Oleanolic acid couple derivatives and their pharmaceutical use

[0081] 1) oleanolic acid-2-bromoethyl ester (1a 1 )

[0082] Suspend OLA (1.0g, 2.19mmol) in 15ml of acetone, add triethylamine (2ml) to dissolve completely, add 1,2-dibromoethane (1.0ml, 11.5mmol) under stirring at room temperature, stir and reflux for 6 hours , filtered off the insoluble matter, concentrated the filtrate, and column chromatography [ethyl acetate:petroleum ether (60~90°C)=1:4(V:V)] gave a white solid 0.80g, yield 65%, mp: 150 ~152°C.

[0083] In the same way, other intermediates such as 1a can be prepared from OLA and other dibromoalkanes, dibromoalkenes, and dibromoalkynes.

[0084] 2) oleanolic acid-2-nitrooxyethyl ester (I 1 )

[0085] 1a 1 (0.4g, 0.71mmol) was dissolved in a mixed solvent of acetonitrile and tetrahydrofuran, silver nitrate (177mg, 1.06mmol) was added, and the light was refluxed for 6 hours, the yellow silver bromide precipitate was filtered off, and the filtrate was concentrated to obtain a light yellow oil The product was subjected...

[0092] 1) 4-bromomethylphenyl 3-trifluoroacetoxy oleanolic acid ester (1b 1 )

[0093] OLA (456mg, 1mmol) was suspended in toluene, added trifluoroacetic anhydride (0.8ml, 4mmol), stirred at room temperature for 10 minutes, then added p-hydroxybenzyl bromide (238mg, 1.4mmol), stirred and refluxed for 6 hours, cooled to room temperature, 10 % sodium bicarbonate was washed to neutrality, the organic layer was washed with water and saturated brine respectively, dried over anhydrous sodium sulfate, filtered, and column chromatography [ethyl acetate: petroleum ether (60-90° C.) = 1: 4 (V: V )] to obtain light yellow oil, yield 67.9%.

[0094] 2) 3-trifluoroacetoxy oleanolic acid 4-nitrooxymethylphenyl ester (I 8 )

[0095] 1b 1 (310mg, 0.51mmol) was dissolved in a mixed solvent of acetonitrile and tetrahydrofuran, silver nitrate (127mg, 0.76mmol) was added, and the reaction was stirred under reflux in the dark for 4 hours, and the silver bromide precipitate was filtered off, an...

[0102] 1) 4-Hydroxy-3-methoxyphenylacrylate-3-bromopropyl ester (2a 1 )

[0103] Ferulic acid (5g, 25.8mmol) was dissolved in 50ml of acetone, 1,3-dibromopropane (20.2g, 100mmol), 10ml of triethylamine were added, and the reaction was heated at an external temperature of 50°C for 4 hours, cooled to room temperature, and A large amount of white solid precipitated, filtered, the filtrate was concentrated, and column chromatography [ethyl acetate:petroleum ether (60-90°C)=1:4 (V:V)] gave 5.53 g of needle-like solid. Yield: 68%, mp: 100-102°C.

[0104] In the same way, other intermediates such as 2a can be prepared from ferulic acid, vanillic acid, p-hydroxycinnamic acid and other dibromoalkanes, dibromoalkenes, and dibromoalkynes.

[0105] 2) 3-O-trifluoroacetyl-oleanolic acid-2-methoxy-4-[2-(3-bromo-propoxycarbonyl)-vinyl]-phenyl ester (2b 1 ) OLA (1.14g, 2.5mmol) was suspended in toluene, trifluoroacetic anhydride (2ml, 14.85mmol) was added under stirring, the reaction solut...