Improved synthesis of functionalized 5,6-dihydro-pyrimido[4,5-b][1,4]oxazepines

Novel synthetic approaches toward 5,6-dihydro-pyrimido[4,5-b][1,4]oxazepines were reported that led to successful introduction of poorly reactive anilines and various 2-hydroxybenzaldehydes to this therapeutically relevant scaffold. More extensive SAR studies on this scaffold hence became possible.     

Novel synthesis of pyridazino[4,5-b][1,4]oxazin-3,8-diones

A novel and effective synthesis of pyridazino[4,5-b][1,4]oxazin-3,8-diones via Smiles rearrangement is presented. Treatment of N-substituted 2-chloro(or hydroxy)acetamide, 2-tetrahydropyranyl-4-chloro-5-hydroxy(or chloro)pyridazin-3-one and cesium carbonate in refluxing acetonitrile was afforded the corresponding pyridazino[4,5-b][1,4]oxazin-3,8-diones in excellent yield.     

Rapid access to multi-substituted pyrimido[4,5-b][1,4]diazepine-2,4,6-trione and pyrimido[4,5-b][1,4]diazepine-2,4-dione as novel and versatile scaffolds for drug discovery

A novel pyrimido[4,5-b][1,4]diazepine-2,4,6-trione was synthesized with an efficient strategy. Especially, the key intermediate 2,4-dimethoxypyrimido[4,5-b][1,4]diazepin-6-one was promoted by one pot tandem reduction-cyclization with Na₂S₂O₄. Subsequently, reduction of lactams 6 with LiAlH₄ afforded a more flexible scaffold of pyrimidodiazepines. The synthetic strategy was versatile since it facilitated the sequential functionalization on the pyrimidodiazepine at three positions. Thus a convenient and effective method for the rapid preparing of multi-substituted pyrimido[4,5-b][1,4]diazepines was developed.     

Synthesis of 2,6-disubstituted pyrido[2,3-b][1,4]oxazines

A new preparative method for pyrido[2,3-b][1,4]oxazines from 6-substituted 3-nitro-2-pyridones is demonstrated. This method consists of two steps: O-alkylation and reductive cyclization. In the former step, the bulkiness of both starting nitropyridones and C2 reagents is found to be essential for avoiding N-alkylation, which undergoes O-alkylation efficiently. The subsequent reductive cyclization affords pyridoxazines with carbon substituents at both the 2- and the 6-positions that have not been available.     

Synthesis of substituted [1,3]thiazolo[4,5-b]pyridines and [1,3]thiazolo[4,5-d][1,2,3]triazines

In this work, we described an easy preparation of substituted 4-amino-5-cyano-1,3-thiazoles. These compounds have been used as starting materials to obtain two classes of compounds. New substituted [1,3]thiazolo[4,5-e]pyridines were synthesized in one step via Friedländer reaction. Diazotation of 4-amino-5-cyano-1,3-thiazoles afforded 4-chloro[1,3]thiazolo[4,5-d][1,2,3]triazines in one step. The later was substituted by a secondary amine to obtain substituted 4-amino[1,3]thiazolo[4,5-d][1,2,3]triazines.     

Synthesis of substituted 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine as new scaffolds for potential bioactive compounds

The title compounds having different substituents on the heterocyclic framework were prepared by several methods from 2-acetamido-3-hydroxypyridine. The condensation of 2-protected-amino-3-hydroxypyridine with 2-chloroacrylonitrile or ethyl 2,3-dibromopropionate provided in several cases two isomeric pyrido-oxazines. Whereas the reaction of 2-acetamido-3-hydroxypyridine with methyl 2,3-dibromopropionate or with α-halocarbonyl compounds gave exclusively the 2-substituted pyrido-oxazine, in a one-step operation.     

Bischler-Napieralski cyclocondensation in the synthesis of new 11H-pyrimido[4,5-b][1,4]benzodiazepines

A synthetic strategy based on nitrosation-aminolysis-nitroso reduction and Bischler-Napieralski cyclocondensation has been developed for the synthesis of a family of 2-amino-4-methoxy-11H-pyrimido[4,5-b][1,4]benzodiazepines.     

Synthesis of 1,4-benzodiazepino[4,5-d][1,4]benzoxazepines

The novel 1,4-benzodiazepino[4,5-d][1,4]benzoxazepine ring system has been constructed via preformed benzoxazepine intermediates. Several derivatives have been prepared as potential anxiolytic agents.     

Coupling to the pyrimido[4,5-b][1,4]oxazine ring system: Synthesis of potential antifolates

The ability of 2-amino-4-hydroxy-7H-pyrimido[4,5-b][1,4]oxazine derivatives to inhibit dihydrofolate reductase led to a search for means of synthesizing new side chain substituted analogs of this marginally stable pyrimidooxazine system. A study of the synthesis and use of 6-functionalized pyrimido[4,5-b][1,4]oxazines for coupling side chains was begun and has now revealed methods for coupling p-aminobenzoic acid with 2-amino-4-hydroxy-6-carboxy-7H-pyrimido[4,5-b][1,4]oxazine and hydrolyzed 2-amino-4-hydroxy-6-carbe-thoxymethylene-6,7-dihdyro-5H-pyrimido[4,5-b][1,4]oxazine. The products are of interest for evaluation as potential antifolates.     

The Synthesis of pyrimido[4,5-b][1,4]diazocines and pyrido[2,3-b][1,4]diazoeines

The reaction conditions for the preparation of 7H,8H-1,3-dimethyl-2,4,6,9-tetraoxopyrimidino[4,5-b][1,4]-diazocine ( 9 ), 1,3-dimethy 1–2,4,6,11-tetraoxobenzo[f]pyrimidino[4,5-b][1,4]diazocine ( 10 ), 7H,8H-1,3-dimethyl-2,4,6,10-tetraoxopyrimidino[4,5-b][1,4]diazonine ( 16 ), and 7H,8H-6,9-dioxopyridino[2,3-b][1,4]diazocine ( 19 ) were determined. The mechanism of the formation of these compounds was established. The scope of these reactions was found to be general for eight and nine ring formation from 2,3-diamino-N-heterocycles.     

A novel approach to functionalised 5,7,8,9-tetrahydropyrimido[4,5-b][1,4]diazepin-6-ones using intramolecular palladium-catalysed amidation

The development of a novel palladium-catalysed amidation approach towards 5,7,8,9-tetrahydropyrimido[4,5-b][1,4]diazepin-6-one templates is highlighted. The route proceeds through the reaction of an amino amide, generated by 1,4-addition of an amine to an acrylamide, with 5-bromo-2,4-dichloropyrimidine and final palladium-catalysed cyclisation to provide the functionalised scaffold in up to 60% isolated yield over three steps. The route offers efficiency advantages over the previously reported nitro-reduction cyclisation approach to these molecules. It also provides alternative means to introduce bulky alkyl substituents at the amide nitrogen. The application of this route in the synthesis of a variety of analogues is described.     

First synthesis and further functionalization of 7-chloro-imidazo[2,1-b][1,3]thiazin-5-ones

A convenient four-step preparation route to novel 7-chloro-imidazo[2,1-b][1,3]thiazin-5-ones is presented, starting from methyl phenylglyoxylate. A unique feature of this synthesis is a heterocyclization strategy, in which a halogen atom is introduced already during the ring closure. 7-Chloro-6-phenyl-imidazothiazinones with a broad range of various substituents in the phenyl and imidazole moieties are obtainable by this method, as well as different chlorinated triazolothiazinones. The chloro function can be easily replaced in nucleophilic substitution reactions by amino, alkoxy and arylthio groups as well as by a fluoro atom.     

Synthesis of pyrimido[4,5-e][1,4]oxazepin-5-ones

Eighteen novel pyrimido[4,5-e][1,4]oxazepin-5-ones were prepared directly via the reaction of either ethyl 4-chloro-2-phenyl-5-pyrimidinecarboxylate (Ia) or ethyl 4-chloro-2-m-chlorophenyl-5-pyrimidinecarboxylate (Ib) with a variety of substituted 2-(alkylamino)ethanols. A typical example was the preparation of 8,9-dihydro-9-methyl-2-phenylpyrimido[4,5-e][1,4]-oxazepin-5(7H)-one (IIa) from the reaction of Ia with 2-(methylamino)ethanol. Hydrolytic cleavage of the lactone ring in IIa with sodium hydroxide solution, followed by acidification with hydrochloric acid afforded 4-[(2-hydroxyethyl)methylamino]-2-phenyl-5-pyrimidinecarboxylic acid (IV). Reactions of IIa with concentrated ammonium hydroxide or hydrazine also caused cleavage of the lactone ring, giving the corresponding amide (V) or hydrazide (VI), respectively. Structural assignments were supported by infrared and nuclear magnetic resonance spectra.     

Synthesis of imidazo[4,5-e][1,4]diazepine-8-one

We have developed a method for synthesis of 1-methyl-4,5,7, 8-tetrahydro-6H-imidazo[4,5-e][1,4]diazepin-8-one. We have shown that in intramolecular cyclization of N-(2-hydroxyethyl)- or N-(2-chloroethyl)amides of 1-methyl-4-aminoimidazolyl-5-carboxylic acids it is not the corresponding tetrahydroimidazo[4,5-e][1,4]diazepin-8-ones which are formed but rather the isomeric 4-amino-5-(oxazolin-2-yl)imidazoles.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1203–1206, September, 1993.     

Synthesis of tricyclic 4-chloro-pyrimido[4,5-b][1,4]benzodiazepines

[reaction: see text] A novel methodology was developed for the efficient synthesis of 4-chloro-pyrimido[4,5-b][1,4]benzodiazepines. The key is the intramolecular Friedel-Crafts cyclization of 5-amino-4-(N-substituted)anilino-6-chloropyrimidine with either a carboxylic acid or its derivatives to construct the 4-chloro-pyrimido[4,5-b][1,4]benzodiazepine core. Subsequent nucleophilic substitution allows the introduction of one more diversity point in the target molecules. This strategy provides an efficient method to access a library of compounds based on privileged substructures that are of great interest in drug discovery.     

Intramolecular amidation: synthesis of novel imidazo[2,1-b][1,3,4]thiadiazole and imidazo[2,1-b][1,3]thiazole fused diazepinones

Novel heterocyclic systems 2-alkyl/aryl-9-(2-hydroxybenzylidene)-7,9-dihydro-8H-[1,3,4]thiadiazolo[2′,3′:2,3]imidazo[4,5-d][1,2]diazepin-8-one and 9-(2-hydroxy-benzylidene)-3,3-dimethyl-3,4,7,9-tetrahydro-2H-11-thia-4b,6,7,10-tetraazaindeno[1,2-a]azulene-1,8-dione are synthesized via an intramolecular amidation reaction. An interesting ring opening and cyclization of 2-alkyl/aryl-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde and 6,6-dimethyl-8-oxo-2-(2-oxo-2H-chromen-3-yl)-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]benzothiazole-3-carbaldehyde are discussed.     

Synthesis of 2-benzylimidazo[2,1-b][1,3]benzothiazoles through palladium-catalyzed heteroannulation of acetylenic compounds

The reaction of 2-imino-3-(2-propynyl)-1,3-benzothiazole with various iodobenzenes in the presence of a palladium catalyst leads to the production of 2-benzylimidazo[2,1-b][1,3]benzothiazoles.