Starting with ethyl nicotinate(4)and 3-chlorobenzyl cyanide(5)as raw materials,through the Claisen condensation,acid hydrolysis and decarboxylation,2-(3-chlorophenyl)-1-(pyridin-3-yl)-1-ethanone(6)was obtained.Compound 3-(3-chlorophenethyl)pyridine(7)was generated by Huang Minglong reduction with hydrazine hydrate.After sodium tungstate catalysis and subsequent oxidation with hydrogen peroxide,followed by the Reissert-Henze pyridine cyanation reaction,3-(3-chlorophenethyl)-2-cyanopyridine(8)was obtained.After hydrolysis and ring closure,8-chloro-10,11-dihydro-4-aza-5H-dibenzo[a,d]cyclohept-5-one(3)was obtained.Then compound 3 reacted with 1-[(5-methylpyridin-3-yl)methyl]-4-piperidone(12)by McMurry coupling reaction and salted with fumaric acid,resulting in rupatadine fumarate(1).The overall yield was 28.0％(based on 4),with a purity of 99.7％.This synthetic route avoids the use of Grignard reagents.Additionally,the cyclization employs a"one-pot"method,providing convenient operation and suitability for industrial production.
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