KR100388108B1 - New process for producing intermediates of cephalosporin antibiotics - Google Patents
New process for producing intermediates of cephalosporin antibiotics Download PDFInfo
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- KR100388108B1 KR100388108B1 KR10-2000-0046554A KR20000046554A KR100388108B1 KR 100388108 B1 KR100388108 B1 KR 100388108B1 KR 20000046554 A KR20000046554 A KR 20000046554A KR 100388108 B1 KR100388108 B1 KR 100388108B1
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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
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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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
Abstract
본 발명은 세팔로스포린계 항생제 제조를 위하여 사용되는 화학식 (1)의 중간체 화합물의 제조방법에 관한것이다. 상세하게는 7β-아미노-3-[5-(메틸-1,2,3,4-테트라졸일)티오메틸]-△3-세펨-4-카복실산의 아민기와 카르복실산의 반응 중 1,3-비스(트리메틸실릴)우레아를 사용하여 직접 실릴화하고, D-α-(4-에틸-2,3-디옥소-1-피페라진 카르복시아미도)-β-(s)-하이드로부틸산을 디메틸아세트아미드와 포스포러스옥시클로라이드로 활성화하여 얻어진 화합물과 아실화 반응시킴으로서 화학식 (1)의 화합물을 얻는 제조방법에 관한 것이다.The present invention relates to a method for preparing the intermediate compound of formula (1) used for the preparation of cephalosporin antibiotics. Specifically 7β- amino-3- [5- (methyl-1,2,3,4-tetrazolyl) thiomethyl] - △ 3 - cephem-4-carboxylic acid of the amine group of the reaction of the carboxylic acid 1,3 Directly silylated with bis (trimethylsilyl) urea and D-α- (4-ethyl-2,3-dioxo-1-piperazine carboxamido) -β- (s) -hydrobutyl acid A method for producing a compound of formula (1) by acylation with a compound obtained by activating dimethylacetamide and phosphorus oxychloride.
본 발명의 제조방법으로 △2이성체 및 부산물 등의 생성없이 고순도, 고수율로 목적화합물을 합성할 수 있다.In the preparation method of the present invention, a target compound can be synthesized in high purity and high yield without generating Δ 2 isomers and by-products.
화학식 1Formula 1
Description
본 발명은 경구투여에 적합한 세팔로스포린 화합물의 제조를 위해 유용한 중간체로 사용되는 하기 화학식 (1)의 화합물 제조방법에 관한 것이다. 특히, 화학식 (1)의 화합물은 3세대 경구용 항생제인 화학식 (2)의 세프부페라존을 제조하기 위해 사용되는 유용한 중간체 물질이다.The present invention relates to a process for the preparation of the compound of formula (1) which is used as a useful intermediate for the preparation of cephalosporin compounds suitable for oral administration. In particular, the compound of formula (1) is a useful intermediate material used to prepare cebubuperazone of formula (2) which is a third generation oral antibiotic.
화학식 (1)의 중간체 화합물의 제조방법이 선행특허 US -4,263,292에 보고되어 있다. 상기 선행특허에 의하면, D-α-(4-에틸-2,3-디옥소-1-피페라진 카르복시아미도)-β-(s)-하이드로부틸산(화학식 3, 이하 2-EDPT라함)과 디페닐메틸-7β-아미노-3-[5-(메틸-1,2,3,4-테트라졸일)티오메틸]-△3-세펨-4-카복실레이트(화학식 4)를 1-메틸 몰포린 염기하에서 반응시켜 화학식 (1)의 중간체 화합물을 제조하였다.A process for the preparation of intermediate compounds of formula (1) is reported in prior patent US Pat. No. 4,263,292. According to the prior patent, D-α- (4-ethyl-2,3-dioxo-1-piperazine carboxamido) -β- (s) -hydrobutyl acid (Formula 3, hereinafter referred to as 2-EDPT) and diphenylmethyl -7β- amino-3- [5- (methyl-1,2,3,4-tetrazolyl) thiomethyl] - △ 3 - cephem-4-carboxylate (IV) 1-methyl-mol Reaction under porin base gave an intermediate compound of formula (1).
상기 선행특허에 있어서, 화학식 (4) 화합물은 화학식 (5)의 7β-아미노-3-[5-(메틸-1,2,3,4-테트라졸일)티오메틸]-△3-세펨-4-카복실산(이하 7-TMCA라함)의 카르복실산에 알킬화반응을 실시한 후 분리하여 출발물질로 사용하게 되는데, 이 방법은 비경제적일 뿐만 아니라, 알킬화반응 과정에서 생성되는 △2이성체 생성을 억제할 수 없다. 또한, 아실화 반응 과정에서도 하기 화학식 (6)의 △2이성체 및 하기 화학식 (7), 화학식 (8)과 같은 부산물 또는 β-락탐 고리의 분해로 인한 다량의 부산물이 생성되는 등 많은 문제점을 가지고 있다. 이러한 부산물들은 실제 수율을 감소시키며, △2이성체의 경우 분리가 매우 어려워 정제공정에 커다란 지장을 줄 뿐 아니라 최종 목적화합물인 세프부페라존의 제조과정에도 부작용을 초래한다.In the prior patent, the formula 4 compounds are 7β- amino-3- [5- (methyl-1,2,3,4-tetrazolyl) thiomethyl] of formula (5) - △ 3 - cephem -4 The carboxylic acid (hereinafter referred to as 7-TMCA) is subjected to alkylation reaction and then separated and used as starting material. This method is not only economical, but also inhibits the formation of Δ 2 isomers generated during the alkylation reaction. Can't. In addition, the acylation reaction has many problems, such as Δ 2 isomers of the following formula (6) and by-products such as the following formulas (7) and (8) or a large amount of by-products due to decomposition of the β-lactam ring. have. These by-products reduce the actual yield, and △ 2 isomers are very difficult to separate, which greatly affects the purification process and also adversely affects the preparation of cebubuperazone, the final target compound.
본 발명자들은 하기 화학식 (5)의 화합물(이하 7-TMCA라함)을 직접 출발물질로 사용하고 △2이성체 및 부산물 등의 생성없이 목적화합물을 제조할 수 있는 방법을 개발하고자 노력하였다.The present inventors have tried to develop a method of preparing a target compound without using a compound of the formula (5) (hereinafter referred to as 7-TMCA) as a direct starting material and generating Δ 2 isomers and by-products.
본 발명자들은 다양한 연구의 결과를 기초로 하여 화학식 (5)의 화합물의 아민기와 카르복실산을 하기 화학식(9)의 1,3-비스(트리메틸실릴)우레아(이하 BSU라함)를 사용하여 반응중에 직접 실릴화하고, 화학식(3)의 화합물을 활성화하여 얻은 화학식 (11)의 화합물과 아실화 반응시켜 화학식(1)의 중간체 화합물을 제조함으로서, 상기 선행기술의 제조방법에서 야기되는 부반응에 의한 △2이성체 및 이로 인한 여러 부산물의 생성을 억제하여 최종 생성물의 수율과 순도를 현저히 높일 수 있고 경제적인 이점을 제공할 수 있다는 것을 발견하고 본 발명을 완성하게 되었다.Based on the results of various studies, the present inventors have carried out the reaction of the amine group of the compound of formula (5) with carboxylic acid using 1,3-bis (trimethylsilyl) urea of formula (9) (hereinafter referred to as BSU). ? Due to side reactions caused in the preparation method of the prior art by directly silylating and acylating the compound of formula (11) to activate the compound of formula (3) The present invention has been completed by discovering that it is possible to suppress the production of isomers and the various by-products thereof, thereby significantly increasing the yield and purity of the final product and providing economic advantages.
본 발명은 a) 하기 화학식 (5)의 7-TMCA를 화학식(9)의 BSU를 사용하여 실릴화하여 화학식 (10)을 제조하는 단계,The present invention comprises the steps of: a) silylating 7-TMCA of formula (5) using BSU of formula (9) to prepare formula (10),
b) 하기 화학식 (3)의 2-EDPT를 디메틸아세트아미드와 포스포러스옥시클로라이드에 의해 활성화 시켜 화학식 (11)의 화합물을 제조하는 단계 및b) activating 2-EDPT of formula (3) with dimethylacetamide and phosphorus oxychloride to prepare a compound of formula (11), and
c) 상기의 반응단계 a)와 b)로부터 제조된 화학식 (10)의 화합물과화학식(11)의 화합물을 아실화 반응시켜 하기 화학식 (1)의 화합물을 수득하는 단계를 포함하는 것을 특징으로 하는 화학식 (1)의 제조방법에 관한 것이다.c) acylating the compound of formula (10) and the compound of formula (11) prepared from the reaction steps a) and b) to obtain a compound of formula (1) It relates to a process for the preparation of formula (1).
(R= 수소 또는 트리메틸실릴기)(R = hydrogen or trimethylsilyl group)
화학식 (5)의 7-TMCA를 실릴화 하기 위하여 사용하는 BSU의 양은 1∼ 2.5당량이 바람직하며, 더욱 바람직하게는 1.9∼ 2.1당량이다. 반응온도는 10∼ 80℃가 바람직하고 더욱 바람직하게는 20∼ 35℃이며, 반응시간은 30분 내지 24시간이 바람직하고, 보다 바람직하게는 1시간 내지 5시간이다.The amount of BSU used for silylating 7-TMCA of the formula (5) is preferably 1 to 2.5 equivalents, more preferably 1.9 to 2.1 equivalents. The reaction temperature is preferably 10 to 80 ° C, more preferably 20 to 35 ° C, and the reaction time is preferably 30 minutes to 24 hours, more preferably 1 hour to 5 hours.
화학식 (3)의 2-EDPT의 활성화 과정에서의 디메틸아세트아미드의 사용량은 1∼ 3당량이 바람직하고, 더욱 바람직하게는 1∼ 1.3당량이다. 포스포러스옥시클로라이드의 사용량은 1∼ 3당량이 바람직하고, 더욱 바람직하게는 1.0∼ 1.5당량이다. 반응온도는 10∼ 30℃가 바람직하고, 더욱 바람직하게는 23∼ 28℃이다. 반응시간은 2∼ 3시간이 바람직하다.The amount of dimethylacetamide used in the process of activating 2-EDPT of the formula (3) is preferably 1 to 3 equivalents, more preferably 1 to 1.3 equivalents. The amount of phosphorus oxychloride used is preferably 1 to 3 equivalents, more preferably 1.0 to 1.5 equivalents. The reaction temperature is preferably 10 to 30 ° C, more preferably 23 to 28 ° C. The reaction time is preferably 2-3 hours.
화학식 (3)의 2-EDPT의 활성화 반응을 수행하기 전 트리메틸실릴클로라이드와 트리에틸아민으로 실릴화를 먼저 선행할 수 있다. 이때 트리메틸실릴클로라이드의 양은 1∼ 2당량이 바람직하고, 더욱 바람직하게는 1.1∼ 1.5당량이다. 트리에틸아민의 양은 1∼ 3당량이 바람직하고, 더욱 바람직하게는 1.5∼ 2.5당량이다. 반응온도는 -5∼ 40℃가 바람직하고, 더욱 바람직하게는 5∼ 15℃이다. 반응시간은 1분 내지 2시간이 바람직하고, 더욱 바람직하게는 20분 내지 40분이다.Silylation with trimethylsilylchloride and triethylamine may first be preceded before carrying out the activation reaction of 2-EDPT of formula (3). At this time, the amount of trimethylsilyl chloride is preferably 1 to 2 equivalents, more preferably 1.1 to 1.5 equivalents. The amount of triethylamine is preferably 1 to 3 equivalents, more preferably 1.5 to 2.5 equivalents. The reaction temperature is preferably -5 to 40 ° C, more preferably 5 to 15 ° C. The reaction time is preferably 1 minute to 2 hours, more preferably 20 minutes to 40 minutes.
화학식 (1)의 화합물을 합성하는 아실화 반응의 반응시간은 1분 내지 1시간이 바람직하고, 더욱 바람직하게는 15분이다. 반응온도는 -30∼ 50℃가 바람직하다.The reaction time of the acylation reaction for synthesizing the compound of the formula (1) is preferably 1 minute to 1 hour, more preferably 15 minutes. As for reaction temperature, -30-50 degreeC is preferable.
화학식 (1)의 화합물의 결정화에 사용되는 알콜은 메탄올, 에탄올, 이소프로필알콜, t-부틸알콜 등이 바람직하고, 에탄올이 더 바람직하다. 알콜 사용량은 1∼ 2당량이 바람직하다. 결정화에서 산은 바람직하게는 염산 또는 황산을 사용하며, 더욱 바람직하게는 염산을 사용한다. 사용량은 1∼ 5당량이다. 결정화 온도는 30∼ 40℃가 바람직하며, 시간은 30분내지 24시간이 바람직하다.The alcohol used for the crystallization of the compound of the formula (1) is preferably methanol, ethanol, isopropyl alcohol, t-butyl alcohol, and more preferably ethanol. The amount of alcohol used is preferably 1 to 2 equivalents. In crystallization, the acid is preferably hydrochloric acid or sulfuric acid, more preferably hydrochloric acid. The amount used is 1 to 5 equivalents. The crystallization temperature is preferably 30 to 40 ° C, and the time is preferably 30 minutes to 24 hours.
상기 반응은 일반적으로 반응에 악영향을 주지 않는 용매의 존재하에서 수행하며 바람직하게는 디클로로메탄, 클로로포름, 아세토니트릴, 아세톤 중에서 선택된 어느 하나의 용매 또는 둘 이상의 혼합용매가 사용될 수 있으며, 더욱 바람직하게는 디클로로메탄을 사용한다.The reaction is generally carried out in the presence of a solvent that does not adversely affect the reaction, preferably any one solvent selected from dichloromethane, chloroform, acetonitrile, acetone, or two or more mixed solvents, more preferably dichloro Methane is used.
본 발명자들은 본 발명을 완성하기 위하여 여러 가지 실험을 수행하였다.The inventors carried out various experiments to complete the present invention.
우선 7-TMCA의 4번 위치의 카르복실산과 7번 위치의 아민기에 실릴화 과정을 반응 중 직접 실시한 후, 2-EDPT를 활성화시켜 얻은 화합물과 아실화 반응을 거쳐 화학식 (1)의 화합물을 합성하였다. 그러나 이 방법은 실릴화 과정에서 △2이성체가 5∼ 10%까지 생성된다는 것을 고속 액체크로마토그래피법(HPLC)으로 분석한 결과 확인하였으며, 이것은 이후 아실화 과정에서도 새로운 부산물의 생성 및 낮은 수율의 원인이 되었다는 것을 알게 되었다.First, the silylation process of the carboxylic acid at position 4 and the amine group at position 7-TMCA is carried out directly during the reaction, and then the compound of formula (1) is synthesized through acylation with a compound obtained by activating 2-EDPT. It was. However, this method confirmed by analysis of high performance liquid chromatography (HPLC) that △ 2 isomer is produced in the silylation process by 5 ~ 10%, which is the cause of new by-products and low yield in the subsequent acylation process. I found out.
따라서 여러 가지 실릴화제를 적용해 본 결과, N,O-비스트리메틸실릴아세트아미드의 경우는 반응 중 △2이성체가 5∼ 6%까지 생성되었으며, 헥사메틸디실라잔의 경우에는 6∼ 8%까지 이성체가 생성되었다. 최종적으로 얻은 화학식 (1)의 정제 과정 후에도 △2이성체가 계속 잔류함을 확인하였다.Therefore, as a result of applying various silylating agents, the N, O-bistrimethylsilylacetamide produced Δ 2 isomers in the reaction of 5 to 6%, and in the case of hexamethyldisilazane, up to 6 to 8%. Isomers were produced. It was confirmed that the Δ 2 isomer still remained after the final purification process of the formula (1).
이 실험 결과로 △2이성체의 생성을 억제하고 이로 인해 생성되는 부산물을 제거함으로써 궁극적으로 최종 화합물을 높은 수율로 얻기 위해서는 효과적인 실릴화 방법을 개발하는 것이 매우 중요한 과제임을 알 수 있었다.As a result of this experiment, it was found that it is very important to develop an effective silylation method in order to suppress the production of Δ 2 isomers and to remove the by-products, thereby ultimately obtaining a high yield of the final compound.
계속적인 연구 결과, 화학식 (5)의 7-TMCA를 화학식 (9)의 BSU를 사용하여 실릴화할 경우 △2이성체가 반응중에 0.05% 미만으로 거의 생성되지 않으며, 이후 2-EDPT와의 아실화 반응에서도 부산물 없이 높은 수율로 최종 화합물을 얻을 수 있었다Subsequent studies have shown that when the 7-TMCA of formula (5) is silylated using BSU of formula (9), Δ 2 isomers are generated less than 0.05% during the reaction, and then even in the acylation reaction with 2-EDPT The final compound was obtained in high yield without any by-products
이하 본 발명을 실시예에 의거하여 더욱 상세히 설명하면 다음과 같은 바, 본발명의 범위가 실시예에 의하여 국한되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following Examples, which are not intended to limit the scope of the present invention.
실시예 1Example 1
7-[[(2R,3S)-2-(4-에틸-2,3-디옥소피페라진-1-일)카르보닐]아미노-3-하이드록시부티릴]아미노-3-[(1-메틸-1H-테트라졸-5-일)티오]메틸-△7-[[(2R, 3S) -2- (4-ethyl-2,3-dioxopiperazin-1-yl) carbonyl] amino-3-hydroxybutyryl] amino-3-[(1- Methyl-1H-tetrazol-5-yl) thio] methyl- △ 33 -세펨-4-카르복실산의 합성.Synthesis of Cefem-4-carboxylic Acid.
1. 2-EDPT의 활성화1. Activation of 2-EDPT
디클로로메탄250 ℓ에 트리에틸아민 22.2 ℓ를 넣고 5℃로 냉각한 후, 2-EDPT 45.85 kg를 5∼ 9℃로 유지하면서 20∼ 30분 동안에 걸쳐서 서서히 첨가하여2-EDPT을 완전히 용해하였다. 트리메틸실릴클로라이드 21.23 ℓ를 10분에 걸쳐서 서서히 적가 시키고 17∼ 19℃에서 30분동안 교반하였다. 반응물의 온도를 15℃로 냉각한 후 디메틸아세트아미드 29.7 ℓ를 첨가하였다. 포스포러스옥시클로라이드 14.6 ℓ를 20∼ 25℃에서 40분 동안에 걸쳐서 서서히 적가하고 기벽에 묻어있는 포스포러스옥시클로라이드를 디클로로메탄2 ℓ로 씻었다. 23∼ 25℃에서 2시간동안 교반 후 -24℃로 냉각시켰다.22.2 L of triethylamine was added to 250 L of dichloromethane, and the mixture was cooled to 5 ° C., and 45.85 kg of 2-EDPT was slowly added over 20 to 30 minutes while maintaining at 5 to 9 ° C. to completely dissolve 2-EDPT. 21.23 L of trimethylsilylchloride was slowly added dropwise over 10 minutes and stirred at 17-19 ° C. for 30 minutes. After cooling the reaction mass to 15 ° C., 29.7 L of dimethylacetamide were added. 14.6 L of phosphorus oxychloride was slowly added dropwise at 20 to 25 DEG C over 40 minutes, and the phosphorus oxychloride on the wall was washed with 2 L of dichloromethane. After stirring for 2 h at 23-25 ° C, it was cooled to -24 ° C.
2. 7-TMCA의 실릴화 반응2. Silylation of 7-TMCA
디클로로메탄500 ℓ에 7-TMCA 50 kg을 넣고 1,3-비스(트리메틸실릴)우레아 65.25 kg을 실온에서 첨가한 후, 20∼ 30분간에 걸쳐서 서서히 가열하여 35℃를 유지하도록 하였다. 25℃에서 3시간동안 교반 시키고 다시 -11℃로 냉각시켰다.50 kg of 7-TMCA was added to 500 l of dichloromethane, and 65.25 kg of 1,3-bis (trimethylsilyl) urea was added at room temperature, followed by gradually heating over 20 to 30 minutes to maintain 35 ° C. Stirred at 25 ° C. for 3 hours and cooled to −11 ° C. again.
3. 아실화 반응3. Acylation Reaction
실릴화된 7-TMCA용액에 활성화된 2-EDPT를 첨가하고 -10∼ -15℃에서 10분동안 교반한 후 반응물 0.1 ㎖를 취하여 HPLC로 반응 진행정도를 확인하였다. 5℃로 냉각된 물 700 ℓ를 반응물에 넣고 3분 동안 강 교반하고, 5∼ 10분 동안 방치한 후 층을 분리하여 유기층을 규조토로 여과하고 디클로로메탄80 ℓ로 씻었다. 이렇게 얻어진 용액에 에탄올 18.3 ℓ를 넣고 35℃로 가열하였다. 여기에 37% HCl 0.3 ㎖를 가하고 결정화하였다. 침전된 물질을 여과하고 감압 건조하여 표제 화합물86.5 ㎏을 얻었다.Activated 2-EDPT was added to the silylated 7-TMCA solution and stirred for 10 minutes at -10 to -15 ° C. 700 L of water cooled to 5 DEG C was added to the reaction, stirred for 3 minutes, left for 5 to 10 minutes, the layers were separated, the organic layer was filtered through diatomaceous earth, and washed with 80 L of dichloromethane. 18.3 L of ethanol was added to the solution thus obtained and heated to 35 ° C. 0.3 ml of 37% HCl was added thereto and crystallized. The precipitated material was filtered off and dried under reduced pressure to give 86.5 kg of the title compound.
수율 : 95%Yield: 95%
1H NMR (DMSO-d6,400MHz) δ: 1.0∼1.8(m, 6H, C(CH3)2), 3.38∼3.42(q, 2H, -CH2-), 3.50∼3.61(m, 2H, N-CH2-), 3.60∼3.74(q, 2H, -CH2-), 3.90∼3.95(m, 2H, -CH2-N), 3.94(s, 3H ,N-CH3), 4.0∼4.1(m, 2H, -CH2-S), 4.2∼4.3(m, 1H, HO-CH-), 4.2∼4.3(m, 1H, -NH-CH-), 5.0∼5.1(d, 1H, -CH-S), 5.7∼5.8(m, 1H, -CH-), 8.95∼8.98(d, 1H, 아미드), 9.20∼ 9.29(d, 1H, 아미드) 1 H NMR (DMSO-d 6, 400 MHz) δ: 1.0 to 1.8 (m, 6H, C (CH 3 ) 2 ), 3.38 to 3.42 (q, 2H, -CH 2- ), 3.50 to 3.61 (m, 2H , N-CH 2- ), 3.60 to 3.74 (q, 2H, -CH 2- ), 3.90 to 3.95 (m, 2H, -CH 2 -N), 3.94 (s, 3H, N-CH 3 ), 4.0 -4.1 (m, 2H, -CH 2 -S), 4.2-4.3 (m, 1H, HO-CH-), 4.2-4.3 (m, 1H, -NH-CH-), 5.0-5.1 (d, 1H , -CH-S), 5.7 to 5.8 (m, 1H, -CH-), 8.95 to 8.98 (d, 1H, amide), 9.20 to 9.29 (d, 1H, amide)
HPLC 분석 : Assay; 99.4%, △2; 0.03%HPLC analysis: Assay; 99.4%, Δ 2 ; 0.03%
비교예 1Comparative Example 1
7-[[(2R,3S)-2-[4-에틸-2,3-디옥소피페라진-1-일)카르보닐]아미노-3-하이드록시부티릴]아미노-3-[(1-메틸-1H-테트라졸-5-일)티오]메틸-△7-[[(2R, 3S) -2- [4-ethyl-2,3-dioxopiperazin-1-yl) carbonyl] amino-3-hydroxybutyryl] amino-3-[(1- Methyl-1H-tetrazol-5-yl) thio] methyl- △ 33 -세펨-4-카르복실산의 합성Synthesis of Cefem-4-carboxylic Acid
1. 2-EDPT 의 활성화1. Activation of 2-EDPT
디클로로메탄50 ℓ에 트리에틸아민 4.44 ℓ를 넣고 5℃로 냉각한 후 2-EDPT 9.17 kg를 5∼ 9℃를 유지하면서 20∼ 30분 동안에 걸쳐서 서서히 첨가하고 2-EDPT 을 완전히 용해하였다. 트리메틸실릴클로라이드 4.24 ℓ를 10분에 걸쳐서 서서히 적가하고 17∼ 19℃에서 30분동안 교반하였다. 반응물의 온도를 15℃로 냉각한 후디메틸아세트아마이드 5.94 ℓ를 첨가하였다. 포스포러스옥시클로라이드 2.92 ℓ를 20∼ 25℃에서 40분 동안에 걸쳐서 서서히 적가하고 기벽에 묻어있는 포스포러스옥시클로라이드를 디클로로메탄0.4 ℓ로 씻었다. 23∼ 25℃에서 2시간 동안 교반후 -24℃로 냉각시켰다.4.44 L of triethylamine was added to 50 L of dichloromethane, cooled to 5 ° C., and 9.17 kg of 2-EDPT was slowly added over 20 to 30 minutes while maintaining 5 to 9 ° C., and 2-EDPT was completely dissolved. 4.24 L of trimethylsilyl chloride was slowly added dropwise over 10 minutes and stirred at 17-19 ° C. for 30 minutes. After cooling the reaction mass to 15 ° C., 5.94 L of dimethylacetamide were added. 2.92 L of phosphorus oxychloride was slowly added dropwise at 20 to 25 DEG C over 40 minutes, and the phosphorus oxychloride on the wall was washed with 0.4 L of dichloromethane. After stirring for 2 hours at 23 to 25 ℃ cooled to -24 ℃.
2. 7-TMCA 의 실릴화 반응2. Silylation of 7-TMCA
디클로로메탄 100 ℓ에 7-TMCA 10 kg을 넣고 트리메틸실릴클로라이드 8.13 ℓ 첨가하였다. 트리에틸아민 9.34 ℓ을 반응온도 5oC에서 2시간 동안 적가하였다. 20분 더 교반 시키고 다시 -11℃로 냉각시켰다.10 kg of 7-TMCA was added to 100 L of dichloromethane, and 8.13 L of trimethylsilyl chloride was added thereto. 9.34 L of triethylamine was added dropwise at a reaction temperature of 5 ° C. for 2 hours. Stirred for 20 more minutes and cooled to -11 ° C again.
3. 아실화 반응3. Acylation Reaction
실릴화된 7-TMCA 용액에 활성화된 2-EDPT 를 첨가하고 -10∼ -15℃에서 10분동안 교반한 후 반응물 0.1 ㎖를 취하여 HPLC로 반응 진행정도를 확인하였다. 5℃로 냉각된 물 140 ℓ를 반응물에 넣고 3분 동안 강 교반하고 5∼ 10분 동안 방치한 후 층을 분리하여 유기층을 규조토로 여과하고 디클로로메탄 16 ℓ로 씻었다. 이렇게 얻어진 용액에 에탄올 3.66 ℓ를 넣고 35℃로 가열하였다. 여기에 37% HCl 0.06 ㎖를 가하고 결정화하였다. 침전된 물질을 여과하고 감압 건조하여 표제 화합물 11.8 ㎏을 얻었다.Activated 2-EDPT was added to the silylated 7-TMCA solution, stirred for 10 minutes at -10 to -15 ° C, and 0.1 ml of the reaction was taken to check the progress of the reaction by HPLC. 140 L of water cooled to 5 ° C. was added to the reaction, stirred vigorously for 3 minutes, left for 5 to 10 minutes, the layers were separated, the organic layer was filtered through diatomaceous earth, and washed with 16 L of dichloromethane. 3.66 L of ethanol was added to the solution thus obtained, and heated to 35 ° C. To this was added 0.06 ml of 37% HCl and crystallized. The precipitated material was filtered off and dried under reduced pressure to give 11.8 kg of the title compound.
수율 : 65%Yield: 65%
1H NMR (DMSO-d6,400MHz) δ: 1.0∼1.8(m, 6H, C(CH3)2), 3.38∼3.42(q, 2H, -CH2-), 3.50∼3.61(m, 2H, N-CH2-), 3.60∼3.74(q, 2H, -CH2-), 3.90∼3.95(m, 2H, -CH2-N), 3.94(s, 3H ,N-CH3), 4.0∼4.1(m, 2H, -CH2-S), 4.2∼4.3(m, 1H, HO-CH-), 4.2∼4.3(m, 1H, -NH-CH-), 5.0∼5.1(d, 1H, -CH-S), 5.7∼5.8(m, 1H, -CH-), 8.95∼8.98(d, 1H, 아미드), 9.20∼9.29(d, 1H, 아미드) 1 H NMR (DMSO-d 6, 400 MHz) δ: 1.0 to 1.8 (m, 6H, C (CH 3 ) 2 ), 3.38 to 3.42 (q, 2H, -CH 2- ), 3.50 to 3.61 (m, 2H , N-CH 2- ), 3.60 to 3.74 (q, 2H, -CH 2- ), 3.90 to 3.95 (m, 2H, -CH 2 -N), 3.94 (s, 3H, N-CH 3 ), 4.0 -4.1 (m, 2H, -CH 2 -S), 4.2-4.3 (m, 1H, HO-CH-), 4.2-4.3 (m, 1H, -NH-CH-), 5.0-5.1 (d, 1H , -CH-S), 5.7 to 5.8 (m, 1H, -CH-), 8.95 to 8.98 (d, 1H, amide), 9.20 to 9.29 (d, 1H, amide)
HPLC 분석 : Assay; 94%, △2; 5%HPLC analysis: Assay; 94%, Δ 2 ; 5%
비교예 2Comparative Example 2
7-[[(2R,3S)-2-[4-에틸-2,3-디옥소피페라진-1-일)카르보닐]아미노-3-하이드록시부티릴]아미노-3-[(1-메틸-1H-테트라졸-5-일)티오]메틸-△7-[[(2R, 3S) -2- [4-ethyl-2,3-dioxopiperazin-1-yl) carbonyl] amino-3-hydroxybutyryl] amino-3-[(1- Methyl-1H-tetrazol-5-yl) thio] methyl- △ 33 -세펨-4-카르복실산의 합성.Synthesis of Cefem-4-carboxylic Acid.
1. 2-EDPT 의 활성화1. Activation of 2-EDPT
크로로메탄250 ℓ에 트리에틸아민 22.2 ℓ를 넣고 5℃로 냉각한 후 2-EDPT 45.85 kg를 5∼ 9℃를 유지하면서 20∼ 30분 동안에 걸쳐서 서서히 첨가하고 2-EDPT을 완전히 용해하였다. 트리메틸실릴클로라이드 21.23 ℓ를 10분에 걸쳐서 서서히 적가하고 17∼ 19℃에서 30분동안 교반하였다. 반응물의 온도를 15℃로 냉각한 후 디메틸아세트아마이드 29.7 ℓ를 첨가하였다. 포스포러스옥시클로라이드 14.6 ℓ를 20∼ 25℃에서 40분 동안에 걸쳐서 서서히 적가하고 기벽에 묻어있는 포스포러스옥시클로라이드를 디클로로메탄2 ℓ로 씻었다. 23∼ 25℃에서 2시간동안 교반 후 -24℃로 냉각시켰다.22.2 L of triethylamine was added to 250 L of chloromethane, and the mixture was cooled to 5 ° C., and 45.85 kg of 2-EDPT was slowly added over 20 to 30 minutes while maintaining 5 to 9 ° C., and 2-EDPT was completely dissolved. 21.23 L of trimethylsilylchloride was slowly added dropwise over 10 minutes and stirred at 17-19 ° C. for 30 minutes. After the reaction was cooled to 15 ° C., 29.7 L of dimethylacetamide were added. 14.6 L of phosphorus oxychloride was slowly added dropwise at 20 to 25 DEG C over 40 minutes, and the phosphorus oxychloride on the wall was washed with 2 L of dichloromethane. After stirring for 2 h at 23-25 ° C, it was cooled to -24 ° C.
2. 7-TMCA 의 실릴화반응2. Silylation of 7-TMCA
디클로로메탄500 ℓ에 7-TMCA 55.6 kg을 넣고 N,O-비스트리메틸실릴아세트아마이드 72.42 kg을 실온에서 첨가하고 25℃에서 3시간동안 교반시켰다. 다시 -11℃로 냉각시켰다.55.6 kg of 7-TMCA was added to 500 l of dichloromethane, and 72.42 kg of N, O-bistrimethylsilylacetamide was added at room temperature and stirred at 25 ° C for 3 hours. Again cooled to -11 ° C.
3. 아실화 반응3. Acylation Reaction
실릴화된 7-TMCA용액에 활성화된 2-EDPT를 첨가하고 -10∼ -15℃에서 10분동안 교반한 후 반응물 0.1 ㎖를 취하여 HPLC로 반응 진행정도를 확인하였다. 5℃로 냉각된 물 700 ℓ를 반응물에 넣고 3분 동안 강 교반하고 5∼ 10분 동안 방치한 후 층을 분리하여 유기층을 규조토로 여과하고 디클로로메탄80 ℓ로 씻었다. 이렇게 얻어진 용액에 에탄올 18.3 ℓ를 넣고 35℃로 가열하였다. 여기에 37% HCl 0.3 ㎖를 가하고 결정화하였다. 침전된 물질을 여과하고 감압 건조하여 표제 화합물 70.9 ㎏을 얻었다.Activated 2-EDPT was added to the silylated 7-TMCA solution and stirred for 10 minutes at -10 to -15 ° C. 700 L of water cooled to 5 ° C. was added to the reaction, stirred vigorously for 3 minutes, left for 5 to 10 minutes, the layers were separated, the organic layer was filtered through diatomaceous earth, and washed with 80 L of dichloromethane. 18.3 L of ethanol was added to the solution thus obtained and heated to 35 ° C. 0.3 ml of 37% HCl was added thereto and crystallized. The precipitated material was filtered and dried under reduced pressure to give 70.9 kg of the title compound.
수율 : 70%Yield: 70%
1H NMR (DMSO-d6,400MHz) δ: 1.0∼1.8(m, 6H, C(CH3)2), 3.38∼3.42(q, 2H,-CH2-), 3.50∼3.61(m, 2H, N-CH2-), 3.60∼3.74(q, 2H, -CH2-), 3.90∼3.95(m, 2H, -CH2-N), 3.94(s, 3H ,N-CH3), 4.0∼4.1(m, 2H, -CH2-S), 4.2∼4.3(m, 1H, HO-CH-), 4.2∼4.3(m, 1H, -NH-CH-), 5.0∼5.1(d, 1H, -CH-S), 5.7∼5.8(m, 1H, -CH-), 8.95∼8.98(d, 1H, 아미드), 9.20∼9.29(d, 1H, 아미드) 1 H NMR (DMSO-d 6, 400 MHz) δ: 1.0 to 1.8 (m, 6H, C (CH 3 ) 2 ), 3.38 to 3.42 (q, 2H, -CH 2- ), 3.50 to 3.61 (m, 2H , N-CH 2- ), 3.60 to 3.74 (q, 2H, -CH 2- ), 3.90 to 3.95 (m, 2H, -CH 2 -N), 3.94 (s, 3H, N-CH 3 ), 4.0 -4.1 (m, 2H, -CH 2 -S), 4.2-4.3 (m, 1H, HO-CH-), 4.2-4.3 (m, 1H, -NH-CH-), 5.0-5.1 (d, 1H , -CH-S), 5.7 to 5.8 (m, 1H, -CH-), 8.95 to 8.98 (d, 1H, amide), 9.20 to 9.29 (d, 1H, amide)
HPLC 분석 : Assay; 93%, △2; 6%HPLC analysis: Assay; 93%, Δ 2 ; 6%
본 발명은 BSU를 사용하여 7-TMCA의 아민기와 카르복실산을 반응 중 직접 실릴화한 후, 2-EDPT를 활성화하여 제조된 화합물과 아실화 반응 시킴으로써, △2이성체 및 부산물 등의 생성없이 고순도, 고수율로 목적화합물을 합성할 수 있어 산업적 및 경제적으로 유용하다.In the present invention, BSI is used to directly silylate an amine group of 7-TMCA with a carboxylic acid in a reaction and then acylate with a compound prepared by activating 2-EDPT, thereby producing high purity without generating Δ 2 isomers and by-products. In addition, the compound can be synthesized in high yield, which is useful industrially and economically.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR100898103B1 (en) | 2007-09-05 | 2009-05-15 | 주식회사 엔지켐 | Novel method for producing cefbuperazone intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5170788A (en) * | 1974-12-13 | 1976-06-18 | Toyama Chemical Co Ltd | Shinkina sefuarosuhorinruino seizoho |
| US4262292A (en) * | 1979-11-19 | 1981-04-14 | Ncr Corporation | Multiplexed scan display circuit |
| JPS56142291A (en) * | 1980-03-24 | 1981-11-06 | Bristol Mayers Kenkyusho Kk | Amtimicrobial agent |
| US4304909A (en) * | 1977-09-27 | 1981-12-08 | Toyama Chemical Co., Ltd. | Process for producing 7-(D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl)acetamido)-3-(5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl)-.DELTA.3 -cephem-4-carboxylic acid and a pharmaceutically acceptable salt thereof |
| JPH03148282A (en) * | 1989-11-02 | 1991-06-25 | Sakai Yakuhin Kk | Production of cephalosporanic acid derivative |
-
2000
- 2000-08-11 KR KR10-2000-0046554A patent/KR100388108B1/en not_active IP Right Cessation
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5170788A (en) * | 1974-12-13 | 1976-06-18 | Toyama Chemical Co Ltd | Shinkina sefuarosuhorinruino seizoho |
| US4304909A (en) * | 1977-09-27 | 1981-12-08 | Toyama Chemical Co., Ltd. | Process for producing 7-(D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl)acetamido)-3-(5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl)-.DELTA.3 -cephem-4-carboxylic acid and a pharmaceutically acceptable salt thereof |
| US4262292A (en) * | 1979-11-19 | 1981-04-14 | Ncr Corporation | Multiplexed scan display circuit |
| JPS56142291A (en) * | 1980-03-24 | 1981-11-06 | Bristol Mayers Kenkyusho Kk | Amtimicrobial agent |
| JPH03148282A (en) * | 1989-11-02 | 1991-06-25 | Sakai Yakuhin Kk | Production of cephalosporanic acid derivative |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100898103B1 (en) | 2007-09-05 | 2009-05-15 | 주식회사 엔지켐 | Novel method for producing cefbuperazone intermediate |
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