KR100739830B1 - Process for preparing Cephalosporin derivative - Google Patents
Process for preparing Cephalosporin derivative Download PDFInfo
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- KR100739830B1 KR100739830B1 KR1020010015310A KR20010015310A KR100739830B1 KR 100739830 B1 KR100739830 B1 KR 100739830B1 KR 1020010015310 A KR1020010015310 A KR 1020010015310A KR 20010015310 A KR20010015310 A KR 20010015310A KR 100739830 B1 KR100739830 B1 KR 100739830B1
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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
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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 세파로스포린 유도체 중의 세포페라존 부생성물의 제조방법에 관한 발명으로, 더욱 상세하게는 7-아미노세파로스포란 산 (7-aminocephalosporanic acid)를 출발물질로 하여 7-[2-[(4-에틸-2,3-디옥소피페라진-1-카보닐)아미노]-2-(4-하이드록시페닐)아세틸아미노]-3-[(4-메틸-5-티옥소-4,5-디하이드로-테트라졸-1-일)메틸]-8-옥소-5-티아-1-아자-바이사이클로[4.2.0]옥트-2-엔-2-카복실산 (7-[2-[(4-Ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-(4-hydroxyphenyl)acetylamino]-3-[(4-methyl-5-thioxo-4,5-dihydro-tetrazol-1-yl)methyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid)을 고순도, 고효율로 합성하는 방법에 관한 발명이다. The present invention relates to a method for producing a cell perazone by-product in a cephalosporin derivative, and more particularly, 7- [2- [with 7-aminocephalosporanic acid as a starting material. (4-ethyl-2,3-dioxopiperazin-1-carbonyl) amino] -2- (4-hydroxyphenyl) acetylamino] -3-[(4-methyl-5-thioxo-4, 5-dihydro-tetrazol-1-yl) methyl] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid (7- [2- [ (4-Ethyl-2,3-dioxopiperazine-1-carbonyl) amino] -2- (4-hydroxyphenyl) acetylamino] -3-[(4-methyl-5-thioxo-4,5-dihydro-tetrazol-1- The present invention relates to a method for synthesizing yl) methyl] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid with high purity and high efficiency.
Description
본 발명은 세파로스포린 유도체의 제조방법에 관한 발명으로, 더욱 상세하게는 세파로스포린 유도체 중의 세포페라존 부생성물의 제조방법에 관한 발명이다. The present invention relates to a method for producing a cephalosporin derivative, and more particularly, to a method for producing a cell perazone by-product in a cephalosporin derivative.
세포페라존(Cefoperazone)은 초기 세파로스포린에 비하여 그램 음성균에 대한 증가된 다양한 스펙트럼을 갖고, 혐기성균에 대하여 적당한 활성을 가지며 감소된 항그램양성활성을 갖는 베타-락탐계 항생물질로 많이 사용되고 있다. Cefoperazone is widely used as a beta-lactam antibiotic with an increased spectrum of gram-negative bacteria compared to early cephalosporins, moderate activity against anaerobic bacteria, and reduced antigram-positive activity. .
또 세포페라존은 합성과정에서 불순물이 존재하는데 세포페라존에 존재하는 불순물의 종류 및 구조는 화학요법의 영역 vol.6, No.2, 94, 1990.에 잘 표기되어 있는 것처럼 여러 가지가 있는데, 그 중 불순물로 존재하는 하기 화학식 1로 표시되는 7-[2-[(4-에틸-2,3-디옥소피페라진-1-카보닐)아미노]-2-(4-하이드록시페닐)아세틸아미노]-3-[(4-메틸-5-티옥소-4,5-디하이드로-테트라졸-1-일)메틸]-8-옥소-5-티아-1-아자-바이사이클로[4.2.0]옥트-2-엔-2-카복실산 (7-[2-[(4-Ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-(4-hydroxyphenyl)acetylamino]-3-[(4methyl-5-thioxo-4,5-dihydro-tetrazol-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid) 화합물은 세포페라존 불순물을 정량 및 정성분석 할 때 주로 사용될 수 있고, 그 외의 용도에 관하여서는 아직 보고된 것이 없다. 또 상기 화학식 1의 화합물은 구조는 알려져 있으나 합성방법은 알려져 있지 않아서 본 발명의 화합물을 얻기 위해서 기존에 사용하는 방법으로는 HPLC 등을 이용하여 분리하는 방법을 사용하였다. 그러나 이러한 분리방법으로는 대량획득이 불가능한 문제점이 있었다.In addition, there are various impurities in the cell perazone, and the types and structures of the impurities in the cell perazone are well indicated in the areas of chemotherapy, vol. 6, No. 2, 94, 1990. And 7- [2-[(4-ethyl-2,3-dioxopiperazin-1-carbonyl) amino] -2- (4-hydroxyphenyl) represented by the following Chemical Formula 1 present as an impurity: Acetylamino] -3-[(4-methyl-5-thioxo-4,5-dihydro-tetrazol-1-yl) methyl] -8-oxo-5-thia-1-aza-bicyclo [4.2 .0] oct-2-ene-2-carboxylic acid (7- [2-[(4-Ethyl-2,3-dioxopiperazine-1-carbonyl) amino] -2- (4-hydroxyphenyl) acetylamino] -3- [ (4methyl-5-thioxo-4,5-dihydro-tetrazol-1-yl) methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid) Compound Silver can be used mainly for quantitative and qualitative analysis of Ceperazone impurities, and there are no reports on other uses. In addition, the compound of Chemical Formula 1 has a known structure but no synthesis method, and thus, a method of separation using HPLC or the like is used as a conventional method for obtaining the compound of the present invention. However, there was a problem that mass acquisition is impossible with this separation method.
[화학식 1][Formula 1]
본 발명은 상기한 문제점을 해결하기 위하여 안출된 것으로서, 본 발명의 목적은 세포페라존 부생성물 중 하나인 화학식 1의 화합물을 고순도, 고수율로 합성하는 방법을 제공하는 것이다.The present invention has been made to solve the above problems, an object of the present invention is to provide a method for synthesizing a compound of formula 1, one of the cell perazone by-products in high purity, high yield.
상기한 목적을 달성하기 위하여, 본 발명에서는 세포페라존에 존재하는 불순물 중 하나를 7-아미노세파로스포란 산 (7-aminocephalosporanic acid)를 출발물질로 하여 고순도, 고수율로 합성하였다.
본 발명에서는 세파로스포린 유도체 중 세포페라존 부 생성물인 하기 화학식 1로 표시되는 7-[2-[(4-에틸-2,3-디옥소피페라진-1-카보닐)아미노]-2-(4-하이드록시페닐)아세틸아미노]-3-[(4-메틸-5-티옥소-4,5-디하이드로-테트라졸-1-일)메틸]-8-옥소-5-티아-1-아자-바이사이클로[4.2.0]옥트-2-엔-2-카복실산 화합물의 제조 방법을 제공한다:
[화학식 1]
상기의 화학식 1의 제조방법은
a) 아세토나이트릴에 1-메틸-1H-테트라졸-5-티올을 넣고 트리에틸아민을 첨가하고 냉각한 후 에틸클로로포메이트를 첨가한 후 보론트리플로라이드 에테레이트, 메탄설폰산, 7-아미노세파로스포란산을 투입하고 30∼40℃에서 5∼10시간 동안 반응한 후 반응액의 온도를 0∼5℃로 냉각한 후, pH 2.5∼4.5로 조절하여 결정을 여과하고 실리카겔을 사용하여 정제하여 하기 화학식 2로 표시되는 7-아미노-3-[(4-메틸-5-티옥소-4,5-디하이드로-테트라졸-1-일)메틸]-8-옥소-5-티아-1-아자-바이사이클로[4.2.0]-옥트-2-엔-카복실산 (7-Amino-3-[(4-methyl-5-thioxo-4,5-dihydro-tetrazol-1-yl)methyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-carboxylic acid) 화합물을 얻는 단계;
b) 아세토나이트릴과 상기 a)단계에서 얻은 화학식 2의 화합물에 비스(트리메틸실릴)아세트아마이드를 혼합하여 15∼25℃에서 1∼2시간 반응시킨 후 반응액의 온도를 -5∼-15℃로 냉각하는 단계; 및
c) N,N-디메틸아세트아마이드에 [(4-에틸-2,3-디옥소피페라진-1-카보닐)아미노]-4-하이드록시페닐아세트산을 투입하고 아세토나이트릴을 투입한 후 용액의 온도를 -25∼-35℃로 조절한 다음 포스포러스 옥시트리클로라이드를 첨가하고, -15∼-25℃에서 1∼2시간 반응을 통하여 얻은 용액을 상기 b)단계의 용액과 반응시키는 단계를 포함한다.
[화학식 2]
이하 본 발명을 실시예를 통하여 더욱 상세하게 설명한다.In order to achieve the above object, in the present invention, one of the impurities present in the cell perazone was synthesized with high purity and high yield using 7-aminocephalosporanic acid as a starting material.
In the present invention, 7- [2-[(4-ethyl-2,3-dioxopiperazin-1-carbonyl) amino] -2- represented by the following Chemical Formula 1, which is a cell perazone side product of the cephalosporin derivative. (4-hydroxyphenyl) acetylamino] -3-[(4-methyl-5-thioxo-4,5-dihydro-tetrazol-1-yl) methyl] -8-oxo-5-thia-1 Provided are methods of preparing aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid compounds:
[Formula 1]
The preparation method of Chemical Formula 1
a) 1-methyl-1H-tetrazol-5-thiol was added to acetonitrile, triethylamine was added, cooled, ethylchloroformate was added, and boron trifluoride etherate, methanesulfonic acid, 7- After adding aminocephalosporranic acid and reacting at 30 to 40 ° C. for 5 to 10 hours, the temperature of the reaction solution was cooled to 0 to 5 ° C., the pH was adjusted to 2.5 to 4.5, and the crystals were filtered out using silica gel. Purified to obtain 7-amino-3-[(4-methyl-5-thioxo-4,5-dihydro-tetrazol-1-yl) methyl] -8-oxo-5-thia- 1-Aza-bicyclo [4.2.0] -oct-2-ene-carboxylic acid (7-Amino-3-[(4-methyl-5-thioxo-4,5-dihydro-tetrazol-1-yl) methyl] Obtaining an 8-oxo-5-thia-1-aza-bicyclo [4.2.0] -oct-2-ene-carboxylic acid compound;
b) acetonitrile and bis (trimethylsilyl) acetamide were mixed with the compound of formula 2 obtained in step a) and reacted at 15 to 25 ° C. for 1 to 2 hours, and then the temperature of the reaction solution was -5 to 15 ° C. Cooling to; And
c) [(4-ethyl-2,3-dioxopiperazin-1-carbonyl) amino] -4-hydroxyphenylacetic acid was added to N, N-dimethylacetamide, followed by acetonitrile. The temperature of the mixture was adjusted to -25 to -35 ° C, followed by adding phosphorus oxytrichloride, and reacting the solution obtained through the reaction at -15 to -25 ° C for 1 to 2 hours with the solution of step b). Include.
[Formula 2]
Hereinafter, the present invention will be described in more detail with reference to Examples.
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실시예 1 : 화학식 1의 화합물의 제조Example 1 Preparation of a Compound of Formula 1
(단계 1) 화학식 2의 화합물의 제조(Step 1) Preparation of Compound of Formula 2
아세토나이트릴 100ml에 1-메틸-1H-테트라졸-5-티올 10g을 넣고 10℃로 냉각한 다음 트리에틸아민 14.3ml를 첨가하고 -5℃로 냉각하였다. 에틸클로로포메이트 9.9ml를 등온도에서 첨가하고 1시간 동안 교반한 후 보론트리플로라이드 에테레이트 29ml, 메탄설폰산 25ml, 7-아미노세파로스포란 산 21g을 순서대로 투입하고 35℃에서 7시간 동안 반응한 후 반응액의 온도를 0∼5℃로 냉각한 후, 냉각한 물 850ml를 반응액에 주입하고 등온도에서 암모니아수를 사용하여 pH 3.5로 조절하였다. 등온도에서 1시간 교반 후 결정을 여과하여 모으고 물, 아세톤으로 세척한 후 건조하면 불순한 생성물이 얻어지며 이것을 물에서 pH 2.0으로 조절하여 용해 후 실리카겔을 사용하여 정제하면 순수한 황백색 결정 17.85g(70.5%)으로 상기 화학식 2의 화합물을 얻었다. 이것의 IR과 NMR 자료는 다음과 같다.10 g of 1-methyl-1H-tetrazol-5-thiol was added to 100 ml of acetonitrile, cooled to 10 ° C., 14.3 ml of triethylamine was added, and cooled to −5 ° C. After adding 9.9 ml of ethylchloroformate at an isothermal temperature and stirring for 1 hour, 29 ml of boron trifluoride etherate, 25 ml of methanesulfonic acid, and 21 g of 7-aminocephalosporranic acid were added in this order and 7 hours at 35 ° C. After reacting for a while, the temperature of the reaction solution was cooled to 0˜5 ° C., and 850 ml of cooled water was injected into the reaction solution and adjusted to pH 3.5 using ammonia water at constant temperature. After stirring for 1 hour at isothermal, the crystals were collected by filtration, washed with water and acetone and dried to obtain an impure product.The mixture was adjusted to pH 2.0 in water and dissolved and purified using silica gel. ) To obtain a compound of formula (2). Its IR and NMR data are as follows.
IR(KBr, cm-1): 1780(C=0)IR (KBr, cm-1): 1780 (C = 0)
1H-NMR(DMSO-d6, δ): 5.38(1H, m, C6-H), 5.01(2H, m, C3-CH 2), 4.97(1H, C7-H), 3.87(3H, s, N-CH3), 3.96, 3.38(2H, mm, C2-2H) 1 H-NMR (DMSO-d 6 , δ): 5.38 (1H, m, C 6 -H), 5.01 (2H, m, C 3 -CH 2 ), 4.97 (1H, C 7 -H), 3.87 ( 3H, s, N-CH 3 ), 3.96, 3.38 (2H, mm, C 2 -2H)
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(단계 2) 화학식 1의 화합물의 제조(Step 2) Preparation of Compound of Formula 1
반응기 (용기 1)에 아세토나이트릴 153ml와 상기 단계 1에서 제조한 화학식 2의 화합물 20g을 투입하고 온도를 0∼5℃로 조절한 다음 비스(트리메틸실릴)아세트아마이드 23.7ml를 투입하고 15∼25℃에서 1시간 반응시킨 후 반응액의 온도를 -10℃로 냉각하였다.
다른 반응기 (용기 2)에 N,N-디메틸아세트아마이드 85ml와 [(4-에틸-2,3-디옥소피페라진-1-카보닐)아미노]-4-하이드록시페닐아세트산 22.2g을 투입하고, 아세토나이트릴 37ml를 투입하고 용액의 온도를 -30℃로 조절한 다음 포스포러스 옥시트리클로라이드 7ml를 10분간 적가하고, -20℃에서 1시간 반응시켰다.
용기 1에 있는 용액의 온도를 -20℃로 유지하면서 용기 2에 20분간 적가하고 -20∼-25℃에서 1.5시간 반응시키고, 30분 동안 반응액의 온도를 0∼5℃로 조절하였다.153 ml of acetonitrile and 20 g of the compound of Formula 2 prepared in Step 1 were added to a reactor (container 1), the temperature was adjusted to 0-5 ° C., and 23.7 ml of bis (trimethylsilyl) acetamide was added thereto, followed by 15-25. After reacting at 1 ° C for 1 hour, the reaction solution was cooled to -10 ° C.
Into another reactor (container 2), 85 ml of N, N-dimethylacetamide and 22.2 g of [(4-ethyl-2,3-dioxopiperazin-1-carbonyl) amino] -4-hydroxyphenylacetic acid were added thereto. , 37 ml of acetonitrile were added, the temperature of the solution was adjusted to -30 ° C, and 7 ml of phosphorus oxytrichloride was added dropwise for 10 minutes, and reacted at -20 ° C for 1 hour.
While maintaining the temperature of the solution in vessel 1 at -20 ° C, it was added dropwise to vessel 2 for 20 minutes, reacted at -20 to -25 ° C for 1.5 hours, and the temperature of the reaction solution was adjusted to 0 to 5 ° C for 30 minutes.
중조를 사용하여 용액의 pH를 1.7∼2.0으로 조절하고 10∼15℃에서 1시간 동안 교반하였다. 물 2,300 ml를 10∼15℃에서 15분간 투입하고 같은 온도에서 30분간 교반하였다. 0∼5℃에서 3∼4시간 동안 교반한 후 여과하고 물 150ml로 세척 후 건조하여 순도 95%이상의 황백색결정인 화학식 1의 화합물 33.4g을 얻었다. 이것의 IR과 NMR 자료는 다음과 같다. The sodium bicarbonate was used to adjust the pH of the solution to 1.7-2.0 and stir at 10-15 ° C. for 1 hour. 2,300 ml of water was added at 10 to 15 ° C. for 15 minutes and stirred at the same temperature for 30 minutes. After stirring for 3 to 4 hours at 0 ~ 5 ℃ filtered, washed with 150ml of water and dried to obtain 33.4g of the compound of formula 1 as an off-white crystals of more than 95% purity. Its IR and NMR data are as follows.
IR(KBr, cm-1): 1755, 1710,(C=O)IR (KBr, cm -1 ): 1755, 1710, (C = O)
1H-NMR(DMSO-d6, δ): 9.70(1H, m, benzyl CH-NH), 9.49(1H, bs, -OH), 9.27(1H, m, C7-NH), 7.20, 6.70(4H, dd, -C6H4-), 5.54(2H, m, C3 -CH2), 5.46(1H, d, benzyl C7-H), 5.17(1H, d, benzyl CH), 4.86(1H, m, C6-H), 3.91, 3.59(4H, mm, piperazine ring -CH2CH2-), 3.82(3H, s, N-CH3), 3.42(2H, m, N-CH2 CH3), 3.18, 3.01(2H, dd, C2-2H), 1.08(3H, t, N-CH2CH3) 1 H-NMR (DMSO-d 6 , δ): 9.70 (1H, m, benzyl CH-NH), 9.49 (1H, bs, -OH), 9.27 (1H, m, C 7 -NH), 7.20, 6.70 (4H, dd, -C 6 H 4- ), 5.54 (2H, m, C 3 -CH 2 ), 5.46 (1H, d, benzyl C 7 -H), 5.17 (1H, d, benzyl CH), 4.86 (1H, m, C 6 -H), 3.91, 3.59 (4H, mm, piperazine ring -CH 2 CH 2- ), 3.82 (3H, s, N-CH 3 ), 3.42 (2H, m, N-CH 2 CH 3 ), 3.18, 3.01 (2H, dd, C 2 -2H), 1.08 (3H, t, N-CH 2 CH 3 )
현재까지 본 발명의 물질은 세포페라존 합성시 생성되는 부생성물들을 HPLC 분리 방법으로 극히 소량씩만 분리하였으나 본 발명은 이 물질을 합성법에 의해 최초로 대량 생산 할 수 있는 제조 방법이다. 세포페라존 부 생성물의 공급이 어려워 정량 및 정성 분석에 사용할 수 없었으나 합성법에 의해 제조가 가능하므로 세포페라존 부 생성물을 확인, 정량에 대한 문제점을 해결할 수 있게 되었다. To date, the material of the present invention has separated only a small amount of by-products generated during the synthesis of cell perazone by HPLC separation method, but the present invention is a production method capable of mass-producing the material for the first time by the synthesis method. Although it was difficult to supply the cell perazone side product, it could not be used for quantitative and qualitative analysis, but it could be manufactured by a synthetic method, so that the problem of quantifying the cell perazone side product could be solved.
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| JPS5517342A (en) * | 1978-07-25 | 1980-02-06 | Toyama Chem Co Ltd | Cephalosporin composition for rectal administaration |
| KR910008352A (en) * | 1989-10-17 | 1991-05-31 | 어얼 버어넬 무어 | Refrigeration system |
| KR19990014669A (en) * | 1995-05-11 | 1999-02-25 | 한스샬러 | Antimicrobial cephalosporin |
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| JPS5517342A (en) * | 1978-07-25 | 1980-02-06 | Toyama Chem Co Ltd | Cephalosporin composition for rectal administaration |
| KR910008352A (en) * | 1989-10-17 | 1991-05-31 | 어얼 버어넬 무어 | Refrigeration system |
| KR19990014669A (en) * | 1995-05-11 | 1999-02-25 | 한스샬러 | Antimicrobial cephalosporin |
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