 ( d, J = 6.8 Hz, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.2 Hz, 1H), 7.53 (s, 1H), 7.51 (s, 1H), 7.29 (t, J = 7.0 Hz, 1H), 7.00 (t, J = 6.6 Hz, 1H), 2.63 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.0, 184.3, 143.9, 140.3, 139.4, 136.2, 136.1, 134.6, 130.9, 128.9, 128.8, 128.7, 128.1, 127.2, 127.1, 125.6, 125.3, 122.4, 117.2, 115.9 , 114.4, 26.7, 26.6; LRMS (ESI) m/z calcd for C 23 H 17 NO 2 [M+Na] + : 339.1, found: 340.2.

화합물 GxF 63 : Compound GxF 63 :

IM-B(61.5 mg, 0.21 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(100 mg, 0.82 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(87.0 mg, 0.82 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-63으로 표시되는 황색 고체의 화합물 GxF 63(56.2 mg, 0.18 mmol, 89.9% 수율)을 수득 하였다.In a solution containing IM-B (61.5 mg, 0.21 mmol) and a mixture of DMF and water 2: 1, phenyl boronic acid (100 mg, 0.82 mmol), tetrakis (triphenyl phosphine) palladium (231 mg, 20.0 mol%) and sodium carbonate (87.0 mg, 0.82 mmol) were added, followed by stirring at 100° C. for 9 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 63 (56.2 mg, 0.18 mmol, 89.9) represented by the following formula 1-63. % Yield) was obtained.

[화학식 1-63][Formula 1-63]

Figure pat00230
Figure pat00230

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 10.04 (d, J = 6.8 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.84 (d, J = 6.8 Hz, 2H), 7.19 (m, 7H), 7.31 (t, J = 7.4 Hz, 1H), 7.27 (dd, J = 6.6 Hz, 1H), 7.25 (dd, J = 6.6 Hz, 1H), 6.94 (t, J = 6.6 Hz, 1H); 13C NMR(100 MHz, CDCl3) δ 183.9, 140.3, 135.9, 134.2, 130.4, 128.5, 128.4, 127.8, 127.5, 126.1, 125.0, 124.6, 121.8, 117.2, 117.1, 113.8; LRMS (ESI) m/z calcd for C21H15NO [M+Na]+ : 297.1, found : 298.1. 1 H NMR (400 MHz, CDCl 3 ), δ 10.04 (d, J = 6.8 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.84 (d, J = 6.8 Hz, 2H), 7.19 ( m, 7H), 7.31 (t, J = 7.4 Hz, 1H), 7.27 (dd, J = 6.6 Hz, 1H), 7.25 (dd, J = 6.6 Hz, 1H), 6.94 (t, J = 6.6 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.9, 140.3, 135.9, 134.2, 130.4, 128.5, 128.4, 127.8, 127.5, 126.1, 125.0, 124.6, 121.8, 117.2, 117.1, 113.8; LRMS (ESI) m/z calcd for C 21 H 15 NO [M+Na] + : 297.1, found: 298.1.

화합물 GxF 64 : Compound GxF 64 :

IM-B(62.0 mg, 0.21 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(129 mg, 0.83 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(88.0 mg, 0.83 mmol)를 첨가한 후, 100℃에서 9시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-64로 표시되는 황색 고체의 화합물 GxF 64(51.4 mg, 0.15 mmol, 74.7% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (129 mg, 0.83 mmol), tetrakis (triphenyl phosphine) palladium in a solution containing IM-B (62.0 mg, 0.21 mmol) and a mixture of DMF and water 2: 1 (231 mg, 20.0 mol%) and sodium carbonate (88.0 mg, 0.83 mmol) were added, followed by stirring at 100° C. for 9 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%), and the yellow solid compound GxF 64 (51.4 mg, 0.15 mmol, 74.7) represented by the following formula 1-64 % Yield) was obtained.

[화학식 1-64][Formula 1-64]

Figure pat00231
Figure pat00231

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 10.03 (d, J = 6.8 Hz, 1H), 7.84 (s, 1H), 7.82 (m, 2H), 7.53 (d, J = 6.8 Hz, 1H), 7.50 (s, 1H), 7.48 (m, 4H), 7.40 (s, 1H), 7.23 (m, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 184.1, 158.3, 140.7, 136.2, 130.7, 128.9, 128.8, 128.8, 128.1, 127.0, 125.0, 124.7, 121.9, 121.3, 117.5, 117.4, 114.2, 114.0, 55.4; LRMS (ESI) m/z calcd for C22H17NO2 [M+Na]+ : 327.1, found : 328.1. 1 H NMR (400 MHz, CDCl 3 ), δ 10.03 (d, J = 6.8 Hz, 1H), 7.84 (s, 1H), 7.82 (m, 2H), 7.53 (d, J = 6.8 Hz, 1H), 7.50 (s, 1H), 7.48 (m, 4H), 7.40 (s, 1H), 7.23 (m, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.1, 158.3, 140.7, 136.2, 130.7, 128.9, 128.8, 128.8, 128.1, 127.0, 125.0, 124.7, 121.9, 121.3, 117.5, 117.4, 114.2, 114.0, 55.4; LRMS (ESI) m/z calcd for C 22 H 17 NO 2 [M+Na] + : 327.1, found: 328.1.

화합물 GxF 65 : Compound GxF 65 :

IM-B(27.5 mg, 0.11 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(149 mg, 0.90 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(95.7 mg, 0.90 mmol)를 첨가한 후, 100℃에서 11시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-65로 표시되는 황색 고체의 화합물 GxF 65(67.0 mg, 0.19 mmol, 87% 수율)을 수득 하였다.In a solution containing IM-B (27.5 mg, 0.11 mmol) and a mixture of DMF and water 2: 1, 4- (dimethylamino) phenyl boronic acid (149 mg, 0.90 mmol), tetrakis (triphenyl phosphine) Fin) palladium (231 mg, 20.0 mol%) and sodium carbonate (95.7 mg, 0.90 mmol) were added, followed by stirring at 100° C. for 11 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 65 (67.0 mg, 0.19 mmol, 87) represented by the following formula 1-65. % Yield) was obtained.

[화학식 1-65][Formula 1-65]

Figure pat00232
Figure pat00232

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 10.02 (d, J = 7.6 Hz, 1H), 7.87 (s, 1H), 7.84 (d, J = 6.4 Hz, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.39 (s, 1H), 7.21 (m, 1H), 6.92 (t, J = 7.0 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 2.99 (s, 6H); 13C NMR(100 MHz, CDCl3) δ 183.9, 149.3, 140.9, 136.2, 130.6, 128.8, 128.7, 128.6, 128.0, 124.7, 124.3, 122.5, 121.8, 121.3, 118.1, 117.7, 113.9, 112.8, 40.7; LRMS (ESI) m/z calcd for C23H20N2O [M+Na]+ : 340.2, found : 341.2. 1 H NMR (400 MHz, CDCl 3 ), δ 10.02 (d, J = 7.6 Hz, 1H), 7.87 (s, 1H), 7.84 (d, J = 6.4 Hz, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.39 (s, 1H), 7.21 (m, 1H), 6.92 (t, J = 7.0 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H), 2.99 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.9, 149.3, 140.9, 136.2, 130.6, 128.8, 128.7, 128.6, 128.0, 124.7, 124.3, 122.5, 121.8, 121.3, 118.1, 117.7, 113.9, 112.8, 40.7; LRMS (ESI) m/z calcd for C 23 H 20 N 2 O [M+Na] + : 340.2, found: 341.2.

<GxF 66 ~ 70><GxF 66 ~ 70>

IN-E : 하기 반응식 15와 같이 합성하였으며, 구체적으로, 피리딘(483 μL, 6.00 mmol) 및 2-브로모-4-메톡시아세토페논(1.44 g, 6.30 mmol)이 포함된 DMF(10.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(320 μL, 3.00 mmol), 구리(II) 아세테이트 모노하이드레이트(1.79 g, 9.00 mmol) 및 소듐 아세테이트(1.47 g, 18.0 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IN-E(467 mg, 1.44 mmol, 48.2%수율)를 수득 하였다. IN-E : Synthesized as in Scheme 15 below, and specifically, DMF (10.0 mL) containing pyridine (483 μL, 6.00 mmol) and 2-bromo-4-methoxyacetophenone (1.44 g, 6.30 mmol) was prepared at 100° C. After stirring overnight at, ethyl acrylate (320 μL, 3.00 mmol), copper (II) acetate monohydrate (1.79 g, 9.00 mmol) and sodium acetate (1.47 g, 18.0 mmol) were added thereto at 100° C. for 16 hours. While stirring. After completion of the reaction, after monitoring by TLC, copper acetate was removed by filtration through a pad of Celite, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water and the organic material was extracted 3 times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (hexane 1-15% containing EtOAc) to obtain a yellow solid compound IN-E (467 mg, 1.44 mmol, 48.2% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.90(d, J = 6.8 Hz, 1H), 8.38(d, J = 8.8 Hz, 1H), 7.85(s, 1H), 7.83(d, J = 3.2 Hz, 2H), 7.42(q, J = 9.0 Hz, 1H), 6.97(t, J = 7.0 Hz, 1H), 7.01(d, J = 8.8 Hz, 2H), 4.38(q, J = 7.1 Hz, 2H), 3.90(s, 3H), 1.40(t, J = 7.0 Hz, 3H); 13C NMR(100 MHz, CDCl3) δ 183.6, 163.6, 162.2, 139.2, 132.1, 131.0, 128.7, 127.6, 127.0, 122.3, 121.6, 119.0, 114.7, 113.5, 105.7, 60.0, 55.4, 14.7; LRMS (ESI) m/z calcd for C19H17NO4 [M+Na]+ : 323.1, found : 324.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.90 (d, J = 6.8 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 7.85 (s, 1H), 7.83 (d, J = 3.2 Hz, 2H), 7.42 (q, J = 9.0 Hz, 1H), 6.97 (t, J = 7.0 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.6, 163.6, 162.2, 139.2, 132.1, 131.0, 128.7, 127.6, 127.0, 122.3, 121.6, 119.0, 114.7, 113.5, 105.7, 60.0, 55.4, 14.7; LRMS (ESI) m/z calcd for C 19 H 17 NO 4 [M+Na] + : 323.1, found: 324.2.

IN-B : IN-E(467 mg, 1.44 mmol)가 포함된 메탄올(10 mL)에 KOH(4.84 g, 86.4 mmol)를 첨가한 후, 실온에서 14시간 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 IN-A를 수득하였다. IN-B : After adding KOH (4.84 g, 86.4 mmol) to methanol (10 mL) containing IN-E (467 mg, 1.44 mmol), the mixture was stirred at room temperature for 14 hours. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water and dried in a drying oven to obtain a white solid compound IN-A.

수득한 화합물 IN-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IN-A이 포함된 DMF(5.0 mL)에 소듐 바이카보네이트(363 mg, 4.32 mmol)를 첨가하고 및 NBS(384 mg, 2.16 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - ethyl acetate 12%)로 정제하여 황색 고체의 화합물 IN-B(350 mg, 1.06 mmol, 73.6% 수율)를 수득 하였다.The obtained compound IN-A was used in the next step without further purification, sodium bicarbonate (363 mg, 4.32 mmol) was added to DMF (5.0 mL) containing IN-A, and NBS (384 mg, 2.16 mmol) ) Was added partially at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8-ethyl acetate 12%) to obtain a yellow solid compound IN-B (350 mg, 1.06 mmol, 73.6% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.83 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 1H), 7.34 (s, 1H), 7.18 (q, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.89 (t, J = 6.8 Hz, 1H), 3.84 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 184.0, 164.1, 162.2, 139.3, 132.0, 130.9, 128.7, 127.9, 127.1, 122.3, 119.1, 114.8, 113.4, 105.3, 55.4, 51.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.83 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 1H), 7.34 ( s, 1H), 7.18 (q, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.89 (t, J = 6.8 Hz, 1H), 3.84 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 184.0, 164.1, 162.2, 139.3, 132.0, 130.9, 128.7, 127.9, 127.1, 122.3, 119.1, 114.8, 113.4, 105.3, 55.4, 51.2.

[반응식 15][Scheme 15]

Figure pat00233
Figure pat00233

화합물 GxF 66 : Compound GxF 66 :

IN-B(50.2 mg, 0.15 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(115 mg, 0.60 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(64.4 mg, 0.60 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-66으로 표시되는 황색 고체의 화합물 GxF 66(48.2 mg, 0.12 mmol, 80.2% 수율)을 수득 하였다.In a solution containing IN-B (50.2 mg, 0.15 mmol) and a mixture of DMF and water 2: 1, 4-trifluorophenyl boronic acid (115 mg, 0.60 mmol), tetrakis (triphenyl phosphine) After adding palladium (231 mg, 20.0 mol%) and sodium carbonate (64.4 mg, 0.60 mmol), the mixture was stirred at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 66 (48.2 mg, 0.12 mmol, 80.2) represented by the following formula 1-66. % Yield) was obtained.

[화학식 1-66][Formula 1-66]

Figure pat00234
Figure pat00234

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.96 (d, J = 6.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 3H), 7.68 (s, 3H), 7.51 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 3H); 13C NMR(100 MHz, CDCl3) δ 183.8, 162.1, 138.4, 136.1, 132.8, 131.1, 129.0, 128.4, 128.1, 127.8, 126.9, 125.8(2), 125.6, 125.4, 125.1, 122.6, 117.2, 115.7, 115.6, 114.4, 113.6, 55.6; LRMS (ESI) m/z calcd for C23H16F3NO2 [M+Na]+ : 395.1, found : 396.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.96 (d, J = 6.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 3H), 7.68 (s, 3H), 7.51 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.8, 162.1, 138.4, 136.1, 132.8, 131.1, 129.0, 128.4, 128.1, 127.8, 126.9, 125.8(2), 125.6, 125.4, 125.1, 122.6, 117.2, 115.7, 115.6, 114.4, 113.6, 55.6; LRMS (ESI) m/z calcd for C 23 H 16 F 3 NO 2 [M+Na] + : 395.1, found: 396.1.

화합물 GxF 67 : Compound GxF 67 :

IN-B(21 mg, 0.06 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(42 mg, 0.25 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(27 mg, 0.25 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-67로 표시되는 황색 고체의 화합물 GxF 67(22.6 mg, 0.06 mmol, 97.1% 수율)을 수득 하였다.In a solution containing IN-B (21 mg, 0.06 mmol) and a mixture of DMF and water 2: 1, 4-acetylphenyl boronic acid (42 mg, 0.25 mmol), tetrakis (triphenyl phosphine) palladium ( 231 mg, 20.0 mol%) and sodium carbonate (27 mg, 0.25 mmol) were added, followed by stirring at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%) to obtain a yellow solid compound GxF 67 (22.6 mg, 0.06 mmol, 97.1) represented by the following formula 1-67. % Yield) was obtained.

[화학식 1-67][Formula 1-67]

Figure pat00235
Figure pat00235

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.96 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 9.2 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.54 (s, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 3.90 (s, 3H), 2.64 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 197.1, 183.4, 161.8, 139.4, 135.7, 134.4, 132.5, 130.7, 128.7, 127.1, 125.1, 124.7, 122.4, 177.0, 115.5, 114.0, 113.3, 55.3, 26.4; LRMS (ESI) m/z calcd for C24H19NO3 [M+Na]+ : 369.1, found :370.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.96 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 9.2 Hz, 2H), 7.86 ( d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.54 (s, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 3.90 (s, 3H), 2.64 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.1, 183.4, 161.8, 139.4, 135.7, 134.4, 132.5, 130.7, 128.7, 127.1, 125.1, 124.7, 122.4, 177.0, 115.5, 114.0, 113.3, 55.3, 26.4; LRMS (ESI) m/z calcd for C 24 H 19 NO 3 [M+Na] + : 369.1, found: 370.2.

화합물 GxF 68 : Compound GxF 68 :

IN-B(20.0 mg, 0.06 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(29.0 mg, 0.24 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(26.0 mg, 0.24 mmol)를 첨가한 후, 100℃에서 13시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-68로 표시되는 황색 고체의 화합물 GxF 68(21.8 mg, 0.06 mmol, 100% 수율)을 수득 하였다.In a solution containing IN-B (20.0 mg, 0.06 mmol) and a mixture of DMF and water 2: 1, phenyl boronic acid (29.0 mg, 0.24 mmol), tetrakis (triphenyl phosphine) palladium (231 mg, 20.0 mol%) and sodium carbonate (26.0 mg, 0.24 mmol) were added, followed by stirring at 100° C. for 13 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%), and a yellow solid compound GxF 68 (21.8 mg, 0.06 mmol, 100) represented by the following formula 1-68 % Yield) was obtained.

[화학식 1-68][Formula 1-68]

Figure pat00236
Figure pat00236

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.97 (d, J = 6.8 Hz, 1H), 7.87 (d, J = 6.4 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.49 (s, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.0 (d, J = 8.4 Hz, 2H), 6.92 (t, J = 6.9 Hz, 1H), 6.89 (t, J = 6.8 Hz, 1H), 3.89 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 183.5, 161.9, 136.0, 134.7, 133.2, 131.0, 128.8, 127.9, 126.4, 126.6, 124.9, 124.6, 123.9, 122.2, 118.6, 117.5, 117.3, 115.4, 114.0, 113.5, 102.3, 55.6; LRMS (ESI) m/z calcd for C22H17NO2 [M+Na]+ : 327.1, found :328.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.97 (d, J = 6.8 Hz, 1H), 7.87 (d, J = 6.4 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.49 ( s, 1 H), 7.44 ( d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.0 (d, J = 8.4 Hz , 2H), 6.92 (t, J = 6.9 Hz, 1H), 6.89 (t, J = 6.8 Hz, 1H), 3.89 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.5, 161.9, 136.0, 134.7, 133.2, 131.0, 128.8, 127.9, 126.4, 126.6, 124.9, 124.6, 123.9, 122.2, 118.6, 117.5, 117.3, 115.4, 114.0, 113.5 , 102.3, 55.6; LRMS (ESI) m/z calcd for C 22 H 17 NO 2 [M+Na] + : 327.1, found: 328.2.

화합물 GxF 69 : Compound GxF 69 :

IN-B(20.8 mg, 0.06 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(38.0 mg, 0.25 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(26.7 mg, 0.25 mmol)를 첨가한 후, 100℃에서 13시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-69로 표시되는 황색 고체의 화합물 GxF 69(22.6 mg, 0.06 mmol, 100% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (38.0 mg, 0.25 mmol), tetrakis (triphenyl phosphine) palladium in a solution containing IN-B (20.8 mg, 0.06 mmol) and a mixture of DMF and water 2: 1 (231 mg, 20.0 mol%) and sodium carbonate (26.7 mg, 0.25 mmol) were added, followed by stirring at 100° C. for 13 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to obtain a yellow solid compound GxF 69 (22.6 mg, 0.06 mmol, 100) represented by the following formula 1-69. % Yield) was obtained.

[화학식 1-69][Formula 1-69]

Figure pat00237
Figure pat00237

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.96 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.42 (s, 1H), 7.19 (m, J = 8.2 Hz, 1H), 6.99 (dd, J = 8.8 Hz, 4H), 6.93 (t, J = 6.8 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H); 13C NMR(100 MHz, CDCl3) δ 183.7, 162.1, 158.6, 136.2, 133.6, 131.3, 129.3, 129.1, 127.5, 124.9, 124.7, 122.4, 117.8, 117.4, 114.6, 114.2, 113.8, 55.9, 55.8; LRMS (ESI) m/z calcd for C23H19NO3 [M+Na]+ : 357.14, found : 358.1. 1 H NMR (400 MHz, CDCl 3 ), δ 9.96 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 7.6 Hz, 1H), 7.48 ( d, J = 8.8 Hz, 2H), 7.42 (s, 1H), 7.19 (m, J = 8.2 Hz, 1H), 6.99 (dd, J = 8.8 Hz, 4H), 6.93 (t, J = 6.8 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.7, 162.1, 158.6, 136.2, 133.6, 131.3, 129.3, 129.1, 127.5, 124.9, 124.7, 122.4, 117.8, 117.4, 114.6, 114.2, 113.8, 55.9, 55.8; LRMS (ESI) m/z calcd for C 23 H 19 NO 3 [M+Na] + : 357.14, found: 358.1.

화합물 GxF 70 : Compound GxF 70 :

IN-B(20.0 mg, 0.06 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(40.0 mg, 0.24 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(26.0 mg, 0.24 mmol)를 첨가한 후, 100℃에서 13시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-70으로 표시되는 황색 고체의 화합물 GxF 70(23.8 mg, 0.06 mmol, 100% 수율)을 수득 하였다.In a solution containing IN-B (20.0 mg, 0.06 mmol) and a mixture of DMF and water 2: 1, 4- (dimethylamino) phenyl boronic acid (40.0 mg, 0.24 mmol), tetrakis (triphenyl phosphine) Fin) palladium (231 mg, 20.0 mol%) and sodium carbonate (26.0 mg, 0.24 mmol) were added, followed by stirring at 100° C. for 13 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 70 (23.8 mg, 0.06 mmol, 100) represented by the following formula 1-70. % Yield) was obtained.

[화학식 1-70][Formula 1-70]

Figure pat00238
Figure pat00238

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.96 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.83 (s,1H), 7.44 (d, J = 6.8 Hz, 2H), 7.41 (s, 1H), 7.17 (dd, J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.90 (t, J = 6.9 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H), 2.99 (s, 6H); 13C NMR(100 MHz, CDCl3) δ 183.3, 161.8, 149.3, 136.0, 133.5, 131.1, 128.7(2), 124.4, 124.0, 122.9, 117.8, 113.8, 113.5, 113.0, 55.6, 40.9; LRMS (ESI) m/z calcd for C24H22N2O2 [M+Na]+ : 370.2, found : 371.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.96 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.83 (s,1H), 7.44 (d, J = 6.8 Hz, 2H), 7.41 (s, 1H), 7.17 (dd, J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.90 (t, J = 6.9 Hz, 1H), 6.83 ( d, J = 8.8 Hz, 2H), 3.89 (s, 3H), 2.99 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.3, 161.8, 149.3, 136.0, 133.5, 131.1, 128.7(2), 124.4, 124.0, 122.9, 117.8, 113.8, 113.5, 113.0, 55.6, 40.9; LRMS (ESI) m/z calcd for C 24 H 22 N 2 O 2 [M+Na] + : 370.2, found: 371.2.

<GxF 71 ~ 75><GxF 71 ~ 75>

IO-E : 하기 반응식 16과 같이 합성하였으며, 구체적으로, 피리딘(695 μL, 6.00 mmol) 및 2-브로모-4'-(다이에틸아미노)아세토페논(1.70 mL, 6.3 mmol)이 포함된 DMF(10.0 mL)을 100℃에서 하룻밤 동안 교반한 다음, 에틸아크릴레이트(320 μL, 3.00 mmol), 구리(II) 아세테이트 모노하이드레이트(1.79 g, 9.00 mmol) 및 소듐 아세테이트(1.47 g, 18.0 mmol)를 첨가하여 100℃에서 16시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 구리아세테이트를 셀라이트 패드를 통한 여과에 의해 제거하고, 생성된 여과액을 진공하에서 농축시켰다. 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EtOAc이 포함된 헥산 1 ~ 15%)로 정제하여 황색 고체의 화합물 IO-E(273 mg, 0.75 mmol, 25.0% 수율)를 수득 하였다. IO-E : Synthesized as in Scheme 16 below, specifically, DMF (10.0 mL) containing pyridine (695 μL, 6.00 mmol) and 2-bromo-4'- (diethylamino) acetophenone (1.70 mL, 6.3 mmol) ) Was stirred at 100° C. overnight, and then ethyl acrylate (320 μL, 3.00 mmol), copper (II) acetate monohydrate (1.79 g, 9.00 mmol) and sodium acetate (1.47 g, 18.0 mmol) were added to 100°C. Stirred at °C for 16 hours. After completion of the reaction, after monitoring by TLC, copper acetate was removed by filtration through a pad of Celite, and the resulting filtrate was concentrated under vacuum. The resulting crude product was washed with water and the organic material was extracted 3 times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (hexane 1-15% containing EtOAc) to obtain a yellow solid compound IO-E (273 mg, 0.75 mmol, 25.0% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.94 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.86 (s,2H), 7.34 (m, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 9.2 Hz, 2H), 4.41 (q, J = 7.2 Hz, 2H), 3.43 (q, J = 7.1 Hz, 4H), 1.43 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2 Hz, 6H).; 13C NMR(100 MHz, CDCl3) δ 186.8, 156.2, 136.0, 134.4, 129.4, 128.8, 127.8, 126.5, 124.8, 124.4, 124.1, 123.0, 122.1, 120.0, 118.5, 117.5, 117.4, 115.4, 114.3, 113.9, 102.5, 27.1, 27.9; LRMS (ESI) m/z calcd for C22H24N2O3 [M+Na]+ : 364.2, found : 365.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.94 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.86 ( s,2H), 7.34 (m, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 9.2 Hz, 2H), 4.41 (q, J = 7.2 Hz, 2H), 3.43 ( q, J = 7.1 Hz, 4H), 1.43 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2 Hz, 6H).; 13 C NMR (100 MHz, CDCl 3 ) δ 186.8, 156.2, 136.0, 134.4, 129.4, 128.8, 127.8, 126.5, 124.8, 124.4, 124.1, 123.0, 122.1, 120.0, 118.5, 117.5, 117.4, 115.4, 114.3, 113.9 , 102.5, 27.1, 27.9; LRMS (ESI) m/z calcd for C 22 H 24 N 2 O 3 [M+Na] + : 364.2, found: 365.2.

IO-B : IO-E(273 mg, 0.74 mmol)가 포함된 메탄올(10 mL)에 KOH(4.20 g, 74.9 mmol)를 첨가한 후, 실온에서 하룻밤 동안 교반하였다. 반응 혼합물에 6N HCl를 첨가하여 산성화시킨 다음, 생성된 고체를 여과를 통해 수득한 후, 물로 세척하고 건조오븐에서 건조시켜 흰색고체의 화합물 IO-A를 수득하였다. IO-B : KOH (4.20 g, 74.9 mmol) was added to methanol (10 mL) containing IO-E (273 mg, 0.74 mmol), followed by stirring at room temperature overnight. After acidification by adding 6N HCl to the reaction mixture, the resulting solid was obtained through filtration, washed with water and dried in a drying oven to obtain a white solid compound IO-A.

수득한 화합물 IO-A는 추가 정제없이 바로 다음 단계에 사용하였으며, IO-A이 포함된 DMF(5.0 mL)에 소듐 바이카보네이트(189 mg, 2.24 mmol)를 첨가하고 및 NBS(200 mg, 1.12 mmol)를 0℃에서 부분적으로 첨가하였다. 상기 반응 혼합물을 상온에서 12시간 동안 교반한 다음, 생성된 조생성물을 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:8 - ethyl acetate 12%)로 정제하여 황색 고체의 화합물 IO-B(187 mg, 0.50 mmol, 67.3% 수율)를 수득 하였다.The obtained compound IO-A was used in the next step without further purification, sodium bicarbonate (189 mg, 2.24 mmol) was added to DMF (5.0 mL) containing IO-A, and NBS (200 mg, 1.12 mmol) ) Was added partially at 0°C. After the reaction mixture was stirred at room temperature for 12 hours, the resulting crude product was washed with water and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:8-ethyl acetate 12%) to obtain a yellow solid compound IO-B (187 mg, 0.50 mmol, 67.3% yield).

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.88 (d, J = 7.2 Hz, 1H), 8.03 (s, 1H), 7.83(s, 1H), 7.69 (dd, J = 8.2 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.41 (s, 1H), 7.28 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 7.0 Hz, 1H), 3.25 (q, J = 6.9 Hz, 4H), 1.10 (t, J = 7.0 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 181.4, 152.2, 136.6, 135.2, 134.9, 128.6, 126.5, 125.1, 122.6, 122.0, 121.9, 120.5, 117.2, 114.6, 89.7, 46.6, 46.43, 12.8, 12.7. 1 H NMR (400 MHz, CDCl 3 ), δ 9.88 (d, J = 7.2 Hz, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 7.69 (dd, J = 8.2 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.41 (s, 1H), 7.28 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 7.0 Hz, 1H), 3.25 (q, J = 6.9 Hz, 4H), 1.10 (t, J = 7.0 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 181.4, 152.2, 136.6, 135.2, 134.9, 128.6, 126.5, 125.1, 122.6, 122.0, 121.9, 120.5, 117.2, 114.6, 89.7, 46.6, 46.43, 12.8, 12.7.

[반응식 16][Scheme 16]

Figure pat00239
Figure pat00239

화합물 GxF 71 : Compound GxF 71 :

IO-B(24 mg, 0.06 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-트리플로로페닐 보론산(49.0 mg, 0.25 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(27.0 mg, 0.25mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-71로 표시되는 황색 고체의 화합물 GxF 71(19.0 mg, 0.04 mmol, 72.5% 수율)을 수득 하였다.4-trifluorophenyl boronic acid (49.0 mg, 0.25 mmol), tetrakis (triphenyl phosphine) in a solution containing IO-B (24 mg, 0.06 mmol) and a mixture of DMF and water 2: 1 After adding palladium (231 mg, 20.0 mol%) and sodium carbonate (27.0 mg, 0.25 mmol), the mixture was stirred at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to form a yellow solid compound GxF 71 (19.0 mg, 0.04 mmol, 72.5) represented by the following formula 1-71. % Yield) was obtained.

[화학식 1-71][Formula 1-71]

Figure pat00240
Figure pat00240

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.97 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.70 (m, 6H), 7.58 (s, 1H), 7.26 (m, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.98 (m, 1H), 2.99 (q, J = 7.0 Hz, 4H), 0.98 (t, J = 7.2 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 183.9, 152.2, 136.3, 134.0, 133.7, 133.1, 130.1, 129.3(2), 129.2, 128.2(2), 126.1(2), 125.7,125.6(2), 123.0, 120.3, 117.5, 115.9, 114.6, 46.2, 30.2, 12.5; LRMS (ESI) m/z calcd for C26H23F3N2O [M+Na]+ : 436.2, found : 437.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.97 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.70 ( m, 6H), 7.58 (s, 1H), 7.26 (m, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.98 (m, 1H), 2.99 (q, J = 7.0 Hz, 4H), 0.98 (t, J = 7.2 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.9, 152.2, 136.3, 134.0, 133.7, 133.1, 130.1, 129.3(2), 129.2, 128.2(2), 126.1(2), 125.7,125.6(2), 123.0 , 120.3, 117.5, 115.9, 114.6, 46.2, 30.2, 12.5; LRMS (ESI) m/z calcd for C 26 H 23 F 3 N 2 O [M+Na] + : 436.2, found: 437.2.

화합물 GxF 72 : Compound GxF 72 :

IO-B(30.0 mg, 0.08 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-아세틸페닐 보론산(53.0 mg, 0.32 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(34.0 mg, 0.32 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:5 - ethyl acetate 40%)로 정제하여 하기 화학식 1-72로 표시되는 황색 고체의 화합물 GxF 72(18.9 mg, 0.04 mmol, 57.5% 수율)을 수득 하였다.In a solution containing IO-B (30.0 mg, 0.08 mmol) and a mixture of DMF and water 2: 1, 4-acetylphenyl boronic acid (53.0 mg, 0.32 mmol), tetrakis (triphenyl phosphine) palladium ( 231 mg, 20.0 mol%) and sodium carbonate (34.0 mg, 0.32 mmol) were added, followed by stirring at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:5-ethyl acetate 40%), and a yellow solid compound GxF 72 (18.9 mg, 0.04 mmol, 57.5) represented by the following formula 1-72 % Yield) was obtained.

[화학식 1-72][Formula 1-72]

Figure pat00241
Figure pat00241

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.95 (d, J = 6.8 Hz, 1H), 8.05 (d, J = 7.2 Hz, 3H), 7.90 (s, 1H), 7.71 (d, J = 8.4 Hz, 3H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.30 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.00 (m, 1H), 3.27 (q, J = 7.0 Hz, 4H), 2.65 (s, 3H), 1.13 (t, J = 7.0 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 197.1, 182.1, 150.4, 143.9, 139.3, 136.1, 135.9, 134.5, 134.1, 131.5, 128.7, 128.6, 128.4, 127.7, 127.1, 125.3, 124.6, 122.1, 121.4, 117.1, 115.7, 114.1, 45.8, 29.6, 26.6, 12.3; LRMS (ESI) m/z calcd for C27H26N2O2 [M+Na]+ : 410.2, found :411.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.95 (d, J = 6.8 Hz, 1H), 8.05 (d, J = 7.2 Hz, 3H), 7.90 (s, 1H), 7.71 (d, J = 8.4 Hz, 3H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.30 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.00 (m, 1H), 3.27 (q, J = 7.0 Hz, 4H), 2.65 (s, 3H), 1.13 (t, J = 7.0 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.1, 182.1, 150.4, 143.9, 139.3, 136.1, 135.9, 134.5, 134.1, 131.5, 128.7, 128.6, 128.4, 127.7, 127.1, 125.3, 124.6, 122.1, 121.4, 117.1 , 115.7, 114.1, 45.8, 29.6, 26.6, 12.3; LRMS (ESI) m/z calcd for C 27 H 26 N 2 O 2 [M+Na] + : 410.2, found: 411.2.

화합물 GxF 73 : Compound GxF 73 :

IO-B(30.0 mg, 0.08 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 페닐 보론산(39.4 mg, 0.32 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(34.0 mg, 0.32 mmol)를 첨가한 후, 100℃에서 13시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-73으로 표시되는 황색 고체의 화합물 GxF 73(22.2 mg, 0.06 mmol, 75.3% 수율)을 수득 하였다.Phenyl boronic acid (39.4 mg, 0.32 mmol), tetrakis (triphenyl phosphine) palladium (231 mg, in a solution containing IO-B (30.0 mg, 0.08 mmol) and a mixture of DMF and water 2: 1) 20.0 mol%) and sodium carbonate (34.0 mg, 0.32 mmol) were added, followed by stirring at 100° C. for 13 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%), and the yellow solid compound GxF 73 (22.2 mg, 0.06 mmol, 75.3) represented by the following formula 1-73 % Yield) was obtained.

[화학식 1-73][Chemical Formula 1-73]

Figure pat00242
Figure pat00242

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.98 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.59 (m, 3H), 7.46 (m, 2H), 7.38 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.20 (m, 1H), 7.12 (dd, J = 8.2 Hz, 1H), 6.94 (d, J = 7.0 Hz, 1H), 3.01 (q, J = 4.4 Hz, 4H), 0.97 (t, J = 7.0 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 183.5, 151.4, 141.1, 135.6, 134.6, 133.0, 132.7, 128.8, 128.5, 128.3, 128.0, 127.6, 126.4, 126.1, 124.5, 124.1, 122.1, 121.1, 119.3, 117.2, 116.8, 113.6, 45.9, 45.5, 12.0; LRMS (ESI) m/z calcd for C25H24N2O [M+Na]+ : 368.2, found : 369.2. 1 H NMR (400 MHz, CDCl 3 ), δ 9.98 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.59 ( m, 3H), 7.46 (m, 2H), 7.38 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.20 (m, 1H), 7.12 (dd, J = 8.2 Hz, 1H), 6.94 (d, J = 7.0 Hz, 1H), 3.01 (q, J = 4.4 Hz, 4H), 0.97 (t, J = 7.0 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.5, 151.4, 141.1, 135.6, 134.6, 133.0, 132.7, 128.8, 128.5, 128.3, 128.0, 127.6, 126.4, 126.1, 124.5, 124.1, 122.1, 121.1, 119.3, 117.2 , 116.8, 113.6, 45.9, 45.5, 12.0; LRMS (ESI) m/z calcd for C 25 H 24 N 2 O [M+Na] + : 368.2, found: 369.2.

화합물 GxF 74 : Compound GxF 74 :

IO-B(39.5 mg, 0.10 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-메톡시페닐 보론산(65.0 mg, 0.42 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(45.0 mg, 0.42 mmol)를 첨가한 후, 100℃에서 13시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-74로 표시되는 황색 고체의 화합물 GxF 74(42.5 mg, 0.10 mmol, 100% 수율)을 수득 하였다.4-methoxyphenyl boronic acid (65.0 mg, 0.42 mmol), tetrakis (triphenyl phosphine) palladium in a solution containing IO-B (39.5 mg, 0.10 mmol) and a mixture of DMF and water 2: 1 (231 mg, 20.0 mol%) and sodium carbonate (45.0 mg, 0.42 mmol) were added, followed by stirring at 100° C. for 13 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%) to obtain a yellow solid compound GxF 74 (42.5 mg, 0.10 mmol, 100) represented by the following formula 1-74. % Yield) was obtained.

[화학식 1-74][Formula 1-74]

Figure pat00243
Figure pat00243

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.95 (d, J = 6.8 Hz, 1H), 7.89 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.44 (s, 1H), 7.22 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 6.8 Hz, 2H), 6.96 (t, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.26 (q, J = 7.1 Hz, 4H), 0.96 (t, J = 7.2 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 182.2, 158.4, 150.4, 136.3, 135.0, 131.8, 129.7, 129.1, 128.9, 128.0, 127.1, 124.7, 124.6, 121.8(2), 117.6, 117.4, 114.4, 114.1, 113.7, 55.5, 46.7, 45.7, 29.9, 12.6; LRMS (ESI) m/z calcd for C26H26N2O2 [M+Na]+ : 398.2, found : 399.4. 1 H NMR (400 MHz, CDCl 3 ), δ 9.95 (d, J = 6.8 Hz, 1H), 7.89 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.44 (s, 1H), 7.22 (m, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 6.8 Hz, 2H), 6.96 (t, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.26 (q, J = 7.1 Hz, 4H), 0.96 (t, J = 7.2 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 182.2, 158.4, 150.4, 136.3, 135.0, 131.8, 129.7, 129.1, 128.9, 128.0, 127.1, 124.7, 124.6, 121.8(2), 117.6, 117.4, 114.4, 114.1, 113.7, 55.5, 46.7, 45.7, 29.9, 12.6; LRMS (ESI) m/z calcd for C 26 H 26 N 2 O 2 [M+Na] + : 398.2, found: 399.4.

화합물 GxF 75 : Compound GxF 75 :

IO-B(73.0 mg, 0.16 mmol)를 포함하고 DMF 및 물이 2 : 1로 혼합되어 있는 용액에 4-(다이메틸아미노)페닐 보론산(109 mg, 0.66 mmol), 테트라키스(트리페닐 포스핀)팔라듐(231 mg, 20.0 mol%) 및 소듐 카보네이트(70.0 mg, 0.66 mmol)를 첨가한 후, 100℃에서 12시간 동안 교반하였다. 반응 완료 후, TLC로 모니터링한 다음, 물로 세척하고 유기물질을 DCM으로 3회 추출하였다. 추출한 유기물질을 합한 다음, 무수 Na2SO4 상에서 건조시킨 후 농축시켰다. 농축된 유기상을 실리카-겔 플래쉬 컬럼 크로마토그래피(EA : Hexane = 1:4 - ethyl acetate 25%)로 정제하여 하기 화학식 1-75로 표시되는 황색 고체의 화합물 GxF 75(257.8 mg, 0.14 mmol, 84.6% 수율)을 수득 하였다.In a solution containing IO-B (73.0 mg, 0.16 mmol) and a mixture of DMF and water 2: 1, 4-(dimethylamino) phenyl boronic acid (109 mg, 0.66 mmol), tetrakis (triphenyl phosphine) Fin) palladium (231 mg, 20.0 mol%) and sodium carbonate (70.0 mg, 0.66 mmol) were added, followed by stirring at 100° C. for 12 hours. After completion of the reaction, it was monitored by TLC, washed with water, and the organic material was extracted three times with DCM. The extracted organic materials were combined, dried over anhydrous Na 2 SO 4 and concentrated. The concentrated organic phase was purified by silica-gel flash column chromatography (EA: Hexane = 1:4-ethyl acetate 25%), and a yellow solid compound GxF 75 (257.8 mg, 0.14 mmol, 84.6) represented by the following formula 1-75 % Yield) was obtained.

[화학식 1-75][Formula 1-75]

Figure pat00244
Figure pat00244

NMR 분석결과는 하기와 같다.The NMR analysis results are as follows.

1H NMR(400 MHz, CDCl3), δ 9.95 (d, J = 6.8 Hz, 1H), 7.89 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 8.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.43 (s, 1H), 7.20 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 6.8 Hz, 1H), 6.84 (d, J = 6.8 Hz, 2H), 3.26 (q, J = 7.1 Hz, 4H), 3.00 (s, 6H), 1.12 (t, J = 7.0 Hz, 6H); 13C NMR(100 MHz, CDCl3) δ 197.5, 197.2, 183.5, 151.8, 146.4, 139.7, 135.9, 135.4, 134.7, 133.6, 133.1, 132.7, 129.7, 129.0, 128.9, 128.7, 128.5, 127.4, 125.3, 124.7, 122.7, 119.8, 117.3, 115.7, 114.2, 45.8, 26.8, 12.2; LRMS (ESI) m/z calcd for C27H29N3O [M+Na]+ : 411.2, found : 412.3. 1 H NMR (400 MHz, CDCl 3 ), δ 9.95 (d, J = 6.8 Hz, 1H), 7.89 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 8.4 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.43 (s, 1H), 7.20 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.94 (t, J = 6.8 Hz, 1H), 6.84 (d, J = 6.8 Hz, 2H), 3.26 (q, J = 7.1 Hz, 4H), 3.00 (s, 6H), 1.12 ( t, J = 7.0 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.5, 197.2, 183.5, 151.8, 146.4, 139.7, 135.9, 135.4, 134.7, 133.6, 133.1, 132.7, 129.7, 129.0, 128.9, 128.7, 128.5, 127.4, 125.3, 124.7 , 122.7, 119.8, 117.3, 115.7, 114.2, 45.8, 26.8, 12.2; LRMS (ESI) m/z calcd for C 27 H 29 N 3 O [M+Na] + : 411.2, found: 412.3.

75종의 GxF 물질들의 광물리학적 특성 확인Confirmation of photophysical properties of 75 kinds of GxF materials

본 발명에서는 상기 실시예 1에서 합성한 75종의 GxF 물질들에 대한 광물리학적 특성을 관찰하였다. In the present invention, 75 kinds of synthesized in Example 1 The photophysical properties of the GxF materials were observed.

최종 형광 화합물의 UV 흡수는 UV-VISIBLE 스펙트로포토미터(JASCO V-670, JASCO, INC. 일본)를 이용하여 측정하였으며, 여기 형광 발광파장은 JASCO 형광 스펙트로포토미터(JASCO FP-8200, JASCO, INC. 일본)를 이용하여 측정하였다. 양자 수득률(absolute quantum yield)은 Absolute PL 양자 수득률 측정 시스템(QE-2000, Otsuka Electronics, Japan)에 의해 측정하였다.UV absorption of the final fluorescent compound was measured using a UV-VISIBLE spectrophotometer (JASCO V-670, JASCO, INC. Japan), and the excitation fluorescent emission wavelength is a JASCO fluorescence spectrophotometer (JASCO FP-8200, JASCO, INC. Japan). Quantum yield (absolute quantum yield) was measured by the Absolute PL quantum yield measurement system (QE-2000, Otsuka Electronics, Japan).

Figure pat00245
Figure pat00245

Figure pat00246
Figure pat00246

(T: Trifluoromethyl, A: Acetyl, H: Hydrogen, TP:4-trifluoromethylphenyl, C: Methyl, MP: 4-methoxyphenyl, DEP: 4-Diethylaminophenyl, M: Methoxy, DM: dimethylamino, L: solution state, S: solid state, λA: Absorption maxima, λE: Emission maxima, ε: extinction coefficient (x104) in solution state, Φ: quantum yield (%) in solution state, H: HOMO energy level (ev), L: LUMO energy level (ev), gap: energy gap between LUMO 및 HOMO (ev))(T: Trifluoromethyl, A: Acetyl, H: Hydrogen, T P :4-trifluoromethylphenyl, C: Methyl, M P : 4-methoxyphenyl, DE P : 4-Diethylaminophenyl, M: Methoxy, DM: dimethylamino, L: solution state , S: solid state, λ A : Absorption maxima, λ E : Emission maxima, ε: extinction coefficient (x10 4 ) in solution state, Φ: quantum yield (%) in solution state, H: HOMO energy level (ev), L: LUMO energy level (ev), gap: energy gap between LUMO and HOMO ( ev))

상기 표 1에 나타난 바와 같이, GxF 물질들은 발광파장이 416 nm에서 620 nm에 이르는 전 가시광선 영역을 아우르는 것을 확인하였고, 특히 도 7에 나타난 바와 같이 고체상 형광현상을 (solid state fluorescence) 나타낼 수 있다는 것을 확인하였다.As shown in Table 1, it was confirmed that the GxF materials cover the entire visible light range from 416 nm to 620 nm, and in particular, as shown in FIG. 7, the GxF materials can exhibit solid state fluorescence. Confirmed.

도 8에 나타난 바와 같이, GxF 63 물질의 경우 용액상에서 용매의 유전율 (dielectric constant)변화에 따라 형광 밝기에 영향을 받는다는 것을 확인하였다.As shown in FIG. 8, in the case of the GxF 63 material, it was confirmed that the fluorescence brightness was affected by the change in the dielectric constant of the solvent in the solution.

또한, GxF 물질이 고체상태 형광을 나타내는지를 확인한 결과, 도 9에 나타난 바와 같이, 4가지의 서로 다른 GxF 물질들(GxF 1, GxF 3, GxF 5, GxF 11)이 고체상태에서도 전 가시 광선영역을 아우르는 발광 파장을 지니고 있음을 확인하였다.In addition, as a result of confirming whether the GxF material exhibits solid state fluorescence, as shown in FIG. 9, four different GxF materials (GxF 1, GxF 3, GxF 5, GxF 11) are in the entire visible light region even in the solid state. It was confirmed that it has an emission wavelength that encompasses.

서로 다른 VOC 노출에 따른 GxF 물질의 고체상에서 형광 변화 관찰Observation of fluorescence changes in the solid phase of GxF substances according to different VOC exposures

본 발명에서는 GxF 물질들이 VOC에 감응하여 고체상태에서 형광 변화가 일어나는지 확인하기 위해, GxF 15, GxF 40, GxF 65 물질을 필름으로 유리 위에 도포한 다음, 3가지 서로 다른 VOC 증기(ethyl acetate, acetic acid, ethylamine)를 노출시켜 형광 변화를 관찰하였다. In the present invention, in order to check whether the fluorescence change occurs in the solid state in response to the GxF substances in response to VOC, substances GxF 15, GxF 40, and GxF 65 are applied as a film on the glass, and then three different VOC vapors (ethyl acetate, acetic acid) are applied. acid, ethylamine) was exposed to observe the change in fluorescence.

구체적으로, 각 물질들은 20 mg/mL의 농도로 클로로포름(CHCl3)에 녹인 다음, 슬라이드 글라스를 증류수(Deionized water), 아세톤, 그리고 이소프로판올에 10분 동안 초음파발생장치로 씻겨준 뒤, 20분 가량 UV에 노출시켜 소독한다. 모액을 슬라이드 글라스에 1분동안 1500 rpm으로 스핀코팅을 하여 도포된 필름을 수득한 다음, 3가지 서로 다른 VOC 증기(Ethyl acetate, acetic acid, ethylamine)를 유리 용기 안에 각 5 mL씩 넣고 포화가 되도록 밀폐하고, 유리 용기 뚜껑 내부에 도포된 필름을 부착시키고 1분 동안 VOC 증기가 포화된 유리 용기에 노출시켰다. 1분의 노출 시간이 지난뒤, 각 필름은 JASCO V-670 분광광도계와 JASCO FP-8200 분광형광계로 흡광과 발광 스펙트럼 데이터를 수득하였다. Specifically, each substance is dissolved in chloroform (CHCl 3 ) at a concentration of 20 mg/mL, and then the slide glass is washed in deionized water, acetone, and isopropanol for 10 minutes with an ultrasonic generator, and then for about 20 minutes. Disinfect by exposure to UV. The mother liquor was spin-coated on a slide glass at 1500 rpm for 1 minute to obtain a coated film, and then 3 different VOC vapors (Ethyl acetate, acetic acid, ethylamine) were added to each of 5 mL in a glass container and saturated It was sealed and the applied film was attached to the inside of the glass container lid and exposed to a glass container saturated with VOC vapor for 1 minute. After 1 minute of exposure time, each film was subjected to absorption and emission spectrum data using a JASCO V-670 spectrophotometer and a JASCO FP-8200 spectrofluorimeter.

그 결과, 도 10에 나타난 바와 같이, 세 가지 물질이 세 가지의 서로 다른 VOC에 노출되어 제각각의 형광 현상의 변화가 유도 될 수 있음을 확인하였다.As a result, as shown in FIG. 10, it was confirmed that the three substances were exposed to three different VOCs to induce changes in the fluorescence phenomena of each.

휘발성 유기 화합물 검출을 위한 형광 센서 어레이 제작Fluorescence sensor array fabrication for volatile organic compound detection

본 발명에서는 화학식 2 내지 화학식 76으로 표시되는 화합물이 패턴화 되어 고정되어 있는 센서 어레이를 제작하였다. In the present invention, a sensor array in which the compounds represented by Chemical Formulas 2 to 76 are patterned and fixed was fabricated.

형광 물질들의 균일한 도포를 위하여 필터 페이퍼 상에 왁스 프린팅을 활용하여 어레이 틀을 제작하였으며, 한컴오피스 한글 2010 프로그램을 이용하여 어레이 틀을 디자인한 뒤, HYUNDAI MICRO 정성 여과지(No. 22)위에 xerox ColorQube 8870을 이용하여 왁스로 프린트를 수행하였다. 어레이 틀로 왁스 코팅된 정성 여과지를 약 150℃온도에서 5분동안 열을 가해주었다. 열을 가하기 전의 선 굵기는 0.7 mm이며 열을 가한 후의 선 굵기는 열에 의해 wax가 녹아 1.0 mm가 된다. 그 다음, 제작된 어레이 틀을 1시간 동안 충분히 식혀준 뒤, 10 mM의 DMSO(Dimethyl Sulfoxide) 용매로 제작된 75개의 GxF 물질의 저장액(stock solution)을 왁스로 코팅한 어레이에 스팟팅(spotting) 한 후, GxF 물질들이 도포된 어레이를 드라이오븐에서 10분동안 말려준다.For uniform application of fluorescent materials, an array frame was manufactured using wax printing on filter paper. After designing the array frame using Hancom Office Hangul 2010 program, xerox ColorQube on HYUNDAI MICRO Qualitative Filter Paper (No. 22) The print was done with wax using 8870. The wax-coated qualitative filter paper as an array frame was heated for 5 minutes at a temperature of about 150°C. The line thickness before heating is 0.7 mm, and the line thickness after heating is 1.0 mm as the wax melts by heat. Then, after cooling the prepared array frame sufficiently for 1 hour, spotting on the array coated with a wax stock solution of 75 GxF materials made with 10 mM DMSO (Dimethyl Sulfoxide) solvent. ) After that, dry the array coated with the GxF materials in a dry oven for 10 minutes.

도 11과 같이, 2.5 cm X 2.5 cm 크기의 형광센서 어레이당 25 가지의 신규 형광체가 들어간 센서 어레이를 제조하였으며, 형광 물질의 발광정도를 UV 상에서 관찰하였다. As shown in FIG. 11, a sensor array containing 25 new phosphors per fluorescent sensor array having a size of 2.5 cm X 2.5 cm was prepared, and the degree of luminescence of the fluorescent material was observed under UV.

VOC 노출에 따른 형광 패턴 변화 관찰Observation of changes in fluorescence pattern according to VOC exposure

본 발명에서 형광 센서 어레이가 VOC와 반응하여 특정 형광 패턴을 형성 할 수 있는지 여부를 확인하기 위하여 75종의 GxF 물질이 각각 25종씩 도포된 3가지의 형광 센서 어레이를 도 12과 같은 밀폐된 용기 안에 도입하여 VOC에 노출 시켰다. 본 발명에서는 이를 위해 3D 프린팅 기술을 활용하여 자외선 광원의 위치와 스마트폰 카메라의 위치를 조절하여 이상적인 빛 구도를 구현할 수 있는 시스템을 고안하였으며, 이를 도 13에 나타내었다. In the present invention, in order to check whether the fluorescent sensor array can react with VOC to form a specific fluorescent pattern, three fluorescent sensor arrays, each of which 25 kinds of 75 kinds of GxF materials are applied, are placed in a sealed container as shown in FIG. 12. Introduced and exposed to VOC. In the present invention, for this purpose, a system capable of implementing an ideal light composition by adjusting the position of the ultraviolet light source and the position of the smartphone camera using 3D printing technology was devised, and is shown in FIG. 13.

구체적으로, 어레이의 색변화 분석을 위하여 스마트폰 카메라로 VOC 노출 전 형광 센서 어레이와 VOC 노출 후 형광 센서 어레이를 촬영한 다음, 두 사진에서 노출 전 형광 센서 내의 75개 형광체의 색과 노출 후 형광 센서 내의 75개 형광체의 색을 추출한 후 해당 색을 RGB, HSV, CIELAB의 색공간으로 나타내었다. 두 색의 차이를 구하기 위해 각 색 공간의 특징에 따른 방법을 사용하였으며, RGB 색공간의 경우, RGB Euclidean distance(도 14의 (3)번 식)를 사용하고, HSV 색공간의 경우 Hue difference(도 14의 (4)번 식)를 사용하였으며, CIELAB 색공간에서는 CIEDE2000(색 차이를 계산하는 산업표준)을 사용하였다. Specifically, in order to analyze the color change of the array, the fluorescence sensor array before VOC exposure and the fluorescence sensor array after VOC exposure are photographed with a smartphone camera, and then the colors of 75 phosphors in the fluorescence sensor before exposure and the fluorescence sensor after exposure in the two pictures. After extracting the colors of 75 phosphors, the colors were expressed in RGB, HSV, and CIELAB color spaces. In order to find the difference between the two colors, a method according to the characteristics of each color space was used, in the case of the RGB color space, the RGB Euclidean distance (expression (3) in Fig. 14) was used, and in the case of the HSV color space, the Hue difference ( Figure 14 (4)) was used, and CIEDE2000 (an industry standard for calculating color differences) was used in the CIELAB color space.

이를 통해 얻어진 형광 센서 어레이의 색변화 정보를 자동으로 분석할 수 있는 머신 러닝 알고리즘을 개발하여 도 14에 나타난 방법과 같이, RGB, HSV, CIELAB의 색공간안에서의 변화 정보를 분석하였다. A machine learning algorithm capable of automatically analyzing the color change information of the fluorescence sensor array obtained through this was developed, and change information in the color space of RGB, HSV, and CIELAB was analyzed as shown in FIG. 14.

35여개의 휘발성 유기화합인 에탄올(Ethanol), 1-부탄올(1-Butanol), 1-(펜탄올(1-Pentanol), 1-헥산올(1-Hexanol), 3-헥산올(3-Hexanol), 페놀(Phenol), 1-헵탄올(1-Heptanol), 1-데칸올(1-Decanol), 2-데칸올(2-Decanol), 3-데칸올(3-Decanol), 1-도데칸올(1-Dodecanol), 사이클로펜탄올(Cyclopentanol), 사이클로헥산올(Cyclohexanol), 사이클로헵탄올(Cycloheptanol), 벤젠(Benzene), 아세톤(Acetone), 2-옥탄온(2-Octanone), 2-피콜린(2-Picoline), 3-피콜린(3-Picoline), 3-아세틸피리딘(3-Acetylpyridine), 4-아세틸피리딘(4-Acetylpyridine), 2-헵틸아민(2-Heptylamine), 디-엔-프로필아민(Di-n-propylamine), 2-페닐에틸아민(2-Phenylethylamine), 사이클로옥틸아민(Cyclooctylaime), 프로피온산(Propionic acid), 3-브롬프로피온산(3-Bromopropionic acid), 2-메틸부티르산(2-Methylbutyric acid), 포름산(Formic acid), 발레르산(Valeric acid), 트리플루오로 아세트산(Trifluoroacetic acid), 브로모아세트산(Bromoacetic acid), 아세트산(Acetic acid), 트리클로로아세트산(Trichloroacetic acid) 및 2-클로로프로피온산(2-Chloropropionic acid)을 상기 실시예 5에서 제조한 센서 어레이에 5반복 노출시킨 다음, 형광 센서들의 각 변화를 모니터링 한 결과, 도 16에 나타난 바와 같이, 인돌리진 기반 형광 센서 어레이가 35가지의 VOC에 반응하여 제각각의 변화 패턴을 보여준다는 것을 확인하였다. Ethanol, 1-Butanol, 1-(Pentanol), 1-Hexanol, 3-Hexanol, and 35 volatile organic compounds ), Phenol, 1-Heptanol, 1-Decanol, 2-Decanol, 3-Decanol, 1-Dode Canol (1-Dodecanol), Cyclopentanol, Cyclohexanol, Cycloheptanol, Benzene, Acetone, 2-Octanone, 2- Picoline (2-Picoline), 3-Picoline (3-Picoline), 3-acetylpyridine (3-Acetylpyridine), 4-acetylpyridine (4-Acetylpyridine), 2-heptylamine (2-Heptylamine), di- Di-n-propylamine, 2-Phenylethylamine, Cyclooctylamine, Propionic acid, 3-Bromopropionic acid, 2-methyl 2-Methylbutyric acid, Formic acid, Valeric acid, Trifluoroacetic acid, Bromoacetic acid, Acetic acid, Trichloroacetic acid ) And 2-Chloropropionic acid were exposed to the sensor array prepared in Example 5 five times, and then, as a result of monitoring each change of the fluorescent sensors, as shown in FIG. 16, indolizine-based fluorescence It was confirmed that the sensor array showed different patterns of change in response to 35 types of VOCs.

상기 VOC 노출에 따른 형광 물질들의 패턴 변화를 확인하기 위해 주성분 분석법 (Principa Component A nalysis)을 수행하였다. 주성분 분석법을 통해 75개 형광 물질 색 변화 패턴 중 가장 전체 데이터를 대표할 수 있는 의미있는 2개의 주성분을 추출하였다. 도 17은 2개의 주성분을 2차원 평면에 나타낸 그래프이다. 노출 전/후의 Hue value (색 정보값)을 이용한 PCA의 결과, 각각의 VOC들이 그래프 상에서 시각적으로 구분될 수 있음을 확인하였으며, 카복실산(Carboxylic acid, 58.1%), 알콜(Alcohol, 57.6%), 지방족 아민(Aliphatic amine, 61.9%) 및 방향족 아민(Aromatic amine, 53.4%)으로 판별이 되는 것을 확인하였다 (도 17). In order to confirm the pattern change of the fluorescent substances according to the VOC exposure, a principal component analysis method (Principa Component Analysis) was performed. Through the principal component analysis method, two significant principal components, which can represent the most complete data, were extracted out of 75 patterns of color change of fluorescent substances. 17 is a graph showing two main components on a two-dimensional plane. As a result of PCA using Hue value (color information value) before/after exposure, it was confirmed that each VOC can be visually distinguished on the graph, carboxylic acid (Carboxylic acid, 58.1%), alcohol (Alcohol, 57.6%), It was confirmed that it was identified as an aliphatic amine (Aliphatic amine, 61.9%) and an aromatic amine (Aromatic amine, 53.4%) (FIG. 17).

머신 러닝 분석을 통한 VOC 판별VOC determination through machine learning analysis

본 발명에서는 상기 결과를 토대로 인공지능을 활용하여 VOC 종류를 더 구분 지어줄 수 있는지 확인하기 위해 형광 센서 어레이의 패턴 변화 정보 중에서 RGB, Hue value, CIEDE2000(색의 밝기와 색의 차이값)를 머신 러닝 알고리즘(machine learning algorithm)에 학습시켜 VOC 판별 정도를 확인하였다. In the present invention, based on the above results, RGB, Hue value, and CIEDE2000 (difference between color brightness and color) are machined from among pattern change information of a fluorescent sensor array in order to check whether the VOC type can be further distinguished using artificial intelligence. The degree of VOC discrimination was confirmed by learning with a machine learning algorithm.

5가지의 대표 VOC 물질에 대해(Acetic acid, Acetone, Ethylendiamine, Phenol, Toluene) 100반복 실험을 진행하였고 각 VOC 물질 당 100개의 데이터 샘플을 무작위로 학습데이터와 검사데이터로 7:3의 비율로 나누었다. 각 데이터 샘플은 75개의 형광 물질 색 변화 패턴으로 이루어져 있다. 그 결과를 이용하여 통계학적 분류법인 K-Means 및 Random forest 같은 머신러닝 알고리즘을 활용하여 학습데이터로부터 75개 형광 물질 색 변화 패턴을 학습시켰다. 이 때, RGB distance, Hue difference, CIEDE2000 등 3가지의 서로 다른 색변화 특징으로 학습시켜 각 알고리즘 당 3개의 VOC 분류 모델을 만들었다. For the five representative VOC substances (Acetic acid, Acetone, Ethylendiamine, Phenol, Toluene), 100 repeated experiments were conducted, and 100 data samples for each VOC substance were randomly divided into training data and test data in a ratio of 7:3. . Each data sample consists of 75 fluorophore color change patterns. Using the results, 75 color change patterns of fluorescent substances were learned from the training data using machine learning algorithms such as K-Means and Random forest, which are statistical classification methods. At this time, three VOC classification models were created for each algorithm by learning with three different color change features such as RGB distance, Hue difference, and CIEDE2000.

그 결과 도 18에 나타난 바와 같이, 학습된 알고리즘이 검사 데이터를 97%의 높은 정확도로 형광 센서 이미지 패턴 변화 분석을 통해 VOC를 정확히 예측해 낼 수 있음을 확인 하였다. 또한 3가지의 색 변화 특징 중 RGB distance와 CIEDE2000 정보가 가장 좋은 성능을 보였다.As a result, as shown in FIG. 18, it was confirmed that the learned algorithm can accurately predict the VOC through analysis of the change in the fluorescence sensor image pattern with a high accuracy of 97% of the inspection data. Also, among the three color change features, RGB distance and CIEDE2000 information showed the best performance.

Claims (10)

하기 화학식 1로 표시되는 형광 화합물:
[화학식 1]
Figure pat00247

상기 화학식1 에서
R1는 수소; 니트릴기; 할로겐; 니트로기; C1-C6의 알콕시기; C6-C20의 아릴기; C5-C20의 시클로헤테로고리기; 보론기; 아자이드기; NR4R5(여기에서, R4 및 R5는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임), 니트릴, C1-C6의 알콕시, 할로겐, 보론기, 하이드록시기 또는 CH2NR4R5 (여기에서, R4 및 R5는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임)로 치환된 C6-C20의 아릴기; C1-C8의 직쇄 또는 측쇄 알킬기; C2-C8의 알케닐기; C2-C8의 알키닐기; C3-C8의 시클로알킬기; 또는 C4-C20의 헤테로아릴기이고,
R2는 수소; C1-C8의 직쇄 또는 측쇄 알킬기; C2-C8의 알케닐기; C2-C8의 알키닐기; C3-C8의 시클로알킬기; 하이드록시기; C1-C6의 알콕시기; 폴리에틸렌글라이콜기; 니트릴기; 니트로기; 카르복실기; 설포닐기; 아자이드기; 메탄설포닐기; 말레이미드기; 터셔리-부틸디메틸실릴기(TBS)로 보호된 알콜; 또는 NR6R7(여기에서, R6 및 R7는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임)이고,
R3는 수소; 할로겐; 니트릴기; 보론기; 하이드록시기; COY(여기에서 Y는 수소, C1-C8의 직쇄 또는 측쇄 알킬기, C2-C8의 알케닐기, C2-C8의 알키닐기, C3-C8의 시클로알킬기, 또는 NR8R9 (여기에서, R8 및 R9는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임]); C1-C6의 알콕시기; C6-C20의 아릴기; 또는 NR10R11(여기에서, R10 및 R11는 각각 독립적으로 수소, C1-C10의 알킬기, C6-C20의 아릴기 또는 C4-C20의 헤테로아릴기임), 니트릴 또는 할로겐으로 치환된 C6-C20의 아릴기이다.
Fluorescent compound represented by the following formula (1):
[Formula 1]
Figure pat00247

In Formula 1 above
R 1 is hydrogen; Nitrile group; halogen; Nitro group; C1-C6 alkoxy group; C6-C20 aryl group; C5-C20 cycloheterocyclic group; Boron group; Azide group; NR 4 R 5 (wherein R 4 and R 5 are each independently hydrogen, C1-C10 alkyl group, C6-C20 aryl group or C4-C20 heteroaryl group), nitrile, C1-C6 alkoxy, halogen , A boron group, a hydroxy group, or CH 2 NR 4 R 5 (wherein R 4 and R 5 are each independently hydrogen, a C1-C10 alkyl group, a C6-C20 aryl group, or a C4-C20 heteroaryl group) A C6-C20 aryl group substituted with; C1-C8 linear or branched alkyl group; C2-C8 alkenyl group; C2-C8 alkynyl group; C3-C8 cycloalkyl group; Or a C4-C20 heteroaryl group,
R 2 is hydrogen; C1-C8 linear or branched alkyl group; C2-C8 alkenyl group; C2-C8 alkynyl group; C3-C8 cycloalkyl group; Hydroxy group; C1-C6 alkoxy group; Polyethylene glycol group; Nitrile group; Nitro group; Carboxyl group; Sulfonyl group; Azide group; Methanesulfonyl group; Maleimide group; Alcohols protected by tertiary-butyldimethylsilyl group (TBS); Or NR 6 R 7 (wherein R 6 and R 7 are each independently hydrogen, a C1-C10 alkyl group, a C6-C20 aryl group or a C4-C20 heteroaryl group),
R 3 is hydrogen; halogen; Nitrile group; Boron group; Hydroxy group; COY (wherein Y is hydrogen, a C1-C8 linear or branched alkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, a C3-C8 cycloalkyl group, or NR 8 R 9 (herein, R 8 and Each R 9 is independently hydrogen, a C1-C10 alkyl group, a C6-C20 aryl group, or a C4-C20 heteroaryl group]); C1-C6 alkoxy group; C6-C20 aryl group; Or NR 10 R 11 (Wherein, R 10 and R 11 are each independently hydrogen, a C1-C10 alkyl group, a C6-C20 aryl group, or a C4-C20 heteroaryl group), a C6-C20 aryl group substituted with nitrile or halogen. .
제1항에 있어서, 상기 R1은 수소; 트리플루오로메틸기(Trifluoromethyl); 아세틸기; 메톡시기; 또는 다이메틸아민기이고,
상기 R2는 메틸; 트리플루오로메틸페닐기; 페닐기; 메톡시페닐기; 또는 다이에틸아민페닐기이며,
상기 R3는 수소; 트리플루오로메틸기(Trifluoromethyl); 또는 아세틸기인 것을 특징으로 하는 형광 화합물.
The method of claim 1, wherein R 1 is hydrogen; Trifluoromethyl group; Acetyl group; Methoxy group; Or a dimethylamine group,
R 2 is methyl; Trifluoromethylphenyl group; Phenyl group; Methoxyphenyl group; Or a diethylamine phenyl group,
R 3 is hydrogen; Trifluoromethyl group; Or a fluorescent compound, characterized in that the acetyl group.
제1항에 있어서, 형광 화합물의 발광 파장은 400nm 내지 620nm이며, 액체상 또는 고체상 형광현상(solid state fluorescence)을 나타내는 것을 특징으로 하는 형광 화합물.
The fluorescent compound according to claim 1, wherein the fluorescent compound has an emission wavelength of 400 nm to 620 nm, and exhibits liquid or solid state fluorescence.
(a) 화학식 A의 화합물 및 화학식 B의 화합물을 반응시켜, 화학식 C의 화합물을 제조하는 단계;
(b) 상기 화학식 C의 화합물과 에틸아크릴레이트(ethyl acrylate), 아세트산나트륨(sodium acetate) 및 구리아세트산 모노수화물(Copper(II) Acetate monohydrate)을 반응시켜 화학식 D의 화합물을 제조하는 단계;
(c) 상기 화학식 D의 화합물 및 NBS(N-Bromosuccinimide)를 반응시켜 화학식 E의 화합물을 제조하는 단계; 및
(d) 상기 화학식 E의 화합물 및 화학식 F의 화합물을 반응시켜 화학식 1의 화합물을 제조하는 단계를 포함하며, 하기 반응식 1로 표시되는 화학식 1의 형광 화합물의 제조방법:
[반응식 1]
Figure pat00248

상기 R1은 수소; 트리플루오로메틸기(Trifluoromethyl); 아세틸기; 메톡시기; 또는 다이메틸아민기이고, 상기 R2는 메틸; 트리플루오로메틸페닐기; 페닐기; 메톡시페닐기; 또는 다이에틸아민페닐기이며, 상기 R3는 수소; 트리플루오로메틸기(Trifluoromethyl); 또는 아세틸기이다.
(a) reacting a compound of formula A and a compound of formula B to prepare a compound of formula C;
(b) reacting the compound of Formula C with ethyl acrylate, sodium acetate, and copper acetic acid monohydrate to prepare a compound of Formula D;
(c) preparing a compound of Formula E by reacting the compound of Formula D and NBS (N-Bromosuccinimide); And
(d) reacting the compound of Formula E and the compound of Formula F to prepare a compound of Formula 1, and a method for preparing a fluorescent compound of Formula 1 represented by the following Scheme 1:
[Scheme 1]
Figure pat00248

R 1 is hydrogen; Trifluoromethyl group; Acetyl group; Methoxy group; Or a dimethylamine group, and R 2 is methyl; Trifluoromethylphenyl group; Phenyl group; Methoxyphenyl group; Or a diethylaminephenyl group, and R 3 is hydrogen; Trifluoromethyl group; Or an acetyl group.
제1항 내지 제3항 중 어느 한 항의 형광 화합물을 포함하는 휘발성 유기화합물(Volatile Organic Compounds; VOC) 검출용 조성물.
A composition for detecting volatile organic compounds (VOC) comprising the fluorescent compound of any one of claims 1 to 3.
제1항 내지 제3항 중 어느 한 항의 형광 화합물을 포함하는 휘발성 유기화합물 검출용 센서 어레이.
A sensor array for detecting volatile organic compounds comprising the fluorescent compound of claim 1.
제6항에 있어서, 상기 상기 휘발성 유기화합물은 에탄올(Ethanol), 1-부탄올(1-Butanol), 1-(펜탄올(1-Pentanol), 1-헥산올(1-Hexanol), 3-헥산올(3-Hexanol), 페놀(Phenol), 1-헵탄올(1-Heptanol), 1-데칸올(1-Decanol), 2-데칸올(2-Decanol), 3-데칸올(3-Decanol), 1-도데칸올(1-Dodecanol), 사이클로펜탄올(Cyclopentanol), 사이클로헥산올(Cyclohexanol), 사이클로헵탄올(Cycloheptanol), 벤젠(Benzene), 아세톤(Acetone), 2-옥탄온(2-Octanone), 2-피콜린(2-Picoline), 3-피콜린(3-Picoline), 3-아세틸피리딘(3-Acetylpyridine), 4-아세틸피리딘(4-Acetylpyridine), 2-헵틸아민(2-Heptylamine), 디-엔-프로필아민(Di-n-propylamine), 2-페닐에틸아민(2-Phenylethylamine), 사이클로옥틸아민(Cyclooctylaime), 프로피온산(Propionic acid), 3-브롬프로피온산(3-Bromopropionic acid), 2-메틸부티르산(2-Methylbutyric acid), 포름산(Formic acid), 발레르산(Valeric acid), 트리플루오로 아세트산(Trifluoroacetic acid), 브로모아세트산(Bromoacetic acid), 아세트산(Acetic acid), 트리클로로아세트산(Trichloroacetic acid) 및 2-클로로프로피온산(2-Chloropropionic acid)으로 구성된 군에서 선택된 1종 이상의 물질인 것을 특징으로 하는 휘발성 유기화합물 검출용 센서 어레이.
The method of claim 6, wherein the volatile organic compound is ethanol (Ethanol), 1-butanol (1-Butanol), 1- (pentanol (1-Pentanol), 1-hexanol (1-Hexanol), 3-hexane 3-Hexanol, Phenol, 1-Heptanol, 1-Decanol, 2-Decanol, 3-Decanol ), 1-Dodecanol, Cyclopentanol, Cyclohexanol, Cycloheptanol, Benzene, Acetone, 2-octanone (2- Octanone), 2-picoline (2-Picoline), 3-picoline (3-Picoline), 3-acetylpyridine (3-Acetylpyridine), 4-acetylpyridine (4-Acetylpyridine), 2-heptylamine (2- Heptylamine), Di-n-propylamine, 2-Phenylethylamine, Cyclooctylamine, Propionic acid, 3-Bromopropionic acid ), 2-Methylbutyric acid, Formic acid, Valeric acid, Trifluoroacetic acid, Bromoacetic acid, Acetic acid, Triclo Roacetic acid (Trichloroacetic acid) and 2-chloropropionic acid (2-Chloropropionic acid) a sensor array for detecting volatile organic compounds, characterized in that at least one material selected from the group consisting of.
제1항 내지 제3항 중 어느 한 항의 형광 화합물을 이용한 휘발성 유기 화합물 검출 방법.
A method for detecting a volatile organic compound using the fluorescent compound according to any one of claims 1 to 3.
제8항에 있어서, 상기 방법은 (a) 형광 화합물이 고정된 휘발성 유기 화합물 검출용 센서 어레이에 휘발성 물질을 노출시킨 후, 형광 패턴 변화를 측정하는 단계; 및
(b) 상기 패턴 변화를 머신 러닝 알고리즘을 통해 학습시키는 단계;를 포함하는 방법으로 수행되는 것을 특징으로 하는 검출 방법.
The method of claim 8, wherein the method comprises: (a) exposing a volatile material to a sensor array for detecting a volatile organic compound to which a fluorescent compound is fixed, and then measuring a change in a fluorescence pattern; And
(b) learning the pattern change through a machine learning algorithm.
제8항에 있어서, 상기 (b) 단계는 패턴의 RGB 거리, 색 정보값(Hue value) 또는 CIEDE2000 정보를 머신 러닝 알고리즘을 통해 학습시키는 것을 특징으로 하는 검출 방법.The detection method of claim 8, wherein in step (b), the RGB distance, hue value, or CIEDE2000 information of the pattern is learned through a machine learning algorithm.
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WO2022065949A1 (en) * 2020-09-28 2022-03-31 아주대학교산학협력단 Indolizine skeleton-based fluorescent compound for ph measurement and use thereof
KR20230020822A (en) * 2021-08-04 2023-02-13 아주대학교산학협력단 Indolizine derivative compound, composition for detecting glucose comprising the same, sensor for detecting glucose and method for detecting glucose

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WO2022065949A1 (en) * 2020-09-28 2022-03-31 아주대학교산학협력단 Indolizine skeleton-based fluorescent compound for ph measurement and use thereof
KR20230020822A (en) * 2021-08-04 2023-02-13 아주대학교산학협력단 Indolizine derivative compound, composition for detecting glucose comprising the same, sensor for detecting glucose and method for detecting glucose

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