KR100296737B1 - The Process of Aceclofenac - Google Patents
The Process of Aceclofenac Download PDFInfo
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- KR100296737B1 KR100296737B1 KR1019990050584A KR19990050584A KR100296737B1 KR 100296737 B1 KR100296737 B1 KR 100296737B1 KR 1019990050584 A KR1019990050584 A KR 1019990050584A KR 19990050584 A KR19990050584 A KR 19990050584A KR 100296737 B1 KR100296737 B1 KR 100296737B1
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- solvent
- diclofenac
- aceclofenac
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- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 229960004420 aceclofenac Drugs 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims abstract description 16
- 229960001259 diclofenac Drugs 0.000 claims abstract description 22
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims abstract description 20
- -1 diclofenac allyl ester Chemical class 0.000 claims abstract description 19
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims abstract description 8
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003377 acid catalyst Substances 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 abstract description 4
- 230000032050 esterification Effects 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- VGGRCVDNFAQIKO-UHFFFAOYSA-N formic anhydride Chemical compound O=COC=O VGGRCVDNFAQIKO-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- WRYJMEQATCHBRJ-UHFFFAOYSA-N 2-(2-phenylacetyl)oxyacetic acid Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1 WRYJMEQATCHBRJ-UHFFFAOYSA-N 0.000 description 1
- YCNFHQIOFCOXNJ-UHFFFAOYSA-N [2-(2,6-dichloroanilino)phenyl] acetate Chemical compound CC(=O)OC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl YCNFHQIOFCOXNJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07C227/02—Formation of carboxyl groups in compounds containing amino groups, e.g. by oxidation of amino alcohols
-
- 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
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
- C07C229/58—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position having the nitrogen atom of at least one of the amino groups further bound to a carbon atom of a six-membered aromatic ring, e.g. N-phenyl-anthranilic acids
Abstract
본 발명은 디클로페낙과 알릴알코올을 다양한 산 촉매 하에서 에스테르화 반응으로 디클로페낙 알릴에스테르를 제조하고, 이것을 오존과 반응시켜 아세클로페낙으로 명명되는 2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세트산을 수득하는 방법에 관한 것이다.The present invention prepares diclofenac allyl ester by esterification of diclofenac and allyl alcohol under various acid catalysts, and reacts with ozone to produce 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid named as aceclofenac. It relates to a method of obtaining.
Description
본 발명은 2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세트산으로 명명되는 하기 화학식 １의 아세클로페낙의 제조방법에 관한 것이다．The present invention relates to a process for producing aceclofenac of the following Chemical Formula 1, which is named 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid.
상기 화학식 1로 표시되는 아세클로페낙은 비스테로이드성 소염진통제로 널리 공지되어 있으며 이의 제조방법 또한 몇몇 문헌에 제시되어 있다.Aceclofenac represented by Formula 1 is well known as a nonsteroidal anti-inflammatory analgesic, and a method for preparing the same is also shown in several documents.
종래의 아세클로페낙의 제조방법으로서，미합중국 특허공보 제4548952호에는 디클로페낙 알칼리 금속염과 벤질 할로아세테이트를 반응시켜 하기 화학식 5의 디클로페낙 벤질 에스테르를 제조한 후，수소환원반응에 의하여 벤질기를 제거하여 아세클로페낙을 제조하는 방법이 개시되어 있다.As a conventional method for producing aceclofenac, U.S. Patent Publication No. 4548952 discloses diclofenac alkali metal salts and benzyl haloacetates to prepare diclofenac benzyl ester of Formula 5, and then removes benzyl groups by hydrogen reduction to produce aceclofenac. A method is disclosed.
그러나 이와 같은 제조방법은 압축된 수소기체를 반응시키기 위한 특수반응 장치가 필요하고 수소 및 촉매를 공업적으로 사용하는 경우 위험성이 크며, 또한 반응에 사용되는 팔라듐 촉매가 고가이어서 경제적으로도 바람직하지 못한 단점이 있다.However, such a production method requires a special reaction device for reacting the compressed hydrogen gas, is dangerous in the case of industrial use of hydrogen and catalyst, and the palladium catalyst used in the reaction is expensive, which is economically undesirable. There are disadvantages.
또 다른 제조방법으로서 대한민국 특허공고 제96-9569호에는，상기 미합중국 특허공보 제4548952호의 디클로페낙 벤질 에스테르를 수소환원 반응시켜 벤질기를 제거하는 대신에 하기 화학식 6의 디클로페낙 2-테트라하이드로푸라닐 에스테르를 사용하여 테트라하이드로푸란 용매 하에서 초산으로 테트라하이드로푸라닐기를 제거하여 아세클로페낙을 제조하는 방법이 개시되어 있다．As another method of preparation, Korean Patent Publication No. 96-9569 uses diclofenac 2-tetrahydrofuranyl ester of the following Chemical Formula 6 instead of hydrogen-reducing the diclofenac benzyl ester of the above-mentioned US Patent Publication No. 4548952 to remove the benzyl group. A method for producing aceclofenac by removing a tetrahydrofuranyl group with acetic acid under a tetrahydrofuran solvent has been disclosed.
상기 제조방법도 수소환원 반응을 거치지 않는다는 장점은 있으나 반응물질 및 반응용매로 고가의 디클로페낙 2-테트라하이드로푸라닐 에스테르와 테트라하이드로푸란을 사용하는 단점이 있으며, 또한 반응물질로 사용되는 디클로페낙 2-테트라하이드로푸라닐 에스테르의 제조공정이 제시되어 있지 않다는 문제점이 있다.The preparation method also has the advantage of not undergoing a hydrogen reduction reaction, but has the disadvantage of using expensive diclofenac 2-tetrahydrofuranyl ester and tetrahydrofuran as a reactant and a reaction solvent, and also diclofenac 2-tetra used as a reactant. There is a problem that a process for producing hydrofuranyl ester is not presented.
또 다른 하나의 제조방법으로 캐나다 특허공보 제2111169호(한국 대응특허 출원번호 제93-27558호)에는 하기 화학식 7의 2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세트산의 3급 알킬 에스테르를 무수 삼불소아세트산 또는 무수 개미산과 반응시켜 아세클로페낙을 얻는 방법이 기재되어 있으나，가격이 비싸고 산업적으로 다루기 어려운 물질인 무수 삼불소아세트산 또는 무수 개미산을 사용하는 문제점이 있다.As another manufacturing method, Canadian Patent Publication No. 2111169 (Korean Patent Application No. 93-27558) describes tert. Of 2-[(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid of Formula 7 below. Although a method of obtaining aceclofenac by reacting an alkyl ester with trifluoroacetic anhydride or formic anhydride has been described, there is a problem of using an expensive trifluoroacetic anhydride or formic anhydride, which is an expensive and industrially difficult material.
상기에서 예시한 종래 제조방법들은 공통적으로 디클로페낙의 카르복실기에 아세테이트기를 반응시키기 위하여 아세테이트기의 카르복실산을 보호하는 벤질기, 테트라하이드로푸라닐기, 삼급-부틸기 등의 보호기를 할로 아세트산에 도입한 다음 디클로페낙과 반응시킨 후, 다시 보호기를 제거하여야 하기 때문에 그 제조공정이 매우 번거롭다는 단점이 있다.The conventional production methods exemplified above commonly introduce protecting groups such as benzyl, tetrahydrofuranyl, and tert-butyl groups to protect the carboxylic acid of the acetate group in order to react the acetate group with the carboxyl group of diclofenac, and then into halo acetic acid. After reacting with diclofenac, there is a disadvantage that the manufacturing process is very cumbersome because the protecting group must be removed again.
본 발명자들은 상기 문제점들을 해결하고자 많은 연구와 노력을 한 결과，짧은 반응시간 내에 저렴한 가격의 알릴알코올을 이용하여 쉽게 에스테르 반응시키고，간단한 장비와 일반적인 유기용매를 사용하여 경제적이며, 고순도로 제조하는 방법을 알게 되어 본 발명을 완성하게 되었다．The present inventors have conducted a lot of research and efforts to solve the above problems, and easily ester-reacted with low-cost allyl alcohol within a short reaction time, and economical and high-purity manufacturing method using simple equipment and a general organic solvent. Knowing this, he completed the invention.
본 발명의 목적은 아세클로페낙의 새로운 제조방법을 제공하는데 있다．The purpose of the present invention is to provide a new method of manufacturing Aceclofenac.
본 발명은 하기 반응식 1에 나타낸 바와 같이, 하기 화학식 2의 디클로페낙 또는 그의 염을 하기 화학식 4의 알릴알코올과 용매 하에서 산 촉매를 사용하여 선택적으로 반응시켜 하기 화학식 3의 화합물을 얻은 후, 하기 화학식 3의 디클로페낙 알릴에스테르를 용매 하에서 오존과 저온반응시켜 하기 화학식 1의 아세클로페낙을 얻는 제조방법에 관한 것이다.As shown in Scheme 1 below, diclofenac of Formula 2 or a salt thereof is selectively reacted with an allyl alcohol of Formula 4 using an acid catalyst under a solvent to obtain a compound of Formula 3, and then The present invention relates to a process for obtaining aceclofenac of formula (I) by reacting diclofenac allyl ester of with low temperature with ozone in a solvent.
(식중, M=H, Na 또는 K)(Wherein M = H, Na or K)
상기 반응식 1을 보다 구체적으로 설명하면 다음과 같다．The reaction scheme 1 is described in more detail as follows.
(1) 상기 화학식 2의 2-[(2,6-디클로로페닐)아미노]벤젠아세트산염으로 명명되는 디클로페낙과 화학식 4의 알릴알코올을 일반적인 유기 용매 하에서 다양한 산 촉매를 사용하여 실온 내지 용매의 비점온도에서 5분 내지 24시간 동안 에스테르화 반응시켜 화학식 3의 디클로페낙 알릴에스테르를 제조하는 공정.(1) The boiling point temperature of the solvent from room temperature to the solvent of diclofenac, which is named 2-[(2,6-dichlorophenyl) amino] benzeneacetate of Formula 2, and allyl alcohol of Formula 4, using various acid catalysts under general organic solvents. Process for producing diclofenac allyl ester of the formula (3) by esterification reaction for 5 minutes to 24 hours.
(2) 상기 결과물에 간단한 후처리 과정을 거치고 감압증류한 후, 용매 중에서 오존과 -10℃ 내지 -90℃에서 5분 내지 5시간 동안 저온반응시켜 화학식 1의 2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세트산으로 명명되는 아세클로페낙을 제조하는 공정.(2) 간단한 The resultant was subjected to a simple post-treatment process and distilled under reduced pressure, and then reacted with ozone in a solvent at low temperature for 5 minutes to 5 hours at -10 ° C to -90 ° C to give 2-[(2,6-dichloro). Phenyl) amino] phenylacetoxyacetic acid to produce aceclofenac.
상기 반응에서 사용되는 산 촉매로는 황산, 티오닐클로라이드, 파라-톨루엔술폰산, 또는 이들의 혼합물을 사용할 수 있으며, 황산을 사용하는 것이 바람직하다.As the acid catalyst used in the reaction, sulfuric acid, thionyl chloride, para-toluenesulfonic acid, or a mixture thereof may be used, and sulfuric acid is preferably used.
상기 (1) 공정에 사용하는 반응용매로는 알코올을 제외한 에틸아세테이트, 디클로로메탄, 클로로포름, 아세토니트릴 등의 극성 유기용매를 사용할 수 있으며, 특히 에틸아세테이트 또는 디클로로메탄을 사용하는 것이 바람직하다. 만약, 알코올을 반응용매로 사용하게 되면 디클로페낙과 반응하여 에스테르를 형성하게 된다.As the reaction solvent used in the step (1), a polar organic solvent such as ethyl acetate, dichloromethane, chloroform, acetonitrile and the like except for alcohol may be used, and ethyl acetate or dichloromethane is particularly preferable. If alcohol is used as the reaction solvent, it will react with diclofenac to form an ester.
또한 상기 (2) 공정에 사용하는 반응용매로는 디클로로메탄, 클로로포름, 메탄올 혹은 이들의 혼합용매를 사용할 수 있으며, 특히 디클로로메탄과 메탄올의 혼합용매를 사용하는 것이 바람직하다.Dichloromethane, chloroform, methanol, or a mixed solvent thereof may be used as the reaction solvent used in the step (2). In particular, it is preferable to use a mixed solvent of dichloromethane and methanol.
상기 공정의 반응시간으로는 (1) 공정의 에스테르화 반응은 5분 내지 24시간 동안 수행할 수 있으며, 특히 3시간 내지 22시간 동안 수행하는 것이 바람직하고, 상기 (2) 공정의 오존 하에서 저온 반응은 5분 내지 5시간 동안 수행할 수 있으며, 특히 30분 내지 2시간동안 수행하는 것이 바람직하다.As the reaction time of the step (1) the esterification reaction of step (1) can be carried out for 5 minutes to 24 hours, particularly preferably for 3 to 22 hours, and the low temperature reaction under ozone of the step (2) May be performed for 5 minutes to 5 hours, and particularly preferably for 30 minutes to 2 hours.
본 발명에서 반응온도로는 (1) 공정의 에스테르화 반응은 실온 내지 용매의 비점온도에서 수행할 수 있으며, 용매의 비점온도가 바람직하고, (2)공정의 저온 반응온도로는 -10℃ 내지 -90℃에서 수행할 수 있으며, -50℃ 내지 -80℃에서 수행하는 것이 바람직하다.In the present invention, as the reaction temperature, (1) the esterification reaction of step (b) may be performed at room temperature to the boiling point of the solvent, and the boiling point of the solvent is preferable, and the low temperature reaction temperature of the step (2) is -10 ° C to It can be carried out at -90 ℃, preferably at -50 ℃ to -80 ℃.
이하 본 발명을 실시예를 통하여 더욱 상세히 설명하지만 이들이 본 발명의 범위를 제한하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, but these examples do not limit the scope of the present invention.
실시예 1Example 1
2-[(2,6-디클로로페닐)아미노]벤젠아세트산염 5 g(17 mmol)을 에틸아세테이트 200 mL에 용해한 후 진한 황산 0.5 g을 첨가하여 잘 교반한다. 이 용액에 알릴알코올 4.9 g(84 mmol)을 첨가한 후 환류교반하여 5시간 동안 반응시킨다. 반응용액을 상온으로 냉각하고 여기에 물 200 mL를 가하여 유기층을 세척하고 황산마그네슘으로 건조한 후 감압증류하여 용매를 제거한다. 이 잔류물을 고 진공상태 하에서 280℃로 증류 정제하여 5.1 g의 목적화합물인 화학식 3의 디클로페낙 알릴에스테르를 엷은 노란색의 오일로 얻었다(수득율: 90%).5 g (17 mmol) of 2-[(2,6-dichlorophenyl) amino] benzeneacetate is dissolved in 200 mL of ethyl acetate, and 0.5 g of concentrated sulfuric acid is added thereto, followed by stirring. 4.9 g (84 mmol) of allyl alcohol was added to the solution, followed by stirring under reflux for 5 hours. The reaction solution is cooled to room temperature, 200 mL of water is added thereto, the organic layer is washed, dried over magnesium sulfate, and distilled under reduced pressure to remove the solvent. This residue was distilled and refine | purified at 280 degreeC under high vacuum, and 5.1 g of the target compounds diclofenac allyl ester of the formula (3) were obtained as pale yellow oil (yield: 90%).
1H-NMR(CDCl3: δ): 3.85(s, 2H, CH2-C=O), 4.65(d, 2H, J=5.8Hz, COO-CH2), 5.21∼5.35(m, 2H, CH=CH2), 5.84∼6.17(m, 1H, CH=CH2), 6.55(d, 1H, J=8.2Hz, H-3), 6.92∼7.02(m, 2H, H-4, H-4'), 7.13(td, 1H, H-5), 7.24(d, 1H, H-6), 7.34(d, 2H, J=8.2Hz, H-3', H-5') 1 H-NMR (CDCl 3 : δ): 3.85 (s, 2H, CH 2 -C═O), 4.65 (d, 2H, J = 5.8 Hz, COO-CH 2 ), 5.21 to 5.35 (m, 2H, CH = CH 2 ), 5.84 to 6.17 (m, 1H, CH = CH 2 ), 6.55 (d, 1H, J = 8.2 Hz, H-3), 6.92 to 7.02 (m, 2H, H-4, H- 4 '), 7.13 (td, 1H, H-5), 7.24 (d, 1H, H-6), 7.34 (d, 2H, J = 8.2 Hz, H-3', H-5 ')
IR(KBr): 3300(N-H stretch), 1720(ester C=O stretch), 1640(alipatic C=C stretch), 1100(C-O-C stretch), 980(vinyl OOP), 930(vinyl OOP)cm-1 IR (KBr): 3300 (NH stretch), 1720 (ester C = O stretch), 1640 (alipatic C = C stretch), 1100 (COC stretch), 980 (vinyl OOP), 930 (vinyl OOP) cm -1
TLC Rf=0.75(전개용매- 에틸아세테이트:헥산=1:8)TLC R f = 0.75 (developing solvent-ethyl acetate: hexane = 1: 8)
실시예 2Example 2
2-[(2,6-디클로로페닐)아미노]벤젠아세트산염 10 g(34 mmol)을 디클로로메탄 300 mL에 용해한 후 진한 황산 1 g을 첨가하여 잘 교반한다. 이 용액에 알릴알코올 9.8 g(168 mmol)을 첨가한 후 환류교반하여 20시간 동안 반응시킨다. 반응용액을 상온으로 냉각하고 여기에 물 500 mL를 가하여 유기층을 세척하고 황산마그네슘으로 건조한 후 감압증류하여 용매를 제거한다. 이 잔류물을 고진공상태하에서 280℃로 증류정제하여 10.7 g의 목적화합물을 엷은 노란색의 오일로 얻었다(수득율: 94%).After dissolving 10 g (34 mmol) of 2-[(2,6-dichlorophenyl) amino] benzeneacetate in 300 mL of dichloromethane, 1 g of concentrated sulfuric acid is added and stirred well. 9.8 g (168 mmol) of allyl alcohol was added to the solution, followed by stirring under reflux for 20 hours. The reaction solution was cooled to room temperature, 500 mL of water was added thereto, the organic layer was washed, dried over magnesium sulfate, and distilled under reduced pressure to remove the solvent. This residue was distilled off and purified at 280 DEG C under a high vacuum to yield 10.7 g of the target compound as a pale yellow oil (yield: 94%).
상기물질은 박층크로마토그래피, NMR과 IR에 의하여 실시예 1의 생성물과 동일한 것임을 확인하였다.The material was confirmed to be the same as the product of Example 1 by thin layer chromatography, NMR and IR.
실시예 3Example 3
2-[(2,6-디클로로페닐)아미노]벤젠아세트산염 5 g(17 mmol)을 에틸아세테이트 200 mL에 용해한 후 파라-톨루엔술폰산 0.5 g을 첨가하여 잘 교반한다. 이 용액에 알릴알코올을 4.9 g(84 mmol)을 첨가한 후 환류교반하여 24시간 동안 반응시킨다. 반응용액을 상온으로 냉각하고 여기에 물 200 ml를 가하여 유기층을 세척하고 황산마그네슘으로 건조한 후 감압증류하여 용매를 제거한다. 이 잔류물을 고 진공상태 하에서 280℃로 증류 정제하여 2.9 g의 목적화합물을 엷은 노란색의 오일로 얻었다(수득율: 50%).5 g (17 mmol) of 2-[(2,6-dichlorophenyl) amino] benzeneacetate is dissolved in 200 mL of ethyl acetate, and 0.5 g of para-toluenesulfonic acid is added thereto and stirred well. 4.9 g (84 mmol) of allyl alcohol was added to the solution, followed by stirring under reflux for 24 hours. The reaction solution is cooled to room temperature, 200 ml of water is added thereto, the organic layer is washed, dried over magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was distilled and purified at 280 ° C. under high vacuum to yield 2.9 g of the desired compound as a pale yellow oil (yield: 50%).
상기물질을 박층크로마토그래피, NMR과 IR에 의하여 실시예 1의 생성물과 동일한 것임을 확인하였다.The material was confirmed to be the same as the product of Example 1 by thin layer chromatography, NMR and IR.
실시예 4Example 4
2-[(2,6-디클로로페닐)아미노]벤젠아세트산염 5 g(17 mmol)을 아세토니트릴 200 mL에 용해한 후 진한 황산 0.5 g을 첨가하여 잘 교반한다. 이 용액에 알릴알코올 4.9 g(84 mmol)을 첨가한 후 환류교반하여 5시간 동안 반응시킨다. 반응용액을 상온으로 냉각하고 여기에 물 200 ml를 가하여 유기층을 세척하고 황산마그네슘으로 건조한 후 감압증류하여 용매를 제거한다. 이 잔류물을 고 진공상태 하에서 280℃로 증류 정제하여 2.6 g의 목적화합물을 엷은 노란색의 오일로 얻었다(수득율: 45%).5 g (17 mmol) of 2-[(2,6-dichlorophenyl) amino] benzeneacetate is dissolved in 200 mL of acetonitrile, and 0.5 g of concentrated sulfuric acid is added thereto, followed by stirring well. 4.9 g (84 mmol) of allyl alcohol was added to the solution, followed by stirring under reflux for 5 hours. The reaction solution is cooled to room temperature, 200 ml of water is added thereto, the organic layer is washed, dried over magnesium sulfate, and distilled under reduced pressure to remove the solvent. This residue was distilled and purified at 280 ° C. under high vacuum to yield 2.6 g of the desired compound as a pale yellow oil (yield: 45%).
상기물질은 박층크로마토그래피, NMR과 IR에 의하여 실시예 1의 생성물과 동일한 것임을 확인하였다.The material was confirmed to be the same as the product of Example 1 by thin layer chromatography, NMR and IR.
실시예 5Example 5
디클로페낙 알릴에스테르 2.5 g(7.4 mmol)을 디클로로메탄 100 mL와 메탄올 50 mL의 혼합용매에 첨가하고, -65℃의 저온조를 설치한다. 반응용액이 -65℃에 이르면 오존을 불어넣어 -65℃에서 1시간 반응시키고, 유기용매를 감압농축한다. 그 잔류물에 98% 개미산 10 mL와 30% 과산화수소수 5 mL를 첨가하여 실온에서 10시간 교반한다. 반응용액을 2시간 동안 환류교반 후 용매를 감압농축한다. 이 잔류물에 에틸에테르 50 mL와 물 50 mL로 추출하여 유기층을 취하고, 물 50 mL로 세척하였다. 유기층을 황산마그네슘으로 건조한 후 감압증류하여 제거하였다. 이 잔류물을에틸아세테이트:헥산(2:1)의 혼합용매를 사용하여 실리카겔 칼럼크로마토그래피로 정제하여 흰색 결정의 목적화합물인 화학식 1의 2-[(2,6-디클로로페닐)아미노]페닐아세톡시아세트산 1.8 g을 얻었다(수득율: 70%).2.5 g (7.4 mmol) of diclofenac allyl ester are added to a mixed solvent of 100 mL of dichloromethane and 50 mL of methanol, and a low temperature bath at -65 ° C is installed. When the reaction solution reaches -65 ° C, ozone is blown to react at -65 ° C for 1 hour, and the organic solvent is concentrated under reduced pressure. 10 mL of 98% formic acid and 5 mL of 30% hydrogen peroxide solution were added to the residue, which was stirred for 10 hours at room temperature. After stirring the reaction solution under reflux for 2 hours, the solvent was concentrated under reduced pressure. The residue was extracted with 50 mL of ethyl ether and 50 mL of water, the organic layer was taken, and washed with 50 mL of water. The organic layer was dried over magnesium sulfate and removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate: hexane (2: 1) to obtain 2-[(2,6-dichlorophenyl) amino] phenylacetate of the general formula (1) as a target compound of white crystals. 1.8 g of oxyacetic acid was obtained (yield: 70%).
1H-NMR(CDCl3: δ): 3.89(s, 2H, CH2-C=O), 4.63(s, 2H, COO-CH2-C=O), 6.26(d, 1H, H-3), 6.83∼6.94(m, 2H, H-11, NH), 7.05(d, 1H, J=8.0Hz, H-4'), 7.16∼7.26(m, 2H, H-6, H-5), 7.52(d, 2H, J=8.0Hz, H-3', H-5'), 8.31(s, 1H, COOH) 1 H-NMR (CDCl 3 : δ): 3.89 (s, 2H, CH 2 -C = O), 4.63 (s, 2H, COO-CH 2 -C = O), 6.26 (d, 1H, H-3 ), 6.83 to 6.94 (m, 2H, H-11, NH), 7.05 (d, 1H, J = 8.0 Hz, H-4 '), 7.16 to 7.26 (m, 2H, H-6, H-5) , 7.52 (d, 2H, J = 8.0 Hz, H-3 ', H-5'), 8.31 (s, 1H, COOH)
IR(KBr): 3300(N-H stretch), 1764(ester C=O stretch), 1719(carboxyl C=O stretch), 1149(C-O-C stretch)cm-1 IR (KBr): 3300 (NH stretch), 1764 (ester C = O stretch), 1719 (carboxyl C = O stretch), 1149 (COC stretch) cm -1
TLC Rf=0.35(전개용매- 에틸아세테이트:헥산=2:1)TLC R f = 0.35 (developing solvent-ethyl acetate: hexane = 2: 1)
실시예 6Example 6
디클로페낙 알릴에스테르 2.5 g(7.4 mmol)을 디클로로메탄 100 mL에 첨가하고, -70℃의 저온조를 설치한다. 반응용액이 -70℃에 이르면 오존을 불어넣어 -70℃에서 1시간 30분 동안 반응시키고, 유기용매를 감압농축한다. 그 잔류물에 98% 개미산 10 mL와 30% 과산화수소수 5 ml를 첨가하여 실온에서 10시간 교반한다. 반응용액을 2시간 동안 환류 교반 후 용매를 감압농축한다. 이 잔류물에 에틸에테르 50 mL와 물 50 mL로 추출하여 유기층을 취하고, 물 50 mL로 세척하였다. 유기층을황산마그네슘으로 건조한 후 감압증류하여 제거하였다. 이 잔류물을 에틸아세테이트:헥산 (2:1)의 혼합용매를 사용하여 실리카겔 칼럼크로마토그래피로 정제하여 흰색 결정의 목적화합물인 아세클로페낙 1.7 g을 얻었다(수득율: 63%).2.5 g (7.4 mmol) of diclofenac allyl ester are added to 100 mL of dichloromethane and a low temperature bath at -70 ° C is set up. When the reaction solution reaches -70 ° C, ozone is blown to react at -70 ° C for 1 hour 30 minutes, and the organic solvent is concentrated under reduced pressure. To the residue was added 10 mL of 98% formic acid and 5 ml of 30% hydrogen peroxide solution and stirred at room temperature for 10 hours. After stirring the reaction solution under reflux for 2 hours, the solvent was concentrated under reduced pressure. The residue was extracted with 50 mL of ethyl ether and 50 mL of water, the organic layer was taken, and washed with 50 mL of water. The organic layer was dried over magnesium sulfate and removed by distillation under reduced pressure. This residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate: hexane (2: 1) to obtain 1.7 g of aceclofenac, the target compound of white crystals (yield: 63%).
상기물질은 박층크로마토그래피, NMR과 IR에 의하여 실시예 5의 생성물과 동일한 것임을 확인하였다.The material was confirmed to be the same as the product of Example 5 by thin layer chromatography, NMR and IR.
실시예 7Example 7
디클로페낙 알릴에스테르 2.5 g(7.4 mmol)을 메탄올 100 mL에 첨가하고, -60℃의 저온조를 설치한다. 반응용액이 -60℃에 이르면 오존을 불어넣어 -60℃에서 1시간 반응시키고, 유기용매를 감압농축한다. 그 잔류물에 98% 개미산 10 mL와 30% 과산화수소 5 mL를 첨가하여 실온에서 10시간 교반한다. 반응용액을 2시간 동안 환류 교반후 용매를 감압농축한다. 이 잔류물에 에틸에테르 50 mL와 물 50 mL로 추출하여 유기층을 취하고, 물 50 mL로 세척하였다. 유기층을 황산마그네슘으로 건조한 후 감압증류하여 제거하였다. 이 잔류물을 에틸아세테이트:헥산(2:1)의 혼합용매를 사용하여 실리카겔 칼럼크로마토그래피로 정제하여 흰색 결정의 목적화합물인 아세클로페낙 1.3 g을 얻었다(수득율: 50%).2.5 g (7.4 mmol) of diclofenac allyl ester are added to 100 mL of methanol and a low temperature bath at -60 ° C is set up. When the reaction solution reaches -60 ° C, ozone is blown to react at -60 ° C for 1 hour, and the organic solvent is concentrated under reduced pressure. 10 mL of 98% formic acid and 5 mL of 30% hydrogen peroxide are added to the residue, which is stirred for 10 hours at room temperature. After stirring the reaction solution under reflux for 2 hours, the solvent was concentrated under reduced pressure. The residue was extracted with 50 mL of ethyl ether and 50 mL of water, the organic layer was taken, and washed with 50 mL of water. The organic layer was dried over magnesium sulfate and removed by distillation under reduced pressure. This residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate: hexane (2: 1) to obtain 1.3 g of aceclofenac, a target compound of white crystals (yield: 50%).
상기물질은 박층크로마토그래피, NMR과 IR에 의하여 실시예 5의 생성물과 동일한 것임을 확인하였다.The material was confirmed to be the same as the product of Example 5 by thin layer chromatography, NMR and IR.
본 발명에 따르면 비스테로이성 소염진통제인 아세클로페낙을 짧은 시간의 반응을 통하여 제조할 수 있고, 저렴한 가격의 알릴알코올을 이용하여 쉽게 에스테르 반응시키고 간단한 장비와 일반적인 유기용매를 사용하여 경제적이며, 고 순도로 제조하는 방법을 제공하는 것이 가능하다.According to the present invention, aceclofenac, a non-steroidal anti-inflammatory analgesic, can be prepared through a short time reaction, can be easily ester-reacted using low-cost allyl alcohol, and economical and high purity using simple equipment and a general organic solvent. It is possible to provide a method for manufacturing.
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| KR100749162B1 (en) * | 2005-10-24 | 2007-08-14 | 주식회사 엔지켐 | Process for preparing aceclofenac aminoacid salt |
| KR102229969B1 (en) | 2019-02-13 | 2021-03-22 | 한국바이오켐제약 주식회사 | Methods for preparing aceclofenac and pharmaceutical composition comprising the same |
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