KR20000010402A - Preparation method of 2-((2,6-dichlorophenyl)amino)phenylacetoxyacetic acid - Google Patents

Preparation method of 2-((2,6-dichlorophenyl)amino)phenylacetoxyacetic acid Download PDF

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KR20000010402A
KR20000010402A KR1019980031302A KR19980031302A KR20000010402A KR 20000010402 A KR20000010402 A KR 20000010402A KR 1019980031302 A KR1019980031302 A KR 1019980031302A KR 19980031302 A KR19980031302 A KR 19980031302A KR 20000010402 A KR20000010402 A KR 20000010402A
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dichlorophenyl
amino
formula
acetic acid
phenyl
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KR100348100B1 (en
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장사정
이점증
유준식
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이규혁
하나제약 주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

PURPOSE: A process for manufacturing 2-((2,6-dichlorophenyl)amino)phenyl acetoxy acetic acid by using an organic amine addition salt of carboxylic acid is provided which has a high yield of reactivity and easiness of removing a protecting group. CONSTITUTION: 2-£(2,6-Dichlorophenyl)amino|phenyl acetic acid is reacted with stoichiometric organic amine in the presence of organic solvent to give 2-£(2,6-dichlorophenyl)amino|phenyl acetic acid. trialkylamine salt, which is reacted with phenacyl 2-haloacetate to give 2-£(2,6-dichlorophenyl)amino|phenyl acetate, which is forced to remove a R1 protecting group to give 2-£(2,6-dichlorophenyl)amino|phenyl acetoxy acetic acid(I). For an example, 2.96g 2-£(2,6-dichlorophenyl)amino|phenyl acetic acid is dissolved in 30 ml ethyl acetate, added slowly with 1.01g triethylamine at 20-30°C.C.C, agitated for 30 min, and mixed with 2.72g 2-methanesulfonylacetate phenacyl ester for 48 hr. The reactant is filtrated to remove an insoluble salt, washed with 1N hydrochloric acid, saturated sodium dicarbonate and water, and recrystallized with methylenechloride-hexane to give 4.63g 2-£(2,6-dichlorophenyl)amino|phenyl acetoxyacetate phenacyl ester, which(1g) is dissolved in 10 ml acetic acid. added with 0.344g zinc and 30ml methylene chloride to give 0.69g 2-((2,6-dichlorophenyl)amino)phenyl acetoxy acetic acid(93%).

Description

2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세트산의 제조방법Method for preparing 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid

본 발명은 소염제 및 진통제로서 활성을 가진 아세클로페낙(Aceclofenac)으로 명명되는 하기 화학식 1의 2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세트산을 제조하는 신규방법에 관한 것이다.The present invention relates to a novel process for preparing 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid of the formula (1) named Aceclofenac which has activity as an anti-inflammatory and analgesic agent.

상기 화학식 1의 화합물을 제조하는 방법은 미국 특허원 제4548952호에 기술되어 있다. 이 방법은 하기 화학식 2의 2-[(2,6-디클로로페닐)아미노]페닐아세트산의 알칼리 금속염을 하기 화학식 3의 2-할로아세트산의 벤질 에스테르와 반응시켜 생성한 하기 화학식 4의 화합물을 적당한 전이금속 촉매를 사용하여 가수소분해시키는 것으로 구성되어 있다.The method for preparing the compound of Formula 1 is described in US Patent No. This method is carried out by reacting an alkali metal salt of 2-[(2,6-dichlorophenyl) amino] phenylacetic acid of formula (2) with a benzyl ester of 2-haloacetic acid of formula (3). It is comprised by hydrogenolysis using a metal catalyst.

(식중, X는 할로겐 원자이다.)(Wherein X is a halogen atom)

그러나 상기 방법은 화학식 2의 화합물의 알칼리 금속염과 화학식 3의 화합물의 반응수율이 높지 않으며, 화학식 4의 화합물의 벤질보호기를 제거하는 가수소분해 반응시 압축된 기체를 취급하기 위한 특수장치가 필요하며, 수소 및 전이금속 촉매를 산업적으로 사용하는 경우 위험성이 수반된다는 문제점이 있다.However, the method does not have a high yield of reaction between the alkali metal salt of the compound of Formula 2 and the compound of Formula 3, and requires a special apparatus for handling the compressed gas during the hydrogenolysis reaction to remove the benzyl protecting group of the compound of Formula 4. In case of industrial use of hydrogen, a transition metal catalyst and the like, there is a problem that the risk is accompanied.

기타 전형적인 에스테르 가수분해 방법을 사용하는 경우에는 화학식 4의 분자 내에 존재하는 2개의 에스테르 그룹에 선택성이 없이 영향을 주므로 유용하지 못하다.The use of other typical ester hydrolysis methods is not useful because it affects two ester groups present in the molecule of formula 4 without selectivity.

또한 상기 방법은 전체 수율이 매우 낮아 경제적이지 못하다는 문제점이 있다.In addition, the method has a problem in that the overall yield is very low and economical.

따라서, 본 발명자들은 상기와 같은 종래 제조방법 상의 문제점을 해결하기 위하여 연구 노력한 결과, 안전하고 간단하게 수율이 높은 2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세트산을 제조할 수 있는 본 발명을 완성하게 되었다.Therefore, the present inventors have made efforts to solve the problems in the conventional manufacturing method as described above, it is possible to produce 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid with high yield safely and simply. The present invention has been completed.

본 발명의 목적은 2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세트산의 제조방법을 제공하는 것이다.It is an object of the present invention to provide a process for the preparation of 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid.

본 발명은 2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세트산의 제조방법에 관한 것이다.The present invention relates to a process for the preparation of 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid.

보다 구체적으로는 다음과 같다.More specifically, it is as follows.

본 발명은 화학식 2의 화합물을 유기용매 속에서 유기 아민과 반응시켜 하기 화학식 5의 화합물인 카르복실산 유기 아민 부가염을 생성하고, 이를 하기 화학식 6의 화합물과 반응시켜 하기 화학식 7의 화합물을 제조한 다음, 화학식 7의 화합물에 존재하는 보호기 R1을 제거함을 특징으로 하여 하기 화학식 1의 화합물을 제조하는 방법에 관한 것이다.The present invention is to react the compound of formula (2) with an organic amine in an organic solvent to produce a carboxylic acid organic amine addition salt which is a compound of formula (5), and reacts with the compound of formula (6) to prepare a compound of formula (7) Next, the present invention relates to a process for preparing the compound of formula 1, characterized in that the protecting group R 1 present in the compound of formula 7 is removed.

(식중, L은 유기아민으로, 바람직하게는 트리메틸아민, 트리에틸아민, N,N'-디메틸에탄올아민을 나타내며, X는 할로겐 원자, 알킬술포닐 라디칼 또는 임의 치환된 아릴술포닐 라디칼이며, 바람직하게는 브롬 또는 메탄술포닐, p-톨루엔술포닐을 나타내고, R1은 페나실을 나타낸다.)(Wherein L represents an organic amine, preferably trimethylamine, triethylamine, N, N'-dimethylethanolamine, X is a halogen atom, an alkylsulfonyl radical or an optionally substituted arylsulfonyl radical, preferably Preferably bromine or methanesulfonyl, p-toluenesulfonyl, and R 1 represents phenacyl.)

화학식 5의 화합물과 화학식 6의 화합물의 생성은 약 0~30℃의 온도에서 유기용매(예:에틸아세테이트, 메틸렌클로라이드, 아세토니트릴)속에서 수행할 수 있다.The production of the compound of Formula 5 and the compound of Formula 6 may be carried out in an organic solvent (eg, ethyl acetate, methylene chloride, acetonitrile) at a temperature of about 0 ~ 30 ℃.

화학식 5의 화합물과 화학식 6의 화합물의 생성은 약 20~70℃의 온도에서 유기용매(예:에틸아세테이트, 메틸렌클로라이드, 아세토니트릴)속에서 수행할 수 있다.The production of the compound of Formula 5 and the compound of Formula 6 may be carried out in an organic solvent (eg, ethyl acetate, methylene chloride, acetonitrile) at a temperature of about 20 ~ 70 ℃.

화학식 7의 화합물에 존재하는 보호기(R1은 페나실)은 유기산 용매(예:아세트산)하에서 아연 촉매를 이용하여 보호기 제거반응을 수행하여 높은 수율로 화학식 1의 화합물을 제조할 수 있다.The protecting group (R 1 is phenacyl) present in the compound of Formula 7 may be prepared in a high yield by performing a protecting group removal reaction using a zinc catalyst in an organic acid solvent (eg, acetic acid).

하기 실시예를 들어 본 발명을 설명하나 본 발명이 이들 실시예에 의해 한정되는 것은 아니다.The present invention will be described with reference to the following examples, but the present invention is not limited to these examples.

실시예 1Example 1

히드록시아세트산 3.046g(0.041mole)을 에틸 아세테이트 30ml에 현탁시키고, 20~30℃에서 트리에틸아민 4.165g(0.045mole), 2-브로모아세토페논 8.205g(0.041mole)을 차례로 가하고 10시간 동안 교반하였다. 반응 혼합물을 여과하여 불용성 염을 제거한 후 여과액을 1N 염산 용액, 포화 탄산수소나트륨 용액, 물로 각각 세척하였다. 에틸 아세테이트상을 마그네슘 술페이트로 건조, 여과하고, 감압, 증류하여 용매를 제거하였다. 잔사를 에틸 아세테이트-헥산으로 재결정하여 백색 결정으로서 2-히드록시아세테이트 페나실 에스테르 7.64g(96%)을 수득하였다.3.046 g (0.041 mole) of hydroxyacetic acid was suspended in 30 ml of ethyl acetate, 4.165 g (0.045 mole) of triethylamine and 8.205 g (0.041 mole) of 2-bromoacetophenone were added sequentially at 20 to 30 ° C. for 10 hours. Stirred. The reaction mixture was filtered to remove insoluble salts, and then the filtrate was washed with 1N hydrochloric acid solution, saturated sodium bicarbonate solution and water, respectively. The ethyl acetate phase was dried over magnesium sulfate, filtered, and distilled under reduced pressure to remove the solvent. The residue was recrystallized from ethyl acetate-hexane to give 7.64 g (96%) of 2-hydroxyacetate phenacyl ester as white crystals.

융점 : 110~116℃Melting Point: 110 ~ 116 ℃

1H NMR(CDCl3) : δ 7.26~7.39(5H, m), 5.47(2H, s), 4.40(2H, d, J=3.93Hz) 1 H NMR (CDCl 3 ): δ 7.26 to 7.39 (5H, m), 5.47 (2H, s), 4.40 (2H, d, J = 3.93 Hz)

실시예 2Example 2

2-히드록시아세테이트 페나실 에스테르 2.74g(14.12mmole)을 메틸렌 클로라이드 30ml에 녹이고, 0~5℃에서 트리에틸아민 1.71g(16.94mmole)을 가한 다음, 메탄술포닐 클로라이드 1.78g(15.53mmole)을 서서히 가하였다. 첨가가 끝나면 30분 동안 더 교반시키고, 반응 혼합물을 여과하여 불용성 염을 제거한 후 여과액을 1N 염산 용액, 포화 탄산수소나트륨 용액, 물로 각각 세척하였다. 메틸렌 클로라이드상을 마그네슘 술페이트로 건조, 여과하고, 감압, 증류하여 용매를 제거하였다. 잔사를 에틸 아세테이트-헥산으로 재결정하여 미황색 결정으로서 2-메탄술포닐아세테이트 페나실 에스테르 3.61g(94%)을 수득하였다.2.74 g (14.12 mmoles) of 2-hydroxyacetate phenacyl ester was dissolved in 30 ml of methylene chloride, 1.71 g (16.94 mmoles) of triethylamine was added at 0-5 DEG C, and then 1.78 g (15.53 mmoles) of methanesulfonyl chloride was added thereto. Slowly added. After the addition, the mixture was further stirred for 30 minutes, and the reaction mixture was filtered to remove insoluble salts, and then the filtrate was washed with 1N hydrochloric acid solution, saturated sodium bicarbonate solution, and water. The methylene chloride phase was dried over magnesium sulfate, filtered, and distilled under reduced pressure to remove the solvent. The residue was recrystallized from ethyl acetate-hexane to give 3.61 g (94%) of 2-methanesulfonyl acetate phenacyl ester as light yellow crystals.

융점 : 87~88℃Melting Point: 87 ~ 88 ℃

1H NMR(CDCl3) : δ 7.45~7.95(5H, m), 5.48(2H, s), 4.96(2H, s), 3.21(3H, s) 1 H NMR (CDCl 3 ): δ 7.45-7.95 (5H, m), 5.48 (2H, s), 4.96 (2H, s), 3.21 (3H, s)

실시예 3Example 3

2-[(2,6-디클로로페닐)아미노]페닐아세트산 2.96g(0.01mole)을 에틸 아세테이트 30ml에 현탁시키고, 20~30℃에서 트리에틸아민 1.01g(0.01mole)을 서서히 가하고 30분간 교반하였다. 그 후, 여기에 2-메탄술포닐아세테이트 페나실 에스테르 2.72g(0.01mole)을 가하고, 48시간 동안 교반하였다. 반응 혼합물을 여과하여 불용성 염을 제거한 후 여과액을 1N 염산 용액, 포화 탄산수소나트륨 용액, 물로 각각 세척하였다. 에틸 아세테이트상을 마그네슘 술페이트로 건조, 여과하고, 감압, 증류하여 용매를 제거하였다. 잔사를 메틸렌 클로라이드-헥산으로 재결정하여 백색 결정으로서 2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세테이트 페나실 에스테르 4.63g(98%)을 수득하였다.2.96 g (0.01 mole) of 2-[(2,6-dichlorophenyl) amino] phenylacetic acid was suspended in 30 ml of ethyl acetate, and 1.01 g (0.01 mole) of triethylamine was slowly added at 20-30 ° C. and stirred for 30 minutes. . Thereafter, 2.72 g (0.01 mole) of 2-methanesulfonyl acetate phenacyl ester was added thereto and stirred for 48 hours. The reaction mixture was filtered to remove insoluble salts, and then the filtrate was washed with 1N hydrochloric acid solution, saturated sodium bicarbonate solution and water, respectively. The ethyl acetate phase was dried over magnesium sulfate, filtered, and distilled under reduced pressure to remove the solvent. The residue was recrystallized from methylene chloride-hexane to give 4.63 g (98%) of 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetate phenacyl ester as white crystals.

융점 : 96~98℃Melting Point: 96 ~ 98 ℃

1H NMR(CDCl3) : δ 6.57~7.90(13H, m), 5.40(2H, s), 4.89(2H, s), 3.96(2H, s) 1 H NMR (CDCl 3 ): δ 6.57 ~ 7.90 (13H, m), 5.40 (2H, s), 4.89 (2H, s), 3.96 (2H, s)

실시예 4Example 4

2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세테이트 페나실 에스테르 1g(2.11mmole)을 아세트산 10ml에 녹이고, 20~30℃에서 아연(dust) 0.344g(5.27mmole)을 가한 후 2시간 동안 교반하였다. 반응혼합물을 물 30ml에 부어 넣고, 메틸렌 클로라이드 30ml를 가한 다음 상을 분리시켰다. 물층을 메틸렌 클로라이드 10ml로 2번 추출하고, 메틸렌 클로라이드상을 모으고 물 30ml로 세척하였다. 메틸렌 클로라이드상을 마그네슘 술페이트로 건조, 여과하고, 감압, 증류하여 용매를 제거하고, 잔사를 에틸 아세테이트-헥산으로 재결정하여 백색 결정으로서 2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세트산 0.69g(93%)을 수득하였다.1 g (2.11 mmoles) of 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetate phenacyl ester was dissolved in 10 ml of acetic acid, and 0.344 g (5.27 mmoles) of zinc was added at 20 to 30 ° C. Stir for hours. The reaction mixture was poured into 30 ml of water, 30 ml of methylene chloride was added and the phases were separated. The water layer was extracted twice with 10 ml of methylene chloride, the methylene chloride phases were combined and washed with 30 ml of water. The methylene chloride phase was dried over magnesium sulfate, filtered, reduced pressure and distilled to remove the solvent, and the residue was recrystallized from ethyl acetate-hexane to give 2-[(2,6-dichlorophenyl) amino] phenylacetoxy as white crystals. 0.69 g (93%) of acetic acid were obtained.

융점 : 149~150℃Melting Point: 149 ~ 150 ℃

상술한 바와 같이 본 발명은 반응중간체로 카르복실산의 유기아민 부가염을 사용함으로써 반응 수율이 높고 보호기 제거도 종래기술보다 간단한 2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세트산을 제조하는 우수한 방법을 제공한다.As described above, the present invention uses 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid having a higher reaction yield and simpler protecting group removal by using an organic amine addition salt of carboxylic acid as a reaction intermediate. It provides an excellent method of manufacturing.

Claims (6)

하기 화학식 2의 화합물(A는 수소)을 유기 용매 속에서 화학양론적 양의 유기 아민과 반응시켜 하기 화학식 5의 카르복실산 유기 아민 부가염을 생성하고, 하기 화학식 6의 화합물과 반응시킨 다음, 생성된 하기 화학식 7의 화합물에 존재하는 보호기 R1을 제거함을 특징으로 하는 하기 화학식 1의 화합물을 제조하는 방법.Reacting a compound of formula 2 (A is hydrogen) with a stoichiometric amount of an organic amine in an organic solvent to produce a carboxylic acid organic amine addition salt of formula 5, and reacting with a compound of formula 6 Process for preparing a compound of formula (1) characterized in that to remove the protecting group R 1 present in the resulting compound of formula (7). (식중, L은 유기아민을 나타내며, X는 할로겐 원자, 알킬술포닐 라디칼 또는 임의 치환된 아릴술포닐 라디칼이며, R1은 페나실이다.)(Wherein L represents an organic amine, X is a halogen atom, an alkylsulfonyl radical or an optionally substituted arylsulfonyl radical, and R 1 is phenacyl). 제1항에 있어서, 화학식 4의 화합물의 L이 트리메틸아민, 트리에틸아민, N,N'-디메틸에탄올아민인 방법.The method of claim 1, wherein L of the compound of formula 4 is trimethylamine, triethylamine, N, N′-dimethylethanolamine. 제1항에 있어서, 화학식 6의 화합물의 X가 브롬, 메탄술포닐, p-톨루엔술포닐인 방법.The method of claim 1, wherein X of the compound of formula 6 is bromine, methanesulfonyl, p-toluenesulfonyl. 제1항에 있어서, 용매가 에틸 아세테이트, 메틸렌 클로라이드, 아세토니트릴임을 특징으로 하는 방법.The method of claim 1 wherein the solvent is ethyl acetate, methylene chloride, acetonitrile. 제1항에 있어서, 반응이 0~70℃의 온도에서 수행되는 방법.The process of claim 1 wherein the reaction is carried out at a temperature of 0-70 ° C. 제1항에 있어서, 보호기 제거반응의 용매가 아세트산이고 촉매가 아연인 방법.The process of claim 1 wherein the solvent of the protecting group removal reaction is acetic acid and the catalyst is zinc.
KR1019980031302A 1998-07-31 1998-07-31 Manufacturing method of 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid KR100348100B1 (en)

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