KR100297802B1 - Method for preparing 2- (3-trifluoromethyl) anilinonicotinic acid 2- (N-morpholine) ethyl. - Google Patents
Method for preparing 2- (3-trifluoromethyl) anilinonicotinic acid 2- (N-morpholine) ethyl. Download PDFInfo
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- KR100297802B1 KR100297802B1 KR1019980048631A KR19980048631A KR100297802B1 KR 100297802 B1 KR100297802 B1 KR 100297802B1 KR 1019980048631 A KR1019980048631 A KR 1019980048631A KR 19980048631 A KR19980048631 A KR 19980048631A KR 100297802 B1 KR100297802 B1 KR 100297802B1
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- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
본 발명은 2-(3-트리플루오로메틸)아닐리노니코틴산 2-(N-몰포린)에틸의 제조방법에 관한 것으로서, 더욱 상세하게는 2-(3-트리플루오로메틸)아닐리노니코틴산과 N-(2-클로로에틸)몰포린·염산염을 주원료로 사용하여 물과 유기용매가 특정함량비를 이루고 있는 혼합용매와 무기염기의 존재하에서 반응시키고, 반응물로부터 목적물을 회수하기 위해서는 간단한 여과과정만을 거쳐 고순도의 다음 화학식 1로 표시되는 2-(3-트리플루오로메틸)아닐리노니코틴산 2-(N-몰포린)에틸을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing 2- (N-morpholin) ethyl 2- (3-trifluoromethyl) anilinonicotinic acid, and more particularly to 2- (3-trifluoromethyl) anilinonicotinic acid. Using N- (2-chloroethyl) morpholine hydrochloride as the main raw material, the reaction is carried out in the presence of an inorganic base and a mixed solvent having a specific content ratio of water and an organic solvent. It relates to a method of producing 2- (N-morpholin) ethyl 2- (3-trifluoromethyl) anilinonicotinic acid represented by the following general formula (1) having high purity.
[화학식 1][Formula 1]
Description
본 발명은 2-(3-트리플루오로메틸)아닐리노니코틴산 2-(N-몰포린)에틸의 제조방법에 관한 것으로서, 더욱 상세하게는 2-(3-트리플루오로메틸)아닐리노니코틴산과 N-(2-클로로에틸)몰포릴·염산염을 주원료로 사용하여 물과 유기용매가 특정함량비를 이루고 있는 혼합용매와 무기염기의 존재하에서 반응시키고, 반응물로부터 목적물을 회수하기 위해서는 간단한 여과과정만을 거쳐 고순도의 다음 화학식 1로 표시되는 2-(3-트리플루오로메틸)아닐리노니코틴산 2-(N-몰포린)에틸을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing 2- (N-morpholin) ethyl 2- (3-trifluoromethyl) anilinonicotinic acid, and more particularly to 2- (3-trifluoromethyl) anilinonicotinic acid. Using N- (2-chloroethyl) morpholyl hydrochloride as the main raw material, water and an organic solvent react in the presence of a mixed solvent and an inorganic base having a specific content ratio. It relates to a method of producing 2- (N-morpholin) ethyl 2- (3-trifluoromethyl) anilinonicotinic acid represented by the following general formula (1) having high purity.
상기 화학식 1로 표시되는 2-(3-트리플루오로메틸)아닐리노니코틴산 2-(N-몰포린)에틸은 소염 진통제로 사용되는 의약품으로 널리 공지되어 있으며, 이는 다단계 제조공정을 거쳐 제조되므로 이의 제조수율이 매우 저조하여 경제성 및 효율성저하 등의 많은 문제점을 내포하고 있다.2- (3-trifluoromethyl) anilinonicotinic acid 2- (N-morpholine) ethyl represented by Chemical Formula 1 is widely known as a medicine used as an anti-inflammatory analgesic agent, and is prepared through a multi-step manufacturing process. The production yield is very low, which implies many problems such as economical efficiency and deterioration.
상기 화학식 1로 표시되는 화합물의 대표적인 종래의 제조방법으로는 다음과 같은 방법들이 있다.Representative conventional methods for preparing the compound represented by Formula 1 include the following methods.
프랑스특허 제7963M호에서는 다음 반응식 1에 나타낸 바와 같은 방법으로 화학식 1로 표시되는 화합물의 염산염을 제조하였다.In French Patent No. 7963M, hydrochloride of the compound represented by Formula 1 was prepared by the method shown in Scheme 1 below.
상기 반응식 1에 따르면, 상기 화학식 2로 표시되는 2-(3-트리플루오로메틸)아닐리노니코틴산과 상기 화학식 3a로 표시되는 N-(2-클로로에틸)몰포린을 이소프로판올 용매에서 반응시켜 상기 화학식 1a로 표시되는 염산염 화합물을 37%의 낮은 수율로 얻고 있다. 또한, 상기 화학식 1a로 표시되는 염샨염 화합물을 실제 적용하기 위해서는 중화과정을 거쳐 화학식 1로 표시되는 화합물로 전환시켜야 하는데, 중화 과정까지 수행하게 되면 수율은 더욱 낮아질 것이다.According to Scheme 1, 2- (3-trifluoromethyl) anilinonicotinic acid represented by Chemical Formula 2 and N- (2-chloroethyl) morpholine represented by Chemical Formula 3a may be reacted in an isopropanol solvent. The hydrochloride compound represented by 1a is obtained in a low yield of 37%. In addition, in order to actually apply the salt salt salt represented by the formula (1a) to be converted to the compound represented by the formula (1) after the neutralization process, the yield will be further lowered until the neutralization process.
또 다른 방법으로서, 프랑스특허 제2187317호에는 다음 반응식 2에 나타낸 방법으로 화학식 1a로 표시되는 염산염 형태의 화합물을 제조하였고, 또한 다음 반응식 3에 나타난 바와 같은 방법으로 화학식 1로 표시되는 화합물을 제조하였다.As another method, French Patent No. 2187317 prepared a compound of hydrochloride form represented by Formula 1a by the method shown in Scheme 2 below, and also a compound represented by Formula 1 by the method shown in Scheme 3 below. .
상기 반응식 2에 따른 제조방법에서는 상기 화학식 2b로 표시되는 2-(3-트리플루오로메틸)아닐리노니코티닐 클로라이드와 화학식 3b로 표시되는 4-몰포리노에탄올을 반응시켜서 목적물을 염산염의 형태로 합성하는데, 이 방법 역시 중화과정을 거쳐 화학식 1로 표시되는 화합물로 전환시켜야 하는 번거러움이 있다.In the preparation method according to Scheme 2, the desired product is synthesized in the form of hydrochloride by reacting 2- (3-trifluoromethyl) anilininonicotinyl chloride represented by Chemical Formula 2b with 4-morpholinoethanol represented by Chemical Formula 3b. This method, too, has to be converted to a compound represented by Chemical Formula 1 through a neutralization process.
상기 반응식 3은 반응식 1에 따른 종래 제법을 한층 개선시킨 발명으로서, 우선적으로 알칼리금속 알콕사이드와 같은 유기염기를 사용하여 상기 화학식 2로 표시되는 2-(3-트리플루오로메틸)아닐리노니코틴산을 알카리금속 염으로 전환시킨 다음, 이를 상기 화학식 3a로 표시되는 N-(2-클로로에틸)몰포린과 반응시켜 화학식 1로 표시되는 목적물을 얻고 있다.Scheme 3 is an invention further improving the conventional method according to Scheme 1, and preferentially alkalis 2- (3-trifluoromethyl) anilinononicotinic acid represented by Formula 2 by using an organic base such as an alkali metal alkoxide. After conversion to a metal salt, it was reacted with N- (2-chloroethyl) morpholine represented by Chemical Formula 3a to obtain a target compound represented by Chemical Formula 1.
그러나, 상기 반응식 3에 따른 방법에서는 화학식 2로 표시되는 화합물을 나트륨염으로 전환시키기 위하여 알칼리금속 알콕사이드를 사용하고 있는 바, 알칼리 금속 알콕사이드는 수분에 노출되어 쉽게 분해되는 특성이 있으므로 이를 이용한 전반응 공정은 공기나 수분의 접촉을 피해야만 하는 어려움이 있다. 예컨대, 반응식 3에서 염기로 적용하고 있는 소디움 에톡사이드의 경우 수분중에 노출되어 쉽게 폭발하는 특성을 가지는 나트륨금속(Na)을 사용하여 제조되고 있고, 수분과의 접촉에 의해 에탄올로 쉽게 분해되므로 이의 취급에 상당한 주의가 요구되므로 공업적으로 적용하기에는 매우 부적합하다.However, in the method according to Scheme 3, an alkali metal alkoxide is used to convert the compound represented by Chemical Formula 2 into sodium salt, and since the alkali metal alkoxide has a property of being easily decomposed due to exposure to water, a pre-reaction process using the same The difficulty is to avoid contact with air or moisture. For example, sodium ethoxide, which is used as a base in Scheme 3, is manufactured using sodium metal (Na), which is easily exploded due to exposure to water, and is easily decomposed into ethanol by contact with water. Significant care is required for the application, which is very unsuitable for industrial application.
또다른 방법으로서, 유럽 특허 제0349902호에는 다음 반응식 4와 5에 나타낸 바와 같은 방법으로 화학식 1로 표시되는 화합물을 제조하였다.As another method, European Patent No. 0349902 prepared a compound represented by Formula 1 by the method shown in Schemes 4 and 5.
상기 반응식 4에 따른 제조방법에서는 먼저, 상기 화학식 4로 표시되는 2-클로로니코티닐 클로라이드를 무수 톨루엔 용매 및 트리에틸아민과 같은 유기 염기존재하에서 상기 화학식 3b로 표시되는 4-몰포리노에탄올과 반응시켜 상기 화학식 5로 표시되는 2-클로로니코틴산 2-(N-몰포린)에틸을 합성하였다. 그리고, 상기 화학식 5로 표시되는 화합물에 상기 화학식 6으로 표시되는 트리플루오로아닐린을 도입하여 목적하는 상기 화학식 1의 화합물을 합성하고 있다. 그러나, 이 방법은 트리에틸아민과 같은 고가의 취급이 용이하지 않은 유기물을 사용할 뿐만 아니라 제조수율이 33% 이하로 매우 낮은 문제가 있다.In the preparation method according to Scheme 4, first, 2-chloronicotinyl chloride represented by Chemical Formula 4 is reacted with 4-morpholinoethanol represented by Chemical Formula 3b in the presence of an organic base such as anhydrous toluene solvent and triethylamine. 2-Chloronicotinic acid 2- (N-morpholine) ethyl represented by Chemical Formula 5 was synthesized. Then, the trifluoroaniline represented by the formula (6) is introduced into the compound represented by the formula (5) to synthesize the desired compound of the formula (1). However, this method not only uses expensive and inexpensive organic materials such as triethylamine, but also has a problem of a very low yield of 33% or less.
상기 반응식 5에 나타낸 방법에 의하면, 상기 화학식 4로 표시되는 2-클로로니코티닐 클로라이드를 출발 물질로 하여 이에 상응하는 메틸 에스테르로 전환시킨 후, 상기 화학식 6으로 표시되는 트리플루오로아닐린과 반응시켜 상기 화학식 7로 표시되는 2-(3-트리플루오로메틸)아닐리노니코틴산의 메틸 에스테르를 합성하였다. 그리고, 여기에 상기 화학식 3b로 표시되는 4-몰포리노에탄올을 트랜스에스테르화 반응시켜 목적으로 하는 상기 화학식 1로 표시되는 화합물을 합성하고 있다. 이 방법은 합성 단계가 길고, 합성 수율이 50% 이하로 매우 저조한 단점을 가지고 있다.According to the method shown in Scheme 5, the 2-chloronicotinyl chloride represented by the formula (4) as a starting material is converted to the corresponding methyl ester, and then reacted with trifluoroaniline represented by the formula (6) to A methyl ester of 2- (3-trifluoromethyl) anilinononicotinic acid represented by Formula 7 was synthesized. Then, a 4-morpholino ethanol represented by the above formula (3b) is transesterified to synthesize a compound represented by the above formula (1). This method has a long synthesis step and a very low synthesis yield of 50% or less.
이에, 본 발명에서는 상기 화학식 1로 표시되는 2-(3-트리플루오로메틸)아닐리노니코틴산 2-(N-몰포린)에틸을 합성함에 있어 수율을 향상시키고 유기용매의 사용을 최대한 배제시키면서도 반응 생성물로부터의 목적물의 회수가 용이하여 복잡한 정제공정이 필요치 않아 전체적인 제조수율이 크게 향상되는 제조방법을 개발하고자 노력하였다. 그 결과, 공업적 적용이 용이한 무기염기를 사용하여 수율을 대폭 향상시켰고, 특정화된 혼합용매계 선정으로 인하여 반응을 촉진하고, 추출 및 재결정과 같은 복잡한 정제공정 대신에 간단한 여과 공정만을 거쳐 고순도의 화합물을 제조함으로써 본 발명을 완성하였다.Thus, in the present invention, the synthesis of 2- (N-morpholine) ethyl 2- (3-trifluoromethyl) anilinonicotinic acid represented by Chemical Formula 1 is improved in yield and the use of organic solvents is minimized. Efforts have been made to develop a production method that greatly improves the overall production yield since the recovery of the target product from the product is not easy and a complicated purification process is not required. As a result, the use of inorganic base, which is easy to apply industrially, greatly improves the yield, and the reaction is promoted by the selection of a specialized mixed solvent system, and it is possible to obtain high purity through simple filtration instead of complex purification process such as extraction and recrystallization. The present invention has been completed by preparing the compound.
따라서, 본 발명은 경제성 및 환경 친화성이 우수하여 2-(3-트리플루오로메틸)아닐리노니코틴산 2-(N-몰포린)에틸의 공업적인 대량 생산에 유용한 신규 제조방법을 제공하는데 그 목적이 있다.Accordingly, the present invention is to provide a novel method for producing industrially-produced 2- (N-morpholine) ethyl 2- (3-trifluoromethyl) anilinonicotinic acid with excellent economical and environmental friendliness. There is this.
본 발명은 2-(3-트리플루오로메틸)아닐리노니코틴산과 몰포린 유도체를 축합반응시키고, 반응종료후에 반응용액으로부터 목적 화합물을 분리하는 방법에 있어서,The present invention provides a method of condensing a 2- (3-trifluoromethyl) anilinonicotinic acid with a morpholine derivative and separating the target compound from the reaction solution after completion of the reaction.
다음 화학식 2로 표시되는 2-(3-트리플루오로메틸)아닐리노니코틴산과 다음 화학식 3으로 표시되는 N-(2-클로로에틸)몰포린·염산염을 유기용매 : 물 = 6 : 4∼ 9 : 1 부피비로 함유된 혼합용매와 무기염기 존재하에서 축합반응시키고, 반응종료 후에는 반응용액에 물을 추가로 투입하여 유기용매 : 물의 부피비가 1 : 2.0∼ 1 : 2.5가 되게 하여 침전물을 생성시킨 후 생성된 침전물을 여과공정에 의해 회수하는 다음 화학식 1로 표시되는 2-(3-트리플루오로메틸)아닐리노니코틴산 2-(N-몰포린)에틸의 제조방법을 그 특징으로 한다.The organic solvent of 2- (3-trifluoromethyl) anilinonicotinic acid represented by the following formula (2) and N- (2-chloroethyl) morpholine hydrochloride represented by the following formula (3): water = 6: 4-9: Condensation reaction in the presence of 1 volume ratio of mixed solvent and inorganic base, after completion of the reaction to add water to the reaction solution to form a precipitate by the volume ratio of organic solvent: water of 1: 2.0 to 1: 2.5 It is characterized by a method for producing 2- (3-trifluoromethyl) anilinononicotinic acid 2- (N-morpholine) ethyl represented by the following formula (1) in which the resulting precipitate is recovered by filtration.
[화학식 1][Formula 1]
이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.
본 발명은 상기 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응사켜 상기 화학식 1로 표시되는 화합물을 제조하되, 최소량의 유기용매와 과량의 물이 혼합되어 있는 혼합용매계 및 무기염기 조건하에서 반응을 수행하여, 반응시간을 단축시키면서도, 제조수율이 향상되고, 정제공정을 용이하게 하는 공업적으로 유리한 상기 화학식 1로 표시되는 화합물의 제조방법에 관한 것이다.The present invention is prepared by reacting the compound represented by Formula 2 with the compound represented by Formula 3 to prepare a compound represented by Formula 1, mixed solvent system and inorganic base conditions in which a minimum amount of organic solvent and excess water is mixed The present invention relates to a process for producing a compound represented by Chemical Formula 1, which is industrially advantageous in that the production yield is improved while the reaction time is shortened and the reaction time is shortened.
본 발명에 따른 제조방법을 간략히 나타내면 다음 반응식 6과 같다.Briefly showing the production method according to the invention it is shown in Scheme 6.
상기 반응식 6에 나타낸 바와 같이, 본 발명에서는 상기 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 N-(2-클로로에틸)몰포린·염산염을 물과 유기용매의 혼합용매내에서 그리고 무기염기 존재하에 가열 교반 반응시켜 목적으로 하는 상기 화학식 1로 표시되는 화합물을 얻는다.As shown in Scheme 6, in the present invention, the compound represented by the formula (2) and the N- (2-chloroethyl) morpholine hydrochloride represented by the formula (3) are present in a mixed solvent of water and an organic solvent, and an inorganic base is present. The resulting mixture is heated and stirred to obtain a compound represented by the above formula (1).
본 발명에서는 반응을 수행함에 있어 반응염기를 사용하여 축합반응과 동시에 중화반응을 수행하여 상기 화학식 1로 표시되는 바와 같이 중화된 상태의 최종생성물을 얻고 있으며, 이로써 종래 제조방법이 염산염 형태로 목적물을 수득하여 별도의 중화공정을 거쳐야 하는 제조방법상의 문제점을 해결하였고, 수율상으로도 월등히 향상된 효과를 보였다. 또한, 반응염기의 종류에 있어서도 종래의 소디움 에톡사이드와 같이 취급상에 문제시 되어온 유기염기를 대신하여 취급이 용이한 무기염기를 선택 사용하고 있어 공업적으로 적용하기에 유리한 장점을 가진다.In the present invention, the neutralization reaction is carried out simultaneously with the condensation reaction using the reaction base to obtain the final product in a neutralized state as represented by the formula (1). Obtained and solved the problem of the manufacturing method to go through a separate neutralization process, and showed a much improved effect in yield. In addition, in the type of reactive base, an inorganic base that is easy to handle is selected in place of an organic base that has been a problem in handling, such as sodium ethoxide, which is advantageous for industrial application.
한편, 본 발명에서는 상기 화학식 3으로 표시되는 화합물을 염산염의 형태로 사용하는 것을 또다른 특징으로하는 바, 화학식 3a로 표시되는 N-(2-클로로에틸)몰포린과 비교해볼 때 화학적 구조상으로는 흡사해보지만 반응용매의 선택에 있어 커다란 차이를 보인다. 예컨대, 화학식 3a로 표시되는 N-(2-클로로에틸)몰포린이 유기용매에 대한 용해도가 높고 물에는 잘 녹지 않는 특성을 가지는데 반하여, 화학식 3으로 표시되는 이의 염산염은 이와는 상반되는 용해특성을 나타낸다.On the other hand, the present invention is characterized by another use of the compound represented by the formula (3) in the form of a hydrochloride, in terms of chemical structure compared to the N- (2-chloroethyl) morpholine represented by the formula (3a) However, there is a big difference in the choice of reaction solvent. For example, while N- (2-chloroethyl) morpholine represented by Chemical Formula 3a has a high solubility in organic solvents and is insoluble in water, its hydrochloride salt represented by Chemical Formula 3 has opposite solubility characteristics. Indicates.
한편, 본 발명은 반응용매계에서도 또다른 특징이 있다. 본 발명에서는 유기용매와 물을 적정비로 함께 사용하여 반응을 촉진시므로써 반응시간을 2시간 이내에 크게 단축시킴은 물론이고 이에 따른 상승효과로 제조수율까지도 향상시키는 기대 이상의 또다른 효과를 얻고 있다. 즉, 유기용매 단독사용에서는 반응원료물질로 사용되는 화학식 2로 표시되는 화합물은 쉽게 용해되지만 화학식 3으로 표시되는 화합물과 무기염기는 용해되지 않아 고-액체상에서 반응이 진행되어 반응온도를 환류조건으로 유지시켜야만 하고, 그 반응속도도 매우 느리다. 그러나, 유기용매와 물이 적정량 혼합된 혼합용매계에서는 화학식 2로 표시되는 화합물은 유기용매에 의해 용해되고 화학식 3으로 표시되는 화합물과 무기염기는 물에 의해 용해되어 액체상에서 반응이 진행되어 환류조건이 아니더라도 반응속도가 빨라져 반응시간을 크게 단축시킬 수 있었다. 결국, 혼합용매계에서의 반응은 온화한 조건(mild condition)하에서 원활하게 수행되므로 목적물에 대한 수율 역시 증가하게 된다.On the other hand, the present invention also has another feature in the reaction solvent system. In the present invention, by using the organic solvent and water together in an appropriate ratio to promote the reaction, the reaction time is greatly shortened within 2 hours, as well as the synergistic effect, thereby obtaining another effect than expected. That is, in the organic solvent alone, the compound represented by Chemical Formula 2, which is used as a reaction raw material, is easily dissolved, but the compound represented by Chemical Formula 3 and the inorganic base are not dissolved, so that the reaction proceeds in a high-liquid phase and the reaction temperature is reduced to reflux conditions. It must be maintained and the reaction rate is very slow. However, in a mixed solvent system in which an appropriate amount of organic solvent and water are mixed, the compound represented by Chemical Formula 2 is dissolved by the organic solvent, and the compound represented by Chemical Formula 3 and the inorganic base are dissolved by water, and the reaction proceeds in a liquid phase to reflux conditions. Even if not, the reaction rate was faster, and the reaction time could be greatly shortened. As a result, the reaction in the mixed solvent system is smoothly performed under mild conditions, so that the yield of the target product is also increased.
또한, 본 발명이 상기한 바와 같은 혼합용매계를 적용하므로써 기존 유기용매계에서 사용된 유기용매의 양을 최대 40%까지 물로 대체가 가능하므로 원료비 절감 및 폐수처리 측면에서도 매우 유리한 효과를 가진다.In addition, since the present invention can replace the amount of the organic solvent used in the existing organic solvent system up to 40% by applying the mixed solvent system as described above has a very advantageous effect in terms of raw material cost reduction and waste water treatment.
이상에서 설명한 바와 같은 본 발명의 제조방법을 보다 자세히 설명하면 다음과 같다.Referring to the manufacturing method of the present invention as described in more detail as follows.
상기 화학식 3으로 표시되는 N-(2-클로로에틸)몰포린·염산염은 화학식 2로 표시되는 화합물에 대하여 1.0 내지 1.2 당량비내에서 투입되는 것이 바람직하다.The N- (2-chloroethyl) morpholine hydrochloride represented by the formula (3) is preferably added in an amount of 1.0 to 1.2 equivalents relative to the compound represented by the formula (2).
한편, 본 발명에 따른 용매계에서 물과 함께 사용될 수 있는 유기용매로는 통상적으로 물과 자유로이 섞이는 것이라면 모두 사용될 수 있고, 특히 바람직하기로는 아세톤, 아세토니트릴, 탄소원자수 1 내지 5의 저급알콜 및 디메틸포름아미드중에서 선택하여 사용하는 것이다. 반응용매로서 유기용매와 물의 혼합용매는 유기용매 : 물의 부피비가 6 : 4 ∼ 9 : 1를 유지하도록 하는 것이 바람직한 바, 상기 범위를 초과하여 과량의 유기용매가 사용되면 반응속도가 느려져 반응시간이 길어지고 유기물질의 사용을 제한하고자하는 본 발명의 목적에 어긋나고, 반면에 상기 범위 미만의 소량의 유기용매가 사용되면 제조수율이 감소하고 목적물의 순도가 저하되는 문제가 있다.On the other hand, the organic solvent that can be used with water in the solvent system according to the present invention can be used as long as it is usually freely mixed with water, and particularly preferably acetone, acetonitrile, lower alcohol of 1 to 5 carbon atoms and dimethyl It is used by selecting from formamide. As a reaction solvent, the mixed solvent of organic solvent and water is preferably maintained in a volume ratio of organic solvent: water of 6: 4 to 9: 1. When an excess of organic solvent is used in excess of the above range, the reaction rate is slowed down. It is contrary to the object of the present invention to lengthen and limit the use of organic materials, while on the other hand, when a small amount of the organic solvent below the above range is used, there is a problem that the production yield is reduced and the purity of the target product is lowered.
상기 반응에서 사용하는 무기염기는 수산화나트륨, 수산화칼륨 등의 알칼리금속 수산화물 및 탄산나트륨, 탄산칼륨 등의 알칼리금속 탄산염 중에서 선택 사용하며, 이는 화학식 2로 표시되는 화합물에 대하여 1.0 ∼ 1.7 당량비 범위내에서 투입되는 것이 바람직하다. 반응 온도는 40 ∼ 100℃ 바람직하기로는 70 ∼ 80℃를 유지하며, 반응시간은 2시간이면 충분하다.The inorganic base used in the reaction is selected from alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate, which is added within the range of 1.0 to 1.7 equivalents relative to the compound represented by the formula (2). It is desirable to be. The reaction temperature is preferably 40 to 100 ° C, preferably 70 to 80 ° C, and the reaction time is sufficient for 2 hours.
상기 반응이 완료되면 반응 용액중에 녹아 있는 상기 화학식 1로 표시되는 목적 화합물을 고형물로 석출시키기 위하여, 본 발명에서는 반응용액에 유기용매에 대한 물의 총비율이 1 : 2 ∼ 2.5 부피비가 되도록 물을 추가로 투입하여 침전물을 생성시키고, 생성된 침전물을 여과하고 건조시키는 정제과정을 수행한다.When the reaction is completed, in order to precipitate the target compound represented by the formula (1) dissolved in the reaction solution as a solid, in the present invention, water is added to the reaction solution so that the total ratio of water to organic solvent is 1: 2 to 2.5 by volume. The precipitate was added to produce a precipitate, and the purified precipitate was filtered and dried.
본 발명에 따른 제조방법이 특별한 정제과정을 필요로 하지 않는데는 반응용매의 선택에 가장 큰 이유가 있다. 또한 반응용액으로부터 목적물을 회수함에 있어서도 유기용매와 물의 비율이 약 1 : 2 ∼ 2.5 부피비를 유지할 때, 반응 중간체로 생성되는 2-(3-트리플루오로메틸)아닐리노니코틴산의 금속염은 물에 용해되고, N-(2-클로로에틸)몰포린은 유기용매에 용해되며, 반응 부생물인 염화나트륨 또는 염화칼륨과 같은 금속염은 물에 용해되고, 이산화 탄소는 기체로 존재하게 되므로, 목적 생성물만이 고체로 존재할 수 있으므로 복잡한 정제과정 없이도 고순도의 목적물을 제조할 수 있다.The production method according to the present invention does not require a special purification process is the biggest reason for the selection of the reaction solvent. Also, in recovering the target product from the reaction solution, the metal salt of 2- (3-trifluoromethyl) anilinonicotinic acid produced as a reaction intermediate is dissolved in water when the ratio of organic solvent and water is maintained at a volume ratio of about 1: 2 to 2.5. N- (2-chloroethyl) morpholine is dissolved in an organic solvent, and metal salts such as sodium chloride or potassium chloride, which are reaction by-products, are dissolved in water, and carbon dioxide is present as a gas. It can be present, so that a high purity target can be prepared without complicated purification.
상기와 같은 축합공정 및 정제공정에 의한 결과, 99% 이상의 고순도의 목적화합물이 90% 이상의 고수율로 제조된다.As a result of the condensation process and the purification process as described above, a target compound having a high purity of 99% or more is produced in a high yield of 90% or more.
이상에서 살펴본 바와 같이, 본 발명의 제조방법에 따른 제조 수율은 90% 이상으로 경제성을 향상시켰고, 저수율에 따른 폐기물이 다량 발생하여 처리 비용이 많이 드는 단점을 개선하였으며, 나트륨금속 등과 같은 독성이 강하거나 폭발의 위험이 있는 원료를 사용하지 않음으로써 산업화시 작업성을 편리하게 하고 설비투자비를 감소시켰으며, 유기염기와 유기용매와 같은 유기 물질의 사용량은 최대한 감소시켜 환경오염배출을 최소화시켰다.As described above, the manufacturing yield according to the manufacturing method of the present invention improved the economical efficiency to more than 90%, a large amount of waste generated according to the low yield improved the disadvantages of high processing cost, strong toxicity such as sodium metal By not using raw materials with the risk of explosion or explosiveness, it facilitates workability during industrialization and reduces the capital investment cost, and minimizes the environmental pollution by minimizing the use of organic materials such as organic base and organic solvent.
이와 같은 본 발명은 다음의 실시예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 실시예에 한정되는 것은 아니다.Such a present invention will be described in more detail based on the following examples, but the present invention is not limited to the examples.
[실시예]EXAMPLE
[2-(3-트리플루오로메틸)아닐리노니코틴산-2-(N-몰포린)에틸의 합성][Synthesis of 2- (3-trifluoromethyl) anilinonicotinic acid-2- (N-morpholine) ethyl]
교반기, 환류기 및 온도계가 장치된 3ℓ 반응기에 2-(3-트리플루오로메틸)아닐리노니코틴산(282 g, 1 mol), N-(2-클로로에틸)몰포린·염산염(204.7 g, 1.1 mol) 및 탄산수소나트륨(91.4 g, 1.1 mol)을 넣은 다음, 반응용매로서 물(100 ㎖)과 디메틸포름아미드(900 ㎖)를 각각 주입하고 서서히 온도를 가열하여 80℃에서 1시간 동안 가열하였다. 반응이 완료되면, 물(2.15 ℓ)을 주입하여 반응을 종료시킨 후 서서히 실온으로 냉각하고, 이 반응 현탄액을 약 1시간 숙성하였다. 반응기 기벽에 고체가 생성되는 것을 확인하고 약 30분간 추가 숙성하였다. 반응물을 여과하고, 물로 세척하여 결정성 분말의 2-(3-트리플루오로메틸)아닐리노니코틴산 2-(N-몰포린)에틸 375 g(0.95 mol, 수율 95%)을 얻었다.2- (3-trifluoromethyl) anilinonicotinic acid (282 g, 1 mol), N- (2-chloroethyl) morpholine hydrochloride (204.7 g, 1.1) in a 3 liter reactor equipped with a stirrer, reflux and thermometer mol) and sodium hydrogen carbonate (91.4 g, 1.1 mol) were added, followed by pouring water (100 mL) and dimethylformamide (900 mL) as reaction solvents, respectively, and gradually heating the temperature to 80 ° C. for 1 hour. . After the reaction was completed, water (2.15 L) was injected to terminate the reaction, and then gradually cooled to room temperature. The reaction suspension was aged for about 1 hour. It was confirmed that solids formed on the reactor wall and further aged for about 30 minutes. The reaction was filtered and washed with water to give 375 g (0.95 mol, 95% yield) of 2- (3-trifluoromethyl) anilinonicotinic acid 2- (N-morpholine) ethyl as crystalline powder.
융점 : 75.5 ∼ 76.5℃Melting Point: 75.5 ~ 76.5 ℃
1H NMR(아세톤-d6, ppm) : δ2.5(t, 4H), 2.7(t, 2H), 3.7(t, 4H), 4.5(t, 2H), 6.7(q, 1H), 7.2(d, 1H), 7,4(t, 1H), 7.8(d, 1H), 8.0(s, 1H), 8.2(q, 1H), 8.4(q, 1H), 10.3(s, 1H) 1 H NMR (acetone-d 6 , ppm): δ2.5 (t, 4H), 2.7 (t, 2H), 3.7 (t, 4H), 4.5 (t, 2H), 6.7 (q, 1H), 7.2 (d, 1H), 7,4 (t, 1H), 7.8 (d, 1H), 8.0 (s, 1H), 8.2 (q, 1H), 8.4 (q, 1H), 10.3 (s, 1H)
다음 표 1은 상기 실시예와 동일한 방법으로 수행하되, 다만 반응용매계를 달리하여 수행한 결과를 나타낸 것이다.The following Table 1 is carried out in the same manner as in the above example, but shows the result of performing by different reaction solvent system.
상기 표 1의 결과에 따르면, 본 발명에 따라 혼합용매계를 적용하고 있는 실시예 1 내지 5는 전반적으로 제조수율 90% 이상 및 99% 이상의 고순도를 나타내는데 반하여, 물 용매를 사용하고 있는 비교예 1은 제조수율 및 순도가 저하되는 단점이 지적되고, 유기용매를 사용하고 있는 비교예 2는 반응시간이 장기화되는 단점이 지적되었다.According to the results of Table 1, Examples 1 to 5 to which the mixed solvent system is applied according to the present invention generally show a production yield of 90% or more and 99% or more of high purity, while Comparative Example 1 using a water solvent. Silver production yield and purity is pointed out the disadvantages, Comparative Example 2 using an organic solvent was pointed out that the reaction time is prolonged.
다음 표 2는 상기 실시예와 동일한 방법으로 수행하되, 다만 염기의 종류를 달리 사용하였다.The following Table 2 was carried out in the same manner as in the above example, but used different kinds of bases.
다음 표 3은 상기 실시예와 동일한 방법으로 수행하되, 다만 반응온도를 달리 하였다.Table 3 is carried out in the same manner as in the above example, but the reaction temperature was different.
[참조예 1]Reference Example 1
[반응식 1에 따른 제법][Preparation according to Scheme 1]
반응기에 2-(3-트리플루오로메틸)아닐리노니코틴산(12.5 g, 0.044 mol)과 N-(2-클로로에틸)몰포린(10.2 g, 0.068 mol) 및 이소프로판올 용매(25 ㎖)를 투입하고 8시간동안 환류시켰다. 이를 이소프로판올에서 재결정하여 2-(3-트리플루오로메틸)아닐리노니코틴산 2-(N-몰포린)에틸 염산염 6.6 g(수율 35%, 순도 98%)을 수득하였다. 얻어진, 2-(3-트리플루오로메틸)아닐리노니코틴산 2-(N-몰포린)에틸 염산염(6.65 g, 0.015 mol)을 탄산 나트륨(2.4 g, 0.022 mol)이 녹아 있는 물 50m1-에테르 70m1의 혼합 용매에서 30분동안 중화 반응 시키고, 이 용액을 분별 깔때기로 옮겼다. 이를 에테르 50m1로 2회 추출하고, 유기층을 분리한 후 황산 마그네슘 1g으로 수분을 거하고, 여과하여 얻어진 용액을 감압화에서 용매(에테르)를 제거하여, 2-(3-트리플루오로메틸)아닐리노니코틴산 2-(N-몰포린)에틸 5.5 g(수율 31.6%, 순도 95.7%)을 얻었다.Into the reactor, 2- (3-trifluoromethyl) anilinonicotinic acid (12.5 g, 0.044 mol), N- (2-chloroethyl) morpholine (10.2 g, 0.068 mol) and isopropanol solvent (25 mL) were charged. It was refluxed for 8 hours. This was recrystallized in isopropanol to give 6.6 g (yield 35%, purity 98%) of 2- (3-trifluoromethyl) anilinonicotinic acid 2- (N-morpholine) ethyl hydrochloride. The obtained 2- (3-trifluoromethyl) anilinonicotinic acid 2- (N-morpholine) ethyl hydrochloride (6.65 g, 0.015 mol) was dissolved in sodium carbonate (2.4 g, 0.022 mol) in 50m1-ether 70m1. The reaction was neutralized in a mixed solvent for 30 minutes, and the solution was transferred to a separatory funnel. The mixture was extracted twice with 50 ml of ether, the organic layer was separated, and then dried over 1 g of magnesium sulfate, and the resulting solution was filtered to remove the solvent (ether) under reduced pressure, thereby obtaining 2- (3-trifluoromethyl) anile. 5.5 g (yield 31.6%, purity 95.7%) of linononicotinic acid 2- (N-morpholine) ethyl were obtained.
[참조예 2]Reference Example 2
[반응식 3에 따른 제법][Preparation according to Scheme 3]
반응기에 나트륨금속(28 g)과 에탄올(850 mol)을 투입하여 소디움 에톡사이드를 형성시켰다. 여기에 2-(3-트리플루오로메틸)아닐리노니코틴산(295 g, 1.04 mol)을 투입하여 상응하는 나트륨염을 형성시켰다. 에탄올을 감압제거하고, 잔류한 나트륨염을 N-(2-클로로에틸)몰포린(191 g, 1.27 mol)이 녹아있는 톨루엔 용액에 투입하였다. 3시간 30분동안 반응용액을 환류시킨 후, 여과하여 NaCl을 제거하였고 여과액은 감압하에서 용매를 제거하여 2-(3-트리플루오로메틸)아닐리노니코틴산 2-(N-몰포린)에틸 343g(수율 83%, 순도 96.5%)을 얻었다.Sodium metal (28 g) and ethanol (850 mol) were added to the reactor to form sodium ethoxide. 2- (3-trifluoromethyl) anilinonicotinic acid (295 g, 1.04 mol) was added thereto to form a corresponding sodium salt. Ethanol was removed under reduced pressure, and the remaining sodium salt was added to a toluene solution containing N- (2-chloroethyl) morpholine (191 g, 1.27 mol). The reaction solution was refluxed for 3 hours and 30 minutes, and then filtered to remove NaCl, and the filtrate was removed under reduced pressure to remove 3 (3 g of 2- (N-morpholine) ethyl 2- (3-trifluoromethyl) anilinonicotinic acid). (Yield 83%, Purity 96.5%) were obtained.
이상에서 설명한 바와 같이, 본 발명에 따른 제조방법은 종래 제조방법으로 제시된 참조예 1 및 참조예 2에 비교하여 그 제조공정이 단순하며 제조수율도 크게 향상된 결과를 나타내는 바, 이는 본 발명이 특정 반응용매계 및 특정 무기염기 선정에 따른 것이다.As described above, the manufacturing method according to the present invention shows a result that the manufacturing process is simple and the production yield is greatly improved as compared with Reference Example 1 and Reference Example 2, which are presented as conventional manufacturing methods, which is a specific reaction of the present invention. Solvent system and specific inorganic base selection.
따라서, 본 발명의 2-(3-트리플루오로메틸)아닐리노니코틴산 2-(N-몰포린)에틸의 제조방법은 간단한 정제공정으로도 고순도 제품 취득이 가능하므로 공정면이나 경제적인 측면 및 환경 친화적인 측면에서 유리한 잇점이 있다.Therefore, the preparation method of 2- (3-trifluoromethyl) anilinonicotinic acid 2- (N-morpholine) ethyl of the present invention can obtain a high-purity product even by a simple purification process. There is an advantage in terms of friendliness.
Claims (4)
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| KR1019980048631A KR100297802B1 (en) | 1998-11-13 | 1998-11-13 | Method for preparing 2- (3-trifluoromethyl) anilinonicotinic acid 2- (N-morpholine) ethyl. |
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| KR1019980048631A KR100297802B1 (en) | 1998-11-13 | 1998-11-13 | Method for preparing 2- (3-trifluoromethyl) anilinonicotinic acid 2- (N-morpholine) ethyl. |
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