2-(3-Acetylamino-2,2-dimethylcyclobutyl)-methyl-4(3H)-quinazolinones

Beckmann rearrangement of N-[3-(1-hydroxyimino)ethyl-2,2-dimethylcyclobutyl]acetylanthranilic acid, and its 5-bromo and 4-chloro derivatives gives the corresponding N-(3-acetylamino-2,2-dimethylcyclobutyl)acetylanthranilic acids. Treatment of these acylanthranilic acids with formamide gives 2-(3-acetylamino-2,2-dimethylcyclobutyl)methyl-4(3H)-quinazoline and its 6-bromo and 7-chloro derivatives.     

Lithiation of 2-Alkyl-3-amino- and 2-Alkyl-3-(methylamino)-4(3H)-quinazolinones(1)

3-Amino-2-methyl-4(3H)-quinazolinone has been doubly lithiated, on nitrogen and in the 2-methyl group, with n-butyllithium. The lithium reagent thus obtained reacts with a variety of electrophiles (D(2)O, benzophenone, cyclohexanone, cyclopentanone, acetophenone, benzaldehyde, tetraisopropylthiuram disulfide (TITD)) to give the corresponding 2-substituted derivatives in very good yields. Reactions of the dilithio reagent with 2 molar equiv of methyl iodide or phenyl isocyanate give disubstituted derivatives. Double lithiation of the 2-ethyl and 2-propyl analogues have been achieved using LDA, and subsequent reactions with most electophiles are then similar. In the reaction of the dianion of the 2-ethyl compound with TITD, deamination from position 3 takes place with the formation of the 2-substituted derivative. In reactions with prochiral ketones, the dianion of the 2-ethyl compound gives very high diastereoselectivity. Lithiation and subsequent reactions of 3-(methylamino) analogues take place in a similar manner, thus providing access to a range of substituted 3-(methylamino)-2-alkyl-4(3H)-quinazolinones by a general procedure. Lithiation of 3-(dimethylamino)-2-ethyl-4(3H)-quinazolinone did not take place under similar conditions. Lithiation of 3-amino-2-unsubstituted-4(3H)-quinazolinone was also unsuccessful.     

Lithiation of 3-(Acylamino)-2-unsubstituted-, 3-(Acylamino)-2-ethyl-, and 3-(Acylamino)-2-propyl-4(3H)-quinazolinones: Convenient Syntheses of More Complex Quinazolinones(1)

3-(Pivaloylamino)- and 3-(acetylamino)-4(3H)-quinazolinones react with alkyllithium reagents to give 1,2-addition products in very good yields. Lithiation takes place with LDA and is regioselective at position 2. The lithium reagents thus obtained react with a variety of electrophiles to give the corresponding substituted derivatives in very good yields. Reactions of the lithium reagents with iodine give oxidatively dimerized cyclic structures. 3-(Pivaloylamino)- and 3-(acetylamino)-2-ethyl-4(3H)-quinazolinones and 3-(pivaloylamino)- and 3-(acetylamino)-2-propyl-4(3H)-quinazolinones are lithiated at the benzylic position with LDA. The lithium reagents so produced also react with a variety of electrophiles to give the corresponding 2-substituted-4(3H)-quinazolinone derivatives in very good yields. However, lithiation of 3-(acylamino)-2-(1-methylethyl)-4(3H)-quinazolinones was unsuccessful, as were lithiations of compounds having a diacetylamino group at position 3. The amide groups have been cleaved in good yield under basic or acidic conditions from some of the products to provide access to the free amino compounds.     

Di-6R,7R1-4(3H)-Oxo-2-quinazolinyl-substituted Cyclobutanes from Pinic and sym-Homopinic Acids

The corresponding diamides were obtained from reaction of cis-3-carboxy-2,2-dimethylcyclobutylacetic acid (pinic acid) and of cis/trans-3-(carboxymethyl)-2,2-dimethylcyclobutylacetic acid (homopinic acid) dichlorides with two equivalents of 5-bromo-, 4-chloro-, and 4,5-dimethoxyanthranilic acids. Treatment of them with formamide leads to the formation of the corresponding 2,2-dimethyl-3-[4(3H)-oxo-2-quinazolinyl]methyl-1-[4(3H)-oxo-2-quinazolinyl]cyclobutanes and 2,2-dimethyl-1,3-di[4(3H)-oxo-2-quinazolinylmethyl]cyclobutanes.     

Di-4(3H)-quinazolinon-2-yl Derivatives from the Diacid Chlorides of Pinic and sym-Homopinic Acids

The corresponding diamides have been synthesized by the interaction of the diacid chlorides of cis-2,2-dimethyl-3-carboxycyclobutaneacetic acid (pinic acid) and cis-2,2-dimethylcyclobutane-1,3-diacetic acid (sym-homopinic acid) with two equivalents of anthranilic acid. Treatment of the diamides with formamide gave 2,2-dimethyl-1-[4(3H)-quinazolinon-2-yl]methyl-3-[4(3H)-quinazolinon-2-yl]cyclobutane and 2,2-dimethyl-1,3-di[4(3H)-quinazolinon-2-ylmethyl]cyclobutane respectively.     

4(3H)-喹唑啉酮类Schiff碱的合成与抗烟草花叶病毒活性

采用邻氨基苯甲酸经醋酐酰化闭环得2-甲基苯并噁嗪-4-酮, 水合肼回流合成2-甲基-3-氨基-4(3H)-喹唑啉酮, 在无水乙醇中与芳醛反应得4(3H)-喹唑啉酮类Schiff碱. 经元素分析, IR, 1H NMR, 13C NMR对所合成的化合物进行了结构确认和表征. 初步生物活性测试表明, 化合物3t具有较高的抗烟草花叶病毒活性.     

Synthesis and antiviral bioactivities of 2-aryl- or 2-methyl-3-(substituted- benzalamino)-4(3H)-quinazolinone derivatives

A simple and general method has been developed for the synthesis of various4(3H)-quinazolinone derivatives by the treatment of the appropriate 3-amino-2-aryl-4(3H)-quinazolinone with a substituted benzaldehyde in ethanol. The structures of the compoundswere characterized by elemental analysis, IR, (1)H-NMR and (13)C-NMR spectra. The title 2-aryl- or 2-methyl-3-(substituted-benzalamino)-4(3H)-quinazolinone compounds III-1~III-31 were found to possess moderate to good antiviral activity. Semi-quantitative PCR andReal Time PCR assays were used to ascertain the target of action of compound III-31against TMV. The studies suggest that III-31 possesses antiviral activity due to inductionof up-regulation of PR-1a and PR-5, thereby inhibiting virus proliferation and movementby enhancement of the activity of some defensive enzyme.     

Derivatives of 1-(2-pyridyl)-4,5,6,7-tetrahydroindazole

In reaction of oxidation of 1-(2-pyridyl)3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole, the corresponding 4,5-dioxoindazole is obtained, and then 1-(2-pyridyl)-3-methyl-4-carboxy-5-(2-methyl-2-carboxypropyl)pyrazole; in bromination reaction, a series of 5-bromo and 7-bromo derivatives is obtained. From 4,5-dioxoindazole with hydrazides of acids, a series of 4-oxo-5-acylhydrazono derivatives is obtained, and also 1-(2-pyridyl)-3,6,6-trimethyl-4-oxo-5-tosylhydroindazole, which, under the action of caustic, gives the 4-oxo-5-diazo derivative.Riga Technical University, Riga LV-1658. Translated from Khimiya Geterotsiklicheskikh Soerdinenii, No. 3, pp. 351–354, March, 1995. Original article submitted December 29, 1994.     

Synthesis and reactions of 1-(2-pyridyl)-3-methyl-4-chloro-5-formyl-6,7-dihydroindazoles

The Vilsmeier formylation of 1-(2-pyridyl)-3-methyl-4-oxo-4,5,6,7-tetrahydroindazole and its 6-phenyl derivative gives 1-(2-pyridyl)-3-methyl-4-chloro-5-formyl-6,7-dihydroindazoles. Reactions of these derivatives with different N- and C-nucleophilic agents, including bisnucleophiles, were studied as a means of obtaining new 4- and 5-functional derivatives of indazole and its condensed systems.Riga Technical University, Riga LV-1658, Latvia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 768–773, June, 1998.     

Synthesis and properties of 2-(2-oxoindolin-3-ylidene)-2-cyanoacetic acid piperidides and morpholides

The reaction of isatins with cyanoacetic acid piperidide or morpholide gives the corresponding derivatives of 2-(2-oxoindolin-3-ylidene)-2-cyanoacetic acid, which may be reduced to give amides of 2-(2-oxoindolin-3-yl)-2-cyanoacetic acid and react with ethanolic alkali to give quinoline derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.12, pp. 1611–1613, December 1992.     

Palladium-catalyzed cyclocarbonylation of o-iodoanilines with heterocumulenes: regioselective preparation of 4(3H)-quinazolinone derivatives

A catalyst system comprising palladium acetate-bidentate phosphine is effective for the cyclocarbonylation of o-iodoanilines with heterocumulenes at 70-100 degrees C for 12-24 h to give the corresponding 4(3H)-quinazolinone derivatives in good yields. Utilizing o-iodoaniline with isocyanates, carbodiimides, and ketenimines for the reaction, 2,4-(1H,3H)-quinazolinediones, 2-amino-4(3H)-quinazolinones and 2-alkyl-4(3H)-quinazolinones were obtained, respectively. The nature of the substrates including the electrophilicity of the carbon center of the carbodiimide, and the stability of the ketenimine, influence the product yields of this reaction. Urea-type intermediates are believed to be generated first in situ from the reaction of o-iodoanilines with heterocumulenes, followed by palladium-catalyzed carbonylation and cyclization to yield the products.     

Synthesis and reactions of 1-(4-bromo-, 4-fluoro-, and 4-trifluoromethylphenyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazoles

From 2-formyldimedone and 4-bromo-, 4-fluoro-, and 4-trifluoromethylphenylhydrazines we have obtained the corresponding 2-arylhydrazinomethylenedimedones, which in acid medium undergo ring closure to form 1-substituted 6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazoles. Oxidation of the latter by selenous acid leads to the corresponding 4,5-dioxo-4,5,6,7-tetrahydroindazoles, which then were converted to derivatives of 4,5-dihydro-3H-pyrazolo[4,3-a]phenazine and 4,5-dihydro-1H(3H)-indazolo[4,5-d]imidazole.Riga Technical University, Riga LV-1658. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1669–1675, December, 1997.     

Reactions of 3-methyl-1-(2-pyridyl)-4-chloro-5-formyl-6,7-dihydroindazole

The reactions of 3-methyl-1-(2-pyridyl)-, 3-methyl-1-phenyl-, and 3-methyl-1,6-diphenyl-4-chloro-5-formyl-6,7-dihydroindazoles with guanidine and benzo- and 3- and 4-pyridinecarbamidines gave the corresponding 8-substituted 1-methyl-3-(2-pyridyl)-and 1-methyl-3-phenyl-4,5-dihydropyrazolo[5,4-h]quinazolines. With acetic anhydride the same indazole derivatives gave the 4-acetoxy-5-formyl derivatives, and with hydroxylamine they gave4-chloro-5-hydroxyiminomethyl-6,7-dihydroindazoles. Thereactionof4-acetoxyl-1-(2-pyridyl)-5-formyl-6,7-dihydroindazole with hydroxylamine gave 8-methyl-6-(2-pyridyl)-4,5-dihydroisoxazolo[5,4-e]indazole, while dehydration of 5-hydroxyiminomethyl-3-methyl-4-chloro-6,7-dihydroindazole gave the 4-chloro-5-cyano derivative. The reaction of the latter with nucleophilic reagents was investigated.Riga Technical University, Riga, Latvia LV-1658. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1209–1213, September, 1998.     

Development of a new synthesis of 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone,sodium salt via an amidine intermediate

A new synthesis of the recently reported 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone, sodium salt ( 1 , MDL-427), an experimental mediator release inhibitor, was developed from: (1) reaction of 5-aminotetrazole 3 and triethyl orthoformate 6 to give ethyl N-(1H-tetrazol-5-yl)formimidate 8 , (2) reaction of methyl anthranilate and imidate 8 to give amidine 11 , and (3) treatment of 11 with base to give 1 . Investigation of each of these steps independently led to a significantly more efficient, facile and higher-yielding 1-pot process. A brief examination of anthranilic acid 13 and its salts and derivatives 14 to 17 in this process found them to have dissimilar reactivities. The formation of amidine 11 as an isolable intermediate was unusual, as was its failure to cyclize under standard neutral or acidic conditions. The absolute requirement for base to effect cyclization of 11 appears to be unprecedented.     

Synthesis and study of 2-(1-pyrazolyl)pyrimidine derivatives

Alkyl derivatives of 2-(1-pyrazolyl)-4(3H)-pyrimidinone were synthesized and converted to 4-chloro-, 4-arylamino-, and 4-hydrazino-2-(1-pyrazolyl)pyrimidines. The corresponding hydrazones were obtained by reaction of 5-ethyl-2-hydrazino-6-methyl-2-(4-ethyl-3,5-di-n-propylpyrazolyl) pyrimidine with isatin and salicylaldehyde. The UV and IR spectra of the synthesized compounds were studied. It was established that the hydrazones contain intra-molecular hydrogen bonds.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1255–1257, September, 1977.     

Potassium Fluoride Promoted Reaction of 3-Acylsubsti-Tuted 2H-1-Benzopyran-2-Ones with Acid Anhydrides. An Improved Method for the Synthesis of 4-(2-Oxoalkyl)-2H-Chroman-2-Ones. Part III1

The reaction of 3-acylsubstituted 2H-1-benzo-pyran-2-ones 1, 5 and 11a-c with acid anhydrides in the presence of potassium fluoride (KF)/molecular sieves 4A gives the 4-(2-oxoalkyl)-2-oxochromans 2, 6 and 12a-c as the main products. Also the 3-carboxylic acid derivatives, such as esters and N,N-dialkylamides, of 2H-1-benzopyran-2-one (11d-g) react with isobutyric acid anhydride in the presence of KF/molecular sieves 4A to give the corresponding 2-oxochroman-4-acetic acid derivatives.     

Synthesis and reactions of 1-(4-chloro-, 3-chloro-, 2-chloro-, 2,4-dichloro-, and 2,4-difluorophenyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazoles

Reaction of the potassium salt of 2-formyldimedone with hydrochlorides of 4-chloro-, 3-chloro-, 2-chloro-, 2,4-dichloro-, and 2,4-difluorophenylhydrazines gave the corresponding 2-arylhydrazinomethylene-dimedones which cyclized in acid media to 1-substituted 6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazoles. Oxidation of the latter with selenious acid gave the corresponding 4,5-dioxo-4,5,6,7-tetrahydroindazoles which were further converted into 3-aryl-5,5-dimethyl-4,5-dihydro-3H-pyrazolo[4,3-a]phenazines and 2,6-diaryl-4,4-dimethyl-4,5-dihydro-1H(3H)-indazolo[4,5-g]imidazoles.Riga Technical University, Riga LV-1658, Latvia; e-mail: marina@osi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, 533–539, April, 2000.     

3-(Hetarylamino)- and 3-[(hetarylmethyl)amino]-isoquinolin-1(2H)-ones

The reaction of 2-(cyanomethyl)benzoic acid with amines RNH₂ (R = Ar, Het, CH₂Ar, CH₂Het) leads to the formation of the corresponding 3-NHR-isoquinolin-1(2H)-ones. When R = CH₂Ar and CH₂Het, there is a side reaction involving hydrolysis of the hydrolytically-unstable intermediates, derivatives of 2-(2-amino-2-iminoethyl)benzoic acid, leading to 2-R-isoquinoline-1,3(2H,4H)-diones.     

Synthesis and properties of 3-cyano-4-(4-cyanophenyl)-1,4-dihydropyridine-2(3H)-thiones

Piperidinium 3-cyano-4-(4-cyanophenyl)-1,4-dihydropyridine-2(3H)-thiolates were obtained by the condensation of 1,3-dicarbonyl compounds, 4-cyanobenzaldehyde, and cyanothioacetamide in the presence of an equimolar amount of piperidine. The acidification of these thiolates gave the corresponding 1,4-dihydropyridine-2(3H)-thiones and pyridine-2(1H)-thione. Alkylation of 1,4-dihydropyridine-2-thiolates or the reaction mixture of the three-carbon condensation using iodacetamide gave 2-carbamoylmethylthio-1,4,5,6-tetrahydro- or 1,4-dihydropyridines, which were characterized by their conversion to 4,7-dihydrothieno[2,3-b]pyridines.Latvian Institute of Organic Synthesis, LV-1006, Riga, LatviaTranslated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 794–798, June, 2000.     

Synthesis of Halomethyl Derivatives of 3- and 4-(Dialkoxyphosphorylmethyl)-5-tert-butylfuran-2-carboxylic Acid and Their Reactions with Nucleophilic Agents

5-tert-Butyl-4-chloromethyl-, 5-tert-butyl-4-(diethoxyphosphorylmethyl)-3-methylfuran-2-carboxylates are effectively brominated with N-bromosuccinimide by the 3-methyl group. The bis(halomethyl)derivative is phosphorylated under conditions of the Arbuzov reaction to give the corresponding chloromethylphosphonate. The obtained organophosphorus derivatives of bromomethyl- and chloromethylfuran-2-carboxylic acid react with secondary amines and sodium butanethiolate to form the corresponding substitution products. Alkyl 5-tert-butyl-4-chloromethyl-3-(diethoxyphosphorylmethyl)-furan-2-carboxylate reacts with sodium acetate in acetic acid to give a 4-acetoxymethyl derivative. It is the first example of a facile reaction with O-nucleophiles of halomethyl derivatives of phosphonomethylated furans.