Patent ID: 6342597
Filing Date: 2002-01-29
Classification: A61K,C07D,C07F,Y10S

Abstract:
A process for the preparation of a compound of formula (I) starting from triethylenetetramine of formula (II), as represented in Scheme 1: said process comprising the steps of:(a) condensing a triethylenetetramine of formula (II) with a glyoxal derivative, in water or in a water-soluble solvent or a mixture thereof, at a temperature of 0-50Â° C., in the presence of a stoichiometric amount or a slight excess of calcium hydroxide to give octahydro-3H,6H-2a,5,6,8a-tetraazacenaphthylene of formula (III); (b) condensing the compound from step a) with an alkylating agent â€”CH2â€”CH2â€”X, in which X is Cl or Br, in amounts from 1 to 5 mols per mol of compound (III), in a dipolar aprotic solvent and in the presence of an alkali or alkaline-earth metal carbonate base, in amounts from 5 to 10 mols per mol of compound (III), and with the addition of NaY, in which Y is I or Br, as catalyst in amounts from 0.1 to 2 mols per mol of compound (III), wherein X and Y are not at the same time Br, at a temperature from 25 to 150Â° C., to give decahydro-2a,4a,6a,8a-tetraazacyclopent [fg]ace-naphthylene of formula (IV); (c) oxidizing compound (IV) with bromine at pH 4-5 to give 2,3,4,6,7,8-hexahydro-1H,5H-4a,6a-diaza-2a,8a-azoniacyclopent[fg] acenaphthylene dibromide of formula (V); (d) forming 2,3,4,6,7,8-hexahydro-1H,5H-4a,6a-diaza-2a,8a-azoniacyclopent[fg]acenaphthylene diperchlorate of formula (VI) by adding perchlorate ions to the solution of compound (V); (e) alkylating compound (VI) with an alkylating agent of formula Râ€”CH(X)COOH, in which X is a halogen, and R is defined above, under basic conditions, to give a compound of formula (VII); (f) hydrolyzing the formyl group of compound (VII) under basic conditions to give a compound of formula (VIII); (g) alkylating compound (VIII) with the alkylating agent of formula Râ€”CH(X)â€”COOH, in which X and R have the meanings defined above, under basic conditions, to give a compound of formula (IX); and finally (h) hydrolyzing compound (IX), under basic conditions, to give a compound of formula (I).