合成路线1

The condensation of racemic (3aRS,4RS,6SR,7aSR)-6-(hydroxymethyl)-4-(2-methoxyphenyl)perhydroisoindol-4-ol (I) with 2(S)-(2-methoxyphenyl)propionic acid (II) by means of hydroxybenzotriazole and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide in dichloromethane gives the diastereomeric amide (III), which is tosylated with tosyl chloride and submitted to chromatography yielding the (3aS,4S,6R,7aR)(S)-enantiomer (IV) as an optically pure isomer. Finally, this compound is allowed to react with potassium cyanide in hot DMSO affording RPR-111905. The starting compounds, the perhydroisoindole (I) and the propionic acid (II) have been obtained as follows: a) The cyclization of 5-(acetoxymethyl)-2-cyclohexen-1-one (V) with N-(butoxymethyl)-N-(trimethylsilylmethyl)benzylamine (VI) by means of trifluoroacetic acid (TFA) in dichloromethane gives racemic (3aRS,6SR,7aSR)-6-(acetoxymethyl)-2-benzylperhydroisoinol-4-one (VII), which is submitted to a Grignard condensation with 2-methoxyphenylmagnesium bromide (VIII) in THF yielding the racemic (3aRS,4RS,6SR,7aSR)(IX). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in hot ethanol affording the desired racemic diol (I). b) The condensation of 2-(2-methoxyphenyl)acetic acid (X) with (4S,5S)-4-methyl-5-phenyloxazolidin-2-one (XI) by means of NaH, pivaloyl chloride and butyllithium gives the acylated oxazolidinone (XII), which is methylated regioselectively with sodium hexamethyldisylazane (Na-HMDS) and methyl iodide in THF yielding the 2(S)-methyl derivative (XIII). Finally, the hydrolysis of the oxazolidinone group of (XIII) with LiOH in THF-water affords the desired 2(S)-(2-methoxyphenyl)propionic acid (II).