KR101005834B1 - Process of preparing pyrazoles - Google Patents

Process of preparing pyrazoles Download PDF

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KR101005834B1
KR101005834B1 KR1020080075988A KR20080075988A KR101005834B1 KR 101005834 B1 KR101005834 B1 KR 101005834B1 KR 1020080075988 A KR1020080075988 A KR 1020080075988A KR 20080075988 A KR20080075988 A KR 20080075988A KR 101005834 B1 KR101005834 B1 KR 101005834B1
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alkenoate
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이상기
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이화여자대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

본 발명은 2-아실-3-아미노-2-알케노에이트를 이용한 피라졸의 신규한 제조방법에 관한 것이다. 본 발명의 제조방법에 따르면, 2-아실-3-아미노-2-알케노에이트와 히드라진을 이용하여 다양한 피라졸을 위치선택적으로 고수율로 제조할 수 있다. The present invention relates to a novel process for the preparation of pyrazoles using 2-acyl-3-amino-2-alkenoate. According to the preparation method of the present invention, various pyrazoles can be regioselectively prepared in high yield using 2-acyl-3-amino-2-alkenoate and hydrazine.

피라졸, 2-아실-3-아미노-2-알케노에이트, 위치선택적, 제조방법 Pyrazole, 2-acyl-3-amino-2-alkenoate, regioselective, preparation method

Description

피라졸의 제조방법 {Process of preparing pyrazoles} Process of preparing pyrazole {Process of preparing pyrazoles}

본 발명은 2-아실-3-아미노-2-알케노에이트를 이용한 피라졸의 신규한 제조방법에 관한 것이다. 보다 구체적으로, 본 발명은 2-아실-3-아미노-2-알케노에이트과 히드라진을 이용하여 다양한 피라졸을 위치선택적으로 고수율로 제조하는 방법에 관한 것이다. The present invention relates to a novel process for the preparation of pyrazoles using 2-acyl-3-amino-2-alkenoate. More specifically, the present invention relates to a process for the preparation of various pyrazoles regioselectively in high yield using 2-acyl-3-amino-2-alkenoate and hydrazine.

피라졸은 중요한 파마코포어(pharmacophore) 중의 하나로서, COX-II 저해제, PDE5저해제 등 생리활성 물질의 중요한 스캐폴드(scaffold)로 이용되어 왔다[참조: T. D. Penning, et al., J. Med . Chem . 1997, 40, 1347; N. K. Terrett, et al., Bioorg . Med . Chem . Lett. 1996, 6, 1819; M. J. Genin, et al., J. Med . Chem. 2000, 43, 1034; A. Guzman-Perez, et al., Biorg . Med . Chem . Lett . 2001, 11, 803; W. T. Ashton, et al., Bioorg . Med . Chem . Lett . 2005, 15, 2253]. Pyrazole is one of the important pharmacophores and has been used as an important scaffold for bioactive substances such as COX-II inhibitors, PDE5 inhibitors. TD Penning, et al., J. Med . Chem . 1997 , 40 , 1347; NK Terrett, et al., Bioorg . Med . Chem . Lett . 1996 , 6 , 1819; MJ Genin, et al., J. Med . Chem. 2000 , 43 , 1034; A. Guzman-Perez, et al., Biorg . Med . Chem . Lett . 2001 , 11 , 803; WT Ashton, et al., Bioorg . Med . Chem . Lett . 2005 , 15 , 2253].

따라서, 다양한 피라졸의 합성방법이 개발되어 왔으며, 1,3-디케톤을 출발물질로 사용하여 치환된 히드라진과 반응시키는 방법이 가장 대표적이다. 그러나, 1 번과 3번 위치에 치환된 치환체가 다른 1,3-디케톤을 출발물질로 사용하여 3,5-이 치환된 비대칭(unsymmetric) 피라졸을 합성할 경우 두 케톤 그룹 사이의 친전자성의 차이가 크지 않아 위치이성질체(regioisomer)가 생성되는 문제점이 있었다. 이러한 문제점을 해결하기 위해서 1,3-디케톤을 아세틸렌 케톤 또는 올레핀 케톤으로 변형 (modify)한 출발물질을 사용하는 방법이 개발되었으나. 이 방법 역시 케톤과 아세틸렌 또는 올레핀에 치환된 치환체의 전자적, 입체적 장애의 정도가 비슷할 경우에는 위치선택적 피라졸의 합성이 어려운 한계성이 있었다 [참조: Y. R. Huang, et al. Org . Lett . 2000, 2, 2833; X.-j. Wang, et al., Tetrahedron Lett . 2000, 41, 4713; A. R. Katritzky, et al., J. Org . Chem . 2001, 66, 6787; S. Peruncheralathan, et al., J. Org . Chem . 2005, 70, 9644]. 따라서, 히드라존과 니트로올레핀의 고리화 반응을 비롯한 다양한 피라졸의 위치선택적 합성방법(regioselective synthesis)에 관한 많은 연구가 진행되어 왔으나, 제한된 출발물질에 국한되어 있어, 다양한 피라졸을 보다 일반적으로 그리고 높은 위치선택성으로 제조할 수 있는 방법의 개발이 절실히 요구되어 왔다[참조: X.-j. Wang, et al, Org . Lett . 2000, 2, 3107; X. Deng, et al., Org . Lett . 2006, 8, 3505; X. Deng, et al., J. Org . Chem . 2008, 73, 2417; S. Fustero, et al., J. Org . Chem . 2008, 73, 3523; T. Persson, et al., Org . Lett . 2006, 8, 3219]. Therefore, various pyrazole synthesis methods have been developed, and a method of reacting with substituted hydrazine using 1,3-diketone as a starting material is most representative. However, when synthesizing 3,5-substituted unsymmetric pyrazoles using 1,3-diketones having different substituents at positions 1 and 3 as starting materials, an electrophile between two ketone groups There was a problem that the regioisomer is produced because the difference in sex is not large. In order to solve this problem, a method of using a starting material obtained by modifying 1,3-diketone to acetylene ketone or olefin ketone has been developed. This method, too, was difficult to synthesize regioselective pyrazoles when the degree of electronic and steric hindrance of the substituents substituted with ketones, acetylenes, or olefins was similar [YR Huang, et al. Org . Lett . 2000 , 2, 2833; X.-j. Wang, et al., Tetrahedron Lett . 2000 , 41, 4713; AR Katritzky, et al., J. Org . Chem . 2001 , 66, 6787; S. Peruncheralathan, et al., J. Org . Chem . 2005 , 70, 9644]. Thus, many studies have been conducted on regioselective synthesis of various pyrazoles, including cyclization reactions between hydrazones and nitroolefins, but are limited to limited starting materials, making the various pyrazoles more commonly and There is an urgent need for the development of methods that can be produced with high regioselectivity. See X.-j. Wang, et al, Org . Lett . 2000 , 2 , 3107; X. Deng, et al., Org . Lett . 2006 , 8, 3505; X. Deng, et al., J. Org . Chem . 2008 , 73 , 2417; In S. Fustero, et al., J. Org . Chem . 2008 , 73 , 3523; T. Persson, et al., Org . Lett . 2006 , 8 , 3219.

본 발명자는 피라졸의 위치선택적 제조방법을 개발하기 위해 예의 연구 검토 한 결과, 2-아실-3-아미노-2-알케노에이트를 출발물질로 이용하여 위치선택적으로 다양한 피라졸을 제조할 수 있음을 발견하고 본 발명을 완성하게 되었다.The present inventors have conducted extensive studies to develop a regioselective preparation method of pyrazole, and thus, various pyrazoles can be prepared regioselectively using 2-acyl-3-amino-2-alkenoate as a starting material. The present invention was completed.

따라서, 본 발명의 목적은 2-아실-3-아미노-2-알케노에이트를 이용한 피라졸의 신규한 제조방법을 제공하는 것이다. It is therefore an object of the present invention to provide a novel process for the preparation of pyrazoles using 2-acyl-3-amino-2-alkenoate.

본 발명은 하기 화학식 1의 2-아실-3-아미노-2-알케노에이트와 하기 화학식 2의 히드라진을 반응시키는 것을 특징으로 하는 하기 화학식 3의 피라졸의 제조방법에 관한 것이다:The present invention relates to a process for preparing pyrazole of formula (3), comprising reacting 2-acyl-3-amino-2-alkenoate of formula (1) with hydrazine of formula (2):

Figure 112008055919281-pat00001
Figure 112008055919281-pat00001

상기 식에서, R1 및 R3는 각각 독립적으로 C1-C10의 알킬기, C3-C10의 사이클로알킬기 또는 아릴기이고, Wherein R 1 and R 3 are each independently an alkyl group of C 1 -C 10 , a cycloalkyl group or an aryl group of C 3 -C 10 ,

R2는 C1-C10의 알킬기이며,R 2 is an alkyl group of C 1 -C 10 ,

R4는 수소, C1-C10의 알킬기, C3-C10의 사이클로알킬기 또는 아릴기다.R 4 is hydrogen, a cycloalkyl group or an aryl wait of C 1 -C 10 alkyl, C 3 -C 10 a.

본 명세서에서 사용되는 C1-C10의 알킬기는 탄소수 1 내지 10개로 구성된 직 쇄형 또는 분지형 탄화수소를 의미하며, 예를 들어 메틸, 에틸, n-프로필, i-프로필, n-부틸, i-부틸, s-부틸, t-부틸, n-펜틸, n-헥실 등이 포함되나 이에 한정되는 것은 아니다.As used herein, an alkyl group of C 1 -C 10 refers to a straight or branched hydrocarbon having 1 to 10 carbon atoms, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i- Butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

본 명세서에서 사용되는 C3-C10의 사이클로알킬기는 탄소수 3 내지 10개로 구성된 고리형 탄화수소를 의미하며, 예를 들어 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실 등이 포함되나 이에 한정되는 것은 아니다. As used herein, a C 3 -C 10 cycloalkyl group means a cyclic hydrocarbon composed of 3 to 10 carbon atoms, and examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. .

본 명세서에서 사용되는 아릴기는 아로메틱기와 헤테로아로메틱기 및 그들의 부분적으로 환원된 유도체를 모두 포함한다. 상기 아로메틱기는 5 내지 15각형으로 이루어진 단순 또는 융합 고리형이며, 헤테로아로메틱기는 산소, 황 또는 질소를 하나 이상 포함하는 아로메틱기를 의미한다. 대표적인 아릴기의 예로는 페닐, 나프틸, 피리디닐(pyridinyl), 푸라닐(furanyl), 티오페닐(thiophenyl), 인돌릴(indolyl), 퀴놀리닐(quinolinyl), 이미다졸리닐(imidazolinyl), 옥사졸릴(oxazolyl), 티아졸릴(thiazolyl), 테트라히드로나프틸 등이 있으나 이에 한정되는 것은 아니다. As used herein, the aryl group includes both aromatic groups and heteroaromatic groups and their partially reduced derivatives. The aromatic group is a simple or fused cyclic consisting of 5 to 15 pentagons, heteroaromatic group refers to an aromatic group containing one or more oxygen, sulfur or nitrogen. Examples of representative aryl groups are phenyl, naphthyl, pyridinyl, furanyl, thiophenyl, indolyl, quinolinyl, imidazolinyl, Oxazolyl, thiazolyl, tetrahydronaphthyl, and the like, but are not limited thereto.

상기 C1-C10의 알킬기, C3-C10의 사이클로알킬기 및 아릴기는 한 개 또는 그 이상의 수소가 C1-C5의 알킬기, C2-C6의 알케닐기, C2-C6의 알키닐기, C3-C10의 시클로알킬기, C1-C5의 알콕시기, C1-C5의 티오알콕시기, C1-C5의 할로알킬기, 아릴기, 아실기, 히드록시, 티오(thio), 할로겐, 아미노, 알콕시카보닐, 카복시, 카바모일, 시아노, 니트로 등으로 치환될 수 있다.The C 1 -C 10 alkyl group, C 3 -C 10 cycloalkyl group and aryl group is one or more hydrogen is C 1 -C 5 alkyl group, C 2 -C 6 alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 10 cycloalkyl group, C 1 -C 5 alkoxy group, C 1 -C 5 thioalkoxy group, C 1 -C 5 haloalkyl group, aryl group, acyl group, hydroxy, thio (thio), halogen, amino, alkoxycarbonyl, carboxy, carbamoyl, cyano, nitro and the like.

본 발명의 제조방법에 있어서, R1 및 R3는 바람직하게는 각각 독립적으로 C1-C5의 알킬기, C1-C5의 알콕시기, C1-C5의 할로알킬기, 아릴기 및 할로겐으로 구성된 군으로부터 선택된 하나 이상의 치환기에 의해 치환되거나 치환되지 않은 C1-C10의 알킬기 또는 아릴기이다. 보다 바람직하게는, R1 및 R3는 각각 독립적으로 치환되지 않은 C1-C10의 알킬기, 하나 이상의 할로겐으로 치환된 C1-C10의 알킬기, In the production method of the present invention, R 1 and R 3 are preferably each independently C 1 -C 5 alkyl group, C 1 -C 5 alkoxy group, C 1 -C 5 haloalkyl group, aryl group and halogen C 1 -C 10 alkyl group or unsubstituted or substituted by one or more substituents selected from the group consisting of. More preferably, R 1 and R 3 are each independently an unsubstituted C 1 -C 10 alkyl group, a C 1 -C 10 alkyl group substituted with one or more halogens,

Figure 112008055919281-pat00002
Figure 112008055919281-pat00002

이며, 상기 식에서 X 및 Y는 각각 독립적으로 수소, C1-C5의 알킬기, C1-C5의 알콕시기, C1-C5의 할로알킬기 또는 할로겐이다. And, wherein X and Y are each independently hydrogen, halogen or a haloalkyl group of C 1 -C 5 alkyl, C 1 -C 5 alkoxy group, C 1 -C 5 in the.

R4는 바람직하게는 수소; C1-C5의 알킬기, C1-C5의 알콕시기, C1-C5의 할로알킬기, 아릴기 및 할로겐으로 구성된 군으로부터 선택된 하나 이상의 치환기에 의해 치환되거나 치환되지 않은 C1-C10의 알킬기 또는 아릴기이다. 보다 바람직하게는, R4는 수소; 치환되지 않은 C1-C10의 알킬기, R 4 is preferably hydrogen; Alkyl group of C 1 -C 5, C 1 -C 5 alkoxy group, C 1 that is substituted or not substituted by one or more substituents selected from a haloalkyl group, an aryl group, and the group consisting of halogen, -C 5 C 1 -C 10 Is an alkyl group or an aryl group. More preferably, R 4 is hydrogen; Unsubstituted C 1 -C 10 alkyl group,

Figure 112008055919281-pat00003
Figure 112008055919281-pat00003

이며, 상기 식에서 X 및 Y는 각각 독립적으로 수소, C1-C5의 알킬기, C1-C5의 알콕시기, C1-C5의 할로알킬기 또는 할로겐이고, n 및 m은 각각 독립적으로 0 내지 4의 정수이다.And, wherein X and Y are each independently a hydrogen, an alkyl group of C 1 -C 5, a haloalkyl group or a halogen C 1 -C 5 alkoxy group, C 1 -C 5 a, n and m are each independently 0 It is an integer of -4.

이하, 본 발명의 제조방법을 보다 상세히 설명하고자 한다. 하기에 기재된 방법은 대표적으로 사용된 방법을 예시한 것일 뿐 단위조작의 순서, 반응시약, 반응조건 등은 경우에 따라 얼마든지 변경될 수 있다.Hereinafter, the manufacturing method of the present invention will be described in more detail. The methods described below are merely illustrative of the methods used, and the sequence of unit operations, reaction reagents, reaction conditions, and the like may be changed as the case may be.

상기 화학식 1의 2-아실-3-아미노-2-알케노에이트와 상기 화학식 2의 히드라진의 반응은 산 촉매 존재하에 수행하는 것이 바람직하다. 산 촉매로는 황산, 염산, 질산, 파라-톨루엔술폰산, 메탄술폰산, 아세트산 등을 사용할 수 있으나 이에 한정되는 것은 아니다. 산 촉매의 사용량은 5~20몰%가 바람직하다. The reaction of 2-acyl-3-amino-2-alkenoate of Chemical Formula 1 with hydrazine of Chemical Formula 2 is preferably performed in the presence of an acid catalyst. The acid catalyst may be sulfuric acid, hydrochloric acid, nitric acid, para-toluenesulfonic acid, methanesulfonic acid, acetic acid and the like, but is not limited thereto. As for the usage-amount of an acid catalyst, 5-20 mol% is preferable.

상기 화학식 2의 히드라진은 상기 화학식 1의 2-아실-3-아미노-2-알케노에이트에 대해 1~10당량으로 사용하는 것이 바람직하다. The hydrazine of the formula (2) is preferably used in 1 to 10 equivalents to 2-acyl-3-amino-2-alkenoate of the formula (1).

반응용매로는 메탄올, 에탄올 등과 같은 알코올 용매, 테트라히드로푸란(THF), 디메틸포름아미드(DMF), 메틸렌클로라이드 등을 사용하는 것이 바람직하다. As the reaction solvent, alcohol solvents such as methanol and ethanol, tetrahydrofuran (THF), dimethylformamide (DMF), methylene chloride, and the like are preferably used.

본 발명의 제조방법에서 출발물질로 사용되는 상기 화학식 1의 2-아실-3-아미노-2-알케노에이트는 계류중인 대한민국 특허출원 제2008-0054013호에 개시된 방법에 따라 용이하게 제조할 수 있다.2-acyl-3-amino-2-alkenoate of Chemical Formula 1 used as a starting material in the preparation method of the present invention can be easily prepared according to the method disclosed in the pending Korean Patent Application No. 2008-0054013. .

본 발명의 제조방법에 따르면, 다양한 피라졸을 2-아실-3-아미노-2-알케노에이트와 히드라진으로부터 고수율로 제조할 수 있다. 특히, 3,5-이치환된 비대칭 피라졸을 위치선택적으로 용이하게 제조할 수 있다. According to the preparation method of the present invention, various pyrazoles can be prepared in high yield from 2-acyl-3-amino-2-alkenoate and hydrazine . In particular, 3,5-disubstituted asymmetric pyrazoles can be readily prepared regioselectively.

이하, 실시예에 의해 본 발명을 보다 구체적으로 설명하고자 한다. 이들 실시예는 오직 본 발명을 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업자에게 있어서 자명하다.Hereinafter, the present invention will be described in more detail with reference to Examples. It is apparent to those skilled in the art that these examples are only for illustrating the present invention, and the scope of the present invention is not limited to these examples.

실시예Example 1:  One: 피라졸(3a)의Of pyrazole (3a) 제조 Produce

2-아실-3-아미노-2-알케노에이트(1a) (110 mg, 0.47 mmol)를 무수 에탄올(1 mL) 에 용해시키고 히드라진 일수화물(0.13 mL, 2.5 mmol)을 가한 다음, 상온에서 1시간 동안 교반하였다. 반응 혼합물을 1시간 동안 천천히 환류 온도까지 가열하고 1.5시간 동안 가열 환류시켰다. 반응 혼합물을 상온으로 냉각시킨 다음, 감압하에서 농축시켰다. 잔유물을 에틸 아세테이트에 용해시키고 유기층을 1N HCl 수용액 및 소금물로 세척하고 MgSO4로 건조시킨 다음, 감압하에서 농축시켰다. 잔유물을 실리카겔 플래시 컬럼 크로마토그래피(Merck 60, 230-400 메쉬)로 정제하여 표제 화합물(92mg, 0.4 mmol, 85 %)를 수득하였다.2-acyl-3-amino-2-alkenoate (1a) (110 mg, 0.47 mmol) was dissolved in anhydrous ethanol (1 mL) and hydrazine monohydrate (0.13 mL, 2.5 mmol) was added, followed by 1 at room temperature. Stir for hours. The reaction mixture was slowly heated to reflux for 1 hour and heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organic layer was washed with 1N aqueous HCl solution and brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (Merck 60, 230-400 mesh) to give the title compound (92 mg, 0.4 mmol, 85%).

1H NMR (250 MHz, CDCl3) δ 12.2 (bs, 1H), 7.56 ~ 7.50 (m, 2H), 7.37 ~ 7.31 (m, 3H), 4.17 (q, J = 7.1 Hz, 2H), 2.12 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 12.2 (bs, 1H), 7.56 to 7.50 (m, 2H), 7.37 to 7.31 (m, 3H), 4.17 (q, J = 7.1 Hz, 2H), 2.12 ( s, 3H), 1.18 (t, J = 7.1 Hz, 3H) ppm

13C NMR (62.5 MHz CDCl3) δ 11.9, 14.1, 59.8, 108.8, 127.9, 128.6, 129.5, 132.1, 147.5, 152.3, 164.1 ppm 13 C NMR (62.5 MHz CDCl 3 ) δ 11.9, 14.1, 59.8, 108.8, 127.9, 128.6, 129.5, 132.1, 147.5, 152.3, 164.1 ppm

실시예Example 2:  2: 피라졸(3b)의Of pyrazole (3b) 제조 Produce

2-아실-3-아미노-2-알케노에이트(1a) (165 mg, 0.5 mmol)를 무수 에탄올(1 mL) 에 용해시키고 페닐히드라진(0.3 mL, 2.5 mmol)과 파라-톨루엔술폰산(5 mg)을 가한 다음, 상온에서 1시간 동안 교반하였다. 반응 혼합물을 1시간 동안 천천히 환류 온도까지 가열하고 1.5시간 동안 가열 환류시켰다. 반응 혼합물을 상온으로 냉각시킨 다음, 감압하에서 농축시켰다. 잔유물을 에틸 아세테이트에 용해시키고 유기층을 포화 NaHCO3 수용액, 1N HCl 수용액 및 소금물로 세척하고 MgSO4로 건조시킨 다음, 감압하에서 농축시켰다. 잔유물을 실리카겔 플래시 컬럼 크로마토그래피(Merck 60, 230-400 메쉬)로 정제하여 표제 화합물(139 mg, 0.45 mmol, 91 %)를 수득하였다.2-acyl-3-amino-2-alkenoate (1a) (165 mg, 0.5 mmol) was dissolved in anhydrous ethanol (1 mL), phenylhydrazine (0.3 mL, 2.5 mmol) and para-toluenesulfonic acid (5 mg). ) Was added, followed by stirring at room temperature for 1 hour. The reaction mixture was slowly heated to reflux for 1 hour and heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organic layer was washed with saturated aqueous NaHCO 3 , 1N HCl aqueous solution and brine, dried over MgSO 4 , and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (Merck 60, 230-400 mesh) to afford the title compound (139 mg, 0.45 mmol, 91%).

1H NMR (250 MHz, CDCl3) δ 7.72 ~ 7.68 (m, 2H), 7.52 ~ 7.39 (m, 8H), 4.26 (q, J = 7.1 Hz, 2H), 2.60 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 7.72 to 7.68 (m, 2H), 7.52 to 7.39 (m, 8H), 4.26 (q, J = 7.1 Hz, 2H), 2.60 (s, 3H), 1.23 ( t, J = 7.1 Hz, 3H) ppm

13C NMR (62.5 MHz, CDCl3 , ppm) δ 12.8, 14.1, 60.0, 110.6, 125.8, 127.7, 128.2, 128.7, 129.3, 129.5, 133.1, 138.8, 144.8, 153.6, 164.2 ppm 13 C NMR (62.5 MHz, CDCl 3 , ppm) δ 12.8, 14.1, 60.0, 110.6, 125.8, 127.7, 128.2, 128.7, 129.3, 129.5, 133.1, 138.8, 144.8, 153.6, 164.2 ppm

실시예Example 3:  3: 피라졸(3c)의Of pyrazole (3c) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1b)를 사용하여 실시예 2와 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 below in the same manner as in Example 2 using 2-acyl-3-amino-2-alkenoate (1b) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 1.12 (t, J = 7.1 Hz, 3H), 2.60 (s, 3H), 4.15 (q, J = 7.1 Hz, 2H), 7.15 ~ 7.32 (m, 1H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 1.12 (t, J = 7.1 Hz, 3H), 2.60 (s, 3H), 4.15 (q, J = 7.1 Hz, 2H), 7.15 to 7.32 (m, 1H) ppm

13C NMR (62.5 MHz, CDCl3) δ 14.0, 14.3, 59.8, 111.9, 125.3, 127.6, 127.9, 128.7, 128.8, 129.9, 130.4, 139.2, 146.3, 151.8, 163.8 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 14.0, 14.3, 59.8, 111.9, 125.3, 127.6, 127.9, 128.7, 128.8, 129.9, 130.4, 139.2, 146.3, 151.8, 163.8 ppm

실시예Example 4:  4: 피라졸(3d)의Of pyrazole (3d) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1c)를 사용하여 실시예 1과 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 in the same manner as in Example 1 using 2-acyl-3-amino-2-alkenoate (1c) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 11.15 (bs, 1H), 7.26 ~ 7.16 (m, 5H), 4.24 (q, J = 7.1 Hz, 2H), 4.21 (s, 2H), 2.40 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 11.15 (bs, 1H), 7.26 to 7.16 (m, 5H), 4.24 (q, J = 7.1 Hz, 2H), 4.21 (s, 2H), 2.40 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H) ppm

13C NMR (62.5 MHz, CDCl3) δ 12.98, 14.32, 33.17, 59.75, 108.79, 126.4, 128.5, 128.7, 138.2, 148.4, 150.9, 164.3 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 12.98, 14.32, 33.17, 59.75, 108.79, 126.4, 128.5, 128.7, 138.2, 148.4, 150.9, 164.3 ppm

실시예Example 5:  5: 피라졸(3e)의Of pyrazole (3e) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1c)를 사용하여 실시예 2와 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 in the same manner as in Example 2 using 2-acyl-3-amino-2-alkenoate (1c) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 7.49 ~ 7.26 (m, 10H), 4.29 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 2.52 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 7.49 to 7.26 (m, 10H), 4.29 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 2.52 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H) ppm

13C NMR (62.5 MHz, CDCl3) δ 12.8, 14.4, 34.0, 59.8, 110.5, 125.7, 125.9, 128.1, 128.5, 128.8, 129.2, 138.8, 139.7, 144.9, 153.4, 164.2 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 12.8, 14.4, 34.0, 59.8, 110.5, 125.7, 125.9, 128.1, 128.5, 128.8, 129.2, 138.8, 139.7, 144.9, 153.4, 164.2 ppm

실시예Example 6:  6: 피라졸(3f)의Of pyrazole (3f) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1d)를 사용하여 실시예 1과 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 in the same manner as in Example 1 using 2-acyl-3-amino-2-alkenoate (1d) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 9.95 (bs, 1H), 7.60 ~ 7.31 (m, 10H), 4.10 (q, J = 7.1 Hz, 2H), 1.02 (t, J = 7.1 Hz, 3H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 9.95 (bs, 1H), 7.60 to 7.31 (m, 10H), 4.10 (q, J = 7.1 Hz, 2H), 1.02 (t, J = 7.1 Hz, 3H) ppm

13C NMR (62.5 MHz, CDCl3) δ 13.7, 60.3, 109.0, 128.1, 128.4, 128.9, 129.1, 130.0, 130.2, 130.7, 133.2, 150.5, 164.0, 170.5 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 13.7, 60.3, 109.0, 128.1, 128.4, 128.9, 129.1, 130.0, 130.2, 130.7, 133.2, 150.5, 164.0, 170.5 ppm

실시예Example 7:  7: 피라졸(3g)의Of pyrazole (3 g) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1d)를 사용하여 실시예 2와 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 below by the same method as Example 2 using 2-acyl-3-amino-2-alkenoate (1d) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 7.80 ~ 7.77 (m, 2H), 7.44 ~ 7.27 (m, 13H), 4.07 (q, J = 7.1 Hz, 2H), 0.97 (t, J = 7.1 Hz, 3H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 7.80 to 7.77 (m, 2H), 7.44 to 7.27 (m, 13H), 4.07 (q, J = 7.1 Hz, 2H), 0.97 (t, J = 7.1 Hz, 3H) ppm

13C NMR (62.5 MHz,CDCl3) δ 13.7, 60.3, 112.1, 125.4, 127.9, 127.9, 128.1, 128.5, 128.8, 129.0, 129.2, 129.6, 130.4, 132.7, 139.2, 146.3, 153.4, 163.8 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 13.7, 60.3, 112.1, 125.4, 127.9, 127.9, 128.1, 128.5, 128.8, 129.0, 129.2, 129.6, 130.4, 132.7, 139.2, 146.3, 153.4, 163.8 ppm

실시예Example 8:  8: 피라졸(3h)의Of pyrazole (3h) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1e)를 사용하여 실시예 1과 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 in the same manner as in Example 1 using 2-acyl-3-amino-2-alkenoate (1e) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 12.74(bs, 1H), 7.39 ~ 7.23 (m, 7H), 6.77 (d, J = 7.1 Hz, 2H), 4.09(q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 12.74 (bs, 1H), 7.39 to 7.23 (m, 7H), 6.77 (d, J = 7.1 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H) , 3.79 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H) ppm

13C NMR (62.5 MHz, CDCl3) δ 13.8, 55.2, 60.2, 108.5, 113.4, 122.7, 127.9, 128.6, 129.1, 130.4, 131.2, 160.0, 164.1 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 13.8, 55.2, 60.2, 108.5, 113.4, 122.7, 127.9, 128.6, 129.1, 130.4, 131.2, 160.0, 164.1 ppm

실시예Example 9:  9: 피라졸(3i)의Of pyrazole (3i) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1e)를 사용하여 실시예 2와 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다. The title compound was obtained in the yield described in Table 1 in the same manner as in Example 2 using 2-acyl-3-amino-2-alkenoate (1e) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 7.77 ~ 7.73 (m, 2H), 7.43 ~ 6.88 (m, 10H), 6.86 (d, J = 8.9 Hz, 2H), 4.09(q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 1.01 (t, J = 7.1 Hz, 3H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 7.77 to 7.73 (m, 2H), 7.43 to 6.88 (m, 10H), 6.86 (d, J = 8.9 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 1.01 (t, J = 7.1 Hz, 3H) ppm

13C NMR (62.5 MHz, CDCl3) δ 13.8, 55.2, 60.2, 111.9, 113.5, 121.5, 125.5, 127.8, 127.9, 128.4, 128.8, 129.2, 131.8, 132.9, 139.3, 146.2, 153.3, 160.0, 163.9 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 13.8, 55.2, 60.2, 111.9, 113.5, 121.5, 125.5, 127.8, 127.9, 128.4, 128.8, 129.2, 131.8, 132.9, 139.3, 146.2, 153.3, 160.0, 163.9 ppm

실시예Example 10:  10: 피라졸(3j)의Of pyrazole (3j) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1f)를 사용하여 실시예 1과 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 in the same manner as in Example 1 using 2-acyl-3-amino-2-alkenoate (1f) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 12.14 (bs, 1H), 7.43 ~ 7.26 (m, 5H), 4.17 (q, J = 7.1 Hz, 2H), 3.60 ~ 3.54 (m, 1H), 1.26 ~ 1.12 (m, 9H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 12.14 (bs, 1H), 7.43 to 7.26 (m, 5H), 4.17 (q, J = 7.1 Hz, 2H), 3.60 to 3.54 (m, 1H), 1.26 to 1.12 (m, 9H) ppm

13C NMR (62.5 MHz, CDCl3) δ 13.9, 21.5, 26.4, 59.8, 107.5, 127.7, 128.4, 129.4, 132.0, 151.6, 157.0, 164.1 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 13.9, 21.5, 26.4, 59.8, 107.5, 127.7, 128.4, 129.4, 132.0, 151.6, 157.0, 164.1 ppm

실시예Example 11:  11: 피라졸(3k)의Of pyrazole (3k) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1f)를 사용하여 실시예 2와 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 below in the same manner as in Example 2 using 2-acyl-3-amino-2-alkenoate (1f) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 7.62 ~ 7.25 (m, 10H), 4.22 (q, J = 7.1 Hz, 2H), 3.35 ~ 3.24 (m, 1H), 1.37 (d, J = 7.1 Hz, 6H), 1.16 (t, J = 7.1 Hz, 3H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 7.62 to 7.25 (m, 10H), 4.22 (q, J = 7.1 Hz, 2H), 3.35 to 3.24 (m, 1H), 1.37 (d, J = 7.1 Hz, 6H), 1.16 (t, J = 7.1 Hz, 3H) ppm

13C NMR (62.5 MHz, CDCl3) δ 13.9, 20.6, 26.6, 60.4, 109.7, 112.5, 126.9, 127.7, 128.1, 129.0, 129.1, 129.2, 133.3, 139.5, 152.9, 153.3, 164.7 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 13.9, 20.6, 26.6, 60.4, 109.7, 112.5, 126.9, 127.7, 128.1, 129.0, 129.1, 129.2, 133.3, 139.5, 152.9, 153.3, 164.7 ppm

실시예Example 12:  12: 피라졸(3l)의Of pyrazole (3 l) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1g)를 사용하여 실시예 1과 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 below by the same method as Example 1 using 2-acyl-3-amino-2-alkenoate (1 g) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 12.27 (bs, 1H), 7.58 ~ 7.53 (m, 2H), 7.39 ~ 7.31 (m, 3H), 4.20 (q, J = 7.1 Hz, 2H), 2.51 (d, J = 7.1 Hz, 2H), 2.02 ~ 1.80 (m, 1H), 1.18 (t, J = 7.1 Hz, 3H), 0.80 (d, J = 6.6 Hz, 6H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 12.27 (bs, 1H), 7.58-7.53 (m, 2H), 7.39-7.31 (m, 3H), 4.20 (q, J = 7.1 Hz, 2H), 2.51 ( d, J = 7.1 Hz, 2H), 2.02 to 1.80 (m, 1H), 1.18 (t, J = 7.1 Hz, 3H), 0.80 (d, J = 6.6 Hz, 6H) ppm

13C NMR (62.5 MHz, CDCl3)δ 14.0, 22.2, 28.5, 34.9, 59.8, 108.4, 127.8, 128.5, 129.5, 132.3, 150.5, 152.5, 164.1 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 14.0, 22.2, 28.5, 34.9, 59.8, 108.4, 127.8, 128.5, 129.5, 132.3, 150.5, 152.5, 164.1 ppm

실시예Example 13:  13: 피라졸(3m)의Of pyrazole (3m) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1g)를 사용하여 실시예 2와 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 in the same manner as in Example 2 using 2-acyl-3-amino-2-alkenoate (1 g) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 7.69 ~ 7.65 (m, 2H), 7.49 ~ 7.36 (m, 8H), 4.23 (q, J = 7.1 Hz, 2H), 2.92 (d, J = 7.3 Hz, 2H), 1.89 ~ 1.83 (m, 1H), 1.21 (t, J = 7.0 Hz, 3H), 0.78 (d, J = 6.7 Hz, 6H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 7.69 to 7.65 (m, 2H), 7.49 to 7.36 (m, 8H), 4.23 (q, J = 7.1 Hz, 2H), 2.92 (d, J = 7.3 Hz, 2H), 1.89-1.83 (m, 1H), 1.21 (t, J = 7.0 Hz, 3H), 0.78 (d, J = 6.7 Hz, 6H) ppm

13C NMR (62.5 MHz, CDCl3) δ 13.9, 22.2, 28.9, 33.8, 59.9, 110.2, 126.7, 127.6, 128.1, 128.8, 129.2, 129.4, 133.1, 139.1, 148.5, 153.5, 164.2 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 13.9, 22.2, 28.9, 33.8, 59.9, 110.2, 126.7, 127.6, 128.1, 128.8, 129.2, 129.4, 133.1, 139.1, 148.5, 153.5, 164.2 ppm

실시예Example 14:  14: 피라졸(3n)의Of pyrazole (3n) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1h)를 사용하여 실시예 2와 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 below in the same manner as in Example 2 using 2-acyl-3-amino-2-alkenoate (1h) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 1.03 (d, J = 6.6 Hz, 6H), 1.12 (t, J = 7.1 Hz, 3H), 2.10 ~ 2.20 (m, 1H), 2.89 (d, J = 7.1 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 7.17 ~ 7.33 (m, 10H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 1.03 (d, J = 6.6 Hz, 6H), 1.12 (t, J = 7.1 Hz, 3H), 2.10 to 2.20 (m, 1H), 2.89 (d, J = 7.1 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 7.17-7.33 (m, 10H) ppm

13C NMR (62.5 MHz, CDCl3) δ 13.9, 22.6, 28.5, 36.9, 59.8, 111.7, 125.3, 127.5, 127.8, 128.7, 130.1, 130.4, 139.2, 146.3, 154.8, 163.9 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 13.9, 22.6, 28.5, 36.9, 59.8, 111.7, 125.3, 127.5, 127.8, 128.7, 130.1, 130.4, 139.2, 146.3, 154.8, 163.9 ppm

실시예Example 15:  15: 피라졸(3o)의Of pyrazole (3o) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1i)를 사용하여 실시예 1과 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 in the same manner as in Example 1 using 2-acyl-3-amino-2-alkenoate (1i) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 11.65 (bs, 1H), 7.53 ~ 7.40 (m, 5H), 4.23 (q, J = 7.1 Hz, 2H),1.23 (t, J = 7.1 Hz, 3H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 11.65 (bs, 1H), 7.53 to 7.40 (m, 5H), 4.23 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H) ppm

13C NMR (62.5 MHz, CDCl3) δ 13.7, 61.1, 109.4, 118.3, 122.6, 127.1, 128.5, 129.0, 130.3, 148.5, 161.6 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 13.7, 61.1, 109.4, 118.3, 122.6, 127.1, 128.5, 129.0, 130.3, 148.5, 161.6 ppm

실시예Example 16:  16: 피라졸(3p)의Of pyrazole (3p) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1i)를 사용하여 실시예 2와 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 in the same manner as in Example 2 using 2-acyl-3-amino-2-alkenoate (1i) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 7.74 ~ 7.71 (m, 2H), 7.51 ~ 7.39 (m, 8H), 4.35 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 7.74 to 7.71 (m, 2H), 7.51 to 7.39 (m, 8H), 4.35 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H) ppm

13C NMR (62.5 MHz, CDCl3) δ 13.8, 61.9, 115.1, 121.3, 128.4, 129.1, 129.2, 129.8, 130.9, 139.0, 151.5, 162.8 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 13.8, 61.9, 115.1, 121.3, 128.4, 129.1, 129.2, 129.8, 130.9, 139.0, 151.5, 162.8 ppm

실시예Example 17:  17: 피라졸(3q)의Of pyrazole (3q) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1j)를 사용하여 실시예 2와 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 below by the same method as Example 2 using 2-acyl-3-amino-2-alkenoate (1j) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 0.97 (t, J = 7.1 Hz, 3H), 4.08 (q, J = 7.1 Hz, 2H), 7.22 ~ 7.48 (m, 10H), 7.60 (d, J = 8.1 Hz, 2H), 7.75 ~ 7.79 (m, 2H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 0.97 (t, J = 7.1 Hz, 3H), 4.08 (q, J = 7.1 Hz, 2H), 7.22 to 7.48 (m, 10H), 7.60 (d, J = 8.1 Hz, 2H), 7.75-7.79 (m, 2H) ppm

13C NMR (62.5 MHz, CDCl3) δ 13.6, 60.4, 112.5, 124.9, 125.1, 125.5, 127.9, 128.3, 128.6, 129.1, 129.3, 131.0, 132.4, 133.3, 138.7, 144.8, 153.6, 163.4 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 13.6, 60.4, 112.5, 124.9, 125.1, 125.5, 127.9, 128.3, 128.6, 129.1, 129.3, 131.0, 132.4, 133.3, 138.7, 144.8, 153.6, 163.4 ppm

실시예Example 18:  18: 피라졸(3r)의Of pyrazole (3r) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1k)를 사용하여 실시예 2와 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 below in the same manner as in Example 2 using 2-acyl-3-amino-2-alkenoate (1k) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 0.96 (t, J = 7.1 Hz, 3H), 4.08 (q, J = 7.1 Hz, 2H), 7.25 ~ 7.39 (m, 10H), 7.70 (d, 2H), 7.93 (d, 2H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 0.96 (t, J = 7.1 Hz, 3H), 4.08 (q, J = 7.1 Hz, 2H), 7.25 to 7.39 (m, 10H), 7.70 (d, 2H) , 7.93 (d, 2H) ppm

13C NMR (62.5 MHz, CDCl3) δ 13.6, 60.4, 112.2, 124.7, 124.8, 124.9, 125.4, 128.1, 129.0, 129.2, 129.4, 129.6, 130.4, 136.4, 139.0, 146.7, 152.0, 162.9 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 13.6, 60.4, 112.2, 124.7, 124.8, 124.9, 125.4, 128.1, 129.0, 129.2, 129.4, 129.6, 130.4, 136.4, 139.0, 146.7, 152.0, 162.9 ppm

실시예Example 19:  19: 피라졸(3s)의Of pyrazole (3s) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1l)를 사용하여 실시예 2와 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 in the same manner as in Example 2 using 2-acyl-3-amino-2-alkenoate (1 l) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 1.17 (t, J = 7.4 Hz, 3H), 1.38 (t, J = 7.1 Hz, 3H), 2.51 (s, 3H), 2.90 (q, J = 7.4 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 7.36 ~ 7.49 (m, 5H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 1.17 (t, J = 7.4 Hz, 3H), 1.38 (t, J = 7.1 Hz, 3H), 2.51 (s, 3H), 2.90 (q, J = 7.4 Hz , 2H), 4.34 (q, J = 7.1 Hz, 2H), 7.36-7.49 (m, 5H) ppm

13C NMR (62.5 MHz, CDCl3) δ 13.7, 14.3, 19.1, 59.7, 109.7, 126.1, 128.7, 129.2, 138.9, 150.4, 151.5, 164.3 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 13.7, 14.3, 19.1, 59.7, 109.7, 126.1, 128.7, 129.2, 138.9, 150.4, 151.5, 164.3 ppm

실시예Example 20:  20: 피라졸(3t)의Of pyrazole (3t) 제조 Produce

하기 표 1에 도시된 2-아실-3-아미노-2-알케노에이트(1n)를 사용하여 실시예 2와 동일한 방법으로 표제 화합물을 하기 표 1에 기재된 수율로 수득하였다.The title compound was obtained in the yield described in Table 1 in the same manner as in Example 2 using 2-acyl-3-amino-2-alkenoate (1n) shown in Table 1 below.

1H NMR (250 MHz, CDCl3) δ 1.31 (t, J = 7.6 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H), 2.51 (s, 3H), 2.96 (q, J = 7.1 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 7.37 ~ 7.44 (m, 5H) ppm 1 H NMR (250 MHz, CDCl 3 ) δ 1.31 (t, J = 7.6 Hz, 3H), 1.37 (t, J = 7.1 Hz, 3H), 2.51 (s, 3H), 2.96 (q, J = 7.1 Hz , 2H), 4.32 (q, J = 7.1 Hz, 2H), 7.37-7.44 (m, 5H) ppm

13C NMR (62.5 MHz, CDCl3) δ 12.6, 13.5, 14.3, 21.7, 59.6, 110.0, 125.6, 128.3, 129.1, 138.8, 144.4, 156.6, 164.3 ppm 13 C NMR (62.5 MHz, CDCl 3 ) δ 12.6, 13.5, 14.3, 21.7, 59.6, 110.0, 125.6, 128.3, 129.1, 138.8, 144.4, 156.6, 164.3 ppm

표 1TABLE 1

Figure 112008055919281-pat00004
Figure 112008055919281-pat00004

Figure 112008055919281-pat00006
Figure 112008055919281-pat00006

[a] 플래시 크로마토그래피후 분리된 생성물의 수율[a] Yield of product isolated after flash chromatography

[b] E/Z 혼합물 사용[b] Using E / Z Mixture

실시예 9 및 11에서의 수율 감소는 전자적 및 입체적으로 밀집된 1,3,4,5-테트라치환된 피라졸이 불안정하여 컬럼 크로마토그래피하는 동안 쉽게 분해되기 때문이다.Yield reductions in Examples 9 and 11 are due to the electronic and steric densely packed 1,3,4,5-tetrasubstituted pyrazoles which are unstable and readily degrade during column chromatography.

Claims (8)

하기 화학식 1의 2-아실-3-아미노-2-알케노에이트와 하기 화학식 2의 히드라진을 반응시키는 것을 특징으로 하는 하기 화학식 3의 피라졸의 제조방법:A process for preparing pyrazole of formula (3), comprising reacting 2-acyl-3-amino-2-alkenoate of formula (1) with hydrazine of formula (2):
Figure 112010069676908-pat00007
Figure 112010069676908-pat00007
 상기 식에서, R1 및 R3는 각각 독립적으로 C1-C10의 알킬기, C3-C10의 사이클로알킬기 또는 아릴기이고, Wherein R 1 and R 3 are each independently an alkyl group of C 1 -C 10 , a cycloalkyl group or an aryl group of C 3 -C 10 , R2는 C1-C5의 알킬기이며,R 2 is an alkyl group of C 1 -C 5 , R4는 수소 또는 페닐기이다.R 4 is hydrogen or a phenyl group. 제1항에 있어서, R1 및 R3가 각각 독립적으로 C1-C5의 알킬기, C1-C5의 알콕시기, C1-C5의 할로알킬기, 아릴기 및 할로겐으로 구성된 군으로부터 선택된 하나 이상의 치환기에 의해 치환되거나 치환되지 않은 C1-C10의 알킬기 또는 아릴기인 것을 특징으로 하는 제조방법.The method of claim 1, wherein, R 1 and R 3 are each independently C 1 -C 5 alkyl, C 1 -C 5 alkoxy group, a C 1 -C 5 haloalkyl group, an aryl group and is selected from the group consisting of halogen, A C 1 -C 10 alkyl or aryl group which is unsubstituted or substituted by one or more substituents. 제1항에 있어서, R1 및 R3가 각각 독립적으로 치환되지 않은 C1-C10의 알킬기, 하나 이상의 할로겐으로 치환된 C1-C10의 알킬기, The alkyl group of claim 1, wherein each of R 1 and R 3 is independently an unsubstituted C 1 -C 10 alkyl group, an alkyl group of C 1 -C 10 substituted with one or more halogens,
Figure 112008055919281-pat00008
Figure 112008055919281-pat00008
 이며, 상기 식에서 X 및 Y는 각각 독립적으로 수소, C1-C5의 알킬기, C1-C5의 알콕시기, C1-C5의 할로알킬기 또는 할로겐인 것을 특징으로 하는 제조방법.And, wherein X and Y are each independently a production process, characterized in that hydrogen, an alkoxy group of the alkyl group of C 1 -C 5, C 1 -C 5, a haloalkyl group or a halogen C 1 -C 5. 삭제delete 삭제delete 제1항에 있어서, 반응이 산 촉매 존재하에서 수행되는 것을 특징으로 하는 제조방법.The process according to claim 1, wherein the reaction is carried out in the presence of an acid catalyst. 제6항에 있어서, 산 촉매가 황산, 염산, 질산, 파라-톨루엔술폰산, 메탄술폰산 또는 아세트산인 것을 특징으로 하는 제조방법.7. A process according to claim 6, wherein the acid catalyst is sulfuric acid, hydrochloric acid, nitric acid, para-toluenesulfonic acid, methanesulfonic acid or acetic acid. 제1항에 있어서, 상기 화학식 2의 히드라진을 상기 화학식 1의 2-아실-3-아미노-2-알케노에이트에 대해 1 내지 10당량으로 사용하는 것을 특징으로 하는 제조방법.The method according to claim 1, wherein the hydrazine of Chemical Formula 2 is used in an amount of 1 to 10 equivalents based on 2-acyl-3-amino-2-alkenoate of Chemical Formula 1.
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