2,6-diisopropylphenol compound as well as preparation method and application thereof
A compound and reaction technology, applied in the field of medicinal chemistry, can solve the problems of narrow thrombolysis time window, patients easily missing the golden treatment period, ischemic lesions, etc.
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Embodiment 1
[0022] Example 1 Preparation of Compound 1
[0023] .
[0024] Dissolve compound 1a (10.0g, 56.18 mmol), hexamethylenetetramine (8.65g, 61.80mmol) in 35mL of trifluoroacetic acid, heat up to 80°C, heat for 30 minutes, cool to 37°C, add 300mL of water and stir , adjusted the pH to about 5 with 10N NaOH solution, extracted with ethyl acetate (3×100mL), combined the organic phases, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated to obtain the crude product, the crude product was obtained by silica gel column (PE / EA :10 / 1) was purified to obtain 3.98g yellow solid (intermediate 1b), yield: 34.4%, which was used for the next reaction.
[0025] Intermediate 1b (3.98g, 19.32mmol) and malonic acid (3.33g, 31.99mmol) prepared above were dissolved in 20mL of pyridine, piperidine (0.50g, 0.53mL, 5.82mmol) was added, and the temperature was raised to 80°C , heated for 3 hours, cooled to 37°C, added 20mL of concentrated hydrochloric acid to adjust the ...
Embodiment 2
[0028] Example 2 Preparation of Compound 2
[0029] .
[0030] Compound 1 (3.85g, 15.52mmol) prepared above was dissolved in 30mL of methanol, concentrated sulfuric acid (4.56g, 2.49mL, 46.51mmol) was slowly added dropwise, the temperature was raised to 65°C, heated for 1.5 hours, concentrated to remove part of the methanol, After cooling to 37°C, 50 mL of water was added, extracted with ethyl acetate (2×50 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 3.09 g of compound 2 as a brown-yellow solid. Rate: 75.9%.
[0031] 1 H-NMR (400 MHz, CDCl 3 ) δ 7.66 (d, J = 15.9 Hz, 1H), 7.25 (s, 2H), 6.32(d, J = 16.0 Hz, 1H), 3.80 (s, 3H), 3.15 (hept, J = 6.9 Hz, 2H ), 1.28 (d, J =6.9 Hz, 12H).
[0032] 13 C-NMR (100 MHz, CDCl 3 ) δ 168.0, 152.4, 145.7, 134.2, 126.9, 126.2, 124.0, 114.6, 51.6, 27.1, 22.6.
Embodiment 3
[0033] Example 3 Preparation of Compound 3
[0034] .
[0035] The compound 2 (2.00g, 7.63mmol) prepared above was dissolved in 20mL of anhydrous tetrahydrofuran, cooled to -50°C, and diisobutylaluminum hydride (3.79g, 17.79mL, 26.68mmol) was added dropwise under nitrogen protection, React at -20°C for 1 hour, slowly add a small amount of 3mL methanol and 3mL water to extract the reaction, add 100mL water, adjust the pH to 1~2 with concentrated hydrochloric acid, extract with ethyl acetate (3×50mL), combine the organic phases, and saturate After washing with brine, drying over anhydrous sodium sulfate, and concentrating to obtain a crude product, the crude product was purified by column chromatography (PE / EA: 20 / 1) to obtain 1.53 g of compound 3 as an orange solid, yield: 86.0%.
[0036] 1 H-NMR (400 MHz, CDCl 3 ) δ 7.10 (s, 2H), 6.56 (dd, J = 15.7, 1.7 Hz, 1H), 6.25 (dt, J = 15.8, 6.0 Hz, 1H), 4.96 – 4.86 (m, 1H), 4.30 (dd, J = 6.1,1.4 Hz, 2H), 3.15 (h, J = 6.9 Hz, 2H),...
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