KR0161803B1 - Terbinafine for fungicide - Google Patents
Terbinafine for fungicide Download PDFInfo
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- KR0161803B1 KR0161803B1 KR1019950022173A KR19950022173A KR0161803B1 KR 0161803 B1 KR0161803 B1 KR 0161803B1 KR 1019950022173 A KR1019950022173 A KR 1019950022173A KR 19950022173 A KR19950022173 A KR 19950022173A KR 0161803 B1 KR0161803 B1 KR 0161803B1
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Abstract
본 발명은 항진균제용 터비나핀 및 그 염산염의 제조방법에 관한 것으로, 팔라디움 커플링반응, 환원반응 및 설포네이트와 아민의 커플링 반응의 3단계 반응을 거침으로서 올레핀의 E-입체화학을 입체특이적으로 합성할 수 있고, 최종물질의 입체특이성 혼합물을 분리할 필요가 없을 뿐만 아니라 높은 수율로 터비나핀 염산염을 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing terbinapine and its hydrochloride for an antifungal agent, wherein the three-step reaction of palladium coupling reaction, reduction reaction and coupling reaction of sulfonate and amine is performed to stereo-specifically the E-stereochemistry of the olefin. The present invention relates to a method for preparing terbinaic hydrochloride in high yields, which can be synthesized in a conventional manner, and that there is no need to separate stereospecific mixtures of the final material.
Description
[발명의 명칭][Name of invention]
항진균제용 터비나핀 및 그 염산염의 제조방법Method for preparing terbinafine and its hydrochloride for antifungal agents
[발명의 상세한 설명]Detailed description of the invention
[발명의 목적][Purpose of invention]
본 발명은 항진균제용 (E)-N-(6,6-디메틸-2-헵텐-4-이닐)-N-메틸-1-나프탈렌메타아민 [일명 터비나핀(Terbinafine)이라고 함] 및 그 염산염의 제조방법에 관한 것으로, 더욱 상세하게는 팔라디움 커플링 반응, 환원반응 및 설포네이트와 아민의 커플링 반응의 3단계 반응을 거침으로서 올레핀의 E- 입체화학을 입체특이적으로 합성할 수 있고, 최종물질을 어려운 분리과정없이 높은 수율로 얻을 수 있는 터비나핀 및 그 염산염의 제조방법에 관한 것이다.The present invention provides (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethamine (also called terbinafine) and its hydrochloride for antifungal agents. It relates to a process for the preparation of, in more detail can be synthesized stereospecifically the olefin E- stereochemistry of the olefin by a three-step reaction of the palladium coupling reaction, the reduction reaction and the coupling reaction of sulfonates and amines, The present invention relates to a process for preparing terbinafine and its hydrochloride, which can be obtained in high yield without difficult separation process.
[발명의 이용분야][Use of invention]
진균류(Fungi)가 일으키는 질병에는 조갑진균증(Onychomycosis), 무좀(tinea), 백선(tinea corporis), 어루러기(pityriasis versicolor), 완선(tinea cruris), 두부백선(tinea capitis), 구강 칸디다증(oral candidosis) 및 칸디다성 질염(vaginal candidosis) 등이 있으며, 이들의 원인균은 피부사상균, 효모균, 몰드 등으로 다양하다.Fungi-related diseases include Onychomycosis, athlete's foot, tinea, tinea corporis, pityriasis versicolor, tinea cruris, tinea capitis, oral candidosis. And vaginal candidosis (vaginal candidosis) and the like, the causative agents of these are various, such as dermatophytes, yeast, mold.
종래 항진균제에 대한 개발은 항세균제에 비하여 성과가 미미하였으며 최근 다양한 항진균제의 개발이 진전되고 있다. 더욱이 진균류에 의한 징병은 주로 피부의 질병으로서 복합감염에 의한 경우가 많아 광범위 항진균제의 개발이 요청되고 있는 실정이다.The development of conventional antifungal agents has been less successful than antibacterial agents, and various antifungal agents have recently been developed. In addition, the draft of the fungus is mainly a skin disease, which is often caused by complex infections, and thus the development of a wide range of antifungal agents is required.
최근 일반적인 스크리닝 방법에 의해 나프티핀(naftifine)이 항진균 효과가 발견된 이래 나프티핀 계열의 유도체에 대한 집중적인 연구결과 본 발명의 목적물인 터비나핀이 매우 강력한 항진균 작용을 나타내는 것을 발견하였다. 본 발명의 터비나핀은 광범위 항진균제로서 독성 또한 적은 우수한 효과를 갖고 있기 때문에 상기한 질병에 널리 이용되고 있다.In recent years, since naftifine has been found to have an antifungal effect by a general screening method, intensive studies on naphtipine derivatives have shown that terbinafine, an object of the present invention, exhibits very strong antifungal action. Terbinafin of the present invention is widely used in the above-mentioned diseases because it has an excellent effect with less toxicity as a broad antifungal agent.
[종래기술][Private Technology]
나프티핀 계열의 항진균제는 알릴아민을 필수 구성요소로 갖고 있으며, 나프티핀 계열 중 가장 우수한 항진균효과를 갖고 있는 본 발명의 목적물인 터비나핀은 (E)-1,3-엔인 치환체(E-1,3-enyne substituent)를 포함하는 알릴아민 유도체로서 아릴아민과 t-부틸아세틸렌이 트란스로 커플링되어 있는 점에 특징이 있다.The naphtipine antifungal agent has allylamine as an essential component, and terbinafine, the object of the present invention having the best antifungal effect among the naphtipine series, is an (E) -1,3-ene substituent (E- Allylamine derivatives containing 1,3-enyne substituent) are characterized in that arylamine and t-butylacetylene are coupled by trans.
다시 말하자면 아릴아민의 이중결합과 t-부틸아세틸렌의 3중 결합이 연결될 때 트란스로 연결된 것만이 항진균효과를 나타내므로, 터비나핀의 제조방법은 E체만을 제조할 수 있는 방향으로 개량을 거듭해오고 있다.In other words, when the double bond of arylamine and the triple bond of t-butylacetylene are connected, only the trans-linked one exhibits an antifungal effect. Thus, the method of preparing terbinafine has been improved in the direction of producing only E-body. have.
최초로 개발된 터비나핀의 합성공정은 알릴브로마이드와 이차아민과를 축합반응 시킨 후 디이소부틸알루미늄 하이드라이드(Diisobuty1 aluminum hydride; DIBAH)로 환원시켜 6.6-디메틸-2E-헵텐-4-이닐 t-아민을 얻은 후 나프탈렌 메틸할라이드와 반응시켜 터비나핀을 얻었다. 그러나, 상기 반응에 의하면 목적물인 터비나핀이 E형 및 Z형의 혼합물로 얻어지므로, 다시 E형만을 분리해야 한다는 결점이 있었다(J. Med. Chem. 1984, 27, 1539-1543, Tetrahedron Vol. 41, No. 23, pp 5685∼5696, 1985).The first process for the synthesis of terbinapine was carried out by condensation reaction of allyl bromide with secondary amine, followed by reduction with diisobuty1 aluminum hydride (DIBAH) to 6.6-dimethyl-2E-hepten-4-ynyl t-. After obtaining an amine, it was reacted with naphthalene methyl halide to obtain terbinafine. However, according to the above reaction, since the target terbinafin is obtained as a mixture of Form E and Form Z, only the Form E is separated again (J. Med. Chem. 1984, 27, 1539-1543, Tetrahedron Vol. 41, No. 23, pp 5685-5696, 1985).
또한 또 다른 제조방법으로는 나프탈렌 메틸아민을 부틸리티움으로 리티에이션 한 후 프로파질 브로마이드를 가하여 프로파질 아민을 만들고 이것을 하이드로지르코네이션 시킨 후 요오드를 가하여 E-비닐 아이오다이드를 만든 후 Bu3Sn - C ≡ C - C(CH3)3등의 주석화합물을 가하여 터비나핀을 만드는 방법이 있다(Tetrahedron Letters; 1988, 29, 13, 1509∼1512).As also another manufacturing method is made after the naphthalene methylamine-butyl lithium as a recreational utility then propargyl bromide was added to it dihydro create a propargyl amine zirconate was Nation after E- vinyl child added iodine iodide Bu 3 There is a method of making terbinafin by adding tin compounds such as Sn-C≡C-C (CH 3 ) 3 (Tetrahedron Letters; 1988, 29, 13, 1509-1512).
이 방법에 의하면 터비나핀의 경우 E형만을 단독으로 고정시킬 수 있다는 잇점이 있으나, 그 자체의 독성으로 인하여 사용이 제한되고 있는 주석화합물을 중간물질로 사용해야 한다는 단점이 있다.This method has the advantage that it is possible to fix only E-type in the case of turbina pin alone, but has the disadvantage of using a tin compound, which is limited in use due to its own toxicity as an intermediate.
그외에 스페인 특허 제550015호에 의하면, 나프탈렌 메틸할라이드와 이차아민을 축합 반응시켜 터비나핀을 제조하는 방법을 제시하고 있으나, 이 특허는 나프탈렌메틸할라이드 등 이차아민 반응을 축합시키는 과정만을 기술한 것으로서 이차아민의 제조방법에 대해서는 언급이 없다.In addition, according to Spanish Patent No. 550015, a method of producing terbinafin by condensation reaction of naphthalene methyl halide and secondary amine is described, but this patent describes only a process of condensing secondary amine reaction such as naphthalene methyl halide. There is no mention of a method for preparing a secondary amine.
이에 본 발명자들은 상기한 문제점들을 해결하기 위하여 연구한 결과 새로운 터비나핀의 제조방법을 발명하였다.Therefore, the inventors have invented a new method of manufacturing turbinafin as a result of research to solve the above problems.
본 발명은 터비나핀 및 그의 염산염을 제조하는 신규한 방법으로서, 본 발명의 방법에 의하면 최종물질의 혼합물을 분리할 필요없이 E형의 터비나핀 및 그의 염산염을 입체특이적으로 높은 수율로 제조할 수 있다.The present invention is a novel process for preparing terbinafine and its hydrochloride. According to the method of the present invention, terbinafine and its hydrochloride of type E are prepared in stereospecific high yield without the need to separate the mixture of final materials. can do.
[발명의 구성][Configuration of Invention]
이하, 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
본 발명은 (1) 하기 구조식Ⅲ으로 표시되는 요오드 프로파길 알코올과 하기 구조식Ⅳ로 표시되는 t-부틸아세틸렌을 팔라디움 촉매하에서 커플링 반응시켜 하기 구조식Ⅴ로 표시되는 6,6-디메틸-2,4-디헵티닐알코올을 얻고, (2) 구조식Ⅴ로 표시되는 6,6-디메틸-2,4-디헵티닐알코올을 테트라하이드로퓨란(이하, THF라 함) 용매하에서 알루미늄계 환원제로 환원반응시켜 하기 구조식Ⅵ으로 표시되는 6,6-디메틸-2E-헵텐-4-이닐알코올을 얻은 후, (3) 구조식Ⅵ로 표시되는 6,6-디메틸-2E-헵텐-4-이닐알코올을 메탄설포닐클로라이드로 반응시켜 설포네이트 중간체를 얻고, 칼륨카보네이트 염기하에서 하기 구조식Ⅶ으로 표시되는 N-메틸-1-나프탈렌메틸아민과 커플링 반응시켜 하기 구조식(Ⅰ)로 표시되는 터비나핀을 얻은 후 메탄올 용매상에서 염산을 처리하여 터비나핀 염산염을 제조함을 특징으로 하는 항진균용 터비나핀 및 그 염산염의 제조방법에 관한 것이다.(1) 6,6-dimethyl-2,4 represented by the following structural formula (V) by coupling a iodine propargyl alcohol represented by the following structural formula (III) with t-butylacetylene represented by the following structural formula (IV) under a palladium catalyst: -Diheptinyl alcohol is obtained, and (2) reduction of 6,6-dimethyl-2,4-diheptinyl alcohol represented by Structural Formula V with an aluminum-based reducing agent in a tetrahydrofuran (hereinafter referred to as THF) solvent is performed. After obtaining 6,6-dimethyl-2E-heptene-4-ynyl alcohol represented by VI, (3) 6,6-dimethyl-2E-heptene-4-ynyl alcohol represented by Structural VI was converted to methanesulfonyl chloride. Reaction was carried out to obtain a sulfonate intermediate, and coupling reaction with N-methyl-1-naphthalenemethylamine represented by the following structural formula Ⅶ under potassium carbonate base to obtain terbinapine represented by the following structural formula (I), followed by hydrochloric acid in a methanol solvent. By processing Turbina It relates to an antifungal terbinafin and a method for producing the hydrochloride, characterized in that the production of the pin hydrochloride.
이하, 본 발명을 더욱 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in more detail.
본 발명에서 구조식Ⅲ로 표시되는 요오드프로파길 알코올은 구조식Ⅱ로 표시되는 프로파길 알코올로부터 종래의 방법에 의하여 제조되며(Bull, Chem. Soc. Jpn, 1972, 45, 2611), 구조식Ⅲ의 화합물과 구조식Ⅳ의 t-부틸아세틸렌을 팔라디움 촉매인 테트라키스(트리페닐포스핀)팔라디움(Ph(PPh3)4), 요오드구리(CuI) 및 디이소프로필아민하에서 커플링 반응시켜 수율 38%의 구조식Ⅴ로 표시되는 6,6-디메틸-2E-디헵티닐알코올을 얻는다.In the present invention, iodine propargyl alcohol represented by formula III is prepared by a conventional method from propargyl alcohol represented by formula II (Bull, Chem. Soc. Jpn, 1972, 45, 2611), and the compound of formula III The t-butylacetylene of Structural Formula IV was coupled to a palladium catalyst, tetrakis (triphenylphosphine) palladium (Ph (PPh 3 ) 4 ), copper iodide (CuI), and diisopropylamine, yielding 38% yield. 6,6-dimethyl-2E-diheptinyl alcohol represented by the above is obtained.
이어서 E-아릴알코올을 얻기 위하여 구조식Ⅴ의 화합물을 THF 용매하에서 소디움 비스(2-메톡시에톡시) 알루미늄 하이드라이드(Sodium bis(2-methoxyethoxy) aluminium hydride) 및 리티움 알루미늄 하이드라이드(LiAlH4)로 부터 선택된 것으로 환원반응시켜 구조식Ⅵ로 표시되는 6,6-디메틸-2E-헵텐-4-이닐알코올을 얻는다.The compound of formula V was then added to sodium bis (2-methoxyethoxy) aluminum hydride and lithium aluminum hydride (LiAlH 4 ) in THF solvent to obtain E-aryl alcohol. Reduction reaction to the one selected from to obtain 6,6-dimethyl-2E-heptene-4-ynyl alcohol represented by the formula (VI).
이 아릴알코올에 2당량의 메탄설포닐클로라이드로 반응을 속히 시켜 설포네이트 화합물을 얻고, 칼륨카보네이트 염기처리하에서 구조식(Ⅶ)으로 표시되는 이차아민과 반응시켜 구조식Ⅰ로 표시되는 터비나핀을 얻은 후 메탄올 용매상에서 염산을 처리하여 터비나핀 염산염을 얻고 에틸아세테이트 용매에서 재결정 한다.This aryl alcohol was rapidly reacted with 2 equivalents of methanesulfonyl chloride to obtain a sulfonate compound, and then reacted with a secondary amine represented by structural formula (I) under potassium carbonate base treatment to obtain terbinapine represented by structural formula (I). Treatment with hydrochloric acid in methanol solvent yields terbinafine hydrochloride and recrystallization in ethyl acetate solvent.
이하, 본 발명을 실시예에 의거 더욱 상세히 설명하겠는 바, 본 발명이 실시예로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to Examples.
실시예에서 각 화합물의 물성은 다음과 같은 방법으로 측정하였다.Physical properties of each compound in the Example was measured by the following method.
(1) 칼럼크로마토그라피는 머크(Merck)사제 실리카겔 60으로 플라스크법에 의거 측정하였다.(1) Column chromatography was measured with a silica gel 60 from Merck based on the flask method.
(2) 융점(m.p)은 토마스-후버 용융점 측정기로 측정하였다.(2) Melting point (m.p) was measured by Thomas-Hover Melting Point gauge.
(3) 핵자기 공명스펙트럼(NMR)은 브루커 ARX300 스펙트로미터로 얻었으며, 이때1H 및13C NMR에 대한 (CH3)4Si 피크를 측정하였다.(3) The nuclear magnetic resonance spectrum (NMR) was obtained with a Bruker ARX300 spectrometer, where (CH 3 ) 4 Si peaks for 1 H and 13 C NMR were measured.
(4) 커플링 상수 J는 Hz로 나타내었으며,(4) the coupling constant J is expressed in Hz,
(5) 적외선 스펙트럼(IR)은 니콜렛 710 FT-IR 스펙트로미터로 측정하였다.(5) Infrared spectrum (IR) was measured with a Nicolet 710 FT-IR spectrometer.
(6) GC-질량분석(MS)은 캐필러리 컬럼이 장착된 휴렛-페커드 MSD5890 시리즈로 행하였다.(6) GC-mass spectrometry (MS) was performed with the Hewlett-Pepard MSD5890 series equipped with a capillary column.
[실시예1]Example 1
6,6-디메틸-2,4-디헵티닐알코올(6,6'-dimethyl-2,4-diheptynyl alcohol)의 합성Synthesis of 6,6-dimethyl-2,4-diheptinyl alcohol (6,6'-dimethyl-2,4-diheptynyl alcohol)
10밀리몰(1.82g)의 3-하이드록시-1-요오드프로핀(구조식Ⅲ), 12밀리몰(1.5ml)의 t-부틸아세틸렌(구조식Ⅳ), Pd(PPh3)4350㎎, CuI 60㎎을 혼합한 THF 40ml에 질소기류하에서 디이소프로필아민 3.0ml를 가하고 상온에서 3시간 교반 후 혼합물을 100ml의 에테르용매로 희석하고, 암모늄클로라이드 포화용액과 증류수로 씻고, 유기용매층을 황산마그네슘으로 건조시켰다. 증류혼합물을 농축시킨 후 실리카겔 크로마토그라피에 의거 분리하여(헥산 : 메틸아세테이트 = 5 : 1) 6,6-디메틸-2,4-디헵티닐알코올(구조식 V) 517㎎을 수율 38%로 얻었다.10 mmol (1.82 g) of 3-hydroxy-1-iodine propine (Formula III), 12 mmol (1.5 ml) of t-butylacetylene (Formula IV), Pd (PPh 3 ) 4 350 mg, CuI 60 mg 3.0 ml of diisopropylamine was added to 40 ml of THF under nitrogen stream, and the mixture was stirred at room temperature for 3 hours, and then the mixture was diluted with 100 ml of ether solvent, washed with saturated ammonium chloride solution and distilled water, and the organic solvent layer was dried over magnesium sulfate. I was. The distilled mixture was concentrated and separated by silica gel chromatography (hexane: methyl acetate = 5: 1) to give 517 mg of 6,6-dimethyl-2,4-diheptinyl alcohol (formula V) in 38% yield.
이때, 6,6-디메틸-2,4-디헵티닐알코올의 물성은 다음과 같았다.At this time, the physical properties of 6,6-dimethyl-2,4-diheptinyl alcohol were as follows.
1H NMR (CDCl3) d 4.32(s, 2H), 1.85(br, 1H), 1.24(s, 9H):13C NMR (CDCl3) d 89.3, 75.0, 70.4, 63.0, 51.2, 30.2, 27.8: MS(M++H) 137.0: IR 2970, 2252, 1022 cm-1 1 H NMR (CDC l3 ) d 4.32 (s, 2H), 1.85 (br, 1H), 1.24 (s, 9H): 13 C NMR (CDCl 3 ) d 89.3, 75.0, 70.4, 63.0, 51.2, 30.2, 27.8 : MS (M + + H) 137.0: IR 2970, 2252, 1022 cm -1
[실시예2]Example 2
6,6-디메틸-2E-헵텐-4-이닐알코올의 합성Synthesis of 6,6-dimethyl-2E-heptene-4-ynyl alcohol
2.57밀리몰(350㎎)의 6,6-디메틸-2,4-디헵티닐알코올(구조식Ⅴ)을 1.5ml THF 용액을 녹인 후, 4.1밀리몰(1.27g)의 60% 소디움 비스(2-메톡시에톡시)알루미늄하이드라이드를 0℃에서 서서히 가하였다.2.57 mmol (350 mg) of 6,6-dimethyl-2,4-diheptinyl alcohol (formula V) was dissolved in 1.5 ml THF solution, followed by 4.1 mmol (1.27 g) of 60% sodium bis (2-methoxy). Oxy) aluminum hydride was added slowly at 0 ° C.
혼합물을 상온으로 올린 후에, 1시간 동안 상온에서 교반시켰다. 반응물에 1.0N 황산용액(1.5ml)을 첨가하여 반응을 중지시키고, 이때 생성되는 흰색 고체를 걸러서 제거시켰다. 에테르(30ml)로 묽힌 후 유기용매층은 증류수로 2번, 포화소금물로 1번 씻어내고, 유기용매를 황산마그네슘으로 건조시켰다. 용매를 감압하에 증발시킨 후 6,6-디메틸-2E-헵텐-4-이닐 알코올(구조식Ⅲ)을 정량적으로 얻었다.The mixture was raised to room temperature and then stirred at room temperature for 1 hour. 1.0N sulfuric acid solution (1.5 ml) was added to the reaction to stop the reaction, and the resulting white solid was filtered off. After diluting with ether (30 ml), the organic solvent layer was washed twice with distilled water and once with saturated brine, and the organic solvent was dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, 6,6-dimethyl-2E-heptene-4-ynyl alcohol (formula III) was obtained quantitatively.
합성된 6,6-디메틸-2E-헵텐-4-이닐알코올의 물성은 다음과 같다.The physical properties of the synthesized 6,6-dimethyl-2E-heptene-4-ynyl alcohol are as follows.
1H NMR (CDCl3) d 6.2(dt, 1H), 5.3(dt, 1H), 4.2(dd, 2H), 1.6(s, 2H), 1.3(s, 9H):13C NMR (CDCl3) d 140.0, 112.0, 99.0, 63.0, 60.5, 31.0, 28.0: MS (M++H) 139.0: IR 2960, 2287, 1265 cm-1 1 H NMR (CDCl 3 ) d 6.2 (dt, 1H), 5.3 (dt, 1H), 4.2 (dd, 2H), 1.6 (s, 2H), 1.3 (s, 9H): 13 C NMR (CDC l3 ) d 140.0, 112.0, 99.0, 63.0, 60.5, 31.0, 28.0: MS (M + + H) 139.0: IR 2960, 2287, 1265 cm -1
[실시예3]Example 3
터비나핀 염산염(Terbinafine HCl Salt)의 합성Synthesis of Terbinafine HCl Salt
2.17밀리몰(300㎎)의 6,6-디메틸-2E-헵텐-4-이닐알코올, 트리에틸아민((CH3CH2)3N), 촉매량의 디메틸아미노피리딘(DMAP)을 디클로메탄 용매에 녹인 후 메탄 설포닐 클로라이드(methane sulfonyl chloride, 3.0ml)를 0℃에서 첨가하였다. 5분 동안 0℃에서 교반한 후 증류수를 넣고 0℃에서 1시간 동안 교반하였다. 디클로로메탄 용매로 희석하고 유기용매를 증류수로 씻은 후 황산마그네슘으로 건조시켰다. 용매를 감압하에 증류시켜서 오일상태의 설포네이트 중간체를 얻었다.2.17 mmol (300 mg) of 6,6-dimethyl-2E-hepten-4-ynyl alcohol, triethylamine ((CH 3 CH 2 ) 3 N), and a catalytic amount of dimethylaminopyridine (DMAP) in dichloromethane solvent After dissolving, methane sulfonyl chloride (3.0 ml) was added at 0 ° C. After stirring at 0 ° C. for 5 minutes, distilled water was added and stirred at 0 ° C. for 1 hour. Diluted with dichloromethane solvent, the organic solvent was washed with distilled water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oily sulfonate intermediate.
이어서 2.0밀리몰(342.4㎎)의 N-메틸-1-나프탈렌메틸아민(N-methy-1-naphthalene methylamine)(구조식Ⅶ)과 10.8밀리몰(1.5g)의 칼륨카보네이트(K2CO3)를 1.5ml 디메틸포름아미드(DMF)에 녹인 용액에 상기 설포네이트화합물을 첨가하였다.Then 1.5 ml of 2.0 mmol (342.4 mg) of N-methy-1-naphthalene methylamine (formula VII) and 10.8 mmol (1.5 g) of potassium carbonate (K 2 CO 3 ) The sulfonate compound was added to a solution dissolved in dimethylformamide (DMF).
상기 반응 혼합물을 상온에서 6시간 교반한 후 증류수를 첨가하여 반응을 종결시켰다. 이 반응용액을 에틸 아세테이트(EtOAc, 20ml)로 희석한 후 증류수로 씻고 유기용매를 황산마그네슘으로 건조시켰다. 용매를 감압하에서 증류시킨 후 기름형태의 화합물을 얻었다. 이 화합물을 메탄올 용매하에 염산으로 처리한 후 메탄올을 증류시켜 결정을 얻은 후 에틸 아세테이트에 재결정하여 수율이 77%이며 융점이 188∼192℃인 흰색고체 1.54몰(448㎎)을 얻었다.The reaction mixture was stirred at room temperature for 6 hours and then distilled water was added to terminate the reaction. The reaction solution was diluted with ethyl acetate (EtOAc, 20 ml), washed with distilled water, and the organic solvent was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oily compound. The compound was treated with hydrochloric acid in a methanol solvent, methanol was distilled to obtain crystals, and recrystallized from ethyl acetate to obtain 1.54 mol (448 mg) of a white solid having a yield of 77% and a melting point of 188 to 192 캜.
[발명의 효과][Effects of the Invention]
본 발명은 종래의 방법과는 전혀 다른 신규한 방법으로서 원료물질 및 중간물질 또한 다르며 반응조건도 다르다, 본 발명의 방법에 의하면 약리활성 물질인 E형이 고정되어 제조되므로 최종물질의 혼합물을 분리하는 단계가 필요없으며, 종래 방법들과는 달리 유해물질을 사용하지 않으므로 안전한 방법이고, 또한 터비나핀을 고수율로 얻을 수 있다.The present invention is a novel method completely different from the conventional method, the raw materials and intermediates are also different and the reaction conditions are different. According to the method of the present invention, the pharmacologically active substance E is fixed and prepared, thereby separating the mixture of the final substances. There is no need for steps, and unlike conventional methods, it is a safe method because it does not use harmful substances, and it is also possible to obtain terbinafine in high yield.
Claims (4)
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| KR100838222B1 (en) * | 2002-03-12 | 2008-06-13 | 삼성테크윈 주식회사 | CAMERA and Method for Optical-volume controlling of CAMERA STROBO |
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