KR100393744B1 - A process for preparing 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one - Google Patents
A process for preparing 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one Download PDFInfo
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Abstract
본 발명은 다음 화학식 1로 표시되는 1,2,3,9-테트라하이드로-9-메틸-3-[(2-메틸-1H-이미다졸-1-일)메틸]-4H-카바졸-4-온의 제조방법에 관한 것으로서, 더욱 상세하게는 종래 제조방법상의 다수의 부반응 물질이 생성되는 문제와 중간체 분리 및 정제를 위한 번거로운 과정을 수행하여야 하는 문제를 해소하고 공업적으로 유리하게 다음 화학식 1로 표시되는 화합물을 제조하는 방법에 관한 것이다.The present invention provides 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4 represented by the following Chemical Formula 1 The present invention relates to a method for preparing a temperature, and more particularly, to solve the problem of generating a large number of side reaction substances in the conventional manufacturing method and the trouble of carrying out a cumbersome process for separating and purifying intermediates. It relates to a method for producing a compound represented by.
화학식 1Formula 1
Description
본 발명은 다음 화학식 1로 표시되는 1,2,3,9-테트라하이드로-9-메틸-3-[(2-메틸-1H-이미다졸-1-일)메틸]-4H-카바졸-4-온의 제조방법에 관한 것으로서, 더욱 상세하게는 다음 화학식 2로 표시되는 4H-카바졸-4-온과 다음 화학식 3으로 표시되는 아민 화합물을 소정의 촉매와 반응시켜 엔아민 중간체를 합성하고, 합성된 엔아민 중간체를 디할로겐화메탄과 2-메틸이미다졸으로 연속적으로 반응시킨 다음 가수분해 반응시켜 다음 화학식 1로 표시되는 화합물을 제조함으로써, 종래 이민 중간체를 경유하는 제조방법에서와 같은 다수의 부반응 물질이 생성되지 않으며 또, 중간체 분리 및 정제를 위한 번거로운 과정을 수행하지 않고서 일용기 반응(one-pot reaction)에 의해 다음 화학식 1로 표시되는 1,2,3,9-테트라하이드로-9-메틸-3-[(2-메틸-1H-이미다졸-1-일)메틸]-4H-카바졸-4-온을 공업적으로 유리하게 제조하는 방법에 관한 것이다.The present invention provides 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4 represented by the following Chemical Formula 1 Regarding a method for preparing -one, more specifically, 4H-carbazol-4-one represented by the following Chemical Formula 2 and an amine compound represented by the following Chemical Formula 3 are reacted with a predetermined catalyst to synthesize an enamine intermediate, The synthesized enamine intermediate was continuously reacted with dihalogenated methane and 2-methylimidazole, and then hydrolyzed to prepare a compound represented by the following formula (1). No side reaction material is produced and 1,2,3,9-tetrahydro-9- represented by the following Chemical Formula 1 by a one-pot reaction without performing a cumbersome process for intermediate separation and purification. Methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4 It relates to a process for producing industrially advantageously.
상기 화학식에서 : R1및 R2는 서로 같거나 다른 것으로서 수소원자, C1∼6알킬기, C3∼7시클로알킬기, C2∼6알케닐기, 페닐기 또는 페닐-C1∼3알킬기이거나, 또는 R1및 R2가 질소원자와 함께 결합하여 피롤리딘 고리, 피페리딘 고리 및 몰포린 고리를 포함하는 5 ∼ 6개의 원소로 고리화 된 헤테로고리를 형성할 수 있다.Wherein R 1 and R 2 are the same as or different from each other and are a hydrogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a C 2-6 alkenyl group, a phenyl group or a phenyl-C 1-3 alkyl group, or R 1 and R 2 may be bonded together with a nitrogen atom to form a heterocyclic ring of 5 to 6 elements including a pyrrolidine ring, a piperidine ring and a morpholine ring.
상기 화학식 1로 표시되는 화합물은 일차 구심성 신경의 말단에 위치한 형태의 "뉴로날" 5-HT 수용기에 대한 길항 작용이 있는 것으로 알려져 있고, 또한 이의 제조방법에 대해서도 다양한 연구가 진행되어 있다.The compound represented by the formula (1) is known to have an antagonistic action on the "neuronal" 5-HT receptor of the form located at the terminal of the primary afferent nerve, and various studies have been conducted on the preparation thereof.
상기 화학식 1로 표시되는 화합물 또는 이의 유도체를 제조하는 종래 방법을 간략히 설명하면 다음과 같다.The conventional method for preparing the compound represented by Formula 1 or a derivative thereof is briefly described as follows.
미국특허 제4,695,578호와 대한민국특허 제53,670호에는 다음 반응식 1에 나타낸 바와 같이, 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 포름알데히드 및 아세트산 존재하에서 반응시켜 이민 유도체를 중간체로 경유하여 아민 화합물을 제조하고, 제조된 아민 화합물을 메틸화 반응시켜 4급 암모늄 화합물을 제조하고, 4급 암모늄 화합물에 알킬이미다졸을 직접 치환반응시켜 목적하는 화합물을 제조하거나, 또는 4급 암모늄 화합물의 아민염을 제거하여 올레핀 화합물을 얻은 다음에 알킬이미다졸을 반응시켜 목적하는 화합물을 제조하는 방법이 기재되어 있다.US Pat. No. 4,695,578 and Korean Patent No. 53,670 disclose an amine by reacting a compound represented by Formula 2 with a compound represented by Formula 3 in the presence of formaldehyde and acetic acid, as shown in Scheme 1, via an imine derivative as an intermediate. To prepare a compound, to prepare a quaternary ammonium compound by methylation reaction of the prepared amine compound, the alkylimidazole is substituted directly to the quaternary ammonium compound to prepare the desired compound, or the amine salt of the quaternary ammonium compound The method for preparing the desired compound is described by removing the olefin compound to obtain an olefin compound and then reacting the alkylimidazole.
상기 반응식 1에서 : Ra은 수소원자, C1∼10알킬기, C3∼7시클로알킬기, C3∼6알케닐기, C3∼7시클로알킬-(C1∼4)알킬기, C3∼6알키닐기, 페닐기 또는 페닐-C1∼3알킬기이고; Rb, Rc및 Rd는 서로 같거나 다른 것으로서 수소원자, C1∼6알킬기, C3∼7시클로알킬기, C2∼6알케닐기, 페닐기 또는 페닐-C1∼3알킬기이다.In Scheme 1, R a represents a hydrogen atom, a C 1-10 alkyl group, a C 3-7 cycloalkyl group, a C 3-6 alkenyl group, a C 3-7 cycloalkyl- (C 1-4 ) alkyl group, C 3-6 An alkynyl group, a phenyl group or a phenyl-C 1-3 alkyl group; R b , R c and R d are the same as or different from each other and are a hydrogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a C 2-6 alkenyl group, a phenyl group or a phenyl-C 1-3 alkyl group.
상기 반응식 1에 따른 종래 제조방법의 경우, 아세트산 존재하에서 반응물로서 포름알데히드를 사용하고 있어 모노치환체가 아닌 디치환체 또는 다이머 또는 폴리머 생성의 가능성으로 인하여 부반응 물질이 다수 생성 되고, 이러한 부반응물 생성으로 인하여 이미다졸 화합물과의 반응에 앞서 중간체 분리 및 정제과정을 수행하여야 하는 제조공정상의 번거로움이 있고, 이러한 분리 정제공정을 수행하지 않고 이미다졸 화합물과의 반응을 수행하게 되면 수율 저하 및 부반응 물질의 생성으로 정제의 어려움이 있다. 더우기 정제된 화합물들과 알킬이미다졸 화합물의 반응으로 목적 화합물을 제조하는 합성단계 자체가 수율이 매우 낮다는 단점이 있다.In the case of the conventional production method according to Scheme 1, formaldehyde is used as a reactant in the presence of acetic acid, and a large number of side reactions are generated due to the possibility of the formation of di-substituted or dimers or polymers instead of mono-substitutes. There is an inconvenience in the manufacturing process that the intermediate separation and purification process must be performed prior to the reaction with the imidazole compound, and the reaction with the imidazole compound without performing such separation and purification process lowers the yield and generates the side reaction material. There is a difficulty of purification. Furthermore, there is a disadvantage in that the yield of the synthesis step itself to prepare the target compound by the reaction of the purified compounds and the alkylimidazole compound is very low.
이에, 본 발명자들은 상기 화학식 2로 표시되는 4H-카바졸-4-온과 상기 화학식 3으로 표시되는 아민 화합물을 출발물질로 사용하여 상기 화학식 1로 표시되는 화합물을 제조하는 종래 제조방법에서의 부반응 물질이 생성되거나 중간체 분리 및정제를 위한 번거로운 과정을 수행하여야 하는 문제점을 해결하고자 노력하였다. 그 결과, 상기 화학식 2로 표시되는 4H-카바졸-4-온과 상기 화학식 3으로 표시되는 아민 화합물을 특정 촉매하에서 반응시켜 엔아민 유도체를 중간체로서 합성하는 과정을 거치고, 또한 합성된 엔아민 중간체는 디할로겐화메탄과 2-메틸이미다졸으로 연속적으로 반응시킨 후에 가수분해 반응을 수행하게 되면 중간체 분리 정제를 위한 번거러운 과정없이 일용기내에서 반응이 완결될 수 있음을 알게됨으로써 본 발명을 완성하였다.Therefore, the present inventors use side reaction in the conventional manufacturing method for preparing the compound represented by the formula (1) using the 4H- carbazol-4-one represented by the formula (2) and the amine compound represented by the formula (3) as a starting material Efforts have been made to solve the problem of material formation or cumbersome processes for intermediate separation and purification. As a result, 4H-carbazol-4-one represented by Chemical Formula 2 and the amine compound represented by Chemical Formula 3 are reacted under a specific catalyst to synthesize an enamine derivative as an intermediate, and the synthesized enamine intermediate The present invention was completed by recognizing that the reaction can be completed in a single container without the cumbersome process for intermediate separation purification if the hydrolysis reaction is performed after continuously reacting with dihalogenated methane and 2-methylimidazole.
따라서, 본 발명은 보다 경제적인 제조방법으로 상기 화학식 1로 표시되는 화합물을 제조하는 방법을 제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide a method for preparing the compound represented by Formula 1 as a more economical manufacturing method.
다음 화학식 2로 표시되는 4H-카바졸-4-온과 다음 화학식 3으로 표시되는 아민 화합물을 출발물질로 사용하여 다음 화학식 1로 표시되는 화합물을 제조하는 방법에 있어서,In the method for preparing a compound represented by the following formula 1 using 4H- carbazol-4-one represented by the following formula (2) and the amine compound represented by the following formula (3) as a starting material,
상기 화학식 2로 표시되는 4H-카바졸-4-온과 상기 화학식 3으로 표시되는 아민 화합물을 티타늄클로라이드, p-톨루엔술폰산 및 무수탄산칼슘 중에서 선택된 촉매하에서 반응시켜 얻어진 엔아민 중간체를 제조하고,Preparing an enamine intermediate obtained by reacting 4H-carbazol-4-one represented by Chemical Formula 2 with an amine compound represented by Chemical Formula 3 under a catalyst selected from titanium chloride, p-toluenesulfonic acid and calcium carbonate anhydride,
상기 엔아민 중간체와 다음 화학식 5로 표시되는 디할로겐화메탄을 반응시킨 후에 연속적으로 2-메틸이미다졸을 반응시킨 다음, 가수분해 반응시켜 제조하는 다음 화학식 1로 표시되는 1,2,3,9-테트라하이드로-9-메틸-3-[(2-메틸-1H-이미다졸-1-일)메틸]-4H-카바졸-4-온 또는 약제학적으로 허용 가능한 이들의 염 또는 이들의 용매화물의 제조방법을 그 특징으로 한다.1,2,3,9 represented by the following Chemical Formula 1 prepared by reacting the enamine intermediate with the dihalogenated methane represented by the following Chemical Formula 5 and subsequently reacting 2-methylimidazole, followed by hydrolysis reaction. -Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one or a pharmaceutically acceptable salt thereof or solvate thereof It characterized by the manufacturing method of the.
화학식 2Formula 2
화학식 3Formula 3
화학식 1Formula 1
상기 화학식에서 : R1및 R2는 서로 같거나 다른 것으로서 수소원자, C1∼6알킬기, C3∼7시클로알킬기, C2∼6알케닐기, 페닐기 또는 페닐-C1∼3알킬기이거나, 또는 R1및 R2가 질소원자와 함께 결합하여 피롤리딘 고리, 피페리딘 고리 및 몰포린 고리를 포함하는 5 ∼ 6개의 원소로 고리화 된 헤테로고리를 형성할 수 있고; X, X1및 X2는 서로같거나 다른 것으로서 요오드, 브롬, 클로라이드를 포함하는 할로겐 원소이다.Wherein R 1 and R 2 are the same as or different from each other and are a hydrogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a C 2-6 alkenyl group, a phenyl group or a phenyl-C 1-3 alkyl group, or R 1 and R 2 may be bonded together with a nitrogen atom to form a heterocycle cyclized with 5 to 6 elements including a pyrrolidine ring, a piperidine ring and a morpholine ring; X, X 1 and X 2 are the same or different and are halogen elements including iodine, bromine and chloride.
본 발명에 따른 상기 화학식 1로 표시되는 화합물 또는 약제학적으로 허용 가능한 이들의 염의 제조과정을 각 과정별로 세분화하여 보다 상세히 설명하면 다음과 같다.Hereinafter, the process of preparing the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention will be described in detail by each process.
먼저, 다음 화학식 2로 표시되는 4H-카바졸-4-온과 다음 화학식 3으로 표시되는 아민 화합물을 반응시켜 다음 화학식 4로 표시되는 엔아민 유도체를 중간체로서 제조한다.First, 4H-carbazol-4-one represented by the following formula (2) is reacted with an amine compound represented by the following formula (3) to prepare an enamine derivative represented by the following formula (4) as an intermediate.
상기한 바와 같은 반응을 수행함에 있어, 상기 화학식 3으로 표시되는 아민 화합물으로서는 피롤린, 피페리딘 및 몰포린과 같은 헤테로고리화된 아민화합물을 사용하는 것이 보다 바람직한 바, 헤테로고리화된 아민화합물 사용하는 반응의 경우 정량적으로 반응하는 유용한 점이 있다.In carrying out the reaction as described above, as the amine compound represented by the formula (3), it is more preferable to use heterocyclic amine compounds such as pyrroline, piperidine and morpholine, heterocyclic amine compounds For the reaction used, there is a useful point to react quantitatively.
상기 화학식 2로 표시되는 4H-카바졸-4-온과 상기 화학식 3으로 표시되는 아민 화합물의 반응은 티타늄 클로라이드, p-톨루엔술폰산, 무수 탄산칼륨 등의 촉매를 사용하여 클로로포름, 메틸렌클로라이드, 벤젠, 톨루엔, 아세토니트릴, 다이옥산 등의 유기용매에서 0 ℃ ∼ 100 ℃에서 수행할 수 있다. 본 발명에 따른 제조방법이 상기 화학식 4로 표시되는 엔아민 유도체를 중간체로 합성하는데 가장 큰특징이 있는 바, 본 발명에서는 상기 화학식 2와 3으로 표시되는 화합물을 반응시킴에 있어 반응촉매로서 특정 촉매를 선택 사용함으로써 엔아민 유도체를 중간체로 합성하였고, 이로써 다음으로 수행되는 디할로겐화메탄과의 반응 및 2-메틸이미다졸과의 연속적인 치환반응을 수행한 후에 가수분해 반응을 거쳐 화학식 1의 목적화합물을 합성하도록 한 것이다. 즉, 본 발명이 상기한 바와 같은 반응조건을 설정하여 엔아민 유도체를 중간체로 생성시키는 반응을 설계함으로써 종래 제조방법이 반응과정중에 생성되는 중간체를 분리 정제한 후에 이미다졸 화합물과의 반응을 수행하여야하는 제조공정상의 번거러움을 완벽히 해소한 것이다.The reaction of 4H-carbazol-4-one represented by Chemical Formula 2 with the amine compound represented by Chemical Formula 3 may be performed by using a catalyst such as titanium chloride, p-toluenesulfonic acid, anhydrous potassium carbonate, or the like. It may be performed at 0 ° C. to 100 ° C. in an organic solvent such as toluene, acetonitrile or dioxane. The production method according to the present invention has the greatest feature in synthesizing the enamine derivative represented by Chemical Formula 4 as an intermediate. In the present invention, a specific catalyst is used as a reaction catalyst in reacting the compounds represented by Chemical Formulas 2 and 3. Enamine derivatives were synthesized as intermediate by selective use, thereby performing the reaction with dihalogenated methane and the subsequent substitution reaction with 2-methylimidazole, followed by hydrolysis reaction, Compounds were synthesized. That is, the present invention is to set the reaction conditions as described above to design the reaction to produce the enamine derivative as an intermediate, the conventional manufacturing method should be carried out after the separation and purification of the intermediate produced during the reaction process with the imidazole compound It completely eliminates the hassle of the manufacturing process.
그리고, 합성된 상기 화학식 4로 표시되는 엔아민 중간체와 다음 화학식 5로 표시되는 디할로겐화메탄과의 반응 및 2-메틸이미다졸과의 반응을 연속적으로 반응시킨 후에 가수분해 반응시켜 다음에 나타낸 바와 같은 메카니즘에 의하여 목적하는 다음 화학식 1로 표시되는 화합물을 직접 제조한다.Then, the reaction of the synthesized enamine intermediate represented by the formula (4) with the dihalogenated methane represented by the following formula (5) and the reaction with 2-methylimidazole are continuously reacted, and then hydrolyzed. By the same mechanism, a desired compound represented by the following formula (1) is prepared directly.
상기 화학식 4로 표시되는 엔아민 중간체와 디할로겐화메탄과의 반응 및 2-메틸이미다졸과의 반응은 알콜류, 클로로포름, 메틸렌클로라이드, 벤젠, 톨루엔, 아세토니트릴, 다이옥산, 디메틸포름아미드 등의 용매하에서 0 ℃ ∼ 100 ℃로 수행한다. 또한, 상기 화학식 5로 표시되는 화합물과 2-메틸이미다졸 각각은 1 ∼ 10 당량비로 투입하는 것이 바람직하다.The reaction between the enamine intermediate represented by Chemical Formula 4 and dihalogenated methane and the reaction of 2-methylimidazole are carried out under solvents such as alcohols, chloroform, methylene chloride, benzene, toluene, acetonitrile, dioxane, dimethylformamide, and the like. It is performed at 0 ° C to 100 ° C. In addition, it is preferable to add each of the compound represented by the formula (5) and 2-methylimidazole in a ratio of 1 to 10 equivalents.
가수분해 반응은 과량의 정제수를 사용하여 실온 ∼ 100 ℃에서 수행한다.The hydrolysis reaction is carried out at room temperature to 100 ° C using excess purified water.
이상에서 설명한 본 발명에 따른 제조방법에서는 각 반응단계에서 생성되는 화합물의 분리없이 연속적으로 반응을 진행시키는 것을 그 특징으로 하며, 필요에 따라 각 반응과정에서 생성되는 중간체를 분리 정제하여 그 다음 반응을 수행할 수도 있다. 본 발명의 제조방법을 수행하는 과정에서 중간체로 합성되는 화합물 또는 목적 화합물의 분리 정제방법은 크로마토그래피 및 재결정화와 같은 통상적인 방법에 의한다.In the preparation method according to the present invention described above it is characterized in that the reaction proceeds continuously without separation of the compound produced in each reaction step, and if necessary to separate and purify the intermediate produced in the reaction process to the next reaction It can also be done. In the process of carrying out the preparation method of the present invention, the method of separating and purifying a compound synthesized as an intermediate or a target compound is performed by conventional methods such as chromatography and recrystallization.
이상의 제조방법으로 제조된 상기 화학식 1로 표시되는 화합물은 화합물 그 자체로는 물론이고 통상의 방법에 의하여 염 또는 용매화물로 합성할 수 있다. 예컨대, 상기 화학식 1로 표시되는 화합물은 산(acid) 예를 들면 염산, 브롬산, 황산, 인산, 아세트산, 시트르산, 푸마르산, 락트산, 말레산, 숙신산 및 타르타르산 등의 유기 또는 무기산, 또는 나트륨, 칼륨 등의 알칼리금속이온이나 암모늄 이온과 함께 약제학적으로 허용 가능한 이들의 염을 형성할 수도 있다.The compound represented by Chemical Formula 1 prepared by the above production method may be synthesized as a salt or a solvate by a conventional method as well as the compound itself. For example, the compound represented by Formula 1 may be an acid, for example an organic or inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, fumaric acid, lactic acid, maleic acid, succinic acid and tartaric acid, or sodium, potassium It is also possible to form pharmaceutically acceptable salts thereof with alkali metal ions and ammonium ions such as these.
한편, 본 발명에서 출발물질로 사용하고 있는 상기 화학식 2로 표시되는 4H-카바졸-4-온과 상기 화학식 3으로 표시되는 아민 화합물은 공지된 화합물으로서,상업적으로 시판되거나 또는 이미 알려진 공지의 합성 방법[Ballantine, J. A.; Barret, C. B.; Beer, R. J. S.; Boggiano, B. G.; Eardley, S.; Jenmings, B. E.; Robertson, A.J. Chem. Soc. 1957 ,2227]을 이용하여 손쉽게 얻을 수 있다.Meanwhile, the 4H-carbazol-4-one represented by Formula 2 and the amine compound represented by Formula 3, which are used as starting materials in the present invention, are known compounds and are commercially available or known synthetically. Method [Ballantine, JA; Barret, CB; Beer, RJS; Boggiano, BG; Eardley, S .; Jenmings, BE; Robertson, A. J. Chem. Soc. 1957 , 2227].
이와 같은 본 발명을 다음의 실시예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이에 한정되는 것은 아니다.The present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.
실시예 1 :1,2,3,9-테트라히드로-9-메틸-3-[(2-메틸이미다졸-1-일)메틸]-4H-카르바졸-4-온 Example 1: 1,2,3,9- tetrahydro-9-methyl-3 - [(2-methylimidazole-1-yl) methyl] -4H- carbazole-4-one
피롤리딘(66.2 g)을 메틸렌클로라이드 0.4 ℓ에 녹이고 0 ℃로 냉각시킨 다음, 티타늄클로라이드(30.2 g)를 메틸렌클로라이드 0.14 ℓ에 희석한 용액을 적가하였다. 5 분동안 교반한 후 9-메틸-2,3-디히드로-4H-카르바졸-4-온(23.9 g)을 한번에 첨가하고 가열하여 4 시간 동안 환류시킨 후, 여과하고 농축하여 잔사를 얻었다. 이때 일부를 취하여 엔아민 중간체의 생성 여부를 확인하였다.Pyrrolidine (66.2 g) was dissolved in 0.4 L of methylene chloride and cooled to 0 ° C., and then a solution of titanium chloride (30.2 g) diluted in 0.14 L of methylene chloride was added dropwise. After stirring for 5 minutes, 9-methyl-2,3-dihydro-4H-carbazol-4-one (23.9 g) was added at once, heated to reflux for 4 hours, filtered and concentrated to give a residue. At this time, a part was taken to determine whether an enamine intermediate was produced.
TLC[실리카 상; 클로로포름/메탄올/암모니아수=4/2/0.1(v/v/v)] : r.f. 0.43TLC [silica phase; Chloroform / methanol / ammonia water = 4/2 / 0.1 (v / v / v)]: r.f. 0.43
1H-NMR(DMSO-d6) : δ1.82∼2.12(m, 5H, 피롤리딘, C2-H), 2.28∼2.39(m, 1H, C2-H), 3.02∼3.34(m, 6H, 피롤리딘, C1-H), 3.56∼3.74(m, 3H, C3-H, N-CH2), 3.78(s, 3H, N-CH3), 7.18∼8.02(m, 4H, Ar-H), 9.24(brd.s, 1H, NHI). 1 H-NMR (DMSO-d 6 ): δ1.82 to 2.12 (m, 5H, pyrrolidine, C 2 -H), 2.28 to 2.39 (m, 1H, C 2 -H), 3.02 to 3.34 (m , 6H, pyrrolidine, C 1 -H), 3.56 to 3.74 (m, 3H, C 3 -H, N-CH 2 ), 3.78 (s, 3H, N-CH 3 ), 7.18 to 8.02 (m, 4H, Ar-H), 9.24 (brd.s, 1H, NHI).
상기 합성된 엔아민 중간체를 다이옥산 0.3 ℓ와 메틸렌클로라이드 0.1 ℓ에 녹인 다음, 디아이오도메탄(35.1 g)을 첨가한 후 80 ℃에서 18 시간 동안 환류시켰다. 용매를 감압증류로 제거하고 얻어진 잔사를 디메틸포름아미드 0.15 ℓ에 녹인 후 2-메틸이미다졸(29.5 g)을 가하고 교반하면서 36 시간 동안 90 ℃로 가열하였다. 정제수 1.0 ℓ를 첨가하고 2 시간동안 이 온도에서 교반하여 가수분해한 후 실온으로 냉각하였다. 생성된 고체를 여과하고 건조한 다음 메탄올 2.4 ℓ에 녹이고 활성탄 처리 후 여과하였다. 여과액을 농축시키고 메탄올로 다시 재결정하여 표제 화합물 20.5 g(수율 57.7%)을 얻었다.The synthesized enamine intermediate was dissolved in 0.3 L of dioxane and 0.1 L of methylene chloride, and then diiodomethane (35.1 g) was added and refluxed at 80 ° C. for 18 hours. The solvent was removed by distillation under reduced pressure, and the obtained residue was dissolved in 0.15 L of dimethylformamide, and 2-methylimidazole (29.5 g) was added thereto and heated to 90 ° C. for 36 hours while stirring. 1.0 L of purified water was added and stirred at this temperature for 2 hours to hydrolyze and then cooled to room temperature. The resulting solid was filtered, dried and dissolved in 2.4 L of methanol, filtered after activated carbon. The filtrate was concentrated and recrystallized again with methanol to give 20.5 g (yield 57.7%) of the title compound.
융점 : 231 ∼ 232 ℃Melting Point: 231 ~ 232 ℃
TLC[실리카 상; 클로로포름/메탄올/물=4/2/0.1(v/v/v)] : r.f. 0.51TLC [silica phase; Chloroform / methanol / water = 4/2 / 0.1 (v / v / v)]: r.f. 0.51
1H-NMR(DMSO-d6) : δ1.81∼1.91(m, 1H, C2-H), 1.98∼2.2(m, 1H, C2-H), 2.33(s, 3H, CH3), 2.82∼3.0(m, 2H, C1-H), 3.01∼3.16(m, 1H, C3-H), 3.7(s, 3H, N-CH3), 4.12(dd, 1H, N-CH2), 4.43(dd, 1H, N-CH2), 6.70∼7.04(d, 2H, 이미다졸), 7.13∼8.03(m, 4H, Ar-H). 1 H-NMR (DMSO-d 6 ): δ1.81 to 1.91 (m, 1H, C 2 -H), 1.98 to 2.2 (m, 1H, C 2 -H), 2.33 (s, 3H, CH 3 ) , 2.82 to 3.0 (m, 2H, C 1 -H), 3.01 to 3.16 (m, 1H, C 3 -H), 3.7 (s, 3H, N-CH 3 ), 4.12 (dd, 1H, N-CH 2 ), 4.43 (dd, 1H, N-CH 2 ), 6.70 to 7.04 (d, 2H, imidazole), 7.13 to 8.03 (m, 4H, Ar-H).
실시예 2 :1,2,3,9-테트라히드로-9-메틸-3-[(2-메틸이미다졸-1-일)메틸]-4H-카르바졸-4-온 염산염 이수화물의 합성 Example 2 Synthesis of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methylimidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate
1,2,3,9-테트라히드로-9-메틸-3-[(2-메틸이미다졸-1-일)메틸]-4H-카르바졸-4-온(20.5 g)에 아세톤(200 ㎖)과 정제수(10 ㎖)를 넣고 교반하면서 진한 염산(7.5㎖)을 서서히 가하였다. 1 시간동안 교반한 후 냉온소에 방치하여 생성된 고체를 여과하였다. 여과된 고체를 아세톤(150 ㎖)과 정제수(10 ㎖)로 재결정하여표제 화합물 17.4 g(수율 67%)을 얻었다.Acetone (200 mL) in 1,2,3,9-tetrahydro-9-methyl-3-[(2-methylimidazol-1-yl) methyl] -4H-carbazol-4-one (20.5 g) ) And purified water (10 mL) were added, and concentrated hydrochloric acid (7.5 mL) was added slowly with stirring. After stirring for 1 hour, the resultant solid was filtered by standing in a cold room. The filtered solid was recrystallized with acetone (150 mL) and purified water (10 mL) to obtain 17.4 g (yield 67%) of the title compound.
융점 : 178.5∼179.5 ℃Melting Point: 178.5 ~ 179.5 ℃
TLC[실리카 상; 클로로포름/메탄올/물=4/2/0.1(v/v/v)] : r.f. 0.50TLC [silica phase; Chloroform / methanol / water = 4/2 / 0.1 (v / v / v)]: r.f. 0.50
1H-NMR(DMSO-d6) : δ1.7∼1.89(m, 1H, C2-H), 1.95∼2.1(m, 1H, C2-H), 2.22(s, 3H, CH3), 2.83∼2.96(m, 2H, C1-H), 3.08∼3.19(m, 1H, C3-H), 3.72(s, 3H, N-CH3), 4.1(dd, 1H, N-CH2), 4.45(dd, 1H, N-CH2), 6.70∼7.07(d, 2H, 이미다졸), 7.20∼8.05(m, 4H, Ar-H) 1 H-NMR (DMSO-d 6 ): δ 1.7 to 1.89 (m, 1H, C 2 -H), 1.95 to 2.1 (m, 1H, C 2 -H), 2.22 (s, 3H, CH 3 ) , 2.83 to 2.96 (m, 2H, C 1 -H), 3.08 to 3.19 (m, 1H, C 3 -H), 3.72 (s, 3H, N-CH 3 ), 4.1 (dd, 1H, N-CH 2 ), 4.45 (dd, 1H, N-CH 2 ), 6.70 to 7.07 (d, 2H, imidazole), 7.20 to 8.05 (m, 4H, Ar-H)
이상에서 설명한 바와 같이, 본 발명에 따른 제조방법은 기존의 방법들에 비해 중간체의 분리 과정 없이 연속적으로 반응을 진행시킬 수도 있어 경제적이며 작업상 용이하다. 특히, 본 발명에 따른 제조방법은 테트라히드로카바졸론 유도체의 α-위치에 다양하게 치환된 아미노 알킬기를 도입하는 데 유용하다.As described above, the production method according to the present invention is economical and easy to operate because the reaction may proceed continuously without separating the intermediate compared to the conventional methods. In particular, the preparation method according to the invention is useful for introducing variously substituted amino alkyl groups at the α-position of a tetrahydrocarbazolone derivative.
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|---|---|---|---|---|
| KR920003064A (en) * | 1990-07-25 | 1992-02-29 | 홀트 알린 알 | Device test system with cable pivot |
| KR100217466B1 (en) * | 1996-10-23 | 1999-09-01 | 유충식 | Process for preparation of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1h-imidazol-1-yl)methyl]-4h-carbazol-4-one |
| KR20010094388A (en) * | 2000-03-30 | 2001-11-01 | 이규혁 | A process for preparing 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one |
-
2000
- 2000-12-02 KR KR10-2000-0072731A patent/KR100393744B1/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR920003064A (en) * | 1990-07-25 | 1992-02-29 | 홀트 알린 알 | Device test system with cable pivot |
| KR100217466B1 (en) * | 1996-10-23 | 1999-09-01 | 유충식 | Process for preparation of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1h-imidazol-1-yl)methyl]-4h-carbazol-4-one |
| KR20010094388A (en) * | 2000-03-30 | 2001-11-01 | 이규혁 | A process for preparing 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one |
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| Publication number | Publication date |
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| KR20020043338A (en) | 2002-06-10 |
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