KR19990079332A - Method for preparing tetrahydrocarbazolone derivative - Google Patents
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Abstract
본 발명은 구토억제제로서 유용한 하기 화학식 1의 테트라하이드로카르바졸론 유도체의 신규한 제조방법에 관한 것이다.The present invention relates to a novel process for the preparation of tetrahydrocarbazolone derivatives of the general formula (1) useful as antiemetic agents.
상기 식에서, R1은 저급알킬기 및 알콕시메틸기를 나타낸다.In the formula, R 1 represents a lower alkyl group and an alkoxymethyl group.
Description
본 발명은 구토억제제로서 유용한 하기 화학식 1의 테트라하이드로카르바졸론 유도체의 신규한 제조방법에 관한 것이다.The present invention relates to a novel process for the preparation of tetrahydrocarbazolone derivatives of the general formula (1) useful as antiemetic agents.
상기 식에서, R1은 저급알킬기 또는 알콕시메틸기를 나타낸다.In the formula, R 1 represents a lower alkyl group or an alkoxymethyl group.
상기 화학식 1의 화합물은 현재 구토억제제로서 널리 사용되고 있으며, 그 제조방법은 현재 여러 가지가 알려져 있으며, 예를 들어 한국 공고특허공보 제92-3064호에 기재되어 있는 제조방법은 하기 반응식 1과 같다.The compound of Formula 1 is currently widely used as an anti-emetic agent, the production method is currently known in various ways, for example, the preparation method described in Korean Patent Publication No. 92-3064 is the same as Scheme 1.
상기 식에 있어서, R1, RaRb및 Rc는 알킬기이고, 특히 메틸기가 유용하다.In the above formula, R 1 , R a R b and R c are alkyl groups, and methyl groups are particularly useful.
상기 화학식 4의 화합물을 2차 아민의 산염 및 포름알데히드와 반응시켜 상기 화학식 5의 화합물을 얻고, 여기에 알킬아이오다이드를 반응시켜 상기 화학식 6의 4차 아민염을 얻으며, 이것을 상기 화학식 2의 화합물과 반응시켜 목적화합물인 화학식 1의 화합물을 얻는 방법이다.The compound of Formula 4 is reacted with an acid salt of a secondary amine and formaldehyde to obtain the compound of Formula 5, and an alkyl iodide is reacted to obtain a quaternary amine salt of Formula 6, which is It is a method of obtaining the compound of Formula 1 which is a target compound by reacting with a compound.
상기 특허에서 목적화합물을 얻는 다른 방법으로서, 상기 화학식 6의 화합물을 염기성 수용액 중에서 반응시켜 상기 화학식 3의 화합물을 얻고, 이를 상기 화학식 2의 화합물과 반응시켜 목적화합물을 얻는 방법도 기재되어 있다.As another method of obtaining the target compound in the patent, a method of obtaining the compound of formula 3 by reacting the compound of formula 6 in a basic aqueous solution, and reacting it with the compound of formula 2 is also described.
그러나 상기 제조방법들은 상기 화학식 6의 화합물을 이용하므로 이탈 물질로서 트리알킬아민이 반응물과 같은 당량이 발생하여 환경문제를 유발할 수 있으며, 또한 상기 화학식 6의 화합물을 제조하기 위하여 포름알데히드 외에 당량 이상의 디알킬아민과 알킬아이오다이드를 추가로 사용해야 하므로 경제적인 방법이라고 하기가 곤란하다. 아울러 상기 화학식 6의 화합물을 상기 화학식 2의 화합물과 반응시키는 방법도 반응시간이 매우 길고 수율이 낮아서 비효율적이다.However, since the preparation methods use the compound of Chemical Formula 6, trialkylamine may be the same as the reactant, causing an environmental problem. Also, in order to prepare the compound of Chemical Formula 6, an equivalent of dialdehyde or more in addition to formaldehyde may be used. Since it is necessary to use alkylamine and alkyl iodide additionally, it is difficult to say economical method. In addition, the method of reacting the compound of Formula 6 with the compound of Formula 2 is also inefficient because the reaction time is very long and the yield is low.
한편 캐나다 특허 제2,106,642호에는 하기 반응식 2에 나타낸 바와 같이 화학식 4의 화합물에 나트륨 알콕사이드와 알킬옥살레이트를 반응시켜 하기 화학식 7의 화합물을 제조하고, 여기에 염기 조건에서 포르말린 용액을 반응시켜 하기 화학식 8의 화합물을 얻은 후, 하기 화학식 2의 화합물과 반응시켜 목적화합물인 화학식 1의 화합물을 제조하는 방법이 기재되어 있다.Meanwhile, in Canadian Patent No. 2,106,642, as shown in Scheme 2, sodium alkoxide and alkyl oxalate are reacted with a compound of Formula 4 to prepare a compound of Formula 7, and then reacting a formalin solution under basic conditions to Formula 8 After obtaining a compound of the following reaction by reacting with a compound of formula (2) to prepare a compound of formula (1) as the target compound.
상기 식에서, R1은 상기 정의한 바와 같고, R3는 저급알킬기이다.Wherein R 1 is as defined above and R 3 is a lower alkyl group.
상기 캐나다 특허 제2,106,642호의 방법은 한국공고 특허공보 제92-3064호의 방법과 비교하여 반응 공정 수는 같지만 당량 이상의 알킬옥살레이트와 그와 같은 당량의 나트륨 알콕사이드가 작용되어야 하는 점과 특히 상기 화학식 7의 화합물을 제조하는 반응 조건에서 상기 화학식 7의 불안정으로 인해 생성되는 불순물을 제거해야 하는 문제점이 있어, 이를 해결하기 위한 공정이 추가되어야 하므로 이 방법 역시 경제적으로 바람직한 방법이라고 할 수는 없다.The method of Canadian Patent No. 2,106,642 is the same as that of Korean Patent Publication No. 92-3064, but at least the same number of alkyloxalates and such equivalents of sodium alkoxide should be acted on. There is a problem in that the impurities produced by the instability of the formula (7) under the reaction conditions for preparing the compound, there is a problem to solve this problem, so this method is not economically preferable method.
본 발명자들은 상기 문제점들을 해결하기 위하여 많은 연구와 노력을 한 결과, 보다 환경 친화적이고 경제적인 새로운 방법을 발견하게 되어 본 발명을 완성하였다.The present inventors have made a lot of research and efforts to solve the above problems, and as a result, have found a new method that is more environmentally friendly and economical, and completed the present invention.
본 발명의 목적은 테트라하이드로카르바졸론 유도체의 신규한 제조방법을 제공하는데 있다.It is an object of the present invention to provide a novel process for the preparation of tetrahydrocarbazolone derivatives.
본 발명은 하기 화학식 1의 테트라하이드로카르바졸론 유도체의 제조방법에 관한 것이다.The present invention relates to a method for preparing a tetrahydrocarbazolone derivative of the formula (1).
상기 식에서, R1은 저급알킬기 또는 알콕시메틸기를 나타낸다.In the formula, R 1 represents a lower alkyl group or an alkoxymethyl group.
본 발명의 테트라하이드로카르바졸론 유도체의 제조방법은 하기 반응식 3과 같이 나타낼 수 있다.Method for producing a tetrahydrocarbazolone derivative of the present invention can be represented by the following scheme 3.
상기 식에서, R1은 저급알킬기 또는 알콕시메틸이고, R2는 저급알킬기, 하이드록시알킬기, 할로알킬기 또는 티오알킬기이다.Wherein R 1 is a lower alkyl group or alkoxymethyl and R 2 is a lower alkyl group, hydroxyalkyl group, haloalkyl group or thioalkyl group.
상기 반응식 3은 화학식 4의 화합물과 포름알데히드 또는 그 전구체를 촉매량의 R2NH2, (R2)2NH 또는 이들의 산염과 반응시켜 화학식 3의 화합물을 얻은 후, 화학식 3의 화합물을 비양성자성(aprotic) 용매 중에서 촉매량의 강염기와 함께 화학식 2의 화합물과 반응시켜 목적화합물인 화학식 1의 테트라하이드로카르바졸론 유도체를 제조하는 방법을 나타낸 것이다.In Scheme 3, a compound of Formula 4 and formaldehyde or a precursor thereof are reacted with a catalytic amount of R 2 NH 2 , (R 2 ) 2 NH or an acid salt thereof to obtain a compound of Formula 3, and then the compound of Formula 3 is not positive. A method of preparing a tetrahydrocarbazolone derivative of the general formula (1) by reacting a compound of the general formula (2) with a catalytic amount of a strong base in an aprotic solvent is shown.
상기 포름알데히드 또는 그 전구체로서는 포르말린수용액, 파라포름알데히드, 1,3,5-트리옥산, 1,3-디옥솔란 등이 바람직하다.As the formaldehyde or its precursor, aqueous formalin solution, paraformaldehyde, 1,3,5-trioxane, 1,3-dioxolane and the like are preferable.
상기 R2NH2및 (R2)2NH은 메틸아민 또는 에탄올아민이고, 그 산염은 염산염 또는 초산염 등이 바람직하다.R 2 NH 2 and (R 2 ) 2 NH are methylamine or ethanolamine, and the salts thereof are preferably hydrochloride or acetate.
상기 비양성자성(aprotic) 용매는 디옥산, THF 또는 아세토니트릴 등을 사용하는 것이 바람직하다.As the aprotic solvent, dioxane, THF or acetonitrile is preferably used.
상기 촉매로 사용되는 강염기로는 MOH [여기서 M은 나트륨, 칼륨, 리튬 등의 알칼리금속 또는 마그네슘(1/2), 칼륨(1/2) 등의 알칼리토금속] 또는 2-메틸이미다졸의 나트륨염을 사용하는 것이 바람직하다.As the strong base used as the catalyst, MOH [where M is an alkali metal such as sodium, potassium, lithium or alkaline earth metal such as magnesium (1/2), potassium (1/2)] or sodium of 2-methylimidazole Preference is given to using salts.
상기 화학식 4의 화합물과 R2NH2, (R2)2NH 또는 이들의 산염의 반응온도는 70~120℃가 바람직하며, 화학식 3의 화합물과 화학식 2의 화합물의 반응온도는 30~120℃가 바람직하다.The reaction temperature of the compound of Formula 4 and R 2 NH 2 , (R 2 ) 2 NH or an acid salt thereof is preferably 70 to 120 ° C., and the reaction temperature of the compound of Formula 3 to compound of Formula 2 is 30 to 120 ° C. Is preferred.
또한 화학식 4의 화합물과 포름알데히드 또는 그 전구체를 촉매량의 R2NH2, (R2)2NH 또는 이들의 산염과 반응시켜 화학식 3의 화합물을 얻은 후, 화학식 3의 화합물을 비양성자성(aprotic) 용매 중에서 2-메틸이미다졸의 나트륨염과 반응시켜 화학식 1의 화합물을 얻고, 여기에 염산을 가하여 화학식 1의 화합물의 염산염 또는 그 수화물을 제조하는 것도 가능하다.In addition, the compound of Formula 4 and formaldehyde or a precursor thereof are reacted with a catalytic amount of R 2 NH 2 , (R 2 ) 2 NH or an acid salt thereof to obtain the compound of Formula 3, and then the compound of Formula 3 is aprotic. It is also possible to react the sodium salt of 2-methylimidazole in a solvent to obtain a compound of formula 1, and to add hydrochloric acid to prepare a hydrochloride salt of the compound of formula 1 or a hydrate thereof.
상기 본 발명의 테트라하이드로카르바졸론 유도체의 제조방법은 종래 공정이 3~4공정을 거쳐야 했던 것에 비해 단 2공정만으로 간단하게 이루어졌으며, 또한 수율이 89%로 높아서 경제적으로도 바람직하다.The method for producing a tetrahydrocarbazolone derivative of the present invention is simple in only two steps, compared with the conventional step that had to go through three to four steps, and the yield is high as 89%, so it is economically preferable.
하기 실시예를 통해 본 발명을 보다 구체적으로 예시하나 이로써 본 발명의 범위를 제한하는 것은 아니다.The following examples illustrate the invention in more detail but do not limit the scope of the invention.
제조예 1. 2-메틸이미다졸 나트륨염Preparation Example 1 2-methylimidazole sodium salt
8.20g의 2-메틸이미다졸을 40ml의 무수 THF에 가하고 실온으로 온도를 유지하면서 2.88g의 나트륨하이드라이드를 서서히 가한 후 2시간 동안 교반하고 40ml의 에틸에테르를 가하여 2시간 더 교반한 후 얻어지는 침전물을 여과하고 건조된 에틸에테르로 세척하고 감압 건조하여 7.9g의 표제물질을 얻었다.8.20 g of 2-methylimidazole was added to 40 ml of anhydrous THF and 2.88 g of sodium hydride was slowly added while maintaining the temperature at room temperature, followed by stirring for 2 hours, followed by further stirring for 2 hours with 40 ml of ethyl ether. The precipitate was filtered off, washed with dried ethyl ether and dried under reduced pressure to obtain 7.9 g of the title substance.
실시예 1. 1,2,3,9-테트라하이드로-9-메틸-3-메틸렌-4H-카르바졸-4-온Example 1. 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one
2.0g의 9-메틸카르바졸-4-온[Chem.Pharm.Bull. 31(8) 2652-2661(1983) 방법으로 제조]과 1.0g의 파라포름알데히드를 20ml의 아세트산 중에서 교반하면서 5ml의 메틸아민의 THF용액(2.0mol)을 가하고 100℃에서 36시간 반응시킨 다음 감압 농축하고 20ml의 물 중에서 실온 교반해서 얻어지는 조생성물을 실리카겔 중에서 에틸아세테이트의 벤젠용액(25%)으로 용출하여 1.62g(76.7%)의 표제 화합물을 얻었다.2.0 g of 9-methylcarbazol-4-one [Chem. Pharm. Bull. 31 (8) 2652-2661 (1983) method] and 1.0 g of paraformaldehyde in 20 ml of acetic acid with 5 ml of methylamine THF solution (2.0 mol) were added thereto, reacted at 100 DEG C for 36 hours, and then The crude product obtained by concentrating and stirring at room temperature in 20 ml of water was eluted with benzene solution (25%) of ethyl acetate in silica gel to obtain 1.62 g (76.7%) of the title compound.
mp 128-129℃mp 128-129 ℃
1H NMR(CDCl3, 200MHz) δ 1 H NMR (CDCl 3 , 200 MHz) δ
8.35~8.30(m,1H), 7.30~7.27(m,3H), 6.15~6.14(d,1H, J=1.9Hz),8.35-8.30 (m, 1H), 7.30-7.27 (m, 3H), 6.15-6.14 (d, 1H, J = 1.9 Hz),
5.38~5.37(d,1H,J=1.9Hz), 3.67(s,3H), 2.99~2.95(m,4H)5.38-5.37 (d, 1H, J = 1.9 Hz), 3.67 (s, 3H), 2.99-2.95 (m, 4H)
IR(KBr) 1654, 1594 cm-1 IR (KBr) 1654, 1594 cm -1
실시예 2. 1,2,3,9-테트라하이드로-9-메틸-3-메틸렌-4H-카르바졸-4-온Example 2. 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one
5.0g의 9-메틸카르바졸-4-온과 2.5g의 파라포름알데히드를 50ml의 클로로벤젠에 가하여 교반하면서 500mg의 메틸아민 염산염을 가한 후 24시간 가열환류 반응시켰다. 여과 후 10ml정도로 감압 농축하고 냉각하여 얻어진 결정을 여과 건조하였다. 여액을 감압 농축하여 얻어진 결정용액을 여과 건조하고 1차 수득물과 합하여 20ml의 에탄올로 재결정하여 4.3g(81%)의 실시예 1과 동일한 물질을 얻었다.5.0 g of 9-methylcarbazol-4-one and 2.5 g of paraformaldehyde were added to 50 ml of chlorobenzene and 500 mg of methylamine hydrochloride was added thereto under stirring, followed by heating under reflux for 24 hours. After filtration, the resulting crystal was concentrated under reduced pressure to about 10 ml and cooled, and the crystals obtained were filtered and dried. The filtrate was concentrated under reduced pressure, and the obtained crystal solution was filtered and dried, and recrystallized with 20 ml of ethanol to obtain the same material as in Example 1 (4.3 g).
실시예 3. 1,2,3,9-테트라하이드로-9-메틸-3-메틸렌-4H-카르바졸-4-온Example 3. 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one
2.0g의 9-메틸카르바졸-4-온과 1.0g의 파라포름알데히드를 30ml의 2-메톡시에틸에테르중에서 152mg의 에탄올아민 염산염을 가하고 100℃로 45시간 교반한 후 실온까지 냉각하고 60ml의 물을 가하여 충분히 여과하여 건조하였다. 얻어진 조생성물을 30ml의 메틸렌 클로라이드에 용해시켜 활성탄 처리후 감압 농축하고 20ml의 물 중에서 실온 교반해서 얻어진 분말을 이소프로판올 수용액으로 재결정하여 1.55g을 얻었다.2.0 g of 9-methylcarbazol-4-one and 1.0 g of paraformaldehyde were added to 152 mg of ethanolamine hydrochloride in 30 ml of 2-methoxyethyl ether, stirred at 100 ° C. for 45 hours, and then cooled to room temperature, followed by 60 ml of Water was added, followed by sufficient filtration and drying. The obtained crude product was dissolved in 30 ml of methylene chloride, activated carbon treatment, concentrated under reduced pressure, and the powder obtained by stirring at room temperature in 20 ml of water was recrystallized with an isopropanol aqueous solution to obtain 1.55 g.
실시예 4. 1,2,3,9-테트라하이드로-9-메틸-3-메틸렌-4H-카르바졸-4-온Example 4 1,2,3,9-Tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one
2.0g의 9-메틸카르바졸-4-온과 2.9g의 35% 포르말린 수용액을 25ml의 아세트산 중에서 교반하면서 500mg의 에탄올아민을 가하고 100℃로 36시간 교반후 감압농축한후 20ml의 물 중에서 교반해서 얻어지는 침전물을 여과 건조하였다. 얻어진 조생성물을 실리카겔에서 에틸아세테이트의 메틸렌클로라이드용액(5%)로 분리하여 1.25g의 실시예 1과 동일한 화합물을 얻었다.500 g of ethanolamine were added while stirring 2.0 g of 9-methylcarbazol-4-one and 2.9 g of 35% formalin aqueous solution in 25 ml of acetic acid, stirred at 100 ° C. for 36 hours, concentrated under reduced pressure, and stirred in 20 ml of water. The precipitate obtained was filtered and dried. The obtained crude product was separated by silica gel with methylene chloride solution (5%) of ethyl acetate to obtain 1.25 g of the same compound as in Example 1.
실시예 5. 1,2,3,9-테트라하이드로-9-메틸-3-메틸렌-4H-카르바졸-4-온Example 5. 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one
2.0g의 9-메틸카르바졸-4-온과 1.0g의 파라포름알데히드를 20ml의 아세트니트릴 중에서 90mg의 비스(2-클로로에틸)아민 염산염을 가하고 24시간 동안 환류 교반한 후 실온까지 냉각하고 30ml의 물을 가하여 충분히 여과하여 건조하였다. 얻어진 분말을 이소프로판올 수용액으로 재결정하면 1.51g의 실시예 1과 동일한 화합물을 얻었다.2.0 g of 9-methylcarbazol-4-one and 1.0 g of paraformaldehyde were added to 90 mg of bis (2-chloroethyl) amine hydrochloride in 20 ml of acetonitrile and stirred at reflux for 24 hours, followed by cooling to room temperature and 30 ml Water was added, followed by filtration and drying. When the obtained powder was recrystallized with an isopropanol aqueous solution, 1.51 g of the same compound as in Example 1 was obtained.
실시예 6. 1,2,3,9-테트라하이드로-9-메틸-3-[(2-메틸-1H-이미다졸-1-일)메틸]-4H-카르바졸-4-온Example 6. 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one
실시예 1에서 제조된 2.11g의 1,2,3,9-테트라하이드로-9-메틸-3-메틸렌-4H-카르바졸-4-온을 25ml의 디옥산에 가하고 교반하면서 1.45g의 2-메틸이미다졸과 제조예 1에서 제조된 150mg의 2-메틸이미다졸나트륨염을 가하고 2시간 가열환류하고 25ml의 물을 가한 후 1야 냉각해서 얻어진 침전물을 여과하고 감압건조한 후 아세토니트릴 수용액으로 재결정하여 2.64g(89.9%)의 표제화합물을 얻었다.2.11 g of 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one prepared in Example 1 was added to 25 ml of dioxane and stirred while 1.45 g of 2- Methylimidazole and 150 mg of 2-methylimidazole sodium salt prepared in Preparation Example 1 were added thereto, heated and refluxed for 2 hours, 25 ml of water was added, and the precipitate obtained by cooling overnight was filtered, dried under reduced pressure, and then acetonitrile aqueous solution. Recrystallization gave 2.64 g (89.9%) of the title compound.
mp 239-240℃(dec)mp 239-240 ° C (dec)
실시예 7. 1,2,3,9-테트라하이드로-9-메틸-3-[(2-메틸-1H-이미다졸-1-일)메틸]-4H-카르바졸-4-온Example 7. 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one
1.30g의 NaOH와 14.5g의 2-메틸이미다졸을 250ml의 디옥산에 가하고 10분간 가열환류후에 실시예 1에서 제조된 21.1g의 1,2,3,9-테트라하이드로-9-메틸-3-메틸렌-4H-카르바졸-4-온을 250ml의 디옥산에 가하고 3시간동안 가열환류반응 후 250ml의 물을 가하고 3시간동안 실온교반하였다. 침전물을 여과, 건조한 후 아세토니트릴수용액으로 재결정하여 실시예5와 동일한 화합물 24.4g(83.2%)을 얻었다.1.30 g of NaOH and 14.5 g of 2-methylimidazole were added to 250 ml of dioxane and heated to reflux for 10 minutes, followed by 21.1 g of 1,2,3,9-tetrahydro-9-methyl- prepared in Example 1. 3-methylene-4H-carbazol-4-one was added to 250 ml of dioxane and heated under reflux for 3 hours followed by 250 ml of water and stirred at room temperature for 3 hours. The precipitate was filtered, dried and recrystallized with acetonitrile aqueous solution to give 24.4 g (83.2%) of the same compound as in Example 5.
실시예 8. 1,2,3,9-테트라하이드로-9-메틸-3-[(2-메틸-1H-이미다졸-1-일)메틸]-4H-카르바졸-4-온·염산염 2수화물Example 8. 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride 2 Luggage
실시예 1에서 제조된 2.11g의 1,2,3,9-테트라하이드로-9-메틸-3-메틸렌-4H-카르바졸-4-온을 25ml의 디옥산에 가하고 교반하면서 1.45g의 2-메틸이미다졸과 50mg의 2-메틸이미다졸나트륨염을 가하고 4시간 동안 가열환류반응 후 진한염산 1.0ml를 6ml의 물에 녹여 적가하고 교반하여 결정이 생성되면 실온 냉각 후 2시간 교반하여 여과하고 디옥산으로 세척 후 감압건조하였다. 얻어진 조생성물을 2.5ml의 물과 12ml의 이소프로필알콜에 가하여 가열용해 후 가온여과하고 얻어진 용액에 12ml의 이소프로필알콜을 서서히 가하고 결정이 생성되면 하룻밤 실온 교반하고 여과 후 이소프로필알콜으로 세척하여 감압건조하여 2.55g의 표제화합물을 얻었다.2.11 g of 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one prepared in Example 1 was added to 25 ml of dioxane and stirred while 1.45 g of 2- Methylimidazole and 50 mg of 2-methylimidazole sodium salt were added, and after heating and refluxing for 4 hours, 1.0 ml of concentrated hydrochloric acid was dissolved in 6 ml of water, and the mixture was added dropwise. When crystals were formed, the mixture was cooled and stirred for 2 hours. After washing with dioxane and dried under reduced pressure. The obtained crude product was added to 2.5 ml of water and 12 ml of isopropyl alcohol, dissolved in heat, and warmed and filtered. 12 ml of isopropyl alcohol was gradually added to the resulting solution. After crystal formation, the mixture was stirred overnight at room temperature, filtered, washed with isopropyl alcohol, and decompressed. Drying gave 2.55 g of the title compound.
mp 177∼179℃mp 177-179 ℃
1H NMR(D2O, 200MHz) δ 1 H NMR (D 2 O, 200 MHz) δ
7.76∼7.73(t,1H,J=3.0Hz), 7.34∼7.21(m,2H), 7.21∼7.18(m,3H),7.76 to 7.73 (t, 1H, J = 3.0 Hz), 7.34 to 7.71 (m, 2H), 7.21 to 7.18 (m, 3H),
4.42∼4.17(m,2H), 3.24(s,1H), 2.76∼2.66(m,2H), 2.57(s,3H),4.42 to 4.17 (m, 2H), 3.24 (s, 1H), 2.76 to 2.66 (m, 2H), 2.57 (s, 3H),
2.52∼2.35(m,1H), 2.12~2.04(m,1H), 1.85~1.62(m,1H)2.52 to 2.25 (m, 1H), 2.12 to 2.04 (m, 1H), 1.85 to 1.62 (m, 1H)
IR(KBr) 3500, 3409, 1638 cm-1 IR (KBr) 3500, 3409, 1638 cm -1
C18H19N3O·HCl·2H2O 수분측정(Karl Fischer 법) : 실측치 10.16%(이론치 9.85%)C 18 H 19 N 3 OHCl 2H 2 O Moisture measurement (Karl Fischer method): found 10.16% (theoretical 9.85%)
본 발명의 테트라하이드로카르바졸론 유도체의 제조방법은 환경문제를 유발시키는 트리알킬아민을 발생시키지 않으므로 보다 환경친화적이고, 제조 공정이 간단하며 간단한 조작만으로 이루어지는 경제적인 새로운 방법을 제공한다.The method for producing a tetrahydrocarbazolone derivative of the present invention does not generate trialkylamine causing environmental problems, thereby providing a new environmentally friendly method that is more environmentally friendly, a simple manufacturing process and simple operation.
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