Study On The Synthesis Of Intermediate Of Ezetimibe

(3R,4S)-1-(4-fluorophenyl)-3-(3-methoxy-3-oxopropyl)-4-(4-benzyloxyphenyl) -2-azetidinone(20)is an important intermediate of Ezetimibe,based on literature,a commercial and pratical synthesis route with glutaric anhydride as start material was chosen.(20)was prepared by monomethylesterification,chlorination,amidation,imine condensing reaction and cyclizing reaction.The route advantage of cheapness,shortness, condition wildness and easiness in controlling.In first monomethylesterification reaction a new method was adopted,sodium methoxide was used as material which reacting in an appropriate solvent at a low temperature to get glutaric acid monomethylester(15),the yield was 70%.In chlorination and amidation reaciton,the mole ratio was optimized,the mol ratio of glutaric acid monomethylester(16)and(4S)-4-phenylo xazolidin-2-one (17)wasl:0.7,andthe yieldwas 97.1%.In imine condensing reaction,side reactions and the mechanism were affirmed, and reaction conditions were optimized,the feed speed of N-(4-(benzyloxy)benzylidene) -4-fluorobenzenamine(4)was 0.5g/5min,mole ratio of(S)-methyl-5-oxo-5-(2-oxo-4-phenyloxazolidin-3-yl) pentanoate(18),N-(4-(benzyloxy)benzylidene)-4-fluorobenzenamine (4)and DIPEA wasl:1.7:2.2,the feed order is TICl₄,titanium isopropoxide,(18),DIPEA and(4).the yield was 63.2%.Those experiments proposed a mechanism of the reaction.In cyclizing reaction,product purification was made by recrystallization in toluene,and reaction conditions were optimized,reaction temperature was 60℃,the mole ratio of(19),BSA and TBAF was 1:2:0.05,and the yield was 67.9%.