Design And Synthesis Of Some Anti-cholinergic Drug Intermediates

Anticholinergic drug is an important neural drug, which is used to treat organophosphorus poisoning. Muscarinic receptor antagonist is one of the important anticholinergic drugs that have been widely used for the treatment of certain diseases, such as chronic obstructive pulmonary disease (COPD) , Parkinsonian syndromes , Alzheimer's disease and urinary incontinence. However, due to the lack of Muscarinic receptor subtype selectivity, many Muscarinic receptor antagonists exhibit great side effects in both the peripheral and central nervous system at present so that their clinical application and therapeutic effects are greatly limited. It has been well established that the receptor selectivity not only depends on the chemical properties but also the stereochemical properties. In order to improve the selectivity and reduce side effects of muscarinic receptor antagonists, it is very important to study the stereostructure-activity relationship of these antagonists.Initially, anticholinergic drugs were extracted from natural plants. With the constant development of science and technology, more and more drugs have been synthesized recently. It has been one of the most hottest themes for people to develop more active, high selective and fast effective anticholinergic drugs. Functionally, most anticholinergic drugs are made up of three parts: including a blockage group(part A), a middle link(part C) and a cationic head(part B), as a typical anticholinergic drug Atropine shown bellow:1,In chapter 1 of this paper, the progress and development of anticholinergic drugs home and abroad at present were reviewed briefly from four parts on the molecular transformation of part A, B and C of the anticholinergic drug molecule and the research of optically active anticholinergic drugs.2,Methyl benzilate is an important anticholinergic drug intermediate, which was synthesized in chapter 2 of this paper with benzaldehyde as raw material and vitamin B₁ as catalyst through benzoin condensation, oxidation by KBrO₃ and esterification finally. The advantage of this synthesis scheme depends on the use of an environment-friendly catalyst vitamin B₁ other than the toxic NaCN or KCN.3,Since 1986, Gedye and his collaborators found that microwave radiation technology could promote organic reactions, microwave chemistry has aroused widespread concern. The application of microwave skill in the synthesis of methyl benzilate has been chiefly studied in chapter 3 and the influencing factors of the yield have been discussed and analyzed in detail, such as the ratio of raw material, the catalyst amount, the microwave power, the reaction time and the reaction temperature. Compared with the traditional synthetic method of methyl benzilate, the advantages of the microwave skill is obviously outstanding.4,In chapter 4 of this paper, two different synthesis schemes of two other medicinal intermediate: methyl and ethyl benzoylates were described respectively. In scheme one methyl and ethyl benzoylates were synthesized with benzaldehyde as raw material through mandelic acid and benzoyl formic acid and in scheme two the target compounds were synthesized with oxalic acid as raw materials through dimethyl and diethyl oxilates and then through Grignard reaction with phenyl magnesium bromide.5,In the last chapter of this paper the synthetic process improvement of an thermosensitive paper sensitizer benzyl-2-naphthyl ether has been presented and the optimized conditions has been also studied. The improved synthetic process would simplify the treatment procedure, lower the production cost and increase economic benefit greatly.