Study On Synthesis And Process Optimization Of Arformterol As ?₂-adrenoceptor Agonists

Arformoterol,(R,R)-N-[2-Hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide, is a long acting ?2-agonist used as a bronchodilator in the therapies of asthma and chronic bronchitis. For its lower toxicity and adverse effects, Arformoterol is widely used in clinical treatment as asthma medications, especially in the control of nocturnal asthma. The synthesis and process optimization of Arformoterol were conducted to reduce the cost of treatment of asthma. The results will provide the experimental basis for its local imitation and also has good social benefit and economic benefit.According to references of synthesis on Arformoterol, the synthetic routes were conducted from the staring materials of p-hydroxyacetophenone and p-methoxypropiophenone. Firstly,(R)-2-(4-benzyloxy)-3-nitrophenyl)oxirane is synthesized from p-hydroxyacetophenone by nitration, alkylation, bromination, catalytic reduction and cyclization. The chiral intermediates with high enantiomeric purity(ee% ? 95.0%), were obtained by the discussion on the main factor of effect of chiral catalysts. Secondly,(R)-1-(4-methoxyphenyl)-2-benzyl-diaminopropane was synthesized by the reaction of p-methoxypropiophenone and benzylamine. The purification method was investigated the effect on the yield. Lastly, Arformoterol was synthesized by the reaction of(R)-2-(4-benzyloxy)-3-nitrophenyl)oxirane and(R)-1-(4-methoxyphenyl)-2-benzyl-diaminopropane via the amination, formylation, debenzylation and saltion. The structures of the intermediates and the target product were verified by NMR and MS. The purity and optical purity of products were confirmed by TLC and HPLC detection.The process optimization of Arformoterol were determined by the discussion in the factors such as reaction temperature, reaction time, material ratio and reaction solvent influencing on the yields of(R)-2-(4-benzyloxy)-3-nitrophenyl)oxirane,(R)-1-(4-methoxyphenyl)-2-benzyl-diaminopropane and Arformoterol. Then, the final products Arformoterol was obtained and meet with the national drug standard requirements(optical purity ?99.80%, related substances ? 0.50%). The results would provide experimental basis for the industrial production of ?2- adrenoceptor agonists.