The cyclization of ethyl isocyanate (I) with sodium azide (II) by means of AlCl3 in refluxing THF gives 1-ethyl-1,4-dihydro-5H-tetrazol-5-one (III), which is alkylated with 1-chloro-2-bromoethane (IV) by means of Na2CO3 and KI in refluxing 4-methyl-2-pentanone to afford 1-ethyl-4-(2-chloroethyl)-1,4-dihydro-5H-tetrazol-5-one (V). Finally, this compound is condensed with N-(4-methoxymethyl-4-piperidinyl)propionanilide (VI) by means of Na2CO4 - KI in refluxing 4-methyl-2-pentanone.
The reaction of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with CHCl3, benzyl triethylammonium chloride and NaOH in THF/water gives the spirooxirane (II), which is treated with aniline (III) and NaOH to yield the anilide (IV). The methylation of the amide nitrogen by means of NaH and CH3I in THF affords the methylated anilide (V). The reaction of (V) with KOH in refluxing isopropanol causes elimination of its ethoxycarbonyl group, providing compound (VI), which is reduced with lithium triethylborohydride in THF to give 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII). The condensation of (VII) with tetrazolone derivative (VIII) by means of KI in refluxing acetonitrile (or propionitrile) yields the adduct (XI), which is methylated with NaH and CH3I in THF to afford the methoxy derivative (XII). Finally, this compound is acylated with propionyl chloride (XIII) in chloroform to provide the target compound. The intermediate tetrazolone derivative (VIII) has been obtained by reaction of 1-ethyl-4,5-dihydro-1H-tetrazol-5-one (IX) with 1,2-dibromoethane (X) by means of TEA in acetonitrile.
The reaction of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with CHCl3, benzyl triethylammonium chloride and NaOH in THF/water gives the spirooxirane (II), which is treated with aniline (III) and NaOH to yield the anilide (IV). The methylation of the amide nitrogen by means of NaH and CH3I in THF affords the methylated anilide (V). The reaction of (V) with KOH in refluxing isopropanol causes elimination of its ethoxycarbonyl group, providing compound (VI), which is reduced with lithium triethylborohydride in THF to give 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII). The condensation of (VII) with 2-(2-thienyl)ethyl mesylate (VIII) by means of K2CO3 in refluxing acetonitrile yields the adduct (XI), which is methylated with NaH and CH3I in THF to afford the methoxy derivative (X). Finally, this compound is acylated with propionyl chloride (XI) in chloroform to provide the target compound.
The reaction of 1-benzyl-4-piperidone (I) with aniline (II) and KCN in acetic acid gives the aminonitrile (III), which is treated with H2SO4 at room temperature to yield the carboxamide (IV). The hydrolysis of (IV) with refluxing aqueous HCl affords the carboxylic acid (V), which is esterified with Ms-OH and methanol to provide the methyl ester (VI). Acylation of the NH group of (VI) with propionic anhydride (VII) gives the propionamide (VIII), which is debenzylated with H2 over Pd/C to yield the piperidine (IX). Finally, this compound is condensed with methyl acrylate (XI) in acetonitrile to afford the target compound.