KR900004931B1 - Process for preparing cephalosporin compounds - Google Patents

Process for preparing cephalosporin compounds Download PDF

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KR900004931B1
KR900004931B1 KR1019880005139A KR880005139A KR900004931B1 KR 900004931 B1 KR900004931 B1 KR 900004931B1 KR 1019880005139 A KR1019880005139 A KR 1019880005139A KR 880005139 A KR880005139 A KR 880005139A KR 900004931 B1 KR900004931 B1 KR 900004931B1
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formula
propylene glycol
compound
acetone
structural formula
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KR1019880005139A
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KR890017257A (en
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조광희
김규완
김영덕
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영진약품공업 주식회사
김생기
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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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  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

A method for preparing cephatrizine propylene glycol of formula (I), comprises suspending cephatrizine hydrate or solvate of formula (II) in 1,2-propylene glycol and conducting heat reaction directly at 40- 90≰C. The starting cpd. is used in an amt. of 1.0 mole part relative to 10 to 50 mole parts of 1,2-propylene glycol. The reaction mixt. is diluted with addn. of solvent such as ethanol, acetonitrile, acetone, water, etc., and the resultant is recovered by filtration. In (II), n is less than 5; X is water, methanol, ethanol, acetonitrle or acetone. (I) is a cephalosporin cpd. useful as antibiotics.

Description

세팔로스포린 화합물의 제조방법Process for preparing cephalosporin compound

본 발명은 다음 구조식(I)로 표시되는 7-[D-α-아미노-α-(4-하이드록시페닐)아세트아미도]-3-(1,2,3-트리아졸-4(5)-일티오메틸)-3-세팸-4-카르복실산 프로필렌글리콜레이트(이하, 세파트리진·프로필렌글리콜레이트라 한다)의 제조 방법에 관한 것이다.The present invention provides 7- [D-α-amino-α- (4-hydroxyphenyl) acetamido] -3- (1,2,3-triazole-4 (5) represented by the following structural formula (I): The present invention relates to a process for producing ylthiomethyl) -3-cepam-4-carboxylic acid propylene glycolate (hereinafter referred to as cefatrizine propylene glycolate).

Figure kpo00001
Figure kpo00001

본 발명은 목적화합물인 상기 구조식(I)의 화합물은 세팔로스포린 유도체로서 항생제로 유용한 공지화합물이다.The compound of formula (I), which is the target compound of the present invention, is a known compound useful as an antibiotic as a cephalosporin derivative.

상기 구조식(I)의 화합물에 대한 종래의 제조방법을 살펴보면 일본특허공개 소 50-105,813호, 제54-95,589호 등에 기술되어 있는 바와 같이, 다음 구조식(II)으로 표시되는 세파트리진·수화물 또는 세파트리진·용매화물을 1,2-프로필렌글리콜 또는 1,2-프로필렌글리콜 수용액중에서 슬러리화하고, 이를 염산등의 산으로 산성화하여 용해시킨 다음, 여기에다 염기를 가하여 pH가 4.0 내지 5.0으로 되도록 하므로서 상기 구조식(I)의 목적 화합물을 얻게 된다.Looking at the conventional manufacturing method for the compound of the above formula (I), as described in Japanese Patent Application Laid-open No. 50-105,813, 54-95,589, etc., Sephatrizin-hydrate represented by the following formula (II) or Sephatriazine-solvate is slurried in an aqueous solution of 1,2-propylene glycol or 1,2-propylene glycol, acidified with an acid such as hydrochloric acid and dissolved, and then a base is added thereto so that the pH is 4.0 to 5.0. The desired compound of formula (I) is obtained.

Figure kpo00002
Figure kpo00002

상기 구조식에서 X는 H2O, CH3OH, C2H5OH, CH3CN, CH3COCH3등의 용매를 나타내고, n은 5이하의 정수를 표시한다.In the structural formula, X represents a solvent such as H 2 O, CH 3 OH, C 2 H 5 OH, CH 3 CN, CH 3 COCH 3 , and n represents an integer of 5 or less.

한편, 상기 구조식(II)으로 표시되는 세파트리진·수화물 또는 세파트리진·용매화물의 제조방법은 일본 특허공개 소 49-31,689호, 소 49-84,696호, 소 55-18,716호, 소 52-136,191호, 소 55-105,687호, 소 57-46,989호와 미국특허 제3,867,380호, 제3,855,213호에 기술되어 있다.On the other hand, the manufacturing method of the Sephatriazine-hydrate or Sephatriazine-solvate represented by Structural Formula (II) is Japanese Patent Laid-Open Nos. 49-31,689, 49-84,696, 55-55,716, 52- 136,191, US 55-105,687, US 57-46,989, and US Pat. Nos. 3,867,380, 3,855,213.

그러나 이와 같은 종래의 방법으로 상기 구조식(I)의 화합물을 제조하게 되면 반응혼합물을 강한 산성조건하에서 용해시켜야 하기 때문에 이를 공업적으로 실시하게 되면 목적화합물이 분해반응을 일으키게 되는 등 많은 문제점이 있다.However, when the compound of formula (I) is prepared by such a conventional method, since the reaction mixture must be dissolved under strong acidic conditions, there are many problems such as causing a decomposition reaction of the target compound.

이에, 본 발명자들은 상기와 같은 종래 기술의 문제점을 해결하고, 또한 종래에 비하여 그 조작공정이 훨씬 간단하게 되는 방법을 연구하므로서 본 발명에 이르게 된 것이다.Therefore, the present inventors have come to the present invention by studying a method of solving the problems of the prior art as described above, and the operation process is much simpler than the prior art.

본 발명은 다음 구조식(II)로 표시되는 세파트리진·수화물 또는 세파트리진·용매화물을 다음 구조식(III)으로 표시되는 1,2-프로필렌글리콜중에서 직접 가온반응시켜 전환시킴을 특징으로 하는 다음 구조식(I)의 세파트리진·프로필렌글리콜레이트의 제조방법인 것이다.The present invention is characterized by converting cephatriazine, a hydrate or a sephatriazine, a solvate represented by the following structural formula (II) by directly warming it in 1,2-propylene glycol represented by the following structural formula (III). It is a manufacturing method of the Sephatrizin propylene glycolate of structural formula (I).

Figure kpo00003
Figure kpo00003

Figure kpo00004
Figure kpo00004

Figure kpo00005
Figure kpo00005

상기 구조식에서 X는 H2O, CH3OH, C2H5OH, CH3CN, CH3COCH3등의 용매를 나타내고, n은 5이하의 정수를 의미한다.In the structural formula, X represents a solvent such as H 2 O, CH 3 OH, C 2 H 5 OH, CH 3 CN, CH 3 COCH 3 , and n means an integer of 5 or less.

이하, 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.

본 발명에서는 상기 구조식(II)으로 표시되는 세파트리진·수화물 또는 세파트리진·용매화물을 상기 구조식(III)으로 표시되는 1,2-프로필렌글리콜 중에 현탁시키고, 이를 직접 가온반응시킨다음, 그 침전물을 여과, 세척, 건조하므로서, 세파트리진 1몰당 프로필렌글리콜 1.0 내지 1.5몰이 결합되어 있는 목적화합물인 상기 구조식(I)의 화합물을 얻는다.In the present invention, the Sephatriazine-hydrate or Sephatriazine-Solvate represented by Structural Formula (II) is suspended in 1,2-propylene glycol represented by Structural Formula (III), and then directly warmed and reacted. The precipitate is filtered, washed and dried to obtain the compound of formula (I), which is a target compound having 1.0 to 1.5 moles of propylene glycol per mole of cefatrizine.

이때, 상기 1,2-프로필렌글리콜의 양은 상기 세파트리진·수화물 또는 세파트리진·용매화물 1몰당 10 내지 50몰을 사용할 수 있으나, 바람직하기로는 20 내지 30몰을 사용하는 것이 좋다.In this case, the amount of 1,2-propylene glycol may be 10 to 50 moles per 1 mole of the cephatrizine hydrate or sephatrizine solvate, but preferably 20 to 30 moles.

또한, 상기 가온반응은 40°내지 90℃의 온도, 바람직하기로는 60°내지 80℃의 온도에서 실시하는 것이 좋은데, 만일 상기 가온반응을 40℃이하의 온도에서 실시하게 되면 전환반응시간이 길어지게 되어 좋지 않고, 반대로 90℃이상의 온도에서 실시하게 되면 반응 생성물이 분해되거나 착색될 우려가 있다. 이때 pH는 6.0으로 조절하는 것이 좋다.In addition, the warming reaction may be performed at a temperature of 40 ° to 90 ° C, preferably at a temperature of 60 ° to 80 ° C. If the heating reaction is performed at a temperature of 40 ° C or less, the conversion reaction time becomes longer. On the contrary, if the reaction product is carried out at a temperature of 90 ° C. or more, the reaction product may be decomposed or colored. At this time, the pH is preferably adjusted to 6.0.

본 발명의 목적화합물인 구조식(I)으로 표시되는 세파트리진·프로필렌글리콜레이트는 상기 1,2-프로필렌글리콜중에 침전되어 있는 침전물의 형태로 얻어지게 되는데, 상기 침전물은 점성이 매우 크기 때문에 직접 여과로는 그 분리가 매우 곤란하다. 따라서 본 발명에서는 이를 극성용매로 희석시킨다음, 침전물을 직접 여과분리하므로서, 이러한 어려움을 해결할 수 있었다. 이때 용매로는 에탄올, 아세토니트릴, 아세톤, 물등을 사용할 수 있는데, 이중에서 아세톤을 사용하는 것이 가장 좋다.Sephatrizin-propylene glycolate represented by Structural Formula (I), which is the target compound of the present invention, is obtained in the form of precipitate precipitated in 1,2-propylene glycol. The separation is very difficult. Therefore, in the present invention, by diluting it with a polar solvent, by separating the precipitate directly, it was possible to solve this difficulty. In this case, ethanol, acetonitrile, acetone, water, etc. may be used as the solvent, of which acetone is best used.

본 발명은 염산등의 강산을 사용하지 않기 때문에 종래와 같이 목적화합물이 분해되는 등의 문제점이 생길 우려가 없고, 전반적인 공정이 훨씬 안전할 뿐 아니라 그 조작도 용이하게 되는 것이다.Since the present invention does not use a strong acid such as hydrochloric acid, there is no fear that the target compound is decomposed as in the prior art, and the overall process is much safer and the operation is easier.

이하, 본 발명에 대한 실시예는 다음과 같다.Hereinafter, embodiments of the present invention are as follows.

[실시예 1]Example 1

프로필렌글리콜 100미리리터에 세파트리진 수화물 5그램(0.01몰)을 현탁시키고, 이를 가온하여 60℃에서 8시간 동안 반응시킨다음, 상온으로 냉각시킨다. 여기에다 아세톤 5미리리터를 가하여 0.5시간동안 교반하고, 그 침전물을 여과하여 메탄올, 아세톤으로 세척한 후 건조하면 목적화합물은 세파트리진 프로필렌글리콜레이트 4.95그램(90%)이 얻어진다.5 grams (0.01 mol) of Sephatrizin hydrate was suspended in 100 milliliters of propylene glycol, which was then heated and reacted at 60 DEG C for 8 hours, followed by cooling to room temperature. 5 ml of acetone was added thereto, stirred for 0.5 hour, and the precipitate was filtered, washed with methanol and acetone, and dried to yield 4.95 g (90%) of cepatrizine propylene glycolate.

Figure kpo00006
Figure kpo00006

[실시예 2]Example 2

프로필렌글리콜 100미리리터에 세파트리진·메탄올레이트 용매화물 5그램(0.0101몰)을 현탁시키고, 여기에다 트리에틸아민을 가하여 그 pH를 6.0으로 되도록 한 다음, 가온하여 60℃의 온도에서 8시간 동안 반응시켜서 상온으로 냉각시킨다.5 g (0.0101 mol) of Sephatrizin-methanol solvate was suspended in 100 milliliters of propylene glycol, triethylamine was added thereto to make the pH 6.0. The mixture was warmed and reacted at a temperature of 60 DEG C for 8 hours. Cool to room temperature.

이어서, 아세톤 25미리리터를 가하고 0.5시간 동안 교반한 다음, 그 침전물을 여과하여 메탄올, 아세톤으로 세척한 후 건조시키면 목적화합물 4.8그램(90%)이 얻어진다.Subsequently, 25 milliliters of acetone was added thereto, stirred for 0.5 hour, and the precipitate was filtered, washed with methanol and acetone, and dried to yield 4.8 grams (90%) of the target compound.

IR,NMR ; 실시예 1의 결과와 동일IR, NMR; Same as the result of Example 1

[실시예 3]Example 3

프로필렌글리콜 100미리리터에 세파트리진·수화물 5그램(0.01몰)을 현탁시키고, 가온하여 60℃의 온도에서 8시간 동안 반응시킨 다음 상온으로 냉각한다. 이어서, 에탄올 25미리리터를 가하여 0.5시간 동안 교반하고, 그 침전물을 여과하여 메탄올, 아세톤으로 세척한 후 건조하면 목적화합물 4.8그램(88%)이 얻어진다.5 grams (0.01 mol) of Sephatrizin hydrate was suspended in 100 ml of propylene glycol, warmed, reacted at a temperature of 60 ° C. for 8 hours, and then cooled to room temperature. Then, 25 ml of ethanol was added thereto, stirred for 0.5 hour, and the precipitate was filtered, washed with methanol and acetone, and dried to yield 4.8 grams (88%) of the title compound.

IR,NMR ; 실시예 1의 결과와 동일IR, NMR; Same as the result of Example 1

[실시예 4]Example 4

프로필렌글리콜 100미리리터에 세파트리진·수화물 5그램(0.01몰)을 현탁시키고, 이를 가온하여 80℃의 온도에서 8시간 동안 반응시킨다음, 상온으로 냉각한다.5 grams (0.01 mol) of Sephatrizin hydrate was suspended in 100 ml of propylene glycol, which was then heated and reacted at a temperature of 80 ° C. for 8 hours, followed by cooling to room temperature.

여기에 아세톤 25미리리터를 가하여 0.5시간 동안 교반하고, 그 침전물을 여과하여 메탄올, 아세톤으로 세척한 다음 건조하면 목적화합물 3.96그램(72%)이 얻어진다.25 ml of acetone was added thereto, stirred for 0.5 hour, and the precipitate was filtered, washed with methanol and acetone, and dried to yield 3.96 grams (72%) of the title compound.

IR,NMR ; 실시예 1의 결과와 동일IR, NMR; Same as the result of Example 1

Claims (4)

다음 구조식(II)으로 표시되는 7-[D-α-아미노-α-(4-하이드록시페닐)아세트아미도]-3-(1,2,3-트리아졸-4(5)-일티오메틸)-3-세팸-4-카르복실산의 수화물 또는 용매화물을 다음 구조식(III)으로 표시되는 1,2-프로필렌글리콜중에서 직접 가온 반응시켜 전환시킴을 특징으로 하는 다음 구조식(I)으로 표시되는 7-[D-α-아미노-α-(4-하이드록시페닐)아세트아미도]-3-(1,2,3-트리아졸-4(5)-일티오메틸)-3-세팸-4-카르복실산· 프로필렌글리콜레이트의 제조방법.7- [D-α-amino-α- (4-hydroxyphenyl) acetamido] -3- (1,2,3-triazole-4 (5) -ylthio represented by the following structural formula (II) A hydrate or solvate of methyl) -3-cepam-4-carboxylic acid is directly converted into a 1,2-propylene glycol represented by the following structural formula (III) and converted into the following structural formula (I). 7- [D-α-amino-α- (4-hydroxyphenyl) acetamido] -3- (1,2,3-triazole-4 (5) -ylthiomethyl) -3-cepam- The manufacturing method of 4-carboxylic acid propylene glycolate.
Figure kpo00007
Figure kpo00007
 제1항에 있어서, 가온 반응은 40℃ 내지 90℃의 온도에서 실시하는 것을 특징으로 하는 방법.The method of claim 1, wherein the warming reaction is carried out at a temperature of 40 ℃ to 90 ℃. 제1항에 있어서, 상기 구조식(III)의 화합물의 양은 상기 구조식(II) 화합물 1.0몰당 10 내지 50몰을 사용하는 것을 특징으로 하는 방법.The method of claim 1, wherein the amount of the compound of formula III is 10 to 50 moles per 1.0 mole of the compound of formula II. 제1항에 있어서, 목적화합물인 상기 구조식(I) 화합물은 에탄올, 아세토니트릴, 아세톤, 물 등의 극성용매로 희석시켜 여과하므로서 분리되는 것을 특징으로 하는 방법.The method of claim 1, wherein the compound of formula (I) as a target compound is separated by dilution with a polar solvent such as ethanol, acetonitrile, acetone, water, and the like.
KR1019880005139A 1988-05-03 1988-05-03 Process for preparing cephalosporin compounds KR900004931B1 (en)

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KR1019880005139A KR900004931B1 (en) 1988-05-03 1988-05-03 Process for preparing cephalosporin compounds
JP63186698A JPH01290682A (en) 1988-05-03 1988-07-26 Production of cephalosporine compound

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Application Number Priority Date Filing Date Title
KR1019880005139A KR900004931B1 (en) 1988-05-03 1988-05-03 Process for preparing cephalosporin compounds

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KR890017257A KR890017257A (en) 1989-12-15
KR900004931B1 true KR900004931B1 (en) 1990-07-12

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CA2570949A1 (en) 2006-12-12 2008-06-12 Apotex Pharmachem Inc. Ibandronate sodium propylene glycol solvate and processes for the preparation thereof
US7834195B2 (en) 2007-01-24 2010-11-16 Apotex Pharmachem Inc. Atorvastatin calcium propylene glycol solvates

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KR890017257A (en) 1989-12-15
JPH01290682A (en) 1989-11-22

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