KR20100114833A - METHOD FOR PREPARATION OF γ-THUJAPLICIN - Google Patents
METHOD FOR PREPARATION OF γ-THUJAPLICIN Download PDFInfo
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- KR20100114833A KR20100114833A KR1020100033584A KR20100033584A KR20100114833A KR 20100114833 A KR20100114833 A KR 20100114833A KR 1020100033584 A KR1020100033584 A KR 1020100033584A KR 20100033584 A KR20100033584 A KR 20100033584A KR 20100114833 A KR20100114833 A KR 20100114833A
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- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
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- C07C49/385—Saturated compounds containing a keto group being part of a ring
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- C07C49/527—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings
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- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
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Abstract
Description
본 발명은 의약의 중간체로서 유용한 γ―투야플리신의 제조방법에 관한 것이다.The present invention relates to a method for producing γ-tuyaplisin, which is useful as an intermediate of medicine.
γ―투야플리신[5-이소프로필트로폴론]은, 아오모리 노송나무의 잎이나 대만 노송나무의 정유(精油) 중에 포함되는 천연물로, 항균·항곰팡이 작용을 갖는 트로폴론 유연체(類緣體)이다. 또한, 항궤양제인 에구알렌나트륨의 제조 중간체이다. 이 γ―투야플리신의 제조방법에 관해서는, 다음에 나타내는 바와 같은 제조방법이 보고되어 있다. 즉,γ-tuyaplicin [5-isopropyltropolone] is a natural product contained in the leaves of Aomori cypress and essential oil of Taiwan cypress, and is a tropolone flexible body having antibacterial and antifungal action. )to be. Moreover, it is the manufacturing intermediate of sodium eguallen which is an anti-ulcer agent. As for the method for producing γ-tuyaplisin, a production method as shown below has been reported. In other words,
(1) 빙초산 중, 2-클로로-5-이소프로필트로폰을 인산과 함꼐 환류하여 γ―투야플리신을 합성하는 방법이 보고되어 있다(비특허문헌 1). 또한, 이 2-클로로-5-이소프로필트로폰을, 4-이소프로필아니솔을 출발원료로 하여 합성하는 방법이 제안되어 있다(특허문헌 1). 이 방법은, 다단계(5공정)이며, 초저온반응을 포함하고 있다. 또한, 위험한 시약을 사용하기 때문에, 조작적으로 위험을 수반한다. 또한, 4-이소프로필아니솔이 고가이다.(1) In glacial acetic acid, a method of synthesizing γ-tuyaplicin by refluxing 2-chloro-5-isopropyltropon with phosphoric acid has been reported (Non-Patent Document 1). Moreover, the method of synthesize | combining this 2-chloro-5-isopropyl tropon as a starting material as 4-isopropyl anisole is proposed (patent document 1). This method is multistage (five steps) and contains the cryogenic reaction. In addition, since dangerous reagents are used, they are dangerously operated. In addition, 4-isopropylanisole is expensive.
(2) 시클로펜타디엔과 그리냐르 시약(에틸마그네슘 브로마이드)을 테트라히드로푸란용매 중, 용매 환류온도에서 반응시킨 후, 이소프로필토실레이트를 반응시켜서 이소프로필시클로펜타디엔을 얻는다. 이 이소프로필시클로펜타디엔에 디클로로케텐을 부가반응시킨 후 염기성 조건하에서 가용매분해하고, 이 조(粗)가용매분해 생성물을 산성으로 하여 트로폴론화합물을 석출시킨다. 이 석출된 트로폴론화합물을 칼럼크로마토그래피에 의해 γ―투야플리신과 그의 이성체인 β―투야플리신을 분리하여, γ―투야플리신을 얻는 방법이 보고되어 있다(비특허문헌 2). 칼럼크로마토그래피를 공업적으로 실시하는데 있어서는, 생산성 및 생산 비용에 문제가 발생한다. 예를 들면, 대량의 용매를 사용하거나, 흡착제의 재생, 처리 등 번잡한 조작이 필요해지는 등, 정제 비용이 비싸져, 공업적으로는 바람직하지 못하다.(2) After cyclopentadiene and Grignard reagent (ethylmagnesium bromide) are reacted at a solvent reflux temperature in a tetrahydrofuran solvent, isopropyltosylate is reacted to obtain isopropylcyclopentadiene. After addition reaction of dichloroketene to this isopropylcyclopentadiene, solvolysis is carried out under basic conditions, and the crude solvolysis product is made acidic to precipitate a tropolone compound. It has been reported that this precipitated tropolone compound separates gamma -tuyaplicin and its isomer β-tuyaflicin by column chromatography to obtain gamma -tuyaplicin (Non-Patent Document 2). In performing column chromatography industrially, problems arise in productivity and production cost. For example, purification costs are high, such as using a large amount of solvent, complicated operations such as regeneration and treatment of the adsorbent, and the like.
(3) 히노키티올(β―투야플리신)의 제조방법으로서, 시클로펜타디엔과 알칼리금속으로부터 시클로펜타디에닐 금속을 조제하는 공정, 그 시클로펜타디에닐 금속과 이소프로필화제를 반응시켜서, 이소프로필시클로펜타디엔을 취득하는 공정, 그 이소프로필시클로펜타디엔 중의 5-이소프로필시클로펜타디엔을 1-이소프로필시클로펜타디엔으로 선택적으로 이성화(異性化)하는 공정, 그 1-이소프로필시클로펜타디엔과 디할로케텐을 반응시켜서 케텐 부가체를 얻는 공정, 그 케텐 부가체를 분해하는 공정으로 되는 히노키티올의 제조방법이 제안되어 있다(특허문헌 2).(3) A method for producing a hinokithiol (β-tuyaplicin), comprising the steps of preparing a cyclopentadienyl metal from a cyclopentadiene and an alkali metal, reacting the cyclopentadienyl metal with an isopropylating agent, and isopropyl A step of obtaining cyclopentadiene, a step of selectively isomerizing 5-isopropylcyclopentadiene in the isopropylcyclopentadiene to 1-isopropylcyclopentadiene, the 1-isopropylcyclopentadiene and There is proposed a method for producing a hinokithiol which is a step of reacting dihaloketen to obtain a ketene adduct and a step of decomposing the ketene adduct (Patent Document 2).
(4) 치환 또는 비치환의 시클로펜타디엔과 디클로로케텐을 부가반응시켜서, 7,7-디클로로비시클로[3.2.0]-헵트-2-엔-온 화합물을 얻고, 이것을 염기의 존재하 분해하여 트로폴론화합물을 제조할 때, 상기 화합물을 염기의 존재하 분해하기 전에 감압 증류 정제하는 공정, 및 염기의 존재하 분해하여 얻은 조(粗)트로폴론화합물을 증류와 정석(晶析)에 의해 정제하는 공정을 행하여 트로폴론화합물, 특히 β―투야플리신을 제조하는 방법이 제안되어 있다(특허문헌 3). 또한, 시클로펜타디엔류와 디클로로케텐을 반응하여 얻은 디클로로케텐 부가체를 가용매분해하여 얻어진 조트로폴론화합물을, 특정 용해도 파라미터의 용매를 사용하여 정석하는 조트로폴론화합물의 정제방법이 제안되어 있다(특허문헌 4).(4) By reacting a substituted or unsubstituted cyclopentadiene with dichloroketene to obtain a 7,7-dichlorobicyclo [3.2.0] -hept-2-en-one compound, which is decomposed in the presence of a base When preparing a polylon compound, a step of distilling under reduced pressure before decomposing the compound in the presence of a base, and refining the crude tropolone compound obtained by decomposing in the presence of a base by distillation and crystallization A method of producing a tropolone compound, in particular β-tuyaplicin, by performing a step has been proposed (Patent Document 3). In addition, a method for purifying a zoropollon compound in which a zotropolone compound obtained by solvolysis of a dichloroketene adduct obtained by reacting cyclopentadienes with dichloroketene is crystallized using a solvent having a specific solubility parameter has been proposed. (Patent Document 4).
상기 (2)~(4)의 제조방법에서 보는 바와 같이, γ―투야플리신이 속하는 트로폴론화합물의 제조에서는, 종래, 시클로펜타디엔을 출발원료로 하고, 여기에 이소프로필화제를 반응시켜서 이소프로필시클로펜타디엔을 합성하고, 추가적으로 디클로로케텐을 반응시켜서 케텐 부가체를 합성하고, 이 케텐 부가체를 가용매분해하여 얻은 조트로폴론화합물의 혼합물을 정제하여 트로폴론화합물 혼합물로 이루며, 이 혼합물로부터 목적의 트로폴론화합물을 분리하고 있다. 그러나, 상기 이소프로필시클로펜타디엔을 얻을 때, N,N-디메틸포름아미드 중에서, 시클로펜타디엔과 나트륨아미드를 반응시켜서 나트륨 시클로펜타디에닐리드를 합성하고, 여기에 이소프로필화제를 반응시킴으로써, 이소프로필시클로펜타디엔의 평형 혼합물을 수율 좋게, 또한 재현성 좋게 얻는 방법은 알려져 있지 않다. 또한, 조트로폴론화합물을 증류나 정석에 의해 정제하는 것은 알려져 있으나, 이 조트로폴론화합물의 혼합물로부터, γ―투야플리신을 정석에 의해 분리하는 것은 알려져 있지 않다.As shown in the manufacturing method of said (2)-(4), in the manufacture of the tropolone compound which gamma-tuyaplicin belongs, conventionally, cyclopentadiene is used as a starting material, and isopropylating agent is made to react here, and isopropyl. Synthesizing cyclopentadiene and further reacting dichloroketene to synthesize a ketene adduct, purifying the mixture of the zotropolone compound obtained by solubilizing this ketene adduct to form a tropolone compound mixture, and from this mixture Separation of the tropolone compound. However, when obtaining the said isopropyl cyclopentadiene, sodium cyclopentadienide is synthesize | combined by making cyclopentadiene and sodium amide react in N, N- dimethylformamide, and isopropylating agent is made to react here, It is not known how to obtain the equilibrium mixture of propylcyclopentadiene with high yield and reproducibility. It is also known to distill or refine the zotropolone compound by crystallization, but it is not known to separate γ-tuyaplicin from the mixture of the zotropolone compound by crystallization.
또한, 나트륨 시클로펜타디에닐리드의 조제법으로서는, (i) 액체 암모니아 중에서, 금속 나트륨과 시클로펜타디엔을 반응하는 방법(비특허문헌 3), (ii) 디메톡시에탄이나 디글라임 등의 유기용매 중에서, 금속 나트륨과 시클로펜타디엔을 반응하는 방법(비특허문헌 4), (iii) 테트라히드로푸란용매 중에서, 수소화나트륨과 시클로펜타디엔을 반응하는 방법(특허문헌 5) 등이 알려져 있다. 그러나, 시클로펜타디엔과 나트륨아미드를 반응시켜서 나트륨 시클로펜타디에닐리드를 얻는 것은 알려져 있지 않고, 이 반응을 N,N-디메틸포름아미드용매 중에서 행하는 것도 알려져 있지 않다.Moreover, as a preparation method of sodium cyclopentadienide, (i) the method of reacting metal sodium and cyclopentadiene in liquid ammonia (nonpatent literature 3), (ii) in organic solvents, such as dimethoxyethane and diglyme The method of reacting a sodium hydride and a cyclopentadiene (patent document 5) etc. are known in the method of reacting metal sodium and cyclopentadiene (nonpatent literature 4), (iii) a tetrahydrofuran solvent. However, it is not known to obtain sodium cyclopentadienide by reacting cyclopentadiene with sodium amide, and it is not known to carry out this reaction in a N, N-dimethylformamide solvent.
본 발명은 상기 사정을 감안하여, γ―투야플리신을 저렴하고 또한 간편하게, 수율 좋게 제조하는 방법을 제공하는 것을 목적으로 한다. In view of the above circumstances, an object of the present invention is to provide a method for producing γ-tuyaplicin inexpensively and simply and with high yield.
본 발명자는 예의 검토를 행한 결과, 나트륨아미드를 사용함으로써, N,N-디메틸포름아미드용매 중에서, 시클로펜타디엔으로부터 나트륨 시클로펜타디에닐리드를 원활하게 조제할 수 있는 것을 발견하고, 또한 이 방법으로 조제한 나트륨 시클로펜타디에닐리드에 이소프로필화제를 반응시켜서, 수율 좋게 또한 재현성 좋게 이소프로필시클로펜타디엔 혼합물을 얻을 수 있으며, 또한 이 혼합물을 사용하여 제조한 조생성물로부터 정석 조작에 의해 고순도의 γ―투야플리신을 분리할 수 있는 것을 발견하고, 본 발명을 완성하였다.MEANS TO SOLVE THE PROBLEM As a result of earnestly examining, it discovered that sodium cyclopentadienide can be smoothly prepared from cyclopentadiene in a N, N- dimethylformamide solvent by using sodium amide, and also by this method The isopropylating agent can be reacted with the prepared sodium cyclopentadienide to yield an isopropylcyclopentadiene mixture with high yield and reproducibility, and from the crude product prepared using this mixture, high purity γ- It has been found that tuyaplisin can be separated and the present invention has been completed.
즉, 본 발명은 다음의 (1)~(3)의 공정:That is, this invention is the process of following (1)-(3):
(1) N,N-디메틸포름아미드용매 중에서, 시클로펜타디엔과 나트륨아미드를 반응시켜서 나트륨 시클로펜타디에닐리드를 조제하고, 이 나트륨 시클로펜타디에닐리드에 이소프로필화제를 반응시켜서 이소프로필시클로펜타디엔의 혼합물을 얻는 제1공정,(1) In a N, N-dimethylformamide solvent, cyclopentadiene and sodium amide are reacted to prepare sodium cyclopentadienide, and isopropyl cyclopenta is reacted with isopropylating agent to disodium cyclopentadienide. A first step of obtaining a mixture of dienes,
(2) 상기 이소프로필시클로펜타디엔의 혼합물에 디클로로케텐을 반응시켜서, 7,7-디클로로비시클로[3.2.0]-헵트-2-엔-6-온 유도체의 혼합물을 얻는 제2공정,(2) a second step of reacting a mixture of isopropylcyclopentadiene with dichloroketene to obtain a mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative;
(3) 상기 7,7-디클로로비시클로[3.2.0]-헵트-2-엔-6-온 유도체의 혼합물을 염기성 조건하에서 가용매분해하고, 얻어지는 조생성물로부터 정석에 의해 γ―투야플리신을 분리하는 제3공정,(3) solvolysis of the mixture of the above 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivatives under basic conditions, and crystallization of gamma -tuyaplicin by crystallization from the crude product obtained Separating third process,
으로 되는 γ―투야플리신의 제조방법이다.It is a manufacturing method of (gamma) -tuyaplicin which becomes.
본 발명에 의해, 의약 등 또는 그의 중간체로서 유용한 γ―투야플리신을, 저렴하고 또한 간편하게, 수율 좋게 제조할 수 있다. 즉, 나트륨 시클로펜타디에닐리드는, N,N-디메틸포름아미드용매 중에서, 나트륨아미드와 시클로펜타디엔의 반응에 의해 조제할 수 있다. 또한, 이것에 이소프로필화제를 반응시킴으로써 이소프로필시클로펜타디엔의 혼합물을 수율 좋게, 또한 재현성 좋게 제조할 수 있다. 추가적으로 7,7-디클로로비시클로[3.2.0]-헵트-2-엔-6-온 유도체 혼합물의 가용매분해 조생성물로부터 정석에 의해 γ―투야플리신을 분리하였기 때문에, γ―투야플리신을 저렴하고 또한 간편하게, 수율 좋게 제조할 수 있는 이점이 있다.According to the present invention, γ-tuyaplicin useful as a medicine or the intermediate thereof can be produced at low cost and simply in high yield. That is, sodium cyclopentadienide can be prepared by reaction of sodium amide and cyclopentadiene in a N, N-dimethylformamide solvent. Moreover, by making an isopropylating agent react with this, the mixture of isopropyl cyclopentadiene can be manufactured with high yield and reproducibility. In addition, γ-tuyaplicin is inexpensive because γ-tuyaplicin has been separated by crystallization from the solvolysis crude product of a 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative mixture. And also, there is an advantage that can be easily produced in a good yield.
본 발명의 γ―투야플리신의 제조방법을 스킴으로 나타내고, 또한 각 공정에 대해서 설명한다. The manufacturing method of gamma-tuyaplicin of this invention is shown by the scheme, and each process is demonstrated.
(식 중, R은 할로겐원자, 메탄설포닐기, 아릴설포닐기, 트리플루오로메탄설포닐기를 나타낸다.)(Wherein R represents a halogen atom, a methanesulfonyl group, an arylsulfonyl group, and a trifluoromethanesulfonyl group.)
제1공정: N,N-디메틸포름아미드용매 중에서, 시클로펜타디엔과 나트륨아미드를 반응시켜서 나트륨 시클로펜타디에닐리드를 조제하고, 이 나트륨 시클로펜타디에닐리드에 이소프로필화제(구조식 I)를 반응시켜서 이소프로필시클로펜타디엔(구조식 II)의 혼합물(이성체의 혼합물)을 얻는 공정이다. 그 때, 조제한 나트륨 시클로펜타디에닐리드의 반응액에, 이소프로필화제(구조식 I)를 첨가하여 반응시킬 수 있다.First step: In a N, N-dimethylformamide solvent, cyclopentadiene and sodium amide are reacted to prepare sodium cyclopentadienide, and isopropylating agent (formula I) is reacted with this sodium cyclopentadienide. To obtain a mixture (mixture of isomers) of isopropylcyclopentadiene (formula II). At this time, an isopropylating agent (structure I) can be added and reacted with the prepared reaction solution of sodium cyclopentadienide.
여기에서 사용하는 이소프로필화제는, 다음의 일반식:The isopropylating agent used here is the following general formula:
(식 중, R은 할로겐원자, 메탄설포닐기, 아릴설포닐기, 트리플루오로메탄설포닐기를 나타낸다.)(Wherein R represents a halogen atom, a methanesulfonyl group, an arylsulfonyl group, and a trifluoromethanesulfonyl group.)
으로 나타내어지는 화합물이다. 예를 들면, 2-클로로프로판, 2-브로모프로판, 2-요오도프로판, 이소프로필메탄설포네이트, 이소프로필벤젠설포네이트, 이소프로필토실레이트, 이소프로필트리플루오로메탄설포네이트 등을 들 수 있으나, 바람직하게는 2-브로모프로판이다.It is a compound represented by. For example, 2-chloropropane, 2-bromopropane, 2-iodopropane, isopropylmethanesulfonate, isopropylbenzenesulfonate, isopropyltosylate, isopropyltrifluoromethanesulfonate, etc. are mentioned. However, preferably 2-bromopropane.
전술한 특허문헌 2에는, 염기로서 수산화칼륨, 이소프로필화제로서 2-브로모프로판을 사용한 이소프로필시클로펜타디엔의 제조방법이 기재되어 있다. 또한, 반응용매에 디메틸설폭시드를 사용하여 칼륨시클로펜타디에닐리드와 2-브로모프로판을 반응시키면 5-이소프로필시클로펜타디에닐이 선택적으로 생성되어, 이것을 선택적으로 1-이소프로필시클로펜타디엔으로 이성화하는 것이 기재되어 있다. 추가적으로, 이 반응을 N,N-디메틸포름아미드용매 중에서 행하면, 2-이소프로필시클로펜타디엔이 약간 우위로 생성되는 것이 기재되어 있다(1-이소프로필시클로펜타디엔/2-이소프로필시클로펜타디엔=41/58).Patent Document 2 described above describes a method for producing isopropylcyclopentadiene using potassium hydroxide as a base and 2-bromopropane as an isopropylating agent. In addition, when potassium cyclopentadienide and 2-bromopropane are reacted with dimethyl sulfoxide in a reaction solvent, 5-isopropylcyclopentadienyl is selectively generated, which is optionally 1-isopropylcyclopentadiene. Isomerization is described. In addition, it is described that when the reaction is carried out in a N, N-dimethylformamide solvent, 2-isopropylcyclopentadiene is slightly produced (1-isopropylcyclopentadiene / 2-isopropylcyclopentadiene =). 41/58).
이에, 특허문헌 2를 참고로 하여, 시클로펜타디엔의 N,N-디메틸포름아미드용액에 수산화칼륨을 첨가하고 반응시키고, 이 반응액을 2-브로모프로판 중에 적하하여 이소프로필시클로펜타디엔의 혼합물을 제조한 바, 수산화칼륨의 N,N-디메틸포름아미드로의 용해가 영향을 미친 탓인지, 칼륨시클로펜타디에닐리드의 조제에 소요되는 반응시간에 편차가 생겨, 그 결과 수율에 편차가 관찰되었다. 하지만, 본 발명에 의하면, 염기로서 나트륨아미드를 사용함으로써, 나트륨 시클로펜타디에닐리드의 조제가 원활히 진행되며, 또한 그 후의 이소프로필화제(I)와의 반응에 의해, 이소프로필시클로펜타디엔(II)의 평형 혼합물을 수율 좋게, 또한 재현성 좋게 얻을 수 있다.Thus, referring to Patent Document 2, potassium hydroxide was added to the N, N-dimethylformamide solution of cyclopentadiene and reacted. The reaction solution was added dropwise into 2-bromopropane to mix the isopropylcyclopentadiene. Was prepared, it was due to the influence of dissolution of potassium hydroxide in N, N-dimethylformamide, or the reaction time required for the preparation of potassium cyclopentadienide occurred, resulting in a deviation in the yield It became. However, according to the present invention, by using sodium amide as a base, preparation of sodium cyclopentadienide proceeds smoothly, and subsequent reaction with isopropylating agent (I) results in isopropylcyclopentadiene (II). The equilibrium mixture of can be obtained with high yield and reproducible.
또한, 상기 나트륨 시클로펜타디에닐리드와 이소프로필화제의 반응을 N,N-디메틸포름아미드 중에서 행하기 위해서는, 전술한 (i)~(iii)의 나트륨 시클로펜타디에닐리드 조제법의 경우에는, 각각의 용매를 N,N-디메틸포름아미드로 치환할 필요가 있기 때문에 제조공정이 번잡해지나, 본 발명에서는, 용매를 N,N-디메틸포름아미드로 치환할 필요가 없는 이점이 있다.In addition, in order to perform reaction of the said sodium cyclopentadienide and an isopropylating agent in N, N- dimethylformamide, in the case of the sodium cyclopentadienide preparation method of above-mentioned (i)-(iii), respectively, The manufacturing process is complicated because it is necessary to replace the solvent with N, N-dimethylformamide, but in the present invention, there is an advantage that the solvent does not need to be replaced with N, N-dimethylformamide.
본 발명의 제1공정에 있어서, 나트륨아미드에 대한 시클로펜타디엔의 몰비는 1~2의 범위이다. 나트륨아미드에 대한 이소프로필화제의 몰비는 1~5이고, 바람직하게는 1~2의 범위이다. 나트륨아미드에 대한 N,N-디메틸포름아미드의 몰비는 1~10이고, 바람직하게는 5~7의 범위이다. 반응은 -78℃~용매 환류온도에서 행해지고, 바람직한 반응온도는 -5℃~40℃의 범위이다. 이소프로필시클로펜타디엔(II)은 증류 정제해도 되나, 반응을 산성수용액으로 퀀칭한 후, 헥산, 헵탄, 톨루엔 등의 탄화수소계 용매로 추출하고, 그 추출액을 그대로 다음 공정에서 사용하는 편이 바람직하다.In the first step of the present invention, the molar ratio of cyclopentadiene to sodium amide is in the range of 1 to 2. The molar ratio of the isopropylating agent to sodium amide is 1-5, preferably in the range of 1-2. The molar ratio of N, N-dimethylformamide to sodium amide is 1-10, preferably in the range of 5-7. The reaction is carried out at -78 ° C to solvent reflux temperature, and the preferred reaction temperature is in the range of -5 ° C to 40 ° C. Although isopropyl cyclopentadiene (II) may be distilled and refine | purified, after quenching reaction with an acidic aqueous solution, it is preferable to extract with hydrocarbon solvents, such as hexane, heptane, and toluene, and to use this extract as it is in the next process.
제2공정: 상기에서 얻은 이소프로필시클로펜타디엔(II)의 혼합물에 디클로로케텐을 반응시켜서, 7,7-디클로로비시클로[3.2.0]-헵트-2-엔-6-온 유도체(구조식 III)의 혼합물을 얻는 공정이다. 디클로로케텐은 디클로로초산 클로라이드와 트리에틸아민으로부터 발생시킬 수 있다. 제1공정에서 사용한 나트륨아미드에 대한 디클로로초산 클로라이드와 트리에틸아민의 몰비는 0.5~2이고, 바람직하게는 0.9~1.2의 범위이다. 반응은 제1공정의 추출액을 그대로 사용하고, -78℃~용매 환류온도에서 행해지며, 바람직한 반응온도는 -5℃~20℃의 범위이다. 얻어진 조(粗) 7,7-디클로로비시클로[3.2.0]-헵트-2-엔-6-온 유도체(III)는 증류 정제하는 것이 바람직하다.Second Step: A 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative was obtained by reacting dichloroketene with a mixture of isopropylcyclopentadiene (II) obtained above. ) Is a process of obtaining a mixture. Dichloroketene can be generated from dichloroacetic acid chloride and triethylamine. The molar ratio of dichloroacetic acid chloride and triethylamine to sodium amide used in the first step is 0.5 to 2, preferably in the range of 0.9 to 1.2. The reaction is carried out at -78 ° C to solvent reflux temperature, using the extract of the first step as it is, and the preferred reaction temperature is in the range of -5 ° C to 20 ° C. It is preferable to distill and refine | purify the obtained crude 7,7- dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III).
제3공정: 상기에서 얻은 7,7-디클로로비시클로[3.2.0]-헵트-2-엔-6-온 유도체(III)의 혼합물을 염기성 조건하에서 가용매분해하고, 얻어지는 조생성물로부터 정석에 의해 γ―투야플리신(구조식 IV)을 분리하는 공정이다. 이 분해반응은, 아세톤-초산-물 혼합용매 중에서 행해진다. 반응액 환류온도에서, 7,7-디클로로비시클로[3.2.0]-헵트-2-엔-6-온 유도체(III)에, 그 유도체(III)에 대해 몰비 1~5의 범위에서 트리에틸아민을 적하한다. 적하 후, 용매 환류온도에서 1~10시간 교반한다. 반응종료 후, 통상의 후처리를 행하고, 얻어진 조생성물에 헥산, 헵탄, 함수 메탄올, 함수 에탄올 등의 용매를 첨가하여 용해하고, 이 용액에 종정(種晶)(γ―투야플리신)을 첨가하여, 0℃~실온에서 교반한 후에, 석출된 γ―투야플리신을 여과하여 모은다. 정석에 사용하는 용매의 양은 7,7-디클로로비시클로[3.2.0]-헵트-2-엔-6-온 유도체(III) 혼합물의 3~10배량이다. 용매를 첨가했을 때 불용물이 관찰되었을 때에는, 데칸테이션에 의해 상징(上澄)을 취해도 된다.
Third Step: The mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) obtained above is solvolyzed under basic conditions to obtain crystallization from the crude product obtained. Is a step of separating γ-tuyaplicin (formula IV). This decomposition reaction is performed in an acetone-acetic acid-water mixed solvent. Triethyl ether at 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) at a reaction liquid reflux temperature in a molar ratio of 1 to 5 relative to the derivative (III). An amine is dripped. After dropping, the mixture is stirred at reflux temperature of the solvent for 1 to 10 hours. After completion of the reaction, normal post-treatment was carried out, and solvents such as hexane, heptane, hydrous methanol and hydrous ethanol were added to the obtained crude product to dissolve it, and seed solution (γ-tuyaplicin) was added to the solution. And after stirring at 0 degreeC-room temperature, the precipitated gamma-tuyaplicin is collected by filtration. The amount of the solvent used for crystallization is 3 to 10 times the mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III). When an insoluble matter is observed when a solvent is added, a symbol may be taken by decantation.
실시예 1Example 1
(1) 이소프로필시클로펜타디엔(II) 혼합물의 제조(1) Preparation of Isopropylcyclopentadiene (II) Mixture
시클로펜타디엔(14.0 g)의 N,N-디메틸포름아미드(76.3 g)용액에 15℃ 이하에서 나트륨아미드(7.3 g, 92.7% 순도)를 첨가한 후, 실온에서 1시간 교반하였다. 반응액에 2-브로모프로판(41.7 g)을 10℃ 이하에서 적하한 후, 1시간 교반하였다. 반응액에 10% 염산수용액(30 mL)과 물(30 mL)을 첨가한 후, n-헥산(250 mL)으로 추출하였다. n-헥산추출액을 물(100 mL로 2회) 세정한 후, 무수 황산나트륨으로 건조하였다. 여과하여, 이소프로필시클로펜타디엔(II) 혼합물의 n-헥산용액을 얻었다.To a solution of cyclopentadiene (14.0 g) in N, N-dimethylformamide (76.3 g) was added sodium amide (7.3 g, 92.7% purity) at 15 ° C. or lower, followed by stirring at room temperature for 1 hour. 2-bromopropane (41.7 g) was added dropwise to the reaction solution at 10 ° C or lower, and then stirred for 1 hour. 10% aqueous hydrochloric acid solution (30 mL) and water (30 mL) were added to the reaction solution, followed by extraction with n-hexane (250 mL). The n-hexane extract was washed with water (2 × 100 mL) and dried over anhydrous sodium sulfate. It filtered and the n-hexane solution of the isopropyl cyclopentadiene (II) mixture was obtained.
(2) 7,7-디클로로비시클로[3.2.0]-헵트-2-엔-6-온 유도체(III) 혼합물의 제조(2) Preparation of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) mixture
상기 이소프로필시클로펜타디엔(II) 혼합물의 n-헥산용액에, 디클로로초산 클로라이드(17.3 mL)를 첨가하였다. 5℃ 이하에서 트리에틸아민(26.5 mL)을 1시간 20분간에 걸쳐 적하한 후, 1시간 30분간 교반하였다. 반응액에 10% 염산수용액(50 mL)과 물(50 mL)을 첨가한 후, 유기층을 분액하였다. 유기층을 물(50 mL로 2회), 포화 탄산수소나트륨수용액(50 mL로 1회), 포화식염수(50 mL로 1회)로 순차 세정한 후, 무수 황산나트륨으로 건조하였다. 여과한 후, 여액을 감압 증류 제거하고, 얻어진 잔사를 증류하여, 7,7-디클로로비시클로[3.2.0]-헵트-2-엔-6-온 유도체(III) 혼합물(23.8 g:비점 105~107℃/5 mmHg의 유분)을 얻었다.To the n-hexane solution of the isopropylcyclopentadiene (II) mixture, dichloroacetic acid chloride (17.3 mL) was added. Triethylamine (26.5 mL) was dripped over 1 hour and 20 minutes at 5 degrees C or less, and it stirred for 1 hour and 30 minutes. 10% aqueous hydrochloric acid solution (50 mL) and water (50 mL) were added to the reaction solution, and the organic layer was separated. The organic layer was washed sequentially with water (twice with 50 mL), saturated aqueous sodium hydrogen carbonate solution (once with 50 mL) and saturated brine (once with 50 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled off under reduced pressure, and the obtained residue was distilled off to obtain a mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) (23.8 g: boiling point 105). Oil at ˜107 ° C./5 mmHg).
(3) γ―투야플리신(IV)의 제조(3) Preparation of γ-tuyaplisin (IV)
상기 7,7-디클로로비시클로[3.2.0]-헵트-2-엔-6-온 유도체(III) 혼합물(42.0 g)의 아세톤(139 g)용액에 초산(11.3 g)과 물(22.6 g)을 첨가한 후, 트리에틸아민(66.8 mL)을 환류온도에서 1시간 16분간에 걸쳐 적하한 후, 동일 온도에서 5시간 교반하였다. 반응액을 방냉하고, 물(140 mL)과 10% 염산수용액(14 mL)을 첨가하였다. 톨루엔(140 mL로 2회) 추출하고, 합한 추출액을 물(70 mL로 2회) 세정한 후, 무수 황산나트륨으로 건조하였다. 여과한 후, 여액을 감압 증류 제거하고, 얻어진 잔사에 n-헥산(160 mL)을 첨가하여, 약 50℃에서 교반한 후, 방냉하였다. 용액부를 데칸테이션으로 분취한 후, 종정(γ―투야플리신)을 첨가하여 실온에서 교반하였다. 석출 결정을 여과하여 모은 후, 건조하여 γ―투야플리신(IV)(8.2 g, GC 순도 99% 이상)을 얻었다.To acetone (139 g) solution of the 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) mixture (42.0 g) was diluted with acetic acid (11.3 g) and water (22.6 g). ), And triethylamine (66.8 mL) was added dropwise at reflux at 1 hour and 16 minutes, followed by stirring at the same temperature for 5 hours. The reaction solution was allowed to cool and water (140 mL) and 10% aqueous hydrochloric acid solution (14 mL) were added. Toluene (twice with 140 mL) was extracted, the combined extracts were washed with water (twice with 70 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled off under reduced pressure, n-hexane (160 mL) was added to the obtained residue, which was stirred at about 50 ° C and then allowed to cool. The solution portion was aliquoted by decantation, followed by addition of seed tablets (γ-tuyaplicin) and stirring at room temperature. The precipitated crystals were collected by filtration and dried to obtain gamma -tuyaplicin (IV) (8.2 g, GC purity of 99% or more).
Claims (2)
(1) N,N-디메틸포름아미드용매 중에서, 시클로펜타디엔과 나트륨아미드를 반응시켜서 나트륨 시클로펜타디에닐리드를 조제하고, 이 나트륨 시클로펜타디에닐리드에 이소프로필화제를 반응시켜서 이소프로필시클로펜타디엔의 혼합물을 얻는 제1공정,
(2) 상기 이소프로필시클로펜타디엔의 혼합물에 디클로로케텐을 반응시켜서, 7,7-디클로로비시클로[3.2.0]-헵트-2-엔-6-온 유도체의 혼합물을 얻는 제2공정,
(3) 상기 7,7-디클로로비시클로[3.2.0]-헵트-2-엔-6-온 유도체의 혼합물을 염기성 조건하에서 가용매분해하고, 얻어지는 조생성물로부터 정석(晶析)에 의해 γ―투야플리신을 분리하는 제3공정,
으로 되는 γ―투야플리신의 제조방법.Process of following (1)-(3):
(1) In a N, N-dimethylformamide solvent, cyclopentadiene and sodium amide are reacted to prepare sodium cyclopentadienide, and isopropyl cyclopenta is reacted with isopropylating agent to disodium cyclopentadienide. A first step of obtaining a mixture of dienes,
(2) a second step of reacting a mixture of isopropylcyclopentadiene with dichloroketene to obtain a mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative;
(3) γ by crystallization from the crude product obtained by solubilizing the mixture of the 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivatives under basic conditions A third step of separating tuyaplisin,
A method for producing γ-tuyaplisin.
이소프로필화제가, 다음의 일반식:
(식 중, R은 할로겐원자, 메탄설포닐기, 아릴설포닐기, 트리플루오로메탄설포닐기를 나타낸다.)
으로 나타내어지는 화합물인 γ―투야플리신의 제조방법.The method of claim 1,
The isopropylating agent has the following general formula:
(Wherein R represents a halogen atom, a methanesulfonyl group, an arylsulfonyl group, and a trifluoromethanesulfonyl group.)
The manufacturing method of (gamma) -tuyaplicin which is a compound represented by these.
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| US6310255B1 (en) | 1998-03-30 | 2001-10-30 | Asahi Kasei Kabushiki Kaisha | Process for producing hinokitiol |
| JP2002255887A (en) | 2001-03-05 | 2002-09-11 | Asahi Kasei Corp | Method for tropolone compound purification |
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| JP5036111B2 (en) * | 2001-08-20 | 2012-09-26 | 旭化成イーマテリアルズ株式会社 | Process for producing substituted cyclopentadiene |
| JP4320197B2 (en) * | 2003-03-25 | 2009-08-26 | 高砂香料工業株式会社 | Process for producing 1-isopropylcyclopentadiene and hinokitiol |
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| JPH03193743A (en) | 1989-12-25 | 1991-08-23 | Takasago Internatl Corp | Production of tropone derivative |
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| CN101863751B (en) | 2014-01-08 |
| JP5193118B2 (en) | 2013-05-08 |
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