KR100844336B1 - Novel Method for Preparing Levobupicaine and its Hydrochloride - Google Patents
Novel Method for Preparing Levobupicaine and its Hydrochloride Download PDFInfo
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- KR100844336B1 KR100844336B1 KR1020070004980A KR20070004980A KR100844336B1 KR 100844336 B1 KR100844336 B1 KR 100844336B1 KR 1020070004980 A KR1020070004980 A KR 1020070004980A KR 20070004980 A KR20070004980 A KR 20070004980A KR 100844336 B1 KR100844336 B1 KR 100844336B1
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Abstract
본 발명은 광학 순도가 높은 레보부피바카인(levobupivacaine) 및 이의 염산염의 제조방법에 관한 것으로, 85% 거울상 이성체 과잉율(enantiomeric excess, ee) 이상의 광학순도를 갖는 (S)-2′,6′-피페콜옥실리디드와 1-브로모부탄을 염기하에서 반응하여 레보부피바카인을 얻은 후, 재결정을 통해 98% ee 이상의 광학 순도를 가지는 레보부피바카인을 얻는 것을 특징으로 하며, 이를 염산과 반응시켜 99% ee 이상의 광학 순도를 가지는 고순도의 레보부피바카인 염산염을 제조하는 것을 특징으로 한다.The present invention relates to a method of preparing levobuivacaine and its hydrochloride having high optical purity, (S) -2 ', 6' having an optical purity of more than 85% enantiomeric excess (ee) -Pefecoloxylidide reacts with 1-bromobutane under a base to obtain levobupivacaine, and then recrystallization to obtain levobupivacaine having an optical purity of 98% ee or more, which is reacted with hydrochloric acid. To prepare a high-purity levobupivacaine hydrochloride having an optical purity of 99% ee or more.
본 발명에 따른 레보부피바카인 및 이의 염산염의 제조방법은 제조공정이 간단하며, 사용하는 시약의 취급이 용이하고, 레보부피바카인의 거울상 이성체 과잉율도 98% ee 이상으로 제조할 수 있으며, 이렇게 제조된 레보부피바카인을 염산염으로 전환하면 99% ee 이상의 광학 순도를 가지는 고순도의 레보부피바카인 염산염을 제조할 수 있는 장점이 있다.According to the present invention, the preparation method of levobupivacaine and its hydrochloride salt is simple, the handling of reagents used is easy, and the enantiomeric excess rate of levobupivacaine can be prepared to 98% ee or more. Converting the prepared levobupivacaine to hydrochloride has the advantage of producing a high-purity levobupivacaine hydrochloride having an optical purity of 99% ee or more.
Description
본 발명은 레보부피바카인 및 이의 염산염의 제조방법에 관한 것으로 특히 광학 순도가 높은 레보부피바카인 및 이의 염산염의 제조방법에 관한 것이다.The present invention relates to a method for preparing levobupivacaine and its hydrochloride, and more particularly to a method for producing levobupivacaine and its hydrochloride having high optical purity.
레보부피바카인(levobupivacaine) 및 로피바카인(ropivacaine)같은 그의 유사체는 국소 마취제로 유용하다. 특히 광학적으로 분할한 순수한 (S)-거울상체(enantiomer)는 라세미체보다도 높은 치료 계수를 갖는 진통제로 널리 사용되고 있다. 또한 (S)-거울상체는 라세미체보다 적은 심장독성을 나타내면서 동일한 마취 효능을 유지 하므로, 임상용으로 유리한 것으로 나타났다.Analogues such as levobuivacaine and ropivacaine are useful as local anesthetics. In particular, optically divided pure (S) -enantiomers are widely used as analgesics with higher therapeutic modulus than racemates. In addition, (S) -enantiomers showed less cardiac toxicity than racemates and thus maintained the same anesthetic efficacy, and thus appeared to be advantageous for clinical use.
J. Med. Chem., (9), 891~892 (1971) 및 미국 특허 공개공보 제 4,180,712호에서는 천연의 (R, R)-주석산을 분해제로 사용하여 부피바카인을 광학 분할 (optical resolution)하여 레보부피바카인을 얻는 방법이 기재되어 있다. 즉, 라세미 부피바카인과 (R, R)-주석산을 반응시켜 (R)-부피바카인 (R, R)-주석산염을 먼저 결정화시켜 제거한 후, 여액에 존재하는 (S)-부피바카인 (R, R)-주석산염을 2차 적으로 결정화하여 레보부피바카인을 얻는 방법으로서 전체 조작 효율이 떨어지고 공업적으로 비실용적이다. 또한 재현 가능한 수율을 얻기 어려우며, 거울상 이성체 과잉율(enantiomeric excess, ee) 값도 가변적이어서 고순도의 레보부피바카인을 얻기 어려운 단점이 있다.J. Med. Chem., (9), 891-892 (1971) and U.S. Patent Publication No. 4,180,712 disclose optical resolution of bupivacaine using natural (R, R) -tin acid as a disintegrant, thereby providing a levobupivaca A method of obtaining phosphorus is described. That is, racemic bupivacaine is reacted with (R, R) -tartrate to crystallize (R) -bupivacaine (R, R) -tartrate first, and then (S) -bupivacaca present in the filtrate. Phosphorus (R, R) -tin salts are crystallized secondarily to obtain levobupivacaine, resulting in poor overall operating efficiency and impractical industrial use. In addition, it is difficult to obtain reproducible yields, and the enantiomeric excess (ee) value is also variable, making it difficult to obtain high purity levobupivacaine.
Org. Pro. Res. & Devel.,4, p530~533 (2000) 및 GB 1995/002513에서는 (S, S)-주석산을 분해제로 사용하여 라세미 부피바카인을 광학 분할하는 방법이 기재되어 있다. 즉, 라세미 부피바카인과 (S, S)-주석산을 반응시켜 (S)-부피바카인 (S, S)-주석산염이 98% ee로 제조되는 방법이지만 분해제로 사용되는 (S, S)-주석산은 천연적으로 구하기 어려워 생산 단가가 높은 단점이 있다. 또한 광학 분할 및 염산과 반응시켜 레보부피바카인 염산염을 얻는 두 단계의 총 수율이 32%로 낮은 단점이 있다. Org. Pro. Res. & Devel., 4, p530-533 (2000) and GB 1995/002513 describe a method for optically splitting racemic bupivacaine using (S, S) -tartrate as a disintegrant. In other words, racemic bupivacaine is reacted with (S, S) -tartrate to produce (S) -bupivacaine (S, S) -tartrate with 98% ee but is used as a disintegrant (S, S ) -Tinic acid is difficult to obtain naturally and has a disadvantage of high production cost. In addition, there is a disadvantage in that the total yield of the two steps of obtaining the levobupivacaine hydrochloride by optical cleavage and reacting with hydrochloric acid is 32%.
Tetrahedron Lett., Vol. 37, No 35, pp6399~6402(1996)에서는 하기 반응식 1과 같이 Nα-CBZ (S)-lysine에서 5 단계를 거쳐 레보부피바카인을 얻는 방법이 기재되어 있다. Nα-CBZ (S)-lysine에서 시작하여 (S)-2′,6′-피페콜옥실리디드를 98% ee로 얻은 후 탄산칼륨과 1-브로모부탄과 반응하여 레보부피바카인을 제조하는 방법이다. 이 방법은 반응 과정이 너무나 길고, 반응 과정 중 생성되는 디아조늄염 중간체는 폭발의 위험성이 커서 산업적으로 제조하기에는 부적합하다.Tetrahedron Lett., Vol. 37, No 35, pp 6399-6640 (1996) describes a method for obtaining levobupivacaine in five steps in N α -CBZ (S) -lysine as shown in Scheme 1 below. Starting with N α -CBZ (S) -lysine to obtain (S) -2 ′, 6′-Pipecoloxyllided as 98% ee and then reacting with potassium carbonate and 1-bromobutane to prepare levobupivacaine That's how. This process is too long and the diazonium salt intermediates produced during the reaction are not suitable for industrial production due to the high risk of explosion.
[반응식 1]Scheme 1
본 발명은 라세미체보다도 순수한 (S)-거울상체(enantiomer)가 높은 치료 계수를 가지는 레보부피바카인 및 이의 염산염을 제조하는데 있어서 산업적으로 제조하기 적합하며 복잡한 공정 없이 항상 일정한 거울상 이성체 과잉율(enantiomeric excess, ee)을 가지는 안정적인 제조방법을 제공하는데 그 목적이 있다.The present invention is suitable for industrial production in the preparation of levobupivacaine and its hydrochloride salts, wherein pure (S) -enantiomers have a higher therapeutic modulus than racemates and are always constant in enantiomeric excess without complex processes. The purpose is to provide a stable manufacturing method having an enantiomeric excess (ee).
즉, 본 발명은 간단하며 산업적으로 적용하기 용이한 제조공정을 통하여 98% ee 이상의 광학 순도를 갖는 레보부피바카인을 제조하는 방법을 제공하는데 목적이 있으며, 또한 상기 98% ee 이상의 광학 순도를 갖는 레보부피바카인으로부터 99% ee이상의 광학순도를 갖는 레보부피바카인 염산염을 제조하는 방법을 제공하는데 또 다른 목적이 있다.That is, an object of the present invention is to provide a method for producing levobupivacaine having an optical purity of 98% ee or more through a simple and easy industrial application process, and also has an optical purity of 98% ee or more. It is another object of the present invention to provide a method for preparing levobupivacaine hydrochloride having an optical purity of 99% ee or more from levobupivacaine.
산업적으로 제조하기에 적합한 제조방법으로서의 제조공정이 간단하며, 사용 하는 시약의 취급이 용이하고, 또한 반응 단계에서 발생하는 부산물로써 유해한 가스나 폐기물이 다량 발생되지 않아야 하고 또한 폭발의 위험성이 없어야 한다. 이러한 조건을 만족하면서도 광학 순도가 높은 레보부피바카인 및 이의 염산염을 제조하기 위하여 연구를 거듭한 결과, 광학 순도가 낮은 (S)-2′,6′-피페콜옥실리디드와 1-브로모부탄을 염기 하에서 반응 후 재결정을 통해 98% ee 이상의 광학 순도를 갖는 (S)-부피바카인 즉, 레보부피바카인을 제조할 수 있었으며 이를 염산과 반응시켜 99% ee 이상의 광학 순도를 가지는 레보부피바카인 염산염 제조할 수 있음을 발견하고 본 발명을 완성하게 되었다.The manufacturing process suitable for industrial production should be simple, easy to handle the reagents to be used, and by-products generated in the reaction step should not generate a large amount of harmful gas or waste, and there is no risk of explosion. In order to satisfy these conditions and to produce high optical purity of levobupivacaine and its hydrochloride salt, research has been carried out to show that (S) -2 ′, 6′-pipecolyoxylide and 1-bromobutane having low optical purity. (S) -Bupivacaine having an optical purity of 98% ee or more, ie, levobupivacaine, was prepared by reaction and recrystallization under a base. It has been found that phosphoric acid hydrochloride can be prepared to complete the present invention.
본 발명은 98% ee 이상의 광학 순도를 갖는 레보부피바카인을 제조하는 방법 및 99% ee 이상의 광학 순도를 갖는 레보부피바카인 염산염을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing levobupivacaine having an optical purity of at least 98% ee and a method for producing levobupivacaine hydrochloride having an optical purity of at least 99% ee.
본 발명에 따른 레보부피바카인의 제조방법은 광학 순도가 낮은 (S)-2′,6′-피페콜옥실리디드와 1-브로모부탄을 염기 하에서 반응 후, 생성물을 특정 유기용매 군에서 선택된 유기용매로 재결정하는 과정을 통해 광학 순도가 높은 레보부피바카인을 제조하는 것을 특징으로 한다.According to the present invention, a method for preparing levobupivacaine is selected from a specific organic solvent group after reacting (S) -2 ′, 6′-pifecoloxylidide with low optical purity with 1-bromobutane under a base. Through recrystallization with an organic solvent, it is characterized in that the manufacturing of high optical purity levobupivacaine.
보다 구체적으로 본 발명에 따른 레보부피바카인의 제조방법은 하기의 단계를 포함하는 것을 특징으로 한다.More specifically, the method for preparing levobupivacaine according to the present invention is characterized by including the following steps.
a) 85% ee 이상의 광학순도를 가지는 화학식 I의 (S)-2′,6′-피페콜옥실리 디드와 1-브로모부탄을 유기 용매 에서 염기 하에 반응시켜 화학식 II의 레보부피바카인을 제조하는 단계; 및a) Levobupivacaine of Formula (II) was prepared by reacting (S) -2 ′, 6′-Pipecocholoxylide of Formula (I) with 1-bromobutane with an optical purity of at least 85% ee under a base in an organic solvent. Doing; And
b) 제조된 화학식 II의 레보부피바카인을 이소프로판올, 아세토니트릴, 시클로헥산, 노말헥산, 톨루엔 또는 아세톤으로부터 선택되는 용매 하에 재결정하여 98% ee 이상의 광학 순도를 가지는 화학식 II의 레보부피바카인을 제조하는 단계.b) Recrystallization of the prepared levobupivacaine of formula II in a solvent selected from isopropanol, acetonitrile, cyclohexane, normal hexane, toluene or acetone to prepare levobupivacaine of formula II having an optical purity of at least 98% ee Steps.
[화학식 I][Formula I]
[화학식 II][Formula II]
상기 레보부피바카인의 제조방법에서 (S)-2′,6′-피페콜옥실리디드는 85% 내지 99%의 거울상 이성체 과잉율(ee)를 갖는 것을 사용할 수 있으며, 상기 (S)-2′,6′-피페콜옥실리디드의 거울상 이성체 과잉율(ee)이 85%ee 미만인 경우에는 레보부피바카인의 광학순도를 98% ee 이상으로 하기 위해 재결정 과정을 반복적으로 수행하여야 하므로 수율이 저하되어 경제적이지 못할 수 있고, 상기 (S)-2′,6′-피페콜옥실리디드의 거울상 이성체 과잉율(ee)이 높을수록 생성물의 광학 순도가 높아져 유리하지만, ee 값이 높을수록 단가가 높아져 제조비용이 상승하는 문제점이 발생하므로 경제적인 면을 고려할 때 85% 내지 95%의 거울상 이성체 과잉율(ee) 을 갖는 것을 사용하는 것이 바람직하다. (S) -2 ′, 6′-Pipecoloxilide in the method for preparing levobubivacaine may be used having an enantiomeric excess (ee) of 85% to 99%, and (S) -2 If the enantiomeric excess (ee) of ′, 6′-Pipecoloxylidide is less than 85% ee, the yield decreases because the recrystallization process must be performed repeatedly to make the optical purity of levobupivacaine more than 98% ee. The higher the enantiomeric excess (ee) of (S) -2 ', 6'- pipepecoloxylidide, the higher the optical purity of the product, and the higher the ee value, the higher the unit cost. Since the production cost increases, it is preferable to use an enantiomeric excess (ee) of 85% to 95% in consideration of economical aspects.
또한, 상기 재결정 단계는 1회 이상 진행할 수 있으며, 재결정을 여러번 하는 경우 광학 순도를 향상시킬 수 있으나 수율이 저하되므로 재결정 횟수는 3회 이하로 하는 것이 바람직하다.In addition, the recrystallization step may be performed more than once, and when recrystallization several times, the optical purity may be improved, but since the yield is reduced, the number of recrystallizations is preferably 3 or less.
또한, 본 발명은 레보부피바카인 염산염의 제조방법에 관한 것으로 구체적으로는 상기의 98% ee 이상의 광학 순도를 가지는 화학식 II의 레보부피바카인을 제조하는 단계 후 유기용매에서 염산과 반응시켜 99% ee 이상의 광학 순도를 가지는 화학식 III의 레보부피바카인 염산염을 제조하는 것을 특징으로 한다.In addition, the present invention relates to a method for preparing levobupivacaine hydrochloride, specifically, 99% by reacting with hydrochloric acid in an organic solvent after the step of preparing levobupivacaine of formula II having an optical purity of 98% ee or more It is characterized in that the preparation of levobupivacaine hydrochloride of formula III having an optical purity of ee or more.
[화학식 III][Formula III]
본 발명에 따른 레보부피바카인의 제조방법은 제조공정이 간단하며, 사용하는 시약의 취급이 용이하고, 레보부피바카인의 거울상 이성체 과잉율 (enantiomeric excess)도 98% ee 이상으로 일정하다. 또한 레보부피바카인 염산염을 99% 이상의 광학 순도로 제조할 수 있는 장점이 있다. The preparation method of levobupivacaine according to the present invention is simple, the handling of reagents to be used is easy, and the enantiomeric excess of levobupivacaine is constant at 98% ee or more. In addition, there is an advantage that can be prepared with the optical purity of levobubivacaine hydrochloride more than 99%.
이하 본 발명을 보다 상세히 설명한다. 이때, 사용되는 기술 용어 및 과학 용어에 있어서 다른 정의가 없다면, 이 발명이 속하는 기술 분야에서 통상의 지식을 가진 자가 통상적으로 이해하고 있는 의미를 가진다. 또한, 종래와 동일한 기술 적 구성 및 작용에 대한 반복되는 설명은 생략하기로 한다.Hereinafter, the present invention will be described in more detail. At this time, if there is no other definition in the technical terms and scientific terms used, it has a meaning commonly understood by those of ordinary skill in the art. In addition, repeated description of the same technical configuration and operation as in the prior art will be omitted.
본 발명은 98% ee 이상의 광학 순도를 갖는 레보부피바카인을 제조하는 방법 및 99% ee 이상의 광학 순도를 갖는 레보부피바카인 염산염을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing levobupivacaine having an optical purity of at least 98% ee and a method for producing levobupivacaine hydrochloride having an optical purity of at least 99% ee.
본 발명에 따른 레보부피바카인 및 이의 염산염의 제조방법을 하기 반응식 2에 나타내었다.Levobupivacaine and its hydrochloride method according to the present invention is shown in Scheme 2 below.
[반응식 2]Scheme 2
상기 반응식 2의 a) 및 b)단계를 거쳐 광학순도 98% ee 이상의 레보부피바카인을 제조하고 이로부터 c)단계의 염산과의 반응을 통해 99% ee 이상의 광학 순도를 갖는 레보부피바카인 염산염을 제조한다.Levobubivacaine hydrochloride having an optical purity of 98% ee or more through the steps a) and b) of Scheme 2, and reacting with hydrochloric acid of step c) therefrom, to produce levobupivacaine hydrochloride having an optical purity of 99% ee or more. To prepare.
출발 물질인 (S)-2′,6′-피페콜옥실리디드는 광학 순도가 85% ee 이상으로 85% 내지 99% ee 값을 가지는 것을 사용할 수 있으나, 상술한 바와 같이 경제성을 고려할 때 85% 내지 95% ee 값을 가지는 것을 사용하는 것이 바람직하다. 상기 (S)-2′,6′-피페콜옥실리디드의 제조방법은 라세미 2′,6′-피페콜옥실리디드를 광학분할하는 방법으로 제조할 수 있으며, 제조된 (S)-2′,6′-피페콜옥실리디드의 광학 순도가 85% ee 값 이상을 가지면 된다.Starting material (S) -2 ′, 6′-Pipecoloxylidide can be used having an optical purity of 85% to 99% ee value of 85% ee or more, but as described above, 85% in consideration of economics Preference is given to using those having a value of from 95% ee. The manufacturing method of the (S) -2 ', 6'- pipepecoloxylidide can be prepared by a method of optically dividing the racemic 2', 6'- pipepecoloxylidide, prepared (S) -2 ' The optical purity of, 6′-pipepeoxyoxylide is required to be at least 85% ee.
85% 내지 95% ee 값을 가지는 (S)-2′,6′-피페콜옥실리디드를 제조하는 보다 바람직한 방법으로서 (S)-2′,6′-피페콜옥실리디드는 라세미 2′,6′-피페콜옥실리디드를 디벤조일 주석산염과 반응시켜 수득하는 방법이 사용될 수 있다. 상기 방법을 사용하여 40%의 고수율로 얻을 수 있어 경제적인 면에서 매우 유리하며, 이후의 재결정 단계에서 광학 순도를 높일 수 있으므로 결과적으로는 높은 광학 순도를 갖는 레보부피바카인을 제조할 수 있다.As a more preferred method for preparing (S) -2 ', 6'-pipecolicoxylidide having a value of 85% to 95% ee, (S) -2', 6'-pipepeoxyoxylidide is used in racemic 2 ', Processes obtained by reacting 6'-pipecolyoxylide with dibenzoyl tartrate may be used. It can be obtained with a high yield of 40% using the above method is very advantageous in terms of economics, it is possible to increase the optical purity in the subsequent recrystallization step, as a result can be produced levobupibacaine with high optical purity. .
상기 반응식 2의 a)단계에서 사용되는 염기는 탄산칼륨, 탄산나트륨, 중탄산나트륨등을 사용하는데 탄산칼륨이 바람직하다. a)단계에서 반응 용매로는 디메틸포름아미드, 이소프로판올, 아세토니트릴등을 사용하는데, 이소프로판올이 수율이 높아 보다 바람직하다.The base used in step a) of Scheme 2 uses potassium carbonate, sodium carbonate, sodium bicarbonate, and the like, preferably potassium carbonate. Dimethylformamide, isopropanol, acetonitrile and the like are used as the reaction solvent in step a), and isopropanol is more preferable because of high yield.
본 발명의 b)단계에서 재결정 용매로는 이소프로판올, 아세토니트릴, 시클로헥산, 노말헥산, 톨루엔 또는 아세톤으로부터 선택된 용매를 사용하는 것이 바람직하고, 시클로헥산 또는 노말헥산의 사용이 수율 및 광학 순도 측면에서 보다 바람직하며, 시클로헥산이 가장 바람직하다.In step b) of the present invention, as the recrystallized solvent, a solvent selected from isopropanol, acetonitrile, cyclohexane, normal hexane, toluene or acetone is preferably used, and the use of cyclohexane or normal hexane is more preferable in terms of yield and optical purity. Preferred, cyclohexane is most preferred.
상기 레보부피바카인 염산염을 제조하는 단계에서 사용하는 용매는 아세톤, 이소프로판올 또는 아세토니트릴로부터 선택된 용매를 사용하는 것이 바람직하고,아세톤을 사용하는 경우 레보부피바카인 염산염의 수율 및 순도 측면에서 더욱 우 수하여 보다 바람직하다.The solvent used in the step of preparing the levobupivacaine hydrochloride is preferably used a solvent selected from acetone, isopropanol or acetonitrile, when acetone is used in terms of yield and purity of levobupivacaine hydrochloride more excellent It is more preferable.
이하 실시예를 통하여 본 발명을 더 구체적으로 설명한다. 단, 하기 실시예는 본 발명의 예시에 불과한 것으로서 본 발명의 특허 청구 범위가 이에 따라 한정되는 것은 아니다.The present invention will be described in more detail with reference to the following examples. However, the following examples are merely examples of the present invention, and the claims of the present invention are not limited thereto.
[제조예 1] 라세미 2′,6′-피페콜옥실리디드의 합성Production Example 1 Synthesis of Racemic 2 ′, 6′-Pipecoloxylate
아세토니트릴 900mL와 헥사클로로에탄 78.9g(0.33mol)의 혼합용액에 트리페닐포스핀 87.4g(0.33mol)을 가한 후 실온에서 1시간 교반한다. 라세미 피페콜릭산 염산염 50g(0.3mol)을 가한 후 55 ℃에서 3시간 교반한다. 2,6-디메틸아닐린 37g (0.3mol)을 30분 동안 적가한 후 5시간 교반한다. Triphenylphosphine 87.4 g (0.33 mol) was added to a mixed solution of 900 mL acetonitrile and hexachloroethane 78.9 g (0.33 mol), followed by stirring at room temperature for 1 hour. 50 g (0.3 mol) of racemic pipecolic acid hydrochloride is added thereto, followed by stirring at 55 ° C. for 3 hours. 37 g (0.3 mol) of 2,6-dimethylaniline was added dropwise for 30 minutes, followed by stirring for 5 hours.
서서히 실온으로 냉각하여 3시간 교반 후 고체를 여과하고 아세토니트릴 100mL로 세척한다. After slowly cooling to room temperature and stirring for 3 hours, the solid is filtered and washed with 100 mL of acetonitrile.
얻어진 고체를 디클로로메탄 195mL와 정제수 195mL의 혼합용액에 현탁한다. 50% 수산화나트륨 용액 20mL를 가한 후 30분간 교반한다. 층 분리 후 수층을 디클로로메탄 65mL로 1회 더 추출한다. 유기층을 합하여 무수황산마그네슘으로 건조하고 용매를 감압 증류한다. 얻어진 잔사에 시클로헥산 263mL를 가하고 1시간 환류하 고, 실온으로 냉각 후 1시간 교반한다. 생성된 결정을 여과하고 0 ℃로 냉각된 시클로헥산 54mL로 세척 후, 60 ℃에서 5시간 건조하여 상기 목적화합물인 라세미 2′,6′-피페콜옥실리디드를 얻는다.The obtained solid is suspended in a mixed solution of 195 mL dichloromethane and 195 mL purified water. 20 mL of 50% sodium hydroxide solution is added and stirred for 30 minutes. After layer separation, the aqueous layer is extracted once more with 65 mL of dichloromethane. The organic layers are combined, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. 263 mL of cyclohexane was added to the obtained residue, and the mixture was refluxed for 1 hour, and stirred for 1 hour after cooling to room temperature. The resulting crystals were filtered off, washed with 54 mL of cyclohexane cooled to 0 ° C., and dried at 60 ° C. for 5 hours to obtain racemic 2 ′, 6′-pipecolyloxylide as the target compound.
수율; 88%, yield; 88%,
순도; 99.85% (HPLC % aera),water; 99.85% (HPLC% aera),
1HNMR (CDCl3) δ 1.65 (m, 5H), 2.01 (s, 1H), 2.13 (m, 1H), 2.22 (m, 1H), 2.78 (m, 1H), 3.10 (m, 1H), 3.42 (m, 1H) 7.08 (m, 3H), 8.23 (br s, 1H). 1 HNMR (CDCl 3 ) δ 1.65 (m, 5H), 2.01 (s, 1H), 2.13 (m, 1H), 2.22 (m, 1H), 2.78 (m, 1H), 3.10 (m, 1H), 3.42 (m, 1 H) 7.08 (m, 3 H), 8.23 (br s, 1 H).
[제조예 2] (S)- 2′,6′-피페콜옥실리디드의 제조Production Example 2 Preparation of (S) -2 ′, 6′-Pipecoloxylidide
라세미 2′,6′-피페콜옥실리디드 50g (0.22mol)을 이소프로판올 340mL에 현탁한 후 60 ℃로 가온한다. (-)-디벤조일-L-타르타르산 1수화물 47.9g (0.12mol)을 이소프로판올 170mL에 녹여 60 ℃로 가온한 용액을 상기의 반응액에 가한다. 10분간 환류시킨 후 1~2시간 동안 서서히 실온으로 냉각한다. 생성된 결정을 여과하고, 이소프로판올 50mL로 세척, 50 ℃에서 6시간 건조한다.50 g (0.22 mol) of racemic 2 ′, 6′-pipecolicoxylidide are suspended in 340 mL of isopropanol and warmed to 60 ° C. 47.9 g (0.12 mol) of (-)-dibenzoyl-L-tartaric acid monohydrate is dissolved in 170 mL of isopropanol, and a solution warmed to 60 DEG C is added to the reaction solution. After refluxing for 10 minutes, the mixture is slowly cooled to room temperature for 1 to 2 hours. The resulting crystals are filtered off, washed with 50 mL of isopropanol and dried at 50 ° C. for 6 hours.
얻어진 고체를 정제수 200mL와 초산에틸 200mL에 현탁하고, 수산화 나트륨수용액으로 pH 11로 조정한다. 분리한 수층을 초산에틸 100mL로 1회 더 추출한다. 유기층을 모아 포화 소금물 100mL로 세척하고, 무수황산마그네슘으로 건조하고 용매 를 감압 증류하여 (S)-2′,6′-피페콜옥실리디드를 얻는다.The obtained solid is suspended in 200 mL of purified water and 200 mL of ethyl acetate and adjusted to pH 11 with aqueous sodium hydroxide solution. The separated aqueous layer is extracted once more with 100 mL of ethyl acetate. Wash combined organic layers with saturated brine 100mL, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure of the solvent (S) - 2 ', 6'-piperazine to obtain the call oksilri bonded.
수율; 40% (90% ee) yield; 40% (90% ee)
[α]D = + 41.8°(c 2.035, 1N HCl).[a] D = + 41.8 ° (c 2.035, 1N HCl).
[실시예 1] 레보부피바카인의 합성 Example 1 Synthesis of Levobupivacaine
a) 제조예 2에서 제조된 (S)-2′,6′-피페콜옥실리디드 10g(43mmol)을 이소프로판올 70mL에 현탁한다. 탄산칼륨 12g (86mmol)과 1-브로모부탄 12g (86mmol)을 가하고 15시간 동안 환류한다. 50℃에서 감압증류하여 얻은 잔사에 정제수 100mL를 가하고 2시간 동안 교반한다. 생성된 결정을 여과하고, 정제수 30mL로 세척한다. 얻어진 결정을 50℃에서 진공 건조한다(수율; 97%). a) the (S) produced in Production Example 2 and a suspension of 2 ', 6'-yl-call oksilri bonded 10g (43mmol) in 70mL of isopropanol. 12 g (86 mmol) of potassium carbonate and 12 g (86 mmol) of 1-bromobutane are added and refluxed for 15 hours. 100 mL of purified water was added to the residue obtained by distillation under reduced pressure at 50 ° C, and stirred for 2 hours. The resulting crystals are filtered off and washed with 30 mL of purified water. The obtained crystals are dried in vacuo at 50 ° C. (yield: 97%).
b) 상기의 얻어진 결정을 시클로헥산 35mL에 가하고 30분간 환류한다. 서서히 실온으로 냉각하여 2시간 교반하여 석출된 결정을 여과한다. 시클로헥산 10mL로 세척한 후 50 ℃에서 건조하여 레보부피바카인을 얻는다. b) The obtained crystals are added to 35 mL of cyclohexane and refluxed for 30 minutes. The mixture was gradually cooled to room temperature, stirred for 2 hours, and the precipitated crystals were filtered out. After washing with 10 mL of cyclohexane and dried at 50 ℃ to obtain levobupivacaine.
수율; 85%, yield; 85%,
mp 136℃,mp 136 ° C.,
[α]D = -79.4°(c 2, 1N HCl). 98.1% ee[α] D = -79.4 ° (c 2, 1N HCl). 98.1% ee
1H-NMR(DMSO-d6) ; δ 0.87(3H, t), 1.26(3H, m), 1.53(4H, m), 1.71(2H, m), 1.81(1H, m), 1.99 (1H, m), 2.12(6H, S), 2.21(1H, m), 2.62(1H, m), 2.84(1H, m), 3.08(1H, m), 7.05(3H, S). 1 H-NMR (DMSO-d 6 ); δ 0.87 (3H, t), 1.26 (3H, m), 1.53 (4H, m), 1.71 (2H, m), 1.81 (1H, m), 1.99 (1H, m), 2.12 (6H, S), 2.21 (1H, m), 2.62 (1H, m), 2.84 (1H, m), 3.08 (1H, m), 7.05 (3H, S).
[실시예 2] 레보부피바카인의 합성Example 2 Synthesis of Levobupivacaine
a) 제조예 2에서 제조된 (S)-2′,6′-피페콜옥실리디드 20g(86mmol)을 디메틸포름아미드 50mL에 현탁한다. 탄산칼륨 14.4g (103.2mmol)과 1-브로모부탄 14.4g (103.2mmol)을 가하고 70℃에서 3시간 동안 교반한다. 반응액을 30℃로 냉각한 후 정제수 225mL를 가하고 2시간 교반한다. 생성된 고체를 여과하고 정제수 50mL로 세척한다. 얻어진 결정을 50℃에서 진공 건조한다(수율; 95%).a) the (S) produced in Production Example 2 and a suspension of 2 ', 6'-yl-call oksilri bonded 20g (86mmol) in 50mL of dimethylformamide. 14.4 g (103.2 mmol) of potassium carbonate and 14.4 g (103.2 mmol) of 1-bromobutane are added and stirred at 70 ° C. for 3 hours. After cooling the reaction solution to 30 ℃, 225 mL of purified water was added and stirred for 2 hours. The resulting solid is filtered and washed with 50 mL of purified water. The obtained crystals are dried in vacuo at 50 ° C. (yield: 95%).
b) 상기의 결정에 시클로헥산 70mL를 가하고 30분간 환류한다. 서서히 실온으로 냉각하여 2시간 교반하여 얻어진 결정을 여과한다. 시클로헥산 20mL로 세척한 후 50 ℃에서 건조하여 레보부피바카인을 얻는다. b) 70 mL of cyclohexane was added to the above crystals and refluxed for 30 minutes. The crystal obtained by cooling gradually to room temperature and stirring for 2 hours is filtered. After washing with 20 mL of cyclohexane, it is dried at 50 ° C to obtain levobupivacaine.
수율; 80%, yield; 80%,
mp 136℃,mp 136 ° C.,
[α]D = -79.6°(c 2, 1N HCl). 98.3% ee[a] D = -79.6 ° (c 2, 1N HCl). 98.3% ee
1H-NMR(DMSO-d6) ; 실시예1의 것과 동일함. 1 H-NMR (DMSO-d 6 ); Same as that of Example 1.
[실시예 3] 레보부피바카인 염산염의 합성Example 3 Synthesis of Levobupivacaine Hydrochloride
실시예 2 또는 실시에 3에서 얻어진 광학 순도 98 % ee 이상의 (S)-부피바카인 9g (31.2mmol)을 아세톤 45mL에 현탁한 후, 염산 13.5mL를 가하고 실온에서 2시간 교반한다. 0℃로 냉각하여 2시간 더 교반하여 생성된 결정을 여과하고 아세톤 9mL로 세척 후, 50 ℃에서 15시간 진공 건조하여 백색의 결정으로서 상기의 레보부피바카인 염산염을 얻는다.9 g (31.2 mmol) of (S) -Bupivacaine having an optical purity of 98% ee or more obtained in Example 2 or 3 was suspended in 45 mL of acetone, and then 13.5 mL of hydrochloric acid was added and stirred at room temperature for 2 hours. The resulting crystals were cooled to 0 ° C. and stirred for 2 hours, filtered and washed with 9 mL of acetone, followed by vacuum drying at 50 ° C. for 15 hours to obtain the above-mentioned levobupivacaine hydrochloride as white crystals.
수율; 85%, yield; 85%,
mp 250℃,mp 250 ° C.,
[α]D = -12.56° (c 2, H2O). > 99% ee [a] D = -12.56 ° (c 2, H 2 O). > 99% ee
1H-NMR(CD3OD); δ 1.0(3H, t), 1.4(2H, m), 1.6~2.1(7H, m), 2.2(6H, s), 2.5(1H, m), 3.2 (3H, m), 3.7(1H, d), 4.2(1H, m), 7.1(3H, m). 1 H-NMR (CD 3 OD); δ 1.0 (3H, t), 1.4 (2H, m), 1.6 ~ 2.1 (7H, m), 2.2 (6H, s), 2.5 (1H, m), 3.2 (3H, m), 3.7 (1H, d ), 4.2 (1H, m), 7.1 (3H, m).
본 발명에 따른 레보부피바카인 및 이의 염산염의 제조방법은 제조공정이 간 단하며, 사용하는 시약의 취급이 용이하고, 레보부피바카인의 거울상 이성체 과잉율도 98% ee 이상으로 제조할 수 있으며, 이렇게 제조된 레보부피바카인을 염산염으로 전환하면 99% ee 이상의 광학 순도를 가지는 고순도의 레보부피바카인 염산염을 제조할 수 있는 장점이 있다.According to the present invention, the preparation method of levobupivacaine and its hydrochloride salt is simple, the handling of reagents used is easy, and the enantiomeric excess rate of levobupivacaine can be prepared to 98% ee or more. Converting the prepared levobupivacaine to hydrochloride has the advantage of producing a high-purity levobupivacaine hydrochloride having an optical purity of 99% ee or more.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103664744A (en) * | 2013-11-30 | 2014-03-26 | 山东永泰化工有限公司 | Preparation method for levobupivacaine |
CN105315196A (en) * | 2015-11-28 | 2016-02-10 | 山东齐都药业有限公司 | High-purity levobupivacaine hydrochloride refining method |
CN105585520A (en) * | 2015-12-24 | 2016-05-18 | 山东齐都药业有限公司 | Levobupivacaine hydrochloride crystal form A and preparation method thereof |
CN107162958A (en) * | 2017-06-27 | 2017-09-15 | 江苏恒瑞医药股份有限公司 | Bupivacaine crystal formation and preparation method thereof |
CN110117250A (en) * | 2018-02-06 | 2019-08-13 | 四川科伦药物研究院有限公司 | A kind of preparation method of Bupivacaine crystal form |
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CN105315196A (en) * | 2015-11-28 | 2016-02-10 | 山东齐都药业有限公司 | High-purity levobupivacaine hydrochloride refining method |
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CN107162958A (en) * | 2017-06-27 | 2017-09-15 | 江苏恒瑞医药股份有限公司 | Bupivacaine crystal formation and preparation method thereof |
CN110117250A (en) * | 2018-02-06 | 2019-08-13 | 四川科伦药物研究院有限公司 | A kind of preparation method of Bupivacaine crystal form |
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