Alkylcarbamoyl naphthalenyloxy-octenoylhydroxyamide derivatives having inhibitory activity against histone deacetylase and preparation thereof
A technology of alkylcarbamoylnaphthyloxyoctenoylhydroxyamide and alkylamino, which is applied in the preparation of carboxylic acid amides, the preparation of organic compounds, chemical instruments and methods, and can solve problems such as interference functions
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preparation example 1
[0107] Preparation 1: 6-Hydroxy-hexenoic acid methyl ester
[0108] ε-caprolactone (12.50 g, 109.51 mM) was dissolved in methanol (125 ml), sulfuric acid solution (1 ml, 0.01 mM) was slowly added thereto, and the mixture was stirred at room temperature for 2 days. After completing the reaction, methanol was removed under reduced pressure and ice water was poured thereinto. The resulting mixture was extracted with ether, and the separated organic layer was washed sequentially with saturated sodium bicarbonate and brine. The resulting residue was subjected to column chromatography (ethyl acetate / n-hexane=1 / 2) to obtain 10.18 g of the title compound (yield: 64%).
[0109] 1 H NMR (200MHz, CDCl 3 )δ1.23(m, 2H, CH 2 ), 1.33~1.42 (m, 4H, CH 2 CH 2 ), 1.44~1.74(t, 4H, CH 2 CH 2 ), 3.66(s, 3H, OCH 3 ).
preparation example 2
[0110] Preparation 2: 6-oxo-hexenoic acid methyl ester (formula 3)
[0111] Pyridinium chlorochromate (16.27 g, 75.48 mM) was dissolved in dichloromethane (140 ml), to which 6- Hydroxy-hexenoic acid methyl ester (10.03 g, 68.61 mM), and the mixture was stirred at 25-30° C. for 2 hours. After completion of the reaction, the reaction mixture was diluted with ether and filtered. The filtrate was distilled under reduced pressure, concentrated and subjected to column chromatography (ethyl acetate / n-hexane=1 / 4) to obtain 5.77 g of the title compound (yield: 59%).
[0112] 1 H NMR (200MHz, CDCl 3 )δ1.66(m, 4H, CH 2 CH 2 ), 2.33 (m, 2H, CH 2 ), 2.46 (m, 2H, CH 2 ), 3.66(s, 3H, OCH 3 ), 9.74 (S, 1H, CH).
preparation example 3
[0113] Preparation 3: 3-Hydroxy-2-methylene-dinonanoic acid 1-tert-butyl 9-methyl ester (Formula 4)
[0114] The 6-oxo-hexenoic acid methyl ester (20 g, 168.72 mM) obtained in Preparation Example 2 was dissolved in a mixture (1:1) (100 mL) of water and dioxane, and tert-butyl acrylate (60.96 ml, 461.17mM), to which 1,4-diazabicyclo[2.2.2]octane (DABCO) (15.56 g, 138.72mM), and the mixture was stirred for 7 days. After completing the reaction, ice water was poured thereinto, and the mixture was extracted with ether. The extract was washed sequentially with 2N hydrochloric acid, saturated sodium bicarbonate and brine, dried, concentrated under reduced pressure, and subjected to column chromatography analysis (ethyl acetate / n-hexane=1 / 9) to obtain 21.7 g of the title compound (yield: 57%).
[0115] 1 H NMR (200MHz, CDCl 3 )δ1.46(m, 2H, CH 2 ), 1.47 (S, 9H, 3CH 3 ), 1.62 (m, 4H, CH 2 CH 2 ), 2.96 (m, 4H, CH 2 CH 2 ), 3.64 (s, 3H, OCH 3 ), 5.67 (s, 1H, CH), 6.09 (s, 1H,...
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