KR950008319B1

KR950008319B1 - Dihydroxy allyl cephem compound and process of their preparation

Info

Publication number: KR950008319B1
Application number: KR1019920012642A
Authority: KR
Inventors: 장문호; 강한영; 고훈영; 배애님; 심상철
Original assignee: 한국과학기술연구원; 서정욱
Priority date: 1992-07-15
Filing date: 1992-07-15
Publication date: 1995-07-27
Also published as: KR940002255A

Abstract

This is new cephalosphorin compd. and its parmaceutically acceptable salt of formula(I). In formula, R1 is H, or trityl, tert-butoxycarbonyl, or formyl; R2 H, p-methoxybenzyl, diphenylmethyl or salting compd. such as Na or K; R3 and R4 are same or different, and H, acetyl, or p-methoxybenzyl; X,Y are H, F, Cl, Br, or I; and Q hydrogen, chloro, vinyl, acetoxymethyl, halomethyl, pyridiniummethyl, N- ethyl pyridiniumyl thiomethyl, N- carboxymethyl pyridiniumyl thiomethyl, carbamoyloxymethyl, and N-methyl-tetrazolyl thiomethyl gp. This compd. is prepared by acylation of the aminothiazol compd of (II) with cephalosphorin of (III). This cephem compd. has good antibacterial activity.

Description

Dihydroxyallyl cefem compound and preparation method thereof

본 발명은 일반식(I)의 광범위한 항균력을 지닌 세파로스포린 화합물 및 그의 약제학적으로 허용되는 염 및 그 제조방법에 관한 것이다.The present invention relates to a cephalosporin compound having a broad antimicrobial activity of general formula (I), a pharmaceutically acceptable salt thereof, and a preparation method thereof.

[화학식 1][Formula 1]

본 발명에서 합성된 화합물들은 그람양성균이나, 그람음성균에서 뛰어난 항균력을 나타내므로 세파로스포린 화합물 계열 의약품에 유용하게 사용할 수 있다. 일반식(I)에서 R₁은 수소 또는 페니실린이나 세파로스포린 화합물에서 일반적으로 사용되는 보호기를 말하는데, 예를들면 트리틸, 3급 부톡시카르닐(t-Boc), 벤질, 클로로아세틸, 트리클로로아세틸, 벤질옥시카르보닐, 파라-메톡시벤질옥시카르보닐, 포르밀, 그리고 트리플루오르아세틸 등이 포함된다. R₂은 수소 또는 카르복시기의 유도체로서, 주로 에스테를 만드는 기이거나, 염을 만드는 원자 혹은 카르복시보호기로 유용한 기이다. 여기에서 카르복시보호기는 페니실린이나, 세파로스포린 화합물의 분야에서 분자의 다른 부분에 특별히 나쁜 영향을 미치지 않으면서 도입되거나, 제거될 수 있는 것을 말한다. 염으로서는 무기염 및 유기염을 들 수 있는 바, 대표적인 무기염을 예를들면, 나트륨 및 칼륨염이 있으며 유기염으로서는 알킬아민(에틸아민,디에틸아민,트리에틸아민과 같은 저급 알킬아민)의 염, 방향족 아민의 염(아닐린,디메틸아닐린 등의 염) 및 방향족 염기의 염(그 예로는 피콜린, 루티딘, 퀴놀린염)을 들 수 있다. 또한 카르복시그룹의 보호기로서는 탄소수 1-8개가 치환된 경우를 포함한 알킬에스테르(그 예를 들면, 메톡, 메톡시메틸, 에틸, 메톡시에틸, 프로필, 이소프로필, 부틸, 이소부틸, t-부틸, 헥실에스테르) 또는 에닐, 인다닐, 벤질, 시아노벤질, 할로벤질, 메틸벤질, 니트로벤질, 파라-메톡시벤질, 페닐벤질 등의 에스테르이다. 의약품으로 유용한 카르복시 유도체는 금속염 또는 약학적으로 유용한 에스테르인 바, 이들은 경구용이나 주사제로서 쓰이며, 항생제의 효과를 보이는 것으로서 구체적으로 살펴보면 잘 알려진 탄소수 3-12의 1위치가 치환된 알킬에스테르, 예를들면, 알카노일옥시알킬에스테르(좀더 상세히는, 아세톡시메틸, 아세톡시에틸, 프로필오닐옥시에틸, 피발로일옥시메틸, 피발로일옥시에틸, 테트라히드로퓨릴, 테트라히드로피라닐에스테르), 탄소수 3-8의 알콕시포르밀옥시알킬에스테르(예로서 에톡시카르보닐옥시에틸에스테르 등), 탄소수 7-15의 치환된 아랄킬에스테르(예로서 페나실, 프탈리딜에스테르), 탄소수 6-12의 치환된 아릴에스테르(예로서 페닐, 크실릴, 인다닐에스테르), 그리고 2-알케닐에스테르(예로서, 알릴, 2-옥소-1,3-디옥솔-4-일메틸에스테르)들이다. R₃,R₄는 H 또는 페놀성 수산기의 보호기 또는 아실기를 말한다. 그 예로는 아세틸, 파라-메톡시벤질, 벤질, 메틸렌 등이 가능하다. X, Y는 수소 또는 플루오르, 클로로, 브로모, 요오드와 같은 할로겐 원자들을 나타내며 이들은 서로 같거나, 다를 수가 있다. 또한, 일반식(I)의 세파로스포린의 7위치에 있는 치환기 안에서 이민 그룹에 연결된 그룹들의 구조를 살펴보면 입체구조적으로는 syn,anti의 2가지 형태의 이성체가 있을 수가 있는데, 일반적으로는 구조와 항균력과의 관계를 고려할때에, syn 이성체가 anti 이성체보다 훨씬 더 높은 항균작용을 보여줄 수 있기 때문에, 그 효용가치 입장에서 보면 syn 이성체가 유용한 것으로 본다. 이들 아미노티아졸 구조에서 토오토머 형태로도 존재할 수 있어 2-아미노티아졸리닐의 구조를 가질 수 있는데, 이 경우에 본 발명의 범위에 포함된다. Q는 일반적으로 세파로스포린 화합물에 유용한 치환체를 말한다. 즉, 수소, 할로겐, 혹은 C₁₄알콕시와 같은 유기 치환체, -CH₂Q' 혹은 -CH=CH-Q'와 같은 치환체를 말한다. 이때 Q'는, 수소, 할로겐, 히드록시, 메르캅토, 시아노, 카르복시, 카르복실릭에스테르, 카르바모일옥시, C₁₄알킬옥시, 아릴, 탄소원자를 통해 결합되어 있는 헤테로고리 치환체, 혹은 질소원자가 포함되어 있는 헤테로고리 치환체등을 말한다. 여기서, 할로겐은 일반적으로 불소, 염소, 브롬 및 요오드등을 말한다. 헤테로고리 치환기로는 불포화된 5 또는 6화 헤테로고리기를 말한다. 이때 헤테로고리는 산소, 황, 질소 원자를 적어도 한개 이상 포함되어 있는 구조를 말한다. 이러한 예로는 치환되거나, 치환되지 않은 티아졸릴티오, 이소티아졸릴티오, 티아디아졸릴티오, 트리아졸릴티오, 트레아지닐티오, 테트라졸릴티오, 트리아졸로피리미디닐티오, 1-치환된 피니리디움-4-일-티오등을 말한다. 질소를 거쳐서 결합되어 있고 질소가 포함되어 있는 헤테로고리 치환기는 피리디늄기로서, C_1-6알킬, C_1-6알콕시, 히드록시알킬, C_1-6알케닐, 알콕시알킬, 카르복시알킬, 술포닐알킬, 카르바모일메틸, 카르바모일, 트리플루오르메틸, 히드록시, 할로겐, 옥소, 혹은 치환되지 않았거나 1개 내지 2개의 치환기로 치환된 아미노알킬기 등으로 치환된 것들을 포함한다.Compounds synthesized in the present invention exhibit excellent antimicrobial activity in Gram-positive bacteria or Gram-negative bacteria, and thus can be usefully used in Separosporin compound-based medicines. In formula (I), R ₁ refers to hydrogen or a protecting group generally used in penicillin or sephalosporin compounds, for example trityl, tert-butoxycarbonyl (t-Boc), benzyl, chloroacetyl, triclo Roacetyl, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, formyl, trifluoroacetyl and the like. R ₂ is a derivative of hydrogen or a carboxy group, which is a group which mainly produces an ester, or a group which is useful as an atom or a carboxy protecting group which forms a salt. Carboxy protecting groups herein refer to those that can be introduced or removed without particularly adversely affecting other parts of the molecule in the field of penicillin or cephalosporin compounds. Salts include inorganic salts and organic salts. Representative inorganic salts include sodium and potassium salts, and organic salts include alkylamines (lower alkylamines such as ethylamine, diethylamine and triethylamine). Salts, salts of aromatic amines (salts such as aniline, dimethylaniline, etc.) and salts of aromatic bases (examples are picoline, lutidine, quinoline salts). Moreover, as a protecting group of a carboxy group, the alkyl ester containing the case where C1-C8 is substituted (for example, methoxy, methoxymethyl, ethyl, methoxyethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, Hexyl ester) or esters such as enyl, indanyl, benzyl, cyanobenzyl, halobenzyl, methylbenzyl, nitrobenzyl, para-methoxybenzyl and phenylbenzyl. Carboxylic derivatives useful as pharmaceuticals are metal salts or pharmaceutically useful esters, which are used as oral or injectables and have an antibiotic effect. Specifically, alkyl esters having 1 to 3 carbon atoms substituted are well known. Alkanoyloxyalkyl esters (more specifically, acetoxymethyl, acetoxyethyl, propylonyloxyethyl, pivaloyloxymethyl, pivaloyloxyethyl, tetrahydrofuryl, tetrahydropyranyl ester) -8 alkoxyformyloxyalkyl esters (e.g., ethoxycarbonyloxyethyl esters, etc.), substituted aralkyl esters of 7-15 carbon atoms (e.g. phenacyl, phthalidyl esters), substitutions of 6-12 carbon atoms Aryl esters (eg phenyl, xylyl, indanyl ester), and 2-alkenyl esters (eg allyl, 2-oxo-1,3-dioxol-4-ylmethyl ester) A. R ₃ and R ₄ refer to a protecting group or an acyl group of H or a phenolic hydroxyl group. Examples are acetyl, para-methoxybenzyl, benzyl, methylene and the like. X and Y represent hydrogen or halogen atoms such as fluorine, chloro, bromo, iodine and they may be the same or different. In addition, when looking at the structure of the group linked to the imine group in the substituent at position 7 of the Sepharosporin of the general formula (I), there may be two types of isomers of syn and anti. Considering the relationship with the antimicrobial activity, the syn isomer is useful from the standpoint of its utility value, since the syn isomer can show much higher antimicrobial activity than the anti isomer. These aminothiazole structures may also exist in their tautomeric form and thus have the structure of 2-aminothiazolinyl, which is included in the scope of the invention in this case. Q generally refers to substituents useful for the cephalosporin compound. That is, an organic substituent such as hydrogen, halogen, or C ₁₄ alkoxy, or a substituent such as -CH ₂ Q 'or -CH = CH-Q'. In this case, Q 'is a heterocyclic substituent or a nitrogen atom bonded to hydrogen, halogen, hydroxy, mercapto, cyano, carboxy, carboxylic ester, carbamoyloxy, C ₁₄ alkyloxy, aryl, a carbon atom Heterocyclic substituents contained therein. Here, halogen generally refers to fluorine, chlorine, bromine and iodine. Heterocyclic substituents refer to unsaturated 5 or 6-membered heterocyclic groups. In this case, the hetero ring refers to a structure containing at least one oxygen, sulfur, nitrogen atom. Examples include substituted or unsubstituted thiazolylthio, isothiazolylthio, thiadiazolylthio, triazolylthio, threazinylthio, tetrazolylthio, triazolopyrimidinylthio, 1-substituted pineinidium -4-yl-thio, etc. The heterocyclic substituents bonded via nitrogen and containing nitrogen are pyridinium groups, which are C _1-6 alkyl, C _1-6 alkoxy, hydroxyalkyl, C _1-6 alkenyl, alkoxyalkyl, carboxyalkyl, sul Polyalkyl, carbamoylmethyl, carbamoyl, trifluoromethyl, hydroxy, halogen, oxo, or an aminoalkyl group which is unsubstituted or substituted with 1 to 2 substituents.

다음은 본 발명의 일반식(I)으로 표시되는 신규한 세파로스포린 화합물들을 합성하는 전형적인 공정이다. 일반식(II로 표시되는 신규 아미노티아졸계열 화합물과 일반물(III)의 세파로스포린 화합물과 반응시켜 제조할 수 있다. 일반식(II)의 화합물은 이미 대한민국 특허출원 제92-5336호에 본 발명자들에 의해 출원되어 있다. 일반식(II)에서 R₁은 수소 또는 페니실린이나 세파로스포린 화합물에서 일반적으로 사용하는 보호기를 말하는데, 예를들면 트리틸, 3급-부톡시카르보닐(t-Boc), 벤질, 클로로아세틸, 트리클로로아세틸, 벤질옥시카르보닐, 파라-메톡시벤질옥시카르보닐, 포르밀, 그리고 트리플르오로아세틸 등이 포함된다. R₃, R₄는 H 또는 페놀성 수산기의 보호기 또는 아실기를 말한다. 그 예로는 아세틸, 파라-메톡시벤질, 벤질, 메틸렌 등이 가능하다. X, Y는 수소 또는 플루오르, 클로로, 브로모, 요오드와 같은 할로겐 원자들을 나타내며 이들은 서로 같거나, 다를 수가 있다. 일반식(III)의 세파로스포린에서의 R₂와 Q 및 일반식(I)의 R₂와 Q는 서로 동일하다.The following is a typical process for synthesizing novel cephalosporin compounds represented by general formula (I) of the present invention. It can be prepared by reacting a novel aminothiazole-based compound represented by the general formula (II) with a cephalosporin compound of the general product (III). The compound of the general formula (II) has already been disclosed in Korean Patent Application No. 92-5336. In general formula (II), R ₁ refers to hydrogen or a protecting group generally used in penicillin or sephalosporin compounds, for example trityl, tert-butoxycarbonyl (t -Boc), benzyl, chloroacetyl, trichloroacetyl, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, formyl, trifluoroacetyl, etc. R ₃ , R ₄ are H or phenolic Protecting or acyl groups of hydroxyl groups, for example, acetyl, para-methoxybenzyl, benzyl, methylene, etc. X, Y represent hydrogen or halogen atoms such as fluorine, chloro, bromo, iodine and they are the same Or may be different. R ₂ and Q in the formula (III) R ₂ and Q and cephalosporin general formula (I) in to a Sepharose is the same as each other.

[반응식 1]Scheme 1

[반응식 2]Scheme 2

반응식(1)에서 보는 바와같이 일반식(II)의 산 화합물과의 아실화반응을 통상적인 반응공정을 거쳐서 얻게된다. 이러한 아실화반응에서 일반식(II)의 화합물들을 활성화된 상태로 만들어 반응시키는 경우, 사용가능한 반응 용매로는 물, 아세톤, 디옥산, 아세토니트릴, 클로로포름, 디클로로메탄, 테트라히드로퓨란, 에틸아세테이트, N,N-디메틸포름아미드, 피리딘 등이 유용하며, 유기염기나 무기염기의 존재하에 반응시킨다. 사용가능한 염기의 예로는 알칼리금속히드록시드, 알칼리금속아세테이트, 트리-(저급)알킬아민, 피리딘, N-저급알킬모르포린, N,N-디(저급)알킬벤질아민, N,N-디-(저급)알킬아닐린 등을 들 수 있으며 반응온도는 일반적으로 상온이나 저온이 적당하다. 여기서 일반식(II)의 카르복실산의 활성화를 위해서는 통상적으로 세팔로스포린 합성에 이용되는 활성화 과정들이 포함될 수 있다. 이 활성화된 유도체로서는 산무수물, 예를들면 대칭형이거나 혼합형의 무수물을 들 수 있다. 이때 일반식(II)의 카르복실산과 산무수물을 이루는 화합물들로서는 무기산(예를들면, 인산, 황산, 할로겐산, 카르보닐반쪽산 등)들이던가, 유기산(예를들면, 알칸산, 아라알칸산, 술폰산), 분자내 산무수물(예를들면 커텐, 이소시아네이트등과의 무수물을 말한다), 산 할라이드, 반응성을 가진 에스테르인 알케닐에스테르(예를들면 비닐에스테르, 이소프로페닐에스테르), 아릴에스테르(예를들면 피리딜에스테르, 벤조트리아졸릴에스테르), N-히드록시 화합물과의 에스테르, 디아실히드록시아민에스테르(예를들면, N-히드록시숙신이미드에스테르, N-히드록시프탈이미드에스테르), 디아실히드록시아민에스테르(예를들면, N-히드록시숙신이미드에스테르, N-히드록시프탈이미드에스테르), 디오에스테르(예를들면 아랄킬티올에스테르, 헤테로고리를 가진 티올에스테르), 혹은 반응성을 갖는 아미드(예를들어 이미다졸, 트리아졸, 2-에톡시-1,2-디히드로퀴놀린과의 아미드, 디아실 아닐리드)를 들 수 있다. 또한 이 아실화반응에서 유기산이나 염 상태에서 결합보조제를 사용하여 직접적으로 아실화반응을 일으킬 수 있다. 예를들면 N,N-디시클로헥실카르보디이미드, N-시클로헥실-N-몰포리노-에틸카롭디이미드, N-시클로헥실-N-(4-디에틸아미노시클로헥실) 카르보디이미드, N,N'-카르보닐비스카롭디이미드, N-시클로헥실-N-(4-디에틸아미노시클로헥실) 카르보디이미드, N,N'-카르보닐미스(2-메틸이미다졸), 펜타메틸렌케텐-N-시클로헥실아민, 에톡시아세틸렌, 에틸폴리포스페이트, 포스포로스트리클롤드, 포스포로스옥시클로리드, 티오닐글로리드, 옥살릴클로리드, 트리페닐포스핀에 의한 방법을 들 수 있다. 최종적으로 일반식(I)의 세파로스포린 화합물의 카르복실기가 R₂그룹으로 보호된 화합물로부터 보호기를 제거하고자 할 경우에는 반응식(2)에서와 같이 화합물들을 염기나 산 존재하에서 반응시키면 R₂가 수소원자인 일반식(I)의 화합물을 제조할 수 있다. 이때에 사용되는 산은 아세트산, 포름산, 트리플루오로아세트산 또는 염화알루미늄 등의 루이스산이 적합하며 첨가량은 일반식(I)의 세파로스포린 화합물에 대해 당량으로 1∼1000배의 산이 적합하며, 바람직하게는 5∼100배가 좋다.As shown in Scheme (1), an acylation reaction with the acid compound of formula (II) is obtained through a conventional reaction step. In the acylation reaction, when the compounds of formula (II) are made to react in an activated state, the reaction solvents that can be used include water, acetone, dioxane, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine and the like are useful and react in the presence of an organic base or an inorganic base. Examples of bases that can be used include alkali metal hydroxides, alkali metal acetates, tri- (lower) alkylamines, pyridine, N-lower alkylmorpholines, N, N-di (lower) alkylbenzylamines, N, N-di -(Lower) alkylaniline, and the like, and the reaction temperature is generally appropriate at room temperature or low temperature. Here, activation of the carboxylic acid of general formula (II) may include activation processes that are commonly used for cephalosporin synthesis. Examples of the activated derivatives include acid anhydrides such as symmetrical or mixed anhydrides. At this time, the compounds forming the carboxylic acid and acid anhydride of the general formula (II) include inorganic acids (e.g., phosphoric acid, sulfuric acid, halogen acid, carbonyl half acid, etc.) or organic acids (e.g., alkanoic acid, araalkane) Acids, sulfonic acids), intramolecular acid anhydrides (eg, anhydrides with curtains, isocyanates, etc.), acid halides, reactive alkenyl esters (eg vinyl esters, isopropenyl esters), aryl esters ( For example, pyridyl ester, benzotriazolyl ester), ester with N-hydroxy compound, diacylhydroxyamine ester (for example, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester ), Diacylhydroxyamine esters (e.g. N-hydroxysuccinimide esters, N-hydroxyphthalimide esters), dioesters (e.g. aralkylthiol esters, tee with heterocycles) Ester) or an amide having a reactive (for example there may be mentioned imidazole, triazole, amide, anilide of the diacyl-1,2-dihydroquinoline-2-a). In addition, in the acylation reaction, acylation reaction can be directly caused by using a binding aid in an organic acid or salt state. For example, N, N-dicyclohexylcarbodiimide, N-cyclohexyl-N-morpholino-ethylcaroplimide, N-cyclohexyl-N- (4-diethylaminocyclohexyl) carbodiimide, N , N'-carbonylbiscarlobidiimide, N-cyclohexyl-N- (4-diethylaminocyclohexyl) carbodiimide, N, N'-carbonylmis (2-methylimidazole), penta And methyleneketene-N-cyclohexylamine, ethoxyacetylene, ethyl polyphosphate, phosphorus trichloride, phosphorus oxcyclolide, thionyl glolide, oxalyl chloride, and triphenylphosphine. Finally, to remove the protecting group from the compound in which the carboxyl group of the cephalosporin compound of formula (I) is protected by the R ₂ group, reacting the compounds in the presence of a base or an acid as in Scheme (2), R ₂ becomes hydrogen. The compound of general formula (I) which is an atom can be manufactured. At this time, the acid used is suitable for Lewis acid such as acetic acid, formic acid, trifluoroacetic acid or aluminum chloride, and the addition amount is preferably 1 to 1000 times the acid equivalent to the sephalosporin compound of general formula (I). 5 to 100 times is good.

[반응식 3]Scheme 3

또한 일반식(I)의 화합물을 제조하기 위해서는 반응식(3)에서 보는 바와같이 먼저 일반식(II)의 화합물과 일반식(IV)의 새펨 화합물과 반응식(1)에서와 같이 아실화 반응을 거쳐 일반식(V)의 화합물을 합성하고, 3위치에서 치환기를 도입하기 위해서는 Nu:(친핵성 헤테로고리 화합물)와 반응시켜 이반 구조식(vi)의 화합물을 얻는다. 최종적으로는 반응식(2)에서와 같은 반응공정으로 보호기를 제거하여 일반식(I)의 화합물을 합성하는 것이다. 상기 일반식에서 Z는 클로로, 브로모, 요오드, 또는 아세톡시를 말한다. R₁, R₂, R₃, R₄, X, Y, Q, Q'는 앞에서 정의한 바와 같다. 다음의 화합물들은 본 발명에서 얻어진 일반식(I)의 구조를 지니는 대표적인 화합물들을 보여준다.In addition, in order to prepare the compound of formula (I), as shown in reaction formula (3), the compound of formula (II) and the sape compound of formula (IV) are subjected to an acylation reaction as in scheme (1). In order to synthesize a compound of formula (V) and introduce a substituent at the 3-position, it is reacted with Nu: (nucleophilic heterocyclic compound) to obtain a compound of the general structure (vi). Finally, the protecting group is removed by a reaction process as in Scheme (2) to synthesize a compound of Formula (I). Z in the general formula is chloro, bromo, iodine, or acetoxy. R ₁ , R ₂ , R ₃ , R ₄ , X, Y, Q, Q 'are as defined above. The following compounds show representative compounds having the structure of formula (I) obtained in the present invention.

화합물 1. 디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노아세트아미도]-3-아세트메틸-3-세펨-4-카르복실레이트Compound 1.Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z) -3- (3,4-di-para-methoxybenzyloxyphenyl ) Isoxazol-5-yl-methoxyiminoacetamido] -3-acetmethyl-3-cepem-4-carboxylate

화합물 2. (6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-3-(3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노아세트아미도]-3-아세톡시메틸-3-세펨-4-카르복실산 및 나트륨염Compound 2. (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z) -3- (3,4-di-hydroxyphenyl) isoxazole-5- Mono-methoxyiminoacetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid and sodium salt

화합물 3. 디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노아세트아미도]-3-세펨-4-카르복실레이트Compound 3. Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z) -3- (3,4-di-para-methoxybenzyloxyphenyl ) Isoxazol-5-yl-methoxyiminoacetamido] -3-cepem-4-carboxylate

화합물 4. (6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-3-(3,4-디히드록시페닐)이소옥사졸-5-일-메톡시이미노아세트아미도]-3-세펨-4-카르복실산 및 나트륨염Compound 4. (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z) -3- (3,4-dihydroxyphenyl) isoxazol-5-yl -Methoxyiminoacetamido] -3-cepem-4-carboxylic acid and sodium salt

화합물 5. 디페닐메틸(6R,7R)-[2-(2-아미노티아졸-4-일)-2(Z)-3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노아세트아미도]-3-카르바모일옥시메틸-세펨-4-카르복실레이트Compound 5. Diphenylmethyl (6R, 7R)-[2- (2-aminothiazol-4-yl) -2 (Z) -3- (3,4-di-para-methoxybenzyloxyphenyl) iso Oxazol-5-yl-methoxyiminoacetamido] -3-carbamoyloxymethyl-cepem-4-carboxylate

화합물 6. (6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도}-3-카바모일옥시메틸-3-세펨-4-카르복실산 및 나트륨염Compound 6. (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-dihydroxyphenyl) isoxazole-5- Mono-methoxyimino} acetamido} -3-carbamoyloxymethyl-3-cepem-4-carboxylic acid and sodium salt

화합물 7. 파라-메톡시벤질(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-[3-(3,4-디-파라-메톡시벤질옥시-페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-클로로메틸-3-세펨-4-카르복실레이트Compound 7. Para-methoxybenzyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-[3- (3,4-di-para-methoxy Benzyloxy-phenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-chloromethyl-3-cepem-4-carboxylate

화합물 8. 파라-메톡시벤질(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-에틸피리디니움-4-일)티오메틸-3-세펨-4-카르복실레이트 요오드Compound 8. Para-methoxybenzyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxy Benzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3- (N-ethylpyridinium-4-yl) thiomethyl-3-cepem-4-carboxylate iodine

화합물 9. (6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-에틸피리디니움-4-일)티오메틸-3-세펨-4-카르복실레이트Compound 9. (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-hydroxyphenyl) isoxazole-5 -Yl-methoxyimino} acetamido] -3- (N-ethylpyridinium-4-yl) thiomethyl-3-cepem-4-carboxylate

화합물 10. 파라-메톡시벤질(6R,7R)-7-[2-(2-트리페닐메틸아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-디페닐메톡시카르보닐 메틸피리디니움-4-일)티오메틸-3-새펨-4-카르복실레이트 요오드Compound 10. Para-methoxybenzyl (6R, 7R) -7- [2- (2-triphenylmethylaminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para -Methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3- (N-diphenylmethoxycarbonyl methylpyridinium-4-yl) thiomethyl-3-sappem 4-carboxylate iodine

화합물 11. (6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(1-카르복시메틸피리디니움-4-일)티오메틸-3-세펨-4-카르복실산 및 나트륨염Compound 11. (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-hydroxyphenyl) isoxazole-5 -Yl-methoxyimino} acetamido] -3- (1-carboxymethylpyridinium-4-yl) thiomethyl-3-cepem-4-carboxylic acid and sodium salt

화합물 12. 디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-50-일-메톡시이미노}아세트아미도]-3-(N-메틸테트라졸-5-일)티오메틸-3-세펨-4-카르복실레이트Compound 12. Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxy Phenyl) isoxazol-50-yl-methoxyimino} acetamido] -3- (N-methyltetrazol-5-yl) thiomethyl-3-cepem-4-carboxylate

화합물 13. (6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-메틸테트라졸-5-일)티오메틸-3-세펨-4-카르복실산 및 나트륨염Compound 13. (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-hydroxyphenyl) isoxazole-5 -Yl-methoxyimino} acetamido] -3- (N-methyltetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid and sodium salt

화합물 14. 파라-메톡시벤질(6$,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-[3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-메톡시메틸-3-세펨-4-카르복실레이트Compound 14. Para-methoxybenzyl (6 $, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-[3- (3,4-di-para-meth Oxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-methoxymethyl-3-cepem-4-carboxylate

화합물 15. (6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-메톡시메틸-3-세펨-4-카르복실산 및 나트륨염Compound 15. (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-hydroxyphenyl) isoxazole-5 -Yl-methoxyimino} acetamido] -3-methoxymethyl-3-cepem-4-carboxylic acid and sodium salt

화합물 16. 파라-메톡시벤질(6R,7R)-7-[2-(2-트리페닐메틸아미노티아졸-4-일)-2(Z)-[3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-피리디니움메틸-3-세펨-4-카르복실레이트 요오드Compound 16. Para-methoxybenzyl (6R, 7R) -7- [2- (2-triphenylmethylaminothiazol-4-yl) -2 (Z)-[3- (3,4-di-para -Methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-pyridiniummethyl-3-cepem-4-carboxylate iodine

화합물 17. (6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-피리디니움메틸-3-세펨-4-카르복실레이트Compound 17. (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-hydroxyphenyl) isoxazole-5 -Yl-methoxyimino} acetamido] -3-pyridiniummethyl-3-cepem-4-carboxylate

화합물 18. 디페닐메틸(6R,7R)-7[2-(2-아미노티아졸-4-일)-2(Z)-{3-2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-아세톡시메틸-3-세펨-4-카르복실레이트Compound 18. Diphenylmethyl (6R, 7R) -7 [2- (2-aminothiazol-4-yl) -2 (Z)-{3-2,5-dichloro-3,4-di-para- Methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-acetoxymethyl-3-cepem-4-carboxylate

화합물 19. (6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-아세톡시메틸-3-세펨-4-카르복실산 및 나트륨염Compound 19. (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-dihydroxyphenyl) Isoxazol-5-yl-methoxyimino} acetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid and sodium salt

화합물 20. 디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-메틸테트라졸-5-일)티오메틸-3-세펨-4-카르복실레이트Compound 20. Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di- Para-methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3- (N-methyltetrazol-5-yl) thiomethyl-3-cepem-4-carboxylate

화합물 21. (6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(메틸테트라졸-5-일)티오메틸-3-세펨-4-카르복실산 및 나트륨염Compound 21. (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-hydroxyphenyl ) Isoxazol-5-yl-methoxyimino} acetamido] -3- (methyltetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid and sodium salt

화합물 22. 파라-메톡시벤질(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아셋아미도]-3-클로로메틸-3-세펨-4-카르복실레이트Compound 22. Para-methoxybenzyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4- Di-para-methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-chloromethyl-3-cepem-4-carboxylate

화합물 23. 파라-메톡시벤질(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-에틸-피리디니움-4-일)-티오메틸-3-세펨-4-카르복실레이트 요오드Compound 23. Para-methoxybenzyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4- Di-para-methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3- (N-ethyl-pyridinium-4-yl) -thiomethyl-3-cepem- 4-carboxylate iodine

화합물 24. 파라-메톡시벤질(6R,7R)-7-[2-(2-트리페닐아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-디페닐메톡시카르보닐메틸-피리디니움-4-일)-티오메틸-3-세펨-4-카르복실레이트 요오드Compound 24. Para-methoxybenzyl (6R, 7R) -7- [2- (2-triphenylaminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3, 4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3- (N-diphenylmethoxycarbonylmethyl-pyridinium-4-yl) -Thiomethyl-3-cepem-4-carboxylate iodine

화합물 25. (6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-카르복시메틸-피리디니움-4-일)-티오메틸-3-세펨-4-카르복실산 및 나트륨염Compound 25. (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-hydroxyphenyl ) Isoxazol-5-yl-methoxyimino} acetamido] -3- (N-carboxymethyl-pyridinium-4-yl) -thiomethyl-3-cepem-4-carboxylic acid and sodium salt

화합물 26. (6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-에틸-피리디니움-4-일)-티오메틸-3-세펨-4-카르복실레이트Compound 26. (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-hydroxyphenyl ) Isoxazol-5-yl-methoxyimino} acetamido] -3- (N-ethyl-pyridinium-4-yl) -thiomethyl-3-cepem-4-carboxylate

화합물 27. 디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-세펨-4-카르복실레이트Compound 27. Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di- Para-methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-cepem-4-carboxylate

화합물 28. (6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-세펨-4-카르복실산 및 나트륨염Compound 28. (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para-hydrate Oxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-cepem-4-carboxylic acid and sodium salt

화합물 29. 디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-비닐-3-세펨-4-카르복실레이트Compound 29. Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di- Para-methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-vinyl-3-cepem-4-carboxylate

화합물 30. (6R,7R)-7-[2-(2-이미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-비닐-3-세펨-4-카르복실산 및 나트륨염Compound 30. (6R, 7R) -7- [2- (2-iminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para-hydrate Oxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-vinyl-3-cepem-4-carboxylic acid and sodium salt

다음의 실시예는 본 발명을 더욱 상세히 예증하여 줄 것이나 본 발명의 범위가 이에 국한된다는 것은 아니다.The following examples will illustrate the invention in more detail, but the scope of the invention is not limited thereto.

[실시예 1]Example 1

디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-아세톡시메틸-3-세펨-4-카르복실레이트Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl) iso Oxazol-5-yl-methoxyimino} acetamido] -3-acetoxymethyl-3-cepem-4-carboxylate

[화학식 2][Formula 2]

건조 디메틸포름아미드 0.5ml에 2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}초산(100mg,0.162mmol)을 녹이고 트리에틸아민 24μl를 가하고 빙냉하에서 파라-톨루엔술포닐클로리드 37mg를 가하고 동온도에서 5분간 교반한 다음 이 혼합물에 디페닐메틸 7-아미노-3-아세톡시메틸-3-세펨-4-카르복실레이트(71mg,0.16mmol)로 가하고 실온에서 30분동안 교반한다. 반응물에 에틸아세테이트 50ml를 가하고 물로 세척(15ml×4)하고 무수황산마그네슘으로 건조시킨 다음 농축시킨다. 이 농축물을 컬럼크로마토그래피(실리카젤, 용매/n-헥산:에틸아세트테이트=1:2)로 분리하면 127mg의 목적화합물을 담황색 고체로 얻는다.2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl) isoxazole-5- in 0.5 ml of dry dimethylformamide Dissolve 1-methoxyimino} acetic acid (100 mg, 0.162 mmol), add 24 μl of triethylamine, add 37 mg of para-toluenesulfonyl chloride under ice-cooling, stir for 5 minutes at the same temperature, and add diphenylmethyl 7-amino to the mixture. 3-Acetoxymethyl-3-cepem-4-carboxylate (71 mg, 0.16 mmol) was added and stirred at room temperature for 30 minutes. 50 ml of ethyl acetate was added to the reaction, washed with water (15 ml × 4), dried over anhydrous magnesium sulfate, and concentrated. The concentrate was separated by column chromatography (silica gel, solvent / n-hexane: ethyl acetate = 1: 2) to yield 127 mg of the target compound as a pale yellow solid.

수율 : 76%Yield: 76%

¹H-NMR(CDCl₃) : δ1.98(3H,s,OAc), 3.40(2H,ABq,SCH₂), 3.83(6H,d,OCH₃), 4.75(2H,ABq,CH₂OAC), 5.05(1H,d,C₆-H), 5.08(6H,d,OCH₃), 5.25∼5.55(6H,m,-OCH₂-OCH₃,=N-OCH₂), 6.06(1H,dd,C₇-H), 6.01(1H,s,이소옥사졸-H), 6.8∼7.6(12H,m,페닐-H,티아졸-H). ¹ H-NMR (CDCl ₃ ): δ 1.98 (3H, s, OAc), 3.40 (2H, ABq, SCH ₂ ), 3.83 (6H, d, OCH ₃ ), 4.75 (2H, ABq, CH ₂ OAC) , 5.05 (1H, d, C ₆ -H), 5.08 (6H, d, OCH ₃ ), 5.25 to 5.55 (6H, m, -OCH ₂ -OCH ₃ , = N-OCH ₂ ), 6.06 (1H, dd , C ₇ -H), 6.01 (1H, s, isoxazole-H), 6.8-7.6 (12H, m, phenyl-H, thiazole-H).

[실시예 2]Example 2

(6R,7R)-7-[2-2(아미노티아졸-4-일)-2(Z)-{3-(3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-아세톡시메틸-3-세펨-4-카르복실산 및 나트륨염(6R, 7R) -7- [2-2 (aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-hydroxyphenyl) isoxazol-5-yl-meth Toxyimino} acetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid and sodium salt

[화학식 3][Formula 3]

디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-아세톡시메틸-3-세펨-4-카르복실레이트(130mg,0.125mmol)를 아니솔 78μl과 메틸렌클로리드 78μl에 녹이고 빙냉하에서 트리플루오르초산 0.78ml를 가하고 동온도에서 1.5시간 교반시킨다. 반응물에 20ml의 이소프로필에테르를 가하고 고체화시키고 고체를 여과하고 에테르로 잘 세척한 후 건조시킨다. 이 고체를 물 2ml에 현탁시키고 탄산수소나트륨 20mg을 가하여 녹이고 교반한 후 불용물을 여과하고, 여액을 역상크로마토그래피(고정상 : SEPRALYTE^TM; 이동상 : 20% 메탄올수용액)으로 분리한 다음 냉동건조시키며 45mg의 목적화합물을 담황색 고체로 얻는다.Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl) iso Oxazol-5-yl-methoxyimino} acetamido] -3-acetoxymethyl-3-cepem-4-carboxylate (130 mg, 0.125 mmol) was dissolved in 78 μl of anisole and 78 μl of methylene chloride and under ice-cooling 0.78 ml of trifluoroacetic acid is added and stirred at the same temperature for 1.5 hours. 20 ml of isopropyl ether is added to the reaction and solidified, the solid is filtered, washed well with ether and dried. The solid was suspended in 2 ml of water, dissolved in 20 mg of sodium bicarbonate, stirred, and filtered with insoluble materials. The filtrate was separated by reverse phase chromatography (fixed phase: SEPRALYTE ^TM ; mobile phase: 20% aqueous methanol solution), and freeze-dried to obtain 45 mg. Obtain the desired compound as a pale yellow solid.

수율 : 52%Yield: 52%

¹H-NMR(CDCl₃) : δ2.21(2H,s,OAc), 3.25(2H,ABq,J=4Hz,28Hz,SCH₂), 4.75(2H,ABq,J=3Hz,16Hz,CH₂OAC), 5.28(1H,d,C₆-H), 5.44(2H,brs,N-OCH₂), 5.83(1H,d,C₇-H), 6.92(1H,s,이소옥사졸-H), 7.01(1H,d,페닐-H), 7.12(1H,s,티아졸-H), 7.29(1H,d,페닐-H), 7.35(1H,s,페닐-H). ¹ H-NMR (CDCl ₃ ): δ2.21 (2H, s, OAc), 3.25 (2H, ABq, J = 4Hz, 28Hz, SCH ₂ ), 4.75 (2H, ABq, J = 3Hz, 16Hz, CH ₂ OAC), 5.28 (1H, d, C ₆ -H), 5.44 (2H, brs, N-OCH ₂ ), 5.83 (1H, d, C ₇ -H), 6.92 (1H, s, isoxazole-H ), 7.01 (1H, d, phenyl-H), 7.12 (1H, s, thiazole-H), 7.29 (1H, d, phenyl-H), 7.35 (1H, s, phenyl-H).

[실시예 3]Example 3

디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-세펨-4-카르복실레이트Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl) iso Oxazol-5-yl-methoxyimino} acetamido] -3-cepem-4-carboxylate

[화학식 4][Formula 4]

2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일}초산(87mg,0.146mmol)를 0.5ml의 건조 디메틸포름아미드에 녹이고 빙냉하에서 트리에틸아민 21μl를 가하고 곧이어 파라-톨루엔술포닐클로리드(28mg,0.146mmol)를 가하고 10분간 동온도에서 교반한다. 이 혼합물에 디페닐메틸(6R,7R)-7-아미노-3-세펨-4-카르복실레이트(52mg,0.146mmol)를 가하고 중탕을 제거하고 실온에서 30분간 교반시킨다. 반응물에 에틸아세테이트 50ml를 가하고 물 세척(10ml×4)하고 포화소금물로 세척한 다음 무수황산마그네슘으로 건조시키고 농축, 건조시키면 72mg의 목적화합물을 담황색 고체로 얻는다. 이 화합물은 정제하지 않고 그래도 사용한다.2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl} acetic acid (87 mg, 0.146 mmol) is dissolved in 0.5 ml of dry dimethylformamide, 21 μl of triethylamine is added under ice-cooling, followed by addition of para-toluenesulfonyl chloride (28 mg, 0.146 mmol) and stirring at the same temperature for 10 minutes. Diphenylmethyl (6R, 7R) -7-amino-3-cepem-4-carboxylate (52 mg, 0.146 mmol) was added to the mixture, the bath was removed and stirred at room temperature for 30 minutes. 50 ml of ethyl acetate was added to the reaction, washed with water (10 ml × 4), washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated and dried to give 72 mg of the target compound as a pale yellow solid. This compound is used without purification.

수율 : 52%Yield: 52%

¹H-NMR(CDCl₃) : δ3.40(2H,ABq SCH₂), 3.73(6H,d,PhOCH₃), 4.81(1H,d,C₆-H), 5.12(4H,d,-PhOCH₂PhOCH₃), 5.42(2H,ABq, =N-OCH₂), 5.99(1H.dd,C₇-H), 6.60(1H,t,C₃-H), 6.67(1H,s,이소옥사졸-H), 6.8∼7.6(12H,m,페닐-H,티아졸-H). ¹ H-NMR (CDCl ₃ ): δ 3.40 (2H, ABq SCH ₂ ), 3.73 (6H, d, PhOCH ₃ ), 4.81 (1H, d, C ₆ -H), 5.12 (4H, d, -PhOCH ₂ PhOCH ₃ ), 5.42 (2H, ABq, = N-OCH ₂ ), 5.99 (1H.dd, C ₇ -H), 6.60 (1H, t, C ₃ -H), 6.67 (1H, s, isooxa Sol-H), 6.8-7.6 (12H, m, phenyl-H, thiazole-H).

[실시예 4]Example 4

(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-세펨-4-카르복실산 및 나트륨염(6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-hydroxyphenyl) isoxazol-5-yl- Methoxyimino} acetamido] -3-cepem-4-carboxylic acid and sodium salt

[화학식 5][Formula 5]

트리플루오로초산 0.6와 아니솔 86μl의 혼합물을 얼음물로 냉각시키고 3ml의 메틸렌클로리드에 녹여 적가한 다음 실온에서 1.5시간 동안 교반시킨다. 교반후 반응물을 감압농축시키고 농축물에 에틸에테르를 과량 가하여 교반시켜 나오는 고체를 여과, 건조시킨다. 이 고체 화합물을 물 3ml에 현탁시키고 탄산수소나트륨(18mg,0.214mmol)를 가하여 녹인다. 불용물을 여과, 제거시키고 여액을 역상크로마토그래피(고정상 : SEPRALYTM^TM; 이동상 : 20% 메탄올 수용액)하여 분리한 다음 냉동건조시키면 35mg의 목적 화합물을 거의 백색 고체로 얻는다.A mixture of 0.6 trifluoroacetic acid and 86 μl of anisole is cooled with ice water, dissolved in 3 ml of methylene chloride and added dropwise, followed by stirring at room temperature for 1.5 hours. After stirring, the reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the concentrate, followed by filtration and drying of the stirred solid. This solid compound is suspended in 3 ml of water and dissolved by addition of sodium bicarbonate (18 mg, 0.214 mmol). Insolubles were filtered off, the filtrate was separated by reverse phase chromatography (fixed phase: SEPRALY ^™ ; mobile phase: 20% aqueous methanol solution), and then lyophilized to yield 35 mg of the target compound as an almost white solid.

수율 : 56%Yield: 56%

¹H-NMR(CDCl₃) : δ3.38(2H,ABq,SCH₂), 5.09(1H,d,C₆-H), 5.34(2H,=N-OCH₂), 5.83(1H,d,C₇-H), 6.23(1H,d,C₃-H), 6.78(1H,s,이소옥사졸-H), 6.92(1H,d,페닐-H), 7.03(1H,s,티아졸-H), 7.15(1H,d,페닐-H), 7.23(1H,s,페닐-H). ¹ H-NMR (CDCl ₃ ): δ 3.38 (2H, ABq, SCH ₂ ), 5.09 (1H, d, C ₆ -H), 5.34 (2H, = N-OCH ₂ ), 5.83 (1H, d, C ₇ -H), 6.23 (1H, d, C ₃ -H), 6.78 (1H, s, isoxazole-H), 6.92 (1H, d, phenyl-H), 7.03 (1H, s, thiazole -H), 7.15 (1H, d, phenyl-H), 7.23 (1H, s, phenyl-H).

[실시예 5]Example 5

디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-카르바모일옥시메틸-세펨-4-카르복실레이트Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl) iso Oxazol-5-yl-methoxyimino} acetamido] -3-carbamoyloxymethyl-cepem-4-carboxylate

[화학식 6][Formula 6]

2-(2-아미노티아졸-4일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}초산(87mg,0.14mmol)를 0.5ml의 건조 디메틸포름아미드에 녹이고 빙냉하에서 트리에틸아민 20μl를 가하고 이어 파라-톨루엔술포닐클로리드(28mg,0.146mmol)를 가하고 동온도에서 5분 동안 교반한 다음 가하고 실온에서 30분간 교반시킨다. 반응물에 50ml에 에틸아세테이트를 가하고 물로 세척(15ml×3)하고 무수황산마그네슘으로 건조시키고 농축한 다음 농축물을 짧은 컬럼크로마토그래피(실리카겔 : 5g, 용매/에틸아세테이트)하여 정제하면 132mg의 목적화합물을 담황색 고체로 얻는다.2- (2-aminothiazol-4yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetic acid ( 87 mg, 0.14 mmol) was dissolved in 0.5 ml of dry dimethylformamide, and 20 µl of triethylamine was added under ice-cooling, followed by addition of para-toluenesulfonyl chloride (28 mg, 0.146 mmol), stirring for 5 minutes at room temperature, followed by room temperature. Stir for 30 minutes at. To the reaction was added 50 ml of ethyl acetate, washed with water (15 ml × 3), dried over anhydrous magnesium sulfate, concentrated, and the concentrate was purified by short column chromatography (silica gel: 5 g, solvent / ethyl acetate) to give 132 mg of the target compound. Obtained as a pale yellow solid.

수율 : 90%Yield: 90%

¹H-NMR(D₂O) : δ3.33(2H,ABq,SCH₂), 3.78(6H,d,PhOCH₃), 4.77(2H,ABq,CH₂OCNH₂), 4.9∼5.2(5H,m,OCH₂Ph,C₆-H), 5.34(2H,ABq,=N-OPCH₂), 5.96(1H,dd,C₇-H), 6.68(1H,s,이소옥사졸-H), 6.8∼7.6(23H,m,페닐-H,CHPh₂, 티아졸-H). ¹ H-NMR (D ₂ O): δ 3.33 (2H, ABq, SCH ₂ ), 3.78 (6H, d, PhOCH ₃ ), 4.77 (2H, ABq, CH ₂ OCNH ₂ ), 4.9 to 5.2 (5H, m, OCH ₂ Ph, C ₆ -H), 5.34 (2H, ABq, = N-OPCH ₂ ), 5.96 (1H, dd, C ₇ -H), 6.68 (1H, s, isoxazole-H), 6.8 to 7.6 (23H, m, phenyl-H, CHPh ₂ , thiazole-H).

[실시예 6]Example 6

(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-카르바모일옥시메틸-3-세펨-4-카르복실산 및 나트륨염(6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-hydroxyphenyl) isoxazol-5-yl- Methoxyimino} acetamido] -3-carbamoyloxymethyl-3-cepem-4-carboxylic acid and sodium salt

[화학식 7][Formula 7]

디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-카르바모일옥시메틸-세펨-4-카르복실레이트(50mg,0.0458mmol)를 아니솔 45μl와 메틸렌클로리드 45μl에 녹이고 빙냉하에서 트리플루오르초산 0.45ml를 가하고 동온도에서 1.5시간 동안 교반시킨다. 반응물에 10ml의 이소프로필에테르를 가하고 고체를 여과한 다음 다시 이소프로필에테르로 잘 세척하고 건조시킨다. 이 고체를 물 2ml에 현탁시키고 탄산수소나트륨 7.6mg을 가하고 교반시킨 다음 불용물을 여과하고 여액을 역상크로마토그래피(고정상:SEPRALYTE^TM; 이동상 : 20% 메탄올 수용액)로 분리하고 냉동건조시키면 19mg의 목적화합물을 담황색 고체로 얻는다.Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl) iso Oxazol-5-yl-methoxyimino} acetamido] -3-carbamoyloxymethyl-cepem-4-carboxylate (50 mg, 0.0458 mmol) was dissolved in 45 μl of anisole and 45 μl of methylene chloride and cooled on ice. 0.45 ml of trifluoroacetic acid is added and stirred at the same temperature for 1.5 hours. 10 ml of isopropyl ether is added to the reaction, the solid is filtered, washed well with isopropyl ether and dried. This solid was suspended in 2 ml of water, 7.6 mg of sodium bicarbonate was added and stirred, the insolubles were filtered off, and the filtrate was separated by reverse phase chromatography (fixed phase: SEPRALYTE ^™ ; mobile phase: 20% aqueous methanol solution) and freeze-dried to obtain 19 mg of the purpose. The compound is obtained as a pale yellow solid.

수율 : 63%Yield: 63%

¹H-NMR(D₂O) : δ3.26(2H,ABq,J=5Hz,28Hz,SCH₂), 4.73(2H,ABq,CH₂OCONH₂), 5.15(1H,d,C₆-H), 5.41(2H,s,=NOCH₂), 5.80(1H,d,C₇-H), 6.95(2H,brs,이소옥사졸-H,페닐-H), 7.10(1H,s,티아졸-H), 7.25(1H,d,페닐-H), 7.30(1H,s,페닐-H). ¹ H-NMR (D ₂ O): δ 3.26 (2H, ABq, J = 5 Hz, 28 Hz, SCH ₂ ), 4.73 (2H, ABq, CH ₂ OCONH ₂ ), 5.15 (1H, d, C ₆ -H ), 5.41 (2H, s, = NOCH ₂ ), 5.80 (1H, d, C ₇ -H), 6.95 (2H, brs, isoxazole-H, phenyl-H), 7.10 (1H, s, thiazole -H), 7.25 (1H, d, phenyl-H), 7.30 (1H, s, phenyl-H).

[실시예 7]Example 7

파라-메톡시벤질(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시-페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-클로로메틸-3-세펨-4-카르복실레이트Para-methoxybenzyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxy- Phenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-chloromethyl-3-cepem-4-carboxylate

[화학식 8][Formula 8]

2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}초산(97mg,0.0157mmol)를 0.5ml의 디메틸포름아미드에 녹이고 빙냉하에서 트리에틸아민(46μl, 0.32mmol)을 가하고 이어서 파라-톨루엔술포닐클로리드(30mg,0.157mmol)를 가하고 10분간 교반한 다음이 혼합물에 파라-메톡시벤질(6R,7R)-7-아미노-3-클로로메틸-3-세펨-4-카르복실레이트 염산염(60mg,1.57mmol)를 가하고 중탕을 제거하고 실온에서 30분간 교반시킨다. 교반후 반응물에 50ml에 에틸아세테트를 가하고 유기용액을 물로 세척(10ml×3)하고 무수황산마그네슘으로 건조시킨 다음 농축,건조시키면 150mg의 목적화합물을 담황색 고체로 얻는다. 그대도 다음 반응에 사용한다.2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetic acid (97 mg, 0.0157 mmol) was dissolved in 0.5 ml of dimethylformamide, triethylamine (46 μl, 0.32 mmol) was added under ice-cooling, followed by addition of para-toluenesulfonyl chloride (30 mg, 0.157 mmol), followed by stirring for 10 minutes. Para-methoxybenzyl (6R, 7R) -7-amino-3-chloromethyl-3-cepem-4-carboxylate hydrochloride (60 mg, 1.57 mmol) is added to the mixture, the bath is removed and stirred at room temperature for 30 minutes. . After stirring, 50 ml of ethyl acetate was added to the reaction mixture. The organic solution was washed with water (10 ml × 3), dried over anhydrous magnesium sulfate, concentrated and dried to obtain 150 mg of the target compound as a pale yellow solid. You use it in your next reaction.

수율 : 99%Yield: 99%

¹H-NMR(D₂O) : δ3.42(2H,ABq,J=4Hz,18Hz,SCH₂), 3.81(9H,d,PhOCH₃), 4.42(2H,ABq,CH₂Cl), 5.00(1H,d,C₆-H), 5.11(4H,d,OCH₂Ph), 5.19(2H,d,CO₂CH₂Ph), 5.92(1H,dd,C₇-H), 6.62(1H,s,이소옥사졸-H), 6.7∼7.6(16H,m,페닐-H,티아졸-H). ¹ H-NMR (D ₂ O): δ 3.42 (2H, ABq, J = 4 Hz, 18 Hz, SCH ₂ ), 3.81 (9H, d, PhOCH ₃ ), 4.42 (2H, ABq, CH ₂ Cl), 5.00 (1H, d, C ₆ -H), 5.11 (4H, d, OCH ₂ Ph), 5.19 (2H, d, CO ₂ CH ₂ Ph), 5.92 (1H, dd, C ₇ -H), 6.62 (1H , s, isoxazole-H), 6.7-7.6 (16H, m, phenyl-H, thiazole-H).

[실시예 8]Example 8

파라-메톡시벤질(6R,7R)-7-[2-(2-아미노티아졸-4일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시-페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-에틸피리디니움-4-일)티오메틸-3-세펨-4-카르복실레이트 요오드Para-methoxybenzyl (6R, 7R) -7- [2- (2-aminothiazol-4yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxy-phenyl ) Isoxazol-5-yl-methoxyimino} acetamido] -3- (N-ethylpyridinium-4-yl) thiomethyl-3-cepem-4-carboxylate iodine

[화학식 9][Formula 9]

파라-메톡시벤질(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시-페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-클로로메틸-3-세펨-4-카르복실레이트(106mg,0.113mmol)를 5ml의 테트라히드로퓨란에 녹이고 빙냉하에서 요오드화나트륨 17mg과 N-에틸-4-피리돈티온을 16ml 가하고 실온에서 3.5시간 교반시킨다.Para-methoxybenzyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxy- Phenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-chloromethyl-3-cepem-4-carboxylate (106 mg, 0.113 mmol) was dissolved in 5 ml of tetrahydrofuran and iodide under ice-cooling. 16 mg of sodium and 16 ml of N-ethyl-4-pyridonethione are added and stirred at room temperature for 3.5 hours.

반응물에 60ml의 메틸렌클로리드를 가하고 포화소금물에 세척하고 무수황산마그네슘으로 건조시킨 다음 농축,건조시키면 93mg의 목적화합물을 얻는다.To the reaction was added 60 ml of methylene chloride, washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated and dried to obtain 93 mg of the target compound.

수율 : 70%Yield: 70%

¹H-NMR(CDCl₃) : δ1.51(3H,t,NCH₂CH₃), 3.45(2H,ABq,SCH₂), 3.78(3H,s,OCH₃), 3.81(6H,d,OCH₃), 4.27(2H,ABq,CH₂s-피리디닐), 4.41(2H,****,NCH₂CH₃), 5.0∼5.3(9H,m,OCH₂Ph,=NOCH₂,C₆-H), 6.87(1H,dd,C₇-H), 6.6∼7.6(17H,m,페닐-H,이소옥사졸-H,티아졸-H), 7.71(1H,d,피리디닐-H), 8.42(1H,d,피리디닐-H). ¹ H-NMR (CDCl ₃ ): δ1.51 (3H, t, NCH ₂ CH ₃ ), 3.45 (2H, ABq, SCH ₂ ), 3.78 (3H, s, OCH ₃ ), 3.81 (6H, d, OCH ₃ ), 4.27 (2H, ABq, CH ₂ s-pyridinyl), 4.41 (2H, ****, NCH ₂ CH ₃ ), 5.0 to 5.3 (9H, m, OCH ₂ Ph, = NOCH ₂ , C ₆ -H), 6.87 (1H, dd, C ₇ -H), 6.6-7.6 (17H, m, phenyl-H, isoxazole-H, thiazole-H), 7.71 (1H, d, pyridinyl-H ), 8.42 (1H, d, pyridinyl-H).

[실시예 9]Example 9

(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-에틸피리디니움-4-일)티오메틸-3-세펨-4-카르복실레이트(6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-dihydroxyphenyl) isoxazol-5-yl-meth Toxyimino} acetamido] -3- (N-ethylpyridinium-4-yl) thiomethyl-3-cepem-4-carboxylate

[화학식 10][Formula 10]

파라-메톡시벤질(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일)-메톡시이미노}아세트아미도]-3-(N-에틸피리디니움-4-일)티오메틸-3-세펨-4-카르복실레이트 요오드(86mg,0.0735mmol)를 80μl의 아니솔에 현탁시키고 빙냉하에서 트리플루오르초산 0.81ml를 가하고 동온도에서 1.5시간 동안 교반시킨다. 교반후 반응물에 이소프로필에테르 20ml를 가하고 나오는 고체를 여과하여 이소프로필에테르로 세척한 다음 얻어진 물질을 5ml의 물에 현탁시키고 7% 탄산수소화나트륨 수용액으로 pH 약 7.5로 조절하고 고체를 여과한다. 다시 물로 세척하고 에틸에테르로 세척한 후 건조시키면 26mg의 목적화합물을 담황체 고체로 얻는다.Para-methoxybenzyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl ) Isoxazol-5-yl) -methoxyimino} acetamido] -3- (N-ethylpyridinium-4-yl) thiomethyl-3-cepem-4-carboxylate iodine (86 mg, 0.0735 mmol) is suspended in 80 μl of anisole and 0.81 ml of trifluoroacetic acid is added under ice-cooling and stirred at the same temperature for 1.5 hours. After stirring, 20 ml of isopropyl ether was added to the reaction mixture, and the solid was filtered and washed with isopropyl ether. The obtained material was suspended in 5 ml of water, adjusted to pH 7.5 with an aqueous 7% sodium bicarbonate solution, and the solid was filtered. Again washed with water, washed with ethyl ether and dried to give 26 mg of the target compound as a pale sulfur solid.

수율 : 50%Yield: 50%

¹H-NMR(DMSO-d₆) : 1.44(3H,t,NCH₂CH₃), 3.30(2H,ABq,SCH₂), 4.51(4H,m,NCH₂CH₃-CH₂SAr), 5.03(1H,d,C₆-H), 5.23(2H,s,=NOCH₂), 5.65(1H,dd,C₇-H), 6.74(1H,s,이소옥사졸-H), 6.95(1H,s,티아졸-H), 6.7∼7.4(5H,m,페닐-H,피리디닐-H), 8.23(2H,d,피리니딜-H), 8.70(2H,d,피리디닐-H), 9.63(1H,d,NH). ¹ H-NMR (DMSO-d ₆ ): 1.44 (3H, t, NCH ₂ CH ₃ ), 3.30 (2H, ABq, SCH ₂ ), 4.51 (4H, m, NCH ₂ CH ₃ -CH ₂ SAr), 5.03 (1H, d, C ₆ -H), 5.23 (2H, s, = NOCH ₂ ), 5.65 (1H, dd, C ₇ -H), 6.74 (1H, s, isoxazole-H), 6.95 (1H , s, thiazole-H), 6.7-7.4 (5H, m, phenyl-H, pyridinyl-H), 8.23 (2H, d, pyridinyl-H), 8.70 (2H, d, pyridinyl-H) , 9.63 (1 H, d, NH).

[실시예 10]Example 10

파라-메톡시벤질(6R,7R)-7-[2-(2-트리페닐메틸아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-디페닐메톡시카르보닐메틸피리디니움-4-일)티오메틸-3-세펨-4-카르복실레이트 요오드Para-methoxybenzyl (6R, 7R) -7- [2- (2-triphenylmethylaminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxy Benzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3- (N-diphenylmethoxycarbonylmethylpyridinium-4-yl) thiomethyl-3-cepem-4- Carboxylate Iodine

[화학식 11][Formula 11]

파라-메톡시벤질(6R,7R)-7-[2-(2-트리틸아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시-페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-클로로메틸-3-세펨-4-카르복실레이트(150mg,0.13mmol)를 10ml의 테트라히드로퓨란에 녹이고 빙냉하에서 요오드화나트륨 23mg(0.15mmol)과 N-디페닐메톡시카르보닐메틸-4-피리도티온을 51mg(0.15mmol) 가하고 실온에서 1.5시간 교반시킨다.Para-methoxybenzyl (6R, 7R) -7- [2- (2-tritylaminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyl Oxy-phenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-chloromethyl-3-cepem-4-carboxylate (150 mg, 0.13 mmol) is dissolved in 10 ml of tetrahydrofuran and ice-cooled 23 mg (0.15 mmol) of sodium iodide and 51 mg (0.15 mmol) of N-diphenylmethoxycarbonylmethyl-4-pyridothione are added thereto, followed by stirring at room temperature for 1.5 hours.

반응물에 50ml에 메틸렌클로리드를 가하고 포화소금물로 세척하고 무수황산마그네슘으로 건조시킨 다음 이소프로필에테르를 사용하여 고체화시키면 165mg(0.10mmol)의 목적화합물을 얻는다.Methylene chloride is added to 50 ml of the reaction, washed with saturated brine, dried over anhydrous magnesium sulfate, and solidified with isopropyl ether to obtain 165 mg (0.10 mmol) of the target compound.

수율 : 83%Yield: 83%

¹H-NMR(CDCl₃) : δ3.21(2H,ABq,C₂-H), 3.70(3H,s,-PhOCH₃), 3.78(6H,s+s,-PhOCH₃), 4.60(2H,ABq,CH₂s-피리디닐), 4.96(1H,d,C₆-H) 5.10∼5.21(6H,m,-OCH₂-), 5.38(2H,s,-NOCH₂-), 5.64(2H,s,-NCH₂), 5.8(1H,q,C₇-H), 6.62∼7.5(43H,m,-CHPh₂,카테콜-H,이소옥사졸-H,티아졸-H), 7.50(2H,d,피리딘-H), 8.35(2H,d,피리딘-H). ¹ H-NMR (CDCl ₃ ): δ 3.21 (2H, ABq, C ₂ -H), 3.70 (3H, s, -PhOCH ₃ ), 3.78 (6H, s + s, -PhOCH ₃ ), 4.60 (2H , ABq, CH ₂ s-pyridinyl), 4.96 (1H, d, C ₆ -H) 5.10 to 5.21 (6H, m, -OCH _2- ), 5.38 (2H, s, -NOCH _2- ), 5.64 ( 2H, s, -NCH ₂ ), 5.8 (1H, q, C ₇ -H), 6.62-7.5 (43H, m, -CHPh ₂ , catechol-H, isoxazole-H, thiazole-H), 7.50 (2H, d, pyridine-H), 8.35 (2H, d, pyridine-H).

[실시예 11]Example 11

(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디히드록시페닐)이소옥사졸-5-일-케녹시이미노}아세트아미도]-3-(1-에틸카르복시메틸피리디니움-4-일)티오메틸-3-세펨-4-카르복실산 및 나트륨염(6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-dihydroxyphenyl) isoxazol-5-yl-kenoxy Cyimino} acetamido] -3- (1-ethylcarboxymethylpyridinium-4-yl) thiomethyl-3-cepem-4-carboxylic acid and sodium salt

[화학식 12][Formula 12]

파라-메톡시벤질(6R,7R)-7-[2-(2-트리페닐메틸아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(1-디페닐메톡시카르보닐메틸피리디니움-4-일)티오메틸-3-세펨-4-카르복실레이트 요오드(150mg,0.09mmol)를 0.4ml의 아니솔에 현탁시키고 빙냉하에서 트리플루오르초산 2.5ml를 가하고 동온도에서 2.5시간 동안 교반시킨다. 교반후 반응물에 이소프로필에테르를 가하고 나오는 고체를 여과하여 이소프로필에테르로 세척한 다음 얻어진 물질을 물에 현탁시키고 5% 탄산수소화나트륨 수용액으로 pH 약 7.5로 조절하고 고체를 용해시키고 C18 역상관크로마토그래피(H₂O:MeOH=4:1)를 사용하여 분리하고 동결건조하면 목적화합물 35mg(0.05mmol)를 얻을 수 있다.Para-methoxybenzyl (6R, 7R) -7- [2- (2-triphenylmethylaminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxy Benzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3- (1-diphenylmethoxycarbonylmethylpyridinium-4-yl) thiomethyl-3-cepem-4- Carboxylate iodine (150 mg, 0.09 mmol) is suspended in 0.4 ml of anisole, 2.5 ml of trifluoroacetic acid is added under ice cooling and stirred at the same temperature for 2.5 hours. After stirring, isopropyl ether was added to the reaction mixture, and the solid was filtered and washed with isopropyl ether. The obtained material was suspended in water, adjusted to pH about 7.5 with 5% aqueous sodium bicarbonate solution, the solid was dissolved, and C18 reversed-choromatography Separation using (H ₂ O: MeOH = 4: 1) and lyophilization yielded 35 mg (0.05 mmol) of the target compound.

수율 : 50%Yield: 50%

¹H-NMR(DMSO-d₆) : 2.81(2H,ABq,C₂-H), 3.81(2H,ABq,-CH₂S-), 4.95(2H,s,-NCH₂), 5.06(1H,d,C₆-H), 5.31(2H,s,-NOCH₂), 5.75(1H,dd,C₇-H), 6.66(1H,s,이소옥사졸-H), 6.71(1H,d,카테클-H), 6.93(1H,s,티아졸-H), 6.95(1H,d,카테콜-H), 7.08(1H,s,카테콜-H), 7l.46(2H,d,피리딘-H), 8.19(2H,d,피리딘-H). ¹ H-NMR (DMSO-d ₆ ): 2.81 (2H, ABq, C ₂ -H), 3.81 (2H, ABq, -CH ₂ S-), 4.95 (2H, s, -NCH ₂ ), 5.06 (1H , d, C ₆ -H), 5.31 (2H, s, -NOCH ₂ ), 5.75 (1H, dd, C ₇ -H), 6.66 (1H, s, isoxazole-H), 6.71 (1H, d , Catecle-H), 6.93 (1H, s, thiazole-H), 6.95 (1H, d, catechol-H), 7.08 (1H, s, catechol-H), 7l.46 (2H, d , Pyridine-H), 8.19 (2H, d, pyridine-H).

[실시예 12]Example 12

디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-메틸테트라졸-5-일)티오메틸)3-세펨-4-카르복실레이트Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl) iso Oxazol-5-yl-methoxyimino} acetamido] -3- (N-methyltetrazol-5-yl) thiomethyl) 3-cepem-4-carboxylate

[화학식 13][Formula 13]

2-(2-아미노티아졸-4-일)-2(8)-{3-(3,4-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노} 초산(60mg, 0.0974mmol)를 디메틸포름아미드 0.5ml에 녹이고 빙냉하에서 트리에틸아민 20μl를 가하고 이어 파라-톨루엔술포닐클로리드를 28mg 가하고 5분 동안 교반시킨 후 이 혼합물에 디페닐메틸(6R, 7R)-7-아미노-3-(N-메틸테트라졸-5-일)티오메틸-3-세펨-4-카르복실레이트(48mg,0.0974mmol)를 가한 다음 실온에서 30분 교반시킨다. 반응물에 에틸아세테이트 50ml를 가하고 물로 세척(15ml×3)하고 무수황산마그네슘으로 건조시킨 다음 농축시킨다. 이 농축물을 감압건조시키면 100mg의 목적화합물을 담황색 고체로 얻는다.2- (2-aminothiazol-4-yl) -2 (8)-{3- (3,4-para-methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetic acid (60 mg , 0.0974 mmol) in 0.5 ml of dimethylformamide, 20 µl of triethylamine were added under ice-cooling, followed by 28 mg of para-toluenesulfonyl chloride and stirring for 5 minutes, followed by diphenylmethyl (6R, 7R) -7. -Amino-3- (N-methyltetrazol-5-yl) thiomethyl-3-cepem-4-carboxylate (48 mg, 0.0974 mmol) was added and stirred at room temperature for 30 minutes. 50 ml of ethyl acetate was added to the reaction, washed with water (15 ml × 3), dried over anhydrous magnesium sulfate, and concentrated. Drying the concentrate under reduced pressure yields 100 mg of the target compound as a pale yellow solid.

수율 : 94%Yield: 94%

¹H-NMR(CDCl₃) : δ3.55∼3.90(11H,m,PhOCH₃,N-CH₃,SCH₂), 4.23(2H,ABq,CH₂S-), 4.9∼5.1(5H,m,OCH₂Ph,C₆-H), 5.29(2H,s,=N-OCH₂), 5.88(1H,dd,C₇-H), 6.7∼7.5(24H,m,페닐-H,티아졸-H,이소옥사졸-H). ¹ H-NMR (CDCl ₃ ): δ 3.55 to 3.90 (11H, m, PhOCH ₃ , N-CH ₃ , SCH ₂ ), 4.23 (2H, ABq, CH ₂ S-), 4.9 to 5.1 (5H, m , OCH ₂ Ph, C ₆ -H), 5.29 (2H, s, = N-OCH ₂ ), 5.88 (1H, dd, C ₇ -H), 6.7-7.5 (24H, m, phenyl-H, thiazole -H, isoxazole-H).

[실시예 13]Example 13

(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-메틸테트라졸-5-일)티오메틸-3-세펨-4-카르복실산 및 나트륨염및 나트륨염(6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-dihydroxyphenyl) isoxazol-5-yl-meth Toxyimino} acetamido] -3- (N-methyltetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid and sodium salt and sodium salt

[화학식 14][Formula 14]

디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-메틸테트라졸-5-일)티오메틸-3-세펨-4-카르복실레이트(100mg,0.0914mmol)를 아니솔 90μl와 메틸렌클로리드 90μl에 녹이고 빙냉하에서 트리플루오르초산 0.9ml를 가한 다음 동온도에서 1.5시간 동안 교반시킨다. 반응물에 20ml에 에틸에테르를 가하고 고체를 여과하고 에틸에테르로 잘 세척한 다음 얻어진 담황색 고체 50mg을 물 2ml에 현탁시키고 탄산수소나트륨 11mg을 가하여 녹이고 불용물을 여과하여 제거하고 여액을 역상크로마토그래피(고정상:SEPRALYTE^TM; 이동상:20% 메탄올 수용액)으로 분리한다. 분리된 용액을 냉동건조시키면 16mg의 목적화합물을 백색 고체로 얻는다.Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl) iso Anisole with oxazol-5-yl-methoxyimino} acetamido] -3- (N-methyltetrazol-5-yl) thiomethyl-3-cepem-4-carboxylate (100 mg, 0.0914 mmol) Dissolve in 90 µl and 90 µl of methylene chloride, add 0.9 ml of trifluoroacetic acid under ice-cooling, and stir at the same temperature for 1.5 hours. To the reaction was added 20 ml of ethyl ether, the solid was filtered and washed well with ethyl ether. 50 mg of the pale yellow solid obtained was suspended in 2 ml of water, dissolved by adding 11 mg of sodium bicarbonate. The insolubles were filtered off and the filtrate was reversed-phase chromatography (fixed phase). (SEPRALYTE ^™ ; mobile phase: 20% aqueous methanol solution). Lyophilization of the separated solution yielded 16 mg of the desired compound as a white solid.

수율 : 25%Yield: 25%

¹H-NMR(D₂O) : δ3.31(2H,ABq,J=5Hz,28Hz,SCH₂), 3.98(3H,s,NCH₃), 4.04(2H,ABq,CH₂S-), 5.12(1H,d,C₆-H), 5.41(2H,s,=N-OCH₂), 5.74(1H,d,C₇-H), 6.89(2H,d,이소옥사졸-H,페닐-H), 7.10(1H,s,티아졸-H), 7.20(1H,d,페닐-H), 7.28(1H,s,페닐-H). ¹ H-NMR (D ₂ O): δ 3.31 (2H, ABq, J = 5 Hz, 28 Hz, SCH ₂ ), 3.98 (3H, s, NCH ₃ ), 4.04 (2H, ABq, CH ₂ S-), 5.12 (1H, d, C ₆ -H), 5.41 (2H, s, = N-OCH ₂ ), 5.74 (1H, d, C ₇ -H), 6.89 (2H, d, isoxazole-H, phenyl -H), 7.10 (1H, s, thiazole-H), 7.20 (1H, d, phenyl-H), 7.28 (1H, s, phenyl-H).

[실시예 14]Example 14

파라-메톡시벤질(6R,7R)-7-[2-(2-아미노티아졸-4일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시-페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-메톡시메틸-3-세펨-4-카르복실레이트Para-methoxybenzyl (6R, 7R) -7- [2- (2-aminothiazol-4yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxy-phenyl ) Isoxazol-5-yl-methoxyimino} acetamido] -3-methoxymethyl-3-cepem-4-carboxylate

[화학식 15][Formula 15]

건조 디메틸포름아미드 0.5ml에 2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}초산(120mg,0.194mmol)를 녹이고 트리에틸아민 28μl를 가하고 빙냉하에서 파라-톨루엔술포닐클로리드 44mg을 가하고 5분간 교반시킨다.2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl) isoxazole-5- in 0.5 ml of dry dimethylformamide Dissolve 1-methoxyimino} acetic acid (120 mg, 0.194 mmol), add 28 μl of triethylamine, and add 44 mg of para-toluenesulfonyl chloride under ice-cooling and stir for 5 minutes.

이 혼합물에 파라-메톡시벤질(6R,7R)-7-아미노-3-메톡시메틸-3-세펨-4-카르복실레이트(120mg,0.329mmol)을 디메틸포름아미드 0.5ml에 녹여 적가한 다음 실온에서 30분간 교반시킨다. 반응물에 에틸아세테이트 50ml를 가하고 물로 세척하고(15ml×4), 무수황산마그네슘으로 건조시키고 농축시킨 다음 컬럼크로마토그래피(실리카겔; 용매; n-헥산; 에틸아세테이트=1:2)로 분리하면 170mg의 목적화합물을 황색고체로 얻는다.To this mixture was dissolved para-methoxybenzyl (6R, 7R) -7-amino-3-methoxymethyl-3-cepem-4-carboxylate (120 mg, 0.329 mmol) in 0.5 ml of dimethylformamide and added dropwise. Stir for 30 minutes at room temperature. 50 ml of ethyl acetate was added to the reaction, washed with water (15 ml × 4), dried over anhydrous magnesium sulfate, concentrated, and separated by column chromatography (silica gel; solvent; n-hexane; ethyl acetate = 1: 2). The compound is obtained as a yellow solid.

수율 : 91%Yield: 91%

¹H-NMR(CDCl₃) : δ3.23(3H,s,-CH₂OCH₃), 3.45(2H,brs,SCH₃), 3.80(9H,s,-PhOCH₃), 4.24(2H,ABq,CH₂OCH₃), 5.01(1H,d,C₆-H), 5.10(4H,d,-OCH₂Ph), 5.19(2H,s,-CH₂OPh), 5.40(2H,ABq,=NOCH₂), 5.99(1H,dd,C₇-H), 6.61(1H,s,이소옥사졸-H), 6.7∼7.6(16H,m,페닐-H,티아졸-H). ¹ H-NMR (CDCl ₃ ): δ 3.23 (3H, s, -CH ₂ OCH ₃ ), 3.45 (2H, brs, SCH ₃ ), 3.80 (9H, s, -PhOCH ₃ ), 4.24 (2H, ABq , CH ₂ OCH ₃ ), 5.01 (1H, d, C ₆ -H), 5.10 (4H, d, -OCH ₂ Ph), 5.19 (2H, s, -CH ₂ OPh), 5.40 (2H, ABq, = NOCH ₂ ), 5.99 (1H, dd, C ₇ -H), 6.61 (1H, s, isoxazole-H), 6.7-7.6 (16H, m, phenyl-H, thiazole-H).

[실시예 15]Example 15

(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-메톡시메틸-3-세펨-4-카르복실산 및 나트륨염(6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-hydroxyphenyl) isoxazol-5-yl- Methoxyimino} acetamido] -3-methoxymethyl-3-cepem-4-carboxylic acid and sodium salt

[화학식 16][Formula 16]

파라-메톡시벤질(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-메톡시메틸-3-세펨-4-카르복실레이트(140mg,0.145mmol)를 아니솔 90μl와 메틸렌클로리드 90μl에 녹이고 빈냉하에서 트리플루오로 초산 0.9ml를 가한다음 동온도에서 1.5시간 동안 교반시킨다. 반응물에 20ml에서 에틸에테르를 가하고 고체를 여과한 후 다시 에틸에테르로 잘 세척한 다음 건조시킨다. 이 고체를 물 2ml에 현탁시키고 탄산 사수나트륨 23mg를 가하고 녹이고 교반한 후 불용물을 여과하고 여액을 역상크로마토그래피(고정상:SEPRALYTE^TM, 이동상:20% 메탄올 수용액)로 분리한 다음 냉각건조시키면 33mg의 목적화합물을 담황체고체로 얻는다.Para-methoxybenzyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl Isoxazol-5-yl-methoxyimino} acetamido] -3-methoxymethyl-3-cepem-4-carboxylate (140 mg, 0.145 mmol) was dissolved in 90 μl of anisole and 90 μl of methylene chloride. 0.9 ml of trifluoroacetic acid was added under poor cooling, followed by stirring at the same temperature for 1.5 hours. Ethyl ether was added to the reaction in 20 ml, the solid was filtered, washed well with ethyl ether and dried. The solid was suspended in 2 ml of water, 23 mg of sodium carbonate added, dissolved and stirred. The insolubles were filtered off, and the filtrate was separated by reverse phase chromatography (fixed phase: SEPRALYTE ^TM , mobile phase: 20% aqueous methanol solution), and then cooled to dryness. The target compound is obtained as a pale sulfur solid.

수율 : 37%Yield: 37%

¹H-NMR(D₂O) : δ3.18(2H,ABq,J=Hz,28Hz,SCH₂), 3.20(3H,s,CH₂OCH₃), 4.067(2H,ABq,J=3Hz,10Hz,CH₂OCH₃), 5.13(1H,d,C₆-H), 5.40(2H,s,=N-OCH₂), 5.76(1H,d,C₇-H), 6.92(1H,s,이소옥사졸-H), 7.01(1H,d,페닐-H), 7.08(1H,s,티아졸-H), 7.27(1H,d,페닐-H), 7.34(1H,s,페닐-H). ¹ H-NMR (D ₂ O): δ 3.18 (2H, ABq, J = Hz, 28 Hz, SCH ₂ ), 3.20 (3H, s, CH ₂ OCH ₃ ), 4.067 (2H, ABq, J = 3 Hz, 10 Hz, CH ₂ OCH ₃ ), 5.13 (1H, d, C ₆ -H), 5.40 (2H, s, = N-OCH ₂ ), 5.76 (1H, d, C ₇ -H), 6.92 (1H, s , Isoxazole-H), 7.01 (1H, d, phenyl-H), 7.08 (1H, s, thiazole-H), 7.27 (1H, d, phenyl-H), 7.34 (1H, s, phenyl- H).

[실시예 16]Example 16

파라-메톡시벤질(6R,7R)-7-[2-(2-트리페닐메틸아미노티아졸-4-일)-2(Z)-[3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-피리디니움메틸-3-세펨-4-카르복실레이트 요오드Para-methoxybenzyl (6R, 7R) -7- [2- (2-triphenylmethylaminothiazol-4-yl) -2 (Z)-[3- (3,4-di-para-methoxy Benzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-pyridiniummethyl-3-cepem-4-carboxylate iodine

[화학식 17][Formula 17]

2-(2-트리페닐메틸아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}초산(272mg,0.317mmol)을 디메틸 포름아미드 2ml에 녹이고 빙냉하에서 트리에틸아민(48μl, 0.344mmol)을 가하고 곧 파라-톨루엔술포닐클로리드(6mg,0.035mmol)을 가하고 10분동안 교반한 다음 이 혼합물에 파라-메톡시벤질(6R,7R)-7-아미노-3-클로로메틸-3-세팸-4-카르복실레이트(117mg,0.317mmol)를 가하고 실온에서 30분 교반한 에틸아세테이트 100ml를 가하고 물로 세척(20ml×3)하고 무수황산마그네슘으로 건조시켜 얻은 280mg의 화합물(고체)을 아세톤 4ml에 녹이고 요오드화나트륨(37mg,0.246mmol)을 가하고 실온에서 2시간 동안 교반한다. 2시간 교반후 반응물을 감압농축시키고 건조 테트라히드로퓨란을 가하고 불용물을 제거한 다음 여액을 농축시키면 약 300mg의 갈색고체화합물을 얻는다. 이 고체화합물을 디메틸술폭시드 0.9ml에 녹이고 피리딘(38ml,0.46mmol)를 가하고 실온에서 2시간동안 교반시킨 다음 과량의 에틸에체르로 첨가하여 요오드염을 침전시키고 침전물에 30ml의 클로로포름과 15ml의 에틸아세테이트 그리고 포화소금 30ml를 가하여 흔들어준 다음 유기층을 분리하고 물로 세척하고(15ml×2), 무수황산마그네슘으로 건조시키고 농축시키면 250mg의 미정제 목적화합물을 진한갈색 고체로 얻는다.2- (2-triphenylmethylaminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl-methoxy Mino} acetic acid (272mg, 0.317mmol) was dissolved in 2ml of dimethyl formamide, triethylamine (48μl, 0.344mmol) was added under ice-cooling, para-toluenesulfonyl chloride (6mg, 0.035mmol) was added and stirred for 10 minutes. Para-methoxybenzyl (6R, 7R) -7-amino-3-chloromethyl-3-cepam-4-carboxylate (117 mg, 0.317 mmol) was added to the mixture, and 100 ml of ethyl acetate was stirred at room temperature for 30 minutes. 280 mg of a compound (solid) obtained by washing with water (20 ml × 3) and drying over anhydrous magnesium sulfate was dissolved in 4 ml of acetone, sodium iodide (37 mg, 0.246 mmol) was added and stirred at room temperature for 2 hours. After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure, dried tetrahydrofuran was added, the insolubles were removed, and the filtrate was concentrated to give about 300 mg of a brown solid compound. This solid compound was dissolved in 0.9 ml of dimethyl sulfoxide, pyridine (38 ml, 0.46 mmol) was added, stirred at room temperature for 2 hours, and then added with excess ethyl cher to precipitate an iodine salt. The precipitate was precipitated with 30 ml of chloroform and 15 ml of ethyl. After shaking with 30 ml of acetate and saturated salt, the organic layer was separated, washed with water (15 ml x 2), dried over anhydrous magnesium sulfate and concentrated to give 250 mg of the crude target compound as a dark brown solid.

수율 : 57%Yield: 57%

¹H-NMR(DMSO-d₆) : δ3.41(2H,ABq,J=4Hz,SCH₂), 3.70(9H,s,-CH₂PhOCH₃), 4.97(1H,d,C₆-H), 5.09(4H,s,-PhOCH₂PhOCH₃), 5.21(2H,s,CO₂CH₂PhOCH₃), 5.2∼5.5(2H,m,CH₂-피리디닐), 5.57(2H,s,=N-OCH₂), 5.83(1H,dd,C₇-H), 6.77(1H,s,이소옥사졸-H), 6.8∼7.6(31H,m,페닐-H,티아졸-H), 8.15, 8.61, 8.92, 8.98(5H,m,피리디닐-H), 9.70(1H,d,NH). ¹ H-NMR (DMSO-d ₆ ): δ3.41 (2H, ABq, J = 4Hz, SCH ₂ ), 3.70 (9H, s, -CH ₂ PhOCH ₃ ), 4.97 (1H, d, C ₆ -H ), 5.09 (4H, s, -PhOCH ₂ PhOCH ₃ ), 5.21 (2H, s, CO ₂ CH ₂ PhOCH ₃ ), 5.2 to 5.5 (2H, m, CH ₂ -pyridinyl), 5.57 (2H, s, = N-OCH ₂ ), 5.83 (1H, dd, C ₇ -H), 6.77 (1H, s, isoxazole-H), 6.8-7.6 (31H, m, phenyl-H, thiazole-H), 8.15, 8.61, 8.92, 8.98 (5H, m, pyridinyl-H), 9.70 (1H, d, NH).

[실시예 17]Example 17

(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(3,4-디히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-피리디니움메틸-3-세펨-4-카르복실레이트(6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (3,4-dihydroxyphenyl) isoxazol-5-yl-meth Toxyimino} acetamido] -3-pyridiniummethyl-3-cepem-4-carboxylate

[화학식 18][Formula 18]

파라-메톡시벤질(6R,7R)-7-[2-(2-트리페닐메틸아미노티아졸-4-일)-2(Z)-{3-(3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노]아세트아미도]-3-피리디니움메틸-3-세펨-4-카르복시레이트 요오드(90mg,0.064mmol)를 아니솔 0.2ml에 녹이고 90% 포름산 160μl와 진한 염산 80μl를 가하고 실온에서 2시간 교반시킨다.Para-methoxybenzyl (6R, 7R) -7- [2- (2-triphenylmethylaminothiazol-4-yl) -2 (Z)-{3- (3,4-di-para-methoxy Benzyloxyphenyl) isoxazol-5-yl-methoxyimino] acetamido] -3-pyridiniummethyl-3-cepem-4-carboxylate iodine (90 mg, 0.064 mmol) was dissolved in 0.2 ml of anisole. 160 µl of 90% formic acid and 80 µl of concentrated hydrochloric acid are added and stirred at room temperature for 2 hours.

교반후 이소프로필알콜 4ml를 가하고 희석시키고 빙냉하에서 25% 암모니아수로 반응물을 pH 약 3.5로 조절하고 실온에서 18시간 교반시킨다.After stirring, 4 ml of isopropyl alcohol was added thereto, diluted, and the reaction was adjusted to pH about 3.5 with 25% ammonia water under ice-cooling and stirred at room temperature for 18 hours.

반응물을 감압농축시키고 잘 건조시킨다음 얻은 고체에 메탄올을 가하고 불용물을 여과 제거한 다음 농축시킨다.The reaction is concentrated under reduced pressure, dried well and methanol is added to the resulting solid, the insolubles are filtered off and concentrated.

여기에 에틸에테르를 가하고 고체화하고 여과시켜 에틸에테르로 잘 세척하고 건조시키면 18mg의 목적화합물을 농확색고체로 얻는다.Ethyl ether was added thereto, solidified, filtered, washed well with ethyl ether, and dried to obtain 18 mg of the target compound as a dark solid.

수율 : 44%Yield: 44%

¹H-NMR(DMSO-d₆) : δ3.43(2H,ABq,SCH₂), 5.06(1H,d,C₆-H), 5.24(2H,d,=N-OCH₂), 5.56(2H,ABq,CH₂-피리디닐), 5.94(1H,dd,C₇-H), 6.7∼7.5(5H,페닐-H,이소옥사졸-H,티아졸-H), 8.19, 8.65, 8.98, 9.03(5H,m,피리디닐-H), 9.78(1H,d,NH). ¹ H-NMR (DMSO-d ₆ ): δ3.43 (2H, ABq, SCH ₂ ), 5.06 (1H, d, C ₆ -H), 5.24 (2H, d, = N-OCH ₂ ), 5.56 ( 2H, ABq, CH ₂ -pyridinyl), 5.94 (1H, dd, C ₇ -H), 6.7-7.5 (5H, phenyl-H, isoxazole-H, thiazole-H), 8.19, 8.65, 8.98 , 9.03 (5H, m, pyridinyl-H), 9.78 (1H, d, NH).

[실시예 18]Example 18

디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미드]-3-아세톡시메틸-3-세펨-4-카르복실레이트Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-para-methoxybenzyl Oxyphenyl) isoxazol-5-yl-methoxyimino} acetamide] -3-acetoxymethyl-3-cepem-4-carboxylate

[화학식 19][Formula 19]

디메틸포름아미드 0.5ml에 2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-파라=메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}초산(92mg,0.135mmol)을 녹이고 트리에틸아민 21μl를 가한 다음 빙수로 냉각시키고 파라-톨루엔술포닐클로리드 28mg을 가하고 5분간 교반한후 디페닐메틸(6R,7R)-7-아미노-3-아세톡시메틸-3-세팸-4-카르복실레이트(60mg,0.135mmol)를 가하고 동온도에서 30분 교반시킨다. 반응물에 50ml의 에틸아세테이트를 가하고 물로 세척(15ml×3)한 다음 무수황산마그네슘으로 건조시키고 농축시킨다. 농축물을 관크로마토그라피(실리카겔, 용리액 ; 핵산; 에틸아세테이트=1:1)하면 72mg의 목적화합물을 담황색고체로 얻는다.2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-para = methoxybenzyloxyphenyl) isoxazole in 0.5 ml of dimethylformamide -5-yl-methoxyimino} acetic acid (92mg, 0.135mmol) was dissolved, triethylamine 21μl was added, cooled with ice water, 28mg of para-toluenesulfonyl chloride was added and stirred for 5 minutes, followed by diphenylmethyl (6R, 7R) -7-amino-3-acetoxymethyl-3-cepam-4-carboxylate (60 mg, 0.135 mmol) was added and stirred at the same temperature for 30 minutes. 50 ml of ethyl acetate was added to the reaction, washed with water (15 ml × 3), dried over anhydrous magnesium sulfate, and concentrated. The concentrate was subjected to tube chromatography (silica gel, eluent; nucleic acid; ethyl acetate = 1: 1) to give 72 mg of the target compound as a pale yellow solid.

수율 : 48%Yield: 48%

¹H-NMR(CDCl₃) : δ2.00(3H,s,-OAc), 3.48(2H,ABq,SCH₂), 3.82(6H,s,OCH₃), 5.00, 5.04(4H,d,OCH₂Ar), 5.80(1H,d,C₆-H), 5.40(2H,brs,=N-OCH₂), 5.47(2H,ABq,CH₂OAc), 6.08(1H,dd,C₇-H), 6.81(1H,s,이소옥사졸-H), 6.82∼7.50(20H,m,페닐-H,-OCHPh₂,티아졸-H), 7.54(1H,s,디클로로페닐-H). ¹ H-NMR (CDCl ₃ ): δ 2.00 (3H, s, -OAc), 3.48 (2H, ABq, SCH ₂ ), 3.82 (6H, s, OCH ₃ ), 5.00, 5.04 (4H, d, OCH ₂ Ar), 5.80 (1H, d, C ₆ -H), 5.40 (2H, brs, = N-OCH ₂ ), 5.47 (2H, ABq, CH ₂ OAc), 6.08 (1H, dd, C ₇ -H ), 6.81 (1H, s, isoxazole-H), 6.82 to 7.50 (20H, m, phenyl-H, -OCHPh ₂ , thiazole-H), 7.54 (1H, s, dichlorophenyl-H).

[실시예 19]Example 19

(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-아세톡시메틸-3-세펨-4-카르복실산 및 나트륨염(6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-hydroxyphenyl) isooxa Zol-5-yl-methoxyimino} acetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid and sodium salt

[화학식 20][Formula 20]

아니솔 50μl과 메틸렌클로리드 50μl에 디페닐메틸(6R,7R)-7-[2-2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-에톡시이미노}아세트아미도]-3-아세톡시메틸-3-세펨-4-카르복실레이트 67mg을 녹이고 빙수로 냉각시키고 트리플루오르초산 0.35ml를 가하고 실온에서 1.5시간 교반한다. 반응물에 이소프로필 에테르 20ml를 가하고 나오는 고체를 여과하여 에테르로 세척한 후 건조시킨다. 건조된 고체를 3ml의 물에 역상 관크로마토그라피(고정상:SEPRALYTE ; 이동상:20% 메탄올수요액)하여 분리한 다음 냉동건조시키면 26mg의 목적화합물을 엷은 회색고체상으로 얻는다.To 50 μl of anisole and 50 μl of methylene chloride, diphenylmethyl (6R, 7R) -7- [2-2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3 Dissolve 67 mg of, 4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl-ethoxyimino} acetamido] -3-acetoxymethyl-3-cepem-4-carboxylate and then with ice water Cool, add 0.35 ml of trifluoroacetic acid and stir at room temperature for 1.5 hours. 20 ml of isopropyl ether is added to the reaction, and the solid is filtered off, washed with ether and dried. The dried solid was separated by reverse phase tube chromatography (fixed phase: SEPRALYTE; mobile phase: 20% methanol demand) in 3 ml of water, and then freeze-dried to obtain 26 mg of the target compound as a pale gray solid.

수율 : 57%Yield: 57%

¹H-NMR(D₂O) : δ2.03(3H,s,-OAc), 3.31(2H,ABq,SCH₂), 4.76(2H,ABq,CH₂OAc), 5.16(1H,d,C₆-H), 5.43(2H,brs,=N-OCH₂), 5.79(1H,d,C₇-H), 7.00(1H,brs,이소옥사졸-H), 7.09(1H,s,티아졸-H), 7.12(1H,s,페닐-H). ¹ H-NMR (D ₂ O): δ2.03 (3H, s, -OAc), 3.31 (2H, ABq, SCH ₂ ), 4.76 (2H, ABq, CH ₂ OAc), 5.16 (1H, d, C ₆ -H), 5.43 (2H, brs, = N-OCH ₂ ), 5.79 (1H, d, C ₇ -H), 7.00 (1H, brs, isoxazole-H), 7.09 (1H, s, thia Sol-H), 7.12 (1H, s, phenyl-H).

[실시예 20]Example 20

디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노-아세트아미드]-3-(N-메틸테트라졸-5-일)티오메틸-3-세펨-4-카르복실레이트Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3-2,5-dichloro-3,4-di-para-methoxy Benzyloxyphenyl) isoxazol-5-yl-methoxyimino-acetamide] -3- (N-methyltetrazol-5-yl) thiomethyl-3-cepem-4-carboxylate

[화학식 21][Formula 21]

디메틸프롬아미드 0.5ml에 2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}초산(100mg,0.146mmol)을 녹이고 트리에틸아민 24μl를 가하고 빙수로 쟁각시키고 파라-톨루엔술포닐클로리드 33mg을 가하고 5분간 교반시킨 다음 디페닐메틸(6R,7R)-7-아미노-3-(N-메틸테트라졸-5-일)-3-세팸-4-카르복실레이트(73mg,0.146mmol)를 가하고 30분간 교반시킨다.가하고 30분간 교반시킨다.2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-para-methoxybenzyloxyphenyl) isoxazole in 0.5 ml of dimethylformamide -5-yl-methoxyimino} acetic acid (100 mg, 0.146 mmol) was dissolved, 24 μl of triethylamine was added and the mixture was condensed with ice water, 33 mg of para-toluenesulfonyl chloride was added and stirred for 5 minutes, followed by diphenylmethyl (6R, 7R). ) -7-amino-3- (N-methyltetrazol-5-yl) -3-cepam-4-carboxylate (73 mg, 0.146 mmol) is added and stirred for 30 minutes. Add and stir for 30 minutes.

반응물에 에틸아세테이트 50ml를 가하고 물로 세척(15ml×3)하고 무수황산마그네슘으로 건조시키고 농축시킨다. 농축물을 관크로마토그라피(고정상:실리카겔 ; 이동상 ; 헥산 ; 에틸아세테이트=1:1)로 분리하면 110mg의 목적화합물을 담황색고체로 얻는다.50 ml of ethyl acetate was added to the reaction, washed with water (15 ml × 3), dried over anhydrous magnesium sulfate, and concentrated. The concentrate was separated by tube chromatography (fixed phase: silica gel; mobile phase; hexane; ethyl acetate = 1: 1) to give 110 mg of the target compound as a pale yellow solid.

수율 : 65%Yield: 65%

¹H-NMR(CDCl₃) : δ3.76(2H,ABq,SCH₂), 3.81, 3.82(6H,d,OCH₃), 4.29(2H,ABq,CH₂STz), 5.03, 5.07(4H,d,OCH₂Ar), 5.09(1H,d,C₆-H), 5.43(2H,ABq,=N-OCH2), 6.05(1H,dd,C₇-H), 6.80(1H,s,이소옥사졸-H), 6.81-7.50(20H,m,페닐-H, -OCHPh₂,티아졸-H), 7.53(1H,s,페닐-H). ¹ H-NMR (CDCl ₃ ): δ 3.76 (2H, ABq, SCH ₂ ), 3.81, 3.82 (6H, d, OCH ₃ ), 4.29 (2H, ABq, CH ₂ STz), 5.03, 5.07 (4H, d, OCH ₂ Ar), 5.09 (1H, d, C ₆ -H), 5.43 (2H, ABq, = N-OCH ₂ ), 6.05 (1H, dd, C ₇ -H), 6.80 (1H, s, iso Oxazole-H), 6.81-7.50 (20H, m, phenyl-H, -OCHPh ₂ , thiazole-H), 7.53 (1H, s, phenyl-H).

[실시예 21]Example 21

(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-메틸테트라졸-5-일)티오메틸-3-세펨-4-카르복실 산 및 나트륨염(6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-hydroxyphenyl) isooxa Sol-5-yl-methoxyimino} acetamido] -3- (N-methyltetrazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid and sodium salt

[화학식 22][Formula 22]

아니솔 100μl과 메(틸렌클로리드 100μl의 혼합용매에 디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-페틸테트라졸-5-일)티오메틸-3-세펨-4-카르복실레이트(80mg,0.0688mmol)를 녹이고 빙냉하에서 트리플루오르초산 0.7ml를 가하고 실온에서 1.5시간 교반시키고, 반응물에 이소프로필에테르 20ml를 가하고 나오는 고체를 여과하고 에테르로 세척한후 건조시킨다. 건조된 고체를 2ml의 물에 현탁시키고 탄산수소나트륨을 12mg가하여 녹이고 역상 관크로마토그라피(고정상:SEPRALYTE ; 이동상:20% 메탄올 수용액)하여 분리한 다음 냉동건조시키면 30mg의 목적화합물을 엷은 회색고체로 얻는다.To a mixed solvent of 100 μl of anisole and 100 μl of me (tilylene chloride) diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2 , 5-dichloro-3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3- (N-petyltetrazol-5-yl) thio Methyl-3-cepem-4-carboxylate (80mg, 0.0688mmol) was dissolved, 0.7 ml of trifluoroacetic acid was added under ice-cooling, and stirred at room temperature for 1.5 hours. 20 ml of isopropyl ether was added to the reaction product, and the solid was filtered and ether was filtered. The dried solid is suspended in 2 ml of water, dissolved by adding 12 mg of sodium hydrogen carbonate, separated by reverse phase tube chromatography (fixed phase: SEPRALYTE; mobile phase: 20% methanol aqueous solution), and freeze-dried to obtain 30 mg of the target compound. Obtained as pale gray solid.

수율 : 56%Yield: 56%

¹H-NMR(D₂O) : δ3.42(2H,ABq,SCH₂), 3.94(3H,s,-NCH₃), 4.05(2HAB,q,CH₂S-), 5.13(1H,d,C₆-H), 5.42(2H,s,=N-OCH₂), 5.73(1H,d,C₇-H), 7.80(2H,s,이소옥사졸-H), 7.05, 7.09(2H,d,티아졸-H,디클로로페닐-H). ¹ H-NMR (D ₂ O): δ3.42 (2H, ABq, SCH ₂ ), 3.94 (3H, s, -NCH ₃ ), 4.05 (2HAB, q, CH ₂ S-), 5.13 (1H, d , C ₆ -H), 5.42 (2H, s, = N-OCH ₂ ), 5.73 (1H, d, C ₇ -H), 7.80 (2H, s, isoxazole-H), 7.05, 7.09 (2H , d, thiazole-H, dichlorophenyl-H).

[실시예 22]Example 22

파라-메톡시벤질(6R,7R)-7-(2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시-페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-클로로메틸-3-세펨-4-카르복실레이트.Para-methoxybenzyl (6R, 7R) -7- (2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para -Methoxybenzyloxy-phenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-chloromethyl-3-cepem-4-carboxylate.

[화학식 23][Formula 23]

2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}초산 120mg(0.175mmol)을 디메틸 포름아미드 0.5ml에 녹이고 0℃로 냉각시킨후 트리에틸아민 48μl(0.344mmol)를 가하고 파라톨루엔술포닐클로리드 33mg(0.175mmol)을 넣고 파라-메톡시벤질(6R,7R)-7-아미노-3-클로로메틸-3-세펨-4-카르복실레이트 60mg(0.159mmol)을 디메틸포름아미드 0.5ml에 녹여 가하고 0℃∼10℃정도로 유지하여 1시간 교반하면 반응이 완결된다. 반응물에 50ml의 에틸아세테이트를 가하고 물 20ml로 세번 씻어준뒤 무수황산마그네슘으로 건조시키고 농축시킨후 헥산:에틸아세테이트(1:3)를 사용하여 컬럼크로마토그래피로 분리하면 90mg(0.089mmol)의 목적화합물을 고체로 얻는다.2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl Dissolve 120 mg (0.175 mmol) of methoxyimino} acetic acid in 0.5 ml of dimethyl formamide, cool to 0 ° C, add 48 μl (0.344 mmol) of triethylamine, and add 33 mg (0.175 mmol) of paratoluenesulfonyl chloride. 60 mg (0.159 mmol) of methoxybenzyl (6R, 7R) -7-amino-3-chloromethyl-3-cepem-4-carboxylate was dissolved in 0.5 ml of dimethylformamide, and maintained at 0 ° C to 10 ° C. Stirring for time completes the reaction. 50 ml of ethyl acetate was added to the reaction mixture, washed three times with 20 ml of water, dried over anhydrous magnesium sulfate, concentrated, and separated by column chromatography using hexane: ethyl acetate (1: 3) to obtain 90 mg (0.089 mmol) of the target compound. Obtained as a solid.

수율 : 56%Yield: 56%

¹H-NMR(CDCl₃) : δ3.4∼3.7(2H,q,C₂), 3.8(9H,s,CH₃O-), 4.4∼4.6(2H,q,C₃-CH₂Cl), 5.0(4H,2s,CH₂Ar), 5.2(2H,s,CH₂Ar), 5.4(2H,br,s,NOCH₂-), 5.45(1H,d,C₆), 6.0(1H,q,C₇), 6.8(1H,s,이소옥사졸-H), 6.9∼7.5(13H,m,아미노티아졸-H,PMB-H), 7.5(1H,s,Ph-H). ¹ H-NMR (CDCl ₃ ): δ 3.4 to 3.7 (2H, q, C ₂ ), 3.8 (9H, s, CH ₃ O-), 4.4 to 4.6 (2H, q, C ₃ -CH ₂ Cl) , 5.0 (4H, 2s, CH ₂ Ar), 5.2 (2H, s, CH ₂ Ar), 5.4 (2H, br, s, NOCH _2- ), 5.45 (1H, d, C ₆ ), 6.0 (1H, q, C ₇ ), 6.8 (1H, s, isoxazole-H), 6.9-7.5 (13H, m, aminothiazole-H, PMB-H), 7.5 (1H, s, Ph-H).

[실시예 23]Example 23

파라-메톡시벤질(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-에틸-피리디니움-4-일)-티오메틸-3-세펨-4-카르복실레이트 요오드.Para-methoxybenzyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para -Methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3- (N-ethyl-pyridinium-4-yl) -thiomethyl-3-cepem-4-car Carboxylate iodine.

[화학식 24][Formula 24]

파라-메톡시벤질(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-클로로메틸-3-세팸-4-카르복실레이트 83mg (0.0824mmol) N-에틸-피리돈-4-티온 11.5mg (0.0824mmol)을 놓고 실온에서 2시간동안 교반하고 메틸렌클로리드 60ml를 가하고 물 50ml, 소금물 50ml로 씻어준뒤 무수황산마그네슘으로 건조시키고 농축시키면 노란고체 50mg을 얻는다.Para-methoxybenzyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para -Methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-chloromethyl-3-cepam-4-carboxylate 83 mg (0.0824 mmol) N-ethyl-pyridone- 11.5mg (0.0824mmol) of 4-thione is added, stirred at room temperature for 2 hours, 60 ml of methylene chloride is added, washed with 50 ml of water and 50 ml of brine, dried over anhydrous magnesium sulfate, and concentrated to give a yellow solid 50 mg.

수율 : 49%Yield: 49%

¹H-NMR(DMSO-D₆,δ):1.5(3H,t,CH₃-CH₂), 3.8(9H,s,PMB-OCH₃), 4.3(2H,s,C₃-CH₂-S), 4.5(2H,q,CH₂-CH₃), 5.0(4H,2s,PMS-CH₂), 5.2(3H,s+d,C₆+PMB-CH₂), 5.3(2H,s,NOCH₂), 5.8(1H,q,C₇), 6.8(1H,s,이소옥사졸-H), 6.9(1H,s,아미노티아졸-H), 6.9∼7.4(12H,m,PMB-H), 7.6(1H,s,Ph-H), 7.9(2H,d,피리딘-H), 8.8(2H,d,피리딘-H), 9.8(1H,d,NH). ¹ H-NMR (DMSO-D ₆ , δ): 1.5 (3H, t, CH ₃ -CH ₂ ), 3.8 (9H, s, PMB-OCH ₃ ), 4.3 (2H, s, C ₃ -CH _2- S), 4.5 (2H, q, CH ₂ -CH ₃ ), 5.0 (4H, 2s, PMS-CH ₂ ), 5.2 (3H, s + d, C ₆ + PMB-CH ₂ ), 5.3 (2H, s , NOCH ₂ ), 5.8 (1H, q, C ₇ ), 6.8 (1H, s, isoxazole-H), 6.9 (1H, s, aminothiazole-H), 6.9-7.4 (12H, m, PMB -H), 7.6 (1H, s, Ph-H), 7.9 (2H, d, pyridine-H), 8.8 (2H, d, pyridine-H), 9.8 (1H, d, NH).

[실시예 24]Example 24

(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-에틸-피리디니움-4-일)-티오메틸-3-세펨-4-카르복실레이트(6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-hydroxyphenyl) isooxa Zol-5-yl-methoxyimino} acetamido] -3- (N-ethyl-pyridinium-4-yl) -thiomethyl-3-cepem-4-carboxylate

[화학식 25][Formula 25]

파라-메톡시벤질(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-에틸-피리디니움-4-일)-티오메틸-3-세팸-4-카르복실레이트 요오드 45mg(0.036mmol)을 아니솔 80μl(0.736mmol)과 메틸렌클로리드 80μl에 녹인후 0℃로 냉각시키고 트리플루오르초산 800μl(10.38mmol)를 가하고 실온으로 올려 1.5시간 교반한 후 이소프로필에테르 20ml를 가하면 고체가 생성된다. 이것을 여과하여 진공건조한 후 건조된 고체를 물 3ml에 현탁시키고 탄산수소나트륨 6mg(0.071mmol)을 가하고 녹인후 20% 메탄올 수용액을 사용하여 액상컬럼크로마토그래피로 분리하여 냉동건조시키면 13mg(0.14mmol)의 목적화합물을 얻는다.Para-methoxybenzyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para -Methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3- (N-ethyl-pyridinium-4-yl) -thiomethyl-3-cepam-4-car 45 mg (0.036 mmol) of carboxylate iodine was dissolved in 80 μl (0.736 mmol) of anisole and 80 μl of methylene chloride, cooled to 0 ° C., 800 μl (10.38 mmol) of trifluoroacetic acid was added and stirred at room temperature for 1.5 hours, followed by isopropyl ether. 20 ml is added to give a solid. After filtration and drying in vacuo, the dried solid was suspended in 3 ml of water, 6 mg (0.071 mmol) of sodium bicarbonate was added, dissolved, and separated by liquid column chromatography using 20% aqueous methanol solution. Obtain the desired compound.

수율 : 40%(2단계)Yield: 40% (2 levels)

¹H-NMR(DMSO-D₆,δ):1.5(3H,t,CH₃-CH₂), 4.4∼4.6(4H,m,CH₂-CH₃,C₃-CH₂), 5.08(1H,d,C₆), 5.3(2H,s,=NOCH₂), 5.65(1H,q,C₇), 6.8(1H,s,이소옥사졸-H), 6.9(1H,s,아미노티아졸-H), 7.1(1H,s,페닐-H), 8.2(2H,br,s,피리딘-H), 8.7(2H,br,s,피리딘-H). ¹ H-NMR (DMSO-D ₆ , δ): 1.5 (3H, t, CH ₃ -CH ₂ ), 4.4-4.6 (4H, m, CH ₂ -CH ₃ , C ₃ -CH ₂ ), 5.08 (1H , d, C ₆ ), 5.3 (2H, s, = NOCH ₂ ), 5.65 (1H, q, C ₇ ), 6.8 (1H, s, isoxazole-H), 6.9 (1H, s, aminothiazole -H), 7.1 (1H, s, phenyl-H), 8.2 (2H, br, s, pyridine-H), 8.7 (2H, br, s, pyridine-H).

[실시예 25]Example 25

파라-메톡시벤질(6R,7R)-7-[2-(2-트리페닐메틸아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-에틸-디페닐메톡시카르보닐메틸-피리디니움-4-일)-티오메틸-3-세펨-4-카르복실레이트 요오드Para-methoxybenzyl (6R, 7R) -7- [2- (2-triphenylmethylaminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4- Di-para-methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3- (N-ethyl-diphenylmethoxycarbonylmethyl-pyridinium-4-yl) -Thiomethyl-3-cepem-4-carboxylate iodine

[화학식 26][Formula 26]

파라-메톡시벤질(6R,7R)-7-[2-(2-트리페닐메틸아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-클로로메틸-3-세팸-4-카르복실레이트 260mg (0.208mmol)을 테트라하이드로퓨란 10ml에 녹인후 요오드화나트륨 37mg(0.249mmol)과 N-디페닐메톡시카르보닐메틸-피리돈-4-티온 83mg(0.249mmol)을 넣고 실온에서 2시간동안 교반하고 메틸렌클로리드 80ml를 가하고 물 60ml, 소금물 600ml로 씻어준뒤 무수황산마그네슘으로 건조시키고 농축시키면 노란고체 280mg(0.167mmol)을 얻는다.Para-methoxybenzyl (6R, 7R) -7- [2- (2-triphenylmethylaminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4- 260 mg (0.208 mmol) of di-para-methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-chloromethyl-3-cepam-4-carboxylate After dissolving in 10ml, 37 mg (0.249 mmol) of sodium iodide and 83 mg (0.249 mmol) of N-diphenylmethoxycarbonylmethyl-pyridone-4-thione were added, stirred at room temperature for 2 hours, 80 ml of methylene chloride was added, and 60 ml of water was added thereto. Wash with 600 ml of brine, dry over anhydrous magnesium sulfate and concentrate to give 280 mg (0.167 mmol) of a yellow solid.

수율 : 80%Yield: 80%

¹H-NMR(DMSO-D_6,δ):3.4-3.7(2H,ABq,C₂), 3.7-3.8(9H,s,PMS-OCH₃), 4.2-4.5(2H,ABq,C₃-CH₂-S), 5.0(5H,d,PMS-CH₂,C₆), 5.2(2H,s,PMS-CH₂), 5.45(2H,s,NOCH₂) 5.8(1H,q,C₇), 6.0(2H,s,피리디니옴), 6.8-7.5(41H,m,PMB,CHPh₂,이소옥사졸-H,페닐-H,아미노티아졸-H,트리틸), 7.6(2H,d,피리디니움-H), 7.9(2H,d,피리딘-H), 8.2(2H,d,피리디니움-H) ¹ H-NMR (DMSO-D _6, δ): 3.4-3.7 (2H, ABq, C ₂ ), 3.7-3.8 (9H, s, PMS-OCH ₃ ), 4.2-4.5 (2H, ABq, C ₃ − CH ₂ -S), 5.0 (5H, d, PMS-CH ₂ , C ₆ ), 5.2 (2H, s, PMS-CH ₂ ), 5.45 (2H, s, NOCH ₂ ) 5.8 (1H, q, C ₇ ), 6.0 (2H, s, pyridinio), 6.8-7.5 (41H, m, PMB, CHPh ₂ , isoxazole-H, phenyl-H, aminothiazole-H, trityl), 7.6 (2H, d, pyridinium-H), 7.9 (2H, d, pyridine-H), 8.2 (2H, d, pyridinium-H)

[실시예 26]Example 26

(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-카르보닐메틸-피리디니움-4-일)-티오메틸-3-세펨-4-카르복실산 및 나트륨염(6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-hydroxyphenyl) isooxa Zol-5-yl-methoxyimino} acetamido] -3- (N-carbonylmethyl-pyridinium-4-yl) -thiomethyl-3-cepem-4-carboxylic acid and sodium salt

[화학식 27][Formula 27]

파라-메톡시벤질(6R,7R)-7-[2-(2-트리페닐아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-(N-디페닐메톡시카르보닐메틸-피리디니움-4-일)-티오메틸-3-세팸-4-카르복실레이트 요오드 150mg(0.09mmol)을 아니솔 0.4ml에 녹인후 0℃로 냉각시키고 트리플루오르초산 2.5ml를 가하고 실온으로 올려 2.5시간 교반한 후 이소프로필에테르를 가하면 고체가 생성된다. 이것을 여과하여 진공건조한 후 건조된 고체를 물에 현탁시키고 5%탄산수소나트륨 수용액을 가하여 녹인후 역상컬럼크로마토그래피(H₂OC;MeOH=4:1)로 분리하여 냉동건조시키면 35mg(0.05mmol)의 목적화합물을 얻는다.Para-methoxybenzyl (6R, 7R) -7- [2- (2-triphenylaminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di -Para-methoxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3- (N-diphenylmethoxycarbonylmethyl-pyridinium-4-yl) -thiomethyl Dissolve 150 mg (0.09 mmol) of -3-cepam-4-carboxylate iodine in 0.4 ml of anisole, cool to 0 ° C, add 2.5 ml of trifluoroacetic acid, raise to room temperature, stir for 2.5 hours, and add isopropyl ether. Is generated. After filtration and drying in vacuo, the dried solid was suspended in water, dissolved by adding 5% aqueous sodium hydrogen carbonate solution, separated by reverse phase chromatography (H ₂ OC; MeOH = 4: 1), and freeze-dried to 35 mg (0.05 mmol). Obtain the desired compound.

수율 : 50%Yield: 50%

¹H-NMR(D₂O-D₆δ):2.81(2H,ABq,C₂-H), 3.81(2H,ABq,-CH₂S), 4.95(2H,s,-NCH₂), 5.06(1H,d,C₆-H), 5.31(2H,s=NOCH₂), 5.75(1H,q,C₇), 6.86(1H,s,이소옥사졸-H), 6.71(1H,d,카테콜-H), 6.93(1H,s,아미노티아졸-H), 6.95(1H,d,카테콜-H), 7.08(1H,s,카테콜-H), 7.46(2H,d,피리딘-H), 8.19(2H,d,피리딘-H). ¹ H-NMR (D ₂ OD ₆ δ): 2.81 (2H, ABq, C ₂ -H), 3.81 (2H, ABq, -CH ₂ S), 4.95 (2H, s, -NCH ₂ ), 5.06 (1H , d, C ₆ -H), 5.31 (2H, s = NOCH ₂ ), 5.75 (1H, q, C ₇ ), 6.86 (1H, s, isoxazole-H), 6.71 (1H, d, catechol -H), 6.93 (1H, s, aminothiazole-H), 6.95 (1H, d, catechol-H), 7.08 (1H, s, catechol-H), 7.46 (2H, d, pyridine-H ), 8.19 (2H, d, pyridine-H).

[실시예 27]Example 27

디펜닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-세펨-4-카르복실레이트Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para-meth Oxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-cepem-4-carboxylate

[화학식 28][Formula 28]

(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}초산 102mg(0.148mmol)을 디메틸포름아미드 0.5ml에 녹이고 0℃로 냉각시킨후 트리에틸아민 21μl(0.15mmol)을 가하고 파라톨루엔술포닐클로리드 28mg(0.147mmol)을 넣고 디페닐메틸(6R,7R)-7아미노-3-세펨-4-카르복실레이트 60mg(0.135mmol)을 디메틸포름아미드 0.5ml에 녹여 가하고 0℃∼10℃에서 1시간동안 교반하고 반응이 완결되면 에틸아세테이트 50ml를 가하고 물과 소금물로 3번 씻어준뒤 무수황산마그네슘으로 건조시키고 농축하여 헥산:에틸아세테이트(1:3)을 사용하여 컬럼크로마토그래피로 분리하면 75mg(0.072mmol)의 목적화합물을 얻을 수 있다.(2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl-meth Dissolve 102 mg (0.148 mmol) of oxyimino} acetic acid in 0.5 ml of dimethylformamide, cool to 0 ° C, add 21 μl (0.15 mmol) of triethylamine, add 28 mg (0.147 mmol) of paratoluenesulfonyl chloride, and add diphenylmethyl ( 60 mg (0.135 mmol) of 6R, 7R) -7amino-3-cepem-4-carboxylate was dissolved in 0.5 ml of dimethylformamide and stirred at 0 ° C. to 10 ° C. for 1 hour. When the reaction was completed, 50 ml of ethyl acetate was added. The mixture was washed three times with water and brine, dried over anhydrous magnesium sulfate, concentrated, and separated by column chromatography using hexane: ethyl acetate (1: 3) to obtain 75 mg (0.072 mmol) of the target compound.

수율 : 54%Yield: 54%

¹H-NMR(CDCl₃,δ:3.4∼3.7(2H,m,C₂), 3.8(6H,s,CH₃O-PMB), 5.0(4H,2s,CH₂-PMB), 5.3(1H,d,C₆), 5.5(2H,q,=NO-CH₂), 6.1(1H,q,C₇), 6.7(1H,d,C₃-H), 6.8∼7.6(18H,m,DPM,PMB,Ph-H,이소옥사졸-H,아미노티아졸-H). ¹ H-NMR (CDCl ₃ , δ: 3.4 to 3.7 (2H, m, C ₂ ), 3.8 (6H, s, CH ₃ O-PMB), 5.0 (4H, 2s, CH ₂ -PMB), 5.3 (1H) , d, C ₆ ), 5.5 (2H, q, = NO-CH ₂ ), 6.1 (1H, q, C ₇ ), 6.7 (1H, d, C ₃ -H), 6.8 to 7.6 (18H, m, DPM, PMB, Ph-H, isoxazole-H, aminothiazole-H).

[실시예 28]Example 28

(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-세펨-4-카르복실산 및 나트륨염(6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para-hydroxyphenyl) Ixoxazol-5-yl-methoxyimino} acetamido] -3-cef-4-carboxylic acid and sodium salt

[화학식 29][Formula 29]

디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미드]-3-세팸-4-카르복실레이트 70mg(0.068mmol)을 메틸렌클로리드 50μl와 아니솔 115μl(1.058mmol)에 녹인후 0℃로 냉각시키고 트리플루오르초산 1.04mg(13.5mmol)를 가하고 실온으로 올려 1.5시간 교반한후 이소프로필에테르 50ml를 가하면 고체가 생성된다. 이것을 여가하여 진공건조한후 물 30ml에 현탁시킨 후 탄산수소나트륨 10mg을 가하여 녹인후 20%메탄올 수용액을 사용하여 역상컬럼크로마토그래피로 분리하여 냉동건조시키면 20mg(0.03mmol)의 목적화합물을 얻는다.Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para-meth 70 mg (0.068 mmol) of oxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamide] -3-cepam-4-carboxylate was dissolved in 50 μl of methylene chloride and 115 μl of anisole (1.058 mmol). After cooling to 0 ° C., 1.04 mg (13.5 mmol) of trifluoroacetic acid were added, the mixture was raised to room temperature, stirred for 1.5 hours, and then 50 ml of isopropyl ether was added to give a solid. After leisure, vacuum drying, and suspended in 30ml of water, and dissolved in 10mg of sodium hydrogen carbonate, and then dissolved by reverse phase column chromatography using 20% methanol solution to obtain 20mg (0.03mmol) of the target compound.

수율 : 44%(2단계)Yield: 44% (2 levels)

¹H-NMR(D₂,δ):3.2∼3.6(2H,m,C₂), 5.1(1H,d,C₆), 5.35(2H,brs,=NOCH₂-), 5.8(1H,q,C₇), 6.25(1H,d,C₃-H), 6.9(1H,s,이소옥사졸-H), 7.0(1H,s,아미노티아졸-H), 7.05(1H,s,Ph-H) ¹ H-NMR (D ₂ , δ): 3.2 to 3.6 (2H, m, C ₂ ), 5.1 (1H, d, C ₆ ), 5.35 (2H, brs, = NOCH _2- ), 5.8 (1H, q , C ₇ ), 6.25 (1H, d, C ₃ -H), 6.9 (1H, s, isoxazole-H), 7.0 (1H, s, aminothiazole-H), 7.05 (1H, s, Ph -H)

[실시예 29]Example 29

디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-비닐-3-세펨-4-카르복실레이트Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para-meth Oxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamido] -3-vinyl-3-cepem-4-carboxylate

[화학식 30][Formula 30]

2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}초산 100mg(0.145mmol)을 디메틸포름아미드 0.5ml에 녹이고 0℃로 냉각시킨후 트리에킬아민 20.33μl(0.145mmol)을 가하고 파라톨루엔술포닐클로리드 28mg(0.145mmol)을 넣고 디페닐메틸(6R,7R)-7-아미노-3비닐-3-세펨-4-카르복실레이트 57mg(0.12mmol)을 디메틸포름아미드 0.5ml에 녹여 가하고 0℃∼10℃에서 1시간 교반한후 에틸아세테이트 50ml를 가하고 물과 소금물로 3번 씻어준 뒤 무수황산마그네슘으로 건조시키고 농축하여 헥산 ; 에틸아세테이트(1:3)을 사용하여 컬럼크로마토그래피로 분리하면 70mg(0.061mmol)의 목적화합물을 Q을 수 있다.2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para-methoxybenzyloxyphenyl) isoxazol-5-yl Dissolve 100 mg (0.145 mmol) of methoxyimino} acetic acid in 0.5 ml of dimethylformamide, cool to 0 ° C, add 20.33 μl (0.145 mmol) of triethylamine, and add 28 mg (0.145 mmol) of paratoluenesulfonyl chloride. 57 mg (0.12 mmol) of diphenylmethyl (6R, 7R) -7-amino-3vinyl-3-cepem-4-carboxylate was dissolved in 0.5 ml of dimethylformamide, and stirred at 0 ° C to 10 ° C for 1 hour. 50 ml of ethyl acetate was added, washed three times with water and brine, dried over anhydrous magnesium sulfate and concentrated to hexane; Separation by column chromatography using ethyl acetate (1: 3) yields 70 mg (0.061 mmol) of the target compound.

수율 : 51%Yield: 51%

¹H-NMR(CDCl₃),δ:3.45∼3.7(2H,q,C₂), 3.8(6H,s,CH₃O-PMB), 5.0(4H,2s,CH₂-PMB), 5.1(1H,d,C₆), 5.3(1H,d,C₃-C=CH₂), 5.45(1H,d,C₃-C=CH₂), 5.5(2H,s,NOCH₂), 6.0(1H,q,C₇), 6.9(4H,d,PMB), 6.95(2H,2s,아미노티아졸-H, +이소옥사졸-H), 7.05(1H,q,C₃-CH=C), 7.2∼7.4(16H,m,PMB+DPM), 7.65(1H,s,Ph-H). ¹ H-NMR (CDCl ₃ ), δ: 3.45 to 3.7 (2H, q, C ₂ ), 3.8 (6H, s, CH ₃ O-PMB), 5.0 (4H, 2s, CH ₂ -PMB), 5.1 ( 1H, d, C ₆ ), 5.3 (1H, d, C ₃ -C = CH ₂ ), 5.45 (1H, d, C ₃ -C = CH ₂ ), 5.5 (2H, s, NOCH ₂ ), 6.0 ( 1H, q, C ₇ ), 6.9 (4H, d, PMB), 6.95 (2H, 2s, aminothiazole-H, + isoxazole-H), 7.05 (1H, q, C ₃ -CH = C) , 7.2 to 7.4 (16H, m, PMB + DPM), 7.65 (1H, s, Ph-H).

[실시예 30]Example 30

(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-히드록시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미도]-3-비닐-3-세펨-4-카르복실산 및 나트륨염(6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para-hydroxyphenyl) Isoxazol-5-yl-methoxyimino} acetamido] -3-vinyl-3-cepem-4-carboxylic acid and sodium salt

[화학식 31][Formula 31]

디페닐메틸(6R,7R)-7-[2-(2-아미노티아졸-4-일)-2(Z)-{3-(2,5-디클로로-3,4-디-파라-메톡시벤질옥시페닐)이소옥사졸-5-일-메톡시이미노}아세트아미드]-3-비닐-3-세팸-4-카르복실레이트 65mg(0.057mmol)을 메틸렌클로리드 100μl와 아니솔 100μl(0.92mmol)에 녹인후 0℃로 냉각시키고 트리플루오르 초산 880mg(11.4mmol)를 가하고 실온으로 올려 1.5시간 교반한후 이소프로필에테르 50ml를 가하면 고체가 생성된다. 이것을 여과하여 진공건조한후 물 3ml에 현탁시킨 후 탄산수소나트륨 10mg을 가하여 녹인후 20%메탄올 수용액을 사용하여 역상컬럼크로마토그래피로 분리하여 냉동건조시키면 24mg(0.036mmol)의 목적화합물을 얻는다.Diphenylmethyl (6R, 7R) -7- [2- (2-aminothiazol-4-yl) -2 (Z)-{3- (2,5-dichloro-3,4-di-para-meth 65 mg (0.057 mmol) of oxybenzyloxyphenyl) isoxazol-5-yl-methoxyimino} acetamide] -3-vinyl-3-cepam-4-carboxylate was added to 100 μl of methylene chloride and 100 μl of anisole (0.92). mmol), cooled to 0 ° C., 880 mg (11.4 mmol) of trifluoroacetic acid were added, the mixture was stirred at room temperature for 1.5 hours, and 50 ml of isopropyl ether was added to give a solid. The resultant was filtered, dried in vacuo, suspended in 3 ml of water, dissolved in 10 mg of sodium bicarbonate, and then dissolved in reverse phase chromatography using a 20% aqueous methanol solution to freeze-dried to obtain 24 mg (0.036 mmol) of the target compound.

수율 : 63%(2단계)Yield: 63% (2 levels)

¹H-NMR(D₂O,δ):3.3(2H,q,C₂), 5.1(1H,d,C₆), 5.2(2H,d,CH₂=C), 5.35(2H,brs,=NOCH₂), 5.7(1H,d,C₇), 6.2(1H,dd,CH-C), 6.9(1H,s,이소옥사졸-H), 70(1H,s,아미노티아졸-H), 7.1(1H,s,Ph-H). ¹ H-NMR (D ₂ O, δ): 3.3 (2H, q, C ₂ ), 5.1 (1H, d, C ₆ ), 5.2 (2H, d, CH ₂ = C), 5.35 (2H, brs, = NOCH ₂ ), 5.7 (1H, d, C ₇ ), 6.2 (1H, dd, CH-C), 6.9 (1H, s, isoxazole-H), 70 (1H, s, aminothiazole-H ), 7.1 (1H, s, Ph-H).

생체의 항균활성 시험 :Antimicrobial activity test of living body:

본 발명에서 합성된 대표적인 화합물들의 생체외 항균력은 뮐러 힐튼 아가(Mueller Hinton Ager)를 사용한 한천희석(Agar Dilution) 방법에 의해 37℃에서 18시간 배양한후 그 2배씩 단계적으로 희석하여 접종한 평판을 일렬로 나열하고 육안으로 관찰하여 표기화합물의 최소발육 억제농도(MIC)를 정하였다.In vitro antimicrobial activity of representative compounds synthesized in the present invention was incubated at 37 ° C. for 18 hours by Agar Dilution using Mueller Hinton Ager, and then inoculated by diluting step by step twice. It was arranged in a line and visually observed to determine the minimum growth inhibition concentration (MIC) of the title compound.

그 시험 결과를 다음표에 제시한다.The test results are shown in the following table.

[표 1]TABLE 1

[표 2]TABLE 2

Claims

Separosporin compound represented by the following general formula (I) and a pharmaceutically acceptable salt.

In Formula (I), R ₁ is H, or trityl, tert-butoxy carbonyl, formyl, and the like, R ₂ is hydrogen or diphenylmethyl group, para-methoxybenzyl group, or salt Na or K are the same atom, R ₃ , R ₄ may be the same or different, H or acetyl, para-methoxybenzyl, X, Y is hydrogen or fluoro, chloro, bromo, iodine, Q Is hydrogen, vinyl, acetoxymethyl, methoxymethyl, halomethyl, pyridiniummethyl, N-ethylpyridiniumylthiomethyl, N-carboxymethylpyridiniumylthiomethyl, carbamoyloxymethyl, N-methyl- Substituents such as tetrazolylthiomethyl.

A process for producing the compound of formula (I) according to claim 1, characterized in that the compound of formula (II) and the compound of formula (III) are acylated.

Wherein R ₁ , R ₂ , R ₃ , R ₄ and Q are the same as defined in claim 1, respectively.