4-Bromo-3-(1,3-dioxolane-2-yl)phenol(3)was synthesized by condensation of 2-bromo-5-hydroxybenzaldehyde(2)with ethylene glycol in toluene under the catalysis of p-toluenesulfonic acid and pyridine.The addition of pyridine buffered the acidity of p-toluenesulfonic acid and solved the problems of reversible reaction and polymer formation.4-[4-Bromo-3-(1,3-dioxolane-2-yl)phenoxy]benzonitrile(4)was synthesized from 3 and 4-fluorobenzonitrile under the action of anhydrous potassium carbonate and tetrabutylammonium bromide.The phase transfer catalyst made the reaction faster.4-(4-Bromo-3-formylphenoxy)benzonitrile(5)was obtained by deprotection of 4.Miyaura borylation of 5 with bis(pinacolato)diboron catalyzed by[1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium[Pd(dppf)Cl2]produced 4-[3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-benzonitrile(6),which avoided the flammable and explosive reagents and intermediates and strict operation conditions.After reduction with sodium borohydride,crisaborole(1)was obtained by cyclization.Sodium borohydride was added dropwise in the form of aqueous solution(containing 5％NaOH)to make the operation safer and more convenient.The total yield of the improved synthesis was 51.7％(based on 2),with the purity more than 99.9％.
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