Synthetic Studies On Transformation Of Aldehyde To Nitrile And Its Application On The Synthesis Of Key Intermediates Of Ozanimod

Ozanimod is a novel oral,selective sphingosine 1 phosphate receptor(S1P1R)modulator,which is developed for the treatment of autoimmune diseases.Its treatment for multiple sclerosis(MS)has been in stage III clinical t and Crohn's disease(CD)project is in Phase II clinical.The focus of this paper is on improving the synthesis process of 3-cyano-4-isopropoxybenzoic acid,an important intermediate of Ozamod,and also developing a simple new method for converting aldehyde groups into cyano groups.This method has wide adaptability(applicable to fatty aldehydes and aromatic aldehydes),high yield and easy industrialization.The content of this article includes two parts:(1)The Synthesis of 3-cyano-4-isopropoxybenzoic acid: The methyl 4-hydroxybenzoate is used as the raw material,followed by formylation,cyanation,isopropyl protection and ester hydrolysis.3-cyano-4-isopropoxybenzoic acid is obtained.The route process was optimized(such as reaction temperature,solvent,feeding mode,etc.)and the synthesis mechanism was discussed.From the determined optimal reaction conditions,we performed a kilogram-scale experiment,and the product structure was confirmed by NMR.The HPLC purity of the product was 99%,the yield was 60%.(2)New method for the synthesis of aldehydes from nitriles: from the previous methodologies for the synthesis of 3-cyano-4-isopropoxybenzoic acid derivatives,from the general aliphatic aldehydes and aromatic aldehydes as starting materials,one pot method facilitates the synthesis of the corresponding Cyano compounds.This method has a good general applicability to most aldehydes and can provide ideas for the industrialization of many compounds.We have developed different types of substrates with a total reaction yield of 54%-94%.The target product structure was identified by nuclear magnetic resonance(NMR)and compared with the standard NMR spectrum,which proved its structural correctness.