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.
The esterification of 1-benzyl-4-(phenylamino)piperidine-4-carboxylic acid (I) with ethanol and H2SO4 gives the corresponding ethyl ester (II), which is reduced with LiAlH2(OCH2CH2OCH3)2 in benzene affording 1-benzyl-4-(phenylamino)piperidine-4-methanol (III) The methylation of (III) with methyl iodide and NaH in HMPA yields 1-benzyl-4-methoxymethyl-4-(phenylamino)piperidine (IV), which is refluxed with propionic anhydride (A) to give N-[4-(methoxymethyl)-1-benzyl-4-piperidyl]propionanilide (V). The hydrogenolysis of (V) with H2 over Raney-Ni in methanol yields N-[4-(methoxymethyl)-4-piperidyl]propionanilide (VI), which is finally condensed with 2-thiopheneethanol methanesulfonate (B) by means of Na2CO3 in methyl isobutyl ketone.
A total synthesis of sufentanil has been described: The cyclization of 2-(2-thienyl)ethylamine (I) with allyltrimethylsilane (II) and formaldehyde gives 4-hydroxy-1-[2-(2-thienyl)ethyl]piperidine (III), which is oxidized with oxalyl chloride in DMSO/dichloromethane to 1-[2-(2-thienyl)ethyl]piperidin-4-one (IV). The epoxidation of (IV) by means of trimethylsulfonium iodide and the sodium salt of DMSO yields the spiro-epoxide (V), which is opened with aniline (VI) and boron trifluoride ethearate giving a 1.8:1 mixture of 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII) and 4-hydroxy-4-(phenylamino)piperidine (VIII) that are conveniently separated. The methylation of the OH group of (VII) with diazomethane and SiO2 affords the methoxymethyl compound (IX), which is finally acylated with propionic anhydride to provide sufentanil.
It can be prepared in two different ways: 1) The hydrolysis of 4-N-anilino-1-benzyl-4-carbamoylpiperidine (I) with refluxing concentrated HCl gives the corresponding acid (II), which is converted into its methyl ester (III) by reaction with NaOH and methyl iodide in HMPT (1). The acylation of (III) with propionic anhydride at reflux temperature affords methyl 4-(N-propionyl-N-phenylamino)-1-benzyl-4-piperidinecarboxylate (IV), which is debenzylated by hydrogenation with H2 over Pd/C in acetic acid yielding the free piperidine (V). Finally this compound is alkylated with (2-bromoethyl)benzene (VI) in hot DMA (2).