KR100461569B1 - Process for producing optically pure 3-hydroxy-pyrrolidine - Google Patents
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- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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Abstract
본 발명은 광학적으로 순수한 3-히드록시-피롤리딘의 제조방법에 관한 것으로서, 더욱 상세하게는 광학활성을 가진 3,4-에폭시-1-부탄올을 출발물질로 하여 암모니아와 알데히드 화합물로 반응하여 4-보호된이미노-부탄-1,3-디올을 제조한 후, C-1 위치의 히드록시기를 선택적으로 활성화함과 동시에 혹은 이어서 산으로 처리하여 이미노기를 아민기로 전환한 후에, 염기 존재 하에 분자내 고리화 반응을 수행함으로써, 경제적이고 간편하게 고수율로 광학적으로 순수한 다음 화학식 1로 표시되는 3-히드록시-피롤리딘을 제조하는 신규 방법에 관한 것이다.The present invention relates to a method for preparing optically pure 3-hydroxy-pyrrolidine, and more particularly, to react with ammonia and an aldehyde compound using 3,4-epoxy-1-butanol having optical activity as a starting material. After preparing the 4-protected imino-butane-1,3-diol, the hydroxy group at the C-1 position is selectively activated, or subsequently treated with an acid to convert the imino group into an amine group, and then in the presence of a base. By carrying out an intramolecular cyclization reaction, it relates to a novel process for producing 3-hydroxy-pyrrolidine represented by the following formula (1) economically and simply in high yield optically.
상기 화학식 1에서 : * 는 광학활성을 갖는 (S) 혹은 (R)화합물을 나타낸다.In Chemical Formula 1, * represents a compound (S) or (R) having optical activity.
Description
본 발명은 광학적으로 순수한 3-히드록시-피롤리딘의 제조방법에 관한 것으로서, 더욱 상세하게는 광학활성을 가진 3,4-에폭시-1-부탄올을 출발물질로 하여 암모니아와 알데히드 화합물로 반응하여 4-보호된이미노-부탄-1,3-디올을 제조한 후, C-1 위치의 히드록시기를 선택적으로 활성화함과 동시에 혹은 이어서 산으로 처리하여 이미노기를 아민기로 전환한 후에, 염기 존재 하에 분자내 고리화 반응을 수행함으로써, 경제적이고 간편하게 고수율로 광학적으로 순수한 다음 화학식 1로 표시되는 3-히드록시-피롤리딘을 제조하는 신규 방법에 관한 것이다.The present invention relates to a method for preparing optically pure 3-hydroxy-pyrrolidine, and more particularly, to react with ammonia and an aldehyde compound using 3,4-epoxy-1-butanol having optical activity as a starting material. After preparing the 4-protected imino-butane-1,3-diol, the hydroxy group at the C-1 position is selectively activated, or subsequently treated with an acid to convert the imino group into an amine group, and then in the presence of a base. By carrying out an intramolecular cyclization reaction, it relates to a novel process for producing 3-hydroxy-pyrrolidine represented by the following formula (1) economically and simply in high yield optically.
[화학식 1][Formula 1]
상기 화학식 1에서 : * 는 광학활성을 갖는 (S) 혹은 (R)화합물을 나타낸다.In Chemical Formula 1, * represents a compound (S) or (R) having optical activity.
광학적으로 순수한 (S) 혹은 (R)-3-히드록시-피롤리딘 유도체등은 다양한 키랄 화합물의 제조를 위한 중간체 화합물로 사용되고 있다. 예를들면, 혈관 확장제(Calcium antagonist: Barnidipine)의 핵심중간체 원료[유럽특허공개 제160,451, J. Med. Chem. 1986, 29, 2504∼2511, 일본특허공개 소61-267577호, 일본특허공개 소61-63652호], 카바페넴 항생제[Heterocycles, vol 24, No 5, 1986, Tetrahedron Lett. 25, 2793, 1984, 국제특허공개 WO88/08845호, J. Org. Chem. 1992, 57, 4352∼4361], 퀴롤론계 항생제[미국특허 제4,916,141호, 유럽특허공개 제391,169호, 유럽특허공개 제304,087호], 진통제(κ-Receptor agonists)[유럽특허공개 제398,720호, 유럽특허공개 제366,327호, J. Med. Chem., 1994, 37, 2138∼2144] 그리고 신경 전달제[국제특허공개 WO01/19817호]의 핵심중간체 원료등으로 키랄 의약품을 제조하는데 있어서 매우 중요한 화합물로서 이에 대한 연구가 많이 진행되어져 왔다.Optically pure (S) or (R) -3-hydroxy-pyrrolidine derivatives are used as intermediate compounds for the preparation of various chiral compounds. For example, the core intermediate material of Calcium antagonist (Barnidipine) [European Patent Publication No. 160,451, J. Med. Chem. 1986, 29, 2504-2511, Japanese Patent Laid-Open No. 61-267577, Japanese Patent Laid-Open No. 61-63652], Kabapenem antibiotic [Heterocycles, vol 24, No 5, 1986, Tetrahedron Lett. 25, 2793, 1984, International Patent Publication No. WO88 / 08845, J. Org. Chem. 1992, 57, 4352-4361], querolone antibiotics (US Patent No. 4,916,141, European Patent Publication 391,169, European Patent Publication No. 304,087), κ-Receptor agonists [European Patent Publication 398,720, Europe Patent Publication No. 366,327, J. Med. Chem., 1994, 37, 2138-2144] and the core intermediates of neurotransmitters (WO 01/19817), etc., are very important compounds in the preparation of chiral pharmaceuticals.
상기에서 언급한 키랄 화합물 제조의 핵심 중간체로서 유용한 광학적으로 순수한 (S) 혹은 (R)-3-히드록시-피롤리딘 유도체의 제조에 관련된 종래의 기술을 살펴보면 다음과 같다.The prior art related to the preparation of optically pure (S) or (R) -3-hydroxy-pyrrolidine derivatives useful as key intermediates for the preparation of the above mentioned chiral compounds is as follows.
L-히드록시-프롤린을 이용한 탈카르복시화에 의해 (R)-3-히드록시-피롤리딘을 얻는 방법이 알려져 있다[Chem. Lett. 893, 1986, Syn. Commun. 23, 2691, 1993, Syn. Commun. 24, 1381, 1994]. 이와 같은 방법은 고가인 출발물질의 L-히드록시-프롤린을 사용하여야 하는 단점이 있다.A method of obtaining (R) -3-hydroxy-pyrrolidine by decarboxylation with L-hydroxy-proline is known [Chem. Lett. 893, 1986, Syn. Commun. 23, 2691, 1993, Syn. Commun. 24, 1381, 1994]. This method has the disadvantage of using expensive starting material of L-hydroxy-proline.
L-말릭산 혹은 L-글루탐산을 원료물질로 하여 여러단계를 거쳐 고리화반응을수행하여 아마이드를 형성한 후, LiAlH4혹은 B2H6로 환원하는 방법이 알려져 있다[Syn. Commun. 15, 587∼598, 1985, J. Med. Chem. 1994, 37, 2138∼2144, Syn. Commun. 16, 1815∼1822, 1986]. 이 기술은 여러 단계의 공정을 거치는 단점과 환원제인 LiAlH4와 B2H6가 값 비싸며 상업적으로 다루는데 어려운 문제점이 있다.L-malic acid or L-glutamic acid as a raw material is subjected to a cyclization reaction through several steps to form an amide and then reduced to LiAlH 4 or B 2 H 6 is known [Syn. Commun. 15, 587-598, 1985, J. Med. Chem. 1994, 37, 2138-2144, Syn. Commun. 16, 1815-1822, 1986. This technique has the disadvantage of going through several stages of process and the reducing agents LiAlH 4 and B 2 H 6 are expensive and difficult to deal with commercially.
β-케토에스터에 촉매를 이용한 환원반응에 의해 4-할로겐-3-히드록시-부타노에이트를 제조하고 환원한 다음, 선택적으로 히드록시기를 술폰산류로 활성화하고 분자내 고리화반응을 수행하여 1-벤질-3-히드록시-피롤리딘을 합성하는 방법이 알려져 있다[유럽특허공개 제450,143호]. 그러나 상기방법은 값비싼 귀금속 촉매를 사용하여 키랄 중심 탄소의 도입에 있어 한쪽방향으로만 선택적인 환원반응을 보내야 하는 어려움이 있다.4-halogen-3-hydroxy-butanoate was prepared and reduced by catalytic reduction of β-ketoester, followed by selective activation of hydroxy groups with sulfonic acids and intramolecular cyclization. A method for synthesizing benzyl-3-hydroxy-pyrrolidine is known (European Patent Publication No. 450,143). However, this method has a difficulty in sending a selective reduction reaction in only one direction in the introduction of chiral center carbon using an expensive precious metal catalyst.
라세믹 C3 화합물을 효소를 이용한 광학분할과 탄소수 늘림반응(KCN)을 통해 키랄 C4 유도체를 제조한 후, 금속 촉매하에 환원반응 및 분자내 고리화반응을 수행하여 3-히드록시-피롤리딘을 합성하는 방법이 보고되었다[유럽특허공개 제347,818호, 유럽특허공개 제431,521호]. 이 방법 역시 키랄 중심 탄소의 도입에 있어 한쪽방향으로만 광학분할을 하여야 하는 어려움이 있다.Chiral C4 derivatives were prepared by racemic C3 compounds through enzyme-assisted optical splitting and carbon number increase (KCN), followed by reduction and intramolecular cyclization under a metal catalyst to yield 3-hydroxy-pyrrolidine. Synthesis methods have been reported (European Patent Publication No. 347,818, European Patent Publication No. 431,521). This method also has the difficulty of optical splitting in only one direction in the introduction of chiral center carbon.
N-치환된-3-피롤린을 비대칭 붕소화 반응하여 키랄 히드록시 그룹을 도입하는 기술이 알려져 있다[J. Org. Chem. 1986, 51, 4296∼4298, J. Am. Chem. Soc., 1986,108, 2049]. 이와 같은 방법은 아직 상업적으로 이용하기에는 적절하지못하다.Techniques for introducing chiral hydroxy groups by asymmetric boronation of N-substituted-3-pyrroline are known [J. Org. Chem. 1986, 51, 4296-4298, J. Am. Chem. Soc., 1986, 108, 2049]. Such a method is not yet suitable for commercial use.
또한, 고전적인 방법에 의한 광학분할, 효소에 의한 가수분해 그리고 효소에 의한 에스터화 등의 기술이 보고되어져 있으나[일본특허공개 평5-32620호, 일본특허공개 평4-164066호, 일본특허공개 소61-63652호, Bull. Chem. Soc. Jpn. 1996, 69, 207, Enatiomer, 1997, 2, 311∼314, Biochem. 1995, 59, 1287], 이는 광학순도와 관계없이 최고 이론 수율이 50%를 넘지 못하는 단점이 있다.In addition, techniques such as optical splitting by conventional methods, hydrolysis by enzymes and esterification by enzymes have been reported [Japanese Patent Laid-Open No. Hei 5-32620, Japanese Patent Laid-Open No. Hei 4-164066, Japanese Patent Laid-Open]. SO 61-63652, Bull. Chem. Soc. Jpn. 1996, 69, 207, Enatiomer, 1997, 2, 311-314, Biochem. 1995, 59, 1287], which has the disadvantage that the maximum theoretical yield does not exceed 50% regardless of optical purity.
그리고, D 혹은 L-아스파틱산을 할로겐화 및 B2H6 환원반응으로 2-할로겐-1,4-부탄디올을 제조한 다음, 에폭시화 및 술폰화반응으로 4-메탄술포닐옥시-1,2-에폭시부탄을 제조하고 암모니아와 반응하여 3-히드록시-피롤리딘을 제조하는 기술이 보고되었다[Heterocycles, 1986, 24, 5]. 그러나, 상기 방법은 본 발명과 유사한 출발물질을 사용하고 있지만, 값비싸고 다루기 어려운 환원제인 B2H6사용하며 또한, 핵심기술인 암모니아와의 반응시 부 반응이 다량 생성되어 수율이 28%로 저하되는 단점이 있고, 또한 3-히드록시-피롤리딘을 정제할 때 보호기 도입이 필수적이다.Then, 2-halogen-1,4-butanediol is prepared by halogenating D or L-aspartic acid and reducing B2H6, and then 4-methanesulfonyloxy-1,2-epoxybutane is reacted by epoxidation and sulfonation. Techniques for preparing and reacting with ammonia to produce 3-hydroxy-pyrrolidine have been reported [Heterocycles, 1986, 24, 5]. However, the method uses a starting material similar to the present invention, but uses a costly and intractable reducing agent, B 2 H 6 , and also produces a large amount of side reactions when reacting with ammonia, which is a core technology, and the yield is reduced to 28%. There are disadvantages and also the introduction of protecting groups is essential when purifying 3-hydroxy-pyrrolidine.
한편, 본 발명에서 언급하고자 하는 3,4-에폭시-1-부탄올을 출발물질로 하여 3-히드록시-피롤리딘을 제조하는 방법은 현재까지 알려진 바가 없다.Meanwhile, a method for preparing 3-hydroxy-pyrrolidine using 3,4-epoxy-1-butanol as a starting material to be mentioned in the present invention is not known until now.
본 발명의 발명자들은 광학적으로 순수하며 상업적으로 손쉽고 경제적으로3-히드록시-피롤리딘를 제조하기 위해 노력하였다. 그 결과, 광학활성을 가진 3,4-에폭시-1-부탄올을 출발물질로 하여 암모니아와 알데히드 화합물로 반응하여 부 생성물없이 정량적으로 4-보호된이미노-부탄-1,3-디올을 중간체로 경유하면서, 동시에 C-1 위치의 히드록시기를 선택적으로 이탈기로 활성화시킨 다음 내부 고리화 반응을 수행하여 목적으로 하는 화합물을 고 수율로 광학적으로 순수하게 제조할 수 있음으로써 본 발명을 완성하게 되었다.The inventors of the present invention sought to make 3-hydroxy-pyrrolidine optically pure and commercially easy and economical. As a result, 3,4-epoxy-1-butanol with optical activity as a starting material was reacted with ammonia and an aldehyde compound, and quantitatively 4-protected imino-butane-1,3-diol without intermediates as intermediates. At the same time, the present invention was completed by activating a hydroxyl group at the C-1 position with a leaving group and then performing an internal cyclization reaction to optically pure the desired compound in high yield.
따라서, 본 발명은 상업적으로 용이하게 고수율로 광학적으로 순수한 3-히드록시-피롤리딘을 대량으로 제조하는 방법을 제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide a method for producing a large amount of optically pure 3-hydroxy-pyrrolidine in high yield easily commercially.
본 발명에 따른 제조방법은 다음의 제조과정이 포함되는 것을 그 특징으로 한다:The manufacturing method according to the invention is characterized in that it comprises the following manufacturing process:
다음 화학식 2로 표시되는 광학활성을 갖는 3,4-에폭시-1-부탄올을 암모니아 및 알데히드 화합물과 반응시켜 다음 화학식 3으로 표시되는 4-보호된이미노-부탄-1,3-디올을 제조하는 과정;Next, by reacting 3,4-epoxy-1-butanol having an optical activity represented by the formula (2) with ammonia and an aldehyde compound to prepare a 4-protected imino-butan-1,3-diol represented by the following formula (3) process;
상기 화학식 3으로 표시되는 화합물을 할로겐화 또는 술폰화 반응시켜 C-1 위치의 히드록시기를 선택적으로 이탈기(할로겐 또는 술포닐옥시기)로 활성화하여 다음 화학식 4로 표시되는 중간체를 경유하고 동시에 혹은 이어서 산으로 처리하여 다음 화학식 5로 표시되는 3-히드록시-1-치환된-부틸아민염을 제조하는 과정; 및Halogenated or sulfonated the compound represented by Formula 3 to selectively activate a hydroxy group at the C-1 position as a leaving group (halogen or sulfonyloxy group) to pass through an intermediate represented by the following Formula 4 and simultaneously or subsequently to an acid. Treating to prepare 3-hydroxy-1-substituted-butylamine salt represented by Formula 5; And
상기 화학식 5로 표시되는 화합물을 염기 존재 하에 분자내 고리화 반응을수행하여 다음 화학식 1로 표시되는 3-히드록시-피롤리딘을 제조하는 과정.A process for preparing 3-hydroxy-pyrrolidine represented by the following Chemical Formula 1 by performing an intramolecular cyclization reaction in the presence of a base in the presence of a compound represented by Chemical Formula 5.
상기 반응식 1에서, R1은 아릴기 혹은 치환된 아릴기를 나타내고, R2는 수소 또는 아실기를 나타내고, HX는 할로겐산 혹은 지방족산를 나타내고, Y는 할로겐, C1∼C12의 알킬술포닐옥시기, 아릴술포닐옥시기 혹은 치환된 아릴술포닐옥시기를 나타낸다.In Scheme 1, R 1 represents an aryl group or a substituted aryl group, R 2 represents hydrogen or an acyl group, HX represents a halogen acid or an aliphatic acid, Y represents a halogen, an alkylsulfonyloxy group of C 1 to C 12 , An arylsulfonyloxy group or a substituted arylsulfonyloxy group is represented.
이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.
본 발명은 종래의 발명과는 달리 광학활성을 갖는 (S) 혹은 (R)-3,4-에폭시-1-부탄올을 출발물질로 하여 부 생성물 없이 고수율로 경제적으로 손쉽게 광학적으로 순수한 (S) 혹은 (R)-3-히드록시-피롤리딘을 제조하는 방법에 관한 것이다.Unlike the conventional invention, the present invention uses (S) or (R) -3,4-epoxy-1-butanol having optical activity as a starting material and economically and easily optically pure with high yield without side products. Or (R) -3-hydroxy-pyrrolidine.
상기 반응식 1에 따른 본 발명의 제조방법을 각 단계별로 구분하여 보다 상세히 설명하면 다음과 같다The method of the present invention according to Scheme 1 will be described in more detail by dividing each step as follows.
우선, 첫 번째 반응은 이민화 반응으로서, 상기 화학식 2로 표시되는 광학적으로 순수한 3,4-에폭시-1-부탄올을 암모니아 및 알데히드 화합물과 반응시켜 상기 화학식 3으로 표시되는 4-보호된이미노-부탄-1,3-디올을 제조하는 과정이다.First, the first reaction is an imidization reaction, wherein the optically pure 3,4-epoxy-1-butanol represented by Formula 2 is reacted with ammonia and an aldehyde compound to form 4-protected imino-butane represented by Formula 3 The process of preparing -1,3-diol.
이때, 출발물질로 사용하고 있는 상기 화학식 2로 표시되는 광학적으로 순수한 (S) 혹은 (R)-3,4-에폭시-1-부탄올은 상업적으로 쉽게 얻을 수 있는 (S)-3-히드록시-γ-부티로락톤을 원료물질로 사용하여 간단하게 공지의 방법에 의해 제조할 수 있다[일본특허공개 평 2-174733호].At this time, the optically pure (S) or (R) -3,4-epoxy-1-butanol represented by the formula (2) used as a starting material is commercially available (S) -3-hydroxy- It can be manufactured simply by a well-known method using (gamma) -butyrolactone as a raw material (Japanese Patent Laid-Open No. 2-174733).
상기한 이민화 반응에서 사용되는 알데히드 화합물로서 아릴기 또는 치환된 아릴기의 알데히드를 사용하며, 바람직하기로는 벤즈알데히드를 사용하는 것이다. 상기 이민화 반응에는 암모니아가 1 ∼ 20 당량 범위, 바람직하기로는 2 ∼ 5 당량 범위로 사용되고, 알데히드 화합물이 1 ∼ 5 당량 범위, 바람직하기로는 1 ∼ 2 당량 범위로 사용한다. 반응용매는 별도로 사용하지 않더라도 반응은 충분히 진행될 수 있으며, 필요에 따라 유기용매 또는 물을 용매로서 사용할 수도 있다. 그리고, 이민화 반응온도는 20 ∼ 80 ℃ 조건, 바람직하기로는 20 ∼ 40 ℃ 조건에서 진행한다. 그리고, 반응시간은 1 ∼ 24 시간, 바람직하기로는 3 ∼ 5 시간이다.As the aldehyde compound used in the above-mentioned imidization reaction, an aryl group or an aldehyde group of a substituted aryl group is used, and preferably benzaldehyde is used. Ammonia is used in the range of 1 to 20 equivalents, preferably in the range of 2 to 5 equivalents, and the aldehyde compound is used in the range of 1 to 5 equivalents, preferably 1 to 2 equivalents. The reaction may proceed sufficiently even if the reaction solvent is not used separately, and an organic solvent or water may be used as the solvent as necessary. And imidation reaction temperature advances on 20-80 degreeC conditions, Preferably it is 20-40 degreeC conditions. And reaction time is 1 to 24 hours, Preferably it is 3 to 5 hours.
본 발명에 따른 두 번째 반응에서는 선택적으로 상기 화학식 3으로 표시되는 화합물의 C-1 위치 히드록시기를 활성화하여 다음 화학식 4로 표시되는 중간체를 경유하고 동시에 혹은 이어서 산으로 처리하여 이미노기를 아민기로 전환하여 상기 화학식 5로 표시되는 3-히드록시-1-치환된-부틸아민 염을 제조하는 과정이다. 즉, 상기 화학식 3으로 표시되는 화합물을 C-1 위치의 히드록시기를 활성화함과 동시에 혹은 인시츄(in situ)로 산 촉매 하에 교반 반응시켜 이미노기를 아민으로 전환한다. 그러나, 상기와 유사한 선택적 활성화 방법은 문헌에 보고되어져 왔으나, 본 발명과 다르게 출발물질이 1,3-부탄디올 혹은 3-벤질옥시-2-메틸프로판-1,2-디올 등의 C-1 위치 선택적 활성화 방법 등이다 [Tetrhedron: Asymmetry 12, 1383∼1388, 2001, J. Org. Chem. 53, 4081∼4084, 1988, J. Chem. Soc., Perkin Trans., 1973, 1214, Organic Synthesis, 63, 140].In the second reaction according to the present invention, by selectively activating the C-1 position hydroxy group of the compound represented by Formula 3, via the intermediate represented by the following Formula 4 and simultaneously or subsequently treated with an acid to convert the imino group into an amine group It is a process of preparing 3-hydroxy-1-substituted-butylamine salt represented by the formula (5). That is, the compound represented by the formula (3) is activated at the same time as the hydroxy group of the C-1 position or in situ (in situ) by stirring under an acid catalyst to convert the imino group into an amine. However, the selective activation method similar to the above has been reported in the literature, but unlike the present invention, the starting material is C-1 position selective, such as 1,3-butanediol or 3-benzyloxy-2-methylpropane-1,2-diol. Activation method, etc. [Tetrhedron: Asymmetry 12, 1383-1388, 2001, J. Org. Chem. 53, 4081-4084, 1988, J. Chem. Soc., Perkin Trans., 1973, 1214, Organic Synthesis, 63, 140].
본 발명에서 C-1 위치에 대한 선택적 활성화는 할로겐화 반응 또는 술폰화 반응에 의해 이루어질 수 있다.In the present invention, selective activation of the C-1 position may be achieved by halogenation or sulfonation.
C-1 위치에 대한 선택적 활성화를 위한 할로겐화 반응을 수행하는 경우, 다음 화학식 4로 표현되는 중간체를 경유하고 화합물 정제시 물을 첨가하는 과정에서 탈 보호화 반응이 이루어지는 것을 특징으로 한다. 이때, 사용되는 할로겐화 반응은 일반적인 할로겐화제 모두가 사용될 수 있으며, 바람직하기로는 할로겐산인 브롬산을 사용하는 것이다. 할로겐화제는 1 ∼ 5 당량, 바람직하기로는 2 ∼ 3 당량 범위로 사용한다. 할로겐화 반응시 반응용매는 별도로 사용하지 않더라도 반응은 충분히 진행될 수 있으며, 필요에 따라 유기용매을 용매로서 사용할 수도 있다. 반응온도는 20 ∼ 60 ℃ 조건으로 진행되며, 바람직하기로는 30 ∼ 50 ℃에서 진행한다. 그리고, 반응시간은 1 ∼ 24 시간 바람직하기로는 3 ∼ 6 시간이다.When the halogenation reaction for selective activation of the C-1 position is performed, the deprotection reaction is performed in the process of adding water when the compound is purified via an intermediate represented by the following formula (4). At this time, the halogenation reaction to be used may be any of the general halogenating agent, preferably to use bromic acid which is a halogen acid. The halogenating agent is used in the amount of 1 to 5 equivalents, preferably 2 to 3 equivalents. The reaction may proceed sufficiently even if the reaction solvent is not used separately in the halogenation reaction, and an organic solvent may be used as a solvent as necessary. The reaction temperature is carried out under the conditions of 20 to 60 ℃, preferably at 30 to 50 ℃. And reaction time is 1 to 24 hours, Preferably it is 3 to 6 hours.
또다른 C-1 위치에 대한 선택적 활성화를 위한 술폰화 반응을 수행하는 경우, 다음 화학식 4로 표시되는 중간체를 경유하는데 필요에 따라 분리정제가 가능하며 혹은 이어서 산 촉매하에 인시츄(in situ)로 반응을 진행할 수 있다. 이때, 사용되는 술포닐화제로는 알킬술폰산의 무수물, 알킬술포닐 클로라이드, 아릴술포닐 클로라이드, 또는 치환된 아릴술포닐 클로라이드를 사용하며, 구체적으로 예시하면 C1∼C12의 알킬술폰산 무수물, C1∼C12의 알킬술포닐 클로라이드, 벤젠술포닐 클로라이드, 또는 p-톨루엔술포닐 클로라이드를 사용하며, 바람직하게는 메탄술포닐 클로라이드 또는 p-톨루엔술포닐 클로라이드를 사용하는 것이다. 술포닐화제는 1 ∼ 3 당량 범위내에서 사용하며, 바람직하기로는 1 ∼ 2 당량 범위로 사용한다. 염기로는 지방족 또는 방향족의 아민류를 사용하며 바람직하게는 트리에틸아민, 디이소프로필에틸아민, 피리딘 등을 사용한다. 상기한 염기는 1 ∼ 3 당량 범위내에서 사용하며, 바람직하기로는 1 ∼ 2 당량 범위로 사용한다. 술폰화 반응을 수행함에 있어 반응용매는 유기용매를 사용하며, 바람직하게는 디클로로메탄, 디클로로에탄, 클로로포름, 디옥산 등을 사용한다. 반응온도는 -20 ∼ 30 ℃ 조건으로 진행되며, 바람직하기로는 -10 ∼ 10 ℃에서 진행한다. 그리고, 반응시간은 1 ∼ 12 시간 바람직하기로는 1 ∼ 3 시간이다.When carrying out the sulfonation reaction for selective activation of another C-1 position, separation and purification is possible as necessary via the intermediate represented by the following formula (4), or subsequently in situ under an acid catalyst. The reaction can proceed. In this case, the sulfonylating agent used may be an anhydride of alkylsulfonic acid, alkylsulfonyl chloride, arylsulfonyl chloride, or substituted arylsulfonyl chloride, specifically, C 1 to C 12 alkylsulfonic anhydride, C Alkylsulfonyl chloride, benzenesulfonyl chloride, or p-toluenesulfonyl chloride of 1 to C 12 is used, and methanesulfonyl chloride or p-toluenesulfonyl chloride is preferably used. The sulfonylating agent is used in the range of 1 to 3 equivalents, preferably in the range of 1 to 2 equivalents. Aliphatic or aromatic amines are used as the base, and triethylamine, diisopropylethylamine, pyridine and the like are preferably used. The base is used in the range of 1 to 3 equivalents, preferably in the range of 1 to 2 equivalents. In performing the sulfonation reaction, the reaction solvent is an organic solvent, preferably dichloromethane, dichloroethane, chloroform, dioxane, or the like. The reaction temperature proceeds at -20 to 30 ° C, preferably at -10 to 10 ° C. And reaction time is 1 to 12 hours, Preferably it is 1-3 hours.
그리고, 상기한 술폰화 반응 완결후에 이미노기를 아민기로 전환하는 반응은 정제후에 산 촉매하에 혹은 인시츄(in situ)로 산 촉매를 사용하여 반응시킨다. 이때, 사용되는 산은 할로겐산 혹은 지방족산 등이 사용되며, 바람직하게는 염산, 브롬산, 초산, 메탄술폰산 등을 사용한다. 상기의 산은 1 ∼ 5 당량 범위에서 사용되며, 바람직하게는 1 ∼ 3 당량을 사용한다. 그리고 반응온도는 5 ∼ 40℃ 조건으로 수행하며, 바람직하기로는 5 ∼ 20 ℃에서 진행하며 반응시간은 1 ∼5 시간 바람직하기로는 1 ∼ 3 시간이다.After completion of the sulfonation reaction, the reaction for converting the imino group to the amine group is carried out after the purification using an acid catalyst under an acid catalyst or in situ. In this case, as the acid used, halogen acid or aliphatic acid is used, and preferably hydrochloric acid, bromic acid, acetic acid, methanesulfonic acid and the like are used. The acid is used in the range of 1 to 5 equivalents, preferably 1 to 3 equivalents. And the reaction temperature is carried out under 5 to 40 ℃ condition, preferably proceeds at 5 to 20 ℃ and the reaction time is 1 to 5 hours, preferably 1 to 3 hours.
다음은 본 발명에 따른 세 번째 반응으로, 상기 화학식 5로 표시되는 화합물을 염기 존재 하에 분자내 고리화 반응을 수행함으로써 본 발명에서 목적으로 하는 화학식 1로 표시되는 화합물을 제조하는 과정이다. 이때, 사용되는 염기는 무기염기 또는 유기염기 모두 사용될 수 있다. 무기염기라 함은 알칼리 금속염 또는 알칼리 토금속염 등을 일컫는 것으로 구체적으로는 알칼리 금속 또는 알칼리 토금속의 수산화물, 알콕시물 또는 탄산염 등이 포함된다. 그리고, 유기염기라 함은 지방족 또는 방향족의 아민류 등을 일컫는 것으로 구체적으로는 알킬아민, 아릴아민 등이 포함된다. 염기는 1 ∼ 10 당량 범위내에서 사용하며, 바람직하기로는 2 ∼ 4 당량 범위로 사용한다. 반응용매는 유기용매 혹은 물을 사용하며, 바람직하게는 물, 메탄올, 에탄올 등을 사용한다. 반응온도는 0 ∼ 80 ℃ 조건으로 진행되며, 바람직하기로는 0 ∼ 30 ℃에서 진행한다. 그리고, 반응시간은 1 ∼ 24 시간 바람직하기로는 1 ∼ 6 시간이다.Next, according to the third reaction according to the present invention, a process of preparing the compound represented by Chemical Formula 1 as an object of the present invention is performed by performing an intramolecular cyclization reaction of the compound represented by Chemical Formula 5 in the presence of a base. At this time, the base used may be used both inorganic bases and organic bases. The inorganic base refers to alkali metal salts or alkaline earth metal salts, and specifically includes hydroxides, alkoxy compounds or carbonates of alkali metals or alkaline earth metals. The organic base refers to aliphatic or aromatic amines, and specifically includes alkylamines, arylamines, and the like. The base is used in the range of 1 to 10 equivalents, preferably in the range of 2 to 4 equivalents. The reaction solvent is an organic solvent or water, preferably water, methanol, ethanol or the like. The reaction temperature is carried out under the conditions of 0 to 80 ℃, preferably at 0 to 30 ℃. And reaction time is 1 to 24 hours, Preferably it is 1 to 6 hours.
이상에서 설명한 바와 같은 본 발명의 제조방법에 의하면, 반응 부산물의 생성을 최대한 억제할 수 있었고 또 목적물의 수율도 높아 공업적으로 이용하는데 특히 유용하다.According to the production method of the present invention as described above, the production of the reaction by-products can be suppressed to the maximum, and the yield of the target product is high, which is particularly useful for industrial use.
본 발명의 제조방법과 관련한 것으로, Synth. Commun., 1973, 3, 177에 의한 방법에 의거하여 상기 화학식 2로 표시되는 화합물을 직접 아미네이션하여 4-아미노-부탄-1,3-디올을 합성하는 방법을 시도하였다. 즉, 3,4-에폭시-1-부탄올을 암모니아로 처리하여 C-4 위치를 아민화하는 반응을 시도하였다. 그러나, 상기화학식 2로 표시되는 3,4-에폭시-1-부탄올을 암모니아와 반응시키게 되면, 목적하는 4-아미노-부탄-1,3-디올 이외에도 이량체(dimer)와 삼량체(trimer)가 부산물로 생성되는 것을 관찰할 수 있었다.Regarding the manufacturing method of the present invention, Synth. On the basis of the method according to Commun., 1973, 3, 177, a method of synthesizing 4-amino-butane-1,3-diol by directly aluminating the compound represented by Formula 2 was attempted. That is, a reaction was attempted to amination of the C-4 position by treating 3,4-epoxy-1-butanol with ammonia. However, when 3,4-epoxy-1-butanol represented by Formula 2 is reacted with ammonia, dimers and trimers in addition to the desired 4-amino-butane-1,3-diol It can be observed that it is produced as a by-product.
그러나, 본 발명에 따른 제조방법에 의거하여 3,4-에폭시-1-부탄올을 상기 화학식 3으로 표시되는 이민 화합물을 중간체로 경유하여 상기 화학식 5로 표시되는 화합물을 제조하게 되면 이량체 또는 삼량체의 생성을 근본적으로 방지할 수 있고, 그 수율도 극대화하는 효과를 얻을 수 있게 된다.However, when the compound represented by the formula (5) is prepared via the imine compound represented by the formula (3) as 3,4-epoxy-1-butanol based on the preparation method according to the present invention, the dimer or trimer It is possible to fundamentally prevent the production of, and to maximize the yield.
또한, 상기의 보호기(이민)를 도입함으로써 손쉽게 C-1위치 선택적 활성화반응을 고 수율로 부생성물없이 수행할 수 있는 효과를 갖는다.In addition, by introducing the above-described protecting group (imine) has the effect that can be easily carried out in the C-1 position selective activation reaction without high by-products.
이와 같은 본 발명을 다음의 실시예에 의거하여 더욱 상세히 설명하면 다음과 같은 바, 본 발명이 이에 한정되는 것은 아니다. 또한, 실시예에서는 특별하게 키랄 화합물을 구분하여 표기하지 않는다.When the present invention is described in more detail based on the following examples, the present invention is not limited thereto. In addition, in an Example, a chiral compound does not distinguish separately.
실시예 1 : 4-벤즈이미노-부탄-1,3-디올의 제조Example 1 Preparation of 4-benzimino-butane-1,3-diol
2 ℓ반응기에 3,4-에폭시-1-부탄올(100 g, 1.13 mol)을 에탄올 400 ㎖에 녹인 후, 벤즈알데히드(121.6 g, 1.15 mol)와 28% 암모니아 수용액(275.6 g, 4.54 mol)을 각각 첨가한 후 40 ℃에서 3 시간 동안 교반하였다. 반응 완료 후, 상온으로 냉각하고 반응용매를 진공 농축하였다. 농축된 액을 디클로로메탄 500㎖에 희석한 후 포화 소금물 50 ㎖로 세척하고, 디클로로메탄 층을 무수 마그네슘 설페이트로 건조하고, 진공 농축하여 목적하는 화합물 201.8 g(수율 92%)을 얻었다.After dissolving 3,4-epoxy-1-butanol (100 g, 1.13 mol) in 400 ml of ethanol in a 2 L reactor, benzaldehyde (121.6 g, 1.15 mol) and 28% aqueous ammonia solution (275.6 g, 4.54 mol) were added, respectively. After addition, the mixture was stirred at 40 ° C. for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solvent was concentrated in vacuo. The concentrated solution was diluted with 500 ml of dichloromethane, washed with 50 ml of saturated brine, the dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 201.8 g (yield 92%) of the title compound.
1H-NMR(CDCl3, ppm) δ1.85(m, 2H), 3.2(br, 1H), 3.63(m, 1H), 3.74(m, 1H), 3.88(m, 2H), 4.16(m, 1H), 7.36∼7.73 (m, 5H), 8.33(s, 1H) 1 H-NMR (CDCl 3 , ppm) δ 1.85 (m, 2H), 3.2 (br, 1H), 3.63 (m, 1H), 3.74 (m, 1H), 3.88 (m, 2H), 4.16 (m , 1H), 7.36-7.73 (m, 5H), 8.33 (s, 1H)
실시예 2 : 4-벤즈이미노-3-히드록시-1-메탄술포닐옥시부탄의 제조Example 2 Preparation of 4-benzimino-3-hydroxy-1-methanesulfonyloxybutane
2 ℓ반응기에 4-벤즈이미노-부탄-1,3-디올(123 g, 0.64 mol)을 디클로로메탄 600 ㎖에 녹인 후, 반응액을 -10 ℃로 냉각하였다. 동온도에서 디이소프로필-에틸아민(90.5 g, 0.70 mol)을 가한 다음, 메탄 술포닐클로라이드(76.6 g, 0.67 mol)를 -10 ℃로 유지하면서 1시간 동안 적가하였다. 이때 반응액을 동온도에서 1시간 동안 교반하고, 0 ℃로 승온시켜 반응을 완결시켰다. 0 ∼ 5 ℃에서 반응액에 물 100 ㎖를 천천히 가하여 세척한 후에 디클로로메탄층을 무수 마그네슘 설페이트로 건조하고, 진공 농축하여 목적 화합물 152 g(수율 88%)을 얻었다.4-benzimino-butane-1,3-diol (123 g, 0.64 mol) was dissolved in 600 mL of dichloromethane in a 2 L reactor, and the reaction solution was cooled to -10 ° C. Diisopropyl-ethylamine (90.5 g, 0.70 mol) was added at the same temperature, and methane sulfonylchloride (76.6 g, 0.67 mol) was added dropwise for 1 hour while maintaining the temperature at -10 ° C. At this time, the reaction solution was stirred at the same temperature for 1 hour, and heated to 0 ° C. to complete the reaction. 100 ml of water was slowly added to the reaction solution at 0 to 5 DEG C, followed by washing. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 152 g (yield 88%) of the title compound.
1H-NMR(CDCl3, ppm) δ1.93(m, 1H), 2.05(m, 1H), 3.05(s, 3H), 3.57(dd, 1H), 3.76(m, 1H), 4.09(m, 1H), 4.46(m, 2H), 7.38∼7.73(m, 5H), 8.35(s, 1H) 1 H-NMR (CDCl 3 , ppm) δ 1.93 (m, 1H), 2.05 (m, 1H), 3.05 (s, 3H), 3.57 (dd, 1H), 3.76 (m, 1H), 4.09 (m , 1H), 4.46 (m, 2H), 7.38-7.73 (m, 5H), 8.35 (s, 1H)
실시예 3 : 3-히드록시-1-메탄술포닐옥시-부틸아민 염산염의 제조Example 3: Preparation of 3-hydroxy-1-methanesulfonyloxy-butylamine hydrochloride
상기 실시예 2에서 얻은 화합물(100 g, 0.37 mol)을 디클로로메탄 400 ㎖에 용해한 후 5℃로 냉각하고 동온도에서 10% 염산 수용액(269 g, 0.74 mol)을 5 ℃를 유지하면서 적가하고 1 시간 동안 교반하였다. 이 반응액에서 층분리하여 물층을 농축하고, 에탄올로 공비 증류하여 목적 화합물의 염산염 77.7 g(수율 96%)을 얻었다.The compound (100 g, 0.37 mol) obtained in Example 2 was dissolved in 400 ml of dichloromethane, cooled to 5 ° C, and 10% aqueous hydrochloric acid solution (269 g, 0.74 mol) was added dropwise while maintaining the temperature at 5 ° C. Stir for hours. The layers were separated from the reaction solution, the water layer was concentrated and azeotropic distillation with ethanol to obtain 77.7 g (yield 96%) of hydrochloride of the target compound.
1H-NMR(D2O, ppm) δ1.74(m, 1H), 1.88(m, 1H), 2.82(m, 1H), 3.03(dd, 1H), 3.89(m, 1H), 4.32(m, 2H) 1 H-NMR (D 2 O, ppm) δ1.74 (m, 1H), 1.88 (m, 1H), 2.82 (m, 1H), 3.03 (dd, 1H), 3.89 (m, 1H), 4.32 ( m, 2H)
실시예 4 : 3-히드록시-1-메탄술포닐옥시-부틸아민 염산염의 제조Example 4: Preparation of 3-hydroxy-1-methanesulfonyloxy-butylamine hydrochloride
실시예 2에 의거하여 반응하고 인시츄(in situ)로 실시예 3의 방법으로 분리 정제없이 반응을 진행하여 목적 화합물의 염산염 123.1 g(수율 88%)을 얻었다.The reaction was carried out according to Example 2, and the reaction was carried out in situ without separation and purification by the method of Example 3 to obtain 123.1 g (yield 88%) of the hydrochloride of the target compound.
1H-NMR(D2O, ppm) δ1.74(m, 1H), 1.88(m, 1H), 2.82(m, 1H), 3.03(dd, 1H), 3.89(m, 1H), 4.32(m, 2H) 1 H-NMR (D 2 O, ppm) δ1.74 (m, 1H), 1.88 (m, 1H), 2.82 (m, 1H), 3.03 (dd, 1H), 3.89 (m, 1H), 4.32 ( m, 2H)
실시예 5 : 3-히드록시-1-브로모-부틸아민 브롬산염의 제조Example 5: Preparation of 3-hydroxy-1-bromo-butylamine bromate
1 ℓ반응기에 4-벤즈이미노-부탄-1,3-디올(100 g, 0.52 mol)을 넣고 33% 브롬산-아세틱산 용액(380.6 g, 1.55 mol)을 가한 후 밀봉하고, 40 ℃에서 5 시간동안 가열하여 반응을 완결시켰다. 반응액을 상온으로 냉각시킨 후, 개폐하여 물150 ㎖를 가하고 동온도에서 1 시간 교반한 다음 감압하에 진공 농축시켰다. 이 농축된 액을 톨루엔 300 ㎖를 가하고 진공 농축시킨 다음 톨루엔을 가하고 2번 반복하여 감압 농축하였다. 이 농축된 액을 디클로로메탄 600 ㎖와 물 200 ㎖로 용해하고 물 층을 얻었다. 이때 디클로로메탄층을 다시 물 200 ㎖를 넣고 재 층 분리하여 물 층을 각각 얻은 다음, 상기 물 층을 합하여 디클로로메탄 200 ㎖로 세척하고 물 층의 목적물을 분석하였다.4-benzimino-butane-1,3-diol (100 g, 0.52 mol) was added to a 1 L reactor, and 33% bromic acid-acetic acid solution (380.6 g, 1.55 mol) was added and sealed. Heat the reaction to complete the reaction. The reaction solution was cooled to room temperature, opened and closed, 150 mL of water was added thereto, stirred at the same temperature for 1 hour, and then concentrated in vacuo under reduced pressure. 300 ml of toluene was added to this concentrated solution, and the mixture was concentrated in vacuo, then toluene was added and concentrated under reduced pressure twice. This concentrated solution was dissolved in 600 ml of dichloromethane and 200 ml of water to obtain a water layer. At this time, the dichloromethane layer was put again 200 ml of water and re-separated to obtain a water layer. The combined water layers were washed with 200 ml of dichloromethane, and the target of the water layer was analyzed.
이때, 물층의 목적물을 NMR로 분석한 결과, 3-아세톡시-1-브로모-부틸아민 브롬산염과 3-히드록시-1-브로모-부틸아민 브롬산염의(4:6 비율) 혼합으로 존재함을 알 수 있었다.At this time, the target material of the water layer was analyzed by NMR, and present as a mixture of 3-acetoxy-1-bromo-butylamine bromate and 3-hydroxy-1-bromo-butylamine bromate (4: 6 ratio). And it was found.
1H-NMR(D2O, ppm) δ2.03(s, 3H), 2.12(m, 2H), 3.12(m, 2H), 3.34(m, 2H), 5.18(m, 1H) 1 H-NMR (D 2 O, ppm) δ 2.03 (s, 3H), 2.12 (m, 2H), 3.12 (m, 2H), 3.34 (m, 2H), 5.18 (m, 1H)
이 물층을 40 ℃에서 1 시간 가열하여 탈 아세틸화한 후 목적물을 감압증류하고 에탄올로 공비 증류하여 목적 화합물의 브롬산염 121.1 g(수율 94%)을 얻었다.The water layer was heated at 40 ° C. for 1 hour to deacetylate, and the target product was distilled under reduced pressure and azeotropically distilled with ethanol to obtain 121.1 g (yield 94%) of bromate of the target compound.
1H-NMR(D2O, ppm) δ1.93(m, 2H), 2.82(m, 1H), 3.03(dd, 1H), 3.46(q, 2H), 3.95(m, 1H) 1 H-NMR (D 2 O, ppm) δ 1.93 (m, 2H), 2.82 (m, 1H), 3.03 (dd, 1H), 3.46 (q, 2H), 3.95 (m, 1H)
실시예 6 : 3-히드록시-피롤리딘의 제조Example 6: Preparation of 3-hydroxy-pyrrolidine
1 ℓ반응기에 3-히드록시-1-메탄술포닐옥시-부틸아민 염산염(70 g, 0.32 mol)을 메탄올 400 ㎖에 용해한 후, 5 ℃로 냉각하고 수산화나트륨(38.2 g, 0.96 mol)을 동온도에서 천천히 가한 다음, 상온까지 승온하여 2 시간 교반하였다. 상기 반응이 완결되면, 반응액을 여과하고 진공 농축한 다음, 디클로로메탄 500 ㎖에 용해시켰다. 이때 녹지 않는 물질은 셀라이트를 이용하여 제거하고, 진공 농축시켰다. 상기의 목적물을 0.2 torr, 65 ℃에서 진공 증류하여 순수하게 목적물 25.6 g(수율 92%)을 얻었다.Dissolve 3-hydroxy-1-methanesulfonyloxy-butylamine hydrochloride (70 g, 0.32 mol) in 400 ml of methanol in a 1 L reactor, cool to 5 ° C. and add sodium hydroxide (38.2 g, 0.96 mol) to copper. The mixture was slowly added at a temperature, then heated up to room temperature and stirred for 2 hours. Upon completion of the reaction, the reaction solution was filtered, concentrated in vacuo and dissolved in 500 ml of dichloromethane. At this time, the insoluble material was removed using celite and concentrated in vacuo. The target product was vacuum distilled at 0.2 torr and 65 ° C. to obtain 25.6 g (yield 92%) of the target product purely.
1H-NMR(CDCl3, ppm) δ1.72(m, 1H), 1.95(m, 1H), 2.79(br, 2H), 2.86(m, 3H), 3.12(m, 1H), 4.39(m, 1H) 1 H-NMR (CDCl 3 , ppm) δ1.72 (m, 1H), 1.95 (m, 1H), 2.79 (br, 2H), 2.86 (m, 3H), 3.12 (m, 1H), 4.39 (m , 1H)
실시예 7 : 3-히드록시-피롤리딘의 제조Example 7: Preparation of 3-hydroxy-pyrrolidine
1 ℓ반응기에 3-히드록시-1-브로모-부틸아민 브롬산염(100 g, 0.40 mol)을 메탄올 500 ㎖에 용해한 후 5 ℃로 냉각하고 수산화나트륨(48.2 g, 1.21 mol)을 동온도에서 천천히 가한 다음, 상온까지 승온하여 1 시간 교반하였다. 상기 반응이 완결되면, 반응액을 여과하고 진공 농축한 다음, 디클로로메탄 600 ㎖에 용해시켰다. 이때 녹지 않는 물질은 셀라이트를 이용하여 제거하고, 진공 농축시켰다. 상기의 목적물을 0.2 torr, 65 ℃에서 진공 증류하여 순수하게 목적물 30.4 g(수율 87 %)을 얻었다.Dissolve 3-hydroxy-1-bromo-butylamine bromate (100 g, 0.40 mol) in 500 ml of methanol in a 1 L reactor, cool to 5 ° C, and slowly add sodium hydroxide (48.2 g, 1.21 mol) at room temperature. After the addition, the mixture was heated to room temperature and stirred for 1 hour. Upon completion of the reaction, the reaction solution was filtered, concentrated in vacuo and dissolved in 600 mL of dichloromethane. At this time, the insoluble material was removed using celite and concentrated in vacuo. The target product was purified by vacuum distillation at 0.2 torr and 65 ° C. to obtain 30.4 g (yield 87%) of the target product purely.
1H-NMR(CDCl3, ppm) δ1.72(m, 1H), 1.95(m, 1H), 2.79(br, 2H), 2.86(m, 3H), 3.12(m, 1H), 4.39(m, 1H) 1 H-NMR (CDCl 3 , ppm) δ1.72 (m, 1H), 1.95 (m, 1H), 2.79 (br, 2H), 2.86 (m, 3H), 3.12 (m, 1H), 4.39 (m , 1H)
시험예 1 : (S) 혹은 (R)-3-히드록시-피롤리딘의 광학순도 분석Test Example 1 Optical Purity Analysis of (S) or (R) -3-hydroxy-Pyrrolidine
본 발명에 의해 제조된 3-히드록시-피롤리딘에 대한 광학순도를 분석하기 위하여 다음과 같은 방법으로 N-트리플로로아세틸-3-트리플로로아세톡시-피롤리딘을 합성하였다.N-trifluoroacetyl-3-trifluoroacetoxy-pyrrolidine was synthesized in the following manner to analyze the optical purity of the 3-hydroxy-pyrrolidine prepared by the present invention.
3-히드록시-피롤리딘 50 mg(0.57 mmol)을 디클로로 메탄 5 ㎖에 녹인 다음,트리플로로아세틱 언하이드라이드 362 mg(1.72 mmol)을 넣고 상온에서 30 분간 교반하였다. 반응이 완결되면, 반응액을 증발 농축시키고 디클로로메탄 10 ㎖를 가하고, 재 증발 농축하여 N-트리플로로아세틸-3-트리플로로아세톡시-피롤리딘을 합성하였다.50 mg (0.57 mmol) of 3-hydroxy-pyrrolidine was dissolved in 5 ml of dichloromethane, and then 362 mg (1.72 mmol) of trifluoroacetic anhydride was added thereto, followed by stirring at room temperature for 30 minutes. When the reaction was completed, the reaction solution was concentrated by evaporation, 10 ml of dichloromethane was added, and the reaction solution was evaporated again to synthesize N-trifluoroacetyl-3-trifluoroacetoxy-pyrrolidine.
1H-NMR(CDCl3, ppm) δ2.26 ∼ 2.41 (m, 2H), 3.70 ∼ 4.04(m, 4H), 5.62(m, 1H) 1 H-NMR (CDCl 3 , ppm) δ 2.26 to 2.41 (m, 2H), 3.70 to 4.04 (m, 4H), 5.62 (m, 1H)
얻어진 N-트리플로로아세틸-3-트리플로로아세톡시-피롤리딘을 디클로로 메탄 5 ㎖에 녹인 뒤, 주사기로 1.0 ㎕를 취하여 GC로 분석하여 광학순도를 분석하였다.The obtained N-trifluoroacetyl-3-trifluoroacetoxy-pyrrolidine was dissolved in 5 ml of dichloromethane, 1.0 µl was taken with a syringe and analyzed by GC to analyze optical purity.
본 발명에 따른 제조방법은 광학활성을 가진 3,4-에폭시-1-부탄올을 출발물질로 하여 4-보호된이미노-부탄-1,3-디올을 중간체로 합성한 후에 C-1 위치의 히드록시를 선택적으로 활성화하는 신규 기술을 이용하여 부 생성물없이 정량적으로 아민기가 도입된 3-히드록시-1-치환된-부틸아민염을 또다른 중간체로 경유하게 되면 간편하게 목적물을 효과적으로 제조할 수 있다.The preparation method according to the present invention synthesizes 4-protected imino-butane-1,3-diol as an intermediate using 3,4-epoxy-1-butanol having optical activity as a starting material, and then By using a novel technique for selectively activating hydroxy, the 3-hydroxy-1-substituted-butylamine salt in which amine groups are introduced quantitatively without side products via another intermediate can be effectively prepared easily. .
따라서, 본 발명은 부 생성물 없이 고 수율로 광학적으로 순수한 3-히드록시-피롤리딘의 대량 생산이 가능함으로써, 종래의 방법에 비해 산업적으로 생산성을 극대화시키는 효과를 가진다.Thus, the present invention enables the mass production of optically pure 3-hydroxy-pyrrolidine in high yield without side products, thereby maximizing industrial productivity compared to conventional methods.
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| PCT/KR2003/000995 WO2003097594A1 (en) | 2002-05-20 | 2003-05-20 | Process for preparing optically pure 3-hydroxy-pyrrolidine |
| AU2003230438A AU2003230438A1 (en) | 2002-05-20 | 2003-05-20 | Process for preparing optically pure 3-hydroxy-pyrrolidine |
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| EP1926709A4 (en) * | 2005-08-25 | 2009-06-24 | Rstech Corp | Process for the preparation of chiral 3-hydroxy pyrrolidine compound and derivatives thereof having high optical purity |
| EP4382529A1 (en) | 2022-12-07 | 2024-06-12 | Bayer Consumer Care AG | A process for preparing pure (3s)-pyrrolidin-3-ol and pure (3s)-pyrrolidin-3-ol hydrochloride |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5756457A (en) * | 1980-08-14 | 1982-04-05 | Koei Chem Co Ltd | Preparation of 3-pyrrolidinol |
| JPS60104061A (en) * | 1983-11-08 | 1985-06-08 | Sankyo Co Ltd | Preparation of pyrrolidine derivative |
| JPH0285249A (en) * | 1988-06-22 | 1990-03-26 | Kanegafuchi Chem Ind Co Ltd | Production of 3-pyrrolidinol |
| JPH03176462A (en) * | 1989-12-02 | 1991-07-31 | Kanegafuchi Chem Ind Co Ltd | Production of 3-pyrrolidinol |
| US5144042A (en) * | 1990-04-11 | 1992-09-01 | Takasago International Corporation | Process for preparing optically active 3-hydroxypyrrolidine derivatives |
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| US5187094A (en) * | 1989-09-06 | 1993-02-16 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Method for the preparation of optically active 3-hydroxypyrrolidine derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5756457A (en) * | 1980-08-14 | 1982-04-05 | Koei Chem Co Ltd | Preparation of 3-pyrrolidinol |
| JPS60104061A (en) * | 1983-11-08 | 1985-06-08 | Sankyo Co Ltd | Preparation of pyrrolidine derivative |
| JPH0285249A (en) * | 1988-06-22 | 1990-03-26 | Kanegafuchi Chem Ind Co Ltd | Production of 3-pyrrolidinol |
| JPH03176462A (en) * | 1989-12-02 | 1991-07-31 | Kanegafuchi Chem Ind Co Ltd | Production of 3-pyrrolidinol |
| US5144042A (en) * | 1990-04-11 | 1992-09-01 | Takasago International Corporation | Process for preparing optically active 3-hydroxypyrrolidine derivatives |
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