151103-09-2Relevant articles and documents
A convenient method for the synthesis of roflumilast
Lin, Yan,Huang, Peijun,Liu, Shuai,Sima, Lifeng,Chen, Ligong,Wang, Donghua
, p. 2107 - 2113 (2013)
A convenient synthetic method has been developed for the synthesis of roflumilast from 4-difluoromethoxy-3-hydroxybenzaldehyde and bromomethyl cyclopropane via O-alkylation, oxidation and N-acylation. With sodium hydroxide as alkali in the last step, the total yield of roflumilast can be up to 68.3 % and the purity of the target product reached 99.2 %. It was obvious that sodium hydroxide showed more economic advantage for scale-up production than sodium hydride or potassium tert-butoxide.
Diastereoselective synthesis and profiling of bicyclic imidazolidinone derivatives bearing a difluoromethylated catechol unit as potent phosphodiesterase 4 inhibitors
Dorokhov, Valentin S.,Golovanov, Ivan S.,Tartakovsky, Vladimir A.,Sukhorukov, Alexey Yu.,Ioffe, Sema L.
supporting information, p. 6900 - 6908 (2018/10/20)
Metal-mediated C-H functionalization of cyclic N-oxides was exploited to access a series of new difluoromethylated analogs of imidazolidinone-based PDE4 inhibitor CMPI in a diastereoselective manner. Among the products synthesized, compounds with fine-tuned activity/selectivity profiles compared to both CMPI and the clinically applied apremilast were identified. From these studies, an unusual fused 1,2-oxazinoimidazolidinone heterocyclic system was suggested as a novel scaffold for the design of potent and selective PDE4 inhibitors. Computational studies suggest that the oxygen atom in the imidazolidinone unit can bind to the metal ion center (most likely Mg2+). DFT calculations of the relative interaction energies of inhibitors with Mg2+ and Zn2+ ions were performed on a model of the bimetal active site of PDE4.
Synthesis method of roflumilast key intermediate
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, (2017/07/21)
The invention discloses a synthesis method of a roflumilast key intermediate. Specifically speaking, the synthesis method comprises the following steps: (1) preparing 3-methoxy-4-difluoro methoxybenzaldehyde; (2) preparing 3-hydroxy-4-difluoro methoxybenzaldehyde; (3) preparing 3-cyclopropyl methoxy-4-difluoro methoxybenzaldehyde; (4) preparing 3-cyclopropyl methoxy-4-difluoro methoxybenzoic acid. Compared with the existing synthesis method, the synthesis method disclosed in the invention has the advantages that low-price raw materials are adopted, thereby greatly reducing the production cost; vanillin serves as a starting material, thereby avoiding generation of similar impurities; column chromatography is replaced with recrystallization which serves as a purification way, thereby facilitating large-scale production application, and the yield and the purity are higher.