O-1924

Chemical Name: (1S,2S,3R,5R,7R)-3-(3,4-Dichlorophenyl)-7-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester
CAS No. 211047-07-3, 187963-42-4 (racemate)
项目整合开发状态: Biological Testing
项目研究机构: Organix (Originator)
合成路线:Acetonedicarboxylic acid (I) was converted to the monomethyl ester (III) via the cyclic anhydride (II).Dialdehyde (V),prepared in situ by acid hydrolysis of 2,5-dimethoxydihydrofuran (IV),was subjected to a double Mannich condensation with keto ester (III) and methylamine to produce a mixture of tropane derivatives.Column chromatography of the obtained crude product provided a mixture of 7-hydroxy- (VI) and 6-hydroxy- (VII) tropanes,which were separated from the minor 6- and 7-methoxy analogues.Treatment of alcohols (VI) and (VII) with dimethoxymethane and p-toluenesulfonic acid generated the corresponding mixture of mixed acetals,from which the desired 7-methoxymethyl isomer (VIII) was isolated by column chromatography.Conversion of (VIII) to the enol triflate (IX) was achieved with N-phenyltrifluoromethanesulfonimide and sodium bis(trimethylsilyl)amide at low temperature.The aryl tropene (XI) was then obtained by Suzuki coupling of triflate (IX) with 3,4-dichlorophenylboronic acid (X),followed by trimethylsilyl bromide-promoted deprotection of the methoxymethyl group.Resolution of the racemic tropenol (XI) was effected by esterification with (1S)-(-)-camphanic chloride followed by separation of the resulting diastereomeric mixture.The desired isomer (XII) was then hydrolyzed with LiOH to provide the enantiopure (1S)-alcohol (XIII).Then,reduction to the saturated tropane derivative by means of samarium iodide at low temperature produced a diastereomeric mixture of 3-aryltropanes from which the title 3alpha-isomer was isolated by flash chromatography.