KR20120113109A - Enviornmentally synthetic method for 2,3-dihydroquinazolinone derivatives and their spirooxindole derivatives - Google Patents

Enviornmentally synthetic method for 2,3-dihydroquinazolinone derivatives and their spirooxindole derivatives Download PDF

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KR20120113109A
KR20120113109A KR1020110030838A KR20110030838A KR20120113109A KR 20120113109 A KR20120113109 A KR 20120113109A KR 1020110030838 A KR1020110030838 A KR 1020110030838A KR 20110030838 A KR20110030838 A KR 20110030838A KR 20120113109 A KR20120113109 A KR 20120113109A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

PURPOSE: An eco-friendly synthesis method for 2,3-dihydroquinazole derivatives and spiro-oxindole derivatives thereof is provided to be usefully applied for mass synthesis. CONSTITUTION: A synthesis method for 2,3-dihydroquinazolinone derivative of chemical formula 1 comprises: a step of reacting isatoic anhydride, amines, and benzaldehydes in water under the presence of EDDA(ethylenediamine diacetate). The synthesis method for 2,3-dihydroquinazolinone derivative of chemical formula 2 comprises a step of reacting isatoic anhydride, amines, and istins in water under the presence of EDDA.

Description

２，３?디하이드로퀴나졸리논 유도체 및 그의 스피로옥스인돌 유도체의 친환경적 합성방법{Enviornmentally synthetic method for 2,3-dihydroquinazolinone derivatives and their spirooxindole derivatives}Environment-friendly synthetic method of 2,3? Dihydroquinazolinone derivatives and their spirooxindole derivatives {enviornmentally synthetic method for 2,3-dihydroquinazolinone derivatives and their spirooxindole derivatives}

본 발명은 다양한 생리활성을 나타내는 2,3-디하이드로퀴나졸리논 유도체 및 2,3-디하이드로퀴나졸리논 고리를 갖는 스피로옥스인돌 유도체의 간편하며 친환경적인 새로운 합성방법에 관한 것이다.The present invention relates to a new method for the simple and eco-friendly synthesis of 2,3-dihydroquinazolinone derivatives and spirooxindole derivatives having 2,3-dihydroquinazolinone rings exhibiting various physiological activities.

2,3-디하이드로퀴나졸리논 유도체는 항암, 항생(antibiotic), 해열, 진통, 항고장(antihypertonic), 이뇨, 항히스타민, 항우울 및 혈관확장의 활성을 포함하는 광범위한 생물학적, 약학적 및 의학적 특성들을 보이는 중요한 융합된 헤테로 고리화합물이다. 또한, 2,3-디하이드로퀴나졸리논류는 몇 가지 종류의 인간 암세포에서 큰 항증식(antiproliferative) 활성을 가지는 강력한 튜불린 억제제로서 작용하는 것이 보고되었다. 더나아가, 이 화합물들은 세포분열을 저지하는 물질인 콜히친과 비슷하게 작용할 수 있다. 2,3-디하이드로퀴나졸리논 유도체는 이사토익 무수화물(isatoic anhydride)(path a) 과 2-아미노벤크알데히드(2-aminobenzaldehyde)(path b)로부터 합성하는 많은 방법들이 알려진 바 있다 (반응식 1). 즉, path a를 통한 방법은 [bmin]BF4, p-TsOH, silica sulfuric acid, Al(H2P)4)3, KAl(SO4)2?12H2O(alum), montmorillonite K-10, zinc perfluorooctanoate, gallium triflate 및 Amberlyst-15/microwave 등의 촉매 하에서 이사토익 무수화물(isatoic anhydride), 1급 아민 및 방향족 알데하이드 화합물의 축합 반응을 이용하였다. path b를 방법은 p-TsOH/DDQ, I2, FeCl3, CuCl2, TiCl4/Zn, 키랄 인산 및 ionic liquid/water의 존재하에서 2-아미노벤즈아미드계를 알데하이드와 축합을 포함한다.2,3-dihydroquinazolinone derivatives possess a wide range of biological, pharmaceutical and medical properties including the activity of anticancer, antibiotic, antipyretic, analgesic, antihypertonic, diuretic, antihistamine, antidepressant and vasodilation. It is an important fused heterocyclic compound shown. In addition, 2,3-dihydroquinazolinones have been reported to act as potent tubulin inhibitors with large antiproliferative activity in several types of human cancer cells. Furthermore, these compounds can act similarly to colchicine, a substance that blocks cell division. Many methods of synthesizing 2,3-dihydroquinazolinone derivatives from isatoic anhydride (path a) and 2-aminobenzaldehyde (path b) are known (Scheme 1). ). That is, the method through path a is [bmin] BF 4 , p-TsOH, silica sulfuric acid, Al (H 2 P) 4 ) 3 , KAl (SO 4 ) 2 -12H 2 O (alum), montmorillonite K-10 The condensation reaction of isatoic anhydride, primary amine and aromatic aldehyde compound was used under the catalyst of zinc, perfluorooctanoate, gallium triflate and Amberlyst-15 / microwave. Path b methods include condensation of 2-aminobenzamide systems with aldehydes in the presence of p- TsOH / DDQ, I 2 , FeCl 3 , CuCl 2 , TiCl 4 / Zn, chiral phosphoric acid and ionic liquid / water.

[반응식 1][Reaction Scheme 1]

Figure pat00001
Figure pat00001

스피로옥스인돌 유도체도 다양한 생물학적 효능을 보여주고 있으며, 그들의 독특한 구조와 매우 중요한 약학적 활성 때문에 스피로옥스인돌 유도체의 합성에 대한 흥미를 자극해 왔다. 최근에 멀티컴포넌트 반응(multicomponent reactions)을 통해 디하이드로퀴나졸리논 고리를 가진 스피로옥스인돌계 화합물에 대한 두가지 합성방법이 개발되었다(반응식 2). 즉, 알려진 내용은 KAl(SO4)2?H2O 촉매를 사용하여 이사틴류(isatins), 아민류, 이사토익 무수화물(isatoic anhydride)을 축합하는 방법과(path c), 키랄(chiral) 인산의 존재하에서 이사틴(isatin)과 2-아미노벤즈아미드의 반응을 통해 스피로옥스인돌 유도체를 합성하는 방법이다 (path d). Spirooxindole derivatives also show a variety of biological efficacy and have been of interest to the synthesis of spirooxindole derivatives because of their unique structure and very important pharmaceutical activity. Recently, two synthetic methods have been developed for spirooxindole compounds having dihydroquinazolinone rings through multicomponent reactions (Scheme 2). That is, the known content of the method of condensing isatins, amines and isatoic anhydride using a KAl (SO 4 ) 2 -H 2 O catalyst (path c) and chiral phosphoric acid Is a method of synthesizing spirooxindole derivatives through the reaction of isatitin and 2-aminobenzamide in the presence of (path d).

[반응식 2]Scheme 2

Figure pat00002
Figure pat00002

2,3-디하이드로퀴나졸리논계와 스피로옥스인돌 유도체들의 합성법들이 개발되어 보고된바 있지만, 아직도 간단하고, 저비용, 환경친화적인 합성방법들이 여전히 요구되고 있다. 최근에, 브론스테드 산과 염기들이 유기합성에서 다양한 반응에 활성 촉매로 널리 사용되고 있다. 특히, 본 발명자는 브론스테드 산 및 염기 촉매로서 에틸렌다이아민다이아세테이트를 사용하여 다양한 형태의 벤조피렌 고리를 합성하는 반응을 개발하였다. Synthesis methods of 2,3-dihydroquinazolinone-based and spiroxoxindole derivatives have been developed and reported, but still simple, low-cost, environmentally friendly synthesis methods are still required. Recently, Bronsted acids and bases have been widely used as active catalysts for various reactions in organic synthesis. In particular, the inventors have developed a reaction for synthesizing various forms of benzopyrene rings using Bronsted acid and ethylenediaminediacetate as base catalysts.

에틸렌다이아민다이아세테이트를 촉매롤 사용하는 계속적인 연구의 결과로, 본 발명자는 이사토익 무수화물(isatoic anhydride), 아민류(amines), 및 벤즈알데히드류(benzaldehydes)를 사용하여 에틸렌다이아민다이아세테이트 촉매하에서 물을 용매로 사용하여 친환경적으로 2,3-디하이드로퀴나졸린-4(1H)-온 유도체(2,3-dihydroquinazolin-4(1H)-one derivatives)를 합성하는 방법을 개발하였다. 또한, 이사토익 무수화물(isatoic anhydride), 아민류(amines), 및 이사틴류(isatins)를 사용하여 에틸렌다이아민다이아세테이트 촉매하에서 디하이드로퀴나졸리논 고리를 포함하는 스피로옥스인돌을 합성하는 방법을 개발하였다. As a result of the ongoing study using ethylenediaminediacetate as a catalyst, the inventors have used isatoic anhydride, amines, and benzaldehydes to purify water under an ethylenediaminediacetate catalyst. A method for synthesizing 2,3-dihydroquinazolin-4 (1H) -one derivatives has been developed using environmentally friendly solvents. In addition, a method for synthesizing spirooxindole containing dihydroquinazolinone rings under an ethylenediaminediacetate catalyst using isatoic anhydride, amines, and isatins .

본 발명의 목적은 효율이 좋으면서 간편하고 친환경적인 2,3-디하이드로퀴나졸리논 유도체 및 2,3-디하이드로퀴나졸리논 고리를 갖는 스피로옥스인돌 유도체의 새로운 합성방법을 제공하는 데에 있다.It is an object of the present invention to provide a novel method for synthesizing a 2,3-dihydroquinazolinone derivative and a spirooxindole derivative having a 2,3-dihydroquinazolinone ring which is efficient and simple and eco-friendly. .

상기 목적을 달성하기 위하여, 본 발명은 이사토익 무수화물(isatoic anhydride), 아민류(amines) 및 벤즈알데히드류(benzaldehydes)를 수중에서 에틸렌다이아민다이아세테이트(EDDA) 촉매 하에서 3요소(three-component) 반응으로 화학식1로 표시되는 2,3-디하이드로퀴나졸리논 유도체(2,3-dihydroquinazolinone derivatives)의 합성방법을 제공한다.In order to achieve the above object, the present invention is a three-component reaction of isatoic anhydride, amines and benzaldehydes in water under an ethylenediamine diacetate (EDDA) catalyst. It provides a method for synthesizing 2,3-dihydroquinazolinone derivatives represented by the formula (1).

[화학식 1][Formula 1]

Figure pat00003
Figure pat00003

상기 화학식 1에서, R1은

Figure pat00004
또는
Figure pat00005
중 어느 하나이고, X는 C1 내지 C4의 알콕시 또는 할로겐 중 어느 하나이며,In Formula 1, R 1
Figure pat00004
or
Figure pat00005
X is any one of C1 to C4 alkoxy or halogen,

R2는 아릴아민으로서,

Figure pat00006
이며, Y1은 수소, CH3CHCH3, C1 내지 C4의 알콕시 또는 할로겐 중 어느 하나이고, Y2은 수소 또는 C1 내지 C4의 알킬 중 어느 하나이며, n은 0 내지 4의 정수이다.R 2 is arylamine,
Figure pat00006
Y 1 is hydrogen, CH 3 CHCH 3 , C 1 to C 4 alkoxy or halogen, Y 2 is hydrogen or C 1 to C 4 alkyl, and n is an integer of 0 to 4.

상기 아민류는

Figure pat00007
,
Figure pat00008
,
Figure pat00009
,
Figure pat00010
,
Figure pat00011
,
Figure pat00012
및
Figure pat00013
으로 이루어진 군에서 선택하여 사용할 수 있다.The amines are
Figure pat00007
,
Figure pat00008
,
Figure pat00009
,
Figure pat00010
,
Figure pat00011
,
Figure pat00012
And
Figure pat00013
Can be selected from the group consisting of.

상기 벤즈알데히드류는

Figure pat00014
,
Figure pat00015
,
Figure pat00016
및
Figure pat00017
으로 이루어진 군에서 선택하여 사용할 수 있다.The benzaldehyde is
Figure pat00014
,
Figure pat00015
,
Figure pat00016
And
Figure pat00017
Can be selected from the group consisting of.

또한, 본 발명은 이사토익 무수화물(isatoic anhydride), 아민류(amines) 및 이사틴류(isatins)를 수중에서 에틸렌다이아민다이아세테이트(EDDA) 촉매 하에서 3요소(three-component) 반응으로 화학식2로 표시되는 디하이드로퀴나졸리논 고리를 포함하는 스피로옥스인돌 유도체의 합성방법을 제공한다.In addition, the present invention is represented by the formula (2) in the three-component reaction of isatoic anhydride, amines (amines) and isatins (isatins) in water under an ethylenediamine diacetate (EDDA) catalyst Provided is a method for synthesizing a spirooxindole derivative comprising a dihydroquinazolinone ring.

[화학식 2][Formula 2]

Figure pat00018
Figure pat00018

상기 화학식 2에서, R1는

Figure pat00019
이며, Y1은 수소, CH3CHCH3, C1 내지 C4의 알콕시 또는 할로겐 중 어느 하나이고, Y2은 수소 또는 C1 내지 C4의 알킬 중 어느 하나이며, n은 0 내지 4의 정수이거나; C1 내지 C7의 알킬이거나;
Figure pat00020
; 또는 수소 중 어느 하나이다.In Formula 2, R 1
Figure pat00019
Y 1 is hydrogen, CH 3 CHCH 3 , C1 to C4 alkoxy or halogen, Y 2 is hydrogen or C1 to C4 alkyl, n is an integer from 0 to 4; C1 to C7 alkyl;
Figure pat00020
; Or hydrogen.

상기 아민류는

Figure pat00021
,
Figure pat00022
,
Figure pat00023
,
Figure pat00024
,
Figure pat00025
,
Figure pat00026
,
Figure pat00027
,
Figure pat00028
,
Figure pat00029
,
Figure pat00030
,
Figure pat00031
, 및
Figure pat00032
으로 이루어진 군에서 선택하여 사용할 수 있다.The amines are
Figure pat00021
,
Figure pat00022
,
Figure pat00023
,
Figure pat00024
,
Figure pat00025
,
Figure pat00026
,
Figure pat00027
,
Figure pat00028
,
Figure pat00029
,
Figure pat00030
,
Figure pat00031
, And
Figure pat00032
Can be selected from the group consisting of.

상기 이사틴류는

Figure pat00033
,
Figure pat00034
, 및
Figure pat00035
으로 이루어진 군에서 선택하여 사용할 수 있다.The isatin is
Figure pat00033
,
Figure pat00034
, And
Figure pat00035
Can be selected from the group consisting of.

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

최근 몇년간 친환경적 기술이 여러 가지 유기 화합물들을 제조하는 데에 많이 이용되고 있다. 이중에서, 물을 용매로 사용하는 기술은 비싸지 않고, 친환경적이며, 독성이 없고 안전하게 사용할 수 있어 가장 친환경적이다. 본 발명자는 먼저 에탄올(ethanol), 아세토니트릴(acetonitrile), 메틸렌클로라이드(methylene chloride), 톨루엔(toluene) 및 물을 포함한 몇개의 용매하에서 이사토익 무수화물(isatoic anhydride, 1), 아닐린(aniline, 2a), 및 벤즈알데히드(benzaldehyde, 3a)가 EDDA를 촉매로한 3요소 반응으로 4a를 합성할 수 있는지 조사하였다 (반응식 3). 물을 용매로 사용하여 에틸렌다이아민다이아세테이트 촉매하에서 반응이 수행되었을 때, 기대했던 생산물인 4a 가 다른 유기 용매들과 비교하여 더 좋은 반응시간과 더 나은 수율( 94%)로 얻어졌다. 비극성 용매인 메틸렌클로라이드와 톨루엔에서는 이사토익 무수화물(isatoic anhydride)의 불용성 때문인지 기대했던 생산물은 생성되지 않았다. 용매로 에탄올을 사용한 경우 수득율이 50-60%로 4a가 얻어졌다. 용매로서 물은 소수성 효과, 큰 유전율, 강한 수소결합, 높은 열용량 및 최적의 산소 용해성을 포함하는 특징 때문에 반응속도를 증가시킨다. 이러한 결과를 표1에 기재하였다. 용매로서 에탄올과 같은 저급알코올을 사용하였을 때는 낮은 수득율로 생산물을 얻을 수 있었고, 따라서 수득율이 높고 빠른 반응을 유도할 수 있으며 친환경적이고 저비용인 물을 용매로 사용하는 것이 가장 바람직하다.In recent years, environmentally friendly technologies have been used to make various organic compounds. Of these, the technology of using water as a solvent is the most environmentally friendly, inexpensive, environmentally friendly, non-toxic and safe to use. The present inventors first determine isatoic anhydride ( 1 ), aniline (aniline, 2a ) in several solvents including ethanol, acetonitrile, methylene chloride, toluene and water. ), And benzaldehyde ( 3a ) was investigated whether 4a can be synthesized by a three-element reaction with EDDA as a catalyst (Scheme 3). When the reaction was carried out under an ethylenediaminediacetate catalyst using water as a solvent, the expected product 4a was obtained with better reaction time and better yield (94%) compared to other organic solvents. The nonpolar solvents of methylene chloride and toluene did not produce the expected product due to the insolubility of isatoic anhydride. When ethanol was used as the solvent, 4a was obtained with a yield of 50-60%. As a solvent, water increases the reaction rate due to features including hydrophobic effect, large dielectric constant, strong hydrogen bonds, high heat capacity and optimum oxygen solubility. These results are shown in Table 1. When a lower alcohol such as ethanol was used as a solvent, a product was obtained at a low yield, and therefore, it is most preferable to use water as a solvent which is high in yield, induces a fast reaction, and is environmentally friendly and low cost.

[반응식 3]Scheme 3

Figure pat00036
Figure pat00036

화합물compound EDDA (mol%)EDDA (mol%) 용매menstruum 조건Condition 수율 (%)Yield (%) 1One -- 에탄올ethanol 환류, 12시간Reflux, 12 hours 2525 22 1010 에탄올ethanol 환류, 12시간Reflux, 12 hours 5050 33 2020 에탄올ethanol 환류, 12시간Reflux, 12 hours 5555 44 4040 에탄올ethanol 환류, 12시간Reflux, 12 hours 6060 55 -- 아세토니트릴Acetonitrile 환류, 12시간Reflux, 12 hours <5<5 66 2020 아세토니트릴Acetonitrile 환류, 12시간Reflux, 12 hours 2020 77 4040 아세토니트릴Acetonitrile 환류, 12시간Reflux, 12 hours 3030 88 2020 메틸렌 클로라이드Methylene chloride 환류, 12시간Reflux, 12 hours -- 99 2020 톨루엔toluene 환류, 12시간Reflux, 12 hours -- 1010 -- 물water 환류, 12시간Reflux, 12 hours 3636 1111 1010 물water 환류, 12시간Reflux, 12 hours 8080 1212 2020 물water 환류, 5시간Reflux, 5 hours 9494

조건을 맞춘후, 다양한 아민과 벤즈알데히드을 이용한 더 많은 반응이 조사되었고, 그 결과는 표2에 수록되어 있다. After conditioning, more reactions with various amines and benzaldehydes were investigated, and the results are listed in Table 2.

화합물compound 아민Amine 알데히드Aldehyde 반응시간(hr)Reaction time (hr) 생성물product 수율 (%)Yield (%) 1One

Figure pat00037
Figure pat00037
Figure pat00038
Figure pat00038
 1010 8686 22
Figure pat00040
Figure pat00040
Figure pat00041
Figure pat00041
 77
Figure pat00042
Figure pat00042
 9393 33
Figure pat00043
Figure pat00043
Figure pat00044
Figure pat00044
 88
Figure pat00045
Figure pat00045
 9191 44
Figure pat00046
Figure pat00046
Figure pat00047
Figure pat00047
 77
Figure pat00048
Figure pat00048
 9090 55
Figure pat00049
Figure pat00049
Figure pat00050
Figure pat00050
 66
Figure pat00051
Figure pat00051
 9292 66
Figure pat00052
Figure pat00052
Figure pat00053
Figure pat00053
 66
Figure pat00054
Figure pat00054
 9090 77
Figure pat00055
Figure pat00055
Figure pat00056
Figure pat00056
 77
Figure pat00057
Figure pat00057
 8989 88
Figure pat00058
Figure pat00058
Figure pat00059
Figure pat00059
 88
Figure pat00060
Figure pat00060
 8888 99
Figure pat00061
Figure pat00061
Figure pat00062
Figure pat00062
 77
Figure pat00063
Figure pat00063
 8787 1010
Figure pat00064
Figure pat00064
 66
Figure pat00066
Figure pat00066
 9292

직접적인 3요소 반응은 전자를 주거나(electron-donating, entries 1 - 5) 또는 전자를 끄는 그룹(electron-withdrawing groups, entries 6 - 7)과, 펜에틸아민(phenethylamine, entries 8 - 9) 및 4-페닐부틸아민(4-phenylbutylamine, entry 10)을 갖는 다양한 아릴아민에서 잘 진행된다. 또한, 벤젠고리에 전자를 주거나 끄는 그룹을 포함한 다양한 벤즈알데히드와 아릴아민의 반응도 높은 수득율로, 기대하는 생산물인 4b-4h를 얻을 수 있다. 방향족 고리를 가진 다른 1차 아민과의 반응은 88-92%의 수득율로 기대하는 생산물인 4i-4k를 얻을 수 있다(entries 8-10). Direct three-element reactions include electron-donating (entries 1-5) or electron-withdrawing groups (entries 6-7), phenethylamine (entries 8-9) and 4- It proceeds well in various arylamines with phenylbutylamine (4-phenylbutylamine, entry 10). In addition, the reaction of various benzaldehydes and arylamines, including groups that give or attract electrons to the benzene ring, also yields the expected product 4b-4h. Reaction with other primary amines with aromatic rings yields the expected product 4i-4k with yields of 88-92% (entries 8-10).

또한, 본 발명은 디하이드로퀴나졸리논 고리를 가지는 스피로옥스인돌 유도체를 합성하는 방법에 관한 것으로서, 이사토익 무수화물(isatoic anhydride, 1), 아닐린(aniline, 2a), 및 이사틴(isatin, 5a)의 에틸렌다이아민다이아세테이트(EDDA) 촉매 하에서 3요소 반응을 수행했다. 물 용매 하에서 에틸렌다이아민다이아세테이트(EDDA)를 촉매로 사용하여 2a 와 5a 및 1을 사용하여 5시간 환류하여 94% 수율로 화합물 6a를 얻었다(반응식4). In addition, the present invention relates to a method for synthesizing a spirooxindole derivative having a dihydroquinazolinone ring, isatoic anhydride ( 1 ), aniline (aniline, 2a ), and isatin (isatin, 5a). The triurea reaction was carried out under ethylenediaminediacetate (EDDA) catalyst. Ethylenediaminediacetate (EDDA) was used as a catalyst under water solvent to reflux for 5 hours using 2a, 5a and 1 to obtain compound 6a in 94% yield (Scheme 4).

[반응식 4]Scheme 4

Figure pat00067
Figure pat00067

이러한 반응의 일반성을 알아보기 위해, 다양한 아민류와 몇 가지의 이사틴(isatin)에 이사토익 무수화물(isatoic anhydride,1)을 첨가하여 반응을 시도했다. 그 결과를 표3에 수록하였다. 벤젠 고리에 전자를 주거나(entries 1-2) 끄는(entry 3) 그룹 모두를 가지는 아닐린과 반응시키면 89-96% 수율로 생산물인 6b-6d가 생산되었다. 방향족 고리를 가진 다른 1차 아민류와 반응시키면 기대했던 6e-6i 가 82-92%의 수율로 생산되었다(entries 4-8). 또한, 사슬과 환상 고리를 가진 지방족 아민을 적용했을 때, 기대했던 환상 물질인 6j 와 6k 가 91-89% 수율로 얻어졌다. 또한, 암모늄 아세테이트로 적용하면 6l 이 생산되었다(93%). 또, 몇가지 아닐린에 5-브로모이사틴(5b) 과 1-메틸이사틴(5e) 를 반응시키면 82-93% 수율로 생산물인 6m-6q가 성공적으로 얻어질 수 있었다(entries 12-16). 이 반응들은 디하이드로퀴나졸리논 부위를 가진 다양한 스피로옥스인돌 유도체인 6b-6q에 빠르게 접근하도록 했다.To find out the generality of this reaction, the reaction was attempted with the addition of isatoic anhydride (1) to various amines and several isatines. The results are listed in Table 3. Reaction with aniline having both groups (entries 1-2) and (entry 3) to the benzene ring yielded the product 6b-6d in 89-96% yield. Reaction with other primary amines with aromatic rings yielded the expected 6e-6i in 82-92% yield (entries 4-8). In addition, when the aliphatic amine having a chain and a cyclic ring was applied, the expected cyclic substances 6j and 6k were obtained in 91-89% yield. Also, application of ammonium acetate yielded 6 l (93%). In addition, reaction of 5-bromoissatin (5b) with 1-methylisatin (5e) to several anilines was able to successfully produce 6m-6q of the product in 82-93% yield (entries 12-16). The reactions allowed rapid access to 6b-6q, a variety of spiroxoxindole derivatives with dihydroquinazolinone sites.

아민Amine 이사틴Isatin 생성물product 반응시간
(h)Reaction time
(h) 수율
(%)yield
(%) 1One

Figure pat00068
Figure pat00068
Figure pat00069
Figure pat00069
Figure pat00070
Figure pat00070
 77 9292 22
Figure pat00071
Figure pat00071
Figure pat00072
Figure pat00072
Figure pat00073
Figure pat00073
 66 9696 33
Figure pat00074
Figure pat00074
Figure pat00075
Figure pat00075
Figure pat00076
Figure pat00076
 99 8989 44
Figure pat00077
Figure pat00077
Figure pat00078
Figure pat00078
Figure pat00079
Figure pat00079
 77 9090 55
Figure pat00080
Figure pat00080
Figure pat00081
Figure pat00081
Figure pat00082
Figure pat00082
 1010 8282 66
Figure pat00083
Figure pat00083
Figure pat00084
Figure pat00084
Figure pat00085
Figure pat00085
 1010 8888 77
Figure pat00086
Figure pat00086
Figure pat00087
Figure pat00087
Figure pat00088
Figure pat00088
 66 9292 88
Figure pat00089
Figure pat00089
Figure pat00090
Figure pat00090
Figure pat00091
Figure pat00091
 77 9292 99
Figure pat00092
Figure pat00092
Figure pat00093
Figure pat00093
Figure pat00094
Figure pat00094
 77 9191 1010
Figure pat00095
Figure pat00095
Figure pat00096
Figure pat00096
Figure pat00097
Figure pat00097
 77 8989 1111 NH4OAcNH 4 OAc
Figure pat00098
Figure pat00098
Figure pat00099
Figure pat00099
 66 9393 1212
Figure pat00100
Figure pat00100
Figure pat00101
Figure pat00101
Figure pat00102
Figure pat00102
 88 9393 1313
Figure pat00103
Figure pat00103
Figure pat00104
Figure pat00104
Figure pat00105
Figure pat00105
 1010 8282 1414
Figure pat00106
Figure pat00106
Figure pat00107
Figure pat00107
Figure pat00108
Figure pat00108
 1010 9090 1515
Figure pat00109
Figure pat00109
Figure pat00110
Figure pat00110
Figure pat00111
Figure pat00111
 88 9292 1616
Figure pat00112
Figure pat00112
Figure pat00113
Figure pat00113
Figure pat00114
Figure pat00114
 88 8888

4a 와 6a 의 형성은 반응식5에서 보여주는 바와 같이, 다음에 제시된 기전에 의해 설명될 수 있다. 에틸렌다이아민다이아세테이트는 브뢴스테드 산으로 작용할 수 있다. 이사토익 무수화물(isatoic anhydride,1)의 카르보닐 그룹은 카르보닐 부위에 아닐린(2a)의 친핵성 공격이 용이하게 된 중간체 7을 생산하기 위해 에틸렌다이아민다이아세테이트에 의해 양성자가 가해질 수 있다. 화합물 7의 탈탄산 및 아닐린(2a)의 친핵적 첨가는 2-아미노벤즈아미드인 8을 생산하였다. 양자가 가해진 벤즈알데하이드와 8의 축합은 이민 9를 생산하였고, 9는 분자내 고리화로 마지막 생산물인 4a 를 생산하였다. 비슷하게, 양자가 가해진 이사틴과 8의 축합 및 에틸렌다이아민다이아세테이트와 반응은 이민 10을 생산하고, 10은 분자내 고리화로 생산물인 6a가 생산되었다. 따라서, 본 발명에 따른 합성방법은 원팟(one-pot) 반응으로서 매우 간편한 방법으로 생산물을 얻을 수 있는 것이다.The formation of 4a and 6a can be explained by the mechanism shown below, as shown in Scheme 5. Ethylenediaminediacetate can act as Bronsted acid. The carbonyl group of isatoic anhydride (1) can be protonated by ethylenediaminediacetate to produce intermediate 7 which facilitates the nucleophilic attack of aniline (2a) at the carbonyl site. The nucleophilic addition of decarbonic acid and aniline (2a) of compound 7 produced 8, 2-aminobenzamide. Condensation of protonated benzaldehyde and 8 produced imine 9, which produced the final product 4a by intramolecular cyclization. Similarly, condensation of protonated isatin with 8 and reaction with ethylenediaminediacetate yielded imine 10, with 10 being the intramolecular cyclization to yield the product 6a. Therefore, the synthesis method according to the present invention is to obtain the product in a very simple method as a one-pot reaction.

[반응식 5]Scheme 5

Figure pat00115
Figure pat00115

본 발명에 따른 합성방법은, 생리활성이 다양한 2,3-디하이드로퀴나졸리논 유도체 및 2,3-디하이드로퀴나졸리논 고리를 갖는 스피로옥스인돌 유도체를 높은 수득율로 얻을 수 있고, 합성이 간편하며, 환경친화적일 뿐만 아니라 대규모의 합성 시 적용가능성이 높은 여러가지 장점이 있다. The synthesis method according to the present invention can obtain a high yield of 2,3-dihydroquinazolinone derivatives and spirooxindole derivatives having a 2,3-dihydroquinazolinone ring with various physiological activities, and the synthesis is easy. In addition, there are various advantages that are not only environmentally friendly but also applicable to large scale synthesis.

이하, 하기 실시예를 통해 본 발명을 보다 상세하게 설명한다. 다만, 이러한 실시예에 의해 본 발명이 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.

이하 모든 실험은 수용액에서 수행되었다. 이사토익 무수화물(isatoic anhydride), 알데히드류(aldehydes), 이사틴류(isatins) 및 아민류(amines)는 알드리치 케미컬사에서 얻었다. 머크사의 형광 표지자로 피복된 실리카겔 플레이트(Art. 5554)는 분석용 TLC에 사용되었다. 1H NMR and 13C NMR 스펙트럼은 용매 화학 이동으로서 DMSO-d6 에서 Bruker Model ARX (각각 300 and 75 MHz) 스펙트로메터에 기록되었다. IR 스펙트럼은 Jasco FTIR 5300 스펙트로메터에 기록되었다. HRMS 스펙트럼은 한국 염기 과학회에서 수행되었다.All experiments below were performed in aqueous solution. Isatoic anhydride, aldehydes, isatitin and amines were obtained from Aldrich Chemical. Silica gel plates (Art. 5554) coated with Merck's fluorescent markers were used for analytical TLC. 1 H NMR and 13 C NMR spectra were recorded on a Bruker Model ARX (300 and 75 MHz, respectively) spectrometer in DMSO-d 6 as solvent chemical shift. IR spectra were recorded on a Jasco FTIR 5300 spectrometer. HRMS spectra were performed by the Korean Society of Base Science.

<< 실시예Example 1> 화합물 4a의 합성 1> Synthesis of Compound 4a

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00116
(1.0 mmol) 및
Figure pat00117
(1.0 mmol)이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 5시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:94%) Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00116
(1.0 mmol) and
Figure pat00117
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 5 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 94%).

mp 205-206 ℃;mp 205-206 ° C;

1H NMR (300MHz, DMSO-d6) δ 7.77 (1H, d, J=7.8Hz),7.64(1H,s),7.42-7.18 (11H, m), 6.79 (1H, d, J=8.1Hz),6.74(1H,t,J=7.2Hz),6.30(1H,s); 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.77 (1H, d, J = 7.8 Hz), 7.64 (1H, s), 7.42-7.18 (11H, m), 6.79 (1H, d, J = 8.1 Hz ), 6.74 (1H, t, J = 7.2 Hz), 6.30 (1H, s);

13CNMR(75MHz, DMSO-d6) δ 162.2, 146.5, 140.7, 140.6, 133.7, 128.5, 128.3, 128.2, 127.9, 126.5, 126.2, 125.9, 117.4, 115.3, 114.7, 72.6; 13 CNMR (75 MHz, DMSO-d 6 ) δ 162.2, 146.5, 140.7, 140.6, 133.7, 128.5, 128.3, 128.2, 127.9, 126.5, 126.2, 125.9, 117.4, 115.3, 114.7, 72.6;

IR (KBr) 3427, 3294, 3061, 2832, 1633, 1511, 1392, 1332, 1257, 1158, 1025, 754 cm-1;IR (KBr) 3427, 3294, 3061, 2832, 1633, 1511, 1392, 1332, 1257, 1158, 1025, 754 cm −1 ;

HRMSm /z(M+) calcd for C20H16N2O:300.1263. Found:300.1265.HRMS m / z (M + ) calcd for C 20 H 16 N 2 O: 300.1263. Found: 300.1265.

<< 실시예Example 2> 화합물 4b의 합성 2> Synthesis of Compound 4b

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00118
(1.0 mmol) 및
Figure pat00119
(1.0 mmol)이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 10시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:86%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00118
(1.0 mmol) and
Figure pat00119
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 10 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 86%).

mp 209-210 ℃;mp 209-210 ° C;

1H NMR (300MHz, DMSO-d6) δ 7.75 (1H, d, J=7.5Hz), 7.54(1H,s),7.33-7.19(5H,m), 7.14(1H,s), 7.03(2H,t,J=8.7Hz), 6.88-6.85(2H,m), 6.77(1H,t,J=8.1Hz), 6.22(1H,s), 3.71(3H,s), 2.27(3H,s); 1 H NMR (300MHz, DMSO-d 6 ) δ 7.75 (1H, d, J = 7.5 Hz), 7.54 (1H, s), 7.33-7.19 (5H, m), 7.14 (1H, s), 7.03 (2H , t, J = 8.7Hz), 6.88-6.85 (2H, m), 6.77 (1H, t, J = 8.1Hz), 6.22 (1H, s), 3.71 (3H, s), 2.27 (3H, s) ;

13CNMR(75MHz, DMSO-d6) δ 162.2, 159.0, 146.5, 140.8, 137.8, 133.6, 132.7, 128.3, 127.9, 127.8, 126.8, 126.6, 123.2, 117.4, 115.4, 114.7, 113.6, 72.3, 55.0, 20.8; 13 CNMR (75 MHz, DMSO-d 6 ) δ 162.2, 159.0, 146.5, 140.8, 137.8, 133.6, 132.7, 128.3, 127.9, 127.8, 126.8, 126.6, 123.2, 117.4, 115.4, 114.7, 113.6, 72.3, 55.0, 20.8 ;

IR (KBr) 3424, 3301, 2961, 2833, 1634, 1507, 1393, 1301, 1248, 1170, 1026, 830, 766 cm-1;IR (KBr) 3424, 3301, 2961, 2833, 1634, 1507, 1393, 1301, 1248, 1170, 1026, 830, 766 cm −1 ;

HRMSm /z(M+) calcd for C22H20N2O2: 344.1525. Found:344.1525.HRMS m / z (M + ) calcd for C 22 H 20 N 2 O 2 : 344.1525. Found: 344.1525.

<< 실시예Example 3> 화합물 4c의 합성 3> Synthesis of Compound 4c

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00120
(1.0 mmol), 및
Figure pat00121
(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:93%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00120
(1.0 mmol), and
Figure pat00121
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 93%).

mp 190-192 ℃;mp 190-192 ° C;

1H NMR (300MHz, DMSO-d6) δ 7.95 (1H, d, J=8.4Hz), 7.74(1H,d,J=6.9Hz), 7.68(1H,d,J=2.4Hz), 7.59(1H,d,J=8.4Hz), 7.37-7.17(7H,m), 6.78-6.71(2H,m), 6.29(1H,d,J=2.4Hz), 2.93-2.84(1H,m), 1.18(6H,d,J=6.9Hz); 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.95 (1H, d, J = 8.4 Hz), 7.74 (1H, d, J = 6.9 Hz), 7.68 (1H, d, J = 2.4 Hz), 7.59 ( 1H, d, J = 8.4Hz), 7.37-7.17 (7H, m), 6.78-6.71 (2H, m), 6.29 (1H, d, J = 2.4Hz), 2.93-2.84 (1H, m), 1.18 (6H, d, J = 6.9 Hz);

13CNMR(75MHz, DMSO-d6) δ 162.05, 146.2, 139.9, 138.4, 133.7, 132.8, 130.1, 128.9, 128.3, 127.02, 126.5, 121.04, 117.6, 115.4, 114.8, 71.8, 32.9, 23.7; 13 CNMR (75 MHz, DMSO-d 6 ) δ 162.05, 146.2, 139.9, 138.4, 133.7, 132.8, 130.1, 128.9, 128.3, 127.02, 126.5, 121.04, 117.6, 115.4, 114.8, 71.8, 32.9, 23.7;

IR(KBr) 3425, 3282, 2960, 1645, 1511, 1390, 1327, 1240, 990, 8826, 754 cm-1;IR (KBr) 3425, 3282, 2960, 1645, 1511, 1390, 1327, 1240, 990, 8826, 754 cm −1 ;

HRMSm /z(M+) calcd for C23H21ClN2O:376.1342. Found:376.1339.HRMS m / z (M + ) calcd for C 23 H 21 ClN 2 O: 376.1342. Found: 376.1339.

<< 실시예Example 4> 화합물 4d의 합성 4> Synthesis of Compound 4d

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00122
(1.0 mmol), 및
Figure pat00123
(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 8시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:91%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00122
(1.0 mmol), and
Figure pat00123
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 8 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 91%).

mp 171-172 ℃;mp 171-172 ° C;

1H NMR (300MHz, DMSO-d6) δ 7.75 (1H, d, J=7.5Hz), 7.55(1H,s), 7.32- 7.21(7H,m), 6.86(2H,d,J=8.4Hz), 6.74(2H,t,J=8.4Hz), 6.19(1H,s), 3.70(3H,s), 2.91-2.82(1H,m), 1.19(6H,d,J=6.9Hz); 1 H NMR (300MHz, DMSO-d 6 ) δ 7.75 (1H, d, J = 7.5 Hz), 7.55 (1H, s), 7.32-7.21 (7H, m), 6.86 (2H, d, J = 8.4Hz ), 6.74 (2H, t, J = 8.4 Hz), 6.19 (1H, s), 3.70 (3H, s), 2.91-2.82 (1H, m), 1.19 (6H, d, J = 6.9 Hz);

13CNMR(75MHz, DMSO-d6) δ 162.1, 159.05, 146.4, 145.9, 138.6, 133.5, 132.8, 127.8, 127.6, 126.3, 125.9, 117.3, 115.4, 114.7, 113.6, 72.2, 54.9, 32.9, 23.7; 13 CNMR (75 MHz, DMSO-d 6 ) δ 162.1, 159.05, 146.4, 145.9, 138.6, 133.5, 132.8, 127.8, 127.6, 126.3, 125.9, 117.3, 115.4, 114.7, 113.6, 72.2, 54.9, 32.9, 23.7;

IR (KBr) 3420, 3298, 2956, 1630, 1508, 1392, 1332, 1249, 1177, 1027, 833, 700 cm-1;IR (KBr) 3420, 3298, 2956, 1630, 1508, 1392, 1332, 1249, 1177, 1027, 833, 700 cm −1 ;

HRMSm /z(M+) calcd for C24H24N2O2:372.1838. Found:372.1840.HRMS m / z (M + ) calcd for C 24 H 24 N 2 O 2 : 372.1838. Found: 372.1840.

<< 실시예Example 5> 화합물 4e의 합성 5> Synthesis of Compound 4e

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00124
(1.0 mmol), 및
Figure pat00125
(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:90%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00124
(1.0 mmol), and
Figure pat00125
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized in ethanol to obtain pure product (yield: 90%).

mp 210-212 ℃;mp 210-212 ° C;

1H NMR (300MHz, DMSO-d6) δ 7.74 (1H, d, J=7.5Hz),7.58(1H,s),7.28-7.18(5H,m),6.94(1H,s),6.83-6.63(4H,m),6.18(1H,s),5.98(2H,s),2.92-2.85(1H,m),1.19(6H,d,J=6.6Hz); 1 H NMR (300MHz, DMSO-d 6 ) δ 7.74 (1H, d, J = 7.5 Hz), 7.58 (1H, s), 7.28-7.18 (5H, m), 6.94 (1H, s), 6.83-6.63 (4H, m), 6.18 (1H, s), 5.98 (2H, s), 2.92-2.85 (1H, m), 1.19 (6H, d, J = 6.6 Hz);

13CNMR(75MHz, DMSO-d6) δ 162.1, 147.3, 147.1, 146.3, 146.0, 138.5, 134.9, 133.6, 127.9, 126.4, 125.8, 119.9, 117.4, 115.4, 114.8, 107.8, 106.6, 101.1, 72.2, 32.9, 23.7; 13 CNMR (75 MHz, DMSO-d 6 ) δ 162.1, 147.3, 147.1, 146.3, 146.0, 138.5, 134.9, 133.6, 127.9, 126.4, 125.8, 119.9, 117.4, 115.4, 114.8, 107.8, 106.6, 101.1, 72.2, 32.9 , 23.7;

IR (KBr) 3437, 2960, 1644, 1509, 1401, 1237, 1028, 755 cm-1;IR (KBr) 3437, 2960, 1644, 1509, 1401, 1237, 1028, 755 cm −1 ;

HRMSm /z(M+) calcd for C24H22N2O3:386.1630. Found:386.1629HRMS m / z (M + ) calcd for C 24 H 22 N 2 O 3 : 386.1630. Found: 386.1629

<< 실시예Example 6> 화합물 4f의 합성 6> Synthesis of Compound 4f

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00126
(1.0 mmol), 및
Figure pat00127
(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 6시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:92%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00126
(1.0 mmol), and
Figure pat00127
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 6 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 92%).

mp 227-228 ℃; mp 227-228 ° C;

1H NMR (300MHz, DMSO-d6) δ 7.74 (1H, d, J = 7.8 Hz), 7.44 (1H, s), 7.31-7.23 (3H, m), 7.15 (2H, d, J = 8.7 Hz), 6.89-6.84 (4H, m) 6.75 (2H, t, J = 7.8 Hz), 6.16 (1H, s), 3.73 (3H, s), 3.70 (3H, s); 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.74 (1H, d, J = 7.8 Hz), 7.44 (1H, s), 7.31-7.23 (3H, m), 7.15 (2H, d, J = 8.7 Hz ), 6.89-6.84 (4H, m) 6.75 (2H, t, J = 7.8 Hz), 6.16 (1H, s), 3.73 (3H, s), 3.70 (3H, s);

13C NMR (75 MHz, DMSO-d6) δ 162.3, 159.1, 157.2, 146.6, 133.5, 132.7, 127.9, 127.8, 127.4, 117.3, 115.2, 114.6, 113.7, 113.6, 72.8, 55.1, 55.0; 13 C NMR (75 MHz, DMSO-d 6 ) δ 162.3, 159.1, 157.2, 146.6, 133.5, 132.7, 127.9, 127.8, 127.4, 117.3, 115.2, 114.6, 113.7, 113.6, 72.8, 55.1, 55.0;

IR (KBr) 3426, 2936, 2837, 1636, 1510, 1394, 1441, 1243, 1174, 1025, 996, 830, 762 cm-1; IR (KBr) 3426, 2936, 2837, 1636, 1510, 1394, 1441, 1243, 1174, 1025, 996, 830, 762 cm -1 ;

HRMS m/z (M+) calcd for C22H20N2O3: 360.1474. Found: 360.1477.HRMS m / z (M + ) calcd for C 22 H 20 N 2 O 3 : 360.1474. Found: 360.1477.

<< 실시예Example 7> 화합물 4g의 합성 7> Synthesis of Compound 4g

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00128
(1.0 mmol), 및
Figure pat00129
(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 6시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 90%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00128
(1.0 mmol), and
Figure pat00129
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 6 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized from ethanol to obtain pure product (yield: 90%).

mp 259-260 ℃;mp 259-260 ° C;

1H NMR (300MHz, DMSO-d6) δ 7.74 (1H, d, J=7.8Hz), 7.49(1H,s), 7.29- 7.12(7H,m), 6.86(2H,d,J=8.7Hz), 6.76(2H,t,J=7.8Hz), 6.23(1H,s), 3.70(3H,s); 1 H NMR (300MHz, DMSO-d 6 ) δ 7.74 (1H, d, J = 7.8 Hz), 7.49 (1H, s), 7.29-7.12 (7H, m), 6.86 (2H, d, J = 8.7Hz ), 6.76 (2H, t, J = 7.8 Hz), 6.23 (1H, s), 3.70 (3H, s);

13CNMR(75MHz, DMSO-d6) δ 162.5, 159.2, 146.8, 133.7, 132.2, 128.8, 128.7, 128.09, 127.9, 117.4, 115.4, 115.1, 115.0, 114.6, 113.6, 72.6, 55.0; 13 CNMR (75 MHz, DMSO-d 6 ) δ 162.5, 159.2, 146.8, 133.7, 132.2, 128.8, 128.7, 128.09, 127.9, 117.4, 115.4, 115.1, 115.0, 114.6, 113.6, 72.6, 55.0;

IR (KBr) 3427, 3302, 1643, 1504, 1390, 1305, 1245, 1026, 994, 832, 760 cm-1;IR (KBr) 3427, 3302, 1643, 1504, 1390, 1305, 1245, 1026, 994, 832, 760 cm −1 ;

HRMSm /z(M+) calcd for C21H17FN2O2:348.1274. Found:348.1272.HRMS m / z (M + ) calcd for C 21 H 17 FN 2 O 2 : 348.1274. Found: 348.1272.

<< 실시예Example 8> 화합물 4h의 합성 8> Synthesis of Compound 4h

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00130
(1.0 mmol), 및
Figure pat00131
(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:89%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00130
(1.0 mmol), and
Figure pat00131
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 89%).

mp 252-253 ℃;mp 252-253 ° C;

1H NMR (300MHz, DMSO-d6) δ 7.74 (1H, d, J=7.5Hz),7.55(1H,s),7.31-7.26(2H,m),7.22-7.14(2H,m),6.95(1H,s),6.86-6.72(5H,m),6.21(1H,s),5.98(2H,s); 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.74 (1H, d, J = 7.5 Hz), 7.55 (1H, s), 7.31-7.26 (2H, m), 7.22-7.14 (2H, m), 6.95 (1H, s), 6.66-6.72 (5H, m), 6.21 (1H, s), 5.98 (2H, s);

13CNMR(75MHz, DMSO-d6) δ 162.4, 147.3, 147.2, 136.7, 134.1, 133.7, 128.8, 128.7, 127.8, 120.5, 117.5, 115.4, 115.1, 114.9, 114.6, 107.7, 106.9, 101.1, 72.7; 13 CNMR (75 MHz, DMSO-d 6 ) δ 162.4, 147.3, 147.2, 136.7, 134.1, 133.7, 128.8, 128.7, 127.8, 120.5, 117.5, 115.4, 115.1, 114.9, 114.6, 107.7, 106.9, 101.1, 72.7;

IR (KBr) 3426, 1641, 1501, 1447, 1393, 1248, 1027, 996, 758 cm-1;IR (KBr) 3426, 1641, 1501, 1447, 1393, 1248, 1027, 996, 758 cm -1 ;

HRMSm /z(M+) calcd for C21H15FN2O3:362.1067. Found:362.1064.HRMS m / z (M + ) calcd for C 21 H 15 FN 2 O 3 : 362.1067. Found: 362.1064.

<< 실시예Example 9> 화합물 4i의 합성 9> Synthesis of Compound 4i

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00132
(1.0 mmol), 및
Figure pat00133
(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 8시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:88%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00132
(1.0 mmol), and
Figure pat00133
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 8 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized from ethanol to obtain pure product (yield: 88%).

mp 183-185 ℃;mp 183-185 ° C;

1H NMR (300MHz, DMSO-d6) δ 7.72 (1H, d, J=7.8Hz),7.35-7.17(9H,m),6.93(2H,d,J=8.7Hz),6.75-6.67(2H,m), 5.82(1H,s), 4.06-3.97(1H,m), 3.73(3H,s), 3.05-2.87(2H,m), 2.76-2.52(1H,m); 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.72 (1H, d, J = 7.8 Hz), 7.35-7.17 (9H, m), 6.93 (2H, d, J = 8.7 Hz), 6.75-6.67 (2H m, 5.82 (1H, s), 4.06-3.97 (1H, m), 3.73 (3H, s), 3.05-2.87 (2H, m), 2.76-2.52 (1H, m);

13CNMR(75MHz, DMSO-d6) δ 162.3, 159.4, 146.5, 139.0, 133.1 132.9, 128.6, 128.5, 128.3, 127.7, 127.4, 126.2, 117.0, 114.7, 114.2, 113.8, 70.3, 55.1, 46.0; 13 CNMR (75 MHz, DMSO-d 6 ) δ 162.3, 159.4, 146.5, 139.0, 133.1 132.9, 128.6, 128.5, 128.3, 127.7, 127.4, 126.2, 117.0, 114.7, 114.2, 113.8, 70.3, 55.1, 46.0;

IR (KBr) 3426, 3299, 1629, 1509, 1408, 1299, 1249, 1173, 1025, 997, 763 cm-1;IR (KBr) 3426, 3299, 1629, 1509, 1408, 1299, 1249, 1173, 1025, 997, 763 cm −1 ;

HRMSm /z(M+) calcd for C23H22N2O2:358.1681. Found:358.1679.HRMS m / z (M + ) calcd for C 23 H 22 N 2 O 2 : 358.1681. Found: 358.1679.

<< 실시예Example 10> 화합물 4j의 합성 10> Synthesis of Compound 4j

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00134
(1.0 mmol), 및
Figure pat00135
(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:87%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00134
(1.0 mmol), and
Figure pat00135
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain a pure product (yield: 87%).

mp 147-148 ℃; mp 147-148 ° C;

1H NMR (300MHz, DMSO-d6) δ 7.65 (1H, d, J = 7.8 Hz) 7.29-7.16 (6H, m), 6.88-6.78 (3H, m), 6.69-6.62 (3H, m), 5.98 (2H, s), 5.76 (1H, s), 4.04-3.88 (1H, m), 3.01-2.84 (2H, m), 2.77-2.67, (1H, m); 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.65 (1H, d, J = 7.8 Hz) 7.29-7.16 (6H, m), 6.88-6.78 (3H, m), 6.69-6.62 (3H, m), 5.98 (2H, s), 5.76 (1H, s), 4.04-3.88 (1H, m), 3.01-2.84 (2H, m), 2.77-2.67, (1H, m);

13C NMR (75 MHz, DMSO-d6) δ 162.1, 147.4, 147.3, 146.3, 139.0, 134.9, 133.1, 128.5, 128.3, 127.3, 126.1, 119.7, 117.0, 114.6, 114.1, 107.9, 106.4, 101.1, 70.2, 46.0, 33.5; 13 C NMR (75 MHz, DMSO-d 6 ) δ 162.1, 147.4, 147.3, 146.3, 139.0, 134.9, 133.1, 128.5, 128.3, 127.3, 126.1, 119.7, 117.0, 114.6, 114.1, 107.9, 106.4, 101.1, 70.2 , 46.0, 33.5;

IR (KBr) 3427, 1634, 1484, 1411, 1248, 1026, 994, 756 cm-1; IR (KBr) 3427, 1634, 1484, 1411, 1248, 1026, 994, 756 cm −1 ;

HRMS m/z (M+) calcd for C23H20N2O3: 372.1474. Found: 372.1471.HRMS m / z (M + ) calcd for C 23 H 20 N 2 O 3 : 372.1474. Found: 372.1471.

<< 실시예Example 11> 화합물 4k의 합성 11> Synthesis of Compound 4k

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00136
(1.0 mmol), 및
Figure pat00137
(1.0 mmol) 이 들어있는 용액에, EDDA(36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 6시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율:92%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00136
(1.0 mmol), and
Figure pat00137
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 6 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 92%).

mp 129-130 ℃;mp 129-130 ° C;

1H NMR (300MHz, DMSO-d6) δ 7.65 (1H, d, J=7.8Hz),7.39-7.11(11H,m), 6.81-6.61(2H,m), 5.83(1H,d,J=2.1Hz), 3.41-3.35(2H,m), 2.53(2H,t,J=6.9Hz), 1.58-1.45(4H,m); 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.65 (1H, d, J = 7.8 Hz), 7.39-7.11 (11H, m), 6.81-6.61 (2H, m), 5.83 (1H, d, J = 2.1 Hz), 3.41-3.35 (2H, m), 2.53 (2H, t, J = 6.9 Hz), 1.58-1.45 (4H, m);

13CNMR(75MHz, DMSO-d6) δ 162.2, 145.9, 142.03, 140.2, 133.2, 132.9, 128.4, 128.26, 128.21, 127.9, 127.4, 125.6, 117.3, 115.0, 114.3, 69.4, 44.3, 34.8, 28.3, 27.1; 13 CNMR (75 MHz, DMSO-d 6 ) δ 162.2, 145.9, 142.03, 140.2, 133.2, 132.9, 128.4, 128.26, 128.21, 127.9, 127.4, 125.6, 117.3, 115.0, 114.3, 69.4, 44.3, 34.8, 28.3, 27.1 ;

IR (KBr) 3426, 3297, 2938, 2859, 1630, 1489, 1437, 1413, 1320, 1089, 996, 826, 749 cm-1;IR (KBr) 3426, 3297, 2938, 2859, 1630, 1489, 1437, 1413, 1320, 1089, 996, 826, 749 cm −1 ;

HRMSm /z(M+) calcd for C24H23ClN2O:390.1499. Found:390.1499.HRMS m / z (M + ) calcd for C 24 H 23 ClN 2 O: 390.1499. Found: 390.1499.

<< 실시예Example 12> 화합물 6a의 합성 12> Synthesis of Compound 6a

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00138
(1.0 mmol) 및
Figure pat00139
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 5시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 94%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00138
(1.0 mmol) and
Figure pat00139
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 5 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 94%).

mp 264-266 ℃;mp 264-266 ° C;

1H NMR (300MHz, DMSO-d6) δ 10.39 (1H, s), 7.68 (1H, d, J=7.5Hz), 7.60(1H,s), 7.53(1H,d,J=7.5Hz), 7.30(1H,t,J=7.8Hz), 7.24-7.12(4H,m), 7.01-6.98(2H,m), 6.92(1H,t,J=7.5Hz), 6.78-6.70(2H,m), 6.64(1H,d,J=7.5Hz); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.39 (1H, s), 7.68 (1H, d, J = 7.5 Hz), 7.60 (1H, s), 7.53 (1H, d, J = 7.5 Hz), 7.30 (1H, t, J = 7.8 Hz), 7.24-7.12 (4H, m), 7.01-6.98 (2H, m), 6.92 (1H, t, J = 7.5 Hz), 6.78-6.70 (2H, m) , 6.64 (1H, d, J = 7.5 Hz);

13CNMR(75MHz, DMSO-d6) δ 175.6, 163.8, 146.3, 141.4, 138.3, 134.2, 134.0, 129.9, 129.7, 129.2, 128.3, 127.9, 118.4, 115.0, 114.6, 114.1, 112.6, 76.8; 13 CNMR (75 MHz, DMSO-d 6 ) δ 175.6, 163.8, 146.3, 141.4, 138.3, 134.2, 134.0, 129.9, 129.7, 129.2, 128.3, 127.9, 118.4, 115.0, 114.6, 114.1, 112.6, 76.8;

IR (KBr) 3447, 3303, 1721, 1644, 1615, 1486, 1358, 1194, 1105, 1012, 964, 865, 752 cm-1;IR (KBr) 3447, 3303, 1721, 1644, 1615, 1486, 1358, 1194, 1105, 1012, 964, 865, 752 cm −1 ;

HRMSm /z(M+) calcd for C21H15N3O2:341.1164. Found:341.1161.HRMS m / z (M + ) calcd for C 21 H 15 N 3 O 2 : 341.1164. Found: 341.1161.

<< 실시예Example 12> 화합물 6b의 합성 12> Synthesis of Compound 6b

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00140
(1.0 mmol), 및
Figure pat00141
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 92%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00140
(1.0 mmol), and
Figure pat00141
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 92%).

mp 274-276 ℃;mp 274-276 ° C;

1H NMR (300MHz, DMSO-d6) δ 10.40 (1H, s), 7.66 (1H, d, J=7.8Hz), 7.59(1H,s), 7.53(1H,d,J=7.2Hz), 7.30(1H,t,J=7.8Hz), 7.15(1H,t,J=7.5Hz), 7.07(1H,t,J=7.2Hz), 6.98-6.90(3H,m), 6.82(1H,s), 6.75(1H,t,J=8.4Hz), 6.70(1H,d,J=8.1Hz), 6.64(1H,d,J=7.5Hz), 2.15(3H,s); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.40 (1H, s), 7.66 (1H, d, J = 7.8 Hz), 7.59 (1H, s), 7.53 (1H, d, J = 7.2 Hz), 7.30 (1H, t, J = 7.8 Hz), 7.15 (1 H, t, J = 7.5 Hz), 7.07 (1 H, t, J = 7.2 Hz), 6.98-6.90 (3H, m), 6.82 (1 H, s ), 6.75 (1H, t, J = 8.4 Hz), 6.70 (1H, d, J = 8.1 Hz), 6.64 (1H, d, J = 7.5 Hz), 2.15 (3H, s);

13CNMR(75MHz, DMSO-d6) δ 174.3, 163.9, 146.5, 143.6, 138.3, 134.1, 131.4, 128.8, 128.7, 127.9, 127.1, 126.6, 123.1, 118.2, 115.1, 114.6, 109.3, 76.6, 21.2 13 CNMR (75 MHz, DMSO-d 6 ) δ 174.3, 163.9, 146.5, 143.6, 138.3, 134.1, 131.4, 128.8, 128.7, 127.9, 127.1, 126.6, 123.1, 118.2, 115.1, 114.6, 109.3, 76.6, 21.2

IR (KBr) 3298, 3206, 3093, 1724, 1643, 1616, 1485, 1361, 1236, 1193, 1100, 1048, 963, 751 cm-1;IR (KBr) 3298, 3206, 3093, 1724, 1643, 1616, 1485, 1361, 1236, 1193, 1100, 1048, 963, 751 cm −1 ;

HRMSm /z(M+) calcd for C22H17N3O2:355.1321. Found:355.1318.HRMS m / z (M + ) calcd for C 22 H 17 N 3 O 2 : 355.1321. Found: 355.1318.

<< 실시예Example 13> 화합물 6c의 합성 13> Synthesis of Compound 6c

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00142
(1.0 mmol), 및
Figure pat00143
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 6시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 96%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00142
(1.0 mmol), and
Figure pat00143
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 6 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized from ethanol to obtain pure product (yield: 96%).

mp 276-278 ℃; mp 276-278 ° C;

1H NMR (300MHz, DMSO-d6) δ 10.36 (1H, s), 7.66 (1H, d, J = 7.5 Hz), 7.56 (1H, s), 7.52 (1H, d, J = 7.5 Hz), 7.29 (1H, t, J = 8.1 Hz), 7.15 (1H, t, J = 7.5 Hz), 7.08-6.87 (5H, m), 6.77-6.63 (3H, m), 2.79-2.73 (1H, m), 1.09 (6H, d, J = 6.9 Hz); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.36 (1H, s), 7.66 (1H, d, J = 7.5 Hz), 7.56 (1H, s), 7.52 (1H, d, J = 7.5 Hz), 7.29 (1H, t, J = 8.1 Hz), 7.15 (1H, t, J = 7.5 Hz), 7.08-6.87 (5H, m), 6.77-6.63 (3H, m), 2.79-2.73 (1H, m) , 1.09 (6H, d, J = 6.9 Hz);

13C NMR (75 MHz, DMSO-d6) δ 175.3, 163.6, 147.4, 146.0, 141.5, 135.6, 133.5, 130.6, 129.0, 127.5, 127.4, 126.3, 126.2, 122.1, 117.6, 114.5, 114.0, 110.0, 76.3, 32.7, 23.6, 23.5; 13 C NMR (75 MHz, DMSO-d 6 ) δ 175.3, 163.6, 147.4, 146.0, 141.5, 135.6, 133.5, 130.6, 129.0, 127.5, 127.4, 126.3, 126.2, 122.1, 117.6, 114.5, 114.0, 110.0, 76.3 , 32.7, 23.6, 23.5;

IR (KBr) 3311, 3066, 2961, 1725, 1632, 1511, 1484, 1359, 1214, 1190, 1105, 1051, 955, 817, 752 cm-1 IR (KBr) 3311, 3066, 2961, 1725, 1632, 1511, 1484, 1359, 1214, 1190, 1105, 1051, 955, 817, 752 cm -1

HRMS m/z (M+) calcd for C24H21N3O2: 383.1634. Found: 383.1630.HRMS m / z (M + ) calcd for C 24 H 21 N 3 O 2 : 383.1634. Found: 383.1630.

<< 실시예Example 14> 화합물 6d의 합성 14> Synthesis of Compound 6d

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00144
(1.0 mmol), 및
Figure pat00145
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 9시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 89%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00144
(1.0 mmol), and
Figure pat00145
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 9 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 89%).

mp 295-296 ℃;mp 295-296 ° C;

1H NMR (300MHz, DMSO-d6) δ 10.47 (1H, s), 7.67 (2H, t, J=3.3Hz), 7.59(1H,d,J=10.5Hz), 7.31(1H,t,J=7.2Hz), 7.18(1H,t,J=7.5Hz), 7.09-6.92(5H,m), 6.78-6.65(3H,m); 1 H NMR (300MHz, DMSO-d 6 ) δ 10.47 (1H, s), 7.67 (2H, t, J = 3.3 Hz), 7.59 (1H, d, J = 10.5 Hz), 7.31 (1H, t, J = 7.2 Hz), 7.18 (1H, t, J = 7.5 Hz), 7.09-6.92 (5H, m), 6.78-6.65 (3H, m);

13CNMR(75MHz, DMSO-d6) δ 175.4, 163.9, 146.3, 141.4, 134.4, 134.3, 134.1, 129.8, 129.7, 127.9, 118.4, 116.2, 115.9, 114.8, 114.6, 114.2, 112.6, 76.9 13 CNMR (75 MHz, DMSO-d 6 ) δ 175.4, 163.9, 146.3, 141.4, 134.4, 134.3, 134.1, 129.8, 129.7, 127.9, 118.4, 116.2, 115.9, 114.8, 114.6, 114.2, 112.6, 76.9

IR (KBr) 3272, 3066, 1726, 1642, 1616, 1509, 1483, 1360, 1328, 1221, 1197, 1154, 1099, 961, 827, 750 cm-1;IR (KBr) 3272, 3066, 1726, 1642, 1616, 1509, 1483, 1360, 1328, 1221, 1197, 1154, 1099, 961, 827, 750 cm −1 ;

HRMSm /z(M+) calcd for C21H14FN3O2:359.1070. Found:359.1068.HRMS m / z (M + ) calcd for C 21 H 14 FN 3 O 2 : 359.1070. Found: 359.1068.

<< 실시예Example 15> 화합물 6e의 합성 15> Synthesis of Compound 6e

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00146
(1.0 mmol), 및
Figure pat00147
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 90%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00146
(1.0 mmol), and
Figure pat00147
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized from ethanol to obtain pure product (yield: 90%).

mp 210-211 ℃; mp 210-211 ° C;

1H NMR (300MHz, DMSO-d6) δ 10.34 (1H, s), 7.72 (1H, d, J = 7.8 Hz), 7.45 (1H, s), 7.36-7.24 (3H, m), 7.17-7.15 (3H, m), 6.93-6.88 (3H, m), 6.83 (1H, d, J = 7.8 Hz), 6.76 (1H, t, J = 7.5 Hz), 6.67 (1H, d, J = 7.5 Hz), 4.48 (1H, d, J = 15.3 Hz), 4.15 (1H, d, J = 15.3 Hz); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.34 (1H, s), 7.72 (1H, d, J = 7.8 Hz), 7.45 (1H, s), 7.36-7.24 (3H, m), 7.17-7.15 (3H, m), 6.93-6.88 (3H, m), 6.83 (1H, d, J = 7.8 Hz), 6.76 (1H, t, J = 7.5 Hz), 6.67 (1H, d, J = 7.5 Hz) , 4.48 (1H, d, J = 15.3 Hz), 4.15 (1H, d, J = 15.3 Hz);

13C NMR (75 MHz, DMSO-d6) δ 175.4, 164.5, 146.4, 142.9, 137.8, 133.8, 131.7, 128.2, 127.8, 127.2, 126.8, 126.7, 122.4, 118.1, 115.1, 114.4, 110.9, 75.5, 46.3. 13 C NMR (75 MHz, DMSO-d 6 ) δ 175.4, 164.5, 146.4, 142.9, 137.8, 133.8, 131.7, 128.2, 127.8, 127.2, 126.8, 126.7, 122.4, 118.1, 115.1, 114.4, 110.9, 75.5, 46.3 .

IR (KBr) 3297, 3090, 2944, 1727, 1625, 1483, 1383, 1323, 1242, 1191, 968. 750 cm-1 IR (KBr) 3297, 3090, 2944, 1727, 1625, 1483, 1383, 1323, 1242, 1191, 968.750 cm -1

HRMS m/z (M+) calcd for C22H17N3O2: 355.1321. Found: 355.1318.HRMS m / z (M + ) calcd for C 22 H 17 N 3 O 2 : 355.1321. Found: 355.1318.

<< 실시예Example 16> 화합물 6f의 합성 16> Synthesis of Compound 6f

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00148
(1.0 mmol), 및
Figure pat00149
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 10시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 82%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00148
(1.0 mmol), and
Figure pat00149
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 10 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 82%).

mp 257-258 ℃;mp 257-258 ° C;

1H NMR (300MHz, DMSO-d6) δ 10.26 (1H, s), 7.70 (1H, d, J=7.8Hz), 7.39(1H,s), 7.35-7.22(3H,m), 6.95-6.89(3H,m), 6.81- 6.71(4H,m), 6.64(1H,d,J=8.1Hz), 4.35(1H,d,J=15.0Hz), 4.18(1H,d,J=15.3Hz), 2.22(3H,s); 1 H NMR (300MHz, DMSO-d 6 ) δ 10.26 (1H, s), 7.70 (1H, d, J = 7.8 Hz), 7.39 (1H, s), 7.35-7.22 (3H, m), 6.95-6.89 (3H, m), 6.81-6.71 (4H, m), 6.64 (1H, d, J = 8.1 Hz), 4.35 (1H, d, J = 15.0 Hz), 4.18 (1H, d, J = 15.3 Hz) , 2.22 (3H, s);

13CNMR(75MHz, DMSO-d6) δ 174.9, 163.9, 145.9, 142.4, 135.7, 134.1, 133.2, 131.1, 128.2, 127.4, 127.3, 126.2, 121.8, 117.5, 114.6, 113.8, 110.3, 74.9, 45.4, 20.6; 13 CNMR (75 MHz, DMSO-d 6 ) δ 174.9, 163.9, 145.9, 142.4, 135.7, 134.1, 133.2, 131.1, 128.2, 127.4, 127.3, 126.2, 121.8, 117.5, 114.6, 113.8, 110.3, 74.9, 45.4, 20.6 ;

IR (KBr) 3322, 3092, 2946, 1726, 1625, 1482, 1435, 1379, 1324, 1242, 1198, 1113, 1027, 963, 747 cm-1;IR (KBr) 3322, 3092, 2946, 1726, 1625, 1482, 1435, 1379, 1324, 1242, 1198, 1113, 1027, 963, 747 cm −1 ;

HRMSm /z(M+) calcd for C23H19N3O2:369.1477. Found: 369.1475.HRMS m / z (M + ) calcd for C 23 H 19 N 3 O 2 : 369.1477. Found: 369.1475.

<< 실시예Example 17> 화합물 6g의 합성 17> Synthesis of Compound 6g

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00150
(1.0 mmol), 및
Figure pat00151
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 10시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 88%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00150
(1.0 mmol), and
Figure pat00151
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 10 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized from ethanol to obtain pure product (yield: 88%).

mp 227-228 ℃; mp 227-228 ° C;

1H NMR (300MHz, DMSO-d6) δ 10.20 (1H, s), 7.71 (1H, d, J = 7.8 Hz), 7.37-7.22 (4H, m), 6.95 (1H, t, J = 7.8 Hz), 6.81-6.62 (7H, m), 4.28 (2H, s), 3.68 (3H, s); 1 H NMR (300MHz, DMSO-d 6 ) δ 10.20 (1H, s), 7.71 (1H, d, J = 7.8 Hz), 7.37-7.22 (4H, m), 6.95 (1H, t, J = 7.8 Hz ), 6.81-6.62 (7H, m), 4.28 (2H, s), 3.68 (3H, s);

13C NMR (75 MHz, DMSO-d6) δ 174.9, 163.9, 158.1, 145.9, 142.5, 133.2, 131.1, 128.9, 127.3, 126.3, 121.9, 117.5, 114.7, 113.8, 113.1, 110.4, 74.8, 54.9, 45.1; 13 C NMR (75 MHz, DMSO-d 6 ) δ 174.9, 163.9, 158.1, 145.9, 142.5, 133.2, 131.1, 128.9, 127.3, 126.3, 121.9, 117.5, 114.7, 113.8, 113.1, 110.4, 74.8, 54.9, 45.1 ;

IR (KBr) 3280, 3062, 2957, 1723, 1640, 1477, 1326, 1118, 1024, 944, 752 cm-1 IR (KBr) 3280, 3062, 2957, 1723, 1640, 1477, 1326, 1118, 1024, 944, 752 cm -1

HRMS m/z (M+) calcd for C23H19N3O3: 385.1426. Found: 385.1423.HRMS m / z (M + ) calcd for C 23 H 19 N 3 O 3 : 385.1426. Found: 385.1423.

<< 실시예Example 18> 화합물 6h의 합성 18> Synthesis of Compound 6h

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00152
(1.0 mmol), 및
Figure pat00153
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 6시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 92%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00152
(1.0 mmol), and
Figure pat00153
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 6 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 92%).

mp 287-288 ℃;mp 287-288 ° C;

1H NMR (300MHz, DMSO-d6) δ 10.56 (1H, s), 7.68 (1H, d, J=7.5Hz), 7.53(1H,d,J=7.2Hz), 7.46-7.41(2H,m),7.28-7.10(5H,m), 6.96(1H,d,J=7.8Hz), 6.80(2H,d,J=8.1Hz), 6.73(1H,t,J=7.2Hz), 6.63(1H,d,J=7.8Hz), 3.36(1H,t,J=11.4Hz), 2.86-2.68(2H,m), 2.57(1H,t,J=7.2Hz); 1 H NMR (300MHz, DMSO-d 6 ) δ 10.56 (1H, s), 7.68 (1H, d, J = 7.5 Hz), 7.53 (1H, d, J = 7.2 Hz), 7.46-7.41 (2H, m ), 7.28-7.10 (5H, m), 6.96 (1H, d, J = 7.8 Hz), 6.80 (2H, d, J = 8.1 Hz), 6.73 (1H, t, J = 7.2 Hz), 6.63 (1H) , d, J = 7.8 Hz), 3.36 (1H, t, J = 11.4 Hz), 2.86-2.68 (2H, m), 2.57 (1H, t, J = 7.2 Hz);

13CNMR(75MHz, DMSO-d6) δ 175.2, 163.3, 145.7, 142.2, 138.6, 133.2, 131.3, 128.4, 128.0, 127.2, 127.1, 126.2, 125.9, 122.4, 117.5, 114.3, 113.7, 110.6, 75.3, 44.9, 34.2; 13 CNMR (75 MHz, DMSO-d 6 ) δ 175.2, 163.3, 145.7, 142.2, 138.6, 133.2, 131.3, 128.4, 128.0, 127.2, 127.1, 126.2, 125.9, 122.4, 117.5, 114.3, 113.7, 110.6, 75.3, 44.9 , 34.2;

IR (KBr) 3279, 3062, 2956, 2873, 1723, 1639, 1513, 1477, 1394, 1325, 1272, 1234, 1189, 1023, 944, 751 cm-1;IR (KBr) 3279, 3062, 2956, 2873, 1723, 1639, 1513, 1477, 1394, 1325, 1272, 1234, 1189, 1023, 944, 751 cm −1 ;

HRMSm /z(M+) calcd for C23H19N3O2:369.1477. Found:369.1479. HRMS m / z (M + ) calcd for C 23 H 19 N 3 O 2 : 369.1477. Found: 369.1479.

<< 실시예Example 19> 화합물 6i의 합성 19> Synthesis of Compound 6i

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00154
(1.0 mmol), 및
Figure pat00155
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 92%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00154
(1.0 mmol), and
Figure pat00155
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 92%).

mp 173-175 ℃;mp 173-175 ° C;

1H NMR (300MHz, DMSO-d6) δ 10.50 (1H, s), 7.62 (1H, d, J=7.5Hz), 7.43(1H,d,J=7.5Hz), 7.37(1H,d,J=8.1Hz), 7.35(1H,s), 7.25-7.20(3H,m), 7.14(1H,d,J=6.9Hz), 7.09-7.02(3H,m), 6.92(1H,d,J=7.8Hz), 6.70(1H,t,J=7.2Hz), 6.60(1H,d,J=8.1Hz), 3.20(1H,t,J=9.3Hz), 2.81(1H,t,J=9.0Hz), 2.33(2H,t,J=6.6Hz), 1.37-1.25(4H,m); 1 H NMR (300MHz, DMSO-d 6 ) δ 10.50 (1H, s), 7.62 (1H, d, J = 7.5 Hz), 7.43 (1H, d, J = 7.5 Hz), 7.37 (1H, d, J = 8.1 Hz), 7.35 (1H, s), 7.25-7.20 (3H, m), 7.14 (1H, d, J = 6.9 Hz), 7.09-7.02 (3H, m), 6.92 (1H, d, J = 7.8 Hz), 6.70 (1H, t, J = 7.2 Hz), 6.60 (1H, d, J = 8.1 Hz), 3.20 (1H, t, J = 9.3 Hz), 2.81 (1H, t, J = 9.0 Hz ), 2.33 (2H, t, J = 6.6 Hz), 1.37-1.25 (4H, m);

13CNMR(75MHz, DMSO-d6) δ 175.7, 163.8, 146.1, 142.6, 142.3, 133.6, 131.7, 128.6, 127.8, 127.5, 126.2, 126.0, 122.8, 117.9, 115.0, 114.2, 111.1, 75.6, 43.1, 35.0, 28.8, 28.1; 13 CNMR (75 MHz, DMSO-d 6 ) δ 175.7, 163.8, 146.1, 142.6, 142.3, 133.6, 131.7, 128.6, 127.8, 127.5, 126.2, 126.0, 122.8, 117.9, 115.0, 114.2, 111.1, 75.6, 43.1, 35.0 , 28.8, 28.1;

IR (KBr) 3260, 2935, 1726, 1689, 1624, 1400, 1365, 1325, 1191, 1030, 749 cm-1;IR (KBr) 3260, 2935, 1726, 1689, 1624, 1400, 1365, 1325, 1191, 1030, 749 cm −1 ;

HRMSm /z(M+) calcd for C25H23N3O2:397.1790. Found:397.1794.HRMS m / z (M + ) calcd for C 25 H 23 N 3 O 2 : 397.1790. Found: 397.1794.

<< 실시예Example 20> 화합물 6j의 합성 20> Synthesis of Compound 6j

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00156
(1.0 mmol), 및
Figure pat00157
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 91%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00156
(1.0 mmol), and
Figure pat00157
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 91%).

mp 170-171 ℃;mp 170-171 ° C;

1H NMR (300MHz, DMSO-d6) δ 10.53, (1H, s),7.66 (1H, d, J=7.8Hz), 7.52(1H,d,J=7.5Hz), 7.42(1H,d,J=7.8Hz), 7.37(1H,s), 7.26(1H,t,J=7.5Hz) 7.12(1H,t,J=7.5Hz), 6.95(1H,d,J=7.8Hz), 6.72(1H,t,J=7.2Hz), 6.62(1H,d,J=8.1Hz), 3.17-3.07(1H,m), 2.83-2.74(1H,m), 1.40-1.22(2H,m), 1.13-1.00(6H,m), 0.74(3H,t,J=6.9Hz); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.53, (1H, s), 7.66 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.5 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.37 (1H, s), 7.26 (1H, t, J = 7.5 Hz) 7.12 (1H, t, J = 7.5 Hz), 6.95 (1H, d, J = 7.8 Hz), 6.72 ( 1H, t, J = 7.2Hz), 6.62 (1H, d, J = 8.1Hz), 3.17-3.07 (1H, m), 2.83-2.74 (1H, m), 1.40-1.22 (2H, m), 1.13 -1.00 (6H, m), 0.74 (3H, t, J = 6.9 Hz);

13CNMR(75MHz, DMSO-d6) δ 175.8, 163.8, 146.1, 142.6, 133.5, 131.7, 127.8, 127.5, 126.3, 122.8, 117.9, 115.0, 114.2, 111.0, 75.6, 43.3, 30.9, 28.0, 26.3, 22.1, 14.2; 13 CNMR (75 MHz, DMSO-d 6 ) δ 175.8, 163.8, 146.1, 142.6, 133.5, 131.7, 127.8, 127.5, 126.3, 122.8, 117.9, 115.0, 114.2, 111.0, 75.6, 43.3, 30.9, 28.0, 26.3, 22.1 , 14.2;

IR (KBr) 3261, 2952, 2930, 2860, 1727, 1690, 1624, 1479, 1325, 1109, 1024, 943, 749 cm-1;IR (KBr) 3261, 2952, 2930, 2860, 1727, 1690, 1624, 1479, 1325, 1109, 1024, 943, 749 cm −1 ;

HRMSm /z(M+) calcd for C21H23N3O2:349.1790. Found:349.1793. HRMS m / z (M + ) calcd for C 21 H 23 N 3 O 2 : 349.1790. Found: 349.1793.

<< 실시예Example 21> 화합물 6k의 합성 21> Synthesis of Compound 6k

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00158
(1.0 mmol), 및
Figure pat00159
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 7시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 89%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00158
(1.0 mmol), and
Figure pat00159
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 7 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 89%).

mp 190-192 ℃;mp 190-192 ° C;

1H NMR (300MHz, DMSO-d6) δ 10.54 (1H, s), 7.66 (1H, d, J=7.5Hz) 7.52(1H,d,J=7.5Hz), 7.39(1H,t,J=7.5Hz), 7.33(1H,s), 7.24(1H,t,J=7.2Hz), 7.11(1H,t,J=7.5Hz), 6.94(1H,d,J=7.8Hz), 6.73(1H,t,J=7.2Hz), 6.64(1H,d,J=7.8Hz), 3.18-3.11(1H,dd,J=6.9&13.8Hz), 2.79- 2.71(1H,dd,J=7.5&13.5Hz), 1.58-1.27(6H,m), 1.06-0.68(5H,m); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.54 (1H, s), 7.66 (1H, d, J = 7.5 Hz) 7.52 (1H, d, J = 7.5 Hz), 7.39 (1H, t, J = 7.5 Hz), 7.33 (1H, s), 7.24 (1H, t, J = 7.2 Hz), 7.11 (1H, t, J = 7.5 Hz), 6.94 (1H, d, J = 7.8 Hz), 6.73 (1H , t, J = 7.2 Hz), 6.64 (1H, d, J = 7.8 Hz), 3.18-3.11 (1H, dd, J = 6.9 & 13.8 Hz), 2.79-2.71 (1H, dd, J = 7.5 & 13. 5 Hz), 1.58-1.27 (6H, m), 1.06-0.68 (5H, m);

13CNMR(75MHz, DMSO-d6) δ 175.7, 164.6, 146.2, 142.6, 133.5, 131.7, 127.7, 127.6, 126.6, 122.6, 117.9, 115.3, 114.2, 110.9, 75.7, 48.9, 37.4, 31.1, 31.0, 26.3, 26.0, 25.9; 13 CNMR (75 MHz, DMSO-d 6 ) δ 175.7, 164.6, 146.2, 142.6, 133.5, 131.7, 127.7, 127.6, 126.6, 122.6, 117.9, 115.3, 114.2, 110.9, 75.7, 48.9, 37.4, 31.1, 31.0, 26.3 , 26.0, 25.9;

IR (KBr) 3265, 2925, 2851, 1732, 1622, 1483, 1440, 1391, 1322, 1189, 1111, 951, 750 cm-1;IR (KBr) 3265, 2925, 2851, 1732, 1622, 1483, 1440, 1391, 1322, 1189, 1111, 951, 750 cm −1 ;

HRMSm /z(M+) calcd for C22H23N3O2:361.1790. Found:361.1791. HRMS m / z (M + ) calcd for C 22 H 23 N 3 O 2 : 361.1790. Found: 361.1791.

<< 실시예Example 22> 화합물 6l의 합성 22> Synthesis of Compound 6l

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol), NH4OAc(1.0 mmol), 및

Figure pat00160
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 6시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 93%).Isatoic anhydride ( 1 ) (1.0 mmol), NH 4 OAc (1.0 mmol), and
Figure pat00160
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). And the reaction mixture was refluxed for 6 hours under nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 93%).

mp 261-263 ℃;mp 261-263 ° C;

1H NMR (300MHz, DMSO-d6) δ 10.25 (1H, s), 8.30 (1H, s), 7.60 (1H, d, J=7.5Hz), 7.46(1H,d,J=6.9Hz), 7.33(1H,t,J=7.5Hz), 7.24(1H,s), 7.20(1H,d,J=8.4Hz), 7.05(1H,t,J=6.9Hz), 6.84(1H,d,J=8.1Hz), 6.68(1H,t,J=7.5Hz), 6.61(1H,d,J=8.1Hz); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.25 (1H, s), 8.30 (1H, s), 7.60 (1H, d, J = 7.5 Hz), 7.46 (1H, d, J = 6.9 Hz), 7.33 (1H, t, J = 7.5 Hz), 7.24 (1 H, s), 7.20 (1 H, d, J = 8.4 Hz), 7.05 (1 H, t, J = 6.9 Hz), 6.84 (1 H, d, J = 8.1 Hz), 6.68 (1H, t, J = 7.5 Hz), 6.61 (1H, d, J = 8.1 Hz);

13CNMR(75MHz, DMSO-d 6) δ 176.4, 164.3, 147.2, 142.5, 133.7, 131.2, 129.9, 127.3, 125.7, 122.7, 117.6, 114.8, 114.3, 110.5, 71.4; 13 CNMR (75MHz, DMSO- d 6 ) δ 176.4, 164.3, 147.2, 142.5, 133.7, 131.2, 129.9, 127.3, 125.7, 122.7, 117.6, 114.8, 114.3, 110.5, 71.4;

IR (KBr) 3474, 3288, 3066, 1708, 1621, 1519, 1478, 1326, 1266, 1192, 1151, 1105, 1048, 960, 750 cm-1;IR (KBr) 3474, 3288, 3066, 1708, 1621, 1519, 1478, 1326, 1266, 1192, 1151, 1105, 1048, 960, 750 cm −1 ;

HRMSm /z(M+) calcd for C15H11N3O2:265.0851. Found:265.0847. HRMS m / z (M + ) calcd for C 15 H 11 N 3 O 2 : 265.0851. Found: 265.0847.

<< 실시예Example 23> 화합물 6m의 합성 23> Synthesis of Compound 6m

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00161
(1.0 mmol), 및
Figure pat00162
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 8시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 93%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00161
(1.0 mmol), and
Figure pat00162
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 8 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 93%).

mp 277-279 ℃;mp 277-279 ° C;

1H NMR (300MHz, DMSO-d6) δ 10.54 (1H, s), 7.74 (1H, s), 7.68 (1H, d, J=8.4Hz), 7.66(1H,s), 7.35-7.18(5H,m), 7.03(2H,d,J=7.8Hz), 6.77(1H,t,J=6.9Hz), 6.70(1H,d,J=8.1Hz), 6.60(1H,d,J=8.1Hz); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.54 (1H, s), 7.74 (1H, s), 7.68 (1H, d, J = 8.4 Hz), 7.66 (1H, s), 7.35-7.18 (5H , m), 7.03 (2H, d, J = 7.8 Hz), 6.77 (1H, t, J = 6.9 Hz), 6.70 (1H, d, J = 8.1 Hz), 6.60 (1H, d, J = 8.1 Hz );

13CNMR(75MHz, DMSO-d6) δ 175.08, 163.2, 145.7, 140.9, 137.8, 133.7, 133.5, 129.4, 129.2, 128.7, 127.7, 127.4, 117.8, 117.6, 114.5, 114.09, 113.6, 112.09, 76.3; 13 CNMR (75 MHz, DMSO-d 6 ) δ 175.08, 163.2, 145.7, 140.9, 137.8, 133.7, 133.5, 129.4, 129.2, 128.7, 127.7, 127.4, 117.8, 117.6, 114.5, 114.09, 113.6, 112.09, 76.3;

IR (KBr) 3372, 3324, 3247, 1742, 1619, 1484, 1361, 1276, 1190, 1067, 873, 814, 750 cm-1;IR (KBr) 3372, 3324, 3247, 1742, 1619, 1484, 1361, 1276, 1190, 1067, 873, 814, 750 cm −1 ;

HRMS m/z(M+) calcd for C21H14BrN3O2:419.0269. Found:419.0272. HRMS m / z (M + ) calcd for C 21 H 14 BrN 3 O 2 : 419.0269. Found: 419.0272.

<< 실시예Example 24> 화합물 6n의 합성 24> Synthesis of Compound 6n

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00163
(1.0 mmol), 및
Figure pat00164
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 10시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 82%).Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00163
(1.0 mmol), and
Figure pat00164
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 10 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and recrystallized from ethanol to obtain pure product (yield: 82%).

mp 275-277 ℃;mp 275-277 ° C;

1H NMR (300MHz, DMSO-d6) δ 10.60 (1H, s), 7.80 (1H, s), 7.70-7.66 (2H, m), 7.38-7.30 (2H, m), 7.14-7.08 (4H, m), 6.78 (1H, t, J=7.2Hz), 6.70(1H,d,J=8.4Hz), 6.64(1H,d,J=8.4Hz); 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.60 (1H, s), 7.80 (1H, s), 7.70-7.66 (2H, m), 7.38-7.30 (2H, m), 7.14-7.08 (4H, m), 6.78 (1H, t, J = 7.2 Hz), 6.70 (1H, d, J = 8.4 Hz), 6.64 (1H, d, J = 8.4 Hz);

13CNMR(75MHz, DMSO-d 6) δ 173.6, 163.6, 146.0, 143.0, 134.0, 133.7, 131.0, 127.4, 126.4, 126.1, 122.8, 117.8, 115.5, 115.3, 114.3, 114.1, 108.9, 76.2. 13 CNMR (75MHz, DMSO- d 6 ) δ 173.6, 163.6, 146.0, 143.0, 134.0, 133.7, 131.0, 127.4, 126.4, 126.1, 122.8, 117.8, 115.5, 115.3, 114.3, 114.1, 108.9, 76.2.

IR (KBr) 3269, 1732, 1641, 1618, 1510, 1482, 1359, 1225, 1195, 954, 823, 750 cm-1;IR (KBr) 3269, 1732, 1641, 1618, 1510, 1482, 1359, 1225, 1195, 954, 823, 750 cm −1 ;

HRMSm /z(M+) calcd for C21H13BrFN3O2:437.0175. Found:437.0174.HRMS m / z (M + ) calcd for C 21 H 13 BrFN 3 O 2 : 437.0175. Found: 437.0174.

<< 실시예Example 25> 화합물 6o의 합성 25> Synthesis of Compound 6o

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00165
(1.0 mmol), 및
Figure pat00166
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 10시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 90%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00165
(1.0 mmol), and
Figure pat00166
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 10 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized from ethanol to obtain pure product (yield: 90%).

mp 238-240 ℃;mp 238-240 ° C;

1H NMR (300MHz, DMSO-d6) δ 7.70 (1H, d, J=7.5Hz), 7.61(2H,d,J=7.8Hz), 7.34-7.13(5H,m), 7.01(1H,t,J=6.9Hz), 6.93(2H,d,J=7.5Hz), 6.85(1H,d,J=8.1Hz), 6.78(1H,t,J=7.5Hz), 6.72(1H,d,J=8.1Hz), 3.02(3H,s); 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.70 (1H, d, J = 7.5 Hz), 7.61 (2H, d, J = 7.8 Hz), 7.34-7.13 (5H, m), 7.01 (1H, t , J = 6.9 Hz), 6.93 (2H, d, J = 7.5 Hz), 6.85 (1H, d, J = 8.1 Hz), 6.78 (1H, t, J = 7.5 Hz), 6.72 (1H, d, J = 8.1 Hz), 3.02 (3H, s);

13CNMR(75MHz, DMSO-d6) δ 173.8, 163.5, 146.0, 143.1, 137.9, 133.6, 130.9, 128.6, 127.6, 127.4, 126.6, 126.1, 122.7, 117.8, 116.2, 114.5, 114.1, 108.9, 76.1, 25.9; 13 CNMR (75 MHz, DMSO-d 6 ) δ 173.8, 163.5, 146.0, 143.1, 137.9, 133.6, 130.9, 128.6, 127.6, 127.4, 126.6, 126.1, 122.7, 117.8, 116.2, 114.5, 114.1, 108.9, 76.1, 25.9 ;

IR (KBr) 3265, 1728, 1636, 1616, 1491, 1362, 1274, 1172, 1128, 1093, 942, 884, 751 cm-1;IR (KBr) 3265, 1728, 1636, 1616, 1491, 1362, 1274, 1172, 1128, 1093, 942, 884, 751 cm −1 ;

HRMS m/z(M+) calcd for C22H17N3O2:355.1321. Found: 355.1318. HRMS m / z (M + ) calcd for C 22 H 17 N 3 O 2 : 355.1321. Found: 355.1318.

<< 실시예Example 26> 화합물 6p의 합성 26> Synthesis of Compound 6p

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00167
(1.0 mmol), 및
Figure pat00168
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 8시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 92%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00167
(1.0 mmol), and
Figure pat00168
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 8 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and then recrystallized from ethanol to obtain pure product (yield: 92%).

mp 232-234 ℃;mp 232-234 ° C;

1H NMR (300MHz, DMSO-d6) δ 7.71 (1H, d, J=8.1Hz), 7.60(1H,d,J=7.5Hz), 7.58(1H,s), 7.36-7.25(2H,m), 7.09-6.94(3H,m), 6.87(1H,d,J=7.5Hz), 6.81-6.71(4H,m), 3.03(3H,s), 2.15(3H,s); 1 H NMR (300MHz, DMSO-d 6 ) δ 7.71 (1H, d, J = 8.1 Hz), 7.60 (1H, d, J = 7.5 Hz), 7.58 (1H, s), 7.36-7.25 (2H, m ), 7.09-6.94 (3H, m), 6.87 (1H, d, J = 7.5 Hz), 6.81-6.71 (4H, m), 3.03 (3H, s), 2.15 (3H, s);

13CNMR(75MHz, DMSO-d6) δ 173.7, 163.4, 146.0, 143.1, 137.8, 133.5, 130.8, 129.5, 128.2, 128.1, 127.3, 126.6, 126.0, 122.6, 117.7, 114.5, 114.0, 108.8, 76.07, 25.8, 20.5; 13 CNMR (75 MHz, DMSO-d 6 ) δ 173.7, 163.4, 146.0, 143.1, 137.8, 133.5, 130.8, 129.5, 128.2, 128.1, 127.3, 126.6, 126.0, 122.6, 117.7, 114.5, 114.0, 108.8, 76.07, 25.8 , 20.5;

IR (KBr) 3283, 3059, 2935, 1727, 1643, 1612, 1487, 1356, 1244, 1167, 1125, 1090, 1038, 965, 872, 751 cm-1;IR (KBr) 3283, 3059, 2935, 1727, 1643, 1612, 1487, 1356, 1244, 1167, 1125, 1090, 1038, 965, 872, 751 cm −1 ;

HRMS m/z(M+) calcd for C23H19N3O2:369.1477. Found: 369.1475. HRMS m / z (M + ) calcd for C 23 H 19 N 3 O 2 : 369.1477. Found: 369.1475.

<< 실시예Example 27> 화합물 6q의 합성 27> Synthesis of Compound 6q

10 mL의 물에 이사토익 무수화물(isatoic anhydride) (1) (1.0 mmol),

Figure pat00169
(1.0 mmol), 및
Figure pat00170
(1.0 mmol) 이 들어있는 용액에 EDDA (36 mg, 0.2 mmol)를 넣었다. 그리고 반응 혼합물은 질소 환경하에서 8시간동안 환류되었다. 반응이 완결된 후에, 반응 혼합물은 상온에서 냉각하고 여과한 후, 에탄올에서 재결정한 후 순수 생산물을 얻을 수 있었다(수득율: 88%). Isatoic anhydride ( 1 ) (1.0 mmol) in 10 mL of water,
Figure pat00169
(1.0 mmol), and
Figure pat00170
EDDA (36 mg, 0.2 mmol) was added to a solution containing (1.0 mmol). The reaction mixture was then refluxed for 8 hours under a nitrogen environment. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and then recrystallized from ethanol to obtain pure product (yield: 88%).

mp 220-222 ℃; mp 220-222 ° C;

1H NMR (300MHz, DMSO-d6) δ 7.68 (1H, d, J = 7.8 Hz), 7.64-7.60(2H, m), 7.34-7.25(2H, m), 7.05-6.95(5H, m), 6.86(1H,d, J = 7.8 Hz), 6.77(1H, t, J = 7.8 Hz), 6.69(1H, d, J= 7.5 Hz), 3.01 (3H, s); 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.68 (1H, d, J = 7.8 Hz), 7.64-7.60 (2H, m), 7.34-7.25 (2H, m), 7.05-6.95 (5H, m) , 6.86 (1H, d, J = 7.8 Hz), 6.77 (1H, t, J = 7.8 Hz), 6.69 (1H, d, J = 7.5 Hz), 3.01 (3H, s);

13C NMR (75 MHz, DMSO-d6) δ 174.1, 164.1, 146.5, 143.5, 134.6, 134.5, 134.2, 131.5, 127.9, 126.9, 126.6, 123.3, 118.3, 116.1, 115.8, 114.8, 114.6, 109.5, 76.7, 26.4; 13 C NMR (75 MHz, DMSO-d 6 ) δ 174.1, 164.1, 146.5, 143.5, 134.6, 134.5, 134.2, 131.5, 127.9, 126.9, 126.6, 123.3, 118.3, 116.1, 115.8, 114.8, 114.6, 109.5, 76.7 , 26.4;

IR (KBr) 3274, 3061, 2943, 1727, 1640, 1613, 1510, 1354, 1219, 1155, 1130, 1093, 1033, 961, 799, 752 cm-1 IR (KBr) 3274, 3061, 2943, 1727, 1640, 1613, 1510, 1354, 1219, 1155, 1130, 1093, 1033, 961, 799, 752 cm -1

HRMS m/z (M+) calcd for C22H16FN3O2: 373.1227. Found: 373.1227.
HRMS m / z (M + ) calcd for C 22 H 16 FN 3 O 2 : 373.1227. Found: 373.1227.

Claims (6)

이사토익 무수화물(isatoic anhydride), 아민류(amines) 및 벤즈알데히드류(benzaldehydes)를 물 중에서 에틸렌다이아민다이아세테이트(EDDA) 존재 하에 반응시켜 화학식 1로 표시되는 2,3-디하이드로퀴나졸리논 유도체(2,3-dihydroquinazolinone derivatives)를 합성하는 것을 특징으로 하는 2,3-디하이드로퀴나졸리논 유도체(2,3-dihydroquinazolinone derivatives)의 합성방법:
[화학식 1]
Figure pat00171

상기 화학식 1에서, R1은
Figure pat00172
또는
Figure pat00173
중 어느 하나이고, X는 C1 내지 C4의 알콕시 또는 할로겐 중 어느 하나이며,
R2는 아릴아민으로서,
Figure pat00174
이며, Y1은 수소, CH3CHCH3, C1 내지 C4의 알콕시 또는 할로겐 중 어느 하나이고, Y2은 수소 또는 C1 내지 C4의 알킬 중 어느 하나이며, n은 0 내지 4의 정수임.2,3-dihydroquinazolinone derivatives represented by the general formula (1) by reacting isatoic anhydride, amines and benzaldehydes in the presence of ethylenediaminediacetate (EDDA) in water (2 Synthesis method of 2,3-dihydroquinazolinone derivatives characterized in that the synthesis of, 3-dihydroquinazolinone derivatives):
[Formula 1]
Figure pat00171

In Formula 1, R 1
Figure pat00172
or
Figure pat00173
X is any one of C1 to C4 alkoxy or halogen,
R 2 is arylamine,
Figure pat00174
And Y 1 is hydrogen, CH 3 CHCH 3 , C 1 to C 4 alkoxy or halogen, Y 2 is hydrogen or C 1 to C 4 alkyl, and n is an integer from 0 to 4. 제1항에 있어서, 상기 아민류는
Figure pat00175
,
Figure pat00176
,
Figure pat00177
,
Figure pat00178
,
Figure pat00179
,
Figure pat00180
및
Figure pat00181
으로 이루어진 군에서 선택한 것을 특징으로 하는 2,3-디하이드로퀴나졸리논 유도체(2,3-dihydroquinazolinone derivatives)의 합성방법. The method of claim 1, wherein the amines
Figure pat00175
,
Figure pat00176
,
Figure pat00177
,
Figure pat00178
,
Figure pat00179
,
Figure pat00180
And
Figure pat00181
Synthesis method of 2,3-dihydroquinazolinone derivatives (2,3-dihydroquinazolinone derivatives) characterized in that selected from the group consisting of. 제1항에 있어서, 상기 벤즈알데히드류는
Figure pat00182
,
Figure pat00183
,
Figure pat00184
및
Figure pat00185
으로 이루어진 군에서 선택한 것을 특징으로 하는 2,3-디하이드로퀴나졸리논 유도체(2,3-dihydroquinazolinone derivatives)의 합성방법. The method of claim 1, wherein the benzaldehyde
Figure pat00182
,
Figure pat00183
,
Figure pat00184
And
Figure pat00185
Synthesis method of 2,3-dihydroquinazolinone derivatives (2,3-dihydroquinazolinone derivatives) characterized in that selected from the group consisting of. 이사토익 무수화물(isatoic anhydride), 아민류(amines) 및 이사틴류(isatins)를 물 중에서 에틸렌다이아민다이아세테이트(EDDA) 존재 하에 반응시켜 화학식 2로 표시되는 디하이드로퀴나졸리논 고리를 포함하는 스피로옥스인돌 유도체를 합성하는 것을 특징으로 하는 디하이드로퀴나졸리논 고리를 포함하는 스피로옥스인돌 유도체의 합성방법:
[화학식 2]
Figure pat00186

상기 화학식 2에서, R1는
Figure pat00187
이며, Y1은 수소, CH3CHCH3, C1 내지 C4의 알콕시 또는 할로겐 중 어느 하나이고, Y2은 수소 또는 C1 내지 C4의 알킬 중 어느 하나이며, n은 0 내지 4의 정수이거나; C1 내지 C7의 알킬이거나;
Figure pat00188
; 또는 수소 중 어느 하나임.
Spirooxindole containing a dihydroquinazolinone ring represented by the formula (2) by reacting isatoic anhydride, amines and isatins in the presence of ethylenediaminediacetate (EDDA) in water A method for synthesizing a spiroxoxindole derivative comprising a dihydroquinazolinone ring, characterized in that the derivative is synthesized:
(2)
Figure pat00186

In Formula 2, R 1
Figure pat00187
Y 1 is hydrogen, CH 3 CHCH 3 , C1 to C4 alkoxy or halogen, Y 2 is hydrogen or C1 to C4 alkyl, n is an integer from 0 to 4; C1 to C7 alkyl;
Figure pat00188
; Or hydrogen.
제4항에 있어서, 상기 아민류는
Figure pat00189
,
Figure pat00190
,
Figure pat00191
,
Figure pat00192
,
Figure pat00193
,
Figure pat00194
,
Figure pat00195
,
Figure pat00196
,
Figure pat00197
,
Figure pat00198
,
Figure pat00199
, 및
Figure pat00200
으로 이루어진 군에서 하나 이상을 선택한 것을 특징으로 하는 디하이드로퀴나졸리논 고리를 포함하는 스피로옥스인돌 유도체의 합성방법.The method of claim 4, wherein the amines
Figure pat00189
,
Figure pat00190
,
Figure pat00191
,
Figure pat00192
,
Figure pat00193
,
Figure pat00194
,
Figure pat00195
,
Figure pat00196
,
Figure pat00197
,
Figure pat00198
,
Figure pat00199
, And
Figure pat00200
Synthesis method of the spiroxoxindole derivative comprising a dihydroquinazolinone ring, characterized in that at least one selected from the group consisting of. 제4항에 있어서, 상기 이사틴류는
Figure pat00201
,
Figure pat00202
, 및
Figure pat00203
으로 이루어진 군중에서 하나 이상을 선택한 것을 특징으로 하는 디하이드로퀴나졸리논 고리를 포함하는 스피로옥스인돌 유도체의 합성방법.


The method of claim 4, wherein the isatin is
Figure pat00201
,
Figure pat00202
, And
Figure pat00203
Method for synthesizing a spiroxoxindole derivative comprising a dihydroquinazolinone ring, characterized in that at least one selected from the group consisting of.


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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104356076A (en) * 2014-10-12 2015-02-18 渤海大学 Synthesis method for substituted 2, 3-dihydro-4(1H)-quinazolinone compound
US9822128B1 (en) 2017-06-01 2017-11-21 King Saud University Substituted spirooxindoles

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104356076A (en) * 2014-10-12 2015-02-18 渤海大学 Synthesis method for substituted 2, 3-dihydro-4(1H)-quinazolinone compound
US9822128B1 (en) 2017-06-01 2017-11-21 King Saud University Substituted spirooxindoles

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