Efficient syntheses of 2-chloro-2'-deoxyadenosine (cladribine) from 2'-deoxyguanosine(1).
We report efficient syntheses of the clinical agent cladribine (2-chloro-2'-deoxyadenosine, CldAdo), which is the drug of choice against hairy-cell leukemia and other neoplasms, from 2'-deoxyguanosine. Treatment of 3',5'-di-O-acetyl- or benzoyl-2'-deoxyguanosine (1) with 2,4,6-triisopropyl- or 4-methylbenzenesulfonyl chloride gave high yields of the 6-O-arylsulfonyl derivatives 2 or 2'b. Deoxychlorination at C6 of 1 also proceeded to give the 2-amino-6-chloropurine derivative 5 in excellent yields. The nonaqueous diazotization/chloro dediazoniation (acetyl chloride/benzyltriethylammonium nitrite) of 2, 2'b, and 5 gave the 2-chloropurine derivatives 3, 3'b, and 6, respectively. The selective ammonolysis at C6 (arylsulfonate with 3 or chloride with 6) and accompanying deprotection of the sugar moiety gave CldAdo (64-75% overall yield from 1).
Janeba
Zlatko
Z
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, USA.
Francom
Paula
P
Robins
Morris J
MJ
D002384:Catalysis; D002855:Chromatography, Thin Layer; D017338:Cladribine / Q000032:analysis* / Q000138:chemical synthesis*; D020650:Combinatorial Chemistry Techniques; D003849:Deoxyguanosine / Q000737:chemistry*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D013329:Structure-Activity Relationship
D017338:Cladribine; D003849:Deoxyguanosine