Lonza Ag

Lonza Inc.

Stefan Hildbrand

Paul Hanselmann

Dario Veghini

Thomas Ruppen

Rudolf Fuchs

Etienne Sterren

Johannes Bartek

The invention relates to &#x3b2;-alanine amides of general formula (I), wherein: Rrepresents hydrogen or Calkyl that is optionally substituted by hydroxy, amino, carboxy, carbamoyl, methylmercapto, guanidino, optionally substituted aryl or heteroaryl, and; Rrepresents hydrogen or Rand R, together, form a group of formula &#x2014;(CH)&#x2014;, wherein n is 3 or 4. Said &#x3b2;-alanine amides are produced without using an amino protective group by reacting the corresponding amine with a cyanoacetic ester in order to form an acetamide and by effecting a subsequent catalytic hydrogenation. The method is suited, in particular, for producing carcinine (&#x3b2;-alanyl-histamine, R?1=imidazol-4-ylmethyl, R=H), a naturally occurring pseudo dipeptide, which is used as an active ingredient having an antioxidative effect in medicaments and cosmetics.

Method for preparing &#x3b2;-alaninamides

Cyanoacetamides of the formula: and corresponding salts thereof; N-(cyanoacetyl)-L-histidines, of the formula: and salts, tautomers and esters thereof; and N-(cyanoacetyl)-3-methyl-L-histidines of the formula: and salts and esters thereof.

The method for producing N-alkoxy-N-alkylamides of general formula (I):wherein Rrepresents C-alkyl, cyclo-C-alkyl, cyclo-C-alkenyl, C-alkenyl, aryl, aryl-C-alkyl, heteroaryl, heteroaryl-C-alkyl or heterocyclyl; and Rrepresents Calkyl. In the process, an ester of general formula (II): RCOOR, wherein Rhas the above-mentioned meaning, and Rrepresents C-alkyl, 4-nitrophenyl, 2,4-dinitrophenyl, succinimido or benzotriazole-1-yl, is reacted with hydroxylamine, a hydroxylamine derivative or with a hydroxylammonium salt, and the reaction product is alkylated in the presence of a phase transfer catalyst.

Method for producing N-alkoxy-N-alkylamides

&#x3b2;-alaninamides of the general formulaWherein Ris hydrogen or Calkyl which is unsubstituted or substituted with hyroxy, amino, carboxy, carbamoyl, methylmercapto, guanidino, unsubstituted or substituted aryl or heteroaryl, and Ris hydrogen, or Rand Rtogether form a group of the formula &#x2014;(CH)&#x2014; where n is 3 or 4, and Ris hydrogen, a negative charge compensated by an equivalent of an inorganic or organic cation or is Calkyl, are prepared, without using an amino-protective group, by reacting the corresponding &#x3b1;-amino acid or the corresponding &#x3b1;-amino acid ester with a cyanoacetic ester to give a cyanoacetamide and by subsequent catalytic hydrogenation. The method is particularly suitable for preparing carnosine (&#x3b2;-alanyl-L-histidine, R=imidazol-4-yl-methyl, R=R=H), a naturally occurring dipeptide which used as a dietary supplement with antioxidative action.

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Riehen, Switzerland

Stefan Hildbrand