URAT1 inhibitor as well as preparation method and application thereof
A compound and a selected technology are applied in the field of hyperuricemia and gout treatment to achieve good inhibitory effect and low uric acid toxicity.
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Embodiment 1
[0043] Synthesis of Intermediate A1
[0044]
[0045] Add 4-chloro-3-iodopyridine (500mg, 2.09mmol), sodium sulfide (195.46mg, 2.50mmol), DMF (3mL) into a 50mL reaction flask, and stir the reaction solution at 80°C for 4h. After the reaction is complete, add 20mL of water and use 1mol·L -1 dilute hydrochloric acid to adjust the pH to 5-6, and a pale yellow solid was precipitated, which was filtered by suction to obtain intermediate A1 (405 mg), with a yield of 82%.
[0046] Synthesis of Intermediate B1
[0047]
[0048] Add Intermediate A (400mg, 1.69mmol), ethyl 2-bromoisobutyrate (337.62mg, 2.03mmol), cesium carbonate (1.66g, 5.08mmol), DMF (5mL), reaction solution to a 50mL reaction flask Stir at 60 °C for 4 h. After the reaction was completed, 20 mL of water was added, extracted three times with ethyl acetate (3×50 ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and passed through a column after ro...
Embodiment 2
[0059] 2-((3-(2-Methyl-pyridin-4-ylethynyl)pyridin-4-yl)mercapto)-2-methylpropionic acid (compound 2) synthesis, 4-bromo-2-methyl Pyridine (344.06 mg, 2.00 mmol) was substituted for 4-bromopyridine in Example 1, and the other steps were exactly the same as in Example 1 to obtain Compound 2 (72 mg), with a total yield of 14%. The structure of Compound 2 is as follows:
[0060]
[0061] The characterization results are as follows: 1 H NMR (500MHz, DMSO-d 6 )δ8.60(s,1H),8.53(d,J=5.1Hz,1H),8.40(d,J=5.5Hz,1H),7.51(d,J=5.5Hz,1H),7.42(s, 1H), 7.34(dd, J=5.1, 1.6Hz, 1H), 1.58(s, 9H).MS: 312.82(M + ).
Embodiment 3
[0063] 2-((3-(2-Methoxy-pyridin-4-ylethynyl)pyridin-4-yl)mercapto)-2-methylpropionic acid (compound 3) was synthesized, 4-bromo-2-methyl Oxypyridine (376.04 mg, 2.00 mmol) was substituted for 4-bromopyridine in Example 1, and the other steps were exactly the same as in Example 1 to obtain Compound 3 (79 mg), with a total yield of 15%. The structure of Compound 3 is as follows:
[0064]
[0065] The characterization results are as follows: 1 H NMR (500MHz, DMSO-d 6 )δ8.67(s,1H),8.47(d,J=5.5Hz,1H),8.29-8.20(m,1H),7.41(d,J=5.5Hz,1H),7.13(dd,J=5.3 ,1.3Hz,1H),6.98(t,J=1.1Hz,1H),3.89(s,3H),1.61(s,6H).MS:328.83(M + ).
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