The Research And Optimization On Synthetic Technology Of Efinaconazole And Apremilast

Efluconazole is developed by pharmaceutical companies Valeant Canada,and it is a topical solution used for local treatment of onychomycosis caused by Trichophyton mentagrophytes and Trichophyton,it is one of the first Triaz-ole antifungal drugs for external use only.Apremilastis developed by biotech-nology company Celgene for the treatment of psoriatic arthritis.This topic research work mainly includes:1.Designa new route for the s-ynthesis of Efluconazole from prop-1-en-2-yl acetate and 2,4-difluoroaniline was designed by inverse synthetic analysis.2.Studying the synthetic technolo-gy of Apremilast.In the design of Efluconazole synthetic route,we have done the following work:1.Synthesizing Efluconazole by Diazo reaction,Knoevenagel reaction,asymmetric reduction of prochiral ketonesusing CBS and so on;2.In optimaz-ing the new route for the synthesis,our research including:1)In the synthesis of 3-(2,4-difluo-rophenyl)but-3-en-2-one,we replace the Morpholine with Piperidine/methanol,reducing the reaction temperature and reaction time,and joined the Hydroquinone with the mass ratio of one percent in order to inhibiting polymerization which can produce impurities.2)In the synthesis of(S)-3-(2,4-difluorophenyl)but-3-en-2-ol by asymmetric reduction of prochiral ketones using CBS,we decreased the reactants/solvent from 1:91.6 to 1:10,and the catalyst dosage decreased by 2 times to 0.2 times the volume,beside,the effect of temperature on the reaction was investigated.3)In an Mitsunobu reactionto synthesizing(2R,3R)-3-(2,4-difluorophenyl)-3,4-epoxy-2-butano-lthere are a large number of by-products which are difficult to remove,we fo-und a purify ication method without the use of chromategraphy column.In the study of synthetic technology of Apremilast,we did the following:1)Attempting to synthesize key intermediates(S)-1-(3-ethoxy-4-methoxyph-enyl)-2-(methylsulfonyl)ethan-l-amine in both Mannichreaction and Knoev-enagelreaction routes.It was found that the compound 1-(3-ethoxy-4-metho-xyphenyl)-2-(methylsulfonyl)-1-(((S)-1-phenylethyl)amino)pentan-3-one synt-hesized by Knoevenagelreaction route was unstable and easily decomposed into 3-ethoxy-4-methoxybenzaldehyde and ethyl 2-(methylsulfonyl)acetate,and the reason was analyzed.2)3-ethoxy-4-methoxybenzaldehyde was reacted with Methyl sulfone under the action of alkali and reacted to form 2-ethoxy-1-methoxy-4-(2-(methylsulfonyl)vinyl)benzene,and then under the action of boric acid,the reaction was carried out with ammonia to obtain 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethan-1-amine,and chiral separation was carried out in a yield of 35.6%by high performance liquid Chromatography,measured ee is equal to 99.83%.