KR100434814B1 - Fungicidal composition for agriculture and horticulture having a 3-alkoxyindole-2-carboxylate derivative - Google Patents
Fungicidal composition for agriculture and horticulture having a 3-alkoxyindole-2-carboxylate derivative Download PDFInfo
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- KR100434814B1 KR100434814B1 KR10-2002-0021507A KR20020021507A KR100434814B1 KR 100434814 B1 KR100434814 B1 KR 100434814B1 KR 20020021507 A KR20020021507 A KR 20020021507A KR 100434814 B1 KR100434814 B1 KR 100434814B1
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
- A01N43/38—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings condensed with carbocyclic rings
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
Abstract
본 발명은 유효성분으로서의 하기 화학식 1의 3-알콕시인돌-2-카복실레이트 유도체 및 약제학적으로 허용되는 담체를 포함하는, 농원예용 살균제 조성물에 관한 것으로, 본 발명의 조성물은 내성균을 비롯한 광범위한 식물 병원균에 대해 선택적으로 높은 살균효과를 나타낸다.The present invention relates to agrohorticultural fungicide composition comprising a 3-alkoxyindole-2-carboxylate derivative of formula 1 as an active ingredient and a pharmaceutically acceptable carrier, the composition of the present invention is a wide range of plant pathogens, including resistant bacteria It selectively shows high bactericidal effect.
상기 식에서,Where
A, B, C 및 D는 단일 또는 이중 결합을 표시하며, A가 단일 결합인 경우, B는 이중 결합, C는 단일 결합, DR3는 없는 결합이고; A가 이중 결합인 경우에는, B와 D는 단일 결합이고, CR3는 없는 결합이고;A, B, C and D represent a single or double bond, and when A is a single bond, B is a double bond, C is a single bond and DR 3 is a bond; When A is a double bond, B and D are single bonds and CR 3 is a missing bond;
R1은 수소; 할로겐 또는 티오알콕시기로 치환되거나 치환되지 않은 C1-C6의직쇄 또는 측쇄 알킬기; 할로겐으로 치환되거나 치환되지 않은 C2-C6의 직쇄 또는 측쇄 알케닐기; 트리알킬실리콘으로 치환되거나 치환되지 않은 C2-C6의 알키닐기; 할로겐으로 치환되거나 치환되지 않은 벤질기; 사이클로부틸기; 및 C1-C3의알콕시카보닐알킬기 중에서 선택된 기이고;R 1 is hydrogen; C 1 -C 6 straight or branched chain alkyl groups, optionally substituted with halogen or thioalkoxy groups; C 2 -C 6 straight or branched alkenyl group optionally substituted with halogen; An alkynyl group of C 2 -C 6 substituted or unsubstituted with trialkylsilicon; Benzyl groups substituted or unsubstituted with halogen; Cyclobutyl group; And a C 1 -C 3 alkoxycarbonylalkyl group;
R2는 C1-C3알킬기이고;R 2 is a C 1 -C 3 alkyl group;
R3는 할로겐, 니트릴, 니트로, 알콕시 또는 티오알콕시기로 치환되거나 치환되지 않은 C1-C10의 직쇄 또는 측쇄 알킬기; 할로겐으로 치환되거나 치환되지 않은 C2-C6의 알케닐기; 트리알킬실리콘으로 치환되거나 치환되지 않은 C2-C6의 알키닐기; 할로겐으로 치환되거나 치환되지 않은 벤질기; 사이클로프로필, 사이클로부틸 또는 옥시라닐메틸기; 아세테이트기; C1-C3의알콕시카보닐알킬기; 및 페나실기 중에서 선택된 기이고;R 3 is a C 1 -C 10 straight or branched alkyl group substituted or unsubstituted with a halogen, nitrile, nitro, alkoxy or thioalkoxy group; An alkenyl group of C 2 -C 6 which is optionally substituted with halogen; An alkynyl group of C 2 -C 6 substituted or unsubstituted with trialkylsilicon; Benzyl groups substituted or unsubstituted with halogen; A cyclopropyl, cyclobutyl or oxiranylmethyl group; Acetate groups; C 1 -C 3 alkoxycarbonylalkyl group; And a phenacyl group;
X는 수소; 할로겐; C1-C5의 직쇄 또는 측쇄 알킬기; C1-C4의 직쇄 또는 측쇄 알콕시기; C1-C3의 알콕시카보닐기; 및 벤질기 중에서 1 내지 3종 선택된 기이다.X is hydrogen; halogen; C 1 -C 5 straight or branched alkyl group; C 1 -C 4 straight or branched alkoxy group; C 1 -C 3 alkoxycarbonyl group; And benzyl groups selected from one to three.
Description
본 발명은 내성균을 비롯한 식물 병원균에 우수한 살균효과를 갖는, 3-알콕시인돌-2-카복실레이트 유도체를 포함하는 농원예용 살균제 조성물에 관한 것이다.The present invention relates to a horticultural germicide composition comprising a 3-alkoxyindole-2-carboxylate derivative having an excellent bactericidal effect on plant pathogens, including resistant bacteria.
최근의 세계적인 농약 개발현황을 살펴보면, 인체 또는 생물에의 유독성 및 환경에의 오염을 우려하여 저약량, 고선택성, 저독성 및 저공해성 농약의 개발이 주류를 이루고 있으며, 세계의 살균제 시장에서 무기 및 유기금속, 및 유기 인계 화합물 등은 정체 및 감소를 보이고 있는 반면, 아졸류 및 벤제노이드류와 같은 침투 이행성 살균제는 성장을 계속하고 있다. 그러나, 이들 살균제를 다량 사용함에 따라 이들에 대해 내성을 갖는 내성균도 빠른 속도로 발현되고 있기 때문에, 내성균의 발현을 줄이기 위해서는 새로운 작용기작을 갖는 살균제의 개발이 절실하게 되었다.Looking at the recent development of pesticides in the world, the development of low dose, high selectivity, low toxicity and low pollution pesticides is mainstream due to concerns about toxicity to the human body or organism and pollution to the environment. Metals, organophosphorus compounds and the like show stagnation and reduction, while penetration-transmitting fungicides such as azoles and benzenoids continue to grow. However, with the use of a large amount of these fungicides, resistant bacteria resistant to them are also rapidly expressed. Therefore, in order to reduce the expression of resistant bacteria, development of a fungicide having a new mechanism of action is urgently needed.
미국 특허 제 5,866,594 호에는 살균 활성을 갖는 하기 일반식의 인돌 화합물이 기술되어 있다:U.S. Patent 5,866,594 describes indole compounds of the general formula having bactericidal activity:
R1은 수소 원자, 하이드록실, C1-4아실, C4-8아실옥시, C1-4알콕시, (C1-4알콕시카보닐)옥시, 페녹시카보닐 또는 C1-4알콕시카보닐이고;R 1 is a hydrogen atom, hydroxyl, C 1-4 acyl, C 4-8 acyloxy, C 1-4 alkoxy, (C 1-4 alkoxycarbonyl) oxy, phenoxycarbonyl or C 1-4 alkoxycarbon Nil;
R2는 C1-4알킬이고;R 2 is C 1-4 alkyl;
R3는 수소 원자, C1-4알킬, C2-4알케닐, 페닐, 시아노, 카바모일, 포르밀, C1-4아실, 카복실, C1-4알콕시카보닐, 하이드록시이미노메틸, (C1-4알콕시이미노)메틸, (C2-4알키닐옥시이미노)메틸, (C1-4아실옥시이미노)메틸, (n-페닐이미노)메틸, (N-C1-4알킬이미노)메틸, (N-벤질이미노)메틸, 아미노메틸, ((C1-4알킬티오)티오카보닐)아미노메틸, (C1-4알킬티오)티오카보닐, 니트로, 아미노, C1-4아실아미노, 3-(C1-4알킬)우레이도, (C1-4알콕시카보닐)아미노, 하이드록시메틸, (C1-4아실옥시)메틸, 할로겐 원자, 2-(C1-4알콕시카보닐)비닐, 2-(C1-4알콕시카보닐)에틸, 벤즈티아졸-2-일, C1-4알킬설페닐, 알킬설피닐, C1-4알킬설포닐, 페닐설페닐, 페닐설피닐 또는 페닐설포닐이고;R 3 is a hydrogen atom, C 1-4 alkyl, C 2-4 alkenyl, phenyl, cyano, carbamoyl, formyl, C 1-4 acyl, carboxyl, C 1-4 alkoxycarbonyl, hydroxyiminomethyl , (C 1-4 alkoxyimino) methyl, (C 2-4 alkynyloxyimino) methyl, (C 1-4 acyloxyimino) methyl, (n-phenylimino) methyl, (NC 1-4 alkyl) Mino) methyl, (N-benzylimino) methyl, aminomethyl, ((C 1-4 alkylthio) thiocarbonyl) aminomethyl, (C 1-4 alkylthio) thiocarbonyl, nitro, amino, C 1 -4 acylamino, 3- (C 1-4 alkyl) ureido, (C 1-4 alkoxycarbonyl) amino, hydroxymethyl, (C 1-4 acyloxy) methyl, halogen atom, 2- (C 1 -4 alkoxycarbonyl) vinyl, 2- (C 1-4 alkoxycarbonyl) ethyl, benzthiazol-2-yl, C 1-4 alkylsulphenyl, alkylsulfinyl, C 1-4 alkylsulfonyl, phenyl Sulfenyl, phenylsulfinyl or phenylsulfonyl;
R4및 R5는 각각 독립적으로 할로겐 원자, C1-4알킬, C1-4알콕시, C1-4할로알킬, C1-4할로알콕시, 벤질, 페닐, 시아노, 니트로, C1-4알킬설페닐 또는 C1-4알킬설포닐을 나타내나,R 4 and R 5 are each independently a halogen atom, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, benzyl, phenyl, cyano, nitro, C 1- 4 alkylsulphenyl or C 1-4 alkylsulfonyl
단, R1및 R3가 수소 원자이고, R4가 메톡시인 경우, R5는 브롬 원자가 아니다.Provided that when R 1 and R 3 are hydrogen atoms and R 4 is methoxy, then R 5 is not a bromine atom.
이에, 본 발명자들은 살균효과를 갖는 화합물에 대한 연구를 계속한 결과, 오염방지성, 항알러지성, 항염증성 및 항우울성 등의 활성을 갖는 것으로 알려진 3-알콕시인돌-2-카복실레이트 유도체가 내성균을 비롯한 광범위한 식물 병원균에 대해 선택적으로 높은 살균효과를 나타냄을 발견하고 본 발명을 완성하게 되었다.Accordingly, the present inventors have continued to study compounds having a bactericidal effect, and as a result, 3-alkoxyindole-2-carboxylate derivatives known to have activities such as anti-fouling, anti-allergic, anti-inflammatory and anti-depressive properties are The present invention has been found to exhibit a selective high bactericidal effect against a wide range of plant pathogens, including resistant bacteria.
따라서, 본 발명의 목적은 내성균을 비롯한 식물 병원균에 대해 광범위하면서도 선택적으로 높은 살균효과를 갖는 화합물을 포함하는, 농원예용 살균제 조성물을 제공하는 것이다.Accordingly, it is an object of the present invention to provide agrohorticultural fungicide composition comprising a compound having a broad and optionally high bactericidal effect against plant pathogens including resistant bacteria.
상기 목적을 달성하기 위하여 본 발명에서는, 하기 화학식 1의 3-알콕시인돌-2-카복실레이트 유도체 및 약제학적으로 허용되는 담체를 포함하는, 농원예용 살균제 조성물을 제공한다:In order to achieve the above object, the present invention provides a horticultural fungicide composition comprising a 3-alkoxyindole-2-carboxylate derivative of the formula 1 and a pharmaceutically acceptable carrier:
화학식 1Formula 1
상기 식에서,Where
A, B, C 및 D는 단일 또는 이중 결합을 표시하며, A가 단일 결합인 경우, B는 이중 결합, C는 단일 결합, DR3는 없는 결합이고; A가 이중 결합인 경우에는, B와 D는 단일 결합이고, CR3는 없는 결합이고;A, B, C and D represent a single or double bond, and when A is a single bond, B is a double bond, C is a single bond and DR 3 is a bond; When A is a double bond, B and D are single bonds and CR 3 is a missing bond;
R1은 수소; 할로겐 또는 티오알콕시기로 치환되거나 치환되지 않은 C1-C6의직쇄 또는 측쇄 알킬기; 할로겐으로 치환되거나 치환되지 않은 C2-C6의 직쇄 또는 측쇄 알케닐기; 트리알킬실리콘으로 치환되거나 치환되지 않은 C2-C6의 알키닐기; 할로겐으로 치환되거나 치환되지 않은 벤질기; 사이클로부틸기; 및 C1-C3의알콕시카보닐알킬기 중에서 선택된 기이고;R 1 is hydrogen; C 1 -C 6 straight or branched chain alkyl groups, optionally substituted with halogen or thioalkoxy groups; C 2 -C 6 straight or branched alkenyl group optionally substituted with halogen; An alkynyl group of C 2 -C 6 substituted or unsubstituted with trialkylsilicon; Benzyl groups substituted or unsubstituted with halogen; Cyclobutyl group; And a C 1 -C 3 alkoxycarbonylalkyl group;
R2는 C1-C3알킬기이고;R 2 is a C 1 -C 3 alkyl group;
R3는 할로겐, 니트릴, 니트로, 알콕시 또는 티오알콕시기로 치환되거나 치환되지 않은 C1-C10의 직쇄 또는 측쇄 알킬기; 할로겐으로 치환되거나 치환되지 않은 C2-C6의알케닐기; 트리알킬실리콘으로 치환되거나 치환되지 않은 C2-C6의 알키닐기; 할로겐으로 치환되거나 치환되지 않은 벤질기; 사이클로프로필, 사이클로부틸 또는 옥시라닐메틸기; 아세테이트기; C1-C3의알콕시카보닐알킬기; 및 페나실기 중에서 선택된 기이고;R 3 is a C 1 -C 10 straight or branched alkyl group substituted or unsubstituted with a halogen, nitrile, nitro, alkoxy or thioalkoxy group; C 2 -C 6 alkenyl groups optionally substituted with halogen; An alkynyl group of C 2 -C 6 substituted or unsubstituted with trialkylsilicon; Benzyl groups substituted or unsubstituted with halogen; A cyclopropyl, cyclobutyl or oxiranylmethyl group; Acetate groups; C 1 -C 3 alkoxycarbonylalkyl group; And a phenacyl group;
X는 수소; 할로겐; C1-C5의 직쇄 또는 측쇄 알킬기; C1-C4의 직쇄 또는 측쇄 알콕시기; C1-C3의 알콕시카보닐기; 및 벤질기 중에서 1 내지 3종 선택된 기이다.X is hydrogen; halogen; C 1 -C 5 straight or branched alkyl group; C 1 -C 4 straight or branched alkoxy group; C 1 -C 3 alkoxycarbonyl group; And benzyl groups selected from one to three.
이하 본 발명에 대하여 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
상기 화학식 1의 구조에서, A, B, C 및 D의 정의와 관련하여, 본 발명의 화합물을 다시 나타내면 다음 화학식 1a 및 1b와 같다:In the structure of Formula 1, in connection with the definition of A, B, C and D, the compound of the present invention is represented as follows:
상기 식에서, R1, R2, R3및 X는 상기 정의한 바와 같다.Wherein R 1 , R 2 , R 3 and X are as defined above.
본 발명에 따른 상기 화학식 1의 인돌 유도체에 있어서, 바람직하게는, R1은 수소이고; R2는 메틸이며; R3는 C1-C4의 알킬, C2-C4의 알케닐 또는 C2-C4의 알키닐이고; X는 메틸, 클로로 또는 플루오로가 1 또는 2종 선택된 기이다.In the indole derivative of Chemical Formula 1 according to the present invention, preferably, R 1 is hydrogen; R 2 is methyl; R 3 is C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl of; X is a group wherein methyl, chloro or fluoro is selected from one or two.
본 발명에 따른 상기 화학식 1의 3-알콕시인돌-2-카복실레이트 유도체는, 하기 반응식 1에서 알 수 있듯이, 화학식 2의 3-히드록시인돌-2-카복실레이트 유도체와 화학식 3의 알킬 할라이드 또는 알킬설포네이트와의 반응에 의해 제조할 수 있으며, 이러한 제조방법은 문헌[Chem. Ber., 104, 1863-1868(1971)] 및 [J. Heterocyclic. Chem., 24, 811-815(1987)]에 기재되어 있다:The 3-alkoxyindole-2-carboxylate derivative of Formula 1 according to the present invention, as can be seen in Scheme 1, the 3-hydroxyindole-2-carboxylate derivative of Formula 2 and the alkyl halide or alkyl of Formula 3 It can be prepared by the reaction with sulfonate, such preparation method is described in Chem. Ber., 104 , 1863-1868 (1971) and J. Heterocyclic. Chem., 24 , 811-815 (1987) .
상기 식에서,Where
R1, R2, R3및 X는 상기 정의한 바와 같고,R 1 , R 2 , R 3 and X are as defined above,
Y는 할라이드(Cl, Br, I 등) 또는 설포네이트(즉, R3-Y는 C1-3의 알킬설포네이트, 벤젠 또는 4-톨루엔 설포네이트 등)를 나타낸다.Y represents halide (Cl, Br, I, etc.) or sulfonate (ie, R 3 -Y is C 1-3 alkylsulfonate, benzene or 4-toluene sulfonate, etc.).
상기 반응에 있어서, 화학식 3의 화합물은 화학식 2의 화합물을 기준으로 1내지 1.2 당량 사용하며, 산 제거제로서 트리에틸아민과 같은 트리알킬아민류, 또는 탄산수소나트륨, 탄산칼륨 및 수산화나트륨과 같은 무기 염류를 화학식 2의 화합물을 기준으로 1 내지 4 당량 가하여 반응시킬 수 있다.In the above reaction, the compound of Formula 3 is used in an amount of 1 to 1.2 equivalents based on the compound of Formula 2, and is used as an acid scavenger, such as trialkylamines such as triethylamine, or inorganic salts such as sodium bicarbonate, potassium carbonate and sodium hydroxide. To 1 to 4 equivalents based on the compound of formula (2) can be reacted.
또한, 상기 반응에 사용되는 용매는 디에틸에테르, 디이소프로필에테르, 테트라히드로푸란, 디옥산, 디페닐에테르 등의 에테르; 디클로로에탄, 클로로포름, 사염화탄소 등의 할로겐화 탄화수소; 디메틸포름아미드, 디메틸아세트아미드 등의 이미드; 및 디메틸설폭시드, 디에틸설폭시드 등의 알킬설폭시드; 및 이들의 혼합물 중에서 선택할 수 있다.In addition, the solvent used for the said reaction is ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, diphenyl ether; Halogenated hydrocarbons such as dichloroethane, chloroform and carbon tetrachloride; Imides such as dimethylformamide and dimethylacetamide; Alkyl sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; And mixtures thereof.
또한, 반응 온도는 -30 내지 50℃이며, 반응 시간은 반응 온도에 따라 달라지나 통상적으로 1 내지 24시간이 바람직하다.In addition, the reaction temperature is -30 to 50 ℃, the reaction time depends on the reaction temperature, but usually 1 to 24 hours is preferred.
반응 종료후 바로 용매를 증류하거나, 또는 반응혼합물에 물을 가하고 디클로로에탄, 디클로로메탄, 클로로포름 및 에틸아세테이트 등과 같은 물에 녹지 않는 유기용매로 추출한 다음 용매를 증류하면, 상기 화학식 1의 화합물의 조생성물이 수득된다. 이 조생성물을 메탄올 및 에탄올과 같은 알콜; 에틸아세테이트 및 메틸아세테이트와 같은 유기산의 에스테르; 펜탄 및 헥산과 같은 탄화수소; 에틸에테르 및 테트라히드로푸란과 같은 에테르; 및 이들의 혼합물 중에서 선택된 용매로부터 재결정하거나, 또는 칼럼 크로마토그래피함으로써, 목적하는 화학식 1의 3-알콕시인돌-2-카복실레이트 유도체를 용이하게 분리정제할 수 있다.Immediately after completion of the reaction, the solvent is distilled off, or water is added to the reaction mixture, extracted with an organic solvent insoluble in water such as dichloroethane, dichloromethane, chloroform and ethyl acetate, and then the solvent is distilled. The crude product of the compound of Chemical Formula 1 Is obtained. This crude product is an alcohol such as methanol and ethanol; Esters of organic acids such as ethyl acetate and methyl acetate; Hydrocarbons such as pentane and hexane; Ethers such as ethyl ether and tetrahydrofuran; And by recrystallization from a solvent selected from a mixture of these, or by column chromatography, the desired 3-alkoxyindole-2-carboxylate derivative of formula (1) can be easily separated and purified.
한편, 본 발명에 따르면, 상기 화학식 2의 3-히드록시인돌-2-카복실레이트 유도체는 하기 반응식 2에 나타낸 바와 같은 방법에 의해 제조할 수있다(문헌[Helvetica Chimica Acta, 36, 708(1953)] 참조):Meanwhile, according to the present invention, the 3-hydroxyindole-2-carboxylate derivative of Chemical Formula 2 may be prepared by a method as shown in Scheme 2 below ( Helvetica Chimica Acta, 36 , 708 (1953) ] Reference):
상기 식에서,Where
X, R1및 R2는 상기 정의한 바와 같고,X, R 1 and R 2 are as defined above,
Z는 Cl, Br 또는 I와 같은 할로겐을 나타낸다.Z represents a halogen such as Cl, Br or I.
특히, 화학식 2의 화합물 중 R1이 수소인 화학식 2a의 화합물은 하기 반응식 3 또는 4에 나타낸 바와 같은 방법에 의해 제조할 수 있다:In particular, compounds of formula 2a in which R 1 is hydrogen in compounds of formula 2 may be prepared by methods as shown in Schemes 3 or 4:
상기 식에서,Where
X 및 R2는 상기 정의한 바와 같고,X and R 2 are as defined above,
R4는 C1-3의 알킬기이다.R 4 is an alkyl group of C 1-3 .
상기 반응식 3에서, 화합물 7로부터 화합물 10의 제조는 문헌[J. Chem. Soc., 629(1944)]에, 화합물 10으로부터 화합물 2a의 제조는 문헌[Tetrahedron Letters, 41, 8217(2000)]에 기재되어 있으며; 상기 반응식 4에서, 화합물 13 또는 14로부터 화합물 16을 거쳐 화합물 2a를 합성하는 방법은 유럽특허 제 572863 호에 기재되어 있다.In Scheme 3, the preparation of compound 10 from compound 7 is described in J. Chem. Soc. , 629 (1944), the preparation of compound 2a from compound 10 is described in Tetrahedron Letters, 41 , 8217 (2000); In Scheme 4, a method for synthesizing compound 2a from compound 13 or 14 via compound 16 is described in EP 572863.
상기와 같은 방법에 의해 제조된, 본 발명에 따른 화학식 1의 3-알콕시인돌-2-카복실레이트 유도체는 식물 병원균에 대해 높은 항균 특성을 나타낸다. 이러한 균의 예로는 벼의 도열병균(Piricularia oryzae), 벼의 잎집무늬마름병균(Rhizoctonia solani), 토마토 회색곰팡이병균(Botrytis cinerea), 오이의 흰가루병균(Sphaerotheca fuliginea), 오이의 노균병균(Pseudoperonospora cubensis), 포도의 노균병균(Plasmopora viticola),토마토의 역병균(Phytophthora infestans), 깨씨무늬병균(Cochliobolus miyabeanus), 땅콩의 갈색무늬병균(Cercopora arachidicola), 보리의 흰가루병균(Erysiphe graminis), 밀의 붉은 녹병균 (Puccinia recondita) 및 밀의 줄기 녹병균(Puccinis graminis) 등이 있으며, 특히 토마토 회색곰팡이병균(Botrytis cinerea)에 대해 탁월한 살균효과를 보여준다.The 3-alkoxyindole-2-carboxylate derivative of formula 1 according to the present invention, prepared by the above method, exhibits high antibacterial properties against plant pathogens. Examples of these bacteria include Piricularia oryzae of rice, Rhizoctonia solani of rice, Botrytis cinerea of tomato, Sphaerotheca fuliginea of cucumber, Pseudoperonospora cuben of cucumber ), downy mildew of grape fungus (Plasmopora viticola), Station pathogens of tomato (Phytophthora infestans), kkaessi pattern germs (Cochliobolus miyabeanus), brown pattern germs of peanut (Cercopora arachidicola), powdery mildew fungus of barley (Erysiphe graminis), wheat red rust ( Puccinia recondita ) and wheat stem rust fungi ( Puccinis graminis ), and particularly excellent against the bacterium Botrytis cinerea .
본 발명에 따르면, 본 발명의 화학식 1의 화합물은 활성성분으로서 조성물의 중량을 기준으로 0.01 내지 90 중량% 사용되어, 고체 또는 액체 담체, 표면활성제, 희석제, 전착제, 상승제, 접착제 및 분산제 등과 같은 적당한 보조제와 함께 혼합하여 농원예용 살균제 조성물로 제제화될 수 있다.According to the present invention, the compound of formula 1 of the present invention is used as an active ingredient 0.01 to 90% by weight based on the weight of the composition, such as solid or liquid carriers, surfactants, diluents, electrodeposition agents, synergists, adhesives and dispersants, etc. It can be formulated into agrohorticultural germicide compositions by mixing with a suitable adjuvant.
본 발명에서 조성물 제제화에 사용가능한 고체 담체로는 활석, 점토, 벤토나이트, 피로필라이트, 카올린, 규조토 및 실리카 등을 들 수 있고, 액체 담체로는 물, 메탄올, 에탄올, 아세톤, 디메틸포름아미드, 에테르, 벤젠, 크실렌, 톨루엔 및 나프탈렌 등을 들 수 있으며, 표면활성제로는 비이온성 표면활성제(예: 폴리옥시에틸렌 알킬페닐에테르 및 폴리옥시에틸렌 지방산에스테르) 및 음이온 표면활성제(예: 알킬벤젠설폰산염, 리그닌설폰산염 및 디나프틸메탄설폰산염) 등을 들 수 있다. 또한, 접착제로서 폴리비닐알콜, CMC 및 아라비아 고무 등을 사용할 수 있다.Solid carriers usable in formulating compositions in the present invention include talc, clay, bentonite, pyrophyllite, kaolin, diatomaceous earth, silica and the like, and liquid carriers include water, methanol, ethanol, acetone, dimethylformamide, ether , Benzene, xylene, toluene and naphthalene, and the like, and nonionic surfactants such as polyoxyethylene alkylphenylether and polyoxyethylene fatty acid esters and anionic surfactants such as alkylbenzenesulfonates, Lignin sulfonate, dinaphthyl methanesulfonate), and the like. Moreover, polyvinyl alcohol, CMC, gum arabic, etc. can be used as an adhesive agent.
본 발명에 따르면, 본 발명의 화학식 1의 화합물을 함유하는 살균제 조성물은 분말 또는 수화분말, 과립, 유화농축물, 현탁액, 훈증제, 기체 및 페이스트 등으로 제조될 수 있으며, 토양 뿐만 아니라 농산물, 묘종 및 종자 등을 살균하는데 사용된다. 예를 들면, 화학식 1의 화합물을 적당한 표면활성제와 함께 탄화수소,아세톤 또는 알콜에 균일하게 용해시켜 유화농축물 또는 용액을 제조할 수 있으며, 또는 무기분말 및 적당한 표면활성제와 혼합하고, 미세분말이 되도록 분쇄 및 균질화하여 수화분말을 제조할 수 있다. 이렇게 제조된 조성물은 바람직한 농도로 물로 희석하여 사용하거나, 또는 무기분말과 혼합하고 균질하게 파쇄 및 혼합하여 분진으로 사용할 수 있다.According to the present invention, the disinfectant composition containing the compound of formula 1 of the present invention may be prepared as a powder or a hydrate powder, granules, emulsion concentrates, suspensions, fumigants, gases and pastes, and the like, as well as agricultural products, seedlings and Used to sterilize seeds, etc. For example, the compound of formula 1 may be uniformly dissolved in a hydrocarbon, acetone or alcohol with a suitable surfactant to prepare an emulsion concentrate or solution, or may be mixed with an inorganic powder and a suitable surfactant to form a fine powder. Hydrated powder can be prepared by grinding and homogenizing. The composition thus prepared may be diluted with water to a desired concentration, or mixed with inorganic powder, crushed and mixed homogeneously, and used as dust.
또한, 본 발명에 따르면, 본 발명의 화학식 1의 화합물을 유효량 함유하도록 희석된 살균제 조성물은 살충제, 살균제, 제초제, 식물성장 조절제 및 살진드기제 등과 같은 다른 농화학물질, 및 영양물질 등과 혼합하여 사용될 수 있다.In addition, according to the present invention, the disinfectant composition diluted to contain an effective amount of the compound of formula 1 of the present invention may be used in admixture with other agrochemicals such as insecticides, fungicides, herbicides, plant growth regulators and mites, and nutritional substances. have.
본 발명에 따른 화학식 1의 3-알콕시인돌-2-카복실레이트 유도체의 구체적인 예를 들어보면 하기 표 1과 같다. 이때, 구조식 1a에 속하는 화합물은 A가 단일 결합이이서 B가 이중 결합, C가 단일 결합이고, DR3가 없는 결합인 경우를 나타내고; 구조식 1b에 속하는 화합물은 A가 이중 결합이어서 B와 D가 단일 결합이고, CR3는 없는 결합인 경우를 나타낸다:To give a specific example of the 3-alkoxyindole-2-carboxylate derivative of the formula 1 according to the present invention are shown in Table 1. Wherein the compound belonging to Structural Formula 1a represents a case where A is a single bond, B is a double bond, C is a single bond, and a bond without DR 3 ; Compounds belonging to Formula 1b show the case where A is a double bond, so that B and D are single bonds and CR 3 is absent:
이하, 본 발명을 하기 제조예 및 실시예에 의거하여 좀더 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐 한정하지는 않는다.Hereinafter, the present invention will be described in more detail based on the following Preparation Examples and Examples. However, the following examples are not intended to limit the invention only.
제조예 1-1 : 반응식 2에 따른 화학식 2의 화합물의 제조Preparation Example 1-1 Preparation of a Compound of Formula 2 According to Scheme 2
1) 디메틸 2-(2,5-디메틸아닐리노)말로네이트(화학식 6-1의 화합물)1) Dimethyl 2- (2,5-dimethylanilino) malonate (Compound 6-1)
디메틸아닐린(242g, 0.2몰)을 톨루엔 150ml에 녹인다음, 디메틸 브로모 말로네이트(211g, 0.1몰)를 상온에서 1시간 동안 적하하고 5시간동안 환류 반응시켰다. TLC로부터 반응이 완료됨을 확인한 후, 상온으로 냉각하고 생성된 고체를 여과하여 제거하였다. 여액은 감압 증류하고 남은 잔류물에 에탄올 200ml을 가하여 결정화시켜 원하는 생성물 170.0g을 68%의 수율로 수득하였다.Dimethyl aniline (242 g, 0.2 mol) was dissolved in 150 ml of toluene, and then dimethyl bromo malonate (211 g, 0.1 mol) was added dropwise at room temperature for 1 hour and refluxed for 5 hours. After confirming that the reaction was completed by TLC, the reaction mixture was cooled to room temperature and the resulting solid was removed by filtration. The filtrate was distilled under reduced pressure and crystallized by adding 200 ml of ethanol to the remaining residue to obtain 170.0 g of the desired product in 68% yield.
1H NMR (CDCl3): δ 6.97-6.33(m, 3H), 4.83-4.72(m, 2H), 3.81(m, 6H), 2.26(s, 3H), 2.21(s, 3H) 1 H NMR (CDCl 3 ): δ 6.97-6.33 (m, 3H), 4.83-4.72 (m, 2H), 3.81 (m, 6H), 2.26 (s, 3H), 2.21 (s, 3H)
2) 메틸 3-히드록시-4,7-디메틸-1H-2-인돌카복실레이트(화학식 2-1의 화합물)2) Methyl 3-hydroxy-4,7-dimethyl-1 H -2-indolecarboxylate (compound of formula 2-1)
상기 단계 1)에서 제조된 디메틸 2-(2,5-디메틸아닐리노)말로네이트(270g, 1.1몰)과 디페닐에테르 50ml 용액을 1시간동안 240-250℃까지 가열 교반시켰다. TLC로부터 반응의 종결이 확인되면 실온으로 냉각하고, 에틸아세테이트를 통해 재결정을 하여 원하는 생성물(130g, 수율 55%)을 얻었다.The dimethyl 2- (2,5-dimethylanilino) malonate (270 g, 1.1 mol) prepared in step 1) and a 50 ml solution of diphenyl ether were heated and stirred to 240-250 ° C. for 1 hour. Upon completion of the reaction from TLC, the reaction mixture was cooled to room temperature and recrystallized through ethyl acetate to obtain the desired product (130 g, yield 55%).
1H NMR (CDCl3): δ7.64(1H, brs), 7.23-6.69(2H, m), 3.94(3H, s), 2.67(3H, s), 2.35(3H, s) 1 H NMR (CDCl 3 ): δ7.64 (1H, brs), 7.23-6.69 (2H, m), 3.94 (3H, s), 2.67 (3H, s), 2.35 (3H, s)
제조예 1-2 내지 1-4 : 반응식 2에 따른 화학식 2의 화합물의 제조Preparation Examples 1-2 to 1-4: Preparation of Compound of Formula 2 According to Scheme 2:
상기 제조예 1-1의 단계 1) 및 2)와 유사한 방법으로 실험을 수행하여 다음과 같은 화학식 6 및 2의 구조를 갖는 화합물 각각을 얻었다.Experiments were performed in a similar manner to Steps 1) and 2) of Preparation Example 1-1 to obtain compounds having the structures of Formulas 6 and 2, respectively.
(제조예 1-2)(Manufacture Example 1-2)
디메틸 2-(2-메틸-3-클로로아닐리노)말로네이트Dimethyl 2- (2-methyl-3-chloroanilino) malonate
1H NMR (CDCl3): δ 6.99-6.38(m, 3H), 4.86(brs, 1H), 4.79(brs, 1H), 3.83(s, 6H), 2.32(s, 3H) 1 H NMR (CDCl 3 ): δ 6.99-6.38 (m, 3H), 4.86 (brs, 1H), 4.79 (brs, 1H), 3.83 (s, 6H), 2.32 (s, 3H)
메틸 3-히드록시-6-클로로-7-메틸-1H-2-인돌카복실레이트Methyl 3-hydroxy-6-chloro-7-methyl-1 H -2-indolecarboxylate
1H NMR (CDCl3): δ7.71(brs, 1H), 7.52-7.06(m, 2H), 3.98(s, 3H), 2.46(s, 3H) 1 H NMR (CDCl 3 ): δ 7.71 (brs, 1 H), 7.52-7.06 (m, 2 H), 3.98 (s, 3 H), 2.46 (s, 3 H)
(제조예 1-3)(Manufacture Example 1-3)
디메틸 2-(4-플루오로아닐리노)말로네이트Dimethyl 2- (4-fluoroanilino) malonate
1H NMR (CDCl3): δ6.96-6.57(m, 4H), 4.74(brs, 2H), 3.83(s, 6H) 1 H NMR (CDCl 3 ): δ 6.96-6.57 (m, 4H), 4.74 (brs, 2H), 3.83 (s, 6H)
메틸 3-히드록시-5-플로오로-1H-2-인돌카복실레이트Methyl 3-hydroxy-5-fluoro-1 H -2-indolecarboxylate
1H NMR (CDCl3): δ7.82(brs, 1H), 7.40-7.10(m, 3H), 3.97(s, 3H) 1 H NMR (CDCl 3 ): δ 7.82 (brs, 1 H), 7.40-7.10 (m, 3 H), 3.97 (s, 3 H)
(제조예 1-4)(Manufacture example 1-4)
디메틸 2-(3,5-디메틸아닐리노)말로네이트Dimethyl 2- (3,5-dimethylanilino) malonate
1H NMR (CDCl3): δ6.46(s, 1H), 6.30(s, 2H), 4.80(brs, 2H), 3.82(s, 6H), 2.24(s, 6H) 1 H NMR (CDCl 3 ): δ6.46 (s, 1H), 6.30 (s, 2H), 4.80 (brs, 2H), 3.82 (s, 6H), 2.24 (s, 6H)
메틸 3-히드록시-4,6-디메틸-1H-2-인돌카복실레이트Methyl 3-hydroxy-4,6-dimethyl-1 H -2-indolecarboxylate
1H NMR (CDCl3): δ 7.69(brs, 1H), 6.83(s, 1H), 6.65(s, 1H), 3.93(s, 3H), 2.66(s, 3H), 2.38(s, 3H) 1 H NMR (CDCl 3 ): δ 7.69 (brs, 1H), 6.83 (s, 1H), 6.65 (s, 1H), 3.93 (s, 3H), 2.66 (s, 3H), 2.38 (s, 3H)
제조예 2 : 반응식 3에 따른 화학식 2a의 화합물의 제조Preparation Example 2 Preparation of Compound of Formula 2a According to Scheme 3
1) 메틸 (3,5-디클로로페닐하이드라조노)프로피오네이트(화학식 9-1의 화합물)1) Methyl (3,5-dichlorophenylhydrazono) propionate (compound of formula 9-1)
3,5-디클로로페닐하이드라진(40g, 0.19몰)과 메틸피루베이트(39.52g, 0.29몰)에 60% 아세트산수용액 150ml을 가하고 실온에서 2시간동안 반응시켰다. 반응이 모두 종결되면 물 200ml로 희석하고 에테르(150ml×3)로 추출했다. 물과 포화 소디움카보네이트와 포화 소금 용액으로 씻어주고 황산 마그네슘으로 건조시킨후 감압증류하여 용매를 제거했다. 이어, 칼럼크로마토그래피로 정제하여 원하는 생성물(44g, 수율 89%)을 얻었다.150 ml of 60% acetic acid solution was added to 3,5-dichlorophenylhydrazine (40 g, 0.19 mole) and methylpyruvate (39.52 g, 0.29 mole) and allowed to react at room temperature for 2 hours. Upon completion of the reaction, the mixture was diluted with 200 ml of water and extracted with ether (150 ml × 3). The mixture was washed with water, saturated sodium carbonate and saturated salt solution, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. Then purified by column chromatography to give the desired product (44g, 89% yield).
1H NMR (CDCl3): δ7.64(brs, 2H), 7.10(s, 2H), 6.95(s, 1H), 3.87(s, 3H), 2.11(s, 3H) 1 H NMR (CDCl 3 ): δ 7.74 (brs, 2H), 7.10 (s, 2H), 6.95 (s, 1H), 3.87 (s, 3H), 2.11 (s, 3H)
2) 메틸 4,6-디클로로-1H-2-인돌카복실레이트(화학식 10-1의 화합물)2) methyl 4,6-dichloro-1 H -2-indolecarboxylate (compound of formula 10-1)
상기 단계 1)에서 제조된 메틸 (3,5-디클로로페닐하이드라조노)프로피오네이트(40g, 0.15몰)과 150ml의 아세트산 용액에 염화 아연(61.33g, 0.45몰)을 가한 후 2시간동안 가열 환류시켰다. 반응이 모두 종결되면 실온으로 냉각한 후 물을 첨가했다. 이어, 생성된 고체를 여과하고 감압건조시켜서 원하는 생성물(15g, 수율 40%)을 얻었다.Methyl (3,5-dichlorophenylhydrazono) propionate (40 g, 0.15 mole) prepared in step 1) and zinc chloride (61.33 g, 0.45 mole) were added to 150 ml of acetic acid solution, followed by heating for 2 hours. It was refluxed. After the reaction was complete, the reaction was cooled to room temperature and water was added. The resulting solid was then filtered and dried under reduced pressure to give the desired product (15 g, yield 40%).
1H NMR (CDCl3): δ9.10(brs, 1H), 7.35(s, 1H) 7.28(s, 1H), 7.19(s, 1H), 3.97(s, 3H) 1 H NMR (CDCl 3 ): δ 9.10 (brs, 1 H), 7.35 (s, 1 H) 7.28 (s, 1 H), 7.19 (s, 1 H), 3.97 (s, 3 H)
3) 메틸 3-포밀-4,6-디클로로-1H-2-인돌카복실레이트(화학식 11-1의 화합물)3) methyl 3-formyl-4,6-dichloro-1 H -2-indolecarboxylate (compound of formula 11-1)
옥시염화인(0.94g, 6.15밀리몰)과 N-메틸 포름아닐라이드(0.83g, 6.15밀리몰)을 실온에서 15분가량 교반하고, 상기 단계 2)에서 제조된 메틸 4,6-디클로로-1H-2-인돌카복실레이트(1g, 4.1밀리몰)과 1,2-디클로로에탄(25ml)을 첨가한 후 가열 환류시켰다. 반응이 모두 종결되면 따뜻한 혼합물을 소디움 아세트산(1g, 15밀리몰)과 얼음물에 붓고, 디클로로메탄(30ml×3)으로 추출하고 3N 염산수용액으로 씻어준 후 황산 마그네슘으로 건조하고, 칼럼크로마토그래피로 정제하여 원하는 생성물(0.59g, 수율 55%)를 얻었다.Phosphorous oxychloride (0.94 g, 6.15 mmol) and N-methyl formanilide (0.83 g, 6.15 mmol) were stirred at room temperature for about 15 minutes, and the methyl 4,6-dichloro-1 H -prepared in step 2) was added. 2-indole carboxylate (1 g, 4.1 mmol) and 1,2-dichloroethane (25 ml) were added and then heated to reflux. After the reaction was completed, the warm mixture was poured into sodium acetic acid (1 g, 15 mmol) and ice water, extracted with dichloromethane (30 ml × 3), washed with 3N aqueous hydrochloric acid solution, dried over magnesium sulfate, and purified by column chromatography. The desired product (0.59 g, yield 55%) was obtained.
1H NMR (CDCl3): δ13.22(brs, 1H), 10.61(s, 1H), 7.54(s, 1H), 7.45(s, 1H), 3.97(s, 3H) 1 H NMR (CDCl 3 ): δ 13.22 (brs, 1 H), 10.61 (s, 1 H), 7.54 (s, 1 H), 7.45 (s, 1 H), 3.97 (s, 3 H)
4) 메틸 3-포밀옥시-4,6-디클로로-1H-2-인돌카복실레이트(화학식 12-1의 화합물)4) Methyl 3-formyloxy-4,6-dichloro-1 H -2-indolecarboxylate (compound of formula 12-1)
상기 단계 3)에서 제조된 메틸 3-포밀-4,6-디클로로-1H-2-인돌카복실레이트(0.3g, 1.1밀리몰), 3-클로로퍼벤조산(0.24g, 1.38밀리몰) 및 4-톨루엔 설폰산(0.26g, 1.38밀리몰)을 디클로로메탄 30ml에 첨가하여 상온에서 교반시켰다. TLC로부터 반응이 완결됨을 확인한 뒤 디메틸 설파이드(0.17g, 1.76밀리몰)를 가하여 교반시킨 후, 용매를 감압 증류하고 남은 잔류물을 칼럼크로마토그래피로 정제하여 원하는 생성물(0.21g, 수율 64%)를 얻었다.Methyl 3-formyl-4,6-dichloro-1 H -2-indolecarboxylate (0.3 g, 1.1 mmol), 3-chloroperbenzoic acid (0.24 g, 1.38 mmol) and 4-toluene prepared in step 3) Sulfonic acid (0.26 g, 1.38 mmol) was added to 30 ml of dichloromethane and stirred at room temperature. After confirming that the reaction was completed by TLC, dimethyl sulfide (0.17 g, 1.76 mmol) was added and stirred, and the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the desired product (0.21 g, yield 64%). .
1H NMR (CDCl3): δ12.53(brs, 1H), 8.69(s, 1H), 7.45(s, 1H), 7.29(s, 1H), 3.86(s, 3H) OneH NMR (CDCl3): δ 12.53 (brs, 1H), 8.69 (s, 1H), 7.45 (s, 1H), 7.29 (s, 1H), 3.86 (s, 3H)
5) 메틸 3-히드록시-4,6-디클로로-1H-2-인돌카복실레이트(화학식 2a-1의 화합물)5) Methyl 3-hydroxy-4,6-dichloro-1 H -2-indolecarboxylate (compound of formula 2a-1)
상기 단계 4)에서 제조된 메틸 3-포밀옥시-4,6-디클로로-1H-2-인돌카복실레이트(0.2g, 0.69밀리몰)와 5% 중탄산 소디움(0.09g, 1.04밀리몰)에 에탄올 20ml를 가한 뒤 4시간동안 환류시켰다. TLC로부터 반응이 완결됨을 확인하고 차가운 묽은 염산에 넣은 뒤 에틸 아세테이트(25ml×3)로 추출하고 포화 소금 용액으로 씻어주었다. 유기층을 분리하여 황산 마그네슘으로 건조시키고, 용매를 감압 증류한 후 남은 잔류물을 칼럼크로마토그래피로 정제하여 원하는 생성물(0.11g, 수율 61%)를 얻었다.20 ml of ethanol was added to methyl 3-formyloxy-4,6-dichloro-1 H -2-indolecarboxylate (0.2 g, 0.69 mmol) and 5% sodium bicarbonate (0.09 g, 1.04 mmol) prepared in step 4). It was refluxed for 4 hours after the addition. After confirming that the reaction was completed by TLC, the mixture was put in cold dilute hydrochloric acid, extracted with ethyl acetate (25ml × 3), and washed with saturated salt solution. The organic layer was separated, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the desired product (0.11 g, 61% yield).
1H NMR (CDCl3): δ11.46(brs, 1H), 8.98(brs, 1H), 7.26(s, 1H), 7.05(s, 1H), 3.86(s, 3H) 1 H NMR (CDCl 3 ): δ 11.46 (brs, 1H), 8.98 (brs, 1H), 7.26 (s, 1H), 7.05 (s, 1H), 3.86 (s, 3H)
제조예 3-1 : 반응식 4에 따른 화학식 2a의 화합물의 제조Preparation Example 3-1 Preparation of a Compound of Formula 2a According to Scheme 4
1) 메틸 2-메톡시카보닐메틸아미노벤조에이트(화학식 16-1의 화합물)1) Methyl 2-methoxycarbonylmethylaminobenzoate (compound of Formula 16-1)
메틸안트라닐레이트(7.59g, 0.05몰), 메틸브로모아세테이트(11.47g, 0.075몰) 및 소디움카보네이트(5.30g, 0.05몰)에 디메틸포름아미드 80ml을 가한 뒤 60-80℃에서 24시간동안 교반하였다. TLC로부터 반응이 완결됨을 확인하고 물 200ml, 메탄올 15ml 및 25% 암모니아 15ml를 가하여 상온에서 2시간 교반하였다. 이 용액을 에틸아세테이트(50ml×3)로 추출하고 황산마그네슘으로 건조한 후, 감압 증류하고 잔류물을 칼럼크로마토그래피로 정제하여 원하는 생성물(9.46g, 수율 85%)를 얻었다.Methyl anthranilate (7.59 g, 0.05 mole), methyl bromoacetate (11.47 g, 0.075 mole) and sodium carbonate (5.30 g, 0.05 mole) were added 80 ml of dimethylformamide and stirred at 60-80 ° C. for 24 hours. It was. After confirming that the reaction was completed by TLC, 200 ml of water, 15 ml of methanol, and 15 ml of 25% ammonia were added thereto, and the mixture was stirred at room temperature for 2 hours. The solution was extracted with ethyl acetate (50ml × 3), dried over magnesium sulfate, distilled under reduced pressure, and the residue was purified by column chromatography to obtain the desired product (9.46g, yield 85%).
1H NMR (CDCl3): δ4.02(d, 2H, J = 5.5Hz), 3.88(s, 3H), 3.79(s, 3H) 1 H NMR (CDCl 3 ): δ 4.02 (d, 2H, J = 5.5 Hz), 3.88 (s, 3H), 3.79 (s, 3H)
2) 메틸 3-히드록시-1H-2-인돌카복실레이트(화학식 2a-2의 화합물)2) methyl 3-hydroxy-1 H -2-indolecarboxylate (compound of formula 2a-2)
상기 단계 1)에서 제조된 메틸 2-메톡시카보닐메틸아미노벤조에이트(4.46g, 0.02몰)에 소디움메톡시드(2.16g, 0.04몰)과 메탄올 40ml를 가하고 2시간 환류시켰다. TLC로부터 반응이 완결됨을 확인하고 메탄올을 감압 증류하여 농축시킨 다음, 얼음물 50g을 가하고 1N HCl로 산성화시켰다. 이 용액을 에틸아세테이트(30ml×3)로 추출하고 황산마그네슘으로 건조한 후, 감압 증류하고 잔류물을 칼럼크로마토그래피로 정제하여 원하는 생성물(3.44g, 수율 90%)을 얻었다.To methyl 2-methoxycarbonylmethylaminobenzoate (4.46 g, 0.02 mol) prepared in step 1) was added sodium methoxide (2.16 g, 0.04 mol) and 40 ml of methanol and refluxed for 2 hours. The reaction was confirmed by TLC to complete the reaction. Methanol was distilled under reduced pressure, concentrated, and then 50 g of ice water was added and acidified with 1N HCl. The solution was extracted with ethyl acetate (30 ml × 3), dried over magnesium sulfate, distilled under reduced pressure, and the residue was purified by column chromatography to obtain the desired product (3.44 g, yield 90%).
1H NMR (CDCl3): δ8.19(br, 1H), 7.85(br, 1H), 7.36(m, 1H), 7.80-7.00(m, 4H), 6.66(m, 1H), 6.52(d, 1H, J = 8.3Hz), 3.97(s, 3H) 1 H NMR (CDCl 3 ): δ 8.19 (br, 1H), 7.85 (br, 1H), 7.36 (m, 1H), 7.80-7.00 (m, 4H), 6.66 (m, 1H), 6.52 (d , 1H, J = 8.3 Hz), 3.97 (s, 3H)
제조예 3-2 내지 3-6 : 반응식 4에 따른 화학식 2a의 화합물의 제조Preparation Examples 3-2 to 3-6: Preparation of Compound of Formula 2a According to Scheme 4:
상기 제조예 3-1과 유사한 방법으로 실험을 수행하여 다음과 같은 화학식 2a의 구조를 갖는 화합물 각각을 얻었다.Experiments were performed in a similar manner as in Preparation Example 3-1 to obtain compounds having the structure of Formula 2a.
(제조예 3-2)(Manufacture example 3-2)
에틸 3-히드록시-1H-2-인돌카복실레이트Ethyl 3-hydroxy-1 H -2-indolecarboxylate
1H NMR (CDCl3): δ7.85(br, 1H), 7.80-7.00(s, 4H), 4.48(q, 2H, J = 7.1Hz), 1.42(t, 3H, J = 7.1Hz) 1 H NMR (CDCl 3 ): δ 7.85 (br, 1H), 7.80-7.00 (s, 4H), 4.48 (q, 2H, J = 7.1 Hz), 1.42 (t, 3H, J = 7.1 Hz)
(제조예 3-3)(Production Example 3-3)
메틸 3-히드록시-6-메톡시카보닐-1H-2-인돌카복실레이트Methyl 3-hydroxy-6-methoxycarbonyl-1 H -2-indolecarboxylate
1H NMR (CDCl3): δ7.78-8.04(m, 3H), 4.00(s, 3H), 3.95(s, 3H) 1 H NMR (CDCl 3 ): δ 7.78-8.04 (m, 3H), 4.00 (s, 3H), 3.95 (s, 3H)
(제조예 3-4)(Manufacture example 3-4)
메틸 3-히드록시-5,7-디클로로-1H-2-인돌카복실레이트Methyl 3-hydroxy-5,7-dichloro-1 H -2-indolecarboxylate
1H NMR (CDCl3): δ8.00(brs, 1H), 7.65(s, 1H), 7.35(s, 1H), 4.00(s, 3H) 1 H NMR (CDCl 3 ): δ 8.00 (brs, 1 H), 7.65 (s, 1 H), 7.35 (s, 1 H), 4.00 (s, 3 H)
(제조예 3-5)(Manufacture Example 3-5)
메틸 3-히드록시-5,6-디플루오로-1H-2-인돌카복실레이트Methyl 3-hydroxy-5,6-difluoro-1 H -2-indolecarboxylate
1H NMR (CDCl3): δ9.01 (brs, 1H), 7.83(brs, 1H), 7.37-7.46(m, 1H), 7.01-7.09(m, 1H), 3.92(s, 3H) 1 H NMR (CDCl 3 ): δ 9.01 (brs, 1H), 7.83 (brs, 1 H), 7.37-7.46 (m, 1 H), 7.01-7.09 (m, 1H), 3.92 (s, 3H)
(제조예 3-6)(Manufacture example 3-6)
메틸 3-히드록시-5,7-디클로로-1H-2-인돌카복실레이트Methyl 3-hydroxy-5,7-dichloro-1 H -2-indolecarboxylate
1H NMR (CDCl3): δ8.00 (br, 1H), 7.86(m, 1H), 7.63(m, 1H), 4.01(s, 3H) 1 H NMR (CDCl 3 ): δ8.00 (br, 1H), 7.86 (m, 1 H), 7.63 (m, 1 H), 4.01 (s, 3 H)
실시예 1 : 메틸 3-메톡시-4,7-디메틸-1H-인돌-2-카복실레이트(화합물 1-1) 및 메틸 2-메틸-3-옥소-2-인돌린 카복실레이트(화합물 1-2)의 제조Example 1 Methyl 3-methoxy-4,7-dimethyl-1 H -indole-2-carboxylate (Compound 1-1) and methyl 2-methyl-3-oxo-2-indolin carboxylate (Compound 1 -2) Preparation
메틸 3-히드록시-4,7-디메틸-1H-인돌-2-카복실레이트(0.5g, 2.28밀리몰)과칼륨카보네이트(0.63g, 4.56밀리몰)을 10ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 요오드화 메탄(0.28ml, 4.56밀리몰)을 첨가하고 10시간동안 실온에서 교반하였다. TLC로부터 반응이 종결되었음을 확인하고 차가운 1N 염산 용액으로 산성화시키고 에틸아세테이트(10ml×3)로 추출한 후, 유기용매층을 물(10ml×3)과 포화 소금 용액으로 씻어준 후 황산 마그네슘으로 건조시켰다. 감압증류 후에 칼럼크로마토그래피로 혼합물을 분리하여 목적하는 화합물 1-1(0.26g, 수율 50%)과 화합물 1-2(0.02g, 수율 9%)를 얻었다.Methyl 3-hydroxy-4,7-dimethyl-1 H -indole-2-carboxylate (0.5 g, 2.28 mmol) and potassium carbonate (0.63 g, 4.56 mmol) were added to 10 ml of dimethylformamide and stirred slowly. Methane iodide (0.28 ml, 4.56 mmol) was added and stirred for 10 hours at room temperature. After confirming that the reaction was terminated by TLC, acidified with cold 1N hydrochloric acid solution and extracted with ethyl acetate (10ml × 3), the organic solvent layer was washed with water (10ml × 3) and saturated salt solution and dried over magnesium sulfate. After distillation under reduced pressure, the mixture was separated by column chromatography to obtain the title compound 1-1 (0.26 g, yield 50%) and compound 1-2 (0.02 g, yield 9%).
화합물 1-1:1H NMR (CDCl3) δ 8.42(brs, 1H), 7.00(d, 1H, J=7.3Hz), 6.78(d, 1H, J=7.3Hz), 4.01(s, 6H), 2.69(s, 3H), 2.44(s, 3H)Compound 1-1: 1 H NMR (CDCl 3 ) δ 8.42 (brs, 1H), 7.00 (d, 1H, J = 7.3 Hz), 6.78 (d, 1H, J = 7.3 Hz), 4.01 (s, 6H) , 2.69 (s, 3H), 2.44 (s, 3H)
화합물 1-2:1H NMR (CDCl3) δ 7.16(d, 1H, J = 7.5Hz), 6.58(d, 1H, J = 7.5Hz), 4.92(brs, 1H), 3.76(s, 3H), 2.53(s, 3H), 2.22(s, 3H), 1.65(s, 3H)Compound 1-2: 1 H NMR (CDCl 3 ) δ 7.16 (d, 1H, J = 7.5 Hz), 6.58 (d, 1H, J = 7.5 Hz), 4.92 (brs, 1H), 3.76 (s, 3H) , 2.53 (s, 3H), 2.22 (s, 3H), 1.65 (s, 3H)
실시예 2 : 메틸 4,7-디메틸-3-(3-클로로-2-프로페닐옥시)-1H-인돌-2-카복실레이트(화합물 1-31) 및 메틸 2-(3-클로로-2-프로페닐)-3-옥소-4,7-디메틸-2-인돌린 카복실레이트(화합물 1-32)의 제조Example 2 Methyl 4,7-dimethyl-3- (3-chloro-2-propenyloxy) -1 H -indole-2-carboxylate (Compound 1-31) and methyl 2- (3-chloro-2 Preparation of -propenyl) -3-oxo-4,7-dimethyl-2-indolin carboxylate (Compound 1-32)
메틸 3-히드록시-4,7-디메틸-1H-인돌-2-카복실레이트(0.5g, 2.28밀리몰)과 칼륨카보네이트(0.63g, 4.56밀리몰)을 10ml의 디메틸포름아미드에 넣고 교반시켜주면서 천천히 1,3-클로로-2-프로펜(0.25g, 2.28밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물 1-31(0.15g, 수율 22%) 및 화합물 1-32(0.05g, 수율 7%)를 얻었다.Methyl 3-hydroxy-4,7-dimethyl-1 H -indole-2-carboxylate (0.5 g, 2.28 mmol) and potassium carbonate (0.63 g, 4.56 mmol) were added to 10 ml of dimethylformamide and stirred slowly. 1,3-chloro-2-propene (0.25 g, 2.28 mmol) was added, followed by the same reaction as in Example 1, to obtain the desired compound 1-31 (0.15 g, yield 22%) and compound 1- 32 (0.05 g, yield 7%) was obtained.
화합물 1-31:1H NMR (CDCl3) δ 8.29(brs, 1H), 7.01(d, 1H, J = 7.0Hz), 6.78(d, 1H, J = 7.0Hz), 6.22(m, 1H), 4.90(m, 1H), 4.65(d, 2H, J = 6.1Hz), 3.99(s, 3H), 2.66(s, 1H), 2.43(s, 3H)Compound 1-31: 1 H NMR (CDCl 3 ) δ 8.29 (brs, 1H), 7.01 (d, 1H, J = 7.0 Hz), 6.78 (d, 1H, J = 7.0 Hz), 6.22 (m, 1H) , 4.90 (m, 1H), 4.65 (d, 2H, J = 6.1 Hz), 3.99 (s, 3H), 2.66 (s, 1H), 2.43 (s, 3H)
화합물 1-32:1H NMR (CDCl3) δ 7.17(d, 1H, J = 7.5Hz), 6.60(d, 1H, J = 6.5Hz), 6.40-6.10(m, 1H), 5.98-5.70(m, 1H), 3.79(s, 3H), 3.20-2.80(m, 2H), 2.51(s, 3H), 2.22(s, 3H)Compound 1-32: 1 H NMR (CDCl 3 ) δ 7.17 (d, 1H, J = 7.5 Hz), 6.60 (d, 1H, J = 6.5 Hz), 6.40-6.10 (m, 1H), 5.98-5.70 ( m, 1H), 3.79 (s, 3H), 3.20-2.80 (m, 2H), 2.51 (s, 3H), 2.22 (s, 3H)
실시예 3 : 메틸 1-벤질-3-벤질옥시-5-클로로-1H-인돌-2-카복실레이트(화합물 1-49) 및 메틸 3-벤질옥시-5-클로로-1H-인돌-2-카복실레이트(O-알킬 화합물)과 메틸 2-벤질-3-옥소-5-클로로-2-인돌린 카복실레이트(N-알킬 화합물)의 혼합물(화합물 1-50)의 제조Example 3 Methyl 1-benzyl-3-benzyloxy-5-chloro-1 H -indole-2-carboxylate (Compound 1-49) and methyl 3-benzyloxy-5-chloro-1 H -indole-2 Preparation of a mixture of carboxylate (O-alkyl compound) and methyl 2-benzyl-3-oxo-5-chloro-2-indolin carboxylate (N-alkyl compound) (Compound 1-50)
메틸 3-히드록시-5-클로로-1H-인돌-2-카복실레이트(0.3g, 1.33밀리몰)와 칼륨카보네이트(0.28g, 2.00밀리몰)을 10ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 브로모벤질(0.23g, 1.33밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물 1-49(0.07g, 수율 16%) 및 O-알킬 화합물과 N-알킬 화합물의 2:1 혼합물인 화합물 1-50(0.17g, 수율 40%)을 얻었다.Methyl 3-hydroxy-5-chloro-1 H -indole-2-carboxylate (0.3 g, 1.33 mmol) and potassium carbonate (0.28 g, 2.00 mmol) were added to 10 ml of dimethylformamide and stirred slowly while bromo Benzyl (0.23 g, 1.33 mmol) was added, followed by the same reaction as in Example 1, to obtain desired compound 1-49 (0.07 g, yield 16%), and O-alkyl compound and N-alkyl compound 2: Compound 1-50 (0.17 g, yield 40%) was obtained as a mixture.
화합물 1-49:1H NMR (CDCl3) δ7.76-6.90(m, 13H), 5.72(s, 2H), 5.19(s, 2H), 3.83(s, 3H)Compound 1-49: 1 H NMR (CDCl 3 ) δ7.76-6.90 (m, 13H), 5.72 (s, 2H), 5.19 (s, 2H), 3.83 (s, 3H)
화합물 1-50:1H NMR (CDCl3) δ8.55(brs, 1H),7.60-7.20(m, 8H), 5.25(s, 2H), 3.94(s, 3H)(O-알킬화합물),1H NMR (CDCl3): δ 7.70-7.20(m, 3H), 5.16(m, 1H), 3.77(s, 3H), 3.60(m, 1H), 2.99(m, 1H)(N-알킬 화합물)Compound 1-50: 1 H NMR (CDCl 3 ) δ8.55 (brs, 1H), 7.60-7.20 (m, 8H), 5.25 (s, 2H), 3.94 (s, 3H) (O-alkyl compound), 1 H NMR (CDCl 3 ): δ 7.70-7.20 (m, 3H), 5.16 (m, 1H), 3.77 (s, 3H), 3.60 (m, 1H), 2.99 (m, 1H) (N-alkyl compounds )
실시예 4 : 메틸 3-프로판옥시-4-메톡시-7-메틸-1H-인돌-2-카복실레이트(화합물 1-55)의 제조Example 4 Preparation of Methyl 3-propaneoxy-4-methoxy-7-methyl-1 H -indole-2-carboxylate (Compound 1-55)
메틸 3-히드록시-4-메톡시-7-메틸-1H-인돌-2-카복실레이트(0.3g, 1.28밀리몰)와 칼륨카보네이트(0.23g, 1.92밀리몰)을 10ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 요오드화프로판(0.22g, 1.28밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물 1-55(0.09g, 수율 20%)를 얻었다.Methyl 3-hydroxy-4-methoxy-7-methyl-1 H -indole-2-carboxylate (0.3 g, 1.28 mmol) and potassium carbonate (0.23 g, 1.92 mmol) were added to 10 ml of dimethylformamide and stirred. Propane iodide (0.22 g, 1.28 mmol) was added slowly, followed by the same reaction as in Example 1 to obtain the desired compound 1-55 (0.09 g, yield 20%).
화합물 1-55:1H NMR (CDCl3) δ 8.20(brs, 1H), 6.98(d, 1H, J = 7.8Hz), 6.37(d, 1H, J = 7.8Hz), 4.10(t, 2H, J = 6.7Hz), 3.94(s, 3H), 3.92(s, 3H), 2.37(s, 3H), 1.85(m, 2H), 1.09(t, 3H, J = 7.3Hz)Compound 1-55: 1 H NMR (CDCl 3 ) δ 8.20 (brs, 1H), 6.98 (d, 1H, J = 7.8 Hz), 6.37 (d, 1H, J = 7.8 Hz), 4.10 (t, 2H, J = 6.7 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 2.37 (s, 3H), 1.85 (m, 2H), 1.09 (t, 3H, J = 7.3 Hz)
실시예 5 : 메틸 1-에틸-3-에톡시-6-클로로-1H-인돌-2-카복실레이트(화합물 1-63)및 메틸 3-에톡시-6-클로로-1H-인돌-2-카복실레이트(화합물 1-64)의 제조Example 5 Methyl 1-ethyl-3-ethoxy-6-chloro-1 H -indole-2-carboxylate (Compound 1-63) and methyl 3-ethoxy-6-chloro-1 H -indole-2 Preparation of Carboxylate (Compound 1-64)
메틸 3-히드록시-6-클로로-1H-인돌-2-카복실레이트(0.3g, 1.33밀리몰)와 칼륨카보네이트(0.28g, 2.00밀리몰)을 10ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 요오드화에탄(0.21g, 1.33밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물 1-63(0.08g, 수율 23%)과 화합물 1-64(0.13g, 수율 39%)를 얻었다.Methyl 3-hydroxy-6-chloro-1 H -indole-2-carboxylate (0.3 g, 1.33 mmol) and potassium carbonate (0.28 g, 2.00 mmol) were added to 10 ml of dimethylformamide and slowly stirred while stirring. (0.21 g, 1.33 mmol) was added, and then the same reaction as in Example 1 was carried out to obtain the desired compound 1-63 (0.08 g, yield 23%) and compound 1-64 (0.13 g, yield 39%). Got it.
화합물 1-63:1H NMR (CDCl3) δ 7.62(d, 1H, J = 8.5Hz), 7.34(s, 1H), 7.05(d, 1H, J = 8.5Hz), 4.46(q, 2H, J = 7.1Hz), 4.22(q, 2H, J = 6.9Hz), 3.95(s, 3H), 1.35(m, 6H)Compound 1-63: 1 H NMR (CDCl 3 ) δ 7.62 (d, 1H, J = 8.5 Hz), 7.34 (s, 1H), 7.05 (d, 1H, J = 8.5 Hz), 4.46 (q, 2H, J = 7.1 Hz), 4.22 (q, 2H, J = 6.9 Hz), 3.95 (s, 3H), 1.35 (m, 6H)
화합물 1-64:1H NMR (CDCl3) δ8.45(brs, 1H), 7.64(d, 1H, J = 8.5Hz), 7.31(s, 1H), 7.08(d, 1H, J = 8.5Hz), 4.32(q, 2H, J = 6.9Hz), 3.95(s, 3H), 1.42(t, 3H, J = 6.9Hz)Compound 1-64: 1 H NMR (CDCl 3 ) δ 8.45 (brs, 1H), 7.64 (d, 1H, J = 8.5 Hz), 7.31 (s, 1H), 7.08 (d, 1H, J = 8.5 Hz ), 4.32 (q, 2H, J = 6.9 Hz), 3.95 (s, 3H), 1.42 (t, 3H, J = 6.9 Hz)
실시예 6 : 메틸 3-프로파길옥시-4,7-디메틸-1H-인돌-2-카복실레이트(화합물 1-71) 및 화합물 1-71과 메틸 2-프로파길-3-옥소-4,7-디메틸-2-인돌린 카복실레이트의 혼합물(화합물 1-72)의 제조Example 6 Methyl 3-propargyloxy-4,7-dimethyl-1 H -indole-2-carboxylate (Compound 1-71) and Compound 1-71 and Methyl 2-propargyl-3-oxo-4, Preparation of 7-dimethyl-2-indolin carboxylate mixture (Compound 1-72)
메틸 3-히드록시-4,7-디메틸-1H-인돌-2-카복실레이트(4g, 18.24밀리몰)과 칼륨카보네이트(3.04g, 22.00밀리몰)을 50ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 프로파질브로마이드(1.63ml, 18.24밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물 1-71(2.05g, 수율 44%) 및 화합물 1-72(1.71g, 수율 37%)를 얻었다.Methyl 3-hydroxy-4,7-dimethyl-1 H -indole-2-carboxylate (4 g, 18.24 mmol) and potassium carbonate (3.04 g, 22.00 mmol) were added to 50 ml of dimethylformamide and stirred slowly. Phazyl bromide (1.63 ml, 18.24 mmol) was added, followed by the same reaction as in Example 1, and the desired compound 1-71 (2.05 g, yield 44%) and compound 1-72 (1.71 g, yield 37%) )
화합물 1-71:1H NMR (CDCl3) δ 8.29(brs, 1H), 7.15(m, 1H), 6.75(m, 1H), 5.28(d, 2H, J = 7.4Hz), 3.98(s, 3H), 2.71(s, 3H), 2.48(m, 1H), 2.42(s, 3H)Compound 1-71: 1 H NMR (CDCl 3 ) δ 8.29 (brs, 1H), 7.15 (m, 1H), 6.75 (m, 1H), 5.28 (d, 2H, J = 7.4 Hz), 3.98 (s, 3H), 2.71 (s, 3H), 2.48 (m, 1H), 2.42 (s, 3H)
화합물 1-72:1H NMR (CDCl3) δ 7.20(m, 1H), 6.60(m, 1H), 5.13(brs, 1H), 3.82(s, 3H), 3.30(m, 1H), 2.60(m, 1H), 2.51(s, 3H), 2.27(s, 3H), 2.05(m, 1H)(C-알킬 화합물),1H NMR (CDCl3) δ 8.29(brs, 1H), 7.15(m, 1H), 6.75(m, 1H), 5.28(d, 2H, J = 7.4Hz), 3.98(s, 3H), 2.71(s, 3H), 2.48(m, 1H), 2.42(s, 3H)(화합물 1-71)Compound 1-72: 1 H NMR (CDCl 3 ) δ 7.20 (m, 1H), 6.60 (m, 1H), 5.13 (brs, 1H), 3.82 (s, 3H), 3.30 (m, 1H), 2.60 ( m, 1H), 2.51 (s, 3H), 2.27 (s, 3H), 2.05 (m, 1H) (C-alkyl compound), 1 H NMR (CDCl 3 ) δ 8.29 (brs, 1H), 7.15 (m , 1H), 6.75 (m, 1H), 5.28 (d, 2H, J = 7.4 Hz), 3.98 (s, 3H), 2.71 (s, 3H), 2.48 (m, 1H), 2.42 (s, 3H) (Compound 1-71)
실시예 7 : 메틸 3-(2-클로로알릴옥시)-6-플루오로-1H-인돌-2-카복실레이트(화합물 1-108)의 제조Example 7 Preparation of Methyl 3- (2-chloroallyloxy) -6-fluoro-1 H -indole-2-carboxylate (Compound 1-108)
메틸 3-히드록시-6-플루오로-1H-인돌-2-카복실레이트(0.2g, 0.96밀리몰)과 칼륨카보네이트(0.2g, 1.44밀리몰)을 8ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 2,3-디클로로-1-프로펜(0.1ml, 1.05밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물 1-108(0.041g, 수율 15%)을 얻었다.Methyl 3-hydroxy-6-fluoro-1 H -indole-2-carboxylate (0.2 g, 0.96 mmol) and potassium carbonate (0.2 g, 1.44 mmol) were added to 8 ml of dimethylformamide and stirred slowly. , 3-Dichloro-1-propene (0.1 ml, 1.05 mmol) was added, followed by the same reaction as in Example 1, to obtain the title compound 1-108 (0.041 g, yield 15%).
화합물 1-108:1H NMR (CDCl3) δ 8.54(s, 1H), 7.71(m, 1H), 6.90(m, 2H), 5.65(s, 1H), 5.45(s, 1H), 4.84(s, 2H), 3.97(s, 3H)Compound 1-108: 1 H NMR (CDCl 3 ) δ 8.54 (s, 1H), 7.71 (m, 1H), 6.90 (m, 2H), 5.65 (s, 1H), 5.45 (s, 1H), 4.84 ( s, 2H), 3.97 (s, 3H)
실시예 8 : 에틸 3-(2-클로로알릴옥시)-1H-인돌-2-카복실레이트(화합물 1-141) 및 에틸 2-(2-클로로알릴)-3-옥소-2-인돌린 카복실레이트(화합물 1-142)의 제조Example 8 ethyl 3- (2-chloroallyloxy) -1 H -indole-2-carboxylate (Compound 1-141) and ethyl 2- (2-chloroallyl) -3-oxo-2-indolin carboxyl Preparation of Rate (Compound 1-142)
에틸 3-히드록시-1H-인돌-2-카복실레이트(0.2g, 0.97밀리몰)과 칼륨카보네이트(0.2g, 1.46밀리몰)을 8ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 1,2-디클로로-2-프로펜(0.11ml, 1.1밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물 1-141(0.071g, 수율 26%)와 화합물 1-142(0.081g, 수율 7%)를 얻었다.Ethyl 3-hydroxy- 1H -indole-2-carboxylate (0.2 g, 0.97 mmol) and potassium carbonate (0.2 g, 1.46 mmol) were added to 8 ml of dimethylformamide and slowly stirred while 1,2-dichloro- 2-propene (0.11 ml, 1.1 mmol) was added, followed by the same reaction as in Example 1, to obtain compound 1-141 (0.071 g, yield 26%) and compound 1-142 (0.081 g, yield). 7%).
화합물 1-141:1H NMR (CDCl3) δ 8.72(brs, 1H), 7.81-7.10(s, 4H), 5.75(s, 1H), 5.47(s, 1H), 4.86(s, 2H, 4.30(m, 2H), 1.46(m, 3H)Compound 1-141: 1 H NMR (CDCl 3 ) δ 8.72 (brs, 1H), 7.81-7.10 (s, 4H), 5.75 (s, 1H), 5.47 (s, 1H), 4.86 (s, 2H, 4.30 (m, 2H), 1.46 (m, 3H)
화합물 1-142:1H NMR (CDCl3) δ7.62-6.86(s, 4H), 5.40(brs, 1H), 5.32(m, 2H), 4.25(q, 2H, J = 6.9Hz), 3.47(m, 2H), 1.46(m, 3H)Compound 1-142: 1 H NMR (CDCl 3 ) δ7.62-6.86 (s, 4H), 5.40 (brs, 1H), 5.32 (m, 2H), 4.25 (q, 2H, J = 6.9 Hz), 3.47 (m, 2H), 1.46 (m, 3H)
실시예 9 : 메틸 3-(2-클로로알릴옥시)-6-메톡시카보닐-1H-인돌-2-카복실레이트(화합물 1-149)의 제조Example 9 Preparation of Methyl 3- (2-chloroallyloxy) -6-methoxycarbonyl-1 H -indole-2-carboxylate (Compound 1-149)
메틸 3-히드록시-6-메톡시카보닐-1H-인돌-2-카복실레이트(0.2g, 0.80밀리몰)과 칼륨카보네이트(0.2g, 1.46밀리몰)을 8ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 1,2-디클로로-2-프로펜(0.081ml, 0.88밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물 1-149(0.0184g, 수율 7%)를 얻었다.Methyl 3-hydroxy-6-methoxycarbonyl-1 H -indole-2-carboxylate (0.2 g, 0.80 mmol) and potassium carbonate (0.2 g, 1.46 mmol) were added to 8 ml of dimethylformamide and stirred. Slowly adding 1,2-dichloro-2-propene (0.081 ml, 0.88 mmol), and then proceeding to the same reaction as in Example 1, to obtain the title compound 1-149 (0.0184 g, yield 7%).
화합물 1-149:1H NMR (CDCl3) δ 8.67(brs, 1H), 8.11(s, 1H), 7.80(s, 2H), 5.66(s, 1H), 5.46(s, 1H), 4.85(s, 2H), 4.00(s, 3H), 3.96(s, 3H)Compound 1-149: 1 H NMR (CDCl 3 ) δ 8.67 (brs, 1H), 8.11 (s, 1H), 7.80 (s, 2H), 5.66 (s, 1H), 5.46 (s, 1H), 4.85 ( s, 2H), 4.00 (s, 3H), 3.96 (s, 3H)
실시예 10 : 메틸 3-(3-트리메틸실릴프로파길옥시)-7-벤질-1H-인돌-2-카복실레이트(화합물 1-166)의 제조Example 10 Preparation of Methyl 3- (3-trimethylsilylpropargyloxy) -7-benzyl-1 H -indole-2-carboxylate (Compound 1-166)
메틸 3-히드록시-7-벤질-1H-인돌-2-카복실레이트(0.28g, 1.0밀리몰)과 칼륨카보네이트(0.28g, 2.0밀리몰)을 10ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 3-브로모-1-트리메틸실릴-1-포르핀(0.23ml, 1.2밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물(0.17g, 수율 43%)을 얻었다.Methyl 3-hydroxy-7-benzyl-1 H -indole-2-carboxylate (0.28 g, 1.0 mmol) and potassium carbonate (0.28 g, 2.0 mmol) were added to 10 ml of dimethylformamide and stirred slowly. Bromo-1-trimethylsilyl-1-formine (0.23 ml, 1.2 mmol) was added, followed by the same reaction as in Example 1 to obtain the target compound (0.17 g, yield 43%).
화합물 1-166:1H NMR (CDCl3) δ 8.08 (brs, 1H), 7.74-7.69 (m, 1H), 7.31-7.21 (m, 6H), 7.11-7.07 (m, 1H), 4.85 (s 2H), 4.19 (s 2H), 3.91 (s 3H), 0.068 (s 9H)Compound 1-166: 1 H NMR (CDCl 3 ) δ 8.08 (brs, 1H), 7.74-7.69 (m, 1H), 7.31-7.21 (m, 6H), 7.11-7.07 (m, 1H), 4.85 (s 2H), 4.19 (s 2H), 3.91 (s 3H), 0.068 (s 9H)
실시예 11 : 메틸 1-알릴-3-알릴옥시-6-플루오로-1H-인돌-2-카복실레이트(화합물 1-256), 메틸 3-알릴옥시-6-플루오로-1H-인돌-2-카복실레이트(화합물 1-257) 및 메틸 2-알릴-3-옥소-6-플루오로-2-인돌린 카복실레이트(화합물 1-258)의 제조Example 11 Methyl 1-allyl-3-allyloxy-6-fluoro-1 H -indole-2-carboxylate (Compound 1-256), methyl 3-allyloxy-6-fluoro-1 H -indole Preparation of 2-carboxylate (Compound 1-257) and methyl 2-allyl-3-oxo-6-fluoro-2-indolin carboxylate (Compound 1-258)
메틸 3-히드록시-6-플루오로-1H-인돌-2-카복실레이트(0.21g, 1.0밀리몰)과 칼륨카보네이트(0.21g, 1.5밀리몰)을 10ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 알릴브로마이드(0.1ml, 1.1밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물 1-256(0.025g, 수율 8%), 화합물 1-257(0.0784g, 수율 31%)과 화합물 1-258(0.1008g, 수율 40%)을 얻었다.Methyl 3-hydroxy-6-fluoro-1 H -indole-2-carboxylate (0.21 g, 1.0 mmol) and potassium carbonate (0.21 g, 1.5 mmol) were added to 10 ml of dimethylformamide and stirred slowly with allyl Bromide (0.1 ml, 1.1 mmol) was added, followed by the same reaction as in Example 1, to obtain the desired compound 1-256 (0.025 g, yield 8%), compound 1-257 (0.0784 g, yield 31%). And compound 1-258 (0.1008g, yield 40%) were obtained.
화합물 1-256:1H NMR (CDCl3) δ 7.65(m, 1H), 7.00-6.84(m, 2H), 6.20-5.90(m, 2H), 5.43-4.84(m, 4H), 5.10(m, 2H), 4.70(m, 2H), 3.93(s, 3H)Compound 1-256: 1 H NMR (CDCl 3 ) δ 7.65 (m, 1H), 7.00-6.84 (m, 2H), 6.20-5.90 (m, 2H), 5.43-4.84 (m, 4H), 5.10 (m , 2H), 4.70 (m, 2H), 3.93 (s, 3H)
화합물 1-257:1H NMR (CDCl3) δ 8.84(brs, 1H), 7.69(m, 1H), 7.02-6.84(m, 2H), 6.20-6.03(m, 1H), 5.46-5.22(m, 2H), 4.87(m, 2H), 3.93(s, 3H)Compound 1-257: 1 H NMR (CDCl 3 ) δ 8.84 (brs, 1H), 7.69 (m, 1 H), 7.02-6.84 (m, 2H), 6.20-6.03 (m, 1H), 5.46-5.22 (m , 2H), 4.87 (m, 2H), 3.93 (s, 3H)
화합물 1-258:1H NMR (CDCl3) δ 7.60(m, 1H), 6.60(m, 2H), 5.80-5.60(m, 1H), 5.42(brs, 1H), 5.24-5.09(m, 2H), 3.77(s, 3H), 3.00(m, 1H), 2.60(m, 1H)Compound 1-258: 1 H NMR (CDCl 3 ) δ 7.60 (m, 1 H), 6.60 (m, 2 H), 5.80-5.60 (m, 1 H), 5.42 (brs, 1 H), 5.24-5.09 (m, 2H) ), 3.77 (s, 3H), 3.00 (m, 1H), 2.60 (m, 1H)
실시예 12 : 메틸 3-프로파길옥시-6-클로로-7-메톡시-1H-인돌-2-카복실레이트(화합물 1-265)와 메틸 1-프로파길-3-프로파길옥시-6-클로로-7-메톡시-1H-인돌-2-카복실레이트(화합물 1-266)의 제조Example 12 Methyl 3-propargyloxy-6-chloro-7-methoxy-1 H -indole-2-carboxylate (Compound 1-265) and methyl 1-propargyl-3-propargyloxy-6- Preparation of Chloro-7-methoxy-1 H -indole-2-carboxylate (Compound 1-266)
메틸 3-히드록시-6-클로로-7-메톡시-1H-인돌-2-카복실레이트(0.24g, 1.0밀리몰)과 칼륨카보네이트(0.28g, 2.0밀리몰)을 10ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 4-톨루엔 프로파길 설포네이트(0.25g, 1.2밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물 1-265(0.1g, 수율 36%)와 화합물 1-266(0.018g, 수율 6%)을 얻었다.Methyl 3-hydroxy-6-chloro-7-methoxy-1 H -indole-2-carboxylate (0.24 g, 1.0 mmol) and potassium carbonate (0.28 g, 2.0 mmol) were added to 10 ml of dimethylformamide and stirred. While slowly adding 4-toluene propargyl sulfonate (0.25 g, 1.2 mmol), the same reaction as in Example 1 was carried out, and the desired compound 1-265 (0.1 g, yield 36%) and compound 1- 266 (0.018 g, 6% yield) was obtained.
화합물 1-265:1H NMR (CDCl3) δ 8.31 (b, s 1H) 7.57 (d J=8.8Hz 1H) 7.14 (d J=8.8Hz 1H), 4.91 (d J=2.4Hz 2H) 3.98 (s 3H) 2.49 (s 3H) 2.47 (t J=2.4Hz 1H)Compound 1-265: 1 H NMR (CDCl 3 ) δ 8.31 (b, s 1H) 7.57 (d J = 8.8 Hz 1H) 7.14 (d J = 8.8 Hz 1H), 4.91 (d J = 2.4 Hz 2H) 3.98 ( s 3H) 2.49 (s 3H) 2.47 (t J = 2.4 Hz 1H)
화합물 1-266:1H NMR (CDCl3) δ 7.55 (d, 1H, J = 8.8Hz), 7.24 (d, 1H, J = 8.8Hz), 5.45 (d, 2H, J = 2.4Hz), 4.78 (d, 2H, J = 2.4Hz), 3.98 (s, 3H), 2.89 (S, 3H), 2.50 (t, 1H, J= 2.4Hz), 2.34 (t, 1H, J= 2.4Hz)Compound 1-266: 1 H NMR (CDCl 3 ) δ 7.55 (d, 1H, J = 8.8 Hz), 7.24 (d, 1H, J = 8.8 Hz), 5.45 (d, 2H, J = 2.4 Hz), 4.78 (d, 2H, J = 2.4 Hz), 3.98 (s, 3H), 2.89 (S, 3H), 2.50 (t, 1H, J = 2.4 Hz), 2.34 (t, 1H, J = 2.4 Hz)
실시예 13 : 메틸 1-프로파길-3-프로파길옥시-4-메틸-7-메톡시-1H-인돌-2-카복실레이트(화합물 1-446), 메틸 3-프로파길옥시-4-메틸-7-메톡시-1H-인돌-2-카복실레이트(화합물 1-447) 및 메틸 2-프로파길-3-옥소-4-메틸-7-메톡시-2-인돌린 카복실레이트(화합물 1-448)의 제조Example 13: Methyl 1-propargyl-3-propargyloxy-4-methyl-7-methoxy-1 H -indole-2-carboxylate (Compound 1-446), methyl 3-propargyloxy-4- Methyl-7-methoxy-1 H -indole-2-carboxylate (Compound 1-447) and methyl 2-propargyl-3-oxo-4-methyl-7-methoxy-2-indolin carboxylate (compound 1-448) Preparation
메틸 3-히드록시-4-메틸-7-메톡시-1H-인돌-2-카복실레이트(0.24g, 1.0밀리몰)과 칼륨카보네이트(0.21g, 1.5밀리몰)을 10ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 4-톨루엔 프로파길 설포네이트(0.25g, 1.2밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물 1-446(0.049g, 수율 16%), 화합물 1-447(0.16g, 수율 58%) 및 화합물 1-448(0.022g, 수율 8%)을 얻었다.Methyl 3-hydroxy-4-methyl-7-methoxy-1 H -indole-2-carboxylate (0.24 g, 1.0 mmol) and potassium carbonate (0.21 g, 1.5 mmol) were added to 10 ml of dimethylformamide and stirred. While slowly adding 4-toluene propargyl sulfonate (0.25 g, 1.2 mmol), the same reaction as in Example 1 was carried out to yield the desired compound 1-446 (0.049 g, yield 16%) and compound 1- 447 (0.16 g, yield 58%) and compound 1-448 (0.022 g, yield 8%) were obtained.
화합물 1-446:1H NMR (CDCl3) δ 7.82(d, 1H, J = 6.7Hz), 7.34(d, 1H, J = 6.7Hz), 5.67(d, 2H, J = 2.4Hz), 4.73(dd, 1H, J = 7.9Hz), 4.69(dd, 1H, J = 7.9Hz), 3.98(s, 3H), 3.93 (s, 3H), 2.64(s, 3H), 2.51(t, 1H, J = 2.4Hz), 2.18(t, 1H, J = 2.4Hz)Compound 1-446: 1 H NMR (CDCl 3 ) δ 7.82 (d, 1H, J = 6.7 Hz), 7.34 (d, 1H, J = 6.7 Hz), 5.67 (d, 2H, J = 2.4 Hz), 4.73 (dd, 1H, J = 7.9 Hz), 4.69 (dd, 1H, J = 7.9 Hz), 3.98 (s, 3H), 3.93 (s, 3H), 2.64 (s, 3H), 2.51 (t, 1H, J = 2.4 Hz), 2.18 (t, 1H, J = 2.4 Hz)
화합물 1-447:1H NMR (CDCl3) δ7.06(d, 1H, J = 7.7Hz), 6.57(d, 1H, J = 7.7Hz), 5.39(brs, 1H), 3.88(s, 3H), 3.80(s, 3H), 3.24(dd, 1H, J = 6.7, 2.6Hz), 2.56(dd1, 1H, J = 6.7, 2.6Hz), 2.46(s, 3H), 2.03(t, 1H, J = 2.6Hz)Compound 1-447: 1 H NMR (CDCl 3 ) δ 7.06 (d, 1H, J = 7.7 Hz), 6.57 (d, 1H, J = 7.7 Hz), 5.39 (brs, 1H), 3.88 (s, 3H ), 3.80 (s, 3H), 3.24 (dd, 1H, J = 6.7, 2.6 Hz), 2.56 (dd1, 1H, J = 6.7, 2.6 Hz), 2.46 (s, 3H), 2.03 (t, 1H, J = 2.6 Hz)
화합물 1-448:1H NMR (CDCl3) δ 8.32(brs, 1H), 7.20-7.12(m, 2H), 6.87-6.4(m, 1H), 4.85(s, 2H), 3.94(s, 3H), 3.83(s, 3H), 2.72(s, 3H)Compound 1-448: 1 H NMR (CDCl 3 ) δ 8.32 (brs, 1H), 7.20-7.12 (m, 2H), 6.87-6.4 (m, 1H), 4.85 (s, 2H), 3.94 (s, 3H ), 3.83 (s, 3H), 2.72 (s, 3H)
실시예 14 : 메틸 3-(2-옥시라닐메틸옥시)-4-메틸-7-클로로-1H-인돌-2-카복실레이트(화합물 1-495)의 제조Example 14 Preparation of Methyl 3- (2-Oxiranylmethyloxy) -4-methyl-7-chloro-1 H -indole-2-carboxylate (Compound 1-495)
메틸 3-히드록시-4-메틸-7-클로로-1H-인돌-2-카복실레이트(0.24g, 1.0밀리몰)과 칼륨카보네이트(0.21g, 1.5밀리몰)을 10ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 글리시딜토실레이트(0.32g, 1.1밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물 41-95(0.0782g, 수율 26%)을 얻었다.Methyl 3-hydroxy-4-methyl-7-chloro-1 H -indole-2-carboxylate (0.24 g, 1.0 mmol) and potassium carbonate (0.21 g, 1.5 mmol) were added to 10 ml of dimethylformamide and stirred. Glycidyl tosylate (0.32 g, 1.1 mmol) was added slowly while giving the same reaction as in Example 1 to obtain the desired compound 41-95 (0.0782 g, yield 26%).
화합물 1-495:1H NMR (CDCl3) δ 8.54(brs, 1H), 7.16(m, 1H), 6.75(m, 1H), 4.42(m, 1H), 4.10(m, 1H), 3.96(s, 3H), 3.42(m, 1H), 2.80(m, 1H), 2.78-2.60(m, 4H)Compound 1-495: 1 H NMR (CDCl 3 ) δ 8.54 (brs, 1H), 7.16 (m, 1H), 6.75 (m, 1H), 4.42 (m, 1H), 4.10 (m, 1H), 3.96 ( s, 3H), 3.42 (m, 1H), 2.80 (m, 1H), 2.78-2.60 (m, 4H)
실시예 15 : 메틸 3-(2-메톡시에톡시)-4,6-디메틸-1H-인돌-2-카복실레이트(화합물 1-542)의 제조Example 15 Preparation of Methyl 3- (2-methoxyethoxy) -4,6-dimethyl-1 H -indole-2-carboxylate (Compound 1-542)
메틸 3-히드록시-4,6-디메틸-1H-인돌-2-카복실레이트(0.22g, 1.0밀리몰)과 칼륨카보네이트(0.21g, 1.5밀리몰)을 10ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 클로로 2-메톡시에탄(0.1ml, 1.1밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물 1-542(0.007g, 수율 3%)를 얻었다.Methyl 3-hydroxy-4,6-dimethyl-1 H -indole-2-carboxylate (0.22 g, 1.0 mmol) and potassium carbonate (0.21 g, 1.5 mmol) were added to 10 ml of dimethylformamide and stirred slowly. Chloro 2-methoxyethane (0.1 ml, 1.1 mmol) was added, followed by the same reaction as in Example 1 to obtain the title compound 1-542 (0.007 g, yield 3%).
화합물 1-542:1H NMR (CDCl3) δ 8.16(brs, 1H), 6.89(s, 1H), 6.69(s, 1H), 4.30(t, 2H, J = 5.1Hz), 3.94(s, 3H), 3.80(m, 2H), 3.46(s, 3H), 2.68(s, 3H), 2.39(s, 3H)Compound 1-542: 1 H NMR (CDCl 3 ) δ 8.16 (brs, 1H), 6.89 (s, 1H), 6.69 (s, 1H), 4.30 (t, 2H, J = 5.1 Hz), 3.94 (s, 3H), 3.80 (m, 2H), 3.46 (s, 3H), 2.68 (s, 3H), 2.39 (s, 3H)
실시예 16 : 메틸 3-메톡시카보닐메톡시-4-메틸-1H-인돌-2-카복실레이트(화합물 1-565)와 메틸 1-메톡시카보닐메틸-3-메톡시카보닐메톡시-4-메틸-1H-인돌-2-카복실레이트(화합물 1-566)Example 16 Methyl 3-methoxycarbonylmethoxy-4-methyl- 1H -indole-2-carboxylate (Compound 1-565) and methyl 1-methoxycarbonylmethyl-3-methoxycarbonylmethoxy- 4-Methyl-1 H -indole-2-carboxylate (Compound 1-566)
메틸 3-히드록시-4-메틸-1H-인돌-2-카복실레이트(0.22g, 1.0밀리몰)과 칼륨카보네이트(0.21g, 1.5밀리몰)을 10ml의 디메틸포름아미드에 넣고 교반시켜 주면서 천천히 메틸 브로모아세테이트(0.18ml, 1.2밀리몰)을 첨가한 다음, 상기 실시예 1과 동일한 반응을 진행하여 목적하는 화합물 1-565(0.17g, 수율 61%)와 화합물 1-566(0.015g, 수율 4.3%)을 얻었다.Methyl 3-hydroxy-4-methyl-1 H -indole-2-carboxylate (0.22 g, 1.0 mmol) and potassium carbonate (0.21 g, 1.5 mmol) were added to 10 ml of dimethylformamide and stirred slowly with methyl bromine. Moacetate (0.18 ml, 1.2 mmol) was added, followed by the same reaction as in Example 1, and the desired compound 1-565 (0.17 g, 61% yield) and compound 1-566 (0.015 g, yield 4.3%) )
화합물 1-565:1H NMR (CDCl3) δ 8.32(brs, 1H), 7.20-7.12(m, 2H), 6.87-6.4(m, 1H), 4.85(s, 2H), 3.94(s, 3H), 3.83(s, 3H), 2.72(s, 3H)Compound 1-565: 1 H NMR (CDCl 3 ) δ 8.32 (brs, 1H), 7.20-7.12 (m, 2H), 6.87-6.4 (m, 1H), 4.85 (s, 2H), 3.94 (s, 3H ), 3.83 (s, 3H), 2.72 (s, 3H)
화합물 1-566:1H NMR (CDCl3) δ 7.28-7.2(m, 1H), 7.05(d, 1H, J = 8.5Hz), 6.89(d, 1H, J = 8.5Hz), 5.21(s, 2H), 4.70(s, 2H), 3.89(s, 3H), 3.85(s, 3H), 3.72(s, 3H), 2.70(s, 3H)Compound 1-566: 1 H NMR (CDCl 3 ) δ 7.28-7.2 (m, 1H), 7.05 (d, 1H, J = 8.5 Hz), 6.89 (d, 1H, J = 8.5 Hz), 5.21 (s, 2H), 4.70 (s, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.72 (s, 3H), 2.70 (s, 3H)
살균효과 시험예Example of bactericidal effect
식물 병원균에 대한 예방효과를 조사하기 위하여, 시험 화합물 25mg을 10ml의 아세톤에 용해시키고, 이 용액에 트윈 20이 함유된 250ppm 수용액 90ml를 첨가하여 그 농도가 250ppm이 되게 조정한 후, 이를 일정 크기의 기주 식물에 50ml씩 엽면 살포하였다. 약제가 살포된 식물을 실내온도에서 24시간동안 방치하여 용매및 물을 휘산시켰다. 이와 같이 살균제 조성물로 처리된 식물체(처리구)와 처리되지 않은 식물체(대조구)에, 각기 하기 시험예와 같이 특정 식물 병원균을 접종하여 동일한 조건(습도 및 온도)하에서 동일한 기간동안 방치한 후, 각 잎의 병반면적율(측정된 병반면적이 잎집면적에 대해 차지하는 비율을 기준으로 하여 작성한 이병면적율 대비표로 구함)을 구해 하기 수학식 1과 같이 방제가(Control Value, %)를 산출하였다. 방제가가 높을수록 살균효과는 우수한 것이다.To investigate the protective effect against plant pathogens, 25 mg of test compound was dissolved in 10 ml of acetone, 90 ml of a 250 ppm aqueous solution containing Tween 20 was added to the solution, and the concentration was adjusted to 250 ppm. 50 ml of foliar spray was applied to host plants. The sprayed plants were left at room temperature for 24 hours to volatilize the solvent and water. In this way, the plants (treatment) and the untreated plants (control) treated with the fungicide composition were inoculated with specific plant pathogens, respectively, and left under the same conditions (humidity and temperature) for the same period of time, as shown in the following test examples. The control area (Control Value,%) was calculated as shown in Equation 1 by obtaining the lesion area ratio (obtained from the ratio of the diseased area ratio prepared based on the ratio of the measured lesion area to the leaf area). The higher the control value, the better the sterilization effect.
시험예 1 : 벼 도열병에 대한 살균효과Test Example 1: bactericidal effect on rice blast
병원균(Pyricularia oryzae)의 균주를 쌀겨 한천배지(Rice Polish 20g, 덱스트로즈 10g, 한천 15g, 증류수 1ℓ)에 접종하여 26℃ 배양기에서 2주간 배양하였다. 병원균이 자란 배지의 표면을 고무쓸개로 긁어 기중균사를 제거하고 형광등이 켜진 25 내지 28oC의 선반에서 48시간동안 포자를 형성시켰다. 병균 접종은 형성된 분생포자를 살균 증류수를 이용하여 일정 농도의 포자현탁액(106개/㎖)을 만든 후, 벼 도열병에 감수성인 낙동벼(3-4엽기)에 흘러내릴 정도로 충분히 분무하였다. 병균 접종된 벼를 습실상에 암상태로 24시간 방치하고, 상대습도 90% 이상 및 26±2oC인 항온항습실에서 5일동안 발병을 유도하여 잎의 병반면적율을 구했다. 이때 3-4엽기 벼의 최상위엽 바로 밑의 완전 전개된 잎에 형성된 병반면적을 측정하였다.Strains of pathogens ( Pyricularia oryzae ) were inoculated in rice bran agar medium (Rice Polish 20g, dextrose 10g, agar 15g, distilled water 1L) and incubated for 2 weeks in a 26 ℃ incubator. The surface of the medium in which the pathogen was grown was scraped off with a rubber gallbladder to remove aerial mycelium and spores were formed for 48 hours on a fluorescent lamp turned on at 25 to 28 ° C. Germ inoculation was sprayed enough to flow into Nakdong rice (3-4 leaves) susceptible to rice blast, after making a spore suspension (106 pieces / ㎖) of a certain concentration using sterilized distilled water. The inoculated rice was incubated for 24 hours in a dark state, and the incidence of leaf area was determined by induction for 5 days in a constant temperature and humidity chamber with a relative humidity of 90% or higher and 26 ± 2 o C. At this time, the lesion area formed on the fully developed leaf just below the top leaf of 3-4 leaf rice was measured.
시험예 2 : 벼잎집무늬 마름병에 대한 살균효과Test Example 2: Bactericidal Effect on Rice Leaf House Blight
적당한 양의 밀기울을 1ℓ 배양병에 넣고 멸균한 후 감자 한천배지(PDA)에서 3일간 자란 병원균(Rhizoctonia solani)의 한천조각을 접종하고, 배양된 균사덩어리를 적당히 잘게 마쇄하여 2-3엽기의 낙동벼가 자란 포트(5cm)에 고르게 접종하고 28±1℃ 및 상대습도 80% 이상인 항온항습실에서 5일동안 발병을 유도하여 2-3엽기 유묘의 잎의 병반면적율을 구했다.Put an appropriate amount of bran into a 1 liter culture bottle and sterilize it, inoculate agar pieces of the pathogen ( Rhizoctonia solani ) grown on potato agar medium (PDA) for 3 days, and finely crush the cultured mycelia. Inoculated evenly in the pot (5cm) and induced the disease for 5 days in a constant temperature and humidity room with a temperature of 28 ± 1 ℃ and a relative humidity of 80% or more to determine the leaf area ratio of the leaves of 2-3 leaves seedlings.
시험예 3 : 토마토 회색곰팡이 병에 대한 살균효과Test Example 3: bactericidal effect on tomato gray mold disease
토마토로부터 분리한 균주(Botrytis cinerea)를 감자 한천배지에 접종하고 25℃의 배양기에 플레이트를 놓아 광암상태하에서 15일간 배양하여 포자를 형성시켰다. 배지에 형성된 포자를 플레이트당 10㎖의 증류수를 넣은 후 붓으로 포자를 긁어 이를 가아제로 걸러서 포자를 수확하고 포자 농도가 106개/㎖가 되게 만들어 1엽기 오이에 분무접종하였다. 이를 20℃ 습실상에서 3일간 발병을 유도하여 본엽 1엽의 병반면적율을 구했다.Strains ( Botrytis cinerea ) isolated from tomatoes were inoculated in potato agar medium and plated in a 25 ° C. incubator to incubate for 15 days under light dark conditions to form spores. Spores formed on the medium were put in 10ml of distilled water per plate, scraped with a brush, spores were filtered with gauze, and spores were harvested to make a spore concentration of 106 / ml and sprayed on single leaf cucumbers. This was induced for 3 days on a 20 ° C wet ground, and the lesion area ratio of one leaf of the main leaf was obtained.
시험예 4 : 토마토역병에 대한 살균효과Test Example 4: bactericidal effect against tomato late blight
역병균(Phytophthora infestans)을 V-8 쥬스 한천배지(V-8 juice 200㎖, CaCO34.5g, 한천 15g, 증류수 800㎖)에 올려놓고 20℃에서 16시간 광처리 및 8시간 암처리하여 14일동안 배양한 후 포자를 수확하였다. 이때, 플레이트에 살균 증류수를 넣고 흔들어서 유주자낭을 균총으로부터 떼어낸 후 4겹 헝겊조각을 사용하여 유주자낭을 걸러냈다. 걸러낸 유주자낭의 농도를 살균 증류수를 사용하여 105개/㎖로 조정하고 이 접종원을 토마토 유묘에 분무접종하여 20℃ 습실상에서 1일동안 습실 처리한 후, 온도 20℃ 및 상대습도 80% 이상의 항온항습실로 옮겨 4일동안 발병시킨 다음 토마토 1엽과 2엽의 병반면적율을 조사하였다. Phytophthora infestans were placed on V-8 juice agar medium (V-8 juice 200ml, CaCO 3 4.5g, agar 15g, distilled water 800ml) and light treated at 20 ℃ for 16 hours and dark treated for 14 hours. Spores were harvested after incubation. At this time, sterile distilled water was added to the plate and shaken to separate the zygote sac from the flora, and then, the 4-stage piece of cloth was used to filter the stool sac. After adjusting the concentration of the filtered zygote sac to 105 / ml using sterile distilled water, the inoculum was sprayed on tomato seedlings, and then wet-treated at 20 ° C. for 1 day, followed by a constant temperature of 20 ° C. and a relative humidity of 80% or more. After transferring to the humidity chamber for 4 days, the lesion area ratio of one and two leaves of the tomato was examined.
시험예 5 : 밀 붉은녹병에 대한 살균효과Test Example 5: bactericidal effect on wheat rust
병원균(Puccinia recondita)은 실험실에서 식물체에 직접 계대배양하여 사용하였다. 균주의 계대배양 및 약효조사를 위해서 일회용 포트(직경: 6.5cm)에 15립씩의 밀종자(은파)를 파종하여 온실에서 7일간 재배한 1엽기의 밀에 포자를 털어 접종하였다. 접종한 1엽기의 밀을 20℃의 습실상에서 1일간 습실처리한 후, 상대습도 70% 및 20℃의 항온항습실로 옮겨 10일동안 발병을 유도한 다음 잎의 병반면적율을 구했다.The pathogen ( Puccinia recondita ) was used for direct passage to plants in the laboratory. For subculture and pharmacological investigation of strains, 15 seed grains (silver onions) were seeded in a disposable pot (diameter: 6.5 cm), and spores were inoculated by sprinkling the wheat of one leaf grown for 7 days in a greenhouse. The inoculated one-leafed wheat was incubated for one day in a 20 ° C. chamber, and then transferred to a constant temperature and humidity chamber at a relative humidity of 70% and 20 ° C. to induce the disease for 10 days, and then calculated the leaf area ratio of the leaves.
시험예 6 : 보리 흰가루병에 대한 살균효과Test Example 6: bactericidal effect on barley powdery mildew
병원균(Erysiphe graminis f.sp.hordei)은 실험실에서 계대 배양하여 사용하였다. 균주의 계대배양 및 약효조사를 위해서 일회용 포트(직경: 6.5cm)에 15립씩의 보리종자(동보리 1호)를 파종하여, 온실(25±5oC)에서 7일간 재배한 1엽기의 보리에 흰가루병 포자를 털어 접종한 후, 상대습도 50% 및 22 내지 24℃의 항온항습실에 옮겨 7일간 발병을 유도한 다음 잎의 병반면적율을 구했다.The pathogen ( Erysiphe graminis f.sp.hordei ) was used by passage in the laboratory. For subculture and pharmacological investigation of strains, seedlings of 15 barley seeds (East barley No. 1) were sown in a disposable pot (diameter: 6.5 cm) and grown in a greenhouse (25 ± 5 o C) for 7 days. After inoculated with powdery mildew spores, it was transferred to a constant temperature and humidity room of 50% relative humidity and 22 to 24 ° C to induce the onset for 7 days, and then the leaf area ratio of the leaves was determined.
상기 시험예 1 내지 6에서 측정한 처리구 및 대조구 잎의 병반면적율을 대입하여 방제가를 산출하고, 그 결과를 활성지수로서 토마토 회색곰팡이병 및 벼 도열병에 대해 각각 하기 표 2 및 3에 나타내었다.The control value was calculated by substituting the lesion area ratios of the treatment and control leaves measured in Test Examples 1 to 6, and the results are shown in Tables 2 and 3 below for tomato gray mold disease and rice blast disease, respectively.
상기 표 2 및 3의 결과로부터 알 수 있듯이, 본 발명에 따른 3-알콕시인돌-2-카복실레이트 유도체를 포함하는 조성물은 식물 병원균에 대해 광범위한 살균효과를 가지며, 특히 벼 도열병 및 토마토 회색곰팡이병에 대해 탁월한 효과를 갖는다. 또한, 침투효과뿐만 아니라 예방 및 치료효과가 뛰어나, 살균제로서 유용하게 사용될 수 있다.As can be seen from the results of Tables 2 and 3, the composition comprising the 3-alkoxyindole-2-carboxylate derivative according to the present invention has a wide range of bactericidal effects against plant pathogens, in particular in rice blast and tomato gray mold disease Has an excellent effect. In addition, it is excellent in the prevention and treatment effect as well as the penetration effect, can be usefully used as a fungicide.
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