Efficient Syntheses of 2-Chloro-2‘-deoxyadenosine (Cladribine) from 2‘-Deoxyguanosine¹

Abstract

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).

A modified thymine for the synthesis of site-specific thymine-guanine DNA interstrand crosslinks

“…1-{O 6 -[3′,5′-O-(bis(tert-butyldimethylsilyl))-2′-deoxyguanosinyl]}-2-{N 3 -[5′-O-(dimethoxytrityl)-3′-O-(tert-butyldimethylsilyl)thymidinyl]}ethane ( 17 ). At 0°C, NaH (9.1 mg, 0.38 mmol) was added to a solution of N 3 -(2-hydroxyethyl-)-5′- O -dimethoxytrityl-3′- O -( tert -butyldimethylsilyl)-thymidine 15 (65 mg, 0.12 mmol) and 2-amino-6-chloro-9-[2′-deoxy-3,5-bis-O-( tert -butyldimethylsi1y1)-β-D-ribofuranosyl]purine 16 ( 29 , 30 ) (91 mg, 0.12 mmol) in DME. The reaction mixture was left at room temperature for 1 h, treated with a saturated solution of NH 4 Cl, extracted with EtOAc, washed with brine and H 2 O and dried over Na 2 SO 4 .…”

2‐Chlorodeoxyadenosine (Cladribine): Rational Development of a Novel Chemotherapeutic Agent

“…Other recent methods include the transformation of 2 0 -deoxyguanosine (Janeba et al, 2003) and heterocyclic modifications to avoid the formation of unwanted N-7 isomeric product (Gupta and Munk, 2004).…”

Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides

“…The synthesis of cladribine has primarily relied on three major methods: (a) glycosylation reactions of a nucleobase with a sugar [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ], and its variations; (b) deoxygenation of the C2′ hydroxyl group of a suitable nucleoside derivative [ 12 , 15 , 19 , 20 ]; (c) enzymatic glycosyl transfer reactions [ 21 , 22 , 23 , 24 ]; and (d) conversion of readily available nucleoside precursors (some utilizing nucleosides for glycosyl transfer reactions) [ 21 , 22 , 24 , 25 , 26 ]. Each of these methods has been used with varying levels of convenience and success.…”