A NEW METHOD FOR THE PREPARATION OF IFOSFAMIDE AND CYCLOPHOSPHAMIDE

The reaction of ethyl)-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide 1 a nd chloro-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide 2 with 2-(trimet hylsilyloxy)ethylamine 3 and bis-[2-(trimethylsiloxy)ethyl]amine 4, re spectively, yielded the trimethylsilylated compounds 5 and 6, analogou s to ifosfamide and cyclophosphamide. The reaction of 5 and 6 with ,3, 5-trimethyl-1,3,5-triaza-2-phosphorin-4,6-dione 7 led to the diphospho rus compounds 8 and 9 which could be transformed to ifosfamide 11 and cyclophosphamide 12 by treatment with sulfuryl chloride. This synthesi s shows that the alkylating agents 2-chloroethylammonium chloride and bis-(2-chloroethyl)ammonium chloride can be avoided and the chlorine a tom can be introduced in the final reaction step of the synthesis of 1 1 and 12.