KR20050032683A - A process for preparing erdosteine - Google Patents
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- KR20050032683A KR20050032683A KR1020030068605A KR20030068605A KR20050032683A KR 20050032683 A KR20050032683 A KR 20050032683A KR 1020030068605 A KR1020030068605 A KR 1020030068605A KR 20030068605 A KR20030068605 A KR 20030068605A KR 20050032683 A KR20050032683 A KR 20050032683A
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Abstract
본 발명은 급성 및 만성 호흡기 질환 치료제로 사용되는 일반명 에르도스테인(Erdosteine), 즉, 다음 구조식(I)의 [(2-옥소-3-테트라히드로티에닐카바모일)-메틸티오]아세트산의 제조방법에 관한 것으로서, 다음 구조식(II)의 D,L-호모시스테인 티오락톤 염산염과 구조식(III)의 클로로아세틸 클로라이드를 반응시켜 다음 구조식(IV)의 3-클로로아세트아미도-2-옥소-테트라히드로티오펜을 제조하는 단계와, 구조식(IV)화합물을 구조식(V)의 티오글리콘산과 반응시켜 다음 구조식(I)의 에르도스테인을 제조하는 단계로 구성된 에르도스테인의 제조 방법에 있어서, 상기 모든 단계의 반응은 염기성 수용액과 유기용매로 이루어진 이상(Two-phase)용액 중에서 각 단계의 반응물을 -10 ~ 20℃의 온도로 2 ~ 3시간 동안 반응시킴으로써 진행되는 것을 특징으로 한다. The present invention relates to a generic name Erdosteine, ie, [(2-oxo-3-tetrahydrothienylcarbamoyl) -methylthio] acetic acid of the formula (I), used as a therapeutic agent for acute and chronic respiratory diseases. A method for preparing the compound, wherein D, L-homocysteine thiolactone hydrochloride of the following formula (II) is reacted with chloroacetyl chloride of the formula (III) to form 3-chloroacetamido-2-oxo- of the following formula (IV) A method for producing erthostein, comprising the steps of preparing tetrahydrothiophene, and reacting a compound of formula (IV) with thioglyconic acid of formula (V) to produce erdostein of formula (I) , The reaction of all the steps is characterized in that by reacting the reactants of each step in a two-phase solution consisting of a basic aqueous solution and an organic solvent for 2 to 3 hours at a temperature of -10 ~ 20 ℃.
Description
본 발명은 에르도스테인의 제조방법에 관한 것으로서, 특히 모든 반응 공정을 염기성 수용액과 유기용매로 이루어진 이상(Two-phase)용액 중에서 수행함으로서, 종래 기술에 비해 고순도의 목적 물질을 고수율로 제조할수 있는 에르도스테인의 새로운 제조방법에 관한 것이다. The present invention relates to a process for producing erdostein, in particular, by performing all the reaction process in a two-phase solution consisting of a basic aqueous solution and an organic solvent, it is possible to produce a high purity target material in high yield compared to the prior art The present invention relates to a new process for producing erdostein.
일반명 에르도스테인(Erdosteine)으로 잘 알려진 다음 구조식(I)의 [(2-옥소-3-테트라히드로티에닐카바모일)-메틸티오]아세트산은 급성 및 만성 호흡기 질환 치료제로 사용되는 공지의 의약물질로서, 국내에서도 '엘도스(ERDOR)'라는 상품명으로 시판되고 있다.[(2-oxo-3-tetrahydrothienylcarbamoyl) -methylthio] acetic acid of the following structural formula (I), well known by the common name Erdosteine, is a known medicament used for treating acute and chronic respiratory diseases. As a substance, it is also marketed under the trade name 'ERDOR' in Korea.
종래 미국특허 제 4,411,909 호에는 다음과 같은 공정으로 이루어진 에르도스테인 제법이 소개되어 있다, 이러한 제조 방법은 우선, 다음 구조식(II)의 D,L-호모시스테인 티오락톤 염산염과 다음 구조식(III)의 클로로아세틸 클로라이드를 염기성 조건하에서 반응시켜서 다음 구조식(IV)의 3-클로로아세트아미도-2-옥소-테트라히드로티오펜을 제조하고, 이어서 구조식(IV)화합물과 다음 구조식(V)의 티오글리콜린산을 염기성 조건하에서 반응시켜 구조식(I)의 에르도스테인을 제조하는 방법이다. Conventional US Patent No. 4,411,909 introduces an erdostein method, which consists of the following steps. First, this preparation method is performed by first preparing D, L-homocysteine thiolactone hydrochloride of the following formula (II) and Chloroacetyl chloride was reacted under basic conditions to prepare 3-chloroacetamido-2-oxo-tetrahydrothiophene of formula (IV), followed by the compound of formula (IV) and thioglycolic acid of formula (V) Is reacted under basic conditions to produce erdostein of Structural Formula (I).
그러나, 상기 미국특허에 소개된 제법은 전 반응공정이 강한 염기성 조건 하에서 진행되기 때문에 반응과정에서 락톤링이 분해된 반응 부산물이 생기며, 이로 인하여 구조식(IV)화합물을 제조하는 제1단계 반응의 수율은 72%, 최종 목적물질을 제조하는 제2단계 반응의 수율은 48%로서 전체 수율이 단지 35%에 불과하여 상업적으로 경제성이 없는 제법이었다. However, the production method introduced in the U.S. patent produces reaction by-products in which the lactone ring is decomposed in the reaction process because the entire reaction process proceeds under strong basic conditions, thereby yielding a first stage reaction for preparing the compound of formula (IV). The yield of the second stage reaction to produce 72% silver, the final target material was 48% and the total yield was only 35%, making it a commercially uneconomical process.
보다 진보된 방법으로서 국내특허 제 278119 호에는 다음 구조식(VI)의 티오디글리콘산을 트리에틸아민과 같은 유기염기 존재하에서 에틸클로로포르메이트와 반응시켜 활성화 시킨 후, 다음 구조식(II)의 D,L-호모시스테인 티오락톤 염산염과 반응하여 목적물질인 구조식(I)화합물을 제조하는 방법이 소개되어 있다.As a more advanced method, Korean Patent No. 278119 discloses that thiodiglyconic acid of the following formula (VI) is activated by reaction with ethylchloroformate in the presence of an organic base such as triethylamine, and then D of the following formula (II) A method for preparing a compound of formula (I) as a target substance by reacting with, L-homocysteine thiolactone hydrochloride is presented.
그러나, 이 국내특허에 소개된 방법은 구조식(VI)의 티오디글리콘산과 에틸클로로포르메이트을 반응시킬 때, 한쪽 부분의 카르복시기만 활성화되는 것이 아니라 양쪽의 카르복시기가 모두 활성화가 되기 때문에 부산물이 생길 가능성이 높으며, 또한 트리에틸아민과 같은 유기용매를 사용함으로서 부생성물이 발생하여 반드시 정제과정을 거쳐야 하는 단점(수율 70∼75%)이 있고, 특히 구조식(VI)의 티오디글리콘산과 같은 고가의 화합물을 사용하기 때문에 경제적으로도 비효율적인 제법이었다.However, the method introduced in this domestic patent, when reacting thiodiglyconic acid of the formula (VI) and ethyl chloroformate, not only the carboxyl group of one portion but also the activation of both carboxyl groups are likely to occur by-products In addition, by using an organic solvent, such as triethylamine, there is a disadvantage (by yield 70-75%) that a by-product is generated and undergoes a purification process, in particular, expensive such as thiodiglyconic acid of formula (VI) Because of the use of the compound, it was economically inefficient.
이외에도, 국내 특허공개 제 2002-0068140 호에 따르면, 다음 구조식(VII)의 티오디글리콘산 무수물을 트리에틸아민과 같은 유기염기 존재하에서 다음 구조식(II)의 D,L-호모시스테인 티오락톤 염산염과 반응하여 목적 화합물(I)을 생성시키는 방법이 소개되어 있다. In addition, according to Korean Patent Publication No. 2002-0068140, the thiodiglyconic anhydride of the following formula (VII) is added to the D, L-homocysteine thiolactone hydrochloride of the following formula (II) in the presence of an organic base such as triethylamine. A method of producing the desired compound (I) by reaction with is introduced.
그러나, 이 방법에서 반응물질로 사용되는 상기 구조식(VII)의 티오디글리콘산 무수물은 상기 구조식(VI)의 티오디글리콘산을 활성화한 것에 불과하여 결국 고가인 구조식(VI)화합물을 사용해야 하며, 트리에틸아민과 같은 유기염기를 사용함에 따라 부생성물이 발생하기 때문에 반드시 정제과정을 거쳐야 하는 등, 이 방법 역시 경제적으로 비효율적인 합성방법이었다. However, the thiodiglyconic anhydride of the formula (VII) used as a reactant in this method only activates the thiodiglyconic acid of the formula (VI) and eventually requires the use of the expensive compound of the formula (VI). In addition, by using an organic base such as triethylamine, by-products are generated, and thus must be purified. This method is also an economically inefficient synthesis method.
이에, 본 발명자들은 상기와 같은 종래 기술의 문제점을 개선하기 위하여 연구 노력한 결과, 기본적으로 상기 미국특허 제 4,411,909 호와 동일한 공정으로 에르도스테인을 제조하되, 전체의 반응 공정을 염기성 수용액과 유기용매로 이루어진 이상(Two-phase)용액에서 진행시키므로서, 부산물의 생성을 억제하고 안전하면서도 경제적으로 고순도의 에르도스테인을 제조하는 방법을 개발하게 되었다. Therefore, the present inventors have been researched to improve the problems of the prior art, as a result, to prepare the ersteine basically the same process as the US Patent No. 4,411,909, the entire reaction process with a basic aqueous solution and an organic solvent By proceeding in a two-phase solution, a method of suppressing the production of by-products and producing safe and economically high-purity ersteines has been developed.
이러한 목적을 달성하기 위한 본 발명의 에르도스테인 제조 방법은 다음 구조식(II)의 D,L-호모시스테인 티오락톤 염산염과 구조식(III)의 클로로아세틸 클로라이드를 반응시켜 다음 구조식(IV)의 3-클로로아세트아미도-2-옥소-테트라히드로티오펜을 제조하는 단계와, 구조식(IV)화합물을 구조식(V)의 티오글리콘산과 반응시켜 다음 구조식(I)의 에르도스테인을 제조하는 단계로 구성된 에르도스테인의 제조 방법에 있어서, 상기 모든 단계의 반응은 염기성 수용액과 유기용매로 이루어진 이상(Two-phase)용액 중에서 각 단계의 반응물을 -10 ~ 20℃의 온도로 2 ~ 3시간 동안 반응시킴으로써 진행되는 것을 특징으로 한다.Erdostein preparation method of the present invention for achieving this object is the reaction of D, L-homocysteine thiolactone hydrochloride of the formula (II) with chloroacetyl chloride of the formula (III) 3- Preparing chloroacetamido-2-oxo-tetrahydrothiophene, and reacting a compound of formula (IV) with thioglyconic acid of formula (V) to prepare erdostein of formula (I) In the method of preparing the erdostein consisting of, the reaction of all the steps in the two-phase solution consisting of a basic aqueous solution and an organic solvent to react the reactants of each step at a temperature of -10 ~ 20 ℃ for 2 to 3 hours It is characterized by proceeding by.
이하, 본 발명을 상세히 설명하면 다음과 같다. Hereinafter, the present invention will be described in detail.
본 발명은 기본적으로 상기 미국특허 제4,411,909호와 동일한 공정으로 에르도스테인을 제조하되, 모든 반응공정을 염기성 수용액과 유기용매로 이루어진 이상(Two-phase)용액 중에서 반응시킨다는데 그 특징이 있다. 본 발명에 따른 염기성 수용액에 사용 가능한 염기로는 어떠한 형태의 무기염도 가능하지만, 바람직하기로는 소듐 히드록사이드, 포타슘 히드록사이드, 소듐 카보네이트, 포타슘 카보네이트를 사용하는 것이 좋다. 또한, 유기용매로는 극성용매가 바람직하나, 보다 바람직하게는 비양성자성 용매가 적당하고, 그 예로는 아세톤, 에틸아세테이트, 디클로로메탄, 클로로포름 등을 들 수 있다. The present invention basically prepares erdostein in the same process as US Pat. No. 4,411,909, but all the reaction processes are characterized in that the reaction in a two-phase solution consisting of a basic aqueous solution and an organic solvent. As the base usable in the basic aqueous solution according to the present invention, any form of inorganic salt may be used. Preferably, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate are used. The organic solvent is preferably a polar solvent, more preferably an aprotic solvent, and examples thereof include acetone, ethyl acetate, dichloromethane and chloroform.
본 발명의 또 다른 특징은 -20 ∼ 50℃, 바람직하게는 -10 ∼ 20℃의 온도범위에서 2 ∼ 3시간 내에 반응시키는 것이다. 이때, 반응온도가 -10℃ 이하이면, 반응성이 저하되어 반응시간이 오래 걸리는 단점이 있고, 반대로 20℃ 이상이 되면 염기에 의한 락톤링의 분해물이 다량 발생하여 수율이 크게 저하되는 문제가 발생한다. 또한, 반응시간이 2시간 이하이면 아직 반응이 충분히 진행되지 않은 상태이고, 3시간을 경과하면 염기조건 하에서 락톤링이 매우 불안정하기 때문에 락톤링이 분해되는 문제가 발생한다.Another feature of the present invention is to react within 2 to 3 hours at a temperature range of -20 to 50 ° C, preferably -10 to 20 ° C. At this time, if the reaction temperature is -10 ℃ or less, there is a disadvantage in that the reactivity is lowered and the reaction takes a long time, on the contrary, when the reaction temperature is 20 ℃ or more, a large amount of decomposition products of the lactone ring by the base is generated, which causes a large decrease in yield. . In addition, if the reaction time is 2 hours or less, the reaction has not been sufficiently progressed yet, and after 3 hours, the lactone ring is very unstable under the basic conditions, causing a problem of decomposing the lactone ring.
이러한 본 발명에 따르면, 종래의 기술과는 달리 염기에 의한 락톤링의 분해물을 0.5%이하(HPLC 순도)로 줄일 수 있어서 별도의 정제과정이 불필요하며, 수율도 전체수율 75%의 고수율로 목적 화합물을 간편하게 제조할 수 있다. According to the present invention, unlike the prior art, it is possible to reduce the decomposition products of the lactone ring by the base to 0.5% or less (HPLC purity), so that no separate purification process is required, and the yield is a high yield of 75% of the overall yield. Compounds can be prepared simply.
이하, 본 발명에 대한 실시예를 들어보면 다음과 같다. 그러나 다음 실시예가 본 발명의 범위를 제한하는 것은 아니다. Hereinafter, examples of the present invention will be described. However, the following examples do not limit the scope of the invention.
실시예 1Example 1 ; 3-클로로아세트아미도-2-옥소-테트라히드로티오펜의 합성 ; Synthesis of 3-chloroacetamido-2-oxo-tetrahydrothiophene
195g의 소듐히드록사이드를 정제수 750ml에 용해하고 아세톤 310ml를 가하여 이상(two-phase)용액을 만든 후, 10℃ 까지 냉각하여 D,L-호모시스테인 티오락톤 염산염 750g을 가하였다. 상기 이상용액을 30분 가량 교반하고, -5℃ 까지 냉각하여 소듐히드록사이드 195g을 정제수 750ml에 용해한 용액과 클로로아세틸 클로라이드 405g을 아세톤 600 ml에 용해한 용액을 동시에 적가 하였다. 상기 용액의 온도를 실온으로 올려 정제수 2250ml를 추가하고 감압하에서 아세톤을 증발시킨 다음, 생성된 고체를 여과하고 정제수 1500ml로 세척한 후, 80℃에서 5시간 건조하여 표제화합물 850g(90%)을 수득하였다.195 g of sodium hydroxide was dissolved in 750 ml of purified water, 310 ml of acetone was added to form a two-phase solution, and then cooled to 10 ° C., and 750 g of D, L-homocysteine thiolactone hydrochloride was added thereto. The ideal solution was stirred for about 30 minutes, cooled to -5 ° C, and a solution containing 195 g of sodium hydroxide in 750 ml of purified water and 405 g of chloroacetyl chloride in 600 ml of acetone were added dropwise at the same time. After raising the temperature of the solution to room temperature, 2250 ml of purified water was added, and acetone was evaporated under reduced pressure. The resulting solid was filtered, washed with 1500 ml of purified water, and dried at 80 ° C. for 5 hours to obtain 850 g (90%) of the title compound. It was.
융 점 : 137∼138℃Melting Point: 137 ~ 138 ℃
IR(KBr) υcm-1 3290, 1708, 1648IR (KBr) υcm -1 3290, 1708, 1648
NMR(CDCl3) 1.9-2.1(m, 2H), 2.85-2.95(m, 2H), 4.0(s, 2H),NMR (CDCl 3 ) 1.9-2.1 (m, 2H), 2.85-2.95 (m, 2H), 4.0 (s, 2H),
4.5-4.6(m, 1H), 7.1(d, 1H) 4.5-4.6 (m, 1 H), 7.1 (d, 1 H)
HPLC 순도 : 99.9%HPLC purity: 99.9%
실시예 2Example 2 ; 3-클로로아세트아미도-2-옥소-테트라히드로티오펜의 합성 ; Synthesis of 3-chloroacetamido-2-oxo-tetrahydrothiophene
아세톤 대신 메틸렌클로라이드를 사용한 것을 제외하고는 실시예 1과 동일한 과정을 거쳐 870g(92%)의 표제화합물을 수득 하였다. 870 g (92%) of the title compound were obtained in the same manner as in Example 1, except that methylene chloride was used instead of acetone.
스펙트럼 데이터는 실시예 1과 동일함. The spectral data is the same as in Example 1.
HPLC 순도 : 100% HPLC purity: 100%
실시예 3Example 3 ; [(2-옥소-3-테트라히드로티에닐카바모일)-메틸티오]아세트산의 합성 ; Synthesis of [(2-oxo-3-tetrahydrothienylcarbamoyl) -methylthio] acetic acid
338g의 소듐히드록사이드를 정제수 750ml에 용해하고 여기에 에틸아세테이트 2250ml를 가하여 이상(two-phase)용액을 만든 후 10℃ 까지 냉각하여 티오글리콘산 398g을 가하였다. 얻어진 이상용액을 30분 교반한 다음, 3-클로로아세트아미도-2-옥소-테트라히드로티오펜 825g을 적가 하고 20℃에서 2시간 교반 하였다. 염산 300ml를 사용하여 pH 3.2로 조정한 다음, 1시간 교반하여 생성된 고체를 여과하고 정제수 1500ml로 세척하여 80℃에서 5시간 건조하여 표제화합물 900g(85%)을 수득하였다. 338 g of sodium hydroxide was dissolved in 750 ml of purified water, and 2250 ml of ethyl acetate was added thereto to form a two-phase solution, which was then cooled to 10 ° C and 398 g of thioglycolic acid was added thereto. The resulting ideal solution was stirred for 30 minutes, and then 825 g of 3-chloroacetamido-2-oxo-tetrahydrothiophene was added dropwise and stirred at 20 ° C for 2 hours. The mixture was adjusted to pH 3.2 using 300 ml of hydrochloric acid, and then stirred for 1 hour. The resulting solid was filtered, washed with 1500 ml of purified water, and dried at 80 ° C. for 5 hours to obtain 900 g (85%) of the title compound.
융 점 : 158∼160℃Melting Point: 158-160 ℃
IR(KBr) υcm-1 3285, 1740, 1685, 1665IR (KBr) υcm -1 3285, 1740, 1685, 1665
NMR(DMSO-d6) 2.1-2.3(m, 2H), 2.9-3.2(m, 2H), 3.8-3.9(m, 4H),NMR (DMSO-d 6 ) 2.1-2.3 (m, 2H), 2.9-3.2 (m, 2H), 3.8-3.9 (m, 4H),
5.1(m, 1H), 9.4(d, 1H) 5.1 (m, 1H), 9.4 (d, 1H)
HPLC 순도 : 99.7%HPLC purity: 99.7%
실시예 4Example 4 ; [(2-옥소-3-테트라히드로티에닐카바모일)-메틸티오]아세트산의 합성 ; Synthesis of [(2-oxo-3-tetrahydrothienylcarbamoyl) -methylthio] acetic acid
에틸아세테이트 대신 메틸렌클로라이드를 사용한 것을 제외하고는 실시예 3과 동일한 과정을 거쳐 880g(83%)의 표제화합물을 수득하였다. 880 g (83%) of the title compound was obtained in the same manner as in Example 3, except that methylene chloride was used instead of ethyl acetate.
스펙트럼 데이터는 실시예 3과 동일함. The spectral data is the same as in Example 3.
HPLC 순도 : 99.6% HPLC purity: 99.6%
본 발명에 따르면, 에르도스테인을 제조함에 있어서 락톤링의 분해를 최소화하여 순도 99.5%이상의 목적물질을 전체 수율 75%이상의 고수율로 제조할 수 있고, 또한 종래 기술에 비해서 보다 경제적인 방법으로 에르도스테인을 제조할 수 있다. According to the present invention, it is possible to produce a target substance having a purity of 99.5% or more in high yield of 75% or more in overall yield by minimizing the decomposition of lactone ring in the production of erdostein, and in a more economical way than in the prior art. Dostain can be prepared.
Claims (3)
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| KR1020030068605A KR100554108B1 (en) | 2003-10-02 | 2003-10-02 | Method of producing erdostein |
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| KR1020030068605A KR100554108B1 (en) | 2003-10-02 | 2003-10-02 | Method of producing erdostein |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20210141203A (en) * | 2020-05-15 | 2021-11-23 | 제이투에이치바이오텍 (주) | Erdosteine derivative and pharmaceutical composition containing the same |
| KR20220148616A (en) * | 2021-04-29 | 2022-11-07 | 대봉엘에스 주식회사 | Individual co-crystal of l, d-erdosteine |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108640900A (en) * | 2018-06-07 | 2018-10-12 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of purification process of Erdosteine |
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- 2003-10-02 KR KR1020030068605A patent/KR100554108B1/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20210141203A (en) * | 2020-05-15 | 2021-11-23 | 제이투에이치바이오텍 (주) | Erdosteine derivative and pharmaceutical composition containing the same |
| KR20220148616A (en) * | 2021-04-29 | 2022-11-07 | 대봉엘에스 주식회사 | Individual co-crystal of l, d-erdosteine |
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