KR100566896B1 - Processes for the preparation of an optically active 5,6-dioxopiperazine-2-carboxylic acid derivative - Google Patents

Processes for the preparation of an optically active 5,6-dioxopiperazine-2-carboxylic acid derivative Download PDF

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KR100566896B1
KR100566896B1 KR1020030060437A KR20030060437A KR100566896B1 KR 100566896 B1 KR100566896 B1 KR 100566896B1 KR 1020030060437 A KR1020030060437 A KR 1020030060437A KR 20030060437 A KR20030060437 A KR 20030060437A KR 100566896 B1 KR100566896 B1 KR 100566896B1
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optically active
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carboxylic acid
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한규성
함흥식
이원구
하현준
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주식회사 이매진
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

본 발명은 (a) 광학적으로 활성인 화학식 2의 화합물과 메틸 클로로옥소아세테이트(methyl chlorooxoacetate)를 반응시키는 단계; 및 (b) (a)단계에서 얻어진 반응산물을 환원시키는 단계를 포함하는 광학적으로 활성인 화학식 1의 화합물의 제조방법에 관한 것이다.The present invention comprises the steps of (a) reacting an optically active compound of formula (2) with methyl chlorooxoacetate (methyl chlorooxoacetate); And (b) relates to a method for preparing an optically active compound of formula 1 comprising the step of reducing the reaction product obtained in step (a).

Figure 112003032398956-pat00001
Figure 112003032398956-pat00001

식중, R1은 아미노 보호기이고, R2는 카르복실산 보호기이다.In formula, R <1> is an amino protecting group and R <2> is a carboxylic acid protecting group.

아지리딘, 2-아지도-3-아미노프로피온산 에스테르, 5,6-디옥소피페라진-2-카르복실산Aziridine, 2-azido-3-aminopropionic acid ester, 5,6-dioxopiperazin-2-carboxylic acid

Description

광학적으로 활성인 5,6-디옥소피페라진-2-카르복실산 유도체의 제조방법{Processes for the preparation of an optically active 5,6-dioxopiperazine-2-carboxylic acid derivative}Processes for the preparation of an optically active 5,6-dioxopiperazine-2-carboxylic acid derivative}

본 발명은 광학적으로 활성인 5,6-디옥소피페라진-2-카르복실산 유도체의 제조방법에 관한 것이다.The present invention relates to a method for preparing an optically active 5,6-dioxopiperazin-2-carboxylic acid derivative.

5,6-디옥소피페라진-2-카르복실산 유도체는 다양한 피페라진 계열의 의약품 중간체로 사용되거나 새로운 피페라진계 화합물 제조시 유용하게 사용될 수 있는 화합물이다(미국특허 제5,902,812호).The 5,6-dioxopiperazin-2-carboxylic acid derivative is a compound that can be used as a pharmaceutical intermediate of various piperazine series or usefully in preparing a new piperazine-based compound (US Pat. No. 5,902,812).

종래, 광학적으로 활성인 5,6-디옥소피페라진-2-카르복실산 유도체는 피페라진 유도체를 광학분리(resolution)하거나 그 자체를 비대칭으로 제조하고 광학분리를 하여 제조하는 방법이 알려져 있다(미국특허 제5,977,364호 및 미국특허 제5,945,534호). 그러나, 종래의 제조방법은 광학적으로 활성인 5,6-디옥소피페라진-2-카르복실산 유도체를 대량으로 합성하는데 많은 제약이 따른다는 문제점이 있다.Conventionally, optically active 5,6-dioxopiperazin-2-carboxylic acid derivatives are known by optical resolution of piperazine derivatives or by asymmetrical preparation of the piperazine derivatives and optical separation ( U.S. Patent 5,977,364 and U.S. Patent 5,945,534). However, the conventional manufacturing method has a problem in that many restrictions are involved in synthesizing optically active 5,6-dioxopiperazin-2-carboxylic acid derivatives in large quantities.

따라서, 광학적으로 활성인 5,6-디옥소피페라진-2-카르복실산 유도체를 높은 순도로 얻을 수 있는 제조방법의 개발이 당업계에 필요하다.Therefore, there is a need in the art for the development of a process for obtaining optically active 5,6-dioxopiperazine-2-carboxylic acid derivatives with high purity.

이에, 본 발명자들은 높은 순도로 광학적으로 활성인 5,6-디옥소피페라진-2-카르복실산 유도체를 제조할 수 있는 방법을 개발하고자 연구를 거듭한 결과, 광학적으로 활성인 아지리딘 유도체로부터 상기 화합물을 제조할 수 있다는 것을 발견하여 본 발명을 완성하게 되었다.Accordingly, the present inventors have conducted research to develop a method for producing an optically active 5,6-dioxopiperazin-2-carboxylic acid derivative with high purity, and as a result, from an optically active aziridine derivative It has been found that the compound can be prepared to complete the present invention.

따라서, 본 발명은 광학적으로 활성인 5,6-디옥소피페라진-2-카르복실산 유도체의 제조방법을 제공하는 것을 목적으로 한다.Accordingly, an object of the present invention is to provide a method for producing an optically active 5,6-dioxopiperazin-2-carboxylic acid derivative.

본 발명의 일 태양에 따라, (a) 광학적으로 활성인(optically active) 화학식 2의 화합물과 메틸 클로로옥소아세테이트(methyl chlorooxoacetate)를 반응시키는 단계; 및 (b) (a)단계에서 얻어진 반응산물을 환원시키는 단계를 포함하는 광학적으로 활성인 화학식 1의 화합물의 제조방법이 제공된다.According to one aspect of the invention, (a) reacting an optically active compound of formula (2) with methyl chlorooxoacetate (methyl chlorooxoacetate); And (b) there is provided a method for preparing an optically active compound of formula 1 comprising the step of reducing the reaction product obtained in step (a).

Figure 112003032398956-pat00002
Figure 112003032398956-pat00002

Figure 112003032398956-pat00003
Figure 112003032398956-pat00003

식중, R1은 아미노 보호기이고, R2는 카르복실산 보호기이다.In formula, R <1> is an amino protecting group and R <2> is a carboxylic acid protecting group.

본 발명에 따른 제조방법에서, 상기 아미노 보호기는, 예를 들어, 벤질, (R)-(α)-메틸벤질, 또는 (S)-(α)-메틸벤질 등과 같은 통상의 아미노 보호기이며, 카르복실산 보호기도 C1∼C4 알킬 또는 멘톨일 등을 포함한 통상의 카르복실산 보호기이다.In the preparation method according to the invention, the amino protecting group is a conventional amino protecting group such as, for example, benzyl, (R)-(α) -methylbenzyl, or (S)-(α) -methylbenzyl, and the like. Acid protecting groups are also common carboxylic acid protecting groups including C 1 -C 4 alkyl, mentholyl and the like.

상기 광학적으로 활성인 화학식 2의 화합물과 메틸 클로로옥소아세테이트를 반응시키는 단계는 염기 존재하에서 반응시키는 것이 바람직하며, 사용가능한 염기는 트리에틸아민, 피리딘, N,N-디이소프로필에틸아민(N,N-diisopropylethylamine, DIEA), 루티닌 등을 포함한다. 또한, 상기 반응은 에틸 아세테이트, 테트라히드로퓨란, 아세토니트릴 등의 유기용매 중에서 수행할 수 있으며, 0 ∼ 25 ℃, 바람직하게는 0 ∼ 10 ℃, 더욱 바람직하게는 약 0 ℃에서 수행할 수 있다. The step of reacting the optically active compound of formula (2) with methyl chlorooxoacetate is preferably carried out in the presence of a base, and available bases are triethylamine, pyridine, N, N-diisopropylethylamine (N, N-diisopropylethylamine, DIEA), rutinine and the like. In addition, the reaction may be carried out in an organic solvent such as ethyl acetate, tetrahydrofuran, acetonitrile, and may be carried out at 0 to 25 ℃, preferably 0 to 10 ℃, more preferably about 0 ℃.

상기 환원시키는 단계는 통상의 환원반응에 의해 수행할 수 있으며, Pd/C 존재하에서 수소 가스를 주입하여 환원반응시키는 것이 더욱 바람직하다.The reducing may be performed by a conventional reduction reaction, and more preferably, reduction is carried out by injecting hydrogen gas in the presence of Pd / C.

상기 화학식 1의 화합물은 통상의 방법에 따라 적절한 탈보호기 제거반응을 수행하고, 원하는 친핵체와 반응시킴으로써 다양한 작용기를 갖는 화합물로 제조될 수 있다.The compound of Formula 1 may be prepared as a compound having various functional groups by performing an appropriate deprotection group removal reaction according to a conventional method and reacting with a desired nucleophile.

본 발명의 제조방법에서 출발물질로 사용되는 광학적으로 활성인 화학식 2의 화합물은 광학적으로 활성인 화학식 3의 화합물과 아지드 염(azide salt)을 반응시켜 제조할 수 있다. The optically active compound of formula 2 used as a starting material in the preparation method of the present invention may be prepared by reacting an optically active compound of formula 3 with an azide salt.

Figure 112003032398956-pat00004
Figure 112003032398956-pat00004

식중, R1 및 R2는 상기에서 정의한 바와 같다.Wherein R 1 and R 2 are as defined above.

상기 화학식 2의 화합물은 의약품 및 촉매 제조시 유용하게 사용할 수 있는 중간체이며(D. Lucet, Angew. Chem. Int. Ed. Engl. 1998, 37, 2580-2627), 특히, 본 발명에 따른 광학적으로 활성인 화학식 1의 화합물을 제조하는 중간체로서도 유용하다. Compound 2 is an intermediate that can be usefully used in the manufacture of pharmaceuticals and catalysts (D. Lucet, Angew. Chem. Int. Ed. Engl. 1998, 37, 2580-2627), in particular, optically in accordance with the present invention It is also useful as an intermediate for preparing an active compound of formula (I).

상기 (2S) 또는 (2R)의 화학식 3의 화합물은 공지의 제조방법(대한민국 특허공개 제2001-195호)에 따라 제조할 수 있으며, 상기 아지드 염은 소듐 아지드(sodium azide)를 포함한 다양한 형태의 염일 수 있다. The compound of Formula 3 of (2S) or (2R) may be prepared according to a known production method (Korean Patent Laid-Open No. 2001-195), and the azide salt may include various kinds of sodium azide. Salts in the form.

화학식 3의 화합물과 아지드 염과의 반응은 AlCl3 또는 그의 수화물(예를들어, AlCl3·6H2O) 존재하에서 수행하는 것이 아지리딘 링에 대하여 선택적인 반응이 일어나도록 할 수 있으므로 더욱 바람직하다.The reaction of the compound of formula 3 with an azide salt is more preferred because the reaction in the presence of AlCl 3 or its hydrate (e.g. AlCl 3 .6H 2 O) may cause a selective reaction to the aziridine ring. Do.

상기 화학식 3의 화합물과 아지드 염과의 반응은 에탄올, 메탄올 등의 극성 유기용매 중에서 수행할 수 있으며, 산성조건에서 반응시키는 것이 바람직하다. 또한, 상기 반응은 20 ∼ 40 ℃, 바람직하게는 약 30 ℃에서 수행할 수 있다.The reaction of the compound of Formula 3 and the azide salt may be performed in a polar organic solvent such as ethanol and methanol, and the reaction is preferably performed under acidic conditions. In addition, the reaction may be carried out at 20 to 40 ℃, preferably about 30 ℃.

본 발명의 제조방법을 전체 반응식으로 나타내면 다음 반응식 1과 같다.The production method of the present invention is represented by the following reaction scheme 1.

Figure 112003032398956-pat00005
Figure 112003032398956-pat00005

상기 반응식에서, R1 및 R2는 상기에서 정의한 바와 같다.In the above scheme, R 1 and R 2 are as defined above.

상기 본 발명의 제조방법은 광학적으로 활성인 화학식 3의 화합물을 출발물질로 사용함으로써, 99%이상의 입체 선택성을 갖는 화학식 1 또는 2의 화합물을 높은 수율로 제조할 수 있다.The production method of the present invention can be prepared in a high yield of the compound of formula 1 or 2 having a stereoselectivity of 99% or more by using an optically active compound of formula (3) as a starting material.

이하, 본 발명을 실시예를 통하여 더욱 구체적으로 설명한다. 그러나, 본 발명이 이들 실시예에 의해 제한되는 것으로 해석되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not to be construed as limited by these examples.

실시예 1. 3-N-[(R)-(+)-α-메틸벤질]아미노-2(S)-아지도프로피온산 멘톨 에스테르의 제조Example 1. Preparation of 3-N-[(R)-(+)-α-methylbenzyl] amino-2 (S) -azidopropionic acid menthol ester

50% 에탄올 40 ml에 3-N-[(R)-(+)-α-메틸벤질]아지리딘-2(R)-카르복실산 멘톨 에스테르(6.2g, 18.82mmole), 소듐 아지드(6.1g, 5.0eq), 및 AlCl3·6H2O(0.1eq) 을 가한 후, 2N 황산을 사용하여 pH를 pH4로 조정한 다음, 12시간 동안 교반하였다. 반응 혼합물에 NaHCO3 수용액을 가하여 pH를 7∼8 로 중화시킨 후, 유기층을 분리하였다. 수층은 CH2Cl2로 세 차례 추출하여, 상기 유기층과 혼합하였다. 얻어진 유기층을 무수 MgSO4로 수분을 제거한 다음, 감압 농축하고 크로마토그래피(에틸 아세테이트 : n-헥산 = 5 : 95)로 정제하여 3-N-[(R)-(+)-α-메틸벤질]아미노-2(S)-아지도프로피온산 멘톨 에스테르(6.0g, 5.8g)를 얻었다.In 40 ml of 50% ethanol 3-N-[(R)-(+)-α-methylbenzyl] aziridine-2 (R) -carboxylic acid menthol ester (6.2 g, 18.82 mmole), sodium azide (6.1 g, 5.0eq), and AlCl 3 .6H 2 O (0.1eq) were added, and then the pH was adjusted to pH 4 with 2N sulfuric acid, followed by stirring for 12 hours. NaHCO 3 aqueous solution was added to the reaction mixture to neutralize the pH to 7-8, and the organic layer was separated. The aqueous layer was extracted three times with CH 2 Cl 2 and mixed with the organic layer. The obtained organic layer was dried with anhydrous MgSO 4 , then concentrated under reduced pressure and purified by chromatography (ethyl acetate: n-hexane = 5: 95) to give 3-N-[(R)-(+)-α-methylbenzyl] Amino-2 (S) -azidopropionic acid menthol ester (6.0 g, 5.8 g) was obtained.

[α]22 D = +63.6o (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) 7.40-7.20 (m, 5H), 4.75 (sex, 1H), 3.99 (dd, 1H), 3.78 (q, 1H), 2.86 (dd, J= 3.05, 1.10 Hz, 1H), 2.77 (dd, J= 6.34, 1.28 Hz, 1H), 2.02 (m, 1H), 1.82 (m, 1H), 1.70 (m, 1H), 1.67 (m, 1H), 1.59 (br, 1H), 1.49 (m, 1H), 1.42 (m, 1H), 1.35 (d, 3H), 1.03 (quin, 3H), 0.91 (d, 3H), 0.87 (d, 3H), 0.72 (d, 3H); 13C NMR (125 MHz, CDCl3) 169.4, 145.0, 128.7, 127.3, 126.7, 76.5, 62.4, 58.0, 48.5, 47.0, 40.9, 34.3, 31.6, 26.2, 24.4, 23.3, 22.1, 21.0, 16.2; Anal. Calcd for C13H18N 2O2: C, 67.71; H, 8.66; N, 15.04. Found: C, 67.74; H, 8.69; N, 15.19.[a] 22 D = +63.6 o (c 1.00, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ) 7.40-7.20 (m, 5H), 4.75 (sex, 1H), 3.99 (dd, 1H), 3.78 (q, 1H), 2.86 (dd, J = 3.05, 1.10 Hz , 1H), 2.77 (dd, J = 6.34, 1.28 Hz, 1H), 2.02 (m, 1H), 1.82 (m, 1H), 1.70 (m, 1H), 1.67 (m, 1H), 1.59 (br, 1H), 1.49 (m, 1H), 1.42 (m, 1H), 1.35 (d, 3H), 1.03 (quin, 3H), 0.91 (d, 3H), 0.87 (d, 3H), 0.72 (d, 3H ); 13 C NMR (125 MHz, CDCl 3 ) 169.4, 145.0, 128.7, 127.3, 126.7, 76.5, 62.4, 58.0, 48.5, 47.0, 40.9, 34.3, 31.6, 26.2, 24.4, 23.3, 22.1, 21.0, 16.2; Anal. Calcd for C 13 H 18 N 2 O 2 : C, 67.71; H, 8. 66; N, 15.04. Found: C, 67.74; H, 8.69; N, 15.19.

실시예 2. 3-N-[(R)-(+)-α-메틸벤질]아미노-2(R)-아지도프로피온산 멘톨 에스테르의 제조Example 2. Preparation of 3-N-[(R)-(+)-α-methylbenzyl] amino-2 (R) -azidopropionic acid menthol ester

3-N-[(R)-(+)-α-메틸벤질]아지리딘-2(S)-카르복실산 멘톨 에스테르(6.0g, 18.82mmole)를 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 반응시켜 표제화합물(5.8g)을 제조하였다.Same method as in Example 1, except using 3-N-[(R)-(+)-α-methylbenzyl] aziridine-2 (S) -carboxylic acid menthol ester (6.0 g, 18.82 mmole) Reaction was carried out to give the title compound (5.8 g).

[α]22 D = 1.5o (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) 7.35-7.28 (m, 3H), 7.26-7.22 (m, 2H), 4.78 (sex, 1H), 3.96 (t, 1H), 3.76 (q, 1H), 2.84 (d, 2H), 2.00 (m, 1H), 1.87 (m, 1H), 1.69 (m, 2H), 1.61 (br, 1H), 1.48 (m, 1H), 1.43 (m, 1H), 1.34 (d, 3H), 1.03 (m, 3H), 0.91 (t, 6H), 0.76 (d, 3H); 13C NMR (125 MHz, CDCl3) 169.3, 145.2, 128.7, 127.3, 126.6, 76.4, 62.6, 58.3, 48.6, 47.1, 40.9, 34.2, 31.6, 26.4, 24.4, 23.5, 22.1, 20.9, 16.4; Anal. Calcd for C13H18N2O2: C, 67.71; H, 8.66; N, 15.04. Found: C, 67.76; H, 8.65; N, 15.12.[a] 22 D = 1.5 o (c 1.00, CHC1 3 ); 1 H NMR (500 MHz, CDCl 3 ) 7.35-7.28 (m, 3H), 7.26-7.22 (m, 2H), 4.78 (sex, 1H), 3.96 (t, 1H), 3.76 (q, 1H), 2.84 (d, 2H), 2.00 (m, 1H), 1.87 (m, 1H), 1.69 (m, 2H), 1.61 (br, 1H), 1.48 (m, 1H), 1.43 (m, 1H), 1.34 ( d, 3H), 1.03 (m, 3H), 0.91 (t, 6H), 0.76 (d, 3H); 13 C NMR (125 MHz, CDCl 3 ) 169.3, 145.2, 128.7, 127.3, 126.6, 76.4, 62.6, 58.3, 48.6, 47.1, 40.9, 34.2, 31.6, 26.4, 24.4, 23.5, 22.1, 20.9, 16.4; Anal. Calcd for C 13 H 18 N 2 O 2 : C, 67.71; H, 8. 66; N, 15.04. Found: C, 67.76; H, 8. 65; N, 15.12.

실시예 3. 4-[(R)-(+)-α-메틸벤질]-5,6-디옥소피페라진-2(R)-카르복실산 멘톨 에스테르의 제조Example 3. Preparation of 4-[(R)-(+)-α-methylbenzyl] -5,6-dioxopiperazin-2 (R) -carboxylic acid menthol ester

에틸 아세테이트(4ml, 0.2mmol)에 실시예 2에서 제조한 3-N-[(R)-(+)-α-메틸벤질]아미노-2(R)-아지도프로피온산 멘톨 에스테르(250mg, 0.67mmole), 트리에틸아민(112㎕, 0.81mmome), 메틸 클로로옥소아세테이트(68㎕, 0.70mmole)를 가한 다음, 0℃에서 넣고 10분 동안 교반하였다. 반응 혼합물에 Pd/C(50mg, 20 wt%)를 넣고, 수소 가스를 주입시켜 환원반응을 수행하였다. 반응 혼합물을 여과하고, 여과액을 감압 농축하고 크로마토그래피(에틸 아세테이트 100%)로 정제하여 4-[(R)-(+)-α-메틸벤질]-5,6-디옥소피페라진-2(R)-카르복실산 멘톨 에스테르를 얻었다(231 mg). 3-N-[(R)-(+)-α-methylbenzyl] amino-2 (R) -azidopropionic acid menthol ester (250 mg, 0.67 mmol) prepared in Example 2 in ethyl acetate (4 ml, 0.2 mmol) ), Triethylamine (112 [mu] l, 0.81 mmol), methyl chlorooxoacetate (68 [mu] l, 0.70 mmol) were added, then added at 0 [deg.] C. and stirred for 10 minutes. Pd / C (50 mg, 20 wt%) was added to the reaction mixture, and hydrogen gas was injected to reduce the reaction. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and purified by chromatography (ethyl acetate 100%) to give 4-[(R)-(+)-α-methylbenzyl] -5,6-dioxopiperazine-2 (R) -carboxylic acid menthol ester was obtained (231 mg).

[α]22 D = 28.3o (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) 7.62 (br, 1H), 7.40-7.20 (m, 5H), 6.00 (q, 1H), 4.74 (sex, 1H), 4.15 (qui, 1H), 3.51 (dd, J= 3.05, 1.10 Hz, 1H), 3.31 (dd, J= 6.34, 1.28 Hz, 1H), 1.98 (m, 1H), 1.82-1.62 (m, 4H), 1.53 (d, 3H), 1.48 (m, 2H), 1.03 (m, 5H), 0.91 (d, 3H), 0.74 (d, 3H); 13C NMR (75 MHz, CDCl3) 170.0, 168.1, 158.1, 156.7, 138.4, 129.0, 128.3, 127.6, 77.6, 52.1, 51.5, 46.7, 42.3, 40.6, 34.0, 31.5, 26.4, 23.3, 22.0, 20.9, 16.4, 15.3, 145.0, 128.7, 127.3, 126.7, 76.5, 62.4, 58.0, 48.5, 47.0, 40.9, 34.3, 31.6, 26.2, 24.4, 23.3, 22.1, 21.0, 16.2; Anal. Calcd for C13H18N2O2: C, 68.97; H, 8.05; N, 6.99. Found: C, 68.91; H, 8.14; N, 6.88.[a] 22 D = 28.3 o (c 1.00, CHC1 3 ); 1 H NMR (500 MHz, CDCl 3 ) 7.62 (br, 1H), 7.40-7.20 (m, 5H), 6.00 (q, 1H), 4.74 (sex, 1H), 4.15 (qui, 1H), 3.51 (dd , J = 3.05, 1.10 Hz, 1H), 3.31 (dd, J = 6.34, 1.28 Hz, 1H), 1.98 (m, 1H), 1.82-1.62 (m, 4H), 1.53 (d, 3H), 1.48 ( m, 2H), 1.03 (m, 5H), 0.91 (d, 3H), 0.74 (d, 3H); 13 C NMR (75 MHz, CDCl 3 ) 170.0, 168.1, 158.1, 156.7, 138.4, 129.0, 128.3, 127.6, 77.6, 52.1, 51.5, 46.7, 42.3, 40.6, 34.0, 31.5, 26.4, 23.3, 22.0, 20.9, 16.4, 15.3, 145.0, 128.7, 127.3, 126.7, 76.5, 62.4, 58.0, 48.5, 47.0, 40.9, 34.3, 31.6, 26.2, 24.4, 23.3, 22.1, 21.0, 16.2; Anal. Calcd for C 13 H 18 N 2 O 2 : C, 68.97; H, 8.05; N, 6.99. Found: C, 68.91; H, 8.14; N, 6.88.

실시예 4. 4-[(R)-(+)-α-메틸벤질]-5,6-디옥소피페라진-2(S)-카르복실산 멘톨 에스테르의 제조Example 4. Preparation of 4-[(R)-(+)-α-methylbenzyl] -5,6-dioxopiperazin-2 (S) -carboxylic acid menthol ester

실시예 1에서 제조한 3-N-[(R)-(+)-α-메틸벤질]아미노-2(S)-아지도프로피온산 멘톨 에스테르(250mg)를 사용한 것을 제외하고는 실시예 3과 동일한 방법으로 반응시켜 표제화합물을 제조하였다(224mg).Same as Example 3 except for using 3-N-[(R)-(+)-α-methylbenzyl] amino-2 (S) -azidopropionic acid menthol ester (250 mg) prepared in Example 1. Reaction was carried out to prepare the title compound (224 mg).

[α]22 D = 49.6o (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) 7.63 (br, 1H), 7.37-7.26 (m, 5H), 5.99 (q, 1H), 4.57 (sex, 1H), 4.28 (q, 1H), 3.72 (m, 1H), 3.30 (dd, 1H), 1.93 (br, 1H), 1.70 (m, 1H), 1.65 (m, 2H), 1.58 (d, 3H), 1.49 (m, 1H), 1.37 (m, 1H), 1.27 (m, 1H), 0.99 (m, 1H), 0.86 (t, 5H), 0.80 (m, 1H), 0.70 (d, 3H), 0.65 (q, 1H); 13C NMR (125 MHz, CDCl3) 168.0, 158.2, 156.9, 138.3, 128.9, 128.4, 127.8, 77.3, 51.7, 46.9, 41.9, 40.2, 34.0, 31.4, 29.8, 26.3, 23.3, 22.0, 20.9, 16.3, 15.5; Anal. Calcd for C13H18N2O 2: C, 68.97; H, 8.05; N, 6.99. Found: C, 68.88; H, 8.01; N, 6.71.[a] 22 D = 49.6 o (c 1.00, CHC1 3 ); 1 H NMR (500 MHz, CDCl 3 ) 7.63 (br, 1H), 7.37-7.26 (m, 5H), 5.99 (q, 1H), 4.57 (sex, 1H), 4.28 (q, 1H), 3.72 (m , 1H), 3.30 (dd, 1H), 1.93 (br, 1H), 1.70 (m, 1H), 1.65 (m, 2H), 1.58 (d, 3H), 1.49 (m, 1H), 1.37 (m, 1H), 1.27 (m, 1H), 0.99 (m, 1H), 0.86 (t, 5H), 0.80 (m, 1H), 0.70 (d, 3H), 0.65 (q, 1H); 13 C NMR (125 MHz, CDCl 3 ) 168.0, 158.2, 156.9, 138.3, 128.9, 128.4, 127.8, 77.3, 51.7, 46.9, 41.9, 40.2, 34.0, 31.4, 29.8, 26.3, 23.3, 22.0, 20.9, 16.3, 15.5; Anal. Calcd for C 13 H 18 N 2 O 2 : C, 68.97; H, 8.05; N, 6.99. Found: C, 68.88; H, 8.01; N, 6.71.

본 발명의 제조방법에 따라, 99%이상의 입체 선택성을 갖는 화학식 1 또는 2의 화합물을 높은 수율로 제조할 수 있다.According to the preparation method of the present invention, the compound of formula 1 or 2 having a stereoselectivity of 99% or more can be prepared in high yield.

Claims (7)

(a) 광학적으로 활성인(optically active) 화학식 2의 화합물과 메틸 클로로옥소아세테이트(methyl chlorooxoacetate)를 반응시키는 단계; 및 (b) (a)단계에서 얻어진 반응산물을 환원시키는 단계를 포함하는 광학적으로 활성인 화학식 1의 화합물의 제조방법.(a) reacting an optically active compound of formula 2 with methyl chlorooxoacetate; And (b) reducing the reaction product obtained in step (a).
Figure 112005051654404-pat00006
,
Figure 112005051654404-pat00007
Figure 112005051654404-pat00006
,
Figure 112005051654404-pat00007
 식중, R1은 벤질, (R)-(α)-메틸벤질, 또는 (S)-(α)-메틸벤질이고, R2는 C1∼C4 알킬 또는 멘톨일이다.Wherein R 1 is benzyl, (R)-(α) -methylbenzyl, or (S)-(α) -methylbenzyl, and R 2 is C 1 -C 4 alkyl or mentholyl. 삭제delete 제1항에 있어서, 상기 (a)단계의 반응이 트리에틸아민, 피리딘, N,N-디이소프로필에틸아민(N,N-diisopropylethylamine), 또는 루티닌 존재하에서 진행되는 것을 특징으로 하는 제조방법.The method of claim 1, wherein the reaction of step (a) is carried out in the presence of triethylamine, pyridine, N, N-diisopropylethylamine, or rutinin. . 삭제delete 제1항에 있어서, 상기 환원시키는 단계가 Pd/C 존재하에서 수소 가스를 주입하여 진행되는 것을 특징으로 하는 제조방법.The method of claim 1, wherein the reducing is performed by injecting hydrogen gas in the presence of Pd / C. 제1항, 제3항, 및 제5항 중 어느 한 항에 있어서, 상기 광학적으로 활성인 화학식 2의 화합물이 화학식 3의 화합물과 아지드 염(azide salt)을 반응시켜 제조된 것임을 특징으로 하는 제조방법. The compound according to any one of claims 1, 3, and 5, wherein the optically active compound of formula (2) is prepared by reacting the compound of formula (3) with an azide salt. Manufacturing method.
Figure 112005051654404-pat00008
Figure 112005051654404-pat00008
 식중, R1 및 R2는 제1항에서 정의한 바와 같다.Wherein R 1 and R 2 are as defined in claim 1. 제6항에 있어서, AlCl3 또는 그의 수화물 존재하에서 화학식 3의 화합물과 아지드(azide) 염을 반응시키는 것을 특징으로 하는 제조방법.The process according to claim 6, wherein the compound of formula 3 is reacted with an azide salt in the presence of AlCl 3 or a hydrate thereof.
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