Methods for the preparation of hcv polymerase inhibitors
A compound, -CN technology, applied in the field of preparation of HCV polymerase inhibitors, can solve problems such as poor efficacy and side effects
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[0491]The preparation method of the compound of the present invention is as follows. It should be understood that the details of the methods described herein are only representative of methods that can be used by those skilled in the art to prepare the compounds of the present invention. In other aspects of the claimed invention, suitable alternatives and equivalents, including alternative reagents, solvents, and temperatures, can be immediately thought of by those skilled in the art and used to prepare the compounds of the invention without extensive experimentation. Therefore, the following description does not and should not be regarded as limiting the scope of the claimed invention in any way.
[0492] The following formula (Ia) compound can be passed through the formula (II) compound (wherein R 1 And R 2 (As defined herein) is prepared by reacting with a compound of formula (IXa),
[0493]
[0494] among them:
[0495] R 1 Is C 1 To C 6 Alkyl or C 3 To C 6 Cycloalkyl
[049...
Embodiment 1
[0566] Example 1 :The preparation method of the glycolic acid salt of (5-amino-1H-1,2,4-triazol-3-yl)methanol
[0567]
[0568] Glycolate
[0569]Add glycolic acid (1 liter, 70% in water, 11.51 moles) to the 5-liter flask. Aminoguanidine bicarbonate (783.33 g, 5.755 mol) was added in batches to control obvious foaming. When solids are added, the solution cools due to endothermic dissolution. During the addition, the solution was gently heated to maintain the internal temperature at 25°C. 10 minutes after the completion of aminoguanidine bicarbonate addition, concentrated nitric acid (6.8 mL) was carefully added. The solution was heated to an internal temperature of 104-108°C (gentle reflux) for 22 hours. The heating is interrupted and the solution is allowed to cool under stirring. At an internal temperature of about 81°C, the solid started to crystallize. After the internal temperature was just below 80°C, ethanol (pure, 375 ml) was slowly added to the mix...
Embodiment 2
[0570] Example 2 :The preparation method of (5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol
[0571]
[0572] The glycolic acid salt of (5-amino-1H-1,2,4-triazol-3-yl)methanol (99.93 g, 0.526 mol), 2,4-pentanedione (0.578 mol, 60 ml), Acetic acid (6.70 mL) and EtOH (550 mL) were charged into a 2-liter 3-neck flask. The mixture was heated to slight reflux. One hour after adding the above reagents, cool the resulting solution to ambient temperature and add CH 2 Cl 2 (500ml) and Celite (25.03g). After stirring for one hour, the mixture was filtered through a 4" Buchner funnel filled with Celite (20 g) and rinsed with EtOH (100 ml). The solution was distilled to 5 volumes and then cooled to 0°C for 1 to 2 hours The slurry was filtered and the filter cake was rinsed with cold EtOH (2 x 100 mL). The solid was dried to give 76.67 g (81.7%) of the title compound.
[0573] 1 H NMR(300MHz, d 6 -DMSO): 2.57 (s, 3), 2.71 (d, 3, J = 0.8), 4.63 (non-uniform d, 2, J = 5.7), 5.49 (...
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