KR100726672B1 - Pyrazole derivatives and preparation method thereof - Google Patents

Pyrazole derivatives and preparation method thereof Download PDF

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KR100726672B1
KR100726672B1 KR1020030027709A KR20030027709A KR100726672B1 KR 100726672 B1 KR100726672 B1 KR 100726672B1 KR 1020030027709 A KR1020030027709 A KR 1020030027709A KR 20030027709 A KR20030027709 A KR 20030027709A KR 100726672 B1 KR100726672 B1 KR 100726672B1
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pyrazole
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이기인
박민섭
박현자
심영기
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    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • 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
    • C07D231/14—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

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Abstract

본 발명은 피라졸 유도체 및 그의 제조방법에 관한 것으로, 본 발명에 따라, 하기 화학식 1의 화합물을 알칼리 염기 존재 하에서 여러가지 친핵체와 친핵 치환 반응시켜 하기 화학식 2의 다양한 피라졸 유도체를 온화한 조건하에서 제조할 수 있으며, 본 발명에 따라 제조된 신규한 피라졸 유도체들은 신약개발을 위한 신규물질이나, COX-2 억제제, 항생제, 살충제 등 여러 가지 생물학적 효능을 지닌 화합물 합성의 중간체로서 유용하게 사용될 수 있다. The present invention relates to a pyrazole derivative and a method for preparing the same. According to the present invention, various pyrazole derivatives of the following Chemical Formula 2 may be prepared under mild conditions by nucleophilic substitution reaction of a compound of the following Chemical Formula 1 with various nucleophiles in the presence of an alkali base. The novel pyrazole derivatives prepared according to the present invention may be useful as intermediates for synthesizing compounds having various biological effects such as novel substances for drug development, COX-2 inhibitors, antibiotics, insecticides, and the like.

Figure 112003015701663-pat00001
Figure 112003015701663-pat00001

Figure 112003015701663-pat00002
Figure 112003015701663-pat00002

상기 식에서,Where

R1은 수소, C1-C5 저급 알킬, C1-C5 저급 할로알킬, 아릴, 아미노, 알킬아미노, 하이드록시 또는 할로겐이고, R 1 is hydrogen, C 1 -C 5 lower alkyl, C 1 -C 5 lower haloalkyl, aryl, amino, alkylamino, hydroxy or halogen,

R2는 수소, C1-C5 저급 알킬, C1-C5 저급 할로알킬, 아릴, 피리딘, 아미노, 알킬아미노 또는 할로겐이고,R 2 is hydrogen, C 1 -C 5 lower alkyl, C 1 -C 5 lower haloalkyl, aryl, pyridine, amino, alkylamino or halogen,

X는 할로겐이며,X is halogen,

Nu는 수소; 피롤, 피라졸, 이미다졸, 피페라진, 모폴린, 피롤리딘과 같은 복소환; 아릴; 하이드록시; 아미노; 알킬아미노 또는 할로겐이다. Nu is hydrogen; Heterocycles such as pyrrole, pyrazole, imidazole, piperazine, morpholine, pyrrolidine; Aryl; Hydroxy; Amino; Alkylamino or halogen.

Description

피라졸 유도체 및 그의 제조방법{PYRAZOLE DERIVATIVES AND PREPARATION METHOD THEREOF}Pyrazole derivatives and its manufacturing method {PYRAZOLE DERIVATIVES AND PREPARATION METHOD THEREOF}

본 발명은 피라졸 유도체 및 그의 제조방법에 관한 것으로, 구체적으로는 하기 화학식 1의 화합물을 염기의 존재 하에서 친핵치환 반응시킴으로써 하기 화학식 2의 다양한 피라졸 유도체를 제조하는 방법 및 이로부터 제조된 다양한 신규의 피라졸 유도체에 관한 것이다.The present invention relates to a pyrazole derivative and a method for preparing the same, and specifically, a method for preparing various pyrazole derivatives of the following Chemical Formula 2 by nucleophilic substitution reaction of a compound of Chemical Formula 1 in the presence of a base, and various novel compounds prepared therefrom. It relates to a pyrazole derivative of.

화학식 1Formula 1

Figure 112003015701663-pat00003
Figure 112003015701663-pat00003

화학식 2 Formula 2                         

Figure 112003015701663-pat00004
Figure 112003015701663-pat00004

상기 식에서,Where

R1은 수소, C1-C5 저급 알킬, C1-C5 저급 할로알킬, 아릴, 아미노, 알킬아미노, 하이드록시 또는 할로겐이고,R 1 is hydrogen, C 1 -C 5 lower alkyl, C 1 -C 5 lower haloalkyl, aryl, amino, alkylamino, hydroxy or halogen,

R2는 수소, C1-C5 저급 알킬, C1-C5 저급 할로알킬, 아릴, 피리딘, 아미노, 알킬아미노 또는 할로겐이고,R 2 is hydrogen, C 1 -C 5 lower alkyl, C 1 -C 5 lower haloalkyl, aryl, pyridine, amino, alkylamino or halogen,

X는 할로겐이며,X is halogen,

Nu는 수소; 피롤, 피라졸, 이미다졸, 피페라진, 모폴린, 피롤리딘과 같은 복소환; 아릴; 하이드록시; 아미노; 알킬아미노 또는 할로겐이다. Nu is hydrogen; Heterocycles such as pyrrole, pyrazole, imidazole, piperazine, morpholine, pyrrolidine; Aryl; Hydroxy; Amino; Alkylamino or halogen.

피라졸 유도체는 여러 가지 생물학적 효능을 갖는 화합물, 예를 들면 항생제, 살충제 등의 합성에 많이 사용되는 중간체이다. 따라서, 종래의 한정적인 개발에서 벗어나 보다 다양한 종류의 피라졸 유도체를 합성하여 이를 이용함으로써 가까운 미래에 기존의 여러 가지 문제점을 해결한 신약, 신농약 등의 개발으로 국내 의약, 농약산업 발달 및 수출 증대에 공헌할 것으로 예상된다. Pyrazole derivatives are intermediates that are frequently used in the synthesis of compounds having various biological effects, such as antibiotics, insecticides and the like. Therefore, the development and export of domestic medicine, pesticide industry and export increase by developing new drugs, new pesticides, etc., which solved various problems in the near future by synthesizing and using more various kinds of pyrazole derivatives from the conventional limited development. It is expected to contribute to.

이에 본 발명자들은 예의 연구를 계속한 결과, 통상적인 방법으로 용이하게 제조할 수 있는 화학식 1의 화합물을 다양한 친핵치환체로 치환반응시킴으로써 여 러 가지 신규의 피라졸 유도체를 용이하게 제조할 수 있음을 알고 본 발명을 완성하게 되었다.
Accordingly, the present inventors have continued their intensive studies and found that various novel nucleophilic derivatives can be easily prepared by substituting the compound of Formula 1 with various nucleophilic substituents, which can be easily prepared by conventional methods. The present invention has been completed.

따라서, 본 발명의 목적은 신약, 신농약 등의 개발에 사용될 수 있는 중간체인 다양한 신규의 피라졸 유도체를 제공하는 것이다.
Accordingly, it is an object of the present invention to provide various novel pyrazole derivatives which are intermediates that can be used in the development of new drugs, new pesticides and the like.

상기 목적을 달성하기 위하여 본 발명에서는, 하기 반응식 1과 같이 유기용매 중에서 알칼리 염기 존재 하에 하기 화학식 1의 화합물을 하기 화학식 3의 친핵치환체로 친핵치환 반응시키는 것을 포함하는, 화학식 2의 피라졸 유도체의 제조방법을 제공한다. In order to achieve the above object, in the present invention, a pyrazole derivative of Formula 2 comprising nucleophilic substitution of the compound of Formula 1 with a nucleophilic substituent of Formula 3 in the presence of an alkali base in an organic solvent as in Scheme 1 below. It provides a manufacturing method.

Figure 112003015701663-pat00005
Figure 112003015701663-pat00005

상기 식에서,Where

R1은 수소, C1-C5 저급 알킬, C1-C5 저급 할로알킬, 아릴, 아미노, 알킬아미노, 하이 드록시 또는 할로겐이고,R 1 is hydrogen, C 1 -C 5 lower alkyl, C 1 -C 5 lower haloalkyl, aryl, amino, alkylamino, hydroxy or halogen,

R2는 수소, C1-C5 저급 알킬, C1-C5 저급 할로알킬, 아릴, 피리디닐, 아미노, 알킬아미노 또는 할로겐이고,R 2 is hydrogen, C 1 -C 5 lower alkyl, C 1 -C 5 lower haloalkyl, aryl, pyridinyl, amino, alkylamino or halogen,

X는 할로겐이고,X is halogen,

Nu는 수소; 피롤, 피라졸, 이미다졸, 피페라진, 모폴린, 피롤리딘과 같은 복소환; 아릴; 하이드록시; 아미노; 알킬아미노 또는 할로겐이고,Nu is hydrogen; Heterocycles such as pyrrole, pyrazole, imidazole, piperazine, morpholine, pyrrolidine; Aryl; Hydroxy; Amino; Alkylamino or halogen,

Y는 수소; 또는 나트륨, 칼륨과 같은 알칼리 금속이다.Y is hydrogen; Or alkali metals such as sodium and potassium.

본 발명에서는 또한, 상기 친핵치환 반응으로부터 제조된 화학식 2의 피라졸 유도체를 제공한다. The present invention also provides a pyrazole derivative of Formula 2 prepared from the nucleophilic substitution reaction.

이하 본 발명에 대하여 보다 상세히 설명한다. Hereinafter, the present invention will be described in more detail.

본 발명에 있어서, 화학식 1의 화합물을 합성하기 위한 β-케토 에스테르는 문헌[J. Org. Chem., Vol. 43, No. 10, 1978, 2087-2088]에 따라 하기 반응식 2와 같은 통상적인 반응 메카니즘에 의해 제조할 수 있으며, 출발물질로서 사용되는 화학식 1의 화합물은 상기 제조된 β-케토 에스테르로부터 문헌[J. Am. Chem. Soc., 80, 599 (1957); J. Org. Chem. 1988, 53, 810-820]의 방법에 따라 반응식 3과 같이 용이하게 제조할 수 있다:In the present invention, the β-keto ester for synthesizing the compound of Formula 1 is described in J. Org. Chem ., Vol. 43 , No. 10, 1978 , 2087-2088, which can be prepared by conventional reaction mechanisms such as Scheme 2 below, and the compounds of formula 1 used as starting materials are described in J. Am. Chem. Soc ., 80 , 599 (1957); J. Org. Chem. 1988 , 53 , 810-820 can be readily prepared as in Scheme 3:

Figure 112003015701663-pat00006
Figure 112003015701663-pat00006

Figure 112003015701663-pat00007
Figure 112003015701663-pat00007

본 발명에 따른 방법의 하나의 실시양태로서, 기존의 통상적인 방법으로 용이하게 제조된 화학식 1의 화합물을 알칼리 염기의 존재 하에서 친핵치환체(Nu-Y)로 친핵치환 반응시킴으로써 화학식 2의 피라졸 유도체를 온화한 조건으로 용이하게 제조할 수 있다. In one embodiment of the process according to the invention, the pyrazole derivatives of formula (2) by nucleophilic substitution of a compound of formula (1) easily prepared by conventional conventional methods with a nucleophilic substituent (Nu-Y) in the presence of an alkali base Can be easily prepared under mild conditions.

본 발명에 사용되는 알칼리 염기의 예로는 수산화나트륨, 수산화칼륨, 수산화리튬, 탄산나트륨, 중탄산나트륨, 탄산세슘 등을 들 수 있으며, 바람직하게는 수산화칼륨 또는 수산화나트륨이다. 이때 염기는 화학식 1의 화합물 1 당량에 대하여 1.2 내지 3 당량, 바람직하게는 1.5 내지 2 당량의 양으로 사용할 수 있다. Examples of the alkali base used in the present invention include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, cesium carbonate and the like, preferably potassium hydroxide or sodium hydroxide. In this case, the base may be used in an amount of 1.2 to 3 equivalents, preferably 1.5 to 2 equivalents, based on 1 equivalent of the compound of Formula 1.                     

또한, 본 발명에 사용되는 화학식 3의 친핵체의 양은 화학식 1의 화합물 1 당량에 대하여 1.2 내지 3 당량, 바람직하게는 1.5 내지 2 당량의 양으로 사용할 수 있다.In addition, the amount of the nucleophile of the general formula (3) used in the present invention may be used in an amount of 1.2 to 3 equivalents, preferably 1.5 to 2 equivalents relative to 1 equivalent of the compound of formula (1).

반응용매로는 통상적인 유기용매를 사용할 수 있으며, 바람직하게는 N,N-디메틸포름아미드(DMF) 또는 디메틸설폭사이드(DMSO)를 사용할 수 있다.As the reaction solvent, a conventional organic solvent may be used, and preferably N, N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO) may be used.

상기 친핵치환 반응은 100 내지 150 ℃, 바람직하게는 110 내지 130 ℃의 온도에서 2 내지 25시간, 바람직하게는 2 내지 5시간 동안 수행한다. The nucleophilic substitution reaction is carried out for 2 to 25 hours, preferably 2 to 5 hours at a temperature of 100 to 150 ℃, preferably 110 to 130 ℃.

이와 같은 본 발명의 방법에 따르면, 여러 가지 생물학적 효능을 갖는 화합물의 합성에 사용되는 중간체인 다양한 신규 피라졸 유도체를 온화한 조건 하에서 용이하게 제조할 수 있다. According to the method of the present invention, various novel pyrazole derivatives, which are intermediates used in the synthesis of compounds having various biological effects, can be easily prepared under mild conditions.

이하 실시예를 통하여 본 발명을 더욱 상세히 설명한다. 단 본 발명의 범위가 하기 실시예만으로 한정되는 것은 아니다.
The present invention will be described in more detail with reference to the following examples. However, the scope of the present invention is not limited only to the following examples.

실시예 1: 5-메틸-2H-피라졸-3-올(R1=Me, R2=H)의 제조 Example 1: Preparation of 5-methyl- 2H -pyrazole-3-ol (R 1 = Me, R 2 = H)

Figure 112003015701663-pat00008
Figure 112003015701663-pat00008

250 ml의 2구 둥근 바닥플라스크에 에틸아세토아세테이트 31.36 g(241 mmol) 및 에탄올 50 ml를 넣고, 여기에 히드라진모노하이드레이트 12.11 g(242 mmol)을 에탄올 20 ml에 희석시킨 용액을 반응액의 온도가 50 ℃를 넘지 않도록 천천히 적가하였다. 이어서, 1시간 30분 동안 환류시킨 후 온도를 낮추고 생성된 고체를 감압여과하여 백색의 고체로서 목적 화합물 20. 725 g(211 mmol, 수율 88%)을 얻었다.Into a 250 ml two-necked round bottom flask, 31.36 g (241 mmol) of ethyl acetoacetate and 50 ml of ethanol were added thereto. It was slowly added dropwise not to exceed 50 ° C. Then, after refluxing for 1 hour 30 minutes, the temperature was lowered, and the resulting solid was filtered under reduced pressure to obtain 20.725 g (211 mmol, yield 88%) of the title compound as a white solid.

1H-NMR(200 MHz, CDCl3) δ 10.3(br, 2H), 5.21(s, 1H), 2.08(s, 3H)
 1 H-NMR (200 MHz, CDCl 3 ) δ 10.3 (br, 2H), 5.21 (s, 1H), 2.08 (s, 3H)

실시예 2: 2,5-디메틸-2,4-디하이드로-피라졸-3-온(R1=Me, R2=Me)의 제조Example 2: Preparation of 2,5-dimethyl-2,4-dihydro-pyrazol-3-one (R 1 = Me, R 2 = Me)

Figure 112003015701663-pat00009
Figure 112003015701663-pat00009

500 ml의 둥근 바닥플라스크에 메틸히드라진 29.0 g(629 mmol) 및 에탄올 90 ml를 넣고, 여기에 에틸아세토아세테이트 81.85 g(628.9 mmol)을 에탄올 40 ml에 희석시킨 용액을 반응액의 온도가 50 ℃를 넘지 않도록 천천히 적가하였다. 이어서, 약 90 ℃의 온도에서 1시간 30분 동안 가열한 후 용매를 감압증류하여 제거함으로써 고체상태로서 목적 화합물 70.0 g(624 mmol, 수율 99%)을 얻었다.29.0 g (629 mmol) of methyl hydrazine and 90 ml of ethanol were added to a 500 ml round bottom flask, and a solution obtained by diluting 81.85 g (628.9 mmol) of ethyl acetoacetate in 40 ml of ethanol was prepared. It was slowly added dropwise not to exceed. Subsequently, the mixture was heated at a temperature of about 90 ° C. for 1 hour 30 minutes, and then the solvent was distilled off under reduced pressure to obtain 70.0 g (624 mmol, 99% yield) of the target compound as a solid.

1H-NMR(200 MHz, CDCl3) δ 3.28(s, 3H), 3.19(s, 2H), 2.10(s, 3H)
 1 H-NMR (200 MHz, CDCl 3 ) δ 3.28 (s, 3H), 3.19 (s, 2H), 2.10 (s, 3H)

실시예 3: 5-메틸-2-페닐-2,4-디하이드로-피라졸-3-온(R1=Me, R2=페닐)의 제조Example 3: Preparation of 5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one (R 1 = Me, R 2 = phenyl)

Figure 112003015701663-pat00010
Figure 112003015701663-pat00010

250 ml의 2구 둥근 바닥플라스크에 에틸아세토아세테이트 12.16 g(92.50 mmol) 및 에탄올 25 ml를 넣고, 여기에 페닐히드라진 10.31 g(92.50 mmol)을 에탄올 10 ml에 희석시킨 용액을 반응액의 온도가 50 ℃를 넘지 않도록 천천히 적가한 후 11시간 동안 환류시켰다. 이어서, 감압증류하여 용매를 제거한 다음 생성된 고체를 헥산과 에틸아세테이트로 세척한 후 건조시켜 목적 화합물 15.42 g(88.5 mmol, 수율 96%)을 얻었다. 12.16 g (92.50 mmol) of ethylacetoacetate and 25 ml of ethanol were added to a 250 ml two-necked round bottom flask, and a solution obtained by diluting 10.31 g (92.50 mmol) of phenylhydrazine in 10 ml of ethanol was prepared at a temperature of 50 Slowly added dropwise so as not to exceed ℃ and refluxed for 11 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and the resulting solid was washed with hexane and ethyl acetate and dried to obtain 15.42 g (88.5 mmol, 96% yield) of the title compound.

1H-NMR(300 MHz, CDCl3) δ 7.86-7.88(d, 2H), 7.38-7.43(t, 2H), 7.17-7.21(t, 2H), 3.43(s, 2H), 2.20(s, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ 7.86-7.88 (d, 2H), 7.38-7.43 (t, 2H), 7.17-7.21 (t, 2H), 3.43 (s, 2H), 2.20 (s, 3H)

실시예 4: 5-메틸-2-피리딘-2-일-2H-피라졸-3-올(R1=Me, R2=2-피리디닐)의 제조 Example 4: Preparation of 5-methyl-2-pyridin-2-yl-2 H -pyrazol-3-ol (R 1 = Me, R 2 = 2-pyridinyl)

Figure 112003015701663-pat00011
Figure 112003015701663-pat00011

100 ml의 2구 둥근 바닥플라스크에 에틸아세토아세테이트 3.61 g(27.5 mmol) 및 에탄올 7 ml를 넣고, 여기에 2-히드라지노피리딘 3.09 g(27.5 mmol)을 에탄올 3 ml에 희석시킨 용액을 반응액의 온도가 50 ℃를 넘지 않도록 천천히 적가한 후 9시간 동안 환류시켰다. 이어서, 감압증류하여 용매를 제거한 다음 생성된 고체를 헥산으로 세척한 후 건조시켜 목적 화합물 4.65 g(26.5 mmol, 수율 97%)을 얻었다.3.61 g (27.5 mmol) of ethylacetoacetate and 7 ml of ethanol were added to a 100 ml two-necked round bottom flask, and a solution of 3.09 g (27.5 mmol) of 2-hydrazinopyridine diluted in 3 ml of ethanol was added to the reaction solution. The mixture was slowly added dropwise so that the temperature did not exceed 50 ° C, and the mixture was refluxed for 9 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and the resulting solid was washed with hexane and dried to obtain 4.65 g (26.5 mmol, 97% yield) of the title compound.

1H-NMR(300 MHz, CDCl3) δ 12.7(s, 1H), 8.15-8.17(d, 1H), 7.72-7.81(m, 2H), 6.99-7.06(m, 1H), 5.34(s, 1H), 2.18(s, 3H)
 1 H-NMR (300 MHz, CDCl 3 ) δ 12.7 (s, 1H), 8.15-8.17 (d, 1H), 7.72-7.81 (m, 2H), 6.99-7.06 (m, 1H), 5.34 (s, 1H), 2.18 (s, 3H)

실시예 5: 5-클로로-1,3-디메틸-1H-피라졸-4-카브알데히드(R1=Me, R2=Me, X=Cl)의 제조Example 5: Preparation of 5-chloro-1,3-dimethyl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = Me, X = Cl)

Figure 112003015701663-pat00012
Figure 112003015701663-pat00012

100 ml의 3구 둥근 바닥플라스크에 DMF 12.1 g(165 mmol)을 넣고 0 ℃로 낮춘 후 POCl3 21.0 g(225 mmol)을 반응액의 온도가 20 내지 25 ℃를 넘지 않도록 천천히 가하였다. 여기에 실시예 2에서 제조한 2,5-디메틸-2,4-디하이드로-피라졸-3-온 16.8 g(150 mmol)을 조금씩 가한 후 110 내지 115 ℃에서 4시간 동안 가열하였다. 여기에 조심스럽게 얼음을 넣은 후 생성된 고체를 감압여과한 다음, 여액을 메틸렌클로라이드로 추출한 후 건조 및 감압증류하여 목적 화합물 20.71 g(130.6 mmol, 수율 87%)을 얻었다. In a 100 ml three-necked round bottom flask, 12.1 g (165 mmol) of DMF was added thereto, and the mixture was lowered to 0 ° C., and then 21.0 g (225 mmol) of POCl 3 was slowly added so that the temperature of the reaction solution did not exceed 20 to 25 ° C. 16.8 g (150 mmol) of 2,5-dimethyl-2,4-dihydro-pyrazol-3-one prepared in Example 2 was added thereto, followed by heating at 110 to 115 ° C. for 4 hours. After carefully adding ice thereto, the resulting solid was filtered under reduced pressure, and the filtrate was extracted with methylene chloride, dried and distilled under reduced pressure to obtain 20.71 g (130.6 mmol, 87% yield) of the title compound.

1H-NMR(200 MHz, CDCl3) δ 9.85(s, 1H), 3.82(s, 3H), 2.45(s, 3H)
 1 H-NMR (200 MHz, CDCl 3 ) δ 9.85 (s, 1H), 3.82 (s, 3H), 2.45 (s, 3H)

실시예 6: 5-클로로-3-메틸-1-페닐-1H-피라졸-4-카브알데히드(R1=Me, R2=페닐, X=Cl)의 제조Example 6: Preparation of 5-chloro-3-methyl-1-phenyl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = phenyl, X = Cl)

Figure 112003015701663-pat00013
Figure 112003015701663-pat00013

100 ml의 3구 둥근 바닥플라스크에 DMF 5.54 g(75.8 mmol)을 넣고 0 ℃로 낮춘 후 POCl3 15.84 g(103.3 mmol)을 반응액의 온도가 20 내지 25 ℃를 넘지 않도록 천천히 가하였다. 이 반응액에 실시예 3에서 제조한 5-메틸-2-페닐-2,4-디하이드로-피라졸-3-온 12.0 g(68.9 mmol)을 조금씩 가한 후 110 내지 115 ℃에서 4시간 동안 가열하였다. 여기에 조심스럽게 얼음을 넣은 후 생성된 고체를 감압여과한 다음, 여액을 메틸렌클로라이드로 추출한 후 건조 및 감압증류하여 목적 화합물 9.21 g(42.2 mmol, 수율 61.3%)을 얻었다.In a 100 ml three-necked round bottom flask, 5.54 g (75.8 mmol) of DMF was added thereto, and the mixture was lowered to 0 ° C., and 15.84 g (103.3 mmol) of POCl 3 was slowly added so that the temperature of the reaction solution did not exceed 20 to 25 ° C. 12.0 g (68.9 mmol) of 5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one prepared in Example 3 was added to the reaction solution little by little, followed by heating at 110 to 115 ° C. for 4 hours. It was. After carefully putting ice therein, the resulting solid was filtered under reduced pressure, and the filtrate was extracted with methylene chloride, dried and distilled under reduced pressure to obtain 9.21 g (42.2 mmol, yield 61.3%) of the title compound.

1H-NMR(300 MHz, CDCl3) δ 10.00(s, 1H), 7.43-7.59(m, 5H), 2.56(s, 3H) 1 H-NMR (300 MHz, CDCl 3 ) δ 10.00 (s, 1H), 7.43-7.59 (m, 5H), 2.56 (s, 3H)

실시예 7: 5-클로로-3-메틸-1-피리딘-2-일-1H-피라졸-4-카브알데히드(R1=Me, R2=2- 피리디닐, X=Cl)의 제조 Example 7: Preparation of 5-chloro-3-methyl-1-pyridin-2-yl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = 2-pyridinyl, X = Cl)

Figure 112003015701663-pat00014
Figure 112003015701663-pat00014

50 ml의 2구 둥근 바닥플라스크에 DMF 1.38 g(18.8 mmol)을 넣고 0 ℃로 낮춘 후 POCl3 3.94 g(25.7 mmol)을 반응액의 온도가 20 내지 25 ℃를 넘지 않도록 천천히 가하였다. 이 반응액에 실시예 4에서 제조한 5-메틸-2-피리딘-2-일-2H-피라졸-3-올 3.00 g(17.1 mmol)을 천천히 가한 후 110 내지 115 ℃에서 4시간 동안 가열하였다. 여기에 조심스럽게 얼음을 넣은 후 생성된 고체를 감압여과한 다음, 여액을 메틸렌클로라이드로 추출한 후 건조 및 감압증류하여 목적 화합물 1.93 g(8.70 mmol, 수율 50.8%)을 얻었다. 1.38 g (18.8 mmol) of DMF was added to 50 ml of a two-necked round bottom flask, and the mixture was lowered to 0 ° C., and then 3.94 g (25.7 mmol) of POCl 3 was slowly added so that the temperature of the reaction solution did not exceed 20 to 25 ° C. Prepared in Example 4 in the reaction solution 5-methyl-2-pyridin-2-yl -2 H - pyrazol-3-ol is heated at 110 to 115 ℃ was added slowly 3.00 g (17.1 mmol) for 4 hours It was. After carefully putting ice therein, the resulting solid was filtered under reduced pressure, and the filtrate was extracted with methylene chloride, dried and distilled under reduced pressure to obtain 1.93 g (8.70 mmol, yield 50.8%) of the title compound.

1H-NMR(300 MHz, CDCl3) δ 9.95(s, 1H), 8.52-8.54(d, 1H), 7.81-7.87(td, 1H), 7.64-7.67(d, 1H), 7.30-7.34(dd, 1H), 2.48(s, 3H)
 1 H-NMR (300 MHz, CDCl 3 ) δ 9.95 (s, 1H), 8.52-8.54 (d, 1H), 7.81-7.87 (td, 1H), 7.64-7.67 (d, 1H), 7.30-7.34 ( dd, 1H), 2.48 (s, 3H)

실시예 8: 5-클로로-3-메틸-1H-피라졸-4-카브알데히드(R1=Me, R2=H, Nu=Cl)의 제조Example 8: Preparation of 5-chloro-3-methyl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = H, Nu = Cl)

Figure 112003015701663-pat00015
Figure 112003015701663-pat00015

100 ml의 3구 둥근 바닥플라스크에 DMF 8.20 g(112 mmol)을 넣고 0 ℃로 낮춘 후 POCl3 24.4 g(153 mmol)을 반응액의 온도가 20 내지 25 ℃를 넘지 않도록 천천히 가하였다. 이 반응액에 실시예 1에서 제조한 5-메틸-2H-피라졸-3-올 10.0 g(102 mmol)을 조금씩 가한 후 110 내지 115 ℃에서 4시간 동안 가열하였다. 여기에 조심스럽게 얼음을 넣은 후 에틸아세테이트로 추출한 다음 건조 및 감압증류하여 목적 화합물 4.645 g(32.10 mmol, 수율 31.5%)을 얻었다.8.20 g (112 mmol) of DMF was added to a 100 ml three-necked round bottom flask, and the mixture was lowered to 0 ° C., and then 24.4 g (153 mmol) of POCl 3 was slowly added so that the temperature of the reaction solution did not exceed 20 to 25 ° C. 10.0 g (102 mmol) of 5-methyl- 2H -pyrazole-3-ol prepared in Example 1 was added to the reaction solution little by little and then heated at 110 to 115 ° C. for 4 hours. Then carefully put ice, extracted with ethyl acetate, dried and distilled under reduced pressure to obtain the title compound 4.645 g (32.10 mmol, yield 31.5%).

1H-NMR(300 MHz, CDCl3) δ 9.72(s, 1H), 2.40(s, 3H)
 1 H-NMR (300 MHz, CDCl 3 ) δ 9.72 (s, 1H), 2.40 (s, 3H)

실시예 9: 1,3-디메틸-5피롤-1-일-1H-피라졸-4-카브알데히드(R1=Me, R2=Me, Nu=피롤)의 제조Example 9: Preparation of 1,3-dimethyl-5pyrrole-1-yl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = Me, Nu = pyrrole)

Figure 112003015701663-pat00016
Figure 112003015701663-pat00016

50 ml의 2구 둥근 바닥플라스크에 KOH 920 mg(16.4 mmol), 실시예 5에서 제조한 5-클로로-1,3-디메틸-1H-피라졸-4-카브알데히드 2.0 g(12.6 mmol), 피롤 2.54 g(37.8 mmol) 및 DMF 20 ml를 넣은 후 120 ℃에서 2시간 동안 가열하였다. 이어서, 감압증류하여 용매를 제거하고, 이 반응액에 물을 가한 후 에틸아세테이트로 추출하고 감압증류한 다음 컬럼 크로마토그래피(헥산:에틸아세테이트 = 7:3을 전개 용매로 사용)로 분리하여 목적 화합물 1.20 g(6.36 mmol, 수율 50.5 %)을 얻었다.In a 50 ml two-necked round bottom flask, 920 mg (16.4 mmol) of KOH, 2.0 g (12.6 mmol) of 5-chloro-1,3-dimethyl-1 H -pyrazole-4-carbaldehyde prepared in Example 5, 2.54 g (37.8 mmol) of pyrrole and 20 ml of DMF were added thereto, followed by heating at 120 ° C. for 2 hours. Subsequently, the solvent was removed by distillation under reduced pressure, water was added to the reaction solution, followed by extraction with ethyl acetate, distillation under reduced pressure, and column chromatography (hexane: ethyl acetate = 7: 3 as a developing solvent) to separate the target compound. 1.20 g (6.36 mmol, yield 50.5%) was obtained.

1H-NMR(200 MHz, CDCl3) δ 9.60(s, 1H), 6.84-6.87(t, 2H), 6.44-6.46(t, 2H), 3.67(s, 3H), 2.50(s, 3H)
 1 H-NMR (200 MHz, CDCl 3 ) δ 9.60 (s, 1H), 6.84-6.87 (t, 2H), 6.44-6.46 (t, 2H), 3.67 (s, 3H), 2.50 (s, 3H)

실시예 10: 5-이미다졸-1-일-1,3-디메틸-1H-피라졸-4-카브알데히드(R1=Me, R2=Me, Nu=이미다졸)의 제조Example 10 Preparation of 5-imidazol-1-yl-1,3-dimethyl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = Me, Nu = imidazole)

Figure 112003015701663-pat00017
Figure 112003015701663-pat00017

50 ml의 2구 둥근 바닥플라스크에 KOH 707 mg(12.6 mmol), 실시예 5에서 제조한 5-클로로-1,3-디메틸-1H-피라졸-4-카브알데히드 2.0 g(12.6 mmol), 이미다졸 2.57 g(37.8 mmol) 및 DMF 20ml를 넣은 후 120 ℃에서 2시간 동안 가열하였다. 이어서, 감압증류하여 용매를 제거하고, 이 반응액에 물을 가한 후 에틸아세테이트로 추출하고 감압증류한 다음 컬럼 크로마토그래피(헥산과 에틸아세테이트의 혼합전개용매로 사용)로 분리하여 목적 화합물 1.354 g(7.12 mmol, 수율 56.5 %)을 얻었다. In a 50 ml two-necked round bottom flask, 707 mg (12.6 mmol) of KOH, 2.0 g (12.6 mmol) of 5-chloro-1,3-dimethyl-1 H -pyrazole-4-carbaldehyde prepared in Example 5, 2.57 g (37.8 mmol) of imidazole and 20 ml of DMF were added and then heated at 120 ° C. for 2 hours. Subsequently, the solvent was removed by distillation under reduced pressure, water was added to the reaction solution, followed by extraction with ethyl acetate, distillation under reduced pressure, and separation by column chromatography (used as a mixed development solvent of hexane and ethyl acetate). 7.12 mmol, yield 56.5%).

1H-NMR(200 MHz, CDCl3) δ 9.62(s, 1H), 7.74(s, 1H), 7.34(s, 1H), 7.18(s, 1H), 3.69(s, 3H), 2.51(s, 3H)
 1 H-NMR (200 MHz, CDCl 3 ) δ 9.62 (s, 1H), 7.74 (s, 1H), 7.34 (s, 1H), 7.18 (s, 1H), 3.69 (s, 3H), 2.51 (s , 3H)

실시예 11: 1,3-디메틸-5-페닐설파닐-1H-피라졸-4-카브알데히드(R1=Me, R2=Me, Nu=티오페닐)의 합성Example 11: Synthesis of 1,3-dimethyl-5-phenylsulfanyl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = Me, Nu = thiophenyl)

Figure 112003015701663-pat00018
Figure 112003015701663-pat00018

50 ml의 2구 둥근 바닥플라스크에 KOH 920 mg(16.4 mmol), 실시예 5에서 제조한 5-클로로-1,3-디메틸-1H-피라졸-4-카브알데히드 2.0 g(12.6 mmol), 티오페놀 4.16 g(37.3 mmol) 및 DMF 20 ml를 넣은 후 120 ℃에서 2시간 동안 가열하였다. 이어서, 감압증류하여 용매를 제거하고, 이 반응액에 물을 가한 후 에틸아세테이트로 추출하고, 5% NaOH 수용액, 물의 순서대로 씻었다. 유기층을 분리하여 감압증류한 다음 컬럼크로마토그래피(헥산:에틸아세테이트 = 7:3을 전개용매로 사용)로 분리하여 목적화합물 2.27 g(9.8 mmol, 수율 77.5%)을 얻었다.In a 50 ml two-necked round bottom flask, 920 mg (16.4 mmol) of KOH, 2.0 g (12.6 mmol) of 5-chloro-1,3-dimethyl-1 H -pyrazole-4-carbaldehyde prepared in Example 5, 4.16 g (37.3 mmol) of thiophenol and 20 ml of DMF were added thereto, followed by heating at 120 ° C. for 2 hours. Subsequently, the solvent was distilled off under reduced pressure, water was added to the reaction solution, followed by extraction with ethyl acetate, followed by washing with 5% aqueous NaOH solution and water. The organic layer was separated, distilled under reduced pressure, and then separated by column chromatography (hexane: ethyl acetate = 7: 3 as a developing solvent) to obtain 2.27 g (9.8 mmol, 77.5%) of the title compound.

1H-NMR(200 MHz, CDCl3) δ 10.01(s, 1H), 7.08-7.30(m, 5H), 3.80(s, 3H), 2.52(s, 3H)
 1 H-NMR (200 MHz, CDCl 3 ) δ 10.01 (s, 1H), 7.08-7.30 (m, 5H), 3.80 (s, 3H), 2.52 (s, 3H)

실시예 12: 1,3-디메틸-5-피롤리딘-1-일-1H-피라졸-4-카브알데히드(R1=Me, R2=Me, Nu=피롤리딘)의 제조Example 12 Preparation of 1,3-dimethyl-5-pyrrolidin-1-yl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = Me, Nu = pyrrolidine)

Figure 112003015701663-pat00019
Figure 112003015701663-pat00019

25 ml의 2구 둥근 바닥플라스크에 KOH 920 mg(16.4 mmol), 실시예 5에서 제조한 5-클로로-1,3-디메틸-1H-피라졸-4-카브알데히드 2.0 g(12.6 mmol), 피롤리딘 2.69 g(37.8 mmol) 및 DMF 20 ml를 넣은 후 120 ℃에서 3시간 동안 가열하였다. 이어서, 감압증류하여 용매를 제거하고, 이 반응액에 물을 가한 후 에틸아세테이트로 추출하고 감압증류한 다음 컬럼 크로마토그래피(에틸아세테이트를 전개용매로 사용)로 분리하여 목적 화합물 0.735 g(0.38 mmol, 수율 30.2 %)을 얻었다.In a 25 ml two-necked round bottom flask, 920 mg (16.4 mmol) of KOH, 2.0 g (12.6 mmol) of 5-chloro-1,3-dimethyl-1 H -pyrazole-4-carbaldehyde prepared in Example 5, 2.69 g (37.8 mmol) of pyrrolidine and 20 ml of DMF were added and then heated at 120 ° C. for 3 hours. Subsequently, the solvent was removed by distillation under reduced pressure, water was added to the reaction solution, followed by extraction with ethyl acetate, distillation under reduced pressure, and column chromatography (ethyl acetate as a developing solvent) to separate the target compound, 0.735 g (0.38 mmol, Yield 30.2%).

1H-NMR(200 MHz, CDCl3) δ 9.87(s, 1H), 3.70(s, 3H), 3.42-3.49(m, 4H), 2.39(s, 3H), 2.00-2.05(s, 3H)
 1 H-NMR (200 MHz, CDCl 3 ) δ 9.87 (s, 1H), 3.70 (s, 3H), 3.42-3.49 (m, 4H), 2.39 (s, 3H), 2.00-2.05 (s, 3H)

실시예 13: 2',5'-디메틸-2'H-[1,3']비피라졸릴-4'-카브알데히드(R1=Me, R2=Me, Nu=피라졸)의 제조Preparation of [1,3 '] non-pyrazolyl-4'-carbaldehyde (R 1 = Me, R 2 = Me, Nu = pyrazole) - 2', 5'-dimethyl -2, H: Example 13

Figure 112003015701663-pat00020
Figure 112003015701663-pat00020

25 ml의 2구 둥근 바닥플라스크에 피라졸 2.57 g(12.6 mmol), 실시예 5에서 제조한 5-클로로-1,3-디메틸-1H-피라졸-4-카브알데히드 2.0 g(12.6 mmol), KOH 0.92 g(16.4 mmol) 및 DMF 20 ml를 넣은 후 120 ℃에서 2시간 동안 가열하였다. 이어서, 감압증류하여 용매를 제거하고, 이 반응액에 물을 가한 후 에틸아세테이트로 추출하고 감압증류한 다음 컬럼 크로마토그래피(헥산:에틸아세테이트 = 1:1을 전개용매로 사용)로 분리하여 목적 화합물 1.606 g(8.4 mmol, 수율 67%)을 얻었다.2.57 g (12.6 mmol) of pyrazole, 2.0 g (12.6 mmol) of 5-chloro-1,3-dimethyl-1 H -pyrazole-4-carbaldehyde prepared in Example 5 in a 25 ml two-necked round bottom flask 0.92 g (16.4 mmol) of KOH and 20 ml of DMF were added and heated at 120 ° C. for 2 hours. Subsequently, the solvent was removed by distillation under reduced pressure, water was added to the reaction solution, followed by extraction with ethyl acetate, distillation under reduced pressure, and column chromatography (hexane: ethyl acetate = 1: 1 as a developing solvent) to separate the target compound. 1.606 g (8.4 mmol, yield 67%) was obtained.

1H-NMR(200 MHz, CDCl3) δ 9.67(s, 1H), 7.82-7.83(m, 2H), 6.52-6.55(m, 1H), 3.77(s, 3H), 2.47(s, 3H)
 1 H-NMR (200 MHz, CDCl 3 ) δ 9.67 (s, 1H), 7.82-7.83 (m, 2H), 6.52-6.55 (m, 1H), 3.77 (s, 3H), 2.47 (s, 3H)

실시예 14: 1,3-디메틸-5-모폴린-4-일-1H-피라졸-4-카브알데히드(R1=Me, R2=Me, Nu=모폴린)의 제조Example 14 Preparation of 1,3-dimethyl-5-morpholin-4-yl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = Me, Nu = morpholine)

Figure 112003015701663-pat00021
Figure 112003015701663-pat00021

25 ml의 2구 둥근 바닥플라스크에 KOH 70 mg(1.3 mmol), 실시예 5에서 제조한 5-클로로-1,3-디메틸-1H-피라졸-4-카브알데히드 200 mg(1.3 mmol), 모폴린 0.34 ml(3.9 mmol) 및 DMF 10 ml를 넣은 후 120 ℃에서 30시간 동안 가열하였다. 이어서, 감압증류하여 용매를 제거하고, 이 반응액에 물을 가한 후 에틸아세테이트로 추출하고 감압증류한 다음 컬럼 크로마토그래피(헥산:EA=1:1을 전개용매로 사용)로 분리하여 목적 화합물 61 mg(0.29 mmol, 수율 23%)을 얻었다.In a 25 ml two-necked round bottom flask, 70 mg (1.3 mmol) of KOH, 200 mg (1.3 mmol) of 5-chloro-1,3-dimethyl-1 H -pyrazole-4-carbaldehyde prepared in Example 5, 0.34 ml (3.9 mmol) of morpholine and 10 ml of DMF were added thereto, followed by heating at 120 ° C. for 30 hours. Subsequently, the solvent was removed by distillation under reduced pressure, water was added to the reaction solution, followed by extraction with ethyl acetate, distillation under reduced pressure, and column chromatography (hexane: EA = 1: 1 as a developing solvent) to separate the target compound 61. mg (0.29 mmol, yield 23%) were obtained.

1H-NMR(200 MHz, CDCl3) δ 9.96(s, 1H), 3.81-3.86(t, 4H), 3.71(s, 3H), 3.16-3.21(t, 4H), 2.42(s, 3H)
 1 H-NMR (200 MHz, CDCl 3 ) δ 9.96 (s, 1H), 3.81-3.86 (t, 4H), 3.71 (s, 3H), 3.16-3.21 (t, 4H), 2.42 (s, 3H)

실시예 15: 5-인돌-1-일-1,3-디메틸-1H-피라졸-4-카브알데히드(R1=Me, R2=Me, Nu=인돌)의 제조 Example 15 Preparation of 5-indol-1-yl-1,3-dimethyl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = Me, Nu = indole)

Figure 112003015701663-pat00022
Figure 112003015701663-pat00022

25 ml의 2구 둥근 바닥플라스크에 인돌 2.95 g(25.2 mmol), 실시예 5에서 제조한 5-클로로-1,3-디메틸-1H-피라졸-4-카브알데히드 2.0 g(12.6 mmol), KOH 920 mg(16.4 mmol) 및 DMF 20 ml를 넣은 후 120 ℃에서 2시간 동안 가열하였다. 이어서, 감압증류하여 용매를 제거하고, 이 반응액에 물을 가한 후 에틸아세테이트로 추출하고 감압증류 한 다음 컬럼 크로마토그래피(헥산:에틸아세테이트 = 1:1을 전개용매로 사용)로 분리하여 목적 화합물 1.983 g(8.3 mmol, 수율 65.8 %)을 얻었다.2.95 g (25.2 mmol) of indole, 2.0 g (12.6 mmol) of 5-chloro-1,3-dimethyl-1 H -pyrazole-4-carbaldehyde prepared in Example 5 in a 25 ml two-necked round bottom flask, KOH 920 mg (16.4 mmol) and 20 ml of DMF were added thereto, followed by heating at 120 ° C. for 2 hours. Subsequently, the solvent was removed by distillation under reduced pressure, water was added to the reaction solution, followed by extraction with ethyl acetate, distillation under reduced pressure, and column chromatography (hexane: ethyl acetate = 1: 1 as a developing solvent) to separate the target compound. 1.983 g (8.3 mmol, yield 65.8%) were obtained.

1H-NMR(200 MHz, CDCl3) δ 9.52(s, 1H), 7.70-7.75(m, 1H), 7.19-7.20(m, 1H), 7.12-7.31(m, 3H), 6.82-6.83(d, 1H), 3.59(s, 3H), 2.57(s, 3H) 1 H-NMR (200 MHz, CDCl 3 ) δ 9.52 (s, 1H), 7.70-7.75 (m, 1H), 7.19-7.20 (m, 1H), 7.12-7.31 (m, 3H), 6.82-6.83 ( d, 1H), 3.59 (s, 3H), 2.57 (s, 3H)

실시예 16: 1,3-디메틸-5-피페라진-1-일-1H-피라졸-4-카브알데히드(R1=Me, R2=Me, Nu=피페라진)의 제조Example 16: Preparation of 1,3-dimethyl-5-piperazin-1-yl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = Me, Nu = piperazine)

Figure 112003015701663-pat00023
Figure 112003015701663-pat00023

50 ml의 2구 둥근 바닥플라스크에 피페라진 3.256 g(37.8 mmol), 실시예 5에서 제조한 5-클로로-1,3-디메틸-1H-피라졸-4-카브알데히드 2.0 g(12.6 mmol), KOH 920 mg(16.4 mmol) 및 DMF 20 ml를 넣은 후 120 ℃에서 12시간 동안 가열하였다. 이어서, 감압증류하여 용매를 제거하고, 이 반응액에 물을 가한 후 에틸아세테이트로 추출하고 감압증류한 다음 컬럼 크로마토그래피(에틸아세테이트:에탄올 = 9:1을 전개용매로 사용)로 분리하여 목적 화합물 0.685 g(3.3 mmol, 수율 26%)을 얻었다.In a 50 ml two-necked round bottom flask, 3.256 g (37.8 mmol) of piperazine, 2.0 g (12.6 mmol) of 5-chloro-1,3-dimethyl-1 H -pyrazole-4-carbaldehyde prepared in Example 5 920 mg (16.4 mmol) of KOH and 20 ml of DMF were added and heated at 120 ° C. for 12 hours. Subsequently, the solvent was removed by distillation under reduced pressure, water was added to the reaction solution, followed by extraction with ethyl acetate, distillation under reduced pressure, and column chromatography (ethyl acetate: ethanol = 9: 1 was used as a developing solvent) to separate the target compound. 0.685 g (3.3 mmol, 26% yield) was obtained.

1H-NMR(200 MHz, CDCl3) δ 9.83(s, 1H), 8.08(s, 1H), 7.98(s, 1H), 3.71(s, 3H), 3.48-3.70(m, 4H), 3.06-3.26(m, 4H), 2.39(s, 3H)
 1 H-NMR (200 MHz, CDCl 3 ) δ 9.83 (s, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 3.71 (s, 3H), 3.48-3.70 (m, 4H), 3.06 -3.26 (m, 4H), 2.39 (s, 3H)

실시예 17: 5-디메틸아미노-1,3-디메틸-1H-피라졸-4-카브알데히드(R1=Me, R2=Me, Nu=디메틸아민)의 제조Example 17 Preparation of 5-dimethylamino-1,3-dimethyl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = Me, Nu = dimethylamine)

Figure 112003015701663-pat00024
Figure 112003015701663-pat00024

50 ml의 2구 둥근 바닥플라스크에 50% 디메틸아민 수용액 4.545 g(50.6 mmol), KOH 920 mg(16.4 mmol), 실시예 5에서 제조한 5-클로로-1,3-디메틸-1H-피라졸-4-카브알데히드 2.0 g(12.6 mmol) 및 DMF 20 ml를 넣고 120 ℃에서 3시간 30분 동안 가열한 후 디메틸아민 4.5 g(50.4 mmol)을 첨가하였다. 이 반응액을 같은 온도로 21시간 동안 추가로 가열하였다. 이어서, 감압증류하여 용매인 DMF를 제거하고, 이 반응액에 물을 가한 후 에틸아세테이트로 추출하고 감압증류한 다음 컬럼 크로마토그로피(헥산:에틸아세테이트 = 1:1을 전개용매로 사용)로 분리하여 목적 화합물 1.419 g(8.5 mmol, 수율 67.4%)을 얻었다. In a 50 ml two-necked round bottom flask, 4.545 g (50.6 mmol) of 50% aqueous dimethylamine solution, 920 mg (16.4 mmol) of KOH, 5-chloro-1,3-dimethyl-1 H -pyrazole prepared in Example 5 2.0 g (12.6 mmol) of -4-carbaldehyde and 20 ml of DMF were added thereto, and heated at 120 ° C. for 3 hours 30 minutes, and 4.5 g (50.4 mmol) of dimethylamine was added thereto. The reaction solution was further heated to the same temperature for 21 hours. Subsequently, distillation under reduced pressure was carried out to remove DMF as a solvent. Water was added to the reaction solution, followed by extraction with ethyl acetate, distillation under reduced pressure, and separation with column chromatography (hexane: ethyl acetate = 1: 1 as a developing solvent). This gave 1.419 g (8.5 mmol, yield 67.4%) of the title compound.

1H-NMR(200 MHz, CDCl3) δ 9.88(s, 1H), 3.61(s, 3H), 2.86(s, 6H), 2.34(s, 3H)
1 H-NMR (200 MHz, CDCl 3 ) δ 9.88 (s, 1H), 3.61 (s, 3H), 2.86 (s, 6H), 2.34 (s, 3H)

실시예 18: 3-메틸-5-페녹시-1-페닐-1H-피라졸-4-카브알데히드(R1=Me, R2=페닐, Nu= 페놀)의 제조Example 18 Preparation of 3-methyl-5-phenoxy-1-phenyl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = phenyl, Nu = phenol)

Figure 112003015701663-pat00025
Figure 112003015701663-pat00025

25 ml의 2구 둥근 바닥플라스크에 KOH 330 mg(5.9 mmol), 실시예 6에서 제조한 5-클로로-3-메틸-1-페닐-1H-피라졸-4-카브알데히드 1.0 g(4.5 mmol), 페놀 1.27 g(13.6 mmol) 및 DMF 10 ml를 넣은 후 115 ℃에서 4시간 동안 가열하였다. 이어서, 감압증류하여 용매를 제거하고, 이 반응액에 물을 가한 후 에틸아세테이트로 추출하고 감압증류한 다음 컬럼 크로마토그래피(헥산:에틸아세테이트 = 1:1을 전개용매로 사용)로 분리하여 목적 화합물 1.004 g(3.6 mmol, 수율 80.2%)을 얻었다.In a 25 ml two-necked round bottom flask, 330 mg (5.9 mmol) of KOH, 1.0 g (4.5 mmol) of 5-chloro-3-methyl-1-phenyl-1 H -pyrazole-4-carbaldehyde prepared in Example 6 ), 1.27 g (13.6 mmol) of phenol and 10 ml of DMF were added and then heated at 115 ° C. for 4 hours. Subsequently, the solvent was removed by distillation under reduced pressure, water was added to the reaction solution, followed by extraction with ethyl acetate, distillation under reduced pressure, and column chromatography (hexane: ethyl acetate = 1: 1 as a developing solvent) to separate the target compound. 1.004 g (3.6 mmol, yield 80.2%) was obtained.

1H-NMR(300 MHz, CDCl3) δ 9.52(s, 1H), 6.93-6.96(d, 2H), 7.03-7.35(m, 6H), 7.54-7.57(d, 2H), 2.48(s, 3H)
 1 H-NMR (300 MHz, CDCl 3 ) δ 9.52 (s, 1H), 6.93-6.96 (d, 2H), 7.03-7.35 (m, 6H), 7.54-7.57 (d, 2H), 2.48 (s, 3H)

실시예 19: 5-이미다졸-1-일-3-메틸-1-페닐-1H-피라졸-4-카브알데히드(R1=Me, R2=페닐, Nu=이미다졸)의 제조Example 19 Preparation of 5-imidazol-1-yl-3-methyl-1-phenyl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = phenyl, Nu = imidazole)

Figure 112003015701663-pat00026
Figure 112003015701663-pat00026

25 ml의 2구 둥근 바닥플라스크에 KOH 330 mg(5.9 mmol), 실시예 6에서 제조한 5-클로로-3-메틸-1-페닐-1H-피라졸-4-카브알데히드 1.0 g(5.9 mmol), 이미다졸 920 mg(13.6 mmol) 및 DMF 10 ml를 넣은 후 120 ℃에서 4시간 동안 가열하였다. 이어서, 감압증류하여 용매를 제거하고, 이 반응액에 물을 가한 후 에틸아세테이트로 추출하고 감압증류한 다음 컬럼 크로마토그래피(헥산:에틸아세테이트 = 9:1을 전개용매로 사용)로 분리하여 목적 화합물 787 mg(3.12 mmol, 수율 69.3%)을 얻었다.In a 25 ml two-necked round bottom flask, 330 mg (5.9 mmol) of KOH, 1.0 g (5.9 mmol) of 5-chloro-3-methyl-1-phenyl-1 H -pyrazole-4-carbaldehyde prepared in Example 6 ), 920 mg (13.6 mmol) of imidazole and 10 ml of DMF were added and then heated at 120 ° C. for 4 hours. Subsequently, the solvent was removed by distillation under reduced pressure, water was added to the reaction solution, followed by extraction with ethyl acetate, distillation under reduced pressure, and column chromatography (hexane: ethyl acetate = 9: 1 was used as a developing solvent) to separate the target compound. 787 mg (3.12 mmol, yield 69.3%) were obtained.

1H-NMR(300 MHz, CDCl3) δ 9.71(s, 1H), 7.58(s, 1H), 7.29-7.33(m, 3H), 7.16(d, 1H), 7.04-7.09(m, 2H), 6.96(d, 1H), 2.54(s, 3H)
 1 H-NMR (300 MHz, CDCl 3 ) δ 9.71 (s, 1H), 7.58 (s, 1H), 7.29-7.33 (m, 3H), 7.16 (d, 1H), 7.04-7.09 (m, 2H) , 6.96 (d, 1H), 2.54 (s, 3H)

실시예 20: 5-인돌-1-일-3-메틸-1-페닐-1H-피라졸-4-카브알데히드(R1=Me, R2=페닐, Nu=인돌)의 제조Example 20 Preparation of 5-indol-1-yl-3-methyl-1-phenyl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = phenyl, Nu = indole)

Figure 112003015701663-pat00027
Figure 112003015701663-pat00027

25 ml의 2구 둥근 바닥플라스크에 KOH 330 mg(5.9 mmol), 실시예 6에서 제조한 5-클로로-3-메틸-1-페닐-1H-피라졸-4-카브알데히드 1.0 g(5.9 mmol), 인돌 1.58 g(13.5 mmol) 및 DMF 10 ml를 넣은 후 120 ℃에서 5시간 동안 가열하였다. 이어 서, 감압증류하여 용매를 제거하고, 이 반응액에 소금물을 가한 후 에틸아세테이트로 추출하고 감압증류한 다음 컬럼 크로마토그래피(헥산:에틸아세테이트 = 7:3을 전개용매로 사용)로 분리하여 목적 화합물 0.931 mg(3.09 mmol, 수율 68.6%)을 얻었다.In a 25 ml two-necked round bottom flask, 330 mg (5.9 mmol) of KOH, 1.0 g (5.9 mmol) of 5-chloro-3-methyl-1-phenyl-1 H -pyrazole-4-carbaldehyde prepared in Example 6 ), 1.58 g (13.5 mmol) of indole and 10 ml of DMF were added and then heated at 120 ° C. for 5 hours. Then, the solvent was removed by distillation under reduced pressure, brine was added to the reaction solution, followed by extraction with ethyl acetate and distillation under reduced pressure, followed by column chromatography (hexane: ethyl acetate = 7: 3 as a developing solvent). 0.931 mg (3.09 mmol, yield 68.6%) was obtained.

1H-NMR(300 MHz, CDCl3) δ 8.12(s, 1H), 7.59-7.61(s, 1H), 7.37-7.50(m, 5H), 7.20-7.28(t, 2H), 7.06-7.11(t, 2H), 6.80(s, 1H), 2.09(s, 3H)
 1 H-NMR (300 MHz, CDCl 3 ) δ 8.12 (s, 1H), 7.59-7.61 (s, 1H), 7.37-7.50 (m, 5H), 7.20-7.28 (t, 2H), 7.06-7.11 ( t, 2H), 6.80 (s, 1H), 2.09 (s, 3H)

실시예 21: 3-메틸-1-페닐-5-피롤리딘-1-일-1H-피라졸-4-카브알데히드(R1=Me, R2=페닐, Nu=피롤리딘)의 제조Example 21: 3-Methyl-1-phenyl-5-pyrrolidin-1-yl-1 H -pyrazole-4-carbaldehyde (R 1 = Me, R 2 = phenyl, Nu = pyrrolidine) Produce

Figure 112003015701663-pat00028
Figure 112003015701663-pat00028

25 ml의 2구 둥근 바닥플라스크에 KOH 330 mg(5.9 mmol), 실시예 6에서 제조한 5-클로로-3-메틸-1-페닐-1H-피라졸-4-카브알데히드 1.0 g(5.9 mmol), 피롤리딘 967 mg(13.6 mmol) 및 DMF 10 ml를 넣은 후 120 ℃에서 3시간 동안 가열하였다. 이어서, 감압증류하여 용매를 제거하고, 이 반응액에 소금물을 가한 후 에틸아세테이트로 추출하고 감압증류한 다음 컬럼 크로마토그래피(헥산:에틸아세테이트 = 7:3을 전개용매로 사용)로 분리하여 목적 화합물 370 mg(1.45 mmol, 수율 32.2%)을 얻 었다.In a 25 ml two-necked round bottom flask, 330 mg (5.9 mmol) of KOH, 1.0 g (5.9 mmol) of 5-chloro-3-methyl-1-phenyl-1 H -pyrazole-4-carbaldehyde prepared in Example 6 ), 967 mg (13.6 mmol) of pyrrolidine and 10 ml of DMF were added and then heated at 120 ° C. for 3 hours. Subsequently, the solvent was removed by distillation under reduced pressure, brine was added to the reaction solution, followed by extraction with ethyl acetate, distillation under reduced pressure, and column chromatography (hexane: ethyl acetate = 7: 3 as a developing solvent) to separate the target compound. 370 mg (1.45 mmol, yield 32.2%) were obtained.

1H-NMR(300 MHz, CDCl3) δ 9.96(s, 1H), 7.36-7.48(m, 5H), 3.23-3.31(m, 4H), 2.49(s, 3H), 1.82-1.90(m, 4H)
 1 H-NMR (300 MHz, CDCl 3 ) δ 9.96 (s, 1H), 7.36-7.48 (m, 5H), 3.23-3.31 (m, 4H), 2.49 (s, 3H), 1.82-1.90 (m, 4H)

실시예 22: 5'-메틸-2'-피리딘-2-일-2'H-[1,3']비피라졸릴-4'-카브알데하이드(R1=Me, R2=2-피리딜, Nu=피라졸)의 제조Example 22: 5'-methyl-2'-pyridin-2-yl-2'H- [1,3 '] bipyrazolyl-4'-carbaldehyde (R 1 = Me, R 2 = 2-pyridyl , Nu = pyrazole)

Figure 112003015701663-pat00029
Figure 112003015701663-pat00029

25 ml의 2구 둥근 바닥플라스크에 KOH 190 mg(3.4 mmol), 실시예 7에서 제조한 5-클로로-3-메틸-1-피리딘-2-일-1H-피라졸-4-카브알데히드 0.5 g(2.25 mmol), 피라졸 460 mg(6.8 mmol) 및 DMF 5ml를 넣은 후 120 ℃에서 2시간 동안 가열하였다. 이어서, 감압증류하여 용매를 제거하고, 이 반응액에 소금물을 가한 후 에틸아세테이트로 추출하고 감압증류한 다음 컬럼 크로마토그래피(헥산:에틸아세테이트 = 1:1을 전개용매로 사용)로 분리하여 목적 화합물 400 mg(1.58 mmol, 수율 70.2%)을 얻었다.190 mg (3.4 mmol) KOH, 5-chloro-3-methyl-1-pyridin-2-yl-1 H -pyrazole-4-carbaldehyde 0.5 prepared in Example 7 in a 25 ml two-necked round bottom flask g (2.25 mmol), 460 mg (6.8 mmol) of pyrazole and 5 ml of DMF were added thereto, followed by heating at 120 ° C. for 2 hours. Subsequently, the solvent was removed by distillation under reduced pressure, brine was added to the reaction solution, followed by extraction with ethyl acetate, distillation under reduced pressure, and column chromatography (hexane: ethyl acetate = 1: 1 as a developing solvent) to separate the target compound. 400 mg (1.58 mmol, yield 70.2%) were obtained.

1H-NMR(300 MHz, CDCl3) δ 9.80(s, 1H), 8.74-7.75(d, 1H), 7.93(m, 1H), 7.80- 7.93(m, 1H), 7.47-7.50(d, 1H), 7.28-7.30(t, 1H), 6.42-6.51(m, 1H), 2.63(s, 3H)
 1 H-NMR (300 MHz, CDCl 3 ) δ 9.80 (s, 1H), 8.74-7.75 (d, 1H), 7.93 (m, 1H), 7.80- 7.93 (m, 1H), 7.47-7.50 (d, 1H), 7.28-7.30 (t, 1H), 6.42-6.51 (m, 1H), 2.63 (s, 3H)

본 발명에 따르면 항생제, 살충제 등과 같은 여러 가지 생물학적 효능을 지닌 화합물의 합성에 사용되는 중간체인 다양한 신규의 피라졸 유도체를 온화한 조건에서 용이하게 제조할 수 있어 앞으로 신약, 신농약 등의 개발에 이용하여 국내 의약, 농약산업의 발달 및 수출증대에 공헌할 수 있다.According to the present invention, various novel pyrazole derivatives, which are intermediates used in the synthesis of compounds having various biological effects, such as antibiotics and insecticides, can be easily produced under mild conditions, and thus will be used in the development of new drugs, new pesticides, etc. It can contribute to the development of domestic medicine and pesticide industry, and to increase exports.

Claims (6)

하기 화학식 2의 피라졸 유도체:A pyrazole derivative of formula 화학식 2Formula 2
Figure 112007023545730-pat00030
Figure 112007023545730-pat00030
 상기 식에서,Where R1은 수소, C1-C5 저급 알킬, C1-C5 저급 할로알킬, 페닐, 아미노, 알킬아미노, 하이드록시 또는 할로겐 원자이고,R 1 is hydrogen, C 1 -C 5 lower alkyl, C 1 -C 5 lower haloalkyl, phenyl, amino, alkylamino, hydroxy or halogen atom, R2는 수소, C1-C5 저급 알킬, C1-C5 저급 할로알킬, 페닐, 피리디닐, 아미노, 알킬아미노 또는 할로겐 원자이고,R 2 is hydrogen, C 1 -C 5 lower alkyl, C 1 -C 5 lower haloalkyl, phenyl, pyridinyl, amino, alkylamino or halogen atom, Nu는 수소, 피롤, 피라졸, 이미다졸, 피페라진, 모폴린, 피롤리딘, 티오페닐, 페닐, 하이드록시, 아미노, 알킬아미노 또는 할로겐 원자이다. Nu is hydrogen, pyrrole, pyrazole, imidazole, piperazine, morpholine, pyrrolidine, thiophenyl, phenyl, hydroxy, amino, alkylamino or halogen atoms. 유기용매 중에서 알칼리 염기 존재 하에 하기 화학식 1의 화합물을 하기 화학식 3의 친핵치환체로 친핵치환 반응시키는 것을 포함하는, 하기 화학식 2의 피라졸 유도체의 제조방법:A method for preparing a pyrazole derivative of formula (II) comprising nucleophilic substitution of a compound of formula (1) with a nucleophilic substituent of formula (3) in an organic solvent in the presence of an alkali base: 화학식 1Formula 1
Figure 112007023545730-pat00031
Figure 112007023545730-pat00031
 화학식 2Formula 2
Figure 112007023545730-pat00032
Figure 112007023545730-pat00032
 NuYNuy 상기 식에서,Where R1은 수소, C1-C5 저급 알킬, C1-C5 저급 할로알킬, 페닐, 아미노, 알킬아미노, 하이드록시 또는 할로겐이고,R 1 is hydrogen, C 1 -C 5 lower alkyl, C 1 -C 5 lower haloalkyl, phenyl, amino, alkylamino, hydroxy or halogen, R2는 수소, C1-C5 저급 알킬, C1-C5 저급 할로알킬, 페닐, 피리딘, 아미노, 알킬아미노 또는 할로겐이고,R 2 is hydrogen, C 1 -C 5 lower alkyl, C 1 -C 5 lower haloalkyl, phenyl, pyridine, amino, alkylamino or halogen, X는 할로겐이며,X is halogen, Nu는 수소, 피롤, 피라졸, 이미다졸, 피페라진, 모폴린, 피롤리딘, 티오페닐, 페닐, 하이드록시, 아미노, 알킬아미노 또는 할로겐이고,Nu is hydrogen, pyrrole, pyrazole, imidazole, piperazine, morpholine, pyrrolidine, thiophenyl, phenyl, hydroxy, amino, alkylamino or halogen, Y는 수소; 또는 나트륨 또는 칼륨이다. Y is hydrogen; Or sodium or potassium. 제 2 항에 있어서,The method of claim 2, 알칼리 염기를 화학식 1의 화합물에 대하여 1.2 내지 3 당량의 양으로 사용하는 것을 특징으로 하는 방법.The alkali base is used in an amount of 1.2 to 3 equivalents based on the compound of formula 1. 제 2 항에 있어서,The method of claim 2, 화학식 3의 친핵체를 화학식 1의 화합물에 대하여 1.2 내지 3 당량의 양으로 사용하는 것을 특징으로 하는 방법.A nucleophile of formula (3) is used in an amount of 1.2 to 3 equivalents relative to compound of formula (1). 제 2 항에 있어서,The method of claim 2, 유기용매가 N,N-디메틸포름아미드(DMF) 또는 디메틸설폭사이드(DMSO)인 것을 특징으로 하는 방법.The organic solvent is N, N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO). 제 2 항에 있어서,The method of claim 2, 친핵치환 반응을 100 내지 150 ℃ 범위에서 2 내지 25시간 동안 수행하는 것을 특징으로 하는 방법.The nucleophilic substitution reaction is carried out in the range of 100 to 150 ℃ for 2 to 25 hours.
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KR101911974B1 (en) 2011-04-21 2018-10-25 바스프 에스이 Novel pesticidal pyrazole compounds

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