Pyridazinone derivative and application thereof
A compound and hydrate technology, applied in the field of pyridazinone derivatives and anti-influenza drugs, can solve the problems of low immunity and low efficacy in young children, and achieve inhibition of influenza virus, low cytotoxicity, excellent in vivo agent kinetic properties and Effects of pharmacodynamic properties in vivo
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Embodiment 1
[0271] 5-(10,11-Dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-10-hydroxy-3,4,4a,5-tetrahydro-1H-pyrido Synthesis of [1,2-b]cinnoline-9,11(2H,11aH)-dione (compound 20):
[0272]
[0273] Compound 20a (23.0 g, 99.9 mmol, 1.00 eq), DMSO (230 mL), cyclohexanone (29.42g, 299.72 mmol, 31.06 mL, 3.00 eq) and pyrrolidine (7.11 g, 99.9 mmol, 8.34 mL, 1.00 eq) were added to the reaction flask together, and the system was stirred at 40-50 degrees for 12 hours. TLC (ethyl acetate: methanol = 20: 1, Rf (R1) = 0.8) spotted the plate to monitor the complete reaction of compound 1. Dilute the reaction solution with 200 mL of DCM, then wash with 1N dilute hydrochloric acid (200 mL), separate the layers, and use saturated aqueous sodium bicarbonate solution (200 mL*2) and saturated aqueous NaCl solution (100 mL*3) for the organic phase. The organic phase was concentrated to obtain a crude product, which was separated and purified by column chromatography, and LCMS showed that the target m / z was ...
Embodiment 2
[0280] 1-(7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiazepine-11-yl)-5-hydroxy-2,3-dihydro-1H-pyrido[1 ,2-b] Synthesis of pyridazine-4,6-dione (compound 21):
[0281]
[0282] Compound 21a (200.0 g, 812.3 mmol, 1.00 eq), ethyl iodide (228.0 g, 1.46 mol, 116.9 mL, 1.80 eq), DBU (185.5 g, 1.22 mol, 183.7 mL, 1.50 eq) in DMF (1000 mL ) solution was stirred at 20-30°C for 60min, TLC (PE: EA=1:1, R f = 0.60) showed that the reaction was complete; the reaction mixture was poured into 4L water and extracted with 3x1000mL ethyl acetate (1000mL*3); the organic layer was washed with 2x1000mL saline (1000mL*2) and concentrated to obtain yellow oily compound 21b (NMR confirmed structure ) (190.0 g, 692.8 mmol, 85.3% yield). 1 HNMR : (400MHz, CHLOROFORM-d) δ 7.74 (d, J = 5.6 Hz, 1H), 7.51 - 7.44 (m, 2H),7.39 - 7.29 (m, 3H), 6.46 (d, J = 5.6 Hz, 1H), 5.36 - 5.23 (m, 2H), 4.33 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H)
[0283] Compound 21b (190.0 g, 692.8 mmol, 1.00 eq), tert-bu...
Embodiment 3
[0290] Example 3: 5-(7,8-difluoro-6,11-dihydrobenzo[b,e]thiazin-11-yl)-10-hydroxy-3,4,4a,5-tetrahydro Synthesis of -1H-pyridine[1,2-b]cinnoline-9,11(2H,11aH)-dione (compound 22):
[0291]
[0292] Compound 1a (23.0 g, 99.9 mmol), DMSO (230 mL), cyclohexanone (29.42 g, 299.72 mmol, 31.06 mL, ) and pyrrolidine (7.11 g, 99.9 mmol, 8.34 mL) were added to the reaction flask , system at 40 ~ Stir at 50 degrees for 12 hours. TLC (ethyl acetate: methanol = 20: 1, Rf (R1) = 0.8) spotted the plate to monitor the complete reaction of compound 1. Dilute the reaction solution with 200 mL of DCM, then wash with 1N dilute hydrochloric acid (200 mL), separate the layers, and use saturated aqueous sodium bicarbonate solution (200 mL*2) and saturated aqueous NaCl solution (100 mL*3) for the organic phase. The organic phase was concentrated to obtain a crude product, which was separated and purified by column chromatography, and LCMS showed that the target m / z was formed. Compound 1b (13....
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