KR100816798B1 - Preparation method of triethylene tetramine dihydrochloride - Google Patents
Preparation method of triethylene tetramine dihydrochloride Download PDFInfo
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Abstract
본 발명은 하기 화학식 1의 의약용 트리에틸렌테트라민 이염산염의 제조방법에 관한 것으로, 구체적으로 반응 용매 하에서 트리에틸렌테트라민에 염산을 첨가하여 불순물을 함유한 트리에틸렌테트라민 이염산염을 제조하는 단계(단계 1); 및 상기 불순물을 함유한 트리에틸렌테트라민 이염산염을 정제하는 단계(단계 2)를 포함하여 이루어지는 의약용 트리에틸렌테트라민 이염산염(트리엔틴)의 제조방법에 관한 것이다. 본 발명은 제조단계가 간단하고, 수율이 높고, 반응 시간이 짧고, 경제적이므로 대량생산이 가능하다.The present invention relates to a method for preparing a medical triethylenetetramine dihydrochloride of the formula (1), specifically the step of preparing triethylenetetramine dihydrochloride containing impurities by adding hydrochloric acid to triethylenetetramine under a reaction solvent (Step 1); And it relates to a method for producing a medical triethylenetetramine dihydrochloride (trientin) comprising the step of purifying triethylenetetramine dihydrochloride containing the impurity (step 2). The present invention is simple in production steps, high in yield, short in reaction time, and economical, so mass production is possible.
<화학식 1><Formula 1>
트리에틸렌테트라민 이염산염, 트리엔틴 Triethylenetetramine dihydrochloride, trientin
Description
본 발명은 의약용 트리에틸렌테트라민 이염산염의 제조방법에 관한 것이다.The present invention relates to a method for producing a medical triethylenetetramine dihydrochloride.
윌슨병은 영국 의사 윌슨이 1912년에 간경화가 동반된 진행성 신경증상이 가족성으로 발생하는 것을 처음으로 발견하고 의학계에 보고함에 따라 널리 알려지게 되었으며, 구체적으로 13번 염색체의 구리운반에 중요한 역할을 하는 단백질 유전자의 돌발적인 돌연변이에 의해서 인체 내의 구리가 정상적으로 담즙으로 배설되지 못하고 축적되어 여러 기관의 손상을 일으키는 질병이다. 이때, 구리는 먼저 간에 축적되고 간의 한계를 넘으면 혈류로 흘러나와 뇌, 각막, 신장 등에 축적되어 해당 장기의 손상을 유발하게 된다.Wilson's disease became widely known when British doctor Wilson first discovered and reported to the medical community that progressive neurologic symptoms with cirrhosis were first reported in 1912, and specifically played an important role in the copper transport of chromosome 13. It is a disease that causes the damage of various organs due to accumulation of copper in the human body due to an unexpected mutation of a protein gene. At this time, copper is first accumulated in the liver, and if the liver exceeds the limits of the flow into the bloodstream and accumulate in the brain, cornea, kidney, etc. will cause damage to the organ.
상기 윌슨병은 간에 구리가 축적되어 증상이 나타나는 병이므로 보통 3 ~ 4세가 지나야 발병하며, 어린 소아 연령에서는 주로 간질환으로 나타나고 20세가 지 나서는 신경증상이 주로 나타난다. 간에 구리가 침착되면 처음에는 간 효소치만 약간 증가된 무증상적 간장 비대를 보이나 결국은 만성 활동성 간염, 간경화, 문맥압 항진증으로 진행한다. 간혹 급성으로 발병하기도 하며 이런 경우 황달, 식욕부진, 권태감, 간 효소치의 급격한 증가 소견을 보이는 전격성 간염으로 되어 급격히 간성 혼수로 빠지면서 사망에 이를 수도 있다. 신경증상으로 나타나는 환자는 사춘기 이전에 증상이 나타나는 경우는 드물며 대개 15세 이후 청소년기에 나타나게 된다. 구리가 뇌에 침착하면 처음에는 손떨림이 오고, 점차 발음이 불명확하여 알아듣기 어려운 구음장애가 오며, 근육 긴장 이상으로 인한 보행장애, 자세이상 등의 신경장애의 증상을 보인다. 이외에 정신이상, 정서, 행동장애도 나타날 수 있으며, 학교성적 저하가 첫 증상으로 나타나기도 하고, 기타 적혈구가 깨져서 오는 용혈성빈혈, 신세뇨관 장애, 골격관절 이상 등의 증상을 보일 수도 있다. 용혈성 빈혈이 자주 오면 담석이 발생하기도 한다.Wilson's disease is a disease caused by the accumulation of copper in the liver, usually 3 to 4 years after the development of the disease, young children appear mainly as a liver disease, 20 years old neurological symptoms appear mainly. Deposition of copper in the liver initially leads to asymptomatic hepatic hypertrophy with only a slight increase in liver enzymes, but eventually progresses to chronic active hepatitis, cirrhosis, hyperportal hypertension. Occasionally acute onset, in this case, jaundice, anorexia, malaise, hepatic hepatitis showing a rapid increase in the enzyme levels of liver can lead to a sudden hepatic coma, leading to death. Patients with neurological symptoms rarely develop before puberty and usually appear in adolescence after age 15. When copper is deposited on the brain, the hand shakes at first, and the pronunciation is gradually unclear, resulting in hard-to-understand oral dysfunction, and neurological disorders such as gait disorder and postural abnormalities caused by abnormal muscle tension. In addition, mental disorders, emotions, behavioral disorders may also appear, school grades may be the first symptoms, and other symptoms may include hemolytic anemia, renal tubular disorders, and skeletal joint abnormalities caused by broken red blood cells. Frequent hemolytic anemia can cause gallstones.
상기 윌슨병에 사용되는 치료제로는 일차적으로 페니실아민(penicillamine)이 있으며, 상기 페니실아민은 구리와 결합하여 구리를 소변으로 배설시키는 약제이다. 그러나 신경증상을 나타내는 환자에는 페니실아민 치료 시작 후 간혹 신경증상의 악화가 올 수 있으므로 치료에 어려운 점이 있다. The therapeutic agent used in the Wilson disease is primarily a penicillamine (penicillamine), the penicylamine is a drug that binds to copper to excrete copper in the urine. However, patients with neurological symptoms are difficult to treat because the symptoms of neurological symptoms may sometimes worsen after initiation of penicylamine treatment.
상기 페니실아민에 부작용이 있는 경우에는 트리에틸렌테트라민 이염산염(트리엔틴)(triethylene tetramine dihydrochloride; trientine)을 사용할 수 있다. 상기 트리에틸렌테트라민 이염산염은 페니실아민 약물 부작용으로 투약을 할 수 없 는 경우 또는 4 ~ 6주 페니실아민 치료로도 신경증상이 호전되지 않는 환자에게 우선적으로 쓸만한 약으로 구리와 결합하여 구리를 소변으로 배설시키는 역할을 한다.When the penicylamine has a side effect, triethylene tetramine dihydrochloride (trientine) may be used. The triethylenetetramine dihydrochloride is a drug that can be used preferentially to patients who are unable to administer due to side effects of penicylamine drugs or whose neurological symptoms do not improve even after 4-6 weeks of penicylamine treatment. It acts to excrete urine.
상기 트리에틸렌테트라민 이염산염은 다음의 화학식 1로 표현된다.The triethylenetetramine dihydrochloride is represented by the following formula (1).
상기 트리에틸렌테트라민 이염산염은 트리에틸렌테드라민의 양 말단에 염산염이 결합된 형태이다. 그러나 상기 트리에틸렌테트라민 이염산염을 제조하는 방법이 국내에는 알려져 있지 않으며, 제조가 까다롭고, 현재 특정 희귀의약품 지정회사를 통하여 외국에서 수입되어 오는 실정이다. 따라서 약물의 가격이 고가이고, 특정 장소에만 유통되고 시중에는 널리 유통되고 있지 않기 때문에 상기 약물을 얻는데 어려움이 있다.The triethylenetetramine dihydrochloride is a form in which hydrochloride is bonded to both ends of triethylenetetramine. However, the method for producing the triethylenetetramine dihydrochloride is not known in Korea, it is difficult to manufacture, and is currently imported from a foreign country through a specific drug designation company. Therefore, the price of the drug is expensive, it is difficult to obtain the drug because it is distributed only in certain places and not widely distributed in the market.
이에 본 발명자들은 제조단계가 간단하고, 수율이 높고, 반응 시간이 짧고, 경제적이므로 대량생산이 가능한 의약용 염산 트리에틸렌테트라민 이염산염의 제조방법을 알아내고 본 발명을 완성하였다.The present inventors have found a method for preparing a medical hydrochloric acid triethylenetetramine dihydrochloride, which has a simple manufacturing step, a high yield, a short reaction time, and is economical, thus completing the present invention.
본 발명의 목적은 제조단계가 간단하고, 수율이 높고, 반응 시간이 짧고, 경제적이므로 대량생산이 가능한 염산 트리에틸렌테트라민 이염산염의 제조방법을 제공하는 것이다. It is an object of the present invention to provide a method for producing triethylenetetramine dihydrochloride hydrochloride, which is simple in production, high in yield, short in reaction time and economical in mass production.
상기 목적을 달성하기 위하여 본 발명은 하기 반응식 1의 트리에틸렌테트라민 이염산염의 제조방법을 제공한다.In order to achieve the above object, the present invention provides a method for preparing triethylenetetramine dihydrochloride of Scheme 1 below.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은The present invention
상기 반응식 1에 나타난 바와 같이, 알콜 용매에 트리에틸렌테트라민(2)을 희석하여 냉각시킨 후, 상기 용액에 염산을 적가하고 실온에서 30분 ~ 2시간 동안 반응시킨 다음, 상기 용매를 제거한 후, 잔사에 이소프로판올을 첨가하여 공비시키고, 상기 공비 혼합물에 결정화용매를 첨가하여 결정화시키는 단계(단계 1); 및As shown in Scheme 1, after diluting and cooling triethylenetetramine (2) in an alcohol solvent, hydrochloric acid was added dropwise to the solution and reacted at room temperature for 30 minutes to 2 hours, and then the solvent was removed. Azeotropic addition of isopropanol to the residue and crystallization by adding a crystallization solvent to the azeotropic mixture (step 1); And
상기 단계 1에서 제조된 트리엔틴 염산염을 알콜 용매에 현탁시켜 30분 ~ 1시간 동안 환류시킨 후, 불용물을 여과하고 잔사를 냉각하여 결정화시키는 단계(단계 2)를 포함하여 이루어지는 트리에틸렌테트라민 이염산염(1)의 제조방법을 제공한다.The triethylenetetramine prepared in step 1 was suspended in an alcohol solvent to reflux for 30 minutes to 1 hour, and then filtered to insoluble materials and the residue was cooled to crystallize (step 2). It provides a method for producing a dihydrochloride (1).
이때, 출발물질인 트리에틸렌테트라민(2)은 공지에 의한 방법으로 합성하여 사용하거나, 시판중인 것을 사용할 수 있으며, 상기 염산은 35 ~ 37% 농도의 염산을 사용하는 것이 바람직하다. At this time, the starting material triethylenetetramine (2) can be synthesized by a known method or may be used commercially available, the hydrochloric acid is preferably used hydrochloric acid of 35 ~ 37% concentration.
본 발명에 따른 트리에틸렌테트라민 이염산염의 제조방법에 있어서, 상기 알콜 용매는 메탄올 또는 에탄올을 사용하는 것이 바람직하다. In the method for producing triethylenetetramine dihydrochloride according to the present invention, the alcohol solvent is preferably methanol or ethanol.
본 발명에 따른 트리에틸렌테트라민 이염산염의 제조방법에 있어서, 먼저 알콜 용매에 상기 트리에틸렌테트라민을 용해시킨 후 0 ℃로 온도를 냉각시킨다. 이는 염산과 트리에틸렌테트라민의 반응시 발열이 매우 심하므로 반응온도를 조절하기 위함이다.In the method for preparing triethylenetetramine dihydrochloride according to the present invention, the triethylenetetramine is first dissolved in an alcohol solvent and then cooled to 0 ° C. This is to control the reaction temperature because the exotherm is very severe during the reaction of hydrochloric acid and triethylenetetramine.
다음으로, 냉각된 트리에틸렌테트라민에 염산을 천천히 적가한 후, 교반시킨다. 상기 염산의 첨가량은 트리에틸렌테트라민 1당량에 대하여 염산 2당량을 첨가하는 것이 바람직하다. 또한, 상기 반응은 실온에서 30분 ~ 2시간 정도 수행하는 것이 바람직하다. 이때, 반응 용매로서 본 발명에 따른 용매가 아닌 아세톤, 물 등의 용매에서 2시간 이상 반응을 수행하는 경우에는 반응 생성물의 색깔이 변색되는 문제가 있다.Next, hydrochloric acid is slowly added dropwise to the cooled triethylenetetramine, followed by stirring. The amount of hydrochloric acid added is preferably 2 equivalents of hydrochloric acid to 1 equivalent of triethylenetetramine. In addition, the reaction is preferably carried out at room temperature for about 30 minutes to 2 hours. At this time, when the reaction is carried out for 2 hours or more in a solvent such as acetone, water and the like as a reaction solvent, there is a problem that the color of the reaction product is discolored.
반응 후, 감압 농축하여 용매를 제거한 후, 용매를 첨가하여 흰색의 트리에틸렌테트라민 이염산염 결정을 형성시킬 수 있다. 이때, 감압 농축하는 온도는 30 ~ 50 ℃이고, 농축 시간은 1 ~ 3시간인 것이 바람직하다. 상기 감압 농축 온도가 50 ℃를 초과하거나 농축 시간이 3시간을 초과하면 생성물이 노란색으로 변하게 되며, 이는 정제를 하더라도 미색으로 남게 된다. 또한 감압 농축 온도가 30 ℃ 미만이거나 농축 시간이 1시간 미만인 경우, 물이 제거되지 않아 수득률이 낮아지는 단점이 있다.After the reaction, the mixture is concentrated under reduced pressure to remove the solvent, and then a solvent may be added to form white triethylenetetramine dihydrochloride crystals. At this time, the temperature to be concentrated under reduced pressure is 30 to 50 ° C, and the concentration time is preferably 1 to 3 hours. If the reduced pressure concentration temperature exceeds 50 ℃ or the concentration time exceeds 3 hours the product turns yellow, which will remain off-white even if purified. In addition, if the reduced pressure concentration temperature is less than 30 ℃ or the concentration time is less than 1 hour, there is a disadvantage that the yield is low because the water is not removed.
상기 결정화 용매는 메탄올/이소프로판올(1:6) 또는 디메틸포름아마이드/에틸아세테이트(5:1)인 것이 바람직하다. 상기 결정화 용매에 아세톤을 사용하면 결정이 잘 이루어지지 않고 에멀전의 상태로 남아있게 되며, 이를 결정화시키기 위하여 2시간 이상 교반하게 되면 생성물이 갈색으로 변하게 되어 목적하는 트리에틸렌테트라민 이염산염 결정을 얻을 수 없다.The crystallization solvent is preferably methanol / isopropanol (1: 6) or dimethylformamide / ethyl acetate (5: 1). When acetone is used in the crystallization solvent, crystals are not well formed and remain in an emulsion state. When the mixture is stirred for 2 hours or more to crystallize, the product turns brown to obtain a desired triethylenetetramine dihydrochloride crystal. none.
상기 생성된 결정은 여과하여 건조하면 목적하는 트리에틸렌테트라민 이염산염을 얻을 수 있으나, 이는 불순물이 포함되어 있으므로 정제과정이 필요하다.The resulting crystals are filtered to dry to obtain the desired triethylenetetramine dihydrochloride, but this requires impurities because it contains impurities.
단계 2는 상기 단계 1에서 제조된 트리엔틴 염산염을 알콜 용매에 현탁시켜 30분 ~ 1시간 동안 환류시킨 후, 불용물을 여과하고 잔사를 냉각하여 결정화시키는 단계이다.Step 2 is a step of suspending the trientine hydrochloride prepared in step 1 in an alcohol solvent to reflux for 30 minutes to 1 hour, and then the insolubles are filtered and the residue is cooled to crystallize.
상기 단계에서 사용되는 알콜 용매는 에탄올이 바람직하며, 상기 알콜 용매를 끓는점에 이를 때까지 가열하여 사용하는 것이 바람직하다. 이로써 정제된 무색 트리에틸렌테트라민 이염산염 결정을 얻을 수 있으며, 수율은 이론치의 약 85% 이상이다.The alcohol solvent used in the step is preferably ethanol, it is preferable to use the alcohol solvent heated to reach the boiling point. This results in purified colorless triethylenetetramine dihydrochloride crystals, with a yield of about 85% or more of theory.
이하 실시예에 의하여 본 발명을 보다 구체적으로 설명한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명이 이들 만으로 한정되는 것은 아니다.The present invention will be described in more detail with reference to the following Examples. However, the following Examples are only for illustrating the present invention, the present invention is not limited to these.
<< 실시예Example 1> 1>
60% 트리에틸렌테트라민 150 g을 메탄올 150 ㎖에 희석시키고 0 ℃로 냉각한 후, 여기에 35% 염산 108.65 ㎖을 천천히 적가하였다. 반응물을 실온에서 1시간 동안 교반한 후, 메탄올과 물을 50 ℃ 이하에서 감압 농축하여 제거하였다. 잔사물에 이소프로판올 50 ㎖을 넣고 공비한 후, 메탄올 75 ㎖와 이소프로판올 450 ㎖을 넣어 교반하였다. 결정이 생성되면 0 ℃로 냉각하여 1시간 동안 교반하고 생성된 결정을 여과하고 냉각된 이소프로판올로 세척하였다. 여과된 결정을 35 ℃에서 진공 건조하여 불순물이 포함된 트리에틸렌테트라민 이염산염 100 g을 얻었다.150 g of 60% triethylenetetramine was diluted in 150 ml of methanol, cooled to 0 ° C., and 108.65 ml of 35% hydrochloric acid was slowly added dropwise thereto. After the reaction was stirred at room temperature for 1 hour, methanol and water were removed by concentration under reduced pressure at 50 占 폚 or lower. 50 ml of isopropanol was added to the residue and subjected to azeotroping, followed by stirring with 75 ml of methanol and 450 ml of isopropanol. When crystals formed, they were cooled to 0 ° C., stirred for 1 hour, and the resulting crystals were filtered and washed with cooled isopropanol. The filtered crystals were dried in vacuo at 35 ° C. to obtain 100 g of triethylenetetramine dihydrochloride containing impurities.
상기 불순물이 포함된 트리에틸렌테트라민 이염산염을 에탄올 300 ㎖에 현탁시키고, 30분 동안 환류 교반하였다. 녹지 않는 물질을 뜨거운 상태로 여과하여 제거하였다. 모액을 서서히 0 ℃까지 냉각시켜 생성된 결정을 여과하고 냉각된 에 탄올로 세척하였다. 여과된 결정을 35 ℃에서 진공 건조하여 85 g(이론치의 85%)을 융점 119 ~ 121 ℃의 무색의 백색의 결정으로서 얻었으며, 하기 NMR 스펙트럼을 통해 의약용으로 사용되는 순수한 트리에틸렌테트라민 이염산염임을 확인하였다.Triethylenetetramine dihydrochloride containing the impurities was suspended in 300 ml of ethanol and stirred under reflux for 30 minutes. Insoluble material was removed by filtration in hot state. The mother liquor was slowly cooled to 0 ° C., resulting crystals were filtered off and washed with cold ethanol. The filtered crystals were vacuum dried at 35 DEG C to obtain 85 g (85% of theory) as colorless white crystals with melting points of 119 to 121 DEG C. Pure triethylenetetramine dichloride used for medical purposes through the following NMR spectrum. It was confirmed that it was an acid salt.
1H NMR(300MHz, D2O): δ2.45 (4H, m), 2.55 (2H, m), 2.73 (4H, m), 2.82 (4H, m), 2.95 (4H, m). 1 H NMR (300 MHz, D 2 O): δ 2.45 (4H, m), 2.55 (2H, m), 2.73 (4H, m), 2.82 (4H, m), 2.95 (4H, m).
<< 실시예Example 2> 2>
99% 트리에틸렌테트라민 20 g을 메탄올 20 ㎖에 희석시키고 0 ℃로 냉각하였다. 35% 염산 24.14 ㎖을 천천히 적가하였다. 실온에서 1시간 동안 교반한 후, 메탄올과 물을 50 ℃ 이하에서 감압농축하여 제거하였다. 잔사물에 이소프로판올 10 ㎖을 넣고 공비한 후, 디메틸포름아미드 50 ㎖, 에틸아세테이드 10 ㎖ 혼합용액을 넣어 결정이 생성될 때까지 실온에서 교반하였다. 결정이 생성되면 0 ℃로 냉각하여 1시간 동안 교반하였으며, 생성된 결정을 여과하고, 35 ℃에서 진공 건조하여 불순물이 포함된 염산 트리에틸렌테트라민 이염산염 30 g을 얻었다. 상기 불순물이 포함된 트리에틸렌테트라민 이염산염의 정제 과정은 상기 실시예 1과 동일한 방법으로 수행하였다.20 g of 99% triethylenetetramine was diluted in 20 mL methanol and cooled to 0 ° C. 24.14 mL of 35% hydrochloric acid was slowly added dropwise. After stirring for 1 hour at room temperature, methanol and water were removed by concentration under reduced pressure at 50 ℃ or less. 10 ml of isopropanol was added to the residue, followed by azeotroping. Then, 50 ml of dimethylformamide and 10 ml of ethyl acetate were added thereto, followed by stirring at room temperature until crystals were formed. When crystals were formed, the mixture was cooled to 0 ° C. and stirred for 1 hour. The resulting crystals were filtered and dried in vacuo at 35 ° C. to obtain 30 g of triethylenetetramine dihydrochloride hydrochloride. Purification of triethylenetetramine dihydrochloride containing the impurities was carried out in the same manner as in Example 1.
1H NMR(300MHz, D2O): δ2.45 (4H, m), 2.55 (2H, m), 2.73 (4H, m), 2.82 (4H, m), 2.95 (4H, m). 1 H NMR (300 MHz, D 2 O): δ 2.45 (4H, m), 2.55 (2H, m), 2.73 (4H, m), 2.82 (4H, m), 2.95 (4H, m).
이상에서 살펴본 바와 같이, 본 발명은 제조단계가 간단하고, 수율이 높고, 반응 시간이 짧고, 경제적이므로 대량생산이 가능하다. As described above, the present invention can be mass-produced because the manufacturing step is simple, the yield is high, the reaction time is short, and economical.
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