Application of diphenyl nucleoside phosphoramidate compound
A compound and hydrate technology, applied in the field of medicinal chemistry, can solve problems such as weight loss and fatigue
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Embodiment 1
[0033] Example 1 (S)-2-[[[(S)-(1,1'-biphenyl-4-oxyl group)]-[((2R, 3R, 4R, 5R)-5-(2, 4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy]phosphoryl]amino]propane isopropyl ester
[0034] Step 1 Synthesis of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine-3',5'-dibenzoate
[0035] (2'R)-N-benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine-3',5'-dibenzoate (8.0kg, 14.0mol), Add acetic acid (64L) and purified water (16L) into a 100L reactor, start stirring, raise the temperature to 120-140°C, and reflux vigorously. After the reaction is complete, centrifuge. The obtained filter cake is stirred with purified water (24.0L), and centrifuged. The resulting filter cake was washed with methanol (8.0 L), centrifuged and dried to obtain 5.6 kg of the title compound with a yield of 85.41%.
[0036] Step 2 1-[(2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl]pyrimidine-2,4-(1H,3H) - Synthesis of diketones
[0037] (2'R)-2'-deo...
Embodiment 2
[0057] Example 2 Detection of anti-HCV-1b replicon activity of compounds of the present invention
[0058] The anti-HCV-1b replicon activity of the compound of formula 1 and formula 1a of the present invention was detected with reference to the method disclosed in Chinese patent application CN105985355A. The compound of formula 1 was prepared according to the method of Example 1 of CN104031104A. Sofosbuvir (GS-7977, purchased from Shanghai Haoyuan Biomedical Technology Co., Ltd., product number HY-15005) was used as a control drug.
[0059] For specific testing steps, see Example 1 of CN105985355A, which is incorporated herein by reference in its entirety.
[0060] As described in CN105985355A, the HCV 1b replicon cells, that is, the Huh7 cell line stably transferred into the HCV genotype 1b replicon, were provided by WuXi AppTec (Shanghai) New Drug Development Co., Ltd.
[0061] Each compound tested was prepared as a 10 mM stock solution with 100% DMSO, diluted to 10 μM wit...
Embodiment 3
[0063] Example 3 Detection of anti-HCV-1a replicon activity of compounds of the present invention
[0064] The anti-HCV-1a replicon activity of the compound of formula 1 and formula 1a of the present invention was detected by referring to the method of Example 2 of Chinese patent application CN105985355A. Sofosbuvir was used as a control drug, and its source was as described in Example 2.
[0065] As described in CN105985355A, the HCV 1a replicon cells, that is, the Huh7 cell line stably transferred into the HCV genotype 1a replicon, were provided by WuXi AppTec (Shanghai) New Drug Development Co., Ltd.
[0066] Each compound tested was prepared as a 10 mM stock solution with 100% DMSO, diluted to 10 μM with complete culture solution containing 0.5% DMSO, and then serially diluted 3 times, a total of 10 concentrations. HCV-1a replicon cells were inoculated 8X10 per well 3 cells at 37°C, 5% CO 2 Cultured in the incubator for 3 days. Experiments were repeated three times.
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