KR100264156B1 - (e)-prophenyl quaternary ammonium cephem compound and method for preparation thereof - Google Patents

(e)-prophenyl quaternary ammonium cephem compound and method for preparation thereof Download PDF

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KR100264156B1
KR100264156B1 KR1019980002915A KR19980002915A KR100264156B1 KR 100264156 B1 KR100264156 B1 KR 100264156B1 KR 1019980002915 A KR1019980002915 A KR 1019980002915A KR 19980002915 A KR19980002915 A KR 19980002915A KR 100264156 B1 KR100264156 B1 KR 100264156B1
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propenyl
carboxylate
7beta
acetamido
aminothiazol
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KR19990068967A (en
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김중협
장문호
김유승
고훈영
김성훈
최경일
배애님
강순방
구창휘
문종택
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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
    • C07D501/02—Preparation
    • 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
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
    • C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings

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  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

PURPOSE: Provided is (E)-prophenyl quaternary ammonium cephem compound and a pharmaceutically acceptable salt and a method for preparation thereof. The prepared compound has excellent antibacterial activity against both gram positive and gram negative strains, and is thus used for Cephalosporin based medicines. CONSTITUTION: (E)-prophenyl quaternary ammonium cephem compound is represented by the formula(1), wherein R1 is hydrogen, formyl, t-buthoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl or trithyl; R2 is hydrogen, methyl, 2-fluoroethyl, formyl, chloroacetyl, benzoyl, p-nitrobenzyl, 2,2,2-trichloroethoxycarbonly, tetrahydropyranyl or trithyl; R3 is hydrogen, group forming carboxylic salt, 2,2,2-trichloroethyl, p-methoxybenzyl, p-nitrobenzyl, benzhydryl or t-butyl; R4 is methoxy, carbamoyl having substituent, or C5 hetero ring substituent represented by oxydiazole or triazole; and n is an integer of 1 or 2.

Description

(E)-프로페닐 4급 암모늄 세펨 화합물 및 이의 제조 방법(E) -propenyl quaternary ammonium cefem compound and preparation method thereof

본 발명은 새로운 세팔로스포린 화합물의 제조 및 이의 제조방법에 관한 것이다.The present invention relates to the preparation of new cephalosporin compounds and methods for their preparation.

세팔로스포린 화합물은 여러 공지자료에 소개되고 있는데, 미국 특허 제 4,258,041 호에는 4급 암모늄기가 치환된 세프타지딤이, 영국 특허 제 2,098,216 호에는 세피롬이 그리고 미국 특허 제 4,406,899 호에는 세페핌 등이 각각 소개되고 있다. 이들 세팔로스포린 화합물은 그람음성균에 대해서는 효과적인 항균력을 나타내고 있으나 최근 사회적으로 문제가 대두되고 있는 그람양성균에 대해서는 활성이 떨어지는 단점을 가지고 있다.Cephalosporin compounds are introduced in a number of publications, such as ceftazidim substituted with a quaternary ammonium group in US Pat. No. 4,258,041, cepirom in UK Pat. No. 2,098,216, and cefepime in US Pat. No. 4,406,899. Each is introduced. These cephalosporin compounds have an effective antimicrobial activity against Gram-negative bacteria, but have a disadvantage in that they are less active against Gram-positive bacteria, which have recently become a social problem.

본 발명은 광범위한 항균력을 지닌 신규한 일반식(Ⅰ)로 표시되는 (E)-프로페닐 4급 암모늄 세펨 화합물 및 이의 약제학적으로 허용되는 염에 관한 것이다.The present invention relates to a (E) -propenyl quaternary ammonium cefem compound represented by the novel general formula (I) having a broad antibacterial activity and a pharmaceutically acceptable salt thereof.

본 발명은 또한 광범위한 항균력을 지닌 신규한 일반식(Ⅰ)로 표시되는 (E)-프로페닐 4급 암모늄 세펨 화합물 및 이의 약제학적으로 허용되는 염의 제조 방법에 관한 것이다.The invention also relates to a process for the preparation of the (E) -propenyl quaternary ammonium cefem compound represented by the novel general formula (I) having a broad antibacterial activity and pharmaceutically acceptable salts thereof.

본 발명은 광범위한 항균력을 지닌 신규한 일반식(Ⅰ)로 표시되는 (E)-프로페닐 4급 암모늄 세펨 화합물과 그의 약제학적으로 허용되는 염 및 이의 제조 방법에 관한 것이다. 본 발명에서 제조된 화합물들은 그람 양성균이나 그람 음성균에 우수한 항균력을 보이므로 세팔로스포린 계열 의약품에 유용하게 사용될 수 있다.The present invention relates to a (E) -propenyl quaternary ammonium cefem compound represented by the novel general formula (I) having a broad antibacterial activity, a pharmaceutically acceptable salt thereof, and a method for preparing the same. Since the compounds prepared in the present invention show excellent antimicrobial activity against Gram-positive bacteria or Gram-negative bacteria, they may be usefully used in cephalosporin-based medicines.

일반식(Ⅰ)에 있어서, R1은 수소 또는 아민의 보호기로서, 예컨대 포밀, t-부톡시카르보닐, 벤질옥시카르보닐, 파라-니트로벤질옥시카르보닐, 트리틸 등 쉽게 제거될 수 있는 보호기를 포함한다. R2는 수소, 메틸, 2-플루오르에틸, 플루오르메틸, 시클로펜틸 및 보호기로서 예컨대, 포밀, 클로로아세틸, 벤조일, 파라-니트로벤질, 2,2,2-트리클로로에톡시카르보닐, 테트라히드로피라닐, 트리틸 등의 알려진 공지방법에 의해 쉽게 제거될 수 있는 것을 포함한다. R3는 수소 또는 카르복실 보호기이며, 보호기의 예로는 2,2,2-트리클로로에틸, 파라-메톡시벤질, 파라-니트로벤질, 벤즈히드릴, t-부틸 등을 들 수 있다. R4는 메톡시, 카바모일, 치환체를 가진 카바모일, 옥사디아졸이나 트리아졸 등의 5환 헤테로 고리이다. n은 1이나 2의 정수이다.In general formula (I), R 1 is a protecting group of hydrogen or an amine, for example, a protecting group which can be easily removed such as formyl, t-butoxycarbonyl, benzyloxycarbonyl, para-nitrobenzyloxycarbonyl, trityl, etc. It includes. R 2 is hydrogen, methyl, 2-fluoroethyl, fluoromethyl, cyclopentyl and protecting groups such as formyl, chloroacetyl, benzoyl, para-nitrobenzyl, 2,2,2-trichloroethoxycarbonyl, tetrahydropyra And those that can be easily removed by known methods such as neil, trityl and the like. R 3 is hydrogen or a carboxyl protecting group, and examples of the protecting group include 2,2,2-trichloroethyl, para-methoxybenzyl, para-nitrobenzyl, benzhydryl, t-butyl and the like. R 4 is a 5-membered heterocyclic ring such as methoxy, carbamoyl, carbamoyl having a substituent, oxadiazole or triazole. n is an integer of 1 or 2.

본 발명의 일반식(Ⅰ)로 표시되는 (E)-프로페닐 4급 암모늄 세펨 화합물은 나트륨, 염산, 아세트산, 숙신산, 시트르산, 벤조산, 푸마르산, 만델산, 말산, 메틸술폰산 또는 파라-톨루엔술폰산 등과의 염이 가능하다.The (E) -propenyl quaternary ammonium cefe compound represented by the general formula (I) of the present invention is sodium, hydrochloric acid, acetic acid, succinic acid, citric acid, benzoic acid, fumaric acid, mandelic acid, malic acid, methylsulfonic acid or para-toluenesulfonic acid, and the like. Salts are possible.

본 발명의 일반식(Ⅰ)로 표시되는 (E)-프로페닐 4급 암모늄 세펨 화합물의 제조방법은 다음과 같은 방법에 의해 제조할 수 있다.The manufacturing method of the (E) -propenyl quaternary ammonium cefe compound represented by general formula (I) of this invention can be manufactured by the following method.

공지방법(J. Antibiotics, 43, 533, 1990)에 의해 제조되는 일반식(Ⅱ)로 표시되는 티아졸계 클로로화합물을 3당량의 NaI와 용매하에 반응시키면 (E)형태의 일반식(Ⅲ)으로 표시되는 티아졸계 요오드화합물을 얻게 된다. 이때에 사용되는 용매는 아세톤, N,N-디메틸포름아미드, 아세토니트릴 등이고 반응온도는 0∼30℃ 범위에서 수행하는 것이 바람직하며, 반응시간은 0.5∼2시간이 바람직하다. 일반식(Ⅰa)로 표시되는 보호기가 있는 (E)-프로페닐 4급 암모늄 세펨 화합물은 일반식(Ⅲ)의 티아졸계 요오드화합물과 일반식(Ⅳ)로 표시되는 아민화합물을 용매하에 짝지움 반응을 시켜 제조할 수 있다. 이때 사용되는 용매는 초산에틸, N,N-디메틸포름아미드, 이염화메탄, 테트라히드로푸란, 사염화탄소, 톨루엔, 클로로포름, 아세토니트릴, 디옥산, 물, 아세톤 등이다. 또한 반응온도는 -30∼50℃가 바람직하나, 더욱 바람직한 온도는 0℃∼30℃이다. 반응시간은 2∼24시간이 바람직하나, 더욱 바람직한 반응시간은 2∼6시간이다. 일반식(Ⅰa)로 표시되는 보호기가 있는 (E)-프로페닐 4급 암모늄 세펨을 용매하에 간단한 탈보호 반응을 통하여 일반식(Ⅰb)로 표시되는 보호기가 없는 (E)-프로페닐 4급 암모늄 세펨을 얻게 된다. 탈보호 반응의 대표적인 예로는 트리플루오르아세트산, 염화알루미늄, 파라-톨루엔설폰산, 염산, 포밀산, 트리메틸실릴 요오드, 아연과 아세트산 또는 페놀 등을 이용하여 실행한다. 이때에 사용되는 용매는 아니솔, 이염화메탄, 아세트산, 테트라히드로푸란, 메탄올, N,N-디메틸포름아미드, 물, 클로로포름, 디옥산, 아세토니트릴 또는 아세톤 등이다. 탈보호 반응은 -30∼50℃에서 실행하나 바람직한 온도는 0∼25℃가 적당하다. 반응시간은 1시간∼5시간이 가능하나, 바람직한 반응시간은 1∼2시간이다.When the thiazole chloro compound represented by the general formula (II) prepared by the known method (J. Antibiotics, 43, 533, 1990) is reacted with 3 equivalents of NaI in a solvent to the general formula (III) in the form (E) The thiazole type iodine compound represented is obtained. At this time, the solvent used is acetone, N, N- dimethylformamide, acetonitrile and the like, the reaction temperature is preferably carried out in the range of 0 ~ 30 ℃, the reaction time is preferably 0.5 to 2 hours. The (E) -propenyl quaternary ammonium cefme compound having a protecting group represented by formula (Ia) reacts a thiazole iodine compound of formula (III) with an amine compound represented by formula (IV) in a solvent. It can be prepared by. The solvent used at this time is ethyl acetate, N, N- dimethylformamide, methane dichloride, tetrahydrofuran, carbon tetrachloride, toluene, chloroform, acetonitrile, dioxane, water, acetone and the like. Moreover, although reaction temperature is -30-50 degreeC, it is preferable, More preferable temperature is 0 degreeC-30 degreeC. The reaction time is preferably 2 to 24 hours, but more preferably 2 to 6 hours. (E) -propenyl quaternary ammonium without protecting group represented by formula (Ib) through simple deprotection reaction of (E) -propenyl quaternary ammonium cefme with protecting group represented by formula (Ia) in a solvent. You get sepem. Representative examples of the deprotection reaction are carried out using trifluoroacetic acid, aluminum chloride, para-toluenesulfonic acid, hydrochloric acid, formic acid, trimethylsilyl iodine, zinc and acetic acid or phenol. The solvent used at this time is anisole, methane dichloride, acetic acid, tetrahydrofuran, methanol, N, N-dimethylformamide, water, chloroform, dioxane, acetonitrile or acetone. The deprotection reaction is carried out at -30 to 50 DEG C, but preferably 0 to 25 DEG C is suitable. The reaction time is 1 hour to 5 hours, but the preferred reaction time is 1 to 2 hours.

일반식(Ⅰa)에 있어서, R1은 아민의 보호기로서, 예컨대 포밀, t-부톡시카르보닐, 벤질옥시카르보닐, 파라-니트로벤질옥시카르보닐, 트리틸 등이 포함된다. R2는 수소, 메틸, 2-플루오르에틸, 플루오르메틸, 시클로펜틸 및 보호기로서 예컨대, 포밀, 클로로아세틸, 벤조일, 파라-니트로벤질, 2,2,2-트리클로로에톡시카르보닐, 테트라히드로피라닐, 트리틸 등 알려진 공지방법에 의해 쉽게 제거될 수 있는 것을 포함한다. R3는 수소 또는 카르복실 보호기이며, 보호기의 예로는 2,2,2-트리클로로에틸, 파라-메톡시벤질, 파라-니트로벤질, 벤즈히드릴 또는 t-부틸 등을 들 수 있다. R4는 메톡시, 카바모일, 치환체를 가진 카바모일, 옥사디아졸이나 트리아졸 등의 5환 헤테로 고리이다. n은 1이나 2의 정수이다.In the formula (Ⅰa), R 1 is a protective group of the amine, such as formyl, t- butoxycarbonyl, benzyloxycarbonyl, para-nitro and the like benzyloxycarbonyl, trityl. R 2 is hydrogen, methyl, 2-fluoroethyl, fluoromethyl, cyclopentyl and protecting groups such as formyl, chloroacetyl, benzoyl, para-nitrobenzyl, 2,2,2-trichloroethoxycarbonyl, tetrahydropyra And those that can be easily removed by known methods such as neil, trityl and the like. R 3 is hydrogen or a carboxyl protecting group, examples of the protecting group include 2,2,2-trichloroethyl, para-methoxybenzyl, para-nitrobenzyl, benzhydryl or t-butyl. R 4 is a 5-membered heterocyclic ring such as methoxy, carbamoyl, carbamoyl having a substituent, oxadiazole or triazole. n is an integer of 1 or 2.

일반식(Ⅰb)에 있어서, R2는 수소, 메틸, 2-플루오르에틸, 플루오르메틸 또는 시클로펜틸이며, R4는 메톡시, 카바모일, 치환체를 가진 카바모일, 옥사디아졸이나 트리아졸 등의 5환 헤테로 고리를 표시하며, n은 1이나 2의 정수이다.In general formula (Ib), R <2> is hydrogen, methyl, 2-fluoroethyl, fluoromethyl, or cyclopentyl, and R <4> is methoxy, carbamoyl, carbamoyl with a substituent, oxadiazole, triazole, etc. 5-membered hetero ring, n is an integer of 1 or 2.

일반식(Ⅱ)에 있어서, R1은 수소 또는 아민의 보호기로서, 예컨대 포밀, t-부톡시카르보닐, 벤질옥시카르보닐, 파라-니트로벤질옥시카르보닐 또는 트리틸 등이 포함된다. R2는 수소, 메틸, 2-플루오르에틸, 플루오르메틸, 시클로펜틸 및 보호기로서 예컨대, 포밀, 클로로아세틸, 벤조일, 파라-니트로벤질, 2,2,2-트리클로로에톡시카르보닐, 테트라히드로피라닐 또는 트리틸 등 알려진 공지방법에 의해 쉽게 제거될 수 있는 것을 포함한다. R3는 수소 또는 카르복실 보호기이며, 보호기의 예로는 2,2,2-트리클로로에틸, 파라-메톡시벤질, 파라-니트로벤질, 벤즈히드릴 또는 t-부틸 등을 들 수 있다.In the formula (Ⅱ), R 1 is a protecting group of a hydrogen, or an amine, such as formyl, t- butoxycarbonyl, benzyloxycarbonyl, para-nitro and the like benzyloxycarbonyl or trityl. R 2 is hydrogen, methyl, 2-fluoroethyl, fluoromethyl, cyclopentyl and protecting groups such as formyl, chloroacetyl, benzoyl, para-nitrobenzyl, 2,2,2-trichloroethoxycarbonyl, tetrahydropyra And those that can be easily removed by known methods such as nil or trityl. R 3 is hydrogen or a carboxyl protecting group, examples of the protecting group include 2,2,2-trichloroethyl, para-methoxybenzyl, para-nitrobenzyl, benzhydryl or t-butyl.

일반식(Ⅲ)에 있어서, R1은 수소 또는 아민의 보호기로서, 예컨대 포밀, t-부톡시카르보닐, 벤질옥시카르보닐, 파라-니트로벤질옥시카르보닐 또는 트리틸 등을 포함한다. R2는 수소, 메틸, 2-플루오르에틸, 플루오르메틸, 시클로펜틸 및 보호기로서 예컨대, 포밀, 클로로아세틸, 벤조일, 파라-니트로벤질, 2,2,2-트리클로로에톡시카르보닐, 테트라히드로피라닐, 트리틸 등 알려진 공지방법에 의해 쉽게 제거될 수 있는 것을 포함한다. R3는 수소 또는 카르복실 보호기이며, 보호기의 예로는 2,2,2-트리클로로에틸, 파라-메톡시벤질, 파라-니트로벤질, 벤즈히드릴, t-부틸 등을 들 수 있다.In formula (III), R 1 includes, for example, formyl, t-butoxycarbonyl, benzyloxycarbonyl, para-nitrobenzyloxycarbonyl or trityl as a protecting group for hydrogen or amine. R 2 is hydrogen, methyl, 2-fluoroethyl, fluoromethyl, cyclopentyl and protecting groups such as formyl, chloroacetyl, benzoyl, para-nitrobenzyl, 2,2,2-trichloroethoxycarbonyl, tetrahydropyra And those that can be easily removed by known methods such as neil, trityl and the like. R 3 is hydrogen or a carboxyl protecting group, and examples of the protecting group include 2,2,2-trichloroethyl, para-methoxybenzyl, para-nitrobenzyl, benzhydryl, t-butyl and the like.

일반식(Ⅳ)에 있어서, R4는 메톡시, 카바모일, 치환체를 가진 카바모일, 옥사디아졸이나 트리아졸 등의 5환 헤테로 고리를 표시하며, n은 1이나 2의 정수이다.In general formula (IV), R <4> represents 5-cyclic hetero rings, such as methoxy, carbamoyl, the carbamoyl which has a substituent, oxadiazole, and triazole, and n is an integer of 1 or 2.

다음 화합물 1에서 화합물 15까지의 화합물은 본 발명에 의해 제조된 신규한 화합물이며, 이의 제조방법은 아래 실시 예로부터 용이하게 제조할 수 있다.The following compound 1 to compound 15 is a novel compound prepared by the present invention, the preparation method thereof can be easily prepared from the following examples.

화합물 1 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-(4-카바모일-5,6,7,8-테트라히드로-1-퀴놀리노)-1-프로페닐]-3-세펨-4-카르복실레이트Compound 1: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- (4-carba Moyl-5,6,7,8-tetrahydro-1-quinolino) -1-propenyl] -3-cepem-4-carboxylate

화합물 2 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(히드록시이미노)아세트아미도]-3-[(E)-3-(4-카바모일-5,6,7,8-테트라히드로-1-퀴놀리노)-1-프로페닐]-3-세펨-4-카르복실레이트Compound 2: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (hydroxyimino) acetamido] -3-[(E) -3- (4-carba Moyl-5,6,7,8-tetrahydro-1-quinolino) -1-propenyl] -3-cepem-4-carboxylate

화합물 3 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-(N'-포밀히드라지노카르보닐)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트Compound 3: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- {4- ( N'-formylhydrazinocarbonyl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-carboxylate

화합물 4 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(히드록시이미노)아세트아미도]-3-[(E)-3-{4-(N'-포밀히드라지노카르보닐)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트Compound 4: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (hydroxyimino) acetamido] -3-[(E) -3- {4- ( N'-formylhydrazinocarbonyl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-carboxylate

화합물 5 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-(N'-아세틸히드라지노카르보닐)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트Compound 5: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- {4- ( N'-acetylhydrazinocarbonyl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cefe-4-carboxylate

화합물 6 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(히드록시이미노)아세트아미도]-3-[(E)-3-{4-(N'-아세틸히드라지노카르보닐)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트Compound 6: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (hydroxyimino) acetamido] -3-[(E) -3- {4- ( N'-acetylhydrazinocarbonyl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cefe-4-carboxylate

화합물 7 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-(5-메틸-2H-[1,2,4]트리아졸-3-일)-5,6,7,8-테트라히드로-1-퀴놀리노)-1-프로페닐]-3-세펨-4-카르복실레이트Compound 7: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- {4- ( 5-methyl-2H- [1,2,4] triazol-3-yl) -5,6,7,8-tetrahydro-1-quinolino) -1-propenyl] -3-cepem-4- Carboxylate

화합물 8 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-(5-메틸-2H-[1,2,4]트리아졸-3-일)-5,6,7,8-테트라히드로-1-퀴놀리노)-1-프로페닐]-3-세펨-4-카르복실레이트Compound 8: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- {4- ( 5-methyl-2H- [1,2,4] triazol-3-yl) -5,6,7,8-tetrahydro-1-quinolino) -1-propenyl] -3-cepem-4- Carboxylate

화합물 9 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-([1,3,4]옥사디아졸-2-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트Compound 9: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- {4- ( [1,3,4] oxadiazol-2-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-carboxylate

화합물 10 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(히드록시이미노)아세트아미도]-3-[(E)-3-{4-([1,2,4]옥사디아졸-2-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트Compound 10: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (hydroxyimino) acetamido] -3-[(E) -3- {4- ( [1,2,4] oxadiazol-2-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-carboxylate

화합물 11 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-(5-메틸-[1,3,4]옥사디아졸-2-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트Compound 11: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- {4- ( 5-methyl- [1,3,4] oxadiazol-2-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-car Carboxylate

화합물 12 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(히드록시이미노)아세트아미도]-3-[(E)-3-{4-(5-메틸-[1,3,4]옥사디아졸-2-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트Compound 12: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (hydroxyimino) acetamido] -3-[(E) -3- {4- ( 5-methyl- [1,3,4] oxadiazol-2-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-car Carboxylate

화합물 13 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-메톡시-2,3-시틀로펜테노-1-피리디노)-1-프로페닐]-3-세펨-4-카르복실레이트Compound 13: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- {4-meth Methoxy-2,3-cytopenteno-1-pyridino) -1-propenyl] -3-cepem-4-carboxylate

화합물 14 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(히드록시이미노)아세트아미도]-3-[(E)-3-{4-메톡시-2,3-시틀로펜테노-1-피리디노)-1-프로페닐]-3-세펨-4-카르복실레이트Compound 14: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (hydroxyimino) acetamido] -3-[(E) -3- {4-meth Methoxy-2,3-cytopenteno-1-pyridino) -1-propenyl] -3-cepem-4-carboxylate

화합물 15 : 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(2-플루오르에톡시이미노)아세트아미도]-3-[(E)-3-{4-메톡시-2,3-시틀로펜테노-1-피리디노)-1-프로페닐]-3-세펨-4-카르복실레이트Compound 15: 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (2-fluoroethoxyimino) acetamido] -3-[(E) -3- { 4-methoxy-2,3-cytopenteno-1-pyridino) -1-propenyl] -3-cepem-4-carboxylate

[생체외 항균활성 시험][In vitro antibacterial activity test]

본 발명에서 제조된 대표적인 화합물들의 생체외 항균력은 뮐러 힌튼 아가(Muller Hinton Agar)를 사용한 한천 희석(Agar Dilution)방법에 의해 37℃에서 18시간 배양한 후 그 2배씩 단계적으로 희석하여 접종한 평판을 일렬로 나열하고 육안으로 관찰하여 표기 화합물의 최소발육억제농도(MIC)를 정하였다. 다음의 표는 제조된 일반식(Ⅰb) 화합물들의 상기 방법으로 측정된 항균력을 보여주고 있다.In vitro antimicrobial activity of the representative compounds prepared in the present invention was incubated at 37 ° C. for 18 hours by agar dilution method using Muller Hinton Agar, followed by diluting the plate by diluting step by step twice. They were lined up and visually observed to determine the minimum growth inhibitory concentration (MIC) of the title compound. The following table shows the antimicrobial activity measured by the above method of the prepared general formula (Ib) compounds.

다음 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

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(메톡시이미노)아세트아미도]-3-[(E)-3-(4-카바모일-5,6,7,8-테트라히드로-1-퀴놀리노)-1-프로페닐]-3-세펨-4-카르복실레이트파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(메톡시이미노)아세트아미도]-3-[3-클로로-1-프로페닐]-3-세펨-4-카르복실레이트 100mg과 요오드화나트륨 54mg(3 당량)을 아세톤 1ml에 녹이고 1시간 동안 교반하였다. 아세톤을 증발시킨 후 초산에틸로 희석하고 10% 나트륨티오설파이드와 포화 염수로 처리하고 무수 황산마그네슘으로 처리한 후 용매를 증발시켜 파라-메톡시벤질 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-요오드-1-프로페닐]-3-세펨-4-카르복실레이트 106mg을 얻었다. 이 화합물을 N,N-디메틸포름아미드 1ml에 녹이고 4-카바모일-5,6,7,8-테트라히드로퀴놀린 20mg을 가한 후 상온에서 4시간 동안 교반하였다. 얼음으로 냉각하고 증류수를 가하여 10분간 교반한 다음 여과하였다. 여과된 고체를 아니솔 1ml에 녹이고 얼음으로 냉각하고 트리플루오르아세트산 1.5ml를 가하고 2시간동안 교반하였다. 에테르로 고체화하고 여과한 후 이 여과된 고체를 역상 관크로마토그래피하여 10mg(13.3%)의 미백색 고체인 목적 화합물을 얻었다.7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(methoxyimino) acetamido] -3-[(E) -3- (4-carbamoyl-5 , 6,7,8-tetrahydro-1-quinolino) -1-propenyl] -3-cepem-4-carboxylatepara-methoxybenzyl 7beta- [2- (2-tritylaminothiazole -4-yl) -2- (Z)-(methoxyimino) acetamido] -3- [3-chloro-1-propenyl] -3-cefe-4-carboxylate and 54 mg sodium iodide ( 3 equivalents) was dissolved in 1 ml of acetone and stirred for 1 hour. Acetone was evaporated, diluted with ethyl acetate, treated with 10% sodium thiosulfide and saturated brine, treated with anhydrous magnesium sulfate, and the solvent was evaporated to yield para-methoxybenzyl 7beta- [2- (2-aminothiazole- 106 mg of 4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3-iodine-1-propenyl] -3-cepem-4-carboxylate was obtained. . The compound was dissolved in 1 ml of N, N-dimethylformamide, 20 mg of 4-carbamoyl-5,6,7,8-tetrahydroquinoline was added, followed by stirring at room temperature for 4 hours. After cooling with ice, distilled water was added, stirred for 10 minutes, and filtered. The filtered solid was dissolved in 1 ml of anisole, cooled with ice, 1.5 ml of trifluoroacetic acid was added and stirred for 2 hours. After solidification with ether and filtration, the filtered solid was subjected to reverse phase column chromatography to obtain 10 mg (13.3%) of the title compound as an off-white solid.

1H-NMR(D2O) : 8.74, 7.85(각 d, 각 1H, J=5.7Hz), 7.01(s, 1H), 6.51(d, 1h, J=16.1Hz), 6.06(dt, 1H, J=5.3Hz), 5.81(d, 1H, J=4.3Hz), 5.30(d, 2H, J=5.3Hz), 5.29(d, 1H, J=4.3Hz), 4.00(s, 3H), 3.66(br s, 2H), 3.17, 3.00(br t, 각 2H,), 1.98, 1.86(br t, 각 2H)1 H-NMR (D 2 O): 8.74, 7.85 (each d, each 1H, J = 5.7 Hz), 7.01 (s, 1H), 6.51 (d, 1h, J = 16.1 Hz), 6.06 (dt, 1H, J = 5.3Hz), 5.81 (d, 1H, J = 4.3Hz), 5.30 (d, 2H, J = 5.3Hz), 5.29 (d, 1H, J = 4.3Hz), 4.00 (s, 3H), 3.66 (br s, 2H), 3.17, 3.00 (br t, 2H each), 1.98, 1.86 (br t, 2H each)

[실시예 2]Example 2

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(히드록시이미노)아세트아미도]-3-[(E)-3-(4-카바모일-5,6,7,8-테트라히드로-1-퀴놀리노)-1-프로페닐]-3-세펨-4-카르복실레이트7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(hydroxyimino) acetamido] -3-[(E) -3- (4-carbamoyl-5 , 6,7,8-tetrahydro-1-quinolino) -1-propenyl] -3-cepem-4-carboxylate

파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(트리틸옥시이미노)아세트아미도]-3-[3-클로로-1-프로페닐]-세펨-4-카르복실레이트 423mg과 요오드화나트륨 171mg(3당량)을 아세톤 4.2ml에 녹이고 65분 동안 교반하였다. 아세톤을 증발시키고 초산에틸로 희석한 다음 10% 나트륨티오설파이드와 포화 염수로 처리하고 무수 황산마그네슘으로 처리한 후 용매를 증발시키고 진공건조하여 파라-메톡시벤질 7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(트리틸옥시이미노)아세트아미도]-3-[(E)-3-요오드-1-프로페닐]-3-세펨-4-카르복실레이트 415mg을 얻었다. 이 중 127mg을 N,N-디메틸포름아미드 0.65ml에 녹이고 4-카바모일-5,6,7,8-테트라히드로퀴놀린 19.6mg을 가하고 상온에서 5시간 14분동안 교반하였다. 얼음으로 냉각하고 물을 가한 후 10분간 교반한 후 여과하고 여과된 고체를 상온에서 건조시켰다. 이 고체를 이염화메탄 1ml와 아니솔 1ml에 녹이고 얼음으로 냉각한 후 트리플루오르아세트산 1.0ml를 가하여 5시간동안 교반하였다. 이염화메탄과 트리플루오르아세트산을 증발시키고 에테르로 고체화하고 여과하였다. 이 여과된 고체에 포름산 1ml를 넣고 1시간동안 교반하였다. 이소프로필에테르로 고체화하고 이 고체를 역상 관크로마토그래피하여 11mg(15.2%)의 미백색 고체인 목적 화합물을 얻었다.Para-methoxybenzyl 7beta- [2- (2-tritylaminothiazol-4-yl) -2- (Z)-(trityloxyimino) acetamido] -3- [3-chloro-1 423 mg of propenyl] -cefe-4-carboxylate and 171 mg (3 equivalents) of sodium iodide were dissolved in 4.2 ml of acetone and stirred for 65 minutes. Acetone was evaporated, diluted with ethyl acetate, treated with 10% sodium thiosulfide and saturated brine, treated with anhydrous magnesium sulfate, the solvent was evaporated and dried under vacuum to yield para-methoxybenzyl 7beta- [2- (2-amino Thiazol-4-yl) -2- (Z)-(trityloxyimino) acetamido] -3-[(E) -3-iodine-1-propenyl] -3-cepem-4-carboxyl Yield 415 mg. 127 mg of this was dissolved in 0.65 ml of N, N-dimethylformamide, and 19.6 mg of 4-carbamoyl-5,6,7,8-tetrahydroquinoline was added and stirred at room temperature for 5 hours and 14 minutes. After cooling with ice, adding water, stirring for 10 minutes, and then filtering and drying the filtered solid at room temperature. The solid was dissolved in 1 ml of methane dichloride and 1 ml of anisole, cooled with ice, and 1.0 ml of trifluoroacetic acid was added and stirred for 5 hours. Methane dichloride and trifluoroacetic acid were evaporated, solidified with ether and filtered. 1 ml of formic acid was added to the filtered solid and stirred for 1 hour. Solidification with isopropyl ether and reverse solids column chromatography gave 11 mg (15.2%) of the title compound as a white, white solid.

1H-NMR(D2O+DMSO-d6) : 8.74, 7.82(각 d, 각 1H, J=6.2Hz), 6.91(s, 1H), 6.60(d, 1H, J=16.1Hz), 6.03(dt, 1H, J=16.1, 5.3Hz), 5.78(d, 1H, J=4.8Hz), 5.27(d, 2H, J=5.3Hz), 5.20(d, 1H, J=4.8Hz), 3.63(br. s, 2H), 3.14, 2.97(br. t, 각 2H), 1.96, 1.83(br. t, 각 2H)1 H-NMR (D 2 O + DMSO-d 6 ): 8.74, 7.82 (each d, each 1H, J = 6.2 Hz), 6.91 (s, 1H), 6.60 (d, 1H, J = 16.1 Hz), 6.03 (dt, 1H, J = 16.1, 5.3 Hz), 5.78 (d, 1H, J = 4.8 Hz), 5.27 (d, 2H, J = 5.3 Hz), 5.20 (d, 1H, J = 4.8 Hz), 3.63 (br. s, 2H), 3.14, 2.97 (br. t, 2H each), 1.96, 1.83 (br. t, 2H each)

[실시예 3]Example 3

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-(N'-포밀히드라지노카르보닐)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(methoxyimino) acetamido] -3-[(E) -3- {4- (N'- Formylhydrazinocarbonyl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cefe-4-carboxylate

실시예 1로부터 얻은 파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(트리틸옥시이미노)아세트아미도]-3-[3-클로로-1-프로페닐]-세펨-4-카르복실레이트 128mg을 N,N-디메틸포름아미드 1ml에 녹이고 5,6,7,8-테트라히드로-4-카르보닐산 N'-포밀히드라지드 30mg을 가한 후 사온에서 2시간 40분 동안 교반하였다. 얼음으로 냉각시키고 물을 가하여 생성된 고체를 여과하였다. 여과된 고체를 아니솔 1ml와 이염화메탄 1.5ml에 녹이고 얼음으로 냉각한 다음 트리플루오르아세트산 1.5ml를 가하고 5시간동안 교반하였다. 에테르로 고체화하고 여과한 다음 이 여과된 고체를 역상 관크로마토그래피하여 10mg(11.4%)의 미백색 고체인 목적 화합물을 얻었다.Para-methoxybenzyl 7beta- [2- (2-tritylaminothiazol-4-yl) -2- (Z)-(trityloxyimino) acetamido] -3- [obtained from Example 1 128 mg of 3-chloro-1-propenyl] -cefe-4-carboxylate is dissolved in 1 ml of N, N-dimethylformamide, and 5,6,7,8-tetrahydro-4-carbonyl acid N'-formylhydra After adding 30 mg of the jid, the mixture was stirred for 2 hours and 40 minutes at room temperature. Cool the ice and add water to filter the resulting solid. The filtered solid was dissolved in 1 ml of anisole and 1.5 ml of dichloromethane, cooled with ice, and then 1.5 ml of trifluoroacetic acid was added and stirred for 5 hours. Solidified with ether, filtered and the filtered solid was reversed-phase column chromatography to give the target compound of 10 mg (11.4%) as an off-white solid.

1H-NMR(D2O) : 8.62, 7.71(각 d, 각 1H, J=5.6Hz), 7.97(s, 1H), 7.03(s, 1H), 6.70(d, 1H, J=16.2Hz), 6.03(dt, 1H, J=16.2, 4.8Hz), 5.84(d, 1H, J=4.8Hz), 5.26(d, 3H, J=4.8Hz), 4.00(s, 3H), 3.65(br. s, 2H), 3.16, 2.97(br. t, 각 2H), 1.97, 1.81(br. t, 각 2H)1 H-NMR (D 2 O): 8.62, 7.71 (each d, each 1H, J = 5.6 Hz), 7.97 (s, 1H), 7.03 (s, 1H), 6.70 (d, 1H, J = 16.2 Hz) , 6.03 (dt, 1H, J = 16.2, 4.8 Hz), 5.84 (d, 1H, J = 4.8 Hz), 5.26 (d, 3H, J = 4.8 Hz), 4.00 (s, 3H), 3.65 (br. s, 2H), 3.16, 2.97 (br. t, 2H each), 1.97, 1.81 (br. t, 2H each)

[실시예 4]Example 4

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(히드록시이미노)아세트아미도]-3-[(E)-3-{4-(N'-포밀히드라지노카르보닐-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(hydroxyimino) acetamido] -3-[(E) -3- {4- (N'- Formylhydrazinocarbonyl-5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-carboxylate

실시예 2로부터 얻은 파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(트리틸옥시이미노)아세트아미도]-3-[(E)-3-요오드-1-프로페닐]-3-세펨-4-카르복실레이트 183mg을 N,N-디메틸포름아미드 1ml에 녹이고 5,6,7,8-테트라히드로-퀴놀린-4-카르보닐산 N'-포밀히드라지드 35.3mg을 가한 후 상온에서 3시간 동안 교반하였다. 얼음으로 냉각하고 물을 가한 후 10분간 교반하고 여과하여 여과된 고체를 상온에서 건조시켰다. 이 고체를 아니솔 2ml에 녹이고 얼음으로 냉각시킨 후 트리플루오르아세트산 2.5ml를 가하고 2시간동안 교반하였다. 트리플루오르아세트산을 증발시키고 에테르로 고체화하여 여과하였다. 이 여과된 고체에 포름산 2ml를 가하고 2시간동안 교반하였다. 에테르로 고체화하고 역상 관 크로마토그래피하여 26mg(29%)의 노란색 고체인 목적 화합물을 얻었다.Para-methoxybenzyl 7beta- [2- (2-tritylaminothiazol-4-yl) -2- (Z)-(trityloxyimino) acetamido] -3- [obtained from Example 2 183 mg of (E) -3-iodine-1-propenyl] -3-cefe-4-carboxylate is dissolved in 1 ml of N, N-dimethylformamide and 5,6,7,8-tetrahydro-quinoline-4- 35.3 mg of carbonyl acid N'-formylhydrazide was added thereto, followed by stirring at room temperature for 3 hours. Cooled with ice, added water, stirred for 10 minutes, filtered and dried the filtered solid at room temperature. This solid was dissolved in 2 ml of anisole, cooled with ice, 2.5 ml of trifluoroacetic acid was added and stirred for 2 hours. Trifluoroacetic acid was evaporated and solidified with ether and filtered. 2 ml of formic acid was added to the filtered solid and stirred for 2 hours. Solidification with ether and reverse phase column chromatography gave the title compound as a 26 mg (29%) yellow solid.

1H-NMR(D2O+DMSO) : 8.90, 8.06(각 d, 각 1H, J=6Hz), 8.37(s, 1H), 7.06(s, 1H), 6.66(d, 1H, J=15.5Hz), 6.16(dt, 1H, J=15.5, 4.6Hz), 5.87(d, 1H, J=4Hz), 5.42(d, 2H, J=4.6Hz), 5.34(d, 1H, J=4Hz), 3.75(br. s, 2H), 3.30, 3.13(각br. s, 각 2H), 2.10, 1.95(br. s, 각 2H)1H-NMR (D 2 O + DMSO): 8.90, 8.06 (each d, each 1H, J = 6 Hz), 8.37 (s, 1H), 7.06 (s, 1H), 6.66 (d, 1H, J = 15.5 Hz ), 6.16 (dt, 1H, J = 15.5, 4.6 Hz), 5.87 (d, 1H, J = 4 Hz), 5.42 (d, 2H, J = 4.6 Hz), 5.34 (d, 1H, J = 4 Hz), 3.75 (br. S, 2H), 3.30, 3.13 (br.s, 2H each), 2.10, 1.95 (br. S, 2H each)

[실시예 5]Example 5

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-(N'-아세틸히드라지노카르보닐)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(methoxyimino) acetamido] -3-[(E) -3- {4- (N'- Acetylhydrazinocarbonyl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cefe-4-carboxylate

실시예 1로부터 얻은 파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(트리틸옥시이미노)아세트아미도]-3-[(E)-3-요오드-1-프로페닐]-3-세펨-4-카르복실레이트 126mg을 N,N-디메틸포름아미드 0.8ml에 녹였다. 얼음으로 냉각한 후 5,6,7,8-테트라히드로퀴놀린-4-카르보닐산 N'-아세틸히드라지드 31.5mg을 가한 후 상온에서 5시간 동안 교반하였다. 얼음으로 냉각하고 증류수를 가하여 10분간 교반하고 여과하였다. 여과된 고체를 이염화메탄 1ml와 아니솔 2ml에 녹이고 얼음으로 냉각하고 트리플루오르아세트산 2.5ml를 가하고 3시간동안 교반하였다. 에테르와 n-헥산으로 고체화하고 여과하였다. 여과된 고체를 역상 관크로마토그래피하여 25mg(28.3%)의 노란색 고체인 목적 화합물을 얻었다.Para-methoxybenzyl 7beta- [2- (2-tritylaminothiazol-4-yl) -2- (Z)-(trityloxyimino) acetamido] -3- [obtained from Example 1 126 mg of (E) -3-iodine-1-propenyl] -3-cefe-4-carboxylate was dissolved in 0.8 ml of N, N-dimethylformamide. After cooling with ice, 31.5 mg of 5,6,7,8-tetrahydroquinoline-4-carbonyl acid N'-acetylhydrazide was added and stirred at room temperature for 5 hours. Cooled with ice, distilled water was added, stirred for 10 minutes, and filtered. The filtered solid was dissolved in 1 ml of methane dichloride and 2 ml of anisole, cooled with ice, 2.5 ml of trifluoroacetic acid was added and stirred for 3 hours. Solidified with ether and n-hexane and filtered. The filtered solid was subjected to reverse phase column chromatography to give 25 mg (28.3%) of the title compound as a yellow solid.

1H-NMR(DMSO-d6) : 10.64, 10.15(각 d, 각 1H, J=4Hz), 9.62(s, 1H), 8.97, 7.91(각 d, 각 1H, J=6.1Hz), 6.76(s, 1H), 6.26(2H, J=Hz), 5.41(ABq, 2H, J=17.1, 6.1Hz), 5.19(d, 1H, J=4.9hz), 3.84(s. 3H), 3.85(ABq, 2H, J=17.1), 3.20, 2.96(br.t, 각 2H), 1.94(s, 3H), 1.91, 1.77(br.t, 각 2H)1 H-NMR (DMSO-d 6 ): 10.64, 10.15 (each d, each 1H, J = 4 Hz), 9.62 (s, 1H), 8.97, 7.91 (each d, each 1H, J = 6.1 Hz), 6.76 ( s, 1H), 6.26 (2H, J = Hz), 5.41 (ABq, 2H, J = 17.1, 6.1 Hz), 5.19 (d, 1H, J = 4.9hz), 3.84 (s. 3H), 3.85 (ABq , 2H, J = 17.1), 3.20, 2.96 (br.t, 2H each), 1.94 (s, 3H), 1.91, 1.77 (br.t, 2H each)

[실시예 6]Example 6

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(히드록시이미노)아세트아미도]-3-[(E)-3-{4-(N'-아세틸히드라지노카르보닐)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(hydroxyimino) acetamido] -3-[(E) -3- {4- (N'- Acetylhydrazinocarbonyl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cefe-4-carboxylate

실시예 2로부터 얻은 파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(트리틸옥시이미노)아세트아미도]-3-[(E)-3-요오드-1-프로페닐]-3-세펨-4-카르복실레이트 254mg을 N,N-디메틸포름아미드 1.6ml에 녹이고 5,6,7,8-테트라히드로퀴놀린-4-카르보닐산 N'-아세틸히드라지드 52mg을 가한 후 상온에서 7시간 동안 교반하였다. 얼음으로 냉각하고 증류수를 가하여 생성된 고체를 여과하고 상온에서 건조하였다. 이 고체를 이염화메탄 2ml와 아니솔 1ml에 녹인 후 얼음으로 냉각하고 트리플루오르아세트산 2ml를 가하여 3시간동안 교반하였다. 이염화메탄과 트리플루오르아세트산을 증발시키고 에테르로 고체화하고 여과하였다. 이 여과된 고체에 포름산 2ml를 가하고 2시간동안 교반한 후 여과하고 초산에틸로 고체화하였다. 여과된 고체를 역상 관크로마토그래피하여 33mg(23.1%)의 미백색 고체인 목적 화합물을 얻었다.Para-methoxybenzyl 7beta- [2- (2-tritylaminothiazol-4-yl) -2- (Z)-(trityloxyimino) acetamido] -3- [obtained from Example 2 (E) -3-Iodine-1-propenyl] -3-cepem-4-carboxylate 254 mg was dissolved in 1.6 ml of N, N-dimethylformamide and 5,6,7,8-tetrahydroquinoline-4- 52 mg of carbonyl acid N'-acetylhydrazide was added, followed by stirring at room temperature for 7 hours. Cooled with ice, distilled water was added, and the resulting solid was filtered and dried at room temperature. This solid was dissolved in 2 ml of methane dichloride and 1 ml of anisole, cooled with ice, and 2 ml of trifluoroacetic acid was added and stirred for 3 hours. Methane dichloride and trifluoroacetic acid were evaporated, solidified with ether and filtered. 2 ml of formic acid was added to the filtered solid, stirred for 2 hours, filtered and solidified with ethyl acetate. The filtered solid was subjected to reverse phase column chromatography to obtain 33 mg (23.1%) of the title compound as an off-white solid.

1H-NMR(D2O) : 8.68, 7.82(각 d, 각 1H, J=6.6Hz), 6.97(s, 1H), 6.61(d, 1H, J=16.2Hz), 6.02(dt, 1H, J=16.2, 6.0Hz), 5.83(d, 1H, J=4.2Hz), 5.26(d, 3H, J=4.2Hz), 3.63(br. s, 2H), 3.15, 3.00(br. t, 각 2H), 2.10(s, 3H), 1.98, 1.83(br. t, 각 2H)1 H-NMR (D 2 O): 8.68, 7.82 (each d, each 1H, J = 6.6 Hz), 6.97 (s, 1H), 6.61 (d, 1H, J = 16.2 Hz), 6.02 (dt, 1H, J = 16.2, 6.0 Hz), 5.83 (d, 1H, J = 4.2 Hz), 5.26 (d, 3H, J = 4.2 Hz), 3.63 (br.s, 2H), 3.15, 3.00 (br.t, each 2H), 2.10 (s, 3H), 1.98, 1.83 (br. T, 2H each)

[실시예 7]Example 7

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-(5-메틸-2H-[1,2,4]-트리아졸-3-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(methoxyimino) acetamido] -3-[(E) -3- {4- (5-methyl -2H- [1,2,4] -triazol-3-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-carboxyl Rate

실시예 1로부터 얻은 파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(메톡시이미노)아세트아미도]-3-[(E)-3-요오드-1-프로페닐]-3-세펨-4-카르복실레이트 113mg을 N,N-디메틸포름아미드 0.6ml에 녹이고 4-(5-메틸-2H-[1,2,4]-트리아졸-3-일)-5,6,7,8-테트라히드로퀴놀린 26mg을 가한 후 상온에서 6시간 동안 교반하였다. 얼음으로 냉각하고 물을 가한 후 생성된 고체를 여과하였다. 여과된 고체를 아니솔 1ml에 녹이고 얼음으로 냉각하고 트리플루오르아세트산 1.5ml를 가한 후 3시간동안 교반하였다. 에테르로 고체화하고 여과한 다음 이 여과된 고체에 초산에틸을 가하고 여과하였다. 여과된 고체를 역상 관크로마토그래피하여 16mg(20.7%)의 노란색의 고체인 목적 화합물을 얻었다.Para-methoxybenzyl 7beta- [2- (2-tritylaminothiazol-4-yl) -2- (Z)-(methoxyimino) acetamido] -3-[(obtained from Example 1 E) -3-mg of Iodine-1-propenyl] -3-cepem-4-carboxylate was dissolved in 0.6 ml of N, N-dimethylformamide and 4- (5-methyl-2H- [1,2,4 ] -Triazol-3-yl) -5,6,7,8-tetrahydroquinoline 26 mg was added and stirred at room temperature for 6 hours. After cooling with ice and adding water, the resulting solid was filtered off. The filtered solid was dissolved in 1 ml of anisole, cooled with ice, 1.5 ml of trifluoroacetic acid was added, and stirred for 3 hours. Solidified with ether and filtered, ethyl acetate was added to the filtered solid and filtered. The filtered solid was subjected to reverse phase column chromatography to give 16 mg (20.7%) of the title compound as a yellow solid.

1H-NMR(D2O+DMSO-d2) : 8.99, 8.48(각d, 각1H, J=6.1Hz), 7.14(d, 1H, J=15.9Hz), 7.14(1H, s), 6.26(dt, 1H, J=15.9Hz), 5.97(d, 1H, J=4.9Hz), 5.52(d, 2H, J=4.9Hz), 5.40(d, 1H, J=3.7Hz), 4.20(3H, s), 3.91, 3.84(ABq, 2H, J=17.1Hz), 3.51, 3.47(br.s, 각2H), 2.80(s, 3H), 2.24, 2.08(br, s, 각2H)1 H-NMR (D 2 O + DMSO-d 2 ): 8.99, 8.48 (each d, each 1H, J = 6.1 Hz), 7.14 (d, 1H, J = 15.9 Hz), 7.14 (1H, s), 6.26 (dt , 1H, J = 15.9 Hz), 5.97 (d, 1H, J = 4.9 Hz), 5.52 (d, 2H, J = 4.9 Hz), 5.40 (d, 1H, J = 3.7 Hz), 4.20 (3H, s ), 3.91, 3.84 (ABq, 2H, J = 17.1 Hz), 3.51, 3.47 (br.s, 2H each), 2.80 (s, 3H), 2.24, 2.08 (br, s, 2H each)

[실시예 8]Example 8

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(히드록시이미노)아세트아미도]-3-[(E)-3-{4-(5-메틸-2H-[1,2,4]-트리아졸-3-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(hydroxyimino) acetamido] -3-[(E) -3- {4- (5-methyl -2H- [1,2,4] -triazol-3-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-carboxyl Rate

실시예 2로부터 얻은 파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(트리틸옥시이미노)아세트아미도]-3-[(E)-3-요오드-1-프로페닐]-3-세펨-4-카르복실레이트 122mg을 N,N-디메틸포름아미드 0.7ml에 녹이고 4-(5-메틸-2H-[1,2,4]-트리아졸-3-일)-5,6,7,8-테트라히드로퀴놀린 23mg을 가한 후 상온에서 5시간 동안 교반하였다. 얼음으로 냉각하고 0.1N hCl수용액을 몇 방울 가하고 증류수를 가하였다. 생성된 고체를 여과하고 진공 건조하였다. 이 고체를 이염화메탄 1.2ml와 아니솔 1.2ml에 녹인 후 얼음으로 냉각하고 트리플루오르아세트산 1.5ml를 가한 다음 3시간 30분 동안 교반하였다. 이염화메탄과 트리플루오르아세트산을 증발시키고 에테르로 고체화하고 여과하였다. 이 여과된 고체에 포름산 1.5ml를 가하고 1시간 50분 동안 교반한 후, 여과한 여액을 초산에틸로 고체화하였다. 여과된 고체를 역상 관크로마토그래피하여 16.8mg(25.3%)의 미백색 고체인 목적 화합물을 얻었다.Para-methoxybenzyl 7beta- [2- (2-tritylaminothiazol-4-yl) -2- (Z)-(trityloxyimino) acetamido] -3- [obtained from Example 2 122E of (E) -3-iodine-1-propenyl] -3-cefe-4-carboxylate was dissolved in 0.7 ml of N, N-dimethylformamide and 4- (5-methyl-2H- [1,2, 4] -triazol-3-yl) -5,6,7,8-tetrahydroquinoline 23 mg was added and stirred at room temperature for 5 hours. After cooling with ice, a few drops of 0.1N hCl aqueous solution was added and distilled water was added. The resulting solid was filtered and dried in vacuo. The solid was dissolved in 1.2 ml of methane dichloride and 1.2 ml of anisole, cooled with ice, 1.5 ml of trifluoroacetic acid was added, and stirred for 3 hours and 30 minutes. Methane dichloride and trifluoroacetic acid were evaporated, solidified with ether and filtered. 1.5 ml of formic acid was added to the filtered solid and stirred for 1 hour and 50 minutes, and the filtrate was solidified with ethyl acetate. The filtered solid was subjected to reverse phase column chromatography to obtain 16.8 mg (25.3%) of a white compound.

1H-NMR(D2O+DMSO-6) : 8.76, 8.20(각d, 각1H, J=6.6Hz), 6.99(s, 1H), 6.77(d, 1H, J=16.0hz), 6.10(dt, 1H, J=16.0, 4.9hz), 5.85(d, 1H, J=4.3hz), 5.35(d, 2H, J=4.9hz), 5.28(d, 1H, J=4.3Hz), 3.71(br.s, 2H), 3.27(br.s, 3H), 2.74, 2.61(br.t, 각2H), 2.05, 1.89(br.t 각2H)1 H-NMR (D 2 O + DMSO- 6 ): 8.76, 8.20 (each d, each 1H, J = 6.6 Hz), 6.99 (s, 1H), 6.77 (d, 1H, J = 16.0 hz), 6.10 (dt, 1H, J = 16.0, 4.9hz), 5.85 (d, 1H, J = 4.3hz), 5.35 (d, 2H, J = 4.9hz), 5.28 (d, 1H, J = 4.3Hz), 3.71 (br. s, 2H), 3.27 (br.s, 3H), 2.74, 2.61 (br.t, 2H each), 2.05, 1.89 (br.t each 2H)

[실시예 9]Example 9

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-(5-메틸-[1,3,4]옥사디아졸-2-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(methoxyimino) acetamido] -3-[(E) -3- {4- (5-methyl -[1,3,4] oxadiazol-2-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-carboxylate

실시예 1로부터 얻은 파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(메톡시이미노)아세트아미도]-3-[(E)-3-요오드-1-프로페닐]-3-세펨-4-카르복실레이트 130mg을 N,N-디메틸포름아미드 0.7ml에 녹이고 4-(5-메틸-[1,3,4]-옥사디아졸-2-일)-5,6,7,8-테트라히드로퀴놀린 30mg을 가한 후 상온에서 7시간 동안 교반하였다. 얼음으로 냉각하고 증류수를 가하여 10분간 교반후 여과하였다. 여과된 고체를 이염화메탄 2ml와 아니솔 1ml에 녹이고 얼음으로 냉각한 후 트리플루오르아세트산 2ml를 가하고 3시간동안 교반하였다. 에테르로 고체화하고 여과하여 여과된 고체에 초산에틸을 가하고 여과하였다. 여과된 고체를 역상 관크로마토그래피하여 20mg(22.5%)의 노란색의 고체인 목적 화합물을 얻었다.Para-methoxybenzyl 7beta- [2- (2-tritylaminothiazol-4-yl) -2- (Z)-(methoxyimino) acetamido] -3-[(obtained from Example 1 E) -3-mg of Iodine-1-propenyl] -3-cepem-4-carboxylate was dissolved in 0.7 ml of N, N-dimethylformamide and 4- (5-methyl- [1,3,4]- 30 mg of oxadiazol-2-yl) -5,6,7,8-tetrahydroquinoline was added, followed by stirring at room temperature for 7 hours. After cooling with ice, distilled water was added, the mixture was stirred for 10 minutes, and filtered. The filtered solid was dissolved in 2 ml of methane dichloride and 1 ml of anisole, cooled with ice, 2 ml of trifluoroacetic acid was added and stirred for 3 hours. Solidified with ether, filtered and ethyl acetate was added to the filtered solid and filtered. The filtered solid was subjected to reverse phase column chromatography to give 20 mg (22.5%) of the title compound as a yellow solid.

1H-NMR(D2O) : 8.83, 8.34(각d, 각1H, J=6.5Hz), 6.97(s, 1H), 6.69(d, 1H, J=16.0Hz), 6.08(dt, 1H, J=16.0, 4.6Hz), 5.81(d, 1H, J=4.5Hz), 5.37(d, 2H, J=4.6Hz), 5.27(d, 1H, J=4.5Hz), 4.00(3H, s), 3.69(br.s, 2H), 3.34, 3.27(각 br.t, 각2H), 2.75(s, 3H), 2.04, 1.92(각 br.d, 각2H)1 H-NMR (D 2 O): 8.83, 8.34 (each d, each 1H, J = 6.5 Hz), 6.97 (s, 1H), 6.69 (d, 1H, J = 16.0 Hz), 6.08 (dt, 1H, J = 16.0, 4.6 Hz), 5.81 (d, 1H, J = 4.5 Hz), 5.37 (d, 2H, J = 4.6 Hz), 5.27 (d, 1H, J = 4.5 Hz), 4.00 (3H, s) , 3.69 (br.s, 2H), 3.34, 3.27 (each br.t, 2H each), 2.75 (s, 3H), 2.04, 1.92 (each br.d, 2H each)

[실시예 10]Example 10

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(히톡시이미노)아세트아미도]-3-[(E)-3-{4-(5-메틸-[1,3,4]옥사디아졸-2-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(methoxyimino) acetamido] -3-[(E) -3- {4- (5-methyl -[1,3,4] oxadiazol-2-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-carboxylate

실시예 2로부터 얻은 파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(트리틸옥시이미노)아세트아미도]-3-[(E)-3-요오드-1-프로페닐]-3-세펨-4-카르복실레이트 210mg을 톨루엔 2ml에 녹이고 0℃로 냉각시킨 후 4-(5-메틸-[1,3,4]-옥사디아졸-2-일)-5,6,7,8-테트라히드로퀴놀린 40mg을 가하였다. 상온에서 8시간 동안 교반한 후 증류수를 가하였다. 트리플루오르아세트산 1.3ml를 가하고 2시간 동안 교반한 다음 이소프로필에테르로 고체화하였다. 역상 관크로마토그래피하여 30mg(26%)의 고체인 목적 화합물을 얻었다.Para-methoxybenzyl 7beta- [2- (2-tritylaminothiazol-4-yl) -2- (Z)-(trityloxyimino) acetamido] -3- [obtained from Example 2 210 mg of (E) -3-iodine-1-propenyl] -3-cefe-4-carboxylate was dissolved in 2 ml of toluene, cooled to 0 ° C., and then 4- (5-methyl- [1,3,4]- 40 mg of oxadiazol-2-yl) -5,6,7,8-tetrahydroquinoline was added. After stirring for 8 hours at room temperature, distilled water was added. 1.3 ml of trifluoroacetic acid was added and stirred for 2 hours and then solidified with isopropyl ether. Reversed phase column chromatography gave 30 mg (26%) of the title compound as a solid.

1H-NMR(D2O) : 8.80, 8.32(각d, 각1H, J=6.4Hz), 7.04(s, 1H), 6.50(d, 1H, J=15.6Hz), 6.11(dt, 1H, J=5.3, 15.6Hz), 5.86(d, 1H, J=4.6Hz), 5.11(d, 1H, J=4.6Hz), 5.00(d, 2H, J=5.3Hz), 3.61(br.s, 2H), 3.11, 3.01(각t, 4H), 2.80(s, 3H), 2.09, 1.99(각각 br.d, 각각2H)1 H-NMR (D 2 O): 8.80, 8.32 (each d, each 1H, J = 6.4 Hz), 7.04 (s, 1H), 6.50 (d, 1H, J = 15.6 Hz), 6.11 (dt, 1H, J = 5.3, 15.6 Hz), 5.86 (d, 1H, J = 4.6 Hz), 5.11 (d, 1H, J = 4.6 Hz), 5.00 (d, 2H, J = 5.3 Hz), 3.61 (br.s, 2H), 3.11, 3.01 (t, 4H), 2.80 (s, 3H), 2.09, 1.99 (br.d, 2H each)

[실시예 11]Example 11

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-([1,3,4]옥사디아졸-2-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(methoxyimino) acetamido] -3-[(E) -3- {4-([1, 3,4] oxadiazol-2-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cefe-4-carboxylate

실시예 1로부터 얻은 파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(메톡시이미노)아세트아미도]-3-[(E)-3-요오드-1-프로페닐]-3-세펨-4-카르복실레이트 116mg을 무수 톨루엔 1ml에 녹이고 4-([1,3,4]-옥사디아졸-2-일)-5,6,7,8-테트라히드로퀴놀린 25mg을 가한 후 상온에서 2시간 40분, 이어서 40℃에서 4시간 20분 동안 교반하였다. 0℃로 냉각하고 생성된 고체를 여과한 후 상온에서 건조시켰다. 이 고체를 이염화메탄 1ml와 아니솔 0.5ml에 녹이고 얼음으로 냉각하여 트리플루오르아세트산 1.0ml를 가하고 2시간 30분 동안 교반하였다. 이염화메탄과 트리플루오르아세트산을 증발시키고 에테르로 고체화하고 여과하여 이 여과된 고체를 역상 관크로마토그래피하여 13mg(16.8%)의 미백색 고체인 목적화합물을 얻었다.Para-methoxybenzyl 7beta- [2- (2-tritylaminothiazol-4-yl) -2- (Z)-(methoxyimino) acetamido] -3-[(obtained from Example 1 E) -3-Iodide-1-propenyl] -3-cepem-4-carboxylate 116 mg was dissolved in 1 ml of anhydrous toluene and 4-([1,3,4] -oxadiazol-2-yl) -5 After 25 mg of 6,7,8-tetrahydroquinoline was added, the mixture was stirred at room temperature for 2 hours 40 minutes, and then at 40 ° C. for 4 hours 20 minutes. Cooled to 0 ℃ and the resulting solid was filtered and dried at room temperature. This solid was dissolved in 1 ml of methane dichloride and 0.5 ml of anisole, cooled with ice, 1.0 ml of trifluoroacetic acid was added, and stirred for 2 hours and 30 minutes. Methane dichloride and trifluoroacetic acid were evaporated, solidified with ether, filtered, and the filtered solid was subjected to reverse phase column chromatography to obtain 13 mg (16.8%) of an off-white solid.

1H-NMR(D2O) : 9.26(s, 1H), 8.87, 8.41(각d, 각1H, J=6.4Hz), 7.02(s, 1H), 6.68(d, 1H, J=15.6Hz), 6.10(dt, 1H, J=15.6, 4.7Hz), 5.83(d, 1H, J=4.7Hz), 5.40(d, 2H, J=4.7Hz), 5.29(d, 1H, J=4.7Hz), 4.02(s, 3H), 3.70(br.s, 2H,), 3.39, 3.28(br.s, 각2H), 2.04, 1.93(br.t 각2H)1H-NMR (D 2 O): 9.26 (s, 1H), 8.87, 8.41 (each d, each 1H, J = 6.4 Hz), 7.02 (s, 1H), 6.68 (d, 1H, J = 15.6 Hz) , 6.10 (dt, 1H, J = 15.6, 4.7 Hz), 5.83 (d, 1H, J = 4.7 Hz), 5.40 (d, 2H, J = 4.7 Hz), 5.29 (d, 1H, J = 4.7 Hz) , 4.02 (s, 3H), 3.70 (br.s, 2H,), 3.39, 3.28 (br.s, 2H each), 2.04, 1.93 (br.t each 2H)

[실시예 12]Example 12

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(히드록시이미노)아세트아미도]-3-[(E)-3-{4-([1,3,4]옥사디아졸-2-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(hydroxyimino) acetamido] -3-[(E) -3- {4-([1, 3,4] oxadiazol-2-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cefe-4-carboxylate

실시예 2로부터 얻은 파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(트리틸옥시이미노)아세트아미도]-3-[(E)-3-요오드-1-프로페닐]-3-세펨-4-카르복실레이트 280mg을 사염화탄소 3ml에 녹이고 0℃로 냉각시키고 4-([1,3,4]-옥사디아졸-2-일)-5,6,7,8-테트라히드로퀴놀린 49mg을 가한 후 30분간 교반하고 상온에서 12시간 동안 교반하였다. 증류수를 가한 후 석출된 고체를 여과하고 진공건조하였다. 이 고체를 아니솔 0.8ml에 녹이고 0℃로 냉각한 다음 트리플루오르아세트산 2ml를 가하여 3시간 동안 교반하고 이소프로필에테르로 고체화하였다. 역상 관크로마토그래피하여 40mg(27%)의 고체 목적물을 얻었다.Para-methoxybenzyl 7beta- [2- (2-tritylaminothiazol-4-yl) -2- (Z)-(trityloxyimino) acetamido] -3- [obtained from Example 2 280 mg of (E) -3-iodine-1-propenyl] -3-cefe-4-carboxylate was dissolved in 3 ml of carbon tetrachloride, cooled to 0 ° C. and 4-([1,3,4] -oxadiazole-2 49 mg of -yl) -5,6,7,8-tetrahydroquinoline was added thereto, followed by stirring for 30 minutes and stirring at room temperature for 12 hours. After adding distilled water, the precipitated solid was filtered and dried in vacuo. The solid was dissolved in 0.8 ml of anisole, cooled to 0 ° C., 2 ml of trifluoroacetic acid was added, stirred for 3 hours, and solidified with isopropyl ether. Reversed-phase column chromatography gave 40 mg (27%) of solid target product.

1H-NMR(D2O) : 9.11(s, 1H), 8.76, 8.29(각d, 각1H, J=6.5hz), 7.00(s, 1H), 6.40(d, 1H, J=15.6Hz), 6.14(dt, 1H, J=5.3, 15.6hz), 5.77(d, 1H, J=4.6Hz), 5.19(d, 1H, J=4.6Hz), 5.09(d, 2H, J=5.3Hz), 3.71(br.s, 2H), 3.10, 2.99(각t, 4H), 2.14, 1.99(각각 br.d, 각각2H)1H-NMR (D 2 O): 9.11 (s, 1H), 8.76, 8.29 (each d, 1H, J = 6.5hz), 7.00 (s, 1H), 6.40 (d, 1H, J = 15.6Hz) , 6.14 (dt, 1H, J = 5.3, 15.6 hz), 5.77 (d, 1H, J = 4.6 Hz), 5.19 (d, 1H, J = 4.6 Hz), 5.09 (d, 2H, J = 5.3 Hz) , 3.71 (br.s, 2H), 3.10, 2.99 (t, 4H), 2.14, 1.99 (br.d, 2H each)

[실시예 13]Example 13

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(메톡시이미노)아세트아미도]-3-[(E)-3-(2,3-시클로펜테노-4-메톡시-1-피리디노)-1-프로페닐]-3-세펨-4-카르복실레이트7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(methoxyimino) acetamido] -3-[(E) -3- (2,3-cyclophene Teno-4-methoxy-1-pyridino) -1-propenyl] -3-cepem-4-carboxylate

실시예 1로부터 얻은 파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(메톡시이미노)아세트아미도]-3-[(E)-3-요오드-1-프로페닐]-3-세펨-4-카르복실레이트 172mg을 톨루엔 2.5ml에 녹여 0℃로 냉각시키고 2,3-시클로펜테노-4-메톡시피리딘 27.6mg을 가한 후 30분간 교반하고 상온에서 3시간 동안 교반하였다. 석출된 고체를 여과하고 아니솔 0.4ml에 녹이고 0℃로 냉각한 다음 트리플루오르아세트산 1ml를 가하여 3시간 동안 교반하고 이소프로필에테르로 고체화하였다. 역상 관크로마토그래피하여 20mg(19%)의 고체 목적물을 얻었다.Para-methoxybenzyl 7beta- [2- (2-tritylaminothiazol-4-yl) -2- (Z)-(methoxyimino) acetamido] -3-[(obtained from Example 1 E) 172 mg of iodine-1-propenyl] -3-cefe-4-carboxylate was dissolved in 2.5 ml of toluene, cooled to 0 ° C., and 27.6 mg of 2,3-cyclopenteno-4-methoxypyridine was added. After the addition, the mixture was stirred for 30 minutes and stirred at room temperature for 3 hours. The precipitated solid was filtered, dissolved in 0.4 ml of anisole, cooled to 0 ° C., 1 ml of trifluoroacetic acid was added, stirred for 3 hours, and solidified with isopropyl ether. Reversed-phase column chromatography gave 20 mg (19%) of solid target.

1H-NMR(D2O) : 8.38, 7.32(각d, 각1H, J=7.3Hz), 7.0(s, 1H), 6.56(d, 1H, J=15.6Hz), 6.01(dt, 1H, J=5.3, 15.6Hz), 5.8(d, 1H, J=4.6Hz), 5.24(d, 1H, J=4.6Hz), 5.04(d, 2H, J=5.3Hz), 4.0, 4.1(각각s, 6H), 3.64(br.s, 2H), 3.01, 3.26(각t, 4H), 2.27(q, 2H)1 H-NMR (D 2 O): 8.38, 7.32 (each d, each 1H, J = 7.3 Hz), 7.0 (s, 1H), 6.56 (d, 1H, J = 15.6 Hz), 6.01 (dt, 1H, J = 5.3, 15.6 Hz), 5.8 (d, 1H, J = 4.6 Hz), 5.24 (d, 1H, J = 4.6 Hz), 5.04 (d, 2H, J = 5.3 Hz), 4.0, 4.1 (s , 6H), 3.64 (br.s, 2H), 3.01, 3.26 (t, 4H), 2.27 (q, 2H)

[실시예 14]Example 14

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(히드록시이미노)아세트아미도]-3-[(E)-3-(2,3-시클로펜테노-4-메톡시-1-피리디노)-1-프로페닐]-3-세펨-4-카르복실레이트7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(hydroxyimino) acetamido] -3-[(E) -3- (2,3-cyclophene Teno-4-methoxy-1-pyridino) -1-propenyl] -3-cepem-4-carboxylate

실시예 2로부터 얻은 파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(트리틸옥시이미노)아세트아미도]-3-[(E)-3-요오드-1-프로페닐]-3-세펨-4-카르복실레이트 167mg을 테트라하이드로푸란 2ml에 녹이고 2,3-시클로펜테노-4-메톡시피리딘 22mg을 가한 후 2시간 동안 교반하였다. 용매를 증발시키고 아니솔 0.6ml와 트리플루오르아세트산 1.2ml를 가하여 3시간 동안 교반하였다. 이소프로필에테르로 고체화시키고 다시 고체에 포름산 1ml를 가하고 1.5시간동안 교반하였다. 에테르로 고체화하고 역상 관크로마토그래피하여 7mg(8.5%)의 미백색 고체인 목적 화합물을 얻었다.Para-methoxybenzyl 7beta- [2- (2-tritylaminothiazol-4-yl) -2- (Z)-(trityloxyimino) acetamido] -3- [obtained from Example 2 (E) -3-Iodine-1-propenyl] -3-cefe-4-carboxylate was dissolved in 2 ml of tetrahydrofuran and 2 mg of 2,3-cyclopenteno-4-methoxypyridine was added for 2 hours. Was stirred. The solvent was evaporated and 0.6 ml of anisole and 1.2 ml of trifluoroacetic acid were added and stirred for 3 hours. Solidified with isopropyl ether, 1 ml of formic acid was added to the solid and stirred for 1.5 hours. Solidification with ether and reverse phase column chromatography gave 7 mg (8.5%) of an off-white solid as the target compound.

1H-NMR(D2O) : 8.41, 7.34(각d, 각1H, J=7Hz), 7.0(s, 1H), 6.57(d, 1H, J=15.6Hz), 6.05(dt, 1H, J=15.6, 5.9Hz), 5.86(d, 1H, J=4.5Hz), 5.07(d, 2H, J=5.9), 4.1(s, 3H), 3.64(br.s, 2H), 3.01, 3.25(각t, 4H), 2.27(q, 2H)1 H-NMR (D 2 O): 8.41, 7.34 (each d, each 1H, J = 7 Hz), 7.0 (s, 1H), 6.57 (d, 1H, J = 15.6 Hz), 6.05 (dt, 1H, J = 15.6, 5.9 Hz), 5.86 (d, 1H, J = 4.5 Hz), 5.07 (d, 2H, J = 5.9), 4.1 (s, 3H), 3.64 (br.s, 2H), 3.01, 3.25 ( T, 4H), 2.27 (q, 2H)

[실시예 15]Example 15

7베타-[2-(2-아미노티아졸-4-일)-2-(Z)-(메톡시이미노)아세트아미도]-3-[(E)-3-(2,3-시클로펜테노-4-메톡시-1-피리디노)-1-프로페닐]-3-세펨-4-카르복실레이트7beta- [2- (2-aminothiazol-4-yl) -2- (Z)-(methoxyimino) acetamido] -3-[(E) -3- (2,3-cyclophene Teno-4-methoxy-1-pyridino) -1-propenyl] -3-cepem-4-carboxylate

파라-메톡시벤질 7베타-[2-(2-트리틸아미노티아졸-4-일)-2-(Z)-(플루오르에톡시이미노)아세트아미도]-3-[(Z)-3-클로로-1-프로페닐]-3-세펨-4-카르복실레이트 184mg과 요오드화나트륨 97mg을 아세톤 2ml에 녹이고 1시간 동안 교반하였다. 아세톤을 증발시키고 초산에틸로 희석하고 10% 나트륨티오설파이드와 포화 염수로 차례로 씻어주고 무수 황산마그네슘으로 처리한 후 용매를 증발시켜 190mg의 1-프로페닐요오드화 세펨을 얻었다. 이 화합물을 톨루엔 2.5ml에 녹이고 2,3-시클로펜테노-4-메톡시피리딘 30mg을 가한 후 2시간 동안 교반하였다. 석출된 고체를 여과하여 168mg의 조 화합물을 얻었다. 이중 151mg을 아니솔 0.5ml와 트리플루오르아세트산 1.5를 가하고 3시간 동안 교반하였다. 이소프로필에테르로 고체화하고 역상 관 크로마토그래피하여 25mg(20.6%)의 미백색 고체인 목적 화합물을 얻었다.Para-methoxybenzyl 7beta- [2- (2-tritylaminothiazol-4-yl) -2- (Z)-(fluoroethoxyimino) acetamido] -3-[(Z) -3 184 mg of -chloro-1-propenyl] -3-cepem-4-carboxylate and 97 mg of sodium iodide were dissolved in 2 ml of acetone and stirred for 1 hour. Acetone was evaporated, diluted with ethyl acetate, washed sequentially with 10% sodium thiosulfide and saturated brine, treated with anhydrous magnesium sulfate, and the solvent was evaporated to obtain 190 mg of 1-propenyl iodide cefe. The compound was dissolved in 2.5 ml of toluene, 30 mg of 2,3-cyclopenteno-4-methoxypyridine was added, followed by stirring for 2 hours. The precipitated solid was filtered to give 168 mg of crude compound. 151 mg of this was added 0.5 ml of anisole and 1.5 of trifluoroacetic acid and stirred for 3 hours. Solidification with isopropyl ether and reverse phase column chromatography gave 25 mg (20.6%) of the title compound as an off-white solid.

1H-NMR(D2O) : 8.35, 7.28(각d, 각1H, J=7.Hz), 7.00(s, 1H), 6.54(d, 1H, J=16Hz), 5.99(dt, 1H, J=6, 16hz), 5.80(d, 1H, J=4.2Hz), 5.23(d, 1H, J=4.2Hz), 5.01(d, 2H, J=6Hz), 4.82(m, 2H), 4.4, 4.50(m, 2H), 4.08(s, 3H), 3.62(br.s, 2H), 2.98, 3.23(각t, 4H), 2.24(q, 2H)1 H-NMR (D 2 O): 8.35, 7.28 (each d, each 1H, J = 7.Hz), 7.00 (s, 1H), 6.54 (d, 1H, J = 16 Hz), 5.99 (dt, 1H, J = 6, 16hz), 5.80 (d, 1H, J = 4.2Hz), 5.23 (d, 1H, J = 4.2Hz), 5.01 (d, 2H, J = 6Hz), 4.82 (m, 2H), 4.4 , 4.50 (m, 2H), 4.08 (s, 3H), 3.62 (br.s, 2H), 2.98, 3.23 (t, 4H), 2.24 (q, 2H)

본 발명에 의한 일반식(Ⅰ)로 표시되는 (E)-프로페닐 4급 암모늄 세펨 화합물 및 그들의 제조방법에 의해 그람 양성균이나 그람 음성균에 우수한 항균력을 가진 세팔로스포린 계열 의약품이 개발되었으므로 앞으로 유용하게 사용될 수 있을 것이다.The cephalosporin-based pharmaceuticals having excellent antimicrobial activity against Gram-positive bacteria or Gram-negative bacteria have been developed by the (E) -propenyl quaternary ammonium cefem compound represented by the general formula (I) according to the present invention and their preparation method. Could be used.

Claims (10)

일반식(Ⅰ)로 표시되는 (E)-프로페닐 4급 암모늄 세펨 화합물 및 약제학적으로 허용되는 염(E) -propenyl quaternary ammonium cefem compound represented by general formula (I) and a pharmaceutically acceptable salt 일반식(Ⅰ)에 있어서, R1은 수소, 포밀, t-부톡시카르보닐, 벤질옥시카르보닐, 파라-니트로벤질옥시카르보닐 또는 트리틸을 표시하며, R2는 수소, 메틸, 2-플루오르에틸, 포밀, 클로로아세틸, 벤조일, 파라-니트로벤질, 2,2,2-트리클로로에톡시카르보닐, 테트라히드로피라닐 또는 트리틸을 표시하며, R3는 수소, 카르복실산염 형성기, 2,2,2-트리클로로에틸, 파라-메톡시벤질, 파라-니트로벤질, 벤즈히드릴 또는 t-부틸을 표시하며, R4는 메톡시, 치환체를 가진 카바모일, 옥사디아졸 또는 트리아졸로 표시되는 5환 헤테로고리 치환체를 표시하며, n은 1 또는 2를 표시한다.In formula (I), R 1 represents hydrogen, formyl, t-butoxycarbonyl, benzyloxycarbonyl, para-nitrobenzyloxycarbonyl or trityl, and R 2 represents hydrogen, methyl, 2- Fluoroethyl, formyl, chloroacetyl, benzoyl, para-nitrobenzyl, 2,2,2-trichloroethoxycarbonyl, tetrahydropyranyl or trityl, R 3 represents hydrogen, carboxylate forming group, 2 , 2,2-trichloroethyl, para-methoxybenzyl, para-nitrobenzyl, benzhydryl or t-butyl, R 4 is methoxy, carbamoyl with substituents, oxadiazole or triazole A 5-membered heterocyclic substituent to be represented, n represents 1 or 2. 제1항에 있어서, 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-(4-카바모일-5,6,7,8-테트라히드로-1-퀴놀리노)-1-프로페닐]-3-세펨-4-카르복실레이트;The method of claim 1, wherein 7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- ( 4-carbamoyl-5,6,7,8-tetrahydro-1-quinolino) -1-propenyl] -3-cepem-4-carboxylate; 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(히드록시이미노)아세트아미도]-3-[(E)-3-(4-카바모일-5,6,7,8-테트라히드로-1-퀴놀리노)-1-프로페닐]-3-세펨-4-카르복실레이트;7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (hydroxyimino) acetamido] -3-[(E) -3- (4-carbamoyl-5 , 6,7,8-tetrahydro-1-quinolino) -1-propenyl] -3-cepem-4-carboxylate; 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-(N'-포밀히드라지노카르보닐)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트;7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- {4- (N'- Formylhydrazinocarbonyl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cefe-4-carboxylate; 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(히드록시이미노)아세트아미도]-3-[(E)-3-{4-(N'-포밀히드라지노카르보닐)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트;7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (hydroxyimino) acetamido] -3-[(E) -3- {4- (N'- Formylhydrazinocarbonyl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cefe-4-carboxylate; 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-(N'-아세틸히드라지노카르보닐)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트;7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- {4- (N'- Acetylhydrazinocarbonyl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cefe-4-carboxylate; 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(히드록시이미노)아세트아미도]-3-[(E)-3-{4-(N'-아세틸히드라지노카르보닐)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트;7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (hydroxyimino) acetamido] -3-[(E) -3- {4- (N'- Acetylhydrazinocarbonyl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cefe-4-carboxylate; 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-(5-메틸-2H-[1,2,4]트리아졸-3-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트;7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- {4- (5-methyl -2H- [1,2,4] triazol-3-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-carboxylate ; 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(히드록시이미노)아세트아미도]-3-[(E)-3-{4-(5-메틸-2H-[1,2,4]트리아졸-3-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트;7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (hydroxyimino) acetamido] -3-[(E) -3- {4- (5-methyl -2H- [1,2,4] triazol-3-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-carboxylate ; 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-([1,3,4]옥사디아졸-2-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트;7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- {4-([1, 3,4] oxadiazol-2-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cefe-4-carboxylate; 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(히드록시이미노)아세트아미도]-3-[(E)-3-{4-([1,3,4]옥사디아졸-2-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트;7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (hydroxyimino) acetamido] -3-[(E) -3- {4-([1, 3,4] oxadiazol-2-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cefe-4-carboxylate; 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-{4-(5-메틸-[1,3,4]옥사디아졸-2-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트;7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- {4- (5-methyl -[1,3,4] oxadiazol-2-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-carboxylate; 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(히드록시이미노)아세트아미도]-3-[(E)-3-{4-(5-메틸-[1,3,4]옥사디아졸-2-일)-5,6,7,8-테트라히드로-1-퀴놀리노}-1-프로페닐]-3-세펨-4-카르복실레이트;7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (hydroxyimino) acetamido] -3-[(E) -3- {4- (5-methyl -[1,3,4] oxadiazol-2-yl) -5,6,7,8-tetrahydro-1-quinolino} -1-propenyl] -3-cepem-4-carboxylate; 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(메톡시이미노)아세트아미도]-3-[(E)-3-(4-메톡시-2,3-시틀로펜테노-1-피리디노)-1-프로페닐]-3-세펨-4-카르복실레이트;7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (methoxyimino) acetamido] -3-[(E) -3- (4-methoxy-2 , 3-cytopenteno-1-pyridino) -1-propenyl] -3-cepem-4-carboxylate; 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(히드록시이미노)아세트아미도]-3-[(E)-3-(4-메톡시-2,3-시틀로펜테노-1-피리디노)-1-프로페닐]-3-세펨-4-카르복실레이트 또는 7베타-[2-(2-아미노티아졸-4-일)-(Z)-2-(플루오르에톡시이미노)아세트아미도]-3-[(E)-3-(4-메톡시-2,3-시틀로펜테노-1-피리디노)-1-프로페닐]-3-세펨-4-카르복실레이트로 이루어진 일반식(Ⅰ)로 표시되는 세팔로스포린 화합물 및 약제학적으로 허용되는 염7beta- [2- (2-aminothiazol-4-yl)-(Z) -2- (hydroxyimino) acetamido] -3-[(E) -3- (4-methoxy-2 , 3-Cyclopenteno-1-pyridino) -1-propenyl] -3-cepem-4-carboxylate or 7beta- [2- (2-aminothiazol-4-yl)-(Z ) -2- (fluoroethoxyimino) acetamido] -3-[(E) -3- (4-methoxy-2,3-cytopenteno-1-pyridino) -1-propenyl] Cephalosporin compound represented by general formula (I) consisting of -3-cefe-4-carboxylate and a pharmaceutically acceptable salt 일반식(Ⅱ)로 표시되는 티아졸계 클로로화합물과 3당량의 NaI를 용매하에 반응시켜(E)형태의 일반식(Ⅲ)으로 표시되는 티아졸계 요오드화합물을 제조하는 제1공정과 일반식(Ⅲ)으로 표시되는 티아졸계 요오드화합물과 일반식(Ⅳ)로 표시되는 아민화합물을 짝지움 반응으로 일반식(Ⅰa)로 표시되는 보호기가 있는 (E)-프로페닐 4급 암노늄 세펨을 제조하는 제2공정 및 일반식(Ⅰa)로 표시되는 보호기가 있는 (E)-프로페닐 4급 암모늄 세펨을 용매하에 탈보호 반응시켜 일반식(Ⅰb)로 표시되는 보호기가 없는 (E)-프로페닐 4급 암모늄 세펨의 제조방법.The first step and the general formula (III) of preparing a thiazole iodine compound represented by formula (III) in the form (E) by reacting a thiazole chloro compound represented by formula (II) with 3 equivalents of NaI in a solvent (E) A process for preparing (E) -propenyl quaternary ammonium cefem having a protecting group represented by formula (Ia) by coupling a thiazole iodine compound represented by) to an amine compound represented by formula (IV). Step 2 and (E) -propenyl quaternary without protecting group represented by formula (Ib) by deprotection reaction of (E) -propenyl quaternary ammonium cefem with protecting group represented by formula (Ia) in solvent Method for preparing ammonium cefem. 상기식들에 있어서, R1은 수소 또는 아민보호기를 표시하며, R2는 수소, 메틸, 2-플루오르에틸 또는 옥심보호기를 표시하며, R3는 수소, 카르복실산염 형성기 또는 카르복실 보호기를 표시하며, R4는 메톡시, 치환체를 가진 카바모일, 옥사디아졸 또는 트리아졸로 표시되는 5환 헤테로고리 치환체를 표시하며, n은 1 또는 2를 표시한다.In the above formulas, R 1 represents hydrogen or an amine protecting group, R 2 represents hydrogen, methyl, 2-fluoroethyl or oxime protecting group, and R 3 represents hydrogen, carboxylate forming group or carboxyl protecting group. R 4 represents a 5-membered heterocyclic substituent represented by methoxy, carbamoyl having substituents, oxadiazole or triazole, and n represents 1 or 2. 제3항에 있어서, 제1공정에서의 용매가 아세톤, N,N-디메틸포름아미드 또는 아세토니트릴인 것이 특징인 일반식(Ⅰb)로 표시되는 (E)-프로페닐 4급 암모늄 세펨의 제조방법.4. The process for producing (E) -propenyl quaternary ammonium cefme represented by formula (Ib) according to claim 3, wherein the solvent in the first step is acetone, N, N-dimethylformamide or acetonitrile. . 제3항에 있어서, 제1공정의 반응이 0∼30℃에서 0.5∼2시간 동안 수행하는 것이 특징인 일반식(Ⅰb)로 표시되는 보호기가 없는 (E)-프로페닐 4급 아모늄 세펨의 제조방법.4. The (E) -propenyl quaternary ammonium cefem having no protecting group represented by the general formula (Ib) according to claim 3, wherein the reaction of the first step is carried out at 0-30 占 폚 for 0.5-2 hours. Manufacturing method. 제3항에 있어서, 제2공정에서의 용매가 초산에틸, N,N-디메틸포름아미드, 이염화메탄, 테트라히드로푸란, 사염화탄소, 톨루엔, 클로로포름, 아세토니트릴, 디옥산, 물 또는 아세톤인 것이 특징인 일반식(Ⅰb)로 표시되는 보호기가 없는 (E)-프로페닐 4급 암모늄 세펨의 제조방법.4. A solvent according to claim 3, wherein the solvent in the second step is ethyl acetate, N, N-dimethylformamide, methane dichloride, tetrahydrofuran, carbon tetrachloride, toluene, chloroform, acetonitrile, dioxane, water or acetone. A process for producing (E) -propenyl quaternary ammonium cefem without protecting group represented by phosphorus general formula (Ib). 제3항에 있어서, 제2공정의 반응이 -30∼50℃에서 2∼6시간 동안 수행하는 것이 특징인 일반식(Ⅰb)로 표시되는 (E)-프로페닐 4급 암모늄 세펨의 제조방법.The method for producing (E) -propenyl quaternary ammonium cefme according to claim 3, wherein the reaction of the second step is performed at -30 to 50 ° C for 2 to 6 hours. 제3항에 있어서, 제3공정에서의 탈보호제가 트리플루오르아세트산, 염화알루미늄, 파라-톨루엔설폰산, 염산, 포밀산, 트리메틸실릴 요오드, 아연과 아세트산 또는 페놀인 것이 특징인 일반식(Ⅰb)로 표시되는 보호기가 없는 (E)-프로페닐 4급 암모늄 세펨의 제조방법.4. The general formula (Ib) according to claim 3, wherein the deprotecting agent in the third step is trifluoroacetic acid, aluminum chloride, para-toluenesulfonic acid, hydrochloric acid, formic acid, trimethylsilyl iodine, zinc and acetic acid or phenol. Method for producing (E) -propenyl quaternary ammonium cefme without protecting group represented by. 제3항에 있어서, 제3공정에서의 용매가 아니솔, 이염화메탄, 아세트산, 테트라히드로푸란, 메탄올, N,N-대메틸포름아미드, 물, 클로로포름, 디옥산, 아세토니트릴 또는 아세톤인 것이 특징인 일반식(Ⅰb)로 표시되는 보호기가 없는 (E)-프로페닐 4급 암모늄 세펨의 제조방법.4. The method of claim 3, wherein the solvent in the third step is anisole, methane dichloride, acetic acid, tetrahydrofuran, methanol, N, N-tomethylformamide, water, chloroform, dioxane, acetonitrile or acetone. A process for producing (E) -propenyl quaternary ammonium cefem without protecting group represented by the general formula (Ib). 제3항에 있어서, 제3공정의 탈보호 반응이 -30∼50℃에서 1∼2시간 동안 수행하는 것이 특징인 일반식(Ⅰb)로 표시되는 보호기가 없는 (E)-프로페닐 4급 암모늄 세펨의 제조방법.4. The (E) -propenyl quaternary ammonium having no protecting group represented by formula (Ib) according to claim 3, wherein the deprotection reaction of the third step is performed at -30 to 50 DEG C for 1 to 2 hours. Method of manufacturing cefem.
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