KR20220100754A - Method for preparing flomoxef of high yield and high purity - Google Patents
Method for preparing flomoxef of high yield and high purity Download PDFInfo
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Abstract
Description
본 발명은 고수율 및 고순도의 플로목세프를 제조하는 방법에 관한 것으로, 보다 상세하게는 그람양성 및 음성균에 작용하는 옥사세펨계 항생제인 (6R,7R)-7-[[2-(디플루오로메틸설파닐)아세틸]아미노]-3-[[1-(2-히드록시에틸)테트라졸-5-일]설파닐메틸]-7-메톡시-8-옥소-5-옥사-1-아자비시클로[4.2.0]옥트-2-엔-2-카르복시산(일명 플로목세프)를 고수율 및 고순도로 제조하는 방법에 관한 것이다. The present invention relates to a method for producing flomoxef in high yield and high purity, and more particularly, (6R,7R)-7-[[2-(difluoro Romethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1- It relates to a method for preparing azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (aka flomoxef) in high yield and high purity.
세펨(Cephem)계 항생제는 세팔로스포린(cephalosporin), 세파마이신(cephamycin), 오랄세펨(oralcephem), 페넴(penem), 카바페넴(carbapenem), 모노박탐(monobactam), 베타락타마제 억제제(β-lactamase inhibitor) 및 옥사세펨(oxacephem) 등으로 구분할 수 있다. 또한 투여경로에 의해 주사제와 경구제로 양분된다. Cephem antibiotics include cephalosporin, cephamycin, oralcephem, penem, carbapenem, monobactam, beta-lactamase inhibitors (β- It can be divided into lactamase inhibitor) and oxacephem. In addition, by the route of administration, it is divided into injection and oral drugs.
플로목세프 소듐(Flomoxef sodium)은 일본 시오노기 제약연구소에 의해 개발된 옥사세펨계에 속하는 주사용 항생물질이다. 화학 구조상 락타목세프(Latamoxef)와 같이 1-옥사세펨 골격을 갖는다 (하기 화학식 1 및 2 참조).Flomoxef sodium (Flomoxef sodium) is an injectable antibiotic belonging to the oxacetem family developed by Shionogi Pharmaceutical Research Institute in Japan. In terms of chemical structure, it has a 1-oxasefem skeleton like Latamoxef (see Formulas 1 and 2 below).
[화학식 1][Formula 1]
[화학식 2][Formula 2]
또한, 플로목세프 소듐은 기존의 세펨계 항생물질과 달리 세팔로스포린 골격의 1위치에 황 원자 대신 산소로 치환하여 항균력을 증가시킨 옥사세펨계를 기본 구조로 하여, 항균범위, 약동력학 특성, 부작용면 그리고 β- 락타마제에 대한 안전성 등에서 보다 증강 보완된 제제이다.In addition, Flomoxef Sodium, unlike the existing cephem-based antibiotics, has an oxacetem-based structure that has increased antibacterial activity by substituting oxygen instead of a sulfur atom in the 1st position of the cephalosporin skeleton as a basic structure. It is a supplement that is enhanced and supplemented in terms of side effects and safety for β-lactamase.
즉, 플로목세프 소듐은, 그람음성균에 대한 항균력을 유지하면서, 제 3세대 cephem 계의 공통된 약점을 보충하고, 그람양성균, 특히 메티실린(Methicillin) 내성포도구균(MRSA)에 대해서도 기존의 세펨계보다 강력한 항균력을 나타내는 최신의 항생물질이다.That is, flomoxef sodium, while maintaining antibacterial activity against Gram-negative bacteria, supplements the common weakness of the third-generation cephem system, and also against Gram-positive bacteria, particularly Methicillin-resistant Staphylococcus aureus (MRSA), the existing cephem system. It is the latest antibiotic with stronger antibacterial activity.
플로목세프는 기존의 대표적인 제3세대 세펨계 주사용 항생제인 락타목세프의 우수한 성질을 가능한 한 살리면서, 미흡한 성질을 개량한 신세대의 광범위 항생물질이다.Flomoxef is a new generation of broad-spectrum antibiotics with improved properties while maximizing the excellent properties of Lactamoxef, a representative third-generation cephem-based antibiotic for injection.
이상 2개의 목표를 달성하기 위하여, 1-옥사세펨 핵의 7위와 3위의 화학적 수식을 행하며 다수의 화합물을 합성하여 플로목세프가 제조되었다.In order to achieve the above two goals, flomoxef was prepared by synthesizing a number of compounds by chemically modifying the 7th and 3rd positions of the 1-oxacefem nucleus.
그 중에서도 7위에 알킬티오아세틸(alkylthioacetyl)기를, 3위에 테트라졸-티오메틸(tetrazol-thiomethyl)기를 갖는 것이, 그람양성균 및 그람음성균 어느 것에 대해서도 우수한 항균력을 나타냄이 밝혀졌다.Among them, it was found that those having an alkylthioacetyl group at position 7 and a tetrazol-thiomethyl group at position 3 exhibit excellent antibacterial activity against both gram-positive bacteria and gram-negative bacteria.
다시, 7위의 앞의 R1과 3위의 테트라졸에 있는 R2에 대하여 약효면에서 그 항균력 및 체내동태의 비교를 행하는 한편, 안전성의 면에서는 디설피람(disulfiram) 양작용과 신독성이 없는 것을 지표로 각종 검토를 행하였다.Again, the antibacterial activity and in vivo kinetics of R1 in the 7th position and R2 in the tetrazole in the 3rd position were compared in terms of drug efficacy, while in terms of safety, disulfiram had no positive action and no nephrotoxicity. Various examinations were performed as an index.
그 결과, R1으로서는 디플루오로메틸(difluoromethyl)기를, R2로서는 히드록시에틸(hydroxyethyl)기를 선택하였다.As a result, a difluoromethyl group was selected as R1 and a hydroxyethyl group was selected as R2.
또한, 대응하는 1-티아(thia)의 세팔로스포린(cephalosporin) 유도체에 비하여, 플로목세프의 그람양성균 및 그람음성균에 대한 항균활성은 2~16배나 강한 것이 확인되었다.In addition, it was confirmed that the antibacterial activity of flomoxef against gram-positive and gram-negative bacteria was 2 to 16 times stronger than that of the corresponding 1-thia cephalosporin derivative.
이들 항생제 중 옥사세펨(oxacephem)계 항생제인 플로목세프(Shionogi, 1988)와 락타목세프(Lilly, 1981) 등이 현재 시판되고 있으나, 이들을 합성하기 위해서는 중간체를 발효하거나 전합성에 의해 제조해야 하며, 세계적으로 Shionogi사와 Lilly를 제외하고는 중간체 및 완제의 원료 공급처가 없는 실정이다. 일본 내에서 Generic 개발을 위한 원료를 수배 중이나, 자체 생산을 제외하고는 공급처가 없다. Among these antibiotics, oxacephem-based antibiotics, such as flomoxef (Shionogi, 1988) and lactamoxef (Lilly, 1981), are currently on the market. In the world, there is no source of raw materials for intermediates and finished products except for Shionogi and Lilly. We are looking for raw materials for Generic development in Japan, but there is no supplier except for our own production.
옥사세펨계 항생제의 경우 제품군의 종류가 작아서 발효에 의한 중간체의 개발에서는 효율성이 있는 균주의 개발이 이루어지고 있지 있으며, 플로목세프의 경우 원발매사가 개발한 도식과 같이 항생제 원제 및 중간체는 전합성으로 진행하여야 한다. 이는 총 24단계의 합성 경로를 거쳐 제조하여야 하기 때문에 쉽게 접근하기는 매우 어려운 품목이므로 새로운 합성법에 대한 개발이 필요하다.In the case of oxacepem antibiotics, the types of product groups are small, so the development of effective strains in the development of intermediates by fermentation is not being carried out. should proceed to It is a very difficult item to access easily because it has to be manufactured through a synthesis route of a total of 24 steps, so a new synthesis method needs to be developed.
한편, 플루오로메틸티오옥사세팔로스포린를 제조하는 방법에 대한 공지된 문헌을 살펴보면, 하기 반응식 1 (플로목세프 합성)를 수행함에 있어서 카르복시 탈 보호를 위해 디클로로메탄(Dichloromathane)에 녹인 액에 아니솔(Anisol) 및 티타늄 테트라클로라이드(Titanium tetrachloride) 또는 알루미늄 클로라이드(Aluminum chloride)를 사용하여 탈 보호 하거나, 알루미늄 클로라이드 대신에 트리플루오로아세트산을 사용한다. On the other hand, looking at the known literature on a method for producing fluoromethylthiooxacephalosporin, anisole in a solution dissolved in dichloromethane for carboxy deprotection in carrying out the following Reaction Scheme 1 (Plomoxef synthesis) (Anisol) and titanium tetrachloride or aluminum chloride for deprotection, or use trifluoroacetic acid instead of aluminum chloride.
[반응식 1][Scheme 1]
따라서, 반응 혼합물을 추출하는 과정이 용이하지 않을 뿐 아니라, 반응 중 여러 부 반응의 생성이 있고 이에 따른 화합물의 순도도 저하된다. Therefore, it is not easy to extract the reaction mixture, and several side reactions are generated during the reaction, and the purity of the compound is reduced accordingly.
따라서, 고수율 및 고순도의 플로목세프를 제조하는 방법에 대한 수요가 여전히 존재한다.Therefore, there is still a need for a method for preparing flomoxef in high yield and high purity.
본 발명은, 그람양성 및 음성균에 작용하는 옥사세펨계 항생제인 (6R,7R)-7-[[2-(디플루오로메틸설파닐)아세틸]아미노]-3-[[1-(2-히드록시에틸)테트라졸-5-일]설파닐메틸]-7-메톡시-8-옥소-5-옥사-1-아자비시클로[4.2.0]옥트-2-엔-2-카르복시산(본 명세서에서 플로목세프 또는 플로목세프-FA(Flomoxef-FA)라 함)를 고수율 및 고순도로 제조하는 방법을 제공하는 것을 기술적 과제로 한다.The present invention provides (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-) Hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (herein It is a technical task to provide a method for preparing flomoxef or flomoxef-FA (referred to as Flomoxef-FA) in high yield and high purity.
상기한 기술적 과제를 해결하고자 본 발명은, (6R,7R)-벤즈히드릴-7-(디플루오로메틸티오)아세트아미도)-3-(((1-(2-히드록시에틸)-1H-테트라졸-5-일)설페닐)메틸)-7-메톡시-8옥소-5-옥사-1-아자-비시클로[4.2.0]옥트-2-엔-2-카르복실레이트와 크레졸, 톨루엔 및 이들의 조합으로 이루어진 군으로부터 선택되는 용매를 반응시키는 제1 단계; 및 제1 단계의 생성물을 결정화하여 플로목세프를 합성하는 제2 단계;를 포함하는 플로목세프의 제조방법을 제공한다.In order to solve the above technical problem, the present invention provides (6R,7R)-benzhydryl-7-(difluoromethylthio)acetamido)-3-(((1-(2-hydroxyethyl)- 1H-tetrazol-5-yl)sulfenyl)methyl)-7-methoxy-8oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate and A first step of reacting a solvent selected from the group consisting of cresol, toluene, and combinations thereof; and a second step of synthesizing flomoxef by crystallizing the product of the first step.
본 발명에 따르면, 플로목세프-BH를 출발물질로 하여, 크레졸, 톨루엔 및 이들의 조합으로 이루어진 군으로부터 선택되는 용매와 반응시켜 고수율 및 고순도의 플로목세프를 제조할 수 있다. 또한, 본 발명에 따르면, 플로목세프를 제조함에 있어서 SUS 반응기와 G/L 반응기를 모두 사용할 수 있다.According to the present invention, flomoxef-BH as a starting material can be reacted with a solvent selected from the group consisting of cresol, toluene, and combinations thereof to prepare flomoxef with high yield and high purity. In addition, according to the present invention, both the SUS reactor and the G/L reactor can be used in manufacturing the flomoxef.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 명세서에서in this specification
플로목세프-Cl은 ((6R,7R)- Benzhydryl 3-(chloromethyl)-7-((1-(((Z)-2-chlorovinyl)oxy)-2-((difluoromethyl)thio)ethyl)amino)-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate)를 의미하며,Flomoxef-Cl is ((6R,7R)-Benzhydryl 3-(chloromethyl)-7-((1-(((Z)-2-chlorovinyl)oxy)-2-((difluoromethyl)thio)ethyl)amino )-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate),
플로목세프-BH는 ((6S,7R)-벤즈히드릴-7-(디플루오로메틸티오)아세트아미도)-3-(((1-(2-히드록시에틸)-1H-테트라졸-5-일)설페닐)메틸)-7-메톡시-8옥소-5-옥사-1-아자-비시클로[4.2.0]옥트-2-엔-2-카르복실레이트)를 의미하며,Flomoxef-BH is ((6S,7R)-benzhydryl-7-(difluoromethylthio)acetamido)-3-(((1-(2-hydroxyethyl)-1H-tetrazole -5-yl)sulfenyl)methyl)-7-methoxy-8oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate),
플로목세프는 ((6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid)를 의미한다. Flomoxef is ((6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8 -oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid).
본 발명의 플로목세프의 제조방법은, (6R,7R)-벤즈히드릴-7-(디플루오로메틸티오)아세트아미도)-3-(((1-(2-히드록시에틸)-1H-테트라졸-5-일)설페닐)메틸)-7-메톡시-8옥소-5-옥사-1-아자-비시클로[4.2.0]옥트-2-엔-2-카르복실레이트 (Flomoxef-BH)와 크레졸을 반응시키는 제1 단계; 및 제1 단계의 생성물을 결정화하여 플로목세프를 합성하는 제2 단계;를 포함한다. The method for preparing flomoxef of the present invention comprises: (6R,7R)-benzhydryl-7-(difluoromethylthio)acetamido)-3-(((1-(2-hydroxyethyl)- 1H-tetrazol-5-yl)sulfenyl)methyl)-7-methoxy-8oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate ( a first step of reacting Flomoxef-BH) with cresol; and a second step of synthesizing flomoxef by crystallizing the product of the first step.
일 구체예에서, 본 발명의 플로목세프 의 제조방법은, 플로목세프-Cl과 side chain을 이용하여 합성된 플로목세프-BH와 크레졸, 예를 들면 m-크레졸을 반응시키고, 이후 반응 생성물을 결정화하여 플로목세프를 합성할 수 있다 (하기 반응식 2 참조).In one embodiment, in the method for preparing flomoxef of the present invention, flomoxef-BH synthesized using a side chain with flomoxef-Cl is reacted with cresol, for example, m-cresol, and then the reaction product can be crystallized to synthesize flomoxef (refer to Scheme 2 below).
[반응식 2] [Scheme 2]
플로목세프-Cl ((6R,7R)- Benzhydryl 3-(chloromethyl)-7-((1-(((Z)-2-chlorovinyl)oxy)-2-((difluoromethyl)thio)ethyl)amino)-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate)와 반응하는 곁사슬(side chain) 로는 1-(2-히드록시에틸)-1H-테트라졸-5-일티올 소듐 염 (1-(2-Hydroxyethyl)-1H-tetrazol-5-ylthiol sodium salt) 등을 사용할 수 있다. Flomoxef-Cl ((6R,7R)-Benzhydryl 3-(chloromethyl)-7-((1-(((Z)-2-chlorovinyl)oxy)-2-((difluoromethyl)thio)ethyl)amino) 1-(2-hydroxyethyl)- as a side chain reacting with -7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate) 1H-tetrazol-5-ylthiol sodium salt (1-(2-Hydroxyethyl)-1H-tetrazol-5-ylthiol sodium salt) and the like may be used.
본 발명의 플로목세프의 제조방법은, (6R,7R)-벤즈히드릴-7-(디플루오로메틸티오)아세트아미도)-3-(((1-(2-히드록시에틸)-1H-테트라졸-5-일)설페닐)메틸)-7-메톡시-8옥소-5-옥사-1-아자-비시클로[4.2.0]옥트-2-엔-2-카르복실레이트 (플로목세프-BH);와 크레졸, 톨루엔 및 이들의 조합으로 이루어진 군으로부터 선택되는 용매를 반응시키는 제1 단계를 포함할 수 있다. The method for preparing flomoxef of the present invention comprises: (6R,7R)-benzhydryl-7-(difluoromethylthio)acetamido)-3-(((1-(2-hydroxyethyl)- 1H-tetrazol-5-yl)sulfenyl)methyl)-7-methoxy-8oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate ( It may include a first step of reacting flomoxef-BH) with a solvent selected from the group consisting of cresol, toluene, and combinations thereof.
종래 기술에서는, 전술한 바와 같이 상기 반응식 2 (플로목세프의 합성)를 수행함에 있어서 카르복시 탈 보호를 디클로로메탄(Dichloromathane)에 녹인 액에 아니솔(Anisol) 및 티타늄 테트라클로라이드(Titanium tetrachloride) 또는 알루미늄 클로라이드(Aluminum chloride)를 사용하여 탈 보호 하거나, 알루미늄 클로라이드 대신에 트리플루오로아세트산을 사용한다. 따라서, 반응 혼합물을 추출하는 과정이 용이하지 않을 뿐 아니라, 반응 중 여러 부 반응의 생성이 있고 이에 따른 화합물의 순도도 저하되는 문제가 있었다. In the prior art, as described above, in performing Scheme 2 (synthesis of flomoxef), carboxy deprotection was performed in a solution dissolved in dichloromathane with anisol and titanium tetrachloride or aluminum Deprotection using aluminum chloride, or use trifluoroacetic acid instead of aluminum chloride. Therefore, it is not easy to extract the reaction mixture, and there is a problem in that several side reactions are generated during the reaction, and the purity of the compound is reduced accordingly.
본 발명의 플로목세프의 제조방법에서는, 카르복시 탈 보호를 위해 플로목세프-BH와 크레졸을 반응시킴으로써, 종래 기술에서 발생되는 문제점들을 해결할 뿐 아니라, 원료가격 면에서도 큰 이점과 수율 향상을 볼 수 있다. 특히, 플로목세프를 제조함에 있어서, SUS 반응기(내부가 스테인레스로 되어 있는 반응기)와 G/L 반응기(내부가 유리로 코팅되어 있는 반응기)를 모두 사용할 수 있다. 종래의 플로목세프 제조 방법의 경우, SUS 반응기에서는 산에 의한 부식으로 인해 사용할 수 없었으나, 본 발명의 플로목세프의 제조방법에서는 SUS 반응기에도 사용할 수 있으므로, 다양한 생산 현장에서 적용할 수 있다. In the method for producing flomoxef of the present invention, by reacting flomoxef-BH with cresol for carboxy deprotection, problems occurring in the prior art are solved, and a great advantage in raw material price and yield improvement can be seen. have. In particular, in manufacturing the flomoxef, both the SUS reactor (the reactor with the inside of stainless steel) and the G/L reactor (the reactor with the inside of which is coated with glass) can be used. In the case of the conventional method for producing flomoxef, it could not be used in a SUS reactor due to acid corrosion.
본 발명의 플로목세프의 제조방법의 제1 단계에서 사용되는 용매는 o-크레졸, m-크레졸, p-크레졸, 톨루엔 및 이들의 조합으로 이루어진 군으로부터 선택되는 것일 수 있으며, 조합의 예로는 m-크레졸 62%+p-크레졸 38%의 혼합물을 사용할 수 있다. The solvent used in the first step of the method for preparing flomoxef of the present invention may be selected from the group consisting of o -cresol, m -cresol, p -cresol, toluene, and combinations thereof. Examples of the combination include m A mixture of -cresol 62%+p-cresol 38% can be used.
본 발명의 플로목세프의 제조방법의 제1 단계에서, 플로목세프-BH 100 중량부 당 반응시키는 크레졸, 톨루엔 및 이들의 조합으로 이루어진 군으로부터 선택되는 용매의 중량은 400 중량부 이상, 420 중량부 이상, 450 중량부 이상 또는 500 중량부 이상일 수 있고, 800 중량부 이하, 750 중량부 이하, 700 중량부 이하 또는 600 중량부 이하일 수 있으며, 예를 들면 400 내지 800 중량부, 420 내지 750 중량부, 450 내지 700 중량부 또는 500 내지 600 중량부일 수 있다. 상기 용매의 중량이 상기 범위보다 낮은 경우 부 반응이 생성되어 수율이 현저히 저하되는 문제가 발생할 수 있고, 상기 범위보다 높은 경우 추가적인 효과가 발생하지 않지만 생산 제조 단가가 상승하는 문제가 발생한다. In the first step of the method for producing flomoxef of the present invention, the weight of the solvent selected from the group consisting of cresol, toluene, and combinations thereof to be reacted per 100 parts by weight of flomoxef-BH is 400 parts by weight or more, 420 parts by weight It may be more than parts by weight, 450 parts by weight or more, or 500 parts by weight or more, and 800 parts by weight or less, 750 parts by weight or less, 700 parts by weight or less, or 600 parts by weight or less, for example 400 to 800 parts by weight, 420 to 750 parts by weight. parts, 450 to 700 parts by weight, or 500 to 600 parts by weight. When the weight of the solvent is lower than the above range, a side reaction is generated and a problem that the yield is significantly lowered may occur.
본 발명의 플로목세프-FA의 제조방법에서, 제1 단계는 주위 온도 내지 선택된 용매의 환류 온도 범위의 온도에서 적합한 용매중에서 수행될 수 있으며, 50℃ 내지 70℃, 예를 들면 55℃ 내지 65℃ 또는 60℃ 내지 70℃의 반응온도에서 수행될 수 있고, 2 내지 8시간, 예를 들면 2 내지 6 시간 또는 3 내지 5시간 동안 수행될 수 있다. 반응온도 및 반응시간이 상기 범위를 벗어나는 경우 플로목세프의 수율이 저하될 수 있다.In the method for preparing flomoxef-FA of the present invention, the first step may be carried out in a suitable solvent at a temperature ranging from ambient temperature to the reflux temperature of the selected solvent, and may be 50° C. to 70° C., for example 55° C. to 65° C. It may be carried out at a reaction temperature of ℃ or 60 ℃ to 70 ℃, may be carried out for 2 to 8 hours, for example, 2 to 6 hours or 3 to 5 hours. If the reaction temperature and reaction time are out of the above ranges, the yield of flomoxef may be reduced.
본 발명의 플로목세프의 제조방법은, 불순물의 제거를 위해 제1 단계의 생성물에 산을 첨가하는 단계를 추가로 포함할 수 있다. 상기 산은 아세트산, 트리플루오로아세트산, 인산, 시트르산 및 이들의 조합으로 이루어진 군으로부터 선택되는 것일 수 있다. The method for preparing flomoxef of the present invention may further include adding an acid to the product of the first step to remove impurities. The acid may be selected from the group consisting of acetic acid, trifluoroacetic acid, phosphoric acid, citric acid, and combinations thereof.
본 발명의 플로목세프의 제조방법은, 제1 단계의 생성물을 결정화하여 플로목세프를 합성하는 제2 단계를 포함한다.The method for producing flomoxef of the present invention includes a second step of synthesizing flomoxef by crystallizing the product of the first step.
제2단계에서는 제1단계의 생성물에 아세톤 및 디클로로메탄의 조합인 용매를 첨가하여 결정화를 수행할 수 있다. In the second step, crystallization may be performed by adding a solvent that is a combination of acetone and dichloromethane to the product of the first step.
본 발명에 따르면, 플로목세프-BH를 출발물질로 하여, 크레졸, 톨루엔 및 이들의 조합으로 이루어진 군으로부터 선택되는 용매와 반응시켜 고수율 및 고순도의 플로목세프를 제조할 수 있다. 또한, 본 발명에 따르면, 플로목세프를 제조함에 있어서 SUS 반응기와 G/L 반응기를 모두 사용할 수 있다.According to the present invention, flomoxef-BH as a starting material can be reacted with a solvent selected from the group consisting of cresol, toluene, and combinations thereof to prepare flomoxef with high yield and high purity. In addition, according to the present invention, both the SUS reactor and the G/L reactor can be used in manufacturing the flomoxef.
이하, 실시예 및 비교예를 통하여 본 발명을 보다 상세하게 설명한다. 그러나, 본 발명의 범위가 이들로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through Examples and Comparative Examples. However, the scope of the present invention is not limited thereto.
실시예Example
합성예: 플로목세프-BH의 합성Synthesis Example: Synthesis of flomoxef-BH
(6R,7R)-benzhydryl 3-(chloromethyl)-7-((1-(((Z)-2-chlorovinyl)oxy)-2-((difluoromethyl)thio)ethyl)amino)-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 100g을 Dimethylformamide 237g에 녹인 후 0±3℃로 냉각시켜 반응을 준비하였다. 1-(2-Hydroxyethyl)-1H-tetrazol-5-ylthiol sodium salt 36.5g을 0±3℃ 유지하며 서서히 가한 후, 1~2 시간 동안 교반하였다. (6R,7R)-benzhydryl 3-(chloromethyl)-7-((1-(((Z)-2-chlorovinyl)oxy)-2-((difluoromethyl)thio)ethyl)amino)-7-methoxy-8 100 g of -oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate was dissolved in 237 g of Dimethylformamide and cooled to 0±3° C. to prepare a reaction. 36.5 g of 1-(2-Hydroxyethyl)-1H-tetrazol-5-ylthiol sodium salt was added slowly while maintaining 0±3℃, followed by stirring for 1-2 hours.
반응이 종결되면 Ethanol 335g+정제수 326g을 반응기에 투입하였다. 20℃~30℃에서 3~4시간동안 결정화를 진행하였다. 정제수 500g을 추가로 투입하여 1~2시간 교반하였다. 생성된 고체를 여과하고 Ethanol 103g+정제수 100g으로 여과한 교체를 세척하였다. 여과하여 얻은 목적화합물 (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(플로목세프-BH) 120g (수율 99.9%, 순도 99.2%)을 얻었다.When the reaction was completed, 335 g of Ethanol + 326 g of purified water was added to the reactor. Crystallization was carried out at 20°C to 30°C for 3-4 hours. 500 g of purified water was additionally added and stirred for 1 to 2 hours. The resulting solid was filtered and washed with 103 g of Ethanol + 100 g of purified water. The target compound obtained by filtration (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8 -oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (flomoxef-BH) 120g (yield 99.9%, purity 99.2%) was obtained.
실시예 1: 플로목세프의 합성 (m-Cresol 사용)Example 1: Synthesis of flomoxef (using m-Cresol)
(6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(플로목세프-BH) 120g을 60℃~70℃로 가온 되어있는 m-Cresol 620g에 투입하였다. 다 녹인 후 65℃~70℃로 유지하고 3 시간동안 교반하였다. (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5- 120 g of oxa-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (flomoxef-BH) was added to 620 g of m-Cresol heated to 60°C to 70°C. After dissolving, the temperature was maintained at 65°C to 70°C and stirred for 3 hours.
반응이 종결된 후, 반응액에 Ethyl acetate 1080g과 brine 1200g을 5 ~ 10℃를 유지하면서 첨가하였다. 여기에 Sodium bicarbonate 16.7g을 같은 온도를 유지하며 첨가하고 교반하여 중성으로 조정한 다음, 정치 후 분리하여 수층을 수거하였다. 유기층에 다시 brine 600g을 첨가하여 추출 후 층 분리하였다. 수층을 모두 모은 후, Ethyl acetate 540g을 넣고 수층을 세척한 후 층 분리하였다. 수층을 수거한 뒤 소금 360g과 Ethyl acetate 1080g을 첨가한 후, Phosphoric acid 31.3g을 투입하여 산성으로 조절한 후, 추출하여 유기층을 수거하였다. 수층은 다시 Ethyl acetate 540g을 사용해 추출하여 유기층을 수거하였다. 유기층을 Magnesium sulfate 24g을 넣고 수분을 제거 후 활성탄 12g을 사용해 탈색한 후, 여과하고 Ethyl acetate 108g으로 세척하였다. 유기층을 진공농축 한 뒤, 농축 잔사에 Acetone 235g을 넣고 용해 시킨 후, Dichloromethane 3192g을 천천히 첨가하였다. 0℃로 온도를 유지하며 12 시간 동안 교반한 뒤, 생성된 고체를 여과하고 Dichloromethane 160g으로 세척하였다. 여과된 고체를 30±3℃에서 12시간 동안 진공 건조하여 목적화합물 (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (플로목세프-FA) 79g (수율 87.8%, 용매보정 값, 순도 99.8%)을 얻었다.After the reaction was completed, 1080 g of ethyl acetate and 1200 g of brine were added to the reaction solution while maintaining 5 to 10°C. Here, 16.7 g of sodium bicarbonate was added while maintaining the same temperature, adjusted to neutrality by stirring, and then separated after standing to collect the aqueous layer. After extraction by adding 600 g of brine to the organic layer, the layers were separated. After collecting all the aqueous layers, 540 g of ethyl acetate was added, the aqueous layer was washed, and the layers were separated. After collecting the aqueous layer, 360 g of salt and 1080 g of ethyl acetate were added, and 31.3 g of phosphoric acid was added to adjust the acidity, followed by extraction to collect the organic layer. The aqueous layer was again extracted using 540 g of ethyl acetate, and the organic layer was collected. The organic layer was decolorized using 12 g of activated carbon after adding 24 g of magnesium sulfate to remove moisture, filtered and washed with 108 g of ethyl acetate. After the organic layer was concentrated in vacuo, 235 g of Acetone was added to the concentrated residue and dissolved, and then 3192 g of Dichloromethane was slowly added. After stirring for 12 hours while maintaining the temperature at 0° C., the resulting solid was filtered and washed with 160 g of Dichloromethane. The filtered solid was vacuum-dried at 30±3℃ for 12 hours to obtain the target compound (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol- 5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (flomoxef-FA) 79g (yield 87.8%, Solvent correction value, purity 99.8%) was obtained.
실시예 2: 플로목세프의 합성 (Example 2: Synthesis of flomoxef ( oo -Cresol 사용)-Use Cresol)
(6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (플로목세프-BH) 120g을 60℃~70℃로 가온 되어있는 o-Cresol 620g에 투입한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적화합물(6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (플로목세프-FA) 69.6g(수율 77.4%, 용매보정 값, 순도 99.8%)을 얻었다.(6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5- Example except that 120 g of oxa-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (flomoxef-BH) was added to 620 g of o -Cresol heated to 60 ℃ ~ 70 ℃ In the same manner as in 1, the target compound (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7- methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (flomoxef-FA) 69.6g (yield 77.4%, solvent correction value, purity 99.8%) got
실시예 3: 플로목세프의 합성 (Example 3: Synthesis of flomoxef ( p-Cresol p-Cresol 사용)use)
(6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(Flomoxef-BH) 120g을 60℃~70℃로 가온 되어있는 p-Cresol 620g에 투입한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적화합물 (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (플로목세프-FA) 58.3g(수율 64.8%, 용매보정 값, 순도 99.4%)을 얻었다.(6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5- Example 1, except that 120 g of oxa-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate (Flomoxef-BH) was added to 620 g of p -Cresol heated to 60 ° C. to 70 ° C. In the same manner, the target compound (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy- 8-oxo-5-oxa-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (flomoxef-FA) 58.3 g (yield 64.8%, solvent correction value, purity 99.4%) was obtained. .
비교예 1: 플로목세프의 합성 (Comparative Example 1: Synthesis of flomoxef ( mm -Cresol 사용)-Use Cresol)
(6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (플로목세프-BH) 120g을 60℃~70℃로 가온 되어있는 m-Cresol 370.8g에 투입한 것을 제외하고, 실시예 1과 동일하게 수행하여 목적화합물(6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (플로목세프-FA) 69.6g(수율 70.2%, 용매보정 값, 순도 99.3%)을 얻었다.(6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5- Conducted except that 120 g of oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (flomoxef-BH) was added to 370.8 g of m -Cresol heated to 60℃~70℃ In the same manner as in Example 1, the target compound (6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7 -methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (flomoxef-FA) 69.6g (yield 70.2%, solvent correction value, purity 99.3% ) was obtained.
Claims (7)
제1 단계의 생성물을 결정화하여 플로목세프를 합성하는 제2 단계;를 포함하는
플로목세프의 제조방법.(6R,7R)-Benzhydryl-7-(difluoromethylthio)acetamido)-3-(((1-(2-hydroxyethyl)-1H-tetrazol-5-yl)sulfenyl from the group consisting of )methyl)-7-methoxy-8oxo-5-oxa-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate with cresol, toluene and combinations thereof a first step of reacting the selected solvent; and
A second step of synthesizing flomoxef by crystallizing the product of the first step; including
A method for preparing flomoxef.
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| JP2023541920A JP2024503655A (en) | 2021-01-08 | 2022-01-05 | Method for producing high yield and high purity flomoxef |
| PCT/KR2022/000152 WO2022149847A1 (en) | 2021-01-08 | 2022-01-05 | Method for producing flomoxef with high yield and high purity |
| CN202280009550.2A CN116783203A (en) | 2021-01-08 | 2022-01-05 | Preparation method of high-yield and high-purity flomoxef |
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| KR101550777B1 (en) * | 2013-10-25 | 2015-09-08 | (주)유케이케미팜 | Process for preparing flomoxef sodium |
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