Heterotactic aryl carboxylic acid compound, preparation method thereof, medicine composition comprising compound and application of compound
A technology of biheteroaryl carboxylic acid and aryl carboxylic acid, which is applied in the fields of drug combination, digestive system, organic chemistry, etc.
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Embodiment 1
[0073] The preparation of the compound of embodiment 1 general formula 4
[0074] Preparation of Compound 4-1
[0075]
[0076] The raw material compound (5-bromo-2-cyanopyridine) 1.82g, nitrophenylboronic acid pinacol 2.62g (1.2 equivalents), bis(triphenylphosphine) palladium dichloride 0.35g (0.05 equivalents), carbonic acid Cesium 6.52 (2 equivalents) was dissolved in DMF, and the reaction system was changed to an inert gas environment, heated to 70-80°C to react overnight, evaporated to remove DMF, added water to dissolve the inorganic matter, filtered, and drained to obtain compound a (crude product); a is dissolved in 50-60% by volume of sulfuric acid, heated to 130-140°C for 2-3 hours, pouring the reaction solution into ice and using NaOH to adjust the pH value to 2-3, filtering, and draining to obtain compound b (crude product);
[0077]
[0078] Compound b 0.5g obtained from the above reaction, 0.446g (1.5 equivalents) of L-tert-leucyl amino ester, O-(IH-benzot...
Embodiment 2
[0128] The preparation of the compound of embodiment 2 general formula I-1
[0129]Preparation of compound yhhu-2407
[0130]
[0131] Step 1: Dissolve compound 4-1 in anhydrous methanol, add 10wt% palladium carbon in a nitrogen atmosphere, add 3 to 4 equivalents of sodium borohydride under ice bath, react for 5 to 6 hours, the reaction is complete, add 1N hydrochloric acid Until no bubbles emerged, the palladium carbon was filtered off, the solvent was removed by rotary evaporation, water and dichloromethane were added, the organic phase was separated, dried over anhydrous sodium sulfate, the organic solvent was removed by rotary evaporation, and compound 5-1 was obtained by column chromatography;
[0132]
[0133] The second step: dissolve compound 5-1 in dry tetrahydrofuran, add 1.5 equivalents of phenyl isocyanate, add two equivalents of triethylamine, react overnight at room temperature, evaporate the organic solvent, add dichloromethane and water, separate the orga...
Embodiment 3
[0286] The preparation of the compound of embodiment 3 general formula 10
[0287] Preparation of compound 10-1
[0288]
[0289] The first step: raw material compound 5-bromo-2-pyridinecarboxylic acid 1.82g, L-proline methyl ester (1.5 equivalents), TBTU are dissolved in 10ml DMF, add diisopropylethylamine (2 equivalent), react overnight at room temperature, remove DMF by rotary evaporation, add water and dichloromethane, separate the organic layer, dry over anhydrous sodium sulfate, remove the solvent by rotary evaporation, and obtain compound 10-1a separated by column chromatography.
[0290]
[0291] The second step: dissolve compound 10-1a, 4-nitrophenylboronic acid pinacol (1.2 equivalents), tetraphenylphosphine palladium (0.05 equivalents), and potassium carbonate (2 equivalents) in a mixed solvent of toluene-ethanol-water In , the reaction system was changed to an inert gas environment, heated to 70-80° C. to react overnight, the solvent was evaporated, dichloro...
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