CN108047216B - A kind of 3,4-diphenylpyrazole compound and its preparation and application - Google Patents
A kind of 3,4-diphenylpyrazole compound and its preparation and application Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims description 13
- -1 3,4-diphenylpyrazole compound Chemical class 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 229940124350 antibacterial drug Drugs 0.000 claims abstract description 7
- 230000000844 anti-bacterial effect Effects 0.000 claims description 4
- ZQSIJRDFPHDXIC-UHFFFAOYSA-N daidzein Chemical compound C1=CC(O)=CC=C1C1=COC2=CC(O)=CC=C2C1=O ZQSIJRDFPHDXIC-UHFFFAOYSA-N 0.000 abstract description 8
- 235000007240 daidzein Nutrition 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 241000588724 Escherichia coli Species 0.000 abstract 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 abstract 1
- 241000191967 Staphylococcus aureus Species 0.000 abstract 1
- 241000194017 Streptococcus Species 0.000 abstract 1
- 238000006396 nitration reaction Methods 0.000 abstract 1
- 238000006722 reduction reaction Methods 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 8
- 239000012346 acetyl chloride Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- MQWYZELNDPRANJ-UHFFFAOYSA-N 4,5-diphenyl-1h-pyrazole Chemical class C1=NNC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 MQWYZELNDPRANJ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 150000003217 pyrazoles Chemical class 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 description 1
- LCIMJULVQOQTEZ-UHFFFAOYSA-N 2-hydroxyacetyl chloride Chemical compound OCC(Cl)=O LCIMJULVQOQTEZ-UHFFFAOYSA-N 0.000 description 1
- BUHYMJLFRZAFBF-UHFFFAOYSA-N 3,4,5-trimethoxybenzoyl chloride Chemical compound COC1=CC(C(Cl)=O)=CC(OC)=C1OC BUHYMJLFRZAFBF-UHFFFAOYSA-N 0.000 description 1
- VIOBGCWEHLRBEP-UHFFFAOYSA-N 3,4-dimethoxybenzoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1OC VIOBGCWEHLRBEP-UHFFFAOYSA-N 0.000 description 1
- NROWLQUIWQQSLF-UHFFFAOYSA-N 4-hydroxy-3-methoxybenzoyl chloride Chemical compound COC1=CC(C(Cl)=O)=CC=C1O NROWLQUIWQQSLF-UHFFFAOYSA-N 0.000 description 1
- YIPHYCQSJTXLFM-UHFFFAOYSA-N 4-hydroxybenzoyl chloride Chemical compound OC1=CC=C(C(Cl)=O)C=C1 YIPHYCQSJTXLFM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 1
- 150000002515 isoflavone derivatives Chemical class 0.000 description 1
- 235000008696 isoflavones Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种3,4‑二苯基吡唑类化合物，包括其药学可接受的水合物，立体异构体或互变异构体，及其在抗菌药物中的应用。本发明的化合物以大豆苷元为原料，经硝化、还原、环化等步骤制备。其对乳链球菌，抗药性金黄色葡萄球菌，大肠杆菌和绿脓杆菌有明显的抑制作用，可用于制备抗菌药物。The invention discloses a 3,4-diphenylpyrazole compound, including its pharmaceutically acceptable hydrate, stereoisomer or tautomer, and its application in antibacterial drugs. The compound of the present invention uses daidzein as a raw material, and is prepared through the steps of nitration, reduction, cyclization and the like. It has obvious inhibitory effect on Streptococcus niles, drug-resistant Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, and can be used for preparing antibacterial drugs.
Description
技术领域technical field
本发明涉及化工制药技术领域，尤其涉及一种3,4-二苯基吡唑化合物及制备并在抗菌药物中的应用。The invention relates to the technical field of chemical pharmacy, in particular to a 3,4-diphenylpyrazole compound and its preparation and application in antibacterial drugs.
背景技术Background technique
目前，临床上各种抗生素使用广泛，造成了各种耐药菌株的出现，细菌的耐药问题日益突出，常用抗菌药物的临床表现越来越差。吡唑类化合物作为含氮杂环化合物不仅具有广谱生理和药理活性，而且具有高效、低毒、环保等优点，在医药和农药等精细化工领域有着广泛的应用。实践证明，吡唑类化合物具有好的抗菌作用，且毒副作用小。At present, various antibiotics are widely used in clinical practice, resulting in the emergence of various drug-resistant strains, the problem of bacterial resistance has become increasingly prominent, and the clinical performance of commonly used antibiotics is getting worse. As nitrogen-containing heterocyclic compounds, pyrazoles not only have broad-spectrum physiological and pharmacological activities, but also have the advantages of high efficiency, low toxicity, and environmental protection. They are widely used in fine chemicals such as medicine and pesticides. Practice has proved that pyrazole compounds have good antibacterial effect and small toxic and side effects.
本发明以大豆苷元为原料，利用异黄酮具有潜在的1,3-二羰基结构，设计合成了3,4-二苯基吡唑类化合物。在分子中引入羟基，利用羟基容易形成分子间氢键,可改善化合物与细菌靶标(特异性酶)的亲合性、抑制细菌菌壁中菌酸成分的合成、干扰脱氧核糖核酸和核糖核酸的合成、达到抑制细菌增殖的特点,提高化合物的抗菌活性，期望发现更有效的抗菌药物。In the present invention, daidzein is used as raw material, and 3,4-diphenylpyrazole compounds are designed and synthesized by utilizing isoflavones with potential 1,3-dicarbonyl structure. The introduction of a hydroxyl group into the molecule can easily form intermolecular hydrogen bonds by using the hydroxyl group, which can improve the affinity of the compound with the bacterial target (specific enzyme), inhibit the synthesis of bacterial acid components in the bacterial wall, and interfere with deoxyribonucleic acid and ribonucleic acid. Synthesize, achieve the characteristics of inhibiting bacterial proliferation, improve the antibacterial activity of compounds, and expect to find more effective antibacterial drugs.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供一种3,4-二苯基吡唑化合物，尤其是该类化合物在制备抗菌药物中的应用。The purpose of the present invention is to provide a 3,4-diphenylpyrazole compound, especially the application of the compound in the preparation of antibacterial drugs.
本发明的另一目的在于提供上述3,4-二苯基吡唑化合物的制备方法。Another object of the present invention is to provide a method for preparing the above-mentioned 3,4-diphenylpyrazole compound.
本发明的再一目的在于提供上述3,4-二苯基吡唑化合物的用途。Another object of the present invention is to provide the use of the above-mentioned 3,4-diphenylpyrazole compound.
以下对本发明进行详细描述。The present invention is described in detail below.
本发明的具有通式（I）的3,4-二苯基吡唑化合物或药学可接受的水合物，包括其立体异构体或互变异构体，结构如下式所示：The 3,4-diphenylpyrazole compound or pharmaceutically acceptable hydrate of the present invention with general formula (I), including its stereoisomers or tautomers, has the structure shown in the following formula:
式（I）中的R分别独立为烷基，H，取代烷基，芳基，取代芳基。R in formula (I) is independently alkyl, H, substituted alkyl, aryl, and substituted aryl.
所述的3,4-二苯基吡唑化合物，代表性的具体实例包括：Representative specific examples of the 3,4-diphenylpyrazole compound include:
本发明还提供了所述化合物的制备方法，该方法如下式：The present invention also provides a preparation method of the compound, the method is as follows:
式中，R 独立为烷基，H，取代烷基，芳基，取代芳基。In the formula, R is independently alkyl, H, substituted alkyl, aryl, substituted aryl.
本发明还提供了上述化合物用于制备抗菌药物的用途。The present invention also provides the use of the above compounds for preparing antibacterial drugs.
具体实施方式Detailed ways
实施例1Example 1
化合物（1）的制备Preparation of compound (1)
将254mg(1.0 mmol)的大豆苷元溶于5mL醋酸和5mLDMF中，加入254mg (1mmol)碘和548mg (1mmol)硝酸铈铵，50℃反应36h，浓缩，柱层析纯化（V甲醇：V二氯甲烷= 1:9），得到8-硝基大豆苷元，收率73%。Dissolve 254 mg (1.0 mmol) of daidzein in 5 mL of acetic acid and 5 mL of DMF, add 254 mg (1 mmol) of iodine and 548 mg (1 mmol) of cerium ammonium nitrate, react at 50 ° C for 36 h, concentrate, and purify by column chromatography (V methanol : V two methyl chloride = 1:9) to obtain 8-nitrodaidzein with a yield of 73%.
将150mg (0.5mmol)的8-硝基大豆苷元加入到4mL甲醇和6mLDMF中，加入96mg Zn粉和80mg 氯化铵，室温反应6h，过滤，浓缩，硅胶柱层析纯化，得到8-氨基大豆苷元，收率87%。150 mg (0.5 mmol) of 8-nitrodaidzein was added to 4 mL of methanol and 6 mL of DMF, 96 mg of Zn powder and 80 mg of ammonium chloride were added, the reaction was carried out at room temperature for 6 h, filtered, concentrated, and purified by silica gel column chromatography to obtain 8-amino The yield of daidzein was 87%.
将269mg (1.0mmol)的8-氨基大豆苷元加入18mLDMF中，再加入86.3mg (1.1mmol)乙酰氯，在350W微波辐射下，50℃反应30min，加入1mL水，搅拌10min，减压浓缩，硅胶柱层析纯化，得到中间体（II)，收率70.3%。269 mg (1.0 mmol) of 8-aminodaidzein was added to 18 mL of DMF, then 86.3 mg (1.1 mmol) of acetyl chloride was added, and under 350 W microwave irradiation, the reaction was carried out at 50 ° C for 30 min, 1 mL of water was added, stirred for 10 min, and concentrated under reduced pressure. Purified by silica gel column chromatography to obtain intermediate (II) in a yield of 70.3%.
将293mg (1.0mmol)的上述中间体（II）加入10mL无水醇中，加热回流，慢慢滴加60mg (1.5mmol)的80%的肼，反应1h，冷至室温，滴入12mLCH2Cl2，析出黄色固体，过滤，柱层析纯化，得到化合物（1）。收率80.2%； 'H NMR (DMSO-d6, 400MHz) δ: 2.35 (s, 3H),4.95 (s, 2H), 6.73 (m, 1H), 6.88 (m, 1H), 7.09 (m, 2H), 7.31 (m, 2H), 7.78(s, 1H), 9.36 (s, 1H); Anal,calcdforC17H13N3O3: C66.44,H 4.26,N 13.67;foundC66.41,H 4.27,N13.66。293 mg (1.0 mmol) of the above intermediate (II) was added to 10 mL of anhydrous alcohol, heated to reflux, 60 mg (1.5 mmol) of 80% hydrazine was slowly added dropwise, reacted for 1 h, cooled to room temperature, and 12 mL of CH 2 Cl was added dropwise 2 , a yellow solid was precipitated, filtered and purified by column chromatography to obtain compound (1). Yield 80.2%; 'H NMR (DMSO-d6, 400MHz) δ: 2.35 (s, 3H), 4.95 (s, 2H), 6.73 (m, 1H), 6.88 (m, 1H), 7.09 (m, 2H) ), 7.31 (m, 2H), 7.78(s, 1H), 9.36 (s, 1H); Anal,calcdforC 17 H 13 N 3 O 3 : C66.44,H 4.26,N 13.67;foundC66.41,H 4.27 , N13.66.
实施例2Example 2
化合物（2）的制备Preparation of compound (2)
用103.4mg (1.1mmol)羟基乙酰氯代替86.3mg (1.1mmol)乙酰氯，其它操作同实施例1，得到化合物（2）。收率69.4%； 'H NMR (DMSO-d6, 400MHz) δ: 2.1 (s, 1H), 4.79(s, 2H), 4.95 (s, 2H), 6.73 (m, 1H), 6.88 (m, 1H), 7.09 (m, 2H), 7.31 (m,2H), 7.78 (s, 1H), 9.36 (s, 1H); Anal,calcdforC17H13N3O4: C63.16,H 4.05,N13.00;foundC 63.14,H 4.02,N13.07。Substitute 86.3 mg (1.1 mmol) of acetyl chloride with 103.4 mg (1.1 mmol) of hydroxyacetyl chloride, and other operations are the same as in Example 1 to obtain compound (2). Yield 69.4%; 'H NMR (DMSO-d6, 400MHz) δ: 2.1 (s, 1H), 4.79 (s, 2H), 4.95 (s, 2H), 6.73 (m, 1H), 6.88 (m, 1H) ), 7.09 (m, 2H), 7.31 (m, 2H), 7.78 (s, 1H), 9.36 (s, 1H); Anal,calcdforC 17 H 13 N 3 O 4 : C63.16,H 4.05,N13. 00; foundC 63.14, H 4.02, N13.07.
实施例3Example 3
化合物（3）的制备Preparation of compound (3)
用253mg (1.1mmol)3,4,5-三甲氧基苯甲酰氯代替86.3mg (1.1mmol)乙酰氯，其它操作同实施例1，得到化合物（3）。收率85.0%； 'H NMR (DMSO-d6, 400MHz) δ: 3.73 (s,9H), 4.95 (s, 2H), 6.44 (s, 2H), 6.73 (m, 1H), 6.88 (m, 1H), 6.99 (m, 2H),7.31 (m, 2H), 7.79 (s, 1H), 9.35 (s, 1H); Anal,calcdforC25H21N3O6: C65.35,H4.61,N 9.15;foundC 65.34,H 4.62,N9.17。Substitute 253 mg (1.1 mmol) of 3,4,5-trimethoxybenzoyl chloride for 86.3 mg (1.1 mmol) of acetyl chloride, and other operations are the same as in Example 1 to obtain compound (3). Yield 85.0%; 'H NMR (DMSO-d6, 400MHz) δ: 3.73 (s, 9H), 4.95 (s, 2H), 6.44 (s, 2H), 6.73 (m, 1H), 6.88 (m, 1H) ), 6.99 (m, 2H), 7.31 (m, 2H), 7.79 (s, 1H), 9.35 (s, 1H); Anal,calcdforC 25 H 21 N 3 O 6 : C65.35,H4.61,N 9.15; foundC 65.34, H 4.62, N9.17.
实施例4Example 4
化合物（4）的制备Preparation of compound (4)
用171mg (1.1mmol)对羟基苯甲酰氯代替86.3mg (1.1mmol)乙酰氯，其它操作同实施例1，得到化合物（4）。收率83.6%； 'H NMR (DMSO-d6, 400MHz) δ: 4.95 (s, 3H),6.73 (m, 1H), 6.88 (m, 1H), 6.99 (m, 4H), 7.31 (m, 4H), 7.81 (s, 1H), 9.36(s, 1H); Anal,calcdforC22H15N3O4: C68.57,H 3.92,N 10.90;foundC 68.54,H 3.92,N10.87。Substitute 86.3 mg (1.1 mmol) of acetyl chloride with 171 mg (1.1 mmol) of p-hydroxybenzoyl chloride, and other operations are the same as in Example 1 to obtain compound (4). Yield 83.6%; 'H NMR (DMSO-d6, 400MHz) δ: 4.95 (s, 3H), 6.73 (m, 1H), 6.88 (m, 1H), 6.99 (m, 4H), 7.31 (m, 4H) ), 7.81(s, 1H), 9.36(s, 1H); Anal, calcd for C 22 H 15 N 3 O 4 : C68.57, H 3.92, N 10.90; foundC 68.54, H 3.92, N10.87.
实施例5Example 5
化合物（5）的制备Preparation of compound (5)
用220mg (1.1mmol)3,4-二甲氧基苯甲酰氯代替86.3mg (1.1mmol)乙酰氯，其它操作同实施例1，得到化合物（5）。收率80.0%； 'H NMR (DMSO-d6, 400MHz) δ: 3.73 (s,6H), 4.95 (s, 2H), 6.73 (m, 2H), 6.88 (m, 2H), 6.93 (m, 1H), 6.99 (m, 2H),7.31 (m, 2H), 7.79 (s, 1H), 9.36 (s, 1H); Anal,calcdforC24H19N3O5: C67.13,H4.46,N 9.79;foundC 67.10,H 4.42,N 9.81。Substitute 220 mg (1.1 mmol) of 3,4-dimethoxybenzoyl chloride for 86.3 mg (1.1 mmol) of acetyl chloride, and other operations are the same as in Example 1 to obtain compound (5). Yield 80.0%; 'H NMR (DMSO-d6, 400MHz) δ: 3.73 (s, 6H), 4.95 (s, 2H), 6.73 (m, 2H), 6.88 (m, 2H), 6.93 (m, 1H) ), 6.99 (m, 2H), 7.31 (m, 2H), 7.79 (s, 1H), 9.36 (s, 1H); Anal,calcdforC 24 H 19 N 3 O 5 : C67.13,H4.46,N 9.79; foundC 67.10, H 4.42, N 9.81.
实施例6Example 6
化合物（6）的制备Preparation of compound (6)
用204mg (1.1mmol)3-甲氧基-4-羟基苯甲酰氯代替86.3mg (1.1mmol)乙酰氯，其它操作同实施例1，得到化合物（6）。收率77.7%； 'H NMR (DMSO-d6, 400MHz) δ: 3.73 (s,3H), 4.95 (s, 3H), 6.73 (m, 2H), 6.88 (m, 2H), 6.93 (m, 1H), 6.99 (m, 2H),7.31 (m, 2H), 7.79 (s, 1H), 9.36 (s, 1H); Anal,calcdforC23H17N3O5: C66.50,H4.12,N 10.12;foundC 66.47,H 4.10,N 10.09。Substitute 204 mg (1.1 mmol) of 3-methoxy-4-hydroxybenzoyl chloride for 86.3 mg (1.1 mmol) of acetyl chloride, and other operations are the same as in Example 1 to obtain compound (6). Yield 77.7%; 'H NMR (DMSO-d6, 400MHz) δ: 3.73 (s, 3H), 4.95 (s, 3H), 6.73 (m, 2H), 6.88 (m, 2H), 6.93 (m, 1H) ), 6.99 (m, 2H), 7.31 (m, 2H), 7.79 (s, 1H), 9.36 (s, 1H); Anal,calcdforC 23 H 17 N 3 O 5 : C66.50,H4.12,N 10.12; foundC 66.47, H 4.10, N 10.09.
实施例7Example 7
化合物（7）的制备Preparation of compound (7)
用183mg (1.1mmol)肉桂酰氯代替86.3mg (1.1mmol)乙酰氯，其它操作同实施例1，得到化合物（7）。收率85.2%； 'H NMR (DMSO-d6, 400MHz) δ: 4.95 (s, 2H), 6.73 (m,2H), 6.88 (m, 1H), 6.99 (m, 4H), 7.14-7.31 (m, 6H), 7.81 (s, 1H), 9.36 (s,1H); Anal,calcdforC24H17N3O3: C 72.90,H 4.33,N 10.63;foundC 72.93,H 4.35,N10.60。Substitute 183 mg (1.1 mmol) of cinnamoyl chloride for 86.3 mg (1.1 mmol) of acetyl chloride, and other operations are the same as in Example 1 to obtain compound (7). Yield 85.2%; 'H NMR (DMSO-d6, 400MHz) δ: 4.95 (s, 2H), 6.73 (m, 2H), 6.88 (m, 1H), 6.99 (m, 4H), 7.14-7.31 (m , 6H), 7.81 (s, 1H), 9.36 (s, 1H); Anal, calcd for C 24 H 17 N 3 O 3 : C 72.90, H 4.33, N 10.63; foundC 72.93, H 4.35, N 10.60.
实施例8Example 8
化合物（8）的制备Preparation of compound (8)
用70.4mg (1.1mmol)甲酰氯代替86.3mg (1.1mmol)乙酰氯，其它操作同实施例1，得到化合物（8）。收率60.7%； 'H NMR (DMSO-d6, 400MHz) δ: 4.95 (s, 2H), 6.73 (m,2H), 6.88 (m, 1H), 6.99 (m, 2H), 7.31 (m, 1H), 7.81 (s, 1H), 7.95 (s, 1H),9.36 (s, 1H); Anal,calcdforC16H11N3O3: C 65.53,H 3.78,N 14.33;foundC 65.51,H3.76,N 14.31。Substitute 70.4 mg (1.1 mmol) of formyl chloride for 86.3 mg (1.1 mmol) of acetyl chloride, and other operations are the same as in Example 1 to obtain compound (8). Yield 60.7%; 'H NMR (DMSO-d6, 400MHz) δ: 4.95 (s, 2H), 6.73 (m, 2H), 6.88 (m, 1H), 6.99 (m, 2H), 7.31 (m, 1H) ), 7.81 (s, 1H), 7.95 (s, 1H), 9.36 (s, 1H); Anal,calcdforC 16 H 11 N 3 O 3 : C 65.53,H 3.78,N 14.33;foundC 65.51,H3.76, N 14.31.
实施例9Example 9
最小抑菌浓度（MIC）测定Minimum inhibitory concentration (MIC) determination
将待测化合物溶解在DMSO中，在96孔微量滴定板中加入适当的肉汤培养液，取适量化合物的DMSO溶液滴加到96孔微量滴定板，以产生从120ug/mL到0.1ug/mL的浓度范围，最后接种一定量的菌液（细菌浊度为0.5麦氏），经37℃恒温培育24小时，测定吸光度，读取化合物的最低抑菌浓度（MIC)。实验结果表明(表1），本发明的3,4-二苯基吡唑化合物均具有良好的抗菌活性。Dissolve the compound to be tested in DMSO, add the appropriate broth medium to a 96-well microtiter plate, and add an appropriate amount of compound in DMSO to the 96-well microtiter plate to generate a range from 120ug/mL to 0.1ug/mL. Finally, inoculate a certain amount of bacterial liquid (bacterial turbidity is 0.5 McFarland), cultivate at a constant temperature of 37 ° C for 24 hours, measure the absorbance, and read the minimum inhibitory concentration (MIC) of the compound. The experimental results show (Table 1) that the 3,4-diphenylpyrazole compounds of the present invention all have good antibacterial activity.
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