KR100201583B1

KR100201583B1 - Novel amino acid amide derivative and process for preparing the same

Info

Publication number: KR100201583B1
Application number: KR1019970007131A
Authority: KR
Inventors: 류요섭; 김성기; 이영호; 유성훈; 전재훈; 편승엽; 최우봉; 전성욱; 전삼재; 이성백; 박현철; 김문정; 조진호
Original assignee: 성재갑; 주식회사엘지화학
Priority date: 1996-03-06
Filing date: 1997-03-04
Publication date: 1999-06-15
Also published as: KR970065509A

Abstract

본 발명은 하기 일반식(Ⅰ)으로 표시되는 신규한 아미노산 아미드 유도체, 그의 입체이성체, 화합물을 제조하는 방법 및 이 화합물을 유효성분으로 함유하는 식물병원균에 의한 발병저해용 조성물에 관한 것이다.The present invention relates to a novel amino acid amide derivative represented by the following general formula (I), a stereoisomer thereof, a method for producing the compound, and a composition for inhibiting pathogenesis by phytopathogens containing the compound as an active ingredient.

상기식에서, X₁및 X₂는 각각 독립적으로 수소, 메톡시, 메틸 또는 할로겐을 나타내거나, X₁및 X₂가 벤젠환상의 인접한 탄소원자에 부착되어 있는 경우에 이들이 상호 결합하여 메틸렌디옥시 그룹을 형성할 수 있고, R₁은 수소, 페닐 또는 -CHR₅R₆(여기서, R₅는 수소 또는 메틸을 나타내고, R₆은 수소, C₁-C₂알킬, 하이드록시, 티올, 알킬티오메틸, 페닐 또는 하이드록시페닐을 나타낸다)을 나타내며, R₂는 수소를 나타내거나, R₂과 함께 프로필렌을 나타내고, R₃은 수소 또는

(여기서, R₄는 사이클로프로필, 클로로메틸, C₁-C₄알킬, C₁-C₄알콕시, C₁-C₃할로알콕시, 아릴옥시 또는 벤질옥시를 나타낸다)을 나타낸다.Wherein X ₁ and X ₂ each independently represent hydrogen, methoxy, methyl or halogen, or when X ₁ and X ₂ are attached to adjacent carbon atoms on a benzene ring, they are bonded to each other to form a methylenedioxy group Wherein R ₁ represents hydrogen, phenyl or —CHR ₅ R ₆ wherein R ₅ represents hydrogen or methyl and R ₆ represents hydrogen, C ₁ -C ₂ alkyl, hydroxy, thiol, alkylthiomethyl , Phenyl or hydroxyphenyl), R ₂ represents hydrogen, or propylene together with R ₂ represents R ₃ represents hydrogen or

Wherein R ₄ represents cyclopropyl, chloromethyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₃ haloalkoxy, aryloxy or benzyloxy.

Description

신규한 아미노산 아미드 유도체 및 그의 제조방법Novel amino acid amide derivatives and preparation method thereof

본 발명은 하기 일반식(Ⅰ)으로 표시되는 신규한 아미노산 아미드 유도체, 그의 입체이성체 및 그 화합물을 제조하는 방법에 관한 것이다.The present invention relates to a novel amino acid amide derivative represented by the following general formula (I), a stereoisomer thereof and a method for producing the compound.

상기 일반식(Ⅰ)의 화합물을 대표적인 유주자균주(Oomycetes)형 식물병원균인 역병균(Pythiaceae) 및 노균(Peronosporaceae)이 일으키는 식물병해에 유용하며, 여러식물을 기주로 잿빛곰팡이군(Botrytis)이 일으키는 병해에도 유용하다. 따라서 본 발명은 또한, 일반식(Ⅰ)의 화합물을 유효성분으로 함유함을 특징으로 하는 식물병원균에 의한 발병 저해용 조성물에 관한 것이다.The compound of Formula (I) is useful for plant diseases caused by Pythiaceae and Peronosporaceae, which are representative strains of Oomycetes-type phytopathogens, and are caused by gray mold groups (Botrytis) based on various plants. It is also useful for diseases. Therefore, the present invention also relates to a composition for inhibiting the onset by phytopathogens, which comprises the compound of formula (I) as an active ingredient.

본 발명과 관련하여 아미노산을 포함하는 유도체들이 역병균 및 노균의 방제에 우수한 효과를 갖는다는 사실이 이미 보고된 바 있으나(참조: DE 4,203,084 A1, DE 3,936,296 A1, EP 0,398,072 A2 및 EP 0,498,683 A1), 지금까지 보고된 기존의 유도체들은 유주자균에 대하여 좋은 활성을 나타내는 반면, 잿빛곰팡이균에 대해서는 방제효과를 나타내지 못하는 문제점을 안고 있었다. 더구나, 역병균, 노균 및 잿빛곰팡이균 등은 내성의 발형이 빠르고 실제로 기존의 약제들에 대한 저항성이 문제되고 있는 실정이므로 고활성 및 저독성을 가진 새로운 구조의 살균제에 대한 개발이 시급히 요구되고 있다.Although it has already been reported in the context of the present invention that derivatives comprising amino acids have an excellent effect on the control of late blight and the fungus (see DE 4,203,084 A1, DE 3,936,296 A1, EP 0,398,072 A2 and EP 0,498,683 A1), Existing derivatives reported so far have a good activity against S. aureus, but have a problem that does not show a control effect against ash fungus. In addition, the late blight bacteria, old bacteria and gray mold bacteria, such as the rapid development of resistance and the actual resistance to existing drugs is a problem that the development of a new structure of fungicide with high activity and low toxicity is urgently required.

이러한 요구에 부응하여 본 발명자들은 유주자균 및 잿빛곰팡이균을 동시에 방제할 수 있을 뿐아니라, 특히 잿빛곰팡이균에 유용한 살균제를 개발하기 위해 예의 연구를 계속한 결과, 상기 일반식(Ⅰ)의 신규 아미노산 아미드 유도체를 개발하고 그 효과를 확인함으로써 본 발명을 완성하게 되었다.In response to this demand, the inventors of the present invention not only can control both S. aureus and ash fungus at the same time, but also continue to study intensively to develop a fungicide useful for ash fungus, and thus, the novel amino acid of general formula (I). The present invention has been completed by developing an amide derivative and confirming its effect.

이하, 본 발명의 구성을 상세히 설명한다.Hereinafter, the configuration of the present invention will be described in detail.

본 발명은 하기 일반식(Ⅰ)의 신규한 아미노산 아미드 유도체를 제공하는 것을 목적으로 한다.An object of the present invention is to provide a novel amino acid amide derivative of the general formula (I).

상기식에서, X₁및 X₂는 각각 독립적으로 수소, 메톡시, 메틸 또는 할로겐을 나타내거나, X₁및 X₂가 벤젠환상의 인접한 탄소원자에 부착되어 있는 경우에 이들이 상호 결합하여 메틸렌디옥시 그룹을 형성할 수 있고, R₁은 수소, 페닐 또는 -CHR₅R₆(여기서, R₅는 수소 또는 메틸을 나타내고, R₆은 수소, C₁-C₂알킬, 하이드록시, 티올, 알킬티오메틸, 페닐 또는 하이드록시페닐을 나타낸다)을 나타내며, R₂는 수소를 나타내거나, R₁과 함께 프로필렌을 나타내고, R₃은 수소 또는

(여기서, R₄는 사이클로프로필, 클로로메틸, C₁-C₄알킬, C₁-C₄알콕시, C₁-C₃할로알콕시, 아릴옥시 또는 벤질옥시를 나타낸다)을 나타낸다.Wherein X ₁ and X ₂ each independently represent hydrogen, methoxy, methyl or halogen, or when X ₁ and X ₂ are attached to adjacent carbon atoms on a benzene ring, they are bonded to each other to form a methylenedioxy group Wherein R ₁ represents hydrogen, phenyl or —CHR ₅ R ₆ wherein R ₅ represents hydrogen or methyl and R ₆ represents hydrogen, C ₁ -C ₂ alkyl, hydroxy, thiol, alkylthiomethyl , Phenyl or hydroxyphenyl), R ₂ represents hydrogen or propylene together with R ₁ represents R ₃ represents hydrogen or

식물병원균에 의한 발병저해에 있어서 뛰어난 효과를 나타내는 상기 일반식(Ⅰ)의 화합물중에서도 바람직한 화합물은 X₁및 X₂는 각각 독립적으로 메톡시, 메틸 또는 할로겐을 나타내거나, X₁및 X₂가 벤젠환상의 인접한 탄소원자에 부착되어 있는 경우에 이들이 상호 결합하여 메틸렌디옥시 그룹을 형성할 수 있고, R₁은 수소, 페닐 또는 -CHR₅R₆(여기서, R₅는 수소 또는 메틸을 나타내고, R₆은 수소, 메틸, 에틸, 이소프로필, 하이드록시, 티올, 알킬티오메틸, 페닐 또는 하이드록시페닐을 나타낸다)을 나타내며, R₂는 수소이고, R₃은 수소 또는

(여기서, R₄는 2-메틸프로필옥시, t-부톡시, 아릴옥시 또는 벤질옥시를 나타낸다)을 나타내는 화합물이다.Among the compounds of the general formula (I) which exhibit excellent effects in the pathogenesis of phytopathogens, preferred compounds are those wherein X ₁ and X ₂ independently represent methoxy, methyl or halogen, or X ₁ and X ₂ are benzene. When attached to cyclic adjacent carbon atoms, they may be bonded to each other to form a methylenedioxy group, where R ₁ represents hydrogen, phenyl or —CHR ₅ R ₆ , wherein R ₅ represents hydrogen or methyl, and R ₆ represents hydrogen, methyl, ethyl, isopropyl, hydroxy, thiol, alkylthiomethyl, phenyl or hydroxyphenyl), R ₂ is hydrogen and R ₃ is hydrogen or

Wherein R ₄ represents 2-methylpropyloxy, t-butoxy, aryloxy or benzyloxy.

상기 일반식(Ⅰ)의 화합물에서 R₁이 수소인 경우에는 메톡시기가 치환된 벤질위치의 탄소원자만이 비대칭 탄소로서 R 또는 S형태와 같은 순수한 거울상이 성체 또는 R 및 S의 혼합물 형태로 존재할 수 있다. 또한, R₁이 수소원자가 아닌 경우에 R₁이 치환되어 있는 탄소원자는 메톡시가 치환되어 있는 벤질위치의 탄소원자와 함께 각각 비대칭 탄소를 형성하고 있으므로, 일반식(Ⅰ)의 화합물(D,L), (D,D), (L,D), (L,L)의 4가지 입체 이성체 형태로 존재할 수 있고, 이들 입체 이성체의 혼합물 형태로도 존재할 수 있다. 따라서, 본 발명의 범위에서 일반식(Ⅰ)의 화합물의 이러한 입체 이성체 및 그의 혼합물도 포함된다.In the compound of Formula (I), when R ₁ is hydrogen, only a carbon atom in the benzyl position in which the methoxy group is substituted may exist as an asymmetric carbon, or a pure enantiomer such as R or S form as an adult or a mixture of R and S. have. In addition, when R ₁ is not a hydrogen atom, the carbon atoms substituted with R ₁ form asymmetric carbons together with the carbon atoms at the benzyl position where methoxy is substituted, and thus compounds of general formula (I) (D, L ), (D, D), (L, D), (L, L) may exist in the form of four stereoisomers, and may also exist in the form of a mixture of these stereoisomers. Accordingly, such stereoisomers of compounds of formula (I) and mixtures thereof are also included within the scope of the present invention.

본 발명에 따른 일반식(Ⅰ)의 화합물중에서 R₃가 t-부톡시카르보닐인 하기 일반식(Ⅰ-1)의 화합물은 하기 반응도식 1에 따라 일반식(Ⅱ)의 2-메톡시-2-페닐-에틸아민 화합물을 탈수제, 용매 및 염기의 존재하에 일반식(Ⅲ)의 아미노산 유도체의 반응시킴으로서 제조할 수 있다.Among the compounds of formula (I) according to the present invention, the compound of formula (I-1) wherein R ₃ is t-butoxycarbonyl is 2-methoxy- of formula (II) according to Scheme 1 below. The 2-phenyl-ethylamine compound can be prepared by reacting an amino acid derivative of formula (III) in the presence of a dehydrating agent, a solvent and a base.

상기식에서, X₁, X₂, R₁및 R₂는 앞에서 정의한 바와 같다.Wherein X ₁ , X ₂ , R ₁ and R ₂ are as defined above.

상기 반응에서 사용가능한 탈수제로는 디사이클로헥실카르보디이미드(DCC), 1-에틸-3-(3-디메틸아미노프로필)카르보디이미드(EDC) 등의 카르보디이미드류 및 실리콘테트라클로라이드 등의 무기탈수제를 언급할 수 있다. 또한, 염기로는 피리딘, 4-디메틸아미노피리딘, 트리에틸아민, N,N-디메틸아닐린, 트리부틸아민, N-메틸모폴린 등의 유기염기를 사용할 수 있고, 용매로는 벤젠, 톨루엔, 크실렌과 같은 방향족 탄화수소류, 디클로로메탄, 1,2-디클로로에탄, 클로로포름과 같은 할로겐화탄화수소류, 디에틸에테르, 디옥산, 1,2-디메톡시에탄, 테트라하이드로푸란과 같은 에테르류, 아세톤, 메틸에틸케톤, 사이클로헥사논과 같은 케톤류, 아세토니트릴, 프리피오니트릴과 같은 니트릴류, 메틸아세테이트, 에틸아세테이트와 같은 에스테르류, N,N-디메틸포름아미드, N,N-디메틸아세트아미드, 디메틸설폭사이드와 같은 극성 용매를 사용할 수 있다. 이와 같은 탈수제, 용매 및 염기의 존재하에 반응은 -30 내지 70℃에서 수행할 수 있으나, 바람직하게는 -10 내지 30℃에서 수행하며, 반응시간은 10분 내지 24시간이 적당하다.Examples of the dehydrating agent that can be used in the reaction include inorganic compounds such as carbodiimides such as dicyclohexylcarbodiimide (DCC) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), and silicon tetrachloride. Mention may be made of dehydrating agents. As the base, organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine, N, N-dimethylaniline, tributylamine, and N-methylmorpholine can be used, and as a solvent, benzene, toluene, xylene Aromatic hydrocarbons such as dichloromethane, 1,2-dichloroethane, halogenated hydrocarbons such as chloroform, diethyl ether, dioxane, ethers such as 1,2-dimethoxyethane, tetrahydrofuran, acetone and methylethyl Ketones, ketones such as cyclohexanone, acetonitrile, nitriles such as preiononitrile, esters such as methyl acetate, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide Polar solvents can be used. In the presence of such a dehydrating agent, a solvent and a base, the reaction may be carried out at -30 to 70 ° C, preferably at -10 to 30 ° C, and a reaction time of 10 minutes to 24 hours is appropriate.

일반식(Ⅰ)의 화합물중에서 R₃가 수소인 하기 일반식(Ⅰ-2)의 화합물은 하기 반응도식 2에 따라 일반식(Ⅰ-1)의 화합물을 과량의 트리플루오로아세트산을 사용하여 가수분해시킴으로서 제조할 수 있다.Among the compounds of formula (I), compounds of formula (I-2), wherein R ₃ is hydrogen, are reacted with an excess of trifluoroacetic acid to a compound of formula (I-1) according to Scheme 2 below. It can be prepared by decomposition.

이때, 트리플루오로아세트산은 일반식(Ⅰ-1)의 화합물을 기준으로하여 3당량배 이상의 과량을 사용하며, -10 내지 30℃의 반응온도 및 30분 내지 5시간의 반응시간이 바람직하다.At this time, trifluoroacetic acid uses an excess of 3 equivalents or more based on the compound of formula (I-1), and a reaction temperature of -10 to 30 ° C and a reaction time of 30 minutes to 5 hours are preferable.

일반식(Ⅰ)의 화합물중에서 일반식(Ⅰ-1) 및 일반식(Ⅰ-2)의 화합물을 제외한 나머지 화합물, 즉 하기 일반식(Ⅰ-3)의 화합물은 하기 반응도식 3에 나타낸 바와 같이 일반식(Ⅰ-2)의 화합물을 염기 및 용매의 존재하에 하기 일반식(Ⅳ)의 산클로라이드 또는 클로로포르메이트와 반응시켜 제조할 수 있다.Among the compounds of the general formula (I), except for the compounds of the general formula (I-1) and the general formula (I-2), that is, the compound of the general formula (I-3) shown in Scheme 3 below The compound of formula (I-2) can be prepared by reaction with an acid chloride or chloroformate of formula (IV) in the presence of a base and a solvent.

상기식에서, X₁, X₂, R₁및 R₂는 앞에서 정의한 바와 같고, R₃′는 앞에서 정의한 R₃와 같으나, 단 수소와 t-부톡시카르보닐은 제외한다.Wherein R, X _1, X _2, R ₁ and R ₂ have the same meanings as defined above, R ₃ 'is R _3, but with defined above, other than stage hydrogen and t- butoxycarbonyl.

상기 반응에서 사용가능한 염기로는 피리딘, 4-디메틸아미노피리딘, 트리에틸아민, N,N-디메틸아닐린, 트리부틸아민, N-메틸모폴린 등의 유기염기를 언급할 수 있고, 용매로는 벤젠, 톨루엔, 크실렌과 같은 방향족 탄화수소류, 디클로로메탄, 1,2-디클로로에탄, 클로로포름과 같은 할로겐화탄화수소류, 디에틸에테르, 디옥산, 1,2-디메톡시에탄, 테트라하이드로푸란과 같은 에테르류, 아세토니트릴, 프로피오니트릴과 같은 니트릴류, N,N-디메틸포름아미드, N,N-디메틸아세트아미드, 디메틸설폭사이드와 같은 극성 용매를 사용할 수 있다. 반응은 -10 내지 40℃에서 10분 내지 24시간동안 수행하는 것이 바람직하다.Examples of the base usable in the reaction may include organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine, N, N-dimethylaniline, tributylamine, N-methylmorpholine, and benzene. Aromatic hydrocarbons such as toluene, xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, ethers such as diethyl ether, dioxane, 1,2-dimethoxyethane, tetrahydrofuran, Nitriles such as acetonitrile and propionitrile, polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, and dimethyl sulfoxide can be used. The reaction is preferably carried out at -10 to 40 ℃ for 10 minutes to 24 hours.

한편, 상기 반응도식 1의 방법에서 출발물질로 사용된 일반식(Ⅱ)의 2-메톡시-2-페닐-에틸아민 화합물은 하기에 설명하는 반응도식 4 또는 5의 방법에 따라 제조할 수 있다.On the other hand, 2-methoxy-2-phenyl-ethylamine compound of the general formula (II) used as a starting material in the scheme of Scheme 1 can be prepared according to the scheme of Scheme 4 or 5 described below. .

먼저, 반응도식 4의 방법은 하기 일반식(8)의 아세토페논 유도체로부터 일반식(Ⅱ)의 2-메톡시-2-페닐-에틸아민을 제조하는 방법이다.First, the method of Scheme 4 is a method of preparing 2-methoxy-2-phenyl-ethylamine of the general formula (II) from an acetophenone derivative of the following general formula (8).

상기 반응도식 4를 설명하면 다음과 같다. 일반식(7)의 화합물은 일반식(8)의 아세토페논 화합물을 브롬화반응시켜 얻을 수 있다. 이때 브롬화 시약으로는 브롬, N-브로모숙신이미드, 브롬화구리(Ⅱ) 등을 사용할 수 있고, 용매로는 벤젠, 톨루엔, 크실렌과 같은 방향족 탄화수소류, 디클로로메탄, 1,2-디클로로에탄, 클로로포름과 같은 할로겐화탄화수소류, 메틸아세테이트, 에틸아세테이트와 같은 에스테르류 등을 사용할 수 있으며, 반응온도는 브롬화시약의 종류에 따라 0 내지 100℃ 범위에서 가능하다.Referring to Scheme 4 is as follows. The compound of the general formula (7) can be obtained by bromination of the acetophenone compound of the general formula (8). In this case, bromination reagent, bromine, N-bromosuccinimide, copper bromide (II), etc. may be used, and as the solvent, aromatic hydrocarbons such as benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, Halogenated hydrocarbons such as chloroform, esters such as methyl acetate, ethyl acetate, and the like may be used, and the reaction temperature may be in the range of 0 to 100 ° C. depending on the type of bromination reagent.

일반식(5)의 하이드록시아지도화합물은 상기에서 수득한 일반식(7)의 화합물을 아지도화 반응시켜 일반식(6-1)의 아지도화합물을 먼저 제조한 후 카르보닐의 환원반응을 거쳐 제조할 수 있으며, 두 반응의 순서를 바꾸어 일반식(6-2)의 할로하이드린 화합물을 거쳐 합성할 수도 있다. 아지도화 반응에서는 아지도화나트륨을 과량(5당량 이상) 사용하며, 용매로는 N,N-디메틸포름아미드, N,N-디메틸아세트아미드, 디메틸설폭사이드등의 극성용매를 사용할 수 있고, 반응온도는 0 내지 30℃ 범위가 바람직하다. 또한, 카르보닐의 환원반응에 있어서 환원제로는 붕수소화나트륨, 수소화알루미늄리튬, 수소화붕소 등을 사용할 수 있으며 촉매 수소화반응도 가능하다. 용매로는 디에틸에테르, 디옥산, 1,2-디메톡시에탄, 테트라하이드로푸란과 같은 에테르류가 바람직하고, 0 내지 80℃의 온도에서 반응을 수행할 수 있다.The hydroxyazido compound of the general formula (5) is prepared by azido-forming the compound of the general formula (7) obtained above, to prepare the azido compound of the general formula (6-1) first, followed by reduction of carbonyl. It can be prepared through, and the order of the two reactions can be reversed and synthesized via a halohydrin compound of the general formula (6-2). In the azido reaction, an excess of sodium azidide (more than 5 equivalents) is used, and polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, and dimethyl sulfoxide may be used as the solvent. The range of 0-30 degreeC is preferable. In addition, in the reduction reaction of carbonyl, sodium borohydride, lithium aluminum hydride, boron hydride, etc. can be used as a reducing agent, and catalytic hydrogenation is also possible. As a solvent, ethers, such as diethyl ether, dioxane, 1,2-dimethoxyethane, tetrahydrofuran, are preferable, and reaction can be performed at the temperature of 0-80 degreeC.

마지막으로 일반식(5)의 하이드록시아지도화합물을 염기 및 용매의 존재하에 요오드화메탄, 디메틸설페이트 등의 메틸화제를 사용하여 일반식(4)의 메톡시아지도화합물로 변화시킨 후 이를 환원시켜 일반식(Ⅱ)의 2-메톡시-2-페닐-에틸아민 화합물을 제조할 수 있다. 메틸화반응에서 염기로는 수산화나트륨, 수산화갈륨, 탄산나트륨, 탄산칼륨, 탄사수소나트륨, 탄산수소칼륨, 수소화나트륨, 수소화칼륨 등의 무기염기를 사용할 수 있는데, 특히 수소화나트륨, 수소화칼륨 등의 금속 수소화물이 적당하며, 용매로는 디에틸에테르, 디옥산, 1,2-디메톡시에탄, 테트라하이드로푸란과 같은 에테르류, 아세톤, 메틸에틸케톤, 사이클로헥사논과 같은 케톤류, 아세토니트릴, 프로피오니트릴과 같은 니트릴류, N,N-디메틸포름아미드, N,N-디메틸아세트아미드, 디메틸설폭사이드 등의 극성용매를 사용할 수 있으나, 그중에서도 에테르류나 아미드류의 극성용매가 바람직하다. 아지도화합물을 이차 아민으로 환원시키는 반응에서 환원제로는 수소화알루미늄리튬, 트리페닐포스핀, 황화수소 등을 사용할 수 있으며, 촉매수소화반응, 아연 등의 금속을 이용한 환원반응도 가능하다. 용매로는 디클로로메탄, 1,2-디클로로에탄, 클로로포름과 같은 할로겐화탄화수소류, 디에틸에테르, 디옥산, 1,2-디메톡시에탄, 테트라이드로푸란과 같은 에테르류 등을 사용할 수 있고 필요에 따라 물과 혼합하여 사용할 수도 있다.Finally, the hydroxyazido compound of formula (5) is converted to the methoxy azido compound of formula (4) using a methylating agent such as methane iodide and dimethyl sulfate in the presence of a base and a solvent, and then reduced 2-methoxy-2-phenyl-ethylamine compound of formula (II) can be manufactured. In the methylation reaction, inorganic bases such as sodium hydroxide, gallium hydroxide, sodium carbonate, potassium carbonate, sodium carbohydrate, potassium hydrogen carbonate, sodium hydride and potassium hydride can be used. Particularly, metal hydrides such as sodium hydride and potassium hydride are used. Suitable solvents include diethyl ether, dioxane, 1,2-dimethoxyethane, ethers such as tetrahydrofuran, acetone, methyl ethyl ketone, ketones such as cyclohexanone, acetonitrile and propionitrile. Although polar solvents such as nitriles, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and the like can be used, polar solvents of ethers and amides are preferable. Lithium aluminum hydride, triphenylphosphine, hydrogen sulfide, etc. may be used as a reducing agent in the reaction for reducing the azido compound to a secondary amine, and a catalytic reaction such as catalytic hydrogenation and reduction using metals such as zinc may be possible. As the solvent, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, diethyl ether, dioxane, 1,2-dimethoxyethane, ethers such as tetrahydrofuran and the like can be used. It can also be mixed with water and used.

반응도식 5의 방법은 하기 일반식(15)의 벤즈알데히드 유도체로부터 일반식(Ⅱ)의 2-메톡시-2-페닐-에틸아민을 제조하는 방법이다.The method of Scheme 5 is a method of preparing 2-methoxy-2-phenyl-ethylamine of the general formula (II) from the benzaldehyde derivative of the following general formula (15).

상기 반응도식 5를 설명하면 다음과 같다. 일반식(13)의 α-하이드록시페닐아세트산은 공지된 방법(참조: JOC, 1954, 487)에 따라 벤즈알데히드(15)로부터 합성하여, 일반식(10)의 2-메톡시-2-페닐-에탄올은 화합물(13)을 염기존재하에 메틸화제와 반응시켜 α-메톡시페닐아세트산(12)으로 바꾼 후 공지된 방법(참조: TL, 1986, 27, 6369)에 따라 무수화합물을 중간체로 거쳐 이를 환원시킴으로서 제조할 수 있다. 또한, 2-메톡시-2-페닐-에탄올(10)을 문헌(참조: TL, 1977, 1977)에 제시된 방법에 따라 염기존재하에 메탄설포닐클로라이드와 반응시켜 일반식(9)의 화합물을 제조한 후 이를 아지도화 반응시켜 일반식(4)의 메톡시아지도화합물을 제조한 다음, 반응도식 4에서와 동일한 방법으로 용매 존재하에 환원시켜 일반식(Ⅲ)의 2-메톡시-2-페닐-에틸아민 화합물을 제조한다.Referring to the reaction scheme 5 is as follows. Α-hydroxyphenylacetic acid of formula (13) is synthesized from benzaldehyde (15) according to a known method (see JOC, 1954, 487), and 2-methoxy-2-phenyl- of formula (10) Ethanol is reacted with a methylating agent in the presence of a base (13) to be converted to α-methoxyphenylacetic acid (12) and then passed through anhydrous compounds as intermediates according to known methods (see TL, 1986, 27, 6369). It can be prepared by reduction. In addition, 2-methoxy-2-phenyl-ethanol (10) was reacted with methanesulfonyl chloride in the presence of a base according to the method given in the literature (see TL, 1977, 1977) to prepare a compound of formula (9). After the azido reaction to prepare a methoxy azido compound of formula (4), and then reduced in the presence of a solvent in the same manner as in Scheme 4 to 2-methoxy-2-phenyl- of formula (III) To prepare an ethylamine compound.

이상 설명한 제조방법들은 하기 제조예 및 실시예에서 보다 구체적으로 설명될 것이며, 이들 방법에 따라 합성한 본 발명에 따른 일반식(Ⅰ)의 화합물중 대표적인 것들은 표 1에 나타낸 바와 같다.The preparation methods described above will be described in more detail in the following Preparation Examples and Examples, and representative ones of the compounds of the general formula (I) according to the present invention synthesized according to these methods are shown in Table 1.

이하, 본 발명을 하기 제조예 및 실시예에 의거하여 보다 구체적으로 설명한다. 그러나, 이는 본 발명에 대한 이해를 돕기위한 것일 뿐 어떤 의미로든 본 발명의 범위가 이들 실시예로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following Preparation Examples and Examples. However, this is only for the understanding of the present invention, and in any sense, the scope of the present invention is not limited to these examples.

제조예 1: 2-(4-메틸-페닐)-2-메톡시-에틸아민의 제조(반응도식 4에 따른 방법)Preparation Example 1 Preparation of 2- (4-methyl-phenyl) -2-methoxy-ethylamine (method according to Scheme 4)

단계 1: 2-브로모-1-(4-메틸-페닐)-에탄온의 합성Step 1: Synthesis of 2-bromo-1- (4-methyl-phenyl) -ethanone

4-메틸아세토페논 35.9g 및 브롬화구리(Ⅱ) 119.5g을 에틸아세테이트 및 클로포름의 1:1 혼합용액(v/v) 200㎖에 가하고 5시간 동안 환류시키면서 교반한 다음 냉각시키고 생성된 고체를 걸러내었다. 여과액을 탄산수소나트륨 용액으로 세척해주고 물 및 에틸아세테이트로 추출한 다음 무수 황산마그네슘으로 건조, 증발시켜 노란 액상의 표제화합물 54.0g을 수득하였다(수율 : 95%).35.9 g of 4-methylacetophenone and 119.5 g of copper bromide were added to 200 ml of a 1: 1 mixed solution of ethyl acetate and chloroform (v / v), stirred at reflux for 5 hours, cooled, and the resulting solid was Filtered The filtrate was washed with sodium hydrogen carbonate solution, extracted with water and ethyl acetate, dried over anhydrous magnesium sulfate and evaporated to give 54.0 g of the title compound as a yellow liquid (yield: 95%).

단계 2: 2-아지도-1-(4-메틸-페닐)-에탄온의 합성Step 2: Synthesis of 2-azido-1- (4-methyl-phenyl) -ethanone

단계 1에서 수득한 2-브로모-1-(4-메틸-페닐)-에탄온 25.9g을 디메틸포름아미드 100㎖에 녹인 후, 여기에 아지드화나트륨 39.6g을 0℃에서 가하였다. 반응혼합액을 1시간 동안 0℃에서 교반한 다음, 물과 에틸아세테이트로 추출하고 무수황산마그네슘으로 건조, 증발시켜 노란액상의 표제화합물 20.4g을 수득하였다(수율 : 95%).25.9 g of 2-bromo-1- (4-methyl-phenyl) -ethanone obtained in Step 1 was dissolved in 100 ml of dimethylformamide, and 39.6 g of sodium azide was added thereto at 0 ° C. The reaction mixture was stirred for 1 hour at 0 ° C., extracted with water and ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated to give 20.4 g of the title compound as a yellow liquid (yield: 95%).

단계 3: 2-아지도-1-(4-메틸-페닐)-에탄올의 합성Step 3: Synthesis of 2-azido-1- (4-methyl-phenyl) -ethanol

단계 2에서 수득한 2-아지도-1-(4-메틸-페닐)-에탄온 20.4g을 테트라하이드로푸란 200㎖에 용해시키고 물을 1㎖ 가한 다음, 수소화붕소나트륨 5.3g을 0℃에서 가하고 동일온도에서 4시간동안 교반하였다. 0℃에서 반응액에 2N 염산수용액을 더이상 거품이 발생하지 않을 때까지 넣어준 다음 감압하에 증발시켰다. 잔류물을 물과 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 노란 액상의 표제화합물 18.5g을 수득하였다(수율 : 90%).20.4 g of 2-azido-1- (4-methyl-phenyl) -ethanone obtained in Step 2 was dissolved in 200 ml of tetrahydrofuran, 1 ml of water was added, and 5.3 g of sodium borohydride was added at 0 ° C. Stirred at the same temperature for 4 hours. 2N aqueous hydrochloric acid solution was added to the reaction solution at 0 ° C. until no more foam was generated, and then evaporated under reduced pressure. The residue was extracted with water and ethyl acetate, dried over anhydrous magnesium sulfate and evaporated to give 18.5 g of the title compound as a yellow liquid (yield: 90%).

단계 4: 1-(2-아지도-1-메톡시-에틸)-4-메틸벤젠의 합성Step 4: Synthesis of 1- (2-azido-1-methoxy-ethyl) -4-methylbenzene

단계 3에서 수득한 2-아지도-1-(4-메틸-페닐)-에탄온 2.05g을 무수 테트라하이드로푸란 20㎖에 용해시킨 후, 0℃의 질소대기하에 수소화나트륨 0.83g을 가하였다. 반응액을 5분간 교반한 다음 요오드화메탄 1.45㎖를 천천히 가하고 4시간 동안 환류시키면서 교반하였다. 반응액을 냉각시킨 후0℃에서 물 5㎖를 천천히 가하하고 감압하에서 용매를 제거하였다. 잔류물을 물과 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 노란 액상의 표제화합물 1.79g을 수득하였다(수율 : 81%).2.05 g of 2-azido-1- (4-methyl-phenyl) -ethanone obtained in Step 3 was dissolved in 20 ml of anhydrous tetrahydrofuran, and 0.83 g of sodium hydride was added under nitrogen atmosphere at 0 ° C. The reaction solution was stirred for 5 minutes, and then 1.45 mL of methane iodide was slowly added and stirred under reflux for 4 hours. After cooling the reaction solution, 5 ml of water was slowly added at 0 ° C, and the solvent was removed under reduced pressure. The residue was extracted with water and ethyl acetate, dried over anhydrous magnesium sulfate and evaporated to yield 1.79 g of the title compound as a yellow liquid (yield: 81%).

단계 5: 2-(4-메틸-페닐)-2-메톡시-에틸아민의 합성Step 5: Synthesis of 2- (4-methyl-phenyl) -2-methoxy-ethylamine

단계 4에서 수득한 1-(2-아지도-1-메톡시-에틸)-4-메틸벤젠 1.51g을 테트라하이드로푸란 10㎖에 용해시킨 후 물을 1 내지 2방울 가하였다. 반응액에 트리페닐포스핀 2.3g을 가하고 8시간 정도 교반한 다음 감압하에 용매를 제거하였다. 잔류물을 디에틸에테르와 2N 염산수용액으로 추출하였다. 수층을 수산화나트륨으로 염기화시킨 후 디에틸에테르로 다시 추출하고 무수 황산마그네슘으로 건조, 증발시켜 무색 액상의 표제화합물 1.1g을 수득하였다(수율 : 85%)1.51 g of 1- (2-azido-1-methoxy-ethyl) -4-methylbenzene obtained in step 4 was dissolved in 10 ml of tetrahydrofuran, and then 1-2 drops of water were added thereto. 2.3 g of triphenylphosphine was added to the reaction solution, the mixture was stirred for about 8 hours, and the solvent was removed under reduced pressure. The residue was extracted with diethyl ether and 2N aqueous hydrochloric acid solution. The aqueous layer was basified with sodium hydroxide, extracted again with diethyl ether, dried over anhydrous magnesium sulfate and evaporated to yield 1.1 g of the title compound as a colorless liquid (yield: 85%).

H NMR(CDCl) : δ 7.18(m, 4H), 4.12(m, 1H), 3.27(s, 3H), 2.90-2.84(m, 1H), 2.35(s, 3H) H NMR (CDCl): δ 7.18 (m, 4H), 4.12 (m, 1H), 3.27 (s, 3H), 2.90-2.84 (m, 1H), 2.35 (s, 3H)

제조예 2: 2-(2,4-디메톡시-페닐)-2-메톡시-에틸아민의 제조(반응도식 4에 따른 방법)Preparation Example 2 Preparation of 2- (2,4-dimethoxy-phenyl) -2-methoxy-ethylamine (method according to Scheme 4)

단계 1: 2-브로모-1-(2,4-디메톡시-페닐)-에탄온의 합성Step 1: Synthesis of 2-bromo-1- (2,4-dimethoxy-phenyl) -ethanone

2,4-디메톡시아세토페논 4.23g 및 브롬화구리(Ⅱ) 10.49g을 에틸아세테이트 및 클로포름의 1:1 혼합용액(v/v) 100㎖에 가하고 5시간 동안 환류시키면서 교반한 다음 냉각시키고 생성된 고체를 걸러내었다. 여과액을 탄산수소나트륨 용액으로 세척해주고 물 및 에틸아세테이트로 추출한 다음 무수 황산마그네슘으로 건조, 증발시켜 노란 액상의 표제화합물 5.72g을 수득하였다(수율 : 94%).4.23 g of 2,4-dimethoxyacetophenone and 10.49 g of copper (II) bromide were added to 100 ml of a 1: 1 mixed solution of ethyl acetate and chloroform (v / v), stirred at reflux for 5 hours, cooled, and formed. Filtered solids. The filtrate was washed with sodium hydrogen carbonate solution, extracted with water and ethyl acetate, dried over anhydrous magnesium sulfate and evaporated to give 5.72 g of the title compound as a yellow liquid (yield: 94%).

단계 2: 2-브로모-1-(2,4-디메톡시-페닐)-에탄올의 합성Step 2: Synthesis of 2-bromo-1- (2,4-dimethoxy-phenyl) -ethanol

단계 1에서 수득한 2-브로모-1-(2,4-디메톡시-페닐)-에탄온 1.14g을 테트라하이드로푸란 10㎖에 용해시키고 물 1 내지 2방울을 가한다음, 수소화붕소나트륨 0.20g을 0℃에서 가하고 동온도에서 4시간동안 교반하였다. 0℃에서 반응액에 2N염산수용액을 더이상 거품이 발생하지 않을 때까지 넣어준 다음 감압하에 증발시켰다. 잔류물을 물과 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 흰색 고체의 표제화합물 0.94g을 수득하였다(수율 : 82%).Dissolve 1.14 g of 2-bromo-1- (2,4-dimethoxy-phenyl) -ethanone obtained in Step 1 in 10 ml of tetrahydrofuran, add 1-2 drops of water, and then 0.20 g of sodium borohydride. Was added at 0 ° C. and stirred at the same temperature for 4 hours. 2N aqueous hydrochloric acid solution was added to the reaction solution at 0 ° C. until no more foam was generated, and then evaporated under reduced pressure. The residue was extracted with water and ethyl acetate, dried over anhydrous magnesium sulfate and evaporated to yield 0.94 g of the title compound as a white solid (yield: 82%).

단계 3: 2-아지도-1-(2,4-디메톡시-페닐)-에탄올의 합성Step 3: Synthesis of 2-azido-1- (2,4-dimethoxy-phenyl) -ethanol

단계 2에서 수득한 2-브로모-1-(2,4-디메톡시-페닐)-에탄올 3.15g을 디메틸포름아미드 20㎖에 녹인 후, 여기에 아지드화나트륨 3.92g을 0℃에서 가하였다. 반응혼합액을 1시간 동안 0℃에서 교반한 다음, 다량의 물과 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 흰색 고체의 표제화합물 2.32g을 수득하였다(수율 : 86%).3.15 g of 2-bromo-1- (2,4-dimethoxy-phenyl) -ethanol obtained in Step 2 was dissolved in 20 ml of dimethylformamide, and 3.92 g of sodium azide was added thereto at 0 ° C. . The reaction mixture was stirred at 0 ° C. for 1 hour, extracted with a large amount of water and ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated to yield 2.32 g of the title compound as a white solid (yield: 86%).

단계 4: 1-(2-아지도-1-메톡시-에틸)-2,4-디메톡시벤젠의 합성Step 4: Synthesis of 1- (2-azido-1-methoxy-ethyl) -2,4-dimethoxybenzene

단계 3에서 수득한 2-아지도-1-(2,4-디메톡시-페닐)-에탄올 0.50g을 무수 테트라하이드로푸란 20㎖에 용해시킨 후, 0℃의 질소대기하에 수소화나트륨 0.16g을 가하였다. 반응액을 5분간 교반한 다음 요오드화메탄 0.28㎖를 천천히 가하고 4시간동안 환류시키면서 교반하였다. 반응액을 냉각시킨 후 0℃에서 물 5㎖를 천천히 가하고 감압하에서 용매를 제거하였다. 잔류물을 물과 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 노란 액상의 표제화합물 0.41g을 수득하였다(수율 : 78%).0.50 g of 2-azido-1- (2,4-dimethoxy-phenyl) -ethanol obtained in Step 3 was dissolved in 20 ml of anhydrous tetrahydrofuran, and then 0.16 g of sodium hydride was added under nitrogen atmosphere at 0 ° C. It was. The reaction solution was stirred for 5 minutes, and then 0.28 ml of methane iodide was slowly added and stirred under reflux for 4 hours. After cooling the reaction solution, 5 ml of water was slowly added at 0 ° C, and the solvent was removed under reduced pressure. The residue was extracted with water and ethyl acetate, dried over anhydrous magnesium sulfate and evaporated to yield 0.41 g of the title compound as a yellow liquid (yield: 78%).

단계 5: 2-(2,4-디메톡시-페닐)-2-메톡시-에틸아민의 합성Step 5: Synthesis of 2- (2,4-dimethoxy-phenyl) -2-methoxy-ethylamine

단계 4에서 수득한 1-(2-아지도-1-메톡시-에틸)-2,4-디메톡시벤젠 0.09g을 테트라하이드로푸란 10㎖에 용해시킨 후 물을 1 내지 2방울 가하였다. 반응액에 트리페닐포스핀 0.11g을 가하고 8시간 정도 교반한 다음 감압하에 용매를 제거하였다. 잔류물을 디에틸에테르와 2N 염산수용액으로 추출하였다. 수층을 수산화나트륨으로 염기화시킨 후 디에틸에테르로 다시 추출하고 무수 황산마그네슘으로 건조, 증발시켜 무색 액상의 표제화합물 0.065g을 수득하였다(수율 : 82%).0.09 g of 1- (2-azido-1-methoxy-ethyl) -2,4-dimethoxybenzene obtained in Step 4 was dissolved in 10 ml of tetrahydrofuran, and then 1-2 drops of water were added thereto. 0.11 g of triphenylphosphine was added to the reaction solution, the mixture was stirred for about 8 hours, and the solvent was removed under reduced pressure. The residue was extracted with diethyl ether and 2N aqueous hydrochloric acid solution. The aqueous layer was basified with sodium hydroxide, extracted again with diethyl ether, dried over anhydrous magnesium sulfate, and evaporated to yield 0.065 g of a colorless liquid title compound (yield: 82%).

H NMR(CDCl) : δ 7.20(m, 1H), 6.45(m, 2H), 4.55(m, 1H), 3.80(d, 6H), 3.27(s, 3H), 2.82(m, 2H) H NMR (CDCl): δ 7.20 (m, 1H), 6.45 (m, 2H), 4.55 (m, 1H), 3.80 (d, 6H), 3.27 (s, 3H), 2.82 (m, 2H)

제조예 3: 2-(2,4-디클로로-페닐)-2-메톡시-에틸아민의 제조(반응도식 5에 따른 합성)Preparation Example 3 Preparation of 2- (2,4-Dichloro-phenyl) -2-methoxy-ethylamine (Synthesis according to Scheme 5)

단계 1: (2,4-디클로로-페닐)-하이드록시-아세토니트릴의 합성Step 1: Synthesis of (2,4-dichloro-phenyl) -hydroxy-acetonitrile

2,4-디클로로-벤즈알데히드 17g 및 시안화나트륨 6g을 디에틸에테르 20㎖에 가하고, 여기에 진한 염산 15㎖를 0℃에서 천천히 떨어뜨렸다. 상온에서 6시간동안 교반한 다음 다량의 물로 세척하였다. 무수 황산마그네슘으로 건조시키고 증발시켜 흰색 고체의 표제화합물 18.9g을 수득하였다(수율 : 97%).17 g of 2,4-dichloro-benzaldehyde and 6 g of sodium cyanide were added to 20 ml of diethyl ether, and 15 ml of concentrated hydrochloric acid was slowly dropped at 0 deg. After stirring for 6 hours at room temperature and washed with a large amount of water. Drying over anhydrous magnesium sulfate and evaporation gave 18.9 g of the title compound as a white solid (yield: 97%).

단계 2: (2,4-디클로로-페닐)-하이드록시-아세트산의 합성Step 2: Synthesis of (2,4-dichloro-phenyl) -hydroxy-acetic acid

단계 1에서 수득한 (2,4-디클로로-페닐)-하이드록시-아세토니트릴 18.9g에 진한 염산 20㎖를 가하고 녹인 후 환류시키면서 4시간 동안 교반하였다. 반응액을 냉각시키고 디에틸에테르로 추출한 후 무수 황산마그네슘으로 건조, 증발시켜 흰색고체의 표제화합물 19.44g을 수득하였다(수율 : 94%).To 18.9 g of (2,4-dichloro-phenyl) -hydroxy-acetonitrile obtained in Step 1 was added 20 ml of concentrated hydrochloric acid, dissolved, and stirred for 4 hours while refluxing. The reaction solution was cooled, extracted with diethyl ether, dried over anhydrous magnesium sulfate, and evaporated to yield 19.44 g of the title compound as a white solid (yield: 94%).

단계 3: (2,4-디클로로-페닐)-메톡시-아세트산의 합성Step 3: Synthesis of (2,4-dichloro-phenyl) -methoxy-acetic acid

단계 2에서 수득한 (2,4-디클로로-페닐)-하이드록시-아세트산 8.0g을 무수 테트라하이드로푸란 80㎖에 녹인 후 0℃의 질소대기하에 수소화나트륨 5.5g을 넣어 주었다. 반응액을 10분간 교반한 후 요오드화메탄 4.6㎖를 천천히 가하고 4시간동안 환류시키면서 교반하였다. 반응액을 냉각시키고 0℃에서 물 50㎖를 천천히 가한 후 감압하에서 용매를 제거하였다. 잔류물을 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 흰색고체의 표제화합물 7.24g을 수득하였다(수율 : 85%).8.0 g of (2,4-dichloro-phenyl) -hydroxy-acetic acid obtained in step 2 was dissolved in 80 ml of anhydrous tetrahydrofuran, and 5.5 g of sodium hydride was added under nitrogen atmosphere at 0 ° C. The reaction solution was stirred for 10 minutes, and then 4.6 mL of methane iodide was slowly added thereto and stirred while refluxing for 4 hours. The reaction solution was cooled, 50 mL of water was slowly added at 0 ° C, and the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated to yield 7.24 g of the title compound as a white solid (yield: 85%).

단계 4: 카르본산[(2,4-디클로로-페닐)-메톡시-아세틸]에스테르 메틸 에스테르의 합성Step 4: Synthesis of Carbonic Acid [(2,4-Dichloro-phenyl) -methoxy-acetyl] ester Methyl Ester

단계 3에서 수득한 (2,4-디클로로-페닐)-메톡시-아세트산 2.5g, 메틸클로로포르메이트 2.0㎖ 및 탄산칼륨 6g을 아세토니트릴 20㎖에 넣고 6시간 동안 환류시키면서 교반하였다. 반응액을 냉각시킨 후 물과 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 흰색고체의 표제화합물 2.76g을 수득하였다(수율 : 88%).2.5 g of (2,4-dichloro-phenyl) -methoxy-acetic acid obtained in Step 3, 2.0 ml of methylchloroformate and 6 g of potassium carbonate were added to 20 ml of acetonitrile and stirred under reflux for 6 hours. The reaction mixture was cooled, extracted with water and ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated to yield 2.76 g of the title compound as a white solid (yield: 88%).

단계 5: 2-(2,4-디클로로-페닐)-2-메톡시-에탄올의 합성Step 5: Synthesis of 2- (2,4-Dichloro-phenyl) -2-methoxy-ethanol

단계 4에서 수득한 카르본산[(2,4-디클로로-페닐)-메톡시-아세틸)]에스테르메틸 에스테르 2.76g을 테트라하이드로푸란 20㎖에 용해시키고 물을 한두방울 넣어 주었다. 반응액에 수소화붕소나트륨 0.43g을 0℃에서 가한 다음 동온도에서 4시간 동안 교반하였다. 0℃에서 2N 염산 수용액을 더이상 거품이 발생하지 않을 때까지 가한 다음 감압하에 증발시켰다. 잔류물을 물과 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 흰색고체의 표제화합물 1.75g을 수득하였다(수율 : 84%).2.76 g of carboxylic acid [(2,4-dichloro-phenyl) -methoxy-acetyl)] estermethyl ester obtained in step 4 was dissolved in 20 ml of tetrahydrofuran, and one or two drops of water were added thereto. 0.43 g of sodium borohydride was added to the reaction solution at 0 ° C. and stirred at the same temperature for 4 hours. At 0 ° C., 2N hydrochloric acid aqueous solution was added until no further foaming occurred and then evaporated under reduced pressure. The residue was extracted with water and ethyl acetate, dried over anhydrous magnesium sulfate and evaporated to yield 1.75 g of the title compound as a white solid (yield: 84%).

단계 6: 메탄설폰산 2-(2,4-디클로로-페닐)-2-메톡시-에틸 에스테르의 합성Step 6: Synthesis of Methanesulfonic Acid 2- (2,4-Dichloro-phenyl) -2-methoxy-ethyl ester

단계 5에서 수득한 2-(2,4-디클로로-페닐)-2-메톡시-에탄올 1.90g을 디클로로메탄 20㎖에 녹이고 트리에틸아민 1.0㎖를 가한 다음, 0℃에서 메탄설포닐클로라이드 0.8㎖를 서서히 가하고 상온에서 4시간 정도 교반하였다. 반응액을 물과 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 흰색고체의 표제화합물 2.43g을 수득하였다(수율 : 94%).1.90 g of 2- (2,4-dichloro-phenyl) -2-methoxy-ethanol obtained in step 5 was dissolved in 20 ml of dichloromethane, 1.0 ml of triethylamine was added, and then 0.8 ml of methanesulfonyl chloride at 0 ° C. Was added slowly and stirred at room temperature for about 4 hours. The reaction solution was extracted with water and ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated to yield 2.43 g of the title compound as a white solid (yield: 94%).

단계 7: 1-(2-아지도-1-메톡시-에틸)-2,4-디클로로벤젠의 합성Step 7: Synthesis of 1- (2-azido-1-methoxy-ethyl) -2,4-dichlorobenzene

단계 6에서 수득한 메탄설폰산 2-(2,4-디클로로-페닐)-2-메톡시-에틸 에스테르 2.43g을 디메틸포름아미드 20㎖에 녹인 후 아지드화나트륨 1.83g을 가하였다. 반응액을 90℃로 가열하면서 4시간 정도 교반한 다음, 다량의 물과 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 흰색고체의 표제화합물 1.85g을 수득하였다(수율 : 93%).2.43 g of methanesulfonic acid 2- (2,4-dichloro-phenyl) -2-methoxy-ethyl ester obtained in step 6 was dissolved in 20 ml of dimethylformamide, and then 1.83 g of sodium azide was added. The reaction solution was stirred for 4 hours while heating to 90 ° C., extracted with a large amount of water and ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated to yield 1.85 g of the title compound as a white solid (yield: 93%).

단계 8: 2-(2,4-디클로로-페닐)-2-메톡시-에틸아민의 합성Step 8: Synthesis of 2- (2,4-dichloro-phenyl) -2-methoxy-ethylamine

단계 7에서 수득한 1-(2-아지도-1-메톡시-에틸)-2,4-디메톡시벤젠 0.09g을 테트라하이드로푸란 10㎖에 녹인 후 물을 1 내지 2방울 넣었다. 반응액에 트리페닐스핀 0.11g을 가하고 8시간 정도 교반한 다음 감압하에 용매를 제거하였다. 잔류물을 디에틸에테르와 2N 염산수용액으로 추출하고, 수층을 수산화나트륨으로 염기화시킨 후 디에틸에테르로 다시 추출하였다. 추출물을 무수 황산마그네슘으로 건조, 증발시켜 흰색고체의 표제화합물 0.065g을 수득하였다(수율 : 82%).0.09 g of 1- (2-azido-1-methoxy-ethyl) -2,4-dimethoxybenzene obtained in Step 7 was dissolved in 10 ml of tetrahydrofuran, and then 1 to 2 drops of water were added thereto. 0.11 g of triphenylspin was added to the reaction solution, the mixture was stirred for about 8 hours, and the solvent was removed under reduced pressure. The residue was extracted with diethyl ether and 2N aqueous hydrochloric acid solution, the aqueous layer was basified with sodium hydroxide and then extracted again with diethyl ether. The extract was dried over anhydrous magnesium sulfate and evaporated to yield 0.065 g of the title compound as a white solid (yield: 82%).

H NMR(CDCl) : δ 7.45-7.23(m, 3H), 4.55(m, 1H), 3.30(s, 3H), 2.95-2.65(m, 2H) H NMR (CDCl): δ 7.45-7.23 (m, 3H), 4.55 (m, 1H), 3.30 (s, 3H), 2.95-2.65 (m, 2H)

상기 제조예 1,2,3에서와 동일한 방법으로 수행하여 일반식(Ⅱ)의 2-메톡시-2-페닐-에틸아민 유도체들을 합성하였다.2-methoxy-2-phenyl-ethylamine derivatives of the general formula (II) were synthesized in the same manner as in Preparation Examples 1,2 and 3 above.

[실시예 1]Example 1

(DL,L)-2-t-부톡시카르보닐아미노-N-12-(4-메틸-페닐)-2-메톡시-에틸]-3-메틸-부티르아미드(8)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-N-12- (4-methyl-phenyl) -2-methoxy-ethyl] -3-methyl-butyramide (8)

N-t-부톡시카르보닐 L-발린 0.13g, 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 염산염 0.12g, 1-하이드록시벤조트리아졸 수화물 0.081g 및 트리에틸아민 0.084㎖를 디메틸포름아미드 5㎖에 가하고 0℃에서 10분간 교반한 다음, 여기에 2-(4-메틸-페닐)-2-메톡시-에틸아민 0.090g을 가하고 2시간 동안 교반하였다. 반응액을 다량의 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 표제화합물 0.16g을 수득하였다(수율 : 82%).0.13 g of Nt-butoxycarbonyl L-valine, 0.12 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.081 g of 1-hydroxybenzotriazole hydrate and 0.084 ml of triethylamine To 5 ml of formamide was added and stirred for 10 minutes at 0 ° C., after which 0.090 g of 2- (4-methyl-phenyl) -2-methoxy-ethylamine was added and stirred for 2 hours. The reaction solution was extracted with a large amount of ethyl acetate, dried over anhydrous magnesium sulfate and evaporated to yield 0.16 g of the title compound (yield: 82%).

[실시예 2]Example 2

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-루신 0.14g을 사용하는 점을 제외하고는 실시예 1과 동일한 방법으로 수행하여 표제화합물 0.17g을 수득하였다(수율 : 84%)0.17 g of the title compound was obtained in the same manner as in Example 1, except that 0.14 g of Nt-butoxycarbonyl L-leucine was used instead of Nt-butoxycarbonyl L-valine (yield: 84 %)

[실시예 3]Example 3

(DL,L)-2-t-부톡시카르보닐아미노-3-메틸-펜탄산[2-(4-메틸-페닐)-2-메톡시-에틸]-아미드(10)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-3-methyl-pentanoic acid [2- (4-methyl-phenyl) -2-methoxy-ethyl] -amide (10)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-이소루신 0.14g을 사용하는 점을 제외하고는 실시예 1에서와 동일한 방법으로 수행하여 표제화합물 0.18g을 수득하였다(수율 : 85%).0.18 g of the title compound was obtained in the same manner as in Example 1, except that 0.14 g of Nt-butoxycarbonyl L-isoleucine was used instead of Nt-butoxycarbonyl L-valine (yield) : 85%).

[실시예 4]Example 4

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(4-메틸-페닐)-2-메톡시-에틸]-3-페닐-프로피온아미드(11)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-N- [2- (4-methyl-phenyl) -2-methoxy-ethyl] -3-phenyl-propionamide (11)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-페닐알라닌 0.15g을 사용하는 점을 제외하고는 실시예 1에서와 동일한 방법으로 수행하여 표제화합물 0.20g을 수득하였다(수율 : 87%).0.20 g of the title compound was obtained in the same manner as in Example 1, except that 0.15 g of Nt-butoxycarbonyl L-phenylalanine was used instead of Nt-butoxycarbonyl L-valine (yield: 87%).

[실시예 5]Example 5

(DL,L)-2-[N-{2-(4-메틸페닐)-2-메톡시-에틸}카르바모일]-피롤리딘-1-카르복실산 t-부틸에스테르(12) 합성(DL, L) -2- [N- {2- (4-methylphenyl) -2-methoxy-ethyl} carbamoyl] -pyrrolidine-1-carboxylic acid t-butyl ester (12) Synthesis

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-프롤린 0.12g을 사용하는 점을 제외하고는 실시예 1에서와 동일한 방법으로 수행하여 표제화합물 0.17g을 수득하였다(수율 : 87%).0.17 g of the title compound was obtained in the same manner as in Example 1, except that 0.12 g of Nt-butoxycarbonyl L-proline was used instead of Nt-butoxycarbonyl L-valine (yield: 87%).

[실시예 6]Example 6

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(4-메틸-페닐)-2-메톡시-에틸]-2-페닐-아세트아미드(13)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-N- [2- (4-methyl-phenyl) -2-methoxy-ethyl] -2-phenyl-acetamide (13)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 (s)-(2)-레닐글리신 0.14g을 사용하는 점을 제외하고는 실시예 1에서와 동일한 방법으로 수행하여 표제화합물 0.18g을 수득하였다(수율 : 85%).The title compound 0.18 was carried out in the same manner as in Example 1, except that 0.14 g of Nt-butoxycarbonyl (s)-(2) -renylglycine was used instead of Nt-butoxycarbonyl L-valine. g was obtained (yield: 85%).

[실시예 8]Example 8

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(2,4-디메톡시-페닐)-2-메톡시-에틸]-3-페닐-프로피온아미드(2)의 합성Of (DL, L) -2-t-butoxycarbonylamino-N- [2- (2,4-dimethoxy-phenyl) -2-methoxy-ethyl] -3-phenyl-propionamide (2) synthesis

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-페닐알라닌 0.11g을 사용하는 점을 제외하고는 실시예 7에서와 동일한 방법으로 수행하여 표제화합물 0.13g을 수득하였다(수율 : 74%).0.13 g of the title compound was obtained in the same manner as in Example 7, except that 0.11 g of Nt-butoxycarbonyl L-phenylalanine was used instead of Nt-butoxycarbonyl L-valine (yield: 74%).

[실시예 9]Example 9

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(3,4-메틸렌디옥시-페닐)-2-메톡시-에틸]-3-페닐-부티르아미드(3)의합성(DL, L) -2-t-butoxycarbonylamino-N- [2- (3,4-methylenedioxy-phenyl) -2-methoxy-ethyl] -3-phenyl-butyramide (3 Synthesis of

N-t-부톡시카르보닐 L-발린 0.11g, 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 염산염 0.097g, 1-하이드록시벤조트리아졸 수화물 0.069g 및 트리에틸아민 0.071㎖를 디메틸포름아미드 5㎖에 가하고 0℃에서 10분간 교반시킨 다음, 2-(벤조[1,3]디옥솔란-5-일)-2-메톡시-에틸아민 0.090g을 가하고 2시간 동안 교반하였다. 반응액을 다량의 물과 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 표제화합물 0.15g을 수득하였다(수율 : 85%).0.11 g of Nt-butoxycarbonyl L-valine, 0.097 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.069 g of 1-hydroxybenzotriazole hydrate and 0.071 ml of triethylamine 5 ml of formamide was added and stirred at 0 ° C. for 10 minutes, and then 0.090 g of 2- (benzo [1,3] dioxolan-5-yl) -2-methoxy-ethylamine was added and stirred for 2 hours. The reaction solution was extracted with a large amount of water and ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated to yield 0.15 g of the title compound (yield: 85%).

[실시예 10]Example 10

(DL,L)-2-t-부톡시카르보닐아미노-4-메틸-펜탄산[2-(3,4-메틸렌디옥시-페닐)-2-메톡시-에틸]-아미드(4)의 합성Of (DL, L) -2-t-butoxycarbonylamino-4-methyl-pentanoic acid [2- (3,4-methylenedioxy-phenyl) -2-methoxy-ethyl] -amide (4) synthesis

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-루신 0.11g을 사용하는 점을 제외하고는 실시예 9에서와 동일한 방법으로 수행하여 표제화합물 0.15g을 수득하였다(수율 : 81%).0.15 g of the title compound was obtained in the same manner as in Example 9, except that 0.11 g of Nt-butoxycarbonyl L-leucine was used instead of Nt-butoxycarbonyl L-valine (yield: 81%).

[실시예 11]Example 11

(DL,L)-2-t-부톡시카르보닐아미노-3-메틸-펜탄산[2-(3,4-메틸렌디옥시-페닐)-2-메톡시-에틸]-아미드(5)의 합성Of (DL, L) -2-t-butoxycarbonylamino-3-methyl-pentanoic acid [2- (3,4-methylenedioxy-phenyl) -2-methoxy-ethyl] -amide (5) synthesis

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-이소루신 0.11g을 사용하는 점을 제외하고는 실시예 9에서와 동일한 방법으로 수행하여 표제화합물 0.16g을 수득하였다(수율 : 83%).0.16 g of the title compound was obtained in the same manner as in Example 9, except that 0.11 g of Nt-butoxycarbonyl L-isoleucine was used instead of Nt-butoxycarbonyl L-valine (yield) : 83%).

[실시예 12]Example 12

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(3,4-메틸렌디옥시-페닐)-2-메톡시-에틸]-3-페닐-프로피온아미드(6)의합성(DL, L) -2-t-butoxycarbonylamino-N- [2- (3,4-methylenedioxy-phenyl) -2-methoxy-ethyl] -3-phenyl-propionamide (6) Synthesis

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-페닐알라닌 0.13g을 사용하는 점을 제외하고는 실시예 9에서와 동일한 방법으로 수행하여 표제화합물 0.15g을 수득하였다(수율 : 82%)0.15 g of the title compound was obtained in the same manner as in Example 9, except that 0.13 g of Nt-butoxycarbonyl L-phenylalanine was used instead of Nt-butoxycarbonyl L-valine (yield: 82%)

[실시예 13]Example 13

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(3,4-메틸렌디옥시-페닐)-2-메톡시-에틸]-3-페닐-아세트아미드(7)의 합성(DL, L) -2-t-butoxycarbonylamino-N- [2- (3,4-methylenedioxy-phenyl) -2-methoxy-ethyl] -3-phenyl-acetamide (7) Synthesis of

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 (s)-(2)-페닐글리신 0.12g을 사용하는 점을 제외하고는 실시예 9에서와 동일한 방법으로 수행하여 표제화합물 0.15g을 수득하였다(수율 : 85%).The title compound was obtained in the same manner as in Example 9, except that 0.12 g of Nt-butoxycarbonyl (s)-(2) -phenylglycine was used instead of Nt-butoxycarbonyl L-valine. g was obtained (yield: 85%).

[실시예 14]Example 14

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(4-클로로-페닐)-2-메톡시-에틸]-3-메틸-부티르아미드(19)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-N- [2- (4-chloro-phenyl) -2-methoxy-ethyl] -3-methyl-butyramide (19)

N-t-부톡시카르보닐 L-발린 0.11g, 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 염산염 0.101g, 1-하이드록시벤조트리아졸 수화물 0.070g 및 트리에틸아민 0.074㎖를 디메틸포름아미드 5㎖에 가하고 0℃에서 10분간 교반한 다음, 여기에 2-(4-클로로-페닐)-2-메톡시-에틸아민 0.090g을 가하고 2시간 동안 교반하였다. 반응액을 다량의 물과 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 표제화합물 0.14g을 수득하였다(수율 : 77%).0.11 g of Nt-butoxycarbonyl L-valine, 0.101 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.070 g of 1-hydroxybenzotriazole hydrate and 0.074 ml of triethylamine To 5 ml of formamide was added and stirred for 10 minutes at 0 ° C., after which 0.090 g of 2- (4-chloro-phenyl) -2-methoxy-ethylamine was added and stirred for 2 hours. The reaction solution was extracted with a large amount of water and ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated to yield 0.14 g of the title compound (yield: 77%).

[실시예 15]Example 15

(DL,L)-2-t-부톡시카르보닐아미노-4-메틸-펜탄산[2-(4-클로로-페닐)2-메톡시-에틸]-아미드(20)의합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-4-methyl-pentanoic acid [2- (4-chloro-phenyl) 2-methoxy-ethyl] -amide (20)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-루신 0.12g을 사용하는 점을 제외하고는 실시예 14에서와 동일한 방법으로 수행하여 표제화합물 0.15g을 수득하였다(수율 : 80%).0.15 g of the title compound was obtained in the same manner as in Example 14, except that 0.12 g of Nt-butoxycarbonyl L-leucine was used instead of Nt-butoxycarbonyl L-valine (yield: 80%).

[실시예 16]Example 16

(DL,L)-2-t-부톡시카르보닐아미노-4-메틸-펜탄산[2-(4-클로로-페닐)2-메톡시-에틸]-아미드(21)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-4-methyl-pentanoic acid [2- (4-chloro-phenyl) 2-methoxy-ethyl] -amide (21)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-이소루신 0.14g을 사용하는 점을 제외하고는 실시예 14에서와 동일한 방법으로 수행하여 표제화합물 0.15g을 수득하였다(수율 : 76%).0.15 g of the title compound was obtained in the same manner as in Example 14, except that 0.14 g of Nt-butoxycarbonyl L-isoleucine was used instead of Nt-butoxycarbonyl L-valine (yield) : 76%).

[실시예 17]Example 17

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-페닐알라닌 0.13g을 사용하는 점을 제외하고는 실시예 14에서와 동일한 방법으로 수행하여 표제화합물 0.16g을 수득하였다(수율 : 78%).0.16 g of the title compound was obtained in the same manner as in Example 14, except that 0.13 g of Nt-butoxycarbonyl L-phenylalanine was used instead of Nt-butoxycarbonyl L-valine (yield: 78%).

[실시예 18]Example 18

(DL,L)-2-[N-{2-(4-클로로페닐)-2-메톡시-에틸}카르바모일]-피롤리딘-1-카르복실산 t-부틸 에스테르(23)의 합성Of (DL, L) -2- [N- {2- (4-chlorophenyl) -2-methoxy-ethyl} carbamoyl] -pyrrolidine-1-carboxylic acid t-butyl ester (23) synthesis

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-프롤린 0.12g을 사용하는 점을 제외하고는 실시예 14에서와 동일한 방법으로 수행하여 표제화합물 0.15g을 수득하였다(수율 : 77%).0.15 g of the title compound was obtained in the same manner as in Example 14, except that 0.12 g of Nt-butoxycarbonyl L-proline was used instead of Nt-butoxycarbonyl L-valine (yield: 77%).

[실시예 19]Example 19

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(3,4-디클로로-페닐)-2-메톡시-에틸]-3-메틸-부티르아미드(24)의 합성Of (DL, L) -2-t-butoxycarbonylamino-N- [2- (3,4-dichloro-phenyl) -2-methoxy-ethyl] -3-methyl-butyramide (24) synthesis

N-t-부톡시카르보닐 L-발린 0.093g, 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 염산염 0.086g, 1-하이드록시벤조트리아졸 수화물 0.061g 및 트리에틸아민 0.063㎖를 디메틸포름아미드 5㎖에 가하고 0℃에서 10분간 교반한 다음, 여기에 2-(3,4-디클로로-페닐)-2-메톡시-에틸아민 0.090g을 가하고 2시간 동안 교반하였다. 반응액을 다량의 물과 에틸아세테이트로 추출한 다음 무수 황산마그네슘으로 건조, 증발시켜 표제화합물 0.15g을 수득하였다(수율 : 85%).0.093 g of Nt-butoxycarbonyl L-valine, 0.086 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.061 g of 1-hydroxybenzotriazole hydrate and 0.063 ml of triethylamine To 5 ml of formamide was added and stirred at 0 ° C. for 10 minutes, and then 0.090 g of 2- (3,4-dichloro-phenyl) -2-methoxy-ethylamine was added thereto and stirred for 2 hours. The reaction solution was extracted with a large amount of water and ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated to yield 0.15 g of the title compound (yield: 85%).

[실시예 20]Example 20

(DL,L)-2-t-부톡시카르보닐아미노-4-메틸-펜탄산[2-(3,4-디클로로-페닐)-2-메톡시-에틸]-아미드(25)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-4-methyl-pentanoic acid [2- (3,4-dichloro-phenyl) -2-methoxy-ethyl] -amide (25)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-루신 0.10g을 사용하는 점을 제외하고는 실시예 19에서와 동일한 방법으로 수행하여 표제화합물 0.15g을 수득하였다(수율 : 80%).0.15 g of the title compound was obtained in the same manner as in Example 19, except that 0.10 g of Nt-butoxycarbonyl L-leucine was used instead of Nt-butoxycarbonyl L-valine (yield: 80%).

[실시예 21]Example 21

(DL,L)-2-t-부톡시카르보닐아미노-3-메틸-펜탄산[2-(3,4-디클로로-페닐)-2-메톡시-에틸]-아미드(26)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-3-methyl-pentanoic acid [2- (3,4-dichloro-phenyl) -2-methoxy-ethyl] -amide (26)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-이소루신 0.10g을 사용하는 점을 제외하고는 실시예 19에서와 동일한 방법으로 수행하여 표제화합물 0.14g을 수득하였다(수율 : 80%).0.14 g of the title compound was obtained in the same manner as in Example 19, except that 0.10 g of Nt-butoxycarbonyl L-isoleucine was used instead of Nt-butoxycarbonyl L-valine (yield) : 80%).

[실시예 22]Example 22

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(3,4-디클로로-페닐)-2-메톡시-에틸]-3-페닐-프로피온아미드(27)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-N- [2- (3,4-dichloro-phenyl) -2-methoxy-ethyl] -3-phenyl-propionamide (27)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-페닐알라닌 0.11g을 사용하는 점을 제외하고는 실시예 19에서와 동일한 방법으로 수행하여 표제화합물 0.15g을 수득하였다(수율 : 78%).0.15 g of the title compound was obtained in the same manner as in Example 19, except that 0.11 g of Nt-butoxycarbonyl L-phenylalanine was used instead of Nt-butoxycarbonyl L-valine (yield: 78%).

[실시예 23]Example 23

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(3,4-디클로로-페닐)2-메톡시-에틸]-2-페닐-아세트아미드(28)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-N- [2- (3,4-dichloro-phenyl) 2-methoxy-ethyl] -2-phenyl-acetamide (28)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 (s)-(2)-페닐글리신 0.13g을 사용하는 점을 제외하고는 실시예 19에서와 동일한 방법으로 수행하여 표제화합물 0.16g을 수득하였다(수율 : 86%).The title compound 0.16 was carried out in the same manner as in Example 19, except that 0.13 g of Nt-butoxycarbonyl (s)-(2) -phenylglycine was used instead of Nt-butoxycarbonyl L-valine. g was obtained (yield: 86%).

[실시예 24]Example 24

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(2,4-디플루오로-페닐)2-메톡시-에틸]-3-메틸-부티르아미드(35)의 합성(DL, L) -2-t-butoxycarbonylamino-N- [2- (2,4-difluoro-phenyl) 2-methoxy-ethyl] -3-methyl-butyramide (35) Synthesis of

N-t-부톡시카르보닐 L-발린 0.097g, 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 염산염 0.090g, 1-하이드록시벤조트리아졸 수화물 0.064g 및 트리에틸아민 0.066㎖를 디메틸포름아미드 5㎖에 가하고 0℃에서 10분간 교반한 다음, 여기에 2-(2,4-디플루오로-페닐)-2-메톡시-에틸아민 0.080g을 가하고 2시간 동안 교반하였다. 반응액을 다량의 물과 에틸아세테이트로 추출한 다음 무수 황산마그네슘으로 건조, 증발시켜 표제화합물 0.13g을 수득하였다(수율 : 77%).0.097 g of Nt-butoxycarbonyl L-valine, 0.090 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.064 g of 1-hydroxybenzotriazole hydrate and 0.066 ml of triethylamine To 5 ml of formamide was added and stirred for 10 minutes at 0 ° C., after which 0.080 g of 2- (2,4-difluoro-phenyl) -2-methoxy-ethylamine was added and stirred for 2 hours. The reaction solution was extracted with a large amount of water and ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated to yield 0.13 g of the title compound (yield: 77%).

[실시예 25]Example 25

(DL,L)-2-t-부톡시카르보닐아미노-4-메틸-펜탄산[2-(2,4-디플루오로-페닐)-2-메톡시-에틸]-아미드(36)의 합성Of (DL, L) -2-t-butoxycarbonylamino-4-methyl-pentanoic acid [2- (2,4-difluoro-phenyl) -2-methoxy-ethyl] -amide (36) synthesis

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-루신 0.10g을 사용하는 점을 제외하고는 실시예 24에서와 동일한 방법으로 수행하여 표제화합물 0.12g을 수득하였다(수율 : 73%).0.12 g of the title compound was obtained in the same manner as in Example 24, except that 0.10 g of Nt-butoxycarbonyl L-leucine was used instead of Nt-butoxycarbonyl L-valine (yield: 73%).

[실시예 26]Example 26

(DL,L)-2-t-부톡시카르보닐아미노-3-메틸-펜탄산[2-(2,4-디플루오로-페닐)-2-메톡시-에틸]-아미드(37)의 합성Of (DL, L) -2-t-butoxycarbonylamino-3-methyl-pentanoic acid [2- (2,4-difluoro-phenyl) -2-methoxy-ethyl] -amide (37) synthesis

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-이소루신 0.13g을 사용하는 점을 제외하고는 실시예 24에서와 동일한 방법으로 수행하여 표제화합물 0.13g을 수득하였다(수율 : 75%).0.13 g of the title compound was obtained in the same manner as in Example 24, except that 0.13 g of Nt-butoxycarbonyl L-isoleucine was used instead of Nt-butoxycarbonyl L-valine (yield) : 75%).

[실시예 27]Example 27

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(2,4-디플루오로-페닐)-2-메톡시-에틸]-3-페닐-프로피온아미드(38)의 합성(DL, L) -2-t-butoxycarbonylamino-N- [2- (2,4-difluoro-phenyl) -2-methoxy-ethyl] -3-phenyl-propionamide (38) Synthesis of

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-페닐알라닌 0.12g을 사용하는 점을 제외하고는 실시예 24에서와 동일한 방법으로 수행하여 표제화합물 0.16g을 수득하였다(수율 :86%).0.16 g of the title compound was obtained in the same manner as in Example 24, except that 0.12 g of Nt-butoxycarbonyl L-phenylalanine was used instead of Nt-butoxycarbonyl L-valine (yield: 86%).

[실시예 28]Example 28

(D,L)-2-t-부톡시카르보닐아미노-N-(2-페닐-2-메톡시-에틸)-3-메틸-부티르아미드(14)의 합성Synthesis of (D, L) -2-t-butoxycarbonylamino-N- (2-phenyl-2-methoxy-ethyl) -3-methyl-butyramide (14)

N-t-부톡시카르보닐 L-발린 0.16g, 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 염산염 0.154g, 1-하이드록시벤조트리아졸 수화물 0.11g 및 트리에틸아민 0.112㎖를 디메틸포름아미드 5㎖에 가하고 0℃에서 10분간 교반한 다음, 여기에 (D)-2-메톡시-2-페닐-에틸아민 0.110g을 가하고 2시간 동안 교반하였다. 반응액을 다량의 물과 에틸아세테이트로 추출한 다음 무수 황산마그네슘으로 건조, 증발시켜 표제화합물 0.20g을 수득하였다(수율 : 78%).0.16 g of Nt-butoxycarbonyl L-valine, 0.154 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.11 g of 1-hydroxybenzotriazole hydrate and 0.112 ml of triethylamine It was added to 5 ml of formamide and stirred at 0 ° C. for 10 minutes, and then 0.110 g of (D) -2-methoxy-2-phenyl-ethylamine was added thereto and stirred for 2 hours. The reaction solution was extracted with a large amount of water and ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated to yield 0.20 g of the title compound (yield: 78%).

[실시예 29]Example 29

(D,D)-2-t-부톡시카르보닐아미노-N-(2-페닐-2-메톡시-에틸)-3-메틸-부티르아미드(15)의 합성Synthesis of (D, D) -2-t-butoxycarbonylamino-N- (2-phenyl-2-methoxy-ethyl) -3-methyl-butyramide (15)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 D-발린 0.16g을 사용하는 점을 제외하고는 실시예 28에서와 동일한 방법으로 수행하여 표제화합물 0.19g을 수득하였다(수율 : 76%).0.19 g of the title compound was obtained in the same manner as in Example 28, except that 0.16 g of Nt-butoxycarbonyl D-valine was used instead of Nt-butoxycarbonyl L-valine (yield: 76%).

[실시예 30]Example 30

(L,L)-2-t-부톡시카르보닐아미노-N-(2-페닐-2-메톡시-에틸)-3-메틸-부티르아미드(16)의 합성Synthesis of (L, L) -2-t-butoxycarbonylamino-N- (2-phenyl-2-methoxy-ethyl) -3-methyl-butyramide (16)

N-t-부톡시카르보닐 L-발린 0.16g, 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 염산염 0.154g, 1-하이드록시벤조트리아졸 수화물 0.11g 및 트리에틸아민 0.112㎖를 디메틸포름아미드 5㎖에 가하고 0℃에서 10분간 교반한 다음, 여기에 (L)-2-메톡시-2-페닐-에틸아민 0.110g을 가하고 2시간 동안 교반하였다. 반응액을 다량의 물과 에틸아세테이트로 추출한 다음 무수 황산마그네슘으로 건조, 증발시켜 표제화합물 0.20g을 수득하였다(수율 : 78%).0.16 g of Nt-butoxycarbonyl L-valine, 0.154 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.11 g of 1-hydroxybenzotriazole hydrate and 0.112 ml of triethylamine It was added to 5 ml of formamide and stirred at 0 ° C. for 10 minutes, and then 0.110 g of (L) -2-methoxy-2-phenyl-ethylamine was added thereto and stirred for 2 hours. The reaction solution was extracted with a large amount of water and ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated to yield 0.20 g of the title compound (yield: 78%).

[실시예 31]Example 31

(DL,L)-2-t-부톡시카르보닐아미노-N-(2-페닐-2-메톡시-에틸)-3-메틸-부티르아미드(17)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-N- (2-phenyl-2-methoxy-ethyl) -3-methyl-butyramide (17)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 D-발린 0.16g을 사용하는 점을 제외하고는 실시예 30에서와 동일한 방법으로 수행하여 표제화합물 0.20g을 수득하였다(수율 : 80%).0.20 g of the title compound was obtained in the same manner as in Example 30, except that 0.16 g of Nt-butoxycarbonyl D-valine was used instead of Nt-butoxycarbonyl L-valine (yield: 80%).

[실시예 32]Example 32

(DL,L)-2-t-부톡시카르보닐아미노-N-(2-페닐-2-메톡시-에틸)-3-메틸-부티르아미드(18)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-N- (2-phenyl-2-methoxy-ethyl) -3-methyl-butyramide (18)

N-t-부톡시카르보닐 L-발린 0.16g, 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 염산염 0.154g, 1-하이드록시벤조트리아졸 수화물 0.11g 및 트리에틸아민 0.112㎖를 디메틸포름아미드 5㎖에 가하고 0℃에서 10분간 교반한 다음, 여기에(DL)-2-메톡시-2-페닐-에틸아민 0.110g을 가하고 2시간 동안 교반하였다. 반응액을 다량의 물과 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 표제화합물 0.18g을 수득하였다(수율 : 73%).0.16 g of Nt-butoxycarbonyl L-valine, 0.154 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.11 g of 1-hydroxybenzotriazole hydrate and 0.112 ml of triethylamine It was added to 5 ml of formamide and stirred at 0 ° C. for 10 minutes, and then 0.110 g of (DL) -2-methoxy-2-phenyl-ethylamine was added thereto and stirred for 2 hours. The reaction solution was extracted with a large amount of water and ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated to yield 0.18 g of the title compound (yield: 73%).

[실시예 33]Example 33

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-3-메틸-부티르아미드(29)의 합성Of (DL, L) -2-t-butoxycarbonylamino-N- [2- (2,4-dichloro-phenyl) -2-methoxy-ethyl] -3-methyl-butyramide (29) synthesis

N-t-부톡시카르보닐 L-발린 0.600g, 1-(3-디메틸아민프로필)-3-에틸카르보디이미드 염산염 0.636g, 1-하이드록시벤조트리아졸 수화물 0.448g 및 트리에틸아민 0.50㎖를 디메틸포름아미드 15㎖에 가하고 0℃에서 10분간 교반한 다음, 여기에 2-(2,4-디클로로-페닐)-2-메톡시-에틸아민 0.636g을 가하고 2시간 동안 교반하였다. 반응액을 다량의 물과 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 표제화합물 0.93g을 수득하였다(수율 : 77%).0.600 g of Nt-butoxycarbonyl L-valine, 0.636 g of 1- (3-dimethylaminepropyl) -3-ethylcarbodiimide hydrochloride, 0.448 g of 1-hydroxybenzotriazole hydrate and 0.50 ml of triethylamine 15 ml of formamide was added and stirred at 0 ° C. for 10 minutes, and then 0.636 g of 2- (2,4-dichloro-phenyl) -2-methoxy-ethylamine was added thereto and stirred for 2 hours. The reaction solution was extracted with a large amount of water and ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated to yield 0.93 g of the title compound (yield: 77%).

[실시예 34]Example 34

(DL,L)-2-t-부톡시카르보닐아미노-4-메틸-펜탄산[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-아미드(30)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-4-methyl-pentanoic acid [2- (2,4-dichloro-phenyl) -2-methoxy-ethyl] -amide (30)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-루신 0.70g을 사용하는 점을 제외하고는 실시예 33에서와 동일한 방법으로 수행하여 표제화합물 0.95g을 수득하였다(수율 : 77%).0.95 g of the title compound was obtained in the same manner as in Example 33, except that 0.70 g of Nt-butoxycarbonyl L-leucine was used instead of Nt-butoxycarbonyl L-valine (yield: 77%).

[실시예 35]Example 35

(DL,L)-2-t-부톡시카르보닐아미노-3-메틸-펜탄산[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-아미드(31)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-3-methyl-pentanoic acid [2- (2,4-dichloro-phenyl) -2-methoxy-ethyl] -amide (31)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-이소루신 0.70g을 사용하는 점을 제외하고는 실시예 3에서와 동일한 방법으로 수행하여 표제화합물 0.99g을 수득하였다(수율 : 80%).0.99 g of the title compound was obtained in the same manner as in Example 3, except that 0.70 g of Nt-butoxycarbonyl L-isoleucine was used instead of Nt-butoxycarbonyl L-valine (yield) : 80%).

[실시예 36]Example 36

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-3-페닐-프로피온아미드(32)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-N- [2- (2,4-dichloro-phenyl) -2-methoxy-ethyl] -3-phenyl-propionamide (32)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-페닐알라닌 0.81g을 사용하는 점을 제외하고는 실시예 33에서와 동일한 방법으로 수행하여 표제화합물 0.10g을 수득하였다(수율 : 83%).0.10 g of the title compound was obtained in the same manner as in Example 33, except that 0.81 g of Nt-butoxycarbonyl L-phenylalanine was used instead of Nt-butoxycarbonyl L-valine (yield: 83%).

[실시예 37]Example 37

(DL,L)-2-[N-{2-(2,4-디클로로-페닐)-2-메톡시-에틸}카르바모일]-피롤리딘 -1-카르복실산 t-부틸 에스테르(33)의 합성(DL, L) -2- [N- {2- (2,4-dichloro-phenyl) -2-methoxy-ethyl} carbamoyl] -pyrrolidine-1-carboxylic acid t-butyl ester ( Synthesis of 33

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-프롤린 0.66g을 사용하는 점을 제외하고는 실시예 33에서와 동일한 방법으로 수행하여 표제화합물 0.91g을 수득하였다(수율 : 77%).0.91 g of the title compound was obtained in the same manner as in Example 33, except that 0.66 g of Nt-butoxycarbonyl L-proline was used instead of Nt-butoxycarbonyl L-valine (yield: 77%).

[실시예 38]Example 38

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-2-페닐-아세트아미드(34)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-N- [2- (2,4-dichloro-phenyl) -2-methoxy-ethyl] -2-phenyl-acetamide (34)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 (s)-(2)-페닐글리신 0.77g을 사용하는 점을 제외하고는 실시예 33에서와 동일한 방법으로 수행하여 표제화합물 0.96g을 수득하였다(수율 : 75%).The title compound 0.96 was carried out in the same manner as in Example 33, except that 0.77 g of Nt-butoxycarbonyl (s)-(2) -phenylglycine was used instead of Nt-butoxycarbonyl L-valine. g was obtained (yield: 75%).

[실시예 39]Example 39

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-3-메틸-부티르아미드(39)의 합성Of (DL, L) -2-t-butoxycarbonylamino-N- [2- (2,4-dichloro-phenyl) -2-methoxy-ethyl] -3-methyl-butyramide (39) synthesis

N-t-부톡시카르보닐 D-발린 0.660g, 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 염산염 0.636g, 1-하이드록시벤조트리아졸 수화물 0.448g 및 트리에틸아민 0.50㎖를 디메틸포름아미드 15㎖에 가하고 0℃에서 10분간 교반한 다음, 여기에 2-(2,4-디클로로-페닐)-2-메톡시-에틸아민 0.636g을 가하고 2시간 동안 교반하였다. 반응액을 다량의 물과 에틸아세테이트로 추출하고 무수 황산마그네슘으로 건조, 증발시켜 표제화합물 0.12g을 수득하였다(수율 : 74%).0.660 g of Nt-butoxycarbonyl D-valine, 0.636 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.448 g of 1-hydroxybenzotriazole hydrate and 0.50 ml of triethylamine 15 ml of formamide was added and stirred at 0 ° C. for 10 minutes, and then 0.636 g of 2- (2,4-dichloro-phenyl) -2-methoxy-ethylamine was added thereto and stirred for 2 hours. The reaction solution was extracted with a large amount of water and ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated to yield 0.12 g of the title compound (yield: 74%).

[실시예 40]Example 40

(DL,D)-2-아미노-N-[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-3-메틸-부티르아미드(55)의 합성Synthesis of (DL, D) -2-amino-N- [2- (2,4-dichloro-phenyl) -2-methoxy-ethyl] -3-methyl-butyramide (55)

0℃에서 1.20g(29mmol)을 트리플루오로아세트산 10㎖에 녹이고 1시간 동안 교반한 후 트리플루오로아세트산을 제거하였다. 반응액에 에틸아세테이트와 물을 가하여 유기층을 추출하고 분리한 유기층을 탄산수소나트륨 수용액으로 세척한 다음 무수망초로 건조시키고 감압 증류하여 표제화합물 0.81g(25mmol)을 수득하였다(수율 : 86%).1.20 g (29 mmol) was dissolved in 10 ml of trifluoroacetic acid at 0 ° C, stirred for 1 hour, and then trifluoroacetic acid was removed. Ethyl acetate and water were added to the reaction mixture, and the organic layer was extracted. The organic layer was washed with an aqueous solution of sodium bicarbonate, dried over anhydrous manganese and distilled under reduced pressure to obtain 0.81 g (25 mmol) of the title compound (yield: 86%).

[실시예 41]Example 41

(DL,L)-N-[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-2-(2,2-디메틸-프로피오닐아미노)-3-메틸-부티르아미드(47)의 합성(DL, L) -N- [2- (2,4-Dichloro-phenyl) -2-methoxy-ethyl] -2- (2,2-dimethyl-propionylamino) -3-methyl-butyrylamide Synthesis of 47

실시예 40에서 수득한 (DL,D)-2-아미노-N-[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-3-메틸-부티르아미드 0.080g(0.25mmol) 및 트리에틸아민 0.040g을 디클로로메탄 5㎖에 녹이고 0℃에서 피발로일클로라이드 0.063g을 가하였다. 반응액을 상온에서 30분간 교반한 후 물을 가하고 유기층을 추출하였다. 분리한 유기층을 무수망초로 건조, 증발시키고 실리카겔 컬럼 크로마토그라피(용출액: 헥산-에틸아세테이트)로 분리하여 표제화합물 0.011g(0.21mmol)을 수득하였다(수율 : 82%).0.080 g (0.25) of (DL, D) -2-amino-N- [2- (2,4-dichloro-phenyl) -2-methoxy-ethyl] -3-methyl-butyamide obtained in Example 40 mmol) and 0.040 g of triethylamine were dissolved in 5 ml of dichloromethane and 0.063 g of pivaloyl chloride was added at 0 ° C. After the reaction solution was stirred at room temperature for 30 minutes, water was added and the organic layer was extracted. The separated organic layer was dried over anhydrous forget-me-not, evaporated, and separated by silica gel column chromatography (eluate: hexane-ethyl acetate) to give 0.011 g (0.21 mmol) of the title compound (yield: 82%).

[실시예 42]Example 42

(DL,L)-2-t-부톡시카르보닐아미노-N-[2,4-디클로로-페닐)-2-메톡시-에틸]-3-메틸-부티르아미드(40)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-N- [2,4-dichloro-phenyl) -2-methoxy-ethyl] -3-methyl-butyramide (40)

0℃에서 (DL,L)-2-아미노-N-[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-3-메틸-부티르아미드 0.085g(0.27mmol) 및 트리에틸아민 0.045g을 디클로메탄 5㎖에 녹이고, 동온도에서 에틸클로로포르메이트 0.045g을 가하였다. 반응액을 상온에서 30분간 교반한 후 물을 가하고 유기층을 추출하였다. 분리한 유기층을 무수망초로 건조, 증발시키고 실리카겔 컬럼 크로마토그라피(용출액: 헥사-에틸아세테이트)로 분리하여 표제화합물 0.095g(0.24mmol)을 수득하였다(수율 : 90%).0.085 g (0.27 mmol) of (DL, L) -2-amino-N- [2- (2,4-dichloro-phenyl) -2-methoxy-ethyl] -3-methyl-butyramide at 0 ° C. and 0.045 g of triethylamine was dissolved in 5 ml of dichloromethane, and 0.045 g of ethylchloroformate was added at the same temperature. After the reaction solution was stirred at room temperature for 30 minutes, water was added and the organic layer was extracted. The separated organic layer was dried over anhydrous forget-me-not, evaporated, and separated by silica gel column chromatography (eluent: hexa-ethyl acetate) to obtain 0.095 g (0.24 mmol) of the title compound (yield: 90%).

[실시예 43]Example 43

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-프로피온아미드(60)의 합성Synthesis of (DL, L) -2-t-butoxycarbonylamino-N- [2- (2,4-dichloro-phenyl) -2-methoxy-ethyl] -propionamide (60)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-알라닌 0.60g을 사용하는 점을 제외하고는 실시예 33에서와 동일한 방법으로 수행하여 표제화합물 0.91g을 수득하였다(수율 : 80%).0.91 g of the title compound was obtained in the same manner as in Example 33, except that 0.60 g of Nt-butoxycarbonyl L-alanine was used instead of Nt-butoxycarbonyl L-valine (yield: 80%).

[실시예 44]Example 44

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-3-하이드록시-프로피온아미드(61)의 합성Of (DL, L) -2-t-butoxycarbonylamino-N- [2- (2,4-dichloro-phenyl) -2-methoxy-ethyl] -3-hydroxy-propionamide (61) synthesis

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-세린 0.65g을 사용하는 점을 제외하고는 실시예 33에서와 동일한 방법으로 수행하여 표제화합물 0.82g을 수득하였다(수율 : 70%).0.82 g of the title compound was obtained in the same manner as in Example 33, except that 0.65 g of Nt-butoxycarbonyl L-serine was used instead of Nt-butoxycarbonyl L-valine (yield: 70%).

[실시예 45]Example 45

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-3-하이드록시-부티르아미드(62)의 합성(DL, L) -2-t-butoxycarbonylamino-N- [2- (2,4-dichloro-phenyl) -2-methoxy-ethyl] -3-hydroxy-butyramide (62) Synthesis of

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-트레오닌 0.70g을 사용하는 점을 제외하고는 실시예 33에서와 동일한 방법으로 수행하여 표제화합물 0.84g을 수득하였다(수율 : 69%).0.84 g of the title compound was obtained in the same manner as in Example 33, except that 0.70 g of Nt-butoxycarbonyl L-threonine was used instead of Nt-butoxycarbonyl L-valine (yield: 69%).

[실시예 46]Example 46

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-4-메틸티오-부티르아미드(63)의 합성(DL, L) -2-t-butoxycarbonylamino-N- [2- (2,4-dichloro-phenyl) -2-methoxy-ethyl] -4-methylthio-butyramide (63) Synthesis of

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-메티오닌 0.79g을 사용하는 점을 제외하고는 실시예 33에서와 동일한 방법으로 수행하여 표제화합물 1.11g을 수득하였다(수율 : 85%).1.11 g of the title compound were obtained in the same manner as in Example 33, except that 0.79 g of Nt-butoxycarbonyl L-methionine was used instead of Nt-butoxycarbonyl L-valine (yield: 85%).

[실시예 47]Example 47

(DL,L)-2-t-부톡시카르보닐아미노-N-[2-(2,4-디클로로-페닐)-2-메톡시-에틸]-3-(4-하이드록시페닐)-프로피온아미드(64)의 합성(DL, L) -2-t-butoxycarbonylamino-N- [2- (2,4-dichloro-phenyl) -2-methoxy-ethyl] -3- (4-hydroxyphenyl) -propion Synthesis of Amide (64)

N-t-부톡시카르보닐 L-발린 대신에 N-t-부톡시카르보닐 L-타이로신 0.89g을 사용하는 점을 제외하고는 실시예 33에서와 동일한 방법으로 수행하여 표제화합물 1.19g을 수득하였다(수율 : 85%).1.19 g of the title compound was obtained in the same manner as in Example 33, except that 0.89 g of Nt-butoxycarbonyl L-tyrosine was used instead of Nt-butoxycarbonyl L-valine (yield: 85%).

상기 실시예에 의거하여 합성한 일반식(Ⅰ) 화합물들의H NMR Data를 표 2에 나타내었다.Of the compounds of the general formula (I) synthesized according toH NMR Data is shown in Table 2.

본 발명에 따른 일반식(Ⅰ) 화합물의 병원균에 대한 방제효력을 검증하기 위하여 하기의 균을 선정하고 다음의 방법으로 항균력을 조사하였다.In order to verify the control effect against the pathogen of the compound of the general formula (I) according to the present invention, the following bacteria were selected and the antibacterial activity was examined by the following method.

오이잿빛곰팡이병 (BC) Botrytis cinereaCucumber Gray Mold Disease (BC) Botrytis cinerea

토마토역병 (PI) Phytophthora infestansTomato Blight (PI) Phytophthora infestans

10% 아세톤 수용액에 각 화합물을 용해시키고 트윈-20을 250ppm이 되게 첨가한 다음 이 혼합물을 일정 크기의 기주 식물에 5㎖씩 엽면살포하였다. 약제가 살포된 식물을 실내온도에서 24시간 동안 방치하여 용매 및 물을 휘산시킨 뒤, 각기 하기에 기재한 바와 같이 준비된 병원균을 접종하고 무처리구와 비교하여 병 예방효과를 산출하였다. 모든 실험은 2회 반복하였으며, 하기 표 3에 나타낸 기준에 따라 등급을 나누어 표시하였다.Each compound was dissolved in a 10% acetone aqueous solution, and Tween-20 was added to 250 ppm, and the mixture was foliated with 5 ml of host plants of a certain size. The plants sprayed with the medicament were left at room temperature for 24 hours to volatilize the solvent and water, and then inoculated with the prepared pathogens as described below, respectively, and the disease prevention effect was calculated in comparison with the non-treated group. All experiments were repeated twice and the grades were divided according to the criteria shown in Table 3 below.

생물학적 시험예 1: 토마토역병에 대한 살균효과Biological test example 1: bactericidal effect against tomato late blight

역병균을 호밀 B 한천배지(Rye 60g, 수크로오스 20g, β-시토스테롤(Sitosterol) 50㎎, 아가 15g, 증류수 1ℓ)에 올려놓고, 20℃에서 16시간의 광처리 및 8시간의 암처리의 배양기에서 14일간 배양하여 유주자낭의 생성을 유도하였다. 플레이트에 멸균증류수를 가하고 생성된 유주자낭을 시약 스푼을 이용하여 균층으로부터 분리한 후 4겹의 가아제로 유주자낭을 걸러내었다. 수확한 유주자낭의 농도를 5x10개/㎖로 조정하여 접종원으로 사용하였다. 접종원을 토마토 유묘 하나당 3㎖씩 분무 접종하였다. 접종한 식물체를 20℃의 습실상에서 5일간 발병시킨 후 병반면적율(%)을 조사하고 상기 표 3의 기준에 따라 등급을 매긴 후 그 결과를 표 4에 나타내었다.Plague bacteria were placed on rye B agar medium (Rye 60g, sucrose 20g, β-sitosterol 50mg, agar 15g, distilled water 1L), 14 in an incubator for 16 hours of light treatment and 8 hours of cancer treatment at 20 ° C. Daily culture was induced to induce the production of drift sac. Sterile distilled water was added to the plate, and the resulting ciliary sac was separated from the bacterial layer using a reagent spoon, and then the ciliary sac was filtered out with four layers of gauze. 5x10 concentrationsIt was used as an inoculum adjusted to dogs / ml. The inoculum was sprayed at 3 ml per tomato seedling. The inoculated plants were incubated for 5 days at 20 ° C. in a humidified area, and then the lesion area ratio (%) was investigated and graded according to the criteria of Table 3 above, and the results are shown in Table 4.

생물학적 시험예 2: 오이잿빛곰팡이병에 대한 살균효과Biological Test Example 2: Bactericidal Effect on Cucumber Gray Mold

토마토로부터 분리한 병원균(Botrytis cinerea KC1)을 쌀겨한천배지(RPA)에 접종하고 20℃의 배양기에서 16시간의 광처리 및 8시간의 암처리를 거쳐 분생포자를 형성시켰다. 배지에 형성된 포자를 감자액체배지(Potato 200g, 덱스트로스 20g, 증류수 1ℓ)에 부은 다음, 포자를 긁고 이를 가아제로 걸러서 포자를 수확하였다. 포자농도가 1×10개/㎖로 되도록 조정하여 이를 접종원으로 사용하였다. 접종원을 1엽기 오이 유묘에 3㎖씩 분무 접종한 후 접종한 식물체를 20℃ 습실상에서 4일간 습실처리한 후 본엽 1엽의 병반면적율(%)을 조사하였다. 상기 표 3의 기준에 따라 등급을 매긴 후 그 결과를 표 4에 나타내었다.Pathogens isolated from tomatoes (Botrytis cinerea KC1) were inoculated in rice bran agar (RPA), and conidia were formed after 16 hours of light treatment and 8 hours of dark treatment in an incubator at 20 ° C. Spores formed on the medium were poured into potato liquid medium (Potato 200g, dextrose 20g, distilled water 1 L), and then spores were scraped and filtered to filter the spores. Spore Concentration 1 × 10It was adjusted to dogs / ml and used as the inoculum. After inoculating 3 ml of cucumber seedlings in one leaf inoculation, the inoculated plants were wet-treated at 20 ° C. for 4 days, and the lesion area ratio (%) of one leaf of the main leaves was investigated. After grading according to the criteria of Table 3, the results are shown in Table 4.

Claims

하기 일반식(Ⅰ)의 아미노산 아미드 유도체 및 그의 입체이성체 :Amino acid amide derivatives of the general formula (I) and stereoisomers thereof:

(여기서, R₄는 사이클로프로필, 클로로에틸, C₁-C₄알킬, C₁-C₄알콕시, C₁-C₃할로알콕시, 아릴옥시 또는 벤질옥시를 나타낸다)을 나타낸다.Wherein X ₁ and X ₂ each independently represent hydrogen, methoxy, methyl or halogen, or when X ₁ and X ₂ are attached to adjacent carbon atoms on a benzene ring, they are bonded to each other to form a methylenedioxy group Wherein R ₁ represents hydrogen, phenyl or —CHR ₅ R ₆ wherein R ₅ represents hydrogen or methyl and R ₆ represents hydrogen, C ₁ -C ₂ alkyl, hydroxy, thiol, alkylthiomethyl , Phenyl or hydroxyphenyl), R ₂ represents hydrogen, or propylene together with R ₂ represents R ₃ represents hydrogen or

(Wherein R ₄ represents cyclopropyl, chloroethyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₃ haloalkoxy, aryloxy or benzyloxy).

제1항에 있어서, X₁및 X₂는 각각 독립적으로 메톡시, 메틸 또는 할로겐을 나타내거나, X₁및 X₂가 벤젠환상의 인접한 탄소원자에 부착되어 있는 경우에 이들이 상호 결합하여 메틸렌디옥시 그룹을 형성할 수 있고, R₁은 수소, 페닐 또는 -CHR₅R₆(여기서, R₅는 수소 또는 메틸을 나타내고, R₆은 수소, 메틸, 에틸, 이소프로필, 하이드록시, 티올, 알킬티오메틸, 페닐 또는 하이드록시페닐을 나타낸다)을 나타내며, R₂는 수소이고, R₃은 수소 또는

(여기서, R₄는 2-메틸프로필옥시, t-부톡시, 아릴옥시 또는 벤질옥시를 나타낸다)을 나타내는 화합물.2. A compound according to claim 1, wherein X ₁ and X ₂ each independently represent methoxy, methyl or halogen, or when X ₁ and X ₂ are attached to adjacent carbon atoms on a benzene ring, they are bonded to each other to form methylenedioxy. Groups may be formed, R ₁ represents hydrogen, phenyl or —CHR ₅ R ₆ , wherein R ₅ represents hydrogen or methyl, and R ₆ represents hydrogen, methyl, ethyl, isopropyl, hydroxy, thiol, alkylthio Methyl, phenyl or hydroxyphenyl), R ₂ is hydrogen, R ₃ is hydrogen or

Wherein R ₄ represents 2-methylpropyloxy, t-butoxy, aryloxy or benzyloxy.

하기 일반식(Ⅱ)의 화합물을 탈수제, 용매 및 염기의 존재하에 하기 일반식(Ⅲ)의 화합물과 반응시킴을 투징으로 하여 하기 일반식(Ⅰ-1)의 화합물을 제조하는 방법.A method for producing a compound of formula (I-1) by reacting a compound of formula (II) with a compound of formula (III) in the presence of a dehydrating agent, a solvent and a base.

상기식에서, X₁, X₂, R₁및 R₂는 제1항에서 정의한 바와 같다.Wherein X ₁ , X ₂ , R ₁ and R ₂ are as defined in claim 1.

제3항에 있어서, 탈수제가 디사이클로헥실카르보디이미드(DCC), 1-에틸-3-(3-디메틸아미노프로필)카르보디이미드(EDC) 및 실리콘테트라클로라이드 중에서 선택된 1종 이상인 방법.The method of claim 3, wherein the dehydrating agent is at least one selected from dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), and silicon tetrachloride.

제3항에 있어서, 염기가 피리딘, 4-디메틸아미노피리딘, 트리에틸아민, N,N-디메틸아닐린, 트리부틸아민, N-메틸모폴린 중에서 선택된 1종 이상인 방법.The method according to claim 3, wherein the base is at least one selected from pyridine, 4-dimethylaminopyridine, triethylamine, N, N-dimethylaniline, tributylamine, N-methylmorpholine.

제3항에 있어서, 용매가 벤젠, 톨루엔, 크실렌, 디클로로메탄, 1,2-디클로로에탄, 클로로포름, 디에틸에테르, 디옥산, 1,2-디메톡시에탄, 테트라하이드로푸란, 아세톤, 메틸에틸케톤, 사이클로헥사논, 아세토니트릴, 프리피오니트릴, 메틸아세테이트, 에틸아세테이트, N,N-디메틸포름아미드, N,N-디메틸아세트아미드, 디메틸설폭사이드중에서 선택된 1종 이상인 방법.The solvent of claim 3 wherein the solvent is benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, diethyl ether, dioxane, 1,2-dimethoxyethane, tetrahydrofuran, acetone, methylethylketone At least one selected from cyclohexanone, acetonitrile, pripyonitrile, methyl acetate, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, and dimethyl sulfoxide.

하기 일반식(Ⅰ-1)의 화합물을 트리플루오로아세트산을 이용하여 가수분해시킴을 특징으로하여 하기 일반식(Ⅰ-2)의 화합물을 제조하는 방법.A method for preparing a compound of formula (I-2), wherein the compound of formula (I-1) is hydrolyzed using trifluoroacetic acid.

하기 일반식(Ⅰ-2)의 화합물을 염기 및 용매의 존재하에 하기 일반식(Ⅳ)의 화합물과 반응시킴을 특징으로 하여 하기 일반식 (Ⅰ-3)의 화합물을 제조하는 방법.A method for preparing a compound of formula (I-3), characterized by reacting a compound of formula (I-2) with a compound of formula (IV) in the presence of a base and a solvent.

상기식에서, X₁, X₂, R₁및 R₂는 제1항에서 정의한 바와 같고, R₃′는 제1항에 정의한 R₃와 같으나, 단 수소와 t-부톡시카르보닐은 제외한다.Wherein R, X _1, X _2, R ₁ and R ₂ are as defined in claim 1, wherein R ₃ 'is R _3, but with defined in claim 1, provided that hydrogen and t- butoxycarbonyl are excluded.

제8항에 있어서, 염기가 피리딘, 4-디메틸아미노피리딘, 트리에틸아민, N,N-디메틸아닐린, 트리부틸아민 및 N-메틸모폴린 중에서 선택된 1종인 방법.The method of claim 8, wherein the base is one selected from pyridine, 4-dimethylaminopyridine, triethylamine, N, N-dimethylaniline, tributylamine and N-methylmorpholine.

제8항에 있어서, 용매가 벤젠, 톨루엔, 크실렌, 디클로로메탄, 1,2-디클로로에탄, 클로로포름, 디에틸에테르, 디옥산, 1,2-디메톡시에탄, 테트라하이드로푸란, 아세토니트릴, 프리피오니트릴, N,N-디메틸포름아미드, N,N-디메틸아세트아미드, 디메틸설폭사이드중에서 선택된 1종 이상인 방법.The solvent of claim 8 wherein the solvent is benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, diethyl ether, dioxane, 1,2-dimethoxyethane, tetrahydrofuran, acetonitrile, pripio At least one selected from nitrile, N, N-dimethylformamide, N, N-dimethylacetamide, and dimethyl sulfoxide.

농약분야에서 통상 사용되는 담체와 함께 제1항에 정의된 일반식(Ⅰ)의 화합물을 유효성분으로 함유함을 특징으로 하는 식물병원균에 의한 발병저해용 조성물.A composition for inhibiting pathogenesis by phytopathogens, comprising a compound of formula (I) as defined in claim 1 together with a carrier commonly used in the pesticide field.