Hepatitis B virus assembly effector
A composition and drug technology, applied in the field of hepatitis B virus assembly effector, can solve problems such as poor tolerance and side effects of interferon alpha
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Embodiment 1- 1
[0120] Example 1 - Synthesis of General Intermediates 6 and 13
[0121] Synthesis of 6-methyl-2-(piperazin-1-yl)-N-(p-tolyl)pyrimidin-4-amine (6)-general intermediate:
[0122]
[0123] Synthesis of 2-chloro-6-methyl-N-(p-tolyl)pyrimidin-4-amine (3):
[0124]
[0125] Under argon, CH 3 To a solution of CN (5 mL) was added p-toluidine 2 (473 mg, 4.41 mmol) and triethylamine (0.77 mL, 5.52 mmol); the mixture was warmed to 80° C. and stirred for 24 h. The reaction was monitored by TLC; after the reaction was complete, the volatiles were removed in vacuo to give crude product. The crude product was purified by silica gel column chromatography using 10% ethyl acetate (EtOAc) / hexanes to afford compound 3 (300 mg, 35%) as an off-white solid. TLC: 20% EtOAc / hexane (R f :0.4); 1 H-NMR (DMSO-d 6 ,400MHz): δ9.76(s,1H),7.42(d,J=8.0Hz,2H),7.16(d,J=8.4Hz,2H),6.52(s,1H), 2.27(s,3H) ,2.25(s,3H).
[0126] Synthesis of tert-butyl 4-(4-methyl-6-(p-tolylamino)pyrimidin-2-yl)piperazi...
Embodiment 2
[0146] Synthesis of embodiment 2-target compound 1-22
[0147] Intermediates 6 and 13 were converted to final products by using commercially available sulfonyl chlorides or by using the sulfonyl chlorides prepared in typical Procedure A, the results are collected in Table 1 below.
[0148] Typical Procedure A: Addition of compound 6 (40 mg, 0.14 mmol) to CH under argon at 0 °C with stirring 2 Cl 2 (5mL) solution was added pyridine (0.06mL, 0.70mmol) and sulfuryl chloride (29.5mg, 0.15mmol); warmed to room temperature and stirred for 4h. The reaction was monitored by TLC; after the reaction was complete, the reaction mixture was washed with CH 2 Cl 2 (30 mL), diluted with water (15 mL), 1N HCl (10 mL), 10% NaHCO 3 The solution (15 mL), washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product. The precipitated material is directly purified by vacuum drying or trituration or by column chromatography to give the desire...
Embodiment 3
[0159] Synthesis of embodiment 3-target compounds 23 and 24
[0160]
[0161] Synthesis of 6-methyl-2-(4-((4-nitrophenyl)sulfonylpiperazin-1-yl)-N-(p-tolyl)pyrimidin-4-amine (64): under argon , at 0°C to CH 2 Cl 2 (5mL) solution was added pyridine (0.15mL, 1.76mmol) and 4-nitrobenzenesulfonyl chloride 63 (78mg, 0.35mmol); warmed to room temperature and stirred for 4h. The reaction was monitored by TLC; after the reaction was complete, the reaction mixture was washed with CH 2 Cl 2 (30mL) diluted with 1N HCl (15mL), 10% NaHCO 3 The solution (20 mL), water (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo gave crude product. The crude product was washed with diethyl ether (2x5 mL) and n-pentane (2x5 mL), and dried in vacuo to give compound 64 (110 mg, 67%) as a white solid. TLC: 5% MeOH / CH 2 Cl 2(R f :0.8); 1 H-NMR (DMSO-d 6 ,400MHz): δ9.00(s,1H),8.41(d,J=8.8Hz,2H),8.01(d,J=8.8Hz,2H),7.38(d,J=8.4Hz,2H),7.08 (d,J=8.4Hz,2H),5.86(s,1H), 3.79(t,J...
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