The Synthesis Of Intermediates Of Loxoprofen Sodium And Ramipril

Loxoprofen sodium is a kind of non-steroidal anti-inflammatory drug which has a structure of aryl propionic acid.It has remarkable effect of anti-inflammatory.Ramipril is non-sulfydryl angiotensin-coverting enzyme inhibitor which is widely used in cure of hypertension,congestive heart-failure and acute myocardial infarction.The thesis mainly studies the synthesis technology of intermediate of loxoprofen sodium named 2-(4-(Bromomethyl)phenyl)propanoic acid.The synthesis technology of intermediate of ramipril named(S,S,S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid hydrochloride is also studied.The thesis consists of two parts.In the first part,the physicochemical and pharmacological properties of loxoprofen sodium are introduced,synthetic routes of 2-(4-(Bromomethyl)phenyl)propanoic acid are also reviewed.Then,a convenient synthesis process was choosen and optimized by three steps of methylation,hydrolyzation and bromination from 2-(p-Tolyl)acetonitrile.By study influencing factors of base catalyst,molar ratios,solvents,phase transfer catalyst,the better reactions were obtained.In bromination reaction,the use of oxidant also enhanced the atom economy of bromine.The overall yield could reach 53% and provides industrial prospect.In the second part,the physicochemical and pharmacological properties of ramipril are introduced,the synthetic routes of intermediate called(S,S,S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid hydrochloride are reviewed.Then we design a route include seven steps: esterification,acylation,ester group elimination,Michael addition,ring formation,chiral resolution and hydrogenation from serine.We optimized the previous four steps by investigating factors of temperature,solvents,molar ratios,etc.The four steps are synthesis of serine methyl ester hydrochloride from serine,synthesis of 2-benzamido-3-methoxy-3-oxopropylbenzoate with benzoylchloride,synthesis of Methyl 2-benzamido-3-(2-oxocylopentyl)propanoate by Michael addition.The previous four steps could reach 42% overall yield.This route has lower cost and industrial prospects.