KR20030063813A - An intermediate of an optically active diarylalanine, its derivatives and process for prepararing the same - Google Patents
An intermediate of an optically active diarylalanine, its derivatives and process for prepararing the same Download PDFInfo
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- KR20030063813A KR20030063813A KR1020020004144A KR20020004144A KR20030063813A KR 20030063813 A KR20030063813 A KR 20030063813A KR 1020020004144 A KR1020020004144 A KR 1020020004144A KR 20020004144 A KR20020004144 A KR 20020004144A KR 20030063813 A KR20030063813 A KR 20030063813A
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- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen 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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
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- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen 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
- C07D203/16—Heterocyclic compounds containing three-membered rings with one nitrogen 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 acylated ring nitrogen atoms
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Abstract
Description
페닐알라닌 보다 페닐 그룹을 하나 더 가지고 있는 다이페닐알라닌은 비천연 아미노산으로서 펩타이드를 응용한 의약품 후보가 될 수 있는 여러 가지의 활성물질의 중요한 부분을 차지하고 있다 (국제특허출원 WO 9825965호 및 국제특허출원 WO 2000039124호).Diphenylalanine, which has one more phenyl group than phenylalanine, is an unnatural amino acid and occupies an important part of various active substances which may be candidates for pharmaceutical applications. (International patent application WO 9825965 and international patent application WO 2000039124 number).
이러한 비천연 아미노산의 일종인 다이페닐알라닌을 입체선택적으로 만들기 위한 노력이 많이 있어 왔다. 다른 아미노산들과 마찬가지로 라세미체를 광학분리하는 방법도 알려졌다 (미국 특허 제5,198,548호). 또 다른 방법은 이미 광학활성물질이 가지고 있는 비대칭 탄소의 입체배열을 그대로 이용하여 몇 가지의 화학적 반응을 거쳐 만드는 방법인데 이들은 한결같이 세린을 그 출발물질로 삼고 있다. 세린을 이용하더라도 세린으로부터 4-옥사졸린카르복실레이트를 만들어 이를 이용하거나 (A. M. P. Koskinen, et. al. Tetrahedron Lett. 1995, 31, 5619) 혹은 옥사졸리딘-2-온-4-카르복실에스테르를 만들어 이를 이용하는 방법(미국 특허제5,623,087호)이 있다. 이들 경우 모두는 천연의 세린을 이용하는 관계로 천연의 세린이 가지는 입체배열을 그대로 가지게 됨으로써 (D)-다이페닐알라닌을 만드는 데에는 적합할 수 있다. 그렇지만 이 방법들은 천연의 세린이 가지는 입체배열을 이용하는 관계로 (D)-다이페닐알라닌을 만드는 데에만 국한되고 (L)-다이페닐알라닌을 만드는 데에는 부적절하며 또한 세린으로부터 옥사졸린이나 옥사졸리딘온의 고리를 만들어야하는 번거로움이 있다.There have been many efforts to stereoselectively make diphenylalanine, which is a kind of such unnatural amino acid. Like other amino acids, a method of optically separating racemates is also known (US Pat. No. 5,198,548). Another method is to make several chemical reactions using the stereosymmetrical arrangement of the asymmetric carbon already present in the optically active material, and they all use serine as its starting material. Even with serine, 4-oxazoline carboxylates can be prepared from serine (AMP Koskinen, et. Al. Tetrahedron Lett. 1995, 31, 5619) or oxazolidin-2-one-4-carboxyesters. And how to use it (US Pat. No. 5,623,087). All of these cases may be suitable for making (D) -diphenylalanine by having a three-dimensional arrangement of natural serine as it is by using natural serine. However, these methods are limited to the production of (D) -diphenylalanine due to the use of the three-dimensional arrangement of natural serine and are inadequate for the production of (L) -diphenylalanine, and they also remove the ring of oxazoline or oxazolidinone from serine. There is a hassle to create.
본 발명은 광학적으로 활성인 아지리딘-2-카르복시산 에스테르 (한국특허출원 제10-2000-0046387호)에 두 몰의 아릴마그네슘할라이드를 첨가하고, 산소친핵체로 아지리딘고리를 열고 가수분해하여, 삼차알코올을 환원하여 다이아릴알라닌올을 만들고 이어 이를 산화함으로서 광학적으로 활성인 다이아릴알라닌을 제조하는 방법에 관한 것이다. 특히 본 발명에서는 광학적으로 활성인 아지리딘-2-카르복시산 에스테르의 입체화학을 적절하게 선택함으로서 (D)-다이아릴알라닌 뿐만 아니라 (L)-다이아릴알라닌도 동일한 방법으로 만들 수 있다. 즉 아지리딘-2-카르복시산 에스테르의 2번위치 입체화학이 (S)로부터 시작하면 (D)-다이페닐알라닌을 얻으며 (R)로부터 시작하면 (L)-다이페닐알라닌을 얻게된다.The present invention adds two moles of arylmagnesium halide to the optically active aziridine-2-carboxylic acid ester (Korean Patent Application No. 10-2000-0046387), and opens the aziridine ring with an oxygen nucleophile to hydrolyze the tertiary The present invention relates to a method for preparing optically active diarylalanine by reducing alcohol to make diarylalanineol and then oxidizing it. In particular, in the present invention, by appropriately selecting the stereochemistry of the optically active aziridine-2-carboxylic acid ester, not only (D) -diarylalanine but also (L) -diarylalanine can be made by the same method. Namely, if the 2-position stereochemistry of the aziridine-2-carboxylic acid ester starts from (S), (D) -diphenylalanine is obtained, and from (R), (L) -diphenylalanine is obtained.
본 발명은 생리활성 물질의 중요한 뼈대를 이루는 비천연 아미노산의 일종인 다이아릴알라닌, 보다 구체적으로 다이페닐알라닌 및 그 유도체를 광학적으로 활성인 아지리딘-2-카르복시산 에스테르로부터 입체선택적으로 만드는 것이다. 종래의 방법은 이소세린을 이용하는 것이었으나, 본 발명은 기존의 이소세린을 이용하는방법이 아니라 아지리딘-2-카르복시산 에스테르를 이용한다. 따라서, 이소세린을 보호기로 보호해야하는 문제가 없을 뿐만 아니라 광학적으로 활성인 아지리딘-2-카르복시산 에스테르의 입체화학을 적절하게 선택함으로서 (D)-다이아릴알라닌, 보다 구체적으로 (D)-다이페닐알라닌 뿐만 아니라 (L)-다이아릴알라닌, 보다 구체적으로 (L)-다이페닐알라닌도 동일한 방법으로 만들 수 있다는 것이다.DETAILED DESCRIPTION OF THE INVENTION The present invention is to stereoselectively make diarylalanine, a type of non-natural amino acid, more particularly diphenylalanine and its derivatives, from optically active aziridine-2-carboxylic acid esters, which form an important backbone of bioactive substances. The conventional method was to use isoserine, but the present invention uses aziridine-2-carboxylic acid ester, not the conventional method using isoserine. Thus, there is no problem of protecting isocerine with a protecting group, and by appropriately selecting the stereochemistry of the optically active aziridine-2-carboxylic acid ester, (D) -diarylalanine, more specifically (D) -diphenylalanine In addition, (L)-diarylalanine, more specifically (L)-diphenylalanine can be made in the same way.
본 발명의 목적은 상기 구조식 (1)의 아지리딘-2-카르복시산 에스테르에 아릴마그네슘할라이드, 보다 구체적으로 아릴마그네슘클로라이드 또는 아릴마그네슘브로마이드를 첨가반응시켜 구조식 (2)를 얻고 이어 아지리딘 고리를 공지의 산소 친핵체, 예컨대 아세트산 등으로 열어 구조식 (3)의 화합물을 얻고서 삼차알코올을 환원하여 구조식 (4)의 다이아릴알라닌올을 제조하고, 일차 알코올의 산화반응에는 참여하지 않고 최종 산물이 가질 보호기 R3을 갖추게 한 후 알코올을 더 산화시켜 구조식 (5)의 다이아릴알라닌을 제조하는 방법이다. 또한, 상기 방법 중 중간체로 이용되는 신규한 물질인 구조식 (2)의 아지리딘다이아릴메탄올 및 구조식 (3)의 2-아미노-1,1,-다이아릴-1,3-다이하이드록시프로판에 관한 것이다.An object of the present invention is to add the aryl magnesium halide, more specifically aryl magnesium chloride or aryl magnesium bromide to the aziridine-2-carboxylic acid ester of the above formula (1) to obtain the formula (2) and then the aziridine ring Opened with an oxygen nucleophile, such as acetic acid, to obtain a compound of formula (3) and to reduce tertiary alcohol to prepare a diarylalanineol of formula (4), which does not participate in the oxidation reaction of the primary alcohol, the protecting group R which the final product will have After preparing 3 , alcohol is further oxidized to produce diarylalanine of formula (5). In addition, aziridine diarylmethanol of formula (2) and 2-amino-1,1, -diaryl-1,3-dihydroxypropane of formula (3), which are novel materials used as intermediates in the above method, It is about.
구조식 (1) 구조식 (2) 구조식(3) 구조식(4) 구조식(5)Structural Formula (1) Structural Formula (2) Structural Formula (3) Structural Formula (4) Structural Formula (5)
이 때, R1은 수소; 알킬; 시클로알킬; 페닐; 4-클로로페닐; 4-메톡시페닐;s-트리아지닐 또는 피리디닐 아실; 벤질; 히드록시, 알콕시, 디알킬아미노, 페닐, 4-클로로페닐, 4-메톡시페닐에 의해 치환된 탄화수소 잔기; 2,4-메톡시페닐; (R)-페닐에틸, 또는 (S)-페닐에틸이고, 보다 바람직하게는 벤질, (R)-페닐에틸, 또는 (S)-페닐에틸이며,At this time, R 1 is hydrogen; Alkyl; Cycloalkyl; Phenyl; 4-chlorophenyl; 4-methoxyphenyl; s-triazinyl or pyridinyl acyl; benzyl; Hydrocarbon residues substituted by hydroxy, alkoxy, dialkylamino, phenyl, 4-chlorophenyl, 4-methoxyphenyl; 2,4-methoxyphenyl; (R) -phenylethyl or (S) -phenylethyl, more preferably benzyl, (R) -phenylethyl, or (S) -phenylethyl,
R2는 수소, 멘톨일, 치환된 또는 비치환된 C1∼C40탄화수소 래디컬, 이때 C1∼C40탄화수소 래디컬의 치환체는 0-40개의 할로겐 원자; 붕소, 질소 산소, 황, 인, 규소 및 셀레늄으로 구성된 군으로부터 선택된 헤테로원자이고, 보다 바람직하게는 C1∼C10또는 멘톨일, 가장 바람직하게는 메틸, 에틸, 프로필 또는 멘톨일이다.R 2 is hydrogen, mentholyl, substituted or unsubstituted C 1 -C 40 hydrocarbon radical, wherein the substituent of C 1 -C 40 hydrocarbon radical is 0-40 halogen atom; Heteroatoms selected from the group consisting of boron, nitrogen oxygen, sulfur, phosphorus, silicon and selenium, more preferably C 1 to C 10 or mentholyl, most preferably methyl, ethyl, propyl or mentholyl.
R3는 R1과 동일한 수소; 알킬; 시클로알킬; 페닐; 4-클로로페닐; 4-메톡시페닐; s-트리아지닐 또는 피리디닐 아실; 벤질; 히드록시, 알콕시, 디알킬아미노, 페닐, 4-클로로페닐, 4-메톡시페닐에 의해 치환된 탄화수소 잔기; 2,4-메톡시페닐; (R)-페닐에틸, 또는 (S)-페닐에틸이거나 이를 다른 질소보호기 역할을 하는 치환체로 바꾼 Boc, Cbz, Fmoc, 아세틸 등이 될 수 있다.R 3 is hydrogen same as R 1 ; Alkyl; Cycloalkyl; Phenyl; 4-chlorophenyl; 4-methoxyphenyl; s-triazinyl or pyridinyl acyl; benzyl; Hydrocarbon residues substituted by hydroxy, alkoxy, dialkylamino, phenyl, 4-chlorophenyl, 4-methoxyphenyl; 2,4-methoxyphenyl; Boc, Cbz, Fmoc, acetyl, or the like, which is (R) -phenylethyl, or (S) -phenylethyl, or has been replaced by a substituent acting as another nitrogen protecting group.
또한, Ar은 페닐, 치환체를 가지는 페닐 및 나프탈렌 혹은 헤테로 방향족 고리화합물이 될 수 있다.Ar may also be phenyl, phenyl with substituents and naphthalene or heteroaromatic cyclic compounds.
보다 구체적으로 설명하면 다음과 같다. 우선 반응식 1에 나와 있는 구조식 (1)의 아지리딘-2-카르복시산의 알킬 에스테르를 출발물질로 과량의 아릴마그네슘할라이드와 반응시키면 구조식 (2)의 아지리딘다이아릴메탄올을 얻을 수 있게 된다. 이 때 아릴은 페닐, 여러 가지 치환체를 가진 페닐, 나프틸, 기타 헤테로고리를 가지는 아릴로 일반화될 수 있는 화합물들을 사용할 수 있으며, 할라이드로는 클로라이드 또는 브로마이드가 바람직하다.More specifically described as follows. First, when the alkyl ester of aziridine-2-carboxylic acid of formula (1) shown in Scheme 1 is reacted with an excess of arylmagnesium halide as a starting material, it is possible to obtain aziridine diarylmethanol of formula (2). At this time, aryl may be a compound that can be generalized to phenyl, phenyl having various substituents, naphthyl, aryl having other heterocycles, and halide or chloride is preferable.
구조식(1) 구조식(2)Structural Formula (1) Structural Formula (2)
다음은 아래의 반응식 2에서와 같이 구조식 (2)의 아지리딘을 공지의 산소 친핵체로 (공지 문헌 Soo-Kyung Choi, Jin-Soo Lee, Jung-Ho Kim and Won Koo Lee , J. Org. Chem. 1997, 62, 743. 참조) 고리를 열고 필요한 경우 자유로운 히드록시메틸이되도록 가수분해하여 구조식이 (3)과 같은 2-아미노-1,1,-다이아릴-1,3-다이하이드록시프로판을 얻는다.Next, as shown in Scheme 2 below, aziridine of structural formula (2) was used as a known oxygen nucleophile (see, eg, Soo-Kyung Choi, Jin-Soo Lee, Jung-Ho Kim and Won Koo Lee, J. Org.Chem. 1997, 62, 743.)) Open the ring and hydrolyze to free hydroxymethyl if necessary to obtain 2-amino-1,1, -diaryl-1,3-dihydroxypropane as shown in formula (3). Get
구조식 (2) 구조식 (3)Structural Formulas (2) Structural Formulas (3)
이렇게 아지리딘 고리가 열려 만들어지는 구조식 (3)의 화합물들에서 삼차알코올의 하이드록시기를 공지의 수소첨가 환원하는 방법(참고문헌 Koskinen, A.M. P., Hassila, H., Myllymaki, V. T., Rissanen, K. Tetrahedron Lett. 1995, 36, 5619-5622 참조, 구체적인 예는 실시예 7 에 설명되어 있음)으로 제거하여 다이아릴알라닌을 얻고 필요한 경우 질소의 작용기에 보호기를 R3로 바꾸거나 혹은 보호기를 제거한다.Thus known hydrogenation of the hydroxyl group of the tertiary alcohol in the compounds of formula (3) in which the aziridine ring is opened (Ref. Koskinen, AMP, Hassila, H., Myllymaki, VT, Rissanen, K. Tetrahedron Lett. 1995, 36, 5619-5622, specific examples are described in Example 7) to obtain diarylalanine and, if necessary, replace the protecting group with R 3 in the functional group of nitrogen or remove the protecting group.
구조식 (3) 구조식 (4)Structural Formulas (3) Structural Formulas (4)
일차 알코올 상태의 구조식 (4)의 다이아릴알라닌올을 일반적인 산화반응으로(참고 문헌 Liu, H. T., Han, I. S. Synth. Commun. 1985, 15, 759-764 참조) 산화하여 카르복시산으로 만들어 구조식 (5)의 다이아릴알라닌을 얻는다. 이때 아민은 적절하게 R3로 보호된 상태로 산화하면 보호기를 그대로 가진 보호된 다이아릴알라닌을 얻게되며 이 보호기를 떼어 냄으로서 자유로운 상태의 다이페닐알라닌을 얻을 수 있게 된다.Diarylaninol of Structural Formula (4) in primary alcohol state is oxidized by general oxidation reaction (see References Liu, HT, Han, IS Synth. Commun. 1985, 15, 759-764) to carboxylic acid. Diarylalanine is obtained. At this time, when the amine is properly oxidized to R 3 protected state, a protected diarylalanine having a protective group is obtained, and a free state of diphenylalanine can be obtained by removing the protecting group.
구조식 (4) 구조식 (5)Structural Formulas (4) Structural Formulas (5)
이하 본 발명을 하기 실시 예에 의거하여 구체적으로 설명한다.Hereinafter, the present invention will be described in detail with reference to the following examples.
실시예 1Example 1
(2S)-[N-(R)-페닐에틸]아지리딘-2-다이페닐메탄올의 획득Acquisition of (2S)-[N- (R) -phenylethyl] aziridine-2-diphenylmethanol
에틸-(2S)-[N-(R)-페닐에틸]아지리딘-2-카르복실레이트 (413 mg, 1.89 mmol)를 10 mL의 THF용액에 녹이고 -78oC로 온도를 낮춘 후 THF용액 중에 있는 브롬화페닐마그네슘 (.2.98M 1.91 mL, 5,67 mmol)을 첨가한다. 그런후 이 용액을 -78oC에서 2시간 동안 교반하고서 5 mL의 물을 넣어 반응을 종결한다. 이 반응 혼합물을 상온까지 온도를 올리고 유기 층을 분리한다. 물 층은 에틸아세테이트 용매 10 mL씩 다섯 차례 추출하고 모든 유기층을 모은다. 이 모아진 유기 층을 20 mL의 포화 염화나트륨 용액으로 씻어내고, 무수 황산나트륨으로 수분을 제거한다. 유기 층을 감압 농축하고 증류하거나 관크로마토그래피로 정제하여 590 mg의 산물을 흰색 고체로 얻는다. [α]D 24= +34.0 (c=0.53, in CHCl3), 1H NMR (200 MHz, CDCl3) δ 7.37-6.86 (m, 15H), 3.81 (br, 1H), 2.76 (q,J=6.6 Hz, 1H), 2.49 (dd,J=6.5 Hz, 1H), 2.02 (d,J=3.6 Hz, 1H), 1.53 (d,J=6.5 Hz, 1H), 1.41 (d,J=6.6Hz, 3H).Dissolve ethyl- (2S)-[N- (R) -phenylethyl] aziridine-2-carboxylate (413 mg, 1.89 mmol) in 10 mL of THF solution, lower the temperature to -78 o C, and then THF solution. Phenyl bromide (.2.98M 1.91 mL, 5,67 mmol) in the middle is added. The solution is then stirred at -78 o C for 2 hours and 5 mL of water is added to terminate the reaction. The reaction mixture is heated to room temperature and the organic layer is separated. The water layer is extracted five times with 10 mL of ethyl acetate solvent and all organic layers are collected. The combined organic layers are washed with 20 mL of saturated sodium chloride solution and the water is removed with anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and distilled or purified by column chromatography to give 590 mg of the product as a white solid. [a] D 24 = +34.0 (c = 0.53, in CHCl 3 ), 1 H NMR (200 MHz, CDCl 3) δ 7.37-6.86 (m, 15H), 3.81 (br, 1H), 2.76 (q, J = 6.6 Hz, 1H), 2.49 (dd, J = 6.5 Hz, 1H), 2.02 (d, J = 3.6 Hz, 1H), 1.53 (d, J = 6.5 Hz, 1H), 1.41 (d, J = 6.6 Hz, 3H).
실시예 2Example 2
(2R)-[N-(S)-페닐에틸]아지리딘-2-다이페닐메탄올의 획득Acquisition of (2R)-[N- (S) -phenylethyl] aziridine-2-diphenylmethanol
에틸-(2S)-[N-(R)-페닐에틸]아지리딘-2-카르복실레이트 대신 에틸-(2R)-[N-(S)-페닐에틸]아지리딘-2-카르복실레이트를 이용하여 실시예 1과 같이 반응하여 목적한 화합물을 얻는다. [α]D 24= -33.5 (c=0.44, in CHCl3)Ethyl- (2R)-[N- (S) -phenylethyl] aziridine-2-carboxylate instead of ethyl- (2S)-[N- (R) -phenylethyl] aziridine-2-carboxylate The reaction is carried out as in Example 1 to obtain the target compound. [α] D 24 = -33.5 (c = 0.44, in CHCl 3 )
실시예 3Example 3
(2S)-[N-(R)-페닐에틸]아미노-1,1,-다이페닐-1,3-다이하이드록시프로판의 획득Acquisition of (2S)-[N- (R) -phenylethyl] amino-1,1, -diphenyl-1,3-dihydroxypropane
(2S)-[N-(R)-페닐에틸]아지리딘-2-다이페닐메탄올(590 mg, 1.79 mmol)을 9 mL의 메틸렌클로라이드에 녹인 용액에 0.31 mL의 아세트산(5.37 mmol)을 가한다. 이 혼합물을 상온에서 4시간동안 교반하고서 2 mL의 포화 탄산수소나트륨 용액을 가하여 반응을 종결시킨다. 유기 층을 분리하고 물 층은 다섯 번에 걸쳐 4 mL씩의 메틸렌클로라이드 용액으로 추출한다. 유기 층을 다 모으고서 20 mL의 포화 염화나트륨 용액으로 씻어내고, 무수 황산나트륨으로 수분을 제거한다. 유기층을 감압 농축하고 8 mL의 에탄올에 녹인다. 이 용액에 KOH (105 mg, 1.98 mmol)를 넣고 상온에서 교반한 후 용액을 감압하여 농축한다. 농축된 용액을 3 mL의 물에 녹이고 5회에 걸쳐 각 회 당 4 mL 의 메틸렌클로라이드로 추출한다. 추출된 유기 층을 20 mL의 포화 염화나트륨 용액으로 씻어내고, 무수 황산나트륨으로 수분을 제거한다. 유기 층을 감압 농축하고 증류하거나 관크로마토그래피로 정제하여 520 mg의 산물을 흰색 고체로 얻는다. [α]D 24= +13.1 (c=1.0, in CHCl3), 1H NMR (300 MHz, CDCl3) δ 7.42-6.95 (m, 15H), 4.11 (br, 1H), 3.77 (m, 2H), 3.58 (dd,J= 11.81Hz, 1H), 3.38 (m, 1H), 1.29 (d,J=6.87Hz, 3H). mp: 78-80oCTo a solution of (2S)-[N- (R) -phenylethyl] aziridine-2-diphenylmethanol (590 mg, 1.79 mmol) in 9 mL of methylene chloride is added 0.31 mL of acetic acid (5.37 mmol). . The mixture is stirred for 4 hours at room temperature and 2 mL of saturated sodium bicarbonate solution is added to terminate the reaction. The organic layer is separated and the water layer is extracted five times with 4 mL of methylene chloride solution. The combined organic layers are washed with 20 mL of saturated sodium chloride solution and the water is removed with anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and dissolved in 8 mL of ethanol. KOH (105 mg, 1.98 mmol) was added to the solution, stirred at room temperature, and the solution was concentrated under reduced pressure. The concentrated solution is dissolved in 3 mL of water and extracted 5 times with 4 mL of methylene chloride each time. The extracted organic layer is washed with 20 mL of saturated sodium chloride solution and the water is removed with anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and distilled or purified by column chromatography to give 520 mg of the product as a white solid. [a] D 24 = +13.1 (c = 1.0, in CHCl 3 ), 1 H NMR (300 MHz, CDCl 3) δ 7.42-6.95 (m, 15H), 4.11 (br, 1H), 3.77 (m, 2H), 3.58 (dd, J = 11.81 Hz, 1H), 3.38 (m, 1H), 1.29 (d, J = 6.87 Hz, 3H). mp: 78-80 o C
실시예 4Example 4
(2R)-[N-(S)-페닐에틸]아미노-1,1,-다이페닐-1,3-다이하이드록시프로판의 획득Acquisition of (2R)-[N- (S) -phenylethyl] amino-1,1, -diphenyl-1,3-dihydroxypropane
(2S)-[N-(R)-페닐에틸]아지리딘-2-다이페닐메탄올 대신 (2R)-[N-(S)-페닐에틸]아지리딘-2-다이페닐메탄올을 사용하여 실시예 3과 같이하여 산물을 얻는다. [α]D 24= -13.6 (c=1.0, in CHCl3)Example using (2R)-[N- (S) -phenylethyl] aziridine-2-diphenylmethanol instead of (2S)-[N- (R) -phenylethyl] aziridine-2-diphenylmethanol Get the product as in 3. [α] D 24 = -13.6 (c = 1.0, in CHCl 3 )
실시예 5Example 5
(D)-다이페닐알라닌올의 획득Acquisition of (D) -diphenylalanineol
(2S)-[N-(R)-페닐에틸]아미노-1,1,-다이페닐-1,3-다이하이드록시프로판 (150 mg, 0.432 mmol)을 3 mL의 포름산에 녹이고 이 용액에 다이하이드록시팔라듐 30 mg을 가한다. 그리고 이 용액을 밀폐된 용기에서 100psi의 압력으로 수소를 가하고 용액을 상온에서 6시간 동안 교반한다. 그런 후 반응물을 감압 증류하여 농축하고 5 mL의 진한 염산을 가한다. 그리고 그 용액을 다시 감압하여 농축하고 얻어진 고체를 에틸아세테이트에서 재결정하여 85 mg 의 흰색 고체의 목적 화합물을 얻는다. [α]D 24= -41.5 (c=0.25, in CHCl3) mp: 109-112oC(2S)-[N- (R) -phenylethyl] amino-1,1, -diphenyl-1,3-dihydroxypropane (150 mg, 0.432 mmol) was dissolved in 3 mL of formic acid and dilute in this solution. 30 mg of hydroxypalladium is added. The solution is then hydrogenated at 100 psi in a closed container and the solution is stirred for 6 hours at room temperature. The reaction is then concentrated by distillation under reduced pressure and 5 mL of concentrated hydrochloric acid is added. Then, the solution was concentrated under reduced pressure again, and the obtained solid was recrystallized from ethyl acetate to obtain 85 mg of the title compound as a white solid. [α] D 24 = -41.5 (c = 0.25, in CHCl 3 ) mp: 109-112 o C
실시예 6Example 6
(L)-다이페닐알라닌올의 획득Acquisition of (L) -diphenylalaninol
(2S)-[N-(R)-페닐에틸]아미노-1,1,-다이페닐-1,3-다이하이드록시프로판 대신에 (2R)-[N-(S)-페닐에틸]아미노-1,1,-다이페닐-1,3-다이하이드록시프로판을 사용하여 실시예 5와 같이 반응하고서 (L)-다이페닐알라닌올을 얻는다. [α]D 24= +40.1 (c=0.33, in CHCl3)(2R)-[N- (S) -phenylethyl] amino- instead of (2S)-[N- (R) -phenylethyl] amino-1,1, -diphenyl-1,3-dihydroxypropane The reaction was carried out as in Example 5 using 1,1, -diphenyl-1,3-dihydroxypropane to obtain (L) -diphenylalaninol. [α] D 24 = +40.1 (c = 0.33, in CHCl 3 )
실시예 7Example 7
N-Boc-(D)-다이페닐알라닌올의 획득Acquisition of N-Boc- (D) -diphenylalaninol
(2S)-[N-(R)-페닐에틸]아미노-1,1,-다이페닐-1,3-다이하이드록시프로판 (329 mg, 0.947 mmol)을 5 mL의 포름산에 녹이고 이 용액에 다이히드록시팔라듐 60 mg을 가한다. 그리고 이 용액을 밀폐된 용기에서 100psi의 압력으로 수소를 가하고 용액을 상온에서 6시간 동안 교반한다. 그런 후 반응물을 감압 증류하여 농축하고 이를 2.5 mL NaOH용액을 가한다. 이 용액에 (Boc)2O (248 mg, 1,14 mmol)과 2.00 mL의 EtOAc를 가한다. 그런 후 이 용액을 상온에서 4시간 동안 교반한 후 유기층을 분리하여 얻는다. 물 층은 4회에 걸쳐 각 회 당 3 mL의 EtOAc로 추출한다. 추출된 유기 층을 20 mL의 포화 염화나트륨 용액으로 씻어내고, 무수 황산나트륨으로 수분을 제거한다. 유기 층을 감압 농축하고 증류하거나 관크로마토그래피로 정제하여 250 mg의 산물을 흰색 고체로 얻는다. [α]D 24= -22.2 (c=1.0, in CHCl3), 1H NMR (500 MHz, CDCl3) δ 7.33-7.16 (m, 10H), 4.63 (m, 1H), 4.47 (br, 1H), 4.15 (d,J=10.74, 1H), 3.67 (dd,J=9.16 Hz, 1H), 3.47 (dd,J= 10.93, 1H), 1.34 (s, 9H)Dissolve (2S)-[N- (R) -phenylethyl] amino-1,1, -diphenyl-1,3-dihydroxypropane (329 mg, 0.947 mmol) in 5 mL of formic acid and add to this solution. Add 60 mg of hydroxypalladium. The solution is then hydrogenated at 100 psi in a closed container and the solution is stirred for 6 hours at room temperature. The reaction was then concentrated by distillation under reduced pressure and 2.5 mL of NaOH solution was added thereto. To this solution is added (Boc) 2 O (248 mg, 1,14 mmol) and 2.00 mL of EtOAc. The solution is then stirred at room temperature for 4 hours and then separated by an organic layer. The water layer is extracted four times with 3 mL of EtOAc each time. The extracted organic layer is washed with 20 mL of saturated sodium chloride solution and the water is removed with anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and distilled or purified by column chromatography to give 250 mg of the product as a white solid. [a] D 24 = -22.2 (c = 1.0, in CHCl 3 ), 1 H NMR (500 MHz, CDCl 3) δ 7.33-7.16 (m, 10H), 4.63 (m, 1H), 4.47 (br, 1H), 4.15 (d, J = 10.74, 1H), 3.67 (dd, J = 9.16 Hz, 1H), 3.47 (dd, J = 10.93, 1H), 1.34 (s, 9H)
mp: 109-111oCmp: 109-111 o C
실시예 8Example 8
N-Boc-(L)-다이페닐알라닌올의 획득Acquisition of N-Boc- (L) -diphenylalaninol
(2S)-[N-(R)-페닐에틸]아미노-1,1,-다이페닐-1,3-다이하이드록시프로판 대신 (2R)-[N-(S)-페닐에틸]아미노-1,1,-다이페닐-1,3-다이하이드록시프로판을 사용하여 실시예 7에서와 같이 반응하여 목적한 화합물을 얻는다. [α]D 24= +21.4 (c=1.0, in CHCl3)(2R)-[N- (S) -phenylethyl] amino-1 instead of (2S)-[N- (R) -phenylethyl] amino-1,1, -diphenyl-1,3-dihydroxypropane The reaction was carried out as in Example 7 using 1,3-diphenyl-1,3-dihydroxypropane to obtain the desired compound. [α] D 24 = +21.4 (c = 1.0, in CHCl 3 )
실시예 9Example 9
N-Boc-(D)-다이페닐알라닌의 획득Acquisition of N-Boc- (D) -diphenylalanine
N-Boc-(D)-다이페닐알라닌올(180 mg, 0.80 mmol)을 7 mL의 아세톤에 녹이고 용액이 붉게 될 때까지 존스 시약을 가한다. 이 다음 반응 혼합물을 교반하고 출발 물질이 없어지면 이소프로필알코올을 첨가하여 반응을 종결한다. 반응물을 셀라이트 필터를 통과시킨 후 통과된 용액을 감압 증류하고 여기에 10 mL의 EtOAc를 가한다. 물 층은 다시금 EtOAc 각 5 mL를 이용하여 세 차례에 걸쳐 유기층을 얻고 이들 유기 층을 모두 모은 후 20 mL의 포화 염화나트륨 용액으로 씻어내고, 무수 황산나트륨으로 수분을 제거하고 목적하는 화합물을 얻는다. [α]D 24= -35.8 (c=0.71, in MeOH), mp. 148-150oC.Dissolve N-Boc- (D) -diphenylalaninol (180 mg, 0.80 mmol) in 7 mL of acetone and add Jones reagent until the solution turns red. The reaction mixture is then stirred and when the starting material is gone the reaction is terminated by addition of isopropyl alcohol. After passing the reaction through a celite filter, the passed solution was distilled under reduced pressure and 10 mL of EtOAc was added thereto. The water layer was once again obtained with an organic layer three times using 5 mL of EtOAc each of which was collected, washed with 20 mL of saturated sodium chloride solution, removed with anhydrous sodium sulfate, and the desired compound. [a] D 24 = -35.8 (c = 0.71, in MeOH), mp. 148-150 o C.
실시예 10Example 10
N-Boc-(L)-다이페닐알라닌의 획득Acquisition of N-Boc- (L) -diphenylalanine
N-Boc-(D)-다이페닐알라닌올 대신 N-Boc-(L)-다이페닐알라닌올을 사용하여 실시예 9와 같이 반응하여 목적한 화합물을 얻는다. [α]D 24= +36.4 (c=0.46, in MeOH)The reaction was carried out as in Example 9 using N-Boc- (L) -diphenylalaninol instead of N-Boc- (D) -diphenylalaninol to obtain the desired compound. [α] D 24 = +36.4 (c = 0.46, in MeOH)
본 발명은 생리활성 물질의 중요한 뼈대를 이루는 비천연 아미노산의 일종인 다이페닐알라닌 및 그 유도체를 광학적으로 활성인 아지리딘-2-카르복시산 에스테르로부터 입체선택적으로 만드는 것이다. 아지리딘-2-카르복시산 에스테르를 이용함으로써 세린을 보호기로 보호해야하는 문제가 없을 뿐만 아니라 광학적으로 활성인 아지리딘-2-카르복시산 에스테르의 입체화학을 적절하게 선택함으로서 (D)-다이페닐알라닌 뿐만 아니라 (L)-다이페닐알라닌도 똑 같은 방법으로 만들 수 있다는 것이다.The present invention is to stereoselectively make diphenylalanine and its derivatives from optically active aziridine-2-carboxylic acid esters, which are a type of non-natural amino acids that form an important skeleton of physiologically active substances. The use of aziridine-2-carboxylic acid esters eliminates the problem of protecting serine with protecting groups, and by appropriately selecting the stereochemistry of the optically active aziridine-2-carboxylic acid esters, it is possible to select not only (D) -diphenylalanine (L) Diphenylalanine can be made in the same way.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5623087A (en) * | 1995-03-10 | 1997-04-22 | Ndsu-Research Foundation | Method for preparation of optically active diarylalanines |
KR20010000195A (en) * | 2000-08-10 | 2001-01-05 | 하현준 | Process for preparing (2r)- and (2s)-aziridine-2-carboxylates, and (2r)- and (2s)-2-hydroxymethylaziridines |
KR20010068029A (en) * | 2001-04-16 | 2001-07-13 | 하현준 | Lipase-mediated stereoslective hydrolysis of aziridine-2-carboxylates |
KR20030031969A (en) * | 2000-08-10 | 2003-04-23 | (주)켐바이오넥스 | Process for preparing alpha-amino acids and their derivatives including phenylalanine and homophenylalanine and their intermediates |
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2002
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5623087A (en) * | 1995-03-10 | 1997-04-22 | Ndsu-Research Foundation | Method for preparation of optically active diarylalanines |
US5939554A (en) * | 1995-03-10 | 1999-08-17 | Ndsu Research Foundation | Diarylaminopropanediol and diarylmethyl-oxazolidinone compounds |
KR20010000195A (en) * | 2000-08-10 | 2001-01-05 | 하현준 | Process for preparing (2r)- and (2s)-aziridine-2-carboxylates, and (2r)- and (2s)-2-hydroxymethylaziridines |
KR20030031969A (en) * | 2000-08-10 | 2003-04-23 | (주)켐바이오넥스 | Process for preparing alpha-amino acids and their derivatives including phenylalanine and homophenylalanine and their intermediates |
KR20010068029A (en) * | 2001-04-16 | 2001-07-13 | 하현준 | Lipase-mediated stereoslective hydrolysis of aziridine-2-carboxylates |
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