KR940011909B1 - Bicyclic sulfonamide derivatives - Google Patents

Abstract

내용 없음.No content.

Description

비시클로환계 술폰아미드 유도체Bicyclo cyclic sulfonamide derivative

본 발명은 의약품의 분야에서 트롬복산에 기인하는 증상을 개선하기 위하여 사용되는 화합물에 관한 것이다. 구체적으로는 항혈전제, 항혈관수축제, 항기관수축제로서 사용되는 하기의 일반식(I)에서 표시되는 화합물에 관한 것이다.The present invention relates to compounds used in the field of pharmaceuticals to ameliorate symptoms caused by thromboxane. Specifically, the present invention relates to a compound represented by the following general formula (I) used as an antithrombogenic agent, an antivascular contraction agent, and an anti-organ contractile agent.

상기식에서, R₁은 수소, 저급알킬 또는 염형성기를 ; A는 메틸렌, 에틸렌, 디메틸메틸렌, 산소 또는 유황을 ; R₂는 치환 또는 비치환의 페닐을 ; p는 0 또는 2를 ; q는 0 또는 1을 각각 나타낸다(단, A가 에틸렌일때 p=2, q=0이고, A가 메틸렌, 디메틸메틸렌, 산소 또는 유황일 때 p=0, q=1이다).Wherein R ₁ is hydrogen, lower alkyl or a salt forming group; A is methylene, ethylene, dimethylmethylene, oxygen or sulfur; R ₂ is substituted or unsubstituted phenyl; p is 0 or 2; q represents 0 or 1, respectively, provided that p = 2 and q = 0 when A is ethylene and p = 0 and q = 1 when A is methylene, dimethylmethylene, oxygen or sulfur.

일반식(I)으로 표시되는 본 발명 화합물은 하기 일반식(II)을 출발물질로 하여 아래와 같이 제조할 수가 있다.The compound of the present invention represented by the general formula (I) can be prepared as follows using the following general formula (II) as a starting material.

하기 일반식(II)으로부터 표시되는 화합물과 하기 일반식(III)으로 표시되는 화합물과를 반응시켜 필요하다면 에스테르화반응, 에피설파이드 형성반응 및/또는 염형성반응을 실행하여 제조할 수 있다.The compound represented by the following general formula (II) and the compound represented by the following general formula (III) may be reacted to prepare the esterification reaction, episulfide formation reaction and / or salt formation reaction if necessary.

상기식에서, R₂는 치환 또는 비치환의 페닐을 ; p는 0 또는 2를 ; q는 0 또는 1을 ; A'는 메틸렌, 에틸렌, 디메틸메틸렌 또는 산소를 각각 나타낸다(단, A'가 에틸렌일 때, p=2, q=0이며, A'가 메틸렌 디메틸메틸렌 또는 산소일 때, p=0, q=1이다). Ar는 방향족 탄화수소기를 나타낸다.In the formula, R ₂ is substituted or unsubstituted phenyl; p is 0 or 2; q is 0 or 1; A 'represents methylene, ethylene, dimethylmethylene or oxygen, provided p = 2 and q = 0 when A' is ethylene and p = 0 and q = when A 'is methylene dimethylmethylene or oxygen. 1). Ar represents an aromatic hydrocarbon group.

심근경색이나 뇌경색의 주원인으로 되는 죽종(atheroma)성 등 맥경화증은 동맥내막으로의 무코이드기질의 집적, 선유아세포의 증식 등으로 시작하여 이어서 변성과 지질, 콜레스테롤의 침착, 내막조직의 파괴, 죽상물의 형성으로 진행하고 점차로 고도의 내막의 국한성 비후를 가져오는 것이 일반적 증상이다. 죽종성 동맥경화증은 옛부터 동맥벽에서의 혈전의 형성과 섬유소(피브린) 침착이 원인으로 되어 왔으나 최근 사무엘손(samuelsson) 등에 의해 트롬복산 A₂(TXA₂)가, 또 베인(Vane) 등에 의해 프로스터 사이클린(PGI₂)이 발견됨으로써 혈소판과 혈관벽의 상호작용이 분명하게 되었다. 혈소판은 죽종성 동맥경화증의 발증과 진행에 중요한 관련을 갖는 것으로 되어 항혈전약, 특히 혈소판 응집억제작용을 갖는 약물의 투여가 죽종성 동맥증 관련 질환의 치료에 유효하다고 인식되어 가고 있다.Cirrhosis, such as atherosclerosis, which is the main cause of myocardial infarction or cerebral infarction, begins with the accumulation of mucoid substrates into the endocardium, proliferation of fibroblasts, and then degeneration and lipid, cholesterol deposition, destruction of endometrial tissues, It is a common symptom to proceed to the formation of water and gradually bring about a high degree of localized thickening of the lining. Atherosclerotic arteriosclerosis has been caused by the formation of blood clots and fibrin deposition in arterial walls since ancient times, but recently thromboxane A ₂ (TXA ₂ ) by samuelsson and others by vane et al. The discovery of stuclin (PGI ₂ ) has made the interaction of platelets and blood vessel walls clear. Platelets have an important role in the development and progression of atherosclerotic arteriosclerosis, and it has been recognized that administration of antithrombotic drugs, particularly drugs with platelet aggregation inhibitory effects, is effective for the treatment of atheromatous artery related diseases.

종래부터의 항혈전약인 헤파린, 쿠마린계 화합물 등에 가하여 어떤 종류의 프로스터글랜딘류가 강한 혈소판 응집 억제작용을 갖는다는 것이 알려져 있다. 이 사실에 착안하여 프로스터글랜딘 유도체가 항혈전제로서 주목되고 있다. 예를들어 프로스터글랜딘 E₁나 프로스터글랜딘 등의 수용체에 대한 길항제의 유연체의 개발을 비롯하여 트롬복산 A₂이 강한 형소판 응집작용과 혈관수축작용을 갖는다는 것에 착안하여 시클로옥시게나아제 억제제, 트롬복산신티아제 억제제 등의 트롬복산 A₂합성 저해물질 또 트롬복산 A₂수용체, 길항제 등도 개발되어 있다. 트롬복산 A₂수용체. 길항제로서는 13-APA[벤톤(Venton D.L.)등, 저어널. 오브. 메디시널. 케미스트리(J.Med.Chem) 제22권, 824면(1979년)], PTA₂[레피(Lefer A.M.) 등프로시이딩스.오브.더.내셔널.아카데미.오브.사이언스.오브.유우.에스.에이(Proc.Natl.Acad.Sci.U.S.A.)제76권, 2566면(1979년)], BM-13177[레피, 드럭스.오브.투데이(Drugs of Today), 제21권, 283면(1985년)], SQ-29548[오클레트리(Ogletree)등, 저어널.오브.파마콜로지.앤드.익스퍼레멘탈,쎄라퓨우틱스(J.Pharmacol.Exp.Ther), 제34권, 제435면(1985년)] 등의 화합물이 있다.It is known that certain types of prostaglandins have a strong platelet aggregation inhibitory effect in addition to heparin, coumarin compounds, and the like, which are conventional antithrombotic drugs. In view of this fact, prostaglandin derivatives are attracting attention as antithrombogenic agents. Cyclooxygena, for example, develops a flexible body of antagonists to receptors such as prostaglandin E ₁ and prostaglandin, and that thromboxane A ₂ has strong platelet aggregation and vasoconstriction. Inhibitors of thromboxane A ₂ synthesis, such as an antase inhibitor and a thromboxane synthase inhibitor, a thromboxane A ₂ receptor and an antagonist have also been developed. Thromboxane A ₂ receptor. Examples of antagonists include 13-APA [Venton DL et al., Journal. Orb. Medicine. Chemistry, Vol. 22, p. 824 (1979), PTA ₂ [Lefer AM, et al.] Proceedings of the National Academy of Sciences of the U.S. Proc.Natl.Acad.Sci.USA, Vol. 76, p. 2566 (1979), BM-13177 [Lep, Drugs of Today, Vol. 21, p. 283 (1985). (J.Pharmacol.Exp.Ther), Vol. 34, No. 435.], SQ-29548 [Ogletree et al., Journal.of.Pharmacy.And.Expermental, Cerafutics. Cotton (1985).

트롬복산 A₂는 혈소판에 트롬빈이 작용하면 시클로옥시게나아제(cyclooxygenase)가 활성화되고, 아라키돈산(arachidonic acid)으로부터 프로스터글랜딘 G₂, H₂를 거쳐 혈소판, 혈관벽을 비롯하여 각종의 세포중에서 효소적으로 생성되어진다. 이것은 여러가지의 강력한 생리적 혹은 병적인 작용을 갖는다. 특히 강한 혈소판 응집작용과 기관지, 관상동맥, 폐동맥 등의 평활근 수축작용은 협심증, 심근경색, 뇌경색, 기관지천식 등의 순환기 호흡기계 질환의 발생이나 진행을 매개하는 요인으로 된다고 생각되고 있다. 더우기 그 강력한 작용발현 농도는 10^-10~10^-11M이라 한다. 그러므로, 항혈전제, 항혈관수축제, 항기관지수축제로서 트롬복산 A₂의 길항제 또는 억제제의 개발이 주목되어 왔다. 억제제로는 트롬복산 A₂이외의 여러가지의 중요한 역활을 갖는 프로스터글랜딘류에도 큰 영향을 미친다는 것, 또 축적되어 오는 기질의 트롬복산 유사한 나쁜 작용을 조절할 수 없다는 것 등의 문제점이 있고 특히 길항제의 개발이 요망되고 있다.Thromboxane A ₂ activates cyclooxygenase when thrombin acts on platelets and passes through prostaglandin G ₂ and H ₂ from arachidonic acid to platelets, blood vessel walls, and other enzymes. Is generated by It has several powerful physiological or pathological actions. In particular, strong platelet aggregation and smooth muscle contraction of the bronchus, coronary artery, and pulmonary artery are thought to be mediating the development and progression of circulatory respiratory diseases such as angina pectoris, myocardial infarction, cerebral infarction, and bronchial asthma. Moreover, its potent action concentration is 10 ^{-10 -10 -11} M. Therefore, the development of antagonists or inhibitors of thromboxane A ₂ as antithrombotic, antivascular contractile, and anti-bronchoconstrictive agents has been noted. Inhibitors have problems such as having a profound effect on prostaglandins, which have various important roles other than thromboxane A ₂ , and the inability to control thromboxane-like adverse actions of the accumulated substrate, especially antagonists. Development is desired.

본 발명자들은 일반식(I)으로 표시되는 비시클로환계 술폰아미드 유도체를 합성하여 이 신규 화합물이 트롬복산 A₂수용체.길항제로서의 강력한 작용을 가지며 또한 화학적, 생화학적으로 안정된 화합물이라는 것을 발견하고 본 발명을 완성하였다.The inventors have synthesized bicyclocyclic sulfonamide derivatives represented by general formula (I) and found that this novel compound is a chemically and biochemically stable compound having a strong function as a thromboxane A ₂ receptor. Was completed.

본 명세서에서 사용하는 어구의 정의는 아래와 같다. 「저급알킬」로서는 C₁~C₇의 직쇄상 또는 측쇄상의 알킬, 예컨대 메틸, 에틸, n-프로필, 이소프로필, 디이소프로필메틸, 부틸, 이소부틸, tert-부틸, 펜틸, 헥실 또는 헵틸 등을 들 수가 있다.The definition of the phrase used in the present specification is as follows. Examples of "lower alkyl" C ₁ ~ C ₇ straight or branched alkyl of on, for example, methyl, ethyl, n- propyl, iso-propyl, diisopropyl, methyl, butyl, isobutyl, tert- butyl, pentyl, hexyl or heptyl Can be mentioned.

페닐의 치환기로서는 저급알킬(예를들어, 메틸 또는 에틸 등), 저급알콕시(예컨대 메톡시), 니트로, 히드록시, 카르복시, 시아노, 아미노, 저급알킬아미노(예를들어, 메틸아미노), 저급알킬이 서로 다르더라도 좋은 디저급알킬아미노(예를들어 디메틸아미노), 알카노일아미노(예를들어 아세트아미드), 할로겐(예를들어 불소, 염소, 브롬 또는 요오드) 등을 들 수가 있다. 알카노일이란 C₁~C₃의 포르밀, 아세틸 또는 프로피오닐 등을 의미한다. 치환기는 모든 가능한 위치에서 1개 또는 그 이상 치환되어 있어도 좋다.Substituents for phenyl include lower alkyl (e.g. methyl or ethyl), lower alkoxy (e.g. methoxy), nitro, hydroxy, carboxy, cyano, amino, lower alkylamino (e.g. methylamino), lower Even if the alkyls are different from each other, there may be mentioned lower dialkylalkyl (for example dimethylamino), alkanoylamino (for example acetamide), halogen (for example, fluorine, chlorine, bromine or iodine). Alkanoyl means C ₁ to C ₃ formyl, acetyl or propionyl and the like. One or more substituents may be substituted by all possible positions.

「방향족 탄화수소기」로서는 페닐 등을 들 수가 있다.Phenyl etc. are mentioned as an "aromatic hydrocarbon group."

일반식(I)에 있어서 보다 바람직한 R₁으로서는 수소 또는 메틸을, 보다 바람직한 R₂로서는 페닐을 들 수가 있다. A가 에틸렌일때 P=2, q=0이며, A가 메틸렌, 디메틸메틸렌, 산소 또는 유황일 때 p=0, q=1이다.In general formula (I), hydrogen or methyl is more preferable as R <_1> , and phenyl is mentioned as more preferable R <_2> . P = 2, q = 0 when A is ethylene and p = 0, q = 1 when A is methylene, dimethylmethylene, oxygen or sulfur.

일반식(I)의 염형성기로서는 리튬, 나트륨 또는 칼륨 등의 알칼리금속, 칼슘 등의 알칼리토류금속, 암모늄, 트리에틸아민 등의 유기염기, N-메틸모르폴린, 디시클로헥실아민, 피리딘 또는 트리메틸아민 또는 글리신, 발린 또는 알라닌 등의 아미노산을 들 수가 있다.As the salt-forming group of formula (I), alkali metals such as lithium, sodium or potassium, alkaline earth metals such as calcium, organic bases such as ammonium and triethylamine, N-methylmorpholine, dicyclohexylamine, pyridine or trimethyl Amino acids, such as an amine or glycine, valine, or alanine, are mentioned.

본 발명에 의해서 제조되는 화합물에는 일반식(I)으로 표시되는 그의 모든 입체이성체(디아스테레오마, 에피머, 에탄티오머 등) 또는 그것들의 혼합물이 포함된다.Compounds produced by the present invention include all stereoisomers thereof (diastereomers, epimers, ethanethiomers, etc.) represented by general formula (I) or mixtures thereof.

본 발명 화합물은 아래에 나타낸 개요에 따라 제조할 수가 있다.The compounds of the present invention can be prepared according to the outlines shown below.

일반식(I)으로 표시되는 본 발명 화합물중 일반식(Ia) 및 (Ib)으로 표시되는 본 발명 화합물은 (dl)-시스-(2-히드록시-시클로벤토-4-에닐)에탄올[엠.알.브스코코빅(M.R.Vskokovic), 저어널.오브.더.아메리칸.케미칼.소사이어티(J.Am.Chem.Soc.), 제95권, 7171면, 1973년]을 출발물질로 하고 또 일반식(Ic)으로 표시되는 본 발명의 화합물은 비시클로[2.2.2]옥타논-2-옥심[에이취.케이.홀, 쥬니어(H.K.Hall, J), 저어널.오브.더, 아메리칸.케미칼.소사이어티(J.Am.Chem.Soc), 제82권, 1209면, 1960년]을 출발물질로서 각각 제조할 수가 있다.Among the compounds of the present invention represented by general formula (I), the compounds of the present invention represented by general formulas (Ia) and (Ib) include (dl) -cis- (2-hydroxy-cyclobento-4-enyl) ethanol [M]. As a starting material for MRVskokovic, Journal of the American Society, J. Am. Chem. Soc., Vol. 95, p. 7171, 1973. Compounds of the present invention represented by general formula (Ic) include bicyclo [2.2.2] octanone-2-oxime [H. K. Hall, Junior (HKHall, J), Journal. Of the American. Chemical Society (J. Am. Chem. Soc), Vol. 82, p. 1209, 1960] can be prepared as starting materials, respectively.

구조식중, 파선은 α- 또는 β-배치 또는 그들의 혼합물을 나탄내다.In the structural formula, dashed lines represent α- or β- batches or mixtures thereof.

공정식 I-1(그의 1)(A가 메틸렌 또는 디메틸메틸렌, p=0, q=1일때)Process formula I-1 (its 1) (when A is methylene or dimethylmethylene, p = 0, q = 1)

공정식 I-1(그의 2)Process Formula I-1 (2 of it)

공정 I-1Process I-1

(제1공정)(Step 1)

본 공정은 화합물 1a(2R*)의 C₄~C₅탄소간에 메틸렌을 도입하는 공정이다. 메틸렌 공여시약으로서는 요오드화메틸렌과 아연-동커플, 아연-은커플, 디에틸아연 또는 에틸요오드화아연 또는 디아조메탄과 할로겐화아연으로부터 생성되는 시몬즈-스미스(Simmons-Smith)시약 또는 유사시약을 사용하면 좋다. 용매로서는 에테르계의 디에틸에테르, 테트라히드로푸란, 글라임 또는 디글라임 등을 사용하면 좋다. 반응은 실온 내지 가열하에서 수시간으로 완료한다. 본 공정에서 메틸렌은 3위치의 히드록시와 같은 쪽에 들어간다.This step is a step of introducing methylene between C ₄ to C ₅ carbons of compound 1a (2R *). As the methylene donor reagent, a mmonium iodide, zinc-copper coupler, zinc-silver coupler, diethylzinc or ethyl iodide or simonom-Smith reagent or pseudo reagent generated from diazomethane and zinc halide may be used. . As the solvent, diethyl ether, tetrahydrofuran, glyme, diglyme, or the like may be used. The reaction is completed in several hours under room temperature to heating. In this process, methylene enters the same side as hydroxy at the 3-position.

(제2공정)(2nd step)

본 공정은 화합물 2b의 히드록시에틸의 히드록시를 보호하는 공정이다. 보호기를 형성하는 화합물로서는 염화메톡시메틸, 염화벤질옥시메틸, 염화벤질, 염화트리페닐메틸, 염화트리메틸실릴, 비스트리메틸실릴아세토아미드 또는 염화디메틸-tert-부틸실릴 등을 들 수가 있다. 반응은 트리에틸아민 또는 피리딘 등의 염기 존재하, 필요에 따라 촉매로서 디메틸아미노피리딘을 사용하며 통상의 방법에 따라 행하면 좋다. 용매로서는 에테르계의 디에틸에테르, 테트라히드로푸란 또는 염소화탄화수소계의 클로로포름, 디클로로메탄 등을 들 수가 있다.This step is a step of protecting the hydroxyethyl hydroxy of compound 2b. Examples of the compound forming the protecting group include methoxymethyl chloride, benzyloxymethyl chloride, benzyl chloride, triphenylmethyl chloride, trimethylsilyl chloride, bistrimethylsilylacetoamide or dimethyl-tert-butylsilyl chloride. The reaction may be carried out according to a conventional method in the presence of a base such as triethylamine or pyridine and, if necessary, dimethylaminopyridine as a catalyst. Examples of the solvent include ether-based diethyl ether, tetrahydrofuran or chlorinated hydrocarbon-based chloroform, dichloromethane and the like.

본 공정은 제1공정에 앞서서 행할 수도 있다.This step may be performed before the first step.

(제3공정)(3rd step)

본 공정은 화합물 2a(3R*-β)의 3위치의 히드록시를 산화하는 공정이다. 산화제로서는 크롬산계의 존즈시약, 콜린즈시약, 피리디늄·클로로클로메이트·피리디늄 디클로메이트를 사용하거나 또는 디메틸술폭시드와 삼산화유황, 무수트리플루오로초산, 무수메탄술폰산, 염화티오닐 또는 염화옥사릴을 조합시켜서 사용하면 좋다. 디메틸술폭시드를 산화제로서 사용할 때는 분해제로서 3급아민의 트리에틸아민, 피리딘 등을 사용하면 좋다. 용매로서 시약의 성질에 따라서 염소화탄화수소계의 클로로포름, 디클로로메탄, 에테르계의 디에틸에테르, 테트라히드로푸란 또는 디메틸포름아미드 등을 사용하면 좋다. 반응은 냉각하 또는 실온에서 수시간에 달성할 수 있다.This step is a step of oxidizing hydroxy at the 3-position of compound 2a (3R * -β). As the oxidizing agent, Jones reagent, Collins reagent, pyridinium, chlorochloromate, pyridinium dichloromate, or dimethyl sulfoxide, sulfur trioxide, trifluoroacetic anhydride, methanesulfonic anhydride, thionyl chloride or oxa chloride may be used. It is good to use combining reels. When dimethyl sulfoxide is used as the oxidizing agent, triethylamine, pyridine or the like of tertiary amine may be used as the decomposition agent. Chlorinated hydrocarbon-based chloroform, dichloromethane, ether-based diethyl ether, tetrahydrofuran or dimethylformamide may be used as the solvent, depending on the nature of the reagent. The reaction can be achieved in a few hours under cooling or at room temperature.

(제4공정)(4th step)

본 공정은 화합물 4(β)의 3위치의 케톤을 옥심으로 변경하는 공정이다. 옥심화는 히드록키실아민염산염 또는 황산염 등을 사용하여 염기물질 존재하 행하면 좋다. 염기물질로서 수산화나트륨, 수산화칼륨, 탄산나트륨 등을 사용하면 좋다. 용매로서는 알코올계의 메탄올, 에탄올을 들 수가 있다.This step is a step of changing the ketone at the 3-position of compound 4 (β) to oxime. The oxime may be carried out in the presence of a base material using hydroxyloxylamine hydrochloride or sulfate. Sodium hydroxide, potassium hydroxide, sodium carbonate or the like may be used as the base material. Alcohols include methanol and ethanol.

(제5공정)(5th process)

본 공정은 옥심 5를 아민 7로 환원하는 공정이다. 본 공정은 먼저 옥심 5를 이민으로 환원하고 다시 아민 7로 유도함으로써 달성된다. 옥심 5를 이민으로 환원하는 반응의 환원제로서 디페닐디술피드, 디벤질디술피드 등의 디술피드류와 n-트리부틸포스핀, 트리메톡시포스핀, 트리에톡시포스핀, 트리페닐포스핀 등의 포스핀을 조합하여 사용하면 좋다. 용매로서는 에테르계의 디에틸에테르, 테트라히드로푸란 등을 사용하면 좋다. 반응은 냉각하 수시간에서 달성된다. 이민을 아민 7로 환원하는 반응의 환원제로서는 수소화알루미늄리튬, 수소화붕소나트륨, 수소화붕소시아노나트륨 등을 들 수가 있다. 용매로서는 알코올계의 매탄올, 에탄올 또는 에테르계의 디에틸에테르, 테트라히드로푸란 등을 들 수가 있다. 본 공정에서는 시약의 성질에 따라 3위치의 측쇄가 α 배위의 것과 β 배위의 것이 얻어진다.This step is a step of reducing oxime 5 to amine 7. This process is accomplished by first reducing oxime 5 to imine and then back to amine 7. Disulphides, such as diphenyl disulfide and dibenzyl disulfide, n-tributyl phosphine, trimethoxy phosphine, triethoxy phosphine, triphenyl phosphine, etc. as a reducing agent of the reaction which reduces oxime 5 to imine. It is good to use a combination of phosphines. As the solvent, diethyl ether, tetrahydrofuran or the like of ether may be used. The reaction is achieved in several hours under cooling. Examples of the reducing agent for the reaction of reducing imine to amine 7 include lithium aluminum hydride, sodium borohydride, sodium borohydride and the like. Examples of the solvent include alcohol-based methanol, ethanol or ether-based diethyl ether, tetrahydrofuran, and the like. In this step, the side chains of the 3-position and the β-coordinate are obtained according to the properties of the reagents.

(제6공정)(Step 6)

본 공정은 아민 7을 술폰아미드 유도체 8에 도입하는 공정이다. 술폰아미드 유도체로 하는 반응은 치환술폰 산할로겐화물로서 예를들어 염화메탄술포닐, 염화에탄술포닐, 염화푸로판술포닐, 염화부탄술포닐, 염화펜탄술포닐, 염화헥산술포닐, 염화헵타술포닐, 염화옥탄술포닐, 염화벤젠술포닐, 염화메톡시벤젠술포닐, 염화니트로벤젠술포닐, 염화아세톡시벤젠술포닐, 염화톨루엔술포닐, 염화에틸벤젠술포닐, 염화아미노벤젠술포닐, 염화아세틸아미노벤젠술포닐 또는 염화디메틸아미노벤젠술포닐 등 소망하는 치환기를 갖는 술폰산 유도체를 사용하여 피리딘, 트리에틸 아민등을 염기물질로서 염소화탄화수소계의 클로로포름, 디클로로메탄, 에테르계의 에틸 에테르, 테트라히드로푸란 또는 방향족계의 벤젠 등의 용매중 실온에서 수십분으로 달성할 수가 있다. 또 필요에 따라 촉매로서 4-디메틸아미노피리딘을 사용하여도 좋다.This step is a step of introducing amine 7 into the sulfonamide derivative 8. Reactions with sulfonamide derivatives are substituted sulfone acid halides, for example methanesulfonyl chloride, ethanesulfonyl chloride, furanpansulfonyl chloride, butanesulfonyl chloride, pentanesulfonyl chloride, hexanesulfonyl chloride, heptasulfonyl chloride Octane sulfonyl chloride, benzenesulfonyl chloride, methoxybenzenesulfonyl chloride, nitrobenzenesulfonyl chloride, acetoxybenzenesulfonyl chloride, toluenesulfonyl chloride, ethylbenzenesulfonyl chloride, aminobenzenesulfonyl chloride, acetyl chloride Using sulfonic acid derivatives having desired substituents such as aminobenzenesulfonyl or dimethylaminobenzenesulfonyl chloride, pyridine, triethylamine and the like are used as chloroform, chloroform, dichloromethane, ether ethyl ether and tetrahydrofuran. Or it can achieve in several minutes at room temperature in solvent, such as aromatic benzene. If necessary, 4-dimethylaminopyridine may be used as the catalyst.

(제7공정)(7th process)

본 공정은 화합물 8의 히드록시 보호기를 제거하는 공정이다. 보호기를 제거하는 반응은 보호기의 종류에 따라 다르다. 알콕시메톡시, 아릴킬옥시메톡시, 아랄킬옥시를 치환기로서 갖는 저급알킬의 경우는 산, 예를 들어 포름산, 초산, 프로피온산, 부티르산, 수산, 말론산 등의 유기산 또는 염산, 브롬화수소산, 황산 등의 광산과 접촉시킴으로써 행하여진다. 아랄킬옥시의 경우는 접촉환원 반응에 의해서도 행하여진다. 반응을 원활하게 행하기 위하여 용매를 사용하여도 좋다. 용매로서 물, 알코올계의 메탄올, 에탄올, 에테르계의 디에틸에테르, 테트라히드로푸란, 디옥산 등을 단독 또는 혼합하여 사용하면 좋다. 반응은 통상의 방법에 다라 실온 또는 가열하 수시간으로부터 수십시간에서 달성된다. 보호기가 트리저급알킬실릴의 경우는 비수용매중 불화트리에틸암모늄과 반응시키거나 수성용매중 산 또는 염기를 접촉시킴으로써 용이하게 달성할 수 있다. 사용되는 산으로서는 불화수소 또는 앞서 언급된 것들, 염기로서는 수산화나트륨, 수산화칼륨, 수산화칼슘 등의 수산화물, 탄산나트륨, 탄산칼륨 등의 탄산염을 들 수가 있다. 용매로서는 에테르계의 디에틸에테르, 테트라히드로푸란, 디옥산 또는 알코올계의 메탄올, 에탄올 등을 물과 혼합하여 사용하면 좋다. 반응을 통상의 방법에 따라 행하면 좋다.This step is a step of removing the hydroxy protecting group of compound 8. The reaction to remove a protecting group depends on the type of protecting group. In the case of lower alkyl having alkoxymethoxy, arylalkyloxymethoxy, and aralkyloxy as a substituent, an acid, for example, an organic acid such as formic acid, acetic acid, propionic acid, butyric acid, hydroxyl, malonic acid or hydrochloric acid, hydrobromic acid, sulfuric acid, etc. It is carried out by contacting with the mine. Aralkyloxy is also carried out by a catalytic reduction reaction. You may use a solvent in order to carry out reaction smoothly. As the solvent, water, alcohol-based methanol, ethanol, ether-based diethyl ether, tetrahydrofuran, dioxane or the like may be used alone or in combination. The reaction is achieved at room temperature or from several hours to several tens of hours according to conventional methods. In the case of trilower alkylsilyl, the protecting group can be easily achieved by reacting with triethylammonium fluoride in the nonaqueous solvent or contacting an acid or base in the aqueous solvent. Examples of the acid to be used include hydrogen fluoride or the aforementioned compounds, and bases include hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, and carbonates such as sodium carbonate and potassium carbonate. As a solvent, diethyl ether, tetrahydrofuran, dioxane or methanol, ethanol, etc. of alcohol type may be mixed and used with water. The reaction may be carried out in a conventional manner.

또 반응조건에 따라 얻어지는 에스테르 화합물을 필요에 따라 염기물질 존재하 가수분해하여도 좋다. 염기로서는 수산화나트륨, 수산화칼륨, 수산화칼슘 등의 수산화물, 탄산나트륨, 탄산칼륨 등의 탄산염을 들 수가 있다. 용매로서 알코올계의 메탄올, 에탄올, 에테르계의 디에틸에테르, 테트라히드로푸란 또는 디메틸 술포시드 등을 단독으로 사용하거나 또는 물과 혼합하여 사용하면 좋다. 반응은 실온 또는 가열하 수시간으로 달성할 수가 있다.Moreover, you may hydrolyze the ester compound obtained according to reaction conditions in presence of a base material as needed. Examples of the base include hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, and carbonates such as sodium carbonate and potassium carbonate. As a solvent, alcoholic methanol, ethanol, ether-based diethyl ether, tetrahydrofuran or dimethyl sulfoxide and the like may be used alone or in combination with water. The reaction can be achieved at room temperature or in several hours under heating.

(제8공정)(Step 8)

본 공정은 히드록시 9를 산화하여 알데히드 IIa를 얻는 공정이다. 본 공정은 제3공정에 준하여 반응을 행하면 좋다. 본 공정에서 얻어지는 알데히드 IIa는 시스체에 대해서는 그의 폐환체인 헤미아세탈 IIa과 평형 상태로 되어 있다. 본 공정에 의해 본 발명 화합물의 출발물질의 알데히드 IIa중 2위치의 측쇄에 대하여 메틸렌이 같은 쪽에 있는 것이 얻어진다.This step is a step of oxidizing hydroxy 9 to obtain aldehyde IIa. This step may be carried out in accordance with the third step. Aldehyde IIa obtained in this step is in equilibrium with hemiacetal IIa, which is a ring-closure thereof, for the cis body. By this step, it is obtained that methylene is on the same side with respect to the side chain at the 2-position in the aldehyde IIa of the starting material of the compound of the present invention.

2위치의 측쇠에 대하여 메틸렌이 반대측에 있는 것은 먼저 출발원료 1a(2R*)의 1위치의 히드록시에틸기의 히드록시를 제2공정 기재의 방법에 준하여 보호해서 1b(2R*)을 얻는다. 다음에 2위치의 히드록시를 반전시킴으로써 화합물 1b(2S*)을 얻는다. 이와 같이 해서 얻어진 화합물 1b(2S*)을 출발원료로서 사용하면 좋다.The methylene is on the opposite side with respect to the branched position in the second position. First, the hydroxyethyl group in the hydroxyethyl group of the starting position 1a (2R *) is protected according to the method described in the second step to obtain 1b (2R *). Next, compound 1b (2S *) is obtained by inverting hydroxy at 2-position. Thus obtained compound 1b (2S *) may be used as a starting material.

반전반응은 화합물 1b(2R*)을 예컨대 트리페닐포스핀과 아조디카르복실산의 에틸과의 조합인 미쓰노부시약의 존재하에 카르복실산 화합물과 반응시킴으로써 행하여진다. 카르복실산 화합물로서는 포름산, 초산, 프로피온산, 피발산 등의 지방족 카르복실산, 벤조산, 페닐초산 등의 방향족 카르복실산 등을 들 수가 있다. 용매로서는 방향족계의 벤젠, 염소화탄화수소계의 클로로포름, 디클로로메탄, 에테르계의 디에틸에테르, 테트라히드로푸란 등을 들 수가 있다.The inversion reaction is carried out by reacting compound 1b (2R *) with a carboxylic acid compound in the presence of a Mitsunobu reagent, for example, a combination of triphenylphosphine and ethyl of azodicarboxylic acid. Examples of the carboxylic acid compound include aliphatic carboxylic acids such as formic acid, acetic acid, propionic acid and pivalic acid, and aromatic carboxylic acids such as benzoic acid and phenylacetic acid. Examples of the solvent include aromatic benzene, chlorinated hydrocarbon chloroform, dichloromethane, ether diethyl ether, tetrahydrofuran and the like.

반응은 냉각하 또는 실온에서 수십분부터 수시간에서 달성된다. 또 반전반응은 과산화칼슘, 초산세슘을 사용하여도 행할 수가 있다. 이 경우 히드록시를 미리 통상의 방법에 따라 메실화해 두어도 좋다. 용매로서 디메틸술폭시드, 디메틸포름아미드, 디메톡시에탄 또는 디에틸에테르를 들 수가 있다. 용해보조제로서 18-크라운-6을 가하여도 좋다. 이들의 반응으로 히드록시가 에스테르화되어 있는 경우에는 염기 물질 존재하, 가수분해하면 좋다. 가수분해는 제7공정에 기재되어 있는 염기에 의한 에스테르 가수분해 반응에 준하여 행하면 좋다.The reaction is achieved from tens of minutes to several hours under cooling or at room temperature. The inversion reaction can also be performed using calcium peroxide or cesium acetate. In this case, hydroxy may be mesylated in advance according to a conventional method. Dimethyl sulfoxide, dimethylformamide, dimethoxyethane or diethyl ether can be mentioned as a solvent. 18-Crown-6 may be added as a dissolution aid. In the case where hydroxy is esterified by these reactions, hydrolysis may be performed in the presence of a base substance. The hydrolysis may be performed in accordance with the ester hydrolysis reaction with a base described in the seventh step.

이후 제1공정, 제3공정~제8공정에 따라 순차로 반응을 행하여 본 발명 화합물의 출발물질인 알데히드 IIa중 2위치의 측쇄에 대하여 메틸렌이 반대측에 있는 것을 얻었다.Thereafter, the reaction was carried out sequentially according to the first step, the third step to the eighth step to obtain that methylene was on the opposite side with respect to the side chain at the 2-position in the aldehyde IIa which is the starting material of the compound of the present invention.

6위치가 메틸, 할로겐, 트리플루오로메틸 등으로 치환된 본 발명 화합물의 출발물질은 이하와 같이 제조할 수 있다.Starting materials of the compound of the present invention wherein the 6-position is substituted with methyl, halogen, trifluoromethyl and the like can be prepared as follows.

(제9공정)(Step 9)

본 공정은 화합물 1b(2R*)의 2위치의 히드록시를 보호하기 위한 공정이며 아실화를 행한다. 아실화제로서는 무수초산, 염화아세틸, 염화피바로일, 염화벤조일 등을 들 수가 있다. 용매로서는 방향족계의 벤젠, 톨루엔 또는 피리딘 등을 사용하면 좋다. 염기로서 트리에틸아민, 피리딘 등을 또 필요에 따라 촉매로서 4-디메틸아미노 피리딘을 가하여도 좋다. 반응은 실온에서 수십분 내지 수시간에서 달성된다.This step is a step for protecting hydroxy at the 2-position of compound 1b (2R *) and performing acylation. Examples of the acylating agent include acetic anhydride, acetyl chloride, pivaloyl chloride, and benzoyl chloride. As the solvent, aromatic benzene, toluene, pyridine or the like may be used. Triethylamine, pyridine and the like may be added as a base, and 4-dimethylamino pyridine may be added as a catalyst, if necessary. The reaction is achieved at tens of minutes to several hours at room temperature.

(제10공정)(Step 10)

본 공정은 화합물 1(2R*)의 C₄~C₅의 탄소간에 치환메틸렌을 도입하는 공정이다. 클로로포름, 브로모포름, 이블화이브롬화탄소 등을 염기, 예를들어 수산화나트륨, 수산화칼륨, 불화칼륨, n-부틸리튬 등으로 처리하여 얻어지는 할로카르벤 또 클로로디플루오로초산나트륨 또는 클로로디플루오로초산리튬 등을 가열하여 얻어지는 할로카르벤을 2중결합에 부가시키면 좋다. 용매로서 염소화탄화수소계의 클로로포름, 디클로로메탄 등을 들 수가 있다. 필요에 따라 물 및 상기 비수용매의 2층 반응을 행한다.This step is a step of introducing a substituted methylene between C ₄ to C ₅ carbons of compound 1 (2R *). Halocarbene, chlorodifluorosodium acetate or chlorodifluoro obtained by treating chloroform, bromoform, carbon dibromide, etc. with a base such as sodium hydroxide, potassium hydroxide, potassium fluoride, n-butyllithium, or the like. What is necessary is just to add the halocarbene obtained by heating lithium acetate etc. to a double bond. Chlorinated hydrocarbon-based chloroform, dichloromethane, etc. are mentioned as a solvent. As needed, two-layer reaction of water and the said non-aqueous solvent is performed.

층간 이동촉매로서 염화트리에틸벤질암모늄 또는 브롬화트리에틸벤질암모늄 등을 사용하면 좋다. 화합물 2(3R*-α)의 6위치가 불소, 메틸, 트리플루오로메틸로 치환시킨 것은 각각 앞서 얻어진 클로로 또는 브롬화합물을 불화칼륨, 불화은, 불화안티몬과 반응시킨 것, 디메틸동리튬, 디메틸티오시안산동리튬, 디메틸시안동리튬과 반응시켜 필요에 따라 그후 다시 요오드화메틸과 반응시킨 것, 동촉매와 요오드화트리플루오로메틸, 비스트리플루오로메틸디아조메탄과 반응시킴으로써 얻어진다. 용매로서 에테르계의 디에틸에테르, 테트라히드로푸란 또는 헥사메틸포스포릭트리아미도 등을 단독 또는 혼합하여 사용하면 좋다.Triethyl benzyl ammonium chloride, triethyl benzyl ammonium bromide, or the like may be used as the interlayer transfer catalyst. Substituted at position 6 of compound 2 (3R * -α) with fluorine, methyl and trifluoromethyl were those obtained by reacting a chloro or bromine compound obtained above with potassium fluoride, silver fluoride, antimony fluoride, dimethyl copper lithium, dimethylthio It is obtained by reacting with lithium copper cyanate and lithium dimethyl cyanide, and then reacting with methyl iodide again if necessary, followed by reaction with a copper catalyst, trifluoromethyl iodide, and bistrifluoromethyldiazomethane. What is necessary is just to use ether type diethyl ether, tetrahydrofuran, hexamethylphosphoric triamide, etc. individually or in mixture as a solvent.

(제11공정)(Step 11)

본 공정은 화합물 2(3R*-α)의 3위치의 히드록시 보호기를 가수분해에 의해 제거하는 공정이다. 반응은 통상의 방법에 따라 행하면 좋다. 용매로서 알코올계의 메탄올, 에탄올, 에테르계의 디에틸에테르, 테트라히드로푸란 또는 물을 단독 또는 혼합하여 사용하면 좋다. 필요에 따라 수산화나트륨, 수산화바륨 등의 염기촉매를 사용하여도 좋다.This step is a step of hydrolyzing the hydroxy protecting group at the 3-position of Compound 2 (3R * -α). The reaction may be performed according to a conventional method. As a solvent, alcohol-based methanol, ethanol, ether-based diethyl ether, tetrahydrofuran or water may be used alone or in combination. If necessary, a base catalyst such as sodium hydroxide or barium hydroxide may be used.

(제12공정)(Step 12)

본 공정은 화합물 2a(3R*-α)의 3위치의 히드록시를 케톤 4(α)으로 산화하는 공정이다. 본 공정은 제3공정에 따라 반응을 행하면 좋다.This step is a step of oxidizing hydroxy at the 3-position of compound 2a (3R * -α) to ketone 4 (α). This step may be reacted according to the third step.

본 공정에서 얻어진 화합물 4(α)을 제4공정~제8공정에 따라 처리함으로써 메틸렌이 2위치의 측쇄에 대하여 반대측에 있는 알데히드 IIa를 얻을 수가 있다.By treating compound 4 (α) obtained in this step in accordance with the fourth to eighth steps, aldehyde IIa in which methylene is opposite to the side chain in the 2-position can be obtained.

(제13공정)(Step 13)

본 공정은 염기 존재하 화합물 4(α)을 화합물 4(β)로 변환시키는 공정이다. 염기로서 디아자비시클로노넨, 디아자비시클로운데센, 트리에틸아민, tert-부톡시드칼륨 등의 강염기 물질을 들 수가 있다. 용매로서 디메틸술폭시드, 디메틸포름아미드, 방향족계의 톨루엔, 크실렌 등을 들 수 있다. 본 공정은 실온 내지 가열하 수시간부터 수십시간 반응시킨 후, 반응액을 냉각한 포름산, 초산, 프로피온산 등의 산의 비수용액중에 가하여 반응시킴으로써 달성된다.This step is a step of converting compound 4 (?) Into compound 4 (?) In the presence of a base. Examples of the base include strong base materials such as diazabicyclononene, diazabicyclo undecene, triethylamine, and tert-butoxide potassium. Dimethyl sulfoxide, dimethylformamide, aromatic toluene, xylene, etc. are mentioned as a solvent. This step is accomplished by reacting for several tens of hours from room temperature to several hours under heating, and then adding the reaction solution to a non-aqueous solution of cooled acid, such as formic acid, acetic acid and propionic acid.

본 공정에서 얻어진 화합물 4(β)을 제4공정~제8공정에 따라서 처리함으로써, 메틸렌이 2위치의 측쇄에 대하여 같은 측에 있는 알데히드 IIa를 얻을 수가 있다.By treating compound 4 (β) obtained in this step in accordance with the fourth to eighth steps, aldehyde IIa in which methylene is on the same side with respect to the side chain in the 2-position can be obtained.

(제14공정)(Step 14)

본 공정은 케톤 4(β)를 히드록시 2a(3R*-β)로 환원하는 공정이다. 환원제로서 수소화알루미늄리튬, 수소화트리에톡시알루미늄리튬, 수소화트리-tert-부톡시알루미늄리튬, 수소화붕소나트륨 등을 사용하면 좋다. 용매로서 에테르계의 디에틸에테르, 테트라히드로푸란, 알코올계의 메탄올, 에탄올 또는 물 등을 시약의 성질에 맞추어서 사용하면 좋다.This step is a step of reducing ketone 4 (β) to hydroxy 2a (3R * -β). Lithium aluminum hydride, lithium hydride triethoxyaluminum, lithium hydride tri-tert-butoxyaluminum, sodium borohydride or the like may be used as the reducing agent. As the solvent, diethyl ether, tetrahydrofuran, alcohol methanol, ethanol or water may be used depending on the properties of the reagent.

(제15공정)(15th process)

본 공정은 제11공정 또는 제14공정에서 얻어진 히드록시 2a(3R*)[2a(3R*-β) 또는 2A(3R*-α)]을 아지도화 하는 공정이다. 아지도화 반응에 앞서서 히드록시 2a(3R*)를 트리에틸아민, 피리딘 등의 염기 존재하, 술폰화한다. 술폰화제로서 염화 p-톨루엔술포닐, 염화메탄술포닐, 트리플루오로술폰산무수물 등을 들 수가 있다. 용매로서 염소화탄화수소계의 클로로포름, 디클로로메탄, 에테르계의 디에틸에테르, 테트라히드로푸란 또는 아세톤, 디메틸포름아미드, 디메틸술폭시드, 초산에틸을 사용하면 좋다. 반응은 냉각하 수분부터 수시간에서 달성할 수 있다. 또 필요에 따라 4-디메틸아미노 피리딘 등의 촉매를 가하여도 좋다. 이와 같이 해서 얻어진 중간체와 아지화나트륨 또는 아지화리튬을 헥사메틸포스파미드, 디메틸 포름아미도, 디메틸술폭시드 또는 디페닐에테르등의 용매중 수십분에서부터 수시간 가열함으로써 아지드 화합물 6을 얻을 수가 있다.This step is a step of azipping hydroxy 2a (3R *) [2a (3R * -β) or 2A (3R * -α)] obtained in the eleventh or fourteenth step. Prior to the azido reaction, hydroxy 2a (3R *) is sulfonated in the presence of a base such as triethylamine, pyridine or the like. Examples of the sulfonating agent include p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluorosulfonic anhydride, and the like. Chlorinated hydrocarbon-based chloroform, dichloromethane, ether-based diethyl ether, tetrahydrofuran or acetone, dimethylformamide, dimethyl sulfoxide and ethyl acetate may be used as the solvent. The reaction can be achieved in several hours from a few minutes under cooling. Moreover, you may add a catalyst, such as 4-dimethylamino pyridine, as needed. The azide compound 6 can be obtained by heating the obtained intermediate and sodium azide or lithium azide for several hours in a solvent such as hexamethylphosphamide, dimethyl formamido, dimethyl sulfoxide or diphenyl ether for several hours. .

(제16공정)(Step 16)

본 공정은 아지드 6을 아민 7(3S*)으로 환원하는 공정이다. 환원제로서 트리페닐포스핀, 수소화알루미늄리튬, 트리에틸아민-황화수소, 트리에틸아민-메르카프탄을 들 수가 있다. 용매로서는 알코올계의 메탄올, 에탄올 또는 에테르계의 디에틸에테르, 테트라히드로푸란 등을 들 수가 있다. 반응은 실온 내지는 가열하 수시간에서 달성할 수가 있다. 또 본 공정은 백금, 팔라듐 등의 촉매를 사용한 접촉환원에 의해 행할 수도 있다.This step is a step of reducing azide 6 to amine 7 (3S *). Examples of the reducing agent include triphenylphosphine, lithium aluminum hydride, triethylamine hydrogen sulfide, and triethylamine mercaptan. Examples of the solvent include alcohol-based methanol, ethanol or ether-based diethyl ether, tetrahydrofuran and the like. The reaction can be achieved at room temperature or under heating for several hours. The present step can also be carried out by catalytic reduction using a catalyst such as platinum or palladium.

본 공정에 의해 얻어지는 아민 7(3S*)을 제6공정~제8공정에 따라 반응시킴으로써 본 발명 화합물의 출발물질인 알데히드 IIa중 2위와 3위의 측쇄가 트랜스의 관계에 있는 것을 얻을 수가 있다.By reacting the amine 7 (3S *) obtained by this process according to the 6th-8th process, it can be obtained that the 2nd- and 3rd-side side chains of the aldehyde IIa which is a starting material of the compound of this invention are in trans relationship.

(제17공정)(Step 17)

본 공정은 알데히드 IIa와 치환술폰산 할로겐화물을 염기 존재하 반응시켜서 본 발명 화합물 술폰아미도 유도체 Ia를 얻는 방법이다.This step is a method of reacting aldehyde IIa with a substituted sulfonic acid halide in the presence of a base to obtain the compound sulfonamido derivative Ia of the present invention.

본 공정은 알데히드 IIa를 일리드와 반응시켜서 본 발명 화합물 Ia를 얻는 공정이다. 알데히드체와 일리드의 반응(2중결합을 생성하는 반응)은 위찌히 반응의 방법에 따라 행하면 좋다. 반응에 사용하는 일리드는 트리페닐포스핀 및 오메가위치에 카르복실기를 갖는 알킬할라이드로부터 얻어지는 포스포늄염에 염기를 작용시켜서 얻을 수가 있다.This step is a step wherein compound Ia of the present invention is obtained by reacting aldehyde IIa with illi. The reaction between the aldehyde body and the lide (reaction for generating a double bond) may be carried out in accordance with the method of reaction. Ilide used for reaction can be obtained by making a base react with the phosphonium salt obtained from the triphenylphosphine and the alkyl halide which has a carboxyl group in an omega position.

본 반응에서 사용하는 할로겐화알칸산으로서는 예를들어 5-클로로펜탄산 또는 5-브로모펜탄산 등이 있다. 염기로서는 수소화나트륨, 디무실나트륨, 디무실칼륨, n-부틸리튬, tert-부톡시칼륨 또는 리튬디이소프로필아미드 등을 들 수가 있다.As a halogenated alkanoic acid used by this reaction, 5-chloropentanoic acid, 5-bromopentanoic acid, etc. are mentioned, for example. Examples of the base include sodium hydride, dimuthyl sodium, dimuthyl potassium, n-butyllithium, tert-butoxy potassium or lithium diisopropylamide.

본 반응은 용매로서는 예컨대 에테르계의 에틸에테르, 테트라히드로푸란 또는 n-헥산, 톨루엔, 디메틸 술폭시드 등을 사용하여 냉각하 또는 실온에서 수시간에서 완료한다. 본 반응에 의해 본 발명 화합물중 유리의 카르복실산 Ia-b를 얻을 수가 있다. 또 본 반응에서는 반응조건에 의해 Z체만 또는 Z체와 E체의 혼합물이 생성된다. 필요에 따라 카르복실산 Ia-b를 에스테르화하여도 좋다. 에스테르화 반응은 카르복실산과 메탄올, 에탄올, n-프로판올, 이스프로판올, 부탄올 또는 펜탄올 등의 알코올을 필요에 따라 건조염화수소, 농황산의 촉매와 함께 반응시키는 방법, 카르복실산을 할로겐화물로서 상기 알코올과 금속마그네슘, 디메틸아닐린, 피리딘, 수산화나트륨 등의 염기와 함께 반응시키는 방법, 디아조메탄에 의한 방법 또는 디메틸황산과 디아자비시클로노넨 또는 디아자비시클로운데센에 의한 방법 등을 통상의 방법에 따라 행하면 좋다. 본 에스테르화반응에 의해 본 발명 화합물중의 카르복실산 에스테르 Ia-a를 얻을 수가 있다.This reaction is completed under cooling or several hours at room temperature using, for example, ether-based ethyl ether, tetrahydrofuran or n-hexane, toluene, dimethyl sulfoxide, or the like as a solvent. By this reaction, free carboxylic acid Ia-b in the compound of the present invention can be obtained. In this reaction, only Z-form or a mixture of Z- and E-forms is produced under the reaction conditions. You may esterify carboxylic acid Ia-b as needed. The esterification reaction is a method in which a carboxylic acid and an alcohol such as methanol, ethanol, n-propanol, ispropanol, butanol or pentanol are reacted with a catalyst of dry hydrogen chloride or concentrated sulfuric acid, if necessary, the carboxylic acid as a halide. And a method of reacting with a base such as metal magnesium, dimethylaniline, pyridine, sodium hydroxide, a method of diazomethane, or a method of dimethyl sulfate and diazabicyclononene or diazabicyclo undecene according to a conventional method. Do it. By this esterification reaction, the carboxylic acid ester Ia-a in the compound of this invention can be obtained.

또 필요에 따라 카르복실산 Ia-b는 나트륨메톡시드, 수산화나트륨, 수산화칼륨, 수산화칼슘, 수산화암모늄, 디시클로헥실아민, 메틸모르포린, 피리딘, 트리에틸아민, 글리신, 발린, 알라닌 등의 염기를 사용하여 통상법에 따라 처리함으로써 일반식(I)으로 표시되는 본 발명 화합물중의 카르복실산염 Ia-c로 변경할 수가 있다.If necessary, the carboxylic acid Ia-b may be selected from a base such as sodium methoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, dicyclohexylamine, methylmorpholine, pyridine, triethylamine, glycine, valine, alanine and the like. It can change into carboxylate (Ia-c) in the compound of this invention represented by General formula (I) by using it and processing according to a conventional method.

공정식 I-2(A가 산소 또는 유황, p=0, q=1일때)Process formula I-2 (When A is oxygen or sulfur, p = 0, q = 1)

공정 I-2Process I-2

(제1공정)(Step 1)

본 공정은 화합물 Ib(2R*)의 히드록시를 아지드로 변경하는 공정이다. 본 공정은 공정 I-1, 제15공정에 따라 행하면 좋다.This step is a step of changing the hydroxy of the compound Ib (2R *) to an azide. This step may be performed in accordance with Steps I-1 and 15th.

(제2공정)(2nd step)

본 공정은 아지드를 아민 3으로 환원하는 공정이다. 본 공정은 공정 I-1, 제16공정에 따라 행하면 좋다.This step is a step of reducing azide to amine 3. This step may be performed in accordance with Steps I-1 and 16th.

(제3공정)(3rd step)

본 공정은 아민 3을 술폰아미드 유도체 4로 변경하는 공정이다. 본 공정은 공정 I-1, 제6공정에 따라 행하면 좋다.This step is a step of changing amine 3 to sulfonamide derivative 4. This step may be performed according to Steps I-1 and 6th.

(제4공정)(4th step)

본 공정은 화합물 4의 히드록시 보호기를 제거하는 공정이다. 본 공정은 공정 I-1, 제7공정에 따라 행하면 좋다.This step is a step of removing the hydroxy protecting group of compound 4. This step may be performed in accordance with Steps I-1 and 7th.

(제5공정)(5th process)

본 공정은 화합물 5a의 2중결합을 에폭시드 6으로 산화시키는 공정이다. 산화제로서는 과산화수소와 천이원소 금속촉매의 조합, 과포름산, 과초산, 과벤조산, 모노과프탈산, 모노과말레산, 과트리플루오로초산, 메타클로로과벤조산 또는 파라니트로과벤조산 등의 과산 또는 과산에스테르를 사용하면 좋다. 사용하는 용매로서는 에테르, 테트라히드로푸란 등의 에테르계, 메탄올, 에탄올 등의 알코올계, 디클로로메탄, 클로로포름 등의 염소화탄화수소계 용매 등을 들 수가 있다. 반응은 0℃로부터 실온에서 수분 내지 수시간에서 달성된다.This step is a step of oxidizing the double bond of compound 5a to epoxide 6. As the oxidizing agent, a combination of hydrogen peroxide and a transition element metal catalyst, performic acid, peracetic acid, perbenzoic acid, monoperphthalic acid, monopermaleic acid, pertrifluoroacetic acid, metachloroperbenzoic acid or paranitroperbenzoic acid, or the like may be used. . Examples of the solvent used may include ethers such as ether and tetrahydrofuran, alcohols such as methanol and ethanol, and chlorinated hydrocarbon solvents such as dichloromethane and chloroform. The reaction is achieved from 0 ° C. at room temperature to several minutes.

(제6공정)(Step 6)

본 공정은 화합물 6의 히드록시를 알데히드 IIb로 산화시키는 공정이다. 본 공정은 공정 I-1의 제3공정에 따라서 행하면 좋다. 본 공정에서 얻어지는 알데히드는 환상헤미아세탈 IIb'과 평형상태로 되어 있다. 본 공정에서 얻어지는 알데히드 IIb는 2위의 측쇄에 대하여 3위의 측쇄가 시스배치로 되어 있는 것이 얻어진다.This step is a step of oxidizing hydroxy of compound 6 to aldehyde IIb. This step may be performed in accordance with the third step of Step I-1. The aldehyde obtained by this process is in equilibrium with cyclic hemiacetal IIb '. As for the aldehyde IIb obtained by this process, it is obtained that the 3rd side chain is cis-batch with respect to the 2nd side chain.

본 공정은 제5공정에 앞서 행할 수도 있다.This step may be performed before the fifth step.

2위치의 측쇄에 대하여 3위치의 측쇄가 트랜스배치로 되어 있는 알데히드 IIb는 아래와 같이 해서 얻을 수가 있다.Aldehyde IIb in which the side chain at the 3 position is translocated with respect to the side chain at the 2 position can be obtained as follows.

먼저 화합물 Ib(2R*)의 2위의 히드록시를 공정 I-1에 기재된 반전반응에 따라 반전시키고, 다음에 얻어진 화합물 Ib(2S*)을 제1공정~제6공정에 따라 반응을 시키면 된다.First, the hydroxy at the second position of compound Ib (2R *) may be inverted according to the inversion reaction described in step I-1, and then the obtained compound Ib (2S *) may be reacted according to the first to sixth steps. .

(제7공정)(7th process)

본 공정은 알데히드 IIb-a(또는 IIb'-a)을 일리드와 반응시켜서 본 발명 화합물의 Ib-a를 얻는 공정이다. 본 공정은 공정 I-1, 제17공정에 따라 행하면 좋다.This step is a step in which aldehyde IIb-a (or IIb'-a) is reacted with illi to obtain Ib-a of the compound of the present invention. This step may be performed in accordance with Steps I-1 and 17th.

본 공정에서는 본 발명 화합물의 카르복실산 에스테르 Ib-aa, 유리의 카르복실산 Ib-ab 또는 카르복실산염 Ib-ac가 얻어진다.In this step, carboxylic ester Ib-aa, free carboxylic acid Ib-ab or carboxylate Ib-ac of the compound of the present invention are obtained.

(제8공정)(Step 8)

본 공정은 에폭시드 Ib-a를 에피-술피드 Ib-b로 변화시키는 공정이다. 본 공정은 아래와 같이 행할 수가 있다.This process is a process of changing the epoxide Ib-a to epi-sulfide Ib-b. This process can be performed as follows.

먼저 에폭시드 Ib-a를 티오시안산과 에테르계 용매, 예를들어 디에틸에테르 또는 테트라히드로푸란 등의 용매중에서 실온으로 수시간 처리함으로써 α-히드록시-티오시아네이트로 바꾸고 다음에 발생한 히드록시를 탈리기로 바꾼다. 계속해서 티오시안네이트 부분을 수산화칼륨 등의 염기를 사용하여 디에틸에테르-메탄올 또는 디에틸에테르-에탄올 등의 혼합용매중에서 실온 또는 가열하에 수십분 내지 수시간 동안 반응시켜서 가수분해함으로써 행하여진다.The epoxide Ib-a was first converted to α-hydroxy-thiocyanate by treatment at room temperature in a thiocyanic acid and a solvent such as diethyl ether or tetrahydrofuran for several hours, followed by hydroxy. Change to Tally. Subsequently, the thiocyanate portion is reacted with a base such as potassium hydroxide and hydrolyzed in a mixed solvent such as diethyl ether-methanol or diethyl ether-ethanol at room temperature or under heating for several tens of minutes to several hours.

본 공정에서 사용되는 탈리기로서 치환술폰산에스테르, 예를들어 메탄술폰산에스테르, 벤젠술폰산에스테르 또는 p-톨루엔술폰산에스테르 등을 들 수가 있다. 본 공정에서 얻어지는 에피-술피드는 최초의 에폭시드의 배치와 반대의 배치를 갖고 있다.Substituted sulfonic acid esters such as methane sulfonic acid ester, benzene sulfonic acid ester or p-toluene sulfonic acid ester may be used as the leaving group used in this step. The epi-sulfide obtained in this process has a configuration opposite to that of the original epoxide.

본 공정에서 본 발명 화합물의 유리의 카르복실산 Ib-ba이 얻어진다. 유리의 카르복실산은 공정 I-1 제17공정에 따라 반응을 행하는 카르복실산에스테르 Ib-ba 또는 카르복실산염 Ib-bc로 변화시킬 수 있다.In this step, free carboxylic acid Ib-ba of the compound of the present invention is obtained. The free carboxylic acid can be changed to carboxylic acid ester Ib-ba or carboxylate Ib-bc which reacts according to the process I-1 17th process.

공정식 II(A가 에틸렌, p=2, q=0일때)Process Formula II (When A is Ethylene, p = 2, q = 0)

공정 IIProcess II

(제1공정)(Step 1)

본 공정은 화합물 1의 2위치에 염기 존재하 알릴을 도입하는 공정이다. 알릴화제로서는 할로겐화알릴, 예를들어 염화알릴, 브롬화알릴, 요오드화알일 또는 술폰산알릴 에스테르 등을 사용한다. 염기로서는 비교적 강한것, 예를들어 n-부틸리튬, 나트륨아미드칼륨-tert-부톡시드, 수소화나트륨, 리튬디이소프로필아미드 등을 사용하면 좋다. 용매로서 에테르계의 디에틸에테르, 테트라히드로푸란, 글라임, 디글라임 등을 들 수가 있다. 반응은 -78℃~25℃의 사이에서 수분 내지는 수시간에서 달성된다.This step is a step of introducing allyl in the presence of a base at position 2 of compound 1. As the allylating agent, allyl halide such as allyl chloride, allyl bromide, allyl iodide or allyl sulfonic acid ester is used. As the base, relatively strong ones such as n-butyllithium, sodium amide potassium-tert-butoxide, sodium hydride, lithium diisopropylamide and the like may be used. Examples of the solvent include ether-based diethyl ether, tetrahydrofuran, glyme and diglyme. The reaction is achieved in a few minutes to several hours between -78 ° C and 25 ° C.

(제2공정)(2nd step)

본 공정은 옥심 2을 아민 3으로 환원하는 공정이다. 환원제로서 수소화알루미늄리튬, 아연 또는 염화 제1주석 등을 들 수가 있다. 용매로서는 알코올계의 메탄올, 에탄올 또는 에테르계의 디에틸에테르, 테트라히드로푸란 등을 들 수가 있다. 또 본 공정은 백금, 팔라듐, 니켈 등을 사용한 접촉환원 또는 알코올 용매 중 금속나트륨에 의한 환원에 의해서도 달성할 수 있다.This step is a step of reducing oxime 2 to amine 3. Examples of the reducing agent include lithium aluminum hydride, zinc or stannous chloride. Examples of the solvent include alcohol-based methanol, ethanol or ether-based diethyl ether, tetrahydrofuran and the like. The present step can also be achieved by catalytic reduction using platinum, palladium, nickel or the like or reduction with sodium metal in an alcohol solvent.

본 공정에 의해 3위의 측쇄가 α-배치의 화합물과 β-배치의 화합물의 혼합물이 얻어진다.In this step, a mixture of a compound having a 3-position side chain having an α-position and a compound having a β-position is obtained.

(제3공정)(3rd step)

본 공정은 아민 3을 술폰아미드 유도체 4에 도입하는 공정이다. 본 공정은 공정 I-1 제6공정과 동일한 반응을 행하면 좋다.This step is a step of introducing amine 3 into sulfonamide derivative 4. This step may be carried out in the same manner as in the step I-1 to 6th step.

(제4공정)(4th step)

본 공정은 화합물 4의 알릴의 이중결합을 에폭시드 5에 산화하는 공정이다. 산화제로서는 과산화수소와 천이금속촉매와의 조합, 과포름산, 과초산, 과벤조산, 모노과프탈산, 모노과말레산, 트리플루오로과초산, 메타클로로벤조산 또는 파라니트로과벤조산 등의 과산 또는 과산에스테르를 사용하면 좋다. 용매로서는 에테르계의 디에틸에테르, 테트라히드로푸란, 알코올계의 메탄올, 에탄올 또는 염소화탄화수소계의 클로로포름, 디클로로메탄을 들 수가 있다. 반응은 0℃ 내지 실온에서 수시간으로 달성된다.This step is a step of oxidizing a double bond of allyl of compound 4 to epoxide 5. As the oxidizing agent, a combination of hydrogen peroxide and a transition metal catalyst, perforic acid, peracetic acid, perbenzoic acid, monoperphthalic acid, monopermaleic acid, trifluoroperacetic acid, metachlorobenzoic acid or paranitroperbenzoic acid, or the like may be used. Examples of the solvent include ether-based diethyl ether, tetrahydrofuran, alcohol-based methanol, ethanol or chlorinated hydrocarbon-based chloroform and dichloromethane. The reaction is achieved at 0 ° C. to room temperature in several hours.

(제5공정)(5th process)

본 공정은 에폭시드 5의 수화에서 생긴 글리콜을 산화적 절단데 의해 탄소수가 하나 적은 알데히드 IIc로 변환하는 공정이다. 수화 촉매를 겸하는 산화제로서는 과요오드산 또는 요로토과요오드산 등을 사용하면 좋다. 용매로서는 물과 섞이는 것이 바람직하고, 예를들어 에테르계의 디에틸에테르, 테트라히드로푸란, 디옥산 또는 알코올계의 메탄올, 에탄올 등을 들 수가 있다. 반응은 실온에서 수십분 내지 수시간에서 완료한다.This process converts glycols from hydration of epoxide 5 to aldehyde IIc with less carbon by oxidative cleavage. As an oxidizing agent which also serves as a hydration catalyst, periodic acid or urototoiodic acid or the like may be used. It is preferable to mix with water as a solvent, For example, ether diethyl ether, tetrahydrofuran, dioxane, or alcohol type methanol, ethanol, etc. are mentioned. The reaction is completed at tens of minutes to several hours at room temperature.

본 공정에 의해 본 발명 화합물 Ic의 출발물질인 알데히드 IIc를 얻을 수가 있다.By this step, aldehyde IIc which is a starting material of the compound Ic of the present invention can be obtained.

(제6공정)(Step 6)

본 공정은 화합물 IIc을 공정 I-1의 제17공정에 따라 반응시켜 본 발명 화합물을 얻는 공정이다.This step is a step wherein compound IIc is reacted according to step 17 of step I-1 to obtain a compound of the present invention.

본 반응에서는 유리의 카르복실산 Ic-b이 얻어진다. 필요에 따라 유리의 카르복실산 Ic-b는 에스테르화 하여도 좋다. 에스테르화 반응은 공정 I-1의 제17공정 기재의 방법에 따라 행하면 좋다. 본 에스테르화 반응에 의해 본 발명 화합물의 카르복실산 에스테르 Ic-a가 얻어진다. 또 유리의 카르복실산 Ic-b을 공정 I-1의 제17공정에 따라서 처리함으로서 카르복실산염 Ic-c를 얻을 수가 있다.In this reaction, free carboxylic acid Ic-b is obtained. As needed, free carboxylic acid Ic-b may be esterified. The esterification reaction may be performed in accordance with the method described in the seventeenth step of Step I-1. By this esterification reaction, the carboxylic acid ester Ic-a of the compound of this invention is obtained. Moreover, carboxylate Ic-c can be obtained by treating free carboxylic acid Ic-b according to the 17th process of process I-1.

공정식중 R₁및 R₂의 정의는 상기와 같은 뜻이다. R₃은 히드록시 보호기를 의미하고 예를들어 메톡시메틸, 벤질옥시메틸, 벤질, 트리페닐메틸 또는 트리메틸실릴 등을 나타낸다. R₄는 알카노일 또는 알로일, 예를들어 포르밀, 아세틸, 프로피오닐, 피발로일, 벤조일 또는 페닐아세틸을 나타낸다. X는 -CH₂CH=CH(CH₂)₃-을, Z는 수소 또는 메틸을 나타내고, 파선은 α 또는 β 배치 또는 그들의 혼합물을 나타낸다.The definitions of R ₁ and R _{2 in} the formula mean the same as above. R ₃ means a hydroxy protecting group and represents, for example, methoxymethyl, benzyloxymethyl, benzyl, triphenylmethyl or trimethylsilyl and the like. R ₄ represents alkanoyl or alloyl, for example formyl, acetyl, propionyl, pivaloyl, benzoyl or phenylacetyl. X represents -CH ₂ CH = CH (CH ₂ ) _3- , Z represents hydrogen or methyl, and dashed lines represent α or β batches or mixtures thereof.

이하에 참고에, 실시예 및 물리항수를 나타내고, 더욱 상세하게는 본 발명의 양태를 명백히 하겠으나, 본 발명의 범위가 이것에 한정되는 것은 아니다.Although an Example and a physical constant are shown to the following, the aspect of this invention is made clear in more detail, but the scope of the present invention is not limited to this.

이하의 참고예 및 실시예에 있어서 각각의 단계에서 생성물은 모두 라세미체이나 편의상 한쪽의 활성체만으로 표시되어 있다.In the following Reference Examples and Examples, the products in each step are all expressed as racemates or only one active substance for convenience.

[실시예 I-1]Example I-1

[참고예 1]Reference Example 1

(dl)-(1β,2α,3α,5β)-2-히드록시에틸-3-히드록시비시클로[3,1,0]헥산 2b-a.(dl)-(1β, 2α, 3α, 5β) -2-hydroxyethyl-3-hydroxybicyclo [3,1,0] hexane 2b-a.

초산은 80mg의 열초산용액 200ml에 13.1g의 아연분말(0.2그램원자)을 가한 후 초산을 제거하고 에테르로 세척함으로서 제조한 아연-은 커플에 120ml에 에테르를 가한다. 교반하 에테르의 완만한 환유가 유지되도록 26.8g의 요오드화메틸렌을 가한다. 또 1시간 가열한 후 (dl)-2-히드록시시클로펜트-4-에닐에탄올 1a(2R*) 6.4g(53.3밀리몰)의 에테르 10ml의 용액을 적하하고, 반응액을 다시 4시간 가열 환류하에서 교반하여 반응시킨다.Acetic acid is added to 120 ml of zinc-silver couples prepared by adding 13.1 g of zinc powder (0.2 gram atoms) to 200 ml of 80 mg of thermal acetic acid solution, removing acetic acid and washing with ether. 26.8 g of methylene iodide is added to maintain a gentle petroleum oil of ether under stirring. After heating for 1 hour, a solution of 10 ml of ether (dl) -2-hydroxycyclopent-4-enylethanol 1a (2R *) 6.4 g (53.3 mmol) was added dropwise, and the reaction solution was further heated under reflux for 4 hours. The reaction is stirred.

반응액을 냉각후 포화염화암모늄 수용액에 붓고 생성물을 초산에틸로 추출한다. 추산에틸층은 포화식염수로 세척후 무수황산마그네슘으로 건조시키고 용매를 증류제거시킨다. 잔류물을 벤젠-초산에틸(1:1)혼액을 용출용매로 하는 실리카겔-컬럼 크로마토그래피에 의해 분리 정제함으로써 3.98g(56%)의 표제 화합물 2b-a을 얻는다.The reaction solution is cooled, poured into a saturated aqueous ammonium chloride solution, and the product is extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. 3.98 g (56%) of the title compound 2b-a was obtained by separation and purification of the residue by silica gel-colum chromatography using a benzene-ethyl acetate (1: 1) mixture as an eluting solvent.

NMR : δ(CDCl₃) ; 0.0~0.5(m, 1H), 0.5~0.8(m, 1H), 1.1α1.14(m, 2H), 1.5~2.0(m, 3H), 2.0~2.8(m, 4H), 3.55~4.1(m, 2H), 4.1~4.35(m, 1H) ppm.NMR: δ (CDCl ₃ ); 0.0 ~ 0.5 (m, 1H), 0.5 ~ 0.8 (m, 1H), 1.1α1.14 (m, 2H), 1.5 ~ 2.0 (m, 3H), 2.0 ~ 2.8 (m, 4H), 3.55 ~ 4.1 ( m, 2H), 4.1-4.35 (m, 1H) ppm.

IR : υmax(CHCl₃) ; 3450cm^-1 IR: ν max (CHCl ₃ ); 3450 cm ^-1

[참고예 2]Reference Example 2

(dl)-(1β,2α,3α,5β)-3-히드록시-2-트리페닐메톡시 에틸비시클로[3,1,0]헥산-2a-a(3R*-β).(dl)-(1β, 2α, 3α, 5β) -3-hydroxy-2-triphenylmethoxy ethylbicyclo [3,1,0] hexane-2a-a (3R * -β).

2.1g(14.8밀리몰)의 (dl)-(1β,2α,3α,5β)-2-히드록시에틸-3-히드록시비시클로[3,1,0]헥산 2b-a 및 4.36g(15.6밀리몰)의 염화트리페닐메틸의 디클로로메탄 50ml의 용액에 빙냉하 2.5ml(17.8밀리몰)의 트리에틸아민, 이어서 100mg의 디메틸아미노피리딘을 가한다. 빙냉하에서 30분, 이어서 실온에서 20시간 반응시킨 후 생성물을 디클로로메탄으로 추출한다. 디클로로메탄층은 포화 식염수로 세척한 후 무수황산마그네슘으로 건조시키고 용매를 증류제거한다. 잔류물을 벤젠-초산 에텔(2:1) 혼액을 용출용매로 하는 실리카겔-컬럼 크로마토그래피에 의해 분리정제함으로써 5.46g(95.7%)의 표제 화합물 2a-a(3R*-β)을 얻었다.2.1 g (14.8 mmol) of (dl)-(1β, 2α, 3α, 5β) -2-hydroxyethyl-3-hydroxybicyclo [3,1,0] hexane 2b-a and 4.36 g (15.6 mmol) To a solution of 50 ml of dichloromethane of triphenylmethyl chloride) 2.5 ml (17.8 mmol) triethylamine, followed by 100 mg of dimethylaminopyridine under ice-cooling. After reacting for 30 minutes under ice-cooling and then 20 hours at room temperature, the product is extracted with dichloromethane. The dichloromethane layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. 5.46 g (95.7%) of the title compound 2a-a (3R * -β) was obtained by purification of the residue by silica gel-colum chromatography using a benzene-acetic acetate (2: 1) mixture as an eluting solvent.

NMR : δ(CDCl₃) ; 0.1~0.4(m, 1H), 0.5~0.8(m, 1H), 1.0~1.35(m, 2H), 1.4~2.5(m, 6H), 2.95~3.28(m, 1H), 3.28~3.55(m, 1H), 4.10(t, J=6Hz, 1H), 7.0~7.6(m, 15H) ppm.NMR: δ (CDCl ₃ ); 0.1 to 0.4 (m, 1H), 0.5 to 0.8 (m, 1H), 1.0 to 1.35 (m, 2H), 1.4 to 2.5 (m, 6H), 2.95 to 3.28 (m, 1H), 3.28 to 3.55 (m , 1H), 4.10 (t, J = 6 Hz, 1H), 7.0-7.6 (m, 15H) ppm.

IR : υmax(CHCl₃) ; 3450cm^-1 IR: ν max (CHCl ₃ ); 3450 cm ^-1

[참고예 3]Reference Example 3

(dl)-(시스)-2-히드록시시클로펜트-4-에틸에탄올트리페닐 메틸에테르 1b-a(2R*).(dl)-(cis) -2-hydroxycyclopent-4-ethylethanoltriphenyl methylether 1b-a (2R *).

14g(109밀리몰)의 (dl)-2-히드록시시클로펜트-4-에틸에탄올 1a(2R*)의 디클로로메탄 500ml 용액에 32g(114밀리몰)의 염화트리페닐메틸의 디클로로메탄 100ml 용액을 가하고 다시 트리에틸아민 19.8ml(142 밀리몰) 및 300mg의 디메틸아미노피리딘을 가하여 실온에서 20시간 반응시킨다.To a 500 ml solution of 14 g (109 mmol) of (dl) -2-hydroxycyclopent-4-ethylethanol 1a (2R *) dichloromethane were added 32 g (114 mmol) of a 100 ml solution of dichloromethane of triphenylmethyl chloride. 19.8 ml (142 mmol) of triethylamine and 300 mg of dimethylaminopyridine were added and reacted at room temperature for 20 hours.

생성물을 디클로로메탄으로 추출한다. 디클로로메탄층은 회염산 수용액, 포화탄산수소나트륨 수용액 및 포화 식염수로 세척한 후 무수황산마그네슘에서 건조시키고 용매를 증류 제거하였다. 잔류물을 n-헥산-초산에틸(4:1) 혼액을 용출용매로 하는 실리카겔-컬럼 크로마토그래피에 의해 분리정제함으로써 36.63g(96%)의 표제 화합물 1b-a(2R*)을 얻었다.The product is extracted with dichloromethane. The dichloromethane layer was washed with an aqueous saline solution, saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was separated and purified by silica gel-colum chromatography using an n-hexane-ethyl acetate (4: 1) mixture as an eluting solvent to obtain 36.63 g (96%) of the title compound 1b-a (2R *).

NMR : δ(CDCl₃) ; 1.5~2(m, 2H), 2.15~2.85(m, 3H), 3.02~3.5(m, 2H), 4.2~4.5(m. 1H), 5.4~5.6(m, 1H), 5.6~5.7(m, 1H), 7.15~7.65(m, 15H) ppm.NMR: δ (CDCl ₃ ); 1.5 to 2 (m, 2H), 2.15 to 2.85 (m, 3H), 3.02 to 3.5 (m, 2H), 4.2 to 4.5 (m. 1H), 5.4 to 5.6 (m, 1H), 5.6 to 5.7 (m , 1H), 7.15-7.75 (m, 15H) ppm.

IR : υmax(CHCl₃) ; 3450cm^-1 IR: ν max (CHCl ₃ ); 3450 cm ^-1

[참고예 4]Reference Example 4

(dl)-(트랜스)-2-벤조일옥시시클로펜트-4-에닐에탄올트리페닐메틸에테르 1-a(2S*).(dl)-(trans) -2-benzoyloxycyclopent-4-enylethanoltriphenylmethyl ether 1-a (2S *).

1.83g(5밀리몰)의 (dl)-(시스)-2-히드록시시클로펜트-4-에닐에탄올트리페닐메틸에테르 1b-a(2R*), 2.62g(10밀리몰)의 트리페닐포스핀 및 1.22g(10밀리몰)의 벤조산의 테트라히드로푸란 100ml용액에 빙냉하 1.74g(10밀리몰)의 디에틸아조디카르복실레이트를 가한 후 실온에서 15분간 반응시킨다. 메탄올 1ml을 가한 후 용매를 증류제거한다. 잔류물에 에테르를 가하여 생성하는 불용물을 여과제거하였다.1.83 g (5 mmol) of (dl)-(cis) -2-hydroxycyclopent-4-enylethanoltriphenylmethylether 1b-a (2R *), 2.62 g (10 mmol) triphenylphosphine and 1.74 g (10 mmol) of diethylazodicarboxylate was added to 1.22 g (10 mmol) of benzoic acid tetrahydrofuran solution under ice-cooling, followed by reaction at room temperature for 15 minutes. After adding 1 ml of methanol, the solvent is distilled off. Ether was added to the residue, and the resulting insolubles were filtered off.

에테르 가용의 생성물을 n-헥산-초산에틸(9:1) 혼액을 용출용매로 하는 실리카겔-컬럼 크로마토그래피에 의해 분리정제함으로써 1.32g(55.6%)의 표제 화합물 1-a(2S*)을 얻었다. 따로 비극성 생성물로서 0.72g(40.9%)의 (dl)-시클로펜트-1,4-디에닐에탄올트리페닐메틸에테르를 얻었다.1.32 g (55.6%) of the title compound 1-a (2S *) was obtained by separation and purification of the ether-soluble product by silica gel-colum chromatography using a mixture of n-hexane-ethyl acetate (9: 1) as an eluting solvent. . Separately, 0.72 g (40.9%) of (dl) -cyclopent-1,4-dienylethanoltriphenylmethyl ether was obtained as a nonpolar product.

NMR : δ(CDCl₃) ; 1.55~1.95(m, 2H), 2.33(d, d, J=12 & 2Hz, 1H), 2.81(d, d, J=12 & 5Hz, 1H), 2.9~3.4(m, 3H), 5.13~5.36(m, 1H), 5.45~5.70(m, 2H), 6.95~8.15(m, 20H) ppm.NMR: δ (CDCl ₃ ); 1.55 to 1.95 (m, 2H), 2.33 (d, d, J = 12 & 2 Hz, 1H), 2.81 (d, d, J = 12 & 5 Hz, 1H), 2.9 to 3.4 (m, 3H), 5.13 to 5.36 (m, 1H), 5.45-5.70 (m, 2H), 6.95-8.15 (m, 20H) ppm.

IR : υmax(CHCl₃) ; 1710cm^-1.IR: ν max (CHCl ₃ ); 1710 cm ^-1 .

[참고예.][Reference example.]

(dl)-(트랜스)-2-히드록시시클로펜트-4-에닐에탄올트리페닐메틸에테르 1b-a(2S*).(dl)-(trans) -2-hydroxycyclopent-4-enylethanoltriphenylmethylether 1b-a (2S *).

1.32g(2.8밀리몰)의 (dl)-(트랜스)-2-벤조일옥시시클로펜트-4-에틸에탄올트리페닐메틸에테르 1-a(2S*) 및 0.85g(5.79밀리몰)의 탄산칼륨을 16ml의 메탄올, 4ml의 물 및 10ml의 테트라히드로푸란 혼액에 용해하고 5시간 가열환류하여 반응시킨다. 냉각시킨 후 생성물을 디클로로메탄으로 추출한다. 디클로로메탄층은 포화 식염수로 세척한 후 무수황산마그네슘으로 건조시키고 용매를 증류제거한다. 잔류물을 벤젠-초산에틸(2:1) 혼액을 용출용매로 하는 실리카겔 컬럼 크로마토그래피에서 분리정제하여 0.98g의 표제 화합물 1b-a(2S*)을 얻었다.16 ml of 1.32 g (2.8 mmol) of (dl)-(trans) -2-benzoyloxycyclopent-4-ethylethanoltriphenylmethylether 1-a (2S *) and 0.85 g (5.79 mmol) of potassium carbonate It is dissolved in methanol, 4 ml of water and 10 ml of tetrahydrofuran mixture and reacted by heating under reflux for 5 hours. After cooling the product is extracted with dichloromethane. The dichloromethane layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue was purified by silica gel column chromatography using a benzene-ethyl acetate (2: 1) mixture as an eluting solvent to obtain 0.98 g of the titled compound 1b-a (2S *).

NMR : δ(CDCl₃) ; 1.83~1.50(m, 3H), 2.06~2.40(m, 1H), 2.47~2.83(m, 2H), 3.05~3.40(m, 2H), 4.0~4.23(m, 1H), 5.43~5.7(m, 2H), 7.10~7.65(m, 15H) ppm.NMR: δ (CDCl ₃ ); 1.83-1.50 (m, 3H), 2.06-2.40 (m, 1H), 2.47-2.83 (m, 2H), 3.05-3.40 (m, 2H), 4.0-4.23 (m, 1H), 5.43-5.7 (m , 2H), 7.10-7.75 (m, 15H) ppm.

IR : υmax(CHCl₃) ; 3450cm^-1.IR: ν max (CHCl ₃ ); 3450 cm ^-1 .

[참고예 6]Reference Example 6

(dl)-(1β,2α,3α,5β)-3-히드록시-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 2a-a(3S*-α).(dl)-(1β, 2α, 3α, 5β) -3-hydroxy-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 2a-a (3S * -α).

초산은 100mg의 열초산용액 80ml에 11.5g(176밀리그램원자)의 아연분말을 가한 후 초산을 제거하고 에테르로 세척함으로써 제조한 아연-은 커플에 60ml의 에테르를 가한다. 교반하 에테르의 완만한 환류가 유지되도록 23.57g(88밀리몰)의 요오드화메틸렌을 가한다. 또다시 1시간 가열한 후 (dl)-(트랜스)-2-히드록시시클로펜트-4-에닐 에탄올트리페닐메틸에테르 1b-a(2S*)8.2g(22밀리몰)의 에테르 10ml 용액을 적가하고, 반응액을 다시 4시간 가열환류에 교반하여 반응시킨다. 반응액을 냉각후 포화 염화암모늄 수용액에 부어 생성물을 초산에틸로 추출한다. 초산에틸층은 포화 식염수로 세척한 후 무수황산마그네슘에서 건조시켜 용매를 증류제거한다.Acetic acid is added to 80 ml of 100 mg thermal acetic acid solution, 11.5 g (176 mg atom) of zinc powder is added, and 60 ml of ether is added to the zinc-silver couple prepared by removing acetic acid and washing with ether. 23.57 g (88 mmol) methylene iodide is added to maintain gentle reflux of the ether under stirring. After another hour of heating, a 10 ml solution of 8.2 g (22 mmol) of (dl)-(trans) -2-hydroxycyclopent-4-enyl ethanoltriphenylmethylether 1b-a (2S *) was added dropwise. The reaction solution is further reacted by stirring at heated reflux for 4 hours. The reaction solution was cooled, poured into a saturated aqueous ammonium chloride solution, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate to distill off the solvent.

잔류물을 n-헥산-초산 에틸(9:1:4:1) 혼액을 용출용매로 하는 실리카겔-컬럼 크로마토그래피에 의해 분리정제함으로써 7.5g(87%)의 표제 화합물 2a-a(3S*-α)을 얻었다.The residue was separated and purified by silica gel-colum chromatography using a mixture of n-hexane-ethyl acetate (9: 1: 4: 1) as an eluting solvent to give 7.5 g (87%) of the title compound 2a-a (3S *- α) was obtained.

NMR : δ(CDCl₃) ; 0.33~0.66(m, 2H), 0.86~1.30(m, 2H), 1.34(s, 3H), 1.43~1.77(m, 3H), 1.81~2.27(m, 2H), 3.28(t, J=6Hz, 2H), 3.95(d, J=6Hz, 1H), 7.2~7.63(m, 15H) ppm.NMR: δ (CDCl ₃ ); 0.33-0.66 (m, 2H), 0.86-1.30 (m, 2H), 1.34 (s, 3H), 1.43-1.77 (m, 3H), 1.81-2.27 (m, 2H), 3.28 (t, J = 6 Hz , 2H), 3.95 (d, J = 6 Hz, 1H), 7.2-77.6 (m, 15H) ppm.

IR : υmax(CHCl₃) ; 3450cm^-1.IR: ν max (CHCl ₃ ); 3450 cm ^-1 .

[참고예 7]Reference Example 7

(dl)-(시스)-2-아세톡시시클로펜트-4-에틸에탄올트리페닐메틸에테르 1-a(2R*).(dl)-(cis) -2-acetoxycyclopent-4-ethylethanoltriphenylmethyl ether 1-a (2R *).

15.3g(41.3밀리몰)의 (dl)-(시스)-2-히드록시시클로펜트-4-에틸에탄올트리페닐메탄에테르 1b-a(2R*)을 60ml의 피리딘에 용해하고 40ml의 무수초산 및 0.1g의 디메틸 아미노피리딘을 가하고 실온에서 2시간 반응시킨다.15.3 g (41.3 mmol) of (dl)-(cis) -2-hydroxycyclopent-4-ethylethanoltriphenylmethaneether 1b-a (2R *) is dissolved in 60 ml of pyridine and 40 ml of acetic anhydride and 0.1 g of dimethyl aminopyridine are added and reacted at room temperature for 2 hours.

용매 및 과잉의 시약을 감압에 의해 증류제거한 후 생성물을 초산에틸로 추출하였다. 초산에틸층은 묽은 황산수소나트륨 수용액, 포화탄산수소나트륨 수용액 및 식염수로 세척한 후 무수황산마그네슘상에서 건조시키고, 용매를 증류제거하였다.The solvent and excess reagent were distilled off under reduced pressure and then the product was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute aqueous sodium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.

잔류물을 n-헥산-초산에틸(9:1) 혼액을 용출용매로 하는 실리카겔-컬럼 크로마토그래피에 의해 정제하여 16.87g(99.0%)의 표제 화합물 1-a(2R*)을 얻었다.The residue was purified by silica gel-colum chromatography with an n-hexane-ethyl acetate (9: 1) mixture as the eluent to afford 16.87 g (99.0%) of the title compound 1-a (2R *).

NMR : δ(CDCl₃) ; 1.5~3.05(m, 5H), 1.9(s, 3H), 3.14(t, J=6Hz, 2H), 5.2~5.45(m, 1H), 5.6(s, 2H), 7.05~7.9(m, 15H) ppm.NMR: δ (CDCl ₃ ); 1.5 ~ 3.05 (m, 5H), 1.9 (s, 3H), 3.14 (t, J = 6Hz, 2H), 5.2 ~ 5.45 (m, 1H), 5.6 (s, 2H), 7.05 ~ 7.9 (m, 15H ) ppm.

IR : υmax(CHCl₃) ; 1720cm^-1.IR: ν max (CHCl ₃ ); 1720 cm ^-1 .

[참고예 8]Reference Example 8

(dl)-(1α,2α,3α,5α)-6,6-디브로모-3-아세톡시-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 2-c(3R*-α).(dl)-(1α, 2α, 3α, 5α) -6,6-dibromo-3-acetoxy-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 2-c (3R * -α).

16.5g(40밀리몰)의 (시스)-2-아세톡시시클로펜트-3-에닐 에탄올트리페닐메틸에테르 1:a(2R*)을 80ml의 디클로로메탄에 용해하여 14ml(160밀리몰)의 브로모포름, 1g의 염화트리에틸벤질암모늄 및 50ml의 40%수산화나트륨 수용액을 가한다. 이 혼합물을 잘 교반하여 50℃에서 20시간 반응시킨다. 냉각후 반응액을 200ml의 디클로로메탄으로 희석하고 불응물을 셀라이트층을 통하여 여과한다. 여액은 물과 포화식염수로 세척한 후 무수황산마그네슘으로 건조시키고, 용매를 증류제거시켰다. 잔류물을 n-헥산-초산에틸(9:1) 혼액을 용출용매로 하는 실리카겔-칼럼 크로마토그래피에 의해 정제하여 19.6g(84%)의 표제 화합물 2-c(3R*-α)을 얻었다.16.5 g (40 mmol) of (cis) -2-acetoxycyclopent-3-enyl ethanoltriphenylmethyl ether 1: a (2R *) is dissolved in 80 ml of dichloromethane to 14 ml (160 mmol) bromoform 1 g of triethylbenzylammonium chloride and 50 ml of 40% aqueous sodium hydroxide solution are added. The mixture is stirred well and reacted at 50 ° C for 20 hours. After cooling, the reaction solution is diluted with 200 ml of dichloromethane and the noncondensate is filtered through a celite bed. The filtrate was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel-colum chromatography with a mixture of n-hexane-ethyl acetate (9: 1) as the eluent to obtain 19.6 g (84%) of the title compound 2-c (3R * -α).

NMR : δ(CDCl₃) ; 1.5~2.55(m, 7H), 1.92(s, 3H), 3.16(t, J=6Hz, 2H), 5.06~5.3(m, 1H), 7.1~7.7(m, 15H) ppm.NMR: δ (CDCl ₃ ); 1.5 to 2.55 (m, 7H), 1.92 (s, 3H), 3.16 (t, J = 6 Hz, 2H), 5.06 to 5.3 (m, 1H), 7.1 to 7.7 (m, 15H) ppm.

IR : υmax(CHCl₃) ; 1735cm^-1.IR: ν max (CHCl ₃ ); 1735 cm ^-1 .

[참고예 9]Reference Example 9

(dl)-(1α,2α,3α,5α)-3-아세톡시-6,6-디메틸-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 2-b(3R*-α).(dl)-(1α, 2α, 3α, 5α) -3-acetoxy-6,6-dimethyl-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 2-b (3R * -α ).

26.3g(216밀리몰)의 티오시안산 제1동의 에테르 250ml의 현탁액을 -50으로부터 -60℃에서 냉각하고 1.4N 메틸리튬의 에테르 용액 283ml(396밀리몰)을 반응온도가 -50℃를 초과하지 않도록 적가한다. 반응액은 30부에 걸쳐서 0℃까지 온도를 올린 후 재차 -20℃에서 냉각하여 11.5g(19밀리몰)의 (dl)-(1α,2α,3α,5α)-3-아세톡시-6,6-디브로모-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 2-c(3R*-α)의 50ml 에테르 용액과 8.56ml(47.5밀리몰)의 헥사메틸포스포릭트리아미드를 가하여 -20℃에서 1시간 반응시킨다.A suspension of 250 ml of 26.3 g (216 mmol) of cupric thiocyanate ether was cooled from −50 to −60 ° C. and 283 ml (396 mmol) of an 1.4 N methyllithium ether solution so that the reaction temperature did not exceed −50 ° C. Add it down. The reaction solution was heated to 0 ° C. over 30 parts and then cooled again at −20 ° C. to 11.5 g (19 mmol) of (dl)-(1α, 2α, 3α, 5α) -3-acetoxy-6,6 -50 ml ether solution of dibromo-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 2-c (3R * -α) and 8.56 ml (47.5 mmol) of hexamethylphosphoric triamide It is added and reacted at -20 ° C for 1 hour.

반응액을 재차 -50℃에서 냉각시킨 후 과량의 요오드화메틸을 가하여 10분간 교반한다. -70℃까지 냉각한 반응액에 염화암모늄 수용액을 가한 후 생성하는 불용물을 셀라이트층을 통하여 여과제거한다. 여과액은 묽은 암모니아 수용액 및 포화 식염수로 세척한 후 무수황산마그네슘에서 건조시키고 용매를 증류제거한다. 얻어진 표제 화합물 2-v(R*α)은 정제하지 않고 다음의 반응에 사용한다.The reaction solution was cooled again at -50 ° C, and excess methyl iodide was added and stirred for 10 minutes. An aqueous ammonium chloride solution was added to the reaction solution cooled to -70 ° C, and the resulting insolubles were filtered off through a celite bed. The filtrate is washed with dilute aqueous ammonia solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The title compound 2-v (R * α) obtained was used in the next reaction without purification.

NMR : δ(CDCl₃) ; 0.93(s, 6H), 0.8~1.4(m, 3H), 1.4~2.2(m, 4H), 1.92(s, 3H), 3.12(t, J=6Hz, 2H), 4.95~5.2 : (m, 1H), 7.05~7.4(m, 15H) ppm.NMR: δ (CDCl ₃ ); 0.93 (s, 6H), 0.8-1.4 (m, 3H), 1.4-2.2 (m, 4H), 1.92 (s, 3H), 3.12 (t, J = 6 Hz, 2H), 4.95-5.2: (m, 1H), 7.05-7.4 (m, 15H) ppm.

IR : υmax(CHCl₃) ; 1725cm^-1.IR: ν max (CHCl ₃ ); 1725 cm ^-1 .

[참고예 10]Reference Example 10

(dl)-(1α,2α,3α,5α)-6,6-디메틸-3-히드록시-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 2a-b(3R*-α)(dl)-(1α, 2α, 3α, 5α) -6,6-dimethyl-3-hydroxy-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 2a-b (3R * -α )

앞서 얻어진 (dl)-(1α,2α,3α,5α)-3-아세톡시-6,6-디메틸-2-트리페닐메톡시에틸비시클로[3,1,0] 헥산 2-b(3R*-α)의 조질 생성물을 메탄올 60ml 및 테트라히드로푸란 60ml의 혼액에 용해하고, 2N 수산화나트륨 수용액 29ml(58밀리몰)을 가하여 3시간 가열 환류한다. 용매를 감압하에 증류제거한 후 생성물을 초산에틸로 추출한다. 초산에틸층은 식염수로 세척한 후 무수황산마그네슘으로 건조시키고, 용매를 증류제거한다. 잔류물을 2% 트리에틸아민을 함유한 n-헥산-초산에틸(5:1) 혼액을 용출용매로 하는 실리카겔-컬럼 크로마토그래피에 의해 정제하여 7.41g(2-c(3R*-α)로부터 95%)의 표제 화합물 2a-b(3R*-α)을 얻는다.(Dl)-(1α, 2α, 3α, 5α) -3-acetoxy-6,6-dimethyl-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 2-b (3R *, obtained previously The crude product of -α) is dissolved in a mixture of 60 ml of methanol and 60 ml of tetrahydrofuran, and 29 ml (58 mmol) of 2N aqueous sodium hydroxide solution are added and heated to reflux for 3 hours. After distilling off the solvent under reduced pressure, the product is extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel-column chromatography using an n-hexane-ethyl acetate (5: 1) mixture containing 2% triethylamine as the eluent to obtain from 7.41 g (2-c (3R * -α)). 95%) of the title compound 2a-b (3R * -α).

NMR : δ(CDCl₃) ; 0.87(s, 3H), 0.93(s, 3H), 0.75~1.1(m, 1H), 1.1~1.4(m, 1H), 1.5~2.1(m, 1H), 2.44(br,s, 1H), 3.0~3.43(m, 2H), 4.12(m, 1H), 7.0~7.8(m, 15H) ppm.NMR: δ (CDCl ₃ ); 0.87 (s, 3H), 0.93 (s, 3H), 0.75 to 1.1 (m, 1H), 1.1 to 1.4 (m, 1H), 1.5 to 2.1 (m, 1H), 2.44 (br, s, 1H), 3.0 to 3.43 (m, 2H), 4.12 (m, 1H), 7.0 to 7.8 (m, 15H) ppm.

IR : υmax(CHCl₃) ; 3420cm^-1.IR: ν max (CHCl ₃ ); 3420cm ^-1 .

[참고예 11]Reference Example 11

(dl)-(1α,2α,5α)-6,6-디메틸-2-트리페닐메톡시에틸비시클로[3,1,0]헥산-3-온 4-b(α).(dl)-(1α, 2α, 5α) -6,6-dimethyl-2-triphenylmethoxyethylbicyclo [3,1,0] hexane-3-one 4-b (α).

0.74ml(8.3밀리몰)의 염화옥시살릴의 디클로로메탄 20ml의 용액을 -78℃에서 냉각하여 디메틸술폭시드 1.2ml(16.9밀리몰)의 디클로로메탄 1ml 용액을 가하고 5분간 교반한다. 이 용액에 2.9g(7.03밀리몰)의 (dl)-(1α,2α,3α,5α)-6,6-디메틸-3-히드록시-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 2a-b(3R*-α)의 디클로로메탄 5ml 용액을 가하고 -60℃에서 20분 반응시킨 후 트리에틸아민 6.86ml(49.2밀리몰)을 가한다. 반응 온도를 서서히 실온까지 올려서 반응시킨 후 생성물을 디클로로메탄으로 추출한다. 디클로로메탄층은 1N염산 수용액, 포화탄산수소나트륨 수용액 및 포화 식염수로 세척한 후 무수황산마그네슘으로 건조시키고 용매를 증류제거한다.A solution of 20 ml of 0.74 ml (8.3 mmol) of dichloromethane of oxysalyl chloride was cooled at -78 ° C, and 1.2 ml (16.9 mmol) of 1 ml of dichloromethane solution of dichloromethane was added and stirred for 5 minutes. To this solution 2.9 g (7.03 mmol) of (dl)-(1α, 2α, 3α, 5α) -6,6-dimethyl-3-hydroxy-2-triphenylmethoxyethylbicyclo [3,1,0 ] 5 ml solution of dichloromethane of hexane 2a-b (3R * -α) was added and reacted at -60 ° C for 20 minutes, followed by 6.86 ml (49.2 mmol) of triethylamine. The reaction temperature is gradually raised to room temperature, followed by reaction, and the product is extracted with dichloromethane. The dichloromethane layer was washed with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off.

잔류물을 n-헥산-초산에틸(2:1) 혼액을 용출용매로하는 실리카겔-컬럼 크로마토그래피에 의해 정제하여 2.86g(99%)의 표제 화합물 4-b(α)을 얻는다.The residue is purified by silica gel-colum chromatography with an n-hexane-ethyl acetate (2: 1) mixture as the eluent to afford 2.86 g (99%) of the title compound 4-b (α).

NMR : δ(CDCl₃) ; 0.82(s, 3H), 1.00(s, 3H), 0.8~1.3(m, 2H), 1.4~2.3(m, 4H), 2.48(d, d, J=20 & 6Hz, 1H), 3.2(t, J=6Hz, 2H), 7.1~7.6(m, 15H) ppm.NMR: δ (CDCl ₃ ); 0.82 (s, 3H), 1.00 (s, 3H), 0.8 ~ 1.3 (m, 2H), 1.4 ~ 2.3 (m, 4H), 2.48 (d, d, J = 20 & 6Hz, 1H), 3.2 (t , J = 6 Hz, 2H), 7.1-7.6 (m, 15H) ppm.

IR : υmax(CHCl₃) ; 1725cm^-1.IR: ν max (CHCl ₃ ); 1725 cm ^-1 .

[참고예 12]Reference Example 12

(dl)-(1β,2α,5β)-6,6-디메틸-2-트리페닐메톡시에틸비시클로[3,1,0]-헥산-3-온 4-b(β).(dl)-(1β, 2α, 5β) -6,6-dimethyl-2-triphenylmethoxyethylbicyclo [3,1,0] -hexan-3-one 4-b (β).

4.5g(11밀리몰)의 (dl)-(1α,2α,5α)-6,6-디메틸-2-트리페닐메톡시에틸비시클로[3,1,0]헥산-3-온 4-b(α) 및 10.86g(96.8밀리몰)의 t-부톡시칼륨을 110ml의 디메틸술폭시드에 용해하여 실온에서 8시간 반응시킨다.4.5 g (11 mmol) of (dl)-(1α, 2α, 5α) -6,6-dimethyl-2-triphenylmethoxyethylbicyclo [3,1,0] hexan-3-one 4-b ( α) and 10.86 g (96.8 mmol) of t-butoxy potassium are dissolved in 110 ml of dimethyl sulfoxide and allowed to react at room temperature for 8 hours.

반응액을 -20℃에서 냉각한 초산 12g(0.2몰)의 디클로로메탄 200ml 용액에 가한 후 생성물을 초산에틸로 추출한다. 초산에틸층은 포화탄산수소나트륨 수용액 및 포화식염수로 세척한 후 무수황산마그네슘으로 건조시키고, 용매를 증류제거한다. 잔류물을 벤젠-초산에틸(9:1) 혼액을 용출용매로 하는 실리카겔-컬럼 크로마토그래피에 의해 정제하여 3.37g(75%)의 표제 화합물 4-b(β)을 얻는다.The reaction solution was added to a 200 ml solution of dichloromethane of 12 g (0.2 mol) of acetic acid cooled at -20 ° C, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue is purified by silica gel-column chromatography using a benzene-ethyl acetate (9: 1) mixture as the eluent to afford 3.37 g (75%) of the title compound 4-b (β).

NMR : δ(CDCl₃) ; 0.80(s, 3H), 0.93(s, 3H), 1.0~1.68(m, 3H), 2.0~2.93(m, 4H), 3.03~3.48(m, 2H), 7.10~7.60(m, 15H) ppm.NMR: δ (CDCl ₃ ); 0.80 (s, 3H), 0.93 (s, 3H), 1.0 to 1.68 (m, 3H), 2.0 to 2.93 (m, 4H), 3.03 to 3.48 (m, 2H), 7.10 to 7.60 (m, 15H) ppm .

IR : υmax(CHCl₃) ; 1725cm^-1.IR: ν max (CHCl ₃ ); 1725 cm ^-1 .

[참고예 13]Reference Example 13

(dl)-(1β,2α,3α,5β)-6,6-디메틸-3-히드록시-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 2a-b(3R*-β).(dl)-(1β, 2α, 3α, 5β) -6,6-dimethyl-3-hydroxy-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 2a-b (3R * -β ).

1.64g(4밀리몰)의 (dl)-(1β,2α,5β)-6,6-디메틸-2-트리페닐메톡시에틸비시클로[3,1,0]-헥산-3-온 4-b(β)의 테트라히드로푸란 164ml 용액에 2.03g(8밀리몰)의 수소화트리(제3급부틸) 알루미늄리튬을 가하여 실온에서 2.5시간 반응시킨다. 물을 가하여 과잉의 시약을 분해시킨 후 생성물을 초산에틸로 추출한다. 초산에틸층은 포화 식염수로 세척한 후 무수황산마그네슘으로 건조시키고 용매를 증류제거한다. 잔류물을 1% 트리에틸아민을 함유한 벤젠을 용출용매로 하는 실리카겔-컬럼 크로마토그래피에 의해 정제하여 988mg(60%)의 표제 화합물 2a-b(3R*-β)을 얻는다.1.64 g (4 mmol) of (dl)-(1β, 2α, 5β) -6,6-dimethyl-2-triphenylmethoxyethylbicyclo [3,1,0] -hexan-3-one 4-b To a 164 ml solution of (β) tetrahydrofuran, 2.03 g (8 mmol) of lithium trihydride (tertiary butyl) aluminum was added and allowed to react at room temperature for 2.5 hours. Water is added to decompose the excess reagents and the product is extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue is purified by silica gel-column chromatography with benzene containing 1% triethylamine as the eluent to afford 988 mg (60%) of the title compound 2a-b (3R * -β).

NMR : δ(CDCl₃) ; 0.77~1.13(m, 2H), 0.88(s, 3H), 1.30(s, 3H), 1.44~1.80(m, 2H), 1.44~1.80(m, 2H), 1.80~2.22(m, 1H), 2.23~2.6(m, 2H), (m, 1H), 3.23~3.52(m, 1H), 4.55(t, J=9Hz, 1H), 7.1~7.6(m, 15H) ppm.NMR: δ (CDCl ₃ ); 0.77 to 1.13 (m, 2H), 0.88 (s, 3H), 1.30 (s, 3H), 1.44 to 1.80 (m, 2H), 1.44 to 1.80 (m, 2H), 1.80 to 2.22 (m, 1H), 2.23 to 2.6 (m, 2H), (m, 1H), 3.23 to 3.52 (m, 1H), 4.55 (t, J = 9 Hz, 1H), 7.1 to 7.6 (m, 15H) ppm.

IR : υmax(CHCl₃) ; 3430cm^-1.IR: ν max (CHCl ₃ ); 3430 cm ^-1 .

[참고예 14]Reference Example 14

(dl)-(1β,2α,3β,5β)-3-아지도-6,6-디메틸-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 6-b(β).(dl)-(1β, 2α, 3β, 5β) -3-azido-6,6-dimethyl-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 6-b (β).

988mg(2.39밀리몰)의 (dl)-(1β,2α,3α,5β)-6,6-디메틸-3-히드록시-2-트리페닐옥시에틸비시클로[3,1,0]헥산 2a-b(3R*-β)의 디클로로메탄 10ml 용액에 빙냉하 0.2ml(2.6밀리몰)의 메탄술포닐클로리드 및 0.43ml(3.12밀리몰)의 트리에틸아민을 가하여 실온에서 30분 반응시킨 후, 생성물을 디클로로메탄으로 추출한다. 디클로로메탄층은 포화 식염수로 세척한 후 용매를 증류제거한다.988 mg (2.39 mmol) of (dl)-(1β, 2α, 3α, 5β) -6,6-dimethyl-3-hydroxy-2-triphenyloxyethylbicyclo [3,1,0] hexane 2a-b 0.2 ml (2.6 mmol) of methanesulfonyl chloride and 0.43 ml (3.12 mmol) of triethylamine were added to a 10 ml solution of (3R * -β) dichloromethane under ice-cooling for 30 minutes at room temperature. Extract with methane. The dichloromethane layer is washed with saturated brine and the solvent is distilled off.

얻어진 (dl)-(1β,2α,3α,5β)-6,6-디메틸-3-메탄술포닐옥시-2-트리페닐옥시에틸비시클로[3,1,0]헥산의 조생성물은 20ml의 디메틸포름아미드에 용해하고 932mg(14.4밀리몰)의 나트륨 아지드를 가한 후 반응액을 75℃에서 7시간 반응시킨다. 냉각후 생성물을 초산에틸로 추출한다. 초산에틸층은 포화 식염수로 세척한 후 무수황산마그네슘에서 건조시키고 용매를 증류제거한다. 잔류물을 1% 트리에틸아민을 함유하는 벤젠-n-헥산 혼액을 용출용매로 하는 실리카겔-컬럼 크로마토그래피에 의해 정제하여 835mg(80%)의 표제 화합물 6-b(β)을 얻는다.The crude product of obtained (dl)-(1β, 2α, 3α, 5β) -6,6-dimethyl-3-methanesulfonyloxy-2-triphenyloxyethylbicyclo [3,1,0] hexane was 20 ml. After dissolving in dimethylformamide and adding 932 mg (14.4 mmol) of sodium azide, the reaction solution was reacted at 75 ° C. for 7 hours. After cooling the product is extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue is purified by silica gel-column chromatography using a benzene-n-hexane mixture containing 1% triethylamine as the eluent to afford 835 mg (80%) of the title compound 6-b (β).

NMR : δ(CDCl₃) ; 0.73~1.2(m, 2H), 0.80(s, 3H), 0.97(s, 3H), 1.4~2.6(m, 5H), 2.98~3.43(m, 3H), 7.1~7.63(m, 15H) ppm.NMR: δ (CDCl ₃ ); 0.73 ~ 1.2 (m, 2H), 0.80 (s, 3H), 0.97 (s, 3H), 1.4 ~ 2.6 (m, 5H), 2.98 ~ 3.43 (m, 3H), 7.1 ~ 7.63 (m, 15H) ppm .

IR : υmax(CHCl₃) ; 2080cm^-1.IR: ν max (CHCl ₃ ); 2080 cm ^-1 .

[참고예 15]Reference Example 15

(dl)-(1β,2α,3β,5β)-3-아미노-6,6-디메틸-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 7-b(3S*-β).(dl)-(1β, 2α, 3β, 5β) -3-amino-6,6-dimethyl-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 7-b (3S * -β) .

앞서 얻어진 830mg(1.9밀리몰)의 (dl)-(1β,2α,3β,5β)-3-아지드-6,6-디메틸-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 6-b(β)을 8ml의 테트라히드로푸란에 용해하여 748mg(2.85밀리몰)의 트리페닐포스핀을 가하여 45℃에서 6시간 반응시킨다.830 mg (1.9 mmol) of (dl)-(1β, 2α, 3β, 5β) -3-azide-6,6-dimethyl-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 6-b (β) is dissolved in 8 ml of tetrahydrofuran, and 748 mg (2.85 mmol) of triphenylphosphine is added thereto and reacted at 45 ° C. for 6 hours.

반응액에 0.8ml의 물을 가하여 45℃에서 다시 2시간 반응시킨 후 생성물을 초산에틸로 추출한다. 초산에틸층은 포화 식염수로 세척한 후 무수황산마그네슘에서 건조시키고 용매를 증류제거한다. 잔류물을 벤젠-초산에틸(1:1) 혼액을 용출용매로 하는 실리카겔-컬럼 크로마토그래피에 의해 정제하여 873mg의 표제 화합물 7-b(3S*-β)을 얻는다. 이 수득된 화합물은 정제하지 않고 후속하는 반응에 사용한다.0.8 ml of water was added to the reaction mixture, and the resultant was reacted at 45 DEG C for 2 hours, and then the product was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue is purified by silica gel-column chromatography using a benzene-ethyl acetate (1: 1) mixture as the eluent to yield 873 mg of the title compound 7-b (3S * -β). This obtained compound is used in the subsequent reaction without purification.

[참고예 16]Reference Example 16

(dl)-(1β,2α,3β,5β)-6,6-디메틸-3-페닐술포닐아미노-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 8-b(3S*-β).(dl)-(1β, 2α, 3β, 5β) -6,6-dimethyl-3-phenylsulfonylamino-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 8-b (3S * -β).

앞서 얻어진 873mg(dl)-(1β,2α,3β,5β)-3-아미노-6,6-디메틸-2-트리페닐옥시에틸비시클로[3,1,0]헥산 7-b(3S*β)의 조정제물을 10ml의 디클로로메탄에 용해하고 빙냉하 0.36ml(2.6밀리몰)의 트리에틸아민 및 0.28ml(2.2밀리몰)의 염화벤젠술포닐을 가한 후 실온에서 15시간 반응시킨다. 재차 반응액을 빙냉하여 묽은 암모니아수를 가하여 과잉의 시약을 분해한 후 생성물을 디클로로메탄으로 추출한다. 디클로로메탄층은 포화식염수로 세척한 후 무수황산마그네슘에서 건조시키고 용매를 증류제거한다. 잔류물을 2% 트리에틸아민을 함유하는 벤젠을 용출용매로 하는 실리카겔-컬럼 크로마토그래피에 의해 정제하여 574mg(6-b(β)에 대해서 55%)의 표제 화합물 8-b(3S*-β)을 얻는다.873 mg (dl)-(1β, 2α, 3β, 5β) -3-amino-6,6-dimethyl-2-triphenyloxyethylbicyclo [3,1,0] hexane 7-b (3S * β obtained previously ) Was dissolved in 10 ml of dichloromethane, and 0.36 ml (2.6 mmol) of triethylamine and 0.28 ml (2.2 mmol) of benzenesulfonyl chloride were added under ice cooling, followed by reaction at room temperature for 15 hours. Again, the reaction solution is ice-cooled, dilute ammonia water is added to decompose the excess reagent, and the product is extracted with dichloromethane. The dichloromethane layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue was purified by silica gel-colum chromatography with benzene containing 2% triethylamine as the eluent to afford 574 mg (55% for 6-b (β)) of the title compound 8-b (3S * -β Get)

NMR : δ(CDCl₃) ; 0.63~1.07(m, 2H), 0.84(s, 3H), 0.89(s, 3H), 1.1~2.4(m, 5H), 2.85~3.4(m, 3H), 4.65(d, J=9Hz), 7.1~7.62(m, 18H), 7.78~7.98(m, 2H) ppm.NMR: δ (CDCl ₃ ); 0.63 to 1.07 (m, 2H), 0.84 (s, 3H), 0.89 (s, 3H), 1.1 to 2.4 (m, 5H), 2.85 to 3.4 (m, 3H), 4.65 (d, J = 9 Hz), 7.1-7.7.6 (m, 18H), 7.78-7.98 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3360, 1320, 1155cm^-1.IR: ν max (CHCl ₃ ); 3360, 1320, 1155 cm ^-1 .

[참고예 17]Reference Example 17

(dl)-(1β,2α,5β)-2-트리페닐메톡시에틸비시클로[3,1,0]헥산-3-온 4-a(β)(dl)-(1β, 2α, 5β) -2-triphenylmethoxyethylbicyclo [3,1,0] hexan-3-one 4-a (β)

5.62g의(dl)-(1β,2α,3α,5β)-3-히드록시-2-트리페닐메톡시에틸비시클로[3,1,0]헤산 2a-a(3R*-β)의 디메틸포름아미드 30ml용액에 빙냉하에서 11.1g(25.5밀리몰)의 피리디늄디클로메이트를 첨가하고 실온에서 3시간 반응시킨다. 반응액을 빙수에 붓고 생성물을 초산에틸로 추출한다. 초산에틸층은 포화식염수로 세척후, 무수황산마그네슘으로 건조시켜서 용매를 증류제거한다. 잔류물을 벤젠-초산에틸(9:1) 혼액을 용출용매로 하는 실리카겔-컬럼 크로마토그래피로서 분리 정제하므로서 3.21g(56.8%)의 표제 화합물 4-a(β)를 얻었다.5.62 g (dl)-(1β, 2α, 3α, 5β) -3-hydroxy-2-triphenylmethoxyethylbicyclo [3,1,0] hesan 2a-a (3R * -β) dimethyl 11.1 g (25.5 mmol) of pyridinium dichloromate is added to a 30 ml solution of formamide under ice-cooling, and reacted at room temperature for 3 hours. The reaction solution is poured into ice water and the product is extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was separated and purified by silica gel-column chromatography using a benzene-ethyl acetate (9: 1) mixture as the eluting solvent to obtain 3.21 g (56.8%) of the title compound 4-a (β).

NMR : δ(CDCl₃) ; -0.35~0.0(m, 1H), 0.45~0.80(m, 1H), 0.9~1.8(m, 3H), 1.95~2.4(m, 2H), 2.47~3.0(m, 2H), 3.0~3.4(m, 2H), 7.1~7.6(m, 15H) ppm.NMR: δ (CDCl ₃ ); -0.35 to 0.0 (m, 1H), 0.45 to 0.80 (m, 1H), 0.9 to 1.8 (m, 3H), 1.95 to 2.4 (m, 2H), 2.47 to 3.0 (m, 2H), 3.0 to 3.4 ( m, 2H), 7.1-7.6 (m, 15H) ppm.

IR : υmax(CHCl₃) ; 1725cm^-1.IR: ν max (CHCl ₃ ); 1725 cm ^-1 .

[참고예 18]Reference Example 18

(dl)-(1β,2α,5β)-3-히드록시이미노-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 5-a(β)(dl)-(1β, 2α, 5β) -3-hydroxyimino-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 5-a (β)

1.11g(16.8밀리몰)의 수산화칼륨이 메탄올 65ml용액에 빙냉하에서 1.17g(16.8밀리몰)의 히드록시아민염산염을 가한다. 이 용액에 3.21g(8.4밀리몰)의 (dl)-(1β,2α,5β)-2-트리페닐메톡시에틸비시클로[3,1,0]헥산-3-온 4-a(β)를 가하고 실온에서 3시간 반응시킨다. 반응액에 물을 가한 후 생성물을 초산에틸로 추출한다. 초산에틸층은 포화식염수로 세척한 다음, 무수황산마그네슘으로 건조시키고, 용매를 증류제거한다. 잔류물을 벤젠-초산에틸(9:1) 혼액을 용출용매로 하는 실리카겔-컬럼 크로마토그래피로서 분리 정제한 후, 벤젠-n-헥산으로 결정화하므로서 3.30g(99%)의 표제 화합물 5-a(β)를 얻는다.1.11 g (16.8 mmol) of potassium hydroxide is added to 65 ml of methanol in 1.17 g (16.8 mmol) of hydroxyamine hydrochloride under ice cooling. To this solution was added 3.21 g (8.4 mmol) of (dl)-(1β, 2α, 5β) -2-triphenylmethoxyethylbicyclo [3,1,0] hexan-3-one 4-a (β). It is added and reacted at room temperature for 3 hours. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was separated and purified by silica gel-column chromatography using a benzene-ethyl acetate (9: 1) mixture as the eluent, and then crystallized with benzene-n-hexane to give 3.30 g (99%) of the title compound 5-a ( β) is obtained.

융점, 58~60℃.Melting point, 58-60 ° C.

NMR : δ(CDCl₃) ; -0.4~0.2(m, 1H), 1.23~1.60(m, 1H), 1.13~1.67(m, 4H), 1.95~2.30(m, 1H), 2.4(d, J=18Hz, 1H), 2.8(d, J=18Hz, 1H), 3.0~3.4(m, 2H), 7.2~7.64(m, 15H), 8.08(s, 1H) ppm.NMR: δ (CDCl ₃ ); -0.4 ~ 0.2 (m, 1H), 1.23 ~ 1.60 (m, 1H), 1.13 ~ 1.67 (m, 4H), 1.95 ~ 2.30 (m, 1H), 2.4 (d, J = 18Hz, 1H), 2.8 ( d, J = 18 Hz, 1H), 3.0 to 3.4 (m, 2H), 7.2 to 7.74 (m, 15H), 8.08 (s, 1H) ppm.

IR : υmax(CHCl₃) ; 3560cm^-1.IR: ν max (CHCl ₃ ); 3560 cm ^-1 .

[참고예 19]Reference Example 19

(dl)-(1β,2α,3β,5β) 및 (1β,2α,3α,5β)-3-벤젠술폰아미드-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 8-a(3S*-β) 및 8-a(3R*-β)(dl)-(1β, 2α, 3β, 5β) and (1β, 2α, 3α, 5β) -3-benzenesulfonamide-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 8-a (3S * -β) and 8-a (3R * -β)

2.91g(7.31밀리몰)의 (dl)-(1β,2α,5β)-3-히드록시이미노-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 5-a(β)의 테트라히드로푸란 20ml용액에 빙냉하에서 1.92g(8.77밀리몰)의 디페닐디술피드 및 3.27ml(13.16밀리몰)의 n-트리부틸포스핀을 가하여 실온에서 1시간 반응시킨다.2.91 g (7.31 mmol) of (dl)-(1β, 2α, 5β) -3-hydroxyimino-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 5-a (β) tetra 1.92 g (8.77 mmol) of diphenyl disulfide and 3.27 ml (13.16 mmol) of n-tributylphosphine were added to a 20 ml solution of hydrofuran under ice-cooling, and reacted at room temperature for 1 hour.

반응액을 -70℃로 냉각시킨 다음 초산 10ml 및 1.65g(26.32밀리몰)의 수소화시아노붕소나트륨을 가하여 -78℃에서 10분 반응시킨 다음 실온까지 서서히 온도를 높힌다. 반응액에 탄산수소나트륨을 가하고 다시 물을 가한 후 생성물을 초산에틸로 추출한다. 초산에틸층은 포화 식염수로 세척한 후 무수황산마그네슘으로 건조시키고, 용매를 증류제거한다. 잔류물은 그대로 30ml의 디클로로메탄에 용해시키고, 빙냉하에서 4.2ml(32.9밀리몰)의 염화벤젠술포닐 및 9.13ml(65.8밀리몰)의 트리에틸아민을 가하고 실온에서 3시간 반응시킨다. 생성물은 초산에틸로서 추출하고, 초산에틸층은 포화 식염수로 세척후 무수황산마그네슘으로 건조시켜서, 용매를 증류제거한다. 잔류물을 벤젠-초산에틸(19:1) 혼액을 용출용매로 하는 실리카겔-컬럼크로마토그래피로서 분리시키므로서 2.18g의 표제 화합물 8-a(3S*-β) 및 8-a(3R*-β)의 혼합물을 얻는다.The reaction solution was cooled to -70 ° C, 10 ml of acetic acid and 1.65 g (26.32 mmol) of sodium cyanoborohydride were added thereto, followed by reaction at -78 ° C for 10 minutes, and then gradually raised to room temperature. Sodium bicarbonate was added to the reaction solution, water was added again, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue is dissolved in 30 ml of dichloromethane as it is, and 4.2 ml (32.9 mmol) of benzenesulfonyl chloride and 9.13 ml (65.8 mmol) triethylamine are added under ice cooling and reacted at room temperature for 3 hours. The product was extracted as ethyl acetate, the ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off. 2.18 g of the title compound 8-a (3S * -β) and 8-a (3R * -β) were separated by silica gel-column chromatography using a benzene-ethyl acetate (19: 1) mixture as the eluent. A mixture of

[참고예 20]Reference Example 20

(dl)-(1β,2α,3β,5β) 및 (1β,2α,3α,5β)-2-히드록시에틸-3-벤젠술폰아미드비시클로[3,1,0]헥산 9-a(3S*-β) 및 9-a(3R*-β)(dl)-(1β, 2α, 3β, 5β) and (1β, 2α, 3α, 5β) -2-hydroxyethyl-3-benzenesulfonamidebicyclo [3,1,0] hexane 9-a (3S * -β) and 9-a (3R * -β)

1.77g(3.38밀리몰)의 (dl)-(1β,2α,3β,5β) 및 (1β,2α,3α,5β)-3-벤젠술폰아미드-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 8-a(3S*-β) 및 8-a(3R*-β)의 혼합물을 50ml의 80%초산(물)에 용해하고 15시간 가열환류하에 반응시킨다. 용매를 증류제거한 후 생성물을 초산에틸로 추출한다. 초산에틸층은 포화탄산수소나트륨 수용액, 다음에 포화식염수로 세척한 후 무수황산마그네슘으로 건조하고 용매를 증류제거하면 (dl)-(1β,2α,3β,5β) 및 (1β,2α,3α,5β)-2-히드록시에틸-3-벤젠술폰아미드비시클로[3,1,0]헥산 및 (dl)-(1β,2α,3β,5β) 및 (1β,2α,3α,5β)-2-아세톡시에틸-3-벤젠술폰아미드비시클로[3,1,0]헥산으로 이루어진 반응 생성물을 얻는다.1.77 g (3.38 mmol) of (dl)-(1β, 2α, 3β, 5β) and (1β, 2α, 3α, 5β) -3-benzenesulfonamide-2-triphenylmethoxyethylbicyclo [3,1 , 0] hexane 8-a (3S * -β) and a mixture of 8-a (3R * -β) are dissolved in 50 ml of 80% acetic acid (water) and reacted under heating and reflux for 15 hours. After distilling off the solvent, the product is extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogen carbonate solution, then saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to remove (dl)-(1β, 2α, 3β, 5β) and (1β, 2α, 3α, 5β) -2-hydroxyethyl-3-benzenesulfonamidebicyclo [3,1,0] hexane and (dl)-(1β, 2α, 3β, 5β) and (1β, 2α, 3α, 5β) -2 A reaction product consisting of acetoxyethyl-3-benzenesulfonamidebicyclo [3,1,0] hexane is obtained.

수득된 화합물은 그대로 716mg의 탄산나트륨의 메탄올 60ml와 물 30ml의 혼액에 용해시켜 5시간 가열 환류하에 반응시킨다. 빙냉후 반응물을 물에 붓고 생성물을 초산에틸로 추출하고, 초산에틸층은 포화 식염수로 세척후 무수황산마그네슘으로 건조시켜, 용매를 증류제거한다. 잔류물을 벤젠-초산에틸(2:1) 혼액을 용출용매로 하는 실리카겔 컬럼 크로마토그래피로 분리시키므로서 표제 화합물인 593mg(63%)의 (dl)-(1β,2α,3β,5β)-2-히드록시에틸-3-벤젠술폰아미드비시클로[3,1,0]헥산-9-a(3S*-β).The obtained compound is dissolved in a mixture of 60 ml of methanol of 716 mg of sodium carbonate and 30 ml of water as it is and reacted under reflux for 5 hours. After cooling with ice, the reaction mixture was poured into water, the product was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was separated by silica gel column chromatography using a mixture of benzene-ethyl acetate (2: 1) as an eluting solvent to give 593 mg (63%) of (dl)-(1β, 2α, 3β, 5β) -2 as the title compound. Hydroxyethyl-3-benzenesulfonamidebicyclo [3,1,0] hexane-9-a (3S * -β).

NMR : δ(CDCl₃) ; -0.14~0.34(m, 2H), 0.94~2.34(m, 8H), 2.54~2.99(m, 1H), 3.69(t, J=6Hz, 2H), 5.39(d, J=8Hz, 1H), 7.29~7.69(m, 3H), 7.77~8.04(m, 2H) ppm.NMR: δ (CDCl ₃ ); -0.14-0.34 (m, 2H), 0.94-2.24 (m, 8H), 2.54-2.99 (m, 1H), 3.69 (t, J = 6 Hz, 2H), 5.39 (d, J = 8 Hz, 1H), 7.29-7.69 (m, 3H), 7.77-8.04 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3650~3100, 3360, 1325, 1160cm^-1.IR: ν max (CHCl ₃ ); 3650 ~ 3100, 3360, 1325, 1160cm ^-1 .

및 154mg(16%)의 (dl)-(1β,2α,3α,5β)-2-히드록시에틸-3-벤젠술폰아미드비시클로[3,1,0]헥산 9-a(3R*-β).And 154 mg (16%) of (dl)-(1β, 2α, 3α, 5β) -2-hydroxyethyl-3-benzenesulfonamidebicyclo [3,1,0] hexane 9-a (3R * -β ).

NMR : δ(CDCl₃) ; -0.98~0.5(m, 2H), 0.94~2.22(m, 8H), 2.3~2.67(m, 1H), 3.44~3.92(m, 3H), 5.08(d, J=8Hz, 1H), 7.32~7.6(m, 3H), 7.67~8.00(m, 2H) ppm.NMR: δ (CDCl ₃ ); -0.98-0.5 (m, 2H), 0.94-2.22 (m, 8H), 2.3-2.67 (m, 1H), 3.44-3.92 (m, 3H), 5.08 (d, J = 8 Hz, 1H), 7.32- 7.6 (m, 3H), 7.67-8.00 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3650~3100, 3360, 1335, 1150cm^-1.IR: ν max (CHCl ₃ ); 3650 ~ 3100, 3360, 1335, 1150cm ^-1 .

을 얻었다.Got.

[참고예 21]Reference Example 21

(dl)-(1β,2α,3β,5β)-2-포르밀메틸-3-벤젠술폰아미드비시클로[3,1,0]헥산 IIa-a(3S*-β)(dl)-(1β, 2α, 3β, 5β) -2-formylmethyl-3-benzenesulfonamidebicyclo [3,1,0] hexane IIa-a (3S * -β)

0.2ml(2.24밀리몰)의 염화옥사릴의 디클로로메탄 10ml용액을 -78℃로 냉각하고 디메틸술폭사이드 0.34ml(4.8밀리몰)을 가하여 5분간 교반한다. 이 용액에 561mg(1.99밀리몰)의 (dl)-(1β,2α,3β,5β)-2-히드록시메틸-3-벤젠술폰아미드비시클로[3,1,0]헥산 9-a(3S*-β)의 디클로로메탄 10ml용액을 가하고, -60℃에서 15분 반응시킨후, 트리에틸아민 3.34ml(24밀리몰)을 가한다. 반응 온도를 서서히 실온까지 올려서 반응시킨 후 생성물을 초산에틸로 추출한다. 초산에틸층은 물, 2N염산 수용액 및 포화 식염수로 세척한 후 무수황산마그네슘으로 건조시키고, 용매를 증류제거한다. 얻어진 표제 화합물 IIa-a(3S*-β)는 정제하지 않고, 다음 반응에 사용한다.A 0.2 ml (2.24 mmol) solution of 10 ml of dichloromethane of oxalyl chloride is cooled to -78 ° C, and 0.34 ml (4.8 mmol) of dimethyl sulfoxide is added and stirred for 5 minutes. To this solution 561 mg (1.99 mmol) of (dl)-(1β, 2α, 3β, 5β) -2-hydroxymethyl-3-benzenesulfonamidebicyclo [3,1,0] hexane 9-a (3S * 10 ml of -β) dichloromethane was added, and reacted at -60 ° C for 15 minutes, followed by addition of 3.34 ml (24 mmol) of triethylamine. The reaction temperature is gradually raised to room temperature, followed by reaction, and the product is extracted with ethyl acetate. The ethyl acetate layer was washed with water, 2N aqueous hydrochloric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The title compound IIa-a (3S * -β) obtained was used in the next reaction without purification.

NMR : δ(CDCl₃) ; -0.13~0.39(m, 2H), 0.98~1.98(m, 5H), 2.08~2.98(m, 3H), 4.78~5.38(br.s, 1H), 7.33~7.65(m, 3H), 7.68~8.01(m, 2H), 9.80(m, 1H) ppm.NMR: δ (CDCl ₃ ); -0.13-0.39 (m, 2H), 0.98-1.98 (m, 5H), 2.08-2.98 (m, 3H), 4.78-5.38 (br.s, 1H), 7.33-7.75 (m, 3H), 7.68- 8.01 (m, 2 H), 9.80 (m, 1 H) ppm.

IR : υmax(CHCl₃) ; 1720, 1340, 1160cm^-1.IR: ν max (CHCl ₃ ); 1720, 1340, 1160cm ^-1 .

[참고예 22]Reference Example 22

(dl)-(1α,2α,5α)-2-트리페닐메톡시에틸비시클로[3,1,0]헥산-3-온-4-a(α)(dl)-(1α, 2α, 5α) -2-triphenylmethoxyethylbicyclo [3,1,0] hexane-3-one-4-a (α)

참고예 17과 같이하여 화합물 4-a(α)를 얻는다.Compound 4-a (α) is obtained in the same manner as in Reference Example 17.

NMR : δ(CDCl₃) ; 0.67~1.0(m, 1H), 1.07~2.09(m, 5H), 2.14~2.37(m, 2H), 2.39~2.77(m, 1H), 3.21(t, J=6Hz, 2H), 7.17~7.67(m, 15H) ppm.NMR: δ (CDCl ₃ ); 0.67 ~ 1.0 (m, 1H), 1.07 ~ 2.09 (m, 5H), 2.14 ~ 2.37 (m, 2H), 2.39 ~ 2.77 (m, 1H), 3.21 (t, J = 6Hz, 2H), 7.17 ~ 7.67 (m, 15 H) ppm.

IR : υmax(CHCl₃) ; 1730cm^-1.IR: ν max (CHCl ₃ ); 1730 cm ^-1 .

[참고예 23]Reference Example 23

참고예 18과 같이하여 하기 화합물을 얻는다.In the same manner as in Reference Example 18, the following compound was obtained.

[1](dl)-(1α,2α,5α)-3-히드록시이미노-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 5-a(α)[1] (dl)-(1α, 2α, 5α) -3-hydroxyimino-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 5-a (α)

NMR : δ(CDCl₃) ; (신 및 안티 혼합물) 0.40~0.77(m, 1H), 0.90~3.40(m, 8H), 3.23(t, J=6Hz, 2H), 7.1~7.7(m, 16H) ppm.NMR: δ (CDCl ₃ ); (Cine and anti-mixture) 0.40 to 0.77 (m, 1H), 0.90 to 3.40 (m, 8H), 3.23 (t, J = 6 Hz, 2H), 7.1 to 7.7 (m, 16H) ppm.

IR : υmax(CHCl₃) ; 3580cm^-1.IR: ν max (CHCl ₃ ); 3580 cm ^-1 .

[2] (dl)-(1α,2α,5α)-6,6-디메틸-3-히드록시이미노-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 5-b(α)[2] (dl)-(1α, 2α, 5α) -6,6-dimethyl-3-hydroxyimino-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 5-b (α)

NMR : δ(CDCl₃) ; (신 및 안티 혼합물) 0.83(s, 3H), 0.93(s, 3H), 0.9~1.4(m, 2H), 1.6~2.1(m, 2H), 2.4~2.8(m, 3H), 3.21(m, 3H), 7.0~7.6(m, 15H), 8.38(br.s, 1H) ppm. 0.83(s, 3H), 0.9(s, 3H), 0.95~2.25(m, 4H), 2.27(d, J=18Hz, 1H), 2.58(d.d, J=18 & 5Hz, 1H), 3.03(m, 1H), 3.2(t, J=6Hz, 2H), 7.0~7.7(m, 16Hz) ppm.NMR: δ (CDCl ₃ ); (Sin and anti-mixture) 0.83 (s, 3H), 0.93 (s, 3H), 0.9 to 1.4 (m, 2H), 1.6 to 2.1 (m, 2H), 2.4 to 2.8 (m, 3H), 3.21 (m , 3H), 7.0-7.6 (m, 15H), 8.38 (br.s, 1H) ppm. 0.83 (s, 3H), 0.9 (s, 3H), 0.95-2.25 (m, 4H), 2.27 (d, J = 18 Hz, 1H), 2.58 (dd, J = 18 & 5 Hz, 1H), 3.03 (m , 1H), 3.2 (t, J = 6 Hz, 2H), 7.0-7.7 (m, 16 Hz) ppm.

IR : υmax(CHCl₃) ; 3490, 3325cm^-1.IR: ν max (CHCl ₃ ); 3490, 3325 cm ^-1 .

[참고예 24]Reference Example 24

참고예 19와 같이하여 하기 화합물을 얻었다.In the same manner as in Reference Example 19, the following compound was obtained.

[1] (dl)-(1α,2α,3β,5α)-3-벤젠술폰아미드-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 8-a(3S*-α)[1] (dl)-(1α, 2α, 3β, 5α) -3-benzenesulfonamide-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 8-a (3S * -α)

NMR : δ(CDCl₃) ; 0.0~0.3(m, 1H), 0.4~0.7(m, 1H), 0.7~2.27(m, 7H), 3.0(t, J=6Hz, 2H), 3.2~3.5(m, 1H), 4.43(d, J=6Hz, 1H), 7.17~7.65(m, 19H), 7.7~7.9(m, 2H) ppm.NMR: δ (CDCl ₃ ); 0.0 to 0.3 (m, 1H), 0.4 to 0.7 (m, 1H), 0.7 to 2.27 (m, 7H), 3.0 (t, J = 6 Hz, 2H), 3.2 to 3.5 (m, 1H), 4.43 (d , J = 6 Hz, 1H), 7.17-7.75 (m, 19H), 7.7-7.9 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3360, 1330, 1160cm^-1.IR: ν max (CHCl ₃ ); 3360, 1330, 1160 cm ^-1 .

[2] (dl)-(1α,2α,3β,5α)-6,6-디메틸-벤젠술폰아미드-2-트리페닐메톡시에틸비시클로[3,1,0]헥산 8-b(3S*-α)[2] (dl)-(1α, 2α, 3β, 5α) -6,6-dimethyl-benzenesulfonamide-2-triphenylmethoxyethylbicyclo [3,1,0] hexane 8-b (3S * -α)

NMR : δ(CDCl₃) ; 0.87(s, 3H), 0.93(s, 3H), 0.6~1.2(m, 5H), 1.2~2.2(m, 5H), 2.9~3.2(m, 2H), 3.2~3.6(m, 1H), 4.98(d, J=8Hz, 1H), 7.1~7.95(m, 18H), 7.7~7.95(m, 2H) ppm.NMR: δ (CDCl ₃ ); 0.87 (s, 3H), 0.93 (s, 3H), 0.6-1.2 (m, 5H), 1.2-2.2 (m, 5H), 2.9-3.2 (m, 2H), 3.2-3.6 (m, 1H), 4.98 (d, J = 8 Hz, 1H), 7.1-7.95 (m, 18H), 7.7-7.95 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3360, 1320, 1160cm^-1.IR: ν max (CHCl ₃ ); 3360, 1320, 1160cm ^-1 .

[참고예 25]Reference Example 25

참고예 20과 같이하여 하기 화합물을 얻는다.In the same manner as in Reference Example 20, the following compound was obtained.

[1] (dl)-(1α,2α,3β,5α)-2-히드록시에틸-3-벤젠술폰아미드비시클로[3,1,0]헥산 9-a(3S*-α)[1] (dl)-(1α, 2α, 3β, 5α) -2-hydroxyethyl-3-benzenesulfonamidebicyclo [3,1,0] hexane 9-a (3S * -α)

NMR : δ(CDCl₃) ; 0.12~0.33(m, 1H), 0.43~0.77(m, 1H), 0.86~2.33(m, 9H), 3.27~3.63(m, 1H), 4.8~5.05(d, J=6Hz, 1H), 7.43~7.67(m, 3H), 7.8~8.0(m, 2H) ppm.NMR: δ (CDCl ₃ ); 0.12-0.33 (m, 1H), 0.43-0.77 (m, 1H), 0.86-2.23 (m, 9H), 3.27-3.63 (m, 1H), 4.8-5.05 (d, J = 6 Hz, 1H), 7.43 ˜7.67 (m, 3H), 7.8-8.0 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3360, 3250, 1330, 1160cm^-1.IR: ν max (CHCl ₃ ); 3360, 3250, 1330, 1160cm ^-1 .

[2] (dl)-(1β,2α,3β,5β)-6,6-디메틸-2-히드록시에틸-3-벤젠술폰아미드비시클로[3,1,0]헥산 9-b(3S*-β)[2] (dl)-(1β, 2α, 3β, 5β) -6,6-dimethyl-2-hydroxyethyl-3-benzenesulfonamidebicyclo [3,1,0] hexane 9-b (3S * -β)

NMR : δ(CDCl₃) ; 0.63~1.3(m, 2H), 0.88(s, 3H), 0.95(s, 3H), 1.3~2.7(m, 6H), 3.0~3.38(m, 1H), 3.68(t, J=6Hz, 2H), 5.33~5.9(m, 1H), 7.32~7.67(m, 3H), 7.79~8.0(m, 2H) ppm.NMR: δ (CDCl ₃ ); 0.63 ~ 1.3 (m, 2H), 0.88 (s, 3H), 0.95 (s, 3H), 1.3 ~ 2.7 (m, 6H), 3.0 ~ 3.38 (m, 1H), 3.68 (t, J = 6Hz, 2H ), 5.33-5.9 (m, 1H), 7.32-7.67 (m, 3H), 7.79-8.0 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3100, 1325, 1155cm^-1.IR: ν max (CHCl ₃ ); 3100, 1325, 1155 cm ^-1 .

[3] (dl)-(1α,2α,3β,5α)-6,6-디메틸-2-히드록시에틸-3-벤젠술폰아미드비시클로[3,1,0]헥산 9-b(3S*-α)[3] (dl)-(1α, 2α, 3β, 5α) -6,6-dimethyl-2-hydroxyethyl-3-benzenesulfonamidebicyclo [3,1,0] hexane 9-b (3S * -α)

NMR : δ(CDCl₃) ; 0.9(s, 3H), 0.94(s, 3H), 0.6~1.3(m, 2H), 1.4~2.15(m, 5H), 2.35(br.s, 1H), 3.43(br.s, 1H), 3.62(t, J=6Hz, 2H), 5.7~6.0(d,J=7Hz, 1H), 7.4~7.7(m, 3H), 7.8~8.1(m, 2H) ppm.NMR: δ (CDCl ₃ ); 0.9 (s, 3H), 0.94 (s, 3H), 0.6-1.3 (m, 2H), 1.4-2.15 (m, 5H), 2.35 (br.s, 1H), 3.43 (br.s, 1H), 3.62 (t, J = 6 Hz, 2H), 5.7-6.0 (d, J = 7 Hz, 1H), 7.4-7.7 (m, 3H), 7.8-8.1 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3500, 3370, 1325, 1165cm^-1.IR: ν max (CHCl ₃ ); 3500, 3370, 1325, 1165cm ^-1 .

[참고예 26]Reference Example 26

참고예 21과 같이하여 하기 화합물을 얻는다.In the same manner as in Reference Example 21, the following compound was obtained.

[1] (dl)-(1β,2α,3α,5β)-2-포르밀메틸-3-벤젠술폰아미드-비시클로[3,1,0]헥산 IIa-a(3R*-β)[1] (dl)-(1β, 2α, 3α, 5β) -2-formylmethyl-3-benzenesulfonamide-bicyclo [3,1,0] hexane IIa-a (3R * -β)

NMR : δ(CDCl₃-CD₃OD) ; -0.1~0.5(m, 2H), 0.80~2.40(m, 7H), 2.9~4.1(m, 1H), 5.17~5.33(d, d, J=7.0 & 3Hz, 0.6H), 5.47~5.3(m, 0.4H), 7.3~7.57(m, 3H), 7.57~7.88(m, 2H) ppm.NMR: δ (CDCl ₃ -CD ₃ OD); -0.1 to 0.5 (m, 2H), 0.80 to 2.40 (m, 7H), 2.9 to 4.1 (m, 1H), 5.17 to 5.33 (d, d, J = 7.0 & 3 Hz, 0.6H), 5.47 to 5.3 ( m, 0.4H), 7.3-7.57 (m, 3H), 7.57-7.88 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3520, 3360, 1155cm^-1.IR: ν max (CHCl ₃ ); 3520, 3360, 1155 cm ^-1 .

[2] (dl)-(1α,2α,3β,5α)-2-포르밀메틸-3-벤젠술폰아미드-비시클로[3,1,0]헥산 IIa-a(3S*-α)[2] (dl)-(1α, 2α, 3β, 5α) -2-formylmethyl-3-benzenesulfonamide-bicyclo [3,1,0] hexane IIa-a (3S * -α)

NMR : δ(CDCl₃) ; 0.27~0.47(m, 1H), 0.53~0.84(m, 1H), 0.87~1.90(m, 3H), 1.95~2.57(m, 4H), 3.23~3.6(m, 1H), 4.85(d, J=6Hz, 1H), 7.4~7.8(m, 3H), 7.89~8.0(m, 2H), 9.68(s, 1H) ppm.NMR: δ (CDCl ₃ ); 0.27-0.47 (m, 1H), 0.53-0.84 (m, 1H), 0.87-1.90 (m, 3H), 1.95-2.57 (m, 4H), 3.23-3.6 (m, 1H), 4.85 (d, J = 6 Hz, 1H), 7.4-7.8 (m, 3H), 7.89-8.0 (m, 2H), 9.68 (s, 1H) ppm.

IR : υmax(CHCl₃) ; 3350, 1715, 1338, 1155cm^-1.IR: ν max (CHCl ₃ ); 3350, 1715, 1338, 1155 cm ^-1 .

[3] (dl)-(1β,2α,3β,5β)-6,6-디메틸-2-포르밀메틸-3-벤젠술폰아미드비시클로[3,1,0]헥산 IIa-b(3S*-β)[3] (dl)-(1β, 2α, 3β, 5β) -6,6-dimethyl-2-formylmethyl-3-benzenesulfonamidebicyclo [3,1,0] hexane IIa-b (3S * -β)

NMR : δ(CDCl₃) ; 0.85~1.2(m, 2H), 0.86(s, 3H), 0.96(s, 3H), 1.2~2.3(m, 3H), 2.53~2.7(m, 2H), 3.05~3.4(m, 1H), 5.25~5.5(m, 1H), 7.47~7.7(m, 3H), 7.8~8.0(m, 2H) ppm.NMR: δ (CDCl ₃ ); 0.85 to 1.2 (m, 2H), 0.86 (s, 3H), 0.96 (s, 3H), 1.2 to 2.3 (m, 3H), 2.53 to 2.7 (m, 2H), 3.05 to 3.4 (m, 1H), 5.25-5.5 (m, 1H), 7.47-7.7 (m, 3H), 7.8-8.0 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3360, 2825, 2725, 1725, 1160cm^-1.IR: ν max (CHCl ₃ ); 3360, 2825, 2725, 1725, 1160cm ^-1 .

[4] (dl)-(1α,2α,3β,5α)-6,6-디메틸-2-포르밀메틸-3-벤젠술폰아미드비시클로[3,1,0]헥산 IIa-b(3S*-α)[4] (dl)-(1α, 2α, 3β, 5α) -6,6-dimethyl-2-formylmethyl-3-benzenesulfonamidebicyclo [3,1,0] hexane IIa-b (3S * -α)

NMR : δ(CDCl₃) ; 0.9(s, 3H), 0.99(s, 3H), 0.55~1.45(m, 3H), 1.7~2.2(m, 2H), 2.4~2.9(m, 2H), 3.2~3.7(m, 1H), 5.67(br.s, 1H), 7.35~7.7(m, 3H), 7.75~8.0(m, 2H), 9.65(s, 1H) ppm.NMR: δ (CDCl ₃ ); 0.9 (s, 3H), 0.99 (s, 3H), 0.55 to 1.45 (m, 3H), 1.7 to 2.2 (m, 2H), 2.4 to 2.9 (m, 2H), 3.2 to 3.7 (m, 1H), 5.67 (br.s, 1 H), 7.35-7.7 (m, 3H), 7.75-8.0 (m, 2H), 9.65 (s, 1H) ppm.

[실시예 1]Example 1

[1] (dl)-(1β,2α,3α,5β)-7-[3-벤젠술폰아미드비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산 Ia-ab(3S*-β)[1] (dl)-(1β, 2α, 3α, 5β) -7- [3-benzenesulfonamidebicyclo [3,1,0] hexane-2-yl]-(5Z) -5-heptenic acid Ia -ab (3S * -β)

60%의 유성 수소화나트륨 430mg(10.8밀리몰)을 10ml의 디메틸술폭시드에 가하여 75℃에서 1.5시간 반응시킨다. 생성된 나트륨 메틸술피닐메티드 용액을 12℃로 유지하고 2.71g(6밀리몰)의 브롬(4-카르복시부틸)-트리페닐포스포늄을 가하고 실온에서 20분간 반응시킨다. 이 용액에 앞서의 (dl)-(1β,2α,3β,5β)-2-포르밀메틸-3-페닐술폰일아미노비시클로[3,1,0]헥산 IIa-a(3S*-β)의 조생성물(1.99밀리몰)의 디메틸술폭시드 10ml용액을 가하고, 실온에서 2시간 반응시킨다. 반응액에 초산에틸 및 물을 가하고, 수층을 2N염산으로 산성화시킨 다음, 생성물을 초산에틸로 추출하고, 초산에틸층은 포화식염수로 세척한후, 무수황산마그네슘으로 건조시키고, 용매를 증류 제거한다. 잔류물을, 벤젠-아세트산에틸(4:1) 혼액을 용출용매로 하는 실리카겔 컬럼 크로마토그래피로서 분리하므로서 634mg(88.6%)의 표제 화합물 Ia-ab(3S*-β)의 조생성물을 얻는다.430 mg (10.8 mmol) of 60% oily sodium hydride are added to 10 ml of dimethyl sulfoxide and reacted at 75 ° C. for 1.5 hours. The resulting sodium methylsulfinylmethide solution was maintained at 12 ° C, and 2.71 g (6 mmol) of bromine (4-carboxybutyl) -triphenylphosphonium was added and allowed to react at room temperature for 20 minutes. (Dl)-(1β, 2α, 3β, 5β) -2-formylmethyl-3-phenylsulfonylaminobicyclo [3,1,0] hexane IIa-a (3S * -β) prior to this solution A crude product (1.99 mmol) of 10 ml of dimethyl sulfoxide solution was added and reacted at room temperature for 2 hours. Ethyl acetate and water were added to the reaction solution, the aqueous layer was acidified with 2N hydrochloric acid, the product was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. . The residue is separated by silica gel column chromatography using a benzene-ethyl acetate (4: 1) mixture as the eluent to afford 634 mg (88.6%) of the title compound Ia-ab (3S * -β).

NMR : δ(CDCl₃) ; -0.07~0.37(m, 2H), 1.00~2.50(m, 13H), 2.60~3.03(m, 1H), 5.0(d, J=9Hz, 1H), 5.20~5.70(m, 2H), 7.47~7.68(m, 3H), 7.83~8.05(m, 2H), 8.00~9.00(br.s, 1H) ppm.NMR: δ (CDCl ₃ ); -0.07 ~ 0.37 (m, 2H), 1.00 ~ 2.50 (m, 13H), 2.60 ~ 3.03 (m, 1H), 5.0 (d, J = 9Hz, 1H), 5.20 ~ 5.70 (m, 2H), 7.47 ~ 7.68 (m, 3H), 7.83-8.05 (m, 2H), 8.00-9.00 (br.s, 1H) ppm.

IR : υmax(CHCl₃) ; 3360, 3250, 1705, 1320, 1155cm^-1.IR: ν max (CHCl ₃ ); 3360, 3250, 1705, 1320, 1155 cm ^-1 .

[2] (dl)-(1β,2α,3β,5β)-7-[3-벤젠술폰아미드비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산메틸에스테르 Ia-aa(3S*-β)[2] (dl)-(1β, 2α, 3β, 5β) -7- [3-benzenesulfonamidebicyclo [3,1,0] hexane-2-yl]-(5Z) -5-heptenate methyl Ester Ia-aa (3S * -β)

634mg(1.76밀리몰)의 (dl)-(1β,2α,3β,5β)-7-[3-벤젠술폰아미드비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산 Ia-ab(3S*-β)의 디클로로메탄 10ml용액에 빙냉하에서 디아조메탄의 에테르 용액을 가한다. 용매를 증류 제거한 후, 생성물을 벤젠아세트산에틸(4:1) 혼액을 용출용매로 하는 실리카겔 컬럼 크로마토그래피에 의해서 정제하여 548mg(IIa-a(3S*-β)에 대해 73.0%)의 표제 화합물 Ia-aa(3S*-β)를 얻는다.634 mg (1.76 mmol) of (dl)-(1β, 2α, 3β, 5β) -7- [3-benzenesulfonamidebicyclo [3,1,0] hexane-2-yl]-(5Z) -5- To a 10 ml solution of dichloromethane of heptenoic acid Ia-ab (3S * -β) is added an ether solution of diazomethane under ice cooling. After distilling off the solvent, the product was purified by silica gel column chromatography using ethyl benzene acetate (4: 1) mixture as the eluting solvent to give 548 mg (73.0% of IIa-a (3S * -β)) as the title compound Ia. -aa (3S * -β) is obtained.

NMR : δ(CDCl₃) ; -0.14~0.3(m, 2H), 0.93~2.36(m, 13H), 2.43~2.96(m, 1H), 3.61(s, 3H), 4.46~4.73(d, J=9Hz, 1H), 5.2~5.3(m, 2H), 7.36~7.6(m, 3H), 7.73-7.93(m, 2H) ppm.NMR: δ (CDCl ₃ ); -0.14-0.3 (m, 2H), 0.93-2.36 (m, 13H), 2.43-2.96 (m, 1H), 3.61 (s, 3H), 4.46-4.73 (d, J = 9 Hz, 1H), 5.2- 5.3 (m, 2H), 7.36-7.6 (m, 3H), 7.73-7.93 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3360, 1725, 1325, 1155cm^-1.IR: ν max (CHCl ₃ ); 3360, 1725, 1325, 1155 cm ^-1 .

[3] (dl)-(1β,2α,3β,5β)-7-[3-벤젠술폰아미드비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산나트륨 Ia-ac(3S*-β)[3] (dl)-(1β, 2α, 3β, 5β) -7- [3-benzenesulfonamidebicyclo [3,1,0] hexane-2-yl]-(5Z) -5-heptanate sodium Ia-ac (3S * -β)

290mg(0.8밀리몰)의(dl)-(1β,2α,3β,5β)-7-[3-벤젠술폰아미드비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산 Ia-ab(3S*-β)를 0.1N의 수산화나트륨용액 8ml에 용해하고, 동결 건조에 의해서 298.8mg의 표제 화합물 Ia-ac(3S*-β)를 얻는다.290 mg (0.8 mmol) of (dl)-(1β, 2α, 3β, 5β) -7- [3-benzenesulfonamidebicyclo [3,1,0] hexane-2-yl]-(5Z) -5- Heptenoic acid Ia-ab (3S * -β) is dissolved in 8 ml of 0.1 N sodium hydroxide solution and freeze-dried to give 298.8 mg of the title compound Ia-ac (3S * -β).

원소분석(C₁₉H₂₄O₄NSNa·1/4H₂O로서)Elemental Analysis (as C ₁₉ H ₂₄ O ₄ NSNa, 1 / 4H ₂ O)

계산치(%) : C ; 58.50, H ; 6.27, N ; 3.59, S ; 8.22, Na ; 5.90.Calculated (%): C; 58.50, H; 6.27, N; 3.59, S; 8.22, Na; 5.90.

실측치(%) : C ; 58.60, H ; 6.33, N ; 3.77, S ; 8.11, Na ; 5.91.Found (%): C; 58.60, H; 6.33, N; 3.77, S; 8.11, Na; 5.91.

실시예 1과 같은 방법으로 실시예 2~5를 행한다. 그 결과를 각각 표 1~4에 표시한다.Examples 2 to 5 are carried out in the same manner as in Example 1. The results are shown in Tables 1 to 4, respectively.

[표 1]TABLE 1

[표 2]TABLE 2

[표 3]TABLE 3

[표 4]TABLE 4

[실시예 I-2]Example I-2

[참고예 27]Reference Example 27

(dl)-(트랜스)-2-아지드시클로펜트-4-에닐에탄올 트리페닐메틸에테르 2(β)(dl)-(trans) -2-azidecyclopent-4-enylethanol triphenylmethyl ether 2 (β)

3.83g(10.6밀리몰) (dl)-(시스)-2-히드록시시클로펜트-4-에닐에탄올 트리페닐메틸에테르 1b-a(2R*) (실시예 I-1의 참고예 3에서 얻음)의 디클로로메탄 50ml용액에 빙점하에서 0.88ml(11.3밀리몰)의 메탄술포닐클로리드 및 1.72ml(12.36밀리몰)의 트리에틸아민을 가하고 빙냉하에서 30분 반응시킨후, 생성물을 디클로로메탄으로 추출한다. 디클로로메탄층은 2N-염산 수용액, 포화탄산수소나트륨 수용액 및 포화식염수로 세척후 용매를 증류 제거한다. 얻어진 (dl)-(시스)-2-메탄술포닐옥시시클로펜트-4-에닐에탄올 트리페닐메틸에테르의 조생성물은 50ml의 디메틸포름아미드 용해하고, 12.05g(185.4밀리몰)의 나트륨아지드를 가한 후, 반응액을 75℃에서 5시간 반응시킨다. 냉각후 반응액에 물을 가한 후 생성물을 초산에틸로서 추출한다. 초산에틸층은 포화식염수로 세척한후, 무수황산마그네슘으로 건조시키고, 용매를 증류 제거한다. 잔류물은, 1% 트리에틸아민을 포함하는 벤젠-초산에틸(9:1) 혼액을 용출 용매로 하는 실리카겔 컬럼크로마토그래피로서 정제하여 3.99g(수율 98%)의 표제 화합물 2(β)를 얻는다.Of 3.83 g (10.6 mmol) (dl)-(cis) -2-hydroxycyclopent-4-enylethanol triphenylmethylether 1b-a (2R *) (obtained in Reference Example 3 of Example I-1) 0.88 ml (11.3 mmol) of methanesulfonyl chloride and 1.72 ml (12.36 mmol) of triethylamine were added to a 50 ml solution of dichloromethane at freezing point, and reacted for 30 minutes under ice-cooling, and then the product was extracted with dichloromethane. The dichloromethane layer is washed with 2N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then the solvent is distilled off. The crude product of the obtained (dl)-(cis) -2-methanesulfonyloxycyclopent-4-enylethanol triphenylmethyl ether was dissolved in 50 ml of dimethylformamide, and 12.05 g (185.4 mmol) of sodium azide was added thereto. After that, the reaction solution is reacted at 75 ° C. for 5 hours. After cooling, water was added to the reaction solution, and the product was extracted as ethyl acetate. The ethyl acetate layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue was purified by silica gel column chromatography using benzene-ethyl acetate (9: 1) mixture containing 1% triethylamine as the elution solvent, to obtain 3.99 g (yield 98%) of the title compound 2 (β). .

NMR : δ(CDCl₃) ; 1.50~1.85(m, 2H), 2.20~3.00(m, 3H), 3.15(t, J=6Hz), 3.50~3.80(m, 1H), 5.59(s, 2H), 7.20~7.60(m, 15H) ppm.NMR: δ (CDCl ₃ ); 1.50 to 1.85 (m, 2H), 2.20 to 3.00 (m, 3H), 3.15 (t, J = 6 Hz), 3.50 to 3.80 (m, 1H), 5.59 (s, 2H), 7.20 to 7.60 (m, 15H ) ppm.

IR : υmax(CHCl₃) ; 2080cm^-1.IR: ν max (CHCl ₃ ); 2080 cm ^-1 .

[참고예 28]Reference Example 28

(dl)-(트랜스)-2-아미노시클로펜트-4-에닐에탄올트리페닐메틸에테르 3(β)(dl)-(trans) -2-aminocyclopent-4-enylethanoltriphenylmethyl ether 3 (β)

앞서 얻어진 3.99g(10.1밀리몰)의 (dl)-(트랜스)-2-아지드시클로펜트-4-에닐에탄올트리페닐메틸에테르 2(β)를 10ml의 테트라히드로푸란에 용해하고 3.54g(13.5밀리몰)의 트리페닐포스핀을 가하여, 실온에서 15시간 반응시킨다. 반응액에 1ml의 물을 가하고 45℃에서 다시 2시간 가열 환류하에 또다시 1시간 반응시킨후, 용매를 증류 제거하고 생성물을 초산에틸로서 추출한다. 초산에틸층은 포화식염수로 세척한후, 무수황산마그네슘으로 건조시키고, 용매를 증류 제거한다. 잔류물을 벤젠-아세트산에틸(4:1) 혼액을 용출 용매로 하는 실리카겔-컬럼 크로마토그래피로서 정제하여 4.67g의 표제 화합물 3(β)를 얻는다. 수득된 화합물은 정제하지 않고 다음 반응에 사용한다.3.99 g (10.1 mmol) of (dl)-(trans) -2-azidecyclopent-4-enylethanoltriphenylmethylether 2 (β) obtained above was dissolved in 10 ml of tetrahydrofuran and 3.54 g (13.5 mmol). Triphenylphosphine) is added and reacted at room temperature for 15 hours. After adding 1 ml of water to the reaction solution and reacting again at 45 DEG C for 2 hours under reflux for 2 hours, the solvent was distilled off and the product was extracted as ethyl acetate. The ethyl acetate layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue is purified by silica gel-column chromatography using a benzene-ethyl acetate (4: 1) mixture as the elution solvent to afford 4.67 g of the title compound 3 (β). The obtained compound is used in the next reaction without purification.

NMR : δ(CDCl₃) ; 1.31(s, 2H), 1.57~1.82(m, 2H), 1.83~2.17(m, 1H), 2.23~2.80(m, 2H), 3.00~3.27(m, 1H), 3.15(t, J=6Hz, 2H), 5.55(s, 2H), 7.03~7.56(m, 15H) ppm.NMR: δ (CDCl ₃ ); 1.31 (s, 2H), 1.57 ~ 1.82 (m, 2H), 1.83 ~ 2.17 (m, 1H), 2.23 ~ 2.80 (m, 2H), 3.00 ~ 3.27 (m, 1H), 3.15 (t, J = 6Hz , 2H), 5.55 (s, 2H), 7.03-7.56 (m, 15H) ppm.

IR : υmax(CHCl₃) ; 2080cm^-1.IR: ν max (CHCl ₃ ); 2080 cm ^-1 .

[참고예 29]Reference Example 29

(dl)-(트랜스)-2-벤젠술폰아미드시클로펜트-4-에닐에탄올 트리페닐메틸에테르 4(β)(dl)-(trans) -2-benzenesulfonamidecyclopent-4-enylethanol triphenylmethyl ether 4 (β)

먼저 얻은 (dl)-(트랜스)-2-아미노시클로펜트-4-에닐에탄올트리페닐메틸에테르 3(β)의 조정제물중 3.6g을 15ml의 디클로로메탄에 용해하고, 빙냉하에서 1.52ml(10.97밀리몰)의 트리에틸아민 및 1.12ml(8.77밀리몰)의 염화 벤젠술포닐을 가한후, 빙냉하에서 30분 반응시킨다. 빙냉하에서 묽은 암모니아수를 가해서 과잉 시약을 분해한후, 생성물을 디클로로메탄으로 추출한다. 디클로로메탄층은 포화식염수로 세척후 무수황산마그네슘으로 건조시키고 용매를 증류 제거한다. 잔류물을, 벤젠-초산에테르(4:1) 혼액을 용출 용매로 하는 실리카겔 컬럼 크로마토그래피로 정제하여 2.16g(2(β)에 대해 수율 55.2%)의 표제 화합물 4(β)를 얻는다.Firstly, 3.6 g of the crude product of (dl)-(trans) -2-aminocyclopent-4-enylethanoltriphenylmethylether 3 (β) was dissolved in 15 ml of dichloromethane, and 1.52 ml (10.97 mmol) under ice-cooling. Triethylamine) and 1.12 ml (8.77 mmol) of benzenesulfonyl chloride are added, followed by reaction for 30 minutes under ice-cooling. Under ice-cooling, dilute ammonia water is added to decompose the excess reagent, and then the product is extracted with dichloromethane. The dichloromethane layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue is purified by silica gel column chromatography using benzene-acetic acid ether (4: 1) mixture as the elution solvent to give 2.16 g (55.2% yield for 2 (β)) of the title compound 4 (β).

NMR : δ(CDCl₃) ; 1.33~1.83(m, 2H), 1.85~2.20(m, 1H), 2.33~2.82(m, 2H), 3.03(t, J-6Hz), 3.32~3.67(m, 1H), 4.76(d, J=8Hz, 1H), 5.49(s, 2H), 7.17~7.57(m, 18Hz), 7.70~7.90(m, 2H) ppm.NMR: δ (CDCl ₃ ); 1.33 to 1.83 (m, 2H), 1.85 to 2.20 (m, 1H), 2.33 to 2.82 (m, 2H), 3.03 (t, J-6 Hz), 3.32 to 3.67 (m, 1H), 4.76 (d, J = 8 Hz, 1H), 5.49 (s, 2H), 7.17-7.57 (m, 18 Hz), 7.70-7.90 (m, 2H) ppm.

IR : νmax(CHCl₃) ; 3360, 1335, 1320, 1155cm^-1.IR: ν max (CHCl ₃ ); 3360, 1335, 1320, 1155 cm ^-1 .

[참고예 30]Reference Example 30

(dl)-(트랜스)-2-벤젠술폰아미드시클로펜트-4-에닐에탄올 5a(β)(dl)-(trans) -2-benzenesulfonamidecyclopent-4-enylethanol 5a (β)

1.37g(2.69밀리몰)의 (dl)-(트랜스)-2-벤젠술폰아미드시클로펜트-4-에닐에탄올트리페닐메틸에테르 4(β)를 5ml의 1N-염산 수용액, 10ml의 테트라히드로푸란 및 10ml의 메탄올 혼액에 용해하고 45℃에서 2시간 반응시킨다. 용매를 증류 제거한후 생성물을 초산에틸로 추출한다. 초산에틸층은 포화탄산수소나트륨 수용액, 이어서 포화식염수로 세척후 무수황산 마그네슘으로 건조시키고, 용매를 증류 제거한다. 잔류물을 벤젠초산에틸(4:1)혼액을 용출 용매로 하는 실리카겔 컬럼 크로마토그래피로 정제하여 2.16g(2(β)에 대해 수율 55.2%)의 표제 화합물 5a(β)를 얻는다.1.37 g (2.69 mmol) of (dl)-(trans) -2-benzenesulfonamidecyclopent-4-enylethanoltriphenylmethylether 4 (β) was dissolved in 5 ml of 1N aqueous hydrochloric acid solution, 10 ml of tetrahydrofuran and 10 ml. It melt | dissolves in the methanol mixed liquid of and makes it react at 45 degreeC for 2 hours. After distilling off the solvent, the product is extracted with ethyl acetate. The ethyl acetate layer is washed with saturated aqueous sodium hydrogen carbonate solution, followed by saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue is purified by silica gel column chromatography using ethyl benzene acetate (4: 1) mixture as the elution solvent to afford 2.16 g (25.2) of yield 55.2% of the title compound 5a (β).

NMR : δ(CDCl₃+CD₃OD) ; 1.40~1.70(m, 2H), 1.90~2.23(m, 1H), 2.30~2.80(m, 2H), 3.50~3.70(m, 1H), 3.60(t, J=6Hz, 2H), 5.59(s, 2H), 7.43~7.67(m, 3H), 7.8~8.0(m, 2H) ppm.NMR: δ (CDCl ₃ + CD ₃ OD); 1.40 to 1.70 (m, 2H), 1.90 to 2.23 (m, 1H), 2.30 to 2.80 (m, 2H), 3.50 to 3.70 (m, 1H), 3.60 (t, J = 6 Hz, 2H), 5.59 (s , 2H), 7.43-77.6 (m, 3H), 7.8-8.0 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3650~3100, 1340, 1320, 1155cm^-1.IR: ν max (CHCl ₃ ); 3650 ~ 3100, 1340, 1320, 1155cm ^-1 .

[참고예 31]Reference Example 31

(dl)-(1α,2α,3β,5α) 및 (1β,2α,3β,5β)-2-히드록시에틸-3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산 6(3S*-α) 및 6(3S*-β)(dl)-(1α, 2α, 3β, 5α) and (1β, 2α, 3β, 5β) -2-hydroxyethyl-3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane 6 (3S * -α) and 6 (3S * -β)

732mg(2.74밀리몰)의 (dl)-(트랜스)-2-벤젠술폰아미드시클로펜트-4-에닐에탄올 5a(β)의 디클로로메탄 10ml용액에 빙냉하 650mg(3.0밀리몰)의 80% 메타클로로와 벤조산을 가해서 0℃에서 15시간 반응시킨다.732 mg (2.74 mmol) of (dl)-(trans) -2-benzenesulfonamidecyclopent-4-enylethanol 5a (β) in a 10 ml solution of dichloromethane under ice-cooling 650 mg (3.0 mmol) of 80% metachloro and benzoic acid It was added and reacted at 0 degreeC for 15 hours.

5% 티오황산나트륨 수용액을 가해서 0℃에서 10시간 교반한후 생성물을 디클로로메탄으로 추출한다. 디클로로메탄층은 포화탄산수소나트륨 수용액 및 포화식염수로 세척후 무수황산마그네슘으로 건조시키고, 용매를 증류 제거한다. 잔류물을 벤젠-초산에틸(1:1) 혼액을 용출 용매로 하는 실리카겔 컬럼 크로마토그래피로서 분리시킴으로서 335mg(수율 43.4%)의 (dl)-(α,2α,3β,5α)-2-히드록시에틸-3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산 6(3S*-α)Aqueous solution of 5% sodium thiosulfate was added thereto, stirred at 0 ° C. for 10 hours, and the product was extracted with dichloromethane. The dichloromethane layer is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue was separated by silica gel column chromatography using a benzene-ethyl acetate (1: 1) mixture as the elution solvent to yield 335 mg (yield 43.4%) of (dl)-(α, 2α, 3β, 5α) -2-hydroxy. Ethyl-3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane 6 (3S * -α)

NMR : δ(CDCl₃) ; 1.00~1.53(m, 2H), 1.62(s, 1H), 1.77~2.06(m, 2H), 2.10~2.43(m, 1H), 3.30~3.80(m, 5H), 5.08(d, J=10Hz, 1H), 7.43~7.63(m. 3H), 7.72~7.95(m, 2H) ppm.NMR: δ (CDCl ₃ ); 1.00 ~ 1.53 (m, 2H), 1.62 (s, 1H), 1.77 ~ 2.06 (m, 2H), 2.10 ~ 2.43 (m, 1H), 3.30 ~ 3.80 (m, 5H), 5.08 (d, J = 10Hz , 1H), 7.43-7.63 (m. 3H), 7.72-7.95 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3100~3650, 1345, 1155cm^-1.IR: ν max (CHCl ₃ ); 3100 ~ 3650, 1345, 1155cm ^-1 .

및 174mg(수율 22.6%) (dl)-(1β,2α,3β,5β)-2-히드록시메틸-3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산 6(3S*-β)를 얻는다.And 174 mg (yield 22.6%) (dl)-(1β, 2α, 3β, 5β) -2-hydroxymethyl-3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane 6 (3S * -β).

NMR : δ(CDCl₃) ; 1.23~2.35(m, 5H), 2.42(broad s, 1H), 2.80~3.20(m, 1H), 3.33~3.48(m, 2H), 3.69(t, J=6Hz, 2H), 5.68(d, J=8Hz, 1H), 7.47~7.63(m, 3H), 7.80~7.95(m, 2H) ppm.NMR: δ (CDCl ₃ ); 1.23 to 2.25 (m, 5H), 2.42 (broad s, 1H), 2.80 to 3.20 (m, 1H), 3.33 to 3.48 (m, 2H), 3.69 (t, J = 6 Hz, 2H), 5.68 (d, J = 8 Hz, 1H), 7.47-7.63 (m, 3H), 7.80-7.95 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3400~3200, 3360, 1320, 1155cm^-1.IR: ν max (CHCl ₃ ); 3400 ~ 3200, 3360, 1320, 1155cm ^-1 .

[참고예 32]Reference Example 32

(dl)-(1α,2α,3β,5α)-2-포르밀메틸-3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산 IIb-a(3S*-α)(dl)-(1α, 2α, 3β, 5α) -2-formylmethyl-3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane IIb-a (3S * -α)

0.105ml(1.2밀리몰)의 염화옥사릴의 디클로로메탄 20ml용액을 -78℃로 냉각하고 디메틸술폭사이드 0.19ml(2.4밀리몰)을 가하여 5분간 교반한다. 이 용액에 271mg(0.96밀리몰)의 (dl)-(1α,2α,3β,5α)-2-히드록시에틸-3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산의 디클로로메탄 5ml용액을 가하고, -60℃에서 15분 반응시킨후, 트리에틸아민 1.67ml(12밀리몰)을 가한다. 반응온도를 서서히 실온까지 올려서 반응시킨후 생성물을 초산에틸로 추출한다. 초산에틸층은 물, 2N염산 수용액 및 포화식염수로 세척후 무수황산 마그네슘으로 건조시키고, 용매를 증류 제거한다. 수득된 표제 화합물 IIb-a(3S*-α) 293mg은 정제하지 않고, 다음 반응에 사용한다.A 0.105 ml (1.2 mmol) solution of 20 ml of dichloromethane of oxalyl chloride is cooled to -78 ° C, and 0.19 ml (2.4 mmol) of dimethyl sulfoxide is added and stirred for 5 minutes. To this solution, 271 mg (0.96 mmol) of dichloro of (dl)-(1α, 2α, 3β, 5α) -2-hydroxyethyl-3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane 5 ml of methane solution was added, and reacted at -60 ° C for 15 minutes, followed by 1.67 ml (12 mmol) of triethylamine. The reaction temperature is gradually raised to room temperature, followed by reaction, and the product is extracted with ethyl acetate. The ethyl acetate layer is washed with water, 2N aqueous hydrochloric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. 293 mg of the title compound IIb-a (3S * -α) obtained was used without purification.

NMR : δ(CDCl₃) ; 1.67~2.17(m, 2H), 2.20~2.67(m, 3H), 3.30~3.63(m, 3H), 4.97~5.35(m, 1H), 7.40~7.67(m, 3H), 9.62(s, 1H) ppm.NMR: δ (CDCl ₃ ); 1.67 ~ 2.17 (m, 2H), 2.20 ~ 2.67 (m, 3H), 3.30 ~ 3.63 (m, 3H), 4.97 ~ 5.35 (m, 1H), 7.40 ~ 7.67 (m, 3H), 9.62 (s, 1H ) ppm.

IR : υmax(CHCl₃) ; 3360, 2820, 2720, 1725, 1345, 1160cm^-1.IR: ν max (CHCl ₃ ); 3360, 2820, 2720, 1725, 1345, 1160cm ^-1 .

[실시예 6]Example 6

① (dl)-(1α,2α,3β,5α)-7-[3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산 Ib-ab(3S*-α)① (dl)-(1α, 2α, 3β, 5α) -7- [3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Tenic acid Ib-ab (3S * -α)

60%의 유성 수소화나트륨 216mg(5.4밀리몰)을 10ml 디메틸술폭시드에 가하고 70℃에서 2.5시간 반응시킨다. 생성된 나트륨 메틸술피닐메티드 용액을 12℃로 유지하고 1.36g(3밀리몰)의 브롬화(4-카르복시부틸)-트리페닐포스포늄을 가하여 실온에서 20분 반응시킨다. 이 용액에 앞서서 (dl)-(1α,2α,3β,5α)-2-포르밀메틸-3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산의 조생성물 293mg의 디메틸술폭시드 3ml용액을 가하고, 실온에서 2시간 반응시킨다. 반응액에 초산에틸 및 물을 가하고, 수층을 2N 염산으로 산성으로 만든 다음, 생성물을 초산에틸로 추출하고, 초산에틸층은 포화식염수로 세척한 다음 무수황산마그네슘으로 건조시켜, 용매를 증류 제거한다. 잔류물을 벤젠-초산에틸(2:1) 혼액을 용출용매로 하는 실리카겔-컬럼 크로마토그래피에 의해서 분리함으로서 153mg(수율 42.0%)의 표제 혼합물 Ib-ab(3S*-α)의 조생성물을 얻는다.216 mg (5.4 mmol) of 60% oily sodium hydride are added to 10 ml dimethyl sulfoxide and reacted at 70 ° C. for 2.5 hours. The resulting sodium methylsulfinylmethide solution was maintained at 12 ° C., and 1.36 g (3 mmol) of brominated (4-carboxybutyl) -triphenylphosphonium was added and allowed to react for 20 minutes at room temperature. Prior to this solution, 293 mg of dimethylsulfoxide as a crude product of (dl)-(1α, 2α, 3β, 5α) -2-formylmethyl-3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane A 3 ml solution of seed was added and reacted at room temperature for 2 hours. Ethyl acetate and water are added to the reaction solution, the aqueous layer is made acidic with 2N hydrochloric acid, the product is extracted with ethyl acetate, the ethyl acetate layer is washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent is distilled off. . The residue was separated by silica gel-column chromatography using a benzene-ethyl acetate (2: 1) mixture as the eluent to yield 153 mg (yield 42.0%) of the title mixture Ib-ab (3S * -α). .

NMR : δ(CDCl₃) ; 1.50~2.20(m, 2H), 2.33(t, J=6Hz, 2H), 3.27~3.63(m, 2H), 4.90~5.60(m, 3H), 7.40~7.65(m, 3H), 7.78~7.97(m, 2H) ppm.NMR: δ (CDCl ₃ ); 1.50-2.20 (m, 2H), 2.33 (t, J = 6 Hz, 2H), 3.27-3.63 (m, 2H), 4.90-5.60 (m, 3H), 7.40-7.57 (m, 3H), 7.78-7.97 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3360, 1705, 1345, 1160cm^-1.IR: ν max (CHCl ₃ ); 3360, 1705, 1345, 1160cm ^-1 .

② (dl)-(1α,2α,3β,5α)-7-[3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산메틸에스테르 Ib-aa(3S*-α)② (dl)-(1α, 2α, 3β, 5α) -7- [3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Tennomethyl Ester Ib-aa (3S * -α)

앞서수득한(dl)-(1α,2α,3β,5α)-7-[3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산 Ib-ab(3S*-α)의 조생성물의 디클로로메탄 5ml용액에 빙냉하에서 디아조메탄의 에테르 용액을 가한다. 용매를 증류 제거한 후, 생성물을 벤젠-아세트산 에틸(2:1) 혼액을 용출 용매로 하는 실리카겔-컬럼 크로마토그래피에 의해서 정제하여 153mg(6(3S*-α) 보다 수율 42.0%)의 표제 화합물 Ib-aa(3S*-α)를 얻는다.Earlier obtained (dl)-(1α, 2α, 3β, 5α) -7- [3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane-2-yl]-(5Z) -5 To an aqueous solution of dichloromethane of a crude product of heptenoic acid Ib-ab (3S * -α) is added an ether solution of diazomethane under ice cooling. After distilling off the solvent, the product was purified by silica gel-colum chromatography using a mixture of benzene-ethyl acetate (2: 1) as the elution solvent to yield 153 mg (42.0% yield over 6 (3S * -α)) of the title compound Ib. -aa (3S * -α) is obtained.

NMR : δ(CDCl₃) ; 1.50~2.16(m, 9H), 2.28(t, J=6Hz, 2H), 3.27~3.60(m, 3H), 3.66(s, 3H), 5.00~5.60(m, 3H), 7.47~7.66(m, 3H), 7.80~7.97(m, 2H) ppm.NMR: δ (CDCl ₃ ); 1.50 to 2.16 (m, 9H), 2.28 (t, J = 6 Hz, 2H), 3.27 to 3.60 (m, 3H), 3.66 (s, 3H), 5.00 to 5.60 (m, 3H), 7.47 to 7.62 (m , 3H), 7.80-7.97 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3350, 1720, 1335, 1155, 1088cm^-1.IR: ν max (CHCl ₃ ); 3350, 1720, 1335, 1155, 1088 cm ^-1 .

③ (dl)-(1α,2α,3β,5α)-7-[3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산나트륨 Ib-ac(3S*-α)③ (dl)-(1α, 2α, 3β, 5α) -7- [3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Sodium Thenate Ib-ac (3S * -α)

67mg(0.18밀리몰)의 (dl)-(1α,2α,3β,5α)-7-[3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산 Ib-ab(3S*-α)을 0.1N의 수산화나트륨용액 8ml에 용해시켜, 동결 건조시킴으로서 69mg의 표제 화합물 Ib-ab(3S*-α)을 얻는다.67 mg (0.18 mmol) of (dl)-(1α, 2α, 3β, 5α) -7- [3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane-2-yl]-(5Z ) -5-heptenic acid Ib-ab (3S * -α) is dissolved in 8 ml of 0.1 N sodium hydroxide solution and lyophilized to give 69 mg of the title compound Ib-ab (3S * -α).

원소분석(C₁₈H₂₂O₄₅NSNa로서)Elemental Analysis (as C ₁₈ H ₂₂ O ₄₅ NSNa)

계산치(%) : C ; 55.80, H ; 5.72, N ; 3.62, S ; 8.28, Na ; 5.93.Calculated (%): C; 55.80, H; 5.72, N; 3.62, S; 8.28, Na; 5.93.

실측치(%) : C ; 55.63, H ; 6.05, N ; 3.72, S ; 8.50, Na ; 5.72.Found (%): C; 55.63, H; 6.05, N; 3.72, S; 8.50, Na; 5.72.

[실시예 7]Example 7

참고예 31에서 얻은 화합물 6(3S*-β)를, 참고예 32 및 실시예 6과 같이해서 반응시켜, 다음 화합물을 얻는다.Compound 6 (3S * -β) obtained in Reference Example 31 was reacted in the same manner as in Reference Example 32 and Example 6 to obtain the following compound.

① (dl)-(1β,2α,3β,5β)-7-[3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산 Ib-ab(3S*-β)① (dl)-(1β, 2α, 3β, 5β) -7- [3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Tenic acid Ib-ab (3S * -β)

NMR : δ(CDCl₃) ; 1.20~2.40(m, 9H), 2.33(t, J=6Hz, 2H), 2.77~3.18(m, 1H), 3.34(s, 2H), 5.25~5.67(m, 3H), 7.40~7.63(m, 3H), 7.77~7.95(m, 2H), 7.60~8.40(m, 1H) ppm.NMR: δ (CDCl ₃ ); 1.20-2.40 (m, 9H), 2.33 (t, J = 6 Hz, 2H), 2.77-3.18 (m, 1H), 3.34 (s, 2H), 5.25-5.67 (m, 3H), 7.40-7.63 (m , 3H), 7.77-7.95 (m, 2H), 7.60-8.40 (m, 1H) ppm.

IR : υmax(CHCl₃) ; 3350, 1705, 1325, 1155cm^-1.IR: ν max (CHCl ₃ ); 3350, 1705, 1325, 1155 cm ^-1 .

② (dl)-(1β,2α,3β,5β)-7-[3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산메틸에스테르 Ib-aa(3S*-β).② (dl)-(1β, 2α, 3β, 5β) -7- [3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Methyl acid ester Ib-aa (3S * -β).

NMR : δ(CDCl₃) ; 1.23~2.45(m, 9H), 2.30(t, J=6Hz, 2H), 2.80~3.23(m, 1H), 3.35(s, 2H), 3.69(s, 3H), 5.10~5.65(m, 3H), 7.43~7.70(m, 3H), 7.80~8.00(m, 2H) ppm.NMR: δ (CDCl ₃ ); 1.23 ~ 2.45 (m, 9H), 2.30 (t, J = 6Hz, 2H), 2.80 ~ 3.23 (m, 1H), 3.35 (s, 2H), 3.69 (s, 3H), 5.10 ~ 5.65 (m, 3H ), 7.43-7.70 (m, 3H), 7.80-8.00 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3360, 1720, 1320, 1155cm^-1.IR: ν max (CHCl ₃ ); 3360, 1720, 1320, 1155 cm ^-1 .

③ (dl)-(1β,2α,3β,5β)-7-[3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산나트륨 Ib-ac(3S*-β).(Dl)-(1β, 2α, 3β, 5β) -7- [3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Sodium tennate Ib-ac (3S * -β).

원소분석(C₁₈H₂₂O₄₅NSNa·1/2H₂O로서)Elemental Analysis (as C ₁₈ H ₂₂ O ₄₅ NSNa 1/2 H ₂ O)

계산치(%) : C ; 54.50, H ; 5.88, N ; 3.53, S ; 8.09, Na ; 5.80.Calculated (%): C; 54.50, H; 5.88, N; 3.53, S; 8.09, Na; 5.80.

실측치(%) : C ; 54.85, H ; 5.91, N ; 3.70, S ; 7.74, Na ; 5.59.Found (%): C; 54.85, H; 5.91, N; 3.70, S; 7.74, Na; 5.59.

상기의 방법을 사용하여, 화합물 Ib-a(2S*)(실시예 I-1의 참고예 5기재의 화합물)로부터, 하기 중간체를 경유해서, 화합물 Ib-a(3R*)을 얻는다.Using the above method, compound Ib-a (3R *) is obtained from compound Ib-a (2S *) (compound of Reference Example 5 of Example I-1) via the following intermediate.

[참고예 33]Reference Example 33

(dl)-(시스)-2-아지드시클로펜트-4-에닐에탄올트리페닐메틸에테르 2(α)(dl)-(cis) -2-azidecyclopent-4-enylethanoltriphenylmethyl ether 2 (α)

NMR : δ(CDCl₃) ; 1.55~2.10(m, 2H), 2.27~3.40(m, 3H), 3.18(t, J=6Hz, 2H), 3.73~4.10(m, 1H), 5.40~5.80(m, 2H), 7.10~7.60(m, 15H) ppm.NMR: δ (CDCl ₃ ); 1.55 ~ 2.10 (m, 2H), 2.27 ~ 3.40 (m, 3H), 3.18 (t, J = 6Hz, 2H), 3.73 ~ 4.10 (m, 1H), 5.40 ~ 5.80 (m, 2H), 7.10 ~ 7.60 (m, 15 H) ppm.

IR : υmax(CHCl₃) ; 2080cm^-1.IR: ν max (CHCl ₃ ); 2080 cm ^-1 .

[참고예 34]Reference Example 34

(dl)-(시스)-3-아미노시클로펜트-4-에닐에탄올트리페닐메틸에테르 3(α)(dl)-(cis) -3-aminocyclopent-4-enylethanoltriphenylmethyl ether 3 (α)

NMR : δ(CDCl₃) ; 1.40~2.00(m, 2H), 2.08~2.20(m, 1H), 2.40~2.85(m, 2H), 3.05~3.35(m, 2H), 3.37~3.70(m, 1H), 5.40~5.80(m, 2H), 7.17~7.63(m, 15H) ppm.NMR: δ (CDCl ₃ ); 1.40 ~ 2.00 (m, 2H), 2.08 ~ 2.20 (m, 1H), 2.40 ~ 2.85 (m, 2H), 3.05 ~ 3.35 (m, 2H), 3.37 ~ 3.70 (m, 1H), 5.40 ~ 5.80 (m , 2H), 7.17-7.63 (m, 15H) ppm.

[참고예 35]Reference Example 35

(dl)-(시스)-3-벤젠술폰아미드시클로펜트-4-에닐에탄올 5a(α)(dl)-(cis) -3-benzenesulfonamidecyclopent-4-enylethanol 5a (α)

NMR : δ(CDCl₃) ; 1.45~1.90(m, 2H), 1.92~2.57(m, 3H), 2.65~3.00(m, 1H), 3.65(t, J=6Hz, 2H), 3.80~4.23(m, 1H), 5.64(s, 2H), 5.97(d, J=9Hz, 1H), 7.43~7.70(m, 3H), 7.85~8.10(m, 2H) ppm.NMR: δ (CDCl ₃ ); 1.45-1.90 (m, 2H), 1.92-2.57 (m, 3H), 2.65-3.00 (m, 1H), 3.65 (t, J = 6 Hz, 2H), 3.80-4.23 (m, 1H), 5.64 (s , 2H), 5.97 (d, J = 9 Hz, 1H), 7.43-77.7 (m, 3H), 7.85-8.10 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3650~3100, 3360, 1325, 1155cm^-1.IR: ν max (CHCl ₃ ); 3650 ~ 3100, 3360, 1325, 1155cm ^-1 .

[참고예 36]Reference Example 36

(dl)-(1β,2α,3β,5β)-2-히드록시에틸-3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산 6(3R*-β)(dl)-(1β, 2α, 3β, 5β) -2-hydroxyethyl-3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane 6 (3R * -β)

NMR : δ(CDCl₃) ; 1.58~2.05(m, 5H), 2.20~2.50(m, 1H), 3.30~3.53(m, 2H), 3.55~3.90(m, 1H), 3.75(s, 3H), 4.92(d, J=11Hz, 1H), 7.40~7.63(m, 3H), 7.83~7.93(m, 2H) ppm.NMR: δ (CDCl ₃ ); 1.58 to 2.05 (m, 5H), 2.20 to 2.50 (m, 1H), 3.30 to 3.53 (m, 2H), 3.55 to 3.90 (m, 1H), 3.75 (s, 3H), 4.92 (d, J = 11 Hz , 1H), 7.40-7.63 (m, 3H), 7.83-7.73 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3650~3100, 3350, 1330, 1150cm^-1.IR: ν max (CHCl ₃ ); 3650 ~ 3100, 3350, 1330, 1150cm ^-1 .

[참고예 37]Reference Example 37

(dl)-(1β,5β)-2-페닐술포닐-3-히드록시-6β,7β-에폭시-2-아자비시클로[3,3,0]옥탄 IIb-a(3R*-α)(dl)-(1β, 5β) -2-phenylsulfonyl-3-hydroxy-6β, 7β-epoxy-2-azabicyclo [3,3,0] octane IIb-a (3R * -α)

NMR : δ(CDCl₃) : 1.5~3.0(m, 3H), 3.2~3.65(m, 2H), 3.65~4.0(m, 1H), 4.5~4.9(m, 1H), 5.4~5.75(m, 1H), 7.3~7.65(m, 3H), 7.75~8.2(m, 2H) ppm.NMR: δ (CDCl ₃ ): 1.5 ~ 3.0 (m, 3H), 3.2 ~ 3.65 (m, 2H), 3.65 ~ 4.0 (m, 1H), 4.5 ~ 4.9 (m, 1H), 5.4 ~ 5.75 (m, 1H), 7.3-7.75 (m, 3H), 7.75-8.2 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3580, 3360, 1350, 1160cm^-1.IR: ν max (CHCl ₃ ); 3580, 3360, 1350, 1160cm ^-1 .

[참고예 38]Reference Example 38

(dl)-(1β,5β)-2-페닐술포닐-3-히드록시-6α,7α-에폭시-2-아자비시클로[3,3,0]옥탄 IIb-a(3R*-β)(dl)-(1β, 5β) -2-phenylsulfonyl-3-hydroxy-6α, 7α-epoxy-2-azabicyclo [3,3,0] octane IIb-a (3R * -β)

NMR : δ(CDCl₃) ; 1.55~2.45(m, 4H), 2.85~3.15(m, 1H), 3.30~3.85(m, 2H), 4.23~4.50(m, 1H), 4.99(d, J=12Hz, 1H), 5.35~5.67(m, 1H), 7.36~7.65(m, 3H), 7.75~8.05(m, 2H) ppm.NMR: δ (CDCl ₃ ); 1.55 to 2.45 (m, 4H), 2.85 to 3.15 (m, 1H), 3.30 to 3.85 (m, 2H), 4.23 to 4.50 (m, 1H), 4.99 (d, J = 12 Hz, 1H), 5.35 to 5.67 (m, 1H), 7.36-7.85 (m, 3H), 7.75-8.05 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3600~3150, 3360, 1325, 1155cm^-1.IR: ν max (CHCl ₃ ); 3600-3150, 3360, 1325, 1155 cm ^-1 .

[참고예 39]Reference Example 39

(dl)-(1α,5α)-2-페닐술포닐-3-히드록시-2-아자비시클로[3,3,0]옥트-6-엔 7(α)(dl)-(1α, 5α) -2-phenylsulfonyl-3-hydroxy-2-azabicyclo [3,3,0] oct-6-ene 7 (α)

0.28ml(3.2밀리몰)의 염화옥자릴의 디클로로에탄 35ml용액을 -78℃로 냉각하고 디메틸술폭사이드 0.45ml(5.7밀리몰)을 가하여 5분간 교반한다. 이 용액에 672mg(2.51밀리몰)의 (dl)-(시스)-3-벤젠술폰아미드시클로펜트-4-에닐에탄올 5a(α)의 디클로로메탄 5ml용액을 가하고, -60℃에서 15분 반응시킨후, 트리에틸아민 4.2ml(30밀리몰)을 가한다. 반응온도를 서서히 실온까지 올려서 반응시킨후 생성물을 초산에틸로 추출한다. 초산에틸층은 물, 2N 염산 수용액 및 포화식염수로 세척후 무수황산마그네슘으로 건조시키고, 용매를 증류 제거한다. 생성물을 벤젠-초산에틸(2:1) 혼액을 용출용액으로 하는 실리카겔-컬럼 크로마토그래피로서 정제하여 456mg(수율 64.0%)의 표제 화합물 7(α)을 얻는다.A 0.28 ml (3.2 mmol) solution of 35 ml of dichloroethane of oxalyl chloride is cooled to -78 ° C, 0.45 ml (5.7 mmol) of dimethyl sulfoxide is added and stirred for 5 minutes. To this solution was added 672 mg (2.51 mmol) of (dl)-(cis) -3-benzenesulfonamidecyclopent-4-enylethanol 5a (a) of 5 ml of dichloromethane and reacted at -60 ° C for 15 minutes. Then, 4.2 ml (30 mmol) of triethylamine are added. The reaction temperature is gradually raised to room temperature, followed by reaction, and the product is extracted with ethyl acetate. The ethyl acetate layer was washed with water, 2N aqueous hydrochloric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The product was purified by silica gel-column chromatography using a mixture of benzene-ethyl acetate (2: 1) as the eluent to yield 456 mg (yield 64.0%) of the title compound 7 (α).

NMR : δ(CDCl₃) ; 1.50~2.20(m, 2H), 2.50~3.00(m, 2H), 3.15~3.65(m, 1H), 4.10~4.45(m, 2H), 5.10~6.40(m, 3H), 7.35~7.70(m, 3H), 7.75~8.05(m, 2H) ppm.NMR: δ (CDCl ₃ ); 1.50 to 2.20 (m, 2H), 2.50 to 3.00 (m, 2H), 3.15 to 3.65 (m, 1H), 4.10 to 4.45 (m, 2H), 5.10 to 6.40 (m, 3H), 7.35 to 7.70 (m) , 3H), 7.75-8.05 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3550, 3200~3450, 1345, 1155cm^-1.IR: ν max (CHCl ₃ ); 3550, 3200 ~ 3450, 1345, 1155cm ^-1 .

[실시예 8]Example 8

① (dl)-(1α,2α,3α,5α)-7-[3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산메틸에스테르 Ib-aa(3R*-α)① (dl)-(1α, 2α, 3α, 5α) -7- [3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Tennomethyl Ester Ib-aa (3R * -α)

NMR : δ(CDCl₃) ; 1.5~1.9(m, 4H), 1.9~2.5(m, 7H), 3.33(s, 2H), 3.45~3.8(m, 1H), 3.67(s, 3H), 4.82(d, J=9Hz, 1H), 5.30~5.56(m, 2H), 7.35~7.65(m, 3H), 7.75~8.0(m, 2H) ppm.NMR: δ (CDCl ₃ ); 1.5 ~ 1.9 (m, 4H), 1.9 ~ 2.5 (m, 7H), 3.33 (s, 2H), 3.45 ~ 3.8 (m, 1H), 3.67 (s, 3H), 4.82 (d, J = 9Hz, 1H ), 5.30-5.56 (m, 2H), 7.35-7.75 (m, 3H), 7.75-8.0 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3375, 1725, 1150, 1095cm^-1.IR: ν max (CHCl ₃ ); 3375, 1725, 1150, 1095 cm ^-1 .

[실시예 9]Example 9

① (dl)-(1β,2α,3α,5β)-7-[3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산 Ib-ab(3R*-β)① (dl)-(1β, 2α, 3α, 5β) -7- [3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Tenic acid Ib-ab (3R * -β)

NMR : δ(CDCl₃) ; 1.50~1.90(m, 4H), 1.93~2.50(m, 7H), 3.41(s, 2H), 3.55~3.90(m, 1H), 4.94(d, J=11Hz, 1H), 5.35~5.57(m, 2H), 7.40~7.63(m, 3H), 7.73~7.97(m, 2H), 8.80~9.60(m, 1H) ppm.NMR: δ (CDCl ₃ ); 1.50 to 1.90 (m, 4H), 1.93 to 2.50 (m, 7H), 3.41 (s, 2H), 3.55 to 3.90 (m, 1H), 4.94 (d, J = 11 Hz, 1H), 5.35 to 5.57 (m , 2H), 7.40-7.63 (m, 3H), 7.73-7.97 (m, 2H), 8.80-9.90 (m, 1H) ppm.

IR : υmax(CHCl₃) ; 3350, 1700, 1340, 1155cm^-1.IR: ν max (CHCl ₃ ); 3350, 1700, 1340, 1155 cm ^-1 .

② (dl)-(1β,2α,3α,5β)-7-[3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산메틸에스테르 Ib-aa(3R*-β)② (dl)-(1β, 2α, 3α, 5β) -7- [3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Tennomethyl Ester Ib-aa (3R * -β)

NMR : δ(CDCl₃) ; 1.50~1.87(m, 4H), 1.92~2.45(m, 7H), 3.39(s, 2H), 3.50~3.87(m, 1H), 3.66(s, 3H), 4.70~4.98(m, 1H), 5.33~5.52(m, 23H), 7.40~7.60(m, 3H), 7.75~7.93(m, 2H) ppm.NMR: δ (CDCl ₃ ); 1.50 to 1.87 (m, 4H), 1.92 to 2.45 (m, 7H), 3.39 (s, 2H), 3.50 to 3.87 (m, 1H), 3.66 (s, 3H), 4.70 to 4.98 (m, 1H), 5.33-5.52 (m, 23H), 7.40-7.70 (m, 3H), 7.75-7.73 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3350, 1720, 1335, 1155cm^-1.IR: ν max (CHCl ₃ ); 3350, 1720, 1335, 1155 cm ^-1 .

③ (dl)-(1β,2α,3α,5β)-7-[3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산나트륨 Ib-ac(3R*-β)(Dl)-(1β, 2α, 3α, 5β) -7- [3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Sodium Thenate Ib-ac (3R * -β)

원소분석(C₁₈H₂₂O₄₅NSNa·1/2H₂O로서)Elemental Analysis (as C ₁₈ H ₂₂ O ₄₅ NSNa 1/2 H ₂ O)

계산치(%) : C ; 54.50, H ; 5.88, N ; 5.53, S ; 8.09, Na ; 5.80.Calculated (%): C; 54.50, H; 5.88, N; 5.53, S; 8.09, Na; 5.80.

실측치(%) : C ; 54.29, H ; 5.87, N ; 3.60, S ; 8.23, Na ; 5.43.Found (%): C; 54.29, H; 5.87, N; 3.60, S; 8.23, Na; 5.43.

[실시예 10]Example 10

(dl)-(1β,2α,3β,5β)-7-[3-벤젠술폰아미드-6-티아비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산메틸에스테르 Ib-ba(3S*-β)(dl)-(1β, 2α, 3β, 5β) -7- [3-benzenesulfonamide-6-thiabicyclo [3,1,0] hexan-2-yl]-(5Z) -5-heptenic acid Methyl Ester Ib-ba (3S * -β)

4.5g(20.6밀리몰)의 티오시안산칼륨의 5ml수용액에서 6.75g의 인산을 얻는다. 에테르 15ml를 가해서 잘 교반한후 에테르층을 분리해냄으로서 티오 시안산의 에테르 용액을 얻는다. 이 용액을 568.5mg(1.5밀리몰)의 (dl)-(1α,2α,3β,5α)-7-[3-벤젠술폰아미드-6-옥사비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산메틸에스테르의 에테르 용액에 빙냉하에서 적하한후, 반응액의 온도를 실온으로 올려, 다시 2시간 반응시킨다. 생성물을 에테르로 추출한다.6.75 g of phosphoric acid are obtained in a 5 ml aqueous solution of 4.5 g (20.6 mmol) of potassium thiocyanate. 15 ml of ether is added, the mixture is stirred well, and the ether layer is separated to obtain an ether solution of thiocyanate. 568.5 mg (1.5 mmol) of (dl)-(1α, 2α, 3β, 5α) -7- [3-benzenesulfonamide-6-oxabicyclo [3,1,0] hexan-2-yl ]-(5Z) -5-heptenic acid methyl ester was dripped under ice-cooling, and then the temperature of the reaction solution was raised to room temperature and reacted again for 2 hours. The product is extracted with ether.

에테르층은 2N-탄산나트륨 수용액 및 포화식염수로 세척후 무수황산마그네슘으로 건조시키고, 용매를 증류 제거함으로서 131mg의 (dl)-7-[1β(또는 2β)-히드록시-2α(또는 -1α)-티오시아노-4β-벤젠술폰아미드시클로펜탄-2α-일]-(5Z)-5-헵텐산메틸에스테르의 혼합물을 얻는다. 얻어진 생성물을 정제하지 않고 10ml의 디클로로메탄에 용해시켜 빙냉하에서 0.128ml(1.65밀리몰)의 염화메탄술포닐 및 0.314ml(2.25밀리몰)의 트리에틸아민을 가하여 빙냉하에서 30분 반응시킨후, 생성물을 디클로로메탄으로 추출한다. 디클로로메탄층은 2N-염산 수용액, 포화 탄산수소나트륨 수용액 및 포화식염수로 세척후 용매를 증류 제거하면 조 생성물로서 145mg의 (dl)-7-[1β(또는 2β)-메탄술포닐옥시-2α(또는 -1α)-티오시아노-4β-벤젠술폰아미드시클로펜탄-2β-일]-(5Z)-5-헵텐산메틸에스테르의 혼합물로 이루어지는 생성물을 얻는다.The ether layer was washed with 2N aqueous sodium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to remove 131 mg of (dl) -7- [1β (or 2β) -hydroxy-2α (or -1α)-. A mixture of thiocyano-4β-benzenesulfonamidecyclopentane-2α-yl]-(5Z) -5-heptenic acid methyl ester is obtained. The obtained product was dissolved in 10 ml of dichloromethane without purification, 0.128 ml (1.65 mmol) of methanesulfonyl chloride and 0.314 ml (2.25 mmol) triethylamine were added under ice cooling, followed by reaction for 30 minutes under ice cooling. Extract with methane. The dichloromethane layer was washed with 2N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine, and then the solvent was distilled off. As a crude product, 145 mg of (dl) -7- [1β (or 2β) -methanesulfonyloxy-2α ( Or -1α) -thiocyano-4β-benzenesulfonamidecyclopentan-2β-yl]-(5Z) -5-heptenic acid methyl ester.

이 생성물은 다시 25ml의 디옥산에 빙냉하에서 15ml의 5% 수산화칼륨의 메탄올 용액을 가한후, 실온에서 다시 12시간 반응시킨 다음 용매를 증류 제거하고, 얻어진 잔류물에 초산에틸과 물을 가해서, 수층을 2N염산으로 산성화시킨 다음 생성물을 초산에틸로 추출한다. 초산에틸층은 2-N염산 수용액 및 포화식염수로 세척후 무수황산마그네슘으로 건조시켜서, 용매를 증류 제거한다. 생성물을 에테르-n-헥산으로부터 결정화하여 444mg의 조질의 (dl)-(1β,2α,3β,5β)-7-[3-벤젠술폰아미드-6-티아비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산 Ib-bb(3S*-β)를 얻는다.This product was further added to 25 ml of dioxane under ice cooling with 15 ml of 5% potassium hydroxide methanol solution, and then reacted again at room temperature for 12 hours. The solvent was distilled off, and ethyl acetate and water were added to the obtained residue. Is acidified with 2N hydrochloric acid, and the product is extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous 2-N hydrochloric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The product was crystallized from ether-n-hexane to yield 444 mg of crude (dl)-(1β, 2α, 3β, 5β) -7- [3-benzenesulfonamide-6-thiabicyclo [3,1,0] hexane 2-yl]-(5Z) -5-heptenic acid Ib-bb (3S * -β).

NMR : δ(CDCl₃) ; 2.50~1.30(m, 1H), 2.90~3.40(m, 3H), 5.20~5.70(m, 3H), 7.37~7.70(m, 3H), 7.60~8.30(m, 1H), 7.76~8.00(m, 2H) ppm.NMR: δ (CDCl ₃ ); 2.50 ~ 1.30 (m, 1H), 2.90 ~ 3.40 (m, 3H), 5.20 ~ 5.70 (m, 3H), 7.37 ~ 7.70 (m, 3H), 7.60 ~ 8.30 (m, 1H), 7.76 ~ 8.00 (m , 2H) ppm.

IR : υmax(CHCl₃) ; 3360, 3350~3100, 1700, 1320, 1155, 1085cm^-1.IR: ν max (CHCl ₃ ); 3360, 3350-3100, 1700, 1320, 1155, 1085 cm ^-1 .

앞서 얻은 생성물중 370mg의 (dl)-(1β,2α,3β,5β)-7-[3-벤젠술폰아미드-6-티아비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산을 5ml의 디클로로메탄에 용해하고, 빙냉하에서 디아조메탄의 에테르용액을 가한다. 용매를 증류 제거해서 얻은 생성물을 벤젠-초산에틸(2:1) 혼액을 용출 용매로 하는 실리카겔-컬럼 크로마토그래피로 정제하여 349mg(Ib-aa(3S*-α)에 대해 88.3%)의 표제 화합물, (dl)-(1β,2α,3β,5β)-7-[3-벤젠술폰아미드-6-티아비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산메틸에스테르 Ib-ba(3S*-β)를 얻는다.370 mg of (dl)-(1β, 2α, 3β, 5β) -7- [3-benzenesulfonamide-6-thiabicyclo [3,1,0] hexane-2-yl]-(5Z in the product obtained previously ) -5-heptenic acid is dissolved in 5 ml of dichloromethane, and ether solution of diazomethane is added under ice-cooling. The product obtained by distilling off the solvent was purified by silica gel-column chromatography using a mixture of benzene-ethyl acetate (2: 1) as an eluting solvent to give 349 mg (88.3% of Ib-aa (3S * -α)) as the title compound. , (dl)-(1β, 2α, 3β, 5β) -7- [3-benzenesulfonamide-6-thiabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Tennomethyl ester Ib-ba (3S * -β) is obtained.

NMR : δ(CDCl₃) ; 1.50~2.50(m, 1H), 3.07~3.46(m, 3H), 3.70(s, 3H), 5.06(d, J=10Hz, 1H), 5.36~5.57(m, 2H), 7.43~7.70(m, 3H), 7.80~7.97(m, 2H) ppm.NMR: δ (CDCl ₃ ); 1.50 to 2.50 (m, 1H), 3.07 to 3.46 (m, 3H), 3.70 (s, 3H), 5.06 (d, J = 10 Hz, 1H), 5.36 to 5.57 (m, 2H), 7.43 to 7.70 (m , 3H), 7.80-7.97 (m, 2H) ppm.

IR : υmax(CHCl₃) ; 3360, 1720, 1325, 1155, 1088cm^-1.IR: ν max (CHCl ₃ ); 3360, 1720, 1325, 1155, 1088 cm ^-1 .

나트륨염 Ib-bc(3S*-β)Sodium Salt Ib-bc (3S * -β)

유리의 카르복실산 Ib-bb(3S*-β)를 실시예 6의 ③과 같은 방법으로 처리하여 나트륨염 Ib-bc(3S*-β)를 얻는다.The free carboxylic acid Ib-bb (3S * -β) is treated in the same manner as in ③ of Example 6 to obtain sodium salt Ib-bc (3S * -β).

원소분석(C₁₈H₂₂NO₄S₂Na·0.4H₂O로서)Elemental Analysis (as C ₁₈ H ₂₂ NO ₄ S ₂ Na.0.4H ₂ O)

계산치(%) : C ; 52.64, H ; 5.60, N ; 3.41, S ; 15.61, Na ; 5.60.Calculated (%): C; 52.64, H; 5.60, N; 3.41, S; 15.61, Na; 5.60.

실측치(%) : C ; 52.83, H ; 5.70, N ; 3.63, S ; 15.25, Na ; 5.52.Found (%): C; 52.83, H; 5.70, N; 3.63, S; 15.25, Na; 5.52.

실시예 10의 방법에 의하여 반응을 실행하여 하기 화합물을 얻는다.The reaction is carried out by the method of Example 10 to obtain the following compound.

[실시예 11]Example 11

① (dl)-(1α,2α,3α,5α)-7-[3-벤젠술폰아미드-6-티아비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산 Ib-bb(3R*-α)① (dl)-(1α, 2α, 3α, 5α) -7- [3-benzenesulfonamide-6-thiabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Tenic acid Ib-bb (3R * -α)

NMR : δ(CDCl₃) ; 1.5~1.9(m, 4H), 1.9~2.6(m, 7H), 3.15(m, 2H), 3.63~4.05(m, 1H), 5.25(d, J=10Hz), 5.25~5.60(m, 2H), 7.4~7.7(m, 3H), 7.8~8.0(m, 3H) ppm.NMR: δ (CDCl ₃ ); 1.5 ~ 1.9 (m, 4H), 1.9 ~ 2.6 (m, 7H), 3.15 (m, 2H), 3.63 ~ 4.05 (m, 1H), 5.25 (d, J = 10Hz), 5.25 ~ 5.60 (m, 2H ), 7.4-7.7 (m, 3H), 7.8-8.0 (m, 3H) ppm.

IR : υmax(CHCl₃) : 3370, 3100~3350, 1700, 1155, 1083cm^-1.IR: ν max (CHCl ₃ ): 3370, 3100-3350, 1700, 1155, 1083 cm ⁻¹ .

② (dl)-(1α,2α,3α,5α)-7-[3-벤젠술폰아미드-6-티아비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산메틸에스테르 Ib-ba(3R*-α)② (dl)-(1α, 2α, 3α, 5α) -7- [3-benzenesulfonamide-6-thiabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Tennic acid methyl ester Ib-ba (3R * -α)

NMR : δ(CDCl₃) ; 1.50~2.50(m, 1H), 3.14(m, 2H), 3.66(s, 3H), 3.73~4.10(m, 1H), 5.14(d, J=10Hz), 5.25~5.65(m, 2H), 7.35~7.63(m, 3H), 7.77~7.97(m, 2H) ppm.NMR: δ (CDCl ₃ ); 1.50 to 2.50 (m, 1H), 3.14 (m, 2H), 3.66 (s, 3H), 3.73 to 4.10 (m, 1H), 5.14 (d, J = 10 Hz), 5.25 to 5.65 (m, 2H), 7.35-7.63 (m, 3H), 7.77-7.97 (m, 2H) ppm.

IRb : υmax(CHCl₃) ; 3370, 1720, 1155, 1088cm^-1.IRb: ν max (CHCl ₃ ); 3370, 1720, 1155, 1088 cm ^-1 .

[실시예 12]Example 12

① (dl)-(1α,2α,3α,5α)-7-[3-벤젠술폰아미드-6-티아비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산메틸에스테르 Ib-ba(3S*-α)① (dl)-(1α, 2α, 3α, 5α) -7- [3-benzenesulfonamide-6-thiabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Tennomethyl Methyl Ester Ib-ba (3S * -α)

NMR : δ(CDCl₃) ; 1.50~2.60(m, 1H), 3.07~3.22(m, 1H), 3.23~3.40(m, 1H), 3.45~3.77(m, 1H), 3.67(s, 3H), 5.00~5.60(m, 3H), 7.43~7.65(m, 3H), 7.77~7.93(m, 2H).NMR: δ (CDCl ₃ ); 1.50-2.60 (m, 1H), 3.07-3.22 (m, 1H), 3.23-3.40 (m, 1H), 3.45-3.77 (m, 1H), 3.67 (s, 3H), 5.00-5.50 (m, 3H ), 7.43-7.75 (m, 3H), 7.77-7.73 (m, 2H).

IR : υmax(CHCl₃) ; 3300, 1723, 1155, 1088cm^-1.IR: ν max (CHCl ₃ ); 3300, 1723, 1155, 1088 cm ^-1 .

② (dl)-(1α,2α,3β,5α)-7-[3-벤젠술폰아미드-6-티아비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산 Ib-bb(3S*-α)② (dl)-(1α, 2α, 3β, 5α) -7- [3-benzenesulfonamide-6-thiabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Tenic acid Ib-bb (3S * -α)

NMR : δ(CDCl₃) ; 1.50~2.60(11H), 3.12(d, J=5Hz, 1H), 3.32(d, d, J=5 & 5Hz, 1H), 3.43~3.74(m, 1H), 5.10~5.65(m, 2H), 7.40~7.63(m, 3H), 7.73~7.92(m, 2H).NMR: δ (CDCl ₃ ); 1.50 to 2.60 (11H), 3.12 (d, J = 5 Hz, 1H), 3.32 (d, d, J = 5 & 5 Hz, 1H), 3.43 to 3.74 (m, 1H), 5.10 to 5.65 (m, 2H) , 7.40-7.63 (m, 3H), 7.73-7.92 (m, 2H).

IR : υmax(CHCl₃) ; 3300, 3200, 2700, 1700, 1155, 1082cm^-1.IR: ν max (CHCl ₃ ); 3300, 3200, 2700, 1700, 1155, 1082 cm ^-1 .

③ (dl)-(1α,2α,3β,5α)-7-[3-벤젠술폰아미드-6-티아비시클로[3,1,0]헥산-2-일]-(5Z)-5-헵텐산나트륨 Ib-bc(3S*-α)(Dl)-(1α, 2α, 3β, 5α) -7- [3-benzenesulfonamide-6-thiabicyclo [3,1,0] hexane-2-yl]-(5Z) -5-hep Sodium Thenate Ib-bc (3S * -α)

원소분석(C₁₈H₂₂NO₄S₂Na·1/4H₂O로서)Elemental Analysis (as C ₁₈ H ₂₂ NO ₄ S ₂ Na · 1 / 4H ₂ O)

계산치(%) : C ; 52.99, H ; 5.56, N ; 3.43, S ; 15.72, Na ; 5.63.Calculated (%): C; 52.99, H; 5.56, N; 3.43, S; 15.72, Na; 5.63.

실측치(%) : C ; 52.62, H ; 5.54, N ; 3.46, S ; 15.38, Na ; 5.91.Found (%): C; 52.62, H; 5.54, N; 3.46, S; 15.38, Na; 5.91.

[실시예 II]Example II

[참고예 1]Reference Example 1

2-아릴-3-히드록시이미노비시클로[2,2,2]옥탄 2의 제조Preparation of 2-aryl-3-hydroxyiminocyclo [2,2,2] octane 2

원료 비시클로[2,2,2]옥탄-2-온옥심 1 3.48g(25밀리몰)을 63ml의 테트라히드로푸란(이하 THF로 약칭함)에 용해시키고, -70℃에서 40ml(60밀리몰)의 n-부틸리튬(1.5몰 헥산 용액)을 직접 첨가한다. 백색 침전이 다량 석출되며, 약 10분간 이 온도에서 교반후, 서서히 실온으로 복귀한다. 실온하에서, 1시간 이내에 백색 침전을 용해시킨후, 2.58ml(30밀리몰)의 브롬화 아릴을 가한다. 약 1시간 정도 교반후, 염화암모늄 수용액에 투입하여, 염석, 에테르 추출을 행한다. 이어서 에테르 추출액을 황산 마그네슘으로 건조시키고(이하, 약칭하여 단지 건조라고 표시함), 용매 증발 제거후, 조질의 백색 결정 2를 얻는다. 이것의 박층크로마토그래피는 목적물 이외의 스팟트를 나타내지 않는다. 수율 : 90%, 이것을 헥산-에테르 혼합용매로서 재결정시키면 융점 : 124~125℃(103℃에서 용해하여 이성화한다)의 순품 2(E, Z혼합물)을 얻는다.3.48 g (25 mmol) of raw material bicyclo [2,2,2] octane-2-one oxime 1 was dissolved in 63 ml of tetrahydrofuran (hereinafter abbreviated as THF), and 40 ml (60 mmol) at -70 ° C. n-butyllithium (1.5 molar hexane solution) is added directly. A large amount of white precipitate precipitates, and after stirring at this temperature for about 10 minutes, gradually returns to room temperature. At room temperature, within 1 hour the white precipitate is dissolved and then 2.58 ml (30 mmol) of aryl bromide are added. After stirring for about 1 hour, the solution is added to an aqueous solution of ammonium chloride, followed by extraction of salt and ether. The ether extract is then dried over magnesium sulfate (hereinafter abbreviated as simply dry) and after evaporation of the solvent, a crude white crystal 2 is obtained. Its thin layer chromatography does not show spots other than the target product. Yield: 90%, when recrystallized with a hexane-ether mixed solvent, a pure product 2 (E, Z mixture) having a melting point of 124 to 125 ° C (dissolved and isomerized at 103 ° C) is obtained.

원소분석치(C₁₁H₁₇NO로서)Elemental Analysis Values (as C ₁₁ H ₁₇ NO)

계산치(%) : C ; 73.70, H ; 9.56, N ; 7.81.Calculated (%): C; 73.70, H; 9.56, N; 7.81.

실험치(%) : C ; 73.64, H ; 9.63, N ; 7.89.Experimental value (%): C; 73.64, H; 9.63, N; 7.89.

NMR : δ(CDCl₃) ; 1.0~3.83(m, 14H), 4.90~5.20(m, 2H), 5.60~6.10(m, 1H) ppm.NMR: δ (CDCl ₃ ); 1.0-3.83 (m, 14H), 4.90-5.20 (m, 2H), 5.60-6.10 (m, 1H) ppm.

IR : υmax(CHCl₃) ; 3590, 3250, 2935, 2860, 1640, 1460, 1440, 1395~1300, 1120, 1090, 990, 915, 850cm^-1.IR: ν max (CHCl ₃ ); 3590, 3250, 2935, 2860, 1640, 1460, 1440, 1395-1300, 1120, 1090, 990, 915, 850 cm ^-1 .

[참고예 2]Reference Example 2

2-아릴-3-아미노비시클로[2,2,2]옥탄 3의 제조Preparation of 2-aryl-3-aminobicyclo [2,2,2] octane 3

얻어진 1.79g(10밀리몰)의 아릴옥심 2를 20ml의 THF에 용해시켜, 836mg의 수소화알루미늄 리튬을 가한후, 4시간 가열 환류시킨다. 반응액에, 빙냉하에서, 함수에테르를 가하여 미반응의 수소화알루미늄 리튬을 실활시킨후, 알루미늄의 침전을 여과 분리하고, 에테르 세척하여, 유기층을 건조시키고, 용매를 감압 증류 제거하면 1.352g의 백색 조결정 3이 얻어진다. 이것을 단리 정제하지 않고 다음의 술폰산아미드로 변환시킨다.The resulting 1.79 g (10 mmol) of aryl oxime 2 was dissolved in 20 ml of THF, and 836 mg of lithium aluminum hydride was added, followed by heating to reflux for 4 hours. To the reaction solution under ice-cooling, hydrous ether was added to inactivate unreacted lithium aluminum hydride, and the precipitate of aluminum was filtered off, washed with ether, dried over an organic layer, and the solvent was distilled off under reduced pressure. Crystal 3 is obtained. This is converted to the following sulfonamide without isolated purification.

[참고예 3]Reference Example 3

2-아릴-3-벤센술폰아미드비시클로[2,2,2]옥탄 4a의 제조Preparation of 2-aryl-3-bensensulfonamidebicyclo [2,2,2] octane 4a

먼저 얻어지는 1.352g(8.2밀리몰)의 3을 15ml의 디클로로메탄에 용해시키고, 교반하여 빙냉하에서, 1.37ml(9.83밀리몰)의 트리에틸아민, 1.25ml(9.80밀리몰)의 염화 벤젠술포닐 순으로 첨가한다. 실온에서 약 1시간 반응후, 빙수에 투입하고, 아세트산에틸로 추출하여, 냉 묽은 염산수, 냉 탄산수소나트륨 수용액, 물에 세척후, 유기층을 건조, 용매 증류 제거하면, 유상물질(일부 결정 석출)을 얻을 수 있다. 이것의 NMR은, 각각 트랜스(δ2.90, t형), 시스체(δ 3.86~4.30, m)의 특징적 흡수를 나타내고, 생성비는 약 (2:1)이다. 이 혼합체를 메르크제로버 실리카겔 컬럼 크로마토그래피를 써서, 얻어지는 결정을 n-헥산에테르 혼합용매로 재결정시키면 850mg의 트랜스에 술폰아미드가 얻어진다. 수율 51.5%, 융점 114~115℃.Firstly, 1.352 g (8.2 mmol) of 3 was dissolved in 15 ml of dichloromethane, stirred and added under ice cooling in order of 1.37 ml (9.83 mmol) of triethylamine and 1.25 ml (9.80 mmol) of benzenesulfonyl chloride. . After the reaction at room temperature for about 1 hour, the mixture is poured into ice water, extracted with ethyl acetate, washed with cold dilute hydrochloric acid, cold aqueous sodium bicarbonate solution and water, and then the organic layer is dried and the solvent is distilled off. ) Can be obtained. This NMR shows characteristic absorption of a trans (δ2.90, t-type) and a sheath body (δ 3.86-4.30, m), respectively, and a production ratio is about (2: 1). The mixture is recrystallized with Mercury Gerber silica gel column chromatography using n-hexane ether mixed solvent to obtain 850 mg of trans sulfonamide. Yield 51.5%, melting point 114-115 degreeC.

원소분석(C₁₇H₂₃NSO₂로서)Elemental Analysis (as C ₁₇ H ₂₃ NSO ₂ )

계산치(%) : C ; 66.85, H ; 7.59, N ; 4.59, S ; 10.50.Calculated (%): C; 66.85, H; 7.59, N; 4.59, S; 10.50.

실험치(%) : C ; 66.84, H ; 7.55, N ; 4.69, S ; 10.50.Experimental value (%): C; 66.84, H; 7.55, N; 4.69, S; 10.50.

IR : υmax(CHCl₃) ; 3390, 2940, 2855, 1640, 1445, 1330, 1160, 1095, 1000, 960, 915cm^-1.IR: ν max (CHCl ₃ ); 3390, 2940, 2855, 1640, 1445, 1330, 1160, 1095, 1000, 960, 915 cm ^-1 .

NMR : δ(CDCl₃) ; 1.0~2.2(m, 12H), 2.90(t형-m, 1H), 4.70~5.10(m, 3H), 5.30~5.80(m, 1H), 7.47~8.06(m, 5H) ppm.NMR: δ (CDCl ₃ ); 1.0 to 2.2 (m, 12H), 2.90 (t-m, 1H), 4.70 to 5.10 (m, 3H), 5.30 to 5.80 (m, 1H), 7.47 to 8.06 (m, 5H) ppm.

[참고예 4]Reference Example 4

(2α,3β)-2-(2,3-에톡시프로필)-3-벤젠술폰아미드비시클로[2,2,2]옥탄 5a 및 (2α,3β)-2-포르밀메틸-3-벤젠술폰아미드비시클로[2,2,2]옥탄 IIc-a의 제조(2α, 3β) -2- (2,3-ethoxypropyl) -3-benzenesulfonamidebicyclo [2,2,2] octane 5a and (2α, 3β) -2-formylmethyl-3-benzene Preparation of Sulfonamide Bicyclo [2,2,2] octane IIc-a

앞서 얻어진 597mg(1.95밀리몰)의 아릴술폰아미드 4a를 6ml의 클로로포름에 용해시켜, 빙냉하에서 516mg(3밀리몰)의 메타클로로과벤조산을 가하고, 실온하에서 수시간 교반 반응시킨다. 이어서, 반응액을 냉아황산수소나트륨 수용액에 투입하고, 초산에틸로 추출하여 유기층을 탄산수소나트륨 수용액, 물로 세척해서 건조하여 용매를 증류 제거하면 에폭시드 5a가 670mg의 유상 조절화합물로서 얻어진다.597 mg (1.95 mmol) of arylsulfonamide 4a obtained above is dissolved in 6 ml of chloroform, 516 mg (3 mmol) of metachloroperbenzoic acid are added under ice cooling, followed by stirring for several hours at room temperature. Subsequently, the reaction solution was poured into cold aqueous sodium hydrogen sulfite solution, extracted with ethyl acetate, the organic layer was washed with aqueous sodium hydrogen carbonate solution and dried with water, and the solvent was distilled off to obtain epoxide 5a as a 670 mg oil phase control compound.

NMR : δ(CDCl₃) ; 1.20~2.00(m, 13H), 2.26~3.10(m, 4H), 5.10~5.35(m, 1H), 7.40~8.00(m, 5H) ppm.NMR: δ (CDCl ₃ ); 1.20-2.00 (m, 13H), 2.26-3.10 (m, 4H), 5.10-5.35 (m, 1H), 7.40-8.00 (m, 5H) ppm.

이어서 얻어지는 625mg(1.95밀리몰)의 에폭시드 5a를 11ml의 디옥산-수(10:3)에 용해시켜, 빙냉하에 827mg(3.9밀리몰)의 과요오드산 HIO₄·2H₂O를 가해서 실온에서 약 3시간 반응시킨다. 반응액, 포화식염수에 투입, 에테르 추출을 하여, 유기층을 건조, 용매를 증류 제거하면 598mg의 조질 알데히드 IIc-a를 얻을 수 있다.Subsequently, 625 mg (1.95 mmol) of epoxide 5a obtained was dissolved in 11 ml of dioxane-water (10: 3), and 827 mg (3.9 mmol) of periodic acid HIO ₄ .2H ₂ O was added under ice-cooling, and the mixture was cooled to about 3 at room temperature. React time. 598 mg of crude aldehyde IIc-a can be obtained by adding the reaction solution, saturated brine and ether extraction to dry the organic layer and distilling off the solvent.

NMR : δ(CDCl₃) ; 1.13~2.00(m, 12H), 2.40(dd, 2H, J=6.0Hz), 2.82(m, 1H), 5.47(d, 1H, J=6.7Hz), 6.40~8.00(m, 5H), 9.57(m, 1H) ppm.NMR: δ (CDCl ₃ ); 1.13 to 2.00 (m, 12H), 2.40 (dd, 2H, J = 6.0 Hz), 2.82 (m, 1H), 5.47 (d, 1H, J = 6.7 Hz), 6.40 to 8.00 (m, 5H), 9.57 (m, 1 H) ppm.

이것을 단리, 정제하지 않고 다음 반응에 이용한다.This is used for the next reaction without isolation and purification.

[실시예 1]Example 1

① 7-[(2α,3β)-3-벤젠술폰아미드비시클로[2,2,2]옥트-2-일]-5-헵텐산메틸에스테르 Ic-aa(2S*-t)의 제조① Preparation of 7-[(2α, 3β) -3-benzenesulfonamidebicyclo [2,2,2] oct-2-yl] -5-heptenic acid methyl ester Ic-aa (2S * -t)

우선, 커플링에 사용하는 윗찌히시약을 코리(Corey)의 방법에 따라 다음과 같이 조정한다. 즉, 2.75g(6.2밀리몰)의 브롬화 5-펜탄산트리페닐포스포늄을 11.7ml의 디메틸술폭시드(이하, DMSO로 약칭한다)에 용해시키고, 질소 대기중에서 수소화나트륨을 가하여 약 70℃에서 약 1시간동안 가열 용해시킨다.First, adjust the reagent used in the coupling according to Corey's method as follows. That is, 2.75 g (6.2 mmol) of brominated 5-pentanoic acid triphenylphosphonium is dissolved in 11.7 ml of dimethyl sulfoxide (hereinafter, abbreviated as DMSO), and sodium hydride is added in a nitrogen atmosphere to about 1 at about 70 ° C. Heat dissolve for hours.

반응액을 약 10℃(고체화하지 않는 정도)로 냉각후, 앞서 얻어진 598mg(1.95밀리몰)의 알데히드 IIc-a의 11ml의 DMSO용액을 적하한다. 반응온도는 약 25~30℃로 상승하여 신속히 반응을 진행시켜 완료한다. 약 1시간정도 실온에서 교반을 계속한 후, 반응액을 포화식염수에 투입하고, 초산에틸로 추출한다. DMSO를 완전히 세척 제거한 후 유기층을 건조하여 용매를 증류제거하면, 유상 조질생성물이 얻어진다. 이것을 THF에 용해시키고 디아조메탄을 써서 에스테르화한 후, 메르크사제 로버 실리카겔 컬럼 크로마토그래피에 의하여 459mg의 순수한 목적 화합물 Ic-aa(2S*-t), 수율 58.2% 및 목적물에 미량의 혼재물을 포함하는 부분(86mg, 10%)을 얻는다. 전자의 NMR, IR은 아래와 같다.After cooling the reaction solution to about 10 ° C. (so as not to solidify), 11 ml of DMSO solution of 598 mg (1.95 mmol) of aldehyde IIc-a obtained above was added dropwise. The reaction temperature is raised to about 25 ~ 30 ℃ to complete the reaction proceeds quickly. After continuing stirring at room temperature for about 1 hour, the reaction solution was poured into saturated brine and extracted with ethyl acetate. After the complete removal of DMSO, the organic layer is dried and the solvent is distilled off to obtain an oily crude product. This was dissolved in THF and esterified with diazomethane and then 459 mg of pure target compound Ic-aa (2S * -t), yield 58.2%, and a trace amount of the mixture by merch rover silica gel column chromatography. Obtain the portion containing (86 mg, 10%). NMR and IR of the former are as follows.

NMR : δ(CDCl₃) ; 1.0~2.10(m, 17-H), 2.27(t, 2H, J=7.5Hz), 2.83(m, 1H), 3.66(s, 3H), 4.93~5.40(m, 3H), 7.40~8.03(m, 5H) ppm.NMR: δ (CDCl ₃ ); 1.0 to 2.10 (m, 17-H), 2.27 (t, 2H, J = 7.5 Hz), 2.83 (m, 1H), 3.66 (s, 3H), 4.93 to 5.50 (m, 3H), 7.40 to 8.03 ( m, 5H) ppm.

IR : υmax(CHCl₃) ; 3370, 2925, 2850, 1720, 1440, 1320, 1150, 1090, 960, 905, 860cm^-1.IR: ν max (CHCl ₃ ); 3370, 2925, 2850, 1720, 1440, 1320, 1150, 1090, 960, 905, 860 cm ^-1 .

② 나트륨염 Ic-ac(2S*-t)의 제조② Preparation of Sodium Salt Ic-ac (2S * -t)

앞서 얻어진 600mg(1.48밀리몰)의 에스테르 Ic-aa(2S*-1)를 7ml의 에탄올에 용해시켜 냉각하에서 2.96ml의 1N-수산화칼륨 수용액을 가한후 실온으로 환원하고 하룻밤 방치하여 반응을 완결시킨다. 이어서 냉수속에 투입, 초산에틸로 세척해서 미반응 원료 등을 제거한 후, 수층부분을 염산 산성으로 만들고, 염석, 초산에틸로 추출한다. 유기층을 수세, 건조후, 고성능 진공펌프로서 용매를 증류제거한다. 이것을 95% 순도(나머지는 용매)로 가정하여 1N수산화나트륨 수용액을 써서 나트륨염으로 만든다. 이것을 동결 건조후 검출시료로 한다.The previously obtained 600 mg (1.48 mmol) of ester Ic-aa (2S * -1) was dissolved in 7 ml of ethanol, 2.96 ml of 1N-potassium hydroxide aqueous solution was added under cooling, then reduced to room temperature and left overnight to complete the reaction. Subsequently, the mixture was poured into cold water, washed with ethyl acetate to remove unreacted raw materials, and the like. The aqueous layer was made acidic with hydrochloric acid, and extracted with salted acid and ethyl acetate. The organic layer is washed with water and dried, and then the solvent is distilled off using a high performance vacuum pump. This is assumed to be 95% pure (the rest of the solvent) to make sodium salt using 1N aqueous sodium hydroxide solution. This is used as a detection sample after freeze drying.

원소분석치(C₂₁H₂₈NSO₄Na·0.2H₂O로서)Elemental analysis value (as C ₂₁ H ₂₈ NSO ₄ Na.0.2H ₂ O)

계산치(%) : C ; 60.47, H ; 6.86, N ; 3.36, S ; 7.69, Na ; 5.51.Calculated (%): C; 60.47, H; 6.86, N; 3.36, S; 7.69, Na; 5.51.

실측치(%) : C ; 60.33, H ; 7.11, N ; 3.33, S ; 7.67, Na ; 60.4.Found (%): C; 60.33, H; 7.11, N; 3.33, S; 7.67, Na; 60.4.

IR : υmax(KBr) ; 3440, 3290, 2950, 2880, 1565, 1450, 1410, 1320~1310, 1160, 1090, 968, 920, 875cm^-1.IR: ν max (KBr); 3440, 3290, 2950, 2880, 1565, 1450, 1410, 1320-1310, 1160, 1090, 968, 920, 875 cm ^-1 .

NMR : δext.TMS(D₂O) ; 1.30~2.47(m, 17H), 2.58(t, 2H, J=7.5Hz), 3.25(m, 1H), 5.40~5.95(m, 2H), 7.80~8.50(m, 5H) ppm.NMR: δ ext. TMS (D ₂ O); 1.30-2.47 (m, 17H), 2.58 (t, 2H, J = 7.5 Hz), 3.25 (m, 1H), 5.40-5.95 (m, 2H), 7.80-8.50 (m, 5H) ppm.

본 발명 화합물은, 트롬복산 A₂수용체에 대하여 강력한 길항제로서 작용하여 트롬복산 A₂에 기인하는 혈소판응집을 현저하게 저해한다. 이로인하여 유용한 항혈전제·항혈관수축제가 될 수 있는 화합물이다. 그 대표적인 화합물에 관하여 in vitro에서의 혈소판 응집억제작용을 아래 실험예로서 표시한다.The compound of the present invention acts as a potent antagonist against the thromboxane A ₂ receptor and significantly inhibits platelet aggregation due to thromboxane A ₂ . This is a compound that can be a useful antithrombotic and antivascular contractile agent. The platelet aggregation inhibitory effect in vitro of the representative compound is shown as the following experimental example.

[시험재료 및 시험방법][Test Materials and Test Methods]

웅성토끼(NIBS-JW, 체중 2.2~2.7kg)의 경동맥으로부터 3.8% 구연산나트륨 0.8ml가 들어있는 프라스틱제 주사기로 혈액 7.2ml, 전량 8ml씩 연속하여 채혈한다. 혈액은 프라스틱제 시험관에 넣어 가볍게 흔들어 혼합후, 20℃, 210g, 10분간 원심분리하여 상청의 다혈소판혈장[PRP(Platelet rich plasma)]을 채취한다. 그리고 나머지 혈액을 20℃, 3000rpm(약 1900g), 10분간 원심분리하여 빈혈소판혈장[PPP : (Platelet poor plasma)]를 얻는다.From the carotid artery of male rabbit (NIBS-JW, body weight 2.2-2.7kg) with a plastic syringe containing 0.8ml of 3.8% sodium citrate, 7.2ml of blood and 8ml of whole blood are collected continuously. The blood is mixed in a plastic test tube, shaken lightly, mixed, and centrifuged at 20 ° C., 210 g for 10 minutes to collect supernatant multi-platelet plasma [PRP (Platelet rich plasma)]. And the remaining blood is centrifuged for 10 minutes at 20 ℃, 3000rpm (about 1900g), to obtain anemia platelet plasma [PPP: (Platelet poor plasma)].

PRP의 혈소판수는 50~55×10⁴/㎕이 되도록 PPP로 희석 조정하여 응집측정에 사용하였다.Platelet count of PRP was adjusted to dilution with PPP to 50 ~ 55 × 10 ⁴ / 사용 was used for the aggregation measurement.

혈소판 응집반응은 본의 방법[Born, G.V.R., 네이쳐(Nature), 194, 927~929(1962)]에 준하여 아그리고메-터(Model AUTO RAM-61, 리까전기공업)을 사용해서 측정하였다. 즉, 혈소판수가 50~55×10⁴/㎕이 되도록 조정한 PRP 400㎕을 측정용 큐벳트에 넣어서 응집계에 셋트하고 37℃로 1시간 교반(1200rpm), 예비가열한 후, 시험 화합물액(생리 식염수에 용해했을때 50㎕, 디메틸술폭시드에 용해했을 경우에는 그 용액 2㎕과 생리 식염수 48㎕)을 가하고, 그 2분후에 응집 야기물질로서 아라키돈산[나트륨염, 시그마(Sigma)]을 500마이크로몰 가해서 응집에 의해서 생긴 투광도의 변화를 경시적으로 기록하였다.The platelet aggregation reaction was measured using an Adhermeter (Model AUTO RAM-61, Rika Electric Co., Ltd.) according to the present method (Born, GVR, Nature, 194, 927-929 (1962)). That is, 400 μl of PRP adjusted to platelet count of 50-55 × 10 ⁴ / μl was put in a measuring cuvette, set in an agglomeration system, stirred at 37 ° C. for 1 hour (1200 rpm), preheated, and then the test compound solution ( 50 µl when dissolved in physiological saline, and 2 µl of the solution and 48 µl of physiological saline when soluble in dimethyl sulfoxide were added. After 2 minutes, arachidonic acid (sodium salt, Sigma) was added as a substance causing aggregation. The change in light transmittance caused by aggregation by addition of 500 micromoles was recorded over time.

혈소판의 응집율은 PRP 및 PPP의 투광도를 각각 0% 및 100%로 하고 응집 야기물질 첨가후의 PRP의 최대 투광도를 최대 응집율로 하였다.The aggregation rate of platelets was 0% and 100%, respectively, and the maximum light transmittance of PRP after addition of the agent causing aggregation was the maximum aggregation rate.

[결과][result]

시험 결과를 하기 제5표에 표시한다. 표준물질로서 프로스터그랜디(PG)E₁을 사용하였다.The test results are shown in Table 5 below. Prostergrande (PG) E ₁ was used as a standard.

[제 5표](그의 1)[Table 5] (1 of him)

실시예 I-1에서 제조한 화합물의 시험결과Test result of compound prepared in Example I-1

[제 5표](그의 2)[Table 5] (his two)

실시예 I-2에서 제조한 화합물의 시험결과Test result of compound prepared in Example I-2

[제 5표](그의 3)[Table 5] (his three)

실시예 II에서 제조한 화합물의 시험결과Test result of compound prepared in Example II

* 화합물번호는 실시예중의 화합물번호에 대응한다.* The compound number corresponds to the compound number in the examples.

비교대조 화합물로서 PG E₁을 사용한 것은 PG E₁의 생체내에서 반감기가 대단히 짧고, 의약품으로서 실용화가 어려운 점이 있어, 그 점을 개선하기 위하여 PG E₁의 작용 레벨을 목표로 해서 신규화합물을 합성한 때문이다. 그결과, 본 발명 화합물은 PG E₁의 작용 레벨까지 상당히 근접할 수가 있었다.The use of PG E ₁ as a comparative compound has a very short half-life in PG E ₁ in vivo, and it is difficult to put it into practical use as a drug. In order to improve the point, PG E ₁ is used to synthesize a novel compound. Because of one. As a result, the compound of the present invention could be quite close to the action level of PG E ₁ .

본 발명 화합물은 아라키돈산에 의한 혈소판 응집에 대해서 강한 저해작용을 나타낸다.The compound of the present invention exhibits a strong inhibitory effect on platelet aggregation by arachidonic acid.

본 발명 화합물은 트롬복산 A₂에 의한 혈소판 응집·혈관수축, 기관수축을 강력히 억제하는 것으로서, 동맥경화, 심근경색, 급성심근허혈협심증, 순환기계쇽크, 돌연사등의 증상의 치료·개선 등에 사용되는 등 그 약리효과의 응용이 기대되는 화합물이다.The compound of the present invention strongly inhibits platelet aggregation, vascular contraction and tracheal contraction by thromboxane A ₂ , and is used for the treatment and improvement of symptoms such as arteriosclerosis, myocardial infarction, acute myocardial ischemia, circulatory mechanical check, and sudden death. It is a compound which the application of the pharmacological effect is expected.

본 발명 화합물은 경구투여에 의하여 또는 비경구로 투여할 수가 있다. 예를들면, 정제, 캡슐제, 환제, 과립제, 세립제, 수제, 유제, 좌제, 정맥내 주사제, 근육내 주사제 또는 피하주사제 등으로 만들 수 있다. 제제화의 경우에는 통상 사용되는 적당한 담체 또는 부형제를 사용한다.The compounds of the present invention can be administered orally or parenterally. For example, it can be made into tablets, capsules, pills, granules, fines, homemade, emulsions, suppositories, intravenous injections, intramuscular injections or subcutaneous injections. In the case of formulation, suitable carriers or excipients which are commonly used are used.

본 발명 목적 화합물은 경구투여에서는 성인 1일 약 10mg~800mg가 투여된다.In the oral administration of the compound of the present invention, about 10 mg to 800 mg per adult is administered.

Claims (1)

하기의 일반식으로 표시되는 화합물.Compound represented by the following general formula.

상기식에서, R₁은 수소, 저급알킬 또는 염형성기를 ; A는 메틸렌, 에틸렌, 디메틸메틸렌, 산소 또는 유황을 ; R₂는 치환 또는 비치환의 페닐을 ; p는 0 또는 2를 ; q는 0 또는 1을 각각 나타낸다(단, A가 에틸렌일때 p=2, q=0이며, A가 메틸렌, 디메틸메틸렌, 산소 또는 유황일때 p=0, q=1이다.)Wherein R ₁ is hydrogen, lower alkyl or a salt forming group; A is methylene, ethylene, dimethylmethylene, oxygen or sulfur; R ₂ is substituted or unsubstituted phenyl; p is 0 or 2; q represents 0 or 1, respectively, except that p = 2 and q = 0 when A is ethylene and p = 0 and q = 1 when A is methylene, dimethylmethylene, oxygen or sulfur.