KR100432425B1 - Novel method for preparation of cephem derivatives or salts thereof - Google Patents
Novel method for preparation of cephem derivatives or salts thereof Download PDFInfo
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- KR100432425B1 KR100432425B1 KR10-2000-0068165A KR20000068165A KR100432425B1 KR 100432425 B1 KR100432425 B1 KR 100432425B1 KR 20000068165 A KR20000068165 A KR 20000068165A KR 100432425 B1 KR100432425 B1 KR 100432425B1
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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
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- 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
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- 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
- C07D501/48—Methylene radicals, substituted by hetero rings
- C07D501/56—Methylene radicals, substituted by hetero rings with the 7-amino radical acylated by carboxylic acids containing hetero rings
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Abstract
본 발명은 하기 화학식 1의 세펨 유도체 또는 그 염의 신규한 제조방법에 관한 것으로, 더 구체적으로는 하기 화학식 2의 화합물을 하기 화학식 3의 화합물과 반응시켜 화학식 1의 유도체 또는 그 염을 얻는 새로운 제조방법에 관한 것이다. 또한, 본 발명은 상기 화학식 1의 세펨 유도체 중 세포티암 화합물을 제조하는데 유용한 신규의 화합물에 관한 것이다.The present invention relates to a novel method for preparing a cefem derivative of Formula 1 or a salt thereof, and more particularly to a method for preparing a derivative of Formula 1 or a salt thereof by reacting a compound of Formula 2 with a compound of Formula 3 below. It is about. In addition, the present invention relates to a novel compound useful for preparing a cytothiar compound in the cefem derivative of Formula 1.
화학식 2Formula 2
화학식 3Formula 3
화학식 1Formula 1
상기 식에서,Where
R1은 H 또는이고,R 1 is H or ego,
R2은 H 또는이다.R 2 is H or to be.
Description
본 발명은 항생물질로 유용한 하기 화학식 1의 세펨 유도체 또는 그 염의 신규한 제조방법에 관한 것이다.The present invention relates to a novel process for preparing cefem derivatives of formula (1) or salts thereof useful as antibiotics.
상기 식에서,Where
R1은 H 또는이고,R 1 is H or ego,
R2은 H 또는이다.R 2 is H or to be.
또한, 본 발명은 상기 화학식 1의 세펨 유도체 중 세포티암 화합물을 제조하는데 유용한 중간체인 신규의 화합물에 관한 것이다.In addition, the present invention relates to a novel compound which is an intermediate which is useful for the preparation of a cytothiamic compound in the cefem derivative of Formula 1.
상기 화학식 1 의 화합물중 (6R, 7R)-7-[2-(2-아미노티아졸-4-일)아세트아미도]-3-[(2-디메틸아미노에틸-1H-테트라졸-5-일)티오메틸]-세프-3-엠-4-카복실산(이하 세포티암이라 함) 2염산염은 미국특허 제4,755,598호에 기재 및 청구되어 있는데, 그람음성균 및 그람양성균에 우수한 항균작용을 나타내며, 동시에 베타락타마제에 대해서도 매우 안정한 항생제로, 이의 합성방법은 대한민국 특허공고 제80-1595호, 제80-1672호, 제83-1415호 및 특허공개 제98-2052호, 제96-31464호 등에 기재되어 있다. 세포티암 2염산염을 제조하기 위한 선행기술들이 이미 공지되어 있지만 이 선행기술들은 제조공정상에 보호기를 사용해야 하는 불편함(특허공고 제80-1595호, 특허공개 제98-2052호)이 있을 뿐만 아니라 보호 및 탈보호를 해야 하므로 공정이 길어(특허공고 제80-1672호, 제83-1415호) 수율 및 함량이 떨어지는 단점을 가지고 있어 문제점이 많은 것으로 나타났다. 대한민국 특허공개 제96-31464호에는 세포티암 2염산염 제조시에 있어서, 포스포러스펜타클로라이드(PCl5)를 이용하여 유기산으로부터 산염화물을 제조하는 것을 특징으로 하고 있는데 포스포러스펜타클로라이드(PCl5)는 취급상의 문제점이 많고 수득되는 세포티암 2염산염의 수율 및 함량이 낮아 공정상에 문제가 많은 것으로 나타났다.(6R, 7R) -7- [2- (2-aminothiazol-4-yl) acetamido] -3-[(2-dimethylaminoethyl-1H-tetrazol-5- in the compound of Formula 1 Yl) thiomethyl] -sef-3-m-4-carboxylic acid (hereinafter referred to as cell thiam) dihydrochloride is described and claimed in US Pat. No. 4,755,598, which exhibits excellent antimicrobial activity against Gram-negative and Gram-positive bacteria. It is a very stable antibiotic for beta-lactamase, and its synthesis method is described in Korean Patent Publication Nos. 80-1595, 80-1672, 83-1415 and 98-5252, 96-31464. It is. Prior arts for the preparation of cytothia dihydrochloride are already known, but these prior arts not only have the inconvenience of using a protecting group in the manufacturing process (Patent Publications 80-1595, Patent Publication Nos. 98-2052) as well as protection. And deprotection has to be a long process (Patent Publication No. 80-1672, 83-1415) has a disadvantage in that the yield and content is falling, there are many problems. Republic of Korea, the cells at the time of manufacture Thiam dihydrochloride Patent Publication No. 96-31464 call, phosphorus pentachloride, and there is characterized in that an acid chloride prepared from an organic acid by the (PCl 5) phosphorus pentachloride (PCl 5) is treated There were many problems in the phase and the yield and content of the obtained cytothia dihydrochloride were low, indicating a lot of problems in the process.
또한, 상기 화학식 1 의 화합물 중 (6R, 7R)-7-[2-(2-아미노티아졸-4-일)메톡시이미노아세트아미도]-3-[(1-메틸-1H-테트라졸-5-일)티오메틸]-세프-3-엠-4-카복실산(이하 세프메녹심이라 함) 1/2염산염은 미국특허 제4,098,888호에 기재 및 청구되어 있는데, 그람음성균에 대하여 우수한 약효를 나타내며, 동시에 베타락타마제에 대하여 매우 안정하므로 유용한 항생제로 널리 사용되고 있다.Further, (6R, 7R) -7- [2- (2-aminothiazol-4-yl) methoxyiminoacetamido] -3-[(1-methyl-1H-tetra) in the compound of Formula 1 Zol-5-yl) thiomethyl] -sef-3-m-4-carboxylic acid (hereinafter referred to as cephmenoxime) 1/2 hydrochloride is described and claimed in US Pat. No. 4,098,888, which has excellent efficacy against Gram-negative bacteria. At the same time, it is widely used as a useful antibiotic since it is very stable against beta lactamase.
본 발명의 목적은 하기 화학식 1의 세펨 유도체 또는 그 염의 신규한 제조방법을 제공하는 것이다.It is an object of the present invention to provide a novel method for preparing a cefem derivative of Formula 1 or a salt thereof.
또한, 본 발명의 목적은 상기 화학식 1의 세펨 유도체 중 세포티암 화합물을 제조하는데 유용한 신규의 화합물을 제공하는 것이다.It is also an object of the present invention to provide a novel compound useful for preparing a cytothiar compound in the cefem derivative of Formula 1.
본 발명은 하기 화학식 1의 세펨 유도체 또는 그 염의 신규한 제조방법에 관한 것으로, 더 구체적으로는 산의 존재하 30∼50℃에서 1∼3 시간동안 하기 화학식 2의 화합물과 하기 화학식 3의 화합물을 반응시켜 하기 화학식 1의 유도체를 제조하는 단계; 및The present invention relates to a novel process for preparing a cefem derivative of Formula 1 or a salt thereof, and more particularly, to a compound of Formula 2 and a compound of Formula 3 for 1 to 3 hours at 30 to 50 ° C. in the presence of an acid. Reacting to prepare a derivative of Formula 1; And
하기 화학식 1의 유도체의 염을 만드는 임의의 단계를 포함하는,Comprising any step of making a salt of a derivative of formula
화학식 1의 세펨 유도체 또는 그 염을 제조하는 새로운 제조방법에 관한 것이다.The present invention relates to a novel preparation method for preparing a cefem derivative of Formula 1 or a salt thereof.
화학식 2Formula 2
화학식 3Formula 3
화학식 1Formula 1
상기 식에서,Where
R1은 H 또는이고,R 1 is H or ego,
R2은 H 또는이다.R 2 is H or to be.
또한, 본 발명은 상기 화학식 1의 세펨 유도체 중 세포티암 화합물을 제조하는데 유용한, R1이 H 인 상기 화학식 2의 화합물에 관한 것이다.In addition, the present invention relates to a compound of Formula 2, wherein R 1 is H, which is useful for preparing a cytothymium compound in the cefem derivative of Formula 1.
상기 염의 예로서는 염, 산부가염 등이 있으며, 상기 산부가염의 예로서는 2염산염, 1/2염산염 등을 들 수 있다.Examples of the salts include salts and acid addition salts, and examples of the acid addition salts include dihydrochloride and 1/2 hydrochloride.
본 발명은 산의 존재하 30∼50℃에서 1∼3 시간동안 화학식 2의 화합물과 화학식 3의 화합물을 반응시켜 화학식 1의 화합물을 얻는 것을 특징으로 하고 있다. 일반적으로는 C-3' 치환반응을 수행한 후 아실화 반응을 통해서 세펨계 목적화합물을 얻고 있다. 이는 C-3' 치환을 아실화 반응 후에 실시할 경우 반응성 및 제품의 함량이 떨어지기 때문이다. 하지만 본 발명에서는 적절한 시약과 반응조건을 검토하여 이러한 문제점을 해결할 수 있었다.The present invention is characterized by obtaining a compound of formula 1 by reacting a compound of formula 2 with a compound of formula 3 for 1 to 3 hours at 30 to 50 ° C in the presence of an acid. In general, the Cemfe-based target compound is obtained through acylation after the C-3 ′ substitution reaction. This is because when the C-3 'substitution is carried out after the acylation reaction, the reactivity and the product content decrease. However, the present invention was able to solve these problems by examining the appropriate reagents and reaction conditions.
본 발명의 화학식 1의 화합물의 개략적인 제조방법을 하기의 반응식 1 에 도시하였다.A schematic method for preparing the compound of Formula 1 of the present invention is shown in Scheme 1 below.
반응식 1Scheme 1
화학식 1Formula 1
화학식 2 화학식 3Formula 2 Formula 3
화학식 4Formula 4
R1이 H 인 화학식 2의 화합물은 신규한 화합물로서 R1이 H 인 화학식 1의 화합물, 즉 세포티암 화합물의 제조에 유용하며, 7-아미노세팔로스포란산(7-ACA)과R1이 H 인 화학식 4의 화합물의 아실화 반응으로부터 제조될 수 있는데, 상기 반응은 트리에틸아민, 피리딘, 트리메틸아민 등의 염기조건하에서 진행되며, 더 바람직하게는 트리에틸아민의 존재하에서 수행된다. 바람직한 반응용매는 아세토니트릴, 메틸렌클로라이드, 아세톤 등이며, 이중에서 아세토니트릴이 더 바람직하다. 반응온도는 -30 ∼ 30℃ 이 적절하며 반응시간은 1 ∼ 4 시간이 적절하다.Compounds of formula 2 R 1 is H is a compound of Formula 1 R 1 H is a novel compound, that is useful in the production of cell Thiam compound 7-amino-cephalostatin spokes is acid (7-ACA) with R 1 This H can be prepared from an acylation reaction of the compound of formula 4, which is carried out under basic conditions such as triethylamine, pyridine, trimethylamine, and more preferably in the presence of triethylamine. Preferred reaction solvents are acetonitrile, methylene chloride, acetone and the like, of which acetonitrile is more preferred. The reaction temperature is preferably -30 to 30 ° C and the reaction time is 1 to 4 hours.
화학식 4Formula 4
R1이인 화학식 2의 화합물은 세포탁심으로 공지되어 있으므로, R1이인 경우에는 화학식 2의 화합물로서 상기 공지 화합물인 세포탁심을 사용할 수 있다.R 1 is Compound of formula (II) is known as cytotaxime, so R 1 is In the case of the compound of formula (2) can be used a cell taxime known as the known compound.
본 발명에서 화학식 1의 화합물은, 화학식 2의 화합물의 C-3' 위치에 화학식 3의 화합물을 도입하는 방법으로 제조할 수 있으며, 이는 매우 신규한 제조방법이다. 또한, 염기의 존재하에서 R1이 H 인 화학식 4의 화합물과 7-아미노세팔로스포란산(7-ACA)을 아실화 반응시켜 R1이 H 인 화학식 2의 화합물을 얻을 수 있다. 상기 아실화 반응은 적절하게는 메틸렌클로라이드, 아세토니트릴 등의 반응용매를 사용할 수 있으나, 아세토니트릴이 가장 적절하며, 염기로는 피리딘, 트리에틸아민, 트리메틸아민 등이 유용하나 트리에틸아민이 적절하다. 상기 아실화 반응은 적절하게는 -30 ∼ 30℃에서 1∼4 시간 동안 진행하며, 가장 적절한 수율을 얻기 위해서는 -5 ∼ 10℃에서 3시간동안 반응시키는 것이 유용하다.In the present invention, the compound of Formula 1 may be prepared by a method of introducing the compound of Formula 3 to the C-3 ′ position of the compound of Formula 2, which is a very novel process. In addition, a compound of formula 4 wherein R 1 is H and acylated 7-aminocephalosporanic acid (7-ACA) in the presence of a base may be obtained to obtain a compound of formula 2 wherein R 1 is H. The acylation reaction may be suitably used a reaction solvent such as methylene chloride, acetonitrile, acetonitrile is most suitable, pyridine, triethylamine, trimethylamine and the like is useful as a base, but triethylamine is suitable. . The acylation reaction suitably proceeds for 1 to 4 hours at -30 to 30 ° C, and it is useful to react for 3 hours at -5 to 10 ° C in order to obtain the most suitable yield.
바람직하게는 아세토니트릴 등의 무수성 유기용매 중에서 산의 존재하에서 위와 같은 방법으로 얻어진 화학식 2의 화합물을 화학식 3의 화합물과 반응시켜 화학식 1의 화합물을 얻을 수 있으며, 반응조건으로는 30 ∼ 50℃에서 1∼3 시간 동안 반응시키는 것이 유용하고, 40℃에서 2시간 동안 반응시키는 것이 가장 적절하다.Preferably, the compound of formula (2) obtained by the above method in the presence of an acid in anhydrous organic solvent such as acetonitrile may be reacted with the compound of formula (3) to obtain a compound of formula (1). It is useful to react for 1 to 3 hours at and most suitable for 2 hours at 40 ° C.
본 발명의 화학식 2의 화합물과 화학식 3의 화합물의 반응시에 사용되는 반응용매의 예로서는 유기용매 등이 있으며, 구체적으로는 아세토니트릴 등의 무수성 유기용매를 포함한다.Examples of the reaction solvent used in the reaction of the compound of the formula (2) and the compound of the formula (3) of the present invention include an organic solvent and the like, and specifically include anhydrous organic solvents such as acetonitrile.
본 발명의 화학식 2의 화합물과 화학식 3의 화합물의 반응시에 사용되는 산으로는 보론트리플루오르 이써레이트, 황산, 메탄술폰산 등과 그 혼합물을 사용할 수 있으며 이들중 보론트리플루오르 이써레이트가 가장 효과적이다. 즉, 보론트리플루오르 이써레이트는 C-3' 치환을 위한 수율, 반응성 등의 면에서 가장 유용한 시약이다. 또한 보론트리플루오르 이써레이트를 메탄술폰산과 함께 사용하면 반응물의 용해성이 증가되어 반응성이 증가한다.As the acid used in the reaction of the compound of Formula 2 and the compound of Formula 3 of the present invention, a mixture of boron trifluoro etherate, sulfuric acid, methanesulfonic acid, and the like may be used, and among these, boron trifluoro etherate is most effective. In other words, borontrifluoro etherate is the most useful reagent in terms of yield, reactivity and the like for C-3 'substitution. In addition, the use of borontrifluoro etherate in combination with methanesulfonic acid increases the solubility of the reactants resulting in increased reactivity.
R1이이고, R2가 H 인 상기 화학식 1의 유도체(세프메녹심)를제조하기 위해서는, 보론트리플루오르 이써레이트의 존재하 30∼50℃에서 1∼3 시간동안 R1이인 상기 화학식 2의 화합물과 R2가 H 인 화학식 3의 화합물을 반응시키는 것이 바람직하다.R 1 is In order to prepare a derivative of Formula 1 (sefmenoxime) wherein R 2 is H, R 1 is formed for 1 to 3 hours at 30 to 50 ° C. in the presence of borontrifluoro etherate. It is preferable to react the compound of Formula 2 wherein R 2 is H.
또한, R1이 H 이고, R2가인 상기 화학식 1의 유도체(세포티암)를 제조하기 위해서는, 보론트리플루오르 이써레이트 및 메탄술폰산의 존재하 30∼50℃에서 1∼3 시간동안 R1이 H 인 상기 화학식 2의 화합물과 R2가인 상기 화학식 3의 화합물을 반응시키는 것이 바람직하다.R 1 is H and R 2 is In order to prepare a derivative of the formula (Cythiathia), the compound of Formula 2 and R 2 wherein R 1 is H for 1 to 3 hours at 30 to 50 ° C. in the presence of borontrifluoro etherate and methanesulfonic acid It is preferable to react the compound of the formula (3).
바람직한 구체예로서, 보론트리플루오르 이써레이트와 메탄술폰산의 존재하에서 화학식 2의 화합물과 화학식 3의 화합물을 40℃에서 2시간동안 반응시켜서 화학식 1의 유도체를 제조할 수 있다.In a preferred embodiment, the derivative of Formula 1 may be prepared by reacting the compound of Formula 2 with the compound of Formula 3 at 40 ° C. for 2 hours in the presence of borontrifluoro etherate and methanesulfonic acid.
본 발명의 화학식 1의 화합물을 얻기 위한 C-3' 치환 반응시 사용되는 반응용매의 예로는 메틸렌클로라이드, 아세토니트릴, 아세톤 및 이들의 혼합용액 등이 유용하나 이에 한정되는 것은 아니며, 이 중 아세토니트릴의 사용이 더 바람직하다.Examples of the reaction solvent used in the C-3 ′ substitution reaction to obtain the compound of Chemical Formula 1 of the present invention include, but are not limited to, methylene chloride, acetonitrile, acetone, and a mixed solution thereof, including but not limited to acetonitrile. Is more preferred.
세포티암 화합물을 제조하는 경우에, 상기 화학식 1의 화합물을 생성하는 C-3' 치환 반응이 완결된 후 염산을 이용하여 용액의 pH를 0.8 ∼ 1.5 로 조절하여 세포티암 2염산염을 얻는다. 이때 사용되는 염산은 2 ∼ 5 N 염산이 바람직하며,2.5N 염산이 가장 적절하다.In the case of preparing a cytothiar compound, after completion of the C-3 ′ substitution reaction to produce the compound of Formula 1, the pH of the solution is adjusted to 0.8 to 1.5 using hydrochloric acid to obtain cytothioma dihydrochloride. The hydrochloric acid used at this time is preferably 2 to 5 N hydrochloric acid, most preferably 2.5 N hydrochloric acid.
세프메녹심 화합물을 제조하는 경우에, C-3' 치환 반응이 종료되면 물을 첨가하고 유기용매를 제거한 후 2∼8 N HCl을 가하여 1/2염산염 형태로 쉽게 백색 결정 형태의 화학식 1의 유도체의 염을 얻을 수 있으며, 결정을 얻기 위한 적절한 pH의 범위는 0.5 ∼ 2 이고 더 바람직하게는 1.2 ∼ 1.5 이며, 반응온도는 0 ∼ 15 ℃가 적절하다.When preparing Cefmenoxime compound, when the C-3 'substitution reaction is completed, water is added, the organic solvent is removed, and 2-8 N HCl is added to easily convert the derivative of Chemical Formula 1 into white crystalline form in 1/2 hydrochloride form. The salt of can be obtained, the range of suitable pH for obtaining a crystal | crystallization is 0.5-2, More preferably, it is 1.2-1.5, The reaction temperature is 0-15 degreeC.
본 명세서내 각 반응에서, 생성물은 당업계에 공지된 통상의 방법에 의하여 반응계로부터 분리 및/또는 정제될 수 있다. 분리 및 정제방법의 예로는, 증류(대기압하 증류 및 감압증류를 포함), 재결정, 칼럼 크로마토그래피, 이온교환 크로마토그래피, 겔 크로마토그래피, 친화성 크로마토그래피, 박층 크로마토그래피, 상 분리, 용매 추출, 세척 등을 이용할 수 있다. 정제는 각 반응후마다, 또는 일련의 반응 후에 수행할 수 있다.In each reaction herein, the product can be separated and / or purified from the reaction system by conventional methods known in the art. Examples of separation and purification methods include distillation (including distillation under atmospheric pressure and distillation under reduced pressure), recrystallization, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, thin layer chromatography, phase separation, solvent extraction, Washing and the like can be used. Purification can be carried out after each reaction or after a series of reactions.
하기에서 실시예를 들어 본 발명을 더 상세히 설명하겠지만, 하기 실시예는 예시의 목적으로만 제공된 것이며, 본 발명의 범주 및 범위가 하기 실시예에 의해 제한되는 것은 아니다.Although the present invention will be described in more detail with reference to the following examples, the following examples are provided for illustrative purposes only, and the scope and scope of the present invention are not limited by the following examples.
[실시예 1]Example 1
2-아미노티아졸-4-일 아세트산 염산염의 제조Preparation of 2-aminothiazol-4-yl acetic acid hydrochloride
3구 플라스크에 2-아미노티아졸-4-일 아세트산 12g을 물 16ml에 현탁시키고 40℃로 가온한 후 12N 염산 12ml를 첨가했다. 70∼80℃로 가온하여 2∼3시간동안반응시키고 0℃로 냉각시켰다. 반응액에 아세톤 100ml를 첨가하고 10분동안 교반시킨 후 고체를 여과하고 20ml의 아세톤으로 세척한 후 건조하여 표제화합물 14g(92%)을 수득하였다.In a three-necked flask, 12 g of 2-aminothiazol-4-yl acetic acid was suspended in 16 ml of water, warmed to 40 ° C, and 12 ml of 12N hydrochloric acid was added. Warmed to 70-80 ° C., reacted for 2-3 hours and cooled to 0 ° C. 100 ml of acetone was added to the reaction mixture, stirred for 10 minutes, the solid was filtered, washed with 20 ml of acetone, and dried to obtain 14 g (92%) of the title compound.
1H NMR (D2O, 300MHz) δ 6.98(s, 1H), 3.65(s, 2H) 1 H NMR (D 2 O, 300 MHz) δ 6.98 (s, 1H), 3.65 (s, 2H)
[실시예 2]Example 2
2-아미노티아졸-4-일 아세틸클로라이드 염산염(화학식 4의 화합물)의 제조Preparation of 2-aminothiazol-4-yl acetylchloride hydrochloride (compound of formula 4)
3구 플라스크에 아세토니트릴 56ml를 투입하고 0∼5℃로 냉각시켰다. 여기에 포스포러스옥시클로라이드 13ml를 첨가하고 N, N-디메틸포름아미드 9ml를 온도를 유지하면서 천천히 첨가한 후 30분 정도 교반시켰다. 여기에 2-아미노티아졸-4-일 아세트산 염산염 14g을 0℃를 유지하면서 천천히 첨가한 후 같은 온도에서 3시간동안 교반시켰다. 생성된 고체를 여과하고 아세토니트릴 20ml로 세척 및 건조하여 표제화합물 13g(85%)을 수득하였다.56 ml of acetonitrile were added to a three neck flask and cooled to 0-5 ° C. 13 ml of phosphorus oxychloride was added thereto, and 9 ml of N and N-dimethylformamide were slowly added while maintaining the temperature, followed by stirring for about 30 minutes. 14 g of 2-aminothiazol-4-yl acetate hydrochloride was slowly added thereto while maintaining at 0 ° C., followed by stirring at the same temperature for 3 hours. The resulting solid was filtered, washed with 20 ml of acetonitrile and dried to give 13 g (85%) of the title compound.
1H NMR (D2O, 300MHz) δ 6.97(s, 1H), 3.62(s, 2H) 1 H NMR (D 2 O, 300 MHz) δ 6.97 (s, 1H), 3.62 (s, 2H)
[실시예 3]Example 3
3-아세톡시메틸-7-[2-(2-아미노티아졸-4-일)아세틸아미노]-세펨-카르복실산(화학식 2의 화합물)의 제조Preparation of 3-acetoxymethyl-7- [2- (2-aminothiazol-4-yl) acetylamino] -cepm-carboxylic acid (compound of formula 2)
3구 플라스크에 아세토니트릴 40ml를 투입하고 0∼5℃로 냉각시켰다. 여기에 7-아미노세팔로스포란산 100g을 투입한 후 물 20ml를 첨가했다. 온도를 유지하면서 트리에틸아민 6ml를 적가하여 용해시켰다. 여기에 2-아미노티아졸-4-일 아세틸클로라이드 염산염 13g을 온도를 유지하면서 천천히 첨가한 후 120분간 교반시켰다. 반응이 완결되면 12N 염산 4ml를 가하여 pH를 1.5 정도로 조절했다. 생성된 고체를 여과하고 10ml의 아세톤으로 세척, 건조하여 표제화합물 12g(95%)을 수득하였다.40 ml of acetonitrile were added to a three neck flask and cooled to 0-5 ° C. 100 g of 7-aminocephalosporranic acid was added thereto and 20 ml of water was added thereto. 6 ml of triethylamine was added dropwise while maintaining the temperature. 13 g of 2-aminothiazol-4-yl acetylchloride hydrochloride was slowly added thereto while maintaining the temperature, followed by stirring for 120 minutes. When the reaction was completed, the pH was adjusted to 1.5 by adding 4 ml of 12N hydrochloric acid. The resulting solid was filtered, washed with 10 ml of acetone and dried to give 12 g (95%) of the title compound.
1H NMR (D2O, 300MHz) δ 6.97(s, 1H), 5.12(d, J=6.8Hz, 1H), 4.83(d, 1 H NMR (D 2 O, 300 MHz) δ 6.97 (s, 1 H), 5.12 (d, J = 6.8 Hz, 1 H), 4.83 (d,
J=7.2Hz, 1H), 4.21(m, 2H), 3.89(s, 3H),J = 7.2 Hz, 1H), 4.21 (m, 2H), 3.89 (s, 3H),
3.62(s, 2H), 3.72(m, 2H)3.62 (s, 2H), 3.72 (m, 2H)
[실시예 4]Example 4
(6R,7R)-7-[2-(2-아미노티아졸-4-일)아세트아미도]-3-[(2-디메틸아미노에틸-1H-테트라졸-5-일)티오메틸]-세프-3-엠-4-카복실산(세포티암; R1이 H 이고 R2가인 화학식 1의 화합물) 2염산염의 제조(6R, 7R) -7- [2- (2-aminothiazol-4-yl) acetamido] -3-[(2-dimethylaminoethyl-1 H-tetrazol-5-yl) thiomethyl]- Cef-3-M-4-carboxylic acid (Cytothiam; R 1 is H and R 2 is Preparation of Phosphorus Dihydrochloride)
3구 플라스크에 아세토니트릴 50ml를 투입하고 0∼5℃로 냉각시킨 후 보론트리플루오르 이써레이트 14ml를 첨가하고 메탄술폰산 12ml를 천천히 첨가했다. 여기에 5-메르캅토-1H-(2-디메틸아미노에틸)-테트라졸 6.7g을 투입하였다. 그 후 3-아세톡시메틸-7-[2-(2-아미노티아졸-4-일)아세틸아미노]-세펨-카르복실산 12g을 투입하고 30℃에서 2시간동안 반응시켰다. 반응액의 온도를 20℃로 조절하고 물 25ml를 가한 후에 20분동안 교반시켰다. 반응액에 암모니아수 20ml를 가하여 용액의 pH를 3.0 ∼ 3.5로 조절한 후 생성된 고체를 여과하여 백색의 결정을 수득하였다. 수득된 백색결정을 물 10 ml 에 희석시키고 진한 염산 5 ml을 가하여 pH 를 1.0 으로 조절한 후 100 ml 의 아세톤을 천천히 적가하여 백색의 결정을 석출시키고 이를 여과, 건조하여 표제화합물 14g(98%)을 수득하였다.50 ml of acetonitrile were added to a three-necked flask, cooled to 0-5 ° C., and 14 ml of borontrifluoro etherate was added, and 12 ml of methanesulfonic acid was added slowly. 6.7 g of 5-mercapto-1H- (2-dimethylaminoethyl) -tetrazole was added thereto. Thereafter, 12 g of 3-acetoxymethyl-7- [2- (2-aminothiazol-4-yl) acetylamino] -cepm-carboxylic acid was added thereto, and the mixture was reacted at 30 ° C. for 2 hours. The temperature of the reaction solution was adjusted to 20 ° C., and 25 ml of water was added thereto, followed by stirring for 20 minutes. 20 ml of ammonia water was added to the reaction solution to adjust the pH of the solution to 3.0 to 3.5, and the resulting solid was filtered to obtain white crystals. The obtained white crystals were diluted in 10 ml of water, 5 ml of concentrated hydrochloric acid was added to adjust the pH to 1.0, and 100 ml of acetone was slowly added dropwise to precipitate white crystals which were filtered and dried to give 14 g (98%) of the title compound. Obtained.
1H NMR (D2O, 300MHz) δ 6.97(s, 1H), 5.13(d, J=6.8Hz, 1H), 4.86(t, 1 H NMR (D 2 O, 300 MHz) δ 6.97 (s, 1 H), 5.13 (d, J = 6.8 Hz, 1 H), 4.86 (t,
J=10.2, 4.8Hz, 2H), 4.83(d, J=7.2Hz, 1H), 4.21(q,J = 10.2, 4.8 Hz, 2H), 4.83 (d, J = 7.2 Hz, 1H), 4.21 (q,
2H), 3.81(t, J=7.8, 6.7Hz, 2H), 3.72(q, 2H),2H), 3.81 (t, J = 7.8, 6.7 Hz, 2H), 3.72 (q, 2H),
3.65(s, 2H), 3.01(s, 6H)3.65 (s, 2H), 3.01 (s, 6H)
[실시예 5]Example 5
(6R, 7R)-7-[2-(2-아미노티아졸-4-일)메톡시이미노아세트아미도]-3-[(1-메틸-1H-테트라졸-5-일)티오메틸]-세프-3-엠-4-카복실산(세프메녹심; R1이이고 R2가 H 인 화학식 1의 화합물) 1/2염산염의 제조(6R, 7R) -7- [2- (2-aminothiazol-4-yl) methoxyiminoacetamido] -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl ] -Cef-3-em-4-carboxylic acid (sefmenoxime; R 1 is And a compound of formula 1 wherein R 2 is H)
3구 플라스크에 아세토니트릴 100ml를 투입하고 온도를 0∼5℃로 냉각시킨 후 보론트리플루오르 이써레이트 14ml 및 메탄술폰산 10ml를 투입하고 10분동안 교반시켰다. 여기에 1-아미노-5-메르캅토-1H-테트라졸 60g을 첨가하고 30분동안 교반시켰다. 완전하게 용해된 후에 세포탁심(하기 화학식 5의 화합물) 45g을 투입하고 40℃에서 60분동안 교반시켰다.100 ml of acetonitrile were added to a three-necked flask, and the temperature was cooled to 0-5 ° C., followed by 14 ml of boron trifluoro etherate and 10 ml of methanesulfonic acid, followed by stirring for 10 minutes. To this was added 60 g of 1-amino-5-mercapto-1H-tetrazole and stirred for 30 minutes. After complete lysis, 45 g of Cytotaxime (compound of Formula 5) was added thereto, followed by stirring at 40 ° C. for 60 minutes.
화학식 5Formula 5
반응이 완결되면 10∼15℃로 냉각시키고 냉각수 30ml를 첨가했다. 30분동안 교반시킨 후 트리에틸아민 30 ml를 적가하여 pH를 3.3 으로 조절하여 백색의 결정을 수득하였다. 수득된 백색결정을 50 ml의 물에 희석시킨 후 진한 염산 18 ml를 적가하여 pH를 1.1로 조절하여 완전히 용해시켰다. 아세톤 300 ml를 천천히 용해액에 적가하여 회백색의 결정을 얻었다. 생성된 고체를 여과하여 (6R, 7R)-7-[2-(2-아미노티아졸-4-일)메톡시이미노아세트아미도]-3-[(1-메틸-1H-테트라졸-5-일)티오메틸]-세프-3-엠-4-카복실산 1/2염산염 50g(89%)을 수득하였다.When the reaction was completed, the mixture was cooled to 10-15 DEG C and 30 ml of cooling water was added. After stirring for 30 minutes, 30 ml of triethylamine was added dropwise to adjust the pH to 3.3 to obtain white crystals. The obtained white crystals were diluted in 50 ml of water, and then 18 ml of concentrated hydrochloric acid was added dropwise to adjust the pH to 1.1 to completely dissolve. 300 ml of acetone were slowly added dropwise to the solution to give off-white crystals. The resulting solid was filtered to give (6R, 7R) -7- [2- (2-aminothiazol-4-yl) methoxyiminoacetamido] -3-[(1-methyl-1H-tetrazol- 50 g (89%) of 5-yl) thiomethyl] -sef-3-m-4-carboxylic acid 1/2 hydrochloride was obtained.
1H NMR (D2O, 300MHz) δ 6.98(s, 1H), 5.75(d, J=7.2Hz, 1H), 5.12(d, 1 H NMR (D 2 O, 300 MHz) δ 6.98 (s, 1H), 5.75 (d, J = 7.2 Hz, 1H), 5.12 (d,
J=6.8Hz, 1H), 4.09(s, 3H), 3.96(s, 3H), 3.85(d,J = 6.8 Hz, 1H), 4.09 (s, 3H), 3.96 (s, 3H), 3.85 (d,
J=7.1Hz, 2H)J = 7.1Hz, 2H)
본 발명에 따르면, 하기 화학식 1의 세펨 유도체 또는 그 염의 신규한 제조방법이 제공된다.According to the present invention, there is provided a novel method for preparing a cefem derivative of Formula 1 or a salt thereof.
특히 세프메녹심을 제조하는 경우에는 기존의 항생제(세포탁심)를 이용하여 다른 항생제를 제조할 수 있다는 공업적인 장점이 있으며 이런 측면에서 경제적인 효과가 크다.In particular, in the case of manufacturing cefemenoxime, there is an industrial advantage that other antibiotics can be prepared by using an existing antibiotic (Cerataxim), and in this aspect, it is economically effective.
또한, 본 발명에 따르면 상기 화학식 1의 세펨 유도체 중 세포티암 화합물을 제조하는데 유용한 신규의 화합물이 제공된다.In addition, according to the present invention there is provided a novel compound useful for preparing a cell thiam compound in the cefem derivative of the formula (1).
Claims (7)
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5287192A (en) * | 1976-01-14 | 1977-07-20 | Roussel Uclaf | 77aminothiazolylacetoamid cephalospolanate derivatives process for preparing same and pharmaceutical composition |
| US4312986A (en) * | 1978-07-06 | 1982-01-26 | Toyama Chemical Co., Ltd. | Process for producing 7-(substituted)amino-3-substituted thiomethyl-Δ3 -cephem-4-carboxylic acids |
| US4317907A (en) * | 1977-02-08 | 1982-03-02 | Toyama Chemical Co., Ltd. | Process for producing 7-(substituted)amino-3-substituted thiomethyl cephem carboxylic acids |
| KR840002163A (en) * | 1981-10-26 | 1984-06-11 | 제롬 제이. 잔 | Piezoelectric Crystal Assemblies and Manufacturing Method Thereof |
| KR850000322A (en) * | 1983-06-30 | 1985-02-26 | 도비야마 가즈오 | Oscillation control method of vehicle with automatic clutch |
| KR960034206A (en) * | 1995-03-30 | 1996-10-22 | 김종인 | Method for preparing cephalosporin intermediate |
| KR970042559A (en) * | 1995-12-22 | 1997-07-24 | 김사웅 | Simple Method of Making Cemfe Derivatives |
-
2000
- 2000-11-16 KR KR10-2000-0068165A patent/KR100432425B1/en not_active IP Right Cessation
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5287192A (en) * | 1976-01-14 | 1977-07-20 | Roussel Uclaf | 77aminothiazolylacetoamid cephalospolanate derivatives process for preparing same and pharmaceutical composition |
| US4317907A (en) * | 1977-02-08 | 1982-03-02 | Toyama Chemical Co., Ltd. | Process for producing 7-(substituted)amino-3-substituted thiomethyl cephem carboxylic acids |
| US4312986A (en) * | 1978-07-06 | 1982-01-26 | Toyama Chemical Co., Ltd. | Process for producing 7-(substituted)amino-3-substituted thiomethyl-Δ3 -cephem-4-carboxylic acids |
| KR840002163A (en) * | 1981-10-26 | 1984-06-11 | 제롬 제이. 잔 | Piezoelectric Crystal Assemblies and Manufacturing Method Thereof |
| KR850000322A (en) * | 1983-06-30 | 1985-02-26 | 도비야마 가즈오 | Oscillation control method of vehicle with automatic clutch |
| KR960034206A (en) * | 1995-03-30 | 1996-10-22 | 김종인 | Method for preparing cephalosporin intermediate |
| KR970042559A (en) * | 1995-12-22 | 1997-07-24 | 김사웅 | Simple Method of Making Cemfe Derivatives |
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