Synthesis of Some Derivatives of the 4H-pyrido[4',3':5,6]pyrano[2,3-d]pyrimidines

Introduction

The theoretical possibility of the synthesis of thousands substances with methods of combinatorial chemistry leads to an understanding of the need to implement rational pre-synthetic selection of the most promising compounds, depending on each specific aim. One the most successful and effective ways of solving this problem is a computer prediction of diverse properties of chemical compounds, which can be considered a tool for application of experiment planning. Intensive development of computer ADMET-technology helps to significantly reduce the risk of penetration of unwanted substances into the following stages of drug development, which can significantly save resources. Furthermore, the virtual database can be filtered using special QSAR models defining target-specific activity of substances [1-6].

Examples of structures with 4H-pyrido[4′,3′:5,6]pyrano[2,3-d]pyrimidine fragment are practically absent in the patent and scientific literature for now. However it should be expected that such compounds will have a high biological activity in analogy with substances containing these cycles or their isosteres in other combinations. For example, among bioisosteric analogues these cyclic systems are known substances with antibacterial, fungicidal, anti-allergic and anti-ulcer properties [7-9].

Taking into account the possible chemical diversity of synthetically available derivatives of 4H-pyrido[4′,3′:5,6]pyrano[2,3-d]pyrimidine, we have developed a chemical scheme for the preparation of S-alkylation products of 4H-pyrido[4′,3′:5,6]pyrano[2,3-d]pyrimidine-4-thiones, namely N-aryl/alkyl-2-(6-hydroxymethyl-9-methyl-2-aryl-5H-pyrido[4′,3′:5,6]pyrimidin-4-ylsulfanyl)acetamides.

Purpose of the Study

Development of the method of synthesis of some S-alkylation derivatives of 4H-pyrido[4′,3′:5,6]pyrano[2,3-d]pyrimidine-4-thiones and confirmation their structure.

Materials and Methods

All solvents and reagents were obtained from the commercial sources. Elemental analysis was performed on an Euro EA-3000 apparatus. Melting points were obtained on a Buchi B-520 device. The NMR-spectra were recorded with a Bruker 170 Avance 500 spectrometer at 500 МHz (DMSO-d6); TMS was used as an internal standard; chemical shifts were reported in ppm.

Analytical TLC was performed on silicagel plates Silufol UV₂₅₄(5 cm´15 cm) in the solvent system ethyl acetate – toluene (1: 1), ethyl acetate – toluene (1:2) ethyl acetate – hexane (1:2).

Experimental

Synthesis of 2-Imino-5-Hydroxymethyl-8-Methyl-2H-Pyrano[2,3-C]Pyridine-3-Thiocarboxamide 2.

In 75 mL of absolute methanol was dissolved 10 mmol (1.00 g) thiocianoacetamide and to the boiling solution was added 10 mmol (2.04 g) of pyridoxal hydrochloride and 12 mmol (1.2 mL) of freshly distilled piperidine. The reaction mixture was under stirring gradually cooled. The resulting precipitate was filtered, washed with methanol (2 x 25 mL), water (2 x 100 mL) and used without further purification. Yield 80 %. Mp 213-14˚C. ІR, cm^-1: 3410, 1645, 1608, 1420, 1003. ¹H-NMR, δ, ppm: 2.47 (s, 3H, CH₃), 4.67 (d, 2H, J = 7.2 Hz, CH₂), 5.43 (t, 1H, J = 5.7 Hz, OH), 8.22 (s, 1H, H  ), 8.92 (s, 1H, H-6), 9.41 (s, 1H, =NH), 10.40 (br.s, 1H, NH), 11.42 (br.s, 1H, NH). Anal. for C₁₁H₁₁N₃O₂S: calc. N, 16.86; S, 12.86; exp. N, 16.84; S, 12.8.

Synthesis of 2-Aryl-6-Hydroxymethyl-9-Methyl-3,5-Dihydro-4H-Pirido[4′,3′:5,6]Pyrano[2,3-D]Pyrimidine-4-Thiones 3

To the 25 mL 1-pentanol was added 10 mmol (2.50 g) of 5-hydroxy-2-methyl-imino-8-methyl-2H-pyrano[2,3-c]pyridine-3-thiocarboxamide, 15 mmol of the corresponding aromatic aldehyde and 1 mmol (0.6 mL) of piperidine. The reaction mixture was refluxed for 10 minutes. The mixture was cooled to 60°C, was added 20 ml of methanol and 20 ml of water, was stirred until complete dissolution of the precipitate, and was added 1 mL of acetic acid. The resulting precipitate was filtered, washed with methanol (10 mL) and water (2×10 mL), crystallized from DMSO.

Synthesis of N-Aryl-2-(6-Hydroxymethyl-9-Methyl-2-Aryl-5H-Pyrido[4′,3′:5,6]Pyrano[2,3-D]Pyrimidin-4-Ilsulfanyl)Acetamides 4

A solution 5 mmol (0.28 g) of KOH in 10 mL methanol and 10 mL water was heated on a magnetic stirrer to 50°C and added to 2.5 mmol of the appropriate 6-hydroxymethyl-9-methyl-2-aryl-3,5-dihydro-4H-pyrido[4′,3′:5,6]pirano[2,3-d]pyrimidin-4-thione. To this solution was added a solution of 6 mmol of the corresponding 2-chloro-N-arylacetamide in 5 mL of methanol and stirring and heating for 30 minutes. The resulting precipitate was filtered, washed with methanol (2 x 5 mL), water (2 x 10 mL) and crystallized from DMF.

Synthesis of N,N-Alkyl-2-(6-Hydroxymethyl-9-Methyl-2-Aryl-5H-Pyrido[4′,3′:5,6]Pyrano[2,3-D]Pyrimidin-4-Ilsulfanyl)Acetamides 5

A solution 5 mmol (0.28 g) of KOH in 10 mL methanol and 10 mL water was heated on a magnetic stirrer to 50°C and added to 2.5 mmol of the appropriate 6-hydroxymethyl-9-methyl-2-aryl-3,5-dihydro-4H-pyrido[4′,3′:5,6]pirano[2,3-d]pyrimidin-4-thione. To this solution was added a solution of 6 mmol of the corresponding 2-chloro-N,N-dialkylacetamide in 5 mL of methanol and stirring and heating for 30 minutes. The resulting precipitate was filtered, washed with methanol (2 x 5 mL), water (2 x 10 mL) and crystallized from DMF.

Results and Discussion

As starting reagent was choose pyridoxal hydrochloride – heteroanalogue of salycilic aldehyde. The first stage of proposed scheme is synthesis of 2-imino-5-hydroxymethyl-8-methyl-2H-pyrano[2,3-c]pyridine-3-thiocarboxamide 2 by Knoevenagel reaction – interaction pyridoxal 1 with thiocyanoacetamide. The reaction was conducted in 2-propanol in the presence of catalytic amounts of piperidine [10] (Scheme 1).

Scheme 1: Synthesis of N-aryl/alkyl-2-(6-hydroxymethyl-9-methyl-2-aryl-5H-pyrido[4′,3′:5,6]pyrimidin-4-ylsulfanyl)acetamides Click here to View figure

 

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