Synthesis Of The γ-Secretase Inhibitor LY411575 Analogues

Alzheimer's disease (AD) is an invariably fatal neurodegenerative disease associated with progressive dementia, and the deterioration of the patient's memory and personality. Current AD therapies only can give the improvement of patient's cognitive functions, and can not supply the method to treat this disease fundamentally.The exact mechanism of its pathogenesis is still not completely known. A hallmark of AD is the formation of cortical plaques consisting mainly of Aβpeptides, and it is well-known that the Aβpeptides and their oligomers play an important role in the pathology of the disease. Inhibition ofγ-secretase has proven to be a better target for drug discovery. One of the first disclosedγ-secretase inhibitors with high activity and drug-like properties was LY411575, a compound which was developed by Lilly company, and efficaciously inhibited Aβproduction in animal models of AD after oral administration.According to the literature, we choose the synthetic route using 2-aminobiphenyl as starting material and prepare the racemic compound 5-methyl-7-amino-5H,7H-dibenzo[b,d]azepin-6-one (Intermediate 5) via acylation, Friedel-Crafts cycloalkylation, N-methylation, nitrosylation and reduction reactions. The key intermediate (S)-5-methyl-7-amino-5H,7H-dibenzo[b,d]azepin-6-one (Intermediate 7) was prepared by the reaction of Intermediate 5 via L-mandelic acid and resolution of column chromatography and acid hydrolization. The y-secretase inhibitor LY411575 analogue (2,2,3,3,3-pentafluoropropyl)-carbamic acid (S)-1-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-ethyl ester (Compound A) and (3,5-Difluorobenzyl)-carbamic acid (S)-1-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b,d]azepin-7-ylcarbamoyl)-ethyl ester (Compound B) were synthesized with (S)-5-methyl-7-amino-5H,7H-dibenzo[b,d]azepin-6-one via condensation and ammoniation reactions. Both analogues were identified by 1H-NMR and LC-MS.In our research work, the importmant intermediate of LY411575 and its analogue was synthesized via chemical resolution to get a multigram intermediate 7, which was important to scaleable synthesis and futher study of LY411575 and its analogue.