cas 169590-42-5, Celecoxib | Articles data

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Bioorthogonal release of sulfonamides and mutually orthogonal liberation of two drugs
Sulfonamide derivatives have been used in pharmaceutics for decades. Here we report a new approach to release sulfonamides efficiently using a bioorthogonal reaction of sulfonyl sydnonimines and dibenzoazacyclooctyne (DIBAC). The second-order rate constant of the cycloaddition reaction can be up to 0.62 M-1 s-1, and the reactants are highly stable under physiological conditions. Most significantly, we also discovered the mutual orthogonality between the sydnonimine-DIBAC and benzonorbornadiene-tetrazine cycloaddition pairs, which can be used for selective and simultaneous liberation of sulfonamide and primary amine drugs.
Shao, Zhuzhou,Liu, Wei,Tao, Huimin,Liu, Fang,Zeng, Ruxin,Champagne, Pier Alexandre,Cao, Yang,Houk,Liang, Yong
p. 14089 - 14092
(2018)
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Synthesis of celecoxib via 1,3-dipolar cycloaddition
A regioselective 1,3-dipolar cycloaddition reaction between a nitrile imine and an enamine is described for the preparation of celecoxib. Nitrile imines are generated in situ from the corresponding hydrazonoyl benzenesulfonates.
Oh, Lynette M.
p. 7943 - 7946
(2006)
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Synthesis of [11C]celecoxib: A potential PET probe for imaging COX-2 expression
[11C]Labeling of celecoxib, a COX-2 selective inhibitor and prescription drug for arthritis and pain has been achieved. The precursor molecule for the radiolabeling was synthesized from 4-bromoacetophenone in 4 steps with 23% overall yield. Stille reaction of N-[bis-(4-methoxyphenyl) phenylmethyi]-4-[5-(4-tributylstannylphenyl)-3-trifluoromethylpyrazol-1-yl] benzenesulfonamide (5) with methyl iodide in presence of catalytic amounts of Pd2(dba)3, tri-o-tolylphosphine, CuCl and excess of K 2CO3 in DMF followed by deprotection of the sulfonamide with 20% trifluoroaceticacid yielded 4-(5-p-tolyl-3-trifluoromethylpyrazol-1-yl) benzenesulfonamide or celecoxib (6) in 30% yield. However, under identical conditions, synthesis of [11C]celecoxib ([11C]6) was unsuccessful. Instead, trapping [11C]CH3I in an argon purged solution of catalytic amounts of Pd2(dba)3 and tri-o-tolylphosphine followed by the addition of the precursor 5 in DMF under argon and heating the mixture at 135°C for 4 min resulted in the incorporation of [11C]CH3 group. Removal of the dimethoxytrityl (DMT) with 20% trifluoroacetic acid afforded [ 11C]celecoxib in 40 min (EOB) and 8 ± 2% yield (EOB) along with a specific activity of 1080 ± 180 Ci/mmol (n = 6) (EOB). Copyright
Prabhakaran, Jaya,Majo, Vattoly J.,Simpson, Norman R.,Van Heertum, Ronald L.,Mann, J. John,Kumar, J. S. Dileep
p. 887 - 895
(2005)
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4-Ethoxy-1,1,1-trifluoro-3-buten-2-one (ETFBO), a Versatile Precursor for Trifluoromethyl-Substituted Heteroarenes - A Short Synthesis of Celebrex (Celecoxib)
4-Ethoxy-1,1,1-trifluoro-3-buten-2-one (ETFBO) serves as a trifluoromethyl-containing building block for the preparation of trifluoromethyl-substituted thiophenes, furans, pyrrols, and piperazines. Key steps are an addition-elimination reaction to ETFBO followed by the thiazolium-catalyzed Stetter reaction. The scope of this chemistry was demonstrated in a new synthetic approach towards the COX-2 selective, nonsteroidal anti-inflammatory drug Celebrex (celecoxib).
Sommer, Heiko,Braun, Max,Schr?der, Benjamin,Kirschning, Andreas
p. 121 - 125
(2018)
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Design and synthesis of novel celecoxib analogues as selective cyclooxygenase-2 (COX-2) inhibitors: Replacement of the sulfonamide pharmacophore by a sulfonylazide bioisostere
A group of celecoxib analogues in which the para-SO2NH 2 substituent on the N1-phenyl ring was replaced by a para-sulfonylazido (SO2N3) 4, or a meta-SO 2N3 8, substituent were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that 4-[5-(4-methylphenyl)-3-trifluoromethyl-1H- pyrazol-1-yl]benzenesulfonyl azide (4) with a para-SO2N3 substituent was a selective COX-1 inhibitor. In contrast, 3-[5-(4-methylphenyl)- 3-trifluoromethylpyrazol-1-yl]benzenesulfonyl azide (8a) having a meta-SO 2N3 substituent (COX-1 IC50 >100 μM; COX-2 IC50=5.16 μM; COX-2 selectivity index >19.3) is a selective COX-2 inhibitor. A molecular modeling (docking) study showed that the SO2N3 group of 8a inserts deep inside the secondary pocket of the COX-2 binding site. The SO2N3 moiety of 8a can undergo a dual H-bonding interaction via one of its SO2 oxygen-atoms, and an electrostatic (ion-ion) interaction via the terminal azido (N3) nitrogen-atom, to the guanidino NH2 of Arg 513 in the secondary pocket of COX-2. These observations indicate that an appropriately positioned SO2N3 moiety is a novel alternative bioisostere to the traditional SO2NH2 and SO2Me pharmacophores present in selective COX-2 inhibitors, that are only capable of H-bonding interactions with the COX-2 isozyme, for use in drug design.
Uddin, Md. Jashim,Rao, P.N. Praveen,Knaus, Edward E.
p. 5273 - 5280
(2003)
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An improved and scalable process for celecoxib: A selective cyclooxygenase-2 inhibitor
An improved, scalable and commercially viable process is developed for an active pharmaceutical ingredient, celecoxib.
Reddy, Anumula Raghupathi,Sampath, Alla,Goverdhan, Gilla,Yakambaram, Bojja,Mukkanti, Kagga,Reddy, Padi Pratap
p. 98 - 101
(2009)
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Application of (MWCNTs)-COOH/CeO2 hybrid as an efficient catalyst for the synthesis of some nitrogen-containing organic compounds
ABSTRACT: Modification of acid functionalized multi-walled carbon nanotubes (MWCNTs)-COOH with CeO2 nanoparticles using Ce(NO3)2.6H2O, produced an efficient catalyst for the synthesis of some nitrogen-containing heterocycles such as celecoxib. The products were identified by CHN analysis, NMR, and FT-IR spectra. On the other hand, synthesis of CeO2 nanoparticles and their conjugation on the surface of (MWCNTs)-COOH have been confirmed by FT-IR, scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and Energy-dispersive X-ray spectroscopy (EDX).
Heidarzadeh, Tahereh,Nami, Navabeh,Zareyee, Daryoush
(2021/08/18)

Copper-Catalyzed Reductive Ring-Cleavage of Isoxazoles: Synthesis of Fluoroalkylated Enaminones and Application for the Preparation of Celecoxib, Deracoxib, and Mavacoxib
We have identified a new reactivity of copper/diamine catalysis for the reductive ring-cleavage of isoxazoles to yield fluoroalkylated enaminones. This protocol has the advantage of using commercially available reagents, ease of setting up, broad tolerance of functionality, and is regiospecific and free of defluorination and reduction of reducible functional groups. The utility was demonstrated by a one-step, regioselective synthesis of fluoroalkylated pyrazole-based drugs such as celecoxib, deracoxib, and mavacoxib.
Wan, Chao,Pang, Jian-Yu,Jiang, Wei,Zhang, Xiao-Wei,Hu, Xiang-Guo
p. 4557 - 4566
(2021/03/01)

Rapid Access to N-Protected Sulfonimidoyl Fluorides: Divergent Synthesis of Sulfonamides and Sulfonimidamides
Herein we report a practical and efficient copper-catalyzed approach for the conversion of various arenediazonium salts to the corresponding N-protected sulfonimidoyl fluorides. This operationally simple protocol tolerates a wide range of functional groups and can be applied to the late-stage modification of complex bioactive molecules. Furthermore, pharmaceutically important primary sulfonamides and sulfonimidamides derived from these valuable N-protected sulfonimidoyl fluoride units were prepared in minimal synthetic steps.
Liu, Yongan,Pan, Qijun,Hu, Xiaojun,Guo, Yong,Chen, Qing-Yun,Liu, Chao
p. 3975 - 3980
(2021/05/26)

Nickel(II)-Catalyzed Addition of Aryl and Heteroaryl Boroxines to the Sulfinylamine Reagent TrNSO: The Catalytic Synthesis of Sulfinamides, Sulfonimidamides, and Primary Sulfonamides
We report a redox-neutral Ni(II)-catalyzed addition of (hetero)aryl boroxines to N-sulfinyltritylamine (TrNSO). The reactions use a catalyst generated from the combination of commercial, air-stable NiCl2·(glyme) and a commercially available bipyridine lig
Lo, Pui Kin Tony,Willis, Michael C.
p. 15576 - 15581
(2021/10/02)

A CONTINUOUS FLOW MICRO-TOTAL PROCESS SYSTEM FOR PREPARATION OF CELECOXIB AND ANALOGS THEREOF
The present invention relates to preparation of pyrazoles. This invention further relates to a continuous flow micro-total process system for preparation of celecoxib, a COX-2 selective non-steroidal anti-inflammatory drug, and analogs thereof.
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Page/Page column 16-17

(2020/08/22)

Preparation method of celecoxib
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.
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Paragraph 0014; 0021

(2020/07/13)

Preparation method of high-purity celecoxib
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.
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Paragraph 0013; 0015; 0016; 0018; 0019; 0021

(2020/02/14)

HFO-1234yf as a CF3-Building Block: Synthesis and Chemistry of CF3-Ynones
Reaction of low cost, readily available 4th generation refrigerant gas 2,3,3,3-tetrafluoropropene (HFO-1234yf) with lithium diisopropylamide (LDA) leads to formation of lithium 3,3,3-trifluoropropynide, addition of which to a range of aldehydes formed CF3-alkynyl alcohol derivatives on multigram scale, which were oxidised using Dess–Martin periodinane (DMP) to give substituted CF3-ynones with minimal purification required. Michael-type additions of alcohol and amine nucleophiles to CF3-ynones are rapid and selective, affording a range of CF3-enone ethers and enaminones in excellent yields with high stereoselectivity for the Z-isomer. By analogous reactions with difunctional nucleophiles, a wide range of CF3-substituted pharmaceutically relevant heterocyclic structures can be accessed, exemplified in the simple synthesis of the anti-arthritis drug celecoxib from HFO-1234yf in just three steps.
Murray, Ben J.,Marsh, Thomas G. F.,Yufit, Dmitri S.,Fox, Mark A.,Harsanyi, Antal,Boulton, Lee T.,Sandford, Graham
p. 6236 - 6244
(2020/09/15)

Cycloaddition of Trifluoroacetaldehyde N-Triftosylhydrazone (TFHZ-Tfs) with Alkynes for Synthesizing 3-Trifluoromethylpyrazoles
A transition-metal-free [3 + 2] cycloaddition between trifluoroacetaldehyde N-triftosylhydrazone (TFHZ-Tfs) and alkynes is reported. This protocol provides an operationally simple and general method for the synthesis of diverse 3-trifluoromethylpyrazoles in good to excellent yields with broad substrate scope, including aryl, heteroaryl, and alkyl terminal alkynes, and electron-deficient internal alkynes. The synthetic potential of this method was further demonstrated by the synthesis of an antiarthritic drug Celecoxib in multigram scale.
Wang, Hongwei,Ning, Yongquan,Sun, Yue,Sivaguru, Paramasivam,Bi, Xihe
supporting information
p. 2012 - 2016
(2020/03/04)

Primary Sulfonamide Synthesis Using the Sulfinylamine Reagent N-Sulfinyl- O-(tert-butyl)hydroxylamine, t-BuONSO
Sulfonamides have played a defining role in the history of drug development and continue to be prevalent today. In particular, primary sulfonamides are common in marketed drugs. Here we describe the direct synthesis of these valuable compounds from organometallic reagents and a novel sulfinylamine reagent, t-BuONSO. A variety of (hetero)aryl and alkyl Grignard and organolithium reagents perform well in the reaction, providing primary sulfonamides in good to excellent yields in a convenient one-step process.
Davies, Thomas Q.,Hall, Adrian,Skolc, David,Tilby, Michael J.,Willis, Michael C.
supporting information
p. 9495 - 9499
(2020/12/21)

One-Pot Synthesis of Indoles and Pyrazoles via Pd-Catalyzed Couplings/Cyclizations Enabled by Aqueous Micellar Catalysis
An effective one-pot synthesis of either indoles or pyrazoles can be achieved via Pd-catalyzed aminations followed by subsequent cyclizations facilitated by aqueous micellar catalysis. This new technology includes efficient couplings with low loadings of palladium, a more stable source of the required hydrazine moiety, greater atom economy for the initial coupling, and reduced reaction temperatures, all leading to environmentally responsible processes.
Akporji, Nnamdi,Braga, Felipe C.,Gabriel, Christopher M.,Landstrom, Evan B.,Lee, Nicholas R.,Lipshutz, Bruce H.
supporting information

(2020/09/02)

Preparation method of celecoxib
The invention provides an efficient preparation method of 4-[3-trifluoromethyl-5-(4-methylphenyl)-1H-pyrazolyl]benzenesulfonamide (celecoxib). The method comprises the following steps of: taking 1, 1,1-trifluoro-4-methylphenyl butenone as a raw material, adding dilute acid and 4-aminosulfonylphenylhydrazine hydrochloride into methanol and water, and performing heating to obtain celecoxib. The method has the characteristics of mild reaction conditions, simple operation, high product yield and purity, and few isomers, and is suitable for industrial production.
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Paragraph 0018-0025

(2020/06/20)

Synthetic method of celecoxib
The invention provides a synthetic route and a preparation method of celecoxib. According to the method, hydrazine hydrate which is low in price and easy to obtain is used as a raw material in the first-step reaction, green and environment-friendly water is used as a solvent, the synthesis yield is high, and aftertreatment is easy and convenient, in the second-step reaction, a compound shown as the formula IV is prepared through aromatic nucleophilic substitution reaction (SNAr), so that the use of a heavy metal catalyst is avoided, the selectivity is high, the generation of byproducts of position isomerism is reduced, and the yield is relatively high. The method has the advantages of simple operation, convenient separation and purification of each step, high yield and good product quality, and can be used for large-scale industrial preparation of the celecoxib.
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Paragraph 0041-0048

(2020/08/18)

CONTINUOUS PROCESSES FOR THE MANUFACTURE OF CELOCOXIB
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.
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Page/Page column 15-17

(2019/04/26)

An Integrated Continuous Flow Micro-Total Ultrafast Process System (μ-TUFPS) for the Synthesis of Celecoxib and Other Cyclooxygenase Inhibitors
Integrated continuous manufacturing has emerged as a promising device for the rapid manufacturing of active pharmaceutical ingredients (APIs). We herein report a newly designed continuous flow micro-total process system platform for the rapid manufacturing of celecoxib, a selective nonsteroidal anti-inflammatory drug. This approach has been proven generally for the synthesis of several alkyl and aryl substituted pyrazoles. In order to minimize the tedious work-up process of potential reaction intermediates/products, we have developed a continuous flow extraction and separation platform to carry out the entire reaction sequence resulting in a short residence time with good yield. The present process was further extended to gram-scale synthesis of the COX-2-related API, viz. celecoxib, in the continuous flow process.
Sthalam, Vinay Kumar,Singh, Ajay K.,Pabbaraja, Srihari
supporting information
p. 1892 - 1899
(2019/10/11)

Preparation method of celecoxib
The invention belongs to the technical field of medicines and in particular relates to a preparation method of celecoxib. The preparation method comprises the following steps: A, adding 4-sulfonamidophenylhydrazine hydrochloride and trifluoroacetaldehyde into a solvent, and carrying out a reaction to obtain 4-(2-(2,2,2-trifluoroethylene)hydrazino)benzenesulfonamide, wherein a reaction equation isas follows; B, adding 1-(1-bromovinyl)-4-toluene and alkali into 4-(2-(2,2,2-trifluoroethylene)hydrazino)benzenesulfonamide obtained by the reaction in the step A, and carrying out a reaction to obtain crude celecoxib; and C, adding the crude celecoxib obtained by the reaction in the step B into a solvent, dissolving the crude celecoxib under the temperature condition of 70-90 DEG C, carrying outactivated carbon decoloration, carrying out filtration, then, further raising the temperature to 90 DEG C, clearing the solvent, then, naturally reducing the temperature to separate out a crystal to obtain fine celecoxib. The method disclosed by the invention is mild in reaction condition, simple in operation, environment-friendly, high in product yield and suitable for industrial production.
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Paragraph 0030; 0032; 0033; 0034; 0036; 0037; 0038; 0040

(2019/02/08)

Synthesis of pyrazolones and pyrazoles via Pd-catalyzed aerobic oxidative dehydrogenation
A palladium-catalyzed oxidative dehydrogenation reaction in the presence of AMS and base to synthesize pyrazolones and pyrazoles was identified. This method can be utilized to a wide range of substrates, operates under mild react conditions and can give high yields. We believe it could be used as an alternative protocol for the classical dehydrogenation reactions.
Zhu, Ye-Fu,Wei, Bo-Le,Wei, Jiao-Jiao,Wang, Wen-Qiong,Song, Wei-Bin,Xuan, Li-Jiang
supporting information
p. 1202 - 1205
(2019/03/29)

Synthesis of Air-stable, Odorless Thiophenol Surrogates via Ni-Catalyzed C?S Cross-Coupling
Thiophenols are versatile synthetic intermediates whose practical appeal is marred by their air sensitivity, toxicity and extreme malodor. Herein we report an efficient catalytic method for the preparation of S-aryl isothiouronium salts, and demonstrate that these air-stable, odorless solids serve as user-friendly sources of thiophenols in synthesis. Diverse isothiouronium salts featuring synthetically useful functionality are readily accessible by nickel-catalyzed C?S cross-coupling of (hetero)aryl iodides and thiourea. Convenient, chromatography-free isolation of these salts is achieved by precipitation, allowing the methodology to be applied directly to large scales. Thiophenols are liberated from the corresponding isothiouronium salts upon treatment with a weak base, enabling an in situ release/S-functionalization strategy that entirely negates the need to isolate, purify or manipulate these noxious reagents.
Magné, Valentin,Ball, Liam T.
p. 8903 - 8910
(2019/06/17)

Preparation method of celecoxib
The invention relates to a preparation method of celecoxib, and belongs to the technical field of preparation methods of bulk drugs. The preparation method of the celecoxib comprises the following steps: firstly, reacting 4-hydrazinobenzenesulfonamide of formula II with acetaldehyde to obtain a reaction solution containing a compound of formula III; secondly, adding p-methylbenzoyl chloride of formula IV into the reaction solution obtained in the first step to obtain a reaction solution of formula V; adding ethanol hydrochloride into the reaction solution obtained in the second step to obtaina compound VI, and cyclizing the compound VI with 1, 1, 1-trifluoroacetone to generate the celecoxib. By change of a ring mode, generation of regional isomer impurities is avoided. According to the preparation method, upper protection, condensation and deprotection are carried out by using one-pot reaction, the reaction conditions are mild, after-treatment operation is simple and convenient, the total yield can reach 90% or above, and the celecoxib is suitable for large-scale industrial production.
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Paragraph 0025-0052

(2019/12/25)

Copper-Catalyzed Trifluoromethylation of Alkyl Bromides
Copper oxidative addition into organohalides is a challenging two-electron process. In contrast, formal oxidative addition of copper to C sp2 carbon-bromine bonds can be accomplished by employing latent silyl radicals under photoredox conditions. This novel paradigm for copper oxidative addition has now been applied to a Cu-catalyzed cross-coupling of C sp3-bromides. Specifically, a copper/photoredox dual catalytic system for the coupling of alkyl bromides with trifluoromethyl groups is presented. This operationally simple and robust protocol successfully converts a variety of alkyl, allyl, benzyl, and heterobenzyl bromides into the corresponding alkyl trifluoromethanes.
Kornfilt, David J.P.,Macmillan, David W.C.
supporting information
p. 6853 - 6858
(2019/05/10)

Sulfonamide compound and synthesis method and application thereof
The invention discloses a synthesis method of a sulfonamide compound represented in a formula (2). According to the method, diazonium salt is used as a reaction raw material, and under the action of an inorganic nitrogen reagent, an inorganic sulfur dioxide reagent, an additive and a phosphine reagent, the diazonium salt is reacted in a solvent at 60-100 DEG C to obtain various sulfonamide compounds. According to the method inorganic salt is used as a nitrogen atom source and a sulfur dioxide source under a metal-free catalytic condition to construct the sulfonamide compound through one step,thereby avoiding the conventional multi-step synthesis of sulfonamide by condensing unstable acid chloride and amine; and the developed sulfonamide synthesis method can be further applied to the synthesis of the arthritis drug celecoxib and the psychotropic drug sulpiride.
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Paragraph 0142-0145

(2019/04/02)

Mild and Regioselective Synthesis of 3-CF3-Pyrazoles by the AgOTf-Catalysed Reaction of CF3-Ynones with Hydrazines
Gold- and silver-catalysed reactions of trifluoromethylated ynones with aryl (alkyl) hydrazines were investigated. The use of (THD-Dipp)AuOTf and AgOTf resulted in quick heterocyclization reactions to selectively give 3-CF3-pyrazoles. AgOTf was found to be the catalyst of choice, and various 3-CF3-pyrazoles were formed in up to 99 % isolated yield with high regioselectivity. The reaction has a broad scope: 3-CF3-pyrazoles with alkyl and aryl substituents as well as different functional groups can be prepared by this approach. The known pyrazole drugs Celebrex and SC-560 were efficiently prepared to demonstrate the utility of the method. Mechanistic investigations revealed that the reaction involves the formation of a hemiaminal as a key intermediate.
Topchiy, Maxim A.,Zharkova, Daria A.,Asachenko, Andrey F.,Muzalevskiy, Vasiliy M.,Chertkov, Vyacheslav A.,Nenajdenko, Valentine G.,Nechaev, Mikhail S.
supporting information
p. 3750 - 3755
(2018/07/31)

Metal-free construction of primary sulfonamides through three diverse salts
In this report, the first metal-free construction of primary sulfonamides through a direct three-component reaction of sodium metabisulfite, sodium azide and aryldiazonium has been established. Readily available inorganic Na2S2O5 and NaN3 were applied as the sulfur dioxide surrogate and nitrogen source respectively. The widely used sulfonamide drugs Celecoxib and Sulpiride, which possess multiple heteroatoms and active hydrogen containing functional groups, are efficiently installed with -SO2NH2 groups at a late stage. Control experiments and kinetic studies demonstrated that aryl radicals, sulfonyl radicals and conjugated phosphine imine radicals are involved in this transformation.
Wang, Ming,Fan, Qiaoling,Jiang, Xuefeng
supporting information
p. 5469 - 5473
(2019/01/03)

Method for preparing celecoxib by using one-pot method
The invention discloses a method for preparing celecoxib by using a one-pot method. The method comprises the following steps: in the presence of ethidene diamine, mixing p-methylacetophenone and ethyltrifluoroacetate, and enabling the components to react completely at 40-80 DEG C without other solvent so as to obtain a reaction liquid of an intermediate DO; putting the reaction liquid into an alcohol solvent, further adding bihydrazino-benzsulfamide hydrochloride, further adding an organic acid to adjust the pH value to 3-6, controlling the temperature of a material liquid to 50-80 DEG C, andenabling the components to react completely; after the reaction is completed, adding water, cooling to 10-30 DEG C to separate out a crystal, and carrying out suction filtration so as to obtain a crude product of celecoxib; dissolving the crude product with methanol, dropping the material liquid into water, controlling the temperature of the material liquid to 40-50 DEG C in the dropping process,cooling to 10-30 DEG C to separate out a crystal after dropping is completed, and carrying out suction filtration, thereby obtaining a finished product of celecoxib. The total yield of the product prepared by using the method is greater than 85%, and HPLC (High Performance Liquid Chromatography) tests show that the purity of the product is greater than or equal to 99.90%.
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Paragraph 0031; 0034; 0035; 0036; 0037; 0038; 0043; 0045

(2018/10/19)

Selective Methylation of Arenes: A Radical C?H Functionalization/Cross-Coupling Sequence
A selective, nonchelation-assisted methylation of arenes has been developed. The overall transformation, which combines a C?H functionalization reaction with a nickel-catalyzed cross-coupling, offers rapid access to methylated arenes with high para selectivity. The reaction is amenable to late-stage methylation of small-molecule pharmaceuticals.
Serpier, Fabien,Pan, Fei,Ham, Won Seok,Jacq, Jér?me,Genicot, Christophe,Ritter, Tobias
p. 10697 - 10701
(2018/07/31)

Preparation method of celecoxib impurity B
The invention discloses a preparation method of celecoxib impurity B. According to the method, the content of the impurity B is increased to be more than 25% through a synthetic method, and then the impurity is purified until the purity is more than 99% through the application of a supercritical fluid chromatography separation technology.
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Paragraph 0040; 0042; 0045

(2018/03/24)

Synthesis of Celecoxib, Mavacoxib, SC-560, Fluxapyroxad, and Bixafen Enabled by Continuous Flow Reaction Modules
Multi-step continuous flow synthesis enables a parallel approach to obtain agrochemicals and pharmaceuticals containing 3-fluoroalkyl pyrazole cores. In this system, fluorinated amines are transformed into pyrazole cores through a telescoped in situ generation and consumption of diazoalkanes. Once synthesized, additional continuous flow and batch reactions add complexity to the pyrazole core via C–N arylation and methylation, TMS cleavage, and amidation. Using this modular assembly line approach, Bixafen and Fluxapyroxad were synthesized in 38 % yield over four continuous flow steps in an overall reaction time of 56 min. Finally, coupling selected continuous flow processes with an offline (batch) Ullmann coupling afforded Celecoxib, Mavacoxib, and SC-560 in 33–54 % yield over two to three steps.
Britton, Joshua,Jamison, Timothy F.
supporting information
p. 6566 - 6574
(2017/12/02)

Selective, Metal-Free Approach to 3- or 5-CF3-Pyrazoles: Solvent Switchable Reaction of CF3-Ynones with Hydrazines
A detailed study of the reaction of trifluoroacetylated acetylenes and aryl (alkyl) hydrazines was performed, aimed to the regioselective synthesis of 3- or 5-trifluoromethylated pyrazoles. It was found that the regioselectivity of reaction depends dramatically on the solvent nature. Highly polar protic solvents (hexafluoroisopropanol) favor the formation of 3-trifluoromethylpyrazoles. In contrast, when the reaction was performed in polar aprotic solvents (DMSO), the formation of their 5-CF3-substituted isomers was preferentially observed. Alternatively, the regioselective assembly of 3-CF3-substituted pyrazoles can be performed via two-step one-pot procedure. The reaction of trifluoromethylated ynones with aryl (alkyl) hydrazines in the presence of acidic catalysts leads to formation of the corresponding hydrazones. The latter can be smoothly transformed into 3-CF3-pyrazoles by treatment with a base. This solvent-switchable procedure was used for the preparation of such important drugs as Celebrex and SC-560 as well as their isomers in gram scale. The possible reaction mechanism is discussed.
Muzalevskiy, Vasiliy M.,Rulev, Alexander Yu.,Romanov, Alexey R.,Kondrashov, Evgeniy V.,Ushakov, Igor A.,Chertkov, Vyacheslav A.,Nenajdenko, Valentine G.
p. 7200 - 7214
(2017/07/26)

A biodegradable impurity and its preparation method, application
The invention belongs to the field of medical chemistry, and particularly relates to a celecoxib impurity, as well as a preparation method and an application thereof as a celecoxib mass control reference standard. The chemical name of the impurity is 4-[5-(4-methyl phenyl)-3-(chlorodifluoromethyl)-1H-pyrazole-1- yl] benzsulfamide.
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Paragraph 0055; 0056; 0057

(2018/01/09)

ANTI-STAPHYLOCOCCAL CELECOXIB DERIVATIVES
A method of treating infection by Staphylococcus in a subject by administering a pharmaceutical composition including a celecoxib derivative of formula I or a pharmaceutically acceptable salt thereof is described. The preparation of numerous celecoxib derivatives for testing as potential anti-staphylococcal agents is also described.
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(2017/12/31)

Isotope labelling by reduction of nitriles: Application to the synthesis of isotopologues of tolmetin and celecoxib
The aryl methyl group is found in many drug-like compounds, but there are limited ways of preparing compounds with an isotope label in this methyl position. The process of cyanation of an aryl halide followed by complete reduction of the nitrile to a methyl group was investigated as a route for preparing stable and radiolabelled isotopologues of drug-like compounds. Using this methodology, carbon-13, deuterium, carbon-14, and tritium labelled isotopologues of the nonsteroidal anti-inflammatory drug tolmetin were produced, as well as carbon-13, deuterium, and carbon-14 labelled isotopologues of another nonsteroidal anti-inflammatory drug, celecoxib. The radiolabelled compounds were produced at high specific activity and the stable isotope labelled compounds with high incorporation making them suitable for use as internal standards in mass spectrometry assays. This approach provides a common synthetic route to multiple isotopologues of compounds using inexpensive and readily available labelled starting materials.
Ellis-Sawyer, Kate,Bragg, Ryan A.,Bushby, Nick,Elmore, Charles S.,Hickey, Michael J.
p. 213 - 220
(2017/04/10)

Oxygen Activated, Palladium Nanoparticle Catalyzed, Ultrafast Cross-Coupling of Organolithium Reagents
The discovery of an ultrafast cross-coupling of alkyl- and aryllithium reagents with a range of aryl bromides is presented. The essential role of molecular oxygen to form the active palladium catalyst was established; palladium nanoparticles that are highly active in cross-coupling reactions with reaction times ranging from 5 s to 5 min are thus generated in situ. High selectivities were observed for a range of heterocycles and functional groups as well as for an expanded scope of organolithium reagents. The applicability of this method was showcased by the synthesis of the [11C]-labeled PET tracer celecoxib.
Heijnen, Dorus,Tosi, Filippo,Vila, Carlos,Stuart, Marc C. A.,Elsinga, Philip H.,Szymanski, Wiktor,Feringa, Ben L.
p. 3354 - 3359
(2017/03/17)

A new crystalline form fills the past cloth A and its preparation method
The invention provides a novel crystal form A of celecoxib and a preparation method thereof. The novel crystal form of celecoxib is prepared by using isopropanol as a solvent system, subjecting a reaction solution to rapid cooling and crystallization and carrying out filtering and drying. The X-ray powder diffraction spectrum of the crystal form has characteristic diffraction peaks at positions where 2theta (DEG, +/- 0.2) is 5.42, 10.80, 13.10, 14.92, 16.18, 19.73, 21.60, 22.28, 27.06 and 29.68. The crystal form A has the advantages of good stability, convenience in production, transportation and storage, capability of meeting requirements for a preparation raw material, etc.
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Paragraph 0050; 0052; 0053

(2017/04/07)

A selective non-steroidal anti-inflammatory analgesics Celebrex ( fills the past cloth ) synthesis method
The invention relates to a synthesis method of a selective non-steroidal anti-inflammatory and analgesic drug Celebrex. Celebrex (with the structure shown in the specification) is synthesized by synthesizing the pyrazole ring of Celebrex through a [3+2] dipolar cycloaddition reaction of a compound 1 and a compound 2 under the common catalysis of copper sulfate and ascorbic acid. The method has the advantages of simple operation, mild reaction conditions and high yield, and is a new effective Celebrex synthesis method.
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Paragraph 0007; 0008

(2017/03/17)

A method for preparing fills the past cloth
The invention relates to a celecoxib preparation method. The method includes the following steps: 1, carrying out mixing dissolved clarification of celecoxib, an alcoholic solvent and ethyl acetate; and 2, adding the obtained dissolved clarified clear liquid into water, stirring for above 10min, filtering, washing with water, and drying. The invention also provides a synthesis method of celecoxib in step 1. Celecoxib prepared through the method in the invention overcomes the easy caking and large dissolution difference among capsules of celecoxib prepared in the prior art, and the obtained raw celecoxib has the advantages of difficult caking and small dissolution difference among capsules.
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Paragraph 0061-0062; 0068-0070

(2017/01/09)

An efficient route to 3-trifluoromethylpyrazole via cyclization/1,5-H shift and its applications in the synthesis of bioactive compounds
A methodology for regioselective synthesis of 3-trifluoromethylpyrazole from the reaction of trifluoromethyl alkenone and tosylhydrazone has been developed. The reaction was proposed to proceed through a tandem cyclization and 1,5-H shift reaction, which can be applied to the synthesis of bioactive compounds like Celecoxib, Mavacoxib, and SC-560.
Wang, Yongdong,Han, Jing,Chen, Jie,Cao, Weiguo
p. 8256 - 8262
(2015/10/05)

Synthesis of Functionalized Pyrazoles via Vanadium-Catalyzed C-N Dehydrogenative Cross-Coupling and Fluorescence Switch-On Sensing of BSA Protein
Vanadium-catalyzed C-N dehydrogenative cross-coupling of alkenyl hydrazones leading to functionalized pyrazoles is described in a 1:1 mixture of toluene/H2O using air as the terminal oxidant. Significant practical features include use of the commercial nontoxic VOSO4 as a recyclable catalyst, mild reaction conditions, scalability, and the broad substrate scope. Some of the product pyrazoles exhibit interesting photophysical properties. Fluorescence light-up sensing of BSA protein by one of the pyrazoles is also highlighted.
Sar, Dinabandhu,Bag, Raghunath,Yashmeen, Afsana,Bag, Subhendu Sekhar,Punniyamurthy, Tharmalingam
supporting information
p. 5308 - 5311
(2015/11/18)

Copper-Catalyzed Trifluoromethylalkynylation of Isocyanides
The title reaction proceeds with acetylenic triflones and isocyanides under mild conditions using copper as a catalyst. This transformation provides an efficient access to (E)-N-alkyl trifluoromethyl alkynyl ketoimines, which are useful building blocks for the synthesis of CF3-containing N-heterocycles, propargylamines, etc.
Lei, Jian,Wu, Xiaoxing,Zhu, Qiang
supporting information
p. 2322 - 2325
(2015/06/02)

Solvent- and transition metal catalyst-dependent regioselectivity in the [3+2]cyclocondensation of trifluoromethyl-α,β-ynones with hydrazines: Switchable access to 3- and 5-trifluoromethylpyrazoles
The regioselectivity of the [3+2]cyclocondensation of trifluoromethyl-α,β-ynones with hydrazines can be readily tuned to preferentially afford either 3- or 5-trifluoromethylpyrazoles through variation of the reaction conditions. Under catalysis with copper(II) acetate (2.0 mol%), cyclocondensation proceeded smoothly to yield 3-trifluoromethylpyrazoles with high regioselectivity. In contrast, when the reaction was conducted in dimethyl sulfoxide under catalyst-free conditions, the formation of 5-trifluoromethylpyrazoles was predominantly observed.
Hsieh, Min-Tsang,Kuo, Sheng-Chu,Lin, Hui-Chang
supporting information
p. 683 - 689
(2015/03/18)

A new efficient synthesis of pyrazoles from hydrazonoyl halides and β-oxophosphonates
A new practical and efficient synthesis of 1,3,5-trisubstituted pyrazoles has been developed by reacting of hydrazonoyl halides with β-oxophosphonates under mild conditions in good yields with excellent regioselectivity. This process employs an addition-elimination sequence. Wide scope, functional group compatibility has been established.
Sun, Aixue,Ye, Jia-Hai,Yu, Haitao,Zhang, Wenchao,Wang, Xiaolong
supporting information
p. 889 - 892
(2015/03/03)

NO-RELEASING NONOATE (NITROGEN-BOUND) SULFONAMIDE-LINKED-COXIB ANTI-CANCER AGENTS
The present invention provides NO-releasing NONOate(nitrogen bound)sulfonamide- linked-coxib anti-cancer agents, having the structure of Formula (I): wherein R1, X, L, R2, R3, R4, and Z are as defined in the detailed description; pharmaceutical compositions comprising at least one compound of Formula (I); and methods useful for healing wounds, preventing and treating cancer, or treating actinic keratosis, cystic fibrosis or acne, using a compound of Formula (I).
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Paragraph 00209; 00210

(2014/02/15)

A new efficient synthesis of pyrazoles from hydrazonoyl halides and β-oxophosphonates
A new practical and efficient synthesis of 1,3,5-trisubstituted pyrazoles has been developed by reacting of hydrazonoyl halides with β- oxophosphonates under mild conditions in good yields with excellent regioselectivity. This process employs an addition-elimination sequence. Wide scope, functional group compatibility has been established.
Sun, Aixue,Ye, Jia-Hai,Yu, Haitao,Zhang, Wenchao,Wang, Xiaolong
supporting information
p. 889 - 892
(2014/02/14)

One-pot oxidation and rearrangement of propargylamines and in situ pyrazole synthesis
Reported here are procedures for a one-pot oxidation and rearrangement of propargylamines to synthesize enaminones, with supporting mechanistic studies. Also reported are the extended one-pot syntheses of pyrazoles, including celecoxib and various heterocyclic compounds.
Chen, Jinshan,Properzi, Roberta,Uccello, Daniel P.,Young, Jennifer A.,Dushin, Russell G.,Starr, Jeremy T.
supporting information
p. 4146 - 4149
(2014/09/29)

Synthesis of 3-trifluoromethylpyrazoles via trifluoromethylation/ cyclization of α,β-alkynic hydrazones using a hypervalent iodine reagent
A mild and efficient method for the synthesis of 3-trifluoromethylpyrazoles has been established via trifluoromethylation/cyclization of α,β-alkynic hydrazones using a hypervalent iodine reagent under transition-metal-free conditions.
Ji, Guojing,Wang, Xi,Zhang, Songnan,Xu, Yan,Ye, Yuxuan,Li, Ming,Zhang, Yan,Wang, Jianbo
supporting information
p. 4361 - 4363
(2014/04/17)

Synthesis of novel dansyl-labeled Celecoxib derivatives
Four novel dansyl-labeled derivatives of Celecoxib, a cyclooxygenase-2 (COX-2) selective inhibitor, were designed and synthesized. To realize the fluorophore-linker-approach divergent and convergent synthetic strategies were applied. Therefore Celecoxib p-benzoic acid, 8, was synthesized in a new and convenient way. The yield and the synthetic route to Celecoxib, 1, its pyrazolylic acid, 7, and its pyrazolylic methyl ester, 6, were improved. Through a convenient synthesis 1,11-diamino-3,6,9-trioxundecane, 19, was obtained in high yield and purity and used as a linker for the dansyl moiety.
Lill, Andreas,Scholich, Klaus,Stark, Holger
supporting information
p. 6682 - 6686
(2013/11/19)

Silver-mediated cycloaddition of alkynes with CF3CHN 2: Highly regioselective synthesis of 3-trifluoromethylpyrazoles
Silver screen: The title reaction provides a convenient and efficient method for the construction of 5-substituted 3-trifluoromethylpyrazoles under mild reaction conditions. By using this protocol, the marketed drug Celecoxib (antiarthritic) could be easily synthesized (see scheme; DMF=N,N- dimethylformamide). Copyright
Li, Feng,Nie, Jing,Sun, Long,Zheng, Yan,Ma, Jun-An
p. 6255 - 6258
(2013/07/05)

A nitrophenyl-based prodrug type for colorectal targeting of prednisolone, budesonide and celecoxib
Celecoxib is a COX-2 inhibitor drug that can be used to reduce the risk of colorectal adenocarcinoma. Glucocorticoids are used in the treatment of inflammatory bowel disease. A limitation to the use of both drug types is that they undergo absorption from the intestinal tract with serious side effects. The prodrug systems introduced here involve forming a nitro-substituted acylsulfonamide group in the case of celecoxib and a nitro-substituted 21-ester for the glucocorticoids. Drug release is triggered by the nitro reductase action of the colonic microflora, liberating a cyclization competent species. The release of the active parent drugs was evaluated in vitro using Clostridium perfringens and epithelial transport through Caco-2 monolayer evaluation was carried out to estimate the absorption properties of the prodrugs compared to the parental drugs.
Marquez Ruiz, Juan F.,Kedziora, Kinga,Pigott, Maria,Keogh, Brian,Windle, Henry,Gavin, Jason,Kelleher, Dermot P.,Gilmer, John F.
p. 1693 - 1698
(2013/04/10)

Synthesis of tri- and tetrasubstituted pyrazoles via Ru(II) catalysis: Intramolecular aerobic oxidative C-N coupling
An unprecedented ruthenium(II)-catalyzed intramolecular oxidative C-N coupling method has been developed for the facile synthesis of a variety of synthetically challenging tri- and tetrasubstituted pyrazoles. Dioxygen gas is employed as the oxidant in this transformation. The reaction demonstrates excellent reactivity, functional group tolerance, and high yields.
Hu, Jiantao,Chen, Shi,Sun, Yonghui,Yang, Jing,Rao, Yu
supporting information
p. 5030 - 5033,4
(2012/12/12)