Sodium hydride (16 mg, 0.40 mmol, 2.0 equivalent) was suspended in dry tetrahydrofuran (7 mL). Then, (s)-3-(1-(dimethylamino)ethyl)phenol (33 mg) was added to the reaction mixture. The resulting reaction mixture was stirred at room temperature for 30 min. Then, (methyl)carbamoyl chloride (49 mg) was dissolved in dry tetrahydrofuran (3 mL) and slowly added dropwise to the mixture. The resulting reaction mixture was stirred at room temperature for 5 h. After the reaction was complete, distilled water (6 mL) with H2O was added to the mixture, followed by saturated K2CO3 solution (6 mL) to adjust the pH of the reaction system to 9–10. The resulting mixture was extracted three times with ethyl acetate (3 × 15 mL). All organic layers were combined, dried on Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain rivastigmine.
Figure: Synthetic Route of Rivastigmine
Rivastigmine was discovered by Marta Weinstock-Rosin of the Department of Pharmacology at the Hebrew University of Jerusalem and sold to Novartis by Yissum for commercial development. Rivastigmine, sold under the brand name Exelon among others, is an acetylcholinesterase inhibitor used for the treatment of dementia associated with Alzheimer's disease and with Parkinson's disease.
ChEBI: A carbamate ester obtained by formal condensation of the carboxy group of ethyl(methyl)carbamic acid with the phenolic OH group of 3-[(1S)-1-(dimethylamino)ethyl]phenol. A reversible cholinesterase inhibitor.
Rivastigmine (Exelon, EA 713) is apseudoirreversible noncompetitive carbamate inhibitor ofAChE. Although the half-life is approximately 2 hours,the inhibitory properties of this agent last for 10 hours becauseof the slow dissociation of the drug from the enzyme.The Food and Drug Administration (FDA) approved its usein mild-to-moderate Alzheimer disease in April 2000. InJuly 2007, rivastigmine was granted approval for use inmanaging mild-to-moderate dementia associated withParkinson disease.
Rivastigmine is a centrally selective, arylcarbamate AChEI that was approved in 2000 for oral administration in the treatment of AD. It has an
elimination half-life of 1.4 to 1.7 hours but is able to inhibit AChE for up to 10 hours. Because of the slow dissociation of the carbamylated
enzyme, it has been referred to as a pseudo-irreversible AChEI. Like donepezil, rivastigmine exhibits a low level of hepatotoxicity. It is
rapidly and extensively hydrolyzed in the CNS by cholinesterase with minimal involvement of CYP450. The phenolic metabolite is excreted
primarily via the kidneys.
Mild-moderate dementia in Alzheimer’s disease
Idiopathic Parkinson’s disease
Potentially hazardous interactions with other drugs
Muscle relaxants: enhances effect of suxamethonium;
antagonises effect of non-depolarising muscle
relaxants.
Rivastigmine is the tertiary amines that
are rapidly absorbed from the gastrointestinal tract, as
are tacrine, donepezil, and galanthamine, whereas quaternary
ammonium compounds are poorly absorbed
after oral administration. Nevertheless, quaternary ammonium
compounds like neostigmine and pyridostigmine
are orally active if larger doses are employed.
Only the quaternary ammonium inhibitors do not readily
enter the CNS. Because of their high lipid solubility
and low molecular weight, most of the organophosphates
are absorbed by all routes of administration;
even percutaneous exposure can result in the absorption
of sufficient drug to permit the accumulation of
toxic levels of these compounds.
