DK453484A - METHOD OF ANALOGUE FOR THE PREPARATION OF N-ARYL-N- (4-PIPERIDYL) -ARYLACETAMIDES - Google Patents

Abstract

1. Analogy method for preparation of N-aryl-N-(4- piperidyl)-arylacetamide derivatives with the general formula <IMAGE>, I or pharmaceutically acceptable acid addition salts thereof, where: L1 means (C1-C10)alkyl, (C3-C6)cycloalkyl, (C3- C6)cycloalkyl-(C1-C6)alkyl or (C3-C6)alkenyl, Ar means phenyl, mono- or di-substituted phenyl, pyridyl or 2-pyrimidyl, where each of the substituents in the mono- or di- substituted phenyl is halogen or (C1-C6)alkyl independently of each other, Ar1 means phenyl, mono- or di-substituted phenyl or thienyl, wherein each of the substituents in the mono- or di-substituted phenyl independently of each other is halogen, (C1-C6)alkyl, hydroxy or (C1-C6)alkyloxy, X means hydrogen, (C1-C6)alkyloxycarbonyl or (C1- C6)alkyloxymethyl, and under the precondition that L1 is different from, (C5- C6)cycloalkyl when Ar and Ar1 are both phenyl or substituted phenyl, and X is hydrogen, characterized in that a) one subjects a compound with the general formula <IMAGE>, IV where Ar, Ar1 and X have the above-given meaning, and Z means benzyl, phenylmethoxycarbonyl or (C1- C6)alkoxycarbonyl, to an elimination reaction, in that the compound, IV, where Z means benzyl, phenylmethoxycarbonyl, is subjected to catalytic hydrogenation making use of a suitable catalyst, and when Z means (C1-C6)alkoxycarbonyl it is subjected to acidic or basic hydrolysis, to produce a compound with the formula <IMAGE>, I-a where Ar, Ar1 and X have the above-given meanings, which compound, I-a, is then N-alkylated, or b) one N-alkylates a compound having the above-given formula, I-a, by familiar methods to produce a compound which has the formula <IMAGE>, I where Ar, Ar1, L1 and X have the above-given meanings, where one preferably performs the N-alkylation by reacting the compound, I-a, with a suitable reactive ester, which has the formula L1-Y, where Y is a suitable reactive ester residue, in a suitable reaction-inert organic solvent, preferably in presence of a base, or c) to prepare a compound with the general formula <IMAGE>, I-c where Ar, Ar1 and X have the above-given meanings, and L2 means (C1-C10)alkyl, (C3-C6)cycloalkyl or (C3- C6)cycloalkyl-(C1-C6)alkyl, and the carbon atom which is bound to the piperidine nitrogen carries at least one hydrogen atom, one catalytically hydrogenates a mixture of a ketone or aldehyde corresponding to the alcohol L2-OH, and a compound with formula, I-a, in presence of a suitable catalyst, or d) one reductively eliminates the benzyl group from a compound which has the formula <IMAGE>, VI where Ar, Ar1, X, L1 and Y have the above-given meanings, making use of catalytic hydrogenation, to produce a compound with formula, I, or e) one acylates a compound with the formula: <IMAGE>, VII with an arylacetylhalide with the formula <IMAGE>, III where Ar, Ar1, L1 and X have the above-given meanings, in a suitable reaction-inert organic solvent, preferably in presence of a base, such that, when Ar1 in the final compound, I, is mono- or di-hydroxyphenyl, a protective group is introduced into the starting compound, III, and after preparation of the final product these protecting groups are removed by alkaline hydrolysis, after which a prepared compound, if desired, is converted into a pharmaceutically acceptable acid addition salt.