Preparation method of levo-flurbiprofen
A flurbiprofen and racemization technology, applied in the field of chiral drug preparation, can solve the problems of high cost, poor purity, low yield and the like, and achieve the effects of satisfying yield and purity requirements, wide sources, and cost reduction.
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Embodiment 1
[0019] Example 1 Synthesis of 1:4;3:6-dianhydro-D-sorbitol-5-benzyl ether
[0020] Add 18.25g (125mmol) of isosorbide, 5.25g (125mmol) of lithium hydroxide monohydrate and 60ml of dimethyl sulfoxide (DMSO) into a 250ml eggplant-shaped bottle, and heat up to 90 O C, stirring for 30min, adding 14.4ml (125mmol) of benzyl chloride dropwise into the constant pressure dropping funnel, 90 O C reacted for 19-20h, adjusted the pH of the reaction solution to 1 with 2M hydrochloric acid, extracted with ethyl acetate (50ml*3), combined the organic layers, washed with water (30ml*2), dried overnight with anhydrous sodium sulfate, filtered and concentrated, and the residue was separated on a silica gel column Chromatographic separation (petroleum ether: ethyl acetate = 5:1) gave a milky white solid, namely 1:4;3:6-dianhydro-D-sorbitol-5-benzyl ether 24.5g, melting point 59-61 O C (Document 61~63 O C).
Embodiment 2
[0021] Example 2 Synthesis of 2-(2-fluoro-4-biphenyl)propionyl chloride
[0022] Add 2.44g (10mmol) of racemic flurbiprofen and 20ml of anhydrous toluene to a 50ml eggplant-shaped bottle, add dropwise 0.8ml (11mmol) of freshly distilled thionyl chloride, N,N-dimethylformamide (DMF) 2 drop, stirred at room temperature for 2 h, and evaporated the solvent under reduced pressure to obtain a pale yellow gum, namely 2-(2-fluoro-4-biphenyl)propionyl chloride, which was used directly in the reaction without isolation.
Embodiment 31
[0023] Example 3.1 Synthesis of 5-isosorbide monobenzyl ether of R-2-(2-fluoro-4-biphenyl)propionate
[0024] Dissolve the acid chloride obtained in Example 2 in 20ml of anhydrous toluene, add 3.5ml of dimethylethylamine dropwise at room temperature, a solid precipitates, stir for about 1 hour, add an ice-salt bath, the bath temperature is minus 10-15°C, at this temperature Stir for about 10 min, then add dropwise the toluene solution of 5-isosorbide monobenzyl ether (2.83 g, 12 mmol) in Example 1 using a constant pressure dropping funnel, keep the reaction temperature, and stir for 8 h. Remove the ice bath, remove the solvent from the reaction solution under reduced pressure, extract the residue with ethyl acetate, wash the extract with water, dry over anhydrous sodium sulfate, remove ethyl acetate under reduced pressure, the residue is a white gel, and recrystallize petroleum ether to obtain a white solid , that is, R-2-(2-fluoro-4-biphenyl)propionic acid 5-isosorbide ...
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