Preparation of 1,2-disubstituted hexahydropyridazine-3-carboxylic acid derivatives, useful as intermediates for pharmaceuticals e.g. cilazapril, by reacting protected hydrazine with disubstituted valerate

摘要

Preparation of 1,2-disubstituted hexahydropyridazine-3-carboxylic acid derivatives (I) comprises reacting a protected hydrazine (II) with a functionalized ester (III) in a mixture of organic solvent and water in presence of a phase-transfer catalyst. Preparation of 1,2-disubstituted hexahydropyridazine-3-carboxylic acid derivatives of formula (I) comprises reacting a protected hydrazine ZNHNHZ (II) with a functionalized ester X(CR2)3-CRR1X (III) in a mixture of organic solvent and water in the presence of a phase-transfer catalyst. [Image] Z : protecting group; R : H or (un)saturated optionally substituted 1-30C alkyl, aryl or aralkyl; X : leaving group; and R1carboxy or ester. An independent claim is also included for preparation of 1-(C(O)Y)-hexahydropyridazine-3-carboxylic acid (IV) from 1,2-di-(C(O)Y)-hexahydropyridazine-3-carboxylic acid ester (V) by: (1) hydrolysis of (V) to produce an aqueous solution of salts of (V); (2) adding acid and alcohol to the solution; (3) separation of the alcohol phase; (4) cooling; and (5) separating the precipitate. Y : benzyloxy, tert-butoxy or fluorenylmethoxy.