KR100351623B1 - A water soluble chiral auxiliary (5R,5'R)-5,5'-bis(oxazolidin-2-one) and its synthetic procedure - Google Patents
A water soluble chiral auxiliary (5R,5'R)-5,5'-bis(oxazolidin-2-one) and its synthetic procedure Download PDFInfo
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Abstract
본 발명은 수용성 키랄 보조제로서의 (5R,5'R)-5,5'-비스(옥사졸리딘-2-온) 및 이의 제조방법에 관한 것으로서, 더욱 상세하게는 종래 비대칭 반응기술에 사용되는 키랄 보조제가 당량으로 사용되고 관 크로마토그래피에 의해 분리하므로 회수가 어려웠던 1-작용기성 구조의 키랄 보조제와는 달리, 수용성으로서 C2 대칭성의 2-작용기성 구조를 가지는 신규한 수용성 키랄 보조제로서의 다음 화학식 1로 표시되는 (5R,5'R)-5,5'-비스(옥사졸리딘-2-온) 및 이의 제조방법에 관한 것이다.The present invention relates to (5R, 5'R) -5,5'-bis (oxazolidin-2-one) as a water-soluble chiral adjuvant and a preparation method thereof, and more particularly to chiral used in conventional asymmetric reaction techniques. Unlike the 1-functional chiral adjuvant which was difficult to recover because the adjuvant was used as an equivalent and separated by column chromatography, it is represented by the following Chemical Formula 1 as a novel water-soluble chiral adjuvant having a C2 symmetric 2-functional structure as water soluble. To (5R, 5'R) -5,5'-bis (oxazolidin-2-one) and a method for preparing the same.
특히, 본 발명은 1 당량의 키랄 보조제로 2 당량의 키랄 화합물을 합성할 수 있어 분자 경제성을 만족시키고, 대부분의 유기물 반응 생성물로부터 고가의 키랄 보조제의 분리가 용이하여 비대칭 반응기술에 사용되기에 효과적이다.In particular, the present invention is capable of synthesizing 2 equivalents of a chiral compound with 1 equivalent of chiral adjuvant to satisfy molecular economics, and to facilitate the separation of expensive chiral adjuvant from most organic reaction products, which is effective for use in asymmetric reaction techniques. to be.
Description
본 발명은 수용성 키랄 보조제로서의 (5R,5'R)-5,5'-비스(옥사졸리딘-2-온) 및 이의 제조방법에 관한 것으로서, 더욱 상세하게는 종래 비대칭 반응기술에 사용되는 키랄 보조제가 당량으로 사용되고 관 크로마토그래피에 의해 분리하므로 회수가 어려웠던 1-작용기성 구조의 키랄 보조제와는 달리, 수용성으로서 C2 대칭성의 2-작용기성 구조를 가지는 신규한 수용성 키랄 보조제로서의 다음 화학식 1로 표시되는 (5R,5'R)-5,5'-비스(옥사졸리딘-2-온) 및 이의 제조방법에 관한 것이다.The present invention relates to (5R, 5'R) -5,5'-bis (oxazolidin-2-one) as a water-soluble chiral adjuvant and a preparation method thereof, and more particularly to chiral used in conventional asymmetric reaction techniques. Unlike the 1-functional chiral adjuvant which was difficult to recover because the adjuvant was used as an equivalent and separated by column chromatography, it is represented by the following Chemical Formula 1 as a novel water-soluble chiral adjuvant having a C2 symmetric 2-functional structure as water soluble. To (5R, 5'R) -5,5'-bis (oxazolidin-2-one) and a method for preparing the same.
특히, 본 발명은 1 당량의 키랄 보조제로 2 당량의 키랄 화합물을 합성할 수 있어 분자 경제성을 만족시키고, 대부분의 유기물 반응 생성물로부터 고가의 키랄 보조제의 분리가 용이하여 비대칭 반응기술에 사용되기에 효과적이다.In particular, the present invention is capable of synthesizing 2 equivalents of a chiral compound with 1 equivalent of chiral adjuvant to satisfy molecular economics, and to facilitate the separation of expensive chiral adjuvant from most organic reaction products, which is effective for use in asymmetric reaction techniques. to be.
화학식 1Formula 1
비대칭 반응기술의 필요성은 광학활성 의약품의 규제강화와 더불어 그 중요성이 날로 증가되어지고 있으며, 특히 키랄 보조제를 이용한 비대칭 반응은 비대칭 탄소-탄소 결합을 만드는데 매우 중요한 반응이다.The necessity of asymmetric reaction technology is increasing in importance with strengthening the regulation of optically active drugs, especially the asymmetric reaction using chiral adjuvant is a very important reaction to make asymmetric carbon-carbon bonds.
이러한 키랄 보조제를 이용한 비대칭 반응기술은 키랄성이 없는 출발물질과 키랄 보조제를 결합하여 키랄 화합물로 전환한 다음, 키랄 보조제의 키랄성을 이용하여 최종 화합물에 새로운 키랄성을 도입하는 것을 기본 기술로 한다.The asymmetric reaction technology using such chiral adjuvant is based on the conversion of a chiral adjuvant and a chiral adjuvant into a chiral compound and then introducing new chirality into the final compound using the chirality of the chiral adjuvant.
현재 알려져 있는 키랄 보조제 중 대표적인 키랄 보조제로서는 예를 들면, 다음 화학식 2로 표시되는 옥사졸리딘계 키랄 보조제를 들 수 있다.As a typical chiral adjuvant among the currently known chiral adjuvant, the oxazolidine type chiral adjuvant represented by following formula (2) is mentioned, for example.
다음 화학식 2로 표시되는 옥사졸리딘계 키랄 보조제를 이용한 비대칭 반응의 경우, 키랄성 전달효과는 탁월하다고 할 수 있지만, 당량의 키랄 보조제를 이용하기 때문에 분자 경제적인 측면에서는 효능이 떨어진다. 그 뿐만 아니라 대부분의 경우 반응 생성물과 키랄 보조제의 용매에 대한 용해도 차이가 거의 없기 때문에 관 크로마토그래피에 의존하는 고가의 키랄 보조제의 분리 및 회수가 용이하지 않다.In the case of an asymmetric reaction using an oxazolidine-based chiral adjuvant represented by the following Chemical Formula 2, the chiral delivery effect is excellent, but the efficacy is low in terms of molecular economy because it uses an equivalent chiral adjuvant. In addition, in most cases, there is little difference in solubility between the reaction product and the chiral adjuvant in the solvent, which makes it difficult to separate and recover the expensive chiral adjuvant depending on the column chromatography.
이러한 한계성을 극복하기 위한 노력으로, 한 분자의 키랄 보조제를 사용하여 두 배의 키랄성 도입을 가능하게 하여 키랄 보조제의 분자 경제성을 증가시키는 방법이 다음의 문헌에 발표된 바 있다[Tetrahedron Letters1991, 32, 4787;Tetrahedron Letters1991, 32, 4791; Tetrahedron: Asymmetry1991, 2, 1001; Tetrahedron Letters1992, 33, 1117; Tetrahedron1993, 49, 4419; Tetrahedron: Asymmetry1994, 5, 585; Tetrahedron1994, 50, 6621]. 상기 문헌에서는 키랄 보조제의 분자 경제성을 증가시키기 위해서, 다음 반응식 1에서 보는 바와 같이 이미 잘 알려진 다음 화학식 2로 표시되는 옥사졸리디논계 키랄 보조제를 C2-대칭화시켜 다음 화학식 3으로 표시되는 2-작용기성(bifunctional)의 키랄 보조제를 제조하는 방법이 기술되어 있다.In an effort to overcome this limitation, a method of increasing the molecular economics of chiral auxiliaries by enabling the introduction of double chirality using a single molecule of chiral auxiliaries has been published in the following literature [Tetrahedron Letters 1991 , 32] 4787; Tetrahedron Letters 1991 , 32, 4791; Tetrahedron: Asymmetry 1991 , 2, 1001; Tetrahedron Letters 1992 , 33, 1117; Tetrahedron 1993 , 49, 4419; Tetrahedron: Asymmetry 1994 , 5, 585; Tetrahedron 1994 , 50, 6621. In this document, in order to increase the molecular economics of the chiral adjuvant, as shown in the following Scheme 1, the well-known oxazolidinone-based chiral adjuvant represented by the following general formula (2) is C2-symmetric to the 2-function represented by the following general formula (3). A method for preparing a bifunctional chiral adjuvant is described.
또 다른 방법으로, 키랄 보조제를 고체상에 도입함으로써 키랄 보조제의 분리 및 회수를 용이하게 하는 연구가 다음 문헌에 보고된 바 있다[Tetrahedron Letters1996, 37, 8023; Tetrahedron Letters1997, 38, 8777; Tetrahedron Letters1998, 39, 2655]. 상기 문헌들에서는 다음 반응식 1에서와 같이 다음 화학식 2로 표시되는 키랄 보조제를 고체상에 결합시켜 회수가 용이한 다음 화학식 4로 표시되는 고체 지지된(solid supported) 키랄 보조제를 제조하는 방법이 기술되어 있다.Alternatively, studies have been reported in the following documents that facilitate the separation and recovery of chiral auxiliaries by introducing chiral auxiliaries in a solid phase [Tetrahedron Letters 1996 , 37, 8023; Tetrahedron Letters 1997 , 38, 8777; Tetrahedron Letters 1998 , 39, 2655. The above documents describe a method for preparing a solid supported chiral adjuvant represented by the following general formula (4), which is easily recovered by binding the chiral adjuvant represented by the following Chemical Formula 2 to the solid phase as shown in the following Scheme 1. .
그러나, 지금까지 개발된 모든 2-작용기성 키랄 보조제의 경우에도 반응이 종결된 후, 키랄 보조제를 분리회수할 때 관 크로마토그래피에 의해 반응 생성물로부터 키랄 보조제를 분리하여야하는 어려움이 남아있다. 또한, 키랄 보조제를 고체상 지지체에 결합시킨 고체 지지된(solid supported) 키랄 보조제의 경우, 비록 키랄 보조제의 분리가 용이할지라도 일반적으로 아주 소량의 키랄 보조제만이 고체상 지지체에 도입이 가능하기 때문에 당량을 사용하여야하는 키랄 보조제를 이용한 비대칭 반응에서 이용되기에는 여전히 부적합하다고 할 수 있다.However, even in the case of all the two-functional chiral adjuvants developed so far, after the reaction is terminated, the difficulty of separating the chiral adjuvants from the reaction product by tube chromatography when separating and recovering the chiral auxiliaries remains. In addition, in the case of solid supported chiral auxiliaries in which the chiral auxiliaries are bound to a solid phase support, even though the chiral auxiliaries are easy to separate, generally only a small amount of chiral auxiliaries can be incorporated into the solid phase support so Still unsuitable for use in asymmetric reactions with chiral auxiliaries to be used.
따라서, 비대칭 반응기술에 사용되기 위한 키랄 보조제의 개발에 있어서, 키랄 보조제의 분자 경제적인 효능을 만족하고 반응 종료후에는 반응 생성물과 키랄 보조제의 분리가 용이한 새로운 개념의 키랄 보조제의 개발이 요구된다.Therefore, in developing a chiral adjuvant for use in asymmetric reaction technology, it is required to develop a new concept of chiral adjuvant which satisfies the molecular economic efficacy of the chiral adjuvant and after which the reaction product is easily separated from the chiral adjuvant. .
이에, 본 발명자들은 종래 비대칭 반응을 위한 키랄 보조제가 당량으로 사용되어 분자 경제적인 효능이 떨어지고 반응 종료 후 분리가 어려운 문제를 해결하기 위하여, 여러 가지 측면에서 연구 노력하였다. 그 결과, C2-대칭성의 2-작용기성 구조를 가지면서 수용성을 나타내는 비대칭 반응을 위한 새로운 키랄 보조제 화합물을 개발함으로써, 2-작용기성 구조로 키랄 보조제의 분자 경제성을 만족시킬 뿐만 아니라, 특히 대부분의 유기물 반응 생성물로부터 키랄 보조제의 분리가 용이함을 알게되어 본 발명을 완성하게 되었다.Thus, the present inventors have tried in various aspects to solve the problem that the conventional chiral adjuvant for the asymmetric reaction is used as an equivalent to reduce the molecular economic efficacy and difficult to separate after the reaction. As a result, by developing a new chiral adjuvant compound for asymmetric reactions having water solubility while having a C2-symmetric 2-functional structure, the 2-functional structure not only satisfies the molecular economics of the chiral adjuvant, in particular most It has been found that the separation of chiral auxiliaries from organic reaction products facilitates the present invention.
따라서, 본 발명의 목적은 광학활성 화합물 합성을 위한 수용성 키랄 보조제로서의 상기 화학식 1로 표시되는 (5R,5'R)-5,5'-비스(옥사졸리딘-2-온) 및 이의 제조방법을 제공하는 것이다.Accordingly, an object of the present invention is (5R, 5'R) -5,5'-bis (oxazolidin-2-one) represented by Chemical Formula 1 as a water-soluble chiral adjuvant for synthesizing an optically active compound, and a preparation method thereof. To provide.
본 발명은 수용성 키랄 보조제로서의 다음 화학식 1로 표시되는 (5R,5'R)-5,5'-비스(옥사졸리딘-2-온)을 그 특징으로 한다.The present invention is characterized by (5R, 5'R) -5,5'-bis (oxazolidin-2-one) represented by the following formula (1) as a water-soluble chiral adjuvant.
화학식 1Formula 1
또한, 본 발명은 1기압 하의 수소분위기 하에서 팔라듐 히드록사이드를 사용하여 1,4-디벤질-2,3-디메틸술포닐테트라히드록시부탄을 수소화 탈벤질화 반응시켜 (2S,3S)-2,3-비스(O-메탄술포닐)-1,2,3,4-테트라히드록시부탄을 제조하는 과정,In addition, the present invention is hydrogenated debenzylation reaction of 1,4-dibenzyl-2,3-dimethylsulfonyltetrahydroxybutane using palladium hydroxide under a hydrogen atmosphere at 1 atm (2S, 3S) -2 A process for preparing 3-bis (O-methanesulfonyl) -1,2,3,4-tetrahydroxybutane,
소듐 하이드라이드하에서 상기 (2S,3S)-2,3-비스(O-메탄술포닐)-1,2,3,4-테트라히드록시부탄과 벤질 이소시아네이트를 가열 환류시켜 (5R,5R')-N,N'-디벤질-5,5'-비스(옥사졸리딘-2-온)을 제조하는 과정, 그리고(2S, 3S) -2,3-bis (O-methanesulfonyl) -1,2,3,4-tetrahydroxybutane and benzyl isocyanate were heated to reflux under sodium hydride to give (5R, 5R ')- Preparing N, N'-dibenzyl-5,5'-bis (oxazolidin-2-one), and
상기 (5R,5R')-N,N'-디벤질-5,5'-비스(옥사졸리딘-2-온)을 액체 암모니아 및 나트륨 금속을 사용하여 탈벤질화 반응시켜 다음 화학식 1로 표시되는 (5R,5'R)-5,5'-비스(옥사졸리딘-2-온)을 제조하는 과정이 포함되는 수용성 키랄 보조제의 제조방법을 포함한다.The (5R, 5R ')-N, N'-dibenzyl-5,5'-bis (oxazolidin-2-one) is debenzylated using liquid ammonia and sodium metal to be represented by the following Chemical Formula 1. It includes a method for producing a water-soluble chiral adjuvant comprising a process for producing (5R, 5'R) -5,5'-bis (oxazolidin-2-one).
이와 같은 본 발명을 더욱 상세하게 설명하면 다음과 같다.The present invention will be described in more detail as follows.
본 발명은 C2-대칭성의 2-작용기성 구조를 가지면서 수용성을 나타내어 키랄 보조제의 분자 경제성을 만족시키고, 분리가 용이하여 비대칭 반응기술에 사용되기에 적합한 수용성 키랄 보조제로서의 (5R,5'R)-5,5'-비스(옥사졸리딘-2-온) 및 이의 제조방법에 관한 것이다.The present invention provides a water-soluble chiral adjuvant (5R, 5'R), which has a C2-symmetric, 2-functional structure, exhibits water solubility, satisfies the molecular economics of chiral adjuvant, and is easy to be used for asymmetric reaction technology. -5,5'-bis (oxazolidin-2-one) and a preparation method thereof.
본 발명에 따른 키랄 보조제를 이용한 비대칭 반응은 광학활성 화합물의 합성에 있어서 매우 중요한 반응이다. 이를 위해서, 많은 종류의 키랄 보조제들이 개발되었으며, 현재 광학활성 화합물의 합성에 널리 이용되어지고 있다.Asymmetric reactions using chiral auxiliaries according to the invention are very important in the synthesis of optically active compounds. To this end, many kinds of chiral auxiliaries have been developed and are now widely used in the synthesis of optically active compounds.
그러나, 상기에서 설명한 바와 같이 종래 키랄 보조제를 이용한 비대칭 반응에서 아직까지 해결하지 못한 문제점의 하나로 비대칭 반응이 완결된 다음 키랄 보조제를 회수하는 것이다. 용매에 대한 용해도의 차이가 큰 일부 키랄 화합물과 키랄 보조제의 경우 키랄 보조제의 회수가 용이하나 대부분의 경우에는 관 크로마토그래피에 의해서 분리가 가능하기 때문에 키랄 보조제를 이용한 광학활성 화합물의 대량 생산에는 한계성이 있다. 키랄 보조제의 회수를 간편하게 하기 위해서 키랄 보조제를 고체상에 도입함으로 키랄 보조제의 회수 문제를 해결하고자 하는 시도가 있었으나, 당량의 보조제를 사용할 때 반응부피가 너무 증가되기 때문에 반응 규모가 증가될 경우 역시 그 한계성을 가지고 있었다.However, as described above, one of the problems that have not been solved in the conventional asymmetric reaction using the chiral adjuvant is to recover the chiral adjuvant after the asymmetric reaction is completed. Some chiral compounds and chiral auxiliaries with large differences in solubility in solvents are easy to recover chiral auxiliaries, but in most cases they can be separated by column chromatography, which limits the mass production of optically active compounds using chiral auxiliaries. have. In order to simplify the recovery of the chiral adjuvant, there have been attempts to solve the problem of the recovery of the chiral adjuvant by introducing the chiral adjuvant into the solid phase, but the limit of the increase in the reaction scale also increases because the reaction volume is increased when the equivalent adjuvant is used. Had
이에 반하여, 본 발명에서는 수용성으로서 키랄 보조제의 회수가 용이할 뿐만 아니라, 한 분자의 키랄 보조제로 두 번의 비대칭 반응이 가능한 2-작용기성의 키랄 보조제로서 상기 화학식 1로 표시되는 (5R,5'R)-5,5'-비스(옥사졸리딘-2-온)을 개발함으로써, 종래 키랄 보조제를 이용한 반응의 문제점을 해결하였다.On the contrary, in the present invention, as a water-soluble chiral adjuvant, the two-functional chiral adjuvant capable of two asymmetric reactions with one molecule of chiral adjuvant is represented by the formula (5R, 5'R). By developing) -5,5'-bis (oxazolidin-2-one), the problem of the reaction using a conventional chiral adjuvant was solved.
이러한 본 발명에 따른 상기 화학식 1로 표시되는 (5R,5'R)-5,5'-비스(옥사졸리딘-2-온)을 그 제조방법에 의거하여 보다 구체적으로 설명하면 다음과 같다.The (5R, 5'R) -5,5'-bis (oxazolidin-2-one) represented by Formula 1 according to the present invention will be described in more detail based on the preparation method as follows.
첫 번째 과정으로, 본 발명은 30 ∼ 40 ℃, 1기압 하의 수소분위기 하에서 팔라듐 히드록사이드를 사용하여 1,4-디벤질-2,3-디메틸술포닐테트라히드록시부탄을 수소화 탈벤질화 반응시켜 (2S,3S)-2,3-비스(O-메탄술포닐)-1,2,3,4-테트라히드록시부탄을 제조하는 과정을 수행한다.In the first process, the present invention is hydrogenated debenzylation of 1,4-dibenzyl-2,3-dimethylsulfonyltetrahydroxybutane using palladium hydroxide under a hydrogen atmosphere at 30 to 40 ° C. under 1 atmosphere. To prepare (2S, 3S) -2,3-bis (O-methanesulfonyl) -1,2,3,4-tetrahydroxybutane.
다음 반응식 2에서 보면, 본 발명에서는 출발물질로서 자연계로부터 쉽게 얻어지는 타르타르산으로부터 합성이 가능한 다음 화학식 5로 표시되는 1,4-디벤질-2,3-디메틸술포닐테트라히드록시부탄을 사용한다.In the following Reaction Scheme 2, the present invention uses 1,4-dibenzyl-2,3-dimethylsulfonyltetrahydroxybutane represented by the following formula (5) which can be synthesized from tartaric acid easily obtained from nature as a starting material.
그리고, 본 발명은 출발물질로 사용하는 상기 화학식 5로 표시되는 화합물을 용매에 녹인 다음, 팔라듐 히드록사이드(palladium hydroxide)를 첨가하여 1기압 하의 수소 분위기 하에서 30 ∼ 40 ℃의 반응온도로 12시간 동안 반응시킴으로써, 수소화 탈벤질화된 상기 화학식 6으로 표시되는 화합물을 얻게 된다. 이때, 상기 팔라듐 히드록사이드의 사용함량은 촉매량인 1 ∼ 5 몰%로 사용한다. 또한, 상기 용매로는 에틸 알콜, 에틸 아세테이트 또는 이들의 혼합용매 중에서 선택하여 사용한다.The present invention dissolves the compound represented by Formula 5, which is used as a starting material, in a solvent, and then adds palladium hydroxide to a reaction temperature of 30 to 40 ° C. under a hydrogen atmosphere at 1 atm for 12 hours. By reacting for a while, the compound represented by Chemical Formula 6 is obtained by hydrogenation debenzylation. At this time, the palladium hydroxide is used in an amount of 1 to 5 mol%, which is a catalytic amount. In addition, the solvent is selected from ethyl alcohol, ethyl acetate or a mixed solvent thereof.
두 번째 과정으로, 본 발명은 소듐 하이드라이드하에서 상기 (2S,3S)-2,3-비스(O-메탄술포닐)-1,2,3,4-테트라히드록시부탄과 벤질 이소시아네이트를 가열 환류시켜 (5R,5R')-N,N'-디벤질-5,5'-비스(옥사졸리딘-2-온)을 제조하는 과정을 수행한다.In a second process, the present invention is heated to reflux the (2S, 3S) -2,3-bis (O-methanesulfonyl) -1,2,3,4-tetrahydroxybutane and benzyl isocyanate under sodium hydride. To prepare (5R, 5R ')-N, N'-dibenzyl-5,5'-bis (oxazolidin-2-one).
상기 반응식 3에서와 같이, 본 발명은 상기 과정에서 제조된 다음 화학식 6으로 표시되는 화합물을 용매로서 테트라히드로퓨란(THF)에 녹인 후, 실온에서 벤질 이소시아네이트를 첨가하고 0 ℃에서 소듐 하이드라이드를 첨가한다. 그런 다음, 반응혼합물을 8 시간 동안 가열 환류시킴으로써, 상기 화학식 7로 표시되는 화합물을 얻을 수 있다.As in Scheme 3, the present invention dissolves the compound represented by the following formula (6) prepared in the above process in tetrahydrofuran (THF) as a solvent, benzyl isocyanate at room temperature and sodium hydride at 0 ℃ do. Thereafter, the reaction mixture is heated to reflux for 8 hours to obtain a compound represented by Chemical Formula 7.
마지막 과정으로서, 본 발명은 상기 (5R,5R')-N,N'-디벤질-5,5'-비스(옥사졸리딘-2-온)을 액체 암모니아 및 나트륨 금속을 사용하여 탈벤질화 반응시켜 상기 화학식 1로 표시되는 (5R,5'R)-5,5'-비스(옥사졸리딘-2-온)을 제조하는 과정을 수행함으로써, 본 발명을 완성하게 된다.As a final procedure, the present invention provides a method for debenzylating (5R, 5R ')-N, N'-dibenzyl-5,5'-bis (oxazolidin-2-one) using liquid ammonia and sodium metal. By reacting to prepare (5R, 5'R) -5,5'-bis (oxazolidin-2-one) represented by Chemical Formula 1, the present invention is completed.
다음 반응식 4에서와 같이, 본 발명은 상기 과정에서 제조된 다음 화학식 7로 표시되는 화합물을 -78 ℃에서 액화시킨 액체 암모니아에 용해시킨 후, -78 ℃에서 나트륨 금속을 소량씩 서서히 첨가한다. 반응이 완결되면 액체 암모니아를 증류로 제거하고 고체 NH4Cl과 소량의 물을 첨가한 후 유기용매로 유기 불순물을 추출하여 제거한다. 그리고, 수용액 층을 분리하여 물을 감압 제거한후 아세토니트닐등의 용매를 이용하여 고체-액체 추출에 의해서 목적하는 수용성의 키랄 보조제인 상기 화학식 1로 표시되는 화합물을 높은 수율로 얻을 수 있는 특징이 있다.As in Scheme 4, the present invention dissolves the compound represented by the following formula (7) in liquid ammonia liquefied at -78 ° C, and then slowly adds a small amount of sodium metal at -78 ° C. Upon completion of the reaction, liquid ammonia is removed by distillation, solid NH 4 Cl and a small amount of water are added, followed by extraction and removal of organic impurities with an organic solvent. After separating the aqueous layer to remove the water under reduced pressure, the compound represented by Chemical Formula 1, which is a water-soluble chiral adjuvant, can be obtained in high yield by solid-liquid extraction using a solvent such as acetonitrile. have.
이상과 같이, 본 발명에 따른 (5R,5'R)-5,5'-비스(옥사졸리딘-2-온)은 수용액층으로부터 건조하여 얻은 수용성 키랄 보조제로서 유기용매로부터 분리가 용이하며, 또한 C-2 대칭성의 2-작용기성의 구조를 가지므로 1 당량의 키랄 보조제로 2 당량의 키랄 화합물을 얻을 수 있어 분자 경제적인 측면에서 효율적이다.As described above, (5R, 5'R) -5,5'-bis (oxazolidin-2-one) according to the present invention is a water-soluble chiral adjuvant obtained by drying from an aqueous solution layer, and is easily separated from an organic solvent. In addition, since it has a C-2 symmetric 2-functional structure, 1 equivalent of a chiral adjuvant yields 2 equivalents of a chiral compound, which is efficient in terms of molecular economy.
따라서, 본 발명에서 개발된 수용성의 2-작용기성 키랄 보조제는 신약 및 의약품 중간체를 비롯한 다양한 광학활성 화합물의 합성에 사용되어지는 비대칭 반응기술에 사용될 수 있다. 특히, 고가의 키랄 보조제의 회수가 용이하여 광학활성 화합물의 대량생산을 기대할 수 있다.Thus, the water-soluble two-functional chiral adjuvant developed in the present invention can be used in the asymmetric reaction technique used in the synthesis of various optically active compounds including new drug and pharmaceutical intermediates. In particular, the recovery of expensive chiral adjuvant is easy, and mass production of an optically active compound can be expected.
이하, 본 발명을 실시예에 의거하여 더욱 상세하게 설명하겠는바, 본 발명이 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by Examples.
실시예 1: (2S,3S)-2,3-비스(O-메탄술포닐)-1,2,3,4-테트라히드록시부탄의 합성Example 1 Synthesis of (2S, 3S) -2,3-bis (O-methanesulfonyl) -1,2,3,4-tetrahydroxybutane
16g의 1,4-디벤질-2,3-디메틸술포닐테트라히드록시부탄을 에틸알콜과 에틸 아세테이트의 1:1 혼합용매(v/v) 100 ㎖에 녹인후, 2g의 5% Pd(OH)2-C을 첨가하였다. 이러한 반응 혼합물을 1 기압의 수소분위기 하에, 40 ℃에서 12시간 동안반응시켰다. 반응이 종결된후 실온으로 냉각하여 촉매를 여과하고 제거한 후, 용매를 증류시켜 제거함으로써 (2S,3S)-2,3-비스(O-메탄술포닐)-1,2,3,4-테트라히드록시부탄을 11g (수득율: 98%) 얻었다.16 g of 1,4-dibenzyl-2,3-dimethylsulfonyltetrahydroxybutane was dissolved in 100 ml of a 1: 1 mixed solvent of ethyl alcohol and ethyl acetate (v / v), followed by 2 g of 5% Pd (OH ) 2 -C was added. This reaction mixture was reacted at 40 DEG C for 12 hours under hydrogen atmosphere at 1 atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, the catalyst was filtered off, and the solvent was distilled off to remove (2S, 3S) -2,3-bis (O-methanesulfonyl) -1,2,3,4-tetra. 11 g (yield: 98%) of hydroxybutane was obtained.
1H NMR(300 MHz, DMSO-d 6) δ 5.32 (t, J = 5.3 Hz, 2H), 4.74 (dt, J = 6.89, 3.5 Hz, 2H), 3.68 (m, 4H), 3.22 (s, 6H); 1 H NMR (300 MHz, DMSO- d 6 ) δ 5.32 (t, J = 5.3 Hz, 2H), 4.74 (dt, J = 6.89, 3.5 Hz, 2H), 3.68 (m, 4H), 3.22 (s, 6H);
13C NMR(75 MHz, DMSO-d 6) δ 82.30, 60.63, 39.02 13 C NMR (75 MHz, DMSO- d 6 ) δ 82.30, 60.63, 39.02
실시예 2: (5R,5'R)-N,N'-디벤질-5,5'-비스(옥사졸리딘-2-온)의 합성Example 2: Synthesis of (5R, 5'R) -N, N'-dibenzyl-5,5'-bis (oxazolidin-2-one)
상기 실시예 1에서 합성된 (2S,3S)-2,3-비스(O-메탄술포닐)-1,2,3,4-테트라히드록시부탄 9.2g을 100 ㎖의 테트라히드로퓨란(THF)에 녹인후 실온에서 12g의 벤질 이소시아네이트를 첨가하였다. 그리고, 반응온도를 0 ℃로 냉각한 후 6.5g의 95% 소듐 하이드라이드(NaH)를 첨가하였다. 반응용기의 내부온도를 환류온도로 가열한 다음 8시간 동안 반응시켰다. 반응이 종결된 다음, 실온으로 냉각하여 20 ㎖의 물을 반응혼합물에 첨가한 후, 100 ㎖의 디클로로메탄 용매로 3번 추출하였다. 추출한 유기용매를 포화 NH4Cl 용액으로 씻어준 다음, 무수 MgSO4로 건조하였다. 용매를 증류하여 제거한 다음 관 크로마토그래피에 의해 분리정제하여 (5R,5'R)-N,N'-디벤질-5,5'-비스(옥사졸리딘-2-온)을 12.4g (수득율: 82%) 얻었다.9.2 g of (2S, 3S) -2,3-bis (O-methanesulfonyl) -1,2,3,4-tetrahydroxybutane synthesized in Example 1 was 100 ml of tetrahydrofuran (THF). After dissolving in, 12 g of benzyl isocyanate was added at room temperature. Then, after cooling the reaction temperature to 0 ℃ 6.5g of 95% sodium hydride (NaH) was added. The internal temperature of the reaction vessel was heated to reflux and then reacted for 8 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, 20 ml of water was added to the reaction mixture, and then extracted three times with 100 ml of dichloromethane solvent. The extracted organic solvent was washed with saturated NH 4 Cl solution, and dried over anhydrous MgSO 4 . The solvent was distilled off and then separated and purified by column chromatography to obtain 12.4 g of (5R, 5'R) -N, N'-dibenzyl-5,5'-bis (oxazolidin-2-one) (yield) : 82%).
1H NMR(300 MHz, CDCl3) δ 7.31∼7.35 (m, 6H), 7.08∼7.11 (m, 4H), 4.38 (d, J = 15.0 Hz, 2H), 4.19 (d, J = 15.0 Hz, 2H), 4.09 (AB q, J = 4.90, 2H), 3.87 (t, J = 9.7 Hz, 2H), 3.73 (m, 2H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.31 to 7.35 (m, 6H), 7.08 to 7.11 (m, 4H), 4.38 (d, J = 15.0 Hz, 2H), 4.19 (d, J = 15.0 Hz, 2H), 4.09 (AB q, J = 4.90, 2H), 3.87 (t, J = 9.7 Hz, 2H), 3.73 (m, 2H);
13C NMR(75 MHz, CDCl3) δ 158.50, 135.72, 129.62, 129.01, 128.55, 62.44, 54.18, 48.01 13 C NMR (75 MHz, CDCl 3 ) δ 158.50, 135.72, 129.62, 129.01, 128.55, 62.44, 54.18, 48.01
실시예 3: (5R,5'R)-5,5'-비스(옥사졸리딘-2-온)의 합성Example 3: Synthesis of (5R, 5'R) -5,5'-bis (oxazolidin-2-one)
상기 실시예 2에서 합성된 (5R,5'R)-N,N'-디벤질-5,5'-비스(옥사졸리딘-2-온) 5g을 -78 ℃에서 액화시킨 액체 암모니아 100 ㎖에 녹인후, -78 ℃의 온도에서 0.6g의 나트륨 금속(Na)을 소량씩 첨가하였다. 반응이 완결된후 냉각장치를 제거하고 액체 암모니아를 증류 제거한후 고체 NH4Cl 0.5g과 물 1 ㎖를 첨가하였다. 그리고, 50 ㎖의 디클로로메탄을 이용하여 유기 불순물을 추출하여 제거한 다음, 수용액층을 분리하였다. 분리된 수용액층에서 물을 감압하여 제거한후 고체 잔류물을 건조하였다. 무수 아세토니트릴을 이용하여 고체 잔류물로부터 (5R,5'R)-5,5'-비스(옥사졸리딘-2-온)을 1.7g (수득율: 72%) 얻었다.100 ml of liquid ammonia liquefying 5 g of (5R, 5'R) -N, N'-dibenzyl-5,5'-bis (oxazolidin-2-one) synthesized in Example 2 at -78 ° C After dissolving in, 0.6 g of sodium metal (Na) was added in small portions at a temperature of -78 ° C. After the reaction was completed, the chiller was removed, the liquid ammonia was distilled off, and 0.5 g of solid NH 4 Cl and 1 ml of water were added. Then, the organic impurities were extracted and removed using 50 ml of dichloromethane, and the aqueous layer was separated. Water was removed under reduced pressure in the separated aqueous layer and the solid residue was dried. 1.7 g (yield: 72%) of (5R, 5'R) -5,5'-bis (oxazolidin-2-one) were obtained from the solid residue using anhydrous acetonitrile.
1H NMR(300 MHz, DMSO-d 6) δ 7.84 (bs, 2H), 4.35 (t, J = 8.9 Hz, 2H), 4.06 (AB q, J = 4.6 Hz, 2H), 3.86 (m, 2H); 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.84 (bs, 2H), 4.35 (t, J = 8.9 Hz, 2H), 4.06 (AB q, J = 4.6 Hz, 2H), 3.86 (m, 2H );
13C NMR(75 MHz, DMSO-d 6) δ 159.79, 66.69, 54.72 13 C NMR (75 MHz, DMSO- d 6 ) δ 159.79, 66.69, 54.72
이상에서 상술한 바와 같이, 본 발명에 따른 상기 화학식 1로 표시되는 키랄 보조제(chiral auxiliary)는 수용성으로서 반응 종료 후 유기 용매로부터 분리회수가 용이하고, 2-작용기성을 나타내어 분자 경제적인 측면에서 효과적이므로 키랄 보조제를 사용한 비대칭 반응기술에 사용되기에 적합하다.As described above, the chiral auxiliary agent represented by Chemical Formula 1 according to the present invention is water-soluble, and is easily recovered from the organic solvent after completion of the reaction, and exhibits two-functionality, which is effective in terms of molecular economy. Therefore, it is suitable for use in asymmetric reaction technology using chiral adjuvant.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0578336A (en) * | 1991-03-11 | 1993-03-30 | Daiso Co Ltd | Optically active oxazolidinone derivative and its production |
| JPH09183782A (en) * | 1995-08-30 | 1997-07-15 | General Electric Co <Ge> | Propenyl ether silicone-based releasing composition curable by ultraviolet ray and electron beam |
| JPH10251254A (en) * | 1997-03-11 | 1998-09-22 | Ube Ind Ltd | Optically active oxazolidinone and its production |
| KR19990060465A (en) * | 1997-12-31 | 1999-07-26 | 박호군 | Bis (ortho-diarylphosphinophenyl) -tetrahydro-ratio (1,3-oxazole) and preparation method thereof |
| US5939554A (en) * | 1995-03-10 | 1999-08-17 | Ndsu Research Foundation | Diarylaminopropanediol and diarylmethyl-oxazolidinone compounds |
| US6034247A (en) * | 1993-02-17 | 2000-03-07 | The Trustees Of The University Of Pennsylvania | Oxazolidinones and methods for the synthesis and use of same |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0578336A (en) * | 1991-03-11 | 1993-03-30 | Daiso Co Ltd | Optically active oxazolidinone derivative and its production |
| US6034247A (en) * | 1993-02-17 | 2000-03-07 | The Trustees Of The University Of Pennsylvania | Oxazolidinones and methods for the synthesis and use of same |
| US5939554A (en) * | 1995-03-10 | 1999-08-17 | Ndsu Research Foundation | Diarylaminopropanediol and diarylmethyl-oxazolidinone compounds |
| JPH09183782A (en) * | 1995-08-30 | 1997-07-15 | General Electric Co <Ge> | Propenyl ether silicone-based releasing composition curable by ultraviolet ray and electron beam |
| JPH10251254A (en) * | 1997-03-11 | 1998-09-22 | Ube Ind Ltd | Optically active oxazolidinone and its production |
| KR19990060465A (en) * | 1997-12-31 | 1999-07-26 | 박호군 | Bis (ortho-diarylphosphinophenyl) -tetrahydro-ratio (1,3-oxazole) and preparation method thereof |
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