KR20030044365A - Novel phase transfer catalyst - Google Patents

Novel phase transfer catalyst Download PDF

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KR20030044365A
KR20030044365A KR1020010075087A KR20010075087A KR20030044365A KR 20030044365 A KR20030044365 A KR 20030044365A KR 1020010075087 A KR1020010075087 A KR 1020010075087A KR 20010075087 A KR20010075087 A KR 20010075087A KR 20030044365 A KR20030044365 A KR 20030044365A
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bromide
benzyl
hydrogen
phase transfer
transfer catalyst
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KR1020010075087A
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Korean (ko)
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주상섭
박형근
정병선
유미숙
이성희
조덕형
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주식회사 아미노젠
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

PURPOSE: A new asymmetric phase-transfer catalyst is obtained from Cinchona alkaloid, and used in the synthesis of amino acid to synthesize alpha amino acid in simplified and productive ways. CONSTITUTION: The compound is expressed by the formula 1 where X is fluorine, chlorine, bromine, iodine, IO4-, CIO4-, OTf-, or HSO4-. In the formula 1, R1 is hydrogen or methoxy, R2 is vinyl or ethyl group, R3 is hydrogen, allyl, benzyl, or alkyl with the carbon numbers of 1-10, R4 is fluorine or cyan group, and R5 and R6 are hydrogen or fluorine.

Description

새로운 비대칭 상 이동 촉매{Novel phase transfer catalyst}Novel phase transfer catalyst

본 발명은 비대칭 상 이동 촉매(chiral phase-transfer catalyst)와 이 촉매를 이용한 비대칭 상 이동 촉매 반응(asymmetric phase-transfer catalysis)에 관한 것으로, 구체적으로는 신코나 알칼로이드(Cinchonaalkaloid)에서 유래된 비대칭 상 이동 촉매 및 이를 촉매로 하는 비대칭 상 이동 촉매 반응을 이용한 알파 아미노산의 비대칭 합성에 관한 것이다.The present invention relates to a chiral phase-transfer catalyst and asymmetric phase-transfer catalysis using the catalyst, specifically, an asymmetric phase derived from Cinchona alkaloid. Asymmetric synthesis of alpha amino acids using a transfer catalyst and an asymmetric phase transfer catalysis using the catalyst.

광학활성을 갖는 알파 아미노산은 생체과학에 널리 이용되는 물질로 합성방법이 최근 크게 주목받고 있다. 그 중에서도 간단하면서도 쉽게 대량반응이 가능한 방법이 상 이동 촉매로써 4급 암모늄염를 사용하는 상 이동 촉매 반응이다.Alpha amino acids having optical activity are widely used in biological sciences, and the synthetic method has attracted much attention recently. Among them, a simple and easy mass reaction method is a phase transfer catalysis that uses a quaternary ammonium salt as a phase transfer catalyst.

키랄한 알칼로이드에서 유래된 암모늄염의 사용은 광학활성을 갖는 알파 아미노산의 비대칭합성을 가능하게 했는데, 오돈넬 (M. J. O'Donnell)에 의해서 키랄 알칼로이드인 신코나 알칼로이드에서 유래된 테트라알킬암모늄 할로겐화물인 상기A의 화합물을 촉매로 하여 알파 아미노산의 비대칭합성이 처음으로 발표되었다. [O'Donnell, M. J.; Bennett, W. D.; Wu, S.J. Am. Chem. Soc. 1989,111, 2353.] 그 후 라이고(B. Lygo) 연구그룹[Lygo, B.; Wainwright, P. G.Tetrahedron Lett. 1997,38, 8595.]과 코리(E. J. Corey) 연구그룹[Corey, E. J.; Xu, F.; Noe, M. C.J. Am. Chem. Soc. 1997,119, 12414.]이 신코나 알칼로이드유래의 새로운 촉매인 상기 B의 화합물을 개발하여 상 이동 촉매작용을 이용한 모노알킬화반응을 통해 알파 아미노산을 비대칭 합성하였다. 또한 Lee등은 신코닌에서 합성한 상기 C의 화합물을 이용하여 특정 기질인 옥신돌 (oxindole)의 알킬화 반응을 수행한 바 있다[Lee, T. B. K.; Wong, J. S. K.. EP 438796,1998]. 그러나 오돈넬의 상기 A의 화합물은 그 광학수율이 약 80%ee정도로 낮고 라이고와 코리등의 상기 B의 화합물은 합성시 경제적인 면에서 단가가 높고 특히 코리의 경우 반응조건이 -78 ℃이어서 실제 공업적인 적용에 한계가 있다. 그밖에 Lee등의 상기 C의 화합물은 5%ee의 매우 낮은 광학수율로 알킬화반응을 수행하여 촉매로서의 효율이 매우 낮다. 따라서 공업적인 적용이 용이한 반응조건하에서 높은 광학수율(95%-99%ee)로 아미노산을 비대칭 합성할 수 있는 촉매가 필요하다.The use of ammonium salts derived from chiral alkaloids has enabled the asymmetric synthesis of alpha amino acids with optical activity, which are tetraalkylammonium halides derived from the chiral alkaloids, cinona alkaloids, by MJ O'Donnell. Asymmetric synthesis of alpha amino acids was first reported using the compound of A as a catalyst. O'Donnell, MJ; Bennett, WD; Wu, S. J. Am. Chem. Soc. 1989 , 111 , 2353.] The B. Lygo Research Group [Lygo, B .; Wainwright, PG Tetrahedron Lett. 1997 , 38 , 8595.] and EJ Corey Research Group [Corey, EJ; Xu, F .; Noe, MC J. Am. Chem. Soc. 1997 , 119 , 12414.] developed a compound of B, a new catalyst derived from synacona alkaloids, and asymmetrically synthesized alpha amino acids through monoalkylation using phase transfer catalysis. In addition, Lee et al. Performed the alkylation reaction of a specific substrate, oxindole, using the compound of C synthesized from synconin [Lee, TBK; Wong, JSK. EP 438796, 1998 ]. However, the compound of A of Odonnell has a low optical yield of about 80% ee and the compound of B such as Lygo and Corey has high economical cost in synthesis, and especially in case of Corey, the reaction condition is -78 ° C. There is a limit to practical industrial applications. In addition, the compound of C, such as Lee, performs an alkylation reaction at a very low optical yield of 5% ee, and thus has very low efficiency as a catalyst. Therefore, there is a need for a catalyst capable of asymmetrically synthesizing amino acids at high optical yields (95% -99% ee) under industrially easy reaction conditions.

본 발명자들은 새로운 비대칭 상 이동 촉매를 찾아내고자 지속적인 연구를 계속한 결과, 벤젠환내에 불소 또는 시안기를 도입할 때 기존의 촉매보다 알킬화 비대칭 상 이동 촉매활성이 월등히 증가함을 발견하였다. 이에 뛰어난 광학수율을 보이는 비대칭 상 이동 촉매 및 이를 이용한 비대칭 상 이동 촉매 반응을 개발하게되어 본 발명을 완성하였다. 따라서 본 발명의 목적은 신코나 알칼로이드에서 유래된 비대칭 상 이동 촉매를 제공하는데 있다. 본 발명의 또 다른 목적은 상기 비대칭 상 이동 촉매를 이용한 알파 아미노산의 비대칭 합성방법을 제공하는데 있다.As a result of continuing research to find a new asymmetric phase transfer catalyst, the inventors found that the alkylated asymmetric phase transfer catalyst activity was significantly increased when introducing fluorine or cyan group into the benzene ring. The present invention was completed by developing an asymmetric phase transfer catalyst and an asymmetric phase transfer catalyst reaction using the same. It is therefore an object of the present invention to provide an asymmetric phase transfer catalyst derived from cinnaco or alkaloids. Another object of the present invention to provide an asymmetric synthesis method of alpha amino acid using the asymmetric phase transfer catalyst.

본 발명은 다음 화학식 1, 2의 신규화합물에 관한 것이다.The present invention relates to novel compounds of the general formulas (1) and (2).

상기식중, X는 불소, 염소, 브롬, 요오드, 또는 IO4 -, ClO4 -, OTf-, HSO4 -이며;In the formula, X is F, Cl, Br, I, or IO 4 -, ClO 4 -, OTf -, HSO 4 - , and;

R1은 수소 또는 메톡시이며;R 1 is hydrogen or methoxy;

R2은 비닐 또는 에틸기이며;R 2 is a vinyl or ethyl group;

R3는 수소, 알릴, 벤질, 또는 탄소수 1-10의 알킬이며 (단 화학식 2에서 R3이 수소이며 R4가 불소인 경우 R5, R6가 수소인 것은 제외한다.);R 3 is (except in stage 2 the formula R 3 is hydrogen, and if R 4 is fluorine R 5, R 6 is not hydrogen.) Hydrogen, allyl, benzyl, or alkyl having a carbon number of 1-10;

R4는 불소 또는 시안기이며;R 4 is fluorine or cyan group;

R5, R6는 수소 또는 불소이다.R 5 and R 6 are hydrogen or fluorine.

본 발명의 화합물은 하기 반응식들에 의해 도시된 방법에 의해 화학적으로 합성될 수 있다. 그러나, 이는 단지 예시를 들기 위한 것으로서 본 발명이 이에 한정되는 것은 아니다.The compounds of the present invention can be chemically synthesized by the method shown by the following schemes. However, this is merely for illustrative purposes and the present invention is not limited thereto.

하기 반응식 1 에서와 같이 신코닌, 신코니딘, 퀴닌, 및 퀴니딘에 해당 치환된 벤질브로마이드를 가하여 N-알킬화반응을 수행한 후 알카리 염기성 조건에서 O(9)-알릴화반응을 수행하여 해당 상전이 촉매를 높은 수율로 합성하였다.As shown in Scheme 1, N-alkylation is performed by adding the corresponding substituted benzyl bromide to Cynconin, Cinconidine, Quinine, and Quinidine, followed by O (9) -allylation under alkaline basic conditions. Phase transfer catalysts were synthesized in high yield.

합성된 상전이 촉매의 효율성을 측정하기 위하여 하기 반응식 2 에서와 같이 N-(디페닐메틸렌)글리신tert-부틸 에스테르를 기질로 한 벤질화반응을 수행한 후 생성된 결과물을 키랄 HPLC(chiral HPLC)로 광학수율을 측정하였다.In order to measure the efficiency of the synthesized phase transfer catalyst, a benzylation reaction based on N- (diphenylmethylene) glycine tert -butyl ester was performed as in Scheme 2 below, and the resultant was subjected to chiral HPLC. Optical yield was measured.

이하 본 발명을 실시예 및 실험예를 통하여 구체적으로 설명하지만, 본 발명이 이들 예에만 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples, but the present invention is not limited only to these examples.

실시예 1 :Example 1: N-N- [(2-플루오로)벤질]신코니디늄 브로마이드[(2-fluoro) benzyl] cinconidinium bromide

50ml 둥근 바닥 플라스크에 (-)-신코니딘 [(-)-cinchonidine] (1g,3.4mmol), 2-플루오로벤질브로마이드 (3.73mmol, 1.1eq)을 넣고 에탄올:N,N-디메틸포름아미드:클로로포름(2.5:3:1) 용매조건에서 4시간동안 환류교반하였다. 반응 혼합물을 상온으로 식혀 에테르에 적가하여 고체형태의 표제화합물 1.3g을 수득하였다.In a 50 ml round bottom flask, (-)-cinconidine [(-)-cinchonidine] (1 g, 3.4 mmol) and 2-fluorobenzylbromide (3.73 mmol, 1.1eq) were added and ethanol: N, N-dimethylformamide The mixture was stirred under reflux for 4 hours in a chloroform (2.5: 3: 1) solvent. The reaction mixture was cooled to room temperature and added dropwise to ether to obtain 1.3 g of the title compound as a solid.

1H NMR (300MHz, DMSO-d 6) : 8.98(d,J=4.4Hz, 1H), 8.34-8.32(m, 1H), 8.10(d,J=8.0Hz, 1H), 7.94-7.63(m, 5H), 7.48-7.41(m, 2H), 6.79(d,J=3.9Hz,1H), 6.56(s, 1H), 5.74-5.62(m, 1H), 5.28-5.13(m, 2H), 5.03-4.93(m, 2H), 4.28(m, 1H), 4.05-3.99(m, 1H), 3.81-3.77(m, 1H), 3.43-3.39(m, 1H), 3.18(m, 1H), 2.72(m, 1H), 2.14-1.99(m, 3H), 1.81(m, 1H), 1.27-1.23(m, 1H) OneH NMR (300MHz, DMSO-d 6): 8.98 (d,J =4.4 Hz, 1H), 8.34-8.32 (m, 1H), 8.10 (d,J =8.0 Hz, 1H), 7.94-7.63 (m, 5H), 7.48-7.41 (m, 2H), 6.79 (d,J =3.9 Hz, 1H), 6.56 (s, 1H), 5.74-5.62 (m, 1H), 5.28-5.13 (m, 2H), 5.03-4.93 (m, 2H), 4.28 (m, 1H), 4.05-3.99 (m, 1H), 3.81-3.77 (m, 1H), 3.43-3.39 (m, 1H), 3.18 (m, 1H), 2.72 (m, 1H), 2.14-1.99 (m, 3H), 1.81 (m , 1H), 1.27-1.23 (m, 1H)

실시예 2 :Example 2: N-N- [(2-시아노)벤질]신코니디늄 브로마이드[(2-cyano) benzyl] cinconidinium bromide

2-플루오로벤질브로마이드 대신에 2-시아노벤질브로마이드를 사용하는것을 제외하고는 실시예 1과 동일한 방법으로 실시하여 고체형태의 표제화합물 1.2g을 수득하였다.1.2 g of the title compound was obtained in the same manner as in Example 1 except for using 2-cyanobenzylbromide instead of 2-fluorobenzylbromide.

1H NMR (400MHz, DMSO-d 6) : 9.00(d,J=4.5Hz, 1H), 8.39(d,J=8.4Hz, 1H), 8.17(d,J=7.8Hz, 1H), 8.12(d,J=8.0Hz, 2H), 7.98-7.95(m, 1H), 7.88-7.82(m, 3H), 7.80-7.76(m, 1H), 6.88(d,J=3.1Hz, 1H), 6.58(s, 1H), 5.69-5.65(m, 1H), 5.37-5.33(m, 2H), 5.21(d,J=17.3Hz, 1H), 4.96(D,J=10.6Hz, 1H),4.48-4.47(m, 1H), 4.07-4.05(m, 1H), 3.96-3.93(m, 1H), 3.46-3.41(m, 1H), 3.33-3.29(m, 1H), 2.68(m, 1H), 2.16-2.11(m, 2H), 2.02(m, 1H), 1.82(m, 1H), 1.27-1.21(m, 1H) OneH NMR (400 MHz, DMSO-d 6): 9.00 (d,J =4.5 Hz, 1H), 8.39 (d,J =8.4 Hz, 1 H), 8.17 (d,J =7.8 Hz, 1H), 8.12 (d,J =8.0 Hz, 2H), 7.98-7.95 (m, 1H), 7.88-7.82 (m, 3H), 7.80-7.76 (m, 1H), 6.88 (d,J =3.1 Hz, 1H), 6.58 (s, 1H), 5.69-5.65 (m, 1H), 5.37-5.33 (m, 2H), 5.21 (d,J =17.3 Hz, 1H, 4.96 (D,J =10.6 Hz, 1H), 4.48-4.47 (m, 1H), 4.07-4.05 (m, 1H), 3.96-3.93 (m, 1H), 3.46-3.41 (m, 1H), 3.33-3.29 (m, 1H) , 2.68 (m, 1H), 2.16-2.11 (m, 2H), 2.02 (m, 1H), 1.82 (m, 1H), 1.27-1.21 (m, 1H)

실시예 3 :Example 3: N-N- [(2,3-디플루오로)벤질]신코니디늄 브로마이드[(2,3-difluoro) benzyl] cinconidinium bromide

2-플루오로벤질브로마이드 대신에 2,3-디플루오로벤질브로마이드를 사용하는것을 제외하고는 실시예 1과 동일한 방법으로 실시하여 고체형태의 표제화합물 1.4g을 수득하였다.1.4 g of the title compound was obtained in the same manner as in Example 1 except for using 2,3-difluorobenzyl bromide instead of 2-fluorobenzyl bromide.

1H NMR (300MHz, DMSO-d 6) : 8.98(d,J=4.4Hz, 1H), 8.32(d,J=8.3Hz, 1H), 8.10(d,J=8.5Hz, 1H), 7.87-7.68(m, 5H), 7.48-7.38(m, 1H), 6.80(d,J=3.7Hz, 1H), 6.54(m, 1H), 5.74-5.62(m, 1H), 5.30-5.04(m, 3H), 4.95(d,J=10.5Hz, 1H), 4.26(m, 1H), 4.05-4.02(m, 1H), 3.80-3.76(m, 1H), 3.48-3.40(m, 1H), 3.26(m, 1H), 2.67(m, 1H), 2.15-1.99(m, 3H), 1.80(m, 1H), 1.27(m, 1H) OneH NMR (300MHz, DMSO-d 6): 8.98 (d,J =4.4 Hz, 1H), 8.32 (d,J =8.3 Hz, 1H, 8.10 (d,J =8.5 Hz, 1H), 7.87-7.68 (m, 5H), 7.48-7.38 (m, 1H), 6.80 (d,J =3.7 Hz, 1H), 6.54 (m, 1H), 5.74-5.62 (m, 1H), 5.30-5.04 (m, 3H), 4.95 (d,J =10.5 Hz, 1H), 4.26 (m, 1H), 4.05-4.02 (m, 1H), 3.80-3.76 (m, 1H), 3.48-3.40 (m, 1H), 3.26 (m, 1H), 2.67 (m , 1H), 2.15-1.99 (m, 3H), 1.80 (m, 1H), 1.27 (m, 1H)

실시예 4 :Example 4: N-N- [(2,4-디플루오로)벤질]신코니디늄 브로마이드[(2,4-difluoro) benzyl] cinconidinium bromide

2-플루오로벤질브로마이드 대신에 2,4-디플루오로벤질브로마이드를 사용하는것을 제외하고는 실시예 1과 동일한 방법으로 실시하여 고체형태의 표제화합물 1.1g을 수득하였다.1.1 g of the title compound was obtained in the same manner as in Example 1 except for using 2,4-difluorobenzylbromide instead of 2-fluorobenzylbromide.

1H NMR (300MHz, DMSO-d 6) : 8.97(d,J=4.4Hz, 1H), 8.32(d,J=8.3Hz, 1H), 8.09(d,J=7.6Hz, 1H), 8.03-7.95(m, 1H), 7.86-7.71(m, 3H), 7.57-7.50(m, 1H), 7.39-7.33(m, 1H), 6.78(d,J=3.9Hz, 1H), 6.55(s, 1H), 5.73-5.62(m, 1H), 5.25-4.93(m, 4H), 4.25(m, 1H), 4.03-3.97(m, 1H), 3.80-3.75(m, 1H), 3.44-3.41(m, 1H), 3.19(m, 1H), 2.66(m, 1H), 2.13-1.98(m, 3H), 1.80(m, 1H), 1.29-1.22(m, 1H) OneH NMR (300MHz, DMSO-d 6): 8.97 (d,J =4.4 Hz, 1H), 8.32 (d,J =8.3 Hz, 1H), 8.09 (d,J =7.6 Hz, 1H), 8.03-7.95 (m, 1H), 7.86-7.71 (m, 3H), 7.57-7.50 (m, 1H), 7.39-7.33 (m, 1H), 6.78 (d,J =3.9 Hz, 1H), 6.55 (s, 1H), 5.73-5.62 (m, 1H), 5.25-4.93 (m, 4H), 4.25 (m, 1H), 4.03-3.97 (m, 1H), 3.80-3.75 (m, 1H), 3.44-3.41 (m, 1H), 3.19 (m, 1H), 2.66 (m, 1H), 2.13-1.98 (m, 3H), 1.80 (m, 1H), 1.29-1.22 (m , 1H)

실시예 5 :Example 5: N-N- [(2,3,4-트리플루오로)벤질]신코니디늄 브로마이드[(2,3,4-trifluoro) benzyl] cinconidinium bromide

2-플루오로벤질브로마이드 대신에 2,3,4-트리플루오로벤질브로마이드를 사용하는것을 제외하고는 실시예 1과 동일한 방법으로 실시하여 고체형태의 표제화합물 1.2g을 수득하였다.1.2 g of the title compound was obtained in the same manner as in Example 1 except for using 2,3,4-trifluorobenzylbromide instead of 2-fluorobenzylbromide.

1H NMR (400MHz, DMSO-d 6) : 8.99(d,J=4.6Hz, 1H), 8.38(d,J=8.4Hz, 1H), 8.10(d,J=8.3Hz, 1H), 7.91-7.81(m, 3H), 7.75(t,J=7.5Hz, 1H), 7.63-7.56(m, 1H), 6.80(d,J=4.2Hz, 1H), 6.56(s, 1H), 5.73-5.65(m, 1H), 5.32(d,J=12.9Hz, 1H), 5.23-5.17(m, 2H), 4.96(d,J=10.5Hz, 1H), 4.34-4.21(m, 1H), 4.09-4.04(m, 1H), 3.87-3.84(m, 1H), 3.48(t,J=11.4Hz, 1H), 3.33-3.27(m, 1H), 2.70-2.62(m, 1H), 2.14-2.07(m, 2H), 2.03-2.01(m, 1H), 1.82-1.80(m, 1H), 1.30-1.24(m, 1H) OneH NMR (400 MHz, DMSO-d 6): 8.99 (d,J =4.6 Hz, 1H), 8.38 (d,J =8.4 Hz, 1 H), 8.10 (d,J =8.3 Hz, 1H), 7.91-7.81 (m, 3H), 7.75 (t,J =7.5 Hz, 1H), 7.63-7.56 (m, 1H), 6.80 (d,J =4.2 Hz, 1H), 6.56 (s, 1H), 5.73-5.65 (m, 1H), 5.32 (d,J =12.9 Hz, 1H), 5.23-5.17 (m, 2H), 4.96 (d,J =10.5 Hz, 1H), 4.34-4.21 (m, 1H), 4.09-4.04 (m, 1H), 3.87-3.84 (m, 1H), 3.48 (t,J =11.4 Hz, 1H), 3.33-3.27 (m, 1H), 2.70-2.62 (m, 1H), 2.14-2.07 (m, 2H), 2.03-2.01 (m, 1H), 1.82-1.80 (m, 1H) , 1.30-1.24 (m, 1 H)

실시예 6 :Example 6: N-N- [(2-플루오로)벤질]하이드로신코니디늄 브로마이드[(2-fluoro) benzyl] hydrocinconidinium bromide

50ml 둥근 바닥 플라스크에 (-)-하이드로신코니딘 [(-)-hydrocinchonidine] (1g, 3.4mmol), 2-플루오로벤질브로마이드 (3.73mmol, 1.1eq)을 넣고 에탄올:N,N-디메틸포름아미드:클로로포름(2.5:3:1) 용매조건에서 4시간동안 환류교반하였다. 반응 혼합물을 상온으로 식혀 에테르에 적가하여 고체형태의 표제화합물 1.5g을 수득하였다.(-)-Hydrocinchonidine [(-)-hydrocinchonidine] (1 g, 3.4 mmol) and 2-fluorobenzyl bromide (3.73 mmol, 1.1 eq) were added to a 50 ml round bottom flask, and ethanol: N, N-dimethylform was added. The mixture was stirred under reflux for 4 hours in an amide: chloroform (2.5: 3: 1) solvent. The reaction mixture was cooled to room temperature and added dropwise to ether to obtain 1.5 g of the title compound as a solid.

1H NMR (400MHz, DMSO-d 6) : 9.01(d,J=4.5Hz, 1H), 8.37(d,J=8.4Hz, 1H), 8.12(d,J=8.4Hz, 1H), 7.90-7.84(m, 3H), 7.78-7.74(m, 1H), 7.69-7.65(m, 1H), 7.48-7.42(m, 2H), 6.78(d,J=4.2Hz, 1H), 6.58(s, 1H), 5.27(d,J=12.8Hz, 1H), 4.95(d,J=12.7Hz, 1H), 4.38-4.23(m, 1H), 4.08-4.03(m, 1H), 3.63-3.32(m, 3H), 3.21-3.13(m, 1H), 2.15-2.05(m, 2H), 1.98-1.90(m, 1H), 1.82-1.74(m, 1H), 1.37-1.31(m, 1H), 1.28-1.12(m, 2H), 0.71(t,J=7.2Hz, 3H) OneH NMR (400 MHz, DMSO-d 6): 9.01 (d,J =4.5 Hz, 1 H, 8.37 (d,J =8.4 Hz, 1 H), 8.12 (d,J =8.4 Hz, 1H), 7.90-7.84 (m, 3H), 7.78-7.74 (m, 1H), 7.69-7.65 (m, 1H), 7.48-7.42 (m, 2H), 6.78 (d,J =4.2 Hz, 1H), 6.58 (s, 1H), 5.27 (d,J =12.8 Hz, 1H, 4.95 (d,J =12.7 Hz, 1H), 4.38-4.23 (m, 1H), 4.08-4.03 (m, 1H), 3.63-3.32 (m, 3H), 3.21-3.13 (m, 1H), 2.15-2.05 (m, 2H) , 1.98-1.90 (m, 1H), 1.82-1.74 (m, 1H), 1.37-1.31 (m, 1H), 1.28-1.12 (m, 2H), 0.71 (t,J =7.2 Hz, 3H)

실시예 7 :Example 7: N-N- [(2,3-디플루오로)벤질]하이드로신코니디늄 브로마이드[(2,3-difluoro) benzyl] hydrocinconidinium bromide

2-플루오로벤질브로마이드 대신에 2,3-디플루오로벤질브로마이드를 사용하는 것을 제외하고는 실시예 6과 동일한 방법으로 실시하여 고체형태의 표제화합물 1.3g을 수득하였다.1.3 g of the title compound was obtained in the same manner as in Example 6 except for using 2,3-difluorobenzylbromide instead of 2-fluorobenzylbromide.

1H NMR (300MHz, DMSO-d 6) : 8.99(d,J=4.6Hz, 1H), 8.30(d,J=8.6Hz, 1H), 8.11(d,J=8.6Hz, 1H), 7.87-7.60(m, 5H), 7.47-7.43(m, 1H), 6.76(d,J=3.9Hz, 1H), 6.53(s, 1H), 5.24(d,J=12.9Hz, 1H), 4.92(d,J=12.9Hz, 1H), 4.30-4.19(m, 1H), 4.06-3.95(m, 1H), 3.42-3.22(m, 3H), 2.18-1.90(m, 3H), 1.84-1.62(m, 2H), 1.41-1.33(m, 1H), 1.23-1.05(m, 2H), 0.71(t,J=7.3Hz, 3H) OneH NMR (300MHz, DMSO-d 6): 8.99 (d,J =4.6 Hz, 1H), 8.30 (d,J =8.6 Hz, 1H, 8.11 (d,J =8.6 Hz, 1H), 7.87-7.60 (m, 5H), 7.47-7.43 (m, 1H), 6.76 (d,J =3.9 Hz, 1H, 6.53 (s, 1H), 5.24 (d,J =12.9 Hz, 1H), 4.92 (d,J =12.9 Hz, 1H), 4.30-4.19 (m, 1H), 4.06-3.95 (m, 1H), 3.42-3.22 (m, 3H), 2.18-1.90 (m, 3H), 1.84-1.62 (m, 2H) , 1.41-1.33 (m, 1H), 1.23-1.05 (m, 2H), 0.71 (t,J =7.3 Hz, 3H)

실시예 8 :Example 8: N-N- [(2,3,4-트리플루오로)벤질]하이드로신코니디늄 브로마이드[(2,3,4-trifluoro) benzyl] hydrocinconidinium bromide

2-플루오로벤질브로마이드 대신에 2,3,4-트리플루오로벤질브로마이드를 사용하는것을 제외하고는 실시예 6과 동일한 방법으로 실시하여 고체형태의 표제화합물 1.4g을 수득하였다.Except for using 2,3,4-trifluorobenzyl bromide instead of 2-fluorobenzyl bromide in the same manner as in Example 6 to give 1.4g of the title compound in the solid form.

1H NMR (400MHz, DMSO-d 6) : 8.99(d,J=4.5Hz, 1H), 8.37(d,J=8.4Hz, 1H), 8.10(d,J=8.3Hz, 1H), 7.86-7.82(m, 3H), 7.76-7.72(m, 1H), 7.62-7.56(m, 1H), 6.77(d,J=4.3Hz, 1H), 6.55(s, 1H), 5.31(d,J=12.9Hz, 1H), 5.05(d,J=12.9Hz, 1H), 4.32-4.25(m, 1H), 4.08-4.04(m, 1H), 3.55-3.52(m, 1H), 3.44-3.35(m, 1H), 3.27-3.24(m, 1H), 2.14-2.05(m, 2H), 2.02-1.95(m, 1H), 1.77-1.71(m, 2H), 1.35-1.30(m, 1H), 1.27-1.09(m, 2H), 0.71(t,J=7.3Hz, 3H) OneH NMR (400 MHz, DMSO-d 6): 8.99 (d,J =4.5 Hz, 1 H, 8.37 (d,J =8.4 Hz, 1 H), 8.10 (d,J =8.3 Hz, 1H), 7.86-7.82 (m, 3H), 7.76-7.72 (m, 1H), 7.62-7.56 (m, 1H), 6.77 (d,J =4.3 Hz, 1 H), 6.55 (s, 1 H), 5.31 (d,J =12.9 Hz, 1H), 5.05 (d,J =12.9 Hz, 1H), 4.32-4.25 (m, 1H), 4.08-4.04 (m, 1H), 3.55-3.52 (m, 1H), 3.44-3.35 (m, 1H), 3.27-3.24 (m, 1H) , 2.14-2.05 (m, 2H), 2.02-1.95 (m, 1H), 1.77-1.71 (m, 2H), 1.35-1.30 (m, 1H), 1.27-1.09 (m, 2H), 0.71 (t,J =7.3 Hz, 3H)

실시예 9 :Example 9: N-N- (2-플루오로)벤질(2-fluoro) benzyl -O-O (9)-알릴신코니디늄 브로마이드(9) -allylicinodinium bromide

상기 실시예 1에서 제조한N-알킬신코니디늄 할로겐화물 (0.5g)을 디클로로메탄(2ml)용매에서 50% 수산화칼륨 수용액(5.0eq), 알릴 브로마이드 (3.0eq)을 가하여 실온에서 4시간동안 격렬히 교반하였다. 반응 혼합물에 물(10ml)을 넣고 디클로로메탄으로 추출한 후 무수 황산마그네슘으로 건조하고 여과하여 농축하였다. 얻은 고체를 디클로로메탄-헥산중에서 재결정하여 고체형태의 표제화합물 0.45g을 수득하였다. N -alkylcinconidinium halide (0.5 g) prepared in Example 1 was added with 50% aqueous potassium hydroxide solution (5.0 eq) and allyl bromide (3.0 eq) in a dichloromethane (2 ml) solvent for 4 hours at room temperature. Stir vigorously. Water (10 ml) was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained solid was recrystallized in dichloromethane-hexane to give 0.45 g of the title compound as a solid.

1H NMR (300MHz, DMSO-d 6) : 9.00(d,J=4.4Hz, 1H), 8.26(d,J=8.3Hz, 1H0, 8.13(d,J=8.3Hz, 1H), 7.89-7.65(m, 5H), 7.49-7.42(m, 2H), 6.45(s, 1H), 6.17-6.05(m, 1H), 5.74-5.63(m, 1H), 5.44(d,J=17.1Hz,1H), 5.30-5.10(m, 3H), 4.98-4.90(m, 2H), 4.29-4.23(m, 1H), 4.06-4.02(m, 3H), 3.73(m, 1H), 3.47-3.43(m, 1H), 3.22(m, 1H), 2.69(m, 1H), 2.22(m, 1H), 2.01(m, 2H), 1.83(m, 1H), 1.38(m, 1H) OneH NMR (300MHz, DMSO-d 6): 9.00 (d,J =4.4 Hz, 1H), 8.26 (d,J =8.3 Hz, 1H0, 8.13 (d,J =8.3 Hz, 1H), 7.89-7.65 (m, 5H), 7.49-7.42 (m, 2H), 6.45 (s, 1H), 6.17-6.05 (m, 1H), 5.74-5.63 (m, 1H), 5.44 (d,J =17.1 Hz, 1H), 5.30-5.10 (m, 3H), 4.98-4.90 (m, 2H), 4.29-4.23 (m, 1H), 4.06-4.02 (m, 3H), 3.73 (m, 1H), 3.47 -3.43 (m, 1H), 3.22 (m, 1H), 2.69 (m, 1H), 2.22 (m, 1H), 2.01 (m, 2H), 1.83 (m, 1H), 1.38 (m, 1H)

실시예 10 :Example 10 N-N- (2-시아노)벤질(2-cyano) benzyl -O-O (9)-알릴신코니디늄 브로마이드(9) -allylicinodinium bromide

상기 실시예 2에서 제조한N-알킬신코니디늄 할로겐화물 (0.5g)을 사용하는것을 제외하고는 실시예 9와 동일한 방법으로 실시하여 고체형태의 표제화합물 0.47g을 수득하였다.0.47 g of the title compound was obtained in the same manner as in Example 9, except that N -alkylcinconidinium halide (0.5 g) prepared in Example 2 was used.

1H NMR (300MHz, DMSO-d 6) : 9.01(d,J=4.4Hz, 1H), 8.31(d,J=8.3Hz,1H), 8.14-8.11(m, 3H), 7.98-7.74(m, 4H), 7.69(d,J=4.4Hz, 1H), 6.49(s, 1H), 6.17-6.08(m, 1H), 5.72-5.64(m, 1H), 5.45-5.13(m, 5H), 4.96(d,J=10.5Hz, 1H), 4.36(dd,J=11.9, 5.1Hz, 1H), 4.24(m, 1H), 4.06-3.96(m, 3H), 3.53-3.45(m, 1H), 3.26(m, 1H), 2.67(m, 1H), 2.24(m, 1H), 2.07-2.04(m, 2H), 1.83(m, 1H), 1.39(m, 1H) OneH NMR (300MHz, DMSO-d 6): 9.01 (d,J =4.4 Hz, 1H), 8.31 (d,J =8.3 Hz, 1H), 8.14-8.11 (m, 3H), 7.98-7.74 (m, 4H), 7.69 (d,J =4.4 Hz, 1H), 6.49 (s, 1H), 6.17-6.08 (m, 1H), 5.72-5.64 (m, 1H), 5.45-5.13 (m, 5H), 4.96 (d,J =10.5 Hz, 1H), 4.36 (dd,J =11.9, 5.1 Hz, 1H), 4.24 (m, 1H), 4.06-3.96 (m, 3H), 3.53-3.45 (m, 1H), 3.26 (m, 1H), 2.67 (m, 1H), 2.24 (m , 1H), 2.07-2.04 (m, 2H), 1.83 (m, 1H), 1.39 (m, 1H)

실시예 11 :Example 11: N-N- (2,3-디플루오로)벤질(2,3-difluoro) benzyl -O-O (9)-알릴신코니디늄 브로마이드(9) -allylicinodinium bromide

상기 실시예 3에서 제조한N-알킬신코니디늄 할로겐화물 (0.5g)을 사용하는것을 제외하고는 실시예 9와 동일한 방법으로 실시하여 고체형태의 표제화합물 0.50g을 수득하였다.Except for using N -alkylcinconidinium halide (0.5g) prepared in Example 3 was carried out in the same manner as in Example 9 to obtain 0.50g of the title compound in the solid form.

1H NMR (300MHz, DMSO-d 6) : 9.00(d,J=4.6Hz, 1H), 8.26(d,J=8.0Hz, 1H), 8.13(d,J=8.5Hz, 1H), 7.90-7.85(m, 1H), 7.80-7.68(m, 4H), 7.47-7.45(m, 1H), 6.43(s, 1H), 6.17-6.07(m, 1H), 5.75-5.63(m, 1H), 5.45(d,J=17.0Hz, 1H), 5.31-5.25(m, 2H), 5.14(d,J=17.8Hz, 1H), 5.03-4.95(m, 2H), 4.28-4.26(m, 1H), 4.07(m, 3H), 3.74(m, 1H), 3.51-3.44(m, 1H), 3.33(m, 1H), 2.67(m, 1H), 2.25(m, 1H), 2.10-2.02(m, 2H), 1.83(m, 1H), 1.39(m, 1H) OneH NMR (300MHz, DMSO-d 6): 9.00 (d,J =4.6 Hz, 1H, 8.26 (d,J =8.0 Hz, 1 H), 8.13 (d,J =8.5 Hz, 1H), 7.90-7.85 (m, 1H), 7.80-7.68 (m, 4H), 7.47-7.45 (m, 1H), 6.43 (s, 1H), 6.17-6.07 (m, 1H), 5.75 -5.63 (m, 1H), 5.45 (d,J =17.0 Hz, 1H), 5.31-5.25 (m, 2H), 5.14 (d,J =17.8 Hz, 1H), 5.03-4.95 (m, 2H), 4.28-4.26 (m, 1H), 4.07 (m, 3H), 3.74 (m, 1H), 3.51-3.44 (m, 1H), 3.33 (m , 1H), 2.67 (m, 1H), 2.25 (m, 1H), 2.10-2.02 (m, 2H), 1.83 (m, 1H), 1.39 (m, 1H)

실시예 12 :Example 12: N-N- (2,3,4-트리플루오로)벤질(2,3,4-trifluoro) benzyl -O-O (9)-알릴신코니디늄 브로마이드(9) -allylicinodinium bromide

상기 실시예 5에서 제조한N-알킬신코니디늄 할로겐화물 (0.5g)을 사용하는것을 제외하고는 실시예 9와 동일한 방법으로 실시하여 고체형태의 표제화합물 0.47g을 수득하였다.0.47 g of the title compound was obtained in the same manner as in Example 9 except for using the N -alkylcinconidinium halide (0.5 g) prepared in Example 5.

1H NMR (400MHz, DMSO-d 6) : 9.02(d,J=4.4Hz, 1H), 8.32(d,J=8.4Hz, 1H), 8.14(d,J=8.4Hz, 1H), 7.90-7.76(m, 3H), 7.70(d,J=4.4Hz, 1H), 7.64-7.58(m, 1H), 6.45(s, 1H), 6.18-6.08(m, 1H), 5.74-5.66(m, 1H), 5.46(d,J=17.1Hz, 1H), 5.31-5.25(m, 2H), 5.21-5.11(m, 2H), 4.98(d,J=10.5Hz, 1H), 4.31(dd,J=12.5, 5.4Hz, 1H), 4.12-3.98(m, 3H), 3.84-3.81(m, 1H), 3.50(t,J=11.4Hz, 1H), 3.33-3.31(m, 1H), 2.73-2.67(m, 1H), 2.33-2.23(m, 1H), 2.14-2.04(m, 2H), 1.86-1.81(m, 1H), 1.42-1.36(m, 1H) OneH NMR (400 MHz, DMSO-d 6): 9.02 (d,J =4.4 Hz, 1H), 8.32 (d,J =8.4 Hz, 1 H), 8.14 (d,J =8.4 Hz, 1H), 7.90-7.76 (m, 3H), 7.70 (d,J =4.4 Hz, 1H), 7.64-7.58 (m, 1H), 6.45 (s, 1H), 6.18-6.08 (m, 1H), 5.74-5.66 (m, 1H), 5.46 (d,J =17.1 Hz, 1H), 5.31-5.25 (m, 2H), 5.21-5.11 (m, 2H), 4.98 (d,J =10.5 Hz, 1H), 4.31 (dd,J =12.5, 5.4 Hz, 1H), 4.12-3.98 (m, 3H), 3.84-3.81 (m, 1H), 3.50 (t,J =11.4 Hz, 1H), 3.33-3.31 (m, 1H), 2.73-2.67 (m, 1H), 2.33-2.23 (m, 1H), 2.14-2.04 (m, 2H), 1.86-1.81 (m, 1H) , 1.42-1.36 (m, 1 H)

실시예 13 :Example 13: N-N- (2-플루오로)벤질(2-fluoro) benzyl -O-O (9)-알릴하이드로신코니디늄 브로마이드(9) -allylhydrocinconidinium bromide

상기 실시예 6에서 제조한N-알킬신코니디늄 할로겐화물 (0.5g)을 사용하는것을 제외하고는 실시예 9와 동일한 방법으로 실시하여 고체형태의 표제화합물 0.43g을 수득하였다.0.43 g of the title compound was obtained in the same manner as in Example 9 except for using the N -alkylcinconidinium halide (0.5 g) prepared in Example 6.

1H NMR (300MHz, DMSO-d 6) : 9.03(d,J=4.6Hz, 1H), 8.30(d,J=8.3Hz, 1H), 8.14(d,J=8.3Hz, 1H), 7.90-7.66(m, 5H), 7.50-7.44(m, 2H), 6.48(s, 1H), 6.20-6.07(m, 1H), 5.45(d,J=17.3Hz, 1H), 5.32-5.15(m, 2H), 4.89(d,J=12.7Hz, 1H), 4.29(dd,J=12.6, 5.2Hz, 1H), 4.08-4.02(m, 3H), 3.50-3.30(m, 2H), 3.27-3.14(m, 1H), 2.27-2.20(m, 1H), 2.07-1.98(m, 2H), 1.91-1.70(m, 2H), 1.47-1.41(m, 1H), 1.29-1.12(m, 2H), 0.71(t,J=7.2Hz, 3H) OneH NMR (300MHz, DMSO-d 6): 9.03 (d,J =4.6 Hz, 1H), 8.30 (d,J =8.3 Hz, 1H, 8.14 (d,J =8.3 Hz, 1H), 7.90-7.66 (m, 5H), 7.50-7.44 (m, 2H), 6.48 (s, 1H), 6.20-6.07 (m, 1H), 5.45 (d,J =17.3 Hz, 1H), 5.32-5.15 (m, 2H), 4.89 (d,J =12.7 Hz, 1H), 4.29 (dd,J =12.6, 5.2 Hz, 1H), 4.08-4.02 (m, 3H), 3.50-3.30 (m, 2H), 3.27-3.14 (m, 1H), 2.27-2.20 (m, 1H), 2.07-1.98 (m, 2H), 1.91-1.70 (m, 2H), 1.47-1.41 (m, 1H), 1.29-1.12 (m, 2H), 0.71 (t,J =7.2 Hz, 3H)

실시예 14 :Example 14 N-N- (2,3-디플루오로)벤질(2,3-difluoro) benzyl -O-O (9)-알릴하이드로신코니디늄 브로마이드(9) -allylhydrocinconidinium bromide

상기 실시예 7에서 제조한N-알킬신코니디늄 할로겐화물 (0.5g)을 사용하는것을 제외하고는 실시예 9와 동일한 방법으로 실시하여 고체형태의 표제화합물 0.48g을 수득하였다.0.48 g of the title compound in the solid form was obtained in the same manner as in Example 9, except that N -alkylcinconidinium halide (0.5 g) prepared in Example 7 was used.

1H NMR (300MHz, DMSO-d 6) : 9.02(d,J=4.4Hz, 1H), 8.27(d,J=8.5Hz, 1H), 8.14(d,J=8.3Hz, 1H), 7.88(t,J=7.6Hz, 1H), 7.80-7.62(m, 4H), 7.50-7.43(m, 1H), 6.43(s, 1H), 6.19-6.16(m, 1H), 5.45(d,J=17.3Hz, 1H), 5.31-5.23(m, 2H), 4.92(d,J=12.9Hz, 1H), 4.27(dd,J=12.7, 5.3Hz, 1H), 4.07-4.01(m, 3H), 3.46-3.28(m, 3H), 2.28-2.20(m, 1H), 2.08-1.98(m, 2H), 1.88-1.68(m, 2H), 1.44-1.40(m, 1H), 1.26-1.11(m, 2H), 0.70(t,J=7.2Hz, 3H) OneH NMR (300MHz, DMSO-d 6): 9.02 (d,J =4.4 Hz, 1H), 8.27 (d,J =8.5 Hz, 1H, 8.14 (d,J =8.3 Hz, 1H), 7.88 (t,J =7.6 Hz, 1H), 7.80-7.62 (m, 4H), 7.50-7.43 (m, 1H), 6.43 (s, 1H), 6.19-6.16 (m, 1H), 5.45 (d,J =17.3 Hz, 1H), 5.31-5.23 (m, 2H), 4.92 (d,J =12.9 Hz, 1H), 4.27 (dd,J =12.7, 5.3 Hz, 1H), 4.07-4.01 (m, 3H), 3.46-3.28 (m, 3H), 2.28-2.20 (m, 1H), 2.08-1.98 (m, 2H), 1.88-1.68 (m, 2H), 1.44-1.40 (m, 1H), 1.26-1.11 (m, 2H), 0.70 (t,J =7.2 Hz, 3H)

실시예 15 :Example 15: N-N- (2,3,4-트리플루오로)벤질(2,3,4-trifluoro) benzyl -O-O (9)-알릴하이드로신코니디늄 브로마이드(9) -allylhydrocinconidinium bromide

상기 실시예 8에서 제조한N-알킬신코니디늄 할로겐화물 (0.5g)을 사용하는것을 제외하고는 실시예 9와 동일한 방법으로 실시하여 고체형태의 표제화합물0.48g을 수득하였다.0.48 g of the title compound was obtained in the same manner as in Example 9 except for using the N -alkylcinconidinium halide (0.5 g) prepared in Example 8.

1H NMR (400MHz, DMSO-d 6) : 9.02(d,J=4.4Hz, 1H), 8.32(d,J=8.4Hz, 1H), 8.14(d,J=8.4Hz, 1H), 7.89-7.85(m, 1H), 7.79-7.75(m, 2H), 7.71(d,J=4.4Hz, 1H) 7.62-7.60(m, 1H), 6.45(s, 1H), 6.16-6.10(m, 1H), 5.45(d,J=17.2Hz, 1H), 5.31-5.23(m, 2H), 5.02(d,J=12.9Hz, 1H), 4.30(dd,J=12.6, 5.3Hz, 1H), 4.12-4.02(m, 3H), 3.58-3.52(m, 1H), 3.46-3.44(m, 1H), 3.35-3.30(m, 1H), 2.28-2.21(m, 1H), 2.13-2.05(m, 1H), 2.01-1.95(m, 1H), 1.77-1.74(m, 1H), 1.47-1.38(m, 1H), 1.25-1.16(m, 2H), 0.71(t,J=7.3Hz, 3H) OneH NMR (400 MHz, DMSO-d 6): 9.02 (d,J =4.4 Hz, 1H), 8.32 (d,J =8.4 Hz, 1 H), 8.14 (d,J =8.4 Hz, 1H), 7.89-7.85 (m, 1H), 7.79-7.75 (m, 2H), 7.71 (d,J =4.4 Hz, 1H) 7.62-7.60 (m, 1H), 6.45 (s, 1H), 6.16-6.10 (m, 1H), 5.45 (d,J =17.2 Hz, 1H), 5.31-5.23 (m, 2H), 5.02 (d,J =12.9 Hz, 1H), 4.30 (dd,J =12.6, 5.3 Hz, 1H), 4.12-4.02 (m, 3H), 3.58-3.52 (m, 1H), 3.46-3.44 (m, 1H), 3.35-3.30 (m, 1H), 2.28-2.21 (m, 1H), 2.13-2.05 (m, 1H), 2.01-1.95 (m, 1H), 1.77-1.74 (m, 1H), 1.47-1.38 (m, 1H), 1.25-1.16 (m, 2H), 0.71 ( t,J =7.3 Hz, 3H)

실시예 16 :Example 16: N-N- [(2-플루오로)벤질]신코니늄 브로마이드[(2-fluoro) benzyl] cinconium bromide

50ml 둥근 바닥 플라스크에 (+)-신코닌 [(+)-cinchonine] (1g, 3.4mmol), 2-플루오로벤질브로마이드 (3.73mmol, 1.1eq)을 넣고 에탄올:N,N-디메틸포름아미드:클로로포름(2.5:3:1) 용매조건에서 4시간동안 환류교반하였다. 반응 혼합물을 상온으로 식혀 에테르에 적가하여 고체형태의 표제화합물 1.4g을 수득하였다.To a 50 ml round bottom flask was added (+)-cinconine [(+)-cinchonine] (1 g, 3.4 mmol) and 2-fluorobenzylbromide (3.73 mmol, 1.1eq) and ethanol: N, N-dimethylformamide: The mixture was stirred under reflux for 4 hours in a chloroform (2.5: 3: 1) solvent. The reaction mixture was cooled to room temperature and added dropwise to ether to obtain 1.4 g of the title compound as a solid.

1H NMR (300MHz, DMSO-d 6) : 8.98(d,J=4.4Hz, 1H), 8.37(d,J=8.0Hz, 1H), 8.10(d,J=7.3Hz, 1H), 7.88-7.81(m, 3H), 7.77-7.63(m, 2H), 7.49-7.41(m, 2H), 6.87(d,J=3.4Hz, 1H), 6.53(s, 1H), 6.06-5.94(m, 1H), 5.24-5.16(m, 2H), 5.07-5.03(m, 2H), 4.24-4.18(m, 1H), 3.98-3.95(m, 2H), 3.39-3.35(m, 1H), 3.16-3.09(m, 1H), 2.72-2.64(m, 1H), 2.31-2.24(m, 1H), 1.87-1.78(m, 3H), 1.10-0.97(m, 1H) OneH NMR (300MHz, DMSO-d 6): 8.98 (d,J =4.4 Hz, 1H), 8.37 (d,J =8.0 Hz, 1 H, 8.10 (d,J =7.3 Hz, 1H), 7.88-7.81 (m, 3H), 7.77-7.63 (m, 2H), 7.49-7.41 (m, 2H), 6.87 (d,J =3.4 Hz, 1H), 6.53 (s, 1H), 6.06-5.94 (m, 1H), 5.24-5.16 (m, 2H), 5.07-5.03 (m, 2H), 4.24-4.18 (m, 1H), 3.98 -3.95 (m, 2H), 3.39-3.35 (m, 1H), 3.16-3.09 (m, 1H), 2.72-2.64 (m, 1H), 2.31-2.24 (m, 1H), 1.87-1.78 (m, 3H), 1.10-0.97 (m, 1H)

실시예 17 :Example 17: N-N- [(2-시아노)벤질]신코니늄 브로마이드[(2-cyano) benzyl] cinconium bromide

2-플루오로벤질브로마이드 대신에 2-시아노벤질브로마이드를 사용하는것을 제외하고는 실시예 16과 동일한 방법으로 실시하여 고체형태의 표제화합물 1.5g을 수득하였다.1.5 g of the title compound was obtained in the same manner as in Example 16, except that 2-cyanobenzylbromide was used instead of 2-fluorobenzylbromide.

1H NMR (300MHz, DMSO-d 6) : 8.99(d,J=4.4Hz, 1H), 8.39(d,J=8.3Hz, 1H), 8.12-8.08(m, 3H), 7.97-7.93(m, 1H), 7.87-7.72(m, 4H), 6.92(d,J=2.4Hz, 1H), 6.54(s, 1H), 6.06-5.94(m, 1H), 5.36-5.13(m, 4H), 4.40-4.34(m, 1H), 4.05-3.98(m, 2H), 3.50-3.37(m, 1H), 3.12-3.09(m, 1H), 2.65-2.62(m, 1H), 2.34-2.32(m, 1H), 1.87-1.80(m, 3H), 1.10-0.97(m, 1H) OneH NMR (300MHz, DMSO-d 6): 8.99 (d,J =4.4 Hz, 1H), 8.39 (d,J =8.3 Hz, 1H), 8.12-8.08 (m, 3H), 7.97-7.93 (m, 1H), 7.87-7.72 (m, 4H), 6.92 (d,J =2.4 Hz, 1H), 6.54 (s, 1H), 6.06-5.94 (m, 1H), 5.36-5.13 (m, 4H), 4.40-4.34 (m, 1H), 4.05-3.98 (m, 2H), 3.50 -3.37 (m, 1H), 3.12-3.09 (m, 1H), 2.65-2.62 (m, 1H), 2.34-2.32 (m, 1H), 1.87-1.80 (m, 3H), 1.10-0.97 (m, 1H)

실시예 18 :Example 18: N-N- [(2,3-디플루오로)벤질]하이드로신코니늄 브로마이드[(2,3-difluoro) benzyl] hydrocinconinium bromide

50ml 둥근 바닥 플라스크에 (+)-하이드로신코닌 [(+)-hydrocinchonine] (1g, 3.4mmol), 2,3-디플루오로벤질브로마이드 (3.73mmol, 1.1eq)을 넣고 에탄올:N,N-디메틸포름아미드:클로로포름(2.5:3:1) 용매조건에서 4시간동안 환류교반하였다. 반응 혼합물을 상온으로 식혀 에테르에 적가하여 고체형태의 표제화합물 1.3g을 수득하였다.In a 50 ml round bottom flask, (+)-hydrocinconin [(+)-hydrocinchonine] (1 g, 3.4 mmol) and 2,3-difluorobenzylbromide (3.73 mmol, 1.1 eq) were added and ethanol: N, N- The mixture was stirred under reflux for 4 hours in a solvent of dimethylformamide: chloroform (2.5: 3: 1). The reaction mixture was cooled to room temperature and added dropwise to ether to obtain 1.3 g of the title compound as a solid.

1H NMR (300MHz, DMSO-d 6) : 8.98(d,J=4.4Hz, 1H), 8.35(d,J=8.3Hz, 1H), 8.10(d,J=7.6Hz, 1H), 7.87-7.82(m, 2H), 7.77-7.64(m, 3H), 7.47-7.43(m, 1H), 6.83(d,J=3.4Hz, 1H), 6.49(s, 1H), 5.13-5.01(m, 2H), 3.98-3.91(m, 3H), 3.44-3.26(m, 1H), 3.12-3.09(m, 1H), 2.25(t,J=11.7Hz, 1H), 1.84-1.73(m, 4H), 1.52-1.45(m, 2H), 1.10-0.95(m, 1H), 0.83(t,J=7.3Hz, 3H) OneH NMR (300MHz, DMSO-d 6): 8.98 (d,J =4.4 Hz, 1H), 8.35 (d,J =8.3 Hz, 1H, 8.10 (d,J =7.6 Hz, 1H), 7.87-7.82 (m, 2H), 7.77-7.64 (m, 3H), 7.47-7.43 (m, 1H), 6.83 (d,J =3.4 Hz, 1H), 6.49 (s, 1H), 5.13-5.01 (m, 2H), 3.98-3.91 (m, 3H), 3.44-3.26 (m, 1H), 3.12-3.09 (m, 1H), 2.25 (t,J =11.7 Hz, 1H), 1.84-1.73 (m, 4H), 1.52-1.45 (m, 2H), 1.10-0.95 (m, 1H), 0.83 (t,J =7.3 Hz, 3H)

실시예 19 :Example 19: N-N- [(2,3,4-트리플루오로)벤질]하이드로신코니늄 브로마이드[(2,3,4-trifluoro) benzyl] hydrocinconinium bromide

2,3-디플루오로벤질브로마이드 대신에 2,3,4-트리플루오로벤질브로마이드를 사용하는것을 제외하고는 실시예 18과 동일한 방법으로 실시하여 고체형태의 표제화합물 1.4g을 수득하였다.In the same manner as in Example 18, except that 2,3,4-trifluorobenzylbromide was used instead of 2,3-difluorobenzylbromide, 1.4 g of the titled compound in the solid form was obtained.

1H NMR (300MHz, DMSO-d 6) : 8.98(d,J=4.4Hz, 1H), 8.42(d,J=8.3Hz, 1H), 8.01(d,J=8.3Hz, 1H), 7.85-7.80(m, 3H), 7.75-7.68(m, 1H), 7.62-7.51(m, 1H), 6.87(d,J=3.2Hz, 1H), 6.49(s, 1H), 5.23(d,J=12.9Hz, 1H), 5.09(d,J=12.7Hz, 1H), 4.05-3.90(m, 3H), 3.46-3.35(m, 1H), 3.17-3.07(m, 1H), 2.27-2.19(m, 1H), 1.83-1.63(m, 3H), 1.54-1.40(m, 3H), 1.07-1.00(m, 1H), 0.83(t,J=7.3Hz, 3H) OneH NMR (300MHz, DMSO-d 6): 8.98 (d,J =4.4 Hz, 1H), 8.42 (d,J =8.3 Hz, 1H, 8.01 (d,J = 8.3Hz, 1H), 7.85-7.80 (m, 3H), 7.75-7.68 (m, 1H), 7.62-7.51 (m, 1H), 6.87 (d,J =3.2 Hz, 1 H), 6.49 (s, 1 H), 5.23 (d,J =12.9 Hz, 1H), 5.09 (d,J =12.7 Hz, 1H), 4.05-3.90 (m, 3H), 3.46-3.35 (m, 1H), 3.17-3.07 (m, 1H), 2.27-2.19 (m, 1H), 1.83-1.63 (m, 3H) , 1.54-1.40 (m, 3H), 1.07-1.00 (m, 1H), 0.83 (t,J =7.3 Hz, 3H)

실시예 20 :Example 20: N-N- (2,3-디플루오로)벤질(2,3-difluoro) benzyl -O-O (9)-알릴하이드로신코니늄 브로마이드(9) -allylhydrocinconinium bromide

상기 실시예 18에서 제조한N-알킬신코니늄 할로겐화물(0.5g)을 디클로로메탄(2ml)용매에서 50% 수산화칼륨 수용액(5.0eq), 알릴 브로마이드 (3.0eq)을 가하여 실온에서 4시간동안 격렬히 교반하였다. 반응 혼합물에 물(10ml)을 넣고 디클로로메탄으로 추출한 후 무수 황산마그네슘으로 건조하고 여과하여 농축하였다. 얻은 고체를 디클로로메탄-헥산중에서 재결정하여 고체형태의 표제화합물 0.48g을 수득하였다. N- alkylcinconium halide (0.5 g) prepared in Example 18 was added with 50% aqueous potassium hydroxide solution (5.0 eq) and allyl bromide (3.0 eq) in a dichloromethane (2 ml) solvent for 4 hours at room temperature. Stir vigorously. Water (10 ml) was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained solid was recrystallized in dichloromethane-hexane to give 0.48 g of the title compound as a solid.

1H NMR (300MHz, DMSO-d 6) : 9.00(d,J=4.4Hz, 1H), 8.33(d,J=8.0Hz, 1H), 8.13(d,J=8.0Hz, 1H), 7.89-7.84(m, 1H), 7.79-7.69(m, 4H), 7.47-7.45(m, 1H), 6.37(s, 1H), 6.18-6.02(m, 1H), 5.46-5.29(m, 2H), 5.10(d,J=12.7Hz, 1H), 4.86(d,J=13.1Hz, 1H), 4.23-4.19(m, 1H), 4.04-4.00(m, 3H), 3.83-3.80(m, 1H), 3.43-3.32(m, 1H), 3.15-3.12(m, 1H), 2.32-2.28(m, 1H), 1.86-1.78(m, 4H), 1.52-1.47(m, 2H), 1.23-1.15(m, 1H), 0.83(t,J=7.3Hz, 3H) OneH NMR (300MHz, DMSO-d 6): 9.00 (d,J =4.4 Hz, 1H), 8.33 (d,J =8.0 Hz, 1 H), 8.13 (d,J =8.0 Hz, 1H), 7.89-7.84 (m, 1H), 7.79-7.69 (m, 4H), 7.47-7.45 (m, 1H), 6.37 (s, 1H), 6.18-6.02 (m, 1H), 5.46 -5.29 (m, 2H), 5.10 (d,J =12.7 Hz, 1H), 4.86 (d,J =13.1 Hz, 1H), 4.23-4.19 (m, 1H), 4.04-4.00 (m, 3H), 3.83-3.80 (m, 1H), 3.43-3.32 (m, 1H), 3.15-3.12 (m, 1H) , 2.32-2.28 (m, 1H), 1.86-1.78 (m, 4H), 1.52-1.47 (m, 2H), 1.23-1.15 (m, 1H), 0.83 (t,J =7.3 Hz, 3H)

실시예 21 :Example 21: N-N- (2,3,4-트리플루오로)벤질(2,3,4-trifluoro) benzyl -O-O (9)-알릴하이드로신코니늄 브로마이드(9) -allylhydrocinconinium bromide

상기 실시예 19에서 제조한N-알킬신코니디늄 할로겐화물 (0.5g)을 사용하는것을 제외하고는 실시예 20과 동일한 방법으로 실시하여 고체형태의 표제화합물 0.5g을 수득하였다.Except for using N -alkylcinconidinium halide (0.5g) prepared in Example 19 was carried out in the same manner as in Example 20 to obtain 0.5g of the title compound in the solid form.

1H NMR (300MHz, DMSO-d 6) : 9.00(d,J=4.4Hz, 1H), 8.41(d,J=8.0Hz, 1H), 8.11(d,J=8.0Hz, 1H), 7.88-7.78(m, 2H), 7.76-7.71(m, 4H), 7.67-7.55(m, 1H), 6.39(s, 1H), 6.16-5.97(m, 1H), 5.43(d,J=17.0Hz, 1H), 5.32-5.23(m, 2H), 4.84(d,J=12.9Hz, 1H), 4.24(dd,J=12.6, 5.5Hz, 1H), 4.17-4.09(m, 3H), 3.84-3.77(m, 1H), 3.49-3.39(m, 1H), 3.18-3.08(m, 1H), 2.35-2.27(m, 1H), 1.86-1.58(m, 4H), 1.52-1.44(m, 2H), 1.29-1.18(m, 1H), 0.83(t,J=7.3Hz, 3H) OneH NMR (300MHz, DMSO-d 6): 9.00 (d,J =4.4 Hz, 1H), 8.41 (d,J =8.0 Hz, 1 H, 8.11 (d,J =8.0 Hz, 1H), 7.88-7.78 (m, 2H), 7.76-7.71 (m, 4H), 7.67-7.55 (m, 1H), 6.39 (s, 1H), 6.16-5.97 (m, 1H), 5.43 (d,J =17.0 Hz, 1H), 5.32-5.23 (m, 2H), 4.84 (d,J =12.9 Hz, 1H), 4.24 (dd,J =12.6, 5.5 Hz, 1H), 4.17-4.09 (m, 3H), 3.84-3.77 (m, 1H), 3.49-3.39 (m, 1H), 3.18-3.08 (m, 1H), 2.35-2.27 (m, 1H), 1.86-1.58 (m, 4H), 1.52-1.44 (m, 2H), 1.29-1.18 (m, 1H), 0.83 (t,J =7.3 Hz, 3H)

실험예: 비대칭 상 이동 촉매 반응 조건하에서의Experimental Example: Asymmetric Phase Transfer Catalysis Under Reaction Conditions N-N- (디페닐메틸렌)글리신(Diphenylmethylene) glycine terttert -부틸 에스테르의 알킬화반응 (벤질화 반응)Alkylation of butyl ester (benzylation)

N-(디페닐메틸렌)글리신tert-부틸 에스테르 (50 mg, 0.17 mmol)과 비대칭 상 이동 촉매 (0.0085 mmol)에 톨루엔/클로로포름 (부피비=7:3, 0.75 mL)과 50% 수산화칼륨 수용액 (0.25 mL, 13.0 mmol)을 가한 후 반응액을 -20 ℃로 냉각한 다음 벤질브로마이드 (0.1 mL, 0.85 mmol)을 가했다. 반응 혼합물을 -20 ℃에서 기질이 없어질 때까지 교반하였다. 반응 혼합물을 에테르 (20 mL)로 희석한 후 유기층을 물로 세척한 뒤 무수 황산마그네슘으로 건조, 여과하고 감압농축하였다. 얻어진 잔사를 컬럼분리(이동상; 헥산:초산에틸=50:1)하여 무색 액상의 목적물, (S)-2-(벤즈하이드릴리덴아미노)-3-페닐프로피온 산tert-부틸 에스테르를 얻었다. 얻어진 목적물의 광학순도는 비대칭 고성능 액체 크로마토그래피로 측정하였다. [기기작동조건; ①컬럼: DAICEL Chiralcel OD, ②이동상: 헥산:2-프로판올=200:1, ③유속: 1.0 mL/min, ④측정온도: 23 ℃, ⑤검출기: 자외부흡광광도계 (파장: 254nm), ⑥머무름 시간:R이성질체 (minor) 12.2분,S이성질체 (major) 22.5분].Toluene / chloroform (volume ratio = 7: 3, 0.75 mL) and 50% aqueous potassium hydroxide solution (0.25) in N- (diphenylmethylene) glycine tert -butyl ester (50 mg, 0.17 mmol) and asymmetric phase transfer catalyst (0.0085 mmol) mL, 13.0 mmol) was added, and the reaction solution was cooled to -20 ° C, and then benzyl bromide (0.1 mL, 0.85 mmol) was added thereto. The reaction mixture was stirred at -20 ° C until the substrate was gone. The reaction mixture was diluted with ether (20 mL), the organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated by column (mobile phase; hexane: ethyl acetate = 50: 1) to obtain a colorless liquid target product, ( S ) -2- (benzhydrylideneamino) -3-phenylpropionic acid tert -butyl ester. The optical purity of the obtained target product was measured by asymmetric high performance liquid chromatography. [Operating conditions of the equipment; ① Column: DAICEL Chiralcel OD, ② Mobile phase: Hexane: 2-propanol = 200: 1, ③ Flow rate: 1.0 mL / min, ④ Measuring temperature: 23 ℃, ⑤ Detector: UV absorbance (wavelength: 254nm), ⑥ stay Time: R isomer 12.2 min, S isomer 22.5 min].

구분division 사용한 비대칭상 이동 촉매Asymmetric Phase Transfer Catalysts Used 화학수율(%)Chemical yield (%) 광학수율(% ee)Optical yield (% ee) 실시예 1Example 1 N-[(2-플루오로)벤질]신코니디늄 브로마이드 N- [(2-fluoro) benzyl] cinconidinium bromide 9393 8989 실시예 2Example 2 N-[(2-시아노)벤질]신코니디늄 브로마이드 N- [(2-cyano) benzyl] cinconidinium bromide 9494 9191 실시예 3Example 3 N-[(2,3-디플루오로)벤질]신코니디늄 브로마이드 N- [(2,3-difluoro) benzyl] cinconidinium bromide 9090 9292 실시예 4Example 4 N-[(2,4-디플루오로)벤질]신코니디늄 브로마이드 N- [(2,4-difluoro) benzyl] cinconidinium bromide 9191 8787 실시예 5Example 5 N-[(2,3,4-트리플루오로)벤질]신코니디늄 브로마이드 N- [(2,3,4-trifluoro) benzyl] cinconidinium bromide 9393 9191 실시예 6Example 6 N-[(2-플루오로)벤질]하이드로신코니디늄 브로마이드 N- [(2-fluoro) benzyl] hydrocinconidinium bromide 9292 9191 실시예 7Example 7 N-[(2,3-디플루오로)벤질]하이드로신코니디늄 브로마이드 N- [(2,3-difluoro) benzyl] hydrocinconidinium bromide 8989 9292 실시예 8Example 8 N-[(2,3,4-트리플루오로)벤질]하이드로신코니디늄 브로마이드 N- [(2,3,4-trifluoro) benzyl] hydrocinconidinium bromide 9595 9494 실시예 9Example 9 N-[(2-플루오로)벤질]신코니늄 브로마이드 N- [(2-fluoro) benzyl] cinconium bromide 8989 88(R)88 (R) 실시예 10Example 10 N-[(2-시아노)벤질]신코니늄 브로마이드 N- [(2-cyano) benzyl] cinconium bromide 8989 85(R)85 (R) 실시예 11Example 11 N-(2-플루오로)벤질-O(9)-알릴신코니디늄 브로마이드 N- (2-Fluoro) benzyl- O (9) -allylconconidinium bromide 9292 9595 실시예 12Example 12 N-(2-시아노)벤질-O(9)-알릴신코니디늄 브로마이드 N- (2-cyano) benzyl- O (9) -allylconconidinium bromide 9595 9696 실시예 13Example 13 N-(2,3-디플루오로)벤질-O(9)-알릴신코니디늄 브로마이드 N- (2,3-difluoro) benzyl- O (9) -allylcinconidinium bromide 9191 9797 실시예 14Example 14 N-(2,4-디플루오로)벤질-O(9)-알릴신코니디늄 브로마이드 N- (2,4-difluoro) benzyl- O (9) -allylcinconidinium bromide 9393 9595 실시예 15Example 15 N-(2,3,4-트리플루오로)벤질-O(9)-알릴신코니디늄 브로마이드 N- (2,3,4-trifluoro) benzyl- O (9) -allylcinconidinium bromide 9090 9595 실시예 16Example 16 N-(2-플루오로)벤질-O(9)-알릴하이드로신코니디늄 브로마이드 N- (2-fluoro) benzyl- O (9) -allylhydrocinconidinium bromide 8888 9494 실시예 17Example 17 N-(2,3-디플루오로)벤질-O(9)-알릴하이드로신코니디늄 브로마이드 N- (2,3-difluoro) benzyl- O (9) -allylhydrocinconidinium bromide 9191 9696 실시예 18Example 18 N-(2,3,4-트리플루오로)벤질-O(9)-알릴하이드로신코니디늄 브로마이드 N- (2,3,4-trifluoro) benzyl- O (9) -allylhydrocinconidinium bromide 9292 9797 비교예 1Comparative Example 1 N-벤질신코니디늄 브로마이드 N- benzylcinonidinium bromide 9191 7979 비교예 2Comparative Example 2 N-벤질-O(9)-알릴신코니디늄 브로마이드 N- benzyl- O (9) -allylconydinium bromide 9494 8181

비교예 1, 2: O'Donnell, M. J.; Bennett, W. D.; Wu, S.J. Am. Chem. Soc. 1989,111, 2353.Comparative Examples 1 and 2: O'Donnell, MJ; Bennett, WD; Wu, S. J. Am. Chem. Soc. 1989 , 111 , 2353.

상기의 실험결과와 같이 비교예 1, 2의 모노벤질 암모늄 촉매인 경우 약80%ee의 광학수율을 보인 반면 10-17의 경우 94-97%ee의 높은 광학수율을 보였다. 또한 이상의 촉매는 제조방법 또한 간단하여 공업적인 알파 아미노산의 합성에 응용돨 수 있을 것으로 생각된다.As described above, the monobenzyl ammonium catalysts of Comparative Examples 1 and 2 showed an optical yield of about 80% ee, whereas 10-17 showed a high optical yield of 94-97% ee. In addition, it is thought that the above catalyst can be applied to the synthesis of industrial alpha amino acids simply because the production method is also simple.

본 발명의 비대칭 상 이동 촉매를 아미노산 합성 반응에 이용하면, 제법이 간단하면서 수율이 높게 알파 아미노산을 합성할 수 있다.When the asymmetric phase transfer catalyst of the present invention is used for the amino acid synthesis reaction, alpha amino acids can be synthesized with high yield and high yield.

Claims (2)

하기 화학식 (1)로 표시되는 화합물.The compound represented by following formula (1). 상기식중, X는 불소, 염소, 브롬, 요오드, 또는 IO4 -, ClO4 -, OTf-, HSO4 -이며;In the formula, X is F, Cl, Br, I, or IO 4 -, ClO 4 -, OTf -, HSO 4 - , and; R1은 수소 또는 메톡시이며;R 1 is hydrogen or methoxy; R2는 비닐 또는 에틸기이며;R 2 is a vinyl or ethyl group; R3는 수소, 알릴, 벤질, 또는 탄소수 1-10의 알킬이며;R 3 is hydrogen, allyl, benzyl, or alkyl of 1-10 carbon atoms; R4는 불소 또는 시안기이며;R 4 is fluorine or cyan group; R5, R6는 수소 또는 불소이다.R 5 and R 6 are hydrogen or fluorine. 하기 화학식 (2)로 표시되는 화합물.The compound represented by following formula (2). 상기 식에서 X 및 R1내지 R6는 제 1항의 정의와 동일하다(단 화학식 (2)에서 R3이 수소이며 R4가 불소인 경우 R5, R6가 수소인 것은 제외한다.).Wherein X and R 1 to R 6 are the same as defined in claim 1 (except that R 5 and R 6 are hydrogen when R 3 is hydrogen and R 4 is fluorine in formula (2)).
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Publication number Priority date Publication date Assignee Title
KR20030057223A (en) * 2001-12-28 2003-07-04 주식회사 티지 바이오텍 A quinoline alkaloide derivative and a pharmaceutical composition comprising the same

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20030057223A (en) * 2001-12-28 2003-07-04 주식회사 티지 바이오텍 A quinoline alkaloide derivative and a pharmaceutical composition comprising the same

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