Hydroxamic acid compound used as histone deacetylase inhibitor and application thereof
A compound and drug technology, applied in the field of hydroxamic acid compounds, can solve the problems of few types of sirtuin inhibitors, high toxicity, and inaccurate curative effect
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Embodiment 1
[0065] Example 1 Preparation of 3-phenyl-5-(chloromethyl)-1,2,4-oxadiazole
[0066]
[0067] Aniline oxime (13.6 g, 0.10 mol) was dissolved in acetone (300 mL), and anhydrous potassium carbonate (13.8 g, 0.10 mol) was added. A solution of chloroacetyl chloride (8.07 mL, 11.3 g, 0.10 mol) in acetone (10 mL) was added dropwise over 75 min at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 h. The solvent was distilled off under reduced pressure to obtain a white solid. The solid was dissolved in ethyl acetate (400 mL), and the organic layer was successively washed with water (3×100 mL), washed with saturated brine (3×100 mL), and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 23.9 g of a white powdery solid O-acylated product (93%).
[0068] The O-acylated product (22.9 g, 0.089 mol) was suspended in 300 mL of xylene and refluxed for 3 h. The solvent was distilled off under...
Embodiment 2
[0069] Example 2 Preparation of methyl 4-{[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]aminomethyl}benzoate
[0070]
[0071] Dissolve 0.015mol of methyl p-aminomethylbenzoate in 50mL of DMF, add 0.025mol of anhydrous potassium carbonate, dropwise add 0.01mol of 3-phenyl-5-(chloromethyl)-1,2,4 - Oxadiazole, stirred at 40°C for 8h. Then it was poured into ice water, extracted with ethyl acetate (3×50 mL), dried over anhydrous magnesium sulfate, and the product could be obtained by column chromatography with a yield of 55%.
[0072] Mp: 41-43°C. 1 H-NMR (500Hz, CDCl 3 ): δ8.08-8.10(m, 2H), 8.01((d, J=8.2Hz, 2H), 7.47-7.51(m, 3H), 7.44((d, J=8.2Hz, 2H), 4.11( s, 2H), 3.98 (s, 2H), 3.90 (s, 3H), 2.10 (br s, 1H). 13 C-NMR (125Hz, CDCl 3 ): δ178.03, 168.31, 166.84, 144.18, 131.22, 129.83, 129.30, 128.86, 128.83, 128.10, 127.47, 127.44, 126.62, 52.58, 51.99, 43.96. MS: (M+H) + 324.1, (M+Na) + 346.1.
Embodiment 3
[0073] Example 3 Preparation of methyl 4-{[tert-butoxycarbonyl ((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)amino]methyl}benzoate
[0074]
[0075] 0.01 mol of methyl 4-{[(3-aryl-1,2,4-oxadiazol-5-yl)methyl]aminomethyl}benzoate and a catalytic amount of DMAP were dissolved in THF, 0.02mol of Boc anhydride was added dropwise and reacted at room temperature for 7h. Evaporate the solvent under reduced pressure, add 0.01 mol of imidazole, stir at room temperature for 1 h, then dissolve in 200 mL of ethyl acetate, wash with 1M aqueous hydrochloric acid solution, wash with saturated brine, dry over anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure to obtain Boc protected product, yield 60%.
[0076] Mp: 69-71°C. 1 H-NMR (300Hz, CDCl 3 ): δ8.00-8.07(m, 4H), 7.45-7.52(m, 3H), 7.38(m, 2H), 4.72(s, 2H), 4.67(s, 1H), 4.54(s, 1H), 3.90 (s, OCH3, 3H), 1.47 (, t-Bu, 9H). 13 C-NMR (125Hz, CDCl 3 ): δ176.05, 168.42, 166.71, 155.07, 142.22, 131.28, 130.03, 129.77...
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