| 摘要 |
Process for the production of mono-N-substituted tetraazacyclododecane and tetraazacyclotetradecane derivatives of general formula I (see formula I) in which n is 2 or 3, and R is .beta.-carboxylalkyl or .beta.-carboxylate alkyl, .beta.-cyanide alkyl, .beta.-carboxamidoalkyl, .beta.-hydroxyalkyl, aminocarbonyl, aminothiocarbonyl, .beta.-sulfamoylalkyl radical or a second tetraazacyclododecane or tetraazacyclotetradecane molecule bound by a bis(p-hydroxy)-alkylene chain, and wherein carboxyl and hydroxy groups are present optionally in protected form. The process comprises reacting a compound of general formula II obtained from 1,4,7,10-tetraazacyclododecane or 1,4,8,11- tetraazacyclotetradecane (see formula II) with an .alpha.,.beta.-unsaturated ester, amide or nitrile, or an epoxide, isocyanate, isothiocyanate, aziridine or a bisepoxide, with or without solvent, at 0 to 220.degree.C, within 1 to 48 hours, and optionally at a pressure up to 100 atm. The thus obtained reaction mixture, after cooling to -20.degree.C to 80.degree.C, is mixed wit h a mixture of water/organic solvent and stirred for 0.5 to 12 hours. The thus formed (optionally to be isolated) intermediate products carrying a formyl group on a nitrogen atom are reacted by adding an inorganic base or an acid at 0 to 150.degree.C, within 1 to72, with stirring, optionally followed by subsequent removal of protecting groups, to obtain the end product of formula I, which can then be isolated preferably as the hydrochloride. The process provides improved yields of the product.
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