720-94-5Relevant articles and documents
Simple synthesis method of celecoxib
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Paragraph 0021; 0036-0037; 0040-0041; 0044-0045, (2022/03/27)
The invention discloses a simple synthesis method of celecoxib. The method comprises the following steps: taking trifluoroacetoacetate and methylbenzene as starting raw materials, firstly synthesizing a compound I through Friedel-Crafts reaction under the catalysis of aluminum trichloride, and reacting the compound I with p-halobenzene sulfonamide in the presence of hydrazine hydrate under an alkaline condition to obtain celecoxib. The method not only avoids the preparation of the 4-hydrazinobenzenesulfonamide hydrochloride in the traditional method, but also avoids the diazotization reaction step in the production process of the 4-hydrazinobenzenesulfonamide hydrochloride, thereby reducing the risk of industrial production. The method has the advantages of short synthesis steps, one-pot method, simple and easily available raw materials and mild reaction conditions, and is suitable for amplification of chemical production.
Further hit optimization of 6-(trifluoromethyl)pyrimidin-2-amine based TLR8 modulators: Synthesis, biological evaluation and structure–activity relationships
Dol?ak, Ana,?ribar, Dora,Scheffler, Alexander,Grabowski, Maria,?vajger, Urban,Gobec, Stanislav,Holze, Janine,Weindl, Günther,Wolber, Gerhard,Sova, Matej
, (2021/09/06)
Toll-like receptor 8 (TLR8) is an endosomal TLR that has an important role in the innate human immune system, which is involved in numerous pathological conditions. Excessive activation of TLR8 can lead to inflammatory and autoimmune diseases, which highlights the need for development of TLR8 modulators. However, only a few small-molecule modulators that selectively target TLR8 have been developed. Here, we report the synthesis and systematic investigation of the structure–activity relationships of a series of novel TLR8 negative modulators based on previously reported 6-(trifluoromethyl)pyrimidin-2-amine derivatives. Four compounds showed low-micromolar concentration-dependent inhibition of TLR8-mediated signaling in HEK293 cells. These data confirm that the 6-trifluoromethyl group and two other substituents on positions 2 and 4 are important structural elements of pyrimidine-based TLR8 modulators. Substitution of the main scaffold at position 2 with a methylsulfonyl group or para hydroxy/hydroxymethyl substituted benzylamine is essential for potent negative modulation of TLR8. Our best-in-class TLR8-selective modulator 53 with IC50 value of 6.2 μM represents a promising small-molecule chemical probe for further optimization to a lead compound with potent immunomodulatory properties.
In Cellulo Generation of Fluorescent Probes for Live-Cell Imaging of Cylooxygenase-2
Kaur, Jatinder,Bhardwaj, Atul,Wuest, Frank
supporting information, p. 3326 - 3337 (2020/12/09)
Live-cell imaging with fluorescent probes is an essential tool in chemical biology to visualize the dynamics of biological processes in real-time. Intracellular disease biomarker imaging remains a formidable challenge due to the intrinsic limitations of conventional fluorescent probes and the complex nature of cells. This work reports the in cellulo assembly of a fluorescent probe to image cyclooxygenase-2 (COX-2). We developed celecoxib-azide derivative 14, possessing favorable biophysical properties and excellent COX-2 selectivity profile. In cellulo strain-promoted fluorogenic click chemistry of COX-2-engaged compound 14 with non/weakly-fluorescent compounds 11 and 17 formed fluorescent probes 15 and 18 for the detection of COX-2 in living cells. Competitive binding studies, biophysical, and comprehensive computational analyses were used to describe protein-ligand interactions. The reported new chemical toolbox enables precise visualization and tracking of COX-2 in live cells with superior sensitivity in the visible range.
Neuroprotective effect of novel celecoxib derivatives against spinal cord injury via attenuation of COX-2, oxidative stress, apoptosis and inflammation
An, Yan,Fan, Mingxing,Li, Jianing,Liu, Yajun
, (2020/07/07)
A novel series of celecoxib derivatives were synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities for benefit in spinal cord injury (SCI). The title compounds were synthesized by conventional methods in good yields and subsequently tested for inhibitory activity against COX-1/COX-2. The most potent COX-2 inhibitor among the tested derivatives was further assayed for protective effect against experimental SCI of Sprague-Dawley rats. The designed compounds showed considerable inhibition of COX-2 as compared to COX-1 revealing compound 7m as most potent inhibitor of COX-2 isoenzyme (IC50 = 0.04 μM). The expression of mitochondrial apoptotic genes (Bcl-2 and Bax) together with COX-2 and iNOS was restored near to normal as evidenced by western blot analysis in SCI rats. Taken altogether, compound 7m was identified as most potent inhibitor of COX-2. It also showed protective action against SCI via attenuation of COX-2, oxidative stress and apoptosis and inflammation in Male Sprague-Dawley rats.
Synthesis, crystal structure and antitumor activity of 3-(2,4-dichlorophenyl)-2-phenyl-5-(p-tolyl)-7-(trifluoromethyl)pyrazolo[1,5-A]pyrimidine
Liu, Jin,Zhao, Juan,Lu, Jiu-Fu
, p. 591 - 596 (2021/02/26)
The title compound, 3-(2,4-dichlorophenyl)-2-phenyl-5-(p-tolyl)- 7-(trifluoromethyl)pyrazolo[1,5-a] pyrimidine (C26H16C12F3N3, Mr = 498.32) has been synthesized by condensation of 4,4,4-trifluoro-1-(p-tolyl)butane- 1,3-dione with 4-(2,4-dichlorophenyl)-3-phenyl-1H-pyrazol-5-amine. The latter was prepared from 2,4-dichlorophenylaceton itrile and ethyl benzoate through Claisen condensation and then cyclization with hydrazine hydrate. The crystal structure of the title compound was determined. In addition, the title compound possesses marked inhibition against the proliferation of human lung adenocarcinoma cell line A549 and human gastric cancer cell line MKN45, displaying promising anticancer activities.
Development of celecoxib-derived antifungals for crop protection
Liu, Xiuxiu,Ma, Yihui,Sun, Xianglong,Yang, Jun,Yang, Lirong
, (2020/02/27)
Selective COX-2 inhibitor celecoxib was found directly inhibiting the growth of tested phytopathogenic fungi with the inhibitory rate ranging from 30 to 40% at 100 μg/ml. Lead optimization of celecoxib led to the identification of compound 12 among its derivatives as the most active antifungal candidate. The antifungal effect of compound 12 was supposed to be independent of COX-2 inhibition. Transcriptome profiling analysis of Fusarium graminearium (PH-1) treated with compound 12 brought about 406 up-regulated and 572 down-regulated differentially express genes (DEGs) respectively.
Preparation method of celecoxib
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Paragraph 0014; 0021, (2020/07/13)
A preparation method of celecoxib comprises the following steps: preparing CEL-A completion liquid, preparing a crude dry celecoxib product, and purifying, drying and crushing the crude dry celecoxibproduct. The celecoxib product prepared by the method has the advantage of high purity.
Preparation method of high-purity celecoxib
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Paragraph 0013; 0014; 0016; 0017; 0019; 0020, (2020/02/14)
The invention discloses a preparation method of high-purity celecoxib. According to the preparation method, a p-methylbenzoyl halide and trifluoroacetone are reacted under the action of an alkali to generate 4, 4, 4-trifluoro-1-(4-methylphenyl)-1, 3-butanedione, and then 4, 4, 4-trifluoro-1-(4-methylphenyl)-1, 3-butanedione is reacted with p-aminosulfonylphenylhydrazine/hydrochloride in an acidicaqueous solution to obtain high-purity celecoxib. According to the invention, the reaction time required for preparing celecoxib is greatly reduced, and the reaction period is only 20-30% of the original reaction period; reaction conditions are mild, and few isomer impurities are generated in the reaction; the output of three wastes is greatly reduced, and the generated wastewater is very easy totreat; and various impurities in the reaction can be effectively controlled without recrystallization.
CONTINUOUS PROCESSES FOR THE MANUFACTURE OF CELOCOXIB
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Page/Page column 12-16, (2019/04/26)
A continuous process for the manufacture of celecoxib includes reacting a stream of a first solution of 4'-methylacetophenone in a first organic solvent and a stream of a second solution of ethyl trifluoroacetate in a second organic solvent in a first reactor in the presence of a base at a first reaction temperature of between 45°C and 90°C and at a first reaction pressure to form 4,4,4-Trifluoro-1-(4-methylphenyl)butane-1,3-dione. The first reaction pressure prevents boiling inside the first reactor. A stream of a first reactor product from the first reactor is continuously withdrawn, the first reactor product including a solution of 4,4,4-Trifluoro-1-(4-methylphenyl)butane-1,3-dione in the first organic solvent and the second organic solvent. A stream of the first reactor product and a stream of a third solution of (4-Sulfamoylphenyl)hydrazine hydrochloride in a third organic solvent are reacted in a second reactor at a second reaction temperature of between 80°C and 110°C and at a second reaction ressure to form celecoxib. The second reaction pressure prevents boiling inside the second reactor. A stream of a second reactor product is continuously withdrawn from the second reactor, the second reactor product including a solution of celecoxib in organic solvent.
Method for preparing Celecoxib dione intermediate
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Paragraph 0019-0025, (2019/11/20)
The invention provides a method for preparing a Celecoxib dione intermediate. The method comprises the steps: subjecting p-methylacetophenone and ethyl trifluoroacetate to a reaction in the presence of sodium methylate, wherein toluene serves as a solvent, and a reaction temperature is 20 DEG C to 40 DEG C; carrying out quenching with a hydrochloric solution after the reaction is complete, then, carrying out washing with purified water, and carrying out standing to separate out an aqueous phase; and subjecting an organic phase to cooling crystallization, thereby obtaining a yellowish solid product. According to the method provided by the invention, the safety of industrial production of the Celecoxib dione intermediate can be improved, the process is very convenient, and meanwhile, the purity and yield of the product are not lowered.
