KR100524145B1 - Preparation methods of high purity chiral 3-hydroxy-γ-butyrolactone - Google Patents
Preparation methods of high purity chiral 3-hydroxy-γ-butyrolactone Download PDFInfo
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- KR100524145B1 KR100524145B1 KR10-2002-0005694A KR20020005694A KR100524145B1 KR 100524145 B1 KR100524145 B1 KR 100524145B1 KR 20020005694 A KR20020005694 A KR 20020005694A KR 100524145 B1 KR100524145 B1 KR 100524145B1
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- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
본 발명은 키랄 3-하이드록시-γ-부티로락톤의 제조방법에 관한 것으로서, 더욱 상세하게는 고순도의 키랄 에피클로로하이드린을 원료물질로 사용하여 공지의 방법으로 쉽게 제조되는 키랄 4-클로로-3-하이드록시부티로니트릴로부터 1단계 공정으로 다음 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤을 높은 순도로 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing chiral 3-hydroxy-γ-butyrolactone, and more particularly, chiral 4-chloro- easily prepared by a known method using high purity chiral epichlorohydrin as a raw material. The present invention relates to a method for preparing chiral 3-hydroxy-γ-butyrolactone represented by the following Chemical Formula 1 in 3-step from 3-hydroxybutyronitrile in high purity.
상기 화학식 1에서, *는 비대칭탄소를 의미한다.In Formula 1, * means asymmetric carbon.
Description
본 발명은 키랄 3-하이드록시-γ-부티로락톤의 제조방법에 관한 것으로서, 더욱 상세하게는 고순도의 키랄 에피클로로하이드린을 원료물질로 사용하여 공지의 방법으로 쉽게 제조되는 키랄 4-클로로-3-하이드록시부티로니트릴로부터 1단계 공정으로 다음 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤을 높은 순도로 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing chiral 3-hydroxy-γ-butyrolactone, and more particularly, chiral 4-chloro- easily prepared by a known method using high purity chiral epichlorohydrin as a raw material. The present invention relates to a method for preparing chiral 3-hydroxy-γ-butyrolactone represented by the following Chemical Formula 1 in 3-step from 3-hydroxybutyronitrile in high purity.
화학식 1Formula 1
상기 화학식 1에서, *는 비대칭탄소를 의미한다.In Formula 1, * means asymmetric carbon.
본 발명이 합성하는 상기 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤은 L-카르니틴, 에이즈치료제 원료인 (S)-3-하이드록시 테트라하이드로퓨란, 또는 (S)-1,2,4-부탄트리올 등의 의약품원료, 농약품 및 그와 관련된 바이오 제품이나 정밀화학 제품 등을 제조하는데 주요하게 쓰이는 필수 핵심 중간체이다. 특히, 다음에 나타낸 바와 같은 키랄 의약품들에 있어서는 상기 화학식 1로 표시되는 키랄 헤테로 고리화합물이 핵심 물질로 사용되어 동 의약품이 원하는 바의 약효를 나타내고 있다.Chiral 3-hydroxy-γ-butyrolactone represented by the formula (1) synthesized by the present invention is L-carnitine, (S) -3-hydroxy tetrahydrofuran, or (S) -1, It is an essential core intermediate used mainly in the manufacture of pharmaceutical raw materials such as 2,4-butanetriol, pesticides and related bioproducts and fine chemicals. In particular, in the chiral medicines as shown below, the chiral heterocyclic compound represented by Chemical Formula 1 is used as a core substance, and thus the drug has the desired effect.
최근에 개발되고 있는 신 의약들은 대부분이 키랄의약이고, 이러한 키랄의약을 제조하기 위해서는 여러 종류의 키랄중간체를 필요로 하고 있다. 상기 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤은 키랄의약 등을 제조하기 위한 중요한 중간체로서 현재 널리 쓰여지고 있다.Most of the new drugs being developed in recent years are chiral medicines, and various kinds of chiral intermediates are required to manufacture such chiral medicines. Chiral 3-hydroxy- [gamma] -butyrolactone represented by Chemical Formula 1 is widely used as an important intermediate for preparing chiral medicine and the like.
상기 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤의 제조방법은 홀링스워스 등에 의해 주로 개발되어 있으며, 동 방법은 락토스나 말토스를 원료물질로 사용하고 분해반응을 경유하는 다단계 제조공정으로 구성된다[미국특허 제5,808,107호]. 상기 방법을 개선한 것으로, 녹말이나 테트리고를 원료물질로 사용하여 보다 높은 수율로 제조하는 방법이 알려져 있다[미국특허 제6,124,122호].The method for preparing chiral 3-hydroxy-γ-butyrolactone represented by Chemical Formula 1 is mainly developed by Hollingsworth et al. The method uses a lactose or maltose as a raw material and passes through a multi-step decomposition reaction. Manufacturing process (US Pat. No. 5,808,107). As an improvement of the above method, a method of producing a higher yield by using starch or tetrigo as a raw material is known (US Pat. No. 6,124,122).
상기한 공지방법들은 높은 광학순도의 목적화합물을 제조하기 위한 방법으로 현재까지 개발된 방법 중 우수한 방법이며, 경제성도 우수한 장점이 있다. 하지만 동 방법들이 다당의 분자들을 분해반응하여 제조하는 방법이기 때문에 분해 과정 중에는 많은 종류의 원하지 않는 화합물들이 생성된다. 다당의 분해반응 중에 생성되는 화합물들로는 글리콜산, 2(5H)-퓨라논, 4-하이드록시메틸-γ-부티로락톤, 2,3-디하이드록시-γ-부티로락톤, 2-하이드록시-5-하이드록시메틸테트라하이드로퓨란 등을 비롯하여 구조가 밝혀지지 않은 여러 화합물들이다. 이들 화합물들의 대부분은 목적 화합물과의 구조적 유사성으로 인해 물리적 성질이 비슷한 바, 이로인해 일반적인 방법으로는 정제나 제거가 매우 어렵거나 공정이 매우 복잡하고 일부 화합물들은 제거가 불가능하기도 하다.The above-mentioned known methods are excellent methods among the methods developed to date as methods for preparing a target compound of high optical purity, and also have excellent economic efficiency. However, because these methods are produced by decomposition of molecules of polysaccharide, many kinds of unwanted compounds are produced during the decomposition process. Compounds formed during the decomposition of polysaccharides include glycolic acid, 2 (5H) -furanone, 4-hydroxymethyl-γ-butyrolactone, 2,3-dihydroxy-γ-butyrolactone, 2-hydroxy -5-hydroxymethyltetrahydrofuran and the like, various compounds of unknown structure. Most of these compounds have similar physical properties due to the structural similarity to the target compound, which makes it difficult to purify or remove them in a general manner, or the process is very complicated, and some compounds cannot be removed.
상기한 바대로, 상기 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤은 그 화합물 자체가 열에 불안정하여 상압에서 증류정제가 불가능하며, 더우기 제조과정 중에 부수적으로 생성되는 불순물들이 끓는점이나, 수용성, 극성 또는 용해성 등의 물리적 특성이 목적 화합물과 유사하여 이를 감압증류나 추출 또는 재결정 등의 일반적으로 사용되는 정제방법으로는 원하지 않는 화합물들을 제거하기가 무척 어려운 단점이 있어서 화학적으로 높은 순도로 제조하기가 곤란하다.As described above, the chiral 3-hydroxy-γ-butyrolactone represented by Chemical Formula 1 cannot be distilled at normal pressure because the compound itself is unstable in heat. Physical properties such as water solubility, polarity or solubility are similar to the target compound, and it is very difficult to remove unwanted compounds by commonly used purification methods such as distillation, extraction or recrystallization. Difficult to manufacture
또한, 상기한 공지 방법들은 천연의 다당류 화합물을 출발물질로 사용하기 때문에 제조되는 3-하이드록시-γ-부티로락톤은 S-형태의 것만 얻을 수 있으며, R-형태의 것을 제조하기 위해서는 (S)-3-하이드록시-γ-부티로락톤으로부터 다단계의 합성과정을 거쳐야만 하는 번거러움이 있다.In addition, the above-mentioned known methods use a natural polysaccharide compound as a starting material, so 3-hydroxy-γ-butyrolactone prepared can be obtained only in the S-form, and in order to prepare the R-form (S There is a need to go through a multi-step synthesis from) -3-hydroxy-γ-butyrolactone.
이처럼 상기 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤의 용도가 다양함에도 불구하고 현재까지 고순도의 제조방법 개발이 미흡하고, 또한 고순도로 제조할 수 있다고 하더라도 기존의 제조방법이 매우 복잡하며 가격이 매우 비싸다는 단점이 지적되어 왔다. 또한 (R)-3-하이드록시-γ-부티로락톤의 제조는 다단계의 합성과정을 더 거쳐야 하므로 가격이 더욱 비싸질 수밖에 없다. 이러한 이유로 인해 현재까지 알려진 방법에 의해서는 고순도의 키랄 3-하이드록시-γ-부티로락톤의 상업적인 공급이 원활하지 못하고, 또 이를 키랄 화합물 제조용 원료로 사용하기에는 순도면에서 부적합한 면이 있다. Thus, despite the variety of uses of the chiral 3-hydroxy- γ-butyrolactone represented by the formula (1), the development of a high-purity manufacturing method is insufficient, and even if it can be manufactured with high purity, the existing manufacturing method is very It has been pointed out that it is complicated and very expensive. In addition, the preparation of (R) -3-hydroxy-γ-butyrolactone requires a more multi-step synthetic process, which is more expensive. For this reason, commercial supply of high purity chiral 3-hydroxy- [gamma] -butyrolactone is not facilitated by the methods known to date, and there is an inadequate aspect in terms of purity for use as a raw material for preparing chiral compounds.
키랄 화합물들은 특히 의약품의 원료물질로 대부분이 사용되므로 인해 고순도로 제조하는 것이 중요하다. 그러한 이유는 키랄 화합물에서는 원하지 않는 광학이성질체 또는 입체이성질체가 약효를 나타내지 않거나 부작용을 나타내기 때문이다. 특히 광학이성질체는 원하지 않는 이성질체를 제거하기가 무척 어렵기 때문에 현재의 많은 연구개발이 고광학순도의 키랄 화합물 제조방법에 집중되고 있다. 홀링스워스 등에 의해 개발된 상기 화학식 1로 표시되는 목적화합물의 경우에도 마찬가지로 고광학순도의 제조방법에 그 노력이 집중되어왔다. 이러한 이유는 목적하지 않은 광학이성질체는 물리적 성질이 동등하거나 유사함으로 인해 증류나, 추출 또는 재결정과 같은 단순한 물리적 방법으로 광학순도를 증대시키기 어렵기 때문이며, 오히려 화학적으로 분자식이 다른 화학 불순물들의 생성은 증류, 추출, 재결정이나 유도체화를 통한 여러 가지 방법에 의해 화학순도를 높일 수 있기 때문이다. 다시말하면, 광학이성질체는 정제가 어려우므로 제조시 높은 광학순도의 키랄 화합물을 얻는 것이 중요하나, 화학적으로 조성이 다른 화합물들은 비교적 용이하게 정제가 가능하기 때문에 키랄화합물의 제조기술(chirotechnology)에 많은 연구가 집중되고 있다.Chiral compounds are particularly important for their high purity because they are used mostly as raw materials for pharmaceuticals. This is because, in chiral compounds, the unwanted optical isomers or stereoisomers show no efficacy or side effects. In particular, since optical isomers are very difficult to remove unwanted isomers, many researches and developments are focused on the preparation method of chiral compounds of high optical purity. In the case of the target compound represented by Chemical Formula 1, developed by Hollingsworth et al., Efforts have been focused on the preparation method of high optical purity. This is because undesired optical isomers are difficult to increase optical purity by simple physical methods such as distillation, extraction or recrystallization due to their equal or similar physical properties. This is because the chemical purity can be increased by various methods such as extraction, recrystallization or derivatization. In other words, optical isomers are difficult to purify, so it is important to obtain chiral compounds with high optical purity during preparation. However, since chemicals with different chemical compositions can be purified relatively easily, many studies have been conducted on chirotechnology. Is concentrated.
이러한 관점에서 볼 때, 상기 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤의 제조방법으로서는 홀링스워스 등에 의해 발명된 제조방법이 현재까지 개발된 방법 중, 경제성이나 광학순도 면에서 우수한 면이 있으나, 앞서 언급한 것처럼 제조과정 중의 부반응에 의해 물리적 성질이 유사한 여러 가지 화합물들이 생성으로 일반적인 정제방법에 의해 제거하기가 무척 어려운 실정이다. 따라서 홀링스워스 등에 의해 제안된 방법으로서는 의약품의 원료 화합물을 합성하기에는 그 한계가 있거나 적합하지가 않다.From this point of view, as a method for preparing chiral 3-hydroxy-γ-butyrolactone represented by the above formula (1), the manufacturing method invented by Hollingsworth et al. Although there is an excellent aspect, as mentioned above, various compounds having similar physical properties are generated by side reactions during the manufacturing process, and thus, it is very difficult to remove them by general purification methods. Therefore, the method proposed by Hollingsworth et al. Is limited or unsuitable for synthesizing raw material compounds of pharmaceutical products.
미국특허 제5,780,649호에는 광학활성의 에틸 4-클로로-3-하이드록시부티레이트를 고리화 반응하여 상기 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤을 제조하는 방법이 공지되어 있고, 또한 일본공개특허 평4-124,157호에는 광학활성의 4-클로로-3-하이드록시부티로니트릴을 산가수분해 반응하고 에스터화 반응하는 다단계 공정을 수행하여 광학활성의 에틸 4-클로로-3-하이드록시부티레이트를 제조하는 방법이 공지되어 있다. 또다른 방법으로서 일본공개특허 평11-228,560호, 유럽특허 제1,052,258호 등에서는 글리시돌, 혹은 그 유도체를 출발 물질로하여 제조하는 방법이 기재되어 있으나 모두 3단계 이상의 제조단계가 필요로 된다.U.S. Patent No. 5,780,649 discloses a method for preparing chiral 3-hydroxy-γ-butyrolactone represented by Chemical Formula 1 by cyclization of optically active ethyl 4-chloro-3-hydroxybutyrate. In addition, Japanese Patent Application Laid-Open No. 4-124,157 discloses an optically active ethyl 4-chloro-3-hydride by carrying out a multi-step process of acid hydrolysis and esterification of optically active 4-chloro-3-hydroxybutyronitrile. Methods of preparing oxybutyrate are known. As another method, Japanese Patent Laid-Open No. 11-228,560, European Patent No. 1,052,258 and the like describe a method for preparing glycidol or a derivative thereof as a starting material, but all require three or more manufacturing steps.
그러나, 광학활성의 4-클로로-3-하이드록시부티로니트릴으로부터 상기 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤을 직접 합성하는 방법이 알려진 바는 없다.However, no method of directly synthesizing chiral 3-hydroxy-γ-butyrolactone represented by Chemical Formula 1 from optically active 4-chloro-3-hydroxybutyronitrile is not known.
본 발명자들은 키랄 에피클로로하이드린을 유용하게 활용할 수 있는 방법을 연구하던 중, 동 제품을 이용하여 제조한 키랄 4-클로로-3-하이드록시부티로니트릴으로부터 상기 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤을 간단한 1단계 제조공정을 통해 고광학순도 및 고화학순도로 제조하는 새로운 제조방법을 개발함으로써 본 발명을 완성하게 되었다.The inventors of the present invention while studying a method for utilizing the chiral epichlorohydrin useful, chiral 3-hydroxy represented by the formula (1) from chiral 4-chloro-3-hydroxybutyronitrile prepared using the product The present invention has been completed by developing a new manufacturing method for preparing oxy-γ-butyrolactone with high optical purity and high chemical purity through a simple one-step manufacturing process.
따라서, 본 발명은 키랄 4-클로로-3-하이드록시부티로니트릴을 원료물질로 사용하고 온화한 반응조건에서 산을 이용하여 고순도의 키랄 3-하이드록시-γ-부티로락톤을 직접 제조하는 방법을 제공하는데 그 목적이 있다. Accordingly, the present invention provides a method of directly preparing high purity chiral 3-hydroxy-γ-butyrolactone using chiral 4-chloro-3-hydroxybutyronitrile as a raw material and using an acid under mild reaction conditions. The purpose is to provide.
본 발명은 다음 화학식 2로 표시되는 키랄 4-클로로-3-하이드록시부티로니트릴을 산 존재하에 50 ∼ 90 ℃ 온도 조건으로 교반하여 다음 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤을 직접 제조하는 방법을 그 특징으로 한다.In the present invention, the chiral 4-chloro-3-hydroxybutyronitrile represented by the following Chemical Formula 2 is stirred at a temperature of 50 to 90 ° C. in the presence of an acid, followed by the chiral 3-hydroxy-γ-butyrie represented by the following Chemical Formula 1 It is characterized by a method for producing lactone directly.
상기에서, *는 비대칭탄소를 의미한다.In the above, * means asymmetric carbon.
이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.
본 발명은 상기 화학식 2로 표시되는 키랄 4-클로로-3-하이드록시부티로니트릴로부터 1단계의 반응공정에 의해 상기 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤을 높은 순도로 제조하는 방법에 관한 것이다.The present invention is a high purity of the chiral 3-hydroxy- γ-butyrolactone represented by the formula (1) by a one-step reaction process from chiral 4-chloro-3-hydroxybutyronitrile represented by the formula (2) It relates to a manufacturing method.
본 발명의 제조방법에 의하면, 상기 화학식 2로 표시되는 키랄 4-클로로-3-하이드록시부티로니트릴을 1 ∼ 4 당량의 산이 포함된 물, 혹은 물과 혼합이 용이한 용매와의 혼합용매 존재하에서 50 ∼ 90 ℃ 온도 조건으로 교반하는 1단계 공정에 의해 상기 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤을 높은 순도로 직접 합성할 수 있다. 즉, 본 발명에 따른 제조방법은 가수분해와 고리화가 동시에 이루어지는 1단계 공정으로 구성된다. 종래 방법으로서, 일본공개특허 평4-124,157호 방법이 상기 화학식 2로 표시되는 광학활성의 4-클로로-3-하이드록시부티로니트릴에 다량의 산을 사용하여 광학활성의 4-클로로-3-하이드록시부티르산을 합성하는데 반하여, 본 발명은 상기와의 방법과는 다르게 온화한 반응조건에서 시행한다는 점에서 그 제조방법상의 차이가 있는 것이다.According to the production method of the present invention, the chiral 4-chloro-3-hydroxybutyronitrile represented by the formula (2) is present in the presence of 1 to 4 equivalents of acid or a mixed solvent with a solvent that is easily mixed with water The chiral 3-hydroxy-γ-butyrolactone represented by Chemical Formula 1 may be directly synthesized in high purity by a one-step process of stirring at 50 to 90 ° C. under a temperature condition. In other words, the production method according to the present invention consists of a one-step process in which both hydrolysis and cyclization are performed. As a conventional method, Japanese Patent Application Laid-Open No. 4-124,157 uses optically 4-chloro-3-hydroxybutyronitrile represented by Formula 2 using a large amount of acid to provide optically active 4-chloro-3- In contrast to the synthesis of hydroxybutyric acid, the present invention is different from the above method in that it is carried out under mild reaction conditions, and there is a difference in the preparation method thereof.
본 발명에 따른 반응에 사용되는 용매는 물; 메탄올, 에탄올, 아이소프로필알콜 중에서 선택된 알콜류와 물의 혼합물; 테트라하이드로퓨란, 1,4-디옥산 중에서 선택된 극성유기용매와 물의 혼합물이 사용될 수 있고, 특히 바람직하기로는 물을 사용하는 것이다. 그리고 사용되는 산으로는 염산, 황산, 인산, 아세트산, p-톨루엔설포닉산 등이 사용되며, 그 사용량은 1 ∼ 4 당량의 범위이다.The solvent used in the reaction according to the present invention is water; A mixture of alcohols selected from methanol, ethanol and isopropyl alcohol and water; Mixtures of polar organic solvents selected from tetrahydrofuran, 1,4-dioxane and water can be used, with water being particularly preferred. In addition, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, p-toluenesulphonic acid, etc. are used as an acid used, The usage-amount is the range of 1-4 equivalents.
이상에서 설명한 본 발명의 제조방법에 따르면, 목적하는 상기 화학식 1로 표시되는 키랄 3-하이드록시-γ-부티로락톤은 순도 99% 이상의 고순도로 합성되며, 생성되는 불필요한 부산물이 적어서 간단한 분리 정제방법으로도 용이하게 제거될 수 있다.According to the manufacturing method of the present invention described above, the chiral 3-hydroxy- γ-butyrolactone represented by the above formula (1) is synthesized with high purity of 99% or more purity, and there is little unnecessary by-products generated, the simple separation and purification method It can also be easily removed.
한편, 본 발명이 원료물질로 사용하는 상기 화학식 2로 표시되는 키랄 4-클로로-3-하이드록시부티로니트릴은 공지 화합물로서, 다음 화학식 3으로 표시되는 키랄 에피클로로하이드린으로부터 공지의 방법[Bull. Soc. Chim. Fr. Vol. 3, 138 (1936), Bull. Acad. R. Belg. Vol. 29, 256 (1943)]을 응용하여 제조할 수 있다.On the other hand, chiral 4-chloro-3-hydroxybutyronitrile represented by the formula (2) used as a raw material of the present invention is a known compound, a known method from chiral epichlorohydrin represented by the following formula (3) [Bull] . Soc. Chim. Fr. Vol. 3 , 138 (1936), Bull. Acad. R. Belg. Vol. 29, 256 (1943).
상기 화학식 3에서, *는 비대칭탄소를 의미한다.In Chemical Formula 3, * means asymmetric carbon.
상기 화학식 3으로 표시되는 키랄 에피클로로하이드린은 키랄성을 갖는 화합물중 가장 작은 분자로서 작용기의 다양한 변환이 가능하여 키랄 의약중간체나 키랄 의약품, 바이오 제품 또는 농약품 등의 핵심물질로서 매우 유용하다. 키랄 에피클로로하이드린은 그의 유용성 때문에 이를 효과적으로 제조하기 위한 연구가 많이 진행되어 왔다. 그 중 제콥슨 등에 의해 개발된 방법이 경제적인 면이나 품질면에서 유리한 장점이 있어 왔다. 그러나 이 방법으로는 아직까지는 범용으로 사용되기에는 가격이 비싼 단점이 있다. 그렇지만 최근에 본 발명자 등에 의해 개발된 방법에 의하면 고품질의 키랄 에피클로로하이드린을 더욱 경제적으로 제조할 수 있게 되었다[국내특허출원 제01-25971호].Chiral epichlorohydrin represented by the formula (3) is the smallest molecule among the compounds having chirality is possible to various conversion of functional groups is very useful as a core material such as chiral pharmaceutical intermediates, chiral pharmaceuticals, bio products or pesticides. Because of its usefulness, chiral epichlorohydrin has been studied a lot to make it effective. Among them, the method developed by Jacobson et al has an advantage in terms of economics and quality. However, this method has a disadvantage that it is still expensive to use universally. However, according to a method recently developed by the present inventors, it is possible to produce high quality chiral epichlorohydrin more economically (Domestic Patent Application No. 01-25971).
이상에서 설명한 바와 같은 본 발명은 다음의 실시예를 통하여 본 발명을 더욱 상세히 설명하겠는 바, 본 발명이 다음의 실시예에 의해 한정되는 것은 아니다. The present invention as described above will be described in more detail the present invention through the following examples, the present invention is not limited by the following examples.
실시예 1 : (S)-3-하이드록시-γ-부티로락톤의 제조Example 1 Preparation of (S) -3-hydroxy-γ-butyrolactone
280 g의 진한 염산에 140 g의 (S)-4-클로로-3-하이드록시부티로니트릴을 넣고 75 ℃에서 2 시간동안 교반하였다. 진한 염산을 30 ℃ 이하에서 감압증류 제거한 후, 300 ㎖의 물을 넣고 다시 30 ℃ 이하에서 남아있는 염산을 감압증류 제거하였다. 에틸 아세테이트와 무수 소듐 설페이트를 가하고 30 분동안 교반 후, 여과하였다. 에틸 아세테이트를 감압증류 제거 후, 농축액을 감압 분별증류(98∼100 ℃/0.3mmHg)하면 84 g의 목적화합물을 99% 이상의 순도로 얻었다. 140 g (S) -4-chloro-3-hydroxybutyronitrile was added to 280 g of concentrated hydrochloric acid and stirred at 75 ° C. for 2 hours. The concentrated hydrochloric acid was removed by distillation under reduced pressure at 30 ° C. or lower, 300 ml of water was added thereto, and the remaining hydrochloric acid was distilled off under reduced pressure at 30 ° C. or lower. Ethyl acetate and anhydrous sodium sulfate were added, stirred for 30 minutes and then filtered. After distilling off the ethyl acetate under reduced pressure, the concentrated solution was subjected to fractional distillation under reduced pressure (98-100 ° C./0.3 mmHg) to obtain 84 g of the target compound having a purity of 99% or more.
[α]20 = -88°(c=0.8, MeOH); 1H-NMR(CDCl3, ppm) δ2.5(1H, d, J=18Hz), 2.8(1H, dd, J=6, 18Hz), 3.3(1H), 4.3(1H, d, J=10Hz), 4.4(1H, dd, J=4, 10Hz), 4.7(1H, m)[a] 20 = -88 ° (c = 0.8, MeOH); 1 H-NMR (CDCl 3 , ppm) δ 2.5 (1H, d, J = 18 Hz), 2.8 (1H, dd, J = 6, 18 Hz), 3.3 (1H), 4.3 (1H, d, J = 10 Hz ), 4.4 (1H, dd, J = 4, 10 Hz), 4.7 (1H, m)
실시예 2 : (S)-3-하이드록시-γ-부티로락톤의 제조Example 2 Preparation of (S) -3-hydroxy-γ-butyrolactone
100 ㎖ 에탄올과 100 ㎖ 물의 혼합용매에 173 g의 진한 황산과 140 g의 (S)-4-클로로-3-하이드록시부티로니트릴을 넣고 6 시간동안 가열 환류하였다. 0 ℃로 냉각하고 소듐 하이드록사이드 수용액으로 중화시켰다. 용매를 감압증류 제거하고 에틸 아세테이트와 무수 소듐 설페이트를 가하고 30 분동안 교반 후, 여과하였다. 에틸 아세테이트를 감압증류 제거 후, 농축액을 감압 분별증류(98∼100 ℃/0.3mmHg)하면 74 g의 목적화합물을 99% 이상의 순도로 얻었다.173 g of concentrated sulfuric acid and 140 g of (S) -4-chloro-3-hydroxybutyronitrile were added to a mixed solvent of 100 ml ethanol and 100 ml water, and the mixture was heated to reflux for 6 hours. Cool to 0 ° C. and neutralize with aqueous sodium hydroxide solution. The solvent was distilled off under reduced pressure, ethyl acetate and anhydrous sodium sulfate were added, stirred for 30 minutes, and filtered. After distilling off the ethyl acetate under reduced pressure, the concentrated solution was subjected to fractional distillation under reduced pressure (98-100 占 폚 /0.3mmHg) to obtain 74 g of the target compound in 99% or more purity.
[α]20 = -88°(c=0.8, MeOH); 1H-NMR(CDCl3, ppm) δ2.5(1H, d, J=18Hz), 2.8(1H, dd, J=6, 18Hz), 3.3(1H), 4.3(1H, d, J=10Hz), 4.4(1H, dd, J=4, 10Hz), 4.7(1H, m)[a] 20 = -88 ° (c = 0.8, MeOH); 1 H-NMR (CDCl 3 , ppm) δ 2.5 (1H, d, J = 18 Hz), 2.8 (1H, dd, J = 6, 18 Hz), 3.3 (1H), 4.3 (1H, d, J = 10 Hz ), 4.4 (1H, dd, J = 4, 10 Hz), 4.7 (1H, m)
실시예 3 : (R)-3-하이드록시-γ-부티로락톤의 제조Example 3 Preparation of (R) -3-hydroxy-γ-butyrolactone
280g의 진한 염산에 140 g의 (R)-클로로-3-하이드록시부티로니트릴을 넣고 75 ℃에서 2 시간동안 교반하였다. 진한 염산을 30 ℃ 이하에서 감압증류 제거한 후, 300 ㎖의 물을 넣고 다시 30 ℃ 이하에서 남아있는 염산을 감압증류 제거하였다. 에틸 아세테이트와 무수 소듐 설페이트를 가하고 30 분동안 교반 후, 여과하였다. 에틸 아세테이트를 감압증류 제거 후, 농축액을 감압 분별증류(98∼100 ℃/0.3mmHg)하면 84 g의 목적화합물을 99% 이상의 순도로 얻었다.140 g of (R) -chloro-3-hydroxybutyronitrile was added to 280 g of concentrated hydrochloric acid, followed by stirring at 75 ° C. for 2 hours. The concentrated hydrochloric acid was removed by distillation under reduced pressure at 30 ° C. or lower, 300 ml of water was added thereto, and the remaining hydrochloric acid was distilled off under reduced pressure at 30 ° C. or lower. Ethyl acetate and anhydrous sodium sulfate were added, stirred for 30 minutes and then filtered. After distilling off the ethyl acetate under reduced pressure, the concentrated solution was subjected to fractional distillation under reduced pressure (98-100 ° C./0.3 mmHg) to obtain 84 g of the target compound having a purity of 99% or more.
[α]20 = +88°(c=0.8, MeOH); 1H-NMR(CDCl3, ppm) δ2.5(1H, d, J=18Hz), 2.8(1H, dd, J=6, 18Hz), 3.3(1H), 4.3(1H, d, J=10Hz), 4.4(1H, dd, J=4, 10Hz), 4.7(1H, m)[a] 20 = + 88 ° (c = 0.8, MeOH); 1 H-NMR (CDCl 3 , ppm) δ 2.5 (1H, d, J = 18 Hz), 2.8 (1H, dd, J = 6, 18 Hz), 3.3 (1H), 4.3 (1H, d, J = 10 Hz ), 4.4 (1H, dd, J = 4, 10 Hz), 4.7 (1H, m)
이상에서 설명한 바와 같이, 본 발명에 따른 제조방법은 반응조건을 적절히 조정하여 가수분해와 고리화가 동시에 이루어지는 것을 특징으로 하여 키랄 4-클로로-3-하이드록시부티로니트릴으로부터 1단계 공정으로 목적하는 키랄 3-하이드록시-γ-부티로락톤을 고순도로 합성할 수 있었다. 따라서, 본 발명의 제조방법은 키랄 화합물 합성을 위한 중간체로 유용한 키랄 3-하이드록시-γ-부티로락톤을 공업적으로 합성하는데 유용하다.As described above, the preparation method according to the present invention is characterized in that the hydrolysis and cyclization are simultaneously performed by appropriately adjusting the reaction conditions, and thus the desired chiral in one step from chiral 4-chloro-3-hydroxybutyronitrile. 3-hydroxy- [gamma] -butyrolactone could be synthesized with high purity. Therefore, the preparation method of the present invention is useful for industrially synthesizing chiral 3-hydroxy-γ-butyrolactone which is useful as an intermediate for the synthesis of chiral compounds.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4119646A (en) * | 1973-09-24 | 1978-10-10 | Mobil Oil Corporation | Hexahydrobenzofuranone compounds |
| JPS6410996A (en) * | 1987-02-06 | 1989-01-13 | Idemitsu Kosan Co | Production of alpha-hydroxy-beta,beta-dimethyl-gamma-butyrolactone |
| US5087751A (en) * | 1988-04-27 | 1992-02-11 | Kanegafuchi Kagaku Kogyo K.K. | Method of preparing optically active 3,4-dihydroxy butyric acid derivatives |
| US6069270A (en) * | 1996-11-20 | 2000-05-30 | Kuraray Co., Ltd. | Optical resolution method of (±)-3,4-dihydroxybutanoic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4119646A (en) * | 1973-09-24 | 1978-10-10 | Mobil Oil Corporation | Hexahydrobenzofuranone compounds |
| JPS6410996A (en) * | 1987-02-06 | 1989-01-13 | Idemitsu Kosan Co | Production of alpha-hydroxy-beta,beta-dimethyl-gamma-butyrolactone |
| US5087751A (en) * | 1988-04-27 | 1992-02-11 | Kanegafuchi Kagaku Kogyo K.K. | Method of preparing optically active 3,4-dihydroxy butyric acid derivatives |
| US6069270A (en) * | 1996-11-20 | 2000-05-30 | Kuraray Co., Ltd. | Optical resolution method of (±)-3,4-dihydroxybutanoic acid |
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