Patent ID: 6042810
Filing Date: 2000-03-28
Classification: C07D

Abstract:
A process for the preparation of complexes of 10-[2,3-dihydroxy-1-(hydroxymethyl)propyl]- 1,4,7,10-tetraazacyclododecane- 1,4,7-triacetic acid with trivalent ions of paramagnetic metals of formula (XII) ##STR13## wherein Me.sup.3+ is the trivalent ion of a paramagnetic metal, said process comprising the steps shown in the following scheme: ##STR14## a) reaction of 1,4,7,10-tetraazacyclododecane with triethyl orthoformate in the absence of solvent and in the presence of an acid catalyst, at an elevated temperature, to give 5H, 9bH-2a, 4a, 7, 9a-octahydrotetraazacycloocta[cd]pentalene of formula (III):b) carboxymethylating compound (III) in water, under basic conditions, with a haloacetic acid, to give the intermediate of formula (IX), which is subjected to the hydrolysis reaction of the subsequent step c) without being isolated;c) hydrolyzing intermediate (IX) in basic conditions, by adding the same base as added in step b), to give an aqueous solution of the salt of formula (X), which undergoes the subsequent step d), without being isolated,d) alkylating in water, with propylene epoxide to give a corresponding salt of 10-(2-hydroxypropyl)- 1,4,7,10-tetracyclododecane- 1,4,7-triacetic acetic which undergoes step e) without being isolated;e) complexing in water by adding a salt of a paramagnetic metal having atomic number ranging from 20 to 31, 42, 43, 44, 49 and from 50 to 57;f) purifying by diafiltration the aqueous solution of compound (XII) to remove most salts and low-molecular weight impurities, optionally preceded by chromatographic purification to remove the lipophilic impurities; final desalting of the aqueous solution on ion exchange resins, and crystallizing or recovering of compound (XII).