KR100503022B1 - A highly efficient synthetic process for the preparation of simvastatin and new intermediates therefor - Google Patents
A highly efficient synthetic process for the preparation of simvastatin and new intermediates therefor Download PDFInfo
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- KR100503022B1 KR100503022B1 KR10-2002-0051116A KR20020051116A KR100503022B1 KR 100503022 B1 KR100503022 B1 KR 100503022B1 KR 20020051116 A KR20020051116 A KR 20020051116A KR 100503022 B1 KR100503022 B1 KR 100503022B1
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
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- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D309/30—Oxygen atoms, e.g. delta-lactones
Abstract
본 발명은 고지혈증 치료제로서 공지된 심바스타틴을 제조하는 새로운 방법 및 이에 사용되는 신규 중간체에 관한 것이다.The present invention relates to a novel method of preparing simvastatin, known as a therapeutic agent for hyperlipidemia, and to novel intermediates used therein.
Description
본 발명은 고지혈증 치료제로서 공지된 심바스타틴(Simvastatin)을 제조하는 새로운 방법 및 이에 사용되는 새로운 중간체와 그를 제조하는 방법에 관한 것이다.The present invention relates to a novel method for preparing simvastatin, known as a therapeutic agent for hyperlipidemia, and to a novel intermediate used therein and a method for producing the same.
심바스타틴을 제조하기 위한 기존의 방법으로는 미국특허 제4,444,784호에 개시된 바와 같이, 로바스타틴을 출발 물질로하여 락톤 고리와 2-메틸부틸 그룹을 가수분해하고, 다시 락톤 고리를 새로이 형성한 후, 락톤 고리의 히드록시기를 삼급-부틸디메틸실릴 그룹으로 보호한 다음, 디메틸부틸 염화물로 에스테르화 반응을 하고, 보호된 히드록시기로부터 삼급-부틸디메틸실릴 그룹을 제거하여 심바스타틴을 제조하는 방법이 최초의 방법이다(하기 반응식 1 참조).Conventional methods for the preparation of simvastatin, as disclosed in U.S. Patent No. 4,444,784, hydrolyze the lactone ring and the 2-methylbutyl group using lovastatin as a starting material, form a new lactone ring, and then lactone ring The first method is to prepare a simvastatin by protecting the hydroxy group of with a tert-butyldimethylsilyl group, then esterifying with dimethylbutyl chloride, and removing the tert-butyldimethylsilyl group from the protected hydroxy group. 1).
[반응식 1]Scheme 1
상기 식에서, TBDMS는 삼급-부틸디메틸실릴기이다.Wherein TBDMS is a tert-butyldimethylsilyl group.
또한 Journal of Organic Chemistry 56, 4929(1991)에는, 부틸아민을 사용하여 락톤 고리를 아미드로 가아미노분해한 후, 삼급-부틸디메틸실릴 그룹으로 두 개의 히드록시기를 보호한 다음, n-부틸리튬과 요오드메탄을 사용하여 메틸화반응을 한 후, 메탄술폰산으로 보호기를 제거하고, 수산화나트륨으로 아미드를 가수분해한 후, 염산 및 암모니아수 처리를 거쳐, 톨루엔 용매 하에서 락톤 고리를 다시 형성시켜 심바스타틴을 제조하는 방법이 발표되어 있다(하기 반응식 2 참조).Journal of Organic Chemistry 56, 4929 (1991) also describes the use of butylamine to further aminoaminolyse the lactone ring to amides, and then protect the two hydroxy groups with tert-butyldimethylsilyl groups, followed by n-butyllithium and iodine After methylation using methane, the protecting group is removed with methanesulfonic acid, hydrolysis of the amide with sodium hydroxide, hydrochloric acid and ammonia water treatment, and the lactone ring is re-formed in toluene to prepare simvastatin. Published (see Scheme 2 below).
[반응식 2]Scheme 2
상기 식에서, TBDMS는 삼급-부틸디메틸실릴기이다.Wherein TBDMS is a tert-butyldimethylsilyl group.
그러나, 상기 미국 특허 공보 제4,444,784호에 따라 심바스타틴을 제조할 경우, 락톤고리 및 2-메틸부틸 그룹의 제거 및 재 락톤화 공정에서 부산물이 과량 생성되어 전체 수율이 48 %로 매우 저조하다. 또한 Journal of Organic Chemistry 56, 4929(1991)에 따라 심바스타틴을 제조할 경우 사용되는 n-부틸리튬이 고가인 것은 물론이고 발화성이 극히 높으며, 또한 철저히 무수조건에서 반응을 진행하는 등 공정관리가 매우 복잡하며, 여러 단계의 공정을 거쳐서 제조하기 때문에 경제성이 떨어지는 문제점이 있다. However, when simvastatin is prepared according to US Pat. No. 4,444,784, by-products are produced in the removal and relactoneization of lactone rings and 2-methylbutyl groups, resulting in very low overall yields of 48%. In addition, according to the Journal of Organic Chemistry 56, 4929 (1991), the preparation of simvastatin is not only expensive n-butyllithium, but also highly ignitable, and the process is very complicated. And, there is a problem in that the economy is poor because it is manufactured through a multi-step process.
이에, 본 발명자들은 상기 종래 기술들의 문제점을 해결하고자 연구를 거듭한 결과, 새로운 중간체를 거쳐 심바스타틴을 제조할 경우 수율이 높고 부산물의 생성이 적다는 것을 발견하여 본 발명을 완성하였다. Accordingly, the present inventors have completed the present invention by finding that the yield is high and the production of by-products is low when simvastatin is prepared through a new intermediate, as a result of the study to solve the problems of the prior art.
따라서, 본 발명의 목적은 심바스타틴 제조에 유용한 중간체를 제공하는 것이다.It is therefore an object of the present invention to provide intermediates useful for the preparation of simvastatin.
또한, 본 발명의 목적은 상기 중간체의 제조방법을 제공하는 것을 포함한다.It is also an object of the present invention to provide a method for producing the intermediate.
또한, 본 발명의 목적은 상기 중간체로부터 심바스타틴을 제조하는 방법을 제공하는 것을 포함한다. It is also an object of the present invention to provide a method for preparing simvastatin from the intermediate.
본 발명은 심바스타틴을 제조하는 새로운 경제적인 방법(하기 반응식 3)을 제공하며, 또한 이에 사용되는 유용한 신규 화합물로서 하기 화학식 1 및 화학식 2의 화합물을 제공한다.The present invention provides a new economical process for preparing simvastatin (Scheme 3 below) and also provides compounds of formulas (1) and (2) as useful novel compounds for use therein.
[반응식 3]Scheme 3
[화학식 1][Formula 1]
[화학식 2][Formula 2]
상기 화학식에서, R은 R1R2R3Si로 나타낼 수 있는 삼알킬실릴 그룹이고, R1, R2, R3는 각각 탄소수 1내지 5의 직쇄 또는 가지달린 알킬그룹을 나타내며, R1 , R2, R3는 각각 동일한 것일 수도 있고 다른 것일 수도 있다.In the above formula, R is a trialkylsilyl group which may be represented by R 1 R 2 R 3 Si, R 1 , R 2 , R 3 each represent a straight or branched alkyl group having 1 to 5 carbon atoms, R 1 , R 2 and R 3 may be the same or different from each other.
대표적예로는 삼급-부틸디메틸실릴, 삼에틸실릴, 삼이소프로필실릴 등이 속한다.Representative examples include tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl and the like.
본 발명의 신규 중간체인 화학식 1 및 화학식 2의 화합물은 로바스타틴의 가수분해로부터 얻어지는 하기 화학식 3의 화합물로부터 간편히 얻어질 수 있으며, 심바스타틴을 합성하는 데에 매우 유용하게 사용될 수 있다.The novel intermediates of the present invention, the compounds of formulas (1) and (2) can be obtained simply from the compounds of formula (3) obtained from the hydrolysis of lovastatin, and can be very useful for the synthesis of simvastatin.
[화학식 3][Formula 3]
본 방법은 심바스타틴을 제조하는 새로운 방법을 제공한다.The method provides a new method of preparing simvastatin.
본 방법에 따라 심바스타틴을 제조하려면 로바스타틴을 통상의 방법으로 가수분해하여 얻어지는 상기 화학식 3의 화합물을 상기 반응식 3과 같이 적당한 불활성의 용매 중에서 R1R2R3Si-Cl로 표시되는 삼알킬실릴 염화물과 적당한 촉매의 존재 하에 반응시켜서 상기 화학식 1의 화합물을 먼저 제조하고, 화학식 1의 화합물을 적당한 불활성의 용매 중에서 2,2-디메틸부티르산, 또는 2,2-디메틸부티르산의 반응성 유도체와 함께 적절한 촉매의 존재하에 또는 촉매 없이 반응시켜서 상기 화학식 2의 화합물을 제조하고, 마지막으로 화학식 2의 화합물을 적당한 탈보호제와 반응시켜서 삼알킬실릴 그룹을 제거하고, 락톤 고리를 형성함으로써 심바스타틴을 합성하는 공정을 완성한다.In order to prepare simvastatin according to the present method, a trialkylsilyl chloride represented by R 1 R 2 R 3 Si-Cl in a suitable inert solvent, such as the compound of Formula 3, obtained by hydrolyzing lovastatin in a conventional manner, is represented in Scheme 3. And reacting in the presence of a suitable catalyst to prepare the compound of Formula 1, wherein the compound of Formula 1 is prepared in a suitable inert solvent with 2,2-dimethylbutyric acid or a reactive derivative of 2,2-dimethylbutyric acid. The compound of formula 2 is prepared by reaction in the presence or without a catalyst, and finally, the compound of formula 2 is reacted with a suitable deprotecting agent to remove trialkylsilyl groups and form a lactone ring to complete the process of synthesizing simvastatin. .
본 발명에 따라 화학식 3의 화합물로부터 화학식 1의 화합물을 제조할 때에 사용할 수 있는 용매로는 테트라히드로푸란, 디옥산, 등의 에테르 종류, 디메틸아세트아미드, 디에틸아세트아미드 등의 아미드 종류, 디메틸술폭시드 등의 술폭시드 종류 등 반응에 직접 영향을 끼치지 아니하는 어떠한 비활성 용매라도 사용 가능하다. 반응의 온도는 통상 0도에서 용매의 비점까지의 사이에서 적절히 반응을 수행할 수 있다.Solvents that can be used when preparing the compound of formula 1 from the compound of formula 3 according to the present invention include ether species such as tetrahydrofuran, dioxane, and the like, amide species such as dimethylacetamide and diethylacetamide, and dimethyl sulfoxide. Any inert solvent that does not directly affect the reaction, such as sulfoxide species such as seeds, can be used. The reaction can be suitably carried out at a temperature of usually from 0 degree to the boiling point of the solvent.
이 때 사용하는 삼알킬실릴 염화물은 통상 화학식 3의 화합물에 대해 3.0 당량 내지 6.0 당량을 사용할 수 있으며, 최적의 결과를 위해서는 3.3 당량 내지 4.5 당량을 사용하는 것이 바람직하다. 이 때는 통상적으로 이미다졸 등의 염기를 사용하여 부생하는 염화수소를 제거하는 것이 바람직하며, 이미다졸 이외에도 다양한 삼급알킬아민을 사용하여 무리없이 반응을 수행할 수 있다.In this case, the trialkylsilyl chloride used may be generally used in the amount of 3.0 to 6.0 equivalents based on the compound of the formula (3), preferably 3.3 to 4.5 equivalents for optimal results. In this case, it is generally preferable to remove by-product hydrogen chloride using a base such as imidazole, and the reaction can be carried out without difficulty using various tertiary alkylamines in addition to imidazole.
화학식 1의 화합물로부터 화학식 2의 화합물을 제조하고자 할 때에 사용할 수 있는 용매로는 반응에 영향을 미치지 아니하는 어떠한 용매라도 사용할 수 있다. 가능한 용매로는 테트라히드로푸란, 디옥산 등의 에테르 종류, 디메틸포름아미드, 디메틸아세트아미드 등의 아미드 종류, 디메틸술폭시드 등의 술폭시드 종류 등이 반응에 영향을 미치지 아니하며 통상적으로 사용가능하다. 2,2-디메틸부티르산은 DCC 등의 아실화제와 함께 그대로 반응에 사용하거나 염화물, 브롬화물 등의 할로겐화물로 만들어서 사용하거나, 또는 다른 반응성 유도체로 만들어서 사용할 수도 있다. 이 때 사용할 수 있는 반응성 유도체로는 활성 혼합산무수물, 활성의 아미드, 활성의 티오에스테르, 활성의 인산 또는 티오인산 에스테르 등이 사용될 수 있다.Any solvent that does not affect the reaction may be used as a solvent that may be used when preparing the compound of Formula 2 from the compound of Formula 1. Possible solvents include ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide and dimethylacetamide, and sulfoxides such as dimethyl sulfoxide, and the like. 2,2-dimethylbutyric acid may be used in the reaction as it is with an acylating agent such as DCC, used as a halide such as chloride or bromide, or as another reactive derivative. At this time, as an active derivative, an active mixed acid anhydride, an active amide, an active thioester, an active phosphoric acid or a thiophosphoric acid ester, or the like can be used.
이 때에 2,2-디메틸부티르산, 또는 이의 활성 유도체는 화학식 2의 화합물에 대해 1.0 당량 내지 5.0 당량의 비율로 사용되는 것이 바람직하며, 더욱 바람직하게는 화학식 2의 화합물에 대해 1.0 내지 2.0 당량의 비율로 사용하는 것이 좋다.In this case, 2,2-dimethylbutyric acid or an active derivative thereof is preferably used in a ratio of 1.0 to 5.0 equivalents based on the compound of Formula 2, and more preferably 1.0 to 2.0 equivalents relative to the compound of Formula 2. It is good to use as.
반응의 온도는 편리하게 0도 내지 용매의 비점 사이에서 정하여 반응을 수행할 수 있으며, 바람직하게는 상온 내지 60도의 범위에서 수행하는 것이 좋다.The temperature of the reaction may be conveniently determined between 0 degrees and the boiling point of the solvent, and the reaction may be performed. Preferably, the reaction is performed in a range of room temperature to 60 degrees.
화학식 2의 화합물은 탈보호 공정을 거쳐서 보호기인 삼알킬실릴 그룹을 모두 제거하고 락톤화 과정을 거쳐서 심바스타틴을 제조하는 데에 유용하게 사용될 수 있다.The compound of formula 2 may be usefully used to prepare simvastatin by removing all the trialkylsilyl groups as a protecting group through a deprotection process and performing a lactonation process.
화학식 2의 화합물로부터 심바스타틴을 제조하기위해서는 먼저 화학식 2의 화합물을 적당한 용매 중에서 실릴 그룹을 제거할 수 있는 탈실릴화제와 함께 반응시켜서 실릴 그룹을 모두 제거하고, 이어서 락톤 고리를 다시 형성함으로써 심바스타틴을 제조한다.In order to prepare simvastatin from the compound of formula (2), simvastatin is prepared by first reacting the compound of formula (2) with a desilylating agent capable of removing the silyl group in a suitable solvent to remove all of the silyl groups and then to form the lactone ring again. do.
실릴그룹을 제거하기 위한 탈실릴화제는 4급암모늄 플루오라이드 등의 플루오라이드 염, 또는 염산, 황산 등의 무기산을 적절히 사용할 수 있으며, 탈실릴화 후 락톤 형성 시에는 통상의 방법(가령, 상기 미국특허 제4,444,784호에 개시된 방법 등)으로 산 촉매 존재 하에 락톤을 형성할 수 있다.The desilylating agent for removing the silyl group may be suitably used a fluoride salt such as quaternary ammonium fluoride or an inorganic acid such as hydrochloric acid or sulfuric acid. Lactones can be formed in the presence of an acid catalyst by the method disclosed in patent 4,444,784.
이하, 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나 이들 실시예에 의해 본 발명이 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited to these examples.
실시예 1: 트리스(삼급-부틸디메틸실릴)트리올 산(화학식 1의 화합물)Example 1 tris (tert-butyldimethylsilyl) triol acid (compound of formula 1)
트리올 산(화학식 3의 화합물) 5 g에 디메틸포름아미드 45 ml를 넣어 용해시켰다. 여기에 이미다졸 3.52 g(3.5 당량)과 TBDMS-Cl 7.5 g(3.5 당량)을 넣고 55-60 ℃에서 16 시간동안 반응하여 반응이 완료되면 냉각한 후 헥산을 넣어 희석하고, 물로 세척하였다. 무수 황산마그네슘으로 건조하고 감압증류하여 용매를 제거하여 유상의 목적물 9.56 g(95 %)을 얻었다.45 g of dimethylformamide was added to 5 g of triol acid (compound of Formula 3) to dissolve it. 3.52 g (3.5 equivalents) of imidazole and 7.5 g (3.5 equivalents) of TBDMS-Cl were added thereto and reacted at 55-60 ° C. for 16 hours. After the reaction was completed, the mixture was cooled, diluted with hexane, and washed with water. After drying over anhydrous magnesium sulfate and distillation under reduced pressure, the solvent was removed to obtain 9.56 g (95%) of the target substance in the oil phase.
1H-NMR(CDCl3, 300MHz) 0.12(d, J=3.3Hz, 12H), 0.26(s, 6H), 0.88(d, J=5.1Hz, 3H), 0.89(m, 27H), 1.19(d, J=7.8Hz, 3H), 1.20-2.5(m, 14H), 3.80(bs, 1H), 4.18(m, 2H), 5.53(bs, 1H), 5.79(m, 1H), 5.97(d, J=6.6Hz, 1H) 1 H-NMR (CDCl 3 , 300 MHz) 0.12 (d, J = 3.3 Hz, 12H), 0.26 (s, 6H), 0.88 (d, J = 5.1 Hz, 3H), 0.89 (m, 27H), 1.19 ( d, J = 7.8Hz, 3H), 1.20-2.5 (m, 14H), 3.80 (bs, 1H), 4.18 (m, 2H), 5.53 (bs, 1H), 5.79 (m, 1H), 5.97 (d , J = 6.6 Hz, 1H)
실시예 2: 2,2-디메틸부티릴-트리스(삼급-부틸디메틸실릴)트리올 산(화학식 2의 화합물)Example 2: 2,2-dimethylbutyryl-tris (tert-butyldimethylsilyl) triol acid (compound of formula 2)
2,2-디메틸부티르산 3.4 g(4.0 당량)에 디클로로메탄 20 ml을 넣어 용해한 후, 트리페닐포스핀 7.7 g(4.0 당량)을 첨가하였다. 반응 혼합물을 0 ℃로 냉각한 후, N-브로모숙시니미드 5.2 g을 첨가한 후 상온에서 30 분간 교반하였다. 0 ℃에서 반응 혼합물에 화학식 1의 화합물 5.0 g을 넣고 N,N-디메틸아닐린 3.6 g을 넣은 후 상온에서 10 시간동안 교반하였다. 5 % 묽은 염산, 물, 포화 탄산수소나트륨 수용액의 순서로 세척하여 유기층을 분리하고, 감압증류하여 용매를 제거한다. 헥산 60 ml를 넣고 0 ℃에서 30 분간 교반하여 여과한 후 여과액을 농축하면 유상의 화합물 5.0 g(88 %)이 생긴다.20 ml of dichloromethane was dissolved in 3.4 g (4.0 equiv) of 2,2-dimethylbutyric acid, followed by addition of 7.7 g (4.0 equiv) of triphenylphosphine. After the reaction mixture was cooled to 0 ° C., 5.2 g of N-bromosuccinimide was added, followed by stirring at room temperature for 30 minutes. 5.0 g of the compound of Formula 1 was added to the reaction mixture at 0 ° C., and 3.6 g of N, N-dimethylaniline was added thereto, followed by stirring at room temperature for 10 hours. 5% diluted hydrochloric acid, water, and saturated aqueous sodium hydrogen carbonate solution are washed in order to separate the organic layer and distilled under reduced pressure to remove the solvent. Add 60 ml of hexane, stir at 0 ° C. for 30 minutes, filter, and concentrate the filtrate to give 5.0 g (88%) of an oily compound.
1H-NMR(CDCl3, 300MHz) 0.15(d, J=3.5Hz, 12H), 0.23(s, 6H), 0.79(t, J=6.9Hz, 3H), 0.88(d, J= 5.5Hz, 3H), 0.91(m, 27H), 1.08(d, J=7.5Hz, 3H), 1.12(s, 3H), 1.13(s, 3H), 1.2-2.5(m, 14H), 2.56(d, J=4.0Hz, 2H), 4.30(m, 1H), 4.58(m, 1H), 5.24(m, 1H), 5.54(m, 1H), 5.56(dd, J=5.1Hz, 1H), 6.0(d, J=10Hz, 1H) 1 H-NMR (CDCl 3 , 300 MHz) 0.15 (d, J = 3.5 Hz, 12H), 0.23 (s, 6H), 0.79 (t, J = 6.9 Hz, 3H), 0.88 (d, J = 5.5 Hz, 3H), 0.91 (m, 27H), 1.08 (d, J = 7.5 Hz, 3H), 1.12 (s, 3H), 1.13 (s, 3H), 1.2-2.5 (m, 14H), 2.56 (d, J = 4.0 Hz, 2H), 4.30 (m, 1H), 4.58 (m, 1H), 5.24 (m, 1H), 5.54 (m, 1H), 5.56 (dd, J = 5.1 Hz, 1H), 6.0 (d , J = 10Hz, 1H)
실시예 3: 심바스타틴의 합성Example 3: Synthesis of Simvastatin
유상의 화학식 2의 화합물 3.0 g을 테트라히드로푸란 24 ml와 1,4-디옥산 1.0 ml의 혼액에 가하였다. 반응물을 0 ℃로 냉각한 다음 진한 염산 0.86 ml를 넣고 6 시간 동안 교반하여 반응이 완료되었다. 반응액에 트리에틸아민을 넣어 pH~1.5로 조정한 후 감압농축한 잔사를 20 ml의 초산에틸에 용해시킨 다음, 물과 소금물로 연속 세척하였다. 초산에틸 용액을 무수 황산마그네슘으로 건조한 다음 감압증류하여 용매를 제거하여 백색의 케이크상으로 목적물을 얻었다. 이 케이크를 17.5 ml의 디클로로메탄에 용해시켜 35 mg의 파라톨루엔설폰산과 함께 상온에서 1 시간 동안 교반하였다. 반응 혼합물을 감압증류하여 농축하고, 7.5 ml의 초산에틸을 가한 후 40 ℃-60 ℃로 가열하여 완전히 용해시켰다. 여기에 헥산 30 ml를 서서히 넣으면서 동시에 상온으로 냉각하여 1 시간 동안 교반하고, 0 ℃로 냉각하여 2 시간 동안 추가로 교반하여 백색의 침전이 생성되었다. 이를 여과하고 건조하여 메탄올 25 ml에 녹이고 소량의 활성탄을 넣어 30 분간 교반 하여 셀라이트 여과상을 통하여 여과하였다. 여액에 물 25 ml를 적가하고 0 ℃에서 2 시간 교반하여 백색 침전이 형성되었다. 이 침전을 여과하고 40 ℃에서 16 시간 진공건조하여 1.37 g(85 %)의 심바스타틴을 얻었다.3.0 g of an oily compound of formula 2 were added to a mixture of 24 ml of tetrahydrofuran and 1.0 ml of 1,4-dioxane. After the reaction was cooled to 0 ° C., 0.86 ml of concentrated hydrochloric acid was added thereto, followed by stirring for 6 hours to complete the reaction. Triethylamine was added to the reaction solution to adjust the pH to 1.5. The concentrated residue was dissolved in 20 ml of ethyl acetate, and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous magnesium sulfate, distilled under reduced pressure, and the solvent was removed to obtain the target product as a white cake. The cake was dissolved in 17.5 ml of dichloromethane and stirred with 35 mg of paratoluenesulfonic acid at room temperature for 1 hour. The reaction mixture was concentrated by distillation under reduced pressure, 7.5 ml of ethyl acetate was added, and the mixture was heated to 40 ° C.-60 ° C. to completely dissolve it. At the same time, 30 ml of hexane was slowly added thereto, and then cooled to room temperature, stirred for 1 hour, cooled to 0 ° C., and further stirred for 2 hours to produce a white precipitate. The filtrate was dried, dissolved in 25 ml of methanol, a small amount of activated carbon was added, stirred for 30 minutes, and filtered through a celite filter. 25 ml of water was added dropwise to the filtrate and stirred at 0 ° C. for 2 hours to form a white precipitate. This precipitate was filtered off and dried in vacuo at 40 ° C. for 16 hours to obtain 1.37 g (85%) of simvastatin.
본 발명에 화학식 1의 화합물을 중간체로 하여 심바스타틴을 제조할 경우, 종래의 제조방법에 비해, 수율이 높고 부산물의 생성이 적은 장점이 있다. When simvastatin is prepared by using the compound of Formula 1 as an intermediate in the present invention, there is an advantage in that the yield is high and the generation of by-products is less than that of the conventional preparation method.
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