Study On The Synthesis Of The Anti-chronic Obstructive Pulmonary Disease Agent Roflumilast And Its Related Substances

Chronic obstructive pulmonary disease(COPD),also known as chronic obstructive airway disease(COAD),chronic airflow limitation(CAL)and chronic obstructive respiratory disease(CORD),is the occurrence of chronic bronchitis or emphysema,a pair of commonly co-existing diseases of the lungs in which the airways narrow over time.This limits airflow to and from the lungs,causing shortness of breath(dyspnea).In clinical practice,COPD is defined by its characteristically low airflow on lung function tests.In contrast to asthma,this limitation is poorly reversible and usually gets progressively worse over time.COPD is the fourth-leading cause of death in most of the world,the third most common in the United States,and the only one of the major causes still steadily increasing.Our epidemiological survey showed that the COPD prevalence was 8.2%during people over the age of 40,the high prevalence is very astonishing.Long-term exposure to lung irritants that damage the lungs and the airways usually is the cause of COPD.In the United States,the most common irritant that causes COPD is cigarette smoke,80 to 90%of cases of COPD are due to smoking.pipe,cigar,and other types of tobacco smoke also can cause COPD,especially if the smoke is inhaled.Breathing in secondhand smoke,air pollution,or chemical fumes or dust from the environment or workplace also can contribute to COPD.Intense and prolonged exposure to workplace dusts found in coal mining,gold mining,and the cotton textile industry and chemicals such as cadmium,isocyanates,and fumes from welding have been implicated in the development of airflow obstruction,even in nonsmokers.Rarely,a genetic condition called alpha-1 antitrypsin deficiency may play a role in causing COPD.People who have this condition have low levels of alpha-1 antitrypsin.Having a low level of the protein can lead to lung damage and COPD if you’re exposed to smoke or other lung irritants.If you have this condition and smoke,COPD can worsen very quickly.The pathogenesis of COPD is not fully understood.In COPD,inflammation causes direct destruction of lung tissues and also impairs defense mechanisms used to repair damaged tissues.This results in not only destruction of lung parenchyma,but also mucus hyper secretion,and airway narrowing and fibrosis.A wide range of inflammation cells and mediators are involved in the pathogenesis of COPD,namely neutrophils,macrophages,and CD8+ T cell in different areas of the lung.Overall,COPD pathogenesis can be summarized as resulting from a combination of genetic susceptibility combined with exposure to one or more risk factors,which leads to inflammatory processes that disrupt the balance of proteases and antiproteases.These abnormal inflammatory mechanisms results in tissue destruction,airway inflammation and remodeling,and ultimately airflow limitation,and the occurrence of COPD,its symptoms are usually chronic cough,sputum,shortness of breath or difficulty breathing,wheezing and chest tightness,and other systemic symptoms.Bronchodilating anticholinergic and beta-2-stimulating agents and anti-inflammatory corticosteroid drugs are the mainstay of COPD treatment.The treatment of COPD also includes administration of inhibitors of PDE4,which is an enzyme found in high levels in the immune and inflammatory cells that specifically inactivates cAMP.Low level of cAMP is responsible for the conditions of COPD like smooth muscle contraction,mast cell mediator release,neutrophil and basophil degranulation and monocyte and macrophage activation.Therefore,inhibition of PDE4 can increase the cAMP levels,reduce the release of inflammatory mediators,and inhibit COPD and other respiratory diseases.Roflumilast,the IUPAC name is 3-(cyclopropylmethoxy)-N-(3,5-dichloro-pyridin-4-yl)-4-(difluoromethoxy)benzamide,is developed by Germany Altana Pharma company(after acquired by Danish Nycomed company),is one of the new developed second generation PDE4 inhibitors.It’s approved for marketing by the European Union in July 2010,and it’s the first one approved by European Union used for COPD therapy in more than a decade.The U.S.Food and Drug Administration(FDA)announced the approval of roflumilast for the treatment of COPD in March 2011,to reduce the frequency of acute exacerbation of COPD and relieve the deterioration of symptoms.It is based on the oral form of administration,the level of intracellular cAMP can be increased,so that the activity of inflammatory cells can be decreased,and it has fewer side effects.In view of a the variety of advantages,roflumilast could become a very potential drug on the anti-COPD market in the future.Objective:The aim is to establish roflumilast’s synthesis method,design and synthesis possible related substances.Methods:By consulting the relevant literature and experimental methods,a synthetic route of roflumilast have been established.Roflumilast was synthesized from 3,4-dihydroxybenzaldehy de(2)and sodium chloro-difluoroacetate to give 4-difluoromethoxy-3-hydroxybenzaldehyde(3),3 reacted with bromomethylcyclopropane to obtain compound 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde(4),compound 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid(5)was prepared from 4 by oxidation with hydrogen peroxide,followed by chlorination with thionyl chloride to obtain 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride(6).The other key intermediate 4-amino-3,5-dichloro-pyridine(7)should be synthesized at the same time.Pyridine(8)as the raw material,pyridine N-oxide(9)was obtained by oxidation with hydrogen peroxide,then via nitrification to give 4-nitropyridine-N-oxide(10),10 was reduction with hydrogen-palladium carbon to obtain 4-aminopyridine(11),then via chlorination to obtain 4-amino-3,5-dichloropyridin(7).Finally 6 reacted with 7 to get the target 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide(1),the overall yield was 21.6%.Designed and synthesized six possible related substances through the study of synthetic route of 3 and 4,and determined another possible related substance of roflumilast by E SI-MS spectrum.Results:The target compound roflumilast(1)was successfully prepared.It is a white to off-white powder,mp.156.3-157.9℃.Six related substances of key intermediates and a related substance of the target compound roflumilast was successfully prepared.Conclusions:Roflumilast is successfully prepared from inexpensive starting material.The overall yield was enhanced through the study of some reaction conditions.Successfully designed and synthesized seven related substances,and it can offer the evidences for further study.