KR100532042B1 - Process for the preparation of n,n-substituted-7-amino-3,5-dihydroxy heptanoic acid derivatives - Google Patents

Process for the preparation of n,n-substituted-7-amino-3,5-dihydroxy heptanoic acid derivatives Download PDF

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KR100532042B1
KR100532042B1 KR10-2003-0051360A KR20030051360A KR100532042B1 KR 100532042 B1 KR100532042 B1 KR 100532042B1 KR 20030051360 A KR20030051360 A KR 20030051360A KR 100532042 B1 KR100532042 B1 KR 100532042B1
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heptanoic acid
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KR20050012408A (en
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김문환
류의상
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한국화학연구원
한국유나이티드제약 주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/08—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups

Abstract

본 발명은 고지혈증 치료제인 아토르바스타틴을 제조하기 위한 핵심 중간체인, 질소가 이중치환된 7-아미노-3,5-디하이드록시 헵탄산 유도체의 제조방법에 관한 것으로, 질소를 이중 보호시킨 케토에스테르를 고압 수소화 반응시키는 것을 포함하는 본 발명의 방법에 의하면, 화학식 2로 표시되는 질소가 이중치환된 7-아미노-3,5-디하이드록시 헵탄산 유도체를 종래의 방법에 비해 온화한 조건하에서 간편하게 고수율로 합성할 수 있다.The present invention relates to a method for preparing a nitrogen-substituted 7-amino-3,5-dihydroxy heptanoic acid derivative, which is a key intermediate for preparing atorvastatin, a therapeutic agent for hyperlipidemia, and a nitrogen-protected ketoester at high pressure. According to the method of the present invention including hydrogenation, the nitrogen-substituted 7-amino-3,5-dihydroxy heptanoic acid derivative represented by the formula (2) can be easily obtained in high yield under mild conditions compared to the conventional method. Can be synthesized.

Description

질소가 이중치환된 7-아미노-3,5-디하이드록시 헵탄산 유도체의 제조방법 {PROCESS FOR THE PREPARATION OF N,N-SUBSTITUTED-7-AMINO-3,5-DIHYDROXY HEPTANOIC ACID DERIVATIVES}Process for the preparation of 7-amino-3,5-dihydroxy heptanoic acid derivatives substituted with nitrogen {substituted with N, N-SUBSTITUTED-7-AMINO-3,5-DIHYDROXY HEPTANOIC ACID DERIVATIVES}

본 발명은 고지혈증 치료제인 아토르바스타틴을 제조하기 위한 핵심 중간체인, 질소가 이중치환된 7-아미노-3,5-디하이드록시 헵탄산 유도체의 효율적인 제조방법에 관한 것이다.The present invention relates to a method for efficiently preparing a nitrogen-substituted 7-amino-3,5-dihydroxy heptanoic acid derivative, which is a key intermediate for preparing atorvastatin, a therapeutic agent for hyperlipidemia.

하기 화학식 1로 표시되는 아토르바스타틴(상품명:리피토)은 워너 램버트 제약사에서 개발되고 화이자 제약사에서 시판되고 있는 고지혈증 치료제로서, HMG-CoA 환원효소 억제 및 ACAT 억제의 작용을 가지며, 화학명은 (3R,5R)-7-[2-(4-플루오르페닐)-5-이소프로필-3-페닐-4-(페닐카보닐)피롤-1-일]-3,5-디하이드록시헵탄산 칼슘염이다. Atorvastatin (trade name: Lipitor) represented by the following formula (1) is a hyperlipidemic therapeutic agent developed by Warner Lambert Pharmaceuticals and marketed by Pfizer Pharmaceuticals. -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbonyl) pyrrol-1-yl] -3,5-dihydroxyheptano acid calcium salt.

아토르바스타틴을 제조하기 위해서는 통상 중간체로서 하기 화학식 2의 질소가 치환된 7-아미노-3,5-디하이드록시 헵탄산 유도체의 합성이 필수적이다.In order to prepare atorvastatin, synthesis of nitrogen-substituted 7-amino-3,5-dihydroxy heptanoic acid derivatives represented by the following general formula (2) is usually necessary as an intermediate.

상기 식에서, Where

R은 C1-6 알킬이고,R is C 1-6 alkyl,

P 및 P1은 각각 독립적으로 벤질, 벤질옥시카보닐, C1-6 알킬옥시카보닐, 벤조일 또는 아세틸이다.P and P 1 are each independently benzyl, benzyloxycarbonyl, C 1-6 alkyloxycarbonyl, benzoyl or acetyl.

상기 화학식 2의 구조를 갖는 중간체 또는 그와 유사한 구조를 갖는 화합물을 합성하는 방법이 여러 문헌에 소개되어 있다. 예를 들어, 워너 램버트 제약사에서 개발한 방법을 보면(참고문헌: US 5,155,251, US 4,970,313, US 5,103,024, WO 9,932,434, US 5,998,633, US 599,521, 한국특허 166,385 및 한국특허 302,431) 할로하이드록시에스테르 또는 활성화된 디하이드록시에스테르로부터 금속시안화물을 반응시킨 후 상기 화학식 2와 유사한 중간체를 합성하고; 일본의 다카사고(Takasago) 제약사에서 개발한 방법을 보면(참고문헌: US 5,599,954, US4,895,979, US 5,430,171 및 EP 0,573,184A1) 모노치환된 아미노 케토에스테르를 루테늄 촉매하에서 고압 반응시켜 하이드록시 케토에스테르를 얻은 후 아세테이트 에스테르의 에놀레이트를 축합 반응시킨 다음 루테늄 촉매하에 고압 수소화 반응시켜 상기 화학식 2와 유사한 중간체를 합성한다.Various methods for synthesizing an intermediate having a structure of Formula 2 or a compound having a structure similar thereto have been introduced in various documents. For example, a method developed by Warner Lambert Pharmaceuticals (Ref .: US 5,155,251, US 4,970,313, US 5,103,024, WO 9,932,434, US 5,998,633, US 599,521, Korean Patent 166,385, and Korean Patent 302,431) is known as halohydroxyester or activated. After reacting the metal cyanide from the dihydroxy ester, an intermediate similar to the above Chemical Formula 2 is synthesized; A method developed by Takasago Pharmaceutical Co., Ltd. in Japan (Ref .: US 5,599,954, US4,895,979, US 5,430,171 and EP 0,573,184A1) reacts hydroxy ketoesters by subjecting monosubstituted amino ketoesters to high pressure under a ruthenium catalyst. After obtaining the condensation reaction of the enolate of the acetate ester and then a high-pressure hydrogenation reaction under a ruthenium catalyst to synthesize an intermediate similar to the formula (2).

미국특허 제 5,599,954 호에 명시된 다카사고 방법을 자세히 분석해 보면 하기 반응식 1과 같다.A detailed analysis of the Takasago accident method described in US Pat. No. 5,599,954 is given in Scheme 1 below.

상기 식에서,Where

P는 벤질, 벤질옥시카보닐, C1-6 알킬옥시카보닐, 벤조일 또는 아세틸이고,P is benzyl, benzyloxycarbonyl, C 1-6 alkyloxycarbonyl, benzoyl or acetyl,

X는 알콜 보호기이며,X is an alcohol protecting group,

Y는 C1-6 알킬이다.Y is C 1-6 alkyl.

상기 반응식 1에서, 보호된 베타 알라닌의 산기를 활성화시킨 후 포타슘 말로네이트 에틸 에스테르를 반응시켜 82%의 수율로 베타케토에스테르를 제조하고, 루테늄 촉매하에서 고압 수소화 환원반응시켜 모노치환된 아미노 하이드록시 에스테르를 83% 수율로 제조하고, 이를 알코올 보호한 후 에스테르를 활성화시켜 반응시킴으로써 79%의 수율로 질소가 보호된 7-아미노-5-하이드록시-3-옥소 헵탄산 유도체를 제조하고, 이를 루테늄 촉매하에 고압 수소화 반응시켜 디하이드록시 화합물을 85% 수율로 얻는다. 이때, 아민이 벤질옥시카보닐로 치환된 화합물은 입체선택성이 83%로 낮고, 아민이 t-부톡시카보닐로 치환된 화합물은 99%의 높은 입체선택성을 나타낸다.In Scheme 1, the beta alanine acid group is activated to react with potassium malonate ethyl ester to produce beta ketoester in a yield of 82%, and a high pressure hydrogenation reduction reaction under a ruthenium catalyst mono-substituted amino hydroxy ester To prepare a 7-amino-5-hydroxy-3-oxo heptanoic acid derivative protected in nitrogen in 79% yield by preparing in 83% yield, by reacting it with alcohol and activating the ester to react with ruthenium catalyst Under high pressure hydrogenation to give the dihydroxy compound in 85% yield. In this case, the compound in which the amine is substituted with benzyloxycarbonyl has low stereoselectivity of 83%, and the compound in which the amine is substituted with t-butoxycarbonyl shows high stereoselectivity of 99%.

그러나, 이러한 다카사고 제약사의 합성방법은 P와 Y의 치환기 종류에 따라 입체선택성과 수율의 편차가 크고(예: P가 벤조일이고 Y가 에틸인 경우의 입체선택성 74%; P가 t-부톡시카보닐이고 Y가 에틸인 경우의 입체선택성 99%), 정제공정이 까다롭고 복잡하다는 단점을 갖는다.However, the synthesis method of Takasago Pharmaceutical Co., Ltd. has a large difference in stereoselectivity and yield depending on the substituents of P and Y (e.g., 74% of stereoselectivity when P is benzoyl and Y is ethyl; P is t-butoxy Stereoselectivity when carbonyl and Y is ethyl), and the purification process is difficult and complicated.

이에 본 발명자들은 종래기술이 가지는 문제점을 해결하고자 예의 연구한 결과, 아민기를 2중 보호하고 반응시킴으로써 아토르바스타틴의 핵심 중간체인 상기 화학식 2의 화합물을 종래의 방법에 비해 간편하고 고수율로 합성할 수 있음을 발견하고 본 발명을 완성하게 되었다. Accordingly, the present inventors have diligently studied to solve the problems of the prior art, and thus, the compound of Formula 2, which is a key intermediate of atorvastatin, may be synthesized in a simple and high yield as compared to the conventional method by double protecting and reacting an amine group. The present invention was completed.

따라서, 본 발명의 목적은 아토르바스타틴의 핵심 중간체인, 질소가 이중치환된 7-아미노-3,5-디하이드록시 헵탄산 유도체를 보다 고수율로 용이하게 제조할 수 있는 개선된 방법을 제공하는 것이다. Accordingly, it is an object of the present invention to provide an improved process for the easier production of nitrogen-substituted 7-amino-3,5-dihydroxy heptanoic acid derivatives, which are key intermediates of atorvastatin, in higher yields. .

상기 목적에 따라 본 발명에서는, In the present invention according to the above object,

(A) 하기 화학식 3의 화합물을 루테늄 촉매하에서 고압 수소화 반응시켜 하기 화학식 4의 화합물을 제조하고,(A) high pressure hydrogenation of a compound of Formula 3 under a ruthenium catalyst to prepare a compound of Formula 4,

(B) 화학식 4의 화합물을 하기 화학식 5의 화합물과 반응시켜 하기 화학식 6의 화합물을 제조하고,(B) reacting a compound of Formula 4 with a compound of Formula 5 to produce a compound of Formula 6,

(C) 화학식 6의 화합물을 루테늄 촉매하에서 고압 수소화 반응시키거나 또는 입체선택적으로 환원시키는 것을 포함하는, 하기 화학식 2의 디하이드록시 헵탄산 유도체의 제조방법을 제공한다:(C) a process for preparing a dihydroxy heptanoic acid derivative of formula (2) comprising the high pressure hydrogenation or stereoselective reduction of a compound of formula (6) under a ruthenium catalyst:

화학식 2Formula 2

상기 식에서, Where

R은 C1-6 알킬이고,R is C 1-6 alkyl,

P 및 P1은 각각 독립적으로 벤질, 벤질옥시카보닐, C1-6 알킬옥시카보닐, 벤조일 또는 아세틸이다.P and P 1 are each independently benzyl, benzyloxycarbonyl, C 1-6 alkyloxycarbonyl, benzoyl or acetyl.

이하 본 발명을 더욱 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in more detail.

본 발명에 따른 제조방법을 반응식으로 나타내면 하기 반응식 2와 같다: Representation of the preparation method according to the present invention is shown in Scheme 2:

상기 식에서, P, P1 및 R은 상기 정의한 바와 같다.Wherein P, P 1 and R are as defined above.

본 발명의 방법에 따른 단계 (A)에서, 화학식 3의 화합물을 루테늄 촉매하에 상온 내지 100℃의 온도 및 30 내지 100기압의 고압에서 수소화 반응시켜 화학식 4의 화합물을 제조한다. 이때, 반응은 유기용매 중에서 수행되는데, 유기용매로는 극성 또는 비극성 용매가 적당하며, 예를 들면 메탄올, 에탄올, 이소프로판올, t-부탄올, 염화메틸렌, 테트라히드로푸란, 아세토니트릴, t-부탄올, 디메틸포름아미드, 디에틸에테르, 에틸아세테이트, 아세톤, 클로로포름 등을 사용할 수 있다.In step (A) according to the process of the present invention, the compound of formula 3 is hydrogenated under a ruthenium catalyst at a temperature of room temperature to 100 ° C. and a high pressure of 30 to 100 atm to prepare a compound of formula 4. At this time, the reaction is carried out in an organic solvent, a polar or non-polar solvent is suitable as the organic solvent, for example methanol, ethanol, isopropanol, t-butanol, methylene chloride, tetrahydrofuran, acetonitrile, t-butanol, dimethyl Formamide, diethyl ether, ethyl acetate, acetone, chloroform and the like can be used.

본 발명에 사용되는 루테늄 촉매의 예로는 Ru2Cl4(BINAP)2NEt3, Ru2Cl4(Tol-BINAP)2NEt3, Ru2Cl2(BINAP)2, Ru2Br 2(BINAP)2, RuHCl(BINAP), Ru(BINAP)CO2(CH3)2 및 Ru(Tol-BINAP)CO2(CH3)2 등을 들 수 있으며(Tol = 톨루엔, BINAP = [2,2'-비스(디페닐포스피노)-1,1'-비나프틸]), 화학식 3의 화합물 1 당량에 대해 0.01 내지 0.002 당량의 촉매량으로 사용할 수 있다.Examples of ruthenium catalysts used in the present invention include Ru 2 Cl 4 (BINAP) 2 NEt 3 , Ru 2 Cl 4 (Tol-BINAP) 2 NEt 3 , Ru 2 Cl 2 (BINAP) 2 , Ru 2 Br 2 (BINAP) 2 , RuHCl (BINAP), Ru (BINAP) CO 2 (CH 3 ) 2 , Ru (Tol-BINAP) CO 2 (CH 3 ) 2 , and the like (Tol = toluene, BINAP = [2,2'-). Bis (diphenylphosphino) -1,1′-binafyl]), and a catalytic amount of 0.01 to 0.002 equivalents based on 1 equivalent of the compound of formula (3).

본 발명의 방법에 사용되는 화학식 3의 화합물은 공지된 방법에 의해 용이하게 제조할 수 있으며, 예를 들어, 하기 반응식 3에 나타낸 바와 같이, 벤질아민과 에틸아크릴레이트를 반응시켜 하기 화학식 7의 3-벤질 아미노 프로피온산 에틸 에스테르를 제조하고(단계 (i)), 이를 벤질 클로로퍼메이트 또는 디-t-부톡시 디카보네이트와 반응시켜 하기 화학식 8의 N,N-이중치환된 프로피온산 에틸 에스테르를 제조하고(단계 (ii)), 이를 수산화칼륨으로 가수분해하여 하기 화학식 9의 화합물을 제조한 다음(단계 (iii)) 이를 카보닐디이미다졸(CDI), 포타시움 말로닉 모노 에틸에스테르 및 MgCl2와 반응시킴으로써(단계 (iv)), 하기 화학식 3a의 화합물을 제조할 수 있다:The compound of formula 3 used in the method of the present invention can be easily prepared by a known method, for example, as shown in Scheme 3 below, by reacting benzylamine and ethyl acrylate 3 -Benzyl amino propionic acid ethyl ester is prepared (step (i)) and reacted with benzyl chloropermate or di-t-butoxy dicarbonate to prepare N, N-disubstituted propionic acid ethyl ester of (Step (ii)), hydrolyzing it with potassium hydroxide to prepare a compound of formula (9) (step (iii)) and then reacting it with carbonyldiimidazole (CDI), potassium malonic mono ethylester and MgCl 2 (Step (iv)), a compound of formula 3a may be prepared:

상기 식에서, Z는 C1-6 알킬이다.Wherein Z is C 1-6 alkyl.

본 발명의 방법에 따른 단계 (B)에서, 화학식 4의 화합물을 화학식 5의 화합물과 -60℃ 내지 상온에서 반응시켜 화학식 6의 화합물을 제조한다. 이때, 화학식 5의 화합물은, 화학식 4의 화합물 1.0 당량에 대하여 1.0 내지 2.0 당량의 양으로 사용할 수 있다.In step (B) according to the method of the present invention, a compound of formula 6 is prepared by reacting a compound of formula 4 with a compound of formula 5 at -60 ° C. In this case, the compound of Formula 5 may be used in an amount of 1.0 to 2.0 equivalents based on 1.0 equivalent of compound of Formula 4.

이어, 본 발명의 방법에 따른 단계 (C)에서, 화학식 6의 화합물을, 상기 단계 (A)와 동일한 조건으로 루테늄 촉매하에서 고압 수소화 반응시키거나, 또는 예를 들어 디에틸메톡시보란 및 소디움보로하이드라이드를 사용하여 -90 내지 -30℃에서 입체선택적으로 환원시켜 목적하는 화학식 3의 디하이드록시 헵탄산 유도체를 제조할 수 있다.Subsequently, in step (C) according to the process of the invention, the compound of formula 6 is subjected to a high pressure hydrogenation under a ruthenium catalyst under the same conditions as in step (A), or, for example, diethylmethoxyborane and sodiumbo The dihydroxy heptanoic acid derivative of the formula (3) may be prepared by stereoselectively reducing at -90 to -30 ° C using a low hydride.

이와 같이 질소를 이중 보호시킨 케토에스테르를 고압 수소화 반응시키는 본 발명의 방법에 의하면, 아토르바스타틴의 핵심 중간체인 상기 화학식 2의 질소가 이중치환된 7-아미노-3,5-디하이드록시 헵탄산 유도체를 종래의 방법에 비해 온화한 조건하에서 간편하게 고수율로 합성할 수 있다. As described above, according to the method of the present invention for high-pressure hydrogenation of a double-protected nitrogen ketoester, a nitrogen-substituted 7-amino-3,5-dihydroxy heptanoic acid derivative of Formula 2, which is a core intermediate of atorvastatin, is prepared. Compared with the conventional method, it can be synthesized easily in high yield under mild conditions.

이하, 본 발명을 실시예에 의거하여 보다 상세하게 설명하고자 하나, 이는 본 발명의 구성 및 작용의 이해를 돕기 위한 것일 뿐이며 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to Examples, which are only intended to assist in understanding the configuration and operation of the present invention, and the scope of the present invention is not limited to these Examples.

제조예 1: 3-벤질아미노-프로피온산 에틸 에스테르(화합물 (7))의 제조Preparation Example 1 Preparation of 3-benzylamino-propionic acid ethyl ester (Compound (7))

벤질아민 500g(4.67mol)을 반응기에 넣고 0℃에서 아크릴산 에틸 에스테르 235g(2.35mol)을 서서히 적가하였다. 실온까지 교반한 후 TLC로 반응의 완결됨을 확인하고 감압증류하여 무색 오일의 표제 화합물 443g(수율 91%)을 얻었다.500 g (4.67 mol) of benzylamine was added to the reactor, and 235 g (2.35 mol) of acrylic acid ethyl ester was slowly added dropwise at 0 ° C. After stirring to room temperature, the reaction was completed by TLC, and distilled under reduced pressure to obtain 443 g (yield 91%) of the title compound as a colorless oil.

1H NMR(CDCl3, ppm) : δ 7.32-7.19(m, 5H), 4.12(q, 2H), 3.78(s, 2H), 2.88(t, 2H), 2.51(s, 2H), 1.24(t, 3H). 1 H NMR (CDCl 3 , ppm): δ 7.32-7.19 (m, 5H), 4.12 (q, 2H), 3.78 (s, 2H), 2.88 (t, 2H), 2.51 (s, 2H), 1.24 ( t, 3H).

제조예 2: 3-(벤질,벤질옥시카보닐아미노)-프로피온산 에틸 에스테르(화합물 (8-1))의 제조Preparation Example 2 Preparation of 3- (benzyl, benzyloxycarbonylamino) -propionic acid ethyl ester (compound (8-1))

반응기에 3-벤질아미노-프로피온산 에틸 에스테르 10.8g(0.052mol), 트리에틸아민 6.8g(0.0676mol) 및 염화메틸렌 100mL를 넣고 0℃에서 20분간 교반한 후, 같은 온도에서 벤질클로로포메이트 11.4g(0.0676mol)을 천천히 적가하고 실온이 될 때까지 계속 교반하였다. 반응이 완료되면 고체는 여과하고 여액은 염화메틸렌과 물로 추출한 뒤 무수황산마그네슘으로 건조 및 감압농축하고, 실리카겔 컬럼 크로마토그래피(헥산/에틸아세테이트=4/1)로 분리정제하여 연한 노란색 오일의 표제 화합물 17.4g(수율 90%)를 얻었다.10.8 g (0.052 mol) of 3-benzylamino-propionic acid ethyl ester, 6.8 g (0.0676 mol) of triethylamine and 100 mL of methylene chloride were added to the reactor, and the mixture was stirred at 0 ° C. for 20 minutes, and then 11.4 g of benzylchloroformate at the same temperature. (0.0676 mol) was slowly added dropwise and stirring continued until room temperature was reached. After the reaction was completed, the solid was filtered, the filtrate was extracted with methylene chloride and water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give the title compound as a pale yellow oil. 17.4 g (90% yield) were obtained.

1H NMR(CDCl3, ppm) : δ 7.37-7.23(m, 10H), 5.16(s, 2H), 4.52(q, 2H), 4.07(s, 2H), 3.55(t, 2H), 2.45(t, 2H), 1.22(t, 3H). 1 H NMR (CDCl 3 , ppm): δ 7.37-7.23 (m, 10H), 5.16 (s, 2H), 4.52 (q, 2H), 4.07 (s, 2H), 3.55 (t, 2H), 2.45 ( t, 2H), 1.22 (t, 3H).

제조예 3: 3-(벤질,t-부톡시카보닐아미노)-프로피온산 에틸 에스테르(화합물 (8-2))의 제조Preparation Example 3 Preparation of 3- (benzyl, t-butoxycarbonylamino) -propionic acid ethyl ester (compound (8-2))

반응기에 3-벤질아미노-프로피온산 에틸 에스테르 10.8g(0.052mol)과 메탄올 120mL를 넣고 0℃에서 10-20분간 교반한 후, 같은 온도에서 디-t-부틸 디카보네이트 14.6g(0.0676mol)을 넣고 실온에서 하루동안 방치하였다. 반응완료 후 에틸아세테이트/물 용액으로 추출하고 유기층은 무수황산마그네슘으로 건조 및 감압농축한 뒤 실리카겔 컬럼 크로마토그래피(헥산/에틸아세테이트=4/1)로 분리정제하여 무색 오일의 표제 화합물 14.4g(수율 90%)을 얻었다.10.8 g (0.052 mol) of 3-benzylamino-propionic acid ethyl ester and 120 mL of methanol were added to the reactor, stirred at 0 ° C. for 10-20 minutes, and then 14.6 g (0.0676 mol) of di-t-butyl dicarbonate was added at the same temperature. It was left at room temperature for one day. After completion of the reaction, the mixture was extracted with ethyl acetate / water solution, the organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 14.4 g of the title compound as a colorless oil (yield). 90%).

1H NMR(CDCl3, ppm) : δ 7.35-7.24(m, 5H), 4.46(s, 2H), 3.52(t, 2H), 2.48(t, 2H), 1.46(s, 9H), 1.23(t, 3H). 1 H NMR (CDCl 3 , ppm): δ 7.35-7.24 (m, 5H), 4.46 (s, 2H), 3.52 (t, 2H), 2.48 (t, 2H), 1.46 (s, 9H), 1.23 ( t, 3H).

제조예 4: 3-(벤질,벤질옥시카보닐아미노)-프로피온산(화합물 (9-1))의 제조Preparation Example 4 Preparation of 3- (benzyl, benzyloxycarbonylamino) -propionic acid (Compound (9-1))

반응기에 3-벤질-벤질옥시카보닐아미노)-프로피온산 에틸 에스테르 5g(0.014mol), 포타슘하이드록사이드 4.1g(0.07mol) 및 에탄올 90mL를 넣고 약 30분동안 환류시켰다. 반응이 완료되면 고체는 여과하고 에탄올은 제거한 뒤 여액을 염화메틸렌과 1N 염산으로 추출하고, 유기층을 다시 물로 추출한 뒤 무수황산마그네슘으로 건조 및 감압농축하여 연한 노란색 오일의 표제 화합물 3.6g(수율 81%)을 얻었다. 5 g (0.014 mol) of 3-benzyl-benzyloxycarbonylamino) -propionic acid ethyl ester, 4.1 g (0.07 mol) of potassium hydroxide and 90 mL of ethanol were refluxed for about 30 minutes. After the reaction was completed, the solid was filtered, the ethanol was removed, the filtrate was extracted with methylene chloride and 1N hydrochloric acid, the organic layer was extracted with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3.6 g of the title compound as a pale yellow oil (yield 81%). )

1H NMR(CDCl3, ppm) : δ 9.17(br, 1H), 7.34-7.16(m, 10H), 5.16(s, 2H), 4.54(s, 2H), 3.59(t, 2H), 2.56(t, 2H). 1 H NMR (CDCl 3 , ppm): δ 9.17 (br, 1H), 7.34-7.16 (m, 10H), 5.16 (s, 2H), 4.54 (s, 2H), 3.59 (t, 2H), 2.56 ( t, 2H).

제조예 5: 3-(벤질,t-부톡시카보닐아미노)-프로피온산(화합물 (9-2))의 제조Preparation Example 5 Preparation of 3- (benzyl, t-butoxycarbonylamino) -propionic acid (Compound (9-2))

반응기에 3-(벤질-t-부톡시카보닐아미노)-프로피온산 에틸 에스테르 5g(0.016mol), 포타슘하이드록사이드 4.3g(0.08mol) 및 에탄올 90mL를 넣고 약 30분동안 환류시켰다. 반응이 완료되면 고체는 여과하고 에탄올은 제거한 뒤 여액을 염화메틸렌과 1N 염산으로 추출하고, 유기층을 다시 물로 추출한 뒤 무수황산마그네슘으로 건조 및 감압농축하여 연한 노란색 오일의 표제 화합물 3.26g(수율 73%)을 얻었다.5 g (0.016 mol) of 3- (benzyl-t-butoxycarbonylamino) -propionic acid ethyl ester, 4.3 g (0.08 mol) of potassium hydroxide and 90 mL of ethanol were refluxed for about 30 minutes. After completion of the reaction, the solid was filtered, the ethanol was removed, the filtrate was extracted with methylene chloride and 1N hydrochloric acid, the organic layer was extracted again with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3.26 g of a pale yellow oil (yield 73%). )

1H NMR(CDCl3, ppm) : δ 9.21(br, 1H), 7.34-7.20(m, 5H), 4.46(s, 2H), 3.47(t, 2H), 2.56(t, 2H), 1.47(s, 9H). 1 H NMR (CDCl 3 , ppm): δ 9.21 (br, 1H), 7.34-7.20 (m, 5H), 4.46 (s, 2H), 3.47 (t, 2H), 2.56 (t, 2H), 1.47 ( s, 9H).

실시예 1: 5-(벤질,t-부톡시카보닐아미노)-3-옥소-펜탄산 에틸 에스테르(화합물 (3-2))의 제조Example 1: Preparation of 5- (benzyl, t-butoxycarbonylamino) -3-oxo-pentanoic acid ethyl ester (Compound (3-2))

반응기에 3-(벤질-t-부톡시카보닐아미노)-프로피온산 2g(0.007mol)과 아세토니트릴 40mL를 넣고 질소하에서 15분간 교반한 후, 1,1'-카보닐디이미다졸 1.3g(0.0084mol)을 넣고 30분간 더 교반한 뒤 온도를 10℃로 낮추고 포타슘 말로네이트 에틸 에스테르 1.84g(0.0105mol)과 염화마그네슘 0.75g(0.0077mol)을 각각 첨가하고 1시간 교반하였다. 이어, 50℃에서 2시간 더 교반한 뒤 반응이 완료되면 실온으로 식히고 감압증류하여 용매를 제거한 후, 에틸아세테이트와 6N 염산용액으로 pH를 4로 조절하여 추출한 다음 유기층을 무수황산마그네슘으로 건조 및 감압농축하여 노란색 오일의 표제 화합물 2.1g(수율 85%)을 얻었다. 2 g (0.007 mol) of 3- (benzyl-t-butoxycarbonylamino) -propionic acid and 40 mL of acetonitrile were added to the reactor and stirred for 15 minutes under nitrogen, followed by 1.3 g (0.0084 mol) of 1,1'-carbonyldiimidazole. After stirring for 30 minutes, the temperature was lowered to 10 ° C., 1.84 g (0.0105 mol) of potassium malonate ethyl ester and 0.75 g (0.0077 mol) of magnesium chloride were added, followed by stirring for 1 hour. After stirring for 2 hours at 50 ° C., the reaction was completed, and the mixture was cooled to room temperature and distilled under reduced pressure to remove the solvent. The mixture was extracted with ethyl acetate and 6N hydrochloric acid, adjusted to pH 4, and the organic layer was dried over anhydrous magnesium sulfate and depressurized. Concentration gave 2.1 g (yield 85%) of the title compound as a yellow oil.

1H NMR(CDCl3, ppm) : δ 7.35-7.23(m, 5H), 4.44(s, 2H), 4.17(q, 2H), 3.45-3.36(m, 4H), 2.81-2.72(m, 2H), 1.45(s, 9H), 1.28(t, 3H) 1 H NMR (CDCl 3 , ppm): δ 7.35-7.23 (m, 5H), 4.44 (s, 2H), 4.17 (q, 2H), 3.45-3.36 (m, 4H), 2.81-2.72 (m, 2H ), 1.45 (s, 9H), 1.28 (t, 3H)

실시예 2: 5-(벤질,벤질옥시카보닐아미노)-3-옥소-펜탄산 에틸 에스테르(화합물 (3-1))의 제조Example 2: Preparation of 5- (benzyl, benzyloxycarbonylamino) -3-oxo-pentanoic acid ethyl ester (compound (3-1))

반응기에 3-(벤질,벤질옥시카보닐아미노)-프로피온산 2.8g(0.009mol)과 아세토니트릴 50mL를 넣고 질소하에서 15분간 교반한 후, 1,1'-카보닐디이미다졸 1.59g(0.0108mol)을 넣고 30분간 더 교반한 뒤 온도를 10℃로 낮추고 포타슘 말로네이트 에틸 에스테르 2.27g(0.0135mol)과 염화마그네슘 0.94g(0.0099mol)을 각각 첨가하고 1시간 교반하였다. 이어, 50℃로 2시간 더 교반한 뒤 반응이 완료되면 실온으로 식히고, 감압증류하여 용매를 제거한 후, 에틸아세테이트와 6N 염산용액으로 pH를 4로 조절하여 추출한 다음 유기층을 무수황산마그네슘으로 건조 및 감압농축하여 노란색 오일의 표제 화합물 2.93g(수율 85%)을 얻었다.2.8 g (0.009 mol) of 3- (benzyl, benzyloxycarbonylamino) -propionic acid and 50 mL of acetonitrile were added to the reactor and stirred for 15 minutes under nitrogen, followed by 1.59 g (0.0108 mol) of 1,1'-carbonyldiimidazole. After stirring for 30 minutes, the temperature was lowered to 10 ° C., and 2.27 g (0.0135 mol) of potassium malonate ethyl ester and 0.94 g (0.0099 mol) of magnesium chloride were added, followed by stirring for 1 hour. After stirring for 2 hours at 50 ° C., the reaction was completed and cooled to room temperature, distilled under reduced pressure to remove the solvent, and the mixture was extracted with ethyl acetate and 6N hydrochloric acid, adjusted to pH 4, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded 2.93 g (yield 85%) of the title compound as a yellow oil.

1H NMR(CDCl3, ppm) : δ 7.36-7.25(m, 5H), 5.16(s, 2H), 4.51(s, 2H), 4.14(q, 2H), 3.59-3.20(m, 4H), 2.84-2.70(m, 2H), 1.24(t, 3H). 1 H NMR (CDCl 3 , ppm): δ 7.36-7.25 (m, 5H), 5.16 (s, 2H), 4.51 (s, 2H), 4.14 (q, 2H), 3.59-3.20 (m, 4H), 2.84-2.70 (m, 2 H), 1.24 (t, 3 H).

실시예 3: 5-(벤질,벤질옥시카보닐아미노)-3(R)-하이드록시펜탄산 에틸 에스테르(화합물 (4-1))의 제조 Example 3: Preparation of 5- (benzyl, benzyloxycarbonylamino) -3 (R) -hydroxypentanoic acid ethyl ester (compound (4-1))

5-(벤질,벤질옥시카보닐아미노)-3-옥소-펜탄산 에틸 에스테르 5g(0.013mol)과 (R)-Ru2(BINAP)2Cl4??Et3N을 메탄올 50mL에 넣고, 고압 반응기에서 수소 100기압, 50∼60℃에서 12시간동안 반응시켰다. 반응 완료 후 감압증류로 메탄올을 제거하고 에틸아세테이트와 물로 추출한 뒤 유기층을 무수황산마그네슘으로 건조 및 농축하고, 실리카겔 컬럼 크로마토그래피(헥산/에틸아세테이트=2/1)로 분리정제하여 노란색오일 4.3g(수율 85%)을 얻었다(HPLC 조건 - 칼럼: 키랄(Chiral)-HAS(100×4.0), 이동상: 3% CH3CN in H2O (0.1m 포스페이트 완충액), 유속: 0.9mL/분, 검출: 254nm, 보유시간: 14.42분).5 g (0.013 mol) of 5- (benzyl, benzyloxycarbonylamino) -3-oxo-pentanoic acid ethyl ester and (R) -Ru 2 (BINAP) 2 Cl 4 ?? Et 3 N were added to 50 mL of methanol, In the reactor, the reaction was carried out at 100 atmospheres of hydrogen at 50 to 60 캜 for 12 hours. After completion of the reaction, methanol was removed by distillation under reduced pressure, extracted with ethyl acetate and water, the organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 4.3 g yellow oil. Yield 85%) (HPLC conditions-column: Chiral-HAS (100 × 4.0), mobile phase: 3% CH 3 CN in H 2 O (0.1 m phosphate buffer), flow rate: 0.9 mL / min, detection : 254 nm, retention time: 14.42 minutes).

1H NMR(CDCl3, ppm) : δ 7.36-7.18(m, 5H), 5.18(s, 2H), 4.58-4.37(m, 2H), 4.14(q, 2H), 4.09-3.90(m, 1H), 3.68(br, 1H), 3.39-3.01(m, 2H), 2.47-2.36(m, 2H), 1.79-1.45(m, 2H), 1.25(t, 3H). 1 H NMR (CDCl 3 , ppm): δ 7.36-7.18 (m, 5H), 5.18 (s, 2H), 4.58-4.37 (m, 2H), 4.14 (q, 2H), 4.09-3.90 (m, 1H ), 3.68 (br, 1H), 3.39-3.01 (m, 2H), 2.47-2.36 (m, 2H), 1.79-1.45 (m, 2H), 1.25 (t, 3H).

생성물을 (R)-(+)-α-메톡시-α-트리플루오로메틸페닐아세틸클로라이드와 반응시켜 표제 화합물을 합성하였다.The product was reacted with (R)-(+)-α-methoxy-α-trifluoromethylphenylacetylchloride to synthesize the title compound.

1H NMR(CDCl3, ppm) : δ 7.45-7.10(m, 15H), 5.25-5.40(m, 1H), 5.18(s, 2H), 4.50(q, 2H), 4.05(s, 2H), 3.50-3.15(m, 5H), 2.65-2.40(m, 2H), 2.00-1.80(m, 2H), 1.15(t, 3H). 1 H NMR (CDCl 3 , ppm): δ 7.45-7.10 (m, 15H), 5.25-5.40 (m, 1H), 5.18 (s, 2H), 4.50 (q, 2H), 4.05 (s, 2H), 3.50-3.15 (m, 5H), 2.65-2.40 (m, 2H), 2.00-1.80 (m, 2H), 1.15 (t, 3H).

19F NMR, 500MHz(CDCl3.ppm) : -71.986(s, 3F). 19 F NMR, 500 MHz (CDCl 3. ppm): -71.986 (s, 3F).

실시예 4: 5-(벤질,t-부톡시카보닐아미노)-3-하이드록시-펜탄산 에틸 에스테르(화합물 (4-2))의 제조Example 4: Preparation of 5- (benzyl, t-butoxycarbonylamino) -3-hydroxy-pentanoic acid ethyl ester (compound (4-2))

5-(벤질,t-부톡시카보닐아미노)-3-옥소-펜탄산 에틸 에스테르 5g(0.014mol)과 (R)-Ru2(BINAP)2Cl4??Et3N을 메탄올 50mL에 넣고 고압 반응기에서 수소 100기압, 50∼60℃에서 12시간동안 반응시켰다. 반응 완료 후 감압증류로 메탄올을 제거하고 에틸아세테이트와 물로 추출한 뒤 유기층을 무수황산마그네슘으로 건조 및 농축하고 실리카겔 컬럼 크로마토그래피(헥산/에틸아세테이트=2/1)로 분리정제하여 노란색오일의 표제 화합물 3.8g(수율 75%)을 얻었다.5 g (0.014 mol) of 5- (benzyl, t-butoxycarbonylamino) -3-oxo-pentanoic acid ethyl ester and (R) -Ru 2 (BINAP) 2 Cl 4 ?? Et 3 N were added to 50 mL of methanol. The reaction was carried out at 100 atmospheres of hydrogen at 50 to 60 ° C. for 12 hours in a high pressure reactor. After completion of the reaction, methanol was removed by distillation under reduced pressure, extracted with ethyl acetate and water, the organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give the title compound as a yellow oil 3.8 g (yield 75%) was obtained.

1H NMR(CDCl3, ppm) : δ 7.34-7.21(m, 5H), 4.58-4.20(m, 2H), 4.12(q, 2H), 4.02-3.92(m, 1H), 3.70(br, 1H), 3.27-2.98(m, 2H), 2.55-2.38(m, 2H), 1.80-1.48(m, 2H) 1.46(s, 9H), 1.26(t, 3H). 1 H NMR (CDCl 3 , ppm): δ 7.34-7.21 (m, 5H), 4.58-4.20 (m, 2H), 4.12 (q, 2H), 4.02-3.92 (m, 1H), 3.70 (br, 1H ), 3.27-2.98 (m, 2H), 2.55-2.38 (m, 2H), 1.80-1.48 (m, 2H) 1.46 (s, 9H), 1.26 (t, 3H).

실시예 5: 7-(벤질,벤질옥시카보닐아미노)-5-하이드록시-3-옥소-헵탄산 t-부틸 에스테르(화합물 (6-1))의 제조 Example 5: Preparation of 7- (benzyl, benzyloxycarbonylamino) -5-hydroxy-3-oxo-heptanoic acid t-butyl ester (Compound (6-1))

반응기에 무수 THF를 넣고 질소하에 온도를 -40℃로 낮추고, 2M 리튬 아세테이트 에놀레이트(LDA) 6.2mL(0.012mol)를 넣었다. 약 10분 뒤 t-부틸 아세테이트 1.44g(0.012mol)을 넣고 1시간동안 교반한 후, 5-(벤질,벤질옥시카보닐아미노)-3(R)-하이드록시-펜탄산 에틸 에스테르 1.2g(0.003mol)을 -40℃에서 천천히 적가하고 2시간동안 더 교반하였다. 반응이 완료되면 반응용액에 물을 첨가하여 교반한 후 톨루엔으로 추출하였다. 유기층을 포화염화나트륨 수용액으로 씻고 무수황산마그네슘으로 건조한 뒤 실리카겔 컬럼 크로마토그래피(헥산/에틸아세테이트=3/1)로 분리정제하여 노란색 오일의 표제 화합물 1.03g(수율 75%)을 얻었다.Anhydrous THF was added to the reactor, the temperature was lowered to -40 ° C under nitrogen, and 6.2 mL (0.012 mol) of 2M lithium acetate enoleate (LDA) was added thereto. After about 10 minutes, 1.44 g (0.012 mol) of t-butyl acetate was added thereto, followed by stirring for 1 hour, followed by 1.2 g of 5- (benzyl, benzyloxycarbonylamino) -3 (R) -hydroxy-pentanoic acid ethyl ester. 0.003 mol) was slowly added dropwise at -40 ° C and stirred for a further 2 hours. After the reaction was completed, water was added to the reaction solution, the mixture was stirred, and extracted with toluene. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 1.03 g (yield 75%) of the title compound as a yellow oil.

1H NMR(CDCl3, ppm) : δ 7.32-7.18(m, 10H), 5.18(s, 2H), 4.67-4.29(m, 2H), 4.02-3.96(m, 2H), 3.72(br, 1H), 3.42-3.09(m, 3H), 2.82-2.51(m, 2H), 1.72-1.57(m, 2H), 1.45(s, 9H). 1 H NMR (CDCl 3 , ppm): δ 7.32-7.18 (m, 10H), 5.18 (s, 2H), 4.67-4.29 (m, 2H), 4.02-3.96 (m, 2H), 3.72 (br, 1H ), 3.42-3.09 (m, 3H), 2.82-2.51 (m, 2H), 1.72-1.57 (m, 2H), 1.45 (s, 9H).

실시예 6: 7-(벤질,t-부톡시카보닐아미노)-5-하이드록시-3-옥소-헵탄산 t-부틸 에스테르(화합물 (6-2))의 제조 Example 6: Preparation of 7- (benzyl, t-butoxycarbonylamino) -5-hydroxy-3-oxo-heptanoic acid t-butyl ester (Compound (6-2))

반응기에 무수 THF를 넣고 질소하에 온도를 -40℃로 낮추고, 2M LDA 12.4mL(0.024mol)를 넣었다. 약 10분 뒤 t-부틸 아세테이트 2.88g(0.024mol)을 넣고 1시간동안 교반한 후, 5-(벤질,t-부톡시카보닐아미노)-3-하이드록시-펜탄산 에틸 에스테르 2g(0.006mol)을 -40℃에서 천천히 적가하고 2시간동안 더 교반하였다. 반응이 완료되면 반응용액에 물을 첨가하여 교반한 후 톨루엔으로 추출하였다. 유기층을 포화염화나트륨 수용액으로 씻고 무수황산마그네슘으로 건조한 뒤 실리카겔 컬럼 크로마토그래피(헥산/에틸아세테이트=3/1)로 분리정제하여 노란색 오일의 표제 화합물 1.82g(수율 72%)을 얻었다. Anhydrous THF was added to the reactor, the temperature was lowered to -40 ° C under nitrogen, and 12.4 mL (0.024 mol) of 2M LDA was added thereto. After about 10 minutes, 2.88 g (0.024 mol) of t-butyl acetate was added thereto, followed by stirring for 1 hour, followed by 2 g (0.006 mol of 5- (benzyl, t-butoxycarbonylamino) -3-hydroxy-pentanoic acid ethyl ester. ) Was slowly added dropwise at -40 ° C and stirred for a further 2 hours. After the reaction was completed, water was added to the reaction solution, the mixture was stirred, and extracted with toluene. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 1.82 g (yield 72%) of the title compound as a yellow oil.

1H NMR(CDCl3, ppm) : δ 7.34-7.20(m, 5H), 4.56-4.19(m, 2H), 4.03-3.95(m, 2H), 3.70(br, 1H), 3.41-3.07(m, 3H), 2.81-2.51(m, 2H), 1.79-1.17(m, 20H). 1 H NMR (CDCl 3 , ppm): δ 7.34-7.20 (m, 5H), 4.56-4.19 (m, 2H), 4.03-3.95 (m, 2H), 3.70 (br, 1H), 3.41-3.07 (m , 3H), 2.81-2.51 (m, 2H), 1.79-1.17 (m, 20H).

실시예 7: 7-(벤질,벤질옥시카보닐아미노)-3(R),5(R)-디하이드록시-헵탄산 t-부틸 에스테르(화합물 (2-1))의 제조 Example 7: Preparation of 7- (benzyl, benzyloxycarbonylamino) -3 (R), 5 (R) -dihydroxy-heptanoic acid t-butyl ester (Compound (2-1))

반응기에 7-(벤질,벤질옥시카보닐아미노)-5(R)-하이드록시-3-옥소-헵탄산 t-부틸 에스테르 2g(0.004mol)와 무수 THF/MeOH=20/5mL를 넣고 아르곤 가스 하에서 -70℃로 온도를 낮춘 후 디에틸메톡시보란 0.5g(0.005mol)을 천천히 적가하고 약 15분간 교반하였다. 같은 온도에서 소듐보로하이드라이드 0.19g(0.005mol)을 첨가하고 3-5시간 교반하였다. TLC로 반응완료가 확인되면 아세트산 1mL를 첨가하고 소듐바이카보네이트 수용액과 에틸아세테이트로 추출하고 유기층을 무수황산마그네슘으로 건조한 후 실리카겔 컬럼 크로마토그래피(헥산/에틸아세테이트=4/1)로 분리, 정제하여 표제 화합물 1.52g(수율 83%)를 얻었다(HPLC 조건 - 칼럼: 키랄(Chiral)-CBH(100×4.0), 이동상: 5% IPA in H2O (10mmol 포스페이트 완충액), 유속: 0.9mL/분, 검출: 254nm, 보유시간: 12.59분).2 g (0.004 mol) of 7- (benzyl, benzyloxycarbonylamino) -5 (R) -hydroxy-3-oxo-heptanoic acid t-butyl ester and THF / MeOH = 20/5 mL of anhydrous argon gas were added to the reactor. After lowering the temperature to −70 ° C., 0.5 g (0.005 mol) of diethylmethoxyborane was slowly added dropwise and stirred for about 15 minutes. At the same temperature, 0.19 g (0.005 mol) of sodium borohydride was added and stirred for 3-5 hours. When the reaction was confirmed by TLC, 1 mL of acetic acid was added, extracted with aqueous sodium bicarbonate solution and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, separated and purified by silica gel column chromatography (hexane / ethyl acetate = 4/1). 1.52 g (yield 83%) of compound was obtained (HPLC conditions-column: Chiral-CBH (100 x 4.0), mobile phase: 5% IPA in H 2 O (10 mmol phosphate buffer), flow rate: 0.9 mL / min, Detection: 254 nm, retention time: 12.59 min).

1H NMR(CDCl3, ppm) : δ 7.35-7.21(m, 10H), 5.19(s, 2H), 4.30-4.22(m, 3H), 4.20(br, 1H), 4.10-4.07(m, 1H), 3.90(br, 1H), 3.52-3.40(m, 2H), 3.27-3.14(m, 2H), 2.43-2.35(m, 2H), 1.70-1.47(m, 2H), 1.44(m, 9H). 1 H NMR (CDCl 3 , ppm): δ 7.35-7.21 (m, 10H), 5.19 (s, 2H), 4.30-4.22 (m, 3H), 4.20 (br, 1H), 4.10-4.07 (m, 1H ), 3.90 (br, 1H), 3.52-3.40 (m, 2H), 3.27-3.14 (m, 2H), 2.43-2.35 (m, 2H), 1.70-1.47 (m, 2H), 1.44 (m, 9H) ).

실시예 8: 7-(벤질,t-부톡시카보닐아미노)-3,5-디하이드록시-헵탄산 t-부틸 에스테르(화합물 (2-2))의 제조Example 8: Preparation of 7- (benzyl, t-butoxycarbonylamino) -3,5-dihydroxy-heptanoic acid t-butyl ester (Compound (2-2))

반응기에 7-(벤질,t-부톡시카보닐아미노)-5-하이드록시-3-옥소-헵탄산 t-부틸 에스테르 1.7g(0.004mol)와 무수 THF/MeOH=20/5mL를 넣고 아르곤가스 하에서 -70℃로 온도를 낮춘 후 디에틸메톡시보란 0.5g(0.005mol)을 천천히 적가하고 약 15분간 교반하였다. 같은 온도에서 소듐보로하이드라이드 0.19g(0.005mol)을 첨가하고 3-5시간 교반하였다. TLC로 반응완료가 확인되면 아세트산 1mL를 첨가하고 소듐비카보네이트 수용액과 에틸아세테이트로 추출하고 유기층을 무수황산마그네슘으로 건조한 후 실리카겔 컬럼 크로마토그래피(헥산/에틸아세테이트=4/1)로 분리, 정제하여 표제 화합물 1.3g(수율 77%)를 얻었다.1.7 g (0.004 mol) of 7- (benzyl, t-butoxycarbonylamino) -5-hydroxy-3-oxo-heptanoic acid t-butyl ester and anhydrous THF / MeOH = 20 / 5mL were added to the reactor, followed by argon gas. After lowering the temperature to −70 ° C., 0.5 g (0.005 mol) of diethylmethoxyborane was slowly added dropwise and stirred for about 15 minutes. At the same temperature, 0.19 g (0.005 mol) of sodium borohydride was added and stirred for 3-5 hours. After completion of the reaction by TLC, 1 mL of acetic acid was added, extracted with aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, separated and purified by silica gel column chromatography (hexane / ethyl acetate = 4/1), Compound 1.3g (yield 77%) was obtained.

1H NMR(CDCl3, ppm) : δ 7.34-7.20(m, 5H), 4.57-4.17(m, 3H), 4.29-4.21(m, 3H), 4.18(ba, 1H), 4.12-4.08(m, 1H), 3.91(ba, 1H), 3.51-3.38(m, 2H), 3.30-3.15(m, 2H), 2.45-2.34(m, 2H), 1.77-1.20)(m, 20H). 1 H NMR (CDCl 3 , ppm): δ 7.34-7.20 (m, 5H), 4.57-4.17 (m, 3H), 4.29-4.21 (m, 3H), 4.18 (ba, 1H), 4.12-4.08 (m , 1H), 3.91 (ba, 1H), 3.51-3.38 (m, 2H), 3.30-3.15 (m, 2H), 2.45-2.34 (m, 2H), 1.77-1.20) (m, 20H).

이와 같이 본 발명의 방법에 의하면, 아토르바스타틴의 핵심 중간체인 상기 화학식 2의 질소가 이중치환된 7-아미노-3,5-디하이드록시 헵탄산 유도체를 종래의 방법에 비해 온화한 조건하에서 간편하게 고수율로 합성할 수 있다. As described above, according to the method of the present invention, a 7-amino-3,5-dihydroxy heptanoic acid derivative of the nitrogen-substituted double-substituted 7-amino-3,5-dihydroxy heptanoic acid derivative, which is a core intermediate of atorvastatin, can be easily obtained in a high yield under the milder conditions than the conventional method. Can be synthesized.

Claims (4)

(A) 하기 화학식 3의 화합물을 루테늄 촉매하에서 고압 수소화 반응시켜 하기 화학식 4의 화합물을 제조하고,(A) high pressure hydrogenation of a compound of Formula 3 under a ruthenium catalyst to prepare a compound of Formula 4, (B) 화학식 4의 화합물을 하기 화학식 5의 화합물과 반응시켜 하기 화학식 6의 화합물을 제조하고,(B) reacting a compound of Formula 4 with a compound of Formula 5 to produce a compound of Formula 6, (C) 화학식 6의 화합물을 루테늄 촉매하에서 고압 수소화 반응시키거나 또는 입체선택적으로 환원시키는 것을 포함하는, (C) high pressure hydrogenation or stereoselectively reducing the compound of formula 6 under a ruthenium catalyst, 하기 화학식 2의 디하이드록시 헵탄산 유도체의 제조방법:To prepare a dihydroxy heptanoic acid derivative of formula (2): 화학식 2Formula 2 화학식 3Formula 3 화학식 4Formula 4 화학식 5Formula 5 화학식 6Formula 6 상기 식에서, Where R은 C1-6 알킬이고,R is C 1-6 alkyl, P 및 P1은 각각 독립적으로 벤질, 벤질옥시카보닐, C1-6 알킬옥시카보닐, 벤조일 또는 아세틸이다.P and P 1 are each independently benzyl, benzyloxycarbonyl, C 1-6 alkyloxycarbonyl, benzoyl or acetyl. 제 1 항에 있어서, The method of claim 1, 단계 (A) 및 (C)에서의 고압 수소화 반응이, 상온 내지 100℃의 온도 및 30 내지 100기압의 조건에서 메탄올, 에탄올, 이소프로판올, t-부탄올, 염화메틸렌, 테트라히드로푸란, 아세토니트릴, t-부탄올, 디메틸포름아미드, 디에틸에테르, 에틸아세테이트, 아세톤 및 클로로포름으로부터 선택된 유기용매 중에서 수행되는 것을 특징으로 하는 방법.The high pressure hydrogenation reaction in steps (A) and (C) is carried out at methanol, ethanol, isopropanol, t-butanol, methylene chloride, tetrahydrofuran, acetonitrile, t at a temperature of room temperature to 100 ° C and a pressure of 30 to 100 atm. A process characterized in that it is carried out in an organic solvent selected from butanol, dimethylformamide, diethyl ether, ethyl acetate, acetone and chloroform. 제 1 항에 있어서, The method of claim 1, 단계 (A) 및 (C)에 사용되는 루테늄 촉매가 Ru2Cl4(BINAP)2NEt3, Ru2Cl4(Tol-BINAP)2NEt3, Ru2Cl2(BINAP)2, Ru2Br 2(BINAP)2, RuHCl(BINAP), Ru(BINAP)CO2(CH3)2 및 Ru(Tol-BINAP)CO2(CH3)2 (Tol = 톨루엔, BINAP = [2,2'-비스(디페닐포스피노)-1,1'-비나프틸])로 이루어진 군으로부터 선택되는 것을 특징으로 하는 방법.The ruthenium catalyst used in steps (A) and (C) is Ru 2 Cl 4 (BINAP) 2 NEt 3 , Ru 2 Cl 4 (Tol-BINAP) 2 NEt 3 , Ru 2 Cl 2 (BINAP) 2 , Ru 2 Br 2 (BINAP) 2 , RuHCl (BINAP), Ru (BINAP) CO 2 (CH 3 ) 2 and Ru (Tol-BINAP) CO 2 (CH 3 ) 2 (Tol = toluene, BINAP = [2,2'-bis (Diphenylphosphino) -1,1'-binafyl]). 제 1 항에 있어서,The method of claim 1, 단계 (C)에서의 입체선택적 환원이, 디에틸메톡시보란 및 소디움보로하이드라이드를 사용하여 -90 내지 -30℃에서 수행되는 것을 특징으로 하는 방법.Wherein the stereoselective reduction in step (C) is carried out at -90 to -30 ° C using diethylmethoxyborane and sodium borohydride.
KR10-2003-0051360A 2003-07-25 2003-07-25 Process for the preparation of n,n-substituted-7-amino-3,5-dihydroxy heptanoic acid derivatives KR100532042B1 (en)

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