Synthesis of N-9- and N-7-[2-hydroxy-3-(phosphonomethoxy)propyl] derivatives of N-6-substituted adenines, 2,6-diaminopurines and related compounds

摘要

Base-catalyzed reactions of diethyl [( oxiranylmethoxy) methyl] phosphonate ( 2) with purine bases ( adenine, 2,6-diaminopurine, 6-chloropurine and 2-amino-6-chloropurine) gave corresponding 9- or 7-[2-hydroxy-3-(phosphonomethoxy) propyl] purines. The adenine and 2,6-diaminopurine derivatives cyclize to cyclic phosphonates 4 and 6. The 9-[2-hydroxy3-( phosphonomethoxy) propyl] derivatives of N-6-substituted adenine and 2,6-diaminopurine ( 15 - 27) were prepared by the treatment of diethyl {[3-(6-chloropurin-9-yl)-2-hydroxypropoxy] methyl} phosphonate ( 11) or diethyl {[ 3-(2-amino-6-chloropurin-9-yl)-2-hydroxypropoxy] methyl} phosphonate ( 13) with primary or secondary amines. The reaction of 6-chloro- or 2-amino-6-chloropurine derivatives ( 11, 13) with thiourea gave the corresponding diethyl purine-6-thiol or 2-aminopurine-6-thiol phosphonates 47, 48. The guanine derivative 49 was prepared by the treatment of compound 13 with 80% acetic acid. All diethyl phosphonates were transformed to free phosphonic acids ( 31 - 43, 50 - 52) by the action of bromotrimethylsilane and subsequent hydrolysis.