KR20080013162A - Preparing method of chromone-3-carboxyl acid derivatives using parallel combinatorial chemistry in solution phase - Google Patents

Preparing method of chromone-3-carboxyl acid derivatives using parallel combinatorial chemistry in solution phase Download PDF

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KR20080013162A
KR20080013162A KR1020060074298A KR20060074298A KR20080013162A KR 20080013162 A KR20080013162 A KR 20080013162A KR 1020060074298 A KR1020060074298 A KR 1020060074298A KR 20060074298 A KR20060074298 A KR 20060074298A KR 20080013162 A KR20080013162 A KR 20080013162A
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신계정
오희숙
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
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Abstract

A preparing method of chromone-3-carboxyl acid derivatives is provided to improve preparation yield and reduce the preparation time by preparing various derivatives in each step through a series of reactions without purification by using parallel combinatorial chemistry in solution phase. A preparing method of chromone-3-carboxyl acid derivatives represented by the formula(1) comprises the steps of: o-acetylsalicylic acid chloride represented by the formula(2) with tertiary butoxycarbonylmethylene triphenylphosphorane represented by the formula(7) in the presence of catalyst to prepare phosphorane compound represented by the formula(3); deacetylating the phosphorane compound represented by the formula(3) in the presence of base to prepare compounds represented by the formula(4); reacting the compounds represented by the formula(4) with an excessive amount of acid chloride in the presence of base and catalyst to prepare compounds represented by the formula(5); preparing compounds represented by the formula(6) from the compounds represented by the formula(5) through Wittig reaction; and deesterifying the compounds represented by the formula(6) under acid condition to remove tertiary butyl group, wherein R1 is hydrogen, chlorine, bromine, methoxy group or methyl group, and R2 is aromatic group or hetero aromatic group substituted by chloride, fluorine, methoxy group, methyl group or hydroxy group.

Description

용액상 평행 조합화학을 이용한 크로몬-3-카복실산 유도체의 제조방법{Preparing method of chromone-3-carboxyl acid derivatives using parallel combinatorial chemistry in solution phase}Preparing method of chromone-3-carboxyl acid derivatives using parallel combinatorial chemistry in solution phase}

본 발명은 용액상 평행 조합화학을 이용한 크로몬-3-카복실산 유도체의 제조방법에 관한 것이다.The present invention relates to a process for the preparation of chromone-3-carboxylic acid derivatives using solution phase parallel combinatorial chemistry.

플라본계 화합물인 크로몬(chromone, 4H-1-benzopyran-4-one)은 식물계로부터 추출된 광범위한 천연물 중의 하나이다. 현재 화학식 1a과 같은 구조를 기본골격으로 한 천연 크로몬 유도체 및 합성 크로몬 유도체들은 여러 가지 효소나 수용체와 결합하여 항종양 작용, 항진균 작용, 항알레르기성 작용, 단백질 키나아제 억제작용, 함염증 작용, 항산화 작용, 성장 촉진작용, 신경호보 작용, 위보호 작용, 면역 결핍 바이러스 억제작용, 위보호 작용, 면역결핍 바이러스 억제작용, 항돌연변이성 작용 등의 다양한 생리활성을 나타내는 것으로 알려져 있다. 따라서 크로몬 유도체 구조의 골격은 신약을 개발하는 데에 있어서 약효를 예견할 수 있는 중 요 골격으로 생각되어 이에 대한 연구가 활발히 진행되고 있다.Chromone (4H-1-benzopyran-4-one), a flavone compound, is one of a wide range of natural products extracted from the plant system. Currently, natural chromone derivatives and synthetic chromone derivatives having a structure based on the structure as shown in Formula 1a are combined with various enzymes or receptors for antitumor action, antifungal action, antiallergic action, protein kinase inhibitory action, inflammatory action, It is known to exhibit various physiological activities such as antioxidant activity, growth promoting action, neuroprotective action, gastric protective action, immunodeficiency virus inhibitory action, gastric protective action, immunodeficiency virus inhibitory action, antimutagenic action and the like. Therefore, the skeleton of the chromone derivative structure is considered to be an important skeleton for predicting drug efficacy in the development of new drugs, and research on this is being actively conducted.

<화학식 1a><Formula 1a>

Figure 112006056442618-PAT00002
Figure 112006056442618-PAT00002

그러나 천연물에서 분리해 낸 생리활성을 지닌 크로몬 유도체들은 대량생산이 불가능하여 가격이 비싸다는 단점이 있다. 따라서 많은 크로몬 유도체들을 합성하여 사용하게 되면서, 효율적인 합성에 대한 관심이 높아지게 되었다. 상기 크로몬과 이의 유도체들에 대한 체계적이고 다양한 연구를 위해서는 이의 다수의 화합물을 단시일 내에 생성시킬 수 있는 효율적인 합성에 관한 연구가 필수적으로 선행되어야 한다.However, chromium derivatives having physiological activities separated from natural products are disadvantageous in that they cannot be mass produced and are expensive. Therefore, as many chromone derivatives are synthesized and used, interest in efficient synthesis has increased. In order to systematically and variously study the chromone and its derivatives, studies on efficient synthesis capable of producing a large number of compounds thereof in a short time should be preceded.

일반적으로 크로몬은 페놀 또는 o-하이드록시아세토페논에 헤테로사이클릭 고리를 만들기 위해 사용되는 측쇄를 붙이는 것으로부터 유도된다. 종래 크로몬의 합성 방법은 다음과 같다. Chromone is generally derived from attaching side chains used to make heterocyclic rings to phenol or o-hydroxyacetophenone. The conventional method of synthesizing chromone is as follows.

Mozingo는 하기와 같이 o-하이드록시아세토페논과 에스테르의 염기 촉매 클라이센 축합(base-catalyzed Claisen condensation)을 통해 1,3-디케톤을 합성한 후, 산 조건에서 쉽게 고리화하여 C-2 위치에 치환기가 있는 크로몬을 합성하였다[Mozingo, R. Org . Synth ., Coll . Vol. 1955, 3, 387].Mozingo synthesizes 1,3-diketone through base-catalyzed Claisen condensation of o-hydroxyacetophenone and ester as described below, and then cyclizes easily under acidic conditions to position C-2. A chromone having a substituent on was synthesized [Mozingo, R. Org . Synth ., Coll . Vol. 1955 , 3 , 387].

Figure 112006056442618-PAT00003
Figure 112006056442618-PAT00003

Wheeler는 하기와 같이 o-하이드로아세토페논의 아실레이션을 통해 크로몬의 선구물질인 1,3-디케톤의 대안인 o-벤조일옥시아세토페논을 합성하였다. 처음에는 방법 (a)처럼 o-벤조일옥시아세토페논으로부터 플라본으로 직접적으로 합성하였으나, 더 높은 수득율과 재현성 때문에 방법 (b)와 같이 염기 촉매 베이커-벤카타라만 재배열(base-catalyzed Baker-Venkataraman rearrangement)을 통해 디케톤 중간체를 합성하였다. 상기 방법은 Mozingo의 방법보다 1,3-디케톤의 중간체를 더 높은 수율로 얻을 수 있다[Wheeler, T. S. Org . Synth ., Coll . Vol. 1963, 4, 478].Wheeler synthesized o-benzoyloxyacetophenone, an alternative to chromone precursor 1,3-diketone, through acylation of o-hydroacetophenone as follows. Initially synthesized directly from the o-benzoyloxyacetophenone to flavones as in method (a), but because of higher yields and reproducibility, base-catalyzed Baker-Venkataraman rearrangement as in method (b) The diketone intermediate was synthesized through This method yields intermediates of 1,3-diketone in higher yield than Mozingo's method [Wheeler, TS Org . Synth ., Coll . Vol. 1963 , 4 , 478.

Figure 112006056442618-PAT00004
Figure 112006056442618-PAT00004

Kostanecki-Robinson은 하기와 같이 o-벤조일옥시아세토페논에 무수산과 지 방족산의 나트륨 염을 함께 넣어 가열하였다. 이후 C-알킬화 및 O-알킬화를 한 후 1,3-디케톤을 베이커-벤카타라만 재배열한 다음에 고리화하여 크로몬 유도체를 합성하였다. 3-아실기의 알칼리 분해가 단리 되는 중에 쉽게 일어나지만 이 반응은 방향족 고리에 치환기를 다양하게 붙이기에 유용하며 크로몬 합성에 널리 사용된다[Flynn, D. G.; Robertson, A. J. Chem . Soc . 1936, 215; Szell, T., Dozsai, L., Zarandy, M., Menyharth, K. Teterahedron . 1969, 25, 715]. Kostanecki-Robinson was heated with sodium salts of anhydrous and aliphatic acids in o-benzoyloxyacetophenone as follows. After C-alkylation and O-alkylation, 1,3-diketone was rearranged only in Baker-Bencataraman and then cyclized to synthesize chromone derivatives. Alkali decomposition of the 3-acyl group occurs easily during isolation, but this reaction is useful for attaching various substituents to aromatic rings and is widely used for chromone synthesis [Flynn, DG; Robertson, A. J. Chem . Soc . 1936 , 215; Szell, T., Dozsai, L., Zarandy, M., Menyharth, K. Teterahedron . 1969 , 25 , 715.

Figure 112006056442618-PAT00005
Figure 112006056442618-PAT00005

또한 2-치환된 크로몬 유도체를 합성하기 위해 산 클로라이드와 반응하는 아실 포스포란이 1,3-디케톤의 역할을 할 수 있다. 예를 들면 하기와 같이 메틸 살리실레이트와 알킬리덴포스포란의 반응으로 아실화 포스포란을 얻을 수 있다.In addition, acyl phospholane, which reacts with acid chloride to synthesize 2-substituted chromone derivatives, may serve as 1,3-diketone. For example, acylated phospholane can be obtained by reaction of methyl salicylate and alkylidene phosphorane as follows.

Figure 112006056442618-PAT00006
Figure 112006056442618-PAT00006

하기 반응식은 보호된 2-하이드록시페닐아세틸렌에 알데히드 및 알키닐리튬의 반응과 그 결과로 생성되는 알코올의 산화 반응을 통해 아세틸렌 케톤을 합성한 후, HBr로 고리화하여 크로몬을 합성하는 방법을 나타낸다[Obrecht, D. Helv. Chem . Acta . 1989, 72, 447]The following scheme is a method for synthesizing acetylene ketones through the reaction of aldehydes and alkynyllithium to the protected 2-hydroxyphenylacetylene and the resulting alcohol oxidation, followed by cyclization with HBr to synthesize chromone. Obrecht, D. Helv. Chem . Acta . 1989 , 72 , 447]

Figure 112006056442618-PAT00007
Figure 112006056442618-PAT00007

하기 반응식은 2-아이오도페놀이 말단 알킨과 백금 촉매 카보닐화하여 o-하이드록시아릴 에티닐 케톤을 합성한 후, 산촉매 고리화를 통해 크로몬을 합성하는 방법을 나타낸다[Torii, S., Okumoto, H., Xu, L. H., Sadakane, M., Shostakovsky, M. V., Ponomaryov, A. B., Kalinin, V. N. Tetrahedron. 1993, 49, 6773] The following scheme shows a method of synthesizing o-hydroxyaryl ethynyl ketone by 2-iodophenol by platinum catalytic carbonylation with terminal alkyne, followed by chromon synthesis via acid catalyst cyclization [Torii, S., Okumoto , H., Xu, LH, Sadakane, M., Shostakovsky, MV, Ponomaryov, AB, Kalinin, VN Tetrahedron. 1993 , 49 , 6773]

Figure 112006056442618-PAT00008
Figure 112006056442618-PAT00008

그러나 상기 방법들은 하나의 반응에 하나의 유도체만이 합성되기 때문에 여러 개의 유도체를 합성할 경우에는 시간과 노력이 많이 걸린다는 문제가 있다.However, these methods have a problem in that it takes much time and effort when synthesizing a plurality of derivatives because only one derivative is synthesized in one reaction.

이에 순수한 개개의 생리 활성을 지닌 다수의 화합물을 단시일 내에 합성하는 방법으로 조합화학 합성법을 사용하게 되었다.Therefore, the combinatorial chemical synthesis was used as a method of synthesizing a large number of compounds having purely individual physiological activities in a short time.

조합화학은 기존의 고전적인 합성법과 같이 한번에 하나의 화합물을 합성하는 것이 아니라 구조적으로 다양한 빌딩 블럭(building block)을 가지고 보다 다양 하고 많은 수의 화합물을 동시에 합성하는 기술이다.Combination chemistry is a technique of synthesizing a greater number of compounds simultaneously with structurally diverse building blocks, rather than synthesizing one compound at a time, as in the classical synthesis method.

이는 1971년 Ugi 박사가 이소니트릴을 이용한 다중조성을 사용하여 용액 상에 한꺼번에 반응시키면 한 번에 다양한 생성물을 얻을 수 있다고 언급한 바 있으나, 1960 ~ 1970년대는 조합화학에 대한 체계적인 연구논리가 정립되지 않다가 1984년 Geysen 박사가 그의 동료들과 함께 생물학적 활성을 측정하기 위하여 수많은 헥사펩타이드의 라이브러리 구축을 한 것이 많은 연구자의 관심을 가지게 되었고, 1994년 Gallop 등이 발표한 두 편의 논문이 발표된 후 조합화학에 대한 체계적이고 논리적인 연구가 수많은 화학자의 관심 속에 본격적으로 가속화되기 시작하였다.In 1971, Dr. Ugi mentioned that multiple compositions with isonitrile could be used to react various reactions at once. However, in the 1960s and 1970s, systematic research logic on combinatorial chemistry was not established. In 1984, Dr. Geysen's work with his colleagues to build a library of numerous hexapeptides to measure biological activity became of interest to many researchers.In 1994, two publications published by Gallop et al. The systematic and logical study of the study began to accelerate in earnest with the attention of numerous chemists.

조합화학 합성법을 수행하기 위한 반응매개체로서는 고체상 합성법과 용액상 합성법이 있다.As a reaction medium for carrying out the combinatorial chemical synthesis, there are a solid phase synthesis method and a solution phase synthesis method.

고체상 합성법은 A, B, C, D 등의 서로 다른 물질을 고체상에 연결 후, A라는 물질과 반응시키면 고체상에 A-A, B-A, C-A, D-A 등과 같은 서로 다른 화합물의 생성이 가능하며, 생성된 이러한 화합물을 고체상 즉 지지체로부터 떼어내어 A-A, B-A, C-A, D-A 등과 같은 많은 분자를 합성하는 방법이다. 상기 방법은 반응 후 처리과정이 신속 편리하고, 다단계 반응공정이 용이하고, 연속적인 반응공정의 자동화가 가능한 반면, 용매와 시료가 과량으로 쓰이며 반응의 진행정도를 알 수가 없다. 또한 다양한 화학반응의 수행이 곤란하고, 반응 규모에 제약을 받으며, 고체상에 화합물을 결합시키고 반응 후에 다시 결합을 끊는 작업에 많은 주의가 필요하다. In the solid phase synthesis method, different materials such as A, B, C, and D are connected to the solid phase, and then reacted with the material A to generate different compounds such as AA, BA, CA, DA, etc. It is a method of synthesizing many molecules such as AA, BA, CA, DA, etc. by removing a compound from a solid phase, ie, a support. While the method is fast and convenient after the reaction, easy to multi-step reaction process, and the automation of the continuous reaction process is possible, the solvent and the sample is used excessively and the progress of the reaction is not known. In addition, it is difficult to carry out various chemical reactions, and is limited in the reaction scale, and much attention is required to bind the compound to the solid phase and to disconnect again after the reaction.

용액상 합성법의 경우에는 반응 규모의 제약이 없어지고, 반응의 진행정도를 확인할 수 있으며, 화학적 반응들의 확대와 광대한 범위로 인해 최대의 구조적 다양성을 제공할 수 있다. 또한 각 단계 후에 정제가 가능하고 또한 고체 지지체에서 반응할 때 거쳐야 하는 연결부에 부착, 분리 전략들이 필요 없다는 장점이 있다. 이때 일반적으로 혼합 및 분리 합성법이 사용되는데, 상기 혼합 및 분리 합성법은 분리의 문제가 중요하기 때문에 최대한 3단계 정도의 반응이 적절하다. 그 이상, 예를 들어 5단계 정도가 되면 분리 및 정제 문제가 시급한 과제로 부각된다.In the case of solution phase synthesis, there is no restriction of the reaction scale, the progress of the reaction can be confirmed, and the expansion and the wide range of chemical reactions can provide the greatest structural diversity. In addition, the purification is possible after each step, and there is an advantage in that no attachment and separation strategies are required when the reaction is performed in the solid support. In this case, a mixing and separation synthesis method is generally used. Since the separation problem is important, a reaction of about three steps is appropriate. Beyond that, for example, about five steps, the problem of separation and purification becomes an urgent task.

한편, 평행합성법은 다중반응기의 각각 분리된 셀(cell) 속에서 화학반응을 시키기 때문에 최종반응 후, 각 화합물에 대한 반응공정의 역추적이 가능하므로 수백 또는 수천의 라이브러리 구축에 효율성이 크다. 그러나 화학반응이 다단계 반응의 경우, 단계마다 반응 후 처리과정, 특히 정제과정에 장시간이 소요된다는 문제가 있다.On the other hand, since the parallel synthesis method allows chemical reactions in separate cells of the multi-reactor, it is possible to trace back the reaction process for each compound after the final reaction, which is highly efficient in building hundreds or thousands of libraries. However, when the chemical reaction is a multi-step reaction, there is a problem that takes a long time in the post-reaction treatment, in particular, the purification process.

이에, 본 발명자들은 반응 후 정제과정에 장시간이 소요되는 종래의 용액상 평행 합성법의 단점을 해결하고 보다 효과적으로 크로몬-3-카복실산 유도체 화합물을 제조하기 위하여 연구하던 중, 매 반응단계에서 정제과정 없이 일련의 반응을 통하여 크로몬 구조를 모체로 한 C-2 위치의 치환기와 벤젠 고리의 치환기에 다양성을 가진 크로몬-3-카복실산 유도체를 제조하는 방법을 개발하고 본 발명을 완성하였다.Thus, the present inventors have been studying to solve the disadvantages of the conventional solution phase parallel synthesis method that takes a long time in the purification process after the reaction and to prepare the chromone-3-carboxylic acid derivative compound more effectively, without purification in every reaction step. Through a series of reactions, a method of preparing a chromone-3-carboxylic acid derivative having a variety of substituents at the C-2 position and a benzene ring based on the chromone structure was completed and the present invention was completed.

본 발명의 목적은 용액상 평행 조합화학을 이용한 크로몬-3-카복실산 유도체의 제조방법을 제공하는 데 있다.It is an object of the present invention to provide a method for preparing chromone-3-carboxylic acid derivative using solution phase parallel combinatorial chemistry.

상기 목적을 달성하기 위하여 본 발명은 용액상 평행 조합화학을 이용하여 하기 화학식 1로 표현되는 크로몬-3-카복실산 유도체의 제조방법을 제공한다.In order to achieve the above object, the present invention provides a method for preparing a chromone-3-carboxylic acid derivative represented by the following Chemical Formula 1 using a solution-phase parallel combination chemistry.

Figure 112006056442618-PAT00009
Figure 112006056442618-PAT00009

상기 화학식에서 R1은 벤젠고리의 5, 6, 7 또는 8번 위치에 치환되는 1 또는 2 이상의 수소, 염소, 브롬, 메톡시기 또는 메틸기이며, R2는 염소, 불소, 메톡시기, 메틸기 또는 하이드록시기로 치환된 방향족기 또는 헤테로 방향족기이다.In the above formula, R 1 is one or more hydrogen, chlorine, bromine, methoxy group or methyl group substituted at the 5, 6, 7 or 8 position of the benzene ring, R 2 is chlorine, fluorine, methoxy group, methyl group or hydride Or an aromatic group substituted with an oxy group.

Figure 112006056442618-PAT00010
Figure 112006056442618-PAT00010

상기 화학식에서 R1 또는 R2는 화학식 1에서 정의한 바와 같다.R 1 in the formula or R 2 is as defined in formula (1).

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

본 발명에 따른 화학식 1의 크로몬-3-카복실산 유도체의 제조방법은 Method for producing a chromone-3-carboxylic acid derivative of formula 1 according to the present invention

상기 반응식 1에서 나타내는 바와 같이, 화학식 2의 o-아세틸살리실산 클로라이드 화합물을 촉매 존재하에서 3차부톡시카보닐메틸렌 트리페닐포스포란 화합물(7)과 반응시켜 화학식 3의 포스포란 화합물을 제조하는 단계(단계1);As shown in Scheme 1, reacting the o-acetylsalicylic acid chloride compound of formula 2 with tert-butoxycarbonylmethylene triphenylphosphorane compound (7) in the presence of a catalyst to prepare a phosphorane compound of formula (3) One);

염기 존재하에 상기 단계 1에서 제조된 화학식 3의 화합물을 탈아세틸화하여 화학식 4의 화합물을 제조하는 단계(단계 2);Preparing a compound of formula 4 by deacetylating the compound of formula 3 prepared in step 1 in the presence of a base (step 2);

염기 및 촉매 존재하에 상기 단계 2에서 제조된 화학식 4의 화합물과 과량의 산 클로라이드를 반응시켜 화학식 5의 화합물을 제조하는 단계(단계 3);Preparing a compound of formula 5 by reacting an excess of acid chloride with the compound of formula 4 prepared in step 2 in the presence of a base and a catalyst (step 3);

상기 단계 3에서 제조된 화학식 5의 화합물을 분자간 위티그(Wittig) 반응을 통하여 화학식 6의 화합물을 제조하는 단계(단계 4); 및Preparing a compound of Chemical Formula 6 through an intermolecular Wittig reaction with the compound of Chemical Formula 5 prepared in Step 3 (Step 4); And

상기 단계 4에서 제조된 화학식 6의 화합물을 산 조건하에서 탈에스테르화시켜 3차부틸기를 제거하여 화학식 1의 화합물을 제조하는 단계(단계 5)를 포함하여 이루어진다. 또한, 상기 단계 3은 반응하고 남은 과량의 산 클로라이드를 수용액층으로 이동시켜 제거하기 위해 지라드-티 시약을 첨가하는 단계를 더 포함할 수 있다. The compound of formula 6 prepared in step 4 is de-esterified under acidic conditions to remove the tertiary butyl group, thereby preparing a compound of formula 1 (step 5). In addition, step 3 may further include adding a Girard-T reagent to remove the excess acid chloride remaining in the reaction by moving to the aqueous solution layer.

Figure 112006056442618-PAT00011
Figure 112006056442618-PAT00011

Figure 112006056442618-PAT00012
Figure 112006056442618-PAT00012

Figure 112006056442618-PAT00013
Figure 112006056442618-PAT00013

Figure 112006056442618-PAT00014
Figure 112006056442618-PAT00014

Figure 112006056442618-PAT00015
Figure 112006056442618-PAT00015

Figure 112006056442618-PAT00016
Figure 112006056442618-PAT00016

Figure 112006056442618-PAT00017
Figure 112006056442618-PAT00017

상기 화학식 2 ~ 8에서 R1 또는 R2는 화학식 1에서 정의한 바와 같다.R 1 in Formulas 2 to 8 or R 2 is as defined in formula (1).

본 발명의 각 제조단계를 구체적으로 설명하면 다음과 같다.Referring to each manufacturing step of the present invention in detail.

단계 1은 화학식 2의 o-아세틸살리실산 클로라이드 화합물을 촉매 존재하에서 3차부톡시카보닐메틸렌 트리페닐포스포란 화합물(7)과 반응시켜 화학식 3의 포스포란 화합물을 제조하는 단계이다. Step 1 is a step of reacting the o-acetylsalicylic acid chloride compound of formula 2 with tert-butoxycarbonylmethylene triphenylphosphorane compound (7) in the presence of a catalyst to prepare a phosphorane compound of formula (3).

이때, 출발물질인 화학식 2의 화합물은 공지에 의한 방법으로 합성하여 사용하거나, 시판중인 것을 사용할 수 있다. 상기 촉매는 N,O-비스트리메틸실릴 아세트아미드 등을 사용하는 것이 바람직하며, 반응 용매로는 벤젠, 테트라하이드로퓨란 등을 사용하는 것이 바람직하다. 상기 반응은 실온에서 이루어지는 것이 바람직하며, 반응 시간은 5 ~ 20시간 정도인 것이 바람직하다.At this time, the compound of the formula (2) as a starting material may be synthesized by a known method or may be commercially available. It is preferable to use N, O-bistrimethylsilyl acetamide etc. as said catalyst, and it is preferable to use benzene, tetrahydrofuran, etc. as a reaction solvent. It is preferable that the said reaction is made at room temperature, and it is preferable that reaction time is about 5 to 20 hours.

다음으로 단계 2는 염기 존재하에 상기 단계 1에서 제조된 화학식 3의 화합물을 탈아세틸화하여 화학식 4의 화합물을 제조하는 단계이다. Next, Step 2 is a step of preparing a compound of Formula 4 by deacetylating the compound of Formula 3 prepared in Step 1 in the presence of a base.

이때, 상기 염기는 디메틸아민, 메틸아민, 암모니아 등을 사용하는 것이 바람직하며, 반응 용매로는 테트라하이드로퓨란, 메탄올, 에탄올 등을 사용하는 것이 바람직하다. 상기 반응은 실온에서 이루어지는 것이 바람직하며, 반응 시간은 5 ~ 10시간 정도인 것이 바람직하다.In this case, it is preferable to use dimethylamine, methylamine, ammonia, etc., and as the reaction solvent, tetrahydrofuran, methanol, ethanol, or the like is preferably used. It is preferable that the said reaction is made at room temperature, and it is preferable that reaction time is about 5 to 10 hours.

다음으로 단계 3은 염기 및 촉매 존재하에 상기 단계 2에서 제조된 화학식 4의 화합물과 과량의 산 클로라이드를 반응시켜 화학식 5의 화합물을 제조하는 단계이다. Next, step 3 is a step of preparing a compound of formula 5 by reacting an excess of acid chloride with a compound of formula 4 prepared in step 2 in the presence of a base and a catalyst.

상기 염기는 N,N-디이소프로필에틸아민, 트리에틸아민 등을 사용할 수 있으며, 상기 촉매는 N,N-디메틸피리딘 등을 사용할 수 있다. 상기 산 클로라이드는 과량으로 사용하되, 바람직하게는 2.0 당량을 사용하여 에스테르화 반응을 일으킨다. 반응하고 남은 산 클로라이드는 크로마토그래피를 이용해 정제하는 대신에 지라드-티(H2NNHCOCH2N(CH3)3Cl) 시약을 사용하여 제거하는 것이 바람직하다. 상기 산 클로라이드는 상기 지라드-티 시약과 반응하여 물에 용해되는 하이드라진 유도체가 되어 목적 화합물인 화학식 6의 화합물만 유기층에 남아있고 나머지는 모두 물 층으로 함유되므로 쉽게 제거가 가능하다.The base may be N, N-diisopropylethylamine, triethylamine and the like, and the catalyst may be N, N-dimethylpyridine and the like. The acid chloride is used in excess, preferably using 2.0 equivalents to cause the esterification reaction. The acid chloride remaining after the reaction is preferably removed by using a Girard-T (H 2 NNHCOCH 2 N (CH 3 ) 3 Cl) reagent instead of purifying by chromatography. The acid chloride is a hydrazine derivative dissolved in water by reacting with the Girard-T reagent, so that only the compound of Formula 6, which is the target compound, remains in the organic layer, and the rest is contained in the water layer.

다음으로 단계 4는 상기 단계 3에서 제조된 화학식 5의 화합물을 분자간 위티그(Wittig) 반응을 통하여 화학식 6의 화합물을 제조하는 단계이다. Next, Step 4 is a step of preparing the compound of Formula 6 through an intermolecular Wittig reaction of the compound of Formula 5 prepared in Step 3.

이때, 반응 용매로는 톨루엔, 크실렌, 메시틸렌 등을 바람직하게 사용할 수 있으며, 8 ~ 24시간 동안 가열 환류하는 것이 바람직하다.At this time, toluene, xylene, mesitylene, and the like may be preferably used as the reaction solvent, and heating and refluxing for 8 to 24 hours is preferable.

다음으로 단계 5는 상기 단계 4에서 제조된 화학식 6의 화합물을 산 조건하에서 탈에스테르화시켜 3차부틸기를 제거하여 화학식 1의 화합물을 제조하는 단계이다. Next, step 5 is a step of preparing a compound of formula 1 by removing the tertiary butyl group by de-esterification of the compound of formula 6 prepared in step 4 under acid conditions.

상기 탈에스테르화 반응은 이염화탄소 용매에서 상기 화합물과 트리플루오르아세트산과의 반응에 의해 수행된다. 이들의 반응에 의해 상기 화학식 6의 크로몬-3-카복실산 부틸 에스테르 화합물에서 3차 부틸기가 제거되어 화학식 1의 크로몬-3-카복실산 화합물을 얻을 수 있다. 종래에는 각 반응단계마다 크로마토그래피를 통해 정제하는 과정을 필요로 하여 정제시 많은 시간이 소비되었으나 본 발명은 생성된 크로몬-3-카복실산 화합물만 1 N NaOH 추출을 통해 물 층으로 보낸 후 산 처리하여 생긴 결정을 여과를 통해 얻게 되므로 많은 시간이 걸리는 정제 과정이 필요하지 않다.The deesterification reaction is carried out by reaction of the compound with trifluoroacetic acid in a carbon dichloride solvent. By these reactions, tertiary butyl groups may be removed from the chromone-3-carboxylic acid butyl ester compound of Chemical Formula 6 to obtain a chromone-3-carboxylic acid compound of Chemical Formula 1. Conventionally, each step of the reaction requires a process of purification through chromatography, but a lot of time was spent on purification, but in the present invention, only the resulting chromone-3-carboxylic acid compound was sent to the water layer through 1 N NaOH extraction and treated with acid. The resulting crystals are obtained by filtration, eliminating the need for time-consuming purification.

본 발명에 있어서, 상기 단계 3 내지 단계 5의 과정은 동일한 용기 내에서 연속된 반응을 통하여 이루어진다. 따라서 반응 단계의 정제화를 거치지 않고 마지막 생성물에만 간단한 후처리를 통해 목적하는 순수한 형태의 크로몬-3-카복실산 유도체를 얻을 수 있다.In the present invention, the process of steps 3 to 5 is carried out through a continuous reaction in the same vessel. Therefore, the desired pure form of chromone-3-carboxylic acid derivative can be obtained through simple post-treatment only on the final product without undergoing purification of the reaction step.

이와 같이, 본 발명의 크로몬-3-카복실산 유도체들의 제조방법을 통해 각 반응단계에서 정제화가 없이 다양한 형태의 순수한 크로몬-3-카복실산 유도체를 용이 하게 얻을 수 있다.As such, through the preparation method of the chromone-3-carboxylic acid derivatives of the present invention, pure chromone-3-carboxylic acid derivatives of various forms can be easily obtained without purification in each reaction step.

이하 실시예에 의하여 본 발명을 보다 구체적으로 설명한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명이 이들 만으로 한정되는 것은 아니다.The present invention will be described in more detail with reference to the following Examples. However, the following Examples are only for illustrating the present invention, the present invention is not limited to these.

<< 실시예Example 1> 2-(3- 1> 2- (3- 플루오로페닐Fluorophenyl )-8-)-8- 메틸methyl -3--3- 크로몬Cromon 산의 제조 Manufacture of acid

Figure 112006056442618-PAT00018
Figure 112006056442618-PAT00018

단계 1Step 1

(3차부톡시카르보닐메틸렌)트리페닐포스포란(10 g, 26.57 mmol, 0.9 eq)을 벤젠 100 ㎖에 용해시키고 0 ℃에서 N,O-비스(트리메틸실릴)아세트아미드(7.79 ㎖, 31.88 mmol, 1.1 eq)를 적가한 후 2-아세톡시-3-메틸 벤조일클로라이드를 적가하였다. 반응혼합물을 상온에서 질소 분위기 하에 16시간 동안 교반하였다. 1 N HCl 및 1 N NaOH로 추출한 다음 유기 용매층을 무수 황산나트륨으로 건조시킨 후 여과하고 감압 증류한다. 이후 불순한 화합물을 에테르용액에서 결정화하여 화합물 3-(2-아세톡시-3-메틸페닐)-3-옥소-2-트리페닐포스폴리덴-프로피온산 3차부틸 에스테르(8.4 g, 57.2%)를 얻었다.(Tert-butoxycarbonylmethylene) triphenylphosphorane (10 g, 26.57 mmol, 0.9 eq) was dissolved in 100 mL of benzene and N, O-bis (trimethylsilyl) acetamide (7.79 mL, 31.88 mmol, 1.1 eq) was added dropwise followed by 2-acetoxy-3-methyl benzoylchloride dropwise. The reaction mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. After extraction with 1 N HCl and 1 N NaOH, the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was crystallized in ether solution to give compound 3- (2-acetoxy-3-methylphenyl) -3-oxo-2-triphenylphosphpolydene-propionic acid tertiary butyl ester (8.4 g, 57.2%).

1H NMR (300 MHz, CDCl3): δ 0.99 (s, 9H), 2.05 (s, 3H), 2.17 (s, 3H), 7.09-7.15 (m, 2H), 7.31 (dd, J= 7.0, 2.0 Hz, 1H), 7.44-7.57 (m, 9H), 7.74-7.81 (m, 6H). 1 H NMR (300 MHz, CDCl 3 ): δ 0.99 (s, 9H), 2.05 (s, 3H), 2.17 (s, 3H), 7.09-7.15 (m, 2H), 7.31 (dd, J = 7.0, 2.0 Hz, 1H), 7.44-7.57 (m, 9H), 7.74-7.81 (m, 6H).

단계 2Step 2

3-(2-아세톡시-3-메틸페닐)-3-옥소-2-트리페닐포스폴리덴-프로피온산 3차부틸 에스테르 8.4 g(15.20 mmol)을 테트라하이드로퓨란(THF)(30.4 ㎖)에 용해시킨 후 0℃에서 1 M 디메틸아민 THF 용액 30.4 ㎖(60.8 mmol, 4eq)를 적가하였다. 상기 반응혼합물을 상온에서 10시간 동안 교반하였다. 용매를 감압 증류 하에 제거한 후 에테르와 헥산으로 결정화하였다. 이후 헥산으로 세척하고 여과한 후 오븐 펌프에 건조시켜 화합물 3-(2-히드록시-3-메틸페닐)-3-옥소-2-트리페닐포스폴리덴-프로피온산 3차부틸 에스테르 7.10 g(91.5%)을 얻었다.8.4 g (15.20 mmol) of 3- (2-acetoxy-3-methylphenyl) -3-oxo-2-triphenylphosphpolydene-propionic acid tert-butyl ester was dissolved in tetrahydrofuran (THF) (30.4 mL). Then 30.4 ml (60.8 mmol, 4eq) of 1 M dimethylamine THF solution was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 10 hours. The solvent was removed under reduced pressure distillation and then crystallized from ether and hexane. Then washed with hexane, filtered and dried in an oven pump 7.10 g (91.5%) of compound 3- (2-hydroxy-3-methylphenyl) -3-oxo-2-triphenylphosphpolydene-propionic acid tert-butyl ester Got.

1H NMR (300 MHz, CDCl3): δ 1.04 (s, 9H), 2.22 (s, 3H), 6.78 (dd, J= 7.5, 7.5 Hz, 1H), 7.18 (d, J= 7.5 Hz, 1H), 7.46-7.59 (m, 9H), 7.76-7.88 (m, 7H), 11.84 (s, 1H). 1 H NMR (300 MHz, CDCl 3 ): δ 1.04 (s, 9H), 2.22 (s, 3H), 6.78 (dd, J = 7.5, 7.5 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H ), 7.46-7.59 (m, 9H), 7.76-7.88 (m, 7H), 11.84 (s, 1H).

단계 3Step 3

3-(2-히드록시-3-메틸페닐)-3-옥소-2-트리페닐포스폴리덴-프로피온산 3차부틸 에스테르 100 mg(0.2 mmol)을 이염화탄소 3 ㎖에 용해시키고 디이소프로필에틸아민 0.068 ㎖(0.4 mmol, 2 eq)와 3-플루오로벤조일클로라이드 0.036 ㎖(0.3 mmol, 1.5 eq)을 적가하고 4-디메틸아미노피리미딘 5 mg을 적가하였다. 상기 반응혼합물을 질소 분위기 하에서 1시간 동안 교반하였다. 이 반응액에 아세트산 0.5 ㎖에 용해시킨 지라드-티 시약 20 mg(0.12 mmol)을 적가한 후 질소 분위기 하에서 1시간 동안 교반하였다. 이후 1 N HCl 및 NaHCO3 포화용액으로 세척한 다음 유기 용매층을 무수 황산나트륨으로 건조시켰다. 이후 여과하고 감압 증류하여 화합물을 제조하였다.100 mg (0.2 mmol) of 3- (2-hydroxy-3-methylphenyl) -3-oxo-2-triphenylphosphpolydene-propionic acid tert-butyl ester were dissolved in 3 ml of carbon dichloride and 0.068 diisopropylethylamine ML (0.4 mmol, 2 eq) and 0.036 mL (0.3 mmol, 1.5 eq) of 3-fluorobenzoylchloride were added dropwise and 5 mg of 4-dimethylaminopyrimidine was added dropwise. The reaction mixture was stirred under nitrogen atmosphere for 1 hour. 20 mg (0.12 mmol) of Girard-T reagent dissolved in 0.5 ml of acetic acid was added dropwise to the reaction solution, followed by stirring for 1 hour under nitrogen atmosphere. After washing with 1N HCl and NaHCO 3 saturated solution, the organic solvent layer was dried over anhydrous sodium sulfate. After filtration and distillation under reduced pressure to prepare a compound.

단계 4Step 4

상기 단계 3에서 제조된 화합물을 톨루엔 8 ㎖에 용해시키고 질소 분위기 하에서 8시간 동안 환류 교반하였다. 교반 후, 용매를 감압 증류하여 제거하여 고체 생성물을 수득하였다.The compound prepared in Step 3 was dissolved in 8 ml of toluene and stirred under reflux for 8 hours under a nitrogen atmosphere. After stirring, the solvent was distilled off under reduced pressure to give a solid product.

단계 5Step 5

상기 단계 4에서 수득한 고체 생성물을 이염화탄소 5 ㎖에 용해시키고 트리플루오로아세트산(TFA) 5 ㎖를 적가하여 질소분위기 하에서 1시간 30분 동안 교반하였다. 용매를 감압 증류하여 제거한 후 에틸아세테이트와 1 N NaOH로 추출한 다음 물층을 1 N HCl 용액으로 처리하여 얻어진 결정을 여과한 후 건조하여 2-(3-플루오로페닐)-8-메틸-3-크로몬산 18.7 mg(32.2%)을 얻었다. The solid product obtained in step 4 was dissolved in 5 ml of carbon dichloride, and 5 ml of trifluoroacetic acid (TFA) was added dropwise and stirred for 1 hour 30 minutes under a nitrogen atmosphere. After distilling off the solvent under reduced pressure, the mixture was extracted with ethyl acetate and 1 N NaOH, and then the crystals obtained by treating the aqueous layer with 1 N HCl solution were filtered and dried to obtain 2- (3-fluorophenyl) -8-methyl-3-chrome. 18.7 mg (32.2%) was obtained.

m.p. 227-229 ℃.m.p. 227-229 ° C.

1H NMR (300 MHz, CDCl3): δ 2.54 (s, 3H), 7.28-7.33 (m, 1H), 7.39 (d, J= 9.3 Hz, 1H), 7.46-7.49 (m. 3H), 7.71 (d, J= 7.5 Hz, 1H), 8.19 (d, J= 8.0 Hz, 1H). 1 H NMR (300 MHz, CDCl 3 ): δ 2.54 (s, 3H), 7.28-7.33 (m, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.46-7.49 (m. 3H), 7.71 (d, J = 7.5 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H).

이하에서는 2-아세톡시-3-메틸 벤조일 클로라이드 대신 하기 표 1에 나타낸 바와 같이, R1의 치환기를 갖는 화학식 2의 화합물을 출발물질로 사용하고, 3-플루오로벤조일클로라이드 대신 R2치환기를 갖는 산 클로라이드(8)를 첨가한 것을 제외하고는 상기 실시예 1과 동일한 방법으로 실시예 2 ~ 78의 화합물을 제조하여 표 2에 나타내었다.Hereinafter, as shown in Table 1, instead of 2-acetoxy-3-methyl benzoyl chloride, a compound of Formula 2 having a substituent of R 1 is used as a starting material, and has a R 2 substituent instead of 3-fluorobenzoyl chloride. Except that the acid chloride (8) was added to the compounds of Examples 2 to 78 in the same manner as in Example 1 shown in Table 2.

Figure 112006056442618-PAT00019
Figure 112006056442618-PAT00019

1One 22 33 44 55 66 77 88 99 1010 1111 AA 실시예2Example 2 실시예 3 Example 3 실시예 4Example 4 실시예 5Example 5 실시예 6Example 6 BB 실시예7Example 7 실시예 8 Example 8 실시예 9Example 9 실시예 10Example 10 실시예 11Example 11 실시예 12Example 12 CC 실시예13Example 13 실시예 14 Example 14 실시예 15Example 15 DD 실시예16Example 16 실시예 17 Example 17 실시예 18Example 18 실시예 19Example 19 실시예 20Example 20 실시예 21Example 21 실시예 22Example 22 실시예 23Example 23 EE 실시예24Example 24 실시예 25 Example 25 실시예 26Example 26 실시예 27Example 27 실시예 1Example 1 실시예 29Example 29 실시예 30Example 30 실시예 31Example 31 실시예 32Example 32 실시예 33Example 33 FF 실시예 34Example 34 실시예 35 Example 35 실시예 36Example 36 실시예 37Example 37 실시예 28Example 28 실시예 38Example 38 실시예 39Example 39 실시예 40Example 40 실시예 41Example 41 실시예 42Example 42 GG 실시예43Example 43 실시예 44 Example 44 실시예 45Example 45 실시예 46Example 46 실시예 47Example 47 실시예 48Example 48 실시예 49Example 49 실시예 50Example 50 실시예 51Example 51 실시예 52Example 52 HH 실시예53Example 53 실시예 54 Example 54 실시예 55Example 55 실시예 56Example 56 실시예 57Example 57 실시예 58Example 58 실시예 59Example 59 II 실시예60Example 60 실시예 61 Example 61 실시예 62Example 62 실시예 63Example 63 실시예 64Example 64 실시예 65Example 65 실시예 66Example 66 실시예 67Example 67 실시예 68Example 68 실시예 69Example 69 JJ 실시예70Example 70 실시예 71 Example 71 실시예 72Example 72 실시예 73Example 73 실시예 74Example 74 실시예 75Example 75 실시예 76Example 76 실시예 77Example 77 실시예 78Example 78

<화학식 2><Formula 2>

Figure 112006056442618-PAT00020
Figure 112006056442618-PAT00020

<화학식 8><Formula 8>

Figure 112006056442618-PAT00021
Figure 112006056442618-PAT00021

실시예Example 화합물 명칭Compound name R1R1 R2R2 mp(℃)mp (℃) 1H NMR(300 MHz, CDCl3) 1 H NMR (300 MHz, CDCl 3 ) 실시예2Example 2 2-(2-퓨라닐)-8-메톡시-3-크로몬산2- (2-furanyl) -8-methoxy-3-chromonic acid 8-OCH3 8-OCH 3

Figure 112006056442618-PAT00022
Figure 112006056442618-PAT00022
198-200198-200 δ 4.08 (s, 3H), 6.71 (dd, J= 3.8, 1.7 Hz, 1H), 7.33 (dd, J= 8.1, 1.3 Hz, 1H), 7.47 (dd, J= 8.1, 8.1 Hz, 1H), 7.83-7.86 (m, 2H), 8.02 (d, J= 3.8 Hz, 1H), 14.50 (s, 1H)δ 4.08 (s, 3H), 6.71 (dd, J = 3.8, 1.7 Hz, 1H), 7.33 (dd, J = 8.1, 1.3 Hz, 1H), 7.47 (dd, J = 8.1, 8.1 Hz, 1H), 7.83-7.86 (m, 2H), 8.02 (d, J = 3.8 Hz, 1H), 14.50 (s, 1H) 실시예3Example 3 2-(3-톨루에닐)-8-메톡시-3-크로몬산2- (3-Toluenyl) -8-methoxy-3-chromonic acid 8-OCH3 8-OCH 3
Figure 112006056442618-PAT00023
Figure 112006056442618-PAT00023
 234-236234-236 δ 2.47 (s, 3H), 4.02 (s, 3H), 7.33 (dd, J= 8.1, 1.2 Hz, 1H), 7.41-7.43 (m, 2H), 7.48-7.53 (m, 3H), 7.89 (dd, J= 8.1, 1.4 Hz, 1H), 14.25 (s, 1H)δ 2.47 (s, 3H), 4.02 (s, 3H), 7.33 (dd, J = 8.1, 1.2 Hz, 1H), 7.41-7.43 (m, 2H), 7.48-7.53 (m, 3H), 7.89 (dd , J = 8.1, 1.4 Hz, 1H), 14.25 (s, 1H) 실시예4Example 4 2-(2-티오페닐)-8-메톡시-3-크로몬산2- (2-thiophenyl) -8-methoxy-3-chromonic acid 8-OCH3 8-OCH 3
Figure 112006056442618-PAT00024
Figure 112006056442618-PAT00024
 234-236234-236 δ 2.47 (s, 3H), 4.02 (s, 3H), 7.33 (dd, J= 8.1, 1.2 Hz, 1H), 7.41-7.43 (m, 2H), 7.48-7.53 (m, 3H), 7.89 (dd, J= 8.1, 1.4 Hz, 1H), 14.25 (s, 1H)δ 2.47 (s, 3H), 4.02 (s, 3H), 7.33 (dd, J = 8.1, 1.2 Hz, 1H), 7.41-7.43 (m, 2H), 7.48-7.53 (m, 3H), 7.89 (dd , J = 8.1, 1.4 Hz, 1H), 14.25 (s, 1H) 실시예5Example 5 2-(3,4-디메톡시페닐)-8-메톡시-3-크로몬산2- (3,4-Dimethoxyphenyl) -8-methoxy-3-chromonic acid 8-OCH3 8-OCH 3
Figure 112006056442618-PAT00025
Figure 112006056442618-PAT00025
 238-239238-239 δ 3.94 (s, 3H), 3.97 (s, 3H), 4.01 (s, 3H), 6.99 (d, J= 8.4 Hz, 1H), 7.27 (d, J= 1.2 Hz, 1H), 7.30 (dd, J= 8.4, 1.2 Hz, 1H), 7.42-7.50 (m, 2H), 7.86 (dd, J= 8.1, 1.4 Hz, 1H)δ 3.94 (s, 3H), 3.97 (s, 3H), 4.01 (s, 3H), 6.99 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 1.2 Hz, 1H), 7.30 (dd, J = 8.4, 1.2 Hz, 1H), 7.42-7.50 (m, 2H), 7.86 (dd, J = 8.1, 1.4 Hz, 1H) 실시예6Example 6 2-(4-클로로페닐)-8-메톡시-3-크로몬산2- (4-Chlorophenyl) -8-methoxy-3-chromonic acid 8-OCH3 8-OCH 3
Figure 112006056442618-PAT00026
Figure 112006056442618-PAT00026
 238-239238-239 δ 4.02 (s, 3H), 7.34 (d, J= 8.0 Hz, 1H), 7.49-7.54 (m, 3H), 7.67 (d, J= 8.5 Hz, 2H), 7.88 (dd, J= 8.0, 1.2 Hz, 1H), 14.30 (s, 1H)δ 4.02 (s, 3H), 7.34 (d, J = 8.0 Hz, 1H), 7.49-7.54 (m, 3H), 7.67 (d, J = 8.5 Hz, 2H), 7.88 (dd, J = 8.0, 1.2 Hz, 1H), 14.30 (s, 1H) 실시예7Example 7 2-(2-퓨라닐)-7-메톡시-3-크로몬산2- (2-furanyl) -7-methoxy-3-chromonic acid 7-OCH3 7-OCH 3
Figure 112006056442618-PAT00027
Figure 112006056442618-PAT00027
 217-219217-219 δ 3.99 (s, 3H), 6.71 (dd, J= 3.7, 1.6 Hz, 1H), 7.03 (d, J= 2.3 Hz, 1H), 7.11 (dd, J= 9.0, 2.3 Hz, 1H), 7.78 (d, J= 1.6 Hz, 1H), 8.01 (d, J= 3.7 Hz, 1H), 8.21 (d, J= 9.0 Hz, 1H), 15.00 (s, 1H)δ 3.99 (s, 3H), 6.71 (dd, J = 3.7, 1.6 Hz, 1H), 7.03 (d, J = 2.3 Hz, 1H), 7.11 (dd, J = 9.0, 2.3 Hz, 1H), 7.78 ( d, J = 1.6 Hz, 1H), 8.01 (d, J = 3.7 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 15.00 (s, 1H) 실시예8Example 8 2-(3-톨루에닐)-7-메톡시-3-크로몬산2- (3-Toluenyl) -7-methoxy-3-chromonic acid 7-OCH3 7-OCH 3
Figure 112006056442618-PAT00028
Figure 112006056442618-PAT00028
 183-184183-184 δ 2.46 (s, 3H), 3.96 (s, 3H), 6.98 (d, J= 2.3 Hz, 1H), 7.14 (dd, J= 9.0, 2.3 Hz, 1H), 7.40-7.46 (m, 4H), 8.25 (d, J= 9.0 Hz, 1H), 14.45 (s, 1H)δ 2.46 (s, 3H), 3.96 (s, 3H), 6.98 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 9.0, 2.3 Hz, 1H), 7.40-7.46 (m, 4H), 8.25 (d, J = 9.0 Hz, 1H), 14.45 (s, 1H) 실시예9Example 9 2-(2-티오페닐)-7-메톡시-3-크로몬산2- (2-thiophenyl) -7-methoxy-3-chromonic acid 7-OCH3 7-OCH 3
Figure 112006056442618-PAT00029
Figure 112006056442618-PAT00029
 205-207205-207 δ 3.97 (s, 3H), 6.95 (d, J= 2.3 Hz, 1H), 7.09 (dd, J= 9.0, 2.3 Hz, 1H), 7.22 (dd, J= 5.0, 4.0 Hz, 1H), 7.79 (dd, J= 5.0, 1.1 Hz, 1H), 8.19 (d, J= 9.0 Hz, 1H), 8.25 (dd, J= 4.0, 1.1 Hz, 1H), 14.98 (s, 1H)δ 3.97 (s, 3H), 6.95 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 9.0, 2.3 Hz, 1H), 7.22 (dd, J = 5.0, 4.0 Hz, 1H), 7.79 ( dd, J = 5.0, 1.1 Hz, 1H), 8.19 (d, J = 9.0 Hz, 1H), 8.25 (dd, J = 4.0, 1.1 Hz, 1H), 14.98 (s, 1H) 실시예10Example 10 2-(3,4-디메톡시페닐)-7-메톡시-3-크로몬산2- (3,4-Dimethoxyphenyl) -7-methoxy-3-chromonic acid 7-OCH3 7-OCH 3
Figure 112006056442618-PAT00030
Figure 112006056442618-PAT00030
 208-210208-210 δ 3.94 (s, 3H), 3.96 (s, 3H), 3.97 (s, 3H), 6.97-6.99 (m, 2H), 7.12 (dd, J= 8.9, 2.3 Hz, 1H), 7.20 (d, J= 1.9 Hz, 1H), 7.34 (dd, J= 8.4, 1.9 Hz, 1H), 8.22 (d, J= 8.9 Hz, 1H)δ 3.94 (s, 3H), 3.96 (s, 3H), 3.97 (s, 3H), 6.97-6.99 (m, 2H), 7.12 (dd, J = 8.9, 2.3 Hz, 1H), 7.20 (d, J = 1.9 Hz, 1H), 7.34 (dd, J = 8.4, 1.9 Hz, 1H), 8.22 (d, J = 8.9 Hz, 1H) 실시예11Example 11 2-(3-플루오로페닐)-7-메톡시-3-크로몬산2- (3-Fluorophenyl) -7-methoxy-3-chromonic acid 7-OCH3 7-OCH 3
Figure 112006056442618-PAT00031
Figure 112006056442618-PAT00031
 214-215214-215 δ 3.96 (s, 3H), 6.97 (d, J= 2.3 Hz, 1H), 7.15 (dd, J= 9.1, 2.3 Hz, 1H), 7.26-7.50 (m, 4H), 8.24 (d, J= 9.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ 56.22, 100.21, 110.10, 115.48, 116.14, 116.91, 118.53, 124.96, 127.77, 129.86, 134.56, 157.54, 160.45, 163.56, 166.12, 172.04, 179.62.δ 3.96 (s, 3H), 6.97 (d, J = 2.3 Hz, 1H), 7.15 (dd, J = 9.1, 2.3 Hz, 1H), 7.26-7.50 (m, 4H), 8.24 (d, J = 9.1 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ): δ 56.22, 100.21, 110.10, 115.48, 116.14, 116.91, 118.53, 124.96, 127.77, 129.86, 134.56, 157.54, 160.45, 163.56, 166.12, 172.04, 179.62. 실시예12Example 12 2-(2-클로로페닐)-7-메톡시-3-크로몬산2- (2-Chlorophenyl) -7-methoxy-3-chromonic acid 7-OCH3 7-OCH 3
Figure 112006056442618-PAT00032
Figure 112006056442618-PAT00032
 130-132130-132 δ 3.96 (s, 3H), 6.98 (d, J= 2.4 Hz, 1H), 7.17 (dd, J= 9.0, 2.4 Hz, 1H), 7.43-7.44 (m, 2H), 7.48-7.56 (m, 2H), 8.28 (d, J= 9.0 Hz, 1H), 14.40 (s, 1H)δ 3.96 (s, 3H), 6.98 (d, J = 2.4 Hz, 1H), 7.17 (dd, J = 9.0, 2.4 Hz, 1H), 7.43-7.44 (m, 2H), 7.48-7.56 (m, 2H ), 8.28 (d, J = 9.0 Hz, 1H), 14.40 (s, 1H) 실시예13Example 13 2-(2-퓨라닐)-6-메톡시-3-크로몬산2- (2-furanyl) -6-methoxy-3-chromonic acid 6-OCH3 6-OCH 3
Figure 112006056442618-PAT00033
Figure 112006056442618-PAT00033
 205-207205-207 δ 3.97 (s, 3H), 6.71 (dd, J= 3.7, 1.7 Hz, 1H), 7.43 (dd, J= 9.2, 3.1 Hz, 1H), 7.60 (d, J= 9.2 Hz, 1H), 7.64 (d, J= 3.1 Hz, 1H), 7.79 (d, J= 1.7 Hz, 1H), 7.99 (d, J= 3.7 Hz, 1H), 14.60 (s, 1H)δ 3.97 (s, 3H), 6.71 (dd, J = 3.7, 1.7 Hz, 1H), 7.43 (dd, J = 9.2, 3.1 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.64 ( d, J = 3.1 Hz, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 3.7 Hz, 1H), 14.60 (s, 1H) 실시예14Example 14 2-(3-톨루에닐)-6-메톡시-3-크로몬산2- (3-Toluenyl) -6-methoxy-3-chromonic acid 6-OCH3 6-OCH 3
Figure 112006056442618-PAT00034
Figure 112006056442618-PAT00034
 198-199198-199 δ 2.46 (s, 3H), 3.98 (s, 3H), 7.27-7.46 (m, 5H), 7.56 (d, J= 9.2 Hz, 1H), 7.67 (d, J= 3.0 Hz, 1H), 14.35 (s, 1H)δ 2.46 (s, 3H), 3.98 (s, 3H), 7.27-7.46 (m, 5H), 7.56 (d, J = 9.2 Hz, 1H), 7.67 (d, J = 3.0 Hz, 1H), 14.35 ( s, 1 H) 실시예15Example 15 2-(2-티오페닐)-6-메톡시-3-크로몬산2- (2-thiophenyl) -6-methoxy-3-chromonic acid 6-OCH3 6-OCH 3
Figure 112006056442618-PAT00035
Figure 112006056442618-PAT00035
 172-174172-174 δ 3.96 (s, 3H), 7.24 (dd, J= 5.0, 4.0 Hz, 1H), 7.43 (dd, J= 9.2, 3.0 Hz, 1H), 7.55 (d, J= 9.2 Hz, 1H), 7.63 (d, J= 3.0 Hz, 1H), 7.81 (dd, J= 5.0, 1.2 Hz, 1H), 8.25 (dd, J= 4.0, 1.2 Hz, 1H), 14.78 (s, 1H)δ 3.96 (s, 3H), 7.24 (dd, J = 5.0, 4.0 Hz, 1H), 7.43 (dd, J = 9.2, 3.0 Hz, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.63 ( d, J = 3.0 Hz, 1H), 7.81 (dd, J = 5.0, 1.2 Hz, 1H), 8.25 (dd, J = 4.0, 1.2 Hz, 1H), 14.78 (s, 1H) 실시예16Example 16 2-(2-퓨라닐)-3-크로몬산2- (2-furanyl) -3-chromic acid HH
Figure 112006056442618-PAT00036
Figure 112006056442618-PAT00036
 202-205202-205 δ 6.72 (dd, J= 3.8, 1.7 Hz, 1H), 7.54-7.60 (m, 1H), 7.65 (d, J= 8.4 Hz, 1H), 7.81-7.89 (m, 2H), 8.01-8.03 (m, 1H), 8.32 (dd, J= 8.0, 1.5 Hz, 1H), 14.45 (s, 1H)δ 6.72 (dd, J = 3.8, 1.7 Hz, 1H), 7.54-7.60 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.81-7.89 (m, 2H), 8.01-8.03 (m , 1H), 8.32 (dd, J = 8.0, 1.5 Hz, 1H), 14.45 (s, 1H) 실시예17Example 17 2-(3-톨루에닐)-3-크로몬산2- (3-Toluenyl) -3-chromonic acid HH
Figure 112006056442618-PAT00037
Figure 112006056442618-PAT00037
 162-164162-164 δ 2.48 (s, 3H), 7.43-7.50 (m, 4H), 7.59-7.65 (m, 2H), 7.86-7.92 (m, 1H), 8.38 (dd, J= 8.0, 1.5 Hz, 1H), 14.20 (s, 1H)δ 2.48 (s, 3H), 7.43-7.50 (m, 4H), 7.59-7.65 (m, 2H), 7.86-7.92 (m, 1H), 8.38 (dd, J = 8.0, 1.5 Hz, 1H), 14.20 (s, 1H) 실시예18Example 18 2-(2-티오페닐)-3-크로몬산2- (2-thiophenyl) -3-chromic acid HH
Figure 112006056442618-PAT00038
Figure 112006056442618-PAT00038
 175-176175-176 δ 7.25 (dd, J= 5.0, 4.1 Hz, 1H), 7.55-7.64 (m, 2H), 7.83-7.89 (m, 2H), 8.29-8.34 (m, 2H), 14.70 (s, 1H)δ 7.25 (dd, J = 5.0, 4.1 Hz, 1H), 7.55-7.64 (m, 2H), 7.83-7.89 (m, 2H), 8.29-8.34 (m, 2H), 14.70 (s, 1H) 실시예19Example 19 2-(3,4-디메톡시페닐)-3-크로몬산2- (3,4-dimethoxyphenyl) -3-chromonic acid HH
Figure 112006056442618-PAT00039
Figure 112006056442618-PAT00039
 237-238237-238 δ 3.94 (s, 3H), 3.99 (s, 3H), 7.00 (d, J= 8.4 Hz, 1H), 7.23 (d, J= 2.1 Hz, 1H), 7.39 (dd, J= 8.4, 2.1 Hz, 1H), 7.56-7.64 (m, 2H), 7.64-7.90 (m, 1H), 8.36 (dd, J= 8.0, 1.6 Hz, 1H), 14.50 (s, 1H)δ 3.94 (s, 3H), 3.99 (s, 3H), 7.00 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 7.39 (dd, J = 8.4, 2.1 Hz, 1H), 7.56-7.64 (m, 2H), 7.64-7.90 (m, 1H), 8.36 (dd, J = 8.0, 1.6 Hz, 1H), 14.50 (s, 1H) 실시예20Example 20 2-(3-플루오로페닐)-3-크로몬산2- (3-fluorophenyl) -3-chromonic acid HH
Figure 112006056442618-PAT00040
Figure 112006056442618-PAT00040
 193-196193-196 δ 7.29-7.55 (m, 4H), 7.60-7.65 (m, 2H), 7.87-7.93 (m, 1H), 8.37-8.40 (m, 1H), 14.19 (s, 1H)δ 7.29-7.55 (m, 4H), 7.60-7.65 (m, 2H), 7.87-7.93 (m, 1H), 8.37-8.40 (m, 1H), 14.19 (s, 1H) 실시예21Example 21 2-(3,5-디플루오로페닐)-3-크로몬산2- (3,5-Difluorophenyl) -3-chromonic acid HH
Figure 112006056442618-PAT00041
Figure 112006056442618-PAT00041
 208-209208-209 δ 7.02-7.08 (m, 1H), 7.16-7.19 (m, 2H), 7.62-66 (m, 2H), 7.89-7.94 (m, 1H), 8.38 (d, J= 8.3 Hz, 1H)δ 7.02-7.08 (m, 1H), 7.16-7.19 (m, 2H), 7.62-66 (m, 2H), 7.89-7.94 (m, 1H), 8.38 (d, J = 8.3 Hz, 1H) 실시예22Example 22 2-(4-클로로페닐)-3-크로몬산2- (4-Chlorophenyl) -3-chromic acid HH
Figure 112006056442618-PAT00042
Figure 112006056442618-PAT00042
 212-213212-213 δ 7.50 (d, J= 8.6 Hz, 2H), 7.58-7.63 (m, 4H), 7.84-7.90 (m, 1H), 8.35 (dd, J= 8.2, 1.7 Hz, 1H), 14.35 (s, 1H)δ 7.50 (d, J = 8.6 Hz, 2H), 7.58-7.63 (m, 4H), 7.84-7.90 (m, 1H), 8.35 (dd, J = 8.2, 1.7 Hz, 1H), 14.35 (s, 1H ) 실시예23Example 23 2-(2-클로로페닐)-3-크로몬산2- (2-Chlorophenyl) -3-chromic acid HH
Figure 112006056442618-PAT00043
Figure 112006056442618-PAT00043
 133-135133-135 δ 7.44-7.46 (m, 2H), 7.49-7.55 (m, 2H), 7.61-7.66 (m, 2H), 7.87-7.93 (m, 1H), 8.40 (dd, J= 8.3, 1.7 Hz, 1H)δ 7.44-7.46 (m, 2H), 7.49-7.55 (m, 2H), 7.61-7.66 (m, 2H), 7.87-7.93 (m, 1H), 8.40 (dd, J = 8.3, 1.7 Hz, 1H) 실시예24Example 24 2-(2-퓨라닐)-8-메틸-3-크로몬산2- (2-furanyl) -8-methyl-3-chromonic acid 8-CH3 8-CH 3
Figure 112006056442618-PAT00044
Figure 112006056442618-PAT00044
 227-228227-228 δ 2.58 (s, 3H), 6.69 (dd, J= 3.6, 1.7 Hz, 1H), 7.32-7.36 (m, 2H), 7.59 (d, J= 7.3 Hz, 1H), 7.76-7.77 (m, 1H), 7.98 (d, J= 7.3 Hz, 1H)δ 2.58 (s, 3H), 6.69 (dd, J = 3.6, 1.7 Hz, 1H), 7.32-7.36 (m, 2H), 7.59 (d, J = 7.3 Hz, 1H), 7.76-7.77 (m, 1H ), 7.98 (d, J = 7.3 Hz, 1H) 실시예25Example 25 2-(3-톨루에닐)-8-메틸-3-크로몬산2- (3-Toluenyl) -8-methyl-3-chromonic acid 8-CH3 8-CH 3
Figure 112006056442618-PAT00045
Figure 112006056442618-PAT00045
 209-211209-211 δ 2.47 (s, 3H), 2.55 (s, 3H), 7.42-7.51 (m, 5H), 7.70 (d, J= 7.1 Hz, 1H), 8.19 (d, J= 7.1 Hz, 1H), 14.25 (s, 1H)δ 2.47 (s, 3H), 2.55 (s, 3H), 7.42-7.51 (m, 5H), 7.70 (d, J = 7.1 Hz, 1H), 8.19 (d, J = 7.1 Hz, 1H), 14.25 ( s, 1 H) 실시예26Example 26 2-(2-티오페닐)-8-메틸-3-크로몬산2- (2-thiophenyl) -8-methyl-3-chromonic acid 8-CH3 8-CH 3
Figure 112006056442618-PAT00046
Figure 112006056442618-PAT00046
 205-206205-206 δ 2.63 (s, 3H), 7.25-7.26 (m, 4H), 7.45 (dd, J= 7.7, 7.7 Hz, 1H), 7.68 (d, J= 7.7 Hz, 1H), 7.83 (dd, J= 5.0, 1.0 Hz, 1H), 8.14 (d, J= 7.7 Hz, 1H), 8.38 (dd, J= 4.0, 1.0 Hz, 1H)δ 2.63 (s, 3H), 7.25-7.26 (m, 4H), 7.45 (dd, J = 7.7, 7.7 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.83 (dd, J = 5.0 , 1.0 Hz, 1H), 8.14 (d, J = 7.7 Hz, 1H), 8.38 (dd, J = 4.0, 1.0 Hz, 1H) 실시예27Example 27 2-(3,4-디메톡시페닐)-8-메틸-3-크로몬산2- (3,4-dimethoxyphenyl) -8-methyl-3-chromonic acid 8-CH3 8-CH 3
Figure 112006056442618-PAT00047
Figure 112006056442618-PAT00047
 210-212210-212 δ 2.58 (s, 3H), 3.96 (s, 3H), 4.00 (s, 3H), 7.01 (d, J= 8.5 Hz, 1H), 7.27 (d, J= 2.1 Hz, 1H), 7.43 (dd, J= 8.5, 2.1 Hz, 1H), 7.48 (dd, J= 7.7, 7.7 Hz, 1H), 7.69 (d, J= 7.7 Hz, 1H), 8.18 (d, J= 7.7 Hz, 1H), 14.45 (s, 1H)δ 2.58 (s, 3H), 3.96 (s, 3H), 4.00 (s, 3H), 7.01 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.43 (dd, J = 8.5, 2.1 Hz, 1H), 7.48 (dd, J = 7.7, 7.7 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 8.18 (d, J = 7.7 Hz, 1H), 14.45 ( s, 1 H) 실시예28Example 28 2-(3-플루오로페닐)-7-메틸-3-크로몬산2- (3-Fluorophenyl) -7-methyl-3-chromonic acid 7-CH3 7-CH 3
Figure 112006056442618-PAT00048
Figure 112006056442618-PAT00048
 227-229227-229 δ 2.54 (s, 3H), 7.28-7.33 (m, 1H), 7.39 (d, J= 9.3 Hz, 1H), 7.46-7.49 (m. 3H), 7.71 (d, J= 7.5 Hz, 1H), 8.19 (d, J= 8.0 Hz, 1H)δ 2.54 (s, 3H), 7.28-7.33 (m, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.46-7.49 (m. 3H), 7.71 (d, J = 7.5 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H) 실시예29Example 29 2-(3,5-디플루오로페닐)-8-메틸-3-크로몬산2- (3,5-Difluorophenyl) -8-methyl-3-chromonic acid 8-CH3 8-CH 3
Figure 112006056442618-PAT00049
Figure 112006056442618-PAT00049
 243-244243-244 δ 2.53 (s, 3H), 7.01-7.06 (m, 1H), 7.26-7.33 (m, 2H), 7.42-7.47 (m. 1H), 7.67 (d, J= 7.0 Hz, 1H), 8.13 (d, J= 7.9 Hz, 1H)δ 2.53 (s, 3H), 7.01-7.06 (m, 1H), 7.26-7.33 (m, 2H), 7.42-7.47 (m. 1H), 7.67 (d, J = 7.0 Hz, 1H), 8.13 (d , J = 7.9 Hz, 1H) 실시예30Example 30 2-(2,3-디플루오로페닐)-8-메틸-3-크로몬산2- (2,3-Difluorophenyl) -8-methyl-3-chromonic acid 8-CH3 8-CH 3
Figure 112006056442618-PAT00050
Figure 112006056442618-PAT00050
 167-169167-169 δ 2.51 (s, 3H), 7.26-7.31 (m, 2H), 7.36-7.43 (m, 1H), 7.48-7.53 (m, 1H), 7.71 (d, J= 7.3 Hz, 1H), 8.20 (d, J= 7.9 Hz, 1H), 14.21 (s, 1H)δ 2.51 (s, 3H), 7.26-7.31 (m, 2H), 7.36-7.43 (m, 1H), 7.48-7.53 (m, 1H), 7.71 (d, J = 7.3 Hz, 1H), 8.20 (d , J = 7.9 Hz, 1H), 14.21 (s, 1H) 실시예31Example 31 2-(2,5-디플루오로페닐)-8-메틸-3-크로몬산2- (2,5-Difluorophenyl) -8-methyl-3-chromonic acid 8-CH3 8-CH 3
Figure 112006056442618-PAT00051
Figure 112006056442618-PAT00051
 170-172170-172 δ 2.54 (s, 3H), 7.20-7.31 (m, 3H), 7.51 (dd, J= 7.6, 7.6 Hz, 1H), 7.73 (d, J= 7.6 Hz, 1H), 8.21 (d, J= 7.6 Hz, 1H), 14.19 (s, 1H)δ 2.54 (s, 3H), 7.20-7.31 (m, 3H), 7.51 (dd, J = 7.6, 7.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 7.6 Hz, 1H), 14.19 (s, 1H) 실시예32Example 32 2-(3,4-디플루오로페닐)-8-메틸-3-크로몬산2- (3,4-Difluorophenyl) -8-methyl-3-chromonic acid 8-CH3 8-CH 3
Figure 112006056442618-PAT00052
Figure 112006056442618-PAT00052
 203-204203-204 δ 2.55 (s, 3H), 7.29-7.38 (m, 1H), 7.45-7.58 (m, 3H), 7.73 (d, J= 6.7 Hz, 1H), 8.20 (d, J= 8.1 Hz, 1H), 14.30 (s, 1H)δ 2.55 (s, 3H), 7.29-7.38 (m, 1H), 7.45-7.58 (m, 3H), 7.73 (d, J = 6.7 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 14.30 (s, 1 H) 실시예33Example 33 2-(4-클로로페닐)-8-메틸-3-크로몬산2- (4-Chlorophenyl) -8-methyl-3-chromonic acid 8-CH3 8-CH 3
Figure 112006056442618-PAT00053
Figure 112006056442618-PAT00053
 217-219217-219 δ 2.53 (s, 3H), 7.46-7.53 (m, 3H), 7.63 (dd, J= 6.7, 2.0 Hz, 2H), 7.70 (d, J= 6.7 Hz, 1H), 8.18 (d, J= 8.0 Hz, 1H), 14.35 (s, 1H)δ 2.53 (s, 3H), 7.46-7.53 (m, 3H), 7.63 (dd, J = 6.7, 2.0 Hz, 2H), 7.70 (d, J = 6.7 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 14.35 (s, 1H) 실시예34Example 34 2-(2-퓨라닐)-7-메틸-3-크로몬산2- (2-furanyl) -7-methyl-3-chromonic acid 7-CH3 7-CH 3
Figure 112006056442618-PAT00054
Figure 112006056442618-PAT00054
 217-218217-218 δ 2.57 (s, 3H), 6.71 (dd, J= 3.7, 1.7 Hz, 1H), 7.37 (dd, J= 8.2, 0.8 Hz, 1H), 7.46 (s, 1H), 7.79 (d, J= 1.7 Hz, 1H), 8.00 (d, J= 3.7 Hz, 1H), 8.18 (d, J= 8.2 Hz, 1H), 14.55 (s, 1H)δ 2.57 (s, 3H), 6.71 (dd, J = 3.7, 1.7 Hz, 1H), 7.37 (dd, J = 8.2, 0.8 Hz, 1H), 7.46 (s, 1H), 7.79 (d, J = 1.7 Hz, 1H), 8.00 (d, J = 3.7 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 14.55 (s, 1H) 실시예35Example 35 2-(3-톨루에닐)-7-메틸-3-크로몬산2- (3-Toluenyl) -7-methyl-3-chromonic acid 7-CH3 7-CH 3
Figure 112006056442618-PAT00055
Figure 112006056442618-PAT00055
 152-155152-155 δ 2.46 (s, 3H), 2.57 (s, 3H), 7.39-7.47 (m, 6H), 8.24 (d, J= 8.5 Hz, 1H), 14.30 (s, 1H)δ 2.46 (s, 3H), 2.57 (s, 3H), 7.39-7.47 (m, 6H), 8.24 (d, J = 8.5 Hz, 1H), 14.30 (s, 1H) 실시예36Example 36 2-(2-티오페닐)-7-메틸-3-크로몬산2- (2-thiophenyl) -7-methyl-3-chromonic acid 7-CH3 7-CH 3
Figure 112006056442618-PAT00056
Figure 112006056442618-PAT00056
 202-203202-203 δ 2.58 (s, 3H), 7.24 (dd, J= 5.0, 4.0 Hz, 1H), 7.37 (d, J= 8.2 Hz, 1H), 7.42 (s, 1H), 7.82 (dd, J= 5.0, 1.1 Hz, 1H), 8.18 (d, J= 8.2 Hz, 1H), 8.28 (dd, J= 4.0, 1.1 Hz, 1H), 14.80 (s, 1H)δ 2.58 (s, 3H), 7.24 (dd, J = 5.0, 4.0 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.42 (s, 1H), 7.82 (dd, J = 5.0, 1.1 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.28 (dd, J = 4.0, 1.1 Hz, 1H), 14.80 (s, 1H) 실시예37Example 37 2-(3,4-디메톡시페닐)-7-메틸-3-크로몬산2- (3,4-dimethoxyphenyl) -7-methyl-3-chromonic acid 7-CH3 7-CH 3
Figure 112006056442618-PAT00057
Figure 112006056442618-PAT00057
 200-201200-201 δ 2.58 (s, 3H), 3.96 (s, 3H), 3.99 (s, 3H), 6.99 (d, J= 8.5 Hz, 1H), 7.22 (d, J= 2.0 Hz, 1H), 7.36-7.43 (m, 3H), 8.22 (d, J= 8.1 Hz, 1H), 14.45 (s, 1H)δ 2.58 (s, 3H), 3.96 (s, 3H), 3.99 (s, 3H), 6.99 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.36-7.43 ( m, 3H), 8.22 (d, J = 8.1 Hz, 1H), 14.45 (s, 1H) 실시예38Example 38 2-(3,5-디플루오로페닐)-7-메틸-3-크로몬산2- (3,5-Difluorophenyl) -7-methyl-3-chromonic acid 7-CH3 7-CH 3
Figure 112006056442618-PAT00058
Figure 112006056442618-PAT00058
 220-222220-222 δ 2.65 (s, 3H), 7.07-7.15 (m, 1H), 7.18-7.26 (m, 2H), 7.50 (d, J= 8.2 Hz, 2H), 8.31 (d, J= 8.2 Hz, 1H), 14.34 (s, 1H)δ 2.65 (s, 3H), 7.07-7.15 (m, 1H), 7.18-7.26 (m, 2H), 7.50 (d, J = 8.2 Hz, 2H), 8.31 (d, J = 8.2 Hz, 1H), 14.34 (s, 1 H) 실시예39Example 39 2-(2,3-디플루오로페닐)-7-메틸-3-크로몬산2- (2,3-Difluorophenyl) -7-methyl-3-chromonic acid 7-CH3 7-CH 3
Figure 112006056442618-PAT00059
Figure 112006056442618-PAT00059
 155-156155-156 δ 2.57 (s, 3H), 7.17-7.27 (m, 3H), 7.42 (d, J= 8.2 Hz, 2H), 8.24 (d, J= 8.2 Hz, 1H), 14.20 (s, 1H)δ 2.57 (s, 3H), 7.17-7.27 (m, 3H), 7.42 (d, J = 8.2 Hz, 2H), 8.24 (d, J = 8.2 Hz, 1H), 14.20 (s, 1H) 실시예40Example 40 2-(2,5-디플루오로페닐)-7-메틸-3-크로몬산2- (2,5-Difluorophenyl) -7-methyl-3-chromonic acid 7-CH3 7-CH 3
Figure 112006056442618-PAT00060
Figure 112006056442618-PAT00060
 156-158156-158 δ 2.59 (s, 3H), 7.15-7.29 (m, 3H), 7.43 (d, J= 8.0 Hz, 2H), 8.12 (d, J= 8.0 Hz, 1H), 14.21 (s, 1H)δ 2.59 (s, 3H), 7.15-7.29 (m, 3H), 7.43 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 8.0 Hz, 1H), 14.21 (s, 1H) 실시예41Example 41 2-(3,4-디플루오로페닐)-7-메틸-3-크로몬산2- (3,4-Difluorophenyl) -7-methyl-3-chromonic acid 7-CH3 7-CH 3
Figure 112006056442618-PAT00061
Figure 112006056442618-PAT00061
 202-204202-204 δ 7.30-7.36 (m, 1H), 7.43 (d, J= 6.9 Hz, 3H), 7.49-7.55 (m, 1H), 8.24 (d, J= 8.7 Hz, 1H), 14.30 (s, 1H)δ 7.30-7.36 (m, 1H), 7.43 (d, J = 6.9 Hz, 3H), 7.49-7.55 (m, 1H), 8.24 (d, J = 8.7 Hz, 1H), 14.30 (s, 1H) 실시예42Example 42 2-(4-클로로페닐)-7-메틸-3-크로몬산2- (4-Chlorophenyl) -7-methyl-3-chromonic acid 7-CH3 7-CH 3
Figure 112006056442618-PAT00062
Figure 112006056442618-PAT00062
 220-222220-222 δ 2.56 (s, 3H), 7.40 (d, J= 6.7 Hz, 2H), 7.48 (dd, J= 6.7, 2.0 Hz, 2H), 7.60 (dd, J= 6.7, 2.0 Hz, 2H), 8.22 (d, J= 8.6 Hz, 1H), 14.35 (s, 1H)δ 2.56 (s, 3H), 7.40 (d, J = 6.7 Hz, 2H), 7.48 (dd, J = 6.7, 2.0 Hz, 2H), 7.60 (dd, J = 6.7, 2.0 Hz, 2H), 8.22 ( d, J = 8.6 Hz, 1H), 14.35 (s, 1H) 실시예43Example 43 2-(2-퓨라닐)-6-메틸-3-크로몬산2- (2-furanyl) -6-methyl-3-chromonic acid 6-CH3 6-CH 3
Figure 112006056442618-PAT00063
Figure 112006056442618-PAT00063
 195-197195-197 δ 2.53 (s, 3H), 6.71 (dd, J= 3.7, 1.7 Hz, 1H), 7.55 (d, J= 8.6 Hz, 1H), 7.66 (dd, J= 8.6, 2.0 Hz, 1H), 7.79 (d, J= 1.7 Hz, 1H), 7.99 (d, J= 3.7 Hz, 1H), 8.09 (s, 1H), 14.55 (s, 1H)δ 2.53 (s, 3H), 6.71 (dd, J = 3.7, 1.7 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.66 (dd, J = 8.6, 2.0 Hz, 1H), 7.79 ( d, J = 1.7 Hz, 1H), 7.99 (d, J = 3.7 Hz, 1H), 8.09 (s, 1H), 14.55 (s, 1H) 실시예44Example 44 2-(3-톨루에닐)-6-메틸-3-크로몬산2- (3-Toluenyl) -6-methyl-3-chromonic acid 6-CH3 6-CH 3
Figure 112006056442618-PAT00064
Figure 112006056442618-PAT00064
 192-195192-195 δ 2.46 (s, 3H), 2.55 (s, 3H), 7.41-7.47 (m, 4H), 7.52 (d, J= 8.6 Hz, 1H), 7.67 (dd, J= 8.6, 2.1 Hz, 1H), 8.14 (d, J= 0.9 Hz, 1H), 14.30 (s, 1H)δ 2.46 (s, 3H), 2.55 (s, 3H), 7.41-7.47 (m, 4H), 7.52 (d, J = 8.6 Hz, 1H), 7.67 (dd, J = 8.6, 2.1 Hz, 1H), 8.14 (d, J = 0.9 Hz, 1H), 14.30 (s, 1H) 실시예45Example 45 2-(2-티오페닐)-6-메틸-3-크로몬산2- (2-thiophenyl) -6-methyl-3-chromonic acid 6-CH3 6-CH 3
Figure 112006056442618-PAT00065
Figure 112006056442618-PAT00065
 153-155153-155 δ 2.54 (s, 3H), 7.24 (dd, J= 5.0, 4.0 Hz, 1H), 7.52 (d, J= 8.6 Hz, 1H), 7.66 (dd, J= 8.6, 2.0 Hz, 1H), 7.82 (dd, J= 5.0, 1.1 Hz, 1H), 8.09 (s, 1H), 8.28 (dd, J= 4.0, 1.1 Hz, 1H), 14.75 (s, 1H)δ 2.54 (s, 3H), 7.24 (dd, J = 5.0, 4.0 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.66 (dd, J = 8.6, 2.0 Hz, 1H), 7.82 ( dd, J = 5.0, 1.1 Hz, 1H), 8.09 (s, 1H), 8.28 (dd, J = 4.0, 1.1 Hz, 1H), 14.75 (s, 1H) 실시예46Example 46 2-(2-티오페닐)-6-메틸-3-크로몬산2- (2-thiophenyl) -6-methyl-3-chromonic acid 6-CH3 6-CH 3
Figure 112006056442618-PAT00066
Figure 112006056442618-PAT00066
 227-228227-228 δ 2.55 (s, 3H), 3.96 (s, 3H), 3.99 (s, 3H), 7.00 (d, J= 8.4 Hz, 1H), 7.22 (d, J= 2.0 Hz, 1H), 7.37 (dd, J= 8.4, 2.0 Hz, 1H), 7.52 (d, J= 8.6 Hz, 1H), 7.67 (dd, J= 8.6, 2.1 Hz, 1H), 8.13 (d, J= 2.1 Hz, 1H), 14.20 (s, 1H)δ 2.55 (s, 3H), 3.96 (s, 3H), 3.99 (s, 3H), 7.00 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 8.4, 2.0 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.67 (dd, J = 8.6, 2.1 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 14.20 ( s, 1 H) 실시예47Example 47 2-(3-플루오로페닐)-6-메틸-3-크로몬산2- (3-Fluorophenyl) -6-methyl-3-chromonic acid 6-CH3 6-CH 3
Figure 112006056442618-PAT00067
Figure 112006056442618-PAT00067
 214-215214-215 δ 2.56 (s, 3H), 7.30-7.33 (m, 1H), 7.35-7.39 (m, 1H), 7.42-7.45 (m, 1H), 7.47-7.54 (m. 2H), 7.69 (dd, J= 8.6, 2.0 Hz, 1H), 8.14 (s, 1H), 14.30 (s, 1H)δ 2.56 (s, 3H), 7.30-7.33 (m, 1H), 7.35-7.39 (m, 1H), 7.42-7.45 (m, 1H), 7.47-7.54 (m. 2H), 7.69 (dd, J = 8.6, 2.0 Hz, 1H), 8.14 (s, 1H), 14.30 (s, 1H) 실시예48Example 48 2-(3,5-디플루오로페닐)-6-메틸-3-크로몬산2- (3,5-Difluorophenyl) -6-methyl-3-chromonic acid 6-CH3 6-CH 3
Figure 112006056442618-PAT00068
Figure 112006056442618-PAT00068
 222-223222-223 δ 7.32-7.38 (m, 2H), 7.44 (d, J= 7.8 Hz, 1H), 7.48-7.55 (m. 2H), 7.97 (dd, J= 9.7, 2.3 Hz, 1H), 8.50 (d, J= 2.3 Hz, 1H), 13.85 (s, 1H)δ 7.32-7.38 (m, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.48-7.55 (m. 2H), 7.97 (dd, J = 9.7, 2.3 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 13.85 (s, 1H) 실시예49Example 49 2-(2,3-디플루오로페닐)-6-메틸-3-크로몬산2- (2,3-Difluorophenyl) -6-methyl-3-chromonic acid 6-CH3 6-CH 3
Figure 112006056442618-PAT00069
Figure 112006056442618-PAT00069
 -- δ 2.55 (s, 3H), 7.24-7.30 (m, 2H), 7.35-7.43 (m, 1H), 7.51 (d, J= 8.6 Hz, 1H), 7.69 (dd, J= 8.6, 2.0 Hz, 1H), 8.14 (s, 1H), 14.15 (s, 1H)δ 2.55 (s, 3H), 7.24-7.30 (m, 2H), 7.35-7.43 (m, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.6, 2.0 Hz, 1H ), 8.14 (s, 1H), 14.15 (s, 1H) 실시예50Example 50 2-(2,5-디플루오로페닐)-6-메틸-3-크로몬산2- (2,5-Difluorophenyl) -6-methyl-3-chromonic acid 6-CH3 6-CH 3
Figure 112006056442618-PAT00070
Figure 112006056442618-PAT00070
 -- δ 2.57 (s, 3H), 7.15-7.30 (m, 3H), 7.52 (d, J= 8.6 Hz, 1H), 7.70 (dd, J= 8.6, 1.9 Hz, 1H), 8.15 (s, 1H), 14.17 (s, 1H)δ 2.57 (s, 3H), 7.15-7.30 (m, 3H), 7.52 (d, J = 8.6 Hz, 1H), 7.70 (dd, J = 8.6, 1.9 Hz, 1H), 8.15 (s, 1H), 14.17 (s, 1 H) 실시예51Example 51 2-(3,4-디플루오로페닐)-6-메틸-3-크로몬산2- (3,4-Difluorophenyl) -6-methyl-3-chromonic acid 6-CH3 6-CH 3
Figure 112006056442618-PAT00071
Figure 112006056442618-PAT00071
 222-223222-223 δ 2.56 (s, 3H), 7.30-7.36 (m, 1H), 7.42-7.47 (m, 1H), 7.49-7.56 (m, 2H), 7.70 (dd, J= 8.5, 1.8 Hz, 1H), 8.14 (s, 1H), 14.20 (s, 1H)δ 2.56 (s, 3H), 7.30-7.36 (m, 1H), 7.42-7.47 (m, 1H), 7.49-7.56 (m, 2H), 7.70 (dd, J = 8.5, 1.8 Hz, 1H), 8.14 (s, 1H), 14.20 (s, 1H) 실시예52Example 52 2-(4-클로로페닐)-6-메틸-3-크로몬산2- (4-Chlorophenyl) -6-methyl-3-chromonic acid 6-CH3 6-CH 3
Figure 112006056442618-PAT00072
Figure 112006056442618-PAT00072
 212-227212-227 δ 2.54 (s, 3H), 7.49 (dd, J= 8.6, 2.7 Hz, 3H), 7.60 (dd, J= 8.6, 1.8 Hz, 2H), 7.67 (dd, J= 8.6, 2.1 Hz, 1H), 8.12 (s, 1H), 14.50 (s, 1H)δ 2.54 (s, 3H), 7.49 (dd, J = 8.6, 2.7 Hz, 3H), 7.60 (dd, J = 8.6, 1.8 Hz, 2H), 7.67 (dd, J = 8.6, 2.1 Hz, 1H), 8.12 (s, 1 H), 14.50 (s, 1 H) 실시예53Example 53 2-(2-퓨라닐)-7-클로로-3-크로몬산2- (2-furanyl) -7-chloro-3-chromonic acid 7-Cl7-Cl
Figure 112006056442618-PAT00073
Figure 112006056442618-PAT00073
 224-225224-225 δ 6.73 (dd, J= 3.7, 1.7 Hz, 1H), 7.52 (dd, J= 8.6, 1.8 Hz, 1H), 7.70 (d, J= 1.8 Hz, 1H), 7.81 (d, J= 1.7 Hz, 1H), 8.04 (d, J= 3.7 Hz, 1H), 8.25 (d, J= 8.6 Hz, 1H), 14.15 (s, 1H)δ 6.73 (dd, J = 3.7, 1.7 Hz, 1H), 7.52 (dd, J = 8.6, 1.8 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 1.7 Hz, 1H), 8.04 (d, J = 3.7 Hz, 1H), 8.25 (d, J = 8.6 Hz, 1H), 14.15 (s, 1H) 실시예54Example 54 2-(3-톨루에닐)-7-클로로-3-크로몬산2- (3-Toluenyl) -7-chloro-3-chromonic acid 7-Cl7-Cl
Figure 112006056442618-PAT00074
Figure 112006056442618-PAT00074
 179-181179-181 δ 2.46 (s, 3H), 7.43-7.46 (m, 4H), 7.56 (dd, J= 8.6, 1.5 Hz, 1H), 7.66 (s, 1H), 8.30 (d, J= 8.6 Hz, 1H), 13.95 (s, 1H)δ 2.46 (s, 3H), 7.43-7.46 (m, 4H), 7.56 (dd, J = 8.6, 1.5 Hz, 1H), 7.66 (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 13.95 (s, 1 H) 실시예55Example 55 2-(2-티오페닐)-7-클로로-3-크로몬산2- (2-thiophenyl) -7-chloro-3-chromonic acid 7-Cl7-Cl
Figure 112006056442618-PAT00075
Figure 112006056442618-PAT00075
 232-223232-223 δ 7.20 (dd, J= 5.0, 4.0 Hz, 1H), 7.42 (dd, J= 8.5, 1.8 Hz, 1H), 7.60 (d, J= 1.8 Hz, 1H), 7.73 (dd, J= 5.0, 1.0 Hz, 1H), 7.93 (dd, J= 4.0, 1.0 Hz, 1H), 8.15 (d, J= 8.5 Hz, 1H)δ 7.20 (dd, J = 5.0, 4.0 Hz, 1H), 7.42 (dd, J = 8.5, 1.8 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.73 (dd, J = 5.0, 1.0 Hz, 1H), 7.93 (dd, J = 4.0, 1.0 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H) 실시예56Example 56 2-(3,4-디메톡시페닐)-7-클로로-3-크로몬산2- (3,4-Dimethoxyphenyl) -7-chloro-3-chromonic acid 7-Cl7-Cl
Figure 112006056442618-PAT00076
Figure 112006056442618-PAT00076
 226-227226-227 δ 3.95 (s, 3H), 3.99 (s, 3H), 6.99 (d, J= 8.4 Hz, 1H), 7.21 (d, J= 2.1 Hz, 1H), 7.38 (dd, J= 8.4, 2.1 Hz, 1H), 7.54 (dd, J= 8.6, 1.8 Hz, 1H), 7.66 (dd, J= 1.8 Hz, 1H), 8.28 (d, J= 8.6 Hz, 1H), 14.10 (s, 1H)δ 3.95 (s, 3H), 3.99 (s, 3H), 6.99 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.54 (dd, J = 8.6, 1.8 Hz, 1H), 7.66 (dd, J = 1.8 Hz, 1H), 8.28 (d, J = 8.6 Hz, 1H), 14.10 (s, 1H) 실시예57Example 57 2-(3-플루오로페닐)-7-클로로-3-크로몬산2- (3-Fluorophenyl) -7-chloro-3-chromonic acid 7-Cl7-Cl
Figure 112006056442618-PAT00077
Figure 112006056442618-PAT00077
 160-163160-163 δ 7.30-7.44 (m, 2H), 7.51 (dd, J= 8.0, 5.4 Hz, 1H), 7.58 (dd, J= 8.6, 1.8 Hz, 1H), 7.66 (d, J= 1.8 Hz, 1H), 7.71-7.75 (m, 1H), 8.31 (d, J= 8.6 Hz, 1H), 15.35 (s, 1H)δ 7.30-7.44 (m, 2H), 7.51 (dd, J = 8.0, 5.4 Hz, 1H), 7.58 (dd, J = 8.6, 1.8 Hz, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.71-7.75 (m, 1H), 8.31 (d, J = 8.6 Hz, 1H), 15.35 (s, 1H) 실시예58Example 58 2-(2,3-디플루오로페닐)-7-클로로-3-크로몬산2- (2,3-Difluorophenyl) -7-chloro-3-chromonic acid 7-Cl7-Cl
Figure 112006056442618-PAT00078
Figure 112006056442618-PAT00078
 -- δ 6.95-7.31 (m, 2H), 7.38-7.46 (m, 1H), 7.69 (dd, J= 8.6, 1.8 Hz, 1H), 7.65 (d, J= 1.8 Hz, 1H), 8.32 (d, J= 8.6 Hz, 1H), 13.85 (s, 1H)δ 6.95-7.31 (m, 2H), 7.38-7.46 (m, 1H), 7.69 (dd, J = 8.6, 1.8 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H), 13.85 (s, 1H) 실시예59Example 59 2-(2,5-디플루오로페닐)-7-클로로-3-크로몬산2- (2,5-Difluorophenyl) -7-chloro-3-chromonic acid 7-Cl7-Cl
Figure 112006056442618-PAT00079
Figure 112006056442618-PAT00079
 147-150147-150 δ 7.26-7.43 (m, 3H), 7.69 (dd, J= 8.6, 1.8 Hz, 1H), 7.75 (d, J= 1.8 Hz, 1H), 8.41 (d, J= 8.6 Hz, 1H), 13.94 (s, 1H)δ 7.26-7.43 (m, 3H), 7.69 (dd, J = 8.6, 1.8 Hz, 1H), 7.75 (d, J = 1.8 Hz, 1H), 8.41 (d, J = 8.6 Hz, 1H), 13.94 ( s, 1 H) 실시예60Example 60 2-(2-퓨라닐)-6-클로로-3-크로몬산2- (2-furanyl) -6-chloro-3-chromonic acid 6-Cl6-Cl
Figure 112006056442618-PAT00080
Figure 112006056442618-PAT00080
 196-198196-198 δ 6.73 (dd, J= 3.8, 1.7 Hz, 1H), 7.62 (d, J= 9.0 Hz, 1H), 7.77-7.81 (m, 2H), 8.04 (dd, J= 3.8, 0.5 Hz, 1H), 8.27 (d, J= 2.5 Hz, 1H), 14.00 (s, 1H)δ 6.73 (dd, J = 3.8, 1.7 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.77-7.81 (m, 2H), 8.04 (dd, J = 3.8, 0.5 Hz, 1H), 8.27 (d, J = 2.5 Hz, 1H), 14.00 (s, 1H) 실시예61Example 61 2-(3-톨루에닐)-6-클로로-3-크로몬산2- (3-Toluenyl) -6-chloro-3-chromonic acid 6-Cl6-Cl
Figure 112006056442618-PAT00081
Figure 112006056442618-PAT00081
 218-220218-220 δ 2.46 (s, 3H), 7.44-7.47 (m, 4H), 7.52 (d, J= 8.9 Hz, 1H), 7.95 (dd, J= 8.9, 2.4 Hz, 1H), 8.49 (d, J= 2.4 Hz, 1H), 13.80 (s, 1H)δ 2.46 (s, 3H), 7.44-7.47 (m, 4H), 7.52 (d, J = 8.9 Hz, 1H), 7.95 (dd, J = 8.9, 2.4 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H), 13.80 (s, 1H) 실시예62Example 62 2-(2-티오페닐)-6-클로로-3-크로몬산2- (2-thiophenyl) -6-chloro-3-chromonic acid 6-Cl6-Cl
Figure 112006056442618-PAT00082
Figure 112006056442618-PAT00082
 202-204202-204 δ 7.24 (dd, J= 5.0, 4.0 Hz, 1H), 7.57 (d, J= 8.9 Hz, 1H), 7.77 (dd, J= 8.9, 2.5 Hz, 1H), 7.84 (dd, J= 5.0, 1.1 Hz, 1H), 8.25 (d, J= 2.5 Hz, 1H), 8.28 (dd, J= 4.0, 1.1 Hz, 1H), 14.45 (s, 1H)δ 7.24 (dd, J = 5.0, 4.0 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.77 (dd, J = 8.9, 2.5 Hz, 1H), 7.84 (dd, J = 5.0, 1.1 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 8.28 (dd, J = 4.0, 1.1 Hz, 1H), 14.45 (s, 1H) 실시예63Example 63 2-(3,4-디메톡시페닐)-6-클로로-3-크로몬산2- (3,4-dimethoxyphenyl) -6-chloro-3-chromonic acid 6-Cl6-Cl
Figure 112006056442618-PAT00083
Figure 112006056442618-PAT00083
 248-249248-249 δ 3.96 (s, 3H), 4.00 (s, 3H), 7.00 (d, J= 8.5 Hz, 1H), 7.22 (d, J= 2.1 Hz, 1H), 7.39 (dd, J= 8.5, 2.1 Hz, 1H), 7.60 (d, J= 8.9 Hz, 1H), 7.80 (dd, J= 8.9, 2.5 Hz, 1H), 8.31 (d, J= 2.5 Hz, 1H)δ 3.96 (s, 3H), 4.00 (s, 3H), 7.00 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 7.39 (dd, J = 8.5, 2.1 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.80 (dd, J = 8.9, 2.5 Hz, 1H), 8.31 (d, J = 2.5 Hz, 1H) 실시예64Example 64 2-(3-플루오로페닐)-6-클로로-3-크로몬산2- (3-Fluorophenyl) -6-chloro-3-chromonic acid 6-Cl6-Cl
Figure 112006056442618-PAT00084
Figure 112006056442618-PAT00084
 216-217216-217 δ 7.29-7.39 (m, 2H), 7.42-7.46 (m, 1H), 7.49-7.56 (m, 1H), 7.60 (d, J= 8.9 Hz, 1H), 7.83 (dd, J= 8.9, 2.5 Hz, 1H), 8.33 (d, J= 2.5 Hz, 1H), 13.80 (s, 1H)δ 7.29-7.39 (m, 2H), 7.42-7.46 (m, 1H), 7.49-7.56 (m, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.83 (dd, J = 8.9, 2.5 Hz , 1H), 8.33 (d, J = 2.5 Hz, 1H), 13.80 (s, 1H) 실시예65Example 65 2-(3,5-디플루오로페닐)-6-클로로-3-크로몬산2- (3,5-Difluorophenyl) -6-chloro-3-chromonic acid 6-Cl6-Cl
Figure 112006056442618-PAT00085
Figure 112006056442618-PAT00085
 207-209207-209 δ 7.09-7.17 (m, 1H), 7.20-7.12 (m, 2H), 7.66 (d, J= 8.9 Hz, 1H), 7.91 (dd, J= 8.9, 2.5 Hz, 1H), 8.40 (d, J= 2.5 Hz, 1H), 14.00 (s, 1H)δ 7.09-7.17 (m, 1H), 7.20-7.12 (m, 2H), 7.66 (d, J = 8.9 Hz, 1H), 7.91 (dd, J = 8.9, 2.5 Hz, 1H), 8.40 (d, J = 2.5 Hz, 1H), 14.00 (s, 1H) 실시예66Example 66 2-(2,3-디플루오로페닐)-6-클로로-3-크로몬산2- (2,3-Difluorophenyl) -6-chloro-3-chromonic acid 6-Cl6-Cl
Figure 112006056442618-PAT00086
Figure 112006056442618-PAT00086
 -- δ 7.24-7.32 (m, 2H), 7.38-7.47 (m, 1H), 7.60 (d, J= 8.9 Hz, 1H), 7.84 (dd, J= 8.9, 2.5 Hz, 1H), 8.35 (d, J= 2.5 Hz, 1H), 13.81 (s, 1H)δ 7.24-7.32 (m, 2H), 7.38-7.47 (m, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.84 (dd, J = 8.9, 2.5 Hz, 1H), 8.35 (d, J = 2.5 Hz, 1H), 13.81 (s, 1H) 실시예67Example 67 2-(2,5-디플루오로페닐)-6-클로로-3-크로몬산2- (2,5-Difluorophenyl) -6-chloro-3-chromonic acid 6-Cl6-Cl
Figure 112006056442618-PAT00087
Figure 112006056442618-PAT00087
 168-170168-170 δ 7.16-7.33 (m, 3H), 7.60 (d, J= 8.9 Hz, 1H), 7.84 (dd, J= 8.9, 2.5 Hz, 1H), 8.34 (d, J= 2.5 Hz, 1H), 13.77 (s, 1H)δ 7.16-7.33 (m, 3H), 7.60 (d, J = 8.9 Hz, 1H), 7.84 (dd, J = 8.9, 2.5 Hz, 1H), 8.34 (d, J = 2.5 Hz, 1H), 13.77 ( s, 1 H) 실시예68Example 68 2-(3,4-디플루오로페닐)-6-클로로-3-크로몬산2- (3,4-Difluorophenyl) -6-chloro-3-chromonic acid 6-Cl6-Cl
Figure 112006056442618-PAT00088
Figure 112006056442618-PAT00088
 195-198195-198 δ 7.31-7.37 (m, 1H), 7.43-7.47 (m, 1H), 7.50-7.61 (m, 2H), 7.83 (dd, J= 8.9, 2.4 Hz, 1H), 8.32 (d, J= 2.4 Hz, 1H)δ 7.31-7.37 (m, 1H), 7.43-7.47 (m, 1H), 7.50-7.61 (m, 2H), 7.83 (dd, J = 8.9, 2.4 Hz, 1H), 8.32 (d, J = 2.4 Hz , 1H) 실시예69Example 69 2-(4-클로로페닐)-6-클로로-3-크로몬산2- (4-Chlorophenyl) -6-chloro-3-chromonic acid 6-Cl6-Cl
Figure 112006056442618-PAT00089
Figure 112006056442618-PAT00089
 227-228227-228 δ 7.50 (d, J= 8.5 Hz, 2H), 7.55-7.62 (m, 3H), 7.80 (dd, J= 8.9, 2.5 Hz, 1H), 8.30 (d, J= 2.5 Hz, 1H), 14.20 (s, 1H)δ 7.50 (d, J = 8.5 Hz, 2H), 7.55-7.62 (m, 3H), 7.80 (dd, J = 8.9, 2.5 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 14.20 ( s, 1 H) 실시예70Example 70 2-(2-퓨라닐)-6-브로모-3-크로몬산2- (2-furanyl) -6-bromo-3-chromonic acid 6-Br6-Br
Figure 112006056442618-PAT00090
Figure 112006056442618-PAT00090
 209-211209-211 δ 6.73 (dd, J= 3.8, 1.6 Hz, 1H), 7.55 (d, J= 8.9 Hz, 1H), 7.80-7.81 (m, 1H), 7.93 (dd, J= 8.9, 2.4 Hz, 1H), 8.03 (d, J= 3.8 Hz, 1H), 8.43 (d, J= 2.4 Hz, 1H), 14.25 (s, 1H)δ 6.73 (dd, J = 3.8, 1.6 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.80-7.81 (m, 1H), 7.93 (dd, J = 8.9, 2.4 Hz, 1H), 8.03 (d, J = 3.8 Hz, 1H), 8.43 (d, J = 2.4 Hz, 1H), 14.25 (s, 1H) 실시예71Example 71 2-(3-톨루에닐)-6-브로모-3-크로몬산2- (3-Toluenyl) -6-bromo-3-chromonic acid 6-Br6-Br
Figure 112006056442618-PAT00091
Figure 112006056442618-PAT00091
 208-210208-210 δ 2.47 (s, 3H), 7.42-7.47 (m, 4H), 7.59 (d, J= 8.9 Hz, 1H), 7.80 (dd, J= 8.9, 2.5 Hz, 1H), 8.32 (d, J= 2.5 Hz, 1H), 13.90 (s, 1H)δ 2.47 (s, 3H), 7.42-7.47 (m, 4H), 7.59 (d, J = 8.9 Hz, 1H), 7.80 (dd, J = 8.9, 2.5 Hz, 1H), 8.32 (d, J = 2.5 Hz, 1H), 13.90 (s, 1H) 실시예72Example 72 2-(2-티오페닐)-6-브로모-3-크로몬산2- (2-thiophenyl) -6-bromo-3-chromonic acid 6-Br6-Br
Figure 112006056442618-PAT00092
Figure 112006056442618-PAT00092
 210-212210-212 δ 7.25 (dd, J= 5.0, 4.1 Hz, 1H), 7.52 (d, J= 8.9 Hz, 1H), 7.86 (dd, J= 5.0, 1.1 Hz, 1H), 7.93 (dd, J= 8.9, 2.4 Hz, 1H), 8.30 (dd, J= 4.1, 1.1 Hz, 1H), 8.44 (d, J= 2.4 Hz, 1H), 14.30 (s, 1H)δ 7.25 (dd, J = 5.0, 4.1 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.86 (dd, J = 5.0, 1.1 Hz, 1H), 7.93 (dd, J = 8.9, 2.4 Hz, 1H), 8.30 (dd, J = 4.1, 1.1 Hz, 1H), 8.44 (d, J = 2.4 Hz, 1H), 14.30 (s, 1H) 실시예73Example 73 2-(3,4-디메톡시페닐)-6-브로모-3-크로몬산2- (3,4-Dimethoxyphenyl) -6-bromo-3-chromonic acid 6-Br6-Br
Figure 112006056442618-PAT00093
Figure 112006056442618-PAT00093
 242-243242-243 δ 3.95 (s, 3H), 3.99 (s, 3H), 6.99 (d, J= 8.4 Hz, 1H), 7.22 (d, J= 2.1 Hz, 1H), 7.38 (dd, J= 8.4, 2.1 Hz, 1H), 7.53 (d, J= 8.9 Hz, 1H), 7.94 (dd, J= 8.9, 2.4 Hz, 1H), 8.48 (d, J= 2.4 Hz, 1H)δ 3.95 (s, 3H), 3.99 (s, 3H), 6.99 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.94 (dd, J = 8.9, 2.4 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H) 실시예74Example 74 2-(3-플루오로페닐)-6-브로모-3-크로몬산2- (3-Fluorophenyl) -6-bromo-3-chromonic acid 6-Br6-Br
Figure 112006056442618-PAT00094
Figure 112006056442618-PAT00094
 222-223222-223 δ 7.32-7.38 (m, 2H), 7.44 (d, J= 7.8 Hz, 1H), 7.48-7.55 (m. 2H), 7.97 (dd, J= 9.7, 2.3 Hz, 1H), 8.50 (d, J= 2.3 Hz, 1H), 13.85 (s, 1H)δ 7.32-7.38 (m, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.48-7.55 (m. 2H), 7.97 (dd, J = 9.7, 2.3 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 13.85 (s, 1H) 실시예75Example 75 2-(3,5-디플루오로페닐)-6-브로모-3-크로몬산2- (3,5-Difluorophenyl) -6-bromo-3-chromonic acid 6-Br6-Br
Figure 112006056442618-PAT00095
Figure 112006056442618-PAT00095
 216-218216-218 δ 7.01-7.08 (m, 1H), 7.14-7.18 (m, 2H), 7.51 (d, J= 8.9 Hz, 1H), 7.97 (dd, J= 8.9, 2.3 Hz, 1H), 8.48 (d, J= 2.3 Hz, 1H), 13.60 (s, 1H)δ 7.01-7.08 (m, 1H), 7.14-7.18 (m, 2H), 7.51 (d, J = 8.9 Hz, 1H), 7.97 (dd, J = 8.9, 2.3 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 13.60 (s, 1H) 실시예76Example 76 2-(2,3-디플루오로페닐)-6-브로모-3-크로몬산2- (2,3-Difluorophenyl) -6-bromo-3-chromonic acid 6-Br6-Br
Figure 112006056442618-PAT00096
Figure 112006056442618-PAT00096
 -- δ 7.17-7.53 (m, 3H), 7.61 (dd, J= 8.8, 2.3 Hz, 1H), 7.91-7.98 (m, 1H), 8.43 (d, J= 2.3 Hz, 1H), 11.80 (s, 1H)δ 7.17-7.53 (m, 3H), 7.61 (dd, J = 8.8, 2.3 Hz, 1H), 7.91-7.98 (m, 1H), 8.43 (d, J = 2.3 Hz, 1H), 11.80 (s, 1H ) 실시예77Example 77 2-(2,5-디플루오로페닐)-6-브로모-3-크로몬산2- (2,5-Difluorophenyl) -6-bromo-3-chromonic acid 6-Br6-Br
Figure 112006056442618-PAT00097
Figure 112006056442618-PAT00097
 152-153152-153 δ 7.16-7.32 (m, 3H), 7.53 (d, J= 8.9 Hz, 1H), 7.98 (dd, J= 8.9, 2.3 Hz, 1H), 8.50 (d, J= 2.3 Hz, 1H), 13.77 (s, 1H)δ 7.16-7.32 (m, 3H), 7.53 (d, J = 8.9 Hz, 1H), 7.98 (dd, J = 8.9, 2.3 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 13.77 ( s, 1 H) 실시예78Example 78 2-(4-클로로페닐)-6-브로모-3-크로몬산2- (4-Chlorophenyl) -6-bromo-3-chromonic acid 6-Br6-Br
Figure 112006056442618-PAT00098
Figure 112006056442618-PAT00098
 211-213211-213 δ 7.47-7.50 (m, 3H), 7.73 (d, J= 8.5 Hz, 2H), 7.87 (dd, J= 8.8, 2.3 Hz, 1H), 8.39 (d, J= 2.3 Hz, 1H)δ 7.47-7.50 (m, 3H), 7.73 (d, J = 8.5 Hz, 2H), 7.87 (dd, J = 8.8, 2.3 Hz, 1H), 8.39 (d, J = 2.3 Hz, 1H)

이상에서 살펴본 바와 같이, 본 발명에 따른 용액상 평행 조합화학을 이용한 크로몬-3-카복실산 유도체 제조방법은 매 반응단계에서 정제과정 없이 일련의 반응을 통하여 다양한 유도체들을 효율적으로 제조할 수 있다.As described above, the method for preparing chromone-3-carboxylic acid derivative using the solution phase parallel combination chemistry according to the present invention can efficiently prepare various derivatives through a series of reactions without purification in every reaction step.

Claims (9)

하기 반응식 1에서 나타내는 바와 같이, 화학식 2의 o-아세틸살리실산 클로라이드 화합물을 촉매 존재하에서 3차부톡시카보닐메틸렌 트리페닐포스포란 화합물(7)과 반응시켜 화학식 3의 포스포란 화합물을 제조하는 단계(단계1);As shown in Scheme 1 below, the step of reacting the o-acetylsalicylic acid chloride compound of formula 2 with tert-butoxycarbonylmethylene triphenylphosphorane compound (7) in the presence of a catalyst to prepare a phosphorane compound of formula 3 (step One); 염기 존재하에 상기 단계 1에서 제조된 화학식 3의 화합물을 탈아세틸화하여 화학식 4의 화합물을 제조하는 단계(단계 2);Preparing a compound of formula 4 by deacetylating the compound of formula 3 prepared in step 1 in the presence of a base (step 2); 염기 및 촉매 존재하에 상기 단계 2에서 제조된 화학식 4의 화합물과 과량의 산 클로라이드를 반응시켜 화학식 5의 화합물을 제조하는 단계(단계 3);Preparing a compound of formula 5 by reacting an excess of acid chloride with the compound of formula 4 prepared in step 2 in the presence of a base and a catalyst (step 3); 상기 단계 3에서 제조된 화학식 5의 화합물을 분자간 위티그(Wittig) 반응을 통하여 화학식 6의 화합물을 제조하는 단계(단계 4); 및Preparing a compound of Chemical Formula 6 through an intermolecular Wittig reaction with the compound of Chemical Formula 5 prepared in Step 3 (Step 4); And 상기 단계 4에서 제조된 화학식 6의 화합물을 산 조건하에서 탈에스테르화시켜 3차부틸기를 제거하여 화학식 1의 화합물을 제조하는 단계(단계 5)를 포함하여 이루어지는 용액상 평행 조합화학을 이용한 크로몬-3-카복실산 유도체의 제조방법.Demonization of the compound of formula 6 prepared in step 4 under acid conditions to remove the tertiary butyl group to prepare a compound of formula 1 (step 5) using a chromone- Process for the preparation of 3-carboxylic acid derivatives. <반응식 1><Scheme 1>
Figure 112006056442618-PAT00099
Figure 112006056442618-PAT00099
 <화학식 1><Formula 1>
Figure 112006056442618-PAT00100
Figure 112006056442618-PAT00100
 <화학식 2><Formula 2>
Figure 112006056442618-PAT00101
Figure 112006056442618-PAT00101
 <화학식 3><Formula 3>
Figure 112006056442618-PAT00102
Figure 112006056442618-PAT00102
 <화학식 4><Formula 4>
Figure 112006056442618-PAT00103
Figure 112006056442618-PAT00103
 <화학식 5><Formula 5>
Figure 112006056442618-PAT00104
Figure 112006056442618-PAT00104
 <화학식 6><Formula 6>
Figure 112006056442618-PAT00105
Figure 112006056442618-PAT00105
 <화학식 7><Formula 7>
Figure 112006056442618-PAT00106
Figure 112006056442618-PAT00106
 <화학식 8><Formula 8>
Figure 112006056442618-PAT00107
Figure 112006056442618-PAT00107
 (상기 화학식에서 R1은 벤젠고리의 5, 6, 7 또는 8번 위치에 치환되는 1 또는 2 이상의 수소, 염소, 브롬, 메톡시기 또는 메틸기이며, R2는 염소, 불소, 메톡시기, 메틸기 또는 하이드록시기로 치환된 방향족기 또는 헤테로 방향족기이다)(In the above formula, R 1 is one or more hydrogen, chlorine, bromine, methoxy group or methyl group substituted at the 5, 6, 7 or 8 position of the benzene ring, R 2 is a chlorine, fluorine, methoxy group, methyl group or Aromatic group or heteroaromatic group substituted with a hydroxy group) 제1항에 있어서, 상기 단계 3은 반응하고 남은 과량의 산 클로라이드를 수용액층으로 이동시켜 제거하기 위해 지라드-티 시약을 첨가하는 단계를 더 포함하는 것을 특징으로 하는 용액상 평행 조합화학을 이용한 크로몬-3-카복실산 유도체의 제조방법.The method of claim 1, wherein step 3 further comprises adding a Girard-T reagent to remove and remove the excess acid chloride remaining in the aqueous solution layer. Method for preparing mon-3-carboxylic acid derivative. 제1항에 있어서, 상기 단계 1의 촉매는 N,O-비스트리메틸실릴 아세트아미드이고, 반응 용매는 벤젠 또는 테트라하이드로퓨란인 것을 특징으로 하는 용액상 평행 조합화학을 이용한 크로몬-3-카복실산 유도체의 제조방법.According to claim 1, wherein the catalyst of step 1 is N, O-bistrimethylsilyl acetamide, and the reaction solvent is benzene or tetrahydrofuran, chromone-3-carboxylic acid derivative using a solution phase parallel combination chemistry Manufacturing method. 제1항에 있어서, 상기 단계 2의 염기는 디메틸아민, 메틸아민, 암모니아 중에서 선택되는 어느 하나이고, 반응 용매는 테트라하이드로퓨란, 메탄올, 에탄올 중에서 선택되는 어느 하나인 것을 특징으로 하는 용액상 평행 조합화학을 이용한 크로몬-3-카복실산 유도체의 제조방법.The solution phase parallel combination of claim 1, wherein the base of step 2 is any one selected from dimethylamine, methylamine, and ammonia, and the reaction solvent is any one selected from tetrahydrofuran, methanol, and ethanol. Method for preparing chromone-3-carboxylic acid derivative using chemistry. 제1항에 있어서, 상기 단계 3의 염기는 N,N-디이소프로필에틸아민 또는 트리에틸아민이고, 촉매는 N,N-디메틸피리딘인 것을 특징으로 하는 용액상 평행 조합화학을 이용한 크로몬-3-카복실산 유도체의 제조방법.The method according to claim 1, wherein the base of step 3 is N, N-diisopropylethylamine or triethylamine, and the catalyst is N, N-dimethylpyridine. Process for the preparation of 3-carboxylic acid derivatives. 제1항에 있어서, 상기 단계 3의 산 클로라이드는 2.0 당량을 사용하는 것을 특징으로 하는 용액상 평행 조합화학을 이용한 크로몬-3-카복실산 유도체의 제조방법.The method of claim 1, wherein the acid chloride of step 3 uses 2.0 equivalents. 제1항에 있어서, 상기 단계 4의 반응 용매는 톨루엔, 크실렌, 메시틸렌 중에서 선택되는 어느 하나인 것을 특징으로 하는 용액상 평행 조합화학을 이용한 크로몬-3-카복실산 유도체의 제조방법.The method of claim 1, wherein the reaction solvent of Step 4 is any one selected from toluene, xylene, and mesitylene. 제1항에 있어서, 상기 단계 5의 탈에스테르화 반응은 이염화탄소 용매에서 상기 화학식 6의 화합물과 트리플루오르아세트산과의 반응에 의해 수행되는 것을 특징으로 하는 용액상 평행 조합화학을 이용한 크로몬-3-카복실산 유도체의 제조방법.The method according to claim 1, wherein the deesterification reaction of step 5 is carried out by reaction of the compound of formula 6 with trifluoroacetic acid in a carbon dichloride solvent. Preparation of carboxylic acid derivatives. 제1항에 있어서, 상기 단계 3 내지 단계 5의 과정은 동일한 용기 내에서 연속된 반응을 통하여 이루어지는 것을 특징으로 하는 용액상 평행 조합화학을 이용한 크로몬-3-카복실산 유도체의 제조방법.The method of claim 1, wherein the process of steps 3 to 5 is performed through a continuous reaction in the same vessel.
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