KR20100096526A - Novel process for preparing statin compound or its salt and intermediate used therein - Google Patents
Novel process for preparing statin compound or its salt and intermediate used therein Download PDFInfo
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- KR20100096526A KR20100096526A KR1020090015435A KR20090015435A KR20100096526A KR 20100096526 A KR20100096526 A KR 20100096526A KR 1020090015435 A KR1020090015435 A KR 1020090015435A KR 20090015435 A KR20090015435 A KR 20090015435A KR 20100096526 A KR20100096526 A KR 20100096526A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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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- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
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- C—CHEMISTRY; METALLURGY
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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
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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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Abstract
Description
본 발명은 고지혈 관련 질환의 치료 및 예방에 유용한 스타틴 화합물 또는 그의 염의 신규 제조방법, 및 이에 사용되는 유용한 중간체에 관한 것이다. The present invention relates to novel methods of preparing statin compounds or salts thereof useful for the treatment and prevention of hyperlipidemia related diseases, and useful intermediates used therein.
피타바스타틴(pitavastatin) 및 로수바스타틴(rosuvastatin)으로 대표되는 스타틴 화합물은, 과콜레스테롤혈증, 과지질단백질혈증 및 아테롬성경화증 등과 같은 고지혈 관련 질환의 치료 및 예방에 사용되는 물질이다.Statin compounds represented by pitavastatin and rosuvastatin are substances used for the treatment and prevention of hyperlipidemia-related diseases such as hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis.
하기 화학식으로 표시되는 피타바스타틴(화학명: (3R,5S,6E)-7-[2-시클로프로필-4-(4-플루오로페닐)-3-퀴놀린일]-3,5-디히드록시-6-헵텐산)과 로수바스타틴(화학명: (3R,5S,6E)-7-[4-(4-플루오로페닐)-6-이소프로필-2-[메틸(메틸술포닐)아미노]-5-피리미딘일]-3,5-디히드록시-6-헵텐산)은 각각 유럽특허 제0,304,063호와 유럽특허 제0,521,471호에 처음으로 개시되었으며, 이들은 구조적으로 매우 유사하 고, 통상 칼슘염으로서 의약품에 사용되고 있다.Phytavastatin represented by the following chemical formula (Chemical name: (3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) -3-quinolinyl] -3,5-dihydroxy -6-heptenic acid) and rosuvastatin (chemical name: (3R, 5S, 6E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] -5-pyrimidinyl] -3,5-dihydroxy-6-heptenic acid) is disclosed for the first time in EP 0,304,063 and EP 0,521,471, respectively, which are structurally very similar and usually calcium It is used in medicine as a salt.
상기 피타바스타틴과 로수바스타틴은 7위치에 퀴놀린 또는 피리미딘 환이 치환된 3,5-디히드록시-6-헵텐산 유도체로서, 두 개의 히드록시기가 결합된 3위치 및 5위치 탄소의 입체화학이 각각 R 및 S 형태로, 또 6위치의 이중결합이 트랜스 (또는 E) 형태로 구성된 복잡한 구조의 화합물이다. The pitavastatin and rosuvastatin are 3,5-dihydroxy-6-heptenic acid derivatives substituted with a quinoline or pyrimidine ring at 7-position, and stereochemistry of 3-position and 5-position carbons having two hydroxy groups bonded thereto It is a compound of complex structure in which the R and S forms, respectively, and the 6-position double bond are formed in the trans (or E) form.
이와 같은 피타바스타틴 및 로수바스타틴의 제조를 위해, 종래 피타바스타틴 및 로수바스타틴 제조방법에서는 6-위치의 트랜스 이중결합 형성시 3위치 및 5위치 탄소의 입체화학이 각각 R 및 S 형태로 이미 도입된 (3R,5S)-3,5-디히드록시헥산 유도체를 반응물질로 사용하였다. 일례로 국제특허공개 WO 1995/011898호 및 WO 2007/132482호에는 하기 반응식에서와 같이 화학식 Q1의 디페닐포스핀 옥시드 화합물 또는 화학식 Q2의 트리페닐포스포늄 화합물을 화학식 Z의 (3R,5S)-3,5-O-이소프로필리덴-3,5-디히드록시-6-옥소헥산 에스테르 화합물과 각각 반응시켜 트랜스 이중결합을 도입한 후 피타바스타틴을 제조하는 방법이 개시되어 있고, 국제특허공개 WO 2000/49014호 및 WO 2005/54207호에는 화학식 P1 또는 화학식 P2의 트리페닐포스포늄 화합물을 상기 화학식 Z의 화합물을 각각 반응시켜 트랜스 이중결합을 도입한 후 로수바스타틴을 제조하는 방법이 개시되어 있다.In order to prepare such pitavastatin and rosuvastatin, in the conventional pitavastatin and rosuvastatin manufacturing method, the stereochemistry of the 3-position and 5-position carbons in the form of 6-positioned trans double bond is in R and S form, respectively. Already introduced (3R, 5S) -3,5-dihydroxyhexane derivatives were used as reactants. For example, WO 1995/011898 and WO 2007/132482 disclose diphenylphosphine oxide compounds of formula Q1 or triphenylphosphonium compounds of formula Q2, as shown in the following schemes: (3R, 5S) A method for preparing pitavastatin after introducing a trans double bond by reacting with -3,5-O-isopropylidene-3,5-dihydroxy-6-oxohexane ester compound, respectively, has been disclosed. WO 2000/49014 and WO 2005/54207 disclose methods for preparing rosuvastatin after introducing a trans double bond by reacting a triphenylphosphonium compound of formula P1 or P2 with a compound of formula Z, respectively. It is.
또한 국제특허공개 WO 2002/098854호, WO 2003/070733호, WO 2006/067456호, WO 2006/126035호, WO 2007/000121호, WO 2008/130683호, WO 2009/009153호 등에도 (3R,5S)-3,5-디히드록시헥산 유도체를 이용하여 피타바스타틴과 로수바스타틴을 제조하는 방법이 개시되어 있다. International Patent Publication Nos. WO 2002/098854, WO 2003/070733, WO 2006/067456, WO 2006/126035, WO 2007/000121, WO 2008/130683, WO 2009/009153 and the like (3R, A method for preparing pitavastatin and rosuvastatin using 5S) -3,5-dihydroxyhexane derivatives is disclosed.
그러나, (3R,5S)-3,5-디히드록시헥산 유도체는 유럽특허 제0,464,817호, 제0,319,847호 및 유럽특허 제0,577,040호 등에 개시된 바와 같이, 별도로 다단계의 복잡하고 어려운 반응공정으로 제조되어야 하기 때문에 수급이 원활하지 못하고, 고가의 물질이기 때문에 이를 이용하여 피타바스타틴과 로수바스타틴을 제조할 경우 경제적인 면에서 유리하지 못하다. However, the (3R, 5S) -3,5-dihydroxyhexane derivatives must be prepared separately in a multi-step complex and difficult reaction process, as disclosed in EP 0,464,817, 0,319,847 and EP 0,577,040. Therefore, supply and demand is not smooth, and since it is an expensive material, it is not economically advantageous to manufacture pitavastatin and rosuvastatin using it.
따라서, 본 발명의 목적은 간편하고 효율적으로 스타틴 화합물 또는 그의 염을 제조할 수 있는 신규 제조방법을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a novel process for producing a statin compound or salt thereof simply and efficiently.
본 발명의 다른 목적은 스타틴 화합물 또는 그의 염의 제조에 사용되는 신규 중간체를 제공하는 것이다.Another object of the present invention is to provide novel intermediates for use in the preparation of statin compounds or salts thereof.
상기 목적을 달성하기 위하여, 본 발명은 In order to achieve the above object, the present invention
(1) 하기 화학식 2의 화합물을 하기 화학식 3의 화합물과 반응시켜 하기 화학식 4의 트랜스-올레핀 화합물을 제조하는 단계;(1) reacting a compound of Formula 2 with a compound of Formula 3 to prepare a trans-olefin compound of Formula 4;
(2) 제조된 화학식 4의 화합물을 하기 화학식 5의 화합물과 반응시켜 하기 화학식 6의 옥소 화합물을 제조하는 단계;(2) reacting the prepared compound of Formula 4 with a compound of Formula 5 to prepare an oxo compound of Formula 6;
(3) 제조된 화학식 6의 화합물의 옥소기를 비대칭 환원시켜 하기 화학식 7의 신-디올(syn-diol) 화합물을 제조하는 단계; 및(3) asymmetrically reducing the oxo group of the compound of Formula 6 to produce a syn-diol compound of Formula 7; And
(4) 제조된 화학식 7의 화합물을 가수분해하여 하기 화학식 1의 스타틴 화합물 또는 그 염을 제조하는 단계를 포함하는, (4) hydrolyzing the prepared compound of formula 7 to prepare a statin compound of formula 1 or a salt thereof,
하기 화학식 1의 스타틴 화합물 또는 그 염의 제조방법을 제공한다:Provided are methods of preparing a statin compound of Formula 1 or a salt thereof:
상기 식에서In the above formula
A는 히드록시기 보호기이고;A is a hydroxy group protecting group;
B는 수소 또는 히드록시기 보호기이며;B is hydrogen or a hydroxy group protecting group;
D는 카르복시기 보호기이고;D is a carboxy group protecting group;
Het는 하기 화학식 8a 또는 화학식 8b의 치환기중 어느 하나이며;Het is any one of substituents of the formula (8a) or (8b);
L은 하기 화학식 9a 내지 화학식 9j의 치환기중 어느 하나이고;L is any one of substituents of the formulas 9a to 9j;
상기 식에서,Where
R1은 저급 알킬 또는 페닐이고;R 1 is lower alkyl or phenyl;
R2는 페닐, 퓨릴 또는 티오페닐이며;R 2 is phenyl, furyl or thiophenyl;
R3는 수소이거나 저급 알킬이고; 그리고R 3 is hydrogen or lower alkyl; And
X는 클로로, 브로모, 요오도, 메탄술포닐, 에탄술포닐, 트리플루오로메탄술포닐, 벤젠술포닐, 4-톨루엔술포닐이다.X is chloro, bromo, iodo, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, 4-toluenesulfonyl.
본 발명은 또한 상기 화학식 1의 스타틴 화합물 또는 그의 염의 제조시 중간체로 사용되는 상기 화학식 4의 화합물을 제공한다.The present invention also provides a compound of formula 4, which is used as an intermediate in the preparation of a statin compound of formula 1 or a salt thereof.
본 발명은 또한 상기 화학식 1의 스타틴 화합물 또는 그의 염의 제조시 중간체로 사용되는 상기 화학식 6의 화합물을 제공한다.The present invention also provides a compound of formula 6, which is used as an intermediate in the preparation of a statin compound of formula 1 or a salt thereof.
본 발명의 방법에 따르면, 고지혈 관련 질환의 치료 및 예방에 유용한 스타틴 화합물 또는 그의 염을 신규한 중간체들로부터 간편하고 효율적으로 제조할 수 있다. According to the method of the present invention, statin compounds or salts thereof useful for the treatment and prevention of hyperlipidemia related diseases can be prepared simply and efficiently from novel intermediates.
본 발명에 따른 스타틴 화합물 또는 그 염의 제조방법은, 상기 화학식 2의 화합물을 화학식 3의 화합물과 반응시켜 얻은 트랜스 형태의 이중 결합이 도입된 트랜스-올레핀 화합물(화학식 4의 화합물), 및 이를 화학식 5의 브로모아세테이트 화합물과 반응시켜 얻은 옥소 화합물(화학식 6의 화합물)을 중간체로 사용하는 것을 특징으로 한다.The method for preparing a statin compound or a salt thereof according to the present invention includes a trans-olefin compound (compound of Formula 4) having a trans bond double bond obtained by reacting a compound of Formula 2 with a compound of Formula 3, and a compound of Formula 5 An oxo compound (compound of formula 6) obtained by reacting with a bromoacetate compound is used as an intermediate.
본 명세서에서 사용되는 용어 "히드록시기 보호기"는 예를 들어, 트리메틸실릴, 트리에틸실릴, 트리이소프로필실릴, tert-부틸디메틸실릴, tert-부틸디페닐실릴, 트리페닐실릴 등을 의미하며, 바람직하게는 tert-부틸디메틸실릴이다.As used herein, the term "hydroxy group protecting group" means, for example, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert -butyldimethylsilyl, tert -butyldiphenylsilyl, triphenylsilyl, and the like. Is tert -butyldimethylsilyl.
본원 명세서에서 사용되는 용어 "카르복시기 보호기"는 예를 들어, 저급 알킬 또는 저급 시클로알킬을 의미한다. The term "carboxyl group protecting group" as used herein means, for example, lower alkyl or lower cycloalkyl.
본원 명세서에서 사용되는 용어 "저급 알킬"은 직쇄 또는 측쇄의 탄소 원자수 1~6의 알킬을 의미하여, 구체적인 예로는 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, sec-부틸, tert-부틸, n-펜틸, 이소펜틸, 네오펜틸, tert-펜틸, n-헥실 및 이소헥실 등을 들 수 있다.As used herein, the term "lower alkyl" refers to straight or branched alkyl having 1 to 6 carbon atoms, specific examples of which include methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, sec- Butyl, tert -butyl, n -pentyl, isopentyl, neopentyl, tert -pentyl, n -hexyl, isohexyl and the like.
본원 명세서에서 사용되는 용어 "저급 시클로알킬"은 탄소 원자수 3~6의 시클로알킬을 의미하며, 구체적인 예로는 시클로프로필, 시클로부틸, 시클로펜틸 및 시클로헥실 등을 들 수 있다. 이들 저급 알킬 또는 저급 시클로알킬은 할로겐, 알킬옥시, 알킬티오, 디알킬아미노, 니트로 및 시아노로 이루어진 군으로부터 선택된 1∼3개의 치환기로 치환되어 있어도 좋다.As used herein, the term "lower cycloalkyl" refers to cycloalkyl having 3 to 6 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. These lower alkyl or lower cycloalkyl may be substituted by 1-3 substituents selected from the group consisting of halogen, alkyloxy, alkylthio, dialkylamino, nitro and cyano.
본원 명세서에서 사용되는 용어 "아릴"은, 탄소 원자수 6∼12의 방향족기를 의미하며, 구체적인 예로는 페닐, 톨루일, 크실릴, 비페닐 및 나프틸 등을 들 수 있다. As used herein, the term "aryl" means an aromatic group having 6 to 12 carbon atoms, and specific examples thereof include phenyl, toluyl, xylyl, biphenyl, naphthyl and the like.
본원 명세서에서 사용되는 용어 "아릴 알킬"은 상기 정의된 탄소 원자수 6∼12의 방향족 아릴기로 치환되어 있는 탄소 원자수 1∼6의 저급 알킬을 의미하며, 아릴 알킬의 구체적인 예로는 벤질, 펜에틸 및 페닐프로필 등을 들 수 있다.The term "aryl alkyl" as used herein refers to lower alkyl having 1 to 6 carbon atoms substituted with an aromatic aryl group having 6 to 12 carbon atoms as defined above, specific examples of aryl alkyl include benzyl, phenethyl And phenylpropyl.
본원 명세서에서 사용되는 용어 "상기 화학식 1의 스타틴 화합물의 염"이란 리튬, 나트륨, 칼륨, 마그네슘, 칼슘 및 스트론튬과 같은 알칼리 또는 알칼리 토금속 염이나; 수소, 저급 알킬, 저급 시클로알킬, 아릴 또는 알릴 알킬이 치환된 암모늄염을 의미한다.As used herein, the term “salt of the statin compound of Formula 1” refers to alkali or alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium and strontium; By ammonium salt substituted hydrogen, lower alkyl, lower cycloalkyl, aryl or allyl alkyl.
본 발명의 상기 화학식 1의 스타틴 화합물은 하기 반응식 1에 나타낸 바와 같이 수행하여 제조할 수 있다:The statin compound of Chemical Formula 1 of the present invention may be prepared by carrying out as shown in Scheme 1 below:
상기 식에서, A, B, D, Het 및 L은 상기에서 정의한 바와 같다.Wherein A, B, D, Het and L are as defined above.
상기 반응식 1에 도시한 바와 같은 본 발명의 스타틴 화합물 또는 그의 염의 제조방법을 단계별로 보다 구체적으로 설명하면 다음과 같다.The method for preparing a statin compound or a salt thereof of the present invention as shown in Scheme 1 will be described in more detail step by step.
<단계 1><Step 1>
단계 1은 하기 반응식 2에서와 같이, 화학식 2의 알데히드 화합물을 유기용매 중에서 염기 존재 하에 화학식 3의 화합물과 반응시킴으로써 화학식 4의 트랜스-올레핀 화합물을 얻는 단계이다.Step 1 is a step of obtaining a trans-olefin compound of Formula 4 by reacting the aldehyde compound of Formula 2 with the compound of Formula 3 in the presence of a base in an organic solvent, as shown in Scheme 2.
상기 식에서, A, B, Het 및 L은 상기에서 정의한 바와 같다.Wherein A, B, Het and L are as defined above.
상기 반응에서 출발물질로서 사용되는 상기 화학식 2의 알데히드 화합물은 하기 반응식 3에 나타난 바와 같이, 화학식 10의 화합물을 통상의 방법으로 산화시킴으로써 용이하게 제조될 수 있다.The aldehyde compound of Formula 2 used as starting material in the reaction can be easily prepared by oxidizing the compound of Formula 10 in a conventional manner, as shown in Scheme 3 below.
상기 식에서, A는 상기에서 정의한 바와 같다.Wherein A is as defined above.
상기 화학식 2의 알데히드 화합물은 단계 (1)의 반응에서 화학식 3의 화합물 1몰 당량에 대하여 1.0 내지 3.0몰 당량으로 사용될 수 있다. The aldehyde compound of Formula 2 may be used in an amount of 1.0 to 3.0 molar equivalents relative to 1 molar equivalent of the compound of Formula 3 in the reaction of Step (1).
또한, 상기 화학식 3의 화합물은 한국 특허출원 제2008-0135857호를 비롯한 공지된 통상의 방법으로 제조될 수 있다.In addition, the compound of Formula 3 may be prepared by known conventional methods, including Korean Patent Application No. 2008-0135857.
상기 유기용매로는 에틸에테르, 이소프로필에테르, tert-부틸메틸에테르, 테트라히드로푸란, 1,4-디옥산, 아세토니트릴, N,N-디메틸포름아미드, N,N-디메틸아세트아미드, 디메틸술폭시드, 1,2-디메톡시에탄, 1,2-디에톡시에탄, 톨루엔 또는 이들의 혼합용매가 사용될 수 있으며, 바람직하게는 테트라히드로푸란이다. The organic solvent is ethyl ether, isopropyl ether, tert -butyl methyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, N , N -dimethylformamide, N , N -dimethylacetamide, dimethyl sulfoxide Seed, 1,2-dimethoxyethane, 1,2-diethoxyethane, toluene or a mixed solvent thereof may be used, preferably tetrahydrofuran.
또한 상기 염기로는 수산화나트륨, 수산화칼륨, 수소화나트륨, 수소화칼륨, 수소화칼슘, 나트륨 메톡시드, 나트륨 에톡시드, 나트륨 tert-부톡시드, 칼륨 tert-부톡시드, 리튬 헥사메틸디실라지드, 나트륨 헥사메틸디실라지드, 칼륨 헥사메틸디실라지드, 리튬 디이소프로필아미드, 리튬 디시클로헥실아미드, 리튬 2,2,6,6-테트라메틸피페리딘, 부틸 리튬, 탄산나트륨, 탄산칼륨, 탄산세슘, 디이소프로필에틸아민, 1,8-디아자비시클로[5.4.0]운데크-7-엔, 1,5-디아자비시클로[4.3.0]논-5-엔, 1,4-디아자비시클로[2.2.2]옥탄, 포스파젠(phosphazene) 등이 사용될 수 있다. The base may also be sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium methoxide, sodium ethoxide, sodium tert -butoxide, potassium tert -butoxide, lithium hexamethyldisilazide, sodium hexamethyl Disilazide, potassium hexamethyldisilazide, lithium diisopropylamide, lithium dicyclohexylamide, lithium 2,2,6,6-tetramethylpiperidine, butyl lithium, sodium carbonate, potassium carbonate, cesium carbonate, di Isopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [ 2.2.2] octane, phosphazene and the like can be used.
상기 염기는 그 종류에 따라 사용량이 적절히 조절될 수 있으나, 바람직하게는 화학식 3의 화합물 1몰 당량에 대하여 1.0몰 당량 내지 10.0몰 당량으로 사용될 수 있다.The amount of the base may be appropriately adjusted according to the type thereof, but may preferably be used in an amount of 1.0 to 10.0 molar equivalents based on 1 molar equivalent of the compound of Formula 3.
상기 단계 (2)에서의 반응은 사용하는 염기의 종류에 따라 -78℃ 내지 용매의 비등점 온도의 온도범위에서 실시되는 것이 바람직하고, 보다 바람직하게는 -40℃ 내지 50℃이다.The reaction in the step (2) is preferably carried out in the temperature range of -78 ℃ to the boiling point temperature of the solvent, more preferably -40 ℃ to 50 ℃ depending on the type of the base to be used.
<단계 2><Step 2>
단계 2는 하기 반응식 4에 나타난 바와 같이, 상기 단계 1에서 수득한 화학식 4의 화합물에서의 니트릴기를 유기용매 중에서 아연 존재 하에 화학식 5의 브로모아세테이트 화합물과 반응시킴으로써 화학식 6의 화합물을 얻는 단계이다.Step 2 is a step of obtaining a compound of formula 6 by reacting the nitrile group in the compound of formula 4 obtained in step 1 with the bromoacetate compound of formula 5 in the presence of zinc in an organic solvent, as shown in Scheme 4 below.
상기 식에서, B, D 및 Het는 상기에서 정의한 바와 같다.Wherein B, D and Het are as defined above.
상기 화학식 5의 브로모아세테이트 화합물은 화학식 4의 화합물 1몰 당량에 대하여 1.0몰 당량 내지 10.0몰 당량으로 사용될 수 있다.The bromoacetate compound of Formula 5 may be used in an amount of 1.0 to 10.0 molar equivalents based on 1 molar equivalent of the compound of Formula 4.
상기 유기용매로는 에틸에테르, 이소프로필에테르, 테트라히드로푸란, tert-부틸메틸에테르, 1,2-디메톡시에탄, 1,2-디에톡시에탄 또는 이들의 혼합용매가 사용될 수 있으며, 바람직하게는 테트라히드로푸란이다. As the organic solvent, ethyl ether, isopropyl ether, tetrahydrofuran, tert -butylmethyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane, or a mixed solvent thereof may be used. Tetrahydrofuran.
또한 반응에 사용되는 아연은 활성화된 분말의 금속 상태를 의미하며, 화학식 4의 화합물 1몰 당량에 대하여 1.0몰 당량 내지 10.0몰 당량으로 사용될 수 있다. In addition, zinc used in the reaction refers to the metal state of the activated powder, it can be used in 1.0 molar equivalents to 10.0 molar equivalents relative to 1 molar equivalent of the compound of formula (4).
상기 단계 (2)에서의 반응은 화학식 4의 화합물, 아연 및 화학식 5의 브로모아세테이트 화합물의 혼합액을 용매의 비등점 온도에서 가열 환류시킴으로써 실시될 수 있으며, 이때 반응을 촉진시키기 위해 상기 혼합액에 반응 촉진제로서 메탄 술폰산을 화학식 4의 화합물 1몰 당량에 대하여 0.01몰 당량 내지 0.20몰 당량으로 추가 첨가할 수 있다.The reaction in step (2) can be carried out by heating and refluxing a mixture of the compound of formula 4, zinc and bromoacetate compound of formula 5 at the boiling point of the solvent, wherein the reaction promoter is added to the mixture to promote the reaction. Methane sulfonic acid may be further added in an amount of 0.01 to 0.20 molar equivalents based on 1 molar equivalent of the compound of formula 4.
상기 화학식 4의 화합물과 화학식 5의 화합물의 반응이 종결된 후에는 결과로 얻어진 반응액을 묽은 염산과 같은 산성 용액과 접촉시킴으로써 화학식 6의 화합물을 수득할 수 있다.After the reaction of the compound of Formula 4 with the compound of Formula 5 is terminated, the compound of Formula 6 may be obtained by contacting the resulting reaction solution with an acidic solution such as dilute hydrochloric acid.
다만, 상기 화학식 4의 화합물에 있어서 Q가 히드록시-보호기인 경우, 화학식 5의 화합물과의 반응에 앞서 화학식 4의 화합물로부터 히드록시-보호기를 제거하는 히드록시 보호기 탈보호 반응을 추가로 실시할 수 있다.However, in the compound of Formula 4, when Q is a hydroxy-protecting group, a hydroxy protecting group deprotection reaction is further performed to remove the hydroxy-protecting group from the compound of Formula 4 prior to the reaction with the compound of Formula 5. Can be.
상기 정의한 히드록시기 보호기로 보호된 화학식 4의 화합물로부터 히드록시기 보호기를 제거하는 단계는, 우츠(P.G.M. Wuts) 및 그린(T.W. Green)이 제시한 여러 가지 방법(Protective Groups in Organic Synthesis, 4th Ed. 2007, Wiely & Sons 참조) 또는 이를 변형한 방법에 따라 수행될 수 있다는 것은 이 분야의 전문가도 잘 인식하고 있다. 일 례로, 실릴 보호기는 수성 알코올 중에서 염산과 또는 테트라히드로푸란 중에서 플루오르화테트라부틸암모늄 등과 반응시켜 제거할 수 있다. Removing the hydroxyl group protecting group from the compound of Formula 4 protected with the hydroxyl group protecting group as defined above may be performed by PGM Wuts and TW Green in various ways ( Protective Groups in Organic Synthesis, 4th Ed. 2007, Wiely). It is well recognized by experts in the field that it can be performed according to the method & For example, the silyl protecting group may be removed by reaction with hydrochloric acid in an aqueous alcohol or tetrabutylammonium fluoride in tetrahydrofuran.
<단계 3><Step 3>
단계 3은, 상기 단계 2에서 얻은 화학식 6의 화합물에서의 옥소기를 비대칭 환원시켜 화학식 7의 신-디올(syn-diol) 화합물을 얻는 단계이다.Step 3 is a step of asymmetrically reducing the oxo group in the compound of formula 6 obtained in step 2 to obtain a syn-diol compound of formula (7).
상세하게는 화학식 6의 화합물에 있어서, B가 수소인 경우 하기 반응식 5에 나타난 바와 같이, 상기 화학식 6의 화합물을 유기용매 중에서 비대칭 환원 유도제(asymmetric reduction inducer) 존재 하에 환원제와 반응시켜 화학식 6의 화합물에서의 옥소기를 비대칭 환원시킴으로써 화학식 7의 신-디올(syn-diol) 화합물을 얻는다.Specifically, in the compound of Formula 6, when B is hydrogen, the compound of Formula 6 is reacted with a reducing agent in the presence of an asymmetric reduction inducer in an organic solvent, as shown in Scheme 5 below. Asymmetric reduction of the oxo group in affords the syn-diol compound of formula (7).
상기 식에서, B는 수소이고, D 및 Het는 상기에서 정의한 바와 같다.Wherein B is hydrogen and D and Het are as defined above.
그러나, 상기 화학식 6에서 B가 히드록시기 보호기인 경우에는, 하기 반응식 6에서와 같이, 화학식 6의 화합물에서의 히드록시기 보호기를 제거하는 히드록시 보호기 탈보호 반응을 실시한 후, 상기 반응식 5에서와 같이 화학식 6의 화합물에서의 옥소기의 비대칭 환원 반응을 실시한다. 이때 상기 히드록시 보호기 탈보호 반응은 앞서 설명한 바와 동일하다.However, in Formula 6, when B is a hydroxy group protecting group, as shown in Scheme 6, after performing a hydroxy protecting group deprotection reaction to remove the hydroxy group protecting group in the compound of Formula 6, as shown in Scheme 5 The asymmetric reduction reaction of the oxo group in the compound of is carried out. At this time, the hydroxy protecting group deprotection reaction is the same as described above.
상기 식에서, B는 히드록시기 보호기이고, D 및 Het는 상기에서 정의한 바와 같다.Wherein B is a hydroxy group protecting group, and D and Het are as defined above.
상기 유기용매로는 테트라히드로푸란, 또는 테트라히드로푸란과 메탄올, 에 탄올, 1-프로판올, 2-프로판올, 1-부탄올, tert-부탄올, 2-프로펜-1-올에서 선택되는 알코올의 혼합용매가 사용될 수 있다. The organic solvent is tetrahydrofuran or a mixed solvent of tetrahydrofuran and an alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, tert -butanol and 2- propen -1-ol. Can be used.
상기 환원제로는 수소화붕소나트륨이 사용될 수 있으며, 이때 상기 환원제는 화학식 6의 화합물 1몰 당량에 대하여 1.0몰 당량 내지 2.0몰 당량으로 사용될 수 있다. Sodium borohydride may be used as the reducing agent, wherein the reducing agent may be used in 1.0 molar equivalent to 2.0 molar equivalent with respect to 1 molar equivalent of the compound of Formula 6.
또한 상기 비대칭 환원 유도제로는 트리에틸보레이트, 트리메틸보레이트, 트리이소프로필보레이트, 디에틸메톡시보란, 디에틸에톡시보란, 디에틸부톡시보란, 디에틸(2-프로펜옥시)보란, 디에틸이소프로폭시보란, 디에틸(tert-부톡시)보란, 디부틸메톡시보란 등이 사용될 수 있으며, 이때 비대칭 환원 유도제는 상기 화학식 6의 화합물 1몰 당량에 대하여 1.0몰 당량 내지 2.0몰 당량으로 사용될 수 있다. In addition, the asymmetric reduction inducing agent is triethyl borate, trimethyl borate, triisopropyl borate, diethyl methoxy borane, diethyl ethoxy borane, diethyl butoxy borane, diethyl (2-propeneoxy) borane, diethyl Isopropoxy borane, diethyl ( tert -butoxy) borane, dibutylmethoxyborane and the like can be used, wherein the asymmetric reduction inducing agent is used in 1.0 molar equivalent to 2.0 molar equivalent with respect to 1 molar equivalent of the compound of Formula 6 Can be.
상기 단계 (3)에서의 반응은 비대칭 환원 유도제의 종류에 따라 실시 온도가 다를 수 있으나, -78℃ 내지 0℃에서 실시될 수 있으며, 바람직하게는 -78℃ 내지 -30℃이다.The reaction in step (3) may be carried out depending on the kind of asymmetric reduction inducing agent, but may be carried out at -78 ℃ to 0 ℃, preferably -78 ℃ to -30 ℃.
<단계 4><Step 4>
단계 4는, 하기 반응식 7에서와 같이, 단계 3에서 얻은 화학식 7의 화합물을 수성 유기용매중에서 염기와 반응시켜 화학식 7의 화합물로부터 카르복시 보호기를 제거함으로써 화학식 1의 스타틴 화합물 또는 그 염을 얻는 단계이다.Step 4 is a step of obtaining a statin compound of Formula 1 or a salt thereof by reacting the compound of Formula 7 obtained in Step 3 with a base in an aqueous organic solvent to remove a carboxy protecting group from the compound of Formula 7 as in Scheme 7 below. .
상기 식에서, D 및 Het는 상기에서 정의한 바와 같다.Wherein D and Het are as defined above.
상기 반응식 7에 따른 카르복실기 보호기는 메탄올, 에탄올, 2-프로판올, 아세톤, 아세토니트릴 및 테트라히드로푸란과 같은 수혼화성 용매와 물의 혼합용매 중에서 화학식 7의 화합물을 수산화나트륨 또는 수산화칼륨 등의 염으로 가수분해 반응시킴으로써 제거될 수 있다.The carboxyl protecting group according to Scheme 7 hydrolyzes the compound of formula 7 with a salt such as sodium hydroxide or potassium hydroxide in a mixed solvent of water and a water miscible solvent such as methanol, ethanol, 2-propanol, acetone, acetonitrile and tetrahydrofuran. Can be removed by reaction.
본 발명에서 사용한 상기 카르복실기 보호기의 탈보호 반응은 우츠(P.G.M. Wuts) 및 그린(T.W. Green)이 제시한 여러 가지 방법[Protective Groups in Organic Synthesis, 4th Ed. 2007, Wiely & Sons 참조] 또는 이를 변형한 방법에 따라 수행될 수 있다는 것을 이 분야의 전문가는 잘 인식하고 있다.The deprotection reaction of the carboxyl protecting group used in the present invention is various methods proposed by PGM Wuts and TW Green [ Protective Groups in Organic Synthesis, 4th Ed. Experts in the field are well aware that it can be performed according to 2007, Wiely & Sons] or a variant thereof.
이어서, 상기 화학식 7의 화합물을 가수분해 반응시켜 얻은 알칼리성 반응액의 pH를 염산 등으로 4 내지 5로 조절한 후, 에틸아세테이트, 에틸에테르, tert-부틸메틸에테르, 디클로로메탄 및 클로로포름 등의 유기용매로 추출하고 추출액을 농축함으로써 본 발명에 따른 화학식 1의 스타틴 화합물을 수득할 수 있다.Subsequently, after adjusting the pH of the alkaline reaction solution obtained by hydrolyzing the compound of Chemical Formula 7 to 4 to 5 with hydrochloric acid or the like, organic solvents such as ethyl acetate, ethyl ether, tert -butylmethyl ether, dichloromethane and chloroform By extraction with a concentrate of the extract can be obtained a statin compound of the formula (1) according to the invention.
본 발명은 상기 화학식 1의 스타틴 화합물의 염을 제공한다.The present invention provides a salt of the statin compound of Chemical Formula 1.
상기 스타틴 화합물의 염으로는 리튬, 나트륨, 칼륨, 마그네슘, 칼슘 및 스트론튬과 같은 알칼리 또는 알칼리 토금속 염; 또는 수소, 저급 알킬, 저급 시클로알킬, 아릴 또는 알릴 알킬이 치환된 암모늄염을 들 수 있다. Salts of the statin compounds include alkali or alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium and strontium; Or ammonium salts substituted with hydrogen, lower alkyl, lower cycloalkyl, aryl or allyl alkyl.
상기 화학식 1의 스타틴 화합물의 염, 일례로 화학식 1의 스타틴 화합물의 칼슘염의 경우 아래의 세 가지 방법 중의 어느 하나의 방법으로 제조될 수 있다:The salt of the statin compound of Formula 1, for example, the calcium salt of the statin compound of Formula 1 may be prepared by any one of the following three methods:
i) 상기 화학식 1의 스타틴 화합물을 메탄올, 에탄올, 2-프로판올, 아세톤, 아세토니트릴 및 테트라히드로푸란과 같은 수혼화성 용매와 물의 혼합용매 중에서 수산화나트륨과 반응시킨 후, 염화칼슘 또는 초산칼슘 등의 칼슘 이온 공급원을 가하여 화학식 1의 스타틴 화합물을 칼슘염으로 수득할 수 있다.i) After reacting the statin compound of Formula 1 with sodium hydroxide in a mixed solvent of water and a water miscible solvent such as methanol, ethanol, 2-propanol, acetone, acetonitrile and tetrahydrofuran and then calcium ions such as calcium chloride or calcium acetate A source can be added to give the statin compound of formula 1 as a calcium salt.
ii) 상기 화학식 7의 화합물의 가수분해 반응시켜 얻은 알칼리성 반응액에 칼슘 이온 공급원을 직접 가하여 침전되는 화학식 1의 스타틴 화합물의 칼슘염을 수득할 수 있다.ii) The calcium salt of the statin compound of Formula 1, which is precipitated by directly adding a calcium ion source to the alkaline reaction solution obtained by the hydrolysis reaction of the compound of Formula 7, may be obtained.
iii) 상기 화학식 1의 스타틴 화합물을 톨루엔 중에서 가열하여 하기 화학식 11의 락톤 화합물을 수득하고, 수득한 락톤 화합물을 메탄올, 에탄올, 2-프로판올, 아세톤, 아세토니트릴 및 테트라히드로푸란과 같은 수혼화성 용매와 물의 혼합용매 중에서 수산화나트륨과 반응시킨 후, 반응용액에 칼슘 이온 공급원을 가하여 침전되는 화학식 1의 스타틴 화합물의 칼슘염을 수득한다. iii) heating the statin compound of formula 1 in toluene to obtain a lactone compound of formula 11, and the obtained lactone compound with a water miscible solvent such as methanol, ethanol, 2-propanol, acetone, acetonitrile and tetrahydrofuran After reacting with sodium hydroxide in a mixed solvent of water, a calcium salt of the statin compound of the formula (1) is precipitated by adding a calcium ion source to the reaction solution.
상기 식에서, Het는 상기에서 정의한 바와 같다.In the above formula, Het is as defined above.
본 발명의 스타틴 제조 공정중에 제조되는 하기 화학식 4 및 화학식 6으로 표시된 올레핀 화합물은, 스타틴 화합물 또는 그 염을 제조하는데 사용되는 매우 중요한 신규의 화합물이다. 따라서 본 발명은 하기 화학식 4 및 화학식 6의 올레핀 화합물을 또한 제공한다.The olefin compounds represented by the following formulas (4) and (6) produced during the statin preparation process of the present invention are very important novel compounds used to prepare statin compounds or salts thereof. Accordingly, the present invention also provides olefin compounds of the following formulas (4) and (6).
<화학식 4><Formula 4>
<화학식 6> <Formula 6>
상기 식에서, B는 수소 또는 히드록시기 보호기이고, 바람직하게는 수소, 트리메틸실릴, 트리에틸실릴, tert-부틸디메틸실릴, tert-부틸디페닐실릴, 트리페닐실릴 또는 트리이소프로필실릴에서 선택되는 것이며; Wherein B is a hydrogen or hydroxy group protecting group, preferably one selected from hydrogen, trimethylsilyl, triethylsilyl, tert -butyldimethylsilyl, tert -butyldiphenylsilyl, triphenylsilyl or triisopropylsilyl;
D는 카르복시기 보호기이고; 그리고D is a carboxy group protecting group; And
Het는 하기 화학식 8a 또는 화학식 8b의 치환기이다.Het is a substituent of Formula 8a or Formula 8b.
<화학식 8a><Formula 8a>
<화학식 8b><Formula 8b>
상기한 바와 같이 본 발명에 따른 제조방법에 따르면, 신규한 중간체 화합물들을 이용함으로써 종래의 방법에 비해 산업적으로 용이한 방법으로 스타틴 화합물 또는 그 염을 효율적으로 제조할 수 있다.According to the production method according to the present invention as described above, it is possible to efficiently prepare a statin compound or a salt thereof by using industrial intermediate compounds in an industrially convenient method compared to the conventional method.
이하, 실시예에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.
제조예 : (S)-3-(Preparation Example: (S) -3- ( terttert -부틸디메틸실릴옥시)-4-옥소부티로니트릴(화학식 2의 화합물)의 제조-Butyldimethylsilyloxy) -4-oxobutyronitrile (compound of formula 2)
(S)-3-(tert-부틸디메틸실릴옥시)-4-히드록시부티로니트릴 30g (0.14 mol)을 디클로로메탄 600㎖ 녹인 후, 1,1,1-트리아세톡시-1,1-디히드로-1,2-벤즈요오도옥솔-3-(1H)-온 65g (0.15 mol)을 0℃에서 서서히 첨가하고 실온에서 1시간 교반하였다. 결과로 얻어진 반응액에 1N 수산화나트륨 수용액을 반응액의 pH가 7에 도달할 때까지 적가하였다. 반응액 내 고체를 여과한 여액에 물 500㎖를 첨가하고 층분리한 후 유기층을 무수 황산마그네슘으로 건조하고, 감압 농축하여, 오일상의 잔사를 얻었다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피(전개용매 : 헥산/에틸아세테이트 = 5/1)로 정제하여 오일상의 표제화합물 25g (수율 85%)로 수득하였다.(S) -3- ( tert -butyldimethylsilyloxy) -4-hydroxybutyronitrile 30 g (0.14 mol) in dichloromethane 600 ml After dissolving, 65 g (0.15 mol) of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodooxol-3- ( 1H ) -one are slowly added at 0 ° C. and room temperature Stirred for 1 hour. 1N sodium hydroxide aqueous solution was added dropwise to the resulting reaction solution until the pH of the reaction solution reached 7. 500 ml of water was added to the filtrate which filtered the solid in the reaction liquid, and the layers were separated, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain an oily residue. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 5/1) to give 25 g (yield 85%) of the title compound as an oil.
1H-NMR (CDCl3, 300MHz, ppm) δ 9.64 (s, 1H), 4.26 (m, 1H), 2.67 (m, 2H), 0.97 (s, 9H), 0.20 (d, 6H). 1 H-NMR (CDCl 3 , 300 MHz, ppm) δ 9.64 (s, 1H), 4.26 (m, 1H), 2.67 (m, 2H), 0.97 (s, 9H), 0.20 (d, 6H).
IR (KBr, cm-1) 2859, 2253, 1741, 1256, 1124, 839.IR (KBr, cm −1 ) 2859, 2253, 1741, 1256, 1124, 839.
[α]D 20 = -19.65o (c=1, CHCl3)[α] D 20 = -19.65 o (c = 1, CHCl 3 )
실시예 1: (3S,4E)-5-[2-시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]-3-(Example 1: (3S, 4E) -5- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3- ( terttert -부틸디메틸실릴옥시)-4-펜텐니트릴(화학식 4의 화합물)의 제조-Butyldimethylsilyloxy) -4-pentenenitrile (compound of formula 4)
테트라히드로푸란 10㎖에 3-[[(벤조티아졸-2-일)술포닐]메틸]-2-시클로프로필-4-(4-플루오로페닐)퀴놀린 1g (2.1 mmol)을 녹인 후, -30℃에서 칼륨 tert-부톡시드 0.28g (2.5 mmol)을 넣고 5분 교반하였다. 결과로 얻어진 반응액에 상기 제 조예에서 수득한 오일상의 (S)-3-(tert-부틸디메틸실릴옥시)-4-옥소부티로니트릴 0.53g (2.5 mmol)을 테트라히드로푸란 5㎖에 녹인 용액을 첨가하고, -30℃에서 2시간 교반하였다. 반응액에 포화 염화암모늄 수용액 10㎖을 더 가하고, 에틸아세테이트 20㎖로 추출하였다. 유기층을 무수황산마그네슘으로 건조하고 감압농축 하여 오일상의 잔사를 얻었다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 7/1)하여 백색 고상의 표제화합물 0.50g (수율 50%)을 수득하였다.Dissolve 1 g (2.1 mmol) of 3-[[(benzothiazol-2-yl) sulfonyl] methyl] -2-cyclopropyl-4- (4-fluorophenyl) quinoline in 10 ml of tetrahydrofuran, 0.28 g (2.5 mmol) of potassium tert -butoxide was added at 30 ° C. and stirred for 5 minutes. A solution obtained by dissolving 0.53 g (2.5 mmol) of (S) -3- ( tert -butyldimethylsilyloxy) -4-oxobutyronitrile in the oil phase obtained in the above Preparation Example in 5 ml of tetrahydrofuran in the resultant reaction solution. Was added and stirred at -30 ° C for 2 hours. 10 ml of saturated ammonium chloride aqueous solution was further added to the reaction solution, and extracted with 20 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oily residue. The obtained residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 7/1) to give 0.50 g (yield 50%) of the title compound as a white solid.
융점 (℃) 120 - 122Melting Point (℃) 120-122
1H-NMR (CDCl3, 300MHz, ppm) δ 7.96 (d, 1H), 7.60 (m, 1H), 7.32 (m, 2H), 7.24-7.18 (m, 4H), 6.71 (dd, 1H), 5.67 (dd, 1H), 4.41 (m, 1H), 2.39-2.31 (m, 3H), 1.37 (m, 2H), 1.05 (m, 2H), 0.88 (s, 9H), 0.04 (d, 6H). 1 H-NMR (CDCl 3 , 300 MHz, ppm) δ 7.96 (d, 1H), 7.60 (m, 1H), 7.32 (m, 2H), 7.24-7.18 (m, 4H), 6.71 (dd, 1H), 5.67 (dd, 1H), 4.41 (m, 1H), 2.39-2.31 (m, 3H), 1.37 (m, 2H), 1.05 (m, 2H), 0.88 (s, 9H), 0.04 (d, 6H) .
IR (KBr, cm-1) 3059, 2934, 2857, 2245, 1646.IR (KBr, cm −1 ) 3059, 2934, 2857, 2245, 1646.
[α]D 20 = -2.67o (c=1, CHCl3)[α] D 20 = -2.67 o (c = 1, CHCl 3 )
실시예 2: (3S,4E)-5-[2-시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]-3-(Example 2: (3S, 4E) -5- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3- ( terttert -부틸디메틸실릴옥시)-4-펜텐니트릴(화학식 4의 화합물)의 제조 -Butyldimethylsilyloxy) -4-pentenenitrile (compound of formula 4)
테트라히드로푸란 50㎖에 디페닐 [2-시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]메틸포스핀 옥시드 5g (10.5 mmol)을 녹인 후, -40℃에서 1.6M 부틸리튬/헥산 용액 7.9㎖ (12.6 mmol)을 1시간 적가하였다. 결과로 얻어진 반응액에 (S)-3-(tert-부틸디메틸실릴옥시)-4-옥소부티로니트릴 2.7g (12.6 mmol)을 테트라히드로푸란 30㎖에 녹인 용액을 첨가하고, -40℃에서 2시간 교반하였다. 반응액에 물 100㎖를 가하고, 에틸아세테이트 100㎖로 추출하였다. 결과로 얻어진 유기층을 무수황산마그네슘으로 건조하고, 감압농축하여 오일상의 잔사를 얻었다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 7/1)하여 백색 고상의 표제화합물 4.0g (수율 80%)을 수득하였다. 수득물은 실시예 1에서 얻은 화합물과 동일하였다.5 g (10.5 mmol) of diphenyl [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] methylphosphine oxide was dissolved in 50 ml of tetrahydrofuran, followed by 1.6M butyl at -40 ° C. 7.9 mL (12.6 mmol) of lithium / hexane solution was added dropwise for 1 hour. A solution of 2.7 g (12.6 mmol) of (S) -3- ( tert -butyldimethylsilyloxy) -4-oxobutyronitrile in 30 ml of tetrahydrofuran was added to the resulting reaction solution, Stir for 2 hours. 100 ml of water was added to the reaction solution, followed by extraction with 100 ml of ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain an oily residue. The obtained residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 7/1) to give 4.0 g (yield 80%) of the title compound as a white solid. The obtained product was identical to the compound obtained in Example 1.
실시예 3: Example 3: terttert -부틸 (5S,6E)-7-[2-시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]-5-(-Butyl (5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -5- ( terttert -부틸디메틸실릴옥시)-3-옥소-7-헵테노에이트(화학식 6의 화합물)의 제조-Butyldimethylsilyloxy) -3-oxo-7-heptenoate (compound of formula 6)
테트라히드로푸란 36㎖에 아연 분말 1.38g (21.2 mmol), 메탄술폰산 0.02g (0.21 mmol)을 가하고 65~68℃에서 1.5시간 교반한 후, 반응액에 tert-부틸브로모아세테이트 2.53g (12.7 mmol)을 30분 동안 적가하고, 65~68℃에서 30분 교반하였다. 결과로 얻어진 반응액에 (3S,4E)-5-[2-시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]-3-(tert-부틸디메틸실릴옥시)-4-펜테노니트릴 2g (4.2 mmol)을 테트라히드로푸란 4㎖에 녹인 용액을 65~68℃에서 1시간 동안 적가하고, 4시간 교반하였다. 0℃에서 반응액의 pH가 3이 될 때까지 1N 염산 수용액을 적가한 후, 반응액의 pH가 7이 될 때까지 포화 탄산수소나트륨 수용액을 가하였다. 반응액 내의 백색 고체를 여과하고, 여액에 에틸아세테이트 50㎖를 첨가하여 추출하였다. 결과로 얻어진 유기층을 포화탄산수소나트륨 수용액으로 세척한 뒤 무수황산마그네슘으로 건조하였다. 건조된 용액을 감압농축하여 잔사를 얻고, 잔사를 실리카겔 컬럼 크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 20/1)하여 오일상의 표제화합물 1.25g (수율 50%)을 수득하였다.Tetrahydrofuran, zinc powder in 36㎖ 1.38g (21.2 mmol), was added methanesulfonic acid 0.02g (0.21 mmol) On the 65 ~ 68 ℃ stirred for 1.5 hours, the reaction mixture tert - butyl bromoacetate 2.53g (12.7 mmol ) Was added dropwise for 30 minutes and stirred at 65-68 ° C. for 30 minutes. To the resulting reaction solution (3S, 4E) -5- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3- ( tert -butyldimethylsilyloxy) -4-phene A solution of 2 g (4.2 mmol) of tenononitrile in 4 ml of tetrahydrofuran was added dropwise at 65-68 ° C. for 1 hour, followed by stirring for 4 hours. 1N hydrochloric acid aqueous solution was added dropwise at 0 ° C. until the pH of the reaction solution reached 3, and then saturated aqueous sodium hydrogen carbonate solution was added until the pH of the reaction solution reached 7. The white solid in the reaction solution was filtered, and 50 ml of ethyl acetate was added to the filtrate and extracted. The resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure to obtain a residue, and the residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 20/1) to give 1.25 g (yield 50%) of the title compound in oil form.
1H-NMR (CDCl3, 300MHz, ppm) δ 7.94 (m, 1H), 7.62 (m, 1H), 7.34-7.22 (m, 6H), 6.65 (dd, 1H), 5.73 (dd, 1H), 4.68(m, 1H), 3.39 (m, 2H), 2.55 (m, 2H), 1.31 (m,2H), 1.06 (m, 2H), 1.50 (m, 9H), 0.88 (s, 9H), 0.01 (dd, 6H). 1 H-NMR (CDCl 3 , 300 MHz, ppm) δ 7.94 (m, 1H), 7.62 (m, 1H), 7.34-7.22 (m, 6H), 6.65 (dd, 1H), 5.73 (dd, 1H), 4.68 (m, 1H), 3.39 (m, 2H), 2.55 (m, 2H), 1.31 (m, 2H), 1.06 (m, 2H), 1.50 (m, 9H), 0.88 (s, 9H), 0.01 (dd, 6H).
IR (KBr, cm-1) 2955, 2931, 1740, 1256, 1006, 937, 839.IR (KBr, cm −1 ) 2955, 2931, 1740, 1256, 1006, 937, 839.
[α]D 20 = +0.02o (c=1, CHCl3)[α] D 20 = +0.02 o (c = 1, CHCl 3 )
실시예 4: Example 4: terttert -부틸 (5S,6E)-7-[2-시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]-5-히드록시-3-옥소-7-헵테노에이트(화학식 6의 화합물)의 제조-Butyl (5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -5-hydroxy-3-oxo-7-heptenoate of formula 6 Compound)
테트라히드로푸란 10㎖에 tert-부틸 (5S,6E)-7-[2-시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]-5-(tert-부틸디메틸실릴옥시)-3-옥소-7-헵테노에이트 1.0g (1.7 mmol)을 녹이고 상온에서 1M 플루오르화테트라부틸암모늄/테트라히드로푸란 용액 2㎖ (2.0 mmol)을 첨가하였다. 결과로 얻어진 반응액을 실온에서 2시간 교반하고 포화 탄산수소나트륨 30㎖를 가한 뒤, 에틸아세테이트 50㎖를 가하고 추출하였다. 결과로 얻어진 유기층을 포화 탄산수소나트륨 30㎖로 세척하고, 무수황산마그네슘으로 건조한 다음, 감압농축 하여 잔사를 얻었다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 10/1)하여 거품 상의 표 제화합물 0.65g (수율 81%)을 얻었다. Tert -butyl (5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -5- ( tert -butyldimethylsilyloxy) -in 10 ml of tetrahydrofuran 1.0 g (1.7 mmol) of 3-oxo-7-heptenoate was dissolved and 2 ml (2.0 mmol) of 1M tetrabutylammonium fluoride / tetrahydrofuran solution was added at room temperature. The resulting reaction solution was stirred at room temperature for 2 hours, 30 ml of saturated sodium hydrogen carbonate was added, and then 50 ml of ethyl acetate was added and extracted. The resulting organic layer was washed with 30 ml of saturated sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain a residue. The obtained residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 10/1) to obtain 0.65 g (yield 81%) of the title compound on the foam.
1H-NMR (CDCl3, 300MHz, ppm) δ 7.94 (d, 1H), 7.35-7.16 (m, 6H), 6.65 (d, 1H), 5.59 (dd, 1H), 4.59 (m, 1H), 3.34 (s, 2H), 2.52 (m, 2H), 2.38 (m, 1H), 1.46 (s, 9H), 1.33 (m, 2H), 1.01 (m, 2H). 1 H-NMR (CDCl 3 , 300 MHz, ppm) δ 7.94 (d, 1H), 7.35-7.16 (m, 6H), 6.65 (d, 1H), 5.59 (dd, 1H), 4.59 (m, 1H), 3.34 (s, 2H), 2.52 (m, 2H), 2.38 (m, 1H), 1.46 (s, 9H), 1.33 (m, 2H), 1.01 (m, 2H).
IR (KBr, cm-1) 3440, 2979, 1730, 1711, 1513, 971, 839.IR (KBr, cm −1 ) 3440, 2979, 1730, 1711, 1513, 971, 839.
[α]D 20 = +0.02o (c=1, CHCl3)[α] D 20 = +0.02 o (c = 1, CHCl 3 )
실시예 5: (3S,4E)-5-[2-시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]-3-히드록시-4-펜텐니트릴(화학식 4의 화합물)의 제조Example 5: of (3S, 4E) -5- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3-hydroxy-4-pentennitrile (compound of formula 4) Produce
테트라히드로푸란 20㎖에 (3S,4E)-5-[2-시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]-3-(tert-부틸디메틸실릴옥시)-4-펜테노니트릴 2g (4.2 mmol)을 녹인 후, 실온에서 1M 플루오르화테트라부틸암모늄/테트라히드로푸란 용액 4.9㎖ (4.9 mmol)을 가하고 3시간 교반하였다. 결과로 얻어진 반응액에 포화 탄산수소나트륨 30㎖를 가한 뒤, 에틸아세테이트 50㎖를 가하고 추출하였다. 결과로 얻어진 유기 층을 포화 탄산수소나트륨 30㎖로 세척하고 무수황산마그네슘으로 건조한 다음 감압농축 하여 잔사를 얻었다. 얻어진 잔사를 실리카겔 컬럼크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 3/1)하여 미황색 고상의 표제화합물 1.35g (수율 90%)을 얻었다.(3S, 4E) -5- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3- ( tert -butyldimethylsilyloxy) -4-phen in 20 ml of tetrahydrofuran After dissolving 2 g (4.2 mmol) of tenonitrile, 4.9 mL (4.9 mmol) of 1M tetrabutylammonium fluoride / tetrahydrofuran solution was added at room temperature, followed by stirring for 3 hours. 30 ml of saturated sodium hydrogencarbonate was added to the resultant reaction solution, and then 50 ml of ethyl acetate was added and extracted. The resulting organic layer was washed with 30 ml of saturated sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain a residue. The obtained residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3/1) to obtain 1.35 g (yield 90%) of the title compound as a pale yellow solid.
융점 (℃) 157 - 159Melting Point (℃) 157-159
1H-NMR (CDCl3, 300MHz, ppm) δ 7.96 (d, 1H), 7.64-7.58 (m, 1H), 7.36-7.32 (m, 2H), 7.29-7.17 (m, 4H), 6.77 (d, 1H), 5.66 (dd, 1H), 4.47 (m, 1H), 2.42 (d, 2H), 2.39-2.30 (m, 1H), 1.38-1.34 (m, 2H), 1.07-1.03 (m, 2H). 1 H-NMR (CDCl 3 , 300 MHz, ppm) δ 7.96 (d, 1H), 7.64-7.58 (m, 1H), 7.36-7.32 (m, 2H), 7.29-7.17 (m, 4H), 6.77 (d , 1H), 5.66 (dd, 1H), 4.47 (m, 1H), 2.42 (d, 2H), 2.39-2.30 (m, 1H), 1.38-1.34 (m, 2H), 1.07-1.03 (m, 2H ).
IR (KBr, cm-1) 3211, 2251, 1453, 972, 833.IR (KBr, cm −1 ) 3211, 2251, 1453, 972, 833.
[α]D 20 = -7.36o (c=1, CHCl3)[a] D 2 ° = -7.36 o (c = 1, CHCl 3 )
실시예 6: Example 6: terttert -부틸 (5S,6E)-7-[2-시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]-5-히드록시-3-옥소-7-헵테노에이트(화학식 6의 화합물)의 제조-Butyl (5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -5-hydroxy-3-oxo-7-heptenoate of formula 6 Compound)
테트라히드로푸란 36㎖에 아연 분말 1.38g (21.2 mmol), 메탄술폰산 0.02g (0.21 mmol)을 가하고 65~68℃에서 1.5시간 교반한 후, 반응액에 tert-부틸브로모아세테이트 2.53g (12.7 mmol)을 30분 동안 적가하고, 65~68℃에서 30분 교반하였다. 결과로 얻어진 반응액에 (3S,4E)-5-[2-시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]-3-히드록시-4-펜텐니트릴 1.5g (4.2 mmol)을 테트라히드로푸란 4㎖에 녹인 용액을 65~68℃에서 1시간 동안 적가하고, 4시간 교반하였다. 0℃에서 반응액의 pH가 3이 될 때까지 1N 염산 수용액을 적가한 후, 반응액의 pH가 7이 될 때까지 포화 탄산수소나트륨 수용액을 가하였다. 반응액 내의 백색 고체를 여과하고 여액에 에틸아세테이트 50㎖를 첨가하여 추출하였다. 결과로 얻어진 유기층을 포화탄산수소나트륨 수용액으로 세척한 뒤 무수황산마그네슘으로 건조하였다. 건조된 용액을 감압농축하여 잔사를 얻었다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 20/1)하여 오일상의 표제화합물 1.25g (수율 48%)을 수득하였다. 수득물은 실시예 4에서 얻은 것과 동일하였다.Tetrahydrofuran, zinc powder in 36㎖ 1.38g (21.2 mmol), was added methanesulfonic acid 0.02g (0.21 mmol) On the 65 ~ 68 ℃ stirred for 1.5 hours, the reaction mixture tert - butyl bromoacetate 2.53g (12.7 mmol ) Was added dropwise for 30 minutes and stirred at 65-68 ° C. for 30 minutes. To the resulting reaction solution, 1.5 g (4.2 mmol of (3S, 4E) -5- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3-hydroxy-4-pentennitrile ) Was added dropwise to tetrahydrofuran 4ml solution for 1 hour at 65 ~ 68 ℃ and stirred for 4 hours. 1N hydrochloric acid aqueous solution was added dropwise at 0 ° C. until the pH of the reaction solution reached 3, and then saturated aqueous sodium hydrogen carbonate solution was added until the pH of the reaction solution reached 7. The white solid in the reaction solution was filtered and extracted by adding 50 ml of ethyl acetate to the filtrate. The resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure to obtain a residue. The obtained residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 20/1) to give 1.25 g (yield 48%) of the titled compound as an oil. The obtained product was the same as obtained in Example 4.
실시예 7: Example 7: terttert -부틸 (3R,5S,6E)-7-[2-시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]-3,5-디히드록시-7-헵테노에이트(화학식 7의 화합물)의 제조-Butyl (3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-7-heptenoate Preparation of the compound
테트라히드로푸란 11㎖에 tert-부틸 (5S,6E)-7-[2-시클로프로필-4-(4-플루오 로페닐)퀴놀린-3-일]-5-히드록시-3-옥소-7-헵테노에이트 0.65g (1.37 mmol)을 녹이고 메탄올 3㎖를 가하였다. 결과로 얻어진 반응에 -78℃에서 디에틸메톡시보란 0.2㎖ (1.50 mmol)를 가하고 30분 교반한 후, 수소화붕소나트륨 0.057g (1.50 mmol)을 가하고 5시간 교반하였다. 반응액에 30% 과산화수소수 10㎖를 가하고, 1시간 교반한 후, 에틸아세테이트 30㎖로 추출하였다. 결과로 얻어진 유기층을 무수황산마그네슘으로 건조하고 감압농축하여 잔사를 얻었다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 3/1)하여 백색 고상의 표제화합물 0.6g (수율 90%)을 얻었다. Tert -butyl (5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -5-hydroxy-3-oxo-7- in 11 ml of tetrahydrofuran 0.65 g (1.37 mmol) of heptenoate was dissolved and 3 ml of methanol was added. 0.2 mL (1.50 mmol) of diethylmethoxyborane was added to the resulting reaction at -78 ° C, and stirred for 30 minutes. Then, 0.057 g (1.50 mmol) of sodium borohydride was added and stirred for 5 hours. 10 ml of 30% hydrogen peroxide solution was added to the reaction mixture, and the mixture was stirred for 1 hour, followed by extraction with 30 ml of ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue. The obtained residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3/1) to obtain 0.6 g of a white solid title compound (yield 90%).
융점 (℃) 121 - 123Melting Point (℃) 121-123
1H-NMR (CDCl3, 300MHz, ppm) δ 7.96-7.93 (d, 1H), 7.62-7.55 (t, 1H), 6.66-6.60 (d, 1H), 5.62-5.30 (q, 1H), 4.40 (m, 1H), 4.08 (m, 1H), 3.71 (s, 1H), 3.28 (s, 1H), 2.45-2.39 (m, 1H), 2.39-2.34 (d, 2H), 1.48 (s, 9H), 1.34-1.26 (m, 4H), 1.07-1.01 (m, 2H). 1 H-NMR (CDCl 3 , 300 MHz, ppm) δ 7.96-7.93 (d, 1H), 7.62-7.55 (t, 1H), 6.66-6.60 (d, 1H), 5.62-5.30 (q, 1H), 4.40 (m, 1H), 4.08 (m, 1H), 3.71 (s, 1H), 3.28 (s, 1H), 2.45-2.39 (m, 1H), 2.39-2.34 (d, 2H), 1.48 (s, 9H ), 1.34-1.26 (m, 4H), 1.07-1.01 (m, 2H).
IR (KBr, cm-1) 3415, 2971, 2933, 1734, 1604 1513, 1368, 1149.IR (KBr, cm −1 ) 3415, 2971, 2933, 1734, 1604 1513, 1368, 1149.
[α]D 20 = +2.76o (c=1, CHCl3)[α] D 20 = +2.76 o (c = 1, CHCl 3 )
실시예 8 : 피타바스타틴 칼슘(화학식 1의 화합물의 칼슘염)의 제조Example 8 Preparation of Pitavastatin Calcium (Calcium Salt of Compound of Formula 1)
아세토니트릴 10㎖에 tert-부틸 (3R,5S,6E)-7-[2-시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]-3,5-디히드록시-7-헵테노에이트 2.0g (4.2 mmol)을 녹이고, 결과로 얻어진 반응액에 2N 수산화나트륨 수용액 2.2㎖를 가하고 35℃에서 2시간 교반하였다. 반응액을 실온으로 냉각하고, 1N 염산 수용액을 가하여 반응액의 pH를 4.8로 조절한 후 에틸아세테이트 30㎖로 추출하였다. 결과로 얻어진 유기층을 무수황산마그네슘으로 건조하고 감압농축하였다. 결과로 얻어진 잔사에 톨루엔 40㎖를 가하고, 3시간 동안 환류시킨 다음 실온으로 냉각하였다. 에틸아세테이트 20㎖를 가하고 포화 탄산수소나트륨 수용액으로 세척한 후 무수황산마그네슘으로 건조하고 감압농축하였다. 결과로 얻어진 잔사를 실리카겔 컬럼 크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 5/1)하여 하기 화학식 11a로 표시되는 (4R,6S)-6-[1(E)-2-[시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]에테닐]테트라히드로-4-히드록시-2H-피란-2-온 1.27g을 수득하였다. Tert -butyl (3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-7- in 10 ml of acetonitrile 2.0 g (4.2 mmol) of heptenoate was dissolved, and 2.2 mL of 2N aqueous sodium hydroxide solution was added to the resulting reaction solution, and the mixture was stirred at 35 ° C for 2 hours. The reaction solution was cooled to room temperature, 1N aqueous hydrochloric acid solution was added to adjust the pH of the reaction solution to 4.8, and extracted with 30 ml of ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 40 ml of toluene was added to the resulting residue, refluxed for 3 hours, and then cooled to room temperature. 20 ml of ethyl acetate was added, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 5/1) to give (4R, 6S) -6- [1 (E) -2- [cyclopropyl-4 represented by the following formula (11a). 1.27 g of-(4-fluorophenyl) quinolin-3-yl] ethenyl] tetrahydro-4-hydroxy- 2H -pyran-2-one were obtained.
상기 화학식 11a의 락톤 화합물에 테트라히드로푸란 10㎖를 가하여 녹인 후, 물 10㎖와 1N 수산화나트륨 수용액 3.3㎖를 가하고 실온에서 1시간 교반하였다. 반응액을 감압농축하여 부피를 반으로 줄인 후 tert-부틸메틸에테르 20㎖로 세척하였다. 수층에 물 40㎖를 가하고 격렬하게 교반하면서 염화칼슘 이수화물 0.29g (1.63 mmol)을 물 5㎖에 녹여 적가하고 실온에서 밤새 교반하였다. 생성된 고체를 여과하고 물 30㎖로 세척한 후 감압하에 40℃에서 건조하여 백색 고체의 피타바스타틴 칼슘 1.01g (수율 74%)을 얻었다.10 ml of tetrahydrofuran was added to the lactone compound of Formula 11a to dissolve, and 10 ml of water and 3.3 ml of 1N sodium hydroxide solution were added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, reduced in half, and washed with 20 ml of tert -butylmethylether. 40 ml of water was added to the aqueous layer, and 0.29 g (1.63 mmol) of calcium chloride dihydrate was dissolved in 5 ml of water dropwise with vigorous stirring, and stirred overnight at room temperature. The resulting solid was filtered, washed with 30 ml of water and dried at 40 ° C. under reduced pressure to obtain 1.01 g (yield 74%) of pitavastatin calcium as a white solid.
융점 (℃) 232 -235 (분해)Melting Point (℃) 232 -235 (Decomposition)
수분 4.0% (칼 피셔 적정기)Moisture 4.0% (Karl Fisher titrator)
[α]D20 = +23.4 (c=1.0, 아세토니트릴/물=1/1) [a] D20 = +23.4 (c = 1.0, acetonitrile / water = 1/1)
1H-NMR (DMSO-d6, 300MHz, ppm) δ 7.86 (d, 1H), 7.62 (m, 1H), 7.42-7.25 (m, 6H), 6.49(d, 1H), 5.61 (dd, 1H), 4.12 (m, 1H), 3.51 (m, 1H), 2.52 (m, 1H), 2.15 -1.77 (m, 2H), 1.53-1.04 (m, 6H). 1 H-NMR (DMSO-d 6 , 300 MHz, ppm) δ 7.86 (d, 1H), 7.62 (m, 1H), 7.42-7.25 (m, 6H), 6.49 (d, 1H), 5.61 (dd, 1H ), 4.12 (m, 1H), 3.51 (m, 1H), 2.52 (m, 1H), 2.15 -1.77 (m, 2H), 1.53-1.04 (m, 6H).
IR (KBr, cm-1) 3452, 3000, 1604, 1520, 1245, 970.IR (KBr, cm −1 ) 3452, 3000, 1604, 1520, 1245, 970.
실시예 9 : 피타바스타틴 칼슘(화학식 1의 화합물의 칼슘염)의 제조Example 9 Preparation of Pitavastatin Calcium (Calcium Salt of Compound of Formula 1)
아세토니트릴 10㎖에 tert-부틸 (3R,5S,6E)-7-[2-시클로프로필-4-(4-플루오로페닐)퀴놀린-3-일]-3,5-디히드록시-7-헵테노에이트 2.0g (4.2 mmol)을 녹이고, 반응액에 2N 수산화나트륨 수용액 2.2㎖를 가하고 35℃에서 2시간 교반하였다. 반응액을 실온으로 냉각한 후, tert-부틸메틸에테르 30㎖로 세척하고 불용물을 여과하였다. 여액에 물 40㎖를 가하고 격렬하게 교반하면서 염화칼슘 이수화물 0.39g (2.21 mmol)을 물 5㎖에 녹여 적가하고, 실온에서 밤새 교반하였다. 생성된 고체를 여과하고 물 30㎖로 세척한 후, 감압하에 40℃에서 건조하여 백색 고체의 피타바스타틴 칼슘 1.55g (수율 84%)을 얻었다. 수득물은 실시예 8에서 얻은 것과 동일하였다. Tert -butyl (3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-7- in 10 ml of acetonitrile 2.0 g (4.2 mmol) of heptenoate was dissolved, 2.2 mL of 2N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was stirred at 35 ° C for 2 hours. The reaction solution was cooled to room temperature, washed with 30 ml of tert -butylmethylether, and the insolubles were filtered off. 40 ml of water was added to the filtrate, and 0.39 g (2.21 mmol) of calcium chloride dihydrate was added dropwise to 5 ml of water with vigorous stirring, and stirred overnight at room temperature. The resulting solid was filtered, washed with 30 ml of water and dried at 40 ° C. under reduced pressure to obtain 1.55 g (yield 84%) of pitavastatin calcium as a white solid. The obtained product was the same as obtained in Example 8.
실시예 10 : (3S,4E)-5-[4-(4-플루오로페닐)-6-이소프로필-2-[메틸(메틸술포닐)아미노]피리미딘-5-일]-3-(Example 10 (3S, 4E) -5- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] -3- ( terttert -부틸디메틸실릴옥시)-4-펜텐니트릴(화학식 4의 화합물)의 제조-Butyldimethylsilyloxy) -4-pentenenitrile (compound of formula 4)
테트라히드로푸란 10㎖에 N-[[[5-(벤조티아졸-2-일)술포닐]메틸]-4-(4-플루오로페닐)-6-이소프로필피리미딘-2-일]-N-메틸메탄술폰아미드 1g (1.9 mmol)을 녹 이고, -30℃에서 칼륨 tert-부톡시드 0.26g (2.3 mmol)을 가하였다. 결과로 얻은 반응액에 0℃에서 상기 제조예 1에서 얻은 (S)-3-(tert-부틸디메틸실릴옥시)-4-옥소부티로니트릴 0.49g (2.3 mmol)을 테트라히드로푸란 5㎖에 녹인 용액을 첨가하고, 실온에서 12시간 교반하였다. 반응액에 포화 염화암모늄 수용액 10㎖을 가하고, 에틸아세테이트 20㎖로 추출하였다. 결과로 얻어진 유기층을 무수황산마그네슘으로 건조하고 감압농축 하여 오일상의 잔사를 얻었다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 8/1)하여 오일상의 표제화합물 0.63g (수율 60%)을 수득하였다.To 10 ml of tetrahydrofuran N -[[[5- (benzothiazol-2-yl) sulfonyl] methyl] -4- (4-fluorophenyl) -6-isopropylpyrimidin-2-yl]- 1 g (1.9 mmol) of N -methylmethanesulfonamide was dissolved and 0.26 g (2.3 mmol) of potassium tert -butoxide was added at -30 ° C. 0.49 g (2.3 mmol) of (S) -3- ( tert -butyldimethylsilyloxy) -4- oxobutyronitrile obtained in Preparation Example 1 was dissolved in 5 ml of tetrahydrofuran at 0 ° C. The solution was added and stirred at room temperature for 12 hours. 10 ml of saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with 20 ml of ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oily residue. The obtained residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 8/1) to give 0.63 g of an oily title compound (yield 60%).
1H-NMR (CDCl3, 300MHz, ppm) δ 7.63 (m, 2H), 7.11 (m, 1H), 6.70 (dd, 1H), 5.48 (dd, 1H), 4.46 (m, 1H), 3.56 (s, 3H0, 3.51 (s, 3H), 3.36 (m 1H), 2.41 (d, 2H), 1.28 (d, 6H), 0.90 (s, 9H), 0.08 (d, 6H). 1 H-NMR (CDCl 3 , 300 MHz, ppm) δ 7.63 (m, 2H), 7.11 (m, 1H), 6.70 (dd, 1H), 5.48 (dd, 1H), 4.46 (m, 1H), 3.56 ( s, 3H0, 3.51 (s, 3H), 3.36 (m 1H), 2.41 (d, 2H), 1.28 (d, 6H), 0.90 (s, 9H), 0.08 (d, 6H).
IR (KBr, cm-1) 2975, 2251, 1701, 1543, 1380, 1155, 964.IR (KBr, cm −1 ) 2975, 2251, 1701, 1543, 1380, 1155, 964.
[α]D 20 = -7.34o (c=1, CHCl3)[α] D 20 = -7.34 o (c = 1, CHCl 3 )
실시예 11 : Example 11: terttert -부틸 (5S,6E)-7-[4-(4-플루오로페닐)-6-이소프로필-2-[메틸(메틸술포닐)아미노]피리미딘-5-일]-5-(-Butyl (5S, 6E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] -5- ( terttert -부틸디메틸실릴옥시)-3-옥소-6-헵테노에이트(화학식 6의 화합물)의 제조 -Butyldimethylsilyloxy) -3-oxo-6-heptenoate (compound of formula 6)
테트라히드로푸란 20㎖에 아연 분말 0.75g (11.4 mmol), 메탄술폰산 0.04g (0.38 mmol)을 가하고, 65~68℃에서 1.5시간 교반하였다. 결과로 얻어진 반응액에 tert-부틸브로모아세테이트 1.48g (7.6 mmol)을 65~68℃에서 30분 동안 적가하고, 30분 교반하였다. 반응액에 (3S,4E)-5-[4-(4-플루오로페닐)-6-이소프로필-2-[메틸(메틸술포닐)아미노]피리미딘-5-일]-3-(tert-부틸디메틸실릴옥시)-4-펜테노니트릴 2g (3.8 mmol)을 테트라히드로푸란 5㎖에 녹인 용액을 65~68℃에서 1시간 동안 적가하고, 4시간 교반하였다. 0℃에서 반응액의 pH가 3이 될 때까지 1N 염산수용액을 적가한 후, 반응액의 pH가 7이 될 때까지 포화 탄산수소나트륨 수용액을 가하였다. 반응액 내 고체를 여과하고 여액에 에틸아세테이트 50㎖를 첨가하여 추출하였다. 결과로 얻어진 유기층을 포화탄산수소나트륨 수용액으로 세척한 뒤 무수황산마그네슘으로 건조하였다. 건조된 용액을 감압농축 하여 잔사를 얻고, 이를 실리카겔 컬럼 크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 20/1)하여 오일상의 표제화합물 1.26g (수율 51%)을 수득하였다.0.75 g (11.4 mmol) of zinc powder and 0.04 g (0.38 mmol) of methanesulfonic acid were added to 20 ml of tetrahydrofuran, and the mixture was stirred at 65 to 68 ° C for 1.5 hours. To the resulting reaction solution, 1.48 g (7.6 mmol) of tert -butylbromoacetate was added dropwise at 65 to 68 ° C. for 30 minutes, followed by stirring for 30 minutes. (3S, 4E) -5- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] -3- ( tert A solution of 2 g (3.8 mmol) of -butyldimethylsilyloxy) -4-pentenonitrile in 5 ml of tetrahydrofuran was added dropwise at 65-68 ° C. for 1 hour, followed by stirring for 4 hours. An aqueous 1N hydrochloric acid solution was added dropwise until the pH of the reaction solution reached 3 at 0 ° C, and then saturated aqueous sodium hydrogen carbonate solution was added until the pH of the reaction solution reached 7. The solid in the reaction solution was filtered and extracted by adding 50 ml of ethyl acetate to the filtrate. The resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure to obtain a residue, which was then subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 20/1) to give 1.26 g (yield 51%) of the title compound as an oil.
1H-NMR (CDCl3, 300MHz, ppm) δ 7.58 (m, 2H), 7.09 (m, 2H), 6.55 (dd, 1H), 5.47 (dd, 1H), 4.67 (m, 1H), 3.56 (s, 3H), 3.50 (s, 3H), 3.31 (m, 1H), 3.30 (s, 2H), 2.69 (dd, 1H), 2.47 (dd, 1H), 1.46 (s, 9H), 1.22 (m, 6H), 0.85 (s, 9H), 0.02 (d, 6H). 1 H-NMR (CDCl 3 , 300 MHz, ppm) δ 7.58 (m, 2H), 7.09 (m, 2H), 6.55 (dd, 1H), 5.47 (dd, 1H), 4.67 (m, 1H), 3.56 ( s, 3H), 3.50 (s, 3H), 3.31 (m, 1H), 3.30 (s, 2H), 2.69 (dd, 1H), 2.47 (dd, 1H), 1.46 (s, 9H), 1.22 (m , 6H), 0.85 (s, 9H), 0.02 (d, 6H).
IR (KBr, cm-1) 2959, 2931, 1733, 1717, 1546, 1381, 1155.IR (KBr, cm −1 ) 2959, 2931, 1733, 1717, 1546, 1381, 1155.
[α]D 20 = -30.24o (c=1, CHCl3)[α] D 20 = -30.24 o (c = 1, CHCl 3 )
실시예 12 : Example 12: terttert -부틸 (5S,6E)-7-[4-(4-플루오로페닐)-6-이소프로필-2-[메틸(메틸술포닐)아미노]피리미딘-5-일]-5-히드록시-3-옥소-6-헵테노에이트(화학식 6의 화합물)의 제조 -Butyl (5S, 6E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] -5-hydroxy- Preparation of 3-oxo-6-heptenoate (compound of formula 6)
테트라히드로푸란 10㎖에 tert-부틸 (5S,6E)-7-[4-(4-플루오로페닐)-6-이소프로필-2-[메틸(메틸술포닐)아미노]피리미딘-5-일]-5-(tert-부틸디메틸실릴옥시)-6-헵테노에이트 1.0g (1.54 mmol)을 녹이고 상온에서 1M 플루오르화테트라부틸암모늄/테트라히드로푸란 용액 2.3㎖ (2.3 mmol)을 첨가하였다. 결과로 얻어진 반응액을 실온에서 2시간 교반하고 포화 탄산수소나트륨 수용액 30㎖를 가한 뒤, 에틸아세테이트 50㎖를 가하고 추출하였다. 결과로 얻어진 유기층을 포화 탄산수소나트륨 30㎖로 세척하고 무수황산마그네슘으로 건조한 다음 감압농축 하여 잔사를 얻었 다. 잔사를 실리카겔 컬럼 크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 10/1)하여 오일 상의 표제화합물 0.70g (수율 85%)을 얻었다. Tert -butyl (5S, 6E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl in 10 ml of tetrahydrofuran ] -5- ( tert -butyldimethylsilyloxy) -6-heptenoate 1.0g (1.54 mmol) was dissolved and 2.3 ml (2.3 mmol) of 1M tetrabutylammonium fluoride / tetrahydrofuran solution at room temperature were added. The resulting reaction solution was stirred at room temperature for 2 hours, 30 ml of saturated aqueous sodium hydrogen carbonate solution was added, and then 50 ml of ethyl acetate was added and extracted. The resulting organic layer was washed with 30 ml of saturated sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 10/1) to obtain 0.70 g (yield 85%) of the title compound on an oil.
1H-NMR (CDCl3, 300MHz, ppm) δ 7.61 (m, 2H), 7.01 (m, 2H), 6.62 (dd, 1H), 5.43 (dd, 1H), 4.62 (m, 1H), 3.54 (s, 3H), 3.49 (s, 3H), 3.35 (s, 2H), 3.33 (m, 1H), 3.08 (d, 1H), 2.62 (d, 2H), 1.44 (s, 9H), 1.24 (d, 6H). 1 H-NMR (CDCl 3 , 300 MHz, ppm) δ 7.61 (m, 2H), 7.01 (m, 2H), 6.62 (dd, 1H), 5.43 (dd, 1H), 4.62 (m, 1H), 3.54 ( s, 3H), 3.49 (s, 3H), 3.35 (s, 2H), 3.33 (m, 1H), 3.08 (d, 1H), 2.62 (d, 2H), 1.44 (s, 9H), 1.24 (d , 6H).
IR (KBr, cm-1) 3518, 2976, 1734, 1713, 1545, 1380, 1153.IR (KBr, cm −1 ) 3518, 2976, 1734, 1713, 1545, 1380, 1153.
[α]D 20 = -12.56o (c=1, CHCl3)[α] D 20 = -12.56 o (c = 1, CHCl 3 )
실시예 13 : (3S,4E)-5-[4-(4-플루오로페닐)-6-이소프로필-2-[메틸(메틸술포닐)아미노]피리미딘-5-일]-3-히드록시-4-펜텐니트릴(화학식 4의 화합물)의 제조Example 13: (3S, 4E) -5- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] -3-hydrate Preparation of Roxy-4-pentenenitrile (Compound of Formula 4)
테트라히드로푸란 20㎖에 (3S,4E)-5-[4-(4-플루오로페닐)-6-이소프로필-2-[메틸(메틸술포닐)아미노]피리미딘-5-일]-3-(tert-부틸디메틸실릴옥시)-4-펜테노니트릴 2g (3.8 mmol)을 녹인 후, 실온에서 1M 플루오르화테트라부틸암모늄/테트라히드로푸란 용액 4.4㎖ (4.4 mmol)을 가하고 3시간 교반하였다. 결과로 얻어진 반 응액에 포화 탄산수소나트륨 30㎖를 가한 뒤, 에틸아세테이트 50㎖를 가하고 추출하였다. 결과로 얻어진 유기층을 포화 탄산수소나트륨 30㎖로 세척하고 무수황산마그네슘으로 건조한 다음 감압농축 하여 잔사를 얻었다. 잔사를 실리카겔 컬럼크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 5/1)하여 미백색 고상의 표제화합물 1.45g (수율 91%)을 얻었다.To 20 ml of tetrahydrofuran (3S, 4E) -5- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] -3 - (tert - butyldimethylsilyloxy) -4-pentenoate was dissolved in acetonitrile 2g (3.8 mmol), 1M tetrabutylammonium fluoride at room temperature / tetrahydrofuran solution was added to 4.4㎖ (4.4 mmol) was stirred for 3 hours. 30 ml of saturated sodium hydrogencarbonate was added to the resulting reaction solution, and then 50 ml of ethyl acetate was added and extracted. The resulting organic layer was washed with 30 ml of saturated sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 5/1) to obtain 1.45 g (yield 91%) of the title compound as a white solid.
융점 (℃) 94 - 96Melting Point (℃) 94-96
1H-NMR (CDCl3, 300MHz, ppm) δ 7.64 (m, 2H), 7.15 (m, 2H), 6.77 (dd, 1H), 5.51 (dd, 1H), 4.51 (m, 1H), 3.57 (s, 3H), 3.52 (s, 3H), 3.35 (m, 1H), 2.52 (m, 2H), 2.20 (d, 1H), 1.28 (d, 6H). 1 H-NMR (CDCl 3 , 300 MHz, ppm) δ 7.64 (m, 2H), 7.15 (m, 2H), 6.77 (dd, 1H), 5.51 (dd, 1H), 4.51 (m, 1H), 3.57 ( s, 3H), 3.52 (s, 3H), 3.35 (m, 1H), 2.52 (m, 2H), 2.20 (d, 1H), 1.28 (d, 6H).
IR (KBr, cm-1) 3444, 2975, 2255, 1551, 1383, 1153.IR (KBr, cm −1 ) 3444, 2975, 2255, 1551, 1383, 1153.
[α]D 20 = -2.46o (c=1, CHCl3)[α] D 20 = -2.46 o (c = 1, CHCl 3 )
실시예 14 : Example 14 terttert -부틸 (5S,6E)-7-[4-(4-플루오로페닐)-6-이소프로필-2-[메틸(메틸술포닐)아미노]피리미딘-5-일]-5-히드록시-3-옥소-6-헵테노에이트(화학식 6의 화합물)의 제조 -Butyl (5S, 6E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] -5-hydroxy- Preparation of 3-oxo-6-heptenoate (compound of formula 6)
테트라히드로푸란 20㎖에 아연 분말 0.75g (11.4 mmol), 메탄술폰산 0.04g (0.38 mmol)을 가하고, 65~68℃에서 1.5시간 교반하였다. 반응액에 tert-부틸브로모아세테이트 1.48g (7.6 mmol)을 65~68℃에서 30분 동안 적가하고, 30분 교반하였다. 결과로 얻어진 반응액에 (3S,4E)-5-[4-(4-플루오로페닐)-6-이소프로필-2-[메틸(메틸술포닐)아미노]피리미딘-5-일]-3-히드록시-4-펜텐니트릴 1.59g (3.8 mmol)을 테트라히드로푸란 5㎖에 녹인 용액을 65~68℃에서 1시간 동안 적가하고, 4시간 교반하였다. 0℃에서 반응액의 pH가 3이 될 때까지 1N 염산수용액을 적가한 후, 반응액의 pH가 7이 될 때까지 포화 탄산수소나트륨 수용액을 가하였다. 반응액 내 고체를 여과하고 여액에 에틸아세테이트 50㎖를 첨가하여 추출하였다. 유기층을 포화탄산수소나트륨 수용액으로 세척한 뒤 무수황산마그네슘으로 건조하였다. 건조된 용액을 감압농축 하여 잔사를 얻고, 이를 실리카겔 컬럼 크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 20/1)하여 오일상의 표제화합물 1.21g (수율 49%)을 수득하였다. 수득물은 실시예 12에서 얻은 것과 동일하였다.0.75 g (11.4 mmol) of zinc powder and 0.04 g (0.38 mmol) of methanesulfonic acid were added to 20 ml of tetrahydrofuran, and the mixture was stirred at 65 to 68 ° C for 1.5 hours. 1.48 g (7.6 mmol) of tert -butylbromoacetate was added dropwise to the reaction solution at 65˜68 ° C. for 30 minutes, followed by stirring for 30 minutes. To the resulting reaction solution (3S, 4E) -5- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] -3 A solution of 1.59 g (3.8 mmol) of hydroxy-4-pentene nitrile in 5 ml of tetrahydrofuran was added dropwise at 65-68 ° C. for 1 hour, followed by stirring for 4 hours. An aqueous 1N hydrochloric acid solution was added dropwise until the pH of the reaction solution reached 3 at 0 ° C, and then saturated aqueous sodium hydrogen carbonate solution was added until the pH of the reaction solution reached 7. The solid in the reaction solution was filtered and extracted by adding 50 ml of ethyl acetate to the filtrate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure to obtain a residue, which was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 20/1) to give 1.21 g (yield 49%) of the title compound as an oil. The obtained product was the same as obtained in Example 12.
실시예 15 : Example 15: terttert -부틸 (3R,5S,6E)-7-[4-(4-플루오로페닐)-6-이소프로필-2-[메틸(메틸술포닐)아미노]피리미딘-5-일]-3,5-디히드록시-6-헵테노에이트(화학식 7 의 화합물)의 제조-Butyl (3R, 5S, 6E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] -3,5 Preparation of -dihydroxy-6-heptenoate (compound of formula 7)
테트라히드로푸란 10㎖에 tert-부틸 (5S,6E)-7-[4-(4-플루오로페닐)-6-이소프로필-2-[메틸(메틸술포닐)아미노]피리미딘-5-일]-5-히드록시-3-옥소-6-헵테노에이트 1g (1.87 mmol)을 녹인 후, 메탄올 3㎖를 가하였다. 결과로 얻어진 반응액에 -78℃에서 디에틸메톡시보란 0.27㎖ (2.04 mmol)를 가하고 30분 교반한 후, 수소화붕소나트륨 0.077g (2.04 mmol)을 가하고 5시간 교반하였다. 반응액에 30% 과산화수소수 10㎖를 가하고, 1시간 교반한 후, 에틸아세테이트 30㎖로 추출하였다. 결과로 얻어진 유기층을 무수황산마그네슘으로 건조하고 감압농축 하여 잔사를 얻었다. 잔사를 실리카겔 컬럼 크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 5/1)하여 백색 고상의 표제화합물 0.87g (수율 87%)을 얻었다. Tert -butyl (5S, 6E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl in 10 ml of tetrahydrofuran 1 g (1.87 mmol) of] -5-hydroxy-3-oxo-6-heptenoate was dissolved and 3 ml of methanol was added thereto. 0.27 ml (2.04 mmol) of diethylmethoxyborane was added to the resulting reaction solution at -78 ° C, and stirred for 30 minutes. Then, 0.077 g (2.04 mmol) of sodium borohydride was added and stirred for 5 hours. 10 ml of 30% hydrogen peroxide solution was added to the reaction mixture, and the mixture was stirred for 1 hour, followed by extraction with 30 ml of ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 5/1) to obtain 0.87 g (yield 87%) of the title compound as a white solid.
융점 (℃) 135 - 137Melting Point (℃) 135-137
1H-NMR (CDCl3, 300MHz, ppm) δ 7.65 (m, 2H), 7.08 (m, 2H), 6.63(dd, 1H), 5.44 (dd, 1H), 4.47 (m, 1H), 4.18(m, 1H), 3.84 (s, 1H), 3.71 (s, 1H), 3.57 (s, 3H), 3.51 (s, 3H), 3.37 (m, 1H), 2.37 (d, 2H), 1.54 (m, 2H), 1.47 (s, 9H), 1.26 (d, 6H). 1 H-NMR (CDCl 3 , 300 MHz, ppm) δ 7.65 (m, 2H), 7.08 (m, 2H), 6.63 (dd, 1H), 5.44 (dd, 1H), 4.47 (m, 1H), 4.18 ( m, 1H), 3.84 (s, 1H), 3.71 (s, 1H), 3.57 (s, 3H), 3.51 (s, 3H), 3.37 (m, 1H), 2.37 (d, 2H), 1.54 (m , 2H), 1.47 (s, 9H), 1.26 (d, 6H).
IR (KBr, cm-1) 3502, 2967, 1736, 1545, 1381, 1152, 961.IR (KBr, cm −1 ) 3502, 2967, 1736, 1545, 1381, 1152, 961.
[α]D 20 = -7.08o (c=1, CHCl3)[a] D 2 ° = -7.08 o (c = 1, CHCl 3 )
실시예 16 : 로수바스타틴 칼슘(화학식 1의 화합물의 칼슘염)의 제조Example 16 Preparation of Rosuvastatin Calcium (Calcium Salt of Compound of Formula 1)
아세토니트릴 20㎖에 tert-부틸 (3R,5S,6E)-7-[4-(4-플루오로페닐)-6-이소프로필-2-[메틸(메틸술포닐)아미노]피리미딘-5-일]-3,5-디히드록시-6-헵테노에이트 3.0g (5.6 mmol)을 녹인 후, 2N 수산화나트륨 수용액 2.9㎖를 가하고 35℃에서 2시간 교반하였다. 결과로 얻어진 반응액을 실온으로 냉각하고, 1N 염산 수용액을 가하여 반응액의 pH를 4.8로 조절한 후 에틸아세테이트 50㎖로 추출하였다. 유기층을 무수황산마그네슘으로 건조하고 감압 농축한 후, 잔사에 톨루엔 40㎖를 가하고 5시간 동안 환류시킨 다음 실온으로 냉각하였다. 반응액에 에틸아세테이트 20㎖를 가하고 포화탄산수소나트륨 수용액으로 세척한 다음 무수황산마그네슘으로 건조하고 감압농축 하였다. 결과로 얻어진 잔사를 실리카겔 컬럼 크로마토그래피 (전개용매 : 헥산/에틸아세테이트 = 10/1)하여 하기 화학식 11b로 표시되는 N-(4-4-플루오로페닐)-5-(E)-2-[(2S,4R)-4-히드록시-6-옥소테트라히드로-2H-피란-2-일]에테닐- 6-이소프로필피리미딘-2-일)-N-메틸메탄술폰아미드 1.81g을 수득하였다. Tert -butyl (3R, 5S, 6E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidine-5- in 20 ml of acetonitrile After dissolving 3.0 g (5.6 mmol) of Japanese] -3,5-dihydroxy-6-heptenoate, 2.9 ml of 2N sodium hydroxide aqueous solution was added, and the mixture was stirred at 35 ° C for 2 hours. The resulting reaction solution was cooled to room temperature, 1N hydrochloric acid aqueous solution was added to adjust the pH of the reaction solution to 4.8, and then extracted with 50 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, 40 ml of toluene was added to the residue, refluxed for 5 hours, and cooled to room temperature. 20 ml of ethyl acetate was added to the reaction mixture, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 10/1) to obtain N- (4-4-fluorophenyl) -5- (E) -2- [ 1.81 g of (2S, 4R) -4-hydroxy-6-oxotetrahydro- 2H -pyran-2-yl] ethenyl-6-isopropylpyrimidin-2-yl) -N -methylmethanesulfonamide Obtained.
상기 화학식 11b의 락톤 화합물에 테트라히드로푸란 20㎖를 가하여 녹인 후, 물 15㎖와 1N 수산화나트륨 4.7㎖를 가하고 실온에서 2시간 교반하였다. 결과로 얻어진 반응액을 농축하여 반응액의 부피를 반으로 줄인 후, tert-부틸메틸에테르 20㎖로 세척하였다. 여액에 물 40㎖를 가하고 격렬하게 교반하면서 염화칼슘 이수화물 0.42g (2.36 mmol)을 물 8㎖에 녹여 40℃에서 적가하고, 실온에서 밤새 교반하였다. 생성된 고체를 여과하고 물 45㎖로 세척한 뒤 감압하에 40℃에서 건조하여 백색 고체의 로수바스타틴 칼슘 1.76g (수율 78%)을 얻었다. 20 ml of tetrahydrofuran was added to the lactone compound of Formula 11b to dissolve, and 15 ml of water and 4.7 ml of 1N sodium hydroxide were added thereto, followed by stirring at room temperature for 2 hours. The resulting reaction solution was concentrated to reduce the volume of the reaction solution by half, and then washed with 20 ml of tert -butylmethylether. 40 ml of water was added to the filtrate, and 0.42 g (2.36 mmol) of calcium chloride dihydrate was dissolved in 8 ml of water and added dropwise at 40 DEG C while stirring vigorously, and stirred at room temperature overnight. The resulting solid was filtered, washed with 45 mL of water and dried at 40 ° C. under reduced pressure to obtain 1.76 g of rosuvastatin calcium (yield 78%) as a white solid.
융점 155-160℃Melting point 155-160 ℃
수분 2.0% (칼 피셔 적정기)Moisture 2.0% (Karl Fischer Titrator)
[α]D20 = +15.0 (c=1.0, 50% 메탄올)[a] D 2 ° = +15.0 (c = 1.0, 50% methanol)
1H-NMR (DMSO-d6, 300MHz, ppm) δ 7.70 (dd, 2H), 7.13 (t, 2H), 6.59(dd, 1H), 5.54 (dd, 1H), 4.35 (m, 1H), 4.01 (m, 1H), 3.53 (s, 3H), 3.51(s, 3H), 3.44 (m, 1H), 2.45 (dd, 1H), 2.41-2.20 (m, 2H), 1.70-1.37 (m, 2H), 1.27 (dd, 6H). 1 H-NMR (DMSO-d 6 , 300 MHz, ppm) δ 7.70 (dd, 2H), 7.13 (t, 2H), 6.59 (dd, 1H), 5.54 (dd, 1H), 4.35 (m, 1H), 4.01 (m, 1H), 3.53 (s, 3H), 3.51 (s, 3H), 3.44 (m, 1H), 2.45 (dd, 1H), 2.41-2.20 (m, 2H), 1.70-1.37 (m, 2H), 1.27 (dd, 6H).
IR (KBr, cm-1) 3418, 2967, 1605, 1547, 1381, 1154, 963. IR (KBr, cm −1 ) 3418, 2967, 1605, 1547, 1381, 1154, 963.
실시예 17 : 로수바스타틴 칼슘(화학식 1의 화합물의 칼슘염)의 제조Example 17 Preparation of Rosuvastatin Calcium (Calcium Salt of Compound of Formula 1)
아세토니트릴 20㎖에 tert-부틸 (3R,5S,6E)-7-[4-(4-플루오로페닐)-6-이소프로필-2-[메틸(메틸술포닐)아미노]피리미딘-5-일]-3,5-디히드록시-6-헵테노에이트 3.0g (5.6 mmol)을 녹인 후, 2N 수산화나트륨 수용액 5.9㎖를 가하고 35℃에서 2시간 교반하였다. 결과로 얻어진 반응액을 실온으로 냉각하고, 감압하에 농축하였다. 잔사에 물 50㎖를 가한 후 tert-부틸메틸에테르 20㎖로 세척하고 불용물을 여과하였다. 여액을 격렬하게 교반하면서 염화칼슘 이수화물 0.52g (2.94 mmol)을 물 8㎖에 녹여 적가하고 실온에서 밤새 교반하였다. 생성된 고체를 여과하고 물 45㎖로 세척한 다음, 감압하에 40℃에서 건조하여 백색 고체의 로수바스타틴 칼슘 2.38g (수율 85%)을 얻었다. 수득물은 실시예 16에서 얻은 것과 동일하였다. Tert -butyl (3R, 5S, 6E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidine-5- in 20 ml of acetonitrile After dissolving 3.0 g (5.6 mmol) of Japanese] -3,5-dihydroxy-6-heptenoate, 5.9 ml of a 2N sodium hydroxide aqueous solution was added and stirred at 35 ° C for 2 hours. The resulting reaction solution was cooled to room temperature and concentrated under reduced pressure. 50 ml of water was added to the residue, followed by washing with 20 ml of tert -butylmethylether, and the insolubles were filtered out. While stirring the filtrate vigorously, 0.52 g (2.94 mmol) of calcium chloride dihydrate was dissolved in 8 ml of water dropwise and stirred overnight at room temperature. The resulting solid was filtered, washed with 45 mL of water and dried at 40 ° C. under reduced pressure to give 2.38 g of rosuvastatin calcium (yield 85%) as a white solid. The obtained product was the same as obtained in Example 16.
이상, 본 발명을 상기 실시예를 중심으로 하여 설명하였으나 이는 예시에 지나지 아니하며, 본 발명은 본 발명의 기술분야에서 통상의 지식을 가진 자에게 자명한 다양한 변형 및 균등한 기타의 실시예를 이하에 첨부한 청구범위 내에서 수행할 수 있다는 사실을 이해하여야 한다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.
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