Synthese und Antitumorwirkung von Iso‐Piritrexim, einem lipophilen Folatantagonisten

Abstract

Two strategies towards the synthesis of Iso-Piritrexim (12) are described. A) The Mannich-reaction of ketone 2 yields the bases 4-HCl and 5-HCl. By means of LC base 4 is separated and treated with in situ generated 3,3-diaminoacrylonitrile (9) to yield the 2-aminonicotinonitrile 11. The cyclocondensation of 11 with guanidine provides Iso-PTX (12). B) Reduction and oxidation of the beta-ketoester 15 leads to the beta-ketoaldehyde 17, which is cyclocondensed with 2,4,6-triaminopyrimidine (18) to yield Iso-PTX (12). In the NCl-tumor-test Iso-PTX (12) shows a moderate activity against some leukemia and lung cancer cell lines.

Synthesis of the Lipophilic Antifolate Piritrexim via a Palladium(0)-Catalyzed Cross-Coupling Reaction

“…That is, for the synthesis of every 2,4-diamino-5-methyl-6-(substituted benzyl)pyrido [2,3-d] As shown in Scheme 1, commercially available 4,4dimethoxy-2-butanone was condensed with malononitrile to form the ylidenemalononitrile 15 21 (cf. also refs 22-24), and the latter was cyclized to 2-amino-4-methyl-3carbonitrile (16) with ammonia in methanol. Halogenation of 16 with N-iodosuccinimide or N-bromosuccinimide in anhydrous DMF 23 afforded the 5-iodo and 5-bromo derivatives 17 and 18, respectively.…”

“…However, the reaction of 10a / 10b with cyanoacetamide was said to afford more than one product, one of which we surmised might be 13 . Thus a possible drawback of this route is that unless 11 and 12 are entirely free of their respective regioisomers 13 and 14 the final product could be a difficulty separable mixture of PTX and the corresponding 7-methyl isomer, i.e., “isoPTX” …”

“…Thus a possible drawback of this route is that unless 11 and 12 are entirely free of their respective regioisomers 13 and 14 the final product could be a difficulty separable mixture of PTX and the corresponding 7-methyl isomer, i.e., "isoPTX". 16 An inefficient feature of all the previously described routes 1,14,15 to 1 is that they are nonconvergent. That is, for the synthesis of every 2,4-diamino-5-methyl-6-(substituted benzyl)pyrido [2,3-d] As shown in Scheme 1, commercially available 4,4dimethoxy-2-butanone was condensed with malononitrile to form the ylidenemalononitrile 15 21 (cf.…”