KR20050010203A - Preparation method of l-carnitine - Google Patents
Preparation method of l-carnitine Download PDFInfo
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- KR20050010203A KR20050010203A KR1020030049198A KR20030049198A KR20050010203A KR 20050010203 A KR20050010203 A KR 20050010203A KR 1020030049198 A KR1020030049198 A KR 1020030049198A KR 20030049198 A KR20030049198 A KR 20030049198A KR 20050010203 A KR20050010203 A KR 20050010203A
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/26—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing carboxyl groups by reaction with HCN, or a salt thereof, and amines, or from aminonitriles
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- C07—ORGANIC CHEMISTRY
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- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/44—Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
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Abstract
Description
[기술분야][Technical Field]
본 발명은 L-카르니틴의 제조방법에 관한 것으로, 더욱 상세하게는 종래의 출발물질보다 가격이 저렴한 (R)-에피브로모히드린을 사용하여, 일련의 다단계 반응을 연속으로 수행하여 이성질체의 분리과정 없이 간단한 방법으로 L-카르니틴을 고수율로 제조할 수 있는 방법에 관한 것이다.The present invention relates to a method for preparing L-carnitine, and more particularly, using (R) -epibromohydrin, which is cheaper than conventional starting materials, to carry out a series of multistage reactions in succession to separate isomers. The present invention relates to a method for producing L-carnitine in a high yield without a simple method.
[종래기술][Private Technology]
L-카르니틴, 그 알카노일 유도체 및 그 염은 식품 및 의약품 등 다양한 용도로 널리 사용되고 있다. 이미 공지된 바와 같이 카르니틴은 입체적 활성을 띄는 탄소원자를 포함하는 물질이며, 이중 하나의 이성질체인 L-카르니틴은 인체에 존재하는 이성질체로 지방산 대사에 필수적이며 세포막을 통한 지방산의 수송에서 핵심적인 역할을 한다. 이러한 이유로, L-카르니틴이 결핍될 경우 생체 활동에 심각한 저해가 초래되며, 이를 방지하기 위한 필수 약물이 바로 L-카르니틴이다. 또한 최근들어 혈액 투석 후 발생하는 결핍증, 에너지 대사, 심장 기능 향상에 유용하게 사용되고 있는 천연물이다. 또한, L-카르니틴 및 그의 유도체들은 혈청 지질 강하제, 경련 방지제 및 혈액 제품 보조제로도 사용되고 있다.L-carnitine, its alkanoyl derivatives and salts thereof are widely used in various applications such as food and pharmaceuticals. As already known, carnitine is a substance containing three-dimensionally active carbon atoms, and one of these isomers, L-carnitine, is an essential part of fatty acid metabolism and plays a key role in the transport of fatty acids through cell membranes. . For this reason, the deficiency of L-carnitine results in severe inhibition of biological activity, and the essential drug for preventing this is L-carnitine. It is also a natural product that has been used to improve deficiency, energy metabolism and cardiac function that occur after hemodialysis. L-carnitine and its derivatives are also used as serum lipid lowering agents, anticonvulsants and blood product adjuvants.
일반적으로, L-카르니틴의 합성에 사용될 수 있는 합성 경로는 다음의 3가지 가 있다.In general, there are three synthetic routes that can be used for the synthesis of L-carnitine.
첫 번째는 비키랄 화합물로부터 출발하여 라세미 중간체를 거쳐 이 중간체들 중 하나의 이성질체를 분리시키는 것이다. 이러한 합성 경로는 비교적 저렴한 출발물질을 사용하는 이점을 제공하지만, 이성질체를 분리해내는 공정상의 한계로 인해 까다로운 공정 조건 및 낮은 수율로 인해 분리후 라세미 중간체를 다시 회수하여 사용해야 하는 단점이 있으며, 최종 생성물의 순도를 맞추는 일도 쉽지가 않다(Tetrahedron Lett. 1992, 33, 1211; J. Org. Chem. 1988, 53, 104).The first is to separate the isomers of one of these intermediates, starting from achiral compounds, through racemic intermediates. This synthetic route offers the advantage of using a relatively inexpensive starting material, but has the disadvantage of having to recover and use the racemic intermediate again after separation due to the difficult process conditions and low yield due to the process limitations of isomer separation. Matching the purity of the product is also not easy (Tetrahedron Lett. 1992, 33, 1211; J. Org. Chem. 1988, 53, 104).
두 번째 방법은 역시 라세미 중간체를 이용하여 촉매 또는 효소를 사용하여 이성질체를 분리하는 방법이다. 그러나, 상기 방법은 촉매가 고비용이며 이성질체를 촉매적으로 생성할 때 통상적으로 생성되는 다른 이성질체에 의해 순수한 이성질체를 생성하기가 어렵고, 많은 부반응으로 인해 최종 생성물로부터 순수한 L-카르니틴을 얻어내는 정제법이 매우 힘들다(Tetrahedron Asymmetry. 1993, 4, 133; Synlett. 1991,193).The second method is also the separation of isomers using catalysts or enzymes using racemic intermediates. However, this method is difficult to produce pure isomers by other isomers which are usually produced when the catalyst is expensive and catalytically generates isomers, and due to many side reactions, purification method of obtaining pure L-carnitine from the final product is difficult. Very difficult (Tetrahedron Asymmetry. 1993, 4, 133; Synlett. 1991, 193).
세 번째 방법은 입체적으로 순수한 출발물질을 이용하여 일련의 반응들을 통해 L-카르니틴을 합성하는 방법이다. 그러나, 상기 방법은 입체적으로 순수한 출발물질의 비용이 라세미 중간체보다 고가인 문제가 있다. 또한, 상기 방법은 문헌상에 많이 나와 있으나, 아직까지 제조가격 및 설비의 이유로 산업적으로 제조가 가능한 유용한 공정이 개발되지 않고 있다(Tetrshedron Letter. 1990, 31, 7323;JACS. 1985, 107, 4028).The third method is to synthesize L-carnitine through a series of reactions using stericly pure starting materials. However, this method has the problem that the cost of three-dimensional pure starting materials is higher than that of racemic intermediates. In addition, many of these methods are described in the literature, but there are still no useful processes that can be industrially manufactured due to manufacturing costs and equipment (Tetrshedron Letter. 1990, 31, 7323; JACS. 1985, 107, 4028).
본 발명은 상기 종래 기술의 문제점을 해결하기 위하여, 가격이 저렴한 (R)-에피브로모히드린을 출발물질로 하여 트리메틸아민을 이용한 개환반응, 및 아세토니트릴과 크라운 에테르를 산성조건하에서 연속으로 반응시켜, 종래 출발물질의 고비용의 문제와 이성질체 분리의 문제점을 해결함으로써 경제적으로 고수율의 L-카르니틴을 제조하는 방법을 제공하는 것을 목적으로 한다.In order to solve the problems of the prior art, the ring-opening reaction using trimethylamine as a starting material (R)-epibromohydrin, which is inexpensive, and the acetonitrile and the crown ether are continuously reacted under acidic conditions It is an object of the present invention to provide a method for producing a high yield of L-carnitine economically by solving the problem of high cost and isomer separation of conventional starting materials.
상기 목적을 달성하기 위하여, 본 발명은In order to achieve the above object, the present invention
((a) (R)-에피브로모히드린과 트리메틸아민을 반응시키고,((a) reacting (R) -epibromohydrin with trimethylamine,
(b) 반응촉매 및 산성조건하에, 상기 (a)에서 얻어진 반응물을 아세토니트릴과 연속으로 반응시키는 단계(b) continuously reacting the reactant obtained in (a) with acetonitrile under reaction catalyst and acidic conditions
를 포함하는 하기 화학식 1로 표시되는 L-카르니틴의 제조방법을 제공한다.It provides a method for producing L-carnitine represented by the following formula (1) comprising a.
[화학식 1][Formula 1]
이하에서 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명자는 종래 L-카르니틴의 상업적 제조의 문제점을 해결하기 위해, (R)-에피브로모히드린을 출발물질로 하여 일련의 다단계 반응을 거쳐 최종적으로 L-카르니틴을 합성하는 신규한 공정을 통해 출발물질의 고비용, 이성질체 분리의문제점을 해결할 수 있는 유용한 공정을 개발하여 본 발명을 완성하였다.In order to solve the problems of conventional commercial production of L-carnitine, the present inventors start through a novel process of finally synthesizing L-carnitine through a series of multi-step reactions using (R) -epibromohydrin as a starting material. The present invention has been completed by developing a useful process that can solve the problem of high cost, isomer separation of materials.
특히, 본 발명은 (R)-에피브로모히드린을 출발물질로 하여 트리메틸아민을 이용한 개환반응, 아세토니트릴과 크라운 에테르를 산성조건하에 반응하는 것을 연속적으로 수행하여 최종 생성물인 L-카르니틴을 고수욜로 제조하는 방법에 관한 것이다.In particular, the present invention is a ring-opening reaction using trimethylamine, (R)-epibromohydrin as a starting material, the reaction of acetonitrile and the crown ether under acidic conditions in succession was carried out to give a high yield of L-carnitine It relates to a method of manufacturing.
본 발명의 L-카르니틴의 제조방법은 하기 반응식 1을 따르며, 이를 보다 구체적으로 설명하면 다음과 같다.The method for preparing L-carnitine of the present invention is according to Scheme 1 below, which will be described in more detail as follows.
[반응식 1]Scheme 1
본 발명에 따르면, 상기 화학식 3의 (R)-에피브로모히드린과 트리메틸아민을 상온을 유지하면서 물에서 반응시킨다. 이 과정을 통해 개환반응으로 상기 화학식 2의 화합물이 얻어진다.According to the present invention, the (R) -epibromohydrin and the trimethylamine of the formula (3) is reacted in water while maintaining the room temperature. Through this process, the ring-opening reaction yields the compound of Formula 2.
상기 개환반응이 완료되면 화학식 2의 반응액에 아세토니트릴을 적정량 넣어준 다음, 반응촉매로 사용되는 18-크라운-6-에테르와 KCN을 촉매량만큼 넣어 환류 교반한다.When the ring-opening reaction is completed, a proper amount of acetonitrile is added to the reaction solution of Chemical Formula 2, and 18-crown-6-ether and KCN used as a reaction catalyst are added under a catalytic amount to reflux and stirred.
이후, 아세토니트릴의 증류와 동시에 일정량의 염산을 가한 후, 적정시간 동안 환류 교반하고 묽은 염화나트륨 수용액으로 pH를 조절하여 L-카르니틴과 소금을 포함하는 생성물을 얻을 수 있다. 최종적으로, 본 발명은 일련의 정제과정을 거쳐 입체적 순도가 적어도 99% 이상인 화학식 1의 L-카르니틴을 얻을 수 있다.Thereafter, a certain amount of hydrochloric acid is added simultaneously with distillation of acetonitrile, and the mixture is stirred under reflux for a predetermined time and the pH is adjusted with a dilute aqueous sodium chloride solution to obtain a product including L-carnitine and salt. Finally, the present invention can be obtained through a series of purification process to obtain the L-carnitine of formula (1) having a stereoscopic purity of at least 99% or more.
상기 반응에 사용된 물의 경우 일반적인 일차증류수를 사용하는 것이 바람직하며, 물의 양은 반응에 큰영향을 미치지는 않는다.In the case of water used in the reaction, it is preferable to use general primary distilled water, and the amount of water does not significantly affect the reaction.
상기 트리메틸아민은 상용 40% 트리메틸아민-물 용액을 사용하는 것이 바람직하다. 상기 트리메틸아민의 사용량은 출발물질로 사용되는 (R)-에피브로모히드린의 중량에 대하여 0.5 내지 10 당량으로 사용하는 것이 바람직하며, 보다 바람직하기로는 1 내지 3 당량으로 사용한다. 상기 트리메틸아민의 함량이 1 당량보다 낮아질 경우 반응이 종결되지 않아 수율 및 순도에 문제점이 생기며, 10 당량을 초과하면 잔량의 트리메틸아민을 제거하기 힘든 문제가 있다.The trimethylamine is preferably used a commercial 40% trimethylamine-water solution. The trimethylamine may be used in an amount of 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, based on the weight of (R) -epibromohydrin used as a starting material. When the content of the trimethylamine is lower than 1 equivalent, the reaction is not terminated, resulting in problems in yield and purity. When the amount of the trimethylamine is exceeded, it is difficult to remove the residual amount of trimethylamine.
본 발명에서 반응용매로 사용되는 아세토니트릴의 경우 (R)-에피브로모히드린의 중량에 대하여 5 내지 100 당량을 사용하며, 가장 바람직하기로는 20 내지 50 당량이다. 상기 아세토니트릴의 함량이 5 당량 미만이면 반응시간이 길어지며 생성물의 수율 또한 낮아지며, 100 당량을 초과하면 부반응의 문제가 생기게 된다.In the case of the acetonitrile used as the reaction solvent in the present invention, 5 to 100 equivalents are used, most preferably 20 to 50 equivalents, based on the weight of (R) -epibromohydrin. If the content of acetonitrile is less than 5 equivalents, the reaction time is long and the yield of the product is also lowered. If the content of acetonitrile exceeds 100 equivalents, there is a problem of side reactions.
본 발명에서 반응촉매로 사용되는 18-크라운-6-에테르의 경우 (R)-에피브로모히드린의 중량에 대하여 0.01 내지 10 당량을 사용하며, 가장 바람직하기로는 0.1 내지 2.0 당량이다. 상기 18-크라운-6-에테르의 함량이 0.01 당량 미만이면 반응시간이 길어지며, 10 당량을 초과하면 제조원가가 높아지는 경제적인 문제가생기게 된다.In the case of 18-crown-6-ether used as the reaction catalyst in the present invention, 0.01 to 10 equivalents are used, and most preferably 0.1 to 2.0 equivalents, based on the weight of (R) -epibromohydrin. If the content of the 18-crown-6-ether is less than 0.01 equivalents, the reaction time is long, and if it exceeds 10 equivalents, there is an economic problem that the manufacturing cost increases.
또한, 반응촉매로 사용되는 KCN의 사용량은 (R)-에피브로모히드린의 중량에 대하여 0.1 내지 20 당량을 사용하며, 가장 바람직하기로는 1.0 내지 2.0 당량이다. 상기 KCN의 함량이 0.1 당량 미만이면 반응이 종결되지 않는 문제점이 있으며, 20 당량을 초과하면 최종 생성물에 금속물의 함량이 높아지는 결과를 가져올 수 있다.In addition, the amount of KCN used as a reaction catalyst is used in an amount of 0.1 to 20 equivalents, and most preferably 1.0 to 2.0 equivalents based on the weight of (R) -epibromohydrin. If the content of KCN is less than 0.1 equivalent, there is a problem that the reaction is not terminated. If it exceeds 20 equivalents, the content of metal in the final product may be increased.
최종 반응에 사용되는 염산의 경우 상용염산을 사용하며, 그 사용량은 (R)-에피브로모히드린의 중량에 대하여 10 내지 100 당량을 사용하며, 가장 바람직하기로는 20 내지 50 당량이다. 상기 염산의 함량이 10 당량 미만이면 반응 종결 시간이 길어지며, 100 당량을 초과하면 차후 최종 생성물의 정제시 중성화를 위한 산가 조절시 많은 시간이 걸리는 문제가 있다.In the case of hydrochloric acid used in the final reaction, commercial hydrochloric acid is used, the amount of which is used in an amount of 10 to 100 equivalents based on the weight of (R) -epibromohydrin, most preferably 20 to 50 equivalents. If the amount of hydrochloric acid is less than 10 equivalents, the reaction termination time is long, and if it exceeds 100 equivalents, there is a problem that it takes a lot of time to adjust the acid value for neutralization in the purification of the final product in the future.
본 발명의 방법으로 제조된 L-카르니틴의 입체적 순도는 99.5% 이상이며, 80% 이상의 수율을 나타내어 종래의 제조방법보다 월등히 높은 수율로 L-카르니틴을 얻을 수 있다. 따라서, 본 발명의 방법으로 제조된 L-카르니틴은 식품 및 의약품 등의 다양한 용도로 사용될 수 있다.The three-dimensional purity of the L-carnitine produced by the method of the present invention is 99.5% or more, and yields 80% or more, so that L-carnitine can be obtained with a much higher yield than the conventional production method. Therefore, L-carnitine prepared by the method of the present invention can be used for various uses such as food and medicine.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐 본 발명이 하기의 실시예에 한정되는 것은 아니다.Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are provided only to more easily understand the present invention, and the present invention is not limited to the following examples.
[실시예]EXAMPLE
실시예 1: L-카르니틴의 합성Example 1 Synthesis of L-Carnitine
(R)-에피브로모히드린 100 g을 증류수 1L에 넣고 잘 섞어 주었다. 반응기의 온도를 상온으로 유지하며, 40% 메틸아민 수용액 160 g을 적가한 다음 같은 온도를 유지하며 6시간 동안 격렬히 교반하였다. 반응이 완료되면 물과 남은 메틸아민을 완전히 진공증류하였다.100 g of (R) -epibromohydrin was added to 1 L of distilled water and mixed well. The temperature of the reactor was maintained at room temperature, and 160 g of 40% aqueous methylamine solution was added dropwise, followed by vigorous stirring for 6 hours while maintaining the same temperature. After the reaction was completed, water and the remaining methylamine were completely distilled under vacuum.
증류가 완료된 반응액에 아세토니트릴 300 ml를 넣어준 다음, 미리 KCN 90 g 및 18-크라운-6 10 g을 녹인 증류수 300 ml을 반응액에 넣어 주었다. 투입이 완료되면 반응기의 온도를 상승시켜 반응이 종결될때까지 환류 교반하였다. 반응이 완료되면 진공증류를 통해 아세토니트릴을 증류하였다. 증류가 완료된 반응액에 염산 30 g을 넣은 다음 24시간 동안 환류 교반한 다음 묽은 염화나트륨 수용액을 이용해 반응액의 pH를 5로 조절하였다. 반응액의 pH 조절 완료후 반응액의 물을 완전 증류하여 L-카르니틴과 소금(NaCl)을 포함하는 조악한(crude) 생성물 결정을 얻었다.300 ml of acetonitrile was added to the reaction solution after distillation was completed, and 300 ml of distilled water in which 90 g of KCN and 10 g of 18-crown-6 were dissolved was added to the reaction solution. When the addition was completed, the temperature of the reactor was increased and the mixture was stirred under reflux until the reaction was completed. After the reaction was completed, the acetonitrile was distilled through vacuum distillation. 30 g of hydrochloric acid was added to the reaction solution after distillation was completed, and the mixture was stirred under reflux for 24 hours, and then the pH of the reaction solution was adjusted to 5 using a diluted aqueous sodium chloride solution. After pH adjustment of the reaction solution was completed, water of the reaction solution was completely distilled to obtain crude product crystals including L-carnitine and salt (NaCl).
생성물: 160 gProduct: 160 g
수율: 소금 포함으로 인해 정제과정에서 계산Yield: calculated during purification due to salt inclusion
입체적 순도: ＞99.5% (HPLC)Three-dimensional purity:> 99.5% (HPLC)
실시예 2. L-카르니틴의 정제Example 2 Purification of L-Carnitine
상기 실시예 1에서 생성된 결정을 물 100 ml에 희석한 다음, 이를 탄산염의 형태로 활성화시킨 앰버라이트(AMBERRITE) IRA 402 컬럼을 통과시켰다. L-카르니틴이 용출되는 액상들을 모두 모아 물을 완전 증류시켰다. 수득한 고체에 아세톤 1L를 투입하여 18시간 동안 상온 교반한 후, 생성된 결정을 여과하여 L-카르니틴95 g(수율: 80%)을 수득하였다.The crystals produced in Example 1 were diluted in 100 ml of water and then passed through an AMBERRITE IRA 402 column which was activated in the form of carbonate. All of the liquid phases from which L-carnitine was eluted were collected to completely distill water. 1 L of acetone was added to the obtained solid, followed by stirring at room temperature for 18 hours. The resulting crystals were filtered to give 95 g of L-carnitine (yield: 80%).
입체적 순도: ＞99.5% (HPLC/이성질체 함량)Stereoscopic Purity:> 99.5% (HPLC / Isomer Content)
화학적 순도: ＞99.5% (HPLC/불순물 함량)Chemical Purity:> 99.5% (HPLC / Impurity Content)
[α]D 25= -30.9°(c=1.0, 증류수)[α] D 25 = -30.9 ° (c = 1.0, distilled water)
1H NMR (D2O,δ) : 2.45 (d, 2H), 3.24 (s, 9H), 3.41(d, 2H), 4.57(m, 1H) 1 H NMR (D 2 O, δ): 2.45 (d, 2H), 3.24 (s, 9H), 3.41 (d, 2H), 4.57 (m, 1H)
이상에서 설명한 바와 같이, 본 발명의 제조방법은 종래의 출발물질보다 가격이 저렴한 (R)-에피브로모히드린을 사용하여 일련의 연속 반응을 통해 최종적으로 L-카르니틴을 제조함으로써, 종래 출발물질의 고비용의 문제와 이성질체 분리의 과정을 실시하지 않아 종래보다 고수율로 L-카르니틴을 얻을 수 있어 경제적이다.As described above, the preparation method of the present invention uses (R) -epibromohydrin, which is less expensive than conventional starting materials, to finally prepare L-carnitine through a series of continuous reactions, thereby reducing the It is economical because L-carnitine can be obtained at a higher yield than the conventional one because the problem of high cost and the isomer separation process are not performed.
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