- Direct Regio- and Diastereoselective Synthesis of δ-Lactams from Acrylamides and Unactivated Alkenes Initiated by RhIII-Catalyzed C?H Activation
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We report a RhIII-catalyzed regio- and diastereoselective synthesis of δ-lactams from readily available acrylamide derivatives and unactivated alkenes. The reaction provides a rapid route to a diverse set of δ-lactams in good yield and stereoselectivity, which serve as useful building blocks for substituted piperidines. The regioselectivity of the reaction with unactivated terminal alkene is significantly improved by using Cpt ligand on the RhIII catalyst. The synthetic utility of the reaction is demonstrated by the preparation of a potential drug candidate containing a trisubstituted piperidine moiety. Mechanistic studies show that the reversibility of the C?H activation depends on the choice of Cp ligand on the RhIII catalyst. The irreversible C?H activation is observed and becomes turnover-limiting with [CptRhCl2]2 as catalyst.
- Lee, Sumin,Rovis, Tomislav,Semakul, Natthawat
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- Design, synthesis and biological evaluation of AZD9291 derivatives as selective and potent EGFRL858R/T790M inhibitors
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Third-generation epidermal growth factor receptor (EGFR)L858R/T790M inhibitors are still the main drugs for the treatment of advanced non-small cell lung cancer (NSCLC), and these drugs have achieved remarkable clinical efficacy. However, there are still many patients suffering from drug-resistant mutations and drug side effects caused by NSCLC. In this study, guided by the molecular simulation, we applied a structure-based drug design strategy (SBDD) and optimized the structure to obtain a series of potent and selective EGFRL858R/T790M inhibitors. The most potent compound 18e demonstrated excellent kinase inhibitory activity and selectivity for EGFRL858R/T790M double mutants and the IC50 value reached nanomolar level. The selectivity of 18e against wild-type EGFR was near to 200-fold. In addition, compound 18e also inhibited H1975 cells proliferation at G2/M phase and induced apoptosis at a concentration of 0.25 μM, which makes it more valuable for potential lung cancer research.
- Zhao, Bingbing,Xiao, Zhen,Qi, Jianguo,Luo, Rong,Lan, Zhou,Zhang, Yanzhuo,Hu, Xiaohan,Tang, Qidong,Zheng, Pengwu,Xu, Shan,Zhu, Wufu
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p. 367 - 380
(2018/12/13)
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- Novel pyrimido-heterocyclic compound and preparation method and application thereof
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The invention discloses a novel pyrimido-heterocyclic compound and a preparation method and application thereof. The structure of the pyrimido-heterocyclic compound disclosed by the invention is as shown in a general formula I, and the definitions of all substituents are described in the specification and claims. The pyrimido-heterocyclic compound disclosed by the invention has much better inhibitory activity and selectivity for double-mutant EGFR kinase than the existing AZD-9291, can be used for preparing anti-tumor drugs, and overcomes the defect of drug tolerance of the first generation ofEGFR inhibitor.
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Paragraph 0180; 0182; 0183; 0184
(2019/02/19)
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- Facile synthesis of fluorovinyl-containing lactams via ring-closing metathesis of N-substituted 2-fluoroallylamides
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A cost-efficient method for the preparation of a series of N-substituted 2-fluoroallylamines and their application in the synthesis of fluoroalkene-containing lactams are described. N-substituted 2-fluoroallylamine could be readily synthesized from methyl 2-fluoroacrylate via aminolysis and subsequently selective reduction of the amide group. These amines were further converted into the corresponding amides with diverse acids bearing a terminal double bond. The Ring-Closing Metathesis (RCM) of the resulting amides led to the formation fluorovinyl-containing lactams in good yields.
- Li, Yang,Li, Kai,Wu, Yue,Ma, Qiaoning,Lei, Xinsheng
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p. 4845 - 4853
(2016/07/18)
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- Quinoline and quinazoline derivatives, preparation method, intermediate, composition and use thereof (by machine translation)
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The invention discloses a quinoline and quinazoline derivative I, a preparation method, an intermediate C, composition and an application. The preparation method comprises two methods, wherein the first method comprises steps as follows: 1, a compound A and a compound B react in a solvent under the action of alkali 1 to obtain a compound C; and 2, the product C obtained in the step 1 reacts with a compound D under the action of alkali 2; and the second comprises step as follows: the compound A and a compound E react in the solvent under the action of the alkali 1. The invention further provides the application of the compound represented in formula I or medicine composition in preparation of an EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor, an A431 or H1975 cell proliferation inhibitor or medicine for preventing or treating tumor diseases. The provided compound has better antitumor activity.
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Paragraph 0407; 0409; 0415; 0416
(2016/11/07)
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- Cytotoxic α-Halogenoacrylic Derivatives of Distamycin A and Congeners
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The mechanism of action of many antitumor agents involves DNA damage, either by direct binding of the drug to DNA or to DNA-binding proteins. However, most of the DNA-interacting agents have only a limited degree of sequence specificity, which implies that they may hit all the cellular genes. DNA minor groove binders, among which the derivatives of distamycin A play an important role, could provide significant improvement in cancer management, increasing gene specificity, due to high selectivity of interaction with thymine-adenine (TA) rich sequences. We now report and discuss the synthesis, the in vitro and in vivo activities, and some mechanistic features of α-halogenoacrylamido derivatives of distamycin A. The final result of this work was the selection of brostallicin 17 (PNU-166196). Brostallicin, presently in phase II clinical trials, shows a broad spectrum of antitumor activity and an apoptotic effect higher than distamycin derivative tallimustine. An important in vitro toxicological feature of brostallicin is the very good ratio between myelotoxicity on human haematopoietic progenitor cells and cytotoxicity on tumor cells, in comparison with clinically tested DNA minor groove binders. A peculiarity of brostallicin is its in vitro reactivity in the DNA alkylation assays only in the presence of glutathione. Moreover brostallicin's antitumor activity, both in in vitro and in vivo tumor models, is higher in the presence of increased levels of glutathione/glutathione-S-tranferases. These findings contribute to the definition of brostallicin as a novel anticancer agent that differs from other minor groove binders and alkylating agents for both the profile of activity and the mechanism of action and to. classify the α-bromoacrylamido derivatives of distamycin as a new class of cytotoxics. Moreover, due to its interaction with glutathione, brostallicin may have a role for the tailored treatment of tumors characterized by constitutive or therapy-induced overexpression of glutathione/glutathione-S-tranferase levels.
- Beria, Italo,Baraldi, Pier Giovanni,Cozzi, Paolo,Caldarelli, Marina,Geroni, Cristina,Marchini, Sergio,Mongelli, Nicola,Romagnoli, Romeo
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p. 2611 - 2623
(2007/10/03)
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- Process for the synthesis of fluoroorganic compounds
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The present invention relates to a fluorination method for the synthesis of halofluoroorganic compounds which can be used, inter alia, as precursors in the synthesis of 2,3-unsaturated fluoroorganic carbonyl compounds comprising a fluorine substituent in the 2 position.
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- α-fluoroacrylic acid esters and polymers thereof
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Esters of α-fluoroacrylic acid are accessible by hydrolysis of an α-hydroxymethyl-α-fluoromalonic acid ester, decarboxylation and dehydration of the hydrolysis product and subsequent esterification of the resulting α-fluoroacrylic acid with an alcohol. The esters are polymerizable and are suitable for use as a starting material for preparing fluoropolymers which in turn are usable as materials for manufacturing transparent articles. The polymers are high-molecular and non-crystalline and have softening temperatures of above 100° C.
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- α-FLUOROACRYLIC ACID CHLORANHYDRIDE
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Kinetic studies were carried out on the reaction of 2-fluoro-3-chloropropanoic acid and other halo- and methoxy-substituted propanoic acids with thionyl chloride at 50-110 deg C.The catalytic dehydro-chlorination of 2-fluoro-3-chloropropanoic acid chloranhydride by tertiary amines and their salts was investigated.Dimethylaniline chlorohydrate was shown to be an effective catalyst, providing maximum dehydrochlorination at a concentration of 20percent.A mechanism for the reaction was proposed.
- Boguslavskaya, L. S.,Morozova, T. V.
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p. 716 - 720
(2007/10/02)
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- REACTION OF HALOGEN FLUORIDES. IX. SYNTHESIS OF DERIVATIVES OF α-FLUOROACRYLIC ACID
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New methods have been proposed for the preparation of derivatives of α-fluoroacrylic acid by the substituent fluorination of 1,2-dibromo-3-chloropropane and methyl 2,3-dibromo-2-chloropropanoate with bromine trifluoride.
- Boguslavskaya, L. S.,Chuvatkin, N.,Morozova, T. V.,Panteleeva, I. Yu.,Kartashov, A. V.,Sineokov, A. P.
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p. 1060 - 1064
(2007/10/02)
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- SYNTHESIS OF 2-FLUOROPROPENOIC ACID DERIVATIVES
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A method is described for the synthesis of 2-fluoropropenoic acid esters, amides, and nitrile from the corresponding derivatives of 2-fluoro-3-(4-toluenesulfonyloxy)propanoic acid by heating with potassium phtalimide in vacuo.The free acid Ia and its chloride have also been synthetized.The reactivity of esters and nitrile of acid Ia has been verified by the Michael addition of diethyl acetamidomalonate to these compounds.
- Tolman, Vladimir,Spronglova, Pavla
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p. 319 - 326
(2007/10/02)
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- Process for making an acrylic monomer
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The invention relates to a novel process for making phenyl fluoroacrylate monomer. The monomer is obtained by reaction of a fluoroacrylic salt with an halogenating agent, followed by condensation of the fluoroacryloyl halogenide with phenol and recovery of the phenyl fluoroacrylate. The obtained monomer is applicable to the manufacture of transparent polymers of high thermal stability.
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