Theobromine → 2,6-dichloro-7-methyl-7H-purine

Participants

Reaction Steps

2,6 dichloro-7-methyl-7H-purine was prepared from theobromine (a-1) in 10% yield following the procedure of Uretskaya, G. Ya., Rybinka, E. I., and Men'shikov, G. P. Zh. Obshch. Ki., 1960, 30, 327 with the modification of N,N, diethylaniline disclosed by Stanovik, B. et at in the Australian Journal of Chemistry, 1981, 34, 1729. 1H NMR was identical in all respects to the material prepared by alkylation of commercially available 2,6 dichloropurine with base and iodomethane. For example, the procedure reported by Feng et al. (WO2004/087053) utilizes 60% NaH as base, dimethylformamide (DMF) as the solvent and iodomethane yielded a 1:1 mixture of the N-7/N-9 methylated products which were separated via silica chromatography. The procedure reported by Lewi et et al (WO2005/028479 A2) utilizes potassium carbonate as the base, acetonitrile as solvent (rt 70 h) and iodomethane and yielded a 2:1 isolated yield of methylated purines after silica chromatography (60% yield N9Me/30% yield N-7 Methylated). Similarly acetone can replace acetonitrile as the solvent and after refluxing with potassium carbonate and iodomethane for 24 h a 3:1 mixture of N9/N7 is obtained. The N-7 methylated product was isolated in 16.3% purified yield after silica chromatography. A report by Chi-Huey Wong et al. (see, Bioorg & Med Chem 13 (2005) 4622-4626) utilizes tetrabutylammonium fluoride as the base (1M solution THF) and iodomethane to give similarity a 3:1 ratio of the N-9/N-7 methylated purines which could be separated by silica chromatography. 1H NMR (400 MHz, DMSO d6) 8.79 (s, 1H, H8), 4.06 (s, 3H, N7Me).

Provenance & Evidence