KR100502390B1 - Process for preparing cephalosporinic acid - Google Patents
Process for preparing cephalosporinic acid Download PDFInfo
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- KR100502390B1 KR100502390B1 KR10-2001-0054986A KR20010054986A KR100502390B1 KR 100502390 B1 KR100502390 B1 KR 100502390B1 KR 20010054986 A KR20010054986 A KR 20010054986A KR 100502390 B1 KR100502390 B1 KR 100502390B1
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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
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
Abstract
본 발명은 하기 화학식 2의 7-아미노세팔로스포린산을 용매중에서 유기 염기의 존재하에 하기 화학식 3의 소듐 티오퓨로에이트와 반응시킴을 특징으로 하여 동물용 항생제 세프티오퍼의 중간체로 유용한 하기 화학식 1의 3-퓨로일티오메틸-7-아미노-3-세펨-4-카르복실산을 고순도 및 밝은 색상으로 제조하는 방법에 관한 것이다. The present invention is characterized by reacting 7-aminocephalosporinic acid of formula 2 with sodium thiopuroate of formula 3 in the presence of an organic base in a solvent, which is useful as an intermediate for the antibiotic ceftioper for animals. It relates to a process for preparing 3-puroylthiomethyl-7-amino-3-cepem-4-carboxylic acid of 1 in high purity and light color.
Description
본 발명은 하기 화학식 2의 7-아미노세팔로스포린산(이하, '7-ACA'라 한다)을 용매중에서 유기 염기의 존재하에 하기 화학식 3의 소듐 티오퓨로에이트와 반응시킴을 특징으로 하여 동물용 항생제 세프티오퍼의 중간체로 유용한 하기 화학식 1의 3-퓨로일티오메틸-7-아미노-3-세펨-4-카르복실산(이하, '7-ACF'라 한다)을 제조하는 방법에 관한 것이다. The present invention is characterized by reacting 7-aminocephalosporinic acid of formula 2 (hereinafter referred to as '7-ACA') with sodium thiopuroate of formula 3 in the presence of an organic base in a solvent. A method for preparing 3-puroylthiomethyl-7-amino-3-cepem-4-carboxylic acid (hereinafter, referred to as '7-ACF') of formula (1) useful as an intermediate of the antibiotic ceftioper for will be.
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 1][Formula 1]
7-ACF는 세프티오퍼와 같은 항생제를 합성하는데 매우 유용하게 사용되는 중간체이며 그의 제조방법은 특허 WO 87/01117에 개시되어 있다. 그러나, 종래 방법에서는 이들 반응물질의 반응성이 좋지 않은 관계로 강한 무기염기 조건하에 반응을 진행시켰다. 또한, 반응액의 pH를 6 내지 6.5로 정밀하게 조절해주는 경우에만 반응이 원활히 수행되므로 pH 조절의 부담을 안겨주는 단점이 있다. 즉, 반응 중 pH가 낮으면 반응이 진행되지 않고 pH가 너무 높으면 반응액의 색상이 진해지고 반응 부산물도 많이 생성되는 문제가 있었다. 따라서, WO 87/01117에서는 강한 무기염기인 수산화나트륨 용액을 사용하여 미리 반응액의 pH를 6.4±0.2로 조절한 다음 반응중 염기나 산을 사용하여 pH를 계속 6 내지 6.5로 조절해주고 있다. 또한, 상기 방법에서는 강염기를 사용함에 따라 반응중에 부산물이 많이 생성되고 합성 후 얻어진 화합물의 색상이 어두운 단점이 있다.7-ACF is an intermediate which is very usefully used for synthesizing antibiotics such as ceftiofer and its preparation is disclosed in patent WO 87/01117. However, in the conventional method, since the reaction of these reactants is poor, the reaction proceeds under strong inorganic base conditions. In addition, since the reaction is performed smoothly only when the pH of the reaction solution is precisely adjusted to 6 to 6.5, there is a disadvantage of burdening the pH control. In other words, when the pH is low during the reaction, the reaction does not proceed, and when the pH is too high, the color of the reaction solution becomes dark and a lot of reaction byproducts are generated. Therefore, in WO 87/01117, the pH of the reaction solution was previously adjusted to 6.4 ± 0.2 using a strong inorganic base sodium hydroxide solution, and then the pH was continuously adjusted to 6 to 6.5 using a base or an acid during the reaction. In addition, the method has a disadvantage in that a lot of by-products are generated during the reaction as the strong base is used, and the color of the compound obtained after synthesis is dark.
이에 본 발명자들은 상기 언급된 종래 방법의 단점을 개선하고자 지속적인 연구를 수행한 끝에, 물을 반응용매로 사용하는 반응에는 무기 염기를 사용해야한다는 기존의 틀을 과감히 깨고 유기 염기를 사용한 결과 밝은 색상 및 고순도의 7-ACF 화합물을 얻을 수 있었으며, 유기 염기를 당량 개념으로 투입하면 반응 중 pH 조절을 할 필요가 전혀 없어 공정이 매우 간편해진다는 사실을 발견한 결과 본 발명을 완성하게 되었다. Therefore, the present inventors have made continuous research to improve the shortcomings of the above-mentioned conventional method, and drastically break the existing framework that an inorganic base should be used for the reaction using water as a reaction solvent. The 7-ACF compound was obtained, and when the organic base was added in the equivalent weight concept, there was no need to adjust the pH during the reaction and found that the process was very simple.
본 발명은 하기 화학식 2의 7-아미노세팔로스포린산을 용매중에서 유기 염기의 존재하에 하기 화학식 3의 소듐 티오퓨로에이트와 반응시킴을 특징으로 하여 하기 화학식 1의 3-퓨로일티오메틸-7-아미노-3-세펨-4-카르복실산을 제조하는 방법에 관한 것이다. The present invention is characterized by reacting 7-aminocephalosporinic acid of formula 2 with sodium thiopuroate of formula 3 in the presence of an organic base in a solvent, 3-puroylthiomethyl-7 of formula 1 It relates to a method for preparing amino-3-cefe-4-carboxylic acid.
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 1][Formula 1]
본 발명을 좀더 구체적으로 설명하면 다음과 같다.The present invention will be described in more detail as follows.
본 발명에 따른 방법에서 유기 염기로는 트리에틸아민, 트리-n-부틸아민, 디이소프로필에틸아민, N,N-디메틸아닐린, 피리딘 등의 3급 알킬아민을 사용할 수 있으며, 이중에서도 트리에틸아민 또는 트리-n-부틸아민을 사용하는 것이 바람직하고, 트리-n-부틸아민이 가장 바람직하다. 염기는 화학식 3의 소듐 티오퓨로에이트를 기준으로 하여 0.3 내지 1.5당량배를 사용하는 것이 좋다. 염기를 0.3당량 미만으로 사용하면 화학식 1의 7-ACF 화합물의 생성 수율이 감소되고 1.5당량을 초과하여 사용하면 염기의 사용량이 불필요하게 많아지고, 부산물이 생성될 뿐아니라 반응후의 분리가 용이치 않기 때문이다In the process according to the present invention, as the organic base, tertiary alkylamines such as triethylamine, tri-n-butylamine, diisopropylethylamine, N, N-dimethylaniline, pyridine, and the like may be used. Preference is given to using amines or tri-n-butylamine, with tri-n-butylamine being most preferred. The base is preferably used 0.3 to 1.5 equivalent times based on sodium thiopuroate of formula (3). If the base is used in less than 0.3 equivalents, the yield of the 7-ACF compound of Formula 1 is reduced. If the base is used in excess of 1.5 equivalents, the amount of base is unnecessarily increased, by-products are generated and separation after the reaction is not easy. Because
본 발명에서 용매로는 물 또는 물과 유기용매의 혼합액을 사용하며, 유기용매로는 아세토니트릴, 에틸아세테이트, 아세톤, 메틸렌클로라이드, 테트라하이드로푸란, 클로로포름 등의 극성 또는 비극성 유기 용매를 모두 사용할 수 있다. 그러나, 용매의 반응성이나 반응완결 후 조작의 용이성을 위하여 아세토니트릴과 물의 혼합용매 또는 물만을 사용하는 것이 바람직하다. 용매는 출발물질인 화학식 3의 소듐 티오퓨로에이트를 용해시킬 수 있는 양이면 충분하지만 반응속도나 불순물 생성 측면을 고려할 때 소듐 티오퓨로에이트 1몰당 4 내지 9리터가 바람직하고, 6 내지 7리터를 사용하면 더욱 바람직하다. 또한, 물과 유기용매의 혼합액을 사용하는 경우에 혼합비(부피비)는 물을 1이라 할 때 유기용매를 0.3 이하로 조절하는 것이 바람직하다. In the present invention, as a solvent, water or a mixture of water and an organic solvent is used, and as the organic solvent, all polar or nonpolar organic solvents such as acetonitrile, ethyl acetate, acetone, methylene chloride, tetrahydrofuran, and chloroform may be used. . However, it is preferable to use only a mixed solvent of acetonitrile and water or water for the reactivity of the solvent or the ease of operation after completion of the reaction. The solvent is sufficient to dissolve the starting material sodium thiopuroate of formula (3), but 4 to 9 liters per mole of sodium thiofuroate is preferable, 6 to 7 liters in consideration of the reaction rate or the generation of impurities It is more preferable to use. In the case of using a mixture of water and an organic solvent, the mixing ratio (volume ratio) is preferably adjusted to 0.3 or less when the water is 1.
출발물질인 화학식 3의 소듐 티오퓨로에이트는 티오퓨로산을 수산화나트륨과 같은 염기를 사용하여 염 형태로 전환시키는 방법에 의해 수득하거나, 2-퓨로일클로라이드를 용매중에서 소듐설파이드와 반응시키는 방법에 의해 수득할 수 있다. 화학식 3의 화합물은 화학식 2의 7-ACA를 기준으로 하여 약간 과량으로 사용하는 것이 반응완결에 바람직하다. 따라서, 화학식 2의 화합물을 기준으로 하여 1.0 내지 1.7당량배, 바람직하게는 1.4 내지 1.6당량배로 사용한다. 화학식 3의 소듐 티오퓨로에이트를 1.0당량배 미만으로 사용하면 반응완결에 필요한 시간이 길어지고 반응이 충분히 수행되지 않으며, 1.7당량배를 초과하면 과다사용으로 인하여 경제적인 측면에서 바람직하지 않다. Sodium thiopuroate of the general formula (3) as a starting material is obtained by converting thiofuroic acid into the salt form using a base such as sodium hydroxide, or by reacting 2-furoylchloride with sodium sulfide in a solvent. It can be obtained by. It is preferable to complete the reaction that the compound of formula 3 is used in a slight excess based on 7-ACA of formula 2. Therefore, 1.0 to 1.7 equivalent times, preferably 1.4 to 1.6 equivalent times, based on the compound of formula (2) is used. If sodium thiopuroate of the formula (3) is used in less than 1.0 equivalent times, the time required for completion of the reaction is long and the reaction is not sufficiently performed. If it exceeds 1.7 equivalent times, it is not preferable economically due to overuse.
본 발명에 따른 방법에서 소듐 티오퓨로에이트, 용매 및 염기의 혼합온도는 반응에 해로운 영향을 주지 않는 한 제한할 필요는 없으나, 대략 20 내지 30℃에서 수행하는 것이 바람직하다. 또한, 반응 온도는 50 내지 70℃에서 수행하는 것이 바람직하며, 60 내지 65℃가 특히 바람직하다. 반응시간은 5시간이면 충분하게 진행되나 4시간이 바람직하다. 반응중 pH는 따로 조절할 필요없이 반응이 진행되면서 6내지 7까지 자연 상승하므로 종래 방법에서와 같이 지속적으로 pH를 6.4±0.2로 조절하는 작업을 수행하지 않아도 된다는 장점이 있다.In the process according to the invention, the mixing temperature of sodium thiopuroate, the solvent and the base need not be limited so long as it does not adversely affect the reaction, but it is preferably carried out at approximately 20 to 30 ℃. In addition, the reaction temperature is preferably carried out at 50 to 70 ℃, particularly preferably 60 to 65 ℃. The reaction time is 5 hours is enough, but 4 hours is preferred. During the reaction, the pH is naturally increased from 6 to 7 as the reaction proceeds without needing to adjust separately, so that there is no need to continuously adjust the pH to 6.4 ± 0.2 as in the conventional method.
본 발명에 따른 제조방법의 바람직한 태양을 반응식으로 도식화하여 나타내면 하기 반응식 1과 같다. A preferred embodiment of the production method according to the present invention is shown in Scheme 1 below.
상기 설명한 방법에 따라 생성된 화학식 1의 7-ACF 화합물은 침전, 여과 및 건조과정을 통해 고순도의 물질로 얻어진다. 구체적으로, 7-ACF 화합물이 생성된 후 산을 이용하여 반응액의 pH를 3 내지 5까지 조절함으로써 7-ACF 침전물을 수득한다. 생성된 침전물을 50 내지 60℃에서 30분 가량 교반하고 여과한 다음 여과된 침전물을 물과 아세톤으로 세척하고 질소로 건조시켜 고순도의 7-ACF 화합물을 높은 수율로 제조한다. 이때, 7-ACF 화합물의 결정화를 위하여 사용하는 산으로는 인산, 염산, 황산 등의 무기산 또는 술폰산, 아세트산 등의 유기산을 언급할 수 있으나, 인산이나 술폰산을 사용하면 결정의 색상이나 결정화 효율이 우수하여 고순도의 7-ACF 화합물을 높은 수율로 얻을 수 있으므로 바람직하다.The 7-ACF compound of Formula 1 produced according to the method described above is obtained as a material of high purity through precipitation, filtration and drying. Specifically, the 7-ACF precipitate is obtained by adjusting the pH of the reaction solution to 3 to 5 using an acid after the 7-ACF compound is produced. The resulting precipitate was stirred at 50 to 60 ° C. for about 30 minutes, filtered and the filtered precipitate was washed with water and acetone and dried with nitrogen to prepare a high purity 7-ACF compound in high yield. In this case, the acid used for crystallization of the 7-ACF compound may include inorganic acids such as phosphoric acid, hydrochloric acid and sulfuric acid, or organic acids such as sulfonic acid and acetic acid. However, when phosphoric acid or sulfonic acid is used, the crystal color or crystallization efficiency is excellent. It is preferable to obtain a high purity 7-ACF compound in high yield.
본 발명에 따라 수득된 7-ACF 화합물은 대한민국특허공개 제2000-0050703호에서와 같이 하기 화학식 4의 화합물을 얻기 위하여 하기 화학식 5의 반응성 유기산 유도체와 아실화반응을 수행할 수 있다:The 7-ACF compound obtained according to the present invention may be subjected to an acylation reaction with a reactive organic acid derivative of Formula 5 to obtain a compound of Formula 4 as in Korean Patent Publication No. 2000-0050703:
상기식에서 In the above formula
R2는 수소, 3급 알킬아민, 또는 알칼리 금속이다.R 2 is hydrogen, tertiary alkylamine, or an alkali metal.
상기식에서 In the above formula
R3는 C1-C4-알킬 또는 페닐이거나, 함께 결합되어 산소 또는 인(P)원자와 함께 5-6원 복소환을 형성할 수 있다.R 3 may be C 1 -C 4 -alkyl or phenyl or may be bonded together to form a 5-6 membered heterocycle with an oxygen or phosphorus (P) atom.
이하, 본 발명을 하기 실시예에 의거하여 보다 구체적으로 설명한다. 그러나, 이들 실시예는 본 발명에 대한 이해를 돕기 위한 것일 뿐, 어떤 의미로든 본 발명의 범위가 이들로 제한되는 것은 아니다. Hereinafter, the present invention will be described in more detail based on the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention in any sense is not limited thereto.
실시예 1Example 1
2-티오퓨로산(37.2g)을 반응기에 넣고 물(1800㎖)을 가하고 20% 수산화나트륨을 가하여 소듐 티오퓨로에이트를 제조하였다. 여기에 7-아미노세팔로스포린산 (52.7g)을 투입하고 교반하면서 트리-n-부틸아민(21.5g)을 10분동안 적가하였다. 반응온도를 60 내지 65℃로 승온시킨 후 4시간 동안 교반하였다.2-thiofuroic acid (37.2 g) was added to the reactor, water (1800 mL) was added, and 20% sodium hydroxide was added to prepare sodium thiofuroate. To this was added 7-aminocephalosporinic acid (52.7 g) and tri-n-butylamine (21.5 g) was added dropwise for 10 minutes while stirring. The reaction temperature was raised to 60 to 65 ℃ and stirred for 4 hours.
반응이 완료되면 50 내지 60℃에서 인산을 이용하여 pH를 4로 조절함으로써 침전을 생성시켰다. 생성된 침전을 동 온도에서 30분간 교반하고 여과한 다음, 물(150㎖)과 아세톤(150㎖)을 사용하여 차례로 세척하고, 질소로 건조시켜 3-퓨로일티오메틸-7-아미노-3-세펨-4-카르복실산(7-ACF) 54g(수율 82%)을 수득하였다. Upon completion of the reaction, precipitation was produced by adjusting the pH to 4 using phosphoric acid at 50 to 60 ° C. The resulting precipitate was stirred for 30 minutes at the same temperature, filtered, washed successively with water (150 mL) and acetone (150 mL), dried over nitrogen and dried to 3-puroylthiomethyl-7-amino-3- 54 g (82% yield) of cefem-4-carboxylic acid (7-ACF) were obtained.
1H NMR(DMSO-d6): δ(ppm) 8.10(1H), 7.45(1H), 6.79(1H), 4.95(1H), 4.78 (1H), 4.26(1H), 3.92(1H), 3.71(1H), 3.43(1H) 1 H NMR (DMSO-d 6 ): δ (ppm) 8.10 (1H), 7.45 (1H), 6.79 (1H), 4.95 (1H), 4.78 (1H), 4.26 (1H), 3.92 (1H), 3.71 (1H), 3.43 (1H)
Mass(FAB) m/z 341(MH+).Mass (FAB) m / z 341 (M−H +).
실시예 2Example 2
2-티오퓨로산(18.6g)을 반응기에 넣고 물(900㎖)을 가하고 20% 수산화나트륨을 가하여 소듐 티오퓨로에이트를 제조하였다. 여기에 7-아미노세팔로스포린산 (26.4g)을 투입하고 교반하면서 트리-n-부틸아민(18.0g)을 10분동안 적가하였다. 반응온도를 60 내지 65℃로 승온시킨 후 4시간 동안 교반하였다.2-thiofuroic acid (18.6 g) was added to the reactor, water (900 mL) was added, and 20% sodium hydroxide was added to prepare sodium thiofuroate. To this was added 7-aminocephalosporinic acid (26.4 g) and tri-n-butylamine (18.0 g) was added dropwise for 10 minutes while stirring. The reaction temperature was raised to 60 to 65 ℃ and stirred for 4 hours.
반응이 완료되면 50 내지 60℃에서 인산을 이용하여 pH를 3.5로 조절함으로써 침전을 생성시켰다. 생성된 침전을 동 온도에서 30분간 교반하고 여과한 다음, 물(80㎖)과 아세톤(80㎖)을 사용하여 차례로 세척하고, 질소로 건조시켜 7-ACF 27.8g (수율 84%)을 수득하였다. Upon completion of the reaction, precipitation was produced by adjusting the pH to 3.5 using phosphoric acid at 50 to 60 ° C. The resulting precipitate was stirred for 30 minutes at the same temperature, filtered, washed successively with water (80 mL) and acetone (80 mL), dried over nitrogen to give 27.8 g (84% yield) of 7-ACF. .
실시예 1과 동일한 방법으로 1H-NMR 및 Mass(FAB)m/z 분석을 수행하여 7-ACF가 생성되었음을 확인하였다. 1 H-NMR and Mass (FAB) m / z analysis was performed in the same manner as in Example 1 to confirm that 7-ACF was generated.
실시예 3Example 3
2-티오퓨로산(18.6g)을 반응기에 넣고 물(900㎖)을 가하고 20% 수산화나트륨을 가하여 소듐 티오퓨로에이트를 제조하였다. 여기에 7-아미노세팔로스포린산 (26.4g)을 투입하고 교반하면서 트리-n-에틸아민(5.88g)을 15분 동안 적가하였다. 반응온도를 60 내지 65℃로 승온시킨 후 3시간 동안 교반하였다.2-thiofuroic acid (18.6 g) was added to the reactor, water (900 mL) was added, and 20% sodium hydroxide was added to prepare sodium thiofuroate. To this was added 7-aminocephalosporinic acid (26.4 g) and tri-n-ethylamine (5.88 g) was added dropwise for 15 minutes while stirring. The reaction temperature was raised to 60 to 65 ℃ and stirred for 3 hours.
반응이 완료되면 50 내지 60℃에서 인산을 이용하여 pH를 4로 조절함으로써 침전을 생성시켰다. 생성된 침전을 동 온도에서 30분간 교반하고 여과한 다음, 물(80㎖)과 아세톤(80㎖)을 사용하여 차례로 세척하고, 질소로 건조시켜 7-ACF 27.3g (수율 83%)을 수득하였다. Upon completion of the reaction, precipitation was produced by adjusting the pH to 4 using phosphoric acid at 50 to 60 ° C. The resulting precipitate was stirred for 30 minutes at the same temperature, filtered, washed sequentially with water (80 mL) and acetone (80 mL), dried over nitrogen to give 27.3 g (7% yield) of 7-ACF. .
실시예 1과 동일한 방법으로 1H-NMR 및 Mass(FAB)m/z 분석을 수행하여 7-ACF가 생성되었음을 확인하였다. 1 H-NMR and Mass (FAB) m / z analysis was performed in the same manner as in Example 1 to confirm that 7-ACF was generated.
실시예 4Example 4
2-소듐 티오퓨로에이트(21.79g)를 반응기에 넣고 물(900㎖)을 가하였다. 여기에 7-아미노세팔로스포린산(26.4g)을 투입하고 교반하면서 트리-n-에틸아민 (9.80g)을 20분 동안 적가하였다. 반응온도를 60 내지 65℃로 승온시킨 후 3시간 동안 교반하였다.2-sodium thiopuroate (21.79 g) was added to the reactor and water (900 mL) was added. To this was added 7-aminocephalosporinic acid (26.4 g) and tri-n-ethylamine (9.80 g) was added dropwise for 20 minutes while stirring. The reaction temperature was raised to 60 to 65 ℃ and stirred for 3 hours.
반응이 완료되면 50 내지 60℃에서 인산을 이용하여 pH를 4로 조절함으로써 침전을 생성시켰다. 생성된 침전을 동 온도에서 30분간 교반하고 여과한 다음, 물(80㎖)과 아세톤(80㎖)을 사용하여 차례로 세척하고, 질소로 건조시켜 7-ACF 27.8g (수율 84%)을 수득하였다. Upon completion of the reaction, precipitation was produced by adjusting the pH to 4 using phosphoric acid at 50 to 60 ° C. The resulting precipitate was stirred for 30 minutes at the same temperature, filtered, washed sequentially with water (80 mL) and acetone (80 mL), dried over nitrogen to give 27.8 g (84% yield) of 7-ACF. .
실시예 1과 동일한 방법으로 1H-NMR 및 Mass(FAB)m/z 분석을 수행하여 7-ACF가 생성되었음을 확인하였다. 1 H-NMR and Mass (FAB) m / z analysis was performed in the same manner as in Example 1 to confirm that 7-ACF was generated.
실시예 5Example 5
2-소듐 티오퓨로에이트(43.58g)를 반응기에 넣고 아세토니트릴(20㎖)과 물(1.8ℓ)를 가하였다. 여기에 7-아미노세팔로스포린산(52.8g)을 투입하고 교반하면서 트리-n-부틸아민(36.0g)을 10분동안 적가하였다. 반응온도를 60 내지 65℃로 승온시킨 후 4시간 동안 교반하였다.2-sodium thiopuroate (43.58 g) was added to the reactor, and acetonitrile (20 mL) and water (1.8 L) were added thereto. To this was added 7-aminocephalosporinic acid (52.8 g) and tri-n-butylamine (36.0 g) was added dropwise for 10 minutes while stirring. The reaction temperature was raised to 60 to 65 ℃ and stirred for 4 hours.
반응이 완료되면 50 내지 60℃에서 인산을 이용하여 pH를 4로 조절함으로써 침전을 생성시켰다. 생성된 침전을 동온도에서 30분간 교반하고 여과한 다음, 물(150㎖)과 아세톤(150㎖)을 사용하여 차례로 세척하고, 질소로 건조시켜 7-ACF 55.6g (수율 84%)을 수득하였다. Upon completion of the reaction, precipitation was produced by adjusting the pH to 4 using phosphoric acid at 50 to 60 ° C. The resulting precipitate was stirred for 30 minutes at the same temperature, filtered, washed successively with water (150 mL) and acetone (150 mL), dried over nitrogen to give 55.6 g (84% yield) of 7-ACF. .
실시예 1과 동일한 방법으로 1H-NMR 및 Mass(FAB)m/z 분석을 수행하여 7-ACF가 생성되었음을 확인하였다. 1 H-NMR and Mass (FAB) m / z analysis was performed in the same manner as in Example 1 to confirm that 7-ACF was generated.
실시예 6Example 6
2-소듐 티오퓨로에이트(21.79g)를 반응기에 넣고 에틸아세테이트(8㎖)과 물(800㎖)을 가하였다. 여기에 7-아미노세팔로스포린산(26.4g)을 투입하고 교반하면서 트리-n-에틸아민(7.0g)을 10분 동안 적가하였다. 반응온도를 60 내지 65℃로 승온시킨 후 3시간 동안 교반하였다.2-sodium thiopuroate (21.79 g) was added to the reactor, and ethyl acetate (8 mL) and water (800 mL) were added thereto. To this was added 7-aminocephalosporinic acid (26.4 g) and tri-n-ethylamine (7.0 g) was added dropwise for 10 minutes while stirring. The reaction temperature was raised to 60 to 65 ℃ and stirred for 3 hours.
반응이 완료되면 50 내지 60℃에서 인산을 이용하여 pH를 5로 조절함으로써 침전을 생성시켰다. 생성된 침전을 동 온도에서 30분간 교반하고 여과한 다음, 물(80㎖)과 아세톤(80㎖)을 사용하여 차례로 세척하고, 질소로 건조시켜 7-ACF 27.0g (수율 82%)을 수득하였다. Upon completion of the reaction, precipitation was produced by adjusting the pH to 5 using phosphoric acid at 50 to 60 ° C. The resulting precipitate was stirred for 30 minutes at the same temperature, filtered, washed successively with water (80 mL) and acetone (80 mL), and dried over nitrogen to give 27.0 g (7% yield) of 7-ACF. .
실시예 1과 동일한 방법으로 1H-NMR 및 Mass(FAB)m/z 분석을 수행하여 7-ACF가 생성되었음을 확인하였다. 1 H-NMR and Mass (FAB) m / z analysis was performed in the same manner as in Example 1 to confirm that 7-ACF was generated.
상기 설명한 바와 같은 본 발명의 방법에 따르면 간편하고 단순한 공정을 통해 색상 및 순도면에서 우수한 화학식 1의 7-ACF 화합물을 합성할 수 있다. According to the method of the present invention as described above, it is possible to synthesize the 7-ACF compound of formula 1 excellent in color and purity through a simple and simple process.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4464367A (en) * | 1980-03-26 | 1984-08-07 | Sanofi | Cephalosporin derivatives, process for preparation thereof and drugs containing said derivatives usable as antibiotics |
| WO1987001117A2 (en) * | 1985-08-12 | 1987-02-26 | The Upjohn Company | Conversion of cephalosporin hydrohalide salt to alkali metal salt |
| KR20000050703A (en) * | 1999-01-14 | 2000-08-05 | 성재갑 | New cephem compouns for preparation of ceftiofur |
| WO2003055893A1 (en) * | 2002-01-04 | 2003-07-10 | Orchid Chemicals And Pharmaceuticals Limited | An improved synthesis of ceftiofur intermediate |
| WO2003059914A1 (en) * | 2002-01-15 | 2003-07-24 | Orchid Chemicals & Pharmaceuticals Limited | An improved synthesis of ceftiofur intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4464367A (en) * | 1980-03-26 | 1984-08-07 | Sanofi | Cephalosporin derivatives, process for preparation thereof and drugs containing said derivatives usable as antibiotics |
| WO1987001117A2 (en) * | 1985-08-12 | 1987-02-26 | The Upjohn Company | Conversion of cephalosporin hydrohalide salt to alkali metal salt |
| US4937330A (en) * | 1985-08-12 | 1990-06-26 | The Upjohn Company | Conversion of cephalosporin hydrohalide salt to alkali metal salt |
| KR20000050703A (en) * | 1999-01-14 | 2000-08-05 | 성재갑 | New cephem compouns for preparation of ceftiofur |
| WO2003055893A1 (en) * | 2002-01-04 | 2003-07-10 | Orchid Chemicals And Pharmaceuticals Limited | An improved synthesis of ceftiofur intermediate |
| WO2003059914A1 (en) * | 2002-01-15 | 2003-07-24 | Orchid Chemicals & Pharmaceuticals Limited | An improved synthesis of ceftiofur intermediate |
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