KR20010068029A - Lipase-mediated stereoslective hydrolysis of aziridine-2-carboxylates - Google Patents

Lipase-mediated stereoslective hydrolysis of aziridine-2-carboxylates Download PDF

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KR20010068029A
KR20010068029A KR1020010020162A KR20010020162A KR20010068029A KR 20010068029 A KR20010068029 A KR 20010068029A KR 1020010020162 A KR1020010020162 A KR 1020010020162A KR 20010020162 A KR20010020162 A KR 20010020162A KR 20010068029 A KR20010068029 A KR 20010068029A
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carboxylic acid
aziridine
phenylethyl
lipase
ester
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KR100483723B1 (en
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박재훈
이원구
하현준
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하현준
(주)켐바이오넥스
강석주
한솔케미언스 주식회사
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds

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Abstract

PURPOSE: A stereoselective hydrolyzing method of an aziridine-2-carboxylic acid ester by using a lipase is provided which respectively provides an optically active hydrolysate of an aziridine-2-carboxylic acid derivative and an optically active unreacted aziridine-2-carboxylic acid ester. CONSTITUTION: The aziridine-2-carboxylic acid ester and a racemic mixture or a partly stereoisomeric mixture, is hydrolyzed in a solvent of tertiary-butyl alcohol, which is saturated with amine, by using a lipase to respectively obtain an optically active hydrolysate of an aziridine-2-carboxylic acid amide and an optically active unreacted aziridine-2-carboxylic acid ester.

Description

리파아제를 이용한 아지리딘-2-카르복시산 에스테르의 입체선택적 가수분해 방법{LIPASE-MEDIATED STEREOSLECTIVE HYDROLYSIS OF AZIRIDINE-2-CARBOXYLATES}Stereoselective Hydrolysis Method of Aziridine-2-carboxylic Acid Ester Using Lipase {LIPASE-MEDIATED STEREOSLECTIVE HYDROLYSIS OF AZIRIDINE-2-CARBOXYLATES}

광학 활성 아지리딘은 그 자체로도 중요하지만 이로부터 간단한 변환을 통해 의약품을 비롯한 여러가지 정밀화학제품을 만드는데 유용한 화합물이다. (D. Tanner, Angew. Chem. Int. Ed. Engl. 1994, 33, 599-619). 이 중에서도 특히 아지리딘 -2-카르복시산 유도체는 여러 가지의 다양한 화합물로 전환이 가능한 키랄 출발물질이 될 수 있다(한국 특허 공개 10-2001-196호 및 10-2000-63913호). 그렇지만 광학활성의 아지리딘-2-카르복시산 유도체를 얻는 것은 간단하지 않다. 따라서 아지리딘을 만드는 기술은 오래 전부터 많이 진행되어 왔으며 그 제조방법은 몇 가지의 큰 범주로 나눌 수 있다. 가장 많이 알려진 방법으로는 아미노산의 하나인 광학활성 세린으로부터 제조하는 방법(J. E. Baldwin, et. al., Tetrahedron Lett., 1996, 37, 3761-3764), 이민으로부터 비대칭 아지리딘화 반응을 통해서 제조하는 방법(J. C. Antilla, et. al., J. Am. Chem. Soc., 1999, 121, 5099-5100), 알켄으로부터 비대칭 아지리딘화 반응을 통해서 제조하는 방법(K. B. Hansen, et. al., Angew. Chem. Int. Ed. Engl. 1995, 34, 676-679)이 있다. 세린으로부터 제조하는 방법은 세린의 천연 입체배열을 가진 아지리딘만을 제조할 수 있으며 다른 비대칭합성 방법으로 제조하는 방법은 많은 양을 반응시키기 어렵고 광학 순도가 99%이상을 가지지 못하는 한계가 있다. 이 밖에 (2R) 및 (2S)-아지리딘-2-카르복실산 (-)-멘톨 에스테르를 얻고, 얻어진 아지리딘을 분별결정으로 각각의 이성질체를 분리하는 방법 (한국 특허 공개 10-2001-195호) 도 개발 되었다. 한편 라세믹 혼합물에서 리파아제 효소를 이용하여 광학분리하는 방법(M. Martres. Tetrahedron Lett. 1994, 35, 8787)이 알려져 있기는 하지만, CCL로 불리는 리파아제를 부틸알코올에서 에스테르전환 방법으로 광학분리 해서 얻어지는 가장 좋은 거울상 선택성이 단지 76% ee 이며 또한 얻어지는 산물과 반응하지 않고 남아 있는 광학활성의 출발 물질을 관 크로마토그래피 등으로 분리를 해야하는 어려움이 있다. 또한 아지리딘의 질소에 작용기의 전환이 불가능한 일반 알킬만 일부 반응됨으로서 공업적 용도로의 발전은 불가능 하였다.Optically active aziridine is important in its own right, but a simple conversion from it is a useful compound for the manufacture of many fine chemicals, including pharmaceuticals. (D. Tanner, Angew. Chem. Int. Ed. Engl. 1994, 33, 599-619). Among these, the aziridine-2-carboxylic acid derivative may be a chiral starting material that can be converted into various various compounds (Korean Patent Publication Nos. 10-2001-196 and 10-2000-63913). However, obtaining an optically active aziridine-2-carboxylic acid derivative is not straightforward. Therefore, the technology of making aziridine has been advanced for a long time, and its manufacturing method can be divided into several large categories. The most well known method is a method for preparing from optically active serine, one of the amino acids (JE Baldwin, et. (JC Antilla, et. Al., J. Am. Chem. Soc., 1999, 121, 5099-5100), prepared from alkene via an asymmetric aziridination reaction (KB Hansen, et. Al., Angew. Chem Int. Ed. Engl. 1995, 34, 676-679). The method of preparing from serine can be prepared only aziridine having a natural three-dimensional array of serine, the method of preparing by other asymmetric synthesis method is difficult to react a large amount and there is a limit that the optical purity does not have more than 99%. In addition, a method of obtaining (2R) and (2S) -aziridine-2-carboxylic acid (-)-menthol ester and separating each isomer by fractional crystallization of the obtained aziridine (Korean Patent Publication No. 10-2001-195 Ho was also developed. On the other hand, optical separation using lipase enzyme from racemic mixture (M. Martres. Tetrahedron Lett. 1994, 35, 8787) is known, but the lipase called CCL is obtained by optical separation from butyl alcohol by ester conversion method. The best enantioselectivity is only 76% ee, and there is also the difficulty of separating the optically active starting material which does not react with the product obtained by column chromatography or the like. In addition, development of industrial applications was not possible due to the partial reaction of only general alkyl, which cannot convert functional groups to nitrogen of aziridine.

본 발명에서는 아지리딘의 질소에 작용기의 전환이 용이한 벤질이나 메틸벤질을 보유하고 있는 아지리딘의 각종 에스테르를 아민으로 포화된 t-부틸알코올의 용매에서 리파아제를 이용하여 가수분해 시킴으로서 광학활성 가수분해 산물인 아지리딘-2-카르복시산 아미드 및 반응하지 않고 남아 있는 광학활성 산물인 아지리딘-2-카르복시산 에스테르를 각각 얻을 수 있다.In the present invention, various active esters of aziridine having benzyl or methylbenzyl, which have easy conversion of functional groups in nitrogen of aziridine, are hydrolyzed by lipase in a solvent of t-butyl alcohol saturated with amine with optically active hydrolysis. The aziridine-2-carboxylic acid amide as a product and the aziridine-2-carboxylic acid ester as the optically active product which remain unreacted can be obtained, respectively.

본 발명은 아지리딘-2-카르복시산 에스테르로부터 리파아제를 이용한 광학분리를 통하여 광학활성의 가수분해산물인 아지리딘-2-카르복시산 유도체 및 반응하지 않고 남아 있는 광학활성 산물인 아지리딘-2-카르복시산 에스테르를 각각 얻는 방법이다. 이렇게 얻어지는 광학활성의 아지리딘-2-카르복시산 유도체는 여러 키랄 아민화합물 제조의 중요한 출발물질이 될 수 있다.The present invention relates to aziridine-2-carboxylic acid derivative which is an optically active hydrolyzate and aziridine-2-carboxylic acid ester which is left unreacted, through optical separation using a lipase from aziridine-2-carboxylic acid ester. How to get each. The optically active aziridine-2-carboxylic acid derivative thus obtained can be an important starting material for the preparation of various chiral amine compounds.

본 발명은 아지리딘-2-카르복시산 에스테르로부터 리파아제를 이용한 광학분리를 통하여 광학활성의 가수분해산물인 아지리딘-2-카르복시산 유도체 및 반응하지 않고 남아 있는 광학활성 산물인 아지리딘-2-카르복시산 에스테르를 각각 얻는 방법에 관한 것이다.The present invention relates to aziridine-2-carboxylic acid derivative which is an optically active hydrolyzate and aziridine-2-carboxylic acid ester which is left unreacted, through optical separation using a lipase from aziridine-2-carboxylic acid ester. It is about how to get each.

본 발명의 목적은 상기 구조식 (1)의 라세믹 혼합물 또는 부분입체이성질체 혼합물인 아지리딘-2-카르복시산 에스테르를 아민으로 포화된 알코올 용매에서 리파아제를 이용하여 가수분해시켜 구조식 (2)의 광학활성 가수분해산물 아지리딘-2-카르복시산 아미드 및 반응하지 않고 남아 있는 구조식 (3)의 광학활성 산물인 아지리딘-2-카르복시산 에스테르를 각각 얻는 방법에 관한 것이며, R1은 벤질, (R)-페닐에틸 또는 (S)-페닐에틸이고, R2는 메틸, 에틸, n-부틸을 포함한다.An object of the present invention is to hydrolyze aziridine-2-carboxylic acid ester, which is a racemic mixture or diastereomeric mixture of formula (1), using a lipase in an alcohol solvent saturated with an amine, to form an optically active valence of formula (2). The decomposition product aziridine-2-carboxylic acid amide and the method for obtaining aziridine-2-carboxylic acid ester which is an optically active product of the structural formula (3) which remain unreacted, respectively, R <1> is benzyl and (R) -phenylethyl Or (S) -phenylethyl and R 2 comprises methyl, ethyl, n-butyl.

우선 반응식 1에 나와 있는 출발 물질인 구조식 (1)의 N-벤질-아지리딘-2-카르복시산, N-[(S)-1-페닐에틸]-아지리딘-2-카르복시산 또는 N-[(S)-1-페닐에틸]-아지리딘-2-카르복시산의 메틸, 에틸, 또는 n-부틸 에스테르를 공지의 방법 (Y. Lim, Tetrhedron Letters, 1995, 36, 8431)으로 제조하고 이를 아민으로 포화된 t-부틸알코올 용매에서 리파아제와 반응시킨다.First, N-benzyl-aziridine-2-carboxylic acid, N-[(S) -1-phenylethyl] -aziridine-2-carboxylic acid or N-[(S Methyl, ethyl, or n-butyl ester of) -1-phenylethyl] -aziridine-2-carboxylic acid is prepared by known methods (Y. Lim, Tetrhedron Letters, 1995, 36, 8431) and saturated with amines. React with lipase in t-butyl alcohol solvent.

이때 한쪽 이성질체에 대해서만 선택적으로 가수분해 반응이 일어나서 에스테르기가 아미드로 전환된 구조식 (2)의 아지리딘-2-카르복시산 아미드(이때 R1은 N-벤질-, N-[(R)-1-페닐에틸]- 또는 N-[(R)-1-페닐에틸])가 물층에서 얻어지며, 유기층에서는 가수분해 반응을 하지않고 남아 있는 출발물질이 얻어지는데, 이 물질은 구조식 (3)의 아지리딘-2-카르복시산 에스테르로서 광학적으로 활성인 한가지 이성질체만을 포함하거나 최소한 한가지 이성질체가 많이 포함되어 있으며 수율이 좋다.At this time, aziridine-2-carboxylic acid amide of the formula (2) in which a hydrolysis reaction occurs selectively to only one isomer and ester group is converted to amide, wherein R 1 is N-benzyl-, N-[(R) -1-phenyl Ethyl]-or N-[(R) -1-phenylethyl]) is obtained in the water layer, and in the organic layer, the remaining starting material is obtained without hydrolysis reaction, which is aziridine- of formula (3). As a 2-carboxylic acid ester, it contains only one isomer which is optically active or contains at least one isomer in large number and yields are good.

한편 상기 구조식 (1)에서 R1은 N-벤질-, N-[(R)-1-페닐에틸]- 또는 N-[(S)-1-페닐에틸] 이며, R2는 메틸, 에틸 또는 n-부틸을 나타낸다. 반응중에 여러 가지의 리파아제에 대하여 약간 또는 다소의 가수분해 반응이 일어나며, 특히 이 반응에서 사용하는 리파아제로서칸디다 안타르티카(Candida antarctica)에서 유래된 리파아제를 사용함으로서 반응 산물은 (2S)의 입체화학을 가지며 반응하지 않고 남아 있는 출발물질은 (2R)의 입체화학을 가지게 된다. 이들의 입체선택성 정도는 98%이상 순수한 하나의 이성질체만을 가지거나 최소한 어느 하나의 이성질체가 대부분인 형태로 구조식 (2)의 화합물 및 구조식 (3)의 화합물을 얻는다.In the above formula (1), R 1 is N-benzyl-, N-[(R) -1-phenylethyl]-or N-[(S) -1-phenylethyl], and R 2 is methyl, ethyl or n-butyl is represented. A bit or some of the hydrolysis with respect to the number of the lipase takes place during the reaction, especially not Candida as a lipase used in this reaction tar urticae reaction product by using a lipase derived from (Candida antarctica) has the stereochemistry of (2S) The starting material which has and remains unreacted has a stereochemistry of (2R). Their degree of stereoselectivity is obtained in the form of having only one isomer pure of at least 98% or at least one isomer most of the compound of formula (2) and the compound of formula (3).

이하 본 발명을 하기 실시예에 의거하여 구체적으로 설명한다.Hereinafter, the present invention will be described in detail with reference to the following examples.

실시예 1Example 1

(2S)-N-벤질아지리딘-2-카르복시산 아미드 및 (2R)-N-벤질아지리딘-2-카르복시산 메틸에스테르의 제조Preparation of (2S) -N-benzylaziridine-2-carboxylic acid amide and (2R) -N-benzylaziridine-2-carboxylic acid methyl ester

라세믹 혼합체의 N-벤질아지리딘-2-카르복시산 메틸에스테르 1.2 g을 암모니아로 포화된 t-부틸알코올 100 mL에 용해시키고 35oC의 온도를 유지하면서칸디다 안타르티카(Candida antarctica)에서 유래된 리파아제 120 mg을 가한다. 반응 혼합물을 35oC의 온도에서 50분간 교반하면 반응의 ½만큼 진행된다. 반응을 마치고 이 반응 혼합물을 셀라이트 필터를 통과시켜 수득된 용액을 감압 증류 해서 모두 증발시킨다. 여기에 10 mL의 물을 가한 후, 생성된 수용액을 50 mL의 에틸아세테이트를 이용하여 2회로 나누어 추출한다. 추출한 유기용매를 증발시키면 반응하지 않고 남아있는 0.6 g의 (2R)-N-벤질아지리딘-2-카르복시산 메틸에스테르를 61% ee로 수득한다. 한편 수용액층을 완전하게 증발시키면 그곳에서 0.5 g의 (2S)-N-벤질아지리딘-2-카르복시산 아미드를 56% ee로 수득한다. (2R)-N-벤질아지리딘-2-카르복시산 메틸에스테르,1H NMR (200 MHz, CDCl3) δ7.34-7.27 (m, 5H), 3.70 (s, 3H), 3.52 (s, 2H), 2.25-2.18 (m, 2H), 1.74 (d,J= 6.6 Hz, H). (2S)-N-벤질아지리딘-2-카르복시산 아미드,1H NMR (200 MHz, CDCl3), δ7.29-7.16 (m, 5H), 4.78 (s, 3H), 3.44 (s, 2H), 2.18-2.04 (m, 2H), 1.54 (d,J= 6.6 Hz, 1H).1.2 g of N-benzylaziridine-2-carboxylic acid methyl ester of the racemic mixture were dissolved in 100 mL of t-butyl alcohol saturated with ammonia and derived from Candida antarctica while maintaining a temperature of 35 ° C. 120 mg of lipase is added. Stir the reaction mixture at a temperature of 35 ° C. for 50 minutes to proceed by ½ of the reaction. After the reaction, the reaction mixture was passed through a celite filter, and the resulting solution was evaporated under reduced pressure. 10 mL of water was added thereto, and the resulting aqueous solution was extracted twice using 50 mL of ethyl acetate. Evaporation of the extracted organic solvent yields 0.6 g of (2R) -N-benzylaziridine-2-carboxylic acid methyl ester remaining unreacted as 61% ee. Complete evaporation of the aqueous layer on the other hand yields 0.5 g of (2S) -N-benzylaziridine-2-carboxylic acid amide as 56% ee. (2R) -N-benzylaziridine-2-carboxylic acid methyl ester, 1 H NMR (200 MHz, CDCl 3 ) δ7.34-7.27 (m, 5H), 3.70 (s, 3H), 3.52 (s, 2H) , 2.25-2.18 (m, 2H), 1.74 (d, J = 6.6 Hz, H). (2S) -N-benzylaziridine-2-carboxylic acid amide, 1 H NMR (200 MHz, CDCl 3 ), δ 7.29-7.16 (m, 5H), 4.78 (s, 3H), 3.44 (s, 2H) , 2.18-2.04 (m, 2H), 1.54 (d, J = 6.6 Hz, 1H).

실시예 2Example 2

(2S)-N-벤질아지리딘-2-카르복시산 아미드 및 (2R)-N-벤질아지리딘-2-카르복시산 에틸에스테르의 제조Preparation of (2S) -N-benzylaziridine-2-carboxylic acid amide and (2R) -N-benzylaziridine-2-carboxylic acid ethyl ester

N-벤질아지리딘-2-카르복시산 메틸에스테르 대신 같은 당량의 N-벤질아지리딘-2-카르복시산 에틸에스테르를 사용하는 것을 제외하고는 실시예 1에서와 동일한 방법으로 반응 시킨다. 반응으로부터 (2S)-N-벤질아지리딘-2-카르복시산 아미드 및 반응않고 남아 있는 (2R)-N-벤질아지리딘-2-카르복시산 에틸에스테르를 얻는다. (2R)-N-벤질아지리딘-2-카르복시산 에틸에스테르의1H NMR (200 MHz, CDCl3) δ7.31-7.27 (m, 5H), 4.24-4.09 (m, 2H), 3.53 (s, 2H), 2.23-2.14 (m, 2H), 1.72 (d,J= 6.4 Hz, H), 1.28-1.20 (m, 3H).The reaction was carried out in the same manner as in Example 1 except for using the same equivalent of N-benzylaziridine-2-carboxylic acid ethyl ester instead of N-benzylaziridine-2-carboxylic acid methyl ester. From the reaction, (2S) -N-benzylaziridine-2-carboxylic acid amide and (2R) -N-benzylaziridine-2-carboxylic acid ethyl ester remaining unreacted are obtained. 1 H NMR (200 MHz, CDCl 3 ) of (2R) -N-benzylaziridine-2-carboxylic acid ethylester δ 7.31-7.27 (m, 5H), 4.24-4.09 (m, 2H), 3.53 (s, 2H), 2.23-2.14 (m, 2H), 1.72 (d, J = 6.4 Hz, H), 1.28-1.20 (m, 3H).

실시예 3Example 3

(2S)-N-벤질아지리딘-2-카르복시산 아미드 및 (2R)-N-벤질아지리딘-2-카르복시산 n-부틸에스테르의 제조Preparation of (2S) -N-benzylaziridine-2-carboxylic acid amide and (2R) -N-benzylaziridine-2-carboxylic acid n-butyl ester

N-벤질아지리딘-2-카르복시산 메틸에스테르 대신 같은 당량의 N-벤질아지리딘-2-카르복시산 n-부틸 에스테르를 사용하는 것을 제외하고는 실시예 1에서와 동일한 방법으로 반응 시킨다. 반응으로부터는 (2S)-N-벤질아지리딘-2-카르복시산 아미드 및 반응않고 남아 있는 (2R)-N-벤질아지리딘-2-카르복시산 n-부틸 에스테르를 얻는다. (2R)-N-벤질아지리딘-2-카르복시산 n-부틸에스테르의1H NMR (200 MHz, CDCl3) δ7.28-7.22 (m, 5H), 4.14-3.98 (m, 2H), 3.65-3.38 (m, 2H), 2.20-2.11 (m, 2H), 1.92-1.24 (m, 5H), 0.87 (t,J= 7.4 Hz, 3H).The reaction was carried out in the same manner as in Example 1 except for using the same equivalent of N-benzylaziridine-2-carboxylic acid n-butyl ester instead of N-benzylaziridine-2-carboxylic acid methyl ester. From the reaction, (2S) -N-benzylaziridine-2-carboxylic acid amide and (2R) -N-benzylaziridine-2-carboxylic acid n-butyl ester remaining unreacted are obtained. 1 H NMR of (2R) -N-benzylaziridine-2-carboxylic acid n-butylester (200 MHz, CDCl 3 ) δ 7.28-7.22 (m, 5H), 4.14-3.98 (m, 2H), 3.65- 3.38 (m, 2H), 2.20-2.11 (m, 2H), 1.92-1.24 (m, 5H), 0.87 (t, J = 7.4 Hz, 3H).

실시예 4Example 4

2(S)-N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 아미드 및 2(R)-N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 메틸에스테르의 제조2 (S) -N-[(R) -1-phenylethyl] aziridine-2-carboxylic acid amide and 2 (R) -N-[(R) -1-phenylethyl] aziridine-2-carboxylic acid methyl ester Manufacture

N-벤질아지리딘-2-카르복시산 메틸에스테르 대신 1.35 g의 54:45의 비율을 가지는 부분입체 입체이성질체의 혼합물인 (2S)-와 (2R)-N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 메틸 에스테르를 사용하는 것을 제외하고는 실시예 1에서와 동일한 방법으로 1시간 20분 동안 반응시키면 광학적으로 순수한 (2S)-N-[(R)-1-페닐에틸]-아지리딘-2-카르복시산 아미드 0.65 g 및 반응하지 않고 남아 있는 광학적으로 순수한 0.5 g의 (2R)-N-[(R)-1-페닐에틸]-아지리딘-2-카르복시산 메틸에스테를 각각 얻는다. (2R)-N-[(R)-1-페닐에틸]-아지리딘-2-카르복시산 메틸에스테의1H NMR (200 MHz, CDCl3), δ7.40-7.21 (m, 5H), 3.75 (s, 3H), 2.53 (q,J= 6.6 Hz, 1H), 2.23-2.04 (m, 2H), 1.60 (d,J= 6.6 Hz, 1H), 1.49 (d,J= 6.6 Hz, 1H). (2S)-N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 아미드의1H NMR (200 MHz, CDCl3), δ7.29-7.06 (m, 5H), 4.78 (s, 3H), 2.53 (q,J= 6.6 Hz, 1H), 2.01-1.71 (m, 3H), 1.28 (d,J= 6.6 Hz, 1H).(2S)-and (2R) -N-[(R) -1-phenylethyl], which is a mixture of diastereostereoisomers having a ratio of 54:45 of 1.35 g instead of N-benzylaziridine-2-carboxylic acid methyl ester The reaction was carried out for 1 hour and 20 minutes in the same manner as in Example 1 except for using aziridine-2-carboxylic acid methyl ester, and optically pure (2S) -N-[(R) -1-phenylethyl]- 0.65 g of aziridine-2-carboxylic acid amide and 0.5 g of (2R) -N-[(R) -1-phenylethyl] -aziridine-2-carboxylic acid methyl ester, which remain unreacted, are obtained, respectively. 1 H NMR of (2R) -N-[(R) -1-phenylethyl] -aziridine-2-carboxylic acid methyl ester (200 MHz, CDCl 3 ), δ 7.40-7.21 (m, 5H), 3.75 ( s, 3H), 2.53 (q, J = 6.6 Hz, 1H), 2.23-2.04 (m, 2H), 1.60 (d, J = 6.6 Hz, 1H), 1.49 (d, J = 6.6 Hz, 1H). 1 H NMR of (2S) -N-[(R) -1-phenylethyl] aziridine-2-carboxylic acid amide (200 MHz, CDCl 3 ), δ 7.29-7.06 (m, 5H), 4.78 (s, 3H), 2.53 (q, J = 6.6 Hz, 1H), 2.01-1.71 (m, 3H), 1.28 (d, J = 6.6 Hz, 1H).

실시예 5Example 5

2(S)-N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 아미드 및 2(R)-N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 에틸 에스테르의 제조2 (S) -N-[(R) -1-phenylethyl] aziridine-2-carboxylic acid amide and 2 (R) -N-[(R) -1-phenylethyl] aziridine-2-carboxylic acid ethyl ester Manufacture

N-벤질아지리딘-2-카르복시산 메틸에스테르 대신 N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 에틸에스테르를 사용하는 것을 제외하고는 실시예 1에서와 동일한 방법으로 반응 시킨다. 상기 반응으로부터 (2S)-N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 아미드 및 반응않고 남아 있는 (2R)-N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 에틸 에스테르를 얻는다. (2R)-N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 에틸에스테르의1H NMR (200 MHz, CDCl3), δ7.41-7.22(m, 5H), 431-4.10 (m, 2H), 2.55 (q,J= 6.6 Hz, 1H), 2.21-2.13 (m, 2H), 1.58 (d,J= 6.2 Hz, 1H), 1.45 (d,J= 6.6 Hz, 2H), 1.30 (t,J= 7.2 Hz, 3H).The reaction was carried out in the same manner as in Example 1, except that N-[(R) -1-phenylethyl] aziridine-2-carboxylic acid ethyl ester was used instead of N-benzylaziridine-2-carboxylic acid methyl ester. (2S) -N-[(R) -1-phenylethyl] aziridine-2-carboxylic acid amide and (2R) -N-[(R) -1-phenylethyl] aziridine- remaining unreacted from the reaction. Obtain 2-carboxylic acid ethyl ester. (2R) -N - [(R ) -1- phenylethyl] -2- aziridine 1 H NMR of the acid ethyl ester (200 MHz, CDCl 3), δ7.41-7.22 (m, 5H), 431-4.10 (m, 2H), 2.55 (q, J = 6.6 Hz, 1H), 2.21-2.13 (m, 2H), 1.58 (d, J = 6.2 Hz, 1H), 1.45 (d, J = 6.6 Hz, 2H) , 1.30 (t, J = 7.2 Hz, 3H).

실시예 6Example 6

2(S)-N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 아미드 및 2(R)-N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 n-부틸 에스테르의 제조2 (S) -N-[(R) -1-phenylethyl] aziridine-2-carboxylic acid amide and 2 (R) -N-[(R) -1-phenylethyl] aziridine-2-carboxylic acid n- Preparation of Butyl Ester

N-벤질아지리딘-2-카르복시산 메틸에스테르 대신 N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 n-부틸에스테르를 사용하는 것을 제외하고는 실시예 1에서와 같은 방법으로 반응 시킨다. 상기 반응으로부터 (2S)-N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 아미드 및 반응않고 남은 (2R)-N-[(R)-1-페닐에틸]아지리딘-2-카르복시산 n-부틸 에스테르를 얻는다. (2R)-N-[(R)-1-페닐에틸]-아지리딘-2-카르복시산 n-부틸에스테르의1H NMR (200 MHz, CDCl3), δ7.43-7.22(m, 5H), 4.28-4.07 (m, 2H), 2.63 (q,J= 6.6 Hz, 1H), 2.54-2.16 (m, 4H), 1.73- 1.17 (m, 7H), 0.99 (t,J= 7.4 Hz, 3H).The reaction was carried out in the same manner as in Example 1, except that N-[(R) -1-phenylethyl] aziridine-2-carboxylic acid n-butylester was used instead of N-benzylaziridine-2-carboxylic acid methyl ester. Let's do it. (2S) -N-[(R) -1-phenylethyl] aziridine-2-carboxylic acid amide and (2R) -N-[(R) -1-phenylethyl] aziridine-2 remaining unreacted from the reaction. -Carboxylic acid n-butyl ester is obtained. 1 H NMR of (2R) -N-[(R) -1-phenylethyl] -aziridine-2-carboxylic acid n-butylester (200 MHz, CDCl 3 ), δ 7.43-7.22 (m, 5H), 4.28-4.07 (m, 2H), 2.63 (q, J = 6.6 Hz, 1H), 2.54-2.16 (m, 4H), 1.73-1.17 (m, 7H), 0.99 (t, J = 7.4 Hz, 3H) .

실시예 7Example 7

2(S)-N-[(S)-1-페닐에틸]아지리딘-2-카르복시산 아미드 및 2(R)-N-[(S)-1-페닐에틸]아지리딘-2-카르복시산 메틸에스테르의 제조2 (S) -N-[(S) -1-phenylethyl] aziridine-2-carboxylic acid amide and 2 (R) -N-[(S) -1-phenylethyl] aziridine-2-carboxylic acid methyl ester Manufacture

실시예 1의 N-벤질아지리딘-2-카르복시산 메틸에스테르 대신 1.35 g의 45:55의 비율을 가지는 부분입체 입체이성질체의 혼합물인 (2S)-와 (2R)-N-[(S)-1-페닐에틸]아지리딘-2-카르복시산 메틸에스테르를 사용하는 것을 제외하고는 실실예 1에서와 동일한 방법으로 21시간 동안 반응시켜 광학적으로 순수한 (2S)-N-[(S)-1-페닐에틸]아지리딘-2-카르복시산 아미드 0.5 g과 반응하지 않고 남아 있는 광학적으로 순수한 0.6 g의 (2R)-N-[(S)-1-페닐에틸]아지리딘-2-카르복시산 메틸에스테를 각각 얻는다. (2R)-N-[(S)-1-페닐에틸]아지리딘-2-카르복시산 메틸에스테르의1H NMR (200 MHz, CDCl3), δ7.32-7.16 (m, 5H), 3.61 (s, 3H), 2.45 (q,J= 7.0 Hz, 1H), 2.30 (d,J= 2.88, 1H), 2.06-1.98 (m, 1H), 1.54 (d,J= 6.6 Hz, 1H), 1.41 (d,J= 6.6 Hz, 3H). (2S)-N-[(S)-1-페닐에틸]아지리딘-2-카르복시산 아미드의1H NMR (200 MHz, CDCl3), δ7.29-7.06 (m, 5H), 4.78 (s, 3H), 2.53 (q,J= 6.6 Hz, 1H), 2.12-1.71 (m, 3H), 1.28 (d,J= 6.6 Hz, 1H).(2S)-and (2R) -N-[(S) -1, which is a mixture of diastereostereoisomers having a ratio of 1.35 g of 45:55 instead of the N-benzylaziridine-2-carboxylic acid methyl ester of Example 1 Except for using -phenylethyl] aziridine-2-carboxylic acid methyl ester in the same manner as in Example 1 was reacted for 21 hours to optically pure (2S) -N-[(S) -1-phenylethyl ] Optically pure 0.6 g of (2R) -N-[(S) -1-phenylethyl] aziridine-2-carboxylic acid methyl ester, each remaining without reacting with 0.5 g of aziridine-2-carboxylic acid amide, is obtained. 1 H NMR of (2R) -N-[(S) -1-phenylethyl] aziridine-2-carboxylic acid methyl ester (200 MHz, CDCl 3 ), δ 7.32-7.16 (m, 5H), 3.61 (s , 3H), 2.45 (q, J = 7.0 Hz, 1H), 2.30 (d, J = 2.88, 1H), 2.06-1.98 (m, 1H), 1.54 (d, J = 6.6 Hz, 1H), 1.41 ( d, J = 6.6 Hz, 3H). 1 H NMR of (2S) -N-[(S) -1-phenylethyl] aziridine-2-carboxylic acid amide (200 MHz, CDCl 3 ), δ 7.29-7.06 (m, 5H), 4.78 (s, 3H), 2.53 (q, J = 6.6 Hz, 1H), 2.12-1.71 (m, 3H), 1.28 (d, J = 6.6 Hz, 1H).

실시예 8Example 8

2(S)-N-[(S)-1-페닐에틸]아지리딘-2-카르복시산 아미드 및 2(R)-N-[(S)-1-페닐에틸]아지리딘-2-카르복시산 에틸에스테르의 제조2 (S) -N-[(S) -1-phenylethyl] aziridine-2-carboxylic acid amide and 2 (R) -N-[(S) -1-phenylethyl] aziridine-2-carboxylic acid ethyl ester Manufacture

N-벤질아지리딘-2-카르복시산 메틸에스테르 대신 N-[(S)-1-페닐에틸]아지리딘-2-카르복시산 에틸에스테르를 사용하는 것을 제외하고는 실시예 1에서와 같은 방법으로 반응시킨다. 상기 반응으로부터 (2S)-N-[(S)-1-페닐에틸]아지리딘-2-카르복시산 아미드 및 반응않고 남아 있는 (2R)-N-[(S)-1-페닐에틸]아지리딘-2-카르복시산 에틸 에스테르를 얻는다. (2R)-N-[(S)-1-페닐에틸]아지리딘-2-카르복시산 에틸 에스테르의1H NMR (200 MHz, CDCl3), δ7.36-7.27 (m, 5H), 4.12 (q,J= 7.0 Hz, 2H), 2.58 (q,J= 6.6 Hz, 1H), 2.35-2.04 (m, 2H), 1.77 (d,J= 6.8 Hz, 1H), 1.49 (d,J= 6.6 Hz, 3H), 1.19 (t,J= 7.0 Hz, 3H).The reaction was carried out in the same manner as in Example 1, except that N-[(S) -1-phenylethyl] aziridine-2-carboxylic acid ethyl ester was used instead of N-benzylaziridine-2-carboxylic acid methyl ester. (2S) -N-[(S) -1-phenylethyl] aziridine-2-carboxylic acid amide and (2R) -N-[(S) -1-phenylethyl] aziridine- remaining unreacted from the reaction. Obtain 2-carboxylic acid ethyl ester. 1 H NMR of (2R) -N-[(S) -1-phenylethyl] aziridine-2-carboxylic acid ethyl ester, 200 MHz, CDCl 3 , δ 7.36-7.27 (m, 5H), 4.12 (q , J = 7.0 Hz, 2H), 2.58 (q, J = 6.6 Hz, 1H), 2.35-2.04 (m, 2H), 1.77 (d, J = 6.8 Hz, 1H), 1.49 (d, J = 6.6 Hz , 3H), 1.19 (t, J = 7.0 Hz, 3H).

본 발명으로 N이 다양하게 치환된 아지리딘-2-카르복시산 에스테르 입체이성질체의 라세믹 혼합물 또는 N이 다양하게 치환된 아지리딘-2-카르복시산 에스테르 부분입체이성질체로부터 광학적으로 순수한 다량의 아지리딘-2-카르복시산 알킬 에스테르 및 아지리딘-2-카르복시산 아미드를 용이하게 얻을 수 있다. 리파아제를 이용한 광학분리를 통하여 아지리딘-2-카르복시산 에스테르를 아민으로 포화된 알코올 용매에서 가수분해 반응을 실시함으로서 광학활성의 가수분해산물로 아지리딘-2-카르복시산 아미드 및 반응하지 않고 남아 있는 광학활성 아지리딘-2-카르복시산 에스테르를 각각 물층과 유기층에서 얻을 수 있다. 이렇게 얻어지는 아지리딘은 의약품등을 비롯하여 여러 정밀화학제품의 중간체로 활용할 수 있다.In the present invention, a large amount of optically pure aziridine-2- from racemic mixtures of aziridine-2-carboxylic acid ester stereoisomers with variously substituted N or aziridine-2-carboxylic acid ester diastereomers with variously substituted N Carboxylic acid alkyl esters and aziridine-2-carboxylic acid amides can be readily obtained. The hydrolysis reaction of aziridine-2-carboxylic acid ester in an amine-saturated alcohol solvent through optical separation using lipase was performed to aziridine-2-carboxylic acid amide as an optically active hydrolyzate and to remain unreacted optical activity. Aziridine-2-carboxylic acid ester can be obtained in the water layer and the organic layer, respectively. The aziridine obtained in this way can be used as an intermediate of various fine chemical products including pharmaceuticals.

Claims (1)

구조식 (1)의 라세믹 혼합물 또는 부분입체이성질체 혼합물인 아지리딘-2-카르복시산 에스테르를 아민으로 포화된 t-부틸알코올의 용매에서 리파아제를 이용하여 가수분해 시켜 구조식 (2)의 광학활성 가수분해산물인 아지리딘-2-카르복시산 아미드 및 반응하지 않고 남아있는 구조식 (3)의 광학활성 아지리딘-2-카르복시산 에스테르를 각각 수득하는 방법:The aziridine-2-carboxylic acid ester, the racemic mixture or diastereomeric mixture of formula (1), is hydrolyzed with lipase in a solvent of t-butyl alcohol saturated with an amine, and the optically active hydrolyzate of formula (2) Process for obtaining phosphorus aziridine-2-carboxylic acid amide and optically active aziridine-2-carboxylic acid ester of structure (3) remaining unreacted, respectively: 구조식 (1)에서 R1은 N-벤질-, N-[(R)-1-페닐에틸]- 또는 N-[(S)-1-페닐에틸]이며 R2는 메틸, 에틸 또는 n-부틸을 나타낸다.In formula (1), R 1 is N-benzyl-, N-[(R) -1-phenylethyl]-or N-[(S) -1-phenylethyl] and R 2 is methyl, ethyl or n-butyl Indicates.
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KR20030063813A (en) * 2002-01-24 2003-07-31 주식회사 이매진 An intermediate of an optically active diarylalanine, its derivatives and process for prepararing the same

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030063813A (en) * 2002-01-24 2003-07-31 주식회사 이매진 An intermediate of an optically active diarylalanine, its derivatives and process for prepararing the same

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