A kind of prodrug of baloxavir and its derivative, its preparation method and use
A pharmacy and compound technology, applied in the field of prodrugs of baloxavir and its derivatives, can solve the problems that cannot meet the clinical needs, affect the absorption and utilization of drugs, and the low bioavailability of baloxavir, so as to improve the biological Utilization, reduction of drug side effects, and improvement of drug efficacy
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Embodiment 1
[0055] step 1:.
[0056] .
[0057] At -10°C, add Y-1 (1 g) into dichloromethane, then add DIPEA (1.21 g) and Y-2 (1.14 g), react for 1 hour, TLC shows no raw material, then add to the reaction solution Y-4 (1.5g), EDCI (1.52g) and DMAP (0.265g) were reacted at -10°C for 2 hours, slowly raised to room temperature, and quenched by adding water after 0.5 hour. The liquid was separated, and the organic phase was successively washed with 0.1N hydrochloric acid, water, aqueous sodium bicarbonate, brine, dried, and spin-dried to obtain 1.86 g of light yellow oil Y-5. The HPLC purity was about 90%, and it was directly used in the next step reaction. MS(m / z):416.1(M+H) + .
[0058] Step 2:.
[0059] .
[0060] Under the protection of nitrogen, Lawson's reagent (2.63 g) was added to the toluene mixture of Y-7 (4.83 g), and stirred at 80 °C for 3 h. TLC showed that there was no raw material, spin-dried, and after column chromatography, 2.65 g of yellow solid Y-8 was obtained,...
Embodiment 2
[0072] step 1:.
[0073] .
[0074] At -10°C, add Y-1 (1 g) into dichloromethane, then add DIPEA (1.21 g) and Y-6 (1.02 g), react for 1 hour, TLC shows no raw material, then add to the reaction solution Y-4 (1.5g), EDCI (1.52g) and DMAP (0.265g) were reacted at -10°C for 2 hours, slowly raised to room temperature, and quenched by adding water after 0.5 hour. The liquid was separated, and the organic phase was successively washed with 0.1N hydrochloric acid, water, aqueous sodium bicarbonate, brine, dried, and spin-dried to obtain 1.78 g of light yellow oil Y-11. The HPLC purity was about 92%, and it was directly used in the next reaction. MS(m / z):402.1(M+H) + .
[0075] Step 2:.
[0076] .
[0077] Under nitrogen protection, Y-8 (450 mg) was added to DMA, followed by Y-11, potassium carbonate and sodium iodide, and reacted at 60°C for 4 hours. TLC showed no starting material. Add ethyl acetate and water, extract and separate, the organic phase was washed with water,...
Embodiment 3
[0082] step 1:.
[0083] .
[0084] Under nitrogen protection, Y-7 (500 mg) was added to DMA, followed by Y-5, potassium carbonate and sodium iodide, and reacted at 60°C for 4 hours. TLC showed no starting material. Add ethyl acetate and water, extract and separate, the organic phase is washed with water, dried over anhydrous sodium sulfate, and spin-dried, and then separated by column chromatography to obtain 582 mg of Y-13 with a yield of 65.2%. MS(m / z):863.3(M+H) + .
[0085] Step 2:.
[0086] .
[0087] Add Y-13 (200 mg) to ethyl acetate hydrochloride, react at room temperature for two hours, filter with suction, wash the filter cake with ethyl acetate, and dry to obtain 176 mg of product E, with a yield of 95.1%. 1 H-NMR (400MHz, DMSO) δ8.51 (m, 1H), 7.88 (m, 1H), 7.33~7.54 (m, 3H), 7.08~7.29 (m, 3H), 6.75~6.99( m, 2H), 6.21(m, 1H), 5.58~6.03(m, 3H), 5.42(m, 1H), 5.17(m, 1H), 4.53(m, 1H), 4.43(m, 1H), 4.05 ~4.25(m, 4H), 3.96(m, 1H), 3.68(m, 1H), 3.36~3.49(m, 2H...
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