KR20010083068A - Novel process for preparing 4-substituted-1H-pyrrole-3-carboxylic acid ester - Google Patents
Novel process for preparing 4-substituted-1H-pyrrole-3-carboxylic acid ester Download PDFInfo
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Abstract
Description
본 발명은 상응하는 알데히드 화합물로부터 호너-에먼스 반응을 통해 α,β-불포화에스테르 화합물을 얻고 별도의 분리과정없이 톨루엔설포닐메틸이소시아네이트(TosMIC; 이하, '토스믹'이라 한다)와 반응시켜 항암제로서 사용되는 파네실 전이효소 억제제 제조의 핵심 중간체로서 중요성을 갖는 피롤에스테르 화합물(참조: Ko, J. S. et al., 국제특허공개 제WO 9905117호, 1999. 2. 4, p129)을 고순도 및 고수율로 제조하는 새로운 방법에 관한 것이다.The present invention obtains an α, β-unsaturated ester compound through a Horner-Emmons reaction from a corresponding aldehyde compound and reacts with toluenesulfonylmethylisocyanate (TosMIC; hereinafter referred to as 'Tosmic') without separate separation process. Pyrrole ester compounds (Ko, JS et al., WO 9905117, Feb. 4, 1999, Feb. 4, p129), which are of importance as a key intermediate for the preparation of panesyl transferase inhibitors, are used in high purity and high yield. It relates to a new method of manufacturing.
종래 피롤 유도체의 합성에 있어서 보편적으로 이용되던 방법은 하기 반응식 1에 나타낸 바와 같이 이소니트릴 화합물과 친 전자성 α,β-불포화 화합물의 고리화 반응을 통해 3,4-치환된 피롤 화합물을 합성하는 것이었다.Conventionally used in the synthesis of pyrrole derivatives is to synthesize a 3,4-substituted pyrrole compound through the cyclization reaction of the isonitrile compound and the electrophilic α, β-unsaturated compound as shown in Scheme 1 below Was.
상기 식에서,Where
R1및 R2는 C1-C4-알킬을 나타낸다.R 1 and R 2 represent C 1 -C 4 -alkyl.
이때, 이소니트릴 화합물로는 Van Leusen에 의해 개발된 토스믹(TosMIC)을 가장 많이 사용하였으며, 최근에 이와 유사한 반응성을 보이는 하기 구조식의 베트믹(BetMIC)이 개발되었다.At this time, as the isonitrile compound, Tosmic (TosMIC) developed by Van Leusen was most used, and recently Betmic (BetMIC) of the following structural formula showing similar reactivity was developed.
처음에 Van Leusen에 의해 발표된 반응은 α,β-불포화 화합물과 토스믹을 염기 존재하에 반응시켜 3,4-치환된 피롤 화합물을 얻는 것이었다. 그 후, 동연구자에 의해 토스믹을 염기 존재하에 카보닐 화합물과 반응시킨 후 POCl3(phosphorous oxychloride)로 처리하여 α,β-불포화 이소니트릴 화합물을 합성하고 이를 활성화된 친핵성 화합물(nucleophile)과 반응시켜 피롤 화합물을 합성하는 하기 반응식 2의 방법이 개발되었다.The reaction first published by Van Leusen was to react an α, β-unsaturated compound with tosmic in the presence of a base to obtain a 3,4-substituted pyrrole compound. Thereafter, the researchers reacted the tosmic with a carbonyl compound in the presence of a base, and then treated with POCl 3 (phosphorous oxychloride) to synthesize an α, β-unsaturated isonitrile compound and activated nucleophile. The method of Scheme 2 below was developed to react to synthesize a pyrrole compound.
상기 식에서,Where
R은 알킬, 알릴 또는 아릴을 나타내고,R represents alkyl, allyl or aryl,
E는 전자흡인기를 나타낸다.E represents an electron withdrawing group.
상기 반응에서는 이소니트릴 화합물이 염기 작용하에 불포화 친전자성 화합물과 반응한 후, 고리화 반응을 통해 2-번 위치가 치환되지 않은 헤테로사이클을 생산해낸다. 이때, 이소니트릴 화합물로는 Van Leusen이 개발한 토스믹(TosMIC)이 가장 보편적으로 사용되는데, 이는 온화한 조건에서 반응이 진행될 뿐아니라 고리화 반응 후 톨루엔설포닐기가 이탈하여 3,4-번 위치가 치환된 피롤 유도체를 만드는데 가장 적합하기 때문이다.In this reaction, the isonitrile compound is reacted with an unsaturated electrophilic compound under a basic action, followed by a cyclization reaction to produce a heterocycle in which the 2-position is unsubstituted. At this time, as the isonitrile compound, tosmic (TosMIC) developed by Van Leusen is most commonly used. This is not only the reaction proceeds under mild conditions but also the toluenesulfonyl group is released after the cyclization reaction, thereby leaving the 3,4-position. This is because it is most suitable for making substituted pyrrole derivatives.
본 발명자들은 상기 선행기술을 검토한 결과, 이소니트릴 고리화 반응을 통해 상응하는 α,β-불포화에스테르를 적당한 염기 존재하에 토스믹(TosMIC)과 반응시키면 목적화합물을 효율적으로 제조할 수 있을 것으로 판단하였다. 아울러, 이러한 고리화 반응의 출발물질인 α,β-불포화에스테르는 Koh 등의 방법(참조: WO 9928315 A1)에 발표된 바와 같이, 잘 알려진 호너-에먼스 반응(참조: Horner, L.,Chem. Ber., 1958,83, 733; Wadsworth, W. S. and Emmons, W. D.,J. Amer. Chem. Soc., 1961,83, 1733)을 이용해 높은 수율로 쉽게 얻을 수 있었다. 그러나, 이 공정을 대량생산에 적용하고자 하였을 때, 다음과 같은 몇가지 문제점이 발견되었다.As a result of examining the prior art, the present inventors have determined that the desired compound can be efficiently prepared by reacting the corresponding α, β-unsaturated ester with TosMIC in the presence of a suitable base through an isonitrile cyclization reaction. It was. In addition, α, β-unsaturated esters, which are the starting materials of the cyclization reaction, are well known Horner-Emmons reactions (Honer, L., Chem ) as published in Koh et al. (See WO 9928315 A1). Ber. , 1958, 83 , 733; Wadsworth, WS and Emmons, WD, J. Amer. Chem. Soc. , 1961, 83 , 1733). However, when attempting to apply this process to mass production, several problems were found.
첫째, α,β-불포화에스테르를 합성함에 있어 호너-에먼스 반응의 개량법으로서 유기합성화학에 보편적으로 응용되는 마사뮨 등의 방법(참조: Masamune, S.,Tetrahedron Lett., 1984,25, 2183)이 대량생산에 효율적이지 못하다는 것이다. 즉, 마사뮨 등의 방법에서는 반응중간체를 안정화시키기 위해 염기로서 염화리튬을 사용하는데, 이 경우 도저히 교반할 수 없을 정도로 반응액이 굳어지는 관계로 다량의 용매를 사용해야 한다. 또한, 물을 이용한 층분리를 통해 화합물이 분리되므로 다음 반응에 영향을 주지않기 위해 수분을 다 제거해야 하는데, 수분제거가 용이하지 않다.First, in synthesizing α, β-unsaturated esters, Masamune et al. (Masamune, S., Tetrahedron Lett ., 1984, 25 , 2183) is not efficient for mass production. In other words, in the method of Massachus et al., Lithium chloride is used as a base to stabilize the reaction intermediate. In this case, a large amount of solvent must be used because the reaction solution is hardly stirred. In addition, since the compound is separated through the water phase separation, the water must be removed in order not to affect the next reaction, but water removal is not easy.
둘째, α,β-불포화에스테르를 TosMIC과 반응시킨 후 용매제거를 통해 목적화합물을 수득하는 과정에서 고체생성물이 일관성없이 엉기는 문제가 야기되어 반응기로부터 수월하게 회수할 수 없는 단점이 있다. 즉, 용매를 감압증류하고 물을 첨가해 고체화할 때 생성된 침전물이 끈끈하게 되어 교반중 서로 엉겨 큰 덩어리가 됨으로써 반응기로부터 도저히 회수할 수 없는 상황이 빈번히 발생한다.Secondly, in the process of obtaining the target compound through the solvent removal after reacting the α, β-unsaturated ester with TosMIC, there is a problem that the solid product is inconsistently entangled and cannot be easily recovered from the reactor. In other words, when the solvent is distilled under reduced pressure and the water is added to solidify, the precipitates become sticky and become entangled with each other during stirring to form a large mass.
이에 본 발명자들은 상기 반응을 약간 개선하여 염기로서 염화리튬을 사용하지 않고, 아세토니트릴과 같은 극성 유기용매중에서 유기염기로 디아자비사이클로 [5.4.0]운데센(DBU)을 이용하여 알데히드 화합물로부터 α,β-불포화에스테르를 제조하고자 시도하였다. 그러나, 이 방법에서는 소량의 잔류 알데히드를 제거하기 위해 산수용액으로 세척하는 공정이 추가로 요구되었으며, 이 과정에서 에스테르가 소량 가수분해되어 수율의 손실이 야기되었고, 분리된 에스테르는 수분의 제거를 위하여 긴 진공건조 과정을 필요로 하였다. 또한, 에스테르를 TosMIC과 반응시키면 피롤에스테르가 생성되었으나 그 수율이 높지 않고 순도가 매우 낮아 약 60 내지 70%의 HPLC 양상을 보였으므로 별도의 정제과정이 항상 필요하였다.Therefore, the present inventors slightly improved the reaction, and did not use lithium chloride as a base, but did not use α chloride from an aldehyde compound using diazabicyclo [5.4.0] undecene (DBU) as an organic base in a polar organic solvent such as acetonitrile. Attempts were made to prepare β-unsaturated esters. However, this method additionally required a step of washing with an acid solution to remove a small amount of residual aldehyde, in which a small amount of ester was hydrolyzed to cause a loss of yield, and the separated ester was used to remove water. A long vacuum drying process was required. In addition, when the ester was reacted with TosMIC, a pyrrole ester was produced, but the yield was not high and the purity was very low, so that the HPLC pattern of about 60 to 70% was always required.
이러한 기술적 배경하에, 본 발명자들은 앞에서 언급한 여러 가지 문제점들을 회피하면서 보다 효율적으로 피롤에스테르 화합물을 대량생산하고자 집중적인연구를 수행하였으며, 그 결과 반응과정에서 사용되는 염기를 일정량으로 한정하는 한편, 생성된 α,β-불포화에스테르를 별도로 분리하지 않고 곧바로 TosMIC과 반응시키면 목적하는 피롤에스테르를 고수율로 효과적으로 제조할 수 있음을 발견하고 본 발명을 완성하게 되었다.Under these technical backgrounds, the present inventors conducted extensive research to mass-produce pyrrole ester compounds more efficiently while avoiding the above-mentioned problems. As a result, the bases used in the reaction process were limited to a certain amount and produced. The present invention was completed by discovering that the desired pyrrole ester can be effectively produced in high yield by directly reacting the α, β-unsaturated ester with TosMIC without separate separation.
따라서, 본 발명의 목적은 하기 화학식 2의 알데히드 화합물을 비활성 용매중에서 화학식 2의 화합물에 대해 1 내지 1.5몰당량의 알칼리금속알콕사이드 염기존재하에 하기 화학식 3의 트리알킬포스포노아세테이트와 반응시켜 하기 화학식 4의 α,β-불포화에스테르 화합물을 제조한 다음, 제조된 α,β-불포화에스테르 화합물을 분리하지 않고 동일 반응계내에 토스믹(TosMIC) 및 화학식 2의 화합물에 대해 1 내지 1.5몰당량의 동일 염기를 가하여 반응시킴으로써 목적하는 하기 화학식 1의 피롤에스테르 유도체를 제조하는 방법을 제공하는 것이다.Accordingly, an object of the present invention is to react the aldehyde compound of formula (2) with trialkylphosphonoacetate of formula (3) in the presence of 1 to 1.5 molar equivalents of alkali metal alkoxide base relative to the compound of formula (2) in an inert solvent To prepare the α, β-unsaturated ester compound of, and then to separate the prepared α, β-unsaturated ester compound in the reaction system to 1 to 1.5 molar equivalents of the same base for TosMIC and the compound of formula (2) It is to provide a method for producing the desired pyrrole ester derivative of the general formula (1) by adding and reacting.
상기 식에서,Where
R은 알킬, 알릴 또는 아릴을 나타내고,R represents alkyl, allyl or aryl,
R1은 C1-C4-알킬을 나타낸다.R 1 represents C 1 -C 4 -alkyl.
본 발명에 따른 제조방법을 도식화하여 하기 반응식 3에 나타내었다.The preparation method according to the present invention is shown in Scheme 3 below.
본 발명에 따른 상기 제조방법에서 알칼리금속알콕사이드 염기는 화학식 2의 화합물을 기준으로 하여 1 내지 1.5몰당량을 사용하는 것이 특히 중요하다. 1몰당량 미만으로 사용하면 출발물질인 알데히드 화합물 및 트리알킬포스포노아세테이트가 반응하지 않고 남게 되는데, 이중 알데히드 화합물은 후속 반응에서 TosMIC과 반응하여 부산물을 생성시킬 수 있고 트리알킬포스포노아세테이트 화합물은 잘 제거되지도 않을 뿐아니라 반응에 악영향을 미칠 수 있으며, 1.5몰당량을 초과 사용하게 되면 생성된 화학식 4의 불포화에스테르 화합물이 가수분해될 수 있기 때문이다. 즉, 상기 범위를 벗어나는 양으로 염기를 사용하면 화학식 4의 불포화에스테르 화합물을 제조하는 반응이 깨끗하게 진행되지 못하게 되고, 그 결과 불포화에스테르 화합물을 분리하지 않고 동일 반응계내에서 계속하여 후속반응을 진행시킨다는 본 발명의 소기 의도를 달성하기 어렵게 된다. 이러한 목적의 알칼리금속알콕사이드 염기로는 알칼리금속메톡사이드, -에톡사이드, -t-부톡사이드, -t-펜톡사이드 등을 모두 사용할 수 있으나, 바람직하게는 소듐- 또는 포타슘-t-부톡사이드 또는 -t-펜톡사이드를 사용한다. 또한, 염기를 1 내지 1.5몰당량 범위에서 사용하는 것으로 반응이 잘 진행되지만 1 내지 1.3몰당량을 사용해도 충분히 알데히드 화합물을 소모할 수 있을 뿐아니라 과량의 염기는 후속 층분리시 가수분해를 일으킬 위험이 있으므로 이를 최소화하기 위해 1 내지 1.3몰당량을 사용하는 것이 바람직하다.In the preparation method according to the present invention, it is particularly important that the alkali metal alkoxide base is used in an amount of 1 to 1.5 molar equivalents based on the compound of Formula 2. When used in less than 1 molar equivalent, the starting aldehyde compound and trialkylphosphonoacetate remain unreacted, of which the aldehyde compound can react with TosMIC in a subsequent reaction to produce a by-product and the trialkylphosphonoacetate compound is well Not only is it removed, but may adversely affect the reaction, and when used in excess of 1.5 molar equivalents, the resulting unsaturated ester compound of Formula 4 may be hydrolyzed. In other words, the use of the base in an amount outside the above range prevents the reaction for preparing the unsaturated ester compound of formula 4 from proceeding cleanly, and as a result, the subsequent reaction is continued in the reaction system without separating the unsaturated ester compound. It is difficult to achieve the intended intention of the invention. Alkali metal methoxide, -ethoxide, -t-butoxide, -t-pentoxide, etc. may be used as the alkali metal alkoxide base for this purpose, but preferably sodium- or potassium-t-butoxide or- t-pentoxide is used. In addition, the reaction proceeds well by using the base in the range of 1 to 1.5 molar equivalents, but the use of 1 to 1.3 molar equivalents not only consumes the aldehyde compound sufficiently, but the excess base may cause hydrolysis upon subsequent layer separation. Because of this, it is preferable to use 1 to 1.3 molar equivalents to minimize this.
본 발명에 따른 제조방법에서 비활성 용매로는 반응에 악영향을 끼치지 않는 것이면 어느 것이라도 사용할 수 있고, 바람직하게는 테트라하이드로푸란, 디메톡시에탄, 톨루엔 또는 이들의 혼합용매를 사용한다.In the production method according to the present invention, any inert solvent may be used as long as it does not adversely affect the reaction. Preferably, tetrahydrofuran, dimethoxyethane, toluene or a mixed solvent thereof is used.
화학식 4 화합물의 제조과정이 실질적으로 종료되면 이 반응액에 토스믹 (TosMIC)과 함께 전반응에서 사용한 것과 동일한 염기를 가하여 α,β-불포화에스테르가 실질적으로 다 소모될 때까지 교반함으로써 화학식 1의 피롤에스테르 화합물을 제조한다. 이때, 토스믹은 화학식 2의 화합물을 기준으로 하여 1 내지 1.3몰당량으로 사용하며, 염기는 상기 화학식 4의 화합물을 제조하는 단계에서와 동일한 범위의 양으로 사용한다. 그 후, 반응액에 물과 섞이지 않는 적당한 추출용매와 함께 물을 첨가하여 40 내지 90℃ 온도(고수율을 목적으로 한다면, 60 내지 90℃가바람직하다)에서 추출한 다음, 층분리하고 유기층을 상온에서 교반하여 침전물을 여과함으로써 화학식 1의 목적화합물을 깨끗이 수득한다. 이 추출과정을 수행하기 전에 반드시 용매를 감압증류로 제거할 필요는 없다. 다만, 반응용매로 테트라하이드로푸란 또는 디메톡시에탄을 사용하는 경우 이들은 물과 잘 섞이는 까닭에 생성물의 손실이 생길 수 있으므로 추출전에 감압증류하여 용매를 미리 제거하면 수율의 향상을 기대할 수 있다. 이러한 목적으로 사용할 수 있는 추출 유기용매로는 톨루엔 또는 n-부틸아세테이트가 바람직하다. 특히, 염기로서 소듐-t-펜톡사이드를 사용하는 경우 이는 추출용매로서 바람직한 톨루엔에 잘 용해되므로 반응용매와 추출용매를 달리 사용함에 따른 번거로움이 없이 간편하다.When the preparation of the compound of Formula 4 is substantially terminated, the reaction solution is added with the same base as used in the pre-reaction together with TosMIC to stir until the α, β-unsaturated ester is substantially used up. A pyrrole ester compound is prepared. In this case, tosmic is used in 1 to 1.3 molar equivalents based on the compound of Formula 2, and the base is used in the same range as in the step of preparing the compound of Formula 4. Thereafter, water is added to the reaction solution together with a suitable extraction solvent which is not mixed with water, followed by extraction at a temperature of 40 to 90 ° C. (60 to 90 ° C. for high yield, preferably). The layers are separated and the organic layer is cooled to room temperature. The precipitate was filtered by stirring at to obtain the target compound of formula (1). It is not necessary to remove the solvent by distillation under reduced pressure before carrying out this extraction. However, when tetrahydrofuran or dimethoxyethane is used as the reaction solvent, since they may be mixed with water well, product loss may occur. Therefore, if the solvent is removed by distillation under reduced pressure before extraction, the yield may be improved. Toluene or n-butyl acetate is preferable as the extracted organic solvent that can be used for this purpose. In particular, in the case of using sodium-t-pentoxide as a base, it is easily dissolved in toluene, which is preferable as an extraction solvent, and thus, it is simple without the trouble of using a reaction solvent and an extraction solvent differently.
화학식 4의 화합물을 제조하는 반응은 -20 내지 40℃의 온도에서 만족할 수준으로 진행되지만, 바람직하게는 10 내지 25℃에서 진행시킨다. 또한, 수득된 화학식 4의 화합물로부터 목적하는 화학식 1의 피롤에스테르 유도체를 제조하는 과정은 0 내지 40℃의 온도범위에서 진행시키는 것이 적합하다.The reaction for preparing the compound of formula 4 proceeds to a satisfactory level at a temperature of -20 to 40 ° C, but preferably at 10 to 25 ° C. In addition, the process for preparing the desired pyrrole ester derivative of the general formula (1) from the obtained compound of the general formula (4) is preferably carried out at a temperature range of 0 to 40 ℃.
본 발명에서는 화학식 4의 불포화에스테르 화합물을 제조한 후 이를 선행기술에서와는 달리 분리, 정제하지 않고 곧바로 토스믹과 반응시키고 있다. 즉, 여러 가지 복잡한 정제과정과 함께 용매를 감압증류로 제거하는 공정의 생략이 가능해졌다. 아울러, 목적하는 화학식 1의 화합물을 제조한 다음 물과 층분리되는 유기용매를 가하여 추출하고 층분리된 유기용매층으로부터 직접 목적화합물을 재결정하는 정제과정을 채택함에 따라 기존의 방법에서처럼 물을 첨가해 고체화하는 경우에 생성된 침전물이 끈끈하게 서로 엉겨 덩어리를 형성하는 상황을 피할 수 있게되었다. 이러한 반응공정상의 개선은 특히 본 발명에 따른 제조방법을 대량생산에 적용하는 경우 매우 큰 잇점을 제공하게 된다.In the present invention, the unsaturated ester compound of Formula 4 is prepared and then reacted with tosmic immediately without separation and purification, unlike in the prior art. That is, it is possible to omit the process of removing the solvent by distillation under reduced pressure together with various complicated purification processes. In addition, by preparing a compound of the formula (1), and then extracted by adding an organic solvent separated by water and recrystallization of the target compound directly from the separated organic solvent layer by adding water as in the conventional method In the case of solidification, it is possible to avoid the situation in which the formed precipitates stick together and form lumps. This improvement in the reaction process provides a very great advantage, especially when the production process according to the invention is applied to mass production.
이하, 본 발명을 하기 실시예에 의거하여 보다 구체적으로 설명한다. 그러나, 이 실시예는 본 발명에 대한 이해를 돕기위한 것일 뿐, 어떤 의미로든 본 발명의 범위가 이 실시예로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples. However, this embodiment is only for the understanding of the present invention, and the scope of the present invention in any sense is not limited to this embodiment.
실시예 1Example 1
에틸 4-(나프탈렌-1-일)-1H-피롤-3-카복실산 에스테르의 제조Preparation of ethyl 4- (naphthalen-1-yl) -1H-pyrrole-3-carboxylic acid ester
질소 대기하에 1-나프탈데히드(35g, 0.224몰)와 트리에틸포스포노아세테이트 (50g, 0.224몰)를 혼합하고 180㎖의 디메톡시에탄(DME)을 넣어 잘 교반하면서 0℃로 냉각하였다. 상기 용액에 포타슘-t-부톡사이드(30g, 1.2몰당량)를 반응온도가 20℃를 넘지않도록 하면서 서서히 첨가하였다. HPLC를 이용해 1-나프탈데히드가 다 소모된 것을 확인한 다음, TosMIC(52.5g, 1.2몰당량)을 첨가하고 잘 혼합한 다음, 포타슘-t-부톡사이드(32g, 1.3몰당량)를 반응온도 20℃ 이하에서 서서히 첨가하였다. HPLC로 α,β-불포화에스테르가 다 소모된 것을 확인한 다음 증류수 70㎖를 첨가해 반응액을 용액상으로 만든 뒤 감압증류하여 DME를 제거하였다. 상기 농축액에 톨루엔 200㎖를 첨가하여 가온한 뒤 증류수 350㎖를 서서히 가해 따뜻한 상태로 추출하고 수층을 분리하였다. 남은 유기층을 공비 증류하여 남은 수분을 제거함으로써 농축되면 서서히 교반하면서 상온에서 바로 결정화하였다. 여과후 잔류물을 차가운 톨루엔 30㎖로 2회 세척하고 증류수 50㎖로 2회 세척하고 건조시켜 백색 분말상의 표제화합물 37g(HPLC 순도 95.2%, 수율 61%)을 수득하였다.1-naphthalaldehyde (35 g, 0.224 mole) and triethylphosphonoacetate (50 g, 0.224 mole) were mixed under a nitrogen atmosphere, and 180 ml of dimethoxyethane (DME) was added thereto, followed by cooling to 0 ° C. with good stirring. To the solution was added potassium-t-butoxide (30 g, 1.2 molar equivalents) slowly, with the reaction temperature not exceeding 20 ° C. After confirming that 1-naphthalaldehyde was exhausted using HPLC, add TosMIC (52.5 g, 1.2 molar equivalents), mix well, and then add potassium-t-butoxide (32 g, 1.3 molar equivalents) to reaction temperature 20 It was added slowly below ℃. After confirming that the α, β-unsaturated ester was exhausted by HPLC, 70 ml of distilled water was added to make the reaction solution into solution, followed by distillation under reduced pressure to remove DME. 200 ml of toluene was added to the concentrate, followed by warming, followed by slowly adding 350 ml of distilled water to extract a warm state, and separating an aqueous layer. The remaining organic layer was azeotropically distilled to remove remaining moisture, and then crystallized immediately at room temperature while slowly stirring. After filtration, the residue was washed twice with 30 ml of cold toluene, twice with 50 ml of distilled water and dried to give 37 g of the title compound as a white powder (HPLC purity 95.2%, yield 61%).
1H NMR(CDCl3, ppm) δ 8.65(1H, br, s), 7.80(3H, m), 7.59(1H, dd, J1=3.2Hz, J2=2.3Hz), 7.41(4H, m), 6.79(1H, t, J=2.3Hz), 3.91(2H, q, J=6.9Hz), 0.71(3H, t, J=6.9Hz) 1 H NMR (CDCl 3 , ppm) δ 8.65 (1H, br, s), 7.80 (3H, m), 7.59 (1H, dd, J 1 = 3.2 Hz, J 2 = 2.3 Hz), 7.41 (4H, m ), 6.79 (1H, t, J = 2.3 Hz), 3.91 (2H, q, J = 6.9 Hz), 0.71 (3H, t, J = 6.9 Hz)
13C NMR(CDCl3, ppm) δ 165.2, 133.8, 133.51, 133.50, 128.0, 127.5, 127.3, 126.7, 125.5, 125.4, 125.2, 124.7, 123.9, 119.3, 115.9, 59.5, 13.7 13 C NMR (CDCl 3 , ppm) δ 165.2, 133.8, 133.51, 133.50, 128.0, 127.5, 127.3, 126.7, 125.5, 125.4, 125.2, 124.7, 123.9, 119.3, 115.9, 59.5, 13.7
융점(미보정) 164-165℃Melting Point (Uncorrected) 164-165 ℃
실시예 2Example 2
에틸 4-(나프탈렌-1-일)-1H-피롤-3-카복실산 에스테르의 제조Preparation of ethyl 4- (naphthalen-1-yl) -1H-pyrrole-3-carboxylic acid ester
500㎖ 용량의 3-구 둥근바닥 플라스크에 온도계와 질소공급라인을 설치하고 1-나프탈데히드(28g, 0.18mol)과 트리에틸포스포노아세테이트(40.35g, 0.18몰)를 넣은 후 180㎖의 톨루엔에 희석하였다. 상기 반응액을 약 0 내지 5℃로 냉각시키고 소듐-t-펜톡사이드(23.8g, 0.216mol)를 반응온도가 약 20℃를 넘지 않도록 천천히 여러번에 걸쳐 나누어 넣었다. 첨가가 완료되면 상온에서 1 내지 2시간동안 교반하고 다시 0 내지 5℃로 냉각시킨 후 TosMIC(36.9g, 0.189mol)과 소듐-t-펜톡사이드 (23.8g, 0.216mol)을 반응온도가 약 20℃를 넘지않도록 천천히 여러번에 걸쳐 나누어 넣었다. 첨가가 완료되면 상온에서 3 내지 6시간동안 교반한 다음 증류수 250㎖를 가하고 약 70℃로 가열하여 교반한 다음, 층분리하고 동온도에서 증류수 250㎖로 한번 더 세척하여 층분리하였다. 분리된 유기층을 공비 증류하여 수분을 제거함으로써 부피가 약 1/2이 되도록 한 후, 약 50℃에서 서서히 교반하면서 결정화하였다. 결정이 침전된 후 온도를 0 내지 5℃로 냉각시켜 더 교반하였다. 여과하여 얻어진 고체를 톨루엔 30㎖로 2회 세척하고 질소로 건조시켜 백색 분말상의 표제화합물 29.6g(HPLC 순도 96%PAR, 수율 62%)을 수득하였다.In a 500 mL three-neck round bottom flask, a thermometer and nitrogen supply line were installed, 1-naphthalaldehyde (28 g, 0.18 mol) and triethylphosphonoacetate (40.35 g, 0.18 mol) were added, followed by 180 ml of toluene. Diluted in. The reaction solution was cooled to about 0 to 5 ° C. and sodium-t-pentoxide (23.8 g, 0.216 mol) was slowly divided into several times so that the reaction temperature did not exceed about 20 ° C. After the addition was complete, the mixture was stirred at room temperature for 1 to 2 hours, cooled to 0 to 5 ° C, and then reacted with TosMIC (36.9 g, 0.189 mol) and sodium-t-pentoxide (23.8 g, 0.216 mol) at about 20 ° C. Divided slowly several times so as not to exceed ℃. After the addition was completed, the mixture was stirred for 3 to 6 hours at room temperature, then 250 ml of distilled water was added thereto, heated to about 70 ° C., stirred, and the layers were separated and washed once more with 250 ml of distilled water. The separated organic layer was azeotropically distilled to remove water to obtain a volume of about 1/2, and then crystallized with gentle stirring at about 50 ° C. After the precipitated crystals, the temperature was cooled to 0-5 ° C and further stirred. The solid obtained by filtration was washed twice with 30 ml of toluene and dried with nitrogen to give 29.6 g (HPLC purity 96% PAR, yield 62%) as a white powder.
본 발명에 따른 제조방법의 개발에 의해, 항암제로서 사용되는 파네실 전이효소 억제제 제조의 핵심 중간체인 화학식 1의 피롤에스테르 화합물을 고순도 및 고수율로 대량생산하는 것이 가능해졌다.By the development of the production method according to the present invention, it is possible to mass-produce a high purity and high yield of the pyrrole ester compound of the formula (1) which is a key intermediate for the preparation of the farnesyl transferase inhibitor used as an anticancer agent.
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| KR10-2000-0081913A KR100412334B1 (en) | 2000-02-22 | 2000-12-26 | Novel process for preparing 4-substituted-1H-pyrrole-3-carboxylic acid ester |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2310629A1 (en) * | 1997-11-28 | 1999-06-10 | Tae Hwan Kwak | Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof |
| KR100388783B1 (en) * | 1998-10-20 | 2003-10-04 | 주식회사 엘지생명과학 | Intermediate of Panesyl Transferase Inhibitor with Pyrrole Structure |
| KR100515905B1 (en) * | 2000-01-31 | 2005-09-21 | 주식회사 엘지생명과학 | New process for preparing pyrrole amide |
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