KR19990069743A - Method for producing synthetic intermediates of cephalosporin antibiotics - Google Patents
Method for producing synthetic intermediates of cephalosporin antibiotics Download PDFInfo
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- KR19990069743A KR19990069743A KR1019980004185A KR19980004185A KR19990069743A KR 19990069743 A KR19990069743 A KR 19990069743A KR 1019980004185 A KR1019980004185 A KR 1019980004185A KR 19980004185 A KR19980004185 A KR 19980004185A KR 19990069743 A KR19990069743 A KR 19990069743A
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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
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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
- C07D501/30—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino-radical acylated by an araliphatic carboxylic acid
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Abstract
본 발명은 하기 화학식 1의 세팔로스포린 중간체를 제조함에 있어서 부반응 물질인 락톤화합물의 생성을 근본적으로 억제하는 경제적인 새로운 제조방법에 관한 것이다.The present invention relates to an economical new process for producing a cephalosporin intermediate of the following formula (1), which essentially suppresses the production of a lactone compound as a side reaction.
(식중, R1은 벤질, 페닐, 페녹시메틸, 직쇄 또는 측쇄의 저급알콕시 또는 벤질옥시를 나타낸다.)(Wherein R 1 represents benzyl, phenyl, phenoxymethyl, straight chain or branched lower alkoxy or benzyloxy).
Description
본 발명은 하기 화학식 1의 세팔로스포린계 항생제의 합성중간체 제조방법에 관한 것이다.The present invention relates to a process for preparing synthetic intermediates of cephalosporin antibiotics of the following formula (1).
(식중, R1은 벤질, 페닐, 페녹시메틸, 직쇄 또는 측쇄의 저급알콕시 또는 벤질옥시를 나타낸다.)(Wherein R 1 represents benzyl, phenyl, phenoxymethyl, straight chain or branched lower alkoxy or benzyloxy).
본 발명의 화합물은 세팔로스포린계 항생물질의 합성에 필수적인 하기 화학식 5의 화합물을 합성하기 위한 전구물질로서 매우 중요한 중간체이다.The compound of the present invention is a very important intermediate as a precursor for synthesizing the compound of the following formula (5) essential for the synthesis of cephalosporin antibiotics.
(식중, R1은 상기 정의한 바와 같고, X는 할로겐 원자를 나타낸다.)(Wherein R 1 is as defined above, and X represents a halogen atom.)
상기 화합물 1에 대한 종래의 제조방법은 다음과 같다.The conventional preparation method for Compound 1 is as follows.
우선 7-아미노 세팔로스포린산을 H2O/MeOH 존재하에서 가성소다로 가수분해하여 아세틸 그룹을 제거하고 7-아미노 그룹을 보호하기 위해 염기 존재하에 해당 아실화제를 반응시켜 목적하는 화합물을 합성하는 방법이 문헌에 알려져 있다[J. Antibiotics, 370-384 (1987);J. Antibiotics, 1300-1310 (1981)].First, 7-amino cephalosporinic acid is hydrolyzed with caustic soda in the presence of H 2 O / MeOH to remove the acetyl group and to protect the 7-amino group, the corresponding acylating agent is reacted in the presence of a base to synthesize the desired compound Methods are known in the literature [ J. Antibiotics , 370-384 (1987); J. Antibiotics , 1300-1310 (1981)].
그러나 상기 방법은 반응조건에 매우 민감하여 염기에 불안정한 베타-락탐환이 개열되는 문제점이 있으며, 더욱이 이로 인해 생성된 베타-락탐 분해산물 때문에 생성물의 분리가 어려워 산업적인 생산 방법에 적합치 않다. 또한 아실화제를 이용한 아실화 반응시 하기 화학식 6의 락톤 화합물이 30%이상 생성되는 심각한 문제점을 안고 있다.However, this method is very sensitive to the reaction conditions, and there is a problem that the unstable beta-lactam ring is cleaved in the base. Further, since the resulting beta-lactam decomposition product is difficult to separate the product, it is not suitable for the industrial production method. Further, the acylation reaction using an acylating agent has a serious problem that 30% or more of the lactone compound represented by the following formula (6) is produced.
(식중, R1은 상기 정의한 바와 같다.)(Wherein R 1 is as defined above).
따라서, 부산물로 생성된 락톤 화합물을 제거하기 위해 별도의 조작이 필요하므로 공정상의 번거로움이 있을 뿐만 아니라 이에 따른 수율감소 및 제조 경비가 증가하는 단점이 있다. 실제로 상기 방법에 따라 목적하는 화합물을 제조할 경우 총수율이 50% 수준을 넘지 못하고 있다.Therefore, since separate operations are required to remove the lactone compound produced as a by-product, there is a disadvantage in not only a complicated process but also a decrease in yield and an increase in manufacturing cost. In fact, when the desired compound is prepared according to the above method, the total yield does not exceed 50%.
한편, 일본특허공보 평4-66584에 보고된 내용에 의하면 7-아미노-3-히드록시메틸-3-세펨-4-카르복실산과 페닐아세틸클로라이드를 반응시켜 목적 화합물인 7-페닐아세트아미도-3-히드록시메틸-3-세펨-4카복실산을 합성하였음을 보고한 바 있다.On the other hand, according to the report reported in Japanese Patent Publication No. 4-66584, 7-amino-3-hydroxymethyl-3-cephem-4- carboxylic acid is reacted with phenylacetyl chloride to obtain the target compound 7-phenylacetamido- Hydroxymethyl-3-cephem-4-carboxylic acid.
본 발명자들이 수회에 걸쳐 상기 방법을 반복하여 수행한 결과 불필요한 락톤 화합물이 30%이상 생성되었으며, 분리정제과정을 통하여 목적 화합물을 단지 50%의 수율로 얻을 수 있었다.The present inventors have repeatedly conducted the above method repeatedly. As a result, more than 30% of unnecessary lactone compounds were produced, and the objective compound was obtained in a yield of only 50% through separation and purification.
따라서 종래의 방법은 불필요한 락톤화합물이 다량으로 생성되어 별도의 정제과정이 필요하므로 공정상의 번거로움 및 수율 저하를 초래하고 이로 인한 제조경비의 증가 등의 문제로 인해 산업적으로 적용할 수 있는 경제적인 방법이라고는 할 수 없다.Therefore, in the conventional method, unnecessary lactone compounds are generated in a large amount and a separate purification process is required. Therefore, it is troublesome in the process and the yield is lowered, and an economical method Can not be said.
본 발명자들은 상기 언급한 선행기술들의 문제점을 개선하고자 장기간에 걸친 조직적인 연구를 수행한 결과 완충용액을 사용하여 반응액의 pH 변화를 억제함으로써 불필요한 락톤화합물이 생성되지 않게 하고, 반응조건을 완화시킬 수 있음을 알게되어 본 발명을 완성하게 되었다.The inventors of the present invention conducted long-term systematic studies to overcome the problems of the above-mentioned prior arts. As a result, the present inventors have found that by inhibiting the pH change of the reaction solution using a buffer solution, unnecessary lactone compounds are not produced, The present invention has been completed.
본 발명의 목적은 세팔로스포린계 항생제의 합성중간체에 대한 제조방법을 제공하는데 있다.It is an object of the present invention to provide a process for preparing synthetic intermediates of cephalosporin antibiotics.
본 발명은 세팔로스포린계 항생제의 합성중간체에 대한 제조방법에 관한 것이다.The present invention relates to a process for the preparation of synthetic intermediates of cephalosporin antibiotics.
본 발명의 제조방법을 도시하면 하기 반응식 1과 같다.The production method of the present invention is shown in the following Reaction Scheme 1.
(식중, R1은 벤질, 페닐, 페녹시메틸, 직쇄 또는 측쇄의 저급알콕시 또는 벤질옥시를 나타내고, Y는 할로겐, 디알킬포스페이트, 디아릴포스페이트 또는 2-메르캅토벤조티아졸을 나타낸다.)Wherein R 1 represents benzyl, phenyl, phenoxymethyl, straight chain or branched lower alkoxy or benzyloxy, and Y represents halogen, dialkyl phosphate, diaryl phosphate or 2-mercaptobenzothiazole.
공지물질인 상기 화학식 4의 화합물을 -30~-10℃를 유지하면서 유기용매와 물의 혼합용매에서 0.5~3시간 동안 가수분해하여 화학식 3의 화합물을 얻고, 이를 분리, 정제하지 않고 pH 7~10의 완충용액하에서 -20~20℃의 온도로 화학식 R1COY의 아실화제를 사용하는 아실화 반응을 수행하여 화학식 2의 화합물을 얻은 후, 이를 통상적인 방법으로 카르복실기를 보호하여 목적하는 화학식 1의 화합물을 얻을 수 있다.The compound of Formula 4, which is a known substance, is hydrolyzed in a mixed solvent of an organic solvent and water at a temperature of -30 to -10 ° C for 0.5 to 3 hours to obtain a compound of Formula 3, after the under buffer solution at a temperature of -20 ~ 20 ℃ to perform the acylation reaction using the acylating agent of formula R 1 COY in the obtained compound of formula (2), of the formula (1) to this purpose to protect the carboxyl group in a conventional manner Compound can be obtained.
상기 제조방법에서 완충용액은 반응초기에 가하여 반응을 시키는 것도 가능하다.In the above production method, the buffer solution may be added at the initial stage of the reaction to effect the reaction.
상기 제조방법에서 아실화반응은 탄산나트륨, 탄산칼슘 등의 무기염기 또는 피리딘, 트리에틸아민, N-메틸모포린, 디아자비시클로운데센(DBU) 등의 유기염기 존재하에서 수행하는 것이 바람직하다.In the above production process, the acylation reaction is preferably carried out in the presence of an inorganic base such as sodium carbonate or calcium carbonate or an organic base such as pyridine, triethylamine, N-methylmorpholine or diazabicyclo-undecene (DBU).
상기 제조방법에서 카르복실기를 보호하는 통상적인 방법은 화학식 2의 화합물에 디페닐디아조메탄을 -10~30℃ 온도에서 반응시키는 것이 바람직하다.A typical method for protecting the carboxyl group in the above-described method is to react diphenyldiazomethane with the compound of formula (2) at a temperature of -10 to 30 ° C.
상기 제조방법에서 유기용매는 테트라하이드로푸란, 메틸렌클로라이드, N,N-디메틸포름아미드, N,N-디메틸아세트아미드, 아세토니트릴, 에틸아세테이트, 아세톤, 메탄올, 에탄올, 이소프로판올, t-부탄올 중에서 선택된 1종 이상 또는 이의 혼합용매를 사용할 수 있다.In the above production process, the organic solvent is selected from the group consisting of tetrahydrofuran, methylene chloride, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, ethyl acetate, acetone, methanol, ethanol, isopropanol, Or a mixed solvent thereof may be used.
상기 제조방법에서 완충용액은 무기염 또는 유기염으로 조성된 pH 7∼10의 완충용액을 사용할 수 있으며, 화학식 R1COY의 아실화제와의 반응시 락톤화합물의 생성을 억제하기 위해 사용된다.In the above preparation method, the buffer solution may be an inorganic or organic salt buffer solution having a pH of 7 to 10, and is used to inhibit the production of a lactone compound upon reaction with an acylating agent of the formula R 1 COY.
상기 반응식 1에서 화학식 R1COY의 아실화제는 통상적인 방법으로 제조하여 사용할 수 있으며, 필요에 따라 분리, 정제하여 사용하거나 반응액을 그대로 사용할 수 있다. 그 양은 화학식 3의 화합물에 대해 1~2배 당량 사용하는 것이 바람직하다.In the above Reaction Scheme 1, the acylating agent of the formula R 1 COY can be prepared and used according to a conventional method. The acylating agent of the formula R 1 COY can be isolated and purified or used as it is or as it is. The amount thereof is preferably 1 to 2 times the amount of the compound of formula (3).
상기 반응식 1에서 화학식 1을 제조하기 위해서는 출발물질인 화학식 4의 화합물로부터 한 용기 내에서 연속적으로 반응을 진행시킬 수 있으며 필요에 따라 각 단계의 화합물을 분리 정제하여 단계별로 수행할 수도 있다.In order to prepare the compound of formula (1) in the above reaction scheme 1, the compound of formula (4) as a starting material may be continuously reacted in a vessel. If necessary, the compound of each step may be separated and purified.
이하 본 발명을 하기 실시예를 통하여 더욱 구체적으로 설명하지만 본 발명이 이들 실시예에 의해 제한되는 것은 아니다.Hereinafter, the present invention will be described more specifically by way of the following examples, but the present invention is not limited by these examples.
실시예 1 : 벤즈히드릴 7-페닐아세트아미도-3-히드록시메틸-3-세펨-4-카복실레이트의 제조Example 1: Preparation of benzhydryl 7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate
3L-플라스크에 MeOH (100 ml)와 H2O (100 ml)을 가하고 NaOH (8.0 g, 0.2 mol)을 넣어 녹였다. 이 반응액에 완충용액 (20 ml, pH 7.0-10.0)를 가한 후 반응액을 -20℃로 냉각하고 7-아미노 세팔로스포린산 (27.3 g, 0.1 mol)를 서서히 가하였다. 반응물을 -20℃로 유지하면서 1시간 동안 교반하여 가수분해하였다[TLC : Rf=0.4 (CH3CN/H2O=4/1)]. 반응이 종결되면 반응액에 c-HCl을 가하여 pH 7.0으로 맞춘 후 -5℃로 유지하면서 페닐아세틸클로라이드 (20 ml, 0.15 mol)를 함유한 초산에틸 (200 ml)용액과 20% Na2CO3용액 (140 ml) 을 동시에 30-40분동안 가하고 pH를 8.0-8.5로 조정한 후 빙냉하에서 1시간 동안 교반하였다. 반응물에 에틸아세테이트 (200ml)를 넣고 3N-HCl로 pH 3.0으로 조정하였다 (TLC: Rf=0.5 CH3CN/H2O=4/1). 반응물을 분리하여 유기층을 얻고 물층을 다시 초산에틸 (200 ml)로 2회 반복하여 추출하였다. 이렇게 얻어진 유기층의 화합물에 디페닐디아조메탄(DPM)의 초산에틸용액 (500 ml, 0.15 mol)을 서서히 가한 후 실온에서 2시간 동안 교반하여 반응을 종결하였다. 반응물을 감압농축하여 용매를 반으로 줄이고 0∼5℃로 냉각한 후 30분간 교반하고 생성된 고체를 여과하였다. 이렇게 하여 목적하는 화학식 1의 화합물을 백색고체(48g, 수율 90%)로 얻었다.MeOH (100 ml) and H 2 O (100 ml) were added to the 3 L-flask, and NaOH (8.0 g, 0.2 mol) was added to dissolve. To the reaction solution was added a buffer solution (20 ml, pH 7.0-10.0), the reaction solution was cooled to -20 캜, and 7-amino cephalosporic acid (27.3 g, 0.1 mol) was slowly added thereto. The reaction was hydrolyzed by stirring for 1 hour while maintaining the temperature at -20 ° C [TLC: Rf = 0.4 (CH 3 CN / H 2 O = 4/1)]. After the reaction was completed, c-HCl was added to the reaction mixture to adjust the pH to 7.0, and a solution of ethyl acetate (200 ml) containing phenylacetyl chloride (20 ml, 0.15 mol) and 20% Na 2 CO 3 The solution (140 ml) was added at the same time for 30-40 minutes, the pH was adjusted to 8.0-8.5, and the mixture was stirred for 1 hour under ice-cooling. Ethyl acetate (200 ml) was added to the reaction mixture and the mixture was adjusted to pH 3.0 with 3N HCl (TLC: Rf = 0.5 CH 3 CN / H 2 O = 4/1). The reaction mixture was separated to obtain an organic layer. The aqueous layer was extracted twice with ethyl acetate (200 ml) repeatedly. An ethyl acetate solution (500 ml, 0.15 mol) of diphenyldiazomethane (DPM) was slowly added to the obtained organic layer compound, and the reaction was terminated by stirring at room temperature for 2 hours. The reaction was concentrated under reduced pressure to reduce the solvent to half, cooled to 0 to 5 ° C, stirred for 30 minutes, and the resulting solid was filtered. Thus, the desired compound of formula (1) was obtained as a white solid (48 g, yield 90%).
녹는점 : 173 ℃Melting point: 173 ℃
1H NMR (DMSO-d6) δ : 3.57 (ABq, J=14.0 Hz, 2H), 3.60 (s, 2H), 4.18∼4.21 (m, 2H), 5.09 (d, J=4.8 Hz, 1H), 5.14 (t, J=5.7 Hz, 1H), 5.70 (dd, J=5.7, 8.3Hz, 1H), 6.89 (s, 1H), 7.26∼7.50 (m, 15H), 9.10 (d, J=8.3 Hz, 1H) 1 H NMR (DMSO-d 6 ) δ: 3.57 (ABq, J = 14.0 Hz, 2H), 3.60 (s, 2H), 4.18~4.21 (m, 2H), 5.09 (d, J = 4.8 Hz, 1H) , 5.14 (t, J = 5.7 Hz, 1 H), 5.70 (dd, J = 5.7, 8.3 Hz, 1 H), 6.89 Hz, 1H)
실시예 2 : 벤즈히드릴 7-페닐아세트아미도-3-히드록시메틸-3-세펨-4-카복실레이트의 제조Example 2: Preparation of benzhydryl 7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate
페닐아세틸클로라이드 대신에 페닐아세트산의 디에틸포스페이트 활성화 에스테르 41g을 사용하는 점을 제외하고는 실시예 1과 동일하게 반응시켜 표제화합물(45.3g, 88%)을 수득하였다.(45.3 g, 88%) was obtained in the same manner as in Example 1, except that 41 g of diethylphosphate activated ester of phenylacetic acid was used instead of phenylacetyl chloride.
분석결과는 실시예 1과 같다.The results of the analysis are the same as in Example 1.
실시예 3 : 벤즈히드릴 7-페닐아세트아미도-3-히드록시메틸-3-세펨-4-카복실레이트의 제조Example 3: Preparation of benzhydryl 7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate
페닐아세틸클로라이드 대신에 페닐아세트산의 2-메르캅토벤조티아졸 활성화 에스테르 43g을 사용하는 점을 제외하고는 상기 실시예 1과 동일하게 반응시켜 표제화합물(45.8g, 89%)을 수득하였다.(45.8 g, 89%) was obtained in the same manner as in Example 1, except that 43 g of 2-mercaptobenzothiazole-activated ester of phenylacetic acid was used instead of phenylacetyl chloride.
분석결과는 실시예 1과 같다.The results of the analysis are the same as in Example 1.
실시예 4 : 벤즈히드릴 7-페녹시아세트아미도-3-히드록시메틸-3-세펨-4-카복실레이트의 제조Example 4: Preparation of benzhydryl 7-phenoxyacetamido-3-hydroxymethyl-3-cephem-4-carboxylate
페닐아세틸클로라이드 대신에 페녹시아세틸클로라이드 25.6g을 사용하는 점을 제외하고는 상기 실시예 1과 동일하게 반응시켜 표제화합물(46.7g, 88%)을 수득하였다.(46.7 g, 88%) was obtained in the same manner as in Example 1, except that phenoxyacetyl chloride (25.6 g) was used instead of phenylacetyl chloride.
녹는점 : 162~163℃Melting point: 162 ~ 163 ℃
1H NMR(DMSO-d6) δ : 3.57(br s, 2H), 4.22(d, J=5.0Hz, 2H), 4.58(s, 2H), 5.02(t, J=5.0Hz, 1H), 5.06(d, J=4.6Hz, 1H), 5.67(dd, J=4.6, 8.2Hz, 1H), 6.65~7.60(m, 16H), 8.98(d, J=8.2Hz, 1H) 1 H NMR (DMSO-d 6 ) δ: 3.57 (br s, 2H), 4.22 (d, J = 5.0Hz, 2H), 4.58 (s, 2H), 5.02 (t, J = 5.0Hz, 1H), J = 4.6 Hz, 1H), 5.67 (dd, J = 4.6, 8.2 Hz, 1H), 6.65-7.60 (m, 16H), 8.98
실시예 5 : 벤즈히드릴 7-벤질옥시아미도-3-히드록시메틸-3-세펨-4-카복실레이트의 제조Example 5: Preparation of benzhydryl 7-benzyloxyamido-3-hydroxymethyl-3-cephem-4-carboxylate
페닐아세틸클로라이드 대신에 벤질클로로포르메이트 25.6g을 사용하는 점을 제외하고는 상기 실시예 1과 동일하게 반응시켜 표제화합물(48.3g, 91%)을 수득하였다.(48.3 g, 91%) was obtained in the same manner as in Example 1, except that 25.6 g of benzyl chloroformate was used instead of phenylacetyl chloride.
녹는점 : 170℃Melting point: 170 ℃
1H NMR (DMSO-d6) δ : 3.62(s, 2H), 4.18~4.21(m, 2H), 5.10(m, 3H), 5.14(t, J=5.7Hz, 1H), 5.70(dd, J=5.7, 8.2Hz, 1H), 6.85(s, 1H), 7.26~7.50(m, 15H), 9.10(d, J=8.2Hz, 1H) 1 H NMR (DMSO-d 6 ) δ: 3.62 (s, 2H), 4.18 ~ 4.21 (m, 2H), 5.10 (m, 3H), 5.14 (t, J = 5.7Hz, 1H), 5.70 (dd, J = 5.7, 8.2 Hz, 1H), 6.85 (s, 1H), 7.26-7.50 (m, 15H), 9.10
본 발명에서 기술한 방법을 이용함에 따라 첫째, 종래의 방법에서는 불가피한 부반응 물질인 락톤 화합물의 생성 및 강염기의 사용에 따른 베타-락탐환의 분해산물의 생성을 획기적으로 억제하였고, 둘째, 이에 따라 기존 방법의 수율이 50%를 넘지 못하고 있으나, 본 발명의 방법을 이용하면 90%의 수율로 목적하는 세팔로스포린 중간체를 합성할 수 있었으며, 셋째, 수율증가에 따라 제조원가를 낮춤으로써 국제 경쟁력을 갖춘 효율적이고 경제적인 합성방법을 개발할 수 있었다. 따라서 본 발명에 따른 화학식 1의 화합물의 제조방법은 세팔로스포린계 항생제의 산업적인 생산에 적용할 수 있는 유용한 방법이 될 것으로 기대된다.First, using the method described in the present invention, production of a lactone compound, which is an inevitable side reaction substance in the conventional method, and formation of a decomposed product of a beta-lactam ring due to use of a strong base are remarkably suppressed. Second, , The desired cephalosporin intermediate can be synthesized at a yield of 90% by using the method of the present invention. Third, it is possible to synthesize the desired cephalosporin intermediate at a yield of 90% Economical synthesis method could be developed. Therefore, the process for preparing the compound of formula (I) according to the present invention is expected to be a useful method applicable to industrial production of cephalosporin antibiotics.
Claims (5)
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