KR960011374B1 - Racemization of octahydroisoquinoline - Google Patents
Racemization of octahydroisoquinoline Download PDFInfo
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- KR960011374B1 KR960011374B1 KR1019920007546A KR920007546A KR960011374B1 KR 960011374 B1 KR960011374 B1 KR 960011374B1 KR 1019920007546 A KR1019920007546 A KR 1019920007546A KR 920007546 A KR920007546 A KR 920007546A KR 960011374 B1 KR960011374 B1 KR 960011374B1
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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Description
본 발명은 라니 구리 촉매를 이용하여 옥타하이드로이소퀴놀린계 광학활성 화합물을 그의 라세미체(racemate)로 전환시키는 방법에 관한 것이다.The present invention relates to a method for converting an octahydroisoquinoline-based optically active compound into its racemate using a Raney copper catalyst.
옥타하이드로이소퀴놀린계 광학활성 화합물은 진해 거담의 약효를 지닌 물질로 알려진 덱스트로메토르판(dextromethorphan)을 합성하는 데에 사용되는 중간체이다.Octahydroisoquinoline-based optically active compounds are intermediates used to synthesize dextromethorphan, which is known as a substance with antitussive expectoration.
이 옥타하이드로이소퀴놀린계 광학활성 화합물은 광학활성체 해상(resolution) 공정을 거쳐서 좌선성(levo) 이성체와 우선성(dextro) 이성체로 분리되며, 그중 좌선성 이성체만이 덱스트로메토르판 제조에 사용되고 우선성 물질은 부산물로 남게 되어 전체 반응 공정의 반응 수율이 1/2 이하로 격감하게 된다. 따라서 부산물로 남은 우선성 이성체를 라세미 혼합물로 전환시켜서 이로부터 다시 좌선성 이성체를 회수하는 방법이 오래전부터 연구되어 왔다.This octahydroisoquinoline-based optically active compound is separated into a levo isomer and a dextro isomer through an optical activator resolution process, of which only the left isomer is used to prepare dextromethorphan Used and preferential materials remain as by-products, resulting in a decrease in reaction yield of less than one half of the overall reaction process. Therefore, a method has been studied for a long time to recover the left isomer by converting the preferred isomer remaining as a by-product to the racemic mixture.
옥타하이드로이소퀴놀린 광학활성 화합물의 라세미화방법(racemization)으로 널리 알려져 있는 방법으로는 고급 금속이온들을 배합한 금속 촉매 반응법과 질소에 붙어 있는 작용기를 염화시키고 이를 수소와 함께 탈착시킨 다음 다시 수소를 첨가하는 일련의 화학 반응을 거치는 방법이 있다. 산업적으로는 주로 고급 금속 촉매를 사용하는 방법이 사용되고 있는데, 이때 사용되는 촉매는 Pd, Co, Pt, Rh 등의 고급 금속 촉매에 Fe++, Fe+3, Zn++, Cu++등의 금속 이온을 입힌 것이다. 지금까지 개발된 고급 금속 촉매를 사용하는 기술은 미국 특허 제2,819,272호, 제2,915,479호, 제2,974,145호, 및 제3,036,973호에 개시되어 있으나 아직까지는 반응 수율이 낮고 금속 촉매의 가격이 매우 고가인데다가 재사용이 어렵다는 단점을 그대로 지니고 있다.Known as the racemization of octahydroisoquinoline optically active compounds, metal catalyzed reactions containing high-grade metal ions and the functional groups attached to nitrogen are chlorided, desorbed with hydrogen, and then hydrogenated again. There is a way to go through a series of chemical reactions. There are industrially generally used a method using a fine metal catalyst, etc. The catalyst used is Pd, Co, Pt, a fine metal catalyst such as Rh Fe ++, Fe +3, Zn ++, Cu ++ of It is coated with metal ions. The techniques using the advanced metal catalysts developed so far are disclosed in US Pat. Nos. 2,819,272, 2,915,479, 2,974,145, and 3,036,973, but the reaction yield is low and the price of the metal catalyst is very expensive and reused. This has the disadvantage of being difficult.
또한, 라세미화 방법에 사용되는 촉매는 수소를 제거할 수 있는 탈수소 활성과 수소를 다시 첨가할 수 있는 수소 첨가 활성을 동시에 지녀야 하는데, 지금까지 개발된 촉매는 반응 활성도 낮고 또한 반응 도중에 촉매의 활성이 쉽게 저하되는 단점을 안고 있다. 미국 특허 제2,819,272호와 제2,915,479호에 기술된, 팔라듐 스펀지에 Fe++, Fe+3, Zn++이온을 입힌 촉매의 라세미화율은 60%선에 그치고 있으며, 미국 특허 제2,974,145호와 제3,036,973호에 기술된, 라니 코발트(Raney Co)에 Cu++를 입힌 촉매의 라세미화율은 74%에 머무르고 있다.In addition, the catalyst used in the racemization method must have both a dehydrogenation activity capable of removing hydrogen and a hydrogenation activity capable of adding hydrogen again. The catalysts developed so far have a low reaction activity and a low It has the disadvantage of being easily degraded. The racemization rate of the catalysts coated with Fe ++ , Fe +3 , Zn ++ ions on the palladium sponge described in US Pat. Nos. 2,819,272 and 2,915,479 is only about 60%, and US Pat. Nos. 2,974,145 and The racemization rate of the catalyst coated with Cu ++ on Raney Co, described in US Pat. No. 3,036,973, remains at 74%.
이에 본 발명자들은 상기 문제점을 해결하고자 예의 연구한 결과, 옥타하이드로이소퀴놀린계 광학 활성화합물을 라세미화시키는데 있어 라니 구리를 사용하게 되면 라세미화율이 향상될 뿐아니라 반응 후 촉매활성의 저하도 감소되어 재사용이 가능함을 알게되어 본 발명을 완성하였다.Accordingly, the present inventors have diligently studied to solve the above problems, and when Raney copper is used to racemize an octahydroisoquinoline-based optically active compound, not only the racemization rate is improved but also the degradation of the catalytic activity after the reaction is reduced. It has been found that re-use is possible to complete the present invention.
즉, 본 발명의 목적은 옥타하이드로이소퀴놀린계 광학 활성화합물을 용매에 녹인 다음 수소가압하에 라니 구리 촉매 존재하에서 가열하여서 라세미체로전환시키는 방법을 제공하는 것이다.That is, an object of the present invention is to provide a method of dissolving an octahydroisoquinoline optically active compound in a solvent and then heating it in the presence of a Raney copper catalyst under hydrogen pressure to convert it into a racemate.
이하 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
본 발명에서 출발 물질로 사용되는 옥타하이드로이소퀴놀린계 화합물은 다음의 일반식(Ⅰ)로 표시될 수 있다.The octahydroisoquinoline compound used as the starting material in the present invention may be represented by the following general formula (I).
상기 식에서, R1은 수소 또는 탄소수 1 내지 8의 탄화수소기이고, R2는 수소 또는 저급 알킬기이다.In the above formula, R 1 is hydrogen or a hydrocarbon group of 1 to 8 carbon atoms, and R 2 is hydrogen or lower alkyl group.
옥타하이드로이소퀴놀린계 광학 활성 화합물을 라세미화시키는 방법은 위 구조식의 1번 탄소에 붙어 있는 수소를 제거하였다가 수소를 다시 첨가시키면 수소가 첨가될 때 화합물의 광학적 특성이 반대로 바뀌기 때문에 우선성 이성체가 좌선성 이성체로 또는 좌선성이성체가 우선성이성체로 전환되어 라세미체가 얻어진다는 사실에 근거하고 있다.The method of racemizing an octahydroisoquinoline-based optically active compound removes the hydrogen attached to the carbon number 1 of the above structural formula, and then adds hydrogen again, thereby changing the optical properties of the compound when hydrogen is added. It is based on the fact that the racemates are obtained by converting to the left isomers or to the left isomers into preferential isomers.
본 발명에 따르면, 제조하기도 간단한 저가의 금속 촉매인 라니 구리(Raney Cu) 촉매를 사용하여 수소 고압 반응기에서 옥타하이드로이소퀴놀린계 광학 활성 화합물을 고순도의 라세미체로 전환시킬 수 있다. 본 발명에서 사용된 라니 구리 금속 촉매는 지금까지 사용되어 왔던 고급 금속 촉매와는 달리 손쉽게 제조되며 제조 비용도 매우 저렴하고, 또한 회수하여 재사용하여도 촉매 활성이 오래 유지되는 장점이 있다. 팔라듐, 코발트, 백금 등의 금속에 여러 가지 금속 이온을 입혀서 만든 고급 금속 촉매는 촉매 제조 과정도 복잡하고 균일한 활성을 얻기도 어려울 뿐만 아니라 사용 후 회수하여 재사용하기 위해서는 다시 활성화 처리를 해야 하고 재처리 후에 촉매의 활성이 감소되는 단점을 지니고 있는 반면, 본 발명의 라니 구리 금속 촉매는 특별한 활성화 처리가 필요없기 때문에 균일한 촉매 활성을 지닐 수 있고 회수하여 재사용하여도 촉매의 활성이 저하됨이 없이 장기간 유지된다.According to the present invention, an octahydroisoquinoline-based optically active compound can be converted into a high purity racemate in a hydrogen high pressure reactor using a Raney Cu catalyst, which is a simple and inexpensive metal catalyst to be manufactured. The Raney copper metal catalyst used in the present invention has an advantage that, unlike the advanced metal catalysts that have been used up to now, it is easily prepared and the manufacturing cost is very low, and the catalyst activity is maintained even after recovery and reuse. Advanced metal catalysts made by applying various metal ions to metals such as palladium, cobalt and platinum are not only complicated and uniformly active in the catalyst manufacturing process, but also need to be reactivated and recovered for reuse after reuse. While the catalyst has a disadvantage in that the activity of the catalyst is reduced later, the Raney copper metal catalyst of the present invention can have a uniform catalytic activity since no special activation treatment is required and can be maintained for a long time without degrading the activity of the catalyst even when recovered and reused. do.
본 발명에 사용되는 라니 구리 금속 촉매의 제조 방법은 널리 알려져 있다. 즉, 구리와 알루미늄 약 50 : 50의 중량비로 섞인 합금을 분말로 곱게 갈고 수산화 나트륨 용액에 넣어 합금속에 들어 있는 알루미늄을 완전히 용해시킴으로써 제조한다. 이때, 제조된 금속 촉매에 알루미늄이 남지 않도록 알루미늄을 완전히 용해시키는 것이 촉매의 활성을 높히는 방법이다. 제조된 금속 촉매에서 수산화나트륨 용액을 완전히 제거하여 통상 물 속에 넣어(본 발명의 촉매는 공지중에서는 산화되어 쉽게 활성을 잃게 되며, 또한 완전히 건조되면 자연 발화될 우려가 있다) 질소를 충진한 상태로 보관하는데, 본 발명에서는 본 반응에 용이하게 사용될 수 있도록, 얻어진 라니 구리 금속 촉매를 물과 메탄올로 세척한 다음, 톨루엔으로 다시 세척하여 톨루엔 속에 넣어서 보관한다.Methods for producing Raney copper metal catalysts used in the present invention are well known. In other words, the alloy mixed in a weight ratio of about 50: 50 copper and aluminum is finely ground into powder, and prepared by dissolving aluminum in the alloy completely in a sodium hydroxide solution. At this time, completely dissolving aluminum so that aluminum does not remain in the prepared metal catalyst is a method of increasing the activity of the catalyst. The sodium hydroxide solution is completely removed from the prepared metal catalyst and placed in water. (The catalyst of the present invention is easily oxidized and loses activity. In addition, the catalyst may spontaneously ignite if completely dried.) In the present invention, the Raney copper metal catalyst obtained is washed with water and methanol, and then washed again with toluene and stored in toluene so that it can be easily used in the present reaction.
이렇게 제조된 라니 구리 촉매는 톨루엔 용매속에서 6개월 이상 장기간동안 보관하여 두어도 활성이 유지된다.The Raney copper catalyst thus prepared retains its activity even when stored for 6 months or longer in a toluene solvent.
본 발명의 옥타하이드로이소퀴놀린계 광학 활성 화합물을 라세미체로 전환시키는 방법은 반응물을 톨루엔 용매에 녹이고 반응 촉매로 제조된 라니 구리 금속 촉매를 투입하여 슬러리 상태로 수소 고압 반응기에 넣어 반응을 시키는 것인데, 반응 온도는 60∼150℃가 적절하고 수소 압력은 200∼1200psig가 유리하다.The method for converting the octahydroisoquinoline-based optically active compound of the present invention to racemate is to dissolve the reactant in a toluene solvent, and to add a Raney copper metal catalyst prepared as a reaction catalyst to a slurry in a hydrogen high pressure reactor to react. A reaction temperature of 60-150 ° C. is appropriate and a hydrogen pressure of 200-1200 psig is advantageous.
상기 반응에 쓰이는 출발 물질인 옥타하이드로이소퀴놀린계 광학 활성 화합물은 보통 두 단계의 합성 반응을 거치는 동안 생성된 부반응 물질들인 여러 가지 아민 유도체를 함유하고 있기 때문에, 라세미화 반응에 쓰이기전에 미리 정제되어야 금속 촉매의 활성을 저해하지 않는다. 이러한 정제 방법으로는 이미 널리 알려진 옥살산을 이용한 정제법이 적절하다(Schnider, Brossi 및 Vogler의 논문 Helvetica Chimica Acta 37, 710(1954)참조).The octahydroisoquinoline-based optically active compound, which is a starting material for the reaction, usually contains various amine derivatives, which are side reactions generated during two stages of the synthesis reaction, and therefore must be purified before use in racemization reaction. It does not inhibit the activity of the catalyst. As such purification method, a well-known purification method using oxalic acid is appropriate (see Schnider, Brossi and Vogler's article Helvetica Chimica Acta 37, 710 (1954)).
라세미화 반응에 쓰이는 촉매의 양은 통상 반응물 무게의 약 5∼20%가 적절한데, 촉매의 사용량이 많을수록 반응시간이 단축된다. 반응 온도는 반응 속도와 반응 생성물의 순도에 가장 큰 영향을 미치는데, 반응 온도가 60℃ 이하로 내려 가면 반응 속도가 크게 느려지고 반응 온도가 135℃를 넘게 되면 반응 속도가 매우 빨라지나 부반응이 증가하기 시작하며 반응 온도가 150℃ 이상으로 올라가면 부반응이 급격히 증가한다. 그러므로, 상기에서 언급했던 바와 같이 반응 온도를 60∼150℃, 바람직하게는 95∼135℃로 한다.The amount of catalyst used in the racemization reaction is usually about 5 to 20% of the weight of the reactant. The higher the amount of catalyst used, the shorter the reaction time. The reaction temperature has the greatest influence on the reaction rate and the purity of the reaction product.When the reaction temperature is lowered below 60 ° C, the reaction rate is greatly slowed down and when the reaction temperature exceeds 135 ° C, the reaction rate becomes very fast but side reactions increase. Beginning, side reactions increase rapidly when the reaction temperature rises above 150 ° C. Therefore, as mentioned above, the reaction temperature is set to 60 to 150 ° C, preferably 95 to 135 ° C.
수소 압력의 영향은 반응 속도보다는 부반응 생성과 밀접한 관계가 있는데, 통상 수소 압력이 400psig 이상이면 부반응이 충분히 억제되나 만일 압력이 200psig 이하로 내려가면 부반응이 증가한다. 수소 압력을 800∼1200psig로 올려도 반응 속도상의 증가나 감소는 별로 없지만, 1200psig 이상에서는 오히려 반응 속도가 느려지는 현상이 있다. 따라서, 수소압력은 일반적으로 200∼1200psig로 하며, 바람직하게는 300∼950psig로 한다.The effect of hydrogen pressure is more closely related to the formation of side reactions than the reaction rate. Usually, if the hydrogen pressure is above 400 psig, the side reactions are sufficiently suppressed, but if the pressure goes below 200 psig, the side reactions increase. Increasing the hydrogen pressure to 800 to 1200 psig does not increase or decrease the reaction rate much, but at 1200 psg or more, the reaction rate is rather slow. Therefore, the hydrogen pressure is generally 200 to 1200 psig, and preferably 300 to 950 psig.
이와 같은 본 발명에 따르면, 옥타하이드로이소퀴놀린계 광학 활성 화합물의 라세미화 반응은 최적 조건에서 라세미화율이 95% 이상까지 상승하고 부반응도 2% 이하로 억제되어 고순도의 라세미화합물을 얻을 수 있다.According to the present invention, the racemization reaction of the octahydroisoquinoline-based optically active compound can be increased to the racemization rate up to 95% or more and the side reaction is suppressed to 2% or less under optimum conditions to obtain a high purity racemic compound .
본 발명의 방법에는 반응 용매로서 친수성 극성 용매는 물론 소수성 비극성 용매도 함께 사용될 수 있는데, 메탄올이나 에탄올과 같은 용매속에서는 반응 속도는 약간 빠르나 부반응이 조금 증가하고, 톨루엔이나 크실렌과 같은 용매속에서는 반응 속도는 약간 느려지나 부반응이 억제된다. 다만, 본 반응에 사용되는 반응물을 정제하는 공정에서 유기 용매 추출과정이 있기 때문에 톨루엔과 같은 소수성 유기 용매를 사용하면 용매를 바꾸기 위하여 용매를 증류하는 공정을 생략할 수 있다는 장점이 있다. 또한, 라니 구리 금속 촉매는 반응물인 옥타하이드로이소퀴놀린계 화합물의 순도가 충분히 높기만 하다면 촉매의 활성 감소가 미미하기 때문에, 반응에 쓰인 다음 회수되어 별도의 활성화 처리없이 단순한 세척 과정만으로도 연속 3회 이상 재 사용이 가능하며, 반응 속도의 보전을 위해서 촉매 사용량을 10% 정도만 늘려주면 만족스러운 반응이 가능하다는 잇점이 있다.In the method of the present invention, a hydrophilic polar solvent as well as a hydrophobic non-polar solvent may be used as the reaction solvent. In a solvent such as methanol or ethanol, the reaction rate is slightly faster but the side reaction is slightly increased, and in a solvent such as toluene or xylene, Slightly slowed but side reactions are suppressed. However, since there is an organic solvent extraction process in the process of purifying the reactants used in the reaction, the use of a hydrophobic organic solvent such as toluene has the advantage that the process of distilling the solvent to change the solvent can be omitted. In addition, the Raney copper metal catalyst is reduced in activity of the catalyst if the purity of the reactant octahydroisoquinoline-based compound is high enough, so that the Raney copper metal catalyst is used after the reaction is recovered and recovered three times or more by a simple washing process without additional activation treatment It can be reused, and the advantage of satisfactory reaction can be achieved by increasing the amount of the catalyst to about 10% to preserve the reaction rate.
이하 본 발명을 실시예에 의거하여 구체적으로 설명하겠다.Hereinafter, the present invention will be described in detail with reference to Examples.
제조예 1 : 본 발명에 따른 라니 구리 촉매의 제조Preparation Example 1 Preparation of Raney Copper Catalyst According to the Present Invention
구리와 알루미늄의 중량비가 50 : 50인 합금을 분말로 곱게 갈고 체로 걸러서 200∼40mesh 크기의 금속 분말을 제조하였다. 약 10% 수산화 나트륨 용액 1000㎖를 세게 교반하면서 준비된 합금 분말 70g을 투입하였다. 투입시 극렬한 발열이 생기므로 합금 분말을 서서히 투입하면서 항온조에서 반응물의 온도를 60℃로 조절하였다. 합금 분말을 완전히 투입한 다음 온도를 60℃로 계속 유지하면서 약 2시간 이상 세게 교반하였다. 알루미늄이 대부분 용해되면 교반을 중지하고 약 10분간 가라않힌 다음 상등액을 조용히 제거하고 다시 물 1000㎖를 가하여 세척하였다. 여과지를 준비하여 제조된 촉매를 걸러서 회수하고 물 2000㎖를 계속 가하면서 여과액의 pH가 9 이하로 내려가도록 세척한 다음 50% 메탄올 수용액 200㎖를 가하고 순수한 메탄올 300㎖를 가하여 수분을 완전히 제거하였다. 수분이 제거된 금속 촉매가 마르기 전에 새로이 톨루엔 500㎖를 가하여 촉매를 세척하여 메탄올을 제거하였다. 여과지로 걸러서 회수된 촉매를 톨루엔 300㎖에 잘 현탁시켜 냉장 보관시켰다.An alloy having a weight ratio of 50:50 of copper and aluminum was finely ground with a powder and sieved to prepare a metal powder having a size of 200 to 40 mesh. 70 g of the prepared alloy powder was added while vigorously stirring 1000 ml of about 10% sodium hydroxide solution. Extremely exotherm occurs during the addition, so that the temperature of the reactant in the thermostat while the alloy powder is slowly added to 60 ℃. The alloy powder was completely added and then stirred vigorously for about 2 hours while maintaining the temperature at 60 ° C. When most of the aluminum was dissolved, the stirring was stopped and allowed to settle for about 10 minutes. Then, the supernatant was quietly removed and washed again by adding 1000 ml of water. Filter paper was prepared to collect the recovered catalyst, washed with 2000ml of water continuously to reduce the pH of the filtrate to 9 or less, 200ml of 50% aqueous methanol solution was added and 300ml of pure methanol was added to completely remove the water. . Before the water-free metal catalyst was dried, fresh 500 ml of toluene was added to wash the catalyst to remove methanol. The recovered catalyst, filtered through filter paper, was suspended in 300 ml of toluene and refrigerated.
실시예 1Example 1
(+)-1-(4-메톡시벤질)-1,2,3,4,5,6,7,8-옥타하이드로이소퀴놀린(순도 98.3%) 50g을 톨루엔 300㎖에 용해시켜 고압반응기에 투입하였다. 여기에 제조예 1에서 제조된 라니 구리 촉매를 젖은 상태의 무게 8g(건조중량 : 5.3g)을 달아서 투입하였다. 고압 반응기에 수소를 채우고 반응온도를 130℃로 올리고 나서 수소 압력을 약 600psig로 상승시켜 7시간동안 반응시켰다. 반응 후 촉매를 걸러서 회수하고 반응 용액에 0.1N 수산화나트륨 용액 300㎖를 가하여 세척한 후 층분리하여 유기 용매 층을 회수하고 난 다음, 유기 용매를 증류하여 완전히 제거하여 라세미화 반응 생성물을 오일상으로 얻었다. 편광계와 키랄(chiral) 크로마토그래피를 사용하여 광학 순도를 측정한 결과 라세미화율(racemization)은 90%였다. 반응 생성물의 물질 순도는 91%였다.50 g of (+)-1- (4-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (purity 98.3%) was dissolved in 300 ml of toluene and Input. Here, the Raney copper catalyst prepared in Preparation Example 1 was weighed and weighed with 8 g (dry weight: 5.3 g) in a wet state. Hydrogen was charged in the high pressure reactor and the reaction temperature was raised to 130 ° C., and then the hydrogen pressure was raised to about 600 psig and reacted for 7 hours. After the reaction, the catalyst was collected by filtration, washed with 300 ml of 0.1 N sodium hydroxide solution, and the layers were separated and the organic solvent layer was recovered. The organic solvent was distilled off to remove the racemization reaction product into an oil phase. Got it. The optical purity was measured using a polarimeter and chiral chromatography, and the racemization was 90%. The material purity of the reaction product was 91%.
실시예 2Example 2
(+)-1-(4-메톡시벤질)-1,2,3,4,5,6,7,8-옥타하이드로이소퀴놀린(순도 96.6%) 116g을 톨루엔 350㎖에 용해시켜 고압반응기에 투입하였다. 여기에 제조예 1에서 제조된 라니 구리 촉매를 젖은 상태의 무게 18g(건조 중량 : 12.0g)을 달아서 투입하였다. 고압 반응기에 수소를 채우고 반응온도를 105℃로 올리고 나서 수소압력을 약 600psig로 상승시켜 45시간동안 반응시켰다. 반응 후 촉매를 걸러서 회수하고 반응 용액에 0.1N 수산화나트륨 용액 400㎖를 가하여 세척한 후 층분리하여 유기 용매 층을 회수하고 난 다음, 유기 용매를 증류하여 완전히 제거하여 라세미화 반응 생성물을 오일상으로 얻었다. 편광계와 키랄 크로마토그래피를 사용하여 광학 순도를 측정한결과 라세미화율은 90%였다. 반응 생성물의 물질 순도는 95%였다.116 g of (+)-1- (4-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (purity 96.6%) in 350 ml of toluene was dissolved in a high pressure reactor. Input. Herein, the Raney copper catalyst prepared in Preparation Example 1 was added with a weight of 18 g (dry weight: 12.0 g) in a wet state. Hydrogen was charged in the high pressure reactor, the reaction temperature was raised to 105 ° C, and the hydrogen pressure was raised to about 600 psig and reacted for 45 hours. After the reaction, the catalyst was collected by filtration, washed with 400 ml of 0.1 N sodium hydroxide solution, and the layers were separated and the organic solvent layer was recovered. The organic solvent was distilled off to remove the racemization reaction product into an oil phase. Got it. The optical purity was measured using a polarimeter and chiral chromatography, and the racemization rate was 90%. The material purity of the reaction product was 95%.
실시예 3Example 3
(+)-1-(4-메톡시벤질)-1,2,3,4,5,6,7,8-옥타하이드로이소퀴놀린(순도 96.6%) 207g을 톨루엔 400㎖에 용해시켜 고압반응기에 투입하였다. 여기에 상기 실시예 2에서와 같은 반응에 2회 재사용한 라니 구리 촉매를 젖은 상태의 무게 25g(건조 중량 : 16.7g)을 달아서 투입하였다. 고압 반응기에 수소를 채우고 반응온도를 105℃로 올리고 나서 수소 압력을 약 600psig로 상승시켜 45시간 동안 반응시켰다. 반응 후 촉매를 걸러서 회수하고 반응 용액에 0.1N 수산화나트륨 용액 500㎖를 가하여 세척한 후 층분리하여 유기 용매 층을 회수하고 난 다음, 유기 용매를 증류하여 완전히 제거하여 라세미화 반응 생성물을 오일상으로 얻었다. 편광계와 키랄 크로마토그래피를 사용하여 광학 순도를 측정한 결과, 라세미화율은 90%였다. 반응 생성물의 물질 순도는 94%였다.207 g of (+)-1- (4-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (purity 96.6%) in 400 ml of toluene was dissolved in a high pressure reactor. Input. The Raney copper catalyst reused twice in the same reaction as in Example 2 was weighed in with a weight of 25 g (dry weight: 16.7 g) in a wet state. Hydrogen was charged in the high pressure reactor and the reaction temperature was raised to 105 ° C, and then the hydrogen pressure was raised to about 600 psig and reacted for 45 hours. After the reaction, the catalyst was collected by filtration, washed with 500 ml of 0.1 N sodium hydroxide solution, and the layers were separated and the organic solvent layer was recovered. The organic solvent was distilled off to remove the racemization reaction product into an oil phase. Got it. The optical purity was measured using a polarimeter and chiral chromatography, and the racemization rate was 90%. The material purity of the reaction product was 94%.
실시예 4Example 4
(+)-1-(4-메톡시벤질)-1,2,3,4,5,6,7,8-옥타하이드로이소퀴놀린(순도 93.3%) 124g을 톨루엔 370㎖에 용해시켜 고압반응기에 투입하였다. 여기에 상기 실시예 2에서와 같은 반응에 3회 재사용한 라니 구리 촉매를 젖은 상태의 무게 25g(건조 중량 : 16.7g)을 달아서 투입하였다. 고압 반응기에 수소를 채우고 반응온도를 105℃로 올리고 나서 수소 압력을 약 400psig로 상승시켜 40시간 동안 반응시켰다. 반응 후 촉매를 걸러서 회수하고 반응 용액에 0.1N 수산화나트륨 용액 400㎖를 가하여 세척한 후 층분리하여 유기 용매 층을 회수하고 난 다음, 유기 용매를 증류하여 완전히 제거하여 라세미화 반응 생성물을 오일상으로 얻었다. 편광계와 키랄 크로마토그래피를 사용하여 광학 순도를 측정한 결과, 라세미화율은 91%였다. 반응 생성물의 물질 순도는 88.8%였다.124 g of (+)-1- (4-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (purity 93.3%) in 370 ml of toluene was dissolved in a high pressure reactor. Input. Here, the Raney copper catalyst reused three times in the same reaction as in Example 2 was weighed and weighed 25 g (dry weight: 16.7 g) in a wet state. Hydrogen was charged in the high pressure reactor and the reaction temperature was raised to 105 ° C, and then the hydrogen pressure was raised to about 400 psig and reacted for 40 hours. After the reaction, the catalyst was collected by filtration, washed with 400 ml of 0.1 N sodium hydroxide solution, and the layers were separated and the organic solvent layer was recovered. The organic solvent was distilled off to remove the racemization reaction product into an oil phase. Got it. The optical purity was measured using a polarimeter and chiral chromatography, and the racemization rate was 91%. The material purity of the reaction product was 88.8%.
실시예 5Example 5
(+)-1-(4-메톡시벤질)-1,2,3,4,5,6,7,8-옥타하이드로이소퀴놀린(순도 96.5%) 43g을 톨루엔 300㎖에 용해시켜 고압반응기에 투입하였다. 여기에 제조예 1에서 제조된 라니 구리 촉매를 젖은 상태의 무게 10g(건조중량 : 6.7g)을 달아서 투입하였다. 고압 반응기에 수소를 채우고 반응온도를 110℃로 올리고 나서 수소 압력을 약 600psig로 상승시켜 20시간 동안 반응시켰다. 반응 후 촉매를 걸러서 회수하고 반응 용액에 0.1N 수산화나트륨 용액 300㎖를 가하여 세척한 후 층분리하여 유기 용매 층을 회수하고 난 다음, 유기 용매를 증류하여 완전히 제거하여 라세미화 반응 생성물을 오일상으로 얻었다. 편광계와 키랄 크로마토그래피를 사용하여 광학 순도를 측정한 결과, 라세미화율은 92%였다. 반응 생성물의 물질 순도는 93%였다.43 g of (+)-1- (4-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (purity 96.5%) in 300 ml of toluene was dissolved in a high pressure reactor. Input. Herein, the Raney copper catalyst prepared in Preparation Example 1 was weighed and weighed with 10 g (dry weight: 6.7 g) in a wet state. Hydrogen was charged in the high pressure reactor and the reaction temperature was raised to 110 ° C., and then the hydrogen pressure was raised to about 600 psig and reacted for 20 hours. After the reaction, the catalyst was collected by filtration, washed with 300 ml of 0.1 N sodium hydroxide solution, and the layers were separated and the organic solvent layer was recovered. The organic solvent was distilled off to remove the racemization reaction product into an oil phase. Got it. The optical purity was measured using a polarimeter and chiral chromatography, and the racemization rate was 92%. The material purity of the reaction product was 93%.
비교실시예 1Comparative Example 1
이 실시예는 본 발명의 온도 범위를 벗어나는 고온에서는, 반응속도는 매우 빠르지만 부반응이 증가함을 보여주는 것이다.This example shows that at high temperatures outside the temperature range of the present invention, the reaction rate is very fast but the side reactions increase.
(-)-1-(4-메톡시벤질)-1,2,3,4,5,6,7,8-옥타하이드로이소퀴놀린(순도 98.3%) 52g을 톨루엔 300㎖에 용해시켜 고압반응기에 투입하였다. 여기에 상기 제조예 1에서 제조된 라니 구리 촉매를 젖은 상태의 무게 7g(건조중량 : 4.7g)을 달아서 투입하였다. 고압 반응기에 수소를 채우고 반응온도를 155℃로 올리고 나서 수소압력을 약 930psig로 상승시켜 3시간동안 반응시켰다. 반응 후 촉매를 걸러서 회수하고 반응 용액에 0.1N 수산화나트륨 용액 300㎖를 가하여 세척한 후 층분리하여 유기 용매 층을 회수하고 난 다음, 유기 용매를 증류하여 완전히 제거하여 라세미화 반응 생성물을 오일상으로 얻었다. 편광계와 키랄 크로마토그래피를 사용하여 광학 순도를 측정한 결과, 라세미화율은 87%였다. 반응 생성물의 물질 순도는 87%였다.52 g of (-)-1- (4-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (purity 98.3%) in 300 ml of toluene was dissolved in a high pressure reactor. Input. The Raney copper catalyst prepared in Preparation Example 1 was added to weigh 7 g (dry weight: 4.7 g) in a wet state. Hydrogen was charged in the high pressure reactor and the reaction temperature was raised to 155 ° C, and then the hydrogen pressure was raised to about 930 psig and reacted for 3 hours. After the reaction, the catalyst was collected by filtration, washed with 300 ml of 0.1 N sodium hydroxide solution, and the layers were separated and the organic solvent layer was recovered. The organic solvent was distilled off to remove the racemization reaction product into an oil phase. Got it. The optical purity was measured using a polarimeter and chiral chromatography, and the racemization rate was 87%. The material purity of the reaction product was 87%.
비교실시예 2Comparative Example 2
이 실시예는 저온 및 본 발명의 범위를 벗어나는 상압에서는, 반응 속도가 느리고 부반응이 증가함을 보여주는 것이다.This example shows that at low temperatures and atmospheric pressure outside the scope of the present invention, the reaction rate is slow and the side reactions increase.
(-)-1-(4-메톡시벤질)-1,2,3,4,5,6,7,8-옥타하이드로이소퀴놀린(순도 98.3%) 12g을 톨루엔 50㎖에 용해시켜 상압반응기에 투입하였다. 여기에 제조예 1에서 제조된 라니 구리 촉매를 젖은 상태의 무게 20g(건조중량 : 13.3g)을 달아서 투입하였다. 반응기에 수소를 상압으로 흘려 보내면서 반응온도를 105℃로 올리고 17시간동안 반응시켰다. 반응 후 촉매를 걸러서 회수하고 반응 용액에 0.1N 수산화나트륨 용액 100㎖를 가하여 세척한 후 층분리하여 유기 용매 층을 회수하고 난 다음, 유기 용매를 증류하여 완전히 제거하여 라세미화 반응 생성물을 오일상으로 얻었다. 편광계와 키랄 크로마토그래피를 사용하여 광학 순도를 측정한 결과, 라세미화율은 18%였다. 반응 생성물의 물질 순도는 88%였다.12 g of (-)-1- (4-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (purity 98.3%) was dissolved in 50 ml of toluene, Input. Here, the Raney copper catalyst prepared in Preparation Example 1 was weighed and weighed with 20 g (dry weight: 13.3 g) in a wet state. The reaction temperature was raised to 105 ° C. while flowing hydrogen to the reactor at atmospheric pressure, and reacted for 17 hours. After the reaction, the catalyst was collected by filtration, washed with 100 ml of 0.1 N sodium hydroxide solution, and the layers were separated and the organic solvent layer was recovered. The organic solvent was distilled off to remove the racemization reaction product into an oil phase. Got it. The optical purity was measured using a polarimeter and chiral chromatography, and the racemization rate was 18%. The material purity of the reaction product was 88%.
비교실시예 3Comparative Example 3
이 실시예는 반응 압력을 높혀도 반응 온도가 낮으면 반응 속도가 매우 느려짐을 보여주는 것이다.This example shows that even if the reaction pressure is increased, the reaction rate is very slow when the reaction temperature is low.
(+)-1-(4-메톡시벤질)-1,2,3,4,5,6,7,8-옥타하이드로이소퀴놀린(순도 93.3%) 73g을 톨루엔 350㎖에 용해시켜 고압반응기에 투입하였다. 여기에상기 제조예 1에서 제조된 라니 구리 촉매를 젖은 상태의 무게 15g(건조중량 : 10.0g)을 달아서 투입하였다. 고압 반응기에 수소를 채우고 반응온도를 95℃로 올리고 나서 수소 압력을 약 450psig로 상승시켜 12시간동안 반응시켰다. 반응 후 촉매를 걸러서 회수하고 반응 용액에 0.1N 수산화나트륨 용액 300㎖를 가하여 세척한 후 층분리하여 유기 용매 층을 회수하고 난 다음, 유기 용매를 증류하여 완전히 제거하여 라세미화 반응 생성물을 오일상으로 얻었다. 편광계와 키랄 크로마토그래피를 사용하여 광학 순도를 측정한 결과, 라세미화율은 10%였다. 반응 생성물의 물질 순도는 93%였다.73 g of (+)-1- (4-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (purity 93.3%) in 350 ml of toluene was dissolved in a high pressure reactor. Input. Here, the Raney copper catalyst prepared in Preparation Example 1 was added with a weight of 15 g (dry weight: 10.0 g) in a wet state. Hydrogen was charged in the high pressure reactor and the reaction temperature was raised to 95 ° C., and then the hydrogen pressure was raised to about 450 psig and reacted for 12 hours. After the reaction, the catalyst was collected by filtration, washed with 300 ml of 0.1 N sodium hydroxide solution, and the layers were separated and the organic solvent layer was recovered. The organic solvent was distilled off to remove the racemization reaction product into an oil phase. Got it. The optical purity was measured using a polarimeter and chiral chromatography, and the racemization rate was 10%. The material purity of the reaction product was 93%.
비교실시예 4Comparative Example 4
이 실시예는 본 발명의 촉매가 아닌 기존의 라니 코발트-구리 촉매를 사용한 실험 결과를 보여주는 것이다. 물 100㎖에 라니 코발트 30g을 넣고 준비된 5% 황산 구리 용액 100㎖를 떨어뜨리면서 세게 교반하였다. 교반은 상온에서 2시간하였다. 침전을 가라앉힌 다음 상부 물을 버리고 다시 물 200㎖를 넣어 교반하였다. 다시 침전을 가라앉힌 다음 상부 물을 버리고 메탄올 200㎖를 넣었다.This example shows the results of experiments using a conventional Raney cobalt-copper catalyst, not the catalyst of the present invention. 30 g of Raney cobalt was added to 100 ml of water, and 100 ml of the prepared 5% copper sulfate solution was dripped while stirring. Stirring was performed at room temperature for 2 hours. After the precipitate had settled, the upper water was discarded, and 200 ml of water was added thereto, followed by stirring. The precipitate was allowed to settle down and the top water was discarded and 200 ml of methanol was added.
(+)-1-(4-메톡시벤질)-1,2,3,4,5,6,7,8-옥타하이드로이소퀴놀린(순도 83.5%) 23.7g을 톨루엔 300㎖에 녹이고 고압 반응기로 옮긴 다음 제조된 반응 촉매를 젖은 상태의 무게 15g(건조중량 : 10g)을 달아서 반응기에 투입하였다. 고압 반응기에 수소를 채우고 반응온도를 125℃로 올리고 나서 수소 압력을 약 600psig로 가압하여 22시간 동안 반응시켰다. 반응 후 촉매를 걸러서 회수하고 메탄올을 증류하였다. 남은 오일에 클로로포름 300㎖와 물 200㎖를 넣고 층 분리하여 유기용매층을 회수하고 난 다음, 유기용매를 증류하여 완전히 제거함으로써 라세미화 반응 생성물을 오일상으로 얻었다. 편광계를 사용하여 광학 순도를 측정한 결과 전환율은 38%였다. 반응 생성물의 물질순도는 69.8%였다.23.7 g of (+)-1- (4-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (purity 83.5%) was dissolved in 300 ml of toluene and After the transfer, the prepared reaction catalyst was weighed and weighed 15 g (dry weight: 10 g) and charged into the reactor. Hydrogen was charged in the high pressure reactor, the reaction temperature was raised to 125 ° C, and the reaction was carried out for 22 hours under pressure of about 600 psig. After the reaction, the catalyst was collected by filtration and methanol was distilled off. 300 ml of chloroform and 200 ml of water were added to the remaining oil, and the layers were separated. The organic solvent layer was recovered. The organic solvent was distilled off to obtain a racemization reaction product in an oil phase. The optical purity was measured using the polarimeter and the conversion rate was 38%. The material purity of the reaction product was 69.8%.
상기 실시예 1 내지 9를 요약하여 다음의 표 1에 나타내었다.Examples 1 to 9 are summarized in Table 1 below.
* 실시예 5에서의 반응물만 1-(4-메톡시벤질)-N-메틸-1,2,3,4,5,6,7,8-옥타하이드로이소퀴놀린 이었고 나머지 실시예의 반응물은 1-(4-메톡시벤질)-1,2,3,4,5,6,7,8-옥타하이드로이소퀴놀린이었다.* Only the reactants in Example 5 were 1- (4-methoxybenzyl) -N-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline and the reactants in the remaining examples were 1- (4-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline.
Claims (7)
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