Synthesis of 5,8-dihydro-5-oxo-2-(3- or 4-pyridinyl)-pyrido[2,3-d]pyrimidine-6-carboxylic acids and the reinvestigation of the thermal cyclization of diethyl (2-hydroxy-4-pyrimidinyl)amino-methylenemalonate

Diethyl [2-(3- or 4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonates 5 prepared by the reaction between 2-(3- or 4-pyridinyl)-4-pyrimidinamines 3 and diethyl ethoxymethylenemalonate ( 4 ) were thermally cyclized to afford ethyl 5,8-dihydro-5-oxo-2-(3- or 4-pyridinyl)pyrido[2,3-d]pyrimidine-6-carboxylates 6 . The later were alkylated with ethyl iodide and then saponified to give 5,8-dihydro-8-ethyl-5-oxo-2-(3- or 4-pyridinyl)pyrido-[2,3-d]pyrimidine-6-carboxylic acids 2 . Thermal cyclization of diethyl (2-hydroxy-4-pyrimidinyl)amino-methylenemalonate ( 8 ) gave ethyl 1,6-dihydro-4,6-dioxo-4H-pyrimido[1,6-a]pyrimidine-3-carboxylate ( 10 ) instead of ethyl 5,8-dihydro-2-hydroxy-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate ( 9 ) as previously claimed.     

Convenient Synthesis of 3-(1-Carboxyalkyl)pyrido[2,3-d]pyrimidine-2,4-diones

A cheap and safe synthetic route to obtain 3-(1-carboxyalkyl)pyrido[2,3-d]pyrimidinediones (carboxyalkyl = -CHRCO₂H; R = H; CH₂; CH₂Ph; Ph; CH₂ (C₃H₃N₂); (CH₂)₂CO₂H; CH₂CO₂H) starting from 2,3-pyridinedicarboxylic acid is described. A process scheme consistent with empirical observations is proposed.     

Synthesis of 3-[5-anilino-(2,3-d)-dioxole-1,3]-1-oxo-1,3-dihydro-2-benzofurane

A microscale synthesis (500 mg) of the product 3-[5-anilino-(2,3-d)-dioxole-1,3]-1-oxo-1, 3-dihydro-2-benzofurane (COR.01.126) is described. This method, which requires only four steps, is principally available for the ¹⁴C-labeled synthesis with labeled phthalic anhydride as starting material.     

Synthesis and Crystal Structure of Ethyl 3-（4-Chlorophenyl）-3,4-dihydro-6-methyl-4-oxo-2- （pyrrolidin-1-yl）furo[2,3-d]pyrimidine-5-carboxylate

The crystal structure of the title compound ethyl 3-（4-chlorophenyl）-3,4-dihydro-6- methyl-4-oxo-2-（pyrrolidin-1-yl）furo[2,3-d]pyrimidine-5-carboxylate （C20H20ClN3O4, Mr= 401.84） has been prepared and determined by single-crystal X-ray diffraction. The crystal is of monoclinic, space group P21/n with a = 20.6215（9）, b = 8.5311（4）, c = 21.6886（9） A^°, β = 91.607（1）°, V = 3814.0（3）A^°^3, Z = 8, Dc = 1.400 g/cm^3, F（000） = 1680, μ = 0.233 mm^-1, R = 0.0718 and wR = 0.1545 for 6717 observed reflections with I 〉 2σ（I）. X-ray diffraction analysis reveals two crystallographically independent molecules in the asymmetric unit.     

Synthesis of 5,6,7,8-tetrahydro-5-oxopyrido[2,3-d]pyrimidine-6-carbonitriles and -6-carboxylic acid esters

Dieckmann ring closure reactions of 4-[(2-cyanoethyl)substituted amino]-2-phenyl-5-pyrimidinecarboxylates (Ha-f) afforded several 5,6,7,8-tetrahydro-5-oxo-2-phenylpyrido[2,3-d]pyrimidine-6- carbonitriles (IIIa-f). The open-chain intermediates (IIa-f) were prepared by dechloroamination of 5-carbethoxy-4-chloro-2-phenylpyrimidine (1a) with several 3-substituted amino- propionitriles. Alkylation of the sodium salt of 5,6,7,8-tetrahydro-8-methyl-5-oxo-2-phenyl-pyrido[2,3-d]pyrimidine-6- carbonitrile (IIIa) with methyl iodide in DMF resulted in methylation at C-6 to afford IV. Tosylation of IIIa in pyridine gave the corresponding tosyl ester (V) of the enolic form. Oxidative dehydrogenation at the 6,7-position resulted when IIIa reacted with thionyl chloride, affording 5,8-dihydro-8-methyl-5-oxo-2-phenylpyrido[2,3-d]pyrimidine-6- carbonitrile (VII). Dechloroamination of la or 5-carbethoxy-4-chloro-2-methylthiopyrimidine (Ib) with ethyl 3-ethylaminopropionate followed by Dieckmann cyclization of the resulting open-chain intermediates gave the corresponding ethyl 5,6,7,8-tetrahydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylates IX'a and IX'b, respectively. These exist predominately in the enol form and undergo alkylation and oxidation reactions similar to IIIa.     

Simple synthesis of alkyl 5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-7-carboxylates from 5-acetyl-4-aminopyrimidines

A method for the synthesis of methyl and ethyl 2-R¹-4-R²-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-7-carboxylates was proposed. The method is based on condensation of 2-R¹-6-R²-5-acetyl-4-aminopyrimidines with ethyl oxalate in the presence of MeONa or EtONa. Products of the Friedländer self-condensation of the starting pyrimidines were also obtained.     

Synthèse des pyrido[2,3-d] el [3,2-d] -s-triazolo[3,4-f] pyrimidines el de (pyrazolyl-1')-4 pyrido[2,3-d] et [3,2-d] pyrimidines

The synthesis of two new heterocycles is described: pyrido-[2,3-d]-.s-triazolo[ 3,4-f] pyrimidine and pyrido[3,2-d]-.s-triayzolo-[3,4-f] pyrimidine. 4-[I'-Pyrazolyl]pyrido[2,3-d]pyrimidines and 4-[1′-pyrazoly1] pyrido[ 3,2-d] pyrimidine are obtained by the action of 4-hydrazinopyrido[2,3-d]pyrimidine and 4-hydrazinopyrido-[3,2-d]pyrimidine with several β-diketones.     

Synthesis of 6-Amino-5-R2-7-(6-R1-4-oxo-3,4-dihydro-2-quinazolyl)-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

It has been found that malonodinitrile and 2-(6-R¹-oxo-3,4-dihydro-2-quinazolyl)acetonitrile in the presence of triethylamine undergo hetarylation by 5,6-dichloro-2,3-pyrazinedicarbonitrile at the active methylene group to give the triethylammonium salt of 2-(3-chloro-5,6-dicyano-2-pyrazinyl)malononitrile or 5-chloro-6-cyano(6-R¹-4-oxo-1,2,3,4-tetrahydro-2-quinazolylidene)methyl-2,3-pyrazinedicarbonitriles. Reaction of these with primary amines leads to annelation of the pyrrole ring at the pyrazine [b] edge to give 6-amino-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3,7-tricarbonitriles and 6-amino-5-R²-7-(6-R¹-4-oxo-3,4-dihydro-2-quinazolyl)-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles respectively.     

Synthesis and properties of 1-aryl-1,4-dihydro-2,7-dimethyl-4-oxopyrido[2,3-d]pyrimidine-6-carboxylic acids and their derivatives

Acetylation of 2-arylamino-5-carbethoxy-6-methylnicotinonitriles gave N-acetyl-2-arylamino-5-carbethoxy-6-methylnicotinonitriles, which, under the influence of hydrogen chloride, are cyclized to 1-aryl-1,4-dihydro-6-carbethoxy-2,7-dimethyl-4-oxopyrido[2,3-d]pyrimidines. The latter can be converted to the corresponding carboxylic and hydroxamic acids, as well as to acetylation products 1-aryl-2-acetonyl-1,4-dihydro-6-carbethoxy-7-methyl-4-oxopyrido [2,3-d]pyrimidines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 535–539, April, 1992.     

Synthesis of derivatives of 2-oxo-2,3-dihydro-1H-thieno[3,4-d]imidazole

Conclusions Derivatives of 2-oxo-2,3-dihydro-1H-thieno[3,4-d]imidazole were synthesized from 4,5-di-substituted 2-imidazolinones.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 10, pp. 2381–2383, October, 1987.     

Synthesis of pyrido[2,3-d]pyrimidines in the reaction of 6-amino-2,3-dihydro-2-thioxo-4(1H)-pyrimidinone with chalcones

6-Amino-2,3-dihydro-2-thioxo-4(1H)-pyrimidinone ( 1 ) reacts in boiling DMF with α,/β-unsaturated ketones 2 yielding the pyrido[2,3-d]pyrimidine systems 5 and 6, respectively. The orientation in the addition process can be determined by nmr measurements, especially by NOE difference spectroscopy. The products do not correspond to a normal Skraup or Doebner-v. Miller synthesis.     

Synthesis of 7-ethyl-4,7-dihydro-4-oxo-2-(4-pyridinyl)thieno[2,3-b]pyridine-5-carboxylic acid

7-Ethyl-4,7-dihydro-4-oxo-2-(4-pyridinyl)thieno[2,3-b]pyridine-5-carboxylic acid ( 4 ), an analog of nalidixic acid, was synthesized in seven steps starting from commercially available 4-methylpyridine. Bacterial susceptibility to compound 4 was tested and the title compound was found to exhibit only weak antibacterial activity against a variety of pathogens including S. Aureus, E. Coli and P. Aeruginosa.     

Synthesis and Properties of Ethyl Esters of 4-Dialkylamino-2-methylthiothieno[2,3-d]pyrimidine-6-carboxylic Acids

The reaction of 4-dialkylamino-6-chloro-2-methylthiopyrimidine-5-carbaldehydes with ethyl mercaptoacetate in the presence of triethylamine gives the corresponding ethyl esters of thieno[2,3-d]pyrimidine-6-carboxylic acids. These esters were subjected to alkaline hydrolysis, hydrazinolysis, and lithium aluminum hydride reduction to give the corresponding acids, hydrazides, and (thieno[2,3-d]pyrimidin-6-yl)methanols.     

Oxidation of 1,3-dimethyl-2,4-dioxo-2,3,4,7-tetrahydro-7-(2-propenyl)-1H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid under the Radziszewski reaction conditions

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