Process for the preparation of fludarabine or fludarabine phosphate from guanosine

A process for the production of 9-.beta.-D-arabinofuranosyl-2-fluoroadenine, comprising:

• (a) subjecting guanosine to amination, whereby the 6-keto group is converted to a 6-amino group;
• (b) subjecting the product of (a) to diazotization/fluorination whereby the 2-amino group is converted to 2-F, and subsequent acylation whereby 2',3',5'-hydroxy groups are converted to acyl-O groups wherein the acyl groups each have up to 12 C atoms;
• (c) subjecting the product of (b) to selective deacylation wherein 2'-O-acyl is converted to 2'-hydroxyl;
• (d) subjecting the product of (c) to sugar conversion whereby the ribofuranosyl moiety is converted to an arabinofuranosyl moiety, wherein
• (1) the 2'-hydroxyl group of the ribofuranosyl moiety is converted to 2'-OSO.sub.2 R.sup.2 by sulfonylation, wherein R.sup.2 is C.sub.1-4 -perfluoroalkyl or perfluorophenyl;
• and
• (2) the 2'-OSO.sub.2 R.sup.2 group of the product of (d)(1) is subjected to nucleophilic displacement with a carboxylate to yield the arabinofuranosyl moiety with a 2'-O-acyl group, wherein said acyl group has up to 12 carbon atoms;
• and
• (e) the product of (d)(2) is subjected to deacylation whereby acyl-O groups in the arabinofuranosyl moiety are converted to hydroxy groups.

A process comprising:

• (a) converting the 6-keto group of guanosine into a 6-amino group;
• (b) thereafter converting the 2-amino group to a 2-fluoro group;
• and
• (c) thereafter converting the ribofuranosyl moiety to an arabinofuranosyl moiety via a 3',5'-di-O-acyl-2'-OSO.sub.2 R.sup.2 intermediate wherein each of the acyl groups have up to 12 C atoms and R.sup.2 is C.sub.1-4 -perfluoroalkyl or perfluorophenyl.

A process comprising:

• (a) converting the 6-keto group into a 6-amino group,
• (b) thereafter converting the 2-amino group into a 2-fluoro group, and
• (c) thereafter converting the ribofuranosyl moiety to an arabinofuranosyl moiety,
• wherein a 2-aminoadenine nucleoside is subjected to diazotization/fluorination in an HF-pyridine medium to obtain an unprotected 2-fluoro intermediate and the 2'-, 3'- and 5'-hydroxy groups of said 2-fluoro intermediate are subjected to acylation performed in said HF-pyridine medium of the prior diazotization/fluorination of said 2-aminoadenine nucleoside.

A process comprising:

• (a) converting the 6-keto group into a 6-amino group,
• (b) thereafter convening the 2-amino group into a 2-fluoro group, and
• (c) thereafter convening the ribofuranosyl moiety to an arabinofuranosyl moiety,
• wherein, following conversion of said 6-keto group to a 6-amino group by amination to obtain 2-aminoadenosine, the 2'-, 3'- and 5'-hydroxy groups of 2aminoadenosine are converted to Ac-O groups, wherein Ac is an acyl group having up to 12 C atoms, the resultant O-acyl protected compound then being subjected to fluorination of the 2-amino group.