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Syntheses of 6,8‐disubstituted‐9‐β‐D‐ribofuranosylpurine 3′,5′‐cyclic phosphates
Author(s) -
Boswell Kay H.,
Christensen Leon F.,
Shuman Dennis A.,
Robins Roland K.
Publication year - 1975
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570120101
Subject(s) - chemistry , phosphate , nucleophilic substitution , phosphoryl chloride , alkylation , nucleophile , medicinal chemistry , hydrolysis , chloride , yield (engineering) , stereochemistry , organic chemistry , catalysis , materials science , metallurgy
A series of 6,8‐disubstituted‐9‐β‐D‐ribofuranosylpurine 3′,5′‐cyclic phosphates were prepared employing preformed 9‐β‐D‐ribofuranosylpurine 3′,5′‐cyclic phosphate precursors. Three synthetic approaches were utilized to accomplish the syntheses. The first approach involved a study of the order of nucleophilic substitution, 6 vs 8, of the intermediate 6,8‐dichloro‐9‐β‐D‐ribofuranosyipurine 3′,5′‐cyclic phosphates ( 2 ) with various nucleophilic agents to yield 8‐amino‐6‐chloro‐, 8‐chloro‐6‐(diethylamino)‐, 6‐chloro‐8‐(diethylamino)‐, 6,8‐ bis ‐(diethylamino)‐ and 8‐(benzylthio)‐6‐chloro‐9‐β‐D‐ribofuranosylpurine 3′,5′‐cyclic phosphate (4, 9, 10, 11, 13) respectively and 6‐chloro‐9‐β‐D‐ribofuranosylpurin‐8‐one 3′,5′‐cyclic phosphate ( 5 ) and 8‐amino‐9‐β‐D‐ribofuranosylpurine‐6‐thione 3′,5′‐cyclic phosphate ( 6 ). The order of substitution was compared to similar substitutions on 6,8‐dichloropurines and 6,8‐dichloropurine nucleosides. The second scheme utilized nucleophilic substitution of 6‐chloro‐8‐substituted‐9‐β‐D‐ribofuranosylpurine 3′,5′‐cyclic, phosphates obtained from the corresponding 8‐subslituted inosine 3′,5′‐cyclic phosphates by phosphoryl chloride, 6,8‐ bis ‐(benzylthio)‐, 6‐(diethylamino)‐8‐(benzylthio),8‐( p ‐chlorophenylthio(‐6‐(diethylamino)‐ and 6,8‐ bis ‐(methyl‐thio)‐9‐β‐D‐ribofuranosylpurine 3′,5′‐cyclic phosphates ( 14, 12, 20 , and 21 ) respectively, were prepared in this manner. The final scheme involved N 1 ‐alkylation of an 8‐substituted adenosine 3′,5′‐cyclic phosphate followed by a Dimroth rearrangement to give 6‐(benzylamino)‐8‐(methylthio)‐ and 6‐(benzylamino)‐8‐bromo‐9‐β‐D‐ribofuranosylpurine 3′,5′‐cyclic phosphate ( 24 and 25 ).