KR19990060686A - Manufacturing method of paclitaxel - Google Patents
Manufacturing method of paclitaxel Download PDFInfo
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- KR19990060686A KR19990060686A KR1019970080929A KR19970080929A KR19990060686A KR 19990060686 A KR19990060686 A KR 19990060686A KR 1019970080929 A KR1019970080929 A KR 1019970080929A KR 19970080929 A KR19970080929 A KR 19970080929A KR 19990060686 A KR19990060686 A KR 19990060686A
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Abstract
본 발명은 (a) 하기 화학식 2의 옥사졸리딘 다이머 유도체 또는 그의 염을 용매중에서 축합제 존재하에 하기 화학식 3의 7-트리할로아세틸-박카틴 III와 커플링시켜 하기 화학식 4의 옥사졸리딘 측쇄-함유 탁산 다이머를 제조하고; (b) 용매중에서 산 존재하에 옥사졸리딘환을 개환시키고 R이 t-부톡시카보닐인 경우에는 추가로 염기 존재하에 벤조일클로라이드와 반응시켜 하기 화학식 5의 7-트리할로아세틸 파클리탁셀을 제조한 다음; (c) 7-위치의 트리할로아세틸을 용매중에서 암모니아 또는 암모니아와 약산과의 염으로 제거함을 특징으로하여 하기 화학식 1의 파클리탁셀을 제조하는 방법에 관한 것이다.The present invention relates to (a) an oxazolidine of formula (4) by coupling an oxazolidine dimer derivative of formula (2) or a salt thereof to a 7-trihaloacetyl-baccatin III of formula (3) in the presence of a condensing agent in a solvent: Preparing a side chain-containing taxane dimer; (b) ring-opening an oxazolidine ring in the presence of an acid in a solvent and reacting with benzoyl chloride in the presence of a base in the case where R is t-butoxycarbonyl to prepare 7-trihaloacetyl paclitaxel of Formula 5 ; (c) a method of preparing paclitaxel of formula (I) characterized by removing trihaloacetyl in 7-position with ammonia or a salt of ammonia and a weak acid in a solvent.
상기식에서In the above formula
R 은 t-부톡시카보닐 또는 벤조일을 나타내고,R represents t-butoxycarbonyl or benzoyl,
R1은 트리할로아세틸을 나타낸다.R 1 represents trihaloacetyl.
Description
본 발명은 하기 화학식 1로 표시되는 파클리탁셀의 신규한 제조방법에 관한 것이다.The present invention relates to a novel method for producing paclitaxel represented by the following formula (1).
화학식 1Formula 1
상기식에서In the above formula
Ph 는 페닐을 나타내고, Ac 는 아세틸을 나타내며, Bz 는 벤조일을 나타내고, 이하 동일한 의미로 사용된다.Ph represents phenyl, Ac represents acetyl, Bz represents benzoyl and is used hereinafter in the same sense.
본 발명은 또한, 상기 화학식 1의 파클리탁셀을 제조하는 과정에서 사용하는 신규한 중간체 및 그의 제조방법에 관한 것이다.The present invention also relates to a novel intermediate used in the process of preparing paclitaxel of Chemical Formula 1 and a method for preparing the same.
상기 화학식 1의 파클리탁셀은 테르펜 탁산계 유도체로서, 광범위한 항백혈병 및 항종양 활성을 갖는 유망한 암화학요법제로 최근 생물 및 화학 양 분야에서 상당한 관심을 끌고있으며, 미합중국을 비롯한 여러국가에서 이미 그 활성을 인정받아 난소암과 유방암에 대한 약제로서 시판하는 것이 허가되어 있다.Paclitaxel of Formula 1 is a terpene taxane-based derivative, a promising cancer chemotherapy agent having a wide range of anti-leukemia and anti-tumor activity, has recently attracted considerable attention in the field of biological and chemical quantities, and has already been recognized for its activity in the United States and other countries. It is approved to market as a drug against ovarian cancer and breast cancer.
지금까지 파클리탁셀은 주로 서양주목의 일종인 탁수스 브레비폴리아(Taxus brevifolia)의 나무껍질로부터 분리, 제공되어 왔는데, 그 분리 및 정제공정이 매우 까다로울뿐 아니라, 성장이 느린 이들 상록수의 나무껍질에는 파클리탁셀이 소량밖에 함유되어 있지 않기 때문에 파클리탁셀에 대해 점점 증가하는 높은 수요를 충족시키기에는 역부족이었다.To date, paclitaxel has been isolated and provided mainly from the bark of Taxus brevifolia, a species of oleander, which is not only very difficult to separate and purify, but also contains paclitaxel in the bark of these slow-growing evergreen trees. Because it contained only a small amount, it was not enough to meet the ever-increasing demand for paclitaxel.
따라서, 최근 화학자들은 파클리탁셀의 제조용으로 실행가능한 반합성 경로(semi-synthesis) 및 이 화합물의 제조에 사용되는 중간체들의 제조방법을 포함한 합성법 개발에 많은 노력을 기울여 왔으나, 발표된 다수의 합성방법들이 완전히 만족스러운 결과를 나타내지는 못하고 있다.Thus, chemists have recently put a lot of effort into the development of synthetic methods, including semi-synthesis viable for the preparation of paclitaxel and methods of preparing intermediates used in the preparation of these compounds, but many of the published synthetic methods are fully satisfied. The results are not as good.
예를들어, 하기 반응식 1에 나타낸 바와 같이, 옥사졸리딘 유도체를 디사이클로헥실카르보디이미드 또는 2-디피리딜카보네이트 존재하에 7-Troc-박카틴 III와 커플링시키는 기술이 문헌에 공지되어 있다(참조: Commercon, et al., Tetrahedron Letters, pp5185-5188, 1992).For example, as shown in Scheme 1, techniques for coupling oxazolidine derivatives with 7-Troc-baccatin III in the presence of dicyclohexylcarbodiimide or 2-dipyridylcarbonate are known in the literature. (Commercon, et al., Tetrahedron Letters, pp5185-5188, 1992).
상기식에서In the above formula
Boc 는 t-부톡시카르보닐을 나타내고, Troc 는 트리클로로에톡시카르보닐을 나타내며, 이하 동일한 의미로 사용된다.Boc represents t-butoxycarbonyl, Troc represents trichloroethoxycarbonyl, and it is used by the same meaning below.
상기 파클리탁셀 제법에서는 탁산의 보호기로 -Troc을 사용하였다. 그러나, 이 새로운 보호기를 사용함에 따라 여러단계의 공정을 거쳐야 하는 불편이 생기게 되었고, 이렇게 여러단계를 거침에도 불구하고 역시 보호기화 및 탈보호기화 공정에서 격렬한 반응조건이 요구되었으며, 이에 따라 수율도 저조하여 바람직하지 못한 것으로 나타났다.In the paclitaxel preparation, -Troc was used as a protector of taxane. However, the use of this new protecting group has caused inconvenience to go through several stages of process, and despite this many stages, violent reaction conditions were required in the protection and deprotection process, and the yield was also low. It turned out to be undesirable.
한편, 대한민국 공개특허 제 95-703548 호의 실시예 11에서는 또다른 옥사졸리딘 유도체를 출발물질로 사용하여 파클리탁셀을 제조하는 하기 반응식 2의 방법을 기술하고 있다.Meanwhile, Example 11 of Korean Patent Application Laid-Open No. 95-703548 describes a method of Scheme 2 below, which prepares paclitaxel using another oxazolidine derivative as a starting material.
상기식에서In the above formula
TES는 트리에틸실릴을 나타내며, 이하 동일한 의미로 사용된다.TES stands for triethylsilyl and is used synonymously below.
상기 반응식 2의 방법에서는 옥사졸리딘 유도체를 7-TES-박카틴 III와 커플링시켜 측쇄-함유 탁산을 생성한 다음 이를 개환시키고 탈보호기화시켜 파클리탁셀을 제조하고 있다. 그러나, 이 방법에서는 커플링시 수율이 54%로 매우 낮을 뿐아니라, 한 공정으로 이루어져 있는 개환 및 탈보호기화 공정의 수율 역시 51.4%로 매우 낮아 전체적인 생산성이 떨어지는 문제점이 있다.In the method of Scheme 2, oxazolidine derivatives are coupled with 7-TES-baccatin III to produce side chain-containing taxanes, which are then ring-opened and deprotected to prepare paclitaxel. However, in this method, the yield is not only very low as 54% at the time of coupling, but also the yield of the ring-opening and deprotection-gasification process consisting of one process is very low as 51.4%.
이와 같이, 옥사졸리딘 유도체를 측쇄 치환체로서 사용하는 기존의 파클리탁셀 제조법들은 여러 공정을 거치면서도 격렬한 반응조건을 요구하거나 생산성이 떨어지는 등의 문제점을 안고 있다.As described above, conventional paclitaxel production methods using oxazolidine derivatives as side chain substituents have problems such as demanding violent reaction conditions or low productivity even though they undergo various processes.
또한, 파클리탁셀의 합성에 있어 중요한 또 하나의 기술이 탁산의 보호기 선택문제인데, 트리에틸실릴기(반응식 2 참조) 또는 트리클로로에톡시카르보닐기(반응식 1 참조)등 현재까지 보고된 보호기들은 모두 그를 제거하는 단계에서, 예를들어 아연 및 AcOH/ MeOH=1:1, 60oC 조건에서 반응시키거나, 0.9N HCl/EtOH 중에서 6시간동안 반응시키는 등의 매우 격렬한 조건을 필요로 하는 문제점을 가지고 있다. 더구나, 이들은 보호기화 단계에서도, 트리에틸실릴기의 경우 고가의 트리에틸실릴 클로라이드를 과량(20당량)으로 사용해야 하고 (참조: 국제특허 제 93/ 06094 호), 트리클로로에톡시카르보닐의 경우 선택성이 없어 복잡한 합성경로를 통해야 하는 등의 문제점이 있다(참조: Commercon, et al., Tetrahedron Letters, pp5185-5188, 1992).In addition, another important technique in the synthesis of paclitaxel is the problem of protecting group selection of taxanes, all of which have been reported to date, such as triethylsilyl (see Scheme 2) or trichloroethoxycarbonyl (see Scheme 1). In the step of, for example, zinc and AcOH / MeOH = 1: 1, 60 ° C conditions, or reacted for 6 hours in 0.9N HCl / EtOH, there is a problem that requires a very vigorous condition . Furthermore, they must use an excess (20 equivalents) of expensive triethylsilyl chloride for the triethylsilyl group even in the protecting grouping step (see International Patent No. 93/06094) and selectivity for trichloroethoxycarbonyl There is a problem such as having to go through a complicated synthetic route due to the absence of such a material (see Commercon, et al., Tetrahedron Letters, pp5185-5188, 1992).
이에 본 발명자들은, 파클리탁셀 제조에 있어서 상기 설명한 바와 같은 선행기술들의 문제점을 개선하고 보다 용이하게 효율적으로 파클리탁셀을 제조할 수 있는 방법을 개발하고자 수년간에 걸쳐 집중적인 연구를 수행하였다. 그 결과, 본 발명자들에 의해 새로이 개발된 옥사졸리딘 다이머 유도체를 7-번 위치의 하이드록실기가 트리할로아세틸에 의해 보호된 탁산 유도체와 커플링시킨 후 보호기를 제거하면 매우 온화한 반응조건에서 간편하게 파클리탁셀을 제조할 수 있음을 발견하고 본 발명을 완성하게 되었다.Accordingly, the present inventors have conducted intensive research for many years to improve the problems of the prior arts as described above in paclitaxel production and to develop a method for producing paclitaxel more easily and efficiently. As a result, when the oxazolidine dimer derivative newly developed by the present inventors was coupled with the taxane derivative protected by the trihaloacetyl group of the hydroxyl group at the 7-position, the protecting group was removed under very mild reaction conditions. The present invention has been accomplished by discovering that paclitaxel can be prepared simply.
따라서, 본 발명은 (a) 하기 화학식 2의 옥사졸리딘 다이머 유도체 또는 그의 염을 용매중에서 축합제 존재하에 하기 화학식 3의 7-트리할로아세틸-박카틴 III와 커플링시켜 하기 화학식 4의 옥사졸리딘 측쇄-함유 탁산 다이머를 제조하고; (b) 용매중에서 산 존재하에 옥사졸리딘환을 개환시키고 R이 t-부톡시카보닐인 경우에는 추가로 염기 존재하에 벤조일클로라이드와 반응시켜 하기 화학식 5의 7-트리할로아세틸 파클리탁셀을 제조한 다음; (c) 7-위치의 트리할로아세틸을 용매중에서 암모니아 또는 암모니아와 약산과의 염으로 제거함을 특징으로하여 하기 화학식 1의 파클리탁셀을 제조하는 방법에 관한 것이다.Accordingly, the present invention is (a) the oxa of the formula (4) by coupling the oxazolidine dimer derivative of formula (2) or a salt thereof with a 7-trihaloacetyl-baccatin III of the formula (3) in the presence of a condensing agent in a solvent Preparing a zolidine side chain-containing taxane dimer; (b) ring-opening an oxazolidine ring in the presence of an acid in a solvent and reacting with benzoyl chloride in the presence of a base in the case where R is t-butoxycarbonyl to prepare 7-trihaloacetyl paclitaxel of Formula 5 ; (c) a method of preparing paclitaxel of formula (I) characterized by removing trihaloacetyl in 7-position with ammonia or a salt of ammonia and a weak acid in a solvent.
화학식 2Formula 2
화학식 3Formula 3
화학식 4Formula 4
화학식 5Formula 5
화학식 1Formula 1
상기식에서In the above formula
R 은 t-부톡시카보닐 또는 벤조일을 나타내고,R represents t-butoxycarbonyl or benzoyl,
R1은 트리할로아세틸을 나타낸다.R 1 represents trihaloacetyl.
본 발명은 또한, 화학식 1의 파클리탁셀을 제조하는데 중간체로서 사용되는 상기 화학식 2의 신규한 옥사졸리딘 다이머 유도체 및 그의 제조방법을 제공한다.The present invention also provides a novel oxazolidine dimer derivative of the above formula (2) used as an intermediate to prepare paclitaxel of the formula (1) and a method for preparing the same.
본 발명에 따라 파클리탁셀을 제조하는 방법은 하기 반응식 3에 도시한 바와 같이 요약하여 나타낼 수 있다.The method for preparing paclitaxel according to the present invention can be summarized as shown in Scheme 3 below.
반응식 3 의 제조과정에 대해 좀더 자세히 설명하면 다음과 같다.Hereinafter, the manufacturing process of Scheme 3 will be described in more detail.
화학식 3 의 7-트리할로아세틸-박카틴 III와 화학식 2의 옥사졸리딘 다이머 유도체를 커플링시켜 화학식 4의 옥사졸리딘 측쇄-함유 탁산 다이머를 제조하는 단계 (a)의 반응은 바람직하게는 40 내지 80oC의 온도범위에서 수행한다. 이때 사용가능한 용매로는 벤젠, 톨루엔, 크실렌 등의 방향족 탄화수소류, 디메틸아세트아미드, 디메틸포름아미드 등의 아미드류로부터 선택된 1 종 이상을 언급할 수 있다. 커플링 반응시 화학식 3의 화합물에 대해 화학식 2의 옥사졸리딘 다이머 유도체 또는 그의 염을 1/2몰배량으로 사용하는 것이 화학양론적 양이지만, 옥사졸리딘 다이머 유도체의 용해도 문제로 인하여 반응완결을 위해서는 1/2 내지 1몰배량 사용하는 것이 바람직하고, 옥사졸리딘 다이머 유도체와 화학식 3의 화합물을 무게비로 동량 사용하는 것이 특히 바람직하다. 커플링 반응은 축합제 존재하에 수행하며, 임의로 활성화제의 존재하에 바람직하게 수행할 수 있다. 사용가능한 축합제로는 카보디이미드류, 예를들어 디사이클로헥실카보디이미드, 또는 반응성 카보네이트류, 예를들어 2-디피리딜카보네이트를 들 수 있고, 활성화제로는 디알킬아미노피리딘류, 예를들어 4-디메틸아미노피리딘 또는 4-피롤리디노피리딘을 들 수 있다. 일반적으로 축합제는 화학식 2의 옥사졸리딘 다이머 유도체에 대해 화학양론적양으로 사용하고 활성화제는 화학식 3의 7-트리할로아세틸-박카틴 III에 대해 화학양론적양 이하의 양으로 사용한다.The reaction of step (a) of coupling the 7-trihaloacetyl-baccatin III of formula 3 with an oxazolidine dimer derivative of formula 2 to prepare an oxazolidine side chain-containing taxane dimer of formula 4 preferably It is carried out at a temperature range of 40 to 80 o C. At this time, as a solvent which can be used, 1 or more types chosen from aromatic hydrocarbons, such as benzene, toluene, xylene, and amides, such as dimethylacetamide and dimethylformamide, can be mentioned. Although the stoichiometric amount of the oxazolidine dimer derivative of Formula 2 or salt thereof with respect to the compound of Formula 3 is used in the coupling reaction in half molar amount, the reaction is completed due to the solubility of the oxazolidine dimer derivative. For this purpose, it is preferable to use 1/2 to 1 molar amount, and it is particularly preferable to use the same amount by weight ratio of the oxazolidine dimer derivative and the compound of the formula (3). The coupling reaction is carried out in the presence of a condensing agent, optionally in the presence of an activating agent. Usable condensing agents include carbodiimides such as dicyclohexylcarbodiimide, or reactive carbonates such as 2-dipyridylcarbonate, and activators include dialkylaminopyridines such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine. Generally, condensing agents are used in stoichiometric amounts for the oxazolidine dimer derivatives of Formula 2 and activators are used in amounts below the stoichiometric amounts for 7-trihaloacetyl-baccatin III of Formula 3.
화학식 2의 옥사졸리딘 다이머 유도체에서 C-2 위치는 비대칭중심을 형성하고 있으므로 단계 (a)에서 제조된 화학식 4의 옥사졸리딘 측쇄-함유 탁산 다이머는 부분입체이성체로 존재할 수 있으며, 이에 따라 TLC 분석에서 2개의 화합물로 분리된다(1H NMR 분석에 의해서도 확인됨). 화학식 2의 화합물 자체로는 TLC 분석에 의해 부분입체이성체를 구분할 수 없었으나, 화학식 3의 화합물과 같은 거대분자가 다이머 형태로 커플링된 이후에는 TLC에 의해서도 이성체의 분리가 가능해진 것이라 판단된다.Since the C-2 position in the oxazolidine dimer derivative of Formula 2 forms an asymmetric center, the oxazolidine side chain-containing taxane dimer of Formula 4 prepared in step (a) may exist as diastereomer, thus TLC It is separated into two compounds in the assay (also confirmed by 1 H NMR analysis). Although the diastereomer was not able to be distinguished by the compound of Formula 2 by TLC analysis, after the macromolecules such as the compound of Formula 3 were coupled in the dimer form, it was determined that the isomer could be separated by TLC.
단계 (b)의 반응은 R 치환체에 따라 반응경로가 달라진다. 즉, R이 t-부톡시카보닐인 경우에는 단계 (a)에서 생성된 화학식 4의 화합물을 용매중에서 산 존재하에 반응시켜 옥사졸리딘환을 개환시킨 다음 염기 존재하에 벤조일 클로라이드와 반응시켜 화학식 5의 화합물을 제조한다. 이때, 개환반응 및 보호기(BOC)제거반응을 동시에 수행하기 위해서는 강산성의 무수조건하에서 반응이 수행되어야 한다. 반면에 R이 벤조일인 경우에는 개환반응만을 수행함으로써 곧바로 화학식 5의 화합물을 제조할 수 있다.The reaction route of step (b) varies depending on the R substituent. That is, when R is t-butoxycarbonyl, the compound of formula 4 produced in step (a) is reacted in the presence of an acid in a solvent to open an oxazolidine ring and then reacted with benzoyl chloride in the presence of a base to Prepare the compound. In this case, in order to simultaneously perform the ring opening reaction and the protecting group (BOC) removal reaction, the reaction must be performed under anhydrous conditions of strong acidity. On the other hand, when R is benzoyl, the compound of Formula 5 may be prepared directly by performing only the ring opening reaction.
어떤 반응경로에서건 반응액의 산도를 조절하기 위하여 사용가능한 산으로는 염산, 황산, 질산, 트리플루오로아세트산, p-톨루엔설폰산, 메탄설폰산 등을 언급할 수 있고, 산은 화학식 4의 화합물에 대해 화학양론적양 이상의 양을 사용하는 것이 바람직하다. 또한, 반응용매로는 테트라하이드로푸란, 디옥산 등의 에테르류, 아세토니트릴 등의 니트릴류, 아세톤, 메틸이소부틸케톤 등의 케톤류, 에틸아세테이트, 이소프로필아세테이트, n-부틸아세테이트 등의 에스테르류, 디클로로메탄, 클로로포름, 1,2-디클로로에탄 등의 염화 탄화수소류, 메탄올, 에탄올, 이소프로판올, n-부탄올 등의 알콜류, 디메틸아세트아미드, 디메틸포름아미드 등의 아미드류로부터 선택된 1 종 이상을 사용할 수 있으며, 반응은 바람직하게는 -20 내지 60oC 의 온도범위에서 수행한다.Acids usable for controlling the acidity of the reaction solution in any reaction path may include hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, and the like. It is preferred to use an amount greater than stoichiometric for. Examples of the reaction solvent include ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, ketones such as acetone and methyl isobutyl ketone, esters such as ethyl acetate, isopropyl acetate and n-butyl acetate, One or more selected from chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, alcohols such as methanol, ethanol, isopropanol and n-butanol, and amides such as dimethylacetamide and dimethylformamide. , The reaction is preferably carried out at a temperature range of -20 to 60 o C.
R이 t-부톡시카보닐인 경우에는 수득된 반응용액을 적절한 염기로 중화시키고 물을 가한후 벤조일클로라이드를 가하여 반응시키는 추가의 공정을 수행함으로써, R이 벤조일인 경우에는 이러한 추가공정을 수행할 필요없이, 화학식 5의 7-트리할로아세틸 파클리탁셀을 제조한다. 전자의 경우 반응물질로 사용된 벤조일클로라이드는 화학식 4의 옥사졸리딘 측쇄-함유 탁산 다이머에 대해 화학양론적양으로, 구체적으로는 2 내지 3당량배로 사용하는 것이 바람직하며, 염기로는 물에 녹을 수 있는 염기로서 중탄산나트륨, 중탄산칼륨, 탄산나트륨, 탄산칼륨, 수산화나트륨 및 수산화리튬 중에서 선택된 1 종 이상을 화학식 4의 화합물에 대해 3 내지 20당량배로 사용한다.If R is t-butoxycarbonyl, the additional reaction step is carried out by neutralizing the obtained reaction solution with an appropriate base, adding water, and then adding benzoyl chloride to react, if R is benzoyl. Without need, 7-trihaloacetyl paclitaxel of Formula 5 is prepared. In the former case, the benzoyl chloride used as the reactant is preferably used in stoichiometric amount, specifically 2 to 3 equivalents, with respect to the oxazolidine side chain-containing taxane dimer of Formula 4, and the base may be dissolved in water. As the base, at least one selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and lithium hydroxide is used in an amount of 3 to 20 equivalents based on the compound of formula (4).
마지막으로 단계 (c)에서는, 화학식 5 화합물의 7-번 위치의 트리할로아세틸 보호기를 암모니아 또는 암모니아와 약산과의 염으로 제거하여 본 발명의 목적화합물인 화학식 1의 파클리탁셀을 제조한다. 이때, 암모니아로는 5 내지 40% 농도의 암모니아수나 동일농도의 암모니아-유기용매 용액을 사용하며, 암모니아의 양은 화학식 5의 화합물에 대해 화학양론적양 또는 그 이상의 양, 바람직하게는 1 내지 5 당량배로 사용한다. 암모니아와 약산과의 염을 사용할 경우 화학식 5의 화합물에 대해 1 내지 5 당량배 범위로 사용하며, 이때 암모니아와 염을 형성할 수 있는 약산은 포름산, 아세트산, 프로피온산 등으로부터 선택하여 사용할 수 있다. 반응용매로는 메탄올, 에탄올, 이소프로필알콜 등의 알콜류, 테트라하이드로푸란, 디옥산 등의 에테르류, 아세토니트릴 등의 니트릴류, 에틸아세테이트, 이소프로필아세테이트, n-부틸아세테이트 등의 에스테르류, 디클로로메탄, 클로로포름, 1,2-디클로로에탄 등의 염화 탄화수소류, 디메틸아세트아미드, 디메틸포름아미드 등의 아미드류로부터 선택된 1 종 이상을 사용할 수 있으며, 반응은 바람직하게는 0 내지 60oC의 온도범위에서 수행한다. 이로써, 지금까지 통상적으로 탁산의 7-번 위치 보호기를 제거하는데 매우 강한 산성조건을 요구했음에 비해 본 발명에서는 암모니아용액 또는 암모니아와 약산과의 염을 이용한 약염기성 또는 거의 중성의 조건에서 극히 용이하게 탁산의 보호기를 제거할 수 있게 되었다.Finally, in step (c), paclitaxel of formula 1, which is the target compound of the present invention, is prepared by removing the trihaloacetyl protecting group at the 7-position of the compound of formula 5 with ammonia or a salt of ammonia and a weak acid. In this case, ammonia water or an ammonia-organic solvent solution having the same concentration may be used as ammonia, and the amount of ammonia may be stoichiometric or higher, preferably 1 to 5 equivalent times, based on the compound of Formula 5. use. When a salt of ammonia and a weak acid is used, it is used in an amount of 1 to 5 equivalents based on the compound of Formula 5, wherein a weak acid capable of forming a salt with ammonia may be selected from formic acid, acetic acid, propionic acid, and the like. Examples of the reaction solvent include alcohols such as methanol, ethanol and isopropyl alcohol, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, esters such as ethyl acetate, isopropyl acetate and n-butyl acetate, and dichloro One or more selected from chlorinated hydrocarbons such as methane, chloroform and 1,2-dichloroethane, and amides such as dimethylacetamide and dimethylformamide may be used, and the reaction is preferably in a temperature range of 0 to 60 ° C. Perform on As a result, in the present invention, very strong acidic conditions are required to remove the 7-position protecting group of taxanes. Thus, the present invention is very easily performed in weakly basic or almost neutral conditions using ammonia solution or a salt of ammonia and weak acid. The protecting group of taxanes can now be removed.
한편, 옥사졸리딘 다이머 형태로 존재하는 상기 화학식 2의 중간체는 신규한 화합물이므로 본 발명은 이와 같이 신규한 화학식 2의 옥사졸리딘 다이머 유도체를 제공함을 또다른 목적으로 한다.On the other hand, since the intermediate of the formula (2) present in the form of oxazolidine dimer is a novel compound, it is another object of the present invention to provide a novel oxazolidine dimer derivative of the formula (2).
화학식 2의 화합물은 하기 화학식 6의 아민기가 보호된 (2R,3S)-페닐이소세린 유도체를 용매중에서 산촉매 존재하에 하기 화학식 7의 화합물과 반응시켜 하기 화학식 8의 화합물을 생성한 다음, 이를 가수분해시켜 제조할 수 있으며, 이 제조방법 역시 본 발명의 대상이 된다.The compound of formula (2) is reacted with a compound of formula (7) in which the (2R, 3S) -phenylisoserine derivative protected by the amine group of formula (6) in the presence of an acid catalyst in a solvent to produce a compound of formula (8), and then hydrolyze it Can be prepared, and this manufacturing method is also a subject of the present invention.
상기식에서In the above formula
R은 앞에서 정의한 바와 같고,R is as defined above,
R2및 R3는 C1-C3알킬을 나타낸다.R 2 and R 3 represent C 1 -C 3 alkyl.
이를 간단하게 반응식으로 나타내면 하기 반응식 4와 같다.If this is simply represented by the reaction scheme shown in Scheme 4.
반응식 4에서 화학식 8의 화합물을 합성함에 있어서, 산촉매로는 p-톨루엔설폰산, 메탄설폰산, 트리플루오로메틸설폰산, 피리디늄 p-톨루엔설포네이트 등을 사용할 수 있으며, 용매로는 벤젠, 톨루엔, 크실렌 등의 방향족 탄화수소류로부터 선택된 1 종 이상을 사용할 수 있다.In synthesizing the compound of Chemical Formula 8 in Scheme 4, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethylsulfonic acid, pyridinium p-toluenesulfonate, etc. may be used as an acid catalyst, and benzene, One or more types selected from aromatic hydrocarbons such as toluene and xylene can be used.
수득된 화학식 8의 화합물은 에스테르형태(R2=알킬)이므로 가수분해공정을 수행함으로써 화학식 2의 화합물을 제조한다. 가수분해제로는 수용성 염기를 사용하는데, 예를들어 수산화물, 바람직하게는 수산화리튬, 수산화나트륨, 수산화칼륨 등의 알칼리금속 수산화물을 사용하며, 화학식 8의 에스테르 화합물에 대해 2 내지 3당량배로 사용한다. 반응용매로는 메탄올, 에탄올, 이소프로필알콜, 테트라하이드로푸란, 디메틸포름아미드, 아세톤 또는 아세토니트릴과 같이 수혼화성 유기용매와 물과의 혼합용매를 사용하며 이때 유기용매와 물의 부피비는 바람직하게는 10:1 내지 100:1이다. 본 반응은 바람직하게는 -20 내지 60oC의 온도범위에서 수행한다. 가수분해가 완료된 후 유기용매를 감압증류로 제거하여 얻어진 화학식 2의 옥사졸리딘 다이머 유도체는 무기염상태(RCO2M)로 존재하는데, 이를 유리산 형태(RCO2H)로 전환시켜주기 위하여 산 또는 pH 5 내지 7 범위의 완충액을 사용한다. 이때, 사용가능한 산으로는 염산, 포름산, 아세트산, 트리플루오로아세트산 등을 언급할 수 있으며, 가수분해 반응에서 사용한 알칼리 금속 수산화물과 같은 당량으로 사용한다.Since the obtained compound of Formula 8 is in ester form (R 2 = alkyl), the compound of Formula 2 is prepared by performing a hydrolysis process. As the hydrolysis agent, a water-soluble base is used, for example, a hydroxide, preferably an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc., and is used in an amount of 2-3 equivalents based on the ester compound of the formula (8). As the reaction solvent, a mixed solvent of water-miscible organic solvent and water such as methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dimethylformamide, acetone or acetonitrile is used, and the volume ratio of the organic solvent and water is preferably 10 : 1 to 100: 1. The reaction is preferably carried out at a temperature range of -20 to 60 o C. After completion of the hydrolysis, the oxazolidine dimer derivative of Formula 2 obtained by removing the organic solvent by distillation under reduced pressure is present in an inorganic salt state (RCO 2 M), which is converted into an acid or free acid form (RCO 2 H). Buffers in the pH range of 5-7 are used. In this case, as the acid which can be used, hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid and the like can be mentioned and used in the same amount as the alkali metal hydroxide used in the hydrolysis reaction.
제조된 화학식 2의 옥사졸리딘 다이머 유도체는 매우 안정한 상태로서 실온에서 장기간 보관할 수 있으나, 커플링 반응시 용해도에 문제가 있으므로 하기 화학식 2a로 나타낸 바와 같은 3차 유기염기와의 염 형태로 사용하는 것이 바람직하다.The prepared oxazolidine dimer derivative of Formula 2 is very stable and can be stored at room temperature for a long time, but there is a problem in solubility during the coupling reaction, so it is used in the form of a salt with a tertiary organic base group represented by Formula 2a. desirable.
상기식에서In the above formula
R은 앞에서 정의한 바와 같고,R is as defined above,
R4, R5및 R6은 각각 독립적으로 C1-C4알킬 또는 페닐알킬을 나타내거나, R5및 R6이 함께 4 내지 7원환을 형성할 수도 있다.R 4 , R 5 and R 6 each independently represent C 1 -C 4 alkyl or phenylalkyl, or R 5 and R 6 may together form a 4 to 7 membered ring.
참고로 상기 반응식 4에서 출발물질로 사용된 화학식 6의 아민기가 보호된 (2R,3S)-페닐이소세린 유도체 및 그의 염은 문헌(참조: 미합중국 특허 제 5,420,337 호; 콤머슨 등, Tetrahedron Letters, 33, 5185-5188(1992); 및 김완주등, 한국 특허출원 제 96-7304 호)에 공지된 방법을 응용하여 제조할 수 있다.For reference, (2R, 3S) -phenylisoserine derivatives having a protected amine group of the formula (6) used as starting materials in Scheme 4 and salts thereof are described in US Pat. No. 5,420,337; Commerson et al., Tetrahedron Letters, 33 , 5185-5188 (1992); and Kim, Wan-Ju et al., Korean Patent Application No. 96-7304).
이하, 본 발명을 하기 실시예에 의거하여 보다 구체적으로 설명한다. 그러나, 이는 본 발명에 대한 이해를 돕기위한 것일 뿐, 어떤 의미로든 본 발명의 범위가 이들 실시예로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples. However, this is only for better understanding of the present invention, and the scope of the present invention is not limited to these examples in any sense.
실시예 1: 10-데아세틸-7-트리클로로아세틸-박카틴 III의 제조Example 1 Preparation of 10-Deacetyl-7-trichloroacetyl-baccatin III
클로로포름 1.35ℓ에 10-데아세틸-박카틴 III 30g(0.055mol)을 용해시킨다음, 피리딘 134㎖(30eq.)를 적가한 후 10분동안 교반하였다. 트리클로로아세틸클로라이드 12g(0.066mol)을 천천히 가하고 실온에서 30분동안 교반한 후 트리클로로아세틸클로라이드 3g(0.017mol)을 다시 가한 후 20분동안 교반시켰다. 감압하에 용매를 제거한 후 잔류물에 물 100㎖를 가하고, 에틸아세테이트 700㎖로 추출하였다. 유기층을 소금물로 세척하고 무수 황산마그네슘으로 수분을 제거한 후 감압증류하였다. 잔류물을 톨루엔 200㎖에 녹인 후 0oC로 냉각시켜 생성된 미세한 고체를 여과하고 n-헥산 200㎖로 세척하여 순수한 표제화합물 36g(수율: 95%)을 수득하였다.30 g (0.055 mol) of 10-deacetyl-baccatin III was dissolved in 1.35 L of chloroform, and then 134 mL (30 eq.) Of pyridine was added dropwise and stirred for 10 minutes. 12 g (0.066 mol) of trichloroacetyl chloride was slowly added and stirred at room temperature for 30 minutes, and then 3 g (0.017 mol) of trichloroacetyl chloride was added again, followed by stirring for 20 minutes. After the solvent was removed under reduced pressure, 100 ml of water was added to the residue, followed by extraction with 700 ml of ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, and distilled under reduced pressure. The residue was dissolved in 200 ml of toluene, cooled to 0 ° C., and the resulting fine solid was filtered and washed with 200 ml of n-hexane to give 36 g (yield: 95%) of pure title compound.
융점: 216oCMelting Point: 216 o C
[a]D 25= -45.3o(c=1, CHCl3)[a] D 25 = -45.3 o (c = 1, CHCl 3 )
1H NMR (300MHz,CDCl3): δ 8.12(d,J=7.3Hz,2H), 7.67-7.49(m,3H), 5.67(d, J=6.9Hz,1H), 5.61-5.55(m,1H), 5.35(s,1H), 5.00(d,J=8.6Hz,1H), 4.90(m,1H), 4.38(d,J=8.5Hz,1H), 4.22(d,J=8.4Hz,1H), 3.99(m,1H), 2.77-2.71(m,1H), 2.32- 1.09(m,18H) 1 H NMR (300 MHz, CDCl 3 ): δ 8.12 (d, J = 7.3 Hz, 2H), 7.67-7.49 (m, 3H), 5.67 (d, J = 6.9 Hz, 1H), 5.61-5.55 (m, 1H), 5.35 (s, 1H), 5.00 (d, J = 8.6 Hz, 1H), 4.90 (m, 1H), 4.38 (d, J = 8.5 Hz, 1H), 4.22 (d, J = 8.4 Hz, 1H), 3.99 (m, 1H), 2.77-2.71 (m, 1H), 2.32- 1.09 (m, 18H)
실시예 2: 7-트리클로로아세틸-박카틴 III의 제조Example 2: Preparation of 7-trichloroacetyl-baccatin III
클로로포름 1.25ℓ에 실시예 1에서 제조한 10-데아세틸-7-트리클로로아세틸- 박카틴 III 36g(0.052mol)을 용해시킨다음, 피리딘 125㎖(30eq.)를 적가한 후 10분동안 교반하였다. 여기에 아세틸브로마이드 38g(0.309mol)을 천천히 가하고 실온에서 3시간동안 교반시켰다. 감압하에 용매를 제거한 후 잔류물에 물 100㎖를 가하고, 에틸아세테이트 700㎖로 추출하였다. 유기층을 소금물로 세척하고 무수 황산마그네슘으로 수분을 제거한 후 감압증류하였다. 잔류물을 톨루엔 200㎖에 녹인 후 0oC로 냉각시켜 생성된 미세한 고체를 여과하고 n-헥산 200㎖로 세척하여 순수한 표제화합물 35.9g(수율: 94%)을 수득하였다.36 g (0.052 mol) of 10-deacetyl-7-trichloroacetyl-baccatin III prepared in Example 1 was dissolved in 1.25 L of chloroform, and then 125 ml (30 eq.) Of pyridine was added dropwise and stirred for 10 minutes. . 38 g (0.309 mol) of acetyl bromide was slowly added thereto, followed by stirring at room temperature for 3 hours. After the solvent was removed under reduced pressure, 100 ml of water was added to the residue, followed by extraction with 700 ml of ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, and distilled under reduced pressure. The residue was dissolved in 200 ml of toluene, cooled to 0 ° C., and the resulting fine solid was filtered and washed with 200 ml of n-hexane to give 35.9 g (yield: 94%) of the title compound.
융점: 180oCMelting Point: 180 o C
[a]D 25= -62.3o(c=1, CHCl3)[a] D 25 = -62.3 o (c = 1, CHCl 3 )
1H NMR(300MHz,CDCl3): δ 8.13(d,J=7.3Hz,2H), 7.67-7.49(m,3H), 6.50 (s, 1H), 5.76-5.67(m,2H), 5.00(d,J=8.8Hz,1H), 4.89(m,1H), 4.37(d,J=9.0Hz,1H), 4.19(d,J=9.4Hz,1H), 4.06(m,2H), 2,73-2.69(m,1H), 2.34-1.11(m,21H) 1 H NMR (300 MHz, CDCl 3 ): δ 8.13 (d, J = 7.3 Hz, 2H), 7.67-7.49 (m, 3H), 6.50 (s, 1H), 5.76-5.67 (m, 2H), 5.00 ( d, J = 8.8Hz, 1H), 4.89 (m, 1H), 4.37 (d, J = 9.0Hz, 1H), 4.19 (d, J = 9.4Hz, 1H), 4.06 (m, 2H), 2, 73-2.69 (m, 1H), 2.34-1.11 (m, 21H)
실시예 3: 테레프탈디카복스알데히드-디(디메틸아세탈)의 제조Example 3: Preparation of Terephthaldicarboxaldehyde-di (dimethylacetal)
테레프탈디카복스알데히드 20.1g(0.15mol)을 메탄올 100㎖에 용해시킨 후, 여기에 트리메틸오르소포메이트 49.2㎖(0.45mol) 및 촉매량의 파라톨루엔설폰산을 첨가하고 1시간동안 실온에서 교반하였다. 트리에틸아민을 사용하여 반응액의 산도를 pH 9로 조절한 후, 감압증류하여 용매를 제거하고 에틸아세테이트 200㎖를 첨가하였다. 유기층을 물 100㎖로 세척하고 무수 황산마그네슘으로 수분을 제거한 후 감압증류시켜 흰색 고체상의 표제화합물 30.5g(수율 90%)을 수득하였다.After dissolving 20.1 g (0.15 mol) of terephthaldicarboxaldehyde in 100 ml of methanol, 49.2 ml (0.45 mol) of trimethylorthoformate and a catalytic amount of paratoluenesulfonic acid were added thereto and stirred at room temperature for 1 hour. After adjusting the acidity of the reaction solution to pH 9 using triethylamine, the solvent was removed by distillation under reduced pressure and 200 ml of ethyl acetate was added. The organic layer was washed with 100 ml of water, dried with anhydrous magnesium sulfate, and distilled under reduced pressure to obtain 30.5 g (yield 90%) of the title compound as a white solid.
1H NMR(300MHz, CDCl3): δ 7.46(s,4H), 5.41(s,2H), 3.33(s,12H) 1 H NMR (300 MHz, CDCl 3 ): δ 7.46 (s, 4H), 5.41 (s, 2H), 3.33 (s, 12H)
실시예 4: 1,4-비스[(4S,5R)-3'-t-부톡시카보닐-4'-페닐-5'-메톡시카보닐-1',3'-옥사졸리딘-2'-일]벤젠의 제조Example 4: 1,4-bis [(4S, 5R) -3'-t-butoxycarbonyl-4'-phenyl-5'-methoxycarbonyl-1 ', 3'-oxazolidine-2 Preparation of '-yl] benzene
(2R,3S)-N-t-부톡시카보닐-3-페닐이소세린 메틸에스테르 8.85g(30mmol) 및 피리디늄-p-톨루엔설포네이트 60mg을 톨루엔 200㎖에 현탁시킨 후 플라스크에 딘-스타크 트랩(Dean-stark trap)을 장치하였다. 반응물을 가열환류시켜(고체의 대부분은 가열즉시 용해됨) 물을 제거한 후 가열을 중지하고 실시예 3에서 수득한 테레프탈디카복스알데히드-디(디메틸아세탈) 3.39g(15mmol)을 적가하였다. 반응액을 2시간동안 가열환류시키고 실온으로 냉각시킨 다음 반응용매를 감압증류로 제거하였다. 잔류물에 디에틸에테르 100㎖을 첨가하여 생성된 고체를 여과하고 건조시켜 엷은 미색의 표제화합물 8.5g(수율: 85%)을 수득하였다.8.85 g (30 mmol) of (2R, 3S) -Nt-butoxycarbonyl-3-phenylisoserine methylester and 60 mg of pyridinium-p-toluenesulfonate were suspended in 200 ml of toluene, followed by a Dean-Stark trap ( Dean-stark trap) was installed. The reaction was heated to reflux (most of the solid dissolved immediately upon heating) to remove water and then stop heating and add 3.39 g (15 mmol) of terephthaldicarboxaldehyde-di (dimethylacetal) obtained in Example 3. The reaction solution was heated to reflux for 2 hours, cooled to room temperature, and the reaction solvent was removed by distillation under reduced pressure. 100 ml of diethyl ether was added to the residue, and the resulting solid was filtered and dried to yield 8.5 g (yield: 85%) of a pale off-white title compound.
1H NMR(300MHz, CDCl3): δ 7.39-7.24(m,14H), 6.46(brs,2H), 5.44(brs,2H), 4.52(brs,2H), 3.47(brs,6H), 1.00(s,18H) 1 H NMR (300 MHz, CDCl 3 ): δ 7.39-7.24 (m, 14H), 6.46 (brs, 2H), 5.44 (brs, 2H), 4.52 (brs, 2H), 3.47 (brs, 6H), 1.00 ( s, 18H)
실시예 5 : 1,4-비스[(4S,5R)-3'-t-부톡시카보닐-4'-페닐-5'-카복실산-1',3'-옥사졸리딘-2'-일]벤젠·디트리에틸아민염의 제조Example 5: 1,4-bis [(4S, 5R) -3'-t-butoxycarbonyl-4'-phenyl-5'-carboxylic acid-1 ', 3'-oxazolidin-2'-yl ] Production of benzene-ditriethylamine salt
실시예 4에서 수득한 화합물 8.5g(12.8mmol)을 메탄올 100㎖에 현탁시키고 3M-수산화리튬 9.38㎖(28.2mmol)을 적가한 후 실온에서 2시간동안 교반하였다. 반응액을 감압증류하여 용매를 제거한 후 물 100㎖ 및 메탄올 20㎖를 첨가하였다. 1N-염산 수용액을 사용하여 반응액의 pH를 2로 조절한 다음 디클로로메탄 50㎖씩으로 2회 추출하였다. 유기층의 수분을 무수 황산마그네슘으로 제거한 후, 트리에틸아민 3.56㎖(2당량)를 첨가하고 감압증류로 용매를 제거하여 흰색 결정의 표제화합물 9.86g(수율: 92%)을 수득하였다.8.5 g (12.8 mmol) of the compound obtained in Example 4 were suspended in 100 ml of methanol, and 9.38 ml (28.2 mmol) of 3M-lithium hydroxide was added dropwise, followed by stirring at room temperature for 2 hours. The reaction solution was distilled under reduced pressure to remove the solvent, and then 100 ml of water and 20 ml of methanol were added. The pH of the reaction solution was adjusted to 2 using 1N aqueous hydrochloric acid, and then extracted twice with 50 ml of dichloromethane. The water of the organic layer was removed with anhydrous magnesium sulfate, and then 3.56 mL (2 equivalents) of triethylamine was added and the solvent was removed by distillation under reduced pressure to obtain 9.86 g (yield: 92%) of the title compound as white crystals.
1H NMR(300MHz, CDCl3): δ 7.47-7.24(m,14H), 6.45(brs,2H), 5.46(brs,2H), 4.44(brs,2H), 2.89-2.85(brs,8H), 1.16(brs,12H), 1.06(s,18H) 1 H NMR (300 MHz, CDCl 3 ): δ 7.47-7.24 (m, 14H), 6.45 (brs, 2H), 5.46 (brs, 2H), 4.44 (brs, 2H), 2.89-2.85 (brs, 8H), 1.16 (brs, 12H), 1.06 (s, 18H)
실시예 6: 1,4-비스[(4S,5R)-3'-벤조일-4'-페닐-5'-메톡시카보닐-1', 3'-옥사졸리딘-2'-일]벤젠의 제조Example 6: 1,4-bis [(4S, 5R) -3'-benzoyl-4'-phenyl-5'-methoxycarbonyl-1 ', 3'-oxazolidin-2'-yl] benzene Manufacture
(2R,3S)-N-벤조일-3-페닐이소세린 메틸에스테르 8g(26.7mmol) 및 피리디늄-p-톨루엔설포네이트 20mg을 톨루엔 200㎖에 현탁시킨 후 플라스크에 딘-스타크 트랩을 장치하였다. 반응물이 맑은 용액으로 될 때까지 가열환류시켜 물을 제거한 후 가열을 중지하고 실시예 3에서 수득한 테레프탈디카복스알데히드-디(디메틸아세탈) 3g(13.4mmol)을 적가하였다. 반응액을 3시간동안 가열환류시키고 실온으로 냉각시켰다. 생성된 결정에 n-헥산 100㎖을 첨가하고 여과한 후 건조시켜 엷은 미색결정의 표제화합물 8g(수율: 86%)을 수득하였다.8 g (26.7 mmol) of (2R, 3S) -N-benzoyl-3-phenylisoserine methylester and 20 mg of pyridinium-p-toluenesulfonate were suspended in 200 ml of toluene followed by a Dean-Stark trap in the flask. The reaction was heated to reflux until a clear solution was removed to remove water, and then the heating was stopped and 3 g (13.4 mmol) of terephthaldicarboxaldehyde-di (dimethylacetal) obtained in Example 3 were added dropwise. The reaction solution was heated to reflux for 3 hours and cooled to room temperature. 100 ml of n-hexane was added to the resulting crystals, filtered and dried to give 8 g (yield: 86%) of the title compound as pale white crystals.
1H NMR(300MHz, CDCl3): δ 7.70-7.11(m,24H), 6.78(brs,2H), 5.58(brs,2H), 4.58(brs,2H), 3.44(brs,6H) 1 H NMR (300 MHz, CDCl 3 ): δ 7.70-7.11 (m, 24H), 6.78 (brs, 2H), 5.58 (brs, 2H), 4.58 (brs, 2H), 3.44 (brs, 6H)
실시예 7: 1,4-비스[(4S,5R)-3'-벤조일-4'-페닐-5'-카복실산-1',3'-옥사졸리딘-2'-일]벤젠·디트리부틸아민염의 제조Example 7: 1,4-bis [(4S, 5R) -3'-benzoyl-4'-phenyl-5'-carboxylic acid-1 ', 3'-oxazolidin-2'-yl] benzene-ditri Preparation of Butylamine Salt
실시예 6에서 수득한 화합물 7g(10mmol)을 메탄올 100㎖에 현탁시키고 3M-수산화리튬 7.3㎖(22mmol)을 적가한 후 실온에서 3시간동안 교반하였다. 반응액을 감압증류하여 용매를 제거한 후 물 100㎖ 및 메탄올 20㎖를 첨가하였다. 1N-염산 수용액을 사용하여 반응액의 pH를 1로 조절한 다음 에틸아세테이트 100㎖로 추출하였다. 유기층의 수분을 무수 황산마그네슘으로 제거한 후 감압증류하여 흰색 결정 6g(수율: 89.5%)을 수득하였다. 수득된 화합물을 디클로로메탄 50㎖에 용해시키고 트리부틸아민 3.33㎖(2당량)을 첨가하여 상온에서 30분간 교반하였다. 유기용매를 감압증류하여 제거하고 잔류물에 디에틸에테르 50㎖를 가하여 생성된 결정을 여과하고 건조시켜 흰색 고체상의 표제화합물 8.5g(수율: 91%)을 수득하였다.7 g (10 mmol) of the compound obtained in Example 6 was suspended in 100 mL of methanol, and 7.3 mL (22 mmol) of 3M lithium hydroxide was added dropwise, followed by stirring at room temperature for 3 hours. The reaction solution was distilled under reduced pressure to remove the solvent, and then 100 ml of water and 20 ml of methanol were added. The pH of the reaction solution was adjusted to 1 using 1N aqueous hydrochloric acid, and then extracted with 100 ml of ethyl acetate. Water in the organic layer was removed with anhydrous magnesium sulfate and distilled under reduced pressure to give 6 g of a white crystal (yield: 89.5%). The obtained compound was dissolved in 50 ml of dichloromethane, and 3.33 ml (2 equivalents) of tributylamine was added thereto, followed by stirring at room temperature for 30 minutes. The organic solvent was removed by distillation under reduced pressure, and 50 ml of diethyl ether was added to the residue. The resulting crystals were filtered and dried to yield 8.5 g (yield: 91%) of the title compound as a white solid.
1H NMR(300MHz, CDCl3): δ 7.62-7.09(m,24H), 6.82(brs,2H), 5.66(brs,2H), 4.51(brs,2H), 2.79(m,12H), 1.50(m,2H), 1.23(m,12H), 0.91(m,18H) 1 H NMR (300 MHz, CDCl 3 ): δ 7.62-7.09 (m, 24H), 6.82 (brs, 2H), 5.66 (brs, 2H), 4.51 (brs, 2H), 2.79 (m, 12H), 1.50 ( m, 2H), 1.23 (m, 12H), 0.91 (m, 18H)
실시예 8: 7-트리클로로아세틸 파클리탁셀의 제조Example 8: Preparation of 7-trichloroacetyl paclitaxel
실시예 2에서 제조한 7-트리클로로아세틸 박카틴 III 3g(4mmol), 실시예 5 에서 제조한 옥사졸리딘 다이머 디트리에틸아민염 3g(3.58mmol), 디사이클로헥실카보디이미드 1.48g(7.16mmol) 및 4-디메틸아미노피리딘 20mg(0.16mmol)을 톨루엔 50㎖에 녹였다. 80℃에서 2시간동안 교반한 후 TLC로 분석하여 7-트리클로로아세틸 박카틴 III가 사라진 것을 확인한 다음, 반응혼합물을 세라이트 패드로 여과하고 감압증류하여 용매를 제거하였다. 잔류물을 실리카겔 칼럼 크로마토그래피(용출제: 에틸아세테이트/n-헥산=1/2, v/v)에 적용하여 2가지 화합물로 각각 분리한 다음,1H NMR로 분석한 결과 이성체 형태의 커플링 생성물 4g(수율: 94.8%)임을 확인할 수 있었다.3 g (4 mmol) of 7-trichloroacetyl baccatin III prepared in Example 2, 3 g (3.58 mmol) of oxazolidine dimer ditriethylamine salt prepared in Example 5, 1.48 g (7.16) of dicyclohexylcarbodiimide mmol) and 20 mg (0.16 mmol) of 4-dimethylaminopyridine were dissolved in 50 ml of toluene. After stirring at 80 ° C. for 2 hours, it was analyzed by TLC to confirm that 7-trichloroacetyl baccatin III disappeared, and then the reaction mixture was filtered through a celite pad and distilled under reduced pressure to remove the solvent. The residue was subjected to silica gel column chromatography (eluant: ethyl acetate / n-hexane = 1/2, v / v), separated into two compounds, and analyzed by 1 H NMR. It was confirmed that the product 4g (yield: 94.8%).
상기 수득한 커플링 생성물 4g을 메탄올 20㎖에 녹인 다음, 여기에 염산가스/메탄올 용액 5㎖를 첨가하고 1시간동안 교반하였다. 감압증류하여 용매를 제거한 후 잔류물에 에틸아세테이트 50㎖를 첨가하였다. 포화 중탄산나트륨 수용액을 가하여 중화시키고, 물 30㎖를 가한 후 벤조일클로라이드 0.45㎖(3.88mmol)를 천천히 적가하였다. 상온에서 10분동안 교반한 후 반응용액을 에틸아세테이트 50㎖로 추출하였다. 무수 황산마그네슘을 사용하여 수분을 제거한 다음, 실리카겔 칼럼 크로마토그라피(용출제: 에틸아세테이트/n-헥산=1/2, v/v)를 수행하여 테레프탈릴알데히드를 제거함으로써 흰색 고체상의 표제화합물 2.87g(수율: 75%)을 수득하였다.4 g of the obtained coupling product was dissolved in 20 ml of methanol, and 5 ml of a hydrochloric acid gas / methanol solution was added thereto, followed by stirring for 1 hour. After distillation under reduced pressure to remove the solvent, 50 ml of ethyl acetate was added to the residue. Saturated aqueous sodium bicarbonate solution was added to neutralize, 30 ml of water was added, and 0.45 ml (3.88 mmol) of benzoyl chloride was slowly added dropwise. After stirring for 10 minutes at room temperature, the reaction solution was extracted with 50 ml of ethyl acetate. Water was removed using anhydrous magnesium sulfate, and then silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/2, v / v) was carried out to remove terephthalyl aldehyde to obtain 2.87 g of the title compound as a white solid. (Yield 75%) was obtained.
1H NMR(300MHz, CDCl3): δ 8.15(d,J=7.2Hz,2H), 7.76(d,J=7.2Hz,2H) 7.64- 7.27(m,11H), 7.04(d,J=8.9Hz,J=8.9Hz,1H), 6.40(s,1H), 6.22(dd,J=8.9Hz,J=8.9Hz, 1H), 5.82(dd,J1=2.5Hz,J2=8.9Hz,1H), 5.75(d,J=10Hz,1H), 5.69(dd,J=7.4Hz,J= 7.4Hz,1H), 4.96(dd,J1=2.3Hz,J2=10Hz,1H), 4.83(dd,J1=2.5Hz,J2=5.0Hz,1H), 4.36 (d,J=7.4Hz,1H), 4.24(d,J=7.4Hz,1H), 3.98(d,J=6.9Hz,1H), 3.80(brs,1H), 3.50 (brs, 1H), 2.70(m,1H), 2.42-1.19(m,21H) 1 H NMR (300 MHz, CDCl 3 ): δ 8.15 (d, J = 7.2 Hz, 2H), 7.76 (d, J = 7.2 Hz, 2H) 7.64-7.27 (m, 11H), 7.04 (d, J = 8.9 Hz, J = 8.9Hz, 1H), 6.40 (s, 1H), 6.22 (dd, J = 8.9Hz, J = 8.9Hz, 1H), 5.82 (dd, J1 = 2.5Hz, J2 = 8.9Hz, 1H) , 5.75 (d, J = 10Hz, 1H), 5.69 (dd, J = 7.4Hz, J = 7.4Hz, 1H), 4.96 (dd, J1 = 2.3Hz, J2 = 10Hz, 1H), 4.83 (dd, J1 = 2.5 Hz, J2 = 5.0 Hz, 1H), 4.36 (d, J = 7.4 Hz, 1H), 4.24 (d, J = 7.4 Hz, 1H), 3.98 (d, J = 6.9 Hz, 1H), 3.80 ( brs, 1H), 3.50 (brs, 1H), 2.70 (m, 1H), 2.42-1.19 (m, 21H)
실시예 9: 파클리탁셀의 제조Example 9 Preparation of Paclitaxel
실시예 8에서 제조한 7-트리클로로아세틸 파클리탁셀 2.87g(2.9mmol)을 메탄올과 테트라하이드로푸란의 혼합액(1/1, v/v) 20㎖에 용해시켰다. 여기에 메탄올에 녹인 2.0M 암모니아 1.45㎖(2.9mmol)를 적가하고 상온에서 1시간동안 교반한 다음 반응용매를 감압증류로 제거하였다. 잔류물을 실리카겔 칼럼 크로마토그래피(용출제: 에틸아세테이트/n-헥산=1/1, v/v)하여 백색고체상의 표제화합물 2.25g(수율: 92%)을 수득하였다.2.87 g (2.9 mmol) of 7-trichloroacetyl paclitaxel prepared in Example 8 was dissolved in 20 ml of a mixed solution of methanol and tetrahydrofuran (1/1, v / v). 1.45 mL (2.9 mmol) of 2.0 M ammonia dissolved in methanol was added dropwise thereto, stirred at room temperature for 1 hour, and the reaction solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluant: ethyl acetate / n-hexane = 1/1, v / v) to give 2.25 g (yield: 92%) of the title compound as a white solid.
1H NMR(300MHz,CDCl3): δ 8.15(d,J=7.2Hz,2H), 7.76(d,J=7.2Hz,2H), 7.64- 7.37(m,11H), 7.04(d,J=8.8Hz,1H), 6.29(s,1H), 6.25(dd,J=8.9Hz,J=8.9Hz,1H), 5.80(dd,J1=2.5Hz,J2=8.7Hz,1H), 5.69(d,J=7.1Hz,1H), 4.95(dd,J1=2.3Hz,J2=10Hz, 1H), 4.81(dd,J1=2.5Hz,J2=5.0Hz,1H), 4.41(m,1H), 4.32(d,J=8.5Hz,1H), 4.22(d, J=8.5Hz,1H), 3.83(d,J=6.9Hz,1H), 3.66(d,J=5.3Hz,1H), 2.54-1.16(m,22H) 1 H NMR (300 MHz, CDCl 3 ): δ 8.15 (d, J = 7.2 Hz, 2H), 7.76 (d, J = 7.2 Hz, 2H), 7.64-7.37 (m, 11H), 7.04 (d, J = 8.8 Hz, 1H), 6.29 (s, 1H), 6.25 (dd, J = 8.9 Hz, J = 8.9 Hz, 1H), 5.80 (dd, J1 = 2.5 Hz, J2 = 8.7 Hz, 1H), 5.69 (d , J = 7.1Hz, 1H), 4.95 (dd, J1 = 2.3Hz, J2 = 10Hz, 1H), 4.81 (dd, J1 = 2.5Hz, J2 = 5.0Hz, 1H), 4.41 (m, 1H), 4.32 (d, J = 8.5Hz, 1H), 4.22 (d, J = 8.5Hz, 1H), 3.83 (d, J = 6.9Hz, 1H), 3.66 (d, J = 5.3Hz, 1H), 2.54-1.16 (m, 22H)
실시예 10: 7-트리클로로아세틸 파클리탁셀의 제조Example 10 Preparation of 7-trichloroacetyl paclitaxel
실시예 2에서 제조한 7-트리클로로아세틸 박카틴 III 1g(1.37mmol), 실시예 7에서 제조한 옥사졸리딘 다이머 디트리부틸아민염 1g(0.96mmol), 디사이클로헥실카보디이미드 0.396g(1.92mmol) 및 4-디메틸아미노피리딘 10mg을 톨루엔 25㎖에 녹였다. 80℃에서 2시간동안 교반한 후 TLC로 분석하여 7-트리클로로아세틸 박카틴 III가 사라진 것을 확인한 다음, 반응혼합물을 셀라이트 패드로 여과하고 감압증류하여 커플링된 조생성물을 수득하였다. 잔류물을 메탄올 25㎖에 녹이고 메탄설폰산 1㎖를 첨가한 후 10시간동안 교반하였다. 물 50㎖를 반응액에 첨가하고 에틸아세테이트 50㎖로 추출한 후 유기층을 포화 소금물 25㎖로 세척하였다. 무수 황산마그네슘을 사용하여 유기층의 수분을 제거한 다음 용매를 감압증류하여 제거하였다. 잔류물을 실리카겔 칼럼 크로마토그래피(용출제: 에틸아세테이트/n-헥산=1/2, v/v)로 정제하여 백색 고체상의 표제화합물 1.2g(수율: 88.9%)을 수득하였다.1 g (1.37 mmol) of 7-trichloroacetyl baccatin III prepared in Example 2, 1 g (0.96 mmol) of oxazolidine dimer ditributylamine salt prepared in Example 7, 0.396 g of dicyclohexylcarbodiimide ( 1.92 mmol) and 10 mg of 4-dimethylaminopyridine were dissolved in 25 ml of toluene. After stirring at 80 ° C. for 2 hours, it was confirmed by TLC that 7-trichloroacetyl baccatin III disappeared, and then the reaction mixture was filtered through a pad of celite and distilled under reduced pressure to obtain a crude crude product. The residue was taken up in 25 ml of methanol, 1 ml of methanesulfonic acid was added and stirred for 10 hours. 50 ml of water was added to the reaction solution, the mixture was extracted with 50 ml of ethyl acetate, and the organic layer was washed with 25 ml of saturated brine. Anhydrous magnesium sulfate was used to remove water from the organic layer, and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluant: ethyl acetate / n-hexane = 1/2, v / v) to give 1.2 g (yield: 88.9%) of the title compound as a white solid.
실시예 11: 파클리탁셀의 제조Example 11: Preparation of Paclitaxel
실시예 10에서 제조한 7-트리클로로아세틸 파클리탁셀 1g(1mmol)을 메탄올과 테트라하이드로푸란의 혼합액(1/1, v/v) 10㎖에 용해시켰다. 여기에 암모늄아세테이트 0.12g(1.5당량)을 첨가하고 5시간동안 교반하였다. 반응액을 감압증류하여 제거하고 에틸아세테이트 50㎖를 첨가한 후 물 30㎖로 유기층을 세척하였다. 무수 황산마그네슘을 사용하여 유기층의 수분을 제거하고 용매를 감압증류한 다음 잔류물을 실리카겔 칼럼 크로마토그래피(용출제: 에틸아세테이트/n-헥산=1/1, v/v)로 정제하여 백색 고체상의 표제화합물 0.8g(수율: 93%)을 수득하였다.1 g (1 mmol) of 7-trichloroacetyl paclitaxel prepared in Example 10 was dissolved in 10 ml of a mixed solution of methanol and tetrahydrofuran (1/1, v / v). 0.12 g (1.5 equivalents) of ammonium acetate was added thereto and stirred for 5 hours. The reaction solution was removed by distillation under reduced pressure, 50 ml of ethyl acetate was added, and the organic layer was washed with 30 ml of water. Water was removed from the organic layer using anhydrous magnesium sulfate, the solvent was distilled under reduced pressure, and the residue was purified by silica gel column chromatography (eluant: ethyl acetate / n-hexane = 1/1, v / v) to obtain a white solid. 0.8 g (yield 93%) of the title compound were obtained.
상기 설명한 바와 같은 본 발명은, 산업적으로 커다란 가치를 지니지만 기존의 분리 또는 합성방법에 의해서는 만족할만한 수준으로 얻을 수 없었던 파클리탁셀을 제조하는데 매우 유용하게 이용될 수 있다.The present invention as described above can be very useful for producing paclitaxel, which has great industrial value but could not be obtained satisfactorily by the existing separation or synthesis method.
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