Microwave Reaction Improved Heterocyclization of Quinazolinone Ring in Synthesis of Erlotinib Analogues

Background Tinibs were a kind of important epidermal growth factor receptor (EGFR) inhibitors used aspotential therapeutic agents in treating non-small cell lung cancer (NSCLC) in clinic. The drug resistance ofclinical used tinibs made the development of more active tinib analogues an attractive field in research.Quinazoline ring was regarded as the key fragment in tinibs and quinazolinone was indispensible intermediatein the synthesis of quinazoline. Thus, synthesis of quinazolinone intermediates was a key step which wouldfurther limit the overall yield of final product of tinib analogues. However, the commonly used synthetic scheme was somewhat complicated and time consuming with relatively low yield in heterocylization ofquinazolinone and its derivatives.Aim In this work, we intended to explore an effective way to improve synthesis of heterocyclization of 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (compound 5), the key fragment of erlotinib analogues, in bothreaction procedure and yield, thus to provide reference to synthesis of other quinazolinone derivatives.Methods A simple microwave-assisted one-pot reaction was employed to improve the synthesis ofheterocyclization of quinazolinone ring. The reaction conditions, including microwave power, temperature andtime of reaction, were screened to achieve high yield under simple operation.Results 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (compound 5) was successfully synthesized fromstarting material of 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile by microwave reaction, which was finished in1 hour just by one step. The yield of heterocyclization was increased from 29.8% of commonly used three-stepscheme to 50% herein.Conclusion Microwave reaction efficiently improved synthesis of heterocyclization of 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one into "quinazolinone in both synthetic procedure and yield. The resultsmay provide valuable reference to synthesis of other quinazolinone derivatives.

The Synthesis, Screening Of Novel 1-Substituted-3-(4-Oxo-2-Phenylquinazolin-3(4h)-Yl) Urea And Thiourea Analogues As Potent Antibacterials

Objective: The proposed study is an attempt to determine antibacterial activity of synthesized novel 1-substituted-3-(4-oxo-2-phenylquinazolin-3(4H)-yl) urea and thiourea analogues as potent antibacterials against S. aureus and E. coli bacteria. Methods: The present study reports new series of 1-substituted-3-(4-oxo-2-phenylquinazolin-3(4H)-yl) urea and thiourea derivatives as potent antibacterial agents. Reagents used in the present study were of synthetic grade and solvents were used after distillation. Novel quinazolinone analogues were synthesized by considering substitution pattern, characterization of the synthesized analogues was performed using various techniques like Thin layer chromatography, Melting point, Infrared spectroscopy, Proton NMR spectrometry and Mass spectrometry. TLC of the synthesized analogues was carried out by using (toluene: methanol in the ratio 2:1), melting point was found by open capillary method, IR spectrum was recorded on JASCO V-530, 1H NMR was recorded on Bruker Avance Spectrometer and Mass spectra were obtained from G6460A, triple quadrupole/MS/MS system. In vitro antibacterial activity was performed against S. aureus and E. coli. Results: Six derivatives of quinazolinone analogues were synthesized. The structures of 1-substituted-3-(4-oxo-2-phenylquinazolin-3(4H)-yl) urea and thiourea derivatives were confirmed by physical and spectral analysis. Synthesized molecules showed Rf of 0.45-0.80 in toluene: methanol mobile phase, melting point was carried out by open capillary method and were in range of 90-210 ° C, IR spectrum was recorded in range of 14000-400 cm-1and showed characteristic peaks of NH and of C-O-NH, 1H NMR of the compounds was distinct to confirm structures with delta values in the range of 7.53-11.960, Mass spectra proved parent peaks of synthesized compounds confirming molecular weight. The compounds were assayed for antibacterial activity against S. aureus and E. coli using ciprofloxacin as standard. The synthesized analogues have shown good yield and comparable antibacterial. Conclusion: The present study delivers a convenient and efficient protocol for the quinazolinone analogues synthesis.

Research progress in quinazoline derivatives with anticancer activity / 中国药学杂志

Quinazoline ring, as a key skeleton structure, can produce a variety of biological activities after combining with multi-kinds of biological macromolecules. Quinazoline compounds have played particularly important roles in the discovery of anticancer drugs. The progress in quinazoline derivatives with anticancer activity was reviewed in this paper. Quinazoline compounds were classified into five types according to different substituent groups. The bioactivities of substituent groups containing quinazoline ring were discussed. And the development trend as well as the prospect of quinazoline derivatives with anticancer activity is summarized.

Three pairs of alkaloid enantiomers from the root of Isatis indigotica

Three pairs of enantiomerically pure alkaloids with diverse structure features, named isatindigoticoic acid A and epiisatindigoticoic acid A [(-)-1 and (+)-1], phaitanthrin A and epiphaitanthrin A [(-)-2 and (+)-2], and isatindopyrromizol A and epiisatindopyrromizol A [(-)-3 and (+)-3], respectively, were isolated from an aqueous extract of the roots of Isatis indigotica. Racemic and scalemic mixtures of these enantiomers were separated by HPLC on a chiral semi-preparative column. Their structures including absolute configurations were determined by extensive spectroscopic analysis in conjunction with the calculation of electronic circular dichroism (ECD) spectra. The enantiomer pairs possess parent structures of 2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylic acid, indolo[2,1-b]quinazolinone, and 3-thioxohexahydro-1H-pyrrolo[1,2-c]imidazol-1-one, respectively. Except for phaitanthrin A [(-)-2] which the configuration was previously undetermined, these compounds are new enantiomeric natural products.

Synthesis of substituted novel quinazolinone compounds / 药学实践杂志

Objective To optimize the synthesis route of substituted quinazolinone and investigate the influence of tem-perature and time in the synthesis of key intermediates .Methods A parallel test was carried out to compare temperature ,time and the ester bond ammonolysis of condensing agent ,including the total analysis of experimental result .And orthogonal experi-mental design was used and the influence of temperature and time on the yield were investigated .Results and Conclusion The structure of the compound was confirmed by 1 H NMR ,MS and 13C NMR .When the reaction temperature was 30 ℃ ,the reac-tion time was 24 h with the condensing agent (DCC) and the reactant ratio of 1 .5∶1 ,the yield of ester bond ammonolysis was higher .The optimal preparation procedure of quinazolinone compounds was more available for industrial production .In vitro antifungal activity test results showed that the lead compounds measured on five clinical pathogenic fungi have the potential an-tifungal activity ,and are worth for further study .

Synthesis and Characterization of a Novel ELF-97-based Fluorescent Probe for Hydrogen Peroxide Detection / 分析化学

A novel 2-( 2’-hydroxy-5’-chlorophenyl )-6-chloro-4 ( 3 H )-quinazolinone ( ELF-97 )-based fluorescent probe (P1) for hydrogen peroxide was prepared from 5-chlorosalicylaldehyde, 4-(bromomethyl) phenylboronic acid and 2-amino-5-chlorobenzamide, and its structure was characterized by 1 H NMR, 13 C NMR and HRMS. Weak fluorescence intensity was observed at 425nm when the solution of probe P1 was excited by 360 nm UV light. After addition of H2 O2 , however, emission peak at 425 nm disappeared while strong peak emission at 515 nm appeared with the same excitation wavelength ( 360 nm ) . The fluorescence intensity at 515 nm was dependent on the concentration of H2 O2 in the linear response range of 5-45 μmol/L. The detection limit of H2O2 was 0. 1 μmol/L (S/N=3) and the recovery rates of added H2O2 in milk were in the range of 94 . 0%-106 . 0%. Probe P1 was potential to become a useful tool for rapid detection of hydrogen peroxide.

Anti-Inflammatory Activity of 3-[(5-Substitued)-1, 3, 4 Oxadiazole-2-Yl) Methyl Amino]-2-Methyl Quinazolin-4(3H)-Ones.

The process of establishing a new drug is exceedingly complexioned involves the talents of people from a variety of disciplines including Pharmaceutical chemistry, biochemistry, physiology, pharmacology, pharmaceutics and medicine. Quinazolinone is a heterocyclic chemical compound. There are two structural isomers, 2-quinazolinone and 4-quinazolinone, with the 4-isomer being the more common. Various novel classes of structurally different quinazolinones have been designed and synthesized depicting potential interventions such as antibacterial, antifungal, antiviral, anticonvulsant, anti-inflammatory, antihistaminic, anticancer CNS depressant, and so on. All the synthesized quinazolinone derivatives were confirmed preliminarily by M.P and TLC and further all the synthesized compounds were screened for anti-inflammatory activity using Phenyl butazone as the standard and carragennin induced paw oedema model used for anti-inflammatory activity.

Studies on chemical constituents in root of Isatis indigotica Ⅲ / 中草药

Object To study chemical constituents of the root of Isatis indigotica Fort Methods The powdered plant material was percolated with 95% ethanol, the percolate was extracted with different solvents, the extract was subject to chromatography on silica gel column and macroporous resin column. The compounds were identitfied by their physicochemical properties and spectral data (MS, 1HNMR, 13 CNMR, UV and IR) Results Two compounds were obtained from the ethanol extracts of the plant root They are 3 (2′ hydroxyphenyl) 4(3H) quinazolinone and isaindigodione respectively Conclusion The two compounds were obtained from I. indigotica for the first time