KR19980082654A - Process for preparing cefuroxime ester derivative - Google Patents

Process for preparing cefuroxime ester derivative Download PDF

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KR19980082654A
KR19980082654A KR1019970017691A KR19970017691A KR19980082654A KR 19980082654 A KR19980082654 A KR 19980082654A KR 1019970017691 A KR1019970017691 A KR 1019970017691A KR 19970017691 A KR19970017691 A KR 19970017691A KR 19980082654 A KR19980082654 A KR 19980082654A
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cefuroxime
crystallization
present
isomer
normal hexane
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KR1019970017691A
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KR100202279B1 (en
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이광혁
윤용식
최광도
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손경식
제일제당 주식회사
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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
    • C07D501/12—Separation; Purification
    • 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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  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

본 발명은 세푸록심 에스테르유도체를 제조하는 개선된 방법에 관한 것이다. 본 발명은 세푸록심 1-아세톡시 에틸 에스테르를 제조함에 있어 출발물질을 염기를 사용하지 않고 보다 중성인 조건하에서 반응시켜 생성물을 결정화하는데 있어서 수율을 극대화하고 R:S 이성체비를 약 1:1로 얻기 위해 이소프로판올과 노말헥산의 용매계를 이용하여서 된다. 상기 용매계의 혼합비율을 1:2의 비율로 하고 이소프로판올로 1차 결정화시킨 후에 노말헥산으로 결정화를 완료한다. 본 발명의 이점은 종래의 방법에 비하여 간편하면서도 고순도, 고수율의 산물을 얻을 수 있다는 특징이 있다.The present invention is directed to an improved process for preparing the cefuroxime ester derivatives. The present invention maximizes the yield in crystallization of the product by reacting the starting material under neutral conditions without using a base in the preparation of cefuroxime 1-acetoxy ethyl ester, and the R: S isomer ratio is about 1: 1. In order to obtain, a solvent system of isopropanol and normal hexane may be used. The solvent-based mixing ratio is 1: 2, and after primary crystallization with isopropanol, crystallization is completed with normal hexane. Advantageous Effects of the Invention The advantage of the present invention is that it is possible to obtain products of high purity and high yield while being simpler than conventional methods.

Description

세푸록심 에스테르 유도체의 제조방법Process for preparing cefuroxime ester derivative

본 발명의 세푸록심 에스테르 유도체를 제조하는 개선된 방법에 관한 것이다. 특히, 본 발명은 하기 구조식(1)로 표시되는 화합물 세푸록심 1-아세톡시 에틸 에스테르(cefuroxime axetil)를 제조하는 개선된 방법에 관한 것이다. 더욱 상세하게는 그람 음성균과 그람 양성균에 대하여 광범위한 항균력을 가지는 공지된 항생물질 (6R,7R)-3-카바모일옥시메틸-7-[(Z)-2-(푸르-2-일)-2-메톡시이미노-아세트아미도]-세프-3-엠-4-카르복실산(이하, 세푸록심이라함)의 에스테르를 제조하는 개선된 방법에 관한 것이다.It relates to an improved process for preparing the cefuroxime ester derivatives of the present invention. In particular, the present invention relates to an improved process for preparing the compound cefuroxime 1-acetoxy ethyl ester (cefuroxime axetil) represented by the following structural formula (1). More specifically, known antibiotics (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2 having a broad antimicrobial activity against gram-negative and gram-positive bacteria -Methoxyimino-acetamido] -sheeps-3-m-4-carboxylic acid (hereinafter referred to as cefuroxime).

상기 구조식(1)의 화합물은 세푸록심 1-아세톡시 에틸 에스테르로서 그람음성 및 그람양성 미생물에 대하여 활성 스펙트럼이 매우 광범위한 항균력을 가지며 특히 그람음성 미생물에 의해 생성되는 β-락탐아제에 대하여 매우 안정하므로 항균성이 증대되고 포유동물에서 내성이 우수하며 항생제로 널리 사용되고 있다. 또한 이 화합물은 경구투여 후 위장관에서 잘 흡수되어 매우 효능이 있는 항생물질로서 이 화합물의 제조방법에 대한 공지 기술로는 영국특허 제1,571,683호 및 제2,145,409호 등을 들 수 있다. 상기 특허의 방법들은 상기 구조식(1)인 세푸록심 1-아세톡시 에틸 에스테르를 제조하기 위하여 하기 구조식(A)로 표시되는 세푸록심 또는 그의 무기염과 하기 구조식(B)로 표시되는 브롬화(RS)-1-아세톡시에틸에 염기를 가하여 에스테르화 시키는 방법을 사용하고 있다.The compound of formula (1) is cefuroxime 1-acetoxy ethyl ester, which has a broad spectrum of antimicrobial activity against gram-negative and gram-positive microorganisms, and is particularly stable against β-lactamase produced by gram-negative microorganisms. It has increased antimicrobial properties, excellent resistance in mammals and is widely used as an antibiotic. In addition, the compound is an antibiotic that is well absorbed in the gastrointestinal tract after oral administration and is very effective, and known methods for preparing the compound include British Patent Nos. 1,571,683 and 2,145,409. The methods of the above patents are for the preparation of cefuroxime 1-acetoxy ethyl ester of formula (1), cefuroxime represented by the following formula (A) or its inorganic salt and brominated (RS) represented by the following formula (B) A method of esterifying by adding a base to -1-acetoxyethyl is used.

위의 식에서 M은 H, Na, K등을 나타낸다.In the above formula, M represents H, Na, K and the like.

영국특허 제1,571,683호는 상기 구조식(A)에서 M이 H인 화합물을 사용하는 기술로서 반응중 염기를 사용하는 공정이 포함되고 반응용액에 무수 무기물을 사용하여 건조시키는 공정을 거쳐야 할 뿐만 아니라 또 결정화시키는 방법이 비효율적이면서 수율이 매우 낮아 공업화하기 어렵다는 단점이 있다. 한편 상기 구조식(A)에서 M이 Na인 화합물을 사용하는 기술인 영국특허 제2,145,409호는 그 목적으로 하는 화합물의 수율은 비교적 양호하나 반응에서 염기를 사용하는 공정이 포함되고 그 결과 불순물(△2이성체 또는 E-이성체)이 0.5~0.7%정도 포함된다는 단점이 있다.British Patent No. 1,571,683 is a technique of using a compound in which M is H in Structural Formula (A), which includes a step of using a base during the reaction and undergoes a step of drying using anhydrous inorganic substances in the reaction solution as well as determining It is difficult to industrialize because the method is inefficient and the yield is very low. Meanwhile, British Patent No. 2,145,409, which uses a compound of M in Na in Structural Formula (A), has a relatively good yield of a target compound, but includes a step of using a base in a reaction, and as a result, impurities (△ 2 isomers). Or E-isomer) has a disadvantage of containing about 0.5 to 0.7%.

따라서, 본 발명은 상기와 같은 문제점을 해결하기 위한 것으로 세푸록심 악세틸의 개선된 제조방법을 제공한다. 세푸록심 또는 그의 무기염과 브롬화 (RS)-1-아세톡시에틸을 염기를 가하여 에스테르화시키는 경우에, 염기를 사용하지 않고 보다 중성적인 조건하에서 반응시키고 새로운 결정화용매를 선택하여 제조방법을 개선하고자 하였다. 수율을 최대화하고 R:S 이성체 비를 약 1:1로 얻기 위해 이소프로판올로 결정화시킨 후에 노말헥산으로 결정화를 완료하였다. 따라서 기존의 방법보다 간편하면서도 불순물 함유량이 적은 고순도의 목적물을 얻는데 그 목적이 있다.Accordingly, the present invention is to solve the above problems and provides an improved method for producing cefuroxime axetyl. When cefuroxime or its inorganic salt and brominated (RS) -1-acetoxyethyl were esterified by addition of a base, reaction was made under neutral conditions without using a base and a new crystallization solvent was selected to improve the preparation method. . Crystallization was complete with normal hexanes after crystallization with isopropanol to maximize the yield and obtain an R: S isomer ratio of about 1: 1. Therefore, there is a purpose to obtain a high-purity target that is simpler than the existing method but less impurities.

따라서, 본 발명을 상기 구조식(1)의 세푸록심 1-아세톡시 에틸 에스테르를 제조함에 있어서 염기를 사용하지 않고 보다 중성인 조건하에서 반응시키고 새로운 결정화 용매의 선택으로 제조방법을 개선하여 최종생성물의 수율을 높힘과 동시에 고순도의 제품을 공업적으로 간편하고 경제적인 방법으로 수득할 수 있는 방법을 제공함을 그 목적으로 한다.Accordingly, the present invention is reacted under neutral conditions without using a base in the preparation of the cefuroxime 1-acetoxy ethyl ester of the above formula (1), and the preparation method is improved by the selection of a new crystallization solvent to yield the final product. It is an object of the present invention to provide a method for obtaining a high-purity product in an industrially simple and economical manner at the same time.

본 발명은 상기 구조식(1)의 세푸록심 1-아세톡시 에틸 에스테르를 제조함에 있어서 상기 구조식(B)는 아세틸 브로마이드와 아세트 알데히드를 반응시켜 제조하고 이를 구조식(A)의 세푸록심 무기염과 에스테르화 반응시킨 후 적절한 결정화 용매의 혼합액을 선택해 1:1의 R,S이성체비를 갖고, △2이성체 및 E-이성체등의 불순물이 현저히 감소된 세푸록심 1-아세톡시 에틸 에스테르의 개선된 제조방법을 제공하므로서 완성된다. 따라서 최초의 개선된 제법특허인 영국특허 제2,145,409에 의하면 △2이성체가 0.1~0.5%, E-이성체가 0.6~0.7%를 함유하나 본 발명에 의하면 △2이성체 및 E-이성체 등의 불순물이 각각 0.05% 이하로 현저히 감소된 고순도의 세푸록심 악세틸을 제공하게 된다.In the present invention, in the preparation of the cefuroxime 1-acetoxy ethyl ester of formula (1), the formula (B) is prepared by reacting acetyl bromide with acetaldehyde, and esterifying it with the cefuroxime inorganic salt of formula (A). After the reaction, a mixture of an appropriate crystallization solvent was selected to have an R, S isomer ratio of 1: 1, and an improved method for preparing cefuroxime 1-acetoxy ethyl ester in which impurities such as △ 2 isomer and E-isomer were significantly reduced. Completed by providing Therefore, according to British Patent No. 2,145,409, the first improved manufacturing method, the △ 2 isomer contains 0.1 to 0.5% and the E-isomer contains 0.6 to 0.7%, but according to the present invention, impurities such as △ 2 isomer and E-isomer are respectively It provides high purity cefuroxime axetyl, which is significantly reduced below 0.05%.

이하, 본 발명을 당업자가 용이하게 실시할 수 있도록 상세히 설명한다.Hereinafter, the present invention will be described in detail so that those skilled in the art can easily implement the present invention.

먼저, 아세틸 브로마이드와 아세트알데히드를 용매없이 반응시킨 다음 유기용매로 추출한 후 농축하여 구조식(B)인 1-브로모에틸 아세테이트를 얻는다. 1-브로모에틸아세테이트와 세푸록심 무기염을 에스테르화 반응을 시켜 목적으로 하는 화합물 세푸록심 악세틸을 얻는다. 이때, 목적물의 결정화 용매로는 수율을 극대화하고 R:S 이성체 비를 약 1:1로 얻기 위해 이소프로판올과 노말헥산의 용매계를 사용하고 결정화 단계는 10~45℃에서 1.0~4.0시간 동안 교반하여 진행시킨다. 생성된 결정을 여과하고 세척한 다음 건조하여 최종생성물 세푸록심 악세틸을 얻는다.First, acetyl bromide and acetaldehyde are reacted without a solvent, extracted with an organic solvent, and then concentrated to obtain 1-bromoethyl acetate of formula (B). Esterification of 1-bromoethyl acetate and the cefuroxime inorganic salt is carried out to obtain the desired compound cefuroxime acetil. In this case, as a crystallization solvent of the target, a solvent system of isopropanol and normal hexane is used to maximize the yield and obtain an R: S isomer ratio of about 1: 1. The crystallization step is stirred at 10 to 45 ° C. for 1.0 to 4.0 hours. Proceed. The resulting crystals are filtered, washed and dried to give the final product cefuroxime axetyl.

이하 본 발명의 구성과 작용을 실시예를 들어 상세히 설명한다.Hereinafter, the configuration and operation of the present invention will be described in detail by way of examples.

[실시예 1]Example 1

디메틸아세트아미드 50ml에 세푸록심 소듐 10g을 교반하면서 3℃로 냉각한 후 1-브로모에틸 아세테이트 5.63g을 가했다. 이 반응액을 3시간 더 반응시킨 후, 아세트산에틸 150ml와 3% 중탄산나트륨 수용액 100ml의 혼합용액에 부어 1시간 동안 교반하였다. 충분리를 수행하여 유기층은 1N 염산용액 50ml와 20% 염화나트륨 50ml로 세척하였다. 다시 충분리하여 유기층은 2% 중탄산나트륨 수용액 15ml와 20% 염화나트륨 50ml로 세척한다. 유기층을 다시 활성탄 1.0g으로 탈색처리한 후 여과하고, 아세트산에틸 20ml로 세척한다. 여액을 40℃에서 감압증류하여 30g으로 증발시키고, 농축액에 이소프로필 알콜 33ml를 가하여 1시간 교반한 후 결정화하고 이에 노말헥산 66ml를 가하여 1시간 동안 교반하여 결정화를 완료시켰다. 생성된 결정을 여과한 후 이소프로필 알콜과 노말헤간 혼합용액으로세척한 다음 35℃에서 건조시켜 결정형 세푸록심 악세틸 9.65g을 얻었다.To 50 ml of dimethylacetamide, 10 g of cefuroxime sodium was cooled to 3 ° C while stirring, and 5.63 g of 1-bromoethyl acetate was added thereto. The reaction solution was further reacted for 3 hours, and then poured into a mixed solution of 150 ml of ethyl acetate and 100 ml of a 3% sodium bicarbonate aqueous solution and stirred for 1 hour. After sufficient completion, the organic layer was washed with 50 ml of 1N hydrochloric acid solution and 50 ml of 20% sodium chloride. Again enough, the organic layer was washed with 15 ml of 2% aqueous sodium bicarbonate solution and 50 ml of 20% sodium chloride. The organic layer was further decolorized with 1.0 g of activated carbon, filtered and washed with 20 ml of ethyl acetate. The filtrate was evaporated under reduced pressure at 40 ° C. and evaporated to 30 g. Then, 33 ml of isopropyl alcohol was added to the concentrate, followed by stirring for 1 hour, followed by crystallization. 66 ml of normal hexane was added thereto, followed by stirring for 1 hour to complete crystallization. The resulting crystals were filtered and washed with a mixture of isopropyl alcohol and normal heganese and dried at 35 ° C. to obtain 9.65 g of crystalline cefuroxime acetyl.

상기 실시예에 의하여 제조된 세푸록심 악세틸은 다음과 같은 이화학적 성질을 갖는다.Sepuroxime axetyl prepared by the above examples has the following physicochemical properties.

[α]D(1% 디옥산용액):+38°[α] D (1% dioxane solution): + 38 °

NMR(δ,CDCl3+DMSO-d3):1.53(1d,3H), 2.07(s,3H), 3.57(br,S,2H), 3.97(s,3H), 4.83(br,S,2H), 5.85(ABq,1H), 6.20(br,S,2H), 6.47~6.8(m,2H), 6.90~7.20(q,1H), 7.60(br,S,1H), 9.63(d,1H)NMR (δ, CDCl 3 + DMSO-d 3 ): 1.53 (1d, 3H), 2.07 (s, 3H), 3.57 (br, S, 2H), 3.97 (s, 3H), 4.83 (br, S, 2H ), 5.85 (ABq, 1H), 6.20 (br, S, 2H), 6.47 ~ 6.8 (m, 2H), 6.90 ~ 7.20 (q, 1H), 7.60 (br, S, 1H), 9.63 (d, 1H )

이성체비(HPLC) 1:1.06Isomer ratio (HPLC) 1: 1.06

HPLC에 의한 불순도:△2이성체0.05%, E-이성체0.05%Impurity by HPLC: △ 2 isomer 0.05%, E-isomer 0.05%

[실시예 2]Example 2

실시예 1과 동일한 방법으로 수행하되 실시예 1에서 처럼 이소프로필 알콜 33ml와 노말헥산 66ml를 분리하여 가하지 않고 이소프로필 알콜과 노말헥산의 혼합용매 70ml를 동시에 가한다음 결정화를 완성하였다.The same process as in Example 1 was carried out, but as in Example 1, 33 ml of isopropyl alcohol and 66 ml of normal hexane were not added separately, but 70 ml of a mixed solvent of isopropyl alcohol and normal hexane was added simultaneously to complete crystallization.

상기 실시예에 의하여 제조된 세푸록심 악세틸은 다음과 같은 이화학적 성질을 갖는다.Sepuroxime axetyl prepared by the above examples has the following physicochemical properties.

이성체비(HPLC) 1:1.06Isomer ratio (HPLC) 1: 1.06

HPLC에 의한 불순물도:△2이성체 0.03%, E-이성체 0.03%Impurity degree by HPLC: △ 2 isomer 0.03%, E-isomer 0.03%

이상과 같이 본 발명에 의하면 이소프로필 알콜과 노말헥산의 혼합용매 중에서 세푸록심 악세틸을 결정화하고 이때 두 혼합용매비율을 1:2로 하여 결정화함에 있어서 이소프로필알콜로 1차 결정화한 후 노말헥산으로 결정화를 완성화하는 방법에 의하여 고순도, 고수율의 세푸록심 악세틸을 얻을 수 있는 효과가 있어 본 발명은 항생제 의약산업상 매우 유용한 발명인 것이다.As described above, according to the present invention, in the mixed solvent of isopropyl alcohol and normal hexane, cefuroxime acetyl is crystallized, and in this case, the first crystallization is performed with isopropyl alcohol in the crystallization with the ratio of the two mixed solvents 1: 2, followed by normal hexane. It is effective to obtain high purity and high yield of cefuroxime acetil by the method of completing the crystallization. The present invention is a very useful invention in the antibiotic medicine industry.

Claims (3)

상기 이소프로필 알콜과 노말헤간의 혼합용매 중에서 세푸록심 1-아세톡시에틸 에스테르 용액으로부터 세푸록심 1-아세톡시에틸 에스테르를 결정화하고, 이 물질을 분리 건조하여 고순도, 고수율의 세푸록심 에스테르 유도체의 제조방법.Sepuroxime 1-acetoxyethyl ester is crystallized from the solution of cefuroxime 1-acetoxyethyl ester in the mixed solvent of isopropyl alcohol and normal hex, and the material is separated and dried to prepare a high purity, high yield cefuroxime ester derivative. Way. 제1항에 있어서, 상기 이소프로필 알콜과 노말헥산의 혼합비율이 1:2임을 특징으로 하는 방법.The method of claim 1, wherein the mixing ratio of isopropyl alcohol and normal hexane is 1: 2. 제1항에 있어서, 상기 세푸록심 에스테르 유도체는 이소프로필 알콜과 1차로 결정화한 후 노말헤산으로 마무리 결정화함을 특징으로 하는 방법.2. The method of claim 1, wherein the cefuroxime ester derivative is crystallized first with isopropyl alcohol and then final crystallized with normal helic acid.
KR1019970017691A 1997-05-08 1997-05-08 Process for preparing cefuroxime ester derivatives KR100202279B1 (en)

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