KR20030066186A - Process for preparation of Terbinafin - Google Patents

Process for preparation of Terbinafin Download PDF

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KR20030066186A
KR20030066186A KR1020020006517A KR20020006517A KR20030066186A KR 20030066186 A KR20030066186 A KR 20030066186A KR 1020020006517 A KR1020020006517 A KR 1020020006517A KR 20020006517 A KR20020006517 A KR 20020006517A KR 20030066186 A KR20030066186 A KR 20030066186A
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methyl
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hydrochloride
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유용상
이동훈
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한솔케미언스 주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings

Abstract

PURPOSE: Provided is a method for economically and simply producing (E)-terbinafine represented by formula 1, or hydrochloride thereof with high yield and high purity, without removing a solvent. CONSTITUTION: The method comprises the steps of (i) reacting N-methyl-1-naphthalene amine or its hydrochloride and (E)-1,3-dichloropropene in aqueous organic solvent or its aqueous solution in the presence of weak base at 0-100 deg.C for 1-15 hours, to form (E)-N-(3-chloro-2-propenyl)-N-methyl-naphthalene methaneamine represented by formula 3; and sequentially adding 0.5-5 mol% of Cu and amine, and 3,3-dimethyl-1-butyne to the reaction product with using 0.5-5 mol% of palladium(Pd(II)) catalyst, to form (E)-terbinafine represented by formula 1 or its hydrochloride.

Description

(Ｅ)-터비나핀 또는 이의 염산염의 제조방법{Process for preparation of Terbinafin}Process for preparation of Terbinafin (E) -terbinafine or hydrochloride thereof

본 발명은 (E)-터비나핀 또는 이의 염산염의 제조방법에 관한 것으로서, 더욱 상세하게는 N-메틸-1-나프탈렌메탄아민 또는 이의 염산염과 (E)-1,3-클로로프로펜을 출발물질로 하고, 상기 출발물질을 약염기 존재 하에 수용성 유기용매 또는 이의 수용액 상에서 반응시켜 (E)-N-(3-클로로-2-프로펜일)-N-메틸-1-나프탈렌메탄아민을 중간체로 제조한 후에, 팔라디움(Ⅱ)을 사용한 3,3-디메틸-1-부틴과의 커플링 반응을 수행하여 고수율, 고순도의 다음 화학식 1로 표시되는 (E)-터비나핀 또는 이의 염산염을 경제적으로 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing (E) -terbinafine or hydrochloride thereof, and more particularly, starting with N-methyl-1-naphthalenemethanamine or hydrochloride thereof and (E) -1,3-chloropropene. As a material, the starting material was reacted in the presence of a weak base on a water-soluble organic solvent or an aqueous solution thereof to prepare (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenmethanamine as an intermediate. Afterwards, a coupling reaction with 3,3-dimethyl-1-butyne using palladium (II) was carried out to economically produce (E) -terbinapine or its hydrochloride salt represented by the following general formula (1) in high yield and purity: It relates to a manufacturing method.

[화학식 1][Formula 1]

상기 화학식 1로 표시되는 터비나핀 또는 이의 염산염은 엔-인 구조를 가지는 항진균제로서 광범위한 약효를 나타내는 것으로 공지되어 있다.Terbinapine or its hydrochloride salt represented by the formula (1) is known to exhibit a wide range of efficacy as an antifungal agent having an en-phosphorus structure.

터비나핀은 곰팡이 스쿠알렌 에폭시다제 억제제(fungal squalene epoxidase inhibitor)로서, 경구용으로 사용 가능하며 독성이 거의 없는 항진균제로 1980년 Sandoz사에 의하여 처음 합성되었다. 지금까지 알려져 있는 상기 화학식 1로 표시되는 터비나핀 또는 이의 염산염의 제조방법과 관련하여서는 특허로서 대한민국 특허공개 제97-61855호(한일합섬), 대한민국 특허 제161,803호(한일합섬), 유럽특허 제24,587호(Sandoz), 미국특허 제4,755,534호(Sandoz), 미국특허 제5,817,875호(Khashayar Krimian, et al.), 유럽특허 제421,302호(Banyu) 등이 있고, 그 외에도 여러 학술문헌으로서, 예컨대J. Med. Chem, 27, 1539(1984),Angew. Chem. Int. Ed. Engl., 26, 320(1987),Tetrahedron Lett., 32, 6109(1996),Tetrahedron Lett., 37, 57(1996),Bull. Korean Chem. Soc., 18, 1218(1997),Tetrahedron Lett., 29, 1509(1988) 등에 기재되어 있다.Terbinafin, a fungal squalene epoxidase inhibitor, is an oral, non-toxic antifungal that was first synthesized by Sandoz in 1980. Regarding the manufacturing method of terbinafine or its hydrochloride represented by the above formula (1) known so far, as a patent, Korean Patent Publication No. 97-61855 (Hanil Synthetic Island), Korean Patent No. 161,803 (Hanil Synthetic Island), European Patent No. 24 587 Ho (Sandoz), US Patent and the like 4,755,534 No. (Sandoz), US Patent 5,817,875 No. (Khashayar Krimian, et al.), European Patent No. 421 302 No. (Banyu), In addition, a number of scientific literature, for example J Med. Chem , 27, 1539 (1984), Angew. Chem. Int. Ed. Engl. , 26, 320 (1987), Tetrahedron Lett. , 32, 6109 (1996), Tetrahedron Lett ., 37, 57 (1996), Bull. Korean Chem. Soc ., 18, 1218 (1997), Tetrahedron Lett ., 29, 1509 (1988) and the like.

상기한 공지 방법들은 디메틸설폭사이드(DMSO) 사용으로 인한 제거의 어려움, 긴 반응시간(유럽특허 제421302호), 산업적으로 다루기 어려운 원료의 사용(유럽특허 제24587호, 미국특허 제4755534호), 트랜스 및 시스 혼합물의 생성(유럽특허 제24587호, 미국특허 제5817875호) 등의 단점들이 지적되어 왔다.The above known methods are difficult to remove due to the use of dimethyl sulfoxide (DMSO), long reaction time (European Patent No. 421302), use of industrially difficult raw materials (Europe Patent No. 24587, US Patent No. 4755534), Disadvantages have been pointed out, such as the production of trans and sheath mixtures (European Patent No. 224587, U.S. Patent No. 5817875).

또한, 본 출원인 등에 의해 개발된 방법이 대한민국특허 제293,121호로 등록된 바도 있다.In addition, the method developed by the present applicant, etc. has been registered in Korean Patent No. 293,121.

본 발명자는 상기와 같은 종래 방법의 단점을 해결하고, 좀 더 경제적인 방법을 찾기 위하여 노력한 결과, 새로운 (E)-터비나핀의 제조방법을 발명하였다.The present inventors have solved the disadvantages of the conventional method as described above, and as a result of trying to find a more economical method, invented a new (E) -terbinafin manufacturing method.

본 발명에 따른 제조방법에서는 유럽특허 제421302호의 특허의 단점을 극복하여 강염기 대신에 약염기를, 그리고 제거하기 쉬운 수용성 유기용매 또는 이의 수용액을 사용하여 고수율, 고순도의 목적화합물을 얻을 수 있었고, 또한Tetrahedron Lett., 32, 6109(1991)와Tetrahedron Lett., 37, 57(1996)을 참고로 하여 엔-인 커플링의 반응시간을 급격히 단축시키는 효과를 갖는다.In the production method according to the present invention, a weak base, and a water-soluble organic solvent or an aqueous solution thereof, which are easy to remove, can be obtained in place of the strong base to overcome the disadvantages of the patent of European Patent No. 421302. With reference to Tetrahedron Lett ., 32, 6109 (1991) and Tetrahedron Lett ., 37, 57 (1996), the reaction time of the en-in coupling is drastically shortened.

본 발명은The present invention

N-메틸-1-나프탈렌메탄아민 또는 이의 염산염과 (E)-1,3-디클로로프로펜을 약염기 존재 하에 수용성 유기용매 또는 이의 수용액 중에서 0 내지 100 ℃의 온도에서 1 내지 15 시간 반응시켜 다음 화학식 3으로 표시되는 트랜스 형태의 N-(3-클로로-2-프로펜일)-N-메틸-1-나프탈렌메탄아민을 제조하고,N-methyl-1-naphthalenemethanamine or a hydrochloride thereof and (E) -1,3-dichloropropene were reacted in a water-soluble organic solvent or an aqueous solution thereof at a temperature of 0 to 100 ° C. for 1 to 15 hours to formula To prepare N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethanamine in the trans form represented by 3,

이어서 팔라디움(Ⅱ) 촉매와, 촉매량의 CuI 및 아민, 3,3-디메틸-1-부틴을 순차적으로 가하여 다음 화학식 1로 표시되는 (E)-터비나핀 및 이의 염산염을 제조하는 방법을 그 특징으로 한다.Subsequently, a palladium (II) catalyst, a catalytic amount of CuI and an amine, and 3,3-dimethyl-1-butyne are sequentially added to prepare (E) -terbinapine and its hydrochloride salt represented by the following formula (1). It is done.

[화학식 1][Formula 1]

이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.

본 발명은 대한민국특허 제293121호의 개량발명으로서, 출발물질로서 입체이성질체인 (E)-1,3-디클로로프로펜을 선택 사용함과 동시에 반응용매를 비롯한 반응조건을 최적으로 유지시키므로써 최종적으로 합성되는 (E)-터비나핀의 수율 및 순도를 극대화시키는 방법에 관한 발명이다.The present invention is an improved invention of Korean Patent No. 293121, which is finally synthesized by using stereoisomer (E) -1,3-dichloropropene as a starting material and optimally maintaining reaction conditions including a reaction solvent. The invention relates to a method for maximizing the yield and purity of (E) -terbinafine.

본 발명에 따른 (E)-터비나핀 또는 이의 염산염의 제조방법을 간략히 나타내면 다음 반응식 1과 같다.The preparation method of (E) -terbinafine or hydrochloride thereof according to the present invention is briefly shown in Scheme 1 below.

상기 반응식 1에 의하면, 먼저 상기 화학식 2로 표시되는 N-메틸-1-나프탈렌메탄아민 또는 이의 염산염을 수용성 유기용매 또는 이의 수용액 중에 용해시킨 후 아세트산 나트륨과 같은 약염기 존재하에 (E)-1,3-디클로로프로펜과 반응시키게 되면, 상기 화학식 3으로 표시되는 N-(3-클로로-2-프로펜일)-N-메틸-1-나프탈렌메탄아민을 고수율(>95%)로 합성할 수 있다. 이때, 본 발명에서는 반응용매로서 수용성 유기용매 또는 이의 수용액을 사용하였는 바, 수용성 유기용매는 아세토니트릴, 아세톤, 테트라하이드로퓨란, 메틸알콜, 에틸알콜 등이 포함되며, 바람직하게는 아세토니트릴, 아세톤 또는 이의 수용액이다. 용매의 양은 사용되는 상기 화학식 2로 표시되는 N-메틸-1-나프탈렌아민의 양에 대하여 4 내지 15배 사용하며, 바람직하게는 7 내지 10배이다. 수용액의 경우, 물의 양은 유기용매의 양에 대하여 1 내지 1/1000의 부피비로 사용하며, 바람직하게는 1/2 ∼ 1/50 부피비이다. 약염기는 아세트산 나트륨, 아세트산 포타슘 등이 포함되며, 바람직하게는 아세트산 나트륨이다. 사용되는 약염기의 양은 N-메틸-1-나프탈렌메탄아민이 유리 형태일때는 1 ∼ 5 당량 범위, 바람직하게는 1.1 ∼ 2 당량 범위로 사용하고, 염산염일때는 2 ∼ 10 당량 범위, 바람직하게는 2.2 ∼ 4 당량 범위로 사용한다. 반응온도는 0 ∼ 100 ℃이며, 바람직하게는 40 ∼ 80 ℃이다. 반응시간은 1 내지 15 시간으로, 바람직하게는 4 내지 7시간이다.According to Scheme 1, first, N-methyl-1-naphthalenemethaneamine or hydrochloride thereof represented by Formula 2 is dissolved in a water-soluble organic solvent or an aqueous solution thereof, and then in the presence of a weak base such as sodium acetate (E) -1,3 When reacted with dichloropropene, N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenmethanamine represented by Chemical Formula 3 can be synthesized in high yield (> 95%). . Herein, in the present invention, a water-soluble organic solvent or an aqueous solution thereof is used as the reaction solvent, and the water-soluble organic solvent includes acetonitrile, acetone, tetrahydrofuran, methyl alcohol, ethyl alcohol, and the like, preferably acetonitrile, acetone or Its aqueous solution. The amount of the solvent is used 4 to 15 times with respect to the amount of N-methyl-1-naphthaleneamine represented by the above formula (2), preferably 7 to 10 times. In the case of the aqueous solution, the amount of water is used in a volume ratio of 1 to 1/1000 with respect to the amount of the organic solvent, preferably 1/2 to 1/50 volume ratio. Weak bases include sodium acetate, potassium acetate and the like, preferably sodium acetate. The amount of weak base to be used is in the range of 1 to 5 equivalents, preferably 1.1 to 2 equivalents when N-methyl-1-naphthalenemethanamine is in the free form, and in the range of 2 to 10 equivalents, preferably 2.2 when hydrochloride. It uses in 4 equivalent range. Reaction temperature is 0-100 degreeC, Preferably it is 40-80 degreeC. The reaction time is 1 to 15 hours, preferably 4 to 7 hours.

합성된 상기 화학식 3으로 표시되는 (E)-N-(3-클로로-2-프로펜일)-N-메틸-1-나프탈렌메탄아민과 팔라디움(Ⅱ) 촉매, 촉매량의 CuI, 아민, 3,3-디메틸-1-부틴을 순차적으로 첨가하고 반응시켜 트랜스 형태의 상기 화학식 1로 표시되는 터비나핀을 짧은시간(1∼6시간)에 고수율(>90%)로 합성한다. 팔라디움(Ⅱ) 촉매로는 비스(벤조니트릴)팔라디움 디클로라이드((PhCN)2PdCl2))를 사용하며, 0.5 ∼ 5 몰% 범위로 사용한다. 아민은 피페리딘을 2 ∼ 10 당량 사용한다. 용매는 톨루엔, 에틸아세테이트, 헥산, 사이클로헥산, 테트라하이드로퓨란, 클로로포름 등을 사용하며, 사용용매를 N-(3-클로로-2-프로펜일)-N-메틸-1-나프탈렌메탄아민 합성 시의 추출용매와 동일 용매를 사용하여 추출용매의 제거없이 바로 반응을 진행시킬 수 있다. 반응온도는 0 내지 50 ℃이며, 바람직하게는 10 내지 30 ℃이다.Synthesized (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethaneamine and palladium (II) catalyst represented by Chemical Formula 3, catalytic amount of CuI, amine, 3,3 -Dimethyl-1-butyne is added sequentially and reacted to synthesize terbinapine represented by Chemical Formula 1 in the trans form in a short time (1 to 6 hours) in high yield (> 90%). Bis (benzonitrile) palladium dichloride ((PhCN) 2 PdCl 2 )) is used as the palladium (II) catalyst and is used in the range of 0.5 to 5 mol%. The amine uses 2 to 10 equivalents of piperidine. Toluene, ethyl acetate, hexane, cyclohexane, tetrahydrofuran, chloroform, and the like are used as the solvent, and the solvent used for the synthesis of N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenmethaneamine The same solvent as the extraction solvent may be used to directly proceed without removing the extraction solvent. The reaction temperature is 0 to 50 ° C, preferably 10 to 30 ° C.

이상의 방법으로 생성된 조 (E)-터비나핀은 공지의 방법[J. Med. Chem., 27(12), 1539, 1984]에 따라 상기 화학식 1a로 표시되는 순수한 (E)-터비나핀 염산염으로 만들 수 있다.The crude (E) -terbinafine produced by the above method is known in the art [ J. Med. Chem. , 27 (12), 1539, 1984] can be made of pure (E) -terbinapine hydrochloride represented by the formula (1a).

이상에서 설명한 바와 같은 본 발명은 다음의 실시예에 의거하여 더욱 상세히 설명하면 다음과 같은 바, 본 발명의 범위가 실시예에 의하여 국한되는 것은 아니다.The present invention as described above will be described in more detail based on the following examples as follows, but the scope of the present invention is not limited by the examples.

실시예 1: (E)-N-(3-클로로-2-프로펜일)-N-메틸-1-나프탈렌메탄아민의 제조Example 1: Preparation of (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenmethanamine

N-메틸-1-나프탈렌메탄아민 20.0 g을 아세토니트릴 200 ㎖에 녹이고, 아세트산 나트륨 11.5 g과 (E)-1,3-디클로로프로펜 12.0 ㎖ 및 물 4 ㎖를 넣어주었다. 반응혼합물을 50 ℃로 가열하며 5 시간 교반하고, 포화 소디움클로라이드 수용액을 가하였다. 에틸아세테이트로 추출하여 황산마그네슘으로 건조하고 감압하에 용매를 제거하여 (E)-N-(3-클로로-2-프로펜일)-N-메틸-1-나프탈렌메탄아민(27.6 g, 수율 96.2%)을 얻었다.20.0 g of N-methyl-1-naphthalenemethanamine was dissolved in 200 ml of acetonitrile, and 11.5 g of sodium acetate, 12.0 ml of (E) -1,3-dichloropropene, and 4 ml of water were added thereto. The reaction mixture was heated to 50 ° C., stirred for 5 hours, and saturated aqueous sodium chloride solution was added. Extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was removed under reduced pressure. (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethanamine (27.6 g, yield 96.2%) Got.

1H-NMR(CDCl3) δ7.40∼8.30(m, 7H), 6.0∼6.2(m, 2H), 3.90(s, 2H), 3.10(d, 2H), 2.24(s, 3H) 1 H-NMR (CDCl 3 ) δ 7.40 to 8.30 (m, 7H), 6.0 to 6.2 (m, 2H), 3.90 (s, 2H), 3.10 (d, 2H), 2.24 (s, 3H)

실시예 2: (E)-N-(3-클로로-2-프로펜일)-N-메틸-1-나프탈렌메탄아민의 제조Example 2: Preparation of (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenmethanamine

N-메틸-1-나프탈렌메탄아민 20.0 g을 아세톤(200 ㎖)에 녹이고, 아세트산 나트륨 11.5 g과 (E)-1,3-디클로로프로펜 12.0 ㎖ 및 물 4 ㎖를 넣어주었다. 반응혼합물을 50 ℃로 가열하며 5 시간 교반한 후 감압하에 용매를 제거하였다. 2N NaOH 용액을 가한 후 헥산으로 추출하고 황산마그네슘으로 건조하고, 감압하에 용매를 제거하여 (E)-N-(3-클로로-2-프로펜일)-N-메틸-1-나프탈렌메탄아민(27.4 g, 수율 95.5%)을 얻었다.20.0 g of N-methyl-1-naphthalenemethanamine was dissolved in acetone (200 mL), and 11.5 g of sodium acetate, 12.0 mL of (E) -1,3-dichloropropene, and 4 mL of water were added thereto. The reaction mixture was heated to 50 ° C. and stirred for 5 hours to remove the solvent under reduced pressure. 2N NaOH solution was added, extracted with hexane, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenmethanamine (27.4 g, yield 95.5%).

실시예 3: (E)-터비나핀의 제조Example 3: Preparation of (E) -terbinafine

(E)-N-(3-클로로-2-프로펜일)-N-메틸-1-나프탈렌메탄아민 20.0 g과 피페리딘 39 ㎖를 에틸아세테이트에 녹이고, 비스(벤조니트릴)팔라디움 디클로라이드 220 mg과 CuI 220 mg 및 3,3-디메틸-1-부틴 11.6. ㎖를 가하고 실온에서 4 시간 교반하였다. 반응이 완료된 후 포화 암모늄클로라이드 수용액으로 세척하고 황산마그네슘으로 건조하여 감압으로 용매를 제거하였다. 실리카겔 컬럼 크로마토그래피를 이용하여 분리하여 오일상의 순수한 (E)-터비나핀(26.7 g, 수율 95.9%)을 얻었다.20.0 g of (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethaneamine and 39 ml of piperidine were dissolved in ethyl acetate, and 220 mg of bis (benzonitrile) palladium dichloride. And CuI 220 mg and 3,3-dimethyl-1-butyne 11.6. ㎖ was added and stirred at room temperature for 4 hours. After the reaction was completed, the mixture was washed with saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and the solvent was removed under reduced pressure. Separation was performed by silica gel column chromatography to obtain oily pure (E) -terbinafine (26.7 g, yield 95.9%).

1H-NMR(CDCl3) δ7.3∼8.3(m, 7H), 6.1∼6.2(m, 1H), 5.68(d, 1H, 15Hz), 3.89(s, 2H), 3.13(d, 2H), 2.22(s, 3H), 1.21(s, 9H) 1 H-NMR (CDCl 3 ) δ7.3 to 8.3 (m, 7H), 6.1 to 6.2 (m, 1H), 5.68 (d, 1H, 15 Hz), 3.89 (s, 2H), 3.13 (d, 2H) , 2.22 (s, 3H), 1.21 (s, 9H)

실시예 4: (E)-터비나핀의 제조Example 4: Preparation of (E) -terbinafine

N-메틸-1-나프탈렌메탄아민 20.0 g을 아세톤(200 ㎖)에 녹이고, 아세트산 나트륨 11.5 g과 (E)-1,3-디클로로프로펜 12.0 ㎖ 및 물 4 ㎖를 넣어주었다. 반응혼합물을 50 ℃로 가열하며 5 시간 교반한 후 감압하에 용매를 제거하였다. 2N NaOH 용액을 가한 후 사이클로헥산으로 추출하고 황산마그네슘으로 건조하였다.20.0 g of N-methyl-1-naphthalenemethanamine was dissolved in acetone (200 mL), and 11.5 g of sodium acetate, 12.0 mL of (E) -1,3-dichloropropene, and 4 mL of water were added thereto. The reaction mixture was heated to 50 ° C. and stirred for 5 hours to remove the solvent under reduced pressure. 2N NaOH solution was added, extracted with cyclohexane, and dried over magnesium sulfate.

여기에 피페리딘 53.0 ㎖, 비스(벤조니트릴)팔라디움 디클로라이드 0.3 g, CuI 0.3 g, 3,3-디메틸-1-부틴 14.5 ㎖를 가하고 실온에서 4시간 교반하였다.반응이 완료된 후 포화 암모늄클로라이드 수용액으로 세척한 후, 황산마그네슘으로 탈수하고 용매를 감압하에서 제거하였다. 실리카겔 컬럼 크로마토그래피를 이용하여 분리하여 오일상의 순수한 (E)-형태의 목적화합물(34.4 g, 수율 89.8%)을 얻었다.53.0 mL of piperidine, 0.3 g of bis (benzonitrile) palladium dichloride, 0.3 g of CuI, and 14.5 mL of 3,3-dimethyl-1-butyne were added thereto, followed by stirring at room temperature for 4 hours. After completion of the reaction, saturated ammonium chloride was added. After washing with an aqueous solution, the solution was dehydrated with magnesium sulfate and the solvent was removed under reduced pressure. Separation was performed by silica gel column chromatography to obtain an oily pure (E) -form of the target compound (34.4 g, yield 89.8%).

실시예 5: (E)-터비나핀·HCl의 제조Example 5: Preparation of (E) -terbinafineHCl

오일상의 (E)-터비나핀 29.1 g에 4N HCl/MeOH 40 ㎖를 가하고 용매를 감압하에서 제거하였다. 이소프로필알콜 50 ㎖를 가하고 가열하여 녹인 후, 이소프로필에테르 150 ㎖를 가하고 여과한 후 건조하여 목적화합물 30.0 g(수율 91.5%)을 얻었다.40 mL of 4N HCl / MeOH was added to 29.1 g of (E) -terbinafine in oil phase and the solvent was removed under reduced pressure. 50 ml of isopropyl alcohol was added thereto, heated to dissolve, 150 ml of isopropyl ether was added, filtered and dried to obtain 30.0 g (yield 91.5%) of the title compound.

1H-NMR(CDCl3+D2O) δ7.5∼8.2(7H, m), 6.37(1H, dt, 15Hz, 7.5Hz), 5.87(1H, d, 15Hz), 4.62(2H, s), 3.72(2H, d, 7.5Hz), 2.60(3H, s), 1.23(9H, s) 1 H-NMR (CDCl 3 + D 2 O) δ 7.5 to 8.2 (7H, m), 6.37 (1H, dt, 15 Hz, 7.5 Hz), 5.87 (1H, d, 15 Hz), 4.62 (2H, s) , 3.72 (2H, d, 7.5 Hz), 2.60 (3H, s), 1.23 (9H, s)

이상에서 설명한 바와 같이, 본 발명에 따른 제조방법은 다음과 같은 우수성을 가지고 있다.As described above, the manufacturing method according to the present invention has the following advantages.

첫째, 선행기술의 경우, 대분분 (E), (Z)-터비나핀이 혼합물로 얻어지므로 순수한 (E)-터비나핀을 합성하기 위해서는 이성체 분리공정을 추가로 수행하여야 하고, 또는 비경제적이거나 산업적 적용이 까다로운 공정이 사용되는 등의 단점이있다. 그러나 본 발명의 기술은 (E)-N-(3-클로로-2-프로펜일)-N-메틸-1-나프탈렌메탄아민의 제조시 저가의 약염기와 제거가 용이한 수용성 유기용매를 선택 사용하는 등의 반응조건을 특이성 있게 구성하므로써 경제적이고 간단한 공정으로 목적하는 (E)-터비나핀을 합성할 수 있는 장점이 있다.First, in the prior art, since most of the (E), (Z) -terbinafine are obtained as a mixture, an isomer separation process must be additionally performed to synthesize pure (E) -terbinafine, or it is uneconomical. Or disadvantages such as the use of industrially demanding processes. However, the technique of the present invention uses a low-cost weak base and a water-soluble organic solvent that can be easily removed in the preparation of (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethanamine. By specifically configuring the reaction conditions, such as the economical and simple process there is an advantage that can be synthesized the desired (E) -terbinafin.

둘째, (E)-N-(3-클로로-2-프로펜일)-N-메틸-1-나프탈렌메탄아민 제조공정의 추출용매와 터비나핀 합성 시의 반응용매를 일치시킴으로써, (E)-N-(3-클로로-2-프로펜일)-N-메틸-1-나프탈렌메탄아민 추출 후 용매의 제거없이 곧바로 반응을 진행시킬 수 있는 장점이 있다.Second, by matching the extraction solvent in the (E) -N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethanamine manufacturing process with the reaction solvent in the synthesis of terbinapine (E)- After the extraction of N- (3-chloro-2-propenyl) -N-methyl-1-naphthalenemethaneamine, there is an advantage that the reaction can proceed immediately without removing the solvent.

Claims (3)

N-메틸-1-나프탈렌메탄아민 또는 이의 염산염과 (E)-1,3-디클로로프로펜을 약염기 존재하에 수용성 유기용매 또는 이의 수용액 중에서 0 내지 100 ℃의 온도에서 1 내지 15 시간 반응시켜 다음 화학식 3으로 표시되는 (E)-N-(3-클로로-2-프로펜일)-N-메틸-나프탈렌메탄아민을 제조하고,N-methyl-1-naphthalenemethanamine or its hydrochloride salt and (E) -1,3-dichloropropene were reacted in a water-soluble organic solvent or an aqueous solution thereof at a temperature of 0 to 100 ° C. for 1 to 15 hours in the presence of a weak base. Prepare (E) -N- (3-chloro-2-propenyl) -N-methyl-naphthalenmethanamine represented by 3, 이어서 팔라디움[Pd(Ⅱ)] 촉매를 0.5 내지 5 몰% 사용하고, 촉매량의 CuI와 아민 및 3,3-디메틸-1-부틴을 순차적으로 가하여 다음 화학식 1로 표시되는 (E)-터비나핀 또는 이의 염산염을 제조하는 방법.Subsequently, 0.5 to 5 mol% of a palladium [Pd (II)] catalyst was used, and a catalytic amount of CuI, an amine, and 3,3-dimethyl-1-butyne was sequentially added thereto to represent (E) -terbinapine represented by the following Chemical Formula 1. Or a method for preparing the hydrochloride thereof. [화학식 3][Formula 3] [화학식 1][Formula 1] 제 1 항에 있어서, 상기 약염기로 아세트산 나트륨, 아세트산 포타슘을 사용하는 것을 특징으로 방법.The method according to claim 1, wherein sodium acetate and potassium acetate are used as the weak base. 제 1 항에 있어서, 상기 수용성 유기용매 또는 이의 수용액이 아세토니트릴, 아세톤, 테트라하이드로퓨란, 메틸알콜 및 에틸알콜 중에서 선택된 유기용매 또는 이의 수용액인 것으로 특징으로 하는 방법.The method of claim 1, wherein the water-soluble organic solvent or an aqueous solution thereof is an organic solvent selected from acetonitrile, acetone, tetrahydrofuran, methyl alcohol and ethyl alcohol or an aqueous solution thereof.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR970006278A (en) * 1995-07-25 1997-02-19 Method for preparing terbinafine and its hydrochloride for antifungal agents
US5935998A (en) * 1995-07-06 1999-08-10 Novartis Ag Use of all allylamine derivatives such as terbinafine, in the manufacture of a medicament for the treatment of helicobacter pylori infection or associated diseases
KR100293121B1 (en) * 1999-04-08 2001-06-15 김완주 Process for preparation of terbinafine and its hydrochloride as an antifungal agent
WO2001077064A1 (en) * 2000-04-07 2001-10-18 Slovakofarma A.S. Method for the preparation of (e)-n-(6,6-dimethyl-2-hepten-4-ynyl)-n-methyl-1-naphthalenemethanamine (terbinafine)
KR20020016276A (en) * 2000-08-25 2002-03-04 김 완 주 Process for the preparation of terbinafine and its hydrochloride as an antifungal agent

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5935998A (en) * 1995-07-06 1999-08-10 Novartis Ag Use of all allylamine derivatives such as terbinafine, in the manufacture of a medicament for the treatment of helicobacter pylori infection or associated diseases
KR970006278A (en) * 1995-07-25 1997-02-19 Method for preparing terbinafine and its hydrochloride for antifungal agents
KR100293121B1 (en) * 1999-04-08 2001-06-15 김완주 Process for preparation of terbinafine and its hydrochloride as an antifungal agent
WO2001077064A1 (en) * 2000-04-07 2001-10-18 Slovakofarma A.S. Method for the preparation of (e)-n-(6,6-dimethyl-2-hepten-4-ynyl)-n-methyl-1-naphthalenemethanamine (terbinafine)
KR20020016276A (en) * 2000-08-25 2002-03-04 김 완 주 Process for the preparation of terbinafine and its hydrochloride as an antifungal agent

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