KR20010084201A - Novel isothiazolylcephem compounds and preparation thereof - Google Patents

Novel isothiazolylcephem compounds and preparation thereof Download PDF

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KR20010084201A
KR20010084201A KR1020000009063A KR20000009063A KR20010084201A KR 20010084201 A KR20010084201 A KR 20010084201A KR 1020000009063 A KR1020000009063 A KR 1020000009063A KR 20000009063 A KR20000009063 A KR 20000009063A KR 20010084201 A KR20010084201 A KR 20010084201A
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vinyl
cepem
carboxylate
para
methoxybenzyl
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KR100380322B1 (en
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고훈영
최경일
조용서
배애님
차주환
김보형
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박호군
한국과학기술연구원
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

PURPOSE: Provided is an isothiazol cephem derivative which has broad range of antimicrobial activity. And its producing method is also provided. CONSTITUTION: The cephalosporin compound represented by formula (1) and its pharmaceutically acceptable salts are produced. In the formula, R1 is hydrogen or an amine protecting group generally used in cephalosporin compound; R2 is hydrogen or an oxim protecting group; R3 is hydrogen or a chloro group; R5 is hydrogen or an ester producing group, a salt producing atom or a carboxy protecting group; and R4 is ring substituent having Q group, in which Q is hydrogen, halogen, hydroxy, mercapto, cyano, carboxy, carboxylic acid ester, carbamoyloxymethyl, N,N-dimethylcarbamoyloxymethyl, carbamoyl, N,N-dimethylcarbamoyl, C1 to C4 alkyl, C1 to C4 alkyloxy, halogen substituted methyl, halogen substituted C1 to C4 alkyloxy, aryl or hetero ring substituent. The cephalosporin derivative of the formula (1) is produced by reacting a compound of formula (7) with a compound of formula (8).

Description

새로운 이소티아졸 세펨 화합물 및 그 제조방법{NOVEL ISOTHIAZOLYLCEPHEM COMPOUNDS AND PREPARATION THEREOF}New isothiazole cefem compound and method for preparing the same {NOVEL ISOTHIAZOLYLCEPHEM COMPOUNDS AND PREPARATION THEREOF}

본 발명은 세팔로스포린의 3-위치에 이소티아졸 비닐로 결합된 새로운 세팔로스포린 계열의 화합물에 관한 것이다.The present invention relates to a new cephalosporin family of compounds bound with isothiazole vinyl at the 3-position of cephalosporin.

세포탁심 (Cefotaxime, 미국 특허 제4098888호), 세프메녹심 (Cefmenoxime, 일본 특허 공개 제7675066호)등 널리 사용되는 소위 제 3세대 세팔로스포린 항생제들과, 세페핌 (Cefepime, 미국 특허 제4910301호)등의 제 4세대 세팔로스포린 항생제는 각 화합물의 7-위치에 아미노티아졸릴-α-(치환 또는 비치환된)히드록시이미노아세틸 그룹의 구조를 지니며 그람 음성균과 그람 양성균주에 대해 광범위한 항생 스페트럼을 가진 뛰어난 항생 작용에 의해서 특징지어진다. 그러나 최근 의약저항성을 가진 임상학적으로 중요한 그람 양성 박테리아균이 점차 증가하고 있는 실정이며 이에 대한 적당한 치료제를 찾는 것이 심각한 문제로 대두되고 있다. 이들 제 3,4세대 항생제들 역시 최근에 임상적인 문제를 야기하는 내성균주에 대해 만족할 만한 약효를 보이지 못하고 있는 바, 그 중에서도 특히 관심이 집중되고 있는 MRSA (Methicillin-Resistant Staphylococcus Aureus) 균주에 강한 활성을 지니는약물의 개발이 동 분야 연구의 주된 과제로 등장하였다.Widely used so-called third generation cephalosporin antibiotics such as Cefotaxime (US Patent No. 4098888) and Cefmenoxime (Japanese Patent Publication No. 7675066), and Cefepime (US Patent No. 4910301). 4th generation cephalosporin antibiotics have a structure of aminothiazolyl-α- (substituted or unsubstituted) hydroxyiminoacetyl groups at the 7-position of each compound and are widely used for Gram-negative and Gram-positive strains. It is characterized by excellent antibiotic action with antibiotic spectrum. However, recently, clinically important Gram-positive bacteria with drug resistance are gradually increasing, and finding an appropriate treatment for them has been a serious problem. These 3rd and 4th generation antibiotics also have not shown satisfactory efficacy against resistant strains that cause clinical problems recently. Among them, strong activity against MRSA (Methicillin-Resistant Staphylococcus Aureus) strains is of particular interest. Drug development has emerged as a major challenge for research in this field.

따라서 본 발명의 목적은 광범위한 그람 양성균 및 그람 음성균에 대해서 항균력을 나타내며, 특히 MRSA를 포함하는 그람양성균에 대해 우수한 항균력을 나타내는 약제학적으로 유용한 신규의 세팔로스포린 화합물 또는 그 염 및 그 제조방법을 제공하는 것이다.Accordingly, an object of the present invention is to provide a novel pharmaceutically useful cephalosporin compound or a salt thereof and a method for preparing the same, which exhibits antibacterial activity against a wide range of Gram-positive bacteria and Gram-negative bacteria, and particularly shows excellent antimicrobial activity against Gram-positive bacteria including MRSA. It is.

본 발명자들은 광범위한 그람 양성균 및 그람 음성균에 대해서 항균력을 나타내며, 특히 MRSA를 포함하는 그람양성균에 대해 우수한 항균력을 나타내는 화학식 1의 세팔로스포린 화합물 또는 그의 염을 합성하는데 성공하였다.The present inventors have succeeded in synthesizing the cephalosporin compound of formula (1) or a salt thereof, which exhibits antimicrobial activity against a wide range of Gram-positive bacteria and Gram-negative bacteria, and particularly shows excellent antimicrobial activity against Gram-positive bacteria including MRSA.

[화학식 1][Formula 1]

상기 화학식 1에서 R1은 수소 또는 세팔로스포린 화합물에서 일반적으로 사용되는 아민보호기; R2는 수소 또는 옥심 보호기; R4는 수소 또는 에스테르를 만드는 기, 염을 만드는 원자 또는 카르복시기의 보호기; R5는 수소 또는 할로겐기; 및 R3는를 나타내며, 여기서 Q는 수소, 할로겐, 히드록시, 머캅토, 시아노,카르복시, 카르복실산에스테르, 카르바모일옥시, 카르바모일, N,N-디메틸카르바모일, C1-4알킬, C1-4알킬옥시, 할로겐이 치환된 메틸, 아릴 또는 헤테로 고리 치환체를 말한다. 할로겐은 일반적으로 불소, 염소, 브롬 또는 요오드를 말한다.In Formula 1, R 1 is an amine protecting group generally used in hydrogen or cephalosporin compound; R 2 is hydrogen or an oxime protecting group; R 4 is a protecting group of a group forming a hydrogen or an ester, an atom forming a salt or a carboxyl group; R 5 is hydrogen or a halogen group; And R 3 is Wherein Q is hydrogen, halogen, hydroxy, mercapto, cyano, carboxy, carboxylic acid ester, carbamoyloxy, carbamoyl, N, N-dimethylcarbamoyl, C 1-4 alkyl, C 1-4 alkyloxy, halogen, substituted methyl, aryl or heterocyclic substituents. Halogen generally refers to fluorine, chlorine, bromine or iodine.

헤테로고리 치환기는 불포화된 5 또는 6환 헤테로고리 치환기를 말한다. 이때 헤테로고리는 산소, 황, 질소원자를 적어도 한 개 이상 포함하고 있는 구조를 말한다. 이러한 예로는 치환되거나, 치환되지 않은 티아졸릴티오, 이소티아졸릴티오, 티아디아졸릴티오, 트리아졸릴티오, 트리아지닐티오, 테트라졸릴티오, 트리아졸로피리미디닐티오, 1-치환된 피리디늄-4-일-티오등을 말한다. 여기서 피리디늄기는 1-위치에 다음과 같은 치환기로 치환되어 있다. 즉 C1-6알킬, 히드록시알킬, 알콜시알킬, 카르복시알킬, 술포닐알킬, 카르바모일메틸, 또는 치환되니 않았거나 1개 내지 2개의 치환기로 치환된 아미노알킬기 등으로 치환된 것들을 포함한다.Heterocyclic substituents refer to unsaturated 5 or 6 ring heterocyclic substituents. The heterocycle refers to a structure containing at least one oxygen, sulfur, nitrogen atom. Examples include substituted or unsubstituted thiazolylthio, isothiazolylthio, thiadiazolylthio, triazolylthio, triazinylthio, tetrazolylthio, triazolopyrimidinylthio, 1-substituted pyridinium-4 -I mean yl-thio. Wherein the pyridinium group is substituted in the 1-position with the following substituents. Ie, C 1-6 alkyl, hydroxyalkyl, alcoholcyalkyl, carboxyalkyl, sulfonylalkyl, carbamoylmethyl, aminoalkyl groups unsubstituted or substituted with 1 to 2 substituents, and the like. .

본 명세서에서 아민 보호기, 카르복시 보호기 또는 옥심 보호기라 함은 화합물 내의 다른 작용기의 반응에 관여하지 아니하도록 아민기, 카르복시기 또는 옥심기를 보호하고, 공지 방법에 의해 용이하게 제거되어 아민기, 카르복시기 또는 옥심기를 다시 회복시킬 수 있는 작용기를 말한다. 아민 보호기의 예로는 트리틸, t-부톡시카르보닐 (t-Boc), 벤질, 클로로아세틸, 트리클로로아세틸, 벤질옥시카르보닐(Cbz), 9-플루오레닐메틸옥시카르보닐(Fmoc), 파라-메톡시벤질옥시카르보닐, 포르밀 및 트리플루오로아세틸 등이 포함된다. 옥심 보호기의 예로는 트리틸, 포밀, 클로로아세틸, 벤조일, p-니트로벤질, 2,2,2-트리클로로에톡시카르보닐, 테트라히드로피라닐 등이 포함된다. 카르복시기의 보호기의 예로는 탄소수 1-8의 알킬기(예를 들면, 메틸 메톡시메틸, 에틸, 메톡시에틸, 프로필, 이소프로필, 부틸, 이소부틸, t-부틸, 펜틸, 이소펜틸, n-헥실, 헵틸, 옥틸 등) 또는 페닐, 인다닐, 벤질, 시아노벤질, 할로벤질, 메틸벤질, 니트로벤질, p-메톡시벤질, 페닐벤질 등의 아릴기 또는 아르알킬기를 들 수 있다.In the present specification, an amine protecting group, carboxy protecting group or oxime protecting group is used to protect an amine group, carboxyl group or oxime group so as not to be involved in the reaction of other functional groups in the compound, and is easily removed by a known method to remove an amine group, carboxyl group or oxime group. A functional group that can be restored again. Examples of amine protecting groups include trityl, t-butoxycarbonyl (t-Boc), benzyl, chloroacetyl, trichloroacetyl, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), Para-methoxybenzyloxycarbonyl, formyl and trifluoroacetyl and the like. Examples of oxime protecting groups include trityl, formyl, chloroacetyl, benzoyl, p-nitrobenzyl, 2,2,2-trichloroethoxycarbonyl, tetrahydropyranyl and the like. Examples of protecting groups for carboxyl groups include alkyl groups having 1 to 8 carbon atoms (e.g., methyl methoxymethyl, ethyl, methoxyethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, n-hexyl And aryl groups or aralkyl groups such as phenyl, indanyl, benzyl, cyanobenzyl, halobenzyl, methylbenzyl, nitrobenzyl, p-methoxybenzyl and phenylbenzyl.

화학식 1의 화합물에 대한 약제학적으로 허용되는 염으로는 무기염 및 유기염이 포함된다. 무기염의 예로는 나트륨, 칼륨 등과 같은 알칼리금속염, 마그네슘, 칼슘 등과 같은 알칼리토금속염 등이 있으며, 나트륨 및 칼륨염이 보다 바람직하다. 유기염의 예로는 알킬아민(에틸아민, 디에틸아민, 트리에틸아민과 같은 저급알킬아민)의 염, 방향족 아민의 염(아닐닌, 디에틸아닐린등의 염) 및 방향족 염기의 염(그 예로는 피콜린, 루티딘, 퀴놀린 등의 염)을 들 수 있다.Pharmaceutically acceptable salts for compounds of formula 1 include inorganic and organic salts. Examples of the inorganic salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium, and the like, and sodium and potassium salts are more preferable. Examples of organic salts include salts of alkylamines (lower alkylamines such as ethylamine, diethylamine, triethylamine), salts of aromatic amines (salts such as aniline, diethylaniline, etc.) and salts of aromatic bases (examples Salts such as picoline, lutidine, quinoline, and the like.

또한 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, 예를 들면, 알카노일옥시에스테르 (좀 더 자세히는, 아세톡시메틸, 아세톡시에틸, 프로피오닐옥시에틸, 피발로일옥시메틸, 피발로일옥시에틸), 탄수소 7-15의 치환된 아랄킬에스테르 (예를 들면 페나실, 또는 프탈리딜에스테르), 탄수소 6-12의 치환된 아릴에스테르 (예로서, 페닐, 크실릴, 인다닐에스테르), 그리고 2-알케닐에스테르 (예로서, 알릴 또는 2-옥소-1,3-디옥솔렌-4-일메틸에스테르) 들이다.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 are substituted. For example, alkanoyloxyesters (more specifically, acetoxymethyl, acetoxyethyl, propionyloxyethyl, pivaloyloxymethyl, pivaloyloxyethyl), substituted aralkyl esters of carbohydrates 7-15 (Eg phenacyl, or phthalidyl ester), substituted aryl esters of carbohydrate 6-12 (eg phenyl, xylyl, indanyl ester), and 2-alkenyl esters (eg allyl or 2-oxo-1,3-dioxolen-4-ylmethyl ester).

또한, 본 발명의 화학식 1의 화합물은 세팔로스포린 유도체의 3위치에 치환되어 있는 알케닐기의 구조식이 아래의 화학식 2에서 보는 바와 같이 시스 (1a), 트란스 (1b) 2가지가 가능한데 이들 모두 본 발명의 범위에 포함된다.In addition, the compound of formula 1 of the present invention is a structural formula of the alkenyl group substituted at the 3-position of the cephalosporin derivative, as shown in the following formula (2) is possible two kinds of cis (1a), trans (1b) It is included in the scope of the invention.

(1a) (1b)(1a) (1b)

화학식 1을 갖는 세팔로스포린계 화합물 또는 그의 염의 제조 방법은 아래의 화학식 3의 화합물과 화학식 4의 화합물을 커플링시켜 화학식 5를 얻고, 얻어진 화학식 5의 화합물을 트리페닐포스핀 또는 트리부틸포스핀과 반응시켜 화학식 6의 포스포늄 염을 얻고, 얻어진 화합물을 염기와 반응시켜 화학식 7의 일리드를 형성한 후, 이것을 화학식 8의 알데히드와 비티히(Wittig) 반응시키는 것으로 구성된다.The method for preparing a cephalosporin-based compound having the formula (1) or a salt thereof is obtained by coupling the compound of the formula (3) and the compound of the formula (4) to obtain a formula (5), and the obtained compound of the formula (5) is triphenylphosphine or tributylphosphine Reaction with a phosphonium salt of formula (6), and the resulting compound is reacted with a base to form an lide of formula (7), which is then reacted with Wittig with an aldehyde of formula (8).

상기 화학식 3, 4, 5, 6, 7 및 8에서 R1, R2, R3, R5및 Q의 정의는 전술한 바와 같고, X는 염소, 브롬 또는 요오드 원자를 말한다.In Formulas 3, 4, 5, 6, 7 and 8, the definitions of R 1 , R 2 , R 3 , R 5 and Q are as described above, and X represents a chlorine, bromine or iodine atom.

제조공정 1: 산과 아민의 커플링Manufacturing process 1: coupling of acid and amine

화학식 3을 갖는 아미노티아졸계열 화합물을 화학식 4의 세팔로스포린 화합물과 반응시켜 화학식 5의 화합물을 얻는 아미드화 반응은 유기 화학분야의 통상적인 반응공정을 거친다. 즉, 상기 화학식 3의 화합물을 활성화한 후, 화학식 4의 화합물과 반응하게 된다(반응식 1).The amidation reaction of reacting an aminothiazole compound having the formula (3) with the cephalosporin compound of the formula (4) to obtain the compound of the formula (5) goes through a conventional reaction process in organic chemistry. That is, after activating the compound of Formula 3, it is reacted with the compound of Formula 4 (Scheme 1).

화학식 3의 화합물을 활성화하는 방법은 당해 유기 화학 분야의 통상을 채용할 수 있으며, 그 예로는 산무수물화, 아실 할라이드화 및 결합 보조제에 의한 활성화를 들 수 있다. 산무수물화는 무기산 (예를 들면 인산, 할로겐산 등) 또는 유기산 (예를 들면, 알칸산, 아랄칸산, 슬폰산)에 의해 성취될 수 있다. 아실 할라이드화는 포스포러스트리클로리드, 티오닐클로리드, 옥살릴클로리드 등을 사용하여 성취할 수 있으며, 반드시 이에 한정하는 것은 아니다. 결합 보조제로는 N,N-디시클로헥실카르보디이미드, N-시클로헥실-N-모르포리노-에틸카르보디이미드, N-시클로헥실-N-(2-디에틸아미노시클로헥실)카르보디이미드, N,N'-카르보닐비스(2-메틸이미다졸) 및 펜타메틸렌케텐-N-시클로-헥실아민 등과 같이 유기 화학 분야에서 통상 사용되는 물질을 사용할 수 있다.The method of activating the compound of the formula (3) may employ a conventional in the field of organic chemistry, and examples thereof include acid anhydride, acyl halide and activation by binding aids. Acid anhydrides can be achieved by inorganic acids (eg phosphoric acid, halogen acids, etc.) or organic acids (eg alkanes, aralcanoes, sulfonic acids). Acyl halides can be achieved using, but not limited to, phosphorus trichloride, thionyl chloride, oxalyl chloride, and the like. Binding aids include N, N-dicyclohexylcarbodiimide, N-cyclohexyl-N-morpholino-ethylcarbodiimide, N-cyclohexyl-N- (2-diethylaminocyclohexyl) carbodiimide Materials commonly used in the field of organic chemistry, such as N, N'-carbonylbis (2-methylimidazole) and pentamethyleneketene-N-cyclohexylamine.

상기 산무수물화에 의한 활성화, 아실 할라이드화에 의한 활성화 및 결합보조제를 사용한 활성화 방법에 있어서, 반응 조건(반응 온도, 반응 시간, 사용시약, 용매, 염기의 사용 등) 및 워크업(work-up) 절차(추출, 여과, 크로마트그래피에 의한 정제 등)는 통상의 방법에 따른다.In the activation method using the acid anhydride, the activation by acyl halide, and the activation aid using a binding aid, reaction conditions (reaction temperature, reaction time, reagent used, solvent, base, etc.) and work-up ) Procedures (extraction, filtration, purification by chromatography, etc.) are in accordance with conventional methods.

제조공정 2: 포스포늄 염의 제조Preparation Process 2: Preparation of Phosphonium Salt

제조 공정 1에서 얻어진 화학식 5의 화합물을 트리페닐포스핀 또는 트리부틸포스핀과 반응시키면 화학식 6를 갖는 포스포늄 염이 제조된다(반응식 2).Reacting the compound of formula 5 obtained in preparation process 1 with triphenylphosphine or tributylphosphine produces a phosphonium salt having formula 6 (Scheme 2).

상기 반응은 통상 요오드화 나트륨, 염화 나트륨, 요오드화 칼륨, 염화 칼륨 등과 같은 금속 염의 존재하에 수행된다. 여기서 가능한 용매로는 아세톤, 디옥산, 아세토니트릴, 클로로포름, 디클로로메탄, 테트라히드로퓨란, 에틸아세테이트, N,N-디메틸포름아미드 등이 유용한데, 아세톤이 바람직하다. 또한, 반응 온도는 -20 ℃ ~ 25 ℃, 바람직하게는 10 ℃ ~ 25 ℃이다.The reaction is usually carried out in the presence of metal salts such as sodium iodide, sodium chloride, potassium iodide, potassium chloride and the like. Possible solvents here include acetone, dioxane, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide and the like, with acetone being preferred. The reaction temperature is -20 ° C to 25 ° C, preferably 10 ° C to 25 ° C.

제조 공정 3 및 4: 일리드의 제조와 비티히 반응Manufacturing Processes 3 and 4: Preparation of Ilid and Reaction of Wittich

화학식 6의 포스포늄 염을 염기와 반응시키면 화학식 7의 일리드가 형성된다(반응식 3). 비티히(Wittig) 반응을 이용하여, 형성된 일리드와 화학식 8의 알데히드를 반응시키면 원하는 목적화합물인 화학식 1의 세펨 화합물을 얻을 수 있다(반응식 4).Reaction of the phosphonium salt of formula 6 with a base forms an lide of formula 7 (Scheme 3). By using the Wittig reaction, reacting the formed lide with the aldehyde of the formula (8) yields the desired compound, the cefem compound of the formula (1).

상기 반응에 사용될 수 있는 염기의 예로는 탄산 나트륨, 탄산수소나트륨, 알칼리금속 히드리드, 알칼리금속아미드, 알칼리금속히드록시드, 알칼리금속아세테이트, 트리-(저급)알킬아민, 피리딘, N-저급알킬모르폴린, N,N-(저급)알킬벤질아민, N,N-디-(저급)알킬아닐린 등을 들 수 있으며, 반응온도는 일반적으로 -40℃ ~ 25℃가 적당하다. 또한, 사용 가능한 용매로는 물, 아세톤, 디옥산, 아세토니트릴, 클로로포름, 디클로로메탄. 테트라히드로퓨란, 에틸아세테이트, N,N-디메틸포름아미드 등이 있다.Examples of bases that can be used in the reaction include sodium carbonate, sodium bicarbonate, alkali metal hydrides, alkali metal amides, alkali metal hydroxides, alkali metal acetates, tri- (lower) alkylamines, pyridine, N-lower alkyl Morpholine, N, N- (lower) alkylbenzylamine, N, N-di- (lower) alkylaniline and the like, and the reaction temperature is generally -40 ° C to 25 ° C. In addition, usable solvents include water, acetone, dioxane, acetonitrile, chloroform and dichloromethane. Tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, and the like.

제조공정 5: 탈보호화(Deprotection)Manufacturing Process 5: Deprotection

각각의 보호기에 대응되는 탈보호화 반응에 의해, R1, R2및 R4가 모두 수소가 아닌 보호된 화합물로부터 비보호된 화합물을 제조할 수 있다(반응식 5).By deprotection reaction corresponding to each protecting group, unprotected compounds can be prepared from protected compounds in which R 1 , R 2 and R 4 are not all hydrogen (Scheme 5).

즉 R1= t-Boc, R2= 트리틸 및 R4= 메틸인 경우, 트리플루오로아세트산과같은 강산으로 처리하여 R1= H, R2= H 및 R4= 메틸인 화합물을 제조할 수 있으며, 이를 다시 NaOH, LiOH 또는 KOH와 같은 염기로 처리하면 R1, R2및 R4가 모두 수소인 비보호된 화합물을 얻을 수 있다. 마찬가지로, R1= 트리틸, R2= 트리틸 및 R4= p-메톡시 벤질인 경우, 트리플루오로아세트산으로 처리하면, R1, R2및 R4가 모두 수소인 비보호된 화합물을 얻을 수 있다. 이와 같은 방식으로 보호기의 종류를 달리하여 각각에 대응되는 탈보호화 반응을 이용하여 일부가 탈보호화된 또는 전체가 탈보호화된 다양한 화합물을 얻을 수 있다. 탈보호화 반응의 반응 조건(반응 온도, 반응 시간, 사용 시약, 용매, 염기의 사용 등) 및 워크업(work-up) 절차(추출, 여과, 크로마트그래피에 의한 정제 등)는 통상의 방법에 따른다.That is, when R 1 = t-Boc, R 2 = trityl and R 4 = methyl, a compound with R 1 = H, R 2 = H and R 4 = methyl can be prepared by treatment with a strong acid such as trifluoroacetic acid. This can be treated again with a base such as NaOH, LiOH or KOH to give an unprotected compound in which R 1 , R 2 and R 4 are all hydrogen. Likewise, when R 1 = trityl, R 2 = trityl and R 4 = p-methoxy benzyl, treatment with trifluoroacetic acid yields an unprotected compound in which R 1 , R 2 and R 4 are all hydrogen Can be. In this manner, various kinds of protecting groups may be used to obtain various compounds in which a part is deprotected or a whole is deprotected by using a corresponding deprotection reaction. The reaction conditions (reaction temperature, reaction time, reagent used, solvent, base used, etc.) and work-up procedures (extraction, filtration, purification by chromatography, etc.) of the deprotection reaction are conventional methods. Follow.

다음의 화합물들은 본 발명에서 얻어진 화학식 1의 구조를 지니는 대표적인 화합물들을 보여준다.The following compounds show representative compounds having the structure of Formula 1 obtained in the present invention.

화합물 1. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실레이트.Compound 1.Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -(Z)-[(1,2,5-thiadiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

화합물 2. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(E)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실레이트.Compound 2. Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -(E)-[(1,2,5-thiadiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

화합물 3. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.Compound 3. Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -[(Isothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

화합물 4. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(3-파라메톡시벤질옥시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.Compound 4. Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -(Z)-[(3-paramethoxybenzyloxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

화합물 5. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(E)-[(3-파라메톡시벤질옥시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.Compound 5. Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -(E)-[(3-paramethoxybenzyloxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

화합물 6. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-[(3-메틸이소티아졸-4-일)비닐]-3-세펨-4-카르복실레이트.Compound 6. Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -[(3-methylisothiazol-4-yl) vinyl] -3-cepem-4-carboxylate.

화합물 7. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(E)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.Compound 7. Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -(E)-[(3-methoxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

화합물 8. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.Compound 8. Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -(Z)-[(3-methoxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

화합물 9. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실레이트.Compound 9. Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetami Fig.]-3- (Z)-[(1,2,5-thiadiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

화합물 10. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(E)-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.Compound 10. Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetami Fig.]-3- (E)-[(isothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

화합물 11. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.Compound 11.Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetami Fig.]-3- (Z)-[(isothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

화합물 12. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(3-파라메톡시벤질옥시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.Compound 12. Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetami Fig.]-3- (Z)-[(3-paramethoxybenzyloxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

화합물 13. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)]-2-트리틸옥시이미노아세트아미도]-3-[(3-메틸이소티아졸-4-일)비닐]-3-세펨-4-카르복실레이트.Compound 13. Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl)]-2-trityloxyiminoacet Amido] -3-[(3-methylisothiazol-4-yl) vinyl] -3-cepem-4-carboxylate.

화합물 14. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(E)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.Compound 14. Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetami Fig.]-3- (E)-[(3-methoxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

화합물 15. 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.Compound 15. Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetami Fig.]-3- (Z)-[(3-methoxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

화합물 16. (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 16. (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z)-[(1 , 2,5-thiadiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid and sodium salt.

화합물 17. (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 17. (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E)-[(1 , 2,5-thiadiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid and sodium salt.

화합물 18. (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 18. (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-[(isothiazole-5 -Yl) vinyl] -3-cepem-4-carboxylic acid and sodium salt.

화합물 19. (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(3-파라메톡시벤질옥시이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 19. (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z)-[(3 -Paramethoxybenzyloxyisothiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid and sodium salt.

화합물 20. (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(3-파라메톡시벤질옥시이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 20. (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E)-[(3 -Paramethoxybenzyloxyisothiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid and sodium salt.

화합물 21. (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-[(3-메틸이소티아졸-4-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 21. (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-[(3-methylisothia Zol-4-yl) vinyl] -3-cepem-4-carboxylic acid and sodium salt.

화합물 22. (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 22. (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E)-[(3 -Methoxyisothiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid and sodium salt.

화합물 23. (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 23. (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z)-[(3 -Methoxyisothiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid and sodium salt.

화합물 24. (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미노]-3-(Z)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 24. (6R, 7R) -7-[(Z) -2- (2-Amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamino] -3- (Z)- [(1,2,5-thiadiazol-5-yl) vinyl] -3-cepem-4-carboxylic acid and sodium salt.

화합물 25. (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 25. (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E) -[(Isothiazol-5-yl) vinyl] -3-cepem-4-carboxylic acid and sodium salt.

화합물 26. (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 26. (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z) -[(Isothiazol-5-yl) vinyl] -3-cepem-4-carboxylic acid and sodium salt.

화합물 27. (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-[(3-히드록시이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 27. (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3-[(3 -Hydroxyisothiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid and sodium salt.

화합물 28. (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)]-2-히드록시이미노아세트아미도]-3-(E)-[(3-메틸이소티아졸-4-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 28. (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl)]-2-hydroxyiminoacetamido] -3- (E )-[(3-methylisothiazol-4-yl) vinyl] -3-cepem-4-carboxylic acid and sodium salt.

화합물 29. (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 29. (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E) -[(3-methoxyisothiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid and sodium salt.

화합물 30. (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염.Compound 30. (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z) -[(3-methoxyisothiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid and sodium salt.

이하 참고예(출발물질의 합성) 및 실시예(본 발명 화합물의 합성)를 통해 본 발명을 보다 상세히 설명할 것이나, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through reference examples (synthesis of starting materials) and examples (synthesis of compounds of the present invention), but the scope of the present invention is not limited to these examples.

참고예 1Reference Example 1

에틸 3-메틸이소티아졸-4-카르복실레이트의 제조Preparation of ethyl 3-methylisothiazole-4-carboxylate

2,3-디아미노프로피온산 모노히드로 클로리드 (5.0 g, 38.71 mmol)을 15 ml의 디메틸포름아미드에 녹인 뒤, -40℃에서 포스포러스옥시클로라이드(3.82 ml, 41.03 mmol)을 5분 동안 서서히 적가하고 25℃에서 교반하였다. 10분 후 반응 혼합물에 70 ml의 물을 녹인 황화나트륨(15.92 g, 66.28 mmol)을 가하고, 얼음물에서 1시간 동안 교반하였다. 반응 종결 후, 반응 혼합물을 벤젠으로 추출하고 물로 세척한 후, 무수 황산 마그네슘으로 건조시키고 감압여과하여 이 용액에 3.9 ml의 벤젠에 녹인 브롬(2 ml)을 적가하였다. 반응 혼합물을 23℃로 유지시킨 후, 물, 포화 탄산칼륨 수용액 및 티오황산나트륨으로 순차 세척하고, 무수 황산마그네슘으로 건조하였다. 건조된 유기층을 여과하고, 여과액을 감압 농축시켰다. 잔사를 관크로마토그래피로 정제하여(전개용액: 에틸 아세테이트/헥산 = 1/4), 목적화합물(2.81 g, 42.3%)을 얻었다.2,3-diaminopropionic acid monohydrochloride (5.0 g, 38.71 mmol) was dissolved in 15 ml of dimethylformamide, and then phosphorus oxychloride (3.82 ml, 41.03 mmol) was slowly added dropwise at -40 ° C for 5 minutes. And stirred at 25 ° C. After 10 minutes, sodium sulfide (15.92 g, 66.28 mmol) in which 70 ml of water was dissolved was added to the reaction mixture, which was stirred for 1 hour in ice water. After completion of the reaction, the reaction mixture was extracted with benzene, washed with water, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and bromine (2 ml) dissolved in 3.9 ml of benzene was added dropwise to this solution. The reaction mixture was kept at 23 ° C., washed sequentially with water, saturated aqueous potassium carbonate solution and sodium thiosulfate, and dried over anhydrous magnesium sulfate. The dried organic layer was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (developing solution: ethyl acetate / hexane = 1/4) to obtain the target compound (2.81 g, 42.3%).

1H NMR(300MHz, CDCl3) δ: 9.17(s, 1H, 이소티아졸-H), 4.22(ABq, 2H, -OCH 2 CH3), 2.61(s, 3H, -CH3), 1.28(t, 3H, -OCH2 CH 3 ) 1 H NMR (300 MHz, CDCl 3 ) δ: 9.17 (s, 1H, isothiazole-H), 4.22 (ABq, 2H, -O CH 2 CH 3 ), 2.61 (s, 3H, -CH 3 ), 1.28 (t, 3H, -OCH 2 CH 3 )

참고예 2Reference Example 2

3-메틸-4-히드록시메틸이소티아졸의 제조Preparation of 3-methyl-4-hydroxymethylisothiazole

에틸 3-메틸이소티아졸-4-카르복실레이트(2.2 g, 12.85 mmol)을 테트라히드로퓨란(20 ml)에 녹이고, 온도를 0℃로 낮춘 뒤, 리튬 알루미늄히드리드(0.49 g, 12.85 mmol)를 서서히 가하였다. 15분 동안 교반한 후, 포화 염화암모늄 수용액을 서서히 적가하여 반응을 종결시키고, 생성된 고체를 여과하여 제거하였다. 여과액을 물로 세척하고, 메틸렌 클로리드로 추출하고 무수 황산마그네슘으로 건조하였다. 건조된 유기층을 여과하고, 여과액을 감압 농축시켜 목적화합물(1.48 g, 89%)을 얻었다.Ethyl 3-methylisothiazole-4-carboxylate (2.2 g, 12.85 mmol) was dissolved in tetrahydrofuran (20 ml) and the temperature was lowered to 0 ° C., followed by lithium aluminum hydride (0.49 g, 12.85 mmol). Was added slowly. After stirring for 15 minutes, the reaction was terminated by the slow dropwise addition of saturated aqueous ammonium chloride solution and the resulting solid was filtered off. The filtrate was washed with water, extracted with methylene chloride and dried over anhydrous magnesium sulfate. The dried organic layer was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (1.48 g, 89%).

1H NMR(300MHz, CDCl3) δ: 8.40(s, 1H, 이소티아졸-H), 4.60(s, 2H, -CH2OH), 2.37(s, 3H, -CH3) 1 H NMR (300 MHz, CDCl 3 ) δ: 8.40 (s, 1H, isothiazole-H), 4.60 (s, 2H, -CH 2 OH), 2.37 (s, 3H, -CH 3 )

참고예 3Reference Example 3

3-메틸-4-포밀이소티아졸의 제조Preparation of 3-methyl-4-formylisothiazole

피리디늄 클로로크로메이트 (1.25 g, 5.80 mmol)을 동량의 실리카겔과 섞어 메틸렌클로리드(6 ml)에 녹이고, 이 혼합물에 3-메틸-4-메틸히드록시이소티아졸(320 mg, 2.48 mmol)이 용해된 메틸렌 클로리드(6 ml) 용액을 가하였다. 반응 혼합물을 실온에서 3시간 동안 교반한 후, 소량의 에테르를 가하고, 관크로마토그래피(전개용매: 100% 에테르)하여 목적화합물(247 mg, 78%)을 얻었다.Pyridinium chlorochromate (1.25 g, 5.80 mmol) was mixed with an equal amount of silica gel and dissolved in methylene chloride (6 ml), and 3-methyl-4-methylhydroxyisothiazole (320 mg, 2.48 mmol) was added to the mixture. A dissolved methylene chloride (6 ml) solution was added. The reaction mixture was stirred at room temperature for 3 hours, after which a small amount of ether was added and tube chromatography (developing solvent: 100% ether) gave the target compound (247 mg, 78%).

1H NMR(300MHz, CDCl3) δ: 10.05 (s, 1H, CHO), 9.23 (s, 1H, 이소티아졸-H), 2.67(s, 3H, CH3). 1 H NMR (300 MHz, CDCl 3 ) δ: 10.05 (s, 1H, CHO), 9.23 (s, 1H, isothiazole-H), 2.67 (s, 3H, CH 3 ).

참고예 4Reference Example 4

상기 참고예 1-3과 같은 방법으로 다음과 같은 화합물을 제조하였다.In the same manner as in Reference Example 1-3, the following compound was prepared.

(1) 3-메톡시-5-포밀이소티아졸(1) 3-methoxy-5-formylisothiazole

1H NMR(300MHz, CDCl3) δ: 10.02 (s, 1H, CHO), 7.11 (s, 1H, 이소티아졸-H), 4.06(s, 3H, -CH3) 1 H NMR (300 MHz, CDCl 3 ) δ: 10.02 (s, 1H, CHO), 7.11 (s, 1H, isothiazole-H), 4.06 (s, 3H, -CH 3 )

(2) 3-(파라메톡시벤질옥시)-5-포밀이소티아졸(2) 3- (paramethoxybenzyloxy) -5-formylisothiazole

1H NMR(300MHz, CDCl3) δ: 10.00 (s, 1H, CHO), 7.40 (d, 2H, Ph-H), 7.12 (s, 1H, 이소티아졸-H), 6.97(d, 2H, Ph-H), 5.36 (s, 2H, -OCH2Ph), 3.87 (s, 3H, -OCH3) 1 H NMR (300 MHz, CDCl 3 ) δ: 10.00 (s, 1H, CHO), 7.40 (d, 2H, Ph-H), 7.12 (s, 1H, isothiazole-H), 6.97 (d, 2H, Ph-H), 5.36 (s, 2H, -OCH 2 Ph), 3.87 (s, 3H, -OCH 3 )

(3) 4-포밀-1,2,5-이소티아졸(3) 4-formyl-1,2,5-isothiazole

1H NMR(300MHz, CDCl3) δ: 10.16 (s, 1H, CHO), 9.01 (s, 1H, 이소티아졸-H) 1 H NMR (300 MHz, CDCl 3 ) δ: 10.16 (s, 1H, CHO), 9.01 (s, 1H, isothiazole-H)

(4) 5-포밀이소티아졸(4) 5-formylisothiazole

1H NMR(300MHz, CDCl3) δ: 10.12 (s, 1H, CHO), 8.64 (s, 1H, 이소티아졸-H), 7.79 (s, 1H, 이소티아졸-H) 1 H NMR (300 MHz, CDCl 3 ) δ: 10.12 (s, 1H, CHO), 8.64 (s, 1H, isothiazole-H), 7.79 (s, 1H, isothiazole-H)

참고예 5Reference Example 5

파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-클로로메틸-3-세펨-4-카르복실레이트의 제조Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3-chloromethyl Preparation of 3-Cefe-4-carboxylate

2-(트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트산 8.68 g (12.92 mmol)과 파라-메톡시벤질 (6R, 7R)-7-아미노-3-클로로메틸-3-세펨-4-카르복실레이트히드로클로리드 5.24 g(12.92 mmol)를 200 mL의 메틸렌 클로리드 용액에 가하고 -5℃로 냉각하였다. 이 용액에 4.18 mL(51.68 mmol)의 피리딘을 가하고 20분간 교반하였다. 이 용액에 다시 2.41 mL(25.84 mmol)의 포스포러스옥시 클로리드를 가하고 30분 동안 교반하였다. 반응의 종결 후, 반응 혼합물을 물, 탄산수소 나트륨 용액 및 포화 소금물로 순차 세척하고, 무수 황산 마그네슘으로 건조 및 여과하였다. 여과액을 감압 농축시키고, 이소프로필 에테르로 고체화하여 생성물 10.83 g(82%)을 얻었다.8.68 g (12.92 mmol) of 2- (tritylaminothiazol-4-yl) -2-trityloxyiminoacetic acid and para-methoxybenzyl (6R, 7R) -7-amino-3-chloromethyl-3- 5.24 g (12.92 mmol) of cefem-4-carboxylate hydrochloride were added to 200 mL of methylene chloride solution and cooled to -5 ° C. 4.18 mL (51.68 mmol) pyridine was added to the solution and stirred for 20 minutes. 2.41 mL (25.84 mmol) of phosphorusoxy chloride was added to this solution and stirred for 30 minutes. After completion of the reaction, the reaction mixture was washed sequentially with water, sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and solidified with isopropyl ether to give 10.83 g (82%) of product.

1H NMR(300MHz, CDCl3) δ: 7.34(m, 32H, Ph), 6.92(d, 2H, Ph), 6.76(s, 1H, 티아졸-H) 6.43(s, 1H, -NH-) 6.07(m, 1H, C7-H), 5.22(s, 2H, -CO2CH2Ph), 5.05(d, 1H, C6-H), 4.55(d, 1H, C3-CH2Cl) 4.43(d, 1H, C3-CH2Cl), 3.84(s, 3H, -OCH3), 3.58(d, 1H, C2-H) 3.30(d, 1H, C2-H) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.34 (m, 32H, Ph), 6.92 (d, 2H, Ph), 6.76 (s, 1H, thiazole-H) 6.43 (s, 1H, -NH-) 6.07 (m, 1H, C7-H), 5.22 (s, 2H, -CO 2 CH 2 Ph), 5.05 (d, 1H, C6-H), 4.55 (d, 1H, C3-CH 2 Cl) 4.43 ( d, 1H, C3-CH 2 Cl), 3.84 (s, 3H, -OCH 3 ), 3.58 (d, 1H, C2-H) 3.30 (d, 1H, C2-H)

참고예 6Reference Example 6

상기 참고예 5와 같은 방법으로 파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-[5-클로로-2-(트리틸아미노)티아졸-4-일]-2-트리틸옥이미노아세트아미도]-3-클로로메틸-3-세펨-4-카르복실레이트를 제조하였다.In the same manner as in Reference Example 5, para-methoxybenzyl (6R, 7R) -7-[(Z) -2- [5-chloro-2- (tritylamino) thiazol-4-yl] -2- Trityloxyiminoacetamido] -3-chloromethyl-3-cepem-4-carboxylate was prepared.

1H NMR(300MHz, CDCl3) δ: 7.48~7.16(m, 32H, ph-H), 6.92(d, 2H, ph-H), 6.06(m, 1H, C7-H), 5.26(s, 2H, -CO2CH2Ph), 5.04(d, 1H, C6-H), 4.48(dd, 2H, C3-CH2Cl), 3.79(s, 3H, -OCH3), 3.41(dd, 2H, C2-H) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.48 to 7.16 (m, 32H, ph-H), 6.92 (d, 2H, ph-H), 6.06 (m, 1H, C7-H), 5.26 (s, 2H, -CO 2 CH 2 Ph), 5.04 (d, 1H, C6-H), 4.48 (dd, 2H, C3-CH 2 Cl), 3.79 (s, 3H, -OCH3), 3.41 (dd, 2H, C2-H)

참고예 7Reference Example 7

파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-(트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-트레페닐포스포니움메틸-3-세펨-4-카르복실레이트 요오드의 제조Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3-trephenylphosphoni Preparation of Ummethyl-3-cepem-4-carboxylate Iodine

파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-(트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-클로로메틸-3-세펨-4-카르복실레이트 6 g(5.87 mmol)을 100 mL의 아세톤에 녹이고 트리페닐포스핀(PPh3) 1.53 g (5.87 mmol)과 요오드화 나트륨 0.88 g(5.87 mmol)을 가하고 실온에서 2시간 동안 교반하였다. 반응 혼합물을 감압 농축시키고, 진공 건조하여 생성물 7.67 g(95%)을 얻었다.Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3-chloromethyl-3 6 g (5.87 mmol) of cefem-4-carboxylate were dissolved in 100 mL of acetone, 1.53 g (5.87 mmol) of triphenylphosphine (PPh 3 ) and 0.88 g (5.87 mmol) of sodium iodide were added thereto, and the mixture was stirred at room temperature for 2 hours. Was stirred. The reaction mixture was concentrated under reduced pressure and dried under vacuum to yield 7.67 g (95%) of product.

참고예 8Reference Example 8

상기 참고예 7과 같은 제조방법으로 파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-[5-클로로-2-(트리틸아미노)티아졸-4-일]-2-트리틸옥시이미노아세트아미도]-3-트리페닐포스포니움메틸-3-세펨-4-카르복실레이트 요오드를 제조하였다.Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- [5-chloro-2- (tritylamino) thiazol-4-yl] -2 in the same manner as in Reference Example 7 -Trityloxyiminoacetamido] -3-triphenylphosphoniummethyl-3-cepem-4-carboxylate iodine was prepared.

실시예 1Example 1

파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-(트리틸아미노)티아졸-4-일]-2-트리틸옥시이미노아세트아미도]-3-[(3-메틸이소티아졸-4-일)-비닐]-3-세펨-4-카르복실레이트의 제조Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (tritylamino) thiazol-4-yl] -2-trityloxyiminoacetamido] -3-[(3 Preparation of -Methylisothiazol-4-yl) -vinyl] -3-cefe-4-carboxylate

파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-(트리틸아미노)티아졸-4-일]-2-트리틸옥시이미노아세트아미도]-3-트리페닐포스포니움메틸-3-세펨-4-카르복실레이트 요오드 0.7 g (0.66 mmol)과 3-메틸-4-포밀이소티아졸 0.1 g(0.58 mmol)을 5 mL의 메틸렌클로리드 용액에 녹이고 4 mL의 5%-탄산 수소나트륨 용액을 가하여 실온에서 1시간동안 교반하였다. 반응 혼합물을 물 및 포화 소금물로 순차 세척하고, 무수 황산 마그네슘으로 건조 및 여과하였다. 여과액을 감압 농축시키고, 잔사를 관크로마토그래피(전개용액; 헥산/에틸 아세테이트 = 2/1)로 정제하여 생성물 133.8 mg(18.2%)을 얻었다.Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (tritylamino) thiazol-4-yl] -2-trityloxyiminoacetamido] -3-triphenylforce 0.7 g (0.66 mmol) of poniummethyl-3-cepem-4-carboxylate iodine and 0.1 g (0.58 mmol) of 3-methyl-4-formylisothiazole were dissolved in 5 mL of methylene chloride solution and 4 mL of 5% sodium hydrogen carbonate solution was added and stirred at room temperature for 1 hour. The reaction mixture was washed sequentially with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (developing solution; hexane / ethyl acetate = 2/1) to obtain 133.8 mg (18.2%) of the product.

트란스 이성질체:1H NMR(300MHz, CDCl3) δ: 8.27(s, 1H), 7.36-7.18(m, overlapping, ph-H), 6.84(d, 2H, ph-H), 6.49(s, 1H, 티아졸-H), 6.35(s, 1H, 이소티아졸-H), 5.80(br, m, 1H, C7-H), 5.25(d, 2H, -OCH 2Ph), 5.00(d, 1H, C6-H), 3.75(s, 3H, -OCH 3), 2.40(s, 2H, C2-H), 2.42(s, 3H, -CH 3),Trans isomer: 1 H NMR (300 MHz, CDCl 3 ) δ: 8.27 (s, 1H), 7.36-7.18 (m, overlapping, ph-H), 6.84 (d, 2H, ph-H), 6.49 (s, 1H , Thiazole-H), 6.35 (s, 1H, isothiazole-H), 5.80 (br, m, 1H, C7-H), 5.25 (d, 2H, -OC H 2 Ph), 5.00 (d, 1H, C6-H), 3.75 (s, 3H, -OC H 3 ), 2.40 (s, 2H, C2-H), 2.42 (s, 3H, -C H 3 ),

시스 이성질체:1H NMR(300MHz, CDCl3) δ: 8.17(s, 1H), 7.36-7.18(m, overlapping, ph-H) 6.84(d, 2H, ph-H), 6.48(d, 1H, -CH=CH-), 6.37(d, 1H, -CH=CH-), 6.46(s, 1H, 티아졸-H), 6.40(s, 1H, 이소티아졸-H), 5.80(br, m, 1H, C7-H), 5.13(d, 2H, -OCH 2Ph), 4.98(d, 1H, C6-H), 3.73(s, 3H, -OCH 3), 3.16(d, 1H, C2-H), 2.98(d, 1H, C2-H), 2.42(s, 3H, -CH 3)Cis isomer: 1 H NMR (300 MHz, CDCl 3 ) δ: 8.17 (s, 1 H), 7.36-7.18 (m, overlapping, ph-H) 6.84 (d, 2H, ph-H), 6.48 (d, 1H, -CH = CH-), 6.37 (d, 1H, -CH = CH-), 6.46 (s, 1H, thiazole-H), 6.40 (s, 1H, isothiazole-H), 5.80 (br, m , 1H, C7-H), 5.13 (d, 2H, -OC H 2 Ph), 4.98 (d, 1H, C6-H), 3.73 (s, 3H, -OC H 3 ), 3.16 (d, 1H, C2-H), 2.98 (d, 1H, C2-H), 2.42 (s, 3H, -C H 3 )

실시예 2Example 2

상기 참고예 1-8 및 실시예 1과 같은 방법으로 반응을 수행하여 다음과 같은 화합물을 제조하였다.The reaction was carried out in the same manner as in Reference Examples 1-8 and Example 1 to prepare the following compounds.

(1) 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실레이트(1) para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -(Z)-[(1,2,5-thiadiazol-5-yl) vinyl] -3-cepem-4-carboxylate

1H NMR(300 MHZ, CDCl3) δ: 8.25(s, 1H,티아디아졸-H), 7.30-7.12(m, 32H, ph-H), 6.76(d, 2H, ph-H), 6.66(d, 1H, -CH=CH-), 6.58(d, 1H, -CH=CH-), 5.79(d, 1H, C7-H), 5.28(d, 1H, C6-H), 3.63(d, 1H, C2-H), 3.29(d, 1H, C2-H) 1 H NMR (300 MHZ, CDCl 3 ) δ: 8.25 (s, 1H, thiadiazole-H), 7.30-7.12 (m, 32H, ph-H), 6.76 (d, 2H, ph-H), 6.66 (d, 1H, -CH = CH-), 6.58 (d, 1H, -CH = CH-), 5.79 (d, 1H, C7-H), 5.28 (d, 1H, C6-H), 3.63 (d , 1H, C2-H), 3.29 (d, 1H, C2-H)

(2) 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(E)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실레이트(2) para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -(E)-[(1,2,5-thiadiazol-5-yl) vinyl] -3-cepem-4-carboxylate

1H NMR(300 MHz, CDCl3) δ: 8.36(s, 1H, 티아디아졸-H), 7.80(d, 1H, -CH=CH-), 7.35-7.13(m, overlapping, 32H, ph-H), 6.83(d, 2H, ph-H), 6.74(d, 1H, -CH=CH-), 6.34(s, 1H, 티아졸-H), 5.98(m, 1H, C7-H), 5.26(d, 1H, -OCH 2Ph), 5.15(d, 1H, , -OCH 2Ph), 4.98(d, 1H, , C6-H), 3.71(s, 3H, -OCH 3), 3.35(s, 2H, C2-H) 1 H NMR (300 MHz, CDCl 3 ) δ: 8.36 (s, 1H, thiadiazole-H), 7.80 (d, 1H, -CH = CH-), 7.35-7.13 (m, overlapping, 32H, ph- H), 6.83 (d, 2H, ph-H), 6.74 (d, 1H, -CH = CH-), 6.34 (s, 1H, thiazole-H), 5.98 (m, 1H, C7-H), 5.26 (d, 1H, -OC H 2 Ph), 5.15 (d, 1H,, -OC H 2 Ph), 4.98 (d, 1H,, C6-H), 3.71 (s, 3H, -OC H 3 ) , 3.35 (s, 2H, C2-H)

(3) 파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.(3) para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -[(Isothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

트란스이성질체1H NMR(300 MHz, CDCl3) δ: 8.38(s, 1H, 이소티아졸-H), 7.11(s, 1H, 이소티아졸-H), 6.94(d, 1H, -CH=CH-), 6.84(d, 2H, ph-H), 6.80(d, 1H, -CH=CH-), 6.48(s, 1H, 티아졸-H), 6.12(m, 1H, C7-H), 5.30(d, 1H, C6-H), 4.82(s, 3H,-OCH 3), 3.51(s, 2H, C2-H),Trans isomer 1 H NMR (300 MHz, CDCl 3 ) δ: 8.38 (s, 1H, isothiazole-H), 7.11 (s, 1H, isothiazole-H), 6.94 (d, 1H, -CH = CH -), 6.84 (d, 2H, ph-H), 6.80 (d, 1H, -CH = CH-), 6.48 (s, 1H, thiazole-H), 6.12 (m, 1H, C7-H), 5.30 (d, 1H, C6-H), 4.82 (s, 3H, -OC H 3 ), 3.51 (s, 2H, C2-H),

시스 이성질체 δ: 8.32(s, 1H, 이소티아졸-H), 7.00(s, 1H, 이소티아졸-H), 6.84(d, 2H, ph-H), 6.68(d, 1H, -CH=CH-), 6.50(d, 1H, -CH=CH-), 6.48(s, 1H, 티아졸-H), 6.12(m, 1H, C7-H), 5.18(t, overlapping, 3H, C6-H & -OCH 2Ph), 4.80(s, 3H, -OCH 3), 3.47(d, 1H, C2-H), 3.22(d, 1H, C2-H)Cis isomer δ: 8.32 (s, 1H, isothiazole-H), 7.00 (s, 1H, isothiazole-H), 6.84 (d, 2H, ph-H), 6.68 (d, 1H, -CH = CH-), 6.50 (d, 1H, -CH = CH-), 6.48 (s, 1H, thiazole-H), 6.12 (m, 1H, C7-H), 5.18 (t, overlapping, 3H, C6- H & -OC H 2 Ph), 4.80 (s, 3H, -OC H 3 ), 3.47 (d, 1H, C2-H), 3.22 (d, 1H, C2-H)

(4) 파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(3-(파라-메톡시벤질옥시)이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.(4) para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -(Z)-[(3- (para-methoxybenzyloxy) isothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

1H NMR(300 MHz, CDCl3) δ: 7.39(d, 2H, ph-H), 7.32-7.25(m, 30H, ph-H), 6.87(d, 2H, ph-H), 6.55(d, 1H, -CH=CH-), 6.45(d, 2H, -CH=CH-& 티아졸-H),6.36(s, 1H, 이소티아졸-H), 6.12(br, m, 1H, C7-H), 5.17(d, overlapping, 3H, -OCH 2Ph & C6-H), 3.95(s, 3H, -OCH 3), 3.80(s, 3H, -OCH 3), 3.50(d, 1H, C2-H), 3.24(d, 1H, C2-H) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.39 (d, 2H, ph-H), 7.32-7.25 (m, 30H, ph-H), 6.87 (d, 2H, ph-H), 6.55 (d , 1H, -CH = CH-), 6.45 (d, 2H, -CH = CH- & thiazole-H), 6.36 (s, 1H, isothiazole-H), 6.12 (br, m, 1H, C7 -H), 5.17 (d, overlapping, 3H, -OC H 2 Ph & C6-H), 3.95 (s, 3H, -OC H 3 ), 3.80 (s, 3H, -OC H 3 ), 3.50 (d , 1H, C2-H), 3.24 (d, 1H, C2-H)

(5) 파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(E)-[(3-(파라-메톡시벤질옥시)이소티아졸 5-일)비닐]-3-세펨-4-카르복실레이트.(5) para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -(E)-[(3- (para-methoxybenzyloxy) isothiazol 5-yl) vinyl] -3-cepem-4-carboxylate.

1H NMR(300 MHz, CDCl3) δ: 7.46(d, 1H,), 7.42-7.24(m, 32H, ph-H), 6.94(d, 2H, ph-H), 6.58(d, 1H, -CH=CH-), 6.46(s, 1H, 티아졸-H), 6.43(s, 1H, 이소티아졸-H), 6.05(br, m, 1H, C7-H), 5.29(d, 2H, -OCH 2Ph), 5.08(d, 1H, C6-H), 4.00(s, 3H, -OCH 3), 3.80(s, 3H, -OCH 3), 3.47(d, 2H, C2-H) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.46 (d, 1H,), 7.42-7.24 (m, 32H, ph-H), 6.94 (d, 2H, ph-H), 6.58 (d, 1H, -CH = CH-), 6.46 (s, 1H, thiazole-H), 6.43 (s, 1H, isothiazole-H), 6.05 (br, m, 1H, C7-H), 5.29 (d, 2H , -OC H 2 Ph), 5.08 (d, 1H, C6-H), 4.00 (s, 3H, -OC H 3 ), 3.80 (s, 3H, -OC H 3 ), 3.47 (d, 2H, C2 -H)

(6) 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(E)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.(6) para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -(E)-[(3-methoxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

1H NMR(300 MHz, CDCl3) δ: 7.46(d, 1H, -CH=CH-), 7.42-7.24(m, 32H, ph-H), 6.94(d, 2H, ph-H), 6.58(d, 1H, -CH=CH-), 6.46(s, 1H, 티아졸-H), 6.43(s, 1H, 이소티아졸-H), 6.05(br, m, 1H, C7-H), 5.29(d, 2H, -OCH 2Ph), 5.08(d, 1H, C6-H), 4.00(s, 3H, -OCH 3), 3.80(s, 3H, -OCH 3), 3.47(d, 2H, C2-H) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.46 (d, 1H, -CH = CH-), 7.42-7.24 (m, 32H, ph-H), 6.94 (d, 2H, ph-H), 6.58 (d, 1H, -CH = CH-), 6.46 (s, 1H, thiazole-H), 6.43 (s, 1H, isothiazole-H), 6.05 (br, m, 1H, C7-H), 5.29 (d, 2H, -OC H 2 Ph), 5.08 (d, 1H, C6-H), 4.00 (s, 3H, -OC H 3 ), 3.80 (s, 3H, -OC H 3 ), 3.47 ( d, 2H, C2-H)

(7) 파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.(7) para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3 -(Z)-[(3-methoxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

1H NMR(300 MHz, CDCl3) δ: 7.39(d, 2H, ph-H), 7.32-7.25(m, 30H, ph-H), 6.87(d, 2H, ph-H), 6.55(d, 1H,-CH=CH-), 6.45(d, 2H, -CH=CH- & 티아졸-H),6.36(s, 1H, 이소티아졸-H), 6.12(br, m, 1H, C7-H), 5.17(d, overlapping, 3H, -OCH 2Ph & C6-H), 3.95(s, 3H, -OCH 3), 3.80(s, 3H, -OCH 3), 3.50(d, 1H, C2-H), 3.24(d, 1H, C2-H) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.39 (d, 2H, ph-H), 7.32-7.25 (m, 30H, ph-H), 6.87 (d, 2H, ph-H), 6.55 (d , 1H, -CH = CH-), 6.45 (d, 2H, -CH = CH- & thiazole-H), 6.36 (s, 1H, isothiazole-H), 6.12 (br, m, 1H, C7 -H), 5.17 (d, overlapping, 3H, -OC H 2 Ph & C6-H), 3.95 (s, 3H, -OC H 3 ), 3.80 (s, 3H, -OC H 3 ), 3.50 (d , 1H, C2-H), 3.24 (d, 1H, C2-H)

(8) 파라-메톡시벤질 (6R, 7R)-7-[(Z)-2- (5-클로로-2-트리틸아미노티아졸-4-일)]-2-트리틸옥시이미노아세트아미도}-3-(Z)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실레이트. (8) para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl)]-2-trityloxyiminoacet Amido} -3- (Z)-[(1,2,5-thiadiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

1H NMR(300 MHz, CDCl3) δ: 7.44-6.24(m, 34H, ph-H), 6.90(d, 2H, ph-H), 6.84(d, 2H, ph-H), 6.52(d, 1H, -CH=CH-), 6.43(d, 1H,- CH=CH-), 6.18(m, 1H,C7-H), 5.34(s, 1H, C6-H), 5.18(d, 2H, -OCH 2Ph), 3.79(s, 3H,-OCH3), 3.78(s, 3H, -OCH3), 3.52(d, 1H, C2-H), 3.12(d, 1H, C2-H) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.44-6.24 (m, 34H, ph-H), 6.90 (d, 2H, ph-H), 6.84 (d, 2H, ph-H), 6.52 (d , 1H, -CH = CH-, 6.43 (d, 1H, -CH = CH-), 6.18 (m, 1H, C7-H), 5.34 (s, 1H, C6-H), 5.18 (d, 2H , -OC H 2 Ph), 3.79 (s, 3H, -OCH 3 ), 3.78 (s, 3H, -OCH 3 ), 3.52 (d, 1H, C2-H), 3.12 (d, 1H, C2-H )

(9) 파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)]-2-트리틸옥시이미노아세트아미도}-3-(E)-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.(9) para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl)]-2-trityloxyiminoacet Amido} -3- (E)-[(isothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

1H NMR(300MHz, CDCl3) δ: 8.42(s, 1H, 이소티아졸-H), 7.56(d, 1H, -CH=CH-), 7.30(m, 32H, ph-H), 7.12(s, 1H, 이소티아졸-H), 6.95(d, 2H, ph-H), 6.24(d, 1H, -CH=CH-), 6.09(m, 1H, C7-H), 5.32(dd, 2H, -OCH 2Ph), 5.11(d, 1H, C6-H), 3.87(s, 3H, -OCH 3), 3.50(dd, 2H, C2-H) 1 H NMR (300 MHz, CDCl 3 ) δ: 8.42 (s, 1H, isothiazole-H), 7.56 (d, 1H, -CH = CH-), 7.30 (m, 32H, ph-H), 7.12 ( s, 1H, isothiazole-H), 6.95 (d, 2H, ph-H), 6.24 (d, 1H, -CH = CH-), 6.09 (m, 1H, C7-H), 5.32 (dd, 2H, -OC H 2 Ph), 5.11 (d, 1H, C6-H), 3.87 (s, 3H, -OC H 3 ), 3.50 (dd, 2H, C2-H)

(10) 파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일]-2-트리틸옥시이미노아세트아미도}-3-(Z)-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트(10) para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl] -2-trityloxyiminoacetami Fig. 3-3- (Z)-[(isothiazol-5-yl) vinyl] -3-cepem-4-carboxylate

시스 이성질체 δ: 8.32(s, 1H, 이소티아졸-H), 7.25(m, 32H, ph-H), 7.02(s, 1H, 이소티아졸-H), 6.89(d, 2H, ph-H), 6.70(d, 1H,), 6.52(d, 1H, -CH=CH-), 6.19(m, 1H, C7-H), 5.20(m, 3H, -OCH 2Ph & C6-H), 3.71(s, 3H, -OCH 3), 3.49(d, 1H, C2-H), 3.12(d, 1H, C2-H)Cis isomer δ: 8.32 (s, 1H, isothiazole-H), 7.25 (m, 32H, ph-H), 7.02 (s, 1H, isothiazole-H), 6.89 (d, 2H, ph-H ), 6.70 (d, 1H,), 6.52 (d, 1H, -CH = CH-), 6.19 (m, 1H, C7-H), 5.20 (m, 3H, -OC H 2 Ph & C6-H) , 3.71 (s, 3H, -OC H 3 ), 3.49 (d, 1H, C2-H), 3.12 (d, 1H, C2-H)

(11) 파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-[(3-파라-메톡시벤질옥시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.(11) para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetami Fig.]-3-[(3-Para-methoxybenzyloxyisothiazol-5-yl) vinyl] -3-cefe-4-carboxylate.

1H NMR(300 MHz, CDCl3) δ: 7.44-6.24(m, 34H, ph-H), 6.90(d, 2H, ph-H), 6.84(d, 2H, ph-H), 6.52(d, 1H, -CH=CH-), 6.43(d, 1H, -CH=CH-), 6.18(m,1H, C7-H), 5.34(s, 1H, C6-H), 5.18(d, 2H, -OCH 2Ph), 3.79(s, 3H,-OCH3), 3.78(s, 3H, -OCH3), 3.52(d, 1H, C2-H), 3.12(d, 1H, C2-H) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.44-6.24 (m, 34H, ph-H), 6.90 (d, 2H, ph-H), 6.84 (d, 2H, ph-H), 6.52 (d , 1H, -CH = CH-, 6.43 (d, 1H, -CH = CH-), 6.18 (m, 1H, C7-H), 5.34 (s, 1H, C6-H), 5.18 (d, 2H , -OC H 2 Ph), 3.79 (s, 3H, -OCH 3 ), 3.78 (s, 3H, -OCH 3 ), 3.52 (d, 1H, C2-H), 3.12 (d, 1H, C2-H )

(12) 파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)]-2-트리틸옥시이미노아세트아미도}-3-[(3-메틸이소티아졸-4-일)비닐]-3-세펨-4-카르복실레이트(12) para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl)]-2-trityloxyiminoacet Amido} -3-[(3-methylisothiazol-4-yl) vinyl] -3-cepem-4-carboxylate

1H NMR(300 MHz, CDCl3) δ: 8.22(s, 1H), 7.40-7.20(m, ph-H), 6.91(d, 2H, ph-H), 6.55(d, 1H, -CH=CH-), 6.45(d, 1H, -CH=CH-), 6.12(br, m, 1H, C7-H), 5.22(d, 2H, -OCH 2Ph), 5.08(d, 1H, C6-H), 3.80(s, 3H, -OCH 3), 3.24(d, 1H, C2-H), 3.04(d, 1H, C2-H), 2.47(s, 3H, -CH 3) 1 H NMR (300 MHz, CDCl 3 ) δ: 8.22 (s, 1H), 7.40-7.20 (m, ph-H), 6.91 (d, 2H, ph-H), 6.55 (d, 1H, -CH = CH-), 6.45 (d, 1H, -CH = CH-), 6.12 (br, m, 1H, C7-H), 5.22 (d, 2H, -OC H 2 Ph), 5.08 (d, 1H, C6 -H), 3.80 (s, 3H, -OC H 3 ), 3.24 (d, 1H, C2-H), 3.04 (d, 1H, C2-H), 2.47 (s, 3H, -C H 3 )

(13) 파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)]-2-트리틸옥시이미노아세트아미도}-3-(E)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.(13) para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl)]-2-trityloxyiminoacet Amido} -3- (E)-[(3-methoxyisothiazol-5-yl) vinyl] -3-cefe-4-carboxylate.

1H NMR(300 MHz, CDCl3) δ: 7.29-6.85(m, overlapping, ph-H), 6.83(d, 2H, ph-H), 6.77(d, 1H, -CH=CH-), 6.55(d, 1H, -CH=CH-), 6.37(s, 1H, 이소티아졸-H),5.99(m, 1H, C7-H), 5.19(d, 2H, -OCH 2Ph), 4.97(d, 1H, C6-H), 3.90(s, 3H, -OCH 3), 3.70(s, 3H, -OCH 3), 3.33(d, 2H, C2-H) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.29-6.85 (m, overlapping, ph-H), 6.83 (d, 2H, ph-H), 6.77 (d, 1H, -CH = CH-), 6.55 (d, 1H, -CH = CH-), 6.37 (s, 1H, isothiazole-H), 5.99 (m, 1H, C7-H), 5.19 (d, 2H, -OC H 2 Ph), 4.97 (d, 1H, C6-H), 3.90 (s, 3H, -OC H 3 ), 3.70 (s, 3H, -OC H 3 ), 3.33 (d, 2H, C2-H)

(14) 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-(트리틸아미노티아졸-4-일)]-2-트리틸옥시이미노아세트아미도}-3-(Z)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.(14) para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2- (tritylaminothiazol-4-yl)]-2-trityloxyiminoa Cetamido} -3- (Z)-[(3-methoxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

1H NMR(300 MHz, CDCl3) δ: 7.30-7.02(m, overlapping, ph-H), 6.76(d, 2H, ph-H), 6.38(d, 1H,), 6.30(d, 1H, -CH=CH-), 6.27(s, 1H,이소티아졸-H), 6.00(m, 1H, C7-H), 5.08(d, 4H, C6-H & -OCH 2Ph), 3.85(s, 3H, -OCH 3), 3.70(s, 3H, -OCH 3), 3.39(d, 1H, C2-H), 3.00(d, 1H, C2-H) 1 H NMR (300 MHz, CDCl 3 ) δ: 7.30-7.02 (m, overlapping, ph-H), 6.76 (d, 2H, ph-H), 6.38 (d, 1H,), 6.30 (d, 1H, -CH = CH-), 6.27 (s, 1H, isothiazole-H), 6.00 (m, 1H, C7-H), 5.08 (d, 4H, C6-H & -OC H 2 Ph), 3.85 ( s, 3H, -OC H 3 ), 3.70 (s, 3H, -OC H 3 ), 3.39 (d, 1H, C2-H), 3.00 (d, 1H, C2-H)

실시예 3Example 3

소디움 (6R, 7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(3-메틸이소티아졸-4-일)비닐]-3-세펨-4-카르복실레이트의 제조Sodium (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z)-[(3-methyl Preparation of Isothiazol-4-yl) vinyl] -3-cepem-4-carboxylate

파라-메톡시벤질 (6R, 7R)-7-[(Z)-2-[2-(트리틸아미노)티아졸-4-일]-2-트리틸옥시이미노아세트아미도]-3-[(3-메틸이소티아졸-4-일)비닐]-3-세펨-4-카르복실레이트 132 mg(0.12 mmol)을 0.38 ml의 아니솔에 녹이고, 0℃로 냉각시켰다. 이 용액에 1.14 mL의 트리플루오로아세트산을 가하고 1시간 동안 교반하였다. 반응 혼합물을 감압 농축시키고, 이소프로필 에테르를 첨가하여 고체화시켰다. 여과 및 여분의 에테르로 세척하여 고체를 얻은 후, 이 고체를 200 ul의 포르밀 산에 녹이고 실온에서 1시간 동안 교반하였다. 생성된 고체를 여과하여 제거하고 이 용액을 이소프로필 에테르로 고체화하고 여과하여 얻는다. 이 고체를 5% 탄산 수소나트륨 용액에 녹이고 (pH=7) 역상 관크로마토그래피 (전개용매; 10% 메탄올)로 정제하고, 동결 건조하여 생성물 18.1 mg(27.4%)을 얻었다.Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- [2- (tritylamino) thiazol-4-yl] -2-trityloxyiminoacetamido] -3- 132 mg (0.12 mmol) of [(3-methylisothiazol-4-yl) vinyl] -3-cepem-4-carboxylate were dissolved in 0.38 ml of anisole and cooled to 0 ° C. To this solution was added 1.14 mL of trifluoroacetic acid and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and solidified by addition of isopropyl ether. After filtration and washing with excess ether to give a solid, the solid was dissolved in 200 ul of formyl acid and stirred at room temperature for 1 hour. The resulting solid is filtered off and the solution is obtained by solidifying with isopropyl ether and filtering. This solid was dissolved in 5% sodium hydrogen carbonate solution (pH = 7) and purified by reverse phase column chromatography (developing solvent; 10% methanol) and lyophilized to give 18.1 mg (27.4%) of product.

시스 이성질체1H NMR (300 MHz, D2O) δ: 8.55(s, 1H, 이소티아졸-H), 6.41(s, 2H, -CH=CH-), 5.79(d, 1H, C7-H) , 5.18(d, 1H, C6-H), 3.40(d, 1H, C2-H), 3.15(d, 1H, , C2-H), 2.34(s, 3H),Cis isomer 1 H NMR (300 MHz, D 2 O) δ: 8.55 (s, 1H, isothiazole-H), 6.41 (s, 2H, -CH = CH-), 5.79 (d, 1H, C7-H ), 5.18 (d, 1H, C6-H), 3.40 (d, 1H, C2-H), 3.15 (d, 1H,, C2-H), 2.34 (s, 3H),

트란스 이성질체 δ: 8.85(s,1H, 이소티아졸-H), 7.18(d, 1H, -CH=CH-) 6.67(d, 1H, -CH=CH-), 6.47(s, 1H, 티아졸-H), 5.86(d, 1H, C7-H), 5.29(d, 1H, C6-H), 3.77(ABq, 2H, C2-H)Trans isomer δ: 8.85 (s, 1H, isothiazole-H), 7.18 (d, 1H, -CH = CH-) 6.67 (d, 1H, -CH = CH-), 6.47 (s, 1H, thiazole -H), 5.86 (d, 1H, C7-H), 5.29 (d, 1H, C6-H), 3.77 (ABq, 2H, C2-H)

실시예 4Example 4

상기 실시예 3와 같은 방법으로 다음과 같은 화합물을 제조하였다.In the same manner as in Example 3, the following compound was prepared.

(1) 소디움 (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실레이트(1) Sodium (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z)-[( 1,2,5-thiadiazol-5-yl) vinyl] -3-cefe-4-carboxylate

1H NMR(300 MHz, D2O) δ: 8.55(s, 1H, 티아디아졸-H), 6.90(s, 1H, 티아졸-H), 6.66(d, 1H,-CH=CH-), 6.58(d, 1H, -CH=CH-) 6.90(d, 1H, C7-H), 5.28(d, 1H, C6-H), 3.63(d, 1H, C2-H), 3.29(d, 1H, C2-H) 1 H NMR (300 MHz, D 2 O) δ: 8.55 (s, 1H, thiadiazole-H), 6.90 (s, 1H, thiazole-H), 6.66 (d, 1H, -CH = CH-) , 6.58 (d, 1H, -CH = CH-) 6.90 (d, 1H, C7-H), 5.28 (d, 1H, C6-H), 3.63 (d, 1H, C2-H), 3.29 (d, 1H, C2-H)

(2) 소디움 (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실레이트(2) Sodium (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E)-[( 1,2,5-thiadiazol-5-yl) vinyl] -3-cefe-4-carboxylate

1H NMR (300 MHz, D2O) δ: 8.76(s, 1H, 티아디아졸-H), 7.60(d, 1H, -CH=CH-), 6.98(d, 1H, -CH=CH-), 6.92(s, 1H, 티아졸-H), 5.81(m, 1H, C7-H), 5.28(m, 1H, C6-H), 3.74(q, 1H, C2-H) 1 H NMR (300 MHz, D 2 O) δ: 8.76 (s, 1H, thiadiazole-H), 7.60 (d, 1H, -CH = CH-), 6.98 (d, 1H, -CH = CH- ), 6.92 (s, 1H, thiazole-H), 5.81 (m, 1H, C7-H), 5.28 (m, 1H, C6-H), 3.74 (q, 1H, C2-H)

(3) 소디움 (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.(3) Sodium (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-[(isothiazole- 5-yl) vinyl] -3-cepem-4-carboxylate.

시스 이성질체1H NMR (300 MHz, D2O) δ: 8.55(s, 1H, 이소티아졸-H), 6.41(s, 2H, -CH=CH-), 5.79(d, 1H, C7-H), 5.18(d, 1H, C6-H), 3.40(d, 1H, C2-H), 3.15(d, 1H, C2-H), 2.34(s, 3H),Cis isomer 1 H NMR (300 MHz, D 2 O) δ: 8.55 (s, 1H, isothiazole-H), 6.41 (s, 2H, -CH = CH-), 5.79 (d, 1H, C7-H ), 5.18 (d, 1H, C6-H), 3.40 (d, 1H, C2-H), 3.15 (d, 1H, C2-H), 2.34 (s, 3H),

트란스 이성질체 δ: 8.85(s,1H, 이소티아졸-H), 7.18(d,1H, -CH=CH-) 6.67(d, 1H, -CH=CH-), 6.47(s, 1H, 티아졸-H), 5.86(d, 1H, C7-H), 5.29(d,1H, C6-H), 3.77(Abq, 2H, C2-H)Trans isomer δ: 8.85 (s, 1H, isothiazole-H), 7.18 (d, 1H, -CH = CH-) 6.67 (d, 1H, -CH = CH-), 6.47 (s, 1H, thiazole -H), 5.86 (d, 1H, C7-H), 5.29 (d, 1H, C6-H), 3.77 (Abq, 2H, C2-H)

(4) 소디움 (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(3-히드록시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.(4) Sodium (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E)-[( 3-hydroxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

1H NMR(300 MHz, D2O) δ: 7.07(d, 1H, -CH=CH-), 6.90(s, 1H, 이소티아졸-H), 6.75(d, 1H, -CH=CH-), 6.30(s, 1H, 티아졸-H), 5.80(d, 1H, C7-H), 5.22(d, 1H, C6-H), 3.65(ABq, 2H, C2-H) OneH NMR (300 MHz, D2O) δ: 7.07 (d, 1H, -CH = CH-), 6.90 (s, 1H, isothiazole-H), 6.75 (d, 1H, -CH = CH-), 6.30 (s, 1H, thiazole-H) , 5.80 (d, 1H, C7-H), 5.22 (d, 1H, C6-H), 3.65 (ABq, 2H, C2-H)

(5) 소디움 (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(3-히드록시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트.(5) Sodium (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z)-[( 3-hydroxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate.

1H NMR(300 MHz, D2O) δ: 6.94(s, 1H, 이소티아졸-H), 6.58(d, 1H, -CH=CH-), 6.41(d, 1H, -CH=CH-), 6.23(s, 1H, 티아졸-H), 5.85(d, 1H, C7-H), 5.36(d, 1H, C6-H), 3.63(d, 1H, C2-H), 3.33(d, 1H, C2-H) 1 H NMR (300 MHz, D 2 O) δ: 6.94 (s, 1H, isothiazole-H), 6.58 (d, 1H, -CH = CH-), 6.41 (d, 1H, -CH = CH- ), 6.23 (s, 1H, thiazole-H), 5.85 (d, 1H, C7-H), 5.36 (d, 1H, C6-H), 3.63 (d, 1H, C2-H), 3.33 (d , 1H, C2-H)

(6) 소디움 (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트(6) Sodium (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E)-[( 3-methoxyisothiazol-5-yl) vinyl] -3-cefe-4-carboxylate

1H NMR(300 MHz, D2O) δ: 7.19(d, 1H, -CH=CH-), 6.95(s, 1H, 티아졸-H), 6.80(d, 1H, -CH=CH-), 6.66(s, 1H, 이소티아졸-H), 5.86(d, 1H, C7-H), 5.29(d, 1H, C6-H), 3.95(s, 3H, -OCH 3), 3.70(Abq, 2H, C2-H) 1 H NMR (300 MHz, D 2 O) δ: 7.19 (d, 1H, -CH = CH-), 6.95 (s, 1H, thiazole-H), 6.80 (d, 1H, -CH = CH-) , 6.66 (s, 1H, isothiazole-H), 5.86 (d, 1H, C7-H), 5.29 (d, 1H, C6-H), 3.95 (s, 3H, -OC H 3 ), 3.70 ( Abq, 2H, C2-H)

(7) 소디움 (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트(7) Sodium (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z)-[( 3-methoxyisothiazol-5-yl) vinyl] -3-cefe-4-carboxylate

1H NMR(300 MHz, D2O) δ: 7.00(s, 1H, 티아졸-H), 6.67(d, 1H, -CH=CH-), 6.62(s, 1H, 이소티아졸-H), 6.53(d, 1H, -CH=CH-), 5.92(d, 1H, C7-H), 5.43(d, 1H, C6-H), 3.95(s, 3H, -OCH 3), 3.65(d, 1H, C2-H), 3.38(d, 1H, C2-H) OneH NMR (300 MHz, D2O) δ: 7.00 (s, 1H, thiazole-H), 6.67 (d, 1H, -CH = CH-), 6.62 (s, 1H, isothiazole-H), 6.53 (d, 1H, -CH = CH-) , 5.92 (d, 1H, C7-H), 5.43 (d, 1H, C6-H), 3.95 (s, 3H, -OCH 3), 3.65 (d, 1H, C2-H), 3.38 (d, 1H, C2-H)

(8) 소디움 (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실레이트(8) sodium (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z )-[(1,2,5-thiadiazol-5-yl) vinyl] -3-cepem-4-carboxylate

1H NMR(300 MHz, D2O) δ: 8.54(s, 1H, 티아디아졸-H), 6.65(d, 1H, -CH=CH-), 6.57(d, 1H, -CH=CH-), 5.78(d, 1H, C7-H), 5.24(d, 1H, C6-H), 3.60(d, 1H, C2-H), 3.28(d, 1H, C2-H) 1 H NMR (300 MHz, D 2 O) δ: 8.54 (s, 1H, thiadiazole-H), 6.65 (d, 1H, -CH = CH-), 6.57 (d, 1H, -CH = CH- ), 5.78 (d, 1H, C7-H), 5.24 (d, 1H, C6-H), 3.60 (d, 1H, C2-H), 3.28 (d, 1H, C2-H)

(9) 소디움 (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트(9) Sodium (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E )-[(Isothiazol-5-yl) vinyl] -3-cepem-4-carboxylate

1H NMR(300MHz, D2O) δ: 8.28(s, 1H, 이소티아졸-H), 7.50(s, 1H, 이소티아졸-H), 7.22(d, 1H, -CH=CH-), 6.87(d, 1H, -CH=CH-), 5.80(d, 1H, C7-H), 5.18(d, 1H, C6-H), 3.68(d, 1H, C2-H), 3.59(d, 1H, C2-H) 1 H NMR (300 MHz, D 2 O) δ: 8.28 (s, 1H, isothiazole-H), 7.50 (s, 1H, isothiazole-H), 7.22 (d, 1H, -CH = CH-) , 6.87 (d, 1H, -CH = CH-), 5.80 (d, 1H, C7-H), 5.18 (d, 1H, C6-H), 3.68 (d, 1H, C2-H), 3.59 (d , 1H, C2-H)

(10) 소디움 (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트(10) Sodium (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E )-[(Isothiazol-5-yl) vinyl] -3-cepem-4-carboxylate

1H NMR(300MHz, D2O) δ: 8.28(s, 1H, 이소티아졸-H), 7.15(s, 1H, 이소티아졸-H), 6.68(d, 1H, -CH=CH-), 6.39(d, 1H, -CH=CH-), 5.84(d, 1H, C7-H), 5.32(d, 1H, C6-H), 3.53(d, 1H, C2-H), 3.26(d, 1H, C2-H) 1 H NMR (300 MHz, D 2 O) δ: 8.28 (s, 1H, isothiazole-H), 7.15 (s, 1H, isothiazole-H), 6.68 (d, 1H, -CH = CH-) , 6.39 (d, 1H, -CH = CH-), 5.84 (d, 1H, C7-H), 5.32 (d, 1H, C6-H), 3.53 (d, 1H, C2-H), 3.26 (d , 1H, C2-H)

(11) 소디움 (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(3-히드록시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트(11) Sodium (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z )-[(3-hydroxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate

1H NMR(300 MHz, D2O) δ: 6.87(d, 1H, -CH=CH-), 6.54(d, 1H, -CH=CH-), 6.33(s, 1H, 이소티아졸-H), 5.97(d, 1H, C7-H), 5.43(d, 1H, C6-H), 3.69(d, 1H, C2-H), 3.40(d, 1H, C2-H) 1 H NMR (300 MHz, D 2 O) δ: 6.87 (d, 1H, -CH = CH-), 6.54 (d, 1H, -CH = CH-), 6.33 (s, 1H, isothiazole-H ), 5.97 (d, 1H, C7-H), 5.43 (d, 1H, C6-H), 3.69 (d, 1H, C2-H), 3.40 (d, 1H, C2-H)

(12) 소디움 (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-[(3-메틸이소티아졸-4-일)비닐]-3-세펨-4-카르복실레이트(12) Sodium (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3-[( 3-methylisothiazol-4-yl) vinyl] -3-cepem-4-carboxylate

트란스 이성징체1H NMR(300 MHz, D2O) δ: 8.85(s, 1H, 이소티아졸-H), 7.18(d, 1H,-CH=CH-), 6.68(d, 1H, -CH=CH-), 6.47(s, 1H), 5.86(d, 1H, C7-H), 5.29(d, 1H, C6-H), 3.86(d, 1H, C2-H), 3.72(d, 1H, C2-H)Trans isomer 1 H NMR (300 MHz, D 2 O) δ: 8.85 (s, 1H, isothiazole-H), 7.18 (d, 1H, -CH = CH-), 6.68 (d, 1H, -CH = CH-), 6.47 (s, 1H), 5.86 (d, 1H, C7-H), 5.29 (d, 1H, C6-H), 3.86 (d, 1H, C2-H), 3.72 (d, 1H , C2-H)

시스 이성질체 δ: 8.62(s, 1H, 이소티아졸-H), 6.95(d, 2H, -CH=CH-), 6.47(s, 1H), 6.47(s, 1H), 5.81(d, 1H, C7-H), 5.26(d, 1H, C6-H), 3.46(d, 1H, C2-H), 3.23(d, 1H, C2-H)Cis isomer δ: 8.62 (s, 1H, isothiazole-H), 6.95 (d, 2H, -CH = CH-), 6.47 (s, 1H), 6.47 (s, 1H), 5.81 (d, 1H, C7-H), 5.26 (d, 1H, C6-H), 3.46 (d, 1H, C2-H), 3.23 (d, 1H, C2-H)

(13) 소디움 (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트(13) Sodium (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E )-[(3-methoxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate

1H NMR(300MHz, D2O) δ: 7.09(d, 1H, -CH=CH-), 6.73(d, 1H, -CH=CH-), 6.59(s, 1H, 이소티아졸-H), 5.78(d, 1H, C7-H), 5.16(d, 1H, C6-H), 3.84(s, 3H, -OCH 3), 3.61(Abq, 2H, C2-H) 1 H NMR (300 MHz, D 2 O) δ: 7.09 (d, 1H, -CH = CH-), 6.73 (d, 1H, -CH = CH-), 6.59 (s, 1H, isothiazole-H) , 5.78 (d, 1H, C7-H), 5.16 (d, 1H, C6-H), 3.84 (s, 3H, -OC H 3 ), 3.61 (Abq, 2H, C2-H)

(14) 소디움 (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트(14) Sodium (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z )-[(3-methoxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate

1H NMR(300 MHz, D2O) δ: 6.60(d, 1H, -CH=CH-), 6.56(s, 1H, 이소티아졸-H), 6.43(d, 1H, -CH=CH-), 5.87(d, 1H, C7-H), 5.35(d, 1H, C6-H), 3.88(s, 3H, -OCH 3), 3.61(d, 1H, C2-H), 3.32(d, 1H, C2-H) 1 H NMR (300 MHz, D 2 O) δ: 6.60 (d, 1H, -CH = CH-), 6.56 (s, 1H, isothiazole-H), 6.43 (d, 1H, -CH = CH- ), 5.87 (d, 1H, C7-H), 5.35 (d, 1H, C6-H), 3.88 (s, 3H, -OC H 3 ), 3.61 (d, 1H, C2-H), 3.32 (d , 1H, C2-H)

본 발명의 화합물은 다양한 그람 양성균 및 그람 음성균, 특히 MRSA 그람 양성균에 대해서 뛰어난 항균 활성을 갖는다.The compounds of the present invention have excellent antimicrobial activity against various Gram-positive and Gram-negative bacteria, in particular MRSA Gram-positive bacteria.

본 발명의 화합물에 대한 생체외 향균력은 뮐러 힌튼 아가(Mueller Hinton Agar)를 사용한 한천희석(Agar Dilution)방법에 의해 37℃에서 18시간 배양한 후 그 2배씩 단계적으로 희석하여 접종한 평판을 일렬로 나열하고 육안으로 관찰하여 표기화합물의 최소발육 억제농도 (MIC, ㎍/mL)를 정하였다. 그 시험 결과를 다음의 표 1에 요약하였다.In vitro antibacterial activity against the compound of the present invention was incubated at 37 ° C. for 18 hours by Agar Dilution using Mueller Hinton Agar, followed by diluting the plate twice in a row to inoculate in a row. Listed and visually observed to determine the minimum growth inhibition concentration (MIC, ㎍ / mL) of the title compound. The test results are summarized in Table 1 below.

대표적 화합물의 최소 발육 억제 농도(MIC, ㎍/mL)Minimal growth inhibitory concentrations of representative compounds (MIC, μg / mL) 균주Strain 화합물 19Compound 19 화합물 22Compound 22 화합물 23Compound 23 세포독심Cytotoxicity Staphyococcus aureus ATCC 29213Staphyococcus aureus ATCC 29213 0.50.5 0.250.25 0.50.5 44 Enteroccus faecailis ATCC 29212Enteroccus faecailis ATCC 29212 0.250.25 1One 0.250.25 ＞32＞ 32 Staphyococcus pyogenes ATCC 8668Staphyococcus pyogenes ATCC 8668 ≤0.12≤0.12 ≤0.12≤0.12 ≤0.12≤0.12 ≤0.12≤0.12 Staphyococcus pyogenes C6003Staphyococcus pyogenes C6003 ≤0.12≤0.12 ≤0.12≤0.12 ≤0.12≤0.12 ≤0.12≤0.12 Staphyococcus pyogenes C6012Staphyococcus pyogenes C6012 ≤0.12≤0.12 ≤0.12≤0.12 ≤0.12≤0.12 ≤0.12≤0.12 Pseudomonas vulgaris C4010Pseudomonas vulgaris C4010 ≤0.12≤0.12 ≤0.12≤0.12 ≤0.12≤0.12 ≤0.12≤0.12 Klebsiella pneumoniae ATCC 10031Klebsiella pneumoniae ATCC 10031 ≤0.12≤0.12 ≤0.12≤0.12 ≤0.12≤0.12 ≤0.12≤0.12

Claims (6)

다음 화학식 1을 갖는 세팔로스포린 화합물 및 약제학적으로 허용되는 그의 염A cephalosporin compound having the formula 1 and a pharmaceutically acceptable salt thereof [화학식 1][Formula 1] 상기 화학식 1에서 R1은 수소 또는 세팔로스포린 화합물에서 일반적으로 사용되는 아민보호기; R2는 수소 또는 옥심 보호기; R4는 수소 또는 에스테르를 만드는 기, 염을 만드는 원자 또는 카르복시기의 보호기; R5는 수소 또는 할로겐기; 및 R3는를 나타내며, 여기서 Q는 수소, 할로겐, 히드록시, 머캅토, 시아노, 카르복시, 카르복실산에스테르, 카르바모일옥시, 카르바모일, N,N-디메틸카르바모일, C1-4알킬, C1-4알킬옥시, 할로겐이 치환된 메틸, 아릴 또는 헤테로 고리 치환체를 말한다.In Formula 1, R 1 is an amine protecting group generally used in hydrogen or cephalosporin compound; R 2 is hydrogen or an oxime protecting group; R 4 is a protecting group of a group forming a hydrogen or an ester, an atom forming a salt or a carboxyl group; R 5 is hydrogen or a halogen group; And R 3 is Wherein Q is hydrogen, halogen, hydroxy, mercapto, cyano, carboxy, carboxylic acid ester, carbamoyloxy, carbamoyl, N, N-dimethylcarbamoyl, C 1-4 alkyl, C 1-4 alkyloxy, halogen, substituted methyl, aryl or heterocyclic substituents. 제1항에 있어서, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실레이트, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(E)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실레이트, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(3-파라메톡시벤질옥시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(E)-[(3-파라메톡시벤질옥시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-[(3-메틸이소티아졸-4-일)비닐]-3-세펨-4-카르복실레이트, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(E)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실레이트, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(E)-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(3-파라메톡시벤질옥시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)]-2-트리틸옥시이미노아세트아미도]-3-[(3-메틸이소티아졸-4-일)비닐]-3-세펨-4-카르복실레이트, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(E)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트, 파라-메톡시벤질 (6R,7R)-7-[(Z)-2-(5-클로로-2-트리틸아미노티아졸-4-일)-2-트리틸옥시이미노아세트아미도]-3-(Z)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실레이트, (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염, (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염, (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염, (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(3-파라메톡시벤질옥시이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염, (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(3-파라메톡시벤질옥시이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염, (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-[(3-메틸이소티아졸-4-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염, (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염, (6R,7R)-7-[(Z)-2-(2-아미노티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염, (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미노]-3-(Z)-[(1,2,5-티아디아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염, (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염, (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염, (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-[(3-히드록시이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염, (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)]-2-히드록시이미노아세트아미도]-3-(E)-[(3-메틸이소티아졸-4-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염, (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(E)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염, (6R,7R)-7-[(Z)-2-(2-아미노-5-클로로티아졸-4-일)-2-히드록시이미노아세트아미도]-3-(Z)-[(3-메톡시이소티아졸-5-일)비닐]-3-세펨-4-카르복실산 및 나트륨 염으로 구성되는 군에서 선택되는 화합물.The method of claim 1, wherein para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido ] -3- (Z)-[(1,2,5-thiadiazol-5-yl) vinyl] -3-cepem-4-carboxylate, para-methoxybenzyl (6R, 7R) -7- [(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3- (E)-[(1,2,5-thiadiazole -5-yl) vinyl] -3-cepem-4-carboxylate, para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl ) -2-trityloxyiminoacetamido] -3-[(isothiazol-5-yl) vinyl] -3-cef-4-carboxylate, para-methoxybenzyl (6R, 7R)- 7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3- (Z)-[(3-paramethoxybenzyloxy Isothiazol-5-yl) vinyl] -3-cepem-4-carboxylate, para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazole- 4-yl) -2-trityloxyiminoacetamido] -3- (E)-[(3-paramethoxybenzyl Ciisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate, para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazole- 4-yl) -2-trityloxyiminoacetamido] -3-[(3-methylisothiazol-4-yl) vinyl] -3-cefe-4-carboxylate, para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3- (E)-[(3 -Methoxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate, para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (2-tritylamino Thiazol-4-yl) -2-trityloxyiminoacetamido] -3- (Z)-[(3-methoxyisothiazol-5-yl) vinyl] -3-cepem-4-car Carboxylate, para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetami FIG.]-3- (Z)-[(1,2,5-thiadiazol-5-yl) vinyl] -3-cepem-4-carboxylate, para-methoxybenzyl (6R, 7R) -7 -[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl) -2-tritylocta Cyiminoacetamido] -3- (E)-[(isothiazol-5-yl) vinyl] -3-cef-4-carboxylate, para-methoxybenzyl (6R, 7R) -7- [ (Z) -2- (5-chloro-2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3- (Z)-[(isothiazol-5- Yl) vinyl] -3-cepem-4-carboxylate, para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazole-4- Yl) -2-trityloxyiminoacetamido] -3- (Z)-[(3-paramethoxybenzyloxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate , Para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl)]-2-trityloxyiminoacetamido ] -3-[(3-methylisothiazol-4-yl) vinyl] -3-cepem-4-carboxylate, para-methoxybenzyl (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3- (E)-[(3-methoxyisothiazol-5-yl) Vinyl] -3-cepem-4-carboxylate, para-methoxybene Quality (6R, 7R) -7-[(Z) -2- (5-chloro-2-tritylaminothiazol-4-yl) -2-trityloxyiminoacetamido] -3- (Z )-[(3-methoxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylate, (6R, 7R) -7-[(Z) -2- (2-aminothiazole -4-yl) -2-hydroxyiminoacetamido] -3- (Z)-[(1,2,5-thiadiazol-5-yl) vinyl] -3-cef-4-carboxyl Acid and sodium salt, (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E)-[ (1,2,5-thiadiazol-5-yl) vinyl] -3-cepem-4-carboxylic acid and sodium salt, (6R, 7R) -7-[(Z) -2- (2-amino Thiazol-4-yl) -2-hydroxyiminoacetamido] -3-[(isothiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid and sodium salt, (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z)-[(3-paramethoxybenzyloxy Isothiazol-5-yl) vinyl] -3-cepem-4-carboxylic acid and sodium salt, (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyimino Cetamido] -3- (E)-[(3-paramethoxybenzyloxyisothiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid and sodium salt, (6R, 7R)- 7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-[(3-methylisothiazol-4-yl) vinyl]- 3-cefem-4-carboxylic acid and sodium salt, (6R, 7R) -7-[(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E)-[(3-methoxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylic acid and sodium salt, (6R, 7R) -7-[(Z)- 2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z)-[(3-methoxyisothiazol-5-yl) vinyl] -3- Cefem-4-carboxylic acid and sodium salt, (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamino ] -3- (Z)-[(1,2,5-thiadiazol-5-yl) vinyl] -3-cepem-4-carboxylic acid and sodium salt, (6R, 7R) -7-[( Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E)-[(isothiazol-5-yl) Nil] -3-cepem-4-carboxylic acid and sodium salt, (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydrate Roxyiminoacetamido] -3- (Z)-[(isothiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid and sodium salt, (6R, 7R) -7-[( Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3-[(3-hydroxyisothiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid and sodium salt, (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl)]-2-hydroxy Iminoacetamido] -3- (E)-[(3-methylisothiazol-4-yl) vinyl] -3-cepem-4-carboxylic acid and sodium salt, (6R, 7R) -7- [(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (E)-[(3-methoxyisothiazole- 5-yl) vinyl] -3-cepem-4-carboxylic acid and sodium salt, (6R, 7R) -7-[(Z) -2- (2-amino-5-chlorothiazol-4-yl) -2-hydroxyiminoacetamido] -3- (Z)-[(3-methoxyisothiazol-5-yl) vinyl] -3-cepem-4-carboxylic acid Compound selected from the group consisting of a sodium salt. 제1항의 화합물을 유효 성분으로 함유하고, 그람 음성균 또는 그람 양상균에 대해서 항균 활성을 갖는 의약 조성물.A pharmaceutical composition containing the compound of claim 1 as an active ingredient and having antimicrobial activity against Gram-negative bacteria or Gram-like bacteria. 화학식 7의 일리드 화합물과 화학식 8의 알데히드 화합물을 비티히 반응시키는 것이 특징인 제1항의 화합물의 제조 방법.A method for preparing the compound of claim 1, characterized by reacting the yilide compound of formula 7 with the aldehyde compound of formula 8. [화학식 7][Formula 7] [화학식 8][Formula 8] 상기 화학식 7 및 8에서, R1, R2, R4, R5및 Q의 정의는 전술한 바와 같다.In Formulas 7 and 8, the definitions of R 1 , R 2 , R 4 , R 5, and Q are as described above. 제4항에 있어서, 용매가 물, 아세톤, 디옥산, 아세트니트릴, 클로로포름, 디클로로메탄, 테트라히드로퓨란, 에틸아세테이트 및 N,N-디메틸포름아미드 중에서 선택된 것을 특징으로 하는 제조방법.The process according to claim 4, wherein the solvent is selected from water, acetone, dioxane, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, ethyl acetate and N, N-dimethylformamide. 제4항에 있어서, 반응온도가 -40℃ ~ 25℃인 것을 특징으로 하는 제조방법.The method of claim 4, wherein the reaction temperature is -40 ℃ to 25 ℃.
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