- Organophotoredox-Catalyzed C-H Alkylation of Imidazoheterocycles with Malonates: Total Synthesis of Zolpidem
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Organophotocatalytic C-H bond functionalization has attracted a lot of attention in the past several years due to the possibility of catalyzing reactions in a metal- and peroxide-free environment. Continuing on these lines, an organophotoredox-catalyzed C-H functionalization of imidazo[1,2- a ]pyridines and related heterocycles with bromomalonates under mild conditions is reported, providing excellent yields of the products at room temperature. This is the first report involving malonates as coupling partners leading to the synthesis of a range of functionalized products including total synthesis of zolpidem, a sedative-hypnotic drug molecule.
- Chaubey, Narendra R.,Kapdi, Anant R.,Maity, Biswanath
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- One-Pot Synthesis of C3-Alkylated Imidazopyridines from α-Bromocarbonyls under Photoredox Conditions
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A convenient strategy is presented for the synthesis of C3-alkylated imidazopyridines through one pot condensation and alkylation of α-bromocarbonyl compounds with 2-aminopyridines. A series of C3-alkylated imidazopyridines were obtained in moderate to hi
- Li, Jingyu,Liu, Ping,Sun, Peipei,Tong, Jinwen,Zhan, Yanling
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- Structure-based discovery of potent and selective small-molecule inhibitors targeting signal transducer and activator of transcription 3 (STAT3)
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STAT3 has been validated as an attractive anticancer target due to its important roles in cancer initiation and progression. However, discovery of potent and selective STAT3 small-molecule inhibitors with druglike properties is still challenging. In this study, two series of substituted 2-phenylquinolines and 2-arylimidazo[1,2-a]pyridines were designed through structure-based drug discovery approach by condensing the privileged structures of STX-119 and SH4-54. Our study has resulted in the discovery of a number of highly potent and selective STAT3 inhibitors, exemplified by compound 39 with the privileged structure of 2-phenylimidazo[1,2-a]pyridine, which selectively inhibits phosphorylation of STAT3 and suppresses subsequent signaling pathway. Moreover, 39 inhibits cell growth, migration and invasion of human triple negative breast cancer (TNBC) cells lines. Consistently, it achieves significant and dose-dependent tumor growth inhibition in both cell line-derived and patient-derived xenograft tumor models in mice. These results clearly indicate that 39 is a highly potent and selective STAT3 inhibitor.
- Huang, Qiuyao,Zhong, Yan,Li, Bingbing,Ouyang, Shumin,Deng, Lin,Mo, Jianshan,Shi, Shuo,Lv, Nan,Wu, Ruibo,Liu, Peiqing,Hu, Wenhao,Zhang, Xiaolei,Wang, Yuanxiang
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- Rhodium(II)-Catalyzed Regioselective C3-Alkylation of 2-Arylimidazo[1,2-a]pyridines with Aryl Diazoesters
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A regioselective C3-alkylation based on the reaction of 2-arylimidazo[1,2-a]pyridines with a wide range of aryl α-diazoesters in the presence of a Rh(II) catalyst in dichloroethane at room temperature was developed. This method could be applied in the synthesis of benzoimidazoquinolizinone and cycloheptaimidazopyridinone, which are novel heterocyclic scaffolds. (Figure presented.).
- Kim, Hyunseok,Byeon, Minhyeon,Jeong, Eunchong,Baek, Yonghyeon,Jeong, Seung Jin,Um, Kyusik,Han, Sang Hoon,Han, Gi Uk,Ko, Gi Hoon,Maeng, Chanyoung,Son, Jeong-Yu,Kim, Dongwook,Kim, Sung Hong,Lee, Kooyeon,Lee, Phil Ho
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p. 2094 - 2106
(2019/03/21)
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- A cyanogen methylation imidazopyridine compound of preparation method (by machine translation)
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The invention discloses a cyanogen methylation imidazopyridine compound of preparation method, in order to imidazo [1, 2 - a] pyridine compound as raw material, with the bromine second grade nitrile or [...] and under the action of the photocatalysis reaction, is obtained. Compared with the prior art, the method of the invention avoids the use of potassium cyanide or sodium cyanide and two connecting, iodomethane, and in the preparation of imidazo [1, 2 - a] pyridine compound of the cyanogen methylation product in the process, the chemical conversion from the original threestep shortened to step. The invention short preparation route, the preparation method is simple, the production cost is low, and the yield is high, have reduced the solvent to use and at the time of blowdown to the environment caused by pollution, easy to implement, easy to realize industrial. (by machine translation)
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Paragraph 0081; 0082
(2019/03/02)
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- 3-ALKYLATED IMIDAZO[1,2-a]PYRIDINE COMPOUNDS AND ITS PREPARATION METHOD
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Of a typic a.a typa/aβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbeta.beteq.a a.sub .beteq.a.sub βbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβbetaβ
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Paragraph 0235-0238; 0239-0242
(2019/11/28)
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- A novel formulation of zolpidem for direct nose-to-brain delivery: synthesis, encapsulation and intranasal administration to mice
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Objectives: Anxiolytic drug zolpidem was incorporated into the microcontainers based on mesoporous calcium carbonate particles modified by diethylaminoethyl-dextran/hyaluronic acid shell. The release of zolpidem in saline solution and in polymer film modelling nasal mucosa was investigated. The anxiolytic effect of zolpidem upon intranasal administration of microcontainers and free medicine was determined by in?vivo experiments on mice. Methods: The structures of all compounds during zolpidem synthesis were established using nuclear magnetic resonance spectroscopy. The loading efficacy and release kinetics of zolpidem were analysed by spectrophotometry. Surface morphology of formulation was investigated by scanning electron microscopy. To determine the effect of zolpidem-loaded containers administration by the intranasal route in?vivo experiments was carried out applying the open field test. Key findings: Nasal administration of zolpidem in the form of the microcontainers based on mesoporous calcium carbonate particles modified by diethylaminoethyl-dextran/hyaluronic acid shell has a pronounced anxiolytic effect on the behaviour of the animals in the open field test. Conclusions: The polyelectrolyte shell deposited together with zolpidem enhances the loading efficacy of the microcontainers. In vivo experiments on mice demonstrate increase in anxiolytic effect of zolpidem in microcontainers compared with upon intranasal administration of free medicine.
- Borodina, Tatiana,Marchenko, Irina,Trushina, Daria,Volkova, Yulia,Shirinian, Valerii,Zavarzin, Igor,Kondrakhin, Evgeny,Kovalev, Georgy,Kovalchuk, Mikhail,Bukreeva, Tatiana
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p. 1164 - 1173
(2018/08/16)
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- A method for preparing [...] (by machine translation)
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The invention discloses a method for synthesizing [...], existing technology with the different is, first of all the toluene with maleic anhydride Friedel-crafts reaction to obtain the 4 - oxo - 4 - (4 - methyl phenyl) - 2 - butenoic, then the same halogen addition to obtain the 3 - halo - 4 - oxo - 4 - (4 - methyl phenyl) - butyric acid, the esterification reaction, the ring, to obtain 2 - (6 - methyl - 2 - P-imidazole [1, 2 - α] pyridine - 3 - yl) acetate, the hydrolysis, acidifying the resulting [...]. The method of the invention, obtaining the high-purity [...], the whole synthetic route less steps, high yield, low cost, less impurities, is suitable for industrial production. (by machine translation)
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- Visible light/Ir(III) photocatalytic initiation of xanthate-based radical-chain reactions: Xanthate group transfer and oxidative addition to aromatic systems
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A photocatalyzed redox generation of radicals from O-ethyl xanthates to generate electrophilic radicals under photoredox catalysis, using Ir(ppy)3 and blue LEDs irradiation is described. The protocol can be used in classical xanthate-based inter- and intra-molecular group transfer reactions and oxidative radical addition to several heteroaromatic systems. The process does not require high temperature and reactions are cleaner compared with the traditional peroxide initiation. In the oxidative addition to aromatic systems, the oxidation process is part of the catalytic cycle and does not require a stoichiometric oxidant such as DLP which is particularly difficult to separate from the product.
- López-Mendoza, Pedro,Díaz, John E.,Loaiza, Alix E.,Miranda, Luis D.
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supporting information
p. 5494 - 5502
(2018/05/16)
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- Visible-Light-Induced Regioselective Cyanomethylation of Imidazopyridines and Its Application in Drug Synthesis
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3-Cyanomethylated imidazopyridines were synthesized via a visible light-promoted reaction of imidazopyridines with bromoacetonitrile or iodoacetonitrile catalyzed by fac-Ir(ppy)3 under mild conditions. For the substrates with various substituents on benzene or pyridine ring, the reaction proceeded smoothly to give the corresponding products in moderate to good yields. The synthetic utility of this visible-light-induced reaction has been illustrated in the efficient synthesis of zolpidem and alpidem.
- Chang, Qing,Liu, Zhengyi,Liu, Ping,Yu, Lu,Sun, Peipei
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p. 5391 - 5397
(2017/05/24)
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- Xanthate-based microwave-assisted C–H radical functionalization of caffeine, 1,3-dimethyluracil, and imidazo[1,2-a]pyridines
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Xanthate-based radical chemistry was used for the regioselective direct alkylation of caffeine, uracil, and imidazo[1,2-a]pyridine systems, using dilauroyl peroxide as initiator and oxidant, under microwave irradiation. Under these conditions, several electrophilic radicals (located alpha to a carbonyl function such as esters, amides, ketones, malonates and cyano groups) were added to the title heterocyclic systems. The methodology allows the intermolecular regioselective construction of a sp2-sp3C–C bond via a C–H functionalization in an aromatic substitution, from readily available starting materials.
- Pérez, Víctor M.,Fregoso-López, Daniela,Miranda, Luis D.
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supporting information
p. 1326 - 1329
(2017/03/10)
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- Copper(II)-Mediated Aerobic Synthesis of Imidazo[1,2-a]pyridines via Cascade Aminomethylation/Cycloisomerization of Alkynes
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A single copper(II)-catalyzed three-component cascade aminomethylation/cycloisomerization of propiolates to form imidazo[1,2-a]pyridines was explored. A straightforward method was developed for the practical synthesis of functionalized imidazo[1,2-a]pyridines from benzaldehydes, 2-aminopyridines, and propiolate derivatives catalyzed by Cu(OAc)2 hydrate in the presence of air. The protocol is marked by excellent yields, functional group tolerance, and, above all, adaptability to synthesize imidazo[1,2-a]pyridine-based drug molecules such as Alpidem.
- Rassokhina, Irina V.,Shirinian, Valerii Z.,Zavarzin, Igor V.,Gevorgyan, Vladimir,Volkova, Yulia A.
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p. 11212 - 11218
(2015/11/18)
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- Flow chemistry synthesis of zolpidem, alpidem and other GABAA agonists and their biological evaluation through the use of in-line frontal affinity chromatography
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The flow of information between chemical and biological research can present a bottleneck in pharmaceutical research. Tools that bridge these disciplines and aid information exchange have therefore clear value. Over the last few years, both synthetic chemistry and biological screening have benefited from automation, and a seamless chemistry-biology interface is now possible. We report here on the use of flow processes to perform synthesis and biological evaluation in an integrated manner. As proof of concept, a flow synthesis of a series of imidazo[1,2-a]pyridines, including zolpidem and alpidem, was developed and connected to a Frontal Affinity Chromatography screening assay to investigate their interaction with Human Serum Albumin (HSA). The Royal Society of Chemistry 2013.
- Guetzoyan, Lucie,Nikbin, Nikzad,Baxendale, Ian R.,Ley, Steven V.
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p. 764 - 769
(2013/03/14)
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- Synthesis of imidazopyridines from the Morita-Baylis-Hillman acetates of nitroalkenes and convenient access to alpidem and zolpidem
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A variety of functionalized imidazo[1,2-a]pyridines have been synthesized through a one-pot, room temperature, and reagent-free reaction between MBH acetates of nitroalkenes and 2-aminopyridines. The reaction involves a cascade inter-intramolecular double aza-Michael addition of 2-aminopyridines to MBH acetates. Our methodology is marked by excellent yield, regioselectivity and, above all, adaptability to synthesize imidazopyridine-based drug molecules such as Alpidem and Zolpidem.
- Nair, Divya K.,Mobin, Shaikh M.,Namboothiri, Irishi N.N.
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p. 4580 - 4583
(2012/11/06)
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- General and efficient copper-catalyzed three-component coupling reaction towards imidazoheterocycles: One-pot synthesis of alpidem and zolpidem
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(Figure Presented) Three is not a crowd: A method for the construction of Imidazopyridine, imidazoquinoline, and imidazoisoquinoline frameworks has been developed. The synthetic utility of this method was demonstrated in a highly efficient one-pot synthesis of the drugs alpidem and Zolpidem (see scheme).
- Chernyak, Natalia,Gevorgyan, Vladimir
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supporting information; experimental part
p. 2743 - 2746
(2010/07/03)
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- Synthesis and binding affinity of 2-phenylimidazo[1,2-α]pyridine derivatives for both central and peripheral benzodiazepine receptors. A new series of high-affinity and selective ligands for the peripheral type
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A number of 6-substituted or 6,8-disubstituted alkyl 2- phenylimidazo[1,2-a]pyridine-3-carboxylates 5a-h,-acetates 5i-s, 6a-g, and - propionates 5t, 6h and of N,N-dialkyl-2-phenylimidazo[1,2-α]pyridlne-3- carboxamides 7a-d, -aceramides 7e-t or -propionamide 7u were prepared following new synthetic methods, and their affinities for both the central (CBR) and the peripheral (PBR) benzodiazepine receptors evaluated. The compounds of the ester series displayed low affinity for both receptor types. Conversely, most of N,N-dialkyl(2-phenylimidazo[1,2-a]pyridin-3-yl)acetamides 7e-t proved to possess high affinity and selectivity for CBR or PBR depending on the nature of substituents at C(6)- and/or C(8) on the heterocyclic ring system. In particular, the 6-substituted compounds 7f-n displayed ratios of IC50 values (IC50(CBR)/IC50(PBR)) ranging from 0.32 (7m) to 232 (7k), while the 6,8-disubstituted compounds 7o-t were more than 1000-fold more selective for PBR versus CBR. Compounds 7f,m were examined in several different benzodiazepine receptor subtypes. Expression of specific GABA(A) receptor subunit assemblies in Xenopus oocytes was utilized to evaluate functionally both the efficacy and potency of the positive modulation of GABA-evoked C1+ currents by 7f and 7m in comparison with Zolpidem. The rank order of potencies of these drugs was 7f (EC50 = 3.2 x 10-8 M) > Zolpidem (EC50 = 3.6 x 10-8 M) > 7m (EC50 = 2.2 x 10-7 M). The actions of these compounds were also tested on α2β2γ2(s) receptors. However, the EC50 of these compounds was increased, compared to α1β2γ2(s) receptors, by 30-, 4-, and 5-fold for 7m, 7f, and Zolpidem, respectively. Finally, these compounds were almost completely devoid of activity at receptors containing the α5 subunit.
- Trapani, Giuseppe,Franco, Massimo,Ricciardi, Laura,Latrofa, Andrea,Genchi, Giuseppe,Sanna, Enrico,Tuveri, Francesca,Cagetti, Elisabetta,Biggio, Giovanni,Liso, Gaetano
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p. 3109 - 3118
(2007/10/03)
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