KR870001807B1 - Process for preparing 3-vinyl-cephalosporin derivatives - Google Patents
Process for preparing 3-vinyl-cephalosporin derivatives Download PDFInfo
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- KR870001807B1 KR870001807B1 KR1019850006544A KR850006544A KR870001807B1 KR 870001807 B1 KR870001807 B1 KR 870001807B1 KR 1019850006544 A KR1019850006544 A KR 1019850006544A KR 850006544 A KR850006544 A KR 850006544A KR 870001807 B1 KR870001807 B1 KR 870001807B1
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- 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
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Abstract
Description
본 발명은 세팔로스포린의 유도체인 구조식(I)의 7-[2-(2-아미노 티아졸-4일)-2-(카르복시 메톡시 이미노) 아세트 아미도]-3-비닐-3-세펨-4-카르복실산의 제조방법에 관한 것이다.The present invention provides 7- [2- (2-aminothiazol-4yl) -2- (carboxymethoxy imino) acet amido] -3-vinyl-3- of formula (I) which is a derivative of cephalosporin. A method for producing cefem-4-carboxylic acid.
본 발명의 목적 화합물인 상기 구조식(I)의 화합물은 공지의 화합물로서 광범위한 항균 스펙트럼을 갖는 경구용 세팔로스포린 제제이다.The compound of formula (I), which is the target compound of the present invention, is an oral cephalosporin preparation having a broad antibacterial spectrum as a known compound.
특히, 장내균속, 구연산 생성균속, 세라티아속, 그리고 인돌양성 변형균에 우수한 항균력을 나타내며 세팔렉신이나 아목시실린에 내성을 나타내는 대장균, 폐렴균 등에도 항균 활성을 나타낸다.In particular, it exhibits excellent antibacterial activity against intestinal bacteria, citric acid producing bacteria, Serratia, and indole-positive bacteria, and E. coli and pneumococci, which are resistant to cephalexin or amoxicillin.
상기 구조식(I)의 화합물을 제조하는 방법은 일본 공개특허 제81-86187호에 기재되어 있는데, 그 제조방법은 구조식(II)의 7-아실아미도-3-하이드록시 메칠-3-세펨-4-카르복실산의 에스테르를 오염화인과 반응시켜 구조식(III)의 7-아실아미도-3-클로로메틸-3-세펨-4-카르복실산 에스테르를 만들고 이를 트리페닐포스핀과 반응시켜 구조식(IV)의 포스포니움 염을 만든 후, 포름알데히드와 위티그 반응을 시켜 구조식(V)의 7-아실아미도-3-베닐-3-세펨-4-카르복실산 에스테르를 얻었다.A process for preparing the compound of formula (I) is described in Japanese Patent Application Laid-Open No. 81-86187, which method is used for preparing 7-acylamido-3-hydroxymethyl-3-cefem- of formula (II). Reacting the ester of 4-carboxylic acid with phosphorus pentachloride to form 7-acylamido-3-chloromethyl-3-cepem-4-carboxylic acid ester of formula (III) and reacting it with triphenylphosphine After the phosphonium salt of (IV) was prepared, 7-acylamido-3-benyl-3-cepem-4-carboxylic acid ester of the structural formula (V) was obtained by reacting Wittig with formaldehyde.
이 에스테르 화합물을 오염화인을 사용하여 탈아실화하여 구조식(VI)의 7-아미노-3-비닐-3-세펨-4-카르복실산에스테르를 만든 후,This ester compound was deacylated with phosphorus pentachloride to produce 7-amino-3-vinyl-3-cefe-4-carboxylic acid ester of formula (VI),
구조식(VII)의 카르복실산 유도체와 반응시켜 구조식(VIII)의 화합물을 얻은 후, 카르복실기 보호기와 아미노기 보호기를 제거하여 목적화합물인 구조식(I)의 화합물을 만들었다.After reacting with the carboxylic acid derivative of formula (VII) to obtain a compound of formula (VIII), the carboxyl protecting group and the amino group protecting group were removed to form a compound of formula (I) as a target compound.
그러나 상기 제조방법을 검토해보면 출발물질인 3-하이드록시 메틸세펨이 고가이고 그리고 위티그 반응시 염기성 수용액에서 반응을 시킴으로써 이 반응조건에서 약한 베타락탐환이 파괴되는 부반응이 일어나 반응수득율이 낮아지는 결점이 있다.However, if the above method is examined, 3-hydroxymethylcefem, which is a starting material, is expensive and a side reaction occurs in which a weak beta lactam ring is destroyed under the reaction conditions in a basic aqueous solution. have.
본 발명은 이상의 단점을 보완하여 보다 간편하고도 높은 수득율로 목적화합물을 제조함에 그특징이 있다.The present invention has the characteristics of preparing the target compound with a simpler and higher yield by supplementing the above disadvantages.
즉, 공지의 화합물인 구조식(IX)의 2-[(2-트리클로로)에톡시 카르보닐 아미노티아졸-4-일]-2-[(2-트리클로로)에톡시 카르보닐 메틸옥시 아미노] 아세트산(Syn-이성체)을 벤조설피마이드와 축합하여 활성화된 아마이드인 구조식(X)의 화합물(Syn-이성체)을 용액상태로 얻은 후 분리함이 없이 구조식(XI) 또는 구조식(XII)의 화합물과 반응시켜 구조식(XIII)의 화합물(Syn-이성체)을 만든 후 아연과 산으로 각 보호기를 동시에 제거함으로써 목적화합물인 구조식(I)(Syn-이성체)의 화합물을 고수율로 얻을 수 있었다.That is, 2-[(2-trichloro) ethoxy carbonyl aminothiazol-4-yl] -2-[(2-trichloro) ethoxy carbonyl methyloxy amino] of the formula (IX) which is a known compound Acetic acid (Syn-isomer) is condensed with benzosulfamide to obtain the activated amide compound (Syn-isomer) in solution, and then separated from the compound of formula (XI) or (XII) without separation. By reacting to form compound (Syn-isomer) of structural formula (XIII), the compound of structural formula (I) (Syn-isomer) as a target compound was obtained in high yield by simultaneously removing each protecting group with zinc and acid.
(상기 구조식에서 R2는 수소 혹은 트리클로로 에틸기이다)(Wherein R 2 is hydrogen or trichloroethyl group)
여기서 상기 구조식(XI)의 화합물은 공지의 화합물인 구조식(XIV)의 7-펜옥시 아세트 아미도-3-엑소 메틸렌 세펨-4-카르복실산 트리클로로에틸에스테르를 유기용매중에서 구조식(XV)의 이미니움염과 반응시켜 구조식(XVI)의 비닐로거스 만니히염기(Vinylogous Mannich base)를 만들고 이를 분리하지 않고 바로 탈리반응시켜 구조식(XVII)의 7-아실아미도-3-비닐-3-세펨-4-카르복실산 트리클로로 에틸 에스테르를 만든 후 탈아실화하여 만들고,Wherein the compound of formula (XI) is a known compound of 7-phenoxy acetamido-3-exo methylene cefe-4-carboxylic acid trichloroethyl ester of formula (XIV) in an organic solvent of formula (XV) Reaction with iminium salts to form a vinyllogus mannich base of formula (XVI) and desorption immediately without separation to 7-acylamido-3-vinyl-3-cefe of formula (XVII) Made by 4-carboxylic acid trichloro ethyl ester followed by deacylation,
구조식(XII)의 화합물은 구조식(XI)의 화합물의 제조방법과 동일한 제조방법으로 만들어진 구조식(XVII)의 화합물을 아연으로 탈에스테르화하여 구조식(XVIII)의 7-아실아미도-3-비닐-3-세펨-4-카르복실산을 만든후 아미다아제(Amidase)로 탈 아실화하여 만든다.The compound of formula (XII) is 7-acylamido-3-vinyl- of formula (XVIII) by de-esterification with zinc of the compound of formula (XVII) made in the same manner as the preparation of the compound of formula (XI). 3-cefem-4-carboxylic acid is prepared and then deacylated with amidase.
이상에서 살펴본 본 발명은 3위의 비닐기를 도입할 때 종래의 물, 유기용매의 이성분계상에서의 반응을 유기용매 속에서 진행시킴으로써 베타 락탐환이 분해되는 등의 부반응이 일어나는 것을 막을 수 있고 또 아실화활때 카르복실산 활성화 그룹으로 사카린을 이용함으로써 반응조건이 완화되고 그리고 산중화제를 사용하지 않고 반응을 시킴으로써 공정이 간편하고 수득율이 높으며 생성물의 순도 또한 매우 높은 장점이 있으며, 한편, 탈 아실화할때 아미다아제를 사용함으로써 공정이 간편하고 반응부산물이 적고 수득율이 높으며 특히 순도가 높아 그 다음 단계의 아실화 반응에서의 수득율 및 순도가 높은 장점이 있다.The present invention as described above can prevent side reactions such as decomposition of beta lactam ring to occur by proceeding the reaction on the binary system of water and organic solvent in the conventional solvent when introducing the vinyl group of the third position and acylation The use of saccharin as the carboxylic acid activating group for activating reduces the reaction conditions, and the reaction is simplified and the yield is high, and the purity of the product is also very high. By using an amidase, there is an advantage in that the process is simple, there are few reaction byproducts, the yield is high, and in particular, the purity is high, and the yield and purity in the next acylation reaction are high.
이하 실시예에서 본 발명을 보다 상세히 설명하기로 한다.In the following Examples will be described the present invention in more detail.
[실시예 1]Example 1
7-펜옥시 아세트 아미도-3-비닐-3-세펨-4-카르복실산 트리클로로에틸 에스테르의 제조.Preparation of 7-phenoxy acet amido-3-vinyl-3-cepem-4-carboxylic acid trichloroethyl ester.
디메톡시에탄 100ml에 7-펜옥시 아세트 아미도-3-엑소메틸렌세펨-4-카르복실산 트리클로로 에틸에스테르 4.8g을 가한 후 -10℃로 냉각시키고 건조 질소 기류를 통하면서 1.8-디아자 비사이클로[5.4.0]운덱-7-엔 1.65ml를 가한 후 디메틸(메틸렌)암모니움 아이오다이드 2.04g을 가한다. 5℃에서 2시간 교반하고, 건조염산 가스를 포화시킨 후 4시간 환류교반한 후 용매를 감압으로 날려 보낸다.4.8 g of 7-phenoxy acet amido-3-exomethylenecefe-4-carboxylic acid trichloroethyl ester was added to 100 ml of dimethoxyethane, followed by cooling to -10 DEG C and 1.8-diaza ratio through a dry nitrogen stream. 1.65 ml of cyclo [5.4.0] undec-7-ene is added followed by 2.04 g of dimethyl (methylene) ammonium iodide. After stirring at 5 ° C. for 2 hours, the hydrochloric acid gas was saturated, and the mixture was stirred under reflux for 4 hours, and then the solvent was blown off at reduced pressure.
잔사에 디클로로 메탄 100ml를 넣어 녹인 후 물 100ml를 넣어 교반후 유기층을 분리해낸다. 유기층을 10% 염산수용액 100ml로 2회 세척후 마그네슘 설페이트로 건조하고 용매를 날려 생성된 오일상의 잔사에틸 아세테이트 20ml를 가하고 0℃에서 2시간 교반하여 생성된 고체를 여과하고 이소프로필 에테르로 세척하면 엷은 갈색의 7-펜옥시아세트아미도-3-비닐-3-세펨-4-카르복실산 트리클로로 에틸 에스테르 3.53g(수득율 72%)를 얻는다.100 ml of dichloromethane was added to the residue to dissolve it, and 100 ml of water was added thereto, followed by stirring. The organic layer was washed twice with 100 ml of 10% aqueous hydrochloric acid solution, dried over magnesium sulfate and blown with a solvent to add 20 ml of oily residue ethyl acetate, which was stirred at 0 ° C. for 2 hours, and the resulting solid was filtered and washed with isopropyl ether. 3.53 g (72% yield) of brown 7-phenoxyacetamido-3-vinyl-3-cepem-4-carboxylic acid trichloro ethyl ester are obtained.
[실시예 2]Example 2
7-펜옥시 아세트 아미도-3-비닐-3-세펨-4-카르복실산의 제조Preparation of 7-phenoxy acet amido-3-vinyl-3-cepem-4-carboxylic acid
아세토니트릴 60ml와 물 10ml의 혼합용매에 7-펜옥시 아세트아미도-3-비닐-3-세펨-4-카르복실산트리클로로 에틸 에스테르 4.92g을 넣어 녹이고 5℃로 냉각한 후 아연 6.5g과 진한 염산 10.8ml를 넣고 90분간 교반한다. 반응액을 여과하고 여액을 암모니아수로 pH4.5로 맞추고 5℃에서 2시간 교반하고 침전을 여과한 후 아세토니트릴로 세척하고 건조하면 엷은 갈색의 7-펜옥시 아세트 아미도-3-비닐-3-세펨-4-카르복실산 3.0g(수득율 83%)을 얻는다.4.92 g of 7-phenoxy acetamido-3-vinyl-3-cepem-4-carboxylic acid trichloro ethyl ester was dissolved in a mixed solvent of 60 ml of acetonitrile and 10 ml of water, and cooled to 5 ° C., followed by 6.5 g of zinc and Add 10.8 ml of concentrated hydrochloric acid and stir for 90 minutes. The reaction solution was filtered, the filtrate was adjusted to pH4.5 with ammonia water, stirred at 5 ° C. for 2 hours, the precipitate was filtered off, washed with acetonitrile and dried to give a pale brown 7-phenoxy acetamido-3-vinyl-3- 3.0 g (83% yield) of cefem-4-carboxylic acid are obtained.
[실시예 3]Example 3
7-아미노-3-비닐-3-세펨-4-카르복실산트리클로로 에틸 에스테르 염산염의 제조방법.Process for the preparation of 7-amino-3-vinyl-3-cepem-4-carboxylic acid trichloro ethyl ester hydrochloride.
디클로로 메탄 50ml에 트리페닐포스파이트 4.13g을 용해시키고 -10℃로 냉각한 후 염소가스를 천천히 통과시킨다.4.13 g of triphenylphosphite was dissolved in 50 ml of dichloromethane, cooled to -10 ° C, and slowly passed chlorine gas.
이 용액에 7-펜옥시 아세트 아미도-3-비닐-3-세펨-4-카르복실산 트리클로로 에틸 에스테르 4.91g을 넣어 15분간 교반한 후 피리딘 1.2ml를 넣고 온도를 실온으로 올린다.4.91 g of 7-phenoxy acetamido-3-vinyl-3-cepem-4-carboxylic acid trichloro ethyl ester was added to the solution, followed by stirring for 15 minutes. Then, 1.2 ml of pyridine was added and the temperature was raised to room temperature.
실온에서 1시간 교반한 후 7ml의 이소부틸 알코올을 넣고 1시간 교반하고 여과하면 흰색의 7-아미노-3-비닐-3-세펨-4-카르복실산 트리클로로에틸 에스테르 염산염 2.84g(수득율 : 72%)을 얻는다.After stirring for 1 hour at room temperature, 7 ml of isobutyl alcohol was added thereto, and the mixture was stirred for 1 hour and filtered. Then, 2.84 g of white 7-amino-3-vinyl-3-cepem-4-carboxylic acid trichloroethyl ester hydrochloride (yield: 72 %)
[실시예 4]Example 4
7-아미노-3-비닐-3-세펨-4-카르복실산의 제조Preparation of 7-amino-3-vinyl-3-cepem-4-carboxylic acid
물 50ml에 7-펜옥시 아세트 아미도-3-비닐-3-세펨-4-카르복실산 3.6g을 넣고 아미다아제 1.5g을 넣은 후 1N 암모니아 수용액을 가해 pH7로 맞춘다. 반응 온도를 28±0.5℃로 유지하면서 1N 암모니아 수용액으로 pH8이 되게 유지하고 강교반한다.To 50 ml of water, add 3.6 g of 7-phenoxy acetamido-3-vinyl-3-cepem-4-carboxylic acid, add 1.5 g of amidase, and add 1N aqueous ammonia to pH 7. While maintaining the reaction temperature at 28 ± 0.5 ℃ to maintain a pH of 8 with 1N aqueous ammonia solution and stirred.
반응액의 pH가 더이상 변화하지 않을때 반응을 끝내고 반응액을 여과한다.When the pH of the reaction solution no longer changes, complete the reaction and filter the reaction solution.
메틸알코올 50ml를 가하고 진한 염산으로 pH4.0으로 맞추고 생성된 침전을 여과하고 건조하면 흰색의 7-아미노-3-비닐-3-세펨-4-카르복실산 1.92g(수득율 : 85%)을 얻는다.50 ml of methyl alcohol is added, adjusted to pH 4.0 with concentrated hydrochloric acid, and the resulting precipitate is filtered and dried to yield 1.92 g (yield: 85%) of white 7-amino-3-vinyl-3-cepem-4-carboxylic acid. .
[실시예 5]Example 5
7-[2-(2-트리클로로 에톡시 카르보닐 아미노 티아졸-4일)-2-(트리클로로에톡시 카르보닐 메톡시 이미노)아세트 아미도]-3-비닐-3-세펨-4-카르복실산 트리클로로 에틸 에스테르의 제조7- [2- (2-trichloroethoxy carbonyl amino thiazol-4yl) -2- (trichloroethoxy carbonyl methoxy imino) acet amido] -3-vinyl-3-cepem-4 Preparation of -carboxylic acid trichloro ethyl ester
디클로로 메탄 50ml에 2-(트리클로로 에톡시 카르보닐 메톡시 아미노)-2-(2-트리클로로 에톡시 카르보닐 이미노 티아졸-4일) 초산(Syn-이성체) 5.52g과 벤조설피마이드 1.83g을 넣어 녹인 후 5℃로 냉각하고 엔, 엔-디사이클로헥실 카아보 디이마이드 2.1g을 가한 후 5℃에서 30분간 교반하고 실온으로 온도를 올린 후 2시간 교반하고 여과하여 생성된 엔, 엔-디사이 클로 헥실우레아틀 여과하여 제거한다.5.52 g of 2- (trichloro ethoxy carbonyl methoxy amino) -2- (2-trichloro ethoxy carbonyl imino thiazol-4yl) acetic acid (Syn-isomer) in 50 ml of dichloromethane and 1.83 sulphamide After adding and melting, the mixture was cooled to 5 ° C., and 2.1 g of N, N-dicyclohexyl carbodiimide was added thereto, stirred at 5 ° C. for 30 minutes, raised to room temperature, stirred for 2 hours, filtered, and produced. Dicylohexylureatle Remove by filtration.
한편, 디클로로메탄 100ml에 7-아미노-3-비닐-3-세펨-4-카르복실산 트리클로로 에틸 에스테르 염산염 3.94g을 넣고 5℃로 냉각 후 트리에틸아민 1.4ml를 넣은 후 위에서 만든 용액을 1시간에 걸쳐 적가한 후 30분 더 교반하고 실온으로 온도를 올리고 2시간 교반한다. 물 100ml를 가해 교반하고 유기층을 취하여 5% 중탄나트륨 용액 100ml로 2회, 물 100ml로 2회 세척하고 마그네슘 설페이트로 건조한 후 용매를 날리면 엷은 갈색의 7-[2-(2-트리클로로 에톡시 카르보닐 아미노 티아졸-4-일)-2-(트리클로로 에톡시 카르보닐 메톡시 이미노)아세트 아미도[-3-비닐-3-세펨-4-카르복실산 트리클로로 에틸에스테르(Syn-이성체) 7.66g(수득율 : 86%)을 얻는다.Meanwhile, 3.94 g of 7-amino-3-vinyl-3-cepem-4-carboxylic acid trichloro ethyl ester hydrochloride was added to 100 ml of dichloromethane, cooled to 5 ° C., and 1.4 ml of triethylamine was added thereto. After dropping over time, the mixture was further stirred for 30 minutes, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. 100 ml of water was added and stirred, the organic layer was taken, washed twice with 100 ml of 5% sodium bicarbonate solution, twice with 100 ml of water, dried over magnesium sulfate, and the solvent was blown to give a pale brown 7- [2- (2-trichloroethoxycarbide. Bonyl amino thiazol-4-yl) -2- (trichloro ethoxy carbonyl methoxy imino) acet amido [-3-vinyl-3- cefe-4-carboxylic acid trichloro ethyl ester (Syn-isomer ) 7.66g (yield 86%).
[실시예 6]Example 6
7-[2-(2-트리클로로 에톡시 카르보닐 아미노 티아졸-4-일)-2-(트리클로로 에톡시 카르보닐 메톡시 이미노)아세트 아미도]-3-비닐-3-세펨-4-카르복실산의 제조7- [2- (2-Trichloro ethoxy carbonyl amino thiazol-4-yl) -2- (trichloro ethoxy carbonyl methoxy imino) acet amido] -3-vinyl-3-cepem- Preparation of 4-carboxylic Acid
디클로로 메탄 50ml에 2-트리클로로 에톡시 카르보닐 메톡시 이미노)-2-(2-트리클로로 에톡시 카르보닐 아미노 티아졸-4-일) 초산(Syn-이성체) 5.52g과 벤조설피마이드 1.83g을 넣어 녹인 후 5℃로 냉각하고 엔, 엔-디사이클로 헥실 카아보디이마이드 2.1g을 가한 후 5℃에서 30분간 교반하고 실온으로 온도를 올린 후 2시간 교반하고 여과하여 생성된 엔, 엔-디사이클로 헥실우레아를 여과하여 제거한다.5.52 g of 2-trichloro ethoxy carbonyl methoxy imino) -2- (2-trichloro ethoxy carbonyl amino thiazol-4-yl) acetic acid (Syn-isomer) in 50 ml of dichloromethane and 1.83 benzosulfide g was dissolved, cooled to 5 ° C., and 2.1 g of N, N-dicyclohexyl carbodiimide was added thereto, stirred at 5 ° C. for 30 minutes, raised to room temperature, stirred for 2 hours, filtered, and produced. The dicyclo hexylurea is filtered off.
한편, 디클로로 메탄 100ml에 7-아미노-3-비닐-3-세펨-4-카르복실산 2.26g을 넣고 5℃로 냉각후 트리에틸아민 1.4ml를 넣은 후, 위에서 만든 용액을 1시간에 걸쳐 적가한 후 30분 더 교반하고 실온으로 온도를 올리고 2시간 교반한다. 물 100ml를 가해 교반하고 유기층을 취하여 물 100ml로 4회 세척하고 마그네슘 설페이트로 건조한 후 용매를 날리면 엷은 갈색의 7-2-(2-트리클로로 에톡시 카르보닐 아미노 티아졸-4-일)-2-(트리클로로 에톡시 카르보닐 메톡시 이미노)아세트 아미도]-3-비닐-3-세펨-4-카르복실산(Syn-이성체) 6.15g(수득율 81%)을 얻는다.Meanwhile, 2.26 g of 7-amino-3-vinyl-3-cepem-4-carboxylic acid was added to 100 ml of dichloromethane, cooled to 5 ° C., 1.4 ml of triethylamine was added, and the solution prepared above was added dropwise over 1 hour. After further stirring for 30 minutes, the temperature was raised to room temperature and stirred for 2 hours. 100 ml of water was added and stirred, the organic layer was taken, washed four times with 100 ml of water, dried over magnesium sulfate, and the solvent was blown to give a pale brown 7-2- (2-trichloroethoxycarbonyl aminothiazol-4-yl) -2. 6.15 g (yield 81%) of-(trichloroethoxy carbonyl methoxy imino) acet amido] -3-vinyl-3-cepem-4-carboxylic acid (Syn-isomer) are obtained.
[실시예 7]Example 7
7-[2-(2-아미노티아졸-4-일)-2-(카르복시메톡시 이미노)아세트 아미도]-3-비닐-3-세펨-4-카르복실산의 제조Preparation of 7- [2- (2-aminothiazol-4-yl) -2- (carboxymethoxy imino) acetamido] -3-vinyl-3-cepem-4-carboxylic acid
아세토 니트릴 80ml와 물 20ml의 혼합용매에 7-[2-(2-트리클로로 에톡시 카르보닐 메톡시 이미노)아세트 아미도]-3-비닐-3-세펨-4-카르복실산트리클로로 에틸 에스테르(Syn-이성체) 8.92g을 넣어 녹이고 5℃로 냉각후 아연 13g과 진한염산 20ml를 넣고 90분간 교반한다. 반응액을 여과하고 여액을 암모니아수로 pH4.5로 맞추고 5℃에서 2시간 교반하고 침전을 여과하고 아세토 니트릴로 세척후 건조하면 흰색의 7-[2-(2-아미노 티아졸-4-일)-2-(카르복시 메톡시 이미노)아세트 아미도]-3-비닐-3-세펨-4-카르복실산(Syn-이성체) 3.49g(수득율 77%)을 얻는다.In a mixed solvent of 80 ml of acetonitrile and 20 ml of water, 7- [2- (2-trichloroethoxycarbonyl methoxy imino) acet amido] -3-vinyl-3-cef-4-carboxylic acid trichloroethyl Dissolve 8.92 g of ester (Syn-isomer), cool to 5 ° C, and add 13 g of zinc and 20 ml of concentrated hydrochloric acid and stir for 90 minutes. The reaction solution was filtered, the filtrate was adjusted to pH4.5 with ammonia water, stirred at 5 ° C. for 2 hours, the precipitate was filtered off, washed with acetonitrile and dried to afford white 7- [2- (2-aminothiazol-4-yl). 3.49 g (yield 77%) of 2- (carboxymethoxy imino) acet amido] -3-vinyl-3-cepem-4-carboxylic acid (Syn-isomer) are obtained.
[실시예 8]Example 8
7-[2-(2-아미노 티아졸-4-일)-2-(카르복시 메톡시 이미노)아세트 아미도]-3-비닐-3-세펨-4-카르복실산의 제조Preparation of 7- [2- (2-aminothiazol-4-yl) -2- (carboxymethoxy imino) acetamido] -3-vinyl-3-cepem-4-carboxylic acid
아세트 니트릴 80ml와 물 20ml의 혼합용매에 7-[2-(2-트리클로로 에톡시 카르보닐 아미노 티아졸-4-일)-2-(트리클로로 에톡시 카르보닐 메톡시 이미노)아세트 아미도]-3-비닐-3-세펨-4-카르복실산(Syn-이성체) 7.6g을 넣어 녹이고 5℃로 냉각후 아연 9.75g과 진한 염산 16.2ml를 넣고 90분간 교반한다.7- [2- (2-trichloroethoxycarbonyl aminothiazol-4-yl) -2- (trichloroethoxycarbonyl methoxy imino) acet amido in a mixed solvent of 80 ml of acetnitrile and 20 ml of water ] 7.6g of 3-vinyl-3-cepem-4-carboxylic acid (Syn-isomer) is dissolved. After cooling to 5 ° C, 9.75g of zinc and 16.2ml of concentrated hydrochloric acid are added and stirred for 90 minutes.
반응액을 여과하고 여액을 암모니아수로 pH4.5로 맞추고 5℃에서 2시간 교반하고 침전을 여과하고 아세토 니트릴로 세척후 건조하면 흰색의 7-[2-(2-아미노티아졸-4-일)-2-(카르복시 메톡시 이미노)아세트 아미도]-3-비닐-3-세펨-4-카르복실산(Syn-이성체) 3.58g(수득율 79%)을 얻는다.The reaction solution was filtered, the filtrate was adjusted to pH4.5 with ammonia water, stirred at 5 ° C. for 2 hours, the precipitate was filtered off, washed with acetonitrile and dried to afford white 7- [2- (2-aminothiazol-4-yl). 3.58 g (yield 79%) of 2- (carboxymethoxy imino) acet amido] -3-vinyl-3-cepem-4-carboxylic acid (Syn-isomer) are obtained.
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| US6384212B1 (en) | 2000-03-20 | 2002-05-07 | Hanmi Fine Chemicals Co., Ltd. | Process for preparing cephalosporin antibiotics using new thiazole compound |
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