KR100204532B1 - Process for the preparation of 5-oxo-2-pyrrolidone carboxylate - Google Patents
Process for the preparation of 5-oxo-2-pyrrolidone carboxylate Download PDFInfo
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- KR100204532B1 KR100204532B1 KR1019970004954A KR19970004954A KR100204532B1 KR 100204532 B1 KR100204532 B1 KR 100204532B1 KR 1019970004954 A KR1019970004954 A KR 1019970004954A KR 19970004954 A KR19970004954 A KR 19970004954A KR 100204532 B1 KR100204532 B1 KR 100204532B1
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- pyridoxine
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- pyrrolidone carboxylate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/12—Glutaric acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
- C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
- C07D213/67—2-Methyl-3-hydroxy-4,5-bis(hydroxy-methyl)pyridine, i.e. pyridoxine
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Abstract
본 발명은 메탄올 용매중에서 피리독신을 동몰량의 피로글루타민산과 반응시키고, 반응용액에 벤젠을 가하여 목적하는 생성물을 재결정화시켜 정제함을 특징으로 하여 화학식 1의 피리독신 5-옥소-2-피롤리돈 카르복실레이트를 제조하는 개선된 방법에 관한 것이다.The present invention is characterized in that pyridoxine is reacted with an equimolar amount of pyroglutamic acid in a methanol solvent, and benzene is added to the reaction solution to recrystallize and purify the desired product. It relates to an improved method of making a carboxylate.
[화학식 1][Formula 1]
Description
본 발명은 하기 구조식 1로 표시되는 피리독신 5-옥소-2-피롤리돈 카르복실레이트의 개선된 제조방법에 관한 것이다.The present invention relates to an improved process for preparing pyridoxine 5-oxo-2-pyrrolidone carboxylate represented by the following structural formula (1).
화학식 1 로 표시되는 피리독신 5-옥소-2-피롤리돈 카르복실레이트의 알코올 중독증상을 치료하거나 개선시키고자 하는 목적으로 사용되는 공지의 물질로서, 본 발명은 이화합물의 공업적인 생산에 있어서 생산원가의 절감, 수율의 향상, 용이한 생산공정 등의 잇점을 제공할 수 있는 산업적으로 유익한 제조방법을 제공하는 것을 목적으로 한다.As a known substance used for the purpose of treating or ameliorating the alcoholism of pyridoxine 5-oxo-2-pyrrolidone carboxylate represented by the formula (1), the present invention is produced in the industrial production of this compound It is an object of the present invention to provide an industrially advantageous manufacturing method that can provide advantages such as cost reduction, yield improvement, and easy production process.
비타민 B6로 알려져 있는 피리독신은 인체에서 피리독살 5-포스페이트로 대사되어 아미노산 탈탄산효소 및 아미노기 전이효소의 보호소로 작용하여 단백질 대사에 중요한 역할을 하며, 급성 알코올 중독증 증상의 개선과 치료에 사용되어온 공지의 약물학적 활성성분이다.[참조: Wordworth V.P., Intravenous Detoxication of Drunkeness, Brit. Med. J., 935, 1953].Pyridoxine, also known as vitamin B 6 , is metabolized to pyridoxal 5-phosphate in the human body and acts as a shelter for amino acid decarboxylase and amino transferases, and plays an important role in protein metabolism. Known pharmacologically active ingredients. See Wordworth VP, Intravenous Detoxication of Drunkeness, Brit. Med. J., 935, 1953.
미합중국 특허 제 4,313,952 호에 의하면 피리독신을 피로글루타민산과 결합시켜 형성되는 피리독신 5-옥소-2-피롤리돈 카르복실레이트는 피리독신을 단독으로 투여하는 것보다 정신운동성의 흥분억제 및 공격적인 행동의 감소에서 더욱 향상된 효능을 나타내는 것으로 밝혀졌다. 이에 따라 피리독신 5-옥소-2-피롤리돈 카르복실레이트는 현재 약제학적 분야에서 단일제제 또는 다른 성분들과의 복합제제로 제형화되어 급성 알코올 증독증 증상의 개선 및 치료제로서 시판되고 있다. 따라서, 약제학적 제제의 중요한 활성성분인 피리독신 5-옥소-2-피롤리돈 카르복실레이트의 공업적으로 유용한 합성방법을 개발하는 것은 매우 중요하다 하겠다.According to US Pat. No. 4,313,952, pyridoxine 5-oxo-2-pyrrolidone carboxylate, formed by combining pyridoxine with pyroglutamic acid, is more effective in inhibiting psychomotor excitability and reducing aggressive behavior than pyridoxine alone. It has been found to exhibit improved efficacy. Accordingly, pyridoxine 5-oxo-2-pyrrolidone carboxylate is currently formulated as a single agent or a combination with other components in the pharmaceutical field and is commercially available as an amelioration and treatment agent for acute alcoholism. Therefore, it is very important to develop an industrially useful method for the synthesis of pyridoxine 5-oxo-2-pyrrolidone carboxylate, which is an important active ingredient of pharmaceutical preparations.
지금까지 피리독신 5-옥소-2-피롤리돈 카르복실레이트를 제조하는 여러 가지 방법이 제안되었으며, 그중 대표적인 것으로 일본국 특허출원공개 제 (소)57-14531호 및 상응하는 호주특허 제 820107 호에는 에탄올 용액중에서 피리독신과 피로글루타민산을 가열하에 반응시켜 냉각하여 피리독신 5-옥소-2-피롤리돈 카르복실레이트를 침전시킨 후에, 이생성물을 이온교환크로마토그라피에 의해 정제하고 마지막으로 에탄올로부터 재결정화시켜 정제된 피리독신 5-옥소-2-피롤리돈 카르복실레이트를 수득하는 방법이 기술되어 있다.To date, various methods for preparing pyridoxine 5-oxo-2-pyrrolidone carboxylate have been proposed, among which, Japanese Patent Application Laid-Open No. 57-14531 and the corresponding Australian Patent No. 820107 Pyridoxine and pyroglutamic acid in ethanol solution were reacted under heating to cool to precipitate pyridoxine 5-oxo-2-pyrrolidone carboxylate, the product was purified by ion exchange chromatography and finally recrystallized from ethanol A method for obtaining purified pyridoxine 5-oxo-2-pyrrolidone carboxylate is described.
또한, 대한민국 공개특허공보 제 94-19708 호에는 고형분말상의 피리독신 염기와 피로글루타민산을 혼합하고 5-10% 의 물을 포함한 소량의 이소프로판올을 첨가하여 반응시킨 후에 이소프로판올로부터 목적하는 피리독신 5-옥소-2-피롤리돈 카르복실레이트를 재결정화시킴으로써 목적하는 피리독신 5-옥소-2-피롤리돈 카르복실레이트를 제조하는 방법이 기술되어 있다.In addition, Korean Patent Publication No. 94-19708 discloses a desired pyridoxine 5-oxo-2 from isopropanol after a solid powder of pyridoxine base and pyroglutamic acid are mixed and reacted by addition of a small amount of isopropanol including 5-10% of water. A method for preparing the desired pyridoxine 5-oxo-2-pyrrolidone carboxylate by recrystallizing pyrrolidone carboxylate is described.
그러나 , 상기 언급한 바와 같은 선행기술의 공지방법에 의한 피리독신 5-옥소-2-피롤리돈 카르복실레이트의 제조과정에서는 생성물의 재결정화에 사용되는 용매가 피리독신 5-옥소-2-피롤리돈 카르복실레이트에 대해 어느 정도의 용해도를 가지고 있어서 재결정화과정에서 목적생성물의 손실이 일어나 수율이 저하되는 단점을 가지고 있다. 즉, 예를 들어 일본국 특허출원공개 제 (소) 57-14531 호 및 상응하는 호주 특허 제 820107 호에 기재된 에탄올을 재결정화 용매로 사용하는 방법에서는 피리독신 5-옥소-2-피롤리돈 카르복실레이트가 재결정화 용매로 사용되는 에탄올에 냉각상태에서도 어느 정도의 용해도를 가지고 있기 때문에 찬 에탄올에 용해되는 용질의 양 만큼의 수율 저하를 가져오며, 또한 수율을 상승시키기 위해서는 재결정후의 여액을 재처리하는 추가의 단계를 수행하여야 하는 단점이 있다. 또한, 대한민국 공개특허공보 제 94-19708 호에 기재된 방법에서 사용하는 재결정화 용매인 이소프로판올도 에탄올과 유사한 문제점을 가지고 있어 재결정화 용매에 의한 생성물 손실의 문제점을 가지고 있다.However, in the preparation of pyridoxine 5-oxo-2-pyrrolidone carboxylate by the known method of the prior art as mentioned above, the solvent used for recrystallization of the product is pyridoxine 5-oxo-2-pyrrolidone It has a certain degree of solubility in carboxylate, so that the loss of the target product in the recrystallization process has a disadvantage that the yield is reduced. That is, for example, pyridoxine 5-oxo-2-pyrrolidone carboxyl in the method using ethanol described in, for example, Japanese Patent Application Laid-Open No. 57-14531 and corresponding Australian Patent No. 820107 as a recrystallization solvent. Since the rate has a certain degree of solubility in ethanol which is used as a recrystallization solvent even in the cooling state, the yield is reduced by the amount of solute dissolved in cold ethanol, and in order to increase the yield, the filtrate after recrystallization is reprocessed. The disadvantage is that additional steps must be performed. In addition, isopropanol, which is a recrystallization solvent used in the method described in Korean Patent Laid-Open Publication No. 94-19708, has a problem similar to that of ethanol, and thus has a problem of product loss due to the recrystallization solvent.
이에 본 발명자들은 이와 같이 재결정화 과정에서 생성물의 손실없이 피리독신 5-옥소-2-피롤리돈 카르복실레이트를 효율적으로 제조할 수 있는 방법을 개발하기 위해 집중적으로 연구를 수행하였으며, 특히 피리독신과 피로글루타민산을 알코올 용매중에서 반응시킨 다음, 여기에 생성물인 피리독신 5-옥소-2-피롤리돈 카르복실레이트를 용해시키지 않는 극성 용매를 첨가함으로써 생성물을 효과적으로 재결정화시킬 수 있을 것으로 판단하고 이러한 다양한 용매를 대상으로 연구를 수행 이에 관한 다수의 실험에 의해, 피리독신 5-옥소-2-피롤리돈 카르복실레이트를 용해시키지 않는 다양한 용매중에서 벤젠에 비해 극성이 다소 높은 에테르, 클로로포름, 디클로로메탄, 아세톤, 테트라하이드로푸란 등은 메탄올 반응용액에 다량을 첨가하여도 목적생성물을 효과적으로 재결정화시킬 수 없고, 헥산 등은 메탄올과 혼화되지 않기 때문에 메탄올 반응용액으로부터 생성물을 재결정화시키지 못하는 반면에, 벤젠은 에테르계, 할로메탄계 또는 케톤계 용매보다 더 극성이 낮은 비극성 용매로 메탄올과 혼화되어 목적생성물을 효과적으로 재결정화시킬 수 있음을 밝혀내었다. 이러한 결과로부터, 본 발명자들은 피리독신과 피로글루타민을 메탄올 용매중에서 반응시키고, 메탄올 반응용액중의 생성물을 벤젠을 가하여 재결정화시킴으로써 목적하는 피리독신 5-옥소-2-피롤리돈 카르복실레이트를 고순도로 98% 이상, 거의 100% 에 가까운 고수율로 제조할 수 있음을 확인하고 본 발명을 완성하게 되었다.In this regard, the present inventors have conducted intensive studies to develop a method for efficiently preparing pyridoxine 5-oxo-2-pyrrolidone carboxylate without loss of product during recrystallization, in particular pyridoxine and fatigue. By reacting glutamic acid in an alcoholic solvent and then adding a polar solvent that does not dissolve the product pyridoxine 5-oxo-2-pyrrolidone carboxylate it is believed that the product can be effectively recrystallized and the various solvents Studies have been conducted on a number of experiments in which ether, chloroform, dichloromethane, acetone and tetra are slightly more polar than benzene in various solvents that do not dissolve pyridoxine 5-oxo-2-pyrrolidone carboxylate. Hydrofuran and the like can be added even if a large amount is added to the methanol reaction solution. While water cannot effectively recrystallize and hexane and the like are not miscible with methanol, they do not recrystallize the product from the methanol reaction solution, while benzene is a less polar nonpolar solvent than ether, halomethane or ketone solvents. It has been found that it can be mixed with methanol to effectively recrystallize the desired product. From these results, the present inventors reacted pyridoxine and pyroglutamine in a methanol solvent, and recrystallized the product in the methanol reaction solution by adding benzene to obtain the desired pyridoxine 5-oxo-2-pyrrolidone carboxylate in high purity 98. The present invention was completed by confirming that it can be produced in high yield of about 100% or more and almost 100%.
따라서, 본 발명은 화학식 1로 표시되는 피리독신 5-옥소-2-피롤리돈 카르복실레이트의 개선된 제조방법에 관한 것이다.Accordingly, the present invention relates to an improved method for preparing pyridoxine 5-oxo-2-pyrrolidone carboxylate represented by the formula (1).
[화학식 1][Formula 1]
본 발명의 방법에 따르면 우선 피리독신과 피로글루타민산을 혼합하고, 여기에 메탄올을 가하여 가온상태에서 완전히 용해시킴으로써 반응시킨다.According to the method of the present invention, first, pyridoxine and pyroglutamic acid are mixed, and methanol is added thereto to completely react in a warm state.
반응에서 출발물질로 사용되는 피리독신은 유리염기 형태의 것일 수 있으나, 경제적인 면을 고려할 때 피리독신 염산염을 사용하는 것이 바람직하다. 피리독신 염산염을 출발물질로 사용하는 경우에는 피로글루타민산과 반응시키기 전에 우선 피리독신 염산염을 메탄올, 에탄올 등과 같은 알코올 용매에 용해시킨 후, 반응용액을 동물량의 알칼리, 예를 들면 수산화나트륨, 수산화칼륨 또는 탄산나트륨 등으로 중화시키고 여과하여 여액을 감압하에 농축시킴으로써 피리독신 유리염기 형태로 전환시킨 후에 피로글루타민산과 반응시킨다.The pyridoxine used as a starting material in the reaction may be in the form of free base, but it is preferable to use pyridoxine hydrochloride in consideration of economical aspects. In the case of using pyridoxine hydrochloride as a starting material, pyridoxine hydrochloride is first dissolved in an alcohol solvent such as methanol, ethanol, etc. before reacting with pyroglutamic acid, and then the reaction solution is made of an animal amount of alkali such as sodium hydroxide, potassium hydroxide or sodium carbonate. Neutralization and the like were filtered and the filtrate was concentrated under reduced pressure to convert into pyridoxine freebase and then reacted with pyroglutamic acid.
이 반응에서 피리독신과 피로글루타민산은 대략 동몰량으로 반응시키는 것이 바람직하다. 이 반응은 메탄올중에서 가온하여, 바람직하게는 50 내지 65 ℃ 로 가온하여, 반응물을 완전히 용해시켜 수행한다. 반응에서 메탄올은 피리독신 1몰에 대하여 15-20 몰, 바람직하게는 17-18 몰의 비로 사용할 수 있다.In this reaction, pyridoxine and pyroglutamic acid are preferably reacted in approximately equimolar amounts. This reaction is carried out by warming in methanol, preferably at 50-65 ° C., to completely dissolve the reactants. In the reaction, methanol can be used in a ratio of 15-20 mol, preferably 17-18 mol, with respect to 1 mol of pyridoxine.
반응이 끝난 후에, 반응용액을 상온으로 냉각시킨 후, 여기에 벤젠을 천천히 적가하여 생성물을 재결정화시킴으로써 목적하는 피리독신 5-옥소-2-피롤리돈 카르복실레이트를 정제된 형태로 수득한다. 이때 메탄올을 함유하는 반응용액에 비극성 용매로서 피리독신 5-옥소-2-피롤리돈 카리복실레이트이 용해하지 않는 벤젠을 가하면 극성용매인 메탄올에 용해되어 있던 생성물이 즉시 육방정형의 결정으로 석출하기 시작한다. 이 재결정화 단계에서 벤젠은 목적생성물의 최적 수율을 고려하여 반응에 사용된 메탄올에 대하여 용량기준으로 0.5 내지 2배, 바람직하게는 0.7 내지 0.8배의 비로 사용하는 것이 적합하다.After the reaction was completed, the reaction solution was cooled to room temperature, and benzene was slowly added dropwise thereto to recrystallize the product to obtain the desired pyridoxine 5-oxo-2-pyrrolidone carboxylate in purified form. At this time, if benzene which pyridoxin 5-oxo-2-pyrrolidone carboxylate does not dissolve as a nonpolar solvent is added to the reaction solution containing methanol, the product dissolved in methanol which is a polar solvent immediately starts to precipitate as a hexagonal crystal. . In this recrystallization step, benzene is suitably used in a ratio of 0.5 to 2 times, preferably 0.7 to 0.8 times, based on the capacity of methanol used in the reaction in consideration of the optimum yield of the desired product.
이 방법으로 수득되는 목적화합물은 이에 대해 공지되어 있는 IR 스펙트럼 및 NMR 스펙트럼에서의 특징적인 피이크로 확인할 수 있다.[참조: 일본국 특허출원 공개 제 (소) 57-14531 호, 호주특허 제 820107 호 및 대한민국 공개특허공보 제 94-19708 호]The target compound obtained by this method can be identified by characteristic peaks in the known IR spectrum and NMR spectrum. See Japanese Patent Application Laid-Open No. 57-14531, Australian Patent No. 820107. And Korean Patent Laid-Open Publication No. 94-19708]
본 발명의 방법에 따라 수득된 화학식 1 의 무취의 백색 결정성분말이며, 분자량이 298.28이고 융점은 96-98℃이다. 이화합물 5g을 물 50㎖에 용해시켰을때의 수소이온농도는4.0이며, 비선광도 [α]D는 -10∼-11 이다.Odorless white crystalline powder of Formula 1 obtained according to the method of the present invention, having a molecular weight of 298.28 and a melting point of 96-98 ° C. When 5 g of this compound is dissolved in 50 ml of water, the hydrogen ion concentration is 4.0, and the specific light intensity [α] D is -10 to -11.
또한 이화합물은 물에 매우 잘 용해하며, 메탄올과 뜨거운 에탄올에 용해되고, 찬 에탄올에는 조금 녹는 반면에 아세톤, 에테르, 벤젠, 클로로포름, 디클로로메탄, 테트라하이드로푸란 등의 통상적인 유기용매에는 용해하지 않는다.The compound is also very soluble in water, soluble in methanol and hot ethanol, slightly soluble in cold ethanol, but insoluble in conventional organic solvents such as acetone, ether, benzene, chloroform, dichloromethane and tetrahydrofuran. .
상술한 바와 같은 본 발명의 방법에 따르면 선행기술의 방법에서 문제시되어 온 재결정화 용매에 의한 생성물의 손실을 막을 수 있을 뿐 아니라, 극성용매인 벤젠의 첨가에 의해 목적생성물이 즉시 재결정화되기 때문에 시간의 경과에 따른 에탄올이나 이소프로판올 등의 용매의 냉각에 의해 결정화가 이루어지는 선행기술의 방법에 비해 재결정 단계에서의 시간이 현저히 단축되고, 재결정화에 사용되는 용매인 벤젠은 선행기술의 방법에서 사용된 에탄올이나 이소프로판올 등에 비해서 저렴한 가격의 용매이므로 경제적인 잇점도 제공하며, 또한 대한민국 특허공보 제 94-19708 등의 선행기술에서의 수율은 93% 정도인데 반해 본 발명에서는 약 99% 이상의 고순도의 생성물의 98% 이상 거의 정량적인 고수율을 제조할 수 있는 잇점이 제공된다.According to the method of the present invention as described above, not only can it prevent the loss of the product by the recrystallization solvent which has been a problem in the method of the prior art, but also because the target product is immediately recrystallized by the addition of benzene, a polar solvent, Compared to the prior art method in which crystallization is performed by cooling of a solvent such as ethanol or isopropanol over time, the time in the recrystallization step is significantly shortened, and benzene, which is a solvent used for recrystallization, is an ethanol used in the prior art method. Compared to the isopropanol and the like, the lower price of the solvent provides economic advantages, and the yield in the prior art, such as Korean Patent Publication No. 94-19708, is about 93%, whereas in the present invention, it is 98% of the high purity product of about 99% or more. This provides the advantage of producing a nearly quantitative high yield.
상술한 바와 같이 본 발명은 하기 실시예에 의해 더욱 구체적으로 설명되나, 본 발명은 이들 실시예에 의해 어떤 식으로든 한정되는 것은 아니다.As described above, the present invention is described in more detail by the following examples, but the present invention is not limited in any way by these examples.
[실시예 1]Example 1
염산피리독신 703.7g 을 에탄올 6ℓ에 50℃ 로 가열하여 용해시키고, 동일 온도를 계속 유지하면서 교반하며 미리 적정하여 함량을 구한 미세한 분말상의 수산화칼륨 220.7g (순수한 수산화칼륨으로 192g )을 천천히 가하였다. 1시간동안 더 교반한 후, 생성된 고체를 여과하여 제거하고 여액은 감압하에 농축시켜 고체를 형성시키고 완전히 건조시켰다. 여기에 피로글루타민산의 동몰 계산량 439.6g 을 가하여 균질하게 혼합한 후, 메탄올 2ℓ를 가하여 투명한 용액이 되도록 60℃ 로 가온하면서 약 30분 동안 교반하였다. 반응액을 상온으로 냉각한 후, 벤젠 1.5ℓ를 가하여 약 12 시간 동안 방치하였다. 생성된 고체를 여과하고 40℃에서 건조시켜 목적화합물인 피리독신 5-옥소-2-피롤리돈 카르복실레이트 약 1㎏ (수율 98.5%)을 수득하였다.703.7 g of pyridoxine hydrochloride was dissolved in 6 l of ethanol at 50 ° C., and 220.7 g of fine powdered potassium hydroxide (192 g of pure potassium hydroxide) was slowly added while stirring and maintaining the same temperature to determine the content. After further stirring for 1 hour, the resulting solid was filtered off and the filtrate was concentrated under reduced pressure to form a solid and dried completely. 439.6 g of an equimolar calculated amount of pyroglutamic acid was added thereto, followed by homogeneous mixing. Then, 2 L of methanol was added thereto, followed by stirring for about 30 minutes while being heated to 60 ° C. to give a clear solution. After the reaction solution was cooled to room temperature, 1.5 L of benzene was added thereto and left for about 12 hours. The resulting solid was filtered and dried at 40 ° C. to obtain about 1 kg (yield 98.5%) of the target compound pyridoxine 5-oxo-2-pyrrolidone carboxylate.
[실시예 2]Example 2
염산피리독신 1㎏을 에탄올 7.5ℓ에 50℃ 로 가온하여 용해시키고, 동일온도를 계속 유지하면서 교반하며 98% 수산화나트륨 198.2g을 천천히 가하였다. 1 시간 동안 더 교반한 후, 생성된 고체를 여과하여 제거하고 여액은 감압하에 농축시켜 고체를 형성시키고 완전히 건조시켰다. 여기에 피로글루타민산의 동몰 계산량 627.9g을 가하여 균질하게 혼합한 후, 메탄올 2.5ℓ를 가하여 투명한 용액이 되도록 60℃ 로 가온하면서 약 30분 동안 교반하였다. 반응액을 상온으로 냉각한 후, 벤젠 1.8ℓ를 가하여 약 12 시간 동안 방치하였다. 생성된 고체를 여과하고 40℃에서 건조시켜 목적화합물인 피리독신 5-옥소-2-피롤리돈 카르복실레이트 약 1.428㎏(수율 98.5%)을 수득하였다.1 kg of pyridoxine hydrochloride was dissolved in 7.5 L of ethanol by heating to 50 DEG C, and 198.2 g of 98% sodium hydroxide was slowly added while stirring while maintaining the same temperature. After further stirring for 1 hour, the resulting solid was filtered off and the filtrate was concentrated under reduced pressure to form a solid and dried completely. To this, 627.9 g of an equimolar amount of pyroglutamic acid was added and mixed homogeneously, and 2.5 liters of methanol were added thereto, followed by stirring for about 30 minutes while heating to 60 ° C. to make a clear solution. After the reaction solution was cooled to room temperature, 1.8 L of benzene was added thereto and left for about 12 hours. The resulting solid was filtered and dried at 40 ° C. to yield about 1.428 kg (yield 98.5%) of the target compound pyridoxine 5-oxo-2-pyrrolidone carboxylate.
[실시예 3]Example 3
염산피리독신 1㎏을 에탄올 7.5ℓ에 50℃ 로 가온하여 용해시키고, 동일온도를 계속 유지하면서 교반하며 무수 탄산나트륨(99%) 287.7g을 천천히 가하였다. 기체의 발생이 없어질 때까지 교반한 후, 반응액을 여과하여 침전을 제거하고 여액은 감압하에 농축시켜 고체를 형성시켰다. 여기에 피로글루타민산의 동몰 계산량 627.9g을 가하여 균질하게 혼합한 후, 메탄올 2.5ℓ를 가하여 투명한 용액이 되도록 60℃ 로 가온하면서 약 30 분 동안 교반하였다. 반응액을 상온으로 냉각한 후, 벤젠 1.8ℓ를 가하여 약 12 시간 동안 방치하였다. 생성된 고체를 여과하고 40℃에서 건조시켜 목적화합물인 피리독신 5-옥소-2-피롤리돈 카르복실레이트 약1.4355㎏(수율 99%)을 수득하였다.1 kg of pyridoxine hydrochloride was dissolved in 7.5 L of ethanol by heating to 50 DEG C, and 287.7 g of anhydrous sodium carbonate (99%) was slowly added while stirring while maintaining the same temperature. After stirring until gas evolution disappeared, the reaction solution was filtered to remove precipitate and the filtrate was concentrated under reduced pressure to form a solid. To this, 627.9 g of an equimolar amount of pyroglutamic acid was added and mixed homogeneously, and 2.5 liters of methanol were added thereto, followed by stirring for about 30 minutes while heating to 60 ° C. to make a clear solution. After the reaction solution was cooled to room temperature, 1.8 L of benzene was added thereto and left for about 12 hours. The resulting solid was filtered and dried at 40 ° C. to obtain about 1.4355 kg (yield 99%) of the target compound pyridoxine 5-oxo-2-pyrrolidone carboxylate.
상술한 바와 같이, 본 발명의 방법에 따르면 재결정화 용매에 의한 생성물의 손실을 막고, 재결정 단계에서의 시간이 현저히 단축되고, 재결정화 용매로 저렴한 가격의 벤젠을 사용하므로 경제적인 잇점도 제공되며, 또한 목적생성물을 고순도, 고수율로 제조할 수 있으므로, 피리독신 5-옥소-2-피롤리돈 카르복실레이트 제조분야에서의 명백한 진보성을 제공한다.As mentioned above, according to the method of the present invention, the loss of the product by the recrystallization solvent, the time in the recrystallization step is significantly shortened, and economical advantages are provided because low-cost benzene is used as the recrystallization solvent, In addition, the desired product can be prepared in high purity, high yield, thus providing a clear advance in the field of pyridoxine 5-oxo-2-pyrrolidone carboxylate preparation.
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