合成路线1

Ibodutant is synthesized (1) starting from commercially available methyl tetrahydro-2H-pyran-4-carboxylate (I), which is hydrolyzed to the corresponding carboxylic acid by treatment with sodium hydroxide (1 M) and immediately transformed to the acyl chloride (II) with oxalyl chloride and catalytic DMF in dichloromethane. Reaction of (II) with isonipecotamide (III) in DMF/dichloromethane in the presence of triethylamine gives the diamide (IV), which is successfully reduced to the corresponding diamine (V) using lithium aluminum hydride in refluxing THF. Coupling of (V) with tert-butyloxycarbonyl-(R )-phenylalanine N-hydroxysuccinimide ester (Boc-D-Phe-OSu) in THF and Boc deprotection with HCl/dioxane gives (VI). Further coupling of (VI) with the N-Boc derivative of aminocyclopentanecarboxylic acid (VII) in the presence of EDC.HCl and HOBT, and deprotection of the Boc group with HCl/dioxane, provides 1-aminocyclopentanecarboxylic acid [2-phenyl-1-(R)-[[1-(tetrahydropyran-4-ylmethyl)piperidin-4-ylmethyl]carbamoyl]ethyl]amide (VIII). The free amine compound (VIII) is in turn coupled with 6-methylbenzo[b]thiophene-2-carbonyl chloride (IX), obtained from the corresponding carboxylic acid by reaction with oxalyl chloride under the usual conditions, finally giving ibodutant. Scheme 1.