KR100218196B1 - Method for the preparation of 2-aminothiazole carboxamide derivatives - Google Patents

Method for the preparation of 2-aminothiazole carboxamide derivatives Download PDF

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KR100218196B1
KR100218196B1 KR1019950041490A KR19950041490A KR100218196B1 KR 100218196 B1 KR100218196 B1 KR 100218196B1 KR 1019950041490 A KR1019950041490 A KR 1019950041490A KR 19950041490 A KR19950041490 A KR 19950041490A KR 100218196 B1 KR100218196 B1 KR 100218196B1
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KR970021078A (en
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편승엽
김성기
류요섭
유성훈
김문정
전재훈
조진호
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성재갑
주식회사엘지화학
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

본 발명은 하기 일반식(Ⅱ)로 표시되는 2-술포닐티아졸 카르복사미드 유도체를 용매 존재하에서 하기 일반식(Ⅲ)으로 표시되는 일차아민과 반응시키는 것을 특징으로 하는 하기 일반식(Ⅰ)로 표시되는 2-아미노티아졸 카르복사미드 유도체의 제조방법에 관한 것이다.The present invention is characterized by reacting a 2-sulfonylthiazole carboxamide derivative represented by the following general formula (II) with a primary amine represented by the following general formula (III) in the presence of a solvent. It relates to a method for producing a 2-aminothiazole carboxamide derivative represented by.

상기식에서, R1은 C1-5직쇄알킬, C1-5측쇄알킬, C1-5할로알킬, C3-5시클로알킬, C3-5알케닐 또는 C3-5알키닐기를 나타내고, R2는 C1-3알킬 또는 C1-3할로알킬기를 나타내고, R3은 C1-5직쇄알킬, C1-5측쇄알킬, C1-5할로알킬, C1-5의 알킬 또는 할로겐이 치환될 수 있는 벤질, C1-5의 알킬 또는 할로겐이 치환될 수 있는 페닐기에 관한 것이다.Wherein R 1 represents a C 1-5 straight alkyl, C 1-5 branched alkyl, C 1-5 haloalkyl, C 3-5 cycloalkyl, C 3-5 alkenyl or C 3-5 alkynyl group, R 2 represents a C 1-3 alkyl or C 1-3 haloalkyl group, R 3 represents C 1-5 straight chain alkyl, C 1-5 branched alkyl, C 1-5 haloalkyl, C 1-5 alkyl or halogen This may be substituted for benzyl, C 1-5 alkyl or phenyl group which may be substituted.

Description

2-아미노티아졸 카르복사미드 유도체의 제조방법Method for preparing 2-aminothiazole carboxamide derivative

본 발명은 하기 일반식(Ⅰ)로 표시되는 2-아미노티아졸 카르복사미드 유도체의 제조방법에 관한 것이다.The present invention relates to a method for producing a 2-aminothiazole carboxamide derivative represented by the following general formula (I).

상기식에서, R1은 C1-5직쇄알킬, C1-5측쇄알킬, C1-5할로알킬, C3-5시클로알킬, C3-5알케닐 또는 C3-5알키닐기이고, R2는 C1-3알킬 또는 C1-3할로알킬기를 나타낸다.Wherein R 1 is C 1-5 straight alkyl, C 1-5 branched alkyl, C 1-5 haloalkyl, C 3-5 cycloalkyl, C 3-5 alkenyl or C 3-5 alkynyl group, R 2 represents a C 1-3 alkyl or C 1-3 haloalkyl group.

상기 일반식(Ⅰ)이 화합물은 역병균과 노균병균이 일으키는 식물병의 퇴치에 사용되는 살균물질로서, 본 발명자들에 의해 출원된 이미 대한민국 특허공개 94-19960호 및 미국특허출원 US08/287,917호, 일본특허출원 JP192529호 및 유럽특허출원 EP94112652.6호로 출원된 바 있다.The compound of general formula (I) is a bactericidal substance used for the eradication of plant diseases caused by late blight and fungal bacteria, and has already been filed by the inventors of Korean Patent Publication Nos. 94-19960 and US Patent Application US08 / 287,917 And Japanese Patent Application JP192529 and European Patent Application EP94112652.6.

본 발명은 하기 일반식(Ⅱ)로 표시되는 2-술포닐티아졸카르복사미드와 하기 일반식(Ⅲ)의 일차아민을 반응시키는 것을 특징으로 하여 상기 일반식(Ⅰ)의 화합물을 제조하는 방법을 제공하는데 있다.The present invention is characterized by reacting 2-sulfonylthiazolecarboxamide represented by the following general formula (II) with a primary amine of the following general formula (III), to prepare a compound of the general formula (I) To provide.

상기에서, R1과 R2는 전술한 의미와 동일하며, R3는 C1-5직쇄알킬, C1-5측쇄알킬, C3-8시클로알킬, C1-5의 알킬 또는 할로겐이 치환될 수 있는 벤질, C1-5의 알킬 또는 할로겐이 치환될 수 있는 페닐기를 나타낸다.In the above, R 1 and R 2 have the same meaning as described above, and R 3 is substituted with C 1-5 linear alkyl, C 1-5 branched alkyl, C 3-8 cycloalkyl, C 1-5 alkyl or halogen Benzyl, C 1-5 alkyl or halogen which may be substituted.

본 발명에서 목적 화합물인 일반식(Ⅰ)의 화합물은 하기 반응도식 Ⅰ에 따라 일반식(Ⅱ)의 화합물을 염기존재하에서 일반식(Ⅲ)의 일차아민과 반응시켜 일반식(Ⅰ)의 목적 화합물을 제조할 수 있다.The compound of formula (I), which is the target compound in the present invention, reacts the compound of formula (II) with the primary amine of formula (III) in the presence of a base according to Scheme I below. Can be prepared.

상기 반응에 사용되는 염기로는 피리딘, 4-디메틸아미노피리딘, 트리에틸아민, N,N-디메틸아닐린, 트리부틸아민, N-메틸모포린등의 유기 염기와 수산화나트륨, 수산화칼륨, 탄산칼륨, 탄산수소나트륨, 탄산수소칼륨, 수소화나트륨, 수소화칼륨등의 무기염기를 들 수 있으며, 바람직하기로는 유기염기가 적당하다. 한편 반응에 참여하는 일차아민 자체를 과량(2당량 내지 4당량)으로 사용하여 염기로 사용할 수 있다. 반응용매로는 벤젠, 톨루엔, 자일렌과 같은 방향족 탄화수소류, 디클로로메탄, 1,2-디클로로에탄, 클로로포름과 같은 할로겐화 탄화수소류, 디에틸에테르, 디옥산, 1,2-디메톡시에탄, 테트라히드로푸란과 같은 에테르류, 아세톤, 메닐에틸케톤, 시클로헥사논과 같은 케톤류, 아세토니트릴, 프로피오니트릴과 같은 니트릴류, 메틸 아세테이트, 에틸 아세테이트 등의 에스테르류, N,N-디메틸포름아미드, 디메틸술폭시드 등의 극성용매를 사용할 수 있으며, 바람직하기로는 에테르류나 극성용매가 적당하다.Bases used in the reaction include organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine, N, N-dimethylaniline, tributylamine, N-methylmorpholine, sodium hydroxide, potassium hydroxide, potassium carbonate, Inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, and the like, and organic bases are preferable. On the other hand, the primary amine itself participating in the reaction can be used as a base using an excess (2 equivalents to 4 equivalents). Reaction solvents include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, diethyl ether, dioxane, 1,2-dimethoxyethane and tetrahydro Ethers such as furan, acetone, menylethyl ketone, ketones such as cyclohexanone, nitriles such as acetonitrile, propionitrile, esters such as methyl acetate, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide Polar solvents, such as these, can be used, Preferably ether and polar solvent are suitable.

본 반응에서 사용되는 일반식(Ⅲ)의 일차아민은 수분을 제거한 후, 염기를 첨가할 경우는 화합물(Ⅱ)에 대해서 1당량 내지 2당량을 사용하는 것이 바람직하며, 염기를 첨가하지 않을 경우는 화합물(Ⅱ)에 대해서 2당량 내지 4당량을 사용하는 것이 바람직하다. 반응온도는 0에서 100범위내에서 가능하나, 보다 바람직하게는 20내지 60가 적당하다.The primary amine of the general formula (III) used in this reaction is preferably one to two equivalents relative to compound (II) when water is removed and then a base is added. It is preferable to use 2 to 4 equivalents based on compound (II). Reaction temperature is 0 In 100 Possible in the range, but more preferably 20 To 60 Is suitable.

이하 본 발명을 실시예에 의거 보다 구체적으로 설명하지만, 본 발명의 기술적 범위가 이들 실시예로 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, but the technical scope of the present invention is not limited to these Examples.

[실시예 1]Example 1

4-에틸2-에틸아미노-티아졸-5-카르복실산(시아노-티오펜-2-일-메틸)-아미드의 합성Synthesis of 4-ethyl2-ethylamino-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl) -amide

방법 1). 테트라히드로푸란 용매와 메틸술폰; 4-에틸-2-메틸술포닐-티아졸-5-카르복실산(시아노-티오펜-1-일-메틸)-아미드(5.0g,14mmol)과 에틸아민(1.4g,2.2당량)을 테트라히드로푸란(15)에 녹이고 밀봉한 상태에서 40에서 4시간동안 교반한 후 물과 에틸아세테이트를 가하여 추출한다. 분리한 유기층을 소금물로 한번 수세한 후 무수망초로 건조시키고 감압증류하여 용매를 제거하여 갈색고체를 얻는다. 물과 에탄올의 혼합용액(부피/부피1/1)에서 재결정하여 표제화합물(3.1g,9.8mmol)을 70의 수율로 얻는다.Method 1). Tetrahydrofuran solvent and methylsulfone; 4-Ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid (cyano-thiophen-1-yl-methyl) -amide (5.0 g, 14 mmol) and ethylamine (1.4 g, 2.2 equiv) Tetrahydrofuran (15 40) with dissolved and sealed After stirring for 4 hours, water and ethyl acetate were added for extraction. The separated organic layer was washed once with brine, dried over anhydrous manganese and distilled under reduced pressure to remove the solvent to obtain a brown solid. Mixed solution of water and ethanol (volume / volume 1/1) recrystallized from the title compound (3.1g, 9.8mmol) 70 To yield.

방법 2). 1,2-디메톡시에탄 용매와 메틸술폰; 4-에틸-2-메틸술포닐-티아졸-5-카르복실산(시아노-티오펜-1-메틸)-아미드(5.0g,14mmol)과 에틸아민(2.5g,4.0당량)을 1,2-디메톡시에탄(10)에 녹이고 밀봉한 상태에서 60에서 2시간동안 교반한 후 감압증류하여 용매를 제거하여 갈색고체를 얻는다. 물과 에탄올의 혼합 용액(부피/부피1/1)에서 재결정하여 표제화합물(4.0g,13mmol)을 90수율로 얻는다.Method 2). 1,2-dimethoxyethane solvent and methylsulfone; 4-Ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid (cyano-thiophen-1-methyl) -amide (5.0 g, 14 mmol) and ethylamine (2.5 g, 4.0 equiv) 2-dimethoxyethane (10 60) with dissolved and sealed After stirring for 2 hours at distilled under reduced pressure to remove the solvent to obtain a brown solid. Mixed solution of water and ethanol (volume / volume 1/1) recrystallized from the title compound (4.0 g, 13 mmol) to 90 Get in yield.

방법 3). N,N-디메틸아세트아미드 용매와 메틸술폰; 4-에틸-2-메틸술포닐-티아졸-5-카르복실산(시아노-티오펜-1-일-메틸)-아미드(3.9g,11mmol)과 에틸아민(1.2g,2.2당량)을 N,N-디메틸아세트아미드(10)에 녹이고 밀봉한 상태에서 60에서 1.5시간 동안 교반한후 물과 에탄올의 혼합용액(부피/부피1/1)을 가하고 재결정하여 표제화합물(3.0g,9.4mmol)을 85의 수율로 얻는다.Method 3). N, N-dimethylacetamide solvent and methylsulfone; 4-Ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid (cyano-thiophen-1-yl-methyl) -amide (3.9 g, 11 mmol) and ethylamine (1.2 g, 2.2 equiv) N, N-dimethylacetamide (10 60) with dissolved and sealed After stirring for 1.5 hours at, mixed solution of water and ethanol (volume / volume 1/1) and recrystallized to give the title compound (3.0g, 9.4mmol) 85 To yield.

[실시예 2]Example 2

2-에틸아미노-4-메틸-티아졸-5-카르복실산(시아노-티오펜-2-일-메틸)-아미드의 합성Synthesis of 2-ethylamino-4-methyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl) -amide

방법 1). 테트라히드로푸란 용매와 메틸술폰; 4-메틸-2-메틸술포닐-티아졸-5-카르복실산(시아노-티오펜-1-일-메틸)-아미드(4.8g,14mmol)과 에틸아민(1.4g,2.2당량)을 테트라히드로푸란(15)에 녹이고 밀봉한 상태에서 40에서 4시간동안 교반한 후 물과 에틸아세테이트를 가하여 추출한다. 분리한 유기층을 소금물로 한번 수세한 후 무수망초로 건조시키고 감압증류하여 용매를 제거하여 갈색고체를 얻는다. 물과 에탄올의 혼합용액(부피/부피1.2/1)에서 재결정하여 표제화합물(3.0g,9.8mmol)을 70의 수율로 얻는다.Method 1). Tetrahydrofuran solvent and methylsulfone; 4-Methyl-2-methylsulfonyl-thiazole-5-carboxylic acid (cyano-thiophen-1-yl-methyl) -amide (4.8 g, 14 mmol) and ethylamine (1.4 g, 2.2 equiv) Tetrahydrofuran (15 40) with dissolved and sealed After stirring for 4 hours, water and ethyl acetate were added for extraction. The separated organic layer was washed once with brine, dried over anhydrous manganese and distilled under reduced pressure to remove the solvent to obtain a brown solid. Mixed solution of water and ethanol (volume / volume 1.2 / 1) recrystallized from the title compound (3.0 g, 9.8 mmol) to 70 To yield.

방법 2). 1,2-디메톡시에탄 용매와 메틸술폰; 4-메틸-2-메틸술포닐-티아졸-5-카르복실산(시아노-티오펜-1-일-메틸)-아미드(5.0g,15mmol)과 에틸아민(2.5g,4.0당량)을 1,2-디메톡시에탄(10)에 녹이고 밀봉한 상태에서 60에서 2시간동안 교반한 후 감압증류하여 용매를 제거하여 갈색고체를 얻는다. 물과 에탄올의 혼합 용액(부피/부피1.2/1)에서 재결정하여 표제화합물(4.0g,13mmol)을 88수율로 얻는다.Method 2). 1,2-dimethoxyethane solvent and methylsulfone; 4-Methyl-2-methylsulfonyl-thiazole-5-carboxylic acid (cyano-thiophen-1-yl-methyl) -amide (5.0 g, 15 mmol) and ethylamine (2.5 g, 4.0 equiv) 1,2-dimethoxyethane (10 60) with dissolved and sealed After stirring for 2 hours at distilled under reduced pressure to remove the solvent to obtain a brown solid. Mixed solution of water and ethanol (volume / volume 1.2 / 1) recrystallized from the title compound (4.0 g, 13 mmol) to 88 Get in yield.

방법 3). N,N-디메틸아세트아미드 용매와 에틸술포닐; 2-에틸술포닐-4-메틸-티아졸-5-카르복실산(시아노-티오펜-1-일-메틸)-아미드(3.9g,11mmol)과 에틸아민(1.2g,2.2당량)을 N,N-디메틸아세트아미드(10)에 녹이고 밀봉한 상태에서 60에서 1.5시간 동안 교반한후 물과 에탄올의 혼합용액(부피/부피1.2/1)을 가하고 재결정하여 표제화합물(2.8g,9.2mmol)을 84의 수율로 얻는다.Method 3). N, N-dimethylacetamide solvent and ethylsulfonyl; 2-ethylsulfonyl-4-methyl-thiazole-5-carboxylic acid (cyano-thiophen-1-yl-methyl) -amide (3.9 g, 11 mmol) and ethylamine (1.2 g, 2.2 equiv) N, N-dimethylacetamide (10 60) with dissolved and sealed After stirring for 1.5 hours at, mixed solution of water and ethanol (volume / volume 1.2 / 1) was added and recrystallized to give the title compound (2.8 g, 9.2 mmol) 84. To yield.

[실시예 3]Example 3

2-시클로프로필아미노-4-메틸-티아졸-5-카르복실산(시아노-티오펜-2-일-메틸)-아미드의 합성Synthesis of 2-cyclopropylamino-4-methyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl) -amide

방법 1). 테트라히드로푸란 용매와 메틸술폰; 4-에틸-2-메틸술포닐-티아졸-5-카르복실산(시아노-티오펜-1-일-메틸)-아미드(5.0g,14mmol)과 시클로프로필아민(1.8g,2.2당량)을 테트라히드로푸란(15)에 녹이고 밀봉한 상태에서 40에서 4시간동안 교반한 후 물과 에틸아세테이트를 가하여 추출한다. 분리한 유기층을 소금물로 한번 수세한 후 무수망초로 건조시키고 감압증류하여 용매를 제거하여 갈색고체를 얻는다. 물과 에탄올의 혼합용액(부피/부피1/1.5)에서 재결정하여 표제화합물(3.0g,9.1mmol)을 65의 수율로 얻는다.Method 1). Tetrahydrofuran solvent and methylsulfone; 4-Ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid (cyano-thiophen-1-yl-methyl) -amide (5.0 g, 14 mmol) and cyclopropylamine (1.8 g, 2.2 equiv) Tetrahydrofuran (15 40) with dissolved and sealed After stirring for 4 hours, water and ethyl acetate were added for extraction. The separated organic layer was washed once with brine, dried over anhydrous manganese and distilled under reduced pressure to remove the solvent to obtain a brown solid. Mixed solution of water and ethanol (volume / volume 1 / 1.5) to recrystallize the title compound (3.0g, 9.1mmol) 65 To yield.

방법 2). 1,2-디메톡시에탄 용매와 시클로헥실술폰; 2-시클로헥실술포닐-4-에틸-티아졸-5-카르복실산(시아노-티오펜-1-일-메틸)-아미드(6.0g,14mmol)과 시클로프로필아민(3.3g,4.0당량)을 1,2-디메톡시에탄(15)에 녹이고 밀봉한 상태에서 60에서 2시간동안 교반한 후 감압증류하여 용매를 제거하여 갈색고체를 얻는다. 물과 에탄올의 혼합 용액(부피/부피1/1.5)에서 재결정하여 표제화합물(3.0g,9.1mmol)을 65수율로 얻는다.Method 2). 1,2-dimethoxyethane solvent and cyclohexylsulfone; 2-cyclohexylsulfonyl-4-ethyl-thiazole-5-carboxylic acid (cyano-thiophen-1-yl-methyl) -amide (6.0 g, 14 mmol) and cyclopropylamine (3.3 g, 4.0 equiv. ) To 1,2-dimethoxyethane (15 60) with dissolved and sealed After stirring for 2 hours at distilled under reduced pressure to remove the solvent to obtain a brown solid. Mixed solution of water and ethanol (volume / volume 1 / 1.5) to recrystallize the title compound (3.0g, 9.1mmol) 65 Get in yield.

방법 3). N,N-디메틸아세트아미드 용매와 메틸술폰; 4-에틸-2-메틸술포닐-티아졸-5-카르복실산(시아노-티오펜-1-일-메틸)-아미드(3.6g,10mmol)과 시클로프로필아민(1.3g,2.2당량)을 N,N-디메틸아세트아미드(10)에 녹이고 밀봉한 상태에서 60에서 2시간 동안 교반한후 물과 에탄올의 혼합용액(부피/부피1/1.5)을 가하고 재결정하여 표제화합물(2.6g,8.0mmol)을 80의 수율로 얻는다.Method 3). N, N-dimethylacetamide solvent and methylsulfone; 4-Ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid (cyano-thiophen-1-yl-methyl) -amide (3.6 g, 10 mmol) and cyclopropylamine (1.3 g, 2.2 equiv) N, N-dimethylacetamide (10 60) with dissolved and sealed After stirring for 2 hours in a mixture of water and ethanol (volume / volume 1 / 1.5) and recrystallized to give the title compound (2.6 g, 8.0 mmol) 80 To yield.

[실시예 4]Example 4

4-에틸-2-프로파질아미노-티아졸-5-카르복실산(시아노-티오펜-2-일-메틸)-아미드의 합성Synthesis of 4-ethyl-2-propazylamino-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl) -amide

방법 1). 테트라히드로푸란 용매와 메틸술폰; 4-에틸-2-메틸술포닐-티아졸-5-카르복실산(시아노-티오펜-1-일-메틸)-아미드(5.0g,14mmol)과 프로파질아민(1.7g,2.2당량)을 테트라히드로푸란(15)에 녹이고 밀봉한 상태에서 40에서 4시간동안 교반한 후 물과 에틸아세테이트를 가하여 추출한다. 분리한 유리층을 소금물로 한번 수세한 후 무수망초로 건조시키고 감압증류하여 용매를 제거하여 갈색고체를 얻는다. 물과 에탄올의 혼합용액(부피/부피1/1.5)에서 재결정하여 표제화합물(2.9g,8.8mmol)을 63의 수율로 얻는다.Method 1). Tetrahydrofuran solvent and methylsulfone; 4-Ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid (cyano-thiophen-1-yl-methyl) -amide (5.0 g, 14 mmol) and propazylamine (1.7 g, 2.2 equiv) Tetrahydrofuran (15 40) with dissolved and sealed After stirring for 4 hours, water and ethyl acetate were added for extraction. The separated glass layer was washed once with brine, dried over anhydrous forget-me-not and distilled under reduced pressure to remove the solvent to obtain a brown solid. Mixed solution of water and ethanol (volume / volume 1 / 1.5) to recrystallize to give the title compound (2.9g, 8.8mmol) 63 To yield.

방법 2). 1,2-디메톡시에탄 용매와 페닐술폰; 4-에틸-2-페닐술포닐-티아졸-5-카르복실산(시아노-티오펜-1-일-메틸)-아미드(4.2g,10mmol)과 프로파질아민(2.2g,4.0당량)을 1,2-디메톡시에탄(10)에 녹이고 밀봉한 상태에서 60에서 2시간동안 교반한 후 감압증류하여 용매를 제거하여 갈색고체를 얻는다. 물과 에탄올의 혼합 용액(부피/부피1/1)에서 재결정하여 표제화합물(2.0g,6.0mmol)을 60수율로 얻는다.Method 2). 1,2-dimethoxyethane solvent and phenylsulfone; 4-Ethyl-2-phenylsulfonyl-thiazole-5-carboxylic acid (cyano-thiophen-1-yl-methyl) -amide (4.2 g, 10 mmol) and propazylamine (2.2 g, 4.0 equiv) 1,2-dimethoxyethane (10 60) with dissolved and sealed After stirring for 2 hours at distilled under reduced pressure to remove the solvent to obtain a brown solid. Mixed solution of water and ethanol (volume / volume 1/1) to recrystallize the title compound (2.0g, 6.0mmol) 60 Get in yield.

방법 3). N,N-디메틸아세트아미드 용매와 메틸술폰; 4-에틸-2-메틸술포닐-티아졸-5-카르복실산(시아노-티오펜-1-일-메틸)-아미드(3.4g,9.5mmol)과 프로파질아민(1.2g,2.2당량)을 N,N-디메틸아세트아미드(10)에 녹이고 밀봉한 상태에서 60에서 4시간 동안 교반한후 물과 에탄올의 혼합용액(부피/부피1/1.5)을 가하고 재결정하여 표제화합물(2.4g,7.2mmol)을 75의 수율로 얻는다.Method 3). N, N-dimethylacetamide solvent and methylsulfone; 4-Ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid (cyano-thiophen-1-yl-methyl) -amide (3.4 g, 9.5 mmol) and propazylamine (1.2 g, 2.2 equiv. ) To N, N-dimethylacetamide (10 60) with dissolved and sealed After stirring for 4 hours in a mixture of water and ethanol (volume / volume 1 / 1.5) and recrystallized to give the title compound (2.4g, 7.2mmol) 75 To yield.

[실시예 5]Example 5

4-알릴아미노-2-에틸-티아졸-5-카르복실산(시아노-티오펜-2-일-메틸)-아미드의 합성Synthesis of 4-allylamino-2-ethyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl) -amide

방법 1). 테트라히드로푸란 용매와 메틸술폰; 4-에틸-2-메틸술포닐-티아졸-5-카르복실산(시아노-티오펜-1-일-메틸)-아미드(3.9g,11mmol)과 알릴아민(1.4g,2.2당량)을 테트라히드로푸란(12)에 녹이고 밀봉한 상태에서 40에서 4시간동안 교반한 후 물과 에틸아세테이트를 가하여 추출한다. 분리한 유기층을 소금물로 한번 수세한 후 무수망초로 건조시키고 감압증류하여 용매를 제거하여 갈색고체를 얻는다. 물과 에탄올의 혼합용액(부피/부피1/1.5)에서 재결정하여 표제화합물(2.4g,7.2mmol)을 65의 수율로 얻는다.Method 1). Tetrahydrofuran solvent and methylsulfone; 4-Ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid (cyano-thiophen-1-yl-methyl) -amide (3.9 g, 11 mmol) and allylamine (1.4 g, 2.2 equiv) Tetrahydrofuran (12 40) with dissolved and sealed After stirring for 4 hours, water and ethyl acetate were added for extraction. The separated organic layer was washed once with brine, dried over anhydrous manganese and distilled under reduced pressure to remove the solvent to obtain a brown solid. Mixed solution of water and ethanol (volume / volume 1 / 1.5) to recrystallize to give the title compound (2.4g, 7.2mmol) 65 To yield.

방법 2). 1,2-디메톡시에탄 용매와 벤질술폰; 2-벤질술포닐-4-에틸-티아졸-5-카르복실산(시아노-티오펜-1-메틸)-아미드(6.0g,14mmol)과 알릴아민(3.3g,4.0당량)을 1,2-디메톡시에탄(15)에 녹이고 밀봉한 상태에서 60에서 2시간동안 교반한 후 감압증류하여 용매를 제거하여 갈색고체를 얻는다. 물과 에탄올의 혼합 용액(부피/부피1/1.5)에서 재결정하여 표제화합물(3.1g,9.4mmol)을 67수율로 얻는다.Method 2). 1,2-dimethoxyethane solvent and benzyl sulfone; 2-benzylsulfonyl-4-ethyl-thiazole-5-carboxylic acid (cyano-thiophen-1-methyl) -amide (6.0 g, 14 mmol) and allylamine (3.3 g, 4.0 equivalent) 2-dimethoxyethane (15 60) with dissolved and sealed After stirring for 2 hours at distilled under reduced pressure to remove the solvent to obtain a brown solid. Mixed solution of water and ethanol (volume / volume 1 / 1.5) to recrystallize to give the title compound (3.1g, 9.4mmol) 67 Get in yield.

방법 3). N,N-디메틸아세트아미드 용매와 메틸술폰; 4-에틸-2-메틸술포닐-티아졸-5-카르복실산(시아노-티오펜-1-일-메틸)-아미드(3.9g,11mmol)과 알릴아민(1.4g,2.2당량)을 N,N-디메틸아세트아미드(10)에 녹이고 밀봉한 상태에서 60에서 1.5시간 동안 교반한후 물과 에탄올의 혼합용액(부피/부피1/1.5)을 가하고 재결정하여 표제화합물(2.9g,8.8mmol)을 80의 수율로 얻는다.Method 3). N, N-dimethylacetamide solvent and methylsulfone; 4-Ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid (cyano-thiophen-1-yl-methyl) -amide (3.9 g, 11 mmol) and allylamine (1.4 g, 2.2 equiv) N, N-dimethylacetamide (10 60) with dissolved and sealed After stirring for 1.5 hours at, mixed solution of water and ethanol (volume / volume 1 / 1.5) and recrystallized to give the title compound (2.9g, 8.8mmol) 80 To yield.

Claims (7)

하기 일반식(Ⅱ)로 표시되는 2-술포닐티아졸 카르복사미드 유도체를 용매 존재하에서 하기 일반식(Ⅲ)으로 표시되는 일차아민과 반응시키는 것을 특징으로 하는 하기 일반식(Ⅰ)로 표시되는 2-아미노티아졸 카르복사미드 유도체의 제조방법.2-sulfonylthiazole carboxamide derivative represented by the following general formula (II) is reacted with a primary amine represented by the following general formula (III) in the presence of a solvent: Method for preparing 2-aminothiazole carboxamide derivatives. 상기식에서, R1은 C1-5직쇄알킬, C1-5측쇄알킬, C1-5할로알킬, C3-5시클로알킬기, C3-5알케닐 또는 C3-5알키닐기를 나타내고, R2는 C1-3알킬 또는 C1-3할로알킬기를 나타내고, R3은 C1-5직쇄알킬, C1-5측쇄알킬, C1-5할로알킬, C1-5의 알킬 또는 할로겐이 치환될 수 있는 벤질, C1-5의 알킬 또는 할로겐이 치환될 수 있는 페닐기를 나타낸다.Wherein R 1 represents a C 1-5 linear alkyl, C 1-5 branched alkyl, C 1-5 haloalkyl, C 3-5 cycloalkyl group, C 3-5 alkenyl or C 3-5 alkynyl group, R 2 represents a C 1-3 alkyl or C 1-3 haloalkyl group, R 3 represents C 1-5 straight chain alkyl, C 1-5 branched alkyl, C 1-5 haloalkyl, C 1-5 alkyl or halogen This may be substituted benzyl, C 1-5 alkyl or halogen represents a phenyl group which may be substituted. 제1항에 있어서, R1은 C1-3알킬, 알릴, 프로파질 또는 시클로프로필기이고, R2는 메틸 또는 에틸기이고, R3은 C1-3알킬, 벤질 또는 페닐기임을 특징으로 하는 일반식(Ⅰ)의 유도체의 제조방법.The compound of claim 1 wherein ROnesilver C1-3Alkyl, allyl, propazyl or cyclopropyl group, R2Is a methyl or ethyl group, R3Silver c1-3Process for the preparation of derivatives of general formula (I) characterized in that they are alkyl, benzyl or phenyl groups. 제1항에 있어서, 일반식(Ⅲ)의 화합물을 일반식(Ⅱ)의 화합물에 대해 2 내지 4당량배 사용하는 방법.The method according to claim 1, wherein the compound of formula (III) is used in an amount of 2 to 4 equivalents based on the compound of formula (II). 제1항에 있어서, 용매가 톨루엔, 자일렌, 디클로로메탄, 1,2-디클로로에탄, 클로로포름, 디에틸에테르, 디옥산, 1,2-디메톡시에탄, 테트라히드로푸란, 아세톤, 메틸 에틸케톤, 시클로헥사논, 아세토니트릴, 프로피오니트릴, 메틸 아세테이트, 에틸 아세테이트, N,N-디메틸포름아미드, N,N-디메틸아세트아미드 및 디메틸술폭시드 중에서 선택된 1종 이상인 방법.The method of claim 1, wherein the solvent is toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, diethyl ether, dioxane, 1,2-dimethoxyethane, tetrahydrofuran, acetone, methyl ethyl ketone, At least one selected from cyclohexanone, acetonitrile, propionitrile, methyl acetate, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, and dimethyl sulfoxide. 제1항에 있어서, 일반식(Ⅲ)의 화합물을 일반식(Ⅱ)의 화합물에 대해 1 내지 2당량배 사용하고, 피리딘, 4-디메틸아미노피리딘, 트리에틸아민, N,N-디메틸아닐린, 트리부틸아민, N-메틸모포린, 수산화나트륨, 수산화칼륨, 탄산나트륨, 탄산칼륨, 탄산수소나트륨, 탄산수소칼륨, 수소화나트륨 및 수소화칼륨중에서 선택된 1종 이상의 염기를 사용하는 방법.The compound according to claim 1, wherein the compound of formula (III) is used in an amount of 1 to 2 equivalents based on the compound of formula (II), and pyridine, 4-dimethylaminopyridine, triethylamine, N, N-dimethylaniline, A method using at least one base selected from tributylamine, N-methylmorpholine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride and potassium hydride. 제1항에 있어서, 반응을 0내지 80에서 수행하는 방법.The reaction of claim 1 wherein the reaction is zero. To 80 How to do it. 제6항에 있어서, 반응을 20내지 60에서 수행하는 방법.The reaction of claim 6 wherein the reaction is 20 To 60 How to do it.
KR1019950041490A 1995-10-31 1995-11-15 Method for the preparation of 2-aminothiazole carboxamide derivatives KR100218196B1 (en)

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