KR20110087977A - Preparation method for optically active 1,4-dideoxy-1,4-imino-arabinitol - Google Patents

Preparation method for optically active 1,4-dideoxy-1,4-imino-arabinitol Download PDF

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KR20110087977A
KR20110087977A KR1020100007674A KR20100007674A KR20110087977A KR 20110087977 A KR20110087977 A KR 20110087977A KR 1020100007674 A KR1020100007674 A KR 1020100007674A KR 20100007674 A KR20100007674 A KR 20100007674A KR 20110087977 A KR20110087977 A KR 20110087977A
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심태보
최환근
하정미
박동식
함영진
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Abstract

PURPOSE: A method for preparing optically active 1,4-dideoxy-1,4-imino-arabinitol is provided to easily synthesize a target compound. CONSTITUTION: A method for preparing 1,4-dideoxy-1,4-imino-arabinitol comprises: a step of oxidizing N-protected aziridinylmethanole compound of chemical formula 2; a step of reacting the compound of chemical formula 2 with a phosphonoacetate compound to prepare an ester compound of chemical formula 3; a step of reacting dihydroxylation of the ester compound of chemical formula 3 to prepare a dihydroxy compound of chemical formula 4; a step of cyclizing the dihydroxy compound of chemical formula 4 under the presence of organic acid of R_3COOH to prepare a lactam compound of chemical formula 5; and a step of reducing the lactam compound of chemical formula 5 deprotecting.

Description

광학활성 1,4-디데옥시-1,4-이미노-아라비니톨의 제조방법 {Preparation method for optically active 1,4-Dideoxy-1,4-imino-arabinitol}Preparation method for optically active 1,4-dideoxy-1,4-imino-arabinitol {Preparation method for optically active 1,4-Dideoxy-1,4-imino-arabinitol}

본 발명은 광학활성 1,4-디데옥시-1,4-이미노-아라비니톨의 제조방법에 관한 것으로, 더욱 상세하게는 상업적으로 쉽게 구입이 가능한 N-보호된 아지리딘일메탄올 화합물을 출발물질로 사용하고, 광학활성 락탐 화합물을 반응 중간체로 합성하는 새로운 경로를 통하여 광학활성 1,4-디데옥시-1,4-이미노-아라비니톨을 보다 용이하게 합성하는 신규 제조방법에 관한 것이다.
The present invention relates to a method for preparing optically active 1,4-dideoxy-1,4-imino-arabinitol, and more particularly, to a N- protected aziridinylmethanol compound which is commercially available commercially. The present invention relates to a novel process for more easily synthesizing optically active 1,4-dideoxy-1,4-imino-aravinitol through a new route for synthesizing an optically active lactam compound into a reaction intermediate.

1,4-디데옥시-1,4-이미노-아라비니톨은 광학활성 탄소를 포함하는 화합물로 1,4-디데옥시-1,4-이미노-D-아라비니톨 (이하, 'DAB'라 약함) 및 1,4-디데옥시-1,4-이미노-L-아라비니톨 (이하, 'LAB'라 약함)의 광학이성질체가 존재한다.1,4-dideoxy-1,4-imino-arabinitol is a compound containing optically active carbon and 1,4-dideoxy-1,4-imino-D-arabinitol (hereinafter referred to as' DAB Optical isomers of 'la weak' and 1,4-dideoxy-1,4-imino-L-arabinitol (hereinafter abbreviated as 'LAB').

Figure pat00001
Figure pat00001

1,4-디데옥시-1,4-이미노-D-아라비니톨 (DAB)은 Fern Arachniodes standishii와 Angylocalyx boutiqueanus의 천연물로부터 처음 분리되었다. DAB는 알파-글루코시다아제에 대한 저해활성을 갖는 것으로 확인되어 탄수화물의 소화를 저해하는 기전의 당뇨병 치료제로서 시장에 출시되어 있다. 최근에는 항암제, 항바이러스제, 세포사멸유도제 등으로 관심을 받고 있으며, 글리코겐 포스포릴라아제 및 신타아제에 대한 저해활성을 갖는 것으로도 잘 알려져 있다. 그리고, DAB는 캔디다 종의 주된 대사체로 혈청 안에 존재하는 아라비니톨의 양을 측정하여 심부성 캔디다증을 진단하기도 한다. 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) was first isolated from the natural products of Fern Arachniodes standishii and Angylocalyx boutiqueanus . DAB has been shown to have inhibitory activity against alpha-glucosidase and is on the market as a therapeutic agent for diabetes that inhibits the digestion of carbohydrates. Recently, it has been of interest as an anticancer agent, an antiviral agent, an apoptosis inducing agent, etc., and is well known to have inhibitory activity against glycogen phosphorylase and synthase. DAB is also a major metabolite of Candida species, and diagnoses deep candidiasis by measuring the amount of arabinitol present in serum.

1,4-디데옥시-1,4-이미노-L-아라비니톨 (LAB)는 효모 알파-글루코시다아제 저해활성에 있어서는 DAB에 비해 미미하지만, 쥐 장의 알파-글루코시다아제에 대한 저해능력은 보다 우수하다. LAB는 모닐리나아 프룩티게나 (Monilinia fructigena)의 알파-L-아라비노푸라노시다아제 Ⅲ (alpha-L-arabinofuranosidase Ⅲ)의 저해효과가 우수한 것으로도 알려져 있다. 특히 LAB는 HIV 저해 효과가 우수하여 이들 유도체를 이용한 항바이러스제 개발가능성에 대해 관심이 집중되고 있으며, 이에 대한 연구 개발이 활발히 진행되고 있다.1,4-dideoxy-1,4-imino-L-arabinitol (LAB) is less than DAB in yeast alpha-glucosidase inhibitory activity, but inhibits rat intestinal alpha-glucosidase. Is better than LAB is known to have an excellent inhibitory effect of alpha-L-arabinofuranosidase III of Monilinia fructigena. In particular, LAB has an excellent effect of inhibiting HIV, and attention is focused on the development of antiviral agents using these derivatives.

이상에서 설명한 바와 같이 1,4-디데옥시-1,4-이미노-아라비니톨의 광학이성질체로서 DAB와 LAB는 의약적으로 그 활용범위가 매우 넓다. 이에, DAB와 LAB를 고 수율 및 고 순도로 제조할 수 있는 효율적인 제조방법의 개발하고자 많은 노력이 있어 왔고 그 노력은 최근까지도 지속적으로 이어지고 있다.As described above, DAB and LAB are optically widely used as optical isomers of 1,4-dideoxy-1,4-imino-arabinitol. Therefore, many efforts have been made to develop an efficient manufacturing method for manufacturing DAB and LAB with high yield and high purity, and the effort has been continued until recently.

미국등록특허 제5,286,877호에는 D-라이소노락톤 (D-lyxonolactone)을 출발물질로 사용하여 총 9단계에 걸친 다단계 제조과정을 통해 LAB를 제조하는 방법을 제시하고 있다. 이 방법은 비교적 높은 수율과 전반적으로 용이한 유기합성 반응으로 이루어져 있으나, 소듐 아자이드 (NaN3)를 사용하는 등 대량생산에 적용하기에는 부적합한 유기합성 반응을 포함하고 있으며, 특히 9단계의 합성과정이라는 많은 제조단계로 이루어져 있는 단점이 있다.US Patent No. 5,286,877 discloses a method for producing LAB through a multi-step manufacturing process of nine steps using D-lyxonolactone as a starting material. This method consists of relatively high yield and overall easy organic synthesis reaction, but it contains organic synthesis reaction which is not suitable for mass production such as using sodium azide (NaN 3 ). There are disadvantages that consist of many manufacturing steps.

Figure pat00002
Figure pat00002

DAB의 제조방법으로서, J. Chem. Soc., Perkin Trans. 1, 2000, 1837 에서는 옥사졸리디논 화합물을 출발물질로 사용하여 총 5단계의 합성과정을 걸쳐 DAB를 제조하는 방법을 제시하고 있다. 하지만, ⅰ) 및 ⅱ)단계의 합성과정이 낮은 온도의 유지와 무수 조건이 필수 요건이므로, 실험실 수준의 합성규모는 가능하지만 대량생산을 위한 제조방법으로는 적합하지 않다.As a method for producing DAB, J. Chem. Soc., Perkin Trans. 1, 2000, and 1837 show a method for preparing DAB using a total of five steps using an oxazolidinone compound as a starting material. However, since the synthesis of steps i) and ii) is a prerequisite for low temperature maintenance and anhydrous conditions, laboratory scale synthesis is possible, but not suitable for manufacturing in mass production.

Figure pat00003
Figure pat00003

J. Med. Chem. 2006, 49, 5687-5701 에서는 D-아라비노스(D-Arabinose)를 출발물질로 사용하여 총 5단계의 합성과정을 거쳐 DAB를 제조하는 방법을 제시하고 있다. 이 방법은 d)단계에서 그람-음성균인 글루코노박터 옥시단스 (gluconobacter oxydans)를 이용한 생화학적 방법에 의한 제조방법을 제시하고 있으나, 이를 이용한 제조단계의 수율이 약 100 g의 잔사로부터 10 g 정도의 최종목적물을 얻는 등 제조방법상 비효율적 요소들이 존재한다. 특히, 최종 e)과정이 5 Bar의 수소기체 압력을 필요로 하기 때문에 대량생산에서의 위험성을 내포하고 있다. J. Med. Chem. In 2006, 49, 5687-5701, a method for preparing DAB using a total of five steps using D-Arabinose as a starting material is presented. This method suggests a biochemical method using a gram-negative bacterium gluconobacter oxydans in step d), but the yield of the preparation step using the same is about 10 g from the residue of 100 g. There are inefficient factors in the manufacturing process, such as obtaining the final object of the process. In particular, the final e) process requires a hydrogen gas pressure of 5 Bar, which poses a risk in mass production.

Figure pat00004
Figure pat00004

ORGANIC LETTERS 2006, Vol. 8, No. 18, 4101-4104 에서는 D-릭소스(D-lyxose)를 출발물질로 사용하여 총 6단계의 합성과정을 거쳐 DAB를 제조하는 방법을 제시하고 있다. 비교적 높은 수율과 입체선택성을 제시하고 있지만, 생성되는 중간체의 대부분이 액상으로 수득되어 대량생산을 위한 용이성 측면에서는 작업이 복잡해질 가능성이 높다.ORGANIC LETTERS 2006, Vol. 8, No. 18, 4101-4104, proposes a method for preparing DAB using 6 steps of synthesis using D-lyxose as a starting material. While relatively high yields and stereoselectivity have been suggested, most of the intermediates produced are obtained in the liquid phase, which is likely to complicate the operation in terms of ease of mass production.

Figure pat00005
Figure pat00005

이상에서 살펴본 바와 같이, 현재까지 알려진 1,4-디데옥시-1,4-이미노-아라비니톨의 제조방법은 개선의 여지가 있는 바, 종래 방법을 개선한 보다 효율적이며 고 순도로 DAB 또는 LAB를 제조하는 방법의 개발은 절실히 요구되어지고 있다.
As described above, the production method of 1,4-dideoxy-1,4-imino-arabinitol known to date has room for improvement, and thus, DAB or Development of a method for producing LAB is urgently required.

본 발명은 종래 제조방법에서 지적된 문제점을 한꺼번에 해결하는 1,4-디데옥시-1,4-이미노-아라비니톨의 개선된 제조방법을 제공하는 것을 목적으로 한다.It is an object of the present invention to provide an improved process for the preparation of 1,4-dideoxy-1,4-imino-aravinitol that solves the problems pointed out in the prior art.

본 발명은 광학이성질체로서 1,4-디데옥시-1,4-이미노-D-아라비니톨(DAB) 또는 1,4-디데옥시-1,4-이미노-L-아라비니톨(LAB)을 고 순도 및 고 수율로 제조하는 방법을 제공하는 것을 목적으로 한다.
The present invention relates to 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) or 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) as an optical isomer. It is an object of the present invention to provide a method for producing a high purity and high yield.

상기 과제 해결을 위하여, 본 발명은 하기의 제조과정을 포함하는 1,4-디데옥시-1,4-이미노-아라비니톨의 라세믹 화합물, 이의 광학이성질체, 또는 이들 이성질체 혼합물의 제조방법을 그 특징으로 한다.In order to solve the above problems, the present invention provides a method for producing a racemic compound of 1,4-dideoxy-1,4-imino-arabinitol, an optical isomer thereof, or a mixture of these isomers, including the following manufacturing process It is characterized by.

a) 하기 화학식 2로 표시되는 N-보호된 아지리딘일메탄올 화합물을 산화 반응(oxidation)한 후에, 하기 화학식 7로 표시되는 포스포노아세테이트 화합물과 반응시켜, 하기 화학식 3으로 표시되는 에스테르 화합물을 제조하는 과정;a) oxidizing the N- protected aziridinylmethanol compound represented by the following Chemical Formula 2, followed by reaction with a phosphonoacetate compound represented by the following Chemical Formula 7, to prepare an ester compound represented by the following Chemical Formula 3. process;

b) 하기 화학식 3으로 표시되는 에스테르 화합물을 디히드록실화 반응(dihidroxylation)시켜, 하기 화학식 4로 표시되는 디히드록시 화합물을 제조하는 과정;b) preparing a dihydroxy compound represented by the following Chemical Formula 4 by dihydroxylation of the ester compound represented by the following Chemical Formula 3;

c) 하기 화학식 4로 표시되는 디히드록시 화합물을 R3COOH로 표시되는 유기산 존재하에서 고리화 반응(cyclization)시켜, 하기 화학식 5로 표시되는 락탐 화합물을 제조하는 과정; 및c) cyclizing a dihydroxy compound represented by the following Chemical Formula 4 in the presence of an organic acid represented by R 3 COOH to prepare a lactam compound represented by the following Chemical Formula 5; And

d) 하기 화학식 5로 표시되는 락탐 화합물을 환원 반응(reduction)한 후에, 탈보호 반응(deprotection)하여 하기 화학식 1로 표시되는 1,4-디데옥시-1,4-이미노-아라비니톨을 제조하는 과정.d) reduction reaction of the lactam compound represented by the following formula (5), followed by deprotection to obtain 1,4-dideoxy-1,4-imino-arabinitol represented by the following formula (1) Manufacturing process.

[반응식 1]Scheme 1

Figure pat00006
Figure pat00006

상기 반응식 1에서, R1은 아민 보호기로서 벤질기, p-메톡시벤질기, 1-페닐에틸기, 벤젠설포닐기, 및 p-톨루엔설포닐기 중에서 선택되고; R2는 C1-6 알킬기, 또는 벤질기를 나타내고; R3은 C1-6 알킬기, 또는 페닐기를 나타낸다.In Scheme 1, R 1 is selected from benzyl group, p-methoxybenzyl group, 1-phenylethyl group, benzenesulfonyl group, and p-toluenesulfonyl group as an amine protecting group; R 2 represents a C 1-6 alkyl group or benzyl group; R 3 represents a C 1-6 alkyl group or a phenyl group.

또한, 본 발명은 상기 반응식 1에 따른 제조과정에서 합성되는 신규 중간체 화합물로서 상기 화학식 5로 표시되는 락탐 화합물 또는 이의 광학이성질체를 그 특징으로 한다.
In addition, the present invention is characterized by a lactam compound represented by the formula (5) or an optical isomer thereof as a novel intermediate compound synthesized in the preparation process according to Scheme 1.

본 발명의 제조방법은 상업적으로 구입이 용이하고 대량생산에 적용되어서도 취급상의 위험이 없는 화합물을 반응물질로 사용하고 있으므로, 산업적으로 이용 가능성이 높다.Since the production method of the present invention uses a compound which is easily commercially available and has no risk of handling even when applied to mass production, it is highly industrially applicable.

본 발명의 제조방법은 1,4-디데옥시-1,4-이미노-아라비니톨의 라세믹 화합물 또는 이성질체 혼합물 상태로 제조하는 것이 가능하다.The production method of the present invention can be prepared in a racemic compound or isomer mixture state of 1,4-dideoxy-1,4-imino-arabinitol.

본 발명의 제조방법은 광학활성 락탐 화합물을 반응 중간체로 합성 경유하여 1,4-디데옥시-1,4-이미노-아라비니톨의 광학이성질체를 제조하는 것이 가능하다.
According to the production method of the present invention, it is possible to prepare an optical isomer of 1,4-dideoxy-1,4-imino-arabinitol by synthesizing an optically active lactam compound as a reaction intermediate.

본 발명에 따른 제조방법을 각 과정별로 구분하여 보다 상세히 설명하면 다음과 같다.The manufacturing method according to the present invention will be described in more detail by dividing each process as follows.

제 1과정은, 상기 화학식 2로 표시되는 N-보호된 아지리딘일메탄올 화합물을 산화 반응하여 알데히드 화합물로 전환한 후에, 알킬 디에틸포스포노아세테이트 또는 벤질 디에틸포스포노아세테이트 등의 포스포노아세테이트 화합물과 반응시켜, 상기 화학식 3으로 표시되는 에스테르 화합물을 제조하는 과정이다.The first step is to convert the N- protected aziridinylmethanol compound represented by the formula (2) to an aldehyde compound by oxidation, and then to phosphonoacetate compounds such as alkyl diethylphosphonoacetate or benzyl diethylphosphonoacetate. The reaction is to prepare an ester compound represented by the formula (3).

본 발명의 제조방법에서 적용되는 산화 반응은 하이드록시 그룹을 알데히드 그룹으로 전환하기 위한 반응으로, 유기합성 분야에서 일반적으로 알려진 산화 반응이 적용될 수 있다. 보다 구체적으로 산화반응은 스원 산화반응(Swern oxidation), 데스-마틴 산화반응(Dess-Martin oxidation) 등을 사용할 수 있으며, 염화메틸렌, 테트라하이드로퓨란 등의 용매 하에서 수행되며, 적절한 반응온도는 -78℃ 내지 실온(대략 30℃) 범위이다.The oxidation reaction applied in the preparation method of the present invention is a reaction for converting a hydroxy group to an aldehyde group, and an oxidation reaction generally known in the field of organic synthesis may be applied. More specifically, the oxidation reaction may be performed using a Swern oxidation, Dess-Martin oxidation, and the like, and is performed under a solvent such as methylene chloride or tetrahydrofuran, and an appropriate reaction temperature is -78. C to room temperature (approximately 30 ° C.).

상기 산화 반응으로 생성된 알데히드 화합물은 상기 화학식 7로 표시되는 포스포노아세테이트 화합물과 반응시켜, 상기 화학식 3으로 표시되는 에스테르 화합물을 제조한다. 이때, 포스포노아세테이트 화합물은 메틸 디에틸포스포노아세테이트, 에틸 디에틸포스포노아세테이트, 프로필 디에틸포스포노아세테이트, 부틸 디에틸포스포노아세테이트, 펜틸 디에틸포스포노아세테이트, 헥실 디에틸포스포노아세테이트, 벤질 디에틸포스포노아세테이트 등이 포함될 수 있다. 포스포노아세테이트 화합물과의 반응은 물, 에탄올, 테트라하이드로퓨란 등의 극성용매 하에서, 그리고 반응온도 10℃ 내지 30℃ 범위, 바람직하기로는 실온 주변의 온도범위에서 수행할 수 있다. The aldehyde compound produced by the oxidation reaction is reacted with the phosphonoacetate compound represented by Chemical Formula 7 to prepare an ester compound represented by Chemical Formula 3. In this case, the phosphonoacetate compound is methyl diethyl phosphono acetate, ethyl diethyl phosphono acetate, propyl diethyl phosphono acetate, butyl diethyl phosphono acetate, pentyl diethyl phosphono acetate, hexyl diethyl phosphono acetate, benzyl Diethylphosphonoacetate, and the like. The reaction with the phosphonoacetate compound may be carried out under a polar solvent such as water, ethanol, tetrahydrofuran, and at a reaction temperature in the range of 10 ° C to 30 ° C, preferably at a temperature around room temperature.

제 2과정은, 상기 화학식 3으로 표시되는 에스테르 화합물을 사산화 오스뮴(OsO4) 촉매와 N-메틸몰폴린 N-옥사이드 존재하에서 디히드록실화 반응(dihidroxylation)시켜, 상기 화학식 4로 표시되는 디히드록시 화합물을 제조하는 과정이다.In the second process, a dihydroxylation reaction of the ester compound represented by Chemical Formula 3 in the presence of an osmium tetraoxide (OsO 4 ) catalyst and N -methylmorpholine N- oxide is carried out. It is a process for preparing a hydroxy compound.

상기 디히드록실화 반응은 물, 에탄올, 테트라하이드로퓨란 등의 극성 용매 하에서 수행하며, 바람직하기로는 물과 테트라하이드로퓨란이 1:1 내지 1:10 부피비를 이루는 혼합용매 하에서 수행하는 것이다. 반응온도는 -20℃ 내지 30℃ 범위, 바람직하기로는 실온 주변의 온도범위를 유지하는 것이다. The dehydroxylation reaction is carried out under a polar solvent such as water, ethanol, tetrahydrofuran, preferably under a mixed solvent in which water and tetrahydrofuran form a volume ratio of 1: 1 to 1:10. The reaction temperature is in the range of -20 ° C to 30 ° C, preferably at a temperature around room temperature.

제 3과정은, 상기 화학식 4로 표시되는 디히드록시 화합물을 R3COOH로 표시되는 유기산 존재하에서 고리화 반응시켜, 상기 화학식 5로 표시되는 락탐 화합물을 제조하는 과정이다.The third process is a process of preparing a lactam compound represented by Chemical Formula 5 by cyclizing the dihydroxy compound represented by Chemical Formula 4 in the presence of an organic acid represented by R 3 COOH.

상기 고리화 반응에서 사용되는 유기산은 지방족 알칸산 또는 방향족 산을 사용할 수 있는데, 구체적으로는 아세트산, 프로피온산, 부티르산, 벤조산 등이 사용될 수 있다. 상기 유기산의 사용량은 상기 화학식 4로 표시되는 디히드록시 화합물에 대하여 1 내지 20 몰비 범위이고, 고리화 반응의 효율성 등을 감안하면 5 내지 15 몰비 범위로 다소 과량을 사용하는 것이 좋다. 고리화 반응온도는 0℃ 내지 100℃ 범위이며, 좋기로는 30℃ 내지 80℃를 유지하는 것이다. 반응용매로는 테트라하이드로퓨란, 디에틸에테르, 에틸아세테이트, 염화메틸렌, 벤젠, 톨루엔 등의 유기용매를 사용할 수 있으며, 바람직하게는 염화메틸렌과 톨루엔을 1:1 내지 1:20 부피비 범위내에서 혼합한 혼합용매를 사용한다.As the organic acid used in the cyclization reaction, aliphatic alkanoic acid or aromatic acid may be used. Specifically, acetic acid, propionic acid, butyric acid and benzoic acid may be used. The amount of the organic acid used is in the range of 1 to 20 molar ratios with respect to the dihydroxy compound represented by Chemical Formula 4, and considering the efficiency of the cyclization reaction, it is preferable to use an excessive amount in the range of 5 to 15 molar ratios. The cyclization reaction temperature is in the range of 0 ° C to 100 ° C, preferably 30 ° C to 80 ° C. As the reaction solvent, organic solvents such as tetrahydrofuran, diethyl ether, ethyl acetate, methylene chloride, benzene, and toluene may be used. Preferably, methylene chloride and toluene are mixed in a volume ratio of 1: 1 to 1:20. One mixed solvent is used.

상기 고리화 반응결과로 생성된 상기 화학식 5로 표시되는 락탐 화합물은 반응생성 혼합물을 감압 증류하여 잔사로 얻는다. 이 잔사로 얻어진 상기 화학식 5로 표시되는 락탐 화합물은 직접 다음 반응에 사용될 수 있다. 필요하다면, 잔사로 얻어진 상기 화학식 5로 표시되는 락탐 화합물은 간단한 정제과정을 거쳐 광학적으로 순수한 하기 화학식 5a 또는 5b로 표시되는 광학이성질체로 각각 분리하여 다음 반응에 사용되어, 광학적으로 순수한 상기 화학식 1로 표시되는 목적 화합물을 얻을 수도 있다.The lactam compound represented by Chemical Formula 5 produced as a result of the cyclization reaction is distilled under reduced pressure to obtain a residue as a residue. The lactam compound represented by the formula (5) obtained as this residue can be used directly for the next reaction. If necessary, the lactam compound represented by Chemical Formula 5 obtained as a residue is separated into optical isomers represented by the following Chemical Formula 5a or 5b through a simple purification process, and then used in the following reaction, to optically pure Chemical Formula 1 The target compound displayed can also be obtained.

Figure pat00007
Figure pat00007

상기 화학식 5로 표시되는 락탐 화합물의 광학이성질체 분리를 위한 정제방법은 관 크로마토그래피법, 결정화법, 분별증류법 등이 적용될 수 있겠으나, 산업적 편리성을 고려하면 결정화법을 이용하는 것이 좋다. 결정화에 사용되는 용매로는 메탄올, 에탄올, 이소프로판올 등의 알코올류 용매, 테트라하이드로 퓨란, 다이에틸에테르, 메틸 t-부틸에테르, 디이소프로필에트 등의 에테르류 용매, 펜탄, 헥산, 펜탄, 옥탄, 벤젠, 톨루엔 등의 포화 또는 불포화 탄화수소류 용매, 염화메틸렌, 클로로포름 등의 유기염소계 용매, 메틸아세테이트, 에틸아세테이트 등의 에스테르류 용매, N,N-디메틸포름아마이드 등의 아마이드류 용매, 디메틸설폭사이드 등의 설폭사이드류 용매, 물 용매 등으로부터 선택된 단독 또는 혼합 용매를 사용하여 수행될 수 있다. 결정화를 수행함에 있어 온도는 -20℃ 내지 100℃ 범위, 바람직하게는 0℃ 내지 실온 주변의 온도를 유지하는 것이다.The purification method for separating the optical isomer of the lactam compound represented by Chemical Formula 5 may be applied by column chromatography, crystallization, fractional distillation, etc., but it is preferable to use crystallization in consideration of industrial convenience. Examples of the solvent used for crystallization include alcohol solvents such as methanol, ethanol and isopropanol, ether solvents such as tetrahydrofuran, diethyl ether, methyl t- butyl ether, diisopropyl ether, pentane, hexane, pentane, octane, Saturated or unsaturated hydrocarbon solvents such as benzene and toluene, organic chlorine solvents such as methylene chloride and chloroform, ester solvents such as methyl acetate and ethyl acetate, amide solvents such as N, N- dimethylformamide, dimethyl sulfoxide and the like. It can be carried out using a single or mixed solvent selected from the sulfoxide solvent, water solvent and the like. In carrying out the crystallization the temperature is to maintain a temperature around -20 ° C to 100 ° C, preferably around 0 ° C to room temperature.

제 4과정은, 상기 화학식 5로 표시되는 락탐 화합물을 환원 반응한 후에, 탈보호 반응하여 본 발명이 목적하는 상기 화학식 1로 표시되는 아라비니톨 유도체를 제조하는 과정이다.The fourth process is a process of preparing an arabinitol derivative represented by Chemical Formula 1 by the deprotection reaction after the reduction reaction of the lactam compound represented by Chemical Formula 5 above.

상기 환원 반응은 리튬 알루미늄 하이드라이드 (LiAlH4), 삼수소화보론-디메틸설파이드 배위화합물 (BH3-DMS) 등의 환원제 존재하에서 수행한다. 환원 반응온도는 -20℃ 내지 30℃ 범위, 바람직하기로는 0℃ 내지 실온 주변의 온도범위를 유지하는 것이다. 반응용매로는 염화메틸렌(DCM), 테트라하이드로퓨란(THF), 디에틸에테르, 1,4-디옥산, 톨루엔 등의 용매를 단독 또는 혼합하여 사용할 수 있다.The reduction reaction is carried out in the presence of a reducing agent such as lithium aluminum hydride (LiAlH 4 ), boron trihydride-dimethylsulfide coordination compound (BH 3 -DMS). The reduction reaction temperature is in the range of -20 ° C to 30 ° C, preferably at 0 ° C to room temperature. As a reaction solvent, solvents, such as methylene chloride (DCM), tetrahydrofuran (THF), diethyl ether, 1, 4- dioxane, toluene, can be used individually or in mixture.

탈보호화 반응은 아민 보호기(R1)을 탈리시키는 반응으로, 백금, 팔라듐 등의 전이금속 촉매와 수소기체를 사용하는 조건하에서 수행하거나, 또는 p-메톡시벤젠 또는 Li, Na 등의 알칼리 금속을 액화 암모니아에서 사용하는 조건하에서 수행할 수 있다. 상기 전이금속 촉매는 구체적으로 PtO2, Pd/C, Pd(OH)2 등이 포함될 수 있다. 상기 탈보호 반응에 사용되는 반응용매는 메탄올, 에탄올, 테트라하이드로퓨란, 디에틸에테르, 에틸아세테이트, 염화메틸렌, 벤젠, 톨루엔 등의 유기용매를 사용할 수 있다. The deprotection reaction is a reaction for desorbing the amine protecting group (R 1 ), which is performed under conditions using a transition metal catalyst such as platinum or palladium and a hydrogen gas, or an alkali metal such as p-methoxybenzene or Li or Na. It can be carried out under the conditions used in liquefied ammonia. The transition metal catalyst may specifically include PtO 2 , Pd / C, Pd (OH) 2, and the like. As the reaction solvent used in the deprotection reaction, organic solvents such as methanol, ethanol, tetrahydrofuran, diethyl ether, ethyl acetate, methylene chloride, benzene, toluene and the like can be used.

이상에서 설명한 바와 같이, 본 발명의 제조방법에 의하면 상기 화학식 1로 표시되는 1,4-디데옥시-1,4-이미노-아라비니톨은 라세믹 화합물, 광학이성질체 화합물 또는 이들 이성질체의 혼합물 상태로 제조될 수 있다. 또한, 제조된 라세믹 화합물 또는 광학이성질체 혼합물은 통상의 분리 정제방법을 통하여 하기 화학식 1a 또는 1b로 표시되는 각각의 광학이성질체로 분리할 수도 있다.As described above, according to the preparation method of the present invention, 1,4-dideoxy-1,4-imino-arabinitol represented by Chemical Formula 1 may be a racemic compound, an optical isomeric compound, or a mixture of these isomers. It can be prepared as. In addition, the prepared racemic compound or optical isomer mixture may be separated into the respective optical isomers represented by the following Chemical Formula 1a or 1b through a conventional separation and purification method.

Figure pat00008
Figure pat00008

한편, 본 발명에 따른 제조방법을 수행하는 과정에서 제조되는 중간체 화합물로서 상기 화학식 4로 표시되는 에스테르 화합물, 상기 화학식 5로 표시되는 락탐 화합물은 신규 화합물에 해당된다. 따라서, 본 발명의 제조방법은 상기 신규 중간체 화합물 및 이로부터 제조된 상기 화학식 1로 표시되는 1,4-디데옥시-1,4-이미노-아라비니톨의 약학적으로 허용 가능한 염의 제조방법도 권리범위로 포함한다. On the other hand, the ester compound represented by the formula (4), the lactam compound represented by the formula (5) as an intermediate compound prepared in the process of performing the preparation method according to the present invention corresponds to a novel compound. Accordingly, the preparation method of the present invention is a method for preparing a pharmaceutically acceptable salt of 1,4-dideoxy-1,4-imino-arabinitol represented by the novel intermediate compound and Formula 1 prepared therefrom. Include as right.

본 발명에서의 약학적으로 허용 가능한 염은 당해 기술 분야에서 통상적인 방법에 의해 제조될 수 있다. 약학적으로 허용된 염은 인체에 독성이 낮고 모화합물의 생물학적 활성과 물리화학적 성질에 악영향을 주지 않아야 한다. 약학적으로 허용된 염은 약학적으로 사용 가능한 유리산과 신규 중간체들의 염기 화합물의 산부가염으로 구성된다. 약학적으로 허용된 염 제조에 사용될 수 있는 유리산은 무기산과 유기산으로 나눌 수 있다. 무기산은 염산, 황산, 질산, 인산, 과염소산, 브롬산 등이 사용될 수 있다. 유기산은 초산, 메탄설폰산, 에탄설폰산, p-톨루엔설폰산, 푸마린산, 말레산, 말론산, 프탈산, 숙신산, 젖산, 구연산, 시트르산, 글루콘산, 타타르산, 살리실산, 말산, 옥살산, 벤조산, 엠본산, 아스파르트산, 글루탐산 등이 사용될 수 있다. 아미노산부가염기 제조에 사용될 수 있는 아미노산은 알라닌, 글라이신 등의 천연아미노산이다. 본 발명에 따른 상기한 신규 중간체들의 상기한 약학적으로 허용된 염과 더불어 모든 수화물 그리고 용매화물도 포함한다. 수화물 및 용매화물은 상기 신규 중간체들을 메탄올, 에탄올, 아세톤, 1,4-디옥산과 같은 물과 섞일 수 있는 용매에 녹인 다음에 유리산을 가한 후에 결정화되거나 또는 재결정화될 수 있다. 그러한 경우, 용매화물(특히 수화물)이 형성될 수 있다. 따라서, 본 발명의 화합물로서 동결건조와 같은 방법으로 제조 가능한 다양한 양의 물 함유 화합물 이외에 수화물을 비롯한 화학 양론적 용매화물도 포함한다.Pharmaceutically acceptable salts in the present invention can be prepared by conventional methods in the art. Pharmaceutically acceptable salts are of low toxicity to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts consist of acid addition salts of pharmaceutically usable free acids and base compounds of novel intermediates. Free acids that can be used to prepare pharmaceutically acceptable salts can be divided into inorganic acids and organic acids. The inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, or the like. Organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, Benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used. Amino acids that can be used to prepare amino acid addition bases are natural amino acids such as alanine, glycine and the like. All hydrates and solvates as well as the pharmaceutically acceptable salts of the novel intermediates described above according to the invention are included. Hydrates and solvates can be crystallized or recrystallized after dissolving the new intermediates in a solvent that can be mixed with water such as methanol, ethanol, acetone, 1,4-dioxane and then adding free acid. In such cases, solvates (particularly hydrates) may be formed. Accordingly, the compounds of the present invention also include stoichiometric solvates, including hydrates, in addition to various amounts of water-containing compounds that can be prepared by methods such as lyophilization.

이상에서 설명한 바와 같은 본 발명은 하기의 실시예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이에 한정되는 것은 아니다.
The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

[실시예]
EXAMPLE

실시예 1. (E)-에틸 3-((S)-1-((R)-1-페닐에틸)아지리딘-2-일)아크릴레이트Example 1. (E) -Ethyl 3-((S) -1-((R) -1-phenylethyl) aziridin-2-yl) acrylate

Figure pat00009
Figure pat00009

둥근 바닥 플라스크에 옥살릴 클로라이드 (2.4 mL, 27.93 mmol, 1.5 eq)를 투입하고 온도를 -78℃로 낮춘 다음에 디메틸설폭사이드 (DMSO; 2.4 mL, 33.52 mmol, 1.8 eq)를 천천히 적가하였다. 30분 경과한 후에 염화메틸렌 (40 mL)에 녹인 ((R)-1-((R)-1-페닐에틸)아지리딘-2-일)메탄올 (3.3 g, 18.62 mmol)을 천천히 적가하였다. 20분 동안 교반한 다음에 트리에틸아민 (13 mL, 93.1 mmol, 5 eq)를 넣고 반응 온도를 실온으로 올렸다. 반응이 종결되면 탄산수소나트륨 수용액을 사용하고 염화메틸렌으로 추출한 다음에 유기층을 무수 황산 마그네슘으로 건조하여 여과하였다. 용매를 감압 증류로 제거한 후 획득한 잔사에 에틸 디에틸포스포노아세테이트 (3.3 mL, 20.09 mmol, 1.1 eq), 탄산칼륨 (12.6 g, 91.3 mmol, 5 eq) 그리고 에탄올 (40 mL)을 넣고 실온에서 교반하였다. 반응이 종결되면 규조토로 여과하고 여과액을 에틸아세테이트와 물을 사용하여 추출하였다. 모아진 유기층을 무수 황산 마그네슘으로 건조하여 여과한 후 용매를 감압 증류로 제거하여 농축하였다. 획득한 잔사를 관 크로마토그래피(EtOAc : n-Hexane = 1 : 2)를 통해 정제하여 (E)-에틸 3-((S)-1-((R)-1-페닐에틸)아지리딘-2-일)아크릴레이트 (3.1 g, 70% 수율)를 얻었다.Oxalyl chloride (2.4 mL, 27.93 mmol, 1.5 eq) was added to a round bottom flask, the temperature was lowered to -78 ° C, and dimethyl sulfoxide (DMSO; 2.4 mL, 33.52 mmol, 1.8 eq) was slowly added dropwise. After 30 minutes, ((R) -1-((R) -1-phenylethyl) aziridin-2-yl) methanol (3.3 g, 18.62 mmol) dissolved in methylene chloride (40 mL) was slowly added dropwise. After stirring for 20 minutes, triethylamine (13 mL, 93.1 mmol, 5 eq) was added and the reaction temperature was raised to room temperature. After the reaction was completed, an aqueous sodium hydrogen carbonate solution was used, extraction was performed with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate and filtered. After distilling off the solvent under reduced pressure, the residue was obtained with ethyl diethylphosphonoacetate (3.3 mL, 20.09 mmol, 1.1 eq) and potassium carbonate (12.6 g, 91.3 mmol, 5 eq). And ethanol (40 mL) was added and stirred at room temperature. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was extracted using ethyl acetate and water. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the solvent was removed by distillation under reduced pressure and concentrated. The obtained residue was purified by column chromatography (EtOAc: n- Hexane = 1: 2) to give (E) -ethyl 3-((S) -1-((R) -1-phenylethyl) aziridine-2 -Yl) acrylate (3.1 g, 70% yield) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.38-7.32 (m, 4H), 7.28-7.23 (m, 1H), 6.76 (dd, J = 7.8 Hz, J = 15.6 Hz, 1H), 6.13 (d, J = 15.6 Hz, 1H), 4.21 (q, J = 6.3 Hz, J = 13.3 Hz, 2H), 2.55 (q, J = 6.5 Hz, J = 13.0 Hz, 1H), 2.16-2.12 (m, 1H), 1.80 (d, J = 3.1 Hz, 1H), 1.66 (d, J = 6.5 Hz, 1H), 1.42 (d, J = 6.5 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.21, 148.44, 144.06, 128.41, 127.22, 126.77, 121.88, 69.96, 60.14, 39.68, 35.97, 23.03, 14.28; HRMS (ESI) m/z Calcd for C15H19NO2 [M+Na]+ 268.1313, found 268.1313
 1 H NMR (400 MHz, CDCl 3 ) δ 7.38-7.32 ( m , 4H), 7.28-7.23 ( m , 1H), 6.76 ( dd , J = 7.8 Hz, J = 15.6 Hz, 1H), 6.13 ( d , J = 15.6 Hz, 1H), 4.21 ( q , J = 6.3 Hz, J = 13.3 Hz, 2H), 2.55 ( q , J = 6.5 Hz, J = 13.0 Hz, 1H), 2.16-2.12 ( m , 1H) , 1.80 ( d , J = 3.1 Hz, 1H), 1.66 ( d , J = 6.5 Hz, 1H), 1.42 ( d , J = 6.5 Hz, 3H), 1.29 ( t , J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 166.21, 148.44, 144.06, 128.41, 127.22, 126.77, 121.88, 69.96, 60.14, 39.68, 35.97, 23.03, 14.28; HRMS (ESI) m / z Calcd for C 15 H 19 NO 2 [M + Na] + 268.1313, found 268.1313

실시예 2. 에틸 2,3-디하이드록시-3-((R)-1-((R)-1-페닐에틸)아지리딘-2-일)프로파노에이트Example 2. Ethyl 2,3-dihydroxy-3-((R) -1-((R) -1-phenylethyl) aziridin-2-yl) propanoate

Figure pat00010
Figure pat00010

둥근 바닥 플라스크에 (E)-에틸 3-((S)-1-((R)-1-페닐에틸)아지리딘-2-일)아크릴레이트 (2.9 g, 11.83 mmol)와 N-메틸몰폴린 N-옥사이드 (NMO; 1.8 g, 13.00 mmol, 1.1 eq), 테트라하이드로퓨란 (23 mL), H2O (7.7 mL)을 넣고 0℃로 맞춘 후 OsO4 (3 mL, 0.47 mmol, 0.04 eq)를 천천히 적가하였다. 반응온도를 천천히 실온으로 올리면서 12시간 동안 교반시킨 후 Na2S2O3을 첨가하여 반응을 종결시킨다. 에틸아세테이트와 물을 사용하여 추출한 다음에 모아진 유기층을 무수 황산 마그네슘으로 건조하여 여과하였다. 용매를 감압 증류로 제거한 후 획득한 잔사를 관 크로마토그래피 (EtOAc : n-Hexane = 1 : 1)를 통해 정제하여 에틸 2,3-디하이드록시-3-((R)-1-((R)-1-페닐에틸)아지리딘-2-일)프로파노에이트 (2.4 g, 73% 수율)를 얻었다.In a round bottom flask, (E) -ethyl 3-((S) -1-((R) -1-phenylethyl) aziridin-2-yl) acrylate (2.9 g, 11.83 mmol) and N -methylmorpholine Add N- oxide (NMO; 1.8 g, 13.00 mmol, 1.1 eq), tetrahydrofuran (23 mL), H 2 O (7.7 mL), adjust to 0 ° C and OsO 4 (3 mL, 0.47 mmol, 0.04 eq) Was slowly added dropwise. After stirring for 12 hours while slowly raising the reaction temperature to room temperature, Na 2 S 2 O 3 was added to terminate the reaction. Extraction was performed using ethyl acetate and water, and the combined organic layers were dried over anhydrous magnesium sulfate and filtered. After distilling off the solvent under reduced pressure, the obtained residue was purified by column chromatography (EtOAc: n- Hexane = 1: 1) to obtain ethyl 2,3-dihydroxy-3-((R) -1-((R ) -1-phenylethyl) aziridin-2-yl) propanoate (2.4 g, 73% yield) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.36-7.29 (m, 8H), 7.28-7.23 (m, 2H), 4.33-4.25 (m, 6H), 3.93 (brs, 1H), 3.75 (brs, 1H), 3.34 (brs, 1H), 3.16 (brs, 1H), 2.63 (q, 1H), 2.58 (q, 1H), 2.02-1.96 (m, 2H), 1.87 (d, J = 3.5 Hz, 1H), 1.72 (d, J = 3.5 Hz, 1H), 1.50-1.45 (m, 6H), 1.33-1.28 (m, 6H); HRMS (ESI) m/z Calcd for C15H21NO4 [M+Na]+ 302.1368, found 302.1367.
 1 H NMR (400 MHz, CDCl 3 ) δ 7.36-7.29 ( m , 8H), 7.28-7.23 ( m , 2H), 4.33-4.25 ( m , 6H), 3.93 ( brs , 1H), 3.75 ( brs , 1H ), 3.34 ( brs , 1H), 3.16 ( brs , 1H), 2.63 ( q , 1H), 2.58 ( q , 1H), 2.02-1.96 ( m , 2H), 1.87 ( d , J = 3.5 Hz, 1H) , 1.72 ( d , J = 3.5 Hz, 1H), 1.50-1.45 ( m , 6H), 1.33-1.28 ( m , 6H); HRMS (ESI) m / z Calcd for C 15 H 21 NO 4 [M + Na] + 302.1368, found 302.1367.

실시예 3. ((2R,3R,4S)-3,4-디히드록시-5-옥소-1-((R)-1-페닐에틸)피롤리딘-2-일)메틸 아세테이트Example 3. ((2R, 3R, 4S) -3,4-dihydroxy-5-oxo-1-((R) -1-phenylethyl) pyrrolidin-2-yl) methyl acetate

Figure pat00011
Figure pat00011

둥근 바닥 플라스크에 에틸 2,3-디하이드록시-3-((R)-1-((R)-1-페닐에틸)아지리딘-2-일)프로파노에이트 (1.3 g, 4.66 mmol)와 아세트산 (3 mL, 46.54 mmol, 10 eq), 염화메틸렌 (15 mL)을 넣고 실온에서 18시간 동안 교반시켰다. 톨루엔(150 mL)을 첨가하고 50℃로 가열하였다. 12시간 동안 교반한 다음에 용매를 감압 증류하여 제거한 후 에틸아세테이트와 물로 추출하고 모아진 유기층을 무수 황산 마그네슘으로 건조하여 여과하였다. 용매를 감압 증류로 제거한 다음에 획득한 잔사를 관 크로마토그래피 (EtOAc : n-Hexane = 2 : 1)를 통해 여과하고 농축하였다. 잔사 (980 mg)를 에탄올 (3 mL)로 용해시키고 0℃에서 12시간 방치하였다. 생성된 고체를 여과하여 ((2R,3R,4S)-3,4-디히드록시-5-옥소-1-((R)-1-페닐에틸)피롤리딘-2-일)메틸 아세테이트 (350 mg, 60% 수율)를 얻었다.In a round bottom flask, ethyl 2,3-dihydroxy-3-((R) -1-((R) -1-phenylethyl) aziridin-2-yl) propanoate (1.3 g, 4.66 mmol) Acetic acid (3 mL, 46.54 mmol, 10 eq) and methylene chloride (15 mL) were added and stirred at room temperature for 18 hours. Toluene (150 mL) was added and heated to 50 ° C. After stirring for 12 hours, the solvent was distilled off under reduced pressure, extracted with ethyl acetate and water, and the combined organic layers were dried over anhydrous magnesium sulfate and filtered. After removing the solvent by distillation under reduced pressure, the obtained residue was filtered through a column chromatography (EtOAc: n- Hexane = 2: 1) and concentrated. The residue (980 mg) was dissolved in ethanol (3 mL) and left at 0 ° C. for 12 hours. The resulting solid was filtered to give ((2R, 3R, 4S) -3,4-dihydroxy-5-oxo-1-((R) -1-phenylethyl) pyrrolidin-2-yl) methyl acetate ( 350 mg, 60% yield).

1H NMR (400 MHz, CDCl3) δ 7.36-7.32 (m, 2H), 7.28-7.26 (m, 3H), 5.32 (q, J = 7.2 Hz, J = 14.4 Hz, 1H), 4.37 (d, J = 6.8 Hz, 1H), 4.13 (m, 2H), 4.05 (dd, J = 3.4 Hz, J = 12.5 Hz, 1H), 3.30 (m, 1H), 1.98 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.18, 170.77, 138.23, 128.82, 127.88, 127.27, 76.12, 73.59, 61.06, 59.55, 51.24, 20.73, 17.77; HRMS (ESI) m/z Calcd for C15H19NO5 [M+Na]+ 316.1161, found 316.1164.
 1 H NMR (400 MHz, CDCl 3 ) δ 7.36-7.32 ( m , 2H), 7.28-7.26 ( m , 3H), 5.32 ( q , J = 7.2 Hz, J = 14.4 Hz, 1H), 4.37 ( d, J = 6.8 Hz, 1H), 4.13 ( m , 2H), 4.05 ( dd , J = 3.4 Hz, J = 12.5 Hz, 1H), 3.30 ( m , 1H), 1.98 ( s , 3H), 1.61 ( d , J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 173.18, 170.77, 138.23, 128.82, 127.88, 127.27, 76.12, 73.59, 61.06, 59.55, 51.24, 20.73, 17.77; HRMS (ESI) m / z Calcd for C 15 H 19 NO 5 [M + Na] + 316.1161, found 316.1164.

실시예 4. (2R,3R,4R)-2-(하이드록시메틸)-1-((R)-1-페닐에틸)피롤리딘-3,4-디올Example 4 (2R, 3R, 4R) -2- (hydroxymethyl) -1-((R) -1-phenylethyl) pyrrolidine-3,4-diol

Figure pat00012
Figure pat00012

둥근 바닥 플라스크에 ((2R,3R,4S)-3,4-디히드록시-5-옥소-1-((R)-1-페닐에틸)피롤리딘-2-일)메틸 아세테이트 (300 mg, 1.02 mmol)와 테트라하이드로퓨란 (10 mL)를 넣고 온도를 0℃로 맞춘 후 삼수소화보론-디메틸설파이드 배위화합물 (BH3-DMS; 5.1 mL, 10.2 mmol, 10 eq)을 천천히 적가하였다. 반응 온도를 실온으로 올리면서 12시간 동안 교반시킨 후 물 (1.0 mL)을 첨가하여 반응을 종결시켰다. 반응물을 무수 황산 마그네슘으로 건조시킨 후 규조토 패드로 여과한 다음에 용매를 감압 증류시켰다. 잔사를 관 크로마토그래피 (DCM : 7N Ammonia solution in MeOH = 10 : 1)를 통해 정제하여 (2R,3R,4R)-2-(하이드록시메틸)-1-((R)-1-페닐에틸)피롤리딘-3,4-디올 (230 mg, 95 % 수율)을 얻었다.In a round bottom flask ((2R, 3R, 4S) -3,4-dihydroxy-5-oxo-1-((R) -1-phenylethyl) pyrrolidin-2-yl) methyl acetate (300 mg , 1.02 mmol) and tetrahydrofuran (10 mL) were added and the temperature was adjusted to 0 ° C., and boron trihydride-dimethylsulfide coordination compound (BH 3 -DMS; 5.1 mL, 10.2 mmol, 10 eq) was slowly added dropwise. After stirring for 12 hours while raising the reaction temperature to room temperature, the reaction was terminated by addition of water (1.0 mL). The reaction was dried over anhydrous magnesium sulfate, filtered through a pad of diatomaceous earth, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (DCM: 7N Ammonia solution in MeOH = 10: 1) to give (2R, 3R, 4R) -2- (hydroxymethyl) -1-((R) -1-phenylethyl) Pyrrolidine-3,4-diol (230 mg, 95% yield) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.34-7.28 (m, 4H), 7.26-7.22 (m, 1H), 3.98 (brs, 1H), 3.88 (brs, 1H), 3.73 (q, J = 6.5 Hz, J = 13.2 Hz, 1H), 3.67-3.64 (m, 2H), 3.32 (d, J = 10.9 Hz, 2H), 2.99 (brs, 2H), 2.91 (dd, J = 3.9 Hz, J = 11.1Hz, 1H), 2.76 (brs, 1H), 1.40 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.51, 128.59, 127.52, 127.29, 81.94, 75.84, 70.66, 62.51, 61.62, 56.96, 19.29; HRMS (ESI) m/z Calcd for C13H19NO3 [M+Na]+ 260.1263, found 260.1264.
 1 H NMR (400 MHz, CDCl 3 ) δ 7.34-7.28 ( m , 4H), 7.26-7.22 ( m , 1H), 3.98 ( brs , 1H), 3.88 ( brs , 1H), 3.73 ( q , J = 6.5 Hz, J = 13.2 Hz, 1H), 3.67-3.64 ( m , 2H), 3.32 ( d , J = 10.9 Hz, 2H), 2.99 ( brs , 2H), 2.91 ( dd , J = 3.9 Hz, J = 11.1 Hz, 1H), 2.76 ( brs , 1H), 1.40 ( d , J = 6.6 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 144.51, 128.59, 127.52, 127.29, 81.94, 75.84, 70.66, 62.51, 61.62, 56.96, 19.29; HRMS (ESI) m / z Calcd for Cl 3 H 19 NO 3 [M + Na] + 260.1263, found 260.1264.

실시예 5. 1,4-디데옥시-1,4-이미노-D-아라비니톨Example 5. 1,4-dideoxy-1,4-imino-D-aravinitol

Figure pat00013
Figure pat00013

둥근바닥 플라스크에 (2R,3R,4R)-2-(하이드록시메틸)-1-((R)-1-페닐에틸)피롤리딘-3,4-디올 (230 mg, 0.91 mmol)과 Pd(OH)2 (23 mg), 메탄올 (3 mL)을 넣고 실온에서 교반시켰다. 3시간 후 반응이 종결하면 규조토 패드로 여과하여 용매를 감압 증류시켰다. 이 화합물을 관 크로마토그래피 (DCM : MeOH : EtOH : 30% 암모니아수 = 5 : 2 : 2 : 1)를 통해 정제하여 1,4-디데옥시-1,4-이미노-D-아라비니톨 (130 mg)을 얻었다.In a round bottom flask, (2R, 3R, 4R) -2- (hydroxymethyl) -1-((R) -1-phenylethyl) pyrrolidine-3,4-diol (230 mg, 0.91 mmol) and Pd (OH) 2 (23 mg) and methanol (3 mL) were added and stirred at room temperature. After 3 hours, when the reaction was completed, the mixture was filtered through a pad of diatomaceous earth, and the solvent was distilled off under reduced pressure. The compound was purified by column chromatography (DCM: MeOH: EtOH: 30% aqueous ammonia = 5: 2: 2: 1) to give 1,4-dideoxy-1,4-imino-D-arabinitol (130 mg).

1H NMR (400 MHz, D2O) δ 4.26-4.22 (m, 1H), 3.98 (t, J = 3.5 Hz, 1H), 3.85 (dd, J = 4.7 Hz, J = 12.0 Hz, 1H), 3.75 (dd, J = 7.4 Hz, J = 12.0 Hz, 1H), 3.39-3.33 (m, 2H), 3.14-3.12 (m, 1H); HRMS (ESI) m/z Calcd for C5H11NO3 [M+Na]+ 156.0637 found 156.0635
 1 H NMR (400 MHz, D 2 O) δ 4.26-4.22 ( m , 1H), 3.98 ( t , J = 3.5 Hz, 1H), 3.85 ( dd , J = 4.7 Hz, J = 12.0 Hz, 1H), 3.75 ( dd , J = 7.4 Hz, J = 12.0 Hz, 1H), 3.39-3.33 ( m , 2H), 3.14-3.12 ( m , 1H); HRMS (ESI) m / z Calcd for C 5 H 11 NO 3 [M + Na] + 156.0637 found 156.0635

실시예 6. (E)-에틸 3-((R)-1-((R)-1-페닐에틸)아지리딘-2-일)아크릴레이트Example 6. (E) -Ethyl 3-((R) -1-((R) -1-phenylethyl) aziridin-2-yl) acrylate

Figure pat00014
Figure pat00014

둥근 바닥 플라스크에 옥살릴 클로라이드 (1.1 mL, 12.69 mmol, 1.5 eq)를 투입하고 온도를 -78℃로 낮춘 다음에 DMSO (1.1 mL, 15.23 mmol, 1.8 eq)를 천천히 적가하였다. 30분 경과한 후에 염화메틸렌(18 mL)에 녹인 ((R)-1-((S)-1-페닐에틸)아지리딘-2-일)메탄올 (1.5 g, 8.46 mmol)을 천천히 적가하였다. 20분 동안 교반한 다음에 트리에틸아민 (5.9 mL, 42.3 mmol, 5 eq)을 넣고 반응 온도를 실온으로 올렸다. 반응이 종결되면 탄산수소나트륨 수용액을 사용하고 염화메틸렌으로 추출한 다음에 유기층을 무수 황산 마그네슘으로 건조하여 여과하였다. 용매를 감압 증류로 제거한 후 획득한 잔사에 에틸 디에틸포스포노아세테이트 (1.9 mL, 9.42 mmol, 1.1 eq), 탄산칼륨 (6 g, 42.8 mmol, 5 eq) 그리고 에탄올 (20 mL)을 넣고 실온에서 교반하였다. 반응이 종결되면 규조토로 여과하고 여과액을 에틸아세테이트와 물을 사용하여 추출하였다. 모아진 유기층을 무수 황산 마그네슘으로 건조하여 여과한 후 용매를 감압 증류로 제거하여 농축하였다. 획득한 잔사를 관 컬럼크로마토그래피 (EtOAc : n-Hexane = 1 : 2)를 통해 정제하여 ((E)-에틸 3-((R)-1-((R)-1-페닐에틸)아지리딘-2-일)아크릴레이트 (1.1 g, 53% 두 단계 수율)를 얻었다.Oxalyl chloride (1.1 mL, 12.69 mmol, 1.5 eq) was added to a round bottom flask, the temperature was lowered to -78 ° C, and DMSO (1.1 mL, 15.23 mmol, 1.8 eq) was slowly added dropwise. After 30 minutes, ((R) -1-((S) -1-phenylethyl) aziridin-2-yl) methanol (1.5 g, 8.46 mmol) dissolved in methylene chloride (18 mL) was slowly added dropwise. After stirring for 20 minutes, triethylamine (5.9 mL, 42.3 mmol, 5 eq) was added thereto, and the reaction temperature was raised to room temperature. After the reaction was completed, an aqueous sodium hydrogen carbonate solution was used, extraction was performed with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate and filtered. After distilling off the solvent under reduced pressure, the residue was obtained with ethyl diethylphosphonoacetate (1.9 mL, 9.42 mmol, 1.1 eq) and potassium carbonate (6 g, 42.8 mmol, 5 eq). And ethanol (20 mL) was added and stirred at room temperature. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was extracted using ethyl acetate and water. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the solvent was removed by distillation under reduced pressure and concentrated. The obtained residue was purified by column column chromatography (EtOAc: n- Hexane = 1: 2) to obtain ((E) -ethyl 3-((R) -1-((R) -1-phenylethyl) aziridine 2-yl) acrylate (1.1 g, 53% two-step yield) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.25-7.16 (m, 5H), 6.60 (dd, J = 7.5 Hz, J = 15.6 Hz, 1H), 5.86 (d, J = 15.6Hz, 1H), 4.08 (q, J = 7.1 Hz, 14.2 Hz, 2H), 2.50 (q, J = 6.56 Hz, J = 13.1 Hz, 1H), 1.96-1.92 (m, 1H), 1.74-1.72 (m, 1H), 1.37 (d, J = 6.6 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.21, 148.09, 144.12, 128.39, 127.04, 126.47, 121.73, 69.88, 60.27, 38.60, 36.93, 23.46, 14.21.
 1 H NMR (400 MHz, CDCl 3 ) δ 7.25-7.16 ( m , 5H), 6.60 ( dd , J = 7.5 Hz, J = 15.6 Hz, 1H), 5.86 ( d , J = 15.6Hz, 1H), 4.08 ( q , J = 7.1 Hz, 14.2 Hz, 2H), 2.50 ( q , J = 6.56 Hz, J = 13.1 Hz, 1H), 1.96-1.92 ( m , 1H), 1.74-1.72 ( m , 1H), 1.37 ( d , J = 6.6 Hz, 3H), 1.19 ( t , J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 166.21, 148.09, 144.12, 128.39, 127.04, 126.47, 121.73, 69.88, 60.27, 38.60, 36.93, 23.46, 14.21.

실시예 7. 에틸 2,3-디하이드록시-3-((S)-1-((R)-1-페닐에틸)아지리딘-2-일)프로파노에이트Example 7. Ethyl 2,3-dihydroxy-3-((S) -1-((R) -1-phenylethyl) aziridin-2-yl) propanoate

Figure pat00015
Figure pat00015

둥근 바닥 플라스크에 ((E)-에틸 3-((R)-1-((R)-1-페닐에틸)아지리딘-2-일)아크릴레이트 (1.1 g, 4.48 mmol)과 N-메틸몰폴린 N-옥사이드 (NMO; 578 mg, 4.93 mmol, 1.1 eq), 테트라하이드로퓨란 (9 mL), H2O (3 mL)을 넣고 0℃로 맞춘 후 OsO4 (1.1 mL, 0.18 mmol, 0.04 eq)를 천천히 적가하였다. 반응온도를 천천히 실온으로 올리면서 12시간 동안 교반시킨 후 Na2S2O3을 첨가하여 반응을 종결시켰다. 에틸아세테이트와 물을 사용하여 추출한 다음에 모아진 유기층을 무수 황산 마그네슘로 건조하여 여과하였다. 용매를 감압 증류로 제거한 후 획득한 잔사를 관 크로마토그래피 (EtOAc : n-Hexane = 1 : 1)를 통해 정제하여 에틸 2,3-디하이드록시-3-((S)-1-((R)-1-페닐에틸)아지리딘-2-일)프로파노에이트 (970 mg, 78% 수율)를 얻었다.In a round bottom flask, ((E) -ethyl 3-((R) -1-((R) -1-phenylethyl) aziridin-2-yl) acrylate (1.1 g, 4.48 mmol) and N- methylmol Pauline N- oxide (NMO; 578 mg, 4.93 mmol, 1.1 eq), tetrahydrofuran (9 mL), H 2 O (3 mL) was added to 0 ° C., OsO 4 (1.1 mL, 0.18 mmol, 0.04 eq The reaction was terminated by slowly adding the reaction temperature slowly to room temperature, followed by addition of Na 2 S 2 O 3 , followed by extraction with ethyl acetate and water, and the combined organic layers were dried over anhydrous magnesium sulfate. The resulting residue was purified by column chromatography (EtOAc: n- Hexane = 1: 1) after removal of the solvent by distillation under reduced pressure, and then purified by ethyl 2,3-dihydroxy-3-((S)). -1-((R) -1-phenylethyl) aziridin-2-yl) propanoate (970 mg, 78% yield) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.37-7.31 (m, 8H), 7.30-7.26 (m, 2H), 4.33-4.25 (m, 6H), 3.90 (m, 1H), 3.72 (m, 1H), 3.52 (m, 1H), 3.47 (m, 1H), 2.63-2.52 (m, 2H), 2.28 (m, 1H), 2.08 (d, J = 3.5 Hz, 1H), 2.02 (m, 1H), 1.96 (d, J = 3.5 Hz, 1H), 1.90-1.83 (m, 2H), 1.62 (d, J = 6.4 Hz, 1H), 1.59 (d, J = 6.5 Hz, 1H), 1.50-1.43 (m, 6H), 1.27-1.21 (m, 6H)
 1 H NMR (400 MHz, CDCl 3 ) δ 7.37-7.31 ( m , 8H), 7.30-7.26 ( m , 2H), 4.33-4.25 ( m , 6H), 3.90 ( m , 1H), 3.72 ( m , 1H ), 3.52 ( m , 1H), 3.47 ( m , 1H), 2.63-2.52 ( m , 2H), 2.28 ( m , 1H), 2.08 ( d, J = 3.5 Hz, 1H), 2.02 ( m , 1H) , 1.96 ( d , J = 3.5 Hz, 1H), 1.90-1.83 ( m , 2H), 1.62 ( d , J = 6.4 Hz, 1H), 1.59 ( d , J = 6.5 Hz, 1H), 1.50-1.43 ( m , 6H), 1.27-1.21 ( m , 6H)

실시예 8. ((2S,3S,4R)-3,4-디히드록시-5-옥소-1-((R)-1-페닐에틸)피롤리딘-2-일)메틸 아세테이트Example 8. ((2S, 3S, 4R) -3,4-dihydroxy-5-oxo-1-((R) -1-phenylethyl) pyrrolidin-2-yl) methyl acetate

Figure pat00016
Figure pat00016

둥근 바닥 플라스크에 에틸 2,3-디하이드록시-3-((S)-1-((R)-1-페닐에틸)아지리딘-2-일)프로파노에이트 (620 mg, 2.22 mmol)와 아세트산 (0.63 mL, 11.1 mmol, 10 eq), 염화메틸렌 (7 mL)을 넣고 실온에서 18시간 동안 교반시켰다. 톨루엔 (70 mL)을 첨가하고 50℃로 가열하였다. 12시간 동안 교반한 다음에 용매를 감압 증류하여 제거한 후 에틸아세테이트와 물로 추출하고 모아진 유기층을 무수 황산 마그네슘으로 건조하여 여과하였다. 용매를 감압 증류로 제거한 다음에 획득한 잔사를 관 크로마토그래피 (EtOAc : n-Hexane = 2 : 1)를 통해 여과하고 농축하였다. 잔사(600 mg)를 에탄올 (2 mL)로 용해시키고 0℃에서 12시간 방치하였다. 생성된 고체를 여과하여 ((2S,3S,4R)-3,4-디히드록시-5-옥소-1-((R)-1-페닐에틸)피롤리딘-2-일)메틸 아세테이트 (330 mg)를 얻었다.In a round bottom flask, ethyl 2,3-dihydroxy-3-((S) -1-((R) -1-phenylethyl) aziridin-2-yl) propanoate (620 mg, 2.22 mmol) Acetic acid (0.63 mL, 11.1 mmol, 10 eq) and methylene chloride (7 mL) were added and stirred at room temperature for 18 hours. Toluene (70 mL) was added and heated to 50 ° C. After stirring for 12 hours, the solvent was distilled off under reduced pressure, extracted with ethyl acetate and water, and the combined organic layers were dried over anhydrous magnesium sulfate and filtered. After removing the solvent by distillation under reduced pressure, the obtained residue was filtered through a column chromatography (EtOAc: n- Hexane = 2: 1) and concentrated. The residue (600 mg) was dissolved in ethanol (2 mL) and left at 0 ° C. for 12 hours. The resulting solid was filtered to give ((2S, 3S, 4R) -3,4-dihydroxy-5-oxo-1-((R) -1-phenylethyl) pyrrolidin-2-yl) methyl acetate ( 330 mg).

1H NMR (400 MHz, CDCl3) δ 7.35-7.29 (m, 5H), 5.42 (q, 1H), 4.27 (m, 1H), 4.17 (m, 1H), 4.01 (dd, J = 3.5 Hz, J = 12.3 Hz, 1H), 3.94 (dd, J = 3.6 Hz, J = 12.5 Hz, 1H), 3.64 (m, 1H),3.07 (d, J = 2.3 Hz, 1H), 2.54 (d, J = 4.1 Hz, 1H), 1.82 (s, 3H), 1.72 (d, J = 7.3 Hz, 3H).
1 H NMR (400 MHz, CDCl 3 ) δ 7.35-7.29 ( m , 5H), 5.42 ( q , 1H), 4.27 ( m , 1H), 4.17 ( m , 1H), 4.01 ( dd , J = 3.5 Hz, J = 12.3 Hz, 1H), 3.94 ( dd , J = 3.6 Hz, J = 12.5 Hz, 1H), 3.64 ( m , 1H), 3.07 ( d , J = 2.3 Hz, 1H), 2.54 ( d , J = 4.1 Hz, 1H), 1.82 ( s , 3H), 1.72 ( d , J = 7.3 Hz, 3H).

실시예 9. (2S,3S,4R)-2-(하이드록시메틸)-1-((R)-1-페닐에틸)피롤리딘-3,4-디올Example 9. (2S, 3S, 4R) -2- (hydroxymethyl) -1-((R) -1-phenylethyl) pyrrolidine-3,4-diol

Figure pat00017
Figure pat00017

둥근 바닥 플라스크에 ((2S,3S,4R)-3,4-디히드록시-5-옥소-1-((R)-1-페닐에틸)피롤리딘-2-일)메틸 아세테이트 (330 mg, 1.13 mmol)을 넣고 온도를 0℃로 맞춘 후 삼수소화보론-디메틸설파이드 배위화합물 (BH3-DMS; 5.2 mL, 10.3 mmol, 10 eq)를 천천히 적가하였다. 반응 온도를 실온으로 올리면서 12시간 동안 교반시킨 후 물 (1.0 mL)을 첨가하여 반응을 종결시켰다. 반응물을 무수 황산 마그네슘으로 건조시킨 후 규조토 패드로 여과한 다음에 용매를 감압 증류시켰다. 잔사를 관 크로마토그래피 (DCM : 7N Ammonia solution in MeOH = 10 : 1)를 통해 정제하여 (2S,3S,4R)-2-(하이드록시메틸)-1-((R)-1-페닐에틸)피롤리딘-3,4-디올 (180 mg, 64 % 수율)을 얻었다.In a round bottom flask ((2S, 3S, 4R) -3,4-dihydroxy-5-oxo-1-((R) -1-phenylethyl) pyrrolidin-2-yl) methyl acetate (330 mg , 1.13 mmol) was added and the temperature was adjusted to 0 ° C., and boron trihydride-dimethylsulfide coordination compound (BH 3 -DMS; 5.2 mL, 10.3 mmol, 10 eq) was slowly added dropwise. After stirring for 12 hours while raising the reaction temperature to room temperature, the reaction was terminated by addition of water (1.0 mL). The reaction was dried over anhydrous magnesium sulfate, filtered through a pad of diatomaceous earth, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (DCM: 7N Ammonia solution in MeOH = 10: 1) to give (2S, 3S, 4R) -2- (hydroxymethyl) -1-((R) -1-phenylethyl) Pyrrolidine-3,4-diol (180 mg, 64% yield) was obtained.

1H NMR (400 MHz, D2O) δ 7.35-7.25 (m, 5H), 3.92 (m, 1H), 3.87 (m, 1H), 3.82 (m, 1H), 3.69-3.59 (m, 2H), 3.32 (d, J = 10.9 Hz, 2H), 2.81 (m, 1H), 2.73 (m, 2H), 1.39 (d, J = 6.7 Hz, 3H).
 1 H NMR (400 MHz, D 2 O) δ 7.35-7.25 ( m , 5H), 3.92 ( m , 1H), 3.87 ( m , 1H), 3.82 ( m , 1H), 3.69-3.59 ( m , 2H) , 3.32 ( d , J = 10.9 Hz, 2H), 2.81 ( m , 1H), 2.73 ( m , 2H), 1.39 ( d , J = 6.7 Hz, 3H).

실시예 10. 1,4-디데옥시-1,4-이미노-L-아라비니톨Example 10 1,4-dideoxy-1,4-imino-L-arabinitol

Figure pat00018
Figure pat00018

둥근바닥 플라스크에 ((2S,3S,4R)-2-(하이드록시메틸)-1-((R)-1-페닐에틸)피롤리딘-3,4-디올 (130 mg, 0.54 mmol)과 Pd(OH)2 (13 mg), 메탄올 (2 mL)을 넣고 실온에서 교반시켰다. 3시간 후 반응이 종결하면 규조토 패드로 여과하여 용매를 감압 증류시켰다. 이 화합물을 관 크로마토그래피(DCM : MeOH : EtOH : 30% 암모니아수 = 5 : 2 : 2 : 1)을 통해 정제하여 1,4-디데옥시-1,4-이미노-L-아라비니톨 (55 mg)을 얻었다.In a round bottom flask, ((2S, 3S, 4R) -2- (hydroxymethyl) -1-((R) -1-phenylethyl) pyrrolidine-3,4-diol (130 mg, 0.54 mmol) Pd (OH) 2 (13 mg) and methanol (2 mL) were added and stirred at room temperature After 3 hours, when the reaction was completed, the mixture was filtered through a pad of diatomaceous earth, and the solvent was distilled off under reduced pressure.The compound was subjected to column chromatography (DCM: MeOH). : EtOH: 30% ammonia water = 5: 2: 2: 1) to obtain 1,4-dideoxy-1,4-imino-L-arabinitol (55 mg).

1H NMR (400 MHz, D2O) δ 4.05-4.02 (m, 1H), 3.75 (m, 1H), 3.65 (dd, J = 4.8 Hz, J = 11.6 Hz, 1H), 3.57-3.52 (m, 2H), 3.06 (dd, J = 5.7 Hz, J = 12.2 Hz, 1H), 2.93 (m, 1H), 2.78 (dd, J = 3.8 Hz, J = 12.2 Hz, 1H).
 1 H NMR (400 MHz, D 2 O) δ 4.05-4.02 ( m , 1H), 3.75 ( m , 1H), 3.65 ( dd , J = 4.8 Hz, J = 11.6 Hz, 1H), 3.57-3.52 ( m , 2H), 3.06 ( dd , J = 5.7 Hz, J = 12.2 Hz, 1H), 2.93 ( m , 1H), 2.78 ( dd , J = 3.8 Hz, J = 12.2 Hz, 1H).

이상에서 설명한 바와 같이, 본 발명에 따른 제조방법은 당뇨병 치료제, 항암제, 항바이러스제 등 다양한 의약적 용도를 가지고 있는 1,4-디데옥시-1,4-이미노-아라비니톨 또는 이의 광학이성질체를 산업적으로 생산하는 방법으로서 유용하다.As described above, the preparation method according to the present invention comprises 1,4-dideoxy-1,4-imino-arabinitol or optical isomer thereof having various medicinal uses, such as diabetes treatment, anticancer, and antiviral. It is useful as an industrial production method.

Claims (10)

a) 하기 화학식 2로 표시되는 N-보호된 아지리딘일메탄올 화합물을 산화 반응(oxidation)한 후에, 하기 화학식 7로 표시되는 포스포노아세테이트 화합물과 반응시켜, 하기 화학식 3으로 표시되는 에스테르 화합물을 제조하는 과정;
Figure pat00019

상기 반응식에서, R1은 아민 보호기로서 벤질기, p-메톡시벤질기, 1-페닐에틸기, 벤젠설포닐기, 및 p-톨루엔설포닐기 중에서 선택되고; R2는 C1-6 알킬기, 또는 벤질기를 나타낸다,
b) 하기 화학식 3으로 표시되는 에스테르 화합물을 디히드록실화 반응(dihidroxylation)시켜, 하기 화학식 4로 표시되는 디히드록시 화합물을 제조하는 과정;
Figure pat00020

상기 반응식에서, R1 및 R2는 각각 상기에서 정의한 바와 같다,
c) 하기 화학식 4로 표시되는 디히드록시 화합물을 R3COOH로 표시되는 유기산 존재하에서 고리화 반응(cyclization)시켜, 하기 화학식 5로 표시되는 락탐 화합물을 제조하는 과정; 및
Figure pat00021

상기 반응식에서, R1 및 R2는 각각 상기에서 정의한 바와 같고, R3은 C1-6 알킬기, 또는 페닐기를 나타낸다,
d) 하기 화학식 5로 표시되는 락탐 화합물을 환원 반응(reduction)한 후에, 탈보호 반응(deprotection)하여 하기 화학식 1로 표시되는 1,4-디데옥시-1,4-이미노-아라비니톨을 제조하는 과정;
Figure pat00022

상기 반응식에서, R1 및 R3은 각각 상기에서 정의한 바와 같다,
을 포함하는 1,4-디데옥시-1,4-이미노-아라비니톨의 제조방법.
a) oxidizing the N- protected aziridinylmethanol compound represented by the following Chemical Formula 2, followed by reaction with a phosphonoacetate compound represented by the following Chemical Formula 7, to prepare an ester compound represented by the following Chemical Formula 3. process;
Figure pat00019

In the above scheme, R 1 is selected from benzyl group, p-methoxybenzyl group, 1-phenylethyl group, benzenesulfonyl group, and p-toluenesulfonyl group as the amine protecting group; R 2 represents a C 1-6 alkyl group or benzyl group,
b) preparing a dihydroxy compound represented by the following Chemical Formula 4 by dihydroxylation of the ester compound represented by the following Chemical Formula 3;
Figure pat00020

In the above scheme, R 1 and R 2 are each as defined above,
c) cyclizing a dihydroxy compound represented by the following Chemical Formula 4 in the presence of an organic acid represented by R 3 COOH to prepare a lactam compound represented by the following Chemical Formula 5; And
Figure pat00021

In the above scheme, R 1 and R 2 are each as defined above, R 3 represents a C 1-6 alkyl group, or a phenyl group,
d) reduction reaction of the lactam compound represented by the following formula (5), followed by deprotection to obtain 1,4-dideoxy-1,4-imino-arabinitol represented by the following formula (1) Manufacturing process;
Figure pat00022

In the above scheme, R 1 and R 3 are each as defined above,
Method for producing 1,4-dideoxy-1,4-imino-aravinitol comprising a.
청구항 1에 있어서,
상기 a)산화 반응은 스원 산화반응(Swern oxidation), 또는 데스-마틴 산화반응(Dess-Martin oxidation)에 의해 수행하는 것을 특징으로 하는 제조방법.
The method according to claim 1,
The a) oxidation reaction is a manufacturing method characterized in that performed by the swine oxidation (Swern oxidation), or Dess-Martin oxidation (Dess-Martin oxidation).
청구항 1에 있어서,
상기 b)디히드록실화 반응은 사산화 오스뮴(OsO4) 촉매와 N-메틸몰폴린 N-옥사이드 존재하에서 수행하는 것을 특징으로 하는 제조방법.
The method according to claim 1,
The b) dihydroxylation reaction is carried out in the presence of an osmium tetraoxide (OsO 4 ) catalyst and N- methylmorpholine N- oxide.
청구항 1에 있어서,
상기 c)고리화 반응은 염화메틸렌과 톨루엔의 혼합용매 및 30℃ 내지 80℃ 온도 조건에서 수행하는 것을 특징으로 하는 제조방법.
The method according to claim 1,
The c) ring reaction is carried out at a mixed solvent of methylene chloride and toluene and at 30 ℃ to 80 ℃ temperature conditions.
청구항 1에 있어서,
상기 d)환원 반응은 리튬 알루미늄 하이드라이드 (LiAlH4), 및 삼수소화보론-디메틸설파이드 배위화합물(BH3-DMS)로부터 선택된 환원제 존재하에서 수행하는 것을 특징으로 하는 제조방법.
The method according to claim 1,
The d) reduction reaction is carried out in the presence of a reducing agent selected from lithium aluminum hydride (LiAlH 4 ), and boron trihydride-dimethylsulfide coordination compound (BH 3 -DMS).
청구항 1에 있어서,
상기 d)탈보호 반응은 전이금속 촉매와 수소기체를 사용하는 조건하에서 수행하는 것을 특징으로 하는 제조방법.
The method according to claim 1,
The d) deprotection reaction is carried out under the conditions using a transition metal catalyst and hydrogen gas.
청구항 1에 있어서,
상기 화학식 5로 표시되는 락탐 화합물은 결정화하여 하기 화학식 5a 또는 5b로 표시되는 광학활성 락탐 화합물로 각각 분리하여 사용하는 것을 특징으로 제조방법.
[화학식 5a]
Figure pat00023

[화학식 5b]
Figure pat00024

상기 화학식 5a 또는 5b에 있어서, R1 및 R3은 각각 상기 청구항 1에서 정의한 바와 같다.
The method according to claim 1,
The lactam compound represented by Chemical Formula 5 is crystallized to produce an optically active lactam compound represented by the following Chemical Formula 5a or 5b, respectively.
[Formula 5a]
Figure pat00023

[Formula 5b]
Figure pat00024

In Formula 5a or 5b, R 1 and R 3 are the same as defined in Claim 1, respectively.
청구항 1 또는 청구항 7에 있어서,
상기 화학식 5a 또는 5b로 표시되는 광학활성 락탐 화합물로부터 하기 화학식 1a로 표시되는 광학활성 1,4-디데옥시-1,4-이미노-D-아라비니톨 또는 하기 화학식 1b로 표시되는 1,4-디데옥시-1,4-이미노-L-아라비니톨을 각각 제조하는 것을 특징으로 제조방법.
[화학식 1a]
Figure pat00025

[화학식 1b]
Figure pat00026

The method according to claim 1 or 7,
From the optically active lactam compound represented by Chemical Formula 5a or 5b, the optically active 1,4-dideoxy-1,4-imino-D-arabinitol represented by Chemical Formula 1a or 1,4 represented by Chemical Formula 1b -A process for producing dideoxy-1,4-imino-L-arabinitol, respectively.
[Formula 1a]
Figure pat00025

[Chemical Formula 1b]
Figure pat00026

 하기 화학식 1a로 표시되는 광학활성 1,4-디데옥시-1,4-이미노-D-아라비니톨 제조를 위한 중간체 화합물로 이용되는, 하기 화학식 5a로 표시되는 광학활성 락탐 화합물 :
[화학식 1a]
Figure pat00027

[화학식 5a]
Figure pat00028

상기 화학식 5a에 있어서, R1 및 R3은 각각 상기 청구항 1에서 정의한 바와 같다.
An optically active lactam compound represented by Chemical Formula 5a, which is used as an intermediate compound for preparing optically active 1,4-dideoxy-1,4-imino-D-arabinitol represented by Chemical Formula 1a:
[Formula 1a]
Figure pat00027

[Formula 5a]
Figure pat00028

In Formula 5a, R 1 and R 3 are the same as defined in Claim 1, respectively.
하기 화학식 1b로 표시되는 광학활성 1,4-디데옥시-1,4-이미노-L-아라비니톨 제조를 위한 중간체 화합물로 이용되는, 하기 화학식 5b로 표시되는 광학활성 락탐 화합물 :
[화학식 1b]
Figure pat00029

[화학식 5b]
Figure pat00030

상기 화학식 5b에 있어서, R1 및 R3은 각각 상기 청구항 1에서 정의한 바와 같다.An optically active lactam compound represented by Chemical Formula 5b, used as an intermediate compound for preparing optically active 1,4-dideoxy-1,4-imino-L-arabinitol represented by Chemical Formula 1b:
[Chemical Formula 1b]
Figure pat00029

[Formula 5b]
Figure pat00030

In Formula 5b, R 1 and R 3 are the same as defined in Claim 1, respectively.
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