2,6,9-Trisubstituted purines

The preparation of purine derivatives substituted at the C-2 position via amine displacement of a halogen is known as a difficult reaction step requiring several days of reaction time. However, Al-Obeidi and coworkers have recently prepared 2,6,9-trisubstituted purines on soUd-phase by employing a synthetic route in which the critical step was performed with microwave irradiation (Fig. 37) [62]. PS resin-bound 2-iodosubstituted purine was treated with diethanolamine or propanolamine in NMP with microwave irradiation at 200 °C for 30 min. Trifluoroacetic acid-mediated cleavage resulted in the 2-amino substituted purines in 45-59% yields and 77-89% purities. 

Austin, R.E., Okonya, J.F., Bond, D.R.S. and Al-Obeidi, F., Microwave-assisted solid-phase synthesis (MASS) of 2,6,9-trisubstituted purines, Tetrahedron Lett., 2002, 43, 6169-6171. 

Schultz and co-workers31 also described the preparation of a 2,6,9-trisubstituted purine library. A preformed 2-fluoro-6-(4-aminobenzylamino) purine was reductively aminated onto the BAL linker 12. Mitsunobu chemistry was employed to alkylate the C9 position on the support-bound intermediate (Scheme 4). Subsequently, SNAr chemistry was used to incorporate amines at C6. The newly introduced primary and secondary amines bear diverse functional groups and the Mitsunobu reaction allows for incorporation of primary and secondary alcohols lacking acidic hydrogens. The support-bound product 13 was cleaved with 90% TFA/10% H20 to give a library with HPLC purities ranging between 51 and 85%. 

Traceless solid-phase synthesis of 2,6,9-trisubstituted purines from resin-bound 6-thiopurines <02T7911>, and microwave assisted solid-phase synthesis of 2,6,9-trisubstituted purines <02TL6169> have been described. A resin-capture and release strategy toward combinatorial libraries of 2,6,9-trisubstituted purines has been reported <02JCO183>. Alkylated purines chlorinated at the 6,8- or 2,6,8-positions can be captured onto a solid support and further elaborated by aromatic substitution or via palladium catalyzed crosscoupling reactions <02JA1594>. 

Scheme 7 Structure of 2,6,9-trisubstituted purines analogs prepared by Raynaud and coworkers as CDK-2 inhibitors for PK profiling...

F.I. Raynaud, P.M. Fischer, B.P. Nutley, P.M. Goddard, D.P. Lane and P. Workman, Cassette dosing pharmacokinetics of a library of 2,6,9-trisubstituted purine cyclin-dependent kinase 2 inhibitors prepared by parallel synthesis, Mol. Cancer Then, 2004, 3, 353. 

R. Sarohia, M. Leost, L. Meijer, P. G. Schultz, Synthesis and application of functionally diverse 2,6,9-trisubstituted purine libraries as CDK inhibitors, Chem. Biol. 1999, 6, 361-375. 

Recently, various scavenger resin approaches have appeared in the literature. For the synthesis of 4000 ureas (400 pools of 10-compound mixtures) [47], a solid-supported amino nucleophile was used to quench the excess of isocyanates, yielding the desired products in good purity. A similar concept has been employed in the synthesis of 2-thioxo-4-dihydropyrimidinones using aminomethylated polystyrene beads to quench isothiocyanates as well as aldehydes [48]. To quench an excess of amine in the synthesis of 2,6,9-trisubstituted purines, formyl polystyrene beads were used to form the corresponding polymer-bound imine, which could be filtered off [49]. 

Discovery In the course of screening mitotic spindle assembly inhibitors in Xenopus egg extract from the combinatorial library of 2,6,9-trisubstituted purines... 

The synthesis of 2,6,9-trisubstituted purines 607 through nucleophilic displacement of iodine at C-2 of resin-bound purine 606 by amines was carried out under MWI. The displacement was accomplished in 30 min with either diethanolamine or propanolamine subsequent cleavage of the polymer gave 30-80% yields (Scheme 119), conventional heating required 8h (02TL6169). 

Scheme 12.8). In the reaction, N9-substituted 2-halo-6-chloropurine 22 or 28 was captured by a resin at the C6 position. Subsequent substitution at the C2 fluoro/iodo position formed resin 24 or 30. The thiol group on 24 and 30 was then oxidized to give sulfone 25 and 31. 2,6,9-Trisubstituted purine derivatives 26 and 32 were then released by C6 substitution with amines and anilines. This approach allows diverse substitution with primary, secondary, and cyclic amines at the C2 position. With the oxidation of the thiol linker just before the cleavage, only the activated polymer-bound purine intermediates 25 and 31 will be released, thus resulting in high purity of the final product. 

Schone 10 A solid supported synthesis of 2,6,9-trisubstituted purines from 2-fluoroadenine... 

Trisubstituted purine derivatives as protein A mimetics for the treatment of autoimmune diseases. Bioorg Med Chem Lett 19 242-246... 

Dorff PH, Gagripati RS (2001) Novel solid-phase preparation of 2,6,9-trisubstituted purines for combinatorial library generation. Tetrahedron I tt 42 2771-2773... 

Schow SR, Mackman RL, Blum CL, Brooks E, Horsma AG, Joly A, Kerwar SS (1997) Synthesis and activity of 2,6,9-trisubstituted purines. Biooig Med Chem Lett 7 2697-2702... 

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