June 27, 2011
Make pyrrolopyrimidines with three reactions in one pot. Inventors M. S. Bednarz, R. C. Kanamarlapudi, and W. Wu state that 5-alkyl-7H-pyrrolo[2,3-d]pyrimidine-4-ols are biologically important, but the patent does not describe specific applications or uses. One reported method for preparing these compounds requires a desulfurization step that produces large amounts of heavy metal wastes. Another procedure uses harsh conditions and gives low yields. Therefore, an improved synthesis is needed.
The inventors’ method for preparing 5-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-ol 1 starts with an aldol condensation of N-phthalimidoacetone (2) and cyanoacetamide (3) in the presence of LiOH. A solution of 2 in THF is added to a mixture of LiOH and 3 in MeOH at ambient temperature for 1.5 h. The product, 4, is not isolated, but it is treated with NaOMe at 65 °C for 2 h to form compound 5. Again without isolation, product 5 reacts at 55 °C with HCO2Et in the presence of NaOMe to give formyl compound 6 after 7 h
Hydrolysis of 6 in 60 °C water forms 1 in 75% yield, based on an analysis of the solution. The pH is adjusted with 6 M HCl at 65 °C, and then the mixture is cooled; the solids are filtered off, and 1 is isolated in 61% yield as a light brown solid with 99% purity (HPLC).
The inventors also carried out the first step with N-acetonylacetamide in place of 2. The overall yield of 1 is 58% with 100% purity (HPLC). Other bases (e.g., LiOMe, NaOMe, or NaOH) can be used in the first step. DMF can also be used as the solvent in this step; a table shows the results with various combinations of base and solvent. Isolated yields of pure product range from 45 to 58%. Some 1H and 13C NMR data are reported for 6 and 1.
The process gives good yields of 5-alkyl-7H-pyrrolo[2,3-d]pyrimidine-4-ols without the need to isolate the intermediates. All reaction conditions are moderate. (Lexicon Pharmaceuticals [The Woodlands, TX]. US Patent 7,951,941, May 31, 2011; Keith Turner)