KR100545002B1 - Process for the preparation of 2-2-thenoylthiopropionylglycine sodium - Google Patents
Process for the preparation of 2-2-thenoylthiopropionylglycine sodium Download PDFInfo
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- KR100545002B1 KR100545002B1 KR1020030010080A KR20030010080A KR100545002B1 KR 100545002 B1 KR100545002 B1 KR 100545002B1 KR 1020030010080 A KR1020030010080 A KR 1020030010080A KR 20030010080 A KR20030010080 A KR 20030010080A KR 100545002 B1 KR100545002 B1 KR 100545002B1
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- sodium
- ethylhexanoate
- tennochiola
- propionylglycine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
본 발명은 급성 및 만성 기관지 염의 치료에 이용되는 테노치올라 소디움, 화학명 2-(2-테노일치오)-프로피오닐글리신 소디움의 신규한 제조방법에 관한 것이다.The present invention relates to a novel process for the preparation of Tennocchiola sodium, chemical name 2- (2-Tenoylchio) -propionylglycine sodium, for use in the treatment of acute and chronic bronchitis.
본 발명의 제조방법은 소디움 2-에틸헥사노에이트를 이용하는 것을 특징으로 하며, 테노치올라를 용매중에서 소디움 2-에틸헥사노에이트와 반응시킴으로써 짧은 시간내에 또한 적은 양의 용매만으로도 용이하게 목적 물질을 제조할 수 있으며, 부산물의 생성없이 고수율 및 고순도의 목적 물질을 간편하고 매우 용이하게 제조할 수 있어 공업적으로 특히 이용가치가 높다.The production method of the present invention is characterized by using sodium 2-ethylhexanoate, and reacting tennochiola with sodium 2-ethylhexanoate in a solvent to easily prepare a target substance in a short time and with a small amount of solvent. It can be produced, and the production of high yield and high purity of the target material can be produced easily and very easily without the production of by-products, and thus the industrial value is particularly high.
2-(2-테노일치오)-프로피오닐글리신 소디움, 테노치올라 소디움, 테노치올라, 소디움 2-에틸헥사노에이트2- (2-tenoylchio) -propionylglycine sodium, tenorchiola sodium, tenorchiola, sodium 2-ethylhexanoate
Description
본 발명은 테노치올라 소디움(Thenothiola Sodium)으로 명명되는 하기 화학식 (1)의 2-(2-테노일치오)-프로피오닐글리신 소디움의 신규한 제조방법에 관한 것이다.The present invention relates to a novel process for the preparation of 2- (2-tennoylchio) -propionylglycine sodium of formula (1), named Thenothiola Sodium.
테노치올라는 화학명이 2-(2-테노일치오)-프로피오닐글리신인 공지의 화합물로서, 과다분비인자에 의한 급성 및 만성 호흡기질환(기관지염, 페기종, 중이염, 비염, 후두염 등)에 효과적인 약물로 알려져 있다. 테노치올라 및 이의 염은 정제, 캅셀제, 주사용앰플, 좌제 등의 형태로 제제화되어 사용되고 있다. 테노치올라의 제조방법은 미국특허 제4,242,354호 및 제4,363,920호에 상세히 개시되어 있다. 미국특허 제4,242,354호는 2-(2-테노일치오)프로피오닐글리신과 그 염, 그의 제조방법 및 이들을 함유하는 약학제제에 대한 것으로, 메르캅토프로피오닐 글리신 분산용액에 포타슘카보네이트 및 티오펜-2-카복실산 클로라이드를 차례로 가하고, 산성화, 여과, 건조 및 아세토니트릴 재결정화 과정을 거쳐 목적 화합물인 테노치올라를 얻는 것을 특징으로 하고 있다. 미국특허 제4,363,920호는 N-[2-(2-테노일)치오프로피오닐]글리신의 제조방법에 대한 것으로, 2-(2-티노일)치오프로피온산의 활성 유도체로 글리신을 N-아실화함으로써 순수하고 안정한 N-[2-(2-테노일)치오프로피오닐]글리신을 얻는 방법을 제시하고 있다.Tennocchiola is a known compound with the chemical name 2- (2-tenoylchio) -propionylglycine, and is effective against acute and chronic respiratory diseases (bronchitis, pedis, otitis, rhinitis, laryngitis, etc.) caused by oversecretion factors. Known as a drug. Tennochiola and its salts are formulated and used in the form of tablets, capsules, injectable ampoules, suppositories, and the like. Methods of making Tennochiola are described in detail in US Pat. Nos. 4,242,354 and 4,363,920. U.S. Pat. No. 4,242,354 relates to 2- (2-tenoylthio) propionylglycine and its salts, methods for preparing the same, and pharmaceutical preparations containing them, wherein potassium carbonate and thiophene-2 are contained in a mercaptopropionyl glycine dispersion solution. Carboxylic acid chloride is added sequentially, followed by acidification, filtration, drying and acetonitrile recrystallization to obtain tenochiola as the target compound. U.S. Patent No. 4,363,920 relates to a process for the preparation of N- [2- (2-tenoyl) chioplopionyl] glycine by N-acylating glycine as the active derivative of 2- (2-tinoyl) chioplopionic acid. A method for obtaining pure and stable N- [2- (2-tenoyl) chioplopionyl] glycine is provided.
또한, 미국특허 제 4,346,234호는 2-메르캅토프로피오닐글리신(2-mercaptopropionylglycine)을 소디움-2-에틸헥사노에이트와 반응시킴으로써, 흡입제 또는 좌제의 형태로 제제화하어 간세포 보호제 및 점액용해제로써 이용가능한 메르캅토프로피오닐글리신 소디움염의 제조방법에 대해 개시하고 있다.In addition, U.S. Patent No. 4,346,234 discloses a mer that can be formulated in the form of an inhalant or suppository by reacting 2-mercaptopropionylglycine with sodium-2-ethylhexanoate to be used as a hepatocyte protector and mucolytic agent. A method for preparing captopropionylglycine sodium salt is disclosed.
본 발명의 화학식 (I)의 2-(2-테노일치오)-프로피오닐글리신 소디움(이하, 테노치올라 소디움이라 함)은 치올기(-SH기)를 티오-에스테르 결합(thio-esteric bond)시킨 화합물로서, -SH기가 점액의 점액 단백섬유를 절단하여 점액의 탄력성과 점성을 정상화시켜 점액섬모수송(mucociliary transport)을 촉진시키는 작용을 한 다. 진해작용, 소염작용, 항기관지경력 작용을 가지며, 과다분비 인자에 의한 호흡기계의 감염성 및 염증성 제 질환의 치료, 부비강염, 삼출성중이염, 비염, 후두기관염의 치료 및 기관지 수술 전후 합병증의 예방 및 치료에 이용되는 화합물이다. 2- (2-Tenoylchio) -propionylglycine sodium of the present invention (hereinafter referred to as tennochiola sodium) is a thio-esteric bond with a thiol group (-SH group). As a compound, -SH groups act to promote mucociliary transport by cutting the mucus protein fibers of the mucus to normalize the elasticity and viscosity of the mucus. It has antitussive action, anti-inflammatory action, anti-bronchial action, and treatment of infectious and inflammatory diseases of the respiratory system by hypersecretory factors, sinusitis, exudative otitis media, rhinitis, laryngeal bronchitis and prevention and treatment of complications before and after bronchial surgery. Compound to be used.
테노치올라 소디움의 제조방법과 관련한 선행기술은 알려져 있지 않으며, 일반적으로 테노치올라를 수용성 또는 메탄올성의 수산화나트륨 용액과 반응시킴으로써 테노치올라 소디움을 얻는 제조방법이 사용되고 있다. There is no known prior art relating to the production of Tennochiola sodium, and generally a production method of obtaining Tennochiola Sodium by reacting Tennochiola with a water-soluble or methanolic sodium hydroxide solution is used.
그러나, 상기 제조방법은 가열시키는 단계, 용매를 감압증류하는 단계 등을 포함하여 그 공정이 복잡하고, 새로운 용매를 가해야 하는 등의 이유로 불편하고 효율적이지 못하였다. 또한, 강한 염기의 사용, 온화하지 못한 반응조건 등으로 인해 치오에스테르 부분의 가수분해가 쉽게 일어나 화학식 (II) 및 화학식 (III)의 부산물들이 생성된다는 문제점이 있었다. 이로 인해 목적물질의 수율이 감소하고, 부산물로 인해 순도가 낮아져 이를 극복하기 위한 추가의 정제과정을 도입해야 하는 등의 비효율적인 문제점들이 있었다.However, the manufacturing method is inconvenient and inefficient due to the complicated process, including the step of heating, distilling the solvent under reduced pressure, and the like to add a new solvent. In addition, due to the use of a strong base, unfavorable reaction conditions, there is a problem that the hydrolysis of the cheoester portion easily occurs to produce by-products of the formulas (II) and (III). As a result, the yield of the target material is reduced, and the purity is lowered due to the by-products, and there are inefficient problems such as the introduction of an additional purification process to overcome this problem.
이에 본 발명자들은 오랫동안 지속적인 연구를 수행한 결과, 테노치올라를 용매중에서 소디움 2-에틸헥사노에이트와 반응시킴으로써 복잡한 공정이나 부반응이 없이 짧은 시간내에 또한 적은 양의 용매만으로도 용이하게 고순도 및 고수율의 테노치올라 소디움을 제조할 수 있을 뿐더러, 공업적으로 특히 이용가치가 높은 본 발명을 완성하게 되었다.Accordingly, the inventors have conducted a long and continuous study, and the reaction of tennochiola with sodium 2-ethylhexanoate in a solvent makes it easy to obtain high purity and high yield easily in a short time and in a small amount of solvent, without complicated processes or side reactions. In addition to being able to manufacture Tennochiola Sodium, the present invention has been completed in the industrially particularly high value.
따라서, 본 발명의 목적은 종래기술의 문제점들을 해결하여 보다 개선된 테노치올라 소디움 제조방법을 제공하는 것이다.
Accordingly, it is an object of the present invention to solve the problems of the prior art and to provide an improved method for producing Tennochiola sodium.
상기 목적을 달성하기 위하여, 본 발명은 소디움 2-에틸헥사노에이트를 이용하는 것을 특징으로 하는 하기 화학식 (I)의 2-(2-테노일치오)-프로피오닐글리신 소디움의 신규한 제조방법을 제공한다.In order to achieve the above object, the present invention provides a novel method for preparing 2- (2-tenoylthio) -propionylglycine sodium of formula (I) characterized in that using sodium 2-ethylhexanoate do.
이하, 본 발명을 보다 구체적으로 설명하면 다음과 같다.Hereinafter, the present invention will be described in more detail.
본 발명의 제조방법은 화학식 (IV)의 테노치올라를 용매중에서 소디움 2-에틸헥사노에이트와 반응시켜 목적물질인 테노치올라 소디움을 제조하는 것을 특징으로 한다. The preparation method of the present invention is characterized in that tenenochiola sodium of formula (IV) is reacted with sodium 2-ethylhexanoate in a solvent to prepare tennochiola sodium as a target substance.
본 발명의 제조 공정은 하기의 반응식에 도시된 방법에 의해 화학적으로 합성될 수 있지만, 이 예로만 한정되는 것은 아니며, 당업자들에 의해 숙지된 시약 및 출발물질의 적당한 변화에 의해 제조될 수 있다.The preparation process of the present invention can be chemically synthesized by the method shown in the following scheme, but is not limited to this example, it can be prepared by appropriate changes in the reagents and starting materials known to those skilled in the art.
본 발명에서 출발물질로 사용되는 테노치올라는 공지의 화합물이며, 이는 적당한 정제과정을 거친 다음 사용할 수 있다.Tennochiol, which is used as a starting material in the present invention, is a known compound, which may be used after proper purification.
용매로는 아세톤, 아세토니트릴, 에틸아세테이트, 클로로포름, 에탄올, 톨루엔 또는 이들의 혼합용매를 사용하는 것이 바람직하며, 보다 바람직하게는, 아세톤, 에틸아세테이트, 톨루엔 또는 이들의 혼합용매를 사용할 수 있다.It is preferable to use acetone, acetonitrile, ethyl acetate, chloroform, ethanol, toluene or a mixed solvent thereof, and more preferably, acetone, ethyl acetate, toluene or a mixed solvent thereof can be used.
소디움염을 얻기 위하여 소디움이온을 함유한 염을 사용하는 것이 바람직하며, 보다 바람직하게는 소디움 2-에틸헥사노에이트를 사용할 수 있다. 소디움 2-에틸헥사노에이트는 용매에 손쉽게 용해되며, 본 발명에서 출발물질로 사용되는 테노치올라와의 반응성이 매우 우수하다. It is preferable to use a salt containing sodium ions in order to obtain a sodium salt, more preferably sodium 2-ethylhexanoate can be used. Sodium 2-ethylhexanoate is easily soluble in a solvent and has a very good reactivity with tenochiola, which is used as a starting material in the present invention.
소디움 2-에틸헥사노에이트는 테노치올라에 대해 0.99 몰당량 내지 2 몰당량으로 사용하는 것이 바람직하고, 보다 바람직하게는 1 몰당량 내지 1.1 몰당량이다.Sodium 2-ethylhexanoate is preferably used in an amount of 0.99 to 2 molar equivalents, more preferably 1 to 1.1 molar equivalents, relative to tenochiola.
또한, 상기 반응은 0 내지 80℃에서 실행되는 것이 바람직하며, 반응시간은 1~2시간이 바람직하다.In addition, the reaction is preferably carried out at 0 to 80 ℃, the reaction time is preferably 1 to 2 hours.
본 발명은 하기의 실시예들에 의해 보다 더 잘 이해될 수 있으며, 하기의 실시예는 본 발명을 예시하기 위한 것이며 한정되는 보호범위를 제한하고자 하는 것은 아니다.The invention can be better understood by the following examples, which are intended to illustrate the invention and are not intended to limit the scope of protection.
실시예 1Example 1
소디움 2-에틸헥사노에이트 85g을 에틸아세테이트 1L에 현탁시킨 후 테노치올라 137g을 가하였다. 생성된 현탁액을 40℃ 까지 가하여 완전 용해 시킨 후 2시간 동안 교반하였다. 반응 혼합물을 0 내지 10℃로 냉각하여 1시간 교반 시킨 후 생성된 고체를 여과하고 에틸아세테이트 500ml로 세척한 뒤 감압건조하여 목적 물질인 테노치올라 소디움 133g(90%)을 수득하였다.85 g of sodium 2-ethylhexanoate was suspended in 1 L of ethyl acetate, followed by addition of 137 g of Tennochiola. The resulting suspension was added to 40 ° C. to complete dissolution and stirred for 2 hours. The reaction mixture was cooled to 0 to 10 ° C., stirred for 1 hour, and the resulting solid was filtered, washed with 500 ml of ethyl acetate, and dried under reduced pressure to obtain 133 g (90%) of Tennochiola sodium as a target substance.
HPLC 순도 : 99.5%HPLC purity: 99.5%
실시예 2Example 2
소디움 2-에틸헥사노에이트 85g을 톨루엔 500ml에 현탁 시킨 후 테노치올라 137g을 가하였다. 생성된 현탁액을 60℃ 까지 가하여 완전 용해 시킨 후 2시간 동안 교반 하였다. 반응 혼합물을 0 내지 10℃로 냉각하여 에틸아세테이트 1L를 가하 여 1시간 교반시켜 생성된 고체를 여과하고 에틸아세테이트 500ml로 세척한 뒤 감압건조하여 목적 물질인 테노치올라 소디움 138g(93%)을 수득하였다.85 g of sodium 2-ethylhexanoate was suspended in 500 ml of toluene, and then 137 g of tenochiola was added. The resulting suspension was added to 60 ° C., completely dissolved, and stirred for 2 hours. The reaction mixture was cooled to 0 to 10 ° C., 1 L of ethyl acetate was added, and the resultant was stirred for 1 hour. The resulting solid was filtered, washed with 500 ml of ethyl acetate, and dried under reduced pressure to obtain 138 g (93%) of Tennochiola sodium as a target substance. It was.
HPLC 순도 : 99.7%HPLC purity: 99.7%
본 발명의 제조방법에 따라 소디움 2-에틸헥사노에이드를 이용함으로써, 짧은 시간내에 또한 적은 양의 용매만으로도 용이하게 목적 물질을 제조할 수 있으며, 부산물의 생성없이 고수율 및 고순도의 목적 물질을 간편하고 매우 용이하게 제조할 수 있어 공업적으로 특히 이용가치가 높다.
By using sodium 2-ethylhexanoate according to the preparation method of the present invention, the target material can be easily produced in a short time and with only a small amount of solvent, and the target material of high yield and high purity can be easily produced without generating by-products. It can be manufactured very easily, and industrially it is especially high in use value.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020030010080A KR100545002B1 (en) | 2003-02-18 | 2003-02-18 | Process for the preparation of 2-2-thenoylthiopropionylglycine sodium |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020030010080A KR100545002B1 (en) | 2003-02-18 | 2003-02-18 | Process for the preparation of 2-2-thenoylthiopropionylglycine sodium |
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| Publication Number | Publication Date |
|---|---|
| KR20040074699A KR20040074699A (en) | 2004-08-26 |
| KR100545002B1 true KR100545002B1 (en) | 2006-01-24 |
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| KR1020030010080A KR100545002B1 (en) | 2003-02-18 | 2003-02-18 | Process for the preparation of 2-2-thenoylthiopropionylglycine sodium |
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| Country | Link |
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| KR (1) | KR100545002B1 (en) |
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