Compound for targeted ubiquitination degradation of ERRalpha protein and pharmaceutical composition and application thereof
A compound, alpha protein technology, applied in the direction of drug combinations, peptide/protein components, medical preparations containing active ingredients, etc., can solve the problems of limited development, large molecular weight, and drug resistance.
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Embodiment 1
[0167] Example 1: (Z)-3-(4-((2,4-bis(trifluoromethyl)benzyl)oxy)-3-methoxyphenyl)-2-fluoroacrylic acid
[0168]
[0169] Step 1: Synthesis of 4-((2,4-bis(trifluoromethyl)benzyl)oxy)-3-methoxybenzaldehyde
[0170]
[0171] Dissolve compound 26 (3.07g, 10mmol) and vanillin (1.52g, 10mmol) in DMF (10ml), add K 2 CO 3 (2g, 14mmol), stirred at 80°C for 3 hours. After cooling to room temperature, the resulting mixture was extracted with ethyl acetate and water. The organic layer was separated, washed with brine, washed with Na 2 SO 4 dry. After the solvent was spin-dried under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=7:1) to obtain the product 27 (3.21 g, 8.50 mmol, 85%) as a white solid: 1 H NMR (400MHz, CDCl 3 )δ9.87(s,1H),7.97(d,J=8.4Hz,2H),7.85(d,J=8.5Hz,1H),7.48(d,J=1.7Hz,1H),7.42(dd, J=8.2,1.8Hz,1H),6.93(d,J=8.2Hz,1H),5.47(s,2H),3.99(s,3H).MS(ESI)m / z 379[M+H] + .
[0172] Step 2: Synthesis of ...
Embodiment 2
[0178] Example 2: (Z)-3-(4-((2,4-bis(trifluoromethyl)benzyl)oxy)-3-methoxyphenyl)-2-(trifluoromethyl) acrylic acid
[0179]
[0180] The difference from the steps in Example 1 is that after compound 27 is synthesized, the following reaction is carried out directly to prepare (Z)-3-(4-((2,4-bis(trifluoromethyl)benzyl)oxy)- 3-methoxyphenyl)-2-(trifluoromethyl)acrylic acid:
[0181] Compound 27 (3.78g, 10mmol), 3,3,3-trifluoropropionic acid (10mmol, 0.88ml) were dissolved in anhydrous THF (20ml) under argon protection. Titanium tetrachloride (16mmol, 1.8ml) was added dropwise at 0°C. Stirring was continued for 30 minutes and triethylamine (5.6ml, 40mmol) was added dropwise. After stirring overnight at room temperature, it was extracted with ethyl acetate and water. The organic layer was separated, washed with brine, washed with Na 2 SO 4 dry. After the solvent was spin-dried under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ...
Embodiment 3
[0182] Example 3: (E)-3-(4-((2,4-bis(trifluoromethyl)benzyl)oxy-3-methoxyphenyl-2-cyanoacrylic acid
[0183]
[0184] The difference from the steps in Example 1 is that after compound 27 is synthesized, the following reaction is directly carried out:
[0185] Compound 27 (2.9g, 7.7mmol) and 2-cyanoacetic acid (977.9mg, 11.4mmol) were dissolved in acetonitrile (20ml), piperidine (1.5ml) was added, and stirred at 80°C for 3 hours. After cooling to room temperature, the resulting mixture was treated with water. Hydrochloric acid (2N) was then added to precipitate a solid. The mixture was extracted with ethyl acetate and water. The organic layer was separated, washed with brine, washed with Na 2 SO 4 dry. After the solvent was spin-dried under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:1) to obtain the product 3 as a pale yellow solid (2.6 g, 5.8 mmol, 75.6%): 1 H NMR (400MHz, DMSO-d 6 )δ13.79(s,1H),8.2...
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