321-69-7Relevant articles and documents
Preparation method of flumazenil
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Paragraph 0076, (2021/06/22)
The invention discloses a preparation method of flumazenil, and belongs to the field of medicine synthesis. The method comprises the following steps: by taking 5-fluoro-2-nitrobenzoic acid as a raw material, carrying out condensation on 5-fluoro-2-nitrobenzoic acid and sarcosine ester, and then carrying out ring closing while reducing, so as to obtain 7-fluoro-3, 4-dihydro-4-methyl-1H-[1, 4] benzodiazepine-2, 5-diketone; and finally, carrying out halogenation and cycloaddition reaction to obtain flumazenil. According to the novel synthesis method of the flumazenil key intermediate 7-fluoro-3, 4-dihydro-4-methyl-1H-[1, 4] benzodiazepine-2, 5-diketone, provided by the invention, a green synthesis process is adopted, an intramolecular cyclization reaction is performed while a nitro group is reduced, and compared with a known flumazenil synthesis method, a strong oxidant, a highly toxic reagent (such as ethyl chloroformate) and the like are not needed, and the yield is higher.
SUBSTITUTED DIHYDROBENZOXAZINONES, DIHYDROQUINOLONES, AND METHODS OF THEIR USE AND SYNTHESIS
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Paragraph 0159; 0160; 0164; 0165, (2021/01/29)
Disclosed are dihydrobenzoxazinone compounds, dihydroquinolone compounds, and methods of their synthesis. The disclosed compounds may be prepared by reacting a benzoxazinedione compound and a ketone compound in the presence of an N-heterocyclic carbine (NHC) catalyst to perform a NHC-catalyzed decarboxylative cycloaddition. The disclosed compounds may be utilized to treat diseases and disorders associated with the biological activity of dihydrobenzoxazinone compounds and dihydroquinolone compounds.
Synthesis of Ring-Fused, N-Substituted 4-Quinolinones Using p Ka-Guided, Base-Promoted Annulations with Isatoic Anhydrides: Total Synthesis of Penicinotam
Khalifa, Muhammad M.,Philkhana, Satish Chandra,Golden, Jennifer E.
, p. 464 - 481 (2019/12/24)
An anionic annulation strategy employing isatoic anhydrides and a wide assortment of enolizable partners was developed to afford over 80 novel ring-fused, N-substituted 4-quinolinones, an underrepresented privileged template. Multiple factors governing the efficiency of the transformation were determined, resulting in a reliable and tunable synthetic platform applicable for a broad range of substrates with variable deprotonation susceptibility, such as tetramic and tetronic acids, cyclic 1,3-diketones, and cycloalkanones. Application to the synthesis of bioactive, pyrrolizine-fused 4-quinolinone, penicinotam 3, resulted in the most brief and highest yielding total synthesis of the alkaloid in three steps and a 36% overall yield.
Benzimidazoquinazolines as new potent anti-TB chemotypes: Design, synthesis, and biological evaluation
Chakraborti, Asit K.,Dhameliya, Tejas M.,Jadhavar, Pradeep S.,Krishna, Vagolu Siva,Patel, Kshitij I.,Saha, Nirjhar,Sriram, Dharmarajan,Vaja, Maulikkumar D.
, (2020/03/31)
In search for new molecular entities as anti-TB agents, the benzimidazoquinazoline polyheterocyclic scaffold has been designed adopting the scaffold hopping strategy. Thirty-two compounds have been synthesized through an improved tandem decarboxylative nucleophilic addition cyclocondensation reaction of o-phenylenediamine with isatoic anhydride followed by further cyclocondensation of the intermediately formed 2-(o-aminoaryl)benzimidazole with trialkyl orthoformate/acetate. The resultant benzimidazoquinazolines were evaluated in vitro for anti-TB activity against M. tuberculosis H37Rv (ATCC27294 strain). Fourteen compounds exhibiting MIC values in the range of 0.4–6.25 μg/mL were subjected to cell viability test against RAW 264.7 cell lines and were found to be non-toxic (30% inhibition at 50 μg/mL). The active compounds were further evaluated against INH resistant Mtb strains. The most active compound 6x [MIC (H37Rv) of 0.4 μg/mL] and the compound 6d [MIC (H37Rv) of 0.78 μg/mL] were also found to be active against INH resistant Mtb strain with MIC values of 12.5 and 0.78 μg/mL, respectively.
Carbene-Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones
Lee, Ansoo,Zhu, Joshua L.,Feoktistova, Taisiia,Brueckner, Alexander C.,Cheong, Paul H.-Y.,Scheidt, Karl A.
supporting information, p. 5941 - 5945 (2019/04/03)
A direct decarboxylative strategy for the generation of aza-o-quinone methides (aza-o-QMs) by N-heterocyclic carbene (NHC) catalysis has been discovered and explored. This process requires no stoichiometric additives in contrast with current approaches. Aza-o-QMs react with trifluoromethyl ketones through a formal [4+2] manifold to access highly enantioenriched dihydrobenzoxazin-4-one products, which can be converted to dihydroquinolones through an interesting stereoretentive aza-Petasis–Ferrier rearrangement sequence. Complementary dispersion-corrected density functional theory (DFT) studies provided an accurate prediction of the reaction enantioselectivity and lend further insight to the origins of stereocontrol. Additionally, a computed potential energy surface around the major transition structure suggests a concerted asynchronous mechanism for the formal annulation.
Dihydroquinozolinone antiport process blocking agent, and preparation method and application thereof
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Paragraph 0110-0113, (2019/11/12)
The invention belongs to the field of pharmaceutical and chemical industry, and relates to dihydroquinozolinone antiport process blocking agent, and a preparation method and application thereof, in particular to a novel dihydroquinozolinone antiport process blocking agent compound, a medicinal salt, isomer, hydrate and solvate thereof, application of the compound and the medicinal salt, isomer, hydrate and solvate thereof to preparation of drugs for preventing and/or first aiding diseases caused by ribosome-inactivating proteins, and application of the compound and the medicinal salt, isomer,hydrate and solvate thereof to preparation of drugs for preventing and/or curing diseases caused by enterovirus, filoviridae or polyomavirus. The compound can effectively resist II-type ribosome-inactivating protein poisoning and/or the diseases caused by enterovirus, filoviridae or polyomavirus.
Discovery of Novel Transient Receptor Potential Vanilloid 4 (TRPV4) Agonists as Regulators of Chondrogenic Differentiation: Identification of Quinazolin-4(3 H)-ones and in Vivo Studies on a Surgically Induced Rat Model of Osteoarthritis
Atobe, Masakazu,Nagami, Takamichi,Muramatsu, Shuji,Ohno, Takeshi,Kitagawa, Masayuki,Suzuki, Hiroko,Ishiguro, Masashi,Watanabe, Atsushi,Kawanishi, Masashi
, p. 1468 - 1483 (2019/02/14)
Osteoarthritis (OA) is a degenerative disease characterized by joint destruction and loss of cartilage. There are many unmet needs in the treatment of OA and there are few promising candidates for disease-modifying OA drugs, particularly, anabolic agents. Here, we describe the identification of novel quinazolin-4(3H)-one derivatives, which stimulate chondrocyte cartilage matrix production via TRPV4 and mitigate damaged articular cartilage. We successfully identified the water-soluble, highly potent quinazolin-4(3H)-one derivative 36 and studied its intra-articular physicochemical profile to use in in vivo surgical OA model studies. Compound 36·HCl provided relief from OA damage in a rat medial meniscal tear (MT) model. Specifically, 36·HCl dose-dependently suppressed cartilage degradation and enhanced the messenger RNA expression of aggrecan and SOX9 in cartilage isolated from MT-operated rat knees compared with knees treated with vehicle. These results suggest that 36 induces anabolic changes in articular cartilage and consequently reduces OA progression.
Palladium-Catalyzed Cyclization Reaction of o-Iodoanilines, CO2, and CO: Access to Isatoic Anhydrides
Zhang, Wen-Zhen,Zhang, Ning,Sun, Yu-Qian,Ding, Yu-Wei,Lu, Xiao-Bing
, p. 8072 - 8076 (2017/12/08)
Isatoic anhydrides, a class of valuable synthetic intermediates and RNA structure probing reagents, are usually prepared with highly toxic phosgene or stoichiometric oxidants. Herein we report a highly selective palladium-catalyzed cyclization reaction for the efficient synthesis of isatoic anhydrides from readily available o-iodoanilines, CO2, and CO. The reaction proceeds under mild conditions and is redox-neutral. Both CO2 and CO are indispensable C1 building blocks for this catalytic reaction.
Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium falciparum (PfNDH2) with Small Molecule To Eliminate Drug-Resistant Malaria
Yang, Yiqing,Yu, You,Li, Xiaolu,Li, Jing,Wu, Yue,Yu, Jie,Ge, Jingpeng,Huang, Zhenghui,Jiang, Lubin,Rao, Yu,Yang, Maojun
supporting information, p. 1994 - 2005 (2017/03/17)
Drug-resistant malarial strains have been continuously emerging recently, which posts a great challenge for the global health. Therefore, new antimalarial drugs with novel targeting mechanisms are urgently needed for fighting drug-resistant malaria. NADH-ubiquinone oxidoreductase of Plasmodium falciparum (PfNDH2) represents a viable target for antimalarial drug development. However, the absence of structural information on PfNDH2 limited rational drug design and further development. Herein, we report high resolution crystal structures of the PfNDH2 protein for the first time in Apo-, NADH-, and RYL-552 (a new inhibitor)-bound states. The PfNDH2 inhibitor exhibits excellent potency against both drug-resistant strains in vitro and parasite-infected mice in vivo via a potential allosteric mechanism. Furthermore, it was found that the inhibitor can be used in combination with dihydroartemisinin (DHA) synergistically. These findings not only are important for malarial PfNDH2 protein-based drug development but could also have broad implications for other NDH2-containing pathogenic microorganisms such as Mycobacterium tuberculosis.
Recyclable (PhSe)2-catalyzed selective oxidation of isatin by H2O2: a practical and waste-free access to isatoic anhydride under mild and neutral conditions
Yu, Lei,Ye, Jianqing,Zhang, Xu,Ding, Yuanhua,Xu, Qing
, p. 4830 - 4838 (2015/10/05)
After a series of careful conditional optimizations and catalyst screenings, a methodology to prepare isatoic anhydrides through organoselenium-catalyzed selective oxidation of isatins by H2O2 under mild and neutral conditions was developed. The reactions were very practical because of the recyclability of the catalyst and solvent and the convenient isolation procedures of the products. This work reports the organoselenium-catalyzed oxidation of heterocycles that greatly expands the application scopes of organoselenium catalysis. It also indicates that the organoselenium catalysts are robust enough to be recycled in industrial production if suitable isolation procedures are developed.
