KR20090088496A

KR20090088496A - 6-(3,6-DIDEOXY-alpha;-L-ARABINO-HEXOPYRANOSYLOXY)HEPTANOIC ACID DERIVA-TIVES, AND PROCESS FOR PREPARATION THEREOF

Info

Publication number: KR20090088496A
Application number: KR1020080013796A
Authority: KR
Inventors: 정만길; 백융기
Original assignee: 연세대학교 산학협력단; (주)케이디알
Priority date: 2008-02-15
Filing date: 2008-02-15
Publication date: 2009-08-20

Abstract

A pheromone compound, 6-(3,6-dideoxy-alpha-L-arabino-hexopyranosyloxy)heptanoic acid derivative which is isolated from C. elegans is provided to massively produce pheromone and use metabolic pathway and signal transduction system development. A 6-(3,6-dideoxy-alpha-L-arabino-hexopyranosyloxy)heptanoic acid derivative is denoted by the chemical formula (I), (II) or (III). A method for producing the 6-(3,6-dideoxy-alpha-L-arabino-hexopyranosyloxy)heptanoic acid derivative comprises: a step of reacting the chemical formula (IV) and (V) to produce the chemical formula (I); a step of performing oxidation/reduction of the compound of the chemical formula (I); and a step of removing a protection residue of the compound of the chemical formula (I).

Description

6-(3,6-디데옥시-α-Ｌ-아라비노-헥소피라노실옥시)헵타노익산 유도체 및 그 제조 방법{6-(3,6-DIDEOXY-α-Ｌ-ARABINO-HEXOPYRANOSYLOXY)HEPTANOIC ACID DERIVA-TIVES, AND PROCESS FOR PREPARATION THEREOF}6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative and preparation method thereof {6- (3,6-DIDEOXY-α-L-ARABINO-HEXOPYRANOSYLOXY) HEPTANOIC ACID DERIVA-TIVES, AND PROCESS FOR PREPARATION THEREOF}

본 발명은 예쁜 꼬마선충에서 발견된 노화와 스트레스 억제에 관련된 페로몬인 6R-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 (6R-(3,6-Dide oxy-α-L-arabino-hexopyranosyloxy)heptanoic acid)을 모체로 하는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산의 신규 유도체에 관한 것이다. The present invention relates to 6R- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid (6R- (3,6) which is a pheromone involved in aging and stress suppression found in pretty nymphs. Novel derivative of 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid based on -Dide oxy-α-L-arabino-hexopyranosyloxy) heptanoic acid) will be.

생리활성물질로서 알려진 페로몬(pheromone)은 동물의 체내에서 생산되고 체외로 분비되어 동종 타 개체에 작용하여 특정의 행동이나 생리적 변화를 일으키는 물질의 총칭이다. 지금까지 알려진 문헌을 통하여 보고된 바에 의하면, 예쁜 꼬마선충(C. elegans)에서 분비되는 매우 적은 양의 페로몬(Riddle, D.L., Science, 218: 578-580, 1982)은, 본 발명의 발명자 등에 의하여 2005년에 처음으로 성공적인 분리 및 정제에 의하여 그 평면 구조(한국특허 10-2002-0070591 참조) 및 3차원 구조가 알려지고, 전합성에 성공하여 페로몬에 의한 활성의 생체 내 정확한 작용위치와 작용기전 및 생리과정을 직접적으로 연구할 수 있는 방법이 열렸다(Nature 2005 433(7025):541-5; 한국특허 10-2004-0007539). Pheromones, known as physiologically active substances, are a generic term for substances that are produced in the body of an animal and secreted out of the body to act on other individuals of the same kind and cause certain behaviors or physiological changes. As reported through the literature known to date, a very small amount of pheromone (Riddle, DL, Science, 218: 578-580, 1982) secreted from pretty C. elegans, according to the inventors of the present invention, etc. The first successful separation and purification in 2005 revealed its planar structure (see Korean Patent No. 10-2002-0070591) and its three-dimensional structure. And a method for directly studying the physiological process has been opened (Nature 2005 433 (7025): 541-5; Korean Patent 10-2004-0007539).

따라서 이 선도 화합물의 광범위한 생체 내 노화억제, 스트레스, 대사경로와 신호전달 체계 및 항암제 개발, 비만, 신경기관의 반응 그리고 이와 관련된 노화, 스트레스억제 약물 개발연구 그리고 이 페로몬의 활성 타깃 단백질의 검색 발굴연구를 위하여 본 페로몬의 대량제조를 해결하기 위한 유도체의 합성개발이 필수적이다.Therefore, the development of a broad range of anti-aging, stress, metabolic pathways and signaling systems and anticancer drugs, obesity, nervous system responses, and related aging, stress-inhibiting drug development, and the discovery of active target proteins of this pheromone In order to solve the mass production of this pheromone it is necessary to develop a synthesis of derivatives.

이에, 본 발명자들은 휴면효과를 증대시킬 수 있는 유도체를 설정한 후, 이에 대한 입체 선택적 전합성을 성공적으로 완성하여 자연에서 존재하는 페로몬과 유사한 목표물을 합성하였고, 합성된 페로몬 유도체는 꼬마선충을 이용한 생체실험에서 장기휴면효과를 유발함을 확인하였다.Thus, the present inventors set a derivative that can increase the dormant effect, and successfully completed stereoselective synthesis for this to synthesize a target similar to the pheromone existing in nature, the synthesized pheromone derivative using In vivo experiments have been shown to cause long-term dormant effect.

따라서 본 발명의 목적은 신규 페로몬 유도체인 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체를 포함하는 노화, 스트레스 억제제를 제공하는 것이다.Accordingly, it is an object of the present invention to provide an aging and stress inhibitor comprising the novel pheromone derivative 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative.

본 발명의 다른 목적은 상기 페로몬 유도체를 고수율로 용이하게 대량 제조하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for easily mass-producing the pheromone derivative in high yield.

본 발명의 또 다른 목적은 상기 페로몬 유도체를 이용하여 관련 약효검색을 시행하고 이 페로몬 유도체의 활성 타깃 단백질의 검색 발굴을 할 수 있는 길을 여는 데 있다.Another object of the present invention is to perform a related drug search using the pheromone derivative and to open a way to search for and discover the active target protein of the pheromone derivative.

상기 목적을 달성하기 위하여, 본 발명은 예쁜 꼬마선충에서 발견된 노화와 스트레스 억제에 관련된 페로몬인 6R-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 (6R-(3,6-Dideoxy-α-L-arabino-hexopyranosyloxy)heptanoic acid)을 모체로 한 신규 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체를 제공한다.In order to achieve the above object, the present invention is 6R- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid which is a pheromone related to aging and stress suppression found in pretty nematodes New 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hep (6R- (3,6-Dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid) as a parent Provided tanoic acid derivatives.

본 발명의 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체는 하기 화학식 (Ⅰ), 화학식 (Ⅱ) 또는 화학식 (Ⅲ)으로 표시될 수 있는 화합물이다.The 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative of the present invention may be represented by the following formula (I), formula (II) or formula (III) Compound.

화학식 (Ⅰ)Formula (I)

상기 식에서, R₁ 및 R₂는 서로 같거나 다르게 수소, C1-C6의 알킬 또는 벤조일기를 나타내고; R₄는 수소 또는 C1-C6의 알킬기를 나타내고, 카이랄 탄소의 절대배열은 R 또는 S이고; (CH₂)n은 n이 1∼15의 알킬, 알케닐 또는 알키닐 그룹을 나타내고; Z₁은 C1-C6의 알킬, C1-C6의 알켄, C1-C6의 산, C1-C6의 알데히드, 알콜, 할로겐, 아민, 에스테르, 아마이드를 나타낸다.In which R ₁ And R ₂ is the same as or different from each other hydrogen, a C1-C6 alkyl or benzoyl group; R ₄ represents hydrogen or an alkyl group of C 1 -C 6, and the absolute arrangement of the chiral carbons is R or S; (CH ₂ ) n represents an alkyl, alkenyl or alkynyl group where n is 1-15; Z ₁ represents alkyl of C1-C6, alkenes of C1-C6, acids of C1-C6, aldehydes of C1-C6, alcohols, halogens, amines, esters, amides.

상기 화학식 (Ⅰ)에서 Z₁은 보다 구체적으로는 에틸렌, 메틸, 카복실산, 메틸에스테르, 알콜, 알데히드, -CH=CHCOOH, 브롬, 아자이드, 3,6-디데옥시-α-L-아라비노-헥소피라노사이드, 설퍼, 메실, -SCOCH₃, 아마이드인 것이 바람직하다.In Formula (I), Z ₁ is more specifically ethylene, methyl, carboxylic acid, methyl ester, alcohol, aldehyde, -CH = CHCOOH, bromine, azide, 3,6-dideoxy-α-L-arabino- Preference is given to hexopyranoside, sulfur, mesyl, -SCOCH ₃ , amide.

상기 아마이드의 아민으로는 메틸아민, 아닐린, 피롤리딘, 모르폴린, 도데실아민, 1-테드라데실아민, 4,7,10-트리오카(trioka)-1,13-트리데칸 디아민 (tridecane diamine), 암모니아, -CONH(CH₂)₂NHCOOC(CH₃)₃, -CONH[(CH₂)₂O]₂(CH₂)₂NHCOOC(CH₃)₃, 4-메틸피페리딘, 사이클로헥실아민, 4-벤질피페리딘, 4-에틸아닐린, 3-니트로아닐린, 2-브로모아닐린, 에틸 메타-아미노벤조에이트(ethyl m-aminobenzoate), 아릴아민, 푸르푸릴아민(furfuryl amine), 세린메틸에스테르(serine methyl ester), N-(2-아미노-에틸)-2-(4-벤조일페녹시)인 것이 바람직하고, 에스테르의 알콜은 3-페녹시벤질알콜, 5-헥센-1-올(5-hexen-1-ol) 그리고 아세트알데히드이다.Amines of the amides include methylamine, aniline, pyrrolidine, morpholine, dodecylamine, 1-tedradecylamine, 4,7,10-trioka-1,13-tridecane diamine diamine), ammonia, -CONH (CH ₂ ) ₂ NHCOOC (CH ₃ ) ₃ , -CONH [(CH ₂ ) ₂ O] ₂ (CH ₂ ) ₂ NHCOOC (CH ₃ ) ₃ , 4-methylpiperidine, cyclo Hexylamine, 4-benzylpiperidine, 4-ethylaniline, 3-nitroaniline, 2-bromoaniline, ethyl meta-aminobenzoate, arylamine, furfuryl amine, It is preferred that it is serine methyl ester, N- (2-amino-ethyl) -2- (4-benzoylphenoxy), and the alcohol of the ester is 3-phenoxybenzyl alcohol, 5-hexene-1- Ol (5-hexen-1-ol) and acetaldehyde.

화학식 (Ⅱ)Formula (II)

상기 식에서 R₁ 및 R₂는 화학식 (Ⅰ)과 동일하고; Z₂는 C1-C6의 지방족 알콜, 사이클로헥사놀(cyclohexanol) 또는 디하이드로캡사이신(dihydrocapsaicin)을 나타낸다. In which R ₁ And R ₂ is the same as in formula (I); Z ₂ represents C 1 -C 6 aliphatic alcohol, cyclohexanol or dihydrocapsaicin.

상기 화학식 (Ⅱ)에서 Z₂는 보다 구체적으로, 3-메틸-부탄-1-올(3-methyl-butane-1-ol), 사이클로헥사놀, 헥산-1-올(hexane-1-ol) 또는 디하이드로캡사이신인 것이 바람직하다.In Formula (II), Z ₂ is more specifically, 3-methyl-butan-1-ol (3-methyl-butane-1-ol), cyclohexanol, hexane-1-ol (hexane-1-ol) Or dihydrocapsaicin.

화학식 (Ⅲ)Formula (III)

상기 식에서 R₄, (CH₂)n 및 Z₁은 화학식 (Ⅰ)과 동일하고; Z₃는 탄수화물을 나타낸다.In which R ₄ , (CH ₂ ) n and Z ₁ are the same as in formula (I); Z ₃ represents a carbohydrate.

상기 화학식 (Ⅲ)에서 Z₃은 보다 구체적으로, 3-데옥시-D-아라비노피라노사이드(3-deoxy-D-arabinopyranoside), D-아라비노피라노사이드, L-람노피라노사이드 (L-rhamnopyranoside), D-만노피라노사이드(D-mannopyranoside)인 것이 바람직하다.In Formula (III), Z ₃ is more specifically, 3-deoxy-D-arabinopyranoside, 3-deoxy-D-arabinopyranoside, D-arabinofyranoside, L-ramnopyranoside ( L-rhamnopyranoside) and D-mannopyranoside are preferred.

본 발명은 꼬마선충(C. elegans)으로부터 분비되는 페로몬 화합물, 6R-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산을 모체로 하여 그 새로운 유도체의 효율적 합성을 성공하였으며, 꼬마선충으로부터 얻어지는 극미량의 페로몬의 미량분리의 한계를 극복하여 이를 대량생산하는 길을 확립하였다. The present invention is based on the pheromone compound secreted from C. elegans, 6R- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid, Efficient synthesis was successfully achieved, and the way of mass production was established by overcoming the limitation of trace separation of trace amounts of pheromones from small nematodes.

따라서 페로몬 유도체에 의하여 유발되는 생체 내 노화, 스트레스, 대사경로와 신호전달 체계 개발, 비만, 그리고 관련된 노화, 스트레스억제약물 개발연구에 많은 효과를 얻을 수 있게 되었다. 또한 이 페로몬 유도체의 활성 타깃 단백질을검색 발굴할 수 있는 길을 열었다.Therefore, the effects of pheromone derivative-induced aging, stress, metabolic pathways and signaling system development, obesity, and related aging and stress inhibitors can be obtained. It also opened the way to search and discover the active target protein of this pheromone derivative.

본 발명의 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체는, 하기 화학식 (Ⅳ)와 화학식(Ⅴ) 화합물의 짝지움 반응을 거쳐 두 가지 방법으로 합성하였다.The 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative of the present invention is subjected to a coupling reaction between the following general formula (IV) and the general formula (V) compound. Synthesis was carried out in two ways.

화학식 (Ⅳ)는 종래 방법(R₃=H, Tetrahedron Lett., 28, 1073-1076 (1987), Carbohydr. Res., 201, 95-114 (1990), Carbohydr. Res., 70, 27-35 (1979); R₃=CNHCCl₃, J. Carbohydr Chem., 21, 89-97 (2002))에 따라 합성하였고, 다른 화학식 (Ⅴ) 또한 종래 방법(Tetrhedron: Asymmetry., 12, 29-31 (2001))에 따라 제조하였다. Formula (IV) is a conventional method (R ₃ = H, Tetrahedron Lett., 28, 1073-1076 (1987), Carbohydr.Res., 201, 95-114 (1990), Carbohydr.Res., 70, 27-35 (1979); R ₃ = CNHCCl ₃ , J. Carbohydr Chem., 21, 89-97 (2002)), and other formulas (V) are also described by the conventional method (Tetrhedron: Asymmetry., 12, 29-31 ( 2001).

화학식 (Ⅳ) Formula (IV)

화학식 (Ⅴ)Formula (Ⅴ)

여기서 R₁, R₂ , R₄, (CH₂)n 및 Z₁은 화학식 (Ⅰ)과 동일하고; R₃는 수소 또는 트리클로로아세토니트릴(CNHCCl₃)기를 나타낸다.Where R ₁ , R ₂ , R ₄ , (CH ₂ ) n and Z ₁ are the same as in formula (I); R ₃ represents a hydrogen or trichloroacetonitrile (CNHCCl ₃ ) group.

상기 화학식 (Ⅳ)의 화합물로서는, 예를 들어 2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노사이드(2,4-Di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexo-pyranoside), 또는 2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실 트리클로로아세트이미데이트(2,4-Di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexo pyranosyl trichloroacetimidate)를 들 수 있고, 화학식 (V)의 화합물로서는, 예를 들어 (2R)-5-헥센-2-올((2R)-5-hexen-2-ol), (2R)-7-옥텐-2-올((2R)-7-Octen-2-ol), (2R)-13-테트라데센-2-올((2R)-13-Tetradecen-2-ol)을 들 수 있다.As the compound of the formula (IV), for example, 2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranoside (2,4-Di-O-benzoyl -3,6-dideoxy-α-L-arabino-hexo-pyranoside), or 2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyl trichloroacet Imidate (2,4-Di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexo pyranosyl trichloroacetimidate) is mentioned, As a compound of General formula (V), it is (2R) -5, for example. -Hexene-2-ol ((2R) -5-hexen-2-ol), (2R) -7-octen-2-ol ((2R) -7-Octen-2-ol), (2R) -13 -Tetradecen-2-ol ((2R) -13-Tetradecen-2-ol) is mentioned.

화학식 (Ⅰ)로 표시되는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체는, 루이스산 촉매하의 반응인 방법 1에서는 보론트리플로라이드 이서레이트(BF₃·Et₂O)를 사용하고, 방법 2에서는 트리메틸실릴 트리플로오르메탄설포네이트(TMS·OTf)를 사용하여 제조하였고, 이를 다음 반응식 1로 나타낸다. 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative represented by the general formula (I) is a boron trifluoride It was prepared using the rate (BF ₃ · Et ₂ O) and in the method 2 using trimethylsilyl trifluoromethanesulfonate (TMS.OTf), which is represented by the following scheme 1.

반응식 1Scheme 1

또한, 본 발명에 따른 상기 화학식 (Ⅰ)로 표시되는 화합물 중에서 여러 가지 다른 치환기를 함유하는 각각의 화합물은 하기 반응식 2 내지 11에 따른 방법으로 제조될 수 있다.In addition, each compound containing various other substituents among the compounds represented by the formula (I) according to the present invention may be prepared by the method according to the following schemes 2 to 11.

반응식 2Scheme 2

상기 반응식 2는 하기 표 1에 기재된 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체 화합물 번호 1~6 또는 7, 8을 얻는 반응식으로, 화학식 (1) 화합물을 팔라디움/카본(Pd/C)을 이용한 환원과 소듐메톡사이드(NaOCH₃) 보호기 제거를 통하여 각각 화학식 (2), 화학식(3) 및 화학식(4) 화합물을 얻는다. Reaction Scheme 2 is a scheme for obtaining 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative compound Nos. 1 to 6 or 7, 8 shown in Table 1 below. Compound (1) is obtained by reduction using palladium / carbon (Pd / C) and removal of sodium methoxide (NaOCH ₃ ) protecting group, respectively, to obtain compounds of formula (2), formula (3) and formula (4).

또한, 화학식 (3)을 아이오도메탄(MeI)을 이용하여 R₁, R₂에 메톡시기가 도입된 화학식 (5)를 얻고, 포타슘퍼망가네이트(KMnO₄)로 산화시켜 화학식 (6)을 얻는다.In addition, formula (3) was obtained by introducing methoxy groups into R ₁ and R ₂ using iodomethane (MeI), and oxidized with potassium permanganate (KMnO ₄ ) to formula (6). Get

반응식 3Scheme 3

상기 반응식 3은 표 1에 기재된 화합물 번호 9~10 또는 11~13을 얻는 반응식으로서, 화학식 (1)을 포타슘퍼망가네이트(KMnO₄) 또는 루세늄트리클로라이드 (RuCl₃)로 산화시켜 화학식 (7)을 얻고, 이어서 보호기 제거와 산 처리를 하여 화학식 (8) 및 화학식 (9)를 각각 얻는다.Reaction Scheme 3 is a scheme for obtaining Compound Nos. 9 to 10 or 11 to 13 shown in Table 1, wherein Formula (1) is oxidized to potassium permanganate (KMnO ₄ ) or ruthenium trichloride (RuCl ₃ ) ), Followed by removal of the protecting group and acid treatment to obtain the formulas (8) and (9), respectively.

반응식 4Scheme 4

상기 반응식 4는 표 1에 기재된 화합물 번호 14~17 또는 18~19을 얻는 반응식으로서, 화학식 (1)을 환원제인 9-보로바이사이클로[3.3.1]노네인(9-BBN)을 이용하여 화학식 (10)을 얻고, 소디움메톡사이드를 이용하여 보호기를 제거한 화학식 (11)과 산화제인 피리디늄 클로로크로메이트(PCC)을 이용하여 화학식 (12)를 각각 얻는다. Reaction Scheme 4 is a scheme for obtaining Compound Nos. 14 to 17 or 18 to 19 shown in Table 1, wherein Formula (1) is represented by using 9-borobicyclo [3.3.1] nonane (9-BBN) as a reducing agent. (10) was obtained, and the general formula (12) was obtained using the general formula (11) which removed the protecting group using sodium methoxide, and pyridinium chloro chromate (PCC) which is an oxidizing agent, respectively.

화학식 (12)를 보호기를 제거하여 n=5인 화학식 (14)를 얻는다. 또한, 화학식 (1)을 오존화 반응을 통하여 화학식 (13)을 얻고, 소디움메톡사이드를 이용하여 보호기를 제거한 n=4인 화학식 (14)를 얻는다.The protecting group is removed from formula (12) to obtain formula (14) with n = 5. In addition, general formula (1) is obtained through the ozonation reaction to obtain general formula (13), and the general formula (14) having n = 4 having the protecting group removed using sodium methoxide is obtained.

반응식 5Scheme 5

상기 반응식 5는 표 1에 기재된 화합물 번호 20~22를 얻는 반응식으로서, 화학식 (12)을 디에틸포스포노아세틱산 에틸에스테르(Diethylphosphonoacetic acid ethyl ester)를 이용한 비티히(Wittig) 반응과 소디움메톡사이드를 이용하여 탄소수가 2개 늘어나고 보호기가 제거된 화학식 (15)를 얻고, 이중결합을 환원하여 화학식 (16), 메틸에스테르기를 리튬하이드록사이드(LiOH)를 이용하여 제거시킴으로써 화학식 (17)를 얻는다.Scheme 5 is a reaction formula for obtaining compound Nos. 20 to 22 shown in Table 1, wherein the reaction of Wittig and sodium methoxide using formula (12) using diethylphosphonoacetic acid ethyl ester To obtain the general formula (15) having two carbon atoms increased and the protecting group removed, the double bond is reduced to remove the general formula (16), the methyl ester group by using lithium hydroxide (LiOH) to obtain a general formula (17).

반응식 6Scheme 6

상기 반응식 6은 표 1에 기재된 화합물 번호 23, 24를 얻는 반응식으로서, 화학식 (10)을 할로겐을 도입하기 위한 이탈기로 메실클로라이드(MsCl)을 이용하여 메실레이션된 화학식 (18)을 얻는다. 이어서 리튬브로마이드(LiBr)를 이용하여 할라이드를 갖는 화학식 (19)를 얻고, 소듐아자이드(NaN3)를 이용하여 할로겐과 치환반응하여 화학식 (21)을 얻는다. 화학식 (19) 및 화학식 (21)은 보호기 제거를 통하여 화학식 (20) 및 화학식 (22)를 각각 얻는다.Scheme 6 is a scheme for obtaining compound Nos. 23 and 24 shown in Table 1, wherein formula (10) is a mesylated formula (18) using mesyl chloride (MsCl) as a leaving group for introducing halogen. Subsequently, formula (19) having a halide is obtained using lithium bromide (LiBr), and substitution reaction with halogen is performed using sodium azide (NaN 3) to obtain formula (21). Formulas (19) and (21) obtain formulas (20) and (22), respectively, through the removal of protecting groups.

반응식 7Scheme 7

여기서 R₃는트리클로로아세토니트릴(CNHCCl₃)이다.Where R ₃ is Trichloroacetonitrile (CNHCCl ₃ ).

상기 반응식 7은 표 1에 기재된 화합물 번호 25를 얻는 반응식으로서, 화학식 (10)을 화학식 (IV)와의 짝지움 반응을 통하여 화학식 (23)를 얻고, 보호기 제거를 통하여 화학식 (24)를 얻는다.Scheme 7 is a scheme for obtaining compound No. 25 shown in Table 1, to obtain formula (23) through the reaction of the formula (10) with the formula (IV), to obtain the formula (24) through the removal of the protecting group.

반응식 8Scheme 8

상기 반응식 8은 표 1에 기재된 화합물 번호 26~28을 얻는 반응식으로서, 화학식 (20)을 포타슘 티오아세테이트(potasium thioacetate)를 이용하여 설퍼기를 도입한 화학식 (25)을 얻고, 보호기를 제거하여 다이머(dimer)인 화학식 (26)을 얻는다. 또한 화학식(20)의 보호기를 제거한 화학식 (27)에 포타슘 티오아세테이트를 이용하여 설퍼기가 도입된 화학식 (28)을 얻는다.Scheme 8 is a reaction formula for obtaining compounds Nos. 26 to 28 shown in Table 1, to obtain the formula (25) in which the sulfur group is introduced using potassium thioacetate (potasium thioacetate), to remove the protecting group dimer (dimer) is obtained. In addition, to the general formula (27) from which the protecting group of the general formula (20) is removed, potassium thioacetate is used to obtain a general formula (28) in which a sulfur group is introduced.

반응식 9Scheme 9

여기서 아민은 메틸아민, 아닐린, 피롤리딘, 모르폴린, 도데실아민, 1-테트라데실아민, 4,7,10-트리오카-1,13-트리데칸 디아민, 암모니아, -CONH(CH₂)₂NH COOC(CH₃)₃, -CONH[(CH₂)₂O]₂(CH₂)₂NHCOOC(CH₃)₃로부터 선택되는 하나의 아민이다.Wherein the amine is methylamine, aniline, pyrrolidine, morpholine, dodecylamine, 1-tetradecylamine, 4,7,10-trioka-1,13-tridecane diamine, ammonia, -CONH (CH ₂ ) ₂ NH COOC (CH ₃ ) ₃ , -CONH [(CH ₂ ) ₂ O] ₂ (CH ₂ ) ₂ NHCOOC (CH ₃ ) ₃ One amine selected from.

상기 반응식 9는 표 1에 기재된 화합물 번호 29~38을 얻는 반응식으로서, 화학식 (7)과 아민을 N,N'-디사이클로헥실카보디이미드(N,N'-dicyclohexylcarbo diimide; DCC) 또는 1-에틸-3-(3-디메틸아미노프로필)카보디이미드(EDC)를 이용하여 아마이드 결합을 통한 화학식 (29)을 얻고 보호기를 제거하여 화학식 (30)을 얻는다.Scheme 9 is a reaction formula for obtaining compounds Nos. 29 to 38 shown in Table 1, wherein the formula (7) and the amine are N, N'-dicyclohexylcarbo diimide (DCC) or 1- Ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) is used to obtain formula (29) via amide bonds and to remove the protecting group to obtain formula (30).

반응식 10Scheme 10

여기서 아민은 4-메틸피페리딘, 사이클로헥실아민, 4-벤질피페리딘, 4-에틸아닐린, 3-니트로아닐린, 2-브로모아닐린, 에틸 메타-아미노벤조에이트, 아릴아민, 푸르푸릴아민, 세린메틸에스터, N-(2-아미노-에틸)-2-(4-벤조일페녹시)아세타마이드이고, 알콜은 3-페녹시벤질 알콜, 또는 5-헥센-1-올(5-hexen-1-ol)이다.Wherein the amine is 4-methylpiperidine, cyclohexylamine, 4-benzylpiperidine, 4-ethylaniline, 3-nitroaniline, 2-bromoaniline, ethyl meta-aminobenzoate, arylamine, furfurylamine , Serine methyl ester, N- (2-amino-ethyl) -2- (4-benzoylphenoxy) acetamide, and the alcohol is 3-phenoxybenzyl alcohol, or 5-hexen-1-ol (5-hexen -1-ol).

상기 반응식 10은 표 1에 기재된 화합물 번호 39~49 또는 50, 51을 얻는 반응식으로서, 화학식 (8)을 아민과 알콜을 1-에틸-3-(3-디메틸아미노프로필)카보디이미드(EDC)를 이용하여 각각 화학식 (30) 및 화학식 (31)을 얻는다.Scheme 10 is a scheme for obtaining compounds Nos. 39 to 49 or 50 and 51 shown in Table 1, wherein amine and alcohol are 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC). To obtain the formula (30) and formula (31), respectively.

반응식 11Scheme 11

여기서 카이랄 탄소의 절대배열은 S이다.Where the absolute configuration of chiral carbon is S.

상기 반응식 11은 하기 표 1에 기재된 화합물 번호 52를 얻는 반응식으로서, 화학식 (32)를 루세늄트리클로라이드(RuCl₃)로 산화시켜 화학식 (33)을 얻고, 보호기 제거로 화학식 (34)를 얻는다.Scheme 11 is a scheme for obtaining compound No. 52 shown in Table 1 below, oxidizing formula (32) with ruthenium trichloride (RuCl ₃ ) to obtain formula (33), and to remove formula (34).

또한 본 발명에서 화학식 (Ⅱ)로 표시되는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체는, 화학식 (Ⅳ)와 Z₂의 짝지움 반응을 거쳐 만 들어지고, 두 가지 방법으로 합성하였다. In the present invention, the 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative represented by the general formula (II) is a combination of the general formula (IV) and Z ₂ . It was made through a reaction and synthesized in two ways.

루이스산 촉매하의 반응인 방법 1은 보론트리플로라이드 이서레이트(BF₃·Et₂O)를 사용하고, 방법 2는 트리메틸실릴 트리플로오르메탄설포네이트(TMS·OTf)를 사용하여 화학식 (Ⅱ)를 얻을 수 있다. 이를 반응식 12로 나타낸다.Method 1, which is a reaction under a Lewis acid catalyst, uses borontrifluoride isate (BF ₃ · Et ₂ O), and method 2 uses trimethylsilyl trifluoromethanesulfonate (TMS.OTf) to formula (II) Can be obtained. This is represented by Scheme 12.

반응식 12Scheme 12

본 발명에 따른 상기 화학식 (Ⅱ) 중에서 여러 가지 치환기를 달리하는 화합물은 상기 반응식 12에 따라 또한 제조될 수 있으며, 하기 표 2에 기재된 화합물 번호 53~56를 얻는다.Compounds varying in the various substituents in the above formula (II) according to the present invention can also be prepared according to Scheme 12, to obtain compound Nos. 53 to 56 described in Table 2 below.

또한 본 발명에서 화학식 (Ⅲ)으로 표시되는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체는, Z₃와 화학식 (V)와의 짝지움 반응을 거쳐 만들어진다. 루이스산 촉매하의 반응으로 보론트리플로라이드 이서레이트(BF₃·Et₂O)를 사용하여 화학식 (Ⅲ)을 얻을 수 있다. 이를 반응식 13으로 나타낸다.In the present invention, the 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative represented by the general formula (III) is a combination of Z ₃ and general formula (V). It is made by reaction. Reaction under a Lewis acid catalyst can yield formula (III) using borontrifluoride isate (BF ₃ · Et ₂ O). This is represented by Scheme 13.

반응식 13Scheme 13

하기 반응식 14는 본 발명에 따른 상기 화학식 (Ⅲ) 중에서 여러 가지 치환기를 달리하는 하기 표 3에 기재된 화합물 번호 57~63을 얻는 반응식으로서, 화학식 (35)를 포타슘퍼망가네이트(KMnO₄) 또는 루세늄트리클로라이드(RuCl₃)로 산화시켜 화학식 (36)를 얻고, 보호기를 제거하여 화학식 (37)를 얻는다.Scheme 14 below is a scheme for obtaining compounds Nos. 57 to 63 shown in Table 3, which differs from the various substituents in the above formula (III), wherein formula (35) is potassium permanganate (KMnO ₄ ) or ruce Oxidation with nium trichloride (RuCl ₃ ) gives formula (36), and the protecting group is removed to give formula (37).

반응식 14Scheme 14

여기서 Z₃은 3-데옥시-D-아라비노피라노사이드, D-아라비노피라노사이드, L-람노피라노사이드, D-만노피라노사이드로부터 선택되는 하나이다.Wherein Z ₃ is one selected from 3-deoxy-D-arabinopyranoside, D-arabinopyranoside, L-ramnopyranoside, D-mannopyranoside.

본 발명은 상기 화학식 (Ⅰ), 화학식 (Ⅱ) 또는 화학식 (Ⅲ)으로 표시되는 신규 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체의 대량 제조를 가능하게 하여, 노화 및 스트레스억제 관련 약효검색을 시행하고 이 페로몬 유도체의 활성 타깃 단백질의 검색 발굴을 할 수 있는 길을 열어 주었다.The present invention relates to a novel 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative represented by Formula (I), Formula (II) or Formula (III). By enabling mass production, we conducted a drug search related to aging and stress suppression, and opened the way to search and discover the active target protein of this pheromone derivative.

본 발명에서 합성한 상기 화학식 (Ⅰ), 화학식 (Ⅱ) 또는 화학식 (Ⅲ)으로 표시되는 신규 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체의 장기휴면효과(dauer effect)를 꼬마선충을 이용하여 측정하였다. 그 결과를표 1~3에 나타내었다. 여러 가지 실험을 해나가기 위해서는 더 많은 페로몬 유도체를 필요로 하는 것이므로, 본 발명의 결과는 앞으로의 연구 방향에 대해서 기초가 될 수 있고, 다양한 유도체의 합성으로 인해 보다 좋은 연구 결과가 기대된다.Novel 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid represented by the formula (I), formula (II) or formula (III) synthesized in the present invention The long-term dormant effect of the derivatives was measured using the nematodes. The results are shown in Tables 1-3. Since more pheromone derivatives are required to conduct various experiments, the results of the present invention may be the basis for future research directions, and better results are expected due to the synthesis of various derivatives.

합성한 페로몬을 먹이, 온도 그리고 군집밀도와 같은 여러 조건을 달리하면서 예쁜 꼬마선충(C. elegans)에 대하여 장기휴면효과를 측정하였다. 특히 적합한 환경인 먹이, 성장하기에 적절한 온도(15-25℃), 낮은 개체 군집 밀도 하에서는 L2 후반부 혹은 L3 전반부에서 L4, 성충(adult) 단계로 넘어가야 하는데도 불구하고, 합성한 페로몬 유도체 물질을 같이 넣었을 때에는 휴면유충기(dauer larva)단계로 들어갔다.The effects of long-term dormancy on the pretty C. elegans were measured for the synthesized pheromones under different conditions such as feeding, temperature and cluster density. Particularly suitable environment for feeding, suitable temperature for growth (15-25 ° C), low population density, L4, adult in the late L2 or in the first half of L3, although the synthesized pheromone derivatives When put in, it entered the stage of the larvae.

휴면유충기의 꼬마선충은 먹지도 않으며, 움직이지 않는 상태로 존재하며 외부의 물리적 자극에 의하여 움직임은 일시적으로 유도된다. 비교 대상으로 그림 1은 휴면유충기의 꼬마선충 7마리와 L4 단계를 지나 성충이 된 꼬마선충 1마리를 비교 관찰함으로써, 본 발명에서 합성된 페로몬 유도체 물질은 장기휴면효과에 크게 영향을 미치는 것으로 판단되고, 사진에서도 성장하지 않고 움직이지 않는 것을 관찰할 수 있었다.Little nematodes of dormant larvae do not eat, remain stationary, and their movement is temporarily induced by external physical stimuli. For comparison, Figure 1 compares the seven nymphs of dormant larvae and one adult nymph after L4 stage, and the pheromone derivative material synthesized in the present invention is judged to have a significant effect on long-term dormant effect. We could observe that it did not move and did not move even in photograph.

그림 1. 합성한 페로몬 유도체를 이용한 예쁜 꼬마선충의 휴면유충기(Dauer larva)와 어린 성충(young adult)의 비교Figure 1.Daeer larva and young adult larvae of a pretty nymph using synthetic pheromone derivatives

이하 본 발명을 실시예를 들어 보다 상세하게 설명하지만, 본 발명의 범위가 하기 기재된 실시예 만으로 한정되는 것은 아니다. 실시예에서 화합물 번호는 표 1~3에 기재된 화합물 번호를 뜻한다.EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited only to the Examples described below. In the Examples, the compound number means the compound number described in Tables 1-3.

실시예 1Example 1

(2R)-2-(3,6-디데옥시-α-L-(2R) -2- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )) 헥스Hex -5-엔(화합물 번호 1)의 합성Synthesis of -5-Yen (Compound No. 1)

1-1.중간체 합성1-1.Intermediate Synthesis

라운드 플라스크에 4Å 분자체(Molecular sieve) 500mg을 넣고, 진공상태에서 질소 기체로 내부를 치환한 후, 디클로로메탄 30㎖를 넣는다. 30분 교반한 후 화학식 (Ⅳ) 2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실 트리클로로아세트이미데이트(1.0g, 1.9mmol)와 화학식 (Ⅴ) (2R)-5-헥센-2-올(220mg, 2.2 mmol)을 디클로로메탄에 녹여서 넣는다. 온도를 -20℃로 낮추고 트리메틸실릴 트리플로오르메탄설포네이트(0.2㎖, 0.1mmol)를 디클로로메탄 2㎖에 묽힌 후 천천히 넣는다. 3시간 동안 교반 후 포화탄산수소나트륨 수용액을 첨가하여 반응을 종결한다. 디클로로메탄으로 3회 추출하고 포화탄산수소나트륨 수용액(20㎖), 증류수(20㎖)로 씻어준 후 유기층을 건조(MgSO₄), 여과한 후 감압 하에 용매를 제거하고 헥산:에틸아세테이트(5:1)의 혼합용매를 용출제로 하는 실리카겔컬럼크로마토그래피로 분리하여 시럽상의 화합물 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥스-5-엔(657mg, 75%)를 얻었다. Into a round flask, 500 mg of 4 μl molecular sieve was added, the inside was replaced with nitrogen gas in a vacuum state, and 30 ml of dichloromethane was added thereto. After stirring for 30 minutes, formula (IV) 2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyl trichloroacetimidadate (1.0 g, 1.9 mmol) (V) (2R) -5-hexen-2-ol (220 mg, 2.2 mmol) is dissolved in dichloromethane. Lower the temperature to -20 ° C, dilute trimethylsilyl trifluoromethanesulfonate (0.2 ml, 0.1 mmol) in 2 ml of dichloromethane and slowly add. After stirring for 3 hours, the reaction is terminated by addition of saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted three times with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution (20 ml) and distilled water (20 ml), and then the organic layer was dried (MgSO ₄ ), filtered and the solvent was removed under reduced pressure, followed by hexane: ethyl acetate (5: Compound (2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino- in syrup form was separated by silica gel column chromatography using a mixed solvent of 1) as an eluent. Hexopyranosyloxy) hex-5-ene (657 mg, 75%) was obtained.

1-2. 보호기 제거1-2. Remove protector

(2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥스-5-엔 100mg(0.20mmol)을 메탄올 10㎖에 녹인다. 온도를 낮추어 0℃에서 소디움메톡사이드 33mg(0.62mmol)을 넣은 후 온도를 상온으로 올린다. 8시간 교반 후 반응이 종결되면 메탄올 용매에 앰버라이트(Amberlite-IR120, H⁺)를 조금씩 넣으면서 중성으로 맞춘다. 감압증류로 용매를 제거한 다음, 증류수와 에틸아세테이트로 3회 추출하고, 브라인(brine, NaCl 용액)으로 씻은 후 유기층을 건조(MgSO₄), 여과한 후 감압 하에 용매를 제거하고 헥산:에틸아세테이트(1:2)의 혼합용매를 용출제로 하는 실리카겔컬럼크로마토그래피로 분리하여 시럽상의 화합물 (2R)-2-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥스-5-엔(44mg 91%)를 얻었다.(2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hex-5-ene 100 mg (0.20 mmol) in methanol 10 Dissolve in ml. Lower the temperature to put sodium methoxide 33mg (0.62mmol) at 0 ℃ and raise the temperature to room temperature. After stirring for 8 hours, the reaction was terminated and neutralized by adding Amberlite (Amberlite-IR120, H ⁺ ) in methanol. After removal of the solvent by distillation under reduced pressure, the mixture was extracted three times with distilled water and ethyl acetate, washed with brine (brine, NaCl solution), the organic layer was dried (MgSO ₄ ), filtered and the solvent was removed under reduced pressure, and hexane: ethyl acetate Compound (2R) -2- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hex- in syrup form was separated by silica gel column chromatography using a mixed solvent of 1: 2 as an eluent. 5-ene (44 mg 91%) was obtained.

¹H-NMR (250MHz, CDCl₃) δ 5.87-5.76(m, 1H), 5.06-4.94(m, 2H), 4.68(s, 1H), 3.86-3.76(m, 2H), 3.74-3.54(m, 2H), 2.90(bs 2H), 2.20-1.99(m, 3H), 1.88-1.46(m, 3H, J = 6.0 Hz), 1.27(d, 2H, J = 6.1 Hz), 1.14(d, 2H, J = 6.5 Hz) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 5.87-5.76 (m, 1H), 5.06-4.94 (m, 2H), 4.68 (s, 1H), 3.86-3.76 (m, 2H), 3.74-3.54 (m , 2H), 2.90 (bs 2H), 2.20-1.99 (m, 3H), 1.88-1.46 (m, 3H, J = 6.0 Hz), 1.27 (d, 2H, J = 6.1 Hz), 1.14 (d, 2H , J = 6.5 Hz)

¹³C-NMR (63MHz, CDCl₃) δ 138.3, 114.7, 95.9, 70.9, 69.9, 69.1, 67.6, 36.3, 35.1, 29.9, 29.7, 18.9, 17.8 ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 138.3, 114.7, 95.9, 70.9, 69.9, 69.1, 67.6, 36.3, 35.1, 29.9, 29.7, 18.9, 17.8

실시예 2Example 2

(2R)-2-(3,6-디데옥시-α-L-(2R) -2- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )) 헥산Hexane (화합물 번호 4)의 합성Synthesis of (Compound No. 4)

(2R)-2-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥스-5-엔(25mg, 0.1 mmol)을 에틸아세테이드 5㎖에 녹인 후, 10%-팔라디움/카본 3mg을 넣고 진공상태로 만들고, 수소기체로 치환시킨다. 0℃에서 5시간 후 반응이 종료되면 여과하고 감압 하에 용매를 제거하고 헥산:에틸아세테이트(1:1)의 혼합용매를 용출제로 하는 실리카겔컬럼크로마토그래피로 분리하여 시럽상의 화합물 (2R)-2-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥산(22.5mg, 89%)을 얻었다.(2R) -2- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hex-5-ene (25 mg, 0.1 mmol) was dissolved in 5 ml of ethyl acetate, 10 Add 3 mg of% -palladium / carbon and place in vacuo and replace with hydrogen gas. After the reaction was completed at 0 ° C. for 5 hours, the reaction mixture was filtered, the solvent was removed under reduced pressure, and the mixed solvent of hexane: ethyl acetate (1: 1) was separated by silica gel column chromatography as an eluent to give a syrup-like compound (2R) -2- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hexane (22.5 mg, 89%) was obtained.

¹H-NMR (250MHz, CDCl₃) δ 4.68(s, 1H), 3.81-3.74(m, 2H), 3.72-3.54(m, 2H), 2.59(bs, 2H), 2.08-2.00(m, 1H), 1.89-1.78(m, 1H), 1.58-1.32(m, 6H), 1.27(d, 3H, J = 6.0 Hz), 1.13(d, 3H, J = 6.1 Hz), 0.93(t, 3H, J = 6.6 Hz) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 4.68 (s, 1H), 3.81-3.74 (m, 2H), 3.72-3.54 (m, 2H), 2.59 (bs, 2H), 2.08-2.00 (m, 1H ), 1.89-1.78 (m, 1H), 1.58-1.32 (m, 6H), 1.27 (d, 3H, J = 6.0 Hz), 1.13 (d, 3H, J = 6.1 Hz), 0.93 (t, 3H, J = 6.6 Hz)

¹³C-NMR (63MHz, CDCl₃) δ 96.1, 71.7, 69.9, 69.3,68.0, 36.9, 35.2, 27.9, 22.7, 19.0, 17.7, 14.1 ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 96.1, 71.7, 69.9, 69.3,68.0, 36.9, 35.2, 27.9, 22.7, 19.0, 17.7, 14.1

실시예 3Example 3

(2R)-2-(2,4-디-O-(2R) -2- (2,4-di-O- 메틸methyl -3,6-디데옥시-α-L--3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )옥트-7-엔(화합물 번호 7)의 합성Synthesis of Oct-7-ene (Compound No. 7)

(2R)-2-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)옥트-7-엔 40mg(0.15 mmol)과 소디움하이드라이드 74.4mg(3.1mmol)을 넣고 진공상태로 만든 후 질소 기체로 치환한다. 증류된 테트라하이드로퓨란 10㎖를 넣고 온도를 40℃로 올려준다. 30분 후 아이오도메탄 0.2㎖(3.1mmol)을 넣은 후 1시간 정도 교반을 시켜 준다. 소디움하이드라이드 28.8mg(1.2mmol)과 아이오도메탄 0.1㎖(1.2mmol)를 질소기체 하에서 넣는다. 7시간 40℃에서 교반 후 반응이 종결되면 반응 혼합물을 실온으로 낮추고 메탄올 50㎖를 넣고 감압 하에 용매를 제거하고 헥산:에틸아세테이트(2:1)의 혼합용매를 용출제로 하는 실리카겔컬럼크로마토그래피로 분리하여 오일상의 화합물 (2R)-2-(2,4-디-O-메틸-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)옥트-7-엔(39mg, 88.4%)를 얻었다.(2R) -2- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) oct-7-ene 40 mg (0.15 mmol) and sodium hydride 74.4 mg (3.1 mmol) After making the state, replace with nitrogen gas. Add 10ml of distilled tetrahydrofuran and raise the temperature to 40 ℃. After 30 minutes, add 0.2ml (3.1mmol) of iodomethane and stir for about 1 hour. 28.8 mg (1.2 mmol) of sodium hydride and 0.1 ml (1.2 mmol) of iodomethane are added under a nitrogen gas. After stirring for 7 hours at 40 ° C., when the reaction was completed, the reaction mixture was cooled to room temperature, 50 ml of methanol was added thereto, the solvent was removed under reduced pressure, and the mixed solvent of hexane: ethyl acetate (2: 1) was separated by silica gel column chromatography. Oily compound (2R) -2- (2,4-di-O-methyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) oct-7-ene (39 mg, 88.4 %) Was obtained.

¹H-NMR (250MHz, CDCl₃) δ 5.725.88(m, 1H, H-2) 4.955.03(m, 2H, H-1) 4.78(s, 1H, H-1') 3.723.80(m, 1H, H-5') 3.613.15(m, 1H, H-3') 3.40(s, 3H, methyl ester) 3.36(s, 3H, methyl ester) 2.172.30(m, 1H) 2.06(s, 2H, H-4) 1.511.68(m, 2H, H-5) 1.22(d, J=6.2, 3H, H-6') 1.10(d, J=6.0, 3H, H-8) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 5.725.88 (m, 1H, H-2) 4.955.03 (m, 2H, H-1) 4.78 (s, 1H, H-1 ′) 3.723.80 ( m, 1H, H-5 ') 3.613.15 (m, 1H, H-3') 3.40 (s, 3H, methyl ester) 3.36 (s, 3H, methyl ester) 2.172.30 (m, 1H) 2.06 ( s, 2H, H-4) 1.511.68 (m, 2H, H-5) 1.22 (d, J = 6.2, 3H, H-6 ') 1.10 (d, J = 6.0, 3H, H-8)

¹³C-NMR (63MHz, CDCl₃) δ 139.6(C-1) 114.4(C-2) 93.5(C-1', α) 78.2(C-2') 77.2(C-4') 71.1(C-5') 68.3(C-7) 57.0(C-7') 56.8(C-8') 37.2(C-6) 33.8(C-3) 28.9(C-4) 28.5(C-3') 25.3(C-5) 19.0(C-6') 18.1(C-8) ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 139.6 (C-1) 114.4 (C-2) 93.5 (C-1 ', α) 78.2 (C-2') 77.2 (C-4 ') 71.1 (C- 5 ') 68.3 (C-7) 57.0 (C-7') 56.8 (C-8 ') 37.2 (C-6) 33.8 (C-3) 28.9 (C-4) 28.5 (C-3') 25.3 ( C-5) 19.0 (C-6 ') 18.1 (C-8)

실시예 4Example 4

(6R)-6-(2,4-디-O-(6R) -6- (2,4-di-O- 메틸methyl -3,6-디데옥시-α-L--3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )헵타노익산(Heptanoic acid 화합물 번호 8)의Of compound number 8) 합성 synthesis

(2R)-2-(2,4-디-O-메틸-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)옥트-7-엔 250mg(0.87mmol)을 넣고 아세톤 20㎖에 녹인 후 탄산수소나트륨 293mg (1.2mmol)을 넣는다. 30분 실온에서 교반 후 포타슘퍼망가네이트 90.0mg(1.8mmol)을 조금씩 넣고 20시간 교반시킨다. 반응이 종결되면 10% 염산(5㎖)으로 반응 종결 및 중성으로 만들고 에틸아세테이트로 3회 추출한다. 브라인으로 씻은 후 유기층을 건조(MgSO₄), 여과한 후 감압 하에 용매를 제거하고 헥산:에틸아세테이트(1:1)의 혼합용매를 용출제로 하는 실리카겔컬럼크로마토그래피로 분리하여 오일상의 화합물 (6R)-6-(2,4-디-O-메틸-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산( 93.4mg, 52.9%)을 얻었다.(2R) -2- (2,4-di-O-methyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) oct-7-ene 250 mg (0.87 mmol) Dissolve in 20ml and add 293mg (1.2mmol) of sodium bicarbonate. After stirring for 30 minutes at room temperature, potassium permanganate 90.0mg (1.8mmol) was added little by little and stirred for 20 hours. After the reaction was completed, the reaction was terminated and neutralized with 10% hydrochloric acid (5 mL), and extracted three times with ethyl acetate. After washing with brine, the organic layer was dried (MgSO ₄ ), filtered, the solvent was removed under reduced pressure, and the mixed solvent of hexane: ethyl acetate (1: 1) was separated by silica gel column chromatography as an eluent to obtain an oily compound (6R). -6- (2,4-di-O-methyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid (93.4 mg, 52.9%) was obtained.

¹H-NMR(250MHz, CDCl₃) δ 8.37(s, 1H) 4.80(s, 1H) 3.773.88(m, 1H) 3.593.71(m, 1H) 3.37(d, J=7.5, 7H, methyl ester) 3.073.12(m, 1H) 2.232.51(m, 3H) 1.511.87(m, 3H) 1.301.49(m, 2H) 1.23(d, J=6.2, 3H) 1.081.17(m, 3H) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 8.37 (s, 1H) 4.80 (s, 1H) 3.773.88 (m, 1H) 3.593.71 (m, 1H) 3.37 (d, J = 7.5, 7H, methyl ester) 3.073.12 (m, 1H) 2.232.51 (m, 3H) 1.511.87 (m, 3H) 1.301.49 (m, 2H) 1.23 (d, J = 6.2, 3H) 1.081.17 (m, 3H)

¹³C-NMR(63MHz, CDCl₃) δ 179.2(C-1) 93.3(C-1', α) 78.1(C-2') 77.2(C-4') 70.8(C-5') 68.3(C-6) 57.0(C-7') 56.8(C-8') 36.9(C-5) 34.0(C-2) 28.3(C-3) 25.2(C-3') 24.7(C-4) 18.9(C-6') 18.0(C-7) ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 179.2 (C-1) 93.3 (C-1 ', α) 78.1 (C-2') 77.2 (C-4 ') 70.8 (C-5') 68.3 (C -6) 57.0 (C-7 ') 56.8 (C-8') 36.9 (C-5) 34.0 (C-2) 28.3 (C-3) 25.2 (C-3 ') 24.7 (C-4) 18.9 ( C-6 ') 18.0 (C-7)

실시예 5Example 5

(4R)-4-(3,6-디데옥시-α-L-(4R) -4- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )) 펜타노익산Pentanoic acid (화합물 번호 9)의 합성Synthesis of (Compound No. 9)

5-1. 중간체의 합성5-1. Synthesis of Intermediates

(2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥스-5-엔(500mg, 1.14mmol)을 넣고 아세토니트릴:디클로로메탄:증류수를 2:2:3 비율로 만든 용매 14㎖에 녹인다. 10분 교반 후 산화제인 소디움퍼아이오데이트 (NaIO₄)(976mg, 4.56mmol)와 루세늄트리클로라이드(RuCl₃)(5mg, 0.028mmol) 촉매를 넣고 실온에서 4시간 동안 교반한다. 반응이 종결되면 증류수를 넣고 디클로로메탄으로 3회 추출한 후, 유기층을 건조(MgSO₄), 여과한 후 감압 하에 용매를 제거하고 헥산:에틸아세테이트(2:1)의 혼합용매를 용출제로 하는 실리카겔컬럼크로마토그래피로 분리하여 시럽상의 화합물 (4R)-4-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)펜타노익산(459mg, 88%)을 얻었다. Add (2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hex-5-ene (500 mg, 1.14 mmol) Acetonitrile: dichloromethane: distilled water is dissolved in 14 ml of a solvent made in a 2: 2: 3 ratio. After stirring for 10 minutes, sodium iodate (NaIO ₄ ) (976 mg, 4.56 mmol) and ruthenium trichloride (RuCl ₃ ) (5 mg, 0.028 mmol) were added to the oxidizing agent and stirred at room temperature for 4 hours. After the reaction was completed, distilled water was added and extracted three times with dichloromethane. The organic layer was dried (MgSO ₄ ), filtered, and the solvent was removed under reduced pressure. A silica gel column using a mixed solvent of hexane: ethyl acetate (2: 1) as an eluent was used. Chromatography to separate compound (4R) -4- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) pentanoic acid (459 mg) , 88%).

5-2. 보호기 제거5-2. Remove protector

(4R)-4-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)펜타노익산(50mg, 0.1mmol)을 메탄올 (5㎖)에 녹이고, 0℃에서 소디움메톡사이드 (18mg, 0.3mmol)를 첨가 후 상온에서 8시간 교반한다. 반응 종결 후 메탄올을 감압 농축하고 증류수(20㎖)에 녹인 후, 디클로로메탄으로 3회 씻어준다. 수용액 층을 앰버라이트(Amberlite IR-120, H⁺)를 이용하여 산성을 맞추고, 여과 후 감압 하에 용매를 제거하고 클로로포름:메탄올(7:1)의 혼합용매를 용출제로 하는 실리카겔 컬럼크로마토그래피로 분리하여 시럽상의 화합물 (4R)-4-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)펜타노익산(24mg, 91%)을 얻었다. (4R) -4- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) pentanoic acid (50 mg, 0.1 mmol) in methanol (5 Ml), and sodium methoxide (18 mg, 0.3 mmol) was added at 0 ° C., followed by stirring at room temperature for 8 hours. After completion of the reaction, methanol was concentrated under reduced pressure, dissolved in distilled water (20 ml), and washed three times with dichloromethane. The aqueous layer was acidified using Amberlite (Amberlite IR-120, H ⁺ ), filtered and the solvent was removed under reduced pressure, and separated by silica gel column chromatography using a mixed solvent of chloroform: methanol (7: 1) as an eluent. Compound (4R) -4- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) pentanoic acid (24 mg, 91%) was obtained in the syrup form.

실시예 6Example 6

메틸methyl -(4R)-4-(3,6-디데옥시-α-L--(4R) -4- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )) 펜타노에이트Pentanoate (( 화합물 번호 11)의Of compound number 11) 합성 synthesis

(4R)-4-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)펜타노익산(50mg, 0.1mmol)을 넣고 메탄올 5㎖에 녹인다. 온도를 낮추어 0℃에서 소디움메톡사이드(18mg, 0.3mmol)을 넣은 후 온도를 상온으로 올린다. 8시간 교반 후 반응이 종결되면 메탄올 용매에 바로 10% 황산을 한 방울 떨어뜨려 강한 산성을 만든다. 6 시간 후 반응이 종결되면 감압증류로 용매를 제거한 다음 증류수와 에틸아세테이트로 3회 추출하고 브라인으로 씻는다. 유기층을 건조(MgSO₄), 여과한 후 감압 하에 용매를 제거하고 클로로포름:메탄올(9:1)의 혼합용매를 용출제로 하는 실리카겔컬럼크로마토그래피로 분리하여 시럽상의 화합물 메틸-(4R)-4-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)펜타노에이트(23mg, 83%)을 얻었다. (4R) -4- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) pentanoic acid (50 mg, 0.1 mmol) was added and methanol 5 Dissolve in ml. Lower the temperature to put sodium methoxide (18mg, 0.3mmol) at 0 ℃ and raise the temperature to room temperature. When the reaction is complete after stirring for 8 hours, a drop of 10% sulfuric acid is immediately added to the methanol solvent to form a strong acid. After 6 hours, the reaction was terminated, the solvent was removed by distillation under reduced pressure, extracted three times with distilled water and ethyl acetate and washed with brine. The organic layer was dried (MgSO ₄ ), filtered, and the solvent was removed under reduced pressure, and a mixed solvent of chloroform: methanol (9: 1) was separated by silica gel column chromatography as an eluent, and the compound methyl- (4R) -4- in syrup form. (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) pentanoate (23 mg, 83%) was obtained.

¹H-NMR (250MHz, CDCl₃) δ 4.68 (s, 1H), 3.87-3.79(m, 2H), 3.68(s, 3H), 3.61-3.58 (m, 2H), 2.70(bs, 2H), 2.44 (t, 2H, J = 7.4 Hz), 2.07-2.02 (m, 1H), 1.88-1.76 (m, 3H), 1.27 (d, 3H, J = 5.2 Hz), 1.16 (d, 3H, J = 6.0 Hz) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 4.68 (s, 1H), 3.87-3.79 (m, 2H), 3.68 (s, 3H), 3.61-3.58 (m, 2H), 2.70 (bs, 2H), 2.44 (t, 2H, J = 7.4 Hz), 2.07-2.02 (m, 1H), 1.88-1.76 (m, 3H), 1.27 (d, 3H, J = 5.2 Hz), 1.16 (d, 3H, J = 6.0 Hz)

¹³C-NMR (63MHz, CDCl₃) δ 174.3, 95.7, 70.2, 70.1, 69.1, 67.8, 51.7, 35.1, 32.1, 30.4, 18.7, 17.7 ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 174.3, 95.7, 70.2, 70.1, 69.1, 67.8, 51.7, 35.1, 32.1, 30.4, 18.7, 17.7

실시예 7Example 7

(2R)-2-(3,6-디데옥시-α-L-(2R) -2- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )) 헥산Hexane -6-올(화합물 번호 14)의 합성Synthesis of -6-ol (Compound No. 14)

7-1. 중간체 합성7-1. Intermediate synthesis

(2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥스-5-엔(100mg, 0.22mmol)을 넣고, 진공상태에서 질소 기체로 내부를 치환한다. 용매 없이 바로 9-보로바이사이클로[3.3.1]노네인(9-BBN)(0.9㎖, 0.45mmol)을 넣고 실온에서 교반시킨다. 1시간 후 과산화수소와 3N-소디움하이드록사이드(1:1) 4㎖를 넣는다. 기체발생 후 증류수와 디에틸에테르로 3회 추출하고, 포화탄산수소나트륨과 브라인으로 씻는다. 유기층을 건조(MgSO₄), 여과한 후 감압 하에 용매를 제거하고 헥산:에틸아세테이트(3:1)의 혼합용매를 용출제로 하는 실리카겔컬럼크로마토그래피로 분리하여 시럽상의 화합물 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아 라비노-헥소피라노실옥시)헥산-6-올(85mg, 82%)를 얻었다.Add (2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hex-5-ene (100 mg, 0.22 mmol) In the vacuum, replace the inside with nitrogen gas. Add 9-borobicyclo [3.3.1] nonane (9-BBN) (0.9 mL, 0.45 mmol) directly without solvent and stir at room temperature. After 1 hour, add 4 ml of hydrogen peroxide and 3N-sodium hydroxide (1: 1). After gas evolution, the mixture was extracted three times with distilled water and diethyl ether, and washed with saturated sodium bicarbonate and brine. The organic layer was dried (MgSO ₄ ), filtered and the solvent was removed under reduced pressure, and the mixed solvent of hexane: ethyl acetate (3: 1) was separated by silica gel column chromatography as an eluent to give a syrup-like compound (2R) -2- ( 2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hexane-6-ol (85 mg, 82%) was obtained.

7-2. 보호기 제거7-2. Remove protector

상기 실시예 1-2의 보호기 제거에서, (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥스-5-엔 대신 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥산-6-올을 사용한 것을 제외하고는 실시예 1-2와 동일한 방법으로 수행하여 (2R)-2-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥산-6-올(25mg, 90%)을 얻었다.In removing the protecting group of Example 1-2, (2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hex- Except for using (2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hexane-6-ol instead of 5-ene And (2R) -2- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hexane-6-ol (25 mg, 90%) in the same manner as in Example 1-2 )

¹H-NMR (250MHz, CDCl₃) δ 4.66(s, 1H). 3.78-3.70(m, 2H), 3.69-3.55(m, 6H), 2.02-1.98(m, 1H), 1.85-1.76(m, 1H), 1.54-1.51(m, 4H), 1.42-1.26(m, 21H), 1.11(d, 3H, J = 5.9 Hz) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 4.66 (s, 1H). 3.78-3.70 (m, 2H), 3.69-3.55 (m, 6H), 2.02-1.98 (m, 1H), 1.85-1.76 (m, 1H), 1.54-1.51 (m, 4H), 1.42-1.26 (m , 21H), 1.11 (d, 3H, J = 5.9 Hz)

¹³C-NMR (63MHz, CDCl₃) δ 96.0, 71.5, 69.8, 69.0, 67.4, 62.6, 37.2, 35.0, 32.6, 29.5, 29.4, 25.7, 19.0, 17.7 ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 96.0, 71.5, 69.8, 69.0, 67.4, 62.6, 37.2, 35.0, 32.6, 29.5, 29.4, 25.7, 19.0, 17.7

실시예 8Example 8

(6R)-6-(3,6-디데옥시-α-L-(6R) -6- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )) 헵타날Heptanal (화합물 번호 18)의 합성Synthesis of (Compound No. 18)

8-1. 중간체 합성8-1. Intermediate synthesis

(2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)옥트-7-엔(100mg, 0.21mmol)을 디클로로메탄 20㎖에 녹인 후 -78℃에서 오존 (O₃) 발생기에 연결된 관을 통하여 버블링(bubbling)한다. 반응 종결 후 디메틸 설파이드 (dimethyl sulfide)를 넣고 24시간 후에 반응이 종결되면 감압 하에 용매를 제거하고 헥산:에틸아세테이트(2:1)의 혼합용매를 용출제로 하는 실리카겔컬럼크로마토그래피로 분리하여 시럽상의 화합물 (6R)-6-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타날(66mg, 65%)을 얻었다.(2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) oct-7-ene (100 mg, 0.21 mmol) It is dissolved in 20 ml of methane and bubbling through a tube connected to an ozone (O ₃ ) generator at -78 ° C. After completion of the reaction, dimethyl sulfide was added, and after 24 hours, when the reaction was terminated, the solvent was removed under reduced pressure, and the mixed solvent of hexane: ethyl acetate (2: 1) was separated by silica gel column chromatography as an eluent to form a syrup-like compound. (6R) -6- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanal (66 mg, 65%) was obtained.

8-2. 보호기 제거8-2. Remove protector

상기 실시예 1-2의 보호기 제거에서, (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥스-5-엔 대신에 (6R)-6-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타날을 사용한 것을 제외하고는 실시예 1-2와 동일한 방법으로 수행하여 (6R)-6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타날(19.5mg, 87%)을 얻었다.In removing the protecting group of Example 1-2, (2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hex- Except for using (6R) -6- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanal instead of 5-ene (6R) -6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanal (19.5 mg, 87%) was obtained in the same manner as in Example 1-2.

¹H-NMR (250MHz, CDCl₃) δ 9.77(s, 1H), 4.70(s, 1H). 3.81-3.77(m, 2H), 3.68-3.57(m, 2H), 2.50-2.44(m, 2H), 2.11-2.02(m, 1H), 1.99(bs, 2H), 1.88-1.78(m, 1H), 1.71-1.37(m, 6H), 1.29(d, 3H, J = 6.2 Hz), 1.14(d, 3H, J = 6.1 Hz) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 9.77 (s, 1H), 4.70 (s, 1H). 3.81-3.77 (m, 2H), 3.68-3.57 (m, 2H), 2.50-2.44 (m, 2H), 2.11-2.02 (m, 1H), 1.99 (bs, 2H), 1.88-1.78 (m, 1H ), 1.71-1.37 (m, 6H), 1.29 (d, 3H, J = 6.2 Hz), 1.14 (d, 3H, J = 6.1 Hz)

¹³C-NMR (63MHz, CDCl₃) δ 202.9, 96.0, 71.1, 69.9, 69.4, 68.2,43.9, 37.0, 35.3, 32.0, 29.8, 25.3, 22.8, 22.1, 19.0, 17.8, 14.2 ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 202.9, 96.0, 71.1, 69.9, 69.4, 68.2,43.9, 37.0, 35.3, 32.0, 29.8, 25.3, 22.8, 22.1, 19.0, 17.8, 14.2

실시예 9Example 9

메틸methyl -(9R)-9-(3,6-디데옥시-α-L--(9R) -9- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )데-2-De-2- 엔오에이트(화합물 번호 20)의Of enoate (compound number 20) 합성 synthesis

소디움메톡사이드109.1mg(2.02mmol)을 넣고 메탄올 20㎖를 첨가한 후, 0℃에서 트리에틸 포스포노아세테이트(Triethyl phosphonoacetate) 0.5㎖(2.02mmol)을 넣고 30분 교반한다. 0℃ 상태에서 (7R)-7-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)옥타날 200mg(1.01mmol)을 메탄올에 녹여서 넣어 준다. 1시간 교반 후 메탄올은 감압 하 제거하고 증류수 100㎖와 에틸아세테이트 200㎖로 3회 추출한다. 브라인으로 씻어 주고 유기층을 건조(MgSO₄), 여과한 후 감압 하에 용매를 제거하고 헥산:에틸아세테이트(1:3)의 혼합용매를 용출제로 하는 실리카겔 컬럼 크로마토그래피로 분리하여 오일상의 화합물 메틸-(9R)-9-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)데-2-엔오에이트 46.0mg(35.5%)을 얻었다.Sodium Methoxide 109.1mg (2.02mmol) was added and methanol 20ml was added, 0.5mL (2.02mmol) of triethyl phosphonoacetate was added at 0 ° C, and stirred for 30 minutes. (7R) -7- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) octanal at 0 ° C. Dissolve 200mg (1.01mmol) in methanol. After stirring for 1 hour, methanol was removed under reduced pressure and extracted three times with 100 ml of distilled water and 200 ml of ethyl acetate. The organic layer was washed with brine, dried (MgSO ₄ ), filtered, and the solvent was removed under reduced pressure. The mixed solvent of hexane: ethyl acetate (1: 3) was separated by silica gel column chromatography as an eluent, and the oily compound methyl- ( 9R) -9- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) de-2-enoate 46.0 mg (35.5%) were obtained.

¹H-NMR(250MHz, CDCl₃) δ 6.91(m, 1H, H-3) 5.79(d, J=15.6, 1H, H-2) 4.68(s, 1H, H-1) 3.80(s, 2H) 3.72(s, 3H, methyl ester) 3.543.66(m, 2H) 2.66(s, 2H, alcohol) 2.162.25(m, 2H, H-4) 2.022.06(m, 1H, H-3' eq) 1.78(t, J=10.5, 1H, H-3' ax) 1.421.56(m, 5H) 1.311.39(m, 3H) 1.25(d, J=5.6, 4H, H-6') 1.10(d, J=6.0, 3H, H-10) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 6.91 (m, 1H, H-3) 5.79 (d, J = 15.6, 1H, H-2) 4.68 (s, 1H, H-1) 3.80 (s, 2H ) 3.72 (s, 3H, methyl ester) 3.543.66 (m, 2H) 2.66 (s, 2H, alcohol) 2.162.25 (m, 2H, H-4) 2.022.06 (m, 1H, H-3 ' eq) 1.78 (t, J = 10.5, 1H, H-3 'ax) 1.421.56 (m, 5H) 1.311.39 (m, 3H) 1.25 (d, J = 5.6, 4H, H-6') 1.10 (d, J = 6.0, 3H, H-10)

¹³C-NMR(63MHz, CDCl₃) δ 167.4(C-1) 149.9 120.9 96.0(C-1', α) 71.4(C-5') 69.92(C-2') 69.26(C-4') 67.8(C-9) 51.5(C-11) 37.1(C-8) 35.1(C-3') 32.2(C-4) 29.1(C-6) 27.9(C-5) 25.5(C-7) 19.0(C-6') 17.7(C-10) ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 167.4 (C-1) 149.9 120.9 96.0 (C-1 ', α) 71.4 (C-5') 69.92 (C-2 ') 69.26 (C-4') 67.8 (C-9) 51.5 (C-11) 37.1 (C-8) 35.1 (C-3 ') 32.2 (C-4) 29.1 (C-6) 27.9 (C-5) 25.5 (C-7) 19.0 ( C-6 ') 17.7 (C-10)

실시예 10Example 10

(9R)-9-(3,6-디데옥시-α-L-(9R) -9- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )) 데카노익산Decanoic acid (화합물 번호 22)의 합성Synthesis of (Compound No. 22)

메틸-(9R)-9-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)데카노에이트 22.0mg(0.069mmol)을 테트라하이드로퓨란:증류수(1:1) 10㎖에 녹여 교반한다. 1N- 리튬하이드록사이드 6㎖를 넣고 실온에서 6시간 교반한다. 반응종결 후 1N 염산 3㎖로 중성화시킨다. 디클로로메탄 50㎖로 3회 추출하고 수용액 층을 모아서 동결 건조하고 클로로포름:메탄올(7:1)의 혼합용매를 용출제로 하는 실리카겔컬럼 크로마토그래피로 분리하여 오일상의 화합물 (9R)-9-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)데카노익산 14.2mg(67.6%)을 얻었다.Methyl- (9R) -9- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) decanoate 22.0 mg (0.069 mmol) in tetrahydrofuran: distilled water (1: 1) 10 Dissolve in ml and stir. 6 ml of 1N lithium hydroxide was added and stirred at room temperature for 6 hours. After completion of the reaction, neutralized with 3 ml of 1N hydrochloric acid. The mixture was extracted three times with 50 ml of dichloromethane, and the aqueous layer was collected and freeze-dried. The mixed solvent of chloroform: methanol (7: 1) was separated by silica gel column chromatography as an eluent to obtain an oily compound (9R) -9- (3, 14.2 mg (67.6%) of 6-dideoxy-α-L-arabino-hexopyranosyloxy) decanoic acid was obtained.

¹H-NMR(250MHz, CDCl₃) δ 4.065.46(m, 2H, alcohol) 4.70(s, 1H, H-1') 3.563.81(m, 4H) 2.31(t, J=7.0, 2H, H-2) 2.032.11(m, 1H, H-3' eq) 1.791.90(m, 1H, H-3' ax) 1.531.61(m, 2H, H-3) 1.411.47(m, 2H, H-8) 1.33(s, 6H) 1.25(d, J=5.9, 4H, H-6') 1.10(d, J=6.0, 3H, H-10) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 4.065.46 (m, 2H, alcohol) 4.70 (s, 1H, H-1 ′) 3.563.81 (m, 4H) 2.31 (t, J = 7.0, 2H, H-2) 2.032.11 (m, 1H, H-3'eq) 1.791.90 (m, 1H, H-3'ax) 1.531.61 (m, 2H, H-3) 1.411.47 (m, 2H, H-8) 1.33 (s, 6H) 1.25 (d, J = 5.9, 4H, H-6 ') 1.10 (d, J = 6.0, 3H, H-10)

¹³C-NMR(63MHz, CDCl₃) δ 178.3(C-1) 95.8(C-1', α) 71.5(C-5') 69.8(C-2') 69.3(C-4') 68.2(C-9') 37.3(C-8) 35.0(C-2) 33.9(C-3') 28.9(C-6) 28.8(C-5) 28.3(C-4) 25.4(C-7) 24.6(C-3) 19.1(C-6') 17.7(C-10) ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 178.3 (C-1) 95.8 (C-1 ', α) 71.5 (C-5') 69.8 (C-2 ') 69.3 (C-4') 68.2 (C -9 ') 37.3 (C-8) 35.0 (C-2) 33.9 (C-3') 28.9 (C-6) 28.8 (C-5) 28.3 (C-4) 25.4 (C-7) 24.6 (C -3) 19.1 (C-6 ') 17.7 (C-10)

실시예 11Example 11

(2R)-2-(2,4-디-O-(2R) -2- (2,4-di-O- 벤조일Benzoyl -3,6-디데옥시-α-L--3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )-8-)-8- 브로모옥탄(화합물 번호 23)의Of bromooctane (compound number 23) 합성 synthesis

11-1. 중간체 합성11-1. Intermediate synthesis

(2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-옥탄올 1.1g(2.27mmol)을 넣고 디클로로메탄 50㎖를 첨가하여 녹인다. 0℃로 낮춘 후 트리에틸아민(Et₃N) 0.35㎖(2.49mmol)을 넣고 10분 교반하여 용매의 상태를 염기성으로 만든다. 메실클로라이드(Mesyl Chloride, Ms) 0.26㎖(3.4mmol)를 넣고 1시간 교반시키고 반응 종료 후, 증류수 5㎖을 첨가하고 디클로로메탄 400㎖로 3회 추출한다. 유기층을 건조(MgSO₄), 여과한 후 감압 하에 용매를 제거하고 헥산:에틸아세테이트(4:1)의 혼합용매를 용출제로 하는 실리카겔컬럼 크로마토그래피로 분리하여 화합물 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-(메탄설포닐옥시)옥탄 1.2g(94%)을 얻었다.1.1 g (2.27 mmol) of (2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8-octanol Dissolve by adding 50 ml of dichloromethane. After lowering to 0 ° C., 0.35 ml (2.49 mmol) of triethylamine (Et ₃ N) was added thereto, followed by stirring for 10 minutes to make the solvent basic. 0.26 ml (3.4 mmol) of mesyl chloride (Mesyl Chloride, Ms) was added thereto, and stirred for 1 hour. After completion of the reaction, 5 ml of distilled water was added and extracted three times with 400 ml of dichloromethane. The organic layer was dried (MgSO ₄ ), filtered and the solvent was removed under reduced pressure, and the mixed solvent of hexane: ethyl acetate (4: 1) was separated by silica gel column chromatography as an eluent to give the compound (2R) -2- (2, 1.2 g (94%) of 4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8- (methanesulfonyloxy) octane was obtained.

이 중간체 480mg(0.85mmol)과 리튬브로마이드(LiBr) 223mg(2.56mmol)을 넣고 진공상태에서 질소 기체로 내부를 치환한 후, 아세톤 30㎖를 넣고 60℃로 가열하면서 교반한다. 2시간 후 반응종료 후 증류수 5㎖를 넣고, 에틸아세테이트 250㎖로 3회 추출하고 브라인으로 씻어준다. 유기층을 건조(MgSO₄), 여과한 후 감압 하에 용매를 제거하고 헥산:에틸아세테이트(4:1)의 혼합용매를 용출제로 하는 실리카겔컬럼 크로마토그래피로 분리하여 화합물 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-브로모옥탄 409mg(87.6%)을 얻었다.480 mg (0.85 mmol) of this intermediate and 223 mg (2.56 mmol) of lithium bromide (LiBr) are added thereto, and the inside is replaced with nitrogen gas in a vacuum state. Then, 30 ml of acetone is added thereto and the mixture is stirred while heating to 60 ° C. After 2 hours, 5 ml of distilled water was added and the mixture was extracted three times with 250 ml of ethyl acetate and washed with brine. The organic layer was dried (MgSO ₄ ), filtered and the solvent was removed under reduced pressure, and the mixed solvent of hexane: ethyl acetate (4: 1) was separated by silica gel column chromatography as an eluent to give the compound (2R) -2- (2, 409 mg (87.6%) of 4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8-bromooctane were obtained.

11-2. 보호기 제거11-2. Remove protector

상기 실시예 1-2의 보호기 제거에서 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥스-5-엔 대신에 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-브로모옥탄을 사용한 것을 제외하고는 실시예 1-2와 동일한 방법으로 수행하여 (2R)-2-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-브로모옥탄(72.4mg, 82.2%)을 얻었다.(2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hex-5 in the protecting group removal of Example 1-2 above Using (2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8-bromooctane instead of -ene (2R) -2- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8-bromooctane (72.4 mg) was carried out in the same manner as in Example 1-2 except for , 82.2%).

¹H-NMR(250MHz, CDCl₃) δ 4.68(s, 1H, H-1') 3.733.80(m, 2H) 3.543.70(m, 2H) 3.38(t, J=7.4, 2H, H-2) 2.92(s, 1H, alcohol) 2.64(s, 1H, alcohol) 2.012.08(m, 1H, H-3' eq) 1.771.91(m, 3H) 1.511.57(m, 1H) 1.341.44(m, 7H) 1.25(d, J=5.8, 3H, H-6') 1.10(d, J=6.0, 3H, H-8) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 4.68 (s, 1H, H-1 ′) 3.733.80 (m, 2H) 3.543.70 (m, 2H) 3.38 (t, J = 7.4, 2H, H— 2) 2.92 (s, 1H, alcohol) 2.64 (s, 1H, alcohol) 2.012.08 (m, 1H, H-3'eq) 1.771.91 (m, 3H) 1.511.57 (m, 1H) 1.341. 44 (m, 7H) 1.25 (d, J = 5.8, 3H, H-6 ') 1.10 (d, J = 6.0, 3H, H-8)

¹³C-NMR(63MHz, CDCl₃) δ 96.0(C-1', α) 71.6(C-5') 69.9(C-2') 69.2(C-4') 67.9(C-7) 37.1(C-6) 35.1(C-2) 34.1(C-1) 32.8(C-3') 28.8(C-4) 28.1(C-3) 25.6(C-5) 19.0(C-6') 17.8(C-8) IR V_MAX cm^-1 3386 2931 2858 1450 1377 1259 1123 1029 983 853 534 ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 96.0 (C-1 ', α) 71.6 (C-5') 69.9 (C-2 ') 69.2 (C-4') 67.9 (C-7) 37.1 (C -6) 35.1 (C-2) 34.1 (C-1) 32.8 (C-3 ') 28.8 (C-4) 28.1 (C-3) 25.6 (C-5) 19.0 (C-6') 17.8 (C -8) IR V _MAX cm ^-1 3386 2931 2858 1450 1377 1259 1123 1029 983 853 534

실시예 12Example 12

(2R)-2-(3,6-디데옥시-α-L-(2R) -2- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )-8-)-8- 아지도옥탄(화합물 번호 24)의Of azidooctane (compound number 24) 합성 synthesis

12-1. 중간체 합성12-1. Intermediate synthesis

(2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-브로모옥탄 260mg(0.47mmol)을 넣고 디메틸포름아마이드(DMF) 20㎖에 녹이고, 소디움아자이드(NaN₃) 62mg(0.94mmol)을 넣고 실온에서 교반한다. 2시간 후 반응은 증류수 100㎖를 넣고 에틸아세테이트 300㎖로 3회 추출 및 포화 암모니움클로라이드로 씻어준다. 유기층을 건조(MgSO₄), 여과한 후 감압 하에 용매를 제거하고 헥산:에틸아세테이트(4:1)의 혼합용매를 용출제로 하는 실리카겔컬럼 크로마토그래피로 분리하여 화합물 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-아지도옥탄 251.7mg (99%)을 얻었다. 260 mg (0.47 mmol) of (2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8-bromooctane Dissolve in 20 ml of dimethylformamide (DMF), add 62 mg (0.94 mmol) of sodium azide (NaN ₃ ) and stir at room temperature. After 2 hours, 100 ml of distilled water was added and extracted three times with 300 ml of ethyl acetate and washed with saturated ammonium chloride. The organic layer was dried (MgSO ₄ ), filtered and the solvent was removed under reduced pressure, and the mixed solvent of hexane: ethyl acetate (4: 1) was separated by silica gel column chromatography as an eluent to give the compound (2R) -2- (2, 251.7 mg (99%) of 4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8-azidooctane were obtained.

12-2. 보호기 제거12-2. Remove protector

상기 실시예 1-2의 보호기 제거에서, (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥스-5-엔 대신에 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-아지도옥탄을 사용한 것을 제외하고는 실시예 1-2와 동일한 방법으로 수행하여 (2R)-2-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-아지도옥탄(118mg, 99%)을 얻었다.In removing the protecting group of Example 1-2, (2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hex- (2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8-azidooctane instead of 5-ene (2R) -2- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8-azidooctane (118 mg) was carried out in the same manner as in Example 1-2, except that , 99%).

¹H-NMR(250MHz, CDCl₃) δ 4.67(s, 1H, H-1') 3.733.80(m, 2H) 3.573.69(m, 2H) 3.373.43(m, 1H, H-7) 3.24(t, J=6.7Hz 3H, H-1) 1.992.04(m, 1H, H-3' eq) 1.781.86(m, 1H, H-3' ax) 1.54(quar, J=5.9, 3H) 1.341.51(m, 7H) 1.24(d, J=5.6, 3H, H-6') 1.10(d, J=6.0, 3H, H-8) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 4.67 (s, 1H, H-1 ′) 3.733.80 (m, 2H) 3.573.69 (m, 2H) 3.373.43 (m, 1H, H-7) 3.24 (t, J = 6.7 Hz 3H, H-1) 1.992.04 (m, 1H, H-3'eq) 1.781.86 (m, 1H, H-3 'ax) 1.54 (quar, J = 5.9, 3H) 1.341.51 (m, 7H) 1.24 (d, J = 5.6, 3H, H-6 ') 1.10 (d, J = 6.0, 3H, H-8)

¹³C-NMR(63MHz, CDCl₃) δ 96.0(C-1', α) 71.4(C-5') 69.8(C-2') 69.1(C-4') 67.6(C-6) 51.4(C-1) 37.0(C-2') 35.1(C-6) 29.1(C-3') 28.8(C-4) 26.6(C-2) 25.5(C-3) 25.3(C-5) 18.9(C-6') 17.7(C-8) ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 96.0 (C-1 ', α) 71.4 (C-5') 69.8 (C-2 ') 69.1 (C-4') 67.6 (C-6) 51.4 (C -1) 37.0 (C-2 ') 35.1 (C-6) 29.1 (C-3') 28.8 (C-4) 26.6 (C-2) 25.5 (C-3) 25.3 (C-5) 18.9 (C -6 ') 17.7 (C-8)

실시예 13Example 13

(2R)-2-(3,6-디데옥시-α-L-(2R) -2- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )-8-(3,6-디데옥시-α-L-) -8- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )옥탄(화합물 번호 25)의 합성Synthesis of Octane (Compound No. 25)

상기 실시예 1의 (2R)-5-헥센-2-올 대신에 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-옥탄올을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 수행하여 (2R)-2-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)옥탄(7mg, 61%)을 얻었다.(2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hex instead of (2R) -5-hexen-2-ol of Example 1 above (2R) -2- (3,6-dideoxy-α-L-arabino-hexopyranosylocta C) -8- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) octane (7 mg, 61%) was obtained.

¹H-NMR (250MHz, CDCl₃) δ 4.54(s, 1H), 4.39(s, 1H), 3.80-3.22(m, 7H), 1,87-1.83(m, 4H), 1.66-1.50(m, 2H), 1.32-1.19(m, 10H), 1.17-1.10(m, 6H), 1.03-1.01(d, 3H) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 4.54 (s, 1H), 4.39 (s, 1H), 3.80-3.22 (m, 7H), 1,87-1.83 (m, 4H), 1.66-1.50 (m , 2H), 1.32-1.19 (m, 10H), 1.17-1.10 (m, 6H), 1.03-1.01 (d, 3H)

¹³C-NMR (63MHz, CDCl₃) δ 100.3, 97.5, 70.8, 69.9, 69.3,68.3, 38.3, 36.5, 35.9, 30.6, 30.4, 27.3, 26.7, 19.3, 18.1 ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 100.3, 97.5, 70.8, 69.9, 69.3,68.3, 38.3, 36.5, 35.9, 30.6, 30.4, 27.3, 26.7, 19.3, 18.1

실시예 14Example 14

(2R)-2-(3,6-디데옥시-α-L-(2R) -2- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )-8-()-8-( 메탄설포닐옥시Methanesulfonyloxy )옥탄(화합물 번호 26)의 합성Synthesis of Octane (Compound No. 26)

상기 실시예 1-2의 보호기 제거에서 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥스-5-엔 대신에 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-(메탄설포닐옥시)옥탄을 사용한 것을 제외하고는 실시예 1-2와 2동일한 방법으로 수행하여 (2R)-2-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-(메탄설포닐옥시)옥탄(180mg, 94%)을 얻었다.(2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hex-5 in the protecting group removal of Example 1-2 above (2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8- (methanesulfonyloxy) (2R) -2- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8- (2) was carried out in the same manner as in Example 1-2 except that octane was used. Methanesulfonyloxy) octane (180 mg, 94%) was obtained.

¹H-NMR(250MHz, CDCl₃) δ 4.61(s, 1H, H-1') 4.14(t, J=6.4, 2H, H-1) 3.74(s, 2H) 3.483.65(m, 2H) 3.24(s, 2H, alcohol) 2.96(s, 3H, methyl ester) 1.941.99(m, 1H, H-3' eq) 1.641.79(m, 3H) 1.311.48(m, 8H) 1.19(d, J=5.4, 3H, H-6') 1.04(d, J=5.9, 3H, H-8) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 4.61 (s, 1H, H-1 ′) 4.14 (t, J = 6.4, 2H, H-1) 3.74 (s, 2H) 3.483.65 (m, 2H) 3.24 (s, 2H, alcohol) 2.96 (s, 3H, methyl ester) 1.941.99 (m, 1H, H-3'eq) 1.641.79 (m, 3H) 1.311.48 (m, 8H) 1.19 (d , J = 5.4, 3H, H-6 ') 1.04 (d, J = 5.9, 3H, H-8)

¹³C-NMR(63MHz, CDCl₃) δ 95.9(C-1', α) 71.3(C-5') 70.3(C-2') 69.8(C-4') 69.0(C-7) 67.5(C-1) 37.3(C-6) 36.9(C-9) 35.0(C-3') 29.0(C-4) 28.9(C-2) 25.4(C-3) 25.3(C-5) 18.9(C-6') 17.7(C-8) ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 95.9 (C-1 ', α) 71.3 (C-5') 70.3 (C-2 ') 69.8 (C-4') 69.0 (C-7) 67.5 (C -1) 37.3 (C-6) 36.9 (C-9) 35.0 (C-3 ') 29.0 (C-4) 28.9 (C-2) 25.4 (C-3) 25.3 (C-5) 18.9 (C- 6 ') 17.7 (C-8)

실시예 15Example 15

S-[(2R)-2-(3,6-디데옥시-α-L-S-[(2R) -2- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )-8-)-8- 옥타닐Octanyl ]] 티오아세테이트Thioacetate (화합물 번호 27)의 합성Synthesis of (Compound No. 27)

(2R)-2-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-(메탄설포닐옥시)옥탄(41mg, 0.115mmol)를 넣고 소량의 디메틸포름아마이드(DMF) 2㎖에 녹인다. 10분 교반 후 포타슘 티오아세테이트(26mg, 0.230mmol)를 넣은 후 40℃ 정도에서 4시간 동안 교반한다. 반응이 종결되면 증류수를 넣고 에틸아세테이트 20㎖로 2회 추출한 후 브라인으로 씻어준다. 유기층을 건조(MgSO₄), 여과한 후 감압 하에 용매를 제거하고 헥산:에틸아세테이트(1:5)의 혼합용매를 용출제로 하는 실리카겔컬럼 크 로마토그래피로 분리하여 화합물 S-[(2R)-2-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-옥타닐]티오아세테이트(30mg, 76%)를 얻었다.(2R) -2- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8- (methanesulfonyloxy) octane (41 mg, 0.115 mmol) was added and a small amount of dimethylformamide was added. Dissolve in 2 ml of (DMF). After stirring for 10 minutes, potassium thioacetate (26mg, 0.230mmol) was added thereto and then stirred at 40 ° C. for 4 hours. After the reaction is completed, distilled water is added and extracted twice with 20 ml of ethyl acetate and washed with brine. The organic layer was dried (MgSO ₄ ), filtered and the solvent was removed under reduced pressure, and the mixed solvent of hexane: ethyl acetate (1: 5) was separated by silica gel column chromatography using eluent to give compound S-[(2R)- 2- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8-octanyl] thioacetate (30 mg, 76%) was obtained.

¹H-NMR (250MHz, CDCl₃) δ 4.69(s, 1H), 3.80-3.75(s, 2H), 3.72-3.66(m, 1H), 3.63-3.48(m, 1H), 2.88-2.83(t, 2H), 2.32(s, 1H), 2.06-2.04(m, 2H) 1.89-1.79(m, 2H), 1.34(s, 8H), 1.29-1.26(d, 3H), 1.13-1.10(d, 3H) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 4.69 (s, 1H), 3.80-3.75 (s, 2H), 3.72-3.66 (m, 1H), 3.63-3.48 (m, 1H), 2.88-2.83 (t , 2H), 2.32 (s, 1H), 2.06-2.04 (m, 2H) 1.89-1.79 (m, 2H), 1.34 (s, 8H), 1.29-1.26 (d, 3H), 1.13-1.10 (d, 3H)

¹³C-NMR (63MHz, CDCl₃) δ 196.6, 96.1, 71.6, 69.9, 69.4, 68.2, 37.2, 35.3, 29.8, 29.4, 29.2, 29.0, 28.7, 25.5, 19.0, 17.8 ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 196.6, 96.1, 71.6, 69.9, 69.4, 68.2, 37.2, 35.3, 29.8, 29.4, 29.2, 29.0, 28.7, 25.5, 19.0, 17.8

실시예 16Example 16

(2R)-2-(3,6-디데옥시-α-L-(2R) -2- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )-8-)-8- 설퍼옥탄Sulfuroctane 디 D 머(화Mer 합물 번호 28)의 합성Synthesis of Compound No. 28)

16-1. 중간체 합성16-1. Intermediate synthesis

상기 실시예 28의 (2R)-2-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-(메탄설포닐옥시)옥탄 대신에 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-(메탄설포닐옥시)옥탄을 사용한 것을 제외하고는 실시예 28과 동일한 방법으로 수행하여 S-[(2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-옥타닐]티오아세테이트(56%)을 얻었다.(2R) -2- in place of (2R) -2- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8- (methanesulfonyloxy) octane of Example 28, above Example 28, except that (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8- (methanesulfonyloxy) octane was used In the same manner as S-[(2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8-octa Nil] thioacetate (56%) was obtained.

16-2. 보호기 제거16-2. Remove protector

상기 실시예 1-2의 보호기 제거에서 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥스-5-엔 대신에 S-[(2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-옥타닐]티오아세테이트를 사용한 것을 제외하고는 실시예 1-2와 동일한 방법으로 수행하여 (2R)-2-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-8-설퍼옥탄 디머(110mg, 80%)를 얻었다.(2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hex-5 in the protecting group removal of Example 1-2 above S-[(2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8-octanyl] instead of -ene; (2R) -2- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -8-sulfur by the same method as in Example 1-2 except that thioacetate was used Octane dimmer (110 mg, 80%) was obtained.

¹H-NMR (250MHz, CDCl₃) δ 4.68(s, 2H), 3.80(s, 4H), 3.69-3.66(m, 2H), 3.61-3.59(m, 2H), 2.17-2.04(m, 4H), 1.85-1.81(m, 4H), 1.69-1.55(m 4H), 1.42-1.33(m, 16H), 1.28-1.26(d, 6H), 1.12-1.11(d, 6H) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 4.68 (s, 2H), 3.80 (s, 4H), 3.69-3.66 (m, 2H), 3.61-3.59 (m, 2H), 2.17-2.04 (m, 4H ), 1.85-1.81 (m, 4H), 1.69-1.55 (m 4H), 1.42-1.33 (m, 16H), 1.28-1.26 (d, 6H), 1.12-1.11 (d, 6H)

¹³C-NMR (63MHz, CDCl₃) δ 97.4, 72.4, 71.1, 69.9, 68.2, 39.6, 38.3, 35.9, 30.2, 30.1, 29.4, 26.7, 24.1, 19.4, 18.1 ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 97.4, 72.4, 71.1, 69.9, 68.2, 39.6, 38.3, 35.9, 30.2, 30.1, 29.4, 26.7, 24.1, 19.4, 18.1

실시예 17Example 17

1-(One-( 메틸아미닐Methylaminyl )-(6R)-6-(3,6-디데옥시-α-L-)-(6R) -6- (3,6-dideoxy-α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )-1-헵타논() -1-heptanone ( 화합물 번호 29)의Of compound number 29) 합성 synthesis

17-1. 중간체 합성17-1. Intermediate synthesis

(6R)-6-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 246mg(0.47mmol)을 넣고 디클로로메탄 10㎖에 녹인다. 메틸아민 0.03㎖(0.95mmol), N,N'-디사이클로헥실카보디이미드(DCC) 293mg(1.42mmol)와 1-하이드록시벤조트리아졸 하이드레이트(1-hyroxybenzotriazole hydrate, HOBt) (30mg, 0.21mmol)를 넣고 실온에서 1시간 교반한다. 반응이 종결되면 증류수를 넣어주고 디클로로메탄 150㎖로 3회 추출하고 브라인으로 씻어준다. 유기층을 건조(MgSO₄), 여과한 후 감압 하에 용매를 제거하고 헥산:에틸아세테이트(3:1)의 혼합용매를 용출제로 하는 실리카겔컬럼 크로마토그래피로 분리하여 화합물 1-(메틸아미닐)-(6R)-6-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-1-헵타논 240mg(96%)을 얻었다.(6R) -6- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid 246 mg (0.47 mmol) was added and dichloromethane 10 Dissolve in ml. 0.03 mL (0.95 mmol) of methylamine, 293 mg (1.42 mmol) of N, N'-dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole hydrate (HOBt) (30 mg, 0.21 mmol ) And stir at room temperature for 1 hour. After the reaction is completed, distilled water is added and extracted three times with 150 ml of dichloromethane and washed with brine. The organic layer was dried (MgSO ₄ ), filtered and the solvent was removed under reduced pressure, and the mixed solvent of hexane: ethyl acetate (3: 1) was separated by silica gel column chromatography as an eluent to obtain compound 1- (methylaminil)-( 6R) -6- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) -1-heptanone 240 mg (96%) were obtained.

17-2. 보호기 제거17-2. Remove protector

상기 실시예 1-2의 보호기 제거에서 (2R)-2-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헥스-5-엔 대신에 1-(메틸아미닐)-(6R)-6-(2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-1-헵타논을 사용한 것을 제외하고는 실시예 1-2와 동일한 방법으로 수행하여 1-(메틸아미닐)-(6R)-6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)-1-헵타논(36.0mg, 34%)을 얻었다.(2R) -2- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hex-5 in the protecting group removal of Example 1-2 above 1- (methylaminyl)-(6R) -6- (2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) instead of ene 1- (Methylaminyl)-(6R) -6- (3,6-dideoxy-α-L-arabino- was carried out in the same manner as in Example 1-2 except that 1-heptanone was used. Hexopyranosyloxy) -1-heptanone (36.0 mg, 34%) was obtained.

¹H-NMR(250MHz, CDCl₃) δ 4.71(s, 1H, H-1') 3.84(s, 1H) 3.78(s, 1H) 3.533.71(m, 2H) 2.78(s, 3H, H-10) 2.33(t, J=7.4, 2H, H-2) 1.992.06(m, 1H, H-3' eq) 1.771.88(m, 1H, H-3' ax) 1.661.71(m, 2H, H-5) 1.441.54(m, 2H, H-4) 1.36(s, 1H) 1.27(d, J=5.7, 3H, H-6') 1.18(d, J=5.9, 3H, H-7) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 4.71 (s, 1H, H-1 ′) 3.84 (s, 1H) 3.78 (s, 1H) 3.533.71 (m, 2H) 2.78 (s, 3H, H- 10) 2.33 (t, J = 7.4, 2H, H-2) 1.992.06 (m, 1H, H-3 ′ eq) 1.771.88 (m, 1H, H-3 ′ ax) 1.661.71 (m, 2H, H-5) 1.441.54 (m, 2H, H-4) 1.36 (s, 1H) 1.27 (d, J = 5.7, 3H, H-6 ') 1.18 (d, J = 5.9, 3H, H -7)

¹³C-NMR(63MHz, CDCl₃) δ 176.7(C-1) 97.4(C-1', α) 72.3(C-5') 71.1(C-2') 69.9(C-4') 68.3(C-6) 38.0(C-5) 36.9(C-2) 35.9(C-3') 26.9(C-3) 26.5(C-10) 26.2(C-4) 19.2(C-6') 18.0(C-7) ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 176.7 (C-1) 97.4 (C-1 ', α) 72.3 (C-5') 71.1 (C-2 ') 69.9 (C-4') 68.3 (C -6) 38.0 (C-5) 36.9 (C-2) 35.9 (C-3 ') 26.9 (C-3) 26.5 (C-10) 26.2 (C-4) 19.2 (C-6') 18.0 (C -7)

실시예 18Example 18

2-2- 메틸methyl -(3,6--(3,6- 디데옥시Dideoxy -α-L--α-L- 아라비노Arabino -- 헥소피라노실옥시Hexopyranosyloxy )부탄(화합물 번호 53)의 합성Synthesis of Butane (Compound No. 53)

상기 실시예 1의 (2R)-5-헥센-2-올 대신에 3-메틸-부탄-1-올을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 수행하여 2-메틸-(3,6-디데옥시-α-L-아라 비노-헥소피라노실옥시)부탄(20.7mg, 86%)을 얻었다.Except for using 2-methyl-butan-1-ol instead of (2R) -5-hexen-2-ol of Example 1, the procedure of Example 1 -Dideoxy-α-L-arabino-hexopyranosyloxy) butane (20.7 mg, 86%) was obtained.

¹H-NMR(250MHz, MeOD) δ 4.48(s, 1H, H-1') 3.683.75(m, 2H) 3.413.57(m, 3H) 3.30(s, 1H, H-4') 1.91(d, J=5.4, 1H, H-3' eq) 1.71-1.80(m, 1H, H-3' ax) 1.21(d, J=5.4, 3H, H-6') 0.89(d, J=6.5, 6H, H-4 5) ¹ H-NMR (250 MHz, MeOD) δ 4.48 (s, 1H, H-1 ') 3.683.75 (m, 2H) 3.413.57 (m, 3H) 3.30 (s, 1H, H-4') 1.91 ( d, J = 5.4, 1H, H-3'eq) 1.71-1.80 (m, 1H, H-3'ax) 1.21 (d, J = 5.4, 3H, H-6 ') 0.89 (d, J = 6.5 , 6H, H-4 5)

¹³C-NMR(63MHz, MeOD) δ 100.5(C-1', α) 70.8(C-5') 69.4(C-2') 68.2(C-4') 66.6(C-1) 39.6(C-2) 36.2(C-3') 27.2(C-3) 18.1(C-6') 16.9(C-4) 11.6(C-5) ¹³ C-NMR (63 MHz, MeOD) δ 100.5 (C-1 ', α) 70.8 (C-5') 69.4 (C-2 ') 68.2 (C-4') 66.6 (C-1) 39.6 (C- 2) 36.2 (C-3 ') 27.2 (C-3) 18.1 (C-6') 16.9 (C-4) 11.6 (C-5)

실시예 19Example 19

(2R)-2-(6-(2R) -2- (6- 데옥시Deoxy -L--L- 만노피라노실옥시Mannopyranosyloxy )) 옥트Oct -7-엔(화합물 번호 57)의 합성Synthesis of -7-En (Compound No. 57)

상기 실시예 1에서 화학식 (Ⅳ)의 2,4-디-O-벤조일-3,6-디데옥시-α-L-아라비노-헥소피라노실 트리클로로아세트이미데이트 대신에 2,3,4-트리-O-벤조일-6-데옥시-α-L-만노피라노실옥실 트리클로로아세트이미데이트을 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 수행하여 (2R)-2-(6-데옥시-L-만노피라노실옥시)옥트-7-엔 58.0mg(88.1%)을 얻었다.2,3,4 instead of 2,4-di-O-benzoyl-3,6-dideoxy-α-L-arabino-hexopyranosyl trichloroacetimidadate of formula (IV) (2R) -2- (6-deoxy) by the same method as Example 1 except for using -tri-O-benzoyl-6-deoxy-α-L-mannopyranosyloxyl trichloroacetimidadate 58.0 mg (88.1%) of -L-mannopyranosyloxy) oct-7-ene was obtained.

¹H-NMR(250MHz, CDCl₃) δ 5.715.87(m, 1H, H-2) 5.02(s, 0.5H) 4.91(d, J=9.7, 1.5H, H-1) 4.85(s, 1H, H-1') 3.85(s, 1H, H-5') 3.643.72(m, 3H) 3.463.50(m, 1H) 2.03(s, 2H) 1.531.59(m, 1H, H-6) 1.36(s, 4H) 1.271.29(m, 4H, H-6') 1.09(d, J=5.9, 3H, H-8) ¹ H-NMR (250 MHz, CDCl ₃ ) δ 5.715.87 (m, 1H, H-2) 5.02 (s, 0.5H) 4.91 (d, J = 9.7, 1.5H, H-1) 4.85 (s, 1H , H-1 ') 3.85 (s, 1H, H-5') 3.643.72 (m, 3H) 3.463.50 (m, 1H) 2.03 (s, 2H) 1.531.59 (m, 1H, H-6 ) 1.36 (s, 4H) 1.271.29 (m, 4H, H-6 ') 1.09 (d, J = 5.9, 3H, H-8)

¹³C-NMR(63MHz, CDCl₃) δ 138.9(C-2) 114.5(C-1) 97.3(C-1', α) 72.6(C-2') 72.1(C-4') 71.7(C-3') 68.5(C-6) 37.0(C-5') 33.7(C-6) 29.8(C-4) 28.8(C-3) 25.2(C-5) 18.9(C-8) 17.6(C-6') ¹³ C-NMR (63 MHz, CDCl ₃ ) δ 138.9 (C-2) 114.5 (C-1) 97.3 (C-1 ', α) 72.6 (C-2') 72.1 (C-4 ') 71.7 (C- 3 ') 68.5 (C-6) 37.0 (C-5') 33.7 (C-6) 29.8 (C-4) 28.8 (C-3) 25.2 (C-5) 18.9 (C-8) 17.6 (C- 6 ')

실시예 20Example 20

(6R)-6-(6-(6R) -6- (6- 데옥시Deoxy -α-L--α-L- 만노피라노실옥시Mannopyranosyloxy )) 헵타노익산Heptanoic acid (화합물 번호 60)의 합성Synthesis of (Compound No. 60)

상기 실시예 4에서 (2R)-2-(2,4-디-O-메틸-3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)옥트-7-엔 대신에 (2R)-2-(2,3,4-트리-O-벤조일-6-데옥시-L-만노피라노실옥시)옥트-7-엔을 사용한 것을 제외하고는 실시예 4와 동일한 방법으로 수행하여 (6R)-6-(6-데옥시-α-L-만노피라노실옥시)헵타노익산 14.8mg(31.6%)을 얻었다.In Example 4 above (2R) -2- (2,4-di-O-methyl-3,6-dideoxy-α-L-arabino-hexopyranosyloxy) oct-7-ene instead of ( 2R) -2- (2,3,4-tri-O-benzoyl-6-deoxy-L-mannopyranosyloxy) oct-7-ene was carried out in the same manner as in Example 4 except that 14.8 mg (31.6%) of (6R) -6- (6-deoxy-α-L-mannopyranosyloxy) heptanoic acid was obtained.

¹H-NMR(250MHz, MeOD) δ 4.79(s, 1H, H-1') 3.713.77(m, 2H) 3.573.66(m, 2H) 3.36(d, J=9.4, 1H, H-3') 3.293.32(m, 1H, H-6) 2.26(t, J=7.2Hz, 2H, H-2) 1.541.61(m, 3H) 1.331.50(m, 4H) 1.28(s, 1H) 1.23(d, J=6.2, 3H, H-6') 1.11(d, J=6.0, 3H, H-7) ¹ H-NMR (250 MHz, MeOD) δ 4.79 (s, 1H, H-1 ′) 3.713.77 (m, 2H) 3.573.66 (m, 2H) 3.36 (d, J = 9.4, 1H, H-3 3.293.32 (m, 1H, H-6) 2.26 (t, J = 7.2 Hz, 2H, H-2) 1.541.61 (m, 3H) 1.331.50 (m, 4H) 1.28 (s, 1H ) 1.23 (d, J = 6.2, 3H, H-6 ') 1.11 (d, J = 6.0, 3H, H-7)

¹³C-NMR(63MHz, MeOD) δ 177.5(C-1) 98.8(C-1', α) 73.9(C-2') 72.9(C-4') 72.5(C-3') 72.4(C-6) 70.0(C-5') 37.9(C-5) 34.8(C-2) 26.3(C-3) 26.0(C-4) 19.1(C-6') 17.9(C-7) ¹³ C-NMR (63 MHz, MeOD) δ 177.5 (C-1) 98.8 (C-1 ', α) 73.9 (C-2') 72.9 (C-4 ') 72.5 (C-3') 72.4 (C- 6) 70.0 (C-5 ') 37.9 (C-5) 34.8 (C-2) 26.3 (C-3) 26.0 (C-4) 19.1 (C-6') 17.9 (C-7)

시험예Test Example

장기휴면효과 활성의 측정.Measurement of long-term dormant effect activity.

본 발명의 페로몬 유도체의 장기휴면효과 확인을 위한 활성 측정 방법은 펩톤이 없는 엔쥐엠(NGM) 배지와 페로몬 유도체를 혼합하여 준비된 배지위에 먹이인 이. 콜라이(E. Coli)를 올려준 후 예쁜꼬마선충을 이용하여 실험에 필요한 온도조건에 따라 활성을 측정하게 된다(Nature 433(7025):541-5). 본 발명의 화합물의 장기 휴면 활성 결과는 표 1~3 및 도 1 에 나타내었다.Activity measuring method for confirming the long-term dormant effect of the pheromone derivative of the present invention is fed to the medium prepared by mixing the pheromone derivative (NGM) medium without peptone. After raising E. Coli, the activity is measured according to the temperature conditions required for the experiment using pretty little nematodes (Nature 433 (7025): 541-5). The long-term dormant activity results of the compounds of the present invention are shown in Tables 1-3 and FIG.

도 1은 본 발명의 화합물의 장기 휴면 활성 결과를 도시한 그래프.1 is a graph depicting the long term dormant activity results of the compounds of the present invention.

Claims

하기 화학식 (Ⅰ), 화학식 (Ⅱ) 또는 화학식 (Ⅲ)으로 표시될 수 있는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체.6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative which may be represented by the following formula (I), formula (II) or formula (III).

화학식 (Ⅰ)Formula (I)

상기 식에서, R₁ 및 R₂는 서로 같거나 다르게 수소, C1-C6의 알킬 또는 벤조일기를 나타내고; R₄는 수소 또는 C1-C6의 알킬기를 나타내고; (CH₂)n은 n이 1∼15의 알킬, 알케닐 또는 알키닐 그룹을 나타내고; Z₁은 C1-C6의 알킬, C1-C6의 알켄, C1-C6의 산, C1-C6의 알데히드, 알콜, 할로겐, 아민, 에스테르, 아마이드를 나타내고, In which R ₁ And R ₂ is the same as or different from each other hydrogen, a C1-C6 alkyl or benzoyl group; R ₄ represents hydrogen or an alkyl group of C 1 -C 6; (CH ₂ ) n represents an alkyl, alkenyl or alkynyl group where n is 1-15; Z ₁ represents C1-C6 alkyl, C1-C6 alkene, C1-C6 acid, C1-C6 aldehyde, alcohol, halogen, amine, ester, amide,

화학식 (Ⅱ)Formula (II)

상기 식에서 R₁ 및 R₂는 화학식 (Ⅰ)과 동일하고; Z₂는 C1-C6의 지방족 알콜, 사이클로헥사놀 또는 디하이드로캡사이신을 나타내고, In which R ₁ And R ₂ is the same as in formula (I); Z ₂ represents a C1-C6 aliphatic alcohol, cyclohexanol or dihydrocapsaicin,

화학식 (Ⅲ)Formula (III)

제1항에 있어서, 상기 Z₁은 에틸렌, 메틸, 카복실산, 메틸에스테르, 알콜, 알데히드, -CH=CHCOOH, 브롬, 아자이드, 3,6-디데옥시-α-L-아라비노-헥소피라노사이드, 설퍼, 메실, -SCOCH₃, 아마이드로 이루어지는 그룹으로부터 선택되는 것을 특징으로 하는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체. The compound of claim 1, wherein Z ₁ is ethylene, methyl, carboxylic acid, methyl ester, alcohol, aldehyde, —CH═CHCOOH, bromine, azide, 3,6-dideoxy-α-L-arabino-hexopyrano 6, wherein is selected from the side, sulfur, mesylate, -SCOCH _3, the group consisting of amide (3,6-dideoxy -α-L- arabino-hexyl Sophie pyrano hexyloxy) heptanoate acid derivative.

제2항에 있어서, 상기 Z₁의 아마이드의 아민은 메틸아민, 아닐린, 피롤리딘, 모르폴린, 도데실아민, 1-테드라데실아민, 4,7,10-트리오카-1,13-트리데칸 디아민, 암모니아, -CONH(CH₂)₂NHCOOC(CH₃)₃, -CONH[(CH₂)₂O]₂(CH₂)₂NHCOOC(CH₃)₃, 4-메틸피페리딘, 사이클로헥실아민, 4-벤질피페리딘, 4-에틸아닐린, 3-니트로아닐린, 2-브로모아닐린, 에틸 메타-아미노벤조에이트, 아릴아민, 푸르푸릴아민, 세린메틸에스테르, N-(2-아미노-에틸)-2-(4-벤조일페녹시)로 이루어지는 그룹으로부터 선택되는 것을 특징으로 하는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체. The amine of claim ₁ , wherein the amine of the amide of Z ₁ is methylamine, aniline, pyrrolidine, morpholine, dodecylamine, 1-tedradecylamine, 4,7,10-trioka-1,13-. Tridecane diamine, ammonia, -CONH (CH ₂ ) ₂ NHCOOC (CH ₃ ) ₃ , -CONH [(CH ₂ ) ₂ O] ₂ (CH ₂ ) ₂ NHCOOC (CH ₃ ) ₃ , 4-methylpiperidine, Cyclohexylamine, 4-benzylpiperidine, 4-ethylaniline, 3-nitroaniline, 2-bromoaniline, ethyl meta-aminobenzoate, arylamine, furfurylamine, serinemethylester, N- (2- 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid, characterized in that it is selected from the group consisting of amino-ethyl) -2- (4-benzoylphenoxy) derivative.

제1항에 있어서, 상기 Z₂는 3-메틸-부탄-1-올, 사이클로헥사놀, 헥산-1-올 또는 디하이드로캡사이신인 것을 특징으로 하는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체.The method of claim 1, wherein Z ₂ is 6- (3,6-dideoxy-α-, characterized in that 3-methyl-butan-1-ol, cyclohexanol, hexane-1-ol or dihydrocapsaicin. L-arabino-hexopyranosyloxy) heptanoic acid derivative.

제1항에 있어서, 상기 R₄의 카이랄 탄소의 절대배열은 R 또는 S 배열인 것을 특징으로 하는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체. The method of claim 1, wherein the absolute configuration of the chiral carbon of R ₄ is 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) hep characterized in that the R or S configuration Tanoic acid derivatives.

제1항에 있어서, 상기 Z₃은 3-데옥시-D-아라비노피라노사이드, D-아라비노피라노사이드, L-람노피라노사이드, D-만노피라노사이드인 것을 특징으로 하는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체. The method according to claim 1, wherein Z ₃ is 3-deoxy-D-arabinopyranoside, D- arabinopyranoside, L-ramnopyranoside, D-mannopyranoside, characterized in that -(3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative.

제1항 내지 제6항 중의 어느 한 항에 있어서, 상기 유도체가 장기휴면효과 활성을 갖는 것을 특징으로 하는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체.The 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) according to any one of claims 1 to 6, wherein the derivative has a long-term dormant effect. Heptanoic acid derivatives.

(1) 하기 화학식 (Ⅳ)와 화학식 (Ⅴ)의 화합물을 반응시켜 하기 화학식 (Ⅰ)을 제조하는 단계;(1) reacting a compound of formula (IV) with a compound of formula (V) to produce formula (I);

(2) 상기 (1)단계에서 얻은 화학식 (Ⅰ) 화합물을 산화 환원 반응시키는 단계; 및(2) redox-reacting the compound of formula (I) obtained in step (1); And

(3) 상기 (2)단계에서 얻은 화학식 (Ⅰ) 화합물의 보호기를 제거하는 단계;(3) removing the protecting group of the compound of formula (I) obtained in step (2);

를 포함하는 화학식 (Ⅰ)로 표시되는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체의 제조방법.A method for producing a 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative represented by Formula (I) comprising a.

화학식 (Ⅳ) Formula (IV)

화학식 (Ⅴ)Formula (Ⅴ)

화학식 (Ⅰ)Formula (I)

상기 식에서 R₁, R₂, R₄, (CH₂)n 및 Z₁은 제1항에서 정의한 바와 같고, R₃는 수소 또는 트리클로로아세토니트릴기이다.Wherein R ₁ , R ₂ , R ₄ , (CH ₂ ) n and Z ₁ are as defined in claim 1, and R ₃ is hydrogen or trichloroacetonitrile group.

(1) 하기 화학식 (Ⅳ)의 화합물을 Z₂와 반응시켜 하기 화학식 (Ⅱ)를 제조하는 단계;(1) reacting a compound of formula (IV) with Z ₂ to produce formula (II);

(2) 상기 (1)단계에서 얻은 화학식 (Ⅱ)의 화합물의 보호기를 제거하는 단계;(2) removing the protecting group of the compound of formula (II) obtained in step (1);

를 포함하는 화학식 (Ⅱ)로 표시되는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체의 제조방법.A method for producing a 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative represented by Formula (II) comprising a.

화학식 (Ⅳ) Formula (IV)

화학식 (Ⅱ)Formula (II)

상기 식에서 R₁, R₂, Z₂는 제1항에서 정의한 바와 같고, R₃는 수소 또는 트리클로로아세토니트릴기이다.Wherein R ₁ , R ₂ and Z ₂ are as defined in claim 1, and R ₃ is hydrogen or trichloroacetonitrile group.

(1) 하기 화학식 (Ⅴ)의 화합물을 Z₃와 반응시켜 하기 화학식 (Ⅲ)를 제조하는 단계;(1) reacting a compound of formula (V) with Z ₃ to produce formula (III);

(2) 상기 (1)단계에서 얻은 화학식 (Ⅲ)의 화합물의 보호기를 제거하는 단 계;(2) removing the protecting group of the compound of formula (III) obtained in step (1);

를 포함하는 화학식 (Ⅲ)으로 표시되는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체의 제조방법.A method for producing a 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative represented by Formula (III) comprising a.

화학식 (Ⅴ)Formula (Ⅴ)

화학식 (Ⅲ)Formula (III)

상기 식에서 R₄, (CH₂)n, Z₁ 및 Z₃는 제1항에서 정의한 바와 같다.Wherein R ₄ , (CH ₂ ) n, Z ₁ and Z ₃ are as defined in claim 1.

제1항의 화학식 (Ⅰ), 화학식 (Ⅱ) 또는 화학식 (Ⅲ)으로 표시될 수 있는 6-(3,6-디데옥시-α-L-아라비노-헥소피라노실옥시)헵타노익산 유도체를 주성분으로 함유하는 노화 및 스트레스 관련 질환 조절제용 약학 조성물.A 6- (3,6-dideoxy-α-L-arabino-hexopyranosyloxy) heptanoic acid derivative which may be represented by the formula (I), formula (II) or formula (III) Pharmaceutical composition for controlling aging and stress-related diseases containing as a main component.