KR100491809B1 - Production of 3-Substituted-3'-hydroxypropionitrile - Google Patents
Production of 3-Substituted-3'-hydroxypropionitrile Download PDFInfo
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- KR100491809B1 KR100491809B1 KR10-2002-0074308A KR20020074308A KR100491809B1 KR 100491809 B1 KR100491809 B1 KR 100491809B1 KR 20020074308 A KR20020074308 A KR 20020074308A KR 100491809 B1 KR100491809 B1 KR 100491809B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/16—Preparation of carboxylic acid nitriles by reaction of cyanides with lactones or compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/11—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton
- C07C255/12—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
Abstract
본 발명은 3-치환된-3'-하이드록시프로피오나이트릴의 제조방법에 관한 것으로서, 더욱 상세하게는 1-치환된-에틸렌 옥사이드를 물 단독용매에서 시안화나트륨 및 시트릭산을 사용하여 pH 7.8 ∼ 8.3 범위로 특정화된 조건으로 개환반응을 수행하여 고 광학순도 및 고 수율로 다음 화학식 1로 표시되는 3-치환된-3'-하이드록시프로피오나이트릴을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing 3-substituted-3'-hydroxypropionitrile, and more specifically, 1-substituted-ethylene oxide using sodium cyanide and citric acid in water alone solvent, pH 7.8- The present invention relates to a method for preparing 3-substituted-3'-hydroxypropionitrile represented by the following Chemical Formula 1 by performing ring-opening reaction under conditions specified in 8.3 range in high optical purity and high yield.
상기 화학식 1에서, R은 발명의 상세한 설명에서 정의한 바와 같다.In Formula 1, R is as defined in the detailed description of the invention.
Description
본 발명은 3-치환된-3'-하이드록시프로피오나이트릴의 제조방법에 관한 것으로서, 더욱 상세하게는 1-치환된-에틸렌 옥사이드를 물 단독용매에서 시안화나트륨 및 시트릭산을 사용하여 pH 7.8 ∼ 8.3 범위로 특정화된 조건으로 개환반응을 수행하여 고 광학순도 및 고 수율로 다음 화학식 1로 표시되는 3-치환된-3'-하이드록시프로피오나이트릴을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing 3-substituted-3'-hydroxypropionitrile, and more specifically, 1-substituted-ethylene oxide using sodium cyanide and citric acid in water alone solvent, pH 7.8- The present invention relates to a method for preparing 3-substituted-3'-hydroxypropionitrile represented by the following Chemical Formula 1 by performing ring-opening reaction under conditions specified in 8.3 range in high optical purity and high yield.
[화학식 1][Formula 1]
상기 화학식 1에서, R은 C1∼C10의 알킬기, C2∼C6 알켄기, C2∼C6 알킨기, C3∼C8의 싸이클로알킬기, C1∼C10의 알콕시기, 페닐기, 카르보닐기, 카르복실기, 케톤기, 알데히드기, 에스터기, 포스포릴기, 포스포네이트기, 포스핀기, 설포닐기, 또는 -(CH2)ℓ-R1 을 나타내고; R1은 C2∼C6 알켄기, C2∼C6 알킨기, C2∼C6 알콕시기, 페닐, 사이클로알킬, 사이클로알케닐, 헤테로사이클 또는 폴리사이클(polycycle), 할로겐원자, 히드록시기, 아미노기, 티올기, 니트로기, 아민기, 이민기, 아미드기, 카르보닐기, 카르복실기, 실릴기, 에테르기, 티오에테르기, 셀레노에테르기, 케톤기, 알데히드기, 에스터기, 포스포릴기, 포스포네이트기, 포스핀기, 설포닐기를 나타내고, ℓ은 0에서 8까지의 정수를 나타낸다.In Chemical Formula 1, R is a C 1 -C 10 alkyl group, a C 2 -C 6 alkene group, a C 2 -C 6 alkyne group, a C 3 -C 8 cycloalkyl group, a C 1 -C 10 alkoxy group, a phenyl group , A carbonyl group, a carboxyl group, a ketone group, an aldehyde group, an ester group, a phosphoryl group, a phosphonate group, a phosphine group, a sulfonyl group, or-(CH 2 ) L -R 1 ; R 1 is a C 2 -C 6 alkene group, C 2 -C 6 alkyne group, C 2 -C 6 alkoxy group, phenyl, cycloalkyl, cycloalkenyl, heterocycle or polycycle, halogen atom, hydroxy group, Amino group, thiol group, nitro group, amine group, imine group, amide group, carbonyl group, carboxyl group, silyl group, ether group, thioether group, selenoether group, ketone group, aldehyde group, ester group, phosphoryl group, phosphonate group , A phosphine group and a sulfonyl group are represented, and L represents an integer from 0 to 8.
상기 화학식 1로 표시되는 3-치환된-3'-하이드록시프로피오나이트릴은 L-카르니틴, 에이즈 치료제 원료인 (S)-3-하이드록시테트라하이드로퓨란 또는 (S)-1,2,4-부탄트리올, 아토르바스타틴의 원료인 에틸 (S)-4-클로로-3-하이드록시부티레이트 또는 에틸 (R)-4-시아노-3-하이드록시부티레이트 등의 의약품 원료, 농약품 및 그와 관련된 바이오 제품이나 정밀화학 제품 등을 제조하는데 주요하게 쓰이는 필수 핵심 중간체이다. 특히, 에틸 (S)-4-클로로-3-하이드록시부티레이트는 3-치환된-3'-하이드록시프로피오나이트릴의 한 예인 (S)-4-클로로-3-하이드록시부티로나이트릴로부터 무수 에탄올을 용매로 하여 HCl 가스를 발생시킬 수 있는 장치나 반응에 의해, 혹은 HCl 가스 저장고를 이용하여 주입하므로써 쉽게 제조된다.3-substituted -3'-hydroxypropionitrile represented by the formula (1) is L-carnitine, (S) -3-hydroxytetrahydrofuran or (S) -1,2,4- which is a raw material for the treatment of HIV Butanetriol, raw materials for pharmaceuticals, such as ethyl (S) -4-chloro-3-hydroxybutyrate or ethyl (R) -4-cyano-3-hydroxybutyrate, which are raw materials for atorvastatin, pesticides and related biomaterials It is an essential core intermediate used mainly in manufacturing products and fine chemicals. In particular, ethyl (S) -4-chloro-3-hydroxybutyrate is derived from (S) -4-chloro-3-hydroxybutyronitrile, which is an example of a 3-substituted-3'-hydroxypropionitrile. It is easily produced by an apparatus or a reaction capable of generating HCl gas using anhydrous ethanol as a solvent, or by injection using an HCl gas reservoir.
상기 화학식 1로 표시되는 3-치환된-3'-하이드록시프로피오나이트릴의 합성방법과 관련한 일반적 제조방법에서는, 다음에 나타낸 바와 같이 에폭시 화합물을 개환반응하여 제조한다. In the general manufacturing method related to the synthesis method of 3-substituted-3'-hydroxypropionitrile represented by Chemical Formula 1, an epoxy compound is prepared by ring-opening reaction as shown below.
상기한 에폭시 개환반응은 일반적으로 산, 염기 및 용매 등을 사용하는 조건에서 수행한다. 그러나, 상기한 에폭시 개환반응은 반응조건에 따라 제조수율이 크게 다르고, 특히나 원료물질이 광학활성을 가지는 물질인 경우 광학순도는 더욱 크게 달라진다.The epoxy ring-opening reaction is generally carried out under conditions using an acid, a base, a solvent and the like. However, in the epoxy ring opening reaction, the production yield is greatly different according to the reaction conditions, and in particular, the optical purity of the raw material is greatly changed when the material has optical activity.
에폭시 개환반응에 의한 상기 화학식 1로 표시되는 3-치환된-3'-하이드록시프로피오나이트릴의 제조방법과 관련된 종래 기술로는 다음과 같은 방법이 공지되어 있다: HCN을 사용하는 방법[Bull. Soc. Chim. Fr. 3, 138(1936), Bull. Acad. R. Belg. 29, 256(1943), Ber., 12, 23(1879), 일본특허공개 평11-39559호]이 있지만, HCN을 사용하는 것은 공업적인 공정상 위험하다. 물용매에서 시안염과 아세트산을 사용하여 pH 8.0 ∼ 10.0의 조건으로 개환반응하는 방법[일본특허공개 소63-316758호]이 있지만, 제조수율이 현저히 적고 순도가 떨어져 공업적 생산에 적용하는데는 한계가 있다. 상기 일본특허의 개량발명으로서, 시안염과 무기산을 사용하여 pH 8.0 ∼ 10.0의 조건으로 개환반응하는 방법[일본특허공개 평5-310671호]이 공지되어 있는 바, 이 방법은 현재까지 개발된 방법 중 가장 우수한 방법으로서 경제성도 우수한 장점이 있지만, 고농도의 진한 황산 등과 시안화칼륨을 사용하므로 작업자에게 위험하고, 반응 후 생성되는 무기염을 여과하여야 하는 추가 공정을 거쳐야 하며, 특히 키랄 화합물의 제조에 적용할 경우 일본특허공개 평5-310671호의 실시예에도 나와 있듯이 출발물질의 광학순도가 유지되지 못하고 수득물의 광학순도가 낮아진다는 결정적인 약점이 있다.Conventional methods related to the preparation of the 3-substituted-3'-hydroxypropionitrile represented by Chemical Formula 1 by epoxy ring-opening reaction are known as follows: Method of using HCN [ Bull. Soc. Chim. Fr. 3 , 138 (1936), Bull. Acad. R. Belg. 29 , 256 (1943), Ber., 12 , 23 (1879), Japanese Patent Laid-Open No. 11-39559], but the use of HCN is dangerous in industrial processes. Although there is a method of ring-opening reaction using cyan salt and acetic acid in water solvent under the condition of pH 8.0 to 10.0 (Japanese Patent Publication No. 63-316758), the production yield is very low and the purity is low, so it is limited to industrial production. There is. As an improved invention of the Japanese patent, a method of ring-opening reaction under conditions of pH 8.0 to 10.0 using cyan salt and an inorganic acid is known [Japanese Patent Laid-Open No. 5-310671], which has been developed so far. Although it has the advantage of excellent economic efficiency as the best method among them, it is dangerous to workers because it uses high concentration of concentrated sulfuric acid and potassium cyanide, and it has to go through the additional process to filter the inorganic salt generated after the reaction, especially for the production of chiral compounds In this case, as shown in the examples of Japanese Patent Application Laid-Open No. 5-310671, the optical purity of the starting material is not maintained and the optical purity of the obtained product is low.
본 발명자들은 수율 향상은 물론 시약을 다루는데 있어 작업자의 위험 부담을 줄여주면서도 특히, 키랄 원료화합물의 광학순도를 유지할 수 있는 보다 개선된 에폭시 개환반응의 조건을 설정하고자 연구 노력하였다. 그 결과, 물 단독용매를 사용하고, 공정상 취급하기 편하고 위험성이 적은 시트릭산과 시안화나트륨을 사용하여 반응용액의 pH가 7.8 ∼ 8.3인 최적범위로 조절하여 에폭시 개환반응을 수행하게 되면 수율 향상효과가 현저하고, 특히 키랄 화합물의 광학순도가 유지될 수 있다는 사실을 알게됨으로써 본 발명을 완성하게 되었다.The present inventors have tried to establish improved epoxy ring-opening reaction conditions that can maintain the optical purity of the chiral raw material compounds, while reducing the operator's risk in handling the reagents as well as improving the yield. As a result, when the epoxy ring-opening reaction was carried out by using the water alone solvent and adjusting the pH of the reaction solution to an optimum range of 7.8 to 8.3 using citric acid and sodium cyanide, which were easy to handle and less dangerous in the process, yield improvement effect was obtained. The present invention has been completed by recognizing that, in particular, the optical purity of the chiral compound can be maintained.
따라서, 본 발명은 상기 화학식 1로 표시되는 3-치환된-3'-하이드록시프로피오나이트릴을 간단한 제조공정을 통해 고 광학순도, 고 화학순도 및 고 수율로 제조하는 개량된 제조방법을 제공하는데 그 목적이 있다. Accordingly, the present invention provides an improved manufacturing method for producing 3-substituted-3'-hydroxypropionitrile represented by Chemical Formula 1 at high optical purity, high chemical purity and high yield through a simple manufacturing process. The purpose is.
본 발명은 다음 화학식 2로 표시되는 에폭시 화합물을 개환반응하여 다음 화학식 1로 표시되는 3-치환된-3'-하이드록시프로피오나이트릴을 제조하는 방법에 있어서, 상기 개환반응은 물 단독용매와 시안화나트륨 및 시트릭산을 사용하여 반응용액의 pH를 7.8 ∼ 8.3 조건으로 특정화하여 수행하는 것을 그 특징으로 한다.The present invention provides a ring-opening reaction of the epoxy compound represented by the following formula (2) to produce a 3-substituted-3'-hydroxypropionitrile represented by the following formula (1), wherein the ring-opening reaction is water alone solvent and cyanide It is characterized by performing by specifying the pH of the reaction solution to 7.8 ~ 8.3 conditions using sodium and citric acid.
상기에서, R은 상기 화학식 1에서 정의한 바와 같다.In the above, R is as defined in the formula (1).
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 에폭시 화합물을 물 단독용매에서 시안화나트륨과 반응시키되 유기산의 일종인 시트릭산을 동시에 첨가하여 pH를 7.8 ∼ 8.3 범위로 유지하도록 하는 개환반응 조건을 특정화하여 상기 화학식 1로 표시되는 3-치환된-3'-하이드록시프로피오나이트릴을 제조하는 방법에 관한 것이다.The present invention is characterized by the ring-opening reaction to react the epoxy compound represented by the formula (2) with sodium cyanide in a single solvent of water but at the same time to add a citric acid which is a kind of organic acid to maintain the pH in the range 7.8 ~ 8.3 It relates to a method for producing the 3-substituted -3'-hydroxypropionitrile represented by.
본 발명의 제조방법에 의하면 반응물의 pH를 7.8 ∼ 8.3으로 유지하는 것이 중요한데, pH를 높게 유지시키면 부산물의 생성이 많아져 수율 저하의 원인이 되고 pH를 낮게 유지시키면 부산물의 생성도 다소 많아지지만 반응시간이 매우 길어져 공업적으로 불리하다. pH를 7.8 ∼ 8.3으로 유지시키기 위해서는 여러 가지 산(acid)들을 이용할 수도 있겠지만, 본 발명에서는 위험성이 없어 작업자가 취급하기에 용이하며 3개의 카르복시기가 치환된 3가산으로서의 시트릭산을 선택 사용한데 가장 큰 기술구성상의 특징이 있는 바, 시트릭산은 물용매에 대한 용해도가 좋아서 농도가 진한 상태로 사용하는데 무리가 없어 공업적으로 유리할 뿐만 아니라 개환반응 결과로 생성되는 본 발명의 목적화합물과의 반응성이 없어 불순물이 생성되지 않는 장점을 가지고 있다. 이에 반하여, 유기산으로서 아세트산을 사용하게되면 생성물의 하이드록시기에 아세틸기가 부가된 3-치환된-3'-아세톡시프로피오나이트릴이 불순물로서 다량 생성되고, 3-치환된-3'-아세톡시프로피오나이트릴은 끓는점이 목적화합물인 3-치환된-3'-하이드록시프로피오나이트릴과 유사하여 증류정제법으로도 제거가 매우 어렵다. 따라서, 본 발명의 제조방법을 수행하는데 있어 시트릭산을 대신하여 아세트산을 대체 사용한다면 목적물의 순도 저하 문제로 공업적 생산방법으로 적용하는데 한계가 있다.According to the preparation method of the present invention, it is important to maintain the pH of the reactants at 7.8 to 8.3. If the pH is kept high, the production of by-products is increased, which causes a decrease in yield. The time is so long that it is disadvantageous industrially. Various acids may be used to maintain the pH between 7.8 and 8.3. However, in the present invention, there is no danger, so it is easy for the worker to handle and the citric acid as the tricarboxylic acid substituted with three carboxyl groups is selected. As a characteristic feature of the technical composition, citric acid has good solubility in water solvents, so it is easy to use it in a concentrated state, which is not only industrially advantageous but also has no reactivity with the target compound of the present invention produced as a result of the ring opening reaction. It has the advantage that no impurities are produced. In contrast, the use of acetic acid as an organic acid produces large amounts of 3-substituted-3'-acetoxypropionitrile to which an acetyl group is added to the hydroxy group of the product as impurities, and 3-substituted-3'-acetoxy Since propionitrile is similar to 3-substituted-3'-hydroxypropionitrile, which has a boiling point of interest, it is very difficult to remove even by distillation purification. Therefore, if acetic acid is substituted for citric acid in carrying out the production method of the present invention, there is a limit to applying it to an industrial production method due to a problem of lowering the purity of a target.
이상에서 설명한 바대로, 본 발명의 방법에 따라 시트릭산을 사용하면 불순물이 거의 생성되지 않으므로 고 화학순도의 목적화합물을 제조하는데 유용하다. As described above, the use of the citric acid in accordance with the method of the present invention is useful for the preparation of the target compound of high chemical purity since little impurities are produced.
특히, 키랄 에폭시화합물을 개환반응에 적용할 경우, 시트릭산은 대체로 pK값이 높아 무기산에 비해 출발물질의 광학순도를 변함없이 유지시켜 원하는 키랄 화합물을 고 광학순도로 얻을 수 있게 한다. In particular, when the chiral epoxy compound is applied to the ring-opening reaction, the citric acid generally has a high pK value, thereby maintaining the optical purity of the starting material invariably compared to the inorganic acid, thereby obtaining a desired chiral compound with high optical purity.
본 발명에서는 시트릭산과 함께 시안화나트륨을 동시에 사용하는 것을 특징으로 하는데, 시안화나트륨은 여러 시안화염들 중에서도 가장 독성이 적은 원료로서 취급하기 용이하다. 시안화나트륨은 1.0 ∼ 2.0 당량 범위로 사용될 수 있고, 바람직하게는 1.3 ∼ 1.5 당량 범위로 사용하는 것이다.In the present invention, it is characterized by using sodium cyanide together with citric acid, sodium cyanide is easy to handle as the least toxic raw material among the various cyanide salts. Sodium cyanide may be used in the range of 1.0 to 2.0 equivalents, preferably in the range of 1.3 to 1.5 equivalents.
본 발명의 에폭시 개환반응은 10 ∼ 30 ℃, 바람직하게는 20 ∼ 25 ℃의 상온에서 수행한다.The epoxy ring-opening reaction of the present invention is carried out at room temperature of 10 to 30 ℃, preferably 20 to 25 ℃.
이상의 개환반응이 완료되면, 반응용기에 유기용매를 넣고 추출 후, 증류장치를 이용하여 목적하는 3-치환된-3'-하이드록시프로피오나이트릴을 증류하여 수득할 수 있는데, 이러한 단순한 후처리 공정 역시 본 발명의 장점이 될 수 있다. When the ring opening is completed, the organic solvent is added to the reaction vessel, followed by extraction, and then the desired 3-substituted-3'-hydroxypropionitrile can be obtained by distillation using a distillation apparatus. It may also be an advantage of the present invention.
본 발명과 관련된 선행기술로서 일본특허공개 소63-316758호와 일본특허공개 평5-310671호의 방법이 수율이 적거나, 작업자에게 위험하고 반응 후 생성되는 무기염을 여과하여야 하는 추가 공정이 필요하며 특히, 출발물질의 광학순도가 유지되지 못하고 수득물의 광학순도가 낮아진다는 결정적인 약점을 가진데 반하여, 본 발명에 따른 제조방법은 공정상 취급하기 편하고 위험성이 적은 시트릭산과 시안화나트륨을 사용하므로써 공업적으로 유리한 반응조건과 후처리 공정으로 이루어진 경제적인 제조방법이라는 점과, 높은 수율과 고 광학순도 및 고 화학순도로 목적하는 상기 화학식 1로 표시되는 3-치환된-3'-하이드록시프로피오나이트릴을 제조한다는 점에서 본 발명은 상기한 종래발명의 개량발명으로서 충분히 진보된 효과를 가지는 것이다.As the prior art related to the present invention, the methods of Japanese Patent Application Laid-Open No. 63-316758 and Japanese Patent Application Laid-open No. 5-310671 require a low yield, an additional process that is dangerous for an operator, and has to filter inorganic salts generated after the reaction. In particular, while the optical purity of the starting material is not maintained and the optical purity of the obtained product is decisive, the manufacturing method according to the present invention is industrially prepared by using citric acid and sodium cyanide, which are easy to handle and have low risk. 3-substituted-3'-hydroxypropionitrile represented by Chemical Formula 1, which is an economical manufacturing method consisting of favorable reaction conditions and post-treatment process, and high yield, high optical purity, and high chemical purity. The present invention has a sufficiently advanced effect as an improved invention of the above-described conventional invention in that it is produced.
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)-4-클로로-3-하이드록시부티로나이트릴의 제조Example 1 Preparation of (S) -4-chloro-3-hydroxybutyronitrile
1.50 kg의 (S)-에피클로로하이드린(99.3% ee)에 3.57 L의 물을 넣고 교반하면서 4.76 kg의 25% 시안화나트륨 수용액과 3.30 kg의 50% 시트릭산 수용액을 pH 7.9 ∼ 8.2, 반응온도 22 ∼ 25 ℃를 유지하면서 1시간 50분동안 적가하였다. 10시간동안 교반한 후, 0.70 kg의 소금을 넣고 녹였다. 여기에 20 L의 에틸 아세테이트를 이용하여 추출하고 층분리하였다. 에틸 아세테이트층에 0.2 kg의 무수 소듐 설페이트를 가하고 30분동안 교반한 후 여과하였다. 에틸 아세테이트를 감압증류 제거 후, 농축액을 박막증류기(110 ℃/1mbar)로 증류하면 1.77 kg(수율 91.3%)의 목적화합물을 99.1%의 화학순도로 얻었다. 3.57 L of water was added to 1.50 kg of (S) -epichlorohydrin (99.3% ee), and 4.76 kg of 25% sodium cyanide and 3.30 kg of 50% citric acid were added at pH 7.9 to 8.2. It was added dropwise for 1 hour 50 minutes while maintaining 22 to 25 ℃. After stirring for 10 hours, 0.70 kg of salt was added and dissolved. It was extracted with 20 L of ethyl acetate and layered. 0.2 kg of anhydrous sodium sulfate was added to the ethyl acetate layer, stirred for 30 minutes, and filtered. After distilling off the ethyl acetate under reduced pressure, the concentrated solution was distilled with a thin film distillator (110 ° C./1 mbar) to obtain 1.77 kg (yield 91.3%) of the title compound in a chemical purity of 99.1%.
광학순도(GC)= 99.3% eeOptical purity (GC) = 99.3% ee
상기 실시예 1의 방법으로 수행하되, 다만 다음 표 1에 나타낸 바와 같이 반응조건을 달리하였다.Performed by the method of Example 1, but the reaction conditions were different as shown in the following Table 1.
실시예 2 : (R)-4-클로로-3-하이드록시부티로나이트릴의 제조Example 2 Preparation of (R) -4-chloro-3-hydroxybutyronitrile
상기 실시예 1과 같은 방법으로 실시하되 (S)-에피클로로하이드린 대신에 (R)-에피클로로하이드린(99.5% ee)을 사용하여 실시하였다. 그 결과, 화학순도 99.1% 및 광학순도(GC) 99.5% ee의 목적화합물을 수율 91.3%로 얻었다.The same procedure as in Example 1 was carried out using (R) -epichlorohydrin (99.5% ee) instead of (S) -epichlorohydrin. As a result, a target compound having a chemical purity of 99.1% and an optical purity (GC) of 99.5% ee was obtained in a yield of 91.3%.
실시예 3 : 라세믹 4-클로로-3-하이드록시부티로나이트릴의 제조Example 3 Preparation of Racemic 4-Chloro-3-hydroxybutyronitrile
상기 실시예 1과 같은 방법으로 실시하되 (S)-에피클로로하이드린 대신에 라세믹 에피클로로하이드린을 사용하여 실시하였다. 그 결과, 화학순도 99.1%의 목적화합물을 수율 91.4%로 얻었다.The same procedure as in Example 1 was carried out using racemic epichlorohydrin instead of (S) -epichlorohydrin. As a result, a target compound having a chemical purity of 99.1% was obtained in a yield of 91.4%.
실시예 4 : 키랄 3-치환된-3'-하이드록시프로피오나이트릴의 제조Example 4 Preparation of Chiral 3-Substituted-3′-hydroxypropionitrile
다음 표 2에서와 같은 키랄 에폭시 화합물(>99% ee) 1.62 몰에 0.36 L의 물을 넣고 교반하면서 476 g의 25% 시안화나트륨 수용액과 330 g의 50% 시트릭산 수용액을 pH 7.9 ∼ 8.2, 반응온도 22 ∼ 25 ℃를 유지하면서 1시간동안 적가하였다. 실온에서 교반한 후, 70 g의 소금을 넣고 녹였다. 여기에 2 L의 에틸 아세테이트를 이용하여 추출하고 층분리하였다. 에틸 아세테이트층에 20 g의 무수 소듐 설페이트를 가하고 30분동안 교반 후 여과하였다. 에틸 아세테이트를 감압증류 제거 후, 고진공으로 분별증류하여 화학순도 99% 이상, 광학순도 99% ee 이상의 목적 화합물들을 각각 수율 99% 이상으로 얻었다.Next, 0.36 L of water was added to 1.62 mol of a chiral epoxy compound (> 99% ee) as shown in Table 2, followed by reaction of 476 g of 25% aqueous sodium cyanide solution and 330 g of 50% aqueous citric acid solution at pH 7.9 to 8.2. It was added dropwise for 1 hour while maintaining the temperature of 22 to 25 ℃. After stirring at room temperature, 70 g of salt was added and dissolved. It was extracted with 2 L of ethyl acetate and layered. 20 g of anhydrous sodium sulfate was added to the ethyl acetate layer, stirred for 30 minutes, and filtered. After distillation under reduced pressure of ethyl acetate, fractional distillation was performed under high vacuum to obtain a target compound having a chemical purity of 99% or more and an optical purity of 99% ee or more in a yield of 99% or more.
이상에서 설명한 바와 같이, 본 발명에 따른 제조방법은 공정상 취급하기 편하고 위험성이 적은 시트릭산과 시안화나트륨을 사용하므로 공업적으로 유리한 반응조건과 후처리 공정, 높은 수율을 장점으로 가지는 경제적인 제조방법으로서 목적하는 3-치환된-3'-하이드록시프로피오나이트릴을 고광학순도 및 고화학순도로 제조하는 새로운 방법이다. 따라서 본 발명의 제조방법은 중간체로 유용한 3-치환된-3'-하이드록시프로피오나이트릴을 공업적으로 제조하는데 유용하다.As described above, the manufacturing method according to the present invention is economical manufacturing method having advantages in terms of industrially advantageous reaction conditions, post-treatment process, high yield because it is easy to handle in the process and uses a low risk of citric acid and sodium cyanide It is a novel process for preparing desired 3-substituted-3'-hydroxypropionitrile as high optical purity and high chemical purity. Therefore, the preparation method of the present invention is useful for industrially preparing 3-substituted-3'-hydroxypropionitrile useful as an intermediate.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63316758A (en) * | 1987-06-18 | 1988-12-26 | Osaka Soda Co Ltd | Production of 4-chloro-3-hydroxybutyronitrile |
| KR920016414A (en) * | 1991-02-26 | 1992-09-24 | 리로이 휘테커 | Positional Selective Synthesis |
| JPH05310671A (en) * | 1992-05-14 | 1993-11-22 | Daiso Co Ltd | Production of 4-chloro-3-hydroxybutyronitrile |
| KR100313668B1 (en) * | 1999-02-03 | 2001-11-26 | 박영구 | A process for preparing (R)-4-cyano-3-hydroxybutyric acid ester |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63316758A (en) * | 1987-06-18 | 1988-12-26 | Osaka Soda Co Ltd | Production of 4-chloro-3-hydroxybutyronitrile |
| KR920016414A (en) * | 1991-02-26 | 1992-09-24 | 리로이 휘테커 | Positional Selective Synthesis |
| JPH05310671A (en) * | 1992-05-14 | 1993-11-22 | Daiso Co Ltd | Production of 4-chloro-3-hydroxybutyronitrile |
| KR100313668B1 (en) * | 1999-02-03 | 2001-11-26 | 박영구 | A process for preparing (R)-4-cyano-3-hydroxybutyric acid ester |
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| KR20220131772A (en) | 2021-03-22 | 2022-09-29 | (주)이알코리아 | Inspection scaffolding for bridge inspection facilities for easy construction work |
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