Study On The Synthesis Process Of The Second Generation Monoamine Oxidase Inhibitor Reshagilan Mesylate

Rasagiline mesylate,a second-generation monoamine oxidase inhibitor developed jointly by Israel's Teva and Denmark's Lundbeck,was approved for the European marketization authorization in February 2005 and approved by the US FDA.Rezagilan is a novel and effective second generation monoamine oxidase B inhibitor(MAO-B).It can safely and effectively treat early phase Parkinson's disease by blocking the decomposition of the neurotransmitter dopamine,and its tolerance of body is good and the the drug effect remains a long time.It is a novel,safe and effective drug to treat Parkingson's disease.Compared with rasagiline mesylate and other salt type,this drug has a good solubility,stability,thermal stability,even under the stress condition,it also has a good stability.Comparing with racemic rasagiline mesylate,it shows high selectivity for MAO-B.In this paper,systematically study the production process of Rasagiline mesylate,and develop a better synthesis rout.1-indan ketone reacts with hydroxylamine sulfate under sodium hydroxide conditions generates 2,3-dihydro-1 H-indene-1-ketoxime(I).Through reduction of nickel alloy aluminum,I reacts with hydrochloric acid to generate 2,3-2H-1H-indene-1-amine hydrochloride(II).II reacts with Propargyl benzenesulfonate to generate 2,3-dihydro-N-H-2-calkynyl-1 indene-1-amine(III).Through tartaric acid,III is divided to [(1 R)-2,3-dihydro-N-2-proyneyl-1H-indane-1-amine]-L-tartrate(IV).The crude product(V)of(1R)-2,3-dihydro-n-2-proyanine-1H-indene-1-ammosulfonate was obtained by IV reacting with methanesulfonic acid.Finally,V is purified by isopropanol to obtained Rasagiline mesylate final product.Select of solvents,material ratio,feeding method,reaction time,reaction temperature,crystallization time,etc.which could impact on quality and yield of product are discussed in detail,and confirm the optimal process condition and to perform validation in kg scale.The results show that the process is stable and controllable,and the process can be scale-up.The product was investigated by elemental analysis,differential thermal analysis DSC,IR,mass spectrometry,ultraviolet and nuclear magnetic resonance,and the results indicate that the obtained product is Rasagiline mesylate.Compared with the traditional process,there is no high temperature,high pressure,deep cold,high vacuum and other special requirements in this synthetic process.It is easy to operate.The property of materials is stable and the materials are easy to purchase.Th process has a feature of safe,controllable,easy to operate,the quantity of three waste is small,and the process is suitable for industrial production.