KR20200033474A - A method for producing 1-ethyl-4-phenylpiperazine derivative by three-component reaction using aromatic compounds, amines and nucleophiles - Google Patents
A method for producing 1-ethyl-4-phenylpiperazine derivative by three-component reaction using aromatic compounds, amines and nucleophiles Download PDFInfo
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- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
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- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
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Abstract
Description
물질, 농약 및 의약, 화학 등 다양한 분야에서 활용성이 높은 1-에틸-4-페닐피페라진 유도체를 합성하는 방법에 관한 발명이다.This invention relates to a method for synthesizing a 1-ethyl-4-phenylpiperazine derivative having high utility in various fields such as substances, pesticides, medicine, and chemistry.
헤테로환형의 생체 활성 분자는 의약품 후보물질 또는 시약으로서 널리 응용되고 있다. 헤테로환형의 생체 활성 분자 중 피페라진 모티프는 물질, 농약 및 의약, 화학 등 다양한 분야에서 사용되는 많은 화합물의 필수적인 구조이다. 특히, 1-에틸-4-페닐피페라진 유도체는 항종양, 항염증제, 항비만증 및 심혈관 활동과 같은 다양한 생화학적 활성을 보유하는 것으로 알려져 있다. Heterocyclic bioactive molecules are widely applied as pharmaceutical candidates or reagents. Among the heterocyclic bioactive molecules, the piperazine motif is an essential structure of many compounds used in various fields such as substances, pesticides, medicine, and chemistry. In particular, 1-ethyl-4-phenylpiperazine derivatives are known to possess various biochemical activities such as anti-tumor, anti-inflammatory, anti-obesity and cardiovascular activity.
1-에틸-4-페닐피페라진 유도체를 합성하기 위하여, 나이트로기(NO2)와 같은 전자 끌게 작용기를 포함하는 방향족 친핵성 치환 반응을 이용한 방법이 있다(1963년 Manuel Finkelstein에 의해 개발된 SNAr 반응, 반응식 1 참조). 그러나, 이 방법은 매우 높은 온도 약 150℃에서 긴 반응시간(약 20시간)이 요구되며, 전자 끌게 작용기(나이트로기, NO2)가 없으면 반응이 진행되지 않는 단점이 있다. 또한, 단 1개의 유기 물질 합성만을 예시로 보이고 있어 제한적이다.In order to synthesize a 1-ethyl-4-phenylpiperazine derivative, there is a method using an aromatic nucleophilic substitution reaction including an electron-withdrawing functional group such as a nitro group (NO 2 ) (S developed by Manuel Finkelstein in 1963) N Ar reaction, see Scheme 1). However, this method requires a long reaction time (about 20 hours) at a very high temperature of about 150 ° C, and there is a disadvantage that the reaction does not proceed without an electron-withdrawing functional group (nitrogen, NO 2 ). In addition, it is limited because only one organic material is shown as an example.
[반응식 1][Scheme 1]
1-에틸-4-페닐피페라진 유도체의 다른 합성 방법으로서, 답코(1,4-diazabicyclo(2.2.2)octane, DABCO))의 활성화기로써 피리딘 옥사이드(pyridine-N-oxide)(2-1) 또는 2-브로모피리딘(2-bromopyridine)을 이용하여 탄소-질소 결합을 절단하는 반응이 개발되어 있지만 다양한 탄소-친핵체 결합 형성의 한계를 가진다(반응식 2 참조).As another method for synthesizing 1-ethyl-4-phenylpiperazine derivatives, pyridine-N-oxide (2-1) is used as an activator of dapco (1,4-diazabicyclo (2.2.2) octane, DABCO)). ) Or 2-bromopyridine (2-bromopyridine) using a reaction to cut the carbon-nitrogen bond has been developed, but has a limit of various carbon-nucleophilic bond formation (see Scheme 2).
[반응식 2][Scheme 2]
본 발명의 목적은 1-에틸-4-페닐피페라진 유도체의 간단한 합성 방법을 제공하는 것이다.It is an object of the present invention to provide a simple method for the synthesis of 1-ethyl-4-phenylpiperazine derivatives.
또한, 본 발명의 목적은 1-에틸-4-페닐피페라진 유도체의 다양한 합성 방법을 제공하는 것이다.It is also an object of the present invention to provide various methods for synthesizing 1-ethyl-4-phenylpiperazine derivatives.
또한, 본 발명의 목적은 1-에틸-4-페닐피페라진 유도체를 높은 수율로 합성할 수 있는 방법을 제공하는 것이다.In addition, an object of the present invention is to provide a method capable of synthesizing a 1-ethyl-4-phenylpiperazine derivative with high yield.
상술한 목적을 달성하기 위한 수단으로서 본 명세서는 트리플루오로메탄설포네이트기와 트리메틸실릴기가 서로 오르토위치에 결합된 방향족 화합물이 아린 중간체로 형성되는 제1반응단계; 아린 중간체가 답코(DABCO)와 반응하여 4차 암모늄염으로 형성되는 제2반응단계; 및 4차 암모늄염과 친핵체를 반응시키는 제3반응단계;를 포함하고, 제1반응단계 내지 제3반응단계는 원팟(one-pot)반응으로 수행되는 것을 특징으로 하는 1-에틸-4-페닐피페라진 유도체의 제조방법에 대하여 개시한다.As a means for achieving the above object, the present specification is a first reaction step in which the trifluoromethanesulfonate group and the trimethylsilyl group are formed of an intermediate in which an aromatic compound is bonded to each other in an ortho position; A second reaction step in which the arine intermediate reacts with dabco to form a quaternary ammonium salt; And a third reaction step of reacting a quaternary ammonium salt with a nucleophile, wherein the first to third reaction steps are carried out in a one-pot reaction. Disclosed is a method for preparing a azine derivative.
본 발명의 각 1-에틸-4-페닐피페라진 유도체의 제조방법에 있어서, 방향족 화합물은 단환 방향족 화합물인 것이 바람직하다.In the production method of each 1-ethyl-4-phenylpiperazine derivative of the present invention, the aromatic compound is preferably a monocyclic aromatic compound.
본 발명의 각 1-에틸-4-페닐피페라진 유도체의 제조방법에 있어서, 방향족 화합물은 하기 화학식 1로 표시되는 화합물인 것이 바람직하다.In the production method of each 1-ethyl-4-phenylpiperazine derivative of the present invention, the aromatic compound is preferably a compound represented by the following formula (1).
[화학식 1][Formula 1]
본 발명의 각 1-에틸-4-페닐피페라진 유도체의 제조방법에 있어서, 방향족 화합물은 플루오르 이온에 의해 아린 중간체로 형성되는 것이 바람직하다.In the production method of each 1-ethyl-4-phenylpiperazine derivative of the present invention, it is preferable that the aromatic compound is formed of an amine intermediate by fluorine ions.
본 발명의 각 1-에틸-4-페닐피페라진 유도체의 제조방법에 있어서, 친핵체는 히드록시기, 티올기, 할로겐기, 카르복실기, 카르복실레이트기 및 디케톤기로 이루어진 군으로부터 선택되는 적어도 하나 이상의 작용기를 포함하는 화합물인 것이 바람직하다.In the method for preparing each 1-ethyl-4-phenylpiperazine derivative of the present invention, the nucleophile is at least one functional group selected from the group consisting of hydroxy group, thiol group, halogen group, carboxyl group, carboxylate group and diketone group. It is preferable that it is a compound containing.
본 발명의 각 1-에틸-4-페닐피페라진 유도체의 제조방법에 있어서, 친핵체는 티올기를 포함하는 선형, 분지형 또는 환형 유기화합물인 것이 바람직하다.In the method for preparing each 1-ethyl-4-phenylpiperazine derivative of the present invention, the nucleophile is preferably a linear, branched or cyclic organic compound containing a thiol group.
본 발명의 각 1-에틸-4-페닐피페라진 유도체의 제조방법에 있어서, 친핵체를 구성하는 탄소 중 적어도 하나 이상이 황(S)으로 치환되는 것이 바람직하다.In the method for producing each 1-ethyl-4-phenylpiperazine derivative of the present invention, it is preferable that at least one of carbons constituting the nucleophile is substituted with sulfur (S).
본 발명에서의 각 합성반응단계는 연속적으로 일어나는 반응으로서 원팟(one-pot)반응이 이루어지므로, 간단하면서도 효율적으로 1-에틸-4-페닐피페라진 유도체를 합성할 수 있다.Since each synthetic reaction step in the present invention is a continuous reaction, a one-pot reaction is performed, and thus 1-ethyl-4-phenylpiperazine derivatives can be synthesized simply and efficiently.
아울러, 본 발명은 3가지 성분을 이용한 1-에틸-4-페닐피페라진 유도체의 다양한 합성 방법을 제공한다. In addition, the present invention provides various methods for synthesizing 1-ethyl-4-phenylpiperazine derivatives using three components.
또한, 본 발명은 높은 수율로 1-에틸-4-페닐피페라진 유도체를 합성할 수 있다.In addition, the present invention can synthesize a 1-ethyl-4-phenylpiperazine derivative with high yield.
본 출원에서 사용하는 용어는 단지 특정한 예시를 설명하기 위하여 사용되는 것이다. 때문에 가령 단수의 표현은 문맥상 명백하게 단수여야만 하는 것이 아닌 한, 복수의 표현을 포함한다. 덧붙여, 본 출원에서 사용되는 "포함하다" 또는 "구비하다" 등의 용어는 명세서 상에 기재된 특징, 단계, 기능, 구성요소 또는 이들을 조합한 것이 존재함을 명확히 지칭하기 위하여 사용되는 것이지, 다른 특징들이나 단계, 기능, 구성요소 또는 이들을 조합한 것의 존재를 예비적으로 배제하고자 사용되는 것이 아님에 유의해야 한다.Terms used in the present application are only used to describe specific examples. Thus, for example, a singular expression includes a plural expression unless the context clearly indicates it. In addition, terms such as “comprise” or “include” as used in the present application are used to clearly indicate the existence of features, steps, functions, components, or combinations thereof described in the specification, and other features. It should be noted that it is not used to preliminarily exclude the presence of a field or step, function, component, or combination thereof.
한편, 다르게 정의되지 않는 한, 본 명세서에서 사용되는 모든 용어들은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 가진 것으로 보아야 한다. 따라서, 본 명세서에서 명확하게 정의하지 않는 한, 특정 용어가 과도하게 이상적이거나 형식적인 의미로 해석되어서는 안 된다.On the other hand, unless defined otherwise, all terms used in this specification should be regarded as having the same meaning as generally understood by a person having ordinary skill in the art to which the present invention pertains. Accordingly, unless explicitly defined herein, certain terms should not be construed in excessively ideal or formal sense.
또한, 본 명세서의 "약", "실질적으로" 등은 언급한 의미에 고유한 제조 및 물질 허용오차가 제시될 때 그 수치에서 또는 그 수치에 근접한 의미로 사용되고, 본 발명의 이해를 돕기 위해 정확하거나 절대적인 수치가 언급된 개시 내용을 비양심적인 침해자가 부당하게 이용하는 것을 방지하기 위해 사용된다. In addition, "about", "substantially", and the like in this specification are used in the sense of or close to the value when manufacturing and substance tolerances unique to the stated meaning are presented, and are used to help understand the present invention. Or, an absolute value is used to prevent unscrupulous use of the disclosed content by unscrupulous intruders.
또한, 본 명세서의 "OTf"는 트리플루오로메탄설포네이트기(trifluoromethanesulfonate)를 의미하고, "TMS"는 트리메틸실릴기(trimethylsilyl)를 의미한다.In addition, "OTf" in the present specification means a trifluoromethanesulfonate group (trifluoromethanesulfonate), "TMS" means a trimethylsilyl group (trimethylsilyl).
또한, 본 명세서의 "답코" 또는 "DABCO"는 1,4-디아자바이사이클로(2.2.2)옥탄(1,4-diazabicyclo(2.2.2)octane)을 의미한다(분자량 112.17g/mol, 화학식 N2(C2H4)3). In addition, "dapco" or "DABCO" in the present specification means 1,4-diazabicyclo (2.2.2) octane (1,4-diazabicyclo (2.2.2) octane) (molecular weight 112.17g / mol, chemical formula) N 2 (C 2 H 4 ) 3 ).
또한, 본 명세서의 "친핵체"는 "Nu"또는 "친핵체(Nu)"로 병용하여 표기된다.In addition, "nucleophile" in the present specification is used in combination with "Nu" or "nucleophile (Nu)".
이하 본 발명의 과제해결수단에 대해 구체적으로 상술한다. Hereinafter, the problem solving means of the present invention will be described in detail.
<본 발명의 1-에틸-4-<1-ethyl-4- of the present invention 페닐피페라진Phenylpiperazine 유도체의 제조방법> Method of manufacturing a derivative>
본 발명의 1-에틸-4-페닐피페라진 유도체의 제조방법은 간략하게는 이하의 반응식 3으로 나타낼 수 있고, 화합물 1의 방향족 화합물, 답코(DABCO) 및 친핵체의 3가지 성분을 원팟(one-pot)반응으로 화합물 2의 1-에틸-4-페닐피페라진 유도체를 합성한다.The method for preparing the 1-ethyl-4-phenylpiperazine derivative of the present invention can be briefly represented by the following Reaction Scheme 3, and the three components of the aromatic compound, dabco (DABCO) and nucleophile of compound 1 are one-pot. pot) reaction to synthesize the 1-ethyl-4-phenylpiperazine derivative of compound 2.
[반응식 3][Scheme 3]
더 상세히는, 본 발명의 1-에틸-4-페닐피페라진 유도체의 제조방법은 트리플루오로메탄설포네이트기(OTf)와 트리메틸실릴기(TMS)가 서로 오르토위치에 결합된 방향족 화합물이 아린 중간체로 형성되는 제1반응단계; 상기 아린 중간체가 답코(DABCO)와 반응하여 4차 암모늄염으로 형성되는 제2반응단계; 및 상기 4차 암모늄염과 친핵체를 반응시키는 제3반응단계;를 포함하고, 상기 제1반응단계 내지 제3반응단계는 원팟(one-pot)반응으로 수행되는 것을 특징으로 한다.More specifically, the method for preparing the 1-ethyl-4-phenylpiperazine derivative of the present invention is an intermediate in which an aromatic compound in which a trifluoromethanesulfonate group (OTf) and a trimethylsilyl group (TMS) are bonded to each other in an ortho position The first reaction step is formed of; A second reaction step in which the arin intermediate is formed of a quaternary ammonium salt by reacting with dabco; And a third reaction step of reacting the quaternary ammonium salt with a nucleophile, wherein the first to third reaction steps are performed in a one-pot reaction.
이하에서는 본 발명 1-에틸-4-페닐피페라진 유도체의 일 제조예에 해당하는 반응식 4를 참조하여, 제1반응단계 내지 제3반응단계 각각에 대하여 설명한다. 반응식 4에서 친핵체(Nu)는 티올(HSR)이다. Hereinafter, each of the first reaction step to the third reaction step will be described with reference to Reaction Scheme 4 corresponding to one preparation example of the 1-ethyl-4-phenylpiperazine derivative of the present invention. In Scheme 4, the nucleophile (Nu) is thiol (HSR).
[반응식 4][Reaction Scheme 4]
본 발명의 1-에틸-4-페닐피페라진 유도체의 제조방법에서의 제1반응단계를 상기 반응식 4를 참조하여 설명한다. 반응식 4에서 제1반응단계는 방향족 화합물 1이 반응용액 내의 플루오르 이온(F-)으로 인하여 벤자인 중간체 2를 형성하는 단계이다. 상술한 반응식 4와 동일한 반응과정이거나 해당 기술 분야 통상의 기술자가 명확히 이해할 수 있는 범위 내에서, 트리플루오로메탄설포네이트기(OTf)와 트리메틸실릴기(TMS)가 서로 오르토위치에 결합된 방향족 화합물(방향족 화합물 1)이 아린 중간체(벤자인 중간체 2) 로 형성되는 반응과정까지가 본 발명의 제1반응단계로 정의될 수 있다.The first reaction step in the method for producing a 1-ethyl-4-phenylpiperazine derivative of the present invention will be described with reference to Scheme 4. In Reaction Scheme 4, the first reaction step is a step in which aromatic compound 1 forms benzine intermediate 2 due to fluorine ions (F − ) in the reaction solution. An aromatic compound in which the trifluoromethanesulfonate group (OTf) and the trimethylsilyl group (TMS) are ortho-bonded to each other within the same reaction process as in Reaction Scheme 4 described above, or within a range clearly understood by those skilled in the art. (Aromatic Compound 1) can be defined as the first reaction step of the present invention until the reaction process is formed of an amine intermediate (Benzaine intermediate 2).
이어서, 본 발명의 1-에틸-4-페닐피페라진 유도체의 제조방법에서의 제2반응단계를 상기 반응식 4를 참조하여 설명한다. 형성된 벤자인 중간체 2는 답코 3의 벤자인 중간체 2에 대한 친핵성 공격으로 인하여, 아릴 답코 암모늄염 4를 형성하는 단계까지를 포함한다. 상술한 반응식 4와 동일한 반응과정이거나 해당 기술 분야 통상의 기술자가 명확히 이해할 수 있는 범위 내에서, 아린 중간체(벤자인 중간체 2) 가 답코와 반응하여 4차 암모늄염(아릴 답코 암모늄염 4)으로 형성되는 반응과정까지가 본 발명의 제2반응단계로 정의될 수 있다.Next, a second reaction step in the method for producing a 1-ethyl-4-phenylpiperazine derivative of the present invention will be described with reference to Reaction Scheme 4. The formed benzain intermediate 2 includes steps up to the formation of aryl dabco ammonium salt 4, due to the nucleophilic attack of dabco 3 to benzain intermediate 2. The same reaction process as in Reaction Scheme 4 described above, or within a range that can be clearly understood by those skilled in the art, a reaction in which the aryl intermediate (benzain intermediate 2) reacts with dapco to form a quaternary ammonium salt (aryl dapko ammonium salt 4) Up to the process can be defined as the second reaction step of the present invention.
다음으로, 본 발명의 1-에틸-4-페닐피페라진 유도체의 제조방법에서의 제3반응단계를 상기 반응식 4를 참조하여 설명한다. 반응식 4 제3반응단계에서는 제2반응단계로 형성된 아릴 답코 암모늄염 4(4차 암모늄염)가 친핵체인 티올(HSR)로 인하여, 답코 부분의 개환반응(탄소-질소 절단 반응)이 일어나, 1-에틸-4-페닐피페라진 유도체 5로 형성된다. 상술한 반응식 4와 동일한 반응과정이거나 해당 기술 분야 통상의 기술자가 명확히 이해할 수 있는 범위 내에서, 제2반응단계의 반응산물인 4차 암모늄염(아릴 답코 암모늄염 4)이 친핵체로 인하여, 답코 부분의 개환반응(탄소-질소 절단 반응)이 일어나, 1-에틸-4-페닐피페라진 유도체 5로 형성되는 반응과정까지가 본 발명의 제3반응단계로 정의될 수 있다. Next, a third reaction step in the method for producing a 1-ethyl-4-phenylpiperazine derivative of the present invention will be described with reference to Reaction Scheme 4. In the third reaction step, the aryl dabco ammonium salt 4 (quaternary ammonium salt) formed in the second reaction step is a ring opening reaction (carbon-nitrogen cleavage reaction) of the dapco portion due to the nucleophilic thiol (HSR), 1-ethyl -4-phenylpiperazine derivative 5. The reaction process is the same as the reaction scheme 4 described above, or within the scope clearly understood by those skilled in the art, the reaction product of the second reaction step is quaternary ammonium salt (aryl dapko ammonium salt 4) due to the nucleophile, the opening of the dapco part The reaction (carbon-nitrogen cleavage reaction) takes place, and up to the reaction process formed with 1-ethyl-4-phenylpiperazine derivative 5 can be defined as the third reaction step of the present invention.
본 발명의 제조방법은 상술한 제1반응단계 내지 제3반응단계에 의해 1-에틸-4-페닐피페라진 유도체를 합성할 수 있으며, 각 반응단계의 중간체를 단리 정제할 필요없이 하나의 반응용기 속에서 다음 단계의 반응물을 계속적으로 가하여 반응시키는 방법으로 1-에틸-4-페닐피페라진 유도체를 얻을 수 있다(원팟(one-pot)반응). 본 발명의 제조방법은 중간체의 단리 정제에 따른 물질의 손실을 피할 수 있으므로, 중간체를 단리 정제하여 다음 단계로 반응을 진행하는 방법에 비해 수율이 향상된다.The production method of the present invention can synthesize 1-ethyl-4-phenylpiperazine derivatives by the first to third reaction steps described above, and one reaction vessel without the need for isolation and purification of the intermediate of each reaction step. 1-ethyl-4-phenylpiperazine derivatives can be obtained by continuously adding the reactants of the next step in the reaction (one-pot reaction). Since the production method of the present invention can avoid the loss of material due to the isolation and purification of the intermediate, the yield is improved compared to the method of isolating and purifying the intermediate to proceed to the next step.
이하에서는 본 발명의 제조방법에서의 반응물을 각각 설명한다.Hereinafter, the reactants in the production method of the present invention will be described.
방향족 화합물Aromatic compounds
본 발명의 방향족 화합물은 트리플루오로메탄설포네이트기(OTf)와 트리메틸실릴기(TMS)가 서로 오르토위치에 결합되는 것을 전제로 다양하게 구성될 수 있다.The aromatic compound of the present invention can be variously configured on the premise that the trifluoromethanesulfonate group (OTf) and trimethylsilyl group (TMS) are bonded to each other in an ortho position.
방향족 화합물은 반응 중간체인 아린 중간체의 수율을 높이는 관점에서, 바람직하게는 단환 방향족 화합물일 수 있다. 단환 방향족 화합물의 예시로, 단환의 적어도 하나 이상의 수소원자가 할로겐원자, 메틸기, 에틸기, 프로필기, t-부틸기 등의 선형 또는 분지형의 알킬기, 메톡시기, 에톡시기 등의 알콕시기 등으로 단일치환 또는 다중치환될 수 있다. The aromatic compound may be a monocyclic aromatic compound, preferably from the viewpoint of increasing the yield of the reaction intermediate, which is the reaction intermediate. As an example of a monocyclic aromatic compound, at least one or more hydrogen atoms of the monocyclic ring are monosubstituted with a linear or branched alkyl group such as a halogen atom, a methyl group, an ethyl group, a propyl group, a t-butyl group, an alkoxy group such as a methoxy group or an ethoxy group. Or it can be multi-substituted.
방향족 화합물은 상술한 관점에서, 더 바람직하게는 하기 화학식 1로 표시되는 화합물과 같이 트리플루오로메탄설포네이트기와 트리메틸실릴기 외에 단환의 다른 수소원자가 치환되지 않은 단환 방향족 화합물일 수 있다.The aromatic compound may be a monocyclic aromatic compound in which, in addition to the trifluoromethanesulfonate group and the trimethylsilyl group, other hydrogen atoms of the monocyclic ring are not substituted, more preferably from the above-mentioned viewpoint, as the compound represented by the following Chemical Formula 1.
[화학식 1][Formula 1]
친핵체Nucleophile
친핵체는 히드록시기, 티올기, 할로겐기, 카르복실기, 카르복실레이트기 및 디케톤기로 이루어진 군으로부터 선택되는 적어도 하나 이상의 작용기를 포함할 수 있으나, 상기 열거된 예시에 한정되지 않는다. 친핵체는 제2반응단계의 반응산물인 4차 암모늄염의 답코(DABCO) 부분의 개환반응(탄소-질소 결합 절단반응)을 통해 1-에틸-4-페닐피페라진 유도체를 합성할 수 있으면 충분하다.The nucleophile may include at least one functional group selected from the group consisting of hydroxy group, thiol group, halogen group, carboxyl group, carboxylate group and diketone group, but is not limited to the examples listed above. It is sufficient if the nucleophile can synthesize a 1-ethyl-4-phenylpiperazine derivative through the ring-opening reaction (carbon-nitrogen bond cleavage reaction) of the dabco portion of the quaternary ammonium salt, which is a reaction product of the second reaction step.
친핵체는 1-에틸-4-페닐피페라진 유도체의 합성 수율의 관점에서, 바람직하게는 티올기를 포함하는 선형, 분지형 또는 환형 유기화합물일 수 있다. The nucleophile can be a linear, branched or cyclic organic compound, preferably containing a thiol group, in view of the synthetic yield of 1-ethyl-4-phenylpiperazine derivatives.
친핵체가 티올기를 포함하는 선형, 분지형 또는 환형 화합물일 경우에는 상술한 관점에서, 보다 더 바람직하게는 친핵체를 구성하는 탄소 중 적어도 하나 이상이 황(S)으로 치환될 수 있다.When the nucleophile is a linear, branched or cyclic compound containing a thiol group, from the above-mentioned viewpoint, more preferably, at least one or more carbons constituting the nucleophile may be substituted with sulfur (S).
이하에서는 본 발명의 1-에틸-4-페닐피페라진 유도체의 제조예에 대하여 상세히 설명한다. 그러나 이는 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 제공되는 것으로서, 본 발명은 여러 가지 상이한 형태로 구현될 수 있으며, 본 발명의 사상이 반드시 아래에 열거하는 예에 한정되는 것은 아니다.Hereinafter, a preparation example of the 1-ethyl-4-phenylpiperazine derivative of the present invention will be described in detail. However, this is provided to be easily carried out by those skilled in the art to which the present invention pertains, and the present invention may be embodied in various different forms, and the spirit of the present invention is necessarily in the examples listed below. It is not limited.
제조예Manufacturing example 1 : 11: 1 -페닐-4-(2-(-Phenyl-4- (2- ( 패닐티오Panilthio )에틸)피페라진(1-Phenyl-4-(2-(phenylthio)ethyl)piperazine) (1a)의 제조) Ethyl) Preparation of piperazine (1-Phenyl-4- (2- (phenylthio) ethyl) piperazine) (1a)
4mL 바이알 내의 아세토니트릴(1mL, 0.1M)에 이하의 화학식 1으로 표시되는 방향족 화합물(30mg, 0.1mmol), DABCO (22.5mg, 0.2mmol), 플루오르화세슘(CsF)(15mg, 0.1mmol)을 첨가하였다. 반응은 실온에서 수 시간동안 교반하여 이루어졌다. TLC(thin-layer chromatography)를 확인한 후에, 친핵체로서 티오페놀(20.0㎕)을 첨가하고 반응물을 100℃에서 18시간 동안 가열하였다. 반응 혼합물을 여과하고 감압 하에 농축시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피로 정제하여 목적하는 1-에틸-4-페닐피페라진 유도체 (1a)를 수득하였다.To the acetonitrile (1 mL, 0.1 M) in 4 mL vial, aromatic compounds represented by the following formula 1 (30 mg, 0.1 mmol), DABCO (22.5 mg, 0.2 mmol), cesium fluoride (CsF) (15 mg, 0.1 mmol) Was added. The reaction was accomplished by stirring at room temperature for several hours. After confirming thin-layer chromatography (TLC), thiophenol (20.0 μl) was added as a nucleophile and the reaction was heated at 100 ° C. for 18 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired 1-ethyl-4-phenylpiperazine derivative (1a).
[화학식 1][Formula 1]
제조예 1에서, 티오페놀을 0.1mmol 첨가하는 경우 (1a)의 수율은 66%이다.In Production Example 1, when 0.1 mmol of thiophenol was added, the yield of (1a) was 66%.
제조예 1에서, 티오페놀을 0.2mmol 첨가하는 경우 (1a)의 수율은 90%이다.In Production Example 1, when 0.2 mmol of thiophenol was added, the yield of (1a) was 90%.
제조예 1에서, 티오페놀을 과잉첨가하는 경우 (1a)의 수율은 96%이다.In Production Example 1, when thiophenol was added excessively, the yield of (1a) was 96%.
제조예Manufacturing example 2 : 1-(3,4-디메틸)-4-(2-(페닐티오)에틸)피페라진2: 1- (3,4-dimethyl) -4- (2- (phenylthio) ethyl) piperazine (1-(3,4-Dimethylphenyl)-4-(2-(phenylthio)ethyl)piperazine) (1b)의 제조Preparation of (1- (3,4-Dimethylphenyl) -4- (2- (phenylthio) ethyl) piperazine) (1b)
제조예 1과 동일한 방법으로 제조하되, 방향족 화합물로서 이하의 화학식 2로 표시되는 화합물 0.1mmol을 사용하는 점이 상이하다. 친핵체로서 티오페놀은 0.2mmol 첨가된다.Prepared in the same manner as in Preparation Example 1, the difference is that 0.1mmol of the compound represented by Formula 2 below is used as an aromatic compound. As a nucleophile, thiophenol is added 0.2mmol.
[화학식 2][Formula 2]
제조예 2에서, (1b)의 수율은 81%이다.In Production Example 2, the yield of (1b) is 81%.
제조예Manufacturing example 3 : 13: 1 -(3,4--(3,4- 디메톡시페닐Dimethoxyphenyl )-4-(2-() -4- (2- ( 페닐티오Phenylthio )에틸)피페라진(1-(3,4-Dimethoxyphenyl)-4-(2-(phenylthio)ethyl)piperazine) (1c)의 제조) Ethyl) Preparation of piperazine (1- (3,4-Dimethoxyphenyl) -4- (2- (phenylthio) ethyl) piperazine) (1c)
제조예 1과 동일한 방법으로 제조하되, 방향족 화합물로서 이하의 화학식 3으로 표시되는 화합물 0.1mmol을 사용하는 점이 상이하다. 친핵체로서 티오페놀은 0.2mmol이 첨가된다.Prepared in the same manner as in Production Example 1, the difference in that the use of 0.1mmol compound represented by the following formula (3) as an aromatic compound. As a nucleophile, 0.2 mmol of thiophenol is added.
[화학식 3][Formula 3]
제조예 3에서, (1c)의 수율은 47%이다.In Production Example 3, the yield of (1c) is 47%.
제조예Manufacturing example 4 : 14: 1 -(2--(2- 페닐티오Phenylthio )에틸-4-(p-) Ethyl-4- (p- 톨릴Tolyl )피페라진(1-(2-() Piperazine (1- (2- ( PhenylthioPhenylthio )ethyl)-4-(p-tolyl)piperazine) (1d)의 제조) ethyl) -4- (p-tolyl) piperazine) (1d)
제조예 1과 동일한 방법으로 제조하되, 방향족 화합물로서 이하의 화학식 4로 표시되는 화합물 0.1mmol을 사용하는 점이 상이하다. 친핵체로서 티오페놀은 0.2mmol 첨가된다.Prepared in the same manner as in Production Example 1, the difference in that 0.1mmol of the compound represented by the following formula (4) as an aromatic compound is used. As a nucleophile, thiophenol is added 0.2mmol.
[화학식 4][Formula 4]
제조예 4에서, (1d)는 위치 이성질체로 수득된다. (1d) 위치 이성질체 혼합물의 수율은 73%이다(단, 위치 이성질체(para:meta)의 비는 1:1이다).In Production Example 4, (1d) is obtained as a positional isomer. (1d) The yield of the positional isomer mixture is 73% (however, the ratio of the positional isomers (para: meta) is 1: 1).
제조예Manufacturing example 5 : 15: 1 -(4-(-(4-( terttert -부틸)페닐-4-(2--Butyl) phenyl-4- (2- 페닐티오Phenylthio )에틸)피페라진(1-(4-() Ethyl) piperazine (1- (4- ( terttert -Butyl)phenyl)-4-(2-(phenylthio)ethyl)piperazine) (1e)의 제조Preparation of -Butyl) phenyl) -4- (2- (phenylthio) ethyl) piperazine) (1e)
제조예 1과 동일한 방법으로 제조하되, 방향족 화합물로서 이하의 화학식 5로 표시되는 화합물 0.1mmol을 사용하는 점이 상이하다. 친핵체로서 티오페놀은 0.2mmol이 첨가된다.Prepared in the same manner as in Production Example 1, the difference is that the use of 0.1mmol compound represented by the following formula (5) as an aromatic compound. As a nucleophile, 0.2 mmol of thiophenol is added.
[화학식 5][Formula 5]
제조예 5에서, (1e)는 위치 이성질체로 수득된다. (1e) 위치 이성질체 혼합물의 수율은 62%이다(단, 위치 이성질체(para:meta)의 비는 0.6:1이다).In Production Example 5, (1e) is obtained as a positional isomer. (1e) The yield of the positional isomer mixture is 62% (however, the ratio of the positional isomers (para: meta) is 0.6: 1).
제조예Manufacturing example 6 : 16: 1 -(4--(4- 클로로페닐Chlorophenyl )-4-(2-() -4- (2- ( 페닐티오Phenylthio )에틸)피페라진(1-(4-) Ethyl) piperazine (1- (4- ChlorophenylChlorophenyl )-4-(2-(phenylthio)ethyl)piperazine) (1f)의 제조) -4- (2- (phenylthio) ethyl) piperazine) (1f) Preparation
제조예 1과 동일한 방법으로 제조하되, 방향족 화합물로서 이하의 화학식 6으로 표시되는 화합물 0.1mmol을 사용하는 점이 상이하다. 친핵체로서 티오페놀은 0.2mmol이 첨가된다.Prepared in the same manner as in Production Example 1, the difference in that 0.1mmol of the compound represented by the following formula (6) as an aromatic compound is used. As a nucleophile, 0.2 mmol of thiophenol is added.
[화학식 6][Formula 6]
제조예 6에서, (1f)는 위치 이성질체로 수득된다. (1f) 위치 이성질체 혼합물의 수율은 73%이다(단, 위치 이성질체(para:meta)의 비는 1:1이다).In preparation example 6, (1f) is obtained as a positional isomer. (1f) The yield of the positional isomer mixture is 73% (however, the ratio of the positional isomers (para: meta) is 1: 1).
제조예Manufacturing example 7 : 17: 1 -(4--(4- 플루오로페닐Fluorophenyl )-4-(2-() -4- (2- ( 페닐티오Phenylthio )에틸)피페라진(1-(4-Fluorophenyl)-4-(2-(phenylthio)ethyl)piperazine) (1g)의 제조) Ethyl) Preparation of piperazine (1- (4-Fluorophenyl) -4- (2- (phenylthio) ethyl) piperazine) (1 g)
제조예 1과 동일한 방법으로 제조하되, 방향족 화합물로서 이하의 화학식 7으로 표시되는 화합물 0.1mmol을 사용하는 점이 상이하다. 친핵체로서 티오페놀은 0.2mmol이 첨가된다.Prepared in the same manner as in Production Example 1, the difference in that 0.1mmol of the compound represented by the following formula (7) as an aromatic compound is used. As a nucleophile, 0.2 mmol of thiophenol is added.
[화학식 7][Formula 7]
제조예 7에서, (1g)는 위치 이성질체로 수득된다. (1g) 위치 이성질체 혼합물의 수율은 65%이다(단, 위치 이성질체(para:meta)의 비는 (1:0.3)이다).In Production Example 7, (1 g) is obtained as a positional isomer. (1 g) The yield of the positional isomer mixture is 65% (however, the ratio of the positional isomers (para: meta) is (1: 0.3)).
제조예Manufacturing example 8 : 18: 1 -(3--(3- 메톡시페닐Methoxyphenyl )-4-(2-() -4- (2- ( 페닐티오Phenylthio )에틸)피페라진(1-(3-) Ethyl) piperazine (1- (3- MethoxyphenylMethoxyphenyl )-4-(2-(phenylthio)ethyl)piperazine) (1h)의 제조) -4- (2- (phenylthio) ethyl) piperazine) (1h) Preparation
제조예 1과 동일한 방법으로 제조하되, 방향족 화합물로서 이하의 화학식 8으로 표시되는 화합물 0.1mmol을 사용하는 점이 상이하다. 친핵체로서 티오페놀은 0.2mmol이 첨가된다.Prepared in the same manner as in Production Example 1, the difference is that the use of 0.1mmol compound represented by the following formula (8) as an aromatic compound. As a nucleophile, 0.2 mmol of thiophenol is added.
[화학식 8][Formula 8]
제조예 8에서, (1h)의 수율은 64%이다.In Production Example 8, the yield of (1h) is 64%.
제조예Manufacturing example 9 : 19: 1 -(나프탈렌-2-일)-4-(2-(-(Naphthalen-2-yl) -4- (2- ( 페닐티오Phenylthio )에틸)피페라진(1-() Ethyl) piperazine (1- ( NaphthalenNaphthalen -2-yl)-4-(2-(phenylthio)ethyl)piperazine) (1i)의 제조Preparation of -2-yl) -4- (2- (phenylthio) ethyl) piperazine) (1i)
제조예 1과 동일한 방법으로 제조하되, 방향족 화합물로서 이하의 화학식 9로 표시되는 화합물 0.1mmol을 사용하는 점이 상이하다. 친핵체로서 티오페놀은 0.2mmol이 첨가된다.Prepared in the same manner as in Production Example 1, the difference in that 0.1mmol of the compound represented by the following formula (9) as an aromatic compound is used. As a nucleophile, 0.2 mmol of thiophenol is added.
[화학식 9][Formula 9]
제조예 9에서, (1i)의 수율은 79%이다.In Production Example 9, the yield of (1i) is 79%.
제조예Manufacturing example 10 : 410: 4 ,4′-bis(4-(2-(, 4′-bis (4- (2- ( 페닐티오Phenylthio )에틸)피페라진-1-일)-1,1′-) Ethyl) piperazin-1-yl) -1,1′- 바이페닐Biphenyl (4,4′-bis(4-(2-(phenylthio)ethyl)piperazin-1-yl)-1,1′-biphenyl) (1j)의 제조Preparation of (4,4′-bis (4- (2- (phenylthio) ethyl) piperazin-1-yl) -1,1′-biphenyl) (1j)
제조예 1과 동일한 방법으로 제조하되, 방향족 화합물로서 이하의 화학식 10으로 표시되는 화합물 0.1mmol을 사용하는 점이 상이하다. 친핵체로서 티오페놀은 0.2mmol이 첨가된다.Prepared in the same manner as in Production Example 1, the difference is that 0.1mmol of the compound represented by the following formula (10) as an aromatic compound is used. As a nucleophile, 0.2 mmol of thiophenol is added.
[화학식 10][Formula 10]
제조예 10에서, (1j)의 이성질체 혼합물을 74% 단리 수율로 수득하였다.In Production Example 10, an isomer mixture of (1j) was obtained in 74% isolated yield.
제조예Manufacturing example 11 : 111: 1 -(2-(나프탈렌-2--(2- (naphthalene-2- 일티오Thio )에틸)-4-) Ethyl) -4- 페닐피페라진Phenylpiperazine (1-(2-((1- (2- ( NaphthalenNaphthalen -2-ylthio)ethyl)-4-phenylpiperazine) (2a)의 제조Preparation of -2-ylthio) ethyl) -4-phenylpiperazine) (2a)
제조예 1과 동일한 방법으로 제조하되, 친핵체로서 이하의 화학식 11으로 표시되는 화합물 0.2mmol을 사용하는 점이 상이하다. Prepared in the same manner as in Production Example 1, the point of using 0.2mmol of the compound represented by Formula 11 below as a nucleophile is different.
[화학식 11][Formula 11]
제조예 11에서, (2a)의 수율은 74%이다.In Production Example 11, the yield of (2a) is 74%.
제조예Manufacturing example 12 : 112: 1 -페닐-4-(2-(p--Phenyl-4- (2- (p- 톨릴티오Tolylthio )에틸)피페라진(1-Phenyl-4-(2-(p-tolylthio)ethyl)piperazine) (2b)의 제조) Ethyl) Preparation of piperazine (1-Phenyl-4- (2- (p-tolylthio) ethyl) piperazine) (2b)
제조예 1과 동일한 방법으로 제조하되, 친핵체로서 이하의 화학식 12로 표시되는 화합물 0.2mmol을 사용하는 점이 상이하다. Prepared in the same manner as in Production Example 1, the point of using 0.2mmol of the compound represented by the following formula (12) as a nucleophile is different.
[화학식 12][Formula 12]
제조예 12에서, (2b)의 수율은 76%이다.In Production Example 12, the yield of (2b) is 76%.
제조예Manufacturing example 13 : 113: 1 -(2-((2,6--(2-((2,6- 디메틸페닐Dimethylphenyl )) 티오Thio )에틸)4-) Ethyl) 4- 페닐피페라진Phenylpiperazine (1-(2-((2,6-Dimethylphenyl)thio)ethyl)-4-phenylpiperazine) (2c)의 제조Preparation of (1- (2-((2,6-Dimethylphenyl) thio) ethyl) -4-phenylpiperazine) (2c)
제조예 1과 동일한 방법으로 제조하되, 친핵체로서 이하의 화학식 13으로 표시되는 화합물 0.2mmol을 사용하는 점이 상이하다. Prepared in the same manner as in Production Example 1, the point of using 0.2mmol of the compound represented by the following formula 13 as a nucleophile is different.
[화학식 13][Formula 13]
제조예 13에서, (2c)의 수율은 63%이다.In Production Example 13, the yield of (2c) is 63%.
제조예Manufacturing example 14 : S- 14: S- (2-(4-페닐피페라진-1-일)에틸)에탄티오에이트(2- (4-phenylpiperazin-1-yl) ethyl) ethanothioate (S-(2-(4-Phenylpiperazin-1-yl)ethyl)ethanethioate) (2d)의 제조Preparation of (S- (2- (4-Phenylpiperazin-1-yl) ethyl) ethanethioate) (2d)
제조예 1과 동일한 방법으로 제조하되, 친핵체로서 이하의 화학식 14로 표시되는 화합물 0.2mmol을 사용하는 점이 상이하다. Prepared in the same manner as in Preparation Example 1, the difference is that 0.2mmol of the compound represented by the following formula 14 as a nucleophile is used.
[화학식 14][Formula 14]
제조예 14에서, (2d)의 수율은 75%이다.In Production Example 14, the yield of (2d) is 75%.
제조예Manufacturing example 15 : 115: 1 -페닐-4-(2-피리딘-2--Phenyl-4- (2-pyridin-2- 일티오Thio )에틸)피페라진(1-Phenyl-4-(2-() Ethyl) piperazine (1-Phenyl-4- (2- ( pyridinpyridine -2-ylthio)ethyl)piperazine) (2e)의 제조Preparation of -2-ylthio) ethyl) piperazine) (2e)
제조예 1과 동일한 방법으로 제조하되, 친핵체로서 이하의 화학식 15로 표시되는 화합물 0.2mmol을 사용하는 점이 상이하다. Prepared in the same manner as in Production Example 1, the difference in that 0.2mmol of the compound represented by the following formula 15 as a nucleophile is used.
[화학식 15][Formula 15]
제조예 15에서, (2e)의 수율은 47%이다.In Production Example 15, the yield of (2e) is 47%.
제조예Manufacturing example 16 : 116: 1 -(2-(-(2-( terttert -- 부틸티오Butylthio )에틸)-4-) Ethyl) -4- 페닐피페라진Phenylpiperazine (1-(2-((1- (2- ( terttert -Butylthio)ethyl)-4-phenylpiperazine) (2f)의 제조Preparation of -Butylthio) ethyl) -4-phenylpiperazine) (2f)
제조예 1과 동일한 방법으로 제조하되, 친핵체로서 이하의 화학식 16으로 표시되는 화합물 0.2mmol을 사용하는 점이 상이하다. Prepared in the same manner as in Preparation Example 1, the difference is that 0.2mmol of a compound represented by the following formula (16) as a nucleophile is used.
[화학식 16][Formula 16]
제조예 16에서, (2f)의 수율은 45%이다.In Production Example 16, the yield of (2f) is 45%.
제조예Manufacturing example 17 : 117: 1 -페닐-4-(2-티오펜-2--Phenyl-4- (2-thiophen-2- 일티오Thio )에틸)피페라진(1-Phenyl-4-(2-(thiophen-2-ylthio)ethyl)piperazine) (2g)의 제조) Ethyl) Preparation of piperazine (1-Phenyl-4- (2- (thiophen-2-ylthio) ethyl) piperazine) (2g)
제조예 1과 동일한 방법으로 제조하되, 친핵체로서 이하의 화학식 17으로 표시되는 화합물 0.2mmol을 사용하는 점이 상이하다. It was prepared in the same manner as in Production Example 1, except that 0.2 mmol of the compound represented by the following Chemical Formula 17 was used as a nucleophile.
[화학식 17][Formula 17]
제조예 17에서, (2g)의 수율은 93%이다.In Production Example 17, the yield of (2g) is 93%.
제조예Manufacturing example 18 : 218: 2 -(2-(4--(2- (4- 페닐피페라진Phenylpiperazine -1-일)-1 day) 에틸티오Ethyl thio )퀴놀린(2-(2-(4-phenylpiperazin-1-yl)ethylthio)quinoline) (2h)의 제조Preparation of quinoline (2- (2- (4-phenylpiperazin-1-yl) ethylthio) quinoline) (2h)
제조예 1과 동일한 방법으로 제조하되, 친핵체로서 이하의 화학식 18으로 표시되는 화합물 0.2mmol을 사용하는 점이 상이하다. Prepared in the same manner as in Production Example 1, the difference in that 0.2mmol of the compound represented by the following formula (18) as a nucleophile is used.
[화학식 18][Formula 18]
제조예 18에서, (2h)의 수율은 85%이다.In Production Example 18, the yield of (2h) is 85%.
제조예Manufacturing example 19 : 219: 2 -((2-(4--((2- (4- 페닐피페라진Phenylpiperazine -1-일)에틸)-1-yl) ethyl) 티오Thio )-4,5-) -4,5- 디히드로티아졸Dihydrothiazole (2-((2-(4-Phenylpiperazin-1-yl)ethyl)thio)-4,5-dihydrothiazole) (2i)의 제조Preparation of (2-((2- (4-Phenylpiperazin-1-yl) ethyl) thio) -4,5-dihydrothiazole) (2i)
제조예 1과 동일한 방법으로 제조하되, 친핵체로서 이하의 화학식 19로 표시되는 화합물 0.2mmol을 사용하는 점이 상이하다. Prepared in the same manner as in Production Example 1, the point of using 0.2mmol of the compound represented by the following formula 19 as a nucleophile is different.
[화학식 19][Formula 19]
제조예 19에서, (2i)의 수율은 93%이다.In Production Example 19, the yield of (2i) is 93%.
제조예Manufacturing example 20 : 220: 2 -- ((2-(4-페닐피페라진-1-일)에틸)티오((2- (4-phenylpiperazin-1-yl) ethyl) thio )) 벤조[d]티아졸(2-((2-Benzo [d] thiazole (2-((2- (4-Phenylpiperazin-1-yl)ethyl)thio)benzo[d]thiazole) (2j)의 제조Preparation of (4-Phenylpiperazin-1-yl) ethyl) thio) benzo [d] thiazole) (2j)
제조예 1과 동일한 방법으로 제조하되, 친핵체로서 이하의 화학식 20으로 표시되는 화합물 0.2mmol을 사용하는 점이 상이하다. Prepared in the same manner as in Production Example 1, the difference is that the use of 0.2mmol of the compound represented by the following formula (20) as a nucleophile.
[화학식 20][Formula 20]
제조예 20에서, (2j)의 수율은 62%이다.In Production Example 20, the yield of (2j) is 62%.
제조예Manufacturing example 21 : 121: 1 -(2-((-(2-(( 3s,5s,7s3s, 5s, 7s )-)- 아다만탄Adamantane -1--One- 일티오Thio )에틸)-4-) Ethyl) -4- 페닐피페라진Phenylpiperazine (1-(2-((3s,5s,7s)-Adamantan-1-ylthio)ethyl)-4-phenylpiperazine) (2k)의 제조Preparation of (1- (2-((3s, 5s, 7s) -Adamantan-1-ylthio) ethyl) -4-phenylpiperazine) (2k)
제조예 1과 동일한 방법으로 제조하되, 친핵체로서 이하의 화학식 21로 표시되는 화합물 0.2mmol을 사용하는 점이 상이하다. Prepared in the same manner as in Production Example 1, the difference in that 0.2mmol of the compound represented by the following formula 21 as a nucleophile is used.
[화학식 21][Formula 21]
제조예 21에서, (2k)의 수율은 46%이다.In Production Example 21, the yield of (2k) is 46%.
제조예Manufacturing example 22 : 122: 1 -페닐-4-(2-(-Phenyl-4- (2- ( 페닐티오Phenylthio )에틸)피페리딘(1-Phenyl-4-(2-(phenylthio)ethyl)piperidine) (2L)의 제조Preparation of) ethyl) piperidine (1-Phenyl-4- (2- (phenylthio) ethyl) piperidine) (2L)
제조예 1과 동일한 방법으로 제조하되, 답코(DABCO) 대신 이하의 화학식 22로 표시되는 화합물(퀴누클리딘, 1-azabicyclo[2.2.2]octane) 0.2mmol을 사용하는 점이 상이하다. It was prepared in the same manner as in Preparation Example 1, except that 0.2mmol of a compound represented by the following Chemical Formula 22 (quinuclidine, 1-azabicyclo [2.2.2] octane) instead of DABCO was used.
[화학식 22][Formula 22]
제조예 22에서, (2L)의 수율은 98%이다.In Production Example 22, the yield of (2L) was 98%.
제조예Manufacturing example 23 : 223: 2 -(4--(4- 페닐피페라진Phenylpiperazine -1-일)에틸 -1-yl) ethyl 아크릴레이트Acrylate (2-(4-(2- (4- PhenylpiperazinPhenylpiperazin -1-yl)ethyl -1-yl) ethyl acrylateacrylate ) (3a)의 제조) (3a) Preparation
4mL 바이알 내의 아세토니트릴:친핵체(0.5mL:0.5mL, 0.2M)에 이하의 화학식 1로 표시되는 방향족 화합물(30mg, 0.1mmol), DABCO (22.5mg, 0.2mmol), 플루오르화세슘(CsF)(15mg, 0.1mmol)을 첨가하고 반응물을 100℃에서 18시간 동안 가열하였다. 반응 혼합물을 여과하고 감압 하에 농축시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피로 정제하여 목적하는 1-에틸-4-페닐피페라진 유도체 (3a)를 수득하였다.Acetonitrile: nucleophile (0.5 mL: 0.5 mL, 0.2 M) in 4 mL vial, aromatic compound represented by the following formula 1 (30 mg, 0.1 mmol), DABCO (22.5 mg, 0.2 mmol), cesium fluoride (CsF) ( 15mg, 0.1mmol) was added and the reaction was heated at 100 ° C for 18 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired 1-ethyl-4-phenylpiperazine derivative (3a).
친핵체로서 이하의 화학식 23로 표시되는 화합물이 사용된다.As a nucleophile, the compound represented by the following formula (23) is used.
[화학식 1][Formula 1]
[화학식 23][Formula 23]
제조예 23에서, (3a)의 수율은 41%이다.In Production Example 23, the yield of (3a) is 41%.
제조예Manufacturing example 24 : 224: 2 -(4-(p--(4- (p- 톨릴Tolyl )피페라진-1-일)에틸 ) Piperazin-1-yl) ethyl 아크릴레이트Acrylate (2-(4-(p-Tolyl)piperazin-1-yl)ethyl (2- (4- (p-Tolyl) piperazin-1-yl) ethyl acrylateacrylate ) (3b)의 제조) Preparation of (3b)
제조예 23와 동일한 방법으로 제조하되, 방향족 화합물로서 이하의 화학식 4로 표시되는 화합물 0.1mmol을 사용하는 점이 상이하다.It was prepared in the same manner as in Production Example 23, except that 0.1 mmol of the compound represented by Formula 4 below was used as the aromatic compound.
[화학식 4][Formula 4]
제조예 24에서, (3b)는 위치 이성질체로 수득된다. (3b) 위치 이성질체 혼합물의 수율은 33%이다(단, 위치 이성질체(para:meta)의 비는 0.8:1이다).In preparation example 24, (3b) is obtained as a positional isomer. (3b) The yield of the positional isomer mixture is 33% (however, the ratio of the positional isomers (para: meta) is 0.8: 1).
제조예Manufacturing example 25 : 225: 2 -(4-(4--(4- (4- 플루오로페닐Fluorophenyl )피페라진-1-일)에틸 ) Piperazin-1-yl) ethyl 아크릴레이트Acrylate (2-(4-(4-Fluorophenyl)piperazin-1-yl)ethyl (2- (4- (4-Fluorophenyl) piperazin-1-yl) ethyl acrylateacrylate ) (3c)의 제조) (3c) Preparation
제조예 23와 동일한 방법으로 제조하되, 방향족 화합물로서 이하의 화학식 7으로 표시되는 화합물 0.1mmol을 사용하는 점이 상이하다.It was prepared in the same manner as in Production Example 23, except that 0.1 mmol of the compound represented by the following Chemical Formula 7 was used as an aromatic compound.
[화학식 7][Formula 7]
제조예 25에서, (3c)는 위치 이성질체로 수득된다. (3c) 위치 이성질체 혼합물의 수율은 33%이다(단, 위치 이성질체(para:meta)의 비는 1:0.6이다).In preparation example 25, (3c) is obtained as a positional isomer. (3c) The yield of the positional isomer mixture is 33% (however, the ratio of the positional isomers (para: meta) is 1: 0.6).
제조예Manufacturing example 26 : 226: 2 -(4--(4- 페닐피페라진Phenylpiperazine -1-일)에틸 아세테이트(2-(4--1-yl) ethyl acetate (2- (4- PhenylpiperazinPhenylpiperazin -1-yl)ethyl acetate) (-1-yl) ethyl acetate) ( 4)의4) of 제조 Produce
4mL 바이알 내의 아세토니트릴:친핵체(0.5mL:0.5mL, 0.1M)에 이하의 화학식 1으로 표시되는 방향족 화합물(30mg, 0.1mmol), DABCO (22.5mg, 0.2mmol), 플루오르화세슘(CsF)(15mg, 0.1mmol)을 첨가하고 반응물을 100℃에서 18시간 동안 가열하였다. 반응 혼합물을 여과하고 감압 하에 농축시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피로 정제하여 목적하는 1-에틸-4-페닐피페라진 유도체 (4)를 수득하였다.Acetonitrile: nucleophile (0.5 mL: 0.5 mL, 0.1 M) in 4 mL vial, aromatic compound represented by the following formula 1 (30 mg, 0.1 mmol), DABCO (22.5 mg, 0.2 mmol), cesium fluoride (CsF) ( 15mg, 0.1mmol) was added and the reaction was heated at 100 ° C for 18 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired 1-ethyl-4-phenylpiperazine derivative (4).
친핵체로서 이하의 화학식 24로 표시되는 화합물이 사용된다.As a nucleophile, the compound represented by the following formula (24) is used.
[화학식 1][Formula 1]
[화학식 24][Formula 24]
제조예 26에서, (4)의 수율은 32%이다.In Production Example 26, the yield of (4) is 32%.
제조예Manufacturing example 27 : 127: 1 -(2--(2- 플루오로에틸Fluoroethyl )-4-)-4- 페닐피페라진Phenylpiperazine (1-(2-(1- (2- fluoroethylfluoroethyl )-4-phenylpiperazine) () -4-phenylpiperazine) ( 5)의5) of 제조 Produce
4mL 바이알 내의 아세토니트릴 (1mL, 0.1M)에 이하의 화학식 1으로 표시되는 방향족 화합물(30mg, 0.1mmol), DABCO (22.5mg, 0.2mmol), 플루오르화칼륨(KF)(174.3mg, 3.0mmol)을 첨가하고 반응물을 100℃에서 18시간 동안 가열하였다. 반응 혼합물을 여과하고 감압 하에 농축시켰다. 잔류물을 실리카겔 컬럼 크로마토그래피로 정제하여 목적하는 1-에틸-4-페닐피페라진 유도체 (5)를 수득하였다.Aromatic compounds represented by the following formula 1 in acetonitrile (1 mL, 0.1 M) in a 4 mL vial (30 mg, 0.1 mmol), DABCO (22.5 mg, 0.2 mmol), potassium fluoride (KF) (174.3 mg, 3.0 mmol) Was added and the reaction was heated at 100 ° C. for 18 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired 1-ethyl-4-phenylpiperazine derivative (5).
친핵체로서 플루오르화칼륨(KF)이 사용된다.Potassium fluoride (KF) is used as the nucleophile.
[화학식 1][Formula 1]
제조예 27에서, (5)의 수율은 45%이다.In Production Example 27, the yield of (5) is 45%.
제조예Manufacturing example 28 : 428: 4 -히드록시-3-(2-(4--Hydroxy-3- (2- (4- 페닐피페라진Phenylpiperazine -1-일)에틸)-1-yl) ethyl) 펜트Pent -3-엔-2-온(4-Hydroxy-3-(2-(4-phenylpiperazin-1-yl)ethyl)pent-3-en-2-one) (-3-en-2-one (4-Hydroxy-3- (2- (4-phenylpiperazin-1-yl) ethyl) pent-3-en-2-one) ( 6)의6) of 제조 Produce
제조예 23와 동일한 방법으로 제조하되, 친핵체로서 이하의 화학식 25로 표시되는 화합물을 사용하는 점이 상이하다.It was prepared in the same manner as in Production Example 23, except that a compound represented by the following Chemical Formula 25 was used as a nucleophile.
[화학식 25][Formula 25]
제조예 28에서, (6)의 수율은 23%이다.In Production Example 28, the yield of (6) is 23%.
이상에서는 본 발명의 제조방법에 따라 제조될 수 있는 제조예를 열거하였으나, 본 발명의 사상은 이에 제한되어 해석되지 않는다. 통상의 기술자가 명확히 이해할 수 있는 범위에서 본 명세서 상에 기재된 방향족 화합물, 친핵체를 적절히 조합할 수 있다. 상술한 각 제조예를 요약하면 이하의 [표 1]로 나타낼 수 있다.In the above, the manufacturing examples that can be produced according to the manufacturing method of the present invention are listed, but the spirit of the present invention is not limited to this and is not interpreted. The aromatic compounds and nucleophiles described herein can be appropriately combined within a range clearly understood by those skilled in the art. In summary, each of the above-described manufacturing examples can be represented by the following [Table 1].
(%)yield
(%)
90
9666
90
96
제조예 1을 참조하면, 친핵체인 티오페놀의 몰량(당량)이 증가함에 따라 1-에틸-4-페닐피페라진 유도체의 수율(이하 '수율')이 향상되는 점을 확인할 수 있다. 상기 결과는 본 발명 제조방법이 각 반응단계의 중간체를 단리 정제할 필요없이 하나의 반응용기 속에서 다음 단계의 반응물을 계속적으로 가하여 반응시키는 방법으로 1-에틸-4-페닐피페라진 유도체를 얻을 수 있는 원팟(one-pot)반응이라는 점에서 비롯된다.Referring to Preparation Example 1, it can be seen that the yield (hereinafter referred to as 'yield') of the 1-ethyl-4-phenylpiperazine derivative improves as the molar amount (equivalent) of the nucleophile, thiophenol, increases. The above results show that the method of the present invention is a method of continuously adding and reacting the reactants of the next step in one reaction vessel without the need to isolate and purify the intermediate of each reaction step to obtain 1-ethyl-4-phenylpiperazine derivatives. It comes from the fact that there is a one-pot reaction.
즉, 본 발명의 제조방법에서는 원팟(one-pot)반응으로 1-에틸-4-페닐피페라진 유도체를 합성하기 때문에, 중간체를 단리 정제하지 않고 반응물을 계속적으로 첨가하는 간단한 방식을 통해 효율적으로 수율을 향상시킬 수 있다. 제조예 1의 결과로부터, 제조예 2 내지 28에서는 첨가하는 친핵체 양을 고정하여 수율을 측정하였으나, 첨가하는 친핵체 양을 더 첨가하는 경우에는 제조예 2 내지 28의 수율 역시 제조예 1의 결과와 마찬가지로 향상될 수 있음을 알 수 있다. That is, in the production method of the present invention, since the 1-ethyl-4-phenylpiperazine derivative is synthesized in a one-pot reaction, the yield is efficiently obtained through a simple method of continuously adding the reactant without isolating and purifying the intermediate. Improve it. From the results of Preparation Example 1, in Production Examples 2 to 28, the yield of the nucleophile added was fixed to measure the yield, but when the amount of the added nucleophile was further added, the yields of Production Examples 2 to 28 were also the same as those of Production Example 1 It can be seen that it can be improved.
제조예 1 내지 10에서는 본 발명의 방향족 화합물의 최적화를 위하여 방향족 화합물을 다양하게 구성하여 1-에틸-4-페닐피페라진 유도체를 합성하였다. 제조예 1과 제조예 9의 수율을 비교하면, 방향족 화합물이 다환 방향족 화합물인 제조예 9의 수율보다 단환 방향족 화합물인 제조예 1의 수율이 더욱 높으므로, 단환 방향족 화합물일때 아린 중간체의 수율이 더 높은 것을 알 수 있다.In Preparation Examples 1 to 10, 1-ethyl-4-phenylpiperazine derivatives were synthesized by variously configuring aromatic compounds for optimization of the aromatic compounds of the present invention. When the yields of Production Example 1 and Production Example 9 are compared, the yield of Production Example 1, which is a monocyclic aromatic compound, is higher than that of Production Example 9, where the aromatic compound is a polycyclic aromatic compound. You can see that it is high.
또한, 방향족 화합물이 단환 방향족 화합물일 경우에도, 트리플루오로메탄설포네이트기(OTf)와 트리메틸실릴기(TMS) 외에 단환의 다른 수소원자가 치환되지 않은 단환 방향족 화합물인 제조예 1의 수율이 단환의 다른 수소원자가 할로겐원자, 메틸기, t-부틸기, 메톡시기 등으로 치환된 제조예 2 내지 8에 비해 수율이 높으므로, 본 발명의 단환 방향족 화합물이 제조예 1의 단환 방향족 화합물일 때 아린 중간체의 수율이 보다 더 높은 것을 알 수 있다.In addition, even when the aromatic compound is a monocyclic aromatic compound, the yield of Production Example 1, which is a monocyclic aromatic compound in which other hydrogen atoms in the monocyclic ring are not substituted in addition to the trifluoromethanesulfonate group (OTf) and trimethylsilyl group (TMS), is monocyclic. Since the yields are higher than those of Preparation Examples 2 to 8 in which other hydrogen atoms were substituted with halogen atoms, methyl groups, t-butyl groups, methoxy groups, etc., when the monocyclic aromatic compound of the present invention was the monocyclic aromatic compound of Preparation Example 1, It can be seen that the yield is higher.
제조예 1, 11 내지 21, 23 및 26 내지 28에서는 본 발명의 친핵체의 최적화를 위하여 친핵체를 다양하게 구성하여 1-에틸-4-페닐피페라진 유도체를 합성하였다. 제조예 23, 26 내지 28과 제조예 1, 11 내지 21의 수율을 비교하면, 티올기를 함유하는 화합물일 경우 수율이 전반적으로 높은 것을 확인할 수 있다.In Preparation Examples 1, 11 to 21, 23 and 26 to 28, 1-ethyl-4-phenylpiperazine derivatives were synthesized by variously constructing nucleophiles for optimization of the nucleophile of the present invention. By comparing the yields of Production Examples 23, 26 to 28 and Production Examples 1, 11 to 21, it can be confirmed that the overall yield is high in the case of a compound containing a thiol group.
또한, 친핵체가 티올기를 함유하는 화합물일 경우에도, 제조예 14 및 16의 분지형 화합물보다 제조예 1, 11 내지 13, 15 및 17 내지 21의 환형 화합물의 수율이 전반적으로 높은 것을 확인할 수 있다.In addition, it can be seen that even when the nucleophile is a compound containing a thiol group, the yields of the cyclic compounds of Preparation Examples 1, 11 to 13, 15 and 17 to 21 are generally higher than those of the branched compounds of Preparation Examples 14 and 16.
또한, 제조예 17, 19와 같이 친핵체를 구성하는 탄소가 황으로 치환되는 경우 수율이 확연히 향상되는 것을 확인할 수 있다.In addition, it can be seen that, as in Production Examples 17 and 19, when the carbon constituting the nucleophile is substituted with sulfur, the yield is significantly improved.
또한, 제조예 22를 참고하면 답코(DABCO) 대신 화학식 22로 표시되는 화합물(퀴누클리딘, 1-azabicyclo[2.2.2]octane)을 사용한 경우, (2L)로 표시되는 화합물이 아주 높은 수율 98%로 수득되었다. 상기 결과로부터 본 발명의 친핵체가 탄소-질소 절단 반응을 이용한 개환반응을 유도할 수 있음을 확인할 수 있다. Also, referring to Preparation Example 22, when a compound represented by Chemical Formula 22 (quinuclidin, 1-azabicyclo [2.2.2] octane) is used instead of DABCO, the compound represented by (2L) has a very high yield 98 %. It can be confirmed from the above results that the nucleophile of the present invention can induce a ring-opening reaction using a carbon-nitrogen cleavage reaction.
상술한 바와 같이, 본 발명은 방향족 화합물, 답코(DABCO) 및 친핵체의 3가지 성분을 이용한 1-에틸-4-페닐피페라진 유도체의 다양한 합성 방법을 제공한다. 종래기술의 1-에틸-4-페닐피페라진 유도체의 합성 방법으로서 사용되는 반응화합물은 다소 제한되는 것에 반하여, 본 발명에 의하면 다양한 방향족 화합물, 답코(DABCO) 및 다양한 친핵체를 이용하여 1-에틸-4-페닐피페라진 유도체를 합성할 수 있다.As described above, the present invention provides various methods of synthesizing 1-ethyl-4-phenylpiperazine derivatives using three components: an aromatic compound, dabco (DABCO) and a nucleophile. While the reaction compound used as a method for synthesizing the 1-ethyl-4-phenylpiperazine derivative of the prior art is somewhat limited, the present invention uses 1-ethyl- using various aromatic compounds, dabco (DABCO) and various nucleophiles. 4-phenylpiperazine derivatives can be synthesized.
아울러, 본 발명에서의 각 합성반응단계인 제1반응단계 내지 제3반응단계는 연속적으로 일어나는 원팟(one-pot)반응으로서 한 반응용기 내에서 합성반응이 이루어지므로, 간단하면서도 효율적으로 1-에틸-4-페닐피페라진 유도체를 합성할 수 있다.In addition, the first reaction step to the third reaction step, each of the synthetic reaction steps in the present invention, is a one-pot reaction that continuously occurs, and the synthesis reaction is performed in one reaction container, so that 1-ethyl is simple and efficient. A -4-phenylpiperazine derivative can be synthesized.
또한, 본 발명은 높은 수율로 1-에틸-4-페닐피페라진 유도체를 합성할 수 있다.In addition, the present invention can synthesize a 1-ethyl-4-phenylpiperazine derivative with high yield.
Claims (7)
상기 아린 중간체가 답코(DABCO)와 반응하여 4차 암모늄염으로 형성되는 제2반응단계; 및
상기 4차 암모늄염과 친핵체를 반응시키는 제3반응단계;를 포함하고,
상기 제1반응단계 내지 제3반응단계는 원팟(one-pot)반응으로 수행되는 것을 특징으로 하는 1-에틸-4-페닐피페라진 유도체의 제조방법.A first reaction step in which an aromatic compound in which a trifluoromethanesulfonate group and a trimethylsilyl group are bonded to each other in an ortho position is formed as an amine intermediate;
A second reaction step in which the arin intermediate is formed of a quaternary ammonium salt by reacting with dabco; And
Including; a third reaction step of reacting the quaternary ammonium salt and the nucleophile,
The first reaction step to the third reaction step 1-ethyl-4-phenyl piperazine derivative production method characterized in that it is carried out in a one-pot (one-pot) reaction.
상기 방향족 화합물은 단환 방향족 화합물인 것을 특징으로 하는 1-에틸-4-페닐피페라진 유도체의 제조방법.According to claim 1,
The aromatic compound is a method for producing a 1-ethyl-4-phenylpiperazine derivative, characterized in that the monocyclic aromatic compound.
상기 방향족 화합물은 하기 화학식 1로 표시되는 화합물인 것을 특징으로 하는 1-에틸-4-페닐피페라진 유도체의 제조방법:
[화학식 1]
The aromatic compound is a method of producing a 1-ethyl-4-phenylpiperazine derivative, characterized in that the compound represented by the formula (1):
[Formula 1]
상기 방향족 화합물은 플루오르 이온에 의해 상기 아린 중간체로 형성되는 것을 특징으로 하는 1-에틸-4-페닐피페라진 유도체의 제조방법.The method according to any one of claims 1 to 3,
The aromatic compound is a method for producing a 1-ethyl-4-phenylpiperazine derivative, characterized in that it is formed of the arin intermediate by fluorine ions.
상기 친핵체는 히드록시기, 티올기, 할로겐기, 카르복실기, 카르복실레이트기 및 디케톤기로 이루어진 군으로부터 선택되는 적어도 하나 이상의 작용기를 포함하는 화합물인 것을 특징으로 하는 1-에틸-4-페닐피페라진 유도체의 제조방법.According to claim 1,
The nucleophile is a compound containing at least one functional group selected from the group consisting of a hydroxy group, a thiol group, a halogen group, a carboxyl group, a carboxylate group, and a diketone group, of 1-ethyl-4-phenylpiperazine derivatives. Manufacturing method.
상기 친핵체는 티올기를 포함하는 선형, 분지형 또는 환형 유기화합물인 것을 특징으로 하는 1-에틸-4-페닐피페라진 유도체의 제조방법.The method of claim 5,
The nucleophile is a method for producing a 1-ethyl-4-phenylpiperazine derivative, characterized in that it is a linear, branched or cyclic organic compound containing a thiol group.
상기 친핵체를 구성하는 탄소 중 적어도 하나 이상이 황(S)으로 치환되는 것을 특징으로 하는 1-에틸-4-페닐피페라진 유도체의 제조방법.
The method of claim 6,
Method for producing a 1-ethyl-4-phenylpiperazine derivative, characterized in that at least one or more of the carbons constituting the nucleophile is substituted with sulfur (S).
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220005312A (en) * | 2020-07-06 | 2022-01-13 | 원광대학교산학협력단 | Piperazine compound and method for producing the same |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0089065A2 (en) * | 1982-03-17 | 1983-09-21 | Chugai Seiyaku Kabushiki Kaisha | Novel phenylpiperazine derivatives and process for producing the same |
| EP0228605A1 (en) * | 1985-12-10 | 1987-07-15 | Nippon Kayaku Kabushiki Kaisha | Phenylpiperazine derivatives |
| US20030166616A1 (en) * | 2002-02-22 | 2003-09-04 | Takashi Ogino | Novel 2-phenylpiperazine derivatives |
| KR101282833B1 (en) | 2004-07-28 | 2013-07-08 | 얀센 파마슈티카 엔.브이. | Substituted propenyl piperazine derivatives as novel inhibitors of hitone deacetylase |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0089065A2 (en) * | 1982-03-17 | 1983-09-21 | Chugai Seiyaku Kabushiki Kaisha | Novel phenylpiperazine derivatives and process for producing the same |
| EP0228605A1 (en) * | 1985-12-10 | 1987-07-15 | Nippon Kayaku Kabushiki Kaisha | Phenylpiperazine derivatives |
| US20030166616A1 (en) * | 2002-02-22 | 2003-09-04 | Takashi Ogino | Novel 2-phenylpiperazine derivatives |
| KR101282833B1 (en) | 2004-07-28 | 2013-07-08 | 얀센 파마슈티카 엔.브이. | Substituted propenyl piperazine derivatives as novel inhibitors of hitone deacetylase |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220005312A (en) * | 2020-07-06 | 2022-01-13 | 원광대학교산학협력단 | Piperazine compound and method for producing the same |
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