KR100856133B1 - Improved process for preparing atorvastatin - Google Patents
Improved process for preparing atorvastatinInfo
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- KR100856133B1 KR100856133B1 KR1020080003530A KR20080003530A KR100856133B1 KR 100856133 B1 KR100856133 B1 KR 100856133B1 KR 1020080003530 A KR1020080003530 A KR 1020080003530A KR 20080003530 A KR20080003530 A KR 20080003530A KR 100856133 B1 KR100856133 B1 KR 100856133B1
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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Abstract
Description
본 발명은 아토르바스타틴의 개선된 제조방법에 관한 것으로서, 더욱 상세하게는 2-(4-플루오로벤젠)-3-페닐-4-카르보아닐린-5-이소프로필-피롤과 시스-t-부틸-7-할로-2-알콕시-3,5-디옥산-헵타노에이트를 출발물질로 사용하여 이들 두 화합물간의 N-알킬화 반응을 수행한 후에 탈보호 및 가수분해 반응을 수행하여, 고지혈증 치료제로 유효한 하기 화학식 1로 표시되는 아토르바스타틴 (Atorvasatin)을 효율적으로 합성하는 방법에 관한 것이다.The present invention relates to an improved process for preparing atorvastatin, more particularly 2- (4-fluorobenzene) -3-phenyl-4-carboaniline-5-isopropyl-pyrrole and cis- t- butyl- N- alkylation reaction between these two compounds using 7-halo-2-alkoxy-3,5-dioxane-heptanoate as starting material, followed by deprotection and hydrolysis reaction, effective as a treatment for hyperlipidemia The present invention relates to a method for efficiently synthesizing atorvastatin represented by Formula 1 below.
[화학식 1][Formula 1]
아토르바스타틴(Atorvasatin)은 HMG Co A 환원효소 억제활성이 우수하여 고지혈증 치료제로 유효하여, 현재 리피토르(Lipitor™)라는 제품명으로 시판되고 있기도 한다.Atorvasatin is effective as a therapeutic agent for hyperlipidemia due to its excellent HMG Co A reductase inhibitory activity, and is currently marketed under the product name Lipitor (Lipitor ™).
아토르바스타틴(Atorvasatin)의 제조방법에 대해서는 많은 연구가 진행되어있다. [국제특허공개 WO98/04543호, 미국특허등록 제5,124,482호, 제5,216,174호, 제5,273,995호, 미국특허공개 제2004/0072893호, 대한민국특허등록 제75791호, J. Med. Chem., 1991, 34, 357∼366]Much research has been conducted on the preparation of atorvastatin. [International Patent Publication No. WO98 / 04543, US Patent Nos. 5,124,482, 5,216,174, 5,273,995, US Patent Publication No. 2004/0072893, Korean Patent Registration No. 75791, J. Med. Chem ., 1991, 34, 357-366.
현재까지 발표된 아토르바스타틴(Atorvasatin)의 가장 일반적인 제조방법은 하기 반응식 1과 같다. 하기 반응식 1에 따른 아토르바스타틴의 제조방법에서는 하기 화학식 20으로 표시되는 화합물을 반응 중간체로 제조한 후 시스-디올의 광학활성 구조를 갖는 화학식 5-A 화합물을 수득하는 단계를 포함하여 이루어진다. The most common method for preparing atorvastatin released to date is shown in Scheme 1 below. The method for preparing atorvastatin according to Scheme 1 includes preparing a compound represented by the following Chemical Formula 20 as a reaction intermediate, and then obtaining the compound of Chemical Formula 5-A having an optically active structure of cis-diol.
즉, 상기 반응식 1에서는 출발물질로서 상기 화학식 17로 표시되는 에틸 α-브로모-4-플루오로벤젠 아세테이트를 사용하고, 이를 에틸디옥살란 에틸아미드와 반응시켜 상기 화학식 18로 표시되는 화합물을 제조하였다. 그런 다음, 상기 화학식 19로 표시되는 3차 아민화합물을 제조하여 고리화 반응시킴으로써, 아토르바스타틴의 골격구조(Structure frame)를 갖는 상기 화학식 20으로 표시되는 화합물을 제조하였다. 그리고, 옥살란기를 알데히드기로 변환시킨 상기 화학식 21로 표시되는 화합물을 제조한 후에 3단계 이상의 다단계 공정을 거쳐 상기 화학식 22로 표시되는 화합물을 제조하였다. 그리고, 상기 화학식 22로 표시되는 화합물의 케톤 그룹을 환원하여 시스-디올의 광학활성 구조를 갖는 상기 화학식 5-A로 표시되는 화합물을 제조한 후, 몇 단계의 과정을 거쳐 아토르바스타틴을 비로서 제조하였다. That is, in Scheme 1, ethyl α-bromo-4-fluorobenzene acetate represented by Chemical Formula 17 was used as a starting material, and the compound represented by Chemical Formula 18 was prepared by reacting with ethyl dioxalane ethylamide. . Thereafter, a tertiary amine compound represented by Chemical Formula 19 was prepared to cyclize to prepare a compound represented by Chemical Formula 20 having a structure frame of atorvastatin. Then, after preparing a compound represented by the formula (21) in which an oxalan group is converted to an aldehyde group, a compound represented by the formula (22) was prepared through a multi-step process of three or more steps. In addition, the ketone group of the compound represented by Chemical Formula 22 was reduced to prepare a compound represented by Chemical Formula 5-A having an optically active structure of cis-diol, and then atorvastatin was prepared as a ratio by a few steps. .
그러나, 상기 반응식 1에 따른 종래 제조방법은 하기와 같은 결정적 이유로 인하여 산업적으로 적용하기에는 한계가 있다 :However, the conventional manufacturing method according to Scheme 1 is limited to industrial application for the following critical reasons:
1) N-알킬화 반응과 고리화 반응 등의 제조공정 이후에 후반기 공정에서 케톤 그룹의 환원반응에 의해 시스-디올의 광학활성(chiral) 구조를 유도하고 있다. 즉, 상기 화학식 5-A로 표시되는 시스-디올의 광학활성 화합물을 후반기 공정으로 유도하기 위해 몇 단계의 제조공정을 우회하고 있어 제조공정이 늘어남으로써 수율이 현격이 떨어져 경제적이지 못하며, 초저온(-78℃)의 가혹한 반응조건이 유지되어야 하는 등 산업적으로 적용하기에는 한계가 있다.1) After the production process such as N -alkylation reaction and cyclization reaction, the chiral structure of cis-diol is induced by the reduction reaction of ketone group in the latter process. That is, in order to induce the optically active compound of the cis-diol represented by the formula 5-A to the latter stage process, several steps are bypassed to increase the production process, resulting in a drop in yield and not economical. There are limitations to industrial applications, such as the harsh reaction conditions of 78 ° C.).
2) 상기 화학식 19로 표시되는 화합물과 N,3-디페닐프로핀아미드와의 고리화 반응은 아세틱안히드리드(Acetic anhydride)하에 100℃ 이상의 고온 속에서 반응해야하며 반응 후 아세틱안히드리드를 농축 제거해야하는 정제과정의 어려움 등으로 고리화 반응의 수율(43%)이 극히 낮은 원인이 되고 있다.2) The cyclization reaction of the compound represented by Chemical Formula 19 with N , 3-diphenylpropynamide should be reacted at high temperature of 100 ° C. or higher under acetic anhydride. Difficulties in the purification process that need to be concentrated and removed cause the yield of cyclization reaction (43%) to be extremely low.
3) 상기 화학식 20으로 표시되는 화합물의 옥살란기를 알데히드기로 변환하는 반응은, 48시간의 긴 반응시간이 소요되고 있고, 반응조건 역시 환류 반응조건으로서 산업적으로 이용하기는 어려움이 있으며, 수율도 68.5%로 낮다. 3) The reaction for converting the oxalane group of the compound represented by the formula (20) to an aldehyde group takes a long reaction time of 48 hours, and the reaction conditions are also difficult to industrially use as reflux reaction conditions, yield 68.5 Low in%
이상에서 살펴본 바와 같은 이유로, 상기 반응식 1에 따른 아토르바스타틴의 일반적 제조방법은 산업적으로 적용되기에는 바람직하지 않다.For the reason as described above, the general method for preparing atorvastatin according to Scheme 1 is not preferable to be applied industrially.
상기 반응식 1에 따른 종래 제조방법을 보완한 아토르바스타틴의 개선된 제조방법이 발표되었고, 이를 간략히 도시하면 하기 반응식 2와 같다.An improved method for preparing atorvastatin, which has been supplemented with the conventional method according to Scheme 1, has been published, which is briefly shown in Scheme 2 below.
상기 반응식 2에 따른 개선된 제조방법에서는, 상기 화학식 23으로 표시되는 화합물과 상기 화학식 24로 표시되는 화합물간의 고리화 반응을 유도하여, 아토르바스타틴의 골격구조(Structure frame)를 갖는 상기 화학식 25로 표시되는 화합물을 제조하였다.In the improved manufacturing method according to Scheme 2, by inducing a cyclization reaction between the compound represented by the formula (23) and the compound represented by the formula (24), having a skeleton frame of the atorvastatin (Structure frame) is represented by the formula (25) The compound was prepared.
또한, 상기 반응식 2에 따른 제조방법에서 고리화 반응에 이용되는 상기 화학식 23으로 표시되는 화합물과 상기 화학식 24로 표시되는 화합물은 각각 하기 반응식 2a와 2b로 표시되는 바와 같은 제조과정을 수행하여 제조하였다.In addition, the compound represented by the formula (23) and the compound represented by the formula (24) used in the cyclization reaction in the production method according to Scheme 2 was prepared by performing the preparation process as shown in the following schemes 2a and 2b, respectively .
그러나, 상기 반응식 2에 따른 개선된 제조방법 역시 하기와 같은 결정적 이유로 인하여 산업적으로 적용하기에는 한계가 있다 : However, the improved manufacturing method according to Scheme 2, too, is limited to industrial application for the following critical reasons:
1) 상기 화학식 25로 표시되는 화합물을 제조하기 위한 고리화 반응이, 100℃ 이상의 고온 조건에서 48시간 이상의 긴 시간동안 수행하는 단점이 있다.1) There is a disadvantage in that the cyclization reaction for preparing the compound represented by Formula 25 is performed for a long time of 48 hours or longer at a high temperature condition of 100 ° C or higher.
2) 상기 고리화 반응에 사용되는 화합물을 다단계 제조과정을 수행하여 제조하고 있으며, 특히 상기 화학식 24로 표시되는 4-(4-플루오로페닐)-2-이소부티릴-3-페닐-4-옥소-N-페닐-부티릴아미드 화합물의 제조수율은 35% 이하로서, 원료물질 합성과정이 경제적이지 못하다는 단점이 있다.2) The compound used for the cyclization reaction is prepared by performing a multi-step preparation process, and in particular, 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4- The production yield of the oxo- N- phenyl-butyrylamide compound is 35% or less, which is a disadvantage that the raw material synthesis process is not economical.
3) 상기 화학식 25로 표시되는 화합물의 광학활성 디히드록시기가 2,2-디메틸디옥산으로 보호화되어 있어, 탈보호화가 용이하지 않은 단점이 있다.3) Since the optically active dihydroxy group of the compound represented by Chemical Formula 25 is protected with 2,2-dimethyldioxane, deprotection is not easy.
4) 상기 화학식 25로 표시되는 화합물을 탈보호하기 위해서는, 과량(반응물 대비 20% w/v 이상)의 산(Acid)을 사용하여 80℃ 이상의 고온 조건에서 8시간 이상 노출해야 탈보호화가 이루어지며, 또한 65% 이하의 낮은 수율을 나타낸다는 단점이 있다. 4) In order to deprotect the compound represented by Chemical Formula 25, the deprotection is performed by exposing at least 80 hours at a high temperature of 80 ° C. using an excess of acid (20% w / v or more of the reactant). In addition, it has the disadvantage of showing a low yield of 65% or less.
이상에서 살펴본 바와 같은 이유로, 상기 반응식 2에 따른 아토르바스타틴의 개선된 제조방법 역시 가혹한 반응조건이 필요하고, 제조수율이 낮을 뿐만 아니라 순도 역시 낮아 산업적으로 적용되기에는 바람직하지 않다.As described above, the improved method for preparing atorvastatin according to Scheme 2 also requires harsh reaction conditions, low yield and low purity, which are not preferable for industrial application.
또 다른 제조방법으로서, 대한민국 공개특허 제2004-84915호에서는 아토르바스타틴 합성용 중간체로서 보호화 반응과 탈보호 반응이 비교적 용이한 화학구조를 갖는 하기 화학식 23-A로 표시되는 화합물이 발표된 바 있다.As another preparation method, Korean Patent Laid-Open Publication No. 2004-84915 discloses a compound represented by the following Chemical Formula 23-A having a chemical structure of relatively easy protection and deprotection reactions as an intermediate for atorvastatin synthesis.
[화학식 23-A][Formula 23-A]
상기 화학식 23-A로 표시되는 화합물은, 디히드록시 보호그룹으로서 2,2-디메틸디옥산을 도입한 상기 화학식 23으로 표시되는 화합물에 비교하여 보호화 반응과 탈보호 반응 조건이 대체로 온화하고 수율이 증대된 효과를 얻고 있다.The compound represented by the formula (23-A) is generally milder than the compound represented by the formula (23) in which 2,2-dimethyldioxane is introduced as a dihydroxy protecting group, and the deprotection reaction conditions are generally mild and yield. This increased effect is obtained.
이상에서 살펴본 바와 같이, 상기 화학식 1로 표시되는 아토르바스타틴 제조를 위한 종래 방법은 산업적으로 이용하기에는 한계가 있는 것으로 지적되고 있다.As described above, the conventional method for preparing atorvastatin represented by Chemical Formula 1 has been pointed out that there is a limit to industrial use.
본 발명은 산업적으로 이용하기에 적합하도록 제조공정이 비교적 간단하면서도 불순물의 생성 없이 높은 수율과 높은 순도로 목적하는 상기 화학식 1로 표시되는 아토르바스타틴을 제조할 수 있는 새로운 제조방법을 제공하는데 그 목적이 있다.The present invention is to provide a novel manufacturing method for producing the atorvastatin represented by the formula (1) in a high yield and high purity without the production of impurities, but relatively simple manufacturing process to be suitable for industrial use .
본 발명은 하기 반응식 3에 나타낸 바와 같이 하기와 같은 제조과정을 포함하여 이루어지는 아토르바스타틴의 제조방법을 그 특징으로 한다 :The present invention is characterized by a method for preparing atorvastatin, which comprises the following preparation process as shown in Scheme 3:
ⅰ) 하기 화학식 2로 표시되는 2-(4-플루오로벤젠)-3-페닐-4-카르보아닐린-5-이소프로필-피롤과 하기 화학식 3으로 표시되는 시스-t-부틸-7-할로-2-알콕시-3,5-디옥산-헵타노에이트를 N-알킬화 반응시켜, 하기 화학식 4로 표시되는 2-(4-플루오로페닐)-3-페닐-4-카르보아닐린-5-이소프로필-1N(시스-t-부틸-2-알콕시-3,5-디옥산-7-아미도-헵타노에이트)피롤을 제조하는 과정, 및Iii) 2- (4-fluorobenzene) -3-phenyl-4-carboaniline-5-isopropyl-pyrrole represented by the following formula (2) and cis- t- butyl-7-halo represented by the following formula (3) N- alkylation reaction of 2-alkoxy-3,5-dioxane-heptanoate to give 2- (4-fluorophenyl) -3-phenyl-4-carboaniline-5- Preparing isopropyl- 1N (cis- t- butyl-2-alkoxy-3,5-dioxane-7-amido-heptanoate) pyrrole, and
ⅱ) 하기 화학식 4로 표시되는 화합물을 알콜 용매 및 산 촉매 조건에서 탈보호 반응시킨 후에 가수분해하여, 하기 화학식 1로 표시되는 아토르바스타틴을 제조하는 과정.Ii) A process of producing atorvastatin represented by the following formula (1) by hydrolysis of the compound represented by the following formula (4) after deprotection reaction in an alcohol solvent and an acid catalyst condition.
상기 반응식 3에서, R은 탄소수 1 내지 6의 알킬기를 나타내고, X는 할로겐원자를 나타낸다.In Scheme 3, R represents an alkyl group having 1 to 6 carbon atoms, and X represents a halogen atom.
또한, 상기 반응식 3에 따른 일련의 제조과정을 수행하는 과정에서 사용되는 출발물질 및 반응중간체로서 상기 화학식 2, 화학식 3, 화학식 4, 화학식 5 및 화학식 6으로 표시되는 화합물 각각은 신규 화합물인 바, 본 발명은 신규 화합물로서 상기 화학식 2, 화학식 3, 화학식 4, 화학식 5 및 화학식 6으로 표시되는 화합물을 그 특징으로 한다.In addition, each of the compounds represented by Formula 2, Formula 3, Formula 4, Formula 5, and Formula 6 as starting materials and reaction intermediates used in a process of preparing a series of reactions according to Scheme 3 is a new compound. The present invention is characterized by a compound represented by the formula (2), (3), (4), (5) and (6) as a novel compound.
본 발명에 따른 상기 화학식 1로 표시되는 아토르바스타틴의 제조방법에서는 하기와 같은 효과를 얻고 있다 :In the method for preparing atorvastatin represented by Formula 1 according to the present invention, the following effects are obtained:
1) 본 발명의 제조방법에서 수행하게 되는 N-알킬화, 탈보호화 및 가수분해 반응의 전 공정이 모두 실온 이하의 온화한 반응조건에서 수행되고 1 내지 2시간 이내에 반응이 완결되므로, 고 순도 및 고 수율로 목적물을 합성하는 것이 가능해진 효과를 갖고 있다.1) All the processes of N- alkylation, deprotection and hydrolysis reaction to be carried out in the production method of the present invention are all performed under mild reaction conditions of room temperature or less and the reaction is completed within 1 to 2 hours, so high purity and high yield It has the effect that it became possible to synthesize | combine the target object.
2) 트리알킬오르쏘포르메이트에 의해 디히드록시기가 보호됨에 따라 탈보호화 반응과 가수분해 반응을 연속적으로 수행할 수 있어 목적하는 아토르바스타틴을 높은 수율과 높은 순도(98% 이상, HPLC Area %)로 수득하는 효과를 얻고 있다.2) As the dihydroxy group is protected by trialkylorthoformate, the deprotection reaction and the hydrolysis reaction can be carried out continuously to obtain the desired atorvastatin in high yield and high purity (98% or more, HPLC Area%). To get the effect.
이상에서 설명한 바와 같은 본 발명의 제조방법을 각 제조과정별로 보다 구체적으로 설명하면 다음과 같다.Referring to the manufacturing method of the present invention as described above in more detail for each manufacturing process as follows.
ⅰ) 과정은 상기 화학식 2로 표시되는 피롤 화합물의 아민을 N-알킬화 반응시켜 3차 아민기로 전환하는 과정이다.Iii) is a process of converting the amine of the pyrrole compound represented by Chemical Formula 2 to the tertiary amine group by N- alkylation reaction.
본 발명이 N-알킬화 반응에서는 상기 화학식 3으로 표시되는 화합물을 알킬화제로 사용한다. 상기 화학식 3으로 표시되는 화합물은 광학활성체이면서도 말단에 할로겐원자가 치환된 할라이드 화합물로서, 상기 화학식 2로 표시되는 피롤 화합물의 아민과 반응하여, 상기 화학식 4로 표시되는 2-(4-플루오로페닐)-3-페닐-4-카르보아닐린-5-이소프로필-1N(시스-t-부틸-2-알콕시-3,5-디옥산-7-아미도-헵타노에이트)피롤을 제조하였다. 상기한 N-알킬화 반응은 0℃ 내지 실온(대략 25 ℃) 온도에서 바람직하기로는 0℃ 내지 10 ℃ 온도에서 수행한다. 본 발명의 N-알킬화 반응은 1 내지 2시간 내에 고 순도(99% 이상)로 목적하는 상기 화학식 4로 표시되는 화합물을 정량적으로 수득할 수 있었다. 적절한 용매로는 테트라히드로퓨란(THF), 디메틸포름아미드(DMF), 디메틸설폭사이드(DMSO), 디에틸에테르, 벤젠, 디클로로메탄, 아세토니트릴, 아세톤, 디옥산 중에서 선택 사용할 수 있으며, 바람직하기로는 테트라히드로퓨란(THF), 아세토니트릴을 사용하는 것이다. 또한, 필요하다면 염기를 추가로 사용할 수 있다. 염기는 당 분야에서 일반적으로 사용되고 있는 무기 또는 유기염기이며, 좋기로는 1급, 2급 또는 3급의 C1-10 알킬아민, 피리딘 등의 유기염기를 사용하는 것이다.In the present invention, the compound represented by the formula (3) is used as the alkylating agent in the N- alkylation reaction. The compound represented by the formula (3) is a halide compound in which a halogen atom is substituted at the terminal while being an optically active compound, and reacted with an amine of a pyrrole compound represented by the formula (2), and represented by 2- (4-fluorophenyl) ) -3-phenyl-4-carboaniline-5-isopropyl-1 N (cis- t- butyl-2-alkoxy-3,5-dioxane-7-amido-heptanoate) pyrrole was prepared. . The N- alkylation reaction described above is carried out at 0 ° C. to room temperature (approximately 25 ° C.) temperature, preferably at 0 ° C. to 10 ° C. temperature. The N- alkylation reaction of the present invention was able to quantitatively obtain the desired compound represented by the formula (4) with high purity (more than 99%) within 1 to 2 hours. Suitable solvents may be selected from tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), diethyl ether, benzene, dichloromethane, acetonitrile, acetone, dioxane, preferably Tetrahydrofuran (THF) and acetonitrile are used. In addition, bases may be further used if necessary. The base is an inorganic or organic base generally used in the art, and preferably is an organic base such as primary, secondary or tertiary C 1-10 alkylamine, pyridine and the like.
ⅱ) 과정은 상기 화학식 4로 표시되는 화합물을 탈보호 및 가수분해하여 본 발명이 목적하는 상기 화학식 1로 표시되는 아토르바스타틴을 제조하는 과정이다.Ii) The process is a process for preparing the atorvastatin represented by the formula (1) for the purpose of the present invention by deprotection and hydrolysis of the compound represented by the formula (4).
탈보호 반응은 탄소수 1 내지 4의 알콜 및 산 촉매 조건에서 0 ℃ 내지 실온(대략 25 ℃)의 비교적 온화한 반응 조건에서 수행한다. 탈보호 반응에서 사용되는 산 촉매로는 황산, 염산, 아세트산, 피발산, 메탄설폰산, 캄포설폰산(CSA), p-톨루엔설폰산 등 중에서 선택하여 반응용매를 기준으로 10∼20 %w/v 범위로 사용할 수 있다. 탈보호 반응은 구체적으로는 2N-HCl의 산 촉매가 들어있는 메탄올 또는 에탄올 수용액 내에서 0 ℃ 내지 10 ℃에서 1 내지 1.5시간 교반하여 상기 화학식 5로 표시되는 화합물을 제조하였다. 또한, 탈보호 반응은 반응용매로서 물, 메탄올, 에탄올, 프로판올, 부탄올, 아세톤, 테트라히드로퓨란(THF), 및 디클로로메탄 중에서 선택된 단독 또는 혼합 용매를 추가로 사용할 수도 있다.The deprotection reaction is carried out at relatively mild reaction conditions from 0 ° C. to room temperature (approximately 25 ° C.) under alcohol and acid catalyzed conditions having 1 to 4 carbon atoms. The acid catalyst used in the deprotection reaction is selected from sulfuric acid, hydrochloric acid, acetic acid, pivalic acid, methanesulfonic acid, camphorsulfonic acid (CSA), p -toluenesulfonic acid, etc. and 10 to 20% w / based on the reaction solvent. Can be used as a v range. Specifically, the deprotection reaction was stirred for 1 to 1.5 hours at 0 ° C. to 10 ° C. in an aqueous methanol or ethanol solution containing an acid catalyst of 2N- HCl to prepare a compound represented by Chemical Formula 5. In addition, the deprotection reaction may further use a single or mixed solvent selected from water, methanol, ethanol, propanol, butanol, acetone, tetrahydrofuran (THF), and dichloromethane as a reaction solvent.
상기한 탈보호 반응이 완료되면 가수분해 반응을 연속적으로 수행할 수 있다. 구체적으로 가수분해 반응은 상기 화학식 5로 표시되는 화합물이 포함된 반응액에 물을 가하여 고체화한 후에 잔류하는 산을 제거하고, 탄소수 1 내지 4의 알콜, 또는 알콜 수용액에 녹인 알칼리금속 수산화물을 가하여 가수분해 반응을 수행하였다. 상기 알칼리금속 수산화물으로는 대표적으로 수산화나트륨(NaOH), 수산화칼륨(KOH)을 사용할 수 있다. 본 발명에 따른 탈보호 반응과 가수분해 반응은 연속적으로 수행할 수 있으며, 연속적으로 두 단계의 제조공정을 수행하게 되면 2 시간이내에 아토르바스타틴 무수물을 94% 이상의 높은 수율과 99% 이상(HPLC Area %)의 고 순도로 합성할 수 있다.When the deprotection reaction is completed, the hydrolysis reaction may be continuously performed. Specifically, the hydrolysis reaction is performed by adding water to the reaction solution containing the compound represented by Chemical Formula 5 to remove the acid remaining after the solidification, and adding an alkali metal hydroxide dissolved in an alcohol having 1 to 4 carbon atoms or an aqueous alcohol solution to add the hydrolysis reaction. The decomposition reaction was carried out. As the alkali metal hydroxide, sodium hydroxide (NaOH) and potassium hydroxide (KOH) may be typically used. The deprotection reaction and the hydrolysis reaction according to the present invention can be carried out continuously. When two steps of the manufacturing process are carried out continuously, atorvastatin anhydride has a high yield of 94% or more and 99% or more (HPLC Area%) within 2 hours. It can be synthesized with high purity.
상기 가수분해 반응이 완결되면 반응용액에 산을 가하여 pH 1 내지 4 범위, 바람직하기로는 pH 2 내지 3의 범위로 조정하여, 목적하는 상기 화학식 1로 표시되는 아토르바스타틴 유리염기(free base)를 수득할 수 있다.Upon completion of the hydrolysis reaction, acid was added to the reaction solution to adjust the pH to a range of pH 1 to 4, preferably pH 2 to 3, to obtain a desired atorvastatin free base represented by Formula 1 above. Can be.
또한, 상기 화학식 1로 표시되는 아토르바스타틴은 통상의 방법에 의하여 나트륨, 칼륨 등의 알칼리금속 이온, 칼슘, 마그네슘 등의 알칼리토금속 이온, 또는 암모늄 이온과 반응하여 약제학적으로 허용 가능한 염을 형성할 수도 있다. 또한, 상기 화학식 1로 표시되는 아토르바스타틴 유리염기 또는 이의 약제학적으로 허용 가능한 염은 무수물(Anhydrous) 또는 수화물(hydrate)의 형태로 수득할 수도 있다. In addition, the atorvastatin represented by Chemical Formula 1 may be reacted with alkali metal ions such as sodium and potassium, alkaline earth metal ions such as calcium and magnesium, or ammonium ions by a conventional method to form a pharmaceutically acceptable salt. . In addition, the atorvastatin free base represented by Formula 1 or a pharmaceutically acceptable salt thereof may be obtained in the form of anhydrous or a hydrate.
이상에서 설명한 바와 같은 본 발명의 제조방법은 그 제조과정이 비교적 간단하고, 반응조건이 온화하면서도 제조수율 및 순도가 높아서 고지혈증 치료제로 유효한 의약품인 아토르바스타틴(Atorvasatin)의 공업적 생산방법으로 적용하기에 매우 적합하다.As described above, the manufacturing method of the present invention is relatively simple to manufacture, and the reaction conditions are mild, and the production yield and purity are high, so that it can be applied to the industrial production method of atorvastatin, which is an effective drug for treating hyperlipidemia. Suitable.
한편, 본 발명에 따른 제조방법에서 출발물질로 사용하는 상기 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물은 각각 신규 화합물이며, 이들 화합물의 제조방법을 간략히 설명하면 다음과 같다.On the other hand, the compound represented by the formula (2) and the compound represented by the formula (3) used as a starting material in the production method according to the present invention are each a novel compound, briefly explaining the preparation method of these compounds are as follows.
상기 화학식 2로 표시되는 2-(4-플루오로벤젠)-3-페닐-4-카르보아닐린-5-이소프로필-피롤은, 하기 반응식 4에 나타낸 바와 같이 하기 화학식 6으로 표시되는 2-아미노-2-(4-플루오로페닐)아세트페논과 하기 화학식 7로 표시되는 4-메틸-3-옥소-N-페닐펜타미드를 크노르 고리화(Knorr cyclization) 반응시켜 제조하여 사용하였다.2- (4-fluorobenzene) -3-phenyl-4-carboaniline-5-isopropyl-pyrrole represented by the formula (2) is 2-amino represented by the following formula (6) as shown in Scheme 4 below. 2- (4-fluorophenyl) acetphenone and 4-methyl-3-oxo- N -phenylpentamide represented by the following formula (7) were prepared by knorr cyclization reaction and used.
상기 반응식 4에 따른 크노르 고리화 반응을 보다 구체적으로 설명하면, 상기 화학식 6으로 표시되는 화합물과 상기 화학식 7로 표시되는 화합물을 산 촉매 존재하에 70℃ 내지 90℃ 온도로 가열하는 조건에서 고리화 반응하게 되면, 83.7%의 높은 수율과 92.4%의 높은 순도로 상기 화학식 2로 표시되는 화합물을 합성할 수 있다. 상기 고리화 반응에 사용되는 용매는 HF, 아세토니트릴, 헵탄, 에테르, 디메틸포름아미드(DMF), 디메틸설폭사이드(DMSO), 디클로로메탄, 디옥산, 톨루엔으로부터 선택된 단일 용매 또는 혼합 용매를 사용할 수 있으며, 좋기로는 헵탄 단일용매 또는 헵탄과 톨루엔의 혼합용매를 사용하는 것이다. 산 촉매로는 황산, 염산, 아세트산, 피발산, 메탄설폰산, 캄포설폰산(CSA), p-톨루엔설폰산 등 중에서 선택하여 반응용매를 기준으로 10∼20 %w/v 범위로 사용할 수 있으며, 좋기로는 피발산, 아세트산을 사용하는 것이다.Referring to the knor cyclization reaction according to Scheme 4 in more detail, the compound represented by the formula (6) and the compound represented by the formula (7) is cyclized under the conditions of heating to 70 ℃ to 90 ℃ temperature in the presence of an acid catalyst When reacted, the compound represented by Chemical Formula 2 may be synthesized in a high yield of 83.7% and a high purity of 92.4%. The solvent used in the cyclization reaction may be a single solvent or a mixed solvent selected from HF, acetonitrile, heptane, ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane, dioxane, toluene Preferably, heptane single solvent or a mixed solvent of heptane and toluene is used. The acid catalyst can be selected from sulfuric acid, hydrochloric acid, acetic acid, pivalic acid, methanesulfonic acid, camphorsulfonic acid (CSA), p -toluenesulfonic acid, etc. and can be used in the range of 10-20% w / v based on the reaction solvent. Preferably, pivalic acid and acetic acid are used.
또한, 상기 반응식 4에 따른 제조방법에서 원료물질로 사용되는 상기 화학식 6으로 표시되는 2-아미노-2-(4-플루오로페닐)아세트페논은 하기 반응식 5에 따른 방법으로 합성하였다.In addition, 2-amino-2- (4-fluorophenyl) acephenone represented by Chemical Formula 6 used as a raw material in the preparation method according to Scheme 4 was synthesized by the method according to Scheme 5 below.
상기 반응식 5에서, X는 할로겐원자를 나타낸다.In Scheme 5, X represents a halogen atom.
즉, 상기 반응식 5에 따른 방법에 의하면, 상기 화학식 8로 표시되는 4-플루오로벤질 할라이드를 벤즈알데히드와의 그리냐드 반응을 수행하여 상기 화학식 9로 표시되는 2차 알콜 화합물을 수득한 후에, 존슨시약(Jone's reagent)으로 알콜 그룹을 케톤 그룹으로 산화 반응하여 상기 화학식 10으로 표시되는 화합물을 수득하였다. 그리고, N-브로모숙신이미드(NBS)를 이용하여 브롬화 반응시켜 상기 화학식 11로 표시되는 화합물을 수득한 후, 암모니아로 포화된 반응용매 예를 들면 테트라히드로퓨란(THF), 디클로로메탄, 클로로포름, 사염화탄소의 용매 속에서 0℃ 내지 실온의 온도 조건에서 1 내지 2시간동안 반응시켜 상기 화학식 6으로 표시되는 화합물을 수득하였으며, 반응 후에는 더 이상의 정제과정 없이 잔류하는 암모니아 가스만 질소로 충진시켜 제거하면 된다. 상기 반응식 5에 나타낸 상기 화학식 6으로 표시되는 화합물의 합성과정은 매우 산업적으로 쉽게 구입이 가능한 원료 물질을 이용하고 있으며, 수율 또한 92% 이상으로 높은 편으로 경제성이 우수하여 산업적 이용가치가 높다는 장점이 있다.That is, according to the method according to Scheme 5, after performing the Grignard reaction of the 4-fluorobenzyl halide represented by the formula (8) with benzaldehyde to obtain a secondary alcohol compound represented by the formula (9), Johnson reagent The compound represented by Chemical Formula 10 was obtained by oxidation of an alcohol group to a ketone group with (Jone's reagent). Then, bromination is carried out using N -bromosuccinimide (NBS) to obtain a compound represented by Formula 11, and then a reaction solvent saturated with ammonia, for example tetrahydrofuran (THF), dichloromethane, chloroform , By reacting for 1 to 2 hours in a solvent of carbon tetrachloride at a temperature of 0 ℃ to room temperature to obtain a compound represented by the formula (6), after the reaction is removed by filling with only ammonia gas remaining in nitrogen without further purification process Just do it. Synthesis process of the compound represented by the formula (6) shown in Scheme 5 uses a raw material that can be easily purchased industrially, the yield is also high as 92% or more, and the economical efficiency is high, the advantage of high industrial use value have.
또한, 상기 반응식 4에 따른 제조방법에서 원료물질로 사용되는 상기 화학식 7로 표시되는 4-메틸-3-옥소-N-페닐펜타미드는 하기 반응식 6에 따른 방법으로 합성하였다.In addition, 4-methyl-3-oxo- N -phenylpentamide represented by Formula 7 used as a raw material in the preparation method according to Scheme 4 was synthesized by the method according to Scheme 6 below.
상기 반응식 6에서, R1은 탄소수 1 내지 6의 알킬기를 나타낸다.In Scheme 6, R 1 represents an alkyl group having 1 to 6 carbon atoms.
즉, 상기 반응식 6에 따른 방법에 의하면, 상기 화학식 12로 표시되는 알킬 4-메틸-3-옥소-펜타에스테르를 아닐린과 1시간 정도의 짧은 시간동안 반응시켜 고수율(90% 이상)로 수득하였다. That is, according to the method according to Scheme 6, the alkyl 4-methyl-3-oxo-pentaester represented by Formula 12 was reacted with aniline for a short time of about 1 hour to obtain a high yield (90% or more). .
또한, 본 발명에 따른 제조방법이 출발물질로 사용하는 상기 화학식 3으로 표시되는 시스-t-부틸-7-할로-2-알콕시-3,5-디옥산-헵타노에이트는 하기 반응식 7에 따른 방법으로 합성하였다. 또한 하기 화학식 3으로 표시되는 화합물을 암모니아 가스로 처리하여 하기 화학식 3a로 표시되는 화합물을 합성하였다.In addition, cis- t- butyl-7-halo-2-alkoxy-3,5-dioxane-heptanoate represented by Chemical Formula 3, which is used as a starting material according to the present invention, is prepared according to Scheme 7 below. Synthesized by the method. In addition, the compound represented by the following formula (3a) was synthesized by treating the compound represented by the formula (3) with ammonia gas.
상기 반응식 7에서, R은 탄소수 1 내지 6의 알킬기를 나타내고, X는 할로겐원자를 나타내고, Pro.는 p-토실(tosyl), 메탄설포닐(Ms), p-니트로벤질(PNB), 트리메틸실릴(TMS), 또는 t-부틸디메틸실릴(TBS) 중에서 선택된 히드록시 보호기를 나타낸다.In Scheme 7, R represents an alkyl group having 1 to 6 carbon atoms, X represents a halogen atom, Pro. Represents p -tosyl, methanesulfonyl (Ms), p -nitrobenzyl (PNB), trimethylsilyl Hydroxy protecting group selected from (TMS) or t -butyldimethylsilyl (TBS).
즉, 상기 반응식 7에 따른 제조방법에 의하면, 먼저 상기 화학식 13으로 표시되는 시스-t-부틸-3,5-디히드록시-6-할로-헥사노에이트를 산 촉매하에서 트리알킬오르쏘포르메이트(trialkylorthoformate)와 보호화 반응시켜, 디히드록시 그룹이 보호된 상기 화학식 14로 표시되는 시스-t-부틸-2-알콕시-3,5-디옥산-6-브로모-헥사노에이트를 합성하였다. 그런 다음, 상기 화학식 14로 표시되는 화합물을 파라포름알데히드와의 그리냐드 반응으로 말단 C6-할로 그룹을 C7-히드록시기로 변환시켜 상기 화학식 15로 표시되는 화합물을 합성하였다. 그런 다음, 상기 화학식 15로 표시되는 화합물을 트리에틸아민과 같은 유기 염기하에서 0℃ 내지 10℃의 온화한 반응조건으로 보호화제와 반응시켜, 말단 히드록시 그룹이 보호된 상기 화학식 16으로 표시되는 화합물을 합성하였다. 이때 사용되는 히드록시기 보호제는 p-톨루엔설포닐(Ts), 메탄설포닐(Ms), p-니트로벤질(PNB), 트리메틸실릴(TMS), t-부틸디메틸실릴(TBS) 그룹을 포함하는 할로겐 화합물이 대표적으로 사용될 수 있다. 그런 다음, 상기 화학식 16으로 표시되는 화합물을 리튬 브로마이드(LiBr)와 같은 할로겐화제와 디메틸포름아미드(DMF), 테트라히드로퓨란(THF), 아세토니트릴과 같은 유기용매 중속에서 치환 반응시켜, 광학활성체이면서 할로겐 말단기를 갖고 있는 아토르바스타틴의 핵심 중간체로서 상기 화학식 3으로 표시되는 시스-t-부틸-2-알콕시-3,5-디옥산-7-할로-헵타노에이트를 합성하였다.That is, according to the preparation method according to Scheme 7, first, cis- t -butyl-3,5-dihydroxy-6-halo-hexanoate represented by Chemical Formula 13 is subjected to trialkyl orthoformate under an acid catalyst. and a protection reaction with trialkylorthoformate to synthesize cis- t -butyl-2-alkoxy-3,5-dioxane-6-bromo-hexanoate represented by the above formula (14) in which a dihydroxy group was protected. . Then, the compound represented by Chemical Formula 15 was synthesized by converting the terminal C6-halo group into a C7-hydroxy group by Grignard reaction with paraformaldehyde. Subsequently, the compound represented by Chemical Formula 15 is reacted with a protecting agent under a mild reaction condition of 0 ° C. to 10 ° C. under an organic base such as triethylamine to obtain a compound represented by Chemical Formula 16, wherein the terminal hydroxy group is protected. Synthesized. The hydroxy group protecting agent used at this time is a halogen compound including p -toluenesulfonyl (Ts), methanesulfonyl (Ms), p -nitrobenzyl (PNB), trimethylsilyl (TMS), t -butyldimethylsilyl (TBS) group This can be used representatively. Subsequently, the compound represented by Chemical Formula 16 is substituted with a halogenating agent such as lithium bromide (LiBr) in an organic solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, and an optically active substance. In addition, cis- t -butyl-2-alkoxy-3,5-dioxane-7-halo-heptanoate represented by Chemical Formula 3 was synthesized as a core intermediate of atorvastatin having a halogen terminal group.
이러한 본 발명은 다음의 실시예에 의거하여 더욱 상세히 설명하겠는바, 본 발명이 다음의 실시예에 의해 한정되는 것은 결코 아니다.The present invention will be described in more detail based on the following examples, but the present invention is not limited by the following examples.
[실시예]EXAMPLE
실시예 1. 2-이소프로필-3-페닐아미드-4-페닐-5-(4-플루오로페닐)피롤 (화학식 2)의 합성Example 1.Synthesis of 2-isopropyl-3-phenylamide-4-phenyl-5- (4-fluorophenyl) pyrrole (Formula 2)
딘스탁이 설치된 반응용기에 2-아미노-2-(4-플루오로페닐)-아세트페논 10 g(43.6 mmol)과 4-메틸-3-옥소-N-페닐펜타아미드 10.7 g(52.36 mmol)을 톨루엔 6 mL와 헵탄 60 mL에 넣고 피발산 1.8 mL를 가한 후 6시간동안 환류하였다. 반응물을 냉각한 후 반응용매를 감압 농축하였다. 반응물을 디클로로메탄 200 mL으로 녹인 후 0.5%-HCl로 세척하고 정제수, 소금물로 순차적으로 세척 후 황산마그네슘으로 건조하였다. 용매를 감압 농축하여 얻은 농축물을 에틸아세테이트로 녹인 후 0℃로 냉각하였다. 소량의 헥산을 가한 후 30분간 교반하였다. 생성된 고체를 여과하여 건조하여 14.5 g(83.7%)을 수득했다.In a reaction vessel equipped with Deanstock, 10 g (43.6 mmol) of 2-amino-2- (4-fluorophenyl) -acetphenone and 10.7 g (52.36 mmol) of 4-methyl-3-oxo- N -phenylpentaamide were added. 6 mL of toluene and 60 mL of heptane were added, and 1.8 mL of pivalic acid was added thereto, followed by reflux for 6 hours. After cooling the reaction, the reaction solvent was concentrated under reduced pressure. The reaction was dissolved in 200 mL of dichloromethane, washed with 0.5% -HCl, washed sequentially with purified water and brine, and dried over magnesium sulfate. The concentrate obtained by concentrating the solvent under reduced pressure was dissolved in ethyl acetate and cooled to 0 ° C. A small amount of hexane was added and stirred for 30 minutes. The resulting solid was filtered and dried to give 14.5 g (83.7%).
1H NMR(CDCl3) δ 1.33(d, 3H), 3.41(m, 1H), 5.1(m, 1H), 6.9∼7.3(m, 14H), 9.4(s, 1H) 1 H NMR (CDCl 3 ) δ 1.33 (d, 3H), 3.41 (m, 1H), 5.1 (m, 1H), 6.9-7.3 (m, 14H), 9.4 (s, 1H)
실시예 2. 2-이소프로필-3-페닐아미드-4-페닐-5-(4-플루오로페닐)피롤 (화학식 2)의 합성Example 2. Synthesis of 2-isopropyl-3-phenylamide-4-phenyl-5- (4-fluorophenyl) pyrrole (Formula 2)
아세틱안히드라이드 40 mL에 2-아미노-2-(4-플루오로페닐)-아세트페논 10 g(43.6 mmol)과 4-메틸-3-옥소-N-페닐펜타아미드 10.7 g(52.36 mmol)을 넣고 피발산 1.8 mL를 가한 후 80℃에서 3시간동안 가열하였다. 반응물을 냉각한 후 감압 농축하고 반응물을 디클로로메탄 200 mL으로 녹인 후 정제수 200 mL으로 2회, 소금물로 반복 세척 후 황산마그네슘으로 건조하였다. 용매를 감압 농축하여 얻은 농축물을 에틸아세테이트로 녹인 후 0℃로 냉각하였다. 소량의 헥산을 가한 후 30분간 교반하였다. 생성된 고체를 여과하여 건조하여 15.1 g(87.4.%)을 수득했다.10 mL (43.6 mmol) of 2-amino-2- (4-fluorophenyl) -acetphenone and 10.7 g (52.36 mmol) of 4-methyl-3-oxo- N -phenylpentaamide were added to 40 mL of acetic anhydride. 1.8 mL of pivalic acid was added thereto, followed by heating at 80 ° C. for 3 hours. The reaction mixture was cooled, concentrated under reduced pressure, and the reaction mixture was dissolved in 200 mL of dichloromethane, washed twice with 200 mL of purified water, and repeatedly washed with brine and dried over magnesium sulfate. The concentrate obtained by concentrating the solvent under reduced pressure was dissolved in ethyl acetate and cooled to 0 ° C. A small amount of hexane was added and stirred for 30 minutes. The resulting solid was filtered and dried to give 15.1 g (87.4.%).
1H NMR(CDCl3) δ 1.33(d, 3H), 3.41(m, 1H), 5.1(m, 1H), 6.9∼7.3(m, 14H), 9.4(s, 1H) 1 H NMR (CDCl 3 ) δ 1.33 (d, 3H), 3.41 (m, 1H), 5.1 (m, 1H), 6.9-7.3 (m, 14H), 9.4 (s, 1H)
실시예 3. 시스-t-부틸-2-에톡시-3,5-디옥산-7-브로모-헵타노에이트 (화학식 3)의 합성Example 3. Synthesis of cis- t- butyl-2-ethoxy-3,5-dioxane-7-bromo-heptanoate (Formula 3)
시스-t-부틸-2-에톡시-3,5-디옥산-7-토실-헵타노에이트 8 g(18.0 mmol)을 무수 THF 50 mL에 녹인 후 0℃로 냉각하였다. 리튬브로마이드 1.9(21.6 mmol)을 넣고 3시간 동안 교반하였다. 실온으로 승온한 후 30분간 교반후 반응물을 진공 농축하였다. 반응물을 에틸 아세테이트 100 mL으로 녹인 후 냉수 50 mL와 소금물로 순차적으로 세척하고 황산마그네슘으로 건조한 후 진공 농축하여 오일 5.5 g(87.4%)을 수득했다.8 g (18.0 mmol) of cis- t- butyl-2-ethoxy-3,5-dioxane-7-tosyl-heptanoate were dissolved in 50 mL of anhydrous THF and cooled to 0 ° C. Lithium bromide 1.9 (21.6 mmol) was added thereto and stirred for 3 hours. After the temperature was raised to room temperature, the reaction was concentrated in vacuo after stirring for 30 minutes. The reaction was dissolved in 100 mL of ethyl acetate, washed sequentially with 50 mL of cold water and brine, dried over magnesium sulfate, and concentrated in vacuo to give 5.5 g (87.4%) of oil.
1H NMR(CDCl3) δ 1.12(m, 5H), 1.34(s, 9H), 1.53(m, 2H), 2.1(m, 2H), 3.32(t, 2H), 4.2∼4.4(m.4H), 5.74(s, 1H). 1 H NMR (CDCl 3 ) δ 1.12 (m, 5H), 1.34 (s, 9H), 1.53 (m, 2H), 2.1 (m, 2H), 3.32 (t, 2H), 4.2 to 4.4 (m.4H ), 5.74 (s, 1 H).
실시예 4. 1-N-(시스-t-부틸-2-에톡시-3,5-디옥산-7-아미노-헥사노에이트)-2-(4-플루오로페닐)-3-페닐-4-카르보아닐린-5-이소프로필-피롤 (화학식 4)의 합성Example 4. 1- N- (cis- t- butyl-2-ethoxy-3,5-dioxane-7-amino-hexanoate) -2- (4-fluorophenyl) -3-phenyl- Synthesis of 4-carboaniline-5-isopropyl-pyrrole (Formula 4)
상기 실시예 1에서 합성한 2-이소프로필-3-페닐아미드-4-페닐-5-(4-플루오로페닐)피롤 10 g(25.11 mmol)을 THF 40 mL에 녹인 후 0℃로 냉각하였다. TEA 4.2 mL을 (30.0 mmol)가하고, 상기 실시예 3에서 합성한 시스-t-부틸-2-에톡시-3,5-디옥산-7-브로모-헵타노에이트 9.7 g(27.5 mmol)을 THF 30 mL에 녹인 용액을 서서히 가하였다. 온도를 유지하면서 30분 더 교반한 후 실온으로 승온 후 1시간 더 교반하였다. 반응물을 진공 농축 후 디클로로메탄 150 mL으로 녹인 후 정제수로 2회 반복 세척하고 소금물로 세척하였다. 황산마그네슘으로 건조하고 감압 농축하여 표제화합물을 백색 고체로 정량적으로 수득하였다.10 g (25.11 mmol) of 2-isopropyl-3-phenylamide-4-phenyl-5- (4-fluorophenyl) pyrrole synthesized in Example 1 was dissolved in 40 mL of THF, and then cooled to 0 ° C. 4.2 mL of TEA was added (30.0 mmol), and 9.7 g (27.5 mmol) of cis- t- butyl-2-ethoxy-3,5-dioxane-7-bromo-heptanoate synthesized in Example 3 was added. The solution dissolved in 30 mL of THF was added slowly. After stirring for 30 minutes while maintaining the temperature, the mixture was stirred for 1 hour after the temperature was raised to room temperature. The reaction was concentrated in vacuo and then dissolved in 150 mL of dichloromethane and washed twice with purified water and then brine. Drying over magnesium sulfate and concentration under reduced pressure gave the title compound as a white solid quantitatively.
1H NMR(DMSO-d6) δ 1.0∼1.1(m, 5H), 1.35(m, 15H), 2.2∼2.3(m, 2H), 2.3∼2.4(m, 2H), 3.1∼3.2(2H), 3.47(m, 1H), 5.74(s, 1H), 6.9∼7.5(m, 14H), 9.82(s, 1H) 1 H NMR (DMSO-d 6 ) δ 1.0 to 1.1 (m, 5H), 1.35 (m, 15H), 2.2 to 2.3 (m, 2H), 2.3 to 2.4 (m, 2H), 3.1 to 3.2 (2H) , 3.47 (m, 1H), 5.74 (s, 1H), 6.9-7.5 (m, 14H), 9.82 (s, 1H)
실시예 5. 1-N-(시스-t-부틸-3,5-디히드록시-7-아미노-헥사노에이트)-2-(4-플루오로페닐)-3-페닐-4-카르보아닐린-5-이소프로필-피롤 (화학식 5)의 합성Example 5. 1- N- (cis- t- butyl-3,5-dihydroxy-7-amino-hexanoate) -2- (4-fluorophenyl) -3-phenyl-4-carbo Synthesis of Aniline-5-isopropyl-pyrrole (Formula 5)
상기 실시예 4에서 합성한 1-N-(시스-t-부틸-2-에톡시-3,5-디옥산-7-아미노-헥사노에이트)-2-(4-플루오로페닐)-3-페닐-4-카르보아닐린-5-이소프로필-피롤 10 g(14.9 mmol)을 메탄올 80 mL에 녹인 후 0℃로 냉각하였다. 반응물에 2N-HCl 20 mL을 가한 후 1.5시간 교반하였다. 생성된 표제의 백색 고체 화합물을 여과한 후 진공 건조하여 표제화합물을 정량적으로 수득하였다.1- N- (cis- t- butyl-2-ethoxy-3,5-dioxane-7-amino-hexanoate) -2- (4-fluorophenyl) -3 synthesized in Example 4 above 10 g (14.9 mmol) of -phenyl-4-carboaniline-5-isopropyl-pyrrole was dissolved in 80 mL of methanol and cooled to 0 ° C. 20 mL of 2 N- HCl was added to the reaction, followed by stirring for 1.5 hours. The resulting white solid compound was filtered and dried in vacuo to yield the title compound quantitatively.
1H NMR(DMSO-d6) δ 1.35(m, 19H), 2.1∼2, 2(m, 2H), 2.49(bs, 2H), 3.1∼3.2(m, 2H), 3.5∼3.6(m, 5H), 6.9∼7.5(m, 14H), 9.79(s, 1H) 1 H NMR (DMSO-d 6 ) δ 1.35 (m, 19H), 2.1 to 2, 2 (m, 2H), 2.49 (bs, 2H), 3.1 to 3.2 (m, 2H), 3.5 to 3.6 (m, 5H), 6.9-7.5 (m, 14H), 9.79 (s, 1H)
실시예 6. 4-메틸-3-옥소-N-페닐펜타아미드(화학식 7)의 합성Example 6. Synthesis of 4-methyl-3-oxo- N -phenylpentaamide (Formula 7)
메틸-4-메틸-3-옥소-펜타에스테르 10 mL(70.26 mmol)을 톨루엔 20 mL에 녹인 후 아닐린 7.04 mL을 가한 후 1.5시간동안 환류 교반하였다. 반응물을 냉각한 후 에틸아세테이트 100 mL와 1N-HCl 100 mL를 가한 후 유기층을 추출 분리하였다. 추출물을 정제수 100 mL, 소금물로 세척 후 황산마그네슘으로 건조하였다. 용매를 감압 농축한 후 얻어진 갈색 오일을 더 이상의 정제 과정 없이 다음 반응에 이용하였다.10 mL (70.26 mmol) of methyl-4-methyl-3-oxo-pentaester was dissolved in 20 mL of toluene, 7.04 mL of aniline was added thereto, and the mixture was stirred under reflux for 1.5 hours. After the reaction was cooled, 100 mL of ethyl acetate and 100 mL of 1 N- HCl were added, and the organic layer was extracted and separated. The extract was washed with 100 mL of purified water and brine, and dried over magnesium sulfate. The brown oil obtained after concentration of the solvent under reduced pressure was used in the next reaction without further purification.
1H NMR(CDCl3) δ 1.14(d, 6H), 2.72(m, 1H), 3.58(s, 2H), 7.11(m, 1H), 7.2∼7.3(m, 2H), 7.54(d, 2H), 9.21(b, 1H) 1 H NMR (CDCl 3 ) δ 1.14 (d, 6H), 2.72 (m, 1H), 3.58 (s, 2H), 7.11 (m, 1H), 7.2 to 7.3 (m, 2H), 7.54 (d, 2H ), 9.21 (b, 1 H)
실시예 7. 2-아미노-2-(4-플루오로페닐)-아세트페논 (화학식 6)의 합성.Example 7. Synthesis of 2-amino-2- (4-fluorophenyl) -acetphenone (Formula 6)
암모니아 가스가 포화된 THF 70 mL에 2-브로모-2-(4-플루오로페닐)-아세트페논 10 g를 넣고 0℃에서 1시간동안 교반하였다. 반응물을 질소로 충진하여 잔류 암모니아 가스를 제거한 후 반응물을 감압 농축하였다. 농축물을 디클로로메탄 200 mL으로 녹인 후 정제수 100 mL으로 2회 반복 세척하였다. 소금물로 세척 후 황산마그네슘으로 건조한 후 감압 농축하여 표제화합물을 정량적으로 수득하였다.10 g of 2-bromo-2- (4-fluorophenyl) -acetphenone was added to 70 mL of THF saturated with ammonia gas, and stirred at 0 ° C. for 1 hour. The reaction was filled with nitrogen to remove residual ammonia gas and the reaction was concentrated under reduced pressure. The concentrate was dissolved in 200 mL of dichloromethane and washed twice with 100 mL of purified water. After washing with brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain the title compound quantitatively.
1H NMR(CDCl3) δ 2.1(br, 2H), 5.32(s, 1H), 7.0∼7.6(m, 7H), 8.03(q, 2H) 1 H NMR (CDCl 3 ) δ 2.1 (br, 2H), 5.32 (s, 1H), 7.0-7.6 (m, 7H), 8.03 (q, 2H)
실시예 8. 2-브로모-2-(4-플루오로페닐)-아세트페논 (화학식 11)의 합성Example 8. Synthesis of 2-bromo-2- (4-fluorophenyl) -acetphenone (Formula 11)
2-(4-플루오로페닐)-아세트페논 10 g(46.71 mmol)을 테트라클로로메탄(CCl4) 200 mL에 녹인 후 AIBS(0.05 g), NBS 10 g(56.0 mmol)을 넣고 3시간동안 환류 교반하였다. 반응물을 냉각한 후 불용물을 여과 제거한 후 정제수와 소금물로 순차적으로 세척 후 황산마그네슘으로 건조 후 감압 농축하여 황색오일의 표제화합물 11.2 g(82.3%)을 수득하였다. 10 g (46.71 mmol) of 2- (4-fluorophenyl) -acetphenone was dissolved in 200 mL of tetrachloromethane (CCl4), followed by AIBS (0.05 g) and 10 g (56.0 mmol) of NBS. It was. After the reaction was cooled, the insolubles were filtered off, washed sequentially with purified water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 11.2 g (82.3%) of the title compound as a yellow oil.
1H NMR(CDCl3) δ 6.32(s, 1H), 7.0∼7.6(m, 7H), 8.03(q, 2H) 1 H NMR (CDCl 3 ) δ 6.32 (s, 1H), 7.0-7.6 (m, 7H), 8.03 (q, 2H)
실시예 9. 2-(4-플루오로페닐)-아세트페논 (화학식 10)의 합성Example 9. Synthesis of 2- (4-fluorophenyl) -acetphenone (Formula 10)
아세톤 150 mL속에 1-히드록시-2-(4-플루오로페닐)-1-페닐에탄 10 g(46.0 mmol)을 넣고 0℃로 냉각한 후 존슨(Jone's)시약을 서서히 가하였다. 반응액이 적색으로 변하면 반응을 종결하고 TEA으로 중화한 후 감압 농축하였다. 반응액을 에틸아세테이트 100 mL으로 녹인 후 1N-HCl 100 mL으로 세척하고 물로 세척한 후 소금물로 세척하였다. 황산마그네슘으로 건조 후 감압 농축하여 표제화합물 8.35 g(84.3%)을 수득하였다.10 g (46.0 mmol) of 1-hydroxy-2- (4-fluorophenyl) -1-phenylethane was added to 150 mL of acetone, and the mixture was cooled to 0 ° C., and Johnson's reagent was slowly added thereto. When the reaction solution turned red, the reaction was terminated, neutralized with TEA, and concentrated under reduced pressure. The reaction solution was dissolved in 100 mL of ethyl acetate, washed with 100 mL of 1 N- HCl, washed with water, and then brine. Drying over magnesium sulfate and concentration under reduced pressure gave 8.35 g (84.3%) of the title compound.
1H NMR(CDCl3) δ 4.18(s, 2H), 7.0∼7.6(m, 7H), 8.03(q, 2H) 1 H NMR (CDCl 3 ) δ 4.18 (s, 2H), 7.0 to 7.6 (m, 7H), 8.03 (q, 2H)
실시예 10. 1-히드록시-2-(4-플루오로페닐)-1-페닐에탄 (화학식 9)의 합성.Example 10. Synthesis of 1-hydroxy-2- (4-fluorophenyl) -1-phenylethane (Formula 9).
Mg(마그네슘) 1.55 g(63.8 mmol)을 THF 150 mL에 넣고 메틸요오드 1방울을 가한 후 30분간 환류 교반하였다. 반응기에 4-플루오로벤질브로마이드 6.6 mL(53.2 mmol)을 조심스럽게 가한 후 마그네슘이 제거될 때까지 환류하였다. 반응액을 0℃로 냉각한 후 벤즈알데히드 6.48 mL(63.8 mmol)을 서서히 가하였다. 온도를 유지하면서 1시간 더 교반 후 실온에서 1시간 더 교반하였다. 반응액을 감압 농축한 후 1N-HCl 100 mL와 에틸아세테이트 200 mL을 가하고 30분간 교반한 후에 층분리하였고, 유기층을 황산마그네슘으로 건조 후 감압 농축하여 표제화합물 10.3 g(89.6%)을 수득하였다.1.55 g (63.8 mmol) of Mg (magnesium) were added to 150 mL of THF, and 1 drop of methyl iodine was added thereto, followed by stirring for 30 minutes at reflux. 6.6 mL (53.2 mmol) of 4-fluorobenzylbromide was carefully added to the reactor and then refluxed until magnesium was removed. After cooling the reaction solution to 0 ° C., 6.48 mL (63.8 mmol) of benzaldehyde was slowly added. After stirring for 1 hour while maintaining the temperature, the mixture was stirred for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure, 100 mL of 1 N- HCl and 200 mL of ethyl acetate were added thereto, stirred for 30 minutes, and the layers were separated. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to obtain 10.3 g (89.6%) of the title compound. .
1H NMR(CDCl3) δ 2.92(d, 2H), 4.92(t, 1H), 7.0∼7.3(m, 9H) 1 H NMR (CDCl 3 ) δ 2.92 (d, 2H), 4.92 (t, 1H), 7.0 to 7.3 (m, 9H)
실시예 11. 시스-t-부틸-2-에톡시-3,5-디옥산-7-(p-토실설파이트)-헵타노에이트에피머 (화학식 16)의 합성.Example 11. Synthesis of cis- t- butyl-2-ethoxy-3,5-dioxane-7- ( p -tosylsulfite) -heptanoate epimer (Formula 16).
시스-t-부틸-2-에톡시-3,5-디옥산-7-히드록시-헵타노에이트 에피머 10 g(25.76 mmol)을 디클로로메탄 70 mL에 녹인 후 0℃로 냉각하였다. TEA 4.3 mL(30.91m mmol)을 가한 후 p-톨루엔설포닐클로라이드 5.9 g(30.91 mmol)을 가한 후 1시간 교반하였다. 반응물에 정제수, 소금물로 세척 후 황산마그네슘으로 건조후 감압 농축하여 표제화합물 14.8 g(97.4%)을 수득하였다.10 g (25.76 mmol) of cis- t- butyl-2-ethoxy-3,5-dioxane-7-hydroxy-heptanoate epimer was dissolved in 70 mL of dichloromethane and cooled to 0 ° C. 4.3 mL (30.91 mmol) of TEA was added, followed by 5.9 g (30.91 mmol) of p- toluenesulfonyl chloride, followed by stirring for 1 hour. The reaction was washed with purified water and brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain 14.8 g (97.4%) of the title compound.
1H NMR(CDCl3) δ 1.12(m, 5H), 1.34(s, 9H), 1.41(m, 2H), 2.14(dd, 2H), 2.38(s, 3H), 4.2∼4.4(m.6H), 5.74(s, 1H), 7.42(d, 2H), 7.82(d, 2H) 1 H NMR (CDCl 3 ) δ 1.12 (m, 5H), 1.34 (s, 9H), 1.41 (m, 2H), 2.14 (dd, 2H), 2.38 (s, 3H), 4.2 to 4.4 (m.6H ), 5.74 (s, 1H), 7.42 (d, 2H), 7.82 (d, 2H)
실시예 12. 시스-t-부틸-2-에톡시-3,5-디옥산-7-히드록시-헵타노에이트 에피머 (15)의 합성.Example 12. Synthesis of cis- t- butyl-2-ethoxy-3,5-dioxane-7-hydroxy-heptanoate epimer (15).
에테르 70 mL속에 마그네슘 0.7 g(29.10 mmol), 메틸요오드 1방울을 가열하였다. 환류가 시작되면 서서히 시스-t-부틸-2-에톡시-3,5-디옥산-6-브로모-헥사노에이트 에피머 8.2 g(24.25 mmol)을 조심스럽게 가하였다. 반응물을 실온 내지 0℃로 냉각한 후 파라포름알데히드 11.1 g(32.01 mmol)을 에테르 10 mL에 녹인 용액을 서서히 가하였다. 1시간 더 교반 후 0.5N-HCl로 세척하고 물, 소금물로 순차적으로 세척하였다. 황산마그네슘으로 건조 후 감압 농축하여 표제화합물 5.9 g(83.2%)을 수득하였다.0.7 g (29.10 mmol) of magnesium and 1 drop of methyl iodine were heated in 70 mL of ether. At the onset of reflux slowly 8.2 g (24.25 mmol) of cis- t- butyl-2-ethoxy-3,5-dioxane-6-bromo-hexanoate epimer were added slowly. After the reaction was cooled to room temperature to 0 ° C., a solution of 11.1 g (32.01 mmol) of paraformaldehyde in 10 mL of ether was slowly added thereto. After stirring for another 1 hour, the mixture was washed with 0.5 N- HCl and sequentially washed with water and brine. Drying over magnesium sulfate and concentration under reduced pressure gave 5.9 g (83.2%) of the title compound.
1H NMR(CDCl3) δ 1.12(m, 5H), 1.34(s, 9H), 1.41(m, 2H), 2.14(dd, 2H), 4.2∼4.4(m.6H), 5.74(s, 1H) 1 H NMR (CDCl 3 ) δ 1.12 (m, 5H), 1.34 (s, 9H), 1.41 (m, 2H), 2.14 (dd, 2H), 4.2 to 4.4 (m.6H), 5.74 (s, 1H )
실시예 13. 시스-t-부틸-2-에톡시-3,5-디옥산-6-브로모-헥사노에이트에피머 (화학식 14)의 합성.Example 13. Synthesis of cis- t- butyl-2-ethoxy-3,5-dioxane-6-bromo-hexanoate epimer (Formula 14).
시스-t-부틸-3,5-디히드록시-6-브로모-헥사노에이트 10 g(35.45 mmol)을 THF 70 mL에 녹인 후 메탄설폰산 2방울 가한 후 트리에틸오르쏘포르메이트 5.14 mL(30.91 mmol)서서히 가한 후 1.5시간 교반하였다. 실온으로 승온하여 1시간 교반하였고, TEA 1방울로 중화 후 반응용매를 감압 농축하였다. 반응물을 에틸아세테이트로 녹인 후 정제수, 소금물로 순차적으로 세척 후 황산마그네슘으로 건조한 후 감압 농축하여 표제화합물의 에피머를 정량적으로 수득하였다.Dissolve 10 g (35.45 mmol) of cis- t- butyl-3,5-dihydroxy-6-bromo-hexanoate in 70 mL of THF, add 2 drops of methanesulfonic acid, and then add 5.14 mL of triethylorthoformate. (30.91 mmol) was added slowly and stirred for 1.5 hours. The temperature was raised to room temperature, the mixture was stirred for 1 hour, and after neutralizing with 1 drop of TEA, the reaction solvent was concentrated under reduced pressure. The reaction was dissolved in ethyl acetate, washed sequentially with purified water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to quantitatively obtain an epimer of the title compound.
1H NMR(CDCl3) δ 1.12(m, 5H), 1.34(s, 9H), 1.41(m, 2H), 2.14(dd, 2H), 3.4∼3.5(m, 2H), 4.2∼4.4(m.4H), 5.74(s, 1H) 1 H NMR (CDCl 3 ) δ 1.12 (m, 5H), 1.34 (s, 9H), 1.41 (m, 2H), 2.14 (dd, 2H), 3.4 to 3.5 (m, 2H), 4.2 to 4.4 (m .4 H), 5.74 (s, 1 H)
실시예 14. 아토르바스타틴의 칼슘염(Atorvastatin Ca salt) (화학식 1) 제조.Example 14 Preparation of atorvastatin Ca salt (Formula 1).
상기 실시예 5에서 합성한 1-N-(시스-t-부틸-3,5-디히드록시-7-아미노-헥사노에이트)-2-(4-플루오로페닐)-3-페닐-4-카르보아닐린-5-이소프로필-피롤 10 g(16.2 mmol)을 메탄올 40 mL에 녹인 후 0℃로 냉각하였다. NaOH 1.94 g(48.3 mmol)을 물 40 mL에 녹인 용액을 서서히 가한 후 실온으로 승온하여 3시간 교반하였다. 가수분해 반응의 완결은 TLC(Tin layer chormato graphy), HPLC를 통해서 출발물질이 완전히 제거되는 것을 확인하였다.1- N- (cis- t- butyl-3,5-dihydroxy-7-amino-hexanoate) -2- (4-fluorophenyl) -3-phenyl-4 synthesized in Example 5 above 10 g (16.2 mmol) of -carboaniline-5-isopropyl-pyrrole was dissolved in 40 mL of methanol and cooled to 0 ° C. A solution of 1.94 g (48.3 mmol) of NaOH in 40 mL of water was slowly added thereto, and then the temperature was raised to room temperature, followed by stirring for 3 hours. Completion of the hydrolysis reaction was confirmed that the starting material was completely removed through TLC (Tin layer chormato graphy), HPLC.
그리고, 아토르바스타틴의 칼슘염을 제조하기 위해 반응물을 0℃로 냉각한 후 pH을 11로 보정해주었다. CaCl2 0.9 g(8.9 mmol)을 물 20 mL에 녹인 용액을 가한 후 6시간동안 실온에서 교반하였다. 반응액에 물 60 mL을 더 가한 후 1시간 더 교반하고 0℃에서 2시간 방치 후 여과하였다. 여과된 백색 고체물을 감압 하에 35∼40℃에서 건조하여 아토르바스타틴 칼슘염의 백색 고체를 정량적으로 수득하였다.And, to prepare a calcium salt of atorvastatin, after cooling the reaction to 0 ℃ was adjusted to pH 11. 0.9 g (8.9 mmol) of CaCl 2 was added to 20 mL of water, and then stirred at room temperature for 6 hours. 60 mL of water was further added to the reaction solution, followed by further stirring for 1 hour, and the mixture was left at 0 ° C. for 2 hours and filtered. The filtered white solid was dried at 35-40 ° C. under reduced pressure to quantitatively obtain a white solid of atorvastatin calcium salt.
1H NMR(DMSO-d6) δ 9.84(s, 1H), 7.4∼7.9(m, 2H), 6.9∼7.0(m, 12H), 3.93(br, 1H), 3.74(br, 2H), 3.0∼3.2(m, 1H) 2.0∼1.93(m, 4H), 1.2∼1.36(m, 9H) 1 H NMR (DMSO-d 6 ) δ 9.84 (s, 1H), 7.4 to 7.9 (m, 2H), 6.9 to 7.0 (m, 12H), 3.93 (br, 1H), 3.74 (br, 2H), 3.0 -3.2 (m, 1H) 2.0-1.93 (m, 4H), 1.2-1.36 (m, 9H)
이상에서 설명한 바와 같이, 본 발명은 아토르바스타틴(Ator vastatin) 제조에 있어 특정 작용기를 도입하기 위하여 불필요한 제조 과정이 없을 뿐더러, 본 발명에 따른 N-알킬화, 탈보호화 및 가수분해 반응이 비교적 온화한 반응조건하에서 수행되며, 또한 짧은 반응시간으로 아토르바스타틴을 높은 수율로 제조되며 상업적 생산이 유효하다.As described above, the present invention does not have an unnecessary manufacturing process for introducing specific functional groups in the preparation of atorvastatin, and under relatively mild reaction conditions of N-alkylation, deprotection and hydrolysis according to the present invention. Atorvastatin is produced in high yield with short reaction time and commercial production is effective.
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| US5128366A (en) * | 1990-07-05 | 1992-07-07 | Shinogi & Co., Ltd. | Pyrrole derivatives |
| WO2006110918A1 (en) * | 2005-04-13 | 2006-10-19 | Ambit Biosciences Corporation | Pyrrole compounds and uses thereof |
| JP2007516227A (en) * | 2003-05-16 | 2007-06-21 | アンビット バイオサイエンシス コーポレーション | Pyrrole compounds and uses thereof |
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| US5128366A (en) * | 1990-07-05 | 1992-07-07 | Shinogi & Co., Ltd. | Pyrrole derivatives |
| JP2007516227A (en) * | 2003-05-16 | 2007-06-21 | アンビット バイオサイエンシス コーポレーション | Pyrrole compounds and uses thereof |
| US7323490B2 (en) * | 2003-05-16 | 2008-01-29 | Ambit Biosciences Corporation | Pyrrole compounds and uses thereof |
| WO2006110918A1 (en) * | 2005-04-13 | 2006-10-19 | Ambit Biosciences Corporation | Pyrrole compounds and uses thereof |
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