Antiviral nucleoside analogs
一种化合物、烷基的技术，应用在治疗动物中病毒感染,抑制病毒RNA或DNA聚合酶领域，能够解决健康问题等问题
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[0343] Preparation of phosphates, phosphonates and triphosphates.
[0344]
[0345] Plan C-2
[0346]
[0347] B and R' 7 Same as in Scenario C-1
[0348] Plan C-3
[0349]
[0350] Prodrugs of such phosphonate esters can be prepared by literature procedures.
[0351] Schemes D-1 and D-2 illustrate the preparation of the prodrugs of the present invention.
[0352] Plan D-1
[0353]
[0354] B and R' 7 Same as Plan C-1
[0355] R' = amino acid ester
[0356] Plan D-2
[0357]
[0358] B and R' 7 Same as Plan C-1
[0359] R'=CH 3 , C(CH 3 ) 3
[0360] Plan E-1
[0361]
[0362] R' 7 = H, CH 3
[0363] X = H, CH 3
Embodiment 1
[0366]
[0367] (2S, 3R, 4R, 5R)-2-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-(hydroxymethyl)-3- Methyltetrahydrofuran-3,4-diol hydrochloride (1k)
[0368]
[0369] a. To a stirred solution of freshly distilled pyrrole (6.79 g, 100.89 mmol) / diethyl ether (100 mL) was slowly added ethylmagnesium bromide (33.6 mL, 100.89 mmol, 3M in ether) at 20°C. The reaction mixture was further stirred at 20 °C for 1 h, and the solvent was removed in vacuo to give 1b. To 1b in dichloromethane (500 mL) was added (3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxymethyl)-3-methyltetrahydrofuran at 0 °C -2-alcohol (1c, WO 2006 / 050161, 10.96g, 25.22mmol) / dichloromethane (100mL) solution and stirred at 4°C for another 72h. The reaction mixture was quenched by adding a saturated solution of ammonium chloride (200 mL), and the organic layer was separated. The aqueous layer was further extracted with dichloromethane (2 x 200 mL). The combined organic extracts were washed with water (2×50 mL) and b...
Embodiment 2
[0386]
[0387] (2S, 3R, 4R, 5R)-2-(4-(Dimethylamino)pyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-(hydroxymethyl )-3-Methyltetrahydrofuran-3,4-diol (2e)
[0388]
[0389] a. A solution of 1i (500 mg, 0.95 mmol, prepared according to Example 1) / EtOH (25 mL) was washed with concentrated NH 4 Treated with OH (28-30%, 9.5 mL) and hydrogen peroxide (30% in water, 0.3 mL), then stirred at room temperature for 20 h. Additional hydrogen peroxide (30% in water, 0.1 mL) was added and stirring was continued for 4 h. The reaction mixture was concentrated to dryness. The residue was treated with chloroform (50 mL) and washed with water (50 mL). The aqueous phase was re-extracted with chloroform (50 mL). The combined extracts were washed with brine (50 mL), washed with MgSO 4 Drying, filtration and concentration gave a yellow syrup (2a, 0.51 g). MS (ES - ): 540.1(M-H) - . Crude 2a (0.48 g) was dissolved in triethylorthoformate (10 mL) and treated with TFA (0.07 mL, 0.91 mmol), then s...
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