Monoglycosyl-containing heterocyclic compound for inhibiting hepatitis C viruses and preparation method
A compound and heterocyclic technology, applied in the field of monosaccharide-containing heterocyclic compounds, to achieve the effect of inhibiting the activity of hepatitis C virus and increasing water solubility
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Embodiment 1
[0084] Example 1 Synthesis of 2,4'-dibromoacetophenone
[0085] Add dichloromethane (1100 ml) and p-bromoacetophenone (100.2 g, 0.503 mol) into a 3000 mL three-neck round bottom flask. Dissolve bromine (83.4 g, 0.52 mol) in dichloromethane (300 ml) in a beaker and transfer to a dropping funnel, turn on electromagnetic stirring and add bromine solution in dichloromethane dropwise within three hours . Then, the reaction mixture was continued to stir for 2 hours, TLC indicated the reaction was complete. Saturated sodium bicarbonate (ca. 500 mL) was added slowly until no bubbles occurred. The solution was transferred to a separatory funnel, the organic phase was separated, the inorganic phase was extracted with dichloromethane (150 mL), the organic phases were combined, washed with saturated brine (400 mL), and dried over anhydrous sodium sulfate. 235 grams of white solid crude product after rotary evaporation. The crude product was recrystallized with ethyl acetate and n-hexa...
Embodiment 2
[0086] Example 2 Synthesis of 2-amino-4-bromoacetophenone hydrochloride
[0087] Chloroform (400 mL) and 2,4'-dibromoacetophenone (20 g, 0.072 mol) and urotropine (10.5 g, 0.0735 mol) were added to a 1000 mL one-necked round bottom flask. The reaction mixture was stirred at room temperature for six hours, and a large amount of precipitate formed. Suction filtration, the filter cake was washed with cold chloroform, and air-dried. Then transfer it to a 500 ml beaker and add 80 ml of 30% HCl and 350 ml of methanol. The mixture was stirred overnight at room temperature. Suction filtration, the filter cake was washed with cold absolute ethanol, and vacuum-dried to obtain 18 g of the product.
Embodiment 3
[0089] In a 500 mL one-necked round bottom flask, DMF (160 mL), N-Boc-L-proline (14.28 g, 0.0663 mole, 2-(7-azobenzotriazole)-N,N,N ',N'-Tetramethyluronium hexafluorophosphate (HATU: 26.65 g, 0.0700 mol), 2-amino-4-bromoacetophenone hydrochloride (16.62 g, 0.0663 mol) and N,N-diisopropyl Ethylethylamine (DIPEA, 36 mL, 206.6 mmol) was added dropwise over 30 minutes and stirred at ambient temperature for 60 minutes. Dimethylformamide was removed in vacuo and ethyl acetate (400 ml) and water (300 ml). The organic layer was washed with water (300 ml) and brine, dried (Na 2 SO 4)overnight. Filtration and concentration to remove the solvent (a little solvent remained) gave an oil. Flash column chromatography gave product (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylamino)pyrrole-1-tert-butyl carboxylate, white solid, yield 22.1 grams (81%). 1H NMR (DMSO-d6, 400MHz): δ8.22-8.12 (m, 1H), 7.90 (br d, J = 8.0, 2H), 7.73 (br d, J = 8.5, 2H), 4.60 (dd, J =18.1,5.6,1H),4.53(dd,J=18....
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