Study on synthetic process of Smo inhibitor SY-1257
In this study,the synthetic process of Smo inhibitor SY-1257 was optimized.The key intermediate[(2S,4S)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxane-4-yl]methyl-4-methylbenzene sulfonate(4)was obtained from(S)-(+)-1,2-isopropylidene glycerol(1)by nucleophilic substitution,hydrolysis and ketel reaction.The intermediate 3-(4-hydroxyphenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester(SY-4)was obtained from p-bromophenol by addition,Buchwald-Hartwig coupling and deprotection.The target compound SY-1257 was produced by deprotection after nucleophilic substitution reaction between intermediates 4 and SY-4.The structure of SY-1257 was confirmed by ESI-MS,1H-NMR and 13C-NMR.The overall yield was 11.1％(from compound 1)with a corresponding purity of 98.2％.The improved process has advantages of milder and economic conditions,and is more conducive for pilot production.
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