KR20020030563A - Process for preparing sodium cefuroxime - Google Patents
Process for preparing sodium cefuroxime Download PDFInfo
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- KR20020030563A KR20020030563A KR1020000061500A KR20000061500A KR20020030563A KR 20020030563 A KR20020030563 A KR 20020030563A KR 1020000061500 A KR1020000061500 A KR 1020000061500A KR 20000061500 A KR20000061500 A KR 20000061500A KR 20020030563 A KR20020030563 A KR 20020030563A
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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
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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Abstract
Description
본 발명은 항생제로서 유용한 세푸록심(cefuroxime)의 나트륨염(sodium salt)(이하, "나트륨 세푸록심"이라 한다)의 신규 제조방법에 관한 것이다. 보다 구체적으로, 본 발명은 고순도 및 고결정성의 나트륨 세푸록심의 제조방법으로서, 특히 나트륨 세푸록심의 안정성을 획기적으로 개선시킨 방법에 관한 것이다.The present invention relates to a novel process for preparing sodium salt of cefuroxime (hereinafter referred to as "sodium cefuroxime") useful as an antibiotic. More specifically, the present invention relates to a method for producing high purity and high crystalline sodium cefuroxime, and in particular, a method for dramatically improving the stability of sodium cefuroxime.
하기 화학식 1로 나타내어지는 세푸록심, 즉 (6R,7R)-7-[Z-2-(푸르-2-일)-2-메톡시이미노아세트아미도]-3-카바모일옥시메틸-세프-3-엠-4-카복실산은 광범위한 그램-양성균 및 그램-음성균에 대해 고도의 활성을 갖는 유용한 광범위 항생제로서 β-락타마제에 대해 매우 안정한 특성이 있다:Sepuroxime represented by the following formula (1), i.e. (6R, 7R) -7- [Z-2- (fur-2-yl) -2-methoxyiminoacetamido] -3-carbamoyloxymethyl-cef 3-M-4-carboxylic acid is a useful broad-spectrum antibiotic with high activity against a wide range of Gram-positive and Gram-negative bacteria, with very stable properties against β-lactamase:
특히, 그의 나트륨염, 즉 나트륨 세푸록심은 주사제로 투여하기에 매우 적합한 것으로 알려져 있으며 근래에는 매우 유용한 항생제로 인정받고 있다.In particular, its sodium salt, ie sodium cefuroxime, is known to be very suitable for administration by injection and has recently been recognized as a very useful antibiotic.
나트륨 세푸록심은 미국특허 제3,974,153호에 기재된 공지의 방법에 따라 결정성 고체로서 제조될 수 있다. 상기 미국특허에서는 극성 유기용매, 예를들어 디메틸아세트아미드, 그들의 혼합용매, 예를들어 디메틸아세트아미드/아세톤 또는 디메틸포름아미드/공업 메탄올 또는 수성 극성 유기용매계, 예를들어 수성 아세톤중의 세푸록심을 알칸올(예: 에탄올), 케톤(예: 아세톤), 염화 탄화수소(예: 메틸렌클로라이드), 에스테르(예: 에틸아세테이트) 또는 에테르(예: 디옥산)중에 용해된 나트륨 2-에틸헥사노에이트와 상온에서 반응시킨후, 필요시 용액을 예를들어 4℃까지 냉각시킨후 침전염을 회수함으로써 나트륨 세푸록심을 제조할 수 있다고 기재되어 있다. 그러나, 상기 방법에 의해 제조된 나트륨 세푸록심은 순도가 낮고 색도가 불량한 단점이 있다.Sodium cefuroxime can be prepared as a crystalline solid according to known methods described in US Pat. No. 3,974,153. The above patent discloses polar organic solvents such as dimethylacetamide, mixed solvents thereof such as dimethylacetamide / acetone or dimethylformamide / industrial methanol or aqueous polar organic solvents such as cefulock in aqueous acetone. Sodium 2-ethylhexanoate dissolved in alkanol (e.g. ethanol), ketone (e.g. acetone), chlorinated hydrocarbon (e.g. methylene chloride), ester (e.g. ethyl acetate) or ether (e.g. dioxane) It is described that sodium cefuroxime can be prepared by reacting with and at room temperature, then cooling the solution to 4 ° C. if necessary and recovering the precipitated salt. However, sodium cefuroxime prepared by the above method has a disadvantage of low purity and poor color.
또한, 대한민국 특허공고 제91-4301호에는 (6R,7R)-7-[Z-2-(푸르-2-일)-2-메톡시이미노아세트아미도]-3-하이드록시메틸세프-3-엠-4-카복실산을 알킬아세테이트 용매중에서 할로설포닐 이소시아네이트와 반응시키고, 세푸록심을 분리하지 않고 생성되는 중간생성물에 약산의 나트륨염을 가하여 나트륨 세푸록심을 형성시킨후 분리하는 방법이 기재되어 있다. 그러나, 상기 방법에서는 중간생성물, 즉 세푸록심에 포함되는 불순물을 효과적으로 제거하기가 어려우므로 그에 따라 제조된 나트륨 세푸록심의 순도가 낮고(HPLC에 의한 불순물 함량 1.8∼2.0% m/m) 안정성이 떨어지는 문제점이 있다.In addition, Korean Patent Publication No. 91-4301 discloses (6R, 7R) -7- [Z-2- (fur-2-yl) -2-methoxyiminoacetamido] -3-hydroxymethylsef- A method of reacting 3-m-4-carboxylic acid with halosulfonyl isocyanate in an alkyl acetate solvent and adding sodium salt of weak acid to the resulting intermediate without isolating cefuroxime is described to form sodium cefuroxime and then to separate it. have. However, in this method, it is difficult to effectively remove the intermediate product, that is, impurities contained in the cefuroxime, so that the purity of the sodium cefuroxime thus prepared is low (impurity content of 1.8 to 2.0% m / m by HPLC) and the stability is poor. There is a problem.
이에 본 발명자들은 상기 종래기술의 문제점을 해결하고자 지속적인 연구를수행한 결과, 상기 언급한 제반 문제점들을 해결할 수 있는 나트륨 세푸록심의 신규 제조방법을 개발해내고 본 발명을 완성하기에 이르렀다.Accordingly, the present inventors have conducted a continuous research to solve the problems of the prior art, and have developed a novel manufacturing method of sodium cefuroxime that can solve the above-mentioned problems and completed the present invention.
따라서, 본 발명의 목적은 고순도 및 고결정성의 나트륨 세푸록심을 제조할 수 있을 뿐아니라 그의 안정성을 획기적으로 개선시킬 수 있는 나트륨 세푸록심의 제조방법을 제공하기 위한 것이다.Accordingly, it is an object of the present invention to provide a method for preparing sodium cefuroxime, which can not only prepare high purity and high crystalline sodium cefuroxime but also dramatically improve its stability.
본 발명은 물과 테트라하이드로푸란의 혼합용매중에 용해된 세푸록심을 물과 에탄올의 혼합용매중에 용해된 약산의 나트륨염과 반응시켜 나트륨 세푸록심을 형성시키고 형성된 나트륨 세푸록심을 분리하여 나트륨 세푸록심을 제조하는 방법을 제공한다.The present invention reacts cefuroxime dissolved in a mixed solvent of water and tetrahydrofuran with sodium salt of weak acid dissolved in a mixed solvent of water and ethanol to form sodium cefuroxime, and separates the formed sodium cefuroxime to separate sodium cefuroxime. It provides a method of manufacturing.
본 방법에 있어서, 물과 테트라하이드로푸란의 혼합용액은 세푸록심 1 중량부를 물 1∼2 용적부 및 테트라하이드로푸란 5∼7 용적부의 비율로 배합된 혼합용매에 용해시킨 것이 바람직하고, 물과 에탄올의 혼합용액은 세푸록심 1 중량부를 기준으로 하여 약산의 나트륨염 4.3∼4.7 중량부를 물 1∼2 용적부 및 에탄올 15∼30 용적부의 비율로 배합된 혼합용매에 용해시킨 것이 바람직하다(단, 본 발명에서 중량이 g을 단위로 할 때 용적은 ㎖를 단위로 하며 이하 동일하다).In this method, the mixed solution of water and tetrahydrofuran is preferably dissolved in 1 part by weight of cefuroxime in a mixed solvent blended at a ratio of 1 to 2 parts by volume of water and 5 to 7 parts by volume of tetrahydrofuran. Is preferably dissolved in a mixed solvent of 4.3 to 4.7 parts by weight of sodium salt of weak acid based on 1 part by weight of cefuroxime in a proportion of 1 to 2 parts by volume of water and 15 to 30 parts by volume of ethanol (however, In the invention, when the weight is in g, the volume is in ml and is the same below).
또한, 반응을 30∼40 ℃의 온도에서 수행하는 것이 바람직하고, 물과 테트라하이드로푸란중의 세푸록심 용액을 물과 에탄올중의 약산의 나트륨염 용액에 적가하는 것이 바람직하다.It is also preferable to carry out the reaction at a temperature of 30 to 40 ° C., and it is preferable to dropwise add the solution of cefuroxime in water and tetrahydrofuran to the sodium salt solution of the weak acid in water and ethanol.
본 방법에 있어서, 약산의 나트륨염은 바람직하게는 나트륨 2-에틸헥사노에이트이다.In the method, the sodium salt of the weak acid is preferably sodium 2-ethylhexanoate.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 방법에 따르면 물/테트라하이드로푸란중의 세푸록심 용액, 바람직하게는 1∼2 용적부의 물 및 5∼7 용적부의 테트라하이드로푸란중의 1 중량부의 세푸록심 용액을 물/에탄올중의 약산의 나트륨염 용액, 바람직하게는 1∼2 용적부의 물 및 15∼30 용적부의 에탄올중의 4.3∼4.7 중량부의 약산의 나트륨염 용액에 가하여 나트륨 세푸록심을 형성시키고, 고순도의 나트륨세푸록심을 분리하여 나트륨 세푸록심을 제조한다.According to the process of the present invention, a solution of cefuroxime in water / tetrahydrofuran, preferably 1 to 2 vol. Of water and 1 part by weight of cefuroxime in 5 to 7 vol. Of tetrahydrofuran, is applied to the weak acid in water / ethanol. Sodium cefuroxime was formed by addition to a sodium salt solution of water, preferably 1 to 2 parts by volume of water and 4.3 to 4.7 parts by weight of a weak acid sodium solution in 15 to 30 parts by volume of ethanol to separate sodium cepuroxime of high purity. Sodium cefuroxime is prepared.
본 방법에 있어서 초기의 물/테트라하이드로푸란/세푸록심 용액중의 각 성분의 함량이 상기 범위를 벗어나는 경우 불순물의 제거가 용이하지 않을뿐 아니라 고체의 결정성이 저하될 수 있으므로 각 성분의 함량이 상기 범위내에 속하게 하는 것이 바람직하다.In the present method, when the content of each component in the initial water / tetrahydrofuran / sepuroxime solution is out of the above range, the removal of impurities may not be easy and the crystallinity of the solid may be lowered. It is desirable to fall within the above range.
또한, 물/에탄올/약산의 나트륨염 용액중의 에탄올의 함량이 15 용적부 미만이면 수율이 저하되고 고체의 결정성이 떨어질 수 있는 반면, 30 용적부를 초과하면 불순물의 제거가 어려워질 수 있으므로 상기 에탄올의 함량은 15∼30 용적부인 것이 바람직하며, 물의 함량이 1 용적부 미만이면 불순물 제거가 어려워질 수 있는 반면, 2 용적부를 초과하면 수율이 저하되고 고체의 결정성이 저하될 수 있으므로, 상기 물의 함량은 1∼2 용적부인 것이 바람직하다.In addition, when the content of ethanol in the sodium salt solution of water / ethanol / weak acid is less than 15 vol. Parts, the yield may be lowered and the crystallinity of the solid may be degraded. On the other hand, if it exceeds 30 vol. It is preferable that the content of ethanol is 15 to 30 parts by volume, and when the content of water is less than 1 part by volume, it may be difficult to remove impurities, while when the amount of water exceeds 2 parts by volume, the yield may be lowered and the crystallinity of the solid may be lowered. It is preferable that the content of water is 1-2 volume parts.
한편, 본 방법에서는 30∼40 ℃의 온도에서 초기의 물/테트라하이드로푸란/세푸록심 용액을 물/에탄올/약산의 나트륨염 용액에 적가하여 나트륨 세푸록심을결정화시키는 것이 바람직한데, 결정화 온도가 30 ℃ 미만이면 불순물의 제거가 어려워질 수 있고, 40 ℃를 초과하면 고체의 결정성이 감소하여 안정성이 저하될 수 있기 때문이다. 또한, 적가 순서를 반대로 하는 경우(즉, 물/에탄올/약산의 나트륨염 용액을 물/테트라하이드로푸란/세푸록심 용액에 적가하는 경우) 고체의 결정성이 감소하여 변색 및 안정성 저하의 우려가 있을 수 있다.On the other hand, in the present method, it is preferable to drop the initial water / tetrahydrofuran / sefuroxime solution dropwise to the sodium salt solution of water / ethanol / weak acid at a temperature of 30 to 40 ° C. to crystallize the sodium cefuroxime. If it is less than ℃, it may be difficult to remove the impurities, if it exceeds 40 ℃, the crystallinity of the solid is reduced and the stability may be lowered. In addition, if the dropping order is reversed (i.e., when the sodium salt solution of water / ethanol / weak acid is added dropwise to the water / tetrahydrofuran / sefuroxime solution), the crystallinity of the solid may decrease, which may cause discoloration and stability. Can be.
본 방법에서 나트륨 세푸록심을 형성하기 위하여 사용될 수 있는 약산의 나트륨염은 "pKa 값이 3.5 이상"인 산의 나트륨염이 바람직하고, 카복실산, 특히 C2-10알카노산의 염이 더욱 바람직하며 그 예로는 나트륨 아세테이트, 나트륨 락테이트, 나트륨 2-에틸헥사노에이트 또는 나트륨 프로피오네이트 등이 있고, 그중에서도 나트륨 2-에틸헥사노에이트가 가장 바람직하다. 상기 결정화가 완료되면 30∼40 ℃의 온도를 유지하면서 0.5∼4 시간, 바람직하게는 0.5∼2 시간동안 교반하고 여과, 세척 및 건조하여 생성된 나트륨 세푸록심을 분리할 수 있다.The sodium salt of the weak acid which can be used to form sodium cefuroxime in the process is preferably the sodium salt of an acid having a "pKa value of at least 3.5", more preferably a salt of a carboxylic acid, in particular a C 2-10 alkanoic acid. Examples include sodium acetate, sodium lactate, sodium 2-ethylhexanoate or sodium propionate and the like, with sodium 2-ethylhexanoate being most preferred. When the crystallization is completed, the sodium cefuroxime produced by stirring, filtration, washing and drying may be separated for 0.5 to 4 hours, preferably 0.5 to 2 hours, while maintaining a temperature of 30 to 40 ℃.
본 발명의 방법에 의해 제조된 나트륨 세푸록심은 불순물 함량(HPLC)이 0.5% m/m 미만이고 순도가 970 ㎍/㎎(무수 기준) 이상으로서 매우 순수하며 장기간 보관시에도 경시적 변화가 거의 없는 탁월한 안정성을 갖는다. 이 물질은 예를들면 매우 순수한 멸균 세푸록심 또는 고순도의 세푸록심 에스테르, 예를들어 세푸록심 악세틸(cefuroxime axetil)을 제조하기 위한 추가 공정에 매우 적합한 것이다.Sodium cefuroxime prepared by the method of the present invention has an impurity content (HPLC) of less than 0.5% m / m and a purity of 970 µg / mg (anhydrous basis), which is very pure and shows little change over time even during long-term storage. Has excellent stability. This material is well suited for further processing to prepare, for example, very pure sterile cefuroxime or high purity cefuroxime esters, for example cefuroxime axetil.
이하, 본 발명을 실시예에 의해 보다 구체적으로 설명하지만, 이에 의해 본 발명의 범위가 어떤 식으로든지 제한되는 것은 아니다.Hereinafter, although an Example demonstrates this invention more concretely, the scope of the present invention is not restrict | limited in any way by this.
[실시예 1]Example 1
나트륨 2-에틸헥사노에이트 4.5 g을 물 1 ㎖와 에탄올 15 ㎖의 혼합용매중에 용해시키고 30 ℃로 가온하였다. 여기에 세푸록심 1 g을 물 1 ㎖와 테트라하이드로푸란 5 ㎖의 혼합용매중에 용해시킨 용액을 1 시간동안 적가하였다. 결정화가 완료된후 용액을 30 ℃에서 1 시간동안 교반하고 여과한후 에탄올 10 ㎖로 세척하고 진공건조(2 mmHg, 35 ℃, 20 시간)하여 나트륨 세푸록심(0.98 g)을 백색 고체로서 수득하였다.4.5 g of sodium 2-ethylhexanoate was dissolved in a mixed solvent of 1 ml of water and 15 ml of ethanol and warmed to 30 ° C. To this was added dropwise a solution of 1 g of cefuroxime dissolved in a mixed solvent of 1 ml of water and 5 ml of tetrahydrofuran for 1 hour. After crystallization was completed, the solution was stirred at 30 ° C. for 1 hour, filtered, washed with 10 ml of ethanol and vacuum dried (2 mmHg, 35 ° C., 20 hours) to give sodium cefuroxime (0.98 g) as a white solid.
수율: 0.98 g(93.2%)Yield: 0.98 g (93.2%)
수분 함량: 2.5%(Karl Fischer)Moisture Content: 2.5% (Karl Fischer)
역가: 979 ㎍/㎎(무수 기준)Titer: 979 μg / mg (anhydrous basis)
[α]20 D: +61.3 °[α] 20 D : +61.3 °
불순물 함량: 0.43% m/m(HPLC)Impurity Content: 0.43% m / m (HPLC)
[실시예 2]Example 2
나트륨 2-에틸헥사노에이트 4.5 g을 물 2 ㎖와 에탄올 30 ㎖의 혼합용매중에 용해시키고 30 ℃로 가온한후 세푸록심 1 g을 테트라하이드로푸란 7 ㎖와 물 2 ㎖중에 용해시킨 용액을 1 시간동안 적가하였다. 결정화가 완료된후 용액을 30 ℃에서 1 시간동안 교반하고 여과한후 에탄올 10 ㎖로 세척하고 진공건조(2 mmHg, 35 ℃, 20 시간)하여 나트륨 세푸록심(1.0 g)을 백색고체로서 수득하였다.4.5 g of sodium 2-ethylhexanoate was dissolved in a mixed solvent of 2 ml of water and 30 ml of ethanol, warmed to 30 ° C, and 1 g of cefuroxime was dissolved in 7 ml of tetrahydrofuran and 2 ml of water for 1 hour. Was added drop wise. After crystallization was completed, the solution was stirred at 30 ° C. for 1 hour, filtered, washed with 10 ml of ethanol and dried in vacuo (2 mmHg, 35 ° C., 20 hours) to give sodium cefuroxime (1.0 g) as a white solid.
수율: 1.0 g(95.0%)Yield: 1.0 g (95.0%)
수분: 2.48%(Karl Fischer)Moisture: 2.48% (Karl Fischer)
역가: 973 ㎍/㎎(무수 기준)Titer: 973 μg / mg (anhydrous basis)
[α]20 D: +61.2 °[α] 20 D : +61.2 °
불순물 함량: 0.47% m/m(HPLC)Impurity Content: 0.47% m / m (HPLC)
[시험예 1]안정성 시험 Test Example 1 Stability Test
실시예 1 및 2에 의해 제조된 나트륨 세푸록심을 바이알내에 충진하고 40 ℃, R/H 75%에서의 경시적 함량 변화를 조사하였다. 그 결과는 하기 표 1에 나타낸 바와 같다.The sodium cefuroxime prepared by Examples 1 and 2 was packed into vials and the change in the content over time at 40 ° C., R / H 75% was investigated. The results are as shown in Table 1 below.
상기 표 2에 나타낸 바와 같이, 본 발명의 방법에 따라 제조된 나트륨 세푸록심은 3 개월 경과후까지 약 99%의 함량을 유지하여 기존의 제품에 비해 유의성 있을 뿐아니라 탁월한 경시 안정성을 가짐을 확인할 수 있었다.As shown in Table 2, the sodium cefuroxime prepared according to the method of the present invention can maintain a content of about 99% until after 3 months, as well as significant compared to the existing product, it can be confirmed that it has excellent stability over time. there was.
본 발명의 방법에 따르면 고순도 및 고결정성의 나트륨 세푸록심을 제조할 수 있을뿐 아니라, 나트륨 세푸록심의 안정성을 획기적으로 개선시킬 수 있다.According to the method of the present invention, it is possible not only to prepare high purity and high crystalline sodium cefuroxime, but also to drastically improve the stability of sodium cefuroxime.
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| CN102617604A (en) * | 2012-02-24 | 2012-08-01 | 天津大学 | Method utilizing coupling reaction crystallization to prepare cefuroxime sodium |
| CN112442048A (en) * | 2020-11-10 | 2021-03-05 | 华北制药河北华民药业有限责任公司 | Preparation method of cefpiramide sodium |
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| GB8320520D0 (en) * | 1983-07-29 | 1983-09-01 | Glaxo Group Ltd | Chemical process |
| KR910000046A (en) * | 1989-06-23 | 1991-01-29 | 다다아끼 사까이 | How to freeze food |
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| CN102617604A (en) * | 2012-02-24 | 2012-08-01 | 天津大学 | Method utilizing coupling reaction crystallization to prepare cefuroxime sodium |
| CN112442048A (en) * | 2020-11-10 | 2021-03-05 | 华北制药河北华民药业有限责任公司 | Preparation method of cefpiramide sodium |
| CN112442048B (en) * | 2020-11-10 | 2022-04-08 | 华北制药河北华民药业有限责任公司 | Preparation method of cefpiramide sodium |
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