Synthesis Of 1-(4-fluorophenyl)-5-bromo-1,3-dihydroisobenzofuran

1-(4-fluorophenyl)-5-bromo-1,3-dihydroisobenzofuran, which is an important medical intermediate, is mainly used for the synthesis of antidepressants citalopram in the current. As a new antidepressant drug which belongs to one of selective serotonin reuptake inhibitors (SSRIs), citalopram proves significant effect in treatment compared to other similar drugs.In this paper, process of synthesis of 1-(4-fluorophenyl)-5-bromoisobenzofuran with o-xylene as raw material through three-step reactions of bromination, oxidation and condensation to synthesize 5-bromophthalide and then another three-step reactions of Grignard, reduction and condensation was researched. First of all, o-xylene was brominated to 4-bromo-o-xylene with liquid bromine; In the process of the atmospheric oxidation 4-bromo-o-xylene to 4-bromo-2-methyl benzoic acid, composite catalyst of manganese acetate/cobalt acetate/sodium bromide was adopted to substitute single catalyst in the application, which contributes to solve the problem of too much usage and the difficulty in recovery. The key intermediate 5-bromophthalide was obtained under the action of intramolecular closed-loop of 4-bromo-2-methyl benzoic acid in sodium bromide/sodium bisulfite. And then, 2-hydroxymethyl-4-bromo-4'-fluorodibenzophenone was obtained based on the Grignard reaction of 5-bromophthalide and the 4-fluorophenyl magnesium bromide in THF. The solvent THF was recovered completely at constant pressure and the crude product could be used directly without purification. The reduction was carried out in 95% ethanol with potassium borohydride catalyzed by lithium chloride as reducing agent. At the end of the reduction, crude product of 2-hydroxymethyl-4-bromo-4'-fluorodiphenylmethanol after ethanol was recovered can be carried out closed-loop dehydration with p-toluenesulfonic acid as catalyst in toluene. So far we obtained the crude 1-(4-fluorophenyl)-5-bromoisobenzofuran after recovery of toluene, then 180～190℃(2mmhg) fraction was collected through rectification. The fraction was recrystallized with methanol to achieve the final product of 1-(4-fluorophenyl)-5-bromoisobenzofuran with white columnar crystals which purity was greater than 99%.The synthetic conditions of 5-bromophthalide and 1-(4-fluorophenyl)-5-bromoiso-benzofuran were discussed by surveying various factors which influence each reaction and the synthesis process was optimized respectively through experimental conditions. Orthogonal tests were applied to study the critical reaction of the oxidation of 4-bromo-o-xylene. Under the optimum conditions, the highest yield of 5-bromophthalide was 36.8% and the overall yield was 20.9%. Compounds including the intermediates and the final product were characterized with different methods.