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A one-step synthesis of methaqualone from N-acetylanthranilic acid and O-toluidine in the absence of a catalyst is described. A rapid diphasic titration procedure for its microestimation in pure and tablet forms, using dioctyl sulfosuccinate and dimethyl yellow screened with oracet blue B, is proposed. The data were compared with those obtained from nonaqueous titration methods.

A metal-free and efficient procedure for the synthesis of pyrrolo[1,2-a]quinoxalines, quinazolinones, and indolo[1,2-a]quinoxaline has been developed. The key features of our method include thein situgeneration of aldehyde from α-hydroxy acid in the presence of TBHP (tert-butyl hydrogen peroxide), and further condensation with various amines, followed by intramolecular cyclization and subsequent oxidation to afford the corresponding quinoxalines, quinazolinones derivatives in moderate to high yields.

Besides the abuse of well-known illicit drugs, consumers discovered new synthetic compounds with similar effects but minor alterations in their chemical structure. Originally, these so-called novel psychoactive substances (NPS) have been created to circumvent law of prosecution because of illicit drug abuse. During the past decade, such compounds came up in generations, the most popular compound was a synthetic cathinone derivative named mephedrone. Cathinones are structurally related to amphetamines; to date, more than 120 completely new derivatives have been synthesized and are traded via the Internet. Cathinones possess a chiral center; however, only little is known about the pharmacology of their enantiomers. However, NPS comprise further chiral compound classes such as amphetamine derivatives, ketamines, 2-(aminopropyl)benzofurans, and phenidines. In continuation of our project, a cheap and easy-to-perform chiral capillary zone electrophoresis method for enantioseparation of cathinones presented previously was extended to the aforementioned compound classes. Enantioresolution was achieved by simply adding native β-cyclodextrin, acetyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, or carboxymethyl-β-cyclodextrin as chiral selector additives to the background electrolyte. Fifty-one chiral NPS served as analytes mainly purchased from online vendors via the Internet. Using 10 mM of the aforementioned β-cyclodextrins in a 10 mM sodium phosphate buffer (pH 2.5), overall, 50 of 51 NPS were resolved. However, chiral separation ability of the selectors differed depending on the analyte. Additionally, simultaneous enantioseparations, the determination of enantiomeric migration orders of selected analytes, and a repeatability study were performed successfully. It was proven that all separated NPS were traded as racemic mixtures.

The generation of a methyl carbon source from renewable and cheap sources is challenging. Herein, we describe a novel and an efficient route for methylation and acetylation of aza-heteroarenes using PEG-400 under O2and TsOH·H2O for the first time by tuning the reaction conditions using a different set of starting materials. The key features of the current protocol are oxidative C-O and C-C bond scission under metal-free conditions with good functional group tolerance, and a broad substrate scope. The potential applicability of the designed methodology was demonstrated for the synthesis of central nervous system (CNS) depressant and anticonvulsant drug molecules by a one-pot strategy.

Biologically important quinazolinones have been synthesized from 2-aminobenzamides and DMSO. The key feature of the reaction is the utilization of DMSO as a methine source for intramolecular oxidative annulation. The CNS depressant drug methaqualone has also been synthesized by our methodology. The present method involves the synthesis of quinazolinones with a broad substrate scope and a good yield.

One-pot synthesis of 3-aryl-4(3H)-quinazolinones has been realized through a cascade annulation. Reaction of aryldiazonium salt with a nitrile provides in situ generation of a reactive nitrilium ion, which is attacked by the amino group of 2-aminobenzoate followed by cyclization to deliver the desired product. This strategy offers a convenient and easy access to a wide range of functionalized quinazolinone.

The invention relates to the technical field of chemical synthesis and especially relates to a one-pot synthesis method of a quinazolinone compound, which includes the steps of: (1) with an alcohol, represented as the formula (I), as a raw material, performing a reaction under effect of a photosensitizer in the conditions of light irradiation, gas and room temperature in a solvent to generate an aldehyde represented as the formula (II); (2), with the aldehyde (II) and an o-aminobenzamide derivative represented as the formula (III) as raw materials, performing a reaction under effect of the photosensitizer and an acidic compound in the conditions of light irradiation, gas and room temperature in a solvent to generate a quinazolinone compound represented as the formula (IV). The method is used for synthesizing the quinazolinone compound through a one-pot process. The method is simple in process and employs simple and accessible raw materials, is free of metal catalyst, is carried out through room-temperature reactions with green photocatalysts, is free of peroxides, is low in raw material cost, is high in yield, and is energy-saving and environment-friendly.

A palladium-catalyzed four-component carbonylative cyclization reaction for the synthesis of 2,3-disubstituted quinazolin-4(3H)-ones has been developed. A range of different 2,3-disubstituted quinazolin-4(3H)-one derivatives were prepared in moderate to good yields employing simple and readily accessible 2-iodoanilines, nitro compounds and acid anhydrides as the synthetic precursors. Mo(CO)6 acted both as a solid CO source and a reductant. Notably, methaqualone as a sedative and hypnotic medication can be prepared easily in 68% yield (4b) under our conditions as well.

Readily available N-substituted amides or their requisite carboxylic acids or acid chlorides have been used to construct 2,3-disubstituted-3H-quinazolin-4-ones in a one-pot procedure. Key transformation in this convergent approach involves Ph3P-I2-mediated formation of amidine upon condensation of an amide or the intermediate amide with methyl anthranilate. Cyclization of the amidine-tethered anthranilate then affords 2,3-disubstituted-3H-quinazolin-4-ones in good to excellent yields under mild conditions.

The invention discloses a synthetic method of a quinazolinone compound. The method can be used for preparing the quinazolinone compound by carrying out reaction at a proper temperature and time by taking a 2-aminobenzamide derivative and a 1, 3-diketone compound as raw materials, taking chiral Bronsted acid or Lewis acid as a catalyst and water and biodegradable ethyl lactate and polyethylene glycol as a mixed solvent. The synthetic method of the quinazolinone compound provided by the invention is mild in reaction condition, low in cost, environment-friendly, high in yield and suitable for industrial production.

Synthesis of a series of tricyclic quinazolinones have been accomplished starting from anthranilamide and 1,3-cyclic dione promoted by TsOH·H2O The protocol presented herein based on retro-Dieckmann type reaction, leading to incorporation of dione as an acyclic unit into the product. Simple reaction conditions, broad scope, excellent yields are the advantages of this protocol. Further, this methodology is extended to the synthesis of pyridopyrimidinones and benzimidazopyridines.

In the presence of (R)-DTBM-SEGPHOS-Pd(OAc)2 catalyst, treatment of various 3-(2,6-dibromophenyl)quinazolin-4-ones with NaBH4 gave optically active N-C axially chiral quinazolinone (mebroqualone) derivatives through reductive asymmet

A mild and greener protocol was developed to synthesize substituted quinazolinones and dihydroquinazolinones via deep eutectic solvent (DES) mediated cyclization with a series of aliphatic, aromatic, and heteroaromatic aldehydes in good to excellent yields. This greener strategy was further utilised to synthesize various quinazolinone natural products and drugs.

We developed a copper-catalyzed tandem reaction of 2-aminobenzamides with tertiary amines for the formation of quinazolinone derivatives. The strategy includes two steps (cyclization and coupling) performed in one pot. A number of substrates reacted well under standard conditions to give the corresponding quinazolinone derivatives in moderate to good yields.

A concise approach for the synthesis of 2-substituted quinazolinones using an iron-catalyzed tandem reaction of 2-aminobenzamides with acyclic or cyclic 1,3-diketones via condensation, intramolecular nucleophilic addition, C-C bond cleavage in an aqueous solution of poly(ethylene glycol) under oxidant-free conditions has been developed.

Simple, convenient, and green synthetic protocols have been developed for the one pot synthesis of 2,3-disubstituted quinazolin-4(3H)-ones and 2-styryl-3-substituted quinazolin-4(3H)-ones under catalyst and solvent free conditions. The multicomponent reaction (3-MCR) involving isatoic anhydride, an amine, and orthoester afforded the 2,3-disubstituted quinazolin-4(3H)-ones in excellent yields under classical heating at 120 °C for 5 h or under microwave irradiation at 140°C for 20-30 min. The use of ammonium acetate instead of the amine provides the 2-substituted quinazolin-4(3H)-ones. The reactions are compatible with various substituted isatoic anhydrides, aryl/heteroaryl/alkyl/cycloalkyl amines, and orthoesters. The strategies are extended to the one pot tandem condensation involving isatoic anhydride, an amine, orthoester, and aldehyde to afford highly functionalized (E)-3-aryl/heteroaryl-2-styrylquinazolin/(2-(heteroaryl)vinyl)quinazolin-4(3H)-ones. The applications of the methodologies are demonstrated through the synthesis of various drugs which act on the central nervous system such as methaqualone, mebroqualone, mecloqualone, piriquialone, and diproqualone.

A facile and green approach was developed for the synthesis of 4(3H)-quinazolinones by using camphorsulfonic acid as a catalyst in an aqueous solution of biodegradable ethyl lactate. Various 2-aryl-, 2-alkyl-, and 2-(4-oxoalkyl)quinazolinones were obtained by cyclization of 2-aminobenzamides with a wide range of acyclic or cyclic 1,3-diketones via C-C bond cleavage in satisfactory to excellent yields.

A series of some novel dihydrofolate reductase inhibitors (DHFR) of 2,3-disubstituted quinazolinone derivatives were synthesized by condensing benzoxazone derivatives with compounds containing primary amino group. The chemical structures of the newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR, Mass spectral data and elemental analysis. The enzyme inhibitory activities were studied by using GLIDE 4.5 module. In vitro cytotoxic activity of the synthesized compounds was evaluated by MTT assay method. Compounds 3g and 5a exhibited good hydrogen bond interactions with the amino acid residue of DHFR and also showed significant cytotoxic activity.

The catalytic aza-Wittig reaction based on a phosphine/phosphine oxide catalytic cycle is reported. The by-product triphenylphosphine oxide (Ph 3PO) was reduced in situ to triphenylphosphine (Ph3P) with good chemselectivity so that the aza-Wittig reaction can be accomplished by using merely a catalytic amount of triphenylphosphine. The reaction has been demonstrated in an efficient synthesis of 4(3H)-quinazolinones and the natural product (S)-vasicinone in high yields, by using a catalytic amount of triphenylphosphine (5%) and the tetramethyldisiloxane/titanium tetraisopropoxide [TMDS/Ti(O-i-Pr)4] reductant system (81-95% yields and >99% ee).

Natural products sclerotigenin, pegamine, deoxyvasicinone, mackinazolinone, and rutaecarpine were synthesized. Core quinazolinone structures were constructed via Ir catalysis. The Royal Society of Chemistry 2012.

CuI/4-hydroxy-l-proline catalyzed coupling of N-substituted o-bromobenzamides with formamide takes place at 80 °C, affording 3-substituted quinazolinones directly. Under these conditions other amides that were tested only provided simple coupling products, which can be converted into 2,3-disubstituted quinazolinones via HMDS/ZnCl2 mediated condensative cyclization.

The present application relates to compounds and methods for treating pain and other conditions related to TRPV3.

Quinazolin-4(3H)-one derivatives were synthesized successfully via a one-pot, three component reaction of isatoic anhydride and an orthoester with ammonium acetate or a primary amine catalyzed by silica sulfuric acid under solvent-free conditions. This is the first report on the synthesis of 2-substituted quinazolin-4(3H)-ones by this procedure.

(Equation presented) A novel and practical synthesis of 3-substituted 3H-pyrimidin-4-ones is described. The key step involves the cyclization of enamide esters, derived from readily available β-keto esters, with trimethylaluminum and various primary amines.

Piriqualone (1) was found to be an antagonist of AMPA receptors. Structure-activity optimization was conducted on each of the three rings in 1 to afford a series of potent and selective antagonists. The sterically crowded environment surrounding the N-3 aryl group provided sufficient thermal stability for atropisomers to be isolated. Separation of these atropisomers resulted in the identification of (+)-38 (CP-465,022), a compound that binds to the AMPA receptor with high affinity (IC50 = 36 nM) and displays potent anticonvulsant activity.

A number of arylfurylvinylquinazolinones were prepared as possible antibacterial agents. The structural elucidations of all the compounds were carried out on the basis of analytical and spectral data. The newly synthesized compounds were screened for their antibacterial properties against both Gram-positive and Gram-negative bacteria.

A series of 4(3H)-quinazolinones structurally related to 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone, 3) were synthesized and evaluated for anticonvulsant activity.Preliminary screening of these compounds revealed that 2--3-aryl-4(3H)-quinazolinones 6l and 8i, 8k, and 8p-r having a single ortho substituent on the 3-aryl group had the most promising anticonvulsant activity.Compounds 6l and 8i possessing 3-o-tolyl and 3-o-chlorophenyl groups, respectively, showed good protection against MES- and scMet-induced seizures, combined with relatively low neurotoxicity after intraperitoneal administration in mice.They also exhibited low toxicity in tests for determining the mean hypnotic dose (HD50) and the median lethal dose (LD50).Although these compounds were markedly more potent as anticonvulsants when administered orally in mice and rats, they were also more neurotoxic.This neurotoxicity was particularly acute in oral tests with rats. which resulted in marginal protective indices.In drug differentiation tests, compound 6l was ineffective against seizures induced by bicuculline, picrotoxin, and strychnine, while 8i showed some protection against picrotoxin-induced seizures.

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It is shown that methaqualone (1) is a chiral molecule. Its enantiomers were enriched by liquid chromatography on triacetylcellulose up to optical purities of 0.75 and 0.68, respectively. The interconversion of (M)- and (P)-1 is slow enough (ΔG? = 131.6 kJ/mol at 135°C) to prevent any thermal racemization at room temperature. Both enantiomers possess anticonvulsive activity, (-)-1 being significantly (p 0.05) more potent than (+)-1.

4(3H)-Quinazolinones 3a-r have been prepared by heating methyl N-acylanthranilates 1a-c and the hydrochlorides of primary aliphatic and aromatic amines with phosphorus pentaoxide and N,N-dimethylcyclohexylamine at 180 deg C. 4-Quinazolinamines 4 and the amidine 7 were isolated as by-products.The carboxamides 5 and 6 were believed to be reaction intermediates.By raising the temperature to 250 deg C 4 was obtained in a preparative yield.

2-Ketoalkyl-4(3H)-quinazolinones of the formula STR1 wherein R1 is an aliphatic, cycloaliphatic or hydrocarbon aromatic group of 1-10 carbon atoms; A is divalent alkylene of 1 to 10 carbon atoms; R2 is an aliphatic, cycloaliphatic, hydrocarbon aromatic or heterocyclic group of 1-10 carbon atoms formed by condensing an acyl ester of the formula R2 COOR' which can be dissociated to form --COR2 and R'OH in which R' is the alcoholic portion of said ester; and R3 and R4 are each hydrogen, hydroxy, amino, halogen, trifluoromethyl, alkyl, alkoxy, alkylthio or alkylsulfonyl each of 1-4 carbon atoms, the substituents other than hydrogen when present being preferably in the 6- and/or 7-position of the quinazolinone nucleus provide compounds having useful activity as CNS depressants and anticonvulsants. A process is provided for preparing such compounds by ester condensation of a corresponding 2-alkyl-3-substituted-4(3H) quinazolinone with a condensable ester and excess sodium hydride in the presence of a strong ionization solvent such as refluxing 1,2-dimethoxyethane.

2-Methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone, 3a), 2,3-dimethyl-4(3H)-quinazolinone (3b), and 2-methyl-3-phenyl-4(3H)-quinazolinone (3c) were converted to the 2-lithiomethyl derivatives 4a, 4b, and 4c, respectively, by means of lithium diisopropylamide in THF-hexane at 0 deg C.Reactions of 4a-c with a series of electrophilic reagents led to elaboration at the original 2-methyl group.Thus, 4a was alkylated with methyl iodide, allyl bromide, and ethyl bromide, sulfenylated with diphenyl disulfide, and condensed with benzaldehyde and cyclohexanone.Although 4a failed to react with benzophenone and showed a preference for enolization with acetone and butanone, the less hindered salt 4b added readily to the carbonyl group of benzophenone and acetone.Lithio salt 4c underwent self-condensation on treatment with cyclohexanone.Photostimulated phenylation of 2-potassiomethyl derivative of 3a was effected with iodobenzene.Lateral acylation of 3a was accomplished with esters of aliphatic and aromatic acids in the presence of excess sodium hydride.

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This invention relates to a process for preparing benzoxazines and more particularly 2-substituted-4H-3,1-benzoxazine-4-ones, obtained by reacting at least at about room temperature in the presence of an effective amount of a tertiary amine an isatoic anhydride with an acylating compound consisting of either a carboxylic acid anhydride or an acyl halide.

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