Trans-diaryl ethylene LSD1 (lysine specific histone demethylase 1) inhibitor, as well as preparation method and application thereof
A diarylethene, reaction technology, applied in the directions of organic chemistry, drug combination, anti-tumor drugs, etc., achieves strong in vitro anti-tumor activity, strong LSD1 inhibitory activity, and is conducive to popularization and application.
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[0026] Example 1 4-Methoxy-3-(pyridin-2-yl)benzaldehyde (1a)
[0027]
[0028] Add 2-bromopyridine (456.5mg, 2.89mmol), toluene (7mL), K 2 CO 3 Aqueous solution (2.76g potassium carbonate dissolved in 10mL water, 2mL), tetrakis(triphenylphosphine)palladium (45.2mg, 0.04mmol), stirred at room temperature under nitrogen protection for 15 minutes, and then added 5-formyl-2-methoxy Phenylboronic acid (400mg, 2.22mmol) in anhydrous ethanol solution (3mL), heated at 92℃ for 4 hours, poured the reaction system into water, extracted with ethyl acetate, combined the ethyl acetate layers, followed by water and saturated brine Washed, dried with anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated under reduced pressure, and the concentrate was separated by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a white solid 414.6mg, yield 87.5%, Mp: 52-53 ℃. 1 H NMR(400MHz, CDCl 3 )δ9.98(s,1H),8.73(m,1H),8.31(d,1H,J=2.4Hz),7.96(dd,1H,J 1 =2.4 Hz, J...
Example Embodiment
[0029] Example 2 4-Methoxy-3-(4-fluoropyridin-2-yl)benzaldehyde (1b)
[0030]
[0031] According to the method of Example 1, replacing 2-bromopyridine with 2-bromo-4-fluoropyridine (508.6 mg, 2.89 mmol) to obtain 395.8 mg of white solid, yield 77.1%, Mp: 73-74°C. 1 H NMR(400MHz, CDCl 3 )δ 10.00(s,1H),8.72(dd,1H,J 1 =5.6Hz,J 2 =8.8Hz), 8.40(t,1H,J=2.0Hz),8.00(dd, 1H,J 1 =1.2Hz,J 2 =8.8Hz), 7.65 (d, 1H, J = 10.4Hz), 7.16 (d, 1H, J = 8.4Hz), 7.05 (m, 1H), 4.01 (s, 3H). 13 C NMR(101MHz, CDCl 3 )δ190.88,175.95,169.87,167.27, 161.69,157.37,157.29,151.61,151.54,134.23,131.67,130.04,128.13,128.10, 113.06,112.87,111.74,110.42,110.25,56.11.HRMS(ESI)calcd for C 13 H 10 FNNaO 2 [M+Na] + :254.0588,Found:254.0582.
Example Embodiment
[0032] Example 3 4-Methoxy-3-(pyrimidin-2-yl)benzaldehyde (1c)
[0033]
[0034] According to the method of Example 1, using 2-bromopyrimidine (445.1mg, 2.80mmol) to replace 2-bromopyridine, a white solid of 414.2mg was obtained, yield 87.1%, Mp: 80-81°C. 1 H NMR(400MHz, CDCl 3 )δ 9.96(s,1H),8.88(d,2H,J=4.8Hz), 8.26(d,1H,J=2.4Hz),8.00(dd,1H,J 1 =2.4 Hz, J 2 =8.8Hz), 7.29 (t, 1H, J = 4.8Hz), 7.16 (d, 1H, J = 8.8Hz), 3.96 (s, 3H). 13 C NMR(101MHz, CDCl 3 )δ190.61,164.71,162.41,157.17,134.47,132.52,129.64,128.77,119.23,112.05,56.44.HRMS(ESI)calcdfor C 12 H 10 N 2 NaO 2 [M+Na] + : 237.0634,Found:237.0639.
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