KR100234626B1 - Process for the preparation of 2-((2,6-dichlorophenyl)amino)phenylacetoxy acetic acid - Google Patents
Process for the preparation of 2-((2,6-dichlorophenyl)amino)phenylacetoxy acetic acid Download PDFInfo
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Abstract
본 발명은 2-((2,6-디클로로페닐)아미노)페닐아세톡시 아세트산의 제조방법에 관한 것으로서, 더욱 상세하게는 질소기류하에 알콜을 제외한 일반적인 유기용매에서 4차 암모늄염(Quaternary ammonium salt)과 NaI, KI 등의 알칼리금속 요오드화물을 반응촉매로 투입하여 디클로페낙 알칼리금속염과 할로아세트산을 반응시켜 다음 화학식 1로 표시되는 2-((2,6-디클로로페닐)아미노)페닐아세톡시 아세트산을 1단계반응(one-step reaction)에 의해 용이하게 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing 2-((2,6-dichlorophenyl) amino) phenylacetoxy acetic acid, and more particularly, quaternary ammonium salt in a general organic solvent excluding alcohol under nitrogen stream. Alkali metal iodides such as NaI and KI were added as reaction catalysts to react diclofenac alkali metal salts with haloacetic acid, thereby reacting 2-((2,6-dichlorophenyl) amino) phenylacetoxy acetic acid represented by Formula 1 below with one step. The present invention relates to a method for producing easily by a one-step reaction.
Description
본 발명은 2-((2,6-디클로로페닐)아미노)페닐아세톡시 아세트산의 제조방법에 관한 것으로서, 더욱 상세하게는 질소기류하에 알콜을 제외한 일반적인 유기용매에서 4차 암모늄염(Quaternary ammonium salt)과 NaI, KI 등의 알칼리금속 요오드화물을 반응촉매로 투입하여 디클로페낙 알칼리금속염과 할로아세트산을 반응시켜 다음 화학식 1로 표시되는 2-((2,6-디클로로페닐)아미노)페닐아세톡시 아세트산을 1단계반응(one-step reaction)에 의해 용이하게 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing 2-((2,6-dichlorophenyl) amino) phenylacetoxy acetic acid, and more particularly, quaternary ammonium salt in a general organic solvent excluding alcohol under nitrogen stream. Alkali metal iodides such as NaI and KI were added as reaction catalysts to react diclofenac alkali metal salts with haloacetic acid, thereby reacting 2-((2,6-dichlorophenyl) amino) phenylacetoxy acetic acid represented by Formula 1 below with one step. The present invention relates to a method for producing easily by a one-step reaction.
화학식 1Formula 1
상기 화학식 1로 표시되는 2-((2,6-디클로로페닐)아미노)페닐아세톡시 아세트산(이하, "아세클로페낙(Aceclofenac)"이라 함)은 비스테로이드성 소염진통제로 널리 공지되어 있으며, 이의 제조방법 또한 몇몇 문헌에 제시되어 있다.2-((2,6-dichlorophenyl) amino) phenylacetoxy acetic acid (hereinafter referred to as "Aceclofenac") represented by Chemical Formula 1 is widely known as a nonsteroidal anti-inflammatory analgesic agent, and a method of preparing the same. It is also presented in some literature.
예를들면, 미합중국 특허공보 제 4,548,952 호에는 다음 반응식 1에 나타낸 바와 같이 디클로페낙 알칼리금속염과 벤질 할로아세테이트를 반응시켜 디클로페낙 벤질에스테르를 제조하고, 그런다음 수소환원 반응에 의하여 벤질기를 제거하여 아세클로페낙을 제조하는 2단계 제조방법이 제시되어 있다.For example, U.S. Patent No. 4,548,952 discloses diclofenac benzyl ester by reacting diclofenac alkali metal salts and benzyl haloacetate as shown in Scheme 1, and then removes the benzyl group by hydrogen reduction to produce aceclofenac. A two step process is shown.
상기 반응식 1에서, M은 알칼리금속원자이고; X는 할로겐원자를 나타낸다.In Scheme 1, M is an alkali metal atom; X represents a halogen atom.
그러나 상기 제조방법은 압축된 수소기체를 반응시키기 위한 특수 반응 장치가 필요하고, 수소 및 촉매를 공업적으로 사용하는 경우 위험성이 크며, 또한 반응에 사용되는 팔라듐 촉매가 고가이어서 경제적으로도 바람직하지 못한 단점이 있다.However, the above production method requires a special reaction device for reacting the compressed hydrogen gas, which is dangerous in the case of industrial use of hydrogen and a catalyst, and the palladium catalyst used for the reaction is expensive, which is economically undesirable. There are disadvantages.
또 다른 제조방법이 대한민국 특허공고 제 96-9569 호에 기재되어 있는 바, 전술한 미합중국 특허공보 제 4,548,952 호에의 제2단계 반응에서 디클로페낙 벤질에스테르를 수소환원 반응시켜 벤질기를 제거하는 대신에 디클로페낙 2-테트라하이드로푸라닐 에스테르를 사용하여 테트라하이드로푸란 용매하에서 초산으로 테트라하이드로푸라닐기를 제거하여 아세클로페낙을 제조하는 방법이다. 이 제조방법은 수소반응 과정을 거치지 않는다는 장점은 있으나, 반응물질 및 반응용매로 고가의 디클로페낙 2-테트라하이드로푸라닐 에스테르와 테트라하이드로푸란을 사용하는 단점이 있으며, 또한 반응물질로 사용되는 디클로페낙 2-테트라하이드로푸라닐 에스테르의 제조공정이 나타나 있지 않다.Another method of preparation is described in Korean Patent Publication No. 96-9569. Diclofenac 2 is used instead of the hydrogen reduction reaction of diclofenac benzyl ester in the second step reaction to the above-mentioned US Patent Publication No. 4,548,952 to remove the benzyl group. A method for preparing aceclofenac by removing tetrahydrofuranyl group with acetic acid in a tetrahydrofuran solvent using tetrahydrofuranyl ester. This manufacturing method has the advantage of not undergoing a hydrogen reaction process, but has the disadvantage of using expensive diclofenac 2-tetrahydrofuranyl ester and tetrahydrofuran as reactants and reaction solvents, and also diclofenac 2- used as reactants. The process for preparing tetrahydrofuranyl ester is not shown.
상기에서 예시한 종래 제조방법들에서는 공통적으로 디클로페낙의 카르복실기에 아세테이트기를 반응시키기 위하여 아세테이트기의 카르복실산을 보호하는 벤질, 테트라하이드로푸라닐 등의 보호기를 할로아세트산에 도입한 다음 디클로페낙과 반응시키고 반응후 다시 보호기를 제거하여야 하기 때문에 그 제조공정이 매우 번거롭다는 단점이 있다.In the above-described conventional production methods, a protecting group such as benzyl and tetrahydrofuranyl, which protects the carboxylic acid of the acetate group, is introduced into haloacetic acid and then reacted with diclofenac to react the acetate group with the carboxyl group of diclofenac. There is a disadvantage that the manufacturing process is very cumbersome because the protector must be removed again.
본 발명에서는 상기 선행기술들에서의 보호기 도입과정 및 탈보호 과정과 같은 번거로운 제조공정을 생략하고 반응물로부터 아세클로페낙을 고수율로 얻을 수 있는 제조방법에 대해 오랜기간 연구하였다. 그 결과 질소기류하에 알콜을 제외한 일반적인 유기용매에서 4차 암모늄염과 알칼리금속 요오드화물을 반응촉매로 투입하여 디클로페낙 알칼리금속염과 할로아세트산을 반응시키면 직접 아세클로페낙을 용이하게 수득할 수 있음을 알게됨으로써 본 발명을 완성하였다.In the present invention, a long time study has been conducted on a manufacturing method capable of obtaining aceclofenac from the reactants in a high yield by eliminating cumbersome manufacturing processes such as a protecting group introduction process and a deprotection process in the prior arts. As a result, when the quaternary ammonium salt and alkali metal iodide were added as a reaction catalyst in a general organic solvent except alcohol under nitrogen stream, the reaction of diclofenac alkali metal salt and haloacetic acid can be easily obtained to directly obtain aceclofenac. Completed.
따라서, 본 발명은 디클로페낙 알칼리금속염과 할로아세트산을 반응물질로하고 1단계반응에 의해 아세클로페낙을 고수율로 제조하는 방법을 제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide a method for producing aceclofenac in a high yield by using a diclofenac alkali metal salt and a haloacetic acid as a reactant.
본 발명은 다음 화학식 2로 표시되는 디클로페낙 알칼리금속염과 다음 화학식 3으로 표시되는 할로아세트산을 반응물질로 하고, 이를 4차 암모늄염, 알칼리금속 요오드화물 또는 이들의 혼합물을 반응촉매로 사용하여 1단계반응(one-step reaction)시키는 다음 화학식 1로 표시되는 아세클로페낙의 제조방법을 그 특징으로 한다.The present invention uses a diclofenac alkali metal salt represented by the following formula (2) and a haloacetic acid represented by the following formula (3) as a reactant, using a quaternary ammonium salt, an alkali metal iodide, or a mixture thereof as a reaction catalyst. It characterized by a method for producing aceclofenac represented by the following formula (1) to a one-step reaction.
화학식 1Formula 1
상기 화학식들에서, M은 알칼리금속원자이고; X는 할로겐원자를 나타낸다.In the above formulas, M is an alkali metal atom; X represents a halogen atom.
이와같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.
본 발명은 디클로페낙 알칼리금속염과 할로아세트산을 반응시키되, 반응촉매로서 4차 암모늄염, 알칼리금속 요오드화물 또는 이들의 혼합물을 사용하여 반응 진행속도가 촉진되도록 하였고, 산화반응을 억제하기 위하여 질소기류하에 반응시켰으며, 또한 반응용매로는 알콜을 제외한 유기용매를 사용하는데 알콜을 반응용매로 사용하게 되면 알칼리에 의한 분해산물이 생성된다.In the present invention, diclofenac alkali metal salt and haloacetic acid are reacted, and the reaction progress is accelerated by using a quaternary ammonium salt, alkali metal iodide or a mixture thereof as a reaction catalyst, and reacted under a nitrogen stream to suppress oxidation. In addition, as a reaction solvent, an organic solvent other than alcohol is used. When alcohol is used as a reaction solvent, decomposition products of alkali are produced.
본 발명에서는 반응물질로서 상기 화학식 2로 표시되는 디클로페낙 알칼리금속염과 상기 화학식 3으로 표시되는 할로아세트산을 사용한다. 할로아세트산을 구체적으로 예시하면 브로모아세트산, 클로로아세트산 등이며, 이는 화학식 2로 표시되는 디클로페낙 알칼리금속염에 대하여 1.1 ∼ 2.0 몰비 범위내에서 사용한다.In the present invention, a diclofenac alkali metal salt represented by Chemical Formula 2 and a haloacetic acid represented by Chemical Formula 3 are used as reactants. Specific examples of haloacetic acid include bromoacetic acid and chloroacetic acid, which are used within the range of 1.1 to 2.0 molar ratio with respect to the diclofenac alkali metal salt represented by the formula (2).
반응촉매로서 4차 암모늄염과 알칼리금속 요오드화물은 각각 단독으로도 사용가능하며, 바람직하기로는 두가지 촉매를 동시에 사용할때 상승 작용에 의하여 반응이 보다 신속하게 진행되는 장점이 있다.As the reaction catalyst, the quaternary ammonium salt and the alkali metal iodide may be used alone, respectively. Preferably, the reaction proceeds more rapidly by synergy when two catalysts are used simultaneously.
4차 암모늄염은 다음 화학식 4로 표시되는 화합물이며, 화학식 2로 표시되는 디클로페낙 알칼리금속염에 대하여 0.1 ∼ 10 중량%, 바람직하기로는 1.0 ∼ 5.0 중량% 범위내에서 사용한다.The quaternary ammonium salt is a compound represented by the following formula (4), and is used in the range of 0.1 to 10% by weight, preferably 1.0 to 5.0% by weight, based on the diclofenac alkali metal salt represented by the formula (2).
화학식 4Formula 4
상기 화학식 4에서,In Chemical Formula 4,
R1, R2, R3및 R4는 각각 C1∼ C5의 알킬기, 페닐기 또는 벤질기를 나타내고;R 1 , R 2 , R 3 and R 4 each represent a C 1 to C 5 alkyl group, a phenyl group or a benzyl group;
A는 할로겐원자, 하이드록시기, HSO4 -, H2PO4 -, CN-, NO3 -, IO4 -또는 CH3COO-를 나타낸다.A is a halogen atom, a hydroxyl group, HSO 4 -, H 2 PO 4 -, CN -, NO 3 - represents a -, IO 4 - or CH 3 COO.
그리고, 알칼리금속 요오드화물으로는 예를들면 NaI, KI 등이 사용되며, 이는 화학식 2로 표시되는 디클로페낙 알칼리금속염에 대하여 1.0 ∼ 1.5 몰비 범위내에서 사용한다.As the alkali metal iodide, for example, NaI, KI, and the like are used, which is used within the range of 1.0 to 1.5 molar ratio with respect to the diclofenac alkali metal salt represented by the formula (2).
또한, 상기에서 예시한 반응촉매 이외에도 탄산나트륨, 탄산칼륨, 탄산수소나트륨, 탄산수소칼륨 등의 염기(base)를 첨가하여 알칼리 상태에서 반응을 진행시키는것이 바람직하다.In addition to the reaction catalysts exemplified above, it is preferable to add a base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like to advance the reaction in an alkaline state.
반응용매로는 알콜을 제외한 모든 유기용매가 사용된다. 예를들면, N,N-디메틸아세트아마이드, 디메틸설폭사이드, 아세톤, 아세토니트릴, 디메틸포름아마이드, 에틸아세테이트, 디클로로메탄, 벤젠, 톨루엔, 테트라하이드로푸란, 클로로포름 등 중에서 선택된 단독용매 또는 2종 이상의 혼합용매이다.As the reaction solvent, all organic solvents except alcohol are used. For example, N, N-dimethylacetamide, dimethyl sulfoxide, acetone, acetonitrile, dimethylformamide, ethyl acetate, dichloromethane, benzene, toluene, tetrahydrofuran, chloroform or the like, or a mixture of two or more thereof. Solvent.
반응온도는 실온 내지 사용된 반응용매의 환류온도범위를 유지하는 것이 반응속도 및 수율면에서 바람직하다.The reaction temperature is preferably maintained at room temperature to the reflux temperature of the reaction solvent used in view of the reaction rate and yield.
상기와 같은 조건하에서 반응을 수행한 결과, 반응시간은 6 ∼ 48시간 소요된다. 반응이 완료되면 반응용액에 묽은 산용액을 첨가하여 반응용액의 pH를 3 ~ 4로 조절하여 반응후 잔존하는 알칼리를 제거한 다음, 통상의 분리·정제방법을 수행하여 본 발명에서 목적으로 하는 상기 화학식 1로 표시되는 아세클로페낙을 60% 이상의 수율로 얻는다.As a result of the reaction under the conditions described above, the reaction time is 6 to 48 hours. After the reaction is completed, a dilute acid solution is added to the reaction solution to adjust the pH of the reaction solution to 3 to 4 to remove the alkali remaining after the reaction, and then by performing a conventional separation and purification method, the above-mentioned general formula Aceclofenac represented by 1 is obtained in a yield of 60% or more.
이와같은 본 발명은 다음의 실시예에 의하여 더욱 구체적으로 설명하는 바, 본 발명이 이에 한정되는 것은 아니다.Such the present invention will be described in more detail by the following examples, but the present invention is not limited thereto.
실시예 1Example 1
소듐 2-((2,6-디클로로페닐)아미노)페닐아세테이트 10g을 30㎖의 아세톤과 30㎖의 디클로로메탄 혼합용매에 분산시킨 다음, 여기에 브로모아세트산 6.5g, 벤질트리부틸암모늄 클로라이드(C6H5CH2C4H9NCl) 0.4g과 탄산나트륨 6g을 가한 다음, 질소기류하에 50℃, 40시간 반응시켰다. 반응 완료후 반응용매를 감압농축하고 잔사에 물 100㎖를 가하여 교반용해시켰다. 이 용액에 10% 염산을 가하여 pH를 3 ∼ 4로 조절한 다음 여과하여 얻는 분말을 아세톤 50㎖로 재결정하여 백색 분말의 아세클로페낙 6.7g(수율 60.2 %)을 얻었다.10 g of sodium 2-((2,6-dichlorophenyl) amino) phenyl acetate was dispersed in 30 ml of acetone and 30 ml of dichloromethane mixed solvent, followed by 6.5 g of bromoacetic acid and benzyltributylammonium chloride (C 0.4 g of 6 H 5 CH 2 C 4 H 9 NCl) and 6 g of sodium carbonate were added, followed by reaction at 50 ° C. for 40 hours under a nitrogen stream. After the reaction was completed, the reaction solvent was concentrated under reduced pressure, and 100 ml of water was added to the residue, followed by stirring and dissolving. 10% hydrochloric acid was added to the solution to adjust the pH to 3-4, and the powder obtained by filtration was recrystallized from 50 ml of acetone to obtain 6.7 g (yield 60.2%) of aceclofenac as a white powder.
융점 : 149 ∼151℃Melting Point: 149∼151 ℃
실시예 2Example 2
소듐 2-((2,6-디클로로페닐)아미노)페닐아세테이트 10g을 40㎖의 아세톤과 20㎖의 클로로포름 혼합용매에 분산시킨 다음, 여기에 브로모아세트산 6.5g, 요오드화나트륨(NaI) 7g과 탄산나트륨 3g을 가한 다음, 질소기류하에 50℃, 45시간 반응시켰다. 이하 상기 실시예1과 동일한 방법에 의한 결과, 백색분말의 아세클로페낙 6.9g(수율 60.9%)을 얻었다.10 g of sodium 2-((2,6-dichlorophenyl) amino) phenyl acetate was dispersed in 40 ml of acetone and 20 ml of chloroform mixed solvent, followed by 6.5 g of bromoacetic acid, 7 g of sodium iodide (NaI), and sodium carbonate. After adding 3 g, it was made to react at 50 degreeC and 45 hours under nitrogen stream. As a result of the same procedure as in Example 1, 6.9 g (yield 60.9%) of aceclofenac of a white powder was obtained.
융점 : 149 ∼151℃Melting Point: 149∼151 ℃
실시예 3Example 3
소듐 2-((2,6-디클로로페닐)아미노)페닐아세테이트 10g을 50㎖의 아세톤에 분산시킨 다음, 여기에 브로모아세트산 6.5g, 테트라부틸암모늄 아이오다이드((C4H9)4NI) 0.3g, 요오드화 칼륨(KI) 5g 그리고 탄산나트륨 5g을 가한 다음, 질소기류하에 50℃, 24시간 반응시켰다. 반응 완료후 반응용매를 감압농축하고 잔사에 물 100㎖를 가하여 교반용해시켰다. 이 용액에 10% 염산을 가하여 pH를 3 ∼ 4로 조절한 다음 여과하여 얻는 분말을 클로로포름 50㎖로 재결정하여 백색 분말의 아세클로페낙 7.1g(수율 63.8 %)을 얻었다.10 g of sodium 2-((2,6-dichlorophenyl) amino) phenylacetate are dispersed in 50 ml of acetone, followed by 6.5 g of bromoacetic acid and tetrabutylammonium iodide ((C 4 H 9 ) 4 NI 0.3 g), 5 g of potassium iodide (KI) and 5 g of sodium carbonate were added, followed by reaction at 50 DEG C for 24 hours under a nitrogen stream. After the reaction was completed, the reaction solvent was concentrated under reduced pressure, and 100 ml of water was added to the residue, followed by stirring and dissolving. 10% hydrochloric acid was added to the solution to adjust the pH to 3-4, and the powder obtained by filtration was recrystallized with 50 ml of chloroform to obtain 7.1 g of aceclofenac (yield 63.8%) as a white powder.
융점 : 149 ∼151℃Melting Point: 149∼151 ℃
실시예 4Example 4
소듐 2-((2,6-디클로로페닐)아미노)페닐아세테이트 20g을 100㎖의 클로로포름에 분산시킨 다음, 여기에 브로모아세트산 14g, 벤질트리메틸암모늄 히드록시드(C6H5CH2(CH3)3NOH) 0.4g, 요오드화나트륨(NaI) 12g, 탄산나트륨 10g을 가하였다. 이하 상기 실시예3과 동일한 방법에 의한 결과, 백색분말의 아세클로페낙 14.5g(수율 65.1%)을 얻었다.20 g of sodium 2-((2,6-dichlorophenyl) amino) phenylacetate are dispersed in 100 ml of chloroform, followed by 14 g of bromoacetic acid and benzyltrimethylammonium hydroxide (C 6 H 5 CH 2 (CH 3). 3 ) NOH) 0.4 g, 12 g sodium iodide (NaI) and 10 g sodium carbonate were added. As a result of the same procedure as in Example 3, 14.5 g of aceclofenac (yield 65.1%) of white powder was obtained.
융점 : 149 ∼151℃Melting Point: 149∼151 ℃
상기에서 설명한 바와 같이, 본 발명에 따른 제조방법은 종래방법에서의 복잡한 보호기도입반응 및 탈보호반응을 생략하고 반응물로부터 목적으로하는 아세클로페낙을 직접 얻을 수 있고, 제조수율도 높아 공업적으로 유리하다.As described above, the production method according to the present invention can directly obtain the desired aceclofenac from the reactants by omitting the complex protection air introduction reaction and the deprotection reaction in the conventional method, and the production yield is also industrially advantageous.
Claims (9)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019970046790A KR100234626B1 (en) | 1997-09-11 | 1997-09-11 | Process for the preparation of 2-((2,6-dichlorophenyl)amino)phenylacetoxy acetic acid |
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| KR1019970046790A KR100234626B1 (en) | 1997-09-11 | 1997-09-11 | Process for the preparation of 2-((2,6-dichlorophenyl)amino)phenylacetoxy acetic acid |
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| KR102229969B1 (en) * | 2019-02-13 | 2021-03-22 | 한국바이오켐제약 주식회사 | Methods for preparing aceclofenac and pharmaceutical composition comprising the same |
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