Study On The Synthesis Of The Anti-chronic Obstructive Pulmonary Disease Agent Aclidinium Bromide

Choronic Obstructive Pulmonary Disease, referred to as COPD, alsoknown as chronic obstructive airway disease (COAD), a common preventableand treatable disease, is characterized by persistent airflow limitation that isusually progressive and associated with an enhanced chronic inflammatoryresponse in the airways and the lung to noxious particles or gases.Exacerbations and comorbidities contribute to the overall severity inindividual patients.COPD is recognized to be a major cause of morbidity, mortality, andhealth care expenditure worldwide, and it is one of the few diseases increasingin prevalence. In the year of2010, COPD has made3million people to death,which made it be the fouth death factor of the world and presumably will bethe third place in2020[1]. In the U.S., COPD is a primary or contributingcause of nearly10%of all hospitalizations, rising to nearly20%in patientsolder than65[2]. It is also a top-ten cause of disability, both in developed anddeveloping nations[3].The most common symptoms of COPD are hard to breath, a productivecough, sputum production, shortness of breath[4]. These symptoms are presentfor a prolonged period of time and typically worsen over time[5].There are four major reasons are likely to cause COPD, includingsmoking, air pollution, environmental pollution and genetic occupation. Firstof all, smoking is the cause in the vast majority of cases. The lining of theairways becomes inflamed and damaged by smoking. Of those who smokeabout20%will get COPD[6], and of those who are lifelong smokers about halfwill get it[7]. Secondly, air pollution is the next important cause to the COPD.In-door air pollution is mostly due to the fire of organic fuels, coupled withpoor ventilation, people who exposed in the invironment is easey to developed COPD, and this is much more common in the developing countries. Thirdly,prolonged exposure to workplace dusts, chemicals and fumes increase the riskof COPD in both smokers and nosmokers. Workplace exposures are believedto be the cause in15%of cases[8]. Also, the genetic risk factor that is bestdocumented is a severe hereditary deficiency of alpha-1antitrypsin in somepatients have a great relationship with COPD. Age, gender and some otherfactors also have influence to COPD.Currently, the mechanism of COPD is not fully clear. It is widelycharacterized by the inflammation of the airway and lung issue. In lung, theinflammatory cells increased and release inflammatory mediators such asleukotriene B4, inteleukin-8et al, so as to exacerbate the inflammatory. Inaddition, the imbalance of proteasome system, oxidation system in lung andthe autonomic nervous system disorders also play an important role in thepathogenesis[9].Now the most common treatment drugs are bronchodilators, includingβ2-agonists, anticholinergics and phosphodiesterase inhibitors. Because manyfactors can cause COPD, sometimes combination of different drugs are used toenhance drug efficacy and reduce the side effects, such as the combination ofdifferent bronchodilators, bronchodilator and corticosteroid and so on.Aclidinium Bromide,(3R)-(2-Hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo [2.2.2] octane bromide, is developed byForest Laboratories and Almirall. It is a long-acting, inhaled anti-cholinergicdrug. FDA approved Tudorza Pressair (active ingredient is aclidinium bromide)for the long-term maintenance treatment of bronchospasm associated withchronic obstructive pulmonary disease, including chronic bronchitis andemphysema. It is an inhalation powder, used twice daily, and can effectivelyimprove the condition of patients. It is convenient to use so can improves thepatient’s compliance, otherwise, it has less adverse reactions. So it is a novel,potential drug for the COPD.Objective: Establish the preparation method for Aclidinium Bromide.Methods: Synthetic route of Aclidinium Bromide is settled by accessing to relevant literature[11-20]and experiment design.2-Bromothiophene (2) wasused as the starting material reacting with the metal Mg give the Grignardreagent and then reacting with dimethyl oxalate give to the compound2-hydroxy-2,2-di(thiophen-2-yl) methyl acetate (4).3-Phenoxypropyl bromide(7) was synthesized by the nucleophilic substitution reaction of phenol (5) and1,3-dibromopropane (6).4-Piperidine formic acid (8), the starting material,reacted with ethanol under the catalysis of sulfoxide chloride to give thecompound ethyl-4-piperidinecarboxylate hydrochloride (9·HCl), which thenoccurs the nucleophilic substitution reaction with ethyl chloroacetate(10)under the alkaline condition to obtain the compoundethyl-2-(2-ethoxy-2-oxoethyl) piperidin-4-carboxylat (11). Then, thecompound11was taken place the Dieckmann condensation under thecondition of potassium tert-butoxide to give the compound ethyl3-oxoquinuclidine-2-carboxylate (12), followed by the decarboxylation underthe acidic condition to give3-quinuclidone (13). Then compound13turn to itshydrochloride (13·HCl) in the hydrochloric acid ethanol solution. Reduction of13·HCl with sodium borohydride give the racemica3-quinuclidinol (14),which then reacted with acid anhydride to obtain the compoundquinuclidin-3-yl acetate(15). R-3-Quinine alcohol (R-14), a key intermediateof Aclidinium Bromide, was obtained by optical resolution of compound (15)with L-(+)-tartaric acid. Because no UV absorption of the compound R-14,we used benzoyl chloride (15) reaction with R-14to give the (R)-benzoic acid-3-quinuclidin ester(R-16) in order to determine the optical purity of R-14.(R)-quinuclidin-3-yl-2-hydroxy-2,2-di(thiophen-2-yl)-acetate(R-17) wasobtained by the reaction of compound4and (R-14). At last, the targatecompound Aclidinium Bromide (R-1) was achieved from compound (R-17)and3-phenoxypropyl bromide (7). The overall yield was52.2%starting withthe compound (4).Results: The targate compound Aclidinium bromide(R-1) wassuccessfully prepared, and the optical resolution and analysis by HPLC forracemic3-quinine alcohol was also preliminary investigated. Aclidinium bromide(R-1) is a white powder, mp.225.2-226.9℃.Conclusions: Aclidinium Bromide was successfully prepared from theinexpensive starting material, including4-piperidinecarboxylic acid, phenoland2-bromothiophene. The optical resolution of racemic3-quinine alcoholwas investigated preliminary.