Cyclic imides. 16. Hydroxy and methoxy derivatives of aminophthalimide and phthalhydrazide

Treatment of N-alkyl derivatives of 3,6-dichlorophthalimide and 4,5-dichlorophthalimide with potassium nitrite gave 3-hydroxy-6-nitro- and 4-hydroxy-5-nitrophthalimides. The potassium salts of these phenols were alkylated by dialkyl sulfates. The products were reduced to the 3-amino-6-alkoxy- and 4-amino-5-alkoxyphthalimides, and the fluorescence emission spectra of these products were measured. Hydrazinolysis of the phthalimides in a toluene medium gave phthalhydrazides. The luminescence spectra of several aminophthalhydrazides were measured. The infrared and proton magnetic resonance spectra of these and of some nitrophthalhydrazides were measured and aspects of these spectra characteristic of phthalhydrazides were identified.     

Reaction of 4,5-diamino, 5-amino-4-glucosylamino and 4-amino-5-glucosylaminopyrimidines with nitrous acid. synthesis,anticancer and anti-aids activities of 8-azapurines

The reaction of the 4,5-diamino, 5-amino-4-glucosylamino and 4-amino-5-glucosylaminopyrimidines 3a, 3b, 3c and 4 with nitrous acid is described. The 8-azapurines 7a, 7c, 8 and the N-nitrosoamino derivative 5 have been obtained. Some of these products were tested for anticancer and anti-AIDS activity.     

Cyclic imides IV. The reaction of some N-substituted nitrophthalimides with sodium methoxide

Treatment of methyl 4-nitrophthalimidoacetate (I) with sodium methoxide in refluxing methanol results in a Gabriel-Colman rearrangement to give 7 - nitro-4-hydroxy-3-carbomethoxy-1(2H) - isoquinolone (II). Under the same conditions, N-substituted 3-nitrophthalimides (IV) yield N-substituted 3-methoxyphthalimides (V).     

Derivatives of 2,3-Dihydrocyclopenta[d] pyrido[1,2-a] pyrimidin-10(1H)one

The annulation of 2-amino-3-hydroxy-, 2-amino-3-carboxy-, and 2-amino-3-methylpyridine with ethyl cyelopenlanone-2-earboxylate led to the 5-hydroxy-, 2 , 5-carboxy-, 3, and 5-methyl-, 4 , derivatives of the 2,3-dihydrocycloperita[d]pyrido[1,2-a]pyrimidin-10(1H) one heterocycle. Alkylation of 2 with α-bromotolue, ne gave the 5-benzyloxy derivative.     

3(2H)isoquinolones. 2. Studies on the structure and formation of aminonaphthols obtained in the preparation of 3(2H)isoquinolones

The reaction of a 2-acylphenylacetic acid derivative (I) with primary amines in glacial acetic acid produces novel, colorless aminonaphthols (III) which are isomeric with the brilliant yellow 3(2H)isoquinolones (II) obtained in the same reaction. A combination of chemical and spectral techniques allowed identification of the isomers as derivatives of 4-amino-2-naphthol. A plausible mechanism of formation of aminonaphthols versus 3(2H)isoquinolones is discussed and supported by chemical synthesis of N-substituted 2-aeylphenylacetamides (VIII) and a 1,4-dihydro-1-hydroxy-3(2H)isoquinolone derivative (IX).     

Synthesis of 4-chloro-7-ethoxy-2(3H)-benzoxazolone-6-carboxylic acid

As a part of metabolic studies of mosapride ( 1 ), a potential gastroprokinetic agent, the synthesis of 4-chloro-7-ethoxy-2(3H)-benzoxazolone-6-carboxylic acid ( 7 ) as a derivative of 4-amino-5-chloro-2-ethoxy-3-hydroxybenzoic acid ( 6 ), which has served a benzoic acid part of the metabolites 4 and 5 , is described. Treatment of methyl 3-amino-4-substituted amino-5-chloro-2-ethoxybenzoate derivatives 11a-c with sodium nitrate in acidic medium gave the benzotriazole derivatives 13x,y instead of the objective 3-hydroxy counterpart. The synthesis of 7 started from o-vanillin acetate ( 15 ) and proceeded through the intermediates 2-hydroxy-3-methoxy-4-nitrobenzaldehyde ( 18 ), methyl 4-amino-2,3-dihydroxybenzoate ( 23 ), and methyl 7-hydroxy-2(3H)-benzoxazolone-6-carboxylate ( 30 ). Compound 30 was alternatively prepared from 23 via methyl 4-ethoxycarbonylamino-2-ethoxycarbonyloxy-3-hydroxybenzoate ( 29 ), which is the product resulting from the migration of the ethoxycarbonyl group of methyl 4-amino-2,3-diethoxycar-bonyloxybenzoate ( 27 ).     

The synthesis of 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidines. II. 4-Hydroxy, 4-mercapto, 2-amino-4-hydroxy and 2,4-dihydroxy derivatives

Several new types of compounds in the 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine series have been prepared. Included are a 6-acyl derivative unsubstituted in the pyrimidine ring, as well as 4-hydroxy, 4-mercapto, 2-amino-4-hydroxy and 2,4-dihydroxy derivatives. These products were derived directly or indirectly from 4-cyano- or 4-carbethoxy-1-acyl-3-amino-3-pyrroline intermediates. 3-Hydroxy, 3-amino, and 3-thioformylamino-1-acyl-3-pyrroline-4-thiocarboxamides have been obtained and the 3-thioformylamino derivatives shown to undergo base-catalyzed cyclization to close a 4-mercaptopyrimidine ring.     

Derivatives of Condensed Pyridopyrimidines. 3. Synthesis of Condensed Imidazo[4,5-b]pyridine and also 4-Oxo- and 2,4-Dioxopyrido[2,3-d]pyrimidines

A convient methods has been developed for the synthesis of condensed imidazo[4,5-b]pyridine and also 4-oxo- and 2,4-dioxopyrido[2,3-d]pyrimidines. The optimum conditions for the Curtius rearrangement of 2-amino-3-azidocarbonyl derivative of pyrano[4,3-b]pyridine have been established.     

Reaction of sulfene and dichloroketene with open-chain N,N-disubstituted α-aminomethyleneketones. Synthesis of 4-dialkylamino-3,4-dihydro-5,6-dimethyl-1,2-oxathiin 2,2-dioxides and of 6,(5)(di)alkyl-3-chloro-4-methylphenylamino-2H-pyran-2-ones

Cycloaddition of sulfene to N,N-disubstituted 4-amino-3-methyl-3-buten-2-ones (III) occurred in fair to good yield only in the case of aliphatic N-substitution to give 4-dialkylamino-3,4-dihydro-5,6-dimethyl-1,2-oxathiin 2,2-dioxides, whereas N,N-disubstituted 1-amino-1-penten-3-ones (II) did not react at all. Cycloaddition of dichloroketene to II, III and N,N-disubstituted 4-amino-3-buten-2-ones occurred only in the case of the methylphenylamino derivative, giving in good to moderate yield 6,(5)(di)alkyl-3,3-dichloro-3,4-dihydro-4-methylphenylamino-2-Hpyran-2-ones, which were dehydrochlorinated with DBN to 6,(5)(di)alkyl-3-chloro-4-methylphenylamino-2H-pyran-2-ones.     

Synthesis of the new ring system,Pyrazolo[3,4-d][1,3]diazepine. A novel route for the synthesis of azolo[1,3]diazepines

A reduction of the nitrile group of 5-amino-4-cyano-1-methylpyrazole ( 3 ) has provided the very versatile compound 5-amino-1-methylpyrazole-4-carboxaldehyde ( 4 ). The amino group of 4 was protected using di-methylformamide dimethylacetal and the aldehyde group was then reacted with trimethylsilyl cyanide to afford the moisture sensitive compound 5-[[(dimethylamino)methylene]amino]-4-[cyano(trimethylsiloxy)-methyl]-1-methylpyrazole ( 10 ). The cyano group of the cyanohydrin 10 was reduced using a cobalt boride catalyst to afford an intermediate aminomethyl group which was involved in an in situ annulation. This reaction provided 1-methyl-1,4,5,6-tetrahydropyrazolo[3,4-d][1,3]diazepin-4-ol, a derivative of the new ring system, pyrazolo[3,4-d][1,3]diazepine.     

Some transformations of 3-amino-4-alkoxycarbonyl-6-hydroxy-2H-1-benzopyran-2-ones. The synthesis of [1] benzopyrano[3,4-d]-[1,3]oxazine and [1] benzopyrano[3,4-d]pyrimidine derivatives

Acylation of 4-alkoxycarbonyl-3-amino-6-hydroxy-2H-1-benzopyran-2-one derivatives 3 and 4 gave under mild conditions the O-substituted derivatives 5–10, N,O -disubstituted derivative 11 and N,N-disubstituted derivative 12 . The compound 4 was transformed with benzoyl chloride under more drastic conditions into 13 , a derivative of a new heterocyclic system 2-benzopyrano[3,4-d][1,3]oxazine. The derivatives of 1-benzopyrano-[3,4-d]pyrimidine 19 and 20 were prepared either from 3 and 4 through the corresponding N-heteroarylformamidines 14 and 15 and N-heteroarylformamide oximes 17 and 18 or by cyclization of thiourea derivative 20 .     

Synthesis of 5-amino-1,3-dimethylpyrazol-4-yl aryl ketones

A convenient preparation of 5-amino-1,3-dialkylpyrazol-4-yl heterocyclic ketones is reported. They are prepared from the reaction of heterocyclic esters with the di-lithio derivative from N-(4-bromo-1,3-dimethyl-1H-pyrazol-5-yl)benzamide ( 1 ).     

Synthetic studies of potential antimetabolites. XIII. Synthesis of 7-amino-3-β-d-ribofuranosyl-3H-imidazo[4,5-b] pyridine (1-deazaadenosine) and related nucleosides

7-Amino-3-β-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine (III, 1-deazaadenosine) was synthesized in 32% yield from the diacetyl derivative prepared from 7-aminoimidazo[4,5-b ]pyridine (1-deazaadenine) and 1,2,3,5-tetra-O-acetyl-β-D-ribose by the fusion method. A synthesis of 7-amino-4-b?-D-ribofuranosyl-4H-imidazo[4,5-b]pyridine (IV) was also achieved.     

Reactivity of some 3-substituted derivatives of 2,6-dihalogenopyridines towards potassium amide in liquid ammonia [a]

Reactions of 2,6-dichloro-3-phenyl-, 2,6-dibromo-3-phenyl-, 2,6-dichloro-3-dimethylamino- and 2,6-dibromo-3-dimethylaminopyridine with potassium amide in liquid ammonia were investigated. Whereas 2,6-dichloro-3-phenylpyridine yields 4-amino-2-benzylpyrimidine, from 2,6-dibromo-3-phenylpyridine as a product of a novel ring fission 2-amino-l-cyano-l-phenyl-but-l-en-3-yne was isolated, together with 4-amino-6-bromo-3-phenylpyridine and 2,6-diamino-3-phenylpyridine. It was shown that neither 2-amino-6-bromo-3-phenyl- nor 6-amino-2-bromo-3-phenylpyridine are intermediates in the formation of the 2,6-diamino derivative, as these bromo compounds are transformed in the basic medium into 1,3-dicyano-l-phenylpropene. From both 2,6-di-chloro-3-dimethylamino- and 2,6-dibromo-3-dimethylaminopyridine mixtures are obtained from which only 2-amino-l-cyano-l-dimethylamino-but-l-en-3-yne and 4-amino-6-halogeno-3-dimethylaminopyridine were isolated. Mechanisms for the reactions studied are proposed, i.e. a S_N(ANRORC) mechanism for the aminodebromination of 2,6-dibromo-3-phenylpyridine into the corresponding 2,6-diamino compound.     

Synthesis of Methyl 3-Amino-3,4-Dideoxy-α and ß-D-Xylo-Hexopyranosides

ABSTRACT

3-Azido-3-deoxy-D-glucose was used as starting material for the syntheses of methyl 3-amino-3,4-dideoxy- ß and α-D-xylo-hexopyranoside 9 and 15 and methyl 3-amino-4-chloro-3,4-dideoxy- ß and α-D-galactopyranoside 11 and 17. The ß-D-anomers 9 and 11 were stereoselectively obtained using Koenigs-Knorr conditions for the glycosidation step with the bromo derivative 3 as intermediate.     

A series of novel acyclic nucleosides. II. Synthesis of acyclic nucleosides bearing an imidazo[4,5-d] [1,3]oxazine ring

Novel acyclic nucleosides 3a,b,c where N-1 of acyclovir is replaced by oxygen atom were prepared. Thus, 1-[(2-acetoxyethoxy)methyl]-5-amino-4-ethoxycarbonylimidazole ( 9 ) was treated with ethoxycarbonyl isothiocyanate or benzoyl isothiocyanate to give 11e,f . Methylation of the latter with methyl iodide afforded S-methylisothiourea derivative 12f which was treated with alkali and subsequently the mixture was neutralized to give 5-amino-3-[(2-hydroxyethoxy)methyl]-3H-imidazo[4,5-d][1,3]oxazin-7-one ( 3a ). Compounds 3b,c were obtained by treatment of acetic anhydride or propionic anhydride with sodium 5-amino-1-[(2-hydroxyethoxy)methyl]imidazole-4-carboxylate ( 7 ) which was prepared via 5-amino-[(2-acetoxyethoxy)methyl]-imidazole-4-carboxamide ( 5 ). Evaluation of acyclic oxanosine analogs for cytotoxicity and activity against herpes simplex virus type 1 (HSV-1) revealed that all the derivatives tested were inactive, but cytotoxicity were similar or less as compared to that of acyclovir.     

Triazoles. III. The alkylation of 3-R′-thio-5-amino-1,2,4-triazoles

The alkylation of 3-R′-thio-5-amino-1H-1,2,4-triazoles 1 or their sodium salt with alkyl and aralkyl halides 2 , respectively, to yield all the four possible monoalkylated derivatives 3, 4, 5 and 6 was studied. The comparison of the spectral data of different type isomers 3, 4, 5 and 6 isolated and their Schiff bases 8, 9 and 10, respectively, was unequivocal evidence in support of their structure which was then further supported by independent synthesis and ring closure reactions. According to an hplc study the main product of the alkylation is derivative 3 , the by-product is derivative 4 , while derivatives 5 and 6 are formed only in insignificant amounts.     

Synthesis of hybrid perillyl-4H-pyrans. Cytotoxicity evaluation against hepatocellular carcinoma HepG2/C3A cell line

A series of 15 new hybrid perillyl-4H-pyrans compounds was straightforwardly synthesized by a strategy combining the multicomponent reaction and the copper-catalyzed alkyne-azide cycloaddition (CuAAC). The 2-amino-4H-pyrans-3-carbonitrile containing the alkyne moiety was prepared via multicomponent reaction between 1,3-dicarbonyl, a propargyloxy aromatic aldehyde and malononitrile or ethyl α-cyanoacetate. The alkyne derivative was sequentially reacted with the perillyl azide component through the copper-catalyzed [3+2] Huisgen cycloaddition reaction. The antiproliferative activity of hybrid compounds were evaluated against the human hepatoma HepG2/C3A cell line.     

On The Chemistry of Cinnoline IV [1]. Synthesis and Reactions of (4-Aminocinnolin-3-yl)-aryl-methanones

 The synthesis of a series of disubstituted (4-aminocinnolin-3-yl)-aryl-methanones from aryl-hydrazonomalononitrile in a one-step procedure is described. Cyclocondensation of (4-amino-6,8-dimethyl-cinnolin-3-yl)-phenyl-methanone with malononitrile, diethylmalonate, and dimethylacetamide-dimethylacetal gave the corresponding pyrido[3,2-c]cinnoline derivatives. Treatment of (4-amino-6,8-dimethyl-cinnolin-3-yl)-phenyl-methanone with triethyl-orthoacetate under reflux readily afforded the corresponding imidoester which underwent cyclization to a pyrido[3,2-c]cinnoline derivative. This starting compound could also be annelated to the corresponding 1,2-dihydro-4-aryl-2-oxo-pyrido[3,2-c]cinnoline derivatives via the (4-acetamidocinnolin-3-yl)-aryl-methanones. Chemical and spectroscopic evidences for the structures of the new compounds are presented. The effect of three of the compounds against sixty cancer types was tested.     

Reaction of sulfene and dichloroketene with open-chain N,N-disubstituted α-aminomethyleneketones. Synthesis of 4-dialkylamino-3,4-dihydro-6-methyl-5-phenyl-1,2-oxathiin 2,2-dioxides and of N,N-disubstituted 4-amino-3-chloro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones

Cycloaddition of sulfene to N,N-disubstituted 4-amino-3-phenyl-3-buten-2-ones (III) occurred in good yield only in the case of aliphatic N-substitution to give 4-dialkylamino-3,4-dihydro-6-methyl-5-phenyl-1,2-oxathiin 2,2-dioxides, whereas N,N-disubstituted 4-amino-1-phenyl-3-buten-2-ones (IV) did not react at all. Polar 1,4-cycloaddition of dichloroketene to III and IV occurred partly in the case of aromatic N-substitution, with the exception of the morpholino derivative IVd, giving in low yield N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones, which were dehydrochlorinated with DBN to the corresponding 4-amino-3-chloro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones (VII) in good yield. In some cases of aliphatic N,N-disubstitution of III and IV, cycloaddition led directly to N,N-dialkyl derivatives VII in low yield.