HIV inhibiting 5,6-substituted pyrimidines
A compound and solvate technology, applied in the field of 5,6-substituted pyrimidine compounds for inhibiting HIV, can solve the problems of multi-drug resistance, limited treatment, inability to completely eliminate HIV, etc.
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Embodiment 1
[0174]
[0175] A mixture of 4-cyanoaniline (0.420 mol) in 2-methoxyethyl ether (250 ml) was stirred at 100°C for 30 minutes. A mixture of cyanamide (0.630 mol) in water (30 ml) was then added portionwise over a period of 45 minutes. After stirring at 100° C. for 24 hours, cyanamide (0.210 mol) was added again. The mixture was then stirred at 100° C. for a further 48 hours and then evaporated to dryness. The residue was crystallized in acetone to afford 70.5 g of A (85% yield, melting point: 225°C).
[0176]
[0177] Add sodium ethylate (21%) (0.0153mol, 1.5 equivalents), methyl 4-methoxyacetylacetate (0.0102 mol, 1 equivalent). The resulting mixture was stirred and refluxed for 6 hours, then cooled to room temperature. Water was added and the mixture was acidified with acetic acid (until pH = 6). The resulting precipitate was filtered to afford 1.5 g of intermediate B (57% yield).
[0178] A mixture of B (0.0056 mol) and phosphorus oxychloride (10 mL) was stirred ...
Embodiment 2
[0190]
[0191] Add bis(triphenylphosphine)palladium(II) chloride (PdCl 2 (PPh3 ) 2 ) (0.00522 mol, 0.2 eq) and triethylamine (0.0112 mol, 4.3 eq). The whole mixture was heated at 110° C. for 48 hours under a pressure of 25 bar carbon monoxide. The resulting mixture was then filtered through a pad of celite, rinsing with tetrahydrofuran. After solvent evaporation, the resulting mixture was subjected to column chromatography (20-45 μm, eluent: CH 2 Cl 2 / methanol 99:1) to obtain 10.65 g of intermediate F (85% yield, melting point: 156° C.).
[0192] To F (5.4g, 0.0112mol) tetrahydrofuran / H 2 O mixture solution (50ml / 15ml) was added LiOH monohydrate (0.0559mol, 5eq). The resulting mixture was stirred overnight at room temperature. The tetrahydrofuran was then evaporated, water was added and the mixture was acidified to pH 1 with 3N HCl solution. The precipitate was then filtered and dried under vacuum to obtain 4.55 g of Intermediate G (89% yield, melting point: 220...
Embodiment 3
[0211]
[0212] Intermediate E (0.00372 mol), palladium acetate (0.000746 mol, 0.2 eq), sodium formate (0.0111 mol, 3 eq) and some MgSO 4 The mixture in 50 ml dimethylformamide was stirred overnight. Pour the mixture into water. The precipitate was filtered off and dried. The crude product was chromatographed on silica gel (eluent: CH 2 Cl 2 / methanol / NH 4 OH: 99 / 1 / 0.1; 15-40 μM) purified. The pure fractions were collected and the solvent was evaporated. Yield: 0.410 g (25%) of intermediate L.
[0213] Method A
[0214] To a mixture of intermediate L (0.0008 mol) in 15 ml tetrahydrofuran was added methylmagnesium chloride (0.00279 mol, 3.5 equiv) at -78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 2 hours, then at room temperature overnight. The reaction mixture was poured into 10% NH 4 Cl, followed by CH 2 Cl 2 extraction. The organic layer was treated with MgSO 4 Dry, filter and evaporate the solvent. The crude product was chromatogra...
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