Synthesis and characterisation of an acetylcholinesterase inhibitor

Acetylcholinesterase (AChE) inhibitors are currently the only effective treatment for people with Alzheimer’s disease (AD), a fatal neurodegenerative disease that affects 50 million people worldwide at present but is expected to rise dramatically over the next 30 years. The aim of this research was to synthesise an AChE inhibitor derivative of tacrine, 4-chloro-2(((1,2,3,4-tetrahydroacridin-9yl)imino)methyl)phenol (chlorophenol tacrine). This was achieved by first synthesising tacrine, evidencing successful synthesis and assaying purity of the product, then, synthesising a simple derivative, acetyl tacrine, before chlorophenol tacrine. At every stage of the investigation comprehensive structural analysis of each product was obtained using FT-IR, CHN analysis, GC-FID, APCI-MS, GC-MS and, predicted NMR, to evidence whether the desired product was produced. The yield of tacrine was 68% and had a melting range of 181.1-182.1ºC, and GC-FID was used to evidence successful synthesis via retention time matching with a reference material (RM), both eluting at 21.6 minutes. APCI-MS and GC-MS results showed tacrine had a molecular mass of 198 g mol-1, and includes an amine group in the structure, as well as an unsaturated ring, due to a retro-Diels-Alder fragmentation. The yield of acetyl tacrine was 37% and had a melting range of 179.1-180.1ºC. FT-IR results offered primary confirmation of synthesis by showing 2º amide absorptions between 3332-3183 cm-1 and carbonyl C=O stretching at 1651 cm-1. Mass spectrometry confirmed synthesis and provided a molecular mass of acetyl tacrine of 240 g mol-1. The yield of chlorophenol tacrine was 72% and determining a melting range was not possible due to residual solvent (DMSO) remaining in the dried sample. APCI-MS results showed a molecular mass of 336 g mol-1 with fragment ions offering structural elucidation. GC-MS results for chlorophenol tacrine were invalid due to the analyte eluting at the very end of the programmed runtime.