Patent EP-2455377-A1 (EP)
Inventor: KAKALIK IVAN
IPC: C07D401/06
Filed: 2010-11-11
Abstract: Use of 4-(phenylamino)-4-(methoxymethyl)piperidine (I) for synthesizing sufentanil or alfentanil, is claimed. Independent claims are included for: (1) preparing (I) comprising either (a) reacting 1-benzyl-piperidin-4-one with phenyl amine to obtain 1-benzyl-4-phenylamino-piperidine-4-carbonitrile, hydrolyzing 1-benzyl-4-phenylamino-piperidine-4-carbonitrile under an acid to obtain 1-benzyl-4-phenylamino-piperidine-4-carboxylic acid amide, reacting 1-benzyl-4-phenylamino-piperidine-4-carboxylic acid amide in ethylene glycol using hydrochloric acid or sodium hydroxide to obtain 1-benzyl-4-phenylamino-piperidine-4-carboxylic acid, reacting 1-benzyl-4-phenylamino-piperidine-4-carboxylic acid with dimethyl sulfonate in dimethylformamide to obtain 1-benzyl-4-phenylamino-piperidine-4-carboxylic acid methyl ester, reducing 1-benzyl-4-phenylamino-piperidine-4-carboxylic acid methyl ester with lithium aluminum hydride in toluene to obtain (1-benzyl-4-phenylamino-piperidin-4-yl)-methanol, reacting (1-benzyl-4-phenylamino-piperidin-4-yl) -methanol with sodium hydride and methyl iodide to obtain (1-benzyl-4-methoxymethyl-piperidin-4-yl)-phenyl-amine and hydrogenating (1-benzyl-4-methoxymethyl-piperidin-4-yl)-phenyl-amine using palladium/carbon, or (b) reacting sodium 1-benzyl-4-(phenylamino)piperidine-4-carboxylate with red aluminum in toluene to obtain (1-benzyl-4-phenylamino-piperidin-4-yl)-methanol, reacting (1-benzyl-4-phenylamino-piperidin-4-yl)-methanol with dimethyl sulfonate and tert-butoxide in tetrahydrofuran to obtain (1-benzyl-4-methoxymethyl-piperidin-4-yl)-phenyl-amine and hydrogenating (1-benzyl-4-methoxymethyl-piperidin-4-yl)-phenyl-amine using palladium/carbon in ethanol; (2) preparing alfentanil comprising either reacting (1-ethyl-4-(2-(4-methoxymethyl)-4-(phenylamino)piperidin-1-yl)ethyl)-1H-tetrazol-5(4H)-one (IV) with ethyl ketone compounds of formula (Z-C(=O)-CH 2-CH 3) (III), optionally in the presence of a solvent comprising dimethylformamide, dichloromethane, dimethylsulfoxide and/or tetrahydrofuran, or preparing (1) by the process (a) as above per se, reacting (I) with 1-(2-chloro-ethyl)-4-ethyl-1,4-dihydro-tetrazol-5-one under base to obtain 1-[2-(4-methoxymethyl-4-phenylamino-piperidin-1-yl)-ethyl]-4-methyl-1,4-dihydro-tetrazol-5-one and reacting 1-[2-(4-methoxymethyl-4-phenylamino-piperidin-1-yl)-ethyl]-4-methyl-1,4-dihydro-tetrazol-5-one with propionyl chloride using triethyl amine; (3) preparing sufentanil comprising preparing (1) by the process (a) as above per se, reacting (I) with 2-(2-thienyl)ethyl-methane sulfonate in the presence of a base to obtain [4-methoxymethyl-1-(2-thiophen-2-yl-ethyl)-piperidin-4-yl]-phenyl-amine and reacting [4-methoxymethyl-1-(2-thiophen-2-yl-ethyl)-piperidin-4-yl]-phenyl-amine with propionyl chloride using triethyl amine; and (4) preparing 4-methoxymethyl-4-(phenylamino)-1-(2-thienyl)-ethylpiperidine comprising reacting (I) with a thiophene compound of formula (II), optionally in the presence of a solvent comprising acetonitrile, 2-propanol, 2-butanol, butan-2-one and/or isobutyl ketone. Y1 : leaving group comprising bromide, iodide, methane sulfonate (preferred), para-toluenesulfonate or chloride; and Z : -OC(O)-C 2H 5, Cl or Br. [Image] ACTIVITY : Anesthetic; Analgesic. MECHANISM OF ACTION : None given.