合成路线1

The cyclopropylamine building block (X) is obtained as follows. Knoevenagel condensation of 3,4-difluorobenzaldehyde (XXII) with malonic acid in the presence of piperidine in hot pyridine produces 3,4-difluorocinnamic acid (XXIII). After conversion of (XXIII) to the corresponding acid chloride (XXIV) by means of SOCl2, condensation with L-menthol (XXV) provides the menthyl difluorocinnamate (XXVI). Cyclopropanation of (XXVI) employing dimethylsulfoxonium methylide (generated from trimethylsulfoxonium iodide and NaOH in DMSO) gives the cyclopropanecarboxylate ester (XXVII), which is hydrolyzed to the carboxylic acid (XXVIII) by means of NaOH in aqueous ethanol. Subsequent chlorination of acid (XXVIII) followed by treatment with aqueous NaN3 in the presence of Na2CO3 and Bu4NBr yields the acyl azide (XXIX), which is converted to the target amine (X) by Curtius rearrangement in hot toluene (3). Scheme 3.